This invention relates to substituted-3-sulfonylindazole derivatives as 5-hydroxytryptamine-6 ligands
BACKGROUND OF THE INVENTION
Serotonin (5-hydroxytryptamine) (5-HT) 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 human 5-HT receptor subtypes 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, first cloned from rat tissue in 1993 (Monsma, F. J.; Shen, Y.; Ward, R. P.; Hamblin, M. W. Molecular Pharmacology 1993, 43, 320-327) and subsequently from human tissue (Kohen, R.; Metcalf, M. A.; Khan, N.; Druck, T.; Huebner, K.; Sibley, D. R. Journal of Neurochemistry 1996, 66, 47-56). The receptor is a G-protein coupled receptor (GPCR) positively coupled to adenylate cyclase (Ruat, M.; Traiffort, E.; Arrang, J-M.; Tardivel-Lacombe, L.; Diaz, L.; Leurs, R.; Schwartz, J-C. Biochemical Biophysical Research Communications 1993, 193, 268-276). The receptor is found almost exclusively in the central nervous system (CMS) areas both in rat and in human. In situ hybridization studies of the 5-HT6 receptor in rat brain using mRNA indicate principal localization in the areas of 5-HT projection including striatum, nucleus accumbens, olfactory tubercle, and hippocampal formation (Ward, R. P.; Hamblin, M. W.; Lachowicz, J. E.; Hoffman, B. J.; Sibley, D. R.; Dorsa, D. M. Neuroscience 1995, 64, 1105-1111).
There are many potential therapeutic uses for 5-HT6 ligands in humans based on direct effects and on indications from available scientific studies. These studies provided information including the localization of the receptor, the affinity of ligands with known in vivo activity, and results obtained from various animal studies conducted so far (Woolley, M. L.; Marsden, C. A.; Fone, K. C. F. Current Drug Targets: CNS & Neurological Disorders 2004, 3(1), 59-79).
One therapeutic use of modulators of 5-HT6 receptor function is in the enhancement of cognition and memory in human diseases such as Alzheimer's. The high levels of receptor found in important structures in 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 memory (Gerard, C.; Martres, M.-P.; Lefevre, K.; Miquel, M.C.; Verge, D.; Lanfumey, R.; Doucet, E.; Hamon, M.; El Mestikawy, S. Brain Research, 1997, 746, 207-219). The ability of known 5-HT6 receptor ligands to enhance cholinergic

transmission also supported the cognition use (Bentley, J. C.; Boursson, A.; Boess, F. G.; Kone, F. C.; Marsden, C. A.; Petit, N.; Sleight, A. J. British Journal of Pharmacology, 1999, 126(7), 1537-1542). Studies have demonstrated that a known 5-HT6 selective antagonist significantly increased glutamate and aspartate levels in the frontal cortex without elevating levels of noradrenaline, dopamine, or 5-HT. This selective elevation of neurochemicals known to be involved in memory and cognition indicates the role 5-HT6 ligands play in cognition (Dawson, L. A.; Nguyen, H. Q.; Li, P. British Journal of Pharmacology, 2000, 130(1), 23-26). Animal studies of memory and learning with a known selective 5-HT6 antagonist found positive effects (Rogers, D. C.; 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 memory including in a novel object 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, C. A.; Sleight, A. J.; Fone, K. C. F. Psychopharmacology, 2003, 170(4), 358-367) and in a water maze model (Rogers, D. C.; Hagan, J. J. Psychopharmacology, 2001, 158(2), 114-119 and Foley, A. G.; Murphy, K. J.; Hirst, W. D.; Gallagher, H. C.; Hagan, J. J.; Upton, N.; Walsh, F. S.; Regan, C. 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 5-HT6 antagonists enhance the activity of the nigrostriatal dopamine pathway and because ADHD has been linked to abnormalities in the caudate (Ernst, M; Zametkin, A. J.; Matochik, J. H.; Jons, P. A.; Cohen, R. M. Journal of Neuroscience 1998, 18(15), 5901-5907), 5-HT6 antagonists attenuate attention deficit disorders.
Early studies examining the affinity of various CNS ligands with known therapeutic utility or a strong structural resemblance to known drugs implicates 5-HT6 ligands in the treatment of schizophrenia and depression. For example, clozapine (an effective clinical antipsychotic) has high affinity for the 5-HT6 receptor subtype. Also, several clinical antidepressants have high affinity for 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).
Further, recent in vivo studies in rats indicate that 5-HT6 modulators are useful in the treatment of movement disorders including epilepsy (Stean, T.; Routledge, C.; Upton, N. British Journal of Pharmacology 1999, 727 Proc.

Supplement 131P and Routledge, C.; Bromidge, S. M.; Moss, S. F.; Price, G. W.; Hirst, W.; Newman, H.; Riley, G.; Gager, T.; Stean, T.; Upton, N.; Clarxe, S. E.; Brown, A. M. British Journal of Pharmacology 2000, 130(7), 1606-1612).
Therefore, it is an object of this invention to provide compounds which are useful as therapeutic agents in the treatment of a variety of central nervous system disorders related to 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 may also be used to further study and elucidate the 5-HT6 receptor.
SUMMARY OF THE INVENTION
The present invention provides a 3-sulfonylindazole compound of formula I
(Formula Removed)
wherein
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;
R1 is H or an alkyl, cycloalkyl, aryl or heteroaryl group each optionally substituted;
R2 is an optionally substituted alkyl, cycloalkyl, aryl or heteroaryl group or an optionally substituted 8- to 13-membered bicyclic or tricyclic ring system having a N atom at the bridgehead and optionally containing 1, 2 or 3 additional 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 alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted, or R5 and R6 may be taken together with the atom to which they are attached to form an optionally substituted 3- to 7-membered ring optionally containing an additional heteroatom selected from O, N or S;
R7 is H, halogen, CN, OR8, CO2R9 CONR10R11, or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
m is an integer of 1, 2 or 3;
R8 is H, COR12 or an alkyl, alkenyl, alkynyl, aryl or heteroaryl group each optionally substituted;
R9 is H or a C1-C6alkyl, aryl or heteroaryl group each optionally substituted;
R10 and RH are each independently H or an optionally substituted alkyl group; and
R12 is an optionally substituted C1-C6alkyl, 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. Its ability to bind a wide range of therapeutic compounds used in psychiatry, coupled with its intriguing distribution in the brain has stimulated significant interest in new compounds which are capable of interacting with or affecting said receptor. Significant efforts are being made to understand the role of the 5-HT6 receptor in psychiatry, cognitive dysfunction, motor function and control, memory, mood and the like. To that end, compounds which demonstrate a binding affinity for the 5-HT6 receptor are earnestly sought both as an aid in the study of the 5-HT6 receptor and as potential therapeutic agents in the treatment of central nervous system disorders, for example see C. Reavill and D. C. Rogers, Current Opinion in Investigational Drugs, 2001, 2(1): 104-109, Pharma Press Ltd and Woolley, M. L; Marsden, C. A.; Fone, K. C. F. Current Drug Targets: CNS & Neurological Disorders 2004, 3(1), 59-79.
Surprisingly, it has now been found that 3-sulfonylindazole compounds of formula I demonstrate 5-HT6 receptor affinity along with significant receptor sub-type selectivity. Advantageously, said formula I compounds are effective therapeutic agents for the treatment of central nervous system (CNS) disorders associated with or affected by the 5-HT6 receptor. Accordingly, the present invention provides a 3-sulfonylindazole compound of formula I
(Formula Removed)
wherein
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;
R1is H or an alkyl, cycloalkyl, aryl or heteroaryl group each optionally substituted;
R2 is an optionally substituted alkyl, cycloalkyl, aryl or heteroaryl group or an optionally substituted 8- to 13-membered bicyclic or tricyclic ring system having a N atom at the bridgehead and optionally containing 1, 2 or 3 additional 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 alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted, or R5 and R6 may be taken together with the atom to which they are attached to form an optionally substituted 3- to 7-membered ring optionally containing an additional heteroatom selected from O, N or S;
R7 is H, halogen, CN, OR8, C02R9, CONR10R11, or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
m is an integer of 1, 2 or 3;
R8 is H, COR12 or an alkyl, alkenyl, alkynyl, aryl or heteroaryl group each optionally substituted;
R9 is H or a C1-C6alkyl, aryl or heteroaryl group each optionally substituted;
RIO and RH are each independently H or an optionally substituted alkyl group; and
R12 is an optionally substituted C1-C6alkyl, cycloalkyl, cycloheteroalkyl, aryl or
heteroaryl group; or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
It is understood that the claims encompass all possible stereoisomers and prodrugs. Moreover, unless stated otherwise, each alkyl, alkenyl, alkynyl, cycloalkyl cycloheteroalkyl, aryl or heteroaryl group is contemplated as being optionally substituted.
An optionally substituted moiety may 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 the modification of such compounds to influence their structure/activity, persistence, absorption, stability or other beneficial property. Specific examples of such substituents include halogen atoms, nitro, cyano, thiocyanato, cyanato, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, formyl, alkoxycarbonyl, carboxyl, alkanoyl, alkylthio, alkylsuphinyl, alkylsulphonyl, carbamoyl, alkylamido, phenyl, phenoxy, benzyl, benzyloxy, heterocyclyl or cycloalkyl groups, preferably halogen atoms or lower alkyl or lower alkoxy groups. Unless otherwise specified, typically, 0-4 substituents may be present. When any of the foregoing substituents represents or contains an alkyl substituent group, this 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 (C1-C10) straight chain and (C3-C12) branched-chain (unless defined otherwise) monovalent saturated hydrocarbon moiety. Examples of saturated hydrocarbon alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higher 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, NR10R11, halogen, phenyl, carbamoyl, carbonyl, alkoxy or aryloxy.
As used herein the term "haloalkyl" designates a CnH2n+1 group having from one to 2n+1 halogen atoms which may be the same or different. Examples of haloalkyl groups include CF3, CH2CI, C2H3BrCI, C3H5F2, or the like.
The term "halogen", as used herein, designates fluorine, chlorine, bromine, and iodine.
The term "alkenyl", as used herein, refers to either a (C2-C8) straight chain or (C3-C10) branched-chain monovalent hydrocarbon moiety containing at least one double bond. Such hydrocarbon alkenyl moieties may be mono or polyunsaturated, and may exist in the E or Z configurations. The compounds of this invention are meant to include all possible E and Z configurations. Examples of mono or polyunsaturated hydrocarbon alkenyl moieties 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 higher homologs, isomers, or the like.
The term "cycloalkyl", as used herein, refers to a monocyclic, bicyclic, tricyclic, fused, bridged, or spiro monovalent saturated hydrocarbon moiety of 3-10 carbon atoms, unless otherwise specified, wherein the carbon atoms are located inside or outside of the ring system. Any suitable ring position of the cycloalkyl moiety may be covalently linked to the defined chemical structure. Examples of cycloalkyl moieties 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 designates a C5-C7cycloalkyl ring system containing 1, 2 or 3 heteroatoms, which may be the same or different, selected from N, O or S and optionally containing one double bond. Exemplary of the cycloheteroalkyl ring systems included in the term as designated herein are the following rings wherein X, is NR', O or S and R is H or an optional substituent as defined hereinbelow.
(FormulaRemoved)
The term "aryl", as used herein, refers to an aromatic carbocyclic moiety of up to 20 carbon atoms, which may be a single ring (monocyclic) or multiple rings (bicyclic, up to three rings) fused together or linked covalently. Any suitable ring position of the aryl moiety may be covalently linked to the defined chemical structure. Examples of aryl moieties 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 designates an aromatic heterocyclic ring system, which may be a single ring (monocyclic) or multiple rings (bicyclic, up to three rings) fused together or linked covalently. Preferably, heteroaryl is a 5- to 6-membered ring. The rings may contain from one to four hetero atoms selected from nitrogen, oxygen, or sulfur, wherein the nitrogen or sulfur atom(s) are optionally oxidized, or the nitrogen atom(s) are optionally quarternized. Any suitable ring position of the heteroaryl moiety may be covalently linked to the defined chemical structure. Examples of heteroaryl moieties 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.
Exemplary of the 8- to 13-membered bicyclic or tricyclic ring systems having a N atom at the bridgehead and optionally containing 1, 2 or 3 additional heteroatoms selected from N, O or S included in the term as designated herein are the following ring systems wherein W is NR1, O or S; and R1 is H or an optional substituent as described hereinbelow:
(Formula Removed)
The compounds of this invention are limited to those that are chemically feasible and stable. Therefore, a combination of substituents or variables in the compounds described above is permissible only if such a combination results in a stable or chemically feasible compound.
Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by a 13C- or 14C-enriched carbon are within the scope of this invention.
The compounds of the present invention may be converted to salts, in particular pharmaceutically acceptable salts using art recognized procedures. 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 salts with ammonia or an organic amine, such as morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine, for example ethyl-tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethylpropylamine, or a mono-, di-, or trihydroxy lower alkylamine, for example mono-, di- or triethanolamine. Internal salts may furthermore be formed. Salts which are unsuitable for pharmaceutical uses but which can be employed, 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, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known acceptable acids when a compound of this invention contains a basic moiety. Salts may also be formed from organic and inorganic bases, preferably alkali metal salts, for example, sodium, lithium, or potassium, when a compound of this invention contains a carboxylate or phenolic moiety, or similar moiety capable of forming base addition salts.
Compounds of the invention include esters, carbamates or other conventional prodrug forms, which in general, are functional derivatives of the compounds of the invention and which are readily converted to the inventive active moiety in vivo. Correspondingly, the method of the invention embraces the treatment of the various conditions described hereinabove with a compound of formula I or with a compound which is not specifically disclosed but which, upon administration, converts to a compound of formula I in vivo. Also included are metabolites of the compounds of the present invention defined as active species produced upon 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 is those formula I compounds wherein n is 2 or 3.
Also preferred are those formula I compounds wherein R2 is an optionally substituted aryl or heteroaryl group or an optionally subtituted 8- to 13-membered bicyclic or tricyclic ring system having a N atom at the bridgehead and optionally containing 1, 2 or 3 additional heteroatoms selected from N, O or S.
More preferred compounds of the invention are those compounds of formula I wherein X is O and R5 and Re are each independently H or C1-C4alkyl. Another group of more preferred compounds is 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)-1H-indazol-5-yl]oxy}propan-1-amine; N-Methyl-N-{2-[3-(phenylsulfonyl)-1H-indazol-5-yl]ethyl}amine; N,N-Dimethyl-N-{2-[3-(phenylsulfonyl)-1H-indazol-5-yl]ethyl}amine; {2-[3-(Phenylsulfonyl)-1H-indazol-7-yl]ethyl}amine; N,N-Dimethyl-N-{2-[3-(phenylsulfonyl)-1H-indazol-7-yl]ethyl}amine; N-{2-[3-(Phenylsulfonyl)-1H-indazol-7-yl]ethyl}cyclopropanamine; N,N-Dimethyl-N-{3-[3-(phenylsulfonyl)-1H-indazol-5-yl]propyl}amine; N-{3-[3-(Phenylsulfonyl)-1H-indazol-5-yl]propyl}cyclopropanamine; {3-[3-(Phenylsulfonyl)-1H-indazol-5-yl]propyl}amine; {4-[3-(Phenylsulfonyl)-1H-indazol-5-yl]butyl}amine; N-Methyl-N-{2-[3-(phenylsulfonyl)-1H-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)-1H-indazol-5-yl]oxy}ethanamine; N-(2-{[3-(1-Naphthylsulfonyl)-1H-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)-1H-indazol-5-yl]oxy}ethanamine; N-(2-{[3-(1 -Naphthylsulfonyl)-! H-indazol-5-yl]oxy}ethyl)butan-1 -amine; N~1~-[3-(1-Naphthylsulfonyl)-1H-indazol-5-yl]-beta-alaninamide; N-Ethyl-2-{[3-(phenylsulfonyl)-1H-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)-1H-indazol-5-yl]oxy}ethanamine; N-Methyl-2-{[3-(1-naphthylsulfonyl)-1H-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)-1H-indazol-5-yl]oxy}ethyl)cyclopropanamine;1-(3-Chlorobenzyl)-3-(1-naphthylsulfonyl)-7-(2-piperidin-1-ylethoxy)-1H-indazole;1-(3-Chlorobenzyl)-3-(1-naphthylsulfonyl)-7-(2-pyrrolidin-1-ylethoxy)-1H-indazole;(2S)-3-Methyl-N~1~-[3-(1-naphthylsulfonyl)-1H-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)-1H-indazol-5-yl]oxy}ethyl)cyclopentanamine;
3-(Phenylsulfonyl)-5-(2-pyrrolidin-1 -ylethoxy)-1 H-indazole;
N-Methyl-2-{[3-(phenylsulfonyl)-1H-indazol-5-yl]oxy}ethanamine;
N-Methyl-2-{[1-methyl-3-(phenylsulfonyl)-1H-indazol-7-yl]oxy}ethanamine;
1 -Methyl-3-(phenylsulfonyl)-7-(2-pyrrolidin-1 -ylethoxy)-1 H-indazole;
(2-{[1-(3-Chlorobenzyl)-3-(phenylsulfonyl)-1H-indazol-7-yl]oxy}ethyl)methylamine;
(2-{[1-(3-Chlorobenzyl)-3-(phenylsulfonyl)-1H-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)-1H-
indazole;
N-Methyl-2-{[3-(phenylsulfonyl)-1H-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)-1H-indazol-7-yl]oxy}ethanamine; N,N-Diethyl-2-{[3-(phenylsulfonyl)-1H-indazol-7-yl]oxy}ethanamine; N-(2-{[3-(Phenylsulfonyl)-1H-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)-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)-1H-indazol-7-yl]oxy}ethanamine; -Naphthylsulfonyl)-1 H-indazol-7-yl]oxy}ethyl)amine;
-(3-Chlorobenzyl)-5-fluoro-3-(1 -naphthylsulfonyl)-1 H-indazol-7-yl]oxy}ethyl)-dimethylamine; (2-{[1-Benzyl-3-(1-naphthylsulfonyl)-1H-indazol-5-yl]oxy}ethyl)methylamine;
-Benzyl-3-(1-naphthylsulfonyl)-1 H-indazol-5-yl]oxy}ethyl)dimethylamine;
-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)-1H-indazol-7-yl]oxy}ethanamine;
5-Fluoro-3-(1-naphthylsulfonyl)-7-(2-pyrrolidin-1-ylethoxy)-1H-indazole;
5-Fluoro-3-(1-naphthylsulfonyl)-7-(2-piperidin-1-ylethoxy)-1H-indazole;
N,N-Diethyl-2-{[5-fluoro-3-(1-naphthylsulfonyl)-1H-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)-1H-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)-1 H-indazol-5-yl]oxy}propan-1-amine; N,N-Diethyl-3-{[3-(1-naphthylsulfonyl)-1H-indazol-5-yl]oxy}propan-1-amine; N-(3-{[3-(1-Naphthylsulfonyl)-1H-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)-1H-indazol-7-yl]oxy}ethyl)methylamine; (2-{[5-Methoxy-3-(1-naphthylsulfonyl)-1H-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)-1H-indazol-5-yl]oxy}ethanamine; N-Ethyl-N-methyl-2-{[1-methyl-3-(1-naphthylsulfonyl)-1H-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)-1H-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)-1H-indazol-5-yl]oxy}propan-1-amine; N-lsopropyl-3-{[3-(1-naphthylsulfonyl)-1H-indazol-5-yl]oxy}propan-1-amine; N-(3-{[3-(1-Naphthylsulfonyl)-1H-indazol-5-yl]oxy}propyl)cyclopentanamine; 5-(3-Morpholin-4-ylpropoxy)-3-(1-naphthylsulfonyl)-1H-indazole; N-(3-{[3-(1-Naphthylsulfonyl)-1H-indazol-5-yl]oxy}propyl)cyclopropanamine; (3-{[3-(1-Naphthylsulfonyl)-1H-indazol-5-yl]oxy}propyl)amine; N-Methyl-4-{[3-(1-naphthylsulfonyl)-1H-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 -naphthylsulfon,'l)-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)-1H-indazol-5-yl]oxy}butyl)amine; (2-{[5-Fluoro-3-(1-naphthylsulfonyl)-1H-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)-1H-indazol-5-yl]propan-1-amine; N,N-Dimethyl-4-[3-(1-naphthylsulfonyl)-1H-indazol-5-yl]butan-1-amine; N,N-Dimethyl-3-[3-(1-naphthylsulfonyl)-1H-indazol-5-yl]propan-1-amine; N-Ethyl-N-methyl-3-[3-(1-naphthylsulfonyl)-1H-indazol-5-yl]propan-1-amine; N-lsopropyl-3-[3-(1-naphthylsulfonyl)-1H-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-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)-1H-indazol-5-yl]butan-1-amine; 5-[(3-Methylpiperazin-1-yl)methyl]-3-(1-naphthylsulfonyl)-1 H-indazole; 5-[(3,5-Dimethylpiperazin-1-yl)methyl]-3-(1-naphthylsulfonyl)-1H-indazol;e N-Ethyl-3-[3-(1-naphthylsulfonyl)-1H-indazol-5-yl]propan-1-amine; {4-[3-(1-Naphthylsulfonyl)-1H-indazol-5-yl]butyl}amine; 5-[1-(4-Methylpiperazin-1-yl)ethyl]-3-(1-naphthylsulfonyl)-1 H-indazole; N.N.N'-Trimethyl-N'-{[3-(-CI-naphthylsulfonyl)-1H-indazol-5-yllmethyl}ethane-l,2-diamine;
N,N-Dimethyl-2-{[3-(1-naphthylsulfonyl)-1H-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)-1H-indazole;
(3S)-N-{[3-(1-Naphthylsulfonyl)-1H-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)-1H-indazole-5-carboxamide;
2-{[5-Fluoro-3-(phenylsulfonyl)-1H-indazol-7-yl]oxy}ethanamine;
N-[3-(1 -Naphthylsulfonyl)-1 H-indazol-6-yl]-beta-alaninamide;
N-[3-(1-Naphthylsulfonyl)-1H-indazol-7-yl]-3-piperidin-1-ylpropanamide;
N~3~,N~3~-Dimethyl-N-[3-(1-naphthylsulfonyl)-1H-indazol-7-yl]-beta-alaninamide;
2-{[3-(Phenylsulfonyl)-1H-indazol-7-yl]oxy}ethanamine;
N-[3-(1-Naphthylsulfonyl)-1H-indazol-7-yl]-beta-alaninamide;
N-[3-(1-Naphthylsulfonyl)-1 H-indazol-7-yl]ethane-1,2-diamine;
N-[3-(1-Naphthylsulfonyl)-1H-indazol-6-yl]-3-piperidin-1-ylpropanamide;
N-[3-(1-Naphthylsulfonyl)-1 H-indazol-6-yl]ethane-1,2-diamine;
N3,N3-diethyl-N-[3-(1-naphthylsulfonyl)-1H-indazol-7-yl]-beta-alaninamide;
N,N-Dimethyl-2-{[3-(1-naphthylsulfonyl)-1H-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)-1H-indazol-6-yl]oxy}ethanamine;
2-{[3-(1 -Naphthylsulfonyl)-1 H-indazol-6-yl]oxy}ethanamine;
a stereoisomer thereof; 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 naphthyl.
In one embodiment R1 is H or optionally substituted alkyl.
In a further embodiment m is 0 or 1. In another embodiment m is 0. In one embodiment R5 and R6 are each independently H or C1-C4 alkyl.
Compounds of the invention may be prepared using conventional synthetic methods and, if required, standard isolation or separation techniques In Schemes I through VII below, Z represents the group (CR3R4)n wherein R3, R4 and n are as defined hereinabove for formula I.
Compounds of formula I wherein X is O (la) may be prepared as illustrated in Scheme I below wherein the chloromethylsulfone 2 is either commercially available
or readily prepared using methods as described by M. Makosza 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 affords the chloromethylsulfone 2. Reaction of 2 with a fluoronitrobenzene 3 under basic conditions gives the benzylsulfonyl derivative 4. Compound 4 is reacted with the diol, HO-(CR3R4)n-OH, under basic conditions to give 5. Tosylation, followed by hydrogenation, of 5 gives the aniline 6. Compound 6 is reacted with sodium nitrite in the presence of an acid to give the indazole 7. Alkylation of the indazole 7 yields the alkylated tosylate compound 8. Displacement of the tosyl groups of either of compounds 7 or 8 with the appropriate amine then gives the desired compound of formula la. The reaction is shown in Scheme I wherein Ts represents p-toluenesulfonyl and Hal represents Cl, Br or l.
(Formula Removed)
Similarly compounds of formula I wherein X is O and R5 and R6 are H (Ib), or compounds of formula la, may be prepared by reacting the nitrobenzene derivative 9 with chloromethylsulfone 2, followed by hydrogenation to give the aniline 10. The anilinelO is converted to the indazole derivative 11, as described hereinabove in Scheme I. Alkylation or protection of the indazole 11 gives compound 12. Reaction of 12 with sodium azide followed by reduction of the azido group yields the desired primary amine Ib. Alternatively, reaction of 11 or 12 with an amine, HNR5R6, gives the compound of la. The reaction is shown in Scheme II wherein Hal represents Cl, Br or I.
SCHEME II
(Formula Removed)
Alternatively, formula la compounds may be prepared by the reaction of an amino alcohol 14 with either a fluoro-nitrobenzene 13 under basic conditions, or a nitrophenol 15 under Mitsunobu conditions, to give the compound 16. Compound 16 is reacted with a chlorosulfone 2, followed by hydrogenation, to give the aniline 17. Subsequent formation of the desired formula la indazoles is carried out as described hereinabove in Schemes I and II. The reaction is shown in Scheme III wherein Hal represents Cl, Br or l. SCHEMEIII
(Formula Removed)
Compounds of formula I wherein X is NR and R and RI are H (Ib) or X is NRCO and R and R1 are H (Ic) may be prepared by reacting a nitroindazole 18 with iodine to give the corresponding 3-iodoindazole 19; coupling 19 with a thiol 20, followed by oxidation with a suitable oxidizing agent such as m-chloroperbenzoic acid (mCPBA) to give the sulfone 21; reducing the nitro group of 21 with Sn/HCI or SnCI2/HCI to obtain the corresponding amine 22; and either reacting 22 with the amino aldehyde 23 under reductive amination conditions to afford the desired compound of formula Ib, or coupling 22 with an amino acid 24 to give the desired compound of formula Ic. The reactions are shown in Scheme IV hereinbelow, wherein Ac represents COCH3.
SCHEME IV
(Formula Removed)
Compounds of formula I wherein X is CH2 and R5 and R6are other than H (Id) may be prepared by reacting the nitrobenzene compound 25 with the the chloromethylsulfonyl compound 2 to obtain the intermediate 26; reducing the nitro group of compound 26 to the corresponding amine and nitrosating said amine, as described in Schemes II and III, to form the desired compound of formula Id wherein R1 is H and optionally alkylating said compound to obtain the desired compound of formula Id wherein R1 is other than H. The reactions are shown in Scheme V hereinbelow, wherein Hal represents Cl, Br or I.
SCHEME V
(Formula Removed)
ompounds of formula Id wherein R5 is H (le) may be prepared in a similar manner by protecting the compound 27 with a suitable protecting group such as t-butyloxycarbonyl (BOC), ethyloxycarbonyl, methyloxycarbonyl, benzyl (Bn), phthalimide, fluorenylmethylcarbonyl (Fmoc), acetyl, benzoly, or the like to give the protected amine 28; reacting compound 28 with the chloromethylsulfonyl 2, followed by reduction and nitrosation as shown hereinabove in Scheme V to obtain the protected compound 29 and deprotecting to give the desired compound of formula le. The reaction is shown in Scheme VI hereinbelow, wherein Hal represents Cl, Br or I.SCHEME VI
(Formula Removed)
Compounds of formula Id may also be prepared by coupling the compound 31 with an alkyne 32 using Sonagashira conditions to give the compound 33; reducing 33 to the fully saturated amine 34; reacting 34 with NaNO2 to give the indazole 35 and converting the hydroxyl group to a leaving group and displacing the leaving group with an amine, HNR5R6, optionally alkylating the resultant product to give the desired compound of formula Id. The reactions are shown in Scheme VII hereinbelow wherein TsCI represents tosyl chloride and Hal represents Cl, Br or I.
SCHEME VII
(Formula Removed) Advantageously, the formula I compounds of the invention are useful for the treatment of CNS disorders related to or affected by the 5-HT6 receptor including motor, mood, personality, behavioral, psychiatric, cognitive, neurodegenerative, or the like disorders, for example Alzheimer's disease, Parkinson's disease, attention deficit disorder, anxiety, epilepsy, depression, obsessive compulsive disorder, sleep disorders, neurodegenerative disorders (such as head trauma or stroke), feeding disorders (such as anorexia or bulimia), schizophrenia, memory loss, disorders associated with withdrawal from drug or nicotine abuse, or the like or certain gastrointestinal disorders such as irritable bowel syndrome. Accordingly, the present invention provides a method for the treatment of a disorder of the central nervous system related to or affected by the 5-HT6 receptor in a patient in need thereof which comprises providing said patient a therapeutically effective amount of a compound of formula I as described hereinabove. The compounds may be provided by oral or parenteral administration or in any common manner known to be an effective administration of a therapeutic agent to a patient in need thereof.
The term "providing" as used herein with respect to providing a compound or substance embraced by the invention, designates either directly administering such a compound or substance, or administering a prodrug, derivative or analog which forms an equivalent amount of the compound or substance within the body.
The inventive method includes: a method for the treatment of schizophrenia; a method for the treatment of a disease associated with a deficit in memory,cognition, and/or learning or a cognitive disorder such as Alzheimer's disease or attention deficit disorder; a method for the treatment of developmental disorders such as schizophrenia; Down's syndrome, Fragile X syndrome, autism or the like; a method for the treatment of behavioral disorders, e.g., anxiety, depression, or obsessive compulsive disorder; a method for the treatment of motion or motor disorders such as Parkinson's disease or epilepsy; a method for the treatment of a neurodegenerative disorder such as stroke or head trauma or withdrawal from drug addiction including addiction to nicotine, alcohol, or other substances of abuse, or any other CNS disease or disorder 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 Disorder or ADHD) in both children and adults. Accordingly, 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 the treatment of each of the conditions listed above in a patient, preferably in a human, said method comprises providing said patient a therapeutically effective amount of a compound of formula I as described hereinabove. The compounds may be provided by oral or parenteral administration or in any common manner known to be an effective administration of a therapeutic agent to a patient in need thereof.
The therapeutically effective amount provided in the treatment of a specific CNS disorder may vary according to the specific condition(s) being treated, the size, age and response pattern of the patient, the severity of the disorder, the judgment of the attending physician and the like. In general, effective amounts for daily oral administration may be about 0.01 to 1,000 mg/kg, preferably about 0.5 to 500 mg/kg and effective amounts for parenteral administration may be about 0.1 to 100 mg/kg, preferably about 0.5 to 50 mg/kg.
In actual practice, the compounds of the invention are provided by administering the compound or a precursor thereof in a solid or liquid form, either neat or in combination with one or more conventional pharmaceutical carriers or excipients. Accordingly, the present invention provides a pharmaceutical composition which comprises a pharmaceutically acceptable carrier and an effective amount of a compound of formula I as described hereinabove.
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 pharmaceutically acceptable carriers, excipients, or diluents. Such
compositions include pharmaceutical compositions for treating or controlling disease states or 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 thereof, and one or more pharmaceutically acceptable carriers, excipients, or diluents. Such compositions are prepared in accordance with acceptable pharmaceutical procedures. Pharmaceutically acceptable carriers are those carriers that are compatible with the other ingredients in the formulation and are biologically acceptable.
The compounds of formula I may be administered orally or parenterally, neat, or in combination with conventional pharmaceutical carriers. Applicable solid carriers can include one or more substances that can 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 carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. 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, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
In certain embodiments, a compound of formula I is provided in a disintegrating tablet formulation suitable for pediatric administration.
Liquid carriers can be used in preparing 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 can 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 as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols e.g. glycols) and their derivatives, and oils (e.g. fractionated
coconut oil and arachis oil). For patenteral administration, the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration. The liquid carrier for pressurized compositions can 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 that are sterile solutions or suspensions can be administered by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Compositions for oral administration can be in either liquid or solid form.
The compounds of formula I may be administered rectally or vaginally in the form of a conventional suppository. For administration by intranasal or intrabronchial inhalation or insufflation, the compounds of formula I can be formulated into an aqueous or partially aqueous solution, which can then be utilized in the form of an aerosol. The compounds of formula I can also be administered transdermally through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, is non-toxic to the skin, and allows delivery of the agent for systemic absorption into the blood stream via the skin. The carrier 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 semisolid emulsions of either the oil-in-water or water-in-oil type. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient can also be suitable. A variety of occlusive devices can be used to release the active ingredient into the blood stream such as a semipermeable membrane covering 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 unit dosage form, e.g. as tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories. In such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient; the unit dosage forms can be packaged compositions, for example, packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
The therapeutically effective amount of a compound of formula I provided to a patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like. In therapeutic applications, compounds of formula I are provided 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. An amount adequate to accomplish this is a "therapeutically effective amount" as described previously herein. The dosage to be used in the treatment of a specific case must be subjectively determined by the attending physician. The variables involved include the specific condition and the size, age, and response pattern of the patient. The treatment of substance abuse follows the same method of subjective drug administration under the guidance of the attending physician. 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 compounds of formula I. The term "prodrug," as used herein, means a compound that is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of formula I. Various forms of prodrugs are known in the art 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. of Pharmaceutical Sciences, 77:285 et seq. (1988); and Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975).
For a more clear understanding, and in order to illustrate the invention more clearly, specific examples thereof are set forth hereinbelow. The following examples are merely illustrative and are not to be understood as limiting the scope and underlying principles of the invention in any way. The terms HNMR, MS and HPLC designate mass spectrum, high performance liquid chromatography and proton nuclear magnetic resonance, respectively. The terms THF, DMF and DMSO designate tetrahydrofuran, dimethyl formamide and dimethylsulfoxide, respectively. All column chromatography is performed using SiO2 as support. Unless otherwise noted, all parts are parts by weight.
Example 1
[2-(3-Benzenesulfonyl-1H-indazol-5-yloxy)-ethyl]-dimethyl-amine Stepl
(Formula Removed)

2-Benzenesulfonylmethyl-4-fluoro-1-nitro-benzene:
To a solution of chloromethylphenyl sulfone (10.51 g, 55.13 mmol) in THF (110 ml) was added 5.9 ml (56 mmol) of 1-fluoro-4-nitrobenzene. The reaction mixture was chilled to 0 °C, and 1.0 M potassium tert-butoxide in THF (145 ml, 145 mmol) was added dropwise. The reaction mixture was stirred under nitrogen at ambient temperature for one hour. Acetic acid (9 ml, 160 mmol) was then added. The reaction mixture was solvent evaporated and partitioned in brine 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 in vacua at 73°C for 12 hours. 2-Benzenesulfonylmethyl-4-fluoro-1 -nitrobenzene as a light brown-yellow solid was obtained (10.24 g, 62.8 %): MP: 169-171 °C; Mass spectrum (-EI, [M-H]') m/z294. 1HNMR (500 MHz, DMSO-d6): 88.10-8.14 (m, 1H), 7.70-7.75 (m, 1H), 7.56-7.63 (m, 4H), 7.45-7.50 (m, 1H), 7.20 (dd, 1H, J = 9.27 Hz and 2.81 Hz), 5.12 ppm (s, 2H). Elemental Analysis for C13H10FNO4S: Calcd: C, 52.88; H, 3.41; N, 4.74; Found: C, 52.63; H, 3.14; N, 4.66;
Step 2
(Formula Removed)
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 fert-butoxide in THF (78 mL, 78 mmol) in THF (50 mL) was refluxed under nitrogen for 30 minutes. After cooling to about ambient temperature, the reaction mixture was solvent evaporated. Water was added to the residue, and it was poured into 2.0 N hydrochloric acid and ice. The mixture was then extracted with ethyl acetate and washed with water and brine. The organic phase was dried with anhydrous magnesium sulfate, filtered, concentrated and dried in vacua at 74 °C for 20 minutes. 2-(3-Benzenesulfonylmethyl-4-nitro-phenoxy)-ethanol as a dark brown gum (1 1.7 g, 100
% yield) was obtained; Mass spectrum (-EI, [M-H]-) m/z 336. 1HNMR (500 MHz, DMSO-d6): 88.01 (d, 1H, J=9.15 Hz), 7.67-7.73 (m, 1H), 7.54-7.63 (m, 4H), 7.10 (dd, 1H, J= 9.51 Hz and 2.93 Hz), 6.85 (d, 1H, J=2.81 Hz), 5.12 (s, 2H), 4.88-4.90 (m, 1H), 3.93-3.96 (m, 2H), 3.65 ppm (d, 2H, J=4.51 Hz). Elemental Analysis for Ci5H15N06S: Gated: C, 53.41; H, 4.48; N, 4.15; Found: C, 53.47; H, 4.69; N, 4.04;
Step 5
(Formula Removed)
Toluene-4-sulfonicacid 2-(3-benzenesulfonylmethyl-4-nitro-phenoxy)-ethyl ester
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 ambient temperature under nitrogen for 4.5 hours. It then was solvent evaporated and partitioned in methylene chloride and aqueous sodium bicarbonate. The organic phase was then washed with brine, dried with anhydrous magnesium sulfate, filtered, concentrated and dried in vacua at 63°C for 30 minutes. The residue was purified by flash chromatography with 100% chloroform and 5% methanol in chloroform. It was dried in vacua at 65 °C for 20 minutes to yield toluene-4-sulfonic acid 2-(3-benzenesulfonylmethyl-4-nitro-phenoxy)-ethyl ester as a yellow solid (8.1 g, 69 %); Mass spectrum (-EI, [M-H]) m/z 490. 1HNMR (300 MHz, DMSO-d6): 67.99 (d, 1H, J=9.02 Hz), 7.67-7.75 (m, 3H), 7.54-7.62 (m, 4H), 7.43 (d, 2H, J=7.93 Hz), 7.00 (dd, 1H, J=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 C22H2iN08S 0.40 mol H2O: Calcd: C, 52.98; H, 4.41; N, 2.81; Found: C, 52.67; H, 4.26; N, 2.61.
Step 4
(Formula Removed)
Toluene-4-sulfonic acid 2-(4-amino-3-benzenesulfonylmethyl-phenoxy)-ethyl ester
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 ded to 10 % palladium on carbon (5.8 g) and hydrogenated on the Parr apparatus with for one hour (starting pressure of 30-40 psi.). The mixture was filtered over Celite, concentrated and dried in vacua at 80 °C for 30 minutes to yield toluene-4-sulfonic acid 2-(4-amino-3-benzenesulfonylmethyl-phenoxy)-ethyl ester as a light yellow solid (11.7 g, 95.1 %): MP: 144-6 °C; Mass spectrum (+EI, [M+H]+) m/z 462. 1HNMR (500 MHz, DMSO-d6): 57.72-7.75 (m, 4H), 7.63-7.66 (m, 1H), 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, 1H), 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: Calcd: C, 57.25; H, 5.02; N, 3.03; Found: C, 57.60; H, 4.98; N, 3.10.

(Formula Removed)

Toluene-4-sulfonic acid 2-(3-benzenesulfonyl-1H-indazol-5-yloxy)-ethyl ester
To a mixture of toluene-4-sulfonic acid 2-(4-amino-3-benzenesulfonylmethyl-phenoxy)-ethyl ester (1 1 .7 g, 25.3 mmol) of in ethanol (350 ml) and 1 .0 N hydrochloric acid (425 mL) was dropwise added sodium nitrite (2.67 g, 38.7mmol) in water (50 ml). After stirring at ambient temperature for 1 .5 hours, solid sodium carbonate was added to basic pH. The reaction mixure was stirred for an additional 2 hours. It was then solvent evaporated and extracted with warm ethyl acetate. The organic phase was washed with water and brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography with 2 % methanol in chloroform to yield toluene-4-sulfonic acid 2-(3-benzenesulfonyl-1H-indazol-5-yloxy)-ethyl ester as an orange solid (9.54 g, 79.5 %): MP: 174-7 °C; Mass Spectrum (-EI, [M-H]') m/z 471. 1HNMR (500 MHz, DMSO-d6): 614.11 (s, 1H), 7.96-7.98 (m, 2H), 7.74-7.77 (m, 2H), 7.62-7.66 (m, 1H), 7.53-7.59 (m, 3H), 7.39 (d, 2H, J=8.05 Hz), 7.24 (d, 1H, J=2.32 Hz), 6.97-7.00 (m, 1H), 4.35-4.37 (m, 2H), 4.21-4.23 (m, 2H), 2.33 ppm (s, 3H).
Step 6
(Formula Removed)
[2-(3-Benzenesulfonyl-1H-indazol-5-yloxy)-ethyl]-dimethyl-amine
A solution of toluene-4-sulfonic acid 2-(3-benzenesulfonyl-1H-indazol-5-yloxy)-ethyl ester (0.341 g, 0.722 mmol) in 2.0 N dimethylamine in THF (9 mL, 18 mmol) of was stirred at 70 °C for 6 hours in a sealed tube. After cooling somewhat, the reaction mixture was solvent evaporated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was washed with water and brine. It 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 brine, dried with anhydrous magnesium sulfate, filtered and concentrated. [2-(3-Benzenesulfonyl-1H-indazol-5-yloxy)-ethyl]-dimethyl-amine as a light yellow-brown solid (0.167 g, 67.1 %) resulted. The compound was dissolved in methanol, and ethereal hydrochloride was added. After concentrating and drying in vacua for 12 hours at 70 °C, the hydrochloride as a light orange foam (94.0 mg) was obtained; Mass Spectrum (+EI, [M+H]+) m/z 346. 1HNMR (500 MHz, DMSO-d6): 614.22 (s, 1H), 10.00 (br, 1H), 7.97-7.99 (m, 2H), 7.56-7.68 (m, 4H), 7.42 (d, 1H, 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

(Formula Removed)
[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 ambient temperature, the reaction mixture was solvent evaporated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was washed with water and brine, dried with anhydrous magnesium sulfate, filtered and concentrated. After drying in vacuo at ambient temperature for 1.5 hours, the resulting buff solid (0.249 g, 89.9%), [2-(3-benzenesulfonyl-1H-indazol-5-yloxy)-
ethyl]-ethyl-methyl-amine, was dissolved in methanol and methylene chloride, and ethereal hydrochloride was added. Concentration and drying at 80 °C for 12 hours yielded the hydrochloride as a light orange foam (0.253 g); Mass Spectrum (+EI, [M+H]+) m/z 360.1HNMR (500 MHz, DMSO-d6): 814.23 (s, 1H), 9.95 (br, s, 1H), 7.97-7.99 (m, 2H), 7.56-7.68 (m, 4H), 7.42 (d, 1H, J=2.32 Hz), 7.19 (dd, 1H, J=9.15 Hz and 2.32 Hz), 4.41-4.43 (m, 2H), 3.55-3.60 (m, 1H), 3.43-3.49 (m, 1H), 3.11-3.17 (m, 1H), 2.82 (d, 3H, J=4.63 Hz), 1.22-1.25 ppm (m, 3H).
Example 3
(Formula Removed)
3-Benzenesulfonyl-5-(2-piperidin-1 -yl-ethoxy)-1 H-indazole
A solution of toluene-4-sulfonic acid 2-(3-benzenesulfonyl-1H-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 ambient temperature, the reaction mixture was solvent evaporated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was washed with water and brine. It was dried with anhydrous magnesium sulfate, filtered and concentrated. Drying in vacua at 80 °C for 20 minutes resulted in 3-benzenesulfonyl-5-(2-piperidin-1-yl-ethoxy)-1 H-indazole as a light yellow solid (0.275 g, 87.3%). This was dissolved in methanol, and ethereal hydrochloride was added. This mixture was concentrated and dried in vacua at 70°C for about 12 hours to yield the hydrochloride as a yellow solid (0.268 g): MP: 249-250 °C; Mass Spectrum (+EI, [M+H]+) m/z 386. 1HNMR (500 MHz, DMSO-d6): 814.24 (s, 1H), 10.02-10.03 (br, 1H), 7.97-7.99 (m, 2H), 7.56-7.68 (m, 4H), 7.41 (d, 1H, J=2.32 Hz), 7.18 (dd, 1H, 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, 1H). Elemental Analysis for C2oH23N303S.1.00 mol HCI 0.15 mol H2O: Calcd: C, 56.57; H, 5.77; N, 9.90; Found: C, 56.34; H, 5.88; N, 9.57.
Example 4
(Formula Removed)
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 rnmol) in 2.0 N ethylarnine 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 solvent evaporated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was then washed with water and brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography using 10 % methanol in chloroform. After drying in vacua at 68 °C for 20 minutes, [2-(3-benzenesulfonyl-1H-indazol-5-yloxy)-ethyl]-ethyl-amine as a light brown gum (0.116 g, 43.9 %) was obtained. This was dissolved in chloroform and methanol, and ethereal hydrochloride was added. Concentrating and drying at 74°C for 13.5 hours in vacua yielded the hydrochloride as a buff solid (0.113 g): MP: 248-50 °C (dec). Mass Spectrum (+EI, [M+HD m/z 346. 1HNMR (500 MHz, DMSO-d6): 514.23 (s, 1H), 8.81 (br, 2H), 7.96-7.98 (m, 2H), 7.56-7.68 (m, 4H), 7.40 (d, 1H, J=2.07 Hz), 7.19 (dd, 1H, J=9.15 Hz and 2.32 Hz), 4.31 (t, 2H, J=5.00 Hz), 3.35 (br, 2H), 3.00-3.05 (m, 2H), 1.18-1.22 ppm (m, 3H).

(Formula Removed)
[2-(3-Benzenesulfonyl-1H-indazol-5-yloxy)-ethyl]-diethyl-amine
A solution of toluene-4-sulfonic acid 2-(3-benzenesulfonyl-1 H-indazol-5-yloxy)-ethyl ester (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) was added, and the reaction mixture was stirred at 80 °C in a sealed tube for an 6 hours. After cooling somewhat, the reaction mixture was solvent evaporated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was then washed with water and brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography using 7.5 % methanol in chloroform. After drying in vacua at 80 °C for 20 minutes, [2-(3-benzenesulfonyl-1H-indazol-5-yloxy)-ethyl]-diethyl-amine as a pale yellow solid (0.155 g, 46.6 %) was obtained. This was dissolved in methanol and chloroform and ethereal hydrochloride was added. The mixture was concentrated and dried in vacua at 74 °C for 13.5 hours to yield the hydrochloride as
a light orange foam (0.163 g); Mass Spectrum (+EI, [M+HD m/z 374. 1HNMR (500 MHz, DMSO-d6): 814.24 (s, 1H), 9.94 (br, 1H), 7.96-7.99 (m, 2H) 7.56-7.68 (m, 4H), 7.41 (d, 1H, J=2.20 Hz), 7.16-7.19 (m, 1H), 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 C19H23C3S
1.00 mol HCI- 0.20 mol H2O: Calcd: C, 55.18; H, 5.95; N, 10.16; Found: C, 54.85; H, 5.85; N, 10.02.
Example 6

(Formula Removed)
[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, 1 2 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) was added, and the reaction mixture was stirred at 80 °C for 6 hours in a sealed tube. After cooling somewhat, the reaction mixture was solvent evaporated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was then washed with water and brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography using 10 % methanol in chloroform. After drying in vacua at 80 °C for 30 minutes, [2-(3-benzenesulfonyl-1 H-indazol-5-yloxy)-ethyl]-isopropyl-amine as a pale yellow solid was obtained (0.1 10 g, 38.2 %). This was dissolved in methanol and chloroform, and ethereal hydrochloride was added. The mixture was concentrated and dried in vacua at 74 °C for 13.5 hours to yield the hydrochloride as an off-white solid (0.117 g): MP: 275-7 °C (dec); Mass Spectrum (+EI, [M+Hf) m/z 360. 1HNMR (500 MHz, DMSO-d6): 814.22 (br, 1H), 8.75 (br, 2H), 7.96-7.98 (m, 2H), 7.56-7.68 (m, 4H), 7.41 (d, 1H, J=2.08 Hz), 7.19 (dd, 1H, J= 9.15 Hz and 2.32 Hz), 4.30-4.33 (m, 2H), 3.34-3.40 (m, 3H), 1.25 ppm (d, 6H, J=6.59 Hz). Elemental Analysis for C18H21N3O3S 1.00 mol HCI 0.10 mol H2O: Calcd: C, 54.36; H, 5.36; N, 10.57; Found: C, 54.02; H, 5.42; N, 10.22.
Example 7
(Formula Removed)

[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 was solvent evaporated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was then washed with water and brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography using 7.5-10 % methanol in chloroform. After drying in vacua at 55 °C for 40 minutes, [2-(3-benzenesulfonyl-1 H-indazol-5-yloxy)-ethyl]-butyl-amine as a light beige semi-solid (0.105 g, 38.2 %) was obtained. This was dissolved in chloroform, and ethereal hydrochloride was added. The resulting solid was filtered and dried in vacua at 75 °C for 16.5 hours to yield the hydrochloride as a white solid (0.0813 g): MP: 271-3 °C dec; Mass Spectrum (+EI, [M+H]+) m/z374. 1HNMR (300 MHz, DMSO-d6): 814.27-14.35 (br, 1H), 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, 1H, J=9.15 Hz and 2.29 Hz), 4.38-4.41 (m, 2H), 3.41-3.44 (m, 2H), 3.03 (t, 2H, J=7.87 Hz), 1.62-1.72 (m, 2H), 1.33-1.45 (m, 2H), 0.94 ppm (t, 3H, J=7.32 Hz). Elemental Analysis for C19H23N3O3S 1.00 mol HCI 0.05 mol H2O: Calcd: C, 55.55; H, 5.91; N, 10.23; Found: C, 55.23; H, 5.87; N, 10.09.
(Formula Removed)
[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) was added, and the reaction mixture was stirred for 6 hours at 80 °C in a sealed tube. After cooling somewhat, the reaction mixture was solvent evaporated and partitioned in ethyl acetate and aqueous sodium
bicarbonate. The organic phase was then washed with water and brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography using 5 % methanol in chloroform. After drying in vacuo at 55 °C temperature for 25 minutes, [2-(3-benzenesulfonyl-1 H-indazol-5-yloxy)-ethyl]-cyclopropyl-amine as a light yellow foam (0.127 g, 50.0 %) was obtained. This was dissolved in chloroform, and ethereal hydrochloride was added. The mixture was concentrated and dried in vacuo at 75 °C for 16.5 hours to yield the hydrochloride as a buff solid (0.131 g): MP: 184-5 °C dec.; Mass Spectrum (+EI, [M+H]+) m/z 358. 1HNMR (300 MHz, DMSO-d6): 814.33 (s, 1H), 9.33 (br, 2H), 8.03-8.06 (m, 2H), 7.60-7.76 (m, 4H), 7.47 (d, 1H, J=2.11 Hz), 7.25 (dd, 1H, 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, 1H), 1.62-1.72 (m, 2H), 0.92-0.97 (m, 2H), 0.77-0.87 ppm (m, 2H).
(Formula Removed)
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 was solvent evaporated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was then washed with water and brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography using 7.5 % methanol in chloroform. After drying in vacuo at 57 °C for 25 minutes, 3-benzenesulfonyl-5-(2-pyrrolidin-1-yl-ethoxy)-1 H-indazole as a yellow foam (0.137 g, 48.8 %) was obtained. This was dissolved in methanol and chloroform, and ethereal hydrochloride was added. The mixture was concentrated and dried in vacuo at 75 °C for 16.5 hours to yield the hydrochloride as a white solid (0.0956 g): MP: 255-8 °C(dec.); Mass Spectrum (+EI, [M+H]+) m/z 386. 1HNMR (300 MHz, DMSO-d6): 814.31-14.41 (br, 1H), 9.13-9.14 (br, 2H), 8.03-8.06 (m, 2H), 7.62-7.76 (m, 4H), 7.46 (d, 1H, J=2.10 Hz) 7.25 (dd, 1H, 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 (m,
2H). Elemental Analysis for C2oH23N3O3S 1.00 mol HCI 0.50 mol H2O: Calcd: C, 55.74; H, 5.85; N, 9.75; Found: C, 55.39; H, 5.74; N, 9.62.
Example 10
(Formula Removed)
3-Benzenesulfonyl-5-(2-morpholin-4-yl-ethoxy)-1H-indazole
A solution of toluene-4-sulfonic acid 2-(3-benzenesulfonyl-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 was solvent evaporated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was then washed with water and brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography using 5 % methanol in chloroform. After drying in vacua at 57 °C for 20 minutes, 3-benzenesulfonyl-5-(2-morpholin-4-yl-ethoxy)-1 H-indazole as an off-white foam (0.0443 g, 15.1 %) was obtained. This was dissolved in methanol and chloroform, and ethereal hydrochloride was added. The mixture was concentrated and dried in vacua at 75 °C for 16.5 hours to yield the hydrochloride as a light orange foam (0.041 1 g). Mass Spectrum (+EI, [M+H]*) m/z 388. 1HNMR (300 MHz, DMSO-d6): 814.31 (s, 1H), 10.82-88 (br, 1H), 8.03-8.07 (m, 2H), 7.62-7.76 (m, 4H), 7.49 (d, 1H, J=2.10 Hz), 7.26 (dd, 1H, J=9.14 Hz and 2.28 Hz), 4.54 (s, 2H), 4.02 (d, 2H, J=11.71 Hz), 3.80-3.87 (m, 2H), 3.51-3.73 (m, 4H), 3.19-3.31 ppm(m,2H).
Example 1 1
(Formula Removed)

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 (0.347 g, 0.734 mmol) and pyrrolidine (1 .0 ml, 12 mmol) in THF (8 mL) was stirred at 70 °C in a sealed tube for 6 hours. After cooling somewhat, the reaction mixture was solvent evaporated and partitioned in ethyl acetate and
aqueous sodium bicarbonate. The organic phase was then washed with water and brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography using 7.5 % methanol in chloroform. After drying at 55 °C in vacua, 3-benzenesulfonyl-5-(2-pyrrolidin-1-yl-ethoxy)-1H-indazole as a pale yellow solid (0.0595 g, 21.8 %) was obtained. This was dissolved in methanol and chloroform, and ethereal hydrochloride was added. The mixture was concentrated and dried in vacua at 75 °C for 16.5 hours to yield the hydrochloride as a yellow foam (0.0598 g). Mass Spectrum (+EI, [M+H]+) m/z 372. 1HNMR (300 MHz, DMSO-d6): 814.30 (s, 1H), 10.35 (br, 1H), 8.05 (d, 2H, J=7.04 Hz), 7.63-7.75 (m, 4H), 7.48 (d, 1H, J=1.83 Hz) 7.25-7.29 (m, 1H), 4.45-4.48 (m, 2H), 3.66 (s, br, 4H), 3.18-3.19 (m, 2H), 1.94-2.06 ppm ( m, 4H).
(Formula Removed)
[2-(3-Benzenesulfonyl-1H-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 2.0 M methylamine in THF (8 ml, 16 mmol) was stirred at 70 °C in a sealed tube for about 15.5 hours. After cooling somewhat, the reaction mixture was solvent evaporated and partitioned in chloroform and aqueous sodium bicarbonate. The organic phase was then washed with brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography using 10 % methanol in chloroform and 1.0 % ammonium hydroxide/10% methanol in chloroform. After drying at 57 °C in vacua for 20 minutes, [2-(3-benzenesulfonyl-1H-indazol-5-yloxy)-ethyl]-methyl-amine as a light yellow semi-solid (0.0461 g, 19.4 %) was obtained. This was dissolved in methanol and chloroform, and ethereal hydrochloride was added. The mixture was concentrated and dried in vacua at 73 °C for 20 hours to yield the hydrochloride as a tan foam (0.0422 g). Mass Spectrum (+EI, [M+H]+) m/z 332. 1HNMR (500 MHz, DMSO-de): 814.24 (s, 1H), 8.89 (s, 2H), 7.96-7.99 (m, 2H), 7.53-7.68 (m, 4H), 7.40 (d, 1H, J=2.19 Hz), 7.25 (dd, 1H, 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

(Formula Removed)
2-(3-Benzenesulfonyl-1H-indazol-5-yloxy)-ethylamine
Over five different reactions, liquid ammonia (about 10 mL) was added to a -78 °C solution of toluene-4-sulfonic acid 2-(3-benzenesulfonyl-1 H-indazol-5-yloxy)-ethyl ester (1.72 g, 3.63 mmol) in THF (48 ml). This was usually allowed to warm to ambient temperature. This was heated in sealed tube for about 16-35 hours at 70-100 °C. After cooling to about ambient temperature, the combined reaction mixtures were then poured into excess sodium bicarbonate solution and extracted with chloroform or methylene chloride. The organic phase was washed with brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chlormatography with 0.75 % ammonium hydroxide/7.5% methanol in chloroform. The residue was further purified by HPLC using 30-80% (chloroform/methanol(8:2)/TEA) in heptane/TEA. Concentrating and drying yielded 2-(3-benzenesulfonyl-1 H-indazol-5-yloxy)-ethylamine as a white solid to which was added methanol and ethereal hydrochloride. Concentration and drying for 30 hours in vacua at 83 °C yielded the hydrochloride as a cream-colored solid (0.0951 g, 7.4 %): MP: >300 °C; Mass Spectrum (-EI, [M-H]') m/z316. 1HNMR (500 MHz, DMSO-d6): 814.24(s, 1H), 8.09 (br,s, 3H), 7.96-7.98 (m, 2H), 7.56-7.68 (m, 4H), 7.39 (d, 1H, J=2.20 Hz), 7.17 (dd, 1H, J= 9.15 Hz and 2.32 Hz), 4.22-4.25 (m, 2H), 3.20-3.24 ppm (m, 2H). Elemental Analysis for C15H15N3O3S 1.00 mol HCI 0.85 mol H2O: Calcd: 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)-1H-indazol-5-yloxy]-propyl}-amine Stepl
(Formula Removed)
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 ambient temperature for 40 minutes, bromochloromethane (90 ml, 1.4 mol) and tetrabutylammonium bromide
(2.87 g, 8.91 mmol) were added. The reaction mixture was then stirred at 75 °C for 14.5 hours. After cooling to ambient temperature, the layers of the reaction mixture were separated, and the organic phase was concentrated. The residue was purified by flash chromatography with 100 % ethyl acetate. Hexane was added after concentration to help solidify, and the mixture was again concentrated. Drying at 80 °C in vacua for 20 minutes yielded 1-chloromethanesulfonyl-naphthalene as a pale yellow solid (19.0 g, 88.8 %). MP 103-5 °C. Mass Spectrum (+EI, M+) m/z 240. 1HNMR (500 MHz, DMSO-d6): 88.64-5 (m, 1H), 8.41 (d, 1H, J=8.23 Hz), 8.27 (dd, 1H, J=7.33 Hz and 1.22 Hz), 8.16-8.18 (m, 1H), 7.71-7.81 (m, 3H), 5.40 ppm, (s, 2H). Elemental Analysis for C11H9CIO2S: Gated: C, 54.89; H, 3.77; N, 0.00; Found: C, 54.98; H, 3.81; N, 0.00.
Step 2

(Formula Removed)
1-(5-Fluoro-2-nitro-phenylmethanesulfonyl)-naphthalene
To a chilled mixture of 1-chloromethanesulfonyl-naphthalene (19.7 g, 81.8 mmol) and 1-fluoro-4-nitrobenzene (8.7 ml, 82 mmol) in dry THF (197 ml_) was dropwise added 1 .OM potassium f-butoxide in THF (205 ml, 205 mmol). The reaction mixture was stirred at ambient temperature under nitrogen for 1.5 hours. Glacial acetic acid (16 mL, 280 mmol) was then added. After stirring at ambient temperature for 1 hour, 40 minutes, the reaction mixture was concentrated and partitioned in warm ethyl acetate and brine. 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 in vacua for 1 hour. This yielded 1-(5-fluoro-2-nitro-phenylmethanesulfonyl)-naphthalene as a brown/rust-colored solid (19.9 g, 70.6 %): MP: 155-160 °C; Mass Spectrum (-EI, [M-H]') m/z 344. 1HNMR (300 MHz, DMSO-d6): 88.50-8.52 (m, 1H), 8.33 (d, 1H, J=8.30 Hz), 8.06-8.14 (m, 2H), 7.97 (dd, 1H, J=7.32 Hz and 1.22 Hz), 7.62-7.74 (m, 3H), 7.44-7.48 (m, 1H), 7.23-7.26 (m, 1H), 5.23 ppm (s, 2H). Elemental Analysis for C17H12 FNO4S: Calcd: C, 59.12; H, 3.50; N, 4.06; Found: C, 58.77; H, 3.30; N, 3.92.
Step 3:
(Formula Removed)
3-[3-(Naphthalene-1-sulfonylmethyl)-4-nitro-phenoxy]-propan-1-ol
To a mixture of 1-(5-fluoro-2-nitro-phenylmethanesulfonyl)-naphthalene (19.9g, 57.6 mmol) and 1,3-propanediol (49 ml, 680 mmol) in dry THF (17 mL) was dropwise added 1.0M potassium fert-butoxide in THF (123 ml, 123 mmol). The reaction mixture was refluxed under nitrogen for 1 hour. It was allowed to cool to ambient temperature. Water was added to the reaction mixture, and it was poured into a mixture of ice and 2.0N hydrochloric acid. It was then extracted with ethyl acetate. The organic phase was washed with brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The 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 (-EI, [M-H]" ) m/z400. 1HNMR (500 MHz, DMSO-d6): 58.50-8.53 (m, 1H), 8.31 (d, 1H, J=8.17 Hz), 8.10-8.12 (m, 1H), 7.95-7.99 (m, 2H), 7.61-7.71 (m, 3H), 7.06 (dd, 1H, 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, 1H), 3.91-3.94 (m, 2H), 3.43-3.47 (m, 2H), 1.71-1.78 ppm (m, 2H).EIemental Analysis for C2oH19NO6S:Calcd: C, 59.84; H, 4.77; N, 3.49; Found: C, 59.78; H, 4.41; N, 3.43.
Step 4
(Formula Removed)

Toluene-4-sulfonic acid 3-[3-(naphthalene-1 -sulfonylmethyl)-4-nitro-phenoxy]-propyl ester
A solution of 3-[3-(naphthalene-1-sulfonylmethyl)-4-nitro-phenoxy]-propan-1-

1 (12.9 g, 32.1 mmol), p-toluenesulfonyl chloride (24.6 g, 129 mmol) and
triethylamine (37 mL, 270 mmol) in methylene chloride (300 ml) was stirred at
ambient temperature under nitrogen. After 2 hours, a second portion of p-
toluenesulfonyl chloride (12.1 g, 63.5 mmol) was added. The reaction was stirred for
2 more hours and then concentrated. The residue was partitioned in methylene
chloride and aqueous sodium bicarbonate. The organic phase was washed with
brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The
residue was purified by flash chromatography with 20-50% 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 toluene-4-s jlfonic acid 2-[3-(naphthalene-1-sulfonylmethyl)-4-nitro-phenoxy]-propyl ester: MP: 162-4°C; Mass Spectrum (-EI, [M-H]') m/z 554. 1HNMR (500 MHz, DMSO-d6): 88.52-8.54 (m, 1H), 8.31 (d, 1H, J=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, 1H, J=9.15 Hz and 2.81 Hz), 6.73 (d, 1H, 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: Calcd: C, 58.37; H, 4.54; N, 2.52; Found: C, 58.13; H, 4.43; N, 2.41.
StepS
(Formula Removed)
Toluene-4-sulfonic acid 3-[4-amino-3-(naphthalene-1 -sulfonylmethyl)-phenoxy]-propyl ester
Ethanol (30 ml) and 10 % palladium on carbon (0.439 g) were added to a hot solution of toluene-4-sulfonic acid 2-[3-(naphthalene-1-sulfonylmethyl)-4-nitro-phenoxy]-propyl ester (0.785 g, 1.41 mmol) in hot, anhydrous THF (40 mL). The reaction mixture was hydrogenated on the Parr apparatus for 2 hours (starting pressure of 43 psi). The reaction mixture was then filtered over Celite and concentrated. It was dried at 75 °C in vacua for 20 minutes to yield toluene-4-sulfonic acid 3-[4-amino-3-(naphthalene-1-sulfonylmethyl)-phenoxy]-propyl ester as a brown-green semi-solid (0.627 g, 84.4 %). Mass Spectrum (+EI, [M+H]+) m/z 526. 1HNMR (500 MHz, DMSO-d6): 88.61 (d, 1H, J=8.42 Hz), 8.25 (d, 1H, J=8.17 Hz), 8.02-8.07 (m, 2H), 7.59-7.72 (m, 5H), 7.39 (d, 2H, J=7.93 Hz), 6.56 (d, 1H, J=8.17 Hz), 6.44-6.47 (m, 1H), 6.01 (d, 1H, J=2.81 Hz), 4.62 (s, 2H), 3.98-4.01 (m, 2H), 3.36-3.39 (m, 2H), 2.35 (s, 3H), 1.71-1.79 ppm (m, 2H).

(Formula Removed)
Toluene-4-sulfonic acid 3-[3-(naphthalene-1 -sulfonyl)-1 H-indazol-5-yloxy]-propyl ester
Isopropanol (205 ml) and 1 .ON hydrochloric acid (200 mL) were added to toluene-4-sulfonic acid 3-[4-amino-3-(naphthalene-1 -sulfonylmethylj-phenoxyj-propyl ester (8.1 g, 15 mmol). The reaction mixture was heated because of limited solubility. Sodium nitrite (1.6 g, 2.3 mmol) in water (22 mL) was then added. More isopropanol (100 ml) was added to reaction mixture for increased solubility. After stirring at ambient temperature for 1 hour, sodium carbonate was added to basic pH. This reaction mixture was then stirred at ambient temperature for 30 minutes. After concentrating, the residue was partitioned in ethyl acetate and water. The organic phase was then washed with brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography using 50 % ethyl acetate in hexane. A light amber semi-solid (3.3 g, 41 %), toluene-4-sulfonic acid 3-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-propyl ester, was obtained. Mass Spectrum (-EI, [M-HV) m/z535. 'HNMR (500 MHz, DMSO-d6): 814.08(s, 1H), 8.78 (d, 1H, J=8.78 Hz), 8.55 (dd, 1H, J=7.44 Hz and 1.22 Hz), 8.28 (d, 1H, J=8.17 Hz), 8.02-8.04 (m, 1H), 7.73-7.77 (m, 1H), 7.55-7.65 (m, 4H), 7.48 (d, 1H, J=9.15 Hz), 7.03-7.06 (m, 3H), 6.88-6.91 (m, 1H), 4.17 (t, 2H, J=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: Calcd: C, 60.23; H, 4.53; N, 5.20; Found: C, 59.92; H, 4.30; N, 5.17.
Step7
(Formula Removed)
Dimethyl-{3-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-propyl}-amine
A solution of toluene-4-sulfonic acid 3-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-propyl ester (1.02 g, 1.89 mmol) in 2.0 M dimethylamine in THF (20 mL, 40 mmol) was stirred for 16 hours at 70 °C in a sealed tube. After cooling to ambient temperature, the reaction mixture was concentrated and partitioned in chloroform and aqueous sodium bicarbonate. The organic phase was washed with brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography using 0.5 % ammonium hydroxide/5.0 % methanol in chloroform. Dimethyl-{3-[3-(naphthalene-1 -sulfonyl)-1 H-indazol-5-yloxy]-propyl}-amine was obtained as a light yellow solid (0.453 g, 58.5 %). Methanol and ethereal hydrochloride were then added to this compound. The resulting solution was concentrated and dried for 14 hours at 84 °C in vacuo. Dimethyl-{3-[3-(naphthalene-
1-sulfonyl)-1H-indazol-5-yloxy]-propyl}-amine hydrochloride as a very light yellow solid (0.455g) was obtained: MP: 264-5 °C; Mass Spectrum (-EI, [M-H]") m/z 408. 1HNMR (500 MHz, DMSO-d6): 814.17(s, 1H), 10.19 (s, 1H), 8.75 (d, 1H, J=8.67 Hz), 8.53 (dd, 1H, J=7.44 Hz and 1.22 Hz), 8.27 (d, 1H, J=8.30 Hz), 8.02-8.04 (m, 1H), 7.71-7.75 (m, 1H), 7.54-7.65 (m, 3H), 7.29 (d, 1H, J=2.08 Hz), 7.07-7.10 (m, 1H), 4.07-4.10 (m, 2H), 3.19-3.23 (m, 2H), 2.76 (s, 6H), 2.11-2.18 ppm (m, 2H).EIemental Analysis for C^HaaNaOaS 1.00 mol HCI: Calcd: C, 59.25; H, 5.42; N, 9.42; Found: C, 58.97; H, 5.58; N, 9.23.
(Formula Removed)

Methyl-{3-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-propyl}-amine
A solution of toluene-4-sulfonic acid 3-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-propyl ester (0.422 g, 0.786 mmol) in 2.0 M methylamine in THF (8.0 ml, 16 mmol). was stirred for 15 hours at 70 °C in a sealed tube. After cooling to ambient temperature, the reaction mixture was concentrated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was washed with brine. The aqueous phases were extracted with chloroform, and both organic phases were combined and dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography using 0.75 % ammonium hydroxide/7.5 % methanol in chloroform. Methyl-{3-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-propyl}-amine was obtained as a light yellow foam (0.209 g, 67.2 %). Methanol and ethereal hydrochloride were added to the compound. The resulting solution was concentrated and dried for 14 hours at 84 °C in vacuo. The hydrochloride was obtained as a light yellow foam (0.217g). Mass Spectrum (-EI, [M-H]-) m/z 394. 1HNMR (500 MHz, DMSO-d6): 814.16 (s, 1H), 8.74-8.76 (m, 1H), 8.67 (s, br, 2H), 8.52 (dd, 1H, J=7.44 Hz and 1.22 Hz), 8.27 (d, 1H, J=8.30 Hz), 8.02-8.05 (m, 1H), 7.70-7.75 (m, 1H), 7.54-7.65 (m, 3H), 7.29 (d, 1H, J=2.19 Hz), 7.08-7.11 (m, 1H), 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 C21H21N3O3S 1.00 mol HCI0.45 mol H2O: Calcd: C, 57.32; H, 5.25; N, 9.55; Found: C, 57.64; H, 5.33; N, 9.39.

Ethyl-{3-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-propyl}-amine
A solution of toluene-4-sulfonic acid 3-[3-(naphthalene-1-sulfonyl)-1 H-indazol-5-yloxy]-propyl ester (0.080 mg, 0.15 mmol) in 10 ml of 2.0 M ethylamine/THF (20 mmoles) was stirred at 90 °C for about 2 hours in a sealed tube. After cooling to ambient temperature the reaction mixture was solvent evaporated. It 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 purified by flash chromatography using 0.75 % ammonium hydroxide/7.5 % methanol in chloroform. Drying at 66 °C in vacua for 20 minutes yielded 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. Concentrating and drying in vacua at 83 °C for 16 hours gave the hydrochloride as a pale yellow semi-solid (41.7 mg, 62.3%). Mass Spectrum (+EI, [M+H]+) m/z410; 1HNMR (500 MHz, DMSO-d6): 814.14-14.18 (br, 1H), 8.74-8.76 (m, 1H), 8.56-8.72 (br, 2H), 8.52 (dd, 1h, J=7.44 Hz and 1.22 Hz), 8.27 (d, 1H, J=8.29 Hz), 8.03-8.05 (m, 1H), 7.71-7.75 (m, 1H), 7.54-7.65 (m, 3H), 7.29 (d, 1H, J=2.08 Hz), 7.07-7.10 (m, 1H), 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 HCI 1.20 mol H2O: Calcd: C, 56.51; H, 5.69; N, 8.99; Found: C, 56.20; H, 5.36; N.8.81.
(Formula Removed)
Ethyl-methyl -{3-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-propyl}-amine
A solution of toluene-4-sulfonic acid 3-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-propyl ester (0.080 mg, 0.15 mmol) and methyethylamine (0.45-0.75 mmol) was stirred at 90 °C for about 2 hours in a sealed tube. After cooling to ambient temperature the reaction mixture was solvent evaporated. It 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 was added. The mixture was then concentrated and dried for 29 hours at 80°C in vacua. Ethyl-methyl-{3-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-propyl}-amine hydrochloride was a tan semi-solid (53.2 mg, 77.1%); Mass Spectrum (+EI, [M+H]+) m/z424. 1HNMR (500 MHz, DMSO-d6): 814.14-14.17 (br, 1H), 9.71-9.77 (br, 1H), 8.74-8.76 (m, 1H), 8.52 (dd, 1H, J=7.44 Hz and 1.22 Hz), 8.27 (d, 1H, J=8.30 Hz), 8.03-8.05 (m, 1H), 7.70-7.74 (m, 1H), 7.56-7.64 (m, 3H), 7.29 (d, 1H, J=2.19 Hz), 7.08-7.10 (m, 1H), 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 C23H23N3O3S 1.00 mol HCI 0.90 mol H2O: Calcd: C, 58.01; H, 5.88; N, 8.82; Found: C, 58.37; H, 5.55; N, 8.50.
(Formula Removed)
Diethyl-{3-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-propyl}-amine
A solution of toluene-4-sulfonic acid 3-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-propyl ester (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 ambient temperature the reaction mixture was solvent evaporated. It 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 in vacua at 80 °C for 17 hours. Diethyl-{3-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-propyl}-amine hydrochloride was a tan foam (69.9 mg, 98.3 %); Mass Spectrum (+EI, [M+H]+) m/z 438. 1HNMR (500 MHz, DMSO-d6): 614.13-14.11 (br, 1H), 9.59-9.63 (br, 1H), 8.75 (d, 1H, J=8.42 Hz), 8.51 (dd, 1H, J=7.44 Hz and 1.10 Hz), 8.27 (d, 1H, J=8.29 Hz), 8.03-8.05 (m, 1H), 7.70-7.74 (m, 1H), 7.52-7.64 (m, 3H), 7.05-7.11 (m, 2H), 4.10 (t, 2H, J=5.98 Hz), 3.11-3.25 (m, 6H), 2.09-2.24 (m, 2H), 1.18 ppm (t, 6H, J=7.20 Hz).
Example 19
(Formula Removed)
Butyl-{3-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-propyl}-amine
A solution of toluene-4-sulfonic acid 3-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-propyl ester (0.080 mg, 0.15 mmol) and butylamine (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 ambient temperature the reaction mixture was solvent evaporated. It 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 was added. Concentrating and drying in vacua at 80 °C for 17 hours yielded butyl-{3-[3-(naphtha!ene-1-sulfonyl)-1H-indazol-5-yloxy]-propyl}-amine hydrochloride as a light orange semi-solid (43.3 mg, 60.9 %); Mass Spectrum (+EI, [M+H]+) m/z438. 1HNMR (500 MHz, DMSO-d6): 813.8-14.2 (br, 1H), 8.75 (d, 1H, J=8.66 Hz), 8.50-8.52 (m, 1H), 8.27 (d, 1H, J=8.30 Hz), 8.03-8.05 (m, 1H), 7.71-7.75 (m, 1H), 7.54-7.64 (m, 3H), 7.29 (d, 1H, J=2.07 Hz), 7.07-7.10 (m, 1H), 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).
Example 20
(Formula Removed)
Cyclopropyl-{3-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-propyl}-amine
A solution of toluene-4-sulfonic acid 3-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-propyl ester (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 ambient temperature the reaction mixture was solvent evaporated. It 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 purified twice by flash chromatography using 0.75% ammonium hydroxide/7.5 % methanol in chloroform and 0.5 % ammonium
hydroxide/5.0 % methanol in chloroform to give cyclopropyl-{3-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-propyl}-amine as a clear yellow film (51.0 mg, 80.7%). This compound was dissolved in methanol, and ethereal hydrochloride was added. Concentrating and drying in vacua for 24 hours at 83 °C gave the hydrochloride as a yellow foam (48.9 mg, 71.2%); Mass Spectrum (+EI, [M+H]+) m/z 422. 1HNMR (500 MHz, DMSO-d6): 814.15 (s, 1H), 9.01 (s, 2H), 8.74-8.76 (m, 1H), 8.51-8.53 (m, 1H), 8.27 (d, 1H, J=8.29 Hz), 8.02-8.05 (m, 1H), 7.71-7.75 (m, 1H), 7.51-7.65 (m, 3H), 7.29 (d, 1H, J=2.19 Hz), 7.08-7.11 (m, 1H), 4.11 (t, 2H, J=6.10 Hz), 3.11-3.20 (br, s, 2H), 2.65-2.75 (m, 1H), 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 HCI 0.70 mol H2O: Calcd: C, 58.70; H, 5.44; N, 8.93; Found: C, 58.70; H, 5.09; N, 8.68.
Example 21
(Formula Removed)
Cyclopentyl-{3-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-propyl}-amine
A solution of toluene-4-sulfonic acid 3-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-propyl ester (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 ambient temperature, the reaction mixture was solvent evaporated. It 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 was 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 beige foam (70.6 mg, 100%). This compound was dissolved in methanol, and ethereal hydrochloride was added. Concentrating and drying in vacua for 12.5 hours at 83 °C gave the hydrochloride as a light brown foam (69.7 mg, 95.6%); Mass Spectrum (+EI, [M+H]*) m/z 450.1HNMR (500 MHz, DMSO-d6): 814.15-14.21 (br, 1H), 8.70-8.83 (m, 3H), 8.51-8.53 (m, 1H), 8.27 (d, 1H, J=8.30 Hz), 8.03-8.05 (m, 1H), 7.71-7.75 (m, 1H), 7.54-7.65 (m, 3H), 7.30 (d, 1H, J=2.20 Hz), 7.09 (dd, 1H, J=9.15 Hz and 2.31 Hz), 4.11 (t, 2H, J=6.10 Hz), 3.43-3.49 (m, 1H), 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 HCI 0.75 mol H2O: Calcd: C, 60.11; H, 5.95; N, 8.41; Found: C, 59.71; H, 5.83; N, 8.25.
Example 22

(Formula Removed)
lsopropyl-{3-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-propyl}-amine
A solution of toluene-4-sulfonic acid 3-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-propyl ester (0.080 mg, 0.15 mmol) and isopropylamine (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 ambient temperature the reaction mixture was solvent evaporated. It 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 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. Concentrating and drying for in vacua 16 hours 83 °C gave isopropyl-{3-[3-(naphthalene-1 -sulfonyl)-1 H-indazol-5-yloxy]-propyl}-amine hydrochloride as a light yellow foam (48.6 mg, 70.4%); Mass Spectrum (+EI, [M+H]+) m/z424. 1HNMR (500 MHz, DMSO-d6): 814.15-14.16 (br, 1H), 8.75 (d, 1H, J=8.78 Hz), 8.60-8.70 (br, 2H), 8.52 (dd, 1H, J=7.45 Hz and 1.22 Hz), 8.27 (d, 1H, J=8.29 hz), 8.03-8.05 (m, 1H), 7.71-7.75 (m, 1H), 7.54-7.65 (m, 3H), 7.30 (d, 1H, J=2.20 Hz), 7.08-7.11 (m, 1H), 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 C23H23N3O3S 1.00 mol HCI 0.55 mol H2O: Calcd: C, 58.79; H, 5.81; N, 8.94; Found: C, 58.46; H, 5.61; N, 8.72.
Example 23
(Formula Removed)
3-(Naphthalene-1 -sulfonyl)-5-(3-pyrrolidin-1 -yl-propoxy)-1 H-indazole
A solution of toluene-4-sulfonic acid 3-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-propyl ester (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 ambient temperature the reaction mixture was solvent evaporated. It 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. Concentrating and drying in vacua at 80 °C for 17 hours gave 3-(naphthalene-1-sulfonyl)-5-(3-pyrrolidin-1-yl-propoxy)-1H-indazole hydrochloride as a brown semi-solid (19.7 mg, 27.8%); Mass Spectrum (+EI, [M+H]+) m/z436. 1HNMR (500 MHz, DMSO-d6): 814.13 (s, 1H), 10.00-10.03 (br, 1H), 8.75 (d, 1H, J=8.66 Hz), 8.51-8.53 (m, 1H), 8.27 (d, 1H, J=8.30 Hz), 8.03-8.05 (m, 1H), 7.71-7.74 (m, 1H), 7.54-7.64 (m, 3H), 7.29 (d, 1H, J=2.20 Hz), 7.07-7.10 (m, 1H), 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), 1.77-1.87ppm(m,2H).
Example 24
(Formula Removed)
3-(Naphthalene-1-sulfonyl)-5-(3-piperidin-1-yl-propoxy)-1H-indazole
A solution of toluene-4-sulfonic acid 3-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-propyl ester (0.080 mg, 0.15 mmol) and piperidine (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 ambient temperature the reaction mixture was solvent evaporated. It 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 was added. Concentrating and drying at 80 °C for 29 hours in vacua gave 3-(naphthalene-1-sulfonyl)-5-(3-piperidin-1-yl-propoxy)-1H-indazole hydrochloride as a brown semi-solid (49.0 mg, 67.2%); Mass Spectrum (-EI, [M-H]') m/z448. 1HNMR (500 MHz, DMSO-de): 814.14 (s, 1H), 9.59-9.66 (br, 1H), 8.75 (d, 1H, J=8.54 Hz), 8.51-8.53 (m, 1H), 8.27 (d, 1H, J=8.30 Hz), 8.03-8.05 (m, 1H), 7.71-7.74 (m, 1H), 7.54-7.65 (m, 3H), 7.29 (d, 1H, J=2.20 Hz), 7.08 (dd, 1H, 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, 1H). Elemental Analysis for C25H27N3O3S 1.00 mol HCI-1.00 mol H2O: Calcd: C, 59.57; H, 6.00; N, 8.34; Found: C, 59.36; H, 5.82; N, 8.24.

Example 25
(Formula Removed)
5-(3-Morpholin-4-yl-propoxy)-3-(naphthalene-1-sulfonyl)-1H-indazole
A solution of toluene-4-sulfonic acid 3-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-propyl ester (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 ambient temperature the reaction mixture was solvent evaporated. It 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 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 as a light yellow solid (74.4 mg, 100%) was obtained. This product was dissolved in methanol, and ethereal hydrochloride was added. Concentrating and drying in vacuo 83 °C for 24 hours yielded the hydrochloride as a yellow foam (74.5 mg, 100 %); Mass Spectrum (+EI, [M+H]*) m/z 452. 1HNMR (500 MHz, DMSO-d6): 814.15 (s, 1H), 10.56-10.62 (br, 1H), 8.75 (d, 1H, J=8.66 Hz), 8.52 (dd, 1H, J=7.44 Hz and 1.22 Hz), 8.27 (d, 1H, J=8.30 Hz), 8.02-8.05 (m, 1H), 7.71-7.75 (m, 1H), 7.54-7.65 (m, 3H), 7.29 (d, 1H, J=2.32 Hz), 7.07-7.10 (m, 1H), 4.10 (t, 2H, J=5.86 Hz), 3.93-3.96 (m, 2H), 3.71-3.77 (m, 2H), 3.43-3.46 (m, 2H), 2.99-3.15 (m, 2H), 2.14-2.22 ppm (m, 2H). Elemental Analysis for C24H25N3O5S 1.00 mol HCI 1.30 mol H2O: Calcd: 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 Stepl
(Formula Removed)
5-(3-Azido-propoxy)-3-(naphthalene-1 -sulfonyl)-1 H-indazole
Sodium azide (0.425 g, 6.54 mmol) was added to a solution of toluene-4-sulfonic acid 3-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-propyl ester (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 ambien; temperature, it was poured into excess water and extracted with ethyl acetate. The organic phase was washed with 10% ammonium chloride/water solution, water and brine. It was dried with anhydrous magnesium sulfate, filtered, concentrated and dried at 73 °C in vacua for 45 minutes to yield 5-(3-azido-propoxy)-3-(naphthalene-1-sulfonyl)-1H-indazole as an amber gum (0.770 g, 87.7 %); Mass Spectrum (-EI, [M-H]') m/z406. 1HNMR (400 MHz, DMSO-d6): 514.05 (br, 1H), 8.64-8.68 (m, 1H), 8.53 (dd, 1H, J=7.42Hz and 1.16 Hz), 8.25-8.28 (m, 1H), 8.01-8.05 (m, 1H), 7.70-7.74 (m, 1H), 7.52-7.64 (m, 3H), 7.26 (d, 1H, 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).
Step 2
(Formula Removed)
3-[3-(Naphthalene-1 -sulfonyl)-1 H-indazol-5-yloxy]-propylamine
5-(3-Azido-propoxy)-3-(naphthalene-1-sulfonyl)-1H-indazole (0.763 g, 1.87 mmol) was dissolved in hot ethanol (125 ml). 10% Palladium on carbon (0.16 g) was added, and the reaction mixture was shaken and hydrogenated on the Parr apparatus for 2 hours, starting pressure 51 psi. Additional 10 % Palladium on carbon (0.32 g) was added, and the reaction mixture was again hydrogenated on the Parr apparatus for 2 hours. It was then filtered over Celite and concentrated. The residue was 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 heptane/TFA. 3-[3-(Naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-propylamine as a light yellow foam (0.229 g, 32.1 %) resulted. Methanol and ethereal hydrochloride were added. The mixture was concentrated and dried at 83 °C in vacua for 12 hours to yield the hydrochloride as a light buff foam (0.235 g). Mass Spectrum (-EI, [M-H]') m/z 380. 1HNMR (500 MHz, DMSO-d6): 814.15 (s, 1H), 8.75 (d, 1H, J=8.67 Hz), 8.50-8.52 (m, 1H), 8.27 (d, 1H, J=8.30 Hz), 8.02-8.05 (m, 1H), 7.86 (s, br, 3H), 7.71-7.75 (m, 1H), 7.54-7.64 (m, 3H), 7.29 (d, 1H, J=2.20 Hz), 7.08-7.11 (m, 1H), 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 HCI 0.40 mol H2O: Calcd: 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-suit ^nyl)-1H-indazol-5-yloxy]-ethyl}-amine Stepl
(Formula Removed)
1-(5-Fluoro-2-nitro-phenylmethanesulfonyl)-naphthalene
To a chilled mixture of 1-chloromethanesulfonyl-naphthalene (21.7 g, 90.1 mmol) and 1-fluoro-4-nitrobenzene (9.6 mL, 90 mmol) in dry THF (220 mL) was dropwise added 1.0 M potassium tert-butoxide in THF (193 mL, 193 mmol). The reaction mixture was stirred at ambient temperature under nitrogen for 1 hour, 10 minutes. Glacial acetic acid (17 mL, 300 mmol) was then added. The reaction mixture was concentrated and partitioned in warm ethyl acetate and brine. 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 vacua for 16 hours. This yielded a brown/rust-colored solid (22.2 g, 71.4 %) as 1-(5-fluoro-2-nitro-phenylmethanesulfonyl)-naphthalene: MP: 155-156 °C; Mass Spectrum (-EI, [M-H]') m/z 344. 1HNMR (300 MHz, DMSO-d6): 68.50-8.52 (m, 1H), 8.33 (d, 1H, J=8.30 Hz), 8.06-8.14 (m, 2H), 7.97 (dd, 1H, J=7.32 Hz and 1.22 Hz), 7.62-7.74 (m, 3H), 7.44-7.48 (m, 1H), 7.23-7.26 (m, 1H), 5.23 ppm (s, 2H). Elemental Analysis for C17H12FNO4S: Calcd: C, 59.12; H, 3.50; N, 4.06; Found: C, 58.77; H, 3.30; N, 3.92.
Step 2
(Formula Removed)
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 terf-butoxide in THF (90 mL, 90 mmol) was refluxed under nitrogen for one hour. After cooling to ambient temperature, the reaction mixture was concentrated. Excess water was added to the residue, and the mixture was poured into ice/2N hydrochloric acid. It was extracted with ethyl acetate and washed with water and brine. It was then dried with anhydrous magnesium sulfate, filtered, concentrated and dried in vacuo at 80 °C for 25 minutes to yield 2-[3-(naphthalene-1-sulfonylmethyl)-4-nitro-phenoxy]-ethanol
as a brown gum (14.3 g, 87.2 %). Mass Spectrum (-EI, [M-H]') m/z 386. 1HNMR (500 MHz, DMSO-d6) 88.56-8.57 (m, 1H), 8.35 (d, 1H, J=8.24 Hz), 8.14-8.15 (m, 1H), 8.00-8.02 (m, 2H), 7.65-7.75 (m, 3H), 7.11-7.13 (m, 1H), 6.89 (d, 1H, J=2.90 Hz), 5.27 (s, 2H), 4.92 (t, 1H, J=5.49 Hz), 3.93-3.95 (m, 2H), 3.67 ppm (dd, 2H, J=9.91 Hz and 5.34 Hz). Elemental Analysis for C19H17NO6S 0.25 mol H2O: Gated: C, 58.23; H, 4.50; N, 3.57; Found: C, 57.83; H, 4.25; N, 3.50.
Step 3
(Formula Removed)
Toluene-4-sulfonic acid 2-[3-(naphthalene-1 -sulfonylmethyl)-4-nitro-phenoxy]-ethyl ester
A solution of 2-[3-(naphthalene-1-sulfonylmethyl)-4-nitro-phenoxy]-ethanol (14.3 g, 36.9 mmol), p-toluenesulfonylchloride (14.9 g, 78.2 mmol) and triethylamine (23 ml, 170 mmol) in methylene chloride (400 ml) was stirred under nitrogen at ambient 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 brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography with 25-75 % ethyl acetate in hexane and 100 % ethyl acetate. Drying for 25 minutes in vacua at 80 °C yielded toluene-4-sulfonic acid 2-[3-(naphthalene-1-sulfonylmethyl)-4-nitro-phenoxy]-ethyl ester as a rust-colored solid (15.7 g, 78.5 %). Mass Spectrum (+EI, [M+H]+) m/z 542. 1HNMR (500 MHz, DMSO-d6): 88.53 (dd, 1H, J= 8.18 Hz and 1.10 Hz), 8.31 (d, 1H, J=8.30 Hz), 8.09-8.11 (m, 1H), 7.94-7.99 (m, 2H), 7.62-7.75 (m, 5H), 7.42 (d, 2H, J=7.93 Hz), 6.98 (dd, 1H, J=9.15 Hz and 2.93 Hz), 6.80 (d, 1H, 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).
Step 4
(Formula Removed)
Toluene-4-sulfonic acid 2-[4-amino-3-(naphthalene-1 -suIfonylmethyl)-phenoxy]-ethyl ester
Ethanol (180 ml) and 10 % palladium on carbon (5.2 g) were added to a hot solution of toluene-4-sulfonic acid 2-[3-(naphthalene-1-sulfonylmethyl)-4-nitro-phenoxyj-ethyl ester (11.5 g, 21.2 mmol) in THF (180 ml). This mixture was shaken on the Parr hydrogenation apparatus for 5 hours, with a starting pressure of 47 psi. It was then filtered over Celite, concentrated and dried in vacua at 80 °C for 30 minutes to give toluene-4-sulfonic acid 2-[4-amino-3-(naphthalene-1-sulfonylmethyl)-phenoxy]-ethyl ester as a dark brown gum (9.5 g, 88.0 %). Mass Spectrum (+EI, [M+H]+) m/z512. 1HNMR (500 MHz, DMSO-d6): 88.61 (d, 1H, J=8.41 Hz), 8.25 (d, 1H, J=8.30 Hz), 8.03-8.08 (m, 2H), 7.59-7.75 (m, 5H), 7.43 (d, 2H, J=7.93 Hz), 6.49-6.53 (m, 2H), 6.11 (d, 1H, 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).
(Formula Removed)
Toluene-4-sulfonic acid 2-[3-(naphthalene-1 -sulfonyl)-1 H-indazol-5-yloxy]-ethyl ester
Ethanol (430 ml) in two portions and 1 N hydrochloric acid (200 mL) were added to toluene-4-sulfonic acid 2-[4-amino-3-(naphthalene-1-sulfonylmethyl)-phenoxy]-ethyl ester (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 in solubility. After stirring at ambient temperature for 2 hours, solid sodium carbonate was added to basic pH. The reaction mixture was stirred at ambient temperature for one hour. It was then solvent evaporated and partitioned in water and ethyl acetate. The organic phase was washed with brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography with 2% methanol in chloroform. Drying at 63 °C in vacuo yielded toluene-4-sulfonic acid 2-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester a buff-colored foam (3.9 g, 59 %); Mass Spectrum (+EI, [M+H]+) m/z 523. 1HNMR (500 MHz, DMSO-d6): 814.09 (s, 1H), 8.76 (d, 1H, J=8.78 Hz), 8.52-8.55 (m, 1H), 8.27 (d, 1H, J=8.30 Hz), 8.02-8.04 (m, 1H), 7.64-7.74 (m, 3H), 7.55-7.63 (m, 2H), 7.50 (d, 1H, J=9.15 Hz), 7.27 (d, 2H, J=8.05 Hz), 7.14 (d, 1H, J=2.20 Hz), 6.94 (dd, 1H, 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: Calcd: C, 59.76; H, 4.24; N, 5.36; Found: C, 59.69; H, 4.28; N, 5.14.
Step 6

(Formula Removed)
Dimethyl-{2-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl}-amine
A solution of toluene-4-sulfonic acid 2-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (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 ambient temperature, the reaction mixture was concentrated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was washed with water and brine, dried with anhydrous magnesium sulfate, filtered and concentrated. Drying at 80 °C for 20 minutes in vacua yielded dimethyl-{2-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl}-amine as a light yellow solid (0.212 g, 73.4 %). Methanol, chloroform and etheric hydrochloride were added. The resulting solution was concentrated and dried for 15 hours at 78 °C in vacua. The hydrochloride as a buff foam (0.217 g) was obtained. Mass Spectrum (+EI, [M+H]+) m/z 396. 1HNMR (500 MHz, DMSO-d6): 614.20 (s, 1H), 10.05 (s, 1H), 8.74-8.77 (m, 1H), 8.52 (dd, 1H, J=7.44 Hz and 1.22 Hz), 8.27 (d, 1H, J=8.17 Hz), 8.03-8.05 (m, 1H), 7.70-7.74 (m, 1H), 7.56-7.65 (m, 3H), 7.37 (d, 1H, J=2.20 Hz), 7.15-7.18 (m, 1H), 4.37-4.39 (m, 2H), 3.51 (t, 2H, J=4.76 Hz), 2.83 ppm (s, 6H). Elemental Analysis for C21H21N3O3S 1.00 mol HCI 0.70 mol H2O: Calcd: C, 56.74; H, 5.31; N, 9.45; Found: C, 56.72; H, 5.33; N, 9.06.
Example 28
(Formula Removed)
lsopropyl-{2-[3-(naphthalene-1-sulfonyl)-1H-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) was added, and the reaction mixture was stirred at 80 °C for 20 hours in a sealed tube. After cooling to ambient 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 was purified by flash chromatography using 0.75 % ammonium hydroxide/7.5% methanol in chloroform. After concentrating and drying in vacua at 72 °C for 25 minutes, isopropyl-{2-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl}-aminewas obtained as a light orange solid (0.313 g, 39.6 %). Methanol, chloroform and ethereal hydrochloride were added to this compound. The resulting solution was concentrated and dried for 16 hours at 84 °C in vacua. The hydrochloride was a light brown foam (0.332g). Mass Spectrum (+EI, [M+H]+) m/z 410. 1HNMR (500 MHz, DMSO-d6): 514.22 (s, 1H), 8.86 (s, 2H), 8.74-8.77 (m, 1H), 8.53 (dd, 1H, J=7.44 Hz and 1.22 Hz), 8.27 (d, 1H, J=8.30 Hz), 8.03-8.05 (m, 1H), 7.71-7.75 (m, 1H), 7.56-7.65 (m, 3H), 7.34 (d, 1H, J=2.32 Hz), 7.16 (dd, 1H, J=9.15 Hz and 2.44 Hz), 4.29-4.32 (m, 2H), 1.25 ppm (d, 6H, J=6.59 Hz). Elemental Analysis for C22H23N3O3S 1.00 mol HCI 0.35 mol H2O: Calcd: C, 58.43; H, 5.50; N, 9.29; Found: C, 58.03; H, 5.25; N, 8.94.
(Formula Removed)
Ethyl-methyl-{2-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl}-amine
A solution of toluene-4-sulfonic acid 2-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (1.18 g, 2.26 mmol) and ethylmethylamine (2.0 ml, 23 mmol) in THF (20 ml) was stirred for 16 hours at 70 °C in a sealed tube. More ethylmethylamine (2.0 ml, 23 mmol) was added, and the reaction mixture was heated to 80 °C for 20 hours in a sealed tube. After cooling to ambient 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 was purified by flash chromatography using 0.75 % ammonium hydroxide/7.5% methanol in chloroform. Drying in vacua at 69 °C for 20 minutes yielded ethyl-methyl-{2-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl}-amine as a buff foam (0.409 g, 44.2 %). Methanol, chloroform and ethereal hydrochloride were added. The resulting solution was concentrated and dried for 16 hours at 84 °C in vacua. The hydrochloride was obtained as a buff semi-solid (0.424g). Mass Spectrum (+EI, [M+HDm/z410. 1HNMR (500 MHz, DMSO-d6): 814.21 (s, 1H), 10.00-10.01 (s, 1H),
8.74-8.77 (m, 1H), 8.52 (dd, 1H, J= 7.44 Hz and 1.22 Hz), 8.27 (d, 1H, J= 8.29 Hz), 8.03-8.05 (m, 1H), 7.73 (dd, 1H, J=8.06 Hz and 7.57 Hz), 7,<56-7.65 (m, 3H), 7.37 (d, 1H, J=2.20 Hz), 7.15-7.18 (m, 1H), 4.40 (t, 2H, J=5.00 Hz), 3.53-3.59 (m, 1H), 3.39-3.49 (m, 1H),3.21-3.25 (m, 1H), 3.10-3.20 (m, 1H), 2.81 (d, 3H, J=4.88 Hz), 1.21-1.25 ppm (m, 3H). Elemental Analysis for C22H23N3O3S 1.00 mol HCI 0.30 mol H20: Calcd: 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 Stept
(Formula Removed)
5-(2-Azido-ethoxy)-3-(naphthalene-1 -sulfonyl)-1 H-indazole
Sodium azide (0.79 g, 12 mmol) was added to a solution of toluene-4-sulfonic acid 2-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (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 ambient temperature, it was poured into excess water and extracted with ethyl acetate. The organic phase was washed with 10% ammonium chloride/water solution, water and brine. It was dried with anhydrous magnesium sulfate, filtered, concentrated and dried at 72 °C in vacua for 40 minutes to yield 5-(2-azido-ethoxy)-3-(naphthalene-1-sulfonyl)-1 H-indazole as a amber gum/foam (1.34 g, 86.5 %). Mass spectrum (-EI, [M-H]') m/z 392. 1HNMR (400 MHz, DMSO-d6): 58.78 (d, 1H, J=8.70 Hz), 8.56 (dd, 1H, J=7.43 Hz and 1.16 Hz), 8.29 (d, 1H, J=8.35 Hz), 8.06 (d, 1H, J=7.66 Hz), 7.72-7.76 (m, 1H), 7.57-7.67 (m, 3H), 7.31 (d, 1H, J=2.32 Hz), 7.12 (dd, 1H, J= 9.16 Hz and 2.32 Hz), 4.22-4.24 (m, 2H), 3.67-3.69 ppm (m, 2H).
Step 2
(Formula Removed)
2-[3~(Naphthalene-1 -sulfonyl)-1 H-indazol-5-yloxy]-ethylamine
To 5-(2-azido-ethoxy)-3-(naphthalene-1-sulfonyl)-1H-indazole (1.34 g, 3.41 mmol) in hot ethanol (210 ml) was added 10 % palladium on carbon (0.8 g). The reaction mixture was hydrogenated on the Parr apparatus for 1.25 hours, starting pressure 49 psi. It was then filtered over Celite and concentrated. The residue was purified by flash chromatography with 0.5 % ammonium hydroxide/5.0 % methanol in chloroform. Drying in vacua at 63 °C for 20 minutes gave 2-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethylamine as a light yellow foam resulted (0.775 g, 57.0 %). Methanol and ethereal hydrochloride were added. Drying in vacuo for 16 hours 68 °C yielded the hydrochloride as a yellow foam (0.825 g). Mass spectrum (-El, [M-H]-) m/z 366. 1HNMR (500 MHz, DMSO-d6): 614.22 (s, 1H), 8.75 (d, 1H, J=8.66 Hz), 8.51-8.53 (m, 1H), 8.27 (d, 1H, J=8.29 Hz), 8.10 (s, br, 3H), 8.03-8.05 (m, 1H), 7.71-7.75 (m, 1H), 7.56-7.65 (m, 3H), 7.33 (d, 1H, J=2.19 Hz), 7.13-7.16 (m, 1H), 4.21 (t, 2H, J=5.00 Hz), 3.23 ppm (s, 2H). Elemental Analysis for C19H17N3O3S 1.00 mol HCI 0.55 mol H2O: Calcd: C, 55.15; H, 4.65; N, 10.15; Found: C, 55.54; H, 4.90; N, 10.12.

(Formula Removed)
Methyl-{2-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl}-amine
A solution of toluene-4-sulfonic acid 2-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (200 mg, 0.383 mmol) in 2.0 M methylamine in THF (10 ml, 20 mmol) was stirred at 70 °C for 2-3 hours in a sealed tube. After cooling to ambient temperature, the reaction mixture was solvent evaporated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was dried with anhydrous magnesium sulfate, filtered and concentrated. It was dissolved in methanol, and ethereal hydrochloride was added. The mixture was concentrated and dried for about 16 hours at 70 °C in vacuo to give methyl-{2-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl}-amine hydrochloride as a pale yellow foam (100 mg, 62.5 %); Mass Spectrum (-EI, [M-H]') m/z 380. 1HNMR (400 MHz, DMSO-d6): 814.21 (br, s, 1H), 8.85-8.91 (s, 2H), 8.74-8.75 (m, 1H), 8.51-8.53 (m, 1H), 8.26-8.28 (m, 1H), 8.03-8.05 (m, 1H), 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).
lemental Analysis for C20H19N3O3S 1.00 mol HCM.40 H2O: Calcd: C, 54.21; H, 5.19; N, 9.48; Found: C, 54.31; H, 1.80; N, 9.10.
Example 32
(Formula Removed)
Ethyl-{2-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl}-amine
A solution of toluene-4-sulfonic acid 2-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (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 ambient temperature, the reaction mixture was solvent evaporated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was dried with anhydrous magnesium sulfate, filtered and concentrated. It was dissolved in methanol, and ethereal hydrochloride was added. The mixture was concentrated and dried for 16 hours in vacua at 70 °C to give ethyl-{2-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl}-amine hydrochloride as a pale yellow foam (30 mg, 18.2%). Mass Spectrum (-EI, [M-HV) m/z 394. 1HNMR (500 MHz, DMSO-d6): 814.18 (s, 1H), 8.75 (d, 3H, J=8.54 Hz), 8.51-8.53 (m, 1H), 8.27 (d, 1H, J=8.17 Hz), 8.03-8.05 (m, 1H), 7.70-7.74 (m, 1H), 7.56-7.65 (m, 3H), 7.34 (d, 1H, J=2.20 Hz), 7.16 (dd, 1H, 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
(Formula Removed)
Diethyl-{2-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl}-arnine
A solution of toluene-4-sulfonic acid 2-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (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 ambient temperature, the reaction mixture was solvent evaporated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was dried with anhydrous magnesium sulfate, filtered and concentrated. It was dissolved in
methylene chloride and methanol, and ethereal hydrochloride was added. The mixture was concentrated and dried in vacua at 67 °C for 16 hours to give diethyl-{2-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl}-amine hydrochloride as an off-white foam (148 mg, 84.1%); Mass Spectrum (-EI, [M-H]') m/z422. 1HNMR (400 MHz, DMSO-d6): 814.20 (s, 1H), 9.91 (s, 1H), 8.75 (d, 1H, J=8.54 Hz), 8.51-8.53 (m, 1H), 8.27 (d, 1H, J=8.29 Hz), 8.03-8.05 (m, 1H), 7.71-7.75 (m, 1H), 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, J=3.91 Hz), 3.12-3.24 (m, 4H), 1.23 ppm (t, 6H, J=7.20 Hz). Elemental Analysis for C23N3O3S '1.00 mol HCI0.80 mol H2O: Calcd: C, 58.23; H, 5.86; N, 8.86; Found: C, 57.92; H, 5.52; N, 8.59.
Example 34
(Formula Removed)
Butyl-{2-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl}-amine
A solution of toluene-4-sulfonic acid 2-[3-(naphthalene-1-sulfonyl)-1 H-indazol-5-yloxy]-ethyl ester (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 ambient temperature, the reaction mixture was solvent evaporated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was dried with anhydrous magnesium sulfate, filtered and concentrated. It was dissolved in methylene chloride and methanol, and ethereal hydrochloride was added. The mixture was concentrated and dried for 16 hours in vacua at 67 °C to give butyl-{2-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl}-amine hydrochloride as a light orange foam (166 mg, 94.3%); Mass Spectrum (-EI, [M-H]') m/z422. 1HNMR (500 MHz, DMSO-d6): 68.74-8.76 (m, 1H), 8.51-8.53 (m, 1H), 8.27 (d, 1H, J=8.29 Hz), 8.03-8.05 (m, 1H), 7.71-7.74 (m, 1H), 7.56-7.65 (m, 3H), 7.34 (d, 1H, 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
(Formula Removed)
Cyclopentyl-{2-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl}-amine
A solution of toluene-4-sulfonic acid 2-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (200 mg, 0.383 mmol) and cyclopentylamine (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 ambient temperature, the reaction mixture was solvent evaporated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was dried with anhydrous magnesium sulfate, filtered and concentrated. It was dissolved in methylene chloride and methanol, and ethereal hydrochloride was added. The mixture was concentrated and dried in vacua at 67 °C for 17 hours to give cyclopentyl-{2-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl}-amine hydrochloride as a brown foam (148 mg, 81.8 %); Mass Spectrum (-EI, [M-H]") m/z 436. 1HNMR (500 MHz, DMSO-d6): 814.20 (s, 1H), 8.89-8.93 (s, br, 2H), 8.74-8.76 (m, 1H), 8.51-8.53 (m, 1H), 8.28 (d, 1H, J=8.29 Hz), 8.03-8.05 (m, 1H), 7.71-7.75 (m, 1H), 7.56-7.65 (m, 3H), 7.34 (d, 1H, J=2.32 Hz), 7.15-7.18 (m, 1H), 4.28-4.30 (m, 2H), 3.51-3.57 (m, 1H), 3.32-3.36 (m, 2H), 1.93-2.00 (m, 2H), 1.44-1.73 ppm (m, 6H). Elemental Analysis for C24H25N3O3S 1.00 HCI 0.70 mol HCI: Calcd: C, 59.48; H, 5.70; N, 8.67; Found: C, 59.67; H, 5.86; N, 8.32.
Example 36

(Formula Removed)
Cyclopropyl-{2-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl}-amine
A solution of toluene-4-sulfonic acid 2-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (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 ambient temperature, the reaction mixture was solvent evaporated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was dried with anhydrous magnesium sulfate, filtered and concentrated. It was dissolved in methanol and ethereal hydrochloride was added. The mixture was concentrated and dried in vacua at 70 °C for 16 hours to give cyclopropyl-{2-[3-(naphthalene-1-
sulfonyl)-1H-indazol-5-y!oxy]-ethyl}-amine hydrochloride as a yellow foam (58 mg, 34 %); Mass spectrum (-til, [M-H]') m/z 406. 1HNMR(400 MHz, DMSO-d6): 814.20 (s, 1H), 9.19 (s, br, 2H), 8.74-8.76 (m, 1H), 8.52 (dd, 1H, J=7.45 Hz and 1.22 Hz), 8.27 (d, 1H, J=8.30 Hz), 8.02-8.05 (m, 1H), 7.71-7.75 (m, 1H), 7.56-7.65 (m, 3H), 7.34 (d, 1H, J=2.19 Hz), 7.16 (dd, 1H, J=9.15 Hz and 2.32 Hz), 4.30-4.33 (m, 2H), 3.43 (br, s, 2H), 2.76-2.77 (m, 1H), 0.84-0.88 (m, 2H), 0.71-0.76 ppm (m, 2H). Elemental Analysis for C22H21N3O4S 1.00 HCI 0.60 mol HCI: Calcd: C, 58.11; H, 5.14; N, 9.24; Found: C, 57.83; H, 4.81; N, 8.91.
Example 37
(Formula Removed)
3-(Naphthalene-1 -sulfonyl)-5-(2-pyrrolidin-1 -yl-ethoxy)-1 H-indazole
A solution of toluene-4-sulfonic acid 2-[3-(naphthalene-1-sulfonyl)-1 H-indazol-5-yloxy]-ethyl ester (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 ambient temperature, the reaction mixture was solvent evaporated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was dried with anhydrous magnesium sulfate, filtered and concentrated. It was dissolved in methanol and ethereal hydrochloride was added. The mixture was concentrated and dried in vacua at 67 °C for 20 hours to give 3-(naphthalene-1-sulfonyl)-5-(2-pyrrolidin-1-yl-ethoxy)-1 H-indazole hydrochloride as a light brown foam (97.8 mg, 55.9 %); Mass Spectrum (-EI, [M-H]') m/z420. 1HNMR (500 MHz, DMSO-d6): 814.19 (s, 1H), 10.26-10.29 (br, 1H), 8.74-8.77 (m, 1H), 8.53 (dd, 1H, J=7.44 Hz and 1.22 Hz), 8.27 (d, 1H, J=8.29 Hz), 8.03-8.05 (m, 1H), 7.71-7.74 (m, 1H), 7.55-7.65 (m, 3H), 7.36 (d, 1H, J=2.19 Hz), 7.16-7.19 (m, 1H), 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

(Formula Removed)
3-(Naphthalene-1 -sulfonyl)-5-(2-piperidin-1 -yl-ethoxy)-1 H-indazole
A solution of the toluene-4-sulfonic acid 2-[3-(naphthalene-1-sulfonyl)-1 H-indazol-5-yloxy]-ethyl ester (200 mg, 0.383 mmol) and piperidine (1.1-1.5 mmol) in 1'HF (10 ml) was stirred in a sealed tube for about 16 hours at 70 °C. After cooling to ambient temperature, the reaction mixture was solvent evaporated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was dried with anhydrous magnesium sulfate, filtered and concentrated. It was dissolved in methanol and chloroform, concentrated and dried in vacuo at 70 °C for 16 hours to give 3-(Naphthalene-1-sulfonyl)-5-(2-piperidin-1-yl-ethoxy)-1 H-indazole hydrochloride as a pale yellow foam (106 mg, 58.6%). Mass Spectrum (-EI, [M-H]") m/z 434. 1HNMR (500 MHz, DMSO-d6): 814.18 (s, 1H), 9.77-9.84 (br, 1H), 8.75 (d, 1H, J=8.78 Hz), 8.51-8.53 (m, 1H), 8.27 (d, 1H, J=8.30 Hz), 8.03-8.05 (m, 1H), 7.70-7.74 (m, 1H), 7.56-7.65 (m, 3H), 7.35 (d, 1H, J=2.20 Hz), 7.15 (dd, 1H, 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 C24H25N3O4S 1.00 HCI 0.70 mol HCI: Calcd: C, 59.48; H, 5.70; N, 8.67; Found: C, 59.22; H, 5.63; N, 8.30.
Example 39
(Formula Removed)
5-(2-Morpholin-4-yl-ethoxy)-3-(naphthalene-1-sulfonyl)-1 H-indazole
A solution of toluene-4-sulfonic acid 2-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (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 ambient temperature, the reaction mixture was solvent evaporated and triturated with ether and ethyl acetate. The resulting solid was then dissolved in ethyl acetate and washed with aqueous 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 was concentrated and dried in vacuo at 67 °C for 17 hours to give 5-(2-morpholin-4-yl-ethoxy)-3-(naphthalene-1-sulfonyl)-1 H-indazole hydrochloride as a light brown semi-solid (0.176 g, 96.7%); Mass Spectrum (+EI, [M+H]+) m/z 438. 1HNMR (500 MHz, DMSO-d6): 814.19 (s, 1H), 10.61-10.66 (br, 1H), 8.74-8.76 (m, 1H), 8.52 (dd, 1H, J=7.44 Hz and 1.22 Hz), 8.27 (d, 1H, J=8.29 Hz), 8.03-8.05 (m, 1H), 7.71-7.75 (m, 1H), 7.56-7.65 (m, 3H), 7.36 (d, 1H, J=1.40 Hz), 7.15-7.17 (dd,
1H, 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 C24H25N3O4S1.00 HCI 0.50 mol HCI: Calcd: 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)-1 H-indazol-5-yloxy]-ethyl}-amine Stepl
(Formula Removed)
Toluene-4-sulfonic acid 2-[1-methyl-3-(naphthalene-1-sulfonyl)-1 H-indazol-5-yloxy]-ethyl ester
Methyliodide (0.06 ml, 0.96 mmol) was added to a chilled mixture of toluene-4-sulfonic acid 2-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (0.401 g, 0.767 mmol) and cesium carbonate (0.29 g, 0.89 mmol) in acetone (10 ml). The reaction mixture was stirred at ambient temperature under nitrogen for 3 hours. It was then partitioned in ethyl acetate and water. The organic phase was washed with brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography with 25-40% ethyl acetate in hexane, 100 % chloroform and 1% methanol in chloroform. Drying at 65 °C in vacua for yielded toluene-4-sulfonic acid 2-[1-methyl-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester as a buff foam (0.224 g, 54.4 %). 1HNMR (400 MHz, DMSO-d6): 58.27 (d, 1H, J=8.54 Hz), 8.55 (dd, 1H, J=7.42 Hz and 1.16 Hz), 8.30 (d, 1H, J=8.35 Hz), 8.05-8.07 (m, 1H), 7.72-7.76 (m, 3H), 7.60-7.70 (m, 3H), 7.31 (d, 2H, J=8.01 Hz), 7.18 (d, 1H, J=2.20 Hz), 7.00-7.03 (m, 1H), 4.35-4.37 (m, 2H), 4.22-4.24 (m, 2H), 4.07 (s, 3H), 2.28 ppm (s, 3H).
Step 2
(Formula Removed)
Methyl-{2-[1 -methyl-3-(naphthalene-1 -sulfonyl)-1 H-indazol-5-yloxy]-ethyl}-amine
A solution of toluene-4-sulfonic acid 2-[1-methyl-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (0.351 g, 0.654 mmol) in 2.0 M methylamine in THF (10 ml, 20 mmol) was heated and stirred in a sealed tube at 78 °C for 1 hour, 40 minutes. Additional methylamine in THF (2.0 ml, 4.0 mmol) of was added, and the reaction mixture was stirred at 80 °C for 16.5 hours in a sealed tube. After cooling to ambient temperature, the reaction mixture was solvent evaporated. It was partitioned with ethyl acetate and aqueous sodium bicarbonate. It was washed with brine, dried with anhydrous magnesium sulfate, filtered, concentrated and dried at 80 °C in vacuo for 20 minutes, resulting in methyl-{2-[1-methyl-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl}-annine as a yellow gum (0.198 g, 76.4 %). This was dissolved in chloroform, and ethereal hydrochloride was added. The solid was filtered and dried at 83 °C in vacuo for 25 hours. A buff solid (0.156 g) was obtained: MP: 272-4°C(dec).; Mass Spectrum (+EI, [M+H]+) m/z 396. 1HNMR (500 MHz, DMSO-d6): 88.89 (s, br, 2H), 8.73-8.75 (m, 1H), 8.50-8.52 (M, 1H), 8.26-8.28 (m, 1H), 8.03-8.05 (m, 1H), 7.71-7.74 (m, 2H), 7.56-7.66 (m, 2H), 7.37 (d, 1H, J= 2.07 Hz), 7.19-7.22 (m, 1H), 4.29-4.31 (m, 2H), 4.05 (s, 3H), 3.34 (t, 2H, J=4.39 Hz), 2.62 ppm (s, 3H). Elemental Analysis for C21H21N3O4S1.00 mol HCI 0.60 mol H2O: Calcd: C, 56.97; H, 5.28; N, 9.49; Found: C, 56.91; H, 5.27; N, 9.14.
Example 41

(Formula Removed)
Dimethyl-{2-[1 -methyl-3-(naphthalene-1 -sulfonyl)-1 H-indazol-5-yloxy]-ethyl}-amine
A solution of toluene-4-sulfonic acid 2-[1-methyl-3-(naphthalene-1-sulfonyl)-1 H-indazol-5-yloxy]-ethyl ester (0.39 g, 0.73 mmol) in 2.0 M dimethylamine in THF (10 ml, 20 mmol) was stirred for 16.5 hours at 80 °C in a sealed tube. After cooling to ambient temperature, the reaction mixture was solvent evaporated. The residue was partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was washed with brine, dried with anhydrous magnesium sulfate, filtered, concentrated and dried at 80 °C in vacuo for 35 minutes to give dimethyl-{2-[1-methyl-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl}-amine a light brown-
orange semi-solid (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 in vacua to give the hydrochloride as a buff-colored foam (0.254 g). Mass Spectrum (+EI, [M+H]+) m/z410. 1HNMR (500 MHz, DMSO-d6): 810.25 (s, 1H), 8.74-8.76 (m, 1H), 8.51 (dd, 1H, J=7.44 Hz and 1.22 Hz), 8.26-8.28 (m, 1H), 8.03-8.05 (m, 1H), 7.71-7.74 (m, 2H), 7.56-7.66 (m, 2H), 7.39 (d, 1H, J=2.08 Hz), 7.22 (dd, 1H, J=9.28 Hz and 2.32 Hz), 4.39-4.42 (m, 2H), 4.05 (s, 3H), 3.50-3.52 (m, 2H), 2.83 ppm (s, 6H).
(Formula Removed)
Ethyl-methyl-{2-[1 -methyl-3-(naphthalene-1 -sulfonyl)-1 H-indazol-5-yloxy]-ethyl}-amine
A solution of toluene-4-sulfonic acid 2-[1-methyl-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (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 ambient temperature, the reaction mixture was solvent evaporated. The residue was partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was washed with brine, dried with anhydrous magnesium sulfate, filtered, concentrated and dried at 80 °C in vacua for 20 minutes to give ethyl-methyl-{2-[1-methyl-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl}-amine as a light brown gum (0.227 g, 72.3 %). This was dissolved in chloroform, and etheric hydrochloride was added. The mixture was concentrated and dried for 25 hours at 83 °C in vacua to give the hydrochloride as a buff-colored foam (0.254 g); Mass Spectrum (+EI, [M+H]+) m/z424. 1HNMR (500 MHz, DMSO-d6): 810.26-10.27 (s, br, 1H), 8.75 (d, 1H, J=8.66 Hz), 8.50-8.53 (m, 1H), 8.27 (d, 1H, J=8.17 Hz), 8.04 (d, 1H, J=7.56 Hz), 7.71-7.75 (m, 2H), 7.56-7.66 (m, 2H), 7.38 (d, 1H, J=2.19 H) 7.22 (dd, 1H, J=9.15 Hz and 2.32 Hz), 4.43 (t, 2H, J=4.88 Hz), 4.05 (s, 3H), 3.40-3.60 (m, 3H), 3.10-3.20 (br, 1H), 2.80 (s, 3H), 1.22-1.26 ppm (m, 3H).
(Formula Removed)
Diethyl-{2-[1 -methyl-3-(naphthalene-1 -sulfonyl)-1 H-indazol-5-yloxy]-ethyl}-amine
A solution of toluene-4-sulfonic acid 2-[1-methyl-3-(naphthalene-1-sulfonyl)-1 H-indazol-5-yloxy]-ethyl ester (0.385 g, 0.717 mmol) and diethylamine (2.0 ml, 19 mmol) in THF (10 mL) was stirred at 80 °C in a sealed tube for 16.5 hours. After cooling to ambient temperature, the reaction mixture was solvent evaporated. The residue was partitioned in chloroform and aqueous sodium bicarbonate. The organic phase was washed with brine, dried with anhydrous magnesium sulfate, filtered, concentrated and dried at 80 °C in vacua for 20 minutes to give diethyl-{2-[1-methyl-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl}-amine a clear amber gum (0.269 g, 85.7 %). This was dissolved in chloroform, and ethereal hydrochloride was added. The mixture was concentrated and dried for 25 hours at 83 °C in vacua to give the hydrochloride as a brown foam (0.253 g); Mass Spectrum (+EI, [M+H]+) m/z 438. 1HNMR (500 MHz, DMSO-d6): 510.11-10.12 (br, 1H), 8.74 (d, 1H, J=8.66 Hz), 8.50-8.52 (m, 1H), 8.27 (d, 1H, J=8.29 Hz), 8.03-8.05 (m, 1H), 7.71-7.75 (m, 2H), 7.56-7.66 (m, 2H), 7.37 (d, 1H, J=2.20 Hz), 7.21 (dd, 1H, 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).
(Formula Removed)
Ethyl-{2-[1 -methyl-3-(naphthalene-1 -sulfonyl)-1 H-indazol-5-yloxy]-ethyl}-amine
A solution of toluene-4-sulfonic acid 2-[1-methyl-3-(naphthalene-1-sulfonyl)-1 H-indazol-5-yloxy]-ethyl ester (0.413 g, 0.770 mmol) and 2.0 M ethylamine in THF (10 ml, 20 mmol) in THF (10 mL) was stirred at 80 °C in a sealed tube for 16.5 hours. After cooling to ambient temperature, the reaction mixture was solvent evaporated. The residue was partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was washed with brine, dried with anhydrous magnesium sulfate, filtered, concentrated and dried at 80 °C in vacuo 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 hydrochloride was added. The mixture was concentrated and dried for 25 hours at 83 °C in vacuo to give the hydrochloride as a beige solid (0.227 g) MP 276-7 °Cdec.; Mass Spectrum (+EI, [M+HD m/z410. 1HNMR (500 MHz, DMSO-d6): 88.95 (s, br, 2H), 8.75 (d, 1H, J=8.79 Hz), 8.52 (dd, 1H, J=7.45 Hz and 1.22 Hz), 8.27 (d, 1H, J=8.30 Hz), 8.04 (d, 1H, J=7.57 Hz), 7.71-7.75 (m, 2H), 7.56-7.66 (m, 2H), 7.36 (d, 1H, J=2.07 Hz), 7.22 (dd, 1H, 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 C23H23O4S1.00 mol HCr 0.40 mol H2O: Calcd: C, 58.31; H, 5.52; N, 9.27; Found: C, 58.62; H, 5.54; N, 9.11.
Example 45

(Formula Removed)
lsopropyl-{2-[1-methyl-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-6thyl}-amine
A solution of toluene-4-sulfonic acid 2-[1-methyl-3-(naphthalene-1-sulfonyl)-1 H-indazol-5-yloxy]-ethyl ester (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) was added, and the reaction mixture was stirred at 80 °C for 21 hours. It was allowed to cool to room temperature, and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was washed with water and brine. It was dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography using 0.25 % ammonium hydroxide/2.5 % methanol in chloroform. Drying at 63 °C in vacuo for 30 minutes yielded isopropyl-{2-[1-methyl-3-(naphthalene-1-sulfonyl)-1H-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 in vacuo for 13 hours to give the hydrochloride as an off-white solid (0.180 g): MP: 274-6 °C (dec).; Mass Spectrum (+EI, [M+H]+) m/z424. 1HNMR (500 MHz, DMSO-d6): 58.83 (s, br, 2H), 8.74 (d, 1H, J=8.79 Hz), 8.51 (dd, 1H, J=7.44 Hz and 1.22 Hz), 8.27 (d, 1H, J=8.30 Hz), 8.03-8.05 (m, 1H), 7.71-7.75
(m, 2H), 7.56-7.66 (m, 2H), 7.36 (d, 1H, J=2.20 Hz), 7.20-7.23 (m, 1H), 4.30-4.33 (m, 2H), 4.06 (s, 3H), 3.30-3.38 (m, 3H), 1.25 ppm (d, 6H, J=6.46 Hz). Elemental Analysis for C23H25N3O4S .1.00 mol HCI. 0.10 mol H2O: Calcd: C, 59.82; H, 5.72; N, 9.10; Found: C, 59.53; H, 5.66; N, 9.06.
(Formula Removed)
1-Methyl-3-(naphthalene-1-sulfonyl)-5-(2-pyrrolidin-1-yl-ethoxy)-1H-indazole
A solution of toluene-4-sulfonic acid 2-[1-methyl-3-(naphthalene-1-sulfonyl)-1 H-indazol-5-yloxy]-ethyl ester (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 ambient temperature, the reaction mixture was solvent evaporated 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 was purified by flash chromatography with 0.25 % ammonium hyrdroxide/2.5 % methanol in chloroform. Drying at 68 °C in vacua for 1 hour resulted in 1-methyl-3-(naphthalene-1-sulfonyl)-5-(2-pyrrolidin-1-yl-ethoxy)-1H-indazole as a light brown semi-solid (0.159 g, 46.5%). This was dissolved in chloroform, and ethereal hydrochloride was added. The precipitate was filtered, dissolved in methanol and concentrated. Drying at 85 °C in vacuo for 13 hours yielded the hydrochloride as a light orange semi-solid (0.156 g); Mass Spectrum (+EI, [M+H]+) m/z436. 1HNMR (500 MHz, DMSO-d6): 810.60-10.61 (s, br, 1H), 8.75 (d, 1H, J=8.66 Hz), 8.51-8.53 (m, 1H), 8.27 (d, 1H, J=8.29 Hz), 8.04 (d, 1H, J=7.93 Hz), 7.71-7.74 (m, 2H), 7.56-7.67 (m, 2H), 7.37 (d, 1H, J=2.20 Hz), 7.22-7.25 (m, 1H), 4.39-4.41 (m, 2H), 4.05 (s, 3H), 3.57-3.60 (m, 4H), 3.06-3.14 (m, 2H), 1.95-2.01 (m, 2H), 1.86-1.92 ppm (m, 2H). Elemental Analysis for C24H25N3O4S1.00 mol HCI 1.00 mol H2O: Calcd: C, 58.82; H, 5.76; N, 8.58; Found: C, 58.77; H, 6.00; N, 8.47.
Example 47
{2-[1 -Benzyl-3-(naphthalene-1 -sulfonyl)-1 H-indazol-5-yloxy]-ethyl}-ethyl-methyl-amine
Stepl
(Formula Removed)
Toluene-4-sulfonic acid 2-[1 -benzyl-3-(naphthalene-1 -sulfonyl)-1 H-indazol-5-yloxy]-ethyl ester
Benzyl bromide (0.46 ml, 3.9 mmol) was added to a stirring suspension of toluene-4-sulfonic acid 2-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (1.85 g, 3.54 mmol) and cesium carbonate (1.28 g, 3.93 mmol) in acetone (60 mL). The reaction mixture was stirred under nitrogen at ambient temperature for 1.5 hours. It was then poured into excess water and extracted with chloroform. The organic phase was washed with brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography with 40-50 % ethyl acetate in hexane. Drying at 80 °C in vacua for 30 minutes yielded toluene-4-sulfonic acid 2-[1-benzyl-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester as a light buff foam (1.39 g, 64.1 %); Mass Spectrum (+EI, [M+H]+) m/z613. 1HNMR (500 MHz, DMSO-d6): 58.74-8.77 (m, 1H), 8.55-8.57 (m, 1H), 8.25-8.27 (m, 1H), 8.01-8.05 (m, 1H), 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, 1H, J=2.19 Hz), 6.94-6.97 (m, 1H), 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: Calcd: C, 63.57; H, 4.72; N, 4.49; Found: C, 63.17; H, 4.63; N, 4.30.
Step 2

(Formula Removed)
{2-[1 -Benzyl-3-(naphthalene-1 -sulfonyl)-1 H-indazol-5-yloxy]-ethyl}-ethyl-methyl-amine
A solution of toluene-4-sulfonic acid 2-[1-benzyl-3-(naphthalene-1-sulfonyl)-1 H-indazol-5-yloxy]-ethyl ester (0.363 g, 0.592 mmol) and ethylmethylamine (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 ambient temperature, the residue was partitioned in ethyl acetate and
aqueous sodium bicarbonate. The organic phase was washed with brine, dried with anhydrous magnesium sulfate, filtered and concentrated. Drying at 80 °C in vacua for 30 minutes gave {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 was added. The mixture was concentrated and dried in vacua for 13 hours to yield the hydrochloride as a buff foam (0.242 g). Mass Spectrum (+EI, [M+H]+) m/z 500. 1HNMR (500 MHz, DMSO-d6): 810.04-10.10 (s, br, 1H), 8.74-8.77 (m, 1H), 8.54-8.56 (m, 1H), 8.27 (d, 1H, J=8.29 Hz), 8.02-8.05 (m, 1H), 7.79 (d, 1H, J=9.28 Hz), 7.70-7.74 (m, 1H), 7.55-7.67 (m, 2H), 7.28 (d, 1H, 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 C29H29N3O4S 1.00 mol HC11.10 mol H2O: Calcd: C, 62.66; H, 5.84; N, 7.56; Found: C, 62.73; H, 6.19; N, 7.17.
Example 48

(Formula Removed)
-Benzyl-3-(naphthalene-1 -sulfonyl)-1 H-indazol-5-yloxy]-ethyl}-methyl-amine
A solution of toluene-4-sulfonic acid 2-[1-benzyl-3-(naphthalene-1-sulfonyl)-1 H-indazol-5-yloxy]-ethyl ester (0.476 g, 0.777 mmol) in 2.0 M methylamine in THF (8.0 ml, 16 mmol) was stirred at 70 °C in a sealed tube for 3 hours. After cooling to ambient temperature and concentrating, the residue was partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was washed with water and brine. It was dried with anhydrous magnesium sulfate, filtered and concentrated. Drying at 80°C in vacuo for 20 minutes gave {2-[1-benzyl-3-(naphthalene-1-sulfonyl)-1 H-indazol-5-yloxy]-ethyl}-methyl-amine as a clear, dark yellow gum (0.324 g, 88.5 %). This was dissolved in chloroform, and ethereal hydrochloride was added. The mixture was concentrated and dried at 81 °C in vacuo for 13 hours. The hydrochloride as a light orange foam (0.330 g) resulted; Mass Spectrum (+EI, [M+H]+) m/z 472. 1HNMR (500 MHz, DMSO-d6): 88.86 (s, 2H), 8.74-8.77 (m, 1H), 8.54-8.56 (m, 1H), 8.27 (d, 1H, J=8.30 Hz), 8.02-8.05 (m, 1H), 7.79 (d, 1H, J=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: Calcd: C, 62.61; H, 5.27; N, 8.11; Found: C, 62.23; H, 5.45; N, 7.72.
(Formula Removed)
{2-[1-Benzyl-3-(naphthalene-1-sulfonyl)>1H-indazol-5-yloxy]-ethyl}-isopropyl-amine
A solution of toluene-4-sulfonic acid 2-[1-benzyl-3-(naphthalene-1-sulfonyl)-1 H-indazol-5-yloxy]-ethyl ester (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 isopropylamine (2.0 ml, 23 mmol) was then 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 solvent evaporated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was then washed with water and brine. It was dried with anhydrous magnesium sulfate, filtered and concentrated. Drying at 80 °C in vacuo for 20 minutes gave {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 was added. The mixture was concentrated and dried for 13 hours in vacuo at 81 °C. The result was the hydrochloride as a buff foam (0.273 g); Mass Spectrum (+EI, [M+H]+) m/z 500. 1HNMR (500 MHz, DMSO-d6): 58.80 (s, 2H), 8.74-8.78 (m, 1H), 8.55 (dd, 1H, J=7.44 Hz and 1.22 Hz), 8.27 (d, 1H, J=8.29 Hz), 8.01-8.05 (m, 1H), 7.79 (d, 1H, J=9.15 Hz), 7.70-7.74 (m, 1H), 7.58-7.65 (m, 2H), 7.27 (d, 1H, J=2.2Q 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, J=6.47 Hz). Elemental Analysis for C29H29N3O3S 1.00 HCI0.7 mol H2O: Calcd: C, 63.48; H, 5.77; N, 7.66; Found: C, 63.10; H, 5.67; N, 7.37.
Example 50

(Formula Removed)
{2-[1-Benzyl-3-(naphthalene-1-su Ifonyl)-1H-indazol-5-yloxy]-ethyl}-diethyl-amine
A solution of toluene-4-sulfonic acid 2-[1-benzyl-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (0.449 g, 0.733 mmol) and diethylamine (2.0 mL, 19 mmol) in THF (7.5 mL) was stirred at 70 °C in a sealed tube for 3 hours. More diethylamine (2.0 mL, 19 mmol) was then 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 solvent evaporated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was then washed with water and brine. It was dried with anhydrous magnesium sulfate, filtered and concentrated. Drying at 82°C in vacua for 35 minutes gave {2-[1-benzyl-3-(naphthalene-1-sulfonyl)-1 H-indazol-5-yloxy]-ethyl}-diethyl-amine as a light brown-yellow semi-solid (0.365 g, 97.1% mmol). This was dissolved in chloroform, and ethereal hydrochloride was added. The mixture was concentrated and dried for 13 hours in vacua at 81 °C. The result was the hydrochloride as a light orange semi-solid (0.332 g); Mass Spectrum (+EI, [M+H]+) m/z514. 1HNMR (500 MHz, DMSO-d6): 610.15-10.18 (s, 1H), 8.74-8.76 (m, 1H), 8.56 (dd, 1H, J=7.44 Hz and 1.22 Hz), 8.26 (d, 1H, J=8.29 Hz), 8.02-8.05 (m, 1H), 7.78 (d, 1H, J=9.15 Hz), 7.70-7.74 (m, 1H), 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 C24H25N3O4S1.00 HCI0.75 mol H2O: Calcd: C, 63.93; H, 5.99; N, 7.46; Found: C, 63.59; H, 5.94; N, 7.23.

(Formula Removed)
{2-[1 -Benzyl -3-(naphthalene-1 -sulfonyl)-1 H-indazol-5-yloxy]-ethyl}-dimethyl-amine
A solution of toluene-4-sulfonic acid 2-[1-benzyl-3-(naphthalene-1-sulfonyl)-1 H-indazol-5-yloxy]-ethyl ester (0.432 g, 0.705mmol) in 2.0 M dimethylamine in THF (8.0 mL, 16 mmol) was stirred at 70 °C in a sealed tube for 3 hours. After cooling somewhat, the reaction mixture was solvent evaporated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was then washed with water and brine. It was dried with anhydrous magnesium sulfate, filtered and concentrated. Drying at 80 °C in vacua for 20 minutes gave {2-[1-benzyl-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl}-dimethyl-amine as a yellow solid (0.288 g, 84.2% mmol). This was dissolved in chloroform, and ethereal hydrochloride was added. The mixture was concentrated and dried for 13 hours in vacua at 81 °C. The result was the hydrochloride as a buff foam (0.294 g); Mass Spectrum (+EI, [M+H]+) m/z486. 1HNMR (500 MHz, DMSO-d6): 610.11 (s, 1H), 8.74-8.77 (m, 1H), 8.54-8.56 (m, 1H), 8.27 (d, 1H, J=8.30 Hz), 8.03-8.05 (m, 1H), 7.79 (d, 1H, J=9.15 Hz), 7.70-7.74 (m, 1H), 7.58-7.65 (m, 2H), 7.30 (d, 1H, 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 C28H27N3O4S1.00 HC11.55 mol H2O: Calcd: C, 61.15; H, 5.70; N, 7.64; Found: C, 61.33; H, 5.59; N, 7.24.
(Formula Removed)
1-Benzyl-3-(naphthalene-1-sulfonyl)-5-(2-pyrrolidin-1-yl-ethoxy)-1H-indazole
A solution of toluene-4-sulfonic acid 2-[1-benzyl-3-(naphthalene-1-sulfonyl)-1 H-indazol-5-yloxy]-ethyl ester (0.379 g, 0.619 mmol) and pyrrolidine (1.0 ml, 12 mmol) in THF (80 ml) was stirred at 70 °C in a sealed tube for 3 hours. The reaction mixture was solvent evaporated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was then washed with water and brine. It was dried with anhydrous magnesium sulfate, filtered and concentrated. Drying at 80 °C in vacua for 25 minutes gave 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 was dissolved in chloroform, and ethereal hydrochloride was added. The mixture was concentrated and dried for 13 hours in vacua at 81 °C. The result was the hydrochloride as a buff foam (0.267g); Mass Spectrum (+EI, [M+H]+) m/z512.
1HNMR (500 MHz, DMSO-d6): 810.42 (s, 1H), 8.74-8.77 (m, 1H), 8.56 (dd, 1H, J=7.44 Hz and 1.22 Hz), 8.27 (d 1H, J=8.30 Hz), 8.02-8.05 (m, 1H), 7.79 (d, 1H, J=9.27 Hz), 7.70-7.74 (m, 1H), 7.55-7.65 (m, 2H), 7.28 (d, 1H, J=2.07 Hz), 7.08-7.20 (m, 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 C30H29N3O4S1.00 HCI1.25 mol H2O: Calcd: C, 63.15; H, 5.74; N, 7.36; Found: C, 62.82; H, 5.74; N, 6.99.
(Formula Removed)
{2-[1 -Benzyl-3-(naphthalene-1 -sulfonyl)-1 H-indazol-5-yloxy]-ethyl}-ethyl-amine
A solution of toluene-4-sulfonic acid 2-[1-benzyl-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (0.430 g, 0.702 mmol) and 2.0 M ethylamine in THF (4.8 mL, 9.6 mmol) was stirred at 70 °C in a sealed tube for 3 hours. After cooling to ambient temperature, the reaction mixture was solvent evaporated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was washed with water and brine. It was dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was 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 was {2-[1-benzyl-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl}-ethyl-amine as a yellow semi-solid (0.0528g, 15.5 %). This was dissolved in chloroform, and ethereal hydrochloride was added. The mixture was concentrated and dried for 14 hours at 82 °C in vacua to give the hydrochloride as a light orange semi-solid (0.0546 g); Mass Spectrum (+EI, [M+H]+) m/z 486. 1HNMR (500 MHz, DMSO-d6): 58.74-8.77 (m, 1H), 8.65-8.72 (br, s, 2H), 8.55 (dd, 1H, J=7.32 Hz and 1.22 Hz), 8.26-8.28 (m, 1H), 8.03-8.05 (m, 1H), 7.79 (d, 1H, J=9.15 Hz), 7.70-7.74 (m, 1H), 7.58-7.65 (m, 2H), 7.27 (d, 1H, 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 C28H27N3O4S 1.00 HCI'0.80 mol H2O: Calcd: 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-(raphthalene-1 -sulfonyl)-1 H-indazol-5-yloxy]-ethyl}-
dimethyl-amine
Stepl
(Formula Removed)
Toluene-4-sulfonic acid 2-[1 -(3-chloro-benzyl)-3-(naphthalene-1 -sulfonyl)-1 H-indazol-5-yloxy]-ethyl ester
3-Chlorobenzylbromide (0.90 ml, 6.8 mmol) was added to a stirring suspension of toluene-4-sulfonic acid 2-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (3.24 g, 6.20 mmol) and cesium carbonate (2.21 g, 6.78 mmol) in acetone (80 ml). The mixture was stirred at ambient temperature under nitrogen for 2 hours. It was then poured into excess water and extracted with chloroform. The organic phase was washed with brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography using 30-35 % ethyl acetate in hexane. Drying at 65 °C in vacua for 30 minutes gave toluene-4-sulfonic acid 2-[1-(3-chloro-benzyl)-3-(naphthalene-1-sulfonyl)-1 H-indazol-5-yloxy]-ethyl ester as a dark yellow foam (2.55 g, 63.6 %); Mass Spectrum (+EI, [M+H]+) m/z647. 1HNMR (500 MHz, DMSO-d6): 68.73-8.75 (m, 1H), 8.55-8.57 (m, 1H), 8.27 (d, 1H, J=8.30 Hz), 8.01-8.04 (m, 1H), 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, 1H, J=9.28 Hz and 2.32 Hz), 5.71 (s, 2H), 4.31-4.33 (m, 2H), 4.15-4.17 (m, 2H), 2.17 ppm (s, 3H). Elemental Analysis for C33H27CIN2O6S2: Calcd: C, 61.25; H, 4.21; N, 4.33; Found: C, 60.93; H, 4.22; N, 4.21.
Step 2
(Formula Removed)
{2-[1-(3-Chloro-benzyl)-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl}-dimethyl-amine
A solution of toluene-4-sulfonic acid 2-[1-(3-chloro-benzyl)-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yioxy]-ethyl ester (0.344 g, 0.532 mmol) in 2.0 M dimethylamine in THF (8.0 ml, 16.0 mmol) was stirred at 70 °C in a sealed tube for 2 hours. After cooling to ambient temperature, the reaction mixture was solvent evaporated. It was partitioned with ethyl acetate and aqueous sodium bicarbonate. The organic phase was washed with brine, dried with anhydrous magnesium sulfate, filtered and concentrated. Drying at 80 °C in vacua for 20 minutes gave {2-[1-(3-chloro-benzyl)-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl}-dimethyl-amine as a dark yellow gum (0.261 g, 94.6 %). This was dissolved in chloroform, and ethereal hydrochloride was added. The mixture was concentrated and dried in vacua at 82 °C for 14 hours. The result was the hydrochloride as a light orange foam (0.252 g); Mass Spectrum (+EI, [M+H]+) m/z 520. 1HNMR (500 MHz, DMSO-d6): 89.92-9.94 (br, s, 1H), 8.73-8.75 (m, 1H), 8.56 (dd, 1H, J=7.32 Hz and 1.10 Hz), 8.27 (d, 1H, J=8.29 Hz), 8.02-8.05 (m, 1H), 7.82 (d, 1H, J=9.15 Hz), 7.70-7.74 (m, 1H), 7.58-7.64 (m, 2H), 7.31 (d, 1H, J=2.32 Hz), 7.15-7.27 (m, 3H), 7.04 (d, 1H, 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

(Formula Removed)
{2-[1 -(3-Chloro-benzyl)-3-(naphthalene-1 -sulfonyl)-1 H-indazol-5-yloxy]-ethyl}-ethyl-methyl-amine
A solution of toluene-4-sulfonic acid 2-[1-(3-chloro-benzyl)-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (0.350 g, 0.541 mmol) and ethylmethylamine (1.0 ml, 12 mmol) in THF (8 ml_) was stirred for 2 hours in a sealed tube at 70 °C. Additional ethylmethylamine (1.0 ml, 12 mmol) was added, and the reaction mixture was stirred at 80 °C in sealed tube for 2 hours. After cooling to ambient temperature, the reaction mixture was solvent evaporated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was then washed with brine, dried with anhydrous magnesium sulfate, filtered and concentrated. It was dried at 80 °C for 20 minutes in vacuoto yield {2-[1-(3-chloro-benzyl)-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl}-ethyl-methyl-amine as a yellow semi-solid (0.268 g, 92.7 %). This was dissolved in chloroform, and ethereal hydrochloride was added. The
mixture was then concentrated and dried in vacua at 82 °C for 14 hours. The result was the hydrochloride as a light orange foam (0.266 g); Mass Spectrum (•;-£!, (M+Hf) m/z 534. 1HNMR (500 MHz, DMSO-d6): 89.90-9.93 (s, br, 1H), 8.73-8.75 (m, 1H), 8.54-8.57 (m, 1H), 8.27 (d, 1H, J=8.29 Hz), 8.02-8.05 (m, 1H), 7.82 (d, 1H, J=9.27 Hz), 7.70-7.74 (m, 1H), 7.56-7.63 (m, 2H), 7.30 (d. 1H, J=2.20 Hz), 7.15-7.26 (m, 4H), 7.04 (d, 1H, 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, 1H), 2.78 (s, 3H), 1.19-1.23 ppm (m, 3H). Elemental Analysis for C29H28CIN3O3S 1.00 HCI0.75 mol H2O: Calcd: C, 59.64; H, 5.26; N, 7.19; Found: C, 59.24; H, 5.17; N, 6.89.
Example 56

(Formula Removed)
{2-[1 -(3-Chloro-benzyl)-3-(naphthalene-1 -sulfonyl)-1 H-indazol-5-yloxy]-ethyl}-diethyl-amine
A solution of toluene-4-sulfonic acid 2-[1-(3-chloro-benzyl)-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (0.338 g, 0.522 mmol) and diethylamine (1.0 mL, 9.7 mmol) in THF (8 ml) was stirred at 70 °C in a sealed tube for 2 hours. Additional diethylamine (1.0 ml, 9.7 mmol) added, and the reaction mixture was stirred at 80 °C in a sealed tube for 2 hours. A third portion of diethylamine (1.0 ml, 9.7 mmol) was added to the reaction mixture, and it was stirred at 80 °C in a sealed tube for 30 hours. The reaction mixture was then solvent evaporated and partitioned in ethyl acetate and brine. It was dried with anhydrous magnesium sulfate, filtered and concentrated. Drying at 80 °C in vacua for 20 minutes yielded {2-[1-(3-chloro-benzyl)-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl}-diethyl-amine as a light brown semi-solid (0.278 g, 97.2%). It was dissolved in chloroform, and ethereal hydrochloride was added. The mixture was concentrated and dried in vacua at 82 °C for 14 hours. The result was the hydrochloride as a brown foam (0.275 g); Mass Spectrum (+EI, [M+H]+) m/z 548. 1HNMR (500 MHz, DMSO-d6): 89.86-9.88 (s, 1H), 8.72-8.75 (m, 1H), 8.56 (dd, 1H, J=7A4 Hz and 1.22 Hz), 8.27 (d, 1H, J=8.30 Hz), 8.02-8.05 (m, 1H), 7.82 (d, 1H, J=9.15 Hz), 7.70-7.74 (m. 1H), 7.57-7.63 (m, 2H), 7.29 (d, 1H, J=2.20 Hz), 7.24-7.26 (m, 1H), 7.15-7.21 (m, 3H), 7.03 (d, 1H, 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 C30H30N3O3S1.00 HCI 0.55 mol H2O: Calcd: C, 60.61; H, 5.44; N, 7.07; Found: C, 60.21; H, 5.44; N, 6.73.
(Formula Removed)
{2-[1 -(3-Chloro-benzyl)-3-(naphthalene-1 -sulfonyl)-1 H-indazol-5-yloxy]-ethyl}-isopropyl-amine
A solution of toluene-4-sulfonic acid 2-[1-(3-chloro-benzyl)-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (0.339 g, 0.524 mmol) and isopropylamine (1.0 ml, 12 mmol) in THF (8 ml) was stirred at 70 °C in a sealed tube for 2 hours. Isopropylamine (1.0 mL, 12 mmol) was added, and the reaction mixture was stirred at 80 °C in a sealed tube for 2 hours. Isopropylamine (1.0 ml, 12 mmol) was added to the reaction mixture, and it was stirred at 80 °C in a sealed tube for 30 hours. After cooling to ambient temperature, the reaction mixture was solvent evaporated and partitioned in ethyl acetate and aqueous sodium bicarbonate. It was washed with brine, dried with anhydrous magnesium sulfate, filtered, concentrated and dried in vacua for 20 minutes at 80 °C to give {2-[1-(3-chloro-benzyl)-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl}-isopropyl-amine as a yellow solid (0.280 g, 100 %). It was dissolved in chloroform, and ethereal hydrochloride was added. The resulting solid was filtered and dried at 82 °C in vacua for 14 hours. The result was the hydrochloride as a pale yellow solid (0.236 g): MP: 206-8 °C; Mass Spectrum (+EI, [M+H]+) m/z 534. 1HNMR (500 MHz, DMSO-d6): 88.65-8.76 (m, 3H), 8.54-8.56 (m, 1H), 8.27 (d, 1H, J=8.17 Hz), 8.02-8.05 (m, 1H), 7.82 (d, 1H, J=9.27 Hz), 7.72 (dd, 1H, 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, 1H, 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 HCI: Calcd: C, 61.05; H, 5.12; N, 7.36; Found: C, 60.68; H, 5.26; N, 7.14.
Example 58

(Formula Removed)
1 -(3-Chloro-benzyl)-3-(naphthalene-1 -sulfonyl)-5-(2-pyrrolidin-1 -yl-ethoxy)-1 H-indazole
A solution of toluene-4-sulfonic acid 2-[1-(3-chloro-benzyl)-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (0.359 g, 0.555 mmol) and pyrrolidine (1.0 ml, 12 mmol) in THF (8 mL) was stirred at 70 °C in a sealed tube for 2 hours. After cooling to ambient temperature, the reaction mixture was solvent evaporated. It was then partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was washed with brine, dried with anhydrous magnesium sulfate, filtered, concentrated and dried in vacua 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 semi-solid (0.266 g, 87.8 %). This was dissolved in chloroform, and ethereal hydrochloride was added. The mixture was concentrated and dried at 82 °C in vacua for 14 hours to yield the hydrochloride as a light orange foam (0.205 g); Mass Spectrum (+EI, [M+H]+) m/z546. 1HNMR (500 MHz, DMSO-d6): 810.18-10.19 (s, 1H), 8.73-8.75 (m, 1H), 8.55-8.57 (m, 1H), 8.27 (d, 1H, J=8.30 Hz), 8.02-8.04 (m, 1H), 7.82 (d, 1H, J=9.15 Hz), 7.70-7.74 (m, 1H), 7.57-7.64 (m, 2H), 7.15-7.29 (m, 5H), 7.04 (d, 1H, 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 C30H28N3O4S 1.00 HCI0.70 mole H2O: Calcd: C, 60.54; H, 5.15; N, 7.06; Found: C, 60.16; H, 5.11; N, 6.74.
(Formula Removed)
{2-[1-(3-Chloro-benzyl)-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl}-methyl-amine
A solution of toluene-4-sulfonic acid 2-[1-(3-chloro-benzyl)-3-(naphthalene-1-sulfonyl)-1 H-indazol-5-yloxy]-ethyl ester (0.367 g, 0.567 mmol) in 2.0 M methylamine
in THF (8.0 ml, 16 mmol) was stirred at 70 °C in a sealed tube for 2 hours. After cooling to ambient temperature, the reaction mixture was solvent evaporated. The residue was partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was then washed with brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by HPLC with 25-60% (chloroform/methanol 8:2/TEA) in heptane/TEA. Concentration and drying at 60 °C in vacua yielded {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 was dissolved in chloroform, and ethereal hydrochloride was added. The mixture was then concentrated and dried in vacuo for 29 hours at 80 °C. The hydrochloride as an off-white foam resulted (0.206 g); Mass Spectrum (+EI, [M+H]+) m/z 506. 1HNMR (500 MHz, DMSO-de): 88.71-8.76 (m, 3H), 8.54-8.56 (m, 1H), 8.27 (d, 1H, J=8.30 Hz), 8.02-8.05 (m, 1H), 7.82 (d, 1H, J=9.27 Hz), 7.70-7.74 (m, 1H), 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 C27H24N3O3S 1.00 HCI1.50 mole H2O: Calcd: C, 56.94; H, 4.96; N, 7.38; Found: C, 56.64; H, 4.88; N, 7.06.
(Formula Removed)
{2-[1 -(3-Chloro-benzyl)-3-(naphthalene-1 -sulfonyl)-1 H-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) was stirred at 70 °C for 3 hours and then at 80 °C for 19 hours. The reaction mixture was allowed to cool to ambient temperature and solvent evaporated. It was partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was washed with brine, dried with magnesium sulfate, filtered and concentrated. Drying in vacuo at 80 °C for 20 minutes resulted in {2-[1-(3-chloro-benzyl)-3-(naphthalene-1-sulfonyl)-1 H-indazol-5-yloxy]-ethyl}-ethyl-amine as an orange semi-solid (0.270 g, 81.1 %). This was dissolved in chloroform, and ethereal hydrochloride was added. The mixture was concentrated and dried in vacuo at 83 °C
for 16 hours. The hydrochloride as a pale orange foam resulted (0.276 g); Mass Spectrum (+EI, [M+H]+) m/z520. 1HNMR (500 MHz, DMSO-d6): 88.71-8.77 (m, 3H), 8.55 (dd, 1H, J=7.44 Hz and 1.22 Hz), 8.27 (d, 1H, J=8.29 Hz), 8.02-8.05 (m, 1H), 7.82 (d, 1H, J=9.15 Hz), 7.70-7.74 (m, 1H), 7.57-7.64 (m, 2H), 7.24-7.28 (m, 2H), 7.16-7.21 (m, 3H) 7.05 (d, 1H, 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 C28H26CIN3O3S 1.00 HCI0.60 mole H2O: Calcd: C, 59.28; H, 5.01; N, 7.41; Found: C, 58.95; H, 5.06; N, 7.14.
Example 61 3-(1 -naphthylsulfonyl)-5-(4-piperidin-1 -ylbutoxy)-1 H-indazole

(Formula Removed)
Stepl 1-(4-Chloro-butoxy)-4-nitro-benzene
A mixture of para-nitrophenol (0.83 g, 6 mmoles), 1-bromo-4-chloro-butane (1.23 g, 7.2 mmoles), and K2CO3 (1.24 g, 9 mmoles) was stirred together in DMF at 80 °C for 1 hour. Reaction mixture was diluted with H2O, extracted with EtOAc, washed with water (2x), brine (1x), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by HPLC using as eluent 30%EtOAc/hexane to afford the title compound as an off-white solid (1.28 g, 5.6 mmoles).
Step 2 1-[5-(4-Chloro-butoxy)-2-nitro-phenylmethanesulfonyl]-naphthalene
A mixture of 1-(4-chloro-butoxy)-4-nitrobenzene (1.28 g, 5.6 mmoles) and 1-chloromethane-sulfonyl-naphthalene (1.6 g, 6.72 mmoles) was stirred in THF (50 ml) at -78 °C, in a round bottom flask under nitrogen. A solution of 1M potassium t-butoxide was added dropwise (16.8 ml, 16.8 mmoles) over a half an hour period. Temperature was allowed to rise to -40 °C, and the reaction mixture was stirred at this temperature for 5 hours. The reaction mixture was poured into cold 2N HCI,
extracted with EtOAc, dried over Na2SO4, and concentrated under vacuum. Compound was recrystallized from CH2CI2/hexane to afford the title compound as an off-white solid (1.94 g, 4.5 mmoles).
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 mmoles) and 10% Pd/C in THF (20 ml_), methanol (20 ml), and formic acid (5 ml) was hydrogenated in a Parr hydrogenation bottle (250 mL) at 40 Ib/in2 for 20 hours. The mixture was filtered through Celite, and the filtrate was diluted with EtOAc, washed with water, dried over Na2SO4) and concentrated under vacuum. The crude product was purified by flash chromatography using as eluent 5% EtOAc/CH2CI2 to afford the title compound as an off-white solid (1.54 g, 3.8 mmoles).
Step 4
5-(4-Chloro-butoxy)-3-(naphthalene-1 -sulfonyl)-1 -H-indazole
A mixture of 4-(4-chloro-butoxy)-2-(naphthalene-1-sulfonylmethyl)-phenyl amine (1.54 g, 3.8 mmoles) in THF (7 ml), and 4M HCI (15 ml) was stirred in a round bottom flask, under nitrogen, at 3 °C. A solution of sodium nitrite (0.34 g, 4.0 mmoles) in H2O (1 ml) was added dropwise. The reaction mixture was poured into a cold solution of saturated sodium bicarbonate (100 ml) and extracted with EtOAc. Compound was dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (1.55 g, 3.75 mmoles).
StepS
A mixture of 5-(4-chloro-butoxy)-3-(naphthalene-1-sulfonyl)-1 -H-indazole (0.065 g, 0.12 mmoles) and piperidine (0.48 mmoles) in DMF (1 mL) was stirred under nitrogen at 100 °C overnight. Mixture was cooled to room temperature, diluted with water, extracted with EtOAc, washed with water (2x), brine (1x), dried over Na2SO4, and concentrated under vacuum. Compound was purified by flash chromatography using as eluent 5% CH3OH/EtOAc. The purified compound was dissolved in methanol, 1M HCI in ether (0.1 ml, 0.1 mmoles) was added, and the compound was dried to afford the title compound 3-(1-naphthylsulfonyl)-5-(4-piperidin-1-ylbutoxy)-1 H-indazole as the HCI salt, MS: (ES+) 463 [M+H] +
Examples 62-67

(Formula Removed)
Using essentially the same procedure described in Example 61, Step 5 and employing an appropriate amine, the compounds shown on Table I were obtained and identified by HPLC and mass spectral analyses.
TABLE I
(Formula and Table Removed)
Example 68 (4-{[3- (1-naphthylsulfonyl)-1H-indazol-5-yl] oxy> butyl) amine

(Formula Removed)Stepl
A mixture of 5-(4-chloro-butoxy)-3-(naphthalene-1-sulfonyl)-1-H-indazole (0.065 g, 0.12 mmoles) and sodium azide (0.24 mmoles) in DMSO (1 mL) was stirred under nitrogen at 90°C for 5 hours. Mixture was cooled to room temperature, diluted
with water, extracted with EtOAc, washed with water (2x), brine (1x), dried over Na2S04, and concentrated under vacuum. Compound was purified by flash chromatography using as eluent 5%CH3OH/EtOAc.
Step 2.
The azide prepared in step 1 was subjected to hydrogenation over 10 %Pd/C in THF (2 ml_), and methanol (8 ml) in a Parr hydrogenation bottle (250 ml) at 52lb/in2 for 2 hours. The mixture was filtered through Celite, and the filtrate was concentrated under vacuum. The crude product was recrystallized from CH2CI2/hexane, 1M HCI in ether (0.9 ml, 0.9 mmoles) was added, then evaporated to afford the title compound - (4-{[3- (1-naphthylsulfonyl)-1H-indazol-5-yl] oxy} butyl) amine as an off-white HCI salt (0.04 g, 0.1 mmoles), MS: (ES~) 394[M-H]~
Example 69
(2-{[1 -(3-Chlorobenzyl)-3-(1 -naphthylsulfonyl)-1 -H-indazol-7-yl] oxy} ethyl) amine
(Formula Removed)
Stepl 1-(2-Chloro-ethoxy)-2-nitro-benzene
A mixture of o/t/jo-nitrophenol (5.0 g, 35.8 mmoles) and 2-chloroethanol (9.5 ml, 143 mmoles) in THF (50 mL), in a round bottom flask, under nitrogen, was stirred at room temperature. Triphenylphosphine (14 g, 53.7 mmoles) was added, followed by diethylazodicarboxylate dropwise (8.5 ml, 53.7 mmoles). The mixture was stirred overnight at room temperature. The reaction mixture was diluted with water, extracted with EtOAc, washed with water (1x), brine (1x), dried (Na2SO4), and concentrated under vacuum. The crude product was purified by flash chromatography using as eluent 40 %EtOAc/hexane to give the title compound as an off-white solid (5.6 g, 28 mmoles).
Step 2 1-Chloromethane-sulfonyl-naphthalene
A mixture of naphthalene-1 -sulfonyl chloride (10.0 g, 44 mmoles), sodium sulfite (11.12 g, 88 mmoles), and sodium bicarbonate (7.4 g, 88 mmole:;) in water (50 ml) was heated to 100 °C for one hour. The crude sodium sulfinate solution was allowed to cool for 30 minutes, and then treated with bromochloromethane (43 ml, 661 mmoles) and tetra-N-butylammonium bromide (1.4 g, 4.4 mmoles). The resultant mixture was heated to 75 °C overnight. All solvents were removed under vacuum. Compound was recrystallized from CH2CI2/hexane to give the title compound as an off white solid (10.62 g, 44 mmoles).
Step 3 1-[3-(2-Chloro-ethoxy)-2-nitro-phenyl-methanesulfonyl]-naphthalene
A mixture of 1-(2-chloro-ethoxy)-2-nitrobenzene (1.2 g, 6 mmoles) and 1-chloromethane-sulfonyl-naphthalene (2.16 g, 9 mmoles) was stirred in THF (50 ml) at -78 °C, in a round bottom flask under nitrogen. A solution of 1M potassium t-butoxide was added drop wise (18 mL, 18 mmoles) over a half an hour period. Temperature was allowed to rise to -40 °C, and the reaction mixture was stirred at this temperature for 5 hours. The reaction mixture was poured into cold 2N HCI, extracted with EtOAc, dried over Na2SO4, and concentrated under vacuum. Compound was recrystallized from CH2CI2/hexane to afford the title compound as an off-white solid (1.4 g, 3 mmoles).
Step 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 mmoles) and 10% Pd/C in THF (20 ml), methanol (5 mL), and formic acid (5 mL) was hydrogenated in a Parr hydrogenation bottle (250 mL) at 40 Ib/in2 for 20 hours. The mixture was filtered through Celite, and the filtrate was diluted with EtOAc, washed with water, dried over Na2SO4, and concentrated under vacuum. The crude product was purified by flash chromatography using as eluent 5% EtOAc/CH2CI2 to afford the title compound as an off-white solid (1.0 g, 3.1 mmoles).
StepS
7-(2-Chloro-ethoxy)-3-(naphthalene-1 -sulfonyl)-1 -H-indazole
A mixture of 2-(2-chloro-ethoxy)-6-(naphthalene-1-sulfonylmethyl)-phenyl amine (0.97 g, 3 mmoles) in THF (7 mL), and 4M HCI (15 mL) was stirred in a round
bottom flask, under nitrogen, at 3 °C. A solution of sodium nitrite (0.21 g, 3.15 mrioles) in H2O (1 ml) was added dropwise. The reaction mixture was poured into a cold solution of saturated sodium bicarbonate (100 ml) and extracted with EtOAc. Compound was dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (0.9 g, 2.7 mmoles).
Step 6 1-(3-Chloro-benzyl)-7-(2-chloro-ethoxy)-3-(naphthalene-1-sulfonyl)-1-H-indazole
A mixture of 7-(2-chloro-ethoxy)-3-(naphthalene-1-sulfonyl)-1-H-indazole (0.7 g, 1.8 mmoles), 3-chloro-benzyl bromide (0.28 ml, 2.17 mmoles), and cesium carbonate (0.7 g, 2.17 mmoles) in DMF (5 ml) was stirred together in a round bottom flask at room temperature for 30 minutes. Reaction mixture was diluted with H2O, extracted with EtOAc, washed with water (2x), brine (1x), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by HPLC using as eluent 30% EtOAc/hexane to afford the title compound as an off-white solid (0.55 g, 1.1 mmoles).
Step 7
7-(2-Azido-ethoxy)-3-(naphthalene-1 -sulfonyl)-1 -H-indazole
A mixture of 1-(3-chloro-benzyl)-7-(2-chloro-ethoxy)-3-(naphthalene-1-sulfonyl)-1-H-indazole (0.25 g, 0.49 mmoles) and sodium azide (0.04 g, 0.58 mmoles) in DMSO (3 mL) was stirred together in a round bottom flask under nitrogen at 90 °C for 3 hours. Reaction mixture was cooled to room temperature, diluted with water, extracted with EtOAC, washed with water (2x), brine (1x), dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (0.23 g, 0.44 mmoles).
StepS
(2-{[1 -(3-Chlorobenzyl)-3-(1 -naphthylsulfonyl)-1 -H-indazol-7-yl] oxy} ethyl)
amine
A mixture of 7-(2-azido-ethoxy)-3-(naphthalene-1-sulfonyl)-1-H-indazole (0.23 g, 0.44 mmoles) and 10% Pd/C in THF (2 ml), and methanol (5 mL) was hydrogenated in a Parr hydrogenation bottle (250 ml) at 52 Ib/in2 for 2 hours. The mixture was filtered through Celite, and the filtrate was concentrated under vacuum. The crude product was purified by flash chromatography using as eluent 5% CH3OH/CH2CI2 to afford an off-white solid (0.2 g, 0.4 mmoles), MS: (ES+) 493 [M+H] +
Example 70
(2-{[1 -(3-Chlorobenzyl)-3-(1 -naphthylsulfonyl)-1 -H-indazol-7-yl] oxy} methylamineethyl)
(Formula Removed)
A mixture of 1-(3-chloro-benzyl)-7-(2-chloro-ethoxy)-3-(naphthalene-1-sulfonyl)-1-H-indazole (0.065 g, 0.12 mmoles) and methylamine (0.48 mmoles) in DMF (1 ml) was stirred under nitrogen at 100 °C overnight. Mixture was cooled to room temperature, diluted with water, extracted with EtOAc, washed with water (2x), brine (1x), dried over Na2SO4, and concentrated under vacuum. Compound was purified by flash chromatography using as eluent 5% CH3OH/EtOAc. The purified compound was dissolved in methanol, 1M HCI in ether (0.1 ml, 0.1 mmoles) was added, and compound was dried to afford the title compound as the HCI salt, MS: (ES+) 507 [M+H]+.
Examples 71-75
(Formula Removed)
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 analyses.
(Formula and Table Removed)
Example 76
(2-{[3-(1 -naphthylsulfonyl)-1 -H-indazol-7-yl]oxy}ethyl)amine
(Formula Removed)
A mixture of 0.075 g of 1-(3-chlorobenzyl)-3-(1-naphthylsulfonyl)-7-(2-amine-1- ylethoxy)-1-H-indazole, DMSO (1 mL) and t-BuOH (0.2 mL) was stirred at room temperature in a round bottom flask under oxygen atmosphere. A solution of potassium f-butoxide (0.98 mL, 0.98 mmoles) was added dropwise and the reaction mixture stirred for 1 hr. Reaction mixture was quenched with saturated ammonium chloride, extracted with EtOAc, dried over Na2SO4, and concentrated under vacuum. Crude compound was purified by flash chromatography using 10% CH3OH/CH2CI2. The purified compounds were dissolved in methanol, 1M HCI in ether (0.1 mL, 0.1 mmoles) was added, and compound was dried to afford the title compound as the HCI salt, MS: (ES+) 368 [M+H]+.
Examples 77-81
(Formula Removed)
Using essentially the same procedure described in Example 76 and employing the appropriate indazol-7-yloxyethanamine substrate, the compounds
shown in Table III were obtained and identified by HPLC and mass spectral analyses.
TABLE HI
(Formula and Table Removed)
Examples 82-93

(Formula Removed)
Stepl
1 -Benzene-sulfonyl-methyl-3- (2-chloro-ethoxy)-2-nitro-benzene
A mixture of 1-(2-chloro-ethoxy)-2-nitrobenzene (1.2 g, 6 mmoles) and chloromethyl phenyl sulfone (2.16 g, 9 mmoles) was stirred in THF (50 ml) at -78 °C, in a round bottom flask under nitrogen. A solution of 1M potassium f-butoxide was added dropwise (18 ml, 18 mmoles) over a half an hour period. Temperature was allowed to rise to -40 °C, and the reaction mixture was stirred at this temperature for 5 hours. The reaction mixture was poured into cold 2N HCI, extracted with EtOAc, dried over Na2SO4, and concentrated under vacuum.
Compound was recrystallized from CH2CI2/hexane to afford the title compound as an off-white solid (1.5 g, 4.2 mmoles). Steps 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 analyses.
TABLE IV
(Formula and Table Removed)
Examples 94-105
(Formula Removed)
Stepl
7-(2-Chloro-ethoxy)-1 -methyl-3- (naphthalene-1 -sulfonyl)-1 H-indazole:
A mixture of 7-(2-chloro-ethoxy)-3-(naphthalene-1-sulfonyl)-1-H-indazole (0.7 g, 1.8 mmoles), rr ethyl iodide (0.28 ml, 2.17 mmoles), and potassium carbonate (0.29 g, 2.17 mmoles) in DMF (10 ml) was stirred together in a round bottom flask at room temperature for 2 hours. Reaction mixture was diluted with H2O, extracted with EtOAc, washed with water (2x), brine (1x), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by HPLC using as eluent 30% EtOAc/hexane to afford the title compound as an off-white solid, 0.55 g, 1.375 mmoles. Step 2
Using essentially the same procedure described in Example 70 and employing the appropriate 3-arylsulfonyl-1-methylindazole substrate and desired amine and conversion into HCI salts, the compounds shown in Table V are obtained and identfied by HPLC and mass spectral analyses.
TABLE V
(Formula Removed)
Example 106
(2-{[1 -(3-Chlorobenzyl)-5-f luoro-3- (1 -naphthylsulfonyl)-1 H-inda;*ol-7-yl] oxy} ethyl) amine

(Formula Removed)
Stepl 2-(2-Chloro-ethoxy)-4-fluoro-1-nitro-benzene
In a round bottom flask under nitrogen, 2-chloro-ethanol (8.3 ml, 120 mmoles) in THF (40 ml) was cooled to 0 °C. LDA (60 ml, 120 mmoles) was added dropwise, while maintaining the temperature constant at 0 °C. The mixture was stirred at this temperature for 15 minutes, followed by the addition of 2,4-difluoronitrobenzene (11 mL, 100 mmoles). The mixture was stirred at room temperature overnight. Reaction mixture was diluted with water, extracted with EtOAc, washed with brine (1x), dried over Na2SO4, and concentrated under vacuum, to afford the title compound as an off-white solid (20.0 g, 91 mmoles). Step 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 mmoles) and 1-chloromethane-sulfonyl-naphthalene (2.16 g, 9 mmoles) was stirred in THF (50 ml) at -78 °C, in a round bottom flask under nitrogen. A solution of 1M potassium f-butoxide was added drop wise (18 ml, 18 mmoles) over a half an hour period. Temperature was allowed to rise to -40 °C, and the reaction mixture was stirred at this temperature for 5 hours. The reaction mixture was poured into cold 2N HCI, extracted with EtOAc, dried over Na2SO4, and concentrated under vacuum. Compound was recrystallized from CH2Cl2/hexane to afford the title compound as an off-white solid (2.25 g, 5.3 mmoles). Step 3
2-(2-Chloro-ethoxy)-4-fluoro-6-(naphthalene-1-sulfonyl-methyl)-phenylamine
A mixture of 1-[3-(2-chloro-ethoxy)-5-fluoro-2-ni1ro-phenylmethanesulfonyl]-naphthalene (1.0 g, 2.36 mmoles) in ethanol (25 ml) was stirred under nitrogen in a round bottom flask at 60 °C. 10% Pd/C was added, and the temperature was increased to 80 °C. Hydrazine hydrate (2.0 ml) was added dropwise and the mixture was stirred at reflux for 3 hours. Reaction mixture was filtered off through Celite, and the solution was washed with H2O (3x), dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (0.91 g, 2.31 mmoles). Step 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 mmoles) in THF (7 ml), and 4M HCI (15 mL) was stirred in a round bottom flask, under nitrogen, at 3 °C. A solution of sodium nitrite (0.16 g, 2.4 mmoles) in H2O (1 ml) was added dropwise. The reaction mixture was poured into a cold solution of saturated sodium bicarbonate (100 ml) and extracted with EtOAc. Compound was dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (0.9 g, 2.2 mmoles). Step 5
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)-1H-indazole (0.9 g, 2.2 mmoles), 3-chlorobenzyl bromide (0.35 ml, 2.7 mmoles), and cesium carbonate (0.87 g, 2.7 mmoles) in DMF (5 mL) was stirred together in a round bottom flask at room temperature for 30 minutes. Reaction mixture was diluted with H2O, extracted with EtOAc, washed with water (2x), brine (1x), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by HPLC using as eluent 30% EtOAc/hexane to afford the title compound as an off-white solid (0.85 g, 2 mmoles). Step 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)-1 H-indazole (0.1 g, 0.19 mmoles) and sodium azide (0.014 g, 0.22 mmoles) in DMSO (3 mL) was stirred together in a round bottom flask under nitrogen at 90 °C for 3 hours. Reaction mixture was cooled to room temperature, diluted with water, extracted with EtOAC, washed with water (2x), brine (1x), dried over Na2SO4,
and concentrated under vacuum to afford the title compound as an off white solid
(0.09 g, 0.1 7 mmoles).
Step 7
(2-{[1 -(3-Chlorobenzyl)-5-f luoro-3-(1 -naphthylsulfonyl)-1 H-indazol-7-yl] oxy}
ethyl) amine
A mixture of 7-(2-azido-ethoxy)-1-(3-chloro-benzyl)-5-fluoro-3-(naphthalene-1-sulfonyl)-1H-indazole (0.09 g, 0.17 mmoles) and 10% Pd/C in THF (5 ml), and methanol (15 ml) was hydrogenated in a Parr hydrogenation bottle (250 ml) at 52 Ib/in2 for 2 hours. The mixture was filtered through Celite, and the filtrate was concentrated under vacuum. The crude product was purified by flash chromatography using as eluent 5 % CH3OH/CH2CI2 to afford the title compound as an off-white solid (0.08 g, 0.14 mmoles), MS: (ES+) 511 [M+H]+.
Example 107
(2-{[1 -(3-chlorobenzyl)-5-fluoro-3- (1 -naphthylsulfonyl)-1 H-indazol-7-yl] oxy} ethyl) methylamine Hydrochloride

(Formula Removed)
A mixture of 1-(3-chloro-benzyl)-7-(2-chloro-ethoxy)-5-fluoro-3-(naphthalene-1-sulfonyl)-1H-indazole (0.075 g, 0.14 mmoles) and methylamine (0.56 mmoles) in DMSO (1 ml) was stirred under nitrogen at 100 °C for 4 hours. Mixture was cooled to room temperature, diluted with water, extracted with EtOAc, washed with water (2x), brine (1x), dried over Na2SO4, and concentrated under vacuum. Compound was purified by flash chromatography using as eluent 5% CH3OH/EtOAc. The purified compound was dissolved in methanol, 1M HCI in ether (0.1 ml, 0.1 mmoles) was added, and compound was dried to afford the title compound as the HCI salt. MS:(ES+)525[M+H] +

Examples 10 M18

(Formula Removed)
Using essentially the same procedures described in Examples 107 and 76 and employing the desired amine, the compounds shown in Table VI were obtained and identified by HPLC and mass spectral analyses.
(Formula and Table Removed)
Examples 119-127
(Formula Removed)
Step 1)
2-{2-Chloroethoxy)-4-methoxy-1 -nitrobenzene
To a mixture of 2-chloroethanol (0.7 ml, 10.5 mmoles) in THF (20 ml), cooled to 0 °C was added 2M LDA (5.25 mL, 10.5 mmoles) dropwise. When the addition of LDA was complete, the mixture was stirred for an additional 15 minutes, and then 2-fluoro-4-methoxy-1-nitrobenzene (1.5 g, 8.8 mmoles) was added. The mixture was allowed to warm to room temperature, and stirred at this temperature overnight. Reaction mixture was diluted with water, extracted with EtOAc, washed with brine (1x), dried over Na2SO4, and concentrated under vacuum. The crude compound was recrystallized from Ch^Cb/hexane to give the title compound (1.5 g, 6.5 mmoles).
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 mmoles) and 1-chloromethane-sulfonyl-naphthalene (1.4 g, 6 mmoles) was stirred in THF (50 ml) at -78 °C, in a round bottom flask under nitrogen. A solution of 1M potassium t-butoxide was added dropwise (18 ml, 18 mmoles) over a half an hour period. Temperature was allowed to rise to -40 °C, and the reaction mixture was stirred at this temperature for 4 hours. The reaction mixture was poured into cold 2N HCI, extracted with EtOAc, dried over Na2SO4, and concentrated under vacuum. Compound was recrystallized from CH2CI2/hexane to afford the title compound as an off-white solid (2 g, 4.6 mmoles).
Step 3)
2-(2-Chloro-ethoxy)-4-methoxy-6- (naphthalene-1 -sulfonylmethyl)-phenylamine
A mixture of 1-[3-(2-chloro-ethoxy)-5-methoxy-2-nitro-phenylmethanesulfonyl]-naphthalene (1.0 g, 2.5 mmoles) in ethanol (25 ml) was
stirred under nitrogen in a round bottom flask at 60 °C. 10% Pd/C was added, and the temperature was increased to 80 °C. Hydrazine hydrate (2.0 mL) was added dropwise and the mixture was stirred at reflux for 3 hours. Reaction mixture was filtered off through Celite, and the solution was washed with H2O (3x), dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (1.0 g, 2.46 mmoles).
Step 4)
7-(2-Chloro-ethoxy)-5-methoxy-3- (naphthalene-1-sulfonyl)-1H-indazole
A mixture of 2-(2-chloro-ethoxy)-4-methoxy-6-(naphthalene-1-sulfonylmethyl)-phenylamine (1.0 g, 2.46 mmoles) in THF (7 mL), and 4M HCI (15 mL) was stirred in a round bottom flask, under nitrogen, at 3 °C. A solution of sodium nitrite (0.17 g, 2.6 mmoles) in H2O (1 mL) was added dropwise. The reaction mixture was poured into a cold solution of saturated sodium bicarbonate (100 mL) and extracted with EtOAc. Compound was dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (1.0 g, 2.39 mmoles).
Step 5) 1 -(3-Chloro-benzyl)-7-(2-chloro-ethoxy-5-methoxy-3-(naphthalene-1 -sulfonyl)-1 H-indazole
A mixture of 7-(2-chloro-ethoxy)-5-methoxy-3-(naphthalene-1-sulfonyl)-1H-indazole (1.0 g, 2.39 mmoles), 3-chlorobenzyl bromide (0.35 mL, 2.7 mmoles), and cesium carbonate (0.87 g, 2.7 mmoles) in DMF (5 mL) was stirred together in a round bottom flask at room temperature for 10 minutes. Reaction mixture was diluted with H2O, extracted with EtOAc, washed with water (2x), brine (1x), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by HPLC using as eluent 30% EtOAc/hexane to afford the title compound as an off-white solid (1.1 g, 2 mmoles).
Steps 6 and 7) Animation and Debenzylation
Using essentially the same procedures described in Examples 107 and 76 and employing the 7-(2-chloroethoxy)-5-methoxy-3-naphthylsulfonylindazole substrate and the desired amine, the compounds shown on Table VII were obtained and identified by HPLC and mass spectral analyses.
TABLE VII
(Formula and Table Removed)
Step 1) 1-(3-Chloro-propoxy)-2-nitro-benzene
(Formula Removed)
A mixture of ortho-nitrophenol (0.83 g, 6 mmoles), 1-bromo-3-chloropropane (1.1 g, 7.2 mmoles), and K2CO3(1.24 g, 9 mmoles) was stirred together in DMF at 80 °C for 1 hour. Reaction mixture was diluted with H20, extracted with EtOAc, washed with water (2x), brine (1x), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by HPLC using as eluent 30% EtOAc/hexane to afford the title compound as an off-white solid (1.2 g, 5.6 mmoles).
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 mmoles) and 1-chloromethane-sulfonyl-naphthalene (2.16 g, 9 mmoles) was stirred in THF (50 mL) at -78 °C, in a round bottom flask under nitrogen. A solution of 1M potassium t-
butoxide was added dropwise (18 ml, 18 mmoles) over a half hour period. Temperature was allowed to rise to -40 °C, and the reaction mixture was stirred at this temperature for 5 hours. The reaction mixture was poured into cold 2N HCI, extracted with EtOAc, dried over Na2SO4, and concentrated under vacuum. Compound was recrystallized from CH2CI2/hexane to afford the title compound as an off-white solid (1.9 g, 4.5 mmoles). Step 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 mmoles) and 10% Pd/C in THF (20 ml), methanol (20 ml_), and formic acid (5 ml) was hydrogenated in a Parr hydrogenation bottle (250 mL) at 40 Ib/in2 for 20 hours. The mixture was filtered through Celite, and the filtrate was diluted with EtOAc, washed with water, dried over Na2SO4, and concentrated under vacuum. The crude product was purified by flash chromatography using as eluent 5% EtOAc/CH2CI2 to afford the title compound as an off-white solid (1.66 g, 4.25 mmoles). Step 4) 7-(3-Chloro-propoxy)-3-(naphthalene-1 -sulfonyl)-1 -H-indazole
A mixture of 2-(3-chloro-propoxy)-6-(naphthalene-1-sulfonylmethyl)-phenyl amine (1.66 g, 4.25 mmoles) in THF (7 mL), and 4M HCI (15 mL) was stirred in a round bottom flask, under nitrogen, at 3 °C. A solution of sodium nitrite (0.3 g, 4.4 mmoles) in H2O (1 mL) was added dropwise. The reaction mixture was poured into a cold solution of saturated sodium bicarbonate (100 mL) and extracted with EtOAc. Compound was dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (1.6 g, 4 mmoles).
Step 5) 1 -(3-Chloro-benzyl)-7-(3-chloro-propoxy)-3-(naphthalene-1 -sulfonyl)-1 -H-indazole
A mixture of 7-(3-chloro-propoxy)-3-(naphthalene-1-sulfonyl)-1 -H-indazole (0.7 g, 1.75 mmoles), 3-chloro-benzylbromide (0.28 mL, 2.17 mmoles), and cesium carbonate (0.7 g, 2.17 mmoles) in DMF (5 mL) was stirred together in a round bottom flask at room temperature for 10 minutes. Reaction mixture was diluted with H2O, extracted with EtOAc, washed with water (2x), brine (1x), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by HPLC using as eluent 30% EtOAc/hexane to afford the title compound as an off-white solid (0.87 g, 1.66 mmoles). Steps 6 and 7) Animation and Debenzylation
Using essentially the same procedures described in Examples 107 and 76 and employing the 7-(3-chloropropoxy)-3-naphthylsulfonylindazole substrate and the
desired amine, the compounds shown in Table VIII were obtained and identfied by HPLC and mass spectral analyses. (Amination was run in parallel manner on a heated carousel in 3-dram vials.)
TABLE VIII
(Formula and Table Removed)
Step 1) 1-Benzenesulfonylmethyl-3- (2-chloroethoxy)-2-nitrobenzene
A mixture of 1-(2-chloro-ethoxy)-2-nitrobenzene (0.5 g, 2.5 mmoles) and 1-chloromethane-sulfonyl-benzene (0.56 g, 2.97 mmoles) was stirred in THF (10 ml) at -78 °C, in a round bottom flask under nitrogen. A solution of 1 M potassium t-
butoxide was added dropwise (7.45 ml, 7.44 mmoles) over a half an hour period. Temperature was allowed to rise to -40 °C, and the reaction mixture was stirred at this temperature for 5 hours. The reaction mixture was poured into cold 2N HCI, extracted with EtOAc, dried over Na2SO4, and concentrated under vacuum. Compound was recrystallized from CH2CI2/hexane to afford the title compound as an off-white solid (0.57 g, 1.6 mmoles). Step 2) 2-Benzenesulfonylmethyl-6- (2-chloro-ethoxy)-phenylamine
A mixture of 1-benzenesulfonylmethyl-3- (2-chloro-ethoxy)-2-nitrobenzene (0.57 g, 1.6 mmoles) in ethanol (10 ml) was stirred under nitrogen in a round bottom flask at 60 °C. 10% Pd/C was added, and the temperature was increased to 80 °C. Hydrazine hydrate (1.5 ml) was added dropwise and the mixture was stirred at reflux for 3 hours. Reaction mixture was filtered off through Celite, and the solution was washed with H2O (3x), dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (0.5 g, 1.53 mmoles). Step 3) 2-(2-Azido-ethoxy)-6-benzene-sulfonylmethyl-phenylamine
A mixture of 2-benzenesulfonylmethyl-6-(2-chloro-ethoxy)-phenylamine (0.5 g, 1.53 mmoles) and sodium azide (0.15 g, 2.29 mmoles) in DMSO (10 ml) was stirred together in a round bottom flask under nitrogen at 90 °C for 3 hours. Reaction mixture was cooled to room temperature, diluted with water, extracted with EtOAC, washed with water (2x), brine (1x), dried over Na2SO4, and concentrated under vacuum. Crude compound was purified by normal phase HPLC using as eluent 40% EtOAc/hexane to afford the title compound as an off white solid (0.39 g, 1.17 mmoles). Step 4) 7-(2-Azido-ethoxy)-3-benzenesulfonyl-1H-indazole
A mixture of 2-(2-azido-ethoxy-6-benzene-sulfonylmethyl-phenylamine (0.39 g, 1.17 mmoles) in THF (2 ml), and 4M HCI (10 mL) was stirred in a round bottom flask, under nitrogen, at 3 °C. A solution of sodium nitrite (0.08 g, 1.23 mmoles) in H2O (1 ml) was added dropwise. The reaction mixture was poured into a cold solution of saturated sodium bicarbonate (100 mL) and extracted with EtOAc. Compound was dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (0.3 g, 0.87 mmoles). Step5) 2-{[3-Phenylsulfonyl)-1H-indazol-7-yl] oxy} ethanamine
A mixture of 7-(2-azido-ethoxy)-3-benzenesulfonyl-1H-indazole (0.3 g, 0.87 mmoles) and 10% Pd/C in THF (2 mL), and methanol (8 mL) was hydrogenated in a Parr hydrogenation bottle (250 mL) at 52 Ib/in2 for 2 hours. The mixture was filtered through Celite, and the filtrate was concentrated under vacuum. The crude product
was recrystallized from CH2CI2/hexane, 1M HCI in ether (0.9 ml, 0.9 mmoles) was added, then dried, to afford the title compound as an off-white HCI salt (0.2 g, 0.6 mmoles), MS: (ES+) 317 [M+H] +
Example 140
2-{[5-Fluoro-3-phenylsulfonyl)-1H-indazol-7-yl] oxy} ethanamine
(Formula Removed)
Step 1) 1-Benzenesulfonylmethyl-3- (2-chloro-ethoxy)-5-fIuoro-2-nitro-benzene
A mixture of 2-(2-chloroethoxy)-4-fluoro-1-nitrobenzene (1.3 g, 6 mmoles) and 1-chloromethane-sulfonyl-benzene (1.7 g, 9 mmoles) was stirred in THF (50 mL) at -78 °C, in a round bottom flask under nitrogen. A solution of 1M potassium t-butoxide was added dropwise (18 ml, 18 mmoles) over a half hour period. Temperature was allowed to rise to -40 °C, and the reaction mixture was stirred at this temperature for 5 hours. The reaction mixture was poured into cold 2N HCI, extracted with EtOAc, dried over Na2SO4, and concentrated under vacuum. Compound was recrystallized from CH2CI2/hexane to afford the title compound as an off-white solid (1.98 g, 5.3 mmoles). Step 2) 2-Benzenesulfonylmethyl-6- (2-chloro-ethoxy)-4-fluorophenylamine
A mixture of 1-benzenesulfonylmethyl-3- (2-chloro-ethoxy)-5-fluoro-2-nitrobenzene (1.98 g, 5.3 mmoles) in ethanol (25 ml) was stirred under nitrogen in a round bottom flask at 60 °C. 10% Pd/C was added, and the temperature was increased to 80 °C. Hydrazine hydrate (2.0 ml) was added dropwise and the mixture was stirred at reflux for 3 hours. Reaction mixture was filtered off through Celite, and the solution was washed with H2O (3x), dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (1.67 g, 4.87 mmoles). Step3) 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 mmoles) and sodium azide (0.38 g, 5.84 mmoles) in DMSO (20 ml) was stirred together in a round bottom flask under nitrogen at 90 °C for 3 hours. Reaction mixture was cooled to room temperature, diluted with water, extracted with EtOAC, washed with water (2x), brine (1x), dried over Na2SO4, and
concentrated under vacuum to afford the title compound as an off white solid (1.44 g,
4.14 mmoles).
Step 4) 7-(2-Azido-ethoxy)-3-benzenesulfonyl-5-fluoro-1H-indazole
A mixture of 2-(2-azido-ethoxy-6-benzene-sulfonylmethyl-4-fluoro-phenylamine (1.44 g, 4.14 mmoles) in THF (5 ml), and 4M HCI (20 ml) was stirred in a round bottom flask, under nitrogen, at 3 °C. A solution of sodium nitrite (0.28 g, 4.34 mmoles) in H2O (2 ml) was added dropwise. The reaction mixture was poured into a cold solution of saturated sodium bicarbonate (100 ml) and extracted with EtOAc. Compound was dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (1.34 g, 3.72 mmoles). Step 5) 2-{[5-Fluoro-3-phenylsulfonyl)-1H-indazol-7-yl] oxy} ethanamine
A mixture of 7-(2-azido-ethoxy)-3-benzenesulfonyl-5-fluoro-1H-indazole (0.3 g, 0.83 mmoles) and 10% Pd/C in THF (2 ml), and methanol (8 ml) was hydrogenated in a Parr hydrogenation bottle (250 ml) at 52 Ib/in2 for 2 hours. The mixture was filtered through Celite, and the filtrate was concentrated under vacuum. The crude product was recrystallized from CH2CI2/hexane, 1M HCI in ether (0.8 mL, 0.8 mmoles) was added, then dried, to afford the title compound as an off-white HCI salt (0.2 g, 0.59 mmoles), MS: (ES+) 336 [M+H] +
Example 141
2-{[3-1 -Naphthylsulfonyl)-1 H-indazol-4-yl] oxy}ethanamine

(Formula Removed)
Step 1) 1-(2-Chloroethoxy)-3-nitrobenzene
A mixture of 3-nitrophenol (0.83 g, 6 mmoles), bromo-chloroethane (1.03 g, 7.2 mmoles), and K2CO3(1.24 g, 9 mmoles) was stirred together in DMF at room temperature for 1 hour. Reaction mixture was diluted with H2O, extracted with EtOAc, washed with water (2x), brine (1x), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by HPLC using as eluent 30% EtOAc/hexane to afford the title compound as an off-white solid (1.12 g, 5.6 mmoles). Step 2) 1 -[2-(2-Chloroethoxy)-6-nitrophenylmethanesulfonyl]naphthalene
A mixture of 1-(2-chloro-ethoxy)-3-nitrobenzene (1.12 g, 5.6 mmoles) and 1-chloromethane-sulfonyl-napHhalene (1.6 g, 6.72 mmoles) was stirred in THF (50 mL) at -78 °C, in a round bottom flask under nitrogen. A solution of 1M potassium t-butoxide was added dropwise (16.8 ml, 16.8 mmoles) over a half an hour period. Temperature was allowed to rise to -40 °C, and the reaction mixture was stirred at this temperature for 5 hours. The reaction mixture was poured into cold 2N HCI, extracted with EtOAc, dried over Na2SO4, and concentrated under vacuum. Compound was purified by normal phase HPLC using as eluent 40% EtOAc/hexane to afford the title compound as an off-white solid (0.9 g, 2.24 mmoles), and 1-[4-(2-chloro-ethoxy)-2-nitro-phenylmethanesulfonyl]-naphthalene (0.79 g, 2.1 mmoles). 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 mmoles) and 10% Pd/C in THF (10 ml), methanol (10 mL), and formic acid (2 mL) was hydrogenated in a Parr hydrogenation bottle (250 mL) at 40 Ib/in2 for 20 hours. The mixture was filtered through Celite, and the filtrate was diluted with EtOAc, washed with water, dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off-white solid (0.78 g, 2.1 mmoles). Step 4) 4-(2-Chloro-ethoxy)-3-(naphthatene-1-sulfonyl)-1 -H-indazole
A mixture of 3-(2-chloro-ethoxy)-2-(naphthalene-1-sulfonylmethyl)-phenyl amine (0.78 g, 2.1 mmoles) in THF (5 mL), and 4M HCI (10 mL) was stirred in a round bottom flask, under nitrogen, at 3 °C. A solution of sodium nitrite (0.15 g, 2.2 mmoles) in H2O (1 mL) was added dropwise. The reaction mixture was poured into a cold solution of saturated sodium bicarbonate (100 mL) and extracted with EtOAc. Compound was dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (0.74 g, 1.93 mmoles). Step 5) 4-{2-Azido-ethoxy)-3-(naphthalene-1-sulfonyl)-1 H-indazole
A mixture of 4-(2-chloro-ethoxy)-3-(naphthalene-1-sulfonyl)-1 -H-indazole (0.2 g, 0.5 mmoles) and sodium azide (0.04 g, 0.62 mmoles) in DMSO (2 mL) was stirred together in a round bottom flask under nitrogen at 90 °C for 3 hours. Reaction mixture was cooled to room temperature, diluted with water, extracted with EtOAC, washed with water (2x), brine (1x), dried over Na2SO4, and concentrated under vacuum. Crude compound was purified by normal phase HPLC using as eluent 40% EtOAc/hexane to afford the title compound as an off white solid (0.17 g, 0.45 mmoles). Step 6) 2-{[3-1-Naphthylsulfonyl)-1H-indazol-4-yl] oxy} ethanamine
A mixture of 4-(2-gzido-ethoxy)-3-(naphthalene-1-sulfonyl)-1H-indazole (0.17 g, 0.45 mmoles) and 10% Pd/C in THF (2 ml), and methanol (8 ml) was hydrogenated in a Parr hydrogenation bottle (250 ml) at 52 Ib/in2 for 2 hours. The mixture was filtered through Celite, and the filtrate was concentrated under vacuum. The crude product was recrystallized from CH2CI2/hexane, 1M HCI in ether (0.4 ml, 0.4 mmoles) was added, then dried to afford the title compound as an off-white HGI salt (0.15 g, 0.4 mmoles), MS: (ES+) 369 [M+H] +
Example 142
N-Methyl-2- {[3-naphthylsulfonyl)-1H-indazol-4-yl] oxy} ethanamine Hydrochloride
(Formula Removed)
A mixture of 4-(2-chloro-ethoxy)-3-(naphthalene-1-sulfonyl)-1-H-indazole (0.075 g, 0.19 mmoles) and methylamine (0.28 mL, 0.56 mmoles) in DMSO (1 mL) was stirred under nitrogen at 100 °C for 4 hours. Mixture was cooled to room temperature, diluted with water, extracted with EtOAc, washed with water (2x), brine (1x), dried over Na2SO4, and concentrated under vacuum. Compound was purified by flash chromatography using as eluent 5% CH3OH/EtOAc. The purified compound was dissolved in methanol, 1M HCI in ether (0.2 ml, 0.2 mmoles) was added, then dried to afford the title compound as the HCI salt (0.07 g, 0.19 mmoles), MS: (ES+) 417[M+H] +
Examples 143-145

(Formula Removed)
Using essentially the same procedure described in Example 142 and employing the desired amine, the compounds shown in Table IX were obtained and identified by HPLC and mass spectral analyses.
TABLE IX
(Formula and Table Removed)
Example 146 2-{[3-(1-Naphtylsulfonyl)-1H-indazol-6-yl] oxy} ethanamine
(Formula Removed)
Step 1) 5-(2-Chloro-ethoxy-2- (naphthalene-l-sulfonylmethyl)-phenylamine
A mixture of 1-[4-(2-chloro-ethoxy)-2-nitro-phenylmethanesulfonyl]-naphthalene (0.79 g, 2.1 mmoles) and 10% Pd/C in THF (10 ml), methanol (10 ml), and formic acid (2 mL) was hydrogenated in a Parr hydrogenation bottle (250 ml) at 40 Ib/in2 for 20 hours. The mixture was filtered through Celite, and the filtrate was diluted with EtOAc, washed with water, dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off-white solid (0.74 g, 1 .99 mmoles). Step 2) 6-(2-Chloro-ethoxy)-3-(naphthalene-1-sulfonyl)-1H-inda2ole
A mixture of 5-(2-chloro-ethoxy)-2-(naphthalene-1-sulfonylmethyl)-phenyl amine (0.74 g, 1.99 mmoles) in THF (5 ml), and 4M HCI (10 ml) was stirred in a round bottom flask, under nitrogen, at 3 °C. A solution of sodium nitrite (0.14 g, 2.08 mmoles) in H2O (1 mL) was added dropwise. The reaction mixture was poured into a cold solution of saturated sodium bicarbonate (100 ml) and extracted with EtOAc. Compound was dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (0.74 g, 1.93 mmoles). Step 3) 6-(2-Azido-ethoxy)-3-(naphthalene-1-sulfonyl)-1W-indazole
A mixture of 6-(2-chloro-ethoxy)-3-(naphthalene-1-sulfonyl)-1-H-indazole (0.19 g, 0.5 mmoles) and sodium azide (0.04 g, 0.62 mmoles) in DMSO (2 ml) was
stirred together in a round bottom flask under nitrogen at 90 °C for 3 hours. Reaction
mixture was cooled to room temperature, diluted with water, extracted with EtOAC,
washed with water (2x), brine (1x), dried over Na2SO4, and concentrated under
vacuum. Crude compound was purified by normal phase HPLC using as eluent 40%
EtOAc/hexane to afford the title compound as an off white solid (0.17 g, 0.45
mmoles).
Step 4) 2-{[3-(1-Naphtylsulfonyl)-1H-indazol-6-yl] oxy} ethanamine
A mixture of 6-(2-azido-ethoxy)-3-(naphthalene-1-sulfonyl)-1H-indazole (0.17 g, 0.45 mmoles) and 10% Pd/C in THF (2 ml), and methanol (8 ml) was hydrogenated in a Parr hydrogenation bottle (250 ml) at 52 Ib/in2 for 2 hours. The mixture was filtered through Celite, and the filtrate was concentrated under vacuum. The crude product was recrystallized from CH2Cl2/hexane, 1M HCI in ether (0.4 mL, 0.4 mmoles) was added, then dried, to afford the title compound as an off-white HCI salt (0.15 g, 0.4 mmoles), MS: (ES+) 368 [M+H] +
Example 147
N-Methyl-2-{[3-(1-naphthylsulfonyl)-1H-indazol-6-yl]oxy}ethanamine Hydrochloride

(Formula Removed)
A mixture of 6-(2-chloro-ethoxy)-3-(naphthalene-1-sulfonyl)-1-H-indazole (0.075 g, 0.19 mmoles) and methylamine (0.28 mL, 0.56 mmoles) in DMSO (1 ml) was stirred under nitrogen at 100 °C for 4 hours. Mixture was cooled to room temperature, diluted with water, extracted with EtOAc, washed with water (2x), brine (1x), dried over Na2SO4, and concentrated under vacuum. Compound was purified by flash chromatography using as eluent 5% CH3OH/EtOAc. The purified compound was dissolved in methanol, 1M HCI in ether (0.2 ml, 0.2 mmoles) was added, then dried, to afford the title compound as the HCI salt (0.07 g, 0.19 mmoles), MS: (ES*) 381 [M+H] +
Examples 148-150
(Formula Removed)
Using essentially the same procedure described in Example 147 and employing the desired amine, the compounds shown in Table X were obtained and identified by HPLC and mass spectral analyses.
TABLE X
(Formula and Table Removed)
Example 151 N-[2-(Dimethylamino)ethyl]-3-(1-naphthylsulfonyl)-1W-indazole-5-carboxamide
(Formula Removed)
Step 1) 3-(Naphthalene 1-sulfonylmethyl)-4-nitro-benzoic acid methyl ester
A mixture of 4-nitro-benzoic acid methyl ester (0.8 g, 4.4 mmoles) and 1-chloromethane-sulfonyl-naphthalene (1.3 g, 5.3 mmoles) was stirred in THF (50 ml) at -78 °C, in a round bottom flask under nitrogen. A solution of 1M potassium t-butoxide was added dropwise (13 ml, 13 mmoles) over a half an hour period.
Temperature was allowed to rise to -40 °C, and the reaction mixture was stirred at this temperature for 5 hours. The reaction mixture wjjs poured into cold 2N HCI, extracted with EtOAc, dried over Na2SO4, and concentrated under vacuum. Compound was purified by normal phase HPLC using as eluent 40% EtOAc/hexane to afford the title compound as an off-white solid (1.5 g, 3.9 mrnoles). Step 2) 4-Amino-3- (naphthalene-l-sulfonylmethyl)benzoic acid methyl ester
A mixture of 3-(naphthalene 1-sulfonylmethyl)-4-nitro-benzoic acid methyl ester (1.5 g, 3.9 mmoles) and 10% Pd/C in THF (10 mL), and methanol (20 mL) was hydrogenated in a Parr hydrogenation bottle (250 mL) at 52 Ib/in2 overnight. The mixture was filtered through Celite, and the filtrate was concentrated under vacuum to afford the title compound as an off-white solid (0.9 g, 2.5 mmoles). Step 3) 3-{Naphthalene-1-sulfonyl)-1W-indazole-5-carboxylic acid methyl ester
A mixture of 4-amino-3-(naphthalene-1-sulfonylmethyl)benzoic acid methyl ester (0.9 g, 2.5 mmoles) in THF (5 ml), and 4M HCI (10 ml) was stirred in a round bottom flask, under nitrogen, at 3 °C. A solution of sodium nitrite (0.18 g, 2.62 mmoles) in H2O (1 mL) was added dropwise. The reaction mixture was poured into a cold solution of saturated sodium bicarbonate (100 mL) and extracted with EtOAc. Compound was dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (0.82 g, 2.25 mmoles).
Step 4) 1 -(3-Chlorobenzyl)-2-(naphthalene-1 -sulfonyl)-1 A/-indazole-5-carboxylic acid methyl ester
A mixture of 3-(napnthalene-1-sulfonyl)-1H-indazole-5-carboxylic acid methyl ester (0.82 g, 2.25 mmoles), 3-chlorobenzyl bromide (0.34 mL, 2.7 mmoles), and cesium carbonate (0.87 g, 2.7 mmoles) in DMF (5 mL) was stirred together in a round bottom flask at room temperature for 30 minutes. Reaction mixture was diluted with H2O, extracted with EtOAc, washed with water (2x), brine (1x), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by HPLC using as eluent 30% EtOAc/hexane to afford the title compound as an off-white solid (1.01 g, 2.07 mmoles),
Step 5) 1-{3-Chloro-benzyl)-3-(naphthalene-1-sulfonyl)-1 H-indazole-5-carboxylic acid(2-dimethyl-amino-ethyl)-amide
To a solution of dimethyl ethylene diamine (0.02 mL, 0.2 mmoles) in THF (2 mL), cooled to 0 °C was added LDA dropwise (0.15 mL, 0.3 mmoles). To this mixture was then added a solution of 1-(3-chloro-benzyl)-2-(naphthalene-1-sulfonyl}-1 H-indazole-5-carboxylic acid methyl ester (0.05 g, 0.1 mmoles) in THF (1 mL). Mixture was allowed to warm slowly to room temperature. Reaction mixture was
diluted with water, extracted with EtOAc (1x), CHrCI2 (1x); the organics were washed
with brine (1x), and concentrated under vacuo to afford the title compound (0.3 g,
0.04 mmoles).
Step 6) N- [2-(Dimethylamino) ethyl]-3-(1-naphthylsulfonyl)-1W-indazole-5-
carboxamide
A mixture of 1-(3-chloro-benzyl)-3-(naphthalene-1-sulfonyl)-1H-indazole-5-carboxylic acid (2-dimethyl-amino-ethyl)-amide (0.3 g, 0.04 mmoles), DMSO (1 ml_) and t-BuOH (0.2 ml) was stirred at room temperature in a round bottom flask under oxygen atmosphere. A solution of potassium f-butoxide (0.05 ml, 0.05 mmoles) was added dropwise and the reaction mixture stirred for 30 min. Reaction mixture was quenched with saturated ammonium chloride, extracted with EtOAc, dried over Na2SO4, and concentrated under vacuum. Crude compound was purified by reverse phase chromatography to afford the title compound, MS: (ES+) 423 [M+H] +
Example 152
3-(1 -Naphtylsulfonyl)-N-(2-piperidin-1 -ylethyl)-1 H-indazole-5-carboxamide
(Formula Removed)
Using essentially the same procedure described in Example 151 and employing 1-(2-aminoethyl)piperidine in step 5, the title compound is obtained and identified by HPLC and mass spectral analyses, MS: (ES+) 463 [M+H]+.
Example 153
N, N, N'-Trimethyl-N'-{[3-(1 -naphthylsulfonyl)-1 H-indazol-5-yl]methyl}ethane-1,2-diamine
(Formula Removed)
Step 1) 2-[3-(Naphthalene-1 -sulfonylmethyi)-4-nitrophenyl]-[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 mmoles) was stirred in THF (50 ml) at -78 °C, in a round bottom flask under nitrogen. A solution of 1M potassium t-butoxide was added dropwise (19 ml, 19 mmoles) over a half an hour period. Temperature was allowed to rise to -40 °C, and the reaction mixture was stirred at this temperature for 5 hours. The reaction mixture was poured into cold 2N HCI, extracted with EtOAc, dried over Na2SO4, and concentrated under vacuum. Compound was purified by normal phase HPLC using as eluent 40% EtOAc/hexane to afford the title compound as an off-white solid (3.03 g, 7.6 mmoles). Step 2) 3-{Naphthalene-1-sulfonylmethyt)-4-nitrobenzaldehyde
A mixture of 2-[3-(naphthalene-1-sulfonylmethyl)-4-nitro-phenyl]-[1,3]dioxolane (3.03 g, 7.6 mmoles), and 2N HCI (4 ml, 8 mmoles) in THF (30 ml) was stirred at 40 °C for 4 hours. The reaction mixture was cooled to room temperature, diluted with waster, extracted with EtOAc, dried over Na2SO4, and concentrated under vacuum to yield the title compound (2.56 g, 7.22 mmoles). Step 3) 4-Amino-3-(naphthalene-1-sulfonylmethyl)benzaldehyde
A mixture of 3-(naphthalene-1-sulfonylmethyl)-4-nitro-benzaldehyde (2.5 g, 7.22 mmoles) and 10% Pd/C in THF (10 mL), and methanol (20 mL) was hydrogenated in a Parr hydrogenation bottle (250 mL) at 52 Ib/in2 overnight. The mixture was filtered through Celite, and the filtrate was concentrated under vacuum to afford the title compound as an off-white solid (2.4 g, 6.85 mmoles). Step 4) 3-(Naphthalene-1-sulfonyl)-1H-indazole-5-carbaldehyde
A mixture of 4-amino-3-(naphthalene-1-sulfonylmethyl)-benzaldehyde (2.4 g, 6.85 mmoles) in THF (10 mL) and 4M HCI (20 ml) was stirred in a round bottom flask at 3 °C. A solution of sodium nitrite (0.49 g, 7.19 mmoles 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. Compound was dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (1.84 g, 5.5 mmoles).
Step 5) N, N, N'-Trimethyl-N'-{[3-(1-anphthylsulfonyl)-1W-indazol-5. yl]methyl}ethane-1,2-diamine
3-(Naphthalene-1-sulfonyl)-1H-indazole-5-carbaldehyde (0.17 g, 0.5 mmol), trimethyl ethylene diamine (0.6 mmol) and sodium triacetoxyborohydride (0.7 mmol) in dichloroethane (5 mL) was stirred at room temperature for 24 hrs. After
completion, the solvent was removed in vacuo, crude material dispersed in water and the pH brought to 3.4. Solid material was filtered off and washed with cold water to afford after drying the target material as a free base. The latter was converted into hydrochloride salt by dissolution in methanol, followed by treatment with the excess of 2N HCI and the evacuation of the volatiles in vacuo to afford the title compound hydrochloride salt, mp > 200 °C; MS (APPI) 423 [M+H]
Example 154
(3S)-N-{[3-(1-Naphthylsulfonyl)-1H-indazol-5-yl]methyl}pyrrolidin-3-amine Hydrochloride
(Formula Removed)Using essentially the same procedure described in Example 153, step 5, and employing Boc-protected S(-)-pyrrolidin-3-ylamine, followed by the removal of the Boc-group by TFA in methylene chloride and treatment of the free base with 2N HCI, 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 - Naphthylsulfonyl)-1 H-indazol-5yl]methyl}ethane-1.2-diamirte(Formula Removed)
3-(Naphthalene-1-sulfonyl)-1H-indazole-5-carbaldehyde (0.3 mmol) was strirred for 24 hrs with the excess of ethylene diamine (1 mmol) in methanol. Sodium borohydride (0.6 mmol) was added and stirring continued for another 24 hrs. After completion, the volatiles were removed in vacuo, crude material diluted with cold water, acidified to pH 3.4, filtered off, washed on a filter with cold water and dried to afford the target material as a free base. The latter was converted into hydrochloride salt by dissolution in methanol, followed by treatment with the excess of 2N HCI and
the evacuation of the volatiles in vacua to afford the title compound, mp > 200 °C; MS(ES+)381[lvHHr
Example 156 A/,A/-Dimethyl-2-{[3-(1-naphthylsulfonyl)-1H-indazol-5-yl]m6thoxy}ethanamine

(Formula Removed)
Step 1) 1 -(3-Chloro-benzyl)-3-naphthalene-1 -sulfonyl)-1 W-indazole-5-carbaldehyde
A mixture of 3-(1-naphthylsulfonyl)-1H-indazole-5-carbaldehyde (0.17 g, 0.5 mmoles), 3-chlorobenzyl bromide (0.07 ml, 0.6 mmoles), and cesium carbonate (0.19 g, 0.6 mmoles) in DMF (5 ml) was stirred together in a round bottom flask at room temperature for 30 minutes. Reaction mixture was diluted with H2O, extracted with EtOAc, washed with water (2x), brine (1x), dried over Na2SO4) and concentrated under vacuum. The crude product was purified by normal phase HPLC using as eluent 30% EtOAc/hexane to afford the title compound as an off-white solid (0.18 g, 0.4 mmoles). Step 2) [1-(3-Chlorobenzyl)-3-(1-naphthylsulfonyl)-1H-indazol-5-yl]-methanol
1-(3-Chloro-benzyl)-3-(naphthalene-1-sulfonyl)-1H-indazole-5-carbaldehyde (0.18g, 0.4 mmo!) was dissolved in THF and treated under nitrogen with the excess of sodium borohydride (0.2 mmol). After 1 hr the reaction mixture was diluted with water and the product extracted with methylene chloride to afford after evaporation of the solvent the title compound as a colorless solid (0.18 g, 0.4 mmoles). Step 3) 1 -(3-Chlorobenzyl)-5-(2-chloroethoxymethy)-3-(1 -naphthylsulfony)-1H-indazole
[1-(3-Chlorobenzyl)-3-(1-naphthylsulfonyl)-1H-indazol-5-yl]-methanol(0.18g, 0.4 mmol) and diisopropyl ethyl amine (1 mmol) in methylene chloride were treated at -20 °C with trifluoromethanesulfonic anhydride (0.14 g, 0.5 mmol). After stirring for 30 min an excess of 2-chloroethanol (2 mmol) was added and the mixture stirred for additional 2 hrs at -20 °C and at room temperature for 12 hrs. The reaction mixture was diluted with water, extracted with ethyl acetate and after evaporation of solvent,
chromatographed on silica gel using 40% ethyl acetate/hexane as an eluent to afford
the target material (0.08 g, 0.16 mmoles).
Step4) {2-[1-(3-Chlorobenzyl)-3-(naphthalene-1-sulfonyl)-1W-indazol-5-
ylmethoxy]ethyl}dimethylamine
A mixture of 1-(3-chlorobenzyl)-5-(2-chloroethoxymethy)-3-(1-naphthylsulfony)-7H-indazole (0.08 g, 0.16 mmoles) and dimethylamine (0.28 ml, 0.56 mmoles) in DMSO (1 ml) was stirred under nitrogen at 100 °C for 4 hours. Mixture was cooled to room temperature, diluted with water, extracted with EtOAc, washed with water (2x), brine (1x), dried over Na2SO4, and concentrated under vacuum. Compound was purified by flash chromatography using as eluent 5% CH3OH/EtOAc to afford the title compound (0.08 g, 0.15 mmoles). Step 5) A/,/V-Dimethyl-2-{[3-(1 -naphthylsulfonyl)-1 «-indazol-5-yl]methoxy} ethanamine
A mixture of {2-[1-(3-chloro-benzyl)-3-(naphthalene-1-sulfonyl)-1H-indazol-5-ylmethxy]-ethyl}-dimethyl-amine (0.08 g, 015 mmoles) in DMSO (1 mL) and f-BuOH (0.2 ml) was stirred at room temperature in a round bottom flask under oxygen atmosphere. A solution of potassium f-butoxide (0.05 ml, 0.05 mmoles) was added dropwise and the reaction mixture stirred for 30 min. Reaction mixture was quenched with saturated ammonium chloride, extracted with EtOAc, dried over Na2SO4, and concentrated under vacuum. Crude compound was converted into the HCI salt as previously described to afford the title compound, mp > 200 °C; MS (ES+) 410[M+H]+.
Example 157
N1 -[3-(Naphthalene-1 -sulfonyl)-1 H-indazol-5-yl]-ethane-1,2-diamine dihydrochloride
Stepl
(Formula Removed)
3-lodo-5-nitro-1 H-indazole Iodine (26.46 g, 104.27 mmol) and potassium hydroxide pellets (11.70 g, 208.54 mmol) were successively added into a DMF (104 ml) solution 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 water). The brown color faded away, and the formed yellow precipitate was filtered
and washed with water and dried in vacuo to provide the title compound as a yellow *olid (14.74 g, 98% yield). MS (ES+) m/e 290 (MH+)
Step 2
(Formula Removed)
3-(Naphthalen-1-ylsulfanyl)-5-nitro-1H-indazole A mixture of 3-iodo-5-nitro-1 H-indazole (10.00 g, 34.60 mmol), 1-naphtylenethiol (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) was heated at 90 °C under nitrogen overnight, cooled, diluted with 30% MeOH in CH2CI2, and passed through a pad of silica gel. The solution was concentrated in vacuo and purified by chromatography with 1% MeOH in CH2CI2 to provide the title compound (5.5 g, 49%). MS (ES+) m/e 322 (MH+).
Step 3
(Formula Removed)
3-(Naphthalene-1-sulfonyl)-1H-indazol-5-ylamine 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 CHCI3 (115 ml) was stirred at room temperature for 4 hr, diluted with EtOAc, washed with Na2SO3 solution, water, brine, dried over Na2SO4, and concentrated in vacuo to affort the crude intermediate which was carried out directly for the next step reaction without further purification. The mixture of the crude sulfone intermediate, tin mossy (15.79 g, 133.01 mmol) in MeOH and cone, hydrochloric acid was heated at 60 °C, diluted with CH2CI2, and neutralized to basic with NaOH or Na2CO3 solution. The aqueous layer was extracted with CH2CI2. Combined organic layers were dried over Na2SO4 and concentrated in vacuo followed by chromatography purification to provide the title compound (2.50 g, 45% overall yield). MS (ES+) m/e 324 (MH+)
Step 4
(Formula Removed)
N1-[3-(Naphthalene-1-sulfonyl)-1H-indazol-5-yl]-ethane-1,2-diamine dihydrochloride A mixture of 3-(naphthalene-1-sulfonyl)-1H-indazol-5-ylamine hydrochloride (334 mg, 0.93 mmol), 2-oxazolidone (81 mg, 0.93 mmol), and diethylene glycol monomethyl ether (0.16 ml) was heated at 170 °C overnight, diluted with MeOH, and purified by reverse phase HPLC followed by conversion to HCI salt by treatment with HCI solution to provide the title compound as a white solid (86 mg, 21% yield). MS (ES+) m/e 367 (MH+)
Example 158

(Formula Removed)
3-Amino-N-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yl]-propionamide hydrochloride A mixture of 3-(naphthalene-1-sulfonyl)-1H-indazol-5-ylamine (500 mg, 1.55 mmol), N-f-Boc-{J-alanine (381 mg, 2.01 mmol), 1-[3-(dimethylamino)propyl)]-3-ethylcarbodimide hydrochloride (386 mg, 2.01 mmol) in CH3CN was stirred at room temperature overnight and concentrated to dryness. The resulting residue was subjected to TFA, concentrated, and purified by reverse phase HPLC followed by treatment with HCI solution to provide the title compound as a white solid (180 mg, 24% yield). MS (ES+) m/e 395 (MH+)
Example 159
Stepl

(Formula Removed){1 -[3-(Naphthalene-1 -sulfonyl)-1 H-indazol-5-ylcarbamoyl]-ethyl}-carbamic acid tert-butyl ester A mixture of 3-(naphthalene-1-sulfonyl)-1H-indazol-5-ylamine (500 mg, 1.55 mmol), N-f-Boc-alanine (381 mg, 2.01 mmol), 1-[3-(dimethylamino)propyl)]-3-ethylcarbodimide hydrochloride (386 mg, 2.01 mmol) in CH3CN was stirred at room
temperature overnight, concentrated, and purified by chromatography with 3% MeOH in CH2CI2 to provide the title compound (110 nig, 48%), characterized by NMR and mass spectral analyses.

(Formula Removed)
N1 -[3-(Naphthalene-1 -sulfonyl)-! H-indazol-5-yl]-propane-1,2-diamine hydrochloride {1 -[3-(Naphthalene-1 -sulfonyl)-1 H-indazol-5-ylcarbamoyl]-ethyl}-carbamic acid fert-butyl ester (120 mg, 0.37 mmol) was subjected to TFA at room temperature for 2 hr and concentrated to dryness. The resulting residue was heated with BH3 in THF (1 M, 4.5 ml) at reflux overnight. To the mixture was slowly added HCI (6 M, 1 ml). The resulting solution was heated at 80 °C for 20 min, concentrated, and purified by reverse phase HPLC followed by treatment with HCI solution to provide the title compound (35 mg, 38%). MS (ES+) m/e 381 (MH+)
Example 160
(Formula Removed)
(S)-3-Methyl-N1-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yl]-butane-1,2-diamine dihydrochloride
Using essentially the same procedure described in Example 159 and employing (SH-Boc-Valine as the starting material, the title compound was obtained, MS(ES+)m/e409(MH+)
Example 161
N1 -[3-(Naphthalene-1 -sulfonyl)-1 H-indazol-7-yl]-ethane-1,2-diamine dihydrochloride
Using essentially the same procedure described in Example 157 (step 4) and employing 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)-1H-indazol-7-yl]-propionamide hydrochloride Stepl
(Formula Removed) 3-(Naphthalene-1-sulfonyl)-1H-indazol-7-ylamine The title compound was prepared according to the procedure described in Example 157 (steps 1-3) and employing 7-nitro-indazole as the starting material.
Step 2
(Formula Removed) 3-Dimethylamino-N-[3-(naphthalene-1-sulfonyl)-1H-indazol-7-yl]-propionamide dihydrochloride The title compound was prepared in a similar manner as described in Example 158 and employing the appropriate starting material. MS (ES+) m/e 423
(Formula Removed)

N-[3-(Naphthalene-1 -sulfonyl)-1 H-indazol-7-yl]-3-piperidin-1 -yl-propionamide hydrochloride The title compound was prepared in a similar manner as described
in Example 158 and employing the appropriate starting material. MS (ES+) m/e 463 (MH+)
Example 164

(Formula Removed)
3-Amino-N-[3-(naphthalene-1-sulfonyl)-1H-indazol-7-yl]-propionamide hydrochloride The title compound was prepared in a similar manner as described in Example 158 and employing the appropriate starting material. MS (ES+) m/e 395 (MH+)
Example 165
(Formula Removed)
3-Amino-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-naphthylsulfonyl)-1H-indazole as the starting material, the title compound was obtained, MS (ES+) m/e 395 (MH+)
Example 166
(Formula Removed)
3-Diethylamino-N-[3-(naphthalene-1-sulfonyl)-1H-indazol-7-yl]-propionamide hydrochloride
sing essentially the same procedure described in Example 158 and employing 7-amino-3-(1-naphthylsulfonyl)-1H-indazole and the desired amino acid as the starting materials, the title compound was obtained. MS (ES+) m/e 451 (MH+)
(Formula Removed)
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 employing 6-amino-3-(1-naphthylsulfonyl)-1H-indazole and the desired amino acid as the starting materials, the title compound was obtained, MS (ES+) m/e 463 (MH+).
Example 168

(Formula Removed)
3-Dimethylamino-N-[3-(naphthalen6-1-sulfonyl)-1H-indazol-6-yl]-propionamide hydrochloride
Using essentially the same procedure described in Example 158 and employing 6-amino-3-(1-naphthylsulfonyl)-1H-indazole and the desired amino acid as starting materials, the title compound was obtained, MS (ES+) m/e 423 (MK+).
Example 169
(Formula Removed)
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-naphthylsulfonyl)-1H-indazole and the desired amino acid as starting materials, the title compound was obtained, MS (ES+) m/e 451 (MH+).

Example 170
(Formula Removed)

1 -[3-(Naphthalene-1 -sulfonyl)-1 H-indazol-6-yl]-ethane-1,2-diamine dihydrochloride
Using essentially the same procedure described in Example 158 and employing 6-amino-3-(1-naphthylsulfonyl)-1H-indazole as starting material, the title compound was obtained, MS (ES*) m/e 367 (MH+).
Example 171
N,N-Dimethyl-N-{2-[3-(phenylsulfonyl)-1H-indazol-7-yl]ethyl}amine hydrochloride Stepl

(Formula Removed)
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 dry THF (100 ml) at -65°C under nitrogen is added 1.0M KOfiu in THF (110 ml, 110 mmol). The deep purple reaction is allowed to warm to 0 °C over 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 CH2CI2 (2 x 400 ml). The extracts are dried (MgSO4) and concentrated in vacua to a light orange solid. Trituration with ethyl acetate and hexanes affords the title compound as a pale yellow solid (13 g, 73%). Mp: 138-141 °C. MS (ES-): 354 (M-H)
Step 2
(Formula Removed)
6-Bromo-2-[(phenylsulfonyl)methyl]aniline Catalytic hydrogenation of 6-bromo-2-nitrobenzyl phenyl sulfone (0.36 g, 1 mmol) in the presence of platinum on carbon, disulfided and hydrogen (45 psi) in ethyl alcohol (40 ml) for 1 hour gives a reaction mixture. The reaction mixture is filtered through celite and concentrated in vacua to
give the title compound as a light brown solid (0.32 g, 99%). Mp: 174 - 177°C. MS (ES+): 326 (M+H)
Step 3
(Formula Removed)
7-Bromo-3-(phenylsulfonyl)-1H-indazole A solution of NaNO2(0.91 g, 13.35 mmol) in H2O (10 ml) was added to a solution of 6-bromo-2-[(phenylsulfonyl)methyl]aniline (2.9 g, 8.9 mmol) in 70 ml of 4 NHCI at approximately 5 °C. The reaction mixture was stirred for 30 min. at 0 °C, and neutralized with 10 % NaOH. The resulting solid was collected by filtration, washed with water and purified by flash chromatography (25% ethyl acetate/petroleum ether) to afford the title compound as a pink solid (2.27g, 91 %) Mp: 173 -175 °C, MS (ES-) 335 (M-H)
Step 4
(Formula Removed)
3-(Phenylsulfonyl)-7-vinyl-1H-indazole A mixture of 7-Bromo-3-(phenylsulfonyl)-1H-indazole (2.72 g, 8.07 mmol) and dichlorobis(tri-o-tolylphosphine)-palladium(ll) (0.94 g, 1.2 mmol) were dissolved in toluene (220 ml) and stirred for 10 minutes at room temperature under a nitrogen atmosphere. Tributyl(vinyl)tin (3.3 mg, 10.55 mmol) was added and the mixture was refluxed for 15 min or until turned black. The mixture was 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 was removed by suction filtration and the organic layer was washed with water (100 ml), then brine and dried over MgSO4, filtered and concentrated in vacuo. Purification by flash chromatography (40% ethyl acetate/petroleum ether) gave the title compound as a light yellow solid (2.02 g, 88%). Mp: 129 - 130 °C. MS (ES+): 285 ( M+H)
Step5
2-[3-(Phenylsulfonyl)-1H-indazol-7-yl]ethanol To a solution of 3-(phenylsulfonyl)-7-vinyMH-indazole (2.0 g, 7.04 mmol) in THF (40 ml) at 0°C was added dropwise BH3-THF (15 mL of 1 M THF solution, 15 mmol). The solution was stirred for 3 hours at 0 °C, and H2O (20 ml) was added slowly. To this mixture was added 10% NaOH (17 ml), 30% H2O2 (15 ml) and the mixture was stirred vigorously at room temperature overnight. The mixture was partitioned between ethyl acetate and H2O, and the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. Silica gel chromatography (50% ethyl acetate/dichloromethane) gave the title compound as a white solid (1.42 g, 66%). Mp: 137-138°C. MS (ES+): 303 (M+H)
Step 6

(Formula Removed)
2-[3-(Phenylsulfonyl)-1H-indazol-7-yl]ethyl 4-methylbenzenesulfonate To a
solution of 2-[3-(phenylsulfonyl)-1H-indazol-7-yl]ethanol (0.64 g, 2.12 mmol) in anhydrous dichloromethane (30 ml) at 0°C was added pyridine (0.43 ml) and toluenesulfonyl chloride (0.475 g, 2.5 mmol). The solution was stirred for 12 hours at room temperature. The mixture was concentrated in vacuo and taken up in ethyl acetate (30 ml). The organic layer was washed with 2 M HCI, (2 x 25 mL), brine, dried (MgSO4), filtered and concentrated under reduced pressure. Silica gel chromatography (50% ethyl acetate/petroleum ether) gave the title compound as a white foam (0.9 g, 93%). Mp: 61 - 64 °C. MS (ES-): 455 (M-H)
Step 7
(Formula Removed)
N,N-Dimethyl-N-{2-[3-(phenylsulfonyl)-1H-indazol-7-yl]ethyl}amine hydrochloride A solution of 2-[3-(phenylsulfonyl)-1 H-indazol-7-yl]ethyl 4-methylbenzenesulfonate (0.137 g, 0.3 mmol) in anhydrous THF (2 mL) was added an excess of dimethylamine (0.5 mL of 2 M THF solution, 1 mmol) and heated to 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, (2x15 mL), brine, dried (MgSO4), filtered and concentrated under reduced pressure. The product was passed through a plug of silica gel eluting with (20% EtOH/2N ammonia/dichloromethane) to give the title compound as a white solid (0.049 g, 77%). This solid was dissolved in diethyl ether and treated with 1 N HCI in diethyl ether (0.12 mL, 0.12 mmol) to afford a white precipitate isolated by vacuum filtration. Mp: 76-80°C. MS (ES-): 328 (M-H)
Example 172 N-{2-[3-(phenylsulfonyl)-1H-indazol-7-yl]ethyl}cyclopropanamine hydrochloride
(Formula Removed)
Using essentially the same procedure described in Example 171, step 7, and employing cyclopropyl amine, the title compound was obtained as a white solid, mp 115-117 °C, MS: (M+H) 342.

Example 173
N-Methyl-N-{2-[3-(phenylsulfonyl)-1H-indazol-7-yl]ethyl}aminetrifluoroacetate

(Formula Removed)
Using essentially the same procedure described in Example 171, step 7, and employing methylamine and substituting trifluoroacetic acid for HCI, the title compound was obtained as a clear glass, MS: (M+H) 316.
Example 174
{2-[3-(Phenylsulfonyl)-1H-indazol-7-yl]ethyl}amineHydrochloride

(Formula Removed)
Step 1) 7-(2-Azidoethyl)-3-(phenylsulfonyl)-1H-indazole
A solution of 2-[3-(phenylsulfonyl)-1 H-indazol-7-yl]ethyl 4-methylbenzene-sulfonate (0.14 g, 0.3 mmol) in anhydrous DMF (2.5 mL) was added sodium azide (0.06 g, 0.9 mmol) and heated to 100°C for 6 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 brine (1x15 mL), dried (MgSO4), filtered and concentrated under reduced pressure. Silica gel chromatography (40% Ethyl acetate/petroleum ether) gave the azide as a white solid (0.08 g, 86%). Mp:105-107°C. MS (ES-): 326 (M-H) Step 2) {2-[3-(Phenylsulfonyl)-1H-indazol-7-yl]ethyl}amine Hydrochloride
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) for 4 hours. The reaction mixture was filtered through Celite and concentrated in vacua to give a white solid (0.06 g, 99%). This solid was dissolved in diethyl ether and treated with 1 N HCI in diethyl ether (0.21 mL, 0.21 mmol) to afford a tan precipitate isolated by vacuum filtration. Mp: 157 -160°C. MS(ES-): 300 (M-H)
Example 175
W-Methyl-W-{2-[3-{phenylsulfonyl)-1H-indazol-5-yl]ethyl}amine Stepl

(Formula Removed)
Methyl [2-(4-nitrophenyl)ethyl]carbamate To a stirred solution of [2-(4-nitrophenyl)ethyl]amine (6.06 g, 30 mmol) in CH2CI2(75 ml), MeOH (5 mL), and TEA (9.5 mL) at 0 °C was added chloromethylformate (3.39 g, 36 mmol) dropwise. The reaction mixture was stirred at room temperature for 1 hr. concentrated in vacua, 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 brine (50 ml). The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure to afford a yellow solid (6.6 g, 98%). Mp: 38 °C. MS (ES-): 223 (M-H). Step 2
(Formula Removed)
Methyl methyl[2-(4-nitrophenyl)ethyl]carbamate To a stirred solution of 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 (256 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 (2x15 ml). The organics were washed with water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. Silica gel chromatography (40% ethyl acetate/ petroleum ether) afforded the title compound as a semi solid (160 mg, 67.2 %). MS (ES+): 239 (M+H)+.
Step5
Formula Removed)
Methyl 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 methyl[2-(4-nitrophenyl)ethyl]carbamate (2.47 g, 10.38 mmol), the title compound was obtained as a white solid, (2.06 g, 51%). Mp: 42 °C, MS (ES+): 393 (M+H)+.
Step 4

(Formula Removed)
Methyl (2-{4-amino-3-[(phenylsulfonyl)methyl]phenyl}ethyl)methylcarbamate
Catalytic hydrogenation of methyl methyl (2-{4-nitro-3-[(phenylsulfonyl)methyl]-phenyl}ethyl)carbamate (1.8 g, 4.6 mmol) in the presence of Raney nickel and hydrogen (45 psi) in ethyl acetate/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%). Mp: 95 - 96 °C. MS (ES+): 363
StepS
(Formula Removed)
Methyl methyl{2-[3-(phenylsulfonyl)-1H-indazol-5-yl]ethyl}carbamate Using
substantially the same procedure described in Example 171, step 3 and employing methyl (2-{4-amino-3-[(phenylsulfonyl)methyl]phenyl}ethyl)methylcarbamate (0.362 g, 1 mmol), the title compound was obtained as a white solid, (0.29 g, 78%). Mp: 145 -147°C, MS (ES+): 374 (M+H)+
Step 6
(Formula Removed)
A/-Methyl-N-{2-[3-(phenylsulfonyl)-1W-indazol-5-yl]ethyl}amine To a solution of methyl methyl{2-[3-(phenylsulfonyl)-1H-indazol-5-yl]ethyl}carbamate (250 mg, 0.67 mmol) in ethylene glycol (7 ml) was added H2NNH2 (110 mg, 3.35 mmol), KOH (1.38 g 10.05 mmol), and heated to 110 °C overnight. The reaction was cooled to room temperature, water was added and the mixture extracted with CH2CI2. The
organic layers were washed with water, brine, dried (MgSO4) and concentrated under reduced pressure to give a residue which is triturated with CH2CI2 to afford the title compound as a off white solid 210 mg (99%) Mp: 186-188 °C, MS (ES+): 316 (M+H)+
Example 176
(Formula Removed)
W,/V-Dimethyl-W-{2-[3-(phenylsulfonyl)-1H-indazol-5-yl]ethyl}amine hydrochloride To a solution of A/-methyl-A/-{2-[3-(phenylsulfonyl)-1H-indazol-5-yl]ethyl}amine (38 mg, 0.12 mmol) in acetonitrile (3 mL) was added NaBH(OAc)3 (100 mg, 0.48 mmol), formaldehyde ( 0.027 mL, 0.36 mmol), and stirred at rt. for 3 hr. The reaction mixture was poured into ice water and MeCN was removed under reduced pressure. The resultant suspension was extracted with CH2CI2. The organic extracts were washed with water, brine, dried (MgSO4) and concentrated to a residue which was dissolved in MeOH and treated with a slight excess of HCI (1N / Et2O) to afford the desired product as the mono HCI salt (43 mg, 98%) as a white solid. Mp: 108-110 °C. MS (ES+): 330 (M+H)+
Example 177
N,N-Dimethyl-N-{3-[3-(phenylsulfonyl)-1H-indazol-5-yl]propyl}amine trifluoroacetate Stepl

(Formula Removed)
5-Bromo-2-nitrobenzyl phenyl sulfone To a stirred solution of 1-bromo-4-nitrobenzene (5.05 g, 25 mmol) and chloromethylphenylsulfone (4.76 g, 25 mmol) in dry THF (50 mL) at -65 °C under nitrogen is added 1 .OM KO'Bu in THF (55 mL, 55 mmol). The deep purple reaction is allowed to warm to 0°C over 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 then extracted with CH2CI2 (2 x 200 mL). The extracts are dried (MgSO4) and concentrated in vacua to a light orange
solid. Trituration with ethyl acetate and hexanes affords the title compound as a pale yellow solid (6.45 g, 72%). Mp: 143 - 144°C. MS (ES-): 354 (M-H)+
Step 2
(Formula Removed)

Methyl (2E)-3-{4-nitro-3-[(phenylsulfonyl)methyl]phenyl}acrylate 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 m) was 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 rt, water was added, and the solution was extracted with ethyl acetate (3x15 mL). The organic layers were washed with water then brine and dried (MgSO4). Evaporation of the solvent under reduced pressure gave a residue that was purified by column chromatography (40% ethyl acetate / hexane) to afford the title compound as a yellow solid (0.30 g, 83%). Mp: 165 - 166°C. MS (ES-): 360 (M-H)+
Step3

(Formula Removed)
Methyl 3-{4-amino-3-[(phenylsulfonyl)methyl]phenyl}propanoate This compound was prepared by catalytic hydrogenation of methyl (2E)-3-{4-nitro-3-[(phenylsulfonyl)methyl]phenyl}acrylate (3.33 g, 9.22 mmol) in the presence of Palladium on carbon and hydrogen (45 psi) in ethyl acetate (100 ml) for 4h. The reaction mixture is filtered through celite and concentrated in vacua to give the title compound as a white solid (3.07 g, 99%). Mp: 59 - 60 °C. MS (ES+): 334 (M+H)+
Step 4

(Formula Removed)
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%). Mp: 115 -117 °C. MS (ES+): 345 (M+H)+
Step5
(Formula Removed)
3-[3-(Phenylsulfonyl)-1H-indazol-5-yi]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 a N2 atmosphere was cooled to -78 °C, trreated with DIBAL-H (1.0 M in THF; 23 ml), allowed to warm to room temperature, stirred for 12 h, cooled to 0 °C, quenched slowly with a saturated solution of Na2SO4 (12 ml) and filtered. The filtercake was washed with ethyl acetate. The combined filtrates were dried over MgSO4 and concentrated under reduced pressure. Purification of the resultant residue by flash chromotagraphy (60% ethyl acetate/ hexanes) gave the title compound as an off white solid (1.56 g, 83%), mp: 92 - 96 °C. MS (ES+): 317
Step 6
(Formula Removed)
3-[3-(Phenylsulfonyl)-1 H-indazol-5-yl]propyl 4-methylbenzenesulfonate Using
substantially the same procedure described in Example 171, step 6, and employing 3-[3-(phenylsulfonyl)-1H-indazol-5-yl]propan-1-ol (1.52 g, 4.8 mmol), the title compound was obtained as a white foam (1.28 g, 57%). Mp: 58 - 60°C. MS (ES+): 471 (M+H)+
Step 7
(Formula Removed)
N,N-Dimethyl-N-{3-[3-(phenylsulfonyl)-1H-indazol-5-yl]propyl}amine trifluoroacetate Using substantially the same procedure describee} in Example 171, step 7, and employing 3-[3-(phenylsulfonyl)-1H-indazol-5-yl]propyl 4-methylbenzenesulfonate (125 mg, 0.26 mmol), the title product was obtained as an off white solid (83 mg, 93%). Mp:75-80°C. MS (ES+): 344 (M+H)+
Example 178
N-{3-[3-(Phenylsulfonyl)-1H-indazol-5-yl]propyl}cyclopropanamine trifluoroacetate
(Formula Removed)
Using essentially the same procedure described in Example 177, step 7 and employing cyclopropyl amine and substituting trifluoroacetic acid for HCI, the title compound was obtained as a white solid, Mp 68 - 169°C, MS (M+H)+ 356
Example 179
N-lsopropyl-N-{3-[3-(phenylsulfonyl)-1H-indazol-5-yl]propyl}amine trifluoroacetate

(Formula Removed)
Using essentially the same procedure described in Example 177, step 7 and employing isopropyl amine and substituting trifluoroacetic acid for HCI, the title compound was obtained as a white solid, mp 169 -171 °C, MS, (M+H)+ 358
Example 180
{3-[3-(Phenylsulfonyl)-1H-indazol-5-yl]propyl}amine trifluoroacetate Stepl

(Formula Removed)
5-(3-Azidopropyl)-3-(phenylsulfonyl)-1H-indazole Using essentially the same procedure described in Example 174, step 1, and employing 3-[3-(phenylsulfonyl)-1H-indazol-5-yl]propyl 4-methylbenzenesulfonate (350 mg, 0.75 mmol), the title compound was obtained as a white solid (220 mg, 86%). Mp: 133 -135 °C. MS '.-): 340(M-H) +
Step 2

(Formula Removed)
{3-[3-(Phenylsulfonyl)-1 H-indazol-5-yl]propyl}amine trifluoroacetate 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), the title product was obtained as an off white solid (120 mg, 67%). Mp: 92 - 94 °C. MS (ES+): 316 (M+H) +
Example 181
{4-[3-(Phenylsulfonyl)-1 H-indazol-5-yl]butyl}amine hydrochloride Stepl
(Formula Removed)
4-{4-Nitro-3-[(phenylsulfonyl)methyl]phenyl}but-3-yn-1-ol A solution of 5-Bromo-2-nitrobenzyl phenyl sulfone (2.5 g, 7.02 mmol), diisopropyl amine (4.92 ml, 35.1 mmol) and homo propargol alcohol (0.59 ml, 7.72 mmol) in degassed toluene (30 ml) was treated simultaneously with Cul (66.8 mg, 0.35 mmol) and tetrakis(triphenylphosphine)-palladium(0) (742 mg, 0.35 mmol), heated to 90 °C, stirred for 1 5 minutes under a nitrogen atmosphere, cooled to room temperature, diluted with ethyl acetate (10 ml), and filtered through celite. The filtrate was washed with water (25 ml), then brine and dried over MgSO4 and concentrated in
vacua. Purification of the resultant residue by flash chromatography (40% ethyl acetate/petroleum ether) gave the title compound as a white solid (2.15 g, 89%). Mp: 129°C. MS(ES-): 344(M-H) +
Step 2

(Formula Removed)
4-{4-Amino-3-[(phenylsulfonyl)methyl]phenyl}butan-1 -ol Catalytic hydrogenation of 4-{4-nitro-3-[(phenylsulfonyl)methyl]phenyl}but-3-yn-1-ol (1.0 g, 2.85 mmol) in the presence of Palladium on carbon and hydrogen (45 psi) in ethyl acetate (30 ml) for 24h gave a reaction mixture. The reaction mixture was filtered through celite and the filtrate was 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+H)+
Step3(Formula Removed)
4-[3-(Phenylsulfonyl)-1H-indazol-5-yl]butan-1-ol Using essentially the same described in Example 171, Step 3, and employing 4-{4-amino-3-[(phenylsulfonyl)-methyl]phenyl}butan-1-ol (0.725 g, 2.27 mmol), the title product was obtained as a red solid light pink solid (0.605 g, 81%). Mp: 215-216 °C. MS (ES+): 331 (M+H)+.
Step 4
(Formula Removed)
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 title compound was obtained as a light orange solid (0.703 g, 95%). Mp: 157-159 °C. MS(ES+): 485(M+H) +
Steps

(Formula Removed)
5-(4-Azidobutyl)-3-(phenylsulfonyl)-1 H-indazole Using substantially the same procedure described in Example 174, Step 1, and employing 4-[3-(phenylsulfonyl)-1H-indazol-5-yl]butyl 4-methylbenzenesulfonate (133 mg, 0.27 mmol), the title compound was obtained as a clear glass (94 mg, 96%). MS (ES+): 356 (M+H)+
Step 6
(Formula Removed)
{4-[3-(Phenylsulfonyl)-1H-indazol-5-yl]butyl}amine Using substantially the same procedure described in Example 174, Step 2, and employing 5-(4-azidobutyl)-3-(phenylsulfonyl)-l H-indazole (94 mg, 0.264 mmol), the title compound was obtained as a white solid (65 mg, 86%). Mp: 120 - 125°C. MS (ES+): 330 (M+H) +
Example 182
N,N-Dimethyl-N-{3-[3-(naphthylsulfonyl)-1H-indazol-5-yl]propyl}amine hydrochloride Stepl
(Formula Removed)
5-Bromo-2-nitrobenzyl naphthyl sulfone Using substantially the same procedure described in Example 177, Step 1, and employing 1-Bromo-4-nitrobenzene (5.05 g, 25 mmol) and chloromethylnaphthylsulfone (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-H) +
Step 2
(Formula Removed)
Methyl (2E)-3-{4-nitro-3-[(naphthylsulfonyl)methyl]phenyl} Using substantially the same procedure described in Example 177, Step 2, and employing 5-bromo-2-nitrobenzyl naphthyl sulfone (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-H) +
Step 3
(Formula Removed)
Methyl 3-{4-amino-3-[(naphthylsulfonyl)methyl]phenyl}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+H) +
Step 4
(Formula Removed)
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] phenyljpropanoate (1.2 g, 3.11 mmol), the title compound was obtained as a light brown solid (1.02 g, 83%). Mp: 60 - 65 °C. MS (ES+): 395(M+H) +
Step5
(Formula Removed)
3-[3-(Naphylsulfonyl)-1H-indazol-5-yl]propan-1-ol Using substantially the same procedure described in Example 177, Step 5, and employing methyl 3-[3-
(naphthylsulfonyl)-1H-indazol-5-yl]propanoate (1.0 g, 2.5 mmol), the title compound was obtained as a white sol d (0.83 g, 89%). Mp: 170 °C. MS (ES+): 367 (M+H) +
StepG
(Formula Removed)
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-indazol-5-yl]propan-1-ol (0.763 g, 2.08 mmol), the title product was obtained as a white foam (0.8 g, 74%). Mp: 66 - 68 °C. MS (ES+): 521 (M+H)+
Step 7
(Formula Removed)
N,N-Dimethyl-N-{3-[3-(naphthylsulfonyl)-1H-indazol-5-yl]propyl}amine hydrochloride 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 title compound was obtained as an off white solid (73 mg, 99%). Mp: 247 - 248 °C. MS (ES+): 394(M+H) +
Examples 183-187

(Formula Removed)
Using essentially the same procedure described in Example 171, Step 7, and employing 3-[3-(naphthylsulfonyl)-1 H-indazol-5-yl]propyl 4-methylbenzenesulfonate and the desired amine, the compounds shown in Table X were obtained and identified by HPLC and mass spectral analyses.
TABLE X
(Formula and Table Removed)
Example 188
(Formula Removed)

{3-[3-{Naphthylylsulfonyl)-1H-indazol-5-yl]propyl}amine Stepl
5-(3-Azidopropyl)-3-(naphthylsulfonyl)-1H-indazole Using essentially the same procedure described in Example 174, Step 1, and employing 3-[3-(naphthylsulfonyl)-1 H-indazol-5-yl]propyl 4-methylbenzenesulfonate (135 mg, 0.26 mmol), the title compound was obtained as a clear glass (97 mg, 96%). MS (ES-): 390 (M-H) +
Step 2
(Formula Removed)
{3-[3-(Naphthylylsulfonyl)-1H-indazol-5-yl]propyl}amine Using essentially the same procedure described in Example 174, Step 2, and employing 5-(3-azidopropyl)-3-(naphthylsulfonyl)-1H-indazole (96 mg, 0.25 mmol), the title compound was obtained as an off white solid (90 mg, 99%). Mp:92-94°C. MS (ES+): 366 (M+H)+
Example 189
(Formula Removed)

{4-[3-(Naphthylsulfonyl)-1H-indazol-5-yl]butyl}aminehydrochlcride Stepl
4-{4-Nitro-3-[(naphthylsulfonyl)methyl]phenyl}but-3-yn-1 -ol Using substantially the same procedure described in Example 181, Step 1, and employing 5-bromo-2-nitrobenzyl naphthyl sulfone (5000 mg, 12.3 mmol), the title compound was obtained as an off yellow solid (4381 mg, 90%). Mp:155°C. MS (ES-): 394(M-H) +
Step 2
(Formula Removed)
4-{4-Amino-3-[(naphthylsulfonyl)methyl]phenyl}butan-1 -ol Using substantially the same procedure described in Example 181, Step 2, and employing 4-{4-nitro-3-[(naphthylsulfonyl)methyl] phenyl}but-3-yn-1-ol (1750 mg, 4.4 mmol), the title compound was obtained as an yellow solid (1616 mg, 99%). Mp: 80 - 85 °C. MS ): 370(M+H) +
Step3
(Formula Removed)
4-[3-(Naphthylsulfonyl)-1H-indazol-5-yl]butan-1-ol Using substantially the same procedure described in Example 171, Step 3, and employing 4-{4-amino-3-[(naphthylsulfonyl)methyl] phenyl}butan-1-ol (1.6 g, 4.3 mmol), the title compound was obtained as a light pink solid (1.64 g, 99%). Mp: 138-139 °C. MS (ES-): 379 (M-H) +
Step 4
(Formula Removed)
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 was obtained as a white foam (2.02 g, 90%). Mp: 63 - 66 °C. MS (ES+): 535(M+H) +
StepS
(Formula Removed)
5-(4-Azidobutyl)-3-(naphthylsulfonyl)-1H-indazole Using substantially the same procedure described in Example 174, Step 1, and employing 4-[3-(naphthylsulfonyl)-1 H-indazol-5-yl]butyl 4-methylbenzenesulfonate (150 mg, 0.28 mmol), the title compound was obtained as a clear glass (104 mg, 92%). MS (ES+): 406 (M+H)+
StepG
(Formula Removed) [3-(Naphthylsulfonyl)-1 H-indazol-5-yl]butyl}amine hydrochloride Using substantially 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 was obtained as a white solid (91 mg, 94%). Mp: 150 - 152°C. MS (ES+): 380 (M+H)+
Examples 190-194
(Formula Removed)
Using essentially the same procedure described in Example 171, Step 7, and employing 3-[3-(naphthylsulfonyl)-1 H-indazol-5-yl]butyl 4-nethylbenzenesulfonate and the desired amine, the compounds shown in Table XI were obtained and identified by HPLC and mass spectral analyses.
TABLE XI
(Formula and Table Removed)
Example 195 3-(1 -Naphthylsulfonyl)-5-(piperazin-1 -ylmethyl)-1 H-indazote
(Formula Removed)
Stepl:
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 mmoles) was stirred in THF (50 ml) at -78 °C, in a round bottom flask under nitrogen. A solution of 1M potassium t-butoxide was added dropwise (19 ml, 19 mmoles) over a half an hour period. Temperature was allowed to rise to - 40 °C, and the reaction mixture was stirred at this temperature for 5
ours. The reaction mixture was poured into cold 2N HCI, extracted with EtOAc, dried over Na2SO4) and concentrated under vacuum. Compound was purified by normal phase HPLC on silica column, using as eluent 40% EtOAc/hexane, to afford the title compound as an off-white solid (3.03 g, 7.6 mmoles). Step 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 HCI (4 ml, 8 mmoles) in THF (30 ml) was stirred at 40 °C for 4 hours. The reaction mixture was cooled to room temperature, diluted with water, extracted with CH2CI2, dried over Na2SO4, and concentrated under vacuum to yield the title compound (2.56 g, 7.22 mmoles). Step 3:
4-Amino-3-(naphthalene-1-sulfonylmethyl)-benzaldehyde A mixture of 3-(naphthalene-1-sulfonylmethyl)-4-nitro-benzaldehyde (2.5 g, 7.22 mmoles) and 10%Pd/C in THF (10 ml), and methanol (20 ml) was hydrogenated in a Parr hydrogenation bottle (250 ml) at 52lb/in2 overnight. The mixture was filtered through Celite, and the filtrate was concentrated under vacuum to afford the title compound as an off-white solid (2.4 g, 6.85 mmoles). Step 4:
3-(Naphthalene-1-sulfonyl)-1H-indazole-5-carbaldehyde A mixture of 4-amino-3-(naphthalene-l-sulfonylmethyl)-benzaldehyde (2.4 g, 6.85 mmoles) in THF (10mL) and 4M HCI (20 mL) was stirred in a round bottom flask at 3 °C. A solution of sodium nitrite (0.49 g, 7.19 mmoles) 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. Compound was dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (1.84 g, 5.5 mmoles). Step 5:
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) was stirred at room temperature for 24 hrs. After completion, the solvent was removed in vacua, crude material dispersed in water and pH brought to 3.4. Solid material was filtered off and washed with cold water to afford after drying the target material as a free base. The latter was converted into hydrochloride salt by dissolution in methanol, followed by treatment with the excess of 2N HCI and
the evacuation of the volatiles in vacuo to afford the title compound as the hydrochloride salt, mp > 200 °C; MS (ES) m/z 406.
Examples 196-201

(Formula Removed)
Using essentially the same reductive amination procedure described in Example195, Step 5, and employing the desired amine and treatment of the free base with HCI; the compounds shown in Table XII were obtained and identified by HPLC and mass spectral analyses.
TABLE XII

(Formula and Table Removed)
4-methylpiperazin-1 -yl
3-methylpiperazin-1 -yl
3,5-dimethylpiperazin-1 -yl
(3S)-3-methylpiperazin-1 -yl
(3R)-3-methylpiperazin-1 -yl
(3R)-3-aminopyrrolidin-1-yl
Example 202 3-(1-Naphthylsulfonyl)-5-(piperazin-1ylcarbonyl)-1W-indazole
(Formula Removed)

Step 1: 3-(Naphthalene-1-sulfonyl)-1H-indazole-5-carboxylic-acid
A mixture of 3-(naphthalene-1-sulfonyl)-1H-indazole-5-carbaldehyde (0.15 g, 0.44 mmoles) and KMnO4(0.03 y, 0.29 moles) was stirred in CH3CN/H2O (4:1) for 1 hour. Reaction mixture was acidified with 2N HCI, stirred with saturated sodium bisulfite for 10 minutes, then extracted with EtOAc, dried over Na2SO4 and concentrated in vacua to afford the title compound (0.13 g, 3.9 mmoles).
Step 2: 3-(1-Naphtylsulfonyl)-5-(piperazin-1ylcarbonyl)-1H-indazole
A mixture of 3-(naphthalene-1-sulfonyl)-1H-indazole-5-carboxylic-acid (0.13 g, 0.39 mmoles) piperazine (0.036 g, 0.42 mmoles), and 1-[3-(Dimethylamino) propyl-3-ethylcarbodiimide hydrochloride (0.08 g, 0.42mmoles) was stirred in CH2CI2 for 1/2 hour. Reaction mixture was diluted with H2O, extracted with EtOAc, washed with water (2x), brine (1x), dried over Na2SO4, and concentrated under vacuum. The product was converted into the hydrochloride salt by dissolution in methanol, followed by treatment with the excess of 2N HCI and the evacuation of the volatiles in vacuo to afford the title compound hydrochloride salt; Mp: > 200 °C; MS (ES) m/z 419.1.
Example 203

(Formula Removed)
5-[1-(4-Methylpiperazin-1-yl)ethyl]-3-(1-naphthylsulfonyl)-1H-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 mmoles) and MeMgBr (0.36 ml of 3M solution in ether, 1.1 mmoles) was stirred in THF at -20 °C to 0 °C for 30 minutes. Reaction mixture was diluted with water, acidified to pH=3 with 2N HCI, then extracted with EtOAc, dried over Na2SO4 and concentrated in vacuo to afford the title compound (0.13 g, 3.9 mmoles).
Step 2: 5-[1-(4-methylpiperazin-1-yl) ethyl]-3-(1-naphthylsulfonyl)-1H-indazole:
A mixture of 1-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yl]ethanol (0.13 g, 0.38 mmoles), methane sulfonic anhydride (0.16 g, 0.95 mmoles), and triethylamine (0.13 ml, 0.95 mmole) was stirred in CH2CI2from 0 °C to room temperature for 5 hours to afford methanesulfonic acid 1-[3-(naphthalene-1-sulfonyl)-1-H-indazol-5-yl]-
ethylester. This reaction mixture was treated with excess N-methyl-piperazine (0.22 g, 2 mmoles). The crude pr jduct was purified by flash chromatography using 5% MeOH/CH2CI2 to afford the title compound; Mp: 183-185 °C, MS (ES) m/z 433.1.
Example 204 Evaluation of 5-HT6 Binding Affinity of Test Compounds
The affinity of test compounds for the serotonin 5-HT6 receptor was evaluated in the following manner. Cultured Hela cells expressing human cloned 5-HT6 receptors were harvested and centrifuged at low speed (1,000 x g) for 10.0 minutes to remove the culture media. The harvested cells were suspended in half volume of fresh physiological phosphate buffered saline solution and recentrifuged at the same speed. This operation was repeated. The collected cells were then homogenized in ten volumes of 50 mM Tris.HCI (pH 7.4) and 0.5 mM EDTA. The homogenate was centrifuged at 40,000 x g for 30.0 min and the precipitate was collected. The obtained pellet was resuspended in 10 volumes of Tris.HCI buffer and recentrifuged at the same speed. The final pellet was suspended in a small volume of Tris.HCI buffer and the tissue protein content was determined in aliquots of 10-25 ul volumes. Bovine Serum Albumin was used as the standard in the protein determination according to the method described in Lowry et al., J. Biol. Chem.. 193: 265 (1951). The volume of the suspended cell membranes was adjusted to give a tissue protein concentration of 1.0 mg/ml of suspension. The prepared membrane suspension (10 times concentrated) was aliquoted in 1.0 ml volumes and stored at -70° C until used in subsequent binding experiments.
Binding experiments were performed in a 96 well microtiter plate format, in a total volume of 200 ul. To each well was added the following mixture: 80.0 ul of incubation buffer made in 50 mM Tris.HCI buffer (pH 7.4) containing 10.0 mM MgCI2 and 0.5 mM EDTA and 20 pi of [3H]-LSD (S.A., 86.0 Ci/mmol, available from Amersham Life Science), 3.0 nM. The dissociation constant, KD of the [3H]LSD at the human serotonin 5-HT6 receptor was 2.9 nM, as determined by saturation binding with increasing concentrations of [3H]LSD. The reaction was initiated by the final addition of 100.0 ul of tissue suspension. Nonspecific binding was measured in the presence of 10.0 uM methiothepin. The test compounds were added in 20.0 ul volume.
The reaction was allowed to proceed in the dark for 120 minutes at room temperature, at which time, the bound ligand-receptor complex was filtered off on a 96 well unifilter with a Packard Filtermate® 196 Harvester. The bound complex
caught on the filter disk was allowed to air dry and the radioactivity is measured in a Packard TopCount® equipped with six photomultiplier detectors, after the addition of 40.0µl Microscint®-20 scintillant to each shallow well. The unifilter plate was heat-sealed and counted in a PackardTopCount® with a tritium efficiency of 31.0%.
Specific binding to the 5-HT6 receptor was defined as the total radioactivity bound less the amount bound in the presence of 10.0µM unlabeled methiothepin. Binding in the presence of varying concentrations of test compound was expressed as a percentage of specific binding in the absence of test compound. The results were plotted as log % bound versus log concentration of test compound. Nonlinear regression analysis of data points with a computer assisted program Prism® yielded both the IC50 and the Ki values of test compounds with 95% confidence limits. A linear regression line of data points was plotted, from which the IC50 value is determined and the Kj value is determined based upon the following equation:
Kj = IC50 / (1 + L/KD)
where L was the concentration of the radioactive ligand used and KD is the
dissociation constant of the ligand for the receptor, both expressed in nM.
Using this assay, the following Ki values were determined. The data are shown in Table XIII, below.
For Table XIII
A = 0.01nM-10nM
B=11nM-25nM
C = 26nM-35nM
D = 36nM-45nM
E = >45nM
TABLE XIII
Test Compound 5-HT6 Binding
(Example No.) Ki (nM)
(Table Removed)
Test Compound 5-HT6 Binding
(Example No.) Ki (nM)
(Table Removed)
Test Compound 5-HT6 Binding
(Example No.) Ki (nM)
(Table Removed)
Test Compound 5-HT6 Binding
(Example No.) Ki (nM)
(Table Removed)

Test Compound 5-HT6 Binding
(Example No.) Ki (nM)
(Table Removed)

Test Compound 5-HT6 Binding
(Table Removed)5-HT6 Binding Ki
Test Compound (Example No.)

(Table Removed)

WE CLAIM:
1. A compound of formula I
(Formula removed)
wherein
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;
R1 is H or an alkyl, cycloalkyl, aryl or heteroaryl group each optionally substituted;
R2 is an optionally substituted alkyl, cycloalkyl, aryl or heteroaryl group or an
optionally substituted 8- to 13-membered bicyclic or tricyclic ring system
having a N atom at the bridgehead and optionally containing 1, 2 or 3
additional 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 alkyl, alkenyl, alkynyl, cycloalkyl,
cycloheteroalkyl, aryl or heteroaryl group each optionally substituted, or R5
and Re may be taken together with the atom to which they are attached to
form an optionally substituted 3- to 7-membered ring optionally containing
an additional heteroatom selected from O, N or S; R7 is halogen, CN, OR8, CO2R9, CONR10Rn, or an alkyl, alkenyl, alkynyl,
cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally
substituted;
m is an integer of 0, 1, 2 or 3; R8 is H, COR12 or an alkyl, alkenyl, alkynyl, aryl or heteroaryl group each
optionally substituted; R9 is H or a C1-C6alkyl, aryl or heteroaryl group each optionally substituted;
R10 and RH are each independently H or an optionally substituted alkyl group;
and Ri2 is an optionally substituted C1-C6alkyl, cycloalkyl, cycloheteroalkyl, aryl or
heteroaryl group; or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1 wherein wherein X is O, NR or
CH2.
3. The compound according to claim 2 wherein X is O.
4. The compound according to any one of claims 1 to 3 wherein n is 2 or
3.
5. The compound according to any one of claims 1 to 4 wherein R2 is an
optionally substituted aryl or heteroaryl group or an optionally subtituted 8- to 13-
membered bicyclic or tricyclic ring system having a N atom at the bridgehead and
optionally containing 1, 2 or 3 additional heteroatoms selected from N, O or S.

6. The compound according to claim 5 wherein R2 is an optionally
substituted phenyl, naphthyl or imidazothiazolyl group.
7. The compound according to any one of claims 1 to 6 wherein R5 and
R6 are each independently H or C1-C4 alkyl

8. The compound according to any one of claims 1 to 7 wherein R2 is
naphthyl and n is 3.
9. The compound according to claim 1 selected from the group
consisting essentially of:
N, N-Dimethyl-3-{[3-(1-naphthylsulfonyl)-1H-indazol-5-yl]oxy}propan-1-amine; N-Methyl-N-{2-[3-(phenylsulfonyl)-1H-indazol-5-yl]ethyl}amine; N,N-Dimethyl-N-{2-[3-(phenylsulfonyl)-1H-indazol-5-yl]ethyl}amine; {2-[3-(Phenylsulfonyl)-1H-indazol-7-yl]ethyl}amine;
N,N-Dimethyl-N-{2-[3-(phenylsulfonyl)-1H-indazol-7-yl]ethyl}amine;
N-{2-[3-(Phenylsulfonyl)-1H-indazol-7-yl]ethyl}cyclopropanamine;
N,N-Dimethyl-N-{3-[3-(phenylsulfonyl)-1H-indazol-5-yl]propyl}amine;
N-{3-[3-(Phenylsulfonyl)-1H-indazol-5-yl]propyl}cyclopropanamine;
{3-[3-(Phenylsulfonyl)-1H-indazol-5-yl]propyl}amine;
{4-[3-(Phenylsulfonyl)-1H-indazol-5-yl]butyl}amine;
N-Methyl-N-{2-[3-(phenylsulfonyl)-1H-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)-! H-indazole;
3-(1-Naphthylsulfonyl)-5-(2-pyrrolidin-1-ylethoxy)-1 H-indazole;
N,N-Dimethyl-2-{[3-(1-naphthylsulfonyl)-1H-indazol-5-yl]oxy}ethanamine;
N-(2-{[3-(1-Naphthylsulfonyl)-1H-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)-1H-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)-1H-indazol-5-yl]-beta-alaninamide;
N-Ethyl-2-{[3-(phenylsulfonyl)-1H-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)-1H-indazol-5-yl]oxy}ethanamine;
N-Methyl-2-{[3-(1-naphthylsulfonyl)-1H-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)-1H-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)-1H-indazol-5-yl]butane-1,2-diamine; (2-{[1-(3-Chlorobenzyl)-3-(1-naphthylsulfonyl)-1H-indazol-7-yl]oxy}ethyl)amine; N-(2-{[3-(Phenylsulfonyl)-1H-indazol-5-yl]oxy}ethyl)cyclopentanamine; 3-(Phenylsulfonyl)-5-(2-pyrrolidin-1-ylethoxy)-1 H-indazole; N-Methyl-2-{[3-(phenylsulfonyl)-1H-indazol-5-yl]oxy}ethanamine; N-Methyl-2-{[1-methyl-3-(phenylsulfonyl)-1H-indazol-7-yl]oxy}ethanamine;1-Methyl-3-(phenylsulfonyl)-7-(2-pyrrolidin-1-ylethoxy)-1H-indazole;(2-{[1-(3-Chlorobenzyl)-3-(phenylsulfonyl)-1H-indazol-7-yl]oxy}ethyl)methylamine;(2-{[1-(3-Chlorobenzyl)-3-(phenylsulfonyl)-1H-indazol-7-yl]oxy}ethyl)ethylamine;1-(3-Chlorobenzyl)-3-(phenylsulfonyl)-7-(2-pyrrolidin-1-ylethoxy)-1H-indazole;1-(3-Chlorobenzyl)-5-methoxy-3-(1-naphthylsulfonyl)-7-(2-piperidin-1-ylethoxy)-1H-indazole;N-Methyl-2-{[3-(phenylsulfonyl)-1H-indazol-7-yl]oxy}ethanamine; (2-{[1-(3-Chlorobenzyl)-3-(1-naphthylsulfonyl)-1H-indazol-7-yl]oxy}ethyl)ethylamine; (2-{[1-(3-Chlorobenzyl)-3-(1-naphthylsulfonyl)-1H-indazol-7-yl]oxy}ethyl)methylamine; N-Ethyl-2-{[3-(phenylsulfonyl)-1H-indazol-7-yl]oxy}ethanamine; N,N-Diethyl-2-{[3-(phenylsulfonyl)-1H-indazol-7-yl]oxy}ethanamine; N-(2-{[3-(Phenylsulfonyl)-1H-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)-1 H-indazole; N-Ethyl-2-{[1-methyl-3-(1-naphthylsulfonyl)-1H-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)-1H-indazol-7-yl]oxy}ethanamine;
-Naphthylsulfonyl)-1 H-indazol-7-yl]oxy}ethyl)amine; {[1 -(3-Chlorobenzyl)-5-fluoro-3-(1 -naphthylsulfonyl)-1 H-indazol-7-yl]oxy}ethyl)-
dimethylamine;
{[1-Benzyl-3-(1-naphthylsulfonyl)-1 H-indazol-5-yl]oxy}ethyl)methylamine; -Benzyl-3-(1 -naphthylsulfonyl)-1 H-indazol-5-yl]oxy}ethyl)dimethylamine; -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)-1H-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)-1H-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)-1H-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)-1H-indazol-5-yl]oxy}propan-1-amine; N-(3-{[3-(1-Naphthylsulfonyl)-1H-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)-1H-indazol-7-yl]oxy}ethyl)methylamine; (2-{[5-Methoxy-3-(1-naphthylsulfonyl)-1H-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)-1H-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)-1H-indazol-7-yl]oxy}propan-1-amine; N,N-Diethyl-3-{[3-(1-naphthylsulfonyl)-1H-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)-1H-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)-1H-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)-1H-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)-1H-indazol-5-yl]oxy}propyl)cyclopentanamine; 5-(3-Morpholin-4-ylpropoxy)-3-(1-naphthylsulfonyl)-1 H-indazole; N-(3-{[3-(1-Naphthylsulfonyl)-1H-indazol-5-yl]oxy}propyl)cyclopropanamine; (3-{[3-(1-Naphthylsulfonyl)-1H-indazol-5-yl]oxy}propyl)amine; N-Methyl-4-{[3-(1-naphthylsulfonyl)-1H-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)-1H-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)-1H-indazole;3-(1-Naphthylsulfonyl)-5-(4-piperidin-1-ylbutoxy)-1H-indazole;
(4-{[3-(1-Naphthylsulfonyl)-1H-indazol-5-yl]oxy}butyl)amine;
(2-{[5-Fluoro-3-(1-naphthylsulfonyl)-1H-indazol-7-yl]oxy}ethyl)methylamine;
5-[(4-Methylpiperazin-1-yl)methyl]-3-(1-naphthylsulfonyl)-1H-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)-1H-indazol-5-yl]propan-1-amine;
N,N-Dimethyl-4-[3-(1-naphthylsulfonyl)-1H-indazol-5-yl]butan-1-amine;
N,N-Dimethyl-3-[3-(1-naphthylsulfonyl)-1H-indazol-5-yl]propan-1-amine;
N-Ethyl-N-methyl-3-[3-(1-naphthylsulfonyl)-1H-indazol-5-yl]propan-1-amine;
N-lsopropyl-3-[3-(1-naphthylsulfonyl)-1H-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-indazol-5-yl]oxy}ethyl)amine;
3-(1-Naphthylsulfonyl)-5-(3-pyrrolidin-1-ylpropyl)-1 H-indazole;
N-lsopropyl-4-[3-(1-naphthylsulfonyl)-1H-indazol-5-yl]butan-1-amine;
3-(1-Naphthylsulfonyl)-5-(4-pyrrolidin-1-ylbutyl)-1 H-indazole;
N-Ethyl-4-[3-(1-naphthylsulfonyl)-1H-indazol-5-yl]butan-1-amine;
5-[(3-Methylpiperazin-1-yl)methyl]-3-(1-naphthylsulfonyl)-1 H-indazole;
5-[(3,5-Dimethylpiperazin-1-yl)methyl]-3-(1-naphthylsulfonyl)-1 H-indazole;
N-Ethyl-3-[3-(1 -naphthylsulfonyl)-1 H-indazol-5-yl]propan-1 -amine;
{4-[3-(1-Naphthylsulfonyl)-1H-indazol-5-yl]butyl}amine;
5-[1-(4-Methylpiperazin-1-yl)ethyl]-3-(1-naphthylsulfonyl)-1 H-indazole;
N.N.N'-Trimethyl-N'-{[3-(-naphthylsulfonyL)-IH-indazol-5-yl]methyllethane-l^-
diamine;
N,N-Dimethyl-2-{[3-(1-naphthylsulfonyl)-1H-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)-1H-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)-1H-indazole-5-carboxamide; 2-{[5-Fluoro-3-(phenylsulfonyl)-1H-indazol-7-yl]oxy}ethanamine; N-[3-(1-Naphthylsulfonyl)-1H-indazol-6-yl]-beta-alaninamide; N-[3-(1-Naphthylsulfonyl)-1H-indazol-7-yl]-3-piperidin-1-ylpropanamide; N~3~,N~3--Dimethyl-N-[3-(1-naphthylsulfonyl)-1H-indazol-7-yl]-beta-alaninamide;2-{[3-(Phenylsulfonyl)-1H-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)-1H-indazol-6-yl]-3-piperidin-1-ylpropanamide;
N-[3-(1-Naphthylsulfonyl)-1 H-indazol-6-yl]ethane-1,2-diamine;
N3,N3-diethyl-N-[3-(1-naphthylsulfonyl)-1H-indazol-7-yl]-beta-alaninamide;
N,N-Dimethyl-2-{[3-(1-naphthylsulfonyl)-1H-indazol-4-yl]oxy}ethanamine;
3-(1-Naphthylsulfonyl)-4-(2-piperidin-1-ylethoxy)-1H-indazole;
3-(1-Naphthylsulfonyl)-4-(2-pyrrolidin-1-ylethoxy)-1H-indazole;
2-{[3-(1-Naphthylsulfonyl)-1H-indazol-4-yl]oxy}ethanamine;
N-Methyl-2-{[3-(1-naphthylsulfonyl)-1H-indazol-6-yl]oxy}ethanamine;
2-{[3-(1-Naphthylsulfonyl)-1H-indazol-6-yl]oxy}ethanamine;
a stereoisomer thereof; and
a pharmaceutically acceptable salt thereof.
10. 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 which
comprises providing to said patient a therapeutically effective amount of a compound
of formula I according to any one of claims 1 to 9.
11. The method according to claim 10 wherein said disorder is a cognitive
disorder, a developmental disorder or a neurodegenerative disorder.
12. The method according to claim 11 wherein said disorder is a cognitive
disorder.
13. The method according to claim 11 wherein said disorder is selected
from the group consisting of: a learning disorder; attention deficit disorder; Down's
syndrome, Fragile X syndrome or autism.
14. The method according to claim 11 wherein said disorder is stroke or
head trauma.
15. A pharmaceutical composition which comprises a pharmaceutically
acceptable carrier and an effective amount of a compound of formula I according to
any one of claims 1 to 9.
16. A process for the preparation of a compound of formula I according to any one of claims 1 to 9 which process comprises: reacting a compound of formula II
(Formula removed)
wherein X, R2, R3,R4, R5, R6, R7, m and n are as described hereinabove for formula I;
with NaNO2 in the presence of an acid to give the formula I compound wherein RI is H; and
optionally reacting said compound with RrHal, wherein Hal is Cl, Br or I and R-\ is an alkyl, cycloalkyl, aryl or heteroaryl group each optionally substituted.
17. A compound of formula 1, a process for preparation of the said compound and its application substantially such as herein described with reference to examples.