CN101312968A

CN101312968A - Indazoles, benzothiazoles, benzoisothiazoles, benzisoxazoles, pyrazolopyridines, isothiazolopyridines, and preparation and uses thereof

Info

Publication number: CN101312968A
Application number: CNA2006800439794A
Authority: CN
Inventors: R·舒马赫; M·D·丹卡; 马建国; B·赫伯特; T·M·阮; 谢文阁; A·泰西姆
Original assignee: Memory Pharmaceuticals Corp
Current assignee: Memory Pharmaceuticals Corp
Priority date: 2005-09-23
Filing date: 2006-09-22
Publication date: 2008-11-26
Also published as: WO2007038367A1; KR20080048550A; CA2622677A1; EP1940833A1; BRPI0617534A2; RU2008115268A; JP2009509964A; RU2450003C2; AU2006295397A1; IL190358A0; SG165417A1; ZA200802342B

Abstract

The present invention relates generally to the field of ligands for nicotinic acetylcholine receptors (nACh receptors), activation of nACh receptors, and the treatment of disease conditions associated with defective or malfunctioning nicotinic acetylcholine receptors, especially of the brain. Further, this invention relates to novel compounds (e.g., indazoles and benzothiazoles), which act as ligands for the a7 nACh receptor subtype, methods of preparing such compounds, compositions containing such compounds, and methods of use thereof.

Description

Indazole, benzothiazole, benzisothiazole, benzoisoxazole, Pyrazolopyridine, isothiazole and pyridine and preparation thereof and purposes

The application requires the right of priority of U.S. Provisional Application of submitting on April 14th, 2,006 60/791,881 and the U.S. Provisional Application of submitting on September 23rd, 2,005 60/719,552, and this paper quotes its disclosed full content as a reference.

The application also with the U.S. Patent application of submitting on March 25th, 2,005 11/089,533 (it requires the U.S. Provisional Application 60/555 submitted on March 25th, 2004, the U.S. Provisional Application 60/616 that on October 6th, 951 and 2004 submitted to, 033 right of priority) and the U.S. Patent application of submitting on September 25th, 2,003 10/669,645 (it requires the U.S. Provisional Application 60/413 submitted on September 25th, 2002, the U.S. Provisional Application 60/448 that on February 21st, 151 and 2003 submitted to, 469 right of priority) relevant, this paper quotes its disclosed separately full content as a reference.

Invention field

The present invention relates generally to following field: the part of nicotinic acetylcholine receptor (nAChR), the activation of nAChR and and the nicotinic acetylcholine receptor defective or the relevant treatment of conditions of dysfunction of nicotinic acetylcholine receptor, particularly brain.In addition, the present invention relates to new compound, these compounds as the part of α 7nAChR hypotype the preparation method, contain these compound compositions and using method thereof.

Background of invention

Two types neurotransmitter is arranged, vagusstoff: muscarinic receptor (mAChR) and nicotinic receptor, they are respectively based on the selectivity of muscarine and nicotine effect.Muscarinic receptor (mAChR) is the G-protein linked receptor.Nicotinic receptor is the member of the ionic channel family of part gate.When being activated, the conductance that ion passes the nicotine ionic channel increases.

Nicotinic alpha-7 receptor albumen is at the paired multiple positively charged ion of body profile (Ca for example ⁺⁺) have an equal pentamer passage of high-permeability.Each nicotinic alpha-7 receptor has four membrane-spanning domains, is called M1, M2, M3 and M4.The wall liner that the M2 territory forms this passage has been proposed.The sequence contrast shows nicotinic alpha-7 high conservative during evolution.In the protein sequence from the chicken to people, the M2 territory that is lining in the passage nexine is identical.About the discussion of alpha-7 receptor, referring to, people (1991) such as Revah for example, Nature, 353,846-849; People such as Galzi (1992), Nature 359,500-505; People such as Fucile (2000), PNAS 97 (7), 3643-3648; People such as Briggs (1999), Eur.J.Pharmacol.366 (2-3), 301-308; And people (1995) such as Gopalakrishnan, Eur.J.Pharmacol.290 (3), 237-246.

The nicotinic alpha-7 receptor passage is expressed in a plurality of brains zone, it is believed that it is relevant with many important biological procedureses in the central nervous system (CNS), comprises learning and memory.Nicotinic alpha-7 receptor is positioned at presynaptic and postsynaptic end, and has proposed it and regulated cynapse and transmit relevant.Therefore, exploitation is important as the part of α 7nACh receptor subtype, the new compound that is used for the treatment of the illness relevant with nicotinic acetylcholine receptor defective or dysfunction.

Summary of the invention

The present invention relates to new compound, the such compound of preparation as the part of α 7nACh receptor subtype method, comprise such compound compositions and using method thereof.

Detailed Description Of The Invention

The present invention includes the compound of formula I, II, III or IV:

With their pharmacologically acceptable salts or solvate (for example hydrate) or N-oxide compound, or the solvate of their pharmacologically acceptable salts, or the pharmacologically acceptable salts or the solvate of their N-oxide compound,

Wherein

A is

X is O or S;

X ¹To X ⁴Be N, CH, CR independently of one another ¹Or C-, wherein C-represent group A and formula (I), (II), (III) or structure (IV) rest part tie point (for example: X ¹, X ², X ³And X ⁴CH or CR respectively do for oneself ¹, group A is connected X in the 3-position with the rest part of formula (I), (II), (III) or structure (IV) ¹, X ²And X ³CH or CR respectively do for oneself ¹, X ⁴Be N, group A is connected X in the 3-position with the rest part of formula (I), (II), (III) or structure (IV) ¹, X ²And X ⁴CH or CR respectively do for oneself ¹, X ³Be N, the rest part with formula (I), (II), (III) or structure (IV) is connected group A in the 3-position, perhaps X ¹, X ³And X ⁴CH or CR respectively do for oneself ¹, X ²Be N, the rest part with formula (I), (II), (III) or structure (IV) is connected group A in the 3-position);

X ⁵To X ⁸Be N, CH, CR independently of one another ³Or C-, wherein C-represent group A and formula (I), (II), (III) or structure (IV) rest part tie point (for example: X ⁵, X ⁶And X ⁸CH or CR respectively do for oneself ³And X ⁷The C-that is connected with the rest part of formula (I), (II), (III) or structure (IV) in its 5-position for group A, perhaps X ⁵, X ⁷And X ⁸CH or CR respectively do for oneself ³And X ⁶The C-that is connected with the rest part of formula (I), (II), (III) or structure (IV) in its 6-position for group A);

X ⁹To X ¹²Be N, CH, CR independently of one another ⁴Or C-, wherein C-represent group A and formula (I), (II), (III) or structure (IV) rest part tie point (for example: X ⁹, X ¹⁰, X ¹¹And X ¹²CH or CR respectively do for oneself ⁴, group A is connected X in the 3-position with the rest part of formula (I), (II), (III) or structure (IV) ⁹, X ¹⁰And X ¹¹CH or CR respectively do for oneself ⁴, X ¹²Be N, the rest part with formula (I), (II), (III) or structure (IV) is connected group A in the 3-position, perhaps X ⁹, X ¹⁰And X ¹²CH or CR respectively do for oneself ⁴, X ¹¹Be N, the rest part with formula (I), (II), (III) or structure (IV) is connected group A in the 3-position, perhaps X ⁹, X ¹¹And X ¹²CH or CR respectively do for oneself ⁴, X ¹⁰Be N, the rest part with formula (I), (II), (III) or structure (IV) is connected group A in the 3-position);

X ¹³To X ¹⁶Be N, CH, CR or C-independently of one another, wherein C-represent group A and formula (I), (II), (III) or structure (IV) rest part tie point (for example: X ¹³, X ¹⁴, X ¹⁵And X ¹⁶Respectively do for oneself CH or CR, group A is connected X in the 3-position with the rest part of formula (I), (II), (III) or structure (IV) ¹³, X ¹⁴And X ¹⁵Respectively do for oneself CH or CR, X ¹⁶Be N, the rest part with formula (I), (II), (III) or structure (IV) is connected group A in the 3-position, perhaps X ¹³, X ¹⁴And X ¹⁶Respectively do for oneself CH or CR, X ¹⁵Be N, the rest part with formula (I), (II), (III) or structure (IV) is connected group A in the 3-position, perhaps X ¹³, X ¹⁵And X ¹⁶Respectively do for oneself CH or CR, X ¹⁴Be N, the rest part with formula (I), (II), (III) or structure (IV) is connected group A in the 3-position);

R ' is H, have the alkyl of 1-4 carbon atom, have 1-4 carbon atom haloalkyl, have the cycloalkyl of 3-7 carbon atom or have the cycloalkylalkyl of 4-7 carbon atom;

R is H, F, Cl, Br, I, OH, CN, COH, NR ⁶R ⁷, carboxyl, CONR ⁶R ⁷, NR ²COR ⁸, NR ²COOR ⁸, NR ²CSR ⁸, NR ²CONR ²R ⁹, NR ²CSNR ²R ⁹, NR ²SO ₂R ¹⁰, NR ²CONR ⁶R ⁷, NR ²CSNR ⁶R ⁷, NR ²R ⁹, SO ₂R ¹⁰, SOR ¹⁰,-O-(C _1-6-alkyl-O) _1-2-C _1-6-alkyl, NR ²-C _1-6-alkyl-NR ⁶R ⁷, NR ²-C _1-6-alkyl-CONR ⁶R ⁷, NR ₂-CO-C _1-6-alkyl-Ar, NR ²-C _1-6-alkyl-CO-O-R ², NR ²-C _1-6-alkyl-NR ²(CO-O-R ²) ,-C _1-6-alkyl-NR ²,-O-C _1-6-alkyl-NR ⁶R ⁷, have 1-4 carbon atom alkyl, have the fluorinated alkyl (CF for example of 1-4 carbon atom ₃), have 2-6 carbon atom thiazolinyl, have the alkynyl (for example ethynyl, proyl, pentenyl) of 2-6 carbon atom, wherein said alkyl, fluorinated alkyl, alkenyl or alkynyl are not substituted separately or are replaced (phenylacetylene C for example by Ar or Het ₆H ₅-C ≡ C-), the cycloalkyl, unsubstituted or that has 3-7 carbon atom by HCO-, C _1-6-alkoxyl group, NR ⁶R ⁷, CO-NR ⁶R ⁷, C _2-6-carbalkoxy or-CO-R ¹⁰The cycloalkenyl group that replaces with 5-8 carbon atom, have 4-7 carbon atom cycloalkylalkyl, have 6-9 carbon atom cycloalkenyl alkyl, have the alkoxyl group (OCH for example of 1-4 carbon atom ₃), have 3-7 carbon atom cycloalkyloxy, have 4-7 carbon atom cycloalkyl alkoxy (for example cyclo propyl methoxy), have the alkylthio (SCH for example of 1-4 carbon atom ₃), have a 1-4 carbon atom fluoridize alkoxyl group (OCH for example ₃, OCHF ₂), have 1-4 carbon atom hydroxyalkyl, have a 1-4 carbon atom fluoridize hydroxyalkyl (for example 2,2,2-three fluoro-1-hydroxyl-1-(trifluoromethyl) ethyls), have 2-4 carbon atom the hydroxy alkoxy base, have the fluoridizing the hydroxy alkoxy base, have an alkylamino of 1-4 carbon atom of 2-4 carbon atom, wherein each alkyl has the dialkyl amido of 1-4 carbon atom, the carbalkoxy with 2-6 carbon atom, Ar, Het, OAr, OHet, Carbo-O, Ar-C independently _1-6-alkyl-O-, Het-C _1-6-alkyl-O-, Het-CO-Het-, Het-C _1-6-alkyl-NR ²-or Ar-C _1-6-alkyl-Het-O-,

Condition is that R is not NH ₂Perhaps

R is one of following formula

N is 2-4;

M is 3-5; Perhaps

Two R can form 5 yuan of condensed ring structures that contain at least one N atom together;

R ¹Be H, F, Cl, Br, I, OH, CN, nitro, NH ₂, COH, NR ⁶R ⁷, carboxyl, CONR ⁶R ⁷, NR ²COR ⁸, NR ²COOR ⁸, NR ²C SR ⁸, NR ²CONR ²R ⁹, NR ²CSNR ²R ⁹, NR ²SO ₂R ¹⁰, NR ²CONR ⁶R ⁷, NR ²CSNR ⁶R ⁷, NR ²R ⁹, SO ²R ¹⁰, SOR ¹⁰,-O-(C _1-6-alkyl-O) _1-2-C _1-6-alkyl, NR ²-C _1-6-alkyl-NR ⁶R ⁷, NR ²-C _1-6-alkyl-CONR ⁶R ⁷, NR ²-CO-C _1-6-alkyl-Ar, NR ²-C _1-6-alkyl-CO-O-R ², NR ²-C _1-6-alkyl-NR ²(CO-O-R ²) ,-C _1-6-alkyl-NR ²,-O-C _1-6-alkyl-NR ⁶R ⁷, have 1-4 carbon atom alkyl, have the fluorinated alkyl (CF for example of 1-4 carbon atom ₃), have 2-6 carbon atom thiazolinyl, have the alkynyl (for example ethynyl, proyl, pentenyl) of 2-6 carbon atom, wherein said alkyl, fluorinated alkyl, alkenyl or alkynyl are not substituted or separately by Ar or Het (phenylacetylene C for example ₆H ₅C ≡ C-) replace, have 3-7 carbon atom cycloalkyl, be not substituted or by HCO-, C _1-6-alkoxyl group, NR ⁶R ⁷, CO-NR ⁶R ⁷, C _2-6-carbalkoxy or-CO-R ¹⁰The cycloalkenyl group that replaces with 5-8 carbon atom, have 4-7 carbon atom cycloalkylalkyl, have 6-9 carbon atom cycloalkenyl alkyl, have the alkoxyl group (OCH for example of 1-4 carbon atom ₃), have 3-7 carbon atom cycloalkyloxy, have 4-7 carbon atom cycloalkyl alkoxy (for example cyclo propyl methoxy), have the alkylthio (SCH for example of 1-4 carbon atom ₃), have a 1-4 carbon atom fluoridize alkoxyl group (OCF for example ₃, OCHF ₂), have 1-4 carbon atom hydroxyalkyl, have a 1-4 carbon atom fluoridize hydroxyalkyl (for example 2,2,2-three fluoro-1-hydroxyl-1-(trifluoromethyl) ethyls), have 2-4 carbon atom the hydroxy alkoxy base, have the fluoridizing the hydroxy alkoxy base, have an alkylamino of 1-4 carbon atom of 2-4 carbon atom, wherein each alkyl has the dialkyl amido of 1-4 carbon atom, the carbalkoxy with 2-6 carbon atom, Ar, Het, OAr, OHet, Carbo-O, Ar-C independently _1-6-alkyl-O-, Het-C _1-6-alkyl-O-, Het-CO-Het-, Het-C _1-6-alkyl-NR ²-or Ar-C _1-6-alkyl-Het-O-; Perhaps

R ¹It is one of following formula

Perhaps

Two R ¹Can form the 5-unit condensed ring structure that contains at least one N atom together;

R ²Be H, have 1-4 carbon atom alkyl, have 1-4 carbon atom fluorinated alkyl, have 3-7 carbon atom cycloalkyl, have 4-7 carbon atom cycloalkylalkyl, fluoridize C _1-4-alkyl-CO-, C _3-7-cycloalkyl-CO-, C _1-4-alkyl-NH-CO-, C _3-7-cycloalkyl-NH-CO-, Het, Ar-C _1-4-alkyl-, Ar-C _1-4-alkyl-CO-, Ar-C _1-4-alkyl-SO ₂-, C _1-4-alkyl-O-C _1-4-alkyl-(CH for example ₂CH ₂-O-CH ₃), Ar-C _1-4-alkyl-NH-CO-or Het-NH-CO-(for example (1-azabicyclo [2.2.2] oct-3-yl)-NH-CO-);

R ³Be H, F, Cl, Br, I, OH, CN, nitro, NH ₂, COH, NR ⁶R ⁷, carboxyl, CONR ⁶R ⁷, NR ²COR ⁸, NR ²COOR ⁸, NR ²CSR ⁸, NR ²CONR ²R ⁹, NR ²CSNR ²R ⁹, NR ²SO ₂R ¹⁰, NR ²CONR ⁶R ⁷, NR ²CSNR ⁶R ⁷, NR ²R ⁹, SO ₂R ¹⁰, SOR ¹⁰,-O-(C _1-6-alkyl-O) _1-2-C _1-6-alkyl, NR ²-C _1-6-alkyl-NR ⁶R ⁷, NR ²-C _1-6-alkyl-CONR ⁶R ⁷, NR ²-CO-C _1-6-alkyl-Ar, NR ²-C _1-6-alkyl-CO-O-R ², NR ²-C _1-6-alkyl-NR ²(CO-O-R ²) ,-C _1-6-alkyl-NR ²,-O-C _1-6-alkyl-NR ⁶R ⁷, have 1-4 carbon atom alkyl, have the fluorinated alkyl (CF for example of 1-4 carbon atom ₃), have 2-6 carbon atom thiazolinyl, have the alkynyl (for example ethynyl, proyl, pentenyl) of 2-6 carbon atom, wherein said alkyl, fluorinated alkyl, alkenyl or alkynyl are not substituted separately or are replaced (phenylacetylene C for example by Ar or Het ₆H ₅-C ≡ C-), have 3-7 carbon atom cycloalkyl, be not substituted or by HCO-, C _1-6-alkoxyl group, NR ⁶R ⁷, CO-NR ⁶R ⁷, C _2-6-carbalkoxy or-CO-R ¹⁰The cycloalkenyl group that replaces with 5-8 carbon atom, have 4-7 carbon atom cycloalkylalkyl, have 6-9 carbon atom cycloalkenyl alkyl, have the alkoxyl group (OCH for example of 1-4 carbon atom ₃), have 3-7 carbon atom cycloalkyloxy, have 4-7 carbon atom cycloalkyl alkoxy (for example cyclo propyl methoxy), have the alkylthio (SCH for example of 1-4 carbon atom ₃), have a 1-4 carbon atom fluoridize alkoxyl group (OCF for example ₃, OCHF ₂), have 1-4 carbon atom hydroxyalkyl, have a 1-4 carbon atom fluoridize hydroxyalkyl (for example 2,2,2-three fluoro-1-hydroxyl-1-(trifluoromethyl) ethyls), have 2-4 carbon atom the hydroxy alkoxy base, have the fluoridizing the hydroxy alkoxy base, have an alkylamino of 1-4 carbon atom of 2-4 carbon atom, wherein each alkyl has the dialkyl amido of 1-4 carbon atom, the carbalkoxy with 2-6 carbon atom, Ar, Het, OAr, OHet, Carbo-O, Ar-C independently _1-6-alkyl-O-, Het-C _1-6-alkyl-O-, Het-CO-Het-, Het-C _1-6-alkyl-NR ²-or Ar-C _1-6-alkyl-Het-O-; Perhaps

R ³It is one of following formula

Perhaps

Two R ³Can form the 5-unit condensed ring structure that contains at least one N atom together;

R ⁴Be H, F, Cl, Br, I, OH, CN, nitro, NH ₂, COH, NR ⁶R ⁷, carboxyl, CONR ⁶R ⁷, NR ²COR ⁸, NR ²COOR ⁸, NR ²CSR ⁸, NR ²CONR ²R ⁹, NR ²CSNR ²R ⁹, NR ²SO ₂R ¹⁰, NR ²CONR ⁶R ⁷, NR ²CSNR ⁶R ⁷, NR ²R ⁹, SO ₂R ¹⁰, SOR ¹⁰,-O-(C _1-6-alkyl-O) _1-2-C _1-6-alkyl, NR ²-C _1-6-alkyl-NR ⁶R ⁷, NR ²-C _1-6-alkyl-CONR ⁶R ⁷, NR ²-CO-C _1-6-alkyl-Ar, NR ²-C _1-6-alkyl-CO-O-R ², NR ²-C _1-6-alkyl-NR ²(CO-O-R ²) ,-C _1-6-alkyl-NR ²,-O-C _1-6-alkyl-NR ⁶R ⁷, have 1-4 carbon atom alkyl, have the fluorinated alkyl (CF for example of 1-4 carbon atom ₃), have 2-6 carbon atom thiazolinyl, have the alkynyl (for example ethynyl, proyl, pentenyl) of 2-6 carbon atom, wherein said alkyl, fluorinated alkyl, alkenyl or alkynyl are not substituted separately or are replaced (phenylacetylene C for example by Ar or Het ₆H ₅-C ≡ C-), have 3-7 carbon atom cycloalkyl, be not substituted or by HCO-, C _1-6-alkoxyl group, NR ⁶R ⁷, CO-NR ⁶R ⁷, C _2-6-carbalkoxy or-CO-R ¹⁰The cycloalkenyl group that replaces with 5-8 carbon atom, have 4-7 carbon atom cycloalkylalkyl, have 6-9 carbon atom cycloalkenyl alkyl, have the alkoxyl group (OCH for example of 1-4 carbon atom ₃), have 3-7 carbon atom cycloalkyloxy, have 4-7 carbon atom cycloalkyl alkoxy (for example cyclo propyl methoxy), have the alkylthio (SCH for example of 1-4 carbon atom ₃), have a 1-4 carbon atom fluoridize alkoxyl group (OCF for example ₃, OCHF ₂), have 1-4 carbon atom hydroxyalkyl, have a 1-4 carbon atom fluoridize hydroxyalkyl (for example 2,2,2-three fluoro-1-hydroxyl-1-(trifluoromethyl) ethyls), have 2-4 carbon atom the hydroxy alkoxy base, have the fluoridizing the hydroxy alkoxy base, have an alkylamino of 1-4 carbon atom of 2-4 carbon atom, wherein each alkyl has the dialkyl amido of 1-4 carbon atom, the carbalkoxy with 2-6 carbon atom, Ar, Het, OAr, OHet, Carbo-O, Ar-C independently _1-6-alkyl-O-, Het-C _1-6-alkyl-O-, Het-CO-Het-, Het-C _1-6-alkyl-NR ²-or Ar-C _1-6-alkyl-Het-O-; Perhaps

R ⁴It is one of following formula

Perhaps

Two R ⁴Can form the 5-unit condensed ring structure that contains at least one N atom together;

R ⁵Be H, F, Cl, Br, I, OH, CN, nitro, NH ₂, carboxyl, CONR ⁶R ⁷, NR ²COR ⁸, NR ²CSR ⁸, NR ²CONR ²R ⁹, NR ²CSNR ²R ⁹, NR ²SO ₂R ¹⁰, NR ²CONR ⁶R ⁷, NR ²CSNR ⁶R ⁷, NR ²R ⁹, SO ₂R ¹⁰, SOR ¹⁰, have 1-4 carbon atom alkyl, have the fluorinated alkyl (CF for example of 1-4 carbon atom ₃), have 2-6 carbon atom thiazolinyl, have the alkynyl (for example ethynyl, proyl, pentenyl) of 2-6 carbon atom, wherein said alkyl, fluorinated alkyl, alkenyl or alkynyl are not substituted separately or are replaced (phenylacetylene C for example by Ar or Het ₆H ₅-C ≡ C-), have 3-7 carbon atom cycloalkyl, have 5-8 carbon atom cycloalkenyl group, have 4-7 carbon atom cycloalkylalkyl, have 6-9 carbon atom cycloalkenyl alkyl, have the alkoxyl group (OCH for example of 1-4 carbon atom ₃), have 3-7 carbon atom cycloalkyloxy, have 4-7 carbon atom cycloalkyl alkoxy (for example cyclo propyl methoxy), have the alkylthio (SCH for example of 1-4 carbon atom ₃), have a 1-4 carbon atom fluoridize alkoxyl group (OCF for example ₃, OCHF ₂), have 1-4 carbon atom hydroxyalkyl, have a 1-4 carbon atom fluoridize hydroxyalkyl (for example 2,2,2-three fluoro-1-hydroxyl-1-(trifluoromethyl) ethyls), have 2-4 carbon atom the hydroxy alkoxy base, have the fluoridizing the hydroxy alkoxy base, have an alkylamino of 1-4 carbon atom of 2-4 carbon atom, wherein each alkyl has the dialkyl amido of 1-4 carbon atom, the carbalkoxy with 2-6 carbon atom, Ar, Het, OAr or OHet independently;

R ⁶And R ⁷Be H independently of one another, have 1-4 carbon atom alkyl, have 2-8 carbon atom alkoxyalkyl, have the cycloalkyl of 3-7 carbon atom or have the cycloalkylalkyl of 4-7 carbon atom, perhaps R ⁶And R ⁷Be to contain 4-6 carbon atom and form the alkylidene group (for example piperidyl, pyrrolidyl) that encircles together with described N atom;

R ⁸Be H, have 1-4 carbon atom alkyl, have the fluorinated alkyl (CF for example of 1-4 carbon atom ₃), have 3-6 carbon atom thiazolinyl, have the alkynyl (for example proyl, pentenyl) of 3-6 carbon atom, wherein said alkyl, fluorinated alkyl, alkenyl or alkynyl are not substituted separately or are replaced (phenylacetylene C for example by Ar or Het ₆H ₅-C ≡ C-), have 3-7 carbon atom cycloalkyl, have 5-8 carbon atom cycloalkenyl group, have 4-7 carbon atom cycloalkylalkyl, have 6-9 carbon atom cycloalkenyl alkyl, have 1-4 carbon atom hydroxyalkyl, have the fluoridizing hydroxyalkyl, have an alkylamino of 1-4 carbon atom of 1-4 carbon atom, wherein each alkyl has dialkyl amido, Ar or the Het of 1-4 carbon atom independently;

R ⁹Be alkyl, Ar with 1-4 carbon atom, wherein moieties has the Ar-alkyl of 1-4 carbon atom, or Het;

R ¹⁰The fluorinated alkyl that is alkyl, has 1-4 carbon atom (CF for example with 1-4 carbon atom ₃), have 3-6 carbon atom thiazolinyl, have the alkynyl (for example proyl, pentenyl) of 3-6 carbon atom, wherein said alkyl, fluorinated alkyl, alkenyl or alkynyl are not substituted separately or are replaced (phenylacetylene C for example by Ar or Het ₆H ₅-C ≡ C-), have 3-7 carbon atom cycloalkyl, have 5-8 carbon atom cycloalkenyl group, have 4-7 carbon atom cycloalkylalkyl, have 6-9 carbon atom cycloalkenyl alkyl, have 2-4 carbon atom hydroxyalkyl, have the fluoridizing hydroxyalkyl, have an alkylamino of 1-4 carbon atom of 2-4 carbon atom, wherein each alkyl has dialkyl amido, the NR of 1-4 carbon atom independently ⁶R ⁷, NR ²R ⁸, Ar or Het;

Ar is the aryl with 6-10 carbon atom, it is not substituted or is replaced one or many by following group: the alkyl with 1-8 carbon atom, alkoxyl group with 1-8 carbon atom, halogen (F, Cl, Br or I, preferred F or Cl), wherein moieties has the dialkyl amido of 1-8 carbon atom separately, amino, cyano group, hydroxyl, nitro, haloalkyl with 1-8 carbon atom, halogenated alkoxy with 1-8 carbon atom, hydroxyalkyl with 1-8 carbon atom, hydroxy alkoxy base with 2-8 carbon atom, alkene oxygen base with 3-8 carbon atom, alkylthio with 1-8 carbon atom, alkyl sulphinyl with 1-8 carbon atom, alkyl sulphonyl with 1-8 carbon atom, alkylamino with 1-8 carbon atom, wherein cycloalkyl is chosen the cycloalkyl amino that is substituted and has 3-7 carbon atom wantonly, wherein aryl moiety is optional is substituted and has a 6-10 carbon atom (phenyl for example, naphthyl, xenyl) aryloxy, wherein aryl moiety is optional is substituted and has a 6-10 carbon atom (phenyl for example, naphthyl, xenyl) arylthio, wherein cycloalkyl is chosen the cycloalkyloxy that is substituted and has 3-7 carbon atom wantonly, sulfo group, sulfonamido, amido (for example acetamido), acyloxy (for example acetoxyl group) or their combination;

Het is a heterocyclic radical, it is for saturated fully, fractional saturation or undersaturated fully, have 5-10 annular atoms, wherein at least one annular atoms is N, O or S atom, described heterocyclic radical is not substituted or is replaced one or many by following group: halogen (F, Cl, Br or I, preferred F or Cl), has 6-10 carbon atom and optional substituted aryl (phenyl for example, naphthyl, xenyl), alkyl with 1-8 carbon atom, alkoxyl group with 1-8 carbon atom, cycloalkyl with 3-7 carbon atom, cycloalkylalkyl (for example cyclopropyl methyl) with 4-7 carbon atom, halogenated alkoxy (OCHF for example with 1-8 carbon atom ₂), have 3-7 carbon atom cycloalkyloxy, have 4-7 carbon atom cycloalkyl alkoxy (for example cyclo propyl methoxy), have the alkoxyalkyl (CH for example of 2-8 carbon atom ₃OCH ₂), wherein each alkyl has the alkyl (haloalkyl) amino (for example methyl (trifluoromethyl) amino) of 1-8 carbon atom, wherein each alkyl has two (haloalkyl) amino of 1-8 carbon atom, (haloalkyl) amino with 1-8 carbon atom, cyano group, (fluorinated alkyl for example is as trifluoromethyl to have the haloalkyl of 1-8 carbon atom, trifluoroethyl), nitro, oxo, OH, alkoxycarbonyl alkyl with 3-8 carbon atom, amino, alkylamino with 1-8 carbon atom, wherein each alkyl has the dialkyl amido of 1-8 carbon atom, SO ₂R ¹¹,-CXR ¹¹, piperidyl ethyl or their combination;

Carbo is the carbon ring group of the undersaturated 5-14 of having of a part carbon atom, and it is not substituted or is replaced one or many by following group: halogen, the alkyl with 1-8 carbon atom, the alkoxyl group with 1-8 carbon atom, hydroxyl, nitro, cyano group, oxo or their combination (for example indanyl, naphthane methyne etc.); And

R ¹¹The haloalkyl that is alkyl, has 1-4 carbon atom (CF for example with 1-4 carbon atom ₃), have 3-6 carbon atom thiazolinyl, have the alkynyl (for example proyl, pentenyl) of 3-6 carbon atom, wherein said alkyl, haloalkyl, alkenyl or alkynyl are not substituted separately or are replaced (phenylacetylene C for example by Ar or Het ₆H ₅-C ≡ C-), have 3-7 carbon atom cycloalkyl, have 5-8 carbon atom cycloalkenyl group, have 4-7 carbon atom cycloalkylalkyl, have 6-9 carbon atom cycloalkenyl alkyl, have 2-4 carbon atom hydroxyalkyl, have the fluoridizing hydroxyalkyl, have an alkylamino of 1-4 carbon atom of 2-4 carbon atom, wherein each alkyl has the dialkyl amido of 1-4 carbon atom independently, or Ar.

According to another compound of the present invention and/or method aspect, described compound is selected from formula I, II, III or IV:

With their pharmacologically acceptable salts or solvate (for example hydrate) or N-oxide compound, or the pharmacologically acceptable salts or the solvate of the solvate of their pharmacologically acceptable salts or their N-oxide compound,

Wherein

A is

X is O or S;

X ⁹To X ¹²Be N, CH, CR independently of one another ⁴Or C-, wherein C-represent group A and formula (I), (II), (III) or structure (IV) rest part tie point (for example: X ⁹, X ¹⁰, X ¹¹And X ¹²²CH or CR respectively do for oneself ⁴, group A is connected X in the 3-position with the rest part of formula (I), (II), (III) or structure (IV) ⁹, X ¹⁰And X ¹¹CH or CR respectively do for oneself ⁴, X ¹²Be N, the rest part with formula (I), (II), (III) or structure (IV) is connected group A in the 3-position, perhaps X ⁹, X ¹⁰And X ¹²CH or CR respectively do for oneself ⁴, X ¹¹Be N, the rest part with formula (I), (II), (III) or structure (IV) is connected group A in the 3-position, perhaps X ⁹, X ¹¹And X ¹²CH or CR respectively do for oneself ⁴, X ¹⁰Be N, the rest part with formula (I), (II), (III) or structure (IV) is connected group A in the 3-position);

R is H, F, Cl, Br, I, OH, CN, COH, NR ⁶R ⁷, carboxyl, CONR ⁶R ⁷, NR ²COR ⁸, NR ²COOR ⁸, NR ²CSR ⁸, NR ²CONR ²R ⁹, NR ²CSNR ²R ⁹, NR ²SO ₂R ¹⁰, NR ²CONR ⁶R ⁷, NR ²CSNR ⁶R ⁷, NR ²R ⁹, SO ₂R ¹⁰, SOR ¹⁰,-O-(C _1-6-alkyl-O) _1-2-C _1-6-alkyl, NR ²-C _1-6-alkyl-NR ⁶R ⁷, NR ²-C _1-6-alkyl-CONR ⁶R ⁷, NR ²-CO-C _1-6-alkyl-Ar, NR ²-C _1-6-alkyl-CO-O-R ², NR ²-C _1-6-alkyl-NR ²(CO-O-R ²) ,-C _1-6-alkyl-NR ²,-O-C _1-6-alkyl-NR ⁶R ⁷, have 1-4 carbon atom alkyl, have the fluorinated alkyl (CF for example of 1-4 carbon atom ₃), have 2-6 carbon atom thiazolinyl, have the alkynyl (for example ethynyl, proyl, pentenyl) of 2-6 carbon atom, wherein said alkyl, fluorinated alkyl, alkenyl or alkynyl are not substituted separately or are replaced (phenylacetylene base C for example by Ar or Het ₆H ₅-C ≡ C-), the cycloalkyl, unsubstituted or that has 3-7 carbon atom by HCO-, C _1-6-alkoxyl group, NR ⁶R ⁷, CO-NR ⁶R ⁷, C _2-6-carbalkoxy or-CO-R ¹⁰The cycloalkenyl group that replaces with 5-8 carbon atom, have 4-7 carbon atom cycloalkylalkyl, have 6-9 carbon atom cycloalkenyl alkyl, have the alkoxyl group (OCH for example of 1-4 carbon atom ₃), have 3-7 carbon atom cycloalkyloxy, have 4-7 carbon atom cycloalkyl alkoxy (for example cyclo propyl methoxy), have the alkylthio (SCH for example of 1-4 carbon atom ₃), have a 1-4 carbon atom fluoridize alkoxyl group (OCF for example ₃, OCHF ₂), have 1-4 carbon atom hydroxyalkyl, have a 1-4 carbon atom fluoridize hydroxyalkyl (for example 2,2,2-three fluoro-1-hydroxyl-1-(trifluoromethyl) ethyls), have 2-4 carbon atom the hydroxy alkoxy base, have the fluoridizing the hydroxy alkoxy base, have an alkylamino of 1-4 carbon atom of 2-4 carbon atom, wherein each alkyl has the dialkyl amido of 1-4 carbon atom, the carbalkoxy with 2-6 carbon atom, Ar, Het, OAr, OHet, Carbo-O, Ar-C independently _1-6-alkyl-O-, Het-C _1-6-alkyl-O-, Het-CO-Het-, Het-C _1-6-alkyl-NR ²-or Ar-C _1-6-alkyl-Het-O-,

Condition is that R is not NH ₂Perhaps

R is one of following formula

N is 2-4;

M is 3-5; Perhaps

R ¹Be H, F, Cl, Br, I, OH, CN, nitro, NH ₂, COH, NR ⁶R ⁷, carboxyl, CONR ⁶R ⁷, NR ²COR ⁸, NR ²COOR ⁸, NR ²CSR ⁸, NR ²CONR ²R ⁹, NR ²CSNR ²R ⁹, NR ²SO ₂R ¹⁰, NR ²CONR ⁶R ⁷, NR ²CSNR ⁶R ⁷, NR ²R ⁹, SO ₂R ¹⁰, SOR ¹⁰,-O-(C _1-6-alkyl-O) _1-2-C _1-6-alkyl, NR ²-C _1-6-alkyl-NR ⁶R ⁷, NR ²-C _1-6-alkyl-CONR ⁶R ⁷, NR ²-CO-C _1-6-alkyl-Ar, NR ²-C _1-6-alkyl-CO-O-R ², NR ²-C _1-6-alkyl-NR ²(CO-O-R ²) ,-C _1-6-alkyl-NR ²,-O-C _1-6-alkyl-NR ⁶R ⁷, have 1-4 carbon atom alkyl, have the fluorinated alkyl (CF for example of 1-4 carbon atom ₃), have 2-6 carbon atom thiazolinyl, have the alkynyl (for example ethynyl, proyl, pentenyl) of 2-6 carbon atom, wherein said alkyl, fluorinated alkyl, alkenyl or alkynyl are not substituted separately or are replaced (phenylacetylene base C for example by Ar or Het ₆H ₅-C ≡ C-), the cycloalkyl, unsubstituted or that has 3-7 carbon atom by HCO-, C _1-6-alkoxyl group, NR ⁶R ⁷, CO-NR ⁶R ⁷, C _2-6-carbalkoxy or-CO-R ¹⁰The cycloalkenyl group that replaces with 5-8 carbon atom, have 4-7 carbon atom cycloalkylalkyl, have 6-9 carbon atom cycloalkenyl alkyl, have the alkoxyl group (OCH for example of 1-4 carbon atom ₃), have 3-7 carbon atom cycloalkyloxy, have 4-7 carbon atom cycloalkyl alkoxy (for example cyclo propyl methoxy), have the alkylthio (SCH for example of 1-4 carbon atom ₃), have a 1-4 carbon atom fluoridize alkoxyl group (OCF for example ₃, OCHF ₂), have 1-4 carbon atom hydroxyalkyl, have a 1-4 carbon atom fluoridize hydroxyalkyl (for example 2,2,2-three fluoro-1-hydroxyl-1-(trifluoromethyl) ethyls), have 2-4 carbon atom the hydroxy alkoxy base, have the fluoridizing the hydroxy alkoxy base, have an alkylamino of 1-4 carbon atom of 2-4 carbon atom, wherein each alkyl has the dialkyl amido of 1-4 carbon atom, the carbalkoxy with 2-6 carbon atom, Ar, Het, OAr, OHet, Carbo-O, Ar-C independently _1-6-alkyl-O-, Het-C _1-6-alkyl-O-, Het-CO-Het-, Het-C _1-6-alkyl-NR ²-or Ar-C _1-6-alkyl-Het-O-; Perhaps

R ¹It is one of following formula

Perhaps

Two R ¹Can form 5 yuan of condensed ring structures that contain at least one N atom together;

R ³Be H, F, Cl, Br, I, OH, CN, nitro, NH ₂, COH, NR ⁶R ⁷, carboxyl, CONR ⁶R ⁷, NR ²COR ⁸, NR ²COOR ⁸, NR ²CSR ⁸, NR ²CONR ²R ⁹, NR ²CSNR ²R ⁹, NR ²SO ₂R ¹⁰, NR ²CONR ⁶R ⁷, NR ²CSNR ⁶R ⁷, NR ²R ⁹, SO ₂R ¹⁰, SOR ¹⁰,-O-(C _1-6-alkyl-O) _1-2-C _1-6-alkyl, NR ²-C _1-6-alkyl-NR ⁶R ⁷, NR ²-C _1-6-alkyl-CONR ⁶R ⁷, NR ²-CO-C _1-6-alkyl-Ar, NR ²-C _1-6-alkyl-CO-O-R ², NR ²-C _1-6-alkyl-NR ²(CO-O-R ²) ,-C _1-6-alkyl-NR ²,-O-C _1-6-alkyl-NR ⁶R ⁷, have 1-4 carbon atom alkyl, have the fluorinated alkyl (CF for example of 1-4 carbon atom ₃), have 2-6 carbon atom thiazolinyl, have the alkynyl (for example ethynyl, proyl, pentenyl) of 2-6 carbon atom, wherein said alkyl, fluorinated alkyl, alkenyl or alkynyl are not substituted separately or are replaced (phenylacetylene base C for example by Ar or Het ₆H ₅-C ≡ C-), the cycloalkyl, unsubstituted or that has 3-7 carbon atom by HCO-, C _1-6-alkoxyl group, NR ⁶R ⁷, CO-NR ⁶R ⁷, C _2-6-carbalkoxy or-CO-R ¹⁰The cycloalkenyl group that replaces with 5-8 carbon atom, have 4-7 carbon atom cycloalkylalkyl, have 6-9 carbon atom cycloalkenyl alkyl, have the alkoxyl group (OCH for example of 1-4 carbon atom ₃), have 3-7 carbon atom cycloalkyloxy, have 4-7 carbon atom cycloalkyl alkoxy (for example cyclo propyl methoxy), have the alkylthio (SCH for example of 1-4 carbon atom ₃), have a 1-4 carbon atom fluoridize alkoxyl group (OCF for example ₃, OCHF ₂), have 1-4 carbon atom hydroxyalkyl, have a 1-4 carbon atom fluoridize hydroxyalkyl (for example 2,2,2-three fluoro-1-hydroxyl-1-(trifluoromethyl) ethyls), have 2-4 carbon atom the hydroxy alkoxy base, have the fluoridizing the hydroxy alkoxy base, have an alkylamino of 1-4 carbon atom of 2-4 carbon atom, wherein each alkyl has the dialkyl amido of 1-4 carbon atom, the carbalkoxy with 2-6 carbon atom, Ar, Het, OAr, OHet, Carbo-O, Ar-C independently _1-6-alkyl-O-, Het-C _1-6-alkyl-O-, Het-CO-Het-, Het-C _1-6-alkyl-NR ²-or Ar-C _1-6-alkyl-Het-O-; Perhaps

R ³It is one of following formula

Perhaps

Two R ³Can form 5 yuan of condensed ring structures that contain at least one N atom together;

R ⁴Be H, F, Cl, Br, I, OH, CN, nitro, NH ₂, COH, NR ⁶R ⁷, carboxyl, CONR ⁶R ⁷, NR ²COR ⁸, NR ²COOR ⁸, NR ²CSR ⁸, NR ²CONR ²R ⁹, NR ²CSNR ²R ⁹, NR ²SO ₂R ¹⁰, NR ²CONR ⁶R ⁷, NR ²CSNR ⁶R ⁷, NR ²R ⁹, SO ₂R ¹⁰, SOR ¹⁰,-O-(C _1-6-alkyl-O) _1-2-C _1-6-alkyl, NR ²-C _1-6-alkyl-NR ⁶R ⁷, NR ²-C _1-6-alkyl-CONR ⁶R ⁷, NR ²-CO-C _1-6-alkyl-Ar, NR ²-C _1-6-alkyl-CO-O-R ², NR ²-C _1-6-alkyl-NR ²(CO-O-R ²) ,-C _1-6-alkyl-NR ²,-O-C _1-6-alkyl-NR ⁶R ⁷, have 1-4 carbon atom alkyl, have the fluorinated alkyl (CF for example of 1-4 carbon atom ₃), have 2-6 carbon atom thiazolinyl, have the alkynyl (for example ethynyl, proyl, pentenyl) of 2-6 carbon atom, wherein said alkyl, fluorinated alkyl, alkenyl or alkynyl are not substituted separately or are replaced (phenylacetylene base C for example by Ar or Het ₆H ₅-C ≡ C-), the cycloalkyl, unsubstituted or that has 3-7 carbon atom by HCO-, C _1-6-alkoxyl group, NR ⁶R ⁷, CO-NR ⁶R ⁷, C _2-6-carbalkoxy or-CO-R ¹⁰The cycloalkenyl group that replaces with 5-8 carbon atom, have 4-7 carbon atom cycloalkylalkyl, have 6-9 carbon atom cycloalkenyl alkyl, have the alkoxyl group (OCH for example of 1-4 carbon atom ₃), have 3-7 carbon atom cycloalkyloxy, have 4-7 carbon atom cycloalkyl alkoxy (for example cyclo propyl methoxy), have the alkylthio (SCH for example of 1-4 carbon atom ₃), have a 1-4 carbon atom fluoridize alkoxyl group (OCF for example ₃, OCHF ₂), have 1-4 carbon atom hydroxyalkyl, have a 1-4 carbon atom fluoridize hydroxyalkyl (for example 2,2,2-three fluoro-1-hydroxyl-1-(trifluoromethyl) ethyls), have 2-4 carbon atom the hydroxy alkoxy base, have the fluoridizing the hydroxy alkoxy base, have an alkylamino of 1-4 carbon atom of 2-4 carbon atom, wherein each alkyl has the dialkyl amido of 1-4 carbon atom, the carbalkoxy with 2-6 carbon atom, Ar, Het, OAr, OHet, Carbo-O, Ar-C independently _1-6-alkyl-O-, Het-C _1-6-alkyl-O-, Het-CO-Het-, Het-C _1-6-alkyl-NR ²-or Ar-C _1-6-alkyl-Het-O-; Perhaps

R ⁴It is one of following formula

Perhaps

Two R ⁴Can form 5 yuan of condensed ring structures that contain at least one N atom together;

R ⁵Be H, F, Cl, Br, I, OH, CN, nitro, NH ₂, carboxyl, CONR ⁶R ⁷, NR ²COR ⁸, NR ²CSR ⁸, NR ²CONR ²R ⁹, NR ²CSNR ²R ⁹, NR ²SO ₂R ¹⁰, NR ²CONR ⁶R ⁷, NR ²CSNR ⁶R ⁷, NR ²R ⁹, SO ₂R ¹⁰, SOR ¹⁰, have 1-4 carbon atom alkyl, have the fluorinated alkyl (CF for example of 1-4 carbon atom ₃), have 2-6 carbon atom thiazolinyl, have the alkynyl (for example ethynyl, proyl, pentenyl) of 2-6 carbon atom, wherein said alkyl, fluorinated alkyl, alkenyl or alkynyl are not substituted separately or are replaced (phenylacetylene base C for example by Ar or Het ₆H ₅-C ≡ C-), have 3-7 carbon atom cycloalkyl, have 5-8 carbon atom cycloalkenyl group, have 4-7 carbon atom cycloalkylalkyl, have 6-9 carbon atom cycloalkenyl alkyl, have the alkoxyl group (OCH for example of 1-4 carbon atom ₃), have 3-7 carbon atom cycloalkyloxy, have 4-7 carbon atom cycloalkyl alkoxy (for example cyclo propyl methoxy), have the alkylthio (SCH for example of 1-4 carbon atom ₃), have a 1-4 carbon atom fluoridize alkoxyl group (OCF for example ₃, OCHF ₂), have 1-4 carbon atom hydroxyalkyl, have a 1-4 carbon atom fluoridize hydroxyalkyl (for example 2,2,2-three fluoro-1-hydroxyl-1-(trifluoromethyl) ethyls), have 2-4 carbon atom the hydroxy alkoxy base, have the fluoridizing the hydroxy alkoxy base, have an alkylamino of 1-4 carbon atom of 2-4 carbon atom, wherein each alkyl has the dialkyl amido of 1-4 carbon atom, the carbalkoxy with 2-6 carbon atom, Ar, Het, OAr or OHet independently;

R ⁸Be H, have 1-4 carbon atom alkyl, have the fluorinated alkyl (CF for example of 1-4 carbon atom ₃), have 3-6 carbon atom thiazolinyl, have the alkynyl (for example proyl, pentenyl) of 3-6 carbon atom, wherein said alkyl, fluorinated alkyl, alkenyl or alkynyl are not substituted separately or are replaced (phenylacetylene base C for example by Ar or Het ₆H ₅-C ≡ C-), have 3-7 carbon atom cycloalkyl, have 5-8 carbon atom cycloalkenyl group, have 4-7 carbon atom cycloalkylalkyl, have 6-9 carbon atom cycloalkenyl alkyl, have 1-4 carbon atom hydroxyalkyl, have the fluoridizing hydroxyalkyl, have an alkylamino of 1-4 carbon atom of 1-4 carbon atom, wherein each alkyl has dialkyl amido, Ar or the Het of 1-4 carbon atom independently;

R ¹⁰The fluorinated alkyl that is alkyl, has 1-4 carbon atom (CF for example with 1-4 carbon atom ₃), have 3-6 carbon atom thiazolinyl, have the alkynyl (for example proyl, pentenyl) of 3-6 carbon atom, wherein said alkyl, fluorinated alkyl, alkenyl or alkynyl are not substituted separately or are replaced (phenylacetylene base C for example by Ar or Het ₆H ₅-C ≡ C-), have 3-7 carbon atom cycloalkyl, have 5-8 carbon atom cycloalkenyl group, have 4-7 carbon atom cycloalkylalkyl, have 6-9 carbon atom cycloalkenyl alkyl, have 2-4 carbon atom hydroxyalkyl, have the fluoridizing hydroxyalkyl, have an alkylamino of 1-4 carbon atom of 2-4 carbon atom, wherein each alkyl has dialkyl amido, the NR of 1-4 carbon atom independently ⁶R ⁷, NR ²R ⁸, Ar or Het;

Ar is the aryl with 6-10 carbon atom, it is not substituted or is replaced one or many by following group: the alkyl with 1-8 carbon atom, alkoxyl group with 1-8 carbon atom, halogen (F, Cl, Br or I, preferred F or Cl), wherein moieties has the dialkyl amido of 1-8 carbon atom separately, amino, cyano group, hydroxyl, nitro, haloalkyl with 1-8 carbon atom, halogenated alkoxy with 1-8 carbon atom, hydroxyalkyl with 1-8 carbon atom, hydroxy alkoxy base with 2-8 carbon atom, alkene oxygen base with 3-8 carbon atom, alkylthio with 1-8 carbon atom, alkyl sulphinyl with 1-8 carbon atom, alkyl sulphonyl with 1-8 carbon atom, alkylamino with 1-8 carbon atom, wherein cycloalkyl is chosen the cycloalkyl amino that is substituted and has 3-7 carbon atom wantonly, wherein aryl moiety is optional is substituted and has a 6-10 carbon atom (phenyl for example, naphthyl, xenyl) aryloxy, wherein aryl moiety is optional is substituted and has a 6-10 carbon atom (phenyl for example, naphthyl, xenyl) arylthio, wherein cycloalkyl is chosen the cycloalkyloxy that is substituted and has 3-7 carbon atom wantonly, sulfo group, sulfonamido, amido (for example kharophen), acyloxy (for example acetoxyl group) or their combination; And

R ¹¹The haloalkyl that is alkyl, has 1-4 carbon atom (CF for example with 1-4 carbon atom ₃), have 3-6 carbon atom thiazolinyl, have the alkynyl (for example proyl, pentenyl) of 3-6 carbon atom, wherein said alkyl, haloalkyl, alkenyl or alkynyl are not substituted separately or are replaced (phenylacetylene base C for example by Ar or Het ₆H ₅-C ≡ C-), have 3-7 carbon atom cycloalkyl, have 5-8 carbon atom cycloalkenyl group, have 4-7 carbon atom cycloalkylalkyl, have 6-9 carbon atom cycloalkenyl alkyl, have 2-4 carbon atom hydroxyalkyl, have the fluoridizing hydroxyalkyl, have an alkylamino of 1-4 carbon atom of 2-4 carbon atom, wherein each alkyl has the dialkyl amido of 1-4 carbon atom independently, or Ar;

Condition is that 1-azabicyclo group is the quaternary ammonium form of following minor:

Wherein Z is the alkyl (for example methyl, ethyl, propyl group) with 1-4 carbon atom, the haloalkyl (for example chloromethyl, chloroethyl) with 1-4 carbon atom, the cycloalkylalkyl (for example cyclopropyl methyl) with 4-7 carbon atom or arylalkyl (for example benzyl) with 7-16 carbon atom, and negatively charged ion A is for example iodide ion, bromide anion, chlorion, trifluoromethanesulfonic acid root (triflate), tosylate or methanesulfonate.

According to another compound of the present invention and/or method aspect, described compound is selected from formula I-IV, wherein:

R ²If present, be H, have 1-4 carbon atom alkyl, have 1-4 carbon atom fluorinated alkyl, have 3-7 carbon atom cycloalkyl, have 4-7 carbon atom cycloalkylalkyl, fluoridize C _1-4-alkyl-CO-, C _3-7-cycloalkyl-CO-, C _1-4-alkyl-NH-CO-, C _3-7-cycloalkyl-NH-CO-, Het, Ar-C _1-4-alkyl-, Ar-C _1-4-alkyl-CO-, Ar-C _1-4-alkyl-SO ₂-, C _1-4-alkyl-O-C _1-4-alkyl-(CH for example ₂CH ₂-O-CH ₃) or Ar-C _1-4-alkyl-NH-CO-; And

Het is a heterocyclic radical, it is for saturated fully, fractional saturation or undersaturated fully, have 5-10 annular atoms, wherein at least one annular atoms is N, O or S atom, described heterocyclic radical are not substituted or are replaced one or many by following group: halogen, optional substituted aryl with 6-10 carbon atom, alkyl with 1-8 carbon atom, alkoxyl group with 1-8 carbon atom, cycloalkyl with 3-7 carbon atom, halogenated alkoxy with 1-8 carbon atom, cycloalkyloxy with 3-7 carbon atom, cycloalkyl alkoxy with 4-7 carbon atom, wherein each alkyl has alkyl (haloalkyl) amino of 1-8 carbon atom, wherein each alkyl has two (haloalkyl) amino of 1-8 carbon atom, (haloalkyl) amino with 1-8 carbon atom, cyano group, haloalkyl with 1-8 carbon atom, nitro, oxo, OH, alkoxycarbonyl alkyl with 3-8 carbon atom, amino, alkylamino with 1-8 carbon atom, wherein each alkyl has the dialkyl amido of 1-8 carbon atom, SO ₂R ¹¹,-CXR ¹¹, piperidyl ethyl or their combination.

In formula I-IV, group A, for example indazolyl, benzothiazolyl, benzisothiazole base, benzoisoxazole base, pyrazolo [3,4-b] pyridyl, pyrazolo [4,3-c] pyridyl or isothiazole [5,4-b] pyridyl also, can be connected with the rest part of this structure through any suitable tie point.

In formula I, when A is the group of minor (a) for example during indazolyl, it particularly is connected with the rest part of described compound through 3 preferably through 3,4 or 7.When A is the group of minor (b) for example during benzothiazolyl, it preferably is connected with the rest part of described compound through its 4 or 7.When A is the group of minor (c) for example during the benzisothiazole base, it particularly is connected with the rest part of described compound through 3 preferably through 3,4 or 7.When A is the group of minor (d) for example during the benzoisoxazole base, it particularly is connected with the rest part of described compound through 3 preferably through 3,4 or 7.

Similarly, in formula II, when A is the group of minor (a) for example during indazolyl, it particularly is connected with the rest part of described compound through 3 preferably through 3,4 or 7.When A is the group of minor (b) for example during benzothiazolyl, it preferably is connected with the rest part of described compound through its 4 or 7.When A is the group of minor (c) for example during the benzisothiazole base, it particularly is connected with the rest part of described compound through 3 preferably through 3,4 or 7.When A is the group of minor (d) for example during the benzoisoxazole base, it particularly is connected with the rest part of described compound through 3 preferably through 3,4 or 7.

Equally, in formula III, when A is the group of minor (a) for example during indazolyl, it particularly is connected with the rest part of described compound through 3 preferably through 3,4 or 7.When A is the group of minor (b) for example during benzothiazolyl, it preferably is connected with the rest part of described compound through its 4 or 7.When A is the group of minor (c) for example during the benzisothiazole base, it particularly is connected with the rest part of described compound through 3 preferably through 3,4 or 7.When A is the group of minor (d) for example during the benzoisoxazole base, it particularly is connected with the rest part of described compound through 3 preferably through 3,4 or 7.

In addition, in formula IV, when A is the group of minor (a) for example during indazolyl, it particularly is connected with the rest part of described compound through 3 preferably through 3,4 or 7.When A is the group of minor (b) for example during benzothiazolyl, it preferably is connected with the rest part of described compound through its 4 or 7.When A is the group of minor (c) for example during the benzisothiazole base, it particularly is connected with the rest part of described compound through 3 preferably through 3,4 or 7.When A is the group of minor (d) for example during the benzoisoxazole base, it particularly is connected with the rest part of described compound through 3 preferably through 3,4 or 7.

Following minor illustration A group for example indazole, benzothiazole, benzisothiazole, benzoisoxazole, pyrazolo [3,4-b] pyridyl, pyrazolo [3,4-c] pyridine, pyrazolo [4,3-c] pyridyl and isothiazole also some between the rest part of [5,4-b] pyridyl and formula I structure preferably be connected.In following each minor, R, R ¹, R ³And/or R ⁴Substituting group is general to be existed 1,2 or 3 time, and preferred 1 or 2 time, more preferably 1 time.

The further illustration of following minor A group for example indazole, benzothiazole, benzisothiazole, benzoisoxazole, pyrazolo [3,4-b] pyridyl, pyrazolo [3,4-c] pyridine, pyrazolo [4,3-c] pyridyl and isothiazole also some between the rest part of [5,4-b] pyridyl and formula II structure preferably be connected.In following each minor, R, R ¹, R ³And/or R ⁴Substituting group is general to be existed 1,2 or 3 time, and preferred 1 or 2 time, more preferably 1 time.

The further illustration of following minor A group for example indazole, benzothiazole, benzisothiazole, benzoisoxazole, pyrazolo [3,4-b] pyridyl, pyrazolo [3,4-c] pyridine, pyrazolo [4,3-c] pyridyl and isothiazole also some between the rest part of [5,4-b] pyridyl and formula III structure preferably be connected.In following each minor, R, R ¹, R ³And/or R ⁴Substituting group is general to be existed 1,2 or 3 time, and preferred 1 or 2 time, more preferably 1 time.

The further illustration of following minor A group for example indazole, benzothiazole, benzisothiazole, benzoisoxazole, pyrazolo [3,4-b] pyridyl, pyrazolo [3,4-c] pyridine, pyrazolo [4,3-c] pyridyl and isothiazole also some between the rest part of [5,4-b] pyridyl and formula IV structure preferably be connected.In following each minor, R, R ¹, R ³And/or R ⁴Substituting group is general to be existed 1,2 or 3 time, and preferred 1 or 2 time, more preferably 1 time.

In all cases, X is preferably O.

In all cases, R ' is preferably H, cyclopropyl methyl or CH ₃, H particularly.

Alkyl herein means has 1-8 carbon atom, the straight or branched aliphatic hydrocarbyl of preferred 1-4 carbon atom.Suitable alkyl includes but not limited to methyl, ethyl, propyl group, sec.-propyl, butyl, sec-butyl and the tertiary butyl.

Thiazolinyl herein means the straight or branched aliphatic hydrocarbyl that preferably has 2-6 carbon atom.Suitable thiazolinyl includes but not limited to vinyl, propenyl, butenyl and pentenyl.

Alkynyl herein means the straight or branched aliphatic hydrocarbyl that preferably has 2-6 carbon atom.Suitable alkynyl includes but not limited to acetylene (ethynyl), propine (proyl), butine (butynyl) etc.

Alkoxyl group means alkyl-O-group, and wherein moieties has 1-8 carbon atom, preferred 1-4 carbon atom.Suitable alkoxyl group includes but not limited to methoxyl group, oxyethyl group, propoxy-, isopropoxy, isobutoxy and sec-butoxy.

Alkoxyalkyl means alkyl-O-alkyl-group, and wherein each moieties has 1-8 carbon atom independently, preferred 1-4 carbon atom.Suitable alkoxyalkyl includes but not limited to methoxymethyl, ethoxyl methyl and methoxy ethyl.

Alkylthio means alkyl-S-group, and wherein moieties preferably has 1-4 carbon atom.Suitable alkylthio includes but not limited to methylthio group and ethylmercapto group.

Cycloalkyl means monocycle, dicyclo or the three ring filling alkyl with 3-7 carbon atom.Suitable cycloalkyl includes but not limited to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.Other suitable cycloalkyl include but not limited to spiral shell amyl group, dicyclo [2.1.0] amyl group and dicyclo [3.1.0] hexyl.

Cycloalkyloxy means cycloalkyl-O-group, and wherein cycloalkyl moiety is preferably monocycle, dicyclo or the three ring filling alkyl with 3-7 carbon atom.

Cycloalkylalkyl contains 4-7 carbon atom.Suitable cycloalkylalkyl includes but not limited to for example cyclopropyl methyl, cyclopropyl ethyl, cyclobutylmethyl and cyclopentyl-methyl.

Cycloalkyl alkoxy contains 4-7 carbon atom.Suitable cycloalkyl alkoxy includes but not limited to for example cyclo propyl methoxy, cyclopropyl oxyethyl group, cyclobutyl methoxy base and cyclopentyl methoxyl group.

Cycloalkyl and cycloalkylalkyl can be replaced by following group, for example: C _1-4-alkyl, C _1-4-alkoxyl group, hydroxyl, amino, have an alkylamino of 1-4 carbon atom and/or wherein each alkyl have the dialkyl amido of 1-4 carbon atom.

Aryl, itself as group or substituting group or as group or a substituent part (for example: Ar, OAr, Ar-C _1-6-alkyl-O-or Ar-C _1-6-alkyl-Het-O-), except as otherwise noted, refer to aromatic carbocyclyl groups with 6-10 carbon atom.Suitable aryl includes but not limited to phenyl, naphthyl and xenyl.The aryl that replaces comprises the above-mentioned aryl that is replaced one or many by following group: halogen, alkyl, hydroxyl, alkoxyl group, nitro, methylene-dioxy, ethylenedioxy, amino, alkylamino, dialkyl amido, hydroxyalkyl, hydroxy alkoxy base, carboxyl, cyano group, acyl group, carbalkoxy, alkylthio, alkyl sulphinyl, alkyl sulphonyl, phenoxy group and acyloxy (for example acetoxyl group).

Heterocyclic radical (for example Het, OHet, Het-C _1-6-alkyl-O-, Het-CO-Het-and Het-C _1-6-alkyl-NR ²The Het part) refer to saturated, fractional saturation and complete undersaturated heterocyclic group, it has 1,2 or 3 annular atoms that encircles and add up to 5-10, wherein at least one annular atoms is N, O or S atom.Preferably, this heterocyclic radical contains 1-3 heterocyclic atom that is selected from N, O and S.Suitable heterocyclic radical saturated and fractional saturation includes but not limited to dihydro pyranyl, THP trtrahydropyranyl, tetrahydrofuran base, tetrahydro-thienyl, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, isoxazoline-3-yl etc.Suitable heteroaryl includes but not limited to furyl, thienyl, thiazolyl, oxazolyl, pyrryl, pyrazolyl, imidazolyl, pyridyl, pyrimidyl, indyl, quinolyl, isoquinolyl, naphthyridinyl etc.Other examples of suitable heterocyclic radical are the 2-furyl, the 3-furyl, the 2-quinolyl, 1,3-Ben Bing Er Evil cyclopentadienyl (1,3-benzodioxyl), the 2-thienyl, the 3-thienyl, 1, the 3-thiazol-2-yl, 1,3-oxazole-2-base, tetramethyleneimine-1-base, 6-tetramethyleneimine-1-base, piperidines-1-base, 6-piperazine-1-base, morpholine-4-base, the 2-benzofuryl, the 2-benzothienyl, the 3-thienyl, 2,3-dihydro-5-benzofuryl, the 4-indyl, the 4-pyridyl, the 3-quinolyl, the 4-quinolyl, 1,4-benzodioxan-6-base, the 3-indyl, the 2-pyrryl, tetrahydrochysene-2H-pyrans-4-base, 3,6-dihydro-2H-pyrans-4-base, the 5-indyl, 1,5-benzo oxepin (benzoxepin)-8-base, the 3-pyridyl, 6-tonka bean camphor base, the 5-benzofuryl, the different imidazol-4 yl of 2-, the 3-pyrazolyl, the 3-carbazyl, hexahydropyrrolo also [1,2-a] pyrazine-2 (1H)-Ji, octahydro-6H-pyrrolo-[3,4-b] pyridine-6-base and 1,4-Diazesuberane-1-base (1,4-diazepan-1-yl).

Heterocyclic group also comprise replacement with unsubstituted azabicyclo and oxa-azabicyclo group, for example: 2,5-diazabicyclo [2.2.1] heptan-2-base, methyl-2,5-diazabicyclo [2.2.1] heptan-2-base, trifluoroethyl-2,5-diazabicyclo [2.2.1] heptan-2-base, 2-oxa--5-azabicyclo [2.2.1] heptan-5-base, 5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-base, 1,4-diazabicyclo [3.2.2] ninth of the ten Heavenly Stems-4-base, 5-methyl-2,5-diazabicyclo [2.2.2] suffering-2-base, 8-methyl-3,8-diazabicyclo [3.2.1] oct-3-yl, 5-cyclopropyl-2,5-diazabicyclo [2.2.1] heptan-2-base and 5-(cyclopropyl carbonyl)-2,5-diazabicyclo [2.2.1] heptan-2-base.

The heterocyclic radical that replaces is meant the above-mentioned heterocyclic radical that is replaced by following group in one or more positions, for example: halogen, aryl, alkyl, alkoxyl group, cyano group, trifluoromethyl, nitro, oxo, amino, alkylamino and/or dialkyl amido.The heterocyclic radical of suitable replacement comprises 2-methylpiperazine-1-base, 3-methylpiperazine-1-base, 4-methylpiperazine-1-base, 3,4-lupetazin-1-base, 4-methyl isophthalic acid, 4-Diazesuberane-1-base, 3-methoxyl group tetramethyleneimine-1-base, 1-methylpyrrolidin-3-base, 1-methyl-4,5-dihydro-1H-imidazoles-2-base, 3-(cyclo propyl methoxy) tetramethyleneimine-1-base, 6-chloroisothiazole also [5,4-b] pyridyl, 4-(cyclopropyl carbonyl) piperazine-1-base and 1-(cyclopropyl carbonyl) octahydro-6H-pyrrolo-[3,4-b] pyridine-6-base.

In each case, the suitable group that is substituted one or many preferably has 1-3 substituting group, particularly 1 or 2 illustrated substituting group.These substituting groups all are independent the selection in each case.Therefore, these substituting groups can be identical or different.Halo group such as haloalkyl are preferably fluorizated, and include but not limited to perhalogeno group such as trifluoromethyl.

According to another compound of the present invention and/or method aspect, R is not NH ₂Or NHCH ₃According to a further aspect in the invention, R is not NH ₂, NHCH ₃Or N (CH ₃) ₂According to a further aspect in the invention, R is not NH ₂, an alkylamino or dialkyl amido.

According to compound of the present invention and/or method aspect, R ²Be Het-NH-CO-.According to another compound of the present invention and/or method aspect, work as R ²When being Het-NH-CO-, the Het group is preferably the azabicyclo group, for example: 1-azabicyclo [2.2.2] oct-3-yl.

According to compound of the present invention and/or method aspect, the cycloalkylalkyl (for example cyclopropyl methyl) that Het is had 4-7 carbon atom replaces.According to another compound of the present invention and/or method aspect, when Het was replaced by cycloalkylalkyl, cycloalkyl moiety preferably had 3-5 carbon atom (for example cyclopropyl), and moieties preferably has 1-2 carbon atom.In addition, described Het group is preferably the azabicyclo group, for example: 2,5-diazabicyclo [2.2.1] heptan-2-base.

According to another compound of the present invention and/or method aspect, Het is a heterocyclic radical, it is saturated fully, fractional saturation or undersaturated fully, have 5-10 annular atoms, wherein at least one annular atoms is N, O or S atom, and described heterocyclic radical is substituted, and wherein at least one is halogenated alkoxy with 1-8 carbon atom (OCHF for example in the substituting group ₂), have 3-7 carbon atom cycloalkyloxy, have 4-7 carbon atom cycloalkyl alkoxy (for example cyclo propyl methoxy), have the cycloalkylalkyl (for example cyclopropyl methyl) of 4-7 carbon atom, non-trifluoromethyl haloalkyl (haloalkyl that for example has a 2-8 or 3-8 carbon atom, for example trifluoroethyl and trifluoro propyl), have the alkoxyalkyl (CH for example of 2-8 carbon atom ₃OCH ₂), wherein each alkyl has that the alkyl (haloalkyl) of 1-8 carbon atom is amino, wherein each alkyl has two (haloalkyls) amino of 1-8 carbon atom or has (haloalkyl) amino of 1-8 carbon atom.

According to another compound of the present invention and/or method aspect, described compound is selected from formula I-IV, wherein at least one R, R ¹, R ³, R ⁴And R ⁵Group is Het or OHet, wherein under every kind of replacement or unsubstituted situation, described Het group is selected from azabicyclo octyl group (for example 1-azabicyclo [2.2.2] oct-3-yl), oxa--azabicyclo heptyl (for example 2-oxa--5-azabicyclo [2.2.1] heptyl), diazabicyclo heptyl (for example 2,5-diazabicyclo [2.2.1] heptan-2-base, 5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-base, trifluoroethyl-2,5-diazabicyclo [2.2.1] heptan-2-base and 5-(cyclopropyl carbonyl)-2,5-diazabicyclo [2.2.1] heptan-2-yl), diazabicyclo nonyl (for example 1,4-diazabicyclo [3.2.2] ninth of the ten Heavenly Stems-4-yl), diazabicyclo octyl group (5-methyl-2 for example, 5-diazabicyclo [2.2.2] suffering-2-base and 8-methyl-3,8-diazabicyclo [3-2.1] oct-3-yl), pyrazolyl, the glyoxalidine base, 1,4-Diazesuberane base (for example 1,4-Diazesuberane-1-base and 4-methyl isophthalic acid, 4-Diazesuberane-1-yl), (for example hexahydropyrrolo also [1 for hexahydropyrrolo and pyrazinyl, 2-a] pyrazine-2 (1H)-yl) and octahydro pyrrolopyridinyl (for example 1-(cyclopropyl carbonyl)-octahydro-6H-pyrrolo-[3,4-b] pyridine-6-yl).

According to another compound of the present invention and/or method aspect, X ¹, X ², X ³And X ⁴In at least one is N; X ⁵, X ⁶, X ⁷And X ⁸In at least one is N; X ⁹, X ¹⁰, X ¹¹And X ¹²In at least one is N; And/or X ¹³, X ¹⁴, X ¹⁵And X ¹⁶In at least one is N.Another embodiment of this respect according to the present invention, X ¹, X ², X ³And X ⁴In at least one is N, remaining X ¹-X ⁴In one or two be CR ¹Another embodiment of this respect according to the present invention, X ⁵, X ⁶, X ⁷And X ⁸In at least one is N, remaining X ⁵-X ⁸In one or two be CR ³Another embodiment of this respect according to the present invention, X ⁹, X ¹⁰, X ¹¹And X ¹²In at least one is N, remaining X ⁹-X ¹²In one or two be CR ⁴Another embodiment of this respect according to the present invention, X ¹³, X ¹⁴, X ¹⁵And X ¹⁶In at least one is N, remaining X ¹³-X ¹⁶In one or two be CR.

According to another compound of the present invention and/or method aspect, X ⁴Be N and X ¹, X ²And X ³CH or CR respectively do for oneself ¹According to another compound of the present invention and/or method aspect, X ³Be N and X ¹, X ²And X ⁴CH or CR respectively do for oneself ¹

According to another compound of the present invention and/or method aspect, X ¹²Be N and X ⁹, X ¹⁰And X ¹¹CH or CR respectively do for oneself ⁴

According to another compound of the present invention and/or method aspect, Het is a heterocyclic radical, it is saturated fully, fractional saturation or undersaturated fully, have 5-10 annular atoms, wherein at least one annular atoms is N, O or S atom, and described heterocyclic radical is substituted, and wherein at least one is halogenated alkoxy with 1-8 carbon atom (OCHF for example in the substituting group ₂), have 3-7 carbon atom cycloalkyloxy, have the cycloalkyl alkoxy (for example cyclo propyl methoxy) of 4-7 carbon atom, non-trifluoromethyl haloalkyl (haloalkyl that for example has a 2-8 or 3-8 carbon atom, for example trifluoromethyl and trifluoro propyl), have the alkoxyalkyl (CH for example of 2-8 carbon atom ₃OCH ₂), wherein each alkyl has that the alkyl (haloalkyl) of 1-8 carbon atom is amino, wherein each alkyl has two (haloalkyls) amino of 1-8 carbon atom or has (haloalkyl) amino of 1-8 carbon atom.

According to another compound of the present invention and/or method aspect, Het is a heterocyclic radical, and it is fully saturated and for substituted, and wherein at least one is halogenated alkoxy with 1-8 carbon atom (OCHF for example in the substituting group ₂), have 3-7 carbon atom cycloalkyloxy, have the cycloalkyl alkoxy (for example cyclo propyl methoxy) of 4-7 carbon atom, non-trifluoromethyl haloalkyl (haloalkyl that for example has a 2-8 or 3-8 carbon atom, for example trifluoroethyl and trifluoro propyl), have the alkoxyalkyl (CH for example of 2-8 carbon atom ₃OCH ₂), wherein each alkyl has that the alkyl (haloalkyl) of 1-8 carbon atom is amino, wherein each alkyl has two (haloalkyls) amino of 1-8 carbon atom or has (haloalkyl) amino of 1-8 carbon atom.

According to another compound of the present invention and/or method aspect, Het is a heterocyclic radical, it is saturated fully, fractional saturation or undersaturated fully, have 5-10 annular atoms, wherein at least one annular atoms is N, O or S atom, and described heterocyclic radical is substituted, and wherein at least one is halogenated alkoxy with 1-8 carbon atom (OCHF for example in the substituting group ₂), have the cycloalkyl alkoxy (for example cyclo propyl methoxy) of 4-7 carbon atom, non-trifluoromethyl haloalkyl (haloalkyl that for example has a 2-8 or 3-8 carbon atom, for example trifluoroethyl and trifluoro propyl), have the alkoxyalkyl (CH for example of 2-8 carbon atom ₃OCH ₂) or wherein each alkyl have alkyl (haloalkyl) amino of 1-8 carbon atom.

According to another compound of the present invention and/or method aspect, Het is complete saturated heterocyclic radical, and described heterocyclic radical is substituted, and wherein at least one is halogenated alkoxy with 1-8 carbon atom (OCHF for example in the substituting group ₂), have the cycloalkyl alkoxy (for example cyclo propyl methoxy) of 4-7 carbon atom, non-trifluoromethyl haloalkyl (haloalkyl that for example has a 2-8 or 3-8 carbon atom, for example trifluoroethyl and trifluoro propyl), have the alkoxyalkyl (CH for example of 2-8 carbon atom ₃OCH ₂) or wherein each alkyl have alkyl (haloalkyl) amino of 1-8 carbon atom.

According to another compound of the present invention and/or method aspect, A is group and at least one R of formula (a) ¹Substituting group is a heterocyclic radical, described heterocyclic radical is saturated fully, fractional saturation or undersaturated fully, have 5-10 annular atoms, wherein at least one annular atoms is N, O or S atom, and described heterocyclic radical is substituted, and wherein at least one is halogenated alkoxy with 1-8 carbon atom (OCHF for example in the substituting group ₂), have 3-7 carbon atom cycloalkyloxy, have the cycloalkyl alkoxy (for example cyclo propyl methoxy) of 4-7 carbon atom, non-trifluoromethyl haloalkyl (haloalkyl that for example has a 2-8 or 3-8 carbon atom, for example trifluoroethyl and trifluoro propyl), have the alkoxyalkyl (CH for example of 2-8 carbon atom ₃OCH ₂), wherein each alkyl has that the alkyl (haloalkyl) of 1-8 carbon atom is amino, wherein each alkyl has two (haloalkyls) amino of 1-8 carbon atom or has (haloalkyl) amino of 1-8 carbon atom.

According to another compound of the present invention and/or method aspect, A is group and at least one R of formula (a) ¹Substituting group is complete saturated heterocyclic radical, and described heterocyclic radical is substituted, and wherein at least one is halogenated alkoxy with 1-8 carbon atom (OCHF for example in the substituting group ₂), have 3-7 carbon atom cycloalkyloxy, have the cycloalkyl alkoxy (for example cyclo propyl methoxy) of 4-7 carbon atom, non-trifluoromethyl haloalkyl (haloalkyl that for example has a 2-8 or 3-8 carbon atom, for example trifluoroethyl and trifluoro propyl), have the alkoxyalkyl (CH for example of 2-8 carbon atom ₃OCH ₂) or wherein each alkyl have alkyl (haloalkyl) amino of 1-8 carbon atom.

According to another compound of the present invention and/or method aspect, A is group and at least one R of formula (c) ⁴Substituting group is a heterocyclic radical, described heterocyclic radical is saturated fully, fractional saturation or undersaturated fully, have 5-10 annular atoms, wherein at least one annular atoms is N, O or S atom, and described heterocyclic radical is substituted, and wherein at least one is halogenated alkoxy with 1-8 carbon atom (OCHF for example in the substituting group ₂), have 3-7 carbon atom cycloalkyloxy, have the cycloalkyl alkoxy (for example cyclo propyl methoxy) of 4-7 carbon atom, non-trifluoromethyl haloalkyl (haloalkyl that for example has a 2-8 or 3-8 carbon atom, for example trifluoroethyl and trifluoro propyl), have the alkoxyalkyl (CH for example of 2-8 carbon atom ₃OCH ₂), wherein each alkyl has that the alkyl (haloalkyl) of 1-8 carbon atom is amino, wherein each alkyl has two (haloalkyls) amino of 1-8 carbon atom or has (haloalkyl) amino of 1-8 carbon atom.

According to another compound of the present invention and/or method aspect, A is group and at least one R of formula (c) ⁴Substituting group is complete saturated heterocyclic radical, and described heterocyclic radical is substituted, and wherein at least one is halogenated alkoxy with 1-8 carbon atom (OCHF for example in the substituting group ₂), have 3-7 carbon atom cycloalkyloxy, have the cycloalkyl alkoxy (for example cyclo propyl methoxy) of 4-7 carbon atom, non-trifluoromethyl haloalkyl (haloalkyl that for example has a 2-8 or 3-8 carbon atom, for example trifluoroethyl and trifluoro propyl), have the alkoxyalkyl (CH for example of 2-8 carbon atom ₃OCH ₂) or wherein each alkyl have alkyl (haloalkyl) amino of 1-8 carbon atom.

According to another compound of the present invention and/or method aspect, A is that group and at least one R substituting group of formula (d) is OH, O-(C _1-6-alkyl-O) _1-2-C _1-6-alkyl ,-O-C _1-6-alkyl-NR ⁶R ⁷, have an alkoxyl group (OCH for example of 1-4 carbon atom ₃), have 3-7 carbon atom cycloalkyloxy, have 4-7 carbon atom cycloalkyl alkoxy (for example cyclo propyl methoxy), have a 1-4 carbon atom fluoridize alkoxyl group (OCF for example ₃, OCHF ₂), have 1-4 carbon atom hydroxyalkyl, have 1-4 carbon atom fluoridize hydroxyalkyl, have 2-4 carbon atom the hydroxy alkoxy base, have a 2-4 carbon atom fluoridize hydroxy alkoxy base, OAr, OHet, Carbo-O, Ar-C _1-6-alkyl-O-, Het-C _1-6-alkyl-O-or Ar-C _1-6-alkyl-Het-O-.

According to another compound of the present invention and/or method aspect, A is that group and at least one R substituting group of formula (d) is OH, O-(C _1-6-alkyl-O) _1-2-C _1-6-alkyl, has the alkoxyl group (OCH for example of 1-4 carbon atom ₃), have 3-7 carbon atom cycloalkyloxy, have 4-7 carbon atom cycloalkyl alkoxy (for example cyclo propyl methoxy), have a 1-4 carbon atom fluoridize alkoxyl group (OCF for example ₃, OCHF ₂), have the hydroxy alkoxy base of 2-4 carbon atom or fluoridize the hydroxy alkoxy base.

According to another compound of the present invention and/or method aspect, A is that group and at least one R substituting group of formula (d) is OH, has an alkoxyl group (OCH for example of 1-4 carbon atom ₃), have a 1-4 carbon atom fluoridize alkoxyl group (OCF for example ₃, OCHF ₂), have the hydroxy alkoxy base of 2-4 carbon atom or fluoridize the hydroxy alkoxy base.

According to another compound of the present invention and/or method aspect, A is group and at least one R of formula (a) ¹Substituting group is the glyoxalidine base.

According to another compound of the present invention and/or method aspect, A is group and at least one R of formula (a) ¹Substituting group is the Het of non-thiazolyl, and R wherein ²Be alkyl, fluorinated alkyl, cycloalkyl, cycloalkylalkyl, fluoridize C with 4-7 carbon atom with 3-7 carbon atom with 1-4 carbon atom with 2-4 carbon atom _1-4-alkyl-CO-, C _3-7-cycloalkyl-CO-, C _1-4-alkyl-NH-CO-, C _3-7-cycloalkyl-NH-CO-, Het, Ar-C _1-4-alkyl-, Ar-C _1-4-alkyl-CO-, Ar-C _1-4-alkyl-SO ₂-, C _1-4-alkyl-O-C _1-4-alkyl-(CH for example ₂CH ₂-O-CH ₃) or Ar-C _1-4-alkyl-NH-CO-.

According to another compound of the present invention and/or method aspect, A is group and at least one R of formula (c) ⁴Substituting group is imidazolyl (for example imidazoles-1-yl), pyrryl, pyrazolyl, C _1-8Alkyl-pyrazolyl (for example 3-methyl isophthalic acid H-pyrazol-1-yl, 5-methyl isophthalic acid H-pyrazol-1-yl), oxa--azabicyclo heptyl (for example 2-oxa--5-azabicyclo [2.2.1] heptyl), diazabicyclo heptyl (for example 2,5-diazabicyclo [2.2.1] heptan-2-yl), C _1-8Alkyl-diazabicyclo heptyl (5-methyl-2 for example, 5-diazabicyclo [2.2.1] heptan-2-yl), halo C _1-8Alkyl-diazabicyclo heptyl (trifluoroethyl-2 for example, 5-diazabicyclo [2.2.1] heptan-2-base, by amino, an alkylamino (C _1-8Alkyl-NH-) or dialkyl amido ((C _1-8Alkyl) ₂N-) piperidyl of Qu Daiing (for example (4-dimethylamino) piperidines-1-yl) is perhaps by hydroxyl, halogenated alkoxy, cycloalkyl alkoxy, amino, an alkylamino (C _1-8Alkyl-NH-), dialkyl amido ((C _1-8Alkyl) ₂N-), the amino pyrrolidyl that replaces of alkoxyalkyl or alkyl (fluorinated alkyl) (3-(cyclo propyl methoxy) tetramethyleneimine-1-base for example, 3-(hydroxyl) tetramethyleneimine-1-base (3-(3R)-hydroxyl pyrrolidine-1-base for example, 3-(3S)-hydroxyl pyrrolidine-1-yl), 3-(difluoro-methoxy) tetramethyleneimine-1-yl), 3-(dimethylamino) tetramethyleneimine-1-base (3-(3S)-(dimethylamino) tetramethyleneimine-1-base for example, 3-(3R)-(dimethylamino) tetramethyleneimine-1-base, 3-methylamino tetramethyleneimine-1-base, 3-(methoxymethyl) tetramethyleneimine-1-base, 3-[methyl (2,2, the 2-trifluoroethyl) amino] tetramethyleneimine-1-yl).

According to a further aspect in the invention, described compound is the compound of formula I-IV, but 1-azabicyclo group is the quaternary ammonium form of following minor:

Wherein Z is the alkyl (for example methyl, ethyl, propyl group) with 1-4 carbon atom, the haloalkyl (for example chloromethyl, chloroethyl) with 1-4 carbon atom, the cycloalkylalkyl (for example cyclopropyl methyl) with 4-7 carbon atom or arylalkyl (for example benzyl) with 7-16 carbon atom, and negatively charged ion A is iodide ion, bromide anion, chlorion, trifluoromethanesulfonic acid root, tosylate or methanesulfonate.In this embodiment, group A is preferably formula (a) or group (c).Equally, X ¹To X ⁴Be preferably CH or CR separately ¹, and X ⁹To X ¹²Be preferably CH or CR separately ⁴

According to a further aspect in the invention, described compound is selected from the compound according to the formula Ip of following subclass:

(i) X ¹³-X ¹⁶Respectively do for oneself CH or CR, wherein X at least ¹³-X ¹⁶In one be not CH;

X is O;

R ' is H, alkyl (CH for example ₃Or C ₂H ₅, CH particularly ₃) or cycloalkylalkyl (for example cyclopropyl methyl, cyclobutylmethyl, cyclopentyl-methyl or cyclopropyl ethyl, particularly cyclopropyl methyl); And

At least one R is alkoxyl group (OCH for example ₃) or Het (3-methoxyl group-tetramethyleneimine-1-base for example

[for example (3R)-3-methoxyl group tetramethyleneimine-1-base, (3S)-3-methoxyl group tetramethyleneimine-1-yl].

According to a further aspect in the invention, described compound is selected from the compound according to the formula Ia-Ij of following subclass:

(i) X is O;

X ¹-X ⁴In one be N, perhaps X ⁹-X ¹²In one be N, and X ¹-X ⁴Or X ⁹-X ¹²In other groups be CH, CR ¹Or CR ⁴

R ' is H, alkyl (CH for example ₃Or C ₂H ₅, CH particularly ₃) or cycloalkylalkyl (for example cyclopropyl methyl, cyclobutylmethyl, cyclopentyl-methyl or cyclopropyl ethyl, particularly cyclopropyl methyl);

R ²Be H; And

R ¹And R ⁴Be independently selected from H, halogen (for example Cl or F), Ar (for example phenyl) or Het (for example 3-dimethylamino tetramethyleneimine-1-yl).

According to another compound of the present invention and/or method aspect, described compound is selected from following subclass:

(a) according to the compound of formula I, X wherein ¹, X ², X ³And X ⁴In at least one is N;

(b) according to the compound of formula Ia, X wherein ¹, X ², X ³And X ⁴In at least one is N;

(c) according to the compound of formula Ij, X wherein ¹, X ², X ³And X ⁴In at least one is N;

(d) according to the compound of formula I, X wherein ⁵, X ⁶, X ⁷And X ⁸In at least one is N;

(e) according to the compound of formula I, X wherein ⁹, X ¹⁰, X ¹¹And X ¹²In at least one is N;

(f) according to the compound of formula I, X wherein ¹³, X ¹⁴, X ¹⁵And X ¹⁶In at least one is N;

(g) according to the compound of formula I, X wherein ¹, X ², X ³And X ⁴In at least one is N and all the other X ¹-X ⁴In one or two be CR ¹

(h) according to the compound of formula Ia, X wherein ¹, X ², X ³And X ⁴In at least one is N and all the other X ¹-X ⁴In one or two be CR ¹

(i) according to the compound of formula Ij, X wherein ¹, X ², X ³And X ⁴In at least one is N and all the other X ¹-X ⁴In one or two be CR ¹

(j) according to the compound of formula I, X wherein ⁵, X ⁶, X ⁷And X ⁸In at least one is N and all the other X ⁵-X ⁸In one or two be CR ³

(k) according to the compound of formula I, X wherein ⁹, X ¹⁰, X ¹¹And X ¹²In at least one is N and all the other X ⁹-X ¹²In one or two be CR ⁴

(l) according to the compound of formula I, X wherein ¹³, X ¹⁴, X ¹⁵And X ¹⁶In at least one is N and all the other X ¹³-X ¹⁶In one or two be CR;

(m) according to the compound of formula I, X wherein ⁴Be N, and X ¹, X ²And X ³CH or CR respectively do for oneself ¹

(n) according to the compound of formula Ia, X wherein ⁴Be N, and X ¹, X ²And X ³CH or CR respectively do for oneself ¹

(o) according to the compound of formula Ij, X wherein ¹²Be N, and X ⁹, X ¹⁰And X ¹¹CH or CR respectively do for oneself ⁴

(p) according to the compound of formula Ia, X wherein ³Be N, and X ¹, X ²And X ⁴CH or CR respectively do for oneself ¹

(q) according to the compound of formula Ia or Ij, its at least one R ¹Or R ⁴Be that at least one is halogenated alkoxy with 1-8 carbon atom (OCHF for example in the Het that replaces and the Het substituting group ₂), have 3-7 carbon atom cycloalkyloxy, have the cycloalkyl alkoxy (for example cyclo propyl methoxy) of 4-7 carbon atom, non-trifluoromethyl haloalkyl (haloalkyl that for example has a 2-8 or 3-8 carbon atom is as trifluoroethyl), have the alkoxyalkyl (CH for example of 2-8 carbon atom ₂OCH ₃), wherein each alkyl has that the alkyl (haloalkyl) of 1-8 carbon atom is amino, wherein each alkyl has two (haloalkyls) amino of 1-8 carbon atom or has (haloalkyl) amino of 1-8 carbon atom;

(r) according to the compound of formula Ia or Ij, its at least one R ¹Or R ⁴Be that at least one is halogenated alkoxy with 1-8 carbon atom (OCHF for example in the Het that replaces and the Het substituting group ₂), have the cycloalkyl alkoxy (for example cyclo propyl methoxy) of 4-7 carbon atom, non-trifluoromethyl haloalkyl (haloalkyl that for example has a 2-8 or 3-8 carbon atom is as trifluoroethyl), have the alkoxyalkyl (CH for example of 2-8 carbon atom ₂OCH ₃) or wherein each alkyl have alkyl (haloalkyl) amino of 1-8 carbon atom;

(s) according to the compound of formula Ia or Ij, its at least one R ¹Or R ⁴Be that at least one is halogenated alkoxy with 1-8 carbon atom (OCHF for example in the complete saturated Het group (for example pyrrolidyl or piperidyl) that replaces and the Het substituting group ₂), have 3-7 carbon atom cycloalkyloxy, have the cycloalkyl alkoxy (for example cyclo propyl methoxy) of 4-7 carbon atom, non-trifluoromethyl haloalkyl (haloalkyl that for example has a 2-8 or 3-8 carbon atom is as trifluoroethyl), have the alkoxyalkyl (CH for example of 2-8 carbon atom ₂OCH ₃), wherein each alkyl has that the alkyl (haloalkyl) of 1-8 carbon atom is amino, wherein each alkyl has two (haloalkyls) amino of 1-8 carbon atom or has (haloalkyl) amino of 1-8 carbon atom;

(t) according to the compound of formula Ia or Ij, its at least one R ¹Or R ⁴Be that at least one is halogenated alkoxy with 1-8 carbon atom (OCHF for example in the complete saturated Het group (for example pyrrolidyl) that replaces and the Het substituting group ₂), have the cycloalkyl alkoxy (for example cyclo propyl methoxy) of 4-7 carbon atom, non-trifluoromethyl haloalkyl (haloalkyl that for example has a 2-8 or 3-8 carbon atom is as trifluoroethyl), have the alkoxyalkyl (CH for example of 2-8 carbon atom ₂OCH ₃) or wherein each alkyl have alkyl (haloalkyl) amino of 1-8 carbon atom;

(u) according to the compound of formula Ip, its at least one R substituting group is OH, O-(C _1-6-alkyl-O) _1-2-C _1-6-alkyl ,-O-C _1-6-alkyl-NR ⁶R ⁷, have an alkoxyl group (OCH for example of 1-4 carbon atom ₃), have 3-7 carbon atom cycloalkyloxy, have 4-7 carbon atom cycloalkyl alkoxy (for example cyclo propyl methoxy), have a 1-4 carbon atom fluoridize alkoxyl group (OCF for example ₃, OCHF ₂), have 1-4 carbon atom hydroxyalkyl, have 1-4 carbon atom fluoridize hydroxyalkyl, have 2-4 carbon atom the hydroxy alkoxy base, have a 2-4 carbon atom fluoridize hydroxy alkoxy base, OAr, OHet, Carbo-O, Ar-C _1-6-alkyl-O-, Het-C _1-6-alkyl-O-or Ar-C _1-6-alkyl-Het-O-;

(v) according to the compound of formula Ip, its at least one R substituting group is OH, O-(C _1-6-alkyl-O) _1-2-C _1-6-alkyl, has the alkoxyl group (OCH for example of 1-4 carbon atom ₃), have 3-7 carbon atom cycloalkyloxy, have 4-7 carbon atom cycloalkyl alkoxy (for example cyclo propyl methoxy), have a 1-4 carbon atom fluoridize alkoxyl group (OCF for example ₃, OCHF ₂), have the hydroxy alkoxy base of 2-4 carbon atom or fluoridize the hydroxy alkoxy base;

(w) according to the compound of formula Ip, its at least one R substituting group is OH, have the alkoxyl group of 1-4 carbon atom (OCH for example ₃), have a 1-4 carbon atom fluoridize alkoxyl group (OCF for example ₃, OCHF ₂) or have the hydroxy alkoxy base of 2-4 carbon atom or fluoridize the hydroxy alkoxy base;

(x) according to the compound of formula Ia, its at least one R substituting group is the glyoxalidine base;

(y) according to the compound of formula Ia, its at least one R ¹Substituting group is the Het of non-thiazolyl, and R wherein ²Be alkyl, fluorinated alkyl, cycloalkyl, cycloalkylalkyl, fluoridize C with 4-7 carbon atom with 3-7 carbon atom with 1-4 carbon atom with 2-4 carbon atom _1-4-alkyl-CO-, C _3-7-cycloalkyl-CO-, C _1-4-alkyl-NH-CO-, C _3-7-cycloalkyl-NH-CO-, Het, Ar-C _1-4-alkyl-, Ar-C _1-4-alkyl-CO-, Ar-C _1-4-alkyl-SO ₂-, C _1-4-alkyl-O-C _1-4-alkyl-(CH for example ₂CH ₂-O-CH ₃) or Ar-C _1-4-alkyl-NH-CO-;

(z) according to the compound of formula Ij, its at least one R ⁴Substituting group is imidazolyl (for example imidazoles-1-yl), pyrryl, pyrazolyl, C _1-8Alkyl-pyrazolyl (for example 3-methyl isophthalic acid H-pyrazol-1-yl, 5-methyl isophthalic acid H-pyrazol-1-yl), oxa--azabicyclo heptyl (for example 2-oxo-5-azabicyclo [2-2.1] heptyl), 2,5-diazabicyclo [2.2.1] heptan-2-base, C _1-8Alkyl-diazabicyclo heptyl (5-methyl-2 for example, 5-diazabicyclo [2.2.1] heptan-2-yl), halo C _1-8Alkyl-diazabicyclo heptyl (trifluoroethyl-2 for example, 5-diazabicyclo [2.2.1] heptan-2-yl), by amino, an alkylamino (C _1-8Alkyl-NH-) or dialkyl amido (C _1-8Alkyl) ₂N-) piperidyl of Qu Daiing (for example (4-dimethylamino) piperidines-1-yl) or by hydroxyl, halogenated alkoxy, cycloalkyl alkoxy, amino, an alkylamino (C _1-8Alkyl-NH-), dialkyl amido ((C _1-8Alkyl) ₂N-), the amino pyrrolidyl that replaces of alkoxyalkyl or alkyl (fluorinated alkyl) (3-(cyclo propyl methoxy) tetramethyleneimine-1-base for example, 3-(hydroxyl) tetramethyleneimine-1-base (3-(3R)-hydroxyl pyrrolidine-1-base for example, 3-(3S)-hydroxyl pyrrolidine-1-yl), 3-(difluoro-methoxy) tetramethyleneimine-1-base, 3-(dimethylamino) tetramethyleneimine-1-base (3-(3S)-(dimethylamino) tetramethyleneimine-1-base for example, 3-(3R)-(dimethylamino) tetramethyleneimine-1-yl), 3-methylamino tetramethyleneimine-1-base, 3-(methoxymethyl) tetramethyleneimine-1-base, 3-[methyl (2,2, the 2-trifluoroethyl) amino] tetramethyleneimine-1-yl);

(aa) according to arbitrary subclass in the above-mentioned subclass (a)-(z), wherein X is O; With

(ab) according to arbitrary subclass in the above-mentioned subclass (a)-(aa), wherein R ' is H or alkyl, particularly H.

According to compound of the present invention and/or method aspect, the compound of formula I-IV is selected from:

1) (3S)-3-({ [6-(cyclo propyl methoxy)-1,2-benzisothiazole-3-yl] carbonyl } amino)-1-(cyclopropyl methyl)-1-azonia dicyclo [2.2.2] octane bromide or formate,

2) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(3-methoxyl group tetramethyleneimine-1-yl)-1,2-benzisothiazole-3-methane amide,

3) N-[(3S)-and 1-azabicyclo [2.2.2] oct-3-yl]-5,6-dimethoxy-1H-indazole-3-methane amide formate,

4) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-1-propyl group-6-(1,3-thiazoles-2-yl)-1H-indazole-3-methane amide,

5) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-1-sec.-propyl-6-(1,3-thiazoles-2-yl)-1H-indazole-3-methane amide,

6) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(tetrahydrofuran (THF)-3-base oxygen base)-1H-indazole-3-methane amide formate,

7) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(tetrahydrochysene-2H-pyrans-4-base oxygen base)-1N-indazole-3-methane amide formate,

8) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(1-methylpyrrolidin-3-yl) the oxygen base]-1H-indazole-3-methane amide formate,

9) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-4-hydroxyl-1H-indazole-3-methane amide formate,

10) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-5-bromo-4-hydroxyl-1H-indazole-3-methane amide formate,

11) N-[(3S)-and 1-azabicyclo [2.2.2] oct-3-yl]-5,7-two bromo-4-hydroxyls-1H-indazole-3-methane amide formate,

12) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-5-hydroxyl-1,2-benzisothiazole-3-methane amide formate,

13) (3S)-and 3-{[(5-hydroxyl-1,2-benzisothiazole-3-yl) carbonyl] amino }-1-methyl isophthalic acid-azonia dicyclo [2.2.2] octane iodide or formate,

14) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(3-furyl methoxyl group)-1,2-benzisothiazole-3-methane amide formate,

15) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-1-ethyl-6-(2-oxo-pyrrolidine-1-yl)-1H-indazole-3-methane amide formate,

16) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-7-hydroxyl-1H-indazole-3-methane amide formate,

17) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-methoxyl group-N-methyl isophthalic acid H-indazole-3-methane amide formate,

18) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-1-methyl-6-{[(propyl group amino) carbonyl] amino }-1H-indazole-3-methane amide formate,

19) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-1-ethyl-6-methoxyl group-1H-indazole-3-methane amide,

20) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-1-ethyl-6-methoxyl group-1H-indazole-3-methane amide,

21) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-1-(difluoromethyl)-6-methoxyl group-1H-indazole-3-methane amide,

22) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-1-(difluoromethyl)-6-(1,3-thiazoles-2-yl)-1H-indazole-3-methane amide,

23) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-the 6-[(cyclopropyl carbonyl) amino]-1-methyl isophthalic acid H-indazole-3-methane amide formate,

24) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-the 6-[(cyclopropyl carbonyl) amino]-1-(difluoromethyl)-1H-indazole-3-methane amide formate,

25) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-1-(difluoromethyl)-6-{[(propyl group amino) carbonyl] amino }-1H-indazole-3-methane amide formate,

26) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-1-cyclopropyl-6-(1,3-thiazoles-2-yl)-1H-indazole-3-methane amide,

27) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(1,3-thiazoles-2-yl)-1-(3-thienyl)-1H-indazole-3-methane amide,

28) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-N-methyl-6-(1,3-oxazole-2-yl)-1H-indazole-3-methane amide,

29) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-N-methyl-6-(1,3-thiazoles-2-yl)-1H-indazole-3-methane amide,

30) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-1-ethyl-6-(1,3-oxazole-2-yl)-1H-indazole-3-methane amide,

31) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-1-(cyclopropyl methyl)-6-(1,3-oxazole-2-yl)-1H-indazole-3-methane amide,

32) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(1,3-oxazole-2-yl)-1-propyl group-1H-indazole-3-methane amide,

33) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-1-ethyl-N-methyl-6-(1,3-oxazole-2-yl)-1H-indazole-3-methane amide,

34) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-N-methyl-6-(tetrahydrochysene-2H-pyrans-4-yl)-1H-indazole-3-methane amide,

35) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-N-methyl-5-(tetrahydrochysene-2H-pyrans-4-yl)-1H-indazole-3-methane amide,

36) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-5-(difluoro-methoxy)-N-methyl isophthalic acid H-indazole-3-methane amide,

37) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(difluoro-methoxy)-N-methyl isophthalic acid H-indazole-3-methane amide,

38) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-1-cyclopropyl-6-[(cyclopropyl carbonyl) amino]-1H-indazole-3-methane amide,

39) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-1-cyclopropyl-6-{[(propyl group amino) carbonyl] amino }-1H-indazole-3-methane amide,

40) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-5-methoxyl group-N-methyl isophthalic acid H-indazole-3-methane amide,

41) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(4S)-4-hydroxyl-2-oxo-pyrrolidine-1-yl]-1H-indazole-3-methane amide formate,

42) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-5-methoxyl group-N-methyl isophthalic acid H-indazole-3-methane amide formate,

43) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-5-(difluoro-methoxy)-N-methyl isophthalic acid H-indazole-3-methane amide formate,

44) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-(difluoro-methoxy)-N-methyl isophthalic acid H-indazole-3-methane amide formate,

45) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-N-methyl-6-(tetrahydrochysene-2H-pyrans-4-yl)-1H-indazole-3-methane amide formate,

46) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-N-methyl-5-(tetrahydrochysene-2H-pyrans-4-yl)-1H-indazole-3-methane amide formate,

47) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-N-methyl-6-(1,3-thiazoles-2-yl)-1H-indazole-3-methane amide formate,

48) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-methoxyl group-N-methyl isophthalic acid, 2-benzisothiazole-3-methane amide formate,

49) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(3-methoxyl group tetramethyleneimine-1-yl)-1,2-benzisothiazole-3-carboxamide hydrochloride,

50) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-hydroxyl-1,2-benzisothiazole-3-methane amide,

51) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-methoxyl group-1,2-benzisothiazole-3-carboxamide hydrochloride,

52) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-methoxyl group-1,2-benzisothiazole-3-carboxamide hydrochloride,

53) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-7-methoxyl group-1,2-benzisothiazole-3-carboxamide hydrochloride,

54) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(2-oxygen-3-propyl imidazole quinoline-1-yl)-1,2-benzisothiazole-3-carboxamide hydrochloride,

55) N-[(3S)-1-oxidation-1-azabicyclo [2.2.2] oct-3-yl]-5-(trifluoromethoxy)-1H-indazole-3-methane amide and

56) 6-methoxyl group-N-[(3S)-1-oxidation-1-azabicyclo [2.2.2] oct-3-yl]-1,2-benzisothiazole-3-methane amide,

Wherein above listed salt also can be free alkali form or another kind of pharmacologically acceptable salts form, and above listed free alkali form also can be the pharmacologically acceptable salts form,

Wherein above listed compound (free alkali form or pharmacologically acceptable salts form) also can be solvate (for example hydrate) form,

Wherein above listed compound (free alkali form or pharmacologically acceptable salts form) also can be the N-oxide form,

Wherein above listed compound (its free alkali form or solvate or N-oxide compound or its pharmacologically acceptable salts or solvate form thereof) also can be the polymorphic form form, and

If wherein described compound exhibits chirality, it can be the mixture (for example racemoid) of enantiomer or the form of mixtures of diastereomer, or can be single enantiomer or single diastereomeric form.

According to another compound of the present invention and/or method aspect, the compound of formula I-IV is selected from:

7) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(tetrahydrochysene-2H-pyrans-4-base oxygen base)-1H-indazole-3-methane amide formate,

49) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(3-methoxyl group tetramethyleneimine-1-yl)-1,2-benzisothiazole-3-carboxamide hydrochloride and

Wherein above listed compound (free alkali form or its solvate, or pharmacologically acceptable salts form or its solvate) also can be the polymorphic form form, and

57) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-fluoro-1H-pyrazolo [3,4-b] pyridine-3-carboxamide formate,

58) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[3-(cyclo propyl methoxy) tetramethyleneimine-1-yl]-1H-indazole-3-methane amide formate,

59) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-1H-pyrazolo [4,3-c] pyridine-3-carboxamide,

60) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-1H-pyrazolo [3,4-c] pyridine-3-carboxamide formate,

61) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-[3-(cyclo propyl methoxy) tetramethyleneimine-1-yl]-1H-indazole-3-methane amide formate,

62) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-(3-methoxyl group tetramethyleneimine-1-yl)-1H-indazole-3-methane amide formate,

63) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-(2-oxo-3-propyl imidazole alkane-1-yl)-1H-indazole-3-methane amide formate,

64) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-tetramethyleneimine-1-base-1,2-benzisothiazole-3-methane amide,

65) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(3-methyl-2-oxo-pyrrolidine-1-yl)-1,2-benzisothiazole-3-methane amide,

66) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(1H-pyrroles-1-yl)-1,2-benzisothiazole-3-methane amide,

67) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(3-ethyl-2-oxo imidazolidine-1-yl)-1,2-benzisothiazole-3-methane amide,

68) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[3-(cyclo propyl methoxy) tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-methane amide,

69) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(3-methoxyl group tetramethyleneimine-1-yl)-1,2-benzoisoxazole-3-methane amide,

70) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-7-(3-methoxyl group tetramethyleneimine-1-yl)-1,2-benzisothiazole-3-methane amide,

71) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-methoxyl group-1,2-benzoisoxazole-3-carboxamide hydrochloride,

72) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-(3-methoxyl group tetramethyleneimine-1-yl)-1,2-benzisothiazole-3-methane amide,

73) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-1-ethyl-6-(1,3-oxazole-2-yl)-1H-indazole-3-methane amide formate,

74) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-1-ethyl-6-(1,3-oxazole-2-yl)-1H-indazole-3-carboxamide hydrochloride,

75) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(3R)-and 3-methoxyl group tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-methane amide,

76) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(3S)-and 3-methoxyl group tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-methane amide,

77) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(2-oxo-3-propyl imidazole alkane-1-yl)-1H-indazole-3-methane amide,

78) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(3-hydroxyl pyrrolidine-1-yl)-1,2-benzisothiazole-3-methane amide,

79) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[3-(difluoro-methoxy) tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-methane amide,

80) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(1H-imidazoles-1-yl)-1,2-benzisothiazole-3-methane amide,

81) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(1H-pyrazol-1-yl)-1,2-benzisothiazole-3-methane amide,

82) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(3-methyl isophthalic acid H-pyrazol-1-yl)-1,2-benzisothiazole-3-methane amide,

83) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(5-methyl isophthalic acid H-pyrazol-1-yl)-1,2-benzisothiazole-3-methane amide,

84) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(3R)-and 3-methoxyl group tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-methane amide,

85) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(3S)-and 3-methoxyl group tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-methane amide,

86) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-methoxyl group-1,2-benzoisoxazole-3-methane amide,

87) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(3-oxyethyl group tetramethyleneimine-1-yl)-7-fluoro-1,2-benzisothiazole-3-methane amide,

88) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-phenyl-1H-pyrazolo [3,4-b] pyridine-3-carboxamide,

89) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-(4,5-dihydro-1H-imidazoles-2-yl)-1H-indazole-3-methane amide,

90) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[3-(dimethylamino) tetramethyleneimine-1-yl]-1H-pyrazolo [3,4-b] pyridine-3-carboxamide,

91) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-[3-(dimethylamino) tetramethyleneimine-1-yl]-1H-pyrazolo [3,4-b] pyridine-3-carboxamide,

92) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-7-fluoro-6-(3-methoxyl group tetramethyleneimine-1-yl)-1,2-benzisothiazole-3-methane amide,

93) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-7-fluoro-6-(3-methoxyl group tetramethyleneimine-1-yl)-1,2-benzisothiazole-3-methane amide,

94) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(3R)-and 3-hydroxyl pyrrolidine-1-yl]-1,2-benzisothiazole-3-methane amide,

95) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(3S)-and 3-hydroxyl pyrrolidine-1-yl]-1,2-benzisothiazole-3-methane amide,

96) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(3S)-and 3-(dimethylamino) tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-methane amide,

97) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(1S, 4S)-the 2-oxa--5-azabicyclo [2.2.1] heptan-5-yl]-1,2-benzisothiazole-3-methane amide,

98) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(3R)-and 3-hydroxyl pyrrolidine-1-yl]-1,2-benzisothiazole-3-methane amide,

99) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(3S)-and 3-hydroxyl pyrrolidine-1-yl]-1,2-benzisothiazole-3-methane amide,

100) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(3S)-and 3-(dimethylamino) tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-methane amide,

101) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-7-[(3R)-and 3-hydroxyl pyrrolidine-1-yl]-1,2-benzisothiazole-3-methane amide,

102) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-7-[(3S)-and 3-hydroxyl pyrrolidine-1-yl]-1,2-benzisothiazole-3-methane amide,

103) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-7-[(3S)-and 3-(dimethylamino) tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-methane amide,

104) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-7-[(1S, 4S)-the 2-oxa--5-azabicyclo [2.2.1] heptan-5-yl]-1,2-benzisothiazole-3-methane amide,

105) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-7-[(3S)-and 3-(dimethylamino) tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-methane amide,

106) N-[(3S)-and 1-azabicyclo [2.2.2] oct-3-yl] isothiazole [5,4-b] pyridine-3-carboxamide formate also,

107) N-[(3R)-and 1-azabicyclo [2.2.2] oct-3-yl] isothiazole [5,4-b] pyridine-3-carboxamide formate also,

108) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(3R)-and 3-methoxyl group tetramethyleneimine-1-yl]-1,2-benzoisoxazole-3-methane amide,

109) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(3S)-and 3-methoxyl group tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-mexolamine,

110) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-7-[(3R)-and 3-methoxyl group tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-methane amide formate,

111) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-7-[(3S)-and 3-methoxyl group tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-methane amide,

112) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-7-[(3R)-and 3-methoxyl group tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-methane amide formate,

113) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-7-[(3S)-and 3-methoxyl group tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-methane amide formate,

114) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-7-fluoro-6-methoxyl group-1,2-benzisothiazole-3-methane amide,

115) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-7-fluoro-6-methoxyl group-1,2-benzisothiazole-3-methane amide,

116) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(1S, 4S)-5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl]-1,2-benzisothiazole-3-methane amide,

117) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(1S, 4S)-5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl]-1,2-benzisothiazole-3-methane amide,

118) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(1S, 4S)-2,5-diazabicyclo [2.2.1] heptan-2-yl]-1,2-benzisothiazole-3-methane amide,

119) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(1S, 4S)-2,5-diazabicyclo [2.2.1] heptan-2-yl]-1,2-benzisothiazole-3-methane amide,

120) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[3-(methylamino) tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-methane amide,

121) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-[3-(methylamino) tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-methane amide,

122) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(1S, 4S)-5-(2,2, the 2-trifluoroethyl)-2,5-diazabicyclo [2.2.1] heptan-2-yl]-1,2-benzisothiazole-3-methane amide,

123) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-{3-[methyl (2,2, the 2-trifluoroethyl) amino] tetramethyleneimine-1-yl }-1,2-benzisothiazole-3-methane amide,

124) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-{3-[methyl (2,2, the 2-trifluoroethyl) amino] tetramethyleneimine-1-yl }-1,2-benzisothiazole-3-methane amide,

125) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[3-(methoxymethyl) tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-methane amide,

126) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-[3-(methoxymethyl) tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-methane amide,

127) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(3R)-and 3-(dimethylamino) tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-methane amide,

128) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(3R)-and 3-(dimethylamino) tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-methane amide,

129) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[4-(dimethylamino) piperidines-1-yl]-1,2-benzisothiazole-3-methane amide and

130) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-[4-(dimethylamino) piperidines-1-yl]-1,2-benzisothiazole-3-methane amide,

Wherein above listed compound (free alkali form or its solvate or N-oxide compound, or pharmacologically acceptable salts form or its solvate) also can be the polymorphic form form, and

If wherein the compound table shows chirality, it can be the mixture (for example racemoid) of enantiomer or the form of mixtures of diastereomer, or can be single enantiomer or single diastereomeric form.

131) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-(2-oxo-3-propyl imidazole alkane-1-yl)-1,2-benzisothiazole-3-methane amide

Or its pharmacologically acceptable salts,

Wherein above listed compound (free alkali form or its solvate or N-oxide compound, or pharmacologically acceptable salts form or its solvate) also can be the polymorphic form form.

132) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-N-methyl-6-[(1S, 4S)-5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl]-1,2-benzisothiazole-3-methane amide diformate,

133) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-N-methyl-6-[(1S, 4S)-5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl]-1,2-benzisothiazole-3-methane amide diformate,

134) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(1R, 4R)-5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl]-1,2-benzisothiazole-3-methane amide,

135) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(1R, 4R)-5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl]-1,2-benzisothiazole-3-methane amide,

136) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-(1,4-diazabicyclo [3.2.2] ninth of the ten Heavenly Stems-4-yl)-1,2-benzisothiazole-3-methane amide diformate,

137) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(1,4-diazabicyclo [3.2.2] ninth of the ten Heavenly Stems-4-yl)-1,2-benzisothiazole-3-methane amide diformate,

138) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-tetramethyleneimine-1-base-1,2-benzisothiazole-3-methane amide,

139) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-(4-methylpiperazine-1-yl)-1,2-benzisothiazole-3-methane amide,

140) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(4-methylpiperazine-1-yl)-1,2-benzisothiazole-3-methane amide,

141) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl)-1,2-benzisothiazole-3-methane amide,

142) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl)-1,2-benzisothiazole-3-methane amide,

143) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-(hexahydropyrrolo is [1,2-a] piperazine-2 (1H)-yl)-1 also, 2-benzisothiazole-3-methane amide,

144) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(hexahydropyrrolo is [1,2-a] pyrazine-2 (1H)-yl)-1 also, 2-benzisothiazole-3-methane amide,

145) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-(5-methyl-2,5-diazabicyclo [2.2.2] suffering-2-yl)-1,2-benzisothiazole-3-methane amide,

146) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(5-methyl-2,5-diazabicyclo [2.2.2] suffering-2-yl)-1,2-benzisothiazole-3-methane amide,

147) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-(8-methyl-3,8-diazabicyclo [3.2.1] oct-3-yl)-1,2-benzisothiazole-3-methane amide,

148) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(8-methyl-3,8-diazabicyclo [3.2.1] oct-3-yl)-1,2-benzisothiazole-3-methane amide,

149) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(1S, 4S)-5-cyclopropyl-2,5-diazabicyclo [2.2.1] heptan-2-yl]-1,2-benzisothiazole-3-methane amide,

150) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(1S, 4S)-5-cyclopropyl-2,5-diazabicyclo [2.2.1] heptan-2-yl]-1,2-benzisothiazole-3-methane amide,

151) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(1S, 4S)-5-(cyclopropyl methyl)-2,5-diazabicyclo [2.2.1] heptan-2-yl]-1,2-benzisothiazole-3-methane amide,

152) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(1S, 4S)-5-(cyclopropyl methyl)-2,5-diazabicyclo [2.2.1] heptan-2-yl]-1,2-benzisothiazole-3-methane amide,

153) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-5-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl)-1,2-benzisothiazole-3-methane amide,

154) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-5-[(3R)-and 3-methoxyl group tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-methane amide,

155) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-5-[(3R)-and 3-methoxyl group tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-methane amide,

156) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-5-[(3S)-and 3-methoxyl group tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-methane amide,

157) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(1-methylpyrrolidin-3-yl) the oxygen base]-1,2-benzisothiazole-3-methane amide,

158) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(1-methylpyrrolidin-3-yl) the oxygen base]-1,2-benzisothiazole-3-methane amide,

159) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-(1-azabicyclo [2.2.2] oct-3-yl oxygen base)-1,2-benzisothiazole-3-methane amide,

160) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(1-azabicyclo [2.2.2] oct-3-yl oxygen base)-1,2-benzisothiazole-3-methane amide,

161) N, N '-two-(3S)-1-azabicyclo [2.2.2] oct-3-yl-1H-indazole-1, the 3-diformamide,

162) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-(1-methyl-4,5-dihydro-1H-imidazoles-2-yl)-1H-indazole-3-methane amide,

163) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(1-methyl-4,5-dihydro-1H-imidazoles-2-yl)-1H-indazole-3-methane amide,

164) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-5-[(3S)-3-(cyclo propyl methoxy) tetramethyleneimine-1-yl]-1H-indazole-3-methane amide,

165) (3S)-and 1-(chloromethyl)-3-[(1H-indazole-3-base carbonyl) amino]-1-azonia dicyclo [2.2.2] octane muriate,

166) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-5-[(3S)-3-methoxyl group tetramethyleneimine-1-yl]-1H-indazole-3-methane amide diformate,

167) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-chloroisothiazole [5,4-b] pyridine-3-carboxamide also,

168) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-(3-methylpiperazine-1-yl)-1,2-benzisothiazole-3-methane amide,

169) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-(octahydro-6H-pyrrolo-[3,4-b] pyridine-6-yl)-1,2-benzisothiazole-3-methane amide,

170) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(octahydro-6H-pyrrolo-[3,4-b] pyridine-6-yl)-1,2-benzisothiazole-3-methane amide,

171) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-piperazine-1-base-1,2-benzisothiazole-3-methane amide,

172) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-piperazine-1-base-1,2-benzisothiazole-3-methane amide,

173) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-(1,4-Diazesuberane-1-yl)-1,2-benzisothiazole-3-methane amide,

174) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(1,4-Diazesuberane-1-yl)-1,2-benzisothiazole-3-methane amide,

175) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-(2-methylpiperazine-1-yl)-1,2-benzisothiazole-3-methane amide,

176) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(2-methylpiperazine-1-yl)-1,2-benzisothiazole-3-methane amide,

177) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-[4-(cyclopropyl carbonyl) piperazine-1-yl]-1,2-benzisothiazole-3-methane amide,

178) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[4-(cyclopropyl carbonyl) piperazine-1-yl]-1,2-benzisothiazole-3-methane amide,

179) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-[1-(cyclopropyl carbonyl) octahydro-6H-pyrrolo-[3,4-b] pyridine-6-yl]-1,2-benzisothiazole-3-methane amide,

180) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[1-(cyclopropyl carbonyl) octahydro-6H-pyrrolo-[3,4-b] pyridine-6-yl]-1,2-benzisothiazole-3-methane amide,

181) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(1S, 4S)-5-(cyclopropyl carbonyl)-2,5-diazabicyclo [2.2.1] heptan-2-yl]-1,2-benzisothiazole-3-methane amide,

182) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(1S, 4S)-5-(cyclopropyl carbonyl)-2,5-diazabicyclo [2.2.1] heptan-2-yl]-1,2-benzisothiazole-3-methane amide,

183) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-(3,4-lupetazin-1-yl)-1,2-benzisothiazole-3-methane amide,

184) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-cyano group-1H-indazole-3-methane amide,

185) 3-[(3S)-and 1-azabicyclo [2.2.2] oct-3-yl amino] carbonyl-1H-indazole-6-carboxylic acid hydrochloride,

186) N (3)-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-N (6), N (6)-dimethyl-1H-indazole-3, the 6-diformamide,

187) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(4-methylpiperazine-1-yl) carbonyl]-1H-indazole-3-methane amide,

188) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(3R)-and 3-methoxyl group tetramethyleneimine-1-yl] carbonyl-1H-indazole-3-methane amide,

189) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-methoxyl group isothiazole [5,4-b] pyridine-3-carboxamide also,

190) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-5-(tetrahydrochysene-2H-pyrans-4-base oxygen base)-1H-indazole-3-methane amide,

If compound exhibits chirality wherein, it can be the mixture (for example racemoid) of enantiomer or the form of mixtures of diastereomer, or can be single enantiomer or single diastereomeric form.

Following table has been listed the structure according to the selected compounds of formula I-IV of the present invention:

Other aspect comprises the pharmaceutical composition of another promoting agent that comprises compound of the present invention and pharmaceutically acceptable carrier and optional following discussion; Stimulate or activate the method for inhibition alpha-7 nicotinic acceptor, for example in external or body (in animal, for example in animal model, or in Mammals or in the mankind) measured by conventional determining method or assay method described herein; The treatment nervous syndrome, the loss of memory for example, the method for particularly long-term memory forfeiture, cognitive disorder or decline, dysmnesia etc.; The treatment Mammals for example among the mankind by the method for the active morbid state of regulating (those diseases of for example mentioning herein) of nicotinic alpha-7.

Compound of the present invention can conventional prepare.More operable currently known methodss are described hereinafter.All raw materials all are known, perhaps can be by known raw material by the conventional preparation of ordinary skill.

Be used to prepare the sour commercially available of dicyclo alkali acid amides, perhaps can be by currently known methods of describing in the document or preparation as mentioned below.For example, indazole-3-carboxylic acid is commercially available.Indazole-3-acid such as many simple replacements of bromo-indazole acid prepares (Snyder, people such as H.R., J.Am.Chem.Soc.1952,74,2009) by basic hydrolysis, diazotization and reduction from corresponding indoline diketone.

The indazole of some replacements-3-acid is by modifying the preparation of existing indazole acid or ester.For example N (1)-and the indazole acid of N (2)-protection can by ester by with methoxy ethoxy methyl chloride (MEM-Cl) or trimethylsilylethoxymethyl chlorine (SEM-Cl) and sodium hydride or diisopropylethylamine prepared in reaction.N (1)-alkylating indazole-3-carboxylic acid is prepared by corresponding indazole ester by standard alkanisation method or three letter (Mitsunobu) methods.The indazole of N (1)-Fangization-3-carboxylic acid is prepared by corresponding indazole ester by the cross-coupling that carries out copper mediation with boric acid.By corresponding bromide, by metal-halogen exchange, capture the indazole lithium aryl, then reduce or acid mediated elimination prepares nonaromatic Hete rocyclic derivatives with ketone.Capture the indazole lithium aryl with acid amides ketone and aldehyde are provided, they are as the useful precursor of reduction amination etc.The indazole that aromaticity replaces-3-acid prepares (Reeder, people such as M.R., Org.Proc.Res.Devel.2003,7,696) through carrying out palladium mediated cross-coupling with boric acid or aryl zincon by corresponding bromide.Use and palladium mediatedly prepare Aminoindazole acid with cross-coupling reaction secondary amine.Prepare phenol derivatives by corresponding methoxyl group acid with boron tribromide.By commercially available 6-fluorine raw material by preparing 6-amino-or 6-phenyl-7-azaindazole-3-carboxylic acid with secondary amine reaction or with cross-coupling that aryl grignard reagent carries out the nickel mediation.

The indazole of some replacements-3-acid is prepared by benzene derivative.For example 5-difluoro-methoxy indazole-3-acid is reacted, is prepared with diethyl malonate reaction, decarboxylation saponification, esterification, nitroreduction and diazotization by 3-bromo-4-nitrophenols and ethyl difluoro.6-difluoro-methoxy indazole-3-acid is prepared by 2-bromo-5-difluoro-methoxy oil of mirbane in a similar manner.2-bromo-5-difluoro-methoxy oil of mirbane by ether form, with as the protected nitroreduction of acid amides, nitrated, amide hydrolysis and carry out sandmeyer reaction with cupric bromide (I) and prepare by the 4-nitrophenols.By the 4-methoxy nitrobenzene, by with as the protected nitroreduction of acid amides, nitrated, amide hydrolysis, carry out sandmeyer reaction with cupric bromide (I) and demethylation prepares 6-benzyloxy indazole-3-carboxylic acid and ester.With phenol bromotoluene alkylation, and make aryl bromide and diethyl malonate reaction, decarboxylation saponification, esterification, nitroreduction and diazotization.Prepare 5-benzyloxy analogue (Parker, K.A. by 4-benzyloxy-2-bromo nitrobenzene in a similar manner; Mindt, T.L.Org.Lett.2002,4,4265).Remove benzyl by hydrogenolysis, and gained phenol is changed into ether derivant through alkylation or three letter reaction conditionss.By the 4-anisidine, by acid amides form, nitrated, amide hydrolysis, carry out sandmeyer reaction, nitroreduction with cupric bromide (I), the indoline diketone forms and indazole is reset, then hydrogenolysis is removed bromine and prepared the acid of 4-methoxyl group indazole.By the 4-chloropyridine, capture, prepare 5-azaindazole-3-acid with hydrazine cyclisation and saponification by metallization and with oxalic acid diethyl ester.6-azaindazole-3-acid is by being prepared by 4-chloro-3-nitropyridine with propanedioic acid anionic reactive, decarboxylation, nitroreduction, diazotization and saponification.

Adopt similar approach to prepare the benzoisoxazole ester by simple benzene derivative.For example: by by the reaction of 2-nitro-1,4 dibromobenzene and dimethyl malonate, order saponification/decarboxylation, esterification, with Isopentyl nitrite prepared in reaction 6-bromobenzene Bing isoxazole-3-carboxylic acid, ethyl ester under alkaline condition.6-methoxyl group benzo isoxazole ester cpds is similarly by 2, and the 4-dinitrochlorobenzene prepares.The 6-nitryl group that reduction generates, then diazotization and oxidation provide 6-oxy-compound.Obtain ether by simple alkylation.

The benzisothia triazole carboxylic acid also adopts and is similar to the method preparation that acid is summarized for indazole.For example: by by 3-methoxybenzenethiol and oxalyl chloride and aluminium reaction, then prepare 6-anisole isothiazole-3-carboxylic acid with azanol, hydrogen peroxide and sodium-hydroxide treatment.By carrying out palladium mediated cross-coupling reaction by the essential amino benzisothiazole acid that replaces of bromide preparation with secondary amine or benzophenone imine.Primary amine that this mode produces and secondary amine are as the intermediate of other parts.For example, adopt standard reduction amination and acylation reaction that amine is changed into tertiary amine and acid amides by persons skilled in the art practice.By by 2-chloronicotinoyl chloride and diethyl malonic acid anionic reactive and decarboxylation, then generate 7-azepine-3-methylbenzene isothiazole and examine and prepare 7-azepine benzisothiazole-3-carboxylic acid with sulphur, ammonium hydroxide and ammonia react.Adopt with the N-bromosuccinamide alkaline permanganate oxidation of carrying out benzyl oxidation and hydrolysis, then carrying out alcohol to prepare described acid.By 7-azepine-3-methyl benzisothiazole nuclear, prepare 7-azepine-6-chlorobenzene and isothiazole-3-acid at 6-position insertion chlorine atom by the oxidation of pyridine ring nitrogen, the rearrangement reaction of following by the triphosgene regulation and control.Should synthetic carry out the benzyl oxidation by the mode that is similar to the acid of unsubstituted azepine benzisothiazole finishes.

Wyovin, 3-amino quinine ring and the R-thereof and the S-enantiomer that are used to prepare dicyclo alkali acid amides are commercially available.N-alkylation rubane is by 3-amino quinine ring acidylate, and then reducing amide prepares.

Dicyclo alkali acid amides is prepared as follows by acid and Wyovin: use standard peptide coupling reagent such as O-(benzotriazole-1-yl)-N, N, N ' N '-tetramethyl-urea hexafluorophosphate (HBTU), O-(7-azepine benzo triazol-1-yl)-N, N, N ' N '-tetramethyl-urea hexafluorophosphate (HATU) or O-(benzotriazole-1-yl)-N, N, N ' N '-tetramethyl-urea hexafluoro borate (TBTU), hydroxybenzotriazole (HOBt) and N-(3-dimethylaminopropyl)-N '-ethyl carbodiimide (EDCI), carbonyl dimidazoles (CDI) and 2-chloro-1,3-methylimidazole quinoline hexafluorophosphate (CIP) coupling, perhaps acid is changed into corresponding acyl chlorides, then with Wyovin reaction (Macor, J.E.; Gurley, D.; Lanthorn, T.; LOCH, J.; Mack, R.A.; Mullen, G.; Tran, O.; Wright, N.; With people such as J.E.Macor, " The 5-HT3-Antagonist Tropisetron (ICS205-930) was a Potent and Selective α-7Nicotinic Receptor Partial Agonist; " Bioorg.Med.Chem.Lett.2001,9,319-321).Coupling was carried out 18-24 hour in room temperature usually.Standard technique such as chromatography or recrystallization method separation and purifying gained adducts by those of ordinary skills' practice.

Alternatively, the nicotine part can be prepared by modifying other nicotine parts.For example, encircle the urea part by the catalytic crosslinking reaction of palladium by corresponding bromide part preparation.By carrying out the similarly palladium mediated amino part that replaces of linked reaction preparation with secondary amine or benzophenone imine.As known to persons of ordinary skill in the art, the primary amine that generates of this mode and secondary amine are as the intermediate of other parts.By carry out palladium mediated crosslinking reaction with pinacol borine (pinacolborane) dipolymer, then oxidation and alkylation prepare 5-alkoxyl group benzo isothiazole part.In some cases, under three creed parts or on indazole nitrogen, carry out the derivatize of indazole rubane acid amides by the linked reaction of carrying out copper mediation with boric acid.By final product and alkylating reagent prepared in reaction rubane quaternary ammonium salt.Prepare the N-oxide compound by final product and oxidant reaction.

Those of ordinary skills will appreciate that the compound of formula I-IV can exist by different tautomerisms and rotamerism form.The form of ownership of these compounds comprises the non-racemic mixture of cis-isomeride, trans-isomer(ide), non-enantiomer mixture, racemoid, enantiomer, pure and pure enantiomer basically, all within the scope of the invention.Basically pure enantiomer contains and is no more than 5w/w%, preferably is no more than 2w/w%, is most preferably not exceeding the corresponding opposite enantiomer of 1w/w%.

Can obtain optically active isomer by resolving racemic mixtures according to conventional methods, for example,, perhaps form the covalency diastereomer by forming diastereomeric salt with optically-active acid or alkali.The example of suitable acid is tartrate, diacetyl tartaric acid, dibenzoyl tartaric acid, dimethylbenzoyl tartrate and camphorsulfonic acid.Non-enantiomer mixture can by method known to those skilled in the art, for example be separated into their single diastereomer according to their physics and/or chemical differences by chromatography or Steppecd crystallization.Then discharge optically-active alkali or acid from isolating diastereomeric salt.The different methods of separating optical isomers comprises use chiral chromatography (for example chirality HPLC post), carries out or do not carry out conventional derivatize, optimally the maximum separation with the acquisition enantiomer of selection.Suitable chirality HPLC post is produced by Diacel, and for example Chiracel OD and Chiracel OJ etc. can conventional select for use.The enzyme that carries out or do not carry out derivatize separates also useful.The optically-active compound of formula I-IV can utilize the optically-active raw material to obtain with the chirality synthetic method under the reaction conditions that does not cause racemization equally.

In addition, those of ordinary skills will appreciate that, can for example be rich in by the different isotopic forms that is rich in ²H, ³H, ¹¹C, ¹³C and/or ¹⁴The form of C is used this compound.In a specific embodiment, described compound is a deuterated.Such deuterate form can be by United States Patent (USP) 5,846, and 514 and 6,334, the method preparation described in 997.As United States Patent (USP) 5,846,514 and 6,334, described in 997, deuterate can be improved the effect of medicine, and increases the action time of medicine.

Deuterium can be synthetic with several different methods for compound, as described in the following document: Dean, DennisC.; Editor.Recent Advances in the Synthesis and Applications of RadiolabeledCompounds for Drug Discovery and Development.[In:Curr., Pharm.Des., 2000; 6 (10)] (2000), 110 pp.CAN 133:68895 AN 2000:473538 CAPLUS; Kabalka, George W.; Varma, Rajender S.The synthesis of radiolabeledcompounds via organometallic intermediates.Tetrahedron (1989), 45 (21), 6601-21, CODEN:TETRAB ISSN:0040-4020.CAN 112:20527 AN1990:20527CAPLUS; And Evans, E.Anthony.Synthesis of radiolabeledcompounds, J.Radioanal.Chem. (1981), 64 (1-2), 9-32.CODEN:JRACBNISSN:0022-4081, CAN 95:76229 AN 1981:476229 CAPLUS.

Under situation about being suitable for, the invention still further relates to the useful form of compound disclosed herein, comprise free alkali form and the pharmacologically acceptable salts or the prodrug of all compounds of the present invention that its salt or prodrug can be prepared.Pharmacologically acceptable salts comprises the salt that obtains as the main compound of alkali and mineral acid or organic acid reaction salify by making, for example hydrochloride, vitriol, phosphoric acid salt, mesylate, camsilate, oxalate, maleate, succinate, Citrate trianion, formate, hydrobromate, benzoate, tartrate, fumarate, salicylate, amygdalate and carbonate.Pharmacologically acceptable salts comprises that also main compound wherein is as acid and the salt that forms with suitable alkali reaction, for example sodium salt, sylvite, calcium salt, magnesium salts, ammonium salt and choline salt.Those skilled in the art can recognize further that the acid salt of claimed compounds can prepare by making described compound and mineral acid or organic acid any reaction in many currently known methodss of suiting.Perhaps, alkali and alkaline earth salt can prepare through multiple currently known methods reaction by making compound of the present invention and the alkali that suits.

It below is can be by more examples of the hydrochlorate that obtains with mineral acid or organic acid reaction: acetate, adipate, alginate, Citrate trianion, aspartate, benzoate, benzene sulfonate, hydrosulfate, butyrates, camphorate, digluconate, cyclopentane propionate, dodecyl sulfate, esilate, gluceptate (glucoheptanoate), glycerophosphate, Hemisulphate (hemisulfate), enanthate, hexanoate, fumarate, hydrobromate, hydriodate, 2-hydroxyl-esilate, lactic acid salt, maleate, mesylate, nicotinate, the 2-naphthalenesulfonate, oxalate, palmitate (palmoates), pectate (pectinates), persulphate, 3-phenylpropionic acid salt, picrate, Pivalate, propionic salt, succinate, tartrate, thiocyanate-, tosylate, mesylate and undecylate.

For example described pharmacologically acceptable salts can be hydrochloride, hydrobromate, formate or maleate.

Salt of the present invention also comprises the quaternary ammonium salt that obtains as the main compound of nucleophilic reagent and the reagent react that has the freestone group by making.The example of these reagent includes but not limited to methyl iodide, monobromethane, methyl chloride, trifluoromethanesulfonic acid methyl esters, toluenesulphonic acids methyl esters, methyl mesylate, iodoethane, monobromethane, monochloroethane, trifluoromethanesulfonic acid ethyl ester, toluenesulphonic acids ethyl ester, ethyl methane sulfonate, iodopropane, N-PROPYLE BROMIDE, chloropropane, cyclopropyl monobromomethane, bromotoluene, methylene dichloride and ethylene dichloride.The example list that one skilled in the art will realize that the reagent of proposition is non-exhaustive, can rationally expand.

For example, can on the N of azabicyclo structure atom, form quaternary ammonium salt, be shown below:

Wherein Z is for example methyl, chloromethyl, ethyl, chloroethyl, propyl group, cyclopropyl methyl or benzyl, and corresponding negatively charged ion A is for example iodide ion, bromide anion, chlorion, trifluoromethanesulfonic acid root, tosylate or methanesulfonate.Referring to for example compound 1,13 and 165.

Preferably, the salt of formation is for being that pharmacy is acceptable for the Mammals administration.Yet the unacceptable salt of the pharmacy of described compound is suitable for as intermediate, for example, separates this compound with salt form, then by handling with alkali reagent it is transformed migration from alkali cpd.For example: can imagine alkylogen additive salt (as salt) by forming with iodomethane reaction.If desired, then free alkali can be changed into the acceptable acid salt of pharmacy.

Those of ordinary skills will appreciate that also some compounds of formula I, II, III and IV can exist by different polymorphic form forms.As known in the art, polymorphism is the ability that compound crystal goes out more than one different crystals or " polycrystalline " material.Polymorphic form is a compound through the solid crystal state of at least twice different rearrangement or the polymorphic form form of solid compounds molecule.The polymorphic form form of any given compound is by identical chemical formula or form definition and different like that with the crystalline structure of two kinds of different compounds on chemical structure.

Those of ordinary skills can recognize further that the solvate form thereof that the compound of formula I, II, III and IV can be different exists.During crystallisation process, when being incorporated in the crystalline network of described compound molecule, solvent molecule also can form the solvate of compound of the present invention.

Compound of the present invention can be individually dosed, or as the delivery of active ingredients of preparation.Therefore, the present invention also comprises the pharmaceutical composition of the compound of formula I-IV, and said composition contains for example one or more pharmaceutically acceptable carriers.

There are many normative documents to describe the method for the many preparations that are used to prepare the administration that is suitable for compound of the present invention.Possible examples of formulations is stated in following document: Handbook ofPharmaceutical Excipients for example, American Pharmaceutical Association (current version); Pharmaceutical Dosage Forms:Tablets (Lieberman, Lachman and Schwartz, editors) current version, by Marcel Dekker, Inc. publish, and Remington ' s PharmaceuticalSciences (Arthur Osol, editor), 1553-1593 (current version).

Because α-7 stimulating activity of compound of the present invention and preferred high selectivity owing to them can be with them to any people's administrations that needs alpha-7 receptor to stimulate.Administration can be carried out according to needs of patients, for example oral, intranasal, parenteral (in subcutaneous, intravenously, intramuscular, the breastbone and infusion), suction, rectum, vagina, part and eye drops.

Can use multiple solid oral dosage form to carry out the administration of compound of the present invention, comprise following solid dosage: tablet, soft capsule, capsule, Caplet, granule, lozenge and powder.Compound of the present invention can be individually dosed or with multiple pharmaceutically acceptable carrier as known in the art, thinner (as sucrose, seminose, lactose, starch) and vehicle, include but not limited to administrations together such as suspending agent, solubilizing agent, buffer reagent, tackiness agent, disintegrating agent, sanitas, tinting material, seasonings, lubricant.Capsule, tablet and gelifying agent that time-delay discharges also are favourable in the administration of compound of the present invention.

Also multiple liquid oral dosage form can be used for the administration of compound of the present invention, comprise the aqueous solution and non-aqueous solution, emulsion, suspensoid, syrup and elixir.Such formulation also can contain suitable inert diluent known in the art such as water, and suitable vehicle known in the art such as sanitas, wetting agent, sweeting agent, seasonings and be used for emulsification and/or the reagent of the compound of the present invention that suspends.For example, compound of the present invention can be used as etc. and to ooze the sterile solution intravenous injection.Other preparations also are possible.

The suppository that is used for the rectal administration of compound of the present invention can prepare by described compound is mixed with the vehicle that suits such as theobroma oil, salicylate and polyoxyethylene glycol.The preparation that is used for vagina administration can be the form of vaginal suppository, tampon, ointment, gelifying agent, paste, foam or sprays, and it also contains appropriate carrier for example known in the art except containing activeconstituents.

For topical, this pharmaceutical composition can be the form that is suitable for to ointment, ointment, liniment, lotion, emulsion, suspensoid, gelifying agent, solution, paste, powder, sprays and the drops of skin, eye, ear or nasal administration.Topical can also comprise by device as the skin administration of passing through through skin medicine exchange premium.

Also can make the aerosol formulation that is suitable for by inhalation.For example, for the treatment of respiratory tract disease, can carry out the administration of compound of the present invention by sucking powder (for example micronized) or atomized soln or form of suspension.Aerosol formulation can be placed the propellent that can pressurize.

This compound can also for example be used for the treatment of the other drug of the cognitive disorder and/or the loss of memory as independent active agent delivery or with other medicaments, as other α-7 agonist, the PDE4 inhibitor, calcium channel blocker, muscarinic m1 and m2 conditioning agent, the Adenosine Receptors conditioning agent, ampakine (amphakines), the NMDA-R conditioning agent, the mGluR conditioning agent, the dopamine modulating agent, the serotonin conditioning agent, cannaboid (canabinoid) conditioning agent and anticholinesterase are (for example: E2020, sharp this bright (rivastigimine) and lycoremine (glanthanamine)) combination medicine-feeding.In such combination, every kind of activeconstituents can according to they the routine dose scope or be lower than its routine dose scope administration.

Compound of the present invention can be united use with " positive modulators " that improve nicotinic receptor agonists usefulness.Referring to for example: disclosed positive modulators among WO 99/56745, WO 01/32619 and the WO 01/32622.Such combined therapy can be used for treating and the relevant condition/disease of nicotine transmission decline.

In addition, thus described compound can with combine A β peptide and suppress this peptide and unite use in conjunction with the compound of α 7nACh receptor subtype.Referring to, for example WO 99/62505.

The present invention also comprises the methods of treatment that relates to the alpha-7 nicotinic receptor activation.Therefore, the present invention includes the method for the alpha-7 nicotinic acceptor among selectively activate/stimulation patient (for example Mammals such as the mankind), wherein activation/stimulation has the treatment effect like this, for example such activation can be alleviated the illness that relates to nervous syndrome, as the loss of memory, particularly long-term memory forfeiture.Such method comprises the compound of the formula I-IV disclosed herein of significant quantity separately or as the part of preparation to patient (for example Mammals such as the mankind) administration.

The method according to this invention aspect provides treatment to suffer from the patient's (for example Mammals such as the mankind) of disease (for example dysmnesia) method, and it comprises to the compound of described patient's administration according to formula I-IV.Preferably, described disease descends relevant with nicotinic acetylcholine receptor activity.

The method according to this invention aspect provides the disease that caused by nicotinic acetylcholine receptor propagation function obstacle among treatment or the prevention patient (for example Mammals such as the mankind) or the method for illness, and it comprises the compound according to formula I-IV of effective dosage.

The method according to this invention aspect, provide among treatment or the prevention patient (for example Mammals such as the mankind) by nicotinic acetylcholine receptor, the particularly disease that causes of the defective of α 7nACh acceptor or dysfunction or the method for illness, it comprises the compound according to formula I-IV of effective dosage.

The method according to this invention aspect, provide among treatment or the prevention patient (for example Mammals such as the mankind) by the nicotinic acetylcholine receptor transmission and be suppressed the disease that causes or the method for illness, it comprises that administration effectively activates the compound according to formula I-IV of the amount of α 7nACh acceptor.

According to other method of the present invention aspect, the method of mental illness, cognitive disorder (as dysmnesia) or neurodegenerative disease among treatment or the prevention patient (for example Mammals such as the mankind) is provided, and it comprises the compound according to formula I-IV of effective dosage.

According to other method of the present invention aspect, the disease that caused by the cholinergic synapse forfeiture among treatment or the prevention patient (for example Mammals such as the mankind) or the method for illness are provided, it comprises the compound according to formula I-IV of effective dosage.

According to other method of the present invention aspect, the method for the neurodegenerative disorders that is caused by α 7nACh receptor activation among treatment or the prevention patient (for example Mammals such as the mankind) is provided, it comprises the compound according to formula I-IV of effective dosage.

According to other method of the present invention aspect, provide the neurone of protection patient (for example Mammals such as the mankind) to avoid the neurovirulent method that causes by α 7nACh receptor activation, it comprises the compound according to formula I-IV of effective dosage.

According to other method of the present invention aspect, the method for the treatment of or preventing neurodegenerative disorders that combines by inhibition patient's (for example Mammals such as the mankind) A β peptide with α 7nACh acceptor is provided, it comprises the compound according to formula I-IV of effective dosage.

According to other method of the present invention aspect, provide the neurone that is used to protect patient (for example Mammals such as the mankind) to avoid neurovirulent method by A β inducing peptide, it comprises the compound according to formula I-IV of effective dosage.

According to other method of the present invention aspect, provide to alleviate among the patient (for example Mammals such as the mankind) method that the cholinergic function by A β inducing peptide suppresses, it comprises the compound of the formula I-IV of effective dosage.

The drug treatment compound is that the individuality or the patient of effective treatment plan of disease or illness is preferably the mankind therein, but can be any animal, comprises the laboratory animal in clinical trial in the context or screening or the activity test.Therefore, understand understandable as those of ordinary skills, method of the present invention, compound and composition are particularly suitable for to any animals administer, particularly Mammals includes but not limited to the mankind, domestic animal such as cat family or Canidae individuality, farm-animals is such as but not limited to ox, horse, goat, sheep and pig individuality, wildlife (no matter wild or zoological park in), zoologize (researchanimal) as mouse, rat, rabbit, goat, sheep, pig, dog, cat etc., birds such as chicken, firebird, song bird etc. promptly are used for veterinary purpose.

Compound of the present invention is nicotinic alpha 7 parts, the agonist, particularly α 7 partial agonists of preferred nicotinic acetylcholine receptor.The active assay method of known mensuration nicotinic acetyl choline in this area.Referring to, people such as Davies A.R for example, Characterisation of the binding of [3H] methyllycaconitine:a new radioligand for labeling alpha 7-type neuronal Nicotinic acetylcholine receptors.Neuropharmacology, 1999.38 (5): 679-90.As α 7nACh receptor stimulant, described compound is used to prevent and treats many diseases relevant with central nervous system or illness.Nicotinic acetylcholine receptor is part-stomach (ligand-gastrol) ionic channel acceptor, and it is made up of 5 protein protomers, and they form central ionic conduction hole.At present, 11 known neurone nACh receptor subunits (α 2-α 9 and β 2-β 4) are arranged.In peripheral nervous system, also express 5 other subunits (α 1, β 1, γ, δ, ε).

The nACh receptor subtype can be equal pentamer (homo-pentameric) or assorted pentamer (heteropentameric).The hypotype of quite being paid close attention to is equal pentamer α 7 receptor subtypes that formed by 5 α 7 subunits.Described α 7nACh acceptor shows high-affinity to nicotine (agonist) and α-bungatotoxin (antagonist).Studies show that α 7nACh receptor stimulant can be used for treating mental disorder, neurodegenerative disease and disturbance in cognition etc.Though nicotine is known agonist, but still need other α 7nACh receptor stimulants, particularly toxicity of exploitation or the side effect selective agonist littler than nicotine.

The compound anabasine, i.e. 2-(3-pyridyl)-3,4,5, the 6-tetrahydropyridine is a naturally occurring toxin in some ocean worm (ribbon wirm worm) and the ant.Referring to, people such as Kem for example, Toxicon, 9:23,1971.Anabasine is effective activator of Mammals nicotinic receptor.Referring to, Kem for example, Amer.Zoologist, 25,99,1985.Some anabasine analogue such as neonicotine and DMAB (3-[4-(dimethylamino) Ben Yajiaji]-3,4,5,6-tetrahydrochysene-2 ', 3 '-dipyridyl) also be known nicotinic receptor agonists.Referring to, for example US 5,602, and 257 and WO 92/15306.A kind of specific anabasine analogue, E-3-[2,4-dimethoxy-Ben Yajiaji]-anabasine, be also referred to as GST-21 and DMXB (referring to, for example US 5,741,802), be the selectivity part α 7nACh receptor stimulant that has been widely studied.For example, unusual sense organ inhibition is that the sense organ in the schizophrenia is handled defective, has found that GST-21 suppresses by increasing sense organ with α 7nACh acceptor interaction.Referring to, people such as Stevens for example, Psychopharmacology, 136:320-27 (1998).

Another compound that is known as selectivity α 7nACh receptor stimulant is a tropisetron, i.e. 1 α H, 5 α H-tropane-3 α-Ji Indole-3-Carboxylic Acid ester.Referring to people such as J.E.Macor, 5-HT3-Antagonist Tropisetron (ICS 205-930) is a Potent and Selective A7 Nicotinic Receptor Partial Agonist.Bioorg.Med.Chem.Lett.2001,319-321).

Point out; be used for the treatment of and/or prevent multiple disease and illness in conjunction with the medicine of nicotinic acetylcholine receptor; mental disorder particularly; the neurodegenerative disease relevant and the illness of memory and/or cognitive disorder with the cholinergic system dysfunction; comprise for example schizophrenia; anxiety disorder; mania; dysthymia disorders; dry mad depression [example of mental illness]; tourette's syndrome; Parkinson's disease; Huntington Chorea [example of neurodegenerative disease]; cognitive illness is (as alzheimer's disease; Lu Yiti (Lewy Body) dementia; amyotrophic lateral sclerosis; dysmnesia; the loss of memory; cognitive defect; attention deficit; attention deficit disorder (ADD)) and other purposes; as treat nicotine addiction, comprise smoking cessation; treatment pain (purposes of promptly easing pain); neuroprotective and treatment jet lag are provided.Referring to, for example WO 97/30998; WO 99/03850; WO 00/42044; WO 01/36417; People such as Holladay, J.Med.Chem., 40:26,4169-94 (1997); People such as Schmitt, Annual Reports Med.Chem., Chapter 5,41-51 (2000); People such as Stevens, Psychopharmatology, (1998) 136:320-27; And people such as Shytle, Molecular Psychiatry, (2002), 7, pp.525-535.

Therefore, according to the present invention, provide treatment to suffer from mental disorder, the neurodegenerative disease relevant and the illness of memory and/or cognitive disorder with the cholinergic system dysfunction, comprise for example schizophrenia, anxiety disorder, mania, dysthymia disorders, dry mad depression [example of mental illness], tourette's syndrome, Parkinson's disease, Huntington Chorea [example of neurodegenerative disease] and/or cognitive illness are (as alzheimer's disease, Lu Yi body dementia, amyotrophic lateral sclerosis, dysmnesia, the loss of memory, cognitive defect, attention deficit, attention deficit disorder (ADD)) patient, Ren Lei method particularly, it comprises the compound according to formula I-IV to described patient's effective dosage.

The neurodegenerative disorders that comprises in the method for the present invention includes but not limited to treat and/or prevent alzheimer's disease, Pick's disease, diffusivity Lu Yi body disease, paralysis (Steel-Richardson syndrome) on the carrying out property nuclear, multisystem sex change (shy-Drager syndrome), motor neurone disease (comprising amyotrophic lateral sclerosis), the sex change ataxia, the sex change of cortex base portion, the compound disease of ALS-parkinsonism dementia in Guam (ALS-Parkinson ' s-Demenia complex of Guam), subacute sclerosing panencephalitis, Huntington Chorea, Parkinson's disease, touch nucleoprotein disease (synucleinopathies), former carrying out property aphasia, striatonigral degeneration, Ma-Yue disease/3 type spinocebellar ataxias, the olivopontocerebellar degeneration, tourette's disease, bulbar paralysis, pseudobulbar paralysis, Duchenne-Arandisease, spinal cord oblongata myatrophy (kennedy's disease), primary lateral sclerosis, familial spastic paraplegia, Wei-Huo disease, Ku-Wei disease, amaurosis idiotica familiaris, sandhoff disease, the familial cramp disease, Wohlfart-Kugelberg-Welander disease, spastic paraparesis, progressive multifocal leukoencephalopathy, prion disease (as: creutzfeldt-jakob disease, Ge-Shi-Sha disease, Kuru disease and family's mortality insomnia), and the neurodegenerative disease that causes by cerebral ischemia or infraction that comprises the inaccessible and thrombus occlusion of embolic, (include but not limited to epidural with intracranialing hemorrhage of any kind, under the dura mater, under the arachnoid membrane and in the brain), and damage in encephalic and the backbone (includes but not limited to dampen, penetrate, shear, the compression and tear).

In addition, α 7nACh receptor stimulant, as compound of the present invention, can be used for treating relevant with the age dull-witted and, comprise dementia, dementia pugilistica and the frontal lobe dementia of dementia, head trauma and the diffuse brain injuries of the loss of memory relevant, aging, vascular dementia, diffusivity white matter disease (binswanger), internal secretion or metabolism cause with the age with other dementias and the illness of the loss of memory.Referring to, WO99/62505 for example.Therefore, according to the present invention, provide treatment to suffer from the dementia relevant and with other dementias of the loss of memory and the patient of illness, particularly Ren Lei method, it comprises the compound according to formula I-IV to described patient's effective dosage with the age.

Therefore, according to another embodiment, the present invention includes treatment and suffer from the amnemonic patient's who is caused by following illness method: alzheimer's disease, by mild cognitive impairment, schizophrenia, Parkinson's disease, Huntington Chorea, Pick's disease, creutzfeldt-jakob disease, dysthymia disorders, ageing, head trauma, apoplexy, central nervous system anoxic, brain aging, multiple cerebral dull-witted and other nervous disorders and HIV and cardiovascular disorder that ageing causes, it comprises the compound of the formula I-IV of effective dosage.

Known amyloid precursor protein (APP) and from its deutero-A β peptide, for example A β _1-40, A β _1-42Relevant with other fragments with the pathology of alzheimer's disease.Described A β _1-42Peptide is not only relevant with neurotoxicity, and known its suppresses the cholinergic transmitter function.In addition, A β peptide and α 7nACh receptors bind have been determined.Therefore, the medicine of blocking-up A β peptide and α-7nACh receptors bind is used for the treatment of neurodegenerative disease.Referring to, WO99/62505 for example.In addition, stimulate α 7nACh avoided and the relevant cytotoxicity of A β peptide by physical efficiency neuroprotective unit.Referring to, people such as Kihara T. for example, Ann.Neurol, 1997,42,159.

Therefore, according to embodiment of the present invention, provide the method that treats and/or prevents the dementia in the patients with Alzheimer disease, the compound according to formula I-IV that it comprises to described patient's drug treatment significant quantity suppresses amyloid beta (preferred A β _1-42) and the nACh acceptor, preferred α 7nACh acceptor, most preferably human α 7nACh receptors bind (and the method that treats and/or prevents other clinical manifestations of alzheimer's disease, described clinical manifestation includes but not limited to cognitive and language defect, apraxia, dysthymia disorders, vain hope and other neural mental symptoms and sign and motion and abnormal gait).

The present invention also provides treatment other amyloidosis diseases, for example heredity cerebro-vascular diseases, non-neuropathic heredity amyloid (nonneuropathic hereditary amyloid), mongolism, macroglobulinemia, Secondary cases familial Mediterranean fever, Mu-Wei syndrome, multiple myeloma, amyloidosis, chronic hemodialysis joint disease (anthropathy) and Finland (Finnish) relevant with pancreas and heart and the method for Iowa (Iowa) amyloidosis.

Point out in addition, nicotinic receptor body alcohol is taken in reply in work.Therefore, α 7nACh receptor stimulant can be used for the abstinence from alcohol treatment and resists in the poisoning therapy.Therefore, according to embodiment of the present invention, provide the treatment patient with abstinence from alcohol or with anti-poisoning therapy for treating patient's method, it comprises the compound according to formula I-IV to described patient's effective dosage.

The agonist of α 7nACh receptor subtype can also be used for the neuroprotective at the damage relevant with the exitotoxicity of apoplexy, ischemic and glutamate induction.Therefore, according to embodiment of the present invention, provide the treatment patient so that the method at the neuroprotective of the damage relevant with the exitotoxicity of apoplexy, ischemic and glutamate induction to be provided, it comprises the compound according to formula I-IV to described patient's effective dosage.

As mentioned above, the agonist of α 7nACh receptor subtype also can be used for treating nicotine addiction, induces smoking cessation, treats pain and treatment jet lag, obesity, diabetes and inflammation.Therefore, according to embodiment of the present invention, provide treatment to suffer from the patient's of nicotine addiction, pain, jet lag, obesity, diabetes and/or inflammation method, or induce the method for smoking cessation in the patient, it comprises the compound according to formula I-IV to described patient's effective dosage.

The inflammatory reflection is to reply the reaction of the autonomic nervous system of inflammatory signal.Behind the perception inflammatory stimulus, autonomic nervous system is replied by vagus nerve by discharging nicotinic alpha 7 acceptors on vagusstoff and the activating macrophage.These scavenger cells discharge cytokine again.The dysfunction of this approach is relevant with the human inflammatory disorders that comprises rheumatoid arthritis, diabetes and sepsis.Scavenger cell is expressed nicotinic alpha 7 acceptors, and may be that this receptor is regulated the cholinergic anti-inflammatory response.Therefore, with scavenger cell on α 7nACh acceptor have the compound of avidity to can be used for comprising rheumatoid arthritis, diabetes and pyemic human inflammatory disorders.Referring to, Czura for example, people such as C J, J.Intern.Med., 2005,257 (2), 156-166.

Therefore, according to embodiment of the present invention, provide treatment to suffer from inflammatory diseases or illness, such as but not limited to the patient's (for example Mammals such as the mankind) of rheumatoid arthritis, diabetes or sepsis method, it comprises the compound according to formula I-IV to described patient's effective dosage.

In addition, because the compound of formula I-IV and the avidity of α 7nACh acceptor, their labeled derivative thing (C for example ¹¹Or F ¹⁸The derivative of mark) can be used for the neuroimaging (neuroimaging) of acceptor in the brain for example.Therefore, use such labeled drug can carry out the in-vivo imaging of acceptor, for example: use the PET imaging.

Amnemonic illness shows as the damage of the ability of learning fresh information and/or can not recall the information of study in the past.Dysmnesia are dull-witted cardinal symptoms, also may be the symptoms relevant with following disease: alzheimer's disease, schizophrenia, Parkinson's disease, Huntington Chorea, Pick's disease, creutzfeldt-jakob disease, HIV, cardiovascular disorder and head trauma and the cognition of being correlated with the age descend.

Therefore, according to embodiment of the present invention, provide treatment to suffer from the patient's of following disease method: mild cognitive impairment (MCI) for example, vascular dementia (VaD), the cognition decline (AACD) relevant with the age, with open heart operations, the amnesia that heart stopping collecting and/or general anesthesia are relevant, the memory impairment that early stage contact anesthesia agent causes, sleep deprivation inductive cognitive disorder, chronic fatigue syndrome, narcolepsy, the dementia relevant with acquired immune deficiency syndrome (AIDS), the cognitive disorder relevant with epilepsy, mongolism, the dementia relevant with alcoholism, medicine/material inductive dysmnesia, dementia pugilistica (DementiaPuglistica) (boxing coach's syndrome) and animal dementia (dog for example, cat, horses etc.), it comprises the compound according to formula I-IV to described patient's effective dosage.

The dosage of compound of the present invention depends on multiple factor, comprises that the particular integration that will treat is levied, the Considerations such as existence of usefulness, toxicology feature, pharmacokinetics feature and any harmful side effect of this syndromic seriousness, route of administration, the number of times of spacing of doses, employed specific compound, this compound.

Compound of the present invention can be to patient's (for example Mammals is particularly human) with the common horizontal administration of typical doses for alpha-7 nicotinic receptor stimulant such as above-mentioned known alpha-7 nicotinic receptor agonist compounds.For example, this compound can potion or multi-agent administration, and the dosage level of oral administration is for example 0.0001-10mg/kg/ days, for example 0.01-10mg/kg/ days.Unit dosage can contain for example 1-200mg active compound.For intravenous administration, can be by potion or the described compound of multi-agent administration.

In implementing method of the present invention, certainly should be appreciated that, mentioned specific buffers, medium, reagent, cell, culture condition etc. do not mean restrictive, and be appreciated that by comprise those of ordinary skills think important or valuable all related substanceses in the specific context discussed of proposition.For example, usually may replace original buffering system or substratum, even and still obtain inequality also similar result with another kind of buffering system or substratum.Those skilled in the art fully understand such system and method, thereby can carry out such replacement in using method disclosed herein and operation under the situation of not carrying out undue experimentation, thereby reach their purpose best.

To further describe the present invention by following non-limiting example now.When implementing the content of these embodiment, should clearly realize that they point out those skilled in the art about the other guide of method disclosed according to the present invention and different embodiments beyond all doubtly.

In aforementioned and following examples, all temperature do not proofread and correct degree centigrade being that unit provides; And unless otherwise noted, all parts and per-cent are all by weight.

Above and the full content of all applications, patents and publications of hereinafter quoting all be incorporated herein for referencial use.

The following compound of method preparation that adopts following method and hereinafter further describe.Also described the synthetic of related compound in U.S. Patent application 11/089,533 and 10/669,645, this paper quotes its full content as a reference.

Embodiment

Unless otherwise indicated, all spectrograms are all by Bruker Instruments NMR record under 300MHz.The unit of coupling constant (J) is hertz (Hz), and listed peak is with respect to TMS (δ 0.00ppm).Use Personal Chemistry Optimizer ^TMMicrowave reactor carries out microwave reaction in 2.5mL or 5mL PersonalChemistry microwave reactor bottle.Unless otherwise indicated, institute responds and all carried out under 200 ℃ 600 seconds, and has the fixed ON that holds time.Sulfonic acid ion exchange resin (SCX) is available from Varian Technologies.Analyze HPLC at 4.6mm * 100mm Xterra RP ₁₈3.5 on the μ post, use the gradient of 20/80 to 80/20 acetonitrile (0.1% formic acid) in 6 minutes/water (0.1% formic acid) to carry out.For compound 57, use the gradient of 5/95 to 60/40 acetonitrile (0.1% formic acid)/water (0.1% formic acid).For compound 116-130, use the gradient of 10/90 to 80/20 acetonitrile (0.1% formic acid) in 8 minutes/water (0.1% formic acid).

HPLC is at 30mm * 100mm Xterra Prep RP in preparation ₁₈Carry out on the 5 μ posts, use the gradient (compound 1-50,54-57,59,60,63-77,79-131 and 149-185) of 20/80 to 80/20 acetonitrile (0.1% formic acid)/water (0.1% formic acid) in (i) 8 minutes; The (ii) gradient (compound 51-53) of 5/95 to 95/5 acetonitrile (0.05% trifluoroacetic acid) in 30 minutes/water (0.05% trifluoroacetic acid); The (iii) gradient (compound 58,61,62,78 and 132-137) of 10/90 to 60/40 acetonitrile (0.1% formic acid) in 8 minutes/water (0.1% formic acid); The (iv) gradient (compound 186-190) of 5/95 to 60/40 acetonitrile (0.1% formic acid) in 8 minutes/water (0-1% formic acid), or (the v) gradient (compound 138-148) of 10/90 to 80/20 acetonitrile (0.1% formic acid)/water (0.1% formic acid) in 8 minutes.

The acid preparation

Following method (1-29) is described the preparation of indazole, benzoisoxazole and the benzisothiazole acid that can not be purchased in detail.

Method 1

Method 1 provides the benzisothiazole-3-carboxylic acid that is replaced by corresponding thiophenol preparation.

In the solution of 3-methoxybenzenethiol (26.7mmol) in ether (20mL), drip oxalyl chloride (43mmol).This mixture heating up was refluxed 1.5 hours, be cooled to room temperature, and vacuum concentration.The gained yellow oil is dissolved in the methylene dichloride (50mL), is cooled to 0 ℃, and divide several partially disposed with aluminum chloride (32.0mmol).This mixture heating up was refluxed 30 minutes, be cooled to room temperature, and under agitation pour in the frozen water.Separate organic layer, and use saturated sodium bicarbonate aqueous solution, water and salt water washing successively.With dried over mgso organic layer, filtration and vacuum concentration.By chromatography purification (4/1 ethyl acetate/hexane) resistates, obtain 6-methoxyl group-1-thionaphthene-2 thus, the 3-diketone, it is an orange solids, yield is 47%.

In the mixture of 30% ammonium hydroxide aqueous solution (2.0mL), add 35% aqueous hydrogen peroxide solution (0.2mL) to diketone (0.44mmol), reaction mixture was placed 12 hours.The sedimentary pink solid of filtering separation washes with water and dry under high vacuum, obtains acid amides thus, and yield is 42%.

In the solution of acid amides (5.46mmol) in methyl alcohol (100mL), add 10N sodium hydroxide (12mL).This mixture heating up was refluxed 12 hours, be cooled to room temperature, and be acidified to pH＜2 by slow adding concentrated hydrochloric acid.With methylene dichloride (2 *) extraction organic layer, and through dried over sodium sulfate.By chromatography (300/50/1 methylene chloride/formic acid) purifying crude product, obtain acid thus, it is a pink solid, yield is 89%.

Adopt the following acid of this method preparation:

6-bromobenzene and isothiazole-3-carboxylic acid

5-bromobenzene and isothiazole-3-carboxylic acid

6-methoxyl group benzo isothiazole-3-carboxylic acid

7-bromobenzene and isothiazole-3-carboxylic acid

Adopt ethanol and sulfuric acid to prepare following ester by acid:

6-bromobenzene and isothiazole-3-carboxylic acid, ethyl ester

6-methoxyl group benzo isothiazole-3-carboxylic acid, ethyl ester

5-bromo-1,2-benzisothiazole-3-carboxylic acid tert-butyl ester

Adopt following method to prepare the benzisothiazole tert-butyl ester:

Di-t-butyl carbonic acid hydrogen ester (128mmol) is added to 6-bromo-1, in 2-benzisothiazole-3-carboxylic acid (46.5mmol) and 4-dimethylaminopyridine (4.26mmol) suspension in the trimethyl carbinol (40.0mL) and tetrahydrofuran (THF) (40.0mL), reaction mixture was heated 16 hours at 65 ℃.Along with mixture becomes evenly, the violent carbonic acid gas of emitting disappears gradually.Concentrated reaction mixture also is dissolved in resistates in the methylene dichloride.Methylene dichloride filters through diatomite (about 50g), and concentrate eluant obtains ester products, and yield is 99%.

Adopt the following ester of this method preparation:

6-bromo-1,2-benzisothiazole-3-carboxylic acid tert-butyl ester

Method 2

Method 2 provides by aniline and has prepared indoline diketone and the method that the indoline diketone is changed into corresponding indazole-3-carboxylic acid.

The solution of aniline (565mL) in 6N hydrochloric acid (106mL) that replaces is added 2,2, in 2-three chloro-1-ethoxy ethanols (678mL) and the suspension of sodium sulfate (3.15mol) in water (1.4L), and with reaction mixture vigorous stirring 1 hour.The solution of disposable adding oxammonium hydrochloride (2.08mol) in water (650mL), and with this reaction mixture in 80 ℃ the heating 1.5 hours.This reaction mixture is cooled to 10 ℃, filter collecting precipitation solid, wash with water and the dry acid amides that obtains, yield is 91%.

To heat 6 hours at 60 ℃ in this acid amides adding sulfuric acid (1.9L) and with this reaction mixture.This reaction mixture is cooled to room temperature also carefully to be poured in the ice (7kg).Filter collecting precipitation solid, wash with water and the dry indoline diketone that obtains, yield is 61%.

The indoline diketone that replaces is changed into corresponding indazole-3-carboxylic acid with identical about indazole-described method of 3-carboxylic acid: Snyder, people such as H.R., J.Am.Chem.Soc.1952,74,2009.The indoline diketone (22.1mmol) that replaces was heated 30 minutes down with 1N sodium hydroxide (24mL) dilution and at 50 ℃.Burgundy solution is cooled to room temperature and placed 1 hour.Reaction mixture is cooled to 0 ℃, and with the 0 ℃ solution-treated of Sodium Nitrite (22.0mmol) in water (5.5mL).Under 0 ℃, add this solution by the dropper below the liquid level of solution that is immersed into the vigorous stirring of sulfuric acid (2.3mL) in water (45mL).15 minutes consuming time of adition process, and reactant placed 30 minutes again.In 10 minutes, in reaction mixture, add tin chloride (II) dihydrate (52.7mmol) cold (0 ℃) solution in concentrated hydrochloric acid (20mL), and reaction mixture was placed 60 minutes.The filtering separation precipitated solid, wash with water and dry, obtain the quantitative material surplus.The purity of this material ( ¹H NMR and LC/MS) be enough to be used in next step and need not to be further purified.Perhaps should acid recrystallization from acetate, obtain pure substance.

Adopt the following acid of this method preparation:

6-bromo-1H-indazole-3-acid.

5-methoxyl group-1H-indazole-3-acid.

6-methoxyl group-1H-indazole-3-acid.

Method 3

Method 3 provides with ketone capture indazole lithium aryl and has reached and the coupling of 3-amino quinine ring, forms the method for Hete rocyclic derivatives.

By reacting, then prepare 6-bromo-indazole-3-carboxylic acid tert-butyl ester by acid with sodium-hydroxide treatment with 2 times of excessive tert-Butyl dicarbonates.(4.8mmol) slowly adding the 6-bromo-indazole-solution of 3-carboxylic acid tert-butyl ester (4.0mmol) in tetrahydrofuran (THF) (4mL) in the suspension in tetrahydrofuran (THF) (40mL) to sodium hydride (60% mineral oil dispersion liquid) under 0 ℃.After stirring 0.5 hour under 0 ℃, this mixture is cooled to-78 ℃, and adds pentane (5.1mmol) solution of 1.7M tert-butyl lithium.At-78 ℃ after following 0.5 hour, drip the solution of Tetrahydro-pyran-4-one (5mmol) in tetrahydrofuran (THF) (1mL).This mixture was descended stirring 1 hour and was warmed to 0 ℃ at-78 ℃.The reaction of reaction mixture is stopped with saturated aqueous ammonium chloride, and this mixture distributes between ethyl acetate (100mL) and water (100mL).Separate organic layer,, and concentrate with salt solution (50mL) washing, dry (sal epsom).By chromatography (70/30 ethyl acetate/hexane) purifying resistates, obtain 6-(4-hydroxy tetrahydro pyrans-4-yl)-1H-indazole-3-carboxylic acid tert-butyl ester colorless solid (68%), it is a colorless solid.

6-(4-hydroxy tetrahydro pyrans-4-yl)-1H-indazole-3-carboxylic acid tert-butyl ester (0.86mmol) is dissolved in the trifluoroacetic acid (3mL), and this mixture was at room temperature placed 16 hours.Go down to desolventize in vacuum, resistates grinds with ethyl acetate, obtains 6-(3,6-dihydro-2H-pyrans-4-yl)-1H-indazole-3-carboxylic acid (76%).Should acid and the coupling of quinine cyclammonium according to method A.

6-(4-hydroxy tetrahydro pyrans-4-yl)-1H-indazole-3-carboxylic acid tert-butyl ester (1.0mmol) places (take up) at trifluoroacetic acid (5mL), triethyl silicane (2mL) and methylene dichloride (3mL), and this mixture was refluxed 16 hours.Solvent removed in vacuo is used the ethyl acetate grinding residues, obtains 6-(tetrahydropyran-4-base)-1H-indazole-3-carboxylic acid (60%), and it is a brown solid.。

Adopt this method following acid of preparation and ester:

5-(tetrahydrochysene-2H-pyrans-4-yl)-1H-indazole-3-carboxylic acid.

6-(tetrahydrochysene-2H-pyrans-4-yl)-1H-indazole-3-carboxylic acid.

Tertiary butyl 6-formyl radical-1H-indazole-3-carboxylic acid.

6-formyl radical-1H-indazole-3-carboxylic acid tert-butyl ester.

Method 4

Method 4 provides the method that is prepared N-1-alkylation indazole-3-carboxylic acid by corresponding indazole ester.

In the 5-methoxyl group indazole-solution of 3-carboxylic acid, ethyl ester (1.50mmol) in acetonitrile (15mL), add salt of wormwood (5.99mmol) and methyl iodide (3.00mol).This is reflected at 60 ℃ heated 4 hours down, be cooled to room temperature, and between water (50mL) and ethyl acetate (50mL), distribute.Separate each layer, with salt solution (25mL) washing organic layer, drying (sal epsom) and concentrated.The resistates chromatography purification, the gradient of employing 95/5 to 80/20 hexane/ethyl acetate by the chromatography purification resistates, obtains the indazole (17%) of 2-replacement and the indazole (44%) that 1-replaces.(61mg 0.26mmol) is suspended in the ethanol (5.0mL) indazole that 1-is replaced and heating is separated with hydrotropy.Add the 5.0M solution aliquots containig of sodium hydroxide in water (2.00mL), and this reaction mixture was at room temperature placed 16 hours.With reaction mixture water (50mL) dilution and use the 6.0N hcl acidifying.(3 * 50mL), the organic layer of merging also concentrates with salt solution (25mL) washing, dry (sal epsom) water layer, obtains acid thus, and yield is 95% with ethyl acetate extraction.

Adopt the following acid of this method preparation:

6-bromo-1-methyl isophthalic acid H-indazole-3-carboxylic acid.

6-bromo-1-ethyl-1H-indazole-3-carboxylic acid.

1-ethyl-6-methoxyl group-1H-indazole-3-carboxylic acid.

Method 5

Method 5 provides by 3-bromo-4-nitrophenols and has prepared the method for 5-difluoro-methoxy indazole-3-acid.

3-bromo-4-nitrophenols (10.0mmol) is added to sodium hydroxide (29.0mmol) at N, in the suspension of dinethylformamide (15mL), and this suspension at room temperature placed 15 minutes.Reaction mixture is cooled to 0 ℃, and handles with chlorine ethyl difluoro (20.0mmol).This reaction mixture is in 70 ℃ of heating 16 hours and concentrated.(3 * 100mL) extract resistates with frozen water (200mL) dilution and with ethyl acetate.The organic layer that merges carries out drying (sal epsom) and concentrates, and obtains difluoro methyl ether, and it is a yellow oil, and yield is 75%.

Under 0 ℃, diethyl malonate (328mmol) is dropped in the suspension of sodium hydride (328mmol) in methyl-sulphoxide (40mL).Reaction mixture is warmed to 60 ℃ and kept 0.5 hour.Drip the solution of difluoro methyl ether (149mmol) in methyl-sulphoxide (80mL), and reaction mixture was heated 5 hours at 100 ℃.Refrigerative solution is poured in the frozen water, with methylene dichloride (3 * 100mL) aqueous layer extracted.The organic layer drying (sal epsom) that merges also concentrates, and obtains the crude product diester, and it is an oil, and yield is 112%.Merge this diester (167mmol), sodium hydroxide (500mmol) and water (335mL), and heated 1 hour down at 60 ℃.This reaction mixture is cooled to room temperature, and (3 * 100mL) wash water layer with methylene dichloride.The pH of water layer carefully is adjusted to 1 with concentrated hydrochloric acid, this reaction mixture was heated 1 hour down at 60 ℃.Suspension is cooled to 5 ℃, and solid collected by filtration is also dry, obtains acid, and yield is 61%.

Under 0 ℃, Acetyl Chloride 98Min. (203mmol) is dropped in the ethanol (300mL).0.5 after hour, add this acid (101mmol), and with reaction mixture reflux 15 hours.Reaction mixture is concentrated, and resistates distributes between methylene dichloride (200mL) and saturated sodium bicarbonate (100mL).Water layer is further used methylene dichloride, and (2 * 200mL) extractions are carried out the organic layer that merges drying (sal epsom) and concentrate obtaining ester, and it is a brown oil, and yield is 60%.

This ester (60.4mmol) is dissolved in the ethanol (103mL), and water (71mL) dilutes, and handles with ammonium chloride (243mmol) and iron powder (301mmol).With reaction mixture reflux 10 minutes, with suspension filtered by diatomite, and with filter cake with washing with alcohol 3 times.Concentrated filtrate is suspended in resistates in the 2N hydrochloric acid, and vigorous stirring 0.5 hour.With ethyl acetate (3 * 50mL) washing water layers, and with 5M sodium hydroxide with pH regulator to 9-10.With chloroform (3 * 100mL) aqueous layer extracted, and the organic layer of dry (sal epsom) merging.In organic layer, add diacetyl oxide (392mmol), Isopentyl nitrite (291mmol) and potassium acetate (51.0mmol), and with suspension reflux 16 hours.Evaporating solns, and resistates distributed between saturated sodium bicarbonate (50mL) and methylene dichloride (100mL).(2 * 100mL) further aqueous layer extracted, the organic layer that dry (sal epsom) merges, and concentrating obtain N-ethanoyl indazole ester, and it is a brown oil, and yield is 79% with methylene dichloride.

Merge this ester (63.8mmol), sodium hydroxide (193mmol) and water (65mL), and reactant was kept 24 hours down at 60 ℃.After being cooled to room temperature, with methylene dichloride (3 * 50mL) washing water layers.With concentrated hydrochloric acid water layer is adjusted to pH 1.Filter the solid of collecting precipitation, water and washed with dichloromethane, and dry, obtain acid, yield is 27%.

Following sour according to this method preparation:

5-(difluoro-methoxy)-1H-indazole-3-carboxylic acid.

Method 6

Method 6 provides the method that is prepared 6-difluoro-methoxy indazole-3-acid by the 4-nitrophenols.

At N, add 4-nitrophenols (162mmol) to sodium hydroxide (485mmol) in the suspension in the dinethylformamide (150mL), and suspension was at room temperature placed 15 minutes.Reaction mixture is cooled to 0 ℃, and handles with chlorine ethyl difluoro (329mmol).Reaction mixture was heated 16 hours down at 70 ℃, and concentrate.Dilute resistates with frozen water (200mL), and (3 * 100mL) extract with ethyl acetate.The organic layer that dry (sal epsom) merges, and concentrate, obtaining difluoro methyl ether, it is a yellow oil, yield is 59%.

Nitro-ether (149mmol) is dissolved in the ethanol (37.5mL), and water (25mL) dilutes, and handles with ammonium chloride (84.7mmol) and iron powder (105mmol).With reaction mixture reflux 30 minutes, and suspension filtered passed through diatomite.With filter cake washing with alcohol 3 times, and concentrate the filtrate that merges.Resistates is dissolved in the water, and with 5M sodium hydroxide with pH regulator to 9-10.With ethyl acetate (3 * 100mL) aqueous layer extracted, the organic layer that dry (sal epsom) merges, and be condensed into yellow oil.This oil is dissolved in the diacetyl oxide (23.5mmol), and reaction mixture was at room temperature placed 16 hours.Water (50mL) diluted reaction mixture, and neutralize with solid sodium bicarbonate.The filtering separation precipitated solid washes with water, and dry, obtains ethanamide, and it is a light yellow solid, and yield is 62%.

In the solution of ethanamide (19.6mmol) in chloroform (20mL), add diacetyl oxide (19.6mmol), and reaction mixture is heated to backflow.Drip nitrosonitric acid (16.0mmol), and with reaction mixture refluxed 30 minutes.Water (20mL) dilution refrigerative solution, and with methylene dichloride (3 * 10mL) aqueous layer extracted.The organic layer that dry (sal epsom) merges, and concentrate, obtaining the nitro acid amides, yield is 83%.

Merge this acid amides (11.0mmol), sodium hydroxide (43.8mmol) and water (10mL), and reaction mixture was kept 1.5 hours down at 60 ℃.Reaction is cooled to room temperature, and the filtering separation precipitated solid, wash with water, and dry, obtaining aniline, it is a light yellow solid, yield is 98%.

Aniline (15.7mmol) and 40% Hydrogen bromide (14.3g) and water (10mL) are mixed, and with reaction mixture heat ester 80-90 ℃ so that aniline dissolve fully.Reaction mixture is cooled to 0 ℃, and in 15 minutes, adds the solution of Sodium Nitrite (23.2mmol) in water (5.3mL).Solution was kept 40 minutes down at 0-5 ℃, and filter.Cupric bromide (I) (18.8mmol) is dissolved in 40% Hydrogen bromide (21mL), and is cooled to 0 ℃.Azide salt solution is slowly added in the copper solutions, and mixture was kept 30 minutes down at 0-10 ℃.With reaction mixture 60 ℃ of down heating 30 minutes, then 100 ℃ down heating 10 minutes react completely guaranteeing.Reaction mixture is cooled to room temperature, and (3 * 40mL) extract with methylene dichloride.Organic layer with 1M sodium hydroxide, water, 1N hydrochloric acid and water washing merging.Dry (sal epsom) organic layer, and concentrate, obtaining the nitro bromide, it is a light yellow solid, yield is 76%.

Under 0 ℃, in the suspension of sodium hydride (25.8mL) in methyl-sulphoxide (5mL), drip diethyl malonate (25.7mmol).Reaction mixture is heated to 60 ℃, and kept 30 minutes.Drip the solution of nitro bromide (11.7mmol) in methyl-sulphoxide (7mL), and reaction mixture was heated 5 hours down at 100 ℃.In refrigerative solution impouring frozen water, and with methylene dichloride (3 * 100mL) aqueous layer extracted.The organic layer that dry (sal epsom) merges, and concentrate, obtaining the crude product diester, it is an oil.Merge this diester (11.7mmol), sodium hydroxide (35mmol) and water (20mL), and heated 1 hour down at 60 ℃.Reaction mixture is cooled to room temperature, and (3 * 100mL) wash water layers with methylene dichloride.With concentrated hydrochloric acid the pH of water layer carefully is adjusted to 1, and with reaction mixture 60 ℃ of heating 1 hour down.Suspension is cooled to 0 ℃, solid collected by filtration, and dry, obtain acid, yield is 64%.

Under 0 ℃, dripping acetyl chloride (15.3mmol) in ethanol (50mL).After 30 minutes, add acid (7.69mmol), and with reaction mixture reflux 15 hours.Concentrated reaction mixture, and resistates distributed between methylene dichloride (20mL) and saturated sodium bicarbonate (10mL).(2 * 20mL) further aqueous layer extracted, the organic layer that dry (sal epsom) merges, and concentrating obtain ester, and it is a brown oil, and yield is 94% with methylene dichloride.

Under 0 ℃, in the suspension of this ester (3.64mmol) and acetate (7.0mL), add diacetyl oxide (6.0mL).In 15 minutes, divide several parts to add zinc powder (14.6mmol), reaction mixture is placed 30 minute down, and then at room temperature placed 1.5 hours at 0 ℃.Add zinc powder (6.15mmol) again, and reaction mixture was placed 3 hours.Suspension filtered is passed through diatomite, and concentrated filtrate.Resistates is distributed between saturated sodium bicarbonate (10mL) and ethyl acetate (20mL).(3 * 20mL) further aqueous layer extracted, the organic layer that dry (sal epsom) merges, and concentrating obtain ethanamide, and it is a brown oil, and yield is 92% with ethyl acetate.

In the solution of this ethanamide (3.92mmol) in chloroform (20mL), add diacetyl oxide (13.7mmol), Isopentyl nitrite (13.7mmol) and potassium acetate (2.04mmol), and with suspension reflux 16 hours.Evaporating solns, and resistates distributed between saturated sodium bicarbonate (10mL) and methylene dichloride (20mL).(2 * 20mL) further aqueous layer extracted, the organic layer that dry (sal epsom) merges, and concentrating obtain crude product N-ethanoyl indazole ester, and it is a brown oil with methylene dichloride.

Merge this ester (3.36mmol), sodium hydroxide (10mmol) and water (5mL), and reactant was kept 24 hours down at 60 ℃.After being cooled to room temperature, with methylene dichloride (3 * 30mL) washing water layers.With concentrated hydrochloric acid water layer is adjusted to pH 1, filters the solid of collecting precipitation, water and washed with dichloromethane, and dry, obtain acid, yield is 26%.

Following sour according to this method preparation:

6-(difluoro-methoxy)-1H-indazole-3-carboxylic acid.

Method 7

Method 7 provides the method for the acid to form heteroaryl and replace of coupling between bromination benzisothiazole-3-carboxylicesters and bromination indazole-3-carboxylicesters and Grignard reagent.

The 0.5M solution of Grignard reagent (75.0mmol) in tetrahydrofuran (THF) with tetrahydrofuran (THF) (150mL) dilution, is cooled to 5 ℃, and handles with zinc chloride solid (165mmol).This reaction mixture is warmed to room temperature, adds bromination ester (28.2mmol) and tetrakis triphenylphosphine palladium (0) (1.64mmol).This suspension is 65 ℃ of heating 16 hours and concentrated down.Reactant is distributed between ethyl acetate (250mL) and 7M ammonium chloride (500mL).(3 * 250mL), the extract of merging is through dried over sodium sulfate and be concentrated into dried with ethyl acetate extraction for water layer.Resistates adopts 100/0 to 97/3 chloroform/methanol gradient by chromatography purification, obtains ester, and yield is 80%.This ester is suspended in the methyl alcohol (100mL) also with 8M sodium hydroxide (30mL) processing.This mixture is cooled to room temperature, filtration and is acidified to pH＜2 by slow adding concentrated hydrochloric acid 60 ℃ of heating 3 hours.Water layer is concentrated, and the resistates water grinds.The solid of Sheng Chenging recrystallization in water obtains acid thus, and yield is 81%.

The Grignard reagent of thiazole is commercially available.Perhaps, lithium aryl and corresponding aryl zincon can be according to Reeder, people such as M.R., and Org.Proc.Res.Devel.2003, the method for general introduction generates in 7,696.Zincon according to this method Zhi Bei oxazole.

Following sour according to this method preparation:

6-(1,3-thiazoles-2-yl)-1H-indazole-3-carboxylic acid.

6-(1,3-oxazole-2-yl)-1H-indazole-3-carboxylic acid.

1-ethyl-6-(1,3-oxazole-2-yl)-1H-indazole-3-carboxylic acid.

Method 8

Method 8 provides by corresponding indazole ester and has adopted alkylation conditions to prepare the indazole acid of N-methoxy ethoxy methyl and the protection of N-trimethylsilylethoxymethyl and the method for ester.

N (1)-alkylating exemplary process: to sodium hydride (60% mineral oil dispersion liquid, 8.1mmol) Dropwise 5-(benzyloxy)-1H-indazole in 0 ℃ of suspension in tetrahydrofuran (THF) (the 54.0mL)-solution of 3-carboxylic acid (2.70mmol) in tetrahydrofuran (THF) (10mL).Reactant was kept 1 hour down at 0 ℃.Add [β-(trimethyl silyl) oxyethyl group] methyl chloride (3.2mmol), and reaction mixture was placed 1 hour.Reactant is distributed between water (50mL) and ethyl acetate (50mL),, and concentrate with salt solution (25mL) washing organic layer, dry (sal epsom).By chromatography (95/5 to 85/15 hexane/ethyl acetate) purifying resistates, obtain protected indazole, yield is 89%.

N (2)-alkylating exemplary process: 2-methoxy ethoxy Methochloride (48.0mmol) is slowly added to 6-bromo-1H-indazole-3-carboxylic acid, ethyl ester (40.0mmol) and N, in the suspension of N-diisopropylethylamine (80.0mmol) in methylene dichloride (80.0mL).This reaction becomes homogeneous phase, and at room temperature places 4 hours.Concentrate this reaction mixture and resistates is distributed between water (50mL) and ethyl acetate (100mL).Separate each layer, organic layer is with salt solution (25mL) washing, dry (sal epsom) and concentrate and obtain enough pure product (89%), is N (2)-and the yellow oil of 2/1 mixture of N (1)-regional isomer.

5.0M sodium hydroxide (52mL) is added to 6-bromo-1-[(2-methoxy ethoxy) methyl]-solution of 1H-indazole-3-carboxylic acid, ethyl ester (18.2mmol) in and reaction mixture placed 16 hours.This solution is used 50mL water (50mL) dilution and used the 6.0N hcl acidifying.Pulpous state liquid also concentrates with ethyl acetate (50mL) extraction, organic layer salt solution (25mL) washing, dry (sal epsom).Resistates is recrystallization from toluene, obtains colorless solid (82%), is the mixture of regional isomer.

Adopt this method following ester of preparation and acid:

6-bromo-1-[(2-methoxy ethoxy) methyl]-1H-indazole-3-carboxylic acid.

6-bromo-1-[(2-methoxy ethoxy) methyl]-1H-indazole-3-carboxylic acid, ethyl ester.

6-benzyloxy-1-[(2-methoxy ethoxy) methyl]-1H-indazole-3-carboxylic acid, ethyl ester.

6-bromo-1-{[2-(trimethyl silyl) oxyethyl group] methyl }-1H-indazole-3-carboxylic acid.

6-bromo-1-{[2-(trimethyl silyl) oxyethyl group] methyl }-1H-indazole-3-carboxylic acid, ethyl ester.

5-bromo-1-{[2-(trimethyl silyl) oxyethyl group] methyl }-1H-indazole-3-carboxylic acid.

6-bromo-2-{[2-(trimethyl silyl) oxyethyl group] methyl }-1H-indazole-3-carboxylic acid.

5-bromo-2-{[2-(trimethyl silyl) oxyethyl group] methyl }-1H-indazole-3-carboxylic acid.

6-bromo-2-{[2-(trimethyl silyl) oxyethyl group] methyl }-1H-indazole-3-carboxylic acid, ethyl ester.

5-bromo-2-{[2-(trimethyl silyl) oxyethyl group] methyl }-1H-indazole-3-carboxylic acid, ethyl ester.

5-bromo-1-{[2-(trimethyl silyl) oxyethyl group] methyl }-1H-indazole-3-carboxylic acid, ethyl ester.

Method 9

Method 9 provides by corresponding benzyloxy indazole ester and has adopted three creed parts to prepare the method for alkoxyl group indazole acid.

With 6-benzyloxy-1-[(2-methoxy ethoxy) methyl]-1H-indazole-3-carboxylic acid, ethyl ester (9.38mmol) adds in the suspension of 10% palladium charcoal (249mg) in ethanol (66.7mL).This is reflected under the nitrogen atmosphere (50psi) and vibrated 4.0 hours.This reaction is by diatomite filtration and concentrate acquisition phenol, and it is a white solid, and yield is 87%.

Diisopropyl azodiformate (0.841mmol) is dropped to 6-hydroxyl-1-[(2-methoxy ethoxy) methyl]-1H-indazole-3-carboxylic acid, ethyl ester (0.765mmol), 1-methyl-3-pyrrolidinol (0.917mmol) and the solution of triphenylphosphine (1.15mmol) in tetrahydrofuran (THF) (4.6mL) in.Should react and place 16 hours and concentrated.(100/0 to 90/10 ethyl acetate/[70/30/2 ethyl acetate/methanol/dimethyl amine] obtains ether products to resistates, and yield is 28% by chromatography purification.This ester saponification is obtained acid, this acid employing method C and the coupling of dicyclo alkali.

Adopt the following acid of this method preparation:

6-hydroxyl-1-[(2-methoxy ethoxy) methyl]-1H-indazole-3-carboxylic acid, ethyl ester.

The 1-[(2-methoxy ethoxy) methyl]-6-[(1-methylpyrrolidin-3-yl) the oxygen base]-1H-indazole-3-carboxylic acid.

The 1-[(2-methoxy ethoxy) methyl]-6-(tetrahydrofuran (THF)-3-base oxygen base)-1H-indazole-3-carboxylic acid.

The 1-[(2-methoxy ethoxy) methyl]-6-(tetrahydrochysene-2H-pyrans-4-base oxygen base)-1H-indazole-3-carboxylic acid.

6-[(1-methylpyrrolidin-3-yl) oxygen base]-1,2-benzisothiazole-3-carboxylic acid.

6-(1-azabicyclo [2.2.2] oct-3-yl oxygen base)-1,2-benzisothiazole-3-carboxylic acid.

Method 10

Method 10 provides the method that is prepared the acid of 4-methoxyl group indazole by the 4-anisidine.

Handle the solution of 4-anisidine (1.63mol) in acetate (244mL) with diacetyl oxide (244mL) and zinc powder (30.8mmol), and with reaction mixture reflux 30 minutes.Suspension is cooled to room temperature, filters, and concentrate.Water (200mL) dilution resistates, and with the pH regulator to 8 of 10% sodium hydroxide with solution.Filter the solid of collecting precipitation, water (1L) washing, and dry, obtain ethanamide, it is the purple solid, yield is 94%.

At room temperature, in the solution of this ethanamide (1.52mol) in methylene dichloride (1.5L), drip concentrated nitric acid (210mL).With reaction mixture reflux 1 hour, and be cooled to room temperature.Water (1.0L), saturated sodium carbonate (1.0L) and water (1.0L) washing reaction mixture.Use the anhydrous sodium sulfate drying organic layer, and concentrate, obtain the nitro ethanamide, it is an orange solids, and yield is 83%.

Handle the solution of this nitro ethanamide (1.27mol) in water (1.27L) with sodium hydroxide (5.07mol), and reaction mixture was heated 2 hours down at 60 ℃.Filter the solid of collecting precipitation, wash with water, and dry, obtaining N-methyl-p-nitroaniline, it is an orange solids, yield is 85%.

In this N-methyl-p-nitroaniline (1.08mol) cold (0-5 ℃) solution in Hydrogen bromide (4.87mol) (by reaction mixture is heated preparation in 2 hours down at 90 ℃), add the solution of Sodium Nitrite (1.48mol) in water (250mL).Reaction mixture was placed 40 minutes, and filtered.Filtrate is splashed into cupric bromide (I) (1.81mol) in cold (0-5 ℃) solution in Hydrogen bromide (640mL), and reaction mixture was placed 30 minutes.Reaction mixture is heated to 60 ℃, and placed 30 minutes.With the reaction mixture reflux and placed 1 hour.Water (2L) diluted reaction mixture, and with methylene dichloride (3 * 1L) extraction.With the organic layer that 10% sodium hydroxide (1.0L), water (2.0L), 10% hydrochloric acid (1.6L) and water (2.0L) washing merge, dry (sal epsom), and concentrate.With resistates recrystallization from ethanol, obtain bromide, it is a yellow solid, yield is 50%.

In the solution of this bromide (216mmol) in ethanol (200mL) and water (140mL), add iron powder (1.08mol) and ammonium chloride (862mmol), and with reaction mixture reflux 1 hour.Filtering suspension liquid also concentrates, with ethyl acetate (3 * 200mL) extracted residues.The organic layer that dry (sodium sulfate) merges, and concentrate, obtaining bromaniline, it is a yellow liquid, yield is 96%.

Add the solution of this bromaniline (208mmol) in 50% hydrochloric acid (40mL) to trichoro-aldehyde hydrate (312mmol) and sodium sulfate (967mmol) in the solution in water (450mL), and reaction mixture was placed 1 hour.Add the solution of oxammonium hydrochloride (793mmol) in water (240mL), and reaction mixture was heated 2 hours down at 60 ℃.Decant water layer, and pass through the reddish oil of chromatography (6/6/1 sherwood oil/dichloromethane/ethyl acetate) purifying remnants, it obtains α-amide oxime placing after fixing, and it is a light yellow solid, and yield is 29%.

In the sulfuric acid (16mL) of (40 ℃) 90% that the disposable adding of this α-amide oxime (58.6mmol) is warm, and with reaction mixture 60 ℃ of heating 30 minutes down.Reaction mixture is cooled to room temperature, and in the impouring frozen water.Filter the orange solids of collecting precipitation, and dry.By chromatography (15/1 petrol ether/ethyl acetate) purifying crude product, obtain the indoline diketone, it is a yellow solid, yield is 57%.

This indoline diketone (20.7mmol) is mixed with 1M sodium hydroxide (23mL), and reaction mixture was heated 30 minutes down at 30-40 ℃.Reaction mixture is cooled to 0 ℃,, and placed 20 minutes with the solution-treated of Sodium Nitrite (20.7mmol) in water (5.1mL).In the vitriol oil (2.24mL) cold (0-5 ℃) solution in water (43.3mL), drip this solution, and reaction mixture was placed 0.5 hour.The tin chloride (II) of dropping in concentrated hydrochloric acid (19.6mL) be solution (50.5mmol), and reaction mixture was placed 1 hour down at 0-5 ℃.The filtering separation precipitated solid, and dry, obtaining indazole acid, it is yellow solid (being 100% in mass).

Under 0 ℃, in methyl alcohol (180mL), add Acetyl Chloride 98Min. (18mL), and reaction mixture was placed 1 hour.Add indazole acid (21.8mmol), and with reaction mixture reflux 3 hours.Solution concentration to doing, is suspended in resistates in the water, and with saturated sodium bicarbonate with pH regulator to 7.With ethyl acetate (3 * 100mL) extraction mixtures, the organic layer that dry (sal epsom) merges, and concentrating.By chromatography (2/1 petrol ether/ethyl acetate) purifying crude product, obtain the indazole ester, it is a yellow solid, yield was 5% (two step).

Under nitrogen atmosphere, this indazole ester (1.02mmol) and 10% palladium/carbon (30mg) and methyl alcohol (20mL) are merged, and at room temperature placed 30 minutes.Remove by filter catalyzer, and concentrate eluant, obtain the indazole ester of debrominateization, it is an orange solids, and yield is 24%.

In the solution of indazole ester (0.243mmol) in methyl alcohol (3.0mL) of this debrominateization, add 1M sodium hydroxide (1.5mL), and reaction mixture was heated 3 hours down at 60 ℃.Concentrate this solution, to 1-2, and solid collected by filtration obtains indazole acid with pH regulator, and it is a yellow solid,, yield is 100%.

Adopt the following acid of this method preparation:

4-methoxyl group-1H-indazole-3-carboxylic acid.

Method 11

Method 11 provides by corresponding bromo nitryl benzene and has prepared the indazole-3-carboxylic acid of benzyloxy-replacement and the method for ester.

In the solution of 4-methoxy nitrobenzene (230mmol) in glacial acetic acid (34mL), add diacetyl oxide (34mL) and zinc powder (4.59mmol), and with reaction mixture reflux 0.5 hour.In reaction mixture impouring water (340mL), and with the pH regulator to 8 of 10% sodium hydroxide with solution.The filtering separation precipitated solid, water (100mL) washing, and dry, obtain ethanamide, yield is 88%.

In 0.5 hour, in the solution of this ethanamide (200mmol) in methylene dichloride (200mL), drip 65% nitric acid (22mL).Reaction mixture is at room temperature placed 1 hour, and reflux 1 hour.Water (200mL), saturated sodium carbonate solution (100mL) and water (200mL) washing reaction mixture.The organic layer that dry (sal epsom) merges, and concentrate, obtaining the nitro ethanamide, it is a yellow solid, yield is 90%.

In 4M sodium hydroxide (180mL), add this nitro ethanamide (180mmol), and reaction mixture was placed 2 hours down at 60 ℃.The filtering separation precipitated solid washes with water, and dry, obtains N-methyl-p-nitroaniline, and it is a red solid, and yield is 70%.

Under 10 ℃, in the solution of 0.5 hour introversive this N-methyl-p-nitroaniline (125mmol) in 40% Hydrogen bromide (110g), drip the solution of Sodium Nitrite (11.8g) in water (28mL).Reaction mixture was placed 40 minutes down at 0-10 ℃, and filtered.Filtrate was splashed into cupric bromide (I) (209mmol) in 0 ℃ of purple solution in Hydrogen bromide (74mL) in 1 hour.Reaction mixture is warmed to room temperature, at room temperature placed 30 minutes, placed 0.5 hour down at 60 ℃, and reflux 1 hour.Reaction mixture is distributed between water (2.0L) and methylene dichloride (600mL), and with the further aqueous layer extracted of methylene dichloride (300mL).With the organic layer that 10% sodium hydroxide (200mL), water (600mL), 10% hydrochloric acid (300mL) and water (600mL) washing merge, dry (sal epsom), and concentrate, obtain the nitro bromide, it is a yellow oil, and yield is 83%.

Under-78 ℃, in the solution of 1 hour introversive this nitro bromide (100mmol) in methylene dichloride (250mL), drip the solution of boron tribromide (250mmol) in methylene dichloride (200mL).Reaction mixture is warmed to room temperature, and placed 30 hours.Reaction mixture is cooled to 0 ℃, water (300mL) termination reaction, and with ethyl acetate (2 * 300mL) aqueous layer extracted.(organic layer that 2 * 300mL) washings merge, dry (sal epsom), and concentrate obtain nitrophenols, and it is brown crystalline solid, and yield is 87% with saturated sodium bicarbonate.

In the solution of this nitrophenols (87.0mmol) in 2/1 acetonitrile/acetone (840mL), add bromotoluene (131mmol) and salt of wormwood (130mmol).With reaction mixture reflux 17 hours, and be concentrated into dried.Resistates is suspended in the ethyl acetate (756mL), filters, water (567mL), 1M hydrochloric acid (2 * 567mL) and salt solution (567mL) wash organic layer.Dry (sal epsom) organic layer, and concentrate, obtaining benzylic ether, yield is 78%.

Under 0 ℃, in the suspension of sodium hydride (520mmol) in methyl-sulphoxide (100mL), drip diethyl malonate (890mmol).Add this benzylic ether (44.0mmol), and reaction mixture was heated 5 hours down at 100 ℃.In reaction mixture impouring frozen water, and with ethyl acetate (3 * 70mL) extraction.The organic layer that dry (sal epsom) merges, and concentrate, the diethyl malonate adduct obtained.Dilute this diethyl malonate adduct with 4M sodium hydroxide (100mL), and reaction mixture was heated 6 hours down at 60 ℃.With methylene dichloride (3 * 50mL) extraction solutions, and water layer is adjusted to pH 1 with concentrated hydrochloric acid.Reaction mixture was heated 1 hour down at 60 ℃, be cooled to room temperature, and (3 * 50mL) extract with ethyl acetate.The organic layer that dry (sal epsom) merges, and concentrate, obtaining toluylic acid, it is a solid, yield is 78%.

In the alcohol hydrochloric acid solution [Acetyl Chloride 98Min. being added in the ethanol (100mL)] of new system, add this toluylic acid (350mmol), and with reaction mixture reflux 20 hours.Reaction mixture is concentrated into dried, and resistates is distributed between saturated sodium bicarbonate (200mL) and ethyl acetate (150mL).(2 * 50mL) aqueous layer extracted, the organic layer that dry (sal epsom) merges filter and concentrate, and obtain ester, and yield is 77% with ethyl acetate.

Nitro ester (27.0mmol) is dissolved in acetate (60mL) and the diacetyl oxide (44mL), and is cooled to 0 ℃.Add zinc powder (153mmol), reaction mixture is warmed to room temperature, and placed 2 hours.In 3 hours, add the zinc powder (2 * 45.9mmol) of amount in addition again.After 1 hour, filter reaction mixture, and with ethanol (100mL) washing leaching cake.Concentrate the filtrate that merges, and resistates is distributed between saturated sodium bicarbonate and ethyl acetate (50mL).(2 * 50mL) extraction solutions, the organic layer that dry (sal epsom) merges filter, and concentrate, and obtain ethanamide, and yield is 82% with ethyl acetate.

In 30 minutes, in the solution of ethanamide (21.0mmol) in chloroform (80mL) and diacetyl oxide (45mL), drip Isopentyl nitrite (47.2g).Divide several parts to add solid potassium acetates (7.13mmol), and with reaction mixture reflux 1.5 hours.Water (2 * 80mL) and salt solution (80mL) washing reaction mixture, dry (sal epsom), and concentrate, obtaining acetylize indazole ester, yield is 68%.

This acetylize indazole ester (15.0mmol) is suspended in the 2M sodium hydroxide (35mL), and reaction mixture was heated 24 hours down at 60 ℃.With concentrated hydrochloric acid with the pH regulator of solution to 1-2, solid collected by filtration, and dry obtains 6-benzyloxy-1H-indazole-3-carboxylic acid, it is a yellow solid, yield is 28%.

In the alcohol hydrochloric acid solution of new system [by ethanol (20mL) and Acetyl Chloride 98Min. (5mL) preparation], add 6-benzyloxy-1H-indazole-3-carboxylic acid (1.85mmol), with reaction mixture reflux 25 hours, and concentrated.Resistates is distributed between saturated sodium bicarbonate (20mL) and ethyl acetate (20mL), and separate each layer.With ethyl acetate (2 * 20mL) aqueous layer extracted, the organic layer that dry (sal epsom) merges, and concentrating.By chromatography (300/1 methylene chloride) purifying resistates, obtain product, yield is 36.4%.Perhaps, can obtain this ester by this acetylize indazole ester by this acetylize material being placed 30 minutes in the 2M ammoniacal liquor in the methyl alcohol.

Adopt the following acid of this method preparation:

6-benzyloxy-1H-indazole-3-carboxylic acid.

5-benzyloxy-1H-indazole-3-carboxylic acid (by 4-benzyloxy-2-bromo nitryl benzene: referring to Parker, K.A.; Mindt, T.L.Org.Lett., 2002,4,4265).

6-benzyloxy-1H-indazole-3-carboxylic acid, ethyl ester.

5-benzyloxy-1H-indazole-3-carboxylic acid, ethyl ester.

Method 12

Method 12 provides the method that is prepared N (1)-difluoromethyl indazole acid by corresponding indazole-3-carboxylic acid.

Acetyl Chloride 98Min. (141mmol) is dropped in the 6-methoxyl group-solution of 3-indazole-carboxylic acid (26.0mmol) in ethanol (200mL), with this reaction mixture refluxed heating 16 hours.Reaction mixture is cooled to room temperature and concentrated.Resistates is dissolved in the ethyl acetate (300mL) also with sodium hydrogen carbonate solution (2 * 50mL) washings.The water layer that merges is stripped (2 * 200mL) with ethyl acetate.With the organic layer that merges salt solution (50mL) washing, dry (sodium sulfate), ester solid concentrated and dry acquisition 4.91g (86%) under vacuum.

With 6-methoxyl group-1H-indazole-3-carboxylic acid, ethyl ester (4.54mmol) at N, drips of solution in the dinethylformamide (6.11mL) adds to sodium hydride (5.45mmol) and N, in the suspension of dinethylformamide (12.2mL), and this reaction mixture at room temperature placed 30 minutes.(17.0mol) blasts this reaction with chlorodifluoromethane, and mixture is warmed to 80 ℃ and placed 2 hours.This mixture water (200mL) dilution, the collecting precipitation thing obtains white solid.Be dissolved in this solid in the ethanol (20.0mL) and add 5.0M sodium hydroxide solution (3.6mL).This reaction mixture was at room temperature placed 2 hours, and water (50mL) dilution is also used the 6.0N hcl acidifying.Collecting precipitation thing and dry acquisition acid, yield is 65%.

Adopt the following acid of this method preparation:

1-(difluoromethyl)-6-methoxyl group-1H-indazole-3-carboxylic acid.

6-bromo-1-(difluoromethyl)-1H-indazole-3-carboxylic acid.

Method 13

Method 13 provides the method that is prepared 5-azaindazole-3-carboxylic acid by the 4-chloropyridine.

Saturated sodium bicarbonate aqueous solution is carefully added in the solution of 4-chloropyridine hydrochloride (56.7mmol) in water (20mL), be alkalescence up to this solution.(3 * 25mL) extract with hexane with this mixture.The organic layer that merges is through dried over mgso and be concentrated into about 25mL, obtains free base solution.

(2.0M 68mmol) drops to N in pentane, in the solution of N-Diisopropylamine (62.3mmol) in tetrahydrofuran (THF) (61.6mmol), this reaction mixture kept 30 minutes with n-Butyl Lithium under 0 ℃.This reaction mixture is cooled to-78 ℃, drips the hexane solution of 4-chloropyridine, this mixture was placed 1 hour.Oxalic acid diethyl ester (56.7mmol) is added in the orange homogeneous phase solution, this mixture is warmed to room temperature.Analyzing the main product of demonstration by LC/MS is not ethyl oxalate, but N, the N-diisopropylamide.This is reflected at distribution between water (50mL) and ethyl acetate (50mL).Separate each layer, organic phase also concentrates with salt solution (25mL) washing, dry (sal epsom).Resistates is dissolved in the ethanol (50.0mL), handles, and this mixture heating up was refluxed 1 hour with hydrazine (160mmol).Concentrate this reaction mixture, resistates obtains 1.20g (8.6%) hydrazone product with the methylene dichloride titration.

N, N-di-isopropyl-1H-pyrazolo [4,3-c] pyridine-3-carboxamide (0.800g, 0.00325mol) and aqueous hydrochloric acid (10M, mixture 3.00mL) in microwave reactor 120 ℃ the heating 10 minutes.This mixture needs heating to be set to avoid accumulated pressure in high light absorption ratio.This reacts dilute with water, and neutralizes with 3N sodium hydroxide.Collect the white precipitate that generates thus, find that it is the mixture of an acid (47%) and a sec.-propyl acid amides (25%).Can use this mixture and need not to be further purified.

Adopt the following acid of this method preparation:

1H-pyrazolo [4,3-c] pyridine-3-carboxylic acid.

Method 14

Method 14 provides the method that is prepared 6-azaindazole-3-carboxylic acid by 4-chloro-3-nitropyridine.

With the third-1, (tetr-butyl ethyl propane-1,3-dioate) (26.6mmol) adds in the suspension of sodium hydride (1.11g) in tetrahydrofuran (THF) (50.0mL) 3-two tert-butyl acrylate ethyl esters under 0 ℃.This reaction mixture is warmed to room temperature and kept 30 minutes.Then this reaction mixture is cooled to 0 ℃, drips 4-chloro-3-nitropyridine (12.6mmol) at tetrahydrofuran (THF)/N, and dinethylformamide (9/1, in solution 10mL).This mixture is warmed to room temperature and kept 1 hour.This reaction water (50mL) stops and is neutralized to pH with acetate being 5 (in and time color by the dark-brown yellowing).This mixture is with ethyl acetate extraction (50mL), the organic layer of merging with salt solution (25mL) washing, dry (sal epsom), and concentrate and obtain product, yield is 94%.

Crude product (3-nitropyridine-4-yl) propanedioic acid tert-butyl ester ethyl ester (12.6mmol) is dissolved in 4/1 methylene dichloride/trifluoroacetic acid (25.0mL) also with this mixture heating up backflow 2 hours.This reaction mixture is concentrated, and resistates distributes between saturated sodium bicarbonate aqueous solution (50mL) and ethyl acetate (50mL).Separate each layer, ethyl acetate layer also concentrates with salt solution (25mL) washing, dry (sal epsom).Resistates carries out purifying (95/5 dichloromethane/ethyl acetate) by chromatography and obtains product, and yield is 77%.

In Pa Er (Parr) voltage-resistant reactor, with ethanol (25.0mL) dilution (3-nitropyridine-4-yl) ethyl acetate (9.66mmol) and 10% palladium charcoal (2.10g).Reaction mixture was vibrated 3 hours down in nitrogen atmosphere (30psi).(diatomite) filter reaction mixture also concentrates to obtain product, and yield is 97%.

Isopentyl nitrite (18.9mmol) is added in (3-aminopyridine-4-yl) ethyl acetate (9.43mmol), potassium acetate (11.3mmol) and the solution of diacetyl oxide (28.3mmol) in chloroform (10.0mL), this is reflected at 60 ℃ and heated 16 hours down.The refrigerative reaction mixture is carefully diluted with sodium bicarbonate aqueous solution, and with dichloromethane extraction (2 * 50mL).The organic layer that merges also concentrates with salt solution (25mL) washing, dry (sal epsom).Resistates is by the mixture of chromatography prepurification (50/50 to 0/100 hexane/ethyl acetate) with acquisition product mixture.This mixture is dissolved in the ethanol (10.0mL), placed 16 hours with 5.0M sodium hydroxide (5.00mL) dilution and with this reaction mixture.Reaction mixture is concentrated into～5mL, water (20mL) dilutes, and neutralizes with acetate.Collect yellow solid to obtain required product by filtering, yield is 18%.

Adopt the following acid of this method preparation:

1H-pyrazolo [3,4-c] pyridine-3-carboxylic acid.

Method 15

Method 15 provides the method that is prepared amino benzisothiazole-3-carboxylic acid by ester.

In microwave container mixed carbonic acid caesium (3.18mmol), acid chloride (II) (0.24mmol) and 2-dicyclohexylphosphontetrafluoroborate-2 ', 4 ', 6 '-three-sec.-propyl-1,1 '-phenylbenzene (0.24mmol) and in this container, charge into nitrogen.Add (R)-(+)-3-pyrrolidinol (3.18mol) and 6-bromo-1, the 2-benzisothiazole-solution of 3-carboxylic acid tert-butyl ester (1.59mol) in tetrahydrofuran (THF) (20.0mL).Seal this container and descend heating 30 minutes at 135 ℃.This reaction mixture is by diatomite filtration (ethyl acetate), concentrated filtrate.Resistates obtains the ester of purifying by chromatography (70/30 to 50/50 hexane/ethyl acetate) purifying.With this ester be dissolved in methylene dichloride/trifluoroacetic acid (4: 1,2.00mL) in and placed 16 hours.This reaction mixture is concentrated to obtain product, and yield is 23%.Can use this product and need not to be further purified.

Perhaps, when adopting 6-bromo-1, during 2-benzisothiazole-3-carboxylic acid, ethyl ester, the solution of this ester in ethanol adopts the saponification of 5N sodium hydroxide.The dilute with water after-filtration is collected this acid and is neutralized with acetate.

Adopt this method following acid of preparation and ester:

6-[(3R)-and 3-hydroxyl pyrrolidine-1-yl]-1,2-benzisothiazole-3-carboxylic acid.

6-[(3S)-and 3-hydroxyl pyrrolidine-1-yl]-1,2-benzisothiazole-3-carboxylic acid.

6-[(3R)-and 3-methoxyl group tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-carboxylic acid.

6-[(3S)-and 3-methoxyl group tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-carboxylic acid.

6-(3-methoxyl group tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-carboxylic acid.

6-[(3S)-and 3-dimethylamino tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-carboxylic acid.

6-[(3R)-and 3-dimethylamino tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-carboxylic acid.

6-(3-oxyethyl group amino-pyrrolidine-1-yl]-1,2-benzisothiazole-3-carboxylic acid.

6-[(1S, 4S)-the 2-oxa--5-azabicyclo [2.2.1] heptan-5-yl]-1,2-benzisothiazole-3-carboxylic acid.

7-bromo-1,2-benzisothiazole-3-carboxylic acid tert-butyl ester.

7-[(3R)-and 3-hydroxyl pyrrolidine-1-yl]-1,2-benzisothiazole-3-carboxylic acid.

7-[(3S)-and 3-hydroxyl pyrrolidine-1-yl]-1,2-benzisothiazole-3-carboxylic acid.

6-[(1S, 4S)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo [2.2.1] heptan-2-yl]-1,2-benzisothiazole-3-carboxylic acid.

6-[(1S, 4S)-5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl]-1,2-benzisothiazole-3-carboxylic acid.

The 6-[3-[(tert-butoxycarbonyl) (methyl) amino] tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-carboxylic acid.

6-[3-(methoxymethyl) tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-carboxylic acid.

6-[4-(dimethylamino) piperidines-1-yl]-1,2-benzisothiazole-3-carboxylic acid.

6-(1,4-diazabicyclo [3.2.2] ninth of the ten Heavenly Stems-4-yl)-1,2-benzisothiazole-3-carboxylic acid.

6-[(1R, 4R)-5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl]-1,2-benzisothiazole-3-carboxylic acid.

6-(tetramethyleneimine-1-yl)-1,2-benzisothiazole-3-carboxylic acid.

6-(4-methylpiperazine-1-yl)-1,2-benzisothiazole-3-carboxylic acid.

6-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl)-1,2-benzisothiazole-3-carboxylic acid.

(hexahydropyrrolo is [1,2-a] pyrazine-2 (1H--yl)-1 also, 2-benzisothiazole-3-carboxylic acid for 6-.

6-(5-methyl-2,5-diazabicyclo [2.2.2] suffering-2-yl)-1,2-benzisothiazole-3-carboxylic acid.

6-(8-methyl-3,8-diazabicyclo [3.2.1] oct-3-yl)-1,2-benzisothiazole-3-carboxylic acid.

5-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl)-1,2-benzisothiazole-3-carboxylic acid.

5-[(3R)-and 3-methoxyl group tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-carboxylic acid.

5-[(3S)-and 3-methoxyl group tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-carboxylic acid.

5-[(3S)-3-(cyclo propyl methoxy) tetramethyleneimine-1-yl]-2-{[2-(trimethyl silyl) oxyethyl group] methyl }-1H-indazole-3-carboxylic acid.

5-[(3S)-3-(methoxyl group) tetramethyleneimine-1-yl]-2-{[2-(trimethyl silyl) oxyethyl group] methyl }-1H-indazole-3-carboxylic acid.

5-((3R)-3-{[2-(trimethyl silyl) oxyethyl group] methoxyl group } tetramethyleneimine-1-yl)-1,2-benzisothiazole-3-carboxylic acid.

5-((3S)-3-{[2-(trimethyl silyl) oxyethyl group] methoxyl group } tetramethyleneimine-1-yl)-1,2-benzisothiazole-3-carboxylic acid.

6-[4-(tert-butoxycarbonyl)-3-methylpiperazine-1-yl]-1,2-benzisothiazole-3-carboxylic acid.

6-[1-(tert-butoxycarbonyl) octahydro-6H-pyrrolo-[3,4-b] pyridine-6-yl]-1,2-benzisothiazole-3-carboxylic acid.

5-[(3S)-3-methoxyl group tetramethyleneimine-1-yl]-1-{[2-(trimethyl silyl) oxyethyl group] methyl }-1H-indazole-3-carboxylic acid.

6-[4-(tert-butoxycarbonyl) piperazine-1-yl]-1,2-benzisothiazole-3-carboxylic acid.

6-[4-(tert-butoxycarbonyl)-1,4-Diazesuberane-1-yl]-1,2-benzisothiazole-3-carboxylic acid, ethyl ester.

6-[4-(tert-butoxycarbonyl)-2-methylpiperazine-1-yl]-1,2-benzisothiazole-3-carboxylic acid.

6-(3,4-lupetazin-1-yl)-1,2-benzisothiazole-3-carboxylic acid.

The 6-[3-[(tert-butoxycarbonyl) (methyl) amino] tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-carboxylic acid, ethyl ester.

Adopt trifluoroacetic acid by the following ester of N-Boc intermediate preparation:

6-[(1S, 4S)-2,5-diazabicyclo [2.2.1] heptan-2-yl]-1,2-benzisothiazole-3-carboxylic acid, ethyl ester.

6-(octahydro-6H-pyrrolo-[3,4-b] pyridine-6-yl)-1,2-benzisothiazole-3-carboxylic acid, ethyl ester.

6-piperazine-1-base-1,2-benzisothiazole-3-carboxylic acid, ethyl ester.

Method 16

Method 16 provides the method that is prepared 6-amino-7-azaindazole-3-carboxylic acid by 6-fluoro-1H-pyrazolo [3,4-b] the pyridine-3-carboxylic acid tert-butyl ester.

3-pyrrolidinol (24.7mmol) is added in the solution of 6-fluoro-1H-pyrazoles [3,4-b] the pyridine-3-carboxylic acid tert-butyl esters (4.22mmol) in toluene (4.00mL) in the microwave reactor.This reaction mixture is carried out microwave radiation 300s at 120 ℃.Reaction mixture is distributed between water (100mL) and ethyl acetate (200mL), separate each layer.Organic layer water (2 * 50mL) and salt solution (25mL) washing and filter by diatomite (50g).Diatomite concentrates the EtOAc solution that merges with 100mL EtOAc washing, obtains product, and yield is 63%.

Methylsulfonyl chloride (5.52mmol) is dropped in cold (0 ℃) 6-(3-hydroxyl pyrrolidine-1-yl)-1H-pyrazolo [3,4-b] the pyridine-3-carboxylic acid tert-butyl esters (2.63mmol) and the solution of triethylamine (6.57mmol) in methylene dichloride (2.7mL).Reaction mixture is at room temperature placed 16 hours, and water (25mL) dilution.The separate dichloromethane layer also is transferred on the silicagel column.This post is with 90/10 to 0/100 hexane/ethyl acetate gradient elution, obtains yield and be 60% two methanesulfonates and yield and be a methanesulfonates of 28%.

In microwave container with 1-(methylsulfonyl)-6-3-[(methylsulfonyl) the oxygen base] tetramethyleneimine-1-base-1H-pyrazolo [3,4-b] pyridine-3-carboxylic acid tert-butyl esters (0.380mmol) is with the solution dilution of 2.0M dimethylamine in tetrahydrofuran (THF) (5.0mL).With reaction mixture 135 ℃ of following microwave radiations 80 minutes.Concentrated reaction mixture, resistates is by the ester of chromatography purification { 100/0 to 90/10 ethyl acetate/[(50/50/2) ethyl acetate/methanol/dimethyl amine] } with the acquisition purifying.This ester is dissolved in 4/1 methylene dichloride/trifluoroacetic acid (5.00mL) and this mixture was at room temperature placed 16 hours.Remove volatile matter and resistates is dissolved in the water.This mixture neutralizes with half saturated sodium bicarbonate, and precipitates to obtain product by solid collected by filtration, and yield is 79%.

Adopt the following acid of this method preparation:

6-[3-(dimethylamino) tetramethyleneimine-1-yl]-1H-pyrazolo [3,4-b] pyridine-3-carboxylic acid.

Method 17

Method 17 provides the method for fluoridizing benzisothiazole-3-carboxylic acid by the ester preparation of corresponding benzisothiazole-3-carboxylic acid.

With 1-fluoro-2,6-dichloropyridine fluoroform hydrochlorate (2.25mmol) adds to 6-(3-methoxyl group tetramethyleneimine-1-yl)-1, in the 2-benzisothiazole-solution of 3-carboxylic acid, ethyl ester (1.87mmol) in methylene dichloride (20.0mL), this reaction mixture was at room temperature placed 6 hours.This reaction mixture filters by silica gel (10g, washed with dichloromethane), concentrate eluant.To obtain product, yield is 22% to resistates by chromatography (90/10 to 70/30 hexane/ethyl acetate) purifying.

With 7-fluoro-6-(3-methoxyl group tetramethyleneimine-1-yl)-1, the solution of 2-benzisothiazole-3-carboxylic acid, ethyl ester (0.177mmol) in ethanol (1.5mL) 5.0M sodium hydroxide (3.0mmol) solution-treated.Separate out gelatinous solid in the several minutes.With this reaction mixture water (50mL) dilution, and use the 6.0N hcl acidifying.By filtering collecting precipitation, obtain product, yield is 80%.Can use this acid and need not to be further purified.

Adopt the following acid of this method preparation:

7-fluoro-6-(3-methoxyl group tetramethyleneimine-1-yl)-1,2-benzisothiazole-3-carboxylic acid.

7-fluoro-6-(3-oxyethyl group tetramethyleneimine-1-yl)-1,2-benzisothiazole-3-carboxylic acid.

7-fluoro-6-methoxyl group-1,2-benzisothiazole-3-carboxylic acid.

Method 18

Method 18 provides the method that is prepared 6-phenyl-1H-pyrazolo [3,4-b] pyridine-3-carboxylic acid by 6-phenyl-1H-pyrazolo [3,4-b] pyridine-3-carboxylic acid tert-butyl ester.

Chlorination [1,3-two (diphenylphosphine) propane] nickel (II) (0.0999mmol) is dissolved in the tetrahydrofuran (THF) (20.0mL) with 6-fluoro-1H-pyrazolo [3,4-b] the pyridine-3-carboxylic acid tert-butyl esters (0.999mmol), this reaction mixture is cooled to 0 ℃.Add the solution of 1.00M phenyl-magnesium-bromide in tetrahydrofuran (THF) (2.40mL), reaction mixture is warmed to room temperature and placed 4 hours.This is reflected between water (50mL) and ethyl acetate (50mL) and distributes.Separate each layer, organic phase also concentrates with salt solution (25mL) washing, dry (sal epsom).To obtain product, yield is 56% to resistates by chromatography (95/5 to 85/15 hexane/ethyl acetate) purifying.

6-phenyl-1H-pyrazolo [3,4-b] pyridine-3-carboxylic acid tert-butyl esters (0.555mmol) are dissolved in 4/1 methylene dichloride/trifluoroacetic acid solution (2.00mL), this are reflected under the room temperature placed 16 hours.Concentrate this reaction mixture, resistates water (5mL) dilution.Reaction mixture is neutralized to pH 5-7, vigorous stirring 1 hour, the solid by filtering collecting precipitation is to obtain acid, and yield is 92%.

Adopt the following acid of this method preparation:

6-phenyl-1H-pyrazolo [3,4-b] pyridine-3-carboxylic acid.

Method 19

Method 19 is described in detail by 2, and 5-two bromo nitrobenzenes prepare 6-bromobenzene and isoxazole-3-carboxylic acid, ethyl ester.

(12.6g, (3.16g is 132mmol) in the suspension in methyl-sulphoxide (60mL) 79mmol) to add sodium hydride with diethyl malonate in 30 minutes.Temperature of reaction rises to 60 ℃, and the mixture clarification.Add 1, (10g 36.0mmol), and places solution 2 hours down at 100 ℃ 4-two bromo-2-oil of mirbane.Reaction mixture is cooled to room temperature, and in the impouring ice (300g-400g).The filtering separation precipitated solid, and dry, obtain 11.0g product (89%).

(32mL, (11.0g 32.0mmol), and at room temperature placed reaction mixture 16 hours 63mmol) to dilute this ester with the 2N sodium hydroxide solution.With methylene dichloride (20mL) aqueous layer extracted, and acidifying.The filtering separation precipitated solid, and dry, obtain 7.00g acid (89%).

Sulfuric acid (1mL) is added acid, and (7.00g is 27.0mmol) in the solution in ethanol (60mL).With the reaction mixture reflux, placed 2 hours, and under reduced pressure concentrate.Resistates is distributed between ethyl acetate (250mL) and saturated sodium carbonate (50mL), with saturated sodium carbonate (50mL) and salt solution (50mL) washing organic layer.Dry (sal epsom) organic layer, and concentrate, obtaining 8.00g (98%) ester, it is a liquid.

(420g 1.46mol) adds Isopentyl nitrite (225mL) in the solution in ethanol (3L), and mixture is warmed to 60 ℃ to this ester in 10L three neck round-bottomed flasks.Dropping is by sodium Metal 99.5 (33.5g, the 1.46mmol) alcohol sodium solution of preparation in ethanol (1L), and reaction mixture placed 2 hours.Reaction mixture is cooled to room temperature, and neutralizes with 2N hydrochloric acid.With ethyl acetate (4 * 2L) extractive reaction mixtures, water (2 * 1L) and salt solution (organic layer that 2 * 1L) washings merge, and dry (sal epsom).By chromatography (1/1 to 0/1 hexane/ethyl acetate) purifying resistates, obtain 110g product (28%).

Referring to for example international publication numbering WO 2004/010995.

Adopt the following ester of this method preparation:

6-bromo-1,2-benzoisoxazole-3-carboxylic acid, ethyl ester.

Method 20

Method 20 is described in detail by 1-chloro-2, and the 4-dinitrobenzene prepares 6-methoxyl group benzo isoxazole-3-carboxylic acid, ethyl ester.

Sodium hydride (417mmol) is added in the solution of ethyl 3-oxobutanoate (129mmol) in tetrahydrofuran (THF) (350mL).Add 1-chloro-2,4-dinitrobenzene (123mmol), the suspension of Sheng Chenging was at room temperature placed 24 hours thus.By adding 3M hydrochloric acid adjusting pH is 5, extracts the solution that generates thus with ethyl acetate (300mL).Organic layer wash with water (3 * 300mL), dry (sal epsom) and concentrate, obtain 2-(2, the 4-dinitrophenyl)-ethyl 3-oxobutanoate, it is a brown solid, yield is 98%.

Propane-1-amine (136mmol) is added in 2-(2, the 4-the dinitrophenyl)-solution of ethyl 3-oxobutanoate (135mmol) in chloroform (500mL).Reaction mixture was at room temperature placed 12 hours and concentrated.To obtain 2-(2, the 4-dinitrophenyl) ethyl acetate, it is a brown oil to resistates by chromatography (20/1 hexane/ethyl acetate) purifying, and yield is 99%.

2-(2, the 4-dinitrophenyl) ethyl acetate (18.1mmol) and the solution of 3-methylbutane base nitrite (73.5mmol) in ethanol (70mL) are warmed to 60 ℃.Adding is placed reaction mixture 1 hour by the solution of the sodium ethylate of sodium (21.7mmol) and ethanol (70mL) preparation.Reaction mixture is cooled to 0 ℃, is 7 by adding 5% hydrochloric acid adjusting pH.The solution with water of Sheng Chenging (500mL) is diluted and is extracted with ethyl acetate (200mL) thus.Organic layer with the salt water washing (4 * 200mL), dry (sal epsom) and concentrate.To obtain 6-nitro benzo [d] isoxazole-3-carboxylicesters, it is an orange solids to resistates by chromatography (30/1 petrol ether/ethyl acetate) purifying, and yield is 70%.

6-nitro benzo [d] isoxazole-3-carboxylic acid, ethyl ester (12.7mmol), iron (53.6mmol) and ammonium chloride (56.1mmol) are mixed, with ethanol (150mL) and water (20mL) dilution.The suspension reflux that generates was thus followed vigorous stirring 2 hours.By diatomite filtration, with salt solution (200mL) dilution, thus obtained solution extracts with ethyl acetate (200mL) with reaction mixture.Organic layer with the salt water washing (3 * 200mL), dry (sal epsom) and concentrate.Resistates obtains amino benzo [d] isoxazole of 6--3-carboxylic acid, ethyl ester by chromatography (20/1 petrol ether/ethyl acetate) purifying, and it is an orange solids, and yield is 49.6%.

With amino benzo [d] isoxazole of 6--3-carboxylic acid, ethyl ester (2.43mmol) solution dilution of sulfuric acid (2.5mL) in water (2.5mL), the mixture of Sheng Chenging was at room temperature placed 30 minutes thus.Drip the solution of Sodium Nitrite (2.67mmol) in water (2.5ml) at 0 ℃, thus obtained mixture was placed 30 minutes down at 0 ℃.The aqueous solution is added to cold (0 ℃) cupric nitrate (II) (149mmol) in the solution in water (80mL), this reaction mixture is warmed to room temperature.After 5 minutes, in mixture, add Red copper oxide (I) (2.78mmol), and this reaction mixture was at room temperature placed 1 hour.With ethyl acetate extraction (3 * 100mL) reaction mixtures carry out drying (sal epsom) with the organic layer that merges and concentrate, obtain crude product 6-hydroxy benzo [d] isoxazole-3-carboxylic acid, ethyl ester, it is a brown oil, yield is 99%.

With salt of wormwood (9.42mmol) and methyl iodide (8.45mmol) add to crude product 6-hydroxy benzo [d] isoxazole-3-carboxylic acid, ethyl ester (2.42mmol) is at N, in the solution in the dinethylformamide (30mL) and with reaction mixture in the dark room temperature placed 48 hours.With reaction mixture water (100mL) dilution and with ethyl acetate extraction (2 * 100mL).The organic layer that merges with the salt water washing (3 * 100mL), dry (sal epsom) and concentrate.Resistates obtains 6-methoxyl group benzo [d] isoxazole-3-carboxylic acid, ethyl ester by chromatography (30/1 petrol ether/ethyl acetate) purifying, and it is a yellow solid, and yield is 19%.

Adopt the following ester of this method preparation:

6-methoxyl group benzo [d] isoxazole-3-carboxylic acid, ethyl ester.

Method 21

Method 21 provides by the 2-chlorine apellagrin and has prepared 7-azepine benzisothiazole-3-carboxylic acid.

2-chlorine apellagrin (317mmol) is diluted with oxalyl chloride (130mL), and the vlil of Sheng Chenging is 18 hours thus.Evaporation is removed volatile matter to obtain the 2-chloronicotinoyl chloride, and it is a white solid, and yield is 98%.

Magnesium chloride (221mmol) and triethylamine (752mmol) are added in the solution of diethyl malonate (375mmol) in toluene (250ml), reaction mixture was placed 1 hour down at 25 ℃.In 2 hours, drip the solution of 2-chloronicotinoyl chloride (313mmol) in toluene (80mL).Reaction mixture was remained on room temperature 3.5 hours, and with cold (0 ℃) water (500mL) termination reaction.Thus obtained solution merges organic layer with ethyl acetate (500mL) extraction.Organic layer with the salt water washing (3 * 300mL), dry (sodium sulfate) and concentrate and obtain 2-(2-chloronicotinoyl base) diethyl malonate, it is a brown oil, yield is 85%.

In 1.5 hours, the drips of solution of 2-(2-chloronicotinoyl base) diethyl malonate (267mmol) in methyl-sulphoxide (100ml) added in water (10mL) solution of 130 ℃ of methyl-sulphoxides (260mL).Reaction mixture remain on again 130 ℃ following 2 hours, then be cooled to room temperature.With reaction mixture with cold (0 ℃) water (500mL) dilution and with ethyl acetate extraction (3 * 200mL).The organic layer that merges with the salt water washing (5 * 200mL), dry (sodium sulfate) and concentrate.Resistates obtains 1-(2-chloropyridine-3-yl) ethyl ketone by chromatography (10/1 petrol ether/ethyl acetate) purifying, and it is a yellow oil, and yield is 52%.

The solution of 1-(2-chloropyridine-3-yl) ethyl ketone (129mmol) in ammonium hydroxide (130mL) and ethanol (500mL) is added under ammonia atmosphere in the 1L high pressure cylinder of steel.In reaction mixture, add sulphur (129mmol), sealed vessel, reaction mixture heated 16 hours down at 130 ℃.Reaction mixture is by diatomite filtration, and elutriant extracts with ethyl acetate (300mL).Organic layer also concentrates with salt solution (100mL) washing, dry (sodium sulfate).Resistates obtains also [5,4-b] pyridine of 3-methyl isothiazole by chromatography (20/1 petrol ether/ethyl acetate) purifying, and it is a white solid, and yield is 22%.

N-bromosuccinamide (10.7mmol) is added to 3-methyl isothiazole also in the solution of [5,4-b] pyridines (10.0mmol) in tetracol phenixin (20mL).Add benzoyl peroxide (0.82mmol) and with reaction mixture reflux 48 hours.Reaction mixture filters by diatomite (ethyl acetate), and concentrate eluant is to obtain also [5,4-b] pyridine of crude product 3-(brooethyl) isothiazole, and it is a yellow solid.

Water (4mL) is handled the also solution of [5,4-b] pyridines (3.49mmol) in methyl-sulphoxide (20mL) of crude product 3-(brooethyl) isothiazole, and reaction mixture was heated 1.5 hours at 80 ℃.This reaction mixture water (100mL) dilution is also used ethyl acetate extraction (3 * 30mL) by diatomite filtration.The organic layer that merges washes with water, dry (sal epsom) also concentrates to obtain also [5,4-b] pyridin-3-yl methyl alcohol of isothiazole, and it is a yellow oil, and yield is 31%.

Potassium permanganate (2.25mmol) and potassium hydroxide (1.79mmol) are added to isothiazole also in the solution of [5,4-b] pyridin-3-yl methyl alcohol (1.08mmol) in water (4mL), and thus obtained solution at room temperature reacted 3 hours.Reaction mixture is also used ethyl acetate extraction (3 * 10mL) by diatomite filtration.Regulate the water layer pH to 2 that merges by adding 0.6M hydrochloric acid.Slurries were stirred 5 minutes, and to obtain also [5,4-b] pyridine-3-carboxylic acid of isothiazole, it is a light yellow solid by solid collected by filtration, and yield is 42%.

Adopt the following acid of this method preparation:

Isothiazole is [5,4-b] pyridine-3-carboxylic acid also.

Method 22

Following process provides preparation 2,2, the method for the acid that the 2-trifluoroethyl replaces.

6-[(1S, 4S)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo [2.2.1] heptan-2-yl]-1, the 2-benzisothiazole-mixture of 3-carboxylic acid, ethyl ester (1.16mmol) in 4/1 methylene dichloride/trifluoroacetic acid (10.00mL) at room temperature placed 16 hours.Reaction mixture is concentrated, and resistates is loaded on the SCX post (10g), and with the washed with methanol of 5 times of volumes.The partially purified product of methanol solution wash-out that then adopts 2.0M ammonia is to obtain amine, and yield is 68%.

With 2,2,2-trifluoroethyl methanesulfonates (0.330mmol) adds to 6-[(1S, 4S)-2,5-diazabicyclo [2.2.1] heptan-2-yl]-1,2-benzisothiazole-3-carboxylic acid, ethyl ester (0.165mmol) is at N, and in the solution of N-diisopropylethylamine (0.20mL) and acetonitrile (15mL), the mixture of Sheng Chenging was at room temperature placed 16 hours thus.Reaction mixture is concentrated, and resistates obtains the ester of purifying by chromatography (90/10 to 70/30 hexane/ethyl acetate) purifying.This ester is dissolved in the ethanol (5.0mL), and the adding aqueous sodium hydroxide solution (5.0M, 2.0mL).This is reflected under the room temperature placed 4 hours, then water (50mL) dilution and neutralize with acetate.By filtering collecting precipitation to obtain 6-[(1S, 4S)-5-(2,2, the 2-trifluoroethyl)-2,5-diazabicyclo [2.2.1] heptan-2-yl]-1,2-benzisothiazole-3-carboxylic acid, yield are 29%.

Adopt the following acid of similar methods preparation:

6-{3-[methyl (2,2, the 2-trifluoroethyl) amino] tetramethyleneimine-1-yl }-1,2-benzisothiazole-3-carboxylic acid.

Method 23

Method 23 provides by corresponding aldehyde and has prepared indazole-3-carboxylic acid that amidine replaces.

With the N-methyl isophthalic acid, 2-quadrol (4.7mmol) adds in the 6-formyl radical-1H-indazole-solution of 3-carboxylic acid tert-butyl ester (4.2mmol) in the trimethyl carbinol (40mL), and this reaction mixture was placed 30 minutes.Add salt of wormwood (10mmol) and iodine (5.3mmol) and slurries are descended heating 3 hours at 70 ℃.Reaction mixture is cooled to room temperature and uses sodium thiosulfate solution (40mL) termination reaction.With 9/1 methylene chloride aqueous layer extracted, the organic layer that merges is carried out drying (sal epsom) and concentrated.Resistates obtains amidine by chromatography [100/0 to 60/40 methylene dichloride/(8/1/1 methylene chloride/in methyl alcohol 7M ammonia)] purifying, and yield is 51%.

6-(1-methyl-4,5-dihydro-1H-imidazoles-2-yl)-1H-indazole-3-carboxylic acid tert-butyl ester (2.2mmol) was at room temperature placed 16 hours with trifluoroacetic acid (3.7mL) dilution and with reaction mixture.To obtain acid, yield is 93% by the filtering separation precipitated product.

Adopt the following acid of this method preparation:

6-(1-methyl-4,5-dihydro-1H-imidazoles-2-yl)-1H-indazole-3-carboxylic acid.

Method 24

Method 24 provides by corresponding amino benzisothiazole-3-carboxylicesters and has prepared the method for N-alkylamino benzisothiazole-3-carboxylic acid.

(8.57mmol) adds to 6-[(1S with sodium cyanoborohydride, 4S)-2,5-diazabicyclo [2.2.1] heptan-2-yl]-1, (0.260g 0.857mmol) and in the solution of 1-oxyethyl group-1-(trimethyl silyl oxygen base) cyclopropane (8.57mmol) in ethanol (11.2mL) and with this reaction mixture heated 6 hours down at 60 ℃ 2-benzisothiazole-3-carboxylic acid, ethyl ester.(2 * 50mL) extract with this reaction mixture water (50mL) dilution and with ethyl acetate.The organic layer that merges is also concentrated with salt solution (25mL) washing, dry (sal epsom).Resistates passes through chromatography (ethyl acetate) purifying to obtain ester.The solution of 5.0M sodium hydroxide in water (4.00mL) is added in the solution of this ester in ethanol (10.0mL), reaction mixture was placed 16 hours.Reactant neutralizes with acetate and is loaded on the SCX post.This post water (200mL) and methyl alcohol (100mL) flushing, product is used in the 2.0M ammonia wash-out in the methyl alcohol (60mL), obtains acid, and yield is 56%.Use this acid and need not to be further purified.

Adopt the following acid of this method preparation:

6-[(1S, 4S)-5-cyclopropyl-2,5-diazabicyclo [2.2.1] heptan-2-yl]-1,2-benzisothiazole-3-carboxylic acid.

Method 25

Method 25 provides by corresponding amino benzisothiazole-3-carboxylicesters and has prepared N-alkylamino benzisothiazole-3-carboxylic acid.

(1.71mmol) adds to 6-[(1S with the cyclopropyl monobromomethane, 4S)-2,5-diazabicyclo [2.2.1] heptan-2-yl]-1, in 2-benzisothiazole-3-carboxylic acid, ethyl ester (0.857mmol) and the suspension of sodium bicarbonate (3.43mmol) in acetonitrile (10.0mL), this reaction mixture heated 6 hours down at 60 ℃.Acetonitrile is inclined to from solid, and solid is washed (2 * 5mL) with acetonitrile.Acetonitrile solution is transferred on the silicagel column, and this mixture is by the ester of chromatography { 9/1 to 7/3 ethyl acetate/[(50/50/2) ethyl acetate/methanol/dimethyl amine] } purifying with the acquisition purifying.5.0M aqueous sodium hydroxide solution (2.00mL) is added in the ethanolic soln (5.0mL) of this ester, reaction mixture was placed 16 hours.Use the acetate neutralization reactant, and reaction mixture is transferred on the SCX post (10g).This post water (200mL) and methyl alcohol (100mL) flushing, product use the methanol solution wash-out of 2.0M ammonia to obtain product, and yield is 50%.Use this acid to need not to be further purified.

Adopt the following acid of this method preparation:

6-[(1S, 4S)-5-(cyclopropyl methyl)-2,5-diazabicyclo [2.2.1] heptan-2-yl]-1,2-benzisothiazole-3-carboxylic acid.

Method 26

Method 26 provides by corresponding methyl-phenoxide and has prepared 6-hydroxy benzo isothiazole-3-carboxylic acid and ester.

The solution (20.00mL) of 1.0M boron tribromide in methylene dichloride is dropped to 6-methoxyl group-1, in 0 ℃ of solution of 2-benzisothiazole-3-carboxylic acid, ethyl ester (12.6mmol) in methylene dichloride (30.0mL).This reaction mixture is warmed to room temperature and placed 16 hours.Reaction mixture inclined to the ice-cold 2N sodium hydroxide of 100mL and with this mixture vigorous stirring 20 minutes.By removing by filter precipitated solid, elutriant washs (2 * 50mL) with ethyl acetate.Water layer obtains the mixture of methoxyl group product (yield～48%) and alcohol acid (yield～37%) with the neutralization of 6N hydrochloric acid and by filtering the brown solid of collecting precipitation.

Under 0 ℃, thionyl chloride (27.0mmol) is dropped in the round-bottomed flask that contains ethanol (50.0mL).Reaction mixture is warmed to room temperature, adds the mixture of hydroxyl and methoxyl group acid after 30 minutes.Reaction mixture was descended heating 4 hours and was concentrated into about 25mL at 95 ℃.Reaction mixture is distributed between ethyl acetate (100mL) and saturated sodium bicarbonate aqueous solution (100mL), and organic layer also concentrates with the salt water washing.Resistates adopts 80/20 to 60/40 hexane/ethyl acetate gradient elution by chromatography purification, obtains product, and yield is 82%.

Adopt this method following acid of preparation and ester:

6-hydroxyl-1,2-benzisothiazole-3-carboxylic acid.

6-methoxyl group benzo [d] isothiazole-3-carboxylic acid.

6-hydroxyl-1,2-benzisothiazole-3-carboxylic acid, ethyl ester.

Method 27

Method 27 provides by the 2-chloronicotinoyl chloride and has prepared 7-azepine-6-chlorobenzene and isothiazole-3-carboxylic acid.

Magnesium metal (1.25mol) was heated 1 hour down at 70-80 ℃ with the dilution of ethanol (250mL) and tetracol phenixin (5mL) and with this suspension.Drip diethyl malonate (1.21mol) in toluene (200mL) solution and reaction mixture placed 2 hours.Reaction mixture is cooled to 0 ℃, drips the solution of 2-chloronicotinoyl chloride (313mmol) in toluene (200mL), maintain the temperature at 0-5 ℃ simultaneously.The solution that generates thus is warmed to room temperature and placed 2 hours.Reaction mixture is with the dilution of 50mL water, and the solid by filtering collecting precipitation is to obtain 104g crude product 2-(2-chloronicotinoyl base) diethyl malonate, and it is a pink solid.

Water (1.3mL) is added in the solution of 2-(2-chloronicotinoyl base) diethyl malonate (31.7mmol) in methyl-sulphoxide (50mL).By add hydrochloric acid with the pH regulator of reaction mixture to 5-6, with reaction mixture 130 ℃ of heating 2 hours down.Then use frozen water (300mL) termination reaction, water layer ethyl acetate extraction (3 * 50mL).The organic layer that merges also concentrates with salt water washing, drying (sal epsom).Resistates obtains 1-(2-chloropyridine-3-yl) ethyl ketone by chromatography (1/20 ethyl acetate/petroleum ether) purifying, and it is a light yellow oil, and yield is 56%.

Ammonium hydroxide (368mL) is added in the mixture of sulphur (386mmol) and 1-(2-chloropyridine-3-yl) ethyl ketone (350mmol), these slurries dilute with methyl alcohol (960mL).Ammonia blasted in the reaction mixture 10 minutes and with reaction mixture 110 ℃ of heating 24 hours down.Reaction mixture is concentrated into dried, resistates water extraction (3 * 500mL).The water layer ethyl acetate extraction (5 * 500mL), the organic layer drying (sal epsom) that merges is also concentrated.Resistates obtains also [5,4-b] pyridine of 3-methyl isothiazole by chromatography (1/25 ethyl acetate/petroleum ether) purifying, and it is a light yellow solid, and yield is 67%.

The drips of solution of metachloroperbenzoic acid (160mmol) in acetate (200mL) added to 3-methyl isothiazole also in the solution of [5,4-b] pyridines (107mmol) in methylene dichloride (200mL).Reaction mixture was placed 6 hours down at 25 ℃.Reaction mixture water (100mL) dilution is regulated pH to 8 with 10% sodium hydroxide, separates each layer.The water layer ethyl acetate extraction (10 * 100mL), the organic layer that merges is carried out drying (sal epsom) and concentrates obtaining also [5,4-b] pyridine-N-oxide of 3-methyl isothiazole, it is a yellow solid, yield is 62%.

In 20 minutes, the drips of solution of triphosgene (190mmol) in methylene dichloride (200mL) added to 3-methyl isothiazole also in-20 ℃ of solution of [5,4-b] pyridine-N-oxide (47.4mmol) in methylene dichloride (150mL).In 1 hour, drip the solution of Diisopropylamine (190mmol) in methylene dichloride (200mL).Reaction mixture is warmed to room temperature and placed 16 hours.Water (40mL) termination reaction is also passed through to add 10% sodium hydroxide and is regulated pH to 7.Organic layer water (100mL) washing.(10 * 100mL), the organic layer of merging carries out drying (sal epsom) and concentrates the water layer that merges with dichloromethane extraction.Resistates is by chromatography (1/80 ethyl acetate/petroleum ether) purifying, obtain 6-chloro-3-methyl isothiazole also [5,4-b] pyridine its be colorless solid, yield is 46%.

AIBN (1.35mmol) is added to 6-chloro-3-methyl isothiazole also in [5,4-b] pyridines (13.5mmol) and the solution of N-bromosuccinamide (27.1mmol) in tetracol phenixin (25mL).This reaction mixture 80 ℃ of heating 6 hours, is cooled to room temperature, by removing by filter precipitated solid.Filtrate is concentrated to obtain also [5,4-b] pyridine of crude product 3-(brooethyl)-6-chloroisothiazole, and it is a yellow oil.

Water (8mL) is added to 3-(brooethyl)-6-chloroisothiazole also in the solution of [5,4-b] pyridines (19.0mmol) in methyl-sulphoxide (40mL), with reaction mixture 80 ℃ of heating 1.5 hours down.Water (50mL) termination reaction, the solution that generates ethyl acetate extraction (3 * 40mL) thus.The organic layer that merges carries out drying (sal epsom) and concentrates, and obtains crude product (the 6-chloroisothiazole is [5,4-b] pyridin-3-yl also) methyl alcohol, and it is a yellow solid.

Potassium permanganate (1.69mmol) is added in batches in the solution of (the 6-chlorobenzene is [d] isothiazole-3-yl also) methyl alcohol (2.50mmol) in water (3mL).Add salt of wormwood (2.90mmol) and reaction mixture is descended placement 30 minutes at 25 ℃.By removing by filter insoluble substance, water layer ethyl acetate extraction (3 * 10mL).Regulate water layer pH to 3-4 by adding 1N hydrochloric acid, reaction mixture was placed 10 minutes.To obtain also [d] isothiazole-3-carboxylic acid of 6-chlorobenzene, it is a white solid by solid collected by filtration, and yield is 15%.

Adopt the following acid of this method preparation:

The 6-chloroisothiazole is [5,4-b] pyridine-3-carboxylic acid also.

Method 28

Method 28 provides by corresponding amino benzisothiazole-3-carboxylicesters and has prepared the amino benzisothiazole of N-acidylate-3-carboxylic acid.

With cyclopropanecarbonyl chloride (0.37mmol) and N, N-diisopropylethylamine (0.49mmol) adds to 6-piperazine-1-base-1, in the 2-benzisothiazole-solution of 3-carboxylic acid, ethyl ester (0.12mmol) in methylene dichloride (3.0mL), reaction mixture was at room temperature placed 1 hour.Placed again 30 minutes with methyl alcohol (10mL) termination reaction and with mixture.This reaction mixture is inclined to 5g SCX post this product methanol-eluted fractions (20mL).5.0M aqueous sodium hydroxide solution (1.2mL) is added in the methanol solution and mixture was placed 2 hours.Neutralize with reaction mixture water (50mL) dilution and with 6N hydrochloric acid soln (1.5mL).Further regulate pH to 5-7 with acetate.Obtain acid by the solid that filters collecting precipitation, yield is 88%.

Adopt the following acid of this method preparation:

6-[4-(cyclopropyl carbonyl) piperazine-1-yl]-1,2-benzisothiazole-3-carboxylic acid.

6-[1-(cyclopropyl carbonyl) octahydro-6H-pyrrolo-[3,4-b] pyridine-6-yl]-1,2-benzisothiazole-3-carboxylic acid.

6-[(1S, 4S)-5-(cyclopropyl carbonyl)-2,5-diazabicyclo [2.2.1] heptan-2-yl]-1,2-benzisothiazole-3-carboxylic acid.

Method 29

Method 29 provides by corresponding bromo-indazole-3-carboxylicesters and has prepared indazole-3-carboxylic acid that nitrile replaces.

Zinc cyanide (1.00mmol) is added to 6-bromo-1H-indazole-3-carboxylic acid, ethyl ester (0.502mmol) and tetrakis triphenylphosphine palladium (0) (0.0502mmol) at N, in the solution in the dinethylformamide (5.00mL), reaction mixture heated 16 hours down at 100 ℃.Reaction mixture with ethyl acetate and water dilution, is separated each layer.Water layer ethyl acetate extraction (2 *), the organic layer of merging salt water washing and dry (sodium sulfate).Resistates is by chromatography purification, and to obtain nitrile, yield is 65% with 70/30 to 50/50 hexane/ethyl acetate wash-out.With this ester with sodium hydroxide in ethanol hydrolysis to obtain acid.

Adopt this method following acid of preparation and ester:

6-cyano group-1H-indazole-3-carboxylic acid, ethyl ester.

6-cyano group-1H-indazole-3-carboxylic acid.

The alkali preparation

Following method (30-35) describe in detail can not be commercially available dicyclo alkali and the preparation of amine.

Method 30

Method 30 provides the method that is prepared N-alkylation 3-amino quinine ring by 3-amino quinine ring.

Acetyl Chloride 98Min. (12mmol) is dropped to (R)-3-amino quinine ring (10mmol) and N, and in the solution of N-diisopropylethylamine (30mmol) in methylene dichloride (100mL), thus obtained solution at room temperature keeps 4 hours, and is evaporated to dried.The crude product acid amides is dissolved in the tetrahydrofuran (THF) (150mL) also with lithium aluminum hydride (66mmol) processing in a small amount in batches.With the reaction of Disodium sulfate decahydrate termination reaction mixture, the slurries of Sheng Chenging are with tetrahydrofuran (THF) dilution and pass through diatomite filtration thus.Concentrated filtrate, resistates dilutes with the methanolic hydrochloric acid (producing by drip the 3mL Acetyl Chloride 98Min. in 30mL methyl alcohol) of prepared fresh, and at room temperature places 15 minutes.By removing the resistates recrystallization (2-propyl alcohol/methyl alcohol) that volatile matter obtains, obtain secondary amine, it is a colorless solid, yield is 41%.

Adopt the following alkali of this method preparation:

(3R)-N-(methyl) rubane-3-amine dihydrochloride.

(3S)-N-(methyl) rubane-3-amine dihydrochloride.

Method 31

Method 31 provides by diamines and has prepared the method for encircling urea.

Methylcarbonate (10.0mmol) is dropped in the mixture of N-propyl group-1 (10.0mmol) and cesium carbonate (2.00mmol), this reaction mixture heated 1 hour down at 70 ℃.Concentrate this reaction mixture and resistates is descended heating 3 hours at 130 ℃.Concentrate this reaction mixture, resistates obtains product (60%) by chromatography [(50/50 to 0/100) hexane/ethyl acetate] purifying, and it is an oil.

Adopt the following ring of this method preparation urea:

1-propyl imidazole alkane-2-ketone.

1-ethyl imidazol(e) alkane-2-ketone.

Method 32

Method 32 provides the method that is prepared 3-alkoxyl group tetramethyleneimine by the N-Boc-3-hydroxyl pyrrolidine.

Under 0 ℃, 1-Boc-3-hydroxyl pyrrolidine (16.1mmol) is added to sodium hydride (22.0mmol) in the suspension of tetrahydrofuran (THF) (40mL) in batches.This reaction mixture dilutes with tetrahydrofuran (THF) (60mL) and is warmed to room temperature.After 1 hour iodine potassium alkane (21.0mmol) added in the cloudy suspensions and with reaction mixture and at room temperature placed 6 hours.Concentrated reaction mixture also is dissolved in the ethyl acetate (100mL) again.Extract washs and dry (sodium sulfate) with saturated ammonium chloride (20mL), water (20mL) and salt solution (20mL).Resistates passes through chromatography (1/4 ethyl acetate/hexane) purifying to obtain ether.The N-Boc product is dissolved in the tetrahydrofuran (THF) (30mL), adds 6N hydrochloric acid (20mL).The mixture that generates was thus stirred 1 hour and concentrated to obtain oil.Add toluene (10mL) and ethanol (10mL), mixture is concentrated obtain the brownish strong water absorbability solid of 1.79g.With solid suspension in ethyl acetate and vigorous stirring 12 hours.By filtering quick collection solid, and dry to obtain product under high vacuum, and it is colorless solid (81%).

The other method that is used to remove the N-Boc group must contact 4 hours with trifluoroacetic acid, then concentrated reaction mixture.This method can be used for preparing the amine as free alkali.

Adopt the following amine of this method preparation:

3-methoxyl group pyrrolidine hydrochloride.

By with saturated sodium carbonate (5mL) neutralized salt resistates, with 9/1 methylene chloride (3 * 20mL) extractions, dry (salt of wormwood) and concentrate, then capture amine also obtains free alkali with the methanol solution wash-out of 2M ammonia on the SCX post:

3-methoxyl group tetramethyleneimine.

3-oxyethyl group tetramethyleneimine.

(3R)-3-methoxyl group tetramethyleneimine.

(3S)-3-methoxyl group tetramethyleneimine.

3-(methoxymethyl) tetramethyleneimine.

Method 33

Method 33 provides the hydroxyl pyrrolidine that is prepared the SEM protection by hydroxyl pyrrolidine.

The solution of 1-Boc-3-hydroxyl-tetramethyleneimine (26.7mmol) in tetrahydrofuran (THF) (20mL) is slowly added in the suspension of sodium hydride (30.8mmol) in tetrahydrofuran (THF) (78mL), this reaction mixture was placed 30 minutes.Add [β-(trimethyl silyl) oxyethyl group] Methochloride (30.7mmol) in tetrahydrofuran (THF) (4.4mL) solution and reaction mixture placed 18 hours.Reactant is distributed between water (50mL) and ethyl acetate (50mL), separate each layer.Organic layer also concentrates with salt solution (25mL) washing, dry (sal epsom).Resistates is by chromatography (95/5 to 80/20 hexane/ethyl acetate) purifying, to obtain the product of Boc-protection.Pure resistates was heated 3 hours down at 350 ℃.The brown oil of Sheng Chenging concentrates the back and obtains brown oil by chromatography [100/0 to 80/20 ethyl acetate/(50/50/2 ethyl acetate/methanol/dimethyl amine)] purifying thus.This oil is dissolved in the ethanol and with this solution of activated carbon treatment, filtration and concentrate to obtain product, yield is 52%.

Adopt the following amine of this method preparation:

3-{[2-(trimethyl silyl) oxyethyl group] methoxyl group } tetramethyleneimine.

Method 34

Method 34 provides by hydroxyl pyrrolidine and has prepared 3-trifluoromethoxy tetramethyleneimine.

Under 0 ℃, the solution of 1-Boc-3-hydroxyl pyrrolidine (26.7mmol) in tetrahydrofuran (THF) (20mL) is slowly added in the suspension of sodium hydride (30.8mmol) in tetrahydrofuran (THF) (78mL).Chlorodifluoromethane (30.7mmol) added in the reactant and with reaction mixture be warmed to room temperature, placed 18 hours.Be reflected between water (50mL) and ethyl acetate (50mL) and distribute, separate each layer.Organic layer also concentrates with salt solution (25mL) washing, dry (sal epsom).Resistates is by the product of chromatography (95/5 to 80/20 hexane/ethyl acetate) purifying with acquisition Boc-protection.Purified product (about 2g) is dissolved in the mixture (20.0mL) of 4/1 methylene dichloride/trifluoroacetic acid and placed 4 hours.Remove and desolvate, resistates is by chromatography [100/0 to 90/10 ethyl acetate/(50/50/2 ethyl acetate/methanol/dimethyl amine)] purifying.This product have beyond thought volatility and in concentration process its major part lost.The ultimate yield of product is 2%.

Adopt the following amine of this method preparation:

3-(difluoro-methoxy) tetramethyleneimine.

Method 35

Method 35 provides by hydroxyl pyrrolidine and has prepared 3-cyclo propyl methoxy tetramethyleneimine.

With the solution of 3-hydroxyl-tetramethyleneimine-hydrochloride (162mmol) in tetrahydrofuran (THF) (100mL) salt of wormwood (210mmol) and the solution-treated of phenmethyl chloro-formic ester (210mmol) in tetrahydrofuran (THF) (50mL).The solution of Sheng Chenging was at room temperature placed 16 hours thus.Concentrate this reaction mixture, resistates is dissolved in the ethyl acetate (200mL).(3 * 100mL) washings, dry (sal epsom) also concentrate to obtain the amine of protection this solution, and it is a yellow liquid, and yield is 90% with salt solution.

Sodium hydride (280mmol) is added to ice-cold (0 ℃) 3-hydroxyl pyrrolidine-1-benzyl carboxylate (76.9mmol) at N, in the solution in the dinethylformamide (100mL) in batches.This mixture was placed 60 minutes, then used (brooethyl) cyclopropane (231mmol) at N, solution in the dinethylformamide (100mL) and potassiumiodide (0.66mmol) are handled.This reaction mixture is warmed to room temperature and placed 30 minutes.This reaction mixture was carried out microwave radiation 2 hours under 90 ℃.Concentrated reaction mixture, resistates separates each layer with ethyl acetate (200mL) and water (200mL) dilution.(3 * 200mL) extract water layer, the organic layer of merging salt water washing (2 * 200mL) also dry (sal epsom) with ethyl acetate.This resistates obtains product by chromatography (20/1 petrol ether/ethyl acetate) purifying, and yield is 81%.

Suspension in ethyl acetate (20mL) and methyl alcohol (20mL) places under the nitrogen atmosphere with 3-(cyclo propyl methoxy) tetramethyleneimine-1-benzyl carboxylate (17.4mmol) and 10% palladium charcoal (600mg).This reaction mixture was placed 16 hours and passed through diatomite filtration.Concentrated filtrate is to obtain product, and it is a yellow liquid, and yield is 86%.

Adopt the following amine of this method preparation:

3-(cyclo propyl methoxy) tetramethyleneimine.

The representative method

Following method (A-AA) is described the preparation of dicyclo alkali analogue in detail.

Method A

Method A provides coupling between 3-amino quinine ring and benzoisoxazole carboxylicesters to form the method for carboxamides derivatives.

With the suspension of (S)-3-amino quinine ring hydrochloride (3.50mmol) in ethanol (5mL) N, N-diisopropylethylamine (4.00mmol) is handled.Add 6-bromo-1,2-benzoisoxazole-3-carboxylic acid, ethyl ester (1.86mmol) also heats this suspension 3 days down at 85 ℃.This reaction mixture is cooled to room temperature, dilutes, and wash with the 10mL saturated sodium bicarbonate with methylene dichloride (30mL).Water layer is stripped with methylene dichloride (30mL), the organic layer of merging salt water washing and dry (sodium sulfate).Organic layer is loaded on the 10g SCX post.Pillar concentrates the ammonia stripping thing with methyl alcohol (50mL), the 2M ammonia stripping in methyl alcohol (60mL).To obtain product, it is a water white oil to resistates by chromatography [40/60 to 0/100 ethyl acetate/(70/30/1 ethyl acetate/methanol/ammonium hydroxide)] purifying, and yield is 63%.

Adopt the following compound of this method preparation:

86) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-methoxyl group-1,2-benzoisoxazole-3-methane amide, ¹H NMR (CD ₃OD) δ 7.94 (d, 1H, J=8.8), 7.24 (d, 1H, J=2), 7.06 (dd, 1H, J=2.1,8.7), 4.51 (m, 1H), 3.91 (s, 1H), 3.84 (m, 1H), 3.38 (m, 1H), 2.38 (m, 1H), 2.22 (m, 1H), 2.09 (m, 2H), 1.94 (m, 1H); LC/MS (EI) t _R3.37, m/z 302.1 (M ⁺+ 1);

N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-bromo-1,2-benzoisoxazole-3-methane amide.

Method B

Method B provides coupling between 3-amino quinine ring and benzisothia triazole carboxylic acid to form the method for carboxamides derivatives.

At 5/1 tetrahydrofuran (THF)/N, add diisopropylethylamine (1.1mmol) and (R)-3-amino quinine ring dihydrochloride (0.6mmol) to benzisothiazole-3-carboxylic acid (0.30mmol) in the solution in the mixture of dinethylformamide (12mL).This mixture is cooled to 0 ℃, disposable adding HATU (0.3mmol).This reaction mixture is warmed to room temperature and placed 16 hours.Mixture distributes between the mixture of unsaturated carbonate aqueous solutions of potassium and 95/5 methylene chloride.Water layer extracts (2 *) with 95/5 methylene chloride, and the organic layer of merging is with the salt water washing and through dried over sodium sulfate.Perhaps, reaction mixture is loaded on the 10g SCX post and, concentrates the ammonia stripping thing with methyl alcohol (50mL), 2M ammonia stripping in methyl alcohol (60mL).Crude product obtains acid amides thus by chromatography { 100/0 to 30/70 ethyl acetate/[(50/50/2) ethyl acetate/methanol/dimethyl amine] } or by preparation HPLC purifying, and it is a colorless solid, and yield is 75%.

Adopt the following compound of this method preparation:

84) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(3R)-and 3-methoxyl group tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-methane amide, ¹H NMR (CD ₃OD) δ 8.47 (d, J=9.1,1H); 6.98 (d, J=1.9,1H); 6.88 (dd, J=2.0/9.2,1H); 4.30 (m, 1H); 4.16 (m, 1H); 3.60-3.35 (m, 5H); 3.38 (s, 3H); 3.3-2.95 (m, 5H); 2.30-2.00 (m, 4H); 1.92 (m, 2H); 1.61 (m, 1H); LC/MS (EI) t _R3.84, m/z 387.2 (M ⁺+ 1);

85) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(3S)-and 3-methoxyl group tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R3.91, m/z 387.2 (M ⁺+ 1);

87) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(3-oxyethyl group tetramethyleneimine-1-yl)-7-fluoro-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R4.82, m/z 419.1 (M ⁺+ 1);

92) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-7-fluoro-6-(3-methoxyl group tetramethyleneimine-1-yl)-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R5.11, m/z 405.2 (M ⁺+ 1);

93) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-7-fluoro-6-(3-methoxyl group tetramethyleneimine-1-yl)-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R5.08, m/z 405.2 (M ⁺+ 1);

94) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(3R)-and 3-hydroxyl pyrrolidine-1-yl]-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R4.25, m/z 373.1 (M ⁺+ 1);

95) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(3S)-and 3-hydroxyl pyrrolidine-1-yl]-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R4.23, m/z 373.1 (M ⁺+ 1);

96) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(3S)-and 3-(dimethylamino) tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R1.92, m/z 400.2 (M ⁺+ 1);

97) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(1S, 4S)-the 2-oxa--5-azabicyclo [2.2.1] heptan-5-yl]-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R4.26, m/z385.1 (M ⁺+ 1);

98) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(3R)-and 3-hydroxyl pyrrolidine-1-yl]-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R4.27, m/z 373.1 (M ⁺+ 1);

99) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(3S)-and 3-hydroxyl pyrrolidine-1-yl]-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R4.23, m/z 373.1 (M ⁺+ 1);

100) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(3S)-and 3-(dimethylamino) tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R1.89, m/z 400.2 (M ⁺+ 1);

101) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-7-[(3R)-and 3-hydroxyl pyrrolidine-1-yl]-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R4.27, m/z 373.1 (M ⁺+ 1);

102) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-7-[(3S)-and 3-hydroxyl pyrrolidine-1-yl]-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R4.26, m/z 373.1 (M ⁺+ 1);

103) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-7-[(3S)-and 3-(dimethylamino) tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R1.92, m/z 400.2 (M ⁺+ 1);

104) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-7-[(1S, 4S)-the 2-oxa--5-azabicyclo [2.2.1] heptan-5-yl]-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R4.36, m/z385.1 (M ⁺+ 1);

105) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-7-[(3S)-and 3-(dimethylamino) tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R1.81, m/z 400.2 (M ⁺+ 1);

106) N-[(3S)-and 1-azabicyclo [2.2.2] oct-3-yl] isothiazole [5,4-b] pyridine-3-carboxamide formate also, LC/MS (EI) t _R2.71, m/z 289.1 (M ⁺+ 1);

107) N-[(3R)-and 1-azabicyclo [2.2.2] oct-3-yl] isothiazole [5,4-b] pyridine-3-carboxamide formate also, LC/MS (EI) t _R2.48, m/z x289.1 (M ⁺+ 1);

114) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-7-fluoro-6-methoxyl group-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R3.8, m/z 336.1 (M ⁺+ 1);

115) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-7-fluoro-6-methoxyl group-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R3.81, m/z 336.1 (M ⁺+ 1);

116) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(1S, 4S)-5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl]-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R1.84, m/z398.2 (M ⁺+ 1);

117) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(1S, 4S)-5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl]-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R1.87, m/z398.2 (M ⁺+ 1);

122) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(1S, 4S)-5-(2,2, the 2-trifluoroethyl)-2,5-diazabicyclo [2.2.1] heptan-2-yl]-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R4.69, m/z 466.1 (M ⁺+ 1);

123) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-{3-[methyl (2,2, the 2-trifluoroethyl) amino] tetramethyleneimine-1-yl }-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R4.77, m/z468.1 (M ⁺+ 1);

124) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-{3-[methoxy (2,2, the 2-trifluoroethyl) amino-pyrrolidine-1-yl }-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R4.75, m/z 468.1 (M ⁺+ 1);

125) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[3-(methoxymethyl) tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R4.98, m/z 401.1 (M ⁺+ 1);

126) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-[3-(methoxymethyl) tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R4.94, m/z 401.1 (M ⁺+ 1);

127) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(3R)-and 3-(dimethylamino) tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R1.55, m/z 400.2 (M ⁺+ 1);

128) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(3R)-and 3-(dimethylamino) tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R1.55, m/z 400.1 (M ⁺+ 1);

129) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[4-(dimethylamino) piperidines-1-yl]-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R1.59, m/z 414.1 (M ⁺+ 1).;

130) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-[4-(dimethylamino) piperidines-1-yl]-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R1.61, m/z 414.2 (M ⁺+ 1);

177) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-[4-(cyclopropyl carbonyl) piperazine-1-yl]-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R3.30, m/z 440 (M ⁺+ 1);

178) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[4-(cyclopropyl carbonyl) piperazine-1-yl]-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R3.30, m/z 440 (M ⁺+ 1);

179) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-[1-(cyclopropyl carbonyl) octahydro-6H-pyrrolo-[3,4-b] pyridine-6-yl]-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R3.81, m/z 480 (M ⁺+ 1);

180) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[1-(cyclopropyl carbonyl) octahydro-6H-pyrrolo-[3,4-b] pyridine-6-yl]-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R3.85, m/z 480 (M ⁺+ 1);

181) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(1S, 4S)-5-(cyclopropyl carbonyl)-2,5-diazabicyclo [2.2.1] heptan-2-yl]-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R3.97, m/z 452 (M ⁺+ 1);

182) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(1S, 4S)-5-(cyclopropyl carbonyl)-2,5-diazabicyclo [2.2.1] heptan-2-yl]-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R3.04, m/z 452 (M ⁺+ 1);

183) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-(3,4-lupetazin-1-yl)-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R1.30, m/z 400 (M ⁺+ 1);

132) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-N-methyl-6-[(1S, 4S)-5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl]-1,2-benzisothiazole-3-methane amide diformate, LC/MS (EI) t _R3.27, m/z 412.2 (M ⁺+ 1);

133) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-N-methyl-6-[(1S, 4S)-5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl]-1,2-benzisothiazole-3-methane amide diformate, LC/MS (EI) t _R3.19, m/z 412.2 (M ⁺+ 1);

134) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(1R, 4R)-5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl]-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R3.26, m/z398.2 (M ⁺+ 1);

135) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(1R, 4R)-5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl]-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R3.2, m/z398.2 (M ⁺+ 1);

136) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-(1,4-diazabicyclo [3.2.2] ninth of the ten Heavenly Stems-4-yl)-1,2-benzisothiazole-3-methane amide diformate, LC/MS (EI) t _R1.61, m/z412.2 (M ⁺+ 1);

137) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(1,4-diazabicyclo [3.2.2] ninth of the ten Heavenly Stems-4-yl)-1,2-benzisothiazole-3-methane amide diformate, LC/MS (EI) t _R3.51, m/z412.1 (M ⁺+ 1);

138) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-tetramethyleneimine-1-base-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R4.66, m/z 357.2 (M ⁺+ 1);

139) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-(4-methylpiperazine-1-yl)-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R1.67, m/z 386.2 (M ⁺+ 1);

140) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(4-methylpiperazine-1-yl)-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R1.63, m/z 386.2 (M ⁺+ 1);

141) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl)-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R1.8, m/z 400.2 (M ⁺+ 1);

142) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl)-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R1.84, m/z 400.2 (M ⁺+ 1);

143) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-(hexahydropyrrolo is [1,2-a] piperazine-2 (1H)-yl)-1 also, 2-benzisothiazole-3-methane amide, LC/MS (EI) t for 6- _R1.79, m/z 412.1 (M ⁺+ 1);

144) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-(hexahydropyrrolo is [1,2-a] pyrazine-2 (1H)-yl)-1 also, 2-benzisothiazole-3-methane amide, LC/MS (EI) t for 6- _R1.81, m/z 412.2 (M ⁺+ 1);

145) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-(5-methyl-2,5-diazabicyclo [2.2.2] suffering-2-yl)-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R1.88, m/z 412.2 (M ⁺+ 1);

146) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(5-methyl-2,5-diazabicyclo [2.2.2] suffering-2-yl)-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R1.88, m/z 412.2 (M ⁺+ 1);

147) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-(8-methyl-3,8-diazabicyclo [3.2.1] oct-3-yl)-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R1.95, m/z 412.2 (M ⁺+ 1);

148) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(8-methyl-3,8-diazabicyclo [3.2.1] oct-3-yl)-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R1.93, m/z 412.2 (M ⁺+ 1);

149) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(1S, 4S)-5-cyclopropyl-2,5-diazabicyclo [2.2.1] heptan-2-yl]-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R3.08, m/z424.1 (M ⁺+ 1);

150) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(1S, 4S)-5-cyclopropyl-2,5-diazabicyclo [2.2.1] heptan-2-yl]-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R3.24, m/z424.1 (M ⁺+ 1);

151) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(1S, 4S)-5-(cyclopropyl methyl)-2,5-diazabicyclo [2.2.1] heptan-2-yl]-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R1.31, m/z 438.2 (M ⁺+ 1);

152) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(1S, 4S)-5-(cyclopropyl methyl)-2,5-diazabicyclo [2.2.1] heptan-2-yl]-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R1.31, m/z 438.2 (M ⁺+ 1);

153) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-5-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl)-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R2.14, m/z 400.2 (M ⁺+ 1);

154) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-5-[(3R)-and 3-methoxyl group tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R3.57, m/z 387.2 (M ⁺+ 1);

155) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-5-[(3R)-and 3-methoxyl group tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R3.57, m/z 387.2 (M ⁺+ 1);

156) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-5-[(3S)-and 3-methoxyl group tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R3.56, m/z 387.2 (M ⁺+ 1);

157) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(1-methylpyrrolidin-3-yl) the oxygen base]-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R1.25, m/z 387.2 (M ⁺+ 1);

158) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(1-methylpyrrolidin-3-yl) the oxygen base]-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R1.25, m/z 387.2 (M ⁺+ 1);

159) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-(1-azabicyclo [2.2.2] oct-3-yl oxygen base)-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R1.33, m/z 413.2 (M ⁺+ 1);

160) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(1-azabicyclo [2.2.2] oct-3-yl oxygen base)-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R1.32, m/z 413.2 (M ⁺+ 1);

N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-5-(bromine)-1,2-benzisothiazole-3-methane amide;

N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(bromine)-1,2-benzisothiazole-3-methane amide;

N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-(bromine)-1,2-benzisothiazole-3-methane amide;

N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(methoxyl group)-1,2-benzisothiazole-3-methane amide.

As mentioned above, adopt this method, then handle, separate and by chromatography or the following compound of preparation HPLC purifying with ion exchange method with trifluoroacetic acid:

118) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(1S, 4S)-2,5-diazabicyclo [2.2.1] heptan-2-yl]-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R1.87, m/z 384.1 (M ⁺+ 1);

119) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(1S, 4S)-2,5-diazabicyclo [2.2.1] heptan-2-yl]-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R1.87, m/z 384.1 (M ⁺+ 1);

120) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[3-(methylamino) tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R1.96, m/z 386.1 (M ⁺+ 1);

121) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-[3-(methylamino) tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R1.94, m/z 386.2 (M ⁺+ 1);

168) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-(3-methylpiperazine-1-yl)-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R1.28, m/z 386.2 (M ⁺+ 1);

169) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-(octahydro-6H-pyrrolo-[3,4-b] pyridine-6-yl)-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R1.33, m/z 412.2 (M ⁺+ 1);

170) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(octahydro-6H-pyrrolo-[3,4-b] pyridine-6-yl)-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R1.35, m/z 412.2 (M ⁺+ 1);

171) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-piperazine-1-base-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R1.29, m/z 372 (M ⁺+ 1);

172) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-piperazine-1-base-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R1.47, m/z 372 (M ⁺+ 1);

173) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-(1,4-Diazesuberane-1-yl)-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R1.74, m/z 386 (M ⁺+ 1);

174) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(1,4-Diazesuberane-1-yl)-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R1.70, m/z 386 (M ⁺+ 1);

175) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-(2-methylpiperazine-1-yl)-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R1.57, m/z 386 (M ⁺+ 1);

176) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(2-methylpiperazine-1-yl)-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R1.55, m/z 386 (M ⁺+ 1).

Method C

Method C provides coupling between 3-amino quinine ring and carboxylic acid to form the method for carboxamides derivatives.

At N, add HBTU (16.1mmol), the dimethyl aminopyridine of catalytic amount, N to carboxylic acid (16.1mmol) in the solution in the dinethylformamide (65mL), N-diisopropylethylamine (96.6mmol) and 4

Activatory molecular sieve (2.6g).This reaction mixture room temperature under nitrogen was placed 2 hours, then add 3-amino quinine ring dihydrochloride (16.1mmol).Removal of solvent under reduced pressure after 18 hours.The oily resistates distributes between saturated sodium bicarbonate aqueous solution (25mL) and methylene dichloride (100mL).Water layer is further used 9/1 methylene chloride, and (5 * 100mL) extractions concentrate the organic layer that merges.Resistates obtains product thus by chromatography [90/10/1 methylene chloride/ammonium hydroxide or 1/1 to 0/1 ethyl acetate/(70/30/1 ethyl acetate/methanol/ammonium hydroxide)] or by preparation HPLC purifying, and yield is 30%-70%.

Adopt the following compound of this method preparation:

42) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-5-methoxyl group-N-methyl isophthalic acid H-indazole-3-methane amide formate, ¹H NMR (CD ₃OD) δ 8.42 (br s, 1H), 7.49 (d, J=9.1,1H), 7.38 (d, J=2.1,1H), 7.09 (dd, J=9.1,2.4,1H), 4.89 (m, 1H), 3.85 (s, 3H), 3.83 (m, 2H), 3.60-3.46 (m, 1H), 3.38-3.30 (m, 2H), 2.57 (m, 2H), 2.36-2.30 (m, 1H), 2.10-1.97 (m, 3H); LC/MS (EI) t _R2.56, m/z 315 (M ⁺+ 1);

43) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-5-(difluoro-methoxy)-N-methyl isophthalic acid H-indazole-3-methane amide formate.LC/MS(EI)t _R2.82，m/z?351(M ⁺+1)；

44) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-(difluoro-methoxy)-N-methyl isophthalic acid H-indazole-3-methane amide formate.LC/MS(EI)t _R2.9，m/z?351(M ⁺+1)；

45) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-N-methyl-6-(tetrahydrochysene-2H-pyrans-4-yl)-1H-indazole-3-methane amide formate.LC/MS(EI)t _R2.55，m/z?369(M ⁺+1)；

46) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-N-methyl-5-(tetrahydrochysene-2H-pyrans-4-yl)-1H-indazole-3-methane amide formate.LC/MS(EI)t _R2.89，m/z?369(M ⁺+1)；

47) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-N-methyl-6-(1,3-thiazoles-2-yl)-1H-indazole-3-methane amide formate.LC/MS(EI)t _R3.33，m/z?368(M ⁺+1)；

48) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-methoxyl group-N-methyl isophthalic acid, 2-benzisothiazole-3-methane amide formate.LC/MS(EI)t _R3.21，m/z?348(M ⁺+1)；

N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-7-methoxyl group-1H-indazole-3-methane amide.

Method D

Method D provides coupling between 3-amino quinine ring and carboxylic acid to form the method for carboxamides derivatives.

At N, add N in the solution in the dinethylformamide (14mL) to carboxylic acid (4.77mmol), N-diisopropylethylamine (19mmol) and 3-amino quinine ring dihydrochloride (4.29mmol).This reaction mixture room temperature in nitrogen was placed 30 minutes, then add HATU (4.76mol).After 18 hours, reaction mixture is passed through diatomite filtration (methyl alcohol drip washing), and evenly divide on 3 SCX posts.Pillar is used in 2M ammonia (the every pillar 100mL) wash-out in the methyl alcohol and concentrates with methyl alcohol (every pillar 100mL) washing, alkaline components.Resistates obtains product, yield 15%-50% thus by chromatography [1/1 to 0/1 ethyl acetate/(70/30/1 ethyl acetate/methanol/ammonium hydroxide)] or preparation HPLC purifying.

Adopt the following compound of this method preparation:

3) N-[(3S)-and 1-azabicyclo [2.2.2] oct-3-yl]-5,6-dimethoxy-1H-indazole-3-methane amide formate, ¹H NMR (CD ₃OD) δ 8.33 (bs, 2H), 7.55 (s, 1H), 7.05 (s, 1H), 4.52 (m, 1H), 3.87 (s, 3H), 3.86 (s, 3H), 3.79 (m, 1H), 3.37 (m, 6H), 2.38 (m, 4H), 2.11 (m, 5H); LC/MS (EI) t _R2.48, m/z 331 (M ⁺+ 1);

17) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-methoxyl group-N-methyl isophthalic acid H-indazole-3-methane amide formate, LC/MS (EI) t _R2.53, m/z 315 (M ⁺+ 1);

19) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-1-ethyl-6-methoxyl group-1H-indazole-3-methane amide, LC/MS (EI) t _R3.55, m/z 329 (M ⁺+ 1);

20) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-1-ethyl-6-methoxyl group-1H-indazole-3-methane amide, LC/MS (EI) t _R3.54, m/z 329 (M ⁺+ 1);

21) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-1-(difluoromethyl)-6-methoxyl group-1H-indazole-3-methane amide, LC/MS (EI) t _R3.75, m/z 351 (M ⁺+ 1);

28) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-N-methyl-6-(1,3-oxazole-2-yl)-1H-indazole-3-methane amide, LC/MS (EI) t _R3.09, m/z 352 (M ⁺+ 1);

29) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-N-methyl-6-(1,3-thiazoles-2-yl)-1H-indazole-3-methane amide, LC/MS (EI) t _R3.33, m/z 368 (M ⁺+ 1);

34) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-N-methyl-6-(tetrahydrochysene-2H-pyrans-4-yl)-1H-indazole-3-methane amide, LC/MS (EI) t _R2.52, m/z 369 (M ⁺+ 1);

35) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-N-methyl-5-(tetrahydrochysene-2H-pyrans-4-yl)-1H-indazole-3-methane amide, LC/MS (EI) t _R2.85, m/z 369 (M ⁺+ 1);

36) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-5-(difluoro-methoxy)-N-methyl isophthalic acid H-indazole-3-methane amide, LC/MS (EI) t _R3.4, m/z 351 (M ⁺+ 1);

37) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(difluoro-methoxy)-N-methyl isophthalic acid H-indazole-3-methane amide, LC/MS (EI) t _R3.48, m/z 351 (M ⁺+ 1);

40) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-5-methoxyl group-N-methyl isophthalic acid H-indazole-3-methane amide, LC/MS (EI) t _R2.51, m/z 315 (M ⁺+ 1);

57) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-fluoro-1H-pyrazolo [3,4-b] pyridine-3-carboxamide formate, LC/MS (EI) t _R2.47, m/z 290 (M ⁺+ 1);

59) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-1H-pyrazolo [4,3-c] pyridine-3-carboxamide, LC/MS (EI) t _R1.29, m/z 272.2 (M ⁺+ 1);

60) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-1H-pyrazolo [3,4-c] pyridine-3-carboxamide formate, LC/MS (EI) t _R1.59, m/z 272.2 (M ⁺+ 1);

73) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-1-ethyl-6-(1,3-oxazole-2-yl)-1H-indazole-3-methane amide formate, LC/MS (EI) t _R3.13, m/z 366 (M ⁺+ 1);

88) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-phenyl-1H-pyrazolo [3,4-b] pyridine-3-carboxamide, LC/MS (EI) t _R4.18, m/z 348.1 (M ⁺+ 1);

90) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[3-(dimethylamino) tetramethyleneimine-1-yl]-1H-pyrazolo [3,4-b] pyridine-3-carboxamide, LC/MS (EI) t _R2.64, m/z 384.2 (M ⁺+ 1);

91) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-[3-(dimethylamino) tetramethyleneimine-1-yl]-1H-pyrazolo [3,4-b] pyridine-3-carboxamide, LC/MS (EI) t _R2.62, m/z 384.2 (M ⁺+ 1);

N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(bromine)-1H-indazole-3-methane amide;

N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-4-methoxyl group-1H-indazole-3-methane amide.

N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-bromo-1-ethyl-1H-indazole-3-methane amide;

N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-bromo-1-methyl isophthalic acid H-indazole-3-methane amide;

N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-bromo-1-difluoromethyl-1H-indazole-3-methane amide;

N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(1,3-thiazoles-2-yl)-1H-indazole-3-methane amide;

N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(1,3-oxazole-2-yl)-1H-indazole-3-methane amide;

N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-bromo-1-[(2-methoxy ethoxy) methyl]-1H-indazole-3-methane amide;

N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-bromo-1-{[2-(trimethyl silyl) oxyethyl group] methyl }-1H-indazole-3-methane amide;

N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-bromo-1-{[2-(trimethyl silyl) oxyethyl group] methyl }-1H-indazole-3-methane amide;

N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-bromo-2-{[2-(trimethyl silyl) oxyethyl group] methyl }-1H-indazole-3-methane amide;

N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-bromo-2-{[2-(trimethyl silyl) oxyethyl group] methyl }-1H-indazole-3-methane amide.

Adopt this method, then remove protecting group, separate and prepare following compound by preparing the HPLC purifying by ion exchange method with 6N hydrochloric acid:

6) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(tetrahydrofuran (THF)-3-base oxygen base)-1H-indazole-3-methane amide formate.LC/MS(EI)t _R2.68，m/z?357(M ⁺+1)；

7) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(tetrahydrochysene-2H-pyrans-4-base oxygen base)-1H-indazole-3-methane amide formate.LC/MS(EI)t _R2.73，m/z?371(M ⁺+1)；

8) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(1-methylpyrrolidin-3-yl) the oxygen base]-1H-indazole-3-methane amide formate.LC/MS(EI)t _R1.4，m/z?370(M ⁺+1)。

Adopt this method, then handle with tetrabutyl ammonium fluoride and prepare following compound:

164) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-5-[(3S)-3-(cyclo propyl methoxy) tetramethyleneimine-1-yl]-1H-indazole-3-methane amide, LC/MS (EI) t _R3.67, m/z 410 (M ⁺+ 1);

166) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-5-[(3S)-3-methoxyl group tetramethyleneimine-1-yl]-1H-indazole-3-methane amide diformate, LC/MS (EI) t _R2.44, m/z 369 (M ⁺+ 1).

Method E

Method E provides coupling between 3-amino quinine ring and carboxylic acid, amine and indazole to form the method for acid amides and urea derivatives.

With 6-(1-methyl-4,5-dihydro-1H-imidazoles-2-yl)-the mixture N of 1H-indazole-3-carboxylic acid (0.500mmol), TBTU (0.624mmol) and (3R)-rubane-3-amine dihydrochloride (0.706mmol), dinethylformamide (4mL) dilution also adds N, N-diisopropylethylamine (2.34mmol).This reaction mixture was at room temperature placed 16 hours.Reaction mixture is loaded into SCX post (10g) to be gone up and washs with methyl alcohol (100mL).Then be used in the partially purified product of 2.0M ammonia wash-out in the methyl alcohol (60mL).Remove and desolvate, by preparation HPLC purifying resistates, obtain product thus, yield is 20%.

Adopt the following compound of this method preparation:

162) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-(1-methyl-4,5-dihydro-1H-imidazoles-2-yl)-1H-indazole-3-methane amide, ¹H NMR (CD ₃OD) δ 8.53 (s, 2H), 8,46 (d, J=8.5,1H, rotational isomer), 8.40 (d, J=8.4,1H, rotational isomer), 8.06 (s, 1H, rotational isomers), 7.90 (s, 1H, rotational isomer), 7.50 (d, J=8.3,1H, rotational isomer), 7.35 (d, J=8.4,1H, rotational isomers), 4.91 (s, 1H), 4.20 (m, 3H), 4.03 (m, 3H), 3.82 (m, 1H), 3.33 (m, 6H), 3.19 (s, 3H), 2.39 (m, 1H), 2.38 (m, 1H), 2.11 (m, 2H), 1.22 (m, 1H); LC/MS (EI) t _R1.43, m/z 352 (M ⁺+ 1);

163) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(1-methyl-4,5-dihydro-1H-imidazoles-2-yl)-1H-indazole-3-methane amide, LC/MS (EI) t _R1.26, m/z 352 (M ⁺+ 1);

167) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-chloroisothiazole [5,4-b] pyridine-3-carboxamide also, LC/MS (EI) t _R2.46, m/z 322 (M ⁺+ 1);

184) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-cyano group-1H-indazole-3-methane amide, LC/MS (EI) t _R2.50, m/z 2.96 (M ⁺+ 1).

Method F

Method F provides coupling between 3-amino quinine ring and carboxylic acid, amine and indazole to form the method for acid amides and urea derivatives.

With N, N-carbonyl dimidazoles (0.62mmol) adds to (S) 3-amino quinine ring hydrochloride (0.500mmol) at N, in the solution in the dinethylformamide (3.0mL).Drip N, N-diisopropylethylamine (1.48mmol) was at room temperature placed reaction mixture 2 hours.Add N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-1H-indazole-3-methane amide (0.370mmol) and reaction mixture placed 16 hours.Reaction mixture is transferred on the SCX post (10g), and this post is with the washed with methanol of 5 times of volumes.Partially purified product then is used in 5% dimethyl amine wash-out in the methyl alcohol.This resistates adopts 50/50 to 30/70 ethyl acetate/[(50/50/2) ethyl acetate/methanol/dimethyl amine] wash-out to obtain urea by chromatography purification, and yield is 61%.

Adopt the following compound of this method preparation:

161) N, N '-two-(3S)-1-azabicyclo [2.2.2] oct-3-yl-1H-indazole-1, the 3-diformamide, ¹HNMR (CD ₃OD) δ 8.34 (d, J=8.5,1H); 8.27 (d, J=8.2,1H); 7.57 (t, J=7.3,1H); 7.40 (t, J=7.3,1H); 4.21 (m, 1H); 4.11 (m, 1H); 3.39 (m, 2H); 3.1-2.7 (m, 10H); 2.12 (m, 2H); 1.97 (m, 2H); 1.81 (m, 4H); 1.59 (m, 2H); LC/MS (EI) t _R1.38, m/z 423.2 (M ⁺+ 1);

N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(bromine)-1,2-benzisothiazole-3-methane amide.

N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-5-(tetrahydrochysene-2H-pyrans-4-base oxygen base)-1-[2-(trimethyl silyl) oxyethyl group] methyl isophthalic acid H-indazole-3-methane amide.

Adopt this method, then prepare following compound with tetrabutyl ammonium fluoride:

190) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-5-(tetrahydrochysene-2H-pyrans-4-base oxygen base)-1H-indazole-3-methane amide, LC/MS (EI) t _R4.46, m/z 370.4 (M ⁺+ 1);

Method G

Method G provides coupling between 3-amino quinine ring and carboxylic acid to form the method for carboxamides derivatives.

Carry out linked reaction and purifying according to method A (benzoisoxazole), method B, E or F (benzisothiazole) or method C, D, E or F (indazole).The 1N hydrochloric acid (3.5mL/mmol starting acid) that free alkali is dissolved in (3.5mL/mmol starting acid) in the methyl alcohol and is used in the ether is handled.Thus obtained suspension dilutes with ether (7mL/mmol starting acid), and at room temperature places 2 hours.By solid collected by filtration, with ether drip washing and dry, obtain hydrochloride thus, yield is 40-60%.

Adopt the following compound of this method preparation:

71) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-methoxyl group-1,2-benzoisoxazole-3-carboxamide hydrochloride, ¹H NMR (CD ₃OD) δ 7.93 (d, J=8.7,1H), 7.23 (s, 1H), 7.05 (d, J=8.7,1H), 4.47 (m, 1H), 3.91 (s, 3H), 3.82-3.69 (m, 1H), 3.35-3.25 (m, 5H), 2.32 (m, 1H), 2.16 (m, 1H), 2.04 (m, 2H), 1.86 (m, 2H); LC/MS (EI) t _R2.75, m/z 302 (M ⁺+ 1);

74) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-1-ethyl-6-(1,3-oxazole-2-yl)-1H-indazole-3-carboxamide hydrochloride, LC/MS (EI) t _R3.07, m/z 366 (M ⁺+ 1);

51) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-methoxyl group-1,2-benzisothiazole-3-carboxamide hydrochloride, LC/MS (EI) t _R14.4, m/z 318 (M ⁺+ 1);

52) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-methoxyl group-1,2-benzisothiazole-3-carboxamide hydrochloride, LC/MS (EI) t _R14.35, m/z 318 (M ⁺+ 1);

53) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-7-methoxyl group-1,2-benzisothiazole-3-carboxamide hydrochloride, LC/MS (EI) t _R15.36, m/z 318 (M ⁺+ 1),

Method H

Method H provides coupling between bromination 3-amino quinine ring methane amide and Grignard reagent to form the method for alkyl-substituted derivatives.

In the 5mL microwave reactor, add two (triphenylphosphine) palladium chloride (II) (0.030mmol, 0.1 equivalent) and bromide (0.30mmol).Evacuated vessel also recharges into argon gas.In independent reaction vessel, at room temperature grignard reagent solution (1.2mmol, 4 equivalents) is added in the 0.5M liquor zinci chloridi (1.2mmol, 4 equivalents) in the tetrahydrofuran (THF).This suspension was placed 30 minutes, and all the elements thing is transferred in the reaction vessel through sleeve pipe.Seal this container, stirred in advance 60 seconds, and 100 ℃ of following microwave radiations 600 seconds.This reaction is with acetate (0.5mL) termination reaction, with the methyl alcohol dilution and transfer on the SCX post.(50mL) washes post with methyl alcohol, and product is used in the 2M ammonia eluted product in the methyl alcohol (50mL) and concentrates.Resistates obtains product thus by chromatography [90/10/1 methylene chloride/ammonium hydroxide or 1/1 to 0/1 ethyl acetate/(70/30/1 ethyl acetate/methanol/ammonium hydroxide)] or by preparation HPLC purifying, and yield is 20-50%.

Adopt the following compound of this method preparation:

22) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-1-(difluoromethyl)-6-(1,3-thiazoles-2-yl)-1H-indazole-3-methane amide. ¹H?NMR(CD ₃OD)δ8.46(s，1H)；8.40(d，J＝8.6，1H)；8.05(d，J＝8.6，1H)；7.98(t，J＝58.3，1H)；7.97(d，J＝3.3，1H)；7.73(d，J＝3.3，1H)；4.57(m，1H)；3.86(m，1H)；3.60-3.20(m，5H)；2.43(m，1H)；2.26(m，1H)；2.16(m，2H)；1.95(m，1H)；LC/MS(EI)t _R4.04，m/z?404(M ⁺+1)。

Method I

Method I provides and makes amino quinine ring methane amide and the alkylating reagent coupling that has aniline or phenol, forms the method for the derivative of secondary aniline or ether replacement.

To N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-hydroxyl-1,2-benzisothiazole-3-methane amide (0.400mol) adds salt of wormwood (2.00mol) and cyclopropyl MB (0.47mmol) at N in the solution in the dinethylformamide (6mL).To react and place solvent removed in vacuo 16 hours.Resistates extracts (3 *) with 10/1 methylene chloride, concentrates the extract that merges.By preparation HPLC, use 95/5 to 20/80 water (0.1% formic acid)/acetonitrile (0.1% formic acid) to carry out 8 minutes gradient elution purifying resistatess, obtain product thus, yield is 32%.

Adopt the following compound of this method preparation:

N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(cyclo propyl methoxy)-1,2-benzisothiazole-3-methane amide formate;

13) (3S)-and 3-{[(5-hydroxyl-1,2-benzisothiazole-3-yl) carbonyl] amino }-1-methyl isophthalic acid-azonia dicyclo [2.2.2] octane iodide or formate, LC/MS (EI) t _R2.55, m/z 318 (M ⁺+ 1);

N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-5-methoxyl group-1,2-benzisothiazole-3-methane amide formate.

Adopt the following compound of this method preparation:

1) (3S)-and 3-({ [6-(cyclo propyl methoxy)-1,2-benzisothiazole-3-yl] carbonyl } amino)-1-(cyclopropyl methyl)-1-azonia dicyclo [2.2.2] octane bromide or formate, LC/MS (EI) t _R5.76, m/z 412 (M ⁺+ 1).

Method J

Method J provides coupling between bromination 3-amino quinine ring benzisothiazole and cyclammonium to form the method for anils.

In microwave reactor, mix tetramethyleneimine (0.361mmol), N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-bromo-1,2-benzisothiazole-3-methane amide (0.259mmol), acid chloride (0.021mmol), 2-dicyclohexylphosphontetrafluoroborate-2 ', 4 ', 6 '-triisopropyl-1,1 '-biphenyl (0.049mmol) and cesium carbonate (0.586mmol).This container is vacuumized and under argon atmospher, recharge.Add tetrahydrofuran (THF) (3.7mL) and seal this container.This is reflected at carried out microwave radiation under 135 ℃ 30 minutes.Reaction mixture is passed through diatomite filtration, and by chromatography [100/0 to 80/20 ethyl acetate/(50/50/2 ethyl acetate/methanol/dimethyl amine)] or preparation HPLC purifying resistates, obtain product, yield is 34%.

Adopt the following compound of this method preparation:

2) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(3-methoxyl group tetramethyleneimine-1-yl)-1,2-benzisothiazole-3-methane amide, ¹H NMR (CD ₃OD) δ 7.91 (d, J=8.9,1H); 7.77 (s, 1H); 7.09 (d, J=8.9,1H); 4.3-4.1 (m, 2H); 3.7-3.3 (m, 8H); 3.1-2.8 (m, 5H); 2.20 (m, 2H); 2.09 (m, 1H); 1.98 (m, 1H); 1.83 (m, 2H); 1.60 (m, 1H); LC/MS (EI) t _R3.7, m/z 387 (M ⁺+ 1);

64) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-tetramethyleneimine-1-base-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R4.13, m/z 357.2 (M ⁺+ 1);

66) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(1H-pyrroles-1-yl)-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R4.04, m/z 353.1 (M ⁺+ 1);

68) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[3-(cyclo propyl methoxy) tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R4.31, m/z 427.2 (M ⁺+ 1);

69) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(3-methoxyl group tetramethyleneimine-1-yl)-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R3.57, m/z 371.2 (M ⁺+ 1);

70) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-7-(3-methoxyl group tetramethyleneimine-1-yl)-1,2-benzoisoxazole-3-methane amide, LC/MS (EI) t _R3.83, m/z 387.2 (M ⁺+ 1);

72) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-(3-methoxyl group tetramethyleneimine-1-yl)-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R3.8, m/z 387.2 (M ⁺+ 1);

75) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(3R)-and 3-methoxyl group tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R3.74, m/z 387.2 (M ⁺+ 1);

76) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(3S)-and 3-methoxyl group tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R3.77, m/z 387.2 (M ⁺+ 1);

79) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[3-(difluoro-methoxy) tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R4.22, m/z 423.2 (M ⁺+ 1);

108) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(3R)-and 3-methoxyl group tetramethyleneimine-1-yl]-1,2-benzoisoxazole-3-methane amide, LC/MS (EI) t _R4.5, m/z 371.1 (M ⁺+ 1);

109) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(3S)-and 3-methoxyl group tetramethyleneimine-1-yl]-1,2-benzoisoxazole-3-methane amide, LC/MS (EI) t _R4.5, m/z 371.1 (M ⁺+ 1);

110) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-7-[(3R)-and 3-methoxyl group tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-methane amide formate, LC/MS (EI) t _R3.92, m/z 387.1 (M ⁺+ 1);

111) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-7-[(3S)-and 3-methoxyl group tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R3.91, m/z 387.1 (M ⁺+ 1);

112) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-7-[(3R)-and 3-methoxyl group tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-methane amide formate, LC/MS (EI) t _R3.91, m/z 387.1 (M ⁺+ 1);

113) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-7-[(3S)-and 3-methoxyl group tetramethyleneimine-1-yl]-1,2-benzisothiazole-3-methane amide formate, LC/MS (EI) t _R3.94, m/z 387.1 (M ⁺+ 1).

By the 3-[(2-trimethylsilylethoxy)) methoxyl group] tetramethyleneimine, adopt this method, then also separate and prepare following compound with the SCX ion exchange method with the acid treatment of 6N salt, preparation HPLC purifying:

78) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(3-hydroxyl pyrrolidine-1-yl)-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R4.44, m/z 373.1 (M ⁺+ 1).

Method K

Method K provides coupling between bromination 3-amino quinine ring indazole and cyclammonium to form the method for anils.

In bottle, mix 2-dicyclohexylphosphontetrafluoroborate-2 ', 4 ', 6 '-triisopropyl-1,1 '-biphenyl (0.0450mmol), acid chloride (II) (0.0150mmol), cesium carbonate (2.25mmol) and 3-(cyclo propyl methoxy) tetramethyleneimine (2.25mmol).Add N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-bromo-2-[2-(trimethyl silyl) oxyethyl group] methyl isophthalic acid H-indazole-3-methane amide (0.751mmol) in toluene (6.36mL) solution and with mixture 80 ℃ of heating 3 days down.Reaction mixture by diatomite filtration, is loaded on the RediSep post (silica gel), adopts 100/0 to 80/20 ethyl acetate/(50/50/2 ethyl acetate/methanol/dimethyl amine) gradient elution.Resistates is transferred on the SCX post (10g), and this post concentrates the ammonia elutriant with methyl alcohol (5 volume), 2.0M ammonia wash-out (removing most of SEM by this method) in methyl alcohol.Resistates by preparation HPLC[in 10 minutes, 90/10 to 50/50 water (0.1% formic acid)/acetonitrile (0.1% formic acid)] purifying obtains required product, yield is 7%.

Adopt the following acid of this method preparation:

58) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[3-(cyclo propyl methoxy) tetramethyleneimine-1-yl]-1H-indazole-3-methane amide formate, ¹H NMR (CD ₃OD) δ 8.44 (br s, 1H); 7.95 (d, J=9.0,1H); 6.75 (d, J=9.0,1H); 6.46 (s, 1H); 4.50 (m, 1H); 4.30 (m, 1H); 3.81 (m, 1H); 3.60-3.20 (m, 9H); 3.36 (d, J=6.9,2H); 2.37 (m, 1H); 2.26 (m, 1H); 2.17 (m, 2H); 2.09 (m, 2H); 1.92 (m, 1H); 1.05 (m, 1H); 0.52 (m, 2H); 0.22 (m, 2H); LC/MS (EI) t _R4.48, m/z410.2 (M ⁺+ 1);

61) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-[3-(cyclo propyl methoxy) tetramethyleneimine-1-yl]-1H-indazole-3-methane amide formate, LC/MS (EI) t _R4.49, m/z 410.2 (M ⁺+ 1);

62) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-(3-methoxyl group tetramethyleneimine-1-yl)-1H-indazole-3-methane amide formate, LC/MS (EI) t _R4.1, m/z 370.3 (M ⁺+ 1).

Method L

Method L provides between amino rubane methane amide of bromination and cyclammonium coupling to form the method for anils.

With 3-methoxyl group pyrrolidine hydrochloride (6.27mmol), N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-bromo-1,2-benzisothiazole-3-methane amide (4.42mmol), 2-dicyclohexylphosphontetrafluoroborate-2 ', 4 ', 6 '-triisopropyl-1,1 '-mixture of biphenyl (0.845mmol), acid chloride (0.363mmol) and cesium carbonate (9.97mmol) vacuumizes and recharges into argon gas.Add tetrahydrofuran (THF) (60mL), should react reflux 67 hours.Reaction mixture is cooled to room temperature and also concentrated by diatomite filtration (methyl alcohol).Resistates is distributed between 9/1 methylene chloride (100mL) and saturated sodium bicarbonate (40mL), separate each layer.(3 * 50mL) extract water layer, the organic layer of merging salt water washing and dry (sodium sulfate) with 9/1 methylene chloride.Resistates obtains free alkali (84%) by chromatography (70/30/1 ethyl acetate/methanol/ammonium hydroxide) purifying, and it is yellow foam.By methylate hydrochlorate preparation [Acetyl Chloride 98Min. in methyl alcohol (5mL) (0.95 equivalent)] hydrochloride and recrystallization from methanol/ethyl acetate.

Adopt the following compound of this method preparation:

49) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(3-methoxyl group tetramethyleneimine-1-yl)-1,2-benzisothiazole-3-carboxamide hydrochloride. ¹H?NMR(CD ₃OD)δ8.48(d，J＝9.1，1H)，7.02(d，J＝1.9，1H)，6.91(dd，J＝9.2，2.1，1H)，4.52-4.48(m，1H)，4.20-4.17(m，1H)，3.87-3.78(m，1H)，3.58(dd，J＝11.0，4.7，1H)，3.50-3.42(m，3H)，3.38(s，3H)，3.36-3.34(m，3H)，2.40-2.37(m，1H)，2.26-2.08(m，3H)，1.95-1.87(m，1H)；LC/MS(EI)t _R3.47，m/z?387(M ⁺1)。

Method M

Method M provides between amino rubane methane amide of bromination and benzophenone imine coupling to form the method for anils.

With bromide (6.30mmol), acid chloride (1.00mmol) and 9,9-dimethyl-4,5-two (diphenylphosphine) xanthene (Xantphos) mixture (0.700mmol) vacuumizes and recharges into argon gas.Solid is handled with tetrahydrofuran (THF) (150mL) dilution and with cesium carbonate (7.00mmol) and benzophenone imine (6.80mmol).This reaction mixture reflux 16 hours.Concentrated reaction mixture also is dissolved in the mixture of tetrahydrofuran (THF) (90mL) and 3N hydrochloric acid (30mL) again.Reaction mixture was placed 2 hours and was concentrated.Resistates adopts 70/30/1 ethyl acetate/methanol/ammonium hydroxide wash-out by chromatography purification, obtains aniline thus, and yield is 79%.In subsequent reactions, can directly use this aniline.

Adopt the following compound of this method preparation:

6-amino-N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-1-(methyl)-1H-indazole-3-methane amide;

6-amino-N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-1-(difluoromethyl)-1H-indazole-3-methane amide;

6-amino-N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-1-cyclopropyl-1H-indazole-3-methane amide;

Method N

Method N provides coupling between amino quinine ring methane amide and acylating reagent to form the method for carboxamides derivatives.

To aniline (0.42mmol) and the N in pyridine (2mL), add sour muriate (0.55mmol) in dinethylformamide (2mL) solution.This mixture was at room temperature placed 16 hours and was concentrated under vacuum.Resistates is by preparation HPLC purifying, and it is the product of 30-80% that yield is provided thus.

Adopt the following compound of this method preparation:

23) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-the 6-[(cyclopropyl carbonyl) amino]-1-methyl isophthalic acid H-indazole-3-methane amide formate, ¹H NMR (CD ₃OD) δ 8.40 (br s, 1H); 8.18 (s, 1H); 8.07 (d, J=8.7,1H); 7.20 (d, J=8.7,1H); 4.50 (m, 1H); 4.09 (s, 3H); 3.81 (m, 1H); 3.60-3.20 (m, 5H); 2.37 (m, 1H); 2.26 (m, 1H); 2.11 (m, 2H); 1.92 (m, 1H); 1.81 (m, 1H); 0.99 (m, 2H); 0.91 (m, 2H); LC/MS (EI) t _R3.15, rm/z 368 (M ⁺+ 1);

24) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-the 6-[(cyclopropyl carbonyl) amino]-1-(difluoromethyl)-1H-indazole-3-methane amide formate.LC/MS(EI)t _R3.79，m/z?404(m ⁺+1)；

38) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-1-cyclopropyl-6-[(cyclopropyl carbonyl) amino]-1H-indazole-3-methane amide.LC/MS(EI)t _R3.65，m/z?394(M ⁺+1)。

Method O

Method O provides coupling between amino quinine ring methane amide and isocyanic ester to form the method for urea derivatives.

To at pyridine (2mL) and N, add isocyanic ester (0.53mmol) in the aniline (0.40mmol) in the mixture of dinethylformamide (1mL).Reaction mixture was at room temperature placed 16 hours and under vacuum, concentrated.Resistates is by preparation HPLC purifying, and it is the product of 50-80% that yield is provided thus.

Adopt the following compound of this method preparation:

18) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-1-methyl-6-{[(propyl group amino) carbonyl] amino }-1H-indazole-3-methane amide formate, ¹H NMR (CD ₃OD) δ 8.50 (br s, 1H); 8.00 (d, J=8.7,1H); 7.92 (s, 1H); 7.01 (d, J=8.7,1H); 4.50 (m, 1H); 4.06 (s, 3H); 3.81 (m, 1H); 3.60-3.30 (m, 5H); 3.20 (t, J=7.1,2H); 2.37 (m, 1H); 2.26 (m, 1H); 2.11 (m, 2H); 1.92 (m, 1H); 1.58 (m, J=7.1,2H); 0.98 (t, J=7.3,2H); LC/MS (EI) t _R3.36, m/z 385 (M ⁺+ 1);

25) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-1-(difluoromethyl)-6-{[(propyl group amino) carbonyl] amino }-1H-indazole-3-methane amide formate.LC/MS(EI)t _R3.81，m/z?421(M ⁺+1)；

39) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-1-cyclopropyl-6-{[(propyl group amino) carbonyl] amino }-1H-indazole-3-methane amide.LC/MS(EI)t _R3.71，m/z?411(M ⁺+1)。

Method P

Method P provides the rubane methane amide demethylation of methoxyl group replacement to form the method for phenol derivatives.

Under 0 ℃, (20.0mmol) adds to N-[(3S with boron tribromide)-1-azabicyclo [2.2.2] oct-3-yl]-6-methoxyl group-1, in the 2-benzisothiazole-solution of 3-methane amide (3.80mmol) in methylene dichloride (100mL).Reaction mixture is warmed to room temperature and placed 3 days.With the reaction of unsaturated carbonate potassium solution (50mL) termination reaction mixture and separate each layer.Water layer is used (10/1) methylene chloride (50mL) extraction again, merges organic layer and concentrated.To obtain product, yield is 70% to resistates by chromatography [(70/30/1) ethyl acetate/methanol/ammonium hydroxide] purifying.

Adopt the following compound of this method preparation:

9) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-4-hydroxyl-1H-indazole-3-methane amide formate. ¹H?NMR(CD ₃OD)δ8.39(s，1H)，7.28(t，J＝8.3，1H)，7.00(d，J＝8.4，1H)，6.54(d，J＝7.6，1H)，4.57(m，1H)，3.83(t，J＝11.4，1H)，3.52-3.31(m，5H)，2.42-2.39(m，1H)，2.27(m，1H)，2.12-2.07(m，2H)，1.98-1.90(m，1H)；LC/MS(EI)t _R3.18，m/z?287(M ⁺+1)；

10) n-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-5-bromo-4-hydroxyl-1H-indazole-3-methane amide formate.LC/MS(EI)t _R3.9，m/z?365/367(M ⁺+1)；

11) N-[(3S)-and 1-azabicyclo [2.2.2] oct-3-yl]-5,7-two bromo-4-hydroxyls-1H-indazole-3-methane amide formate.LC/MS(EI)t _R4.26，m/z?443/445/447(M ⁺+1)；

16) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-7-hydroxyl-1H-indazole-3-methane amide formate.LC/MS(EI)t _R2.48，m/z?287(M ⁺+1)；

50) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-hydroxyl-1,2-benzisothiazole-3-methane amide.LC/MS(EI)t _R2.58，m/z?304(M ⁺+1)。

Method Q

Method Q provides the method that is prepared Cydic amide derivatives by corresponding Quinium Bromide ring derivatives.

With acid chloride (II) (0.09mmol) add to 2,2 '-two (diphenylphosphine)-1,1 '-solution of dinaphthyl (0.14mmol) in toluene (10mL) in, the standing and reacting mixture thoroughly dissolves up to each composition.The yellow solution that will generate thus under nitrogen atmosphere is transferred in the mixture of bromide (0.33mmol), cesium carbonate (0.60mmol) and acid amides (1.00mmol), and reaction mixture was heated 16 hours down at 100 ℃.Reaction mixture filters on diatomite and concentrates.Resistates obtains product thus by the HPLC purifying, and yield is 72%.

Adopt the following compound of this method preparation:

15) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-1-ethyl-6-(2-oxo-pyrrolidine-1-yl)-1H-indazole-3-methane amide formate, ¹H NMR (CD ₃OD) δ 8.40 (br s, 1H); 8.15 (d, J=8.9,1H); 7.88 (s, 1H); 7.54 (d, J=8.9,1H); 4.55 (m, 1H); 4.49 (q, J=7.2,2H); 3.99 (t, J=7.0,2H); 3.81 (m, 1H); 3.60-3.30 (m, 5H); 2.63 (t, J=8.1,2H); 2.38 (m, 1H); 2.26 (m, 1H); 2.19 (m, 2H); 2.10 (m, 2H); 1.92 (m, 1H); 1.51 (t, J=7.2,3H); LC/MS (EI) t _R2.59, m/z 382 (M ⁺+ 1);

65) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(3-methyl-2-oxo-pyrrolidine-1-yl)-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R2.93, m/z 385.2 (M ⁺+ 1).

Adopt this method, then removing protecting group with 6N hydrochloric acid prepares following compound:

41) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(4S)-4-hydroxyl-2-oxo-pyrrolidine-1-yl]-1H-indazole-3-methane amide formate.LC/MS(EI)t _R1.39，m/z?370(M ⁺+1)；

Method R

Method R provides amino quinine ring methane amide and alcohol through the method for three creed part couplings with formation N (1)-alkyl derivative.

(0.212mmol) drops to N-[(3S with diisopropyl azodiformate)-1-azabicyclo [2.2.2] oct-3-yl]-6-(1,3-oxazole-2-yl)-and 1H-indazole-3-methane amide (0.141mmol), cyclopropyl-carbinol (0.283mmol), triphenylphosphine (0.283mmol) and N, in the solution of dinethylformamide (1.00mL).Reaction mixture is at room temperature placed 16 hours, and be loaded on the silicagel column.To obtain product (20%), it is a solid to this mixture by chromatography { 95/5 to 85/15 ethyl acetate/[(50/50/2) ethyl acetate/methanol/dimethyl amine] } purifying.This product contains 7% the 2-cyclopropyl methyl isomer of having an appointment.

Adopt the following compound of this method preparation:

4) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-1-propyl group-6-(1,3-thiazoles-2-yl)-1H-indazole-3-methane amide, ¹H NMR (CD ₃OD) δ 8.44 (br s, 1H); 8.27 (d, J=8.6,1H); 8.25 (s, 1H); 7.94 (d, J=3.3,1H); 7.85 (d, J=8.5,1H); 7.68 (d, J=3.3,1H); 4.55 (m, 1H); 4.53 (t, J=7.0,2H); 3.83 (m, 1H); 3.60-3.25 (m, 5H); 2.40 (m, 1H); 2.25 (m, 1H); 2.12 (m, 2H); 2.08 (m, 2H); 2.00 (m, 1H); LC/MS (EI) t _R4.02, m/z 396 (M ⁺+ 1);

5) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-1-sec.-propyl-6-(1,3-thiazoles-2-yl)-1H-indazole-3-methane amide.LC/MS(EI)t _R3.9，m/z?396(M ⁺+1)；

30) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-1-ethyl-6-(1,3-oxazole-2-yl)-1H-indazole-3-methane amide.LC/MS(EI)t _R3.61，m/z?366(M ⁺+1)；

31) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-1-(cyclopropyl methyl)-6-(1,3-oxazole-2-yl)-1H-indazole-3-methane amide.LC/MS(EI)t _R3.88，m/z?392(M ⁺+1)；

32) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(1,3-oxazole-2-yl)-1-propyl group-1H-indazole-3-methane amide.LC/MS(EI)t _R3.79，m/z?380(M ⁺+1)；

33) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-1-ethyl-N-methyl-6-(1,3-oxazole-2-yl)-1H-indazole-3-methane amide.LC/MS(EI)t _R3.79，m/z?380(M ⁺+1)。

Method S

Method S provides the method that adopts three creed parts to be formed ether derivant by corresponding phenolic.

(0.618mmol) drops to N-[(3S with diisopropyl azodiformate)-1-azabicyclo [2.2.2] oct-3-yl]-6-hydroxyl-1,2-benzisothiazole-3-methane amide (0.594mmol), 3-furfuralcohol (0.594mmol) and triphenylphosphine (0.594mmol) are at N, in the solution in the dinethylformamide (3.40mL).Reaction mixture was placed 16 hours and concentrated.Resistates obtains product by chromatography { 100/0 to 90/10 ethyl acetate/[(70/30/2) ethyl acetate/methanol/dimethyl amine] } purifying, and yield is 26%.

Adopt the following compound of this method preparation:

14) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(3-furans methoxyl group)-1,2-benzisothiazole-3-methane amide formate. ¹H?NMR(CD ₃OD)δ8.50-8.41(m，1H)，7.86-7.80(m，1H)，7.70-7.69(m，1H)，7.27-7.22(m，1H)，7.01-6.93(m，1H)，6.64-6.59(m，1H)，4.52(m，1H)，4.30(m，2H)，3.98-3.89(m，1H)，3.56-3.38(m，5H)，2.41-2.39(m，1H)，2.29(m，2H)，2.15-2.13(m，1H)，2.00(m，1H)；LC/MS(EI)t _R3.58，m/z?384(M ⁺+1)。

Method T

Method T provides the method that is prepared the rubane methane amide of phenol replacement by the bromide derivative.

With potassium acetate (0.600mmol), acid chloride (0.060mmol), two (pinacols), two boron (bis (pinacolato) diboron) (0.800mmol) and 2-dicyclohexylphosphontetrafluoroborate-2 ', 4 ', 6 '-triisopropyl-1,1 '-phenylbenzene (0.200mmol) adds to N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-5-bromo-1, in the 2-benzisothiazole-suspension of 3-methane amide (0.500mmol) in toluene (8mL).Reaction mixture was carried out microwave radiation (150 ℃) 5 minutes.Reaction mixture is cooled to room temperature, filters concentrated filtrate by diatomite (methyl alcohol).Resistates obtains product by preparation HPLC purifying, and yield is 60%.

(0.500mmol) adds to N-[(3S with hydrogen peroxide)-1-azabicyclo [2.2.2] oct-3-yl]-5-(4,4,5,5-tetramethyl--1,3,2-two oxa-s borine-2-yl)-1, in the 2-benzisothiazole-solution of 3-methane amide (0.200mmol) in acetone (3mL).Reaction mixture is at room temperature placed 2 hours, and water (2mL) dilution.This product is 70% product with the acquisition yield with (9/1) methylene chloride extraction, concentrated extract.This phenol is directly used in subsequent reactions.

Adopt the following compound of this method preparation:

12) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-5-hydroxyl-1,2-benzisothiazole-3-methane amide formate. ¹H?NMR(CD ₃OD)δ8.55(d，1H，J＝9)，7.36(d，1H，J＝2)，7.05(dd，1H，J＝2,9)，4.51(m，1H)，3.83(m，1H)，3.38(m，5H)，2.40(m，1H)，2.38(m，1H)，2.12(m，2H)，1.94(m，1H)；LC/MS(EI)t _R2.58，m/z?304(M ⁺+1)；

(3-[(3S)-and 1-azabicyclo [2.2.2] oct-3-yl amino] carbonyl-1,2-benzisothiazole-5-yl) boric acid;

(3-[(3S)-and 1-azabicyclo [2.2.2] oct-3-yl amino] carbonyl-1,2-benzisothiazole-6-yl) boric acid.

Method U

Method U provides coupling between 3-amino quinine ring benzisothiazole boric acid to form the method for aromatics anils.

In microwave container, mix (3-[(3S)-1-azabicyclo [2.2.2] oct-3-yl amino] carbonyl-1,2-benzisothiazole-6-yl) boric acid (0.604mmol), 1H-imidazoles (1.8mmol), venus crystals (1.21mmol), triethylamine (3.0mmol), pyridine (4.8mmol) and tetrahydrofuran (THF) (8.5mL).With reaction mixture 140 ℃ of microwave radiations 600 seconds.Concentrated reaction mixture, resistates obtain the product of prepurification by chromatography [95/5 to 85/15 ethyl acetate/(1/1/0.1 ethyl acetate/methanol/dimethyl amine)] purifying, and it is a yellow oil.Resistates is further purified by preparation HPLC, and merging contains the part of required product and is loaded on the 5g SCX post.This post concentrates the ammonia elutriant to obtain product with methyl alcohol (120mL), the 2.0M ammonia stripping in methyl alcohol, and it is a white solid, and yield is 14%.

Adopt the following compound of this method preparation:

80) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(1H-imidazoles-1-yl)-1,2-benzisothiazole-3-methane amide, ¹H NMR (CD ₃OD) δ 8.87 (d, J=8.9,1H); 8.35 (m, 2H); 7.81 (d, J=8.9,1H); 7.75 (s, 1H); 7.22 (s, 1H); 4.20 (m, 1H); 3.35 (m, 1H); 3.20-2.75 (m, 5H); 2.09 (m, 1H); 1.95 (m, 1H); 1.82 (m, 2H); 1.56 (m, 1H); LC/MS (EI) t _R1.7, m/z 354.1 (M ⁺+ 1);

81) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(1H-pyrazol-1-yl)-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R3.27, m/z 354.1 (M ⁺+ 1);

82) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(3-methyl isophthalic acid H-pyrazol-1-yl)-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R3.85, m/z 368.1 (M ⁺+ 1);

83) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(5-methyl isophthalic acid H-pyrazol-1-yl)-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R3.47, m/z 368.1 (M ⁺+ 1).

Method V

Method V provides coupling between indazole rubane methane amide and boric acid to form the method for N (1)-alkylation and arylation carboxamides derivatives.

With N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(1,3-thiazoles-2-yl)-1H-indazole-3-methane amide (0.280mmol), cyclopropylboronic acid (0.840mmol) and venus crystals (II) mixture (5.60mmol) dilute with triethylamine (1.40mmol), pyridine (2.2mmol) and tetrahydrofuran (THF) (3.00mL).Reaction mixture was carried out microwave radiation 600 seconds under 140 ℃.Filter reaction mixture also is transferred on the SCX post.This post washs with methyl alcohol (5 times of volumes), and this product then is used in the 2.0M ammonia wash-out in the methyl alcohol, obtains light yellow solid thus.To obtain product, yield is 22% to resistates by chromatography { 90/10 to 80/20 ethyl acetate/[(50/50/2) ethyl acetate/methanol/dimethyl amine] } purifying.Final product contains 3% the regional isomer of having an appointment.

Adopt the following compound of this method preparation:

26) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-1-cyclopropyl-6-(1,3-thiazoles-2-yl)-1H-indazole-3-methane amide, ¹H NMR (CD ₃OD) δ 8.28 (s, 1H); 8.21 (d, J=8.6,1H); 7.91 (d, J=3.3,1H); 7.80 (d, J=8.6,1H); 7.65 (d, J=3.3,1H); 4.20 (m, 1H); 3.82 (m, 1H); 3.35 (m, 1H); 3.20-2.80 (m, 5H); 2.07 (m, 1H); 1.95 (m, 1H); 1.81 (m, 2H); 1.57 (m, 1H); 1.25 (m, 4H); LC/MS (EI) t _R3.9, m/z 394 (M ⁺+ 1);

27) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(1,3-thiazoles-2-yl)-1-(3-thienyl)-1H-indazole-3-methane amide, LC/MS (EI) t _R4.28, m/z 436 (M ⁺+ 1);

N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-bromo-1-cyclopropyl-1H-indazole-3-methane amide.

Method W

Method W provides between bromine amino quinine ring benzisothiazole and ring urea coupling to form the method for urea derivatives.

With 1-propyl imidazole alkane-2-ketone (19.0mmol), N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-bromo-1,2-benzisothiazole-3-methane amide (10.0mmol), acid chloride (II) (1.00mmol) and di-t-butyl (2 ', 4 ', 6 '-tri isopropyl biphenyl-2-yl) mixture of phosphine (2.00mmol) dilutes with toluene (100mL) and tetrahydrofuran (THF) (50mL).This reaction mixture heated 16 hours down at 100 ℃, and reaction mixture filters and concentrates by diatomite (methyl alcohol).Resistates is transferred on the SCX post also with methyl alcohol (100mL) washing.Crude product is used in the 7M ammonia wash-out in the methyl alcohol (100mL), concentrates the product part that merges.Resistates obtains product by chromatography [(70/35/1) ethyl acetate/methanol/ammonium hydroxide] purifying, and yield is 90%.By methylate hydrochlorate [Acetyl Chloride 98Min. in methyl alcohol (5mL) (0.95 equivalent)] preparation one hydrochloride, and from methanol/ethyl acetate recrystallization.

Other method: with the 1-ethyl imidazol(e) alkane in the microwave tube-2-ketone (41.2mg, 0.000361mol), N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-bromo-1,2-benzisothiazole-3-methane amide (95.0mg, 0.000259mol), acid chloride (II) (4.8mg, 0.000021mol), 2-dicyclohexylphosphontetrafluoroborate-2 ', 4 ', 6 '-triisopropyl-1,1 '-biphenyl (23.2mg, 0.0000488mol) and cesium carbonate (191mg, 0.000586mol) mixture vacuumize, and under argon atmospher, recharge.(3.7mL 0.045mol), carried out microwave radiation 30 minutes with container sealing and with reaction mixture under 135 ℃ to add tetrahydrofuran (THF).Reaction mixture is by diatomite filtration and concentrated.Resistates obtains product by chromatography [100/0 to 80/20 ethyl acetate/(50/50/2 ethyl acetate/methanol/dimethyl amine)] purifying, and yield is 24%.

Adopt the following compound of this method preparation:

67) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(3-ethyl-2-oxo imidazolidine-1-yl)-1,2-benzisothiazole-3-methane amide, ¹H NMR (CD ₃OD) δ 8.64 (d, J=9.1,1H); 8.16 (d, J=1.8,1H); 7.93 (dd, J=1.9/9.1,1H); 4.20 (m, 1H); 3.98 (m, 2H); 3.61 (m, 2H); 3.60-3.35 (m, 1H); 3.37 (q, J=7.3,2H); 3.1-2.75 (m, 5H); 2.08 (m, 1H); 1.92 (m, 1H); 1.81 (m, 2H); 1.55 (m, 1H); 1.20 (t, J=7.3,3H); LC/MS (EI) t _R3.25, m/z 400.2 (M ⁺+ 1);

131) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-(2-oxo-3-propyl imidazole alkane-1-yl)-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R3.76, m/z 414.2 (M ⁺+ 1);

54) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(2-oxo-3-propyl imidazole quinoline-1-yl)-1,2-benzisothiazole-3-carboxamide hydrochloride.LC/MS(EI)t _R3.68，m/z?414(M ⁺+1)。

Method X

Method X provides between bromine amino quinine ring indazole and ring urea coupling to form the method for urea derivatives.

In microwave tube with 1-propyl imidazole alkane-2-ketone (0.5684mmol), N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-bromo-2-[2-(trimethyl silyl) oxyethyl group] methyl isophthalic acid H-indazole-3-methane amide (0.409mmol), acid chloride (0.034mmol), 2-dicyclohexylphosphontetrafluoroborate-2 ', 4 ', 6 '-triisopropyl-1,1 '-mixture of biphenyl (0.0768mmol) and cesium carbonate (0.924mmol) vacuumizes and recharges under argon atmospher.Add tetrahydrofuran (THF) (5.8mL), sealed vessel.Reaction mixture was carried out microwave radiation 30 minutes under 135 ℃.Reaction mixture is by diatomite filtration and concentrated.Resistates obtains the product of the SEM protection of purifying by chromatography [100/0 to 80/20 ethyl acetate/(50/50/2 ethyl acetate/methanol/dimethyl amine)] purifying.Resistates is dissolved in tetrahydrofuran (THF) (5mL) and the 6N hydrochloric acid (5mL) and with reaction mixture under 140 ℃, carried out microwave radiation 600 seconds.Reaction mixture is transferred on the SCX post (10g), and this post concentrates the ammonia elutriant with methyl alcohol (120mL) and the flushing of the 2.0M ammonia (60mL) in methyl alcohol.Resistates is by preparation HPLC purifying, and merging contains the part of required product and is transferred on the SCX post (10g).Wash this post with methyl alcohol (120mL) and the 2.0M ammonia (60mL) in methyl alcohol, concentrate the ammonia elutriant and obtain product, yield is 28%.

Adopt the following compound of this method preparation:

77) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(2-oxo-3-propyl imidazole alkane-1-yl)-1H-indazole-3-methane amide, ¹H NMR (CD ₃OD) δ 8.09 (d, J=9.0,1H); 7.72 (s, 1H); 7.51 (d, J=9.0,1H); 4.18 (m, 1H); 3.90 (m, 2H); 3.51 (m, 2H); 3.35 (m, 1H); 3.23 (t, J=7.2,2H); 3.15-2.75 (m, 5H); 2.05 (m, 1H); 1.95 (m, 1H); 1.79 (m, 2H); 1.60 (m, 1H); 1.59 (m, J=7.3,2H); 0.95 (t, J=7.3,3H); LC/MS (EI) t _R3.03, m/z 397.2 (M ⁺+ 1);

63) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-(2-oxo-3-propyl imidazole alkane-1-yl)-1H-indazole-3-methane amide formate, LC/MS (EI) t _R4.14, m/z 397.3 (M ⁺+ 1).

Method Y

Method Y provides oxidation rubane methane amide to form the method for N-oxide derivative.

Metachloroperbenzoic acid (0.266mmol) is added in-78 ℃ of suspension of rubane acid amides (0.21mmol) in methylene dichloride (3mL) in batches, reaction mixture is warmed to room temperature and placed 16 hours.With reaction mixture with methyl alcohol dilution and be loaded on the SCX post.This post concentrates ammonia stripping liquid with methyl alcohol (50mL), the 2M ammonia stripping in methyl alcohol (60mL).Crude product obtains 26.5mg (38%) product thus by preparation HPLC purifying.

Adopt the following compound of this method preparation:

55) N-[(3S)-1-oxidation-1-azabicyclo [2.2.2] oct-3-yl]-5-(trifluoromethoxy)-1H-indazole-3-methane amide, ¹H NMR (CD ₃OD) δ 8.31 (br m, 1H), 8.08 (s, 1H), 7.69 (d, J=9.1,1H), 7.36 (dd, J=9.0,1.3,1H), 4.72-4.69 (m, 1H), 4.13-4.04 (m, 1H), 3.80-3.63 (m, 5H), and 2.45-2.35 (m, 3H), 2.28-2.25 (m, 1H), 2.15-2.11 (m, 1H); LC/MS (EI) t _R3.99, m/z 371 (M ⁺+ 1);

56) 6-methoxyl group-N-[(3S)-1-oxidation-1-azabicyclo [2.2.2] oct-3-yl]-1,2-benzisothiazole-3-methane amide, LC/MS (EI) t _R3.65, m/z 334 (M ⁺+ 1).

Method Z

Method Z provides the method that amino quinine ring methane amide nitrile is converted into the glyoxalidine derivative with diamines.

(90mg is 0.31mmol) in the solution in ethanol (6mL) to make hydrogen sulfide pass through 6-cyano group-N-(rubane-3-yl)-1H-indazole-3-methane amide in the intrinsic pressure pipe in following 30 minutes at 0 ℃.Sealed vessel heats reaction mixture 16 hours down and concentrates at 80 ℃.Resistates heated 16 hours down with quadrol (4mL) dilution and at 100 ℃.Concentrated reaction mixture obtains 110mg (94%) glyoxalidine, and it is a brown solid.

Adopt the following compound of this method preparation:

89) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-(4,5-dihydro-1H-imidazoles-2-yl)-1H-indazole-3-methane amide, ¹H NMR (CD ₃OD) δ 8.27 (d, J=8.5,1H), 8.08 (s, 1H), 7.66 (d, J=8.5,1H), 4.22 (m, 1H), 3.87 (s, 3H), 3.69 (s, 1H), 3.37 (m, 6H), 2.91 (m, 8H), 2.08 (m, 2H), 1.82 (m, 2H), 1.55 (m, 1H); LC/MS (EI) t _R1.63, m/z 339.2 (M ⁺+ 1).

Method AA

Method AA provides 3-amino quinine ring methane amide and electrophilic reagent reaction to form the method for quaternary ammonium salt derivative.

With N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-1H-indazole-3-methane amide (3.26mmol) is dissolved in the methylene dichloride (50.0mL), and reaction mixture at room temperature placed 3 days.Behind the several minutes, it is muddy that mixture becomes, white precipitate apparition after 1 hour.By filtering the solid that collecting precipitation goes out, with methylene dichloride and ethyl acetate washing and dry, obtain product, it is a colorless solid, yield is 92%.Show that by the analysis of analyzing LC/MS this product is polluted by a small amount of raw material (about 5%).

To (3S)-1-(chloromethyl)-3-[(1H-indazole-3-base carbonyl) amino]-add the MP-diisopropylethylamine in the solution of 1-azonia dicyclo [2.2.2] octane muriate (0.999mmol) in methyl alcohol (10.0mL) (to load 415mmol/g; 41.5mol) and MP-carbonic ether (loading 3.5mmol/g; 0.050mmol).Reaction mixture vibration 24 hours is by the solids removed by filtration support agent.Solvent evaporation to about 3mL, is added ethyl acetate (15mL).The solid of collecting precipitation obtains product, and yield is 94%.

Adopt the following compound of this method preparation:

165) (3S)-and 1-(chloromethyl)-3-[(1H-indazole-3-base carbonyl) amino]-1-azonia dicyclo [2.2.2] octane muriate, ¹H NMR (CD ₃OD) δ 8.19 (d, J=8.2,1H); 7.60 (d, J=8.5,1H); 7.43 (t, J=8.5,1H); 7.26 (t, J=8.2,1H); 5.23 (s, 2H); 4.63 (m, 1H); 4.10 (m, 1H); 3.55-3.85 (m, 5H); 2.48 (m, 1H); 2.41 (m, 1H); 2.23 (m, 2H); 2.09 (m, 1H); LC/MS (EI) t _R2.38, m/z 321/319 (M ⁺+ 1).

Method AB

Method AB provides 3-amino quinine ring nitrile to be hydrolyzed into carboxylic acid, then with the method for amine coupling with the formation amide derivatives.

(7.0mmol) adds to N-[(3S with potassium hydroxide)-1-azabicyclo [2.2.2] oct-3-yl]-the 6-cyano group-1H-indazole-solution of 3-methane amide (2.3mmol) in 1 (6mL) in, reaction mixture is 140 ℃ of down heating 7 hours.Reaction is cooled to the 1M salt acid treatment that room temperature is also used 6mL.By the precipitation of filtering separation formation, and dry under vacuum, obtaining product, it is a hydrochloride, yield is 45%.

In bottle, add 3-[(3S)-1-azabicyclo [2.2.2] oct-3-yl amino] carbonyl-1H-indazole-6-carboxylic acid hydrochloride (0.3mmol), TBTU (0.4mmol) and dimethylamine (0.432mmol).Add N, dinethylformamide (2mL) and N, the N-diisopropylethylamine (0.249mL, 1.43mmol), and at room temperature placed 16 hours by reaction mixture.Reaction mixture is loaded into SCX post (10g) to be gone up and washes with methyl alcohol (200mL).Then be used in the partially purified product of 7.0M ammonia wash-out in the methyl alcohol (60mL).Resistates carries out purifying by preparation HPLC, product is partly merged and is loaded on the SCX post (10g).The 7.0M ammonia that this post with methyl alcohol (200mL), then is used in the methyl alcohol (60mL) washes.The vaporized ammonia layer is to obtain acid amides, and yield is 30%.

Adopt the following compound of this method preparation:

185) 3-[(3S)-and 1-azabicyclo [2.2.2] oct-3-yl amino] carbonyl-1H-indazole-6-carboxylic acid hydrochloride, LC/MS (EI) t _R1.50, m/z 315 (M ⁺+ 1);

186) N (3)-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-N (6), N (6)-dimethyl-1H-indazole-3, the 6-diformamide, ¹HNMR (CD ₃OD) δ 8.22 (s, 1H), 7.74 (s, 1H), 7.25 (s, 1H), 4.78 (s, 6H), 4.58 (m, 1H), 3.67 (m, 1H), 3.33 (m, 6H), 2.39 (m, 1H), 2.38 (m, 1H), 2.11 (m, 2H), 1.22 (m, 1H); LC/MS (EI) t _R2.50, m/z 342 (M ⁺+ 1);

187) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(4-methylpiperazine-1-yl) carbonyl]-1H-indazole-3-methane amide, LC/MS (EI) t _R2.40, m/z 397 (M ⁺+ 1);

188) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(3R)-and 3-methoxyl group tetramethyleneimine-1-yl] carbonyl-1H-indazole-3-methane amide, LC/MS (EI) t _R2.50, m/z 398 (M ⁺+ 1).

Method AC

Method AC provides the method that is prepared the ether derivant of 7-azepine benzisothiazole by the corresponding chlorinated thing.

(30.0mmol) adds to N-[(3S with sodium methylate)-1-azabicyclo [2.2.2] oct-3-yl]-the 6-chloroisothiazole is also in the solution of [5,4-b] pyridine-3-carboxamides (0.3mmol) in methyl alcohol (2mL), reaction mixture reflux 16 hours.Reaction mixture is cooled to room temperature, with methyl alcohol termination reaction and concentrated.Resistates merges the product part and is loaded into (10g) on the SCX post by preparation HPLC purifying.The 7.0M ammonia that this post with methyl alcohol (200mL), then is used in the methyl alcohol (60mL) washes.The vaporized ammonia layer obtains product, and yield is 30%.

Adopt the following compound of this method preparation:

189) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-methoxyl group isothiazole [5,4-b] pyridine-3-carboxamide also, LC/MS (EI) t _R3.25, m/z 319 (M ⁺+ 1).

In conjunction with the embodiments: [ ³ H] the MLA combination

Material:

Rat brain: Pel-Freez Biologicals, CAT No.56004-2

Proteinase inhibitor cocktail tablet (cocktail tablet): Roche, CAT No.1697498 membrane prepare

Will the rat brain in the ice-cold 0.32M sucrose of 20 volumes (w/v) and proteinase inhibitor (1/50ml) be set to 11 times with 10 seconds of polytron homogenizing, then under 4 ℃ and 1000g centrifugal 10 minutes.With supernatant liquor under 4 ℃ and 20000g centrifugal again 20 minutes.Bead is resuspended in binding buffer liquid, and (pH 7.5 for 200mM TRIS-HCl, 20mM HEPES, 144mM NaCl, 1.5mM KCl, 1mMMgSO ₄, 2mM CaCl ₂, 0.1% (w/v) BSA) in, and the membrane prepare thing is stored under-80 ℃.

For saturation analysis, 200 μ L in binding buffer liquid measure mixture and contain 200 μ g membranins, 0.2-44nM[ ³H] MLA.Use 1M MLA definition non-specific binding.Use 2nM[ ³H] MLA and need the compound of the scope mensuration that is at war with.To measure mixture in 22 ℃ of following incubations 2 hours, then use the Tomtec harvester, use the GF/B filter collection of the 0.3%PEI in binding buffer liquid pre-soaked.Filter is washed three times with binding buffer liquid, and write down radioactivity with Trilux.

The binding affinity of preferred compound of the present invention is 2nM to 25 μ M, particularly 2nM to 2.5 μ M.

Can be by coming the embodiment of repetition front and obtain similar success with used reactant and/or operational condition in general or specifically described reactant of the present invention and/or the operational condition replacement previous embodiment.

Though illustration specific compound and preparation, obviously can under the situation that does not deviate from design of the present invention or scope, change and revise the present invention.

Claims

1. the compound of formula I, II, III or IV:

With their pharmacologically acceptable salts or solvate or N-oxide compound, or the solvate of their pharmacologically acceptable salts, or the pharmacologically acceptable salts or the solvate of their N-oxide compound,

Wherein

A is

X is O or S;

X ¹To X ⁴Be N, CH, CR independently of one another ¹Or C-, wherein C-represents the tie point of the rest part of group A and formula (I), (II), (III) or structure (IV);

X ⁵To X ⁸Be N, CH, CR independently of one another ³Or C-, wherein C-represents the tie point of the rest part of group A and formula (I), (II), (III) or structure (IV);

X ⁹To X ¹²Be N, CH, CR independently of one another ⁴Or C-, wherein C-represents the tie point of the rest part of group A and formula (I), (II), (III) or structure (IV);

X ¹³To X ¹⁶Be N, CH, CR or C-independently of one another, wherein C-represents the tie point of the rest part of group A and formula (I), (II), (III) or structure (IV);

R is H, F, Cl, Br, I, OH, CN, COH, NR ⁶R ⁷, carboxyl, CONR ⁶R ⁷, NR ²COR ⁸, NR ²COOR ⁸, NR ²CSR ⁸, NR ²CONR ²R ⁹, NR ²CSNR ²R ⁹, NR ²SO ₂R ¹⁰, NR ²CONR ⁶R ⁷, NR ²CSNR ⁶R ⁷, NR ²R ⁹, SO ₂R ¹⁰, SOR ¹⁰,-O-(C _1-6-alkyl-O) _1-2-C _1-6-alkyl, NR ²-C _1-6-alkyl-NR ⁶R ⁷, NR ²-C _1-6-alkyl-CONR ⁶R ⁷, NR ²-CO-C _1-6-alkyl-Ar, NR ²-C _1-6-alkyl-CO-O-R ², NR ²-C _1-6-alkyl-NR ²(CO-O-R ²) ,-C _1-6-alkyl-NR ²,-O-C _1-6-alkyl-NR ⁶R ⁷, have 1-4 carbon atom alkyl, have 1-4 carbon atom fluorinated alkyl, have 2-6 carbon atom thiazolinyl, have the alkynyl of 2-6 carbon atom, wherein said alkyl, fluorinated alkyl, alkenyl or alkynyl are not substituted or are replaced, have by Ar or Het the cycloalkyl, unsubstituted or by HCO-, C of 3-7 carbon atom separately _1-6-alkoxyl group, NR ⁶R ⁷, CO-NR ⁶R ⁷, C _2-6-carbalkoxy ,-CO-R ¹⁰Or the cycloalkenyl group with 5-8 carbon atom of their combination replacement, cycloalkylalkyl with 4-7 carbon atom, cycloalkenyl alkyl with 6-9 carbon atom, alkoxyl group with 1-4 carbon atom, cycloalkyloxy with 3-7 carbon atom, cycloalkyl alkoxy with 4-7 carbon atom, alkylthio with 1-4 carbon atom, the alkoxyl group of fluoridizing with 1-4 carbon atom, hydroxyalkyl with 1-4 carbon atom, the hydroxyalkyl of fluoridizing with 1-4 carbon atom, hydroxy alkoxy base with 2-4 carbon atom, what have 2-4 carbon atom fluoridizes the hydroxy alkoxy base, alkylamino with 1-4 carbon atom, wherein each alkyl has the dialkyl amido of 1-4 carbon atom independently, carbalkoxy with 2-6 carbon atom, Ar, Het, OAr, OHet, Carbo-O, Ar-C _1-6-alkyl-O-, Het-C _1-6-alkyl-O-, Het-CO-Het-, Het-C _1-6-alkyl-NR ²-or Ar-C _1-6-alkyl-Het-O-,

Condition is that R is not NH ₂Perhaps

R is one of following formula

N is 2-4;

M is 3-5; Perhaps

R ¹Be H, F, Cl, Br, I, OH, CN, nitro, NH ₂, COH, NR ⁶R ⁷, carboxyl, CONR ⁶R ⁷, NR ²COR ⁸, NR ²COOR ⁸, NR ²CSR ⁸, NR ²CONR ²R ⁹, NR ²CSNR ²R ⁹, NR ²SO ₂R ¹⁰, NR ²CONR ⁶R ⁷, NR ²CSNR ⁶R ⁷, NR ²R ⁹, SO ₂R ¹⁰, SOR ¹⁰,-O-(C _1-6-alkyl-O) _1-2-C _1-6-alkyl, NR ²-C _1-6-alkyl-NR ⁶R ⁷, NR ²-C _1-6-alkyl-CONR ⁶R ⁷, NR ²-CO-C _1-6-alkyl-Ar, NR ²-C _1-6-alkyl-CO-O-R ², NR ²-C _1-6-alkyl-NR ²(CO-O-R ²) ,-C _1-6-alkyl-NR ²,-O-C _1-6-alkyl-NR ⁶R ⁷, have 1-4 carbon atom alkyl, have 1-4 carbon atom fluorinated alkyl, have 2-6 carbon atom thiazolinyl, have the alkynyl of 2-6 carbon atom, wherein said alkyl, fluorinated alkyl, alkenyl or alkynyl are not substituted or are replaced, have by Ar or Het the cycloalkyl, unsubstituted or by HCO-, C of 3-7 carbon atom separately _1-6-alkoxyl group, NR ⁶R ⁷, CO-NR ⁶R ⁷, C _2-6-carbalkoxy ,-CO-R ¹⁰Or the cycloalkenyl group with 5-8 carbon atom of their combination replacement, cycloalkylalkyl with 4-7 carbon atom, cycloalkenyl alkyl with 6-9 carbon atom, alkoxyl group with 1-4 carbon atom, cycloalkyloxy with 3-7 carbon atom, cycloalkyl alkoxy with 4-7 carbon atom, alkylthio with 1-4 carbon atom, the alkoxyl group of fluoridizing with 1-4 carbon atom, hydroxyalkyl with 1-4 carbon atom, the hydroxyalkyl of fluoridizing with 1-4 carbon atom, hydroxy alkoxy base with 2-4 carbon atom, what have 2-4 carbon atom fluoridizes the hydroxy alkoxy base, alkylamino with 1-4 carbon atom, wherein each alkyl has the dialkyl amido of 1-4 carbon atom independently, carbalkoxy with 2-6 carbon atom, Ar, Het, OAr, OHet, Carbo-O, Ar-C _1-6-alkyl-O-, Het-C _1-6-alkyl-O-, Het-CO-Het-, Het-C _1-6-alkyl-NR ²-or Ar-C _1-6-alkyl-Het-O-; Perhaps

R ¹It is one of following formula

Perhaps

R ²Be H, have 1-4 carbon atom alkyl, have 1-4 carbon atom fluorinated alkyl, have 3-7 carbon atom cycloalkyl, have 4-7 carbon atom cycloalkylalkyl, fluoridize C _1-4-alkyl-CO-, C _3-7-cycloalkyl-CO-, C _1-4-alkyl-NH-CO-, C _3-7-cycloalkyl-NH-CO-, Het, Ar-C _1-4-alkyl-, Ar-C _1-4-alkyl-CO-, Ar-C _1-4-alkyl-SO ₂-, C _1-4-alkyl-O-C _1-4-alkyl-(CH for example ₂CH ₂-O-CH ₃), Ar-C _1-4-alkyl-NH-CO-or Het-NH-CO-;

R ³Be H, F, Cl, Br, I, OH, CN, nitro, NH ₂, COH, NR ⁶R ⁷, carboxyl, CONR ⁶R ⁷, NR ²COR ⁸, NR ²COOR ⁸, NR ²CSR ⁸, NR ²CONR ²R ⁹, NR ²CSNR ²R ⁹, NR ²SO ₂R ¹⁰, NR ²CONR ⁶R ⁷, NR ²CSNR ⁶R ⁷, NR ²R ⁹, SO ₂R ¹⁰, SOR ¹⁰,-O-(C _1-6-alkyl-O) _1-2-C _1-6-alkyl, NR ²-C _1-6-alkyl-NR ⁶R ⁷, NR ²-C _1-6-alkyl-CONR ⁶R ⁷, NR ²-CO-C _1-6-alkyl-Ar, NR ²-C _1-6-alkyl-CO-O-R ², NR ²-C _1-6-alkyl-NR ²(CO-O-R ²) ,-C _1-6-alkyl-NR ²,-O-C _1-6-alkyl-NR ⁶R ⁷, have 1-4 carbon atom alkyl, have 1-4 carbon atom fluorinated alkyl, have 2-6 carbon atom thiazolinyl, have the alkynyl of 2-6 carbon atom, wherein said alkyl, fluorinated alkyl, alkenyl or alkynyl are not substituted or are replaced, have by Ar or Het the cycloalkyl, unsubstituted or by HCO-, C of 3-7 carbon atom separately _1-6-alkoxyl group, NR ⁶R ⁷, CO-NR ⁶R ⁷, C _2-6-carbalkoxy ,-CO-R ¹⁰Or the cycloalkenyl group with 5-8 carbon atom of their combination replacement, cycloalkylalkyl with 4-7 carbon atom, cycloalkenyl alkyl with 6-9 carbon atom, alkoxyl group with 1-4 carbon atom, cycloalkyloxy with 3-7 carbon atom, cycloalkyl alkoxy with 4-7 carbon atom, alkylthio with 1-4 carbon atom, the alkoxyl group of fluoridizing with 1-4 carbon atom, hydroxyalkyl with 1-4 carbon atom, the hydroxyalkyl of fluoridizing with 1-4 carbon atom, hydroxy alkoxy base with 2-4 carbon atom, what have 2-4 carbon atom fluoridizes the hydroxy alkoxy base, alkylamino with 1-4 carbon atom, wherein each alkyl has the dialkyl amido of 1-4 carbon atom independently, carbalkoxy with 2-6 carbon atom, Ar, Het, OAr, OHet, Carbo-O, Ar-C _1-6-alkyl-O-, Het-C _1-6-alkyl-O-, Het-CO-Het-, Het-C _1-6-alkyl-NR ²-or Ar-C _1-6-alkyl-Het-O-; Perhaps

R ³It is one of following formula

Perhaps

R ⁴Be H, F, Cl, Br, I, OH, CN, nitro, NH ₂, COH, NR ⁶R ⁷, carboxyl, CONR ⁶R ⁷, NR ²COR ⁸, NR ²COOR ⁸, NR ²CSR ⁸, NR ²CONR ²R ⁹, NR ²CSNR ²R ⁹, NR ²SO ₂R ¹⁰, NR ²CONR ⁶R ⁷, NR ²CSNR ⁶R ⁷, NR ²R ⁹, SO ₂R ¹⁰, SOR ¹⁰,-O-(C _1-6-alkyl-O) _1-2-C _1-6-alkyl, NR ²-C _1-6-alkyl-NR ⁶R ⁷, NR ²-C _1-6-alkyl-CONR ⁶R ⁷, NR ²-CO-C _1-6-alkyl-Ar, NR ²-C _1-6-alkyl-CO-O-R ², NR ²-C _1-6-alkyl-NR ²(CO-O-R ²) ,-C _1-6-alkyl-NR ²,-O-C _1-6-alkyl-NR ⁶R ⁷, have 1-4 carbon atom alkyl, have 1-4 carbon atom fluorinated alkyl, have 2-6 carbon atom thiazolinyl, have the alkynyl of 2-6 carbon atom, wherein said alkyl, fluorinated alkyl, alkenyl or alkynyl are not substituted or are replaced, have by Ar or Het the cycloalkyl, unsubstituted or by HCO-, C of 3-7 carbon atom separately _1-6-alkoxyl group, NR ⁶R ⁷, CO-NR ⁶R ⁷, C _2-6-carbalkoxy ,-CO-R ¹⁰Or the cycloalkenyl group with 5-8 carbon atom of their combination replacement, cycloalkylalkyl with 4-7 carbon atom, cycloalkenyl alkyl with 6-9 carbon atom, alkoxyl group with 1-4 carbon atom, cycloalkyloxy with 3-7 carbon atom, cycloalkyl alkoxy with 4-7 carbon atom, alkylthio with 1-4 carbon atom, the alkoxyl group of fluoridizing with 1-4 carbon atom, hydroxyalkyl with 1-4 carbon atom, the hydroxyalkyl of fluoridizing with 1-4 carbon atom, hydroxy alkoxy base with 2-4 carbon atom, what have 2-4 carbon atom fluoridizes the hydroxy alkoxy base, alkylamino with 1-4 carbon atom, wherein each alkyl has the dialkyl amido of 1-4 carbon atom independently, carbalkoxy with 2-6 carbon atom, Ar, Het, OAr, OHet, Carbo-O, Ar-C _1-6-alkyl-O-, Het-C _1-6-alkyl-O-, Het-CO-Het-, Het-C _1-6-alkyl-NR ²-or Ar-C _1-6-alkyl-Het-O-; Perhaps

R ⁴It is one of following formula

Perhaps

R ⁵Be H, F, Cl, Br, I, OH, CN, nitro, NH ₂, carboxyl, CONR ⁶R ⁷, NR ²COR ⁸, NR ²CSR ⁸, NR ²CONR ²R ⁹, NR ²CSNR ²R ⁹, NR ²SO ₂R ¹⁰, NR ²CONR ⁶R ⁷, NR ²CSNR ⁶R ⁷, NR ²R ⁹, SO ₂R ¹⁰, SOR ¹⁰Alkyl with 1-4 carbon atom, fluorinated alkyl with 1-4 carbon atom, thiazolinyl with 2-6 carbon atom, alkynyl with 2-6 carbon atom, wherein said alkyl, fluorinated alkyl, alkenyl or alkynyl is not substituted separately or is replaced by Ar or Het, cycloalkyl with 3-7 carbon atom, cycloalkenyl group with 5-8 carbon atom, cycloalkylalkyl with 4-7 carbon atom, cycloalkenyl alkyl with 6-9 carbon atom, alkoxyl group with 1-4 carbon atom, cycloalkyloxy with 3-7 carbon atom, cycloalkyl alkoxy with 4-7 carbon atom, alkylthio with 1-4 carbon atom, the alkoxyl group of fluoridizing with 1-4 carbon atom, hydroxyalkyl with 1-4 carbon atom, the hydroxyalkyl of fluoridizing with 1-4 carbon atom, hydroxy alkoxy base with 2-4 carbon atom, what have 2-4 carbon atom fluoridizes the hydroxy alkoxy base, alkylamino with 1-4 carbon atom, wherein each alkyl has the dialkyl amido of 1-4 carbon atom independently, carbalkoxy with 2-6 carbon atom, Ar, Het, OAr or OHet;

R ⁶And R ⁷Be H independently of one another, have 1-4 carbon atom alkyl, have 2-8 carbon atom alkoxyalkyl, have the cycloalkyl of 3-7 carbon atom or have the cycloalkylalkyl of 4-7 carbon atom, perhaps R ⁶And R ⁷Be to contain 4-6 carbon atom and form the alkylidene group that encircles together with described N atom;

R ⁸Be H, alkyl with 1-4 carbon atom, fluorinated alkyl with 1-4 carbon atom, thiazolinyl with 3-6 carbon atom, alkynyl with 3-6 carbon atom, wherein said alkyl, fluorinated alkyl, alkenyl or alkynyl is not substituted separately or is replaced by Ar or Het, cycloalkyl with 3-7 carbon atom, cycloalkenyl group with 5-8 carbon atom, cycloalkylalkyl with 4-7 carbon atom, cycloalkenyl alkyl with 6-9 carbon atom, hydroxyalkyl with 1-4 carbon atom, the hydroxyalkyl of fluoridizing with 1-4 carbon atom, alkylamino with 1-4 carbon atom, wherein each alkyl has the dialkyl amido of 1-4 carbon atom independently, Ar or Het;

R ¹⁰It is alkyl with 1-4 carbon atom, fluorinated alkyl with 1-4 carbon atom, thiazolinyl with 3-6 carbon atom, alkynyl with 3-6 carbon atom, wherein said alkyl, fluorinated alkyl, alkenyl or alkynyl is not substituted separately or is replaced by Ar or Het, cycloalkyl with 3-7 carbon atom, cycloalkenyl group with 5-8 carbon atom, cycloalkylalkyl with 4-7 carbon atom, cycloalkenyl alkyl with 6-9 carbon atom, hydroxyalkyl with 2-4 carbon atom, the hydroxyalkyl of fluoridizing with 2-4 carbon atom, alkylamino with 1-4 carbon atom, wherein each alkyl has the dialkyl amido of 1-4 carbon atom independently, NR ⁶R ⁷, NR ²R ⁸, Ar or Het;

Ar is the aryl with 6-10 carbon atom, and it is not substituted or is replaced one or many by following group: the alkyl with 1-8 carbon atom, alkoxyl group with 1-8 carbon atom, halogen, wherein moieties has the dialkyl amido of 1-8 carbon atom separately, amino, cyano group, hydroxyl, nitro, haloalkyl with 1-8 carbon atom, halogenated alkoxy with 1-8 carbon atom, hydroxyalkyl with 1-8 carbon atom, hydroxy alkoxy base with 2-8 carbon atom, alkene oxygen base with 3-8 carbon atom, alkylthio with 1-8 carbon atom, alkyl sulphinyl with 1-8 carbon atom, alkyl sulphonyl with 1-8 carbon atom, alkylamino with 1-8 carbon atom, wherein cycloalkyl has the alkyl that 3-7 carbon atom also randomly had 1-4 carbon atom, alkoxyl group with 1-4 carbon atom, hydroxyl, amino, alkylamino with 1-4 carbon atom, wherein each alkyl has the dialkyl amido of 1-4 carbon atom or the cycloalkyl amino that their combination replaces, wherein aryl moiety has 6-10 carbon atom also randomly by halogen, alkyl with 1-8 carbon atom, hydroxyl, alkoxyl group with 1-8 carbon atom, nitro, methylene-dioxy, ethylenedioxy, amino, alkylamino with 1-8 carbon atom, wherein each alkyl has the dialkyl amido of 1-8 carbon atom, hydroxyalkyl with 1-8 carbon atom, hydroxy alkoxy base with 1-8 carbon atom, carboxyl, cyano group, acyl group, wherein alkoxyl group has the carbalkoxy of 1-8 carbon atom, alkylthio, alkyl sulphinyl with 1-8 carbon atom, alkyl sulphonyl with 1-8 carbon atom, phenoxy group, the aryloxy that acyloxy or their combination replace, wherein aryl moiety has 6-10 carbon atom also randomly by halogen, alkyl with 1-8 carbon atom, hydroxyl, alkoxyl group with 1-8 carbon atom, nitro, methylene-dioxy, ethylenedioxy, amino, alkylamino with 1-8 carbon atom, wherein each alkyl has the dialkyl amido of 1-8 carbon atom, hydroxyalkyl with 1-8 carbon atom, hydroxy alkoxy base with 1-8 carbon atom, carboxyl, cyano group, acyl group, wherein alkoxyl group has the carbalkoxy of 1-8 carbon atom, alkylthio, alkyl sulphinyl with 1-8 carbon atom, alkyl sulphonyl with 1-8 carbon atom, phenoxy group, the arylthio that acyloxy or their combination replace, wherein cycloalkyl has the alkyl that 3-7 carbon atom also randomly had 1-4 carbon atom, alkoxyl group with 1-4 carbon atom, hydroxyl, amino, alkylamino with 1-4 carbon atom, wherein each alkyl has the dialkyl amido of 1-4 carbon atom or the cycloalkyloxy that their combination replaces, sulfo group, sulfonamido, amido, acyloxy or their combination;

Het is a heterocyclic radical; it is for saturated fully; fractional saturation or undersaturated fully; have 5-10 annular atoms; wherein at least one annular atoms is N; O or S atom, described heterocyclic radical are not substituted or are replaced one or many by following group: halogen; randomly by halogen; alkyl with 1-8 carbon atom; hydroxyl; alkoxyl group with 1-8 carbon atom; nitro; methylene-dioxy; ethylenedioxy; amino; alkylamino with 1-8 carbon atom; wherein each alkyl has the dialkyl amido of 1-8 carbon atom; hydroxyalkyl with 1-8 carbon atom; hydroxy alkoxy base with 1-8 carbon atom; carboxyl; cyano group; acyl group; wherein alkoxyl group has the carbalkoxy of 1-8 carbon atom; alkylthio; alkyl sulphinyl with 1-8 carbon atom; alkyl sulphonyl with 1-8 carbon atom; phenoxy group; the aryl that acyloxy or their combination replace with 6-10 carbon atom; alkyl with 1-8 carbon atom; alkoxyl group with 1-8 carbon atom; cycloalkyl with 3-7 carbon atom; cycloalkylalkyl with 4-7 carbon atom; halogenated alkoxy with 1-8 carbon atom; cycloalkyloxy with 3-7 carbon atom; cycloalkyl alkoxy with 4-7 carbon atom; alkoxyalkyl with 2-8 carbon atom; wherein each alkyl has alkyl (haloalkyl) amino of 1-8 carbon atom; wherein each alkyl has two (haloalkyl) amino of 1-8 carbon atom; (haloalkyl) amino with 1-8 carbon atom; cyano group; haloalkyl with 1-8 carbon atom; nitro; oxo; OH; alkoxycarbonyl alkyl with 3-8 carbon atom; amino; alkylamino with 1-8 carbon atom; wherein each alkyl has the dialkyl amido of 1-8 carbon atom; SO ₂R ¹¹,-CXR ¹¹, piperidyl ethyl or their combination;

Carbo is the undersaturated carbon ring group of part with 5-14 carbon atom, and it is not substituted or is replaced one or many by following group: halogen, the alkyl with 1-8 carbon atom, the alkoxyl group with 1-8 carbon atom, hydroxyl, nitro, cyano group, oxo or their combination; And

R ¹¹It is alkyl with 1-4 carbon atom, haloalkyl with 1-4 carbon atom, thiazolinyl with 3-6 carbon atom, alkynyl with 3-6 carbon atom, wherein said alkyl, haloalkyl, alkenyl or alkynyl is not substituted separately or is replaced by Ar or Het, cycloalkyl with 3-7 carbon atom, cycloalkenyl group with 5-8 carbon atom, cycloalkylalkyl with 4-7 carbon atom, cycloalkenyl alkyl with 6-9 carbon atom, hydroxyalkyl with 2-4 carbon atom, the hydroxyalkyl of fluoridizing with 2-4 carbon atom, alkylamino with 1-4 carbon atom, wherein each alkyl has the dialkyl amido of 1-4 carbon atom independently, or Ar;

Wherein said compound also can be the polymorphic form form,

If wherein described compound exhibits chirality, the form of mixtures that it can be the mixture or the diastereomer of enantiomer perhaps can be single enantiomer or single diastereomeric form, and

Wherein at least one R, R ¹, R ³, R ⁴And R ⁵Group is Het or OHet, wherein said Het group is selected from azabicyclo octyl group replacement or unsubstituted, oxa--azabicyclo heptyl, diazabicyclo heptyl, diazabicyclo nonyl, diazabicyclo octyl group, pyrazolyl, glyoxalidine base, 1,4-Diazesuberane base, hexahydropyrrolo and pyrazinyl and octahydro pyrrolopyridinyl in each case.

2. according to the compound of claim 1, wherein at least one R, R ¹, R ³, R ⁴And R ⁵Group is 1-azabicyclo [2.2.2] oct-3-yl oxygen base, 2-oxa--5-azabicyclo [2.2.1] heptyl), diazabicyclo heptyl (for example 2,5-diazabicyclo [2.2.1] heptan-2-base, 5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-base, trifluoroethyl-2,5-diazabicyclo [2.2.1] heptan-2-base, 5-(cyclopropyl carbonyl)-2,5-diazabicyclo [2.2.1] heptan-2-base, 1,4-diazabicyclo [3.3.2] ninth of the ten Heavenly Stems-4-yl), 5-methyl-2,5-diazabicyclo [2.2.2] suffering-2-base, 8-methyl-3,8-diazabicyclo [3.2.1] oct-3-yl), pyrazolyl, the glyoxalidine base, 1,4-Diazesuberane-1-base, the 4-methyl isophthalic acid, 4-Diazesuberane-1-base, hexahydropyrrolo also [1,2-a] pyrazine-2 (1H)-yl) or 1-(cyclopropyl carbonyl)-octahydro-6H-pyrrolo-[3,4-b] pyridine-6-yl).

3. according to the compound of claim 1, wherein

Het is a heterocyclic radical; it is for saturated fully; fractional saturation or undersaturated fully; have 5-10 annular atoms; wherein at least one annular atoms is N; O or S atom, described heterocyclic radical are not substituted or are replaced one or many by following group: halogen; randomly by halogen; alkyl with 1-8 carbon atom; hydroxyl; alkoxyl group with 1-8 carbon atom; nitro; methylene-dioxy; ethylenedioxy; amino; alkylamino with 1-8 carbon atom; wherein each alkyl has the dialkyl amido of 1-8 carbon atom; hydroxyalkyl with 1-8 carbon atom; hydroxy alkoxy base with 1-8 carbon atom; carboxyl; cyano group; acyl group; wherein alkoxyl group has the carbalkoxy of 1-8 carbon atom; alkylthio; alkyl sulphinyl with 1-8 carbon atom; alkyl sulphonyl with 1-8 carbon atom; phenoxy group; the aryl that acyloxy or their combination replace with 6-10 carbon atom; alkyl with 1-8 carbon atom; alkoxyl group with 1-8 carbon atom; cycloalkyl with 3-7 carbon atom; halogenated alkoxy with 1-8 carbon atom; cycloalkyloxy with 3-7 carbon atom; cycloalkyl alkoxy with 4-7 carbon atom; alkoxyalkyl with 2-8 carbon atom; wherein each alkyl has alkyl (haloalkyl) amino of 1-8 carbon atom; wherein each alkyl has two (haloalkyl) amino of 1-8 carbon atom; (haloalkyl) amino with 1-8 carbon atom; cyano group; haloalkyl with 1-8 carbon atom; nitro; oxo; OH; alkoxycarbonyl alkyl with 3-8 carbon atom; amino; alkylamino with 1-8 carbon atom; wherein each alkyl has the dialkyl amido of 1-8 carbon atom; SO ₂R ¹¹,-CXR ¹¹, piperidyl ethyl or their combination;

R ²Be H, have 1-4 carbon atom alkyl, have 1-4 carbon atom fluorinated alkyl, have 3-7 carbon atom cycloalkyl, have 4-7 carbon atom cycloalkylalkyl, fluoridize C _1-4-alkyl-CO-, C _3-7-cycloalkyl-CO-, C _1-4-alkyl-NH-CO-, C _3-7-cycloalkyl-NH-CO-, Het, Ar-C _1-4-alkyl-, Ar-C _1-4-alkyl-CO-, Ar-C _1-4-alkyl-SO ₂-, C _1-4-alkyl-O-C _1-4-alkyl-(CH for example ₂CH ₂-O-CH ₃) or Ar-C _1-4-alkyl-NH-CO-; And

At least one R, R ¹, R ³, R ⁴And R ⁵Group be replace or unsubstituted diazabicyclo heptyl or oxa-azabicyclo heptyl.

4. according to the compound of claim 3, wherein at least one R, R ¹, R ³, R ⁴And R ⁵Group is 2,5-diazabicyclo [2.2.1] heptan-2-base, methyl-2,5-diazabicyclo [2.2.1] heptan-2-base, trifluoroethyl-2,5-diazabicyclo [2.2.1] heptan-2-base or 2-oxa--5-azabicyclo [2.2.1] heptan-the 5-base.

5. according to the compound of formula I, II, III or IV:

Wherein

A is

X is O or S;

R ¹Be H, F, Cl, Br, I, OH, CN, nitro, NH ₂, COH, NR ⁶R ⁷, carboxyl, CONR ⁶R ⁷, NR ²COR ⁸, NR ²COOR ⁸, NR ²CSR ⁸, NR ²CONR ²R ⁹, NR ²CSNR ²R ⁹, NR ²SO ₂R ¹⁰, NR ²CONR ⁶R ⁷, NR ²CSNR ⁶R ⁷, NR ²R ⁹, SO ₂R ¹⁰, SOR ¹⁰,-O-(C _1-6-alkyl-O) _1-2-C _1-6-alkyl, NR ²-C _1-6-alkyl-NR ⁶R ⁷, NR ²-C _1-6-alkyl-CONR ⁶R ⁷, NR ²-CO-C _1-6-alkyl-Ar, NR ²-C _1-6-alkyl-CO-O-R ², NR ²-C _1-6-alkyl-NR ²(CO-O-R ²) ,-C _1-6-alkyl-NR ²,-O-C _1-6-alkyl-NR ⁶R ⁷, have 1-4 carbon atom alkyl, have 1-4 carbon atom fluorinated alkyl, have 2-6 carbon atom thiazolinyl, have the alkynyl of 2-6 carbon atom, wherein said alkyl, fluorinated alkyl, alkenyl or alkynyl be not substituted separately or by Ar or Het replace, have 3-7 carbon atom cycloalkyl, be not substituted or by HCO-, C _1-6-alkoxyl group, NR ⁶R ⁷, CO-NR ⁶R ⁷, C _2-6-carbalkoxy ,-CO-R ¹⁰Or the cycloalkenyl group with 5-8 carbon atom of their combination replacement, cycloalkylalkyl with 4-7 carbon atom, cycloalkenyl alkyl with 6-9 carbon atom, alkoxyl group with 1-4 carbon atom, cycloalkyloxy with 3-7 carbon atom, cycloalkyl alkoxy with 4-7 carbon atom, alkylthio with 1-4 carbon atom, the alkoxyl group of fluoridizing with 1-4 carbon atom, hydroxyalkyl with 1-4 carbon atom, the hydroxyalkyl of fluoridizing with 1-4 carbon atom, hydroxy alkoxy base with 2-4 carbon atom, what have 2-4 carbon atom fluoridizes the hydroxy alkoxy base, alkylamino with 1-4 carbon atom, wherein each alkyl has the dialkyl amido of 1-4 carbon atom independently, carbalkoxy with 2-6 carbon atom, Ar, Het, OAr, OHet, Carbo-O, Ar-C _1-6-alkyl-O-, Het-C _1-6-alkyl-O-, Het-CO-Het-, Het-C _1-6-alkyl-NR ²-or Ar-C _1-6-alkyl-Het-O-; Perhaps

R ¹It is one of following formula

Perhaps

R ⁴Be H, F, Cl, Br, I, OH, CN, nitro, NH ₂, COH, NR ⁶R ⁷, carboxyl, CONR ⁶R ⁷, NR ²COR ⁸, NR ²COOR ⁸, NR ²CSR ⁸, NR ²CONR ²R ⁹, NR ²CSNR ²R ⁹, NR ²SO ₂R ¹⁰, NR ²CONR ⁶R ⁷, NR ²CSNR ⁶R ⁷, NR ²R ⁹, SO ₂R ¹⁰, SOR ¹⁰,-O-(C _1-6-alkyl-O) _1-2-C _1-6-alkyl, NR ²-C _1-6-alkyl-NR ⁶R ⁷, NR ²-C _1-6-alkyl-CONR ⁶R ⁷, NR ²-CO-C _1-6-alkyl-Ar, NR ²-C _1-6-alkyl-CO-O-R ², NR ²-C _1-6-alkyl-NR ²(CO-O-R ²) ,-C _1-6-alkyl-NR ²,-O-C _1-6-alkyl-NR ⁶R ⁷, have 1-4 carbon atom alkyl, have 1-4 carbon atom fluorinated alkyl, have 2-6 carbon atom thiazolinyl, have the alkynyl of 2-6 carbon atom, wherein said alkyl, fluorinated alkyl, alkenyl or alkynyl be not substituted separately or by Ar or Het replace, have 3-7 carbon atom cycloalkyl, be not substituted or by HCO-, C _1-6-alkoxyl group, NR ⁶R ⁷, CO-NR ⁶R ⁷, C _2-6-carbalkoxy ,-CO-R ¹⁰Or the cycloalkenyl group with 5-8 carbon atom of their combination replacement, cycloalkylalkyl with 4-7 carbon atom, cycloalkenyl alkyl with 6-9 carbon atom, alkoxyl group with 1-4 carbon atom, cycloalkyloxy with 3-7 carbon atom, cycloalkyl alkoxy with 4-7 carbon atom, alkylthio with 1-4 carbon atom, the alkoxyl group of fluoridizing with 1-4 carbon atom, hydroxyalkyl with 1-4 carbon atom, the hydroxyalkyl of fluoridizing with 1-4 carbon atom, hydroxy alkoxy base with 2-4 carbon atom, what have 2-4 carbon atom fluoridizes the hydroxy alkoxy base, alkylamino with 1-4 carbon atom, wherein each alkyl has the dialkyl amido of 1-4 carbon atom independently, carbalkoxy with 2-6 carbon atom, Ar, Het, OAr, OHet, Carbo-O, Ar-C _1-6-alkyl-O-, Het-C _1-6-alkyl-O-, Het-CO-Het-, Het-C _1-6-alkyl-NR ²-or Ar-C _1-6-alkyl-Het-O-; Perhaps

R ⁴It is one of following formula

Perhaps

R ⁶And R ⁷Independently of one another for H, have 1-4 carbon atom alkyl, have 2-8 carbon atom alkoxyalkyl, have the cycloalkyl of 3-7 carbon atom or have the cycloalkylalkyl of 4-7 carbon atom, perhaps R ⁶And R ⁷Be to contain 4-6 carbon atom and form the alkylidene group that encircles together with described N atom;

Wherein said compound also can be the polymorphic form form,

Condition is:

A is group and at least one R of formula (a) ¹Substituting group is the Het of non-thiazolyl, and R ²Be alkyl, fluorinated alkyl, cycloalkyl, cycloalkylalkyl, fluoridize C with 4-7 carbon atom with 3-7 carbon atom with 1-4 carbon atom with 2-4 carbon atom _1-4-alkyl-CO-, C _3-7-cycloalkyl-CO-, C _1-4-alkyl-NH-CO-, C _3-7-cycloalkyl-NH-CO-, Het, Ar-C _1-4-alkyl-, Ar-C _1-4-alkyl-CO-, Ar-C _1-4-alkyl-SO ₂-, C _1-4-alkyl-O-C _1-4-alkyl-or Ar-C _1-4-alkyl-NH-CO-; Perhaps

A is group and at least one R of formula (c) ⁴Substituting group is imidazolyl, pyrryl, pyrazolyl, C _1-8Alkyl-pyrazolyl, oxa--azabicyclo heptyl, diazabicyclo heptyl, C _1-8Alkyl-diazabicyclo heptyl, halo C _1-8Alkyl-diazabicyclo heptyl, amino, the C of quilt _1-8Alkyl-NH-or (C _1-8Alkyl) ₂The piperidyl that N-replaces or by hydroxyl, halogenated alkoxy, cycloalkyl alkoxy, amino, an alkylamino (C _1-8Alkyl-NH-), dialkyl amido ((C _1-8Alkyl) ₂N-), the amino pyrrolidyl that replaces of alkoxyalkyl or alkyl (fluorinated alkyl).

6. according to the compound of claim 5, wherein

Het is a heterocyclic radical; it is for saturated fully; fractional saturation or undersaturated fully; have 5-10 annular atoms; wherein at least one annular atoms is N; O or S atom, described heterocyclic radical are not substituted or are replaced one or many by following group: halogen; randomly by halogen; alkyl with 1-8 carbon atom; hydroxyl; alkoxyl group with 1-8 carbon atom; nitro; methylene-dioxy; ethylenedioxy; amino; alkylamino with 1-8 carbon atom; wherein each alkyl has the dialkyl amido of 1-8 carbon atom; hydroxyalkyl with 1-8 carbon atom; hydroxy alkoxy base with 1-8 carbon atom; carboxyl; cyano group; acyl group; wherein alkoxyl group has the carbalkoxy of 1-8 carbon atom; alkylthio; alkyl sulphinyl with 1-8 carbon atom; alkyl sulphonyl with 1-8 carbon atom; phenoxy group; the aryl that acyloxy or their combination replace with 6-10 carbon atom; alkyl with 1-8 carbon atom; alkoxyl group with 1-8 carbon atom; cycloalkyl with 3-7 carbon atom; halogenated alkoxy with 1-8 carbon atom; cycloalkyloxy with 3-7 carbon atom; cycloalkyl alkoxy with 4-7 carbon atom; alkoxyalkyl with 2-8 carbon atom; wherein each alkyl has alkyl (haloalkyl) amino of 1-8 carbon atom; wherein each alkyl has two (haloalkyl) amino of 1-8 carbon atom; (haloalkyl) amino with 1-8 carbon atom; cyano group; haloalkyl with 1-8 carbon atom; nitro; oxo; OH; alkoxycarbonyl alkyl with 3-8 carbon atom; amino; alkylamino with 1-8 carbon atom; wherein each alkyl has the dialkyl amido of 1-8 carbon atom; SO ₂R ¹¹,-CXR ¹¹, piperidyl ethyl or their combination; And

R ²Be H, have 1-4 carbon atom alkyl, have 1-4 carbon atom fluorinated alkyl, have 3-7 carbon atom cycloalkyl, have 4-7 carbon atom cycloalkylalkyl, fluoridize C _1-4-alkyl-CO-, C _3-7-cycloalkyl-CO-, C _1-4-alkyl-NH-CO-, C _3-7-cycloalkyl-NH-CO-, Het, Ar-C _1-4-alkyl-, Ar-C _1-4-alkyl-CO-, Ar-C _1-4-alkyl-SO ₂-, C _1-4-alkyl-O-C _1-4-alkyl-(CH for example ₂CH ₂-O-CH ₃) or Ar-C _1-4-alkyl-NH-CO-.

7. according to the compound of claim 5 or 6, wherein said compound is the compound of formula I.

8. according to the compound of claim 5 or 6, wherein said compound is the compound of formula II.

9. according to the compound of claim 5 or 6, wherein said compound is the compound of formula III.

10. according to the compound of claim 5 or 6, wherein said compound is the compound of formula IV.

11. according to each compound among the claim 5-10, wherein A be minor (a) group and through 3,4 or 7 be connected with the rest part of described compound.

12. according to each compound among the claim 5-11, wherein A be minor (c) group and through 3,4 or 7 be connected with the rest part of described compound.

13. according to the compound of claim 11, wherein A is the group of minor (a) and is connected with the rest part of described compound through its 3.

14. according to the compound of claim 12, wherein A is the group of minor (c) and is connected with the rest part of described compound through its 3.

15. compound according to formula I, II, III or IV:

Wherein

A is

X is O or S;

Condition is that R is not NH ₂Perhaps

R is one of following formula

N is 2-4;

M is 3-5; Perhaps

R ¹It is one of following formula

Perhaps

R ³It is one of following formula

Perhaps

R ⁴Be H, F, Cl, Br, I, OH, CN, nitro, NH ₂, COH, NR ⁶R ⁷, carboxyl, CONR ⁶R ⁷, NR ²COR ⁸, NR ²COOR ⁸, NR ²CSR ⁸, NR ²CONR ²R ⁹, NR ²CSNR ²R ⁹, NR ²SO ₂R ¹⁰, NR ²CONR ⁶R ⁷, NR ²CSNR ⁶R ⁷, NR ²R ⁹, SO ₂R ¹⁰, SOR ¹⁰,-O-(C _1-6-alkyl-O) _1-2-C _1-6-alkyl, NR ²-C _1-6-alkyl-NR ⁶R ⁷, NR ²-C _1-6-alkyl-CONR ⁶R ⁷, NR ²-CO-C _1-6-alkyl-Ar, NR ²-C _1-6-alkyl-CO-O-R ², NR ²-C _1-6-alkyl-NR ²(CO-O-R ²) ,-C _1-6-alkyl-NR ²,-O-C _1-6-alkyl-NR ⁶R ⁷, have 1-4 carbon atom alkyl, have 1-4 carbon atom fluorinated alkyl, have 2-6 carbon atom thiazolinyl, have the alkynyl of 2-6 carbon atom, wherein said alkyl, fluorinated alkyl, alkenyl or alkynyl are not substituted or are replaced, have by Ar or Het the cycloalkyl, unsubstituted or by HCO-, C of 3-7 carbon atom separately _1-6-alkoxyl group, NR ⁶R ⁷, CO-NR ⁶R ⁷, C _2-6Carbalkoxy ,-CO-R ¹⁰Or the cycloalkenyl group with 5-8 carbon atom of their combination replacement, cycloalkylalkyl with 4-7 carbon atom, cycloalkenyl alkyl with 6-9 carbon atom, alkoxyl group with 1-4 carbon atom, cycloalkyloxy with 3-7 carbon atom, cycloalkyl alkoxy with 4-7 carbon atom, alkylthio with 1-4 carbon atom, the alkoxyl group of fluoridizing with 1-4 carbon atom, hydroxyalkyl with 1-4 carbon atom, the hydroxyalkyl of fluoridizing with 1-4 carbon atom, hydroxy alkoxy base with 2-4 carbon atom, what have 2-4 carbon atom fluoridizes the hydroxy alkoxy base, alkylamino with 1-4 carbon atom, wherein each alkyl has the dialkyl amido of 1-4 carbon atom independently, carbalkoxy with 2-6 carbon atom, Ar, Het, OAr, OHet, Carbo-O, Ar-C _1-6-alkyl-O-, Het-C _1-6-alkyl-O-, Het-CO-Het-, Het-C _1-6-alkyl-NR ²-or Ar-C _1-6-alkyl-Het-O-; Perhaps

R ⁴It is one of following formula

Perhaps

Wherein said compound also can be the polymorphic form form,

Wherein said compound has at least one Het group, it is for saturated fully, fractional saturation or undersaturated fully, have 5-10 annular atoms, wherein at least one annular atoms is N, O or S atom, and described Het group is substituted, wherein at least one is the halogenated alkoxy with 1-8 carbon atom in the substituting group, cycloalkyloxy with 3-7 carbon atom, cycloalkyl alkoxy with 4-7 carbon atom, cycloalkylalkyl with 4-7 carbon atom, haloalkyl with 2-8 carbon atom, alkoxyalkyl with 2-8 carbon atom, wherein each alkyl has alkyl (haloalkyl) amino of 1-8 carbon atom, wherein each alkyl has two (haloalkyl) amino of 1-8 carbon atom, perhaps for having (haloalkyl) amino of 1-8 carbon atom.

16. compound according to claim 15, wherein said compound has at least one Het group, it is for saturated fully, fractional saturation or undersaturated fully, have 5-10 annular atoms, wherein at least one annular atoms is N, O or S atom, and described Het group is substituted, wherein at least one is the halogenated alkoxy with 1-8 carbon atom in the substituting group, cycloalkyloxy with 3-7 carbon atom, cycloalkyl alkoxy with 4-7 carbon atom, haloalkyl with 2-8 carbon atom, alkoxyalkyl with 2-8 carbon atom, wherein each alkyl has alkyl (haloalkyl) amino of 1-8 carbon atom, wherein each alkyl has two (haloalkyl) amino of 1-8 carbon atom, perhaps for having (haloalkyl) amino of 1-8 carbon atom.

17. according to the compound of claim 15 or 16, wherein R ²For H, have 1-4 carbon atom alkyl, have 1-4 carbon atom fluorinated alkyl, have 3-7 carbon atom cycloalkyl, have 4-7 carbon atom cycloalkylalkyl, fluoridize C _1-4-alkyl-CO-, C _3-7-cycloalkyl-CO-, C _1-4-alkyl-NH-CO-, C _3-7-cycloalkyl-NH-CO-, Het, Ar-C _1-4-alkyl-, Ar-C _1-4-alkyl-CO-, Ar-C _1-4-alkyl-SO ₂-, C _1-4-alkyl-O-C _1-4-alkyl-or Ar-C _1-4-alkyl-NH-CO-.

18. compound according to formula I, II, III or IV:

Wherein

A is

X is O or S;

Condition is that R is not NH ₂Perhaps

R is one of following formula

N is 2-4;

M is 3-5; Perhaps

R ¹It is one of following formula

Perhaps

R ³It is one of following formula

Perhaps

R ⁴It is one of following formula

Perhaps

Wherein said compound also can be the polymorphic form form,

X wherein ¹, X ², X ³And X ⁴In at least one is N; X ⁵, X ⁶, X ⁷And X ⁸In at least one is N; X ⁹, X ¹⁰, X ¹¹And X ¹²In at least one is N; Perhaps X ¹³, X ¹⁴, X ¹⁵And X ¹⁶In at least one is N.

19. according to the compound of claim 18, wherein

20. according to the compound of claim 18 or 19, wherein

X ¹, X ², X ³And X ⁴In at least one is N, and remaining X ¹-X ⁴In one or two be CR ¹

X ⁵, X ⁶, X ⁷And X ⁸In at least one is N, and remaining X ⁵-X ⁸In one or two be CR ³

X ⁹, X ¹⁰, X ¹¹And X ¹²In at least one is N, and remaining X ⁹-X ¹²In one or two be CR ⁴Perhaps

X ¹³, X ¹⁴, X ¹⁵And X ¹⁶In at least one is N, and remaining X ¹³-X ¹⁶In one or two be CR.

21. according to each compound among the claim 1-20, wherein

A be minor (a) group and through 3,4 or 7 be connected with the rest part of described compound,

A is the group of minor (b) and is connected with the rest part of described compound through its 4 or 7,

A be minor (c) group and through 3,4 or 7 be connected with the rest part of described compound, or

A be minor (d) group and through 3,4 or 7 be connected with the rest part of described compound.

22. according to the compound of claim 21, wherein said compound is the compound of formula I.

23. according to the compound of claim 21, wherein said compound is the compound of formula II.

24. according to the compound of claim 21, wherein said compound is the compound of formula III.

25. according to the compound of claim 21, wherein said compound is the compound of formula IV.

26. according to each compound among the claim 1-25, wherein A be minor (a) group and through 3,4 or 7 be connected with the rest part of described compound.

27. according to each compound among the claim 1-25, wherein A be minor (c) group and through 3,4 or 7 be connected with the rest part of described compound.

28. according to the compound of claim 26, wherein A is the group of minor (a) and is connected with the rest part of described compound through its 3.

29. according to the compound of claim 27, wherein A is the group of minor (c) and is connected with the rest part of described compound through its 3.

30. according to the compound of claim 21, wherein A is minor (a), (c) or group (d) and is connected with the rest part of described compound through its 3.

31. compound according to formula I, II, III or IV:

With their pharmacologically acceptable salts or solvate or the N-oxide compound that comprises quaternary ammonium salt, or the solvate of their pharmacologically acceptable salts, or the pharmacologically acceptable salts or the solvate of their N-oxide compound,

Wherein

A is

X is O or S;

Condition is that R is not NH ₂Perhaps

R is one of following formula

N is 2-4;

M is 3-5; Perhaps

R ¹It is one of following formula

Perhaps

R ³It is one of following formula

Perhaps

R ⁴It is one of following formula

Perhaps

R ¹¹It is alkyl with 1-4 carbon atom, haloalkyl with 1-4 carbon atom, thiazolinyl with 3-6 carbon atom, alkynyl with 3-6 carbon atom, wherein said alkyl, haloalkyl, alkenyl or alkynyl is not substituted separately or is replaced by Ar or Het, cycloalkyl with 3-7 carbon atom, cycloalkenyl group with 5-8 carbon atom, cycloalkylalkyl with 4-7 carbon atom, cycloalkenyl alkyl with 6-9 carbon atom, hydroxyalkyl with 2-4 carbon atom, the hydroxyalkyl of fluoridizing with 2-4 carbon atom, alkylamino with 1-4 carbon atom, wherein each alkyl has the dialkyl amido of 1-4 carbon atom independently, or Ar

Wherein said compound also can be the polymorphic form form, and

If wherein described compound exhibits chirality, the form of mixtures that it can be the mixture or the diastereomer of enantiomer perhaps can be single enantiomer or single diastereomeric form;

Wherein Z is alkyl, the haloalkyl with 1-4 carbon atom with 1-4 carbon atom, has the cycloalkylalkyl of 4-7 carbon atom or have the arylalkyl of 7-16 carbon atom, and negatively charged ion A is iodide ion, bromide anion, chlorion, trifluoromethanesulfonic acid root, tosylate or methanesulfonate.

31. according to the compound of claim 30, wherein group A is formula (a) or group (c).

32. according to the compound of claim 31, wherein X ¹-X ⁴Each is CH or CR naturally ¹, perhaps X ⁹-X ¹²Each is CH or CR naturally ⁴

33. according to each compound among the claim 1-32, wherein X is O.

34. according to each compound among the claim 1-33, wherein R ' is H, cyclopropyl methyl or CH ₃

35. compound, it is selected from:

54) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-(2-oxo-3-propyl imidazole alkane-1-yl)-1,2-benzisothiazole-3-carboxamide hydrochloride,

55) N-[(3S)-1-oxidation-1-azabicyclo [2.2.2] oct-3-yl]-5-(trifluoromethoxy)-1H-indazole-3-methane amide,

109) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[(3S)-and 3-methoxyl group tetramethyleneimine-1-yl]-1,2-benzoisoxazole-3-methane amide,

129) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-[4-(dimethylamino) piperidines-1-yl]-1,2-benzisothiazole-3-methane amide,

131) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-(2-oxo-3-propyl imidazole alkane-1-yl)-1,2-benzisothiazole-3-methane amide,

189) N-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-6-methoxyl group isothiazole also [5,4-b] pyridine-3-carboxamide and

The wherein above listed free alkali form or the compound of pharmacologically acceptable salts form also can be solvate form thereof,

The wherein above listed free alkali form or the compound of pharmacologically acceptable salts form also can be the N-oxide forms,

Wherein the compound of the compound of above listed free alkali form or its solvate or N-oxide compound or pharmacologically acceptable salts form or its solvate also can be the polymorphic form form, and

If wherein described compound exhibits chirality, the form of mixtures that it can be the mixture or the diastereomer of enantiomer perhaps can be single enantiomer or single diastereomeric form.

36. according to the compound of claim 35, wherein said compound is selected from:

44) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-(difluoro-methoxy)-N-methyl isophthalic acid H-azoles-3-methane amide formate,

37. according to the compound of claim 35, wherein said compound is selected from:

38. according to the compound of claim 35, wherein said compound is selected from:

39. according to the compound of claim 35, wherein said compound is selected from:

131) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-(2-oxo-3-propyl imidazole alkane-1-yl)-1,2-benzisothiazole-3-methane amide and its pharmacologically acceptable salts,

40. according to the compound of claim 35, wherein said compound is selected from:

143) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-6-(hexahydropyrrolo is [1,2-a] pyrazine-2 (1H)-yl)-1 also, 2-benzisothiazole-3-methane amide,

190) N-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-5-(tetrahydrochysene-2H-pyrans-4-base oxygen base)-1H-indazole-3-methane amide

41. pharmaceutical composition, it comprises according to each compound and pharmaceutically acceptable carrier among the claim 1-40.

42. according to the pharmaceutical composition of claim 41, wherein said composition also comprises at least a other medicament that is selected from other α-7 agonist, PDE4 inhibitor, calcium channel blocker, muscarinic m1 conditioning agent, muscarinic m2 conditioning agent, Adenosine Receptors conditioning agent, ampakine, NMDA-R conditioning agent, mGluR conditioning agent, dopamine modulating agent, serotonin conditioning agent, cannabinoid modulators and anticholinesterase.

43. the method for the alpha-7 nicotinic acceptor among selectively activate/stimulation patient, wherein such activation/stimulation has therapeutic action, described method comprise to patient's effective dosage that these needs are arranged according to claim 1-40 in each compound.

44. treatment suffers from patient's the method for the illness of psychosis, the neurodegenerative disease relevant with the cholinergic system dysfunction and/or memory and/or cognitive disorder, it comprise to described patient's effective dosage according to claim 1-40 in each compound.

45. according to the method for claim 44, wherein said patient suffers from schizophrenia, anxiety disorder, mania, dysthymia disorders, manic depression, tourette's syndrome, Parkinson's disease, Huntington Chorea, alzheimer's disease, Lu Yi body dementia, amyotrophic lateral sclerosis, dysmnesia, the loss of memory, cognitive defect, attention deficit and/or attention deficit disorder (ADD).

46. treatment suffers from patient's the method that dementia and/or other have the illness of the loss of memory, it comprise to described patient's effective dosage according to claim 1-40 in each compound.

47. treatment suffers from the amnemonic patient's who is caused by following illness method: by mild cognitive impairment, alzheimer's disease, schizophrenia, Parkinson's disease, Huntington Chorea, Pick's disease, creutzfeldt-jakob disease, dysthymia disorders, ageing, head trauma, apoplexy, central nervous system anoxic, brain aging, multiple cerebral dementia, HIV and/or the cardiovascular disorder that ageing causes, it comprise to described patient's effective dosage according to claim 1-40 in each compound.

48. treat and/or prevent the method for the dementia in the patients with Alzheimer disease, it comprise to described patient's drug treatment significant quantity according to claim 1-40 in each compound suppress combining of amyloid beta and nACh acceptor.

49. the treatment patient is with abstinence from alcohol or with anti-poisoning therapy for treating patient's method, it comprise to described patient's effective dosage according to claim 1-40 in each compound.

50. the treatment patient to be providing the method at the neuroprotective of the excitotoxicity of damage relevant with apoplexy and ischemic and glutamate induction, it comprise to described patient's effective dosage according to claim 1-40 in each compound.

51. treatment suffers from patient's the method for nicotine addiction, pain, jet lag, obesity and/or diabetes, it comprise to described patient's effective dosage according to claim 1-40 in each compound.

52. the method for inducing the patient to give up smoking, it comprise to described patient's effective dosage according to claim 1-40 in each compound.

53. treatment suffers from mild cognitive impairment (MCI), vascular dementia (VaD), the cognition decline (AACD) that age is relevant, the amnesia relevant with open heart operation, asystole, general anesthesia, the memory impairment that the contact anesthesia efficacy-enhancing ingredient rises, the cognitive disorder that sleep deprivation causes, chronic fatigue syndrome, narcolepsy, AIDS is relevant dull-witted, the epilepsy cognitive disorder of being correlated with, mongolism, alcoholism is relevant dull-witted, the dysmnesia that medicine/material causes, the patient's of dementia pugilistica (boxer's syndrome) or animal dementia method, it comprise to described patient's effective dosage according to claim 1-40 in each compound.

54. the method for the treatment loss of memory, it comprise to patient's effective dosage that these needs are arranged according to claim 1-40 in each compound.

55. treatment suffers from amnemonic patient's method, it comprise to described patient's administration according to claim 1-40 in each compound.

56. according to the method for claim 55, wherein said dysmnesia are descended by nicotinic acetylcholine receptor activity and cause.

57. the disease that causes by nicotinic acetylcholine receptor propagation function obstacle among treatment or the prevention patient or the method for illness, it comprise to described patient's effective dosage according to claim 1-40 in each compound.

58. the disease that causes by nicotinic acetylcholine receptor defective or dysfunction among treatment or the prevention patient or the method for illness, it comprise to described patient's effective dosage according to claim 1-40 in each compound.

59. suppress the disease cause or the method for illness by the nicotinic acetylcholine receptor transmission among treatment or the prevention patient, it comprise to described patient's effective dosage according to claim 1-40 in each compound.

60. the disease that causes by cholinergic synapse forfeiture among treatment or the prevention patient or the method for illness, it comprise to described patient's effective dosage according to claim 1-40 in each compound.

61. be used for protecting patient's neurone to avoid the neurovirulent method that causes by α 7nACh receptor activation, it comprise to described patient's effective dosage according to claim 1-40 in each compound.

62. by suppressing the method for the treatment of or preventing neurodegenerative disorders that combines of A β peptide and α 7nACh acceptor among the patient, it comprise to described patient's effective dosage according to claim 1-40 in each compound.

63. treatment suffers from patient's the method for inflammatory diseases, it comprise to described patient's effective dosage according to claim 1-40 in each compound.

64. according to the method for claim 63, wherein said inflammatory diseases is rheumatoid arthritis, diabetes or sepsis.

65. according to each method among the claim 40-64, wherein said patient is human.