HK1116484A - Therapeutic pyrazolo[3,4-b] pyridines and indazoles - Google Patents

Description

Therapeutic pyrazolo [3, 4-b ] pyridines and indazoles

Background

The monoamines noradrenaline and 5-hydroxytryptamine have various effects as neurotransmitters. These monoamines are taken up by neurons after being released into the synaptic cleft. Norepinephrine and 5-hydroxytryptamine are taken up from the synaptic cleft by their respective norepinephrine and 5-hydroxytryptamine transporters.

Drugs that inhibit the noradrenaline and 5-hydroxytryptamine transporters may prolong the effects of noradrenaline and 5-hydroxytryptamine, respectively, in the synapse, providing treatment for a variety of diseases. For example, the 5-hydroxytryptamine reuptake inhibitor fluoxetine (fIoxotine) has been found to be useful in the treatment of depression and other neurological disorders. The noradrenaline reuptake inhibitor atomoxetine has been approved as STRATTERA^®For use in the treatment of Attention Deficit Hyperactivity Disorder (ADHD). In addition, the noradrenaline and 5-hydroxytryptamine transporter inhibitor milnacipran (milnacipran) is being developed for the treatment of fibromyalgia, a disease that affects about 2% of the adult population in the united states. However, the FDA currently does not have any approved drug for the treatment of fibromyalgia. Thus, there is a continuing need in the art for compounds that are inhibitors of the norepinephrine transporter and also inhibitors of the 5-hydroxytryptamine transporter, and that inhibit both the norepinephrine transporter and the 5-hydroxytryptamine transporter, for the treatment of diseases including fibromyalgia, ADHD, neuropathic pain, urinary incontinence, generalized anxiety disorder, depression, schizophreniaAnd (6) treating the disease.

Disclosure of Invention

One aspect of the present invention provides a compound of formula I:

wherein: x is N or C (R)⁴)；R²Is 2-pyridyl or phenyl, wherein said 2-pyridyl or said phenyl may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, methyl, ethyl, CF₃Methoxy radical, CH₂F，CHF₂And CH₂OH; l is absent or methylene; r³Selected from the group consisting of 3-pyrrolidinyl, 4-piperidinyl, 3-piperidinyl, and 2-morpholinyl; r⁴，R⁵，R⁶And R⁷Is H; or R⁴，R⁵，R⁶And R⁷Three of (a) are H, and R is⁴，R⁵，R⁶And R⁷One of which is selected from the group consisting of halogen, methoxy, and C₁-C₃Alkyl groups. As independently selected from hydrogen, halogen, methyl, ethyl, CF₃Methoxy radical, CH₂F，CHF₂And CH₂R of phenyl substituted with 1 to 3 substituents of the group consisting of OH²Examples of (a) include, but are not limited to: 3-chlorophenyl, 2, 6-dibromophenyl, 2, 4, 6-tribromophenyl, 2, 6-dichlorophenyl, 4-trifluoromethylphenyl, 3-methyl-phenyl, 4-methyl-phenyl, 3, 5-dimethyl-phenyl, 3, 4, 5-trimethoxy-phenyl, 3, 5-dimethoxy-phenyl, 3, 4-dimethoxy-phenyl, 3-methoxy-phenyl, 4-methoxy-phenyl, 3, 5-difluoro-phenyl, 4-chloro-phenyl, 3-trifluoromethyl-phenyl, 3, 5-dichloro-phenyl, 2-methoxy-5-methyl-phenyl, 2-fluoro-5-methyl-phenyl, 4-chloro-2-trifluoromethyl-phenyl, and the like.

In certain embodiments of formula I, X is C (R)⁴)，R²Is phenyl, and R⁴，R⁵，R⁶And R⁷Is H; or R⁴，R⁵，R⁶And R⁷Three of (A) are H, and R is⁴，R⁵，R⁶And R⁷One of which is selected from the group consisting of halogen, methoxy, and C₁-C₃Alkyl groups-compounds of formula II. In certain embodiments of formula II, R⁴，R⁵，R⁶And R⁷Is H, R²Optionally substituted with 1 or 2 substituents independently selected from the group consisting of hydrogen and fluorine. In certain embodiments of formula II, R³Is 3-pyrrolidinyl. Wherein R is³Examples of compounds of formula II that are 3-pyrrolidinyl include: (R) -1- (2, 5-difluoro-phenyl) -3- (pyrrolidin-3-ylmethoxy) -1H-indazole; (R) -1- (2, 4-difluoro-phenyl) -3- (pyrrolidin-3-ylmethoxy) -1H-indazole; (S) -1- (2, 4-difluoro-phenyl) -3- (pyrrolidin-3-ylmethoxy) -1H-indazole; (S) - (-) -1- (2-fluorophenyl) -3- (pyrrolidin-3-ylmethoxy) -1H-indazole; (S) -1- (2, 6-difluoro-phenyl) -3- (pyrrolidin-3-ylmethoxy) -1H-indazole; (R) -1-phenyl-3- (pyrrolidin-3-ylmethoxy) -1H-indazole; and (S) - (-) -1- (2-fluorophenyl) -3- (pyrrolidin-2-yloxy) -1H-indazole. In certain embodiments of formula II, R³Is 3-or 4-piperidinyl. Wherein R is³Examples of compounds of formula II that are 3-or 4-piperidinyl include: (±) -1- (2, 5-difluoro-phenyl) -3- (piperidin-3-ylmethoxy) -1H-indazole; 1- (3-fluoro-phenyl) -3- (piperidin-4-yloxy) -1H-indazole; 1-phenyl-3- (piperidin-4-yloxy) -1H-indazole; 1- (2, 6-difluoro-phenyl) -3- (piperidin-4-yloxy) -1H-indazole; 1- (2, 5-difluoro-phenyl) -3- (piperidin-4-yloxy) -1H-indazole; and (±) -1- (3-fluoro-phenyl) -3- (piperidin-3-ylmethoxy) -1H-indazole. Wherein R is³Other compounds of formula II that are 3-or 4-piperidinyl include: (S) - (-) -1- (2-fluorophenyl) -3- (piperidin-3-ylmethoxy) -1H-indazole; (S) -1- (2, 6-difluoro-phenyl) -3- (piperidin-3-ylmethoxy) -1H-indazole; and (S) - (-) -1-phenyl-3- (piperidin-3-ylmethoxy) -1H-indazole. In certain embodiments of formula IIIn, R³Is 2-morpholinyl. Wherein R is³Examples of compounds of formula II that are 2-morpholinyl include: (S) - (+) -1- (2, 5-difluorophenyl) -3- (morpholin-2-ylmethoxy) -1H-indazole; (S) -1- (2, 6-difluoro-phenyl) -3- (morpholin-2-ylmethoxy) -1H-indazole; (S) - (+) -1- (2, 4-difluorophenyl) -3- (morpholin-2-ylmethoxy) -1H-indazole; (S) -1- (3, 4-difluoro-phenyl) -3- (morpholin-2-ylmethoxy) -1H-indazole; (S) - (+) -1- (2-fluorophenyl) -3- (morpholin-2-ylmethoxy) -1H-indazole; and (S) - (+) -3- (morpholin-2-ylmethoxy) -1-phenyl-1H-indazole. In certain embodiments, the compound of formula I is (S) -1- (2, 6-difluoro-phenyl) -3- (morpholin-2-ylmethoxy) -1H-indazole, or a pharmaceutically acceptable salt thereof.

In certain embodiments, the present invention provides 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole, or pharmaceutically acceptable salts thereof. In another embodiment, the present invention provides 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole L-tartrate.

In certain embodiments of formula I, X is C (R)⁴)，R²Is phenyl, R⁶Selected from the group consisting of halogen, methoxy, and C₁-C₃Alkyl groups-compounds of formula III. In certain embodiments of formula III, R²Optionally substituted with 1 or 2 substituents independently selected from the group consisting of hydrogen and fluorine. In certain embodiments of formula III, R³Is 3-pyrrolidinyl. Wherein R is³An example of a compound of formula III that is 3-pyrrolidinyl is (R) -1- (2, 5-difluoro-phenyl) -5-fluoro-3- (pyrrolidin-3-ylmethoxy) -1H-indazole. In certain embodiments of formula III, R³Is 4-piperidyl or 3-piperidyl. Wherein R is³An example of a compound of formula III that is 4-piperidinyl or 3-piperidinyl is 1- (2, 6-difluoro-phenyl) -5-fluoro-3- (piperidin-4-yloxy) -1H-indazole. In certain embodiments of formula III, R³Is 2-morpholinyl. Wherein R is³Examples of compounds of formula II that are 2-morpholinyl include: (S) -1- (2, 6-difluoro-phenyl) -5-fluoro-3- (morpholin-2-ylmethoxy) -1H-indazole; (S) -1- (2, 5-difluoro-phenyl) -5-fluoro-3- (morpholin-2-ylmethoxy) -1H-indazole; (S) - (+) -1-(2, 4-difluorophenyl) -5-fluoro-3- (morpholin-2-ylmethoxy) -1H-indazole; and (S) - (+) -5-fluoro-1- (2-fluorophenyl) -3- (morpholin-2-ylmethoxy) -1H-indazole. In certain embodiments, the compound of formula I is (S) -1- (2, 5-difluoro-phenyl) -5-fluoro-3- (morpholin-2-ylmethoxy) -1H-indazole, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of formula I is (S) - (+) -1- (2, 4-difluorophenyl) -5-fluoro-3- (morpholin-2-ylmethoxy) -1H-indazole, or a pharmaceutically acceptable salt thereof.

In certain embodiments of formula I, X is C (R)⁴)，R²Is phenyl, R⁷Selected from the group consisting of halogen, methoxy, and C₁-C₃Alkyl groups-compounds of formula IV. In certain embodiments of formula IV, R²Optionally substituted with 1 or 2 substituents independently selected from the group consisting of hydrogen and fluorine. In certain embodiments of formula IV, R³Is 3-pyrrolidinyl. In certain embodiments of formula IV, R³Is 3-or 4-piperidinyl. Wherein R is³Examples of compounds of formula IV that are 3-or 4-piperidinyl include: 4-fluoro-1- (2-fluoro-phenyl) -3- (piperidin-4-yloxy) -1H-indazole; 1- (2, 5-difluoro-phenyl) -4-fluoro-3- (piperidin-4-yloxy) -1H-indazole; 1- (2, 4-difluoro-phenyl) -4-fluoro-3- (piperidin-4-yloxy) -1H-indazole; (S) -1- (2, 5-difluoro-phenyl) -4-fluoro-3- (piperidin-3-ylmethoxy) -1H-indazole; and (S) -4-fluoro-1- (2-fluoro-phenyl) -3- (piperidin-3-ylmethoxy) -1H-indazole. In certain embodiments of formula IV, R³Is 2-morpholinyl. Wherein R is³An example of a compound of formula IV that is 2-morpholinyl is (S) -1- (2, 5-difluoro-phenyl) -4-fluoro-3- (morpholin-2-ylmethoxy) -1H-indazole.

In certain embodiments of formula I, X is C (R)⁴)，R²Is phenyl, R⁵Selected from the group consisting of halogen, methoxy, and C₁-C₃Alkyl groups-compounds of formula V. In certain embodiments of formula I, X is C (R)⁴)，R²Is phenyl, R⁴Selected from the group consisting of halogen, methoxy, and C₁-C₃Alkyl group-a compound of formula VI. In certain embodiments of formula IX is C (R)⁴)，R²Is a 2-pyridyl-compound of formula VII. In certain embodiments of formula I, X is N, R²Is phenyl-a compound of formula VIII. In certain embodiments of formula I, X is N, R²Is a 2-pyridyl-compound of formula IX. In certain embodiments of formula I, X is C (R)⁴)，R²Is phenyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of hydrogen and fluoro (e.g., 2, 6-difluoro-phenyl, 2-fluoro-phenyl, 4-fluoro-phenyl, 2, 4-difluoro-phenyl, 2, 5-difluoro-phenyl, or 3, 4-difluoro-phenyl).

In certain embodiments of formula I, X is C (R)⁴)，R²Is phenyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of hydrogen and fluorine, and-L-R³Comprises the following steps:

wherein the wavy line indicates the point of attachment to the remainder of the compound.

In certain embodiments of formula I, X is C (R)⁴)，R²Is phenyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of hydrogen and fluorine, and-L-R³Comprises the following steps:

wherein the wavy line indicates the point of attachment to the remainder of the compound.

In certain embodiments of formula I, X is C (R)⁴)，R²Is phenyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of hydrogen and fluorine, and-L-R³Comprises the following steps:

wherein the wavy line indicates the point of attachment to the remainder of the compound. In certain embodiments, -L-R³Is composed of

Wherein the wavy line indicates the point of attachment to the remainder of the compound.

In certain embodiments of formula I, X is C (R)⁴)，R²Is phenyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of hydrogen and fluorine, and-L-R³Comprises the following steps:

wherein the wavy line indicates the point of attachment to the remainder of the compound.

Another aspect of the invention provides a compound of formula XI:

or a pharmaceutically acceptable salt thereof; wherein: x is N or C (R)⁴)；R²Is 2-pyridyl or phenyl, wherein said 2-pyridyl or said phenyl may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, methyl, ethyl, CF₃Methoxy radical, CH₂F，CHF₂And CH₂OH; l is absent or methylene; r⁴，R⁵，R⁶And R⁷Is H; or R⁴，R⁵，R⁶And R⁷Three in (B) are H, R⁴，R⁵，R⁶And R⁷One of which is selected from the group consisting of halogen, methoxy, and C₁-C₃Alkyl groups; r³Selected from the group consisting of 3-pyrrolidinyl, 4-piperidinyl, 3-piperidinyl, and 2-morpholinyl, wherein the nitrogen in the ring of the 3-pyrrolidinyl, 4-piperidinyl, 3-piperidinyl, or 2-morpholinyl is bound by C₁-C₃Alkyl or-C (O) -O-C₁-C₄Alkyl substitution. In certain embodiments, compounds of formula XI can be prepared by removing the C from the nitrogen in the ring of the 3-pyrrolidinyl, 4-piperidinyl, 3-piperidinyl, or 2-morpholinyl group using suitable reagents and conditions₁-C₃Alkyl or-C (O) -O-C₁-C₄Alkyl, to form a compound of formula I.

Another aspect of the invention provides a method of treating a mammal suffering from a condition mediated by noradrenaline and/or mediated by 5-hydroxytryptamine comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula I.

Another aspect of the invention provides a method of treating Attention Deficit Hyperactivity Disorder (ADHD) comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula I.

Another aspect of the invention provides a method of treating a disorder or condition selected from neuropathic pain, stress urinary incontinence, anxiety, depression, and schizophrenia, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula I.

Another aspect of the invention provides a method of treating fibromyalgia comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula I. In certain embodiments, the present invention provides methods of treating fibromyalgia comprising administering to a mammal in need of such treatment a therapeutically effective amount of 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole, or pharmaceutically acceptable salts thereof. In certain embodiments, the present invention provides methods of treating fibromyalgia comprising administering to a mammal in need of such treatment a therapeutically effective amount of 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole L-tartrate.

Another aspect of the invention provides a method of treating a mammal having a condition mediated by noradrenaline and/or mediated by 5-hydroxytryptamine, comprising administering to a mammal in need of such treatment: (a) a compound of formula I or a pharmaceutically acceptable salt thereof; (b) the other is a pharmaceutically active compound that is an antidepressant or anxiolytic, or a pharmaceutically acceptable salt thereof; and (c) a pharmaceutically acceptable carrier; wherein the active compounds "a" and "b" are used in amounts such that the composition is effective for treating such disorders or conditions.

Another aspect of the present invention provides a pharmaceutical composition comprising: a therapeutically effective amount of a compound of formula I and a pharmaceutically acceptable carrier. In certain embodiments, such compositions are useful for treating disorders mediated by noradrenaline and/or by 5-hydroxytryptamine.

Another aspect of the invention provides crystalline 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole or pharmaceutically acceptable salts thereof. In one embodiment, the present invention provides crystalline 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole L-tartrate. In certain embodiments, crystalline 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole L-tartrate has an X-ray powder diffraction pattern measured using cuka radiation comprising 2-theta values ± 0.1 as follows: 22.0, 20.9, and 18.6. In certain embodiments, crystalline 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole L-tartrate has an X-ray powder diffraction pattern measured using cuka radiation comprising 2-theta values ± 0.1 as follows: 13.2, 11.8, and 18.7.

In certain embodiments, crystalline 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole L-tartrate has an X-ray powder diffraction pattern measured using cuka radiation comprising 2-theta values ± 0.1 as follows: 37.8, 33.8, 16.8, 11.9, 13.2, 29.0, 19.5, 27.6, 31.9, 25.5, 17.9, 23.8, 20.1, 26.0, 23.2, 29.6, 21.4, 22.0, 20.9, and 18.6.

In certain embodiments, crystalline ethanedisulfonic acid 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole has an X-ray powder diffraction pattern measured using CuKa radiation comprising 2-theta values ± 0.1 as follows: 22.5, 20.0, and 21.2. In certain embodiments, crystalline ethanedisulfonic acid 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole has an X-ray powder diffraction pattern measured using CuKa radiation comprising 2-theta values ± 0.1 as follows: 33.0, 15.7, 12.4, 14.1, 28.2, 30.1, 17.3, 27.1, 19.0, 25.5, 24.1, 11.6, 22.5, 20.0, and 21.2.

In certain embodiments, crystalline 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole fumarate has an X-ray powder diffraction pattern measured using CuK α radiation comprising 2-theta values ± 0.1 as follows: 24.6, 20.1, and 23.2. In certain embodiments, crystalline 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole fumarate has an X-ray powder diffraction pattern measured using CuK α radiation comprising 2-theta values ± 0.1 as follows: 12.7, 31.5, 11.7, 27.8, 22.4, 26.6, 20.9, 17.2, 15.9, 29.5, 28.4, 25.3, 18.1, 24.6, 20.1, and 23.2.

In certain embodiments, crystalline 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole hydrobromide has an X-ray powder diffraction pattern measured using CuK α radiation comprising 2-theta values ± 0.1 as follows: 23.8, 16.8, and 25.1. In certain embodiments, crystalline 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole hydrobromide has an X-ray powder diffraction pattern measured using CuK α radiation comprising 2-theta values ± 0.1 as follows: 18.0, 21.6, 38.0, 15.4, 14.1, 30.4, 26.3, 33.5, 28.0, 25.6, 12.6, 29.3, 20.1, 24.0, 23.8, 16.8, 25.1, and 20.9.

In certain embodiments, crystalline hemi-L-tartaric acid 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole has an X-ray powder diffraction pattern measured using CuK α radiation comprising 2-theta values ± 0.1 as follows: 34.5, 36.2, and 39.2. In certain embodiments, crystalline hemi-L-tartaric acid 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole has an X-ray powder diffraction pattern measured using CuK α radiation comprising 2-theta values ± 0.1 as follows: 10.3, 14.9, 15.7, 17.0, 19.0, 20.5, 21.6, 22.7, 23.9, 24.7, 25.6, 27.7, 29.8, 32.6, 34.5, 36.2, and 39.2.

In certain embodiments, crystalline 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole L-malate has an X-ray powder diffraction pattern measured using CuK α radiation comprising 2-theta values ± 0.1 as follows: 21.9, 21.5, and 20.1. In certain embodiments, crystalline 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole L-malate has an X-ray powder diffraction pattern measured using CuK α radiation comprising 2-theta values ± 0.1 as follows: 36.8, 24.5, 26.3, 28.7, 12.2, 25.2, 23.1, 18.2, 30.4, 27.3, 14.7, 20.9, 11.4, 19.2, 16.7, 21.9, 21.5, and 20.1.

In certain embodiments, crystalline 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole phosphate has an X-ray powder diffraction pattern measured using CuK α radiation comprising 2-theta values ± 0.1 as follows: 21.2, 24.3, and 23.2. In certain embodiments, crystalline 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole phosphate has an X-ray powder diffraction pattern measured using CuK α radiation comprising 2-theta values ± 0.1 as follows: 12.1, 34.7, 14.0, 30.9, 25.6, 29.3, 33.4, 16.9, 20.6, 15.6, 26.9, 22.8, 20.0, 27.3, 17.9, 21.2, 24.3, and 23.2.

In certain embodiments, crystalline 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole sulfate has an X-ray powder diffraction pattern measured using CuK α radiation comprising 2-theta values ± 0.1 as follows: 24.3, 20.2, and 12.1. In certain embodiments, crystalline 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole sulfate has an X-ray powder diffraction pattern measured using CuK α radiation comprising 2-theta values ± 0.1 as follows: 26.7, 27.6, 17.2, 21.4, 25.4, 29.7, 16.4, 15.0, 20.0, 18.3, 23.0, 24.3, 20.2, and 12.1.

Definition of

The term "alkyl group" or "alkyl" includes straight chainOr a branched carbon chain group. The term "alkylene" refers to a divalent radical of an unsubstituted or substituted alkane. For example, "C_1-6Alkyl "is an alkyl group having 1 to 6 carbon atoms. C₁-C₆Examples of straight chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, and n-hexyl. Examples of branched alkyl groups include, but are not limited to, isopropyl, tert-butyl, isobutyl, and the like. Examples of alkylene groups include, but are not limited to, -CH₂-，-CH₂-CH₂-，-CH₂-CH(CH₃)-CH₂-, and- (CH)₂)_1-3-. The alkylene group may be substituted with groups as set forth below for alkyl.

The term alkyl includes both "unsubstituted alkyls" and "substituted alkyls," the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents are independently selected from the group consisting of halogen, I, Br, Cl, F, -OH, -COOH, trifluoromethyl, -NH₂，-OCF₃And O-C₁-C₃Alkyl groups.

Typical substituted alkyl groups are thus 2, 3-dichloropentyl, 3-hydroxy-5-carboxyhexyl, 2-aminopropyl, pentachlorobutyl, trifluoromethyl, methoxyethyl, 3-hydroxypentyl, 4-chlorobutyl, 1, 2-dimethyl-propyl, and pentafluoroethyl.

"halogen" includes fluorine, chlorine, bromine, and iodine.

Some of the compounds of the present invention may exist as stereoisomers, including enantiomers, diastereomers and geometric isomers. Geometric isomers include the alkenyl-bearing compounds of the present invention, which may exist in either the E or Z configuration, in which case all geometric forms thereof, including the E and Z forms, cis and trans, and mixtures thereof, are within the scope of the present invention. Some compounds of the present invention have a cycloalkyl group, which may be substituted at more than one carbon atom, in which case all geometric forms thereof (cis and trans, and mixtures thereof) are within the scope of the present invention. All such forms, including (R), (S), epimers, diastereomers, cis, trans, homolateral (syn), heterolateral (anti), (E), (Z), solvates (including hydrates), tautomers, and mixtures thereof, are contemplated as being included in the compounds of the present invention.

Drawings

FIGS. 1-8 are powder x-ray diffraction (PXRD) patterns of the following compounds: l-tartaric acid 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole (fig. 1); ethanedisulfonic acid 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole (FIG. 2); fumaric acid 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole (fig. 3); hydrobromic acid 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole (figure 4); hemil-tartaric acid 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole (fig. 5); l-malic acid 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole (fig. 6); 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole phosphate (fig. 7); and 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole sulfate (fig. 8).

FIGS. 9-16 are differential scanning calorimetry traces of the following compounds: l-tartaric acid 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole (fig. 9); ethanedisulfonic acid 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole (fig. 10); 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole fumarate (fig. 11); hydrobromic acid 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole (figure 12); hemil-tartaric acid 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole (fig. 13); l-malic acid 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole (fig. 14); 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole phosphate (fig. 15); and 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole sulfate (fig. 16).

FIG. 17 is a calculated powder x-ray diffraction (PXRD) pattern for L-tartaric acid 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole.

Detailed Description

Preparation of compounds

The compounds of the invention (e.g., compounds of formula I) can be prepared by applying synthetic methods known in the art and outlined in the schemes below.

Scheme 1

Phenylhydrazine b (e.g., 2-fluorophenylhydrazine) or pyridylhydrazine (e.g., 2-hydrazinopyridine), which has been treated with or without a base such as N, N-diisopropylethylamine or triethylamine in a suitable solvent (e.g., ethanol or Tetrahydrofuran (THF)), is reacted with an anhydride a (e.g., isatoic anhydride) to give a hydrazide c (e.g., 2-amino-benzoic acid N' - (2-fluoro-phenyl) -hydrazide). C is then acidified and reacted with sodium nitrite followed by ethanol to yield indazole d (e.g., 1- (2-fluoro-phenyl) -1H-indazol-3-ol).

The compound d1- (2-fluoro-phenyl) -1H-indazol-3-ol, the compound e (LG-O-L-R)³-PG) and a base to give f (e.g., 4- [1- (2-fluoro-phenyl) -1H-indazol-3-yloxy)]Piperidine-1-carboxylic acid tert-butyl ester), wherein the base is for example a hydride base (e.g. sodium hydride, potassium hydride), 2-tert-butylimino-2-diethylamino-1, 3-dimethyl-perhydro-1, 3, 2-diazaphospho-cyclohexane (BEMP), 2-tert-butylimino-2-diethylamino-1, 3-dimethyl-perhydro-1, 3, 2-diazaphospho-cyclohexane on polystyrene (PS-BEMP resin), Na in anhydrous DMF (dimethylformamide)₂CO₃，K₂CO₃Or Cs₂CO₃And the like. LG of e is a suitable leaving group such as methanesulphonyloxy, benzenesulphonyloxy, toluene-4-sulphonyloxy, and trifluoromethanesulphonyloxy. PG of e is a suitable amine protecting group such as t-butyl-ester (BOC). One skilled in the art will recognize that a wide variety of protecting groups other than BOG may be presentTo be used as appropriate for R³Amine protecting Groups of (e.g., see Greene and Wuts, Protective Groups in Organic Synthesis, Wiley-lnterscience; 3rd edition (1999)). Thus, an example of e is tert-butyl 4-methanesulfonyloxy-piperidine-1-carboxylate. Subsequently, the PG substituent of f is removed to yield g (e.g., 1- (2-fluoro-phenyl) -3- (piperidin-4-yloxy) -1H-indazole). Groups such as BOC can be hydrolyzed under acidic conditions.

Scheme 2

Scheme 2 describes the synthesis of anhydride a. a (e.g., 6-fluoro-1H-benzo [ d ] [1, 3] oxazine-2, 4-dione) can be synthesized by: 2-aminobenzoic acid j (e.g., 2-amino-5-fluorobenzoic acid) is reacted with a base, such as sodium carbonate in water, followed by addition of a phosgene solution in toluene.

Scheme 3

In scheme 3, another alternative synthetic route to c is depicted. Reacting 2-amino-benzoic acid j (e.g., 2-amino-5-chloro-benzoic acid) with hydrazine b (e.g., 2, 5-difluoro-phenyl) -hydrazine) in the presence of a coupling agent such as 1- [3- (dimethylamino) propyl ] -3-Ethylcarbodiimide (EDCI), Dicyclohexylcarbodiimide (DCC), 1, 1 '-Carbonyldiimidazole (CDI) and a base such as Dimethylaminopyridine (DMAP), N-Diisopropylethylamine (DIPEA) or triethylamine to give c (e.g., 2-amino-5-chloro-benzoic acid N' - (2, 5-difluoro-phenyl) -hydrazide). Alternatively, j may be reacted with b and HOBT (1-hydroxybenzotriazole hydrate) in a solvent such as anhydrous THF (tetrahydrofuran). N-methyl-morpholine (NMM) was then added and EDAC-HCl (1- [3- (dimethylamino) propyl ] -3-ethylcarbodiimide hydrochloride) was then added to give compound c.

Scheme 4

Scheme 4 describes the synthesis of 1H-pyrazolo [3, 4-b ] pyridine q. Nicotinoyl chloride k (e.g., 2-chloronicotinoyl chloride) is reacted with hydrazine m (e.g., phenylhydrazine) and a base such as triethylamine in a solvent such as anhydrous dichloromethane to give o (e.g., 1-phenyl-1H-pyrazolo [3, 4-b ] pyridin-3-ol). Then, compound o is cyclized by heating at 175 ℃ to give p. P is reacted as in the conversion of d to g in scheme 1 to provide q.

Evaluation of Compounds

The compounds of the invention (e.g., compounds of formula I and pharmaceutically acceptable salts thereof) can be assayed for their ability to inhibit the norepinephrine transporter and/or the 5-hydroxytryptamine transporter.

The ability of the compounds of the present invention to inhibit the norepinephrine transporter and/or 5-hydroxytryptamine transporter can be determined using conventional radioligand receptor transfer assays. The receptor may be expressed heterologously in a cell line and the experiments are performed in a membrane preparation obtained from a cell line expressing the noradrenaline transporter and/or the 5-hydroxytryptamine transporter.

In certain embodiments, compounds of formula I may be assayed for their ability to alleviate capsaicin-mediated mechanical nociception in rats (e.g., Sluka, KA, (2002) J of neuroscience, 22 (13): 5687-. For example, a rat model of mechanical nociceptive dysesthesia mediated by capsaicin can be performed as follows:

on day 0, male Sprague-Dawley rats (-150 g) in dark cycles were placed in suspended cages with cable bottomsAnd allowed to settle for 0.5 hours in a dark and quiet room. Day 0 Paw Withdrawal Thresholds (PWT) were determined for the left hind paw by Von Frey Hair assessment using the Dixon Up and Down method. After evaluation, the plantar muscles of the right hind paw were injected with 100 μ l capsaicin (0.25% concentration in 10% ethanol, 10% Tween 80 in sterile saline). On day 6, the PWT of the left hind paw (contralateral to the injection site) was determined for each animal. Animals with a read-ahead value of PWT < 11.7g from day 6 onwards were considered nociceptive paresthetic responders and were regrouped so that each cage had a similar average PWT value. On day 7, responders were given (e.g., orally, intraperitoneally, subcutaneously, etc.) 10 ml/kg vehicle (0.5% HPMC (hydroxy-propylmethylcellulose)/0.2% Tween)^TM80) Or a carrier plus compound. 2 hours after a single dose (or at approximately the time corresponding to the estimated C) without the investigator knowing the dosing regimen_maxTime of (d) to determine the PWT value of the contralateral side. One skilled in the art can determine an appropriate time (e.g., 1 hour, 2 hours, etc.) for determining the PWT value for the contralateral side.

For each animal, the 2 hour PWT value was subtracted from the day 6 PWT value to give a Δ PWT value, which represents the change in PWT due to 2 hour drug treatment. In addition, the PWT of day 0 was subtracted from the PWT of day 6 to give a baseline window of nociceptive abnormalities for each animal. To determine the percent inhibition (%) of nociceptive paresthesia for each animal normalized to the vehicle control experiment, the following formula was used:

% nociceptive dysesthesia ═ 100 × (Δ PWT (drug) -mean Δ PWT (vehicle))/(baseline-mean Δ PWT (vehicle)).

Pharmaceutically acceptable salts and solvates

The compounds for use in the present invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, solvated forms (including hydrated forms) are intended to be included within the scope of the present invention.

The compounds of the present invention (e.g., compounds of formula I) can further form pharmaceutically acceptable salts, including but not limited to acid addition salts and base salts. Pharmaceutically acceptable salts of the compounds of formula I include acid addition salts and base salts (including double salts) thereof. Examples of suitable Salts can be found, for example, in Stahl and Wermuth, "Handbook of Pharmaceutical Salts: properties, Selection, and Use ", Wiley-VCH, Weinheim, Germany (2002); and "Pharmaceutical Salts" by Berge et al, J. of Pharmaceutical Science, 1977: 66-1-19.

Pharmaceutically acceptable acid addition salts of the compounds of formula I include non-toxic salts derived from inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, phosphorus and the like, as well as organic acids such as aliphatic mono-and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids and the like. Thus, such salts include the acetate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate, borooctanoate, camphorsulfonate, chlorobenzoate, citrate, edisylate (1, 2-ethanedisulfonate), dihydrogenphosphate, dinitrobenzoate, ethanesulfonate (ethanesulfonate), fumarate, glucoheptanoate, gluconate, glucuronate, hexahenate (hibenzate), hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isobutyrate, monohydrogenphosphate, isethionate, D-lactate, L-lactate, malate, maleate, malonate, mandelate, methanesulfonate (methanesulfonate), metaphosphate, methylbenzoate, methyl benzoate, salts of the compound of formula I, Methosulfate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, phenylacetate, phosphate, phthalate, propionate, pyrophosphate, pyrosulfate, saccharate, sebacate, stearate, suberate, succinate, sulfate, sulfite, D-tartrate, L-tartrate, tosylate, hydroxynaphthoate (xinafoate), and the like. Other salts are amino acid salts (e.g., arginine salts), gluconate salts, galacturonate salts, and the like.

Acid addition salts of basic compounds can be prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt. The free base form can be regenerated by contacting the salt form with a base and isolating the base. The free base form differs somewhat from its corresponding salt form in certain physical properties such as solubility in polar solvents.

Pharmaceutically acceptable base addition salts may be formed with metals or amines, such as alkali or alkaline earth metal hydroxides, or organic amines. Examples of metals used as cations are aluminum, calcium, magnesium, potassium, sodium, and the like. Examples of suitable amines include arginine, choline, chloroprocaine, N' -benzhydrylethylenediamine, diethylamine, diethanolamine (diolamine), ethylenediamine (ethane-1, 2-diamine), glycine, lysine, meglumine, N-methylmethacetamine, ethanolamine, procaine (benzathine), and tromethamine.

Base addition salts of acidic compounds can be prepared by contacting the free acid form with a sufficient amount of the desired base to form a salt. The free acid form can be regenerated by contacting the salt form with an acid and isolating the acid. The free acid form differs somewhat from its corresponding salt form in certain physical properties such as solubility in polar solvents.

Pharmaceutical compositions and methods of administration

The present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, diluent, or excipient therefor. The term "pharmaceutical composition" refers to a composition suitable for administration as a medicine or veterinary use. The term "therapeutically effective amount" means an amount of a compound or a pharmaceutically acceptable salt thereof that is sufficient to inhibit, arrest or allow amelioration of the disease being treated, when administered alone or in combination with another agent or treatment in a particular subject or population of subjects. The therapeutically effective amount can be determined experimentally, either in the laboratory or clinically, for a particular disease and subject being treated, e.g., in humans or other mammals.

It is understood that determination of the appropriate dosage form, dosage amount and route of administration is within the skill of one of ordinary skill in the pharmaceutical and medical arts, and will be described below.

The compounds of the present invention may be formulated into pharmaceutical compositions in the form of syrups, elixirs, suspensions, powders, granules, tablets, capsules, lozenges, tablets, aqueous solutions, ointments, salves, lotions, gels, emulsions, and the like. Preferably, the compounds of the invention will result in a decrease (as measured quantitatively or qualitatively) in a syndrome or disease index associated with a disorder mediated by noradrenaline and/or mediated by 5-hydroxytryptamine.

For preparing pharmaceutical compositions from the compounds of the present invention, the pharmaceutically acceptable carrier may be solid or liquid. Solid form preparations include powders, tablets, pills, capsules, sachets, suppositories, and dispersible granules. A solid carrier may be one or more substances which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid which forms a mixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

Powders and tablets contain from 1% to 95% (w/w) of the active compound. In certain embodiments, the active compound is 5% to 70% (w/w). Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term "preparation" is intended to include a formulation of an active compound encapsulated with an encapsulating material as a carrier, wherein the active ingredient is surrounded by, and thus associated with, the carrier, either together with or in the absence of other carriers. Similarly, kits and lozenges are included. Tablets, powders, capsules, pills, sachets and lozenges may be used as solid dosage forms suitable for oral administration.

To prepare suppositories, a low melting wax (such as a mixture of fatty acid glycerides or cocoa butter) is first melted and the active ingredient is uniformly dispersed therein by stirring. The molten homogeneous mixture is then poured into suitably sized moulds, cooled and thereby solidified.

Liquid form preparations include solutions, suspensions and emulsions, for example, water or water/propylene glycol solutions. For parenteral injection, liquid preparations may be formulated as solutions in aqueous polyethylene glycol solutions.

Aqueous solutions suitable for oral use may be prepared by: the active ingredient is dissolved in water and colorants, flavors, stabilizers, and thickeners are added as needed. Aqueous suspensions suitable for oral use may be prepared by: finely divided active components are dispersed in water using a variety of viscous materials such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.

Also included are solid form preparations which are intentionally converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. In addition to the active ingredients, these formulations may contain coloring agents, flavoring agents, stabilizing agents, buffering agents, synthetic and natural sweeteners, dispersing agents, thickening agents, solubilizing agents, and the like.

The pharmaceutical formulation is preferably in unit dosage form. In such form, the preparation is subdivided into a plurality of unit doses containing appropriate quantities of the active component. The unit dosage form may be a packaged preparation, the package containing discrete quantities of the preparation, in packaged tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form may be a capsule, tablet, packet or lozenge itself, or it may be any of the appropriate number of capsules, tablets, packets or lozenges in packaged form.

The amount of active ingredient in a unit dose formulation may vary or be adjusted from 0.1mg to 1000mg, preferably 1.0mg to 100mg, or from 1% to 95% (w/w) of the unit dose, depending on the particular application and the potency of the active ingredient. For example, a unit dose may comprise 10, 15, 20, 25, 30, 40, or 50mg of a compound of the invention. The compositions may also contain other compatible therapeutic agents, if desired.

Pharmaceutically acceptable carriers are determined, in part, by the particular composition being administered and the particular method used to administer the composition. Thus, there are a number of suitable formulations of The pharmaceutical compositions of The present invention (see, e.g., Remington: The Science and Practice of Pharmacy, 20 The., Gennaro et al, eds., Lippincott Williams and Wilkins, 2000).

The compounds of the present invention, alone or in combination with other suitable components, may be formulated into aerosol formulations (i.e., they may be "nebulized") for administration via inhalation. Aerosol formulations may be placed in pressurized acceptable propellants such as dichlorodifluoromethane, propane nitrogen, and the like.

Formulations suitable for parenteral administration (e.g., by intravenous, intramuscular, intradermal, and subcutaneous routes) include aqueous and non-aqueous isotonic sterile injection solutions (which may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient), and aqueous or non-aqueous sterile suspensions (which may include suspending agents, solubilizers, thickeners, and preservatives). In the practice of the invention, the composition may be administered, for example, by intravenous drip, orally, topically, intraperitoneally, intravesically or intrathecally. Formulations of the compounds may be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials. Injectable solutions and suspensions may be prepared from sterile powders, granules, and tablets of the type described previously.

In the context of the present invention, the dose administered to a subject should be sufficient to elicit a beneficial therapeutic response in the subject over a period of time. The term "subject" refers to a member of the mammalian class. Examples of mammals include, but are not limited to, humans, primates, chimpanzees, rodents, rats, mice, rabbits, horses, livestock, dogs, cats, sheep, and cows. In certain embodiments, a "subject" is a human.

The dosage will be determined by the effect of the particular compound employed and the condition of the subject, as well as the weight or surface area of the subject being treated. The size of the dose will also be determined by the presence, nature and extent of any adverse side effects that accompany the administration of the particular compound in a particular subject. In determining the effective amount of a compound to be administered in the treatment or prevention of a disease to be treated, a physician can assess such factors as the circulating plasma level of the compound, the toxicity of the compound, and/or the extent of disease progression. Typically, for a typical subject, the dose equivalent of a compound is about 1 μ g/kg to 100 mg/kg. Many different methods of administration are known to those skilled in the art.

For administration, the compounds of the invention may be administered at a rate determined by factors including, but not limited to, the pharmacokinetic properties of the compound, contraindicated drugs, and side effects of compounds at various concentrations (as applied to large and generally healthy subjects). Administration can be accomplished by single or multiple doses.

Examples of typical tablets include the following:

tablet formulation example 1

Tablet formulation
		Composition (I)	Dosage of
A compound of formula I	50mg
		Lactose	80mg
Corn starch (for mixing)	10mg
		Corn starch (for paste)	8mg
Magnesium stearate (1%)	2mg
			150mg

The compounds of the invention (e.g., a compound of formula I, or a pharmaceutically acceptable salt thereof) can be mixed with lactose and corn starch (for blending) and blended to powder homogeneity. Corn starch (for paste) was suspended in 6ml of water and heated while stirring to form a paste. Paste is added to the mixed powder and the mixture is granulated. The wet granules were passed through a No.8 hard sieve (hardscreen) and dried at 50 ℃. The mixture was lubricated with 1% magnesium stearate and compressed into tablets. The tablet is administered to a patient at a rate of 1-4 tablets per day to treat a noradrenaline-mediated and/or 5-hydroxytryptamine-mediated disorder.

By usingMethods for treating disorders mediated by noradrenaline and/or 5-hydroxytryptamine

The compounds of the invention and pharmaceutical compositions comprising the compounds of the invention can be administered to treat subjects suffering from a noradrenaline-mediated and/or 5-hydroxytryptamine-mediated disorder, including central nervous disorders, that is alleviated by inhibition of a noradrenaline transporter and/or a 5-hydroxytryptamine transporter.

Disorders mediated by noradrenaline and/or by 5-hydroxytryptamine can be prevented, treated for a short period of time, treated for a long period of time with the compounds of the present invention, depending on the nature of the disease. Typically, the subject or subject in each of these methods is a human, but other mammals may also benefit from administration of the compounds of the invention.

In therapeutic applications, the compounds of the present invention may be prepared and administered in a variety of oral and parenteral dosage forms. The term "administering" refers to the method of contacting a compound with a subject. Thus, the compounds of the present invention may be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, parenterally, or intraperitoneally. Also, the compounds described herein may be administered by inhalation, for example, by intranasal administration. In addition, the compounds of the present invention may be administered transdermally, topically, and via implantation. In certain embodiments, the compounds of the present invention are delivered orally. The compounds may also be delivered rectally, buccally, intravaginally, ocularly, or by insufflation.

The compounds used in the pharmaceutical methods of the present invention may be administered at an initial dose of about 0.001mg/kg to about 100mg/kg per day. In certain embodiments, the daily dose ranges from about 0.1mg/kg to about 10 mg/kg. However, the dosage may vary depending on the requirements of the subject, the severity of the condition being treated and the compound being used. Determining the appropriate dosage for a particular situation is a fundamental skill of the practitioner. Typically, treatment is initiated at a smaller dose, which is less than the optimal dose of the compound. Thereafter, the dose is increased in small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dose may be divided into multiple portions and administered, if desired, multiple times during the day. The term "treatment" includes the short-term, long-term, or prophylactic alleviation or relief of at least one symptom or feature associated with or caused by the condition being treated. For example, treatment may include alleviation of several signs of a disease, inhibition of the progression of the disease pathology, or complete elimination of the disease.

The invention also relates to a method of treating a disorder mediated by noradrenaline and/or mediated by 5-hydroxytryptamine comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula I. Examples of disorders mediated by noradrenaline and/or by 5-hydroxytryptamine include fibromyalgia, single-or repeated-onset major depressive disorder, dysthymic disorder, depressive neurosis and neurotic depression, melancholic depression (including anorexia, weight loss, insomnia, early awakening, or mental retardation); atypical or reactive depression (including bulimia, lethargy, psychomotor agitation or irritability, seasonal affective disorder, and childhood depression), bipolar affective disorder or manic depression (e.g., bipolar affective disorder, and mood disorder); a behavioral disorder; attention Deficit Hyperactivity Disorder (ADHD); destructive behavioral disorders; behavioral disturbances associated with mental retardation, autism, and behavioral disturbances; anxiety disorders (such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder), specific phobias (e.g., specific animal phobias, social anxiety disorder, social phobia), obsessive-compulsive disorder, stress disorders (including post-traumatic stress disorder and acute stress disorder, and generalized anxiety disorder); borderline personality disorder; schizophrenia and other psychotic disorders, for example, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, sympathogenic disorder, psychotic disorder associated with delusions or hallucinations, anxious psychotic stage, anxiety associated with psychosis, psychotic mood disorder (such as major depressive disorder); mood disorders associated with psychotic disorders (such as acute mania and depression associated with bipolar disorder), mood disorders associated with schizophrenia; delirium, dementia and amnestic and other cognitive or neurodegenerative disorders such as Parkinson's Disease (PD), Huntington's Disease (HD), alzheimer's disease, senile dementia, dementia of the alzheimer's type, memory impairment, loss of executive function, vascular dementia and other dementias, for example dementia due to HIV disease, head trauma, parkinson's disease, huntington's disease, pick's disease, Creutzfeldt-Jakob disease or dementia due to multiple etiologies; movement disorders (such as akinesia, dyskinesias, including familial paroxysmal dyskinesias), spasticity, Tourette's syndrome, Scott syndrome, paralysis (e.g., Bell paralysis, cerebral paralysis, pediatric paralysis, brachial paralysis, wasting paralysis, ischemic paralysis, progressive bulbar paralysis and other paralysis), and akinesia-rigidity syndrome; extrapyramidal motor syndromes such as drug-induced dyskinesias, e.g. parkinson's disease with antipsychotics, antipsychotic malignant syndrome, acute dystonia with antipsychotics, acute akathisia with antipsychotics, tardive dyskinesia with antipsychotics and drug-induced postural tremor; chemical dependence and addiction (e.g., alcohol, heroin, cocaine, benzodiazepines, nicotine, or phenobarbital) and behavioral addiction, such as gambling addiction; and ophthalmic diseases such as glaucoma and ischemic retinopathy.

In one embodiment, a patient suffering from fibromyalgia is administered a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof. Patients with fibromyalgia often exhibit a wide history of pain, and pain is present at 11 of the 18 points at palpation (see, e.g., Wolfe et al (1990) Arthritis rheum.33: 160-. Fibromyalgia patients often exhibit abnormal pain perception in the form of both painful paresthesia (pain caused by a non-noxious stimulus) and hyperalgesia (increased sensitivity to a painful stimulus).

Fibromyalgia patients also often exhibit a range of other syndromes, including sleep disturbances and fatigue. Although not as common as pain, fatigue and sleep problems, a variety of other syndromes may also occur. These include headache, morning stiffness, difficulty concentrating, circulatory problems affecting the small blood vessels of the skin (raynaud's phenomenon), and irritable bowel syndrome. As with many conditions that cause chronic pain, anxiety and depression are common in patients with fibromyalgia, and this makes the syndrome worse. The synthesis can be repeated. There may be a period of persistence (onset) of the syndrome, which may be followed by a period of disappearance (remission) of the syndrome. Some fibromyalgia patients find the syndrome worsened by cold, humid weather, emotional stress, exertion, and other factors.

A more specific embodiment of the invention relates to the above method wherein the disorder or condition being treated is selected from major depression, single episode depression, recurrent depression, childhood abuse depression, postpartum depression, dysthymia, environmental mood disorders and bipolar disorder.

Another more specific embodiment of the present invention relates to the above method wherein the disorder or condition being treated is selected from the group consisting of schizophrenia, schizoaffective disorder, delusional disorder, substance-induced psychotic disorder, brief psychotic disorder, sympathogenic disorder, psychotic disorder due to general medical condition (schizophrenia), and schizophreniform disorder.

Another more specific embodiment of the present invention relates to the above method wherein the disorder or condition being treated is selected from the group consisting of autism, pervasive development disorder, and attention deficit hyperactivity disorder.

Another more specific embodiment of the invention relates to the above method wherein the disorder or condition to be treated is selected from the group consisting of generalized anxiety disorder, panic disorder, obsessive compulsive disorder, post-traumatic stress disorder and phobias (including social phobia, agoraphobia and specific phobia).

Another more specific embodiment of the present invention relates to the above method, wherein the disorder or condition to be treated is selected from the group consisting of dyskinesias, such as akinesia, dyskinesias (including familial paroxysmal dyskinesia), spasticity, Tourette's syndrome, Scott syndrome, paralysis (e.g., Bell paralysis, cerebral paralysis, pediatric paralysis, brachial paralysis, wasting paralysis, ischemic paralysis, progressive bulbar paralysis and other paralysis), and akinesia-rigidity syndrome, extrapyramidal motor syndrome, such as drug-induced dyskinesia, e.g., antipsychotic-induced parkinson's disease, antipsychotic malignant syndrome, antipsychotic-induced acute dystonia, antipsychotic-induced acute akathisia, antipsychotic-induced tardive dyskinesia and drug-induced postural tremor.

Another more specific embodiment of the present invention relates to the above method wherein the disorder or condition being treated is pain. Pain refers to acute as well as chronic pain. Acute pain is usually short in duration, and chronic pain is usually defined as pain lasting from 3 months to 6 months, including somatic and psychogenic pain. Other pain is painful.

Examples of the types of pain that can be treated by the compounds of formula I of the present invention and pharmaceutically acceptable salts thereof include pain caused by soft tissue and peripheral nerve injury, such as acute trauma, pain associated with osteoarthritis and rheumatoid arthritis, musculoskeletal pain, such as pain experienced after trauma; spinal pain, toothache, myofascial pain syndrome, perineotomy pain, and pain resulting from burns; deep and visceral pain such as heart pain, muscle pain, eye pain, orofacial pain (e.g. dental pain), abdominal pain, gynaecological pain (e.g. dysmenorrhea, childbirth pain and pain associated with endometriosis; pain associated with nerve and root injuries such as pain associated with peripheral nerve disorders, e.g. nerve compression and brachial plexus injury, amputation, peripheral neuropathy, cramps, atypical facial pain, nerve root injury, trigeminal neuralgia, neuropathic low back pain, neuropathic pain associated with HIV, neuropathic pain associated with cancer, diabetic neuropathic pain, and arachnoiditis; neuropathic and non-neuropathic pain associated with tumours (commonly referred to as cancer pain), central nervous system pain such as pain due to spinal cord or brain stem injury; low back pain; sciatica; limb pain, headache pain (including migraine and other vascular headaches, acute or chronic tension-type headache, cluster headache, temporomandibular pain and maxillary sinus pain, pain caused by ankylosing spondylitis and gout, pain caused by increased bladder contraction, post-operative pain, wound pain, and chronic non-neuropathic pain such as that associated with fibromyalgia, HIV, rheumatoid and osteoarthritis, joint pain and myalgia, sprains, strains and wounds (such as bone fractures), and post-surgical pain.

Still other pain is pain caused by injury or infection of peripheral sensory nerves. Including, but not limited to, pain caused by peripheral nerve trauma, herpes virus infection, diabetes, fibromyalgia, burning pain, brachial plexus injury, neuroma, amputation and vasculitis. Neuropathic pain may also result from nerve damage caused by chronic alcoholism, HIV viral infection, hypothyroidism, uremia, or vitamin deficiency. Neuropathic pain includes, but is not limited to, pain resulting from nerve injury, for example, pain suffered by a diabetic patient.

Cardiogenic pain is pain that occurs without an organic source, such as low back pain, atypical facial pain, and chronic headache.

Other types of pain are: inflammatory pain, osteoarthritis pain, trigeminal neuralgia, cancer pain, diabetic neuropathy, restless legs syndrome, acute herpes zoster and postherpetic neuralgia, causalgia, brachial plexus injury, occipital neuralgia, gout, phantom limb pain, burns, and other forms of neuralgia, neuropathic and congenital pain syndromes.

Another more specific embodiment of the invention relates to the above method, wherein the disorder or condition to be treated is selected from delirium, dementia and amnestic and other cognitive or neurodegenerative disorders such as Parkinson's Disease (PD), Huntington's Disease (HD), alzheimer's disease, senile dementia, dementia of the alzheimer's type, memory disorders, loss of executive function, vascular dementia and other dementias, for example dementia due to HIV disease, head trauma, parkinson's disease, huntington's disease, pick's disease, Creutzfeldt-Jakob disease or dementia due to multiple etiologies.

The compounds of the present invention may be co-administered to a subject. The term "co-administration" refers to the administration of two or more different agents or treatments (e.g., radiation therapy) that are administered to a subject by combination in the same pharmaceutical composition or in separate pharmaceutical compositions. Thus, co-administration includes administration of one pharmaceutical composition comprising two or more agents at the same time or administration of two or more different compositions to the same subject at the same time or at different times. For example, a subject is administered a first dose of a compound of the invention at 8 am and then a second therapeutic agent after 1-12 hours (e.g., 6 pm on the same day), the subject is administered the compound of the invention in combination with the second therapeutic agent. Alternatively, for example, a subject may be administered a single dose comprising a compound of the invention and a second therapeutic agent at 8 am, and the subject is then administered the compound of the invention in combination with the second therapeutic agent.

The compounds of the present invention may also be administered in combination with one or more agents useful for treating one or more symptoms of fibromyalgia, said one or more agents selected from the group consisting of: non-steroidal anti-inflammatory drugs (hereinafter NSAIDs), such as piroxicam (piroxicam), loxoprofen (loxoprofen), diclofenac (diclofenac), propionic acids such as naproxen (naproxen), flurbiprofen, fenoprofen (fenoprofen), ketoprofen (ketoprofen) and ibuprofen (ibupropen), ketorolac tromethamine (k) (NSAID), and the likeetorolac), nimesulide (nimesulide), acetaminophen (acetominophen), fenamates such as mefenamic acid (mefenamic acid), indomethacin (indomethacin), thiaindac (sulindac), apazone (apazone), pyrazolones such as phenylbutazone (phenylbutazone), salicylates such as aspirin, COX-2 inhibitors such as CELEBREX^®(celecoxib), BEXTRA^®(valdecoxib) and etoricoxib (etoricoxib); sterols, corticosterone (cortisone), prednisone (prednisone), myorelaxants (including cyclobenzaprine and tizanidine); hydrocodone (hydrocodone), dexpropoxyphene (dexopropoxyphene), lidocaine (lidocaine), opioids, morphine, Fentanyl (Fentanyl), tramadol (tramadol), codeine (codeine), Paroxetine (PAXIL)^®) Diazepam (Diazepam), non-moxidene (Femoxetine), Carbamazepine (Carbamazepine), milnacipran (IXEL)^®) Vestra ®, venlafaxine (EFFEXOR ®), duloxetine (CYMBALTA)^®)，Topisetron(NAVOBAN^®) Interferon alpha (Veldona), cyclobenzaprine, CPE-215, Sodium oxybate (XYREM)^®)，Celexa^TM(citalopram hydrobromide (citalopram HBr)), ZOLOFT^®(sertraline hydrochloride (sertraline HCl)), antidepressants, tricyclic antidepressants, amitriptyline (amitriptyline), fluoxetine (PROZAC)^®) Topiramate (topiramate), citalopram (escitalopram), benzodiazepines (including diazepam, bromoepam and tetrahydroepam), mianserin (mianserin), clomipramine (clomipramin), imipramine (imipramine), topiramate and nortriptyline (nortriptyline). The compounds of the invention may also be administered in combination with an alpha-2-delta ligand. Examples of alpha-2-delta ligands useful in the present invention are disclosed generally or specifically in U.S. Pat. No.4,024,175 (specifically gabapentin (NEURONTIN)^®) EP641330 (in particular pregabalin (LYRICA))^®) Us patent nos. 5563175, WO9733858, WO9733859, WO9931057, WO9931074, WO9729101, WO02085839 (specifically [ (1R, 5R, 6S) -6- (aminomethyl) bicyclo [3.2.0 ] n]Hept-6-yl]Acetic acid, WO9931075 (specifically 3- (1-aminomethyl-ring)Hexylmethyl) -4H- [1, 2, 4]Oxadiazol-5-ones and C- [1- (1H-tetrazol-5-ylmethyl) -cycloheptyl]Methylamine), WO9921824 (in particular (3S, 4S) - (1-aminomethyl-3, 4-dimethyl-cyclopentyl) -acetic acid), WO0190052, WO0128978 (in particular (1 α,3 α,5 α) (3-amino-methyl-bicyclo [ 3.2.0)]Hept-3-yl) -acetic acid), EP0641330, WO9817627, WO0076958 (in particular (3S, 5R) -3-aminomethyl-5-methyl-octanoic acid), PCT/IB03/00976 (in particular (3S, 5R) -3-amino-5-methyl-heptanoic acid), (3S, 5R) -3-amino-5-methyl-nonanoic acid and (3S, 5R) -3-amino-5-methyl-octanoic acid), EP1178034, EP1201240, WO9931074, WO03000642, WO0222568, WO0230871, WO0230881, WO02100392, WO02100347, WO0242414, WO0232736 and WO0228881, and pharmaceutically acceptable salts and solvates thereof, all of which are incorporated herein by application.

For the treatment of depression, anxiety, schizophrenia or any other disorder or condition mentioned above in the description of the methods and pharmaceutical compositions of the invention, the compounds of the invention may be used in combination with one or more antidepressants or anxiolytics. Examples of classes of antidepressants which may be used in combination with the active compounds of the present invention include norepinephrine reuptake inhibitors, selective 5-hydroxytryptamine reuptake inhibitors (SRI), NK-1 receptor antagonists, monoamine oxidase inhibitors (MAOI), reversible inhibitors of monoamine oxidase (RIMA), 5-hydroxytryptamine and norepinephrine reuptake inhibitors (SNRI), Corticotropin Releasing Factor (CRF) antagonists, alpha-adrenoceptor antagonists, alpha-2-delta ligands (A2D) (e.g., NEURONTIN)^®And LYRICA^®[ (1R, 5R, 6S) -6- (aminomethyl)]Bicyclo [3.2.0]Hept-6-yl) acetic acid, 3- (1-aminomethyl-cyclohexylmethyl) -4H- [1, 2, 4]Oxadiazol-5-ones and C- [1- (1H-tetrazol-5-ylmethyl) -cycloheptyl]-methylamine, (3S, 4S) - (1-aminomethyl-3, 4-dimethyl-cyclopentyl) -acetic acid, (1 α,3 α,5 α) (3-amino-methyl-bicyclo [ 3.2.0)]Hept-3-yl) -acetic acid, (3S, 5R) -3-aminomethyl-5-methyl-octanoic acid, (3S, 5R) -3-amino-5-methyl-heptanoic acid, (3S, 5R) -3-amino-5-methyl-nonanoic acid and (3S, 5R) -3-amino-5-methyl-octanoic acid and the like), and atypical antidepressants. Combination of Chinese herbsSuitable noradrenaline reuptake inhibitors include tertiary amine tricyclic and secondary amine tricyclic species. Suitable tertiary and secondary amine tricyclic agents include amitriptyline (amitriptyline), clomipramine (clomipramine), doxepin (doxepin), imipramine (imipramine), trimipramine (trimipramine), dothiepin (dotipin), butripyline (iprindoe), lofopramine (lofepramine), nortriptyline (nortriptyline), protriptyline (protriptyline), amoxapine (amonapine), desipramine (desipramine) and maprotiline (maprotiline). Suitable selective 5-hydroxytryptamine reuptake inhibitors include fluoxetine (fluoxetine), fluvoxamine (fluvoxamine), paroxetine (parooxetine), citalopram (citalopram) and sertraline (sertraline). Examples of monoamine oxidase inhibitors include isocarboxazid, phenelzine and trylcyclopramine. Suitable reversible inhibitors of monoamine oxidase include moclobemide (moclobemide). Suitable 5-hydroxytryptamine and norepinephrine reuptake inhibitors for use in the present invention include venlafaxine (venlafaxine) and duloxetine (duloxetine). Suitable CRF antagonists include those described in international patent application nos. WO 94/13643, WO 94/13644, WO 94/13661, WO 94/13676 and WO 94/13677. Suitable atypical antidepressants include bupropion (bupapion), lithium, nefazodone (nefazodone), trazodone (trazodone) and viloxazine (viloxazine). Suitable NK-1 receptor antagonists include those mentioned in International patent publication WO 01/77100. Suitable A2D ligands include those mentioned in International patent publications WO99/21824, WO 01/90052, WO 01/28978, WO 98/17627, WO 00/76958, and WO 03/082807, and in particular NEURONTIN^®And LYRICA^®。

Suitable classes of anxiolytics that can be used in combination with the active compounds of the present invention include benzodiazepines and 5-hydroxytryptamine IA (5-HT)_IA) Agonists or antagonists, especially 5-HT_IATopical agonists, and Corticotropin Releasing Factor (CRF) antagonists. Suitable benzodiazepines include alprazolam (alprazolam), chlordiazepoxide (chlorazepoxide), clonazepam (clonazepam), diazepamPotassium chlordiazepoxide (chlorazepam), diazepam (diazepam), halazepam (halazepam), lorazepam (lorazepam), oxazepam (oxazepam), and pramipeam (prazepam). Suitable 5-HT_IAReceptor agonists or antagonists include buspirone (buspirone), fluocinolone (flesinoxan), gepirone (gepirone) and ixabepilone (ipsapirone).

Suitable antipsychotics include both conventional and atypical antipsychotics.

Conventional antipsychotics are antagonists of the dopamine (D2) receptor. Atypical antipsychotics also have D2 antagonist properties, but have different binding kinetics to these receptors and are directed against other receptors (particularly 5-HT)_2A，5-HT_2CAnd 5-HT_2D) Activity of (2). (Schmidt B et al, Soc. neurosci. Abstr.24: 2177, 1998).

The class of atypical antipsychotics includes clozapine (clozapine, clozapil)^®) 8-chloro-11- (4-methyl-1-piperazinyl) -5H-dibenzo [ b, e][1，4]Diazepine (U.S. Pat. No.3,539,573); risperidone (risperidone, RISPERDAL)^®)3- [2- [4- (6-fluoro-1, 2-benzisoxazol-3-yl) piperidino]Ethyl radical]-2-methyl-6, 7, 8, 9-tetrahydro-4H-pyrido [1, 2-a ]]Pyrimidin-4-one (U.S. Pat. No.4,804,663); olanzapine (olanzapine, ZYPREXA)^®) 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2, 3-b][1.5]Benzodiazepines (U.S. Pat. No.5,229,382); quetiapine (SEROQUEL)^®) 5- [2- (4-dibenzo [ b, f ]][1，4]Thiazepin-11-yl-1-piperazinyl) ethoxy]Ethanol (U.S. Pat. No.4,879,288); aripiprazole (Alipiprazole, ABILIFY)^®) 7- {4- [4- (2, 3-dichlorophenyl) -1-piperazinyl]-butoxy } -3, 4-dihydroquinolone and 7- {4- [4- (2, 3-dichlorophenyl) -1-piperazinyl]-butoxy } -3, 4-dihydro-2 (1H) -quinolinone (U.S. patent nos.4,734,416 and 5,006,528); sertindole (sertindole), 1- [2- [4- [ 5-chloro-1- (4-fluorophenyl) -1H-indol-3-yl]-1-piperidinyl group]Ethyl radical]Imidazolidin-2-one (U.S. Pat. No.4,710,500); amisulpride (U.S. patent No.4,410,822); and ziprasidone (zi)prasidone) (GEODON ®), 5- [2- [4- (1, 2-benzisothiazol-3-yl) piperazin-3-yl ] hydrochloride]Ethyl radical]-6-chloroindolin-2-one hydrate (U.S. Pat. No.4,831,031).

Examples

Example 1: 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole hydrochloride

To a slurry of 2-fluorophenylhydrazine hydrochloride (40.1g, 246.7mmol) in 411ml of EtOH was added diisopropylethylamine (47.27ml, 271.4mmol) followed by solid isatoic anhydride (40.0g, 246.7 mmol). The slurry was heated to reflux. At reflux, all solids went into solution and reflux continued for 1.5 hours. The reaction mixture was cooled to room temperature and left overnight. The precipitated solid was filtered and washed with EtOH (ethanol). The filtrate was concentrated to dryness, and the residual material was taken up in EtOAc (ethyl acetate), washed with water and washed over Na₂SO₄And drying. The EtOAc solution was concentrated and the residual oil phase was taken up with minimal ether. The ether solution was then triturated with heptane. The recovered solid was combined with the previous one to give 34.89g of hydrazide. The hydrazide was slurried in 307ml of 1M HCl solution. The slurry was cooled to 0 ℃ and 100ml of sodium nitrite in water (19.62g, 284.4mmol) was added. Next, 582ml of EtOH was added and the slurry was refluxed for 2 hours and then allowed to stand at room temperature overnight. The resulting slurry was filtered and washed with EtOH. The filtrate was further concentrated to give more solid. After combining with the first batch of solid, the material was recrystallized from 95: 5 EtOH: i-PrOH (isopropanol) to give 23.45g of 1- (2-fluoro-phenyl) -1H-indazol-3-ol (intermediate 1) ms (apci): 229(M +1, 100%).

To a mixture of tert-butyl 4-hydroxy-1-piperidinecarboxylate (0.94g, 4.66mmol) and methanesulfonyl chloride (0.43ml, 5.56mmol) in 10ml of anhydrous CH₂Cl₂To the solution at 0 ℃ was added triethylamine (0.71ml, 5.09 mmol). The colorless solution turned into a white suspension. The reaction mixture was stirred at 0 ℃ for 2 hours. Ether (50ml) was added to the white suspension and the precipitate was removed by filtration. The residue is used10ml ether was washed twice. The combined filtrate and washings were concentrated on a rotary evaporator. The residual oil was chromatographed on silica gel with 50% EtOAc in hexane to give 1.06g of intermediate 2 (tert-butyl 4-methanesulfonyloxy-piperidine-1-carboxylate) as a white solid. Ms (apci): 224 (100%), 180 (32%).

A mixture of intermediate 1(0.41g, 1.80mmol), intermediate 2(0.53g, 1.90mmol) and sodium hydride (60% dispersion in mineral oil, 0.099g, 2.48mmol) in 13ml anhydrous DMF (dimethylformamide) was stirred at 100 ℃ for 7 hours. After cooling to room temperature, saturated NH was added₄Cl solution (40ml) and water (15ml) to stop the reaction. The mixture was extracted three times with 50ml ether. The combined extracts were extracted over MgSO₄Dried and then concentrated on a rotary evaporator. The residual oil was chromatographed on silica gel with 20% EtOAc in hexane to give 0.52g of intermediate 3(4- [1- (2-fluoro-phenyl) -1H-indazol-3-yloxy) as a pale yellow oil]-piperidine-1-carboxylic acid tert-butyl ester). Ms (apci): 412(M +1, 62%), 356 (46%), 312 (100%).

To a solution of intermediate 3(0.52g, 1.26mmol) in 4ml EtOAc at room temperature was added 4ml of a 4M solution of HCl in dioxane. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated on a rotary evaporator. EtOAc (30ml) was added to dissolve the oily residue. The solution was again concentrated on a rotary evaporator to remove the last traces of dioxane. Methanol (3ml) was added to redissolve the oily residue. Ether (30ml) was slowly added to the solution. The cloudy solution was concentrated on a rotary evaporator to give a solid material. The solid was triturated with 5ml EtOAc in ether (1: 1) for 15 minutes. An additional 20ml of ether was added and the precipitate was collected by filtration. After washing twice with 5ml ether, the solid was dried overnight at 95 ℃ under vacuum to give 0.36g of the title product as a white powder.

Example 2: maleic acid (S) - (+) -1- (2-fluorophenyl) -3- (morpholin-2-ylmethoxy) -1H-indazole

Procedure described in J.Med.chem.1998, 41, 1934-Preparation of (S) -3-hydroxymethyl morpholine. Intermediate 5((S) -2-hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester) was prepared under standard conditions (NaOH, di-tert-butyl dicarbonate, H)₂O/THF，0℃)。MP＝67-68℃。

Intermediate 6 (tert-butyl 2-methanesulfonyloxymethyl-morpholine-4-carboxylate) was prepared according to the procedure described above for the preparation of intermediate 2, using intermediate 5 as the starting material. [ alpha ] to]_D ²⁴＝+18.4°(CHCl₃，c＝8.9)，MS(APCI)：240(95％)，196(100％)。

Intermediate 7((S) -2- [1- (2-fluoro-phenyl) -1H-indazol-3-yloxymethyl) -7 was prepared according to the procedure described above for the preparation of intermediate 3, starting with intermediate 6 and stirring at 100 ℃ for 3.5 hours]-morpholine-4-carboxylic acid tert-butyl ester). [ alpha ] to]_D ²⁴＝+16.0°(CHCl₃，c＝5.0)，MS(APCI)：410(M+H，80％)，310(100％)。

To a solution of intermediate 7(0.86g, 2.00mmol) in 6ml EtOAc was added 6ml of a 4M solution of HCl in dioxane at room temperature. The reaction mixture was stirred at room temperature for 2.5 hours. The reaction mixture was concentrated on a rotary evaporator. The residue was loaded onto a Varian Mega Bond Elut SCX column prewashed with 5% HOAc in methanol. The column was washed 4 times with 50ml of MeOH to remove HCl. The amine is reacted with 1N NH₃Elution as a solution in MeOH (3X 40ml) provided 0.52g of the free base as a colorless oil. The oil was then dissolved in 75ml of ether. A solution of maleic acid (0.187g, 1.61mmol) in 2ml MeOH was slowly added to the amine solution at room temperature. A white precipitate formed and the suspension was stirred at room temperature for 10 minutes. The white solid was collected by filtration. It was washed twice with 10ml ether and then dried overnight under vacuum at 100 ℃ to give 0.661g of the title product as a white powder.

Example 3: maleic acid (S) - (+) -1- (2, 4-difluorophenyl) -3- (morpholin-2-ylmethoxy) -1H-indazole

To a slurry of 2, 4-difluorophenylhydrazine hydrochloride (15.2 g) in 140ml EtOH at room temperature was added 15.64ml diisopropylethylamine. The mixture was stirred for 20 minutes until the geometric total mass went into solution, then isatoic anhydride (14.0g) was added. The mixture was heated to reflux to form a solution. After 1.5 hours, the reaction was cooled to room temperature and left overnight. The precipitated solid was filtered off, washed with EtOH and dried to give 9.36g (44% yield) of 2-amino-benzoic acid N' - (2, 4-difluoro-phenyl) -hydrazide (intermediate 17): ms (apci): (M +1) ═ 264, (M-1) ═ 262.

Intermediate 17(9.80g, 37.3mmol) was stirred in 82ml of 1M HCl (aq), cooled to 0 ℃ and a solution of sodium nitrite (5.1g, 74mmol) in 18ml of water was added continuously via a pipette. A viscous suspension formed. 106ml of EtOH was added and the reaction was heated to reflux. A viscous foam formed without stirring. The reaction was cooled to room temperature and the reaction solution was cooled to room temperature using 100ml of 1: 1 EtOH: H₂O diluted, good stirring was restarted, and the mixture was heated to reflux for 2 hours. The reaction was cooled to room temperature and left overnight, the precipitate was filtered off and washed with H₂O wash and dry on Buchner funnel to give as product 7.55g of a putty-like coloured solid, 1- (2, 4-difluoro-phenyl) -1H-indazol-3-ol (intermediate 18): ms (apci): (M +1) ═ 247.

Intermediate 19(2- [1- (2, 4-difluoro-phenyl) -1H-indazol-3-yloxymethyl) -19 was prepared according to the procedure described above for the preparation of intermediate 3, starting with intermediate 6 and intermediate 18 and stirring at 100 ℃ for 3 hours]-morpholine-4-carboxylic acid tert-butyl ester). [ alpha ] to]_D ²⁴＝+19.4°(CHCl₃，c＝5.4)，MS(APCI)：446(M+H，100％)，346(90％)。

The title product was prepared from intermediate 19 following the procedure described above for the preparation of example 2.

Examples 4-13 were synthesized in a similar manner as described for example 1.

Example 14: (R) -1-phenyl-3- (pyrrolidin-3-ylmethoxy) -1H-indazole hydrochloride

To a slurry of isatoic anhydride (50.0g, 308.3mmol) in 514ml EtOH was added phenylhydrazine (30.33ml, 308.3mmol) and the slurry was heated to reflux. At reflux, all solids went into solution and reflux continued for 1.5 hours. The reaction mixture was cooled to room temperature and left overnight. The precipitated solid was filtered off and washed with EtOH to give 46.55g (66% yield) of a white solid as the desired hydrazide. The hydrazide (46.55g, 204.8mmol) was slurried in 442.3ml of 1M HCl solution. The slurry was cooled to 0 ℃ and sodium nitrite (28.26g, 409.6mmol) in 100ml water was added. Next, 582ml EtOH was added and the slurry was heated to reflux for 2 hours, then cooled to room temperature and left to stand overnight. The resulting slurry was filtered to give 15g of a yellow solid. The filtrate phase volume was reduced and more solids were recovered. These solids were combined and recrystallized from 95: 5 EtOH: iPrOH to give 26.50g (61%) of intermediate 28 (1-phenyl-1H-indazol-3-ol) as a pale yellow solid: MP 209-.

Intermediate 29((R) -3- (1-phenyl-1H-indazol-3-yloxymethyl) -pyrrolidine-1-carboxylic acid tert-butyl ester) was prepared following the procedure described above for the preparation of intermediate 3, starting with intermediate 28(0.250g, 1.19mmol) and (R) -3-methanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.370g, 1.30mmol, prepared according to j.med.chem.1999, 42, 677), and heating at 100 ℃ for 18 hours using 1.70mmol 95% NaH, followed by addition of 1.70mmol 60% NaH and heating at 100 ℃ for 20 hours. The residual oil was chromatographed on silica gel with 10% acetone in hexane to give 0.275g of intermediate 29 as a clear oil. MS (M +1) ═ 394, 294 (M-BOC).

Intermediate 29(0.275g, 0.699mmol) was dissolved in 2.3ml EtOAc and 2.3ml HCl (4M in dioxane) was added at room temperature. After stirring overnight, the solvent was evaporated. The residue was treated with-30 ml EtOAc, then concentrated. This operation was repeated to remove all dioxane and HCl. The resulting white solid was purified with-20 ml 1: 2 EtOAc: trituration of ether, filtration, washing twice with 5ml ether and drying overnight under vacuum at 60 ℃ gave the title product as a pale tan powder (0.192g, 83% yield).

Examples 15-26 were synthesized in a similar manner as described for example 14.

Example 27: 1- (2, 5-difluoro-phenyl) -3- (piperidin-4-yloxy) -1H-indazole hydrochloride

Intermediate 33(1- (2, 5-difluoro-phenyl) -1H-indazol-3-ol) was prepared according to the procedure described above for the preparation of intermediate 28, starting with 2, 5-difluorophenylhydrazine (15.1g, 105mmol) and isatoic anhydride (17.0g, 101mmol), and the reaction was heated at reflux for 3.5 hours. The hydrazide was isolated as a light sandy solid (15.6g, 59% yield): ms (apci): (M +1) ═ 264, (M-1) ═ 262. Following the same procedure, the hydrazide (15.6g, 59.3mmol) was converted to intermediate 33(12.89g, 88% yield) as a putty-like colored solid: ms (apci): (M +1) ═ 247, (M-1) ═ 245.

To a solution of intermediate 33(0.300g, 1.22mmol) in 12ml DMF was added 0.600g (1.80mmol) cesium carbonate followed by intermediate 2(0.370g, 1.30 mmol). The mixture was heated to 80 ℃ for 24 hours and then cooled to room temperature. Using saturated NH₄Cl and an amount of additional water were stopped, then Et₂And extracting for 3 times by using O. Extracting with hydrogen₂Washed once with O and then once with brine over MgSO₄Dried above and concentrated to 0.515g of yellow oil. The product was purified by flash chromatography (5-10% EtOAc/hexanes, 90g silica) to isolate intermediate 34(4- [1- (2, 5-difluoro-phenyl) -1H-indazol-3-yloxy) as a yellow oil]-piperidine-1-carboxylic acid tert-butyl ester) (0.340g, 65% yield): MS (M +1) ═ 430 (secondary), 330 (M-BOC).

Following the procedure for intermediate 30, intermediate 34(0.334g, 0.778mmol) was treated with HCl in dioxane/EtOAc and stirred at room temperature for 3.5 hours. After conventional work-up, the solid was triturated with 20ml 1: 1 EtOAc: ether, filtered, washed twice with 5ml ether and dried in a vacuum oven at 60 ℃ to give the title product as a white powder (0.240g, 84% yield): ms (apci): (M +1) ═ 330.

Examples 28-40 were synthesized in a similar manner as described for example 27.

Example 41: 1- (4-chloro-phenyl) -3- (piperidin-4-yloxy) -1H-indazole hydrochloride

4-chlorophenylhydrazine hydrochloride (2.105g, 14.76mmol) was suspended in EtOH (25ml), treated with diisopropylethylamine (2.253ml, 12.93mmol) and stirred for 30 min, isatoic anhydride (1.918g, 11.76mmol) was added and the mixture heated to reflux for 3 h. The reaction mixture was cooled to room temperature and stirred overnight. The material was concentrated to dryness and the resulting residue was partitioned between EtOAc (-25 ml) and 50% saturated NaCl (3 × 30 ml). The organic layer (also containing a small amount of emulsion that does not dissipate for more than 3 extractions) was placed over MgSO₄Dried above and concentrated to an orange solid. The material was triturated with EtOAc, filtered and washed with additional EtOAc. The filtrate was concentrated to dryness and treated with DCM (dichloromethane). The mixture was stirred overnight. The mixture was filtered, washed with DCM, and the solid was dried to give 1.538g (50%) of 2-amino-benzoic acid N' - (4-chloro-phenyl) -hydrazide (intermediate 40) as a purple solid. Ms (apci): 262.1 (M +1) ═ 260.0 (M-1).

Intermediate 40(1.538g, 5.877mmol) was suspended in 1M HCl (12ml), cooled to 0 ℃ and treated with a dropwise solution of sodium nitrite (811mg, 11.75mmol) in water (5 ml). The mixture was stirred at 0 ℃ for 10 minutes with 1: 1 EtOH/H₂O (25ml) was diluted, heated to reflux for 3 hours, then cooled to room temperature and stirred for about 1 hour. The mixture was filtered and washed with water. The isolated solid was washed with Et₂O and EtOAc treatment followed by 1N NaOH. The bulk of the solid remains undissolved. The mixture was poured into a separatory funnel and separated. All solids were partitioned into the organic layer, and the aqueous layer was drained (designated as aqueous layer 1). The organic layer was then treated with additional 1N NaOH. The solids are then partitioned into the aqueous layer and the aqueous layer is drained (along with the solids-designated aqueous layer 2). Both aqueous layers were treated with concentrated HCl until largeCan be neutral. The aqueous layer 1 formed a fine solid which was filtered, washed with water and dried. The solid was dried in a vacuum oven at 50 ℃ for 2 days to give 141mg (9.8%) of 1- (4-chloro-phenyl) -1H-indazol-3-ol as a tan solid (intermediate 41). Whereas the aqueous layer 2 forms a large milky solid. The material was allowed to stand at room temperature for 2 days and then stirred vigorously until all lumps were broken up. Ethyl acetate was then added. The mixture was made basic with 1N NaOH and the solid was filtered and washed with EtOAc. The solid was dried in a vacuum oven at 50 ℃ for 3 days to give 522mg (36%) of the intermediate as a white solid. Ms (apci): (M +1) ═ 245.1, (M-1) ═ 243.0.

Intermediate 41(300mg, 1.226mmol) was combined with anhydrous DMF (10ml), treated with PS-BEMP resin (2-t-butylimino-2-diethylamino-1, 3-dimethyl-perhydro-1, 3, 2-diazophosphacyclohexane on polystyrene) (1.115g) and stirred for 30 min. A solution of intermediate 2(377mg, 1.349mmol) in anhydrous DMF (5ml) was then slowly added dropwise and the mixture was heated to 70 ℃ and held overnight. The mixture was filtered to remove the resin, and the resin was washed with hot DMF. The filtrate was concentrated in vacuo. The crude material was chromatographed on 20g silica gel eluting with 8% EtOAc in hexanes. The desired fractions were combined and concentrated to give 212mg (40%) of 4- [1- (4-chloro-phenyl) -1H-indazol-3-yloxy ] -piperidine-1-carboxylic acid tert-butyl ester as a colorless glass (intermediate 42). Ms (apci): (M-1) ═ 426.2.

Intermediate 42(212mg, 0.495mmol) was dissolved in EtOAc (2ml), treated with 4M HCl in dioxane (1.61ml, 6.44mmol) and stirred at room temperature overnight. The mixture was concentrated in vacuo, treated with EtOAc and concentrated again. This process was repeated 5 times. The resulting white solid was used in Et₂Grinding with O, filtering, and treating with Et₂O clean, and dry in a vacuum oven at 50 deg.C to yield 155mg (86%) of the title product, 1- (4-chloro-phenyl) -3- (piperidin-4-yloxy) -1H-indazole hydrochloride as a white solid.

Examples 42-43 were synthesized in a similar manner to that described for example 41, except that diisopropylethylamine was replaced with triethylamine and ethanol was replaced with Tetrahydrofuran (THF).

Example 44: maleic acid (S) - (-) -3- (piperidin-3-ylmethoxy) -1-pyridin-2-yl-1H-indazole

A mixture of isatoic anhydride (3.51g, 2.15mmol) and 2-hydrazinopyridine (2.40g, 2.20mmol) in 35ml EtOH was refluxed for 17 hours. After 15 minutes of reflux, the suspension turned into a brown solution and gas formation was observed. At the end of 17 hours, the reaction mixture was cooled to room temperature and the brown solution was concentrated on a rotary evaporator. The residue was chromatographed on silica gel with 65% EtOAc in ethane. The product containing fractions were collected and concentrated. The solid was triturated with ether (100ml) for 15 minutes and collected by filtration. This was air dried to give 2.68g of 2-amino-benzoic acid N' -pyridin-2-yl-hydrazide as a white solid (intermediate 9). Ms (apci): 229(M +1, 100%).

To a solution of intermediate 9(1.38g, 6.04mmol) in 21ml of a 1M HCl solution at 0 deg.C was added a solution of sodium nitrite (0.90g, 1.31mmol) in 5ml of water. A white precipitate was obtained upon addition of sodium nitrite solution. Then, EtOH (30ml) was added, and the mixture was refluxed for 2 hours. The white suspension turned into a yellow solution during reflux. After 2 hours, the mixture was cooled to room temperature. The orange solution turned into an orange suspension. The mixture was concentrated on a rotary evaporator. The solid residue was dissolved in EtOAc (70ml), THF (30ml), saturated NaHCO₃Solution (80ml) and water (40 ml). The mixture was stirred at room temperature for 15 minutes. The organic layers were collected and the aqueous layer was extracted 2 times with 70ml EtOAc. The combined organic layers were washed with MgSO 2₄Dried and concentrated to give 1.05g of 1-pyridin-2-yl-1H-indazol-3-ol as a pale yellow solid (intermediate 10). Ms (apci): 212(M +1, 100%).

Intermediate 11((S) -3-methanesulfonyloxymethyl-piperidine-1-carboxylic acid tert-butyl ester) was prepared according to the procedure described above for the preparation of intermediate 2, using (S) -3-hydroxymethyl-1-N-Boc-piperidine (Astatech) as the starting material. (Boc ═ t-butyloxycarbonyl) [ α ]]_D ²⁴＝+18.8°(CHCl₃，c＝4.9)，MS(APCI)：238(100％)，194(73％)。

Intermediate 12((S) -3- (1-pyridin-2-yl-1H-indazol-3-yloxymethyl) -piperidine-1-carboxylic acid tert-butyl ester) was prepared according to the procedure described above for the preparation of intermediate 3, starting with intermediate 11 and intermediate 10, and stirring at 100 ℃ for 1.5 hours. [ alpha ] to]_D ²⁴＝+21.8°(CHCl₃，c＝5.5)，MS(APCI)：409(M+H，100％)，309(100％)。

The title product was prepared from intermediate 12 following the procedure described above for the preparation of example 2.

Example 45: maleic acid (S) - (-) -5-fluoro-1- (2-fluorophenyl) -3- (piperidin-3-ylmethoxy) -1H-indazole

To a solution of 2-amino-5-fluorobenzoic acid (15.34g, 98.86mmol) and sodium carbonate (10.66g, 100.6mmol) in 260ml of water at room temperature was slowly added a 1.93M solution of phosgene in toluene (63ml, 121.6mmol) with vigorous stirring. A yellow precipitate formed during the addition. After the addition of phosgene was complete, the mixture was stirred at room temperature for 30 minutes. The precipitate was collected by filtration and washed 4 times with 100ml of water. The solid was air dried for 30 minutes and then washed with a 1: 1 mixture of ether in hexane (3X 40 ml). The solid was again air-dried to obtain 17.36g of intermediate 21 (6-fluoro-1H-benzo [ d ] as a yellow solid][1，3]Oxazine-2, 4-dione).¹HNMR(400MHz，DMSO-d₆)δ ppm 7.16(dd，J＝8.78，3.90Hz，1H)7.62(dd，J＝8.66，3.29Hz，1H)7.66(m，1H)11.75(s，1H)。

A mixture of intermediate 21(8.42g, 46.48mmol) and 2-fluorophenylhydrazine (6.00g, 47.57mmol) in 100ml dry THF was refluxed for 4 hours. The reaction mixture gradually changed from a yellow suspension to an orange solution. At the end of 4 hours, the reaction mixture was cooled to room temperature and the mixture was concentrated on a rotary evaporator. The residue was triturated with a 1: 1 mixture of ether in hexane (2X 15ml) for 15 minutes and the solid was collected by filtration. This was air dried to give 7.62g of intermediate 22 (2-amino-5-fluoro-benzoic acid N' - (2-fluoro-phenyl) -hydrazide) as a white solid. Ms (apci): 264(M +1, 100%).

To a suspension of intermediate 22(7.61g, 28.92mmol) in 65ml of 1M HCl solution at 0 ℃ was added a solution of sodium nitrite (4.20g, 60.93mmol) in 17ml of water. Subsequently, EtOH (95ml) was added, and the slurry was refluxed for 2 hours. The reaction mixture was cooled to room temperature. Then concentrated on a rotary evaporator. Saturated NaCl solution (40ml), water (30ml), EtOAc (150ml) and THF (100ml) were added to dissolve the solid material. The organic layer was collected and the aqueous layer was extracted with EtOAc (100 mL). The combined organic layers were washed with MgSO 2₄Dried and then concentrated on a rotary evaporator. The residue was triturated with ether (40ml) and the solid collected by filtration. The solid was washed again with a 1: 1 mixture of ether in hexane (2X 10ml) and air dried to give 5.66g of intermediate 23 (5-fluoro-1- (2-fluoro-phenyl) -1H-indazol-3-ol) as an off-white solid. Ms (apci): 247(M +1, 100%), 248 (27%).

Intermediate 24((S) -3- [ 5-fluoro-1- (2-fluoro-phenyl) -1H-indazol-3-yloxymethyl ] -piperidine-1-carboxylic acid tert-butyl ester) was prepared according to the procedure described above for the preparation of intermediate 3, starting with intermediate 11 and intermediate 23, and stirring at 100 ℃ for 4 hours.

The title product was prepared from intermediate 24 following the procedure described above for the preparation of example 2.

Example 46: maleic acid (S) - (+) -5-fluoro-1- (2-fluorophenyl) -3- (morpholin-2-ylmethoxy) -1H-indazole

Intermediate 26((S) -2- [ 5-fluoro-1- (2-fluoro-phenyl) -1H-indazol-3-yloxymethyl ] was prepared according to the procedure described above for the preparation of intermediate 3, starting with intermediate 6 and intermediate 23, and stirring at 100 ℃ for 3 hours]-morpholine-4-carboxylic acid tert-butyl ester). [ alpha ] to]_D ²⁴＝+18.2°(CHCl₃，c＝5.1)，MS(APCI)：446(M+H，86％)，447(22％)，390(21％)，346(100％)，347(20％)。

The title product was prepared from intermediate 26 following the procedure described above for the preparation of example 2.

Examples 47-49 were synthesized in a similar manner as described for example 45.

Example 50 was synthesized in a similar manner to that described for example 45, except that GDI (1, 1' -carbonyldiimidazole) was used instead of phosgene.

Example 51: hydrochloric acid 5-fluoro-1- (2-fluoro-phenyl) -3- (piperidin-4-yloxy) -1H-indazole

Intermediate 23(1.00g, 4.10mmol) was dissolved in 41ml CH₃CN and 10ml DMF. To the solution at 50 ℃ was added 2.0g of cesium carbonate (6.10 mmol). After 10 min, intermediate 2(1.14g, 4.06mmol) was added and the mixture was heated to 80 ℃. After 22 hours, the reaction was cooled to room temperature and saturated NH₄Cl and an amount of additional H₂O stop the reaction and then Et₂And extracting for 3 times by using O. Extracting with hydrogen₂O1 time and then 1 time with brine over MgSO₄Dried and concentrated to 2.61g of yellow oil. The crude product was purified by flash chromatography (1X 10-20% EtOAc/hexanes, 1X 10% EtOAc/hexanes) to isolate intermediate 31(4- [ 5-fluoro-1- (2-fluoro-phenyl) -1H-indazol-3-yloxy) as a yellow oil]-piperidine-1-carboxylic acid tert-butyl ester) (1.13g, 65%): ms (apci): (M +1) ═ 430, 330 (M-BOC).

Intermediate 31(1.13g, 2.63mmol) was treated with HCl in dioxane/EtOAc according to the procedure of example 14, stirring overnight at room temperature. After conventional work-up, the solid was taken up in 40ml Et₂Triturate with O, filter and use greater than 2 parts Et₂O wash to give the title product as a white solid (0.721g, 75% yield): MS (M +1) ═ 330.

Examples 56-57 were synthesized in a similar manner as described for example 51.

Example 52: hydrochloric acid 5-fluoro-1- (2-fluoro-phenyl) -3- (1-methyl-piperidin-3-ylmethoxy) -1H-indazole

To a solution of piperidine-1, 3-dicarboxylic acid 1-tert-butyl ester (5.00g, 21.81mmol) in 20% MeOH/toluene (100ml) at room temperature was added 14.18ml of (trimethylsilyl) diazomethane (2.0M, 28.35mmol) dropwise and the reaction was monitored by TLC until complete, then concentrated under reduced pressure to give 4.44g (83.7%) piperidine-1, 3-dicarboxylic acid 1-tert-butyl ester-3-methyl ester (intermediate 53).¹H NMR(400MHz，CDCl₃)δ ppm 1.4(s，9H)，1.6(d，J＝3.4Hz，1H)，1.6(m，1H)，1.7(m，1H)，2.0(m，1H)，2.4(m，1H)，2.8(m，1H)，3.0(s，1H)，3.7(s，3H)，3.9(d，J＝13.2Hz，1H)，4.1(s，1H)。

To a stirred solution of intermediate 53(2.22g, 9.13mmol) in anhydrous THF (30ml) at-78 deg.C was added dropwise NaHMDS (sodium hexamethyldisilazane) (1.0M in THF, 10.03 mmol). The reaction was stirred at this temperature for 30 minutes, then methyl iodide (0.682ml, 10.95mmol) was added dropwise. The reaction can be warmed to room temperature and kept overnight with good stirring. The reaction was cooled and then saturated NH₄The reaction was stopped with Cl. The layers were separated and the aqueous layer was extracted 3 times with 20ml EtOAc and the organic extracts were combined. The organic phase is washed with Na₂SO₄Dried, filtered and concentrated under reduced pressure. This oil was purified by silica chromatography using hexane/EtOAc (0- > 15%) to give 2.25g (95.8%) of 1-tert-butyl 3-methyl-piperidine-1, 3-dicarboxylate (intermediate 54).¹HNMR(400MHz，CDCl₃)δ ppm 1.0(s，3H)，1.3(s，9H)，1.4(m，2H)，1.9(m，2H)，3.0(d，J＝13.2Hz，1H)，3.1(m，1H)，3.3(m，1H)，3.5(s，3H)，3.7(d，J＝13.4Hz，1H)。

To a stirred solution of intermediate 54(1.17g, 4.56mmol) in anhydrous THF (20ml) at 0 deg.C was added LiAlH dropwise₄(1.0M in THF, 9.11ml, 9.11mmol) the reaction was allowed to warm to room temperature. When the reaction was complete (as indicated by TLC), the reaction was saturated with NH₄Cl carefully stop the reaction and add EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (3X 15mL) and the organic extracts were combined. The organic phase is washed with Na₂SO₄Dried, filtered and concentrated under reduced pressure to give 0.844g (42.1%) of 3-hydroxymethyl3-methyl-piperidine-1-carboxylic acid tert-butyl ester (intermediate 55).¹H NMR(400MHz，CDCl₃)δ ppm 0.9(s，3H)，1.3(m，2H)，1.5(s，9H)，1.5(m，3H)，2.9(s，1H)，3.1(s，1H)，3.5(d，J＝11.5Hz，1H)，3.8(m，2H)。

To intermediate 55(0.844g, 3.68mmol) in anhydrous CH₂Cl₂Et was added to a stirred solution at 0 ℃ in (25ml)₃N (0.513ml, 3.682mmol) and the reaction was stirred for 15 min. Methanesulfonyl chloride (0.285ml, 3.682mmol) was added dropwise and the reaction allowed to warm to room temperature and held overnight with good stirring. The reaction was allowed to complete (by TLC) and Et was added₂O (100 ml). The mixture was filtered and washed with additional Et₂And washing the filter cake. The filtrate was then concentrated under reduced pressure. The residue was chromatographed using hexane/EtOAc (0- > 25%) to give 1.05g (93.1%) of 3-methanesulfonylmethyl-3-methyl-piperidine-1-carboxylic acid tert-butyl ester (intermediate 56).¹H NMR(400MHz，CDCl₃)δ ppm 1.0(s，3H)，1.4(m，1H)，1.4(s，9H)，1.6(m，3H)，3.0(s，3H)，3.2(s，1H)，3.5(s，2H)，4.0(d，J＝2.4Hz，2H)。

To intermediate 23(0.300g, 1.22mmol) in dry DMF (10ml) was added Cs₂CO₃(0.596g, 1.83mmol) and the mixture stirred for 30 minutes. Intermediate 56(0.412g, 1.34mmol) was added and the reaction heated to 80 ℃ and held overnight with good stirring. The reaction was found to be incomplete by HPLC (81% conversion), but heating was stopped and the reaction was allowed to cool to room temperature. With saturated NH₄Cl stopped the reaction and then a small amount of H was added₂O, then Et₂And (4) in O. Separate the aqueous layer from Et₂O (3X 15ml) extraction. The organic extracts were combined and washed with Na₂SO₄Dried, filtered and concentrated under reduced pressure. The oil was purified by silica chromatography using hexane/EtOAc (0- > 10%) to give 0.127g (22.8%) of 3- [ 5-fluoro-1- (2-fluoro-phenyl) -1H-indazol-3-yloxymethyl]-3-methyl-piperidine-1-carboxylic acid tert-butyl ester (intermediate 57). Ms (apci): (M +1) ═ 458.¹H NMR(400MHz，CDCl₃)δ ppm 1.1(s，3H)，1.4(s，9H)，1.5(m，1H)1.6(m，2H)，1.7(m，1H)，3.3(s，1H)，3.5(m，3H)，4.2(d，J＝30.0Hz，2H)，7.2(m，2H)，7.3(s，1H)，7.3(s，1H)，7.3(m，2H)，7.6(m，1H)。

To a stirred solution of intermediate 57(0.127g, 0.278mmol) in EtOAc (0.925ml) at room temperature was added 0.902ml of a 4.0M HCl in dioxane. The reaction was stirred at room temperature overnight. When the reaction was complete (as indicated by HPLC), the reaction was concentrated under reduced pressure. EtOAc was added to the solid, then concentrated under reduced pressure. This process was repeated 5 times. The solid was washed with EtOAc/Et₂Triturate with O (2: 1), filter the solid, then use Et₂O (2X 15ml) wash. The solid was placed in a drying oven under reduced pressure to yield 0.089g (81.7%) of the title product.

Example 53: 1- (2-fluoro-phenyl) -3- (3-methyl-piperidin-3-ylmethoxy) -1H-indazole hydrochloride

The title product was synthesized from intermediate 1 in the same manner as in example 52 to yield 0.121g (76.1%) of product.

Example 54: hydrochloric acid 5-fluoro-1- (2-fluoro-phenyl) -3- (4-methyl-piperidin-4-ylmethoxy) -1H-indazole

The compound was synthesized in the same manner as in example 52 from 5-fluoro-1- (2-fluoro-phenyl) -1H-indazol-3-ol (intermediate 23) and tert-butyl 4-methanesulfonyloxymethyl-4-methyl-piperidine-1-carboxylate (synthesized from mono-tert-butyl piperidine-1, 4-dicarboxylate in the same manner as intermediate 56) to give 0.068g (50.3%) of the title product.

Example 55: maleic acid (R) -5-fluoro-1- (2-fluoro-phenyl) -3- (piperidin-3-ylmethoxy) -1H-indazole

3- [ 5-fluoro-1- (2-fluoro-phenyl) -1H-indazol-3-yloxymethyl ] methyl prepared from intermediate 23(0.500g, 2.03mmol) and (R) -3-methanesulfonyloxymethyl-piperidine-1-carboxylic acid tert-butyl ester (0.655g, 2.23mmol) according to the procedure for intermediate 57]-piperidine-1-carboxylic acid tert-butyl ester. A stirred solution of carbamate in EtOAc (5.43ml) at room temperature was treated with 5.30ml of a 4.0M HCl in dioxane. Will be reversedThe reaction was stirred at room temperature overnight and concentrated under reduced pressure, triturated with EtOAc, and concentrated again under reduced pressure. This process was repeated 3 times. Attempts to recrystallize the foam from hexane/EtOAc and acetone/hexane were unsuccessful. The free base was formed by adding Dowex 550a (oh) anion exchange resin to a stirred solution of the salt in MeOH (10 ml). The mixture was stirred for 30 minutes, filtered, and the beads were washed three times with 20ml methanol. The organic phase was concentrated under reduced pressure to give 0.3628g of the free base as a yellow oil. To a stirred solution of the oil in EtOAc (10ml) was added maleic acid (0.111g, 1.0 eq). A solid precipitated out and the mixture was concentrated under reduced pressure. The solid was washed with hexane/Et₂Triturate with O, filter and use Et₂And O washing. The white solid was dried in an oven under reduced pressure at 80 ℃ overnight to yield 0.390g (69.6%) of the title maleate salt.

Example 58: hydrochloric acid 5-chloro-1- (2, 5-difluoro-phenyl) -3- (piperidin-4-yloxy) -1H-indazole

A solution of 2-amino-5-chloro-benzoic acid (3.0g, 17.0mmol) and hydrochloric acid (2, 5-difluoro-phenyl) -hydrazine (3.2g, 17.5mmol) in dry THF (tetrahydrofuran) (20ml) was treated with HOBT (1-hydroxybenzotriazole hydrate) (5.4g, 35.0 mmol). The resulting mixture was cooled to about-12 ℃. N-methyl-morpholine (3.7g, 36.7mmol) was added and the mixture was stirred for 5 minutes, then EDAC-HCl (1- [3- (dimethylamino) propyl hydrochloride) was added]-3-ethylcarbodiimide) (3.4g, 17.5 mmol). The mixture was stirred at-12 ℃ for 1 hour, then warmed to room temperature and stirred overnight. The reaction was partitioned between EtOAc (50ml) and water (50 ml). The layers were separated and the organic layer was washed 4 times with saturated aqueous NaCl solution over MgSO₄Dried and concentrated in vacuo. The resulting solid was triturated with ether, filtered and dried in a vacuum oven at 70 ℃ and 15mm Hg overnight to give intermediate 36 (2-amino-5-chloro-benzoic acid N' - (2, 5-difluoro-phenyl) -hydrazide) as a light yellow solid (4.0g, 77% yield): ms (apci): (M +1) ═ 298.0.

To a solution of intermediate 36(3.9g, 13.0mmol) in 1M HCl (35ml) at 0 ℃ was slowly added NaNO₂Dissolution in 10ml of waterAnd (4) liquid. The resulting mixture was stirred for 10 minutes, then 1: 1 EtOH/H₂Dilution with O (50 ml). The mixture was heated to reflux for 3 hours, cooled to room temperature and stirred for 1 hour. The solid was filtered off, washed 2 times with 20ml of water and dried in a vacuum oven at 70 ℃ (15mm Hg) overnight to give intermediate 37 (5-chloro-1- (2, 5-difluoro-phenyl) -1H-indazol-3-ol) (3.7g, 95% yield) as a brown solid: ms (apci): (M +1) ═ 281.0.

Intermediate 38 was prepared according to the procedure described above for intermediate 34, starting from intermediate 37(0.5g, 1.8mmol) and intermediate 2 to give the desired product, intermediate 38(4- [ 5-chloro-1- (2, 5-difluoro-phenyl) -1H-indazol-3-yloxy ] -piperidine-1-carboxylic acid tert-butyl ester) (0.48g, 58% yield): ms (apci): (M +1) ═ 464.0.

Intermediate 39 was prepared according to the procedure described above for example 14, starting from intermediate 38(0.45g, 0.97mmol) to give the desired title product 5-chloro-3-cyclohexyloxy-1- (2, 5-difluoro-phenyl) -1H-indazole hydrochloride (0.35g, 90% yield).

Examples 59-95 were synthesized in a similar manner to that described for example 58, using the appropriate 2-amino-benzoic acid. Examples 96-97 were synthesized in a similar manner as described for example 58, except that the indazol-3-ol and Cs were present₂CO₃In the reaction of (1), CH is used₃CN/DMF instead of DMF. Example 98 was synthesized in a similar manner to that described for example 58, except that NaH was used instead of Cs₂CO₃. Example 99 was synthesized in a similar manner as described for example 58, except that pyridylhydrazine was used in place of phenylhydrazine.

Example 100: hydrochloric acid 4-fluoro-1- (2-fluoro-phenyl) -3- (piperidin-4-yloxy) -1H-indazole

2-amino-6-fluorobenzoic acid (2.00g, 12.89mmol) was combined with 2-fluorophenylhydrazine hydrochloride (2.096g, 12.89mmol) and HOBt (3.949g, 25.79mmol) in dry THF (75ml) and cooled to about-12 ℃. N-methylmorpholine (2.835ml, 25) was added79mmol), the mixture was stirred for 5 minutes, then EDC hydrochloride (2.66g, 13.88mmol) was added. The mixture was kept at a temperature between-14 and-10 ℃ for 1 hour, then slowly warmed to room temperature and stirred for 18 hours. The mixture was cooled to 0 ℃ and then passed through CELITE^®(celite) filtration. The filtrate was diluted with EtOAc and saturated NaHCO₃And (4) processing and layering. The organic layer was washed with 50% saturated NaHCO₃Washed 2 times and then over MgSO₄Dried and concentrated. The resulting solid was triturated with dichloromethane, filtered, washed with a very small amount of dichloromethane and dried. The filtrate from the triturate was triturated with a small amount of dichloromethane, filtered, washed with a very small amount of dichloromethane and dried. The filtrate was concentrated to dryness and taken up in a small amount of Et₂Triturate, filter, rinse with a very small amount of ether and dry. The three solids were combined to give 2-amino-6-fluoro-benzoic acid N' - (2-fluoro-phenyl) -hydrazide as an off white solid in a total amount of 2.182g (64%) (intermediate 44). MS (APCD (M-1) ═ 262.0.

Intermediate 44(2.182g, 8.289mmol) was suspended in 1M HCl (20ml), cooled to 0 ℃ and treated dropwise with a solution of sodium nitrite (1.144g, 16.58mmol) in water (7 ml). The mixture was stirred at 0 ℃ for 10 minutes with 1: 1 EtOH/H₂O (30ml) was diluted and heated under reflux for 3 hours, followed by stirring at room temperature for 18 hours. The solid was filtered, washed with water, and dried to give 1.939g (95%) of 4-fluoro-1- (2-fluoro-phenyl) -1H-indazol-3-ol as a tan solid (intermediate 45). Ms (apci): (M +1) ═ 247.1, (M-1) ═ 245.0.

4- [ 4-fluoro-1- (2-fluoro-phenyl) -1H-indazol-3-yloxy ] -piperidine-1-carboxylic acid tert-butyl ester (intermediate 46) was prepared as described above for intermediate 42 using intermediate 45(300mg, 1.218mmol), PS-BEMP resin (1.108g) and 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (intermediate 2) (374mg, 1.34mmol) in DMF (10ml) to give 265mg (51%) of intermediate 46 as a yellow oil. MS (M +1) ═ 430.2.

The title product was prepared as described above for example 41 using intermediate 46(265mg, 0.617mmol) and HCl in 4M dioxane (2.00ml) in EtOAc (2ml) to give 202mg (89%) of a white solid.

Example 101-103 was synthesized in a similar manner as described for example 100.

Example 104: (S) - (-) -1-phenyl-3- (piperidin-3-ylmethoxy) -1H-pyrazolo [3, 4-b ] pyridine hydrochloride

To a solution of 2-chloronicotinyl chloride (5.05g, 2.87mmol) in 50ml of anhydrous dichloromethane at 0 deg.C was added triethylamine (4.5ml, 3.23mmol) followed by phenylhydrazine (2.9ml, 2.95 mmol). The reaction mixture was concentrated on a rotary evaporator. Water (40ml) was added and the mixture was extracted 3 times with 80ml EtOAc. The combined organic layers were washed with MgSO 2₄Dried and then concentrated. The solid residue was triturated with a 1: 1 mixture of EtOAc and hexane (60 mL). The solid was collected by filtration and then air dried after washing twice with 10ml ether. The neat solid was then heated to 175 ℃ and held for approximately 15 minutes. The solid initially melted to an orange liquid at 175 deg.C and then solidified to give 1.84g of a brown solid, intermediate 14 (1-phenyl-1H-pyrazolo [3, 4-b)]Pyridin-3-ol). Ms (apci): 212(M +1, 100%).

Intermediate 15(3- (1-phenyl-1H-pyrazolo [3, 4-b) was prepared according to the procedure described above for the preparation of intermediate 3, starting from intermediate 11 and intermediate 14 and stirring at 100 ℃ for 1.5 hours]Pyridin-3-yloxymethyl) -piperidine-1-carboxylic acid tert-butyl ester). [ alpha ] to]_D ²⁴＝+17.4°(CHCl₃，c＝10.8)，MS(APCI)：409(M+H，60％)，309(100％)。

To a solution of intermediate 15(0.72g, 1.75mmol) in 7ml EtOAc at room temperature was added a solution of 4M HCl in dioxane (5ml, 20.0 mmol). The light yellow solution turned to a bright yellow solution and after stirring for 5 minutes a precipitate formed. The mixture was stirred at room temperature for 2 hours. The solid was collected by filtration and washed with ether (5X 10 ml). The yellow solid was dried overnight under vacuum at 90 ℃ to give 0.52g of the title hydrochloride salt as a white solid.

Example 105 was synthesized in a similar manner as described for example 104.

Example 106: l-tartaric acid 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole

To a stirred suspension of 2-fluorophenylhydrazine hydrochloride (100g, 0.614moles) in ethanol (1.0L) was added a stream of triethylamine (68.4g, 0.68moles) at 22-23 deg.C over a period of 10 minutes. The suspension was stirred for 5 minutes, then isatoic anhydride (100g, 0.614moles) was added. The resulting suspension was stirred at the temperature at which reflux was reached (78 ℃) over the next 1 hour to form a solution. The solution was stirred at reflux for 2.5 hours. It was then stirred at-10 ℃ for 2 hours and filtered. The solid was washed with ethyl acetate (100ml) and dried under reduced pressure. The solid was suspended in water (400ml) and stirred at room temperature for 0.5 h. The solid was filtered off, washed with water (5X 30ml) and dried under reduced pressure. Further drying under vacuum at 33 ℃ for 17 h gave 63.3g (42%) of intermediate 48 (2-amino-benzoic acid N' - (2-fluoro-phenyl) -hydrazide). The organic filtrate was concentrated to dryness in vacuo. The residue was triturated with water (500ml then 3 × 200ml) and suspended in ethanol: in ethyl acetate (1: 1, 150 ml). The solid was filtered off, washed with ethyl acetate (50ml) and dried under reduced pressure. Further drying under vacuum at 32 ℃ for 6 hours gave a further 13.7g (9%) of product. The total yield was 77.0g (51%).¹H NMR(DMSO-ofe)δ：10.1(s，1H)，7.6(m，1H)，7.2(t，1H)，7.1(m，1H)，6.95(m，1H)，6.8(t，1H)，6.7(m，2H)，6.5(t，1H)，6.4(s，2H)。

To a stirred suspension of intermediate 48(150g, 0.257moles) in 1N HCl (560ml) at-3 ℃ to-2 ℃ was added dropwise a solution of sodium nitrite (35.5g, 0.514moles) in water (175ml) over 40 minutes. Note the generation of gas. The foamy suspension is stirred at 0 ℃ to-5 ℃ for 0.5 hour. Ethanol (1.05L) was added and the solution heated to reflux for 45 minutes. The suspension was stirred at reflux for 1.5 hours. Within the next 45 minutes, ethanol (. about.250 ml) was distilled off at atmospheric pressure. Cooling the suspension to-10 deg.C under stirring, maintaining for 0.5 hr, and filtering. The solid was washed 4 times with 30ml of isopropanol and dried under negative pressure. Further vacuum drying at 58 ℃ for 7 hours gave 52.5g (89.5%) of intermediate 1(1- (2-fluoro-phenyl) -1H-indazol-3-ol).¹H NMR(DMSO-Cf6)δ：7.7(d，1H)，7.6(t，1H)，7.3-7.5(m，4H)，7.2(m，1H)，7.1(t，1H)。

To intermediate 1(52g, 0.228moles) in dimethylformamide (480ml) was added cesium carbonate (111.5g, 0.342moles) with stirring. The mixture was stirred at room temperature for 0.5 hour. 4-Methanesulfonamidooxy-piperidine-1-carboxylic acid tert-butyl ester intermediate 2(70g, 0.251moles) was added and the mixture was stirred at 80-85 ℃ for 18 hours. The resulting suspension was cooled to 10 ℃ with an ice water bath. Over 20 minutes, a stream of saturated aqueous ammonium chloride (250ml) was added. The mixture was poured into stirred ice water (2L). The mixture was extracted with ether (1L, 500 ml). The extract was dried over magnesium sulfate and concentrated in vacuo to an orange-amber oil (124 g). This oil was dissolved in a mixture of hexane: ethyl acetate (1: 8, 150 ml). Silica gel (230-400mesh, 150g) was added to the turbid solution. The slurry was poured onto silica gel (230- & 400mesh, 850g) plates. The plate was eluted with ethyl acetate in hexane (5% → 8%). The total volume of the solvent used was 21L. The combined eluates were concentrated in vacuo to 88g (94%) of intermediate 3(4- [1- (2-fluoro-phenyl) -1H-indazol-3-yloxy) as a pale yellow gum]-piperidine-1-carboxylic acid tert-butyl ester).¹H NMR(CDCl₃)δ：7.7(d，1H)1 7.6(t，1H)，7.4(t，1H)，7.2-7.4(m，4H)，7.15(t，1H)，5.1(m，1H)，3.8(m，2H)，3.4(m，2H)，2.1(m，2H)，2.05(s，3H)，1.9(m，2H)，1.5(s，9H)。

To a stirred solution of intermediate 3(85g, 0.207moles) in ethyl acetate (600ml) at 21 ℃ was added HCl in 4M dioxane (600ml) in a thin stream over 35 minutes, raising the temperature to 24 ℃. The solution was stirred at 22-23 ℃ for 3 hours. The solution was concentrated in vacuo to a viscous oil that began to solidify. Ethyl acetate (200ml) was added and the resulting viscous suspension was stirred at 0 ℃ for 1 hour. The solid is filtered off, washed with 30ml of ethyl acetate and dried under negative pressure. Further vacuum drying at 35 deg.C for 16 hr to obtain66.5g (93%) of 1- (2-fluoro-phenyl) -3- (piperidin-4-yloxy) -1H-indazole hydrochloride.¹H NMR(CD₃OD)δ：7.7(d，1H)，7.6(t，1H)，7.5-7.6(m，2H)，7.3-7.5(m，2H)，7.25(m，1H)，7.2(t，1H)，5.2(m，1H)，3.4-3.5(m，2H)，3.2-3.3(m，2H)，2.3-2.4(m，2H)，2.2-2.3(m，2H).MS(APCI)：(M+1)＝311。

A mixture of 1- (2-fluoro-phenyl) -3- (piperidin-4-yloxy) -1H-indazole hydrochloride (9.0g, 0.026moles) in tetrahydrofuran (20ml) and water (100ml) was stirred at room temperature for 0.5 hour to form a solution. Sodium carbonate (15g, 0.142moles) was added portionwise over 5 minutes followed by ether (150 ml). The mixture was shaken and the layers were separated. The aqueous layer was extracted with ether (100 ml). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to a gum (8.0g, 99% crude yield). To this gum was added a solution of L-tartaric acid (4.0g, 0.0267mol) in water (80ml) in one portion. The mixture was stirred for-2 minutes at which time a complete solution formed. Stirring was continued and after-2 minutes the solid began to precipitate. The suspension was stirred at 0 ℃ for 3 hours and filtered. The solid was washed with water (15ml) and dried under negative pressure. Further drying under vacuum at 50 ℃ for 16 hours gave 10.2g (85.5%) of L-tartrate: l-tartaric acid 1- (2-fluoro-phenyl) -3- (piperidin-4-yloxy) -1H-indazole.

Example 107: l-tartaric acid (S) -5-fluoro-1- (2-fluorophenyl) -3- (piperidin-3-ylmethoxy) -1H-indazole

2-amino-5-fluoro-benzoic acid (20.0g, 129mmol) was dissolved in anhydrous THF (390 ml). 1, 1' -carbonyldiimidazole (CDI, 22.0g, 135mmol) was added in one portion. Some gas generation was observed and a very viscous beige solid precipitated. The suspension was stirred at room temperature for 1 hour 20 minutes. And finally, refining the precipitate. N, N-diisopropylethylamine (DIPEA, 27ml, 155mmol) was added which allowed the precipitate to dissolve completely, followed by the addition of (2-fluoro-phenyl) -hydrazine hydrochloride (23.1g, 142 mmol). The mixture was stirred at room temperature for 18 hours. The reaction was carefully stopped with water (1L) and ethyl acetate (500ml) was added. The two layers were separated and the aqueous layer was washed 2 times with 200ml water and then with 100ml saturated NaHCO₃Aqueous washing2 times, then washed with saturated brine and over MgSO₄And drying. Removal of the solvent gave 32.21g (95% yield) of intermediate 22 (2-amino-5-fluoro-benzoic acid N' - (2-fluoro-phenyl) -hydrazide) as a tan solid. Ms (apci): (M +1) ═ 264.¹H and¹⁹the F NMR spectrum was consistent with this structure. The solid was used in the next step without further purification.

A500-ml, three-necked round bottom flask equipped with a magnetic stirrer, additional funnel and thermometer was charged with a suspension of intermediate 22(10.00g, 38mmol) in 1N HCl (130ml) and ethanol (130 ml). The suspension was heated to 76 ℃ to completely dissolve the solid. NaNO was added dropwise over 15 minutes₂(5.24g, 76mmol) in water (12 ml). Gas generation was observed and after a few minutes, a beige solid precipitated from the solution. When NaNO is present₂When the addition of the solution was complete, the mixture was refluxed for 1 hour. The mixture was allowed to cool to room temperature and the solid was filtered, washed with water (3 × 50ml) and dried in a vacuum oven at 50 ℃ at 17torr for 24 hours to give 4.18g (92%) of intermediate 23 (5-fluoro-1- (2-fluoro-phenyl) -1H-indazol-3-ol) as a beige solid. Ms (apci): (M +1) ═ 247.¹H and¹⁹the F NMR spectrum was consistent with the structure. The solid was used in the next step without further purification.

Intermediate 23(9.86g, 40mmol) was dissolved in DMF (100 ml). Addition of K₂CO₃(8.30g, 60mmol), and the mixture was stirred at room temperature for 10 minutes. A solution of (S) -3-methanesulfonyloxy-methyl-piperidine-1-carboxylic acid tert-butyl ester intermediate 11(11.75g, 40mmol) in 10ml DMF was then added in one portion and the resulting mixture was stirred at 80-85 ℃ for 18 h. Addition of saturated NH₄Aqueous Cl (200ml) and water (1L) and the aqueous phase was extracted with MTBE (methyl tert-butyl ether) (3X 200 ml). The combined organic extracts were washed 2 times with 100ml of water, then with saturated brine and over MgSO₄And drying. The solvent was removed in vacuo to give a brown solid which was passed through a silica gel column (hexane/ethyl acetate 3/1 as mobile phase) to give 16.37g (92% yield) of intermediate 24((S) -3) as a yellow oil in the form of a very viscous solid- [ 5-fluoro-1- (2-fluoro-phenyl) -1H-indazol-3-yloxymethyl]-piperidine-1-carboxylic acid tert-butyl ester) ms (apci): (M +1) ═ 444.¹H and¹⁹the F NMR spectrum was consistent with the structure.

Intermediate 24(20.6g, 46mmol) was dissolved in ethyl acetate (150ml) and the solution was cooled in an ice-water bath. HCl in 4M dioxane (150ml) was added in one portion and the mixture warmed to room temperature. After 1 hour, the solvent was removed in vacuo to give a very viscous pale yellow oil. Ethyl acetate was added to redissolve the oil and it was removed under vacuum to give a yellow solid as a foam. Diethyl ether (300ml) was added to the oil and the suspension was slurried at room temperature for 18 hours. The resulting solid was filtered, washed 2 times with 50ml diethyl ether and dried in vacuo at 50 ℃ for 24 hours in a vacuum oven to give 15.39g (87%) of (S) -5-fluoro-1- (2-fluoro-phenyl) -3- (piperidin-3-ylmethoxy) -1H-indazole hydrochloride as a pale yellow solid. Ms (apci): (M +1) — 344.¹H and¹⁹the F NMR spectrum was consistent with the structure.

(S) -5-fluoro-1- (2-fluoro-phenyl) -3- (piperidin-3-ylmethoxy) -1H-indazole hydrochloride (14.0g, 37mmol) was suspended in ethyl acetate (100ml) and 1M K was added₂CO₃Solution in water (100 ml). The resulting mixture was stirred vigorously to allow complete dissolution of the solid. After 1 hour, two layers separated. And the aqueous layer was extracted 2 times with 50ml ethyl acetate. The combined organic extracts were washed with brine, over MgSO₄And drying. The solvent was removed in vacuo to give 11.9g (94%) of the free base (S) -5-fluoro-1- (2-fluoro-phenyl) -3- (piperidin-3-ylmethoxy) -1H-indazole as a very viscous yellow oil.¹H and¹⁹the F NMR spectrum was consistent with the structure.

The free base (20.9g, 61mmol) was dissolved in methanol (200 ml). L-tartaric acid (9.1g, 61mmol) was added in one portion and the mixture was stirred at room temperature for 10 min to give a clear solution. The solvent was removed in vacuo to give a pale yellow solid which was slurried in diethyl ether (500ml) for 2 hours. The solid was filtered, washed with diethyl ether (50ml) and dried in a vacuum ovenAt 50 ℃ for 2 hours at 17torr and then at room temperature for 48 hours, 27.8g (93%) of L-tartrate as a white solid are obtained: l-tartaric acid (S) -5-fluoro-1- (2-fluorophenyl) -3- (piperidin-3-ylmethoxy) -1H-indazole.¹H and¹⁹the F NMR spectrum was consistent with the structure. HPLC: chemical purity: 98.7% a/a; chirality: 100% ee. Combustion (CHN) analysis: and (4) passing.

Example 108-111 was synthesized in a similar manner to that described for example 107, except that Cs was used₂CO₃In place of K₂CO₃And HCl was used for deprotection and salt formation.

Ex.#	Name (R)	MSMP(℃)CHNNMRand[α]D 24
			1	1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole hydrochloride	210-211℃Found for C18H18FN3O.HCl.0.25H2O：C，61.32；H，5.59；N，11.71；F，5.39；Cl，10.091H NMR(400MHz，DMSO-D6)δppm 2.06(m，2H)，2.28(ddd，J＝10.31，7.02，3.42Hz，2H)，3.11(ddd，J＝12.63，8.60，3.66Hz，2H)，3.26(m，2H)，5.11(ddd，J＝11.35，7.56，3.54Hz，1H)，7.19(t，J＝7.44Hz，1H)，7.27(dd，J＝8.54，3.42Hz，1H)，7.37(dt，J＝8.48，4.18Hz，1H)，7.46(dd，J＝8.30，0.98Hz，1H)，7.49(m，2H)，7.62(m，1H)，7.75(d，J＝8.05Hz，1H)，9.09(s，2H)
2	Maleic acid (S) - (+) -1- (2-fluorophenyl) -3- (morpholin-2-ylmethoxy) -1H-indazole	MS(APCI)M+1＝328158-160℃Found for C18H18FN3O2.C4H4O4：C，59.71；H，4.84；N，9.44；F，4.441H NMR(400MHz，DMSO-D6)δ ppm 3.03(td，J＝12.20，3.42Hz，2H)，3.21(d，J＝13.18Hz，1H)，3.39(d，J＝11.96Hz，1H)，3.74(td，J＝12.38，2.56Hz，1H)，4.03(dd，J＝12.57，3.05Hz，1H)，4.15(m，1H)，4.45(ddd，J＝14.76，11.47，4.76Hz，2H)，5.99(m，2 H)，7.21(m，1H)，7.28(dd，J＝8.54，3.66Hz，1H)，7.38(m，1H)，7.49m，3H)，7.61(m，1H)，7.73(d，J＝8.05Hz，1H)，8.82(s，2H)[α]D 24＝+2.9 degrees(MeOH，c＝6.5)
			3	Maleic acid (S) - (+) -1- (2, 4-difluorophenyl) -3- (morpholin-2-ylmethoxy) -1H-indazole	MS(APCI)M+1＝346150-151℃Found for C18H17F2N3O2.C4H4O4：C 57.09；H，4.42；N，8.99；F，8.02[α]D 24＝+1.6 degrees(MeOH，c＝5.1)
4	1- (2-fluorophenyl) -3- (piperidin-3-ylmethoxy) -1H-indazole hydrochloride	MS(APCI)M+1＝326131-133℃Found for C19H2OFN3O.HCl.0.4H2O：C，61.87；H，6.16；N，11.37；F，5.08；CI，9.61
			5	(R) - (-) -1- (2-fluorophenyl) -3- (morpholin-2-ylmethoxy) hydrochloride1H-indazole	MS(APCI)M+1＝328103-104℃Found for C18H18FN3O2.HCl.0.15H2O：C，59.00；H，5.32；N，11.12；F，5.42；Cl，9.55[α]D 24＝-4 degrees(MeOH，c＝5.0)
6	(S) - (-) -1- (2-fluorophenyl) -3- (piperidin-3-ylmethoxy) -1H-indazole hydrochloride	MS(APCI)M+1＝326196-197℃Found for C19H20FN3O.HCl.0.2H2O：C，62.45；H，5.96；N，11.22；F，5.19；Cl，69[α]D 24＝-15.7degrees(MEOH，c＝5.1)
			7	(S) - (-) -1- (2-fluorophenyl) -3- (pyrrolidin-3-ylmethoxy) -1H-indazole hydrochloride	MS(APCI)M+1＝312100-101℃Found for C18H18FN3O.HCl.0.45H2O：C，60.78；H，5.70；N，11.97；F，5.43；Cl，9.96[α]D 24＝-1 degree(NeOH，c＝5.0)

8	(S) -1- (2, 4-difluorophenyl) -3- (pyrrolidin-3-ylmethoxy) -1H-indazole hydrochloride	MS(APCI)M+1＝330.1Found for C18H17F2N3O HCl.0.47 H2O；C，57.38；H，4.91；N，10.99；F，9.78；Cl，9.681H NMR(400MHz，DMSO-D6)δ ppm 1.8(m，1H)，2.1(m，1H)，2.9(m，1H)，3.1(dd，J＝11.7，7.1Hz，1H)，3.2(m，1H)，3.3(m，1H)，3.4(dd，J＝11.8，8.2Hz，1H)，4.4(m，2H)，7.2(t，J＝7.4Hz，1H)，7.3(m，2H)，7.5(m，1H)，7.6(m，1H)，7.7(td，J＝8.9，5.9Hz，1H)，7.8(d，J＝8.1Hz，1H)，9.1(bs，2H).
			9	(R) -1- (2, 4-difluorophenyl) -3- (pyrrolidin-3-ylmethoxy) -1H-indazole hydrochloride	MS(APCI)M+1＝330.1Found for C18H17F2N3O HCl.0.38H2O；C，57.64；H，4.94；N，11.16；F，9.80；Cl，9.611H NMR(400MHz，DMSO-D6)δppm 1.8(m，1H)，2.1(m，1H)，2.9(m，1H)，3.1(dd，J＝11.7，7.1Hz，1H)，3.2(m，1H)，3.3(m，1H)，3.4(dd，J＝11.6，7.9Hz，1H)，4.4(m，2H)，7.2(m，1H)，7.3(m，2H)，7.5(m，1H)，7.6(m，1H)，7.7(td，J＝8.9，6.1Hz，1H)，7.8(d，J＝81Hz，1H)，9.1(bs，2H)
10	1- (2, 4-difluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole hydrochloride	MS(APCI)M+1＝330.1Found for C18H17F2N3O.1.2 HCl；C，58.32；H，4.88；N，11.22；F，9.61；Cl，11.371H NMR(400MHz，DMSO-D6)δ ppm 2.1(m，2H)，2.3(m，2H)，3.1(m，2H)，3.3(m，2H)，5.1(m，1H)，7.2(m，1H)，7.3(m，2H)，7.5(m，1H)，7.6(m，1H)，7.7(td，J＝8.9，6.1Hz，1H)，7.8(d，J＝9.0Hz，1H)，9.0(bs，2H).
			11	(R) -1- (2-fluorophenyl) -3- (pyrrolidin-3-ylmethoxy) -1H-indazole hydrochloride	MS(APCI)M+1＝312.1Found for C18H18F1N3O1.05 HCl.0.46 H2O；C，60.33；H，5.59；N，11.61；F，5.40；Cl，10.771H NMR(400MHz，DMSO-D6)δ ppm 1.8(m，1H)，2.1(m，1H)，2.9(m，1H)，3.1(m，1H)，3.2(m，1H)，3.3(m，1H)，3.4(dd，J＝11.5，8.1Hz，1H)，4.4(m，2H)，7，2(t，J＝7.6Hz，1H)，7.3(dd，J＝8.5，3.7Hz，1H)，7.4(m，1H)，7.5(m，3H)，7.6(t，J＝7.8Hz，1H)，7.8(d，J＝7.8Hz，1H)，9.2(bs，2H).
12	(S) - (-) -1- (2-fluorophenyl) -3- (pyrrolidin-2-yloxy) -1H-indazole hydrochloride	MS(APCI)M+1＝298130-131℃Found for C17H16FN3O.1.05HCl.0.3H2O：C，59.98；H，5.27；N，12.26；F，5.53；Cl，10.76[α]D 24＝-10.5 degrees(MeOH，c＝6.1)
			13	Maleic acid (R) - (+) -1- (2-fluorophenyl) -3- (pyrrolidin-2-yloxy) -1H-indazole	MS(APCI)M+1＝298116-117℃Found for C17H16FN3O.C4H4O4：C，60.97；H，4.81；N，10.13；F，4.67[α]D 24＝+10.1 degrees(MeOH，c＝7.3)
14	(R) -1-phenyl-3- (pyrrolidin-3-ylmethoxy) -1H-indazole hydrochloride	MS(APCI)M+1＝294.1Found for C18H19N3O.1.0 HCl.0.23 H2O；C，64.35；H，6.17；N，12.21；Cl，10.521H NMR(400MHz，DMSO-D6)δ ppm 1.9(m，1H)，2.2(m，1H)，2.9(m，1H)，3.1(m，1H)，3.2(m，1H)，3.3(m，1H)，3.4(dd，J＝11.7，8.1Hz，1H)，4.5(m，2H)，7.2(m，1H)，7.3(t，J＝7.9Hz，1H)，7.5(m，3H)，7.7(d，J＝8.8Hz，2H)，7.8(dd，J＝15.7，8.9Hz，2H)，9.2(bs，2H).

15	(±) -1-phenyl-3- (piperidine-3-yloxy) -1H-indazole hydrochloride	MS(APCI)M+1＝294183-184℃Found for C18H19N3O.HCl：C，65.31；H，6.15；N，12.66；Cl，10.72
			16	(±) -1-phenyl-3- (piperidine-3-yl methoxy) -1H-indazole hydrochloride	MS(APCI)M+1＝308215-216℃Found for C19H21N3O.HCl：C，66.41；H，6.43；N，12.05；Cl，10.40
17	(±) -1-phenyl-3- (piperidine-4-yl methoxy) -1H-indazole hydrochloride	MS(APCI)M+1＝308218-219℃Found for C19H21N3O.HCl：C，66.22；H，6.56；N，12.01；Cl，10.32
			18	(R) - (+) -1-phenyl-3- (piperidin-3-ylmethoxy) -1H-indazole hydrochloride	MS(APCI)M+1＝308163-164℃Found for C19H21N3O.HCl：C，66.04；H，6.50；N，12.13；Cl，10.35[α]D 24＝+14.4 degrees(MeOH，c＝5.0)
19	(S) - (-) -1-phenyl-3- (piperidin-3-ylmethoxy) -1H-indazole hydrochloride	MS(APCI)M+1＝308165-166℃Found for C19H21N3O.HCl：C，66.02；H，6.49；N，12.04；Cl，10.11[α]D 24＝-17.1 degrees(MeOH，c＝4.9)
			20	1-phenyl-3- (piperidin-4-yloxy) -1H-indazole hydrochloride	MS(APCI)M+1＝294154-156℃Found for C18H19N3O.HCl：C，65.28；H，6.05；N，12.58；Cl，10.90
21	S) - (+) -3- (morpholin-2-ylmethoxy) -1-phenyl-1H-indazole hydrochloride	MS(APCI)M+1＝310165-166℃Found for C18H19N3O2.HCl：C，62.22；H，5.79；N，12.00；Cl，10.54[α]D 24＝-+3.3 degrees(MeOH，c＝1 0.2)
			22	(S) -1-phenyl-3- (pyrrolidin-3-ylmethoxy) -1H-indazole hydrochloride	MS(APCI)M+1＝294.1Found for C18H19N3O.1.05 HCl.0.39 H2O；C，63.79；H，5.96；N，12.12；Cl，11.161H NMR(400MHz，DMSO-D6)δ ppm 1.9(m，1H)，2.2(m，1H)，2.9(m，1H)，3.1(m，1H)，3.2(m，1H)3.3(m，1H)，3.4(dd，J＝11.6，7.9Hz，1H)，4.5(m，2H)，7.2(m，1H)，7.3(t，J＝7.4Hz，1H)，7.5(m，3H)，7.7(d，J＝7.6Hz，2H)，7.8(dd，J＝14.9，8.3Hz，2H)，9.3(bs.2H).
23	(S) -1- (3, 4-difluorophenyl) -3- (morpholin-2-ylmethoxy) -1H-indazole hydrochloride	177-179℃Found for C18H17F2N3O2.1.05 HCl.0.15 H2O；C，55.67；H，4.43；N，10.67；Cl，9.38；F，10.00
			24	(S) -1- (2, 6-difluorophenyl) -3- (morpholin-2-ylmethoxy) -1H-indazole hydrochloride	217-218℃Found for C19H19F2N3O1.1.0 HCl；C，56.45；H，4.55；N，10.95；Cl，9.26[α]D 24＝+2.2 degrees(MeOH，c＝7.2)

25	Maleic acid (S) -1- (2, 6-difluorophenyl) -3- (piperidin-3-ylmethoxy) -1H-indazole	139-141℃Found for C19H19F2N3O1.1.0 C4H4O4；C，59.76；H，5.02；N，8.99；F，8.27[α]D 24＝-8，9 degrees(MeOH，c＝7.2)
			26	Maleic acid (S) -1- (2, 5-difluorophenyl) -5-fluoro-3- (morpholin-2-ylmethoxy) -1H-indazole	169-170℃Found for C18H16F3N3O2.C4H4O4：C，55.10；H，4.14；N，8.67；F，11.91[α]D 24＝+4.2 degrees(MeOH，c＝8.8)
27	1- (2, 5-difluoro-phenyl) -3- (piperidin-4-yloxy) -1H-indazole hydrochloride	MS(APCI)M+1＝330.1Found for C18H17F2N3O.1.0 HCl；C，58.78；H，4.79；N，11.35；F，10.24；Cl，9.921H NMR(400MHz，DMSO-D6)δ ppm 2.1(m，2H)，2.3(m，2H)，3.1(m，2H)，3.3(m，2H)，5.1(m，1H)，7.2(t，J＝7.9Hz，1H)，7.4(m，2H)，7.5(m，3H)，7.8(d，J＝8.1Hz，1H)，8.8(bs，2H).
			28	Maleic acid (S) - (+) -1- (2, 5-difluorophenyl) -3- (morpholin-2-ylmethoxy) -1H-indazole	MS(APCI)M+1＝346156-157℃Found for C18H17F2N3O2.C4H4O4：C，57.44；H，4.64；N，9.08；F，8.26[α]D 24＝+3.8 degrees(MeOH，c＝5.5)
29	1- (3, 5-dichlorophenyl) -3- (piperidin-4-yloxy) -1H-indazole hydrochloride	MS(APCI)M+1＝362.11H NMR(400MHz，DMSO-D6)δ ppm 2.1(m，2H)，2.3(m，2H)，3.2(ddd，J＝12.6，8.6，3.7Hz，2H)，3.3(m，2H)，5.2(ddd，J＝7.6，4.1，3.9Hz，1H)，7.3(m，1H)，7.5(t，J＝1.8Hz，1H)，7.6(ddd，J＝8.5，7.1，1.0Hz，1H)，7.8(m，3H)，7.9(d，J＝8.5Hz，1H)，8.8(s，2H)
			30	(R) -1- (2, 5-difluorophenyl) -3- (pyrrolidin-3-ylmethoxy) -1H-indazole hydrochloride	MS(APCI)M+1＝330.11H NMR(4D0MHz，DMSO-D6)δppm 1.8(m，1H)，2.1(m，1H)，2.9(m，1H)，3.1(dd，J＝11.7，7.1Hz，1H)，3.2(m，1H)，3.3(m，1H)，3.4(dd，J＝11.6，7.9Hz，1H)，4.4(m，2H)，7.2(t，J＝7.2Hz，1H)，7.4(m，2H)，7.6(m，3H)，7.8(d，J＝8.1Hz，1H)，9.1(bs，2H).
31	(±) -1- (2, 5-difluorophenyl) -3- (piperidin-3-ylmethoxy) -1H-indazole hydrochloride	MS(APCI)M+1＝344.2Found for C19H19F2N3O.1.0 HCl.0.03 H2O；C，59.72；H，5.36；N，10.78；F，9.59；Cl，9.381H NMR(400MHz，DMSO-D6)δ ppm 1.4(m，1H)，1.7(m，1H)，1.9(m，2H)，2.4(m，1H)，2.8(m，2H)，3.2(d，J＝11.5Hz，1H)，3.4(d，J＝11.5Hz，1H)，4.3(dd，J＝10.4，7.2Hz，1H)，4.4(m，1H)，7.2(t，J＝7.4Hz，1H)，7.4(m，2H)，7.6(m，3H)，7.8(d，J＝8.1Hz，1H)，9.0(m，1H)，9.1(m，1H).
			32	(S) -1- (2, 5-difluorophenyl) -3- (pyrrolidin-3-ylmethoxy) -1H-indazole hydrochloride	MS(APCI)M+1＝330.1Found for C18H17F2N3O.1.0 HCl.0.40 H2O；C，58.30；H，4，96；N，11.12；F，9.79；Cl，9.811H NMR(400MHz，DMSO-D6)δ ppm 1.8(m，1H)，2.1(m，1H)，2.9(m，1H)，3.1(m，1H)，3.2(m，1H)，3.3(m，1H)，3.4(m，1H)，4.4(m，2H)，7.2(t，J＝7.4Hz，1H)，7.4(m，2H)，7.6(m，3H)，7.8(d，J＝8.1Hz，1H)，9.3(bs，2H).

33	(S) -1- (3, 4-difluorophenyl) -3- (piperidin-3-ylmethoxy) -1H-indazole hydrochloride	MS(APCI)M+1＝344.21H NMR(400MHz，DMSO-D6)δ ppm 1.36(m，1H)，1.77(m，3H)，2.38(m，2H)，2.77(m，2H)，3.20(d，J＝12.45Hz，1H)，3.36(d，J＝11.96Hz，1H)，4.33(m，2H)，7.20(t，J＝7.45Hz，1H)，7.53(m，3H)，7.75(m，3H)，9.06(s，2H).
			34	1- (3, 4-difluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole hydrochloride	MS(APCl)M+1＝330.21H NMR(400MHz，DMSO-D6)δ ppm 2.04(m，2H)，2.27(m，2H)，3.10(m，2H)，3.24(dd，J＝7.32，4.15Hz，2H)，5.14(m，1H)，7.20(t，J＝7.20Hz，1H)，7.54(m，3H)，7.76(m，3H)，9.05(bs，2H)
35	(S) -1- (3,4-difluoro-phenyl) -3- (pyrrolidin-3-ylmethoxy) -1H-indazole	MS(APCI)M+1＝330.21H NMR(400MHz，DMSO-D6)δ ppm 1.79(m，1H)，2.11(m，1H)，2.85(m，1H)，3.06(dd，J＝11.47，7.08Hz，1H)，3.14(m，1H)，3.24(m，1H)，3.35(dd，J＝11.60，7.93Hz，1H)，4.43(m，2H)，7.20(t，J＝7.20Hz，1H)，7.54(m，3H)，7.76(m，3H)，9.15(bs，2H).
			36	1- (2, 6-difluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole hydrochloride	MS(APCI)M+1＝330.21H NMR(400MHz，DMSO-D6)δ ppm 2.00(m，2H)，2.23(m，2H)，3.07(m，2H)，3.24(m，2H)，5.04(m，1H)，7.17(m，2H)，7.36(t，J＝8.42Hz，2H)，7.44(m，1H)，7.60(m，1H)，7.73(d，J＝8.06Hz，1H)，9.01(bs，2H).
37	(S) -1- (2, 6-difluorophenyl) -3- (pyrrolidin-3-ylmethoxy) -1H-indazole hydrochloride	MS(APCI)M+1＝330.21H NMR(400MHz，DMSO-D6)δ ppm 1.78(m，1H)，2.08(m，1H)，2.81(m，1H)，3.19(m，4H)，4.34(m，2H)，7.17(m，2H)，7.36(t，J＝8.30Hz，2H)，7.44(m，1H)，7.60(m，1H)，7.73(m，J＝8.06Hz，1H)，9.32(bs，2H).
			38	(S) -1- (2, 5-difluorophenyl) -3- (piperidin-3-ylmethoxy) -1H-indazole hydrochloride	MS(APCI)M+1＝344.21H NMR(400MHz，DMSO-D6)δ ppm 1.4(m，1H)，1.7(m，1H)，1.9(m，2H)，2.4(m，1H)，2.8(m，2H)，3.2(d，J＝12.7Hz，1H)，3.4(m，J＝12.6，2.6Hz，1H)，4.3(m，2H)，7.2(t，J＝7.4Hz，1H)，7.4(m，2H)，7.6(m，3H)，7.8(d，J＝7.8Hz，1H)，8.9(bs，2H).
39	1- (2, 5-difluorophenyl) -5-fluoro-3- (piperidin-4-yloxy) -1H-indazole hydrochloride	MS(APCI)M+1＝348.21H NMR(400MHz，DMSO-D6)δ ppm 2.1(m，2H)，2.3(m，2H)，3.1(m，2H)，3.3(m，2H)，5.1(dq，J＝7.4，3.7Hz，1H)，7.4(m，3H)，7.6(m，3H)，9.1(s，1H).
			40	(R) -1- (2, 5-difluorophenyl) -5-fluoro-3- (pyrrolidin-3-ylmethoxy) -1H-indazole hydrochloride	MS(APCI)M+1＝348.21H NMR(400MHz，DMSO-D6)δ ppm 1.8(m，1H)，2.1(td，J＝13.2，7.8Hz，1H)，2.9(dt，J＝14.3，7.1Hz，1H)，3.1(dd，J＝11.6，7.0Hz，1H)，3.2(m，1H)，3.3(m，2H)，4.4(ddd，J＝17.1，10.4，6.7Hz，2H)，7.4(m，3H)，7.5(m，3H)，9.3(s，1H).
41	1- (4-chlorophenyl) -3- (piperidin-4-yloxy) -1H-indazole hydrochloride	MS(APCI)M+1＝328.11H NMR(400MHz，DMSO-D6)δ ppm 2.1(m，2H)，2.3(m，2H)，3.1(ddd，J＝12.6，8.5，3.8Hz，2H)，3.3(m，2H)，5.2(ddd，J＝7.5，4.0，3.8Hz，1H)，7.2(t，J＝7.4Hz，1H)，7.5(ddd，J＝8.5，7.1，1.2Hz，1H)，7.6(m，2H)，7.8(m，4H)，8.9(s，2H)
			42	1- (4-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole hydrochloride	MS(APCI)M+1＝312.21H NMR(400MHz，DMSO-D6)δ ppm 2.0(m，2H)，2.3(m，2H)，3.1(ddd，J＝12.7，8.6，3.5Hz，2H)，3.3(m，2H)，5.1(dt，J＝7.6，3.9Hz，1H)，7.2(t，J＝7.2Hz，1H)，7.4(m，2H)，7.5(ddd，J＝8.4，7.1，1.1Hz，1H)，7.7(m，4H)，8.8(s，2H)

43	1- (3-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole hydrochloride	MS(APCI)M+1＝312.21H NMR(400MHz，DMSO-D6)δ ppm 2.0(m，2H)，2.3(m，2H)，3.1(m，2H)，3.3(m，2H)，5.2(m，1H)，7.1(m，1H)，7.2(m，1H)，7.6(m，4H)，7.8(d，J＝7.8Hz，1H)，7.9(d，J＝8.5Hz，1H)，8.7(s，2H)
			44	Maleic acid (S) - (-) -3- (piperidin-3-ylmethoxy) -1-pyridin-2-yl-1H-indazole	MS(APCI)M+1＝309181-183℃Found for C18H20N4O.C4H4O4：C，62.24；H，5.38；N，13.12[α]D 24＝-12.1 degrees(MeOH，c＝6.6)
45	Maleic acid (S) - (-) -5-fluoro-1- (2-fluorophenyl) -3- (piperidin-3-ylmethoxy) -1H-indazole	MS(APCI)M+1＝344141-142℃Found for C19H19F2N3O.C4H4O4：C，59.76；H，5.04；N，9.10；F，8.101H NMR(400MHz，DMSO-D6)δppm 1.39(m，1H)，1.63(m，1H)，1.84(m，2H)，2.31(m，1H)，2.81(m，2H)，3.25(d，J＝13.18Hz，1H)，3.43(dd，J＝12.20，3.66 Hz，1H)，4.26(dd，J＝10.49，7.08Hz，1H)，4.35(m，1H)，5.99(s，2H)，7.35(m，3H)，7.51(m，3H)，7.61(m，1H)，8.45(s，2H)[α]D 24＝-11.0 degrees(MeOH，c＝5.8)
			46	Maleic acid (S) - (+) -5-fluoro-1- (2-fluorophenyl) -3- (morpholin-2-ylmethoxy) -1H-indazole	MS(APCI)M+1＝346155-156℃Found for C18H17F2N3O2.C4H4O4：C，57.35；H，4.55；N，9.04；F.8.101H NMR(400MHz，DMSO-D6)δ ppm 3.03(m，2H)，3.21(d，J＝12.69Hz，1H)，3.38(d，J＝11.47Hz，1H)，3.73(td，J＝12.44，2.44Hz，1H)，4.02(dd，J＝12.81，3.05Hz，1H)，4.14(ddd，J＝11.35，6.83，4.76Hz，1H)，4.44(ddd，J＝13.97，11.41，4.64Hz，2H)，5.99(s，2H)，7.37(m，3H)，7.51(m，3H)，7.62(m，1H)，8.82(s，2H)[α]D 24＝+3.8 degrees(MeOH，c＝6.1)
47	(S) - (-) -5-fluoro-1- (2-fluorophenyl) -3- (piperidin-3-ylmethoxy) -1H-indazole hydrochloride	MS(APCI)M+1＝326205-207℃Found for C19H20FN3O.HCl：C，62.75；H，5.62；N，11.49；F，5.39；CI，9.96[α]D 24＝-13.1 degrees(MeOH，c＝7.0)
			48	Maleic acid (S) - (+) -1- (2, 4-difluorophenyl) -5-fluoro-3- (morpholin-2-ylmethoxy) -1H-indazole	MS(APCI)M+1＝364151-152℃Found for C18H16F3N3O2.C4H4O4：C，54.88；H，4.14；N，8.72；F，12.29[α]D 24＝+3.2 degrees(MeOH，c＝7.4)
49	(S) - (-) -1- (2, 4-difluorophenyl) -5-fluoro-3- (piperidin-3-ylmethoxy) -1H-indazole hydrochloride	MS(APCI)M+1＝362201-203℃Found for C19H18F3N3O.HCl：C，57.20；H，4.75；N，10.48；F，14.37；Cl，8.99[α]D 24＝-11.8 degrees(MeOH，c＝5.6)
			50	(S) -1- (2, 6-difluorophenyl) -5-fluoro-3- (morpholin-2-ylmethoxy) -1H-indazole hydrochloride	247-249℃Found for C18H16F3N3O2.1.0 HCl；C，54.06；H，4.19；N，10.44；F，14.14；Cl，8.84[α]D 24＝+2.1 degrees(MeOH，c＝7.1)

51	Hydrochloric acid 5-fluoro-1- (2-fluoro-phenyl) -3- (piperidin-4-yloxy) -1H-indazole	MS(APCI)M+1＝330.1Found for C18H17F2N3O1.1.0 HCl.0.85 H2O；C，56.34；H，5.30；N，10.87；F，9.99；Cl，9.411H NMR(400MHz，DMSO-D6)δ ppm 2.1(m，2H)，2.3(m，2H)，3.1(m，2H)，3.3(m，2H)，5.1(m，1H)，7.4(m，3H)，7.5(m，2H)，7.6(dd，J＝8.4，2.3Hz，1H)，7.6(t，J＝7.8Hz，1H)，9.1(bd，J＝21.0Hz，2H).
			52	Hydrochloric acid 5-fluoro-1- (2-fluorophenyl) -3- (1-methyl-piperidin-3-ylmethoxy) -1H-indazole	MS(APCI)M+1＝3581H NMR(400MHz，METHANOL-D4)δ ppm 1.3(s，3H)，1.6(m，1H)，1.9(m，3H)，3.2(m，4H)，3.3(s，1H)，4.3(m，2H)，7.3(m，2H)，7.4(m，2H)，7.4(m，2H)，7.6(m，1H).
53	1- (2-fluorophenyl) -3- (3-methyl-piperidin-3-ylmethoxy) -1H-indazole hydrochloride	MS(APCI)M+1＝3401H NMR(400MHz，METHANOL-D4)δ ppm 1.3(s，3H)，1.7(m，1H)，1.9(m，3H)，3.2(m，3H)，3.3(s，1H)，4.4(m，2H)，7.2(m，2H)，7.4(m，2H)，7.5(m，2H)，7.6(m，1H)，7.7(d，J＝8.1Hz，1H).
			54	Hydrochloric acid 5-fluoro-1- (2-fluorophenyl) -3- (4-methyl-piperidin-4-ylmethoxy) -1H-indazole	MS(APCI)M+1＝3581H NMR(400MHz，METHANOL-D4)δ ppm 1.3(s，3H)1.8(m，2H)2.0(m，2H)3.2(m，3H)3.3(m，2H)4.3(s，2H)7.3(m，2H)7.4(m，3H)7.5(m，1H)7.6(m，1H).
55	Maleic acid (R) -5-fluoro-1- (2-fluorophenyl) -3- (piperidin-3-ylmethoxy) -1H-indazole	MS(APCI)M+1＝3441H NMR(400MHz，METHANOL-D4)δ ppm 1.5(m，1H)，1.8(m，1H)，2.0(d，J＝12.2Hz，2H)，2.4(m，1H)，3.0(m，2H)，3.4(d，J＝12.9Hz，1H)，3.6(d，J＝15.9Hz，1H)，4.3(m，1H)，4.5(m，1H)，6.2(s，2H)，7.3(m，2H)，7.4(m，J＝25.4Hz，3H)，7.5(m，1H)，7.6(m，1H).
			56	1- (2, 4-difluorophenyl) -5-fluoro-3- (piperidin-4-yloxy) -1H-indazole hydrochloride	MS(APCI)M+1＝348.1Found for C18H16F3N3O1.1.0 HCl.0.12 H2O；C，55.62；H，4.31；N，10.61；F，14.57；Cl，9.111H NMR(400MHz，DMSO-D6)δ ppm 2.1(m，2H)，2.2(m，2H)，3.1(m，2H)，3.3(m，2H)，5.1(m，1H)，7.3(m，2H)，7.4(td，J＝9.0，2.4Hz，1H)，7.6(m，2H)，7.7(td，J＝8.8，6.0Hz，1H)，8.9(bs，2H).
57	(±) -5-fluoro-1- (2-fluorophenyl) -3- (piperidin-3-ylmethoxy) -1H-indazole hydrochloride	MS(APCI)M+1＝344.1FoundforC19H19F2N3O1.1.0HCl.0.29 H2O；C，58.87；H，5.23；N，10.87；F，9.62；Cl，9.491H NMR(400MHz，DMSO-D6)δ ppm 1.4(m，1H)，1.8(m，3H)，2.4(m，1H)，2.8(m，2H)，3.2(d，J＝12.2Hz，1H)，3.4(dd，J＝12.3，3.0Hz，1H)，4.3(dd，J＝10.4，7.0Hz，1H)，4.4(m，1H)，7.4(m，3H)，7.5(m，2H)，7.6(dd，J＝8.4，2.1Hz，1H)，7.6(m，1H)，9.1(bs，2H).
			58	Hydrochloric acid 5-chloro-1- (2, 5-difluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole	MS(APCI)M+1＝364.11H NMR(400MHz，DMSO-D6)δ ppm 2.1(m，2H)，2.2(m，2H)，2.3(d，J＝3.9Hz，1H)，3.1(ddd，J＝12.4，8.1，3.9Hz，2H)，3.3(m，2H)，5.1(ddd，J＝7.2，3.8，3.7Hz，1H)，7.4(m，2H)，7.5(m，3H)，7.9(d，J＝1.5Hz，1H)，9.1(s，2H)

59	Hydrochloric acid 7-methyl-1-phenyl-3- (piperidin-4-yloxy) -1H-indazole	MS(APCI)M+1＝308.21H NMR(400MHz，DMSO-D6)δ ppm 2.0(m，5H)，2.2(m，2H)，3.1(td，J＝8.7，4.4Hz，2H)，3.2(m，2H)，5.0(ddd，J＝7.7，4.0，3.9Hz，1H)，7.0(m，1H)，7.2(d，J＝7.1Hz，1H)，7.5(m，5H)，7.5(d，J＝7.8Hz，1H)，8.7(s，2H)
			60	Hydrochloric acid 7-methoxy-1-phenyl-3- (piperidin-4-yloxy) -1H-indazole	MS(APCI)M+1＝324.21H NMR(400MHz，DMSO-D6)δ ppm 2.0(m，2H)，2.2(ddd，J＝10.4，7.1，3.5Hz，2H)，3.1(ddd，J＝12.7，8.7，3.5Hz，2H)，3.2(m，2H)，3.7(s，3H)，5.0(m，1H)，7.0(d，J＝7.1Hz，1H)，7.1(t，J＝7.8Hz，1H)，7.3(m，2H)，7.4(m，4H)，8.9(s，2H)
61	Hydrochloric acid 7-chloro-1-phenyl-3- (piperidin-4-yloxy) -H-indazole	MS(APCI)M+1＝328.11H NMR(400MHz，DMSO-D6)δ ppm 2.0(m，2H)，2.2(m，2H)，3.1(m，2H)，3.3(m，2H)，5.1(dt，J＝7.6，3.9Hz，1H)，7.2(m，1H)，7.4(m，5H)，7.5(m，1H)，7.7(dd，J＝8.1，1.0Hz，1H)，8.8(s，2H)
			62	Hydrochloric acid 4-methyl-1-phenyl-3- (piperidin-4-yloxy) -1H-indazole	MS(APCI)M+1＝308.21H NMR(400MHz，DMSO-D6)δ ppm 2.1(m，2H)，2.3(m，2H)，2.6(s.3H)，3.2(m，4H)，5.2(dt，J＝6.6，3.4Hz，1H)，6.9(d，J＝7.1Hz，1H)，7.3(m，2H)，7.5(m，3H)，7.7(dt，J＝8.6，1.7Hz，2H)，9.0(s，2H)
63	Hydrochloric acid 6-fluoro-1- (2-fluoro-phenyl) -3- (piperidin-4-yloxy) -1H-indazole	MS(APCI)M+1＝330.11H NMR(400MHz，DMSO-D6)δ ppm 2.0(m，2H)，2.2(ddd，J＝10.3，7.1，3.7Hz，2H)，3.1(m，2H)，3.2(m，2H)，5.1(ddd，J＝7.7，4.0，3.9Hz，1H)，7.1(m，2H)，7.3(m，1H)，7.5(m，2H)，7.6(m，1H)，7.8(dd，J＝8.8，5.4Hz，1H)，9.0(s，2H)
			64	Hydrochloric acid 6-chloro-1-phenyl-3- (piperidin-4-yloxy) -1H-indazole	MS(APCI)M+1＝328.11H NMR(400MHz，DMSO-D6)δ ppm 2.0(m，J＝14.2，7.3，3.7，3.5Hz，2H)，2.2(m，2H)，3.1(m，2H)，3.3(m，2H)，5.1(dt，J＝7.3，3.6Hz，1H)，7.3(m，1H)，7.5(m，3H)，7.7(dt，J＝8.7，1.6Hz，2H)，7.8(d，J＝9.8Hz，1H)，7.8(d，J＝1.5Hz，1H)，8.9(s，2H)
65	1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -7- (trifluoromethyl) -1H-indazole hydrochloride	MS(APCI)M+1＝380.11H NMR(400MHz，DMSO-D6)δ ppm 2.0(m，2H)，2.2(m，2H)，3.1(m，2H)，3.2(m，2H)，5.0(ddd，J＝7.8，4.2，4.0Hz，1H)，7.3(m，3H)，7.6(m，J＝7.7，7.7，5.7，1.8Hz，2H)，7.8(d，J＝7.3Hz，1H)，8.1(d，J＝7.8Hz，1H)，8.9(s，2H)
			66	(±) -1- (3-fluorophenyl) -3- (piperidin-3-ylmethoxy) -1H-indazole hydrochloride	MS(APCI)M+1＝326.21H NMR(400MHz，DMSO-D6)δ ppm 1.4(m，1H)，1.7(m，1H)，1.9(m，2H)，2.4(m，1H)，2.8(m，2H)，3.2(m，1H)，3.4(dd，J＝12.2，3.4Hz，1H)，4.3(dd，J＝10.5，7.1Hz，1H)，4.4(m，1H)，7.1(m，1H)，7.2(m，1H)，7.6(m，4H)，7.8(d，J＝7.8Hz，1H)，7.9(d，J＝8.8Hz，1H)，8.7(s，1H)
67	(±) -1- (4-fluorophenyl) -3- (piperidin-3-ylmethoxy) -1H-indazole hydrochloride	MS(APCI)M+1＝326.21H NMR(400 MHz，DMSO-D6)δ ppm 1.4(m，1 H)，1.7(m，1 H)，1.8(m，2 H)，2.4(m，1 H)，2.8(m，2 H)，3.2(m，1 H)，3.4(dd，J＝12.2，4.1Hz，1H)，4.3(dd，J＝10.5，7.1Hz，1H)，4.4(m，1H)，7.2(m，1H)，7.4(m，2H)，7.5(ddd，J＝8.5，7.1，1.2Hz，1H)，7.7(m，4H)，8.7(s，2H)

68	(±) -1- (4-chlorophenyl) -3- (piperidin-3-ylmethoxy) -1H hydrochloride-indazoles	MS(APCI)M+1＝342.21H NMR(400MHz，DMSO-D6)δ ppm 1.4(qd，J＝12.3，3.8Hz，1H)，1.7(m，1H)，1.8(m，2H)，2.4(m，1H)，2.8(m，2H)，3.2(d，J＝12.2Hz，1H)，3.4(dd，J＝12.5，3.4Hz，1H)，4.3(dd，J＝10.5，7.1Hz，1H)，4.4(m，1H)，7.2(m，1H)，7.5(m，3H)，7.7(m，3H)，7.8(d，J＝8.5Hz，1H)，8.8(s，2H)
			69	(±) -5-chloro-1-phenyl-3- (piperidin-3-ylmethoxy) -1H-indazole hydrochloride	MS(APCI)M+1＝342.21H NMR(400MHz，DMSO-D6)δ ppm 1.4(m，1H)，1.6(m，1H)，1.8(m，2H)，2.3(m，1H)，2.8(m，2H)，3.2(m，1H)，3.4(dd，J＝12.2，3.7Hz，1H)，4.3(dd，J＝10.5，7.1Hz，1H)，4.4(m，1H)，7.3(m，1H)，7.5(m，3H)，7.7(ddd，J＝8.7，1.7，1.6Hz，2H)，7.8(m，2H)，8.7(s，2H)
70	(±) -6-fluoro-1- (2-fluorophenyl) -3- (piperidin-3-ylmethoxy) -1H-indazole hydrochloride	MS(APCI)M+1＝344.11H NMR(400MHz，DMSO-D6)δ ppm 1.4(td，J＝12.2，8.5Hz，1H)，1.7-1.8(m，3H)，2.4(d，J＝9.8Hz，1H)，2.8(m，2H)，3.2(d，J＝12.0Hz，1H)，3.3(s，1H)，3.4(m，1H)，4.3(dd，J＝10.5，7.1Hz，1H)，4.3(m，1H)，7.1(m，2H)，7.4(m，1H)，7.5(m，2H)，7.6(t，J＝7.9Hz，1H)，7.8(dd，J＝8.8，5.1Hz，1H)，9.0(s，2H)
			71	Hydrochloric acid 6-methyl-1-phenyl-3- (piperidin-4-yloxy) -1H-indazole	MS(APCI)M+1＝308.21H NMR(400MHz，DMSO-D6)δ ppm 2.0(m，2H)，2.3(m，2H)，2.4(s，3H)，3.1(ddd，J＝12.7，8.7，3.8Hz，2H)，3.3(m，2H)，5.1(ddd，J＝7.4，3.9，3.8Hz，1H)，7.0(d，J＝8.3Hz，1H)，7.3(m.1H)，7.5(m，2H)，7.6(s，1H)，7.6(d，J＝8.3Hz，1H)，7.7(dt，J＝8.6，1.7Hz，2H)，8.8(s，2H)
72	1- (2-fluorophenyl) -6-methyl-3- (piperidin-4-yloxy) -1H-indazole hydrochloride	MS(APCI)M+1＝326.21H NMR(400MHz，DMSO-D6)δ ppm 2.0(m，2H)，2.3(ddd，J＝10.4，7.1，3.3Hz，2H)，2.4(s，3H)，3.1(ddd，J＝12.6，8.7，3.7Hz，2H)，3.3(dd，J＝7.7，4.5Hz，2H)，5.1(ddd，J＝7.7，4.0，3.9Hz，1H)，7.0(m，2H)，7.4(ddd，J＝8.4，5.4，3.1Hz，1H)，7.5(m，2H)，7.6(m，2H)，8.8(s，2H)
			73	Hydrochloric acid 5-chloro-1- (2-fluorophenyl) -3- (piperidin-3-ylmethoxy) -1H-indazole	Found for C19H19ClFN3O·0.6HCl：C，54.94；H，4.54；N，9.92.1H NMR(400MHz，DMSO-D6)δ ppm 1.4(m，1H)，1.7(m，1H)，1.8(m，2H)，2.3(m，1H)，2.8(m，2H)，3.2(m，1H)，3.4(m，1H)，4.3(m，1H)，4.4(m，1H)，7.4(m，2H)，7.5(m，3H)，7.8(s，1H)，8.9(s，2H).
74	1- (2-fluorophenyl) -6-methyl-3- (piperidin-3-ylmethoxy) -1H-indazole hydrochloride	MS(APCI)M+1＝340.21H NMR(400MHz，DMSO-D6)δ ppm 1.4(m，1H)，1.7(m，1H)，1.8(m，2H)，2.3(m，1H)，2.4(s，3H)，2.8(m，2H)，3.2(m，1H)，3.4(m，1H)，4.2(dd，J＝10.5，7.1Hz，1H)，4.3(m，1H)，7.0(dd，J＝8.3，0.7Hz，1H)，7.0(d，J＝3.4Hz，1H)，7.4(m，1H)，7.5(m，2H)，7.6(t，J＝7.9Hz，2H).8.8(s，2).
			75	Hydrochloric acid 5, 6-difluoro-1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole	MS(APCI)M+1＝348.11H NMR(400MHz，DMSO-D6)δ ppm 2.0(m，2H)，2.2(m，2H)，3.1(m，2H)，5，1(m，1H)，7.4(m，1H)，7.5(m，3H)，7.6(m，1H)，7.9(m，1H)，8.8(m，2H).

76	Hydrochloric acid 5, 6-difluoro-1- (2-fluorophenyl) -3- (piperidin-3-ylmethoxy) -1H-indazole	MS(APCI)M+1＝362.11H NMR(400MHz，DMSO-D6)δ ppm 1.4(m，1H)，1.7(m，1H)，1.8(m，2H)，2.8(s，2H)，3.4(s，1H)，4.3(m，2H)，7.36-7.52(m，5H)，7.60-7.64(m，1H)，7.81-7.64(m，1H)，8.7(s，2H).
			77	Hydrochloric acid 5-fluoro-1- (3-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole	MS(APCI)M+1＝330.11H NMR(400MHz，DMSO-D6)δ ppm 2.1(m，2H)，2.3(m，2H)，3.1(m，2H)，3.3(m，2H)，5.2(dt，J＝7.4，3.8Hz，1H)，7.1(m，1H)，7.4(td，J＝9.2，2.7Hz，1H)，7.6(m，4H)，7.9(dd，J＝9.3，3.9Hz，1H)，8.8(s，2H).
78	(S) -5-fluoro-1- (3-fluorophenyl) -3- (piperidin-3-ylmethoxy) -1H-indazole hydrochloride	MS(APCI)M+1＝344.11H NMR(400MHz，DMSO-D6)δ ppm 1.4(m，1H)，1.7(m，1H)，1.8(m，2H)，2.4(m，1H)，2.8(m，2H)，3.2(m，1H)，3.4(dd，J＝12.4，3.2Hz，1H)，4.3(dd，J＝10.5，7.1Hz，1H)，4.4(m，1H)，7.1(m，1H)，7.4(td，J＝9.2，2.4Hz，1H)，7.6(m，4H)，7.9(dd，J＝9.3，3.9Hz，1H)，8.9(s，2H).
			79	Hydrochloric acid 5-fluoro-1- (4-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole	MS(APCI)M+1＝330.11H NMR(400MHz，DMSO-D6)δppm 2.0(m，2H)，2.2(m，2H)，3.1(m，2H)，3.3(m，2H)，5.1(ddd，J＝7.4，3.9，3.8Hz，1H)，7.4(m，3H)，7.6(dd，J＝8.4，2.1Hz，1H)，7.7(m，3H)，8.7(s，2H).
80	(S) -5-fluoro-1- (4-fluorophenyl) -3- (piperidin-3-ylmethoxy) -1H-indazole hydrochloride	MS(APCI)M+1＝344.11H NMR(400MHz，DMSO-D6)δ ppm 1.4(m，1H)，1.7(m，1H)，1.8(m，2H)，2.3(m，1H)，2.8(q，J＝11.5Hz，2H)，3.2(d，J＝12.5Hz，1H)，3.4(m，1H)，4.3(dd，J＝10.5，7.1Hz，1H)，4.4(m，1H)，7.4(m，3H)，7.5(dd，J＝8.3，2.4Hz，1H)，7.7(m，3H)，8.8(s，2H).
			81	4-fluoro-1- (3-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole hydrochloride	MS(APCI)M+1＝330.11H NMR(400MHz，DMSO-D6)δ ppm 2.0(m，2H)，2.3(m，2H)，3.1(m，2H)，3.2(m，2H)，5.2(ddd，J＝7.7，4.0，3.9Hz，1H)，7.0(dd，J＝10.4，7.7Hz，1H)，7.2(m，1H)，7.5(m，2H)，7.6(dt，J＝6.9，1.7Hz，2H)，7.6(d，J＝8.5Hz，1H)，8.9(s，2H).
82	(S) -4-fluoro-1- (3-fluorophenyl) -3- (piperidin-3-ylmethoxy) -1H-indazole hydrochloride	MS(APCI)M+1＝344.11H NMR(400MHz，DMSO-D6)δ ppm 1.4(m，1H)，1.7(m，1H)，1.8(m，2H)，2.4(m，1H)，2.8(m，2H)，3.2(d，J＝12.5Hz，1H)，3.4(m，1H)，4.3(m，2H)，7.0(dd，J＝10.3，7.8Hz，1H)，7.2(m，1H)，7.5(m，4H)，7.6(d，J＝8.5Hz，1H)，9.0(s，2H).
			83	4-fluoro-1- (4-fluorophenyl) -3- (piperidin-3-yloxy) -1H-indazole hydrochloride	MS(APCI)M+1＝330.21H NMR(400MHz，DMSO-D6)δ ppm 2.0(m，2H)，2.2(m，2H)，3.1(m，2H)，3.2(m，2H)，5.1(m，1H)，6.9(m，1H)，7.4(m，2H)，7.4(m，2H)，7.7(m，2H)，8.8(s，2H).
84	(S) -4-fluoro-1- (4-fluorophenyl) -3- (piperidin-3-ylmethoxy) -1H-indazole hydrochloride	MS(APCI)M+1＝344.21H NMR(400MHz，DMSO-D6)δ ppm 1.3(m，1H)，1.6(m，1H)，1.8(m，2H)，2.3(m，1H)，2.8(m，2H)，3.2(m，1H)，3.3(m，1H)，4.3(dd，J＝10.5，7.3Hz，1H)，4.3(m，1H)，6.9(m，1H)，7.4(m，2H)，7.4(m，2H)，7.7(m，2H)，8.7(s，1H).

85	(S) -4-fluoro-1- (2-fluorophenyl) -3- (piperidin-3-ylmethoxy) -1H-indazole hydrochloride	MS(APCI)M+1＝344.21H NMR(400MHz，DMSO-D6)δ ppm 1.3(m，1H)，1.7(m，1H)，1.8(m，2H)，2.3(m，1 H)，2.7(m，2H)，3.2(d，J＝12.5Hz，1H)，3.3(m，1H)，4.2(dd，J＝10.5，7.3 Hz，1H)，4.3(m，1H)，6.9(dd，J＝10.5，7.8 Hz，1H)，7.0(dd，J＝8.4，3.3 Hz，1H)，7.4(m，2H)，7.5(m，2H)，7.6(td，J＝7.9，1.5Hz，1H)，8.8(s，1H).
			86	Hydrochloric acid 5, 6-difluoro-1-phenyl-3- (piperidin-3-ylmethoxy) -1H-indazole	MS(APCI)M+1＝344.21H NMR(400MHz，DMSO-D6)δppm 1.4(m，1H)，1.7(m，1H)，1.8(m，2H)，2.4(m，1H)，2.8(m，2H)，3.2(m，1H)，3.4(m，1H)，4.3(m，1H)，4.4(m，1H)，7.3(m，1H)，7.5(m，2H)，7.7(m，2H)，7.9(m，2H)，8.9(br s，2H).
87	Hydrochloric acid 5, 6-difluoro-1-phenyl-3- (piperidin-4-yloxy) -1H-indazole	MS(APCI)M+1＝330.21H NMR(400MHz，DMSO-D6)δ ppm 2.1(m，2H)，2.3(m，2H)，3.1(m，2H)，3.3(m，2H)，5.1(m，1H)，7.3(m，1H)，7.5(m，2H)，7.7(m，2H)，7.9(m，2H)，9.0(br s，2H).
			88	1- (2, 4-difluorophenyl) -4-fluoro-3- (piperidin-4-yloxy) -1H-indazole hydrochloride	MS(APCI)M+1＝348.21H NMR(400MHz，DMSO-D6)δ ppm 2.0(m，2H)，2.2(m，2H)，3.1(m，2H)，3.2(m，2H)，5.1(m，1H)，7.0(dd，J＝10.5，7.8Hz，1H)，7.1(dd，J＝8.5，2.7Hz，1H)，7.3(m，1H)，7.4(td，J＝8.2，5.1Hz，1H)，7.6(ddd，J＝11.2，8.8，2.9 Hz，1H)，7.7(td，J＝8.8，6.0Hz，1H)，8.7(s，1H).
89	(S) -1- (2, 4-difluorophenyl) -4-fluoro-3- (piperidin-3-ylmethoxy) -1H-indazole hydrochloride	MS(APCI)M+1＝362.21H NMR(400 MHz，DMSO-D6)δ ppm 1.4(m，1H)，1.6(m，1H)，1.8(m，2H)，2.3(m，1H)，2.8(t，J＝12.1Hz，2H)，3.2(m，1H)，3.4(m，1H)，4.3(dd，J＝10.5，7.3 Hz，1H)，4.3(m，1H)，7.0(dd，J＝10.6，7.4Hz，1H)，7.1(dd，J＝8.4，2.8Hz，1H)，7.3(m，1H)，7.4(td，J＝8.2，5.1Hz，1H)，7.6(m，1H)，7.7(td，J＝8.9，5.9Hz，1H)，8.5(s，1H).
			90	1- (2, 5-difluorophenyl) -4-fluoro-3- (piperidin-4-yloxy) -1H-indazole hydrochloride	MS(APCI)M+1＝348.21H NMR(400MHz，DMSO-D6)δ ppm 2.0(m，2H)，2.3(m，2H)，3.1(m，2H)，3.2(m，2H)，5.1(m，1H)，7.0(dd，J＝10.5，7.6Hz，1H)，7.2(dd，J＝8.4，3.5 Hz，1H)，7.4(m，1H)，7.5(td，J＝8.2，5，1Hz，1H)，7.6(m，2H)，8.6(s，1H).
91	(S) -1- (2, 5-difluorophenyl) -4-fluoro-3- (piperidin-3-ylmethoxy) -1H-indazole hydrochloride	MS(APCI)M+1＝362.21H NMR(400MHz，DMSO-D6)δ ppm 1.3(m，1H)，1.6(m，1H)，1.8(m，2H)，2.3(m，1H)，2.7(t，J＝11.7Hz，2H)，3.2(m，1H)，3.4(m，1H)，4.3(m，2H)，7.0(dd，J＝10.5，7.6 Hz，1 H)，7.1(dd，J＝8.5，3.4Hz，1H)，7.4(m，1H)，7.4(td，J＝8.2，5.1Hz，1H)，7.5(m，2H)，8.5(s，1H).
			92	(R) -1- (2, 4-difluorophenyl) -4-fluoro-3- (pyrrolidin-3-ylmethoxy) -1H-indazole hydrochloride	MS(APCI)M+1＝348.21H NMR(400MHz，DMSO-D6)δ ppm 1.8(m，1H)，2.1(m，1H)，2.8(ddd，J＝14.5，7.2，7.1Hz，1H)，3.0(dd，J＝11.7，7.1Hz，1H)，3.2(m，1H)，3.2(m，2H)，4.4(ddd，J＝17.6，10.4，7.0Hz，2H)，6.9(dd，J＝10.4，7.7Hz，1H)，7.1(dd，J＝8.5，2.7Hz，1H)，7.3(m，1H)，7.4(td，J＝8.2，5.1Hz，1H)，7.6(ddd，J＝11.1，8.8，2.8Hz，1H)，7.7(td，J＝8.9，6.1Hz，1H)，9.2(s，1H).
93	(R) -1- (2, 5-difluorophenyl) -4-fluoro-3- (pyrrolidin-3-ylmethoxy) -1H-indazole hydrochloride	MS(APCI)M+1＝348.21H NMR(400 MHz，DMSO-D6)δ ppm 1.8(m，1H)，2.1(m，1H)，2.9(m，1H)，3.0(dd，J＝11.6，7.2Hz，1H)，3.2(m，1H)，3.3(m，2H)，4.4(ddd，J＝17.2，10.3，7.0Hz，2H)，7.0(dd，J＝10.5，7.8Hz，1H)，7.1(dd，J＝8.5，3.7Hz，1H).7.4(m，1H)，7.5(td，J＝8.2，5.1Hz，1H)，7.6(m，2H)，9.2(s，1H).

94	(S) -1- (2, 4-difluorophenyl) -4-fluoro-3- (morpholin-2-ylmethoxy) -1H-indazole hydrochloride	172-174℃Found for C18H16F3N3O2.1.0 HCl；C，53.94；H，4.08；N，10.31；F，14.03；Cl，8.76[α]D 24＝+1.8 degrees(MeOH，c＝8.4)
			95	(S) -l- (2, 5-difluorophenyl) -4-fluoro-3- (morpholin-2-ylmethoxy) -1H-indazole hydrochloride	190-192℃Found for C18H16F3N3O2.1.0 HCl：C，54.04；H，3.98；N，10.31；F，14.08；Cl，8.84[α]D 24＝+3.7 degrees(MeOH，c＝8.4)
96	(±) -1- (3, 4-difluorophenyl) -5-fluoro-3- (piperidin-3-ylmethoxy) -1H-indazole hydrochloride	MS(APCI)M+1＝362.2Found for C19H18F3N3O1.1.0 HCl；C，57.19；H，4.79；N，10.42；F，13.95；Cl，8.951H NMR(400MHz，CD3CN)δ ppm 1.5(m，1H)，1.7(m，1H)，1.9(m，2H)，2.4(m，1H)，2.9(m，2H)，3.3(m，1H)，3.5(m，1H)，4.3(m，1H)，4.4(m，1H)，7.3(td，J＝9.2，2.6Hz，1H)，7.4(m，3H)，7.6(m，1H)，7.7(dd，J＝9.3，3.9Hz，1H).
			97	1- (3, 4-difluorophenyl) -5-fluoro-3- (piperidin-4-yloxy) -1H-indazole hydrochloride	MS(APCI)M+1＝348.1Found for C18H16F3N3O1.1.1 HCl.0.35 H2O；C，54.58；H，4.17；N，10.51；F，14.08；Cl，9.151H NMR(400MHz，DMSO-D6)δ ppm 2.1(m，2H)，2.3(m，2H)，3.1(m，2H)，3.3(m，2H)，5.2(m，1H)，7.4(td，J＝9.2，2.4Hz，1H)，7.6(m，3H)，7.8(m，1H)，7.9(dd，J＝9.0，3.9Hz，1H)，9.0(bs，2H).
98	Maleic acid (S) - (+) -4-fluoro-1- (2-fluorophenyl) -3- (morpholin-2-ylmethoxy) -1H-indazole	139-140℃Found for C18H17F2N3O2.C4H4O4：C，57.54；H，4.51；N，9.04；F，8.60[α]D 24＝+3.2 degrees(MeOH，c＝7.6)
			99	Hydrochloric acid 5-fluoro-3- (piperidin-3-ylmethoxy) -1-pyridin-2-yl-1H-indazole	MS(APCI)M+1＝327.21H NMR(400 MHz，DMSO-D6)δppm 1.4(m，1H)，1.7(m，1H)，1.9(m，2H)，2.4(m，1H)，2.8(m，2H)，3.2(m，1H)，3.4(m，1H)，4.3(dd，J＝10.5，7.1Hz，1H)，4.4(m，1H)，7.2(ddd，J＝6.7，5.6，1.0Hz，1H)，7.5(td，J＝9.2，2.6Hz，1H)，7.6(dd，J＝8.2，2.6Hz，1H)，7.8(d，J＝8.3 Hz，1 H)，7.9(m，1H)，8.5(m，1H)，8.7(dd，J＝9.2，4.5Hz，1H)，8.8(m，1H)，9.0(m，1H).
100	4-fluoro-1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole hydrochloride	MS(APCI)M+1＝330.11H NMR(400 MHz，DMSO-D6)δ ppm 2.0(m，2 H)，2.3(d，J＝13.7Hz，2H)，3.1(ddd，J＝12.8，8.7，3.7Hz，2H)，3.2(m，2H)，5.1(dt，J＝7.9，4.0Hz，1H)，6.9(dd，J＝10.5，7.8Hz，1H)，7.1(dd，J＝8.4，3.1Hz，1H)，7.4(m，2H)，7.5(m，2H)，7.6(m，1H)，8.9(s，2H)
			101	Hydrochloric acid 5-chloro-1-phenyl-3- (piperidin-4-yloxy) -1H-indazole	MS(APCI)M+1＝328.11H NMR(400MHz，DMSO-D6)δppm 2.1(m，2H)，2.2(m，2H)，3.1(m，2H)，3.3(m，2H)，5.1(dt，J＝7.1，3.5Hz，1H)，7.3(t，J＝7.3Hz，1H)，7.5(m，3H)，7.7(m，2H)，7.8(d，J＝9.0Hz，1H)，7.9(d，J＝1.5Hz，1H)，8.9(s，2H)

102	Hydrochloric acid 5-chloro-1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole	MS(APCI)M+1＝346.11H NMR(400MHz，DMSO-D6)δ ppm 2.0(m，2H)，2.2(m，2H)，3.1(ddd，J＝12.4，8.0，3.8Hz，2H)，3.3(dd，J＝8.1，3.9Hz，2H)，5.1(m，1H)，7.3(dd，J＝9.0，3.4Hz，1H).7.4(ddd，J＝8.3，5.3，3.3Hz，1H)，7.5(m，3H)，7.6(t，J＝7.8Hz，1H)，7.9(d，J＝2.2Hz，1H)，9.0(s，2H)
			103	Hydrochloric acid 4-fluoro-1-phenyl-3- (piperidin-4-yloxy) -1H-indazole	MS(APCI)M+1＝312.11H NMR(400MHz，DMSO-D6)δ ppm 2.1(m，2H)，2.3(m，2H)，3.1(ddd，J＝12.7，8.7，3.5Hz，2H)，3.2(m，2H)，5.1(ddd，J＝7.4，4.2，3.8Hz，1H)，6.9(dd，J＝10.5，7.8Hz，1H)，7.3(t，J＝7.4Hz，1H)，7.4(td，J＝8.2，5.1Hz，1H)，7.5(m.3H)，7.7(m，2H)，8.9(s，2H)
104	(S) - (-) -1-phenyl-3- (piperidin-3-ylmethoxy) -1H-pyrazolo [3, 4-b ] hydrochloride]Pyridine compound	MS(APCI)M+1＝309247-249℃Found for C18H20N4O.HCl：C，62.41；H，5.96；N，16.01；Cl，10.50[α]D 24＝-14.3 degrees(MeOH，c＝5.3)
			105	(S) - (+) -3- (morpholin-2-ylmethoxy) -1-phenyl-1-pyrazolo [3, 4-b ] hydrochloride]Pyridine compound	MS(APCI)M+1＝311109-115℃(dec)Found for C17H18N4O2.HCl.0.25H2O：C，58.07；H，5.52；N，15.86；Cl，10.06[α]D 24＝+5.7 degrees(MeOH，c＝7.2)
106	L-tartaric acid 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole	MS(APCI)+1＝150，3111H NMR(DMSO)δppm7.7(d，1H)，7.6(t，1H)，7.47.5(m，3H)7.3-7.4(m，1H)，7.25(m，1H)，7.2(t，1H)，5.1(m，1H)，3.3(m，2H)，3.1(m，2H)，2.2(m，2H)，2.0(m，2H).
			107	L-tartaric acid (S) -5-fluoro-1- (2-fluorophenyl) -3- (piperidin-3-ylmethoxy) -1H-indazole	MS(APCI)M+1＝344181-182℃
108	1- (2, 6-difluorophenyl) -5-fluoro-3- (piperidin-4-yloxy) -1H-indazole hydrochloride	MS(APCI)M+1＝348.21H NMR(400MHz，DMSO-D6)δ ppm 2.0(m，2H)，2.2(m，2H)，3.1(m，2H)，3.3(m，2H)，5.1(m，1H)，7.3(dd，J＝9.0，3.7Hz，1H)，7.4(m，3H)，7.6(m，2H)，8.9(bs，2H).
			109	1- (2, 6-difluorophenyl) -4-fluoro-3- (piperidin-4-yloxy) -1H-indazole hydrochloride	MS(APCI)M+1＝348.21H NMR(400MHz，DMSO-D6)δ ppm 2.0(m，2H)，2.3(m，2H)，3.1(m，2H)，3.2(m，2H)，5.1(m，1H)，7.0(dd，J＝10.4，7.7Hz，1H)，7.5(td，J＝8.2，5.1Hz，1H)，7.6(m，3H)，7.8(ddd，J＝11.8，7.2，2.2Hz，1H)，8.9(s，1H).
110	(S) -1- (2, 6-difluorophenyl) -4-fluoro-3- (piperidin-3-ylmethoxy) -1H-indazole hydrochloride	MS(APCI)M+1＝362.21H NMR(400MHz，DMSO-D6)δ ppm 1.3(m，1H)，1.7(m，1H)，1.8(m，2H)，2.4(m，1H)，2.8(t，J＝12.0Hz，2H)，3.2(m，1H)，3.4(m，1H)，4.3(m，2H)，7.0(dd，J＝10.3，7.6Hz，1H)，7.5(m，1H)，7.6(m，3H)，7.8(ddd，J＝11.8，7.1，2.1Hz，1H)，8.8(s，1H).
			111	(S) -I- (2, 6-difluorophenyl) -5-fluoro-3- (piperidin-3-ylmethoxy) -1H-indazole hydrochloride	MS(APCI)M+1＝362.21H NMR(400MHz，DMSO-D6)δ ppm 1.4(m，1H)，1.7(m，1H)，1.9(m，2H)，2.3(m，1H)，2.8(m，2H)，3.2(d，J＝12.9Hz，1H)，3.4(dd，J＝12.6，3.0Hz，1H)，4.3(m，2H)，7.3(dd，J＝9.2，3.8Hz，1H)，7.4(m，3H)，7.6(m，2H)，9.0(bs，2H).

Example 112-L-tartaric acid 1- (2-fluoro-phenyl) -3- (piperidin-4-yloxy) -1H-indazole

Preparation of 4-Methanesulphonyloxy-piperidine-1-carboxylic acid tert-butyl ester

A stirred solution of 250g (1.24mole) of tert-butyl 4-hydroxy-piperidine-1-carboxylate in 2.3L of dichloromethane was cooled to-10 ℃. 188g (1.86mole) of triethylamine were added in a thin stream over 20 minutes. The temperature did not change significantly. The resulting solution was stirred at-10 ℃ for 30 minutes, then 172g (1.50mole) of methanesulfonyl chloride was added dropwise over 30 minutes. During the addition, the temperature rose to 0 ℃. The resulting suspension was stirred at a temperature of 21 ℃ for a subsequent 18 hours. The mixture was filtered and the solid was washed with 800ml of ethyl acetate. The washings were added to the filtrate and concentrated to about 2L. The residual suspension was diluted with 1L ethyl acetate and filtered. The solid was washed with 500ml of ethyl acetate. The wash solution was added to the filtrate, which was passed through a silica gel (230-400 mesh) plate containing 350g of adsorbent. The plate was washed with 600ml ethyl acetate. The washings were added to the filtrate, concentrated to about 800mL and diluted with 400mL of hexane. The suspension was stirred at-10 ℃ for 2 hours and filtered. The solid was washed with ethyl acetate: hexane (2: 1, 300mL) and dried under negative pressure. Further drying in vacuo at 32 ℃ for 19 h gave 307g (89%) of product.

Preparation of 2-amino-benzoic acid N' - (2-fluoro-phenyl) -hydrazide

A stirred suspension of 845g (5.03mole) 97% hydrochloric acid (2-fluoro-phenyl) -hydrazine at 21-22 ℃ in 7.6L ethanol was added as a stream to 563g (5.57mole) triethylamine over 20 minutes. Initially a white gas is formed. The resulting black mixture was stirred at 21 ℃ for 20 minutes and 854g (5.03mole) of 96% 1H-benzo [ d ] [1, 3] oxazine-2, 4-dione were then added. The resulting mixture was heated to reflux (78 ℃) over the next 1 hour. During this time, vigorous gas evolution was observed. Reflux was maintained for 2 hours and then the suspension was stirred at room temperature for 16 hours. The solid was collected by filtration, washed once with 150ml ethanol and then once with 150ml ethanol: ethyl acetate (1: 1) and dried under reduced pressure. Further drying under vacuum at 35 ℃ for 7 hours gave 498g (40%) of product. A second batch of 51g (4%) material was obtained from the mother liquor.

Preparation of C.1- (2-fluoro-phenyl) -1H-indazol-3-ol

A stirred suspension of 105g (0.429mole) 2-amino-benzoic acid N' - (2-fluoro-phenyl) -hydrazide in 1250ml ethanol and 1250ml 1N hydrogen chloride was heated to 55 ℃. A solution of 59g (0.858mole) of sodium nitrite in 200ml of water is added dropwise over 30 minutes. At about 10 minutes after the start of the addition, the solid began to separate. The external heating was continued until the reaction temperature reached 65 ℃, and then the external heating was stopped. The temperature was maintained between 65-68 ℃ during the addition and gas evolution became severe about half way through the addition. Near the end of the addition, the gas evolution slowed and the temperature dropped below 65 ℃. External heating was reapplied and the mixture was stirred at 70 ℃ for 3 hours. The mixture was cooled to-10 ℃ and filtered. The solid was washed once with 50ml of ethanol and then once with 100ml of water and dried under reduced pressure. Further drying under vacuum at 35 ℃ for 7 hours gave 92g (94%) of product.

Preparation of 4- [1- (2-fluoro-phenyl) -1H-indazol-3-yloxy ] -piperidine-1-carboxylic acid tert-butyl ester

To a stirred solution of 173g (0.76mole) of 1- (2-fluoro-phenyl) -1H-indazol-3-ol in 1.5L N, N-dimethylformamide at room temperature was added 371g (1.14mole) of cesium carbonate. The resulting mixture was stirred at room temperature for 2 hours, then 230g (0.83mole) of 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester were added. The resulting mixture was stirred at 85-90 ℃ for 17 hours, cooled to room temperature, and then concentrated in vacuo to about 1L. The residue was quenched by dropwise addition of 500ml of saturated aqueous ammonium chloride. The resulting mixture was stirred at room temperature for 15 minutes and then poured into 2.5L of stirred ice-water. The resulting mixture was extracted 1 time with 1.5L of dichloromethane and then 2 times with 0.75L of dichloromethane. During these extractions, some emulsion formation occurs. The combined extracts were dried over magnesium sulfate and concentrated in vacuo to an oil. The remaining N, N-dimethylformamide was removed using a vacuum pump. The residue was taken up in 1.2L of ether. The mixture was stirred at room temperature for 10 minutes and filtered. The insoluble solids were washed with ether and a washing solution was added to the filtrate. The solid was dried under vacuum at 30 ℃ for 6 hours to give 11.6g of recovered 1- (2-fluoro-phenyl) -1H-indazol-3-ol. The filtrate was concentrated in vacuo to 268g (86%) of the product as a viscous red oil.

E. Preparation of 1- (2-fluoro-phenyl) -3- (piperidin-4-yloxy) -1H-indazole hydrochloride

To 187g (0.456mole) of 4- [1- (2-fluoro-phenyl) -1H-indazol-3-yloxy-solution in 30 minutes]A stirred solution of tert-butyl-piperidine-1-carboxylate in 600ml of ethyl acetate was added dropwise to 300ml of 4M hydrogen chloride in dioxane. During the addition, the temperature rose from 21 ℃ to 24 ℃. When the addition was complete, gas evolution was observed and the temperature rose to 28 ℃. The temperature was reduced to 18 ℃ using a cold water bath. After about 40 minutes of stirring, the solid began to separate. Stirring was continued at 18-20 ℃ for 3 hours and then at-10 ℃ for 1 hour (ice-acetone bath). The solid was collected by filtration, washed with 60ml of ethyl acetate and dried under reduced pressure. Further drying under vacuum at 30 ℃ for 16 hours gave 87.3g (55%) of product. The combined filtrate and washings were concentrated to near dryness in vacuo. The residue is taken up in 250ml of ethyl acetate and the suspension is stirred for 2 hours at-10 ℃. The solid was collected by filtration, washed with 30ml of ethyl acetate and dried under reduced pressure. Further vacuum drying at 30 ℃ for 16 h gave an additional 23.2g (15%) of product. The total yield was 110.5g (70%).¹H NMR(CD₃OD)δ ppm：7.7(d，1H)，7.6(t，1H)，7.5-7.6(m，2H)，7.3-7.5(m，2H)，7.25(m，1H)，7.2(t，1H)，5.2(m，1H)，3.4-3.5(m，2H)，3.2-3.3(m，2H)，2.3-2.4(m，2H)，2.2-2.3(m，2H)。

F.L preparation of 1- (2-fluoro-phenyl) -3- (piperidin-4-yloxy) -1H-indazole tartrate

A mixture of 276g (0.794mole) of 1- (2-fluoro-phenyl) -3- (piperidin-4-yloxy) -1H-indazole hydrochloride in 525ml of tetrahydrofuran and 3.0L of water was stirred until most (> 98%) of the solids dissolved. Filtering the solution with a small amount of insoluble materialAnd (5) separating. To the stirred filtrate was slowly added 135g (1.28mole) of sodium carbonate. The resulting mixture was stirred vigorously for 5 minutes, then extracted 2 times with 2L of ether and 1 time with 1L of ether. The combined extracts were dried over magnesium sulfate and concentrated to dryness in vacuo. The residual viscous oil (236g, 96%) was dissolved in 600ml of tetrahydrofuran. A solution of L-tartaric acid in 2.4L of water was added to the stirred tetrahydrofuran solution. The resulting solution was concentrated in vacuo to remove tetrahydrofuran while isolating the solid. The resulting suspension was stirred at 5 ℃ for 1 hour and filtered. The solid was washed 1 time with 30ml of tetrahydrofuran and then 1 time with 100m1 of water and dried under reduced pressure. Further drying under vacuum at 35 ℃ for 16 hours gave 234.8g (67%) of product. A second batch of 35.5g (10%) product was obtained from the mother liquor. The total yield was 270.3g (77%).¹H NMR(DMSO)δ ppm：7.7(d，1H)，7.6(t，1H)，7.4-7.5(m，3H)，7.3-7.4(m，1H)，7.25(m，1H)，7.2(t，1H)，5.1(m，1H)，3.3(m，2H)，3.1(m，2H)，2.2(m，2H)，2.0(m，2H)。

Example 113.Synthesis of a salt of 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole

L-tartaric acid 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole

65.9mg L-tartaric acid was added to 136.68mg 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole (clear oil) in 12.45ml methanol. Placing the mixture in N₂The air flows until only about 1ml of solution remains. Precipitation of the salt was observed during this step. Approximately 5ml of acetone was added and the resulting solution was stirred briefly (-2 minutes). The white solid was recovered using vacuum filtration using a membrane filter. The solid was dried in a vacuum desiccator at ambient temperature (pressure not controlled).

B. Ethanedisulfonic acid 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole

3.145mg of ethanedisulfonic acid was added to 0.56ml of a solution of 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole in MeOH (methanol) (concentration ═ 10.3 mg/ml). Heating and stirring the solution in a non-capped vialStirring, and placing in N₂The air flows down. These steps are repeated until about 0.100ml or less of solution remains. Then about 0.500ml of MTBE (methyl tert-butyl ether) was added. Precipitation was observed and the suspension was capped and stirred for 3 hours or less. The vial was then opened and stirred for approximately 16 hours. Leaving a dry white solid.

C. Fumaric acid 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole

2.162mg of fumaric acid were added to a 0.58ml solution of 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole in MeOH (concentration 10.3 mg/ml). The solution was heated and stirred in an unsealed vial and then placed in N₂The air flows down. These steps are repeated until about 0.100ml or less of solution remains. Approximately 0.500ml of MTBE was then added. Precipitation was observed and the suspension was capped and stirred for 3 hours or less. The vial was then opened and stirred for approximately 16 hours. Leaving a dry white solid.

D. Hydrobromic acid 1- (2-fluorophenyl) -3- (piperidine-4-yloxy) -1H-indazole

4.840mg of concentrated hydrobromic acid were added to 0.89ml of a solution of 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole in MeOH (concentration 10.3 mg/ml). Placing the solution in N₂The air flows until no solvent remains. Approximately 0.5ml of MTBE was then added and the sample was left open and stirred overnight. A white solid remained upon recovery.

E. hemi-L-tartaric acid 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole

9.94mg of L-tartaric acid was added to 4ml of a solution of 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole in MeOH (concentration 10.3 mg/ml). Placing the solution in N₂Air flow until approximately 0.2ml of solution remained. About 0.75ml of IPA (isopropyl alcohol) was then added and the solution was returned to the gas flow described above for a period of less than 1 minute. A precipitate was observed and the suspension was capped. The suspension was stirred overnight and the solution became a gel. About 3ml of acetone was added and observedTo precipitate. The solids were recovered on a membrane filter using vacuum filtration.

F.L-malic acid 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole

2.383mg of L-malic acid were added to a 0.55ml solution of 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole in MeOH (concentration 10.3 mg/ml). The solution was heated and stirred in an unsealed vial and then placed in N₂The air flows down. These steps are repeated until about 0.100ml or less of solution remains. Approximately 0.500ml of MTBE was then added. Precipitation was observed and the suspension was capped and stirred for 3 hours or less. A spherical gel was observed and no solids were seen. The vial was then opened and stirred for approximately 16 hours. Leaving a dry white solid. Subsequent attempts to repeat the process on a larger scale have not produced solid materials.

G. 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole phosphate

2.09mg of concentrated phosphoric acid was added to 0.58ml of a solution of 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole in MeOH (concentration 10.3 mg/ml). The solution was heated and stirred in an unsealed vial and then placed in N₂The air flows down. These steps are repeated until about 0.100ml or less of solution remains. Approximately 0.500ml of MTBE was then added. Precipitation was observed and the suspension was capped and stirred for 3 hours or less. The vial was then opened and stirred for approximately 16 hours. Leaving a dry white solid.

H. 1- (2-fluorophenyl) -3-piperidin-4-yloxy) -1H-indazole sulfate

1.9mg of concentrated sulfuric acid was added to a 0.58ml solution of 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole in MeOH (concentration 10.3 mg/ml). The solution was heated and stirred in an unsealed vial and then placed in N₂The air flows down. These steps are repeated until about 0.100ml or less of solution remains. Approximately 0.500ml of MTBE was then added. Precipitation was observed and the suspension was capped and stirred for 3 hours or less. Then will beThe vial was opened and stirred for approximately 16 hours. Leaving a dry white solid.

I.

In analogy to the previous procedure, samples of citric acid, benzoic acid, camphorsulfonic acid, and methanesulfonic acid were added to an equimolar sample of 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole. No solids were produced using these conditions.

Example 114 powder X-ray diffraction (PXRD)

Experimental powder X-ray Diffraction patterns of several 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole salts from example 114 were determined using a Bruker D8X-ray powder diffractometer with a GADD (General Area Diffraction Detector System) C2 System (with a Goebel mirror configuration). Scanning was performed with a detector at 15.0 cm. θ 1, or collimator, at 7 °; θ 2, or detector, at 17 °. The scan axis is 2-omega and the width is 3 deg.. At the end of each scan, θ 1 is at 10 °, and θ 2 is at 14 °. The sample was subjected to 60 second operation using CuK α (λ 1.5419 angstroms) radiation at 40kV and 40 mA. The scans were integrated from 6.4 ° to 41 ° 2 q. The samples were handled in an ASC-6 sample holder (available from Gem Dugout, State College, Pa.). The sample was placed in the middle cavity of the sample holder and scraped flat with a spatula to be flush with the surface of the holder. All analyses were performed at room temperature (typically 20 ℃ to 30 ℃). The scans were evaluated using Diffracplus software with Eva version 9.0.0.2 (release 2003). PXRD patterns are reported in figures 1-8: l-tartaric acid 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole (fig. 1); ethanedisulfonic acid 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole (FIG. 2); fumaric acid 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole (fig. 3); hydrobromic acid 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole (figure 4); half-L-wine 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole (fig. 5); l-malic acid 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole (fig. 6); 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole phosphate (fig. 7); and 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole sulfate (FIG. 8).

A summary of the angle (2 θ) values and intensity values (percentage of the value relative to the highest peak) are reported in tables 1-8 below.

TABLE 1L-tartaric acid 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole

Angle (2 theta)	Strength%	Angle (2 theta)	Strength%
				37.8°	16.7	17.9°	22.2
33.8°	17.5	23.8°	22.6
				16.8°	17.5	20.1°	23.4
11.9°	17.6	26.0°	27.6
				13.2°	18.5	23.2°	28.6
29.0°	18.9	29.6°	30
				19.5°	20.9	21.4°	30.5
27.6°	21	22.0°	37.3
				31.9°	21.1	20.9°	49.4
25.5°	21.7	18.6°	100

TABLE 2 Ethanedisulfonic acid 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole

Angle (2 theta)	Strength%	Angle (2 theta)	Strength%
				33.0°	26.8	19.0°	56.2
15.7°	27.3	25.5°	57.9
				12.4°	27.4	24.1°	58.2
14.1°	34.1	11.6°	79.5
				28.2°	35	22.5°	94.8
30.1°	39	20.0°	97.5
				17.3°	46.4	21.2°	100
27.1°	46.7

TABLE 3 fumaric acid 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole

Angle (2 theta)	Strength%	Angle (2 theta)	Strength%
				12.7°	22	15.9°	36.3
31.5°	24.6	29.5°	45.8
				11.7°	25.3	28.4°	50.4
27.8°	29.6	25.3°	52.2
				22.4°	31	18.1°	67.9
26.6°	31	24.6°	70.6
				20.9°	35.1	20.1°	85.8
17.2°	36.1	23.2°	100

TABLE 4 hydrobromic acid 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole

Angle (2 theta)	Strength%	Angle (2 theta)	Strength%
				18.0°	20.5	25.6°	37.9
21.6°	20.5	12.6°	38.1
				38.0°	22.2	29.3°	44.3
15.4°	23.8	20.1°	57.7
				14.1°	25	24.0°	67.9
30.4°	25.8	23.8°	70.3
				26.3°	28.1	16.8°	71.2
33.5°	32	25.1°	92.7
				28.0°	34.9	20.9°	100

TABLE 5 half L-tartaric acid 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole

Angle (2 theta)	Strength%	Angle (2 theta)	Strength%
				10.3°	24.9	24.7°	15.7
14.9°	51.3	25.6°	14.4
				15.7°	10.2	27.7°	8.6
17.0°	23.8	29.8°	16.7
				19.0°	100	32.6°	9.9
20.5°	20.3	34.5°	15.2
				21.6°	58.9	36.2°	12.5
22.7°	20.7	39.2°	8.7
				23.9°	32.7

TABLE 6L-malic acid 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole

Angle (2 theta)	Strength%	Angle (2 theta)	Strength%
				36.8°	16.9	27.3°	28.9
24.5°	17.7	14.7°	34.7
				26.3°	20.7	20.9°	34.8
28.7°	20.8	11.4°	36.1
				12.2°	21.5	19.2°	39.9
25.2°	22.3	16.7°	50.1
				23.1°	23	21.9°	51.3
18.2°	24.5	21.5°	51.5
				30.4°	25.1	20.1°	100

TABLE 7 phosphoric acid 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole

Angle (2 theta)	Strength%	Angle (2 theta)	Strength%
				12.1°	20.2	15.6°	34.9
34.7°	20.3	26.9°	43.1
				14.0°	20.7	22.8°	46.5
30.9°	21	20.0°	48.1
				25.6°	22.2	27.3°	49.3
29.3°	23.5	17.9°	56.3
				33.4°	28	21.2°	72.5
16.9°	32.1	24.3°	74.2
				20.6°	34.6	23.2°	100

TABLE 8 sulfuric acid 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole

Angle (2 theta)	Strength%	Angle (2 theta)	Strength%
				26.7°	14.8	15.0°	32.6
27.6°	16	20.0°	35.7
				17.2°	19.3	18.3°	37.9
21.4°	20.6	23.0°	44.1
				25.4°	21.5	24.3°	44.5
29.7°	24.4	20.2°	49.8
				16.4°	27.9	12.1°	100

Example 115 Differential Scanning Calorimetry (DSC)

Differential Scanning Calorimetry (DSC) was performed on the L-tartrate, ethanedisulfonate, fumarate, hydrobromide, hemi-L-tartrate, L-malate, phosphate, and sulfate salts of 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole of example 113 on TA Instruments DSC Q1000V 8.1 Build 261(TA Instruments, NewCastle, DE). Samples were prepared by weighing 2-4mg of sample into aluminum pans which were then capped with perforated aluminum caps (TA Instruments' part numbers 900786.901 (bottom tray) and 900779.901 (top cap)). Data were analyzed using a Universal Analysis 2000 for Windows 95/98/2000/NT/Me/XP version 3.8B, Build 3.8.019.

The temperature rise rates were the same for all experiments except for the L-tartrate salt. The experiment was started at ambient temperature and the sample was heated at 20 deg.C/min under a nitrogen gas flow (flow rate 50 ml/min). The L-tartrate salt was heated at 10 deg.C/min.

The ethanedisulfonate, hydrobromide, hemi-L-tartrate and sulphate salts were heated to 350 ℃. The fumarate, L-malate and phosphate salts were heated to 250 ℃. The L-tartrate salt was heated to 300 ℃. The melting point onset (c) of the salts is reported in table 9:

TABLE 9

Name (R)	Melting Point starting Point (. degree.C.)
		L-tartaric acid 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole	199.98℃
Ethanedisulfonic acid 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole	Uncertainty
		Fumaric acid 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole	185.68℃
Hydrobromic acid 1- (2-fluorophenyl) -3- (piperidine-4-yloxy) -1H-indazole	134.46℃
		hemi-L-tartaric acid 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole	178.74℃
L-malic acid 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole	145.55℃
		1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole phosphate	192.97℃
1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole sulfate	Uncertainty

Example 116 Single Crystal X-ray data and calculation of PXRD for 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole L-tartrate

The single crystal structure of L-tartaric acid 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole was analyzed from the material synthesized as described above in example 113. Data were collected at room temperature using an APEX (Bruker-AXS) diffractometer. Using orthorhombic space group P2₁(where Z is 4 (a) 9.585(3)), b 14.978(5)), and c is 14.952(5)), the structure is analyzed. The structural solution contains two free form L-tartrate counterion pairs on the asymmetric unit. Finding the hydrogen atoms, the remaining hydrogen atoms, located on the hetero atoms by experimental meansThe child is placed in the calculated position. The crystal structure shows that each 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole has one L-tartaric acid counter ion.

The crystal structure (not shown) is consistent with the formula L-tartaric acid 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole. The final model was refined to a goodness of fit (R) of 1.009₁＝0.0481(I＞2sigma(I))，wR₂0.0863(I > 2sigma (I)). The stereochemistry of 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole was determined from the known stereochemistry of the L-tartaric acid counter ion. Using Reitveld refinement, the calculated PXRD plots were obtained from the Material students software Package (FIG. 16). A summary of the angle (2 θ) values and intensity values (percentage of the value relative to the highest peak) from the calculated spectra is reported in table 10 below.

Watch 10

Angle (2 theta)	Strength%	Angle (2 theta)	Strength%
				20.1°	16.0	20.7°	21.1
21.2°	16.5	23.4°	21.3
				29.7°	17.1	20.9°	31.9
21.4°	19.2	13.2°	32.7
				17.9°	20.0	11.8°	66.1
22.1°	20.7	18.7°	100.0

Biological example 1

hNET receptor binding:

a cell paste of HEK-293 cells transfected with human noradrenaline transporter cDNA was prepared. The cell paste was resuspended in 400 to 700ml of Krebs-HEPES assay buffer (25mM HEPES, 122mM NaCl, 3mM KCl, 1.2mM MgSO 2. sup. m₄，1.3mM CaCl₂And 11mM glucose, pH 7.4) while being treated with a Polytron homogenizer at level 7 for 30 seconds. The membrane sample (5mg/ml protein) was stored in liquid nitrogen until use.

Binding assay analytes were placed in Beckman deep well polypropylene plates, with a total volume of 250 μ Ι comprising: test Compound (10)^-5M to 10^-12M), a cell membrane, and 50pM¹²⁵I]RTI-55(Perkin Elmer, NEX-272; specific activity 2200 Ci/mmol). The reaction was incubated at room temperature for 90 minutes with gentle stirring and stopped by filtration through Whatman GF/C filter plates using a Brandel 96-well plate collector. Scintillation fluid (100. mu.l) was added to each well and bound [2 ] was determined using a Wallac Trilux Beta Plate counter¹²⁵I]-RTI-55. The procedure for the test compounds was repeated twice and specific binding was defined as the difference between binding in the presence and absence of 10 μ M desipramine (desipramine).

Excel and GraphPad Prism software was used for data calculation and analysis. Using the Cheng-Prusoff equation, the IC is tested₅₀Conversion of value to K_iThe value is obtained. K for hNET_iThe values (nM) are reported in Table 11 below.

hSERT receptor binding

A cell paste of HEK-293 cells transfected with 5-hydroxytryptamine transporter cDNA was prepared. The cell paste was resuspended in 400 to 700ml of Krebs-HEPES assay buffer (25mM HEPES, 122mM NaCl, 3mM KCl, 1.2mM MgSO 2. sup. m₄，1.3mM CaCl₂And 11mM glucose, pH 7.4) while being treated with a Polytron homogenizer at level 7 for 30 seconds. The membrane sample (5mg/ml protein) was stored in liquid nitrogen until use.

The analytes were placed in FlashPlates pre-coated with 0.1% PEI, where a total volume of 250 μ Ι comprised: test Compound (10)^-5M to 10^-12M), a cell membrane, and 50pM¹²⁵I]RTI-55(Perkin Elmer, NEX-272; specific activity 2200 Ci/mmol). The reaction was incubated at room temperature for 90 minutes with gentle stirring and stopped by removing the analyte volume. The Plate was covered, and bound [ alpha ], [ Beta ] Plate was measured using a Wallac Trilux Beta Plate counter¹²⁵I]-RTI-55. Repeat the procedure for test Compound two timesNext, and specific binding was defined as the difference between binding in the presence and absence of 10 μ M citalopram (citalopram).

Excel and GraphPad Prism software was used for data calculation and analysis. Using the Cheng-Prusoff equation, the IC is tested₅₀Conversion of value to K_iThe value is obtained. K for hSERT_iThe values (nM) are reported in Table 11 below.

TABLE 11

Ex.#	NET Ki	SERTKi	Ex.#	NET Ki	SERTKi	Ex.#	NET Ki	SERTKi
									1	3.14	51.11	29	4055.00	342.30	57	18.13	52.19
2	9.28	1622.00	30	4.44	64.64	58	55.98	133.60
									3	3.40	831.50	31	6.58	133.50	59	69.14	32.72
4	3.00	270.33	32	3.41	33.56	60	221.00	76.75
									5	84.00	1607.00	33	19.16	197.90	61	20.43	21.67
6	1.65	191.50	34	30.02	80.95	62	495.00	313.80
									7	5.30	54.72	35	24.04	82.60	63	39.54	19.42
8	5.19	39.03	36	5.16	82.72	64	512.40	271.90
									9	5.63	81.57	37	6.05	104.80	65	4327.00	81.22
10	14.30	36.09	38	6.09	199.40	66	16.93	120.50
									11	13.96	279.00	39	9.57	34.35	67	19.72	190.50
12	12.50	1010.00	40	5.02	30.75	68	219.50	359.30
									13	131.00	5289.00	41	299.00	79.66	69	98.03	339.40
14	13.05	100.37	42	25.86	80.99	70	33.58	199.50
									15	329.00	1458.50	43	17.92	137.60	71	95.50	20.51
16	21.50	224.00	44	100.00	365.00	72	27.38	9.76
									17	150.50	28.00	45	3.20	47.50	73	29.34	303.80
18	95.50	121.00	46	5.70	413.00	74	60.50	791.70
									19	5.43	486.00	47	13.00	47.00	75	36.39	39.77
20	20.17	122.32	48	10.20	297.50	76	40.36	157.80
									21	12.50	1120.50	49	98.50	20.50	77	24.81	49.55
22	25.69	68.22	50	5.20	1141.50	78	10.16	39.92
									23	11.48	1526.75	51	11.86	53.74	79	32.81	23.72
24	9.65	5427.33	52	35.69	45.35	80	15.04	23.88
									25	3.20	670.50	53	54.09	145.70	81	49.80	448.70
26	6.90	346.00	54	274.10	28.46	82	23.23	635.40
									27	6.34	42.29	55	71.17	125.60	83	49.26	191.40
28	5.10	640.00	56	6.13	9.99	84	38.13	486.80

Ex.#	NET Ki	SERTKi	Ex.#	NET Ki	SERTKi	Ex.#	NET Ki	SERTKi
									85	12.50	1007.00	96	49.53	172.30	107
86	113.90	100.90	97	28.51	39.52	108	5.72	42.97
									87	197.30	56.98	98	27.33	3856.50	109	46.17	279.00
88	16.26	88.08	99	319.20	258.70	110	16.33	422.50
									89	22.43	402.80	100	4.63	101.50
90	10.16	142.10	101	607.00	304.00
									91	7.88	610.20	102	71.54	129.30
92	28.47	126.30	103	34.15	292.80
									93	16.35	224.50	104	89.00	1579.50
94	40.25	2848.75	105	294.25	4239.75
									95	5.47	3465.67	106

Biological example 2

Compounds of the invention can be assayed for relief of capsaicin-mediated mechanical allodynia in a rat model (e.g., Sluka (2002) J of Neuroscience, 22 (13): 5687-5693). For example, a rat model of mechanical painful paresthesia mediated by capsaicin is performed as follows:

on day 0, male Sprague-Dawley rats (-150 g) in a dark period were placed in suspended cages with cable bottoms and allowed to acclimate for 0.5 hours in a dark quiet room. Day 0 Paw Withdrawal Thresholds (PWT) were determined for the left hind paw by Von Frey Hair assessment using the Dixon Up and Down method. After evaluation, the plantar muscles of the right hind paw were injected with 100 μ l capsaicin (0.25% concentration in 10% ethanol, 10% Tween 80 in sterile saline). On day 6, the PWT of the left hind paw (contralateral to the injection site) was determined for each animal. Animals with a read-ahead value of PWT < 11.7g from day 6 onwards were considered nociceptive paresthetic responders and were regrouped so that each cage had a similar average PWT value.

Subcutaneous administration

On day 7, 30mg of the compound of example 7 per kg body weight, 10mg of the compound of example 48 per kg body weight, or vehicle alone, were administered subcutaneously to the responder. The vehicle was 2% cremophor^®Phosphate buffered saline (BASF) of EL.

The animal of example 7 was administered

For animals dosed with the compound of example 7, contralateral PWT values were determined 2 hours after a single dose without knowledge of the dosing schedule.

For each animal, the 2 hour PWT value for the 10mg/kg dose was subtracted from the PWT value on day 6 to give a Δ PWT value, which represents the change in PWT due to 1 hour drug treatment. In addition, the PWT of day 0 was subtracted from the PWT of day 6 to give a baseline window of nociceptive abnormalities for each animal. To determine the percent inhibition (%) of nociceptive paresthesia for each animal normalized to the vehicle control experiment, the following formula was used:

% nociceptive dysesthesia ═ 100 × (Δ PWT (drug) -mean Δ PWT (vehicle))/(baseline-mean Δ PWT (vehicle)).

The mean percent inhibition of the allodynia values (for the 8 animals analyzed) are shown in table 12. Compounds that exhibit greater than 30% inhibition in the pain sensory abnormality assay are considered active.

The animal to which example 48 was administered

For animals dosed with the compound of example 48, contralateral PWT values were determined 1 hour after a single dose without knowledge of the dosing schedule.

For each animal, the 1 hour PWT value for the 10mg/kg dose was subtracted from the PWT value on day 6 to give a Δ PWT value, which represents the change in PWT due to 1 hour drug treatment. In addition, the PWT of day 0 was subtracted from the PWT of day 6 to give a baseline window of nociceptive abnormalities for each animal. To determine the percent inhibition (%) of nociceptive paresthesia for each animal normalized to the vehicle control experiment, the following formula was used:

% nociceptive dysesthesia ═ 100 × (Δ PWT (drug) -mean Δ PWT (vehicle))/(baseline-mean Δ PWT (vehicle)).

The mean percent inhibition of the pain allodynia values (for 8 animals analyzed) ± mean Standard Error (SEM) are shown in table 12. Compounds that exhibit greater than 30% inhibition in the pain sensory abnormality assay are considered active.

TABLE 12

EX.#	Dosage (mg compound/kg body weight)	Inhibition of painful sensory abnormalities% + -SEM
			7	30mg/kg	71.5±4.6
48	10mg/kg	74.9±14.8

Oral administration

On day 7, the responders were dosed orally with 10mg of compound per kg of body weight, or with vehicle alone. The vehicle contained 0.5% HPMC (hydroxy-propylmethyl cellulose) and 0.2% TWEEN^TM80 of phosphate buffered saline. The test compounds are formulated in a vehicle for administration. Contralateral PWT values were determined 2 hours after a single administration without knowledge of the dosing schedule.

For each animal, the 2 hour PWT value was subtracted from the day 6 PWT value to give a Δ PWT value, which represents the change in PWT due to 2 hour drug treatment. In addition, the PWT of day 0 was subtracted from the PWT of day 6 to give a baseline window of nociceptive abnormalities for each animal. To determine the percent inhibition (%) of nociceptive paresthesia for each animal normalized to the vehicle control experiment, the following formula was used:

% nociceptive dysesthesia ═ 100 × (Δ PWT (drug) -mean Δ PWT (vehicle))/(baseline-mean Δ PWT (vehicle)).

The mean percent inhibition of the pain allodynia values (for 8 animals analyzed) ± mean Standard Error (SEM) are shown in table 13. Compounds that exhibit greater than 30% inhibition in the pain sensory abnormality assay are considered active.

Watch 13

EX.#	Inhibition of painful sensory abnormalities% + -SEM
		1	67.7±8.3
7	12.2±8.3
		8	11.5±9.0

9	34.1±8.7
		14	30.8±9.7
20	27.5±10.4
		20	41.1±9.1
20	27.3±6.3
		27	27.0±3.0
30	68.0±13
		30	67.7±13.5
31	47.0±13.0
		31	46.7±13.2
32	60.7±15.1
		42	31.7±9.9
43	55.4±16.7
		45	46.2±10.7
51	26.0±7.0
		56	11.0±10.0
57	26.0±23.0
		57	25.7±22.8
100	8.7±9.2

It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference for all purposes.

Claims (36)

1. A compound of formula I

Or a pharmaceutically acceptable salt thereof, wherein:

x is N or C (R)⁴)；

R²Is 2-pyridyl or phenyl, said 2-pyridyl or said phenyl may be optionally substituted with 1 to 3 substituents, said substituents being independentlySelected from hydrogen, halogen, methyl, ethyl, CF₃Methoxy radical, CH₂F，CHF₂And CH₂OH;

l is absent or methylene;

R³selected from the group consisting of 3-pyrrolidinyl, 4-piperidinyl, 3-piperidinyl, and 2-morpholinyl; and

R⁴，R⁵，R⁶and R⁷Is H; or R⁴，R⁵，R⁶And R⁷Three of (a) are H, and R is⁴，R⁵，R⁶And R⁷One of which is selected from the group consisting of halogen, methoxy, and C₁-C₃Alkyl groups.

2. The compound of claim 1, wherein X is C (R)⁴)，R²Is phenyl, and R⁴，R⁵，R⁶And R⁷Is H; or R⁴，R⁵，R⁶And R⁷Three of (A) are H, and R is⁴，R⁵，R⁶And R⁷One of which is selected from the group consisting of halogen, methoxy, and C₁-C₃Alkyl groups.

3. The compound of claim 2, wherein R⁴，R⁵，R⁶And R⁷Is H, R²Optionally substituted with 1 or 2 substituents independently selected from the group consisting of hydrogen and fluorine.

4. A compound of claim 3, wherein R³Is 3-pyrrolidinyl.

5. The compound of claim 4, wherein the compound or pharmaceutically acceptable salt thereof is selected from the group consisting of:

(R) -1- (2, 5-difluoro-phenyl) -3- (pyrrolidin-3-ylmethoxy) -1H-indazole;

(R) -1- (2, 4-difluoro-phenyl) -3- (pyrrolidin-3-ylmethoxy) -1H-indazole;

(S) -1- (2, 4-difluoro-phenyl) -3- (pyrrolidin-3-ylmethoxy) -1H-indazole;

(S) - (-) -1- (2-fluorophenyl) -3- (pyrrolidin-3-ylmethoxy) -1H-indazole;

(S) -1- (2, 6-difluoro-phenyl) -3- (pyrrolidin-3-ylmethoxy) -1H-indazole;

(R) -1-phenyl-3- (pyrrolidin-3-ylmethoxy) -1H-indazole; and

(S) - (-) -1- (2-fluorophenyl) -3- (pyrrolidin-2-yloxy) -1H-indazole.

6. A compound of claim 3, wherein R³Is 3-piperidyl or 4-piperidyl.

7. The compound of claim 6, wherein the compound or pharmaceutically acceptable salt thereof is selected from the group consisting of:

(±) -1- (2, 5-difluoro-phenyl) -3- (piperidin-3-ylmethoxy) -1H-indazole;

1- (3-fluoro-phenyl) -3- (piperidin-4-yloxy) -1H-indazole;

1-phenyl-3- (piperidin-4-yloxy) -1H-indazole;

1- (2, 6-difluoro-phenyl) -3- (piperidin-4-yloxy) -1H-indazole;

1- (2, 5-difluoro-phenyl) -3- (piperidin-4-yloxy) -1H-indazole;

(±) -1- (3-fluoro-phenyl) -3- (piperidin-3-ylmethoxy) -1H-indazole;

(S) - (-) -1- (2-fluorophenyl) -3- (piperidin-3-ylmethoxy) -1H-indazole;

(S) -1- (2, 6-difluoro-phenyl) -3- (piperidin-3-ylmethoxy) -1H-indazole; and

(S) - (-) -1-phenyl-3- (piperidin-3-ylmethoxy) -1H-indazole.

8. A compound of claim 3, wherein R³Is 2-morpholinyl.

9. The compound of claim 8, wherein-L-R³Comprises the following steps:

10. the compound of claim 8, wherein the compound or pharmaceutically acceptable salt thereof is selected from the group consisting of:

(S) - (+) -1- (2, 5-difluorophenyl) -3- (morpholin-2-ylmethoxy) -1H-indazole;

(S) -1- (2, 6-difluoro-phenyl) -3- (morpholin-2-ylmethoxy) -1H-indazole;

(S) - (+) -1- (2, 4-difluorophenyl) -3- (morpholin-2-ylmethoxy) -1H-indazole;

(S) -1- (3, 4-difluoro-phenyl) -3- (morpholin-2-ylmethoxy) -1H-indazole;

(S) - (+) -1- (2-fluorophenyl) -3- (morpholin-2-ylmethoxy) -1H-indazole; and

(S) - (+) -3- (morpholin-2-ylmethoxy) -1-phenyl-1H-indazole.

11. The compound of claim 2, wherein R⁶Selected from the group consisting of halogen, methoxy, and C₁-C₃Alkyl groups; and is

R²Optionally substituted with 1 or 2 substituents independently selected from the group consisting of hydrogen and fluorine.

12. The compound of claim 11, wherein R³Is 3-pyrrolidinyl.

13. The compound of claim 12, wherein the compound or pharmaceutically acceptable salt thereof is (R) -1- (2, 5-difluoro-phenyl) -5-fluoro-3- (pyrrolidin-3-ylmethoxy) -1H-indazole.

14. The compound of claim 11, wherein R³Is 3-piperidyl or 4-piperidyl.

15. The compound of claim 14, wherein the compound or pharmaceutically acceptable salt thereof is 1- (2, 6-difluoro-phenyl) -5-fluoro-3- (piperidin-4-yloxy) -1H-indazole.

16. The compound of claim 11, wherein R³Is 2-morpholinyl.

17. The compound of claim 6, wherein-L-R³Comprises the following steps:

18. the compound of claim 16, wherein the compound or pharmaceutically acceptable salt thereof is selected from the group consisting of:

(S) -1- (2, 6-difluoro-phenyl) -5-fluoro-3- (morpholin-2-ylmethoxy) -1H-indazole;

(S) -1- (2, 5-difluoro-phenyl) -5-fluoro-3- (morpholin-2-ylmethoxy) -1H-indazole;

(S) - (+) -1- (2, 4-difluorophenyl) -5-fluoro-3- (morpholin-2-ylmethoxy) -1H-indazole; and

(S) - (+) -5-fluoro-1- (2-fluorophenyl) -3- (morpholin-2-ylmethoxy) -1H-indazole.

19. The compound of claim 2, wherein R⁷Selected from the group consisting of halogen, methoxy, and C₁-C₃Alkyl groups; and is

R²Optionally substituted with 1 or 2 substituents independently selected from the group consisting of hydrogen and fluorine.

20. The compound of claim 17, wherein R³Is 3-piperidyl or 4-piperidyl.

21. The compound of claim 18, wherein the compound or pharmaceutically acceptable salt thereof is selected from the group consisting of:

4-fluoro-1- (2-fluoro-phenyl) -3- (piperidin-4-yloxy) -1H-indazole;

1- (2, 5-difluoro-phenyl) -4-fluoro-3- (piperidin-4-yloxy) -1H-indazole;

1- (2, 4-difluoro-phenyl) -4-fluoro-3- (piperidin-4-yloxy) -1H-indazole;

(S) -1- (2, 5-difluoro-phenyl) -4-fluoro-3- (piperidin-3-ylmethoxy) -1H-indazole; and

(S) -4-fluoro-1- (2-fluoro-phenyl) -3- (piperidin-3-ylmethoxy) -1H-indazole.

22. The compound of claim 17, wherein R³Is 2-morpholinyl.

23. The compound of claim 20, wherein the compound or pharmaceutically acceptable salt thereof is (S) -1- (2, 5-difluoro-phenyl) -4-fluoro-3- (morpholin-2-ylmethoxy) -1H-indazole.

1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole, or pharmaceutically acceptable salts thereof.

L-tartaric acid 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole.

26. A method of treating Attention Deficit Hyperactivity Disorder (ADHD) comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound as claimed in claim 1.

27. A method of treating a disorder or condition selected from neuropathic pain, stress urinary incontinence, anxiety, depression, and schizophrenia, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 1.

28. A method of treating fibromyalgia comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 1.

29. A method of treating fibromyalgia comprising administering to a mammal in need of such treatment a therapeutically effective amount of 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole or pharmaceutically acceptable salts thereof.

30. A pharmaceutical composition comprising:

a therapeutically effective amount of a compound of claim 1, and a pharmaceutically acceptable carrier.

31. Crystalline L-tartaric acid 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole.

32. The crystalline L-tartaric acid 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole of claim 31, having an X-ray powder diffraction spectrum measured with cuka radiation comprising the following 2 Θ values ± 0.1: 13.2, 11.8 and 18.7.

33. Use of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of attention deficit hyperactivity disorder.

34. The use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof in the treatment of a disease selected from neuropathic pain, stress urinary incontinence, anxiety, depression, and schizophrenia.

35. Use of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of fibromyalgia.

36. The use of claim 35, wherein the compound is 1- (2-fluorophenyl) -3- (piperidin-4-yloxy) -1H-indazole or pharmaceutically acceptable salts thereof.