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

BACKGROUND OF THE INVENTION

There are two types of receptors for the neurotransmitter, which is acetylcholine: muscarinic and nicotinic receptors, which division is based on the selectivity of muscarinic and nicotine, respectively. Muscarinic receptors are G-protein coupled receptors. Nicotinic receptors are members of the ligand-gated ion channel family. When activated, there is an increase in ion conductivity through nicotine ion channels.

The alpha-7 nicotinic receptor protein forms a homopentameric channel in vitro that is highly permeable to various cations (e.g., Ca ++). Each alpha-7 nicotin3 receptor has four transmembrane domains, referred to as M1, M2, M3 and M4. It is suggested that the M2 domain forms the lining of the channel wall. Sequencing showed that the alpha-7 nicotinic receptor is highly preserved during evolution. From chicken to human, the protein sequence of the M2 domain covering the channel liner is identical. For a discussion of issues related to the alpha-7 receptor, see, for example: Revah et al (1991), Nature 353, pages 846-849; Galzi

<td>and others</td><td> (1992),</td><td>Nature</td><td>359, pages 500-505;</td><td>Fucile</td><td>and others</td>

<td> 10 (2000),</td><td>PNAS 97 (</td><td colspan="2">7), pages 3643-3648; Briggs</td><td>and others</td><td> (1999),</td>

<td>Eur. J.</td><td colspan="2">Pharmacol. 366</td><td>(2-3), pages 301-308</td><td>; and</td><td>Gopala-</td>

<td>krishnan</td><td>and others</td><td> (1995)</td><td>, Eur. J. Pharmacol.</td><td> 290 (3),</td><td>page</td>

237-246.

EP 1219622 and WO 02/096911 disclose nicotinic receptor modulators that are 1,4-diazabicyclo [3.2.2] nonane derivatives.

The alpha-7 receptor nicotinic channel is expressed in various brain regions and is thought to be involved in many important biological processes in the central nervous system (CNS), including learning and memory. Alpha-7 nicotinic receptors are found on both presynaptic and postsynaptic terminals and are thought to be involved in modulating synaptic transmission. Therefore, there is an interest in developing new compounds that act as ligands on the nAChR α7 subunit for the treatment of disease states associated with malfunction or malfunctioning of nicotinic cholinergic receptors.

SUMMARY OF THE INVENTION

The subject of this invention are new compounds that act as ligands for the α7 subunit of the nAChR receptor, methods for preparing such compounds, compositions containing these compounds, as well as methods of their use.

DETAILED DESCRIPTION OF THE INVENTION

The present invention includes compounds of formulas I, II or

III:

<img file="PL1697378T3_D0001.tif" />

(AND)

<img file="PL1697378T3_D0002.tif" />

(II)

<img file="PL1697378T3_D0003.tif" />

(III) in which:

A is -CH2- or

<img file="PL1697378T3_D0004.tif" />

<img file="PL1697378T3_D0005.tif" />

BY is O or S;

each of the substituents from X¹ to X⁴ is independently CH, CR¹ or N, with at most one of the substituents from X¹ to X⁴ is N;

each of the substituents from X⁵ to X⁸ is independently CH, CR² or N, with at most one of the substituents from X⁵ to X⁸ is N;

each of the substituents from X⁹ to X¹² is independently CH,

CR³ or N, with at most one of the substituents from

X⁹ to X¹² is N;

each of the substituents R¹, R² and R³ means independently:

H, C._1-6-alkyl (e.g. CH₃) which is unsubstituted or substituted by one or more groups such as F, Cl, Br, I, CN, OH, an alkoxy group having 1 to 4 carbon atoms (for example OCH₃), NO⁴R⁵, SH, SR⁴, SOR⁴, C3-8-cycloalkyl, SO2R⁴, SO2NR⁴R⁵, aryl, Het or combinations thereof,

C_2-6-alkenyl which is unsubstituted or substituted by one or more groups such as F, Cl, Br, I,

CN, OH, an alkoxy group having 1 to 4 carbon atoms (for example OCH₃), NO⁴R⁵, SH, SR⁴, SOR⁴, C3-8-cycloalkyl, SO2R⁴, SO2NR⁴R⁵, Ar, Het or their combinations,

C_2-6-alkynyl which is unsubstituted or substituted by one or more groups such as F, Cl, Br, I,

CN, OH, an alkoxy group having 1 to 4 carbon atoms (for example OCH₃), NO⁴R⁵, SH, SR⁴, SOR⁴, C3-8-cycloalkyl, SO2R⁴, SO2NR⁴R⁵, Ar, Het or their combinations,

C_3-8-cycloalkyl which is unsubstituted or substituted by one or more groups such as F, Cl, Br,

I, CN, OH, an alkoxy group having 1 to 4 carbon atoms (for example OCH₃), NO⁴R⁵, SH, SR⁴, SOR⁴, unsubstituted C3-8-cycloalkyl, SO2R⁴, SO2NR⁴R⁵, aryl, Het or combinations thereof, halogen (e.g. F, Cl, Br, I,),

CN, NO₂, NO⁴R⁵, SH, SR⁴, SOR⁴, SO2R⁴, SO2NR⁴R⁵, CONR⁴R⁵, COOR⁴, NO⁴COR⁵, NO⁴WHAT₂R⁵, NO⁴CONR⁴R⁵,

Ar,

NO⁴SO₂R⁵,

Het or

R⁶ABOUT-;

each of the substituents R⁴ and R⁵ is independently H or Ar, aryl (C_1-4-alkyl), Het, C_1-4-alkyl (e.g. CH₃), C._3-8-cycloalkyl (e.g. cyclopropyl) or C_4-8-cycloalkylalkyl (e.g. cyclopropylmethyl), each of these substituents being unsubstituted or substituted by one or more groups such as F, Cl, Br, I, CN, OH, an alkoxy group having from 1 to 4 carbon atoms (e.g. OCH₃), monoalkylamino group, dialkylamino group (e.g. diethylamino group), C_3-8-cycloalkyl or combinations thereof;

R⁶ means:

H

C_1-6-alkyl (e.g. CH₃) which is unsubstituted or substituted by one or more groups such as F, Cl, Br, I, CN, OH, an alkoxy group having 1 to 4 carbon atoms (for example OCH₃), NO⁴R⁵, SH, SR⁴, SOR⁴, C3-8-cycloalkyl, SO2R⁴, SO2NR⁴R⁵, Ar, Het or their combinations,

C_3-6-alkenyl which is unsubstituted or substituted by one or more groups such as F, Cl, Br, I, CN, OH, an alkoxy group having 1 to 4 carbon atoms (for example OCH₃), NO⁴R⁵, SH, SR⁴, SOR⁴, C3-8-cycloalkyl, SO2R⁴, SO2NR⁴R⁵, Ar, Het or their combinations,

C_3-6-alkynyl which is unsubstituted or substituted by one or more groups such as F, Cl, Br, I, CN, OH, an alkoxy group having from 1 to 4 carbon atoms (for example OCH₃), NO⁴R⁵, SH, SR⁴, SOR⁴, C3-8-cycloalkyl, SO2R⁴, SO2NR⁴R⁵, Ar, Het or their combinations,

C_3-8-cycloalkyl which is unsubstituted or substituted by one or more groups such as F, Cl, Br, I, CN, OH, an alkoxy group having from 1 to 4 carbon atoms (for example OCH₃), NO⁴R⁵, SH, SR⁴, SOR⁴, unsubstituted C3-8-cycloalkyl, SO2R⁴, SO2NR⁴R⁵, Ar, Het or their combinations,

C_3-8-cycloalkylalkyl which is unsubstituted or substituted by one or more groups such as F, Cl, Br, I, CN, OH, an alkoxy group having 1 to 4 carbon atoms (for example OCH₃), NO⁴R⁵, SH, SR⁴, SOR⁴, unsubstituted C3-8-cycloalkyl, SO2R⁴, SO2NR⁴R⁵, Ar, Het or their combinations,

Ar or

Het;

R⁷ means H or Ci_-4-alkyl (e.g. CH₃) which is unsubstituted or substituted by one or more groups such as F, Cl, Br, I, CN, OH, an alkoxy group having 1 to 4 carbon atoms (for example OCH₃), NO⁴R⁵ or their combinations;

m is 1, 2 or 3;

Ar is aryl containing from 6 to 10 carbon atoms, which is unsubstituted or substituted by one or more groups such as alkyl containing from 1 to 8 carbon atoms, alkoxy group containing from 1 to 8 carbon atoms, halogen (F, Cl, Br or I, preferably F or Cl), the dialkylamino group in which each of the alkyl fragments contains from 1 to 8 carbon atoms, amino group, cyano group, hydroxy group, nitro group, halogenated alkyl containing from 1 to 8 carbon atoms, halogenated alkoxy group containing from 1 to 8 carbon atoms, hydroxyalkyl containing from 2 to 8 carbon atoms, hydroxyalkoxy group containing from 2 to 8 carbon atoms, alkenyloxy group containing from 3 to 8 carbon atoms, alkylthio group containing from 1 to 8 carbon atoms, alkylsulfinyl containing from 1 to 8 carbon atoms, alkylsulfonyl containing from 1 to 8 carbon atoms, monoalkylamino group containing from 1 to 8 carbon atoms, a cycloalkylamino group in which the cycloalkyl group contains from 3 to 7 carbon atoms and is optionally substituted, an aryloxy group in which the aryl fragment contains from 6 to 10 carbon atoms (e.g. phenyl, naphthyl, biphenyl) and is optionally substituted, the arylthio group in which aryl contains from 6 to 10 carbon atoms (for example phenyl, naphthyl, biphenyl) and is optionally substituted, cycloalkyloxy group in which the cycloalkyl group contains from 3 to 7 carbon atoms and is optionally substituted, sulfone group, sulfonylamino group, acylamide group (e.g. acetamide group), acyloxy group (e.g. acetoxy group), carboxy group, alkoxycarbonyl, alkylaminocarbonyl or their connections; and

Het is a heterocyclic group that is fully saturated, partially saturated or completely unsaturated, which has from 5 to 10 ring-forming atoms, of which at least one is an atom such as N, O or S, which group is unsubstituted or substituted with one or more groups like halogen (F,

Cl, Br or I, preferably F or Cl), aryl containing from up to 10 carbon atoms (e.g. phenyl, naphthyl, biphenyl) which is optionally substituted, arylalkyl having in the aryl part from 6 to 10 carbon atoms and in the alkyl part from 1 to 10 4 carbon atoms, a heterocyclic group that is completely saturated, partially saturated or completely unsaturated and which has from 5 to 10 ring-forming atoms, of which at least one is an atom such as N, O or S, alkyl having from 1 to 8 carbon atoms, alkoxy containing from

1 up to 8 carbon atoms, cyano group, trifluoromethyl, nitro group, oxo group, amino group, monoalkylamino group containing from 1 to 8 carbon atoms, dialkylamino group in which each alkyl contains from 1 to 8 carbon atoms, alkyloxycarbonyl, alkylaminocarbonyl or their combinations ; and their pharmaceutically acceptable salts.

According to an additional variation, each of the R substituents⁴ and R⁵, appearing in formulas I, II and III, is independently H, Ar, Het or C_1-4-alkyl (e.g. CH₃) which is unsubstituted or substituted by one or more groups such as F, Cl, Br, I, CN, OH, an alkoxy group having 1 to 4 carbon atoms (for example OCH₃), a monoalkylamino group, a dialkylamino group (e.g., diethylamino group),

C_3-8-cycloalkyl or combinations thereof and R¹, R² and R³ are not such groups as NR⁴WHAT₂R⁵ or NO⁴CONR⁴R⁵.

As used herein, the term alkyl means a straight or branched chain aliphatic hydrocarbon group containing preferably from 1 to 4 carbon atoms. Suitable alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl.

The term alkoxy means groups having the formula alkyl-O-, wherein the alkyl part preferably contains from 1 to 4 carbon atoms. Suitable alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, isobutoxy and sec-butoxy.

The term cycloalkyl means a cyclic, bicyclic or tricyclic saturated hydrocarbon group containing from 3 to 8 carbon atoms. Suitable cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Other suitable alkyl groups include spiropentyl, bicyclo [2.1.0] pentyl and bicyclo [3.1.0] hexyl.

Cycloalkyl groups may be substituted by C_1-4-alkyl, group C_1-4-alkoxy, hydroxy group, amino group, monoalkylamino group containing from 1 to 4 carbon atoms and / or dialkylamino group in which each alkyl group contains from 1 to 4 carbon atoms.

The term cycloalkylalkyl means cycloalkylalkyl groups in which the cycloalkyl part and the alkyl part have the meaning as previously defined. Suitable examples of these groups include cyclopropylmethyl and cyclopentylmethyl.

Unless otherwise indicated, the term aryl, as a group or substituent in itself or as part of a group or substituent, refers to a carbocyclic aromatic group containing from 6 to 10 carbon atoms. Suitable aryl groups include phenyl, naphthyl and biphenyl. Substituted aryl groups include the aryl groups described above, which are substituted by one or more groups such as halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl , hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, a phenoxy group and an acyloxy group (e.g., acetoxy).

The term arylalkyl refers to an arylalkyl group in which the aryl portion and the alkyl portion have the meanings as previously defined. Suitable examples include benzyl, 1-phenylethyl, 2-phenylethyl, phenylpropyl, phenylbutyl, phenylpentyl and naphthylmethyl. The term Ar-alkyl also means an arylalkyl group in which the aryl portion has the meaning as previously described. Suitable examples include benzyl and fluorobenzyl.

The term heterocyclic groups refers to saturated, partially saturated and completely unsaturated heterocyclic groups having one, two or three rings and a total number of atoms forming a ring from 5 to 10, wherein at least one of the atoms forming the ring is an atom such as N, O or S. Preferably, the heterocyclic group contains 1 to 3 ring heteroatoms selected from N, O and S. Suitable, saturated and partially saturated heterocyclic groups include tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidine !, piperazinyl, morpholinyl, isoxazolinyl and the like. Suitable, but not limited to, heteroaryl groups include furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, isoquinolinyl, naphthyridinyl and the like. Other examples of suitable heterocyclic groups include 2-quinolinyl, 1,3-benzodioxyl, 2-thienyl, 2-benzofuranyl, 2-benzothiophenyl, 3-thienyl, 2,3-dihydro-5-benzofuranyl, 4-indolyl, 4-pyridyl, 3-quinolinyl, 4-quinolinyl, 1,4-benzodioxan-6-yl, 3-indolyl, 2-pyrrolyl, 3,4-1,2-benzopyran-6-yl, 5-indolyl, 1,5-benzoxepine 8-yl, 3-pyridyl, 6-coumarinyl, 5-benzofuranyl, 2-isoimidazol-4-yl, 3-pyrazolyl and 3-carbazolyl.

The term substituted heterocyclic groups refers to the heterocyclic groups described above that are substituted at one or more sites, for example, by halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, amino , an alkylamino group and a dialkylamino group.

Groups that are substituted one or more times preferably contain from 1 to 3 substituents, particularly from 1 to 2 substituents among the substituents given herein as examples. Halogenated groups such as halogenated alkyl groups are preferably fluorinated groups and include groups in which all hydrogen atoms have been substituted with halogen, such as trifluoromethyl.

In compounds of formula I, R¹ preferably represents such groups as H, OR⁶, NO⁴R⁵, NO⁴COR⁵, NO⁴CONR⁴R⁵, CF₃, Br, substituted or unsubstituted thienyl (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 (e.g. 2- furyl, 3-furyl and methylfuryl, such as 2- (5-methyl) furyl), phenyl which is unsubstituted or substituted (e.g., 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-dihydropyran-4-yl).

In compounds of formula II, R¹ preferably represents such groups as 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 (e.g., 2-furyl, 3-furyl and methylfuryl, such as 2- (5-methyl) fury) or phenyl which is unsubstituted or substituted (e.g., fluorophenyl, such as 3-fluorophenyl and 4-fluorophenyl, and methoxyphenyl, such as 4-methoxyphenyl).

In compounds of formula III with the group R³ is preferably H, cyclopropyl or OR⁶.

R⁴ preferably H or methyl and R⁵ is preferably H, methyl, cyclopropyl, cyclopentyl, cyclopropylmethyl, propyl or Ar-methyl.

R⁶ preferably methyl, ethyl, CF₃, CHF₂, cyclopentyl or cyclopropylmethyl.

R⁷ preferably H, methyl or ethyl.

In compounds of formulas I, II and III, A is preferably

-WHAT-. Also in compounds of formulas I, II and III, m is preferably 1 or 2.

Ar (aryl) is preferably phenyl which is unsubstituted or substituted (e.g., fluorophenyl, such as 3-fluorophenyl and 4-fluorophenyl, and methoxyphenyl, such as

4-methoxyphenyl).

Het is preferably 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) or furyl which is unsubstituted or substituted ( e.g

2-furyl, 3-furyl and methylfuryl such as 2- (5-methyl) furyl).

In formula I, each group from X¹ to X⁴ is preferably CH or CR¹. In formula II, each group from X⁴ to X⁸ is preferably CH or CR². In formula III, each group from X⁹ to X¹²is preferably CH or CR³.

According to an aspect of the invention relating to the compounds of the invention, the compounds of formulas I, II and III are selected from such compounds as:

3 - [(1S, 4S) -2,5-diazabicyclo [2.2.1] hept-2-yl-carbonyl] -1H-indazole hydrochloride, 3 - {[(1S, 4S) -5-methyl-2 hydrogen formate, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1,2-benzisothiazole,

3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1,2-benzisothiazole, 3 - {[(1S, 4S) hydrogen formate 5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -5- (trifluoromethoxy) -1H-indazole, 3 - {[(1S, 4S) -5-methyl-2 hydrogen formate, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (trifluoromethyl) -1H-indazole, 5-bromo-3 - [(1S, 4S) -2,5-diazabicyclo [2.2.1] hydrochloride ] hept-2-ylcarbonyl] -1H-indazole 5-methoxy-3 - {[(1S, 4S) -5-methyl-2,510-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole hydrogen formate, 6-bromo-3 - [[1S] hydrochloride , 4S) -2,5-diazabicyclo [2.2.1] hept-2-ylcarbonyl] -1H-indazole, 6-ethoxy-3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [... 2.2.1] hept-2-yl] carbonyl} 15 -1,2-benzisothiazole, 6-methoxy-3 - {[(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 [2.2.1] 20 hept-2-yl] carbonyl} -1,2-benzisothiazole, 7-methoxy-3 hydrogen formate - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1,2-benzisothiazole, 3 - {[(1S, 4S) -5 hydrogen formate -methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -5- (2-thienyl) -1H-indazole, 3 - {[(1S, 4S) -5-methyl-2 hydrogen formate , 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -5- (4-methyl-2-thienyl) -1H-indazole, 3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -5- (5-methyl-2-thienyl) -1H-indazole hydrogen formate 3-hydrogen formate - {[(1S, 4S) -5-methyl-2,5-diazabicyclo5 [2.2.1] hept-2-yl] carbonyl} -5-phenyl-1H-indazole, 3 - {[(1S, 4S) hydrogen formate -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (2-thienyl) -1H-indazole, 3 - {[(1S, 4S) -5-methyl hydrogen formate -2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (3-thienyl) -1H-indazole, 3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (4-methyl-2-thienyl) -1H-indazole hydrogen formate, 3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (5-methyl-2-furyl) 15 -1H-indazole hydrogen formate , 3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (5-methyl-2-thienyl) -1H-indazole hydrogen formate hydrogen formate 5- (2-furyl) -3 - {[(1S, 4S) -5-methyl-2,520-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole, 5- (3-Fluoro-phenyl) -3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole hydrogen formate, 5- ( 4-fluorophenyl) -3 - {[(1S, 4S) -5-methyl25 -2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole, 5- (4-methoxyphenyl) hydrogen formate -3 - {[(1S, 4 S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole, 6- (2-furyl) -3- hydrogen formate {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole, 6- (3-furyl) -3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole hydrogen formate, 3 - {[ (1S, 4S) -5-ethyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole, 3 - {[(1S, 4S) -5-methyl-2 hydrogen formate, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole, 3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2- hydrogen formate yl] carbonyl} -5- (3-thienyl) -1H-indazole, 5- (3-furyl) -3 - {[(1S, 4S) -5-methyl-2,510-diazabicyclo [2.2.1] hept- 2-yl] carbonyl} -1H-indazole,

5-bromo-3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole, and their pharmaceutically acceptable salts.

According to an aspect of the invention relating to the compounds of the invention, the compounds of formulas I, II and III are selected from such compounds as:

3- (2,5-diazabicyclo [2.2.2] oct-2-ylcarbonyl) -6- (1,3-thiazol-2-yl) -1H-indazole hydrochloride,

3- (2,5-diazabicyclo [2.2.2] oct-2-ylcarbonyl) -620- (1,3-thiazol-2-yl) -1H-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) hydrochloride -1H-indazole,

3- (2,5-diazabicyclo [2.2.2] oct-2-ylcarbonyl) -1H-indazole, 3 - [(5-methyl-2,5-diazabicyclo [2.2.2] oct-2-yl) carbonyl hydrogen formate ] -1H-indazole

3 - [(5-methyl-2,5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -1H-indazole, 3 - [(5-methyl-2,5-diazabicyclo [2.2.2] hydrogen formate 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) -1H-indazole,

3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole, 3 - {[(1S, 4S) -5- hydrogen formate 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- (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) -1H-indazole,

3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -5- (3-thienyl) -1H-indazole,

3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -5- (4-methyl-2-thienyl) -1H-indazole,

3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -5- (5-methyl-2-thienyl) -1H-indazole,

3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -5- (trifluoromethoxy) -1H-indazole,

3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -5-phenyl-1H-indazole, 3 - {[(1S, 4S hydrogen formate ) -5-methyl-2,5-diazabicyclo [2.2.1] 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 , 3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (1,3-thiazol-2-yl) -1H hydrogen formate -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 [2.2.1] hept-2-yl] carbonyl} -6- (2-thienyl) -1H-indazole,

3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (3-thienyl) -1H-indazole, 3 - {hydrogen formate [ (1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (4-methyl-1,3-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) -1H-indazole, 3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (4-methyl-2-thienyl) - 1H-indazole, 3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (5-methyl-1,3-thiazole hydrogen formate -2-yl) -1H-indazole,

3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (5-methyl-1,3-thiazol-2-yl) -1H-indazole, 3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (5-methyl-2-furyl) - 1H-indazole,

3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (5-methyl-2-thienyl) -1H-indazole, hydrogen formate 3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (tetrahydro-2H-pyran-4-yl) -1H-indazole .

3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (tetrahydro-2H-pyran-4-yl) -1H-indazole , 3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (trifluoromethoxy) -1H-indazole hydrogen formate,

3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] 5 carbonyl} -6- (trifluoromethoxy) -1H-indazole,

3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (trifluoromethyl) -1H-indazole, 3 - {[(1S hydrogen formate , 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -7- (trifluoromethoxy) 10 -1H-indazole,

3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -7- (trifluoromethoxy) -1H-indazole, 5- (2-furyl) -3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole,

5- (3-fluorophenyl) -3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole,

5- (3-furyl) -3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole,

5- (4-fluorophenyl) -3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo20 [2.2.1] hept-2-yl] carbonyl} -1H-indazole,

5- (4-methoxyphenyl) -3 - {[(1S, 4 S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole, 5- (hydrogen formate) cyclopentyloxy) -3 - {[(1S, 4 S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole,

5- (cyclopentyloxy) -3 - {[(1S, 4 S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole, 5- (cyclopropylmethoxy) hydrogen formate -3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole,

5- (cyclopropylmethoxy) -3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole,

5-amino-3 - [(5-methyl-2,5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -1H-indazole,

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, 5-bromo-3 - [(1S, 4S) -2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl] -1H-indazole,

5-hydroxy-3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] 10 hept-2-yl] carbonyl} -1H-indazole, 5-methoxy-3- hydrogen hydrogen formate (5-methyl-2,5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -1H-indazole, 3- (2,5-diazabicyclo [2.2.2] oct-2-ylcarbonyl) hydrochloride -5 methoxy-1H-indazole

3- (2,5-diazabicyclo [2.2.2] oct-2-ylcarbonyl) -5-methoxy-1H-indazole, 5-methoxy-3 - {{(1S, 4S) -5-methyl-2,5 hydrogen formate diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole,

5-methoxy-3 - {{(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] 20 hept-2-yl] carbonyl} -1H-indazole,

6- (2-furyl) -3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole, 6- (3-hydrogen formate) , 6-dihydro-2H-pyran-4-yl) -3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} 25 -1H- indazole,

6- (3,6-dihydro-2H-pyran-4-yl) -3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole,

6- (3-furyl) -3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole, 6- (cyclopentyloxy hydrogen formate) ) -3 - {[(1S, 4 S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole,

6- (cyclopentyloxy) -3 - {[(1S, 4 S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole, 6- (cyclopropyl) hydrogen formate -3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1,2-benzisothiazole,

6- (cyclopropyl) -3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1,2-benzisothiazole,

6-ethoxy-3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1,2-benzisothiazole, 3- (2.5 hydrochloride) -diazabicyclo [2.2.2] oct-2-ylcarbonyl) -6-methoxy-1H-indazole

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) -1H-indazole,

6-methoxy-3 - [(5-methyl-2,5-diazabicyclo- [2.2.2] oct-2-ylcarbonyl) -1H-indazole, 6-methoxy-3 - {[(1S, 4S) -5 hydrochloride -methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole, 6-methoxy-3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole,

6-methoxy-3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole,

7- methoxy-3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1,2-benzisothiazole, N- (3- { [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazol-5-yl) -N'-propylurea,

N- (3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazol-5-yl) -N'-propylurea, N- {3 - [(5-methyl-2,5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -1H-indazol-5-yl} 5-cyclopropanecarboxamide hydrogen formate,

N- {3 - [(5-methyl-2,5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -1H-indazol-5-yl} cyclopropanecarboxamide, N- {3 - [(5- methyl-2,5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -1H-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 their salts approved for use in pharmacy.

According to a further aspect of the invention relating to the compounds of the invention, the compounds of formulas I, II and III are selected from such compounds as:

3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1,2-benzisoxazole hydrogen formate,

3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1,2-benzisoxazole, 3 - {[(1S, 4S) hydrogen formate 5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -5- (4-methyl-1,3-thiazol-2-yl) -1H-indazole,

3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -5- (4-methyl-1,3-thiazol-2-yl) -1H-indazole, 3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -5- (5-methyl-1,3- thiazol-2-yl) -1H-indazole,

3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -5- (5-methyl-1,3-thiazol-2-yl) -1H-indazole, 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] 5 carbonyl} -5- (tetrahydro-2H-pyran-4-yl) -1H- indazole, 5- (3,6-dihydro-2H-pyran-4-yl) -3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl hydrogen formate. ] carbonyl} -1H-indazole,

5- (3,6-dihydro-2H-pyran-4-yl) -3 - {[(1S, 4S) -5-methyl-2,510-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H -indazole, 5- (difluoromethoxy) -3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole hydrogen formate,

5- (difluoromethoxy) -3 - {[(1S, 4 S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole, 6- (difluoromethoxy) hydrogen formate -3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole,

6- (difluoromethoxy) -3 - {[(1S, 4 S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole, 7-fluoro-6 hydrogen formate -methoxy-3 - {[(1S, 4S) -5-methyl20 -2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole,

7- fluoro-6-methoxy-3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole, N- (hydrogen formate) 3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazol-5-yl) cyclopropanecarboxamide,

N- (3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazol-5-yl) cyclopropane carboxamide, N- (hydrogen formate) 4-fluorobenzyl) -N '- (3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazol-5-yl) urea,

N- (4-fluorobenzyl) -N '- (3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazol-5 -yl) urea, N- (4-fluorobenzyl) -N '- {3 - [(5-methyl-2,5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -1H-indazol-5 hydrogen formate 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] -1H-indazole-5-amine,

N- (cyclopropylmethyl) -3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole-5-amine, N hydrogen formate, N-dimethyl-3 - [(5-methyl-2,5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -1H-indazole-5-amine,

N, N-dimethyl-3 - [(5-methyl-2,5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -1H-indazole-5-amine, N, N-dimethyl-3- hydrogen formate {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole-5-amine,

N, N-dimethyl-3 - {[(1S, 4 S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole-5-amine, N-hydrogen formate , N-dimethyl-3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazol-6-amine,

N, N-dimethyl-3 - {[(1S, 4 S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole-6-amine, N-hydrogen formate -cyclopentyl-N '- (3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazol-5-yl) urea

N-cyclopentyl-N '- (3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazol-5-yl) urea , N-cyclopentyl-N '- {3 - [(5-methyl-2,5-diazabicyclo [2.2.2] oct-2-yl] carbonyl} -1H-indazol-5-yl) urea hydrogen formate,

N-cyclopentyl-N '- {3 - [(5-methyl-2,5-diazabicyclo [2.2.2] oct-2-yl] carbonyl} -1H-indazol-5-yl) urea, and their salts approved for use in pharmacy.

In a preferred aspect, the invention includes: pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable carrier and optionally another active ingredient as discussed below; a method of stimulating or activating inhibition of alpha-7 nicotinic receptors, as for example determined by a standard assay, either described in this patent, either in vitro or in vivo (in an animal, e.g. in an animal model, or in a mammal or human); a method of treating neurological syndrome, for example, memory loss, especially long-term memory, impairment or cognition decline, memory impairment and the like; a method of treating a disease state modulated by alpha-7 nicotinic receptor activity in a mammal, e.g., a human subject, e.g., those referred to herein.

The compounds of the present invention can be prepared in a traditional manner. Some known processes that can be used are described below. All substrates are known or can be prepared from known raw materials using traditional methods.

The synthesis of similar compounds is disclosed in the simultaneous application serial number 10 / 669.645, filed on September 25, 2003, which disclosure is incorporated herein by reference.

Acids that can be used to make bicyclic base amides are commercially available, they can be prepared using 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 using basic hydrolysis, diazotization and reduction [Snyder, HR et al., J. Am. Chem. Soc., 1952, 7 4, page 2009]. Benzisoxazole-3-carboxylic acid can be prepared from 2,5-dibromonitrobenzene by reacting with diethylmalonate and then carrying out saponification with decarboxylation, reesterification, reaction with isoamyl nitrite under basic conditions, hydrogenolysis reaction and finally saponification [Angell RM, Baldwin IR, ., Deboeck NM, Longstaff T., Swanson S., WO 04010995 A1]. 3-Benzisothiazole carboxylic acid can be prepared from thiophenol by reaction with oxalyl chloride and aluminum chloride followed by treatment with hydroxylamine, hydrogen peroxide and sodium hydroxide. Bicycloamines that can be used to make bicyclic base amides are commercially available as well as can be prepared using known procedures described in the literature or as described below. For example (1S, 4S-2tert-butoxycarbonyl-2,5-diazabicyclo [2.2.1] heptane hydrochloride is commercially available. (1S, 4S) -2-methyl-2,5-diazabicyclo [2.2.1] 28 heptane can be prepared by the reduction reaction of tert-butyl carbamate with lithium aluminum hydride or by a sequence of amination under reducing conditions followed by deprotection. 2,5-Diazabicyclo [2.2.2] octane can be prepared as described in the literature (Newman H., J. Heterocyclic Chem., 1974, 11, page 449. Sturm PA, Henry DW, J. Med. Chem., 1974, 17, page 481). 2-Methyl-2,5-diazabicyclo [2.2.2] acetate can be prepared from 2,5-diaminohexanedioic acid diethyl ester by N-benzyl cyclization reaction of the intermediate derivative followed by successive reduction of tertiary amides, hydrogenolysis, selective protection, amination under reducing conditions and deprotection.

The bicyclic base amide can be produced by coupling acids with bicycloamine and HBTU or HOBt and EDCl in DMF or by converting the acids into the corresponding acid chloride followed by reaction with bicycloamine (Macor JE, Gurley D., Lanthom T., Loch J., Mack RA , Mullen G., Tran O., Wright N., and Macor JE, Bioorg. Med. Chem. Lett., 2001, 9, page 319.). Coupling is usually carried out at room temperature for 4 to 8 hours. Thioamide analogues can be prepared from amides by reaction with Lawesson's reagent (Wipf P., Kim Y., Goldstein DM, J. Am. Chem. Soc., 1995, 117, page 11106). Bicyclic basic methyleneamine analogues can be prepared from bicyclic base amides using standard reduction procedures, for example as described below. The resulting compounds can be isolated and purified using standard techniques, such as chromatography or recrystallization, which are used by those skilled in the art.

A person skilled in the art is aware that compounds of formulas I-III may exist in various, tautomeric and geometric isomeric forms. All these compounds, including cis isomers, trans isomers, diastereomeric mixtures, racemates, non-racemic mixtures of enantiomers and largely pure and pure enantiomers are within the scope of the present invention. Significantly pure enantiomers contain no more than 5% (by weight) of the corresponding opposite enantiomer, preferably no more than 2% and most preferably no more than

1%.

Optical isomers can be obtained by resolution of racemic mixtures by traditional processes, for example by formation of diastereomeric salts, using an optically active acid or base, or by formation of covalent diastereomers. Examples of suitable acids include tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid and camphorsulfonic acid. Mixtures of diastereomers may be separated into their individual diastereomers, based on their physical and / or chemical differences, using methods known to those skilled in the art, for example, using chromatography or fractional crystallization. Then optically active bases or acids are released from the separated diastereomeric salts. The use of chiral chromatography (e.g., using a chiral HPLC column) with or without traditional derivatization, optimally selected to maximize enantiomer separation, is associated with various processes for the separation of optical isomers. Suitable chiral HPLC columns are manufactured by Diacel, for example Chiracel OD and Chiracel OJ, selected from many others, all of which are suitable for routine selection. Enzymatic separations, with or without derivatization, are also useful. Optically active compounds of formulas I-III can also be obtained by using optically active substrates in a chiral synthesis process under reaction conditions that will not cause racemization.

In addition, it is known to those skilled in the art that the compounds may be used in various enriched isotope forms, for example enriched in content ²H ³H ¹¹C ¹³C and / or ¹⁴C. In one particular embodiment, the compounds are deuterated. Such deuterated forms can be prepared using the procedure given 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 efficacy and extend the duration of action of drugs.

Compounds substituted with deuterium can be synthesized by 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., Pharm. Des., 2000, 6 (10)] (2000), page 110, CAN 133: 68895 AN 2000: 473538 CAPLUS; Kabalka George W., Varma Rajender S., The synthesis of radiolabeled compounds via organometallic intermediates, Tetrahedron (1989), 45 (21), pages 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. pages 9-32, CODEN: JRACBN ISSN: 0022-4081,

1981: 476229 CAPLUS.

(1981), 64(1-2),

CAN 95: 76229 AN

Where applicable, the present invention also provides useful forms of the compounds as disclosed herein, such as pharmaceutically acceptable salts or prodrugs of all compounds of the present invention for which salts and prodrugs can be prepared. Pharmaceutically acceptable salts include those salts that have been obtained by reacting the main compound acting as a base with an inorganic or organic acid to form a salt, e.g. with hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salic acid, coal. Pharmaceutically acceptable salts also include those salts in which the main compound acts as an acid and is reacted with a suitable base to form the sodium salt, potassium salt, calcium salt, magnesium salt, ammonium salt and choline salt. In addition, it is known to those skilled in the art that the addition salts of the claimed compounds with acid can be prepared by reacting the compounds with the appropriate inorganic or organic acid using any of many known methods. Alternatively, alkali metal and alkaline earth metal salts can be prepared by reacting the compounds of the invention with the appropriate base using any of a number of known methods.

The following are additional examples of acid salts that can be prepared by reaction with inorganic and organic acids: These are acetates, adipates, alginates, citrates, aspartates, benzoates, benzenesulfonates, bisulfates, butyrates, camphor salts, digluconates, cyclopentanopropionates, dodecyl sulfates, ethanesulfonates, glucoheptanoates, glycerophosphates, heptophosphates, heptophosphates, heptanoates, hydroxyethanesulfonates, lactates, maleates, methanesulfonates, nicotinates, 2-naphthalenesulfonates, oxalates, palmitate, pectinates, peroxodisulfates, 3-phenylpropionates, picrates, pivalates, propionates, succinates, tartrates, thiocyanates, tosylates, mesylates and undecanoates.

Preferably, the salts formed are pharmaceutically acceptable salts intended for administration to mammals. However, pharmaceutically unacceptable salts of the compounds are useful as intermediates, for example to isolate the compound in the form of a salt and then, by reaction with an alkaline reagent, convert the salt to the free base of this compound. If desired, the free base form can then be converted to a pharmaceutically acceptable acid addition salt.

The compounds of the invention may be administered alone or as an active ingredient in the dosage form. Thus, the present invention also provides pharmaceutical compositions of compounds of Formula I-III, containing, for example, one or more pharmaceutically acceptable carriers.

A number of standard literature sources are available in which procedures suitable for use in the preparation of various dosage forms suitable for administration of the compounds of the invention are described. Examples of potential dosage forms and preparations are, for example, found in the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (current edition); Pharmaceutical Dosage Forms: Tablets (editors: Lieberman, Lachman and Schwartz), current edition published by Marcel Dekker, Inc .; as well as in Remington's Pharmaceutical Sciences (editor Arthur Osol), pages 1553-1593 (current edition).

In view of their activity associated with stimulation of alpha-7 receptors and their high degree of selectivity, the compounds of the present invention can be administered to any individual that requires stimulation of alpha-7 receptors. The method of administration is synchronized with the needs of the patient, for example, it is administered orally, nasally, parenterally (subcutaneously, intramuscularly, intravenously, intra-sternum and by infusion), by inhalation, rectal, vaginal, topical and ocular.

Various solid dosage forms can be used to administer the compounds of the invention, such as gel capsules, capsules, cachets, granules, lozenges and loose powders. The compounds of the present invention can be administered alone or in combination with various pharmaceutically acceptable carriers, diluents (such as sucrose, mannitol, lactose, starches) and excipients known in the art, including suspending agents, solubilizing agents , buffers, binders, disintegrants, preservatives, dyes, flavors, lubricants and the like, but not limited to them. Preferably, sustained release capsules, tablets and gels are also suitable for the administration of the compounds of the present invention.

Various liquid oral dosage forms may also be used to administer the compounds of the invention, including aqueous and non-aqueous solutions, emulsions, suspensions, syrups and elixirs. Dosage forms of this type may also contain suitable inert diluents known in the art, such as water, as well as additives known in the art, such as preservatives, wetting agents, sweeteners, flavors and agents used in the preparation of compounds of the invention emulsions and suspensions. The compounds of the present invention may be in the form of an injectable drug, for example for intravenous injection, in the form of an isotonic, sterile solution. Other usage forms are also possible.

Suppositories for rectal administration of the compounds of the present invention can be made 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 in the form of a spray, in addition to containing in addition to the active ingredient such suitable carriers as are known in the art.

For topical administration, the pharmaceutical compositions may be in the form of creams, ointments, liniment, lotion, emulsion, suspensions, gels, solutions, pastes, powders, spray forms and drops suitable for administration to the skin, eyes, mouth and mouth. to nose. For topical administration, transdermal administration may also be employed using such dosage forms as transdermal patches.

Aerosol dosage forms suitable for administration by inhalation may also be prepared. For example, in the treatment of respiratory disorders, the compounds of the invention may be administered in the form of inhalation powder (e.g. micronized powder) or in the form of spray solutions or suspensions. The aerosol formulation may be placed in a propellant suitable for use in a pressurized container.

The compounds can be administered as an individual active agent or in combination with other pharmaceutical agents such as other agents used to treat cognitive impairment or memory loss such as, for example, other α-7 receptor antagonists, PDE4 inhibitors, calcium channel blockers, m1 muscarinic receptor modulators and m2, adenosine receptor modulators, NMDA-R ampakin modulators, mGluR receptor modulators, dopamine modulators, serotonin modulators, cannabinoid receptor modulators and cholinesterearase inhibitors (for example donepezil, rivastigmine and glanthanamine). In such combinations, each active ingredient may be administered either in accordance with its normal dose range or below its normal dose range.

The compounds of the invention may be used in conjunction with "positive modulators" that enhance the efficacy of nicotinic receptor agonists. Positive modulators have been disclosed, for example, in international patent publications WO 99/56745, WO 01/32619 and WO 01/32622. Such combined therapy can be used to treat conditions / diseases associated with reduced nicotine transmission.

In addition, the compounds can be used in conjunction with compounds that bind to Ae peptides (β amyloid protein) and thereby inhibit the binding of peptides to a7nAChr receptor subtypes. See for example WO 99/62505.

The present invention further includes treatment methods that utilize activation of α-7 nicotinic receptors. Thus, the present invention includes methods for the selective activation / stimulation of α-7 nicotinic receptors in animals, e.g., mammals, especially in humans in which such activation / stimulation has such a therapeutic effect that, as a result of activation, may relieve conditions associated with neurological syndromes such as memory loss, especially long-term memory. Such methods include administering to an animal in need of such treatment, especially a mammal and above all a human, an effective amount of a compound of formulas I-III, alone or as part of a formulation, as disclosed herein.

According to 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 medical condition (e.g., memory impairment), which comprises administering to the patient a compound of formulas I, II or III. Preferably, this disease state requires reduced nicotinic cholinergic receptor activity.

In accordance with one aspect of the method of the invention, there is provided a method of treating a disease or condition or preventing a disease, or conditions that result from nicotinic cholinergic receptor transmission dysfunction in a mammal, e.g., a human, which method comprises administering an effective amount of a compound of formulas I, II or III.

According to one aspect of the method of the invention, a method is provided for treating a disease or condition or preventing a disease, or conditions that result from faulty or malfunctioning in a mammal, e.g., a human, of nicotinic cholinergic receptors, particularly a7nACh receptors, which method comprises administering an effective amount of a compound of formulas I, II or III.

In accordance with one aspect of the method of the invention, there is provided a method of treating a disease or condition or preventing the disease or conditions that result from suppression of nicotinic cholinergic receptor transmission in a mammal, e.g., a human, which method comprises administering a compound of formulas I, II or III in an amount effective to cause activation of? 7nACh receptors.

In accordance with another aspect of the method of the invention, there is provided a method for treating a psychotic disorder, cognitive impairment (e.g., memory impairment), or a disease causing degeneration of a nerve tissue in a mammal, e.g., a human, or a method of preventing these diseases, which method comprises administering an effective amount compounds of formulas I, II or III.

In accordance with another aspect of the method of the invention, there is provided a method for treating a disease or condition or preventing the disease or conditions that result from the loss of cholinergic synapses in a mammal, e.g., a human, which method comprises administering an effective amount of a compound of formulas I, II or III.

In accordance with another aspect of the method of the invention, a method of treating or preventing a disease that causes neurodegeneration is provided by activating? 7nACh receptors in a mammal, e.g., a human, which activation comprises administering an effective amount of compounds of formulas I, II or III .

In accordance with another aspect of the method of the invention, a method of protecting neurons in a mammal, e.g., a human, from neurotoxicity induced by activation of? 7nACh receptors is provided, which method comprises administering an effective amount of a compound of formulas I, II or III.

In accordance with another aspect of the method of the invention, there is provided a method for treating or preventing a neurodegenerative disorder by inhibiting the binding of Ae peptides to a7nACh receptors in a mammal, e.g., a human, which method comprises administering an effective amount of a compound of formulas I, II or III.

According to another aspect of the method of the invention, a method is provided for protecting neurons in a mammal, e.g., a human, from neurotoxicity caused by Ae peptides, which method comprises administering an effective amount of a compound of formulas I, II or III.

According to another aspect of the method of the invention, a method is provided for ameliorating inhibition of cholinergic function caused by Ae peptides in a mammal, e.g., a human, which method comprises administering an effective amount of a compound of formulas I, II or III.

The compounds of the present invention are alpha-7 nicotinic receptor ligands, preferably agonists, particularly partial agonists of the alpha-7 nicotinic cholinergic receptor. Assays for determining the activity of nicotinic cholinergic receptors are known in the art. See, for example, Davies AR, 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): pp. 679-90. As agonists of? -7nAChR receptors, the compounds are useful in prophylactic activities and in the treatment of various diseases and conditions associated with the central nervous system. Nicotinic cholinergic receptors are receptors of the "ligandgastrol" ion channel, which consist of five protein subunits forming a centrally located ion-conducting opening. Currently, eleven known neural subunits of the nAChR receptor (α2 - α9 and β2 - β4) stand out. There are also five further subunits that result from expression in the peripheral nervous system (α1, β1, γ, δ, ε).

The nAChR receptor subtypes may be homopentameric or heteropentameric. The subunit that has become the focus of particular attention is the homopentametric α7 receptor subtype consisting of five α7 subunits. Α7nAChR receptors have a high affinity for nicotine (agonist) and α-bungarotoxin (antagonist). Studies have shown that α7-nAChR receptor agonists may be, inter alia, useful in the treatment of psychotic diseases, diseases that cause neurodegeneration and cognitive impairment. Although nicotine is a known agonist, there is a need for progress in the development of other α7-nAChR receptor agonists, particularly selective agonists, which have less toxicity and less side effects than nicotine.

Anabazeine, i.e. 2- (3-pyridyl) -3,4,5,6-tetrahydropyridine is a toxin of natural origin found in certain marine worms (marine worms of the species Nemertinea) and in ants. See, for example, Kern et al., Toxicon, 9: page 23, 1971. Anabazeine is a potential activator of mammalian nicotinic receptors. See, for example, Kern, Amer. Zoologist, 25, page 99, 1985. Certain analogs of anabazeine, such as anabazine and DMAB (3- [4- (dimethylamino) benzylidene] 3,4,5,6-tetrahydro-2'3'-bipyridine) are also known nicotinic receptor agonists. See, for example, US Patent No. 5,602,257 and International Patent Publication No. WO 92/15306. One particular analogue of anabazeine (E-3- [2,4-dimethoxybenzylidene] anabazeine, also known as GTS-21 and DMXB (see, for example, US Patent No. 5,741,802) is a selective, partial? 7-nAChR receptor agonist thoroughly researched. For example, abnormal sensory inhibition is a deficiency in sensory processing in schizophrenics, and GTS-21 has been found to increase sensory inhibition by interacting with? 7 -nAChR receptors. See, for example, Stevens et al., Psychopharmacology, 136, pp. 320-27 (1998).

Another compound that is known to be a selective? 7-nAChR receptor agonist is tropisetron, i.e. 1aH, 5aH-tropan-3a-yl indole-3-carboxylate. See, JE Macor et al., "The 5-HT3-Antagonist Tropisetron (ICS 205-930) is a Potent and Selective A7 Nicotinic Receptor Partial Agonist", Bioorg. Med. Chem. Lett., 2001, pp. 319-321).

Agents that bind to nicotinic cholinergic receptors have been shown to be useful in the treatment and / or prophylaxis of various diseases and conditions, particularly psychotic diseases, diseases that cause neurodegeneration associated with cholinergic system dysfunction and memory and / or cognitive disorders, including for example, schizophrenia, anxiety, manic agitation, depression, manic depression [examples of psychotic disorders], Tourette syndrome, Parkinson's disease, Huntington's disease [examples of diseases causing degeneration of the nervous tissue], cognitive disorders (such as Alzheimer's disease, dementia with Lewi bodies, amyotrophic lateral sclerosis, memory impairment, memory loss, cognitive deficiency, attention deficit disorder, attention deficit hyperactivity disorder) as well as other uses, such as treating nicotine addiction, smoking cessation, pain treatment (i.e. analgesic use), neuroprotective protection, treatment of sudden time zone syndrome (jetlag), treatment of inflammation or sepsis. See, for example, international patent publications number WO 97/30998; WO 99/03850;

WO 00/42044; WO 01/36417; Holladay et al., J.Med.Chem., 40:26, pp. 4169-94 (1997); Schmitt et al., Annual Reports Med. Chem., Chapter 5, pages 41-51 (2000); Stevens et al. Psychopharmatology, 136, pp. 320-27 (1998); and Shytle et al., Molecular Psychiatry, (2002), 0, pages 525-535.

Thus, the subject of the invention is a method of treating a patient, especially a human suffering from psychotic diseases, diseases causing degeneration of the nervous tissue causing dysfunction of the cholinergic system and states of memory and / or cognitive impairment, including, for example, schizophrenia, anxiety, manic agitation. depression, manic depression [examples of psychotic disorders], Tourette syndrome, Parkinson's disease, Huntington's disease [examples of diseases causing neurodegeneration] and / or cognitive disorders (such as Alzheimer's disease, Lewy body dementia, amyotrophic lateral sclerosis, memory impairment, memory loss, cognitive deficiency, attention deficiency, attention deficit hyperactivity disorder), comprising administering to the patient an effective amount of a compound of formulas I-III.

Degenerative disorders of the nervous tissue encompassed by the method of the present invention include, but are not limited to, treatment and prophylaxis for Alzheimer's disease, Pick's disease, the spread of dementia with Lewi bodies, progressive supranuclear paralysis (Stealth-Richardson syndrome) multi-system degeneration (Shy-Driller syndrome), motor neuron diseases including amyotrophic lateral sclerosis, degenerative clumsiness (ataxia), cortico-basal degeneration, endemic syndrome for Guam: amyotrophic lateral sclerosis (ALS) - Parkinson's disease-dementia, subacute, sclerosing encephalitis, Huntington's disease, Parkinson's disease, synucleinopathies, primary, progressive aphasia, striatostatic degeneration, Machado-Joseph's disease / cerebellar ataxia type 3, olive-bridge-cerebellar degeneration, Gilles De La Tourette's disease, bulb disease, pseudo-paralyzed palsy, musculo-vertebral atrophy, spinal-muscular atrophy (Kennedy's disease), primary lateral sclerosis, familial spasmodic paraplegia, Werdnig-Hoffmann disease, Kugelberg-Welander disease, Tay-Sach disease, Sandhoff disease, familial spasmodic disease, Wohlfart-KugelbergWander disease, lower limb spasmodic paresis, progressive multifocal white matter inflammation, diseases caused prions (such as Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker disease, Kuru disease and fatal familial insomnia) and disorders resulting in neurodegeneration resulting from cerebral ischemia or myocardial infarction, including embolic and thrombotic occlusion, as well as any type of intracranial hemorrhage (including epidural hemorrhage, subdural hemorrhage, and intracranial hemorrhage) but not limited to them) and intracranial and intra-vertebral pathologies (including contusion, penetration, felling, squeezing and mutilation but not limited to them).

In addition, α-7nAChR receptor agonists such as the compounds of the invention can be used to treat age-related dementia and other dementias and conditions associated with memory loss, including age-related memory loss, old age, vascular dementia, and white matter thinning disease ( Binswanger disease), dementia of endocrine or metabolic origin, dementia caused by head injuries and the spread of brain damage, dementia of boxers and dementia of the frontal lobe. See for example WO 99/62505. Thus, according to the invention, a method of treating a patient, especially a human, suffering from age-related dementia and other dementias and conditions associated with memory loss is provided, which method comprises administering to the patient an effective amount of a compound of formulas IIII.

Thus, according to an additional variant thereof, the present invention relates to a method of treating patients suffering from memory impairment, e.g. due to mild age-related cognitive impairment, Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeld's disease Jakob, depression, aging, head injury, stroke, hypoxia of the central nervous system, senile weakness of the brain, dementia after a number of heart attacks and other neurological conditions, as well as HIV infection and cardiovascular diseases, which involves administering an effective amount of a compound with formulas

I-III.

It is known that the amyloid precursor protein (APP) and Ae peptides derived therefrom, e.g. Ae_1-40 and Ae_1-42 as well as other fragments, are involved in the pathology of Alzheimer's disease. Ae peptides are also known_1-42 they are not only involved in neurotoxicity but also inhibit the action of the cholinergic transmitter. In addition, Ae peptides were found to bind to alpha-7 nAChR receptors. Thus, agents that block the binding of Ae peptides to alpha-7 nAChR receptors are useful in the treatment of diseases that cause neurodegeneration. See, for example, International Patent Publication No. WO 99/62505. In addition, stimulation of alpha-7 nAChR receptors may protect neurons against cytotoxicity associated with Ae peptides. See, for example, Kihara T., et al., Ann. Neurol., 1997, 42, page 159.

Thus, according to one embodiment thereof, the present invention provides a method of treating and / or preventing dementia in an Alzheimer's patient, which comprises administering to the subject a therapeutically effective amount of a compound of formulas I-III to inhibit the binding of amyloid β peptide (preferably Ae_1-42) with nAChR receptors, preferably with alpha-7 nAChR receptors, most preferably with human alpha-7 nAChR receptors (as well as a method of treatment and / or prevention of other clinical manifestations of Alzheimer's disease, which include other neuropsychiatric symptoms and symptoms as well as movement abnormalities) and walking but not limited to them).

The present invention also relates to methods for treating other diseases associated with amyloidosis, e.g. hereditary cerebral angiopathy, non-neuropathic hereditary amyloidosis, Down syndrome, macroglobulinemia, secondary, familial Mediterranean fever, Muckle-Wells syndrome, multiple myeloma, pancreatic and heart diseases associated with amyloidosis. chronic intropathy associated with Finnish and Iowa hemodialysis and amyloidosis.

In addition, nicotinic receptors are thought to be involved in the body's response to alcohol intake. Thus, α7nAChR receptor agonists can be used to assist recovery from alcoholism and in alcohol detoxification therapy. Thus, according to one variation thereof, the subject of the invention is a method of treating a patient comprising assisting recovery from alcoholism or treating the patient by detoxification method, which method comprises administering to the patient an effective amount of a compound of formulas I, II or III.

The α-7nAChR agonists of the nicotinic receptor subtype can be used to provide neurological protection against damage after stroke and ischemia, and excessive glutamate stimulation of neurons. Thus, according to one embodiment thereof, the subject of the invention is a method of treating a patient in order to provide neurological protection (neuroprotection) against damage caused by stroke and in case of ischemia and excessive excitation of neurons by glutamate, which method comprises administering to the patient an effective amount of a compound of formulas I, II or III.

As noted above, α-7nAChR subtypes agonists can also be used to treat nicotine addiction, to stop smoking, to treat pain, and to treat sudden time zone syndrome (jetlag), obesity, diabetes, inflammation and sepsis. Thus, according to one embodiment thereof, the subject of the invention is a method of treating a patient suffering from nicotine addiction, pain, treating sudden time zone syndrome (jetlag), obesity and / or diabetes, or a method of causing smoking cessation in a patient, which the method comprises administering to the patient an effective amount of a compound of formulas I, II or III.

In addition, because of their affinity for? -7nAChR receptors, labeled derivatives of compounds of formulas I-III (e.g., labeled derivatives ²¹C or ¹⁸F) can be used for neuroimaging receptors, for example inside the brain. Thus, using such labeled agents, in vivo imaging of receptors can be performed using, for example, PET imaging.

Memory impairment is manifested by a weakening of the ability to learn new information and / or the inability to recall previously learned information. Memory impairment is the initial symptom of dementia and can also be a symptom associated with such diseases as Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeld-Jakob disease, HIV infection, cardiovascular disease and head injury as well as weakness cognitive depend on age.

According to one embodiment, the subject of the invention is a method of treating a patient suffering, for example, from mild cognitive impairment (MCI), vascular dementia (VaD), aging-related cognitive deficit (AACD), memory loss associated with open heart surgery cardiac arrest and / or general anesthesia, memory loss due to early exposure to anesthetics, cognitive impairment due to lack of sleep, chronic fatigue syndrome, seizure sleep, dementia associated with AIDS, epileptic cognitive impairment, Down syndrome, alcoholism-related dementia, drug / chemical related memory impairment, fist dementia (boxing syndrome) and dementia in animals (e.g. dogs, cats, horses and the like), the method comprising administering to the patient an effective amount of a compound of formulas IIII.

The dosage of the compounds of the present invention depends on various factors, including those considered, the specific treatment syndrome, the severity of the symptoms, route of administration, frequency of administration, type of compound used, efficacy, toxicity, pharmacokinetics of the compound, and the occurrence of harmful side effects.

The compounds of the invention can be administered to mammals, especially humans, using standard dose levels, standard for α-7 receptor agonists, such as the compounds mentioned above known as α-7 nicotinic agonists. For example, the compounds may be administered in single or multiple dose forms, by oral administration using a dosage level of, for example, 0.0001-10 mg / kg / day, e.g. 0.01-10 mg / kg / day. Unit dosage forms may, for example, contain from 1 to 200 mg of active compound. For intravenous administration, the compounds may be administered in single or multiple doses.

When carrying out the procedures of the present invention, it is of course understood that reference to specific buffers, reagent media, cells, culture conditions and the like should not be construed as limiting but that this reference includes all related materials that a person skilled in the art will use. judged as interesting or valuable in the specific context in which this discussion is presented. For example, it is often possible to replace one buffer system or culture medium with another system or medium and still achieve similar, if not identical, results. Specialists in this field will have appropriate knowledge of such systems and methods of operation and will be able, without unnecessary experimentation, to make such substitutions which will serve the purposes for which the methods and procedures disclosed in this description are intended.

The present invention will now be further described with reference to the following non-limiting examples. When using the disclosure of these examples, it should of course be remembered that other and various variations of the methods disclosed in the present invention will undoubtedly impose themselves on those skilled in the relevant field.

In the above and in the following examples, all temperatures are given in degrees Celsius, the temperatures are not corrected and unless otherwise indicated, all parts and percentages are by weight.

The disclosures of all applications, patents and publications cited above and below are incorporated herein by reference in their entirety.

EXAMPLES

Unless otherwise specified, all spectra were recorded at 300 MHz on a Bruker Instruments NMR spectrometer.

Coupling constants (J) are given in hertz (Hz) and the peaks are ordered relative to TMS (δ 0.00 ppm). Microwave reactions were carried out using a Personal Chemistry Optimizer ™ microwave reactor equipped with 2.5 ml or 5 ml Personal Chemistry vials. Unless otherwise specified, all reactions were carried out at 200⁰C for 600 s, keeping the response time constant (setting "ON"). Sulphonated ion exchange resins (SCX cationites) were purchased from Varian Technologies. Unless otherwise specified, HPLC analytical studies were carried out on 4.6 mm x 100 mm Xterra RP18 columns, filled with 3.5 μ, using for 6 minutes a gradient elution using a mixture of water (0.1% formic acid) / acetonitrile (0.1% formic acid) in a ratio of 20/80 to 80/20.

Acid production:

The following procedures (1-10) describe in detail methods for the preparation of indazole acids, benzisoxazole acids and benzisothiazole acids, which were not commercially available.

Procedure 1:

In procedure 1, a method for producing an acid is described

6-nitroindazole-3-acid and coupling with bicyclic bases to generate derivatives substituted with a nitro group.

3-iodo-6-nitroindazole (1 mmol), copper (I) cyanide (2 mmol) and N, N-dimethylformamide (3 ml) were charged into a 5 ml reaction vessel placed in a microwave reactor. The vessel was sealed and at 185⁰C was subjected to microwave radiation for 600 s. 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 separated, washed with brine, dried (magnesium sulfate) and concentrated to give 122 mg of a 10/1 mixture of 3/1 cyano-6-nitroindazole and 6-nitroindazole as a yellow solid. A 10/1 mixture of 3-cyano-6-nitroindazole and 6-nitroindazole, dissolved in 10 N sodium hydroxide solution and then the light orange solution was heated for 1 hour at 100⁰C. The mixture was allowed to cool to room temperature and carefully acidified (pH = 1) with a 3 N hydrochloric acid solution. The solid was isolated and triturated with ethyl acetate to give 51 mg of 6-nitroindazole-3-carboxylic acid as a brown solid. The acid was coupled with a bicyclic base according to procedure A.

The following acid was prepared using this method: 6-nitro-1H-indazole-3-carboxylic acid.

Procedure 2:

Procedure 2 describes a method for nitrating indazole acid and coupling with a bicyclic base to form derivatives substituted with a nitro group.

Ethyl indazole-3-carboxylate (73.7 mmol) was dissolved in 20 mL concentrated sulfuric acid and then the reaction mixture was cooled to 0⁰C. A mixture of concentrated sulfuric acid (12 ml) and 70% nitric acid (12 ml) was added dropwise over a period of 1 hour. The mixture was stirred further at 0⁰C for 1 hour, then poured onto crushed ice (200 g). The solid was isolated by suction filtration, washed with several portions of water and dried in vacuo. The dried solid was suspended in 250 ml of acetonitrile, and then the mixture was heated for 2 hours while refluxing. The mixture was allowed to cool to room temperature and then the solid was isolated and dried in vacuo to give ethyl 5-nitroindazole-3-carboxylate (53%) as a colorless solid. Alkaline hydrolysis gave an acid which was subjected to a coupling reaction with a bicyclic base according to procedure A.

Literature reference: Org. Synthesis, Coll. Vol. 1., page 372.

The following acid was prepared using this method:

5-nitro-1H-indazole-3-carboxylic acid.

Procedure 3:

Procedure 3 describes the method of trapping indazolaryl lithiums with ketones and then coupling with bicyclic bases to form heterocyclic derivatives.

Tert-butyl 6-bromoindazole-3-carboxylate was prepared from acid by reaction with a double excess of di-tert-butyldicarbonate and then treated with sodium hydroxide. To a suspension of sodium hydride (60% dispersion in mineral oil) (4.8 mmol) in tetrahydrofuran (40 ml), kept at 0⁰C, a solution of tert-butyl 6-bromoindazole-3-carboxylate (4.0 mmol) in tetrahydrofuran (4 mL) was added slowly. After mixing for 0.5 hours at 0⁰C, the mixture was cooled to -78⁰C and then added

1.7 M solution of tert-butyllithium in pentane (5.1 mmol). After half an hour at -78⁰C, a solution of tetrahydropyran-4-one (5 mmol) in tetrahydrofuran (1 mL) was added dropwise. The mixture was stirred for 1 hour at -78⁰C and then warmed to 0⁰C. The reaction mixture was quenched with saturated ammonium chloride solution, and then the mixture was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was separated, then washed with brine (50 mL), dried (magnesium sulfate) and concentrated. The residue was purified by chromatography (70/30 ethyl acetate / hexane) to give 6- (4-hydroxytetrahydropyran-4-yl) -1H-indazole-3-carboxylic acid tert-butyl ester (68%) as a colorless solid.

6- (4-Hydroxytetrahydropyran-4-yl) -1H-indazole-3-carboxylic acid tert-butyl ester (0.86 mmol) was dissolved in trifluoroacetic acid (3 mL), and the reaction was maintained for 16 hours at room temperature. The solvent was removed in vacuo and then the residue was triturated with ethyl acetate to give 6- (3,6-dihydro-2H-pyran-4-yl) -1H-indazole-3-carboxylic acid (76%). The acid was coupled with a bicyclic base according to procedure A.

6- (4-Hydroxytetrahydropyran-4-yl) -1H-indazole-3-carboxylic acid tert-butyl ester (1.0 mmol) was dissolved in trifluoroacetic acid (5 mL), triethylsilane (2 mL) and dichloromethane (3 mL) after which the reaction was refluxed for 16 hours. The solvent was removed in vacuo and then the residue was triturated with ethyl acetate to give 6- (tetrahydropyran-4-yl) -1H-indazole-3-carboxylic acid (60%) as a light brown solid. The acid was coupled with a bicyclic base according to procedure A.

Using this method, the following acids were prepared: 6- (3,6-dihydro-2H-pyran-4-yl) -1H-indazole-3-carboxylic acid, 6- (tetrahydro-2H-pyran-4-yl) -1H -indazole-3-carboxylic acid.

Procedure 4:

Procedure 4 describes the method of converting substituted isatins to the corresponding indazole-3-carboxylic acids.

The method for converting substituted isatines to the corresponding indazole-3-carboxylic acids is essentially the same as the conversion method for indazole-3-carboxylic acid: Snyder HR et al., J. Am. Chem. Soc., 1952,

74, page 2009. Substituted isatin (22.1 mmol) was diluted with 1 N sodium hydroxide solution (24 mL) and then heated for 30 minutes at 50⁰C. The burgundy color solution was allowed to cool to room temperature and left for 1 hour. The reaction mixture was cooled to 0⁰C and treated with a solution of sodium nitrite (22.0 mmol) in water (5.5 ml) cooled to 0⁰C. This solution was introduced with a pipette submerged under the surface kept at 0⁰C and a vigorously mixed solution of sulfuric acid (2.3 ml) in water (45 ml). The addition lasted 15 minutes, after which the reaction was held for an additional 30 minutes. A cold solution was added to the reaction mixture over 10 minutes (0⁰C) Tin (II) chloride dihydrate (52.7 mmol) in concentrated hydrochloric acid (20 mL), after which the reaction was held for 60 min. The precipitated solids were isolated by filtration, washed with water and dried to give quantitative yield (quantitative mass balancing). Purity of this product (¹NMR and LC / MS) was suitable for use in the next step without further purification. Proceeding differently, the acid was recrystallized from acetic acid to obtain a pure substance.

The following acids were prepared using this method:

5- bromoindazole-3-acid,

6- bromoindazole-3-acid,

5- trifluoromethoxyindazole-3-acid,

6- trifluoromethoxyindazole-3-acid,

5-metoksyindazolo-3-acid.

Procedure 5:

Procedure 5 describes a method for producing substituted benzisothiazole-3-carboxylic acids from 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 heated for 1.5 hours, refluxed, then cooled to room temperature and concentrated in vacuo. The yellow oil substance formed was dissolved in dichloromethane (50 mL) and then cooled to 0⁰C and treated with aluminum chloride (4.30 g, 32.0 mmol) divided into portions. The mixture was heated for 30 minutes, refluxed, then cooled to room temperature and poured onto an ice / water mixture with stirring. The organic layer was separated and washed successively with saturated aqueous sodium bicarbonate solution, water and brine. The organic layer was dried over magnesium sulfate, then filtered and concentrated in vacuo. The residue was purified by chromatography (4/1 ethyl acetate / hexanes) to give 2.46 g (47%) of 6-methoxy-1-benzothiophene-2,3-dione as an orange solid.

To a mixture of dione (86 mg, 0.44 mmol) in 30% aqueous ammonium hydroxide (2.0 mL) was added 35% aqueous hydrogen peroxide (0.2 mL), after which the reaction was held for 12 hours. Precipitated pink solids were separated by filtration, then washed with water and dried under high vacuum to give 39 mg (42%)

6-methoxy-benzisothiazole-3-carboxamide.

To a solution of amide (1.14 g, 5.46 mmol) in methanol (100 mL) was added a 10 N sodium hydroxide solution (12 mL). The mixture was heated for 12 hours under reflux and then cooled to room temperature, then acidified to pH &lt;2, slowly adding concentrated hydrochloric acid. The organic layer was extracted with dichloromethane (2 x) then dried over sodium sulfate. The crude product was purified by chromatography (300/50/1 dichloromethane / methanol / formic acid mixture) to obtain 1.02 g (89%) of 6-methoxybenzoisotriazole-3-carboxylic acid as a pink solid.

The following acids were prepared using this method: benzo [d] isothiazole-3-carboxylic acid, 6-bromobenzo [d] isothiazole-3-carboxylic acid, 5-bromobenzo [d] isothiazole-3-carboxylic acid, 5-methoxybenzo acid [d ] isothiazole-3-carboxylic acid, 6-methoxybenzo [d] isothiazole-3-carboxylic acid, 7-methoxybenzo [d] isothiazole-3-carboxylic acid, 6-ethoxybenzo [d] isothiazole-3-carboxylic acid.

Procedure 6:

Procedure 6 describes a method for coupling brominated benzisothiazole-3-carboxylic acid esters and brominated indazole-3-carboxylic acid esters and Grignard reagents to produce alkyl and heterocyclic substituted acids.

0.5 M cyclopropyl magnesium bromide solution (25.0 mmol,

3.7 equivalents) in tetrahydrofuran was diluted with tetrahydrofuran (60 ml) and then reacted at room temperature with a 0.5 M solution of zinc chloride (25.0 mmol, 3.7 equivalents) in tetrahydrofuran. After 10 minutes, brominated ethyl benzisothiazole-3-carboxylate (0.30 mmol) and bis (triphenylphosphine) palladium (II) chloride (0.95 mmol, 0.1 equivalent) were added to the suspension. The reaction mixture was held for 1 hour at ambient temperature and then for 1 hour at 65⁰C. The reaction was quenched using saturated ammonium chloride solution and then extracted with dichloromethane (3 x). The extracts were dried over sodium sulfate and concentrated to dryness. The residue was purified by chromatography, eluting with a gradient of 100/0 to 90/10 dichloromethane / methanol to give the cyclopropyl substituted amide. The amide was dissolved in methanol / tetrahydrofuran / water (90/10/20 ml) and then treated with sodium hydroxide (5.8 g). The mixture was heated for 12 hours under reflux and then cooled to room temperature, filtered and then acidified to pH &lt;2 by slowly adding concentrated hydrochloric acid. The aqueous layer was extracted with ethyl acetate (2 x) and then the organic phase was dried over anhydrous sodium sulfate. Concentration of the extracts gave the acid in 38% yield. The acid was coupled with a bicyclic base according to procedure A.

This procedure was used, with minor modifications, to produce brominated indazole-3-piperidinecarboxamide derivatives by reaction with various Grignard reagents. Grignard thiazole reagent is commercially available. Otherwise, the aryl lithium reagent and the corresponding aryl zinc reagent can be prepared following the procedure described by Reeder MR et al. In Org. Proc. Res. Devel. 2003, 7, page 696. Oxazole, 4-methylthiazole and 5-methylthiazole zinc reagents were prepared following this procedure.

The following acids were prepared using this method: 6-cyclopropylbenzo [d] isothiazole-3-carboxylic acid, 6- (1,3-thiazol-2-yl) -1H-indazole-3-carboxylic acid, 5- (1,3-thiazol-2-yl) -1H-indazole-3-carboxylic acid, 5- (4-methyl-1,3-thiazol-2-yl) -1H-indazole-3-carboxylic acid, 5- (5-methyl-1,3-thiazol- 2-yl) -1H-indazole-3-carboxylic acid, 6- (4-methyl-1,3-thiazol-2-yl) -1H-indazole-3-carboxylic acid, 6- (5-methyl-1,3- thiazol-2-yl) -1H-indazole-3-carboxylic acid, 6- (1,3-oxazol-2-yl) -1H-indazole-3-carboxylic acid.

Procedure 7:

Procedure 7 describes a method for producing an acid

7-fluoro-6-methoxy-1H-indazole-3-carboxylic acid.

To a solution of ethyl 6-methoxy-1H-indazole-3-carboxylate (500 mg, 2.27 mmol) in acetonitrile (15.0 mL) was added 1-chloromethyl-4-fluoro-1,4-diazoniobicyclo [2.2.2] octanobis (tetrafluoroborate) (1.00 g, 2.82 mmol), after which the reaction mixture was kept at room temperature for 18 hours. The reaction mixture was partitioned between water (50 mL) and ethyl acetate (50 mL), then the separated organic layer was washed with brine (25 mL), dried (magnesium sulfate) and concentrated. The residue was purified by chromatography (95/5 to 80/20 hexane / ethyl acetate mixture) to obtain 541 mg (23%) of a fluorinated ester. A solution of the ester (124 mg, 0.520 mmol) in ethanol (5.00 mL) was diluted with 5.0 M sodium hydroxide solution (2.00 mL), and then the mixture was kept at room temperature for 18 hours. The reaction mixture was acidified with a 6 N hydrochloric acid solution and partitioned between water (50 ml) and ethyl acetate (50 ml). The layers were separated, then the organic layer was washed with brine (25 mL), dried (magnesium sulfate) and concentrated in vacuo to give 109 mg (84%) of the acid. The acid was coupled with a bicyclic base according to procedure A.

The following acid was prepared using this method: 7-fluoro-6-methoxy-1H-indazole-3-carboxylic acid.

Procedure 8:

Procedure 8 describes a method for producing benzisoxazole-3-carboxylic acid from 2,5-dibromonitrobenzene.

To a suspension of sodium hydride (3.16 g, 132 mmol) in dimethyl sulfoxide (60 mL) was added diethyl malonate (12.6 g, 79 mmol) over 30 minutes. The reaction temperature has risen to 60⁰C and as a result the mixture became clear. Added

1,4-dibromo-2-nitrobenzene (10 g, 36.0 mmol) and then the solution was held at 100 for 2 hours⁰C. The reaction mixture was allowed to cool to room temperature and poured into ice (300 g - 400 g). The precipitated solids were isolated by filtration and dried, yielding 11 g of product (89%).

The ester (11.0 g, 32.0 mmol) was diluted with 2 N sodium hydroxide solution (32 mL, 63 mmol), and then the reaction mixture was kept at room temperature for 16 hours. The aqueous layer was extracted with dichloromethane (20 mL) and then acidified. The precipitated solids were isolated by filtration and dried, yielding 7.00 g of acid (89%).

To a solution of acid (7.00 g, 27.0 mmol) in ethanol (60 mL) was added sulfuric acid (1 mL). The reaction mixture was heated to reflux, then held for 2 hours, then concentrated under reduced pressure. The residue was partitioned between ethyl acetate (250 ml) and saturated sodium carbonate solution (50 ml) and then the organic layer was washed with saturated sodium carbonate solution (50 ml) and brine (50 ml). The organic layer was dried (sodium sulfate) and concentrated to give 8.00 g (98%) of the ester in liquid form.

In the atmosphere of₂, sodium ethoxide was prepared by introducing sodium (33.5 g, 1.46 mol) into ethanol (1.0 L). To a solution of the ester (420 g, 1.46 mol) in ethanol (3 L), placed in a 10 L round-bottomed flask, wasoamyl nitrite (225 mL) was added, and the mixture was heated to 60⁰C. A solution of sodium ethoxide, prepared from metallic sodium (33.5 g, 1.46 mmol) in ethanol (1 L) was added dropwise and the reaction was then held for 2 hours. The reaction mixture was allowed to cool to room temperature and then neutralized with 2N aqueous hydrochloric acid. The reaction mixture was extracted with ethyl acetate (4 x 2 L), then the combined organic layers were washed with water (2 x 1 L) and brine (2 x 1 L) and then dried (sodium sulfate). The residue was purified by chromatography (1/1 to 0/1 ratio hexane / ethyl acetate) to obtain 110 g of product (28%).

To a solution of ethyl 6-bromobenzoisoxazole-3-carboxylate (20 g, 0.081 mol) in ethanol (300 ml), kept under nitrogen and at 0⁰C, 10% palladium on carbon (1.5 g) and triethylamine (7.5 g, 82.4 mmol) were added. Then, nitrogen was removed using vacuum and hydrogen was replaced and the reaction was held for 1 hour. The hydrogen atmosphere was removed by reduced pressure and replaced with nitrogen, after which palladium was removed by filtration through celite. The filter cake was washed with ethanol (3 x 50 mL) and then the filtrates were concentrated. The residue was dissolved in dichloromethane (200 mL) and then the solution was washed with water (4 x 50 mL), dried (sodium sulfate) and evaporated to give 13.0 g of the product as a yellow solid (96%). An acid was obtained after saponification of the ester with sodium hydroxide.

The acid was coupled with a bicyclic base according to procedure A.

Literature reference: Angell RM, Baldwin IR, Bamborough P., Deboeck NM, Longstaff T., Swanson S.,

WO 04010995 A1.

The following acid was prepared using this method:

1,2-benzisoxazole-3-carboxylic acid.

Procedure 9:

Procedure 9 describes a method for producing 5-difluoromethoxyindazole-3-acid from 3-bromo-4-nitro-phenol.

To a suspension of sodium hydroxide (29.0 mmol) in N, N-dimethylformamide (15 mL) was added 3-bromo-4-nitrophenol (10.0 mmol) and then the suspension was kept for 15 minutes at room temperature. The reaction mixture was cooled to 0⁰C followed by treatment with ethyl chlorodifluoroacetate (20.0 mmol). The reaction mixture was heated at 70 for 16 hours⁰C and then concentrated. The residue was diluted with ice water (200 mL), followed by extraction with ethyl acetate (3 x 100 mL). The combined organic layers were dried (magnesium sulfate) and concentrated to give difluoromethyl ether in 75% yield as a yellow oil.

Diethyl malonate (328 mmol) was added dropwise at temperature

0⁰C to a suspension of sodium hydride (328 mmol) in dimethyl sulfoxide (40 mL). The reaction mixture was warmed to temperature

60⁰C and then held at this temperature for 0.5 hours. A solution of difluoromethyl ether (149 mmol) in dimethyl sulfoxide (80 mL) was added dropwise, and the reaction mixture was heated at 100 for 5 hours⁰C. The cooled solution was poured into ice water and then 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 for 1 hour at 60⁰C. The reaction mixture was allowed to cool to room temperature then and then the aqueous layer was washed with dichloromethane (3 x 100 mL). The aqueous layer was carefully acidified to pH 1 with concentrated hydrochloric acid and then the reaction mixture was heated for 1 hour at 60⁰C. The suspension was cooled to 5⁰C, after which solids were isolated by filtration and dried to give the acid in 61% yield.

To ethanol (300 ml) was added dropwise at 0⁰C acetyl chloride (203 mmol). After half an hour, acid (101 mmol) was added, and then the reaction mixture was heated for 15 hours under reflux. The reaction mixture was concentrated and the residue was partitioned between dichloromethane (200 mL), and saturated sodium bicarbonate solution (100 mL). The aqueous layer was extracted with additional dichloromethane (2 x 200 mL), the combined organic layers were dried (magnesium sulfate) and then concentrated to give the ester in 60% yield as a brown oil.

The ester (60.4 mmol) was dissolved in ethanol (103 mL), diluted with water (71 mL) and reacted with ammonium chloride (243 mmol) and powdered iron (301 mmol). The reaction mixture was heated for 10 minutes under reflux, then the suspension was filtered through celite, and the filter cake was washed three times with ethanol. The filtrate was concentrated, the residue suspended in 2 N hydrochloric acid and then stirred vigorously for 0.5 hours. The aqueous layer was washed with ethyl acetate (3 x 50 mL), the pH was adjusted to 9-10 with a 5 M sodium hydroxide solution. The aqueous layer was extracted with chloroform (3 x 100 mL), then 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, and then the suspension was heated to reflux for 16 hours. The solution was evaporated and then the residue was partitioned between saturated sodium bicarbonate solution (50 ml) and dichloromethane (100 ml). The aqueous layer was extracted with additional dichloromethane (2 x 200 mL), the combined organic layers were dried (magnesium sulfate) and then concentrated to give the N-acetylindazole ester in 79% yield as a brown oil.

The ester (63.8 mmol), sodium hydroxide (193 mmol) and water (65 ml) were mixed and the reaction was kept at 60⁰C for 24 hours. After cooling to room temperature, the aqueous layer was washed with dichloromethane (3 x 50 mL). The pH of the aqueous layer was adjusted to 1 with concentrated hydrochloric acid. The precipitated solids were isolated by filtration, washed with water and dichloromethane and dried to give the acid in 27% yield.

The following acids were prepared using this method: 5- (difluoromethoxy) -1H-indazole-3-carboxylic acid.

Procedure 10:

Procedure 10 describes a method for producing 6-difluoromethoxyindazole-3-acid from 4-nitrophenol.

To a suspension of sodium hydroxide (485 mmol) in N, N-dimethylformamide (150 mL) was added 4-nitrophenol (162 mmol) and then the suspension was kept for 15 minutes at room temperature. The reaction mixture was cooled to 0⁰C and treated with ethyl chlorodifluoroacetate (329 mmol). The reaction mixture was heated at 70 for 16 hours⁰C and then concentrated. The residue was diluted with ice water (200 mL), followed by extraction with ethyl acetate (3 x 100 mL). The combined organic layers were dried (magnesium sulfate) and concentrated to give difluoromethyl ether in 59% yield as a yellow oil.

Nitroether (149 mmol) was dissolved in ethanol (37.5 mL), diluted with water (25 mL) and treated with ammonium chloride (84.7 mmol) and powdered iron (105 mmol). The reaction mixture was heated for 30 minutes, refluxed, and then the suspension was filtered through a pad of celite. The filter cake was washed three times with ethanol and then the combined filtrates were concentrated. The residue was dissolved in water and the pH was adjusted to 910 using a 5 M sodium hydroxide solution. The aqueous layer was extracted with ethyl acetate (3 x 100 mL), then the combined organic layers were dried (magnesium sulfate) and concentrated to give a yellow oil. The oil was dissolved in acetic anhydride (23.5 mmol), and the reaction mixture was held at room temperature for 16 hours. The reaction mixture was diluted with water (50 mL) and neutralized with sodium bicarbonate solution. The precipitated solids were isolated by filtration, then washed with water and dried to give 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. Then fuming nitric acid (16.0 mmol) was added dropwise, after which the reaction mixture was refluxed for 30 minutes. The cooled solution was diluted with water (20 mL), then the aqueous layer was extracted with dichloromethane (3 x 10 mL). The combined organic layers were dried (magnesium sulfate) and concentrated to give nitroamide in 83% yield.

The amide (11.0 mmol), sodium hydroxide (43.8 mmol) and water (10 mL) were mixed and the reaction was held for 1.5 hours at 60⁰C. The reaction mixture was allowed to cool to room temperature and then the precipitated solids were separated by filtration, washed with water and dried to give aniline in 98% yield as a light yellow solid.

Aniline (15.7 mmol) was mixed with 40% hydrobromic acid solution (14.3 g) and water (10 ml) and then, to completely dissolve the aniline, the reaction mixture was heated to 80-90⁰C. The reaction mixture was cooled to 0⁰C, followed by a solution of sodium nitrite (23.2 mmol) in water (5.3 mL) over 15 minutes. The solution was kept for 40 minutes at 0-5⁰C and filtered. Copper (I) bromide (18.8 mmol) was dissolved in 40% hydrobromic acid (21 mL) and then cooled to 0⁰C. The diazonium salt solution was added slowly to the copper solution and then the reaction mixture was held for 30 minutes at 0-10⁰C. The reaction mixture was heated for 30 minutes at 60⁰C and then for 10 minutes at 100⁰C to complete the reaction. The reaction mixture was allowed to cool to room temperature, followed by extraction with dichloromethane (3 x 40 mL). The combined organic layers were washed with 1 M sodium hydroxide solution, water, 1 N hydrochloric acid solution and water. The organic layer was dried (magnesium sulfate) and concentrated to give a nitrobromide in 76% yield as a light yellow oil. Diethyl malonate (25.7 mmol) was added dropwise at 0⁰C to a suspension of sodium hydride (25.8 mmol) in dimethyl sulfoxide (5 mL). The reaction mixture was heated to 60⁰C and held at this temperature for 30 minutes. A solution of nitrobromide (11.7 mmol) in dimethyl sulfoxide (7 ml) was added dropwise and then the reaction mixture was heated for 5 hours at 100⁰C. The cooled solution was poured into ice water, 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. Combined diester (11.7 mmol), sodium hydroxide (35 mmol) and water (20 ml) and heated for 1 hour at 60⁰C. The reaction mixture was allowed to cool to room temperature and then the aqueous layer was washed with dichloromethane (3 x 100 mL). The aqueous layer was carefully acidified to pH 1 with concentrated hydrochloric acid and then the reaction mixture was heated for 1 hour at 60⁰C. The suspension was cooled to 0⁰C, after which solids were isolated by filtration and dried to give the acid in 64% yield.

To ethanol (50 ml) was added dropwise at 0⁰C acetyl chloride (15.3 mmol). After half an hour, acid (7.69 mmol) was added, and then the reaction mixture was heated for 15 hours under reflux. The reaction mixture was concentrated, then the residue was partitioned between dichloromethane (20 mL) and saturated sodium bicarbonate solution (10 mL). The aqueous layer was extracted with additional dichloromethane (2 x 20 mL) and then the combined organic layers were dried (magnesium sulfate) and then concentrated to give the ester in 94% yield as a brown oil.

To the suspension of ester (3.64 mmol) and acetic acid (7.0 mL) was added at 0⁰C acetic anhydride (6.0 mL). Zinc dust (14.6 mmol) was then added in portions over 15 minutes, and then the reaction mixture was held for 30 minutes at 0⁰C, followed by 1.5 hours at room temperature. An additional amount of zinc dust (6.15 mmol) was added and then the reaction was carried out for 3 hours. The suspension was filtered through a celite pad, and the filtrate was concentrated. The residue was partitioned between saturated sodium bicarbonate solution (10 mL) and ethyl acetate (20 mL). The aqueous layer was extracted with additional ethyl acetate (3 x 20 mL), then the combined organic layers were dried (magnesium sulfate) and concentrated to give acetamide in 92% yield as a brown oil.

To a solution of acetamide (13.92 mmol) in chloroform (20 mL) was added acetic anhydride (13.7 mmol), isoamyl nitrite (13.7 mmol) and potassium acetate (2.04 mmol) and then the suspension was heated for 16 hours maintaining under reflux. The solution was evaporated and then the residue was partitioned between saturated sodium bicarbonate solution (10 ml) and dichloromethane (20 ml). The aqueous layer was extracted with additional dichloromethane (2 x 20 mL) and then the combined organic layers were dried (magnesium sulfate) then 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 mixed and the reaction mixture was kept for 24 hours at 60⁰C. After cooling to room temperature, the aqueous layer was washed with dichloromethane (3 x 30 mL). The aqueous layer was adjusted to pH = 1 using concentrated hydrochloric acid, then the precipitated solids were separated by filtration, washed with water and dichloromethane and dried to give the acid in 26% yield.

The following acids were prepared using this method:

6- (difluoromethoxy) -1H-indazole-3-carboxylic acid.

Procedure 11:

Amine production:

Procedure 11 describes in detail the method for producing 2-methyl-2,5-diazabicyclo [2.2.2] octane from 2,5-diaminohexanedioic acid diethyl ester.

To a solution of 2,5-diaminokexanedioic acid diethyl dihydrochloride dihydrochloride (10.0 mmol) in anhydrous ethanol (75 mL) and acetic acid (10 mL) was added benzaldehyde (21.8 mmol) at room temperature. The resulting mixture was heated for 2 hours at 80⁰C. The reaction mixture was allowed to cool to room temperature and then sodium triacetoxyborohydride (54.2 mmol) was added in small portions. The resulting white suspension was kept for 16 hours at room temperature and then concentrated. The residue was diluted with water, then cooled to 0⁰C and the pH was adjusted to 9 with 1 N sodium hydroxide solution. The aqueous layer was extracted with ethyl acetate (3 x 100 mL), then the combined organic layers were washed with brine, dried (magnesium sulfate) and concentrated to give 3.05 g of a white solid. Sodium methoxide (25% by weight, 23 mmol) was added to a solution of dibenzylamine in ethanol (200 mL), and the reaction mixture was heated for 16 hours while refluxing. 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 solution, dried (then magnesium sulfate) and concentrated to give bicyclic lactam in 47% yield as a colorless solid.

Sulfuric acid (15.8 mmol) was added dropwise to a suspension of lithium aluminum hydride (31.6 mmol) in tetrahydrofuran (50 mL) maintained under a nitrogen atmosphere. The mixture was held for 30 minutes and then the supernatant was added dropwise at 0⁰C to a solution of bicyclic lactam (1.5 mmol) in tetrahydrofuran (50 ml). The reaction mixture was allowed to warm to room temperature and kept under these conditions for 16 hours. The reaction mixture was quenched carefully by adding solid sodium sulfate decahydrate (2.5 g) in portions. The reaction mixture was diluted with 2 M sodium hydroxide solution (10 mL), then filtered through celite, and then the filtrate was concentrated. The residue was diluted with 2 N hydrochloric acid solution (100 mL and then extracted with ethyl acetate. The pH of the aqueous layer was adjusted to 9 with 2 M sodium hydroxide solution, followed by extraction 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 reacted with a methanolic hydrogen chloride solution which was prepared in situ by adding acetyl chloride (0.5 mL) to methanol (10 mL) for 10 minutes at room temperature. The volatiles were removed under reduced pressure to obtain bicyclic diamine dihydrochloride in 92% yield as a grayish foamed 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 an atmosphere of hydrogen and kept there for 16 hours. The catalyst was isolated by filtration, after which the filter cake was washed with water. The filtrate was concentrated to give bicyclic diamine dihydrochloride in 88% yield as a colorless solid.

A solution of di-tert-butyl dicarbonate (6.5 mmol) in isopropanol (15 ml) was added dropwise at 0⁰C to a solution of diamine (7.06 mmol) in isopropanol (100 ml), water (35 ml) and 1 M sodium hydroxide solution (6.5 ml). The reaction mixture was held for 1.5 hours at 0⁰C and then concentrated to a volume of about 50 ml. The aqueous suspension was saturated with solid sodium chloride and then the pH was adjusted to 10 with a 2 M sodium hydroxide solution. The aqueous layer was extracted with ethyl acetate (3 x 35 mL), then the combined organic layers were washed with brine and dried (magnesium sulfate). The volatiles were removed under reduced pressure to give crude mono-protected diamine in 42% yield as a light yellow oil.

Formaldehyde (37% aqueous solution, 7.43 mmol) and acetic acid (4.46 mmol) were added to a solution of the crude amine (2.97 mmol) in tetrahydrofuran (25 mL). After 10 minutes, solid sodium triacetoxyborohydride (5.94 mmol) was added in small portions to the reaction mixture, and then the reaction mixture was held for 16 hours. The reaction mixture was diluted with 10% aqueous sodium bicarbonate (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 pale yellow residue. The residue was dissolved in dioxane (25 ml) and diluted with concentrated hydrochloric acid (12.5 ml). Volatiles were removed after 30 minutes and 73 notes to give a monomethyl bicyclic base in 40% yield as a colorless solid. The N-methylation procedure followed by removal of the carbamate protecting group was used to prepare 2-methyl-2,5-diazabicyclo [2.2.1] heptane dihydrochloride.

Literature references: Newman HJ Heterocydic Chem. 1974, χ, page 449; Sturm PA, Henry DW, J. Med. Chem., 1974, 17, page 481.

The following bases were prepared using this method: 2-methyl-2,5-diazabicyclo [2.2.2] octane dihydrochloride; (1S, 4S) -2-methyl-2,5-diazabicyclo [2.2.1] heptane dihydrochloride.

Synthetic procedures:

Methods for producing derivatives of substituted bicyclic bases are described in detail in the following procedures (AG).

Procedure A:

Procedure A describes a method for coupling bicyclic bases and carboxylic acids to form carboxamide derivatives.

To a solution of carboxylic acid (1 mmol) in tetrahydrofuran (10 mL) and in N, N-dimethylformamide (1 mL) was added N, N-diisopropylethylamine (3 mmol) and a basic bicyclic amine dihydrochloride (1 mmol). The reaction mixture was held for 30 minutes under nitrogen at room temperature, after which HATU (1.00 mmol) was added. After 18 hours, the reaction mixture was partitioned between saturated aqueous potassium carbonate solution and a 95/5 dichloromethane / methanol mixture. The aqueous layer was extracted with a 95/5 (2x) dichloromethane / methanol mixture and then the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by high performance silica gel column chromatography using a 90/10/1 dichloromethane / methanol / ammonium hydroxide mixture as the eluent to give the product as a carboxamide.

Using procedure A, the following exemplary compounds were prepared:

Example 1: 3 - [(1S ', 4S') - 2,5-diazabicyclo [2.2.1] hept-2-ylcarbonyl] -1H-indazole hydrochloride.

<img file="PL1697378T3_D0006.tif" />

The compound of Example 1 was prepared using procedure A. A 28% yield was obtained. ¹1 H NMR (CD₃OD), δ: 8.22 (m, 1H); 7.61 (m, 1H); 7.45 (m, 1H); 7.27 (m, 1H); 3.82 (m, 1H); 3.51 (m, 2H); 2.30 (m, 1H); 2.07 (m, 1H). LC / MS (EI):

t_R = 3.55 min, m / z = 243 (M ++ 1).

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

<img file="PL1697378T3_D0007.tif" />

Performance relationship.

LC / MS (EI) prepared:

using procedure A. A 30% vol_R = 3.04 min, m / z = 340 (M ++ 1).

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

<img file="PL1697378T3_D0008.tif" />

The compound was prepared using procedure A. A 30% yield was obtained. LC / MS (EI): vol_R = 2.85 min, m / z = 257 (M ++ 1).

Example 4: 3 - [(5-methyl-2,5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -1H-indazole hydrogen formate.

<img file="PL1697378T3_D0009.tif" />

The compound was prepared using procedure A. 25% yield was obtained. LC / MS (EI): vol_R = 2.83 min, m / z = 271 (M ++ 1).

Example 5: 3 - [(5-methyl-2,5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -6- (1,3-thiazol-220 hydrogen formate

yl) -1H-indazole.

<img file="PL1697378T3_D0010.tif" />

The compound was prepared using procedure A. 20% yield was obtained. LC / MS (EI): vol_R = 2.87 min, m / z = 376 (M ++ 1).

Example 6: 3 - {[(1S ', 4S') - 5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1,2-benzothiazole hydrogen formate.

<img file="PL1697378T3_D0011.tif" />

The compound was prepared using procedure A. 56% yield was obtained. LC / MS (EI): vol_R = 2.53 min, m / z = 274 (M ++ 1).

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

<img file="PL1697378T3_D0012.tif" />

The compound was prepared using procedure A. 77% yield was obtained. LC / MS (EI): vol_R = 2.75 min, m / z = 274 (M ++ 1).

Example 8: 3 - {[(1S ', 4S') - 5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl) carbonyl] -1,2-benzisoxazole hydrogen formate.

<img file="PL1697378T3_D0013.tif" />

The compound was prepared using procedure A. 20% yield was obtained. LC / MS (EI): vol_R = 3.48 min, m / z = 258 (M ++ 1).

Example 9: 3 - {[(1S ', 4S') - 5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl) carbonyl] -5- (1,3-thiazol-2- yl) -1H-indazole.

<img file="PL1697378T3_D0014.tif" />

The compound was prepared using procedure A. 25% yield was obtained. LC / MS (EI): vol_R = 2.87 min, m / z = 340 (M ++ 1).

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

<img file="PL1697378T3_D0015.tif" />

The compound was prepared using a yield procedure. LC / MS (EI): vol_R = 2.76 min, m / z =

A. Obtained 354 (M⁺+1).

30%

Example 11: 3 - {[(1S ', 4S') - 5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -5- (5-methyl-1,3- thiazol-2-yl) -1H-indazole.

<img file="PL1697378T3_D0016.tif" />

<img file="PL1697378T3_D0017.tif" />

The compound was prepared using procedure A. A 30% yield was obtained. LC / MS (EI): vol_R = 2.9 min, m / z = 354 (M ++ 1).

Example 12: 3 - {[(1S ', 4S') - 5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -5- (tetrahydro-2H-pyran-4- hydrogen hydrogen formate yl) -1H-indazole.

<img file="PL1697378T3_D0018.tif" />

The compound was prepared using procedure A. 25% yield was obtained. LC / MS (EI): vol_R = 2.85 min, m / z = 339 (M ++ 1).

Example 13: 3 - {[(1S ', 4S') - 5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -5- (trifluoromethoxy) -1H-indazole hydrogen formate.

<img file="PL1697378T3_D0019.tif" />

The compound was prepared using procedure A. A 45% yield was obtained. LC / MS (EI): vol_R = 4.82 min, m / z = 341 (M ++ 1).

Example 14: 3 - {[(1S ', 4S') - 5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (1,3-oxazol-2- yl) -1H-indazole.

<img file="PL1697378T3_D0020.tif" />

The compound was prepared using procedure A. A 30% yield was obtained. LC / MS (EI): vol_R = 5.25 min, m / z = 324 (M ++ 1).

Example 15: 3 - {[(1S ', 4S') - 5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (1,3-thiazol-2- yl) -1H-indazole.

<img file="PL1697378T3_D0021.tif" />

The compound was prepared using procedure A. Yields were obtained. LC / MS (EI): vol_R = 2.69 min, m / z = 362 (M ++ 1).

25%

Example 16: 3 - {[(1S, 4S) -5-methyl-2.55-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (4-methyl-1,3-thiazol- hydrogen formate 2-yl) -1H-indazole.

<img file="PL1697378T3_D0022.tif" />

The compound was prepared using procedure A. Yields were obtained. LC / MS (EI): vol_R = 5.18 min, m / z = 354 (M ++ 1).

25%

Example 17: 3 - {[(1S ', 4S') - 5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (5-methyl-1,3- thiazol-2-yl) -1H-indazole.

<img file="PL1697378T3_D0023.tif" />

using the procedure

The compound was made

AND.

obtained

25% efficiency. LC / MS (EI): vol_R = 5.18 min, m / z = 354 (M ++ 1).

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

<img file="PL1697378T3_D0024.tif" />

The compound was prepared using procedure A. 25% yield was obtained. LC / MS (EI): vol_R = 2.79 min, m / z = 341 (M ++ 1).

Example 19: 3 - {[(1S ', 4S') - 5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (trifluoromethoxy) -1H-indazole hydrogen formate.

<img file="PL1697378T3_D0025.tif" />

The compound was prepared using procedure A. 25% yield was obtained. LC / MS (EI): vol_R = 5.04 min, m / z = 341 (M ++ 1).

Example 20: 3 - {[(1S ', 4S') - 5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (trifluoromethyl) -1H-indazole hydrogen formate.

<img file="PL1697378T3_D0026.tif" />

ABOUT

ji

H OH

The compound was prepared using procedure A. A 45% yield was obtained. LC / MS (EI): vol_R = 3.85 min, m / z = 325 (M ++ 1).

Example 21: 3 - {[(1S ', 4S') - 5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -7- (trifluoromethoxy) -1H-indazole hydrogen formate.

<img file="PL1697378T3_D0027.tif" />

The compound was prepared using procedure A. 25% yield was obtained. LC / MS (EI): vol_R = 4.66 min, m / z = 341 (M ++ 1).

Example 22: 5- (3,6-dihydro-2H-pyran-4-yl) -3 - {[(1S ', 4S') - 5-methyl-2,5-diazabicyclo [2.2.1] heptoformate -2-yl] carbonyl} -1H-indazole.

<img file="PL1697378T3_D0028.tif" />

<img file="PL1697378T3_D0029.tif" />

The compound was prepared using procedure A. A 30% yield was obtained. LC / MS (EI): vol_R = 2.83 min, m / z = 339 (M ++ 1).

Example 23: 5- (Difluoromethoxy) -3 - {[(15.45) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole hydrogen formate.

<img file="PL1697378T3_D0030.tif" />

Compound produced yields. LC / MS (EI):

using procedure A. vol_R = 2.52 min, m / z = 323

Obtained (M⁺+1).

35%

Example 24: 5-Bromo-3 - [(1S, 4S) -2,5-diazabicyclo [2.2.1] hept-2-ylcarbonyl] -1H-indazole hydrochloride.

<img file="PL1697378T3_D0031.tif" />

The compound was prepared using procedure A. A 45% yield was obtained. LC / MS (EI): vol_R = 4.76 min, m / z = 321/323 (M ++ 1).

Example 25: 5-Methoxy-3 - [(5-methyl-2,5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -1H-indazole hydrogen formate.

<img file="PL1697378T3_D0032.tif" />

Compound produced yields. LC / MS (EI):

using procedure A. vol_R = 2.85 min, m / z = 301

Obtained (M⁺+1).

20%

Example 26: 3- (2,5-Diazabicyclo [2.2.2] oct-2-ylcarbonyl) -5-methoxy-1H-indazole hydrochloride.

<img file="PL1697378T3_D0033.tif" />

The compound was prepared using procedure A. A 30% yield was obtained. LC / MS (EI): vol_R = 2.87 min, m / z = 287 (M ++ 1).

Example 27: 5-Methoxy-3- {[(1S ', 4S') -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole hydrochloride.

<img file="PL1697378T3_D0034.tif" />

The compound was prepared using procedure A. 35% yield was obtained. LC / MS (EI): vol_R = 2.85 min, m / z = 287 (M ++ 1).

Example 28: 5-methoxy-3 - {[(1S ', 4S') - 5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} hydrogen formate

<img file="PL1697378T3_D0035.tif" />

The compound was prepared using procedure A. A 45% yield was obtained. LC / MS (EI): vol_R = 2.51 min, m / z = 287 (M ++ 1).

Example 29: 6- (3,6-dihydro-2H-pyran-4-yl) -3 - {[(1S ', 4S') - 5-methyl-2,5-diazabicyclo [2.2.1] heptoformate -2-yl] carbonyl} -1H-indazole.

<img file="PL1697378T3_D0036.tif" />

The compound was prepared using procedure A. 25% yield was obtained. LC / MS (EI): vol_R = 2.8 min, m / z = 339 (M ++ 1).

Example 30: 6- (difluoromethoxy) -3 - {[(1S ', 4S') -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole hydrogen formate.

<img file="PL1697378T3_D0037.tif" />

The compound was prepared using procedure A. 35% yield was obtained. LC / MS (EI): vol_R = 2.47 min, m / z = 323 (M ++ 1).

Example 31: 6-Bromo-3 - [(1S ', 4S') - 2,5-diazabicyclo [2.2.1] hept-2-ylcarbonyl] -1H-indazole hydrochloride.

<img file="PL1697378T3_D0038.tif" />

The compound was prepared using procedure A. A 45% yield was obtained. LC / MS (EI): vol_R = 3.71 min, m / z = 321/323 (M ++ 1).

Example 32: 6-Cyclopropyl-3 - {[(1S ', 4S') - 5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1,2-benzisothiazole hydrogen formate.

<img file="PL1697378T3_D0039.tif" />

The compound was prepared using procedure A. 56% yield was obtained. LC / MS (EI): vol_R = 4.48 min, m / z = 314 (M ++ 1).

Example 33: 6-Ethoxy-3 - {[(1S ', 4S') -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1,2-benzisothiazole hydrogen formate.

<img file="PL1697378T3_D0040.tif" />

The compound was prepared using procedure A. A 43% yield was obtained. LC / MS (EI): vol_R = 3.79 min, m / z = 318 (M ++ 1).

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

<img file="PL1697378T3_D0041.tif" />

ClH

The compound was prepared using procedure A. A 30% yield was obtained. LC / MS (EI): vol_R = 2.89 min, m / z = 287 (M ++ 1).

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

<img file="PL1697378T3_D0042.tif" />

Compound produced yields. LC / MS (EI):

using procedure A. vol_R = 2.83 min, m / z = 301

Obtained (M⁺+1).

Example 36: 6-Methoxy-3 - {[(1S ', 4S') -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1,2-benzisothiazole hydrogen formate.

28%

<img file="PL1697378T3_D0043.tif" />

The compound was prepared using procedure A. 64% yield was obtained. LC / MS (EI): vol_R = 2.97 min, m / z = 304 (M ++ 1).

Example 37: 6-Methoxy-3 - {[(1S ', 4S') -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1,2-benzisothiazole.

<img file="PL1697378T3_D0044.tif" />

The compound was prepared using procedure A. 85% yield was obtained. LC / MS (EI): vol_R = 3.06 min, m / z = 304 (M ++ 1).

Example 38: 6-Methoxy-3 - {[(1S ', 4S') -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} 15 -1H-indazole hydrochloride.

<img file="PL1697378T3_D0045.tif" />

The compound was prepared using procedure A. 35% yield was obtained. LC / MS (EI): vol_R = 2.83 min, m / z = 287 (M ++ 1).

Example 39: 6-Methoxy-3 - {[(1S ', 4S') -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole hydrogen formate.

<img file="PL1697378T3_D0046.tif" />

The compound was prepared using procedure A. 35% yield was obtained. LC / MS (EI): vol_R = 2.83 min, m / z = 287 (M ++ 1).

Example 40: 7-Fluoro-6-methoxy-3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2 carbonyl} -1H-indazole hydrogen formate.

<img file="PL1697378T3_D0047.tif" />

<img file="PL1697378T3_D0048.tif" />

The compound was prepared using procedure A. A 31% yield was obtained. LC / MS (EI): vol_R = 2.54 min, m / z = 305 (M ++ 1).

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

<img file="PL1697378T3_D0049.tif" />

The compound was prepared using procedure A. A 50% yield was obtained. LC / MS (EI): vol_R = 2.6 min, m / z = 304 (M ++ 1).

Procedure B:

The subject of procedure B is a process for the preparation of aryl or heteroaryl substituted derivatives comprising the coupling of brominated or iodinated bicyclic carboxamides with boronic acids.

Brominated bicyclic base carboxamide (0.3 mmol), boronic acid (0.6 mmol), tris (dibenzylideneacetone) dipalladium (0) (0.03 mmol), tri-tert-butylphosphine tetrafluoroborate were introduced into a 5 ml microwave reactor vessel. , 06 mmol) and potassium carbonate (0.8 mmol). Air was removed from the vessel using vacuum, the vessel was then filled with argon and then the contents of the vessel were diluted with N, N-dimethylformamide (5.0 mL). The vessel was sealed and at 200⁰C was subjected to microwave irradiation for 600 s. The reaction mixture was filtered through celite (washing with methanol) and loaded onto a 5 g SCX column. The column was washed with methanol (50 ml), then the product was eluted with a 2 M solution of ammonia in methanol and then concentrated. The residue was purified by chromatography [eluting with a mixture of ethyl acetate from 1/1 to 0/1 / (70/30/1 ethyl acetate / methanol / ammonium hydroxide)] and then by preparative HPLC using a gradient elution for 8 minutes with a mixture of water from 95 / 5 to 20/80 (0.1% formic acid) / acetonitrile (0.1% formic acid), resulting in a heteroaryl substituted product.

Using procedure B, the following exemplary compounds were prepared:

Example 42: 3 - {[(1S ', 4S') - 5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -5- (2-thienyl) -1H-indazole hydrogen formate .

<img file="PL1697378T3_D0050.tif" />

<td>Relationship</td><td>made using</td><td>procedure B.</td><td>25% obtained</td>

<td>performance.</td><td>¹1 H NMR (CD₃OD) δ ppm:</td><td>8.48 (m, 2H);</td><td>7.75 (m, 1H);</td>

<td>7.58 (m, 1H)</td><td>; 7.32 (m, 2H); 7.08 liters</td><td>m, 1H); 4.25</td><td>(m, 1H); 3.70</td>

<td>(m, 2H); 3</td><td>32 (m, 1H); 2.85 (d,</td><td>3H); 2.22 (</td><td>m, 2H). LC / MS</td>

<td>(EI): tR = 5,</td><td colspan="2">03 min, m / z = 339 (M ++ 1).</td><td></td>

Example 43: 3 - {[(1S ', 4S') - 5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -5- (4-methyl-2-thienyl) hydrogen formate -1H-indazole.

<img file="PL1697378T3_D0051.tif" />

H OH

B. 25% obtained

The compound was prepared using a yield procedure. LC / MS (EI): vol_R = 5.33 min, m / z = 353 (M ++ 1).

Example 44: 3 - {[(1S ', 4S') - 5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -5- (5-methyl-2-thienyl) hydrogen formate -1H-indazole.

<img file="PL1697378T3_D0052.tif" />

The compound was prepared using procedure B. 25% yield was obtained. LC / MS (EI): vol_R = 5.32 min, m / z = 353 (M ++ 1).

Example 45: 3 - {[(1S ', 4S') - 5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -5-phenyl-1H-indazole hydrogen formate.

<img file="PL1697378T3_D0053.tif" />

The compound was prepared using procedure B. 25% yield was obtained. LC / MS (EI): vol_R = 5.17 min, m / z = 333 (M ++ 1).

Example 46: 3 - {[(1S ', 4S') - 5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (2-thienyl) -1H-indazole hydrogen formate .

<img file="PL1697378T3_D0054.tif" />

The compound was prepared using procedure B. 25% yield was obtained. LC / MS (EI): vol_R = 5.13 min, m / z = 339 (M ++ 1).

Example 47: 3 - {[(1S ', 4S') - 5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (3-thienyl) -1H-indazole hydrogen formate .

<img file="PL1697378T3_D0055.tif" />

<img file="PL1697378T3_D0056.tif" />

The compound was prepared using procedure B. 25% yield was obtained. LC / MS (EI): vol_R = 4.3 min, m / z = 339 (M ++ 1).

Example 48: 3 - {[(1S ', 4S') - 5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (4-methyl-2-thienyl) hydrogen formate -1H-indazole.

<img file="PL1697378T3_D0057.tif" />

The compound was prepared using procedure B. A 20% yield was obtained. LC / MS (EI): vol_R = 5.35 min, m / z = 353 (M ++ 1).

Example 49: 3 - {[(1S ', 4S') - 5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -6- (5-methyl-2-furyl) hydrogen formate -1H-indazole.

<img file="PL1697378T3_D0058.tif" />

The compound was prepared using procedure B. Yields were obtained. LC / MS (EI): vol_R = 5.35 min, m / z = 337 (M ++ 1).

25%

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

<img file="PL1697378T3_D0059.tif" />

The compound was prepared using procedure B. Yields were obtained. LC / MS (EI): vol_R = 4.67 min, m / z = 353 (M ++ 1).

25%

Example 51: 5- (2-furyl) -3 - {[(1S ', 4S') -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole hydrogen formate .

<img file="PL1697378T3_D0060.tif" />

The compound was prepared using procedure B. Obtained

25% efficiency. LC / MS (EI): vol_R 41 min, m / z = 323 (M ++ 1).

Example 52: 5- (3-Fluoro-phenyl) -3 - {[(1S ', 4S') - 5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole hydrogen formate .

<img file="PL1697378T3_D0061.tif" />

The compound was prepared using procedure B. 25% yield was obtained. LC / MS (EI): vol_R = 5.28 min, m / z = 351 (M ++ 1).

Example 53: 5- (4-Fluoro-phenyl) -3 - {[(1S ', 4S') - 510-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole hydrogen formate .

<img file="PL1697378T3_D0062.tif" />

The compound was prepared using a B. yield procedure. LC / MS (EI): vol_R = 5.25 min, m / z = 351

Obtained (M⁺+1).

25%

Example 54: 5- (4-Methoxyphenyl) -3 - {[(1S ', 4S') -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole hydrogen formate .

<img file="PL1697378T3_D0063.tif" />

The compound was prepared using procedure B. A 20% yield was obtained. LC / MS (EI): vol_R = 5.19 min, m / z = 363 (M ++ 1).

Example 55: 6- (2-furyl) -3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole hydrogen formate.

<img file="PL1697378T3_D0064.tif" />

<img file="PL1697378T3_D0065.tif" />

The compound was prepared using procedure B. 25% yield was obtained. LC / MS (EI): vol_R = 4.9 min, m / z = 323 (M ++ 1).

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

<img file="PL1697378T3_D0066.tif" />

The compound was prepared using procedure B. 25% yield was obtained. LC / MS (EI): vol_R = 3.93 min, m / z = 323 (M ++ 1).

Procedure C:

The subject of procedure C is a process for the preparation of tertiary amine derivatives, comprising coupling under the conditions of reducing carboxamides of bicyclic bases with carboxaldehydes.

To the suspension of bicyclic base carboxamide hydrochloride (0.4 mmol), carboxaldehyde (1.0 mmol), N, N-diisopropylethylamine (1.2 mmol) and acetic acid (0.48 mmol), sodium triacetoxyborohydride (0.68 mmol) was added. ). The reaction mixture was kept for 2 hours at ambient temperature, then poured into water and extracted with a 95/5 dichloromethane / methanol mixture (2 x 30 ml) and then the combined extracts were concentrated. The residue was purified by preparative HPLC using a gradient elution for 8 minutes with a water mixture of 95/5 to 20/80 (0.1% formic acid) / acetonitrile (0.1% formic acid) to give the product as a tertiary amine .

Using procedure C, the following exemplary compounds were prepared:

Example 57: 3 - {[(1S ', 4S') - 5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole hydrogen formate.

<img file="PL1697378T3_D0067.tif" />

The compound was prepared using procedure C. A 30% yield was obtained. ¹1 H NMR (CD₃OD) δ ppm: 8.42 (s, 1H); 8.23 (m, 1H); 7.85 (m, 1H); 7.77 (m, 1H); 7.64 (m, 1H); 4.15 (m, 2H); 4.01 (m, 2H); 2.51 (d, 3H); 2.11 (m, 2H). LC / MS (EI): vol_R = 2.5 min, m / z = 257 (M ++ 1).

Example 58: 3 - {[(1S ', 4S') - 5-ethyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole.

<img file="PL1697378T3_D0068.tif" />

The compound was prepared using procedure C. A 45% yield was obtained. LC / MS (EI): vol_R = 2.77 min, m / z = 271 (M ++ 1).

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

<img file="PL1697378T3_D0069.tif" />

The compound was prepared using procedure C. 70% yield was obtained. LC / MS (EI): vol_R = 1.33 min, m / z = 340 (M ++ 1).

Example 60: N- (Cyclopropylmethyl) -3 - {[(1S ', 4S') - 5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole-5- amine.

<img file="PL1697378T3_D0070.tif" />

The compound was prepared using procedure C. 80% yield was obtained. LC / MS (EI): vol_R = 1.36 min, m / z = 326 (M ++ 1).

Example 61: W, W-Dimethyl-3 - [(5-methyl-2,5-diazabicyclo [2.2.2] oct-2-yl] carbonyl} -1H-indazole-5-amine hydrogen formate.

<img file="PL1697378T3_D0071.tif" />

The compound was prepared using procedure C. 58% yield was obtained. LC / MS (EI): vol_R = 1.49 min, m / z = 314 (M ++ 1).

Example 62: W, W-Dimethyl-3 - {[(1S ', 4S') - 5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole-5 hydrogen formate amine.

100

<img file="PL1697378T3_D0072.tif" />

The compound was prepared using procedure C. A 51% yield was obtained. LC / MS (EI): vol_R = 1.5 min, m / z = 300 (M ++ 1).

Example 63: W, W-dimethyl-3 - {[(1S ', 4S') -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole-6 hydrogen formate amine.

<img file="PL1697378T3_D0073.tif" />

The compound was prepared using procedure C. A 59% yield was obtained. LC / MS (EI): vol_R = 1.5 min, m / z = 300 (M ++ 1).

Example 64: 5-bromo-3 - {[(1S ', 4S') -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole.

<img file="PL1697378T3_D0074.tif" />

The compound was prepared using procedure C or A. Obtained

25% efficiency. LC / MS (EI): vol_R = 3.57 min, m / z = 335/337 (M ++ 1).

101

Example 65: 3 - {[(1S ', 4S') - 5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -5- (3-thienyl) -1H-indazole hydrogen formate .

25%

<img file="PL1697378T3_D0075.tif" />

The compound was prepared using yields. LC / MS (EI): vol_R = procedure C or B. Obtained 417 min, m / z = 339 (M⁺+1).

Example 66: 5- (3-Furyl) -3 - {[(1S ', 4S') -5-methyl-2,5-diazabicyclo [2.2 carbonyl} -1H-indazole hydrogen formate.

1] hept-2-yl] -

<img file="PL1697378T3_D0076.tif" />

H OH

The compound was prepared using procedure C or B. A 15% yield was obtained. LC / MS (EI): vol_R = 4.1 min, m / z = 323 (M ++ 1).

Procedure D:

The subject of procedure D is a method for the methylation of methoxy substituted indazolobicyclobasad amides to produce phenol derivatives followed by the reaction of phenol with various alkylating agents.

Methoxyindazolobicycloslide amide (6.98 mmol) was diluted with dichloromethane (60 mL) and dichloroethane (15 mL), after

102 where the solution was cooled to -78⁰C. 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 left for 20 hours. An additional amount of boron tribromide in dichloromethane (6 mmol) was added and then the reaction was carried out for an additional 16 hours. The reaction was quenched slowly with methanol (30 mL) and concentrated to dryness. The residue was purified by chromatography using a dichloromethane / methanol mixture (90/10) and then eluting with a dichloromethane / methanol / ammonium hydroxide mixture (90/10/1) to produce phenol (54%) in brown solids. Phenol (0.734 mmol) was dissolved in N, N-dimethylformamide (10 mL) and then treated with potassium carbonate (1.46 mmol) and alkyl bromide (0.95 mmol). The reaction mixture was kept for 16 hours at ambient temperature, then filtered and concentrated to dryness.

The residue was purified by preparative HPLC, using a gradient of 8 minutes eluting with a water mixture of 95/5 to 20/80 (0.1% formic acid) / acetonitrile (0.1% formic acid) for 8 minutes, thereby obtaining the ether product .

Using procedure D, the following exemplary compounds were prepared:

Example 67: 5-hydroxy-3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole.

103

<img file="PL1697378T3_D0077.tif" />

The compound was prepared using procedure D. 64% was obtained.

<td>performance. ¹H</td><td>NMR</td><td>((CH3) 2SO-d6</td><td>) δ</td><td>ppm:</td><td> 10,76</td><td>(S,</td><td>1H);</td><td> 8,90</td>

<td>(s, 1H); 8.25</td><td>(M,</td><td>2H); 7.99</td><td>(S,</td><td>1H);</td><td> 7,85</td><td>(M,</td><td>1H);</td><td> 4,46</td>

<td>5 (br, 1H); 3.62</td><td>(m</td><td>, 1H); 3.38</td><td>(M,</td><td>1H);</td><td> 3,20</td><td>(M,</td><td>3H);</td><td> 2,20</td>

<td>(m, 2H); 1.85 (</td><td>m</td><td>2H). LC / MS (</td><td>EI):</td><td>tR =</td><td> 0,75</td><td>min,</td><td>m / z</td><td> = 273</td>

(M⁺+1).

Example 68: 5- (Cyclopentyloxy) -3 - {[(1S ', 4S') 10 -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole hydrogen formate.

<img file="PL1697378T3_D0078.tif" />

The compound was prepared using the D. yield procedure. ¹1 H NMR (CD₃OD) δ ppm: 8.48 (m, 2H);

7.58 (m, 1H); 7.32 (m, 2H); 7.08 (m, 1H); 4.25 (m, 2H); 3.32 (m, 1H); 2.85 (d, 3H); 2.22 ((EI): vol_R = 5.25 min, m / z = 341 (M ++ 1).

25% obtained

7.75 (m, 1H);

(m, 1H); 3.70 m, 2H). LC / MS

Example 69: 5- (Cyclopropylmethoxy) -3 - {[(1S ', 4S') -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazole hydrogen formate.

104

<img file="PL1697378T3_D0079.tif" />

Performance relationship.

LC / MS (EI) prepared:

using the procedure D._R = 2.85 min, m / z = 327

Obtained (M⁺+1).

25%

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

<img file="PL1697378T3_D0080.tif" />

The compound was prepared using procedure D. A 30% yield was obtained. LC / MS (EI): vol_R = 6.1 min, m / z = 341 (M ++ 1).

Procedure E:

The subject of procedure E is a method for producing aniline derivatives by reduction of nitro-substituted bicyclic base amides.

To a solution of the nitro substituted bicyclic base (3.8 mmol), prepared as described in procedure A, in methanol (100 ml), 10% palladium on carbon (200 mg) was added.

The reaction mixture was placed in a vessel filled with hydrogen at 60 psi (0.041 MPa) and shaken overnight. The catalyst was removed by filtration through

105 layer of celite, which was then washed with methanol (100 mL).

The combined filtrates were concentrated to give the desired product.

Using procedure E, the following exemplary compounds were prepared:

Example 71: 5-Amino-3 - [(5-methyl-2,5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -1H-indazole.

<img file="PL1697378T3_D0081.tif" />

The compound was prepared using procedure E. A 92% yield was obtained. ¹1 H NMR (CD₃OD) δ ppm: 7.36 (d, J = 12.0, 1H), 7.31 (s, 1H), 7.0 (d, J = 12.0, 1H), 4.03 (m, 1H), 3.62 (m, 1H), 3.31 (s, 3H), 3.10 (m, 2H), 3.01 (m, 2H), 2.30-2.00 (m, 2H ), 1.98-1.75 (m, 2H). LC / MS (EI): vol_R = 1.71 min, m / z = = 286 (M ++ 1).

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

<img file="PL1697378T3_D0082.tif" />

The compound was prepared using procedure E. 74% yield was obtained. LC / MS (EI): vol_R = 1.76 min, m / z = 272 (M ++ 1).

106

Procedure F:

The subject of procedure F is a method of reacting bicyclic aniline bases with acid chlorides and anhydrides to produce amide derivatives.

Carbonyl chloride (0.59 mmol) was added to a solution of aniline (0.460 mmol) in pyridine (4 mL). The reaction mixture was left for 2 hours and then concentrated to dryness. The residue after concentration was purified by preparative HPLC using a gradient elution for 8 minutes with a mixture of 95/5 to 20/80 water (0.1% formic acid) / acetonitrile (0.1% formic acid) to give the product as amide.

Using procedure F, the following exemplary compounds were prepared:

Example 73: W- {3 - [(5-methyl-2,5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -1H-indazol-5-yl} cyclopropanecarboxamide hydrogen formate.

<img file="PL1697378T3_D0083.tif" />

The compound was prepared using procedure F. A 28% yield was obtained. ¹1 H NMR (CD₃OD) δ ppm: 8.53 (s, 1H), 8.40 (s, 1H),

7.86 (s, 1H), 4.70 (m, 1H), 4.33 (m, 1H), 4.20 (m, 1H), 3.90 (m, 1H), 3.90 (m , 1H), 3.60-3.40 (m, 2H), 3.0 (s, 3H),

2.50-2.10 (m, 2H), 2.10-1.90 (m, 2H), 1.80 (m, 1H), 0.93 (m 2H), 0.85 (m, 2H) ). LC / MS (EI): vol_R = 2.83 min, m / z = 354 (M ++ 1).

107

Example 74: W- {1- (cyclopropylcarbonyl) -3 - [(5-methyl-2,5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -1H-indazol-5-yl} cyclopropanecarboxamide hydrogen formate .

<img file="PL1697378T3_D0084.tif" />

Performance relationship.

is prepared

LC / MS (EI):

using the procedure t_R = 5.13 min, m / z =

F. Obtained 422 (M⁺+1).

9,4%

Example 75: W- (3 - {[(1S ', 4S') - 5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazol-5-yl) cyclopropanecarboxamide hydrogen formate.

<img file="PL1697378T3_D0085.tif" />

The compound was prepared using procedure F. A 35% yield was obtained. LC / MS (EI): vol_R = 2.78 min, m / z = 340 (M ++ 1).

Procedure G:

The subject of procedure G is a method of reacting aniline bicyclic bases with isocyanates to produce urea derivatives.

108

Isocyanate (0.72 mmol) was added to a solution of aniline (0.550 mmol) in pyridine (4 mL). The reaction mixture was left for 16 hours and then concentrated to dryness. The residue was purified by preparative HPLC using a gradient elution for 8 minutes with a mixture of 95/5 to 20/80 water (0.1% formic acid) / acetonitrile (0.1% formic acid) to give the product as urea.

Using procedure G, the following exemplary compounds were prepared:

Example 76: W- (3 - {[(1S ', 4S') - 5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazol-5-yl) formate -W'-propylurea.

<img file="PL1697378T3_D0086.tif" />

The compound was prepared using procedure G

29% obtained

<td>performance</td><td> . ¹1 H NMR</td><td>(CD3OD) δ</td><td>ppm:</td><td> 8.42</td><td>(band</td><td>wide,</td><td>1H),</td>

<td> 8,21-8,14</td><td>(m, 2H),</td><td>7.47 (m,</td><td>1H),</td><td> 4,40-4</td><td>, 20 (m,</td><td>1H), 3.60</td><td>(M,</td>

<td>1H), 3.30</td><td>(s, 3H),</td><td>3.20 (m,</td><td>2H);</td><td> 3,10 (</td><td>t, J =</td><td>6.0, 2H),</td><td> 2,90</td>

<td>(m, 2H), 2</td><td> ,50-2,10</td><td>(m, 2H),</td><td> 2,10</td><td> -1,85</td><td>(m, 2H)</td><td>, 1.50 (q,</td><td>J =</td>

<td>6.0, 2H),</td><td>0.98 (t,</td><td>J = 6.0,</td><td>, 3H)</td><td>LC / MS</td><td>(EI):</td><td>tR = 2.84</td><td>min,</td>

m / z = 357 (M⁺+1).

109

Example 77: 3 - [(5-methyl-2,5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -N-propyl-5 - {[(propylamino) carbonyl] amino} -1H-indazolo hydrogen formate -

-1-carboxamide hydrochloride.

<img file="PL1697378T3_D0087.tif" />

<img file="PL1697378T3_D0088.tif" />

Performance relationship.

LC / MS (EI) prepared:

using the procedure t_R = 5.11 min, m / z =

G. Obtained 456 (M⁺+1).

7,8

Example 78: W- (4-Fluoro-benzyl-W '- (3 - {[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H- hydrogen formate indazol-5-yl) urea.

<img file="PL1697378T3_D0089.tif" />

The compound was prepared using procedure G. A 27% yield was obtained. LC / MS (EI): vol_R = 4.74 min, m / z = 423 (M ++ 1).

110

Example 79: N- (4-fluorobenzyl-5 - ({[(4-fluorobenzyl) amino] carbonyl} amino) -3 - [(5-methyl-2,5-diazabicyclo [2.2.2] oct-2- hydrogen hydrogen formate yl) carbonyl] -1H-indazole) -1-carboxamide.

<img file="PL1697378T3_D0090.tif" />

<img file="PL1697378T3_D0091.tif" />

OH

The compound was prepared using a G. yield procedure. LC / MS (EI): vol_R = 5.9 min, m / z = 588

5.2% was obtained (M⁺+1).

Example 80: N-Cyclopentyl-N '- (3 - {[(15.45) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1H-indazol-5 hydrogen formate yl) urea.

<img file="PL1697378T3_D0092.tif" />

<img file="PL1697378T3_D0093.tif" />

32% efficiency was obtained. LC / MS (EI): vol_R = 2.85 min, m / z = 383 (M ++ 1).

111

Example 81: W-Cyclopentyl-5 - {[(cyclopentylamino) carbonyl] amino} -3 - [(5-methyl-2,5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -1H-indazolo hydrogen formate -1-carboxamide hydrochloride.

<img file="PL1697378T3_D0094.tif" />

The compound was prepared using procedure G. 6.6% yield. LC / MS (EI): vol_R = 5.46 min, m / z = 508 (M ++ 1).

Example 82: W- (4-fluorobenzyl) -W- {3 - [(5-methyl-2,5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -1H-indazol-5-yl} hydrogen formate urea.

<img file="PL1697378T3_D0095.tif" />

Performance relationship.

is prepared

LC / MS (EI):

using the procedure G._R = 4.78 min, m / z = 437

22% was obtained (M⁺+1).

Example 83: W- {3 - [(5-methyl-2,5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -1H-indazol-5-yl} - hydrogen formate

-W'-propylurea.

112

33%

<img file="PL1697378T3_D0096.tif" />

Performance relationship.

is prepared

LC / MS (EI): t using the procedure _R= 3.11 min, m / z =

G.

372

Obtained (M⁺+1).

Example 84: W-Cyclopentyl-W- {3 - [(5-methyl-2,5-diazabicyclo [2.2.2] oct-2-yl) carbonyl] -1H-indazol-5-yl} urea hydrogen formate.

<img file="PL1697378T3_D0097.tif" />

The compound was prepared using procedure G. Obtained 34^;performance. LC / MS (EI): vol_R = 2.9 min, m / z = 397 (M ++ 1).

Example 85: Binding [³H] MLA.

materials:

Rat brain: Pel-Freez Biologicals, catalog number

56004-2;

Cocktail of protease inhibitors in the form of tablets: Roche, catalog number 1697498.

Membrane preparation:

Rat brains in 20 volumes (mass concentration) of ice-cold 0.32 M sucrose solution containing

113 prosthesis inhibitors (1 tablet per 50 ml), homogenized for 10 seconds using a "polytron" homogenizer with the speed regulator set at 11 and then centrifuged for 10 minutes at 4⁰C, at 1000 g. The supernatant was centrifuged again for 20 minutes at 20,000 g, at 4⁰C. The granules were resuspended in binding buffer (200 mM TRIS-HCl, 20 mM HEPES, pH 7.5, 144 mM NaCl, 1.5 mM KCl, 1 mM MgSO₄, 2 mM CaCl₂, 0.1% (mass concentration) BSA), after which the membrane preparation was stored at -80⁰C.

To determine saturation, a sample of the 200 μl mixture in the binding buffer contained 200 μg of membrane protein and from 0.2 nM to 44 nM [³H] MLA. Non-specific binding was determined using 1 μM MLA. The competition test was carried out with 2 nM [³H] MLA and with a number of compounds of interest. The test mixture was incubated for 2 hours at 22⁰C, then the culture was harvested with a GF / B filter, pre-soaked in 0.3% PEI solution in binding buffer, using a Tomtec collection device. The filter was washed three times with binding buffer, then the radioactivity was counted with a Trilux device.

Binding affinities for preferred compounds of the invention were from 26 micromolar to 64 nanomolar, especially from 2.5 micromolar to 64 nanomolar.

The previously described examples can be repeated with similarly good results, using the reagents and / or operating conditions described in this invention, generically or in detail, instead of those used in the previous examples.

Although the invention has been illustrated with reference to preparation methods and individual compounds, it is obvious that changes and modifications may be made to the invention without departing from its spirit and scope.