MXPA06007168A - Indoles, 1h-indazoles, 1,2-benzisoxazoles, and 1,2-benzisothiazoles, and preparation and uses thereof - Google Patents

Abstract

The present invention relates generally to the field of ligands for nicotinic acetylcholine receptors (nAChR), activation of nAChRs, and the treatment of disease conditions associated with defective or malfunctioning nicotinic acetylcholine receptors, especially of the brain. Further, this invention relates to novel compounds for example, indoles, 1H-indazoles, 1,2-benzisoxazoles, and 1,2-benzisothiazoles, which act as ligands for the alpha7 nAChR subtype, methods of preparing such compounds, compositions containing such compounds, and methods of use thereof.

Description

INDONES, 1H-INDAZQLES, 1, 2-BENZYSOXAZQLES, AND 1,2- BENCISQTIAZQLES, AND PREPARATION AND USE OF THEMSELVES FIELD OF THE INVENTION The present invention relates generally to the field of ligands for nicotinic acetylcholine receptors (nAChR), activation of nAChRs, and the treatment of disease conditions associated with acetylcholine, nicotinic, defective or malfunctioning receptors. , especially of the brain. ' In addition, this information refers to new compounds, for example, Índoles, IH-indazoles, 1,2-bencisoxazoles, and 1,2-biscisothiazoles, which act as ligands for the nAChR subtype, methods for preparing these compounds, compositions comprising these compounds, and methods of using them.

BACKGROUND OF THE INVENTION There are two types of receptors for the neurotransmitter acetylcholine: muscarinic receptors and nicotinic receptors, based on the selectivity of action of the drug nicotine and nicotine, respectively. Muscarinic receptors are G-protein coupled receptors. Nicotinic receptors are members of the family of ion channels controlled by ligands. When activated, the conductance of the ions is increased through the nicotinic ion channels. The nicotinic alpha-7 receptor protein forms a homo-pentameric channel in vitro that is highly permeable to a variety of cations (eg, Ca ++). Each nicotinic alpha-7 receptor has four transmembrane domains, called Ml, M2, M3, and M4. The M2 domain has been suggested to form the wall that forms the channel. The sequence alignment shows that nicotinic alpha-7 is highly conserved during evolution. The M2 domain that was from the channel is identical in chicken-to-human protein sequence. For analysis of the alpha-7 receptor see, for example Revah et al. (1991), Nature, 353, 846-849; Galci et al-. (1992), Nature 359, 500-505; Fucile et al. (2000), PNAS 91. { tí), 3643-3648; Briggs et al. (1999), Eur. I Pharmacol. 366 (2-3), 301-308; and Gopala rishnan et al. (1995), Eur. J Pharmacol. 290 (3), 237-246. The nicotinic alpha-7 receptor channel is expressed in several brain regions and is believed to be involved in many important biological processes in the central nervous system (C? S), including learning and memory. The nicotinic alpha-7 receptors are located in both presynaptic and post-synaptic terminals and it has been suggested that they are included in the modulation of synaptic transmission. Therefore, it is of interest to develop new compounds, which act as ligands for the nAChR subtype a7, for the treatment of disease conditions associated with acetylcholine, nicotinic, defective or malfunctioning receptors.

BRIEF DESCRIPTION OF THE INVENTION This invention relates to novel compounds that act as ligands for nAChR subtype a, 7, methods for preparing these compounds, compositions comprising these compounds, and methods and use thereof.

DETAILED DESCRIPTION OF THE INVENTION The present invention includes compounds of the Formulas II, II, or III: where A is -CH2-, or B is And it is 0 or S; X1 to X4 are each, independently, CH, CR1, or N, wherein at most one of X1 to X4 is N; X5 to X8 are each, independently, CH, CR2, or N, wherein at most one of X5 to X8 is N; X9 to X12 are each, independently, CH, CR3, or N, wherein at most one of X9 to X12 is N; R1, R2 and R3 are each, independently, H, C? -6-alkyl (eg, CH3) which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, OH, alkoxy have from 1 to 4 carbon atoms (eg, 0CH3), NRRS, SH, SR4, SOR4, C3-8-cycloalkyl, S02R4, S02NR4R5, Ar, Het, or combinations thereof, C2-6 ~ alkenyl which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, OH, alkoxy having from 1 to 4 carbon atoms (eg, 0CH3), NR4R5, SH, SR4, SOR4, C3-8-cycloalkyl , S02R4, S02NR4R5, Ar, Het, or. combinations thereof, C2_6-alkynyl which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, OH, alkoxy having from 1 to -4 carbon atoms (eg, OCH3), NRR5, SH, SR4, SOR4, C3.8- cycloalkyl, S02R4, S02NR4R5, Ar, Het, or combinations thereof, 'C3_8-cycloalkyl which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms (eg, OCH 3), NRR5, SH, SR4, SOR4, C3-8-unsubstituted cycloalkyl, S02R4, S02NR4R5, Ar, Het, or combinations thereof, halogen (e.g., F, Cl, Br, I,) CN, N02, NR4R5, SH, SR4, SOR4, S02R4, S02NR4R5, NR4S02R5, CONR4R5, COOR4, NR4COR? , NR4C02R5, NR4CONRR5, Ar, Het, or R60-; - 'R4 and R5 are each independently H or Ar, Ar-C? -4-alkyl, Het, Ci_4-alkyl (e.g.

CH3), C3-8-cycloalkyl (for example, cyclopropyl), or C4-8-cycloalkylalkyl (for example, cyclopropylmethyl), each of which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, OH, alkoxy having from 1 to 4 carbon atoms (eg, 0CH3), monoalkylamino, dialkylamino (eg, diethylamino), C3.8-cycloalkyl, or combinations thereof, R6 is H, Cx- g-alkyl (e.g., CH3) which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, OH, alkoxy having from 1 to 4 carbon atoms (eg, OCH3), NRR5, SH, SR4, SOR4, C3-8-cycloalkyl, S02R4, S02NR4R5, Ar, Het, or combinations thereof, C3.6-alkenyl which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, OH, alkoxy having from 1 to 4 carbon atoms ( for example, OCH3), NR4R5, SH, SR4, SOR4, C3,8-cycloalkyl, S02R4, S02NRR5, Ar, Het, or combinations thereof, C3-6-alkynyl which is unsubstituted or substituted one or more times by F , Cl, Br, I, CN, OH, alkoxy having from 1 to 4 carbon atoms (e.g., OCH3), NRR5, SH, SR4, SOR4, C3-8-cycloalkyl, S02R4, S02NR4R5, Ar, Het, or combinations thereof, ~ • C3-8-cycloalkyl which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN , OH, alkoxy having from 1 to 4 carbon atoms (e.g., OCH 3), NRR5, SH, SR4, SOR4, C3-8-unsubstituted cycloalkyl, S02R4, S02NRR5, Ar, Het, or combinations thereof, C4.8-cycloalkylalkyl which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, OH, alkoxy having from 1 to 4 carbon atoms ( for example, OCH3), NR4R5, SH, SR4, SOR4, C3.8-unsubstituted cycloalkyl, S02R4, S02? RR5, Ar, Het, or combinations thereof,? r, o -Het; R7 is H, or C? _4-alkyl (eg, CH3) which is unsubstituted or substituted one or more times by F, Cl, Br, I, C ?, OH, alkoxy having from 1 to 4 carbon atoms ( for example, OCH3),? R4R5, or combinations thereof; m is 1, 2 or 3; Ar is an aryl group containing from 6 to 10 carbon atoms which is unsubstituted or substituted one or more times by alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 8 carbon atoms, halogen (F, Cl, Br, or i, preferably F or Cl), dialkylamino, wherein the alkyl portions each have 1 to 8 carbon atoms, amino, cyano, hydroxyl, nitro, halogenated alkyl having 1 to 8 atoms carbon, halogenated alkoxy having 1 to 8 carbon atoms, hydroxyalkyl having 2 to 8 carbon atoms, hydroxyalkoxy having 2 to 8 carbon atoms, alkenyloxy having 3 to 8 carbon atoms, alkylthio it has from 1 to 8 carbon atoms, alkylsulfinyl having from 1 to 8 carbon atoms, alkylsulfonyl having from 1 to 8 carbon atoms, monoalkylamino having from 1 to 8 carbon atoms, cycloalkylamino wherein the cycloalkyl group has from 3 to 7 carbon atoms and is optionally substituted, aryloxy wherein the aryl portion contains from 6 to 10 carbon atoms (eg, phenyl, naphthyl, biphenyl) and is optionally substituted, arylthio wherein the aryl portion contains from 6 to 10 carbon atoms (per axis) mplo, phenyl, naphthyl, biphenyl) and is optionally substituted, cycloalkyloxy wherein the cycloalkyl group has from 3 to 7 carbon atoms and is optionally substituted, sulfo, sulfonylamino, acylamido (eg, acetamido), acyloxy (e.g. acetoxy), carboxy, alkoxycarbonyl, alkylaminocarbonyl or combinations thereof; and Het is a heterocyclic group, which is fully saturated, partially saturated or completely unsaturated, having from 5 to 10 ring atoms in which at least 1 ring atom is "ü? N, O or S atom, which is unsubstituted or substituted one or more times by halogen (F, Cl, Br, or I, preferably F or Cl), aryl having from 6 to 10 carbon atoms (eg, phenyl, naphthyl, biphenyl) and is optionally substrates, arylalkyl having from 6 to 10 carbon atoms in the aryl portion and from 1 to 4 carbon atoms in the alkyl portion, a heterocyclic group, which is fully saturated, partially saturated or completely unsaturated, and having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 8 carbon atoms, cyano, trifluoromethyl, nitro, oxo, amino, monoalkylamino having 1 to 8 carbon atoms, dialkyl amino in which each alkyl group has from 1 to 8 carbon atoms, alkoxycarbonyl, alkylaminocarbonyl, or combinations thereof; and pharmaceutically acceptable salts thereof. According to a further embodiment, in Formulas I, II, and III, R4 and R5 are each independently H, Ar, Het, or C? -4-alkyl (e.g., CH3) which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, OH, alkoxy having from 1 to 4 carbon atoms (e.g., OCH3), monoalkylamino, dialkylamino (e.g., diethylamino), C3.8-cycloalkyl or combinations of the same, and R1, R2, and R3 are not NR4C02R? or NR4CONR4R5. ~ Alkyl means from start to finish a straight chain or branched chain aliphatic hydrocarbon radical preferably having 1 to 4 carbon atoms. Suitable alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl. Alkoxy means alkyl-O- groups in which the alkyl portion preferably has 1 to 4 carbon atoms. Suitable alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, and sec-butoxy. Cycloalkyl means a saturated cyclic, bicyclic or tricyclic hydrocarbon radical having from 3 to 8 carbon atoms. Suitable cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Other suitable cycloalkyl groups include spiropentyl, bicyclo [2.1.0] pentyl, and bicyclo [3.1. Ojhexilo. The cycloalkyl groups may be substituted by C 4 -4 alkyl, C 4 4 alkoxy, hydroxy, amino, monoalkylamino having 1 to 4 carbon atoms, and / or dialkylamino in which each alkyl group has 1 to 4 carbon atoms. Cycloalkylalkyl refers to cycloalkyl-alkyl radicals in which the cycloalkyl and alkyl portions are in accordance with the above analyzes. Suitable examples include cyclopropylmethyl and cyclopentylmethyl. -Aryl, as a group or substituent per se or as part of a substituent group, refers to an aromatic carbocyclic radical containing from 6 to 10 carbon atoms, unless otherwise indicated. Suitable aryl groups include phenyl, naphthyl and biphenyl. Substituted aryl groups include the aryl groups described above which are substituted one or more times by halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, and acyloxy (for example, acetoxy). Arylalkyl refers to an aryl-alkyl radical in which the aryl and alkyl portions are in accordance with the above descriptions. Suitable examples include benzyl, 1-phenethyl, 2-phenethyl, phenpropyl, phenbutyl, phenpentyl, and naphthylmethyl. Ar-alkyl is also an arylalkyl radical in which the aryl portion is in accordance with the above description of Ar. Suitable examples include benzyl and fluorobenzyl. Heterocyclic groups refer to saturated heterocyclic groups, partially saturated and completely unsaturated, having one, two or three rings and a total number of 5 to 10 ring atoms wherein at least one of the ring atoms is an N, O or S atom. Preferably, the The heterocyclic group contains from 1 to 3 ring heteroatoms selected from N, O and S. Suitable heterocyclic, saturated and partially saturated groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, isoxazolinyl, and the like. . Suitable heteroaryl groups include, without limitation, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, isoquinolinyl, naphthyridinyl, and the like. Other examples of suitable heterocyclic groups are 2-quinolinyl, 1,3-benzodioxyl, 2-thienyl, 2-benzofuranyl, 2-benzothiophenyl, 3-thienyl, 2,3-dihydro-5-benzofuranyl, 4-indoyl, 4-pyridyl. , 3-quinolinyl, 4-quinolinyl, 1,4-benzodioxan-6-yl, 3-indoyl, 2-pyrrolyl, 3, 4-1, 2-benzopyran-6-yl, 5-indolyl, 1,5-benzoxepin -8-yl, 3-pyridyl ', -6-coumarinyl, 5-benzofuranyl, 2-isoimidazol-4-yl, 3-pyrazolyl, and 3-carbazolyl. Substituted heterocyclic groups refer to the heterocyclic groups described above, which are substituted at one or more places by, for example, halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, and dialkylamino. Radicals which are substituted one or more times preferably have 1 to 3 substituents, especially 1 to 2 substituents of the exemplified substituents. Halogenated radicals such as halogenated alkyls are preferably fluorinated and include perhalo radicals such as trifluoromethyl. In the compounds of Formula I, R1 is preferably H, ORG, NR4R5, NR4COR5, NR4CONR4R5, CF3, Br, thienyl which is unsubstituted or substituted (eg, 2-thienyl, 3-thienyl, and methylthienyl such as 2- (4-methyl) thienyl and 2- (5-methyl) thienyl), furyl which is unsubstituted or substituted (e.g., 2-furyl, 3-furyl, and methylfuryl such as 2- (5-methyl) furyl), phenyl which is unsubstituted. or replaced (for example, fluorophenyl such as 3-fluorophenyl and 4-fluorophenyl), methoxyphenyl such as 4-methoxyphenyl, thiazolyl such as 2-thiazolyl, 2- (4-methyl) thiazolyl, and 2- (5-methyl) thiazolyl, oxazolyl such as 2-oxazolyl, and pyranyl such as 4-tetrahydropyranyl and 3,6-dihydro-pyran-4-yl). In the compound of Formula II, R2 is preferably H, OR6, CF3, Br, thienyl which is unsubstituted or substituted (e.g., 2-thienyl, 3-thienyl, and methylthienyl such as 2- (4-methyl) thienyl and 2- (5-methyl) thienyl), furyl which is unsubstituted or substituted (eg, 2-furyl, 3-furyl and methylfuryl such as 2- (5-methyl) furyl), or phenyl which is unsubstituted or substituted (for example, fluorophenyl such as 3-fluorophenyl and 4-fluorophenyl and methoxyphenyl such as 4-methoxyphenyl). In the compounds of Formula III, R3 is preferably H, cyclopropyl, or OR6. R 4 is preferably H or methyl, and R 5 is preferably H, methyl, cyclopropyl, cyclopentyl, cyclopropylmethyl, propyl or Ar-methyl. Rs is preferably methyl, ethyl, CF3, CHF2, cyclopentyl or cyclopropylmethyl. R7 is preferably H, methyl, or ethyl. In the compounds of Formulas I, II, and III, A is preferably -CO-. Also, in the compounds of Formulas II, II, and III, m is preferably 1 or 2. Ar is preferably phenyl which is unsubstituted or substituted (eg, fluorophenyl such as 3-fluorophenyl and 4-fluorophenyl, and methoxyphenyl such as 4-methoxyphenyl). Het is preferably thi-enyl which is unsubstituted or substituted (for example, 2-thienyl, 3-thienyl and methylthienyl such as 2- (4-methyl) thienyl and 2- (5-methyl) thienyl), or furyl which is unsubstituted or substituted (for example, 2-furyl, 3-furyl, and methylfuryl such as 2- (5-methyl) furyl). In Formula I, each of X1 through X4 is preferably CH or CR1. In Formula II, each of X4 to X8 is preferably CH or CR2. In Formula II -? -, - each of X9 to X12 are preferably CH or CR3. According to an aspect of compounds of the invention, the compounds of Formulas I, II and III are selected from: 3- [(1S, 4S) -2,5-Diazabicyclo [2.2.1] -hept-2 Hydrochloride -carbonyl] -IH-indazole, Hydroformate of 3-. { [(1S, 4S) -5-Methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1, 2-benzisothiazole, 3-. { [(SS, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1, 2-benzisothiazole, Hydroformate of 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2. l] hept-2yl] carbonyl} -5- (trifluoromethoxy) -1H-indazole, Hydroformate of 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} -6- (trifluoromethyl) -1H-indazole, 5-Bromo-3- [(1S, 4S) -2,5-diazabicyclohydrochloride [2.2. l] hept-2-ylcarbonyl] -IH-indazole, Hydrochloride of 5-Methoxy-3-. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.l] hept-2-yl] carbonyl} -lH-indazole, 6-Bromo-3- [(1S, 4S) -2,5-diazabicyclohydrochloride [2.2. l] hept-2-ylcarbonyl] -IH-indazole, 6-Ethoxy-3- Hydroformate. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1,2-benzisothiazole, Hydroformate of, 6-methoxy-3-. { [(ÍS, 4S) -5-metei.l-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} - !, 2-benzisothiazole, 6-methoxy-3-. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} -1, 2-benzisothiazole, Hydroformate of 7-methoxy-3-. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1, 2-benzisothiazole, Hydroformate of 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} -5- (2-thienyl) -lH-indazole, Hydroformate of 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -5- (4-methyl-2-thienyl) -1H-indazole, Hydroformate of 3-. { [(1S, 4S) -5-Methyl-2,5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} -5- (5-methyl-2-thienyl) -1H-indazole, Hydroformate of 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} -5-phenyl-1H-indazole, Hydroformate 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (2-thienyl) -1H-indazole, Hydroformate of 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (3-thienyl) -IH-indazole, Hydroformate of 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (4-methyl-2-thienyl) -1H-indazole, Hydroformate of 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (5-methyl-2-furyl) -1H-indazole, - Hydroformate of 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} -6- (5-methyl-2-thienyl) -1H-indazole, Hydroformate of 5- (2-Furyl) -3-. { [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -lH-indazole, 5- (3-Fluorophenyl) -3- Hydroformate. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -lH-indazole, 5- (4-Fluorophenyl) -3- Hydroformate. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.T] hept-2-yl] carbonyl} -lH-indazole, 5- (4-Methoxyphenyl) -3- Hydroformate. { [(SS, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -lH-indazole, Hydroformate of 6- (2-Furil) -3-. { [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} lH-indazole, Hydroformate of .6- (3-Furil) -3-. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} -lH-indazole, 3-. { [(SS, 4S) -5-Ethyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -lH-indazole, Hydroformate of 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} -lH-indazole, Hydroformate of 3-. { [(SS, 4S) -5-Met.-ethyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -5- (3-thienyl) -lH-indazole, Hydroformate of 5- (3-Furyl) -3-. { [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -IH-indazole, 5-Bromo-3- [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} -lH-indazole, and pharmaceutically acceptable salts thereof. According to an aspect of compounds of the invention, the compounds of Formulas I, II and III are selected from: 3- (2,5-Diazabicyclo [2.2.2] oct-2-ylcarbonyl) -6- hydrochloride (1,3-thiazol-2-yl) -IH-indazole, 3- (2,5-Diazabicyclo [2.2.2] oct-2-ylcarbonyl) -6- (1,3-thiazol-2-yl) - ÍH-indazole, 3- [(1S, 4S) -2,5-Diazabicyclo [2.2.1] hept-2-ylcarbonyl] -lH-indazole, 3- (2, 5-Diazabicyclo [2.2.2] oct. -2-ylcarbonyl) -IH-indazole, 3- (2,5-Diazabicyclo [2.2.2] oct-2-ylcarbonyl) -1H-indazole, Hydroformate of 3- [(5-Methyl-2, 5-diaza- bicyclo [2.2.2] oct-2-yl) carbonyl] -lH-indazole, 3- [(5-Methyl-2,5-diazabicyclo [2.2.2] 'oct-2-yl) carbonyl] -IH-indazole , Hydrochloride of 3- [(5-Methyl-2,5-diaza-bicyclo [2.2.2] oct-2-yl) carbonyl] -6- (1,3-thiazol-2-yl) -1H-indazole, 3- [(5-Methyl-2, 5-diazabicyclo [2.2.2] oct-2-yl) -carbonyl] -6- (1,3-thiazol-2-yl) -IH-indazole, 3-. { [(SS, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -lH-indazole, - Hydroformate of 3-. { [(ÍS, 4S) -5-Methyl-2, 5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} -5- (1,3-thiazol-2-yl) -1H-indazole, 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -5- (1, 3-thiazol-2-yl) -lH-indazole, 3-. { [(1S, 4S) -5-Methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -5- (2-thienyl) -1H-indazole, 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -5- (3-thienyl) -lH-indazole, 3-. { [(SS, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -5- (4-methyl-2-thienyl) -lH-indazole,. 3-. { [(1S, 4S) -5-Methyl-2,5-diazabicyclo [2.2..1] hept-2-yl] carbonyl} -5- (5-methyl-2-thienyl) -IH-indazole, 3-. { [(1S, S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -5- (trifluoromethoxy) -IH-indazole, 3-. { [(1S, 4S) -5-Methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -5-phenyl-1H-indazole, Hydroformate of 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} -6- (1, 3-oxazol-2-yl) -1H-indazole, 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (1, 3-oxazol-2-yl) -IH-indazole, Hydroformate of 3-. { [(1S, 4S) -5-Methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (1,3-thiazol-2-yl) -1H-indazole, - 3-. { [(1S, 4S) -5-Methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (1, 3-thiazol-2-yl) -1H-indazole, 3-. { [(1S, 4S) -5-Methyl-2,5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} -6- (2-thienyl) -1H-indazole, 3-. { [(SS, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (3-thienyl) -IH-indazole, Hydroformate of 3-. { [(ÍS, 4S) -5-Methyl-2, 5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} -6- (4-methyl-l, 3-thiazol-2-yl) -1H-indazole, 3-. { [(1S, 4S) -5'-Methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (4-methyl-1,3-thiazol-2-yl) -lH-indazole, 3-. { [(1S, 4S) -5-Methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (4-methyl-2-thienyl) -IH-indazole, Hydroformate -of 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (5-methyl-l, 3-thiazol-2-yl) -lH-indazole, 3-. { [(SS, 4S) -5-Methyl-2, 5-diazabicyclo 1-2.2.1] hept-2-yl] carbonyl} -6- (5-methyl-l, 3-thiazol-2-yl) -lH-indazole, 3-. { [(SS, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (5-methyl-2-furyl) -IH-indazole, 3-. { [(SS, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (5-methyl-2-thienyl) -lH-indazole, Hydroformate of 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} -6- (tetrahydro-2H-pyran-4-yl) -lH-indazole, - • 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (tetrahydro-2H-pyran-4-yl) -IH-indazole, Hydroformate of 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} -6- (trifluoromethoxy) -1H-indazole, 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (trifluoromethoxy) -IH-indazole, 3-. { [(SS, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (trifluoromethyl) -lH-indazole, Hydroformate of 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -7- (trifluoromethoxy) -1H-indazole, 3-. { [(SS, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -7- (trifluoromethoxy) -lH-indazole, 5- (2-Furyl) -3-. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -lH-indazole, 5- (3-Fluorophenyl) -3-. { [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} -1H-indazole, 5- (3-Furil) -3-. { 1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} -lH-indazole, 5- (4-fluorophenyl) -3-. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.l] hept-2-yl] carbonyl} -lH-indazole, 5- (4-methoxyphenyl) -3 ~. { [(SS, 4S) -5-methyl-2, 5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} -lH-indazole, Hydroformate of 5- (Cyclopentyloxy) -3-. { [(1S ~, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -lH-indazole, 5- (Cyclopentyloxy) -3-. { [(SS, 4S) -5-methyl-2, 5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} -lH-indazole, Hydroformate of 5- (cyclopropylmethoxy) -3-. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -lH-indazole, 5- (Cyclopropylmethoxy) -3-. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} -1H-indazole, 5-Amino-3- [(5-Methyl-2,5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -lH-indazole, 5-Amino-3-. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} -6- (1, 3-thiazol-2-yl) -1H-indazole, 5-Bromo-3- [(1S, 4S) -2,5-diazabicyclo [2.2.1] ept-2-ylcarbonyl] -1H - indazole, 5-Hydroxy-3-. { [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (1, 3-thiazol-2-yl) -1H-indazole, 5-Methoxy-3- [(5-methyl-2, 5-diazabicyclo [2.2.2] oct-2-yl) carbonyl hydroformate ] -IH-indazole, 3- (2,5-Diazabicyclo [2.2.2] oct-2-ylcarbonyl) -5-methoxy-1H-indazole, 3- (2,5-Diazabicyclo [2.2.2] oct] Hydrochloride -2-ylcarbonyl) -5-methoxy-lH-indazole, Hydrochloride of 5-methoxy-3-. { [(SS, 4S) -5-methyl-2, 5-diazabicyclo [2.2.l] hept-2-yl] carbonyl} -lH-indazole, - - 5-Methoxy-3-. { [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -lH- inda zol, 6- (2-Furil) -3-. { [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] ept-2-yl] carbonyl} -1H- indazole, Hydroformate of 6- (3,6-Dihydro-2H-pyran-4-yl) -3-. { [(1S, 4S) -5-methyl -2,5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} -IH-indazole, 6- (3,6-Dihydro-2H-pyran-4-yl) -3-. { 1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} -lH-indazole, 6- (3-Furil) -3-. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.l] hept-2-yl] carbonyl} -1H-indazole, Hydroformate of 6- (Cyclopentyloxy) -3-. { [(SS, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole, 6- (Cyclopentyloxy) -3-. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} -lH-indazole, Hydroformate of 6-Cyclopropyl-3-. { [(SS, 4S) -5-methyl-2, 5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} -1, 2-benzisothiazole, 6-Cyclopropyl-3-. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -l, 2-benzisothiazole, 6-ethoxy-3-. { [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -l, 2- benzisothiazole, 3- (2,5-Diazabicyclo [2.2.2] oct-2-ylcarbonyl) -6-methoxy-HH-indazole hydrochloride, 3- (2,5-Diazabicyclo [2.2.2] oct-2-ylcarbonyl) -6-methoxy-1H-indazole, - • Hydrochloride of 6-methoxy-3- [(5-methyl-2, 5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] - 1H-indazole, 6-Methoxy-3- [(5-methyl-2,5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -1H-indazole, Hydrochloride of 6-methoxy-3-. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -lH-indazole, 6-Methoxy-3- [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl hydroformate} -lH-indazole, 6-methoxy-3-. { [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -IH-indazole, 7-methoxy-3-. { [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -!, 2-benzisothiazole, N- (3 { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl-lH-indazole- Hydroformate 5-yl) -N'-propylurea, N- (3- [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl-lH-indazole-5- il) - N'-propylurea, N- Hydroformate. { 3 - [(5-Methyl-2, 5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -lH-indazol-5-yl} cyclopropanecarboxamide, N-. { 3 - [(5-Methyl-2,5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -lH-indazol-5-yl} Cyclopropanecarboxamide, Hydroformate of N-. { 3- [(5-Methyl-2, 5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -! H -indazol-5-yl} -N'-propylurea, - N-. { 3 - [(5-Methyl-2,5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -IH-indazol-5-yl} -N-propylurea, and pharmaceutically acceptable salts thereof. According to a further aspect of compounds of the invention, the compounds of Formulas I, II and III are selected from: Hydroformate of 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.l] hept-2-yl] carbonyl} -l, 2-benzisoxazole, 3-. { [(SS, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] ept-2-yl] carbonyl} -1,2-benzisoxazole, Hydroformate of 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} -5- (4-methyl-l, 3-thiazol-2-yl) -lH-indazole, 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -5- (4-methyl-l, 3-thiazol-2-yl) -IH-indazole, Hydroformate of 3-. { [(1S, 4S) -5-Methyl-2,5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} -5- (5-methyl-l, 3-thiazol-2-yl) -lH-indazole, 3-. { [(SS, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -5- (5-methyl-l, 3-thiazol-2-yl) -lH-indazole, Hydroformate of 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -5- (tetrahydro-2H-pyran-4-yl) -1H-indazole, 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -5- (Tetrahydro-2H-pyran-4-yl) -IH-indazole, - Hydropormate of 5- (3,6-Dihydro-2H-pyran-4-yl) -3-. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -IH-indazole, 5- (3,6-Dihydro-2H-pyran-4-yl) -3-. { [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -IH-indazole, Hydroformate of 5- (difluoromethoxy) -3-. { [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -! H-indazole, 5- (Difluoromethoxy) -3- [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -IH-indazole, Hydroformate of 6- (Difluoromethoxy) -3- [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.l] hept-2-yl] carbonyl} -lH-indazole, 6- (Difluoromethoxy) -3- [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -IH-indazole, Hydroformate of 7-Fluoro-6-methoxy-3-. { [(SS, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole, 7-Fluoro-6-methoxy-3-. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} -lH-indazole, N- (3- {[[(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -IH-indazole hydroformate. -5-yl) cyclopropanecarboxamide, N- (3. {[[(1S, 4S) -5-Methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl] -lH-indazole -5-yl) cyclopropanecarboxamide, N- (4-Fluorobenzyl) -N- (3- {[[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-Hydroformate] il] carbonyl.} - lH-indazol-5-yl) urea, - N- (4-Fluorobenzyl) -N'- (3 { [(1S, 4S) -5-methyl-2, 5- diazabicyclo [2.2.1] hept-2-yl] carbonyl.] - lH-indazol-5-yl) urea, N- (4-Fluorobenzyl) -N '- hydroformate. { 3- [(5-methyl-2,5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -lH-indazol-5-yl) urea, N- (4-Fluorobenzyl) -N'-. { 3- [(5-methyl-2, 5-diazabicyclo [2.2.2] oct-2-yl) carbonyl]! - IH-indazol-5-yl} urea, N- (Cyclopropylmethyl) -3- [(5-methyl-2, 5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -lH-indazol-5-amine, N- (Cyclopropylmethyl) -3 - [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2 l] hept-2-yl] carbonyl-1H-indazole-5-amine, N, N-Dimethyl-3-hydroformate [(5 -methyl-2, 5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -IH-indazol-5-amine, N, N-Dimethyl-3 - [(5-methyl-2, 5-diazabicyclo [ 2.2.2] oct-2-yl) carbonyl] -IH-indazol-5-amine,?,? -? Dimethyl-3- [(S, S) -5-methyl-2, 5-diazabicyclo [2.2. 1] hept-2-yl] carbonyl} -lH-indazol-5-amine,?,? - Dimethyl-3- [(1S, 4S) -5-methyl-2,5- '. diazabicyclo [2.2.1] hept-2-yl] carbonyl-lH-indazol-5-amine, Hydroformate of?,? - Dimethyl-3-. { [(SS, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -! H-indazol-6-amine, ?,? - Dimethyl-3- [(S, S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -lH-indazol-6-amine, Hydroformate of? -Cyclopentyl-? ' - (3- { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl] -! H -indazol-5-yl) urea, -? -Ciclopentil-? ' - (3- { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl]. -l-H-indazol-5-yl) urea, Hydrochloride of? -Cyclopentyl-? ' -. { 3- [(5-methyl-2,5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -lH-indazol-5-yl} urea,? -Cyclopentyl-N '-. { 3- [(5-methyl-2, 5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] '- lH-indazol-5-yl} urea, and pharmaceutically acceptable salts thereof.

Preferred aspects include pharmaceutical compositions comprising a compound of this invention and a pharmaceutically acceptable carrier and, optionally, another active agent as discussed below; a method for stimulating or activating the inhibition of nicotinic alpha-7 receptors, for example, as determined by a conventional assay or one described herein, either in vitro or in vivo (in an animal, for example, in a model of animal, or in a mammal or a human); a method for treating a neurological syndrome, eg, memory loss, especially long-term memory, cognitive impairment or decline, memory impairment, etc., a method of treating a disease state modulated by alpha-7 nicotinic activity, in a mammal, for example, a human, for example, those mentioned herein. The compounds of the present invention can be prepared in conventional manner. Some of the known processes can be used as described below. All starting materials are known or can be prepared in a conventional manner from known starting materials. The synthesis of similar compounds is described in copending application serial number 10 / 669,645 filed on September 25, 2003, the full description of which is incorporated herein by reference. The acids that can be used in the preparation of the bicyclobase amide are commercially available, they can be prepared by known procedures, described in the literature, or as described below. For example, indazole-3-carboxylic acid is commercially available. Bromoindazole acids can be prepared from the corresponding isatins by basic hydrolysis, diazotization and reduction [Snyder, H.R.; et al. J. Am. Chem. Soc. 1952, 74, 2009]. Benzisoxazole-3-carboxylic acid can be prepared from 2,5-dibromonitrobenzene by reaction with diethylmalonate, saponification with decarboxylation, followed by pro-esterification, reaction with isoamyl nitrite under basic conditions, hydrogenolysis, and saponification [Angelí, R.M.; Baldwin, I.R .; Bamborough, P .; Deboeck, N.M .; Longstaff, T.; Swanson, S. WO04010995A1]. The 3-benzisothiazole carboxylic acid can be prepared from thiophene-nol by reaction with oxalyl chloride and aluminum chloride followed by treatment with hydroxylamine, hydrogen peroxide, and sodium hydroxide. The bicycloamines that can be used in the preparation of bicyclobase amides are commercially available, can be prepared by known procedures described in the literature, or as described below. For example, the hydrochloride of (SS, 4S) -2-tert-butyloxycarbonyl-2,5-diazabicyclo [2.2.1] heptane is commercially available. (LS, 4S) -2-Methyl-2, 5-diazabicyclo [2.2.1] heptane can be prepared by the reduction of tert-butyl carbamate with lithium aluminum hydride or by the reductive amination sequence followed by deprotection. 2,5-Diazabicyclo [2.2.2] octane can be prepared as described in the literature (Newman, H. Heterocyclic Chem. 1974, 12, 449. Sturm, P.A.; Henry, D.W. Med. Chem. 1974, 17, 481). 2-Methyl-2, 5-diazabicyclo [2.2.2] octane can be prepared from diethyl 2,5-diaminohexanedioate by cyclization of the N-benzyl intermediate, reduction of tertiary amides, hydrogenolysis, selective protection, amination reductive and deprotection. The bicyclobase amide can be prepared by the coupling reaction of acids with bicycloamine and HBTU or HOBt and EDCI in DMF, or by converting the acids to the corresponding acid chloride and then reaction with bicycloamine (Macor, JE; Gurley, D.; Lanthorn, T .; Loch, J.; Mack, RA; Mullen, G.; Tran, O .; Wright, N.; and JE Macor, JE Bioorg, Med. Chem. Lett., 2001, 9,319.). The couplings are generally carried out at ambient temperatures for 4-8 hours. Thioamide analogs can be prepared from the amides by reaction with Lawesson's reagent (Wipf P .; Kim, Y .; Goldstein, D.M., Am. Chem. Soc., 1995, 117, 11106). Bicyclobase methyleneamine analogs can be prepared from bicyclobase amides by normal reduction methods as described, for example, below. The resulting adducts can be isolated and encoded by standard techniques, such as chromatography or recrystallization, practiced by one skilled in the art. One skilled in the art will recognize that the compounds of Formulas II-III can exist in different geometric isomeric and tautomeric forms. All those compounds, including cis isomers, trans isomers, diastereomeric mixtures, racemates, non-racemic mixtures of enantiomers, substantially pure, and pure enantiomers are within the scope of the present invention. The substantially pure enantiomers contain not more than 5% w / w of the corresponding opposite enantiomer, preferably not more than 2%, more preferably not more than 1%. The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereomeric salts using an optically active acid or base, or formation of covalent diastereomers. Examples of suitable acids are tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, and camphorsulfonic acid. Mixtures of diastereomers can be separated into their individual diastereomers on the basis of their physical and / or chemical differences by methods known to those skilled in the art, for example, by chromatography or fractional crystallization. The optically active bases or acids are then released from the separated diastereomeric salts. , A different process for the separation of optical isomers comprises the use of chiral chromatography (for example, chiral HPLC columns), with or without conventional derivatization, optionally chosen to maximize the separation of the enantiomers. Appropriate chiral HPLC columns are made by Diacel, for example, Chiracel OD and Chiracel OJ among many others, all selectable by routine. Enzymatic separations, with or without derivatization, are also useful. The optically active compounds of Formulas I-III can also be obtained by using optically active starting materials in chiral synthesis processes under reaction conditions and do not cause racemisation. In addition, one skilled in the art will recognize that the compounds can be used in different enriched isotropic forms, for example, enriched in the content of 2 H, 3 H, X 1 C, 13 C and / or 14 C. In a particular embodiment, the compounds are deuterated. These deuterated forms can be formed by the process described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve efficiency and increase the duration of action of drugs. Deuterium substituted compounds can be synthesized using various methods such as described in: Dean, Dennis C; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharr. Des., 2000; 6 (10)] (2000), 110 pp. CAN 133: 68895 AN 2000: 473538 CAPLUS; Kabalka, George.; Varma, Raj ender S. The synthesis of radiolabeled compounds via organometallic intermediates. Tetrahedron (1989), 45 (21), 6601-21, CODEN: TETRAB ISSN: 0040-4020. CAN 112: 20527 AN 1990: 20527 CAPLUS; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem. (1981), 64 (1-2), 9-32. CODEN: - JRACBN ISSN: 0022-4081, CAN 95: 76229 AN 1981: 476229 CAPLUS. Where applicable, the present invention also relates to useful forms of the compounds as described herein, such as pharmaceutically acceptable salts or prodrugs of all compounds of the present invention for which salts or prodrugs may be prepared. Pharmaceutically acceptable salts include those which are obtained by reacting the parent compound, functioning as a base, with an organic or inorganic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulphonic acid, camphor sulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, and carbonic acid. Pharmaceutically acceptable salts also include those in which the parent compound functions as an acid and is reacted with an appropriate base to form, for example, sodium, potassium, calcium, magnesium, ammonium, and choline salts. Those skilled in the art will additionally recognize that the acid addition salts of the claimed compounds can be prepared by reaction of the compounds with the appropriate organic and inorganic acid by any of several known methods. Alternatively, alkali metal and alkaline earth metal salts can be prepared to react the compounds of the invention with the appropriate base by a variety of known methods. The following are additional examples of acid salts obtainable by reaction with organic and inorganic acids: acetates, adipates, alginates, citrates, aspartates, benzoates, benzenesulfonates, bisulfates, butyrates, camphorates, digluconates, cyclopentanepropionates, dodecyl sulphates, ethanesulfonates, glucoheptanoates , glycerophosphates, hemisulfates, heptanoates, hexanoates, fumarates, hydrobromides, iodohydrates, 2-hydroxy-ethanesulfonates, lactates, maleates, methanesulfonates, nicotinates, 2-naphthalenesulfonates, oxalates, palmoates, pectinates, persulfates, 3-phenylpropionates, picrates, pivalates, propionates , succinates, tartrates, thiocyanates, tosylates, mesylates and undecanoates. Preferably, the salts formed are pharmaceutically acceptable for administration to mammals. However, pharmaceutically acceptable salts of the compounds are suitable as intermediates, for example, to isolate the compound as a salt and then convert the salt back to the free base compound by treatment with an alkaline reagent. The free base can then be converted, if desired, to a pharmaceutically acceptable acid addition salt. The compounds of the invention can be administered alone or as an active ingredient of a formulation. In this manner, the present invention also includes pharmaceutical compositions of compounds of Formulas I-III containing, for example, one or more pharmaceutically acceptable carriers. Numerous standard references are available describing methods for preparing various formulations suitable for the administration of the compounds according to the invention. Examples of potential formulations and preparations are contained, for example in Handbook of Pharmaceutical Excipients. American Pharmaceutical Association (current edition); Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman and Schwartz, editors) current edition, published by Marcel Dekker, Inc., as well as Remington's Pharmaceutical Sciences (Arthur Osol, editor), 1553-1593 (current edition). In view of their alpha-7 stimulating activity and preferably their high degree of selectivity, the compounds of the present invention can be administered to anyone in need of stimulation of alpha-7 receptors. The administration can be achieved according to the needs of patients, for example orally, nasally, parenterally (subcutaneously, intravenously, intramuscularly, intrasternally and by infusion) by inhalation, rectally, vaginally, topically or by ocular administration. Various forms of solid oral doses can be used to administer the compounds of the invention including solid forms such as tablets, gel capsules, capsules, solid core capsules, granules, pellets and bulk powders. The compounds of the present invention can be administered alone or in combination with various carriers, diluents (such as sucrose, mannitol, lactose, starches) and pharmaceutically acceptable excipients, known in the art, including but not limited to suspending agents , solubilizers, buffering agents, binders, disintegrants, preservatives, colorants, flavorings, lubricants and the like. Time-release capsules, tablets and gel are also advantageous in the administration of the compounds of the present invention. Various liquid, oral dosage forms can be used to administer the compounds of the invention, including aqueous and non-aqueous solutions, emulsions, suspensions, syrups and elixirs. Such dosage forms may also contain suitable inert diluents, known in the art, such as water and suitable excipients known in the art such as preservatives, wetting agents, sweeteners, flavorings, as well as agents for emulsifying and / or suspending the compounds of the invention. invention. The compounds of the present invention can be injected, for example, intravenously, in the form of a sterile, isotonic solution. Other preparations are also possible.

Suppositories for rectal administration of the compounds of the present invention can be prepared by mixing the compound with a suitable excipient such as cocoa butter, salicylates and polyethylene glycols. Formulations for vaginal administration may be in the form of a pessary, tampon, cream, gel, paste, foam, or spray formulation - containing, in addition to the active ingredient, these suitable carriers as is known in the art. For topical administration, the pharmaceutical composition may be in the form of creams, ointments, liniments, lotions, emulsions, suspensions, gels, solutions, pastes, powders, sprays, and drops suitable for administration to the skin, or eye, ear or nose Topical administration may also comprise transdermal administration by means such as transdermal patches. Aerosol formulations suitable for administration by inhalation can also be prepared. For example, for treatment of disorders of the respiratory tractors, the compounds according to the invention can be administered by inhalation in the form of a powder (for example, micronized) or in the form of atomized solutions or suspensions. The aerosol formulation can be placed in an acceptable, pressurized propellant.

The compounds can be administered as the sole active agent or in combination with other pharmaceutical agents such as other agents used in the treatment of cognitive impairment and / or memory loss, for example, other α-agonists, PDE4 inhibitors, calcium channel, muscarinic ml and m2 modulators, adenosine receptor modulators, NMDA-4 modulators of amphacinas, modulators of mGluR, modulators of dopamine, modulators of serotonin, modulators of cannabinoids, and inhibitors of cholinesterase (for example, donepecil, rivastigimine, and glantanamine). In these combinations, each active ingredient will be administered either according to its usual dose range or a dose below its usual dose range. The compounds of the invention can be used in conjunction with "positive modulators" that improve the efficiency of nicotinic receptor agonists. See, for example, the positive modulators described in WO 99- / 56745, WO 01/32619, and WO 01/32622. This combination therapy can be used in the treatment of conditions / diseases associated with reduced nicotinic transmission. In addition, the compounds can be used in conjunction with compounds that bind to the Aβ peptides and thereby inhibit the binding of the peptides to the nAChr a-1 subtypes. see, for example, WO 99/62505.

The present invention further includes methods of treatment comprising the activation of nicotinic receptors a-1. Thus, the present invention includes methods for selectively activating / stimulating a-7 nicotinic receptors in animals, e.g., mammals, especially humans, wherein this activation / stimulation has a therapeutic effect, such as where this activation may depend of conditions that comprise neurological syndromes, such as memory loss, especially long-term memory. These methods comprise administering to an animal in need thereof, especially a mammal, more especially a human, an effective amount of a compound of Formulas I-III, alone or as part of a formulation, as described herein. In accordance with one aspect of the method of the invention, there is provided a method of treating a patient (e.g., a mammal such as a human) suffering from a disease state (e.g., memory impairment) comprising administering to the patient a compound according to Formulas I, II or III. Preferably, the disease state comprises decreased activity of the nicotinic acetylcholine receptor. In accordance with one aspect of the method of the invention, there is provided a method for the treatment or prophylaxis of a disease or condition resulting from the dysfunction of the transmission of nicotinic acetylcholine receptors in a mammal., for example, a human, which comprises administering an effective amount of a compound according to Formulas I, II or III. According to one aspect of the method of the invention, there is provided a method for the treatment or prophylaxis of a disease or condition resulting from nicotinic acetylcholine receptors, defective or malfunctioning, particularly receptors "of nACh a-7, in a mammal, for example, a human comprising administering an effective amount of a compound according to Formulas I, II or III In accordance with a method aspect of the invention, a method is provided for the treatment or prophylaxis in disease or condition resulting from suppressed transmission of nicotinic acetylcholine receptor in a mammal, eg, a human, which comprises administering an amount of a compound according to Formula II, II or III effective to activate the nACh a-7 receptors. In accordance with another aspect of the method of the invention, a method for the treatment or prophylaxis of a psychotic disorder, a cognitive impairment, is provided. ón (for example, memory impairment), or neurodegenerative disease in a mammal, for example, a human, which comprises administering an effective amount of a compound according to Formulas II, II or III. According to another aspect of method of the invention, there is provided a method for the treatment or prophylaxis of a disease or condition resulting from loss of cholinergic synapses in a mammal, eg, a human, which comprises administering an effective amount of a Composed according to Formulas II, II or III. According to another aspect of the method of the invention, there is provided a method for the treatment or prophylaxis of a neurodegenerative disorder by activation of nACh a-7 receptors in a mammal, eg, a human, which comprises administering an effective amount of a compound according to Formulas II, II or III. According to another aspect of method of the invention, there is provided a method for protecting neurons in a mammal, eg, a human, from neurotoxicity induced by activation of nACh a-7 receptors comprising administering an effective amount of a compound according to to Formulas II, II or III. According to another aspect of method of the invention, there is provided a method for the treatment or prophylaxis of a neurodegenerative disorder by inhibiting the binding of Aβ peptides to nACh receptors a-7 in a mammal, eg, a human, which it comprises administering an effective amount of a compound according to Formulas II, II or III. According to another method aspect of the invention, there is provided a method for protecting neurons in a mammal, eg, a human, from Aβ peptide-induced neurotoxicity comprising administering an effective amount of a compound according to Formula II. , II or III. According to another aspect of the method of the invention, there is provided a method for alleviating the inhibition of cholinergic function induced by Aβ peptides in a mammal, for example, a human, which comprises administering an effective amount of a compound according to Formulas II, II or III. The compounds of the present invention are alpha-7 nicotinic ligands, preferably agonists, especially partial agonists, for the nicotinic alpha-7 acetylcholine receptor. Assays for determining nicotinic acetylcholine activity are known within the art. See, for example, Davies, A.R., et al., "Characterization of the binding of [3H] methyllycaconitine: a new radioligand for labeling alpha 7-type neuronal nicotinic acetylcholine receptors, "Neuropharmacology, 1999. 38 (5): p.679-90. As agonists for nAChRs a-7, the compounds are useful in the prophylaxis and treatment of a variety of diseases and conditions associated with the central nervous system Nicotinic acetylcholine receptors are ligand-gastrol ion channel receptors that are composed of five subunit proteins that form a central ion-conducting pore.There are currently eleven known neuronal subunits of nAChR (a2 - a9 and ß2 - ß4) There are also five additional subunits expressed in the peripheral nervous system (al, ßl,?, d, e) .The nAChR receptor subtypes can be homopentameric or heteropentameric.The subtype that has received considerable attention is the subtype of a-7 homopentameric receptor formed of five subunits a-7. The nAChR a-7 inhibit a high affinity for nicotine (agonist) and for a-bungarotoxin (antagonist). shown that nAChR a-7 agonists may be useful in the treatment of psychotic diseases, neurodegenerative diseases, and cognitive impairment, among other things. While nicotine is a known agonist, it is a need for development of other nAChR a-7 agonists, especially selective agonists that are less toxic or that exhibit fewer side effects than nicotine. The compound anabaseine, that is, 2- (3-pyridyl) -3,4,5,6-tetrahydropyridine is a toxin that occurs naturally in certain marine worms (nemerteous worms) and ants. See, for example, Kern et al., Toxicon, 9:23, 1971. Anabaseine is a potent activator of mammalian nicotinic receptors. See, for example, Kern, Amer. Zoologist, 25, 99, 1985. Certain analogs of anabaseine such as anabasine and DMAB (3- [4- (dimethylamino) benzylidene] -3,4,5,6-tetrahydro-2 ', 3'-bipyridine) are also agonists known nicotinic receptors. See, for example, U.S. Patent No. 5,602,257 and WO 92/15306. A particular anabaseine analogue, (E-3- [2,4-dimethoxy-benzylidene] -anabaseine, also known as GTS-21 and DMXB (see, for example, United States patent number ,741,802), is a partial, selective nAChR agonist that has been studied extensively. For example, abnormal sensory inhibition is a deficit of sensory processing in schizophrenics and GTS-21 has been found to increase sensory inhibition through interaction with nAC r a-7. See, for example, Stevens et al., Psychopharmacology, 136: 320-27 (1998). Another compound known to be a nAChR a-7 selective agonist is Tropisetron, ie, H, 5aH-tropan-3a-yl indole-3-carboxylate. See J. E. Macor et al., "The 5-HT3-Antagonist Tropisetron (ICS 205-930) is a Potent and Selective A-7 Nicotinic Agonist Partial Receptor," Bioorg. Med. Chem. Lett. 2001, 319-321).

Agents that bind nicotinic acetylcholine receptors have been indicated as useful in the treatment and / or prophylaxis of various diseases and conditions, particularly psychotic diseases, neurodegenerative diseases comprising cholinergic system dysfunction, and conditions of memory impairment and / o cognition, which include, for example, schizophrenia, anxiety, mania, depression, manic depression [examples of psychotic disorders], Tourette syndrome, Parkinson's disease, Huntington's disease [examples of neurodegenerative diseases], cognitive disorders ( such as Alzheimer's disease, Lewy body dementia, amyotrophic lateral sclerosis, memory impairment, memory loss, cognition deficit, attention deficit, attention deficit hyperactivity disorder), and other uses such as addiction treatment nicotine, induction of cessation of smoking, pain treatment (is dec go, analgesic use), which provides neuroprotection, treatment of maladaptation, inflammation, or sepsis. See, for example, WO 97/30998; WO 99/03850; WO 00/42044; WO 01/36417; Holladay et al., J. Med. Chem., 40:26, 4169-94 (1997); Schmitt et al., 7Annual Reports Med. Chem., Chapter 5, 41-51 (2000); Stevens et al., Psychopharmatology, (1998) 136: 320-27 (1998); and Shytle et al., Molecular Psychiatry, (2002), 7, pp. 525-535.

Thus, according to the invention, there is provided a method for treating a patient, especially a human, suffering from psychotic diseases, neurodegenerative diseases comprising cholinergic system dysfunction, and conditions of memory and / or impairment of cognition, which include, for example, schizophrenia, anxiety, mania, depression, manic depression [examples of psychotic disorders], Tourette's syndrome, Parkinson's disease, Huntington's disease [examples of neurodegenerative diseases], and / or cognitive disorders (such as disease Alzheimer's disease, dementia due to Lewy bodies, amyotrophic lateral sclerosis, memory impairment, memory loss, cognition deficit, attention deficit, attention deficit hyperactivity disorder), which comprises administering to the patient an effective amount of a compound of according to Formulas I-III. Included neurodegenerative disorders within the methods of the present invention include, without limitation, treatment and / or prophylaxis of Alzheimer's disease, Pick's disease, diffuse Lewy body disease, progressive supranuclear palsy (Steel syndrome). -Richardson), multi-system degeneration (Shy-Drager syndrome), motor neuron diseases including amyotrophic lateral sclerosis, degenerative ataxias, cortical basal degeneration, ALS-Parkinson-dementia Gua complex, subacute sclerosing panencephalitis, Huntington's disease , Parkinson's disease, synucleinopathies, primary progressive aphasia, striatonigral degeneration, Machado-Joseph disease / spinocerebellar ataxia type 3, olivopontocerebellar degenerations, Gilles de La Tourette disease, bulbar and pseudobulbar palsy, spinal muscular atrophy, spinobulbar muscular atrophy Kennedy), lateral sclerosis pr imaria, familial spastic paraplegia, Werdnig-Hoff ann disease, Kugelberg-Welander disease, Tay-Sach disease, Sandhoff's disease, familial spastic disease, Wohlfart-Kugelbert-Welander disease, spastic paraparesis, progressive multifocal leukoencephalopathy, prions (such as Creutzfeldt-Jakob disease, Gerstmann-Stráussler-Scheinker disease, fatal familial insomnia and Kuru), and neurodegenerative disorders resulting from cerebral ischemia or infarction including embolic occlusion and thrombotic occlusion as well as intracranial hemorrhage of any kind (including , enunciatively and without limitation, epidural, subdural, subarachnoid and intracerebral), intracranial and intravertebral lesions (including, but not limited to, contusion, penetration, cutting, compression and laceration). In addition, nAChR agonists a-7, such as the compounds of the present invention can be used to treat age-related dementia and other dementias and conditions with memory loss including memory loss related to age, senility, vascular dementia, diffuse white matter disease (Binswanger's disease), dementia of endocrine or metabolic origin, dementia of brain trauma and diffuse brain dementia, pugilistic dementia and frontal lobe dementia. See, for example, WO 99/62505. Thus, according to the invention there is provided a method for treating a patient, especially a human, suffering from dementia related to age and other dementias and conditions with memory loss comprising administering to a patient an effective amount of a compound according to Formulas II-III. Thus, according to a further embodiment, the present invention includes methods for treating patients suffering from memory impairment due to, for example, moderate cognitive impairment due to aging, Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington, Pick disease, Creutzfeld-Jakog disease, depression, aging, head trauma, attack, central nervous system hypoxia, cerebral senility, multi-infarct dementia and other neurological conditions, as well as cardiovascular and HIV diseases, comprising administering an effective amount of a compound according to Formulas I-III. Amyloid precursor protein (APP) and peptides Aβ derivatives thereof, for example, Aβ! -40, Aβ? .42, and other fragments, are known to be included in the pathology of Alzheimer's disease. The Aßx_42 peptides are not only involved in neurotoxicity, but are also known to inhibit the function of cholinergic transmitters. Additionally, it has been determined that Aβ peptides bind to nAChR a-7. In this way, agents that block the binding of the Aβ peptides to nAChR a-7 to treat neurodegenerative diseases are useful. See, for example, WO 99/62505. In addition, stimulation of nAChR a-7 can protect neurons against cytotoxicity associated with Aβ peptides. See, for example, Kihara, T. et al., Ann. Neurol., 1997, 42, 159. Thus, according to one embodiment of the invention, there is provided a method for treating / preventing dementia in a patient with Alzheimer's, which comprises administering to the subject a therapeutically effective amount of a compound of according to Formulas I-III for inhibiting the binding of an amyloid-beta peptide (preferably, β! _42) with nAChR, preferably nAChR a-7, preferably nAChR a-7 human (as well as a method to treat and / or prevent other clinical manifestations of Alzheimer's disease that include, but are not limited to, language and cognitive deficits, apraxia, depression, lack of illusions and other neuropsychiatric symptoms and signs, and gait abnormalities and movement). The present invention also provides methods for treating other diseases of amyloidosis, for example, hereditary cerebral angiopathy, non-neuroplagic amyloid-hereditary, Down syndrome, macroglobulinemia, secondary familial Mediterranean fever, Muckle-Wells syndrome, multiple myeloma, amyloidosis related to pancreas and cardiac, chronic hemodialysis antropathy, and Finnish and Iowa amyloidosis. In addition, nicotinic receptors have been implicated as playing a role in the body's response to alcohol ingestion. In this way, agonists for nAChR a-7 can be used in the treatment of alcohol withdrawal and anti-poisoning therapy. Thus, according to one embodiment of the invention, there is provided a method for treating a patient for alcohol withdrawal or for treating a patient with anti-poisoning therapy comprising administering an effective amount of a compound according to Formula I -III.

Agonists for nAChR a-7 subtypes can also be used for neuroprotection against damage associated with attacks and ischemia and glutamate-induced excitotoxicity. Thus, according to one embodiment of the invention, there is provided a method of treating a patient to provide neuroprotection against damage associated with attacks and glutamate induced ischemia and excitotoxicity comprising administering an effective amount of a compound according to the Formulas I-III. As noted above, agonists can also be used for nAChR a-7 subtypes in the treatment of nicotine addiction, inducing cessation of smoking, pain treatment and maladaptive treatment. I would pray, obesity, diabetes, inflammation and sepsis. Thus, according to one embodiment of the invention, there is provided a method for treating a patient suffering from nicotine addiction, pain, maladjustment, obesity and / or diabetes, or a method to induce smoking cessation in a patient. patient comprising administering an effective amount of a compound according to Formulas I-III. In addition, due to their affinity to nAChR a-7, the labeled derivatives of the compounds of Formulas I-III (for example, derivatives labeled with Cu or Fi8), can be used in the formation of neural images of receptors within, for example, the brain. In this way, by using the agents labeled in vivo, the imaging of the receptors can be performed using for example PET image information. The condition of memory deterioration is manifested by impairment of the ability to learn new information and / or the inability to remember information previously learned. The deterioration of memory is an important symptom of dementia and may also be a symptom associated with diseases such as Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeld-Jakob, HIV, cardiovascular disease, head trauma as well as cognitive decline related to age. Thus, according to one embodiment of the invention, there is provided a method for treating a patient suffering from, for example, moderate cognitive impairment (MCI), vascular dementia (VaD), cognitive decline associated with age (AACD). , amnesia associated with open heart surgery, cardiac arrest, and / or general anesthesia, memory deficit of early exposure of anesthetic agents, cognitive impairment induced sleep deprivation, chronic fatigue syndrome, narcolepsy, AIDS-related dementia, cognitive impairment related to epilepsy, Down syndrome, dementia related to alcoholism, drug / substance induced memory impairment, puglistic dementia (boxer syndrome), and dementia in animals (eg, dogs, cats, horses, etc.) to a patient, which comprises administering to the patient an effective amount of a compound according to Formulas I-III. The doses of the compounds of the present invention depend on a variety of factors including the particular syndrome to be treated, the severity of the symptoms, the route of administration, the frequency of the dose range, the particular compound used, the efficiency, toxicology profile, pharmacokinetic profile of the compound, and the presence of any harmful side effects, among other considerations. The compounds of the invention can be administered to mammals, particularly humans, at typical levels of usual doses for a-7 nicotinic receptor agonists such as known a-7 nicotinic receptor agonist compounds mentioned above. For example, the compounds can be administered, in single or multiple doses, by oral administration at a dose level of, for example, 0.0001-10mg / kg / day, for example, 0.01-10 mg / kg / day. The unit dosage forms may contain, for example, 1-200 mg of active compound. For intravenous administration, the compounds can be administered, in single or multiple doses. In carrying out the methods of the present invention it will of course be understood that the reference to buffers, media, reagents, cells, particular culture conditions and the like is not intended to be limiting, but must be read to include all the related materials that one skilled in the art will recognize as being of interest or value in the particular context in which the analysis is presented. For example, it is often possible to replace a buffer system or culture medium with. another and still achieve similar results, if not identical. Those skilled in the art will have sufficient knowledge of these systems and methodologies to be able, without undue experimentation, to make these substitutions since they will serve their purposes optimally by using the methods and methods described herein. The present invention will now be further described in the manner of the following non-limiting examples. In applying the description of these examples, it should be clearly kept in mind that other and different embodiments of the methods described according to the present invention will not suggest self-doubt to those skilled in the art. In the above and in the following examples, all temperatures are exposed uncorrected in degrees Celsius; and, unless otherwise indicated, all parts and percentages are by weight. The full descriptions of all the applications, patents and publications, cited before and after, are thus incorporated by reference.

Examples All spectra were recorded at 300 MHz on a Bruker NMR instrument unless it was. signal otherwise. The coupling constants (J) are in Hertz (Hz) and the peaks are listed in relation to TMS (d 0.00 ppm).

The reactions with microwave were performed using a Personal Chemistry Optimizer ™ microwave reactor in 2.5 mL or 5 mL Personal Chemistry microwave bottles. All reactions were performed at 200 ° C for 600 s with the fixed retention time ON unless stated otherwise. Sulphonic acid ion exchange resins (SCX) from Varian Technologies were purchased. Analytical HPLC analysis was performed on Xterra RP18 3.5μ 4.6 mm x 100 mm columns using a gradient of 20/80 to 80/20 of water (0.1% formic acid) / acetonitrile (0.1% formic acid) for 6 minutes unless stated otherwise.

Acid preparations: The following procedures (1-10) detail the preparation of indazole, benzisoxazole, and benzisothiazole acids that were not commercially available.

Process 1: The procedure 1. provides a method for the preparation of 6-nitroindazol-3-acid and coupling with bicyclobases to form nitro-substituted derivatives. A 5 mL microwave reaction vessel was charged with 3-iodo-6-nitroindazole (1 mmol), copper cyanide (I) (2 mmol) and N, N-dimethylformamide (3 mL). The container was sealed and subjected to microwave irradiation at 1885 ° C for 600 seconds. The reaction mixture was partitioned between ethyl acetate (100 mL) and water (100 mL) and the mixture was filtered through celite. The organic layer was collected, washed with brine, dried (magnesium sulfate), and concentrated to give 122 mg of a 10/1 mixture of 3-cyano-6-nitroindazole and 6-nitroindazole as a yellow solid. The 10/1 mixture of 3-cyano-6-nitroindazole and 6-nitroindazole was dissolved in 10 N sodium hydroxide and the light orange solution was heated at 100 ° C for 1 hour. The mixture was allowed to cool to room temperature and was carefully acidified (pH = 1) with 3N hydrochloric acid. The solid was isolated and triturated with EtOAc to give 51 mg of 6-nitroindazol-3-carboxylic acid as a brown solid. The acid was coupled with the bicyclobase according to procedure A. The following acid was prepared using this method: 6-nitro-lH-indazole-3-carboxylic acid.

Method 2: Method 2 provides a method for indazole-nitration nitration and coupling with bicyclobases to form nitro-substituted derivatives. Ethyl indazole-3-carboxylate (73.7 mmol) was dissolved in 20 mL of concentrated sulfuric acid and the reaction mixture was cooled to 0 ° C. A mixture of concentrated sulfuric acid (12 mL) and 70% nitric acid (12 mL) was added dropwise over the course of 1 hour. The mixture was stirred for an additional 1 hour at 0 ° C and poured onto crushed ice (200 g). The solid was collected by vacuum filtration, washed with several portions of water and dried in vacuo. The dried solid was suspended in 250 mL of acetonitrile and the mixture was heated to reflux for 2 hours. The mixture was allowed to cool to room temperature and the solid was collected and dried in vacuo to give ethyl 5-nitroindazol-3-carboxylate (53%) as a colorless solid. The acid, obtained by basic hydrolysis, was coupled with the bicyclobase according to procedure A.

Literature reference: Org. Synthesis, Coll. Vol. I, page 372. The following acid was prepared using this method: 5-nitro-lH-indazole-3-carboxylic acid.

Method 3: Method 3 provides a method for trapping indazole-aryl lithium with ketones and coupling with bicyclobases to form heterocyclic derivatives. Terbium-6-bromoindazole-3-carboxylate was prepared from the acid by reaction with an excess twice of di-tert-butyldicarbonate followed by treatment with sodium hydroxide. To a suspension of sodium hydride (60% mineral oil dispersion) (4.8 mmol) in tetrahydrofuran (40 mL) at 0 ° C was slowly added a solution of 6-bromoindazole-3-carboxylic acid tert -butyl ester (4.0 mmol. ) in tetrahydrofuran (4 mL). After stirring for 0.5 h at 0 ° C, the mixture was cooled to -78 ° C and a 1.7 M solution of tert-butyl lithium in pentane was added. (5.1 mmol). After 0.5 h at -78 ° C, a solution of tetrahydropyran-4-one (5 mmol) in tetrahydrofuran (1 mL) was added dropwise. The mixture was stirred at -78 ° C for 1 hour and heated to 0 ° C. The reaction mixture was quenched with saturated aqueous ammonium chloride and the mixture was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was separated, washed with brine (50 mL), dried (magnesium sulfate) and concentrated. The residue was purified by chromatography (70/30 ethyl acetate / hexanes) to produce the 6- (4-hydroxytetrahydropyran-4-yl) -1H-indazole-3-carboxylic acid tert-butyl ester (68%) as a colorless solid. The 6- (4-hydroxytetrahydropyran-4-yl) -lH-indazole-3-carboxylic acid tert-butyl ester (0.86 mmol) was dissolved in trifluoroacetic acid (3 mL) and the mixture was kept at room temperature for 16 hours. hours. The solvent was removed in vacuo and the residue was triturated with ethyl acetate to provide 6- (3, 6-dihydro-2H-pyran-4-yl) -lH-indazole-3-carboxylic acid (76%). The acid was coupled with the bicyclobase according to procedure A. The 6- (4-hydroxytetrahydropyran-4-yl) -lH-indazole-3-carboxylic acid tert-butyl ester (1.0 mmol) was dissolved in trifluoroacetic acid (5). mL), triethylsilane (2 mL), and dichloromethane (3 mL) and the mixture was refluxed for 16 hours. The solvent was removed in vacuo and the residue was triturated with ethyl acetate to give 6- (tetrahydropyran-4-yl) -lH-indazole-3-carboxylic acid. (60%) as a light brown solid. The acid was coupled to the bicyclobase according to procedure A. The following acids were prepared using this method: 6- (3,6-dihydro-2H-pyran-4-yl) -lH-indazole-3-carboxylic acid. 6- (Tetrahydro-2H-pyran-4-yl) -lH-indazole-3-carboxylic acid.

Process 4: Process 4 provides a method for the conversion of substituted isatins to the corresponding indazole-3-carboxylic acids. The conversion of the substituted isatins to the corresponding indazole-3-carboxylic acids is essentially the same method as described for indazole-3-carboxylic acid: Snyder, H.R., et. to the. J. Am. Chem. Soc. 1952, 74, 2009. Substituted isatin (22.1 mmol) was diluted with 1 N sodium hydroxide (24 mL) and heated at 50 ° C for 30 minutes. The burgundy solution was allowed to cool to room temperature and was held for 1 hr. The reaction mixture was cooled to 0 ° C and treated with a 0 ° C solution of sodium nitrite (22.0 mmol) in water (5.5 ml). This solution was added through a submerged pipette below a surface of a vigorously stirred solution of sulfuric acid (2.3 mL) in water (45 mL) at 0 ° C. The addition took 15 minutes and the reaction was maintained for an additional 30 minutes. A cold (O ° C) solution of tin (II) chloride dihydrate (52.7 mmol) in concentrated hydrochloric acid (20 mL) was added to the reaction mixture for 10 minutes and the reaction mixture was maintained for 60 minutes. The precipitated solids were isolated by filtration, washed with water, and dried to give a basic quantitative equilibrium. This material was of sufficient purity (RMN ^? And LC / MS) to be used in the next step without further purification. Alternatively, the acid was recrystallized from acetic acid to provide pure material. . The following acids were prepared using this method: 5-bromoindazole-3-acid; 6-bromoindazol-3-acid; 5-trifluoromethoxy-indazole-3-acid; 6-trifluoromethylindazole-3-acid; 5-methoxy-indazole-3-acid.

Method 5: Process 5 provides a preparation of substituted benzisothiazole-3-carboxylic acids of the corresponding thiophenols. To a solution of 3-methoxythiophenol (3.75 g, 26.7 mmol) in ether (20 mL) was added oxalyl chloride (3.7 mL, 43 mmol) dropwise. The mixture was refluxed for 1.5 h, cooled to room temperature and concentrated in vacuo. The resulting yellow oil was dissolved in dichloromethane (50 mL), cooled to 0 ° C, and treated with aluminum chloride (4.30 g, 32.0 mmol) in portions. The mixture was refluxed for 30 minutes, cooled to room temperature, and poured into ice water with stirring. The organic layer was separated and washed successively with saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (ethyl acetate / hexane to 4/1) which afforded 2.46 g (47%) of 6-methoxy-1-benzothiophene-2,3-dione as an orange solid. To the mixture of dione (86 mg, 0.44 mmol) of 30% aqueous solution of ammonium hydroxide (2.0 mL) was added hydrogen peroxide in 35% aqueous solution. (0.2 mL) and the reaction mixture was maintained for 12 hours. The precipitated pink solids were isolated by filtration, washed with water, and dried under high vacuum to give 39 mg (42%) of 6-methoxybenzisothiazole-3-carboxamide. To a solution of the amide (1.14 g, 5.46 mmol) in methanol (100 mL) was added 10 N sodium hydroxide (12 mL). The mixture was refluxed for 12 hours, cooled to room temperature, and acidified to pH < 2 by the slow addition of concentrated hydrochloric acid. The organic layer was quenched with dichloromethane (2x) and dried over sodium sulfate. The crude product was purified by chromatography (dichloromethane / methanol / formic acid 300/50/1) to provide 1.02 g (89%) of 6-methoxybenzisothiazole-3-carboxylic acid as a pink solid. The following acids were prepared by this method: Benzo [d] isothiazole-3-carboxylic acid; 6-Bromobenzo [d] isothiazole-3-carboxylic acid; 5-Bromobenzo [d] isothiazole-3-carboxylic acid; 5-methoxybenzo [d] isothiazole-3-carboxylic acid; 6-methoxybenzo [d] isothiazole-3-carboxylic acid; 7-Methoxybenzo [d] isothiazole-3-carboxylic acid; 6-ethoxybenzo [d] isothiazole-3-acid.

Method 6: Process 6 provides a method for coupling brominated benzisothiazole-3-carboxylic esters and brominated indazole-3-carboxylic esters and Grignard reagents to form alkyl-substituted and heterocycle-substituted acids. A 0.5 M solution of cyclopropylmagnesium bromide (25.0 mmol, 3.7 equivalent) in tetrahydrofuran was diluted with tetrahydrofuran (60 L) and treated with a 0.5 M solution of zinc chloride (25.0 mmol, 3.7 equivalent) in tetrahydrofuran at room temperature. After 10 minutes, brominated benzisothiazole-3-carboxylate ethyl (0.30 mmol) bis (triphenylphosphine) palladium (II) chloride (0.95 mmol, 0.1 equivalent) was added to the suspension. The reaction mixture was kept for 1 hour at room temperature then at 65 ° C for 1 hour. The reaction was quenched with saturated ammonium chloride and extracted with dichloromethane (3x). The extracts were dried over sodium sulfate and concentrated to dryness. The residue was purified by chromatography using a gradient of dichloromethane / methanol 100/0 to 90/10 to provide the cyclopropyl-substituted amide. The amide was dissolved in a methanol / tetrahydrofuran / water mixture (90/10/20 mL) and treated with sodium hydroxide (5.8 g). The mixture was refluxed for 12 hours, cooled to room temperature, filtered and acidified to pH < 2 by the slow addition of concentrated hydrochloric acid. The aqueous layer was extracted with ethyl acetate (2x) and dried over sodium sulfate. The concentration of the extracts gave the acid in 38% yield. The acid was coupled to bicyclobases according to procedure A. This procedure was used, with slight modifications, to derivatize brominated indazole-3-piperidine carboxamides with various Grignard reagents. The thiazole Grignard reagent is commercially available. Alternatively, the aryl lithium and the corresponding arylzinc reagent can be generated according to the procedure summarized by Reeder, M.R .; et. to the. Org. Proc. Res. Devel. 2003, .7, 696. The zinc reactants of oxazole, 4-methylthiazole, and 5-methylthiazole were prepared according to this procedure. The following acids were prepared using this method: 6-Cyclopropylbenzo [d] isothiazole-3-carboxylic acid; 6- (1, 3-thiazol-2-yl) -lH-indazole-3-carboxylic acid; 5- (1, 3-thiazol-2-yl) -lH-indazole-3-carboxylic acid; 5- (4-Methyl-l, 3-thiazol-2-yl) -lH-indazole-3-carboxylic acid; - 5- (5-Methyl-l, 3-thiazol-2-yl) -lH-indazole-3-carboxylic acid; 6- (4-Methyl-l, 3-thiazol-2-yl) -lH-indazole-3-carboxylic acid; 6- (5-Methyl-l, 3-thiazol-2-yl) -lH-indazole-3-carboxylic acid; 6- (1, 3-Oxazol-2-yl) -lH-indazole-3-carboxylic acid.

Method 7: Process 7 provides a method for the preparation of 7-fluoro-6-methoxy-lH-indazole-3-carboxylic acid. Bis (tetrafluoroborate) l-chloromethyl-4-fluoro-1,4-diazoniabicyclo [2.2.2] octane (1.00 g, 2.82 mmol) was added to a solution of ethyl 6-methoxy-lH-indazole-3-carboxylate ( 500 mg, 2.27 mmol) in acetonitrile (15.0 mL) and the reaction mixture was kept at room temperature for 18 hours.

The reaction was divided between water (50 mL) and ethyl acetate (50 mL) and the separated organic layer was washed with brine (25 mL), dried (magnesium sulfate), and concentrated. The residue was purified by chromatography (hexanes / ethyl acetate 95/5 to 80/20) to yield 541 mg (23%) of the fluorinated ester. A solution of the ester (124 mg, 0.520 mmol) in ethanol (5.0 mL) was diluted with 5.0 M sodium hydroxide. (2.00 mL) and the mixture was kept at room temperature for 18 hours. The reaction was acidified with 6 N hydrochloric acid and partitioned between water (50 mL) and ethyl acetate (50 mL). The layers were separated and the organic layer was washed with brine (25 mL), dried (magnesium sulfate), and concentrated in vacuo to yield 109 mg (84%) of the acid. The acid was coupled with the bicyclobase according to procedure A. The following acid was prepared using this method: 7-Fluoro-6-methoxy-lH-indazole-3-carboxylic acid.

Method 8: Process 8 details the preparation of benzisoxazole-3-carboxylic acid from 2,5-dibromonitrobenzene. Diethyl malonate (12.6 g, 79 mmol) was added to a suspension of sodium hydride (3.16 g, 132 mmol) in dimethylsulfoxide (60 ml) for 30 minutes. The reaction temperature increased to 60 ° C and the mixture was clarified. 1,4-Dibromo-2-nitrobenzene (10 g, 36.0 mmol) was added and the solution was kept for 2 hours at 100 ° C. The reaction mixture was allowed to cool to room temperature and poured onto ice (300 g -400 g). The precipitated solids were isolated by filtration and dried to provide 11.0 g of the product (89%). The ester (11.0 g, 32.0 mmol) was diluted with a 2 N solution of sodium hydroxide (32 mL, 63 mmol) and the reaction mixture was kept at room temperature for 16 hours. The aqueous layer was extracted with dichloromethane (20 mL) and acidified. The precipitated solids were isolated by filtration and dried to provide 7.00 g of the acid (89%).

Sulfuric acid (1 mL) was added to a solution of the acid (7.00 g, 27.0 mmol) in ethanol (60 mL). The reaction mixture was heated to reflux, maintained for 2 hours, and concentrated under reduced pressure. The residue was partitioned between ethyl acetate (250 mL) and saturated sodium carbonate (50 mL) and the organic layer was washed with saturated sodium carbonate (50 mL) and brine (50 mL). The organic layer was dried (sodium sulfate) and concentrated to provide 8.0 g (98%) of the ester as a liquid. Under N atmosphere, sodium ethylate was formed with sodium (33.5 g, 1.46 mol) in ethanol (1.0 L). Isoamyl trite (225 mL) was added to a solution of the ester (420 g, 1.46 mol) in ethanol (3 L) in a 10 L three neck round bottom flask and the mixture was heated to 60 ° C. A solution of sodium ethoxide, prepared from sodium metal (33.5 g, 1.46 mmol) in ethanol (1 L) was added dropwise and the reaction mixture was kept for 2 hours. The reaction mixture was allowed to cool to room temperature and neutralized with 2N hydrochloric acid. The reaction mixture was extracted with ethyl acetate (4 x 2L) and the combined organic layers were washed with water. (2 x 1 L) and brine (2 x 1 L) and dried (sodium sulfate). The residue was purified by hexane / ethyl acetate chromatography l / l to 0/1) to provide 110 g of the product (28%).

Palladium 10% in carbon (1.5 g) and triethylamine (7.5 g, 82.4 mmol) was added to a solution of ethyl 6-bromobenzisoxazole-3-carboxylate (20 g, 0.081 mol) in ethanol (300 ml) at 0 ° C. under a nitrogen atmosphere. The nitrogen atmosphere was removed by evacuation and replaced with hydrogen gas, and the reaction mixture was maintained for 1 hour. The hydrogen atmosphere was removed by evacuation and replaced with nitrogen gas, and the palladium was removed by filtration through celite. The filter cake was washed with ethanol "(3 x 50) and the filtrates were concentrated.The residue was dissolved in dichloromethane (200 L) and the solution was washed with water (4 x 50 mL), dried (sodium sulfate). ) and evaporated to provide 13.0 g of the product as a yellow solid (96%) The ester was saponified using sodium hydroxide to provide the acid The acid was coupled with the bicyclobase according to procedure A. Literature reference: Angeli , RM, Baldwin, IR, Bamborough, P .; Deboeck, NM; Longstaff, T.; Swanson, S. WO04010995A1 The following acid was prepared using this method: 1,2-benzisoxazole-3-carboxylic acid.

Method 9: Process 9 provides a method for the preparation of 5-difluoromethoxy-indazole-3-acid from 3-bromo-4-nitrophenol. 3-Bromo-4-nitrophenyl (10.0 mmol) was added to a suspension of sodium hydroxide (29.0 mmol) in N, N-dimethylformamide (15 mL) and the suspension was kept for 15 minutes at room temperature. The reaction mixture was cooled to 0 ° C and treated with ethyl chlorodifluoroacetate (20.0 mmol). The reaction mixture was heated at 70 ° C for 16 hours and concentrated. The residue was diluted with ice water (200 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried (magnesium sulfate) and concentrated to give the difluoromethyl ether in 75% yield as a yellow oil. Diethyl malonate (328 mmol) was added dropwise to a suspension of sodium hydride (328 mmol) in dimethylsulfoxide (40 mL) at 0 ° C. The reaction mixture was heated to 60 ° C and maintained for 0.5 h. A solution of the difluoromethyl ether (149 mmol) in dimethylsulfoxide (80 mL) was added dropwise and the reaction mixture was heated at 100 ° C for 5 hours. The cooled solution was poured into ice water, and the aqueous layer was extracted with dichloromethane (3 x 100 mL). The combined organic layers were dried (magnesium sulfate) and concentrated to give the crude diester in 112% yield as an oil. The diester (167 mmol), sodium hydroxide (500 mmol) and water (335 mL) were combined and heated at 60 ° C for 1 hour. The reaction mixture was allowed to cool to room temperature and the aqueous layer was washed with dichloromethane (3 x 100 mL). The pH of the aqueous layer was adjusted with concentrated hydrochloric acid and the reaction mixture was heated at 60 ° C for 1 hour. The suspension was cooled to 5 ° C and the solids were collected by filtration and dried to provide the acid in 61% yield. Acetyl chloride (203 mmol) was added dropwise to ethanol (300 mL) at 0 ° C. After 0.5 h, the acid (101 mmol) was added and the reaction mixture was heated to reflux for 15 h. The reaction mixture was concentrated and the residue was partitioned between dichloromethane (200 mL) and saturated sodium bicarbonate (100 mL). The aqueous layer was further extracted with dichloromethane (2 x 200 mL) and the combined organic layers were dried (magnesium sulfate) and concentrated to provide the ester in? & % yield as a brown oil. The ester (60.4 mmol) was dissolved in ethanol (103 mL), diluted with water (71 mL), and treated with ammonium chloride (243 mmol) and iron powder (301 mmol). The reaction mixture was heated to reflux for 10 minutes and the suspension was filtered through celite and the filter cake was washed with ethanol three times. The filtrate was concentrated, the residue was suspended in 2 N hydrochloric acid and stirred vigorously for 0.5 h. The aqueous layer was washed with ethyl acetate (3 x 50 mL) and the pH was adjusted to 9-10 with 5 M sodium hydroxide. The aqueous layer was extracted with chloroform (3 x 100 mL) and the combined organic layers were dried (magnesium sulfate). Acetic anhydride (392 mmol), isoamyl nitrite (291 mmol), and potassium acetate (51.0 mmol) were added to the organic layer, the suspension was heated to reflux for 16 hours. The solution was evaporated and the residue was partitioned between saturated sodium bicarbonate (50 mL) and dichloromethane (100 mL). The aqueous layer was further extracted with dichloromethane (2 x 100 mL) and the combined organic layers were dried (magnesium sulfate) and concentrated to give the α-acetylindazole ester in 79% yield as a brown oil. The ester (63.8 mmol), sodium hydroxide (193 mmol), and water (65 mL) were combined and the reaction was maintained for 24 hours at 60 ° C. After cooling to room temperature, the aqueous layer was washed out with chloroquine (3 x 50 mL). The aqueous layer was adjusted to pH 1 with concentrated hydrochloric acid. The precipitated solids were collected by filtration, washed with water and dichloromethane, and dried to provide the acid in 27% yield. The following acids were prepared according to this method: 5- (difluoromethoxy) -lH-indazole-3-carboxylic acid, Method 10: Method 10 provides a method for the preparation of 6-difluoromethoxy-indazol-3-acid from 4-nitrophenol. 4-Nitrophenyl (162 mmol) was added to a hydroxide suspension. of sodium (485 mmol) in N, N-dimethylformamide (150 mL) and the suspension was maintained for minutes at room temperature. The reaction mixture was cooled to 0 ° C and treated with ethyl chlorodifluoroacetate (329 mmol). The reaction mixture was heated to. 70 ° C for 16 hours and concentrated. The residue was diluted with ice water (200 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried (magnesium sulfate) and concentrated to give the difluoromethyl ether in 59% yield as a yellow oil. The nitro-ether (149 mmol) was dissolved in ethanol (37.5 mL), diluted with water (25 mL), and treated with ammonium chloride (84.7 mmol) and iron powder (105 mmol).

The reaction mixture was heated to reflux for 30 minutes and the suspension was filtered through celite. The filter cake was washed with ethanol three times and the combined filtrates were concentrated. The residue was dissolved in water and the pH was adjusted to 9-10 with 5 M sodium hydroxide. The aqueous layer was extracted with ethyl acetate (3 x 100 mL) and the combined organic layers were dried (magnesium sulfate) and concentrated in a yellow oil. The oil was dissolved in acetic anhydride (23.5 mmol) and the reaction mixture was kept at room temperature for 16 hours. The reaction mixture was diluted with water (50 mL) and neutralized with solid sodium bicarbonate. The precipitated solids were isolated by filtration, washed with water, and dried to give the acetamide in 62% yield as a light yellow solid. Acetic anhydride (19.6 mmol) was added to a solution of acetamide (13.2 mmol) in chloroform (20 mL) and the reaction mixture was heated to reflux. Steamy nitric acid (16.0 mmol) was added dropwise and the reaction mixture was refluxed for 30 minutes. The cooled solution was diluted with water (20 mL) and the aqueous layer was extracted with dichloromethane (3 x 10 mL). The combined organic layers were dried (magnesium sulfate) and concentrated to provide the nitro-amide in 83% yield. The amide (11.0 mmol), sodium hydroxide (43.8 mmol), and water (10 mL) were combined and the reaction mixture was maintained for 1.5 hours at 60 ° C. The reaction was allowed to cool to room temperature and the precipitated solids were isolated by filtration, and washed with water, dried to give the aniline in 98% yield as a light yellow solid. The aniline (15.7 mmol) was mixed with 40% hydrobromic acid (14.3 g) and water (10 mL) and the reaction mixture was heated to 80-90 ° C in order to completely dissolve the aniline. The reaction mixture was cooled to 0 ° C and a solution of sodium nitrite (23.2 mmol) in water (5.3 mL) was added over a period of 15 minutes. The solution was maintained for 40 minutes at 0-5 ° C and filtered. Copper (I) bromide (18.8 mmol) was dissolved in 40% hydrobromic acid (21 mL) and cooled to 0 ° C. The solution of the diazo salt was slowly added to the copper solution and the mixture was maintained for 30 minutes at 0-10 ° C. The reaction mixture was heated at 60 ° C for 30 minutes and then at 100 ° C for 10 minutes to ensure completion. The reaction mixture was allowed to cool to room temperature and extracted with dichloromethane (3 x 40 mL). The combined organic layers were washed with 1 M sodium hydroxide, water, 1 N hydrochloric acid, and water. The organic layer was dried (magnesium sulfate) and concentrated to give the nitro-bromide in 76% yield as a light yellow solid. Diethyl malonate (25.7 mmol) was added dropwise to a suspension of sodium hydride (25.8 mmol) in dimethyl sulfoxide (5 mL) at 0 ° C. The reaction mixture was heated to 60 ° C and maintained for 30 minutes. A solution of nitro-bromide (11.7 mmol) in dimethylsulfoxide (7 mL) was added dropwise and the reaction mixture was heated at 100 ° C for 5 hours. The cooled solution was poured into ice water and the aqueous layer was extracted with dichloromethane (3 x 100 mL). The combined organic layers were dried (magnesium sulfate) and concentrated to give the crude diester as an oil. The diester (11.7 mmol), sodium hydroxide (35 mmol), and water (20 mL) were combined and heated at 60 ° C for 1 hour. The reaction mixture was allowed to cool to room temperature and the aqueous layer was washed with dichloromethane (3 x 100 mL). The pH of the aqueous layer was carefully adjusted to 1 with concentrated hydrochloric acid and the reaction mixture was heated at 60 ° C for 1 hour. The suspension was cooled to 0 ° C and the solids were collected by filtration and dried to provide acid- in 64% yield. Acetyl chloride was added dropwise (15.3 mmol) to ethanol (50 mL) at 0 ° C. After 30 minutes, the acid (7.69 mmol) was added and the reaction mixture was heated to reflux for 15 hours. The reaction mixture was concentrated and the residue was partitioned between dichloromethane (20 mL) and saturated sodium bicarbonate (10 mL). The aqueous layer was further extracted with dichloromethane (2 x 20 mL) and the combined organic layers were dried (magnesium sulfate) and concentrated to give the ester in 94% yield as a brown oil. Acetic anhydride (6.0 mL) was added to a suspension of the ester (3.64 mmol), and acetic acid (7.0 mL) at 0 ° C. Zinc powder (14.6 mmol) was added in portions over 15 minutes and the reaction mixture was maintained for 30 minutes at 0 ° C and then for 1.5 h at room temperature. Additional zinc dust (6.15 mmol) was added and the reaction was maintained for 3 hours. The suspension was filtered through celite and the filtrate was concentrated. The residue was partitioned between saturated sodium bicarbonate (10 mL) and ethyl acetate (20 mL). The aqueous layer was further extracted with ethyl acetate (3 x 20 mL) 6 the combined organic layers were dried (magnesium sulfate) and concentrated to afford the acetamide in 92% yield as a brown oil. ~ Acetic anhydride (13.7 mmol), isoamyl nitrite (13.7 mmol), and potassium acetate (2.04 mmol) were added to a solution of acetamide (3.92 mmol) in chloroform (20 mL) and the suspension was heated to reflux for 16 hours. The solution was evaporated and the residue was partitioned between saturated sodium bicarbonate (10 mL) and dichloromethane (20 mL). The aqueous layer was further extracted with dichloromethane (2 x 20 ml) and the combined organic layers were dried (magnesium sulfate) and concentrated to give the crude N-acetylindazole ester as a brown oil. The ester (3.36 mmol), sodium hydroxide (10 mmol) and water (5 mL) were combined and the reaction was maintained for 24 hours at 60 ° C. After cooling down to room temperature, the aqueous layer was washed with dichloromethane (3 x 20 mL). The aqueous layer was adjusted to pH 1 with concentrated hydrochloric acid and the precipitated solids were collected by filtration, washed with water and dichloromethane, and dried to provide the acid in 26% yield. The following acids were prepared according to this method: 6- (difluoromethoxy) -lH-indazole-3-carboxylic acid.

Amine preparations: Process 11: Process 11 details the preparation of 2-methyl-2, 5-diazabicyclo [2.2.2] octane from diethyl 2,5-diaminohexanedioate. Benzaldehyde (21.8 mmol) was added to a solution of diethyl 2,5-diaminohexanedioate dihydrochloride (10.0 mmol) in absolute ethanol (75 mL) and acetic acid (10 mL) at room temperature. The resulting mixture was heated at 80 ° C for 2 hours. The reaction mixture was allowed to cool to room temperature and sodium triacetoxyborohydride (54.2 mmol) was added in small portions. The resulting white suspension was maintained at room temperature for 16 hours and concentrated. The residue was diluted with water, cooled to 0 ° C, and the pH was adjusted to 9 with 1 N sodium hydroxide. The aqueous layer was extracted with ethyl acetate (3 x 100 mL) and the combined organic layers were washed with brine, dried (magnesium sulfate), and concentrated to provide 3.05 g of white solid. Sodium methoxide (25% by weight, 23 mmol) was added to a solution of the dibenzylamine in ethanol (200 mL) the reaction mixture was heated at reflux for 16 hours. The reaction mixture was cooled to room temperature and concentrated. The residue was diluted with ethyl acetate (200 mL), washed with 1 N hydrochloric acid, dried (magnesium sulfate) and concentrated to yield the bicyclic lactam in 47% yield as a colorless solid. Sulfuric acid (15.8 mmol) was added dropwise to a stirred suspension of lithium aluminum hydride (31.6 mmol) in tetrahydrofuran (50 mL) under a nitrogen atmosphere. The mixture was maintained for 30 minutes and the supernatant was added dropwise to a solution of the bicyclic lactam (1.5 mmol) in tetrahydrofuran (50 mL) at 0 ° C. The reaction mixture was allowed to warm to room temperature and was maintained for 16 hours. The reaction mixture was carefully cooled by the addition of solid sodium sulfate decahydrate (2.5 g) in portions. The reaction mixture was diluted with 2 M sodium hydroxide (10 mL), it was filtered through Celite, and the. filtered was concentrated. The residue was diluted with 2N hydrochloric acid (100 mL) and extracted with ethyl acetate. The pH of the aqueous layer was adjusted to 9 with 2 M sodium hydroxide and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried (magnesium sulfate), and concentrated. The resulting light yellow oil was then treated with methanolic hydrogen chloride, was generated in situ by adding acetyl chloride (0.5 mL) to methanol (10 mL), at room temperature for 10 minutes. The volatiles were removed under reduced pressure to provide the bicyclic diamine dihydrochloride in 92% yield as a whitish foamy solid. A suspension of diamine (3.00 mmol) and 10% palladium on carbon (200 mg) in methanol (100 mL) and concentrated hydrochloric acid (2 mL) was placed under a hydrogen atmosphere and maintained for 16 hours. The catalyst was removed by filtration and the filter cake was washed with water. The filtrate was concentrated to provide the bicyclic diamine dihydrochloride in 88% yield as a colorless solid. A solution of di-tert-butyldicarbonate (6.5 mmol) in isopropanol (15 mL) was added dropwise to a solution of the diamine (7.06 mmol) in isopropanol (100 mL), water (35 mL), and sodium hydroxide. 1 M (6.5 mL) at 0 ° C. The reaction mixture was maintained for 1.5 h at 0 ° C and concentrated to approximately -50 mL. The aqueous slurry was saturated with solid sodium chloride and the pH was adjusted to 10 with 2 M sodium hydroxide. The aqueous layer was extracted with ethyl acetate (3 x 35 mL) and the combined organic layers were washed with brine and they dried up (magnesium sulphate) . The volatiles were removed under reduced pressure to give the crude mono-protected diamine in 42% yield as a light yellow oil. Formaldehyde was added (37 aqueous solution %, 7.43 mmol) and acetic acid (4.46 mmol) to a solution of the crude amine - (2.97 mmol) in tetrahydrofuran (25 mL). Sodium triacetoxyborohydride (5.94 mmol) was added in small portions to the reaction mixture after 10 minutes and the reaction mixture was maintained for 16 hours. The reaction mixture was diluted with a 10% aqueous sodium bicarbonate solution (100 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with brine, dried (magnesium sulfate), and concentrated to give a light yellow residue. The residue was dissolved in dioxane (25 mL) and diluted with concentrated hydrochloric acid (12.5 mL). The volatiles are. they were removed after 30 minutes, thus providing the bicyclic mono-methyl base in 40% yield as a colorless solid. The procedure for N-methylation and the removal of the carbamate protecting group is. used for the production of 2-methyl-2, 5-diazabicyclohydrochloride [2.2. l] heptane. Literature references: Newman, H. J. "Heterocyclic Chem. 1974, 11, 449. Sturm, PA; Henry, DW J \ 'Med. Chem. 1974, 17, 481. The following bases were prepared using this method: Dihydrochloride of 2-methyl-2,5-diazabicyclo [2.2.2] octane; (S, 4S) -2-methyl-2,5-diazabicyclo [2.2.1] heptane dichloride.

Synthesis procedures: The following procedures (A-G) detail the preparation of the substituted bicyclic derivatives.

Process A: Process A provides a method for the coupling between bicyclobases and carboxylic acids to form carboxamide derivatives. To a solution of carboxylic acid (1 mmol) in tetrahydrofuran (10 mL) and N, N-dimethylformamide (1 mL) was added N, N-diisopropylethylamine (3 mmol) and amine dihydrochloride of bicyclobase (1 mmol). The reaction mixture was kept at room temperature for 30 minutes under nitrogen and then HATU (1.00 mmol) was added. After 18 hours, the reaction mixture was partitioned between saturated aqueous potassium carbonate solution and 95/5 dichloromethane / methanol. The aqueous layer was extracted with dichloromethane / methanol 95/5 (2X), and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using the mixture of [dichloromethane / methanol / ammonium hydroxide 90/10/1] as the eluent, thereby providing the carboxamide product. The following examples were prepared according to procedure A: Example 1: 3- [(SS, 4S) -2,5-Diazabicyclo [2.2.1] hept-2-ylcarbonyl] -IH-indazole hydrochloride.

Prepared using Procedure A in 28% yield. X H NMR (CD30D) d 8.22 (m, 1 H); 7.61 (m, 1 H); 7. 45 (m, 1 H); 7.27 (m, 1 H); 3.82 (m, 1 H); 3.51 (m, 2 H); 2. 30 (m, 1 H); 2.07 (m, 1 H). LC / MS (El) tR 3.55 min, m / z 243 (M ++ l).

Example 2: 3- (2,5-Diazabicyclo [2.2-.2] oct-2-ylcarbonyl) -6- (1,3-thiazol-2-yl) -lH-indazole hydrochloride.

Prepared using Procedure A in 30% yield. LC / MS (El) tR 3.04 min, m / z 340 (M ++ l).

Example 3: 3- (2,5-Diazabicyclo [2.2.2] oct-2-ylcarbonyl) -1H-indazole hydrochloride.

Prepared using Procedure A in 30% yield. LC / MS (El) tR 2.85 min, m / z 257 (M ++ l).

Example 4: 3- [(5-Methyl-2, 5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -IH-indazole hydroformate.

Prepared using Procedure A in 25% yield. LC / MS (El) tR 2.83 min, m / z 271 (M ++ l).

Example 5: Hydroformate of 3- [(5-Methyl-2,5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -6- (1,3-thiazol-2-yl) -IH-indazole.

Prepared using Procedure A in 20% yield. LC / MS (El) tR 2. 81 min, m / z 376 (M ++ l).

Example 6: hydroformate of 3-. { [(SS, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} - !, 2-benzisothiazole.

Prepared using Procedure A in 56% yield. LC / MS (El) tR 2.53 min, m / z 274 (M ++ l).

Example 7: 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -l, 2- benzisothiazole.

Prepared using Procedure A in 77% yield. LC / MS (El) tR 2.75 min, m / z 274 (M ++ l).

Example 8: hydroformiago of 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1, 2-benzisoxazole.

Prepared using Procedure A in 20% yield. LC / MS (El) tR 3.48 min, m / z 258 (M ++ l).

Example 9: hydroformate of 3-. { [(S, S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.2] hept-2-yl] carbonyl} -5- (1,3-thiazol-2-yl) lH-indazole.

Prepared using Procedure A in 25% yield. LC / MS (El) tR 2.87 min, m / z 340 (M ++ l).

Example 10: hydroformate of 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -5- (4-methyl-l, 3-thiazol-2-yl) -1H-indazole.

Prepared using Procedure A in 30% yield. LC / MS (El) tR 2.76 min, m / z 354 (M ++ l). '" Example 11: hydroformate of 3-. { [(SS, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -5- (5-methyl-l, 3-thiazol-2-yl) -lH-indazole.

Prepared using Procedure A in 30% yield. LC / MS (El) tR 2.9 min, m / z 354 (M ++ l).

Example 12: hydroformate of 3-. { [(SS, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -5- (tetrahydro-2H-pyran-4-yl) -lH-indazole.

Prepared using Procedure A in 25% yield. LC / MS (El) tR 2.85 min, m / z 339 (M ++ l).

Example 13: hydroformate of 3-. { [(SS, 4S) -5-Met-il-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -5- (trifluoromethoxy) -IH-indazole.

Prepared using Procedure A in 45% yield. LC / MS (El) tR 4.82 min, m / z 341 (M ++ l).

Example 14: Hydroformate of 3-. { [(SS, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (1, 3-oxazol-2-yl) -IH-indazole.

Prepared using Procedure A in 30% yield. LC / MS (El) tR5.25 min, m / z 324 (M ++ l).

Example 15: hydroformate of 3-. { [(SS, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (1, 3-thiazol-2-yl) -lH-indazole.

Prepared using Procedure A in 25% yield. LC / MS (El) tR 2.69 min, m / z 362 (M ++ l).

Example 16: hydroformate of 3-. { [(SS, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] ept-2-yl] carbonyl} -6- (4-methyl-l, 3-thiazol-2-yl) -lH-indazole.

Prepared using Procedure A in 25% yield. LC / MS (El) tR 5.18 min, m / z 354 (M ++ l).

Example 17: hydroformate of 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (5-methyl-l, 3-thiazol-2-yl) -IH-indazole.

Prepared using Procedure A in 25% yield. LC / MS (El) tR 5.18 min, in / z 354 (M ++ l).

Example 18: hydroformate of 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (tetrahydro-2H-pyran-4-yl) -lH-indazole.

Prepared using Procedure A in 25% yield. LC / MS (El) tR 2.79 min, m / z 341 (M ++ l).

Example 19: hydroformate 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (trifluoromethoxy) lH-indazole.

Prepared using Procedure A in 25 performance. LC / MS (El) tR 5.04 min, m / z 341 (M ++ l).

Example 20: hydroformate of 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (trifluoromethyl) -1H-indazole.

Prepared using the Procedure in 45% yield. LC / MS (El) tR 3.85 min, nz / z 325 (M ++ l).

Example 21: hydroformate of 3-1 [(SS, 4S) -5-Methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -7- (trifluoromethoxy) -1H-indazole.

Prepared using Procedure A in 25% yield. LC / MS (El) tR 4.66 min, in / z 341 (M ++ l).

Example 22: hydroformate of 5- (3,6-Dihydro-2H-pyran-4-yl) -3-. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} -lH-indazole.

Prepared using Procedure A in 30% yield. LC / MS (El) tR 2.83 min, m / z 339 (M ++ l).

Example 23: Hydroformate of 5- (Difluoromethoxy) -3-. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.2.1] hept-2-yl] carbonyl} -1H-indazole.

Prepared using Procedure A in 35% yield. LC / MS (El) tR 2.52 min, Í? / Z 323 (M ++ l).

Example 24: 5-Bromo-3- [(lS 4S) -2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl hydrochloride} -lH-indazole.

Prepared using Procedure A in 45% yield. LC / MS (El) tR 4.76 min, m / z 321/323 (M ++ l).

Example 25: 5-Methoxy-3- [(5-methyl-2,5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -lH-indazole hydroformate.

Prepared using Procedure A in 20% yield. LC / MS (El) tR 2. 85 min, m / z 301 (M ++ l).

Example 26: 3- (2,5-Diazabicyclo [2.2.2] oct-2-ylcarbonyl) -5-methoxy-lH-indazole hydrochloride.

Prepared using Procedure A in 30% yield. LC / MS (El) tR 2.87 min, m / z 287 (M ++ l).

Example 27: 5-Methoxy-3- hydrochloride. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-y] icarbonyl} -lH-indazole.

Prepared using Procedure A in 35% yield. LC / MS (El) tR 2.85 min, m / z 287 (M ++ l).

Example 28: 5-Methoxy-3- hydroformate. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.2] hept-2-yl] carbonyl} -lH-indazole.

Prepared using Procedure A in 45% yield. LC / MS (El) tR 2.51 min, m / z 287 (M ++ l).

Example 29: hydroformate of 6- (3,6-Dihydro-2H-pyran-4-yl) 3-. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} -lH-indazole.

Prepared using Procedure A in 25% yield. LC / MS (El) tR 2 .8 min, m / z 339 (M ++ l).

Example 30: Hydroformate of 6- (Difluoromethoxy) -3-. { [(SS, 4S) 5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -lH-indazole.

Prepared using Procedure A in 3'5% yield. LC / MS (El) tR 2.47 min, m / z 323 (m ++ l).

Example 31: 6-Bromo-3- [(1S, 4S) -2,5-diazabicyclo [2 .2,11] hept-2-ylcarbonyl] -lH-indazole hydrochloride Prepared using Procedure A in 45% yield. LC / MS (El) tR 3.71 min, m / z 321/323 (M ++ l).

Example 32: Hydroformate of 6-Cyclopropyl-3-. { [(SS, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -l, 2-benzisothiazole.

Prepared using Procedure A in 56% yield. LC / MS (El) tR 4.48 min, m / z 314 (M ++ l).

Example 33: Hydrochloride of 6-Ethoxy-3-. { [(SS, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -l, 2-benzisothiazole.

Prepared using Procedure A in 43% yield. LC / MS (El) tR 3.79 min, m / z 318 (M ++ l).

Example 34: 3- (2,5-Diazabicyclo [2.2.2] oct-2-ylcarbonyl) -6-methoxy-1H-indazole hydrochloride.

Prepared using Procedure A in 30% yield. LC / MS (El) tR 2.89 min, m / z 287. (M ++ l).

Example 35: 6-Methoxy-3- [(5-methyl-2, 5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -1H-indazole hydroformate.

Prepared using Procedure A in 28% yield. LC / MS (El) tR 2.83 min, m / z 301 (M ++ l).

Example 36: Hydrochloride of 6-methoxy-3-. { [(SS, 4S) -5-methyl-2,5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} - !, 2-benzisothiazole. gg Prepared using Procedure A in 64% yield. LC / MS (El) tR 2. 91 min, m / z 304 (M ++ l).

Example 37: 6-Methoxy-3-. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -l, 2-benzisothiazole Prepared using Procedure A in 85% yield. LC / MS (El) tR 3.06 min, m / z 304 (M ++ l).

Example 38: 6-Methoxy-3- hydrochloride. { [(SS, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -lH-indazole.

Prepared using Procedure A in 35% yield. LC / MS (El) tR 2.83 min, m / z 287 (M ++ l).

Example 39: Hydroformate of 6-methoxy-3-. { [(SS, 4S) -5-methyl-2, 5-diazabicyclo [2.2.2] hept-2-yl] carbonyl} -IH-indazole.

Prepared using Procedure A 'at' 35% yield. LC / MS (El) tR 2.83 min, in / z 287 (M ++ l).

Example 40: Hydroformate of 7-Fluoro-6-methoxy-3-. { [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -lH-indazole.

Prepared using Procedure A in 31% yield. LC / MS (El) ta 2.54, in / z 305 (M ++ l).

Example 41: 7-Methoxy-3- hydroformate. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1, 2-benzisothiazole.

Prepared using Procedure A in 50% yield. LC / MS (El) tB 2.6 min, in / z 304 (M ++ l).

Method B: Process B provides a method for the coupling between brominated and iodated bicyclobase carboxamides and boronic acids to form substituted aryl or substituted heteroaryl derivatives. Into a 5 mL microwave reaction vessel was added carboxamide (0.3 mmol) of brominated bicarbonate, boronic acid (0.6 mmol), and tris (dibenzylideneacetone) dipalladium (0) (0.03 mmol), tri-ternary tetrafluoroborate. butylphosphine (0.06 mmol), and potassium carbonate (0.8 mmol). The vessel was evacuated, refilled with argon gas, and the contents were diluted with N, N-dimethylformamide (5.0 mL). The container was sealed and subjected to microwave irradiation at 200 ° C for 600 seconds. The contents of the reaction were filtered through celite (methanol wash) and loaded onto a 5 g SCX column. The column was washed with methanol (50 mL) and the product was eluted with 2 M ammonia in methanol and concentrated. The residue was purified by chromatography [ethyl acetate / (ethyl acetate / methanol / ammonium hydroxide 70/30/1) l / la 0/1] followed by preparative HPLC using an 8 minute gradient of water (formic acid 0.1 %) / acetonitrile (0.1% formic acid) from 95/5 to 20/80, thereby providing the substituted heteroaryl product. The following examples were prepared according to procedure B: Example 42: hydroformate of 3-. { [(SS, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -5- (2-thienyl) -1H-indazole.

Prepared using Procedure B in 25% yield. Zn NMR (CD3OD) d 8.48 (m, 2H); 7.75 (m, ÍH); 7.58 (m, 1H); 7.32 (m, 2H); 7.08 (m, ÍH); 4.25 (m, ÍH); 3.70 (m, 2H); 3.32 (m, ÍH); 2.85 (d, 3H); 2.22 (m, 2H), LC / MS (El) tR 5.03 min, m / z 339 (M ++ l). - ' Example 43: hydroformate of 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -5- (4-methyl-2-thienyl) -lH-indazole.

Prepared using Procedure B in 25% yield. LC / MS (El) tR 5.33 min, m / z 353 (M ++ l).

Example 44: 3- { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} -5- (5-methyl-2-thienyl) -IH-indazole.

Prepared using Procedure B in 25% yield. LC / MS (El) tR 5.32 min, m / z 353 (M ++ l).

Example 45: hydroformate of 3-. { [(SS, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -5-phenyl-lH-indazole.

Prepared using Procedure B in - 25% yield. LC / MS (El) tR 5.17 min, m / z 333 (M ++ l).

Example 46: hydroformate of 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (2-thienyl) -1H-indazole.

Prepared using Procedure B in 25% yield. LC / MS (El) tR 5.13 min, m / z 33g (M ++ l).

Example 47: hydroformate of 3-. { [(1S, -4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (3-thienyl) -1H-indazole.

Prepared using Procedure B in 25% yield. LC / MS (El) tR 4.3 min, m / z 339 (M ++ l).

Example 48: hydroformate of 3-. { [(SS, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (4-methyl-2-thienyl) -IH-indazole.

Prepared using Procedure B in 20% yield. LC / MS (El) tR 5.35 min, m / z 353 (M ++ l).

Example 49: hydroformate of 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (5-methyl-2-furyl) -lH-indazole.

Prepared using Procedure B in 25% yield. LC / MS (El) tR 5.35 min, / z 337 (M ++ l).

Example 50: hydroformate of 3-. { [(SS, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (5-methyl-2-thienyl) -1H-indazole.

H A OH Prepared using Procedure B in 25% yield. LC / MS (El) tR 4. 61 min, m / z 353 (M ++ l).

Example 51: Hydroformate of 5- (2-Furyl) -3-. { [(SS, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -lH-índazol.

Prepared using Procedure B in 25% yield. LC / MS (El) tR 41 min, / z 323 (M ++ l).

Example 52: 5- (3-Fluorophenyl) -3- hydroformate. { [(SS, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -lH-indazole.

Prepared using Procedure B in 25% yield. LC / MS (El) t * 5.28 min, m / z 351 (M ++ l).

Example 53: 5- (4-Fluorophenyl) -3- hydroformate. { [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -lH-indazole.

Prepared using Procedure B 'in 25% yield. LC / MS (El) tR 5.25 min, m / z 351 (M ++ l).

Example 54: 5- (4-Methoxy-enyl) -3- hydroformate. { [(SS, 4S) 5-methyl-2, 5 -diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole.

Prepared using Procedure B in 20% yield. LC / MS (El) tR 5.19 min, m / z 363 (M ++ l). - Example 55: Hydroformate of 6- (2-Furyl) -3-. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -lH-indazole.

H A OH Prepared using Procedure B in 25% yield. LC / MS (El) tR 4.9 min, m / z 323 (M ++ l).

Example 56: Hydroformate of 6- (3-Furyl) -3-. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -lH-indazole.

Prepared using Procedure B in 25% yield. LC / MS (El) tR 3. g3 min, m / z 323 (M ++ l).

Process C: Process C provides a method for reductive coupling between carboxamides of bicyclobase and cargo xaldehydes to form tertiary amine derivatives. To the suspension of carboxylide hydrochloride of bicyclobase (0.4 mmol), carboxaldehyde (1.0 mmol), N, N-diisopropylethylamine (1.2 mmol), and acetic acid (0.48 mmol) was added sodium triacetoxyborohydride (0.68 mmol). The reaction mixture was kept at room temperature for 2 hours and then poured into water, extracted with dichloromethane / methanol 95/5 (2 x 30 mL), and the combined extracts were concentrated. The residue was purified by preparative HPLC using an 8 minute gradient of water (0.1% formic acid) / acetonitrile (0.1% formic acid) 95/5 to 20/80, thereby providing the tertiary amine product. The following examples were prepared according to procedure C.

Example 57: hydroformate of 3-. { [(SS, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -IH-indazole.

Prepared using Procedure C or A in 30% yield. X H NMR (CD3OD) d 8.42 (s, 1 H); 8.23 (m, 1 H); 7.85 (m, 1 H); 7.77 (m, 1 H); 7.64 (m, 1 H); 4.15 (m, 2 H); 4.01 (m, 2 H); 2.51 (d, 3 H); 2.11 (m, 2 H). LC / MS (El) tR 2.5 min, m / z 257 (M ++ l).

Example 58: 3-. { [(1S, 4S) -5-Ethyl-2, 5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} -lH-indazole.

Prepared using Procedure C in 45% yield. LC / MS (El) tR 2.77 min, / z 271 (M ++ l).

Example 59: N- (Cyclopropylmethyl) -3- [(5-methyl-2,5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -1H-indazol-5-amine.

Prepared using Procedure C in 70% yield. LC / MS (El) tR 1.33 min, m / z 340 (M ++ l).

Example 60: N- (Cyclopropylmethyl) -3-. { [(1S, 4S) -5-met? L-2, 5-diazabicyclo [2.2.1] -hept-2-yl] carbonyl} -lH-indazol-5-amine.

Prepared using Procedure C in 80% yield. LC / MS (El) tR 1.36 min, m / z 326 (M ++ l).

Example 61: N, N-Dimethyl-3- [(5-methyl-2, 5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -lH-indazol-5-amine hydroformate.

Prepared using Procedure C in 58% yield. LC / MS (El) tR 1.49 min, m / z 314 (M ++ l).

Example 62: N, N-Dimethyl-3-hydroformate. { [(SS, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -lH-indazol-5-amine.

Prepared using Procedure C in 51% yield. LC / MS (El) tR 1.5 min, m / z 300 (M ++ l). _ Example 63: N, N-Dimethyl-3-hydroformate. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -IH-indazol-6-amine.

Prepared using Procedure C in 59% yield. LC / MS (El) tR 1.5 min, m / z 300 (M ++ l).

Example 64 5-Bromo-3-. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -IH- indazol.

Prepared using Procedure C or A in 25% yield. LC / MS (El) tR3.57 min, m / z 335/337 (M ++ l).

Example 65: hydroformate of 3-. { [(SS, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-y] carbonyl} -5- (3-thienyl) -lH- ~ indazole.

Prepared using Procedure C or B in 25% yield. LC / MS (El) tR 417 min, m / z 339 (M ++ 1).

Example 66: hydroformate of 5- (3-Furyl) -3-. { [(SS, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -IH-indazole.

Prepared using Procedure C or B in 15% yield. LC / MS (El) tR 4.1 min, m / z 323 (M l).

Method D: Method D provides a method for the demethylation of methoxy-substituted indazole bicyclobase amides to form phenol derivatives and the subsequent reaction of the phenol with various alkylating agents. The methyloxy-indazole bicyclobase amide (6.98 mmol) was diluted with dichloromethane (60 mL) and dichloroethane (15 mL) and the solution was cooled to -78 ° C. A 1.0 M solution of boron tribromide in dichloromethane (35 mmol) was added dropwise over 30 minutes. The reaction mixture was allowed to warm to room temperature and was maintained for 20 hours. An additional aliquot of boron tribromide in dichloromethane (6 mmol) was added and the reaction was maintained for an additional 16 hours. The reaction was cooled slowly with MeOH (30 mL) and concentrated to dryness. The residue was purified by chromatography using a dichloromethane / methanol (90/10) followed by elution with a mixture of dichloromethane / methanol / ammonium hydroxide (90/10/1) to provide the phenol (54%) as a brown solid. The phenol (0.734 mmol) was dissolved in N, N-dimethylformamide (10 mL) and treated with potassium carbonate (1.46 mmol) and alkyl bromide (0.95 mmol). The reaction was maintained for 16 hours at room temperature and filtered and concentrated to dryness. The residue was purified by preparative HPLC using an 8 minute gradient of water (0.1% formic acid) / acetonitrile (0.1% formic acid) from 95/5 to 20/80 of water, thereby providing the ether product . The following examples were prepared according to procedure D: Example 67: 5-Hydroxy-3-. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (1, 3-thiazol-2-yl) -lH-indazole.

Prepared using Procedure D in 64% yield. X H NMR (Me 2 SO-d 6) d 10.76 (s, 1 H); 8.90 (s, ÍH); 8. 25 (m, 2H); 7.99 (s, ÍH); 7.85 (m, ÍH); 4.46 (br, 1H); 3.62 (m, ÍH); 3.38 (m, ÍH); 3.20 (m, 3H); 2.20 (m, 2H); 1.85 (m, 2H), LC / MS (El) tR 0.75, complexion 273 (M ++ l).

Example 68: hydroformate of 5- (Cic! Opentyloxy) -3-. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -lH-indazole.

Prepared using Procedure D in 25% yield. X H NMR (CD3OD) d 8.48 (m, 2H); 7.75 (m, ÍH); 7. 58 (m, 1H); 7.32 (m, 2H); 7.08 (m, 1H); 4.25 (m, 1H); 3.70 (m, 2H); 3.32 (m, ÍH); 2.85 (d, 3H); 2.22 (m, 2H), LC / MS (El) ta 5.25 min, m / z 341 (M ++ l).

Example 69: Hydroformate of 5- (Cyclopropylmethoxy) -3-. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} -lH-indazole.

H OH Prepared using Procedure D in 25% yield. LC / MS (El) tR 2.85 min, m / z 327 (M ++ l).

Example 70: Hydropromate of 6- (Cyclopentyloxy) -3-. { [(SS, 4S) 5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole.

Prepared using Procedure D in 30% yield. LC / MS (El) tR 6.1 min, m / z 341 (M ++ l).

Method E: Process E provides a method for the reduction of nitro-substituted bicyclobase amides to form aniline derivatives. To a solution of the nitro-sust-ituide bicyclobase (3.8 mmol), prepared by procedure A, in methanol (100 mL) was added 10% palladium on carbon (200 mg). The reaction was placed under a hydrogen gas atmosphere (60 psi) and stirred overnight. The catalyst was removed by filtration through a pad of celite, and washed with methanol (100 ml). The combined filtrates were concentrated to give the desired product. The following examples were prepared according to procedure E: Example 71: 5-Amino-3- [(5-Methyl-2,5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -1H-indazole.

Prepared using Procedure E in 2% yield. XH NMR (CD3OD) d 7.36 (d, J = 12.0, 1 H), 7.31 (s, 1 H), 7.0 (d, J = 12.0, 1 H), 4.03 (m, 1 H), 3.62 (m, 1 H), 3.31 (s, 3 H), 3.10 (m, 2 H), 3.01 (m, 2 H), 2.30-2.00 (m, 2 H), 1.98-1.75 (m, 2 H). LC / MS (El) tR 1.71 min, m / z 286 (M ++ l).

Example 72_: 5-Amino-3-. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (1,3-thiazol-2-yl) -1H-indazole.

Prepared using Procedure E in 74% yield. LC / MS (El) tR 1.76 min, rn / z 272 (M ++ l) Method F: Method F provides a method for the reaction of the aniline bicyclobases with acid chlorides and anhydrides to form amide derivatives. To a solution of the aniline (0.460 mmol) in pyridine (4 mL) was added carbonyl chloride (0.59 mmol). The reaction mixture was kept for 2 hours and concentrated to dryness. The resulting residue was purified by preparative HPLC using an 8 minute gradient of water (0.1% formic acid) / acetonitrile (0.1% formic acid) 95/5 to 20/80, thereby providing the amide product. The following examples were prepared according to procedure F: Example 73: Hydroformate of N-. { 3- [(5-Methyl-2, 5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -1H-indazol-5-yl} cyclopropanecarboxamide.

Prepared using Procedure F in 28% yield. NMR XH (CD3OD) d 8.53 (s, 1 H), 8.40 (s, 1 H), 7.86 (s, 1 H), 4.70 (m, 1 H), 4.33 (m, 1 H), 4.20 (m, 1 H), 3.90 (m, 1 H), 3.90 (m, 1 H), 3.60-3.40 (m, 2 H), 3.0 (s, 3 H), 2.50-2.10 (m, 2 H), 2.10- 1.90 (m, 2 H), 1.80 (m, 1 H), 0.93 (2 H), 0.85 (m, 2 H). LC / MS (El) tR 2.83 min, in / z 354 (M ++ l).

Example 74: N- (l- (Cyclopropylcarbonyl) -3 - [(5-methyl-2, 5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -lH-indazol-5-yl hydroformate. Cyclopropanecarboxamide Prepared using Procedure F in 9.4% yield. LC / MS (El) tR 5.13 min, m / z 422 (M ++ l).

Example 75: N- (3- {[[(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -lH-indazol-5 hydroformate -yl) -cyclopropancarboxamide.

Prepared using Procedure F in 35% yield. LC / MS (El) tR 2. 18 min, III / Z 340 (M ++ l).

Method G: Process G provides a method for the reaction of aniline bicyclobases with isocyanates to form urea derivatives. To a solution of the aniline (0.550 mmol) in pyridine (4 mL) was added the isocyanate (0.72 mmol). The reaction mixture was maintained for 16 hours and concentrated to dryness The residue was purified by preparative HPLC using an 8 minute gradient of water (0.1% formic acid) / acetonitrile (0 ... 1% formic acid). ) from 95/5 to 20/80, thus providing the urea product The following examples were prepared according to procedure G: Example 76: N- (3- {[[(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -lH-indazole-5 hydroformate -yl) -N'-propylurea.

OH Prepared using Procedure G in 29% yield. XH NMR (CD3OD) d 8.42 (broad, 1 H), 8.21-8.14 (m, 2 H), 7.47 (m, 1 H), 4.40-4.20 (m, 1 H), 3.60 (m, 1 H), 3.30 (s, 3 H), 3.20 (m, 2 H), 3.10 (t, 6.0, 2 H), 2.g? (m, 2 H), 2.50-2.10 (m, 2 H), 2.10-1.85 (m, 2 H), 1.50 (q, J = 6.0, 2 H), O. d (t, J = 6.0, 3 H). LC / MS (El) tR 2.84 min, ni / z 357 (M ++ l).

Example 77: 3- [(5-Methyl-2,5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -N-propyl-5-hydroformate. { [(propylamino) carbonyl] amino} -IH-indazol-l-carboxamide.

Prepared using Procedure G in 7 ^ -8% yield. LC / MS (El) tR 5.11 min, in / z 456 (M ++ l).

Example 78: Hydroformate of N- (4-Fluorobenzyl) -N '- (3 { [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl .}. -IH-indazol-5-yl) urea.

Prepared using Procedure G in performance 27. LC / MS (El) tR 4.74 min, m / z 423 (M ++ l).

Example 7: Hydroformate of N- (4-Fluorobenzyl) -5- ( { [(4-fluorobenzyl) amino] carbonyl}. Amino) -3 - [(5-methyl-2, 5-diazabicyclo [2.2. 2] oct-2-yl) carbonyl] -lH-indazole-1-carboxamide.

Prepared using Procedure G in 5.2% yield. LC / MS (El) tR 5.g min, m / z 588 (M ++ l).

Example 80: Hydroformate of N-Cyclopentyl-N '- (3- {[[(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} - lH-indazol-5-yl) urea.

Prepared using Procedure G in 32% yield. LC / MS (El) tR 2.85 min, m / z 383 (M ++ l).

Example 81: Hydroformate of N-Cyclopentyl-5-. { [(cyclopentylamino) carbonyl] amino} -3- [(5-Methyl-2,5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -lH-indazole-1-carboxamide.

Prepared using Procedure G in 6.6% yield. LC / MS (El) tR 5.46 min, m / z 508 (M ++ l).

Example 82: N- (4-Fluorobenzyl) -N '- hydroformate. { 3- [(5-methyl-2, 5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -lH-indazol-5-yl} urea.

Prepared using Procedure G • in 22% yield. LC / MS (El) tR 4.78 min, m / z 437 (M ++ 1).

Example 83_: N- hydroformate. { 3- [(5-Methyl-2, 5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -lH-indazol-5-yl} -N'-propylurea.

Prepared using, Procedure G in 33% yield. LC / MS (El) tR 3.11 min, m / z 372 (M ++ l).

Example 84: N-Cyclopentyl-N '- hydroformate. { 3- [(5-methyl-2, 5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -lH-indazol-5-yl} urea Prepared using Procedure G in 34% yield. LC / MS (El) tR 2.9 min, m / z 397 (M ++ l).

Example 85: Labeling with [3H] MLA Materials: Rat brain: Pel-Freez Biologicals, CAT No. 56004-2 Protease inhibitor cocktail tablets: Roche, CAT No. 16974g8 Membrane preparation Rat brains in 20 vol (p / v) sucrose 0.32 M cooled with ice cqn protease inhibitors (one tablet per 50 ml), were homogenized with a polytron for 10 seconds in setting 11, then centrifuged 10 min at 1000 g, 4 ° C. The supernatant was centrifuged again for 20 minutes at 20,000 g, 4 ° C. The elements were resuspended in binding buffer (200 mM TRIS-HC1, 20 mM HEPES, pH 7.5, 144 mM NaCl, 1.5 mM KCl, MgSO41 mM, 2 mM CaCl 2, 0.1% BSA (w / v)) and stored the membrane preparation at -80 ° C. For the saturation assay, 200 μl of the assay mixture in the binding buffer contains 200 μg of membrane protein, 0.2 to 44 nM of [3 H] MLA. The non-specific binding was defined using 1 μM MLA. The competition assay was carried out with [3 H] MLA 2 nM and a desired range of compounds. The test mixture was incubated at 22 ° C for 2 hours, then collected with a GF / B filter pre-wetted with 0.3% PEI in the test buffer using Tomtec harvester. The filter was washed three times with binding buffer and the radioactivity was counted with Trilux. The binding affinities for the preferred compounds of the invention were 26 micromolar to 64 nanomolar, especially 2.5 micromolar to 64 nanomolar. The preceding examples were repeated with similar success by substituting the described reagents in a generic or specific manner and / or the operating conditions of this invention for those used in the previous examples. Since the invention has been illustrated with respect to the production of particular compounds, it will be apparent that variations and modifications of the invention can be made without departing from the spirit or scope of the invention. '

Claims (7)

1. CLAIMS 1. A compound of Formulas I, II, or III where A is -CH2 B is And it is O or S; X1 to X4 are each, independently, CH, CR1, or N, wherein at most one of X1 to X4 is N; X5 to X8 are each, independently, CH, CR2, or N, where at most one of X5 to X8 is?; X9 to X12 are each, independently, CH, CR3, or?, Wherein at most one of X9 to X12 is N; R1, R2 and R3 are each, independently, H, C? -e-alkyl which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, OH, alkoxy having from 1 to 4 carbon atoms; carbon, NR4R5, SH, SR4, SOR4, C3-8-cycloalkyl, S02R4, S02NR4Rs, Ar, Het, or combinations thereof, C2.6-alkenyl which is unsubstituted or substituted one or more times by F, Cl, Br , I, CN, OH, alkoxy having from 1 to 4 carbon atoms, NR4R5, SH, SR4, SOR4, C3-8-cycloalkyl, S02R4, S02NR4R5, Ar, Het, or combinations thereof, C2_6-alkynyl which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, OH, alkoxy having from 1 to 4 carbon atoms, NR4R5, SH, SR4, SOR4, C3-8 ~ cycloalkyl, S02R4, S02NR4R5, Ar, Het, or combinations thereof, C3-8-cycloalkyl which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, OH, alkoxy having from 1 to 4 carbon atoms, NRR5, SH, SR4, SOR4, C3.8-unsubstituted cycloalkyl, S02R4, S02NR4R5, Ar, Het, or combinations thereof, halogen C ?, N02,? R R5, SH, SR4, SOR4, S02R4, S02? R4R5,? R4S02R5, CO? R4R5, COOR4,? R4C0R5,? R4C02R5,? R4CO? R4R5, Ar, Het, or R60-; R4 and R5 are each independently H or Ar, Ar-C? _4-alkyl, Het, Ci-4-alkyl, C3.8-cycloalkyl, or C4.8-cycloalkylalkyl, each of which is unsubstituted or substituted or more times by F, Cl, Br, I, CN, OH, alkoxy having from 1 to 4 carbon atoms, monoalkylamino, dialkylamino, C3-8 ~ cycloalkyl, or combinations thereof, Re is H, C? - 6-alkyl which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, OH, alkoxy having from 1 to 4 carbon atoms, NR4R5, SH, SR4, SOR4, C3_8-cycloalkyl, S02R4, S02NR R? , Ar, Het, or combinations thereof, C3.6-alkenyl which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, OH, alkoxy having from 1 to 4 carbon atoms, NR4R5 , SH, SR4, SOR4, C3_8-cycloalkyl, S02R4, S02NR4R5, Ar, Het, or combinations thereof, C3.6-alkynyl which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, OH, alkoxy having from 1 to 4 carbon atoms, NR4R5, SH, SR4, SOR4, C3.8-cycloalkyl, S02R4, S02NR4R5, Ar, Het, or combinations thereof, C3_8-cycloalkyl which is unsubstituted or substituted or more times by F, Cl, Br, I, CN, OH, alkoxy having from 1 to 4 carbon atoms, NR4R5, SH, SR4, SOR4, C3,8-unsubstituted cycloalkyl, S02R4, S02NR4R5, Ar, Het, or combinations thereof, C_8-cycloalkylalkyl which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, OH, alkoxy having from 1 to 4 carbon atoms, NR4R5, SH, SR4, SOR4, C3_8-unsubstituted cycloalkyl, S02R4, S02NRR5, Ar, Het, or combinations thereof, Ar, or Het; R7 is H, or C? _4-alkyl which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, OH, alkoxy having from 1 to 4 carbon atoms - (e.g., OCH3), NR4R5, or combinations thereof; m is 1, 2 or 3; Ar is an aryl group containing from 6 to 10 carbon atoms which is unsubstituted or substituted one or more times by alkyl having from 1 to 8 carbon atoms, alkoxy having from 1 to 8 carbon atoms, halogen, dialkylamino, wherein the alkyl portions each have from 1 to 8 carbon atoms, amino, cyano, hydroxyl, nitro, halogenated alkyl having from 1 to 8 carbon atoms, halogenated alkoxy having from 1 to 8 carbon atoms, hydroxyalkyl which has from 2 to 8 carbon atoms, hydroxyalkoxy having from 2 to 8 carbon atoms, alkenyloxy having from 3 to 8 carbon atoms, alkylthio having from 1 to 8 carbon atoms, alkylsulfinyl having from 1 to 8 carbon atoms, alkylsulfonyl having from 1 to 8 carbon atoms, monoalkylamino having from 1 to 8 carbon atoms, cycloalkylamino wherein the group cycloalkyl has from 3 to 7 carbon atoms and is optionally substituted, aryloxy wherein the aryl portion contains from 6 to 10 carbon atoms and is optionally substituted, arylthio wherein the aryl portion contains from 6 to 10 carbon atoms and is optionally substituted, cycloalkyloxy wherein the cycloalkyl group has from 3 to 7 carbon atoms and is optionally substituted, sulfo, sulfonylamino, acylamido, acyloxy, carboxy, alkoxycarbonyl, alkylaminocarbonyl or combinations thereof; and Het is a heterocyclic group, which is fully saturated, partially saturated or completely unsaturated, having from 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or more times by halogen, aryl having from 6 to 10 carbon atoms and optionally subscriptions, arylalkyl having from 6 to 10 carbon atoms in the aryl portion and from 1 to 4 carbon atoms in the alkyl portion, heterocyclic group, which is completely saturated, partially saturated or completely unsaturated, and which has 5 a. 10 ring atoms in which at least 1 ring atom is an N, O or S atom, alkyl having from 1 to 8 carbon atoms, alkoxy having from 1 to 8 carbon atoms, cyano, trifluoromethyl, nitro , oxo, amino, monoalkylamino having from 1 to 8 carbon atoms, dialkylamino wherein each alkyl group has from 1 to 8 carbon atoms, alkoxycarbonyl, alkylaminocarbonyl, or combinations thereof; or pharmaceutically acceptable salts thereof. 2. Compound according to claim 1, wherein R4 and R5 are each independently H or Ar, Het, or Ci-4-alkyl each of which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, OH, alkoxy having from 1 to 4 carbon atoms, monoalkylamino, dialkylamino , C3_8-cycloalkyl, or combinations thereof, and R1, R2 and R3 are not NR4C02R5 or NR4CONR4R5 3. Compound according to claim 1, wherein the compound is of Formula I. 4. Compound in accordance with Claim 3, wherein R 1 is H, OR 6, CF 3, Br, thienyl which is unsubstituted or substituted, furyl which is unsubstituted or substituted, or phenyl which is unsubstituted or substituted. is H, OR6, NR4R5, NR4COR5, NR4CONRR5, CF3, Br,
2. 2-thienyl,
3. 3-thienyl, methylthienyl, 2-furyl, 3-furyl, phenyl, fluorophenyl, methoxyphenyl, thiazolyl, oxazolyl, tetrahydropyranyl or dihydropyranyl. 6. Compound according to claim 1, wherein the compound is of formula II: 7. Compound in accordance with claim 6, wherein R1 is H, OR6, CF3, Br, thienyl which is unsubstituted or substituted, furyl which is unsubstituted or substituted, or phenyl which is unsubstituted or substituted. 8. Compound in accordance with the claim 7, wherein R1 is NRR5, NR4COR5, NR4CONR4R5, CF3, Br, 2-thienyl, 3-thienyl, methylthienyl, 2-furyl, 3 -furyl, "phenyl, fluorophenyl, methoxyphenyl, thiazolyl, oxazolyl, tetrahydropyranyl or dihydropyranyl. Compound according to claim 1, wherein the compound is of the formula III 10. Compound according to claim 1, wherein R3 is H, cyclopropyl or OR6 11. Compound according to claim 1, wherein where R4 is H or methyl 12. Compound according to claim 1, wherein R5 is H, methyl, cyclopropyl, cyclopentyl, cyclopropylmethyl, propyl, or Ar-methyl 13. Compound in accordance with claim 1, wherein R6 is methyl, ethyl, CF3, CHF2, cyclopentyl or cyclopentylmethyl. 14. Compound according to claim 1, wherein R7 is H, methyl or ethyl. 15. Compound in accordance with the claim 1, where A is -CO-. 16. Compound according to claim 1, wherein m is 1 or 2. 17. Compound according to claim g, wherein Y is S. 18. Compound according to claim 1, wherein Ar is phenyl. is unsubstituted or substituted. 19. Compound according to claim 1, wherein Het is thienyl which is unsubstituted or substituted or furyl which is unsubstituted or substituted. 20. The compound according to claim 3, wherein each X1 to X4 is CH or CR1. 21. Compound according to claim 6, wherein X4 to X8 is CH or CR2. 22. The compound according to claim 9, wherein X9 to X12 is CH or CR3. 23. The compound according to claim 1, wherein the compound is selected from: 3- [(SS, 4S) -2,5-Diazabicyclo [2.2.1] ept-2-ylcarbonyl] -lH-indazole hydrochloride, Hydroformate of 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.l] hept-2-yl] carbonyl} - !, 2-benzisothiazole, 3-. { [(1S, 4S) -5-Methyl-2, 5 -diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1,2-benzisothiazole, Hydroformate of 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2. l] hept-2yl] carbonyl} -5- (trifluoromethoxy) -1H-indazole, Hydroformate of 3-. { [(SS, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (trifluoromethyl) -1H-indazole, Chlorohydrate. 5-Bromo-3- [(SS, 4S) -2,5-diazabicyclo [2.2.1] hept-2-ylcarbonyl] -IH-indazole, Hydrochloride of 5-methoxy-3-. { [(1S, 4S) -5-metll-2, 5-diazabicyclo [2.2.1] ept-2-yl] carbonyl} - IH-indazole, 6-Bromo-3- [(SS, 4S) -2,5-diazabicyclohydrochloride [2.2. l] hept-2-ylcarbonyl] -IH-indazole, 6-Ethoxy-3- Hydroformate. { [(S, S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonl} -l, 2-benzisothiazole, 6-methoxy-3- hydroformate. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1, 2-benzisothiazole, 6-methoxy-3-. { [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} -1, 2-benzisothiazole, Hydroformate of 7-methoxy-3-. { [(SS, 4S) -5-methyl-2,5-diazabicyclo [2.2.l] hept-2-yl] carbonyl} -1,2-benzisothiazole, Hydroformate of 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.l] hept-2-yl] carbonyl} -5- (2-thienyl) -lH-indazole, Hydroformate - from 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} -5- (
4. 4-methyl-2-thienyl) -1H-indazole, Hydroformate of 3-. { [(? S, 4S) -
5. 5-Methyl-2,5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} -5- (5-methyl-2-thienyl) -1H-indazole, Hydroformate of 3-. { [(1S, 4S) -5-Methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -5-phenyl-lH-indazole, Hydroformate3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} -
6. 6- (2-thienyl) -lH-indazole, Hydroformate of 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.l] hept-2-yl] carbonyl} -6- (3-thienyl) -lH-indazole, Hydroformate of 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} -6- (4-methyl-2-thienyl) -lH-indazole, Hydroformate of 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (5-methyl-2-furyl) -1H-indazole, Hydroformate of 3-. { [(1S, 4S) -5-Methyl-2,5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} -6- (5-methyl-2-thienyl) -1H-indazole, Hydroformate of 5- (2-Furyl) -3-. { [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} -lH-indazole, Hydroformate of 5- (3-fluorophenyl) -3-. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H- indazole, Hydroformate of 5- (4-fluorophenyl) -3-. { [(1S, 4S) -5-methyl -2,5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} -lH- indazol, 5- (4-Methoxyphenyl) -3- hydrochloride. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} -! H- indazol, Hydroformate of 6- (2-Furil) -3-. { [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} lH- indazol, Hydroformate of 6- (3-Furil) -3-. { [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} -IH- indazol, 3-. { [(SS, 4S) -5-Ethyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -lH-indazole, Hydroformate of 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -lH- indazol, Hydroformate of 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -5- (3-thienyl) -1H-indazole, Hydroformate of 5- (3-Furil) -3-. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -lH-índazole, 5-Bromo-3 - [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -lH-indazole, and pharmaceutically acceptable salts thereof. 24. Compound according to claim 1, wherein the compound is selected from: 3- (2,5-Diazabicyclo [2.2.2] oct-2-ylcarbonyl) -6- (1,3-thiazol-2-yl) hydrochloride ) -lH-indazole, 3- (2,5-Diazabicyclo [2.2.2] oct-2-ylcarbonyl) -6- (1,3-thiazol-2-yl) -lH-indazole, 3- [(1S, 4S) -2, 5-Diazabicyclo [2.2.1] hept-2-ylcarbonyl] -1H-indazole, 3- (2,5-Diazabicyclo [2.2.2] oct-2-ylcarbonyl) -lH-indazole hydrochloride, 3- (2,5-Diazabicyclo [2.2.2] oct-2-ylcarbonyl) -1H-indazole, 3- [(5-Methyl-2, 5-diazabicyclo [2.2.2] oct-2-yl) Hydroformate) carbonyl] -lH-indazole, 3- [(5-Methyl-2, 5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -lH-indazole, Hydroformate of 3- [(5-Methyl-2, 5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -6- (1,3-thiazole-2 ^ 1) -1H-indazole, 3- [(5-Methyl-2,5-diazabicyclo [2.2 .2] oct-2-yl) carbonyl] -6- (1,3-thiazol-2-yl) -lH-indazole, 3-. { [(SS, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -lH-indazole, Hydroformate of 3-. { [(SS, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -5- (1, 3-thiazol-2-yl) -1H-indazole, 3 -. { [(SS, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -5- (1, 3-thiazol-2-yl) -1H-indazole, 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -5- (2-thienyl) -IH-indazole, 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -5- (3-thienyl) -IH-indazole, 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -5- (4-methyl-2-thienyl) -lH-indazole, 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -5- (5-methyl-2-thienyl) -lH-indazol, 3-. { t (1S, 4S) -5-Methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -5- (trifluoromethoxy) -IH-indazole, 3-. { [(1S, 4S) -5-Methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -5-phenyl-1H-indazole, Hydroformate of 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.l] hept-2-yl] carbonyl} -6- (1, 3-oxazol-2-yl) -1H-indazole, 3-. { [(1S, 4S) -5-Methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (1, 3-oxazol-2-yl) -1H-indazole, Hydroformate of 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbsnil} -6- (1, 3-thiazol-2-yl) -1H-indazole, 3-. { [(SS, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (1, 3-thiazol-2-yl) -IH-indazole, 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (2-thienyl) -IH-indazole, 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (3-thienyl) -IH-indazole, Hydroformate of 3-. { [(1S, 4S) -5-Methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (4-methyl-l, 3-thiazol-2-yl) -IH-indazole, 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] ept-2-yl] carbonyl} -6- (4-methyl-l, 3-thiazol-2-yl) -1H-indazole, 3-. { [(SS, 4S) -5-Methyl-2, 5-diazabicic? Or [2.2.1] hept-2-yl] carbonyl} -6- (4-methyl-2-thienyl) -lH-indazole, Hydroformate of 3-. { [(1S, 4S) -5-Methyl-2,5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} -6- (5-methyl-l, 3-thiazol-2-yl) -lH-indazole, 3-. { [(1S, 4S) -5-Methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (5-methyl-l, 3-thiazol-2-yl) -lH-indazole, 3-. { [(SS, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (5-methyl-2-furyl) -IH-indazole, 3-. { [(SS, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (5-methyl-2-thienyl) -IH-indazole, Hydroformate of 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} -6- (tetrahydro-2H-pyran-4-yl) -IH-indazole, 3-. { [(1S, 4S) -5-Methyl-2,5-diazabicyclo [2.2.1] ept-2-yl] carbonyl} -6- (tetrahydro-2H-pyran-4-yl) -lH-indazole, hydrsformiate of 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} -6- (trifluoromethoxy) -1H-indazole, 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (trifluoromethoxy) -1H-indazole, 3-. { [(1S, 4S) -5-Methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (trifluoromethyl-) -IH-indazole, Hydroformate of 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} -
7. 7- (trifluoromethoxy) -1H-indazole, 3-. { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -7- (trifluoromethoxy) -lH-indazole, 5- (2-Furyl) -3-. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -lH-indazole, 5- (3-Fluorophenyl) -3-. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} -lH-indazole, 5- (3-Furil) -3-. { 1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -lH-indazole, 5- (4-fluorophenyl) -3-. { [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} -IH-indazole, 5- (4-Methoxyphenyl) -3-. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} -lH-indazole, Hydroformate of 5- (Cyclopentyloxy) -3-. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] ept-2-yl] carbonyl} -1H-indazole, 5- (Cyclopentyloxy) -3-. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -lH-indazole, Hydroformate of 5- (cyclopropylmethoxy) -3-. { [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} -lH-indazole, 5- (Cyclopropylmethoxy) -3-. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} -lH-indazole, 5-Amino-3- [(5-Methyl-2,5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -IH-indazole, 5-Amin? -3-. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} -6- (1,3-thiazol-2-yl) -1H-indazole, 5-Bromo-3- [(1S, 4S) -2,5-diazabicyclo [2.2. l] hept-2-ylcarbonyl] -1H-indazole, 5-Hydroxy-3-. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (1, 3-thiazol-2-yl) -1H-inda zol, 5-Methoxy-3- [(5-methyl-2, 5-diazabicyclo [2.2.2] oct-2-yl) Hydroformate) carbonyl] -lH-indazole, 3- (2,5-Diazabicyclo [2.2. "2] oct-2-ylcarbonyl) -5-methoxy-iH-indazole, 3- (2,5-diazabicyclo [2.2.2] ] oct-2-ylcarbonyl) -5-methoxy-lH-indazole, 5-Methoxy-3 { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept hydroformate) 2-yl] carbonyl.} - -H-indazole, 5-Metoxy-3-. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.l] hept-2-yl] carbonyl} -lH-indazole, 6- (2-Furil) -3-. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -lH-indazole, Hydroformate of 6- (3,6-Dihydro-2H-pyran-4-yl) -3-. { [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -IH-indazole, 6- (3,6-Dihydro-2H-pyran-4-yl) -3-. { 1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -lH-indazole, 6- (3-Furil) -3-. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -lH-indazole, Hydroformate of 6- (Cyclopentyloxy) -3-. { [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] ept-2-yl] carbonyl} -IH-indazole, 6- (Cyclopentyloxy) -3-. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -lH-indazole, Hydroformate of 6-Cyclopropyl-3-. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.l] hept-2-yl] carbonyl} -1, 2-benzisothiazole, 6-Cyclopropyl-3-. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -l, 2-benzisothiazole, 6-ethoxy-3-. { [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -l, 2- benzisothiazole, 3- (2,5-Diazabicyclo [2.2.2] oct-2-ylcarbonyl) -6-methoxy-1H-indazole hydrochloride, 3- (2,5-Diazabicyclo [2.2.2] oct-2-ylcarbonyl) -6-methoxy-1H-indazole, 6-Methoxy-3- [(5-methyl-2,5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -hydroformate] indazole, 6-methoxy-3- [(5-methyl-2,5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -lH-indazole, 6-methoxy-3-chlorohydrate. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.l] hept-2-yl] carbonyl} -IH-indazole, 6-Methoxy-3- [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl hydroformate} -lH- indazole, 6-methoxy-3-. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} -lH-indazole, 7-Met? xi-3-. { [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -!, 2-benzisothiazole, N- (3 { [(S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl-lH-indazole- Hydroformate. 5-yl) -N'-propylurea,? - (3- [(lS, 4S) -5-Methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl-lH-indazole-5- il) -? ' -propylurea, Hydroformate of N-. { 3- [(5-Met il-2, 5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -lH-indazol-5-yl} Cyclopropancarboxamide, "N- {3 - [(5-Methyl-2,5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -lH-indazol-5-yl}. cyclopropanecarboxamide, N-Hydroformate. - {3- [(5-methyl -2,5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -lH-indazol-5-yl.} - N '-propylurea, N-. {3 - [(5-Methyl-2, 5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -1H-indazol-5-yl}.-N'-propylurea, and pharmaceutically acceptable salts of 25. The compound according to claim 1, wherein it is selected from: Hydroformate of 3- { [(1S, 4S) -5-Methyl-2,5-diazabicyclo [2.2.1] hept-2. -yl] carbonyl.} -1,2-benzisoxazole, 3- { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl}. -1,2-benzisoxazole, - Hydroformate of 3-. {[[(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl] -5- ( 4-methyl-l, 3-thiazol-2-yl) -IH-indazole, 3-. {[[(1S, 4S) -5-Methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] ] carbonyl.}. -5- (4-methyl-l, 3-thiazol-2-yl) -IH-indazole, Hydroformate of 3- . { [(1S, 4S) -5-Methyl-2,5-diazabicyclo [2.2.l] hept-2-yl] carbonyl} -5- (5-methyl-l, 3-thiazol-2-yl) -IH-indazole, 3-. { [(SS, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -5- (5-methyl-l, 3-thiazol-2-yl) -lH-indazole, Hydroformate of 3-. { [(1S, 4S) -5-Met "il-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl] -5- (tetrahydro-2H-pyran-4-iD-lH-indazole , 3- { [(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl}. -5- (tetrahydro-2H-pyran-4-yl. ) -IH-indazole, Hydrochloride of 5- (3,6-Dihydro-2H-pyran-4-yl) -3- { [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2. 1] hept-2-yl] carbonyl.} -1H-indazole, 5- (3,6-Dihydro-2H-pyran-4-yl) -3-. {[[(1S, 4S) -5-methyl] -2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl.] - lH-indazole, 5- (Difluoromethoxy) -3- (. ([S, S]) -5-methyl- Hydroformate 2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl].-LH-indazole, 5- (difluoromethoxy) -3- [(1S, 4S) -5-methyl-2, -5-diazabicyclo [2.2.1] hept-2-yl] carbonyl.}. -lH-indazole, Hydroformate of -6- (Difluoromethoxy) -3- [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2. l] hept-2-yl] carbonyl} -1H-indazole, 6- (Difluoromethoxy) -3- [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -IH-indazole, Hydroformate of 7-Fluoro-6-methoxy-3-. { [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -lH-indazole, 7-Fluoro-6-methoxy-3-. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -lH-indazole, N- (3- {[[(1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -IH-indazole hydroformate. -5-yl) cyclopropanecarboxamide, N- (3 { [(S, S) -5-Methyl-2, 5-diazabicyclo [2.2.1] "Eept-2-yl] carbonyl.] -lH- indazol-5-yl) cyclopropanecarboxamide, N- (4-Fluorobenzyl) -N- (3- {[[(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-Hydroformate] -yl] carbonyl.} - lH-indazol-5-yl) urea, N- (4-Fluorobenzyl) -N '- (3 { [(SS, 4S) -5-methyl-2, 5- diazabicyclo [2.2.l] hept-2-yl] carbonyl.] - IH-indazol-5-yl) urea, N- (4-Fluorobenzyl) -N1 -. {3- (N- (4-methyl-) -hydroformate) 2,5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -IH-indazol-5-yl) urea, N- (4-Fluorobenzyl) -N'-. { 3- [(5-methyl-2,5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -1H-indazol-5-yl} urea, N- (Cyclopropylmethyl) -3- [(5-methyl-2, 5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -lH-indazol-5-amine, N- (Cyclopropylmethyl) -3 - [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2 l] hept-2-yl] carbonyl-lH-indazol-5-amine, N, N-Dimethyl-3- hydroformate [(5 -methyl-2, 5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -lH-indazol-5-amine, N, N-Dimethyl-3- [(5-methyl-2, 5-diazabicyclo [ 2.2.2] oct-2-yl) carbonyl] -lH-indazol-5-amine, N, N-Dimethyl-3- [(1S, 4S) -5-methyl-2, 5-diazabicyclohydroformate [2.2. 1] hept-2-yl] carbonyl} -lH-indazol-5-amine, N, N-Dimethyl-3- [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2. l] hept-2-yl] carbonyl-lH-indazol-5-amine, N, N-Dimethyl-3-hydroformate. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -lH-indazol-6-amine, N, N-Dimethyl-3- [(SS, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -lH-indazol-6-amine, N-Cyclopentyl-N '- (3 { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl Hydroformate] ] carbonyl.} - lH-indazol-5-yl) urea, N-Cyclopentyl-N'- (3 - { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl.] - lH-indazol-5-yl) urea, N-Cyclopentyl-N '- Hydroformate. { 3- [(5-methyl-2, 5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -lH-indazol-5-yl} urea, N-Cyclopentyl-N '-. { 3- [(5-methyl-2, 5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -lH-indazol-5-yl} urea, and pharmaceutically acceptable salts thereof. 26. Pharmaceutical composition, comprising a compound according to any of claims 1 to 25 and a pharmaceutically acceptable carrier. 27. Method of selective activation / stimulation of a7 nicotinic receptors in a mammal, wherein this activation / stimulation has a therapeutic effect, which comprises administering to a mammal in need thereof an effective amount of a compound according to any of the claims 1 to 25. 28. Method for treating a patient suffering from a psychotic disease, a neurodegenerative disease comprising a dysfunction of the cholinergic system, and / or a condition of memory and / or cognitive impairment, comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 25. 29. Method according to claim 28, wherein the patient suffers from schizophrenia, anxiety, mania, depression, manic depression, Tourette syndrome, Parkinson's disease, disease of Huntington, Alzheimer's disease, Lewy Body Dementia, Amyotrophic Lateral Sclerosis, memory impairment, loss of memory, cognitive deficit, attention deficit, Attention Deficit Hyperactivity Disorder. 30. Method for treating a patient suffering from dementia and / or another condition with memory loss, comprising administering to the patient an effective amount of a compound according to any of claims 1 to 25. 31. Method for treating a patient suffering from memory impairment due to benign cognitive impairment due to aging, Alzheimer's disease, schizophrenia, Parkinson's, Huntington's disease, Pick's disease, Creutzfeld-Jakob disease, depression, aging, brain trauma, stroke, CNS hypoxia , cerebral senility, dementia of mui-infarction, HIV and / or cardiovascular disease, characterized in that the patient is administered an effective amount of a compound according to any of claims 1 to 25. 32. Method for treating and / or preventing dementia in a patient with Alzheimer's disease, comprising administering to the patient an effective amount of a compound in accordance with any of the Vindications 1 to 25 to inhibit the binding of a beta-amyloid peptide with nAChR. 33. Method for treating a patient by alcohol withdrawal or treating a patient with anti-poisoning therapy, comprising administering to the patient an effective amount of a compound according to any of claims 1 to 25. 34. Method for treating a patient provided for neuroprotection against damage associated with attacks and ischemia and excitotocicity induced by glutamate, which comprises administering to the patient an effective amount of a compound according to any of claims 1 to 25. 35. Method for treating a patient suffering from nicotine addiction, pain, maladjustment, obesity and / or diabetes, which comprises administering to the patient an effective amount of a compound according to any of claims 1 to 25. 36. Method for inducing smoking cessation in a patient, comprising administering to the patient an effective amount of a compound in accordance with any of claims 1 to 25. 37. Method for treating a patient suffering from benign cognitive impairment (MCI), vascular dementia (VaD), cognitive decline associated with age (AACD), amnesia associated with open heart surgery, cardiac arrest , general anesthesia, memory deficit from exposure to anesthetic agents, cognitive impairment induced by sleep abstention, fatigue syndrome c kidney disease, narcolepsy, dementia related to AIDS, cognitive damage related to epilepsy, Down syndrome, dementia related to alcoholism, drug-induced memory impairment / substance, pugilistic dementia (Boxing Syndrome), or animal dementia, which comprises administering The method comprises treating the patient with an effective amount of a compound according to any one of claims 1 to 25, 38. Method for treating memory loss, comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 25. 39. Method for treating a patient suffering from memory impairment, comprising administering to the patient an effective amount of a compound according to any of claims 1 to 25. 40. Method according to claim 3g, wherein Memory impairment is due to decreased nicotinic acetylcholine receptor activity. 41. Method for the treatment or prophylaxis of a disease or condition resulting from the transmission of nicotinic acetylcholine receptor dysfunction in a mammal, which comprises administering to the mammal an effective amount of a compound according to any of claims 1 to 25. . 42. Method for the treatment or prophylaxis of a disease or condition resulting from nicotinic acetylcholine receptors defective or malfunctioning in a mammal, comprising administering to the mammal an effective amount of a compound according to any of claims 1 to 25. 43 Method for the - treatment or prophylaxis of a disease or condition resulting from the suppression of transmission of nicotinic acetylcholine receptor in a mammal, comprising administering to the mammal an effective amount of a compound according to any of claims 1 to 25 44. Method for the treatment or prophylaxis of a disease or condition resulting from the loss of cholinergic synapses in a mammal, comprising administering to the mammal an effective amount of a compound according to any of claims 1 to 25. 45. Method for the protection of neurons "in a mammal from the neurotoxicity induced by the activation of nACh a7 receptors, which comprises administering to the mammal an effective amount of a compound according to any of claims 1 to 25. 46. Method for the treatment or prophylaxis of a neurodegenerative disease to inhibit the binding of Aβ peptides to nACh a7 receptors in a mammal, comprising administering to the mammal an effective amount of a compound according to any of claims 1 to 25.