MX2008002250A - Substituted-3-sulfonylindazole derivatives as 5-hydroxytryptamine-6 ligands - Google Patents

Abstract

The present invention provides a compound of formula (I) and the use thereof for the treatment of a central nervous system disorder related to or affected by the 5-HT6 receptor.

Description

DERIVATIVES OF 3-SULFONILINDAZOL REPLACED AS LIGANDS OF 5-HIDROXITRIPTAMINA-6 BACKGROUND OF THE INVENTION The (5-hydroxytryptamine) (5-HT) serotonin receptors play a critical role in many physiological and behavioral functions in humans and animals. These functions are mediated through various 5-HT receptors distributed throughout the body. There are now approximately fifteen different types of human 5-HT receptors that have been cloned, many with well-defined roles in humans. One of the most recently identified 5-HT receptor subtypes is the 5-HT6 receptor, initially cloned from a rat tissue in 1993 (Monsma, FJ; Shen, Y .; Ward, RP; Hamblin, MW Molecular Pharmacology 1993, 43, 320-327) and subsequently human tissue (Kohen, R .; Metcalf, MA; Khan, N .; Druck, T .; Huebner, K .; Sibley, DR Journal of Neurochemistry 1996, 66, 47-56) . The receptor is a G-protein coupled receptor (GPRC) positively coupled to adenylate cyclase (Ruat, M .; Traiffort, E .; Arrang, JM; Tardivel-Lacombe, L.; Diaz, L.; Leurs, R. Schwartz, JC Biochemical Biophysical Research Communications 1993, 193, 268-276). It has been found that the receptor is almost exclusively in the central nervous system (CNS) in both rats and humans. In situ hybridization studies of the 5-HT6 receptor in the rat brain using mRNA indicate that the main location is in the areas of the 5-HT projection including the striatum, the nucleus accumbens, the olfactory tubercle, and the hippocampal formation ( Ward, RP, Hamblin, MW, Lachowicz, JE, Hoffman, BJ, Sibley, DR, Dorsa, DM Neuroscience 1995, 64, 1105-1111).

There are different potential therapeutic uses for 5-HT6 ligands in humans based on direct effects and on the indications of available scientific studies. These studies provide information that includes the location of the receptor, the affinity of the ligands with known in vivo activity, and the results obtained from various animal studies conducted so far (Woolley, M. L .; Marsden, C. A .; Fone, K. Or F. Current Drug Targets: SNC & Neurological Disorders 2004, 3 (1), 59-79).

A therapeutic use of the modulators of the 5-HT6 receptor function is in the promotion or improvement of cognition and memory in human diseases such as Alzheimer's disease. The high levels of the receptor found in important structures of the forebrain, including the caudate / putamen, hippocampus, nucleus accumbens, and cortex indicate a role for the receptor in memory and cognition since these areas are known to play a vital role in the memory (Gerard, O; Martres, M.-P .; Lefevre, K .; Miquel, MC; Verge, D .; Lanfumey, R .; Doucet, E .; Hamon, M .; Mestikawy, S. Brain Research , 1997, 746, 207-219). The ability of known 5-HT6 receptor ligands to improve cholinergic transmission also supported the use of cognition (Bentley, J. O. Boursson, A., Boess, FG, Kone, F. O., Marsden, CA; , N .: Sleight, AJ British Journal of Pharmacology, 1999, 126 (7), 1537-1542). Studies have shown that a known selective 5-HT6 antagonist significantly increases the levels of glutamate and aspartate in the frontal cortex without raising the levels of noradrenaline, dopamine, or 5-HT. It is known that this selective elevation of neurochemicals is involved in memory and cognition indicates the role it plays in 5-HT6 ligands in cognition (Dawson, LA, Nguyen, HQ, Li, P. British Journal of Pharmacology, 2000, 130 (1), 23-26). Animal studies of memory and knowledge-HT6 antagonist known selective 5 gave positive effects (Rogers, D. O; Hatcher, P. D .; Hagan, J. J. Society of Neuroscience, Abstracts 2000, 26, 680). More recent studies have supported this finding in several additional animal models of cognition and regarding memory including a novel objective discrimination model (King, M. V.; Sleight, A. J .; Wooley, M. L .; Topham, I. A .; Marsden, C. A .; Fone, K. C. F. Neuropharmacology 2004, 47 (2), 195-204 and Wooley, M. L; Marsden, O A .; Sleight, A. J .; Fone, K. Or F. Psychopharmacology, 2003, 170 (4), 358-367) and in a water maze model (Rogers, D. O. Hagan, JJ Psychopharmacology, 2001, 158 (2), 114-119 and Foley, AG; Murphy, KJ; Hirst, WD; Gallagher, H. O; Hagan, J., J. Upton, N .; Walsh, FS; Regan, O M. Neuropsychopharmacology 2004, -29 (1), 93-100).

A related therapeutic use for 5-HT6 ligands is the treatment of attention deficit disorders (ADD, also known as attention deficit hyperactivity disorder or ADHD) in both children and adults. Because the 5-HT6 antagonists promote the activity of the nigrostriatal dopamine pathway and because ADHD has been linked or linked to abnormalities in the caudate (Ernst, M; Zametkin, AJ¡ Matochik, JH; Jons, PA, Cohen, RM Journal of Neuroscience 1998, 18 (15), 5901-5907), 5-HT6 antagonists attenuate attention deficit disorders.

Initial studies examining the affinity of various CNS ligands with known therapeutic utility or a strong structural similarity to known drugs involve 5-HT6 ligands in the treatment of schizophrenia and depression. For example, closapine (an effective clinical antisychotic) has a high affinity for the 5-HT6 receptor subtype. Also, various clinical antidepressants have high affinity to the receptor as well and act as antagonists at this site (Branchek, T. A., Blackburn, T.P. Annual Reviews in Pharmacology and Toxicology 2000, 40, 319-334).

Additionally, recent in vivo studies in rats indicate that 5-HT6 modulators are useful in the treatment of movement disorders including epsy (Stean, T., Routledge, O; Upton, N. British Journal of Pharmacology 1999, 727 Proc. Supplement 131P and Routledge, O; Bromidge, SM; Moss, SF; Price, GW; Hirst, W .; Newman, H. Riley, G .; Gager, T .; Stean, T .; Upton, N. Clarke, SE; Brown, AM British Journal of Pharmacology 2000, 130 (7), 1606-1612).

Therefore, it is an object of this invention to provide compounds that are useful as therapeutic agents in the treatment of a variety of central nervous system disorders related or affected by the 5-HT6 receptor.

It is another object of this invention to provide therapeutic methods and pharmaceutical compositions useful for the treatment of central nervous system disorders related to or affected by the 5-HT6 receptor.

It is a feature of this invention that the compounds provided can also be used for further studies and to elucidate the 5-HT6 receptor.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides a 3-sulfonylindazole compound of the formula wherein X is O, S, NR, CH2, CH2Y, CH2Z, CO, CONR cFNRCO; And it is O, S or NR; Z is CO; n is 0 or an integer of 1, 2, 3, 4, 5 or 6 when X is CH2; n is an integer of 1, 2, 3, 4, 5 or 6 when X is CH2Z, CO or NRCO; n is an integer of 2, 3, 4, 5 or 6 when X is O, S, NR, CH2Y or CONR; R is H or an optionally substituted alkyl group; T is H or an optionally substituted alkyl, cycloalkyl, aryl or heteroaryl group; R2 is an optionally substituted alkyl, cycloalkyl, aryl or heteroaryl group an optionally substituted 8- to 13-membered bicyclic or tricyclic ring system having an N atom on the bridge head and optionally containing 1, 2 or 3 heteroatoms selected from N, O or S; R3 and R are each independently H, or an optionally substituted alkyl group; R5 and R6 are each independently H, or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group, or R5 and Re can be taken together with the atom to which they are linked to form a ring optionally substituted 3- to 7- membered optionally containing an additional heteroatom selected from O, N or S; R7 is H, halogen, CN, OR8, CO2R9, CONR? 0Rn, or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group; m is an integer of 1, 2 or 3; R8 is H, COR12 or an optionally substituted alkyl, alkenyl, alkynyl, aryl or heteroaryl group; R9 is H or a C6-C6alkyl or an aryl or heteroaryl group each optionally substituted; Rio and R11 are each independently H or an optionally substituted alkyl group; Y R 2 is a C 6 alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group; or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

The present invention also provides methods and compositions useful for the therapeutic treatment of central nervous system disorders related to or affected by the 5-HT6 receptor.

DETAILED DESCRIPTION OF THE INVENTION The 5-hydroxytryptamine-6 (5-HT6) receptor has been identified by molecular cloning. Your ability to unite; A wide range of therapeutic compounds used in psychiatry, coupled with their mysterious distribution in the brain has stimulated significant interest in new compounds that are able to interact with or be affected by that receptor. Significant efforts are being made to understand the role of the 5-HT6 receptor in psychiatry, cognitive dysfunction, motor function and motor control, memory, mood and the like. For this purpose, compounds demonstrating an affinity for binding to the 5-HT6 receptor are first seen both as an adjuvant in the study of the 5-HT6 receptor and as potential therapeutic agents in the treatment of disorders of the central nervous system, for example. see O Reavill and D. O Rogers, Current Opinion in Investigational Drugs, 2001, 2 (1): 104-109, Pharma Press Ltd and Woolley, M. L; Marsden, C. A .; Fone, K. Or F. Current Drug Targets: SNC & Neurological Disorders 2004, 3 (7;, 59-79.

Surprisingly, "I know. has now found that the 3-sulfonylindazole compounds of formula I demonstrate affinity for the 5-HT6 receptor together with significant selectivity of the receptor subtype. Advantageously, said compounds of formula I are effective therapeutic agents for the treatment of central nervous system (CNS) disorders associated with or affected by the 5-HT6 receptor. According to the above, the present invention provides a 3-solfonylindazole compound of formula I CD where X is O, S, NR, CH2, CH2Y, CH2Z, CO, CONR or NRCO; And it is O, S or NR; Z is CO; n is 0 or an integer of 1, 2, 3, 4, 5 or 6 when X is CH2; n is an integer of 1, 2, 3, 4, 5 or 6 when X is CH2Z, CO or NRCO; n is an integer of 2, 3, 4, 5 or 6 when X is O, S, NR, CH2Y or CONR; R is H or an optionally substituted alkyl group; Ri is H or an optionally substituted alkyl, cycloalkyl, aryl or heteroaryl group; R2 is an optionally substituted alkyl, cycloalkyl, aryl or heteroaryl group an optionally substituted 8- to 13-membered bicyclic or tricyclic ring system having an N atom on the bridge head and optionally containing 1, 2 or 3 heteroatoms selected from N, O or S; R3 and R are each independently H, or an optionally substituted alkyl group; R5 and R6 are each independently H, or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group, or R5 and R6 can be taken together with the atom to which they are linked to form a ring 3-7-optionally substituted optionally containing an additional heteroatom selected from O, N or S; R7 is H, halogen, CN, OR8, CO2R9, CONR10Rn, or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group; m is an integer of 1, 2 or 3; R8 is H, COR12 or an optionally substituted alkyl, alkenyl, alkynyl, aryl or heteroaryl group; R9 is H or a CrC6 alkyl, or an aryl or heteroaryl group each optionally substituted; Rio and R11 are each independently H or an optionally substituted alkyl group; Y R 12 is a C, C, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl alkyl group; or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

It is understood that the claims involve all possible steroisomers and prodrugs. Moreover, unless otherwise stated, each alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group should be viewed as optionally substituted.

An optionally substituted part can be substituted with one or more substituents. The substituent groups, which are optionally present, may be one or more of those customarily employed in the development of pharmaceutical compounds or in the modification of such compounds to influence their structure / activity, persistence, absorption, stability and other genetic properties. Specific examples of such substituents include halogen atom groups, nitro, cyano, thiocyanate, cyanate, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, formyl, alkoxycarbonyl, carboxyl, alkanoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, carbamoyl , alkylamido, phenyl, phenoxy, benzyl, benzyloxy, heterocyclic or cycloalkyl groups, preferred halogen atoms or lower alkyl or lower alkoxy groups. Unless otherwise specified, typically, 0-4 substituents may be present. When any of the above substituents represents or contains an alkyl substituent group, it may be linear or branched and may contain up to 12 carbon atoms, preferably up to 6 carbon atoms, more preferably up to 4 carbon atoms.

As used herein the term "alkyl" includes both straight chain monovalent saturated hydrocarbon portions with (C C10) and branched chain with (C3-C12) (unless otherwise defined). Examples of saturated hydrocarbon portions of alkyls include but are not limited to chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tere-butyl, isobutyl, sec-butyl; older homologs such as n-pentyl, n-hexyl, and the like. Specifically included within the definition of "alkyl" are those alkyl groups that are optionally substituted. Suitable alkyl substitutions include, but are not limited to, CN.OH, NR10Rn, halogen, phenyl, carbamoyl, carbonyl, alkoxy or aryloxy.

As used herein the term "haloalkyl" designates a group CnH2n +? which has from 1 to 2n + 1 halogen atoms which may be the same or different. Examples of haloalkyl groups include CF3, CH2CI, C2H3BrCl, C3H5F2, and the like.

The term "halogen" as used herein, designates fluorine, chlorine, bromine and iodine.

The term "alkenyl", as used herein, refers to a straight chain (C2-C8) or branched chain (C3-C10) monovalent hydrocarbon portion containing at least one double bond. Such a hydrocarbon alkenyl portion may be mono or polyunsaturated, and may exist in E or Z configurations. The compounds of this invention mean that they include all possible E and Z configurations. Examples of mono- or polyunsaturated alkenyl hydrocarbon parts include, but are not limited to, chemical groups such as vinyl, 2-propenyl, isopropenyl, crotyl, 2-isopentenyl, butadienyl, 2- (butadienyl), 2,4-pentadienyl, 3- (1,4-pentadienyl), and major homologs , isomers or the like.

The term "cycloalkyl" as used herein, refers to a monovalent, bicyclic, tricyclic, fused, bridged, or spiro monovalent saturated hydrocarbon portion of 3-10 carbon atoms, unless otherwise specified in which atoms of carbon are located inside or outside the ring system. Any suitable ring position of the cycloalkyl part can be covalently bonded to the chemical structure defined examples of cycloalkyl part include, but are not limited to, chemical groups such as cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, cyclohexylethyl, cycloheptyl, norbornyl, adamantyl, spiro [4.5] decanyl, and homologs, isomers, or the like.

The term "cycloheteroalkyl" as used herein refers to a C5-C7 cycloalkyl ring system containing 1, 2 or 3 heteroatoms, which may be the same or different, selected from N, O or S and optionally contain a double bond. Examples of cycloheteroalkyl ring systems included in the term as denoted herein are the following rings wherein Xi is NR ', O or S and R is H or an optional substituent as defined hereinafter.

The term "aryl", as used herein, refers to an aromatic carbocyclic part of up to 20 carbon atoms, which may be a single ring (monocyclic) or multiple rings (bicyclic, up to three rings) fused or covalently linked. Any suitable ring position of the aryl part can be covalently bonded to the defined chemical structure. Examples of aryl portions include, but are not limited to, chemical groups such as phenyl, 1 -naphthyl, 2-naphthyl, biphenyl, anthryl, phenanthryl, fluorenyl, indanyl, biphenylenyl, acenaphthenyl, acenaphthylenyl, and the like.

The term "heteroaryl" as used herein denotes an aromatic heterocyclic ring system, which may be a single ring (monocyclic) or multiple rings (bicyclic, up to three rings fused together or covalently linked.) Preferably, the heteroaryl is a ring with -6 members The rings may contain between 1 to 4 heteroatoms selected from nitrogen, oxygen, or sulfur, wherein the nitrogen or sulfur atoms are optionally oxidized, or the nitrogen atoms are optionally quaternized.Any suitable ring position of the Heteroaryl part may be covalently bound to the defined chemical structure Examples of heteroaryl part include, but are not limited to, heterocycles such as furan, thiophene, pyrrole, pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, triazole, pyridine, pyrimidine, pyrazine, pyridazine, benzimidazole, benzoxazole, benzisoxazole, benzothiazole, benzofuran, benzothiophene, thianthrene, dibenzofuran, dibenzothiophene, indole, indazole, quinoline, isoquinoline, quinazoline, quinoxaline, purine, or the like.

Illustrative of bicyclic or tricyclic ring systems, with 8 to 13 members having an N atom in the front of the bridge and optionally containing 1, 2 or 3 additional heteroatoms selected from among N, O or S included in the term as designated herein are the following ring systems where W is NR ', O or S; and R 'is H or an optional substituent as described hereinafter: XX w X? _? _ ^ Ji ^ < \ X -MXr 1 c The compounds of this invention are limited to those that are stable and chemically feasible. Therefore, a combination of substituents or variables in the compounds described above is permissible only if such combinations result in a stable and chemically feasible compound.

Unless otherwise stated, the structures illustrated herein also mean that they include all stereochemical forms of the structure; that is, the R and S configurations for each asymmetric center. Therefore, the unique stereochemical isomers as well as the enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention. Unless stated otherwise the structures illustrated herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structures present except for replacements of a hydrogen by a deuterium or tritium, or the replacement of a carbon with a carbon enriched 13C or 1C are within the scope of this invention.

The compounds of the present invention can be converted to salts, in particular pharmaceutically acceptable salts using recognized methods of the art. Suitable salts with bases are, for example, metal salts, such as alkali metal or alkaline earth metal salts, for example sodium potassium or magnesium salts or alkaline earth metal salts, for example sodium, potassium or magnesium salts or salts with ammonia or an organic amine, such as morpholine, thiomorpholine, piperidine, pyrrolidine, a lower mono-, di- or tri-alkylamine for example ethyl-tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethylpropylamine, or a mono-, di- or trihydroxyalkylamine lower, for example mono-, di- or triethanolamine. The internal salts can be further formed. Salts which are not suitable for pharmaceutical uses but which can be used, for example, for the isolation or purification of free compounds or their pharmaceutically acceptable salts, are also included. The term "pharmaceutically acceptable salt", as used herein, refers to salts derived from organic and inorganic acids such as, for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, italic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, naphthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic and similar acids commonly acceptable when a compound of this invention contains a basic part. The salts can also be formed from organic and inorganic bases, preferably alkali metal salts, for example sodium, lithium or potassium when a compound of this invention comprises a phenolic or carboxylate part, or a similar part capable of forming salts of basic addition.

The compounds of the invention include conventional esters, carbamates or other forms of prodrug which, in general, are functional derivatives of the compounds of the invention and which are readily converted to the inventive active part in vivo. Correspondingly, the method of the invention encompasses the treatment of various conditions described hereinbefore with a compound of formula I or with a compound that has not been specifically described but which, after administration, is converted to a compound of formula I in vivo Also included are metabolites of the compounds of the present invention defined as active species produced after the introduction of these compounds into a biological system.

Preferred compounds of the invention are those compounds of formula I wherein X is O, NR or CH2.

Another group of preferred compounds are those compounds of formula I wherein N is 2 or 3.

Also preferred are those compounds of formula I wherein R2 is an optionally substituted aryl or heteroaryl group or an optionally substituted 8 to 13 membered bicyclic or tricyclic ring system having an N atom on the bridgehead and optionally containing 1, 2 or 3 additional heteroatoms selected from N, O or S. < .

The most preferred compounds of the invention are those compounds of formula I wherein X is O and R5 and Re are each independently H or alkyl with 1 to 4 carbons. Another group of more preferred compounds are those compounds of formula I wherein X is O and N is 3. A further group of more preferred compounds are those compounds of formula I wherein X is O; N is 3 and R2 is naphthyl.

Among the preferred compounds of the invention are: N, N-Dimethyl-3-. { [3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] oxy} propan-1 -amine; N-Methyl-N-. { 2- [3- (phenylsulfonyl) -1 H -indazol-5-yl] ethyl} amine; N, N-Dimethyl-N-. { 2- [3- (phenylsulfonyl) -1 H -indazol-5-yl] ethyl} amine; . { 2- [3- (phenylsulfonyl) -1 H -indazol-7-yl] ethyl} amine; N, N-Dimethyl-N-. { 2- [3- (phenylsulfonyl) -1 H -indazol-7-yl] ethyl} amine; N-. { 2- [3- (phenylsulfonyl) -1 H -indazol-7-yl] ethyl} cyclopropanamine; N, N-Dimethyl-N-. { 3- [3- (phenylsulfonyl) -1 H -indazol-5-yl] propyl} amine; N-. { 3- [3- (phenylsulfonyl) -1 H -indazol-5-yl] propyl} cyclopropanamine; . { 3- [3- (phenylsulfonyl) -1 H -indazol-5-yl] propyl} amine; . { 4- [3- (phenylsulfonyl) -1 H -indazol-5-yl] butyl} amine; N-Methyl-N-. { 2- [3- (phenylsulfonyl) -1 H -indazol-7-yl] ethyl} amine; N- [3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] ethane-1,2-diamine; N, N-Dimethyl-2-. { [3- (phenylsulfonyl) -1H-indazol-5-yl] oxy} ethanamine; 3- (phenylsulfonyl) -5- (2-piperidin-1-ylethoxy) -1 H -indazole; 3- (1-naphthylsulfonyl) -5- (2-pyrrolidin-1-ylethoxy) -1 H -indazole; N, N-Dimethyl-2-. { [3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] oxy} ethanamine; N- (2- {[[3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] oxy} ethyl) cyclopentanamine; 5- (2-Morpholin-4-ylethoxy) -3- (1-naphthylsulfonyl) -1 H -indazole; N-Ethyl-N-methyl-2-. { [3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] oxy} ethanamine; N- (2- {[3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] oxy} ethyl) butan-1 -amine; N ~ 1 - [3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] -beta-alaninamide; N-Ethyl-2-. { [3- (phenylsulfonyl) -1 H -indazol-5-yl] oxy} ethanamine; N- (2- {[[3- (phenylsulfonyl) -1H-indazol-5-yl] oxy} ethyl) propan-2-amine; N- (2- {[3- (1-naphthylsulfonyl) -1H-indazol-5-yl] oxy} ethyl) propan-2-amine; N-Ethyl-2-. { [3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] oxy} ethanamine; N-Methyl-2-. { [3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] oxy} ethanamine; 1-Methyl-3- (1-naphthylsulfonyl) -7- (2-piperidin-1-ylethoxy) -1 H -indazole; 3- (1-naphthylsulfonyl) -5- (2-piperidin-1-ylethoxy) -1 H-indazole; 3- (2-Aminoethyl) -1 - [(2,5-dimethoxyphenyl) sulfonyl] -1,3-dihydro-2H-imidazo [4,5-b] pyridin-2-one; N, N-Diethyl-2-. { [3- (1-naphthylsulfonyl) -1H-indazol-5-yl] oxy} ethanamine; N- (2- {[[3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] oxy} ethyl) cyclopropanamine; 1- (3-Chlorobenzyl) -3- (1-naphthylsulfonyl) -7- (2-piperidin-1-ylethoxy) -1 H-indazole; 1- (3-ChloroBenzyl) -3- (1-naphthylsulfonyl) -7- (2-pyrrolidin-1-ylethoxy) -1H-indazole; (2S) -3-Methyl-N ~ 1 - [3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] butane-1,2-diamine; (2- { [1- (3-Chlorobenzyl) -3- (1-naphthylsulfonyl) -1 H -indazol-7-yl] oxy} ethyl) amine; N- (2- {[[3- (phenylsulfonyl) -1 H -indazol-5-yl] oxy} ethyl) cyclopentanamine; 3- (phenylsulfonyl) -5- (2-pyrrolidin-1-ylethoxy) -1H-indazole; N-Methyl-2-. { [3- (phenylsulfonyl) -1 H -indazol-5-yl] oxy} ethanamine; N-Methyl-2-. { [1-methyl-3- (phenylsulfonyl) -1 H -indazol-7-yl] oxy} ethanamine; 1 -Methyl-3- (phenylsulfonyl) -7- (2-pyrrolidin-1-ylethoxy) -1H-indazole; (2- { [1- (3-Chlorobenzyl) -3- (phenylsulfonyl) -1 H -indazol-7-yl] oxy} ethyl) methylamine; (2- {[1- (3-Chlorobenzyl) -3- (phenylsulfonyl) -1 H -indazol-7-yl] oxy} ethyl) ethylamine; 1- (3-ChloroBenzyl) -3- (phenylsulfonyl) -7- (2-pyrrolidin-1-ylethoxy) -1 H-indazole; 1- (3-ChloroBenzyl) -5-methoxy-3- (1-naphthylsulfonyl) -7- (2-piperidin-1-ylethoxy) -1 H -indazole; N-Methyl-2-. { [3- (phenylsulfonyl) -1 H -indazol-7-yl] oxy} ethanamine; (2- {[1- (3-Chlorobenzyl) -3- (1-naphthylsulfonyl) -1H-indazol-7-yl] oxy} ethyl) ethylamine; (2- {[(3-Chlorobenzyl) -3- (1-naphthylsulfonyl) -1H-indazol-7-yl] oxy} ethyl) methylamine; N-Ethyl-2-. { [3- (phenylsulfonyl) -1 H -indazol-7-yl] oxy} ethanamine; N, N-Diethyl-2-. { [3- (phenylsulfonyl) -1 H -indazol-7-yl] oxy} ethanamine; N- (2- {[[3- (phenylsulfonyl) -1 H -indazol-7-yl] oxy} ethyl) butan-1-amine; 3- (phenylsulfonyl) -7- (2-pyrrolidin-1-ylethoxy) -1 H -indazole; 3- (phenylsulfonyl) -7- (2-piperidin-1-ylethoxy) -1 H-indazole; N, N-Diethyl-2-. { [1-methyl-3- (1-naphthylsulfonyl) -1H-indazol-7-yl] oxy} ethanamine; 1 -Methyl-3- (1-naphthylsulfonyl) -7- (2-pyrrolidin-1-ylethoxy) -1H-indazole; N-Ethyl-2-. { [1-methyl-3- (1-naphthylsulfonyl) -1 H -indazol-7-yl] oxy} ethanamine; 3- (1-naphthylsulfonyl) -7- (2-piperidin-1-ylethoxy) -1 H -indazole; 3- (1-naphthylsulfonyl) -7- (2-pyrrolidin-1-ylethoxy) -1 H-indazole; N-Ethyl-2-. { [3- (1-naphthylsulfonyl) -1 H -indazol-7-yl] oxy} ethanamine; (2- {[[3- (1-naphthylsulfonyl) -1 H -indazol-7-yl] oxy} ethyl) amine; (2- {[1- (3-Chlorobenzyl) -5-fluoro-3- (1-naphthylsulfonyl) -1 H -indazol-7-yl] oxy} ethyl) -dimethylamine; (2- {[1-Benzyl-3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] oxy} ethyl) methylamine; (2- {[1-Benzyl-3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] oxy} ethyl) dimethylamine; (2- {[1-Benzyl-3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] oxy} ethyl) ethylamine; N-Methyl-2-. { [3- (1-naphthylsulfonyl) -1H-indazol-7-yl] oxy} ethanamine; N, N-Dimethyl-2-. { [3- (1-naphthylsulfonyl) -1 H -indazol-7-yl] oxy} ethanamine; 5-Fluoro-3- (1-naphthylsulfonyl) -7- (2-pyrrolidin-1-ylethoxy) -1 H -indazole; 5-Fluoro-3- (1-naphthylsulfonyl) -7- (2-piperidin-1-ylethoxy) -1 H -indazole; N, N-Diethyl-2-. { [5-fluoro-3- (1-naphthylsulfonyl) -1 H -indazol-7-yl] oxy} ethanamine; (2- {[5-Fluoro-3- (1-naphthylsulfonyl) -1 H -indazol-7-yl] oxy} ethyl) dimethylamine; N-Ethyl-2-. { [5-fluoro-3- (1-naphthylsulfonyl) -1 H -indazol-7-yl] oxy} ethanamine; (2- { [1 - (3-Chlorobenzyl) -3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] oxy} ethyl) -dimethylamine; N-methyl-3-. { [3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] oxy} propan-1 -amine; N-Ethyl-N-methyl-3-. { [3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] oxy} propan-1 -amine; 3- (1-naphthylsulfonyl) -5- (3-piperidin-1-ylpropoxy) -1 H-indazole; N, N-Dimethyl-3-. { [3- (1-naphthylsulfonyl) -1H-indazol-5-yl] oxy} propan-1 -amine; N, N-Diethyl-3-. { [3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] oxy} propan-1 -amine; N- (3- { [3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] oxy}. Propyl) butan-1 -amine; 3- (1-naphthylsulfonyl) -5- (3-pyrrolidin-1-ylpropoxy) -1H-indazole; (2- {[5-methoxy-3- (1-naphthylsulfonyl) -1 H -indazol-7-yl] oxy} ethyl) methylamine; (2- {[5-methoxy-3- (1-naphthylsulfonyl) -1 H -indazol-7-yl] oxy} ethyl) dimethylamine; 5-methoxy-3- (1-naphthylsulfonyl) -7- (2-pyrrolidin-1-ylethoxy) -1 H -indazole; 5-methoxy-3- (1-naphthylsulfonyl) -7- (2-piperidin-1-ylethoxy) -1 H -indazole; (2- {[1 - (3-Chlorobenzyl) -3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] oxy} ethyl) ethylamine; (3- { [1- (3-Chlorobenzyl) -3- (1-naphthylsulfonyl) -1 H -indazol-7-yl] oxy} propyl) -diethylamine; 1- (3-ChloroBenzyl) -3- (1-naphthylsulfonyl) -7- (3-pyrrolidin-1-ylpropoxy) -1H-indazole; N-methyl-3-. { [3- (1-naphthylsulfonyl) -1H-indazol-7-yl] oxy} propan-1 -amine; N, N-Diethyl-3-. { [3- (1-naphthylsulfonyl) -1 H -indazol-7-yl] oxy} propan-1-amine; N-Methyl-2-. { [1-methyl-3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] oxy} ethanamine; N, N-Dimethyl-2-. { [1-methyl-3- (1-naphthylsulfonyl) -1H-indazol-5-yl] oxy} ethanamine; N-Ethyl-N-methyl-2-. { [1-methyl-3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] oxy} ethanamine; N-Ethyl-2-. { [1-methyl-3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] oxy} ethanamine; N, N-Diethyl-2-. { [1-methyl-3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] oxy} ethanamine; N- (2- {[1-Methyl-3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] oxy} ethyl) propan-2-amine; 1 -Methyl-3- (1-naphthylsulfonyl) -5- (2-pyrrolidin-1-ylethoxy) -1 H -indazole; . { 3- [3- (1-naphthylsulfonyl) -1H-indazol-5-yl] propyl} amine; (2- {[1-Methyl-3- (1-naphthylsulfonyl) -1 H -indazol-7-yl] oxy} ethyl) amine; N-Ethyl-3-. { [3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] oxy} propan-1 -amine; N-lsopropyl-3-. { [3- (1-naphthylsulfonyl) -1 H-: indazol-5-yl] oxy} propan-1 -amine; N- (3- {[[3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] oxy} propyl) cyclopentanamine; 5- (3-Morpholin-4-ylpropoxy) -3- (1-naphthylsulfonyl) -1 H -indazole; N- (3-. {[3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] oxy}. Propyl) cyclopropanamine; (3- {[[3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] oxy} propyl) amine; N-methyl-4-. { [3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] oxy} butan-1 -amine N, N-Dimethyl-4-. { [3- (1-naphthylsulfonyl) -1H-indazol-5-yl] oxy} butan-1 -amine; N-Ethyl-4-. { [3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] oxy} butan-1 -amine; N, N-Diethyl-4-. { [3- (1-naphthylsulfonyl) -1H-indazol-5-yl] oxy} butan-1-amine; N-methyl-4-. { [3- (1-naphthylsulfonyl) -1H-indazol-5-yl] oxy} -N-propylbutan-1 -amine; 3- (1-naphthylsulfonyl) -5- (4-pyrrolidin-1-ylbutoxy) -1 H -indazole; 3- (1-naphthylsulfonyl) -5- (4-piperidin-1-ylbutoxy) -1 H -indazole; (4- { [3- (1-naphthylsulfonyl) -1H-indazol-5-yl] oxy} butyl) amine; (2- {[5-Fluoro-3- (1-naphthylsulfonyl) -1 H -indazol-7-yl] oxy} ethyl) methylamine; 5 - [(4-Methylpiperazin-1-yl) methyl] -3- (1-naphthylsulfonyl) -1 H -indazole; 3- (1-naphthylsulfonyl) -5- (piperazin-1-ylmethyl) -1 H -indazole; N-. { [3- (1-naphthylsulfonyl) -1H-indazol-5-yl] methyl} ethane-1, 2-diamine; N-Methyl-3- [3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] propan-1 -amine; N, N-Dimethyl-4- [3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] butan-1 -amine; N, N-Dimethyl-3- [3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] propan-1 -amine; N-Ethyl-N-methyl-3- [3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] propan-1 -amine; N-lsopropyl-3- [3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] propan-1 -amine; N-Ethyl-N-methyl-4- [3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] butan-1 -amine; (2- {[[3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] oxy} ethyl) amine; 3- (1-naphthylsulfonyl) -5- (3-pyrrolidin-1-ylpropyl) -1 H -indazole; N-lsopropyl-4- [3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] butan-1 -amine; 3- (1-naphthylsulfonyl) -5- (4-pyrrolidin-1-ylbutyl) -1 H -indazole; N-Ethyl-4- [3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] butan-1-amine; 5 - [(3-Methylpiperazin-1-yl) methyl] -3- (1-naphthylsulfonyl) -1 H -indazole; 5 - [(3,5-Dimethyl-piperazin-1-yl) methyl] -3- (1-naphthylsulfonyl) -1 H -indazole; N-Ethyl-3- [3- (1-naphthylsulfonyl) -1H-indazol-5-yl] propan-1 -amine; . { 4- [3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] butyl} amine; 5- [1- (4-Methylpiperazin-1-yl) ethyl] -3- (1-naphthylsulfonyl) -1 H -indazole; N.N.N'-Trimethyl-N'-yl-naphthylsulfoni-IH-indazol-S-illmethi ethane-l-diamine; N, N-Dimethyl-2-. { [3- (1-naphthylsulfonyl) r 1 H-indazol-5-yl] methoxy} ethanamine; 5-. { [(3R) -3-Methylpiperazin-1-yl] methyl} -3- (1-naphthylsulfonyl) -1 H-indazole; 5-. { [(3S) -3-Methylpiperazin-1-yl] methyl} -3- (1-naphthylsulfonyl) -1 H-indazole; (3S) -N-. { [3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] methyl} pyrrolidin-3-amine; (3R) -1-. { [3- (1-naphthylsulfonyl) -1H-indazol-5-yl] methyl} pyrrolidin-3-amine; N- [2- (Dimethylamino) ethyl] -3- (1-naphthylsulfonyl) -1 H -indazole-5-carboxamide; 2-. { [5-Fluoro-3- (phenylsulfonyl) -1H-indazql-7-yl] oxy} etamine; N- [3- (1-naphthylsulfonyl) -1 H -indazol-6-yl] -beta-alaninamide; N- [3- (1-naphthylsulfonyl) -1 H -indazol-7-yl] -3-piperidin-1-ylpropanamide; N ~ 3 ~, N ~ 3 ~ -Dimethyl-N- [3- (1-naphthylsulfonyl) -1 H -indazol-7-yl] -beta-alaninamide; 2-. { [3- (phenylsulfonyl) -1 H -indazol-7-yl] oxy} ethanamine; N- [3- (1-naphthylsulfonyl) -1 H -indazol-7-yl] -beta-alaninamide; N- [3- (1-naphthylsulfonyl) -1 H -indazol-7-yl] ethane-1,2-diamine; N- [3- (1-naphthylsulfonyl) -1 H -indazol-6-yl] -3-piperidin-1-ylpropanamide; N- [3- (1-naphthylsulfonyl) -1 H -indazol-6-yl] ethane-1,2-diamine; N 3, N 3 -diethyl-N- [3- (1-naphthylsulfonyl) -1 H -indazol-7-yl] -beta-alaninamide; N, N-Dimethyl-2-. { [3- (1-naphthylsulfonyl) -1 H -indazol-4-yl] oxy} ethanamine; 3- (1-naphthylsulfonyl) -4- (2-piperidin-1-ylethoxy) -1 H -indazole; 3- (1-naphthylsulfonyl) -4- (2-pyrrolidin-1-ylethoxy) -1 H -indazole; 2-. { [3- (1-naphthylsulfonyl) -1 H -indazol-4-yl] oxy} ethanamine; N-Methyl-2-. { [3- (1-naphthylsulfonyl) -1 H -indazol-6-yl] oxy} ethanamine; 2-. { [3- (1-naphthylsulfonyl) -1 H -indazol-6-yl] oxy} ethanamine; a stereoisomer of them; or a pharmaceutically acceptable salt thereof.

In one embodiment X is O. In one embodiment n is 3. In one embodiment R2 is an optionally substituted phenyl, naphthyl or imidazothiazolyl group. In another embodiment R2 is nartyl. In an R-mode it is H or an optionally substituted alkyl.

In a further embodiment m is 0 or 1. In another embodiment m is 0. In a modality R5 and R6 are each independently H or an alkyl with 1 to 4 carbons.

The compounds of the invention can be prepared using conventional synthetic methods and, if required, standard isolation or separation techniques. In schemes I to VII below, Z represents the group (CR3R) n where R3, R and are as defined above for formula I.

Compounds of formula I wherein X is O (la) can be prepared as illustrated in Scheme I below wherein chloromethylsulfone 2 is commercially available or easily prepared using the methods as described by M. Makosa and J. Golinski in J. Org. Chem., 1984, 49, 1488-1494; or by Antane, S .; Bernotas, R., Li, Y .; McDevitt, R .; Yan, Y. Synthetic Communications 2004, 34 (13), 2443- 2449 or by other known methods. Reaction of a sulfonylchloride 1 with sodium sulfite under basic conditions followed by reaction with chloro-bromo-methane gives chloromethylsulfone 2. Reaction of 2 with a fluoronitrobenzene 3 under basic conditions gives the benzylsulfonyl derivative 4. Compound 4 it reacts with the diol, HO- (CR3R4) n-OH, under basic conditions to give 5. The tosylation, followed by hydrogenation, of 5 of the aniline 6. The compound 6 is reacted with sodium nitrite in the presence of an acid to give the indazole 7. The alkylation of indazole 7 yields the alkylated tosylate compound 8. The displacement of the tosyl groups of any of the compounds 7 or 8 with the appropriate amona then gives the desired compound of the formula la. The reaction is shown in Scheme I where Ts represents p-toluenesulfonyl and Hal represents Cl, Br or I.

Scheme HNR5R6 HNR5R6 (la) (la) Similarly, the compounds of formula I wherein X is O and R5 and R6 are H (Ib), or the compounds of formula la, can be prepared by reacting the nitrobenzene derivative 9 with chloromethyl sulfone 2, followed by hydrogenation to give the aniline 10. The aniline 10 is converted to the indazole derivative 11, as described above in Scheme I. The alkylation or protection of indazole 11 gives the compound 12. The reaction of 12 with azide of sodium followed by reduction of the azido group provides the desired primary amine Ib. Alternatively, the reaction of 11 or 12 with an amine, HNR5R6, gives the compound of. The reaction is shown in Scheme II where Hal represents Cl, Br or I.

SCHEME II (the) Alternatively, compounds of the formula la can be prepared by the reaction of an alcoholamino 14 with a fluoro-nitrobenzene under basic conditions, or a nitrophenol under Mitsunobu conditions, to give the compound 16. The compound 16 is reacted with chlorosulfone 2, followed by hydrogenation, to give the aniline 17. After the formation of the desired formula the indazoles are carried out as described above in Schemes I and II. The reaction is shown in Scheme III where Hal represents Cl, Br or I.

SCHEME III .OH DO NOT, 17 NaN02 / HCI Na2C03 (the) The compounds of formula I wherein X is NR and R and RT are H (Ib) or X is NRCO and R and Ri are H (le) can be prepared by reacting a nitroindazole 18 with iodine to give 3-iodoindazole. correspondent; coupling 19 with a thiol 20, followed by oxidation with a suitable oxidation agent such as m-chloroperbenzoic acid (mCPBA) to give sulphone 21; reduce the nitro group of 21 with Sn / HCl or SnCl2 / HCI to obtain the corresponding amine 22; and reacting 22 with the amino aldehyde 23 under reductive amination conditions to provide the desired compound of formula Ib, or coupling 22 with an amino acid 24 to give the desired compound of formula I The reactions are shown in Scheme IV below, where Ac represents COCH3 SCHEME IV The compounds of formula I wherein X is CH2 and Rs and Re are different from H (Id) can be prepared by reacting the nitrobenzene compound with the chloromethylsulfonyl compound 2 to obtain intermediate 26. Reduce the nitro group of the compound 26 to the corresponding amine and nitrosing said amine, as described in Schemes II and III, to form the desired compound of formula Id wherein R is H and optionally assaying said compound to obtain the desired compound of formula Id wherein Ri is different from H. The reactions are shown in Scheme V below, where Hal represents Cl, Br or I.

SCHEME V (Yo hice) The compound of formula Id wherein R5 is H (le) can be prepared in a similar manner by protecting compound 27 with a suitable protecting group such as t-butyloxycarbonyl (BOC), ethyloxycarbonyl, methyloxycarbonyl, Benzyl (Bn), phthalimide, fluorenylmethylcarbonyl (Fmoc), acetyl, benzoyl, and the like to give the protected amine 28; reacting compound 28 with chloromethylsulfonyl 2, followed by reduction and nitrosation as shown hereafter in Scheme V to obtain protected compound 29 and deprotect to give the desired compound of formula le. The reaction is shown in Scheme VI below, where Hal represents Cl, Br or I.

SCHEME VI The compounds of formula Id can also be prepared by coupling compound 31 with an alkyne 32 using the Sonagashira conditions to give compound 33; reduce 33 to the fully saturated amine 34; reacting 34 with NaNO2 to give the indazole 35 and converting the hydroxyl group to an exit group and displacing the leaving group with an amine, HNR5R6 optionally assaying the resulting product to give the desired compound of formula Id. The reactions are shown in Scheme VII that follows where TsCI represents tosyl chloride and Hal represents Cl, Br or I.

SCHEME Vil 3. 4 Advantageously, the compounds of formula I of the invention are useful for the treatment of CNS disorders related to or affected by the 5-HT6 receptor which include motor, mood, personality, behavioral, psychiatric, cognitive, neurodegenerative or similar disorders. , for example Alzheimer's disease, Parkinson's disease, attention deficit disorder, anxiety, epilepsy, depression, obsessive compulsive disorder, sleep disorders, neurodegenerative disorders (such as trauma or blows to the head), disorders of feeding (such as anorexia or bulimia), schizophrenia, memory loss, disorders associated with withdrawal from drug or nicotine abuse, or similar or certain gastrointestinal disorders such as irritable bowel syndrome. Accordingly, the present invention provides a method for the treatment of a central nervous system disorder related to or affected by the 5-HT 6 receptor in a patient in need thereof comprising providing said patient with a therapeutically effective amount of a composed of formula I as described herein above. The compounds can be delivered by oral or parenteral administration in a cnly known manner of effectively administering a therapeutic agent to a patient in need thereof.

The term "supply" as used herein with respect to supplying a compound or substance encompassed by the invention, means directly administering such a compound or substance, or administering a prodrug, derivative or analog that forms an equivalent amount of the compound or substance within the scope of the invention. body.

The method of the invention includes: a method for the treatment of schizophrenia; a method for treating a disease associated with a deficit in memory, cognition, and / or learning or a cognitive disorder such as Alzheimer's disease or an attention deficit disorder; a method for the treatment of developmental disorders such as schizophrenia; Down syndrome, Fragile X chromosome syndrome, autism or the like; a method for the treatment of behavioral disorders, for example, anxiety depression or obsessive-compulsive disorder; a method for the treatment of movement or motor disorders such as Parkinson's disease or epilepsy; a method for the treatment of a neurodegenerative disorder such as a stroke or head trauma or an elimination of a drug addiction that includes addiction to nicotine, alcohol, or other substances or abuse, or any other disease or disorder of the CNS associated with or related to the 5-HT6 receptor.

In one embodiment, the present invention provides a method for treating attention deficit disorders (ADD, also known as attention deficit hyperactivity disorders or ADHD) in both children and adults. In accordance with the above, in this embodiment, the present invention provides a method for treating attention deficit disorders in a pediatric patient. The present invention therefore provides a method for treating each of the conditions listed above in a patient, preferably in a human, said method comprising supplying said patient with a therapeutically effective amount of a compound of formula I as described above. . The compounds can be delivered by oral or parenteral administration or in a cnly known manner which is an effective administration of a therapeutic agent to a patient in need thereof.

The therapeutically effective amount delivered in the treatment of a specific CNS disorder may vary according to the specific conditions to be treated, the size, age and pattern of response of the patient, the severity of the disorder, the judgment of the physician and the like. . In general, the amounts effective for daily oral administration may be between 0.1 to 1000 mg / kg, preferably about 0.5 to 500 mg / kg and effective amounts for parenteral administration may be between 0.1 to 100 mg / kg preferably about 0.5. at 50 mg / kg.

In actual practice, the compounds of the invention are provided for administration of the compound or a precursor thereof in a solid or liquid form, be it clear or in combination with one or more conventional pharmaceutical carriers or pharmaceutical excipients. Accordingly, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound of formula I as described above.

In one embodiment, the invention relates to compositions comprising at least one compound of formula I, or a pharmaceutically acceptable salt thereof, and one or more excipient carriers, or pharmaceutically acceptable diluents. Such compositions include pharmaceutical compositions for treating or controlling conditions of disease conditions of the central nervous system. In certain embodiments, the compositions comprise mixtures of one or more compounds of formula I.

In certain embodiments, the invention relates to compositions comprising at least one compound of formula I or a pharmaceutically acceptable salt of, and one or more pharmaceutically acceptable carriers, excipients, or diluents. Such compositions are prepared according to acceptable pharmaceutical methods. Pharmaceutically acceptable vehicles with those vehicles that are compatible with the other ingredients in the formulation and are biologically acceptable.

The compounds of formula I can be administered orally or parenterally, alone, or in combination with conventional pharmaceutical vehicles. Applicable solid carriers may include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders, tablet disintegrating agents, or encapsulating materials. In powders, the carrier is a finely divided solid that is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a vehicle having the necessary compression properties in suitable proportions and compacted in the desired shape and size. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, low melting waxes, and ion exchange resins.

In certain embodiments, a compound of formula I is delivered in a disintegrating tablet formulation suitable for pediatric administration.

Liquid vehicles can be used to prepare solutions, suspensions, emulsions, syrups, and elixirs. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both, or a pharmaceutically acceptable oil or fat. The liquid carrier may contain other suitable pharmaceutical additives such as, for example, solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives such as the above, for example cellulose derivatives preferably a solution of sodium carboxymethylcellulose), alcohols (including monohydric alcohols and polyhydric alcohols for example glycols. , and oils (for example fractionated coconut oil or arachis oil) For parenteral administration, the vehicle can also be an oily ester such as ethyl oleate and isopropyl myristate.The sterile liquid carriers are used in sterile liquid form for parenteral administration compositions The liquid vehicle for pressurized compositions may be halogenated hydrocarbon or other pharmaceutically acceptable propellant.

In certain embodiments, a liquid pharmaceutical composition is provided wherein said composition is suitable for pediatric administration. In other embodiments, the liquid composition is a syrup or suspension.

Liquid pharmaceutical compositions which are sterile solutions or suspensions may be administered by, for example, intramuscularly, intraperitoneally or subcutaneously by injection. Sterile solutions can also be administered intravenously. Compositions for oral administration may be in liquid or solid form.

The compounds of formula I can be administered rectally or vaginally in the form of conventional suppositories. For administration by intranasal or intrabronchial inhalation or insufflation, the compounds of formula I can be formulated in an aqueous or partially aqueous solution, which can then be used in the form of an aerosol. The compounds of formula I can also be administered transdermally by means of the use of a transdermal patch containing the active compound and a vehicle that is inert to the active compound, that is not toxic to the skin, and that allows the supply of the agent by absorption. systemic within the bloodstream through the skin. The vehicle can take any number of forms such as creams and ointments, pastes, gels and occlusive devices. The creams and ointments can be viscous liquid or semi-solid emulsions of oil in water or water in oil. Pastes comprising powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient may also be suitable. A variety of occlusive devices can be used to release the active ingredient into the bloodstream such as a semipermeable membrane that covers a reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient. Other occlusive devices are known in the literature. Preferably the pharmaceutical composition is in a unit dosage form, for example as tablets, capsules, powders, solutions, suspensions, emulsions, granules or suppositories. In such form the composition is subdivided into appropriate amounts containing unit doses of the active ingredient, the unit dosage forms can be packaged compositions, for example, packaged powders, flasks, ampoules, prefilled syringes or bags containing liquids. The unit dosage form may be, for example, a capsule or tablet itself, or it may be an appropriate number of any such compositions in a packet form.

The therapeutically effective amount of a compound of formula I delivered to a patient will vary depending on what is administered, the purpose of administration, such as prophylaxis, the condition of the patient, the manner of administration, and the like. In therapeutic applications, the compounds of formula I are delivered to a patient suffering from a condition in an amount sufficient to treat or at least partially treat the symptoms of the condition and its complications.

A suitable amount to accomplish this is a "therapeutically effective amount" as previously described herein. The dosage to be used in the treatment of a specific case must be determined subjectively by the attending physician. The variables involved include the specific condition and size, age, and response pattern of the patient. Substance abuse treatment follows the same method of subjective drug administration under the guidance of the doctor who understands it. Generally, a starting dose is about 5 mg per day with gradual increase in the daily dose to about 150 mg per day, to provide the desired dosage level in the patient.

In certain embodiments, the present invention is directed to prodrugs of the compounds of formula I. The term "prodrug," as used herein, means a compound that is convertible in vivo by metabolic means (eg, by hydrolysis) to a compound of Formula I. Various forms of prodigies in the art are known such as those discussed in, for example, Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al., (Ed). "Design and Application of Prodrugs, Textbook of Drug Design and Development, chapter 5, 113-191 (1991), Bundgaard, et al., Journal of Drug Delivery Reviews, 8: 1-38 (1992), Bundgaard, J. Pharmaceutical Sciences, 77: 285 et seq. (1988); and Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975).

For a clearer understanding, and to be able to illustrate the invention more clearly, specific examples thereof are set forth herein. The following examples are illustrative only and should not be construed as limiting the scope and the underlying principles of the invention in any way. The terms MNR, MS and HPLC designate mass spectrum, high performance liquid chromatography and proton nuclear magnetic resonance, respectively. The term THF, DMF and DMSO designates tetrahydrofuran, dimethylformamide and dimethylsulfoxide, respectively. All column chromatography is carried out using SiO2 as support. Unless otherwise stated, all parts are parts by weight.

Example 1 [2- (3-Benzenesulfonyl-1H-indazol-5-yloxy) -ethyl] -dimethyl-amine Stage 1 2-Benzenesulfonylmethyl-4-fluoro-1-nitro-benzene: To a solution of chloromethylphenyl sulfone (10.51 g, 55.13 mmol) in THF (110 mL) is added 5.9 mL (56 mmol) of 1-fluoro-4-nitrobenzene. The reaction mixture was cooled to 0 ° C, and 1.0 M of potassium tert-butoxide in THF (145 mL, 145 mmol) was added dropwise. The reaction mixture was stirred under nitrogen at room temperature for one hour. Then acetic acid (9 mL, 160 mmol) is added. To the reaction mixture the solvent was evaporated and partitioned in saline and ethyl acetate. The organic phase was then dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was stirred in diethyl ether, filtered and dried under vacuum at 73 ° C for 12 hours. 2-Benzenesulfonylmethyl-4-fluoro-1-nitrobenzene was obtained as a light brown-yellow solid (10.24 g, 62.8%): MP: 169-171 ° C; Mass spectrum (-El, [MH] ") m / z 294. 1 H NMR (500 MHz, DMSO-d 6): 58.10-8.14 (m, 1 H), 7.70-7.75 (m, 1 H), 7.56-7.63 (m, 4H), 7.45-7.50 (m, 1 H), 7.20 (dd, 1 H, J = 9.27 Hz and 2.81 Hz), 5.12 ppm (s, 2H).

Elemental Analysis for d3H10FNO4S: Cale: C, 52.88; H, 3.41; N, 4.74; Found: C, 52.63; H, 3.14; N, 4.66; Stage 2 2- (3-Benzenesulfonylmethyl-4-nitro-phenoxy) -ethanol A mixture of 2-benzenesulfonylmethyl-4-fluoro-1-nitrobenzene (10.2 g, 34.7 mmol), ethylene glycol (80 mL, 1.4 mol), and 1 M potassium tert-butoxide in THF (78 mL, 78 mmol) in THF (50 mL) was placed under nitrogen for 30 minutes. After cooling to near room temperature, the reaction mixture was evaporated to remove the solvent. Water is added to the residue, and this was poured into hydrochloric acid at 2.0 N and ice. The mixture was then extracted with ethyl acetate and washed with water and saline. The organizing phase was dried with anhydrous magnesium sulfate, filtered, concentrated and dried under vacuum at 74 ° C for 20 minutes. 2- (3-Benzenesulfonylmethyl-4-nitro-phenoxy) -ethanol was obtained as a dark brown gum (11.7 g, 100% yield); Mass spectrum (-El, [MH] -) m / z 336. 1 H NMR (500 MHz, DMSO-d 6): 58.01 (d, 1 H, = 9.15 Hz), 7.67-7.73 (m, 1 H), 7.54-7.63 (m, 4H), 7.10 (dd, 1 H, J = 9.51 Hz and 2.93 Hz), 6.85 (d, 1 H, J = 2.81 Hz), 5.12 (s, 2H), 4.88-4.90 (m , 1 H), 3.93-3.96 (m, 2H), 3.65 ppm (d, 2H, J = 4.51 Hz). Elemental analysis for dsH ^ NOeS: Cale: C, 53.41; H, 4.48; N, 4.15; Found: C, 53.47; H, 4.69; N, 4.04; Stage 3 2- (3-Benzenesulfonylmethyl-4-nitro-phenoxy) -etiol Toluene-4-sulfonic acid A mixture of 2- (3-benzenesulfonylmethyl-4-nitro-phenoxy) -ethanol (8.2 g, 24 mmol) , p-toluenesulfonyl chloride (9.39 g, 49.3 mmol) and triethylamine (19 mL, 140 mmol) in methylene chloride (85 mL) was stirred at room temperature under nitrogen for 4.5 hours. Then the solvent was evaporated and partitioned in methylene chloride and aqueous sodium bicarbonate. The organic phase is then washed with saline, dried with anhydrous magnesium sulfate, filtered, concentrated and dried under vacuum at 63 ° C for 30 minutes. The residue is purified by flash chromatography with 100% chloroform and 5% methanol in chloroform. This was dried under vacuum at 65 ° C for 20 minutes to provide 2- (3-benzenesulfonylmethyl-4-nitro-phenoxy) -ethyl ester of tapne-4-sulfonic acid as a yellow solid (8.1 g, 69%); Mass spectrum (-El, [MH] ") m / z 490. 1 H NMR (300 MHz, DMSO-d 6): 57.99 (d, 1 H, J = 9.02 Hz), 7.67-7.75 (m, 3H), 7.54-7.62 (m, 4H), 7.43 (d, 2H, = 7.93 Hz), 7.00 (dd, 1H, = 9.15 Hz and 2.80 Hz), 6.78 (d, 1H, J = 2.81 Hz), 5.09 (s, 2H), 4.29-4.31 (m, 2H), 4.13-4.15 (m, 2H), 2.37 ppm (s, 3H) Elemental Analysis for C22H21NO8S 0.40 mol H2O: Cale: C, 52.98; H, 4.41; N, 2.81; Found: C, 52.67; H, 4.26; N, 2.61.

Stage 4 2- (4-amino-3-benzenesulfonylmethyl-phenoxy) -ethyl ester of toluene-4-sulfonic acid A solution of toluene-4-sulfonic acid 2- (3-benzenesulfonylmethyl-4-nitro-phenoxy) -ethyl ester (13.1 g, 26.7 mmol) in THF (350 mL) and ethanol (250 mL) was added to 10% of palladium on carbon (5.8 g) and hydrogenated on the Parr apparatus for one hour (starting pressure 30 to 40 psi). The mixture was filtered over Celite, concentrated and dried under vacuum at 80 ° C for 30 minutes to give toluene-4-sulfonic acid 2- (4-amino-3-benzenesulfonylmethyl-phenoxy) -ethyl ester as a yellow solid. clear (11.7 g, 95.1%): PF: 144-6 ° C; Mass spectrum (+ EI, [M + H] +) m / z 462. 1 H NMR (500 MHz, DMSO-d 6): 57.72-7.75 (m, 4 H), 7.63-7.66 (m, 1 H), 7.52 -7.56 (m, 2H), 7.44 (d, 2H, J = 8.05 Hz), 6.52 (d, 2H, J = 1.58 Hz), 6.29-6.30 (m, 1 H), 4.65 (s, 2H), 4.46 (s, 2H), 4.16-4.18 (m, 2H), 3.79-3.82 (m, 2H), 2.38 ppm (s, 3H). Elemental Analysis for C22H23NO6S: Cale: C, 57.25; H, 5.02; N, 3.03; Found: C, 57.60; H, 4.98; N, 3.10.

Stage 5 2- (3-benzenesulfonyl-1 H-indazol-5-yloxy) -ethyl ester of toluene-4-sulfonic acid To a mixture of 2- (4-amino-3-benzenesulfonylmethyl-phenoxy) -ethyl ester of toluene- 4-sulfonic acid (11.7 g, 25.3 mmol) in ethanol (350 mL) and 1.0 N hydrochloric acid (425 mL) was added dropwise sodium nitrite (2.67 g, 38.7 mmol) in water (50 mL). After stirring at room temperature for 1.5 hours, solid sodium carbonate is added at basic pH. The reaction mixture was stirred for an additional 2 hours. The solvent was then removed by evaporation and extracted with hot ethyl acetate. The organic phase was washed with water and saline, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue is purified by flash chromatography with 2% methanol in chloroform to give 2- (3-benzenesulfonyl-1 H-indazol-5-yloxy) -ethyl ester of toluene-4-sulfonic acid as an orange solid (9.54 g, 79.5%): PF: 174-7 ° C; Mass spectrum (-El, [MH] ") m / z 471. 1 H NMR (500 MHz, DMSO-d 6): 514.11 (s, 1H), 7.96-7.98 (m, 2H), 7.74-7.77 (m, 2H), 7.62-7.66 (m, 1 H), 7.53-7.59 (m, 3H), 7.39 (d, 2H, = 8.05 Hz), 7.24 (d, 1 H, = 2.32 Hz), 6.97-7.00 (m , 1 H), 4.35-4.37 (m, 2H), 4.21-4.23 (m, 2H), 2.33 ppm (s, 3H).

Stage 6 [2- (3-Benzenesulfonyl-1H-indazol-5-yloxy) -ethyl] -dimethyl-amine A solution of 2- (3-benzenesulfonyl-1 H-indazol-5-yloxy) -ethyl ester of toluene-4 acid Sulfonic acid (0.341 g, 0.722 mmol) in 2.0 N dimethylamine in THF (9 mL, 18 mmol) was stirred at 70 ° C for 6 hours in a sealed tube. After cooling somewhat, the reaction mixture was evaporated from the solvent and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was washed with water and saline. This was dried with anhydrous magnesium sulfate, filtered and concentrated the residue was partitioned in ethyl acetate / aqueous potassium carbonate. The organic phase was washed with water and saline, dried with anhydrous magnesium sulfate, filtered and concentrated. [2- (3-Benzenesulfonyl-1 H -indazol-5-yloxy) -ethyl] -dimethyl-amine resulted as a light yellow-brown solid (0.167 g, 67.1%). The compound was dissolved in methanol, and ethereal hydrochloride is added. After concentrating and drying in vacuo for 12 hours at 70 ° C, the hydrochloride was obtained with a clear orange foam (94.0 mg); Mass Spectrum (+ EI, [M + H] +) m / z 346. 1 H NMR (500 MHz, DMSO-d 6): 514.22 (s, 1 H), 10.00 (br, 1 H), 7.97-7.99 ( m, 2H), 7.56-7.68 (m, 4H), 7.42 (d, 1 H, J = 2.20 Hz), 7.17-7.20 (m, 1H), 4.39-4.42 (m, 2H), 3.52-3.53 (m , 2H), 2.84 ppm (s, 6H).

Example 2 [2- (3-Benzenesulfonyl-1H-indazol-5-yloxy) -ethyl] -ethyl-methyl-amine A solution of toluene-4-sulfonic acid 2- (3-benzenesulfonyl-1 H-indazol-5-yloxy) -ethyl ester (0.364 g, 0.770 mmol) and N-ethylmethylamine (0.95 mL, 11 mmol) in THF ( 8 mL) was stirred for 6 hours at 70 ° C in a sealed tube. After cooling somewhat to room temperature, the solvent was evaporated to the reaction mixture and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase is washed with water and saline solution, dried with anhydrous magnesium sulfate, filtered and concentrated. After drying in vacuo at room temperature for 1.5 hours, the resulting light-colored solid (0.249 g, 89.9%), [2- (3-benzenesulfonyl-1 H-indazol-5-yloxy) -ethyl] -ethyl-methyl- amine, was dissolved in methanol and methylene chloride, and ethereal hydrochloride is added. Concentration and drying at 80 ° C for 12 hours produced the hydrochloride as a light orange foam (0.253 g); Mass spectrum (+ EI, [M + H] +) m / z 360. 1 H NMR (500 MHz, DMSO-d 6): 514.23 (s, 1 H), 9.95 (br, s, 1 H), 7.97- 7.99 (m, 2H), 7.56-7.68 (m, 4H), 7.42 (d, 1 H, = 2.32 Hz), 7.19 (dd, 1 H, J = 9.15 Hz and 2.32 Hz), 4.41-4.43 (m, 2H), 3.55-3.60 (m, 1 H), 3.43-3.49 (m, 1 H), 3.11-3.17 (m, 1 H), 2.82 (d, 3H, J = 4.63 Hz), 1.22-1.25 ppm ( m, 3H).

Example 3 3-Benzenesulfonyl-5- (2-piperidin-1-yl-ethoxy) -1H-indazole A solution of toluene-4-sulfonic acid 2- (3-benzenesulfonyl-1 H-indazol-5-yloxy) -ethyl ester (0.386 g, 0.817 mmol) and piperidine (1.0 mL, 10 mmol) in THF (8 mL ) was stirred at 70 ° C for 6 hours in a sealed tube. After cooling somewhat to room temperature, the reaction mixture is evaporated from the solvent and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was washed with water and saline. This was dried with anhydrous magnesium sulfate, filtered and concentrated. Drying under vacuum at 80 ° C for 20 minutes resulted in 3-benzenesulfonyl-5- (2-piperidin-1-yl-ethoxy) -1H-indazole as a light yellow solid (0.275 g, 87.3%). This was dissolved in methanol, and ethereal hydrochloride is added. This mixture was concentrated and dried under vacuum at 70 ° C for about 12 hours to give the hydrochloride as a yellow solid (0.268 g): MP: 249-250 ° C; Mass spectrum (+ EI, [M + H] +) m / z 386. 1 H NMR (500 MHz, DMSO-d 6): 514.24 (s, 1 H), 10.02-10.03 (br, 1 H), 7.97- 7.99 (m, 2H), 7.56-7.68 (m, 4H), 7.41 (d, 1 H, J = 2.32 Hz), 7.18 (dd, 1 H, J = 9.15 Hz and 2.33 Hz), 4.44-4.46 (m , 2H), 3.48-3.51 (m, 4H), 2.94-3.04 (m, 2H), 1.65-1.77 (m, 5H), 1.31-1.42 ppm (m, 1 H). Elemental Analysis for C20H23N3O3S. 1.00 mol HCl. 0.15 mol H2O: Cale: C, 56.57; H, 5.77; N, 9.90; Found: C, 56.34; H, 5.88; N, 9.57.

Example 4 [2- (3-Benzenesulfonyl-1H-indazol-5-yloxy) -ethyl] -ethyl-amine A solution of toluene-4-sulfonic acid 2- (3-benzenesulfonyl-1 H-indazol-5-yloxy) -ethyl ester (0.361 g, 0.764 mmol) in 2.0 N ethylamine in THF (9 mL, 18 mmol) it was stirred at 70 ° C for 6 hours in a sealed tube. After cooling somewhat, the reaction mixture is evaporated from the solvent and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase is then washed with water and saline, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue is purified by flash chromatography using 10% methanol in chloroform. After drying under vacuum at 68 ° C for 20 minutes, [2- (3-benzenesulfonyl-1 H-indazol-5-yloxy) -ethyl] -ethyl-amine was obtained as a light brown gum (0.116 g, 43.9% ). This was dissolved in chloroform and methanol, and ethereal hydrochloride was added. After concentrating and drying at 74 ° C for 13.5 hours under vacuum, it gives the hydrochloride as a skin-colored solid (0.113 g): MP: 248-50 ° C (dec). Mass Spectrum (+ EI, [M + H] +) m / z 346. 1 H NMR (500 MHz, DMSO-d 6): 514.23 (s, 1 H), 8.81 (br, 2 H), 7.96-7.98 (m , 2H), 7.56-7.68 (m, 4H), 7.40 (d, 1 H, = 2.07 Hz), 7.19 (dd, 1 H, J = 9.15 Hz and 2.32 Hz), 4.31 (t, 2H, = 5.00 Hz ), 3.35 (br, 2H), 3.00-3.05 (m, 2H), 1.18-1.22 ppm (m, 3H). P Example 5 [2- (3-Benzenesulfonyl-1H-indazol-5-yloxy) -ethyl] -diethyl-amine A solution of toluene- 2- (3-benzenesulfonyl-1 H-? Ndazol-5-yloxy) -ethyl ester 4-Sulfonic acid (0.420 g, 0.889 mmol) and diethylamine (1.0 mL, 9.7 mmol) in THF (8 mL) was stirred at 70 ° C for 6 hours in a sealed tube. Additional diethylamine (1.0 mL, 9.7 mmol) is added, and the reaction mixture is stirred at 80 ° C in a sealed tube for about 6 hours. After cooling somewhat, the reaction mixture is evaporated from the solvent and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase is then washed with water and saline, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue is purified by flash chromatography using 7.5% methanol in chloroform. After drying under vacuum at 80 ° C for 20 minutes, [2- (3-benzenesulfonyl-1 H -indazol-5-yloxy) -ethyl] -diethyl-amine as a pale yellow solid (0.155 g, 46.6%). This was dissolved in methanol and chloroform and ethereal hydrochloride was added. The mixture is concentrated and dried under vacuum at 74 ° C for 13.5 hours to give the hydrochloride as a light orange foam (0.163 g); Mass Spectrum (+ EI, [M + H] +) m / z 374. 1 H NMR (500 MHz, DMSO-d 6): 514.24 (s, 1 H), 9.94 (br, 1 H), 7.96-7.99 ( m, 2H), 7.56-7.68 (m, 4H), 7.41 (d, 1 H, J = 2.20 Hz), 7.16-7.19 (m, 1 H), 4.40-4.43 (m, 2H), 3.52 (br, 2H), 3.19-3.23 (m, 4H), 1.23 ppm (t, 6H, J = 7.20 Hz). Elemental Analysis for C? 9H23N3O3S .1.00 mol HCl. 0.20 mol H2O: Cale: C, 55.18; H, 5.95; N, 10.16; Found: C, 54.85; H, 5.85; N, 10.02.

Example 6 [2- (3-Benzenesulfonyl-1H-indazol-5-yloxy) -ethyl] -isopropyl-amine A solution of toluene-4-sulfonic acid 2- (3-benzenesulfonyl-1 H-indazol-5-yloxy) -ethyl ester (0.378 g, 0.800 mmol) and isopropylamine (1.0 mL, 12 mmol) in THF (8 mL ) was stirred at 70 ° C for 6 hours in a sealed tube. Additional isopropyl amine (1.0 mL, 12 mmol) is added, and the reaction mixture is stirred at 80 ° C for 6 hours in a sealed tube. After cooling somewhat, the solvent was evaporated to the reaction mixture and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase is then washed with water and saline, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue is purified by flash chromatography using 10% methanol in chloroform. After drying under vacuum at 80 ° C for 30 minutes, [2- (3-benzenesulfonyl-1 H-indazol-5-yloxy) -ethyl] -isopropyl-amine was obtained as a pale yellow solid (0.110 g, 38.2 %). This was dissolved in methanol and chloroform and ethereal hydrochloride was added. The mixture is concentrated and dried under vacuum at 74 ° C for 13.5 hours to give the hydrochloride as a very white solid (0.117 g): MP: 275-7 ° C (dec); Mass Spectrum (+ EI, [M + H] +) m / z 360. 1 H NMR (500 MHz, DMSO-d 6): 514.22 (br, 1 H), 8.75 (br, 2 H), 7.96-7.98 (m , 2H), 7.56-7.68 (m, 4H), 7.41 (d, 1H, J = 2.08 Hz), 7.19 (dd, 1 H, J = 9.15 Hz and 2.32 Hz), 4.30-4.33 (, 2H), 3.34 -3.40 (m, 3H), 1.25 ppm (d, 6H, J = 6.59 Hz). Elemental Analysis for C18H21N3O3S.1.00 mol HCl. 0.10 mol H2O: Cale: C, 54.36; H, 5.36; N, 10.57; Found: C, 54.02; H, 5.42; N, 10.22.

Example 7 [2- (3-Benzenesulfonyl-1H-indazol-5-yloxy) -ethyl] -butyl-amine A solution of toluene-4-sulfonic acid 2- (3-benzenesulfonyl-1 H-indazol-5-yloxy) -ethyl ester (0.348 g, 0.736 mmol) and N-butylamine (1.0 mL, 10 mmol) in THF ( 8 mL) was stirred at 70 ° C for 6 hours in a sealed tube. After cooling somewhat, the reaction mixture is evaporated from the solvent and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase is then washed with water and saline, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue is purified by flash chromatography using 7.5 to 10% methanol in chloroform. After drying under vacuum at 55 ° C for 40 minutes, [2- (3-benzenesulfonyl-1 H-indazol-5-yloxy) -ethyl] -butyl-amine was obtained as a light cream semi-solid (0.105 g. , 38.2%). This was dissolved in chloroform and ethereal hydrochloride was added. The resulting solid is filtered and dried in vacuo at 75 ° C for 16.5 hours to provide the hydrochloride as a white solid (0.0813 g): MP: 271-3 ° C dec; Mass Spectrum (+ EI, [M + H] +) m / z 374. 1 H NMR (300 MHz, DMSO-de): 514.27-14.35 (br, 1 H), 8.98-9.00 (br, 2H), 8.03 -8.06 (m, 2H), 7.62-7.76 (m, 4H), 7.46 (d, 1H, J = 2.19 Hz) 7.25 (dd, 1 H, J = 9.15 Hz and 2.29 Hz), 4.38-4.41 (m, 2H), 3.41-3.44 (m, 2H), 3.03 (t, 2H, = 7.87 Hz), 1.62-1.72 (m, 2H), 1.33-1.45 (m, 2H), 0.94 ppm (t, 3H, = 7.32 Hz). Elemental Analysis for C19H23N3O3S .1.00 mol HCl. 0.05 mol H2O: Cale: C, 55.55; H, 5.91; N, 10.23; Found: C, 55.23; H, 5.87; N, 10.09.

Example 8 [2- (3-Benzenesulfonyl-1H-indazol-5-yloxy) -ethyl] -cyclopropyl-amine A solution of toluene-4-sulfonic acid 2- (3-benzenesulfonyl-1 H-indazol-5-yloxy) -ethyl ester (0.336 g, 0.711 mmol) and cyclopropylamine (1.0 mL, 14 mmol) in THF (8 mL ) was stirred at 70 ° C for 6 hours in a sealed tube. Additional cyclopropylamine (1.0 mL, 14 mmol) is added, and the reaction mixture is stirred at 80 ° C for 6 hours in a sealed tube. After cooling somewhat, the reaction mixture is evaporated from the solvent and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase is then washed with water and saline, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue is purified by flash chromatography using 5% methanol in chloroform. After drying under vacuum at 55 ° C for 25 minutes, [2- (3-benzenesulfonyl-1 H-indazol-5-yloxy) -ethyl] -cyclopropyl-amine was obtained as a light yellow foam (0.127 g, 50.0% ). This was dissolved in methanol and chloroform and ethereal hydrochloride was added. The mixture is concentrated and dried under vacuum at 75 ° C for 16.5 hours to provide the hydrochloride as a skin-colored solid (0.131 g): MP: 184-5 ° C dea; Mass Spectrum (+ EI, [M + Hf) m / z 358. 1 H NMR (300 MHz, DMSO-d 6): 514.33 (s, 1 H), 9.33 (br, 2H), 8.03-8.06 (m, 2H ), 7.60-7.76 (m, 4H), 7.47 (d, 1 H, .7 = 2.11 Hz), 7.25 (dd, 1 H, J = 9.15 Hz and 2.38 Hz), 4.40-4.43 (m, 2H), 3.49-3.52 (m, 2H), 2.81-2.88 (m, 1 H), 1.62-1.72 (m, 2H), 0.92-0.97 (m, 2H), 0.77-0.87 ppm (m, 2H).

Example 9 3-Benzenesulfonyl-5- (2-pyrrolidin-1-yl-ethoxy) -1 H-indazole A solution of toluene-4-sulfonic acid 2- (3-benzenesulfonyl-1 H-indazol-5-yloxy) -ethyl ester (0.345 g, 0.730 mmol) and cyclopentylamine (1.0 mL, 10 mmol) in THF (8 mL ) was stirred in a sealed tube at 70 ° C for 6 hours and 80 ° C for 6 hours. After cooling somewhat, the reaction mixture is evaporated from the solvent and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase is then washed with water and saline. This was dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was dried by flash chromatography using 7.5% methanol in chloroform. After drying under vacuum at 57 ° C for 25 minutes, 3-benzenesulfonyl-5- (2-pyrrolidin-1-yl-ethoxy) -1H-indazole was obtained as a yellow foam (0.137 g, 48.8%). This was dissolved in methanol and chloroform, and ethereal hydrochloride was added. The mixture is concentrated and dried under vacuum at 75 ° C for about 16.5 hours to provide the hydrochloride as a white solid (0.0956 g): MP: 255-8 ° C (dea); Mass Spectrum (+ EI, [M + H] +) m / z 386. 1 H NMR (300 MHz, DMSO-d 6): 514.31-14.41 (br, 1 H), 9.13-9.14 (br, 2H), 8.03 -8.06 (m, 2H), 7.62-7.76 (m, 4H), 7.46 (d, 1 H, J = 2.10 Hz) 7.25 (dd, 1 H, J = 9.15 Hz and 2.29 Hz), 4.39-4.42 (m , 2H), 3.58-3.63 (m, 1H), 3.41 (s, 2H), 1.99-2.05 (m, 2H), 1.67-1.82 (m, 4H), 1.53-1.62 ppm (, 2H). Elemental Analysis for C20H23N3O3S. 1.00 mol HCl. 0.50 mol H2O: Cale: C, 55.74; H, 5.85; N, 9.75; Found: C, 55.39; H, 5.74; N, 9.62.

Example 10 3-Benzenesulfonyl-5- (2-morpholin-4-yl-ethoxy) -1H-indazole A solution of toluene-4-sulfonic acid 2- (3-benzenesulfonyl-l-1 H-indazol-5-yloxy) -ethyl ester (0.359 g, 0.760 mmol) and morpholine (1.0 mL, 11 mmol) in THF ( 8 mL) was stirred at 70 ° C for 6 hours in a sealed tube. After cooling somewhat, the reaction mixture is evaporated from the solvent and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase is then washed with water and saline. This was dried with anhydrous magnesium sulfate, filtered and concentrated. The residue is purified by flash chromatography using 5% methanol in chloroform. After drying under vacuum at 57 ° C for 20 minutes, 3-benzenesulfonyl-5- (2-pyrrolidin-1-yl-ethoxy) -1H-indazole was obtained as a very white foam (0.443 g, 15.1%). This was dissolved in methanol and chloroform, and ethereal hydrochloride is added. The mixture is concentrated and dried under vacuum at 75 ° C for about 16.5 hours to provide the hydrochloride as a light orange foam (0.0411 g). Mass Spectrum (+ EI, [M + H] +) m / z 388. 1 H NMR (300 MHz, DMSO-d 6): 514.31 (s, 1 H), 10.82-88 (br, 1 H), 8.03-8.07 (m, 2H), 7.62-7.76 (m, 4H), 7.49 (d, 1H, J = 2.10 Hz), 7.26 (dd, 1 H, = 9.14 Hz and 2.28 Hz), 4.54 (s, 2H), 4.02 (d, 2H, = 11.71 Hz), 3.80-3.87 (m, 2H), 3.51-3.73 (m, 4H), 3.19-3.31 ppm (m, 2H).

Example 11 3-Benzenesulfonyl-5- (2-pyrrolidin-1-yl-ethoxy) -1 H-indazole A solution of 2- (3-benzenesulfonyl-1 H-indazol-5-yloxy) -ethyl ester of toluene-4-acid Sulfonic acid (0.347 g, 0.734 mmol) and pyrrolidine (1.0 mL, 12 mmol) in THF (8 mL) is stirred at 70 ° C in a sealed tube for 6 hours. After cooling somewhat, the solvent is evaporated from the reaction mixture and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase is then washed with water and saline, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue is purified by flash chromatography using 7.5% methanol in chloroform. After drying at 55 ° C under vacuum 3-benzenesulfonyl-5- (2-pyrrolidin-1-yl-ethoxy) -1 H-indazole was obtained as a pale yellow solid (0.595 g, 21.8%). This was dissolved in methanol and chloroform, and ethereal hydrochloride was added. The mixture is concentrated and dried under vacuum at 75 ° C for 16.5 hours to provide the hydrochloride as a yellow foam (0.0598 g). Mass Spectrum (+ EI, [M + H] +) m / z 372. 1 H NMR (300 MHz, DMSO-d 6): 514.30 (s, 1 H), 10.35 (br, 1 H), 8.05 (d, 2H, J = 7.04 Hz), 7.63-7.75 (m, 4H), 7.48 (d, 1 H, = 1.83 Hz) 7.25-7.29 (m, 1 H), 4.45-4.48 (m, 2H), 3.66 (s) , br, 4H), 3.18-3.19 (m, 2H), 1.94-2.06 ppm (m, 4H).

Example 12 [2- (3-Benzenesulfonyl-1 H-indazol-5-yloxy) -ethyl] -methyl-amine A solution of toluene-4-sulfonic acid 2- (3-benzenesulfonyl-1 H-indazol-5-yloxy) -ethyl ester (0.340 g, 0.720 mmol) in methylamine at 2.0 in THF (8 mL, 16 mmol) was stirred at 70 ° C for 6 hours in a sealed tube for about 15.5 hours. After cooling something, the solvent is evaporated to the reaction mixture and this is partitioned in chloroform and aqueous sodium bicarbonate. The organic phase is then washed with saline, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue is purified by flash chromatography using 10% methanol in chloroform and 1.0% ammonium hydroxide / 10% methanol in chloroform. After drying at 57 ° C under vacuum for 20 minutes, [2- (3-benzenesulfonyl-1 H-indazol-5-yloxy) -ethyl] -methyl-amine was obtained as a light yellow semi-solid (0.0461 g, 19.4%). This was dissolved in methanol and chloroform, and ethereal hydrochloride was added. The mixture is concentrated and dried under vacuum at 73 ° C for 20 hours to provide the hydrochloride as a tan foam (0.0422 g). Mass Spectrum (+ EI, [M + H] +) m / z 332. 1 H NMR (500 MHz, DMSO-d 6): 514.24 (s, 1 H), 8.89 (s, 2 H), 7.96-7.99 (m , 2H), 7.53-7.68 (m, 4H), 7.40 (d, 1 H, = 2.19 Hz), 7.25 (dd, 1 H, J = 9.15 Hz and 2.32 Hz), 4.30-4.32 (m, 2H), 3.33-3.35 (m, 2H), 2.60-2.63 ppm (m, 3H).

Example 13 2- (3-Benzenesulfonyl-1H-indazol-5-yloxy) -ethylamine Over five different reactions, liquid ammonia (about 10 mL) is added to a solution at -78 ° C of 2- (3-benzenesulfonyl-H-indazol-5-yloxy) -ethyl ester of toluene-4-sulfonic acid (1.72). g, 3.63 mmol) in THF (48 mL). This is usually allowed to warm up at room temperature. This was heated in a sealed tube for about 16 to 35 hours between 70 to 100 ° C. After cooling to about room temperature, the combined reaction mixtures were then poured into an excess sodium bicarbonate solution and extracted with chloroform or methylene chloride. The organic phase was washed with saline, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue is purified by flash chromatography with 0.75% ammonium hydroxide / 7.5% methanol in chloroform. The residue was further purified by HPLC using 30 to 80% (chloroform / methanol (8: 2) / TEA) in heptane / TEA. Concentrate and dry yielding 2- (3-benzenesulfonyl-1H-indazol-5-yloxy) -ethylamine- as a white solid to which methanol and ethereal hydrochloride are added. It was concentrated and dried for 30 hours in vacuo at 83 ° C, producing the hydrochloride as a cream colored solid (0.0951 g, 7.4%): PF: > 300 ° C; Mass Spectrum (-El, [MH] ") m / z 316. 1 H NMR (500 MHz, DMSO-d 6): 514.24 (s, 1 H), 8.09 (br, s, 3 H), 7.96-7.98 (m , 2H), 7.56-7.68 (, 4H), 7.39 (d, 1 H, = 2.20 Hz), 7.17 (dd, 1 H, J = 9.15 Hz and 2.32 Hz), 4.22-4.25 (m, 2H), 3 20-3.24 ppm (m, 2H) Elemental Analysis for C? 5H15N3O3S 1.00 mol HCl 0.85 mol H2O: Cale: C, 48.81; H, 4.83; N, 11.38; Found: C, 48.65; H, 4.77; N, 11.00 Example 14 Dimethyl-. { 3- [3- (naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -propyl} -amine Stage 1 1 - . 1-Chloromethanesulfonyl naphthalene A mixture of 1-naphthalene sulfonyl chloride (20.2 g, 89.1 mmol), sodium sulfite (22.5 g, 178 mmol) and sodium bicarbonate (15.1 g, 180 mmol) in water (125 mL) was stirred at 100 ° C. for one hour After cooling to room temperature, for 40 minutes, bromochloromethane (90 mL, 14 moles) and tetrabutylammonium bromide (2.87 g, 8.91 mmol) are added. The reaction mixture was then stirred at 75 ° C for 14.5 hours. After cooling to room temperature, the layers of the reaction mixture were separated, and the organic phase was concentrated. The residue is purified by flash chromatography with 100% ethyl acetate. Hexane is added after concentration to help solidify, and the mixture is again concentrated. Dry at 80 ° C under vacuum for 20 minutes to give 1-chloromethanesulfonyl-naphthalene as a pale yellow solid (19.0 g, 88.8%). MP 103-5 ° C. Mass Spectrum (+ EI, M +) m / z 240. 1 H NMR (500 MHz, DMSO-d 6): 58.64-5 (m, 1 H), 8.41 (d, 1 H, J = 8.23 Hz), 8.27 (dd) , 1 H, J = 7.33 Hz and 1.22 Hz), 8.16-8.18 (m, 1 H), 7.71-7.81 (m, 3H), 5.40 ppm, (s, 2H). Elemental Analysis for CnHgCIO? S: Cale: C, 54.89; H, 3.77; N, 0.00; Found: C, 54.98; H, 3 81; N, 0.00 Stage 2 1- (5-Fluoro-2-nitro-phenylmethanesulfonyl) -naphthalene To a cold mixture of 1-chloromethanesulfonyl-naphthalene (19.7 g, 81.8 mmol) and 1-fluoro-4-nitrobenzene (8.7 L, 82 mmol) in dry THF (197 mL) is added dropwise potassium t-butoxide to the 1.0M in THF (205 mL, 205 mmol). The reaction mixture was stirred at room temperature under nitrogen for 1.5 hours. Glacial acetic acid (16 mL, 280 mmol) was then added. After stirring at room temperature for 1 hour, 40 minutes, the reaction mixture was concentrated and partitioned in hot ethyl acetate and saline. The organic phase was dried with anhydrous magnesium sulfate, filtered and concentrated. The solid residue was stirred in ether, filtered and dried at 82 ° C under vacuum for 1 hour. This produced 1- (5-fluoro-2-nitro-phenylmethanesulfonyl) -naphthalene as a brown / oxide colored solid (19.9 g, 70.6%): MP: 155-160 ° C; Mass Spectrum (-El, [MH]) m / z 344. 1 H NMR (300 MHz, DMSO-d 6): 58.50-8.52 (m, 1 H), 8.33 (d, 1 H, J = 8.30 Hz), 8.06-8.14 (, 2H), 7.97 (dd, 1 H, = 7.32 Hz and 1.22 Hz), 7.62-7.74 (m, 3H), 7.44-7.48 (m, 1 H), 7.23-7.26 (m, 1 H ), 5.23 ppm (s, 2H). Elemental Analysis for C17H12 FNO4S: Cale: C, 59.12; H, 3.50; N, 4.06; Found: C, 58.77; H, 3.30; N, 3.92.

Stage 3: 3- [3- (Naphthalene-1-sulfonylmethyl) -4-nitro-phenoxy] -propan-1-ol To a mixture of 1- (5-fluoro-2-nitro-phenylmethanesulfonyl) -naphthalene (19.9 g, 57.6 mmol) and 1,3-propanediol (49 L, 680 mmol) in dry THF (17 mL) is added dropwise to drop 1.0 M potassium tert-butoxide in THF (123 mL, 123 mmol). The reaction mixture was refluxed under nitrogen for 1 hour. It is allowed to cool to room temperature, water is added to the reaction mixture, and it is poured into a mixture of ice and hydrochloric acid at 2.0N. This was then extracted with ethyl acetate. The organic phase was washed with saline, dried over anhydrous magnesium sulfate, filtered and concentrated. The solid residue was purified by flash chromatography using 60% ethyl acetate in hexane and 100% ethyl acetate. The resulting yellow solid (12.9 g, 55.8% yield), 3- [3- (naphthalene-1-sulfonylmethyl) -4-nitro-phenoxy] -propan-1-ol, was obtained: MP: 134-5 ° C; Mass Spectrum (-El, [MH] ") m / z 400. 1 H NMR (500 MHz, DMSO-d 6): 58.50-8.53 (m, 1 H), 8.31 (d, 1 H, J = 8.17 Hz) , 8.10-8.12 (m, 1 H), 7.95-7.99 (m, 2H), 7.61-7.71 (m, 3H), 7.06 (dd, 1 H, J = 9.15 Hz and 2.80 Hz), 6.78 (d, 1H , J = 2.81 Hz), 5.23 (s, 2H), 4.52-4.55 (m, 1 H), 3.91-3.94 (m, 2H), 3.43-3.47 (m, 2H), 1.71-1.78 ppm (m, 2H) ). Elemental Analysis for C20H19NO6S: Calc: C, 59.84; H, 4.77; N, 3.49; Found: C, 59.78; H, 4.41; N, 3.43.

Stage 4 3- [3- (naphthalene-1-sulfonylmethyl) -4-nitro-phenoxy] -propyl ester of toluene-4-sulfonic acid A solution of 3- [3- (naphthalene-1-sulfonylmethyl) -4-nitro-phenoxy] -propan-1-ol (12.9 g, 32. 1 mmol), p-toluenesulfonyl chloride (24.6 g, 129 mmol) and triethylamine (37 mL, 270 mmol) in methylene chloride (300 L) was stirred at room temperature under nitrogen. After 2 hours, a second portion of p-toluenesulfonyl chloride (12.1 g, 63.5 mmol) is added. The reaction was stirred for a further 2 hours and then concentrated. The residue was partitioned in methylene chloride and aqueous sodium bicarbonate. The organic phase was washed with saline, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue is purified by flash chromatography with 20 to 50% ethyl acetate in hexane, 100% ethyl acetate and then 100% methylene chloride (due to limited solubility). A yellow solid (13.0 g, 73.0%) was obtained as 2- [3- (naphthalene-1-sulfonylmethyl) -4-nitro-phenoxy] -propyl ester of toluene-4-sulfonic acid: MP: 162-4 ° C; Mass Spectrum (-El, [MH] -) m / z 554. 1 H NMR (500 MHz, DMSO-de): 58.52-8.54 (m, 1 H), 8.31 (d, 1 H, = 8.18 Hz), 8.09-8.11 (m, 1H), 7.97-8.00 (m, 2H), 7.62-7.73 (m, 5H), 7.35 (d, 2H, J = 7.93 Hz), 6.92 (dd, 1 H, J = 9.15 Hz and 2.81 Hz), 6.73 (d, 1 H, J = 2.80 Hz), 5.22 (s, 2H), 4.09. (t, 2H, J = 5.98 Hz), 3.79-3.82 (m, 2H), 2.29 (s, 3H), 1.91-1.97 ppm (m, 2H). Elemental Analysis for C27H25NO8S2: Cale: C, 58.37; H, 4.54; N, 2.52; Found: C, 58.13; H, 4.43; N, 2.41.

Stage 5 3- [4-amino-3- (naphthalene-1-sulfonylmethyl) -phenoxy] -propyl ester of toluene-4-sulfonic acid Ethanol (30 mL) and 10% palladium on carbon (0.439 g) are added to a hot solution of 2- [3- (naphthalene-1-sulfonylmethyl) -4-nitro-phenoxy] -propyl ester of tap-4 acid. -sulfonic acid (0.785 g, 1.41 mmol), in anhydrous THF (40 mL). The reaction mixture was hydrogenated over the Parr apparatus for 2 hours (starting pressure 43 psi). The reaction mixture was then filtered over Celite and concentrated. This was dried at 75 ° C under vacuum for 20 minutes to provide 3- [4-amino-3- (naphthalene-1-sulfonylmethyl) -phenoxy] -propyl ester of toluene-4-sulfonic acid as a semi-solid coffee- green (0.627 g, 84.4%). Mass Spectrum (+ EI, [M + H] +) m / z 526. 1 H NMR (500 MHz, DMSO-de): 58.61 (d, 1 H, = 8.42 Hz), 8.25 (d, 1 H, = 8.17 Hz), 8.02-8.07 (m, 2H), 7.59-7.72 (m, 5H), 7.39 (d, 2H, = 7.93 Hz), 6.56 (d, 1 H, J = 8.17 Hz), 6.44-6.47 ( m, 1 H), 6.01 (d, 1 H, J = 2.81 Hz), 4.62 (s, 2H), 3.98-4.01 (, 2H), 3.36-3.39 (m, 2H), 2.35 (s, 3H), 1.71-1.79 ppm (m, 2H).

Stage 6 3- [3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -propyl ester of toluene-4-sulfonic acid Isopropanol (205 mL) and 1.0 N hydrochloric acid (200 mL) were added to 3- [4-amino-3- (naphthalene-1-sulfonylmethyl) -phenoxy] -propyl ester of toluene-4-sulfonic acid (8.1 g, 15 mmol). The reaction mixture was heated due to limited solubility. Then sodium nitrite (1.6 g, 2.3 mmol) in water (22 mL) is added. More isopropanol (100 mL) was added to the reaction mixture to increase the solubility. After stirring at room temperature for 1 hour, sodium carbonate is added at a basic pH. This reaction mixture was then stirred at room temperature for 30 minutes. After concentrating, the residue was partitioned in ethyl acetate and water. The organic phase is then washed with saline, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue is purified by flash chromatography using 50% ethyl acetate in hexane. A light amber semisolid (3.3 g, 41%) of 3- [3- (naphthalene-1-sulfonyl) -1 H-indazol-5-yloxy] -propyl ester of toluene-4-sulfonic acid was obtained . Mass spectrum (-El, [MH]) m / z 535. H NMR (500 MHz, DMSO-d6): D 14.08 (S, 1 H), 8.78 (d, 1 H, J = 8.78 Hz), 8.55 (dd, 1 H, J = 7.44 Hz and 1.22 Hz), 8.28 (d, 1 H, = 8.17 Hz), 8.02-8.04 (m, 1 H), 7.73-7.77 (m, 1 H), 7.55-7.65 (m, 4H), 7.48 (d, 1 H, J = 9.15 Hz), 7.03-7.06 (m, 3H), 6.88-6.91, (m, 1 H), 4.17 (t, 2H, = 5.98 Hz), 3.85-3.88 (m, 2H), 2.00-2.03 (m, 2H), 1.97 ppm (s, 3H). Elemental Analysis for C27H24N2O6S2 0.10 mol H2O: Cala: C, 60.23; H, 4.53; N, 5.20; Found: C, 59.92; H, 4.30; N, 5.17.

Stage 7 Dimethyl-. { 3- [3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -propyl} -amine A solution of 3- [3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -propyl ester of toluene-4-sulfonic acid (1.02 g, 1898 mmol) in dimethylamine at 2.0 m in THF (20 g. mL, 40 mmol) was stirred for 16 hours at 70 ° C in a sealed tube. After cooling to room temperature, the reaction mixture was concentrated and partitioned in chloroform and aqueous sodium bicarbonate. The organic phase was washed with saline, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue is purified by flash chromatography using 0.5% ammonium hydroxide / 5.0% methanol in chloroform. Dimethyl- was obtained. { 3- [3- (naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -propyl} -amine as a light yellow solid (0.453 g, 58.5%). Methanol and ethereal hydrochloride were then added to this compound. The remaining solution was concentrated and dried for 14 hours at 84 ° C under vacuum. Dimethyl- was obtained. { 3- [3- (naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -propyl} -amine as hydrochloride as a very light yellow solid (0.455 g): MP: 264-5 ° C; Mass Spectrum (-El, [MH] ") m / z 408. 1 H NMR (500 MHz, DMSO-de): D 14.17 (S, 1 H), 10.19 (s, 1 H), 8.75 (d, 1 H, J = 8.67 Hz), 8.53 (dd, 1 H, J = 7.44 Hz and 1.22 Hz), 8.27 (d, 1 H, J = 8.30 Hz), 8.02-8 04 (m, 1 H), 7.71- 7.75 (m, 1 H), 7.54-7.65 (m, 3H), 7.29 (d, 1 H, J = 2.08 Hz), 7.07-7.10 (m, 1 H), 4.07-4.10 (m, 2H), 3.19 -3.23 (m, 2H), 2.76 (s, 6H), 2.11-2.18 ppm (m, 2H) Elemental Analysis for C22H23N3O3S 1.00 mol HCl: Cala: C, 59.25; H, 5.42; N, 9.42; Found: C 58.97; H, 5.58; N, 9.23.

Example 15 Methyl-. { 3- [3- (naphthalene-1-sulfonyl) -1 H -ndazol-5-yloxy] -propyl} -amine A solution of 3- [3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -propyl ester of toluene-4-sulfonic acid (0.422 g, 0.786 mmol) in 2.0 M methylamine in THF (8.0 mL, 16 mmol). It was stirred for 15 hours at 70 ° C in a sealed tube. After cooling to room temperature, the reaction mixture was concentrated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was washed with saline. The aqueous phases were extracted with chloroform, and both organic phases were combined and dried with anhydrous magnesium sulfate, filtered and concentrated. The residue is purified by flash chromatography using 0.75% ammonium hydroxide / 7.5% methanol in chloroform. Methyl- was obtained. { 3- (naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -propyl} -amine as a light yellow foam (O.209g, 67.2%). Methanol and ethereal hydrochloride are added to the compound. The resulting solution was concentrated and dried for 14 hours at 84 ° C under vacuum. The hydrochloride was obtained as a light yellow foam (0.217 g). Mass spectrum (-El, [MH]) m / z 394. 1 H NMR (500 MHz, DMSO-d 6): D 14.16 (s, 1 H), 8.74-8.76 (m, 1 H), 8.67 (s) , br, 2H), 8.52 (dd, 1 H, J = 7.44 Hz and 1.22 Hz), 8.27 (d, 1 H, J = 8.30 Hz), 8.02-8.05 (m, 1 H), 7.70-7.75 (m , 1 H), 7.54-7.65 (m, 3H), 7.29 (d, 1 H, J = 2.19 Hz), 7.08-7.11 (m, 1 H), 4.09 (t, 2H, J = 5.98 Hz), 3.05 (s, br, 2H), 2.55 (s, 3H), 2.05-2 11 ppm (m, 2H). Elemental Analysis for C2? H21N3O3S 1.00 mol HCl 0.45 mol H2O: Cala: C, 57.32; H, 5.25; N, -9, 55; Found: C, 57.64; H, 5.33; N, 9 39.

Example 16 Etil- { 3 - [- (naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -propyl} -amine A solution of 3- [3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy [-propyl ester of toluene-4-sulfonic acid (0.080 mg, 0.15 mmol) in 10 mL of ethylamine at 2.0 M / THF (20 mmol) was stirred at 90 ° C for about 2 hours in a sealed tube. After cooling to room temperature the reaction mixture was stripped of the solvent by evaporation. This was dissolved in ethyl acetate and washed twice with aqueous sodium bicarbonate. The organic phase was dried over anhydrous magnesium sulfate, filtered and And concentrated. The residue is purified by flash chromatography using 0.65% ammonium hydroxide / 7.5% methanol in chloroform. Drying at 66 ° C under vacuum for 20 minutes produced ethyl-. { 3- [3- (naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -propyl} -amine as a light yellow foam (43.0 mg, 70.0%). This was dissolved in methanol and ethereal hydrochloride was added. After concentrating and drying under vacuum at 83 ° C for 16 hours gave the hydrochloride as a pale yellow semi-solid (41.7 mg, 62.3%). Mass spectrum (+ EI, [M + Hf) m / z 410; 1 H NMR (500 MHz, DMSO-d 6): D14.14-14.18 (br, 1 H), 8.74-8.76 (m, 1 H), 8.56-8.72 (br, 2H), 8.52 (dd, 1 h, J = 7.44 Hz and 1.22 Hz), 8.27 (d, 1 H, J = 8.29 Hz), 8.03-8.05 (m, 1 H), 7.71-7.75 (, 1 H), 7.54-7.65 (m, 3H), 7.29 (d, 1 H, J = 2.08 Hz), 7.07-7.10 (m, 1 H), 4.09-4.12 (m, 2H), 3.03-3.07 (m, 2H), 2.90-2.97 (m, 2H), 2.05 -2.12 (m, 2H), 1.15-1.19 ppm (m, 3H). Elemental Analysis for C22H23N3O3S 1.00 mol HCl 1 20 mol H2O: Cala: C, 56.51; H, 5.69; N..8.99; Found: C, 56.20; H, 5.36; N, 8.81.

Example 17 Ethyl-methyl-. { 3- [3- (naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -propyl} -amine A solution of 3- [3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -propyl ester of toluene-4-sulfonic acid (0.080 mg, 0.15 mmol) and methylethylamine (0.45-0.75 mmol) is stirred at 90 ° C for about 2 hours in a sealed tube. After cooling to room temperature the reaction mixture was stripped of the solvent by evaporation. This was ß dissolved in ethyl acetate and washed twice with aqueous sodium bicarbonate. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was dissolved in methanol and ethereal hydrochloride was added. The mixture was then concentrated and dried for 29 hours at 80 ° C under vacuum. Ethylmethyl-hydrochloride was obtained. { 3- [3- (naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -propyl} -amine as a semi-solid cream (53.2 mg, 77.1%); Mass Spectrum (+ EI, [M + H] +) m / z 424. 1 H NMR (500 MHz, DMSO-de): D14.14-14.17 (br, 1 H), 9.71-9.77 (br, 1 H ), 8.74-8.76 (m, 1 H), 8.52 (dd, 1 H, J = 7.44 Hz and 1.22 Hz), 8.27 (d, 1 H, = 8.30 Hz), 8.03-8.05 (m, 1 H), 7.70-7.74 (m, 1 H), 7.56-7.64 (m, 3H), 7.29 (d, 1 H, J = 2.19 Hz), 7.08-7.10 (m, 1 H), 4.08-4.11 (m, 2H) , 3.04-3.25 (m, 2H), 2.72 (s, 3H), 1.18-1.21 ppm (m, 3H). Elemental Analysis for C23H25N3O3S 1.00 mmol HCl 0.90 mol H2O: Cala: C, 58.01; H, 5.88; N, 8.82; Found: C, 58.37; H, 5.55; N, 8.50. '•' '.

Example 18 Diethyl- { 3- [3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -propyl} -amine A solution of 3- [3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -propyl ester of toluene-4-sulfonic acid (0.080 mg, 0.15 mmol) and diethylamine (0.45-0.75 mmol) ) in THF (10 mL) was stirred at 90 ° C for about 2 hours in a sealed tube. After cooling to room temperature the reaction mixture was stripped of the solvent by evaporation. This was dissolved in ethyl acetate and washed twice with aqueous sodium bicarbonate. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was dissolved in methanol and chloroform, and ethereal hydrochloride was added. The mixture was concentrated and dried under vacuum at 80 ° C for 17 hours. Diethyl- hydrochloride was obtained. { 3- [3- (naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -propyl} -amine as a tan foam (69.9 mg, 98.3%); Mass Spectrum (+ EI, [M + H] +) m / z 438. 1 H NMR (500 MHz, DMSO-d 6): D14.13-14.11 (br, 1 H), 9.59-9.63 (br, 1 H ), 8.75 (d, 1 H, = 8.42 Hz), 8.51 (dd, 1 H, J = 7.44 Hz and 1.10 Hz), 8.27 (d, 1 H, J = 8.29 Hz), 8.03-8.05 (m, 1 H), 7.70-7.74 (m, 1 H), 7.52-7.64 (m, 3H), 7.05-7.11 (m, 2H), 4.10 (t, 2H, = 5.98 Hz), 3.11-3.25 (m, 6H) , 2.09-2.24 (m, 2H), 1.18 ppm (t, 6H, J = 7.20 Hz). • useful Example 19 Butil-. { 3- [3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -propl} -amine A solution of 3- [3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -propyl ester of toluene-4-sulfonic acid (080 mg, 0.15 mmol) and propylamine (0.45-0.75 mmol) in THF (10 mL) was stirred at 90 ° C for about 2 hours in a sealed tube. After cooling to room temperature the reaction mixture is removed by evaporation. This was dissolved in ethyl acetate and washed twice with aqueous sodium bicarbonate. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was dissolved in methanol, and ethereal hydrochloride is added. After concentrating and drying under vacuum at 80 ° C for 17 hours, butyl- hydrochloride was produced. { 3- [3- (naphthalene-1-sulfonyl) -1 H -nane, azol-5-yloxy] -propyl} -amine as a light orange semisolid (43.3 mg, 60.9%), mass spectrum (+ EI, [M + H] +) m / z 438. 1 H NMR (500 MHz, DMSO-de): G13.8-14.2 (br, 1 H), 8.75 (d, 1 H, J = 8.66 Hz), 8.50-8.52 (m, 1 H), 8.27 (d, 1 H, J = 8.30 Hz), 8.03-8.05 (m, 1 H), 7.71-7.75 (m, 1 H), 7.54-7.64 (m, 3H), 7.29 (d, 1 H, = 2.07 Hz), 7.07-7.10 (m, 1 H), 4.08-4.11 (m, 2H), 3.04-3.08 (m, 2H), 2.86-2.90 (m, 2H), 2.06-2.13 (m, 2H), 1.52-1.59 (m, 2H), 1.26-1.33 (m, 4H), 0.88- 0.84 ppm (m, 3H). u?. 'i Example 20 Cyclopropyl- { -3- [3- (naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -propyl} -amine A solution of 3- [3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -propyl ester of toluene-4-sulfonic acid (0.080 mg, 0.15 mmol) and cyclopropylamine (0.45-0.75 mmol) ) in THF (10 mL) was stirred at 90 ° C for about 2 hours in a sealed tube. After cooling to room temperature the reaction mixture is removed by evaporation. It was dissolved in ethyl acetate and washed twice with sodium bicarbonate. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified twice by flash chromatography using 0.75% ammonium hydroxide / 7.5% methanol in chloroform and 0.5% ammonium hydroxide / 5.0% ethanol in chloroform to give cyclopropyl-. { -3- [3- (naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -propyl} -amine as a light yellow film (51.0 mg, 80.7%). This compound was dissolved in methanol and ethereal hydrochloride was added. Upon concentration and drying in vacuo for 24 hours at 83 ° C, it gave the hydrochloride as a yellow foam (48.9 mg, 71.2%); Mass Spectrum (+ EI, [M + Hf) m / z 422. 1 H NMR (500 MHz, DMSO-d 6): D 14.15 (s, 1 H), 9.01 (s, 2 H), 8.74-8.76 (m , 1.H), 8.51-8.53 (m, 1 H), 8.27 (d, 1 H, J = 8.29 Hz), 8.02-8.05 (m, 1 H), 7.71-7.75 (m, 1 H) p7: 51-7.65 (m, 3H), 7.29 (d, 1 H, = 2.19 Hz), 7.08-7.11 (m, 1 H), 4.11 (t, 2H, = 6.10 Hz), 3.11-3.20 (br, s, 2H), 2.65-2.75 (m, 1 H), 2.08-2.15 (m, 2H), 0.83-0.87 (m, 2H), 0.70-0.77 ppm (m, 2H). Elemental Analysis for C23H23N3O3S 1.00 mol HCl 0.70 mol H2O: Cala: C, 58.70; H, 5.44; N, 8.93; Found: C, 58.70; H, 5.09; N, 8.68.

Example 22 Cyclopentyl-. { 3- [3- (naphthalene-1-su! Fo.nil) -1H-indazol-5-yloxy] -propyl} -amine A solution of 3- [3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -propyl ester of toluene-4-sulfonic acid (0.080 mg, 0.15 mmol) and cyclopentylamine (0.45-0.75 mmol) in THF (10 mL) was stirred at 90 ° C for 2 hours in a sealed tube. After cooling to room temperature, the reaction mixture is stripped of the solvent by evaporation. This was partitioned in ethyl acetate and washed twice with aqueous sodium bicarbonate. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue is purified by flash chromatography using 0.75% ammonium hydroxide / 7.5% methanol in chloroform to give cyclopentyl-. { 3- [3- (naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -propyl} -amine as a cream colored foam (70.6 mg, 100%). This compound was dissolved in methanol, and ethereal hydrochloride was added. After concentrating and drying under vacuum for 12.5 hours at 83 ° C, it gave the hydrochloride as a light brown foam (69.7 mg, 95.6%); Mass Spectrum (+ EI, [M + H] +) m / z 450. 1 H NMR (500 MHz, DMSO-de): D14.15-14.21 (br, 1 H), 8.70-8.83 (m, 3H) , 8.51-8.53 (m, 1 H), 8.27 (d, 1 H, = 8.30 Hz), 8.03-8.05 (m, 1 H), 7.71-7.75 (m, 1 H), 7.54-7.65 (m, 3H ), 7.30 (d, 1 H, J = 2.20 Hz), 7.09 (dd, 1 H, J = 9.15 Hz and 2.31 Hz), 4.11 (t, 2H, J = 6.10 Hz), 3.43-3.49 (m, 1 H), 3.06 (br, s, 2H), 2.05-2.14 (m, 2H), 1.88-1.96 (m, 2H), 1.43-1.71 ppm (m, 6H). Elemental Analysis for C25H27N3O3S 1.00 mol HCl 0.75 mol H2O: Cala: C, 60.11; H, 5.95; N, 8.41; Found: C, 59.71; H, 5.83; N, 8.25.

Example 22 lsopropyl-. { 3- [3- (naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -propyl} -amine A solution of 3- [3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -propyl ester of toluene-4-sulfonic acid (0.080 mg, 0.15 mmol) and isopropylamine (0.45-0.75 mmol) in THF (10 mL) was stirred at 90 ° C for about two hours in a sealed tube. After cooling to room temperature the reaction mixture is removed by evaporation. This was dissolved in ethyl acetate and washed and washed twice with aqueous sodium bicarbonate. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue is purified by flash chromatography using 0.75%) ammonium hydroxide / 7.5% methanol in chloroform. The compound was dissolved in methanol and ethereal hydrochloride was added. After concentrating and drying under vacuum for 16 hours at 83 ° C, he gave isopropyl- hydrochloride. { 3- [3- (naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -propyl} -amine as a light yellow foam (48.6 mg, 70.4%); Mass Spectrum (+ EI, [M + H] +) m / z 424. 1 H NMR (500 MHz, DMSO-d 6): D 14.15-14.16 (br, 1 H), 8.75 (d, 1 H, = 8.78 Hz), 8.60-8.70 (br, 2H), 8.52 (dd, 1 H, J = 7.45 Hz and 1.22 Hz), 8.27 (d, 1 H, J = 8.29 hz), 8.03-8.05 (m,, 1 H) ), 7.71-7.75 (m, 1 H), 7.54-7.65 (m, 3H), 7.30 (d, 1 H, J = 2.20 Hz), 7.08-7.11 (m, 1 H), 4.09-4.13 (m, 2H), 3.05 (s, br, 2H), 2.07-2.13 (m, 2H), 1.22 ppm (d, 6H, J = 6.46 Hz) Elemental Analysis for C23H25N3? 3S 1.00 mol HCl 0.55 mol H2O: Cala: C, 58.79; H, 5.81; N, 8.94; Found: C, 58.46; H, 5.61; N, 8.72.

Example 23 3- (Naphthalene-1-sulfonyl) -5- (3-pyrrolidin-1-yl-propoxy) -1H-indazole A solution of 3- [3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -propyl ester of toluene-4-sulfonic acid (0.080 mg, 0.15 mmol) and pyrrolidine (0.45-0.75 mmol) in THF (10 mL) was stirred at 90 ° C for about 2 hours in a sealed tube. After cooling to room temperature the reaction mixture is removed by evaporation. This was dissolved in ethyl acetate and washed twice with aqueous sodium bicarbonate. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was dissolved in methanol and chloroform, and ethereal hydrochloride was added. After concentrating and drying in vacuo at 80 ° C for 17 hours it gave 3- (naphthalene-1-sulfonyl) -5- (3-pyrrolidin-1-IL-21-propoxy) -1H-indazole hydrochloride as a semi-solid coffee (19.7 mg, 27.8%); Mass Spectrum (+ EI, [M + H] +) m / z 436. 1 H NMR (500 MHz, DMSO-de): D14.13 (s, 1H), 10.00-10.03 (br, 1H), 8.75 ( d, 1 H, J = 8.66 Hz), 8.51-8.53 (m, 1 H), 8.27 (d, 1 H, J = 8.30 Hz), 8.03-8.05 (m, 1 H), 7.71-7.74 (m, 1 H), 7.54-7.64 (m, 3H), 7.29 (d, 1 H, = 2.20 Hz), 7.07-7.10 (m, 1 H), 4.08-4.11 (m, 2H), 3.51-3.58 (m, 2H), 2.95-3.06 (m, 2H), 2.10-2.17 (m, 2H), 1.89-1.99 (m, 2H), 1.77-1.87 ppm (m, 2H).

Example 24 3- (Naphthalene-1-sulfonyl) -5- (3-piperidin-1-yl-propoxy) -1H-indazole A solution of 3- [3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -propyl ester of toluene-4-sulfonic acid (0.080 mg, 0.15 mmol) and piperidine (0.45-0.75 mmol) THF (10 mL) was stirred at 90 ° C for about 2 hours in a sealed tube. After cooling to room temperature the reaction mixture is removed by evaporation. This was dissolved in lime acetate and washed twice with aqueous sodium bicarbonate. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was dissolved in methanol, and ethereal hydrochloride is added. After concentrating and drying at 80 ° for 29 hours under vacuum, he gave 3- (Naphthalene-1-sulfonyl) -5- (3-piperidin-1-yl-propoxy) -1H-indazole hydrochloride as a brown semisolid (49.0 mg, 67.2%); Masá spectrum ^ -EI, [MH] ") m / z 448. 1 H NMR (500 MHz, DMSO-d6): D14.14 (s, 1 H), 9.59-9.66 (br, 1 H), '8.75 (d, 1 H, J = 8.54 Hz), 8.51-8.53 (m, 1 H), 8.27 (d, 1 H, J = 8.30 Hz), 8.03-8.05 (m, 1 H), 7.71-7.74 (m , 1 H), 7.54-7.65 (m, 3H), 7.29 (d, 1 H, J = 2.20 Hz), 7.08 (dd, 1 H, J = 9.15 Hz and 2.32 Hz), 4.09 (t, 2H, J = 5.98 Hz), 3.42-3.45 (m, 2H), 3.16-3.25 (m, 2H), 2.82-2.96 (m, 2H), 2.13-2.29 (m, 2H), 1.58-1.80 (m, 5H), 1.30-1.40 ppm (m, 1 H) Elemental Analysis for C25H27N3O3S 1.00 mol HCl 1.00 mol H2O: Cala: C, 59.57; H, 6.00; N, 8.34; Found: C, 59.36; H, 5.82; N, 8.24.

Example 25 - (3-Morpholin-4-yl-propoxy) -3- (naphthalene-1-sulfonyl) -1 H-indazole A solution of 3- [3- (naphthalene-1-sulfonyl) -1H-indazole-5 -alloxy] -propyl ester of toluene-4-sulfonic acid (0.080 mg, 0.15 mmol) and morpholine (0.45-0.75 mmol) in THF (10 mL) was stirred at 90 ° C for about 2 hours in a sealed tube. After cooling to room temperature the reaction mixture is removed by evaporation. This was dissolved in ethyl acetate and washed twice with aqueous sodium bicarbonate. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue is purified by flash chromatography using 0.5% ammonium hydroxide / 5.0% methanol in chloroform. 5- (3-Morpholin-4-yl-propoxy) -3- (naphthalene-1-sulfonyl) -1H-indazole was obtained as a light yellow solid (74.4 mg, 100%). This product was dissolved in methanol, and ethereal hydrochloride is added. After concentrating and drying under vacuum at 83 ° C for 24 hours, the hydrochloride was produced as a yellow foam (74.5 mg, 100%); Mass Spectrum (+ EI, [M + H] +) m / z 452. 1 H NMR (500 MHz, DMSO-de): D14.15 (s, 1 H), 10.56-10.62 (br, 1 H), 8.75 (d, 1 H, = 8.66 Hz), 8.52 (dd, 1 H, = 7.44 Hz and 1.22 Hz), 8.27 (d, 1 H, J = 8.30 Hz), 8.02-8.05 (m, 1 H), 7.71-7.75 (m, 1 H), 7.54-7.65 (m, 3H), 7.29 (d, 1 H, J = 2.32 Hz), 7.07-7.10 (m, 1 H), 4.10 (t, 2H, J = 5.86 Hz), 3.93-3.96 (m, 2H), 3.71-3.77 (m, 2H), 3.43-3.46 (, 2H), 2.99-3.15 (m, 2H), 2.14-2.22 ppm (m, 2H). Elemental Analysis for C24H25N3O5S 1.00 mol HCl 1.30 mol H2O: Cala: C, 56.36; H, 5.36; N, 8.22; Found: C, 56.05; H, 5.65; N, 8.09.

Example 26 3- [3- (Naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -propylamine Step 1 - (3-Azido-propoxy) -3- (naphthalene-1-sulfonyl) -1 H-indazole Sodium azide (0.425 g, 6.54 mmol) was added to a solution of 3- [3- (naphthalene-1-sulfonyl) -1H-indazol-5: yloxy] -propyl ester of toluene-4-sulfonic acid (1.16 g) , 2.16 mmol) in DMF (20 mL). The reaction mixture was stirred at 80 ° C for 15 hours in a sealed tube. After cooling to room temperature, it was poured into excess water and extracted with ethyl acetate. The organic phase was washed with 10% ammonium chloride / water in solution, water and saline. This was dried with anhydrous magnesium sulfate, filtered, concentrated and dried at 73 ° C in vacuum for 45 minutes to give 5- (3-Azido-propoxy) -3- (naphthalene-1-sulfonyl) -1H-indazole as an amber gum (0.770 g, 87.7%); Mass Spectrum (-El, [MH] ") m / z 406. 1 H NMR (400 MHz, DMSO-d 6): D14.05 (br, 1H), 8.64-8.68 (m, 1 H), 8.53 (dd) , 1 H, = 7.42 Hz and 1.16 Hz), 8.25-8.28 (m, 1 H), 8.01-8.05 (, 1 H), 7.70-7.74 (m, 1 H), 7.52-7.64 (m, 3H), 7.26 (d, 1 H, J = 2.08 Hz), 7.08 (dd, 1H, J = 9.16 Hz and 2.32 Hz), 4.06 (t, 2H, J = 6.14 Hz), 3.49-3.52 (m, 2H), 1.96 -1.99 ppm (m, 2H).

Stage 2 YP 3- [3- (Naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -propylamine - (3-Azido-propoxy) -3- (naphthalene-1-sulfonyl) -1 H -indazole (0.763 g, 1.87 mmol) was dissolved in hot ethanol (125 mL). 10% palladium on charcoal (0.16 g) is added, and the reaction mixture was stirred and hydrogenated on the Parr apparatus for 2 hours, starting pressure 51 psi. 10% palladium on additional carbon (0.32 g) was added, and the reaction mixture was hydrogenated again on the Parr apparatus for 2 hours. This was then filtered on Celita and concentrated. The residue is purified by flash chromatography with 0.75% ammonium hydroxide / 7.5% methanol in chloroform. The product was further purified by HPLC using a gradient of chloroform / methanol in ethane / TFA. It results 3- [3- (naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -propylamine as a light yellow foam (0.229 g, 32.1%). Methanol and ethereal hydrochloride are added. The mixture was concentrated and dried at 83 ° C under vacuum for 12 hours to provide the hydrochloride as a light-colored foam (0.235 g). Mass Spectrum (-El, [MH] ") m / $ 380. 1 H NMR (500 MHz, DMSO-d6): 014.15 (s, 1 H), 8.75 (d, 1 H, J = 8.67 Hz), 8.50- 8.52 (m, 1 H), 8.27 (d, 1 H, = 8.30 Hz), 8.02-8.05 (m, 1 H), 7.86 (s, br, 3H), 7.71-7.75 (m, 1 H), 7.54 -7.64 (m, 3H), 7.29 (d, 1 H, J = 2.20 Hz), 7.08-7.11 (m, 1 H), 4.09 (t, 2H, J = 6.10 Hz), 2.94-2.99 (m, 2H) ), 2.00-2.07 ppm (m, 2H) Elemental Analysis for C2oH19N3O3S 1.00 mol HCl 0.40 mol H2O: Cala: C, 56.51; H, 4.93; N, 9.88; Found: C, 56.21; H, 5.12; N, 9.56 .

Example 27 Dimethyl-. { 2- [3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -ethyl} -amina Stage 1 1- (5-Fluoro-2-nitro-phenylmethanesulfonyl) -naphthalene To a cooled mixture of 1-chloromethanesulfonyl-naphthalene (2121.7 g, 90.1 mmol) and 1-fluoro-4-nitrobenzene (9.6 mLf * 90 mmol) in dry THF (220 mL) is added dropwise to 1.0 M potassium tert-butoxide in THF (193 mL, 193 mmol). The reaction mixture was stirred at room temperature under nitrogen for 1 hour, 10 minutes. Glacial acetic acid (17 L, 300 mmol) is then added. The reaction mixture was concentrated and partitioned in hot ethyl acetate and saline. The organic phase was dried with anhydrous magnesium sulfate, filtered and concentrated. The solid residue was stirred in ether, filtered and dried at 65 ° C in vacuo for 16 hours. This produced a brown / oxide colored solid (22.2 g, 71.4%) such as 1- (5-fluoro-2-nitro-phenylmethanesulfonyl) -naphthalene: PF: 155-156 ° C; Mass Spectrum (-El, [MH] ") m / z 344. 1 H NMR (300 MHz, DMSO-d 6): D8.50-8.52 (m, 1H), 8.33 (d, 1 H, J = 8.30 Hz ), 8.06-8.14 (m, 2H), 7.97 (dd, 1 H, = 7.32 Hz and 1.22 Hz), 7.62-7.74 (m, 3H), 7.44-7.48 (m, 1 H), 7.23-7.26 (m , 1 H), 5.23 ppm (s, 2H) Elemental Analysis for C17H12FNO4S: Cala: C, 59.12; H, 3.50; N, 4.06; Found: C, 58.77; H, 3.30; N, 3.92.

Stage 2 'V 2- [3- (Naphthalene-1-sulfonylmethyl) -4-nitro-phenoxy] -ethanol A mixture of 1- (5-fluoro-2-nitro-phenylmethanesulfonyl) -naphthalene (14.6 g, 42.3 mmol) and ethylene glycol (35 mL, 630 mmol) in 1.0 N potassium tert-butoxide in THF (90 mL, 90 mmol) was placed under reflux under nitrogen for 1 hour. After cooling to room temperature, the reaction mixture was concentrated. Excess water is added to the residue, and the mixture was poured into ice / 2N hydrochloric acid. This was extracted with ethyl acetate and. avada with water and saline solution. This was then dried with anhydrous magnesium sulfate, filtered, concentrated and dried under vacuum at 80 ° C for 25 minutes to provide 2- [3- (naphthalene-1-sulfonylmethyl) -4-nitro-phenoxy] -ethanol as a brown gum (14.3 g, 87.2%). Mass Spectrum (-El, [MH] ") m / z 386. 1 H NMR (500 MHz, DMSO-d 6): 08.56-8.57 (m, 1 H), 8.35 (d, 1 H, J = 8.24 Hz) , 8.14-8.15 (m, 1 H), 8.00-8.02 (m, 2H), 7.65-7.75 (m, 3H), 7.11-7.13 (m, 1 H), 6.89 (d, 1 H, J = 2.90 Hz ), 5.27 (s, 2H), 4.92 (t, 1 H, J = 5.49 Hz), t 3.93-3.95 (m, 2H), 3.67 ppm (dd, 2H, J = 9.91 Hz and 5.34 Hz). para 9H17NO6S 0.25 mol H2O: Cala: C, 58.23; H, 4.50; N, 3.57; Found: C, 57.83; H, 4.25; N, 3.50.

Stage 3 2- [3- (naphthalene-1-sulfonylmethyl) -4-nitro-phenoxy] -ethyl ester of Toluene-4-sulfonic acid A solution of 2- [3- (naphthalene-1-sulfonylmethyl) -4-nitro-phenoxy] -ethanol (14.3 g, 36.9 mmol), p-toluene chloride (14.9 g / 78.2 mmol) and triethylamine (23 mL, 170 mmol) in methylene chloride 00 mL) was stirred under nitrogen at room temperature for 2 hours, 45 minutes. The reaction mixture was then concentrated and partitioned in methylene chloride and aqueous sodium bicarbonate. The organic phase was washed with saline, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue is purified by flash chromatography with 25 to 75% ethyl acetate in hexane and 100% ethyl acetate. Dry for 25 minutes in vacuo at 80 ° C and produce 2- [3- (naphthalene-1-sulfonylmethyl) -4-nitro-phenoxy] -ethyloluene-4-sulfonic acid ester as an oxide-colored solid (15.7 g, 78.5%). Mass Spectrum (+ EI, [M + H] +) m / z 542. 1 H NMR (500 MHz, DMSO-d 6): 08.53 (dd, 1 H, J = 8.18 Hz and 1.10 Hz), 8.31 (d, 1 H, J = 8.30 Hz), 8.09-8.11 (m, 1 H), 7.94-7.99 (m, 2H), 7.62-7.75 (, 5H), 7.42 (d, 2H, J = 7.93 Hz), 6.98 ( dd, 1 H, J = 9.15 Hz and 2.93 Hz), 6.80 (d, 1 H, J = 2.81 Hz), 5.20 (s, 2H), 4.28-4.30 (m, 2H), 4.10-4.12 (m, 2H ) < /2.37 ppm (s ^ 3H).

Stage 4 2- [4-amino-3- (naphthalene-1-sulfonylmethyl) -phenoxy] -ethyl ester of toluene-4-sulfonic acid Ethanol (180 mL) and 10% palladium on charcoal (5.2 g) are added to a hot solution of 2- [3- (naphthalene-1-sulfonylmethyl) -4-nitro-phenoxy] -ethyl toluene-4-ethyl ester. sulfonic acid (11.5 g, 21.2 mmol) in THF (180 mL). This mixture was stirred on a Parr hydrogenation apparatus for 5 hours, with a starting pressure of 47 psi. This was then filtered over Celite, concentrated and dried under vacuum at 80 ° C for 30 minutes to give 2- [4-amino-3- (naphthalene-1-sulfonylmethyl) -phenoxy] -ethyl ester of cethanol-4 acid. - sulphonic as a dark brown gum (9.5 g, 88.0%). Mass Spectrum (+ EI, [M + H] +) m / z 512. 1 H NMR (500 MHz, DMSO-d 6): D8.61 (d, 1 H, = 8.41 Hz), 8.25 (d, 1 H , J = 8.30 Hz), 8.03-8.08 (m, 2H), 7.59-7.75 (m, 5H), 7.43 (d, 2H, = 7.93 Hz), 6.49-6.53 (m, 2H), 6.11 (d, 1 H, J = 2.68 Hz), 4.65-4.77 (br, 2H), 4.59 (s, 2H), 4.09-4.11 (m, 2H), 3.63-3.65 (m, 2H), 2.38 ppm (s, 3H).

*? "Stage 5 2- [3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -ethyl ester of toluene-4-sulfonic acid Ethanol (430 mL) is added in two portions and hydrochloric acid at 1 N (200 mL) to 2- [4-amino-3- (naphthalene-1-sulfonylmethyl) -phenoxy] -ethyl ester of toluene-4-sulfonic acid ( 6.5 g, 13 mmol). A solution of sodium nitrite (1.5 g, 22 mmol) in water was then added to the reaction mixture. The reaction was heated to aid solubility. After stirring at room temperature for 2 hours, solid sodium carbonate is added at a basic pH. The reaction mixture was stirred at room temperature for 1 hour. This was then evaporated to remove the solvent and partitioned in water and ethyl acetate. The organic phase was washed with saline, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue is purified by flash chromatography with 2% methanol in chloroform. It was then dried at 63 ° C in vacuo and gave 2- [3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -ethyl-4-sulfonic acid ester as a leather-colored foam (3.9 g 59%); Mass Spectrum (+ EI, [M + H) m / z 523. 1 H NMR (500 MHz, DMSO-d 6): D 14.09 (s, 1 H), 8.76 (d, 1 H, J = 8.78 Hz) , 8.52-8.55 (m, 1 H), 8.27 (d, 1 H, J = 8.30 Hz), 8.02-8.04 (m, 1 H), 7.64-7.74 (m, 3H), 7.55-7.63 (m, 2H ), 7.50 (d, 1 H, J = 9.15 Hz), 7.27 (d, 2H, J = 8.05 Hz), 7.14 (d, 1 H, J = 2.20 Hz), 6.94 (dd, 1 H, J = 9.15 Hz and 2.44 Hz), 4.32-4.34 (m, 2H), 4.18-4.20 (m, 2H), 2.25 ppm (s, 3H). Elemental Analysis for C26H22N2O6S2: Cala: C, 59.76; H, 4.24; N, 5.36; Found: C, 59.69; H, 4.28; N, 5.14. ? -r Stage 6 Dimethyl-. { 2- [3- (naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -ethyl} -amine A solution of 2- [3-naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -ethyl ester of toluene-4-sulfonic acid (0.382 g, 0.731 mmol) in 2.0 M dimethylamine in THF (8 mL, 16 mmol) was stirred for 4 hours at, 70 ° C in a sealed tube. After cooling to room temperature the reaction mixture was concentrated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was washed with water and salt water, dried with anhydrous magnesium sulfate, filtered and concentrated. Drying at 80 ° C for 20 minutes under vacuum produced dimethyl-. { 2- [3- (naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -ethyl} -amine as a light yellow solid (0.212 g, 73.4%). Methanol, chloroform and etheric hydrochloride are added. The resulting solution was concentrated and dried for 15 hours at 78 ° C under vacuum. The hydrochloride as a leather colored foam (0.217 g) was obtained. Mass spectrum (+ EI, [M + H] +) m / z 396. 1 H NMR (500 MHz, DMSO-d 6): 014.20 (s, 1 H), 10.05 (s, 1 H), 8.74-8.77 ( m, 1 H), 8.52 (dd, 1 H, J = 7.44 Hz and 1.22 Hz), 8.27 (d, 1 H, J = 8.17 Hz), 8.03-8.05 (, 1 H), 7.70-7.74 (m, 1 H), 7.56-7.65 (m, 3H), 7.37 (d, 1H, = 2.20 Hz), 7.15-7.18 (m, 1 H), 4.37-4.39 (m, 2H), 3.51 (t, 2H, = 4.76 Hz), 2.83 ppm (s, 6H). Elemental Analysis for C21H21N3O3S 1.00 mol HCl 0.70 mol H2O: Cala: C, 56.74; H, 5.31; N, 9.45; Found: C, 56.72; H, 5.33; N, 9.06. lsopropyl-. { 2- [3- (naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -ethyl} -amine A solution of step 6 (1.01 g, 1.93 mmol) and isopropylamine (2.0 mL, 23 mmol) in THF (25 mL) was stirred for 16 hours at 70 ° C in a sealed tube. More isopropylamine (2.0 mL, 23 mmol) were added, and the reaction mixture was stirred at 80 ° C for 20 hours in a sealed tube. After cooling to room temperature, the reaction mixture was concentrated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was washed with brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue is purified by flash chromatography using 0.65% ammonium hydroxide / 7.5% methanol in chloroform. After concentrating and drying under vacuum at 72 ° C for 25 minutes, isopropyl- was obtained. { 2- [3- (naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -ethyl} -amine as a light orange solid (0.313 g, 39.6%). Methanol, chloroform and ethereal hydrochloride are added to this compound. The resulting solution was concentrated and dried for 16 hours at 84 ° C under vacuum. The hydrochloride was a light brown foam (0.332 g). Mass Spectrum (+ EI, [M + H] +) m / z 410. 1 H NMR (500 MHz, DMSO-d 6): 014.22 (s, 1 H), 8.86 (s, 2 H), 8.74-8.77 (m , 1 H), 8.53 (dd, 1 H, J = 7.44 Hz and 1.22 Hz), 8.27 (d, 1 H, = 8.30 Hz), 8.03-8.05 (m, 1 H), 7.71-7.75 (m, 1 H), 7.56-7.65 (m, 3H), 7.34 (d, 1 H, = 2.32 Hz), 7.16 (dd, 1 H, J = 9.15 Hz and 2.44 Hz), 4.29-4.32 (m, 2H), 1.25 ppm (d, 6H, = 6.59 Hz). Elemental Analysis for C22H23N3? 3S 1.00 mol HCl 0.35 mol H2O: Cala:, C, 58.43; H, 5.50; N, 9.29; Found: C, 58.03; H, 5.25; N, 8.94.

Example 29 Ethyl-methyl-. { 2- [3- (naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -ethyl} -amine A solution of 2- [3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -ethyl ester of toluene-4-sulfonic acid (1.18 g, 2.26 mmol) and ethyl methylamine (2.0 mL, 23 mmol) in THF (20 mL) is stirred for 16 hours at 70 ° C in a sealed tube. Additional ethylmethylamine (2.0 mL, 23 mmol) was added, and the reaction mixture was heated at 80 ° C for 20 hours in a sealed tube. After cooling to room temperature, the reaction mixture was concentrated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was washed with saline, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue is purified by flash chromatography using 0.75% ammonium hydroxide / 7.5% methanol in chloroform. Dry in vacuo at 69 ° C for 20 minutes provides ethyl-methyl-. { 2- [3- (naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -ethyl} -amine as a leather-colored foam (0.409 g, 44.2%). Methanol, chloroform and ethereal hydrochloride are added. The resulting solution was concentrated and dried for 16 hours at 84 ° C under vacuum. The chlorite idrate was obtained as a leather-colored semi-solid (0.424 g). Mass Spectrum (+ EJ, [M + H] +) m / z 410. 1 H NMR (500 MHz, DMSO-d 6): 014.21 (s, 1 H), 10.00-10.01 (s, 1 H), 8.74- 8.77 (m, 1 H), 8.52 (dd, 1 H, J = 7.44 Hz and 1.22 Hz), 8.27 (d, 1 H, J = 8.29 Hz), 8.03-8.05 (m, 1 H), 7.73 (dd) , 1 H, J = 8.06 Hz and 7.57 Hz), 7.56-7.65 (m, 3H), 7.37 (d, 1 H, J = 2.20 Hz), 7.15-7.18 (m, 1 H), 4.40 (t, 2H , J = 5.00 Hz), 3.53-3.59 (m, 1 H), 3.39-3.49 (m, 1 H), 3.21-3.25 (m, 1 H), 3.10-3.20 (m, 1H), 2.81 (d, 3H, 1.00 mol HCl 0.30 mol H2O: Cala: C, 58.54; H, 5.49; N, 9.31; Found: C, 58.30; H, 5.52; N, 8.91.

Example 30 2- [3- (Naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -ethylamine Step 1 - (2-Azido-ethoxy) -3- (naphthalene-1-sulfonyl) -1 H-indazole Sodium azide (0.79 g, 12 mmol) was added to a solution of 2- [3- (naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -ethyl ester of toluene-4-sulfonic acid (2.06 g). 3.94 mmol) in DMF (20 mL). The reaction mixture was stirred at 80 ° C for 12 hours in a sealed tube. After cooling to room temperature, it was poured into excess water and extracted with ethyl acetate. The organic phase was washed with 10% ammonium chloride. water in solution, water and saline solution. This was dried with anhydrous magnesium sulfate, filtered, concentrated and dried at 72 ° C under vacuum for 40 minutes to give 5- (2-azido-ethoxy) -3- (naphthalene-1-sulfonyl) -1 H-indazole as a gum / amber foam (1.34 g) , 86.5%). Mass Spectrum (-El, [MH]) m / z 392. 1 H NMR (400 MHz, DMSO-de): 08.78 (d, 1 H, = 8.'7 '? Hz), 8.56 (dd, 1 H , = 7.43 Hz and 1.16 Hz), 8.29 (d, 1 H, J = 8.35 Hz), 8.06 (d, 1 H, J = 7.66 Hz), 7.72-7.76 (m, 1 H), 7.57-7.67 (m , 3H), 7.31 (d, 1 H, = 2.32 Hz), 7.12 (dd, 1 H, J = 9.16 Hz and 2.32 Hz), 4.22-4.24 (m, 2H), 3.67-3.69 ppm (m, 2H) .

Stage 2 2- [3- (Naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -ethylamine VA 5- (2-azido-ethoxy) -3- (naphthalene-1-sulfonyl) -1 H -indazole ( 1.34 g, 3 41 mmol) in hot ethanol (210 mL) is added 10% palladium on carbon (0.8 g). The reaction mixture was hydrogenated over the peer apparatus for 1.25 hours starting pressure 49 psi. Then it filtered over Celita and concentrated. The residue is purified by flash chromatography with 0.5% ammonium hydroxide / 5.0% methanol in chloroform. Dry in vacuo at 63 ° C for 20 minutes gave 2- [3- (naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -ethylamine as a light yellow foam (0.775 g, 57.0%). methane and ethereal hydrochloride were added. Dry in vacuum for 16 hours at 68 ° C produced the hydrochloride as a yellow foam (0.825 g). Mass Spectrum (-El, [MH] ") m / z 366. H NMR (500 MHz, DMSO-de): 014.22 (s, 1 H), 8.75 (d, 1 H, J = 8.66 Hz), 8.51 -8.53 (m, 1 H), 8.27 (d, 1 H, = 8.29 Hz), 8.10 (s, br, 3H), 8.03-8.05 (m, 1 H), 7.71-7.75 (m, 1 H), 7.56-7.65 (m, 3H), 7.33 (d, 1 H, J = 2.19 Hz), 7.13-7.16 (m, 1 H), 4.21 (t, 2H, = 5.00 Hz), 3.23 ppm (s, 2H) Elemental Analysis for C? 9H17N3O3S 1.00 mol HCl 0.55 mol H2O: Cala: C, 55.15; H, 4.65; N, 10.15; Found: C, 55.54;, H, 4.90; N, f.0.12. Example 31 Methyl-. { 2- [3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -ethyl} -amina A solution of 2- [3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -ethyl ester of toluene-4-sulfonic acid (200 mg, 0.383 mmol) in 2.0 M methylamine in THF ( 10 mL, 20 mmol) was stirred at 70 ° C for 2 to 3 hours in a sealed tube. After cooling to room temperature, the reaction mixture is removed by evaporation and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was dried with anhydrous magnesium sulfate, filtered and concentrated. This was dissolved in methanol, and ethereal hydrochloride were added. The mixture was concentrated and dried for about 16 hours at 70 ° C in vacuo to give methyl- hydrochloride. { 2- [3- (naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -ethyl} -amine as a pale yellow foam (100 mg, 62.5%); Mass Spectrum (-El, [MH] ") m / z 380. 1. H NMR (400 MHz, DMSO-d6): 014.21 (br, s, 1 H), 8.85-8.91 (s, 2H), 8.74 -8.75 (m, 1 H), 8.51-8.53 (m, 1 H), 8.26-8.28 (m, 1 H), 8.03-8.05 (m, 1 H), 7.71-7.74 (m, 1H), 7.56- 7.64 (m, 3H), 7.34 (d, 1H, J = 2.20 Hz), 7.14-7.17 (m, 1H), 4.27-4.30 (m, 2H), 3.32-3.34 (m, 2H), 2.61 ppm (s) , 3H) Elemental Analysis for C20H19N3O3S 1.00 mol HCI 1.40 H2O: Cala: C, 54.21; H, 5.19; N, 9.48; Found: C, 54.31; H, 4.80; N, 9.10.

Example 32 Etil- { 2- [3- (naphthalene-1-sulfonyl) -l 1 H -indazol-5-yloxy] -ethyl} -amine A solution of 2- [3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -ethyl ester of toluene-4-sulfonic acid (200 mg, 0.383 mmol) in 2.0 M ethylamine (10 mL , 20 mmol) was stirred at 70 ° C for 2-3 hours in a sealed tube. After cooling to room temperature, the reaction mixture is evaporated to remove the solvent and partitioned into ethyl acetate and aqueous sodium bicarbonate. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. This was dissolved in ethanol and ethereal hydrochloride is added. The mixture was concentrated and dried for 16 h in vacuo at 70 ° C to give ethyl- hydrochloride. { 2- [3- (naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -ethyl} -amine as a pale yellow foam (30 mg, 18.2%). Mass Spectrum (-El, [MH]) m / z 394. 1 H NMR (500 MHz, DMSO-d 6): 014.18 (s, 1 H), 8.75 (d, 3 H, J = 8.54 Hz), 8.51-8.53 (m, 1 H), 8.27 (d, 1 H, J = 8.MHz), 8.03-8.05 (m, 1 H), 7.70-7.74 (m, 1 H), 7.56-7.65 (m, 3H) , 7.34 (d, 1 H, = 2.20 Hz), 7.16 (dd, 1 H, J = 9.15 Hz and 2.32 Hz), 4.26-4.29 (m, 2H), 3.31-3.34 (m, 2H), 3.01-3.05 (s, br, 2H), 1.18-1.21 ppm (m, 3H).

Example 33 Diethyl- { 2- [3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -ethyl} -amine A solution of 2- [3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -ethyl ester of toluene-4-sulfonic acid (200 mg, 0.383 mmol) and diethylamine (1.1-1.5 mmol) in THF (10 mL) was stirred at 70 ° C for 2-3 hours in a sealed tube. After cooling to room temperature, the reaction mixture was evaporated to remove the solvent and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was dried with anhydrous magnesium sulfate, filtered and concentrated. This was dissolved in methylene chloride and methanol, and ethereal hydrochloride is added. The mixture is concentrated and dried under vacuum at 67 ° C for 16 hours to give diethyl hydrochloride. { 2- [3- (naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -ethyl} -amine as a very white foam (148 mg, 84.1%); Mass Spectrum (-El, [MH] ") m / z 422. 1 H NMR (400 MHz, DMSO-d 6): 014.20 (s, 1 H), 9.91 (s, 1 H), 8.75 (d, 1 H, = 8.54 Hz), 8.51-8.53 (, 1 H), 8.27 (d, 1 H, = 8.29 Hz), 8.03-8.05 (m, 1 H), 7.71-7.75 (m, 1 H), 7.55-7.65 ( m, 3H), 7.36 (d, 1H, J = 2.20 Hz), 7.15 (dd, 1H, J = 9.15 Hz and 2.32 Hz), 4.39 (t, 2H, J = 4.39 Hz), 3.51 (d, br, 2H, = 3.91 Hz), 3.12-3.24 (m, 4H), 1.23 ppm (t, 6H, J = 7.20 Hz) Elemental Analysis for C23H25N3? 3S 1.00 mol HCl 0.80 mol H2O: Cala: C, 58.23; H, 5.86; N, 8.86; Found: C, 57.92; H, 5.52; N, 8.59.

Example 34 Butil-. { 2- [3-naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -ethyl} -amine A solution of 2- [3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -ethyl ester of toluene-4-sulfonic acid (200 mg, 0.383 mmol) and butylamine (1.1-1.5 mmol) ) in THF (10 mL) was stirred at 70 ° C for 2-3 hours in a sealed tube. After cooling to room temperature, the reaction mixture is evaporated to remove the solvent and partitioned into ethyl acetate and aqueous sodium bicarbonate. The organic phase was dried with anhydrous magnesium sulfate, filtered and concentrated. This was dissolved in methylene chloride and methanol, and ethereal hydrochloride is added. The mixture was concentrated and dried for 16 hours under vacuum at 67 ° C to give butyl- hydrochloride. { 2- [3-naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -ethyl} -amine as a light orange foam (166 mg, 94.3%); Mass Spectrum (-El, [MH] ") m / z 422. 1 H NMR (500 MHz, DMSO-d 6): 08.74-8.76 (m, 1 H), 8.51-8.53 (m, 1 H), 8.27 ( d, 1 H, J = 8.29 Hz), 8.03-8.05 (m, 1 H), 7.71-7.74 (m, 1 H), 7.56-7.65 (m, 3H), 7.34 (d, 1 H, J = 2.20 Hz), 7.16 (dd, 1 H, J = 9.15 Hz and 2.22 Hz), 4.28-4.30 (m, 2H), 3.32-3.35 (m, 2H), 2.93-2.97 (m, 2H), 1.55-1.63 ( m, 2H), 1.27-1.36 (m, 2H), 0.85-0.89 ppm (m, 3H).

Example 35 Cyclopentyl-. { 2- [3- (naphthalene-1-sjj-fonyl) -1 H -indazol-5-yloxy] -ethyl} -amine A solution 2- [3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -etherester of toluene-4-sulfonic acid (200 mg, 0.383 mmol) and cyclopentylamine (1.1-1.5 mmol) in THF (10 mL) was stirred at 70CC for 2: 3 * hours in a sealed tube. After cooling to room temperature, the reaction mixture is evaporated to remove the solvent and partitioned into ethyl acetate and aqueous sodium bicarbonate. The organic phase was dried with anhydrous magnesium sulfate, filtered and concentrated. This was dissolved in methylene chloride and methanol, and ethereal hydrochloride is added. The mixture is concentrated and dried under vacuum at 67 ° C for 17 hours to give cyclopentyl- hydrochloride. { 2- [3- (naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -ethyl} -amine as a brown foam (148 mg, 81.8%); Mass Spectrum (-El, [MH] ") m / z 436. 1 H NMR (500 MHz, DMSO-d 6): 014.20 (s, 1 H), 8.89-8.93 (s, br, 2H), 8.74-8.76 (m, 1 H), 8.51-8.53 (, 1 H), 8.28 (d, 1 H, = 8.29 Hz), 8.03-8.05 (m, 1 H), 7.71-7.75 (m, 1 H), 7.56- 7.65 (m, 3H), 7.34 (d, 1 H, J = 2.32 Hz), 7.15-7.18 (m, 1 H), 4.28-4.30 (m, 2H), 3.51-3.57 (m, 1 H), 3.32 -3.36 (m, 2H), 1.93-2.00 (m, 2H), 1.44-1.73 ppm (m, 6H) Elemental Analysis for C2 H25N3? 3S 1.00 HCl 0.70 mol HCl: Cala: C, 59.48; H, 5.70; N, 8.67; Found: C, 59.67; H, 5.86; N, 8.32.

Example 36 Cyclopropyl- { 2- [3- (naphthalene-1-s, ulfonyl) -1 H -indazol-5-yloxy] -etl} -amine A solution of 2- [3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -ethyl ester of toluene-4-sulfonic acid (200 mg, 0.383 mmol) and cyclopropylamine (1.1-1.5 mmol) in THF (10 mL) was stirred at 70 ° C for 2-3 hours in a sealed tube. After cooling to room temperature, the reaction mixture was evaporated to remove the solvent and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was dried with anhydrous magnesium sulfate, filtered and concentrated. This was dissolved in methanol and ethereal hydrochloride was added. The mixture is concentrated and dried under vacuum at 70 ° C for 16 hours to give cyclopropyl hydrochloride. { 2- [3- (naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -ethyl} -amine as a yellow foam (58 mg, 34%); Mass Spectrum (-El, [MH] ") m / z 406. 1 H NMR (400 MHz, DMSO-d 6): 014.20 (s, 1 H), 9.19 (s, br, 2H), 8.74-8.76 (m , 1 H), 8.52 (dd, 1 H, = 7.45 Hz and 1.22 Hz), 8.27 (d, 1 H, J = 8.30 Hz), 8.02-8.05 (m, 1 H), 7.71-7.75 (m, 1 H), 7.56-7.65 (m, 3H), 7.34 (d, 1 H, J = 2.19 Hz), 7.16 (dd, 1 H, = 9.15 Hz and 2.32 Hz), 4.30-4.33 (m, 2H), 3.43 (br, s, 2H), 2.76-2.77 (m, 1 H), 0.84-0.88 (m, 2H), 0.71-0.76 ppm (m, 2H) Elemental Analysis for C22H21N3O4S 1.00 HCl 0.60 mol HCl: Cala: C , 58.11; H, 5.14; N, 9.24; Found: C, 57.83; H, 4.81; N, 8.91, and Example 37 3- (Naphthalene-1-sulfonyl) -5- (2-pyrrolidin-1-yl-ethoxy) -1H-indazole A solution of 2- [3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -ethyl ester of toluene-4-sulfonic acid (200 mg, 0.383 mmol) and pyrrolidine (1.1-1.5 mmol) in THF (10 mL) was stirred at 70 ° C for 2-3 hours in a sealed tube. After cooling to room temperature, the reaction mixture is evaporated to remove the solvent and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was dried with anhydrous magnesium sulfate, filtered and concentrated. This was dissolved in methanol and ethereal hydrochloride was added. The mixture was concentrated and dried in vacuum at 67 ° C for 20 hours to give 3- (naphthalene-1-sulfonyl) -5- (2-pyrrolidin-1-yl-ethoxy) -1H-indazole hydrochloride as a foam. light coffee (97.8 mg, 55.9%); Mass Spectrum (-El, [MH] ") m / z 420. 1 H NMR (500 MHz, DMSO-d 6): 014.19 (s, 1 H), 10.26-10.29 (br, 1 H), 8.74-8.77 ( m, 1H), 8.53 (dd, 1H, = 7.44 Hz and 1.22 Hz), 8.27 (d, 1H, J = 8.29 Hz), 8.03-8.05 (, 1H), 7.71-7.74 (m, 1 H), 7.55 -7.65 (m, 3H), 7.36 (d, 1 H, J = 2.19 Hz), 7.16-7.19 (m, 1 H), 4.36-4.38 (m, 2H), 3.58 (s, br, 4H), 3.06 -3.19 (s, br, 2H), 1.81-2.05 ppm (br, m, 4H).

-? Example 38 3- (Naphthalene-1-sulfonyl) -5- (2-piperidin-1-yl-ethoxy) -1H-indazole A solution of 2- [3- (naphthalene-1-sulfonyl) -1 H -ndazol-5-yloxy] -ethyl ester of toluene-4-sulfonic acid (200 mg, 0.383 mmol) and piperidine (1.1-1.5 mmol) in THF (10 mL) was stirred in a sealed tube for about 16 hours at 70 ° C. After cooling to room temperature, the reaction mixture was evaporated to remove the solvent and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was dried with anhydrous magnesium sulfate, filtered and concentrated. This was dissolved in methanol and chloroform, concentrated and each in vacuo at 70 ° C for 16 hours to give 3- (Naphthalene-1-sulfonyl) -5- (2-piperidin-1-yl-ethoxy) -1 hydrochloride. H-indazole as a pale yellow foam (106 mg, 58.6%). Mass Spectrum (-El, [MH] ") m / z 434. 1 H NMR (500 MHz, DMSO-de): 014.18 (s, 1 H), 9.77-9.84 (br, 1 H), 8.75 (d, 1 H, J = 8.78 Hz), 8.51-8.53 (m, 1 H), 8.27 (d, 1 H, J = 8.30 Hz), 8.03-8.05 (m, 1 H), 7.70-7.74 (m, 1 H ), 7.56-7.65 (m, 3H), 7.35 (d, 1 H, J = 2.20 Hz), 7.15 (dd, 1 H, J = 9.15 Hz and 2.32 Hz), 4.40-4.41 (m, 2H), 3.44 -3.50 (m, 3H), 2.90-3.06 (m, 2H), 1.61-1.76 (m, 5H), 1.31-1.41 ppm (m, 2H) Elemental Analysis for C2 H25N3O4S 1.00 HCl 0.70 mol HCl: Cala: C , 59.48; H, 5.70; N, 8.67; found: C, 59.22; H, 5.63; N, 8.30.

Example 39 - (2-Morpholin-4-yl-ethoxy) -3- (naphthalene-1-sulfonyl) -1 H -indazole A solution of 2- [3- (naphthalene-1-sulfonyl) -1H-indazole-5 -alloxy] -ethyl ether of toluene-4-sulfonic acid (200 mg, 0.383 mmol) and morpholine (1.1-1.5 mmol) in THF (10 mL) was stirred at 70 ° C for 2-3 hours in a sealed tube. After cooling to room temperature, the reaction mixture was evaporated to remove the solvent and triturated with ether and ethyl acetate. The resulting solid was then dissolved in ethyl acetate and washed with a gauzy sodium bicarbonate. The organic phase was dried with anhydrous magnesium sulfate, filtered, concentrated. The residue was dissolved in methylene chloride and methanol and ethereal hydrochloride was added. The mixture is concentrated and dried under vacuum at 67 ° C for 17 hours to give 5- (2-morpholin-4-yl-ethoxy) -3- (naphthalene-1-sulfonyl) -1H-indazole hydrochloride as a light brown semisolid (0.176 g, 96.7%); Mass Spectrum (+ EI, [M + H] +) m / z 438. 1 H NMR (500 MHz, DMSO-d 6): 014.19 (s, 1 H), 10.61-10.66 (br, 1 H), 8.74- 8.76 (m, 1 H), 8.52 (dd, 1 H, J = 7.44 Hz and 1.22 Hz), 8.27 (d, 1 H, J = 8.29 Hz), 8.03-8.05 (m, 1 H), 7.71-7.75 (m, 1 H), 7.56-7.65 (m, 3H), 7.36 (d, 1 H, J = 1.40 Hz), 7.15-7.17 (dd, 1 H, J = 9.15 Hz and 2.32 Hz), 4.44 (s) , br, 2H), 3.93-3.96 (m, 2H), 3.72-3.78 (m, 2H), 3.42-3.69 (m, 4H), 3.12-3.23 ppm (m, 2H). Elemental Analysis for C23H23N3O4S 1.00 HCl 0.50 mol HCl: Cala: C, 57.20; H, 5.22; N, 8.70; Found: C, 57.28; H, 5.24; N, 8.45.

Example 40 Methyl-. { 2- [1-methyl-3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -ethyl} -amine Stage 1 2- [1-Methyl-3 (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -ethyl ester of toluene-4-sulfonic acid Methyliodide (0.06 mL, 0.96 mmol) is added to a cooled mixture of 2- [3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -ethyl ester of toluene-4-sulfonic acid (0.401 g, 0.767 mmol) and cesium carbonate (0.29 g, 0.89 mmol) in acetone (10 mL). The reaction mixture was stirred under nitrogen for 3 hours. This was then partitioned into ethyl acetate and water. The organic phase was washed with saline, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue is purified by flash chromatography with 25-40% ethyl acetate in hexane, 100% chloroform and 1% methanol in chloroform. Dry at 65 ° C under vacuum to produce 2- [1-methyl-3 (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -ethyl ester of toluene-4-sulfonic acid as a foam colored leather (0.224 g , 54.4%). 1 H NMR (400 MHz, DMSO-d 6): 08.27 (d, 1 H, J = 8.54 Hz), 8.55 (dd, 1 H, = 7.42 Hz and 1.16 Hz), 8.3.0 f. (D, 1 H, = 8.35 Hz), 8.05-8.07 (m, 1 H), 7.72-7.76 (m, 3H), 7.60-7.70 (, 3H), 7.31 (d, 2H, J = 8.01 Hz), 7.18 (d, 1 H) , = 2.20 Hz), 7.00-7.03 (m, 1 H), 4.35-4.37 (m, 2H), 4.22-4.24 (m, 2H), 4.07 (s, 3H), 2.28 ppm (s, 3H).

Stage 2 Methyl-. { 2- [1-methyl-3- (naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -ethyl} -amine A solution of 2- [1-methyl-3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -ethyl ester of toluene-4-sulfonic acid (0.351 g, (0 (654 mmol) efn methylamine at 2.0 M in THF (10 mL, 20 mmol) was heated and stirred to a sealed tube at 78 ° C for 1 hour, 40 minutes Additional methylamine in THF (2.0 mL, 4.0 mmol) was added and the reaction mixture it was stirred at 80 ° C for 16.5 hours in a sealed tube.After cooling to room temperature, the reaction mixture was evaporated to remove the solvent, which was partitioned with ethyl acetate and aqueous sodium bicarbonate. saline, dried over anhydrous magnesium sulfate, filtered, concentrated and dried at 80 ° C in vacuo for 20 minutes, resulting in methyl-. {2- 2- [1-methyl-3- (naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -ethyl-amine as a yellow gum (0.198 g, 76.4%), which was dissolved in chloroform, and ethereal hydrochloride was added.The solid was filtered and dried at 83 ° C under vacuum for 2 hours. 5 hours A solid leather color (0.156 g) was obtained: MP: 272-4 ° C (dec); Mass Spectrum (+ EI, [M + H] +) m / z 396. 1 H NMR (500 MHz, DMSO-d 6): 08.89 (s, br, 2 H), 8.73-8.75 (m, 1 H), 8.50 ^ 8.52 (M, 1 H); 8.26-8.28 (m, 1 H), 8.03-8.05 (, 1 H), 7.71-7.74 (m, 2H), 7.56-7.66 (m, "2H), 7.37 (d, 1 H, J = 2.07 Hz) , 7.19-7.22 (m, 1 H), 4.29-4.31 (m, 2H), 4.05 (s, 3H), 3.34 (t, 2H, = 4.39 Hz), 2.62 ppm (s, 3H) Elemental Analysis for C21H21N3O3S 1.00 mol HCl 0.60 mol H2O: Cale .: C, 56.97; H, 5.28; N, 9.49; Found: C, 56.91; H, 5.27; N, 9.14.

Example 41 Dímetil- { 2- [1-methyl-3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -ethyl} -amine YB A solution of 2- [1-rt? etl-3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -ethyl ester of toluene-4-sulfonic acid (0.39 g, 0.73 mmol) in 2.0 M dimethyl amine in THF (10 mL, 20 mmol) was stirred for 16.5 hours at 80 ° C in a sealed tube. After cooling to room temperature, the reaction mixture was evaporated to remove the solvent. The residue was partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was washed with saline, dried with anhydrous magnesium sulfate, filtered, concentrated and dried at 80 ° C under vacuum for 35 minutes to give dimethyl-. { 2- [1-methyl-3- (naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -ethyl} -amine as a light orange coffee semisolid (0.257 g, 86.2%). This was dissolved in chloroform and ethereal hydrochloride was added. The mixture was concentrated and dried for 25 hours at 83 ° C under vacuum to give the hydrochloride as a leather colored foam (0.254 g). Mass Spectrum (+ EI, [M + H] +) m / z 410. 1 H NMR (500 MHz, DMSO-d 6): 010.25 (s, 1 H), 8.74-8.76 (m, 1 H), 8.51 ( dd, 1 H, j = 7.44 Hz and 1.22 Hz), 8.26-8.28 (m, 1 H), 8.03-8.05 (m, 1 H), 7.71-7.74 (m, 2H), 7.56-7.66 (m, 2H ), 7.39 (d, 1 H, J = 2.08 Hz), 7K22 (dd, 1 H, J = 9.28 Hz and 2.32 Hz), 4.39-4.42 (m, 2H), 4.05 (s, 3H), 3.50-3.52 (m, 2H), 2 < S3 ppm (s, 6H).

Example 42 Ethyl-methyl-. { 2- [1-methyl-3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -ethyl} -amine A solution of 2- [1-methyl-3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -ethyl ester of toluene-4-sulfonic acid (0.398 g, 0.742 mmol) and ethylmethylamine (2.0 mL , 23 mmol) in THF (10 mL) was stirred at 80 ° C in a sealed tube for 16.5 hours. After cooling to room temperature, the reaction mixture was evaporated to remove the solvent. The residue was partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was washed with saline, dried with anhydrous magnesium sulfate, filtered, concentrated and dried at 80 ° C under vacuum for 20 minutes to give ethyl-methyl-. { 2- [1-methyl-3- (naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -ethyl} -amine as a light brown gum (0.227 g, 72.3%). This was dissolved in chloroform and etheric hydrochle is added. The mixture was concentrated and dried for 25 hours at 83 ° C under vacuum to give the hydrochle as a leather-colored foam (0.254 g); Mass Spectrum (+ EI, [M + H] +) m / z 424. 1 H NMR (500 MHz, DMSO-d 6): 010.26-10.27 (s, br, 1 H), 8.75 (d, 1 H, J = 8.66 Hz), ppm (m, 3H).

Diethyl- { 2- [1-methyl-3- (naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -ethyl} -amine A solution of 2- [1-methyl-3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -ethyl ester of toluene-4-sulfonic acid (0.385 g, 0.717 mmol) and diethylamine (2.0 mL , 19 mmol) in THF (10 L) was stirred at 80 ° C in a sealed tube for 16.5 hours. After cooling to room temperature, the reaction mixture was evaporated to remove the solvent. The residue was partitioned into chloroform and aqueous sodium bicarbonate. The organic phase was washed with saline, dried with anhydrous magnesium sulfate, filtered, concentrated and dried at 80 ° C under vacuum for 20 minutes to give diethyl. { 2- [1-methyl-3- (naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -ethyl} -amine as a light amber gum (0.269 g, 85.7%). This was dissolved in chloroform, and ethereal hydrochle is added. The mixture was concentrated and dried for 25 hours at 83 ° C in vacuo to provide the hydrochle as a brown foam (0.253 g); Mass Spectrum (+ EI, [M + H] +) m / z 438. 1 H NMR (500 MHz, DMSO-d 6): 010.11-10.12 (br, 1 H), 8.74 (d, 1 H, = 8.66 Hz ), 8.50-8.52 (m, 1 H), 8.27 (d, 1 H, J = 8.29 Hz), 8.03-8.05 (rM, 1 H), 7.71-7.75 (m, 2H), 7.56-7.66 (m, 2H), 7.37 (d, 1 H, J = 2.20 Hz), 7.21 (dd, 1 H, J = 9.27 Hz and 2.32 Hz), 4.41-4.43 (m, 2H), 4.05 (s, 3H), 3.49- 3.52 (m, 2H), 3.15-3.25 (m, 4H), 1.22-1.25 ppm (m, 6H).

Example 44 Etil- { 2- [1-methyl-3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -ethyl} -amine A solution of 2- [1-methyl-3t (naphthalene-17-sulfonyl) -1H-indazol-5-yloxy] -ethyl ester of toluene-4-sulfonic acid (0.413 g, 0.70 mmol) and ethylamine at 2.0 M in THF (10 mL, 20 mmol) in THF (10 mL) is stirred at 80 ° C in a sealed tube for 16.5 hours. After cooling to room temperature, the reaction mixture was evaporated to remove the solvent. The residue was partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was washed with saline, dried with anhydrous magnesium sulfate, filtered, concentrated and dried at 80 ° C under vacuum for 20 minutes to give ethyl-. { 2- [1-methyl-3- (naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -ethyl} -amine as a dark yellow solid (0.292 g, 92.7%). This was dissolved in chloroform and methanol, and ethereal hydrochle was added. The mixture was concentrated and dried for 25 hours at 83 ° C under vacuum to give the hydrochle as a cream solid (0.227 g) MP 276-7 ° Cdea; Mass Spectrum (+ EI, [M + Hf) m / z 410. 1 H NMR (500 MHz, DMSO-d 6): 08.95 (s, br, 2 H), 8.75 (d, 1 H, J = 8.79 Hz), 8.52 (dd, 1 H, = 7.45, Hz and 1.22 Hz), 8.27 (d, 1 H, J = 8.30 Hz), 8.04 (d, 1 H, J = 7.57 Hz), 7.71-7.75 (m, 2H) , 7.56-7.66 (m, 2H), 7.36 (d, 1 H, = 2.07 Hz), 7.22 (dd, 1 H, J = 9.15 Hz and 2.31 Hz), 4.30-4.33 (m, 2H), 4.05 (s) , 3H), 3.33-3.34 (m, 2H), 2.99-3.05 (m, 2H), 1.19-1.23 ppm (m, 3H). Elemental Analysis for C22H23N3O3S 1.00 mol HCl 0.40 mol H2O: Cala: C, 58.31; H, 5.52; N, 9.27; Found: C, 58.62; H, 5.54; N, 9.11. lsopropyl-. { 2- [1-methyl-3- (naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -ethyl} -amine A solution of 2- [1-methy]: (naphthalene-1-iSulfonyl) -1H-indazol-5-yloxy] -ethyl ester of i'- 'toluene-4-sulfonic acid (0.433 g, 0.807 mmol) and isopropylamine (1.0 mL, 12 mmol) in THF (10 mL) was stirred at 80 ° C in a sealed tube for 15 hours. Additional isopropylamine (1.0 mL, 12 mmol) is added, and the reaction mixture is stirred at 80 ° for 21 hours. It is allowed to cool to room temperature, and partition into ethyl acetate and aqueous sodium bicarbonate. The organic phase was washed with water and saline. This was dried with anhydrous magnesium sulfate, filtered and concentrated.

The residue is purified by flash chromatography using 0.25% ammonium hydroxide / 2. 5% methanol in chloroform.- Dry at 63 ° C in vacuum for 30 minutes to provide isopropyl-. { 2- [1-methyl-3- (naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -ethyl} -amine as a yellow semi-solid (0.198 g, 57.9%). This was dissolved in chloroform and ethereal hydrochloride was added. The precipitate was filtered and dried at 85 ° C under vacuum for 13 hours to give the hydrochloride as a very white solid (0.180 g): MP: 274-6 ° C (dec); w Mass Spectrum (+ EI, [M + H] +) m / z 424. 1 H NMR (500 MHz, DMSO-d 6): 08.83 (s, br, 2 H), 8.74 (d, 1 H, J = 8.79 Hz), 8.51 (dd, 1 H, J = 7.44 Hz and 1.22 Hz), 8.27 (d, 1 H, J = 8.30 Hz), 8.03-8.05 (m, 1 H), 7.71-7.75 (m, 2H) , 7.56-7.66 (m, 2H), 7.36 (d, 1 H, J = 2.20 Hz), 7.20-7.23 (m, 1 H), 4.30-4.33 (m, 2H), 4.06 (s, 3H), 3.30 -3.38 (m, 3H), 1.25 ppm (d, 6H, = 6.46 Hz). Elemental Analysis for C ^ HzsNaOsS .1.00 mol HCl. 0.10 mol H2O: Cala: C, 59.82; H, 5.72; N, 9.10; Found: C, 59.53; H, 5.66; N, 9.06.

Example 46 1-Methyl-3 (naphthalene-1-sulfonyl) -5- (2-pyrrolidin-1-yl-ethoxy) -1H-indazole A solution of 2- [1-methyl-3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -ethyl ester of toluene-4-sulfonic acid (0.421 g, 0.785 mmol) and pyrrolidine (1.0 mL) , 12 mmol) in THF (10 mL) was stirred at 80 ° C in a sealed tube for 15 hours. After cooling to room temperature, the reaction mixture was evaporated to remove the solvent and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was washed with saline, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography with 0 25% ammonium hydroxide / 2.5% methanol in chloroform. Drying at 68 ° C under vacuum for 1 hour resulted in 1-methyl-3 (naphthalene-1-sulfonyl) -5- (2-pyrrolidin-1-yl-ethoxy) -1H-indazole as a light brown semisolid (0.159) g, 46.5%). It is dissolved in chloroform and ethereal hydrochloride is added. The precipitate was filtered, dissolved in methanol and concentrated. Drying at 85 ° C under vacuum for 13 hours produced the hydrochloride as a light orange semisolid (0.156 g); Mass spectrum (+ EI, [M + H] +) m / z 436. 1 H NMR (500 MHz, DMSO-d 6): 010.60-10.61 (s, br, 1 H), 8.75 (d, 1 H, = 8.66 Hz), 8.51-8.53 (m, 1 H), 8.27 (d, 1 H, J = 8.29 Hz), 8.04 (d, 1 H, J = 7.93 Hz), 7.71-7.74 (m, 2H), 7.56 -7.67 (m, 2H), 7.37 (d, 1 H, J = 2.20 Hz), 7.22-7.25 (m, 1 H), 4.39-4 41 (m, 2H), 4.05 (s, 3H), 3.57- 3.60 (m, 4H), 3.06-3.14 (m, 2H), 1.95-21 (m, 2H), 1.86-1.92 ppm (m, 2H). Elemental Analysis for C24H25N3O3S 1.00 mol HCl 1.00 mol H2O: Cala: C, 58.82; H, 5.76; N, 8.58; Found: C, 58.77; H, 6.00; N, 8.47. i, Example 47 . { 2- [1-Benzyl-3- (Naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -ethyl} -ethyl-methyl-amine Stage 1 2- [1-Benzyl-3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -ethyl ester of toluene-4-sulfonic acid Benzyl bromide (0.46 mL, 3.9 mmol) is added to a stirred suspension of 2- [3- (naphthalene-1-sulfonyl) -1 H-indazol-5-yloxy] -ethyl ester of toluene-4-sulfonic acid (1.85 mL). g, 3.54 mmol) and cesium carbonate (1.28 g, 3.93 mmol) in acetone (60 mL). The reaction mixture was stirred under nitrogen atmosphere at room temperature for 1.5 hours. It was then poured into excess water and extracted with chloroform. The organic phase was washed with saline, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue is purified by flash chromatography with 40-50% ethyl acetate in hexane. Drying at 80 ° C under vacuum for 30 minutes yielded 2- [1-Benzyl-3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -ethyl ester of toluene-4-sulfonic acid as a colored foam light leather (1.39 g, 54.1%); Mass Spectrum (+ EI, [M + H] +) m / z 613. 1 H NMR (500 MHz, DMSO-d 6): 08.74-8.77 (m, 1 H), 8.55-8.57 (m, 1 H), 8.25-8.27 (m, 1 H), 8.01-8.05 (m, 1 H), 7.64-7.76 (m, 4H), 7.58-7.64 (m, 2H), 7.25 (d, 2H, J = 7.93 Hz ), 7.10-7.19 (m, 5H), 7.07 (d, 1 H, J = 2.19 Hz), 6.94-6.97 (m, 1 H), 5.69 (s, 2H), 4.30-4.32 (m, 2H), 4.14-4.16 (m, 2H), 2.18 ppm (s, 3H). Elemental Analysis for C33H28N2O6S2 0.60 mol H2O: Cale .: C, 63.57; H, 4.72; N, 4.49; Found: C, 63.17; H, 4.63; N, 4.30.

Stage 2 . { 2- [1-Benzyl-3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -ethyl} -ethyl-methyl-amine A solution of 2- [1-Benzyl-3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -ethyl ester of toluene-4-sulfonic acid (0.363 g, 0.592 mmol) and ethylmethyl amine (2.0 mL, 23 mmol) in THF (8 mL) was stirred at 70 ° C for 2.5 hours in a sealed tube. After cooling to room temperature, the residue was partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was washed with saline, dried with anhydrous magnesium sulfate, filtered and concentrated. Dry at 80 ° C under vacuum for 30 minutes. { 2- [1-Benzyl-3- (naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -ethyl} -ethyl-methyl-amine as a yellow foam / gum (0.241 g, 81.4%). This was dissolved in chloroform, and ethereal hydrochloride is added. The mixture was concentrated and dried in vacuo for 13 hours to provide the hydrochloride as a leather colored foam (0.242 g). Mass Spectrum (+ EI, [M + H] +) m / z 500. 1 H NMR (500 MHz, DMSO-d 6): 010.04-10.10 (s, br, 1 H), 8.74-8.77 (m, 1 H ), 8.54-8.56 (m, 1 H), 8.27 (d, 1 H, J = 8.29 Hz), 8.02-8.05 (, 1 H), 7.79 (d, 1 H, J = 9.28 Hz), 7.70-7.74 (m, 1 H), 7.55-7.67 (m, 2H) 7.28 (d, 1 H, J = 2.19 Hz), 7.04-7.20 (m, 6H), 5.70 (s, 2H), 4.35 (s, 2H) , 3.33-3.41 (br, 2H) ', 3.01-3.19 (br, 2H), 2.73 (s, 3H), 1.17-1.21 ppm (m, 3H). Elemental Analysis for C29H29N3O3S 1.00 mol HCl 1.10 mol H2O: Cala: C, 62.66; H, 5.84; N, 7.56; Found: C, 62.73; H, 6.19; N, 7.17.

Example 48 . { 2- [1-Benzyl-3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -ethyl} -methyl-amine A solution of 2- [1-Benzyl-3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -ethyl ester of toluene-4-sulfonic acid (0.476 g, 0.777 mmol) in methylamine at 2.0 M in THF (8.0 mL, 16 mmol) was stirred at 70 ° C in a sealed tube for 3 hours. After cooling to room temperature and concentrating, the residue was partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was washed with water and saline. This was dried with anhydrous magnesium sulfate, filtered and concentrated. Dry at 80 ° C under vacuum for 20 minutes. { 2- [1-Benzyl-3- (naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -ethyl} -methyl-amine as a light dark yellow gum (0.324 g, 88.5%). This was dissolved in chloroform, and ethereal hydrochloride is added. The mixture was concentrated and dried at 81 ° C under vacuum for 13 hours. The hydrochloride as a light orange foam (0.330 g) Results; Mass Spectrum (+ EI, [M + Hf) m / z 472. 1 H NMR (500 MHz, DMSO-d 6): 08.86 (s, 2 H), 8.74-8.77 (m, 1 H), 8.54-8.56 (m , 1 H), 8.27 (d, 1 H, = 8.30 Hz), 8.02-8.05 (m, 1 H), 7.79 (d, 1H, = 9.15 Hz), 7.70-7.74 (m, 1H), 7.58-7.65 (m, 2H), 7.27 (d, 1H, J = 3.30 Hz), 7.09-7.18 (m, 6H), 5.70 (s, 2H), 4.24-4.27 (m, 2H), 2.59 ppm (s, 3H) . Elemental Analysis for C27H25N3O3S2.1.00 HCI.0.55 mol H2O: Cala: C, 62.61; H, 5.27; N, 8.11; Found: C, 62.23; H, 5.45; N, 7.72. , Example 49 . { 2- [1-Benzyl-3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -etl} -isopropyl-amine A solution of 2- [1-Benzyl-3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -ethyl ester of pacido toluene-4-sulfonic acid (0.444 g, 0.725 mmol) and isopropylamine (2.0 mL , 23 mmol) in THF (8 mL) was stirred at 70 ° C in a sealed tube for 3 hours. More sopropylamine (2.0 mL, 23 mmol) was added, and the reaction mixture was stirred at 80 ° C in a sealed tube for 16.5 hours. After cooling somewhat, the reaction mixture was evaporated to remove the solvent and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase is then washed with water and saline. This was dried with anhydrous magnesium sulfate, filtered and concentrated. Dry at 80 ° C under vacuum for 20 minutes. { 2- [1-Benzyl-3- (naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -ethyl} -isopropyl-amine as a yellow semi-solid (0.290 g, 80.1% mmol). This was dissolved in chloroform, and ethereal hydrochloride is added. The mixture was concentrated and dried for 13 hours under vacuum at 81 ° C. The result was the hydrochloride as a leather colored foam (0.273 g); Mass Spectrum (+ EI, [M + H] +) m / z 500. 1 H NMR (500 MHz, DMSO-d 6): D8.80 (s, 2H), 8.74-8.78 (m, 1 H), 8.55 (dd, 1 H, = 7.44 Hz and 1.22 Hz), 8.27 (d, 1 H, = 8.29 Hz), 8.01-8.05 (m, 1 H), 7.79 (d, 1 H, = 9.15 Hz), 7.70- 7.74 (m, 1 H), 7.58-7.65 (m, 2H), 7.27 (d, 1 H, J = 2.20 Hz), 7.09-7.19 (m, 6H), 5.70 (s, 2H), 4.26-4.28 ( m, 2H), 3.31 (s, 3H), 1.23 ppm (d, 6H, = 6.47 Hz). Elemental Analysis for C29H29N3O3S 1.00 HCl 0.7 mol H2O: Cala: C, 63.48; H, 5.77; N, 7.66; Found: C, 63.10; H, 5.67; N, 7.37.

Example 50 . { 2- [1-Benzyl-3- (naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -ethyl} -dietl-amine A solution of 2- [1-benzyl-3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -ethyl ester of toluene-4-sulfonic acid (0.449 g, 0.733 mmol) and diethylamine (2.0 mL, 19 mmol) in THF (7.5 mL) is stirred at 70 ° C in a sealed tube for 3 hours. Then more diethylamine (2.0 mL, 19 mmol) is added, and the reaction mixture is stirred at 80 ° C in a sealed tube for 16.5 hours. After cooling somewhat, the reaction mixture is evaporated from the solvent and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase is then washed with water and saline. This is dried with anhydrous magnesium sulfate, filtered and concentrated. Dry at 82 ° C under vacuum for 35 minutes. { 2- [1-benzyl-3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -ethyl} Diethylamine as a light brown yellow semisolid (0.365 g, 97.1% mmol). This is dissolved in chloroform, and ethereal hydrochloride is added. The mixture is concentrated and dried for 13 hours under vacuum at 81 ° C. The result is the hydrochloride as a light orange semisolid (0.332 g); Mass Spectrum (+ EI, [M + Hf) m / z 514. 1 H NMR (500 MHz, DMSO-d 6): 510.15-10.18 (s, 1 H), 8.74-8.76 (m, 1 H), 8.56 ( dd, 1 H, J = 7.44 Hz and 1.22 Hz), 8.26 (d, 1 H, J = 8.29 Hz), 8.02-8.05 (m, 1 H), 7.78 (d, 1 H, J = 9.15 Hz), 7.70-7.74 (m, 1 H), 7.58-7.65 (m, 2H), 7.26 (s, 1H), 7.08-7.19 (m, 6H), 5.70 (s, 2H), 4.25 (s, br, 2H) , 3.39-3.55 (br, s, 2H), 3.15 (br, s, 3H), 1.13-1.19 ppm (s, br, 6H). Elemental Analysis for C30H31N3O3S 1.00 HCI 0.75 mol H2O: Calculated: C, 63.93; H, 5.99; N, 7.46; Found: C, 63.59; H, 5.94; N, 7.23.

Example 51 . { 2- [1-Benzyl-3- (naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -ethyl} -dimethyl-amine A solution of 2- [1-benzyl-3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -ethyl ester of toluene-4-sulfonic acid (0.432 g, 0.705 mmol) in dimethylamine 2.0 M in THF (8.0 mL, 16 mmol) is stirred at 70 ° C in a sealed tube for 3 hours. After cooling somewhat, the reaction mixture is evaporated from the solvent and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase is then washed with water and saline. This is dried with anhydrous magnesium sulfate, filtered and concentrated. Dry at 80 ° C under vacuum for 20 minutes. { 2- [1-benzyl-3- (naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -ethyl} dimethyl amine as a yellow solialo (0.288 g, 84.2% mmol). This is dissolved in chloroform, and ethereal hydrochloride is added. The mixture is concentrated and dried for 13 hours under vacuum at 81 ° O. The result is the hydrochloride as a leather-colored foam (0.294 g); Mass Spectrum (+ EI, [M + H] +) m / z 486. 1 H NMR (500 MHz, DMSO-d 6): 510.11 (s, 1 H), 8.74-8.77 (m, 1 H), 8.54- 8.56 (m, 1 H), 8.27 (d, 1 H, J = 8.30 Hz), 8.03-8.05 (m, 1 H), 7.79 (d, 1 H, J = 9.15 Hz), 7.70-7.74 (m, 1 H), 7.58-7.65 (m, 2H), 7.30 (d, 1 H, J = 2.20 Hz), 7.08-7.19 (m, 6H), 5.70 (s, 2H), 4.34-4.37 (m, 2H) , 3.48 (t, 2H, J = 4.76 Hz), 2.80 ppm (s, 6H). Elemental Analysis for C28H27N3O3S 1.00 HCl 1.55 mol H2O: Calculated: C, 61.15; H, 5.70; N, 7.64; Found: C, 61.33; H, 5.59; N, 7.24.

,? - Example 52 1 - . 1-Benzyl-3- (naphthalene-1-sulfonyl) -5- (2-pyrrolidin-1-yl-ethoxy) -1 H-indazole A solution of 2- [1-benzyl-3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -et? L-toluene-4-sulfonic acid ester (0.379 g, 0.619 mmol) and pyrrolidine (1.0 L, 12 mmol) in THF (80 mL) is stirred at 70 ° C in a sealed tube for 3 hours. The reaction mixture is evaporated from the solvent and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase is then washed with water and saline. This is dried with anhydrous magnesium sulfate, filtered and concentrated. Dry at 80 ° C under vacuum for 25 minutes to give 1-benzyl-3- (naphthalene-1-sulfonyl) -5- (2-pyrrolidin-1-yl-ethoxy) -1H-indazole as a yellow-orange solid ( 0.259 g, 82.0% mmol). This is dissolved in chloroform, and ethereal hydrochloride is added. The mixture is concentrated and dried for 13 hours under vacuum at 81 ° C. The result is the hydrochloride as a leather-colored foam (0.267 g).; Mass Spectrum (+ EI, [M + H] +) m / z 512. 1 H NMR (500 MHz, DMSO-d 6): 510.42 (s, 1 H), 8.74-8.77 (m, 1 H), 8.56 ( dd, 1 H, J = 7.44 Hz and 1.22 Hz), 8.27 (d, 1 H, J = 8.30 Hz), 8.02-8.05 (m, 1 H), 7.79 (d, 1 H, J = 9.27 Hz), 7.70-7.74 (m, 1 H), 7.55-7.65 (m, 2H), 7.28 (d, 1 H, J = 2.07 Hz), 7.08-7.20 (, 6H), 5.70 (s, 2H), 4.33-4.36 (m, 2H), 3.54 (br, s, 4H), 3.07 (s, br, 2H), 1.79-2.01 ppm (m, 4H). Elemental Analysis for C3oH29N3? 3S 1.00 HCl 1.25 mol H2O: Calculated: C, 63.15; H, 5.74; N, 7.36; Found; ^, 62.82; H, 5.74; N, 6.99.

Example 53 . { 2- [1-Benzyl-3- (naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -ethyl} -ethyl-amine A solution of 2- [1-benzyl-3R (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -ethyl ester of toluene-4-sulfonic acid (0.430 g, 0.702 mmol) and ethylamine 2.0 M in THF (4.8 mL, 9.6 mmol) is stirred at 70 ° C in a sealed tube for 3 hours. After cooling to room temperature, the reaction mixture is evaporated from the solvent and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase is washed with water and saline. This is dried with anhydrous magnesium sulfate, filtered and concentrated. The residue is purified by flash chromatography with 5.0-7.5% methanol in chloroform and by HPLC with 5-50% (chloroform / methanol (8: 2) / TEA) in heptane / TEA. The result is . { 2- [1-benzyl-3- (naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -ethyl} -ethyl-amine as a yellow semi-solid (0.0528 g, 15.5%). This is dissolved in chloroform, and ethereal hydrochloride is added. The mixture is concentrated and dried for 14 hours at 82 ° C under vacuum to give the hydrochloride as a light orange semisolid (0.0546 g); Mass Spectrum (+ EI, [M + H] +) m / z 486. 1 H NMR (500 MHz, DMSO-d 6): 58.74-8.77 (m, 1 H), 8.65-8.72 (br, s, 2H) , 8.55 (dd, 1 H, J = 7.32 Hz and 1.22 Hz), 8.26-8.28 (m, 1 H), 8.03-8.05 (m, 1 H), 7.79 (d, 1 H, J = 9.15 Hz), 7.70-7.74 (m, 1 H), 7.58-7.65 (rn, 2H), 7.27 (d, 1 H, J = 2.07 Hz), 7.09-7.18 (m, 6H), 5.70 (s, 2H), 4.23 -4.26 (m, 2H), 3.29-3.32 (m, 2H), 2.97-3.02 (m, 2H), 1.16-1.19 ppm (m, 3H). Elemental Analysis for C28H27N3O3S 1.00 HCl 0.80 mol H2O: Calculated: C, 62.69; H, 5.56; N, 7.83; Found: C, 62.38; H, 5.38; N, 7.58.

Example 54 . { 2- [1- (3-Chloro-benzyl) -3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -ethyl} -dimethyl-amine Stage 1 2- [1- (3-Chloro-benzyl) -3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -ethyl ester of toluene-4-sulfonic acid 3-Chlorobenzylbromide (0.90 mL, 6.8 mmol) is added to a stirred suspension of 2- [3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -ethyl ester of toluene-4-sulfonic acid ( 3.24 g, 6.20 mmol) and cesium carbonate (2.21 g, 6.78 mmol) in acetone (80 mL). The mixture is stirred at room temperature under nitrogen for 2 hours. This is poured into excess water and extracted with chloroform. The organic phase is washed with saline, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue is purified by flash chromatography using 30-35% ethyl acetate in hexane. Dry at 65 ° C in vacuo for 30 minutes to give 2- [1- (3-chloro-benzyl) -3- (naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -ethyl ester toluene-4 acid -sulfonic as a dark yellow foam (2.55 g, 63.6%); Mass Spectrum (+ EI, [M + H] +) m / z 647. 1 H NMR (500 MHz, DMSO-d 6): 58.73-8.75 (m, 1 H), 8.55-8.57 (m, 1 H), 8.27 (d, 1 H, J = 8.30 Hz), 8.01-8.04 (m, 1 H), 7.67-7.75 (m, 4H), 7.56-7.63 (m, 2H), 7.17-7.27 (m, 5H), 7.05-7.07 (m, 2H), 6.98 (dd, 1 H, J = 9.28 Hz and 2.32 Hz), 5.71 (s, 2H), 4.31-4.33 (, 2H), 4.15-4.17 (m, 2H), 2.17 ppm (s, 3H). Elemental Analysis for C33H27CIN2O6S2: Calculated: C, 61.25; H, 4.21; N, 4.33; Found: C, 60.93; H, 4.22; N, 4.21.

Stage 2 . { 2- [1 - (3-Chloro-benzyl) -3- (naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -ethyl} -dimetil-amina A solution of 2- [1- (3-chloro-benzyl) -3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -ethyl ester of toluene-4-sulfonic acid (0.344 g, 0.532 mmol) in 2.0 M dimethylamine in THF (8.0 mL, 16.0 mmol) is stirred at 70 ° C in a sealed tube for 2 hours. After cooling to room temperature, the reaction mixture is evaporated. The solvent is partitioned with ethyl acetate and aqueous sodium bicarbonate. The organic phase is washed with saline, dried with anhydrous magnesium sulfate, filtered and concentrated. Dry at 80 ° C under vacuum for 20 minutes. { 2- [1- (3-chloro-benzyl) -3- (naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -ethyl} dimethyl-amine as a dark yellow gum (0.261 g, 94.6%). it dissolves in chloroform, and ethereal hydrochloride is added. The mixture is concentrated and dried under vacuum at 82 ° C for 14 hours. The result is the hydrochloride as a light orange foam (0.252 g); Mass Spectrum (+ EI, [M + H] +) m / z 520. 1 H NMR (500 MHz, DMSO-d 6): 59.92-9.94 (br, s, 1 H), 8.73-8.75 (m, 1 H ), 8.56 (dd, 1 H, J = 7.32 Hz and 1.10 Hz), 8.27 (d, 1 H, J = 8.29 Hz), 8.02-8.05 (m, 1 H), 7.82 (d, 1 H, J = 9.15 Hz), 7.70-7.74 (m, 1 H), 7.58-7.64 (m, 2H), 7.31 (d, 1 H, J = 2.32 Hz), 7.15-7.27 (m, 3H), 7.04 (d, 1 H, j = 7.68 Hz), 5.73 (s, 2H), 4.34-4.37 (m, 2H), 3.47-3.49 (m, 2H), 2.81 ppm (s, 6H) Example 55 . { 2- [1- (3-Chloro-benzyl) -3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -ethyl} -ethyl-methyl-amine A solution of 2- [1 - (, 3-chloro-benzyl) -3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -ethyl ester of toluene-4-sulfonic acid (0.350 g, 0.541 mmol) and ethylmethylamine (1.0 mL, 12 mmol) in THF (8 mL) is stirred for 2 hours in a sealed tube at 70 ° C. Additional ethylmethylamine (1.0 mL, 12 mmol) is added, and the reaction mixture is added. Stir at 80 ° C in a sealed tube for 2 hours. After cooling to room temperature, the reaction mixture is evaporated from the solvent and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase is then washed with saline, dried with anhydrous magnesium sulfate, filtered and concentrated. This is dried at 80 ° C for 20 minutes under vacuum to produce. { 2- [1- (3-chloro-benzyl) -3- (naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -ethyl} -ethyl-methyl-amine as a yellow semi-solid (0.268 g, 92.7%). This is dissolved in chloroform, and ethereal hydrochloride is added. The mixture is then concentrated and dried under vacuum at 82 ° C for 14 hours. The result is the hydrochloride as a light orange foam (0.266 g); Mass Spectrum (+ EI, [M + H] +) m / z 534. 1 H NMR (500 MHz, DMSO-d 6): 59.90-9.93 (s, br, 1 H), 8.73-8.75 (m, 1 H ), 8.54-8.57 (m, 1 H), 8.27 (d, 1 H, J = 8.29 Hz), 8.02-8.05 (m, 1 H), 7.82 (d, 1 H, J = 9.27 Hz), 7.70- 7.74 (m, 1 H), 7.56-7.63 (m, 2H), 7.30 (d.1 H, J = 2.20 Hz), 7.15-7.26 (m, 4H), 7.04 (d, 1 H, J = 7.57 Hz ), 5.73 (s, 2H), 4.36-4.38 (m, 2H), 3.40-3.55 (m, 3H), 3.09-3.14 (br, 1 H), 2.78 (s, 3H), 1.19-1.23 ppm (m , 3H). Elemental Analysis for C29H? 2ßCIN3? 3S 1500 HCL0.75 mol H2O: Calculated: C, 59.64; H, 5.26; N, 7.19; Found CPC, 59.24; H, 5.17; N, 6.89.

Example 56 . { 2- [1 - (3-Chloro-benzyl) -3- (naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -ethyl} -diethyl-amine A solution of 2- [1- (3-cJar? O-benzyl) -3- (paftalene-1-s? Lfonyl) -1 H-indazol-5-yloxy] -ethyl ester of toluene-4-sulphonic acid (0.338 g, 0.522 mmol) and diethylamine (1.0 mL, 9.7 mmol) in THF (8 mL) is stirred at 70 ° C in a sealed tube for 2 hours. Additional diethylamine (1.0 mL, 9.7 mmol) is added, and the reaction mixture is stirred at 80 ° C in a sealed tube for 2 hours. A third portion of diethylamine (1.0 mL, 9.7 mmol) is added to the reaction mixture, and this is stirred at 80 ° C in a sealed tube for 30 hours. The reaction mixture is then evaporated from the solvent and partitioned into ethyl acetate and saline. This is dried with anhydrous magnesium sulfate, filtered and concentrated. Dry at 80 ° C under vacuum for 20 minutes. { 2- [1- (3-chloro-benzyl) -3- (naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -ethyl} -diethyl-amine as a light brown semisolid (0.278 g, 97.2%). This is dissolved in chloroform, and ethereal hydrochloride is added. The mixture is concentrated and dried under vacuum at 82 ° C for 14 hours. The result is the hydrochloride as a brown foam (0.275 g); Mass Spectrum (+ EI, [M + H] +) m / z 548. 1 H NMR (500 MHz, DMSO-d 6): 59.86-9.88 (s, 1 H), 8.72-8.75 (m, 1 H), 8. 56 (dd, 1 H, J = 7.44 Hz and 1.22 Hz), 8.27 (d, 1 H, J = 8.30 Hz), 8.02-8.05 (m, 1 H), 7.82 (d, Pei '-1 H, J = 9.15 Hz), 7.70-7.74 (m.1 H), 7.57-7.63 (m, 2H), 7.29 (d, 1 H, J = 2.20 Hz), 7.24-7.26 (m, 1 H), 7.15-7.21 (m, 3H), 7.03 (d, 1 H, J = 7.68 Hz), 5.73 (s, 2H), 4.35-4.38 (m, 2H), 3.49 (d, br, 2H, J = 4.52 Hz), 3.14 -3.25 (m, 4H), 1.19-1.23 ppm (m, 6H). Elemental Analysis for C30H30CIN3O3S 1.00 HCl 0.55 mol H2O: Calculated: C, 60.61; H, 5.44; N, 7.07; Found: C, 60.21; H, 5.44; N, 6.73.

Example 57 . { 2- [1- (3-Chloro-benzyl) -3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -ethyl} -isopropyl-amine A solution of 2- [1- (3-chloro-benzyl) -3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -ethyl ester of toluene-4-sulfonic acid (0.339 g, 0.524 mmol) and isopropylamine (1.0 mL, 12 mmol) in THF (8 mL) is stirred at 70 ° C in a sealed tube for 2 hours. Isopropylamine (1.0 mL, 12 mmol) is added, and the reaction mixture is stirred at 80 ° C in a sealed tube for 2 hours. Isopropylamine (1.0 mL) is added, 12 mmol) is added to the reaction mixture, and this is stirred at 80 ° C in a sealed tube for 30 hours. After cooling to room temperature, the reaction mixture is evaporated from the solvent and partitioned in ethyl acetate and aqueous sodium bicarbonate. This is washed with saline, dried with anhydrous magnesium sulfate, filtered, concentrated and dried under vacuum for 20 minutes at 80 ° C to give. { 2- [1: (3-chloro-benzyl) -3- (naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -ethyl} -isopropyl-ami? a as a yellow solid (0.280 g, 100%). This is dissolved in chloroform, and ethereal hydrochloride is added. The resulting solid is filtered and dried at 82 ° C in vacuum for 14 hours. The result is the hydrochloride as a pale yellow solid (0.236 g): MP: 206-8 ° C; Mass Spectrum (+ EI, [M + H] +) m / z 534. 1 H NMR (500 MHz, DMSO-d 6): 58.65-8.76 (m, 3 H), 8.54-8.56 (m, 1 H), 8.27 (d, 1 H, J = 8.17 Hz), 8.02-8.05 (, 1 H), 7.82 (d, 1 H, J = 9.27 Hz), 7.72 (dd, 1 H, J = 8.07 Hz and 7.57 Hz), 7.57-7.63 (m, 2H), 7.24-7.28 (m, 2H), 7.16-7.21 (m, 3H), 7.05 (d, 1 H, J = 7.81 Hz), 5.73 (s, 2H), 4.27 (t , 2H, J = 5.00 Hz), 3.31-3.37 (m, 3H), 1.23 ppm (d, 6H, J = 6.69 Hz). Elemental Analysis for C29H28CIN3O3S 1.00 HCl: Calculated: C, 61.05; H, 5.12; N, 7.36; Found: C, 60.68; H, 5.26; N, 7.14.

Example 58 1 - . 1 - (3-Chloro-benzyl) -3- (naphthalene-1-sulfonyl) -5- (2-pyrrolidin-1-yl-ethoxy) -1H-indazole A solution of 2- [1- (3-chloro-benzyl) -3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -ethyl ester of toluene-4-sulfonic acid (0.359 g, 0.555 mmol) and pyrrolidine (1.0 mL, 12 mmol) in THF (8 mL) is stirred at 70 ° C in a sealed tube for 2 hours. After cooling to room temperature, the reaction mixture will evaporate the solvent. This is then partitioned into ethyl acetate and aqueous sodium bicarbonate. The organic phase is washed with saline, dried with anhydrous magnesium sulfate, filtered, concentrated and dried under vacuum at 80 ° C for 20 minutes to give 1- (3-chloro-benzyl) -3- (naphthalene -1-sulfonyl) -5- (2-pyrrolidin-1-yl-ethoxy) -1H-indazole as a yellow semisolid (0.266 g, 87.8%). This is dissolved in chloroform, and ethereal hydrochloride is added. The mixture is concentrated and dried at 82 ° C under vacuum for 14 hours to produce the hydrochloride as a light orange foam (0.205 g); Mass Spectrum (+ EI, [M + H] +) m / z 546. 1 H NMR (500 MHz, DMSO-d 6): 510.18-10.19 (s, 1 H), 8.73-8.75 (m, 1 H), 8.55- 8.57 (m, 1 H), 8.27 (d, 1 H, J = 8.30 Hz), 8.02-8.04 (m, 1 H), 7.82 (d, 1 H, J = 9.15 Hz), 7.70- 7.74 ( m, 1 H), 7.57-7.64 (m, 2H), 7.15-7.29 (m, 5H), 7.04 (d, 1 H, J = 7.69 Hz), 5.73 (s, 2H), 4. 33-4.35 (m, 2H), 3.55 (br, s, 4H), 3.07-3.15 (s, br, 2H), 1.81-2.02 ppm (br, m, 4H). Elemental Analysis for C30H28CIN3O3S 1.00 HCl 0.70 mol H2O: Calculated: C, 60.54; H, . fifteen; N, 7.06; Found: C, 60.16; H, 5.11; N, 6.74.

Example 59 . { 2- [1- (3-Chloro-benzyl) -3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -ethyl} -methyl-amine A solution of 2- [1- (3-chloro-benzyl) -3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -ethyl ester of toluene-4-sulfonic acid (0.367 g, 0.567 mmol) in 2.0 M methylamine in THF (8.0 L, 16 mmol) is stirred at 70 ° C in a sealed tube for 2 hours. After cooling to room temperature, the reaction mixture will evaporate the solvent. The residue is partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase is then washed with saline, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue is purified by HPLC with 25-60% (chloroform / methanol 8: 2 / TEA) in heptane / TEA. Concentration and drying at 60 ° C under vacuum produces. { 2- [1- (3-chloro-benzyl) -3- (naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -ethyl} -methyl-amine as a light yellow foam (0.190 g, 66.2%). This is dissolved in chloroform, and ethereal hydrochloride is added. The mixture is then concentrated and dried under vacuum for 29 hours at 80 ° C. The hydrochloride as a very white foam (0.206 g); Mass Spectrum (+ EI, [M + H] +) m / z 506. 1 H NMR (500 MHz, DMSO-d 6): 58.71 -8.76 (m, 3 H), 8.54-8.56 (m, 1 H), 8.27 (d, 1 H, J = 8.30 Hz), 8.02-8.05 (m, 1 H), 7.82 (d, 1 H, J = 9.27 Hz), 7.70-7.74 (m, 1 H), 7.57-7.63 ( m, 2H), 7.24-7.28 (m, 2H), 7.16-7.20 (m, 3H), 7.05 (d, 1H, J = 7.69 Hz), 5.73 (s, 2H), 4.24-4.26 (m, 2H) , 3.30-3.32 (m, 2H), 2.60 ppm (s, 4H). Elemental Analysis for C27H24CIN3O3S 1.00 HCl 1.50 mol H2O: Calculated: C, 56.94; H, 4.96; N, 7.38; Found: C, 56.64; H, 4.88; N, 7.06. . { 2- [1- (3-Chloro-benzyl) -3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -ethyl} -ethyl-amine A solution of toluene-4-sulfonic acid 2- (1- (3-chloro-benzyl) -3- (naphthalene-1-sulfonyl) -1H-indazol-5-yloxy] -ethyl ester (0.415 g, 0.641 mmol) in 2.0 M ethylamine in THF (8.0 mL, 16.0 mmol) is stirred at 70 ° C for 3 hours and then at 80 ° C for 19 hours. The reaction mixture is allowed to cool to room temperature and the solvent is evaporated. This is partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase is washed with saline solution, dried over magnesium sulfate, filtered and concentrated. Drying * in vacuo at 80 ° C for 20 minutes resulted. { 2- [1 - (3-chloro-benzyl) -3- (naphthalene-1-sulfonyl) -1 H -indazol-5-yloxy] -ethyl} -ethyl-amino as an orange semi-solid (0.270 g, 81.1%). This is dissolved in chloroform, and ethereal hydrochloride is added. The mixture is concentrated and dried in vacuo at 83 ° C for 16 hours. Hydrochloride as a pale orange foam resulted (0.276g); Mass Spectrum (+ EI, [M + H] +) m / z 520. 1HNMR (500 MHz, DMSO-d6): dd.71-8.77 (m, 3H), 8.55 (dd, 1 H, J = 7.44 Hz and 1.22 Hz), 8.27 (d, 1 H, J = 8.29 Hz), 8.02-8.05 (m, 1 H), 7.82 (d, 1 H, J = 9.15 Hz), 7.70-7.74 (m, 1 H ), 7.57-7.64 (m, 2H), 7.24-7.28 (m, 2H), 7.16-7.21 (m, 3H) 7.05 (d, 1 H, J = 7.56 Hz), 5.73 (s, 2H), 4.24- 4.27 (m, 2H), 3.30-3.32 (m, 2H), 2.97-3.03 (m, 2H), 1.16-1.20 ppm (m, 3H). Elemental Analysis for C28H26CIN3? 3S 1.00 HCl 0.60 mol H2O: Cale: C, 59.28; H, 5.01; N, 7.41; Found: C, 58.95; H, 5.06; N. 7.14. - iS < Example 61 3- (1-naphthylsulfonyl) -5- (4-piperidin-1-ylbutoxy) -1H-indazole 5) H Step 1 1- (4-Chloro-butoxy) -4-nitro-benzene A mixture of para-nitrophenol (0.83 g, 6 mmol), 1-bromo-4-chloro-butane (1.23 g, 7.2 mmol), and K2CO3 (1.24 g, 9 mmol) is stirred together with the DMF at 80 ° C for 1 hour. The reaction mixture is diluted with H2O, extracted with EtOAc, washed with water (2x), saline (1x), dried over Na2SO, and concentrated under vacuum. The crude product is purified by HPLC using 30% EtOAc / hexane as eluent to afford the title compound as an off white solid (1.28 g, 5.6 mmol).

Stage 2 1- [5- (4-Chloro-butoxy) -2-nitro-phenylmethanesulfonyl] -naphthalene. { A mixture of 1- (4-chloro-butoxy) -4-nitrobenzene (1.28 g, 5.6 mmol) and 1-chloromentane-sulfonyl-naphthalene (1.6 g, 6.72 mmol) is stirred in THF (50 ml) at -78 °. C, in a bottom vessel rounded under nitrogen. A solution of 1 M potassium t-butoxide is added dropwise (16.8 ml, 16.8 mmoles) over a period of half an hour. The temperature is allowed to rise to -40 ° C, and the reaction mixture is stirred at this temperature for 5 hours. The reaction mixture is poured into cold 2N HCl, extracted with EtOAc, dried over Na2SO, and concentrated in vacuo. The compound was recrystallized from CH2Cl2 / hexane to obtain the title compound as an off white solid (1.94 g, 4.5 mmol).

Step 3 4- (4-Chloro-butoxy) -2- (naphthalene-1-sulfonylmethyl) -phenyl amine A mixture of 1- [5- (4-chloro-butoxy) -2-nitro-phenyl-methanesulfonyl] -naphthalene (1.94 g, 4.5 mmol) and 10% Pd / C in THF (20 mL), methanol (20 mL) ), and formic acid (5 mL) is hydrogenated in a Parr hydrogenation bottle (250 mL) at 40 lb / in2 for 20 hours. The mixture is filtered through Celite, and the filtrate is diluted with EtOAc, washed with water, dried over Na2SO4, and concentrated under vacuum. The crude product is purified by flash chromatography using 5% EtOAc / CH 2 Cl 2 as eluent to afford the title compound as an off white solid (1.54 g, 3.8 mmol).

Stage 4 - (4-Chloro-butoxy) -3- (naphthalene-1-sulfonyl) -1H-indazole A mixture of 4- (4-chloro-butoxy) -2- (naphthalene-1-sulfonylmethyl) -phenyl amine (1.54 g, 3. 8 mmol) in THF (7 mL), and 4M HCl (15 mL) is stirred in a vessel with a rounded bottom, under nitrogen, at 3 ° C. A solution of sodium nitrite (0.34 g, 4.0 mmol) in H2O (1 mL) is added dropwise. The reaction mixture was poured into a cold solution of saturated sodium bicarbonate (100 mL) and extracted with EtOAc. The compound is dried over Na2SO, and concentrated in vacuo to afford the title compound as an off white solid (1.55 g, 3.75 mmol).

Stage 5 A mixture of 5- (4-chloro-butoxy) -3- (naphthalene-1-sulfonyl) -1H-indazole (0.065 g, 0. 12 mmole) and piperidine (0.48 mmole) in DMF (1 mL) is stirred under nitrogen at 100 ° C overnight. The mixture is cooled to room temperature, diluted with water, extracted with EtOAc, washed with water (2x), saline (1x), dried over Na2SO4, and concentrated under vacuum. The compound is purified by flash chromatography using CH3OH / 5% EtOAc as eluent. The purified compound is dissolved in methanol, 1 M HCl in ether (0.1 mL, 0.1 mmol) is added, and the compound is dried to obtain the title compound 3- (1-naphthylsulfonyl) -5- (4-piperidin-1). -ylbutoxy) -1 H-indazole as the HCl salt, MS: (ES +) 463 [M + Hf Example 62-67 Using essentially the same procedure described in Example 61, Step 5 and using an appropriate amine, the compounds shown in Table I were obtained and identified by HPLC and mass spectral analysis.

TABLE I Ex. * - No. R5 R6 [M + H] + 62 CH3 H 465 63 C2Hs H 424 64 CH3 CH3 424 65 CH3 n-propyl 452 66 C2Hd C2Hs 452 67 -CH2CH2CH2CH2- 450 Example 68 (4- { [3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] oxy} butyl) amine Stage 1 A mixture of 5- (4-chloro-butoxy) -3- (naphthalene-1-sulfonyl) -1H-indazole (0.065 g, 0.12 mmol) and sodium acid (0.24 mmol) in; DMSO (1 mL) it is stirred under nitrogen at 90 ° C for 5 hours. The mixture is cooled to room temperature, diluted with water, extracted with EtOAc, washed with water (2x), saline (1x), dried over Na2SO, and concentrated under vacuum. The compound is purified by flash chromatography using CH3OH / 5% EtOAc as eluent.

Stage 2 The azide prepared in step 1 is subjected to hydrogenation over 10% Pd / C in THF (2mL), and methanol (8mL) in a Parr hydrogenation bottle (250mL) at 52lb / in2 for 2 hours. The mixture is filtered through Celite, and the filtrate is concentrated under vacuum. The crude pro is recrystallized from CH 2 Cl 2 / hexane) 1 M HCl in ether (0.9 ml, 0.9 mmol) is added, then evaporated to obtain the title compound - (4- { [3- (1-naphthylsulfonyl) - 1 H-indazol-5-yl] oxy} butyl) amine as a white off-HCl salt (0.04 g, 0.1 mmol), MS: (ES ") 394 [MH] \ Example 69 (2- { [1 - (3-Chlorobenzyl) -3- (1-naphthylsulfonyl) -1H-indazol-7-yl] oxy} ethyl) amine Stage 1 1- (2-Chloro-ethoxy) -2-nitro-benzene A mixture of ortho-nitrophenol (5.0 g, 35.8 mmol) and 2-chloroethanol (9.5 mL, 143 mmol) in THF (50 mL), in a round bottom vessel, under nitrogen, is stirred at room temperature. Triphenylphosphine (14 g, 53.7 mmol) is added, followed by diethylasodicarboxylate dropwise (8.5 mL, 53.7 mmol). The mixture is stirred overnight at room temperature. The reaction mixture is diluted with water, extracted with EtOAc, washed with water (1x), saline (1x), dried (Na2SO), and concentrated in vacuo. The crude pro is purified by flash chromatography using 40% EtOAc / hexane as eluent to give the title compound as an off white solid (5.6 g, 28 mmol).

Stage 2 1 - . 1-Chloromethane-sulfonyl-naphthalene A mixture of chloride of. Naphthalene-1-sulfonyl (10.0 g, 44 mmol), sodium sulfite (11.12 g, 88 mmol), and sodium bicarbonate (7.4 g, 88 mmol) in water (50 mL) is heated at 100 ° C for one hour . The crude sodium sulfinate solution is allowed to cool for 30 minutes, and then treated with bromochloromethane (43 mL, 661 mmol) and tetra-N-butylammonium bromide (1.4 g, 4.4 mmol). The resulting mixture is heated at 75 ° C overnight. All solvents were removed under vacuum. The compound is recrystallized from CH2Cl2 / hexane to give the title compound as an off white solid (10.62 g, 44 mmol).

Stage 3 1- [3- (2-Chloro-ethoxy) -2-nitro-phenyl-methanesulfonyl] -naphthalene A mixture of 1- (2-chloro-ethoxy) -2-nitrobenzene (1.2 g, 6 mmol) and 1-chloromethane-sulfonyl-naphthalene (2.16 g, 9 mmol) is stirred in THF (50 mL) at -78 ° C, in a bottom vessel rounded under nitrogen. A solution of 1M potassium t-butoxide is added dropwise (18 mL, 18 mmol) over a period of half an hour. At the temperature it is allowed to rise to -40 ° C, and the reaction mixture is stirred at this temperature for 5 hours. The reaction mixture is poured into cold 2N HCl, extracted i * with EtOAc, dried over Na2SO, and concentrated in vacuo. The compound is recrystallized from CH2Cl2 / hexane to obtain the title compound as an off white solid (1.4 g, 3 mmol).

Stage 4 2- (2-Chloro-ethoxy) -6- (naphthalene-1-sulfonylmethyl) -phenyl amine A mixture of 1- [3- (2-chloro-ethoxy) -2-nitro-phenyl-methanesulfonyl] -naphthalene (1.24 g, 3.5 mmol) and 10% Pd / C in THF (20 mL), methanol (5 mL) , and formic acid (5mL) is hydrogenated in a Parr hydrogenation bottle (250mL) at 40 lb / in2 for 20 hours. The mixture is filtered through Celite, and the filtrate is diluted with EtOAc, washed with water, dried over Na2SO4, and concentrated under vacuum. The crude pro is purified by flash chromatography using 5% EtOAc / CH 2 Cl 2 as eluent to afford the title compound as an off white solid (1.0 g, 3.1 mmol).

Stage 5 7- (2-Chloro-ethoxy) -3- (naphthalene-1-sulfonyl) -1H-indazole KJ 'A mixture of 2- (2-chloroethoxy) f6- (naphthalene-1-sulfonylmethyl) -phenyl amine (0.97 g, 3 mmol) in THF (7mL), and HÓ1 4M (15mL) is stirred in a beaker. Rounded bottom, under nitrogen, at 3 ° C. The solution of sodium nitrite (0.21 g, 3.15 mmol) in H2O (1 mL) is added dropwise. The reaction mixture was poured into a cold solution of saturated sodium bicarbonate (100mL) and extracted with EtOAc. The compound is dried over Na2SO, and concentrated in vacuo to afford the title compound as an off white solid (0.9 g, 2.7 mmol).

Stage 6 1 - . 1 - (3-Chloro-benzyl) -7- (2-chloro-ethoxy) -3- (naphthalene-1-sulfonyl) -1H-indazole .Y i) i- A mixture of 7- (2-chloro-ethoxy) -3- (naphthalene-1-sulfonyl) -1H-indazole (0.7 g, 1.8 mmol), 3-chloro-benzyl bromide (0.28) mL, 2.17 mmole), and cesium carbonate (0.7 g, 2. 17 mmol) in DMF (5 mL) is stirred together in a bottom-rounded container at room temperature for 30 minutes. The reaction mixture is diluted with H2O, extracted with EtOAc, washed with water (2x), saline (1x), dried over Na2SO4, and concentrated under vacuum. The crude product is purified by HPLC using 30% EtOAc / hexane as eluent to achieve the title compound as an off white solid (0.55 g, 1.1 mmol). ¡ Stage 7 7- (2-Acid-ethoxy) -3- (naphthalene-1-sulfonyl) -1H-indazole A mixture of 1- (3-chloro-benzyl) -7- (2-chloro-ethoxy) -3-naphthalene-1-sulfonyl) -1H-indazole (0.25 g, 0.49 mmol) and sodium (0.04 g) g, 0.58 mmole) in DMSO (3 mL) is stirred together in a round bottom flask under nitrogen at 90 ° C for 3 hours. The reaction mixture is cooled to room temperature, diluted with water, extracted with EtOAC, washed with water (2x), saline (1x), dried over Na2SO and concentrated under vacuum for the title compound as a solid white off (0.23 g, 0.44 mmol).

Stage 8 (2- { [1- (3-Chlorobenzyl) -3- (1-naphthylsulfonyl) -1-H-indazol-7-yl] oxy} ethyl) amine A mixture of 7- (2-acid-ethoxy) -3- (naphthalene-1-sulfonyl) -1H-indazole (0.23 g, 0.44 mmol) and 10% of Pd / C in THF (2mL), and methanol (5mL) is hydrogenated in a Parr hydrogenation bottle (250mL) at 52 jk / in2 for 2 > hours. The mixture is filtered through Celite, and the filtrate is concentrated under vacuum. The crude product is purified by flash chromatography using 5% CH3OH / CH2Cl2 as eluant to achieve an off white solid (0.2 g, 0.4 mmol), MS: (ES +) 493 [M + H] + EXAMPLE 70 (2- ({(1- (3-Chlorobenzyl) -3- (1-naphthylsulfonyl) -1H-indazol-7-yl] oxy]. Ethyl) methylamine A mixture of 1- (3-chloro-benzyl) -7- (2-chloro-ethoxy) -3- (naphthalene-1-sulfonyl) -1-H-indazole (0.065 g, 0.12 mmol) and methylamine (0.48 mmol) ) in DMF (1 mL) is stirred under nitrogen at 100 ° C overnight. The mixture is cooled to room temperature, diluted with water, extracted with EtOAc, washed with water (2x), saline (1x), dried over Na2SO4, and concentrated under vacuum. The compound is purified by flash chromatography using CH3OH / 5% EtOAc as eluent. The purified compound is dissolved in methanol, 1M HCl in ether (0.1 mL, 0.1 mmol) is added and the compound is dried to obtain the title compound as an HCl salt, MS: (ES +) 507 [M + H] + .

Using essentially the same procedure described in Example 70 and employing an appropriate amine, the compounds shown in Table II were obtained and identified by HPLC and mass spectral analysis.

TABLE II Ex. No. R5 R6 [M + H] + 71 C2Hs H 522 72 C2Hs. , t. C2H5 549 73 n-butyl H 549 74 -CH2CH2CH2CH2CH2-561 75-p2 H2CH2CH - 547 Example 76 (2- {[[3- (1-naphthylsulfonyl) -1H-indazol-7-yl] oxy} ethyl) amine A mixture of 0.075 g of 1- (3-chlorobenzyl) -3- (1-naphthylsulfonyl) -7- (2-amino-1-ylethoxy) -1H-indazole, DMSO (1 mL) and t-BuOH (0.2mL) is stirred at room temperature in a rounded bottom vessel under an oxygen atmosphere. A solution of potassium t-butoxide (0.98 mL, 0.98 mmol) is added dropwise and the reaction mixture is stirred for 1 hr. The reaction mixture is quenched with saturated ammonium chloride, extracted with EtOAc, dried over Na2SO, and concentrated in vacuo. The crude compound is purified by flash chromatography using CH3OH / CH2CI2 10%. The purified compounds were dissolved in methanol, 1M HCl in ether (0.1 mL, 0.1 mmol) was added and the compound was dried to obtain the title compound as the HCl salt, MS: (ES +) 368 [M + H] +.

Examples 77-81 Using essentially the same procedure described in Example 76 and employing the appropriate indazol-7-yloxyethamine substrate, the compounds shown in Table III were obtained and identified by HPLC and mass spectral analysis.

TABLE III Ex. No. R5. { , R6 [M + H] + 77 CH3 H 382 78 CH3 CH3 396 79 C2Hs H 396 80 -CH2CH2CH2CH2CH2- 436 81 -CH2CH2CH2CH2-422 Examples 82-93 Stage 1 1-Benzene-sulfonyl-methyl-3- (2-chloro-ethoxy) -2-nitro-benzene A mixture of 1- (2-chloro-ethoxy) -2-nitrobenzene (1.2 g, 6 mmol) and chloromethyl phenyl sulfone (2.16 g, 9 mmol) is stirred in THF (50 mL) at -78 ° C, in a bottom vessel rounded under nitrogen. A solution of 1M potassium t-butoxide is added dropwise (18 mL, 18 mmol) over a period of half an hour. At the temperature it is allowed to rise to -40 ° C, and the reaction mixture is stirred at this temperature for 5 hours. The reaction mixture is poured into cold 2N HCl, extracted with EtOAc, dried over Na2SO, and concentrated in vacuo. The compound is recrystallized from CH2Cl2 / hexane to obtain the title compound as an off white solid (1.5 g, 4.2 mmol). i l Ki Stages 2-6 Using essentially the same procedures described in Example 69, steps 3-4, and Examples 70 and 76, the compounds shown in Table IV were obtained and identified by HPLC and mass spectral analysis.

TABLE IV « Ex. No R1 R5 R6 [M + H] + 82 3-CI-benzyl CH3 H 457 83 3-CI-benzyl C2H5 H 471 84 3-CI-benzyl C2H5 C2Hs 499 85 3-CI-benzyl < ^ n-butyl H 499 86 3-CI-benzyl-CH CH2CH2CH2-497 87 3-CI-benzyl-CH2CH2CH CH2CH2- 511 88 H CH3 H 332 89 H C2Hd H 346 90 H C2H5 C2Hs 374 91 H n-butyl H 374 92 H -CH2CH2CH2CH2- 372 93 H -CH2CH2CH2CH2CH2- 386 Examples 94-105 Step 1 7- (2-Chloro-ethoxy) -1-methyl-3- (naphthalene-1-sulfonyl) -1 H-indazole: A mixture of 7- (2-chloro-ethoxy) -3- (naphthalene-1-sulfonyl) -1H-indazole (0.7 g, 1.8 mmol), methyl iodide (0.28 mL, 2.17 mmol), and carbonate of Potassium (0.29 g, 2.17 mmol) in DMF (10 mL) is stirred together in a bottom-rounded vessel at room temperature for 2 hours. The reaction mixture is diluted with H2O, extracted with EtOAc, washed with water (2x), saline (1x), dried over Na2SO4, and concentrated under vacuum. The crude product is purified by HPLC used as eluent EtOAc / hexane to obtain the title compound as an off white solid, 0.55 g, 1375 mmol.

Stage 2 Using essentially the same procedure described in Example 70, and employing the appropriate 3-arylsulfonyl-1-methylindazole substrate and the desired amine and conversion to HCl salts, the compounds shown in Table V were obtained and identified by HPLC and spectral analysis of dough.

TABLE V Ex. No. R2 R5 R6 [M + H] + 94 1 -naphthyl HH 419 95 1 -naphthyl C2Hs H 410 96 1 -naphthyl CH3 CH3 410 97 1 -naphthyl C2Hs C2Hs 438 98 1 -naphthyl n -butyl H 438 99 1 -naphthyl -CH2CH2CH2CH2CH2- 450 100 1 -naphthyl -CH2CH2CH2CH2 - 436 101 phenyl CH3 H 346 102 phenyl C2Hs H 360 103 phenyl C2Hs C2H5 388 104 phenyl -CH2CH2CH2CH2-386 105 phenyl -CH CH2CH2CH2CH2- 400 Example 106 (2- {[(3-chlorobenzyl) -5-fluoro-3- (1-naphthylsulfonyl) -1H-indazol-7-yl] oxy} ethyl) amine 6) NaN3 7) Pd / C, H2 Stage 1 2- (2-Chloro-ethoxy) -4-fluoro-1-nitro-benzene In a bottom vessel rounded under nitrogen, 2-chloro-ethanol (8.3 mL, 120 mmol) in THF (40 mL) is cooled to 0 ° C. LDA (60 mL, 120 mmol) is added dropwise, while maintaining the constant temperature at 0 ° C. The mixture is stirred at this temperature for 15 minutes, followed by the addition of 2,4-difluoronitrobenzene (11 mL, 100 mmol). The mixture is stirred at room temperature overnight. The reaction mixture is diluted with water, extracted with EtOAc, washed with saline (1x), dried over Na2SO4, and concentrated under vacuum, to achieve the title compound as an off white solid (20.0 g, mmoles).

Stage 2 1- [3- (2-Chloro-ethoxy) -5-fluoro-2-nitro-phenylmethanesulfonyl] -naphthalene A mixture of 2- (2-chloro-ethoxy) -4-fluoro-1-nitrobenzene (1.3 g, 6 mmol) and 1-chloromethane-sulfonyl-naphthalene (2.16 g, 9 mmol) were stirred in THF (50 mL) at -78 ° C, in a bottom vessel rounded under nitrogen. A solution of 1 M potassium t-butoxide is added dropwise (mL, 18 mmol) over a period of half an hour. At the temperature it is allowed to rise to -40 ° C, and the reaction mixture is stirred at this temperature for 5 hours. The reaction mixture is poured into 2N HCl, extracted with EtOAc, dried over Na2SO, and concentrated under vacuum. The compound is recrystallized from CH2Cl2 / hexane to obtain the title compound as an off white solid (2.25 g, 5.3 mmol).

Stage 3 2- (2-Chloro-ethoxy) -4-fluoro-6- (naphthalene-1-sulfonyl-methyl) -phenylamine A mixture of 1- [3- (2-chloro-ethoxy) -5-fluoro-2-nitro-phenylmethanesulfonyl] -naphthalene (1.0 g, 2.36 mmol) in ethanol (25 L) is stirred under nitrogen in a bottom vessel rounded at 60 ° O 10% Pd / C is added, and the temperature is increased to 80 ° O Hydrazine hydrate (2.0r L) is added dropwise and the mixture is stirred at reflux for 3 hours. The reaction mixture is filtered through Cerite, and the solution is washed with H2O (3x), dried over Na2SO, and concentrated under vacuum to obtain the title compound as an off white solid (0.91 g, 2.31 mmol). .

Stage 4 7- (2-Chloro-ethoxy) -5-fluoro-3- (naphthalene-1-sulfonyl) -1 H-indazole A mixture of 2- (2-chloro-ethoxy) -4-fluoro-6- (naphthalene-1-sulfonyl-methyl) -phenylamine (0.91 g, 2.31 mmol) in THF (7 mL), and 4M HCl (15 mL) are Stir in a vessel with a rounded bottom, under nitrogen, at 3 ° C. A solution of sodium nitrite (0.16 g, 2.4 mmol) in H 2 O (1 mL) is added dropwise. The reaction mixture was poured into a cold solution of saturated sodium bicarbonate (100mL) and extracted with EtOAc. The compound is dried over Na 2 SO 4 Y and concentrated under vacuum to obtain the title compound as an off white solid (0.9 g, 2.2 mmol).

Stage 5 1 - . 1 - (3-Chloro-benzyl) -7- (2-chloro-ethoxy) -5-fluoro-3- (naphthalene-1-sulfonyl) -1 H-indazole A mixture of 7- (2-chloro-ethoxy) -5-fluoro-3- (naphthalene-1-sulfonyl) -1 H -acezole (0.9 g, 2.2 mmol), 3-chlorobenzyl bromide (0.35 mL, 2.7 mmol) , and cesium carbonate (0.87 g, 2.7 mmol) in DMF (5 mL) is stirred together in a bottom-rounded container at room temperature for 30 minutes. The reaction mixture is diluted with H2O, extracted with EtOAc, washed with water (2x), saline (1x), dried over Na2SO, and concentrated under vacuum. The crude product is purified by HPLC using 30% EtOAc / hexene as eluent to afford the title compound as an off white solid (0.85 g, 2 mmol).

Stage 6 7- (2-Azido-ethoxy) -1 - (3-chloro-benzyl) -5-fluoro-3- (naphthalene-1-sulfonyl) -1 H-indazole A mixture of 1- (3-chloro-benzyl) -7- (2-chloro-ethoxy) -5-fluoro-3- (naphthalene-1-sulfonyl) -1H-indazole (0.1 g, 0.19 mmol) and azide Sodium (0.014 g, 0.22 mmol) in DMSO (3 mL) is stirred together in a bottom-rounded vessel under nitrogen at 90 ° C for 3 hours. The reaction mixture is cooled to room temperature, diluted with water, extracted with EtOAc, washed with water (2x), saline (1x), dried over Na2SO4, and concentrated under vacillate to achieve the title compound as an off white solid (0.09 g, 0.17 mmol).

Stage 7 (2- { [1 - (3-Chlorobenzyl) -5-fluoro-3- (1-naphthylsulfonyl) -1 H -indazol-7-yl] oxy} ethyl) amine A mixture of 7- (2-acide-ethoxy) -1- (3-chloro-benzyl) -5-fluoro-3- (naphthalene-1-sulfonyl) -1H-indazole (0.09 g, 0.1.7 mmol) and 10% Pd / C in THF (5mL), and methanol (15mL) is hydrogenated in a Parr hydrogenation bottle (250 mL) at 52 lb / in2 for 2 hours. The mixture is filtered through Celite, and the filtrate is concentrated under vacuum. The crude product is purified by flash chromatography using 5% CH3OH / CH2Cl2 as eluent to afford the title compound as an off white solid (0.08 g, 0.14 mmol), MS: (ES +) 511 [M + H] +.

And Example 107 (2- {[1 - (3-Chlorobenzyl) -5-fluoro-3- (1-naphthylsulfonyl) -1 H -indazol-7-yl] oxy} ethyl} methylamine hydrochloride.

A mixture of 1- (3-chloro-benzyl) -7- (2-chloro-ethoxy) -5-fluoro-3- (naphthalene-1-sulfonyl) -1H-indazole (0.075 g, 0.14 mmol) and methylamine (0.56 mmole) in DMSO (1 mL) is stirred under nitrogen at 100 ° C for 4 hours. The mixture is cooled to room temperature, diluted with water, extracted with EtOAc, washed with water (2x), saline (1x), dried over Na2SO4? and concentrate under vacuum. The compound is purified by flash chromatography using CH3OH / 5% EtOAc as eluent. The purified compound is dissolved in methanol, 1M HCl in ether (0.1 mL, 0.1 mmol) is added, and the compound is dried to obtain the title compound as an HCl salt. MS: (ES +) 525 [M + H] +.

Examples 108-118 Using essentially the same procedures described in Example 107 and 76, and employing the desired amine, the compounds shown in Table VI were obtained and identified by HPLC and mass spectral analysis. f TABLE VI Ex. No. R1 R5 R6 [M + H] + 108 3-CI-benzyl C2Hs H 539 109 3-CI-benzyl CH3 CH3 539 110 3-CI-bencil - 'v C2Hs C2H5 567 111 3-CI-benzyl '-CH2CH2CH2CH2CH2-579 112 3-CI-bencil -CH2CH2CH2CH2-56 113 H CH3 H 400 114 H C2H5 H 414 115 H CH3 CH3 414 TABLE VI. Cont.

Ex. No. R1 R5 R6 [M + H] + 117 H -CH CH CH2CH2CH2- 454 118 H -CH2CH2CH2CH2- 440 Examples 119 - 127 / \ ^ OH 1) Cl 6a) HNR5Rß (6b1t HCI I 7) KOt-Bu I Stage 1) 2- (2-Chloroethoxy) -4-methoxy-1-nitrobenzene To a mixture of 2-chloroethanol (0.7 mL, 10.5 mmol) in THF (20 mL), cooled to 0 ° C Add 2M LDA (5.25 mL, 10.5 mmol) dropwise. When the addition of LDA is complete, the mixture is stirred for an additional 15 minutes, and 2-fluoro-4-methoxy-1-nitrobenzene (1.5 g, 8.8 mmol) is added. The mixture is allowed to warm to room temperature, and is stirred at this temperature overnight. The reaction mixture is diluted with water, extracted with EtOAc, washed with saline (1x), dried over Na2SO, and concentrated in vacuo. The crude compound is recrystallized from CH2Cl2 / hexane to give the title compound (1.5 g, 6.5 mmol).

Step 2) 1- [3- (2-Chloro-ethoxy) -5-methoxy-2-nitro-phenylmethanesulfonyl] -naphthalene A mixture of 2- (2-chloro-ethoxy) -4-methoxy-1-nitrobenzene (1.4 g, 6 mmol) and 1-chloromethane-sulfonyl-naphthalene (1.4 g, 6 mmol) is stirred in THF (50 mL) at -78 ° C, in a bottom vessel rounded under nitrogen. A solution of 1 M potassium t-butoxide is added dropwise (18 mL, 18 mmol) over a period of half an hour. At the temperature it is allowed to rise to -40 ° C, and the reaction mixture is stirred at this temperature for 4 hours. The reaction mixture is poured into cold 2N HCl, extracted with EtOAc, dried over Na2SO4, and concentrated in vacuo. The crude compound is recrystallized from CH2Cl2 / hexane to obtain the title compound as an off white solid (2 g, 4.6 mmol).

Step 3) 2- (2-Chloro-ethoxy) -4-methox- (naphthalene-1-sulfonylmethyl) -phenylamine A mixture of 1- [3- (2-chloro-ethoxy) -5-methoxy-2-nitro-phenylmethanesulfonyl] -naphthalene (1.0 g, 2.5 mmol) in ethanol (25 mL) is stirred under nitrogen in a bottom vessel rounded to 60 ° C. 10% Pd / C is added, and the temperature is increased to 80 ° C. Hydrazine hydrate (2.0mL) is added dropwise and the mixture is stirred at reflux for 3 hours. The reaction mixture is filtered through Celite, and the solution is washed with H2O (3x), dried over Na2SO4, and concentrated under vacuum to achieve the title compound as an off white solid 1.0 g, 2.46 mmol).

Step 4) 7- (2-Chloro-ethoxy) -5-methoxy-3- (naphthalene-1-sulfonyl) -1 H-indazole A mixture of 2- (2-chloro-ethoxy) -4-methoxy-6- (naphthalene-1-sulfonylmethyl) -phenylamine (1.0 g, 2.46 mmol) in THF (7mL), and 4M HCl (15mL) is stirred in a vessel with a rounded bottom, under nitrogen, at 3 ° G, a solution of sodium nitrite (0.17 g, 2.6 mmol) in H2O (1 mL) is added dropwise. The reaction mixture was poured into a cold solution of saturated sodium bicarbonate (100mL) and extracted with EtOAc. The compound is dried over Na2SO, and concentrated in vacuo to afford the title compound as an off white solid (1.0 g, 2.39 mmol).

Step 5) 1- (3-Chloro-benzyl) -7- (2-chloro-ethoxy-5-methoxy-3- (naphthalene-1-sulfonyl) -1H-indazole Y A mixture of 7- (2-chloro- ethoxy) -5-methoxy-3- (naphthalene-1-sulfonyl) -1 H-indazole (1.0 g, 2.39 mmol), 3-chlorobenzyl bromide (0.35 mL, 2.7 mmol), and cesium carbonate (0.87 g, 2.7 mmol) in DMF (5 mL) is stirred together in a bottom vessel Y & 'rounded to an ambient temperature for 10 minutes. The reaction mixture is O 'diluted with H2O, extracted with EtOAc, washed with water (2x), saline (1x), dried over Na2SO, and concentrated under vacuum. The crude product is purified by HPLC using 30% EtOAc / hexane as eluent to afford the title compound as an off white solid (1.1 g, 2 mmol).

Stage 6 and 7) Amination and debenzylation Using essentially the same procedures described in Examples 107 and 76, and employing the substrate 7- (2-chloroethoxy) -5-methoxy-3-naphthylsulfonylindazole and the desired amine, the compounds shown in Table VII were obtained and identified by HPLC. and mass spectral analysis.

TABLE VII ? v «L Ex. No. R1 R5 R6 [M + H] + 119 3-CI-benzyl 'CH3 H 537 120 3-CI-benzyl C2H5 H 551 121 3-CI-benzyl CH3 CH3 551 122 3-CI-benzyl-CH2CH CH2CH2CH2- 591 123 3-CI-benzyl-CH2CH2CH2CH2-577 124 H CH3 H 412 125 H .. • »• CH33 CH3 426 126 H -CH2CH2CH2CH2CH2- 466 127 H -CH2CH2CH2Cr? 2- 452 Examples 128-138 6a) HNR5R6 (6b) HCl 7) KOt-Bu! • Stage 1) 1- (3-Chloro-propoxy) -2-nitro-benzene A mixture of ortho-nitrophenol (0.83 g, 6 mmol), 1-bromo-3-chloropropane (1.1 g, 7.2 mmol), and K2CO3 (1.24 g, 9 mmol) is stirred together in DMF at 80 ° C for 1 hr. hour. The reaction mixture is diluted with H2O, extracted with EtAOc, washed with water (2x), saline (1x), dried over Na2SO, and concentrated under vacuum. The crude product is purified by HPLC 'using 30% EtOAc / hexane as eluent to achieve the title compound as an off white solid (1.2 g, 5.6 mmol).

Step 2) 1- [3- (3-Chloro-propoxy) -2-nitro-phenyl-methanesulfonyl] -naphthalene A mixture of 1- (3-chloro-propoxy) -2-nitrobenzene (1.2 g, 6 mmol) and 1-chloromethane-sulfonyl-naphthalene (2.16 g, 9 mmol) is stirred in THF (50 mL) at -78 ° C. , in a bottom vessel rounded under nitrogen. A solution of 1 M potassium t-butoxide is added dropwise (18 mL, 18 mmol) over a period of half an hour. At the temperature it is allowed to rise to -40 ° C, and the reaction mixture is stirred at this temperature for 5 hours. The reaction mixture is poured into cold 2N HCl, extracted with EtOAc, dried over Na2SO4, and concentrated in vacuo. The compound is recrystallized from CH2Cl2 / hexane to obtain the title compound as an off white solid (1.9 g, 4.5 mmol). - ü Stage 3) 2- (3-Chloro-propoxy) -6- (naphthalene-1-sulfonylmethyl) -phenyl amine A mixture of 1- [3- (3-chloro-propoxy) -2-nitro-phenyl-methanesulfonyl] -naphthalene (1.9 g, 4.5 mmol) and 10% Pd / C in THF (20 mL), methanol (20 mL) , and formic acid (5mL) is hydrogenated in a Parr hydrogenation bottle (250 mL) at 40 lb / in2 for 20 hours. The mixture is filtered through Celite, and the filtrate is diluted with EtOAc, washed with water, dried over Na2SO and concentrated under vacuum. The crude product is purified by flash chromatography using 5% EtOAc / CH 2 Cl 2 as eluent to afford the title compound as an off white solid (1.66 g, 4.25 mmol).

Step 4) 7- (3-Chloro-propoxy) -3- (naphthalene-1-sulfonyl) -1H-indazole A mixture of 2- (3-chloro-propoxy) -6- (naphthalene-1-sulfonylmethyl) -phenyl amine (1.66 g, 4.25 mmol) in THF (7 mL), and 4M HCl (15 mL) is stirred in a Rounded bottom, under nitrogen, at 3 °. { . A solution of sodium nitrite (0.3 g, 4.4 mmol) in H2O (1 mL) is added dropwise. The reaction mixture was poured into a cold solution of saturated sodium bicarbonate (100 mL) and extracted with EtOAc. The compound is dried over Na2SO4, and concentrated under vacuum to obtain the title compound as an off white solid (1.6 g, 4 mmol).

Step 5) 1 - (3-Chloro-benzyl) -7- (3-chloro-propoxy) -3- (naphthalene-1-sulfonyl) -1H-indazole A mixture of 7- (3-chloro-propoxy) -3- (naphthalene-1-sulfonyl) -1H-indazole (0.7 g, 1.75 mmol), 3-chloro-benzylbromide (0-28 mL, 2.17 mmol) , and cesium carbonate (0.7 g, 2.17 mmol) in DMF (5 mL) is stirred together in a bottom-rounded container at room temperature for 10 minutes. The reaction mixture is diluted with H2O, extracted with EtOAc, washed with water (2x), saline (1x), dried over Na2SO4, and concentrated under vacuum. The crude product is purified by HPLC using 30% EtOAc / hexane as eluent to afford the title compound as an off white solid (0.87 g, 1.66 mmol).

Stage 6 and 7) Amination and debenzylation Using essentially the same procedures described in Examples 107 and 76, and employing the substrate 7- (3-chloropropoxy) -3-naphthylsulfonylindazole and the desired amine, the compounds shown in Table VIII were obtained and identified by HPLC and spectral analysis of dough. (The amination is done in parallel on a carrousel heated in vials of 3 drachms). ^ Y 'TABLE VIII Ex. No. R1 R5 R6 [M + H] + 128 3-CI-benzyl CH3 H 521 129 3-CI-benzyl C2Hs H 535 130 3-CI-benzyl CH3 CH3 535 131 3-CI-benzyl C2Hd C2Hd 563 132 3-CI-benzyl-CH2CH2CH2CH CH-575 133 3- CI-benzyl-CH CH2CH CH-561 134 H CH3 H 396 135 H C2H5 H 410 136 H CH3 CH3 410 i 137 H C2Hd C2Hs 438 138 H -CH2CH2CH2CH2CH2- 450 Example 139 2- . { [3-Phenylsulfonyl) -1 H -indazol-7-yl] oxy} Ethanamine Step 1) 1- Benzeneslufonylmethyl-3- (2-chloroethoxy) -2-nitrobenzene A mixture of 1- (2-chloro-ethoxy) -2-nitrobenzene (0.5 g, 2.5 mmol) and 1-chloromethane-sulfonyl-benzene (0.56 g, 2.97 mmol) is stirred in THF (10 mL) at -78 ° C. , in a container with a rounded bottom. A solution of 1 M potassium t-butoxide is added dropwise (7.45 mL, 7.44 mmol) over a period of half an hour. At the temperature it is allowed to rise to -40 ° C, and the reaction mixture is stirred at this temperature for 5 hours. The reaction mixture is poured into cold 2N HCl, extracted with EtOAc, dried over Na2SO, and concentrated in vacuo. The compound is recrystallized from CH2Cl2 / hexane to obtain the title compound as an off white solid (0.57 g, 1.6 mmol). 1 ?-. '' Stage 2) 2-Benzenesulfonylmethyl-6- (2-chloro-ethoxy) -phenylamine A mixture of 1-benzenesulfonylmethyl-3- (2-chloro-ethoxy) -2-nitrobenzene (0.57 g, 1.6 mmol) in ethanol (10 mL) is stirred under nitrogen in a bottom-rounded vessel at 60 ° C. Pd / is added C at 10%, and the temperature is increased to 80 ° C. Hydrazine hydrate (1.5 mL) is added dropwise and the mixture is stirred at reflux for 3 hours. The reaction mixture is filtered through Celite, and the solution is washed with H2O (3x), dried over Na2SO, and concentrated under vacuum to obtain the title compound as an off white solid (0.5 g, 1.53 mmol).

Step 3) 2- (2-Acid-ethoxy) -6-benzenesulfonylmethyl-phenylamine A mixture of 2-benzenesulfonylmethyl-6- (2-chloro-ethoxy) -phenylamine (0.5 g, 1.53 mmol) and sodium acid (0.15 g, 29 mmol) in DMSO (10 mL) is stirred together in a bottom vessel rounded under nitrogen at 90 ° C for 3 hours. The reaction mixture is cooled to room temperature, diluted with water, extracted with EtOAc, washed with water (2x), saline (1x), dried over Na2SO4? and concentrate under vacuum. The crude compound is purified by normal phase HPLC using 40% EtOAc / hexane as eluent to achieve the title compound as an off white solid (0.39 g, 1.17 mmol).

Step 4) 7- (2-Acid-ethoxy) -3-benzenesulfonyl-1 H-indazole A mixture of 2- (2-acid-ethoxy) -6-benzene-sulfonylmethyl-phenylamine (0.39 g, 1.17 mmol) in THF (2 mL), and 4M HCl (10 mL) is stirred in a rounded bottom vessel, under nitrogen , at 3 ° O A solution of sodium nitrite (0.08 g, 1.23 mmole) in H2O (1 mL) is added dropwise. The reaction mixture was poured into a solution of sodium bicarbonate (100mL) and extracted with EtOAc. The compound was dried over Na2SO4. and concentrated under vacuum to obtain the title compound as an off white solid (0.3 g, 0.87 mmol).

Stage 5) 2-. { [3-Phenylsulfonyl) -1H-indazol-7-yl] oxy} Ethanamine , A mixture of 7- (2-acid-ethoxy) -3-benzenesulfonyl-1 H-indazole (0.3 g, 0.87 mmol) and 10% Pd / C in THF (2 mL), in methanol (8 mL) is hydrogenated in a Parr hydrogenation bottle (250 mL) at 52 lb / in2 for 2 hours. The mixture is filtered through Celite, and the filtrate is concentrated under vacuum. The crude product is recrystallized from CH 2 Cl 2 / hexane, 1 M HCl in ether (0.9 mL, 0.9 mmol) is added, then dried, to achieve the title compound with a white off HGI salt (0.2 g, 0.6 mmol), MS: (ES +) 317 [M + H] + Example 140 2- . { [5-Fluoro-3-phenylsulfonyl) -1H-indazol-7-yl] oxy} Ethanamine Step 1) 1 -Bancanosulfonylmethyl-3- (2-chloro-ethoxy) -5-fluoro-2-nitro-benzene < 5 yi - A mixture of 2- (2-chloroethoxy) -4-fluoro-1-nitrobenzene (1.3 g, 6 mmol) and 1-chloromethane-sulfonyl-benzene (1.7 g, 9 mmol) is stirred in THF (50 mL) ) at -78 ° C, in a bottom vessel rounded under nitrogen. A solution of 1M potassium t-butoxide is added dropwise (18 mL, 18 mmol) over a period of half an hour. At the temperature it is allowed to rise to -40 ° C, and the reaction mixture is stirred at this temperature for 5 hours. The reaction mixture is poured into cold 2N HCl, extracted with EtOAc, dried over Na2SO4, and concentrated in vacuo. The compound is recrystallized from CH2Cl2 / hexane to obtain the title compound as an off white solid (1.98 g, 5.3 mmol).

Stage 2) 2-Benzenesulfonylmethyl-6- (2-chloro-ethoxy) -4-flurophenylamine A mixture of 1-benzenesulfonylmethyl-3- (2-chloro-ethoxy) -5-fluoro-2-nitrobenzene (1.98 g, 5.3 mmol) in ethanol (25 mL) is stirred under nitrogen in an bottom rounded at 60 ° O 10% Pd / C is added, and the temperature is increased to 80 ° C. Hydrazine hydrate (2.0mL) is added dropwise and the mixture is stirred at reflux for 3 hours. The reaction mixture is filtered through Celite, and the solution is washed with H2O (3x), dried over Na2SO4, and concentrated under vacuum to achieve the title compound as an off white solid (1.67 g, 4.87 mmol). .

Step 3) 2- (2-Azido-ethoxy) -6-benzenesulfonylmethyl-4-fluoro-phenylamine A mixture of 2-benzenesulfonylmethyl-6- (2-chloro-ethoxy) -4-fluorophenylamine (1.67 g, 4.87 mmol) and sodium acid (0.38 g, 5.84 mmol) in DMSO (20 mL) is stirred together in a Bottom vessel rounded under nitrogen at 90 ° C for 3 hours. The reaction mixture is cooled to room temperature, diluted with water, extracted with EtOAc, washed with water (2 *), saline (1x), dried over Na2SO, and concentrated under vacuum to achieve the compound of the title as an off white solid (1.44 g, 4.14 mmol).

Step 4) 7- (2-Azido-ethoxy) -3-benzenesulfonyl-5-fluoro-1 H-indazole A mixture of 2- (2-acid-ethoxy-6-benzenesulfonylmethyl-4-fluoro-phenylamine (1.44 g, 4.14 mmol) in THF (5 mL) y and 4M HCl (20 mL) is stirred in a round-bottomed container , under nitrogen, at 3 ° O A solution of sodium nitrite (0.28 g, 4-34 mmol) in H 2 O (2 mL) is added dropwise The reaction mixture is poured into a cold solution of saturated sodium bicarbonate ( 100mL) and extracted with EtOAc The compound is dried over Na2SO, and concentrated under vacuum to obtain the title compound as an off white solid (1.34 g, 3.72 mmol) YES P Stage 5) 2-. { [5-Fluoro-3-phenylsulfonyl) -1H-indazol-7-yl] oxy} ethanamine A mixture of 7- (2-acid-ethoxy) -3-benzenesulfonyl-5-fluoro-1 H-indazole (0.3 g, 0.83 mmol) and 10% Pd / C in THF (2 mL), and methanol (8 mL) ) is hydrogenated in a Parr hydrogenation bottle (250 mL) at 52 lb / in2 for 2 hours. The mixture is filtered through Celite, and the filtrate is concentrated under vacuum. The crude product is recrystallized from CH 2 Cl 2 / hexane, 1 M HCl in ether (0.8 L, 0.8 mmol) is added, then dried, to achieve the title compound as an off white HCl salt (0.2 g, 0.59 mmol), MS: (ES +) 336 [M + H] +.

^ Example 141 i Y 2-. { [3-1-Naphthylsulfonyl) -1H-indazol-4-yl] oxy} Ethanamine ) NaN3 6) Pd / C, H2 Stage 1) 1- (2-Chloroethoxy) -3-nitrobenzene A mixture of 3-nitrophenol 0.83 g, 6 mmol), bromo-chloroethane (1.03 g, 7.2 mmol), and K2CO3 (1.24 g, 9 l? Nols) is stirred together in DMF at room temperature for 1 hour. The reaction mixture is diluted with H2O, extracted with EtOAc, washed with water (2x), saline (1x), dried over Na2SO4, and concentrated under vacuum. The crude product is purified by HPLC using 30% EtOAc / hexane as eluent to achieve the title compound as an off white solid (1.12 g, 5.6 mmol).

Step 2) 1- [2- (2-Chloroethoxy) -6-nitrophenylmethanesulfonyl] naphthalene A mixture of 1- (2-chloro-ethoxy) -3-nitrobenzene (1.12 g, 5.6 mmol) and 1-chloromethane-sulfonyl-naphthalene (1.6 g, 6.72 mmol) is stirred in THF (50 mL) at -78 ° C. C, in iHi a bottom vessel rounded under nitrogen. A solution of 1 M potassium t-butoxide (16.8 mL, 16.8 mmol) is added dropwise over a period of half an hour. At the temperature it is allowed to rise to -40 ° C, and the reaction mixture is stirred at this temperature for 5 hours. The reaction mixture is poured into cold 2N HCl, extracted with EtOAc, dried over Na2SO4, and concentrated in vacuo. The compound is purified by normal phase HPLC using 40% EtOAc / hexane as eluant to afford the title compound as an off white solid (0.9 g, 2.24 mmol), and 1- [4 (2-chloro-ethoxy) - 2-Nitro-phenylr-methanesulfonyl] -naphthalene (0.79 g, 2.1 mmol).

Step 3) 3- (2-Chloro-ethoxy) -2- (naphthalene-1-sulfonylmethyl) -phenyl amine A mixture of 1- [2- (2-Chloro-ethoxy) -6-nitro-phenylmethanesulfonyl] -naphthalene (0.9 g, 2.24 mmol) and 10% Pd / C in THF (10 mL), methanol (10 mL), and Formic acid (2mL) is hydrogenated in a Parr hydrogenation bottle (250 mL) at 40 lb / in2 for 20 hours. The mixture is filtered through Celitef and the filtrate is diluted with EtOAc, washed with water, dried over Na 2 SO 4. and concentrated under vacuum to achieve the title compound as an off white solid (0.78 g, 2.1 mmol).

Step 4) 4- (2-Chloro-ethoxy) -3- (naphthalene-1-sulfonyl) -1H-indazole A mixture of 3- (2-chloro-ethoxy) -2- (naphthalene-1-sulfonylmethyl) -phenyl amine (0.78 g, 2.1 mmol) in THF (5 mL), 4M HCl (10 mL) is stirred in a bottom vessel rounded, under nitrogen at 3 ° C. A solution of sodium nitrite (0.15 g, 2.2 mmol) in H 2 O (1 mL) is added dropwise. The reaction mixture was poured into a cold solution of saturated sodium bicarbonate (100mL) and extracted with EtOAc. The compound is dried over Na2SO4, and concentrated in vacuo to afford the title compound as an off white solid (0.74 g, 1.93 mmol). P; '"• Stage 5) 4- (2-Azido-toxy) -3- (naphthalene-1-sulfonyl) -1 H-indazole A mixture of 4- (2-chloro-ethoxy) -3- (naphthalene-1-sulfonyl) -1H-indazole (0.2 g, 0.5 mmol) and sodium azide (0.04 g, 0.62 mmol) in DMSO (2 mL) ) is stirred together in a rounded bottom vessel under nitrogen at 90 ° C for 3 hours. The reaction mixture is cooled to room temperature, diluted with water, extracted with EtOAc, washed with water (2x), saline (1x), dried over Na2SO, and concentrated under vacuum. The crude compound is purified by normal phase HPLC using 40% EtOAc / hexane as eluent to achieve the title compound as an off white solid (0.17 g, 0.45 mmol).

Stage 6) 2-. { [3-1-Naphthylsulfonyl) -1 H -i? Dazol-4-yl] oxy} Ethanamine: A mixture of 4- (2-acid-ethoxy) -3- (naphthalene-1-sulfonyl) -1 H-indazole (0.17 g, 0.45 mmol) and 10% Pd / C in THF (2mL), and methanol (8mL) is hydrogenated in a Parr hydrogenation bottle (250mL) at 52 lb / in2 for 2 hours. The mixture is filtered through Celite, and the filtrate is concentrated under vacuum. The crude product is recrystallized from CH2Cl2 / hexane, Add 1M HCl in ether (0.4 mL, 0.4 mmol), then dry to obtain the title compound as an off white HCl salt (0.15 g, 0.4 mmol), MS: (ES +) 369 [M + H] + Example 142 N-Methyl-2- hydrochloride. { [3-naphthylsulfonyl) -1 H -indazol-4-yl] oxy} Ethanamine A mixture of 4- (2-chloro-ethoxy) -3- (naphthalene-1-sulfonyl-1H-indazole (0.075 g, 0.19 mmol) and methylamine (0.28 mL, 0.56 mmol) in DMSO (1 mL) were added. The mixture is cooled to room temperature, diluted with water, extracted with EtOAc, washed with water (2x), saline (1x), dried over Na2SO4, and stirred under nitrogen at 100 ° C for 4 hours. The compound is purified by flash chromatography using CH3OH / EtOAc as eluent. The purified compound is dissolved in methanol, 1M HCl in ether (0.2 mL, 0.2 mmol) is added, then dried to obtain the compound of the title compound. title as an HCl salt (0.07 g, 0.19 mmol), MS: (ES +) 417 [M + H] + ? > Examples 143-145 Using essentially the same procedure described in Example 142, and using the desired amine, the compounds shown in Table IX were obtained and identified by HPLC and mass spectral analysis.

TABLE IX Ex. No. R5 R6 [M + H] + 143 CH3 CH3 397 144 -CH2CH2CH2CH2CH2- 437 145 -CH2CH2CH2CH2- 423 Example 146 2- . { [3- (1-Naphthylsulfonyl) -1H-indazol-6-yl] oxy} Ethanamine Step 1) 5- (2-Chloro-ethoxy-2- (naphthalene-1-sulfonylmethyl) -phenylamine A mixture of 1- [4- (2-chloro-ethoxy) -2-nitro-phenylmethanesulfonyl] -naphthalene (0.79 g, 2.1 mmol) and 10% Pd / C in THF (10 mL), methanol (10 mL), and Formic acid (2mL) is hydrogenated in a Parr hydrogenation bottle (250 mL) at 40 lb / in2 for 20 hours. The mixture is filtered through Celite, and the filtrate is diluted with EtOAc, washed with water, dried over Na2SO4, and concentrated under vacuum to achieve the title compound as an off white solid (0.74 g, 1.99 mmol). .

Step 2) 6- (2-Chloro-ethoxy) -3- (naphthalene-1-sulfonyl) -1 H-indazole A mixture of 5- (2-chloro-ethoxy) -2- (naphthalene-1-sulfonylmethyl) -phenyl amine (0.74 g, 1.99 mmol) in THF (5mL), and, 4M HCl (10mL) is stirred in a vessel with a rounded bottom, under nitrogen, at 3 ° C. A solution of sodium nitrite (0.14 g, 2.08 mmol) in H2O (1 mL) is added dropwise. The reaction mixture was poured into a cold solution of saturated sodium bicarbonate (100mL) and extracted with EtOAc. The compound is dried over Na2SO4, and concentrated in vacuo to afford the title compound as an off white solid (0.74 g, 1.93 mmol).

Step 3) 6- (2-acid-ethoxy) -3- (naphthalene-1-sulfonyl) -1H-indazole A mixture of 6- (2-chloro-ethoxy) -3- (naphthalene-1-sulfonyl) -1H-indazole (0.19 g, 0.5 mmol) and sodium azide (0.04 g, 0.62 mmol) in DMSO (2 mL) ) is stirred together in a rounded bottom vessel under nitrogen at 90 ° C for 3 hours. The reaction mixture is cooled to room temperature, diluted with water, extracted with EtOAc, washed with water (2x), saline, 1x), dried over Na 2 SO 4, and concentrated in vacuo. The crude compound is purified by normal phase HPLC using 40% EtOAc / hexane as eluent to achieve the title compound as an off white solid (0.17 g, 0.45 mmol).

Step 4) 2 - ([3- (1-Naphthylsulfonyl) -1H-indazol-6-yl] oxy} ethanamine A mixture of 6- (2-acid-ethoxy) -3- (naphthalene-1-sulfonyl) -1H-indazole (0.17 g, 0.45 mmol) and 10% Pd / C in THF (2 mL), and methanol ( 8mL) is hydrogenated in a Parr hydrogenation bottle (250 mL) at 52 lb / in2 for 2 hours. The mixture is filtered through Celite, and the filtrate is concentrated under vacuum. The crude product is recrystallized from CH2Cl2 / hexane, 1M HCl in ether (0.4 mL, 0.4 mmol) is added, then dried, to achieve the title compound as an off white HCl salt (0.15 g, 0.4 mmol), MS : (ES +) 368 [M + H] +. * " Example 147 N-Methyl-2- hydrochloride. { [3- (1-naphthylsulfonyl) -1 H -indazol-6-yl] oxy} Ethanamine A mixture of 6- (2-chloro-ethoxy) -3- (naphthalene-1-sulfonyl) -1H-indazole (0.075 g, 0.19 mmole) and methylamine (0.28 mL, 0.56 mmole) in DMSO (1 mL) stir under nitrogen at 100 ° C for 4 hours. The mixture is cooled to room temperature, diluted with water, extracted with EtOAc, washed with water (2x), saline (1x), dried over Na2SO4? and concentrate under vacuum. The compound is purified by flash chromatography using CH3OH / 5% EtOAc as eluent. The purified compound is dissolved in methanol, 1 M HCl in ether (0.2 mL, 0.2 mmol) is added, then dried, to obtain the title compound as an HCl salt (0.07 g, 0.19 mmol), MS: (ES +) 381 [M + H] + Example 148-150 Using essentially the same procedure described in Example 147, and using the desired amine, the compounds shown in Table X were obtained and identified by HPLC and mass spectral analysis.

TABLE X Ex. No. R5 R6 [M + H] + 148 CH3 CH, 396 149 -CH2CH2CH2CH CH2- 436 150 -CH2CH2CH2CH2- 422 Example 151 N- [2- (Dimethylamino) ethyl] -3- (1-naphthylsulfonyl) -1H-indazole-5-carboxamide. 6) KOf-Bu Stage 1) methyl ester of 3- (Naphthalene-1-sulfonylmethyl) -4-nitro-benzoic acid A mixture of methyl ester of 4-nitro-benzoic acid (0.8 g, 4.4 mmol) and 1-chloromethane-sulfonyl-naphthalene (1.3 g, 5.3 mmol) is stirred in THF (50 mL) at -78 ° C in a vessel of bottom rounded under nitrogen. A solution of 1 M potassium t-butoxide is added dropwise (13 mL, 13 mmol) over a period of half an hour. At the temperature it is allowed to rise to -40 ° C, and the reaction mixture is stirred at this temperature for 5 hours. The reaction mixture is poured into cold 2N HCl, extracted with EtOAc, dried over Na2SO4? and concentrate under vacuum. The compound is purified by normal phase HPLC using 40% EtOAc / hexane as eluent to achieve the title compound as an off white solid (1.5 g, 3.9 mmol).

Stage 2) 4-Amino-3- (naphthalene-1-sulfonylmethyl) benzoic acid methyl ester A mixture of methyl ester of 3- (naphthalene-1-sulfonylmethyl) -4-nitro-benzoic acid (1.5 g, 3.9 mmol) and 10% Pd / C in THF (10mL), and methanol (20mL) is hydrogenated in a Parr (250mL) hydrogenation bottle at 52 lb / in2 overnight. The mixture is filtered through Celite, and the filtrate is concentrated under vacuum to achieve the title compound as an off white solid (0.9 g, 2.5 mmol).

Step 3) 3- (Naphthalene-1-sulfonyl) -1H-indazole-5-carboxylic acid methyl ester A mixture of 4-amino-3- (naphthalene-1-sulfonylmethyl) benzoic acid methyl ester (0.9 g, 2.5 mmol) in THF (5mL), and 4M HCl (10mL) is stirred in a rounded bottom vessel, under nitrogen, at 3 ° C. A solution of sodium nitrite (0.18 g, 2.62 mmol) in H 2 O (1 mL ) It is added drop by drop. The reaction mixture was poured into a cold solution of saturated sodium bicarbonate (100 mL) and extracted with EtOAc. The compound is dried over Na2SO, and concentrated under vacuum to obtain the title compound as an off white solid (0.82 g, 2.25 mmol).

Step 4) 1- (3-Chlorobenzyl) -2- (naphthalene-1-sulfonyl) -1H-indazole-5-carboxylic acid methyl ester A mixture of 3- (naphthalene-1-sulfonyl) -1H-indazole-5-carboxylic acid methyl ester (0.82 g, 2.25 mmol), -3-chlorobenzyl bromide (0.34 mL, 2.7 mmol), and cesium carbonate (0.87 g, 2.7 mmol) in DMF (5 mL) is stirred together in a rounded bottom flask at room temperature for 30 minutes. The reaction mixture is diluted with H2O, extracted with EtOAc, washed with water (2x), saline (1x), dried over Na2SO, and concentrated under vacuum. The crude product is purified by HPLC using 30% EtOAc / hexane as eluent to afford the title compound as an off white solid (1.01 g, 2.07 mmol).

Step 5) 1- (3-Chloro-benzyl) -3- (naphthalene-1-sulfonyl) -1H-indazole-5-carboxylic acid (2-dimethyl-amino-ethyl) -amide To a solution of dimethyl ethylene diamine (0.02 mL, 0.2 mmol) in THF (2 mL), cooled to 0 ° C. LDA (0.15 mL, 0.3 mmol) is added dropwise. To this mixture is then added a solution of 1- (3-chloro-benzyl) -2- (naphthalene-1-sulfonyl) -1H-indazole-5-carboxylic acid methyl ester (0.05 g, 0.1 mmol) in THF (1 mL).

The mixture is allowed to slowly warm up to room temperature. The reaction mixture is diluted with water, extracted with EtOAc (1x), CH2Cl2 (1X); the organics were washed with water (1x), and concentrated under vacuum to obtain the title compound (0.3 g, 0.04 mmol).

Step 6) N- [2- (Dimethylamino) ethyl] -3- (1-naphthylsulfonyl) -1H-indazole-5-carboxamide A mixture of 1- (3-dimethyl-amino-ethyl) -amide -chloro-benzyl) -3- (naphthalene-1-sulfonyl) -1H-indazole-5-carboxylic acid (0.3 g, 0.04 mmol), DMSO (1 mL) and t-BuOH (0.2 mL) is stirred at room temperature in a rounded bottom container under an oxygen atmosphere. A 1 * solution of potassium t-butoxide (0.05 mL, 0.05 mmol) is added dropwise and the reaction mixture is stirred for 30 min. The reaction mixture is quenched with saturated ammonium chloride, extracted with EtOAc, dried over Na2SO4 and concentrated in vacuo. The crude compound is purified by reverse phase chromatography to achieve the title compound, MS: (ES +) 423 [M + H] + Example 152 3- (1-Naphthylsulfonyl) -N- (2-piperidin-1-ylethyl) -1 H -indazol-5-carboxamide Using essentially the same procedure described in Example 151 and employing 1- (2-aminoethyl) piperidine in step 5, the title compound was obtained and identified by HPLC and mass spectral analysis, MS: (ES +) 423 [M + H] + Example 153 N, N, N'-Trime Step 1) 2- [3- (Naphthalene-1-sulfonylmethyl) -4-nitrophenyl] - [1,3] dioxolane A mixture of 2- (4-Nitro-phenyl) - [1, 3] dioxolane (1.85 g, 9.5 mmol) and 1-chloromethane-sulfonyl-naphthalene (2.74 g, 11.4 mmol) is stirred in THF (50 mL) at - 78 ° C, in a bottom vessel rounded under nitrogen. A solution of 1M potassium t-butoxide is added dropwise (19 mL, 19 mmol) over a period of half an hour. At the temperature it is allowed to rise to -40 ° C, and the reaction mixture is stirred at this temperature for 5 hours. The reaction mixture is poured into cold 2N HCl, extracted with EtOAc, dried over Na2SO4, and concentrated in vacuo. The compound is purified by normal phase HPLC using 40% EtOAc / hexane as eluent to achieve the title compound as an off white solid (3.03 g, 7.6 mmol).

Stage 2) 3- (Naphthalene-1-sulfonylmethyl) -4-nitrobenzaldehyde A mixture of 2- [3- (naphthalene-1-sulfonylmethyl) -4-nitro-phenyl] - [1, 3] dioxolane (3.03 g, 7.6 mmol), and 2N HCL (4mL, 8 mmol) in THF ( 30 ml) is stirred at 40 ° C for 4 hours. The reaction mixture is cooled to room temperature, diluted with water, extracted with EtOAc, dried over Na2SO, and concentrated under vacuum to yield the title compound (2.56 g, 7.22 mmol).

Stage 3) 4-amino-3- (naphthalene-1-sulfonylmethyl) benzaldehyde A mixture of 3- (naphthalene-1-sulfonylmethyl) -4-nitro-benzaldehyde (2.5 g, 7.22 mmol) and Pd / 10% in THF (10 m!), ^ Methanol ((20 mL) is hydrogenated in a Parr hydrogenation bottle (250 mL) at 52 psi overnight The mixture is stirred overnight through the Celite, and the filtrate is concentrated under vacuum to achieve the title compound as a solid Off white (2.4 g, 6.85 mmol) Step 4) 3- (naphthalene-1-sulfonyl) -1 H -indazol-5-carbaldehyde A mixture of 4-amino-3- (naphthalene-1-sulfonylmethyl) -benzaldehyde (2.4 g, 6.85 mmol) in THF (10 mL) and 4M HCL (20 mL) is stirred in a bottom-rounded vessel at 3 ° C. . A solution of sodium nitrate (0.49 g, 7.19 mmol in H2O (2 mL) was added.The reaction mixture was poured into a cold solution of saturated sodium bicarbonate (100 mL) and extracted with EtOAc. Na2SO, and concentrated in vacuo to achieve the title compound as an off white solid (1.84 g, 5.5 mmol).

Step 5) N, N'-Trimethyl-N'-. { [3- (1-amphiphysulfonyl) -1H-indazol-5-yl] methyl} ethane-1,2-diamine 3- (Naphthalene-1-sulfonyl) -1 H -indazol-5-carbaldehyde (0.17 g, 0.5 mmol), trimethyl ethylene diamine (0.6 mmol) and sodium triacetoxyborohydride (0.7 mmol) in dichloroethane (5 mL) is stirred at room temperature for 24 hours. After completion, the solvent is removed in vacuo, the crude material is dispersed in water and the pH is brought to 3.4. The solid material is filtered and washed with cold water to achieve after drying the white material as a free base. The latter is converted to the hydrochloride salt by dissolution in methanol, followed by treatment with the excess 2N HCl and evacuation of the volatiles in vacuo to achieve the title compound hydrochloride salt, mp; 200 ° C; MS (APPI) 423 [M + H]. * - Example 154 (3S) -N- hydrochloride. { [3- (1-N-phenylsulfoni) -1 H -indazol-5-yl] methyl} pirolidin-3-amine Using essentially the same procedure described in example 153, step 5, and using S (-) - pyrolidin-3-ylamine protected with Boc, followed by removal of the Boc group by TFA in methylene chloride and treatment of the free base with HCL 2N, the title product was obtained, mp; 200 ° C; MS (ES) (M + H) + 407.1; MS (ES) (M + H + Na) + 429.1.

Example 155 N.- { [3- (1-N-phenylsulfonyl) -1 H -indazol-5-yl] methyl} ethane-1, 2-diamine * .1 * 3- (Naphthalene-1-sulfonyl) -1H-indazole-5-carbaldehyde (0.3 mmol) is stirred for 24 hours with excess ethylene diamine (1 mmol) in methanol. Sodium borohydride is added and stirring is continued for 24 hours. After being made solid, the volatiles were removed in vacuo, the crude material is diluted with cold water, acidified to pH 3.4, filtered, washed on a filter with cold water and dried to last the white material as a free base. . The latter is converted to the hydrochloride salt by dissolving in methanol, followed by treatment with excess 2N HCL and evacuation of the volatiles in vacuo to achieve the title compound, mp; 200 ° C; MS (ES +) 381 [M + H] +.

Example 156 N, N-Dimethyl-2-. { [3- (1-naphthylsulfonyl) -1H-indazol-5-yl] methoxy} Ethanamine 5a) KOí-Bu 5b) HCl Step 1) 1- (3-Chloro-benzyl) -3-naphthalene-1-sulfonyl) -1H-indazole-5-carbaldehyde A mixture of 3- (1-naphthylsulfonyl) -1 H-indazole-5-carbaldehyde (0.17 g, 0.5 mmol), 3-chlorobenzyl bromide (0.07 mL, 0.6 mmol), and cesium carbonate (0.19 g, 0.6 mmol) DMF (5 mL) is stirred together in a bottom-rounded container at room temperature for 30 minutes. The reaction mixture is diluted with H2O, extracted with EtOAc, washed with water (2x), saline (1x), dried over Na2SO4, and concentrated under vacuum. The crude product is purified by normal phase HPLC using 30% EtOAc / hexane as eluent to achieve the title compound as an off white solid (0.18 g, 0.4 mmol).

Step 2) [1- (3-chlorobenzyl) -3- (1-naphthylsulfonyl) -1 H -medazol-5-yl] -methanol. 1- (3-Chloro-benzyl) -3- (naphthalene-1-sulfonyl) -1 H -indazol-5-carbaldehyde (0.18 g, 0.4 mmol) is dissolved in THF and treated under nitrogen with excess borohydride. sodium (0.2 mmol). After 1 hour the reaction mixture is diluted with water and the product extracted with methylene chloride to achieve after evaporation of the solvent the title compound as? a colorless solid (0.18 g, 0.4 mmol).

Step 3) 1 - (3-chlorobenzyl) -5- (2-chloroethoxymethyl) -3- (1 -naphthylsulfoni) -1H-indazole. [1- (3-Chlorobenzyl) -3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] -methanol (0.18 g, 0.4 mmol) and diisopropyl ethyl amine (1 mmol) in mutilen chloride were treated -20 ° C with trifluoromethanesulfonic anhydride (0.14 g, 0.5 mmol). After stirring for 30 min. An excess of 2-chloroethanol (2 mmol) is added and the mixture is stirred for an additional 2 hours at -20 ° C at room temperature for 12 hours. The reaction mixture is diluted with water, extracted with ethyl acetate and after evaporation of the solvent, chromatography on silica gel using 40% ethyl acetate / hexane as an eluent to achieve the white material (0.08 g, 0.16 mmol). ) Step 4) [2- [1- (3-Chlorobenzyl) -3- (naphthalene-1-sulfonyl) -1H-indazol-5-ylmethoxy] ethyl} dimethylamine. , N0, A mixture of 1- (3-chlorobenzyl) -5- (2-chloroethoxymethyl) -3- (1-naphthylsulfoni) -1H-indazole (0.08 g, 0.16 mmol) and dimethylamine (0.28 mL, 0.56 mmol) in DMSO ( 1 mL) is stirred under nitrogen at 100 ° C for 4 hours. The mixture was cooled to room temperature, diluted with water, extracted with EtOAc, washed with water (2x), saline (1x), dried over Na2SO4, and concentrated under vacuum. The compound is purified by flash chromatography using CH30H / 5% EtOAc as diluent to achieve the title I compound (0.08 g, 0.15 mmol).

Step 5) N, N-Dimethyl -2-. { [3- (1-naphthalenesulfonyl) -1H-indazol-5-yl] methoxy} Ethanamine A mix of . { 2 - ['1- (3-chloro-benzyl) -3- (naphthalene-1-sulfonyl) -1 H -indazol-5-ylmethoxy] -ethyl} dimethyl-amine (0.08 g, 0.15 mmol) DMSO (1 mL) and t-BuOH (0.2 mL) is stirred at room temperature in a bottom-rounded vessel under an oxygen atmosphere. A solution of potassium t-butoxide (0.05 ml, 0.05 mmol) is added dropwise and the reaction mixture is stirred for 30 min. The reaction mixture is quenched with saturated ammonium chloride, extracted with EtOAc, dried over Na2SO, and concentrated in vacuo. The crude compound is converted to the HCL salt as previously described to achieve the title compound, PF > 200 ° C; MS (ES +) 410 [M + H] +.

Example 157 N1- [3- (Naphthalene-1-sulfonyl) -1H-indazol-5-yl] -ethane-1,2-diamine dihydrochloride Stage 1 Iodide of 3-iodo-5-nitro-1 H-indazole (26.46 g, 104.27 mmol) and potassium hydroxide beads (11.70 g, 208.54 mmol) were successively added in a DMF solution (104 mL) of 5-nitroindazole ( 8.50 G, 52.13 mmol) at room temperature and stirred for 4 days. The reaction mixture was then poured into NaHSO3 solution (11.06 g, in 200 mL of water). The brown color disappeared, and a yellow precipitate formed which is filtered and washed with water and dried in vacuo to give the title compound as a yellow solid (14.74 g, 98% yield). Ms (ES +) m / e 290 (MH +).

P * Stage 2 3- (Naphthalene-1-ildsulfanyl) -5-nitro-1 H-indazole. A mixture of 3-iodo-5-nitro-1 H-indazole (10.00 g, 34.60 mmol), 1-naphthylenethiol (5.54 g, 34.60 mmol), Cul (0.659 g, 3.46 mmol), ethylene glycol (4.30 g, 69.20 mmol) in isopropanol (49.40 mL) is heated at 90 ° C under nitrogen overnight, cooled, diluted with 30% MeOH in CH2Cl2, and passed through a pad of silica gel. The solution is concentrated in vacuo and purified by chromatography to 1% MeOH in CH 2 Cl 2 to give the title compound (5.5 g, 49%). MS (ES +) m / e 322 (MH +).

Stage 3 3- (Naphthalene-1-sulfonyl) -1 H -indazol-5-ylamine. To a mixture of 3- (naphthalen-1-ylsulfanyl) -5-nitro-1 H-indazole (5.50 g, 17.11 mmol) and 3-chloroperoxybenzoic acid (17.91 g, 103.80 mmol) in CHCl3 (115 mL) is stirred at Room temperature for 4 h, diluted with EtOAc, washed with Na2SO3 solution, water, saline, dried over Na2SO4, and concentrated in vacuo to achieve the crude intermediate which was carried out directly during the next reaction step without additional purification. The mixture of crude sulfone intermediate, tin moss (15.79 g, 133.01 mmol) in MeOH and concentrated hydrochloric acid is heated to 60 ° C, diluted with CH2Cl2, and neutralized to a base with NaOH or a solution of NA2CO3. The aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated in vacuo followed by purification of chromatography to give the title compound (2.50 g, 45% total yield). MS (ES +) m / e 324 (MH +).

Stage 4 N1 - [3- (naphthalene-1-sulfonyl) -1 H -indazol-5-yl] -ethane-1,2-diamine dihydrochloride.

A mixture of 3- (nasphthalene-1-sulfonyl) -1H-indazol-5-ylamine hydrochloride (334 mg, 0.93 mmol), 2-oxazolidone (81 mg, 0.93 mmol), and diethylene glycol monomethylether (0.16 mL) were added. heat at 170 ° C overnight, dilute with MeOH, and purify by reverse phase HPLC followed by conversion to HCl salt by treatment with HCl solution to give the title compound as a white solid (86 mg , 21% yield). MS (ES +) m / e 367 (MH +).

Example 158 e (3¡ 3-Amino-N- [3- (naphthalene-1-sulfonyl) -1H-indazol-5-yl] -propionamide hydrochloride. A mixture of 3- (naphthalene-1-sulfonyl) -1 H -indazol-5-ylamine (500 mg, 1.55 mmol), Nt-Boc-alanine (381 mg, 2.01 mmol), hydrochloride of 1- [3- ( dimethylamino) propyl] -3-ethylcarbodiimide (386 mg, 2.01 mmol) in CH3CN is stirred at room temperature overnight and concentrated to dryness. The resulting residue is subjected to TFA, concentrated, and purified by reverse phase HPLC followed by treatment with HCl solution to deliver the title compound as a white solid (180 mg, 24% yield) MS (ES +) m / e 395 (MH +).

Example 159 Stage 1 acid tert-butyl ester. { 1- [3- (naphthalene-1-sulfonyl) -1H-indazol-5-ylcarbamoyl] -ethyl} -carbámico A mixture of 3- (naphthalene-1-sulfonyl) -1H-indazol-5-ylamine (500 mg, 1.55 mmol), Nt-Boc-alanine (381 mg, 2.01 mmol), 1- [3- (dimethylamino ) propyl)] - 3-ethylcarbodiimide (386 mg, 2.01 mmol) in CH3CN is stirred at room temperature overnight, concentrated, and purified by chromatography with 3% MeOH in CH2Cl2 to provide the title compound (110 mg, 48%), characterized by NMR and mass spectral analysis.

Stage 2 N1 - [3- (naphthalene-1-sulfonyl) -1 H -indazol-5-yl] -propane-1,2-diamine hydrochloride Pert-butyl acid ester. { 1-7 (naphthalene-1 + sulfonyl) -1 H -ndazol-5-lcarcarnoyl] -ethyl} -carbamic acid (120 mg, 0.37 mmol) was subjected to TFA at room temperature for 2 h and concentrated to dryness. The resulting residue is heated with BH3 in THF (1 M, 4.5 mL) at reflux overnight. To the mixture HCL (6 M, 1 mL) is added slowly. The resulting solution is heated at 80 ° C for 20 min, concentrated, and purified by reverse phase HPLC followed by treatment with HCl solution to deliver the title compound (35 mg, 38%). MS (ES +) m / e 381 (MH +).

Example 160 (S) -3-Methyl-N 1 - [3- (naphthalene-1-sulfonyl) -1 H -i ndazol-4-yl] -butane-1,2-diamine dihydrochloride.

Using essentially the same procedure described in Example 159 and using (S) -t-Boc-Valine as a starting material, the title compound was obtained, MS (ES +) m / e 409 (MH +).

Example 161 N1- [3- (naphthalene-1-sulfonyl) -1H-indazol-7-yl] -ethane-1,2-diamine dihydrochloride Using essentially the same procedure described in example 157 (step 4) and using product from example 162 (step 1) as the starting material, the title compound was obtained, MS (ES +) m / e 367 (MH +).

Example 162 3-Dimethylamino-N- [3- (naphthalene-1-sulfonyl) -1 H -indazol-7-yl] -propionamide hydrochloride.

Stage 1 3- (naphthalene-1-sulphoryl) -1H-indazol-7-ylamine the title compound is prepared according to the procedure described in example 157 (steps 1-3) and using 7-nitro-indazole as the material of departure.

Stage 2 3-Dimethylamino-N- [3- (naphthalene-1-sulfonyl) -1H-indazol-7-yl] -propionamide dihydrochloride. The title compound is prepared in a manner similar to that described in example 158 and using the appropriate starting material. MS (ES +) m / e 423 (M H +).

Example 163 N- [3- (naphthalene-1-sulfonyl) -1H-indazol-7-yl] -3-piperidin-1-yl-propionamide hydrochloride. The title compound is prepared in a manner similar to that described in example 158 and using the appropriate starting material. MS (ES +) m / e 463 (MH +).

Example 164 3-amino-N- (3-) naphthalene-1-sulfonyl) -1H-indazol-7-yl] -propionamide hydrochloride. The title compound is prepared in a manner similar to that described in example 158 and using the appropriate starting material. MS (ES +) m / e 395 (MH +).

- Example 165 3-amino-N- [3- (naphthalene-1-sulfonyl) -1H-indazol-6-yl] -3-propionamide hydrochloride.

Using essentially the same procedure described in Example 158 and using 6-amino-3 (1-naphthisulfonyl) -1H-indazole as the starting material, the title compound was obtained, MS (ES +) m / e 395 (MH +) .

Example 166 3-Diethylamino-N- [3- (naphthalene-1-sulfonyl) -1H-indazol-7-yl] -propionamide hydrochloride.

Using essentially the same procedure described in Example 158 and employing 7-amino-3- (1-naphthisulfonyl) -1H-indazole and the desired amino acid as the starting materials, the title compound, MS (ES +) m was obtained. / e 451 (MH +) ..

Example 167 N- [3- (naphthalene-1-sulfonyl) -1H-indazol-6-yl] -3-piperidin-1-yl-propionamide hydrochloride.

Using essentially the same procedure described in Example 158 and using 6-amino-3- (1-naphthysulfonyl, il) -1H-indazole and the desired amino acid as starting materials, the was obtained. compound of title, MS (ES +) m / e 463 (MH +).

Example 168 3-Dimethylamino-N- [3- (naphthalene-1-sulfonyl) -1 H -indazol-6-yl] -propionamide hydrochloride.

Using essentially the same procedure described in Example 158 and employing e-amino-S-O-naphthisulfon ^ -l H-indazole and. { and the desired amino acid as the starting materials, the title compound was obtained, MS (ES +) m / e 423 (MH +).

Example 169 3-Diethylamino-N- [3- (naphthalene-1-sulfonyl) -1H-indazol-6-yl] -propionamide hydrochloride.

Using essentially the same procedure described in Example 158 and employing 6-amino-3- (1-naphthysulfhenyl) -1H-indazole and the desired amino acid as the starting materials, the title compound, MS (ES +) m was obtained. / e 451 (MH +).

Example 170 N1- [3- (naphthalene-1-sulfonyl) -1H-indazol-6-yl] -ethane-1,2-diamine dihydrochloride.

Using essentially the same procedure described in Example 158 and employing 6-amino-3- (1-naphthisulfonjJ) -1H-indazole as the starting material, the title compound was obtained, MS (ES +)? / e 367 (MH +).

Example 171 N, N-Dimethyl-N-. { 2- [3- (phenylsulfonyl) -1 H -indazol-7-yl] ethyl} amine Stage 1 CICH2S02Ph 3-Bromo-2-nitrobenzyl phenyl sulfone. To a stirred solution of 1-bromo-2-nitrobenzene (10. 1 g, 50 mmol) and chloromethylphenylsulfone (9.5 g, 50 mmol) in a dry THF (100 mL) at ~ 65 ° C under nitrogen KOtBu 1.0 M is added in THF (110 mL, 110 mmol). The deep purple reaction is allowed to warm to 0 ° C for 1.5 hours and then treated with glacial acetic acid (8 Ml). The reaction is diluted with water (200 mL) and saturated aqueous NaHCO3 (200 mL), and then extracted with CH2Cl2 (2 X 400 mL). The extracts were dried (MgSO4) and concentrated in vacuo as a light orange solid. Trituration with ethyl acetate and hexane affords the title compound as a pale yellow solid (13 g, 73%). pF: 138-141 ° C. MS (ES-): 354 (M-H) Stage 2 6-Bromo-2 - [(phenylsulfonyl) methyl] aniline. The catalytic hydrogenation of 6-bromo-2-nitrobenzyl phenyl sulfone (0.36 g, 1 mmol) in the presence of platinum on disulfurized carbon and hydrogen (45 psi) in ethyl alcohol (40 mL) for 1 hour gives a reaction mixture. The reaction mixture was filtered through celite and concentrated in vacuo to give the title compound as a light brown solid (0.32 g, 99%). pF: 174-177 ° C. MS (ES +) 326 (M + H).

Stage 3 7-Bromo-3- (phenylsulfonyl) -1 H -indazole. A solution of NaNO2 (1.91 g, 13.35 mmol) in H2O (10 mL) is added to a solution of 6-bromo-2 - [(phenylsulfonyl) methyl] aniline (2.9 g, 8.9 mmol) in 70 mL of 4 NHCl at about 5 ° C. The reaction mixture is stirred for 30 minutes at 0 ° C, and neutralized with 10 ° of NaOH. The resulting solid was collected by filtration, washed with water and purified by flash chromatography (ethyl acetate / petroleum ether 25%) to obtain the title compound as a pink solid (2.27 g, 91%) MP: 173 - 175 ° C, MS (ES-) 335 (MH) Stage 4 3- (phenylsulfonyl) -7-vinyl-1 H-indazole. A mixture of 7-bromo-3- (phenylsulfonyl) -1 H-indazole (2.72 g, 8.07 mmol) and dichlorobis (tri-o-tolylphosphine) -palladium (II) (0.94 g, 1.2 mmol) were dissolved in toluene ( 220 mL) and stirred for 10 minutes at room temperature under nitrogen atmosphere. Tributyl (vinyl) tin (3.3 mg, 10.55 mmol) is added and the mixture is refluxed for 15 minutes or until it turns black. The mixture is cooled to room temperature, diluted with ethyl acetate (150 mL), 1 M KF (25 mL) and stirred for 12 hours. The resulting tin salt precipitate is removed by suction filtration and the organic layer is washed with water (100 mL), then saline and dried over MgSO, painted and concentrated in vacuo. Purification by flash chromatography (ethyl acetate / ether oil 40%) and a title compound as a light yellow solid (2.02 g, 88%? PF: 129-130 ° C MS (ES +): 285 ( M + H) Stage 5 2- [3- (phenylsulfonyl) -1 h -indazol-7-yl] ethanol. To a solution of 3- (phenylsulfonyl) -7-vinyl-iH-indazole (2.0 g, 7.04 mmol) in THF (40 mL) at 0 ° C BH3-THF is added dropwise (15 mL of a THF solution). 1 M, 15 mmol). The solution is stirred for 3 hours at 0 ° C, and Se J?; s 3 slowly add H2O (20 mL). This mixture is added 10% NaOH (17 mL), 30% H 2 O 2 (15 mL) and the mixture is stirred vigorously at room temperature overnight. The mixture is partitioned between ethyl acetate and H2O and the aqueous layer extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with saline, dried (MgSO), filtered and concentrated under reduced pressure). Chromatography of silica gel (ethyl acetate / dichloromethane 50%) and the title compound as a white solid (1.42 g, 66%). pF: 137-138 ° C. MS (ES +): 303 (M + H) Stage 6 2- [3- (phenylsulfonyl) -1 H -indazol-7-y?] Ethyl 4-methylbenzenesulfonate. To a solution of 2- [3- (phenylsulfonyl) -1H-7-yl] ethanol (0.64 g, 2.12 mmol) in anhydrous dichloromethane (30 mL) at 0 ° C Pyridine (0.43 mL) and toluenesulfonyl fluoride ( 0.475 g, 2.5 mmol). The solution is stirred for 12 hours at room temperature. The mixture was concentrated in vacuo and ethyl acetate (30 mL) was taken. The organic layer is washed with 2 M HCl, (2 x 25 mL), saline, dried (MgSO4), filtered and concentrated under reduced pressure. Chromatography of silica gel (ethyl acetate / petroleum ether) gave the title compound as a white foam. (0.9 g ", 93%) .pF: 61-64 ° C. MS (ES-): 455 (M-H) Stage 7 N, N-Dimethyl-N- hydrochloride. { 2- [3- (phenylsulfonyl) -1 H -indazol-7-yl] ethyl} amine. A solution of 2- [3- (phenylsulfonyl) -1H-indazol-7-yl] ethyl 4-methylbenzenesulfonate (0.137 g, 0.3 mmol) in anhydrous THF (2 mL) adds an excess of dimethylamine (0.5 mL of THF solution). 2 M, 1 mmol) and heated at 71 ° C for 24 hours. The mixture was partitioned between ethyl acetate and H2O, and the aqueous layer was extracted with ethyl acetate (10 mL). The combined organic layers were washed with 2 M NaOH, (2 x 15 mL), saline, dried (MgSO), filtered and concentrated under reduced pressure. The product was passed through a plug of silica gel eluting with (20% EtOH / 2N ammonium / dichloromethane) to give the title compound as a white solid (0.049 g, 77%). This solid is dissolved in diethylether and treated with 1 N HCl in diethylether (0.12 mL, 0.12 mmol) to achieve a white precipitate isolated by vacuum filtration. pF: 76-80 ° C. MS (ES-): 328 (M-H)? Example 172 N- hydrochloride. { -2- [3- (phenylsulfonyl) -1 H -indazol-7-yl) ethyl} cyclopropanamine Using essentially the same procedure described in Example 171, step 7, and using cyclopropylamine, the title compound was obtained as a white solid, mp 115-117 ° C, MS (M + H) 342. y. ,. { \ Example 173 N-Methyl-N- trifluoroacetate. { 2- [3- (phenylsulfonyl-1 H -indazol-7-yl] ethyl.} Amine Using essentially the same procedure described in example 171, step 7, and employing methylamine and substituting trifluoroacetic acid for HCl, the title compound was obtained as a clear glass, MS: (M + H) 316. > r ',!' Example 174 Hydrochloride. { 2- [3- (phenylsulfonyl) -1H-indazol-7-yl] ethyl} amine Step 1) 7- (2-azidoethyl) -3- (phenylsulfonyl) -1H-indazole A solution of 2- [3- (phenylsulfonyl) -1 H -indazol-7-yl] ethyl 4-methylbenzenesulfonate (0.14 g, 0.3 mmol) in anhydrous DMF (2.5 mb). Sodium azide (0.06 g, 0.9) is added. mmol) and heated at 100 ° C for 6 hours / The mixture was partitioned between ethyl acetate and H 2 O and the aqueous layer was extracted with ethyl acetate (10 mL) The combined organic layers were washed with saline (1 × 15 mL), dried (MgSO), filtered and concentrated under reduced pressure, silica gel chromatography (ethyl acetate / petroleum ether 40%) gave azide as a white solid (0.08 g, 86%). : 105-107 ° C MS (ES-): 326 (MH) Stage 2 Hydrochloride. { 2- [3- (phenylsulfonyl) -1 H -indazol-7-yl] ethyl} amine 7- (2-azidoethyl) -3- (phenylsulfonyl) -1H-indazole (0.08 g, 0.20 mmol) was reduced by catalytic hydrogenation in the presence of palladium on carbon and hydrogen (40 psi) in ethanol (30 mL) during 4 hours. The reaction mixture is filtered through Celite and concentrated in vacuo to give a white solid (0.06 g, 99%). This solid is dissolved in diethyl ether and treated with 1 N H HCl in diethyl ether (0.21 mL, 0.21 mmol) to achieve a tanned precipitate isolated by vacuum filtration. pF: 157-160 ° C. MS (ES-): 300 (M-H).

Example 175 N-Methyl-N-. { 2- [3- (phenylsulfonyl) -1 H -indazol-5-yl] ethyl} Amine Stage 1 Methyl [2- (4-nitrophenyl) ethyl] carbamate. To a stirred solution of [2- (4-nitrophenyl) ethyl] amine (6.06 g, 30 mmol) in CH2Cl2 (75 mL), MeOH (5 mL), and TEA (9.5 mL) at 0 ° C was added chloromethylformate ( 3.39, 36 mmol) dropwise. The reaction mixture is stirred at room temperature for 1 h, concentrated in vacuo, and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water (50 mL) and saline (50 mL). The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure to obtain a yellow solid (6.6 g, 98%). pF: 38 ° C. MS (ES-): 223 (M-H). t \ < £ Stage 2 Methyl [2- (4-nitrophenyl) ethyl] carbamate. To a stirred solution of methyl methyl [2- (4-nitrophenyl) ethyl] carbamate (224 mg, 1 mmol) in THF (2 mL) was added KO'Bu (201 mg, 1.8 mmol) and Mel 8256 mg, 1.8 mmol) sequentially. The reaction mixture was stirred for 12 h at room temperature. The reaction was diluted with water (5 mL), extracted with EtOAc (2 x 15 L). The organics were washed with water and saline, dried (MgSO 4), filtered and concentrated under reduced pressure. Silica gel chromatography (ethyl acetate / 40% petroleum ether) achieves the title compound as a semi-solid (160 mg, 67.2%). MS (ES +): 239 (M + H) +.

Stage 3 Methyl (2- {4-nitro-3- [phenylsulfonyl) methyl] phenyl} ethyl) carbamate. Using substantially the same manner as described in Example 171, Step 1, and employing Methyl (2-. {4-nitrilium, l) ethyl] carbamate methyl (2.47 g, 10.38 mmol), the title compound was obtained co or a white solid, (2.06 g, 51%). pF: 42 °, MS (ES +). 393 (M + H) +.

Stage 4 Methyl (2- {4-amino-3 - [(phenylsulfonyl) methyl] phenyl} ethyl) methylcarbamate Catalytic hydrogenation of methyl (2. {4-nitro-3 - [(phenylsulfonyl) methyl] -phenyl} ethyl) carbamate methyl (1.8.1 $, 4.6 mmol); in the presence of Raney nickel and hydrogen (45 psi) in acetate, "ethyl / ethanol (60 mL) for 2 h gives a reaction mixture. The reaction mixture is filtered through celite and concentrated in vacuo to give the title compound as a light brown solid (1.36 g, 82%). pF: 95-96 ° C. MS (ES +): 363 (M + H) + Step 5 Methyl { 2- [3- (phenylsulfonyl) -1 H -indazol-5-yl] ethyl} methyl carbamate. Using substantially the same procedure described in example 171, step 3, and employing methyl (2- {4-amino-3 - [(phenylsulfonyl) methyl] phenyl} ethyl) methylcarbamate (362 g, 1 mmol) , the title compound was obtained as a white solid, (0.29 g, 78%). pF: 145-147 ° C, MS (ES +): 374 (M + H) *.

Stage 6 N-Methyl-N-. { 2- [3- (phenylsulfonyl) -1 h -indazol-5-yl] ethyl} amine. To a solution of methyl. { 2- [3- (phenylsulfonyl) -1 H -indazol-5-yl] ethyl} Methyl carbamate (250 mg, 0.67 mmol) in ethylene glycol (7 mL) was added H2NNH2 (10 mg, 3.35 mmol), KOH (1.38 g 10.05 mmol) and heated at 1 10 ° C overnight. The reaction mixture is cooled to room temperature, water is added and the mixture is extracted with CH2Cl2. The organic layers were washed with water, saline, dried (MgSO) and concentrated under reduced pressure to give a residue which is triturated with CH2Cl2 to afford the title compound as a white off solid 210 mg (99%) pF: 186-188 ° C, MS (ES +): 316 (+ H) +. - > !to? -, Example 176 t. I », N, N-Dimethyl-N- hydrochloride. { 2- [3- (phenylsulfonyl) -1 H -indazol-5-yl] ethyl} amine. To a solution of N-methyl-N-. { 2- [3- (phenylsulfonyl) -1 H -indazol-5-yl] ethyl} Amine (38 mg, 0.12 mmol) in acetonitrile (3 mL) Add NaBH (OAc) 3 (100 mg, 0.48 mmol), formaldehyde (0.027 mL, 0.36 mmol), and stir at room temperature for 10 h. The reaction mixture is poured into ice water and MeCN is removed under reduced pressure. The resulting suspension was extracted with CH2Cl2. The organic extracts were washed with water, saline, dried (HgSO) and concentrated in a residue which is dissolved in MeOH and treated with a slight excess of HCl (γ / ET2O) to achieve the desired product as the salt of mono HCl (43 mg, 98%) as a white solid. pF: 108-110 ° C, MS (ES +): 330 (M + H) + Example 177 N, N-Dimethyl-N-. { 3- [3-phenylsulfonyl) -1 H -indazol-5-yl] propyl} amine Stage 1 CICH2S02P -Bromo-2-nitrobenzyl phenyl sulfone. To a stirred solution of 1-bromo-4-nitro-nitrobenzene (5.05 g, 25 mmol) and methylmethylphenylsulphone (4.76 g, 25 mmol) in dry THF (50 mL) at -65 ° C under nitrogen was added KO'Bu 1.0 M in THF (55 mL, 55 mmol). A The deep purple reaction is allowed to warm to 0 ° C for 1.5 h and then treated with glacial acetic acid (4 mL). The reaction is diluted with water (100 mL) and saturated aqueous NaHCO3 (100 mL) and extracted with CH2Cl2 (2 x 200 mL). The extracts were dried (MgSO4) and concentrated in vacuo in a light orange solid. Trituration with ethyl acetate and hexane gave the title compound as a pale yellow solid (6.45 g, 72%). pF: 143-144 ° C. MS (ES-): 354 (M-H) +.

Stage 2 Methyl (2E) -3-. { 4-Nitro-3 - [(phenylsulfonyl) methyl] phenyl} Acrylate To a solution of 5-bromo-2-nitrobenzyl phenyl sulfone (0.356 g, 1 mmol) and methyl acrylate (0.172 g, 2 mmol) in dry DMF (3 mL) is heated at 100 ° C under nitrogen in the presence of diisopropyl amine (0.21 ML, 1.75 mmol), Pd (AOc) 2 (5 mg, 0.02 mmol) and PPH3 (10 mg, 0.04 mmol) for 3 days. After being cooled to room temperature, water was added, and the solution was extracted with ethyl acetate 83 x 15 @jL). The organic layers were washed with water then saline and dried (MgSO). Evaporation of the solvent under reduced pressure gave a residue which is purified by column chromatography (ethyl acetate / hexane 40%) to achieve the title compound as a yellow solid (0.30, 83%). pF: 165-166 ° C. MS (ES-): 360 (M-H) + Stage 3 Methyl 3- [4-amino-3 - [(phenylsulfonyl) methyl] phenyl} propanoate. This compound was prepared by the catalytic hydrogenation of methyl (2E) -3-. { 4-Nitro-3 - [(phenylsulfonyl) methyl] phenyl} Z. $ g acrylate, 9.22 mmol) in the presence of palladium on carbon and hydrogen (45 psi) in ethyl acetate (100 ml) for 4 h. The reaction mixture was filtered through celite and concentrated in vacuo. to give the title compound as a white solid (3.07 g, 99%). pF: 59-60 ° C. MS (ES +): 334 (M + H) + Stage 4 Methyl 3- [3- (phenylsulfonyl) -1H-indazol-5-yl] propanoate Using substantially the same procedure described in example 171, step 3, and employing Methyl 3- [4-amino-3 - [(phenylsulfonyl ) methyl] phenyl} propanoate (2.8 g, 8.4 mmol), the title compound was obtained as a red solid (2.2 g, 73%). pF: 115-117 ° C. MS (ES +): 345 (M + H) \ Stage 5 3- [3- (phenylsulfonyl) -1H-indazol-5-yl] propan-1-ol. A solution of methyl 3- [3- (phenylsulfonyl) -1H-indazol-5-yl] propanoate (2.0 g, 5.8 mmol) in anhydrous THF (120 ml) under an atmosphere of N2 is cooled to -78 ° C, treated with DIBAL-H (1.0 M in THF, 23 mL), allowed to warm to room temperature, set for 12 h, cooled to 0 ° C, quenched slowly with saturated Na 2 SO 4 solution (12 mL) and It is filtered. The filter cake is washed with ethyl acetate. The combined filtrates were dried over MgSO and concentrated under reduced pressure. Purification of the resulting residue by flash chromatography ethyl acetate / hexanes 60%) gave the title compound as a off white solid 1.56 g, 83%, pF. 92-96 ° C. MS (ES +): 317 (M + H) +.

Stage 6 k 't? 3- [3- (Phenylsulfonyl) -1 H -indazol-5-yl] propyl 4-methylbenzenesulfonate. Using substantially the same procedure described in Example 1, step 6, and employing 3- [3- (phenylsulfonyl) -1H-indazol-5-yl] propan-1-ol (1.52 g, 4.8 mmol), the compound was obtained of title as a white foam (1.28 g, 57%). pF: 58-60 ° C. MS (ES +): 471 8M + H) +.

Stage 7 N, N-Dimethyl-N-. { 3- [3- (phenylsulfonyl) -1H-indazol-5-yl] propyl} amine trifluoroacetate.

Using substantially the same procedure described in example 171, step 7, and using 3- [3- (phenylsulfonyl) -1 H -indazol-5-yl] propyl 4-methylbenzenesulfonate (125 mg, 0.26 mmol), the product was obtained of the title as a white off solid (83 mg, 93%). pF: 75-80 ° C. MS 8ES +): 344 8M + H) +.

Example 178 N-3-3- (phenylsulfonyl) -1H-indazol-5-yl] propyl trifluoroacetate} cyclopropanamine Using essentially eY < The procedure described in example 177, step 7, and using cyclopropylamine and substituting trifluoroacetic acid for HCl, gave the title compound as a white solid, pF: 68-169 ° C, MS, (M + H) + 356 Example 179 N-isopropyl-N- trifluoroacetate. { 3- [3- (phenylsulfonyl) -1 H -indazol-5-yl] propyl} amine .:: Orl Using essentially the same procedure described in example 177, step 7 and using isopropylamine and substituting trifluoroacetic acid for HCl, the title compound was obtained as a white solid, mp 169-171 ° C, MS, (M + H) + 358 Example 180 Trifluoroacetate of. { 3- [3- (phenylsulfonyl) -iH-indazol-5-yl] propyl} amine Stage 1 Í • ÍA 5- (3-azidopropyl) -3- (phenylsulfonyl) -: 1 H-indazole. Using essentially the same procedure described in example 174, step 1, and using 3- [3- (phenylsulfonyl) -1H-indazol-5-yl] propyl 4-methylbenzenesulfonate (350 mg, 0.75 mmol), the compound was obtained of the title as a white solid (220 mg, 86%). pF: 133 - 135 ° C. MS (ES-): 340 (M-H) + Stage 2 Trifluoroacetate of. { 3- [3- (Ferii |? Ulfonil) -1H-mdazol-5-yl] propyl} amine. Using essentially the same procedure described in example 174, step 2, and employing 5- (3-azidopropyl) -3- (phenylsulfonyl) -1H-indazole (200 mg, 0.59 mmol), it was obtained in the title product as a white solid off (120 mg, 67%). pF: 92-94 ° C. MS (ES +): 316 (M + H) + Example 181 Hydrochloride. { 4- [3- (Phenylsulfonyl) -1 H -indazol-5-M] butyl} amine Stage 1 4-. { 4-Nitro-3 - [(phenylsulfonyl) methyl] phenyl} but-3-in-1-ol A solution of 5-bromo-2-nitrobenzyl phenyl sulfone (2.5 g, 7.02 mmol), diisopropylamine (4.98 mL, 35.1 mmol) and homo propargol alcohol 80.59 Ml, 7.72 mmol) in degassed toluene (30 mL) was treated simultaneously with 66.8 mg, 0.35 mmol), and tetrakis (triphenylphosphine) -palladium (O) (742 mg, 0.35 mmol), warm to 90 ° C, stir for 15 minutes under nitrogen atmosphere, cool to room temperature, dilute with ethyl acetate (10 mL), and filtered through celite. The filtrate is washed with water (25 mL), then saline and dried over MgSO4 and concentrated in vacuo. The resulting residue is purified by flash chromatography (ethyl acetate / 40% petroleum ether) and gives the title compound as a white solid (2.15 g, 89%): Mp: 129 ° C. MS (ES-): 344 (M-H) +.

Stage 2 4-. { 4-amino-3-uten ?? su? Ton? I) met ?? jten? I Dutan -? - or? The catalytic niorogenation of 4-. { 4-Nitro-3 - [(phenylsulfonyl) methyl] phenyl} but-3-in-1-ol (1.0 g), 2.85 mmol) in the presence of palladium on carbon and hydrogen f 5 psi) in ethyl acetate (30 ml) for 24 h gave a reaction mixture. The reaction mixture is filtered through celite and the filtrate is concentrated in vacuo to give the title compound as a yellow solid (0.907 g, 99%) Mp: 70-72.5 ° C. MS (ES +): 320 (M + Hf.

Stage 3 4- [3- (phenylsulfonyl) -1H-indazol-5-yl] butan-1-ol Using essentially the same as described in Example 171, Step 3 and using 4-. { 4-amino-3 - [(phenylsulfonyl) -methyl] phenyl} butan-1-ol (0.725 g, 2.27 mmol), the title product was obtained as a light pink solid (0.605 g, 81%). PfP l5-216 ° C. IV? S (ES +): 331 (M + Hf.

Stage 4 4- [3- (phenylsulfonyl) -1 H -indazol-5-yl] butyl 4-methylbenzenesulfonate. Using substantially the same procedure described in Example 171, Step 6, and employing 4- [3-phenylsulfonyl) -1H-indazol-5-yl] butan-1-ol (0.5 g, 1.53 mmol), the compound of title as a light orange solid (0.703 g, 95%). Mp: 157-159 ° C. MS (ES +): 485 (M + H) +.

Step 5 '; - (4-azidobutyl) -3- (phenylsulfonyl) -1H-jndazole. Using substantially the same procedure described in Example 174, Step 1, and employing 4- [3- (phenylsulfonyl) -1H-indazol-5-yl] butyl 4-methyl benzenesulfonate (133 mg, 0.27 mmol), the compound of the title as a clear glass (94 mg, 96%). MS (ES +): 356 (M + Hf.

Stage 6 . { 4- [3- (phenylsulfonyl) -1 H -indazol-5-yl] butyl} Amine Using substantially the same procedure described in Example 174, Step 2, and using 5-4-azidobutyl) -3- (phenylsulfonyl) -1H-indazole (94 mg, 0.264 mmol), the title compound was obtained as a white solid (65 mg, 86%). Pf:, 2P-1250C. MSL¡ (ES +): 330 (M + Hf. '*% Example 182 N, N-Dimethyl-N- hydrochloride. { 3-3-naphthylsulfonyl) -1 H -indazol-5-N] propyl} amine.

Stage 1 CICH2S02Na f -Bromo-2-nitrobenzyl naphthyl sulfone. Using substantially the same procedure described in Example 177, Step 1, and employing 1-bromo-4-nitrobenzene P í? ' vft . 05 g, 25 mmol) and chloroethylnaphthylsulfone (7.1 g, 30 mmol), the title product was obtained as a light tan solid (8.6 g, 85%). Mp: 165-168 ° C. MS (ES-): 404 (M-Hf.

Stage 2 Me? 2C Methyl (2E) -3- "4-nitro-3 - [(naphthylsulfonyl) methyl] phenyl], Using substantially in the same procedure described in Example 177, Step 2, and employing 5-bromo-2-nitrobenzylnaphthylsulfone ( 0.540 g, 1.33 mmol), the title product was obtained as a light tan solid (0.438 g, 80%). MP: 178 ° C. MS (ES-): 410 (M-Hf.

Stage 3 Methyl-3-. { 4-amino-3 - [(naphthylsulfonyl) methylphenyl} propanoate. Using substantially the same procedure described in Example 177, Step 3, and employing methyl (2E) -3-. { 4-Nitro-3- [naphthylsulfonyl) methyl] phenyl} Acrylate (2.5 g, 6.0 mmol), the title compound was obtained as a brown gum (2.1 g, 90%). MS (ES +): 384 (M + Hf.

Stage 4 Methyl 3- [3- (naphthylsulfonyl) -1H-indazol-5-yl] propanoate. Using substantially the same procedure described in Example 171, Step 3, and employing methyl 3-. { 4- amino-3 - [(naphthylsulfonyl) methyl] phenyl} propanoate (1.2 g, 3.11 mmol), the title compound was obtained as a light brown solid (1.0 2g, 83%). Mp: 60-65 ° C. MS (ES +): 395 (M + Hf.

Stage 5 • • ' 3- [3- (Naphthylsulfonyl) -1H-indazol-5-yl] propan-1-ol Using substantially the same procedure described in Example 177, Step 5, and employing methyl 3- [3- (naphthylsulfonyl) -1 H-indazol-5-yl] propanoate (1.0 g, 2.5 mmol), the title compound is obtained as a white solid (0.83 g, 89%). MP: 170 ° C. MS (ES +): 367 (M + Hf Stage 6 3- [3- (Naphthylsulfonyl) -1H-indazol-5-yl] propyl 4-methylbenzenesulfonate Using substantially the same procedure described in Example 171, Step 6, and employing 3- [3- (naphthylsulfonyl) -1H-indazole -5-yl] propan-1-ol (0.763 g, 2.08 mmol), the title product is obtained as a white foam (0.8 g, 74%). PF: 66 -68 ° O MS (ES +): 521 (M + Hf Stage 7 N, N-Dimethyl-N- hydrochloride. { 3- [3- (naphthylsulfonyl) -1 H -indazol-5-yl] propyl} amine Using substantially the same procedure described in Example 171, Step 7, and employing 3- [3- (naphthylsulfonyl) -1 H -indazol-5-yl] propyl 4-methylbenzenesulfonate (100 mg, 0.19 mmol), the compound is obtained of the title as an off white solid (73 mg, 99%). PF: 247-248 ° O MS (ES +): 394 (M + Hf Examples 183-187 Using essentially the same procedure described in Example 171, Step 7, and employing 3- [3- (naphthylsulfonyl) -1H-indazol-5-yl] propyl 4-methylbenzenesulfonate and the desired amine, the compounds shown in Table X are obtained and identified by HPLC and mass spectral analysis Ex. No. R5 R6 pf ° C [M + H] + 183 CH3 H 155-160 380 184 C2H5 H 228-232 393 185 isopropyl H 160-163 408 186 C2H5 CH3 205-207 408 187 -CH2CH2CH2CH2- 135-138 Example 188 . { 3- [3- (Naphthylsulfonyl) -1H-indazol-5-yl] propyl} amine Stage 1 - (3-Azidopropyl) -3- (naphthylsulfonyl) -1H-indazole Using essentially the same procedure described in Example 174, Step 1, and employing 3- [3- (naphthylsulfonyl) -1H-indazole-5- il] propyl 4-methylbenzenesulfonate (135 mg, 0.26 mmol), the title compound is obtained as a clear glass (97 mg, 96%). MS (ES-): 390 (M-Hf Stage 2 i - . { 3- [3- (Naphthylsulfonyl) -1H-indazol-5-yl] propyl} amine Using essentially the same procedure described in Example 174, Step 2, and employing 5- (3-azidopropyl) -3- (naphthylsulfonyl) -l H-indazole (96 mg, 0.25 mmol), the title compound is obtained as an off white solid (90 mg, 99%). PF: 92-94 ° O MS (ES +): 366 (M + Hf Example 189 Hydrochloride. { 4- [3- (Naphthylsulfonyl) -1 H -indazol-5-yl] butyl} amine Stage 1 4-. { 4-Nitro-3 - [(naphthylsulfonyl) methyl] phenyl} but-3-in-1-ol Using substantially the same procedure described erjt, Example 181, Step 1, and employing 5-bromo-2-nitrobenzyl naphthyl sulfone (5000 mg, 12.3 mmol), the title compound is obtained as a dull yellow solid (4381 mg, 90%). PF: 155 ° C. MS (ES-): 394 (M-Hf Stage 2 4-. { 4-Amino-3 - [(naphthylsulfonyl) methyl] phenyl} butan-1-ol Using substantially the same procedure described in Example 181, Step 2, and using 4-. { 4-Nitro-3 - [(naphthylsulfonyl) methyl] phenol} but-3-in-1-pl ((1750 mg, 4j4 mmol), the title compound is obtained as a yellow solid (161.6,, mg, 99%) .PF: 80-85 ° O MS (ES +) : 370 (M + Hf Stage 3 4- [3- (Naphthylsulfonyl) -1 H -indazol-5-yl] butan-1-ol Using substantially the same procedure described in Example 171, Step 3, and using 4-. { 4-amino-3- [(naphthylsulfonyl) methyl] phenyl} butan-1-ol (1.6 g, 4.3 mmol), the title compound is obtained as a light pink solid (1.64 g, 99%). PF: 138-139 ° C. MS (ES-): 379 (M-Hf Stage 4 4- [3- (Naphthylsulfonyl) -1 H -indazol-5-yl] butyl 4-methylbenzenesulfonate Using substantially the same procedure described in Example 171, Step 6, and employing 4- [3- (naphthylsulfonyl) -1 H- indazol-5-yl] butan-1-ol (1.6 g, 4.2 mmol), the title compound is obtained as a white foam (2.02 g, 90%). PF: 63-66 ° C. MS (ES +): 535 (M + Hf Stage 5 - (4-Azidobutyl) -3- (naphthylsulfonyl) -1H-indazole Substantially using the same procedure described in Example 174, Step 1, and employing 4- [3- (naphthylsulfonyl) -1H-indazole-5- il] butyl 4-methylbenzenesulfonate (150 mg, 0.28 mmol), the title compound is obtained as a clear glass (104 mg, 92%). MS (ES +): 406 (M + Hf Stage 6 L K Hydrochloride. { 4- [3- (Naphthylsulfonyl) -1H-indazol-5-yl] butyl} Amine Substantially using the same procedure described in Example 17 Step 2, and employing 5- (4-azidobutyl) -3- (naphthylsulfonyl) -1H-indazole (104 mg, 0.25 mmol), the title compound is obtained as a white solid (91 mg, 94%). PF: 150-152 ° c. MS (ES +): 380 (M + Hf Examples 190-194 Using essentially the same procedure described in Example 171, Step 7, and employing 3- [3- (naphthylsulfonyl) -1 H -indazol-5-yl] butyl 4-methylbenzenesulfonate and the desired amine, the compounds shown in Table XI they are obtained and identified by HPLC and mass spectral analysis.

TABLE XI Ex No. R5 R6 pf ° C [M + H] + 190 CH3 CH3 232-233 408 191 C2Hs H 140-145 408 192 isopropyl H 145-150 422 193 C2H5 CH3 195-198 422 194 -CH2CH2CH2CH - 238-240 434 Example 195 3- (1-N-phenylsulfonyl) -5- (piperazin-1-ylmethyl) -1 H-indazole Stage 1 : 2- [3- (Naphthalene-1-sulfonylmethyl) -4-nitro-phenyl] - [1,3] dioxolane A mixture of 2- (4-nitro-phenyl) - [1,3] dioxolane (1.85 g, 9.5 mmoles) and 1-chloromethane-sulfonyl-naphthalene (2.74 g, 11.4 mmol) is stirred in THF (50 ml) at -78 ° C, in a bottom vessel rounded under nitrogen. A solution of 1 M potassium t-butoxide is added dropwise (19 ml, 19 mmol) over a period of half an hour. The temperature is allowed to rise to -40 ° C, and the reaction mixture is stirred at this temperature for 5 hours. The reaction mixture is poured into cold 2N HCl, extracted with EtOAc, dried over Na2SO, and concentrated under vacuum. The compound is purified by normal phase HPLC on a silica column, using as eluent 40% EtOAc / hexane, to achieve the title compound as an off white solid (3.03 g, 7.6 mmol).

Stage 2: 3- (Naphthalene-1-sulfonylmethyl) -4-nitro-benzaldehyde A mixture of 2- [3- (naphthalene-1-sulfonylmethyl) -4-nitro-phenyl] - [1,3] dioxolane (3.03 g, 7.6 mmoles ), and 2N HCl (4 mL, 8 mmol) in THF (30 mL) is stirred at 40 ° C for 4 hours. The reaction mixture is cooled to room temperature, diluted with water, extracted with CH 2 Cl 2, dried over Na 2 SO 4, and concentrated under vacuum to yield the title compound (2.56 g, 7.22 mmol). .ays r7 Stage 3: 4-Amino-3- (naphthalene-1-sulfonylmethyl) -benzaldehyde A mixture of 3- (naphthalene-1-sulfonylmethyl) -4-nitro-benzaldehyde (2.5 g, 7.22 mmol) and 10% Pd / C in THF ( 10 mL), and methanol (20 mL) is hydrogenated in a Parr hydrogenation bottle (250 mL) at 52 lb / in2 overnight. The mixture is filtered through Celite, and the filtrate is concentrated under vacuum to obtain the title compound as an off white solid (2.4 g, 6.85 mmol).

Stage 4: 3- (Naphthalene-1-sulfonyl) -1 H-indazole-5-carbaldehyde A mixture of 4-amino-3- (naphthalene-1-sulfonylmethyl) -benzaldehyde (2.4 g, 6.85 mmol) in THF (10mL) and HCl 4M (20 mL) is stirred in a bottom vessel rounded to 3 ° O. A solution of sodium nitrite (0.49 g, 7.19 mmol) in H2O (2 mL) is added. The reaction mixture a cold solution of saturated sodium bicarbonate (100 mL) and extracted with EtOAc. The compound is dried over Na2SO4, and concentrated under vacuum to obtain the title compound as an off white solid (1.84 g, 5.5 mmol).

Step 5: j, 3- (1-Naphthylsulfonyl) -5- (piperazin-1-ylmethyl) -1H-indazole A mixture of 3- (naphthalene-1-sulfonyl) -1H-indazole-5-carbaldehyde (0.17 g, 0.5 mmol), piperazine (0.2 mL, 2.0 mmol) and sodium triacetoxyborohydride (0.15 g, 0.7 mmol) in dichloroethane (5 mL) is stirred at room temperature for 24 hours. After completion, the solvent is removed under vacuum, the crude material is dispersed in water and the pH is brought to 3.4. The solid material is filtered and washed after the drying of the target material as a free base. The latter is converted to the hydrochloride salt by dissolving in methanol, followed by treatment with the excess 2N HCl and evacuation of the volatiles in vacuo to achieve the title compound as the hydrochloride salt, mp; 200 ° C; MS (ES) m / z 406.

Examples 196-201 Using essentially the same reductive amination procedure described in Example 195, Step 5, and employing the desired amine and treatment of the free base with HCl; The compounds shown in Table XII are obtained and identified by HPLC and mass spectral analysis.

Ex-MS No. NR5R6 pf ° C m / z 196 4-methylpiperazin-1-yl > 200 419.1197 3-methylpiperazin-1-yl > 200 421.1 198 3,5-d? Met? Lp? Perazin-1-yl > 200 433.1 199 (3S) -3-methylpiperazin-1-yl 178-181 419.2 200 (3R) -3-methylpiperazin-1-yl 179-181 419.2 201 (3R) -3-aminopyrrolidin-1-yl > 200 405.1 Example 202 3- (1-N-phenylsulfonyl) -5- (piperazin-1-ylcarbonyl) -1H-indazole Stage 1: 3- (Naphthalene-1-sulfonyl) -1H-indazole-5-carboxylic acid A mixture of 3- (naphthalene-1-sulfonyl) -1 H-indazole-5-carbaldehyde (0.15 g, 0.44 mmol) and KMnO 4 (0.03 g, 0.29 mol) is stirred in CH 3 CN / H 2 O (4: 1) for 1 hour. The reaction mixture is acidified with 2N HCl, stirred with saturated sodium bisulfite for 10 minutes, then extracted with EtOAc, dried over Na2SO4 and concentrated in vacuo to afford the title compound (0.13 g, 3.9 mmol). .

Step 2: 3- (1-Naphthylsulfonyl) -5- (piperazin-1-ylcarbonyl) -1H-indazole A mixture of 3- (Naphthalene-1-sulfonyl) -1H-indazole-5-carboxylic acid (0.13 g, 0.39 mmol) piperazine (0.036 g, 0.42 mmol), and 1- [3- (Dimethylamino) propyl hydrochloride -3-ethylcarbodiimide (0.08 g, 0.42 mmol) is stirred in CH2Cl2 for! hour. The reaction mixture is diluted with H2O, extracted with EtOAc, washed with water (2x), saline (1x), dried over Na2SO4, and concentrated under vacuum. The product is converted to the hydrochloride salt by dissolving in methanol, followed by treatment with the excess 2N HCl and evacuation of the volatiles in vacuo to achieve the hydrochloride salt of the compound; PF: > 2Q0 ° C; MS (ES) m / z 419.1.

Example 203 - [1 - (4-Methylpiperazin-1-yl) ethyl] -3- (1-naphthylsulfonyl) -1 H-indazole Step 1: 1- [3- (Naphthalene-1-sulfonyl) -1H-indazol-5-yl] -ethanol A mixture of 3- (naphthalene-1-sulfonyl) -1H-indazole-5-carbaldehyde (0.15 g, 0.44 mmol) and MeMgBr (0.36 mL of 3M ether solution, 1.1 mmol) is stirred in THF at -20 ° C. C at 0 ° C for 30 minutes. The reaction mixture is diluted with water, acidified to pH = 3 with 2N HCl, then extracted with EtOAc, dried over Na2SO4 and concentrated in vacuo to obtain the title compound (0.13 g, 3.9 mmol).

Step 2: 5- [1- (4-Methylpiperazin-1-yl) ethyl] -3- (1-naphthylsulfonyl) -1H-indazole: A mixture of 1- [3- (naphthalene-1-sulfonyl) -1 H -indazol-5-yl] ethanol (0.13 g, 0.38 mmol), methane sulfuric anhydride (0.16 g, 0.95 mmol), and triethylamine (0.13 ml) , 0.95 mmole) is stirred in CH 2 Cl 2 from 0 ° C at room temperature for 5 hours to achieve 1- [3- (naphthalene-1-sulfonyl) -1-H-indazol-5-yl] -ethyl methanesulfonic acid ester. This reaction mixture is treated with excess N-methyl-piperazine (0.22 g, 2 mmol). The crude product is purified by flash chromatography using 5% MeOH / CH 2 Cl 2 to achieve the title compound; MP: 183-185 ° C, MS (ES) m / z 433.1.

Example 204 Affinity Evaluation of 5-HT6 Binding of Test Compounds The affinity of the serotonin 5-HT6 receptor assay compounds is evaluated in the following manner. Cultured Hela cells expressing human cloned 5-HT6 receptors are harvested and centrifuged at low speed (1000 x g) for 10.0 minutes to remove the culture medium. The harvested cells are suspended in half the volume of the fresh phosphate buffered saline solution and centrifuged at the same rate. This operation is repeated. The harvested cells are homogenized in 10 volumes of 50 mM Tris.HCl (pH 7.4) and 0.5 mM EDTA. The homogenate is centrifuged at 40, -000 x g for 30.0 min the precipitate is collected. The obtained globule is resuspended in 10 volumes of Tris buffer. HCl and centrifuged at the same speed. The final globule is suspended in a small volume of Tris buffer. HCl and tissue protein content is determined in aliquots of 10-25 μl volumes. Sero Bovine Albumin is used as the standard in protein determination according to the method described in Lowry et al., J. Biol. Chem., 193: 265 (1951). The volume, -cle the membranes of suspended cells is adjusted to give a tissue concentration of 1.0 mg / ml of suspension. The suspension of the prepared membrane (10 times concentrated) is put into aliquots of 1.0 ml volumes and stored at -70 ° C until used in subsequent binding experiments.

The binding experiments are carried out in a 96-well microtiter plate format, in a total volume of 200 μl. The following mixture is added to each well: 80.0 μl of incubation buffer made in 50 mM Tris buffer. HCl (pH 7. 4) containing 10.0 mM MgCl 2 and 0.5 mM EDTA and 20 μl of [3 H] -LSD (S.A., 86.0 Ci / mmol, available from Amersham Life Science), 3.0 nM. The dissociation constant, KD of [3 H] LSD at the human serotonin 5-HT 6 receptor: was 2.9 nM, as determined by saturation binding with increasing concentrations of [3 H] LSD. The reaction is initiated by the final addition of 100.0 μl of tissue suspension. The non-specific binding is measured in the presence of 10.0 μM of methiothepin. The test compounds are added in 20.0 μl volume.

The reaction is allowed to proceed in the dark for 120 minutes at room temperature, at which time, the bound ligand-receptor complex is filtered on a 96-well unifilter with a Packard Filtermate® 196 Harvester. The binding complex taken on the disk The filter is allowed to air dry and the radioactivity is measured in a Packard TopCount® equipped with photomulticap detectors after the addition of 40.0μl Microscint®-20 scintillating in each shallow well. The unifiltro plate is heat sealed and counted in a PackardTopCount® with tritium efficiency of 31.0%. / μ1 iJ The specific binding of the receptor 5-HT6 receptor is defined as the total radioactivity bound less than the amount bound in the presence of 10.0 μM unlabeled methionine. The binding in the presence of varying concentrations of the test compound is expressed as a percentage of the specific binding in the absence of the test compound. The results are plotted as log% bound versus the log concentration of the test compound. Analysis of linear regression analysis of the data points with a computer-assisted Prism® program yields both the IC50 and K values of the test compounds with 95% confidence limits. A linear regression line of data points is graphical, of which the IC50 value is determined in the K value, determined based on the following equation: K, = IC50 / (1 + L / KD) Where L is the concentration of the radioactive ligand and KD is the ligand dissociation constant for the receptor, both expressed in nM.

Using this assay, the following Ki values are determined. The data is shown in TABLE Xlll, below.

For TABLE Xlll A = 0.01 nM-10 nM B = 11 nM-25 nM C = 26 nM-35 nM D = 36 nM-45 nM E = > 45 nM?. oo uJ? < "Q? Ü ü? Uj < co Q < < < < < < < < < < < < < < < CM CO m co 00 O) or CM CO • > * LO CD CM CO LO CD co> CM CM CM CM CM CM CM ITL L? Oo H CN CM "< < < < < < < < < < < < < < < -" < J < < < < < < o o o Q m .j (i? cQ -j -J ü o o 00 r »co s > O t- C \ J CO J- lO CO f- co s > o CM CO - ^ T LO CD h ~ CO C35 or T- CM CO • < 3- LO CD r ~ - oo M CM CM CO CO C CO CO CO CO CO CO CO or • < ! - ^ - M- - «a- -« a- • • WHAT LO LO m LO LO LO LO ? n L? o LD O N CM n > to H or L? or L? L? o 00 00 00 00 00 00 oo oo 00 -vi -vi -vi -vi "vi -vi -vi -v | - i -vi Oi Oi Oi Oi Oi Oi Oi Oi Ol o co oo -yes or in 4- ? oo 00 -vi s > oí -t ».? M -» o CO 00 -vi O Ol - &. 00 - »• oo > > > m or m m or r > > so > > > aj > m or ro aj or > > > > > > > > aj m 91 A 92 A 93 A 94 B 95 A 96 E 97 A 98 C 99 A 100 B 101 B 102 C 103 E 104 C 105 E 106 E 107 E 108 E 109 B 110 E 111 E 112 E 113 A 114 A 115 B 116 B 117 A 118 A 119 E 120 E ? u < uj m co < m uj uj Lu m o m co Q Q? Q < < ? < < m m co uJ -j? u < -j m co CM CO -T m CD tv- CO O) O - CM CO - < ím CD | v- CO Oi or CM co • < a- LO CD (v- CO O) or CM CM CM CM CM CM CM CM CM CM CO CO CO CO CO CO co co co co co - * - < a- • * -ÑT "3- • * • < a- - * - • r m m LO L? o L? o CN N n m m m < < < m < m < m < m o? a w m < m < < < m? ? w? or < < < 00 co? o cD r - co s > ? - M c? '> f io cD i. or s) or CM co • «a- LO CD r. co s O i- CM CO IO lo mm in m cD co CD CD CD co co co CD (v. r. | v. r * - (v. | v- r. (v- | v- r. CO CO CO oo L? L? or L? or H CN N ro 186 A 187 A 188 A 189 A 190 A 191 A 192 A 193 A 194 B 195 A 196 A 197 A 198 A 199 B 200 A 201 A 202 E 203 A twenty

Claims (9)

1. CLAIMS A compound of formula I (0 of X is O, S, NR, CH2, CH2Y, CH2Z, CO, CONR or NRCO, Y is O, S or NR, Z is CO, n is 0 or an integer of 1, 2, 3, 4, 5 or 6 when X is CH2, n is an integer of 1, 2, 3, 4, 5 or 6 when X is CH2Z, CO or NRCO, n is an integer of 2, 3, 4, 5 or 6 when X is O, S, NR, CH2Y or CONR; R is H or an optionally substituted alkyl group; RT is H or an optionally substituted alkyl, cycloalkyl, aryl or heteroaryl group; R2 is an optionally substituted alkyl, cycloalkyl, aryl or heteroaryl group an optionally substituted 8- to 13-membered bicyclic or tricyclic ring system having an N atom on the bridge head and optionally containing 1, 2 or 3 heteroatoms selected from N, O or S; R3 and R4 are each independently H, or an optionally substituted alkyl group; R5 and R6 are each independently H, or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group, or R5 and R6 can be taken together with the atom to which they are linked to form a ring 3-7-7 optionally substituted optionally containing an additional heteroatom selected from O, N or S; ^ v R7 is H, halogen, CN, OR8, CO2R9, CONR10Rn, or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group; m is an integer of 1, 2 or 3; R8 is H, COR12 or an optionally substituted alkyl, alkenyl, alkynyl, aryl or heteroaryl group; R9 is H or a C6 alkyl, or an aryl or heteroaryl group each optionally substituted; Rio and Rn are each independently H or an optionally substituted alkyl group; and R 12 is a C 1 -C 6 alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group; or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
2. 2. The compound according to claim 1 wherein X is O, NR or CH23.
3. The compound according to claim 2 wherein X is O.
4. 4. The compound according to any one of claims 1 to 3 wherein n is 2 or 3.
5. 5. The compound according to any one of claims 1 to 4 wherein R 2 is an aryl or heteroaryl group optionally substituted with an optionally substituted 8- to 13-membered bicyclic or tricyclic ring system having an N atom at the head of the bridge and optionally contains 1, 2 or 3 heteroatoms selected from, O or S.
6. 6. The compound according to claim 5 wherein R 2 is an optionally substituted phenyl, naphthyl or imidazothiazolyl group.
7. 7. The compound according to any one of claims 1 to 6 wherein R 5 and R 6 are each independently H or d-C alkyl.
8. 8. The compound according to any one of claims 1 to 7 wherein R 2 is naphthyl and n is 0 3. ,
9. 9. The compound according to claim 1 is selected from the group consisting essentially of: N, N-Dimethyl-3-. { [3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] oxy} propan-1 -amine; N-Methyl-N-. { 2- [3- (phenylsulfonyl) -1 H -indazol-5-yl] ethyl} amine; N, N-Dimethyl-N-. { 2- [3- (phenylsulfonyl) -1 H -indazol-5-yl] ethyl} amine; . { 2- [3- (Phenylsulfonyl) -1 H -indazol-7-jl] ethyl} amine; N, N-Dimethyl-N-. { 2- [3- (phenylsulfonyl) -1 H -indazol-7-yl] ethyl} amine; N-. { 2- [3- (Phenylsulfonyl) -1 H -indazol-7-yl] ethyl} cyclopropanamine; N, N-Dimethyl-N-. { 3- [3- (phenylsulfonyl) -1 H -indazol-5-yl] propyl} amine; N-. { 3- [3- (Phenylsulfonyl) -1 H -indazol-5-yl] propyl} cyclopropanamine; . { 3- [3- (Phenylsulfonyl) -1 H -indazol-5-yl] propyl} amine; . { 4- [3- (Phenylsulfonyl) -1 H -indazol-5-yl] butyl} amine; N-Methyl-N-. { 2- [3- (phenylsulfonyl) -1 H-indazol-7-yl] ethyl} amine; N- [3- (1-Naphthylsulfonyl) -1 H -indazol-5-yl] ethane-1,2-diamine; N, N-Dimethyl-2-. { [3- (phenylsulfonyl) -1 H -indazol-5-yl] oxy} ethanamine; 3- (Phenylsulfonyl) -5- (2-piperidin-1-ylethoxy) -1H-indazole; 3- (1-Naphthylsulfonyl) -5- (2-pyrrolidin-1-ylethoxy) -1 H-indazole; N, N-Dimethyl-2-. { [3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] oxy} ethanamine; N- (2- { [3- (1-N-phenylsulfonyl) -1 H -indazol-5-yl] oxy} ethyl) cyclopentanamine; 5- (2-Morpholin-4-ylethoxy) -3- (1-naphthylsulfonyl) -1 H -indazole; N-Ethyl-N-methyl-2-. { [3- (1-naphthylsulfoñil) -1 H -indazol-5-yl] oxy} ethanamine; N- (2- {[3- (1-Naphthylsulfonyl) -1 H -indazol-5-yl] oxy} ethyl) butan-1 -amine; N ~ 1 ~ - [3- (1-Naphthylsulfonyl) -1 H -indazol-5-yl] -beta-alaninamide; N-Ethyl-2-. { [3- (phenylsulfonyl) -1 H -indazol-5-yl] oxy} etanamina; N- (2- {[[3- (Phenylsulfonyl) -1 H -indazol-5-yl] oxy} ethyl) propan-2-amine; N- (2- {[[3- (1-Naphthylsulfonyl) -1 H -indazol-5-yl] oxy} ethyl) propan-2-amine; N-Ethyl-2-. { [3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] oxy} ethanamine; N-Methyl-2-. { [3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] oxy} ethanamine; 1-Methyl-3- (1-naphthylsulfonyl) -7- (2-piperidin-1-ylethoxy) -1 H -indazole; 3- (1-Naphthylsulfonyl) -5- (2-piperidin-1-ylethoxy) -1 H-indazole; 3- (2-Aminoethyl) -1 - [(2,5-dimethoxyphenyl) sulfonyl] -1,3-dihydro-2H-imidazo [4,5-b] pyridin-2-one; N, N-Diethyl-2-. { [3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] oxy} ethanamine; N- (2- {[[3- (1-Naphthylsulfonyl) -1 H -indazol-5-yl] oxy} ethyl) cyclopropanamine; 1- (3-Chlorobenzyl) -3- (1-naphthylsulfonyl) -7- (2-piperidin-1-ylethoxy) -1 H -indazole; 1- (3-Chlorobenzyl) -3- (1-naphthylsulfonyl) -7- (2-pyrrolidin-1-ylethoxy) -1 H-indazole; (2S) -3-Methyl-N ~ 1 - [3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] butane-1,2-diamine; (2- { [1- (3-Chlorobenzyl) -3- (1-naphthylsulfinyl) -1 H -indazol-7-yl] oxy} ethyl) amine; N- (2- { [3- (Phenylsulfonyl) -1 H -indazol-5-yl] oxy] ethyl) cyclopentanamine; 3- (Phenylsulfonyl) -5- (2-pyrrolidin-1-ylethoxy) -1 H -indazole; N-Methyl-2-. { [3- (phenylsulfonyl) -1 H -indazol-5-yl] oxy} ethanamine; N-Methyl-2-. { [1-methyl-3- (phenylsulfonyl) -1 H -indazol-7-yl] oxy} ethanamine; 1 -Methyl-3- (phenylsulfonyl) -7- (2-pyrrolidin-1-ylethoxy) -1H-indazole; (2- { [1 - (3-Chlorobenzyl) -3- (phenylsulfonyl) -1 H -indazol-7-yl] oxy} ethyl) methylamine; (2- {[(3-Chlorobenzyl) -3- (phenylsulfonyl) -1 H -indazol-7-yl] oxy} ethyl) ethylamine; 1- (3-Chlorobenzyl) -3- (phenylsulfonyl) -7- (2-pyrrolidin-1-ylethoxy) -1 H -indazole; 1- (3-Chlorobenzyl) -5-methoxy-3- (1-naphthylsulfonyl) -7- (2-piperidin-1-ylethoxy) -1 H -indazole; N-Methyl-2-. { [3- (phenylsulfonyl) -1 H -indazol-7-yl] oxy} ethanamine; (2- { [1 - (3-Chlorobenzyl) -3- (1-naphthylsulfonyl) -1 H -indazol-7-yl] oxy} ethyl) ethylamine; (2- { [1- (3-Chlorobenzyl) -3- (1-naphthylsulfonyl) -1 H -indazol-7-yl] oxy} ethyl) methylamine; N-Ethyl-2-. { [3- (phenylsulfonyl) -1 H -indazol-7-yl] oxy} ethanamine; N, N-Diethyl-2-. { [3- (phenylsulfonyl) -1 H -indazol-7-yl] oxy} ethanamine; N- (2- { [3- (Phenylsulfonyl) -1 H -indazol-77 I] oxy} ethyl) butan-1 -amine; 3- (Phenylsulfonyl) -7- (2-pyrrolidin-1-ylethoxy) -1 H-indazole; 3- (Phenylsulfonyl) -7- (2-piperidin-1-ylethoxy) -1 H -indazole; N, N-Diethyl-2-. { [1-methyl-3- (1-naphthylsulfonyl) -1 H -indazol-7-yl] oxy} ethanamine; 1-Methyl-3- (1-naphthylsulfonyl) -7- (2-pyrrolidin-1-ylethoxy) -1 H -indazole; N-Ethyl-2-. { [1-methyl-3- (1-naphthylsulfonyl) -1 H -indazol-7-yl] oxy} ethanamine; 3- (1-Naphthylsulfonyl) -7- (2-piperidin-1-ylethoxy) -1 H -indazole; 3- (1-Naphthylsulfonyl) -7- (2-pyrrolidin-1-ylethoxy) -1 H -indazole; N-Ethyl-2-. { [3- (1-naphthylsulfonyl) -1 H -indazol-7-yl] oxy} ethanamine; (2- {[[3- (1-N-phenylsulfonyl) -1 H -indazol-7-yl] oxy} ethyl) amine; (2- {[[(3-Chlorobenzyl) -5-fluoro-3- (1-naphthylsulfonyl) -1H-indazol-7-yl] oxy} ethyl) -dimethylamine; (2- {[1-Benzyl-3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] oxy} ethyl) methylamine; (2- {[1-Benzyl-3- (1-naphthylsulfonyl) -1 H-in.dazol-5-yl] oxy} ethyl) dimethylamine; (2- {[1-Benzyl-3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] oxy} ethyl) ethylamine; N-Methyl-2-. { [3- (1-naphthylsulfonyl) -1 H -indazol-7-yl] oxy} ethanamine; N, N-Dimethyl-2-. { [3- (1-naphthylsulfonyl) -1 H -indazol-7-yl] oxy} ethanamine; 5-Fluoro-3- (1-naphthylsulfonyl) -7- (2-pyrrolidin-1-ylethoxy) -1 H-indazole; 5-Fluoro-3- (1-naphthylsulfonyl) -7- (2-piperidin-1-ylethoxy) -1 H -indazole; N, N-Diethyl-2-. { [5-fluoro-3- (1-naphthylsulfonyl) -1 H -indazol-7-yl] oxy} ethanamine; (2- {[5-Fluoro-3- (1-naphthylsulfonyl) -1H-indazol-7-yl] oxy} ethyl) dimethylamine; N-Ethyl-2-. { [5-fluoro-3- (1-naphthylsulfonyl) -1 H -indazol-7-yl] oxy} ethanamine; (2- { [1 - (3-Chlorobenzyl) -3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] oxy} ethyl) -dimethylamine; N-methyl-3-. { [3- (1-naphthylsulfonyl) -1H-indazol-5-yl] oxy} propan-1 -amine; N-Ethyl-N-methyl-3-. { [3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] oxy} propan-1 -amine; 3- (1-Naphthylsulfonyl) -5- (3-piperidin-1-ylpropoxy) -1 H-indazole; N, N-Dimethyl-3-. { [3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] oxy} propan-1-amine; N, N-Diethyl-3-. { [3- (1-naphthylsulfonyl) -1 H-ir.dazol-5-yl] oxy} propan-1-amine; N- (3- { [3- (1-Naphthylsulfonyl) -1 H -indazol-5-yl] oxy}. Propyl) butan-1 -amine; 3- (1-Naphthylsulfonyl) -5- (3-pyrrolidin-1-ylpropoxy) -1 H-indazole; (2- {[5-Methoxy-3- (1-naphthylsulfonyl) -1 H -indazol-7-yl] oxy} ethyl) methylamine; (2- {[5-Methoxy-3- (1-naphthylsulfonyl) -1 H -indazol-7-yl] oxy} ethyl) dimethylamine; 5-Methoxy-3- (1-naphthylsulfonyl) -7- (2-pyrrolidin-1-ylethoxy) -1 H -indazole; 5-Methoxy-3- (1-naphthylsulfonyl) -7- (2-piperidin-1-ylethoxy) -1 H -indazole; (2- { [1 - (3-Chlorobenzyl) -3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] oxy} ethyl) ethylamine; (3- { [1- (3-Chlorobenzyl) -3- (1-naphthylsulfonyl) -1 H -indazol-7-yl] oxy}. Propyl) -diethylamine; 1- (3-Chlorobenzyl) -3- (1-naphthylsulfonyl) -7- (3-pyrrolidin-1-ylpropoxy) -1 H-indazole; N-methyl-3-. { [3- (1-naphthylsulfonyl) -1 H -indazol-7-yl] oxy} propan-1 -amine; N, N-Diethyl-3-. { [3- (1-naphthylsulfonyl) -1 H -indazol-7-yl] oxy} propan-1-amine; N-Methyl-2-. { [1-methyl-3- (1-naphthylsulfonyl) -1H-indazol-5-yl] oxy} ethanamine; N, N-Dimethyl-2-. { [1-methyl-3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] oxy} ethanamine; N-Ethyl-N-methyl-2-. { [1-methyl-3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] oxy} ethan-amine; N-Ethyl-2-. { [1-methyl-3- (1-naphthylsulfonyl) -1H-indazol-5-yl] oxy} ethanamine; N, N-Diethyl-2-. { [1-methyl-3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] oxy} ethanamine; N- (2- {[1-Methyl-3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] oxy} ethyl) propan-2-amine; 1 -Methyl-3- (1-naphthylsulfonyl) -5- (2-pyrrolidin-1-ylethoxy) -1 H -indazole; . { 3- [3- (1-Naphthylsulfonyl) -1 H -indazol-5-yl] propyl} amine; (2- {[1-Methyl-3- (1-naphthylsulfonyl) -1 H -indazol-7-yl] oxy} ethyl) amine; N-Ethyl-3-. { [3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] oxy} propan-1 -amine; N-lsopropyl-3-. { [3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] oxy} propan-1 -amine; N- (3- {[[3- (1-Naphthylsulfonyl) -1 H -indazol-5-yl] oxy} propyl) cyclopentanamine; 5- (3-Morpholin-4-ylpropoxy) -3- (1-naphthylsulfonyl) -1 H -indazole; N- (3-. {[3- (1-Naphthylsulfonyl) -1 H -indazol-5-yl] oxy}. Propyl) cyclopropanamine, (3- {[[3- (1-Naphthylsulfonyl) -1H-indazol-5-yl] oxy} propyl) amine; N-methyl-4-. { [3- (1-naphthylsulfonyl) -1 H -i? Dazol-5-yl] oxy} butan-1 -amine N, N-Dimethyl-4-. { [3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] oxy} butan-1 -amine; N-Ethyl-4-. { [3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] oxy} butan-1 -amine; N, N-Diethyl-4-. { [3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] oxy} butan-1 -amine; N-methyl-4-. { [3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] oxy} -N-propylbutan-1 -amine; 3- (1-Naphthylsulfonyl) -5- (4-pyrrolidin-1-ylbutoxy) -1 H -indazole; 3- (1-Naphthylsulfonyl) -5- (4-piperidin-1-ylbutoxy) -1 H-indazole; (4- { [3- (1-Naphthylsulfonyl) -1 H -indazol-5-yl] oxy} butyl) amine; (2- {[5-Fluoro-3- (1-naphthylsulfonyl) -1 H -indazol-7-yl] oxy} ethyl) methylamine; 5 - [(4-Methylpiperazin-1-yl) methyl] -3- (1-naphthylsulfonyl) -1 H -indazole; 3- (1-Naphthylsulfonyl) -5- (piperazin-1-ylmethyl) -1 H -indazole; N-. { [3- (1-Naphthylsulfonyl) -1 H -indazol-5-yl] methyl} ethane-1, 2-diamine; N-Methyl-3- [3- (1-naphthylsulfonyl) -1 H -ndazol-5-yl] propan-1 -amine; N, N-Dimethyl-4- [3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] butan-1 -amine; N, N-Dimethyl-3- [3- (1-naphthylsulfonyl) -l H - "? Ndazol-5-yl] propan-1-amine; N-Ethyl-N-methyl-3- [3- (1 - naphthylsulfonyl) -1 H -indazol-5-yl] propan-1 -amine; N-lsopropyl-3- [3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] propan-1 -amine; N- Ethyl-N-methyl-4- [3- (1-naphthylsulfonyl) -1H-indazol-5-yl] butan-1 -amine; (2 { [3- (1-Naphthylsulfonyl) -1 H -indazole -5-yl] oxy}, ethyl) amine, 3- (1-N-phenylsulfonyl) -5- (3-pyrrolidin-1-ylpropyl) -1 H-indazole, N-lsopropyl-4- [3- (1- naphthylsulfonyl) -1 H -indazol-5-yl] butan-1 -amine; 3- (1-Naphthylsulfonyl) -5- (4-pyrrolidin-1-ylbutyl) -1H-indazole; N-Ethyl-4- [3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] butan-1-amine; 5 - [(3-Methylpiperazin-1-yl) methyl] -3- (1-naphthylsulfonyl) -1 H -indazole; 5 - [(3,5-Dimethyl-piperazin-1-yl) methyl] -3- (1-naphthylsulfontyl) -1H-indazole; N-Ethyl-3- [3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] propan-1 -amine; . { 4- [3- (1-Naphthylsulfonyl) -1 H -indazol-5-yl] butyl} amine; 5- [1- (4-Methylpiperazin-1-yl) ethyl] -3- (1-naphthylsulfonyl) -1 H -indazole; N, N, N'-Trimethyl-N'-. { [3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] methyl} ethane-1, 2-diamine; N, N-Dimethyl-2-. { [3- (1-naphthylsulfonyl) -1 H -indazol-5-yl] methoxy} ethanamine; 5-. { [(3R) -3-Methylpiperazin-1-yl] methyl} -3- (1-naphthylsulfonyl) -1 H-indazole; 5-. { [(3S) -3-Methylpiperazin-1-yl] methyl} -3- (1-naphthylsulfonyl) -1 H-indazole; (3S) -N-. { [3- (1-Naphthylsulfonyl) -1 H -indazol-5-yl] methyl} pyrrolidin-3-amine; (3R) -1-. { [3- (1-Naphthylsulfonyl) -1 H -indazol-5-yl] methyl} pyrrolidin-3-amine; N- [2- (Dimethylamino) ethyl] -3- (1-naphthylsulfonyl) -1 H -indazole-5-carboxamide; 2-. { [5-Fluoro-3- (phenylsulfonyl) -1 H -indazol-7-yl] oxy} ethanamine; N- [3- (1-Naphthylsulfonyl) -1 H -indazol-6-yl] -beta-alaninamide; N- [3- (1-Naphthylsulfonyl) -1 H -indazol-7-yl] -3-piperidin-1-ylpropanamide; N ~ 3 ~, N ~ 3 ~ -Dimethyl-N- [3- (1-naphthylsuJpphenyl) -1 H -indazol-7-yl] -beta-alaninamide; 2-. { [3- (Phenylsulfonyl) -1 H -indazol-7-yl] pxi} ethanamine; N- [3- (1-Naphthylsulfonyl) -1 H -indazol-7-yl] -beta-alaninamide; N- [3- (1-Naphthylsulfonyl) -1 H -indazol-7-yl] ethane-1,2-diamine; N- [3- (1-Naphthylsulfonyl) -1 H -indazol-6-yl] -3-piperidin-1-ylpropanamide; N- [3- (1-Naphthylsulfonyl) -1 H -indazol-6-yl] ethane-1,2-diamine; N 3, N 3 -diethyl-N- [3- (1-naphthylsulfonyl) -1 H -indazol-7-yl] -beta-alaninamide; N, N-Dimethyl-2-. { [3- (1-naphthylsulfonyl) -1 H -indazol-4-yl] oxy} ethanamine; 3- (1-Naphthylsulfonyl) -4- (2-piperidin-1-ylethoxy) -1 H -indazole; 3- (1-Naphthylsulfonyl) -4- (2-pyrrolidin-1-ylethoxy) -1 H -indazole; 2-. { [3- (1-N-phenylsulfonyl) -1 H -indazol-4-yl] oxy} ethanamine; N-Methyl-2-. { [3- (1-naphthylsulfonyl) -1 H -indazol-6-yl] oxy} ethanamine; 2-. { [3- (1-Naphthylsulfonyl) -1 H -indazol-6-yl] oxy} ethanamine; a stereoisomer of these; and a pharmaceutically salt thereof. "^ . A method for the treatment of a central nervous system disorder related to or affected by the 5-HT6 receptor in a patient in need thereof comprising administering to said patient a therapeutically effective amount of the compound of formula I in accordance with a any of claims 1 to 9. . The method according to claim 10 wherein said disorder is a cognitive disorder, a developmental disorder or a neurodegenerative disorder. - V! %. The method according to claim 11 wherein said disorder is a cognitive disorder. . The method according to claim 11 wherein said disorder is selected from the group consisting of: a learning disorder; an attention deficit disorder; Down syndrome, fragile X syndrome or autism . The method according to claim 11 wherein said disorder is apoplexy or cranial trauma. . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound of formula I according to any one of claims 1 to 9. A process for the preparation of a compound of formula I according to any one of claims 1 to 9. whose process comprises: reacting a compound of formula II (") wherein X, R2, R3, R, R5, R6, R7, m and n are as described here above for formula I; with NaNO2 in the presence of an acid to give the compound of formula I wherein Ri is H; Y optionally reacting said compound with R Hal, wherein HHaall eess CCll ,, BBrr .. or II and y RRii eess uunn ggrruuppoo alkyl, cycloalkyl, aryl or - 1 < P Yi-heteroaryl each optionally substituted.