MXPA06009176A

MXPA06009176A - Indazole-carboxamide compounds as 5-ht4 receptor agonists

Info

Publication number: MXPA06009176A
Application number: MXPA/A/2006/009176A
Authority: MX
Inventors: D Long Daniel; Marquess Daniel; Liu Jyanwei; Choi Seokki; R Fatheree Paul; Gendron Roland; A Goldblum Adam; Derek Turner S
Original assignee: Choi Seokki; R Fatheree Paul; Gendron Roland; A Goldblum Adam; Liu Jyanwei; D Long Daniel; Marquess Daniel; Theravance Inc; Derek Turner S
Priority date: 2004-02-18
Filing date: 2006-08-11
Publication date: 2007-04-10

Abstract

The invention provides novel indazole-carboxamide 5-HT4 receptor agonist compounds. The invention also provides pharmaceutical compositions comprising such compounds, methods of using such compounds to treat diseases associated with 5-HT4 receptor activity, and processes and intermediates useful for preparing such compounds.

Description

COMPOSITE OF INDAZOL-CARBOXAMIDE AS ANTAGONISTS OF THE RECEIVER 5-HYDROXYRIPTAMINE 4 (5-HT4) Field of the Invention The invention is directed to indazole -carboxamide compounds which are useful as 5-HT4 receptor agonists. The invention is also directed to pharmaceutical compositions comprising such compounds, methods of using such compounds to treat medical conditions mediated by the activity of the 5-HT4 receptor, and processes and intermediates useful in preparing such compounds.

BACKGROUND OF THE INVENTION Serotonin (5-hydroxy-tryptamine, 5-HT) is a neurotransmitter that is widely distributed throughout the body, both in the central nervous system and in peripheral systems. At least 7 subtypes of serotonin receptors have been identified and the interaction of serotonin with these different receptors is linked to a wide variety of physiological functions. However, there is a substantial interest in developing therapeutic people who target the 5-HT receptor subtypes. In particular, the characterization of 5-HT4 receptors and identification of pharmaceutical agents that interact with these has been the focus of a recent important activity. REF: 174637 (see, for example, the review by Langlois and Fischmeister, J. Med. Chem. 2003, 46, 319-344). The 5-HT receptor agonists are useful for the treatment of disorders of reduced mobility of the gastrointestinal tract. Such disorders include irritable bowel syndrome (IBS), chronic constipation, functional dyspepsia, delayed gastric emptying, gastroesophageal reflux disease (GERD), gastroparesis, post operative ileus, pseudo intestinal obstruction, and delayed drug-induced transit. In addition, it has been suggested that some 5-HT receptor agonist compounds can be used in the treatment of central nervous system disorders including cognitive disorders, behavioral disorders, mood disorders, and autonomic function control disorders. Despite the wide utility of pharmaceutical agents for modulating the activity of the 5-HT4 receptor, some 5-HT receptor agonist compounds are in clinical use or currently. One agent, cisapride, which is used extensively for the treatment of gastrointestinal tract mobility disorders, was withdrawn from the market because it reported cardiac side effects. The last clinical stage trials of another agent, prucalopride, have been discontinued. Accordingly, there is a need for new 5-HT receptor agonists that achieve their desired effects with minimal side effects. Preferred agents may possess, among other properties, improved selectivity, potency, pharmacokinetic properties, and / or duration of action.

Brief Description of the Invention The invention provides novel compounds possessing 5-HT4 receptor agonist activity. Among other properties, the compounds of the invention have been found to be potent and selective 5-HT receptor agonists. In addition, the compounds of the invention have been found to exhibit favorable pharmacokinetic properties that are predictable from good bioavailability during oral administration. Accordingly, the invention provides a compound of the formula (I): wherein: R 1 is hydrogen, halo, hydroxy, C 1 alkyl or C 1 -4 alkoxy R 2 is C 3-4 alkyl, or C 3-6 cycloalkyl; and W is selected from: (i) a group of the formula (II) W wherein X is: NC (0) R wherein Ra is C 1 _ 3 alkyl or tetrahydrofuranyl, wherein C 1-3 alkyl is optionally substituted with -OH or C 1 3 alkoxy; S (0) 2; or NS (0) 2Rb, wherein Rb is methyl, optionally substituted with -OH, C? _3alkoxy, cycloalkyl s-β, or -S (Q) 2-C? _3alkyl; (ii) a group of the formula (III) wherein: Ry is -OH or C_3 alkoxy; P is 0 or 1; n is 1 or 2; and Y is: N (Rc) C (0) Rd, wherein Rc is hydrogen or C? _3 alkyl and Rd is C? _3 alkyl optionally substituted with -OH or C?-3 alkoxy, or N (Re) S ( O) 2Rf, wherein Re is hydrogen and Rf is C? _3 alkyl, optionally substituted with -OH, C? _3 alkoxy, C5_6 cycloalkyl or -S (0) 2-C_3 alkyl; and (iii) a group of the formula (IV): (W) wherein: Rz is hydrogen, C? _3 alkyl, or C2_3 alkyl substituted with -OH or C? _3 alkoxy; m is 1 or 2; q is 1 or 2, with the proviso that the sum of m and q is not equal to 4; and Z is: NC (0) Rg, wherein Rg is C_3 alkyl, optionally substituted with -OH or C, _3 alkoxy, s (0) 2; or NS (0) 2Rh, wherein Rh is methyl, optionally substituted with -OH, C 1 -C 3 alkoxy, C 5 -C 6 cycloalkoxy, or -S (0) 2 -C 3 alkyl; or a pharmaceutically acceptable salt or solvate or stereoisomer thereof. The invention also provides a pharmaceutical composition comprising the compound of the invention and a pharmaceutically acceptable carrier. The invention also promotes a method for treating a disease or condition associated with 5-HT receptor activity, for example, a reduced mobility disorder of the gastrointestinal tract, the method comprising administering to the mammal a therapeutically effective amount of the compound of the invention. In addition, the invention promotes a method for treating a disease or condition associated with 5-HT receptor activity in a mammal, the method comprising administering to the mammal a therapeutically effective amount of the pharmaceutical composition of the invention. The compounds of the invention can also be used as research tools, that is, to study biological systems or samples, or to study the activity of other chemical compounds. Accordingly, in another of these aspects of method, the invention promotes a method for using a compound of the formula (I), or a pharmaceutically acceptable salt or solvate or stereoisomer thereof, as a developmental tool for studying the biological system or sample or for discovering new 5-HT4 receptor agonists, the method comprises contacting the biological system or sample with the compound of the invention and determine the effects caused by the compound in the biological system or sample. In separate and distinct aspects, the invention also provides synthetic processes in intermediates described herein, which are useful for preparing compounds of the invention. The invention also provides a compound of the invention as described herein for use in medical therapy, as well as the use of a compound of the invention in the manufacture of a medicament formulation for treating a disease or condition associated with activity. of the 5-HT receptor, for example, a reduced mobility tract-gastrointestinal disorder, in a mammal.

Detailed Description of the Invention The invention provides novel indazole carboxamide 5-HT4 receptor agonists of the formula (I), or pharmaceutically acceptable salts or solvates or stereoisomers thereof. The following substituents and values are intended to provide representative examples of various aspects of this invention. These representative values are intended to further define such aspects and are not intended to exclude other values or limit the scope of the invention. In a specific aspect of the invention, R1 is hydrogen, halo, C? _ Alkyl, or C? _ Alkoxy. In other specific aspects, R1 is hydrogen, halo, or C? _ Alkyl; or R1 is hydrogen or halo; or R1 is fluoro. Still in another specific aspect, Rx is hydrogen. In a specific aspect, R2 is C3_alkyl or C3_6 cycloalkyld. In other specific aspects, R2 is C3_4 alkyl. Representative R2 groups include n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl. In other specific aspects, R2 is isopropyl. In yet another specific aspect, R2 is cyclobutyl or cyclopentyl. In a specific aspect, W is a group of the formula (II) wherein all the variables as in the formula (II). In another specific aspect, W is a group of the formula (II), wherein Ra is C? _3 alkyl and Rb is methyl. In another specific aspect, W is a group of formula (II) wherein X is NC (0) Ra wherein Ra is defined as in formula (II). In other specific aspects, W is a group of the formula (II), wherein X is NC (0) Ra, wherein Ra is C? -3 alkyl, specifically methyl, ethyl, n-propyl, or isopropyl, or tetrahydrofuran -2-ilo or tetrahydrofuran-3-yl; or Ra is alkyl C? _3. In yet another specific aspect, W is a group of the formula (II), wherein X is NC (0) CH3, whose W forms have the value 4-acetyl-piperazin-1-yl. In another specific aspect, W is a group of the formula (II), wherein X is S (0) 2. In another specific aspect, W is a group of the formula (II), wherein X is NS (0) 2Rb, wherein Rb is defined as in the formula (II). In other specific aspects, W is a group of formula (II), wherein X is NS (0) 2R, wherein Rb is CH3 optionally substituted with C5_6 cycloalkyl or with -S (0) 2- C3_3 alkyl. Representative Rb values within this aspect include methyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -CH2S02CH3, and -CH2S02C2H5. In yet another specific aspect, W is a group of the formula (II) wherein X is NS (0) 2CH3, which forms W having the value 4-methanesulfonyl-piperazin-1-yl. In another specific aspect, it is a group of the formula (III) wherein R? is-OH In other specific aspects, W is a group of the formula (II) wherein Ry is C 1 --3 alkoxy, for example Ry is -OCH 3, -OC 2 H 5, or -OC 3 H 7. In another specific aspect W is a group of the formula (III) wherein p is 0, or where p is 1. In other specific aspects W is a group of the formula (III) wherein n is 1, this is W is an optionally substituted pyrrolidinyl ring; or wherein n is 2, that is, W is an optionally substituted piperidinyl ring. In another specific aspect, W is a group of the formula (III) wherein Y is N (Rc) C (0) Rd wherein Rc and Rd is defined as in formula (III). In other specific aspects, W is a group of the formula (III) wherein Y is N (Rc) C (0) Rd wherein Rc is hydrogen; and wherein Rc is C? -3 alkyl. In another specific aspect, W is a group of the formula (III) wherein Y is N (Rc) C (0) R wherein Rd is C! _3 alkyl optionally substituted with -OH or C? _3 alkoxy. Representative values of Rd within this aspect include methyl, ethyl, -CH2OH, and -CH (OH) CH3. In another specific aspect, W is a group of the formula (III) wherein Y is NCH3C (O) CH. In yet another specific aspect, W is a group of the formula (III) wherein Y is NHC (0) CH3. In another specific aspect, W is a group of the formula (III) wherein Y is N (Re) S (0) 2Rf wherein Re and Rf is defined as in the formula (III). In other specific aspects, W is a group of the formula (III) wherein Y is N (Re) S (0) 2Rf wherein Rf is C? _3 alkyl optionally substituted with C5_6 cycloalkyl or with -S (O) 2- alkyl C? -3. Representative values of Rf within this aspect include methyl, CH 2 cyclopentyl, -CH 2 cyclohexyl, -CH 2 S0 2 CH 3, and CH S 0 C 2 H 5 - In another specific aspect, the compounds of formula (I) are compounds wherein W is a group of the formula (III) wherein p is 0 and n is 1. Still in another specific aspect, the compounds of the formula (I) are compounds wherein W is a group of the formula (III) where is p is 0, n is 1, and Y is N (Rc) C (0) Rd. In another specific aspect, W is a group of the formula (IV), wherein Rz is hydrogen. In another specific aspect, W is a group of the formula (IV), wherein Rz is C? _3 alkyl, for example, methyl, ethyl, and the like. In other specific aspects, W is a group of the formula (IV), wherein Rz is C2_3 alkyl substituted with -OH or with C3_3 alkoxy, for example, Rz is hydroxyethyl, methoxyethyl, and the like. In other specific aspects, it is a group of the formula (IV), wherein Rz is methyl. In a specific aspect, it is a group of the formula (IV) where m is 1. In another specific aspect, W is a group of the formula (IV) wherein i is 2. In a specific aspect, W is a group of the formula (IV) wherein q is 1. In another specific aspect, W is a group of the formula (IV) wherein q is 2. In a specific aspect, W is a group of the formula (IV) wherein Z is NC (0) Rg where Rg is defined as in formula (IV).-In other specific aspects, W is a group of formula (IV) where Z is NC (0) Rg where, Rg is alkyl C? _3, optionally substituted with -OH; or Rg is methyl. In a specific aspect, W is a group of the formula (IV) wherein Z is S (0) 2. In a specific aspect, W is a group of formula (IV) wherein Z is NS (0) 2Rh, where Rh is defined as in formula (IV). In other specific aspects, W is a group of the formula (IV) wherein Z is NS (0) 2Rh wherein Rh is methyl optionally substituted with C5_6 cycloalkyl or with -S (O) 2-C ?_3 alkyl. Representative values of R include methyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -CH2S02CH3, and -CH2S02C2H5. In yet another specific aspect, W is a group of the formula (IV) wherein Z is NS (0) 2CH3. In another specific aspect, the compounds of formula (I) are compounds wherein W is a group of the formula (IV) wherein m is 1 and q is 1. Still in another specific aspect, the compounds of the formula (I) are compounds wherein W is a group of the formula (IV) where ai is 1, q is 1, and Rz is methyl. In one aspect, the invention provides a compound of formula (I) wherein R 1 is hydrogen or halo; R 2 is isopropyl, or C-s cycloalkyl; and is defined as the formula (I). In another aspect, the invention provides a compound of the formula (I) wherein: R 1 is hydrogen or halo; R2 is C4 alkyl or C4_5 cycloalkyl; and W is selected from: (i) a group of the formula (II) wherein X is NC (0) CH3, S (0) 2, or NS (0) 2CH3; (ii) a group of the formula (III) - wherein p is 0, n is 1, and Y is NCH3C (0) CH3; And (iii) a group of the formula (IV) wherein Rz is methyl, m is 1, q is 1, and Z is NC (0) CH3, S (0) 2, or NS (0) 2CH3. In another aspect, the invention provides a compound of the formula (I) wherein R 1 is hydrogen or halo; R2 is C3- alkyl or C4_s cycloalkyl; and W is a group of the formula (II) wherein X is NC (0) CH3; S (0) 2; or NS (0) 2CH3. In another aspect, the invention provides a compound of the formula (I) which is a compound of the formula (V): (V) in "where: R1, R2, and X take any of the generic, specific or exemplary values described above. In still another aspect, the invention provides a group of the formula (VI): (SAW) where R1, R2, and take the values shown in table I.

Table I The chemical naming conventions used herein are illustrated for the compounds of Example 1: what is designated. { (SS, 3R, 5R) -8- [2- (4-acetyl-piperazin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-ylamide of 1-isopropyl-1H-indazole- 3-carboxylic, according to AutoNom software, provided by information systems MDL, GmbH (Frankfurt, Germany). The designation (1S, 3R, 5R) describes the relative orientation of the bonds associated with the bicyclic ring system which is described as solid and dotted wedges. The compound is alternatively indicated as N- [(3-endo) -8- [2- (4-acetyl-piperazin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-yl] -1 - (1-methylethyl) -lH-indazole-3-carboxamide. In all of the compounds described in Table I above, the indazole carboxamide is endo for the azabicyclooctyl group. The particular mention can be made of the following compounds:. { (SS, 3R, 5R) -8- [2- (4-acetylpiperazin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-yl} 1-isopropyl-lH-indazole-3-carboxylic acid amide; . { (SS, 3R, 5R) -8- [2- (1, l-dioxo-l6-thiomorpholin-4-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-yl} 1-isopropyl-lH-indazole-3-carboxylic acid amide; . { (1S, 3R, 5R) -8- [2- (4-methanesulfonyl-piperazin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-yl} 1-isopropyl-lH-indazole-3-carboxylic acid amide; . { (SS, 3R, 5R) -8- [2- (3- (acetyl-methyl-amino) pyrrolidin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-yl} 1-isopropyl-lH-indazole-3-carboxylic acid amide; . { (1S, 3R, 5R) -8- [2- ((R) -3- (acetyl-methylamino) pyrrolidin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-yl} 1-isopropyl-lH-indazole-3-carboxylic acid amide; . { (SS, 3R, 5R) -8- [2- ((S) -3- (acetyl-methylamino) pyrrolidin-1-yl) -ethyl] -8-azabicyclo [3.2.1] oct-3-yl} 1-isopropyl-lH-indazole-3-carboxylic acid amide; . { (1S, 3R, 5R) -8- [2- [(L-Acetyl-pyrrolidin-3-yl) -methylamino] ethyl] -8-azabicyclo [3.2.1] oct-3-yl} l-isopropyl-lH-indazole-3-carboxylic acid amide; . { (SS, 3R, 5R) -8- [2- [((R) -l-Acetyl-pyrrolidin-3-yl) methylamino] ethyl] -8-azabicyclo [3.2.1] oct-3-yl} l-isopropyl-lH-indazole-3-carboxylic acid amide; . { (SS, 3R, 5R) -8- [2- [((S) -l-acetyl-pyrrolidin-3-yl) methylamino] ethyl] -8-aza-bicyclo [3.2.1] oct-3-yl} l-isopropyl-lH-indazole-3-carboxylic acid amide; ((1S, 3R, 5R) -8-. {2- 2- [(1-methanesulfonyl-pyrrolidin-3-yl) methylamino] ethyl] -8-azabicyclo [3.2.1] oct-3-yl) amide of l-isopropyl-lH-indazole-3-carboxylic acid; ((1S, 3R, 5R) -8- { 2- [((R) -l-methanesulfonylpyrrolidin-3-yl) methylamino] ethyl]. 8-azabicyclo [3.2.1] oct-3-yl. ) l-isopropyl-lH-indazole-3-carboxylic acid amide; ((1S, 3R, 5R) -8-. {2- 2- (((S) -l-methanesulfonyl-pyrrolidin-3-yl) methylamino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl. ) l-isopropyl-lH-indazole-3-carboxylic acid amide; . { (1S, 3R, 5R) -8- [2- ((1, l-dioxo-tetrahydro-l6-thiophen-3-yl) methylamino) ethyl] -8-azabicyclo [3.2.1] oct-3- il} l-isopropyl-lH-indazole-3-carboxylic acid amide; . { (SS, 3R, 5R) -8- [2- ((R) - (1, l-dioxo-tetrahydro-l6-thiophen-3-yl) methylamino) ethyl] -8-azabicyclo [3.2.1] oct-3-yl l-isopropyl-lH-indazole-3-carboxylic acid lamido; Y . { (SS, 3R, 5R) -8- [2- ((S) - (1, l-dioxo-tetrahydro-l6-thiophen-3-yl) methylamino) ethyl] -8-azabicyclo [3.2.1] oct-3-yl l-isopropyl-lH-indazole-3-carboxylic acid lamido; As illustrated above, the compounds of the invention may contain a chiral center. Accordingly, the invention includes racemic mixtures, pure stereoisomers, and mixtures enriched with stereoisomers of such isomers, unless otherwise indicated. When a particular stereoisomer is shown, it should be understood by one of ordinary skill in the art, that minor amounts of other stereoisomers may be present in the compositions of the invention unless otherwise indicated, providing that the utility of the composition as a everything is not eliminated by the presence of such isomers.

Definitions When the compounds, compositions and methods of the invention are described, the following terms have the following meanings, unless otherwise indicated. The term "alkyl" means monovalent saturated hydrocarbon group, which may be linear or branched or combinations thereof. Unless defined otherwise, such alkyl group typically contain from 1 to 10 carbon atoms. Representative alkyl groups include, by way of example, methyl, ethyl, n-propyl (n-Pr), isopropyl (i-Pr), n-butyl (n-Bu), sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like. The term "alkoxy" means a monovalent -O-alkyl group, wherein alkyl is defined as above. Representative alkoxy groups include, by way of example, methoxy, ethoxy, propoxy, butoxy, and the like. The term "cycloalkyl" means a saturated monovalent carbocyclic group which may be monocyclic or multicyclic. Unless indicated otherwise, such cycloalkyl groups typically contain from 3 to 10 carbon atoms. Representative cycloalkyl groups include, by way of example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. The term "halo" means fluorine, chlorine, bromine and iodine.

The term "therapeutically effective amount" means an amount sufficient to effect a treatment when administered to a patient in need of treatment. The term "treatment" as used herein, means the treatment of a disease, disorder or medical condition in a patient, such as a mammal (particularly a human), which includes: (a) preventing the disease, disorder, or medical condition is present, that is, prophylactic treatment of a patient; (b) alleviating the disease, disorder, or medical condition, that is, eliminating or causing a regression of the disease, disorder, or medical condition in a patient; (c) suppressing the disease, disorder, or medical condition, that is, retarding or arresting the development of the disease, disorder, or medical condition in a patient; or (d) alleviating the symptoms of the disease, disorder, or medical condition in a patient.

The term "pharmaceutically acceptable salt" refers to a salt prepared from a base or acid that is acceptable for administration to a patient, such as a mammal. Such salts may be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids. Typically, the pharmaceutically acceptable salts of the compounds of the present invention are prepared from acids. Salts derived from pharmaceutically acceptable acids include, but are not limited to, acetic, adipic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pantothenic, phosphoric, propionic, salicyclic, succinic, sulfuric, tartaric, p-toluenesulfonic, xinaphoic (l-hydroxy-2-naphthoic acid), naphthalene-1, 5-disulfonic and the like. The term "solvate" means a complex or aggregate formed by one or more molecules of a solute, that is, a compound of the invention or a pharmaceutically acceptable salt thereof, and one or more molecules of a solvent. Such solvates are typically crystalline solids having a substantially fixed molar ratio of solute and solvent. Representative solvents include, by way of example, water, methanol, ethanol, isopropanol, acetic acid, and the like. When the solvent is water, the solvate formed is a hydrate. It will be appreciated that the term "or a pharmaceutically acceptable salt or solvate of the stereoisomer thereof" is intended to include all permutations of salts, solvates and stereoisomers, such as a solvate of a pharmaceutically acceptable salt of a stereoisomer of the compound of the formula ( I). The term "amino protecting group" means an appropriate protecting group to prevent undesirable reactions at the amino nitrogen. Representative protective amino groups include, but are not limited to, formyl; acyl groups, for example alkanoyl groups, such as acetyl; alkoxycarbonyl groups, such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl groups, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl groups, such as benzyl (Bn), trityl (Tr), and 1,1-di- (4'-methoxyphenyl) methyl; silyl groups, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS); and similar.

General Synthetic Procedures The compounds of the invention can be prepared from readily available starting materials using the following general methods and procedures. Although a particular aspect of the present invention is illustrated in the reaction schemes below, those skilled in the art will recognize that all aspects of the present invention can be prepared using the methods described herein or using other methods, reagents and methods. starting materials known to those skilled in the art. It will also be appreciated that where typical or preferred process conditions (ie, reaction temperatures, times, related molar reagents, solvents, pressures, etc.) are given, other process conditions may also be used unless otherwise stated. The optimal reaction conditions may vary with the particular reagents or solvents used, but such conditions can be determined by one skilled in the art by routine optimization procedures. Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from experiencing unwanted reactions. The choice of the appropriate protecting group for the particular functional group, as well as the appropriate conditions for protection and deprotection, are well known in the art. For example, numerous protective groups, and their introduction and removal, are described in T.W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein. In a synthesis method, the compounds of the formula (I) are prepared as illustrated in Reaction Scheme A.

(The substituents and variables shown in the following reaction schemes have the definitions provided above, unless otherwise indicated).

Reaction scheme A where P1 represents an amino protecting group such as tert-butoxycarbonyl (Boc) or benzyloxycarbonyl (Cbz). As shown in Reaction Scheme A, the protected aminoazabicyclooctane, or commonly, aminotropane 1 is first reacted with the substituted iH-indazole carboxylic acid 2. Typically, this reaction is conducted by first converting 2 to an acid chloride by contacting the 2 with at least one equivalent, typically between about 1 and about 2 equivalents of an activating agent, such as thionyl chloride or sodium chloride. oxalyl in an aromatic diluent, such as toluene, benzene, xylene, or the like. The reaction is typically conducted at a temperature in the range from about 80 ° C to about 120 ° C for about 15 minutes to about 2 hours, or until the reaction is substantially complete. The acid chloride solution is typically added to a biphasic mixture of about 1 equivalent of aminotropane 1 to form the protective intermediate, which is extracted by standard procedures. The biphasic mixture of 1 is generally prepared by dissolving 1 in an aromatic diluent, such as the one used above, and adding an aqueous solution containing an excess of base, such as sodium hydroxide or potassium hydroxide, for example around 2 to 5 base equivalents.

Alternatively, the amide coupling of intermediate 1 with carboxylic acid 2 can be carried out by converting 2 to an activated ester, such as an N-hydroxy succinimide ester (NHS) or a p-nitrophenyl ester, or an acid imidazole, which is then react with aminotropane 1. Still in another alternative, carboxylic acid 2 is reacted with intermediate 1 in the presence of a coupling agent such as 1,3-dicyclohexylcarbodiimide (DCC), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDC), or benzotriazol-1-yloxytripyrrolidino-phosphonium hexafluorophosphate (PyBop), optionally combined with l-hydroxy-7-azabenzotriazole (HOAt). The protecting group P1 is removed by standard procedures to provide an intermediate of the formula 3. For example, the protective group Boc, is typically removed by treatment with an acid, such as trifluoroacetic acid. The Cbz protecting group, for example, is conveniently removed by hydrogenolysis on an appropriate metal catalyst such as palladium on carbon. Intermediate 3 is then N-alkylated reductively by reaction with dimethoxyacetaldehyde to provide an intermediate of formula 4. This reaction is typically conducted by contacting 3 with between about 1 and about 4 equivalents of dimethoxyacetaldehyde in an inert diluent in the presence between about 1 and about 2 equivalents of a reducing agent. The reaction is typically conducted at room temperature for about 1 to about 2 hours, or until the reaction is substantially complete. Suitable inert diluents include dichloromethane, trichloromethane, 1,1,2,2-tetrachloroethane, and the like. Typical reducing agents include sodium triacetoxyborohydride, sodium borohydride, and sodium cyanoborohydride. The product 4 is isolated by standard procedures. Next, the dimethoxyethyl intermediate 4 is hydrolyzed in an aqueous solution of a strong acid, for example 3N or 6N HCl, to provide the dihydroxyethyl intermediate 5. It will be understood that although the intermediate 5 is shown in Reaction Scheme A in the form of an aldehyde hydrate, intermediate 5 can be described equivalently in the form of an aldehyde. The reaction is typically conducted at a temperature in the range of about 50 ° C to about 100 ° C for about 15 minutes to about 2 hours, or until the reaction is substantially complete. The product 5 can be isolated in salt form, for example as the HCl salt, or as neutral species after alkaline extraction. Alternatively, the crude intermediate 5 can be used in the final stage without further manipulation.

Finally, intermediate 5 is reductively coupled to the primary or secondary amine of formula H-W, to provide the product of formula (I). Typically, a solution was prepared from between about 1 and about 3 equivalents, for example about 2 equivalents, of the amine and a reducing agent, such as sodium triacetoxyborohydride or the like, in an inert diluent such as dichloromethane. Intermediate 5 is added to the amine mixture. The reaction is typically conducted at room temperature for about 15 minutes to about 2 hours, or until the reaction is substantially complete. The crude product of the formula (I) is extracted by conventional procedures. The product can be purified in the form of a salt by crystallization from an inert diluent, for example, ethanol, isopropyl alcohol, methanol, acetonitrile, dichloroethane, or mixtures thereof. Alternatively, the compounds of the formula (I) can be prepared by an N-alkylated compound of the formula (I) in which R2 is hydrogen, which can be prepared according to the reaction scheme A. The N-alkylation reaction is typically conducted by contacting a compound of the formula (I) in which R2 is hydrogen with between about 1 and about 4 equivalents of a compound of the formula L-R2 in which L is a leaving group such as iodine or bromine. This reaction is typically conducted in a polar aprotic solvent such as dimethylformamide in the presence of between about 2 and about 4 equivalents of a strong base, such as potassium tert-butoxide. Typically, the reaction is carried out at a temperature between about 60 and about 100 ° C between about 6 and about 24 hours, or until the reaction is substantially complete. The protected aminotropane 1 used in the reactions described in this application was prepared from readily available starting materials. For example, when the protecting group Pl is Boc, the protected 1 'endo-aminotropane was prepared by the procedure illustrated in reaction scheme B.

Reaction scheme B 1 'As described in detail in the example below, to prepare the protective intermediate 1', first, 2,5-dimethoxy tetrahydrofuran 6 is contacted with between about 1 and 2 equivalents, preferably about 1.5 equivalents of benzyl amine and a slight excess, for example about 1.1 equivalents, of 1,3-acetonicarboxylic acid 7 in an aqueous acid solution in the presence of a buffering agent such as sodium acid phosphate. The reaction mixture was heated to between about 60 and about 100 ° C to ensure decarboxylation of any of the carboxylated intermediates in the product, 8-benzyl-8-azabicyclo [3.2. l] octan-3-one 8, commonly N-benzyltropanone. Intermediate 8 is typically reacted with a slight excess of di-tert-butyl dicarbonate (commonly (Boc) 20), for example, about 1.1 equivalents, under an atmosphere of hydrogen in the presence of a transition metal catalyst to provide the protective intermediate Boc 9, tert-butyl ester of 3-oxo-8-azabicyclo [3.2.1] octane-8-carboxylic acid. The reaction is typically conducted at room temperature for about 12 to about 72 hours. Finally, the intermediate 9 is contacted with a large excess, for example at least about 25 equivalents, of ammonium formate in an inert diluent, such as methanol, in the presence of a transition metal catalyst to provide the product. 'in the endo configuration with high stereospecificity, for example endo ratio up to exo ratio of > 99. The reaction is typically conducted at room temperature for about 12 to about 72 hours or until the reaction is substantially complete. This was advantageously added to the ammonium formate reagent in portions. For example, the intermediate 9 is contacted with an initial portion of ammonium formate of about 15 up to about equivalents. After an interval of about 12 to about 36 hours, an additional portion of about 5 to about 10 equivalents of ammonium formate was added. The subsequent addition may be repeated after a similar interval. The 1-product can be purified by conventional procedures, such as alkaline extraction. The lH-indazole carboxylic acid 2 was easily prepared by methods known in the art, and is described, for example, in the literature by Harada et al. Chem. And Pharm Bull. 1995, 43, 1912-30 and in the examples below. Amines H-W are commercially available or are easily prepared by standard procedures from common starting materials. With respect to additional details the specific reaction conditions and other procedures for preparing representative compounds of the invention or intermediates thereof are described in the examples below. Accordingly, in one aspect of the method, the invention provides a process for preparing a compound of the formula (I), or a salt or stereoisomer or protective derivative thereof, the processes comprising reacting a compound of the formula 5 with a amine of the formula HW to provide a compound of the formula (I), or a salt or stereoisomer or protected derivative thereof. The invention further provides a compound of formula 5, or a salt or stereoisomer or protected derivative thereof, wherein R1 and R2 are defined as in formula (I).

In an alternative method of synthesis, the compounds of the formula (I) are prepared by coupling the substituted lH-indazole carboxylic acid 2 with an intermediate of the formula 10 as illustrated in Reaction Scheme C.

Reaction scheme C The reaction of reaction scheme C is typically conducted under the amide coupling conditions described above by the reaction of carboxylic acid 2 with intermediate 1. Intermediates of formula 10 can be prepared or deprotected an intermediate of formula 11 where P 1 represents a protective amino group. The intermediates of formula 11 can be prepared from readily available starting materials using procedures analogous to alkylation, reductive amination and other reactions described above and / or use of alternative reactions known to those skilled in the art. The exemplary process routes (i) to (v) for the preparation of intermediary 11 are illustrated in the Reaction D scheme: Diagram of reaction D where L denotes a starting group such as bromine or iodine. In yet another alternative method of synthesis, the compounds of the formula (I) are prepared by coupling an intermediate of the formula 3, detailed in Reaction Scheme A, with an intermediate of the formula 12. It will be understood that although the intermediate 12 is shown in the Reaction D scheme in the form of an aldehyde, the. intermediary 12 can be described equivalently in the form of an aldehyde hydrate.

Pharmaceutical Compositions The indazole carboxamide compounds of the invention are typically administered to a patient in the form of a pharmaceutical composition. Such pharmaceutical compositions can be administered to the patient by any acceptable route of administration, including, but not limited to, oral, rectal, vaginal, nasal, inhaled, topical (including transdermal), and parenteral modes of administration. Accordingly, in one of these compositional aspects, the invention is directed to a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a therapeutically effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof. Optionally, such pharmaceutical compositions may contain other therapeutic agents and / or formulants if desired. The pharmaceutical compositions of the invention typically contain a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof. Typically, such pharmaceutical compositions should contain from about 0.1 to about 95% by weight of the active agent; including from about 1 to about 70% by weight; such as from about 5 to about 60% by weight of the active agent. Any conventional carrier or excipient may be used in the pharmaceutical compositions of the invention. The choice of a carrier or excipient or combinations of carriers or excipients, depends on the mode of administration use to treat a particular patient or type of medical condition or disease state. In this regard, the preparation of a pharmaceutically acceptable composition for a particular mode of administration will be within the scope of those of skill in the pharmaceutical art. Additionally, the ingredients for such compositions are commercially available from, for example, Sigma, P. O. Box 14508, St. Louis, MO 63178. By way of further illustration, conventional formulation techniques are described in Remington: The Science and Practice of Pharmacy, 20th Edition, Lippincott Williams & White, Baltimore, Maryland (2000); and H.C. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edition, Lippincott Williams & White, Baltimore, Maryland (1999). Representative examples of the materials which can serve as a pharmaceutically acceptable carrier include, but are not limited to, the following: (1) sugars, such as lactose, glucose and sucrose; (2) starch, such as corn starch and potato starch; (3) cellulose, such as microcrystalline cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and acetate cellulose; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) damping agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline solution; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other compatible non-toxic substances employed in pharmaceutical compositions.

The pharmaceutical compositions of the invention are typically prepared by thoroughly or intimately mixing or combining a compound of the invention with a pharmaceutically acceptable carrier and one or more optional ingredients. If necessary or desired, the resulting uniformly mixed mixture can then be formed or loaded into tablets, capsules, pills and the like using conventional methods and equipment. The pharmaceutical compositions of the invention are packaged in a dosage unit form. The term "dose unit form" refers to a discrete unit physically suitable for dosing, that is, each unit contains an amount of active agent calculated to produce the desired therapeutic effect either alone or in combination with one or more units additional For example, such dosage unit form can be capsules, tablets, pills and the like.

In a preferred embodiment, the pharmaceutical compositions of the invention are suitable for oral administration. Pharmaceutical compositions suitable for oral administration may be in the form of capsules, tablets, pills, pouches, lozenges, dragees, powders, granules; or as a solution or suspension in an aqueous or non-aqueous liquid; or as a liquid emulsion of oil in water or water in oil; or as an elixir or syrup; and the like; each contains a predetermined amount of a compound of the present invention as an active ingredient. When attempted by oral administration in a solid dosage form (ie, as a capsule, tablets, pills and the like), the pharmaceutical compositions of the invention typically comprise a compound of the present invention as the active ingredient and one or more pharmaceutically carriers. acceptable, such as sodium citrate or dicalcium phosphate. Optionally or alternatively, such solid dosage forms may also comprise: (1) fillers or diluents, such as starches, microcrystalline cellulose, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) linkers, such as carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and / or sodium carbonate; (5) agents that retard the solution, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as cetyl alcohol and / or glycerol monostearate; (8) absorbers, such as kaolin and / or bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and / or mixtures thereof; (10) coloring agents and (11) buffering agents. Release agents, wetting agents, coating agents, humectants, flavors and perfuming agents, preservatives and antioxidants can also be presented in the pharmaceutical compositions of the invention, examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfate, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like. Coating agents for tablets, capsules, pills and the like include those used by enteric coating, such as cellulose acetate phthalate (CAP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose phthalate, methacrylic acid-ester copolymer of methacrylic acid, cellulose acetate trimellitate (CAT), carboxymethyl ethyl cellulose (CMEC), hydroxypropyl methyl cellulose acetate succinate (HPMCAS), and the like.

If desired, the pharmaceutical compositions of the present invention can also be formulated to provide low or controlled release of the active ingredient using, for example, hydroxypropyl methyl cellulose in various proportions; or other matrices of polymer, liposomes and / or microspheres. In addition, the pharmaceutical compositions of the present invention may optionally contain opacifying agents and may be formulated as those which release the active ingredient only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a detailed way. Examples of embedded compositions which may include polymeric substances and waxes. The active ingredient may also be in the form of an icro-capsule, if appropriate, with one or more of the excipients described above. Liquid dosage forms suitable for administration include, by way of illustration, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. Such liquid dosage forms typically comprise the active ingredient and an inert diluent, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzoate. of benzyl, propylene glycol, 1,3-butylene glycol, oils (esp., cottonseed, peanut, corn, germ, olive, castor bean, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and fatty acid ester of sorbitan and mixtures thereof. Suspensions, in addition to the active ingredient, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanhydroxide, bentonite, agar and tragacanth, and mixtures thereof. same. Alternatively, the pharmaceutical compositions of the. invention are formulated by administration by inhalation. Pharmaceutical compositions suitable for administration by inhalation will typically be in the form of an aerosol or a powder. Such compositions are generally administered using well-known delivery devices, such as a metered dose inhaler, a dry powder inhaler, a nebulizer or a similar delivery device. When administered by inhalation using a pressurized content, the pharmaceutical compositions of the invention typically comprise the active ingredient and a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.

Additionally, the pharmaceutical composition may in the form of a capsule or cartridge (made, for example, from gelatin) comprising a compound of the invention and a powder suitable for use in a powder inhaler. Suitable powder bases include, by way of example, lactose or starch. The compounds of the invention can also be transdermally administered using known transdermal delivery systems and excipients. For example, a compound of the invention can be mixed with permeation enhancers, such as propylene glycol, polyethylene glycol monolaurate, azacycloalkan-2-ones and the like, and incorporated into a batch or similar delivery system. Additional excipients include gelling agents, emulsifiers and buffers, can be used in such transdermal compositions if desired. The following formulations illustrate representative pharmaceutical compositions of the present invention: Formulation of Example A Hard gelatin capsules for oral administration are prepared as follows: Representative procedure: The ingredients are mixed thoroughly and then loaded into a hard gelatin capsule (260 mg of composition per capsule) Formulation of Example B Hard gelatin capsules for oral administration are prepared as follows: Representative procedure: The ingredients are mixed thoroughly and then passed through a mesh screen E.Ü.A. No. 45 and are loaded in a hard gelatin capsule (200 mg of the composition per capsule) Formulation of Example C Capsules for oral administration are prepared as follows: Representative procedure: The ingredients are mixed thoroughly and then loaded into a gelatin capsule (310 mg of composition per capsule). Formulation of Example D Tablets for administration are prepared as follows: Representative procedure: The active ingredient, starch and cellulose are passed through mesh screen of E.U.A. No. 45 and they are completely mixed. The solution of polyvinylpyrrolidone was mixed with the resulting powders and this mixture was then passed through a mesh screen of E.Ü.A. No. 14. The produced granules are dried at 50-60 ° C and passed through a mesh screen of E.U.A. No. 18. Sodium carboxymethyl starch, magnesium stearate and talcum (previously passed through a U.S. No. 60 mesh screen) are then added to the granules. After mixing, the mixture is condensed in a tablet machine to provide a 100 mg tablet.

Formulation of Example E Tablets for oral administration were prepared as follows: Representative procedure: The ingredients are mixed thoroughly and then condensed to form tablets (440 mg of composition per tablet).

Formulation of Example F Single-brand tablets for oral administration were prepared as follows: Representative procedure: The ingredients are thoroughly mixed and condensed to form a single-registration tablet (215 mg of the compositions per tablet).

Formulation of Example G A suspension of oral administration was prepared as follows: Representative procedure: The ingredients were mixed to form a suspension containing 10 mg of the active ingredient per 10 ml of suspension.

Formulation of Example H A dry powder for administration by inhalation was prepared as follows: Representative procedure: The active ingredient was icronizo and then mixed with lactose. This mixture was then loaded into a gelatin inhalation cartridge. The content of the cartridge was administered using a powder inhaler.

Formulation of Example I A dry powder for administration by inhalation in a metered dose inhaler was prepared as follows: Representative procedure: A suspension containing 5% by weight of a compound of the invention and 0.1% by weight of lecithin was prepared per 10 g dispersant of the active compound as micronized particles with media of size less than 10 μm in a solution formed of 0.2 g of lecithin dissolved in 200 ml of demineralized water. The suspension was spray-dried and the resulting material micronised to give particles having a diameter medium of less than 1.5 μm. The particles were loaded in pressurized 1, 1, 1, 2-tetrafluoroethane cartridges.

Formulation of Example J An injectable formulation was prepared as follows: Representative procedure: The ingredients above were mixed and the pH was adjusted to 4 ± 0.5 using 0.5 N HCl or 0.5 N NaOH.

Formulation of Example K Capsules for oral administration are prepared as follows: Representative procedure: The ingredients are thoroughly mixed and then loaded into a gelatin capsule (size # 1, White, Opaque) (264 mg of the composition per capsule).

Formulation of Example L Capsules for oral administration were prepared as follows: Representative procedure: The ingredients were thoroughly mixed and then loaded into a gelatin capsule (size # 1, White, Opaque) (148 mg of the composition per capsule). It should be understood that any form of the compounds of the invention (ie, , free base, pharmaceutical salt, or solvate 9 which is suitable for the particular mode of administration, can be used in the pharmaceutical compositions discussed above.

Utility The indazole carboxamide compounds of the invention are 5-HT4 receptor agonists and are therefore expected to be useful for the treatment of medical conditions mediated by 5-HT4 receptors or associated with the 5-HT activity receptor, that is, medical conditions which are improved by treatment with a 5-HT4 receptor agonist. Such medical condition include, but is not limited to, irritable bowel syndrome (IBS), chronic constipation, functional dyspepsia, delayed gastric emptying, gastroesophageal reflux disease (GERD), gastroparesis, diabetic and idiopathic gastropathy, postoperative ileus, intestinal pseudo-obstruction , and delayed drug-induced transit. In addition, this suggests that some of the 5-HT receptor agonist compounds can be used in the treatment of central nervous system disorders including, cognitive disorders, behavioral disorders, mood disorders, and autonomic function control disorders. In particular, the compounds of the invention increase the mobility of the gastrointestinal tract (Gl) and thus are expected to be useful for treating disorders of the Gl tract caused by reduced mobility in mammals, including humans. Such Gl mobility disorders include, by way of illustration, chronic constipation, irritable bowel syndrome with predominant constripation (C-IBS), diabetic and idiopathic gastroparesis, and functional dyspepsia. In one aspect, therefore, the invention provides a method for increasing the mobility of the gastrointestinal tract in a mammal, the method comprising administering to the mammal a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of the invention. . When used to treat reduced mobility disorders of the Gl tract or other conditions mediated by 5-HT4 receptors, the compounds of the invention will typically be administered orally in a single dose daily or in multiple doses per day, although other forms of administration they can be used The amount of active agent administered per dose or total amount administered per day will typically be determined by a physician, in the clarity of relevant circumstances, including the condition to be treated, the designated route of administration, the current compound administered and this relative activity, the age, weight, and response of the individual patient, the severity of the patient's symptoms and the like. Suitable doses for treating disorders of reduced mobility of the Gl tract or other disorders mediated by 5-HT4 receptors are expected in the range from about 0.0007 to about 20 mg / kg / day of the active agent, including from about 0.0007 to about of 1 mg / kg / day. For a human of 70kg on average, this amount will be from around 0.05 to around 70 mg per day of the active agent. In one aspect of the invention, the compounds of the invention are used to treat chronic constipation. When used to treat chronic constipation, the compounds of the invention will typically be administered orally in a single dose daily or in multiple doses per day. The dose to treat chronic constipation is expected in the range from about 0.05 to about 70 mg per day. In another aspect of the invention, the compounds of the invention are used to treat irritable bowel syndrome. When used to treat irritable bowel syndrome of predominant constipation, the compounds of the invention are typically administered orally in a single daily dose or in multiple doses per day. The dose for the treatment of predominant constipation irritable bowel syndrome is expected to range from about 0.05 to about 70 mg per day. In another aspect of the invention, the compounds of the invention are used to treat diabetic gastroparesis. When used to treat diabetic gastroparesis, the compounds of the invention are typically administered orally in a single daily dose or in multiple doses per day. The dose for the treatment of diabetic gastroparesis is expected to range from about 0.05 to about 70 mg per day. In still another aspect of the invention, the compounds of the invention are used to treat functional dyspepsia. When used to treat functional dyspepsia, the compounds of the invention are typically administered orally in a single daily dose or in multiple doses per day. The dose for functional dyspepsia treatment is expected to range from about 0.05 to about 70 mg per day. The invention also provides a method for treating a mammal having a disease or condition associated with 5-HT4 receptor activity, the method comprising administering to the mammal a therapeutically effective amount of a compound of the invention or a pharmaceutical composition comprising a compound of the invention. As, described above, compounds of the invention are 5-HT receptor agonists. The invention further provides, therefore, a method for agonizing a 5-HT4 receptor in a mammal, the method comprising administering a compound of the invention to the mammal. In addition, the compounds of the invention are also useful as search tools for investigating or studying biological systems or samples having 5-HT4 receptors, or for discovering new 5-HT receptor agonists. On the other hand, since compounds of the invention show binding selectivity for 5-HT4 receptors compared to binding to other 5-HT subtype receptors, particularly 5-HT3 receptors, such compounds are particularly useful for studying the effects of selective agonism of 5-HT4 receptors in a biological system or sample. Any suitable biological system or sample having 5-HT4 receptors can be employed in such studies which can be conducted either in vitro or in vivo. Suitable representative biological systems or samples for each study include, but are not limited to, cells, cell extracts, plasma membranes, tissue samples, mammals (such as mice, rats, guinea pigs, rabbits, dogs, pigs, etc.). ) and similar. In this aspect of the invention, a biological system or sample comprises a 5-HT4 receptor that is contacted with an amount that agonizes the 5-HT4 receptor of a compound of the invention. The effects of agonizing the 5-HT receptor are then determined using conventional methods and equipment, such as radioligand binding assays and functional assays. Such functional assays include ligand-mediated changes in intracellular cyclic adenosine monophosphate (cAMP), ligand-mediated changes in adenylyl cyclase enzyme activity (which synthesizes cAMP), ligand-mediated changes in incorporation of guanosine triphosphate (GTP) analogs , such as [35S] GTP? S (guanosine 5 '-O- (? -thio) triphosphate) or GTP-Eu, in membranes isolated by means of catalyzed exchange of GTP analogue analogs for GDP analogues, ligand-mediated changes in free intracellular calcium ions (measured, for example, with a fluorescence-linked imaging plate reader or FLIPR® from Molecular Devices, Inc.), and measurement of mitogen-activated protein kinase (MAPK) activation. A compound of the invention can agonize or increase activation of 5-HT receptors in any of the functional assays listed above, or assays of a similar nature. An amount that agonizes the receiver. 5-HT of a compound of the invention will typically be in the range from about 1 nanomolar to about 500 nanomolar. Additionally, the compounds of the invention can be used as search tools to discover new 5-HT4 receptor agonists. In this embodiment, 5-HT receptor binding or functional data for a test compound or a group of test compounds is compared to the 5-HT receptor binding or functional data for a compound of the invention to identify test compounds that have top link or functional activity, in any. This aspect of the invention includes, as separate embodiments, both the generation of comparison data (using the appropriate analyzes) and the analysis of the test data to identify test compounds of interest. Among other properties, the compounds of the invention have been found to be potent agonists of the 5-HT4 receptor and to exhibit substantial selectivity for the 5-HT receptor subtype on the 5-HT3 receptor subtype in radioligand binding assays. In addition, compounds of the invention have demonstrated superior pharmacokinetic characteristics in a rat model. Compounds of the invention are thus expected to be highly bioavailable upon oral administration. In addition, these compounds have not been shown to inhibit the potassium ion current in a closed-loop model in vitro using isolated whole cells expressing the hERG cardiac potassium channel. The closed voltage test is an accepted pre-clinical method of evaluating the potential for pharmaceutical agents to change the pattern of cardiac repolarization, specifically to cause, prolongation called QT, which has been associated with cardiac arrhythmia. (Cavero et al., Opinion on Pharmacotherapy, 2000, 1, 947-73, Fermini et al., Nature Reviews Drug Discovery, 2003, 2, 439-447) Accordingly, pharmaceutical compositions comprising compounds of the invention are expected. to be free of such cardiac side effects. These characteristics, as well as the utility of the compounds of the invention, can be demonstrated using various in vitro and in vivo assays well known to those skilled in the art. Representative tests are described in further detail in the following examples.

EXAMPLES The following synthetic and biological examples are offered to illustrate the invention, and are not constructed in any way as limiting the scope of the invention. In the examples below, the following abbreviations have the following meaning unless otherwise indicated. The abbreviations not defined below have their meanings generally accepted. Boc = tert-butoxycarbonyl (Boc) 20 = di-tert-butyl dicarbonate DCM = dichloromethane DMF = N, -dimethylformamide DMSO = dimethyl sulfoxide EtOAc = ethyl acetate mCPBA = m-chlorobenzoic acid MeCN = acetonitrile MTBE = tert-butyl ether -butyl methyl PyBop = benzotriazole-1-yloxytripyrrolidino-phosphonium hexafluorophosphate Fr = retention factor TA = room temperature TFA = trifluoroacetic acid THF = tetrahydrofuran Reagents (including secondary amines) and solvents were purchased from commercial suppliers (Aldrich, Fluka, Sigma, etc.), and are used without further purification. The reactions were run under a nitrogen atmosphere, unless otherwise indicated. The progress of the reaction mixtures was observed by thin layer chromatography (CCD), high performance analytical liquid chromatography (HPLC anal.), And mass spectrometry, the details of which are given below and separately in specific examples of reactions . The reaction mixtures are worked up as specifically described in each reaction; they are commonly purified by extraction and other purification methods such as temperature-, and solvent-dependent crystallization, and precipitation. In addition, the reaction mixtures were routinely purified by preparative HPLC: a general protocol is described below. The characterization of the reaction products was carried out routinely by mass and 1 H-NMR spectrometry. For the NMR measurement, the samples were dissolved in deuterated solvent (CD3OD, CDC13, or DMSO-d6), and XH-NMR spectrum, were acquired with a Varian Gemini 2000 (300 MHz) instrument under standard observation conditions. Mass spectrometric identification of compounds was performed by an electro-ionization ionization method (ESMS) with an Applied Biosystems (Foster City, CA) EX instrument model API 150 or an Agilent (Palo Alto, CA) LC / MSD model 1100 instrument.

General Protocol for CLAR analysis The crude compounds were dissolved in 50% MeCN / H2O (with 0.1% TFA) at a concentration of 0.5-1.0 mg / mL, and analyzed using the following conditions: Column: Zorbax Bonus-RP (3.5 μm in size) of particle, 2.1 x 50 mm) Flow rate: 0.5 mL / min Detector wavelength: 214, 254, and 280 nm.

General Protocol for the purification of preparative HPLC Raw compounds were dissolved in acetic acid 50% in water at a concentration of 50-100 mg / mL, filter, and fractionate using the following procedure: Column: YMC Pack-Pro C18 (50a x 20mm, ID = 5μm) Flow rate: 40 mL / min Phases Mobiles: A = MeCN90% / H20 10% / TFA 0.1% B = H20 98% / MeCN 2% / TFA 0.1% Gradient: A 10% / B 90% up to A 50% / B 50% for 30 min (linear) Detector wavelength: 214 nm.

Preparation of secondary amines Thiomorpholine-1, 1-dioxide was prepared from the thiomorpholine by protection of the secondary amine to thiomorpholine N-Boc ((Boc) 20, MeOH), oxidation to sulfone (mCPBA, CH2C12, 0 ° C) , and deprotection of the N-Boc group to provide the free amine (CF3C02H, CH2C12). (m / z): [M + H] + calculated for C4H9N02S, 136.04; found, 135.9. The piperazine N-sulfonyl derivatives were prepared from piperazine N-Boc by reacting with respective sulfonyl chloride (iPr2NEt, CH2C12, 0- ° C), and deprotecting the N-Boc group (CF3C02H, CH2C12). 1-Methanesulfonyl-piperazine: ^? - 'NMR (CDC13; neutral): d (ppm) 3.1 (t, 4H), 2.9 (t, 4H), 2.7 (s, 3H). 1- (Methylsulfonyl) methanesulfonyl-piperazine: "" "H-NMR (CD3OD): d (ppm) 2.90 (s, 3H), 3.02 (, 4H), 3.38 (m, 4H), 4.61 (s, 2H). The racemic or single chiral isomer forms of 3-acetylaminopyrrolidine were prepared by treating N1-Boc-3-aminopyrrolidine (racemate, 3R, or 3S) with acetyl chloride (iPr2NEt, CH2C12, 0 ° C), and deprotecting the N group -Boc (CF3C02H, CH2C12) 3- (Acetamido) pyrrolidine: ^ -RMN (DMS0-d6; salt TFA): d (ppm) 4.2 (quin, 1H), 3.3-3.1 (m, 3H), 2.9 (m, ÍH), 2.0 (m, 1H), 1.8 (br s, 4H). 3- ((R) -2-Hydroxypropionamido) pyrrolidine was prepared after the amidation of N1-Boc-3-aminopyrrolidine (L-lactic acid, PyBOP, DMF, TA), and deprotection of the N-Boc group (CF3C02H, CH2C12). (m / z): [M + H] + calculated for C7H? N202, 159.11; found, 159.0. 1H-NMR (CD3OD, TFA salt): d (ppm) 4.4 (quin, 1H), 4.1 (q, 1H), 3.5-3.4 (m, 2H), 3.3-3.2 (, 2H), 2.3 (m, 1H) ), 2.0 (m, ÍH), 1.3 (d, 3H). The N3-alkanesulfonyl derivatives of (3R) -aminopyrrolidine were obtained by treating N1-Boc- (3R) -aminopyrrolidine with propionylsulfonyl chloride or cyclohexylmethylsulfonyl chloride (i-Pr2NEt, CH2C12, 0 ° C), and deprotecting the N group -Boc (CF3C02H, CH2C12). 3- (N-Acetyl-N-methylamido) piperidine was prepared from the t-butyl ester of N3-Cbz protected 3-amino-piperidine-1-carboxylic acid (De Costa, B., et al. Med. Chem. 1992, 35, 4334-43) after four synthetic steps: i) Mel, n-BuLi, THF, -78 ° ca TA; ii) H2 (1 atm), Pd / C 10%, EtOH; iii) AcCl, i-Pr2NEt, CH2C12; iv) CF3C02H, CH2C12. m / z: [M + H] + calculated for C8H? 6N20: 157.13; found, 157.2. XH-NMR (CD30D, TFA salt): d (ppm) 4.6 (m, 1H), 3.3 (m, HH), 3.2 (m, HH), 3.0 (m, HH), 2.9 (s, 3H), 2.8 (m, ÍH), 2.0 (s, 3H), 1.9-1.7 (m, 4H). 3- (N-Acetyl-amido) piperidine was prepared from tert-butyl ester of 3-amino-piperidine-l-carboxylic acid after N-acetylation and deprotection of the N-Boc group: i) AcCl, i -Pr2NEt, CH2C12; ii) CF3C02H, CH2C12. 1H-NMR (CD3OD, TFA salt): d (ppm) '3.9 (m, HH), 3.3 (dd, HH), 3.2 (, HH) ", 2.9 (dt, HH), 2.75 (dt, 1H), 2.0-1.9 (m, 2H), 1.9 (s, 3H), 1.8-1.4 (m, 2H) The N3-alkanesulfonyl derivatives of 3-aminopiperidine were synthesized by reacting the chiral or racemic forms of tert-butyl ester of 3-amino-piperidine-l-carboxylic acid with the respective alkanesulfonyl chloride (i- Pr2NEt, CH2C12) and deprotecting the N-Boc group (CF3C02H, CH2C12). (3S) -3- (ethanesulfonylamido) piperidine: ^? -RMN (CD30D): d (ppm) 1.29 (t, 3H, Ji = 7.4 Hz), 1.50-1.80 (, 2H), 1.90-2.10 (, -2H), 2.89 (m, 2H), 3.05 (q, 2H, Jx = 7.4 Hz), 3.27 (m, 2H), 3.40 (d of d (br), ÍH), 3.52 (m, ÍH). 3S-Methylsulfonylmethanesulfonylamido-piperidine: 1H-NMR (CD3OD): d ( ppm) 2.13-2.30 (m, 2H), 2.40-2.57 (m, 2H), 2.98 (m, 2H), 3.15 (s, 3H), 3.21 (m, 2H), 3.30 (br d, 1H), 3.74 (m, ÍH) 3- (Methylamino) -1-acetylpyrrolidine was prepared from 3- (methylamino) -1-benzylpyrrolidine (T CI America) after four stages: i) (Boc) 20, MeOH, ta; ii) H2 (1 atm), Pd / C 10%, EtOH; iii) AcCl, i-Pr2NEt, CH2C12; iv) CF3C02H, CH2C12. (m / z): [M + H] + calculated for C7H? 4N20: 143.12; found, 143.0. 3- (Methylamino) -1- (methanesulfonyl) pyrrolidine was prepared from 3- (methylamino) -1-benzylpyrrolidine after four steps: i) (Boc) 20, MeOH, ta; ii) H2 (1 atm), Pd / C 10%, EtOH; iii) CH3S02C1, i-Pr2NEt, CH2C12; iv) CF3C02H, CH2C12. (m / z): [M + H] + calculated for C6H? 4N202S: 179.08; found, 179.2. 3R-Methylamino-1- (methanesulfonyl) pyrrolidine was prepared in a similar form to (3R) - (methylamino) -1-benzylpyrrolidine. The tetrahydro-3-thiophenamine-1,1-dioxide derivatives were prepared following the protocol of Loev, B. J. Org. Chem. 1961, 26, 4394-9 by reacting 3-sulfolene with a requirement of primary amine in methanol (cat.KOH, ta). N-Methyl-3-tetrahydrothiopheneamine-1, l-dioxide (TFA salt): 1 H-NMR (DMSO-de): d (ppm) 9.4 (br s, 2 H), 4.0-3.8 (quin, 1 H), 3.6- 3.5 (dd, 1H), 3.4-3.3 (m, ÍH), 3.2-3.1 (m, 2H), 2.5 (s, 3H), 2.4 (m, 1H), 2.1 (, ÍH). N-2- (1-hydroxy) ethyl-3-tetrahydrothiopheneamine-1,1-dioxide: (m / z): [M + H] + calculated for C 6 H 3 N0 3 S: 180.07; found, 180.2. N-Methyl-tetrahydro-2H-thiopyran-4-amine-1,1-dioxide was prepared from tetrahydro-4H-thiopyran-4-one: i) MeNH2, NaBH4; ii) (Boc) 20, MeOH; iii) mCPBA, CH2C12, 0 ° C; iv) CF3C02H, CH2C12. (m / z): [M + H] + calculated for C6H? 3N02S 164.07; found, 164.9. 1 H-NMR (CD30D, TFA salt): d (ppm) 3.4-3.1 (m, 5H), 2.7 (s, 3H), 2.4 (br d, 2H), 2.1 (br m, 2H). L-Acetyl-3- (methylamino) piperidine was prepared from protected 3-methylamino-piperidine N3-Cbz: i) AcCl, i-Pr2NEt, CH2C12; ii) H2 (1 atm), Pd / C 10%, EtOH. XH-NMR (CD30D): d (ppm) 4.0 (, ÍH), 3.6 (m, 1H), 3.4-3.2 (m, 2H), 3.0 (m, HH), 2.6 (s, 3H), 2.1 (s) , 3H), 1.8-1.6 (m, 4H). 1- (Methanesulfonyl) -3- (methylamino) piperidine was prepared from protected 3-methylamino-piperidine N3-Cbz: i) CH3S02C1, i-Pr2NEt, CH2C12; ii) H2 (1 atm), Pd / C 10%, EtOH. (m / z): [M + H] + calculated for C7H? 6N202S 193.10; found, 193.0. 1 H-NMR (DMSO-d 6; TFA salt): d (ppm) 3.4 (dd, 1H), 3.2 (m, 2H), 3.10 (s, 3H), 3.0-2.9 (m, 2H), 2.8 (s, 3H), 1.85-1.75 (m, 2H), 1.6-1.4 (, 2H).

Example 1: Synthesis of. { (1S, 3R, 5R) -8- [2- (4-acetylpiperazin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-yl} 1- isopropyl-lH-indazol-3-carboxylic acid amide a. Preparation of 8-benzyl-8-azabicyclo [3.2.1] octan-3-one The concentrated hydrochloric acid (30 mL) was added to a heterogeneous solution of 2,5-dimethoxy tetrahydrofuran (82.2 g, 0.622 mol) in water ( 170 mL) during stirring. In a separating flask cooled to 0 ° C (ice bath), "concentrated hydrochloric acid (92 mL) was slowly added to a solution of benzyl amine (100 g, 0.933 mol) in water (350 mL). , 5-dimethoxytetrahydrofuran was stirred for about 20 min, diluted with water (250 mL), and then the benzyl amine solution was added, followed by the addition of a solution of 1,3-acetonadicarboxylic acid (100 g, 0.684 mol) in water (400 L) and then the addition of sodium hydrogen phosphate (44 g, 0.31 mol) in water (200 mL) The pH was adjusted from pH 1 to pH 4.5 using 40% NaOH. Turbid and pale resulting was stirred overnight.The solution was then acidified to pH 3 from pH 7.5 using 50% hydrochloric acid, heated to 85 ° C and stirred for 2 hours.The solution was cooled to room temperature, basified to pH 12 using 40% NaOH, and extracted with dichloromethane (3 x 500 mL). Each was washed with brine, dried (MgSO 4), filtered and concentrated under reduced pressure to yield the crude title intermediate as a brown viscous oil (52 g). To a solution of the crude intermediate in methanol (1000 mL) was added di-tert-butyl dicarbonate (74.6 g, 0.342 mol) at 0 ° C. The solution was allowed to warm to room temperature and stirred overnight. The methanol was removed under reduced pressure and the resulting oil was dissolved in dichloromethane (1000 mL). The intermediate was extracted in 1 M H3P04 (1000 mL) and washed with dichloromethane (3 x 250 mL). The aqueous layer was basified to pH 12 using aqueous NaOH, and extracted with dichloromethane (3 x 500 mL). The combined organic layers were dried (MgSO), filtered and concentrated under reduced pressure to yield the title intermediate as a light brown, viscous oil (54 g). 2H-NMR (CDC13) d (ppm) 7.5-7.2 (, 5H, C6H5), 3.7 (s, 2H, CH2Ph), 3.45 (broad s, 2H, CH-NBn), 2.7-2.6 (dd, 2H, CH2CO ), 2.2-2.1 (dd, 2H, CH2CO), 2.1-2.0 (m, 2H, CH2CH2), 1.6 (m, 2H, CH2CH2). (m / z): [M + H] + calculated for C? 4H? 7NO 216.14; found, 216.0. b. Preparation of 3-oxo-8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester To a solution of 8-benzyl-8-azabicyclo [3.2.1] octane-3-one (75 g , 0.348 mol) in EtOAc (300 mL) was added a solution of di-tert-butyl dicarbonate (83.6 g, 0.383 mol, 1.1 eq) in EtOAc (300 mL). The resulting solution and rinsed (100 mL EtOAc) was added to a hydrogenation vessel Parr 1 L containing 23 g of palladium hydroxide (20% by weight Pd, dry base, on carbon, ~ 50% wet with water, eg, Pearlman's catalyst) under a stream of nitrogen. The reaction vessel was degassed (alternate vacuum and N2 five times) and pressurized to 60 psi (4.218 kg / cm2) of H2. The reaction solution was stirred for two days and recharged with H2 as necessary to maintain the H2 pressure at 60 psi (4.218 kg / cm2) until the reaction was complete as observed by silica thin layer chromatography. The black solution was then filtered through a pad of Celite® and concentrated under reduced pressure to yield the title intermediate quantitatively as a viscous yellow-orange oil (51 g). This was used in the next stage without additional treatment. "" "H NMR (CDCl 3) d (ppm) 4.5 (broad, 2H, CH-NBoc), 2.7 (broad, 2H, CH2C0), 2.4-2.3 (dd, 2H, CH2CH2), 2.1 (broad m, 2H, CH2CO), 1.7-1.6 (dd, 2H, CH2CH2), 1.5 (s, 9H, (CH3) 3COCON)). c. Preparation of (1S, 3R, 5R) -3-amino-8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester To a solution of the product from the previous step (75.4 g, 0.335 'mol ) in methanol (1 L) was added ammonium formate (422.5 g, 6.7 mol), water (115 mL) and 65 g of palladium on activated carbon (10% on dry basis, ~ 50% wet with water, type Degussa El 01NE / W) under a stream of N2 during the stirring by means of mechanical agitator. After 24 and 48 hours, additional portions of ammonium format (132g, 2.1 mol) were added each time. Once the reaction progression ended, as observed by anal. CLAR, Celite® (> 500g) was added and the resulting coarse slurry was filtered and then the collected solid was rinsed with methanol (~ 500 mL).

The filtrates were combined and concentrated under reduced pressure until all the methanol had been removed. The resulting cloudy, biphasic solution was then diluted with IM phosphoric acid to a final volume of ~ 1.5 to 2.0 L at a pH of 2 and washed with dichloromethane (3 x 700 mL). The aqueous layer was basified to pH 12 using 40% aqueous NaOH, and extracted with dichloromethane (3 x 700 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated by rotary evaporation, then left at high vacuum 52 g (70%) of the title intermediate, commonly N-Boc-endo-3-aminotropane, as a white solid. to pale yellow. The ratio of the endo to exo amine isomer of the product was > 99 based on 1 H-NMR analysis (> 96% purity by analytical HPLC). XH NMR (CDC13) d (ppm) 4.2-4.0 (broad d, 2H, CHNBoc), 3.25 (t, ÍH, CHNH2), 2.1-2.05 '(, 4H), 1.9 (m, 2H), 1.4 (s, 9H, "(CH3) 3OCON), 1.2-1.1 (broad, 2H). (M / z): [M + H] + calculated for C? 2H22N202 227.18; found, 227.2. Analytical HPLC (isocratic method; (A: B) to 90:10 (A: B) for 5 min): retention time = 2.14 min. d. Preparation of l-isopropyl-lH-indazole-3-carboxylic acid To indazole-3-carboxylic acid (40 g, 247 mmol) suspended in methanol (700 mL) was added concentrated H2SO4 (10 mL) slowly while stirring the mixture . The mixture was stirred and refluxed at 80 ° C for 24 h. The mixture was cooled, filtered, and concentrated under reduced pressure to provide a pale yellow solid. The solid was suspended in water (700 mL), ground to fine powder, collected by filtration, and rinsed with water (~ 400 mL). The product was suspended in toluene, and evaporated to dryness under reduced pressure, affording methyl ester of indazole-3-carboxylic acid as a pale yellow solid (45 g,> 95% pure). (m / z): [M + H] + calculated for C9H8N202 177.07; found, 177.0. 2 H-NMR (CD30D, 300 MHz): d (ppm) 8.0 (1 H, d), 7.5 (H, d), 7.4 (H, t), 7.2 (H, t), 3.9 (3 H, s). To a solution of indazole-3-carboxylic acid methyl ester (40.7 g, 231 mmol) in anhydrous tetrahydrofuran (700 L) cooled in an ice bath was slowly added solid potassium tert-butoxide (28.3 g, 252 mmol) . The mixture was stirred at the same temperature for 1 hr after the addition of 2-iododopropane (34.4 mL, 367 mmol). The final mixture was stirred for 12 h at room temperature, and refluxed for 12 h. After cooling to room temperature, the mixture was filtered, and the collected solid was rinsed with tetrahydrofuran (100 mL). The filtrates were combined, and concentrated to dryness under reduced pressure, yielding methyl ester of crude 1-isopropyl-1H-indazole-3-carboxylic acid (49.7 g) as a pale yellow oil. The crude material was purified by flash silica gel chromatography eluting with hexane / ethyl acetate (9/1 to 3/1) to yield l-isopropyl-lH-indazole-3-carboxylic acid methyl ester (43 g, 197 mmol,> 99% pure). ^ -NMR (CD3OD, 300 MHz): d (ppm) 8.1-8.0 (lH, d), 7.6 (lH, d), 7.4 (lH, t), 7.2 (lH, t), 5.0 (lH, l) , 3.9 (s, 3H), 1.5 (6H, d). To a solution of the methyl ester dissolved in tetrahydrofuran (400 mL) was added 1M NaOH (400 mL). The mixture was stirred for 24 h at room temperature. The reaction was terminated by washing with ethyl acetate (2 x 400 mL), keeping the aqueous layer. The aqueous layer was acidified slowly by adding concentrated HCl (~40 mL) in an ice bath, which leads to the separation of a pale yellow oily product. The product was extracted with ethyl acetate (1000 mL), and the organic layer was dried over MgSO4 and evaporated under reduced pressure to yield the title intermediate as a pale yellow to white solid (34 g, >98% pure), which was further purified by crystallization from ethyl acetate to provide the title intermediate as colorless needles, (m / z): [M + Na] + calculated for CnH12N202 226.07; found, 226.6. aH-NMR (CD3OD, 300 MHz): d (ppm) 8.1-8.0 (1H, d), 7.6 (H, d), 7.4 (H, t), 7.2 (H, t), 5.0 (H, quin), 1.5 (6H, d). and. Preparation of (1S, 3R, 5R) -3- [l-isopropyl-lH-indazole-3-carbonyl) amino] -8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester A suspension of l-isopropyl-lH-indazole-3-carboxylic acid (56.35 g, 0.276 mol) in toluene (500 mL) was stirred and heated for 5 min after the addition of thionyl chloride (30.2 mL, 0.414 mol). After heating at 100 ° C for 15 min, the mixture becomes a homogeneous solution, which continues to be stirred at the same temperature for an additional 90 min. In a separate reaction flask, (1S, 3R, 5R) -3-amino-8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester was prepared as in step c, (62.43 g, 0.276 mol) was dissolved in 250 mL of toluene and followed by addition of NaOH (66.3 g) dissolved in 250 mL of water. This biphasic mixture was cooled in an ice bath. The indazole acid chloride solution prepared above was cooled to room temperature, and added for 15 min to the biphasic solution, which was stirred vigorously in an ice bath. After stirring for 1.5 h, the reaction mixture was transferred to a separatory funnel. First, the aqueous layer was separated from the toluene layer (saved), and extracted with EtOAc (2 x 500 mL). The toluene layer was concentrated under reduced pressure, and the residue obtained was dissolved in the organic extract (1 L, EtOAc). The solution was washed with 1 M H3P04 (400 mL), saturated NaHCO3 (400 L), and then brine solution (400 mL). After drying over MgSO4, the organic solution was evaporated to dryness under reduced pressure to provide 119.2 g of the title intermediate. 1 H-NMR (DMSO-d 6): d (ppm) 1.41 (s, 9H), 1.51 (d, 6H), 1.82 (, 2H), 1.97 (bs, 4H), 2.09 (m, 2H), 4.10 (, 3H), 5.10 (sept, 1H), 7.23 (t, ÍH), 7.42 (t, 1H), 7.79 (d, ÍH), 7.82 (d, ÍH), 8.18 (d, ÍH). (m / z): [M + H] + calculated for C 23 H 32 N 3, 413.26; found, 413.1. Retention time (anal HPLC: MeCN 2-95% / H20 for 6 min) = 4.85 min.

F. Preparation of . { (ΔS, 3R, 5R) -8-aza-bicyclo [3.2.1] oct-3-yl l-isopropyl-lH-indazole-3-carboxylic acid The product for the previous step was solubilized in dichloromethane (200 mL ), cooled in an ice bath, and then mixed with 200 mL of trifluoroacetic acid. The reaction mixture was stirred for 1 h at room temperature. This was then added dropwise to ethyl ether (2 L) in a flask while stirring, which gives the title intermediate as its mono (trifluoroacetic acid) salt (102.7 g after drying, 87% yield for two steps ). ""? -RMN (DMSO-de): d (ppm) 1. 54 (d, 6H), 2.05 (, 2H), 2.24 (m, "6H), 4.03 (s, 2H), 4.12 (q, ÍH), 5.09 (sept, ÍH), 7.28 (t, ÍH), 7.45 (t, ÍH), 7.81 (d, ÍH), 8.00 (d, 1H), 8.11 (d, ÍH), 8.54 (bd, 2H). (m / z): [M + H] + calculated for C? 8H24N40, 313. twenty; found, 313 1.

Retention time (anal HPLC: MeCN 2-95% / H20 for 6 min) = 2. 65 min. g. Preparation of . { (ÍS, 3R, 5R) -8- (2, 2-dimethoxyethyl) -8-aza-bicyclo [3.2.1] oct-3-yl lamide of 1-isopropyl-lH-indazole-3-carboxylic acid To one solution from . { (ΔS, 3R, 5R) -8-aza-bicyclo [3.2.1] oct-3-yl l-isopropyl-lH-indazole-3-carboxylic acid (52.7 g, 0.124 mol) was dissolved in 500 mL of dichloromethane was added diisopropylethylamine (43.1 mL) and dimethoxy acetaldehyde in methyl tert-butyl ether (45% conc, 44.5 mL, 0.173 mmol). After stirring 35 min at room temperature, sodium triacetoxyborohydride (36.7 g, 0.173 mol) was added to this mixture. The reaction was quenched after 90 min by slowly adding water (50 mL) and saturated NaHCO 3 solution (100 mL) in an ice bath. The mixture was diluted with 500 mL of dichloromethane, and transferred to a separatory funnel. The organic layer was collected, and washed with saturated NaHCO3 (250 L), and brine solution (350 mL). This was dried over MgSO, and evaporated under reduced pressure to provide the title intermediate (58.8 g). 1H-RN (CDC13): d (ppm) 1.60 (d, 6H), 1.77 (m, 2H), 1.96-2.09 (m, 4H), 2.29 (, 2H), 2.55 (m, 2H), 3.33 (m , 2H), 3.41 (s, 6H), 4.33 (q, 1H), 4.47 (m, 1H), 4.87 (sept, 1H), 7.26 (t, ÍH), 7.37-7.46 (, 2H), 7.56 (d , ÍH), 8.36 (d, ÍH). (m / z): [M + H] + calculated for C22H32N03 401.26; found, 401.3. Retention time (anal HPLC: MeCN 2-50% / H2O for 6 min) = 4.20 min. h. Preparation of . { (1S, 3R, 5R) -8- (2, 2-dihydroxyethyl) -8-aza-bicyclo [3.2.1] oct-3-yl lamide of 1-isopropyl-lH-indazole-3-carboxylic acid The product of the previous stage (55.2 g) was suspended in 500 mL of 6 M hydrochloric acid and heated at 70 ° C for 1 h. The reaction mixture was cooled to 0 ° C, and diluted with dichloromethane (500 mL) after basification of the aqueous layer by slow addition of 6M NaOH (800 mL). This was further mixed with 800 mL of dichloromethane, and transferred to a separatory funnel. The organic layer was collected, washed with brine, dried over MgSO4, and evaporated to dry to provide the title intermediate (45.1 g). (m / z): [M + H] + calculated for C2oH28N4? 3, 373.22; found, 373.2. Retention time (anal HPLC: MeCN 2-50% / H2O for 6 min) = 3.77 min. i. Synthesis { (SS, 3R, 5R) -8- [2- (4-acetyl-piperazin-1-yl) ethyl] -8-aza-bicyclo [3.2.1] oct-3-yl 1-isopropyl-lH acid -indazole-3-carboxylic acid, alternatively, N- [(3-endo) -8- [2- (4-acetylpiperazin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-yl] - 1- (1-Methylethyl) -lH-indazole-3-carboxamide To a flask containing 450 mL of dichloromethane was added 1-acetylpiperazine (19.3 g, 0.151 mol), sodium triacetoxyborohydride (34.4 g). This was stirred for 5 min after the addition of the product from the previous step (45.1 g). The final mixture was stirred for 1 h, at which time the reaction was completed based on HPLC and mass spectrometric analysis. Water (200 mL) was added slowly and the mixture was diluted with 600 mL of dichloromethane, and stirred in a funnel before collecting the organic layer. This was washed with ÍM NaOH (400 mL) and brine (500 L). Drying over MgSO4, and evaporation afforded the title compound as a colorless solid (47.6 g). The crude product was purified by crystallization from ethanol as the HCl salt (> 30 g, purity> 98%). ^ -NMR (DMSO-d6; free base): d (ppm) 1.52 (d, 6H), 1.69 (m, 2H), 1.83 (m, 2H), 1.97 (s, 3H), 1.92-2.10 (m, 4H), 2.33 (t, 2H), 2.42 (m, 6H), 2.50 (m, 2H), 3.21 (bs, 2H), 3.38 (m, 4H), 4.09 (q, ÍH), 5.07 (sept, ÍH) ), 7.26 (t, ÍH), 7.43 (t, 1H), 7.79 (d, 1H), 8.12 (d, ÍH). (m / z): [M + H] + calculated for C 26 H 38 602, 467.31; found, 467.5. Retention time (anal HPLC: MeCN 2-50% / H2O for 6 min) = 3.52 min.

Example 2: Synthesis of. { (1S, 3R, 5R) -8- [2- (4- (tetrahydrofuran-2-carbonyl) piperazin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-11} l-isopropyl-lH-indazole-3-carboxylic acid amide To a solution of N- [2-tetrahydrofuroyl] piperazine bromohydrate (40 mg, 0.15 mmol) and N, N-diisopropylethylamine (12 μL, 0.3 mmol) in dichloromethane ( 1.5 mL) was added sodium triacetoxyborohydride (64 mg, 0.3 mmol), and then. { (1S, 3R, 5R) -8- (2, 2-dihydroxyethyl) -8-aza-bicyclo [3.2.1] oct-3-yl lamide of 1-isopropyl-lH-indazole-3-carboxylic acid (HCl salt) ) (39 mg, 0.1 mmol). The mixture was stirred at room temperature for 15 min. After concentration under reduced pressure, the reaction mixture was dissolved in 50% aqueous acetic acid, and purified by preparative HPLC to provide the trifluoroacetic acid salt of the title compound (97% purity). (m / z): [M + H] + calculated for C29H42N603, 523.34; found 523.2. Retention time (anal HPLC: MeCN 5-65% / H20 for 5 min) = 2.7 min.

Examples 3-20 Using processes similar to that of Example 2, except replacing the N- [2-tetrahydrofuroyl] piperazine bromohydrate with the appropriate sequential amine, the compounds of Examples 3-20 were prepared.

Example 3 { (SS, 3R, 5R) -8- [2- (1, l-dioxo-l6-thiomorpholin-4-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-yl lamide of acid 1 -isopropyl-lH-indazole-3-carboxylic acid; (m / z): [M + H] + calculated for C24H35N5? 3S, 474.25; found 474.2. Retention time (anal HPLC: MeCN 5-75% / H20 for 5 min) = 2.20 min.

Example 4 { (1S, 3R, 5R) -8- [2- (4-methanesulfonylpiperazin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-yl lamide of 1-isopropyl-lH-indazole-3 -carboxylic; (m / z): [M + H] + calculated for C25H38N603S, 503.28; Found 503.2. Retention time (anal HPLC: MeCN 5-65% / H20 for 4 min) = 2.12 min.

Example 5 { (SS, 3R, 5R) -8- [2- (4-cyclohexylmethane sulfonylpiperazin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-yl-l-isopropyl-lH-indazole- 3-carboxylic; (m / z): [M + H] + calculated for C31H48 6? 3S, 585.35; Found 585.4. Retention time (anal HPLC: MeCN 5-75% / H20 for 5 min) = 2.67 min.

Example 6 { (ΔS, 3R, 5R) -8- [2- (4-methanesulfonyl methanesulfonylpiperazin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-yl-l-isopropyl-lH- indazole-3-carboxylic acid; (m / z): [M + H] + calculated for C25H4oN6? 5S2, 581.26; Found 581.2. Retention time (anal HPLC: MeCN 5-75% / H20 for 5 min) = 2.22 min.

Example 7 { (SS, 3R, 5R) -8- [2- (3- (Acetyl-methylamino) pyrrolidin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-yl lamide of 1-isopropyl- lH-indazole-3-carboxylic acid; (only): [M + H] + calculated for C27H4oN602, 481.32; Found 481.3. Retention time (anal HPLC: MeCN 5-75% / H20 for 5 min) = 2.07 min.

Example 8 { (1S, 3R, 5R) -8- [2- (3- (Acetylamino) pyrrolidin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-yl lamide of 1-isopropyl- lH-indazole-3-carboxylic acid; (m / z): [M + H] + calculated for C26H38 6? 2, 467.31; found 467.4. Retention time (anal HPLC: MeCN 5-75% / H20 for 5 min) = 1.89 min.

Example 9 { (ΔS, 3R, 5R) -8- [2- ((R) -3- (acetylamino) pyrrolidin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-yl acid lamide 1- isopropyl-lH-indazole-3-carboxylic acid; (m / z): [M + H] + calculated for C 26 H 38 N 602, 467.31; found 467.4. Retention time (anal HPLC: MeCN 5-75% / H20 for 5 min) = 2.04 min.

Example 10 { (ΔS, 3R, 5R) -8- [2- ((S) -3- (acetylamino) pyrrolidin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-yl acid lamide 1-isopropyl-lH-indazole-3-carboxylic acid; (m / z): [M + H] + calculated for C 26 H 38 N 602, 467.31; found 467.4. Retention time (anal HPLC: MeCN 5-75% / H20 for 5 min) = 2.07 min.

Example 11 ((SS, 3R, 5R) -8- { 2- [3- ((S) -2-hydroxypropionylamino) pyrrolidin-1-yl] ethyl.}. -8-azabicyclo [3.2.1] oct -3-yl) 1-isopropyl-lH-indazole-3-carboxylic acid amide; (m / z): [M + H] + calculated for C27H40N6? 3, 497.32; found 497.2. Retention time (anal HPLC: MeCNO 5-65% for 5 min) = 2.07 min.

Example 12 ((SS, 3R, 5R) -8- { 2- [(3S, 4S) -3- (acetylmethylamino) -4-hydroxypyrrolidin-1-yl] ethyl.}. -8-azabicyclo [3.2. 1-oct-3-yl) l-isopropyl-lH-indazole-3-carboxylic acid amide; (m / z): [M + H] + calculated for C27H40N6O3, 497.32; found 497. 2. Retention time (anal HPLC: MeCN 5-65% / H20 for 5 min) = 2. 15 min.

Example 13 { (SS, 3R, 5R) -8- [2- ((R) -3- ethanesulfonylaminopyrrolidin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-yl lamide of 1-isopropyl-lH acid - indazole-3-carboxylic acid; (m / z): [M + H] + calculated for C 26 H 4 o N 6? 3 S, 517.30; Found 517.2. Retention time (anal HPLC: MeCN 5-75% / H20 for 5 min) = 2.12 min.

Example 14 { (SS, 3R, 5R) -8- [2- ((R) -3-cyclohexylmethane sulfonylaminopyrrolidin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-yl-isopropyl-l-lamide lH-indazole-3-carboxylic acid; (m / z): [M + H] + calculated for C3iH48N6? 3S, 585.36; Found 585.4. Retention time (anal HPLC: MeCN 5-75% / H20 for 5 min) = 2.52 min.

Example 15 ((SS, 3R, 5R) -8- { 2- [3- (acetyl-methylamino) piperidin-1-yl] ethyl.}. -8-azabicyclo [3.2.1] oct-3-yl. ) 1-isopropyl-lH-indazole-3-carboxylic acid amide; (m / z): [M + H] + calculated for C28H42N602, 495.34; found 495.4. Retention time (anal HPLC: MeCN 5-75% / H20 for 5 min) = 1.94 min.

Example 16 { (SS, 3R, 5R) -8- [1- (3-acetylaminopiperidin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-yl lamide of 1-isopropyl-lH-indazol-3 acid -carboxylic; (m / z): [M + H] + calculated for C27H0N6O2, 481.33; found 481.2. Retention time (anal HPLC: MeCN 5-75% / H20 for 5 min) = 2.01 min.

Example 17 { (SS, 3R, 5R) -8- [2- (3-methanesulfonylaminopiperidin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-yl lamide of 1-isopropyl-lH-indazol-3 acid -carboxylic; (m / z): [M + H] + calculated for C26H40N6? 3S, 517.30; found 517.4. Retention time (anal HPLC: MeCN 5-75% / H20 for 5 min) = 1.97 min.

Example 18 { (1S, 3R, 5R) -8- [2- ((S) -3-methanesulfonylaminopiperidin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-yl lamide of 1-isopropyl-lH -indazole-3-carboxylic acid; (m / z): [M + H] + calculated for C 26 H 4 o N 603 S, 517.30; found 517.4. Retention time (anal HPLC: MeCN 5-75% / H20 for 5 min) = 1.99 min.

Example 19 { (1S, 3R, 5R) -8- [2- ((S) -3-Ethanesulfonilaminopiperidin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-yl lamide of 1-isopropyl- lH-indazole-3-carboxylic acid; (m / z): [M + H] + calculated for C27H 2N603S, 531.31; Found 531.4. Retention time (anal HPLC: MeCN 5-75% / H20 for 5 min) = 2.04 min.

Example 20 { (1S, 3R, 5R) -8- [2- ((S) -3-Methanesulfonylmethane sulfonylaminopiperidin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-yl-amide of l-isopropyl-1H -indazole-3-carboxylic acid; (m / z): [M + H] + calculated for C27H2N6? 5S2, 595.27; Found 595.2. Retention time (anal HPLC: MeCN 5-75% / H20 for 5 min) = 2.07 min.

Example 21: Synthesis of ((1S, 3R, 5R) -8- { 2- [(1-acetylpyrrolidin-3-yl) methylamino] ethyl]} - 8-azabicyclo [3.2.1] oct-3- il) l-isopropyl-lH-indazole-3-carboxylic acid amide To a solution of 3- (methylamino) -1-acetylpyrrolidine (43 mg, 0.3 mmol) and N, N-diisopropylethylamine (12 μL, 0.3 mmol) in dichloromethane (1.5 mL) was added sodium triacetoxyborohydride (128 mg, 0.6 mmol), and then. { (1S, 3R, 5R) -8- (2, 2-dihydroxyethyl) -8-aza-bicyclo [3.2.1] oct-3-yl lamide of l-isopropyl-lH-indazole-3-carboxylic acid (HCl salt ) (78 mg, 0.2 mmol). The mixture was stirred at room temperature for 15 min. After concentration under reduced pressure, the reaction mixture was dissolved in 50% aqueous acetic acid, and purified by preparative HPLC to provide the trifluoroacetic acid salt of the title compound (56 mg, 99% purity). (m / z): [M + H] + calculated for C27H40N6O2, 481.33; found 481.2. Retention time (anal HPLC: 5-65% MeCN / H20 for 5 min) = 2.00 min.

Examples 22-30 Using processes similar to that of Example 21, except by replacing 3- (methylamino) -1-acetylpyrrolidine with the appropriate sequential amine, the compounds of Examples 22-30 were prepared.

Example 22 ((ΔS, 3R, 5R) -8- { 2- [((R) -l-acetylpyrrolidin-3-yl) methylamino] ethyl.}. -8-azabicyclo [3.2.1] oct-3 -l) l-isopropyl-lH-indazole-3-carboxylic acid amide; (m / z): [M + H] + calculated for C2H40N6O2, 481.33; found 481.4. Retention time (anal HPLC: MeCN 10-50% / H2O for 5 min) = 2.52 min.

Example 23 (IS, 3R, 5R) -8-. { 2- [((S) -l-acetylpyrrolidin-3-yl) methylamino] ethyl} L-isopropyl-lH-indazole-3-carboxylic acid-8-azabicyclo [3.2.1] oct-3-yl) amide; (m / z): [M + H] + calculated for C2H40N6? 2, 481.33; found 481.4. Retention time (anal HPLC: 10-50% MeCN / H20 for 5 min) = 2.52 min.

Example 24 ((1S, 3R, 5R) -8- {2- [(1-methanesulfonylpyrrolidin-3-yl) methylamino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl) amide of l-isopropyl-lH-indazole-3-carboxylic acid; (m / z): [M + H] + calculated for C26H40N6? 3S, 517.30; Found 517.2. Retention time (anal HPLC: MeCN 5-75% / H20 for 5 min) = 2.04 mm, Example 25 ((1S, 3R, 5R) -8- { 2- [((R) -1-methanesulfonylpyrrolidin L-isopropyl-lH-indazole-3-carboxylic acid (3-yl) methylamino] ethyl] -8-azabicyclo [3.2.1] oct-3-yl) amide (oral): [M + H] + calculated for C26H4o 6? 3S, 517.30; Found 517.2. Retention time (HPLC analysis: 5-65% MeCN / H20 for 5 min) = 2.20 min.

Example 26 ((ÍS, 3R, 5R) -8-. {2- [(1, 1-dioxo-tetrahydro-l6-thiophen-3-yl) methylamino] etill-8-azabicyclo [3.2.1] oct-3-yl) l-isopropyl-lH-indazole-3-carboxylic acid amide; (m / z): [M + H] + calculated for C25H37N503S, 488.27; Found 488.2. Retention time (HPLC analysis: 5-75% MeCN / H20 for 5 min) = 2.22 min.

Example 27 ((SS, 3R, 5R) -8-. {2- [(1, 1-dioxo-tetrahydro-l6-thiophen-3-yl) - (2-hydroxyethyl) amino] ethyl}. 1-isopropyl-lH-indazole-3-carboxylic acid-8-azabicyclo [3.2.1] oct-3-yl) amide; (m / z): [M + H] + calculated for C 26 H 39 N 504 S, 518.28; found 518.2. Retention time (HPLC analysis: 5-65% MeCN / H20 for 5 min) = 2.25 min.

Example 28 ((ΔS, 3R, 5R) -8-. {2- [(L-Acetyl-piperidin-3-yl) methylamino] ethyl]} - 8-azabicyclo [3.2.1] oct-3-yl. ) l-isopropyl-lH-indazole-3-carboxylic acid amide; (m / z): [M + H] + calculated for C 26 H 38 N 602, 495. 3. 4; found 495. Four . Retention time (HPLC analysis: 5-75% MeCN / H20 for 5 min) = 1. 95 min.

Example 29 ((SS, 3R, 5R) -8-. {2- [(1,1-dioxo-hexahydro-l6-thiopyran-4-yl) methylamino] ethyl]. 8-azabicyclo [3.2. 1-oct-3-yl) l-isopropyl-lH-indazole-3-carboxylic acid amide; (m / z): [M + H] + calculated for C26H39N5? 3S, 502.29 found 502.2. Retention time (HPLC analysis: 5-65% MeCN / H20 for 5 min) = 2.12 min.

Example 30 ((SS, 3R, 5R) -8-. {2- [(1-methanesulfonylpiperidin-3-yl) methylamino] ethyl] -8-azabicyclo [3.2.1] oct-3-yl) amide of l-isopropyl-lH-indazole-3-carboxylic acid; (m / z): [M + H] + calculated for C27H42N6? 3S, 531.31; Found 531.4. Retention time (HPLC analysis: 5-75% MeCN / H20 for 5 min) = 2.07 min.

Example 31: Synthesis of. { (1S, 3R, 5R) -8- [2- (4-acetylpiperazin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-yl} 5-Fluoro-l-isopropyl-lH-indazole-3-carboxylic acid amide a. Preparation of 5-fluoro-l-isopropyl-lH-indazole-3-carboxylic acid The methyl ester of 5-Fluoro-lH-indazole-3-carboxylic acid was prepared according to the protocol described in (Buu-Hoi, NP, et al., J. Hetereocyclic Chem. 1964, 1, 239-41. aH-NMR (DMSO-d6): d (ppm) 7.8 (dd, 2H), 7.35 (dt, ÍH), 3.8 (s, 3H). The methyl ester was attached to N1 with isopropyl iodide in the presence of potassium tert-butoxide under reflux THF, XH-NMR (CDC13): d (ppm) 7.8 (dd, 1H), 7.6 (dd, 1H), 7.1 ( dt, HH), 4.8 (hept, HH), 1.6 (d, 6H) The methyl isopropyl ester was then hydrolyzed (1M NaOH / THF, TA) to provide the title intermediate. b. Preparation of . { (SS, 3R, 5R) -8-aza-bicyclo [3.2.1] oct-3-yl} 5-Fluoro-l-isopropyl-lH-indazole-3-carboxylic acid amide The title intermediate was prepared according to the procedure of Example 1 parts e and f, using the intermediate from the previous step in place of 1-isopropyl-1H acid -indazole-3-carboxylic acid. '' "H-NMR (DMSO-d6): d (ppm) 7.9 (br, ÍH), 7.7 (dd, ÍH), 7.6 (dd, ÍH), 7.2 (dt, ÍH), 4.9 (m, ÍH) , 4.2 (br, 1H), 4.0 (br, 2H), 2.3-2.1 (br m, 8H), 1.5 (d, 6H). (M / z): [M + H] + calculated for C? 8H23FN40, 331.19; found, 331.4 Retention time (HPLC analysis: 10-40% MeCN / H20 for 6 min) = 3.43 min. c. Preparation of . { (SS, 3R, 5R) -8- (2, 2-dimethoxyethyl) -8-aza-bicyclo [3.2.1] oct-3-yl lamide of 5-fluoro-l-isopropyl-lH-indazol-3-acid carboxylic The product of the previous step is reacted with dimethoxy acetaldehyde according to the process of example 1 step g to provide the title intermediate, (m / z): [M + H] + calculated for C22H3? FN403 419.25; found, 419.3. d. Preparation of . { (SS, 3R, 5R) -8- (2,2-dihydroxyethyl) -8-aza-bicyclo [3.2. l] -oct-3-yl 5-fluoro-l-isopropyl-lH-indazole-3-carboxylic acid lamide The intermediate of the previous step (1.0 g) was suspended in 10 mL of 6M hydrochloric acid and heated to 70 ° C for 1 h. The reaction mixture was cooled, and evaporated under reduced pressure to dry to give the hydrochloric acid salt of the title intermediate, (m / z): [M + H] + calculated for C20H27FN4O3, 391.21; found, 391.4. and_. Synthesis of . { (1S, 3R, 5R) -8- [2- (4-acetylpiperazin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-yl lamide of 5-fluoro-1-isopropyl-1H -indazole-3-carboxylic acid To 1 flask containing 40 mL of dichloromethane was added 1-acetylpiperazine (613 mg, 4.78 mmol) and sodium triacetoxyborohydride (1.01 g). This was stirred for 5 min prior to the addition of the product from the previous step (~ 1 g). The final mixture was stirred for 1 h, at which time the reaction was completed based on HPLC and mass spectrometric analysis. Water (20 L) was added slowly and the mixture was diluted with 300 mL of dichloromethane, and stirred in a funnel before the organic layer was collected. This was washed with 1M NaOH (100 mL) and brine (100 mL). It was dried over MgSO4, and evaporated to provide the title compound which was purified by preparative HPLC to provide 380 mg of the pure product with the TFA salt. 1 H- NMR (DMSO-de; free base): d (ppm) 8.0 (br, 1H), 7.8 (dd, ÍH), 7.6 (dd, ÍH), 7.23 (dt, 1H), 5.0 (hept, 1H), 4.0-3.9 (br, 3H ), 3.5 (br, 2H), 3.2-2.8 (br, 10H), 2.2 (br m, 8H), 1.9 (s, 3H), 1.4 (d, 6H). (m / z): [M + H] + calculated for C26H37FN602, 485.30; found, 485.5. Retention time (HPLC analysis: 10-70% MeCN / H20 for 6 min) = 2.28 min.

Example 32: Synthesis of. { (1S, 3R, 5R) -8- [2- (4-acetylpiperazin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-yl} 1-propyl-lH-indazol-3-carboxylic acid amide a. Preparation of . { (1S, 3R, 5R) -8- [2- (4-acetylpiperazin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-yl lamelic acid 1H-indazole-3-carboxylic acid The intermediate of the title was prepared according to the procedure of Example 1 using lH-indazole-3-carboxylic acid in place of 1-isopropyl-lH-indazole-3-carboxylic acid in step e. (m / z): [M + H] + calculated for C23H32N602, 425.27; found, 425.4.

Retention time (HPLC analysis: 10-40% MeCN / H20 for 6 min) = 1.47 min. b. Alternative synthesis from . { (1S, 3R, 5R) -8- [2- (4-acetylpiperazin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-yl lamide of l-isopropyl-lH-indazole-3 carboxylic acid To a solution of anhydrous DMF (2 mL) containing the TFA salt of the intermediary from the previous step (80 mg, 0.123 mmol) was added potassium tert-butoxide (48 mg, 0.43 mmol) and isopropyl iodide. (37 μL, 0.368 mmol). The mixture was stirred at 85 ° C for 12 h, and then evaporated to dryness, yielding the pale brown residue, which was dissolved in 50% aqueous acetic acid and fractionated by preparative HPLC to provide the title compound. (m / z): [M + H] + calculated for 'C26H38N602, 467.31; obs. 467.2 [M + H] +. Retention time (HPLC analysis: 5-65% MeCN / H20 for 6 min) = 2.09 min. c. Synthesis of . { (SS, 3R, 5R) -8- [2- (4-acetylpiperazin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-yl lamide of 1-propyl-lH-indazole-3 acid carboxylic A process similar to that of step b was used, except that the isopropyl iodide was replaced with n-propyl iodide, the title compound was prepared. (m / z): [M + H] + calculated for C 26 H 38 N 602, calculated 467.31; obs. 467.4 [M + H] +. Retention time (HPLC analysis: 5-65% MeCN / H20 for 6 min) = 2. 05 min.

Examples 33-35 A process similar to that of Example 32 was used, except that the isopropyl iodide was replaced with the appropriate alkyl halide, the compounds of Examples 33-35 were prepared.

Example 33 ((ΔS, 3R, SR) -8- [2- (4-acetylpiperazin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-yl lamide of 1-butyl-lH- indazole-3-carboxylic acid (m / z): [M + H] + calculated for C27H40N6O2, 481.33, found 481.4 Retention time (HPLC analysis: 5-65% MeCN / H20 for 6 min) = 2.26 min.

Example 34 ((S, 3R, 5R) -8- [2- (4-acetylpiperazin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-yl lamide of 1-cyclobutyl-1H- indazole-3-carboxylic acid (m / z): [M + H] + calculated for C27H38N602, 479.31, found 479.4 Retention time (HPLC analysis: 5-65% MeCN / H20 for 6 min) = 2.20 min.

Example 35 ((ΔS, 3R, 5R) -8- [2- (4-acetylpiperazin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-yl lamide of 1-cyclopentyl-1H- indazole-3-carboxylic acid (m / z): [M + H] + calculated for C28H40N6O2, 493.33, found 493.2 Retention time (HPLC analysis: 5-65% MeCN / H20 for 6 min) = 2.34 min.

Examples 36-40 A similar process was used for those described above, the compounds of examples 36-40 can be prepared.

Example 36 { (SS, 3R, 5R) -8- [2- ((R) -3- (acetyl-methylamino) pyrrolidin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-yl} l-isopropyl-lH-indazole-3-carboxylic acid amide.

Example 37 { (ΔS, 3R, 5R) -8- [2- ((S) -3- (acetyl-methylamino) pyrrolidin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-yl acid lamide l-isopropyl-lH-indazole-3-carboxylic acid.

EXAMPLE 38 ((SS, 3R, 5R) -8- { 2- [((S) -1-methanesulfonylpyrrolidin-3-yl) methylamino] ethyl]. 8-azabicyclo [3.2.1] oct-3 -l) l-isopropyl-lH-indazole-3-carboxylic acid amide.

Example 39 ((SS, 3R, 5R) -8-. {2- [(R) - (1,1-dioxo-tetrahydro-l6-thiophen-3-yl) methylamino] ethyl] -8 L-isopropyl-lH-indazole-3-carboxylic acid azabicyclo [3.2.1] oct-3-yl) amide.

Example 40 ((1S, 3R, 5R) -8- { 2- [(6) - (1,1-dioxo-tetrahydro-l6-thiophen-3-yl) methylamino] ethyl] -8 L-isopropyl-lH-indazole-3-carboxylic acid azabicyclo [3.2.1] oct-3-yl) amide.

Example 41: Chlorohydrate synthesis of. { (1S, 3R, 5R) -8- [2- (4-Acetylpiperazin-1-yl) ethyl] -8-azabicyclo [3.2. l] oct-3-il} l-isopropyl-lH-indazole-3-carboxylic acid amide a. Preparation of (1S, 3R, 5R) -3- [l-isopropyl-lH-indazole-3-carbonyl) amino] -8- azabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester A flask of round bottom of three necks of 5L equipped with a magnetic stirring bar, a reflux condenser, an addition funnel, a nitrogen inlet and a thermometer was charged with l-isopropyl-lH-indazole-3-carboxylic acid (250 g, 1224 mol, 1.1 eq) and 2.5 L of toluene. The resulting suspension was stirred and heated to 70-80 ° C. To this suspension was added thionyl chloride (218.4 g, 1.836 mol, 1.65 eq) over a period of 40 min. The mixture was heated to 90-100 ° C for 1 h and cooled to 25 ° C. A separate 12 L three-necked round bottom flask equipped with a mechanical stirrer, an addition funnel, a nitrogen inlet and a thermometer was charged with 2.5 L of toluene and 3 N NaOH (prepared from diluting 356 g of 50% NaOH with water up to 1.48 L), and (1S, 3R, 5R) -3-amino-8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (251.9 g, 1113 mol, 1 eq). The resulting suspension was stirred at 23 ° C for 10 minutes and cooled to 5 ° C. To this suspension was added the acid chloride solution in toluene for a period of 90 minutes keeping the internal temperature at ~ 5 ° C during the addition period. The mixture was stirred for 30 min. The reaction was heated to 25 ° C; the aqueous layer was discarded (1. 58 L, pH> 13). The organic layer was washed with 1 L of 20% by weight of brine; and the aqueous layer was discarded '(1.005 L, ~ pH 8). The organic layer was collected (5.3 L) and concentrated to half the volume (-2.6 L), and used in the next step without purification. b. Preparation of . { (1S, 3R, 5R) -8-aza-bicyclo [3.2.1] oct-3-yl} l-isopropyl-lH-indazole-3-carboxylic acid amide A 12L three-necked round bottom flask equipped with a mechanical stirrer, an addition funnel, a nitrogen inlet and a thermometer was charged with the product from the stage previous. To this solution was added trifluoroacetic acid (0.65 L) for a period of 10 min. The resulting mixture was stirred for 1 h at room temperature. Water (3.3 L) was added to the reaction mixture. The resulting suspension was stirred at 23 ° C for 10 minutes and allowed to settle to give a three layer mixture. The two upper layers were discarded and the bottom layer (820 mL) was collected, and added to MTBE (6560 mL) for a period of 90 min. The resulting suspension was cooled to 5 ° C and stirred for 1 h. The suspension was filtered; the wet cake was washed with MTBE (500 mL), and dried under reduced pressure (80 mm Hg) for 60 h to give the title intermediate (386 g, 81% yield, 99.2% purity by HPLC) as a solid sandy white opaque. c. Preparation of . { (ÍS, 3R, 5R) -8- (2, 2-dimethoxyethyl) -8-aza-bicyclo [3.2.1] oct-3-yl lamide of 1-isopropyl-lH-indazole-3-carboxylic acid A flask of 3L round three-neck bottom equipped with a magnetic stirrer, a nitrogen inlet and a thermometer was charged with the intermediary from the previous stage (84 g, 0.197 mol), dichloromethane (840 mL), and sodium triacetoxyborohydride (62.6 g) , 0.295 mol). The resulting suspension was stirred for 10 minutes, cooled to 10 ° C and 60% by weight aqueous dimethoxyacetaldehyde (51.3 g, 0.295 mol) was added. This solution was stirred for 30 min, heated to 25 ° C, and stirred for 1 h. The mixture was filtered through Celite, washed with dichloromethane (150 mL) and then with 5% by weight of brine solution (400 g). The aqueous and organic layers were separated and the organic layer was concentrated to a dark oil (~150 mL), which was used in the next step without purification. d. Preparation of (1S, 3R, 5R) -8- (2, 2-dihydroxyethyl) -8-azabicyclo [3.2.1] oct-3-yl lamide of 1-isopropyl-lH-indazole-3-carboxylic acid 1L round neck flask equipped with a magnetic stirrer, a nitrogen inlet and a thermometer were charged with the product from the previous stage and water (250 mL) and heated to 50-55 ° C. To this solution was added 3N HCl (82 mL, 0.985 mol). The resulting mixture was stirred at 75 ° C for 1 h. The reaction mixture was cooled to 25 ° C and neutralized with 25% by weight of NaOH (159 g, 0.99 mol) to pH 3.51. After about 20 minutes, the lower layer was collected (~ 120 mL) to provide the title intermediate, which was used in the next step without purification. and. Chlorohydrate synthesis of. { (SS, 3R, 5R) -8- [2- (4-acetylpiperazin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-yl} l-isopropyl-lH-indazole-3-carboxylic acid amide A 3-L three-necked round bottom flask equipped with a magnetic stirrer, a nitrogen inlet and a thermometer was charged with sodium triacetoxyborohydride (84 g, 0.349 mol) and dichloromethane (800 mL). The resulting mixture was stirred at 25 ° C and charged with 1-acetylpiperazine (51 g, 0.394 mol). The addition assembly was rinsed with dichloromethane (20 mL). The mixture was stirred for 5 minutes and loaded with the product from the previous step (-120 mL) in 15 minutes keeping the internal temperature at less than 25"C. The mixture was stirred for 15 minutes, filtered through celite and washed with dichloromethane (2 x 100 mL) The filtrate was washed with IN NaOH (500 mL) The layers were separated and the lower organic layer was collected and concentrated to -150 L. Absolute ethanol (250 mL) was added and the mixture was concentrated to -200 L. To this mixture, absolute ethanol (800 mL) was added and the mixture was heated to 40 ° C. To this mixture, 3 N HCl (33 mL, 0.396 mol) was added. The mixture was stirred for 10 minutes and the crystallization started.The resulting suspension was stirred at 55 ° C for 2 h and cooled to 25 ° C. The mixture was filtered through a Whatman # 2 filter paper and the wet cake was washed with absolute ethanol (2 x 100 L) .The product was dried under nitrogen for 30 minutes and then under vacuum at 40-50 ° C during 24 h to provide the title compound (82 g).

Example 42: Synthesis of dibromohydrate of. { (1S, 3R, 5R) -8- [2- (4-acetylpiperazin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-yl} l-isopropyl-lH-indazole-3-carboxylic acid amide A 500 mL three-necked round bottom flask equipped with a magnetic stirrer, a nitrogen inlet and a thermometer was charged with water (120 L) and dichlorohydrate ( 1S, 3R, 5R) -8- [2- (4-acetylpiperazin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-yl} 1- isopropyl-lH-indazole-3-carboxylic acid amide (12 g, 22.2 mmol). The resulting mixture was stirred to give a clear light yellow solution. To this solution was added 25% by weight of NaOH (7.83 g, 24.4 mmol) in 2 minutes to give a white milky suspension. The dichloromethane (120 mL) was added and the mixture was stirred for 30 minutes to give a clear two-layered solution. The layers were separated to give an aqueous layer (113 mL) and an organic layer (125 mL), which was washed with 10% aqueous NaBr (120 mL). The layers were separated to give an organic layer (120 mL) which was concentrated to about a quarter volume. Absolute ethanol (250 mL) was added and the mixture was distilled to give ~ 200 mL of the total volume. The solution was stirred at 58 ° C and 48% by weight of aqueous HBr (8.2 g, 49 mmol) was added in 2 min. Precipitation was observed when more than half of the HBr was added. The mixture was stirred at 55 ° C to 62 ° C for 1 h and then cooled to room temperature and filtered. The filtrate was washed with absolute ethanol (40 mL), dried under nitrogen for 20 minutes and dried at 45 ° C under vacuum for 48 hours to give the title compound (13.42 g) as a white solid.

Example 43: Synthesis of the fumaric acid salt of. { (SS, 3R, 5R) -8- [2- (4-acetylpiperazin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-yl} 1-isopropyl-lH-indazole-3-carboxylic acid amide To a solution of. { (SS, 3R, 5R) -8- [2- (4-acetylpiperazin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-yl lamide of 1-isopropyl-lH-indazole-3 carboxylic acid (0.1 g, 0.21 mmol) in 50% acetonitrile / water (1 mL) was added a solution of fumaric acid IMM entanol (0.44 mL 0.42 mmol). The resulting solution was lyophilized overnight and then mixed with ethyl acetate (1 mL). Hot ethanol was added to this mixture with heating until a homogeneous solution was obtained (0.4 mL). The resulting clear solution was then allowed to crystallize at room temperature. The resulting solid was filtered, washed with ethanol, and dried under vacuum to give the title compound as a solid (0.13 g).

Example 44: Synthesis of the phosphoric acid salt of. { (1S, 3R, 5R) -8- [2- (4-acetylpiperazin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-yl} amide of 1-isopropyl-lH-indazol-3-carboxylic acid To a solution of. { (SS, 3R, 5R) -8- [2- (4-acetylpiperazin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-illamide of l-isopropyl-lH-indazole-3-acid carboxylic acid (0.2 g, 0.43 mmol) in methanol (3 mL) was added a solution of ethanolic phosphoric acid (0.43 mL, 0.43 mmol). The resulting heterogeneous solution was then heated to solubilize, filtered, and allowed to cool overnight. The resulting solid was filtered, washed with methanol and dried under vacuum to give the title compound as a solid (0.08 g).

Example 45: Synthesis of the salt of p-toluene sulfonic acid of. { (SS, 3R, 5R) -8- [2- (4-acetylpiperazin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-yl} 1-isopropyl-lH-indazole-3-carboxylic acid amide A solution of. { (SS, 3R, 5R) -8- [2- (4-acetylpiperazin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-ylamide of 1-isopropyl-1H-indazole-3- acid carboxylic acid (38.7 mg, 0.08 mmol) in isopropanol (2 mL) was heated in a water bath at 75 ° C and solid p-toluenesulfonic acid monohydrate (32.3 mg, 0.17 mmol) was added. The resulting solution was heated until the solids dissolved and then allowed to cool to room temperature. The crystals of the title compound were formed overnight.

Example 46: Synthesis of the salts of the acid of. { (SS, 3R, 5R) -8- [2- (4-acetylpiperazin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-yl} 1-isopropyl-1H-indazole-3-carboxylic acid amide. Process similar to those of Examples 43-45, the following acid salts of (1S, 3R, 5R) -8- [2- (4-acetylpiperazine -l-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-illamide of l-isopropyl-lH-indazole-3-carboxylic acid were prepared as a solid using the number of equivalents of the acid indicated in parentheses : acetate (2); benzoate (2); nitrate (2); propionate (1); tartrate (2); phosphate (0.5).

Example 47: Radioligand Linkage Assay in Human Receptors 5-HT4 (c) a. Preparation of 5-HT Membrane (C) HEK-293 cells (human embryonic kidney) stably transfected with human 5-HT4 (C) receptor cDNA (Bmax = ~ 6.0 pmol / mg protein, as determined using the binding assay membrane radioligand [3H] -GR113808) are grown in T-225 flasks in Dulbecco's Modified Eagle Medium (DMEM) containing 4,500 mg / L of D-glucose and pyridoxine hydrochloride (GIBCO-Invitrogen Corp., Carlsbad CA: Cat # 11965) supplemented with 10% fetal bovine serum (FBS) (GIBCO-Invitrogen Corp .: Cat # 10437), 2 mM L-glutamine and (100 units) penicillin- (100 μg) streptomycin / ml (GIBCO-Invitrogen Corp.: Cat # 15140) in a 5% C02 humidifier incubator at 37 ° C. The cells are grown under continuous selection pressure by the addition of 800 μg / mL of geneticin (GIBCO-Invitrogen Corp .: Cat # 10131) to the medium. The cells are grown to approximately 60-80% confluence (< 35 subculture passages). At 20-22 hours before harvest, the cells are washed twice and fed with serum-free DMEM. All stages of the membrane preparation are carried out on ice. The cell monolayer is lifted by gentle mechanical agitation and trituration with a 25 mL pipette. The cells are collected by centrifugation at 1000 rpm (5 min). For membrane preparation, cell pellets are re-suspended in ice-cold 50 mM 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid (HEPES), pH 7.4 (membrane preparation buffer) (40 mL / total cell yield of 30-40 flasks T225) and homogenized using a polytron disruptor (set 19, 2 x 10 s) on ice. The resulting homogenates are centrifuged at 1200 g for 5 min at 4 ° C. The pellet is discarded and the supernatant is centrifuged at 40,000 g (20 min). The pellet is washed once by resuspension with membrane preparation buffer and centrifugation to 40,000 g (20 min). The final pellet was resuspended in 50 mM HEPES, pH 7.4 (assay buffer) (equivalent 1 flask T225 / 1 mL). The protein concentration of the membrane suspension is determined by the Bradford method (Bradford, 1976). The membranes are stored frozen in aliquots at -80 ° C. b. Radioligand Linkage Assays Radioligand linkage assays are performed on 96 deep well polypropylene assay plates. 1. 1 mL (Axygen) in a total assay volume of 400 μL containing 2 μg of membrane protein in 50 mM HEPES pH 7.4, containing 0.025% bovine serum albumin (BSA). Saturation binding studies for determination of the radioligand Kd values were performed using [3H] -GR113808 (Amersham Inc., Bucks, UK: Cat # TRK944; specific activity ~82 Ci / mmol) at 8-12 different concentrations in the range from 0.001 nM-5.0 nM. The displacement tests for determination of pKi values. of compounds were made with [3H] -GR113808 at 0.15 nM and eleven different concentrations of the compound in the range from 10 pM-100mM. Test compounds are received as 10 mM stock solutions in DMSO and diluted to 400 μM in 50 mM HEPES pH 7.4 at 25 ° C, containing 0.1% BSA, and serial dilutions (1: 5) are made in the same buffer solution. The non-specific binding is determined in the presence of 1 μM of unlabeled GR113808. The assays are incubated for 60 min at room temperature, and then the binding reactions are terminated by rapid filtration on 96 well GF / B glass fiber filter plates (Packard BioScience Co., Meriden, CT) previously wetted in polyethylene imine. 0.3%. The filter plates are washed three times with filter buffer (ice-cooled 50 mM HEPES, pH7.4) to remove unbound radioactivity. Plates are dried, 35 μL of Microscint-20 liquid scintillation fluid (Packard BioScience Co., Meriden, CT) is added to each well and plates are counted in a Packard Topcount liquid scintillation counter (Packard BioScience Co., Meriden , CT). Link data is analyzed by non-linear regression analysis with the GraphPad Prism Software package (GraphPad Software, Inc., San Diego, CA) using the parameter model 3 for site competition. The FUND (minimum curve) is set to the value for non-specific binding, as determined in the presence of 1 μM GR113808. The values K¡. for test compounds are calculated, in Prism, of the IC50 values best placed, and the Kd value of the radioligand, using the Cheng-Prusoff equation (Cheng and Prusoff, Biochemical Pharmacology, 1973, 22, 3099-108): K = IC50 / (1 + [L] / Kd) where [L] = concentration [3H] -GR113808. The results are expressed as the negative decadic logarithm of the K ± values, pKi. The test compounds having a higher pKi value in this assay have a higher binding affinity for the 5-HT receptor. The compounds of the invention that are tested in this assay have a pK value in the range from about 6.3 to about 9.0, typically in the range from about 7.0 to about 8.6.

Example 48: Radioligand Linkage Assay in Human Receptors 5-HT3A: Determination of Selectivity of the Receptor Subtype a. Preparation of Membrane 5-HT3A HEK-293 cells (human embryonic kidney) stably transfected with human 5-HT3A receptor cDNA are obtained from Dr. Michael Bruess (University of Bonn, ALE) (Bmax = ~ 9.0 pmol / mg protein, as is determined using membrane radioligand binding assay [3H] -GR65630). Cells are grown in T-225 flasks or cell factories in 50% Dulbecco Modified Eagles Medium (DMEM) (GIBCO-Invitrogen Corp., Carlsbad, CA: Cat # 11965) and 50% Ham F12 (GIBCO- Invitrogen Corp.: Cat # 11765) supplemented with 10% heat-inactivated fetal bovine serum (FBS) (Hyclone, Logan, UT: Cat # SH30070.03) and (50 units) penicillin- (50 μg) streptomycin / ml (GIBCO-Invitrogen Corp.: Cat # 15140) in a humidified incubator with 5% C0 at 37 ° C. The cells are grown to approximately 70-80% confluence (<; 35 subculture passages). All stages of the membrane preparation are carried out on ice. To harvest the cells, the medium is aspirated and the cells are rinsed with Ca2 +, buffered saline in Mg2 + free Dulbecco's phosphate (dPBS). The cell monolayer is raised by gentle mechanical agitation. The cells are collected by centrifugation at 1000 rpm (5 min). The subsequent steps of the membrane preparation follow the protocol described above for the membranes expressing the 5-HT4 receptors (C). b. Radioligand Linkage Assay Radioligand linkage assays are performed on 96-well polypropylene assay plates in a total assay volume of 200 μL containing 1.5-2 μg membrane protein in 50 mM HEPES pH 7.4, containing buffer solution of 0.025% BSA test. Saturation binding studies for determination of the radioligand Kd values were performed using [3 H] -GR65630 (PerkinElmer Life Sciences Inc., Boston, MA: Cat # NET1011, specific activity ~ 85 • Ci / mmol) at twelve different concentrations in the range from 0.005 nM to 20 nM. The displacement tests for determination of pKi values. of compounds were made with [3 H] -GR65630 at 0.50 nM and eleven different concentrations of the compound in the range from 10 pM to 100 μM. Compounds are received as 10 mM stock solutions in DMSO (see section 3.1), diluted to 400 μM in '50 mM HEPES pH 7. 4 at 25 ° C, containing 0.1% BSA, and then serial dilutions (1: 5) are made in the same buffer solution. The non-specific binding is determined in the presence of 10 μM of unlabeled MDL72222. The assays are incubated for 60 min at room temperature, then the binding reactions are terminated by rapid filtration on 96 well GF / B glass fiber filter plates (Packard BioScience Co., Meriden, CT) previously wetted in 0.3% polyethylenimine. %. The filter plates are washed three times with filter buffer (ice-cooled 50 mM HEPES, pH7.4) to remove unbound radioactivity. The plates are dried, 35 μL of Microscint-20 liquid scintillation fluid (Packard BioScience Co., Meriden, CT) is added to each well and plates are counted in a Packard Topcount liquid scintillation counter (Packard BioScience Co., Meriden , CT). The link data is analyzed using the non-linear regression procedure described above to determine K¿ values. The FUND (minimum curve) is set to the value for non-specific binding, as determined in the presence of MDL72222 10 μM. The quantity [L] in the Cheng-Prusoff equation is defined as the concentration [3H] -GR65630. The selectivity for the subtype of the 5-HT4 receptor with respect to the subtype of the 5-HT3 receptor is calculated as the K¿ (5-HT3A) / K¿ (5-HT4 (C)) ratio. The compounds of the invention that are tested in this assay have a selectivity to the 5-HT4 / 5-HT3 receptor subtype in the range from about 25 to about 4000, typically in the range from about 100 to about 4000.

Example 49: Accumulation Plate Assay of Full-Cell CAMP with HEK-293 Cells Expressing Human 5-HT4 (C) Receptors In this test, the functional potency of the test compound is determined by measuring the amount of cyclic AMP produced when the HEK-293 cells expressing the 5-HT4 receptors are contacted with different concentrations of the test compound. to. Cell Culture Cells HEK-293 (human embryonic kidney) stably transfected with cloned human 5-HT4 (c) cDNA were prepared so that they express the receptor at two different densities: (1) at a density of about 0.5-0.6 pmol / mg protein, as determined using a membrane radioligand binding assay [3H] -GR113808, and (2) at a density of about 6.0 pmol / mg protein. Cells are grown in T-225 flasks in Dulbecco's Modified Eagles (DMEM) medium containing 4,500 mg / L of D-glucose (GIBCO-Invitrogen Corp.: Cat # 11965) supplemented with 10% fetal bovine serum ( FBS) (GIBCO-Invitrogen Corp .: Cat # 10437) and (100 units) penicillin- (100 μg) streptomycin / ml (GIBCO-Invitrogen Corp.: Cat # 15140) in a 5% C02 humidifier incubator at 37 ° C C. The cells are grown under continuous selection pressure by the addition of geneticin (800 μg / mL: GEBCO-Invitrogen Corp.: Cat # 10131) to the medium. b. Cell Preparation The cells are grown to approximately 60-80% confluency. Twenty to twenty-two hours before the rehearsal, the cells are washed twice, and fed, with serum-free DMEM containing 4,500 mg / L of D-glucose (GIBCO-Invitrogen Corp.: Cat # 11965). To harvest the cells, the medium is aspirated and 10 mL of Versene (GIBCO-Invitrogen Corp .: Cat # 15040) was added to each T-225 flask. The cells were incubated for 5 min at room temperature and then discharged from the flask by mechanical agitation. The cell suspension is transferred to a centrifuge tube containing an equal volume of previously heated dPBS (37 ° C) and centrifuged for 5 min at 1000 rpm. The supernatant is discarded and the pellet is resuspended in previously heated stimulation buffer (37 ° C) (10 mL equivalent for 2-3 T-225 flasks). This time is noted and marked as zero time. The cells were counted with a Coulter counter (count above 8 μm, the yield of the flask was 1-2 x 107 cells / flask). The cells are resuspended at a concentration of 5 x 10 5 cells / ml in previously heated stimulation buffer (37 ° C) (as provided in the instant plate kit) and pre-incubated at 37 ° C for 10 min. . The cAMP assays are performed in a radioimmunoassay format using the instantaneous plate adenylyl cyclase activation assay system with 125 I-cAMP (SMP004B, PerkinElmer Life Sciences Inc., Boston, MA), in accordance with the manufacturer's instructions. The cells are grown and prepared as described above. The final cell concentrations in the assay were 25 x 103 cells / well and the final assay volume was 100 μL. Test compounds are received as 10 mM stock solutions in DMSO, diluted to 400 μM in 50 mM HEPES pH 7.4 at 25 ° C, containing 0.1% BSA, and then serial dilutions (1: 5) are made in the same buffer solution. The cyclic AMP accumulation assays were performed with 11 different concentrations of the compound in the range from 10 pM to 100 μM (final assay concentrations). The 5-HT concentration response curve (10 pM to 100 μM) is included in each plate. The cells are incubated, with shaking, at 37 ° C for 15 min and the reaction is terminated by the addition of 100 μl of ice-cold detection solution (as provided in the flash plate kit) to each well. The plates are sealed and incubated at 4 ° C overnight. The bound radioactivity was quantified by scintillation proximity spectroscopy using the Topcount (Packard BioScience Co., Meriden, CT). The amount of cAMP produced per mL of reaction is extrapolated from the standard cAMP curve, in accordance with the instructions provided in the manufacturer's user manual. The data is analyzed by non-linear regression analysis with the GraphPad Prism Software package using the 3-parameter sigmoidal dose response model (pending contracted for unit). The power data are reported as pEC50 values, the negative decadic logarithm of the EC5o value, where EC5o is the effective concentration for a 50% maximum response. Test compounds exhibiting a higher value in this assay have a higher potency to agonize the 5-HT4 receptor. The compounds of the invention that are tested in this assay, for example, in the cell line (1) that have a density of about 0.5-0.6 pmol / mg protein, have a value pECso in the range from about 6.3 to about of 9.0, typically in the range from about 7.5 to about 8.5.

Example 50: In vitro Voltage Clamp Test of Potassium Ion Current Inhibition in Whole Cells Expressing the Cardiac Potassium Channel hERG CHO-K1 cells stably transfected with hERG cDNA from Gail Robertson are obtained at the University of Wisconsin. The cells are kept in cryogenic storage until it is necessary. The cells are expanded and passed in Dulbecco's Modified Eagles / F12 medium supplemented with 10% fetal bovine serum and 200 μg / mL of geneticin. Cells are seeded on poly-D-lysine coated glass slides (100 μg / mL), in 35 mm2 dishes (containing 2 mL of medium) at a density that allows isolated cells to be selected for voltage studies closed of complete cell. The dishes are kept in an environment of C02 at 5%, humidified at 37 ° C. The extracellular solution is prepared at least every 7 days and stored at 4 ° C when not in use. The extracellular solution contains (mM): NaCl (137), KCl (4), CaCl2 (1.8), MgCl2 (1), Glucose (10), 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid (HEPES) (10), pH 7.4 with NaOH. The extracellular solution, in the absence or presence of the test compound, is stored in reservoirs, from which it is flowed in the recording chamber at approximately 0.5 mL / min. The intracellular solution is prepared, aliquoted and stored at -20 ° C until the day of use. The intracellular solution contains (mM): KCl (130), MgCl2 (1), salt of ethylene glycol bis (beta-aminoethyl ether) N, N, N ', N' -tetraacetic acid (EGTA) (5), MgATP (5), 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid (HEPES) (10), pH 7.2 with KOH. All the experiments were carried out at room temperature (20-22 ° C).

The slides in which the cells are seeded are transferred to a recording chamber and continuously refuted. Gigaohm seals are formed between the cell and the patch electrode. Once a stable patch is reached, registration begins in closed voltage mode, with an initial waiting potential at -80 mV. After the stable whole cell current is reached, the cells are exposed to the test compound. The standard voltage protocol was: stage of the waiting potential from -80 mV to +20 mV for 4.8 sec, repolarization to -50 mV for 5 sec and then return to the original waiting potential (-80 mV). This voltage protocol is run once every 15 sec (0.067 Hz). The peak current amplitudes during the repolarization phase are determined using the pClamp software. Test compounds at a concentration of 3 μM are perfused over the cells for 5 minutes, followed by a 5 minute washout period in the absence of the compound. Finally, the positive control (cisapride, 20 nM) was added to the perfusion product to test the function of the cell. The stage from -80 mV to +20 mV activates the hERG channel, which results in an outward current. The stage returns to -50 mV resulting in an outward tail current, as the channel recovers from inactivation and is deactivated. The peak current amplitudes during the repolarization phase are determined using the pCLAMP software. The control data and test article are exported to the Origin® (OriginLab Corp., Northampton MA) where the individual current amplitudes are normalized to the initial current amplitude in the absence of the compound. The normalized current averages and standard errors for each condition are calculated and grouped against the time course of the experiment. Comparisons are made between the K + current inhibitions observed after the five-minute exposure to either the test item or vehicle control (usually 0.3% DMSO). Statistical comparisons between the experimental groups are made using an independent t-test, from two populations (Microcal Origin v. 6.0).

The differences are important to p < 0.05. The smaller the percentage of inhibition for the potassium ion current in this assay, the smaller the potential for test compounds to change the cardiac repolarization pattern when used as therapeutic agents. The compounds of the invention that are tested in this assay at a concentration of 3 μM exhibit an inhibition of the potassium ion current of less than about 20%, typically, less than about 15%.

Example 51: In vitro Model of Oral Bioavailability: Caco-2 Permeation Assay The Caco-2 Permeation Assay was performed for the ability model of the test compounds to pass through the intestine and remain in the bloodstream after administration. oral administration. The ratio at which the test compounds in the solution permeates the cell monolayer designed to mimic the tight junction of the monolayers of the human small intestine is determined. Caco-2 cells (colon, adenocarcinoma, human) are obtained from the ATCC (American Type Culture Collection, Rockville, MD). For the permeation study, the cells are seeded at a density of 63,000 cells / cm2 in polycarbonate filters from previously wetted transverse wells (Costar, Cambridge, MA). The cell monolayer is formed after 21 days in culture. After cell culture in the transverse well plate, the membrane containing the cell monolayer is removed from the transverse well plate and inserted into the diffusion chamber (Costar, Cambridge, MA).

The diffusion chamber is inserted in the heating block that is equipped with external circulation water, thermostatically regulated at 37 ° C for temperature control 95% 02/5% C02 to each half of the diffusion chamber and a laminar flow pattern is created through the cell monolayer, which is effective to reduce the limit layer without shaking. The permeation study was performed with concentrations of test compound at 100 μM and with 14C-mannitol to monitor the integrity of the monolayer. All experiments are conducted at 37 ° C for 60 min. Samples are taken at 0, 30 and 60 min from the sides both donor and receiver of the camera. The samples are analyzed by HPLC or liquid scintillation counting for the test compound and mannitol concentrations. The permeation coefficient (Kp) in cm / sec was calculated. In this test, the Kp value greater than about 10 x 10"6 cm / sec is considered to indicate favorable bioavailability The compounds of the invention tested in this assay exhibit Kp values of between about 15 x 10" 6 cm / sec and about 50 x 10"6 cm / sec, typically between about 20 x 10 ~ 6 cm / sec and about 40 x 10 ~ 6 cm / sec.

Example 52: Rat Pharmacokinetic Study Aqueous solution formulations of the test compounds are prepared in 0.1% lactic acid at a pH between about 5 and about 6. Male Sprague-Dawley rats are dosed (CD strain, Charles River Laboratories, Wilmington, MA) with test compounds by intravenous (IV) administration at a dose of 2.5 mg / kg or by oral priming (PO) at a dose of 5 mg / kg. The dosage volume was 1 mL / kg for IV and 2 mL / kg for PO administration. Blood samples are collected in series of previously dosed animals, and at 2 (only IV), 5, 15, and 30 min, and at 1, 2, 4, 8, and 24 hours after the dose. The concentrations of the test compounds in the blood plasma were determined by mass spectrometry-liquid chromatography (LC-MS / MS) analysis (MDS SCIEX, API 4000, Applied Biosystems, Foster City, CA) with a lower limit of quantification of 1 ng / mL. Standard pharmacokinetic parameters are evaluated by non-computational analysis (Model 201 for IV and Model 200 for PO) using WinNonlin (Version 4.0.1, Pharsight, Mountain View, CA). The maximum in the curve of the concentration of the test compound in the blood plasma vs. Cmax is denoted. The area under the concentration curve vs. Time from the dosing time for the last measurable concentration (AUC (0-t)) is calculated by the linear trapezoidal rule. Oral bioavailability (F (%)), that is, the normalized dose ratio of AUC (0-t) per PO administration for AUC (0-t) per IV administration, is calculated as: F (%) = AUCPo / AUCIV x DosageIV / DosiSp0 x 100% Test compounds that exhibit larger values of the Cm ?, AUC (0-t), and F (%) parameters in this assay are expected to have greater bioavailability when administered orally. The compounds of the invention that are tested in this assay have Cmax values in the range from about 0.05 to about 0.35 μg / mL, typically ranging from about 0.1 to about 0.35 μg / mL and AUC values (0 -t) in the range from about 0.15 to about 0.8 μg-hr / mL, typically in the range from about 0.25 to about 0.8 μg-hr / mL. By way of example, the compound of Example 1 has a Cmax value of 0.25 μg / mL, an AUC value (0-t) of 0.73 μg-hr / mL and oral bioavailability (F (%)) in the rat model of around 100%. Although the present invention has been described with reference to specific embodiments thereof, it will be understood by those skilled in the art that various changes and equivalents may be made without departing from the real spirit and scope of the invention. In addition, many modifications can be made to adapt a particular situation, material, composition of matter, process, step or stages of the process, to the purpose, spirit and scope of the present invention. All modifications are intended to be within the scope of the claims appended thereto. Additionally, all publications, patents, and patent documents cited above are incorporated by reference herein in their entirety, as if they will be incorporated individually by reference. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims

CLAIMS Having described the invention as above, the content of the following claims is claimed as property. 1. A compound of the formula (I): characterized in that: R1 is hydrogen, halo, hydroxy, C4_4alkyl or C4_4alkoxy; R2 is C3_alkyl, or C3-cycloalkyl; and W is selected from: (i) a group of the formula (II): wherein X is: NC (0) R wherein R is C? _3 alkyl or tetrahydrofuranyl, wherein C? _3 alkyl is optionally substituted with -OH or C? _3 alkoxy; S (0) 2; or NS (0) 2Rb, wherein Rb is methyl, optionally substituted with -OH, C? _3alkoxy, C5-6 cycloalkyl, or -S (O) 2-C? _3alkyl; (ii) a group of the formula (III): wherein: (JLll R? is -OH or C3_3alkoxy; P is 0 or 1; n is 1 or 2; and Y is: RcC (0) Rd, where Rc is hydrogen or C? _3 alkyl and Rd is C C _3 alkyl optionally substituted with -OH or C? _3 alkoxy, or NReS (0) 2Rf, wherein R8 is hydrogen and Rf is C1-3 alkyl, optionally substituted with -OH, C1-3 alkoxy, C5-6 cycloalkyl or -S (0) 2-C3_3alkyl; AND (iii) a group of the formula (IV): where: (IV) Rz is hydrogen, C3_3alkyl, or C2_3alkyl substituted with -OH or C1-3alkoxy; neither is 1 or 2; q is 1 or 2, with the proviso that the sum of m and q is not equal to 4; and Z is: NC (0) Rg, wherein Rg is C? _3 alkyl, optionally substituted with -OH or C? _3 alkoxy, S (0) 2; or NS (0) 2Rh, wherein Rh is methyl, optionally substituted with -OH, C?-C3 alkoxy, C5-6 cycloalkoxy, or -S (O) 2-C ?3 alkyl; or a pharmaceutically acceptable salt or solvate or stereoisomer thereof.
2. The compound according to claim 1, characterized in that R1 is hydrogen or halo.
3. The compound according to claim 1, characterized in that R2 is isopropyl or C4_5 cycloalkyl.
4. The compound according to claim 1, characterized in that W is a group of the formula (II).
5. The compound according to claim 4, characterized in that Ra is C? _3 alkyl and Rb is methyl.
6. The compound according to claim 1, characterized in that W is a group of the formula (III).
The compound according to claim 6, characterized in that p is 0.
8. The compound according to claim 6, characterized in that n is 1.
9. The compound according to claim 1, characterized in that it is a group of the formula (IV).
10. The compound according to claim 1, characterized in that m is 1 and q is 1.
The compound according to claim 1, characterized in that: R1 is hydrogen or halo; R2 is C3_alkyl or C_5cycloalkyl; and W is selected from the group consisting of: (i) a group of the formula (II) wherein X is NC (0) CH3, S (0) 2, or NS (0) 2CH3; (ii) a group of the formula (III) wherein p is 0, n is 1, and Y is NCH3C (0) CH3; And (iii) a group of the formula (IV) wherein Rz is methyl, m is 1, q is 1, and Z is NC (0) CH3, S (0) 2, or NS (0) 2CH3.
12. The compound according to claim 11, characterized in that W is a group of the formula (II) wherein X is NC (0) CH3, S (0) 2 or NS (0) 2CH3.
The compound according to claim 1, characterized in that the compound is selected from: { (1S, 3R, 5R) -8- [2- (4-acetylpiperazin-1-yl) -ethyl] -8-azabicyclo [3.2.1] oct-3-ylamide of 1-isopropyl-1H-indazole-3-acid carboxylic; . { (1S, 3R, 5R) -8- [2- (4- (tetrahydrofuran-2-carbonyl) piperazin-1-yl) ethyl] -8-azabicyclo [3.2. l] l-isopropyl-lH-indazole-3-carboxylic acid oct-3-illamide; . { (SS, 3R, 5R) -8- [2- (1,1-dioxo-l6-thiomorpholin-4-yl)) ethyl] -8-azabicyclo [3.2.1] oct-3-yl}. 1-isopropyl-lH-indazole-3-carboxylic acid amide; {. (ÍS, 3R, 5R) -8- [2- (4-methanesulfonyl-piperazin-1-yl) ethyl] -8-azabicyclo [3.2 .1] 1-isopropyl-1H-indazole-3-carboxylic acid oct-3-illamide; {. (IS, 3R, SR) -8- [2- (4-cyclohexylmethanesulfonylpiperazin-1-yl) ethyl] - 8-azabicyclo [3.2.-l] oct-3-illamide of 1-isopropyl-lH-indazole-3-carboxylic acid; . { (1S, 3R, 5R) -8- [1- (4-methanesulfonylmetanesulfonylpiperazin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-yl) amide of 1-isopropyl-lH-indazole- 3-carboxylic; . { (1S, 3R, 5R) -8- [2- (3- (Acetyl-methylamino) pyrrolidin-1-yl) ethyl] -8-azabicyclo [3.2. l] oct-3-il} 1-isopropyl-lH-indazole-3-carboxylic acid amide; . { (SS, 3R, 5R) -8- [2- (3- (acetylamino) pyrrolidin-1-yl) ethyl] -8-azabicyclo [3.2. l] 1-isopropyl-1H-indazole-3-carboxylic acid oct-3-illamide; . { (SS, 3R, 5R) -8- [2- ((R) -3- (acetylamino) pyrrolidin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-yl} 1-isopropyl-lH-indazole-3-carboxylic acid amide; . { (1S, 3R, 5R) -8- [2- ((S) -3- (Acetylamino) pyrrolidin-1-yl) ethyl] -8-azabicyclo [3.2.l] oct-3-ylamide of acid 1 -isopropyl-lH-indazole-3-carboxylic acid; ((1S, 3R, 5R) -8- {2- [3- ((S) -2- hydroxypropionylamino) pyrrolidinyl-1-yl] ethyl] -8-azabicyclo [3.2.1] oct-3 -l) 1-isopropyl-1H-indazole-3-carboxylic acid amide; ((ÍS, 3R, 5R) -8- { 2- [(3S, 4S) -3- (acetylmethylamino) -4- 5 hydroxypyrrolidin-1-yl] ethyl.}. -8-azabicyclo [3.2.1 l-isopropyl-lH-indazole-3-carboxylic acid] oct-3-yl) amide; . { (1S, 3R, 5R) -8- [2- ((R) -3-ethanesulfonylaminopyrrolidin-1-yl) ethyl] -8-azabicyclo [3.2. l] oct-3-il} 1- isopropyl-lH-indazole-3-carboxylic acid amide; 1.0. { (1S, 3R, 5R) -8- [2 - ((R) -3-cyclohexylmethanesulfonylaminopyrrolidin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-ylamide of 1-isopro-yl- lH-indazole-3-carboxylic acid; • ((1S, 3R, 5R) -8- { 2- [3- (acetyl-methylamino) piperidin-l-5-yl] ethyl} -8-azabicyclo [3.2.1] oct-3-yl. ) 1-isopropyl-lH-indazole-3-carboxylic acid amide; . { (1S, 3R, 5R) -8- [2- (3-Acetylaminopiperidin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-ylamide of 1-isopropyl-lH-indazol-3-acid carboxylic; 0 { (1S, 3R, 5R) -8- [2- (3-methanesulfonylaminopiperidin-1-yl) ethyl] -8-azabicyclo [3.2.l] oct-3-yl} 1- isopropyl-lH-indazole-3-carboxylic acid amide; . { (1S, 3R, 5R) -8- [2- ((S) -3-methanesulfonylaminopiperidin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-ylamide of the acid 1-isopropyl-1H -indazole-3-carboxylic acid; . { (SS, 3R, 5R) -8- [2- ((S) -3-ethanesulfonylaminopiperidin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-yl} 1- isopropyl-lH-indazole-3-carboxylic acid amide; . { (1S, 3R, 5R) -8- [2 - ((S) -3-methanesulfonylmetanesulfonylaminopiperidin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-yl] amide of 1-isopropyl- 1H-indazole-3-carboxylic acid; ((1S, 3R, 5R) -8-. {2- [(L-acetylpyrrolidin-3-yl) ethylamino] ethyl} - 8-azabicyclo [3.2.l] oct-3-yl) acid amide l-isopropyl-lH-indazole-3-carboxylic acid; ((1S, 3R, 5R) -8- { 2- [((R) -l-acetylpyrrolidin-3-yl) ethylamino] ethyl] -8-azabicyclo [3.2.1] oct-3-yl. ) 1-isopropyl-lH-indazole-3-carboxylic acid amide; ((1S, 3R, 5R) -8- {2- [((S) -l-acetylpyrrolidin-3-yl) ethylamino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl. ) l-isopropyl-lH-indazole-3-carboxylic acid amide; ((1S, 3R, 5R) -8-. {2- 2- [(1-methanesulfonylpyrrolidin-3-yl) methylamino] ethyl} - 8-azabicyclo [3.2.l] oct-3-yl) acid amide l-isopropyl-lH-indazole-3-carboxylic acid; ((1S, 3R, 5R) -8- { 2- [((R) -1-methanesulfonylpyrrolidin-3-yl) methylamino] ethyl]. 8-azabicyclo [3.2.1] oct-3-yl. ) 1-isopropyl-lH-indazole-3-carboxylic acid amide; ((ÍS, 3R, 5R) -8- {2- [(1, l-dioxo-tetrahydro-l6-thiophen-3-yl) methylamino] etill-8-azabicyclo [3.2.1] oct- 3-yl) l-isopropyl-lH-indazole-3-carboxylic acid amide; ((1S, 3R, 5R) -8- {2- [(1, 1-dioxo-tetrahydro-l6-thiophen-3-yl) - (2-hydroxyethyl) amino] ethyl.} -8 L-isopropyl-lH-indazole-3-carboxylic acid azabicyclo [3.2.1] oct-3-yl) amide; ((1S, 3R, 5R) -8-. {2- [(1-Acetylpiperidin-3-yl) methylamino] ethyl) -8-azabicyclo [3.2.1] oct-3-yl) -amide of l-acid isopropyl-lH-indazole-3-carboxylic acid; l-isopropyl-lH-indazole-3-carboxylic ((lS, 3R, 5R) -8-. {2- 2- (1,1-dioxo-hexahydro-l6-thiopyran-4-yl) methylamino] ethyl ) -8-azabicyclo [3.2.1] oct-3-yl) amide; ((1S, 3R, 5R) -8- {2- [(1-methanesulfonylpiperidin-3-yl) methylamino] ethyl} -8-azabicyclo [3.2.l] oct-3-yl) amide - - of l-isopropyl-lH-indazole-3-carboxylic acid; . { (SS, 3R, 5R) -8- [2- (4-acetylpiperazin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-yl} 5-Fluoro-l-isopropyl-lH-indazole-3-carboxylic acid amide; . { (1S, 3R, 5R) -8- [2- (4-acetylpiperazin-1-yl) ethyl] -8-azabicyclo [3.2.l] oct-3-yl} 1-propyl-1H-indazole-3-carboxylic acid amide; ((1S, 3R, 5R) -8- [2- (4-acetylpiperazin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-yl.] 1-butyl-1H acid amide -indazole-3-carboxylic acid ((S, 3R, 5R) -8- [2- (4-acetylpiperazin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-yl} amide of 1-cyclobutyl-lH-indazole-3-carboxylic acid; ((SS, 3R, 5R) -8- [2- (4-acetylpiperazin-1-yl) ethyl] -8-azabicyclo [3.2.l] oct- 3-yl) 1-cyclopentyl-1H-indazole-3-carboxylic acid amide; ((SS, 3R, 5R) -8- [2- ((R) -3- (acetyl-methylamino) pyrrolidin-1-yl) ) ethyl] -8-azabicyclo [3.2.l] oct-3-yl.} - 1-isopropyl-lH-indazole-3-carboxylic acid amide; {. (1S, 3R, 5R) -8- [2 - (1-isopropyl-1H-indazole-3-carboxylic acid ((S) -3- (acetyl-methylamino) pyrrolidin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-yl) amide; - ((lS, 3R, 5R) -8- { 2- [((S) -1-methanesulfonylpyrrolidin-3-yl) methylamino] ethyl) -8-azabicyclo [3.2.1] oct-3-yl ) l-isopropyl-lH-indazole-3-carboxylic acid amide; ((lS, 3R, 5R) -8-. {2- [(R) - (1, l-dioxo-tetrahydro-l? 6) thiophen -3-yl) methylamino] ethyl} L-isopropyl-lH-indazole-3-carboxylic acid-8-azabicyclo [3.2.1] oct-3-yl) amide; l-isopropyl-lH-indazole-3-carboxylic acid ((SS, 3R, 5R) -8-. {2- 2- (S) - (1, l-dioxo-tetrahydro-l6-thiophen-3-yl) methylamino] ethyl.}. 8-azabicyclo [3.2.l] oct-3-yl) amide; and pharmaceutically acceptable salts and solvates and stereoisomers thereof.
14. The compound according to claim 1, characterized in that the compound is selected from:. { (1S, 3R, 5R) -8- [2- (4-acetylpiperazin-1-yl) -ethyl] -8-azabicyclo [3.2.1] oct-3-yl) 1-isopropyl-1H-indazole acid -3-carboxylic acid; . { (1S, 3R, 5R) -8- [2- (1, 1-dioxo-l6-thiomorpholin-4-yl) ethyl] -8- azabicyclo [3.2.1] oct-3-yl) acid amide l-isopropyl-1H-indazole-3-carboxylic acid; . { (SS, 3R, 5R) -8- [2- (4-methanesulfonyl-piperazin-1-yl) -ethyl] -8-azabicyclo [3.2.1] oct-3-yl} 1-isopropyl-lH-indazole-3-carboxylic acid amide; . { (SS, 3R, 5R) -8- [2- (3- (Acetylmethyl-amino) pyrrolidin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-ylamide of 1-isopropyl-1H -indazole-3-carboxylic acid; . { (SS, 3R, 5R) -8- [2- ((R) -3- (acetyl-methyl-amino) pyrrolidin-1-yl) ethyl] -8-azabicyclo [3.2.1] oct-3-yl) 1- isopropyl-lH-indazole-3-carboxylic acid amide; . { (SS, 3R, 5R) -8- [2- ((S) -3- (acetyl-methylamino) pyrrolidin-1-yl) ethyl] -8-azabicyclo [3.2.l] oct-3-ylamide of acid 1 -isopropyl-lH-indazole-3-carboxylic acid; . { (ΔS, 3R, 5R) -8- [l-isopropyl-1H-indazole [l-acetylpyrrolidin-3-yl] methylamino] ethyl] -8-azabicyclo [3.2.1] oct-3-ylamide -3-carboxylic acid; . { (ÍS, 3R, 5R) -8- [2- [((R) -l-acetyl-pyrrolidin-3-yl) ethylamino] ethyl] -8-azabicyclo [3.2.1] oct-3-yl-amide acid l-isopropyl-lH-indazole-3-carboxylic acid; . { (1S, 3R, 5R) -8- [2- [((S) -l-Acetyl-pyrrolidin-3-yl) ethylamino] ethyl] -8-azabicyclo [3.2. l] 1-isopropyl-lH-indazole-3-carboxylic acid oct-3-illamide; ((1S, 3R, 5R) -8-Í2- [(1-methanesulfonyl-pyrrolidin-3-yl) methylamino] ethyl] -8-azabicyclo [3.2.l] oct-3-yl) -amide of the acid -isopropyI-lH-indazole-3-carboxylic acid; ((1S, 3R, 5R) -8- { 2- [((R) -l-methanesulfonyl-pyrrolidin-3-yl) methylamino] ethyl]. 8-azabicyclo [3.2.1] oct-3 -l) l-isopropyl-lH-indazole-3-carboxylic acid amide; ((1S, 3R, 5R) -8- { 2- [((S) -1-methanesulfonyl-pyrrolidin-3-yl) methylamino] ethyl]. 8-azabicyclo [3.2.1] oct-3 -l) l-isopropyl-lH-indazole-3-carboxylic acid amide; ((1S, 3R, 5R) -8- [2- ((1, l-dioxo-tetrahydro-l6-thiophen-3-yl) methylamino) ethyl] -8-azabicyclo [3.2.1] oct-3 -yl.} - l-isopropyl-lH-indazole-3-carboxylic acid amide; ((1S, 3R, 5R) -8- [2- ((R) - (1, l-dioxo-tetrahydro-l) 1-6-thiophen-3-yl) methylamino) ethyl] -8-azabicyclo [3.2.1] oct-3-yl-amide of 1-isopropy1-1H-indazole-3-carboxylic acid;. (LS, 3R, 5R) -8- [2- ((S) - (1, l-dioxo-tetrahydro-l6-thiophen-3-yl) methylamino) ethyl] -8-azabicyclo [3.2.1] oct-3-ylamide of l-isopropyl-lH-indazole-3-carboxylic acid and pharmaceutically acceptable salts and solvates and stereoisomers thereof
15. The compound according to claim 1, characterized in that it has the chemical name ((1S, 3R, 5R) -8- [2- (4-acetylpiperazin-1-yl) ethyl] -8-aza-bicyclo [3.2.1] oct-3-illamide of l-isopropyl-1H-indazole-3-carboxylic acid; a pharmaceutically acceptable salt or solvate thereof
16. A pharmaceutical composition, characterized in that it comprises a therapeutical amount Effectively effective of the compound according to any one of claims 1 to 15 and a pharmaceutically acceptable carrier.
17. A compound according to claims 1 to 15, characterized in that it is for use in therapy.
18. The use of a compound according to any of claims 1 to 15 for the manufacture of a medicament.
19. The use according to claim 18, wherein the medicament is for the treatment of a medical condition in a mammal associated with 5-HT4 receptor activity.
20. The use according to claim 19, wherein the disease or condition is a disease of reduced mobility of the gastrointestinal tract.
21. A process for preparing a compound according to any of claims 1 to 15, characterized in that it comprises reacting a compound of the formula Or a salt or stereoisomer or protective derivative thereof with an amine of the formula H-W in the presence of a reducing agent to provide a compound of the formula (I) or a pharmaceutically acceptable salt or solvate or stereoisomer thereof.
22. The product characterized in that it is prepared by the processes according to claim 21.
23. A compound of the formula 5: characterized in that R1 is hydrogen, halo, hydroxy, C? _ alkyl, or C? _ alkoxy, and R2 is C3-4 alkyl, or C3_6 cycloalkyl, or a salt or stereoisomer or, protected derivative thereof.
24. A process for preparing a compound according to any of claims 1 to 15, characterized in that it comprises reacting a compound of the formula 2 With a compound of formula 10 10 under amida coupling conditions to provide a compound of the formula (I) or a pharmaceutically acceptable salt or solvate or stereoisomer thereof.
25. A process for preparing tert-butyl ester of (1S, 3R, 5R) -3-amino-8-azabicyclo [3.2. l] octane-8-carboxylic acid, characterized in that it comprises reacting tert-butyl ester of 3-oxo-8-azabicyclo [3.2.1] octane-8-carboxylic acid with at least 25 equivalents of amino formate in the presence of a transition metal catalyst to provide tert-butyl ester of (SS, 3R, 5R) -3-amino-8-azabicyclo [3.2.1] octane-8-carboxylic acid.
26. A method for the study of biological system or sample, characterized in that it comprises a 5 ~ HT4 receptor, comprises: (a) contacting the biological system or sample with a compound of any of claims 1 to 15; and (b) determining the effect caused by the compound in the biological system or sample.