Indian Patents
Title of Invention

"AN AZABICYCLO-INDAZOLE COMPOUND"
Abstract An azabicyclo-indazole compound according to Formula I:
Full Text The present invention relates to an azabicyclo-indazole compound.
This application claims the benefit of application Serial No. 60/530,891, filed December 22, 2003, and application Serial No. 60/606,897, filed September 3, 2004, the entire disclosure of which is incorporated by reference.
FIELD OF THE INVENTION
The present invention relates generally to the field of ligands for nicotinic acetylcholine receptors (nAChR), activation of nAChRs, and the treatment of disease conditions associated with defective or malfunctioning nicotinic acetylcholine receptors, especially of the brain. Further, this invention relates to novel compounds, for example, indoles, lH-indazoles, 1,2-benzisoxazoles, and 1,2-benzisothiazoles, which act as ligands for the α7 nAChR subtype, methods of preparing such compounds, compositions comprising such compounds, and methods of use thereof.
BACKGROUND OF THE INVENTION
There are two types of receptors for the neurotransmitter, acetylcholine: muscarinic receptors and nicotinic receptors, based on the selectivity of action of muscarine and nicotine, respectively. Muscarinic receptors are G-protein coupled receptors. Nicotinic receptors are members of the ligand-gated ion channel family. When activated, the conductance of ions across the nicotinic ion channels increases.
Nicotinic alpha-7 receptor protein forms a homo-pentameric channel in vitro that is highly permeable to a variety of cations (e.g., Ca14). Each nicotinic alpha-7 receptor has four transmembrane domains, named M1, M2, M3, and M4. The M2 domain has been suggested to form the wall lining the channel. Sequence alignment shows that nicotinic alpha-7 is highly conserved during evolution. The M2 domain that lines the channel is identical in protein sequence from chicken to human. For discussions of the alpha-7
receptor, see, e.g., Revah et al. (1991), Nature, 353, 846-849; Galzi et al. (1992), Nature 359,500-505; Fucile et al. (2000), PNAS 97(7), 3643-3648; Briggs et al. (1999), Eur. J. Pharmacol. 366 (2-3), 301-308; and Gopalakrisbnan et al. (1995), Eur. J. Pharmacol 290(3), 237-246.
The nicotinic alpha-7 receptor channel is expressed in various brain regions and is believed to be involved in many important biological processes in the central nervous system (CNS), including learning and memory. Nicotinic alpha-7 receptors are localized on both presynaptic and postsynaptic terminals and have been suggested to be involved in modulating synaptic transmission. It is therefore of interest to develop novel compounds, which act as ligands for the o7 nAChR subtype, for the treatment of disease conditions associated with defective or malfunctioning nicotinic acetylcholine receptors.
SUMMARY OF THE INVENTION
This invention relates to novel compounds, which act as ligands for the a7 nAChR subtype, methods of preparing such compounds, compositions comprising such compounds, and methods of use thereof.
DETAILED DESCRIPTION OF THE INVENTION
The present invention includes compounds of Formulas I, II, or III:
(Figure Removed)




wherein
A is -CH2-, or B is
R7
Y is O or S;
X1 to X4 are each, independently, CH, CR1, or N, wherein at most one of X1 to X4
isN;
X5 to X8 are each, independently, CH, CR2, or N, wherein at most one of X5 to X8
isN;
X9 to X12 are each, independently, CH, CR3, or N, wherein at most one of X9 to
Xl2isN;
R1, R2 andR3 are each, independently, H,
.g., CHa) which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms (e.g.,

OCH3),NR4RS, SH, SR4, SOR4, C3.8-cycloalkyl, SO2R4, SOzNR^R5, at, Het, or combinations thereof,
C2-6-alkenyl which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms (e.g., OCH3), NR4R5, SH, SR4, SOR4, C3.8-cycloalkyl, SO2R4, SO2NR4R5, Ar, Het, or combinations thereof,
-alkynyl which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms (e.g., OCH3), NR4R5, SH, SR4, SOR4, C3-8-cycloalkyl, S02R4, SO2NR4R5, Ar, Het, or combinations thereof,
C3-8-cycloalkyl which is unsubstituted or substituted one or more times by
F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms (e.g., OCH3),
4 4 4
, SH, SR, SOR, unsubstituted C3.8-cycloalkyl, SOzR4, Ar, Het, or combinations thereof,
halogen (e.g., F, Cl, Br, I,)
CN, N02, NR4R5, SH, SR4, SOR4, SO2R4, SO2NR4R5, NR4SO2R5, CONR4R5, COOR4, NR4COR5, NR4C02R5, NR4CONR4R5,
Ar,
Het, or R60-; R4 and R5 are each independently H or

ar, Ar-Ci-4-alkyl, Het, C1-4-alkyl (e.g., CH3), C3-8-cycloalkyl (e.g., cyclopropyl), or C4-8-cycloalkylalkyl (e.g., cyclopropyhnethyl), each of which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, OH, allcoxy having 1 to 4 carbon atoms (e.g., OCH3), monoalkylamino, dialkylaroino (e.g., diethylamino), C3-8-cycloalkyl, or combinations thereof,
R6 is H,
C1-6-alkyl (e.g., CH3) which is unsubstituted or substituted one or more by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms (e.g., OCH3), NR4R5, SH, SR4, SOR4, C3.8-cycloalkyl, S02R4, SO2NR4R5, Ar, Het, or combinations thereof,
C3.6-alkenyl which is unsubstituted or substituted one or more by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms (e.g., OCH3), NR4R5, SH, SR4, SOR4, C3.8-cycloalkyl, SO2R4, SO2NR4R5, Ar, Het, or combinations thereof,
Cs-e-alkynyl which is unsubstituted or substituted one or more by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms (e.g., OCH3), NR4R5, SH, SR4, SOR4, C3.8-cycloalkyl, S02R4, SO2NR4R5, Ar, Het, or combinations thereof,
C3-8-cycloalkyl which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms (e.g., OCH3), NR4R5, SH, SR4, SOR4, unsubstituted C3.8-cycloalkyl, SO2R4, S02NR4R5, Ar, Het, or combinations thereof,
C4.8-cycloalkylalkyl which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms (e.g.,

OCH3), NR4R5, SH, SR4, SOR4, unsubstituted C3-8-cycloalkyl, SO2R4, S02NR4R5, at, Het, or combinations thereof,
Ar, or Het; R7 is H, or
(e.g., CH3) which is unsubstituted or substituted one or more by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms (e.g., OCH3), NR4R5, or combinations thereof;
m is 1,2 or 3;
Ar is an aryl group containing 6 to 10 carbon atoms which is unsubstituted or substituted one or more times by alkyl having 1 to 8 C atoms, alkoxy having 1 to 8 C atoms, halogen (F, Cl, Br, or I, preferably F or Cl), dialkylamino wherein the alkyl portions each have 1 to 8 C atoms, amino, cyano, hydroxyl, nitro, halogenated alkyl having 1 to 8 C atoms, halogenated alkoxy having 1 to 8 C atoms, hydroxyalkyl having 2 to 8 C atoms, hydroxyalkoxy having 2 to 8 C atoms, alkenyloxy having 3 to 8 C atoms, alkylthio having 1 to 8 C atoms, alkylsulphinyl having 1 to 8 C atoms, alkylsulphonyl having 1 to 8 C atoms, monoalkylamino having 1 to 8 C atoms, cycloalkylamino wherein the cycloalkyl group has 3 to 7 C atoms and is optionally substituted, aryloxy wherein the aryl portion contains 6 to 10 carbon atoms (e.g., phenyl, naphthyl, biphenyl) and is optionally substituted, arylthio wherein the aryl portion contains 6 to 10 carbon atoms (e.g., phenyl, naphthyl, biphenyl) and is optionally substituted, cycloalkyloxy wherein the cycloalkyl group has 3 to 7 C atoms and is optionally substituted, sulfo, sulfonylamino, acylamido (e.g.,

acetamido), acyloxy (e.g., acetoxy), carboxy, alkoxycarbonyl, alkylaminocarbonyl or combinations thereof; and
Het is a heterocyclic group, which is fully saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, which is unsubstituted or substituted one or more times by halogen (F, Cl, Br, or I, preferably F or Cl), aryl having 6 to 10 carbon atoms (e.g., phenyl, naphthyl, biphenyl) and is optionally substituted, arylalkyl having 6 to 10 carbon atoms in the aryl portion and 1 to 4 carbon atoms in the alkyl portion, a heterocyclic group, which is fully saturated, partially saturated or fully unsaturated, and has 5 to 10 ring atoms in which at least 1 ring atom is a N, 0 or S atom, alkyl having 1 to 8 C atoms, alkoxy having 1 to 8 C atoms, cyano, trifluoromethyl, nitro, oxo, ammo, monoalkylamino having 1 to 8 C atoms, dialkylamino wherein each alkyl group has 1 to 8 C atoms, alkoxycarbonyl, alkylaminocarbonyl, or combinations thereof; and
pharmaceutically acceptable salts thereof.
According to a further embodiment, in Formulas I, II, and III, R4 and R5 are each independently H, Ar, Het, or C1-4-alkyl (e.g., CHs) which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms (e.g., OCHa), monoalkylamino, dialkylamino (e.g., diethylamino), Ca-s-cycloalkyl or combinations thereof, and R1, R2, and R3 are not NR4CO2R5 or NR4CONR4RS.
Alkyl throughout means a straight-chain or branched-chain aliphatic hydrocarbon radical having preferably 1 to 4 carbon atoms. Suitable alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

Alkoxy means alkyl-0- groups in which the alkyl portion preferably has 1 to 4 carbon atoms. Suitable alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, and sec-butoxy.
Cycloalkyl means a cyclic, bicyclic or tricyclic saturated hydrocarbon radical having 3 to 8 carbon atoms. Suitable cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Other suitable cycloalkyl groups include spiropentyl, bicyclo[2.1.0]pentyl, and bicyclo[3.1.0]hexyl.
The cycloalkyl groups can be substituted by Ci4-alkyl, C1-4-alkoxy, hydroxyl, amino, monoalkylamino having 1 to 4 carbon atoms, and/or dialklyamino in which each alkyl group has 1 to 4 carbon atoms.
Cycloalkylalkyl refers to cycloalkyl-alkyl radicals in which the cycloalkyl and alkyl portions are in accordance with previous discussions. Suitable examples include cyclopropylmethyl and cyclopentylmethyl.
Aryl, as a group or substituent per se or as part of a group or substituent, refers to an aromatic carbocyclic radical containing 6 to 10 carbon atoms, unless indicated otherwise. Suitable aryl groups include phenyl, napthyl and biphenyl. Substituted aryl groups include the above-described aryl groups which are substituted one or more times by halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, phenoxy, and acyloxy (e.g., acetoxy).
Arylalkyl refers to an aryl-alkyl-radical in which the aryl and alkyl portions are hi accordance with the previous descriptions. Suitable examples include benzyl, 1-phenethyl, 2-phenethyl, phenpropyl, pheributyl, phenpentyl, and napthylmethyl. Ar-alkyl also is an arylalkyl radical in which the aryl portion is in accordance with the prior description of Ar. Suitable examples include benzyl and fluorobenzyl.
Heterocyclic groups refer to saturated, partially saturated and fully unsaturated heterocyclic groups having one, two or three rings and a total number of 5 to 10 ring atoms wherein at least one of the ring atoms is an N, O or S atom. Preferably, the heterocyclic group contains 1 to 3 hetero-ring atoms selected from N, O and S. Suitable saturated and partially saturated heterocyclic groups include, but are not limited to tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, isoxazolinyl and the like. Suitable heteroaryl groups include but are not limited to furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, isoquinolinyl, naphthyridinyl and the like. 'Other examples of suitable heterocyclic groups, are 2-quinolinyl, 1,3-benzodioxyl, 2-thienyl, 2-benzofuranyl, 2-benzothiophenyl, 3-thienyl, 2,3-dihydro-5-benzofuranyl, 4-indoyl, 4-pyridyl, 3-quinolinyl, 4-quinolinyl, l,4-benzodioxan-6-yl, 3-indoyl, 2-pyrrolyl, 3,4-l,2-benzopyran-6-yl, 5-indolyl, 1,5-benzoxepin-8-yl, 3-pyridyl, 6-coumarinyl, 5-benzofuranyl, 2-isoimidazol-4-yl, 3-pyrazolyl, and 3-carbazolyl.
Substituted heterocyclic groups refer to the heterocyclic groups described above, which are substituted in one or more places by, for example, halogen, aryl, alkyl, alkoxy, cyano, trifluorornethyl, nitro, oxo, amino, alkylamino, and dialkylamino.
Radicals that are substituted one or more times preferably have 1 to 3 substituents, especially 1 or 2 substituents of the exemplified substituents. Halogenated radicals such as halogenated alkyls are preferably fluorinated and include perhalo radicals such as trifluorornethyl.

In the compounds of Formula I, R1 is preferably H, OR6, NR4R5, NR4COR5, NR4CONR4R5, CFa, 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)furyl), phenyl which is unsubstituted or substituted (e.g., fluorophenyl such as 3-fluorophenyl and 4-fluorophenyl), methoxyphenyl such 4-methoxyphenyl, tiiiazolyl such as 2-thiazolyl, 2-(4-methyl)thiazolyl, and 2-(5-methyl)thiazolyl, oxazolyl such as 2-oxazolyl, andpyranyl such as 4-tetrahydropyranyl and 3,6-dihydro-pyran-4-yl).
In the compounds of Formula II, R2 is preferably H, OR6, CFs, 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)furyl), or phenyl which is unsubstituted or substituted (e.g., fluorophenyl such as 3-fluorophenyl and 4-fluorophenyl, and methoxyphenyl such 4-methoxyphenyl).
In the compounds of Formula HI, R3 is preferably H, cyclopropyl, or OR6.
R4 is preferably H or methyl, and R5 is preferably H, methyl, cyclopropyl, cyclopentyl, cyclopropylmethyl, propyl, or Ar-methyl.
R6 is preferably methyl, ethyl, CFa, CHF2, cyclopentyl or cyclopropylmethyl. R7 is preferably H, methyl, or ethyl.
In the compounds of Formulas I, n, and III, A is preferably -CO-. Also, in the compounds of Formulas I, II, and m, m is preferably 1 or 2.
Ar is preferably phenyl which is unsubstituted or substituted (e.g., fiuorophenyl such as 3 -fiuorophenyl and 4-fluorophenyl, and methoxyphenyl such 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 of X1 to X4 is preferably CH or CR1. In Formula II, each of X4 to X8 is preferably CH or CR2. In Formula III, each of X9 to X12 are preferably CH or CR3.
According to a compound aspect of the invention, the compounds of Formulas I, II and III are selected from: 3-[(15r,41S)-2,5-Diazabicyclo[2.2.1]hept-2-ylcarbonyl]-l^-indazolehydrochloride,
hydroformate,
3-{[(liSl,4^-5-Methyl-235-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-l,2-benzisotbiazole, 3-{[(15',41S)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(trifluoromethoxy)-l#-indazole hydroformate,
l#-indazole hydroformate,
5-Bromo-3-[(15',45)-2,5-diazabicyclo[2.2.1]hept-2-ylcarbonyl]-l/f-indazole
hydrochloride,
5-Methoxy-3-{[(l.S',45)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-lJy-
indazole hydroformate,
6-Bromo-3-[(l1S',4S)-2,5-diazabicyclo[2.2.1]hept-2-ylcarbonyl]-l//'-indazole
hydrochloride,
6-Ethoxy-3-{[(l,S,41S)-5-methyl-2J5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-l,2-
benzisothiazole hydroformate,

6-Methoxy-3-{[(15r)4,S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-l,2-benzisothiazole hydroformate,
benzisothiazole,
7-Methoxy-3-{[(l1S')45)-5-methyl-2>5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-l)2-
benzisothiazole hydroformate,
3-{[(15)4lS)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(2-thienyl)-l^'-
indazole hydroformate,
3-{[(15,45)-5-Methyl-2)5-diazabicyclo[2.2.1]hspt-2-yl]carbonyl}-5-(4-methyl-2-thienyl)-
l//"-indazole hydroformate,
3-{[(15,4,S)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(5-methyl-2-tMenyl)-
l#-indazole hydroformate,
3-{[(15')4-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-phenyl-lJY-rndazole
hydroformate,
3-{[(1S,4S}-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(2-thienyl)-l/H-
indazole hydroformate,
3-{[(lS,4S)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(3-thienyl)-lH-
indazole hydroformate,
3-{[(1S,4S)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(4-methyl-2-thienyl)-
1H-indazole hydroformate,
3-{[(1S,4S-5-Methl-2,5 diazabicyclo[22.1]hept-2-yl]carbonyl}-6-(5-methyl-2-furyl)-
Ifi'-indazole hydroformate,
3-{[(15,45)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(5-methyl-2-thienyl)-
1/f-indazole hydroformate,
5-(2-Furyl)-3-{[(l1S,45)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-l/f-
indazole hydroformate,
IJf-indazole hydroformate,
5-(4-Fluorophenyl)-3-{[(15')4iS)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-l^T-indazole hydroformate,

5-(4-Meihoxypliejiyl)-3-{[(15,45)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-l£T-indazole hydroformate,
6-(2-Furyl)-3-{[(15rJ4,S)-5-inethyl-2)5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-l/Z'-indazole hydroformate,
indazole hydroformate,
3-{[(15'>45)-5-Bthyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-lff-indazole,
3-{[(l.S',4JS)-5-Methyl-255-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-l/r-indazole
hydroformate,
3-{[(l1S,41S)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(3-thienyl)-17y-
indazole hydroformate,
5-(3-Furyl)-3-{[(15,4,S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-m-
indazole hydroformate,
5-Bromo-3-{[(l1S',45)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-lff-indazole,
and pharmaceutically acceptable salts thereof.
According to a compound aspect of the invention, the compounds of Formulas I, II and III are selected from:
3-(2,5-Dia2abicyclo[2.2.2]oct-2-ylcarbonyl)-6-(l,3-thiazol-2-yl)-l//-mdazole hydrochloride, 3-(2,5-Diazabicyclo[2.2.2]oct-2-ylcarbonyl)-6-(l,3-thiazol-2-yl)-l/Z'-indazole,
3-(2,5-Diazabicyclo[2.2.2]oct-2-ylcarbonyl)-lH-indazole hydrochloride,
3-(2,5-Diazabicyclo[2.2.2]oct-2-ylcarbonyl)-lfl'-indazole,
3-[(5-Methyl-2,5-diazabicyclo[2.2.2]oct-2-yl)carbonyl]-llf-indazole hydroformate,
3-[(5-Methyl-2,5-diazabicyclo[2.2.2]oct-2-yl)carbonyl]-lJ?:f-indazole,
3-[(5-Memyl-2,5-diazabicyclo[222]oct-2-yl)carbonyl]-6-(l,3-thiazol-2-yl)-ljy'-indazole
hydroformate,
3-[(5-Methyl-2J5-diazabicyclo[2.2.2]oct-2-yl)carbonyl]-6-(l,3-thiazol-2-yl)-lfl"-mdazole>
3-{[(lS,4S)-5-Methyl-2)5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-lF-indazole,

3-{[(15,4)S)-5-Metiiyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(l)3-tliiazol-2-yl)-
l-fif-indazole hydroformate,
3-{[(lS')4)S)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carboiiyl}-5-(l)3-thiazol-2-yl)-
l#-indazole,
3-{[(l5,45}-5-Methyl-2J5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(2-thienyl)-lJH'-
indazole,
indazole,
3-{[(1^4 l.£f-indazole,
3-{[(15,455-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(5-methyl-2-thienyl)-
l//-indazole,
3-{[(15,45)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(trifluoromethoxy)-
3-{[(liSl,41S)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-phenyl-lF-indazole,
3-{[(15)45)-5-Methyl-2s5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(l,3-oxazol-2-yl)-
1/if-indazole hydroformate,
3-{[(liS,41S)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(l,3-oxazol-2-yl)-
Lfr-indazole,
3-{[(15,4^-5-Methyl-2,5-diazabicyclo[2.2.1]liept-2-yl]carbonyl}-6-(l,3-tbia2»l-2-yl)-
Ijfl-indazole hydroformate,
3- {[(l1S',4S)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl} -6-(l ,3-tMazol-2-yl)-
IH-indazolc,
3-{[(15,4S)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(2-tbienyl)-lJY-
indazole,
indazole,
3-{[(15,4JS)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(4-methyl-l,3-thiazol-2-yl)-ll/'-indazole hydroformate,
3-{[(15,4,S)-5-Methyl-2)5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(4-methyl-l>3-tbiazol-2-yl)- Iff-indazole,
3-{[(15J4,S}-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(4-methyl-2-thienyl)-
IK-indazole,
3-{[(liSI,4,S)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(5-mefliyl-l>3-
thiazol-2-yl)- IF-indazole hydroformate,
3-{[(l,S,45)-5-Methyl-2,5-diazabicyclo[2.2.1]liept-2-yl]carbonyl}-6-(5-niethyl-l,3-
tbaazol-2-yl)- 1 iMndazole,
3-{[(15,45)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(5-methyl-2-furyl)-
l-fif-indazole,
3-{[(l,S')45)-5-Methyl-2)5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(5-methyl-2-thienyl)-
l//-indazole,
3-{[(15l,45)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(tetrahydro-2H-
pyran-4-yl)-l/f-indazole hydrofoimate,
3-{[(15545)-5-Methyl-2,5-diazabicyclo[2.2.1]liept-2-yl]carbonyl}-6-(tetrahydro-2H-
pyran-4-yl)-l//-indazole,
3-{[(15'J45)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(trifluoromethoxy)-
1/f-indazole hydroformate,
3-{[(15,45)-5-Methyl-2>5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(trifluoromethoxy)-
IF-indazole,
IH-indazole,
3- {[(1 5l,4«S)-5-Methyl-2,5-diazabicyclo[2.2. l]hept-2-yl]carbonyl} -7-(trifluoromethoxy)-
IJ^-indazole hydroformate,
3- {[(1 ^^^-S-Methyl^.S-diazabicyclo^^.ljhepW-yllcarbonyl} -7-(trifluoromethoxy)-
1/f-indazole,
5-(2-Furyl)-3-{[(15,45)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyI}-l//'-
indazole,
5-(3-FluorophenyI)-3-{[(l1y)45)-5-metliyl-2)5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-Ijy-indazole,
5-(3-Furyl)-3-{[(1^41S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-l//'-indazole,
5-(4-Fluorophenyl)-3-{[(15r,4JS)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-
l/f-indazole,
5-(4-Methoxyphenyl)-3-{[(15,41S)-5-methyl-2,5-diazabicyclo[2.2.13hept-2-yl]carbonyl}-
1/f-indazole,
5-(Cyclopentyloxy)-3-{[(l,S,41y)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-
IH-indazole hydroformate,
5-(Cyclopentyloxy)-3-{[(15',45)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-
1/f-indazole,
5-(Cyclopropylmethoxy)-3-{[(15,4^)-5-methyl-2,5-diazabicyclo[2.2.13hept-2-
yl]carbonyl}-lH-indazole hydroformate,
5-(Cyclopropylmethoxy)-3-{[(l,S',4^)-5-methyl-2,5-diazabicyclo[2J2.1]hept-2-
yl]carbonyl}-l/7-indazole,
5-Amino-3-[(5-Methyl-2,5-diazabicyclo[2.2.2]oct-2-yl)carbonyl]-l/f-indazoleJ
5-Amino-3-{[(l5'J4^-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(l53-
tbiazol-2-yl)- 1/f-bdazole,
5-Bromo-3-[(l.S',41S)-255-diazabicyclo[2.2.1]hept-2-ylcarbonyl3-lF-mdazole)
5-Hydroxy-3-{[(l,S',41S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(l,3-
tMazol-2-yl)-l//-indazole,
5-Methoxy-3-[(5-methyl-2J5-diazabicyclo[2.2.2]oct-2-yl)carbonyl]-l//-indazole hydroformate,
3-(2,5-Diazabicyclo[2.2.2]oct-2-ylcarbonyl)-5-methoxy-lflr-indazolehydrochloride, 3-(2,5-Diazabicyclo[2.2.2]oct-2-ylcarbonyl)-5-methoxy-l^r-indazole,
indazole hydroformate,
indazole,
6-(2-Furyl)-3-{[(l)S',41S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-l^-indazole,
6-(3,6-Dihydro-2H-pyran-4-yl)-3-{[(l)S)45)-5-methyl-2,5-diazabicyclo[2.2.1]b.ept-2-yl]carbonyl}-l//-indazole hydroformate,
6-(3)6-Dihydro-2H-pyran-4-yl)-3-{[(15s46)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-l#-indazole,
indazole,
6-(Cyclopentyloxy)-3-{[(liSr,4,S)-5-methyl-2,5-diazabicyclo[2.2.1]liept-2-yl]carbonyl}-
Lff-indazole hydrofonnate,
6-(Cyclopentyloxy)-3-{[(15r,45)-5-raethyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-
l#-indazole,
6-Cyclopropyl-3-{[(l,S',45)-5-methyl-2>5-diazabicyclo[2.2.13hept-2-yl]carbonyl}-l,2-
benzisothiazole hydrofonnate,
6-Cyclopropyl-3-{[(l,S',41y)-5-methyl-2,5-diazabicyclo[2.2.1]liept-2-yl]carbonyl}-l,2-
benzisothiazole,
6-Ethoxy-3-{[(15,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-l,2-
benzisothiazole,
3-(2,5-Diazabicyclo[2.2.2]oct-2-ylcarbonyl)-6-methoxy-lfT-indazolehydrochloride,
3-(2,5-Diazabicyclo[2.2.2]oct-2-ylcarbonyl)-6-methoxy-l/Z-indazole,
6-Methoxy-3-[(5-methyl-2,5-diazabicyclo[2.2.2]oct-2-yl)carbonyl]-l//-indazole
hydrofonnate,
6-Methoxy-3-[(5-methyl-2,5-diazabicyclo[2.2.2]oct-2-yl)carbonyl]-l^/-indazole,
6-Methoxy-3-{[(15,4^-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-lF-
indazole hydrochloride,
6-Methoxy-3-{[(l,Sl,4)S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-ll/'-
indazole hydrofonnate,
6-Methoxy-3-{[(15r,41S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-lJ:f-
indazole,
7-Methoxy-3-{[(15',41S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-l,2-
benzisothiazole,
^3-{[(15,45)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-l^-indazol-5-yl)-
7V-propylurea hydrofoimate,
^-(3-{[(15,4^-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-l^-indazol-5-yl)-
TV-propylurea,
jV-{3-[(5-Methyl-2,5-diazabicyclo[22.2]oct-2-yl)carbonyl]-lfir-indazol-5-
yljcyclopropanecarboxamide hydroformate,
^_{3.[(5.Methyl-2J5-diazabicyclo[2.2.2]oct-2-yl)carbonyl]-l/f-indazol-5-
yl} cyclopropanecarboxamide,
AT-{3-[(5-Metiiyl-2)5-diazabicyclo[2.2.2]oct-2-yl)carbonyl]-lJy-indazol-5-yl}-A'-
propylurea hydroformate,
A'-{3-[(5-Methyl-2,5-diazabicyclo[2.2.2]oct-2-yl)caibonyl]-lfl'-indazol-5-yl}-^'-
propylurea,
and pharmaceutically acceptable salts thereof.
According to a further compound aspect of the invention, the compounds of Formulas I, II and HI are selected from:
3-{[(1^4,S)-5-Methyl-2,5-diazabicyclo[2.2. l]hept-2-yl]carbonyl} -1 ,2-benzisoxazole hydroformate,
3-{[(15,4,S)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(4-methyl-l,3-
thiazol-2-yl)-l#-iridazole hydroformate,
3-{[(l^,45)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(4-methyl-l,3-
thiazol-2-yl)-l/Wndazole,
3-{[(15,4S)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(5-methyl-l,3-
thiazol-2-yl)-l^-indazole hydroformate,
3-{[(l)S545)-5-Metiiyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(5-methyl-lJ3-
thiazol-2-yl)- IJf-indazole,
3-{[(1^45)-5-Memyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(tetrahydro-2/f-
pyran-4-yl)-lJy-uidazole hydroformate,
3-{[(15,45)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(tetrahydro-2//-
pyran-4-yl)-l#-indazole,
5-(3,6-Dihydro-2H-pyran-4-yl)-3-{[(1^45}-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-
yl]carbonyl}-l^T-indazole hydroformate,
5-(3,6-Dihydro-2H-pyran-4-yl)-3-{[(15,45)-5-methyl-2>5-diazabicyclo[2.2.1]hept-2-
yl]carbonyl}-l.ff"-indazole,
5-(Difluoromethoxy)-3-{[(1^46)-5-methyl-2)5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-l-indazole hydroformate,
l-indazole,
6-(Difluoromethoxy)-3-{[(15,45)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-
l#-indazole hydroformate,
6-(Difluoromethoxy)-3-{[(16I,4^)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-
1/f-indazole,
7-Fluoro-6-methoxy-3-{[(liS'J4)S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-
1/Z-indazole hydroformate,
Iff-indazole,
JV-(3-{[(15rJ4,S)-5-Methyl-255-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-l^-indazol-5-
yl)cyclopropanecarboxamide hydroformate,
JV-(3-{[(15,45)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-lJH'-indazol-5-
yl)cyclopropanecarboxamide,
A-(4-Fluorobenzyl)-]V1-(3-{[(l1SJ45)-5-methyl-2J5-diazabicyclo[2.2.1]hept-2-
yl]carbonyl}-l#-indazol-5-yl)urea hydroformate,
J?V-(4-Fluoroben2yl)-^/I-(3-{[(lJS'345)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-
yl]carbonyl} -l^-indazol-5-yl)urea,
JV-(4-Fluorobenzyl)-Nl-{3-[(5-methyl-2,5-diazabicyclo[2.2.2]oct-2-yl)carbonyl]-l^-
indazol-5-yl} urea hydroformate,
jV-(4-Fluorobenzyl)-N'-{3-[(5-methyl-2,5-diazabicyclo[2.2.2]oct-2-yl)carbonyl]-lfl'-
hidazol-5-yl}urea,
A-CyclopropyhTie1hyl)-3-[(5-methyl-2,5-diazabicyclo[2.2.2]oct-2-yl)carbonyl]-l/f-
indazol-5-amine,
-(Cyclopropykoethyl)-3-{[(llS'J45)-5-methyl-255-diazabicyclo[2.2.1]hept-2-
yl]carbonyl}-17?-indazol-5-amine,
A-Dimethyl-3-[(5-methyl-2,5-diazabicyclo[2.2.2]oct-2-yl)carbonyl]-l^-mdazol-5-
amine hydroformate,
,JV-Dimethyl-3-[(5-methyl-2J5-diazabicyclo[2.2.2]oct-2-yl)carbonyl]-lJ!f-indazol-5-
amine, AT,JV-Dime%l-3-{[(16',4^-5-methyl-2)5-diazabicyclo[2.2J]hept-2-yl]carbonyl}-l//-
indazol-5-amine hydroformate,
A-Dimethyl-3-{[(l5,4,S)-5-me1iiyl-2J5-diazabicyclo[2.2.l]hept-2-yl]carbonyl}-l//'-
indazol-5-amine,
ACJV-Dimethyl-3- {[(15,45)-5-metbiyl-2,5-diazabicyclo[2.2. l]hept-2-yl]carbonyl} -\H-
indazol-6-amine hydrofoimate,
AT,Ar-Dime1liyl-3-{[(lJS',4lS)-5-methyl-2,5-diazabicyclo[2.2.l]hept-2-yl]carbonyl}-lfl'-
indazol-6-amine,
JV-Cyclopentyl-7V-(3-{[(15',41S)-5-methyl-2J5-diazabicyclo[2.2.1]hept-2-yl]carboiiyl}-lfi'-
indazol-5-yl)urea hydroformate,
A-Cyclopentyl-A^-(3-{[(l,S,41S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-lF-
indazol-5-yl)urea,
//-Cyclopentyl-JV?-{3-[(5-methyl-2,5-diazabicyclo[2.2.2]oct-2-yl)carbonyl]-lff-indazol-5-
yl}urea hydroformate,
JV-Cyclopentyl-jy-{3-[(5-methyl-2,5-dazabicyclo[2.2.2]oct-2-yl)carboriyl]-lJy-iadazol-5-
yl}urea,
and pharmaceutically acceptable salts thereof.
Preferred aspects include pharmaceutical compositions comprising a compound of this invention and a pharmaceutically acceptable carrier and, optionally, another active agent as discussed below; a method of stimulating or activating inhibiting alpha-7 nicotinic receptors, e.g., as determined by a conventional assay or one described herein, either in vitro or in vivo (in an animal, e.g., in an animal model, or in a mammal or in a human); a method of treating a neurological syndrome, e.g., loss of memory, especially long-term memory, cognitive impairment or decline, memory impairment, etc. method of treating a disease state modulated by nicotinic alpha-7 activity, in a mammal, e.g., a human, e.g., those mentioned herein.
The compounds of the present invention may be prepared conventionally. Some of the known processes that can be used are described below. All starting materials are known or can be conventionally prepared from known starting materials.
The synthesis of similar compounds is disclosed in copending application Serial No. 10/669,645, filed September 25,2003, the entire disclosure of which is hereby incorporated by reference.
Acids that can be used in the preparation of the bicyclobase amide are commercially available, can be prepared by known procedures described in the literature, or as described below. For example, indazole-3-carboxylic acid is commercially available. Bromoindazole acids can be prepared from the corresponding isatins by basic hydrolysis, diazotization, and reduction [Snyder, H.R.; et al. J. Am. Chem. Soc. 1952, 74, 2009], Benzisoxazole-3-carboxylic acid can be prepared from 2,5-dibromonitrobenzene by reaction with diethylmalonate, saponification with decarboxylation, followed by re-esterification, reaction with isoamyl nitrite under basic conditions, hydrogenolysis, and saponification [Angell, R.M.; Baldwin, I.R.; Bamborough, P.; Deboeck, N.M.; Longstaff, T.; Swanson, S. WO04010995A1]. 3-Benzisothiazolecarboxylic acid can be prepared from thiophenol by reaction with oxallyl chloride and aluminum chloride followed by treatment with hydroxylamine, hydrogen peroxide, and sodium hydroxide. Bicycloamines that can be used in the preparation of the bicyclobase amides are commercially available, can be prepared by known procedures described in the literature, or as described below. For example, (liS",4)S)-2-fert-butyloxycarbonyl-2,5-diazabicyclo[2.2.1]heptane hydrochloride is commercially available. (liSyiiS^-methyl-2,5-diazabicyclo[2.2.1]heptane can be prepared by the reduction of the terf-butyl carbamate with lithium aluminum hydride or by the sequence of reductive amination followed by deprotection. 2,5-Diazabicyclo[2.2.2]octane can be prepared as described in the literature (Newman, H. J. Heterocydic Chem. 1974, .Z7,449. Sturm, P.A.; Henry, D.W. J. Med. Chem. 1974,17,481). 2-Methyl-2,5-diazabicyclo[2.2.2]octane can be prepared from diethyl 2,5-diaminohexanedioate by cyclization of the N-benzyl
intermediate, reduction of the tertiary amides, hydrogenolysis, selective protection, reductive amination and deprotection.
The bicyclobase amide can be prepared by the coupling reaction of acids with Hie bicycloamine and HBTU or HOBt and EDCI in DMF, or by converting the acids to the corresponding acid chloride and then reaction with the bicycloamine (Macor, J.E.; Gurley, D.; Lanthorn, T.; Loch, J.; Mack, R.A.; Mullen, G.; Tran, O.; Wright, N.; and J. E. Macor, J.E. Bioorg. Med. Chem. Lett. 2001,9,319.). The couplings are generally performed at room temperatures for 4-8 hours. Thioamide analogs can be prepared from the amides by reaction with Lawesson's reagent (Wipf P.; Kim, Y.; Goldstein, D.M., J. Am. Chem. Soc., 1995, 111, 11106). Bicyclobase methylenamine analogs maybe prepared from bicyclobase amides by standard reduction procedures as described, for example, below. The resultant adducts can be isolated and purified by standard techniques, such as chromatography or recrystallization, practiced by those skilled in the art.
One of ordinary skill in the art will recognize that compounds of Formulas I-III can exist in different tautomeric and geometrical isomeric forms. All of these compounds, including cis isomers, trans isomers, diastereomic mixtures, racemates, nonracemic mixtures of enantiomers, substantially pure, and pure enantiomers, are within the scope of the present invention. Substantially pure enantiomers contain no more than 5% w/w of the corresponding opposite enantiomer, preferably no more than 2%, most preferably no more than 1%.
The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers. Examples of appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric and camphorsulfonic acid. Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known to those skilled in the art, for example, by chromatography or fractional crystallization. The optically active bases or acids are then
liberated from the separated diastereomeric salts. A different process for separation of optical isomers involves the use of chiral chromatography (e.g., chiral HPLC columns), with or without conventional derivation, optimally chosen to maximize the separation of the enantiomers. Suitable chiral HPLC columns are manufactured by Diacel, e.g., Chiracel OD and Chiracel OJ among many others, all routinely selectable. Enzymatic separations, with or without derivitization, are also useful. The optically active compounds of Formulas I-III can likewise be obtained by utilizing optically active starting materials in chiral synthesis processes under reaction conditions which do not cause racemization.
In addition, one of ordinary skill in the art will recognize that the compounds can be used in different enriched isotopic forms, e.g., enriched in the content of 2H, 3H, 11C, 13C and/or 14C. In one particular embodiment, the compounds are deuterated. Such deuterated forms can be made the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve the efficacy and increase the duration of action of drugs.
Deuterium substituted compounds can be synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development [In: Curr., Pharm. Des., 2000; 6(10)] (2000), 110pp. 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), 6601-21, CODEN:TETRAB ISSN:0040-4020. CAN 112:20527 AN 1990:20527 CAPLUS; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem. (1981), 64(1-2), 9-32. CODEN:JRACBN ISSN:0022-4081, CAN 95:76229 AN 1981:476229 CAPLUS.
Where applicable, the present invention also relates to useful forms of the compounds as disclosed herein, such as pharmaceutically acceptable salts or prodrugs of all the compounds of the present invention for which salts or prodrugs can be prepared.
Pharmaceutically acceptable salts include those obtained by reacting the main compound, functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, and carbonic acid. Pharmaceutically acceptable salts also include those in which the main compound functions as an acid and is reacted with an appropriate base to form, e.g., sodium, potassium, calcium, magnesium, ammonium, and choline salts. Those skilled in the art will further recognize that acid addition salts of the claimed compounds maybe prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods. Alternatively, alkali and alkaline earth metal salts can be prepared by reacting the compounds of the invention with the appropriate base via a variety of known methods.
The following are further examples of acid salts that can be obtained by reaction with inorganic or organic acids: acetates, adipates, alginates, citrates, aspartates, benzoates, benzenesulfonates, bisulfates, butyrates, camphorates, digluconates, cyclopentanepropionates, dodecylsulfates, ethanesulfonates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, fumarates, hydrobromides, hydroiodides, 2-hydroxy-ethanesulfonates, lactates, maleates, methanesulfonates, nicotinates, 2-naphthalenesulfonates, oxalates, palmoates, pectinates, persulfates, 3-phenylpropionates, picrates, pivalates, propionates, succinates, tartrates, thiocyanates, tosylates, mesylates and undecanoates.
Preferably, the salts formed are pharmaceutically acceptable for administration to mammals. However, pharmaceutically unacceptable salts of the compounds are suitable as intermediates, for example, for isolating the compound as a salt and then converting the salt back to the free base compound by treatment with an alkaline reagent. The free base can then, if desired, be converted to a pharmaceutically acceptable acid addition salt.
The compounds of the invention can be administered alone or as an active ingredient of a formulation. Thus, the present invention also includes pharmaceutical compositions of compounds of Formulas I-III containing, for example, one or more pharmaceutically acceptable carriers.
Numerous standard references are available that describe procedures for preparing various formulations suitable for administering the compounds according to the invention. Examples of potential formulations and preparations are contained, for example, in the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (current edition); Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman and Schwartz, editors) current edition, published by Marcel Dekker, Inc., as well as Remington's Pharmaceutical Sciences (Arthur Osol, editor), 1553-1593 (current edition).
In view of their alpha-7 stimulating activity and, preferably their high degree of selectivity, the compounds of the present invention can be administered to anyone needing stimulation of alpha-7 receptors. Administration maybe accomplished according to patient needs, for example, orally, nasally, parenterally (subcutaneously, intraveneously, intramuscularly, intrasternally and by infusion) by inhalation, rectally, vaginally, topically and by ocular administration.
Various solid oral dosage forms can be used for administering compounds of the invention including such solid forms as tablets, gelcaps, capsules, caplets, granules, lozenges and bulk powders. The compounds of the present invention can be administered alone or combined with various pharmaceutically acceptable carriers, diluents (such as sucrose, mannitol, lactose, starches) and excipients known in the art, including but not limited to suspending agents, solubilizers, buffering agents, binders, disintegrants, preservatives, colorants, flavorants, lubricants and the like. Time release capsules, tablets and gels are also advantageous in administering the compounds of the present invention.
Various liquid oral dosage forms can also be used for administering compounds of the inventions, including aqueous and non-aqueous solutions, emulsions, suspensions, syrups, and elixirs, Such dosage forms can also contain suitable inert diluents blown in the art such as water and suitable excipients known in the art such as preservatives, wetting agents, sweeteners, flavorants, as well as agents for emulsifying and/or suspending the compounds of the invention. The compounds of the present invention may be injected, for example, intravenously, in the form of an isotonic sterile solution. Other preparations are also possible.
Suppositories for rectal administration of the compounds of the present invention can be prepared by mixing the compound with a suitable excipient such as cocoa butter, salicylates and polyethylene glycols. Formulations for vaginal administration can be in the form of a pessary, tampon, cream, gel, paste, foam, or spray formula containing, in addition to the active ingredient,, such suitable carriers as are known in the art.
For topical administration the pharmaceutical composition can be in the form of creams, ointments, liniments, lotions, emulsionss suspensions, gels, solutions, pastes, powders, sprays, and drops suitable for administration to the skin, eye, ear or nose. Topical administration may also involve transdermal administration via means such as transdermal patches.
Aerosol formulations suitable for administering via inhalation also can be made. For example, for treatment of disorders of the respiratory tract, the compounds according to the invention can be administered by inhalation in the form of a powder (e.g., micronized) or in the form of atomized solutions or suspensions. The aerosol formulation can be placed into a pressurized acceptable propellent.
The compounds can be administered as the sole active agent or in combination with other pharmaceutical agents such as other agents used in the treatment of cognitive impairment and/or memory loss, e.g., other a-7 agonists, PDE4 inhibitors, calcium channel blockers, muscarinic ml and m2 modulators, adenosine receptor modulators,
amphakines NMDA-R modulators, mQluR modulators, dopamine modulators, serotonin modulators, canabinoid modulators, and cholinesterase inhibitors (e.g., donepezil, rivastigimine, and glanthanamine). In such combinations, each active ingredient can be administered either in accordance with their usual dosage range or a dose below their usual dosage range.
The compounds of the invention can be used in conjunction with "positive modulators" which enhance the efficacy of nicotinic receptor agonists. See, e.g., the positive modulators disclosed in WO 99/56745, WO 01/32619, and WO 01/32622. Such combinational therapy can be used in treating conditions/diseases associated with reduced nicotinic transmission.
Further the compounds may be used in conjunction with compounds that bind to Ap peptides and thereby inhibit the binding of the peptides to aTnAChr subtypes. See, e.g., WO 99/62505.
The present invention further includes methods of treatment that involve activation of o>7 nicotinic receptors. Thus, the present invention includes methods of selectively activating/stimulating a-7 nicotinic receptors in animals, e.g., mammals, especially humans, wherein such activation/stimulation has a therapeutic effect, such as where such activation may relieve conditions involving neurological syndromes, such as the loss of memory, especially long-term memory. Such methods comprise administering to an animal in need thereof, especially a mammal, most especially a human, an effective amount of a compound of Formulas I-III, alone or as part of a formulation, as disclosed herein.
In accordance with a method aspect of the invention, there is provided a method of treating a patient (e.g., a mammal such as a human) suffering from a disease state (e.g., memory impairment) comprising administering to the patient a compound according to Formulas I, II or III. Preferably, the disease state involves decreased nicotinic acetylcholine receptor activity.
In accordance with a method aspect of the invention there is provided a method for the treatment or prophylaxis of a disease or condition resulting from dysfunction of nicotinic acetylcholine receptor transmission in a mammal, e.g. a human, comprising administering an effective amount of a compound according to Formulas I, II or HI.
In accordance with a method aspect of the invention there is provided a method for the treatment or prophylaxis of a disease or condition resulting from defective or malfunctioning nicotinic acetylcholine receptors, particularly aVnACh receptors, in a mammal, e.g. a human, comprising administering an effective amount of a compound according to Formulas I, II or III.
In accordance with a method aspect of the invention there is provided a method for the treatment or prophylaxis of a disease or condition resulting from suppressed nicotinic acetylcholine receptor transmission in'a mammal, e.g., a human, comprising administering an amount of a compound according to Formulas I, II or III effective to activate a7nACh receptors.
In accordance with another method aspect of the invention there is provided a method for the treatment or prophylaxis of a psychotic disorder, a cognition impairment (e.g., memory impairment), or neurodegenerative disease in a mammal, e.g., a human, comprising administering an effective amount of a compound according to Formulas I, II orlE.
In accordance with another method aspect of the invention there is provided a method for the treatment or prophylaxis of a disease or condition resulting from loss of cholinergic synapses in a mammal, e.g., a human, comprising administering an effective amount of a compound according to Formulas I, II or III.
In accordance with another method aspect of the invention there is provided a method for the treatment or prophylaxis of a neurodegenerative disorder by activation of
a7nACh receptors in a mammal, e.g., a human, comprising administering an effective amount of a compound according to Formulas I, II or III.
In accordance with another method aspect of the invention there is provided a method for protecting neurons in a mammal, e.g., a human, from neurotoxicity induced by activation of In accordance with toother method aspect of the invention there is provided a method for the treatment or prophylaxis of a neurodegenerative disorder by inhibiting the binding of Ap peptides to otVnACh receptors in a mammal, e.g., a human, comprising administering an effective amount of a compound according to Formulas I, II or HI.
In accordance with another method aspect of the invention there is provided a method for protecting neurons in a mammal, e.g., a human, from neurotoxicity induced by Ap peptides comprising administering an effective amount of a compound according to Formulas I, II or III.
In accordance with another method aspect of the invention there is provided a method for alleviating inhibition of cholinergic function induced by Ap peptides in a mammal, e.g., a human, comprising administering an effective amount of a compound according to Formulas I, II or IH
The compounds of the present invention are nicotinic alpha-7 ligands, preferably agonists, especially partial agonists, for the alpha-7 nicotinic acetylcholine receptor. Assays for determining nicotinic acetylcholine activity are known within the art. See, e.g., Davies, A.R., et al., "Characterisation of the binding of [3H]methyllycaconitine: a new radioligand for labelling alpha 7-type neuronal nicotinic acetylcholine receptors," Neuropharmacology, 1999.38(5): p. 679-90. As agonists for a-7 nAChRs, the compounds are useful in the prophylaxis and treatment of a variety of diseases and conditions associated with the central nervous system. Nicotinic acetylcholine receptors
are ligand-gastrol ion-channel receptors that are composed of five subunit proteins that form a central ion-conducting pore. Presently, there are eleven known neuronal nAChR subunits (o2 - a9 and (32 - p4). There are also five further subunits expressed in the peripheral nervous system (al, pi, y, 8, &).
The nAChR receptor subtypes can be homopentameric or heteropentameric. The subtype which has received considerable attention is the homopentameric a? receptor subtype formed from five a7 subunits. The a7nAChRs exhibit a high affinity for nicotine (agonist) and for a-bungarotoxin (antagonist). Studies have shown the a7-nAChR agonists can be useful in the treatment of psychotic diseases, neurodegenerative diseases, and cognitive impairments, among other things. While nicotine is a known agonist, there is a need for the development of other a7-nAChR agonists, especially selective agonists that are less toxic or exhibit fewer side effects than nicotine.
The compound anabaseine, i.e., 2-(3-pyridyl)-3,4,5,6-teti'ahydropyridine is a
naturally occurring toxin in certain marine worms (nemertine worms) and ants. See, e.g.,
Kern et al., Toxicon, 9:23,1971. Anabaseine is a potent activator of mammalian ,
nicotinic receptors. See, e.g., Kem, Amer. Zoologist, 25,99,1985. Certain anabaseine analogs such as anabasine and DMAS (3-[4-(dimethylamino)benzylidene]-3,4,5,6-tetrahydro-2',35-bipyridine) are also known nicotinic receptor agonists. See, e.g., US 5,602,257 and WO 92/15306. One particular anabaseine analog, (E-3-[2,4-dimethoxy-benzylidene]-anabaseine, also known as GTS-21 and DMXB (see, e.g., US 5,741,802), is a selective partial a7-nAChR agonist that has been studied extensively. For example, abnormal sensory inhibition is a sensory processing deficit in schizophrenics and GTS-21 has been found to increase sensory inhibition through interaction with ct7-nAChRs. See, e.g., Stevens et al., Psychopharmacology, 136: 320-27 (1998).
Another compound which is known to be a selective a7-nAChR agonist is Tropisetron, i.e., loH, 5oH-tropan-3a-yl indole-3-carboxylate. See J. E. Macor et al., "The 5-HT3-Antagonist Tropisetron (ICS 205-930) is a Potent and Selective A7 Nicotinic Receptor Partial Agonist," Bioorg. Med. Chem. Lett. 2001,319-321).
Agents that bind to nicotinic acetylcholine receptors have been indicated as useful in the treatment and/or prophylaxis of various diseases and conditions, particularly psychotic diseases, neurodegenerative diseases involving a dysfunction of the cholinergic system, and conditions of memory and/or cognition impairment, including, for example, schizophrenia, anxiety, mania, depression, manic depression [examples of psychotic disorders], Tourette's syndrome, Parkinson's disease, Huntington's disease [examples of neurodegenerative diseases], cognitive disorders (such as Alzheimer's disease, Lewy Body Dementia, Amyotrophic Lateral Sclerosis, memory impairment, memory loss, cognition deficit, attention deficit, Attention Deficit Hyperactivity Disorder), and other uses such as treatment of nicotine addiction, inducing smoking cessation, treating pain (i.e., analgesic use), providing neuroprotection, treating jetlag, inflammation, or sepsis. See, e.g., WO 97/30998; WO 99/03850; WO 00/42044; WO 01/36417; Holladay et al., J.Med. Chem., 40:26,4169-94 (1997); Schmitt et al., Annual Reports Med. Chem., Chapter 5,41-51 (2000); Stevens et al., Psychopharmatology, (1998) 136: 320-27 (1998); and Shytle et al., Molecular Psychiatry, (2002), 7, pp. 525-535.
Thus, in accordance with the invention, there is provided a method of treating a patient, especially a human, suffering from psychotic diseases, neurodegenerative diseases involving a dysfunction of the cholinergic system, and conditions of memory and/or cognition impairment, including, for example, schizophrenia, anxiety, mania, depression, manic depression [examples of psychotic disorders], Tourette's syndrome, Parkinson's disease, Huntington's disease [examples of neurodegenerative diseases], and/or cognitive disorders (such as Alzheimer's disease, Lewy Body Dementia, Amyotrophic Lateral Sclerosis, memory impairment, memory loss, cognition deficit, attention deficit, Attention Deficit Hyperactivity Disorder) comprising administering to the patient an effective amount of a compound according to Formulas I-III.
Neurodegenerative disorders included within the methods of the present invention include, but are not limited to, treatment and/or prophylaxis of Alzheimer's diseases, Pick's disease, diffuse Lewy Body disease, progressive supranuclear palsy (Steel-
Richardson syndrome), multisystem degeneration (Shy-Drager syndrome), motor neuron diseases including amyotrophic lateral sclerosis, degenerative ataxias, cortical basal degeneration, ALS-Parkinson's-Dementia complex of Guam, subacute sclerosing panencephalitis, Huntington's disease, Parkinson's disease, synucleinopathies, primary progressive aphasia, striatonigral degeneration, Machado-Joseph disease/spinocerebellar ataxia type 3, olivopontocerebellar degenerations, Gilles De La Tourette's disease, bulbar, pseudobulbar palsy, spinal muscular atrophy, spinobulbar muscular atrophy (Kennedys disease), primary lateral sclerosis, familial spastic paraplegia, Werdnig-Hoffmann disease, Kugelberg-Welander disease, Tay-Sach's disease, Sandhoff disease, familial spastic disease, Wohlfart-Kugelberg-Welander disease, spastic paraparesis, progressive multifocal leukoencephalopathy, prion diseases (such as Creutzfeldt-Jakob, Gerstmann-Straussler-Scheinker disease, Kuru and fatal familial insomnia), and neurodegenerative disorders resulting from cerebral ischemia or infarction including embolic occlusion and thrombotic occlusion as well as intracranial hemorrhage of any type (including, but not limited to, epidural, subdural, subarachnoid and intracerebral), and intracranial and intravertebral lesions (including, but not limited to, contusion, penetration, shear, compression and laceration).
In addition, a-7nAChRs agonists, such as the compounds of the present invention can be used to treat age-related dementia and other dementias and conditions with memory loss including age-related memory loss, senility, vascular dementia, diffuse white matter disease (Binswanger's disease), dementia of endocrine or metabolic origin, dementia of head trauma and diffuse brain damage, dementia pugilistica and frontal lobe dementia. See, e.g., WO 99/62505. Thus, in accordance with the invention, there is provided a method of treating a patient, especially a human, suffering from age-related dementia and other dementias and conditions with memory loss comprising administering to the patient an effective amount of a compound according to Formulas I-M.
Thus, in accordance with a further embodiment, the present invention includes methods of treating patients suffering from memory impairment due to, for example, mild cognitive impairment due to aging, Alzheimer's disease, schizophrenia, Parkinson's
disease, Huntington's disease, Pick's disease, Creutzfeld-Jakob disease, depression, aging, head trauma, stroke, CNS hypoxia, cerebral senility, multiinfarct dementia and other neurological conditions, as well as HTV and cardiovascular diseases, comprising administering an effective amount of a compound according to Formulas I-III.
Amyloid precursor protein (APP) and Ap peptides derived therefrom, e.g., Api_42 . and other fragments, are known to be involved in the pathology of Alzheimer's disease. The Apuz peptides are not only implicated in neurotoxicity but also are known to inhibit cholinergic transmitter function. Further, it has been determined that Ap peptides bind to a-7 nAChRs. Thus, agents that block the binding of the Ap peptides to a-7 nAChRs are useful for treating neurodegenerative diseases. See, e.g., WO 99/62505. In addition, stimulation a-7 nAChRs can protect neurons against cytotoxicity associated with Ap peptides. See, e.g., Kihara, T. et al., Ann. Neurol., 1997, 42, 159.
Thus, in accordance with an embodiment of the invention there is provided 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 according to Formulas I-ni to inhibit the binding of an amyloid beta peptide (preferably, APM2) with nAChRs, preferable a-7 nAChRs, most preferably, human a-7 nAChRs (as well as a method for treating and/or preventing other clinical manifestations of Alzheimer's disease that include, but are not limited to, cognitive and language deficits, apraxias, depression, delusions and other neuropsychiatric symptoms and signs, and movement and gait abnormalities).
The present invention also provides methods for treating other amyloidosis diseases, for example, hereditary cerebral angiopathy, nonneuropathic hereditary amyloid, Down's syndrome, macroglobulinemia, secondary familial Mediterranean fever, Muckle-Wells syndrome, multiple myeloma, pancreatic- and cardiac-related amyloidosis, chronic hemodialysis anthropathy, and Finnish and Iowa amyloidosis.
In addition, nicotinic receptors have been implicated as playing, a role in the body's response to alcohol ingestion. Thus, agonists for a-7nAChR's can be used in the treatment of alcohol withdrawal and in anti-intoxication therapy. Thus, in accordance with an embodiment of the invention there is provided a method of treating a patient for alcohol withdrawal or treating a patient with anti-intoxication therapy comprising administering to the patient an effective amount of a compound according to Formulas I-
Agonists for the a-7nAChR subtypes can also be used for neuroprotection against damage associated with strokes and ischemia and glutamate-induced excitotoxicity. Thus, in accordance with an embodiment of the invention there is provided a method of treating a patient to provide for neuroprotection against damage associated with strokes and ischemia and glutamate-induced excitotoxicity comprising administering to the patient an effective amount of a compound according to Formulas I-HL
As noted above, agonists for the In addition, due to their affinity to The condition of memory impairment is manifested by impairment of the ability to learn new information and/or the inability to recall previously learned information. Memory impairment is a primary 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, cardiovascular disease, and head trauma as well as age-related cognitive decline.
Thus, in accordance with an embodiment of the invention there is provided a method of treating a patient suffering from, for example, mild cognitive impairment (MCI), vascular dementia (VaD), age-associated cognitive decline (AACD), amnesia associated w/open-heart-surgery, cardiac arrest, and/or general anesthesia, memory deficits from early exposure of anesthetic agents, sleep deprivation induced cognitive impairment, chronic fatigue syndrome, narcolepsy, ALDS-related dementia, epilepsy-related cognitive impairment, Down's syndrome, Alcoholism related dementia, drug/substance induced memory impairments, Dementia Puglistica (Boxer Syndrome), and animal dementia (e.g., dogs, cats, horses, etc.) patient comprising administering to the patient an effective amount of a compound according to Formulas I-III.
The dosages of the compounds of the present invention depend upon a variety of factors including the particular syndrome to be treated, the severity of the symptoms, the route of administration, the frequency of the dosage interval, the particular compound utilized, the efficacy, toxicology profile, pharmacokinetic profile of the compound, and the presence of any deleterious side-effects, among other considerations.
The compounds of the invention can be administered to mammals, particularly humans, at typical dosage levels customary for a-7 nicotinic receptor agonists such as the known a-7 nicotinic receptor agonist compounds mentioned above. For example, the compounds can be administered, in single or multiple doses, by oral administration at a dosage level of, for example, 0.0001-10 mg/kg/day, e.g., 0.01-10 mg/kg/day. Unit dosage forms can contain, for example, 1-200 mg of active compound. For intravenous administration, the compounds can be administered, in single or multiple dosages.
In carrying out the procedures of the present invention it is of course to be understood that reference to particular buffers, media, reagents, cells, culture conditions
and the like are not intended to be limiting, but are to be read so as to include all related materials that one of ordinary skill in the art would recognize as being of interest or value in the particular context in which that discussion is presented. For example, it is often possible to substitute one buffer system or culture medium for another and still achieve similar, if not identical, results. Those of skill in the art will have sufficient knowledge of such systems and methodologies so as to be able, without undue experimentation, to make such substitutions as will optimally serve their purposes in using the methods and procedures disclosed herein.
The present invention will now be further described by way of the following non-limiting examples. In applying the disclosure of these examples, it should be kept clearly in mind that other and different embodiments of the methods disclosed according to the present invention will no doubt suggest themselves to those of skill in the relevant art.
In the foregoing and in the following examples, all temperatures are set forth uncorrected in degrees Celsius; and, unless otherwise indicated, all parts and percentages are by weight.
The entire disclosures of all applications, patents and publications, cited above and below, are hereby incorporated by reference.
EXAMPLES
All spectra were recorded at 300 MHz on a Bruker Instruments NMR unless otherwise stated. Coupling constants (J) are in Hertz (Hz) and peaks are listed relative to IMS (8 0.00 ppm). Microwave reactions were performed using a Personal Chemistry Optimizer™ microwave reactor in 2.5 mL or 5 mL Personal Chemistry microwave reactor vials. All reactions were performed at 200 °C for 600 s with the fixed hold time ON unless otherwise stated. Sulfonic acid ion exchange resins (SCX) were purchased from Varian Technologies. Analytical HPLC was performed on 4.6 mm x 100 mm Xterra RP18 3.5 n columns using a gradient of 20/80 to 80/20 water (0.1% formic acid)/acetonitrile (0.1% formic acid) over 6 min unless stated otherwise.
Acid preparations;
The following procedures (1-10) detail the preparation of the indazole, benzisoxazole, and benzisothiazole acids that were not commercially available.
Procedure 1;
Procedure 1 provides a method for the preparation of 6-nitroindazole-3-acid and the coupling with bicyclobases to form nitro-substirated derivatives.
A 5 mL microwave reaction vessel was charged with 3-iodo-6-nitroindazole (1 mmol), copper (I) cyanide (2 mmol) and JVA'-dimethylformamide (3 mL). The vessel was sealed and subjected to microwave irradiation at 185 °C for 600 sec. The reaction mixture was partitioned between ethyl acetate (100 mL) and water (100 mL) and the mixture was filtered through Celite. The organic layer was collected, washed with brine, dried (magnesium sulfate), and concentrated to give 122 mg of a 10/1 mixture of 3-cyano-6-nitroindazole and 6-nitroindazole as a yellow solid. The 10/1 mixture of 3-cyano-6-nitroindazole and 6-nitroindazole was dissolved in 10 N sodium hydroxide and the bright orange solution was heated at 100 °C for 1 h. The mixture was allowed to cool to room temperature and carefully acidified (pH = 1) with 3 N hydrochloric acid. The solid was isolated and triturated with EtOAc to provide 51mg of 6-nitroindazole-3-carboxylic acid as a brown solid. The acid was coupled with the bicyclobase according to procedure A.
The following acid was prepared using this method: 6-Nitro-lfi"-indazole-3-carboxylic acid.
Procedure 2;
Procedure 2 provides a method for the nitration of indazole acid and the coupling with bicyclobases to form nitro-substituted derivatives.
Ethyl indazole-3-carboxylate (73.7 mmol) was dissolved in 20 mL concentrated sulfuric acid and the reaction mixture was cooled to 0 °C. A mixture of concentrated sulfuric acid (12 mL) and 70% nitric acid (12 mL) was added dropwise over the course of 1 h. The mixture was stirred for an additional 1 h at 0 °C and was poured onto of crushed ice (200 g). The solid was collected by vacuum filtration, washed with several portions of water and dried in vacuo. The dried solid was suspended in 250 mL acetonitrile and the mixture was heated at reflux for 2 h. The mixture was allowed to cool to room temperature and the solid was collected and dried in vacuo to provide ethyl 5-nitroindazole-3-carboxylate (53%) as a colorless solid. The acid, obtained by basic hydrolysis, was coupled with the bicyclobase according to procedure A.
Literature reference: Ore. Synthesis. Coll. Vol. 1. page 372.
The following acid were prepared using this method: 5-Nitro-l//-indazole-3-carboxylicacid.
Procedure 3;
Procedure 3 provides a method for the trapping of indazole aryllithiums with ketones and the coupling with bicyclobases to form heterocyclic derivatives.
tert-Butyl 6-bromoindazole-3-carboxylate was prepared from the acid by reaction with a 2-fold excess of di-tert-butyldicarbonate followed by treatment with sodium hydroxide. To a suspension of sodium hydride (60% mineral oil dispersion) (4.8 mmol) hi tetrahydrofuran (40 mL) at 0 °C was slowly added a solution of tert-butyl 6-bromoindazole-3-carboxylate (4.0 mmol) in tetrahydrofuran (4 mL). After stirring for 0.5 h at 0 °C, the mixture was cooled to -78 °C and a 1.7 M solution of tert-butyllithium in pentane (5.1 mmol) was added. After 0.5 h at -78 °C, a solution of tetrahydropyran-4-one (5 mmol) in tetrahydrofuran (1 mL) was added dropwise. The mixture was stirred at -78 °C for 1 h and warmed to 0 °C. The reaction mixture was quenched with saturated aqueous ammonium chloride and the mixture was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was separated, washed with brine (50 mL),
dried (magnesium sulfate), and concentrated. The residue was purified by chromatography (70/30 ethyl acetate/hexanes) to yield 6-(4-hydroxytetrahydropyran-4-yl)-l#-indazole-3-carboxylic acid tert-butyl ester (68%) as a colorless solid.
6-(4-Hydroxytetrahydropyran-4-yl)-lJy-indazole-3-carboxylic acid tert-butyl ester (0.86 mmol) was dissolved in trifluoroacetic acid (3 mL) and the mixture was maintained at room temperature for 16 h. The solvent was removed in vacua and the residue was triturated with ethyl acetate to provide 6-(3,6-dmydro-2#-pyran-4-yl)-l#-indazole-3-carboxylic acid (76%). The acid was coupled with the bicyclobase according to procedure A.
6-(4-Hydroxytetrahydropyran-4-yl)-l^/-rndazole-3-carboxylic acid tert-butyl ester (1.0 mmol) was dissolved in trifluoroacetic acid (5 mL), triethylsilane (2 mL), and dichloromethane (3 mL) and the mixture was refluxed for 16 h. The solvent was removed in vacua and the residue was triturated with ethyl acetate to provide 6-(tetrahydropyran-4-yl)-l#-mdazole-3-carboxylic acid (60%) as a tan solid. The acid was coupled with the bicyclobase according to procedure A.
The following acids were prepared using this method:
6-(3,6-Dihydro-2/f-pyran-4-yl)-lffindazole-3-carboxylicacid.
6-(Tetxahydro-2/f-pyran-4-yl)-l£r-indazole-3-carboxylicacid.
Procedure 4:
Procedure 4 provides a method for the conversion of substituted isatrns to the corresponding indazole-3-carboxylic acids.
The conversion of the substituted isatins to the corresponding indazole-3-carboxylic acids is essentially the same method as described for indazole-3-carboxylic acid: Snyder, H.R., et. al. J. Am. Chetn. Soc. 1952, 74, 2009. The substituted isatin (22.1 mmol) was diluted with 1 N sodium hydroxide (24 mL) and was heated at 50 °C for 30 min. The burgundy solution was allowed to cool to rt and was maintained for Ih. The reaction mixture was
cooled to 0 °C and was treated with a 0 °C solution of sodium nitrite (22.0 mmol) in water (5.5 mL). This solution was added through a pipet submerged below the surface of a vigorously stirred solution of sulfuric acid (2.3 mL) in water (45 mL) at 0 °C. The addition took 15 min and the reaction was maintained for an additional 30 min, A cold (0 °C) solution of tin (II) chloride dihydrate (52.7 mmol) in concentrated hydrochloric acid (20 mL) was added to the reaction mixture over 10 min and the reaction mixture was maintained for 60 min. The precipitated solids were isolated by filtration, washed with water, and dried to give a quantitative mass balance. This material was of sufficient purity (!H NMR and LC/MS) to use in the next step without further purification. Alternatively, the acid was recrystallized from acetic acid to provide pure material.
The following acids were prepared using this method:
5-Bromoindazole-3-acid.
6-Bromoindazole-3 -acid.
5-Trifluoromethoxyindazole-3-acid.
6-Trifiuoromethylindazole-3-acid.
5-Methoxyindazole-3-acid.
Procedure 5;
Procedure 5 provides a preparation of 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 at reflux for 1.5 h, cooled to rt, and concentrated in vacua. The resulting yellow oil was dissolved in dichloromethane (50 mL), cooled to 0 °C, and was treated with aluminum chloride (4.30 g, 32.0 mmol) in portions. The mixture was heated at reflux for 30 min, cooled to rt, and poured onto ice water with stirring. The organic layer was separated and successively washed with saturated, aqueous sodium bicarbonate, water, and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was
purified by chromatography (4/1 ethyl acetate/hexane) which provided 2.46 g (47%) of 6-methoxy-l-benzothiophene-2,3-dione as an orange solid.
To a mixture of the dione (86 mg, 0.44 mmol) in 30% aqueous solution of ammonium hydroxide (2.0 mL) was added 35% aqueous solution hydrogen peroxide (0.2 mL) and the reaction mixture was maintained for 12 h. The precipitated pink solids were isolated by filtration, washed with water, and dried under high vacuum to afford 39 mg (42%) of 6-methoxybenzisothiazole-3-carboxamide.
To a solution of the amide (1.14 g, 5.46 mmol) in methanol (100 mL) was added ION sodium hydroxide (12 mL). The mixture was heated at reflux for 12 h, cooled to rt, and was acidified to pH The following acids were prepared by this method: Benzo[(f]isothiazole-3-carboxylic acid. 6-Bromobenzo[d]isothiazole-3-carboxylic acid. 5-Bromobenzo[d]iso1;hiazole-3-carboxylicacid. 5-Methoxybenzo[d]isotbiazole-3-carboxylic acid. 6-Memoxybenzo[ Procedure 6;
Procedure 6 provides a method for the coupling between brominated benzisothiazole-3-carboxylic esters and brominated indazole-3-carboxylic esters and Grignard reagents to form alkyl- and heterocycle-substituted acids.
A 0.5 M solution of cyclopropylmagnesium bromide (25.0 mmol, 3.7 eq) in tetrahydrofuran was diluted with tetrahydrofuran (60 mL) and treated with a 0.5 M solution of zinc chloride (25.0 mmol, 3.7 eq) in tetrahydrofuran at rt. After 10 min, the brominated ethyl benzisotbiazole-3-carboxylate (0.30 mmol) and Ms(triphenylphospMne)paUadium (n) chloride (0.95 mmol, 0.1 eq) were added to the suspension. The reaction mixture was maintained for 1 h at ambient temperature then at 65 °C for 1 h. The reaction was quenched with saturated ammonium chloride and was extracted with dichloromethane (3 x). The extracts were dried over sodium sulfate and concentrated to dryness. The residue was purified by chromatography using a gradient of 100/0 to 90/10 dichloromethane/methanol to provide the cyclopropyl-substituted amide. The amide was dissolved in a mixture of methanol/tetrahydrofuran/water (90/10/20 mL) and was treated with sodium hydroxide (5.8 g). The mixture was heated at reflux for 12 h, cooled to rt, filtered, and was acidified to pH This procedure was used, with slight modifications, to derivatize brominated indazole-3-piperidine carboxamides with various Grignard reagents. The Grignard reagent of thiazole is commercially available. Alternatively, the aryllithium and the corresponding arylzinc reagent can be generated according to the procedure outlined by Reeder, M.R.; et. al. Org. Proc. Res. Devel. 2003, 7, 696. The zinc reagents of oxazole, 4-methylthiazole, and 5-methylthiazole were prepared according to this procedure.
The following acids were prepared using this method: 6-Cyclopropylbenzo [rf]isothiazole-3 -carboxylic acid. 6-(l,3-Tbiazol-2-yl)-lH-indazole-3-carboxylicacid. 5-(l,3-TMazol-2-yl)-l#-indazole-3- carboxylic acid. 5-(4-Methyl-l,3-thiazol-2-yl)-l/f-indazole-3- carboxylic acid. 5-(5-Methyl-l,3-thiazol-2-yl)-l/f-indazole-3- carboxylic acid. 6-(4-Methyl-l,3-thiazol-2-yl)-lff-indazole-3- carboxylic acid.
6-(5-Methyl-l,3-tfuazol-2-yl)-l#-indazole-3- carboxylic acid. 6-(l,3-Oxazol-2-yl)-l#-indazole-3- carboxylic acid.
Procedure 7;
Procedure 7 provides a method for the preparation of 7-fluoro-6-methoxy-l^-indazole-3 -carboxylic acid.
l-Chloromethyl-4-fiuoro-l,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (1.00 g, 2.82 mmol) was added to a solution of ethyl 6-methoxy-l/f-mdazole-3-carboxylate (500 mg, 2.27 mmol) in acetonitrile (15.0 mL) and the reaction mixture was maintained at rt for 18 h. The reaction was partitioned between water (50 mL) and ethyl acetate (50 mL) and the separated organic layer was washed with brine (25 mL), dried (magnesium sulfate), and concentrated. The residue was purified by chromatography (95/5 to 80/20 hexanes/ethyl acetate) to yield 541 mg (23%) of the fluorinated ester. A solution of the ester (124 mg, 0.520 mmol) in ethanol (5.00 mL) was diluted with 5.0 M of sodium hydroxide (2.00 mL) and the mixture was maintained at rt for 18 h. The reaction was acidified with 6 N hydrochloric acid and partitioned between water (50 mL) and ethyl acetate (50 mL). The layers were separated and the organic washed with brine (25 mL), dried (magnesium sulfate), and concentrated in vacuo to yield 109 mg (84%) of the acid. The acid was coupled with the bicyclobase according to procedure A.
The following acid was prepared using this method: 7-Fluoro-6-methoxy-1 #-indazole-3 -carboxylic acid.
Procedure 8;
Procedure 8 details the preparation of benzisoxazole-3-carboxylic acid from 2,5-dibromonitrobenzene.
Diethyl malonate (12.6 g, 79 mmol) was added to a suspension of sodium hydride (3.16 g, 132 mmol) in dimethylsulfoxide (60 ml) over 30 min. The temperature of the reaction rose to 60 °C and the mixture clarified. l,4-Dibromo-2-nitrobenzene (10 g, 36.0 mmol)
was added and the solution was maintained for 2 h at 100 °C. The reaction mixture was allowed to cool to rt and was poured into ice (300g-400g). The precipitated solids were isolated by filtration and dried to provide 11.0 g of the product (89%).
The ester (11.0 g, 32.0 mmol) was diluted with a 2 N solution of sodium hydroxide (32 mL, 63 mmol) and the reaction mixture was maintained at room temperature for 16 h. The aqueous layer was extracted with dichloromethane (20 mL) and was acidified. The precipitated solids were isolated by filtration and dried to provide 7.00 g of the acid (89%).
Sulfuric acid (1 mL) was added to a solution of the acid (7.00 g, 27.0 mmol) in ethanol (60 ml). The reaction mixture was warmed to reflux, maintained for 2 h, and was concentrated under reduce pressure. The residue was partitioned between ethyl acetate (250 mL) and saturated sodium carbonate (50 mL) and the organic layer was washed with saturated sodium carbonate (50 mL) and brine (50 mL). The organic layer was dried (sodium sulfate) and concentrated to provide 8.00 g (98%) of the. ester as a liquid.
Under Nj atmosphere, sodium ethylate was formed with sodium (33.5 g, 1.46 mol) in ethanol (l.OL).
Isoamylnitrite (225 mL) was added to a solution of the ester (420 g, 1.46 mol) in ethanol (3 L) in a 10 L three-necked round bottom flask and the mixture was warmed to 60 °C. A solution of sodium ethoxide, prepared from sodium metal (33.5 g, 1.46 mmol) in ethanol (1 L) was added dropwise and the reaction mixture was maintained for 2 h. The reaction mixture was allowed to cool to rt and was neutralized with 2 N hydrochloric acid. The reaction mixture was extracted with ethyl acetate (4 x 2L) and the combined organic layers were washed with water (2 x 1 L) and brine (2 x 1 L) and dried (sodium sulfate). The residue was purified by chromatography (1/1 to 0/1 hexane/ethyl acetate) to provide 110 g of the product (28%).
10% Palladium on carbon (1.5g) and triethylamine (7.5 g, 82.4 mmol) were added to a solution of ethyl 6-bromobenzisoxazole-3-carboxylate (20g, O.OSlmol) in ethanol
(300ml) at 0 °C under an atmosphere of nitrogen. The nitrogen atmosphere was removed by evacuation and replaced with hydrogen gas, and the reaction mixture was maintained for 1 hour. The hydrogen atmosphere was removed by evacuation and replaced with nitrogen gas, and the palladium removed by filtration through Celite. The filter cake was washed with ethanol (3 x 50 mL) and the filtrates were concentrated. The residue was dissolved hi dichloromethane' (200 mL) and the solution was washed with water (4 x 50 mL), dried (sodium sulfate) and evaporated to provide 13.0 g of the product as a yellow solid (96%). The ester was saponified using sodium hydroxide to provide the acid. The acid was coupled with the bicyclobase according to procedure A.
Literature reference: Angell, R.M.; Baldwin, I.R.; Bamborough, P.; Deboeck, N.M.; Longstaff, T.; Swanson, S. W004010995A1
The following acid was prepared using this method: l,2-Benzisoxazole-3-carboxylic acid.
Procedure 9;
Procedure 9 provides a method for the preparation of 5-difluoromethoxyindazole-3-acid from 3-bromo-4-nitrophenol.
3-Bromo-4-nitrophenol (10.0 mmol) was added to a suspension of sodium hydroxide (29.0 mmol) in N,AWimethylformamide (15 mL) and the suspension was maintained for 15 min at rt. The reaction mixture was cooled to 0 °C and was treated with ethyl chlorodifluoroacetate (20.0 mmol). The reaction mixture was heated at 70 °C for 16 h and was concentrated. The residue was diluted with ice water (200 mL) and was extracted with ethyl acetate (3x100 mL). The combined organic layers were dried (magnesium sulfate) and concentrated to provide the difluoromethyl ether in 75% yield as a yellow oil.
Diethyl malonate (328 mmol) was added dropwise to a suspension of sodium hydride (328 mmol) in dimethylsulfoxide (40 mL) at 0 °C. The reaction mixture was warmed to
60 °C and maintained for 0.5 h. A solution of the difluoromethyl ether (149 mmol) in dimethylsulfoxide (80 mL) was added dropwise and the reaction mixture was heated at 100 °C for 5 h. The cooled solution was poured onto ice water, and the aqueous layer was extracted with dichloromethane (3x100 mL). The combined organic layers were dried (magnesium sulfate) and concentrated to give the crude diester in 112% yield as an oil. The diester (167 mmol), sodium hydroxide (500 mmol), and water (335 mL) were combined and heated at 60 °C for 1 h. The reaction mixture was allowed to cool to rt and the aqueous layer was washed with dichloromethane (3x100 mL), The pH of the aqueous layer was cautiously adjusted to 1 with concentrated hydrochloric acid and the reaction mixture was heated at 60 °C for 1 h. The suspension was cooled to 5 °C and the solids were collected by filtration and dried to provide the acid in 61% yield.
Acetyl chloride (203 mmol) was added dropwise to ethanol (300 mL) at 0 °C. After 0.5 h, the acid (101 mmol) was added and the reaction mixture was heated at reflux for 15 h. The reaction mixture was concentrated and the residue was partitioned between dichloromethane (200 mL) and saturated sodium bicarbonate (100 mL). The aqueous layer was further extracted with dichloromethane (2x200 mL) and the combined organic layers were dried (magnesium sulfate) and concentrated to provide 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 was treated with ammonium chloride (243 mmol) and iron powder (301 mmol). The reaction mixture was heated at reflux for 10 minutes and the suspension was filtrated through Celite and the filter cake was washed with ethanol three times. The filtrate was concentrated, the residue was suspended in 2 N hydrochloric acid and was stirred vigorously for 0.5 h. The aqueous layer was washed with ethyl acetate (3x50mL) and the pH adjusted to 9-10 with 5 M sodium hydroxide. The aqueous layer was extracted with chloroform (3xlOOmL) and the combined organic layers were dried (magnesium sulfate). Acetic anhydride (392 mmol), isoamyl nitrite (291 mmol), and potassium acetate (51.0 mmol) were added to the organic layer and the suspension was heated at reflux for 16 h. The solution was evaporated and the residue was partitioned between saturated sodium
bicarbonate (50 mL) and dichloromethane (100 mL). The aqueous layer was further extracted with dichloromethane (2x100 mL) and the combined organic layers were dried (magnesium sulfate) and concentrated to provide the JV-acetylindazole ester in 79% yield as a brown oil.
The ester (63.8 mmol), sodium hydroxide (193 mmol), and water (65 mL) were combined and the reaction was maintained for 24 h at 60 °C. After cooling to rt, the aqueous layer was washed with dichloromethane (3x50mL). The aqueous layer was adjusted to pH 1 with concentrated hydrochloric acid. The precipitated solids were collected by filtration, washed with water and dichloromethane, and dried to provide the acid in 27% yield.
The following acids were prepared according to this method: 5-(Difluoromethoxy)-l/f-indazole-3-carboxylicacid.
Procedure 10;
Procedure 10 provides a method for the preparation of 6-difluoromethoxyindazole-3-acid from 4-nitrophenol.
4-Nitrophenol (162 mmol) was added to a suspension of sodium hydroxide (485 mmol) in A^JV-dimethylformamide (150 mL) and the suspension was maintained for 15 min at rt. The reaction mixture was cooled to 0 °C and was treated with ethyl chlorodifluoroacetate (329 mmol). The reaction mixture was heated at 70 °C for 16 h and was concentrated. The residue was diluted with ice water (200 mL) and was extracted with ethyl acetate (3x100 mL). The combined organic layers were dried (magnesium sulfate) and concentrated to provide the difluoromethyl ether in 59% yield as a yellow oil.
The nitro ether (149 mmol) was dissolved in ethanol (37.5 mL), diluted with water (25 mL), and was treated with ammonium chloride (84.7 mmol) and iron powder (105 mmol). The reaction mixture was heated at reflux for 30 minutes and the suspension was
filtered through Celite. The filter cake was washed with ethanol three times and the combined filtrates were concentrated. The residue was dissolved in water and the pH adjusted to 9-10 with 5 M sodium hydroxide. The aqueous layer was extracted with ethyl acetate (SxlOOmL) and the combined organic layers were dried (magnesium sulfate) and concentrated to a yellow oil. The oil was dissolved in acetic anhydride (23.5 mmol) and the reaction mixture was maintained at rt for 16 h. The reaction mixture was diluted with water (50 mL) and was neutralized with solid sodium bicarbonate. The precipitated solids were isolated by filtration, washed with water, and dried to provide the acetamide in 62% yield as a light yellow solid.
Acetic anhydride (19.6 mmol) was added to a solution of the acetamide (13.2 mmol) in chloroform (20 mL) and the reaction mixture was warmed to reflux. Fuming nitric acid (16.0 mmol) was added dropwise and the reaction mixture was maintained at reflux for 30 min. The cooled solution was diluted with water (20 mL) and the aqueous layer was extracted with dichloromethane (3x1 OmL). The combined organic layers were dried (magnesium sulfate) and concentrated to provide the nitro- amide in 83% yield.
The amide (11.0 mmol), sodium hydroxide (43.8 mmol), and water (10 mL) were combined and the reaction mixture was maintained for 1.5 hour at 60 °C. the reaction was allowed to cool to rt and the precipitated solids were isolated by filtration, and washed with water, and dried to provide the aniline in 98% yield as a light yellow solid.
The aniline (15.7 mmol) was mixed with 40% hydrobromic acid (14.3 g) and water (10 mL) and the reaction mixture was warmed to 80-90 °C in order to completely dissolve the aniline. The reaction mixture was cooled to 0 °C and a solution of sodium nitrite (23.2 mmol) in water (5.3 mL) was added during a 15 min period. The solution was maintained for 40 minutes at 0-5 °C and filtered. Copper (I) bromide (18.8 mmol) was dissolved in 40% hydrobromic acid (21 mL) and was cooled to 0 °C. The solution of the diazo salt was added slowly to the copper solution and the mixture was maintained for 30 min at 0-10 °C. The reaction mixture was heated at 60 °C for 30 min and then at 100 °C for 10 min to ensure completion. The reaction mixture was allowed to cool to it and was
extracted with dichloromethane (3x40mL). The combined organic layers were washed with 1 M sodium hydroxide, water, 1 N hydrochloric acid, and water. The organic layer was dried (magnesium sulfate) and concentrated to provide the nitro bromide in 76% yield as a light yellow solid,
Diethyl malonate (25.7 mmol) was added dropwise to a suspension of sodium hydride (25.8 mmol) in dimethylsulfoxide (5 mL) at 0 °C. The reaction mixture was warmed to 60 °C and maintained for 30 min. A solution of the nitro bromide (11.7 mmol) in dimethylsulfoxide (7 mL) was added dropwise and the reaction mixture was heated at 100 °C for 5 h. The cooled solution was poured onto ice water and the aqueous layer was extracted with dichloromethane (3x100 mL). The combined organic layers were dried (magnesium sulfate) and concentrated to give the crude diester as an oil. The diester (11.7 mmol), sodium hydroxide (35 mmol), and water (20 mL) were combined and heated at 60 °C for 1 h. The reaction mixture was allowed to cool to rt and the aqueous layer was washed with dichloromethane (3x100 mL). The pH of the aqueous layer was cautiously adjusted to 1 with concentrated hydrochloric acid and the reaction mixture was heated at 60 °C for 1 h. The suspension was cooled to 0 °C and the solids were collected by filtration and dried to provide the acid in 64% yield.
Acetyl chloride (15.3 mmol) was added dropwise to ethanol (50 mL) at 0 °C. After 30 min, the acid (7.69 mmol) was added and the reaction mixture was heated at reflux for 15 h. The reaction mixture was concentrated and the residue was partitioned between dichloromethane (20 mL) and saturated sodium bicarbonate (10 mL). The aqueous layer was further extracted with dichloromethane (2x20 mL) and the combined organic layers were dried (magnesium sulfete) and concentrated to provide the ester in 94% yield as a brown oil.
Acetic anhydride (6.0 mL) was added to a suspension of the ester (3.64 mmol), and acetic acid (7.0 mL) at 0 °C. Zinc dust (14.6 mmol) was added in portions over 15 min and the reaction mixture was maintained for 30 min at 0 °C and then for 1.5 h at rt. Additional zinc powder (6.15 mmol) was added and the reaction maintained for 3 h. The suspension
was filtered through Celite and the filtrate was concentrated. The residue was partitioned between saturated sodium bicarbonate (10 mL) and ethyl acetate (20 mL). The aqueous layer was further extracted with ethyl acetate (3x20mL) and the combined organic layers were dried (magnesium sulfate) and concentrated to provide the acetamide in 92% yield as a brown oil.
Acetic anhydride (13.7 mmol), isoamyl nitrite (13.7 mmol), and potassium acetate (2.04 mmol) were added to a solution of the acetamide (3.92 mmol) in chloroform (20 mL) and the suspension was heated at reflux for 16 h. The solution was evaporated and the residue was partitioned between saturated sodium bicarbonate (10 mL) and dichloromethane (20 mL). The aqueous layer was further extracted with dichloromethane (2x20 mL) and the combined organic layers were dried (magnesium sulfate) and concentrated to provide the crude N-acetylindazole ester as a brown oil.
The ester (3.36 mmol), sodium hydroxide (10 mmol) and water (5 mL) were combined and the reaction was maintained for 24 h at 60 °C. After cooling to rt, the aqueous layer was washed with dichloromethane (3x30mL). The aqueous layer was adjusted to pH 1 with concentrated hydrochloric acid and the precipitated solids were collected by filtration, washed with water and dichloromethane, and dried to provide the acid in 26% yield.
The following acids were prepared according to this method: 6-(Difluoromethoxy)-lff-indazole-3-carboxylic acid.
Amine preparations; Procedure 11;
Procedure 11 details the preparation of 2-methyl-2,5-diazabicyclo[2.2.2]octane from diethyl 2,5-diaminohexanedioate.
Benzaldehyde (21.8 mmol) was added to a solution of diethyl 2,5-diaminohexanedioate dihydrochloride (10.0 mmol) in absolute ethanol (75 mL) and acetic acid (10 mL) at
room temperature. The resulting mixture was heated at 80 °C for 2 hours. The reaction mixture was allowed to cool to room temperature and sodium triacetoxyborohydride (54.2 mmol) was added in small portions. The resulting white suspension was maintained at RT for 16 h and was concentrated. The residue was diluted with water, cooled to 0 °C, and the pH adjusted to 9 with 1 N sodium hydroxide. The aqueous layer was extracted with ethyl acetate (3 x 100 mL) and the combined organic layers were washed with brine, dried (magnesium sulfate), and concentrated to provide 3.05 g of white solid. Sodium methoxide (25% by weight, 23 mmol) was added to a solution of the dibenzylamine in ethanol (200 mL) and the reaction mixture was heated at reflux for 16 h. The reaction mixture was cooled to RT and concentrated. The residue was diluted with ethyl acetate (200 mL), washed with 1 N hydrochloric acid, dried (magnesium sulfate) and concentrated to provide the bicyclic lactam in 47% yield as a colorless solid.
Sulfuric acid (15.8 mmol) was added drop wise to a stirred suspension of lithium aluminum hydride (31.6 mmol) in tetrahydrofuran (50 mL) under a nitrogen atmosphere. The mixture was maintained for 30 min and the supernatant was added drop wise to a solution of the bicyclic lactam (1.5 mmol) in tetrahydrofuran (50 mL) at 0 °C. The reaction mixture was allowed to warm to RT and maintained for 16 h. The reaction mixture was carefully quenched by the addition of solid sodium sulfate'decahydrate (2.5 g) in portions. The reaction mixture was diluted with 2 M sodium hydroxide (10 mL), filtered through Celite, and the filtrate was concentrated. The residue was diluted with 2 N hydrochloric acid (100 mL) and extracted with ethyl acetate. The pH of the aqueous layer was adjusted to 9 with 2 M sodium hydroxide and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried (magnesium sulfate), and concentrated. The resulting light yellow oil was then treated with methanolic hydrogen chloride, generated in situ by adding acetyl chloride (0.5 mL) to methanol (10 mL), at room temperature for 10 minutes. The volatiles were removed under reduced pressure to provide the bicyclic diamine dihydrochloride hi 92% yield as an off-white, foaming solid.
A suspension of the 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 maintained for 16 h. The catalyst was removed by filtration and the filter cake was washed with water. The filtrate was concentrated to provide the bicyclic diamine dihydrochloride in 88% yield as a colorless solid.
A solution of di-tert-butyldicarbonate (6.5 mmol) in isopropanol (15 mL) was added drop wise to a solution of the diamine (7.06 mrnol) in isopropanol (100 mL), water (35mL), and 1 M sodium hydroxide (6.5 mL) at 0 °C. The reaction mixture was maintained for 1.5 h at 0 °C and was concentrated to ~50 mL. The aqueous slurry was saturated with solid sodium chloride and the pH adjusted to 10 with 2 M sodium hydroxide. The aqueous layer was extracted with ethyl acetate (3 x 35 mL) and the combined organic layers were washed with brine and dried (magnesium sulfate). The volatiles were removed under reduced pressure to afford the 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). Solid sodium triacetoxyborohydride (5.94 mmol) was added in small portions to the reaction mixture after 10 min and the reaction mixture was maintained for 16 h. The reaction mixture was diluted with a 10% aqueous sodium, bicarbonate solution (100 mL) and was extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with brine, dried (magnesium sulfate), and concentrated to provide a light yellow residue. The residue was dissolved in dioxane (25 mL) and diluted with concentrated hydrochloric acid (12.5 mL). The volatiles were removed after 30 minutes, thus providing the mono-methyl bicyclic base in 40% yield as a colorless solid. The procedure for JV-methylation and removal of the carbamate protecting group was used for the production of 2-methyl-2,5-diazabicyclo[2.2.1]heptane dihydrochloride.
Literature references: Newman, H. J. Heterocydic Chern. 1974, 11, 449. Sturm, P.A.; Henry, D.W. J. Med. Cheat. 1974,17,481.
The following bases were prepared using this method: 2-Methyl-2,5-diazabicyclo[2.2.2]octanedihydrochloride.
Synthetic Procedures:
The following procedures (A-G) detail the preparation of the substituted bicyclobase derivatives.
Procedure A:
Procedure A provides a method for the coupling between bicyclobases and carboxylic acids to form carboxamide derivatives.
To a solution of carboxylic acid (1 mmol) in tetrahydrofuran (10 mL) and N,N-dimethylformamide (1 mL) was added ^Mdiisopropylethylamine (3 mmol) and bicyclobase amine dihydrochloride (1 mmol). The reaction mixture was maintained at room temperature for 30 min under nitrogen and then HATU (1.00 mmol) was added. After 18 h, the reaction mixture was partitioned between saturated aqueous potassium carbonate solution and 95/5 dichloromethane/methanol. The aqueous layer was extracted with 95/5 dichloromethane /methanol (2X), and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacua. The residue was purified by silica gel flash column chromatography using a mixture of [90/10/1 dichloromethane /methanol/ammonium hydroxide] as the eluent, thus providing the carboxamide product.
The following examples were prepared according to procedure A:
Example 1: 3-[(LS,45)-2,5-Diazabicyclo[2.2.1]hept-2-ylcarbonyl]-lflr-indazole hydrochloride.
(Figure Removed)

Prepared using Procedure A in 28% yield. 1H NMR (CD3OD) 6 8.22 (m, 1 H); 7.61 (m, 1 H); 7.45 (m, 1 H); 7.27 (m, 1 H); 3.82 (m, 1 H); 3.51 (m, 2 H); 2.30 (m, 1 H); 2.07 (m, 1 H). LC/MS (El) to 3.55 min, mfz 243
Example 2 : 3-(2,5-Diazabicyclo[2.2.2]oct-2-ylcarbonyl)-6-(l,3-thiazol-2-yl)-lfT-indazole hydrochloride.
(Figure Removed)


Prepared using Procedure A in 30% yield. LC/MS (El) to 3.04 min, mfa 340
Example 3: 3-(2,5-Diazabicyclo [2.2.2] oct-2-ylcarbonyl)-l.H-indazole hydrochloride.
(Figure Removed)

Prepared using Procedure A in 30% yield. LC/MS (El) to 2.85 min, m/z 257
Example 4: 3-[(5-Methyl-2,5-diazabicyclo[2.2.2]oct-2-yl)carbonyl]-lfr-indazole hydroformate.
(Figure Removed)

yield. LC/MS (El) tR 2.83 min, m/z 271 (MN-1).
Example 5: 3-[(5-Methyl-2,5-diazabicyclo[2.2.2]oct-2-yl)carbonyI]-6-(l,3-thiazol-2-yl)-l.H-iiidazole hydroformate.

(Figure Removed)

Prepared using Procedure A in 20% yield. LC/MS (El) tR 2.87 min, m/z 376
Example 6: 3-{[(15,45)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-l,2-benzisothiazole hydroformate.


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

Example 7: 3-{[(l>S,45)-5-Methyl-2,5-diazabicyclo[2.2.1]liept-2-yl]carbonyl}-l^-benzisothiazole.
(Figure Removed)

H

Prepared using Procedure A in 77% yield. LOMS (El) ft 2.75 min, m/z 274
Example 8: 3-{[(151,45)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-l,2-benzisoxazole hydroformate.
(Figure Removed)

Prepared using Procedure A in 20% yield. LC/MS (El) ft 3.48 min, m/z 258
Example 9: 3-{[(LS,45)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yllcarbonyl}-5-(l,3-thiazol-2-yl)-l£T-indazole hydroformate.

(Figure Removed)
Prepared using Procedure A in 25% yield. LC/MS (El) tR 2.87 min, m/z 340 (MH).
Example 10: 3-{ methyl-l53-thiazol-2-yl)-l#4ndazolehydroformate.

(Fiure Removed)
Prepared using Procedure A in 30% yield. LC/MS (El) fe 2.76 min, m/z 354
Example 11: methyl-l,3-thiazol-2-yl)-lJ3-indazolehydroformate.

Prepared using Procedure A in 30% yield. LC/MS (El) tR 2.9 min, m/z 354
Example 12: 3-{[(l1S',45)-5-Methyl-2,S-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(tetrahydro-2fl-pyran-4-yl)-lJ?-indazolehydroformate.

Prepared using Procedure A in 25% yield. LC/MS (El) fo 2.85 min, m/z 339
Example 13: (trifluoromethoxy)4ff-indazolehydroformate.
(Figure Removed)



Prepared using Procedure A in 45% yield. LC/MS (El) tR 4.82 min, m/z 341 (MM).
Example 14: 3-{[(15,45)-5-Methyl-2,5-diazabicyclo[2Jl.l]hept-2-yl]carbonyl}-6-(l,3-oxazol-2-yl)-Lff-indazolehydroformate.

Prepared using Procedure A in 30% yield. LC/MS (El) tR 5.25 min, /m/z 324 (M*+l).
Example 15: 3-{[(LM5)-5-Meth^-2,5-diazabicyclo[2^.1]hq»t-2-thiazol-2-yl)-lfl-mdazolehydroformate.

(Figure Removed)
Prepared using Procedure A in 25% yield. LC/MS (El) fc 2.69 min, w/z 362 (M*+l).
Example 16: 3-{[(15r,4,S)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyI}-6-(4-methyl-l^-thiazol-2-yl)-l£T-indazole hydroformate.
(Figure Removed)

Prepared using Procedure A in 25% yield. LC/MS (El) fe 5.18 min, m/z 354 (IVT^+l).
Example 17: methyl-l,3-thiazol-2-yl)-lflr-indazole hydroformate.
(Figure Removed)

Prepared using Procedure A in 25% yield. LC/MS (El) ft 5.18 nan, m/z 354 QVf+1).
Example 18: 3-{[(15,45)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(tetrahydro-2fl-pyran-4-yl)-lH-mdazolehydroformate.

Prepared using Procedure A in 25% yield. LC/MS (El) fe 2.79 min, m/z 341 (M*+l).
Example 19: 3-{l(15545)-5-Methyl-2,5-dlazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(trifluoromethoxy)-lff-mdazole hydroformate.
(Figure Removed)

Prepared using Procedure A in 25% yield. LC/MS (El) tR 5.04 min, w/z 341
Example 20: (trifluoromethyl)-lJT-indazole hydroformate.
(Figure Removed)

Prepared using Procedure A in 45% yield. LC/MS (El) tR 3.85 min, m/z 325
Example 21: 3-{[(15,45)-S-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yI]carbonyl}-7-(trifluoromethoxy)-l#-indazole hydroformate.

.
Prepared using Procedure A in 25% yield. LC/MS (El) tR 4.66 rnin, m/z 341
Example 22: 5-(3,6-Dihydro-2fl-pyran-4-yl)-3-{[(llSJ45)-5-methyl-2,5-
diazabicyclo[2.2.1]hept-2-yl]carbonyl}-l#-indazole hydroformate.

Prepared using Procedure A in 30% yield. LC/MS (El) tR 2.83 min, m/z 339
Example 23: 5-(Difluoromethoxy)-3-{[(15,45)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl] carbonyl}-lJ7-indazole hydroformate.


Prepared using Procedure A in 35% yield. LC/MS (El) to 2.52 min, m/z 323
Example 24: indazole hydrochloride

Prepared using Procedure A in 45% yield. LC/MS (El) tR 4.76 min, m/z 321/323 (M4*!).
Example 25: 5-Methoxy-3-[(5-methyI-2,5-diazabicycIo[2.2.2]oct-2-yl)carbonyl]-lfl-indazole hydroformate.
(Figure Removed)


Prepared using Procedure A in 20% yield. LC/MS (El) fe 2.85 min, m/z 301 (M*+l).
Example 26: 3-(2,5-Diazabicyclo[2.2.2]oct-2-ylcarbonyl)-5-methoxy-LGT-indazole hydrochloride.

.
Prepared using Procedure A in 30% yield. LC/MS (El) tR 2.87 min, m/z 287 (M*+l).
Example 27: 5-Methoxy-3-{[(15,45)-S-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyI}-LH-indazolehydrochloride.
Prepared using Procedure A in 35% yield. LC/MS (El) to 2.85 min, m/z 287
Example 28: 5-Methoxy-3-{[(l1S,45)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl] carbonyl}-lff-indazole hydroformate.


Prepared using Procedure A in 45% yield. LC/MS (El) t& 2.51 min, m/z 287
Example 29: 6-(3,6-Dihydro-2£r-pyran-4-yl)-3-{[(l,4-S)-5-methyl-2,5-
diazabi cycle [2.2.1] hept-2-yl] carbonyl}-lJ7-indazole hydroformate.

Prepared using Procedure A in 25% yield. LC/MS (El) fe 2.8 min, /«// 339
Example 30: 6-(Difluoromethoxy)-3-{[(15,45)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl] carbonylJ-lJET-indazole hydroformate.

1
Prepared using Procedure A in 35% yield. LC/MS (El) fc 2.47 min, m/z 323
Example 31 : indazole ydrochloride.


Prepared using Procedure A in 45% yield. LC/MS (El) t* 3.71 min, m/z 321/323
Example 32: 6-Cyclopropyl-3-{[(l1S',4iS)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-l,2-benasothiazolehydroformate.
Prepared using Procedure A in 56% yield. LC/MS (El) fe 4.48 min, m/z 314 (M !).
Example 33: 6-Ethoxy-3-{[(15,45)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-l,2-benzisothiazolehydroformate.


Prepared using Procedure A in 43 % yield. LC/MS (El) ft 3 .79 min, m/z 3 1 8
Example 34: 3-(2,5-Diazabicyclo[2.2.2]oct-2-yIcarbonyl)-6-methoxy-LH-indazole hydrochloride.

Prepared using Procedure A in 30% yield. LC/MS (El) & 2.89 min, m/z 287
Example 35: 6-Methoxy-3-[(5-methyl-2,5-diazabicyclo[2.2.21oct-2-yl)carbonyl]-lfl-indazole hydroformate.

Prepared using Procedure A in 28% yield. LC/MS (El) tR 2.83 min, m/z 301
Example 36: 6-Methoxy-3-{[(LS',45)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-l,2-benzisotliiazolehydroformate.


Prepared using Procedure A in 64% yield. LC/MS (El) tR 2.97 min, m/z 304 (M^fl).
Example 37: yl]carbonyl}-l,2-benzisothiazol



Prepared using Procedure A in 85% yield. LC/MS (El) tR 3.06 min, tn/z 304
Example 38: yl]carbonyl}-lJ7-idazolehydrochloride
Prepared using Procedure A in 35% yield. LC/MS (El) fe 2.83 min, ra/z 287
Example 39: 6-Methoxy-3-{[(15,45)-5-methyl-2,5-diazabicyclo [2.2.1]hept-2-.yl]carbonyl}-lff-indazolehydroformate.
Prepared using Procedure A in 35% yield. LC/MS (El) fc 2.83 min, m/z 287 (M++1).
Example 40: 7-Fluoro-6-methoxy-3-{[(15l,4iS)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-l#-indazoIehydroformate.

Prepared using Procedure A in 3 1% yield. LC/MS (El) /* 2.54, w/z 305
Example 41: yl]carbonyl}-l,2-benzisothiazolehydroforraate.



Prepared using Procedure A in 50% yield. LC/MS (El) fe 2.6 min, w/z 304
Procedure B:
Procedure B provides a method for the coupling between brominated and iodinated bicyclobase carboxamides and boronic acids to form aryl-substituted or heteroaryl substituted derivatives.
In a 5 mL microwave reaction vessel was added brominated bicyclobase carboxamide (0.3 mmol), boronic acid (0.6 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.03 mmol), tri-tert-butylphosphine tetrafluoroborate (0.06 mmol), and potassium carbonate (0.8 mmol). The vessel was evacuated, back-filled with argon gas, and the contents diluted with ^//-dimethylformamide (5,0 mL). The vessel was sealed and subjected to microwave irradiation at 200 °C for 600 s. The contents of the reaction were filtered through Celite (methanol wash) and loaded on a 5 g SCX column. The column was washed with methanol (50 mL) and the product was ehrted with 2 M ammonia in methanol and concentrated. The residue was purified by chromatography [1/1 to 0/1 ethyl acetate/(70/30/l ethyl acetate/methanol/ammonium hydroxide)] followed by preparative HPLC using an 8 ruin gradient of 95/5 to 20/80 water (0.1% formic acid)/acetonitrile (0.1% formic acid), thus providing the heteroaryl-substituted product.
The following examples were prepared according to procedure B:
Example 42: 3-{[(15,4)S)-5-Methyl-2s5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-S-(2-thienyl)-l£r-indazole hydroformate.

Prepared using Procedure B in 25% yield. :H NMR (CD3OD) 8 8.48 (m,2H); 7.75 (m, IH); 7.58 (m, IH); 7.32 (m, 2H); 7.08 (m, IH); 4.25 (m, IH); 3.70 (m, 2H); 3.32 (m, IH); 2.85 (d, 3H); 2.22 (m, 2H), LC/MS (El) tR 5.03 min, m/z 339
Example 43: 3-{[(l
Prepared using Procedure B in 25% yield. LC/MS (El) fe 5.33 min, m/z 353 (MN-1).
Example 44: 3-{[(15,45)-5-Methyl-2,5-diazabicycIo[2.2.1]hept-2-yl]carbonyl}-5-(5-methyl-2-thienyl)-Lff-indazolehydroformate.

(Figure Removed
Prepared using Procedure B in 25% yield. LC/MS (El) to 5.32 min, m/z 353
Example 45: 3-{[(15f,4,S)-S-MethyI-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-phenyl-ljfiT-indazole hydroformate.

Prepared using Procedure B in 25% yield. LC/MS (El) ^ 5.17 min, m/z 333
Example 46: 3-{[(15,45)-5-Methyl-2,5-diazabicydo[2.2.1]hept-2-yI]carbonyl}-6-(2-thienyl)-lfl-mdazole hydroformate.

Prepared using Procedure B in 25% yield. LC/MS (El) tR 5.13 min, m/z 339
Example 47: 3-{[(l&4S)-5-Methyl-2,5-diazabicyclo[2.21]hept-2-yl] carbonyl}-6-(3-thienyl)-l#-indazole hydroformate.

Prepared using Procedure B in 25% yield. LC/MS (El) ft 4.3 min, m/z 339
Example 48: 3-{[(l1S,4JS)-5-Methyl-255-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(4-methyI-2-thienyl)-lJ7-indazole hydroformate.

Prepared using Procedure B in 20% yield. LC/MS (El) to 5.35 min, m/z 353
Example 49: methyl-2-furyl)-lfl4ndazolehydroformate.
(Figure Removed)


Prepared using Procedure B in 25% yield. LC/MS (El) tR 5.35 min, m/z 337
Example 50: 3-{[(15',45)-5-Methyl-2}5-diazabicyclo[2.2.1]hept-2-yI]carbonyl}-6-(5-methyl-2-thienyl)-lJy-indazolehydroformate.


Prepared using Procedure B in 25% yield. LC/MS (El) tR 4.67 min, m/z 353 (M*+l).
Example 51: 5-(2-Furyl)-3-{[(liS,4,S)-5-methyl-2,5-diazabicyclo [2.2.1]hept-2-yl] carbonyl}-LH-mdazole hydroformate.

(Figure Removed)
Prepared using Procedure B in 25% yield. LC/MS (El) b 41 min, m/z 323
Example 52: 5-(3-Fluorophenyl)-3-{[(l.S,41S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-lff-indazolehydroformate.
(Figure Removed)


Prepared using Procedure B in 25% yield. LC/MS (El) tR 5.28 rain, m/z 351
Example 53: 5-(4-Fluorophenyl)-3-{[(15,45)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-lJ5r-indazolehydroformate.

Prepared using Procedure B in 25% yield. LC/MS (El) ^ 5.25 min, m/z 351
Example 54: 5-(4-Methoxyphenyl)-3-{[(15,45)-5-methyl-2,5-diazabicyclo[2.2.1]liept-2-yl] carbonyI}-lJ7-indazole hydroformate.

Prepared using Procedure B in 20% yield. LC/MS (El) ft 5.19 min, m/z 363 (M*"+l).
Prepared using Procedure B in 25% yield. LC/MS (El) tR 4.9 min, m/z 323
Example 56: e^ yl]carbonyI}-LH-indazolehydroformate.
Example 55: 6-(2-FuryI)-3-{[(lJSr,45)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-lff-indazolehydroformate.
Prepared using Procedure B in 25% yield. LC/MS (El) tR 3.93 min, m/z 323
Procedure C:
Procedure C provides a method for the reductive coupling between bicyclobase carboxamides and carboxaldehydes to form tertiary amine derivatives.
To the suspension of bicyclobase carboxamide hydrochloride (0.4 mmol), carboxaldehyde (1.0 mmol), W,N-ctiisopropylemylamine (1.2 mmol), and acetic acid (0.48 mmol) was added sodium triacetoxyborohydride (0.68 mmol). The reaction mixture was maintained at ambient temperature for 2 h and was poured into water, extracted with 95/5 dichloromethane/methanol (2 x 30 mL), and the combined extracts
were concentrated. The residue was purified by preparative HPLC using an 8 min gradient of 95/5 to 20/80 water (0.1% formic acid)/acetonitrile (0.1% formic acid), thus providing the tertiary amine product.
The following examples were prepared according to procedure C:
Example 57: 3-{[(15,45)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-lff-indazole hydroformate.

Prepared using Procedure C or A in 30% yield. 1E NMR (CD3OD) 8 8.42 (s, 1 H); 8.23 (m, 1 H); 7.85 (m, 1 H); 7.77 (m, 1 H); 7.64 (m, 1 H); 4.15 (m, 2 H); 4.01 (m, 2 H); 2.51 (d , 3 H); 2.1 1 (m, 2 H). LC/MS (El) fe 2.5 min, m/z 257
Prepared using Procedure C in 45% yield. LC/MS (El) tR 2.77 min, m/z 271
Example 58: S^Kl^^-S-Ethyl-ZjS-diazabicyclopJ.llhept-Z-yl] carbonyl}-lff-indazole. xample 59: 7V-(Cyclopropylmethyl)-3-[(5-methyl-2,S-dia2abicydo[2.2.2]oct-2-yl)carbonyl]-l#-indazol-5-amine.

Prepared using Procedure C in 70% yield. LC/MS (El) tR 1 .33 min, m/z 340
Example 60: ^-(CyclopropylmethyI)-3-{[(l^,45)-5-methyl-2,5-diazabicyclo[2.2.1]-hept-2-yl]carbonyl}-LH-indazol-5-amine.

Prepared using Procedure C in 80% yield. LC/MS (El) t£ 1 .36 min, m/z 326
Prepared using Procedure C in 58% yield. LC/MS (El) fe 1.49 min, m/z 314

Example 61 : AyV-Dimethyl-3-[(5-methyl-2,5-diazabicyclo[2.2.2]oct-2-yl)carbonyl]-LH-indazol-5-amine hydroformate.
Example 62: AyV-Dimethyl-3-{[(15,45)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-LH-indazol-5-aminehydroformate.
ed using Procedure C in 51% yield. LC/MS (El) tR 1.5 min, m/z 300 (M*+l).
Example 63:
yl] carbonyl}-13r-indazol-6-amine hy droformate.
Prepared using Procedure C in 59% yield. LC/MS (El) tR 1.5 min, /w/z 300 (M++l).
Example 64: 5-Bromo-3-{[(15,45)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl] carbonyl}-lH-indazole.


Prepared using Procedure C or A in 25% yield. LC/MS (El) t& 3.57 min, m/z 335/337
Prepared using Procedure C or B in 25% yield. LC/MS (El) tR 417 rain, m/z 339 (M*+l).
Example 66: S-f
yl] carbonyl}-lH-indazoIe hydroformate.
Example 65: 3-{[(l^,4,S)-5-Methyl-2,S-diazabicycIo[2.2.1]hept-2-yl]carbonyl}-5-(3-thienyl)-l/T-indazole hydroformate.


Prepared using Procedure C or B in 15% yield. LC/MS (El) t& 4.1 min, m/z 323
Procedure D;
Procedure D provides a method for the demethylation of methoxy-substituted indazole bicyclobase amides to form phenol derivatives and the subsequent reaction of the phenol with various alkylating agents.
The methoxy indazole bicyclobase amide (6.98 mmol) was diluted with dichloromethane (60 mL) and dichloroethane (15 mL) and the solution was cooled to -78 °C. A 1.0 M solution of boron tribromide in dichloromethane (35 mmol) was added dropwise over 30 min. The reaction mixture was allowed to warm to room temperature and was maintained for 20 h. An additional aliquot of boron tribromide in dichloromethane (6 mmol) was added and the reaction was maintained for an additional 16 h. The reaction
was slowly quenched with MeOH (30 mL) and concentrated to dryness. The residue was purified by chromatography using a dichloromethane/methanol (90/10) followed by elution with a mixture of dichloromethane/methanol/ammonium hydroxide (90/10/1) to provide the phenol (54%) as a brown solid. The phenol (0.734 mmol) was dissolved in N,N-dimethylformamide (10 mL) and was treated with potassium carbonate (1.46 mmol) and the alkyl bromide (0.95 mmol). The reaction was maintained for 16 h at ambient temperature and was filtered and concentrated to dryness. The residue was purified by preparative HPLC using an 8 min gradient of 95/5 to 20/80 water (0.1% formic acid)/acetonitrile (0.1% formic acid), thus providing the ether product.
The following examples were prepared according to procedure D:
Example 67: 5-Hydroxy-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2i1]hept-2-yl]carbonyl}-1H-indazole.
(Formula Removed)
Prepared using Procedure D in 64% yield. lH NMR (Me2SO-d6) δ 10.76 (s, 1H); 8.90 (s, 1H); 8.25 (m,2H); 7.99 (s, 1H); 7.85 (m, 1H); 4.46 (br, 1H); 3.62 (m, 1H); 3.38 (m, 1H); 3.20 (m, 3H); 2.20 (m, 2H); 1.85 (m, 2H), LC/MS (EI) tR 0.75, rn/z 273 (M++1).
Example 68: 5-(Cyclopentyloxy)-3-{[(1S,4S)-methyl-,25-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole hydroformate.
(Formula Removed)
The following examples were prepared according to procedure D:
Example 67: 5-Hydroxy-3-{[(15,45)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(l,3-tMazol-2-yl)4ff-indazole.

Prepared using Procedure D in 64% yield. 1H NMR (MeaSO-cfe) 8 10.76 (s, 1H); 8.90 (s, 1H); 825 (m£H); 7.99 (s, 1H); 7.85 (m, 1H); 4.46 (br, 1H); 3.62 (m, 1H); 3.38 (m, 1H); 3.20 (m, 3H); 2.20 (m, 2H); 1.85 (m, 2H), LC/MS (El) fe 0.75, mk 273 (M++1).
Example 68: 5-(Cyclopentyloxy)-3-{[(l1S',45)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-lff-indazolehydroformate.

Prepared using Procedure D in 25% yield. 'H NMR (CD3OD) 5 8.48 (m,2H); 7.75 (m, 1H); 7.58 (m, 1H); 7.32 (m, 2H); 7.08 (m,1H); 4.25 (m, 1H); 3.70 (m, 2H); 3.32 (m, 1H); 2.85 (d, 3H); 2.22 (m, 2H), LC/MS (El) tR 5.25 min, m/z 341 (M++1).
Example 5-(Cyclopropylmethoxy)-3-{[(15',4S)-5-methyl-2,5-
diazabicyclo[2.2.1] hept-2-yl]carbonyl}-L9-indazole hydroformate.

Prepared using Procedure D in 25% yield. LC/MS (El) tR 2.85 min, m/z 327
Example 70: 6-(Cyclopentyloxy)-3-{ [(l,S,4S>5-methyl-2,5-diazabicyclo [2.2.1]hept-2-yl]carbonyl}-l£T-indazole hydroformate.

Prepared using Procedure D in 30% yield. LC/MS (El) t» 6.1 min, jn/z 341
Procedure E:
Procedure E provides a method for Hie reduction of nitre-substituted bicyclobase amides to form aniline derivatives.
To a solution of the nitre-substituted bicyclobase (3.8 mmol), prepared by procedure A,
in methanol (100 mL) was added 10% palladium on carbon (200 mg). The reaction was placed under an atmosphere of hydrogen gas (60 psi) and was shaken overnight. The catalyst was removed by filtration through a pad of Celite, which was washed with methanol (100 ml). The combined filtrates were concentrated to give the desired product
The following examples were prepared according to procedure E:
Example 71: 5-Amino-3-[(5-Methyl-2,5-diazabicyclo[2.2.2]oct-2-yl)carbonyl]-lJ5r-indazole.Prepared using Procedure E in 92% yield. 1E NMR (CD3OD) 8 7.36 (d, J= 12.0,1 H), 7.31 (s, 1 H), 7.0 (d, /= 12.0,1 H), 4.03 (m, 1 H), 3.62 (m, 1 H), 3.31 (s, 3 H), 3.10 (m, 2 H), 3.01 (m, 2 H), 2.30-2.00 (m, 2 H), 1.98-1.75 (m, 2 H). LC/MS (El) tR 1.71 min, m/z 286 (M++1).
Prepared using Procedure E in 74% yield.
Example 72: 5-Amino-3-{[(lJS',45)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(l,3-thiazol-2-yl)-Lff-indazole.Procedure F;
Procedure F provides a method for the reaction of the aniline bicyclobases with acid chlorides and anhydrides to form amide derivatives.
To a solution of the aniline (0.460 mmol) in pyridine (4 mL) was added the carbonyl chloride (0.59 mrnol). The reaction mixture wa maintained for 2 h and was concentrated to dryness. The resulting residue was purified by preparative HPLC using an 8 min gradient of 95/5 to 20/80 water (0.1% formic acid)/acetonitrile (0.1% formic acid), thus providing the amide product.
The following examples were prepared according to procedure F:
Example 73: JV-{3-[(5-Methyl-2,5-diazabicyclo[2.2.2]oct-2-yl)carboayl]-lfl-indazol-5-yl}cyclopropanecarboxamidehydroformate.
Prepared using Procedure F in 28% yield. 'H NMR (CD3OD) 5 8.53 (s, 1 H), 8.40 (s, 1 H), 7.86 (s, 1 H), 4.70 (m, 1 H), 4.33 (m, 1 H), 4.20 (m, 1 H), 3.90 (m, 1 H), 3.90 (m, 1 H), 3.60-3.40 (m, 2 H), 3.0 (s, 3 H), 2.50-2.10 (m, 2 H), 2.10-1.90 (m, 2 H), 1.80 (m, 1 H), 0.93 (m 2 H), 0.85 (m, 2 H). LC/MS (El) fe 2.83 min, m/z 354 (M*+l).
Example 74: AT-{l-(Cyclopropylcarbonyl)-3-[(5-methyl-255-diazabicyclo[2.2.2]oct-2-y^carbonyll-ljff-indazol-S-ylJcyclopropanecarboxamidehydrofonnate.

repared using Procedure F in 9.4% yield. LC/MS (El) tR 5.13 min, m/z 422 (M*+l).
Example 75: J/V-(3-{[(l1S,45)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-U?-indazol-5-yl)cyclopropanecarboxarmdehydroformat
Prepared using Procedure F in 35% yield. LC/MS (El) tR 2.78 min, m/z 340 (JV^+l).
Procedure G:
Procedure G provides a method for the reaction of the aniline bicyclobases with isocyanates to form urea derivatives.
To a solution of the aniline (0.550 mmol) in pyridine (4 mL) was added the isocyanate (0.72 mmol). The reaction mixture was maintained for 16 h and was concentrated to dryness. The residue was purified by preparative HPLC using an 8 min gradient of 95/5 to 20/80 water (0.1% formic acid)/acetonitrile (0.1% formic acid), thus providing the urea product.
The following examples were prepared according to procedure Q:
Example 76: JV-(3-{[(l^,4JS)-5-Methyl-2,5-diazabLcyclop.2.1]hept-2-yl]carbonyl}-lJar-indazol-5-yl)-JV-propyIurealiydrofonnate.

Prepared using Procedure G in 29% yield. 1H NMR (CD3OD) 8 8.42 (broad, 1 H), 8.21 -8.14 (m, 2 H), 7.47 (m, 1 H), 4.40-4.20 (m, 1 H), 3.60 (m, 1 H), 3.30 (s, 3 H)3 3.20 (m, 2 H), 3.10 (t, /= 6.0,2 H), 2.90 (m, 2 H), 2.50-2.10 (m, 2 H), 2.10-1.85 (m, 2 H), 1.50 (q, / = 6.0,2 H), 0.98 (t, J= 6.0,3 H). LC/MS (El) fe 2.84 min, w/^ 357 (Nf'+l).
Example 77; 3-[(5-Methyl-2,5-diazabicycIo[2.2.2]oct-2-yl)carbonyl]-^-propyl-5-{[ftTOpylanunoJcarbonylJaminoJ-lfT-indazoIe-l-carboxamidehydroformate.

Prepared using Procedure G in 7.8% yield. LC/MS (El) & 5.11 min, ;«/z 456
Example 78: AT-(4-Fluorobenzyl)-7V-(3-{[(15l,4)S)-5-methyl-2,5-
diazabicyclo[2.2.1]liept-2-yl]carbonyl}-119r-indazol-5-yl)ureahydroformate.

Prepared using Procedure G in 27% yield. LC/MS (El) fe 4.74 min, m/z 423 (MN-1).
Example 79: Ar-(4-Fluorobenzyl)-5-({[(4-fluorobenzyl)amino] carbonyl}amino)-3-[(5-
methyl-2,5-diazabicyclo[2.2.2]oct-2-yI)carbonyl]-lJT-indazole-l-carboxamide
Prepared using Procedure Gin 5.2% yield. LC/MS (El) ^ 5.9 min, m/z 588
hydroformate.
(Figure Removed)
Example 80: Ar_Cyclopentyl-JV-(3-{[(l'Sr545)-5-methyl-2,5-diazabicycIo[2.2.1]hept-2-yl]carbonyl}-Lfif-indazol-5-yl)ureahydroformate.

Prepared using Procedure G in 32% yield. LC/MS (El) tR 2.85 min, m/z 383 (M*+l).
Example 81: JV-CycIopentyI-5-{ [(cyclopentylamino)carbonyl] amino}-3-[(5-methyI-2,5-diazabicyclo[2.2.2]oct-2-yl)carbonyl]-lfl-indazole-l-carboxamidehydroformate.

Prepared using Procedure G in 6.6% yield. LC/MS (El) fe 5.46 min, m/z 508 (M^-M).
Example 82: yl)carbonyl]-lJET-indazol-5-yl}ureahydroformate.

Prepared using Procedure G in 22% yield. LC/MS (El) fc 4.78 min, ?w/z 437 (M*"+l).
Example 83: ^-{3-[(5-Methyl-2,5-diazabicyclo[2.2.2]oct-2-yl)carbonyl]-llT-indazol-5-yl}-W-propylurea hydroformate.
Prepared using Procedure G in 33% yield. LC/MS (El) ^ 3.11 min, tn/z 372 (M++1).
Example 84: JV-Cyclopentyl-JV-{3-[(5-methyl-2,5-diazabicyclo[2.2.2]oct-2-yl)carbonyl]-lfl-indazol-5-yl}urea hydroformate.

Prepared using Procedure G in 34% yield. LC/MS (El) fe 2.9 min, »i/z 397 (MM). Example 85: [3H] ML A binding
Materials:
Rat Brain: Pel-Freez Biologicals, CAT No. 56004-2 Protease inhibitor cocktail tablet: Roche, CAT No. 1697498
Membrane preparation
Rat brains in 20 vol (w/v) of ice-cold 0.32 M sucrose with protease inhibitors (one tablet per 50 ml,) were homogenized with a polytron for 10 sec at setting 11, then
centrifiiged 10 min at 1000 g, 4 °C. The supernatant was centrifuged again for 20 min at 20,000 g, 4 °C. The pellets were resuspeaded in binding buffer (200 mM TRIS-HC1,20 mM HEPES, pH 7.5,144 mM NaCl, 1.5 mM KC1,1 mM MgSO4,2 mM CaCl2,0.1% (w/v) BSA) and stored membrane prep at -80 °C.
For saturation assay, the 200 ul assay mixture in binding buffer contains 200 ug of membrane protein, 0.2 to 44 nM of [3H] MLA. The nonspecific binding was defined using 1 uM MLA. Competition assay was carried out with 2 nM [^ MLA and a desirable range of compounds. The assay mixture was incubated at 22 °C for 2 hours, then harvested with GF/B filter presoaked with 0.3% PEI in binding buffer using Tomtec harvester. The filter was washed three time with binding buffer and the radioactivity was counted with Trilux.
Binding affinities for the preferred compounds of the invention were 26 micromolar to 64 nanomolar, especially 2.5 micromolar to 64 nanomolar.
The preceding examples can be repeated with similar success by substituting the genetically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.
While the invention has been illustrated with respect to the production and of particular compounds, it is apparent that variations and modifications of the invention can be made without departing from the spirit or scope of the invention.






We Claim:
1. An azabicyclo-indazole compound according to Formula I:
wherein
(Formula Removed)
X1 to X4 are each, independently, CH, CR1, or N, wherein at most one of X1 to X4 M is N;
R1 is each, independently,
H,
C1-6-alkyl which is unsubstituted or substituted one or more times by F, C1, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms, NR4R5, SH, SR4, SOR4, C3-8-cycloalkyl, SO2R4, SO2NR4R5, Ar, Het, or combinations thereof,
C2-6-alkenyl which is unsubstituted or substituted one or more times by F, C1, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms, NR4R5, SH, SR4, SOR4, C3-8-cycloalkyl, SO2R4, SO2NR4R5, Ar, Het, or combinations thereof,
C2-6-alkynyl which is unsubstituted or substituted one or more times by F, C1, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms, NR4R5, SH, SR4, SOR4, C3-8-cycloalkyl, SO2R4, So2NR4R5, Ar, Het, or combinations thereof,
C3-8-cycloalkyl which is unsubstituted or substituted one or more times by F, C1, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms, NR4R5, SH, SR4, SOR4, unsubstituted C3-8-cycloalkyl, SO2R4, SO2NR4R5, Ar, Het, or combinations thereof,
halogen,
CN, NO2, NR4R5, SH, SR4, SOR4, SO2R4, SO2NR4R5, NR4SO2R5, CONR4R5, COOR4, NR4COR5, NR4CO2R5, NR4CONR4R5,
Ar,
Het, or
R6O-;
R4 and R5 are each independently H, or
Ar, Ar-C1-4-alkyl, Het, C1-4-alkyl, C3-8-cycloalkyl, or C4.g-cycloalkylalkyl, each of which is unsubstituted or substituted one or more times by F, C1, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms, monoalkylamino, dialkylamino, C3.8-cycloalkyl, or combinations thereof;
R6 is H,
C1-6-alkyl which is unsubstituted or substituted one or more by F, C1, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms, NR4R5, SH, SR4, SOR4, C3-8-cycloalkyl, SO2R4, SO2NR4R5, Ar, Het, or combinations thereof,
C3-6-alkenyl which is unsubstituted or substituted one or more by F, C1, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms, NR4R5, SH, SR4, SOR4, C3-8-cycloalkyl, SO2R4, SO2NR4R5, Ar, Het, or combinations thereof,
C3-6-alkynyl which is unsubstituted or substituted one or more by F, C1, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms, NR4R5, SH, SR4, SOR4, C3-8-cycloalkyl, SO2R4, SO2NR4R5, Ar, Het, or combinations thereof,
C3-8-cycloalkyl which is unsubstituted or substituted one or more times by F, C1, Br, I, CN, OH, alkoxy having 1 to. 4 carbon atoms, NR4R5, SH, SR4, SOR4, unsubstituted C3-8-cycloalkyl, SO2R4, SO2NR4R5, Ar, Het, or combinations thereof,
C4-8-cycloalkylalkyl which is unsubstituted or substituted one or more times by F, C1, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms, NR4R5, SH, SR4, SOR4, unsubstituted C3-8-cycloalkyl, SO2R4, SO2NR4R5, Ar, Het, or combinations thereof,
Ar, or
Het;
R7 is H, or
C1-4-alkyl which is unsubstituted or substituted one or more by F, C1, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms, NR4R5, or combinations thereof;
m is 1, 2 or 3;
Ar is phenyl or naphthyl group which is unsubstituted or substituted one or more times by alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 8 carbon atoms, halogen, dialkylamino wherein the alkyl portions each have 1 to 8 carbon atoms, amino, cyano, hydroxyl, nitro, halogenated alkyl having 1 to 8 carbon atoms, halogenated alkoxy having 1 to 8 carbon atoms, hydroxyalkyl having 2 to 8 carbon atoms, hydroxyalkoxy having 2 to 8 carbon atoms, alkenyloxy having 3 to 8 carbon atoms, alkylthio having 1 to 8 carbon atoms, alkylsulphinyl having 1 to 8
carbon atoms, alkylsulphonyl having 1 to 8 carbon atoms, monoalkylamino having 1 to 8 carbon atoms, cycloalkylamino wherein the cycloalkyl group has 3 to 7 carbon atoms and is optionally substituted, aryloxy wherein the aryl portion is phenyl or naphthyl and is optionally substituted, arylthio wherein the aryl portion is phenyl or naphthyl carbon atoms and is optionally substituted, cycloalkyloxy wherein the cycloalkyl group has 3 to 7 carbon atoms and is optionally substituted, sulfo, sulfonylamino, acylamido, acyloxy, carboxy, alkoxycarbonyl, alkylaminocarbonyl or combinations thereof; and
Het is a heterocyclic group, which is fully saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms and wherein the heteroatoms are selected from N, O and S atoms, which is unsubstituted or substituted one or more times by halogen, phenyl or naphthyl which is optionally substituted, arylalkyl the aryl portion is phenyl or naphthyl and the alkyl portion contains 1 to 4 carbon atoms, a heterocyclic group, which is fully saturated, partially saturated or fully unsaturated, and has 5 to 10 ring atoms in which the heteroatoms are selected from N, 0 and or S atoms atom, alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 8 carbon atoms, cyano, trifluoromethyl, nitro, oxo, amino, monoalkylamino having 1 to 8 carbon atoms, dialkylamino wherein each alkyl group has 1 to 8 carbon atoms, alkoxycarbonyl, alkylaminocarbonyl, or combinations thereof; or
a pharmaceutically acceptable salt thereof,
wherein if the compound exhibits chirality it can be in the form of a mixture of enantiomers or a mixture of diastereomers, or can be in the form of a single enantiomer or a single diastereomer.
2. A compound as claimed in claim 1, wherein R4 and R5 are each independently H, Ar, Het, or C1-4-alkyl which is unsubstituted or substituted one or more times by F, C1, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms, monoalkylamino, dialkylamino, C3-8-cycloalkyl or combinations thereof, and R1 is not NR4CO2R5 or NR4CONR4R5.
3. A compound as claimed in claim 1, wherein R1 is H, OR6, CF3, Br, thienyl which is unsubstituted or substituted, furyl which is unsubstituted or substituted, or phenyl which is unsubstituted or substituted.
4. A compound as claimed in claim 3, wherein R1 is H, OR6, NR4R5, NR4COR5, NR4CONR4R5, CF3, Br, 2-thienyl, 3-thienyl, methylthienyl, 2-furyl, 3-furyl, phenyl, fluorophenyl, methoxyphenyl, thiazolyl, oxazolyl tetrahydropyranyl or dihydropyranyl.
5. A compound as claimed in claim 1, wherein R4 is H or methyl.
6. A compound as claimed in claim 1, wherein R5 is H, methyl, cyclopropyl, cyclopentyl, cyclopropylmethyl, propyl, or Ar-methyl.
7. A compound as claimed in claim 1, wherein R6 is methyl, ethyl, CF3, CHF2, cyclopentyl or cyclopropylmethyl.
8. A compound as claimed in claim 1, wherein R7 is H, methyl, or ethyl.
9. A compound as claimed in claim 1, wherein A is -CO-.
10. A compound as claimed in claim 1, wherein m is 1 or 2.
11. A compound as claimed in claim 1, wherein Ar is phenyl which is unsubstituted or substituted.
12. A compound as claimed in claim 1, wherein Het is thienyl which is unsubstituted or substituted or furyl which is unsubstituted or substituted.
13. A compound as claimed in claim 1, wherein each of X1 to X4 is CH or CR1.
14. A compound as claimed in claim 1, wherein said compound is selected from: 3-[(1S,4S)-2,5-Diazabicyclo[2.2.1]hept-2-ylcarbonyl]-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}-6-(trifluoromethyl)-1H-indazole,
5-Bromo-3-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-ylcarbonyl]-1H-indazole, 5-Methoxy-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole, 6-Bromo-3-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-ylcarbonyl]-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-Methyl2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-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-phenyl-H-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-{[(1S,4S)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-1-yl]carbonyl}-6-methyl-2-thienyl)-
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,
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-(4-Fluorophenyl)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-
1H-indazole,
5-(4-Methoxyphenyl)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]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-Furyl)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-
indazole,
3-{[(1S,4S)-5-Ethyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
3-{[(1S,4S)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
3-{[(1S,4S)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(3-thienyl)-1H-
indazole,
5-(3-Furyl)-3-{[(1S,4S)-5-methyl-2,5-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 pharmaceutically acceptable salts thereof
wherein the compound can be in the form of a mixture of enantiomers or a mixture of
diastereomers, or can be in the form of a single enantiomer or a single diastereomer.
15. A compound as claimed in claim 1, wherein said compound is selected from: 3-(2,5-Diazabicyclo[2.2.2]oct-2-ylcarbonyl)-6-(l,3-thiazol-2-yl)-1H-indazole, 3-[(15',45)-2,5-Diazabicyclo[2.2.1]hept-2-ylcarbonyl]-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]-1H-indazole, 3-[(5-Methyl-2,5-diazabicyclo[2.2.2]oct-2-yl)carbonyl]-6-(l,3-thiazol-2-yl)-1H-indazole, 3-{[(1S,4S)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole, 3-{[(15,45)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(l,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-Methyl2,5-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-yllcarbonyl}-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)-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-indazole,
3-{[(1S,4S)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(2-thienyl)-li/-indazole,
3-{[(1S,4S)-5-Methyl-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-l,3-thiazol-2-yl)-1H-indazole,
3-{[(1S,4S)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(4-methyl-2-thienyl)-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,
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,
3-{[(1S,4S)-5-Methyl2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(trifluoromethyl)-
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-{[(lS,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-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-
1H-indazole,
5-(4-Methoxyphenyl)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-
1H-indazole,
5-(Cyclopentyloxy)-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-{[(lS,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(l,3-
thiazol-2-yl)-1H-indazole,
5-Bromo-3-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-ylcarbonyl]-1H-indazole,
5-Hydroxy-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-
indazole,
5-Methoxy-3-[(5-methyl-2,5-diazabicyclo[2.2.2]oct-2-yl)carbonyl]-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-diazabicyclo[2.2.1]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-(3,6-Dihydro-2H-pyran-4-yl)-3-{[(1S,4S)-methyl-2,5-diazabicycl[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)-3-{[(15',45)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-
1H-indazole,
6-Cyclopropyl-3-{[(1S,4S)--5methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1,2-
benzisothiazole,
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-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-
indazole,
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} cyclopropanecarboxamide,
N-{3-[(5-Methyl-2,5-diazabicyclo[2.2.2]oct-2-yl)carbonyl]-1H-indazol-5-yl}-N-
propylurea,
and pharmaceutically acceptable salts thereof
wherein the compound can be in the form of a mixture of enantiomers or a mixture of
diastereomers, or can be in the form of a single enantiomer or a single diastereomer.
16. A compound as claimed in claim 1, wherein said compound is selected from:
3-{[(1S,4S)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(4-methyl-l,3-thiazol-2-yl)-1H-indazole,
3-{[(1S,4S)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(5-methyl-l,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,
5-(3,6-Dihydro-2H-pyran-4-yl)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl} -1H-indazole,
5-(Difluoromethoxy)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-
1H-indazole,
6-(Difluoromethoxy)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-
1H-indazole,
7-Fluoro-6-methoxy-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-
1H-indazole,
N-(3-{[(1S,4S)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol-5-
yl)cyclopropanecarboxamide,
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-yl}urea,
N-(Cyclopropylmethyl)-3-[(5-methyl-2,5-diazabicyclo[2.2.2]oct-2-yl)carbonyl]-H-
indazol-5-amine,
N-(Cyclopropylmethyl)-3-{[(1S,4S)-5-methyl2,5-diazabicyclo[2.2.1]hept-2-
yl]carbonyl}-1H-indazol-5-amine,
N,N-Dimethyl-3-[(5-methyl-2,5-diazabicyclo[2.2.2]oct-2-yl)carbonyl]-1H-indazol-5-
amine,
N, N-Dimethyl-3-{ [(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1 ]hept-2-yl]carbonyl}-1H-
indazol-5-amine,
N,N-Dimethyl-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-
indazol-6-amine,
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,
and pharmaceutically acceptable salts thereof,
wherein the compound can be in the form of a mixture of enantiomers or a mixture of
diastereomers, or can be in the form of a single enantiomer or a single diastereomer.
17. A compound as claimed in claim 14, wherein said compound is a hydrochloride salt or a hydroformate salt.
18. A compound as claimed in claim 17, wherein said compound is selected from: 3-[(1S',4S)-2,5-Diazabicyclo[2.2.1]hept-2-ylcarbonyl]-1H-indazole hydrochloride,
3-{[1S,4S)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(trifluoromethoxy)-
1H-indazole hydroformate,
3-{[(1S,4S)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(trifluoromethyl)-
1H-indazole hydroformate,
5-Bromo-3-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-ylcarbonyl]-1H-indazole
hydrochloride,
5-Methoxy-3 - {[(1S,4S)-5 -methyl-2,5 -diazabicyclo [2.2.1 ]hept-2-yl]carbonyl} -1H-
indazole hydroformate,
6-Bromo-3-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-ylcarbonyl]-1H-indazole
hydrochloride,
3-{[(1S,4S)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(2-thienyl)-1H-
indazole hydroformate,
3-{[(1S,4S)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(4-methyl-2-thienyl)-
1H-indazole hydroformate,
3-{[(1S,4S)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(5-methyl-2-thienyl)-
1H-indazole hydroformate,
3-{[(1S',4S)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-phenyl-1H-indazole
hydroformate,
3-{[(1S,4S)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(2-thienyl)-1H-
indazole hydroformate,
3-{[(1S,4S)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(3-thienyl)-1H-
indazole hydroformate,
3-{[(1S,4S)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-methyl-2-thienyl)-
1H-indazole hydroformate,
3-{[(1S,4S)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]-carbonyl}-6-(6-methyl-2-furyl)-
1H-indazole hydroformate,
3-{[(1S,4S)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(6-methyl-2-thienyl)-
1H-indazole hydroformate,
5-(2-Furyl)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-
indazole hydroformate,
5-(3-Fluorophenyl)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-
1H-indazole hydroformate,
5-(4-Fluorophenyl)-3-{[(1S',4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-
1H-indazole hydroformate,
5-(4-Methoxyphenyl)-3-{[(1S',4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-
1H-indazole hydroformate,
6-(2-Furyl)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-
indazole hydroformate,
6-(3-Furyl)-3- {[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl} -1H-
indazole hydroformate,
3-{[(1S,4S)-5-Methyl2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole
hydroformate,
3-{[(lS,4S)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(3-thienyl)-1H-
indazole hydroformate,
5-(3-Furyl)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-
indazole hydroformate, and
5-Bromo-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
wherein the compound can be in the form of a mixture of enantiomers or a mixture of
diastereomers, or can be in the form of a single enantiomer or a single diastereomer.
19. A compound as claimed in claim 15, wherein said compound is a hydrochloride salt or a hydroformate salt.
20. A compound as claimed in claim 19, wherein said compound is selected from: 3-(2,5-Diazabicyclo[2.2.2]oct-2-ylcarbonyl)-6-(l,3-thiazol-2-yl)-1H-indazole hydrochloride,
3-(2,5-Diazabicyclo[2.2.2]oct-2-ylcarbonyl)-1H-indazole hydrochloride, 3-[(5-Methyl-2,5-diazabicyclo[2.2.2]oct-2-yl)carbonyl]-1H-indazole hydroformate, 3-[(5-Methyl-2,5-diazabicyclo[2.2.2]oct-2-yl)carbonyl]-6-(l,3-thiazol-2-yl)-1H-indazole hydroformate,
3-{[(1S,4S)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(l,3-thiazol-2-yl)-1H-indazole hydroformate,
3-{[(1S,4S)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(l,3-oxazol-2-yl)-1H-indazole hydroformate,
3-{[(1S,4S)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(l,3-thiazol-2-yl)-1H-indazole hydroformate,
3-{[(1S,4S)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(4-methyl-l,3-thiazol-2-yl)-1H-indazole hydroformate,
3-{[(1S,4S)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(5-methyl-l,3-thiazol-2-yl)-1H-indazole hydroformate,
3-{[(1S,4S)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(tetrahydro-2H-pyran-4-yl)- 1H-indazole hydroformate,
3-{[1S,4S)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(trifluoromethoxy)-
1H-indazole hydro formate,
3-{[(1S,45)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-7-(trifluoromethoxy)-
1H-indazole hydroformate,
5-(Cyclopentyloxy)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-
1H-indazole hydroformate,
5-(Cyclopropylmethoxy)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-
yl]carbonyl}-1H-indazole hydroformate,
5-Methoxy-3-[(5-methyl-2,5-diazabicyclo[2.2.2]oct-2-yl)carbonyl]-1H-indazole
hydroformate,
3-(2,5-Diazabicyclo[2.2.2]oct-2-ylcarbonyl)-5-methoxy-1H-indazole hydrochloride,
5-Methoxy-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-
indazole hydroformate,
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 hydroformate,
6-(Cyclopentyloxy)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-
1H-indazole hydroformate,
3-(2,5-Diazabicyclo[2.2.2]oct-2-ylcarbonyl)-6-methoxy-l1H-indazole hydrochloride,
6-Methoxy-3-[(5-methyl-2,5-diazabicyclo[2.2.2]oct-2-yl)carbonyl]-1H-indazole
hydroformate,
6-Methoxy-3-{[lS,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-
indazole hydrochloride,
6-Methoxy-3 - {[(1S,4S)S -methyl-2,5 -diazabicyclo [2.2.1 ]hept-2-yl]carbonyl} -1H-
indazole hydroformate,
N-(3-{[(15,45)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol-5-yl)-
N-propylurea hydroformate, and
N-{3-[(5-Methyl-2,5-diazabicyclo[2.2.2]oct-2-yl)carbonyl]-1H-indazol-5-
yl}cyclopropanecarboxamide hydroformate indazole,
wherein the compound can be in the form of a mixture of enantiomers or a mixture of
diastereomers, or can be in the form of a single enantiomer or a single diastereomer.
21. A compound as claimed in claim 16, wherein said compound is a hydrochloride salt or a hydroformate salt.
22. A compound as claimed in claim 21, wherein said compound is selected from:
3-{[(1S,4S)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(4-methyl-l,3-
thiazol-2-yl)- 1H-indazole hydroformate,
3-{[(1S,4S)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(5-methyl-l,3-
thiazol-2-yl)- 1H-indazole hydroformate,
3-{[(1S,4S-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(tetrahydro-2H-
pyran-4-yl)-1H-indazole hydroformate,
5-(3,6-Dihydro-2H-pyran-4-yl)-3-{[(lS,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-
yl]carbonyl}-1H-indazole hydroformate,
5-(Difluoromethoxy)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-
1H-indazole hydroformate,
6-(Difluoromethoxy)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-
1H-indazole hydroformate,
7-Fluoro-6-methoxy-3-{[(1S,4S)-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-
1H-indazole hydroformate,
N-(3-{[(1S,4S)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol-5-
yl)cyclopropanecarboxamide hydroformate,
N-(4-Fluorobenzyl)-N'[-(3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-
yl] carbonyl} -1H-indazol -5 -yl)urea hydroformate,
N-(4-Fluorobenzyl)-N'-{3-[(5-methyl-2,5-diazabicyclo[2.2.2]oct-2-yl)carbonyl]-1H-
indazol-5-yl}urea hydroformate,
N,N-Dimethyl-3-[(5-methyl-2,5-diazabicyclo[2.2.2]oct-2-yl)carbonyl]-1H-indazol-5-
amine hydroformate,
N,N-Dimethyl-3-{[(15,45)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-
indazol-5 -amine hydroformate,
N,N-Dimethyl-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-
indazol-6-amine hydroformate,
N-Cyclopentyl-N-(3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-
indazol-5-yl)urea hydroformate, and
N-Cyclopentyl-N'-{3-[(5-methyl-2,5-diazabicyclo[2.2.2]oct-2-yl)carbonyl]-1H-indazol-5-
yl}urea hydroformate indazole,
wherein the compound can be in the form of a mixture of enantiomers or a mixture of
diastereomers, or can be in the form of a single enantiomer or a single diastereomer.
23. A compound as claimed in claim 1, wherein said compound is selected from: 3-[2,5-Diazabicyclo[2.2.1]hept-2-ylcarbonyl]-1H- indazole,
3-{[5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(trifluoromethoxy)-1H-
indazole,
3-{[5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(trifluoromethyl)-1H-
indazole,
5-Bromo-3-[2,5-diazabicyclo[2.2.1]hept-2-ylcarbonyl]-1H-indazole,
5-Methoxy-3-{[5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
6-Bromo-3-[2,5-diazabicyclo[2.2.1]hept-2-ylcarbonyl]-li7-indazole,
3-{[5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(2-thienyl)-1H-indazole,
3-{[5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(4-methyl-2-thienyl)-1H-
indazole,
3-{[5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(5-methyl-2-thienyl)-lH-
indazole,
3-{[5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-phenyl-1H-indazole,
3-{[5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(2-thienyl)-1H-indazole,
3-{[5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(3-thienyl)-1H-indazole,
3-{[5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(4-methyl-2-thienyl)-1H-
indazole,
3-{[5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(5-methyl-2-furyl)-1H-
indazole,
3-{[5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(5-methyl-2-thienyl)-1H-
indazole,
5-(2-Furyl)-3-{[5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
5-(3-Fluorophenyl)-3-{[5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-
indazole,
5-(4-Fluorophenyl)-3-{[5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-
indazole,
5-(4-Methoxyphenyl)-3-{[5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-
indazole,
6-(2-Furyl)-3-{[5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
6-(3-Furyl)-3-{[5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
3-{[5-Ethyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
3-{[5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
3-{[5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(3-thienyl)-1H-indazole,
5-(3-Furyl)-3-{[5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
5-Bromo-3-{[5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
and pharmaceutically acceptable salts thereof,
wherein the compound can be in the form of a mixture of enantiomers or a mixture of diastereomers, or can be in the form of a single enantiomer or a single diastereomer.
24. A compound as claimed in claim 1, wherein said compound is selected from: 3-(2,5-Diazabicyclo[2.2.2]oct-2-ylcarbonyl)-6-(l,3-thiazol-2-yl)-1H-indazole, 3-[2,5-Diazabicyclo[2.2.1]hept-2-ylcarbonyl]-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]-1H-indazole, 3-[(5-Methyl-2,5-diazabicyclo[2.2.2]oct-2-yl)carbonyl]-6-(l,3-thiazol-2-yl)-1H-indazole, 3-{[5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole, 3-{[5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(l,3-thiazol-2-yl)-1H-indazole,
3-{[5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(2-thienyl)-1H-indazole, 3-{[5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(3-thienyl)-1H-indazole, 3-{[5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(4-methyl-2-thienyl)-1H-indazole,
3-{[5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(5-methyl-2-thienyl)-1H-indazole,
3-{[5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(trifluoromethoxy)-1H-indazole,
3-{[5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-phenyl-1H-indazole, 3-{[5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(l,3-oxazol-2-yl)-1H-indazole,
3-{[5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(l,3-thiazol-2-yl)-1H-indazole,
3-{[5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(2-thienyl)-1H-indazole, 3-{[5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(3-thienyl)-1H-indazole, 3-{[5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(4-methyl-l,3-thiazol-2-yl)-1H-indazole,
3-{[5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(4-methyl-2-thienyl)-1H-indazole,
3-{[5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(5-methyl-l,3-thiazol-2-yl)-1H-indazole,
3-{[5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(5-methyl-2-furyl)-1H-indazole,
3-{[5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(5-methyl-2-thienyl)-1H-
indazole,
3-{[5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(tetrahydro-2H-pyran-4-yl)-
1H-indazole,
3-{[5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(trifluoromethoxy)-1H-
indazole,
3-{[5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(trifluoromethyl)-1H-
indazole,
3-{[5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-7-(trifluoromethoxy)-1H-
indazole,
5-(2-Furyl)-3-{[5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
5-(3-Fluorophenyl)-3-{[5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-
indazole,
5-(3-Furyl)-3-{[5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
5-(4-Fluorophenyl)-3-{[5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-
indazole,
5-(4-Methoxyphenyl)-3-{[5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-
indazole,
5-(Cyclopentyloxy)-3-{[5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-
indazole,
5-(Cyclopropylmethoxy)-3-{[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-{[5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(l,3-thiazol-2-yl)-
1H-indazole,
5-Bromo-3-[2,5-diazabicyclo[2.2.1]hept-2-ylcarbonyl]-1H-indazole,
5-Hydroxy-3-{[5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
5-Methoxy-3-[(5-methyl-2,5-diazabicyclo[2.2.2]oct-2-yl)carbonyl]-1H-indazole,
3-(2,5-Diazabicyclo[2.2.2]oct-2-ylcarbonyl)-5-methoxy-1H-indazole,
5-Methoxy-3-{[5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
6-(2-Furyl)-3-{[5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
6-(3,6-Dihydro-2H-pyran-4-yl)-3-{[5-methyl-2,5-diazabicyclo[2.2.1]hept-2-
yl]carbonyl} -1H-indazole,
6-(3-Furyl)-3-{[5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
6-(Cyclopentyloxy)-3-{[5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-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[2.2.1 ]hept-2-yl]carbonyl}-1H-indazole,
N-(3-{[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}cyclopropanecarboxamide,
N-{3-[(5-Methyl-2,5-diazabicyclo[2.2.2]oct-2-yl)carbonyl]-1H-indazol-5-yl}-N-
propylurea,
and pharmaceutically acceptable salts thereof,
wherein the compound can be in the form of a mixture of enantiomers or a mixture of
diastereomers, or can be in the form of a single enantiomer or a single diastereomer.
25. A compound as claimed in claim 1, wherein said compound is selected from:
3-{[5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(4-methyl-l,3-thiazol-2-yl)-
1H-indazole,
3-{[5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(5-methyl-l,3-thiazol-2-yl)-
1H-indazole,
3-{ [5-Methyl-2,5-diazabicyclo[2.2.1 ]hept-2-yl]carbonyl}-5-(tetrahydro-2H-pyran-4-yl)-
1H-indazole,
5-(3,6-Dihydro-2HH-pyran-4-yl)-3-{[5-methyl-2,5-diazabicyclo[2.2.1]hept-2-
yl]carbonyl} -1H-indazole,
5-(Difluoromethoxy)-3-{[5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-
indazole,
6-(Difluoromethoxy)-3-{[5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-
indazole,
7-Fluoro-6-methoxy-3-{[5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-
indazole,
N-(3-{[5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol-5-
yl)cyclopropanecarboxamide,
N-(4-Fluorobenzyl)-N-(3-{[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-yl}urea,
N-(Cyclopropylmethyl)-3-[(5-methyl-2,5-diazabicyclo[2.2.2]oct-2-yl)carbonyl]-1H-
indazol-5-amine,
N-(Cyclopropylmethyl)-3-{[5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-
indazol-5-amine,
N,N-Dimethyl-3-[(5-methyl-2,5-diazabicyclo[2.2.2]oct-2-yl)carbonyl]-1H-indazol-5-
amine,
N,N-Dimethyl-3-{[5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol-5-
amine,
N,N-Dimethyl-3-{[5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol-6-
amine,
N-Cyclopentyl-N'-(3-{[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,
and pharmaceutically acceptable salts thereof,
wherein the compound can be in the form of a mixture of enantiomers or a mixture of
diastereomers, or can be in the form of a single enantiomer or a single diastereomer.
26. A compound as claimed in claim 1, wherein said compound is selected from:
5-Methoxy-3-{[5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
3-{[5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(trifluoromethoxy)-1H-
indazole,
3-{[5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(trifluoromethoxy)-1H-
indazole,
3-{[5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-7-(trifluoromethoxy)-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[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
5-(Difluoromethoxy)-3-{[5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-
indazole,
6-(Difluoromethoxy)-3-{[5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-
indazole,
7-Fluoro-6-methoxy-3-{[5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-
indazole,
and pharmaceutically acceptable salts thereof,
wherein the compound can be in the form of a mixture of enantiomers or a mixture of diastereomers, or can be in the form of a single enantiomer or a single diastereomer.

Documents:

3547-DELNP-2006-Abstract-(18-11-2011).pdf

3547-delnp-2006-abstract.pdf

3547-DELNP-2006-Claims-(18-11-2011).pdf

3547-delnp-2006-claims.pdf

3547-DELNP-2006-Correspondence Others-(18-11-2011).pdf

3547-DELNP-2006-Correspondence Others-(27-10-2011).pdf

3547-delnp-2006-correspondence-others 1.pdf

3547-delnp-2006-correspondence-others.pdf

3547-DELNP-2006-Description (Complete)-(18-11-2011).pdf

3547-delnp-2006-description (complete).pdf

3547-DELNP-2006-Form-1-(18-11-2011).pdf

3547-delnp-2006-form-1.pdf

3547-DELNP-2006-Form-13-(18-11-2011).pdf

3547-delnp-2006-form-18.pdf

3547-DELNP-2006-Form-2-(18-11-2011).pdf

3547-delnp-2006-form-2.pdf

3547-DELNP-2006-Form-3-(18-11-2011).pdf

3547-delnp-2006-form-3.pdf

3547-delnp-2006-form-5.pdf

3547-DELNP-2006-GPA-(18-11-2011).pdf

3547-delnp-2006-gpa.pdf

3547-delnp-2006-pct-210.pdf

3547-delnp-2006-pct-220.pdf

3547-delnp-2006-pct-237.pdf

3547-delnp-2006-pct-301.pdf

3547-delnp-2006-pct-304.pdf

3547-delnp-2006-pct-308.pdf

3547-DELNP-2006-Petition-137-(18-11-2011).pdf


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Patent Number 251990
Indian Patent Application Number 3547/DELNP/2006
PG Journal Number 17/2012
Publication Date 27-Apr-2012
Grant Date 19-Apr-2012
Date of Filing 20-Jun-2006
Name of Patentee MEMORY PHARMACEUTICALS CORPORATION
Applicant Address 100 PHILIPS PARKWAY, MONTVALE, NJ 07645, USA,
Inventors:
# Inventor's Name Inventor's Address
1 BRIAN HERBERT 3 GRANDVIEW AVENUE, STOCKHOLM, NEW JERSEY 07460, USA,
2 JIANGOU MA 20C ROLLING RIDGE ROAD, MONTVALE, NEW JERSEY 07645, USA
3 TRUC MINH NGUYEN 3 EAST 101ST STREET, APT. 5E, NEW YORK, NEW YORK 10029, USA,
4 RICHARD SCHUMACHER 16 DOROTHY DRIVE, MONROE, NEW YORK 10950, USA,
5 CLARA-MARIA GAUSS 4 WASHINGTON SQUARE VILLAGE # 5P, NEW YORK, NEW YORK 10012, USA,
6 ASHOK TEHIM 26 N. WALNUT STREET, RIDGEWOOD, NEW JERSEY, USA,
7 WENGE XIE 2347 PEMBROKE COURT, MAHWAH, NEW JERSEY 07430, USA,
PCT International Classification Number C07D 487/18
PCT International Application Number PCT/US2004/042852
PCT International Filing date 2004-12-22
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/606,897 2004-09-03 U.S.A.
2 60/530,891 2003-12-22 U.S.A.