CN1918129A - Therapeutic agent - Google Patents
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- CN1918129A CN1918129A CNA2005800049765A CN200580004976A CN1918129A CN 1918129 A CN1918129 A CN 1918129A CN A2005800049765 A CNA2005800049765 A CN A2005800049765A CN 200580004976 A CN200580004976 A CN 200580004976A CN 1918129 A CN1918129 A CN 1918129A
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Abstract
The present invention relates to compounds of formula (I) and processes for preparing such compounds, their use in the treatment of obesity, psychiatric and neurological disorders, to methods for their therapeutic use and to pharmaceutical compositions containing them.
Description
Invention field
The present invention relates to the compound of some formula I, prepare the method for this compounds, its application in treatment obesity, psychosis and neuropathic obstacle, its treatment application method and the pharmaceutical composition that contains them.
Background of invention
Known some CB
1Conditioning agent (being called antagonist or inverse agonist) can effectively be treated obesity, psychosis and neuropathic obstacle (WO01/70700 EP 658,546 and EP 656,354).Yet, need have the CB that improves physicochemical property and/or DMPK character and/or pharmacodynamic properties
1Conditioning agent.
Pyrazoles with anti-inflammatory activity is disclosed among WO 95/15316, WO 96/38418, WO97/11704, WO99/64415, EP418845 and the WO 2004050632.WO2004050632 discloses [2-[4-[3-[(ethylmethylamino) carbonyl]-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group] ethyl] carboxylamine 1,1-dimethyl ethyl ester, 5-[4-(2-amino ethoxy) phenyl]-N-ethyl-1-(4-p-methoxy-phenyl)-N-methyl isophthalic acid H-pyrazole-3-carboxamide, 1-[[5-[4-(2-amino ethoxy) phenyl]-1-(4-p-methoxy-phenyl)-1H-pyrazole-3-yl] carbonyl] piperidines and [2-[4-[1-(4-p-methoxy-phenyl)-3-(piperidino carbonyl)-1H-pyrazoles-5-yl] phenoxy group] ethyl]-carboxylamine 1,1-dimethyl ethyl ester.All compounds of giving an example among the WO 2004050632 and its salt are not included in the scope that the present invention protects compound.
1,5-diaryl pyrazole-3-carboxamide derivative is at US 5,624,941, WO 01/29007, WO 2004/052864, WO 03/020217, US 2004/0119972, Journal ofMedicinal Chemistry, 46 (4), 642-6452003, Bioorganic ﹠amp; MedicinalChemistry Letters, 14 (10), 2393-23962004, Biochemical Pharmacology, 60 (9), 1315-13232000, Journal of Medicinal Chemistry, 42 (4), be disclosed among 769-7761999 and the US patent application publication US 2003199536 and have CB
1Regulate active.
Summary of the invention
The present invention relates to the compound of formula (I)
And pharmaceutically acceptable salt, wherein
R
1The C that expression a) is replaced by one or more following groups
1-3Alkoxyl group i) ii) group NR of fluorine
cR
d, R wherein
cAnd R
dRepresent H independently, C
1-6Alkyl or C
1-6Alkoxy carbonyl, condition are R
cAnd R
dOne of be not H or iii) 1,3-dioxolane-2-base; B) R
1The C that expression is randomly replaced by one or more following groups
4-6Alkoxyl group i) ii) group NR of fluorine
cR
d, R wherein
cAnd R
dRepresent H independently, C
1-6Alkyl or C
2-6Alkoxy carbonyl, condition are R
cAnd R
dOne of be not H or iii) 1,3-dioxolane-2-base; C) formula phenyl (CH
2)
pThe group of O-, wherein p be 1,2 or 3 and the group randomly represented by 1,2 or 3 Z of phenyl ring replace; D) R
5S (O)
2O or R
5S (O)
2NH, wherein R
5The C that expression is randomly replaced by one or more fluorine
1-6Alkyl, or R
5Optional phenyl or the heteroaryl that replaces of group that expression is represented by 1,2 or 3 Z respectively; E) formula (R
6)
3The group of Si, wherein R
6Expression C
1-6Alkyl, its identical or different or f) formula R
bThe group of O (CO) O, wherein R
bThe C that expression is randomly replaced by one or more fluorine
1-6Alkyl;
R
aThe expression halogen, C
1-3Alkyl or C
1-3Alkoxyl group;
M is 0,1,2 or 3;
R
2Expression C
1-3Alkyl, C
1-3Alkoxyl group, hydroxyl, nitro, cyano group or halogen;
N is 0,1,2 or 3;
R
3Expression is radicals X-Y-NR a)
7R
8, wherein X is CO or SO
2, Y does not exist or represents randomly by C
1-3The NH that alkyl replaces; And R
7And R
8Expression independently: chosen wantonly the C that replaces by the group that 1,2 or 3 W represents
1-6Alkyl;
Randomly the group of being represented by 1,2 or 3 W is chosen the (C that replaces wantonly
3-15Cycloalkyl) C
1-3Alkylidene group;
-(CH
2)
r(phenyl)
s, wherein r is 0,1,2,3 or 4, and s is 1 otherwise s is 1 or 2 when r is 0
And the independent group of randomly being represented by 1,2 or 3 Z of phenyl replaces;
Contain a nitrogen and randomly contain one of following saturated 5-8 element heterocycle group: oxygen, sulphur or additional nitrogen, wherein this heterocyclic group is randomly by one or more C
1-3Alkyl, hydroxyl or benzyl replace;
-(CH
2)
tHet, wherein t is 0,1,2,3 or 4 and this alkylidene chain randomly by one or more C
1-3Alkyl replaces and Het represents randomly to be selected from C by 1,2 or 3
1-5Alkyl, C
1-5The aromatic heterocycle that alkoxy or halogen replaces, wherein this alkyl and alkoxyl group are independent is randomly replaced by one or more fluorine;
Or R
7Expression H and R
8Definition as above;
Or R
7And R
8Represent saturated or the unsaturated 5-8 element heterocycle of part group with the nitrogen-atoms that it connected, this heterocyclic group contains a nitrogen and randomly contains one of following: oxygen, sulphur or additional nitrogen; Wherein this heterocyclic group is randomly by one or more C
1-3Alkyl, hydroxyl, fluorine or benzyl replace; Or b) azoles base, different azoles base, thiazolyl, isothiazolyl, the di azoly, thiadiazolyl group, pyrryl, pyrazolyl, imidazolyl, triazolyl, tetrazyl, thienyl, furyl or azoles quinoline base are randomly replaced by 1,2 or 3 group Z separately;
R
4Expression H, halogen, hydroxyl, cyano group, C
1-6Alkyl, C
1-6Alkoxyl group or C
1-6Alkoxy C
1-6Alkylidene group wherein contains maximum 6 carbon atoms, and each group is randomly replaced by one or more fluorine or cyano group;
Z represents C
1-3Alkyl, C
1-3Alkoxyl group, hydroxyl, halogen, trifluoromethyl, trifluoromethylthio, difluoro-methoxy, trifluoromethoxy, trifluoromethyl sulfonyl, nitro, amino, one or two C
1-3Alkylamino, C
1-3Alkyl sulphonyl, C
1-3Alkoxy carbonyl, carboxyl, cyano group, formamyl, one or two C
1-3Alkyl-carbamoyl and ethanoyl; With
W represents hydroxyl, fluorine, C
1-3Alkyl, C
1-3Alkoxyl group, amino, one or two C
1-3Alkylamino, C
1-6Alkoxy carbonyl or heterocyclic amine are selected from morpholinyl, pyrrolidyl, and piperidyl or piperazinyl, wherein heterocyclic amine is randomly by C
1-3Alkyl or hydroxyl replace; But do not comprise [the 2-[4-[3-[(ethylmethylamino) carbonyl]-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group] ethyl] carboxylamine 1,1-dimethyl ethyl ester and [2-[4-[1-(4-p-methoxy-phenyl)-3-(piperidino carbonyl)-1H-pyrazoles-5-yl] phenoxy group] ethyl] carboxylamine 1,1-dimethyl ethyl ester.
The present invention relates to the compound of formula (I) in one embodiment
And pharmaceutically acceptable salt, wherein
R
1The C that expression a) is replaced by one or more fluorine
1-3Alkoxyl group or by the optional C that replaces of one or more fluorine
4-6Alkoxyl group, b) formula phenyl (CH
2)
pThe group of O-, wherein p be 1,2 or 3 and the group randomly represented by 1,2 or 3 Z of this phenyl ring replace c) R
5S (O)
2O or R
5S (O)
2NH, wherein R
5Expression is by the optional C that replaces of one or more fluorine
1-6Alkyl, or R
5Expression phenyl or heteroaryl, its group of randomly being represented by 1,2 or 3 Z separately replaces; D) (R
6)
3The group of Si, wherein R
6Expression C
1-6Alkyl, it can identical or different or e) formula R
bThe group of O (CO) O, wherein R
bExpression is by the optional C that replaces of one or more fluorine
1-6Alkyl;
R
aThe expression halogen, C
1-3Alkyl or C
1-3Alkoxyl group;
M is 0,1,2 or 3;
R
2Expression C
1-3Alkyl, C
1-3Alkoxyl group, hydroxyl, nitro, cyano group or halogen;
N is 0,1,2 or 3;
R
3Expression
A) radicals X-Y-NR
7R
8
Wherein X is CO or SO
2, Y does not exist or represents by C
1-3The optional NH that replaces of alkyl;
And R
7And R
8Expression independently:
The C that replaces of the group of being represented by 1,2 or 3 W randomly
1-6Alkyl;
The C that replaces of the group of being represented by 1,2 or 3 W randomly
3-15Cycloalkyl;
(the C of the optional replacement that replaces of the group of being represented by 1,2 or 3 W randomly
3-15Cycloalkyl) C
1-3Alkylidene group;
-(CH
2)
r(phenyl)
s, wherein r is 0,1,2,3 or 4, when r is 0 s be 1 otherwise s be 1 or 2 and the group randomly represented by 1,2 or 3 Z of this phenyl replace;
Contain a nitrogen and randomly contain one of following saturated 5-8 element heterocycle group: oxygen, sulphur or additional nitrogen, wherein this heterocyclic group is randomly by one or more C
1-3Alkyl, hydroxyl or benzyl replace; Group-(CH
2)
tHet, wherein t is 0,1,2,3 or 4 and this alkylidene chain randomly by one or more C
1-3Alkyl replaces and Het represents randomly to be selected from C by 1,2 or 3
1-5Alkyl, C
1-5The aromatic heterocycle that alkoxy or halogen replaces;
Or R
7Expression H and R
8Definition as above;
Or R
7And R
8Represent saturated or part does not contain a nitrogen and randomly contains one of following saturated 5-8 element heterocycle group: oxygen, sulphur or additional nitrogen with the nitrogen-atoms that it connected; Wherein this heterocyclic group is randomly by one or more C
1-3Alkyl replaces, hydroxyl, fluorine or benzyl; Or b) azoles base, different azoles base, thiazolyl, isothiazolyl, the di azoly, thiadiazolyl group, pyrryl, pyrazolyl, imidazolyl, triazolyl, tetrazyl, thienyl, furyl or azoles quinoline base are randomly replaced by 1,2 or 3 group Z separately;
R
4Expression H, halogen, hydroxyl, cyano group, C
1-6Alkyl, C
1-6Alkoxyl group or C
1-6Alkoxy C
1-6Alkylidene group, it contains 6 carbon atoms at most, and it is randomly replaced by one or more fluorine or cyano group separately;
Z represents C
1-3Alkyl, C
1-3Alkoxyl group, hydroxyl, halogen, trifluoromethyl, trifluoromethylthio, difluoro-methoxy, trifluoromethoxy, trifluoromethyl sulfonyl, nitro, amino, one or two C
1-3Alkylamino, C
1-3Alkyl sulphonyl, C
1-3Alkoxy carbonyl, carboxyl, cyano group, formamyl, one or two C
1-3Alkyl-carbamoyl and ethanoyl; With
W represents hydroxyl, fluorine, C
1-3Alkyl, C
1-3Alkoxyl group, amino, one or two C
1-3Alkylamino, C
1-6Alkoxy carbonyl or heterocyclic amine are selected from morpholinyl, pyrrolidyl, and piperidyl or piperazinyl, wherein this heterocyclic amine is randomly by C
1-3Alkyl or cyano group replace.
The present invention relates to the compound of formula (I) in another embodiment
And pharmaceutically acceptable salt, wherein
R
1The C that expression a) is replaced by one or more fluorine
1-3Alkoxyl group or by the optional C that replaces of one or more fluorine
4-6Alkoxyl group, b) formula phenyl (CH
2)
pThe group of O-, wherein p be 1,2 or 3 and the group randomly represented by 1,2 or 3 Z of this phenyl ring replace c) radicals R
5S (O)
2O or R
5S (O)
2NH, wherein R
5Expression is by the optional C that replaces of one or more fluorine
1-6Alkyl, or R
5Expression phenyl or heteroaryl, its group of randomly being represented separately by 1,2 or 3 Z replace or, d) (R
6)
3The group of Si, wherein R
6Expression C
1-6Alkyl, it can be identical or different;
R
aThe expression halogen, C
1-3Alkyl or C
1-3Alkoxyl group
M is 0,1,2 or 3;
R
2Expression C
1-3Alkyl, C
1-3Alkoxyl group, hydroxyl, nitro, cyano group or halogen
N is 0,1,2 or 3;
R
3Expression is radicals X-Y-NR a)
7R
8,
Wherein X is CO or SO
2,
Y does not exist or represents randomly by C
1-3The NH that alkyl replaces;
And R
7And R
8Expression independently:
The C that replaces of the group of being represented by 1,2 or 3 W randomly
1-6Alkyl;
The C that replaces of the group of being represented by 1,2 or 3 W randomly
3-15Cycloalkyl;
(the C of the optional replacement that replaces of the group of being represented by 1,2 or 3 W randomly
3-15Cycloalkyl) C
1-3Alkylidene group;
Group-(CH
2)
r(phenyl)
s, wherein r is 0,1,2,3 or 4, when r is 0 s be 1 otherwise s be 1 or 2 and the group randomly represented by 1,2 or 3 Z of this phenyl replace;
Contain a nitrogen and randomly contain one of following saturated 5-8 element heterocycle group: oxygen, sulphur or additional nitrogen, wherein this heterocyclic group is randomly by one or more C
1-3Alkyl, hydroxyl or benzyl replace; Group-(CH
2)
tHet, wherein t is 0,1,2,3 or 4 and this alkylidene chain randomly by one or more C
1-3Alkyl replaces and Het represents randomly to be selected from C by 1,2 or 3
1-5Alkyl, C
1-5The aromatic heterocycle that alkoxy or halogen replaces;
Or R
7Expression H and R
8Definition as above;
Or R
7And R
8Represent saturated or part does not contain a nitrogen and randomly contains one of following saturated 5-8 element heterocycle group: oxygen, sulphur or additional nitrogen with the nitrogen-atoms that it connected; Wherein this heterocyclic group is randomly by one or more C
1-3Alkyl replaces, hydroxyl, fluorine or benzyl;
Or b) azoles base, different azoles base, thiazolyl, isothiazolyl, the di azoly, thiadiazolyl group, pyrryl, pyrazolyl, imidazolyl, triazolyl, tetrazyl, thienyl, furyl or azoles quinoline base are randomly replaced by 1,2 or 3 group Z separately;
R
4Expression H, C
1-6Alkyl, C
1-6Alkoxyl group or C alkoxy C
1-6Alkylidene group, it contains 6 carbon atoms at most, and it is randomly replaced by one or more fluorine or cyano group separately;
Z represents C
1-3Alkyl, C
1-3Alkoxyl group, hydroxyl, halogen, trifluoromethyl, trifluoromethylthio, difluoro-methoxy, trifluoromethoxy, trifluoromethyl sulfonyl, nitro, amino, one or two C
1-3Alkylamino, C
1-3Alkyl sulphonyl, C alkoxy carbonyl, carboxyl, cyano group, formamyl, one or two C
1-3Alkyl-carbamoyl and ethanoyl; Represent hydroxyl with W, fluorine, C
1-3Alkyl, C
1-3Alkoxyl group, amino, one or two C
1-3Alkylamino, or heterocyclic amine is selected from morpholinyl, pyrrolidyl, piperidyl or piperazinyl, wherein this heterocyclic amine is randomly by C
1-3Alkyl or hydroxyl replace.
In the particular group of formula I compound described in above-mentioned three embodiments, R
3Expression as above-mentioned paragraph be described group a).The wherein R of another particular group in above-mentioned these embodiments
3Expression as above-mentioned paragraph a) in the described compound, do not comprise wherein R
3Expression N, N-two C
1-6Alkyl-carbamoyl or R
3Expression radicals X-Y-NR
7R
8Compound, wherein X is CO, Y does not exist and R
7And R
8Represent saturated or part does not contain a nitrogen and randomly contains one of following saturated 5-8 element heterocycle group: oxygen, sulphur or additional nitrogen with the nitrogen-atoms that it connected; Wherein this heterocyclic group is randomly by one or more C
1-3Alkyl, hydroxyl, fluorine or benzyl replace.In first three above-mentioned embodiments in the compound of the formula I of another particular group, R
3Expression piperidines-1-base formamyl.
Should understand when substituting group Z is present on the more than one group, these substituting groups are selected independently and can be identical or different.W is also like this.R then when m is 2 or 3 similarly
aSelect independently so that they can be identical or different, and radicals R then when n is 2 or 3 similarly
2Select so that they can be identical or different independently.
Term C
3-15Cycloalkyl comprises monocycle, dicyclo, three ring and spiro system, for example cyclopentyl, cyclohexyl and adamantyls.
The term heteroaryl is meant fragrant 5-, 6-or 7-person's monocycle ring or 9-or 10-person's dicyclo ring, has at the most 5 and is selected from oxygen, the ring hetero atom of nitrogen and sulphur.Suitable fragrant heteroaryl comprises, furyl for example, pyrryl, thienyl, azoles base, different azoles base, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, di azoly, thiadiazolyl group, triazolyl, tetrazyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, 1,3,5-triazenyl, benzofuryl, indyl, benzothienyl, the benzoxazol base, benzimidazolyl-, benzothiazolyl, indazolyl, benzo furazan base, quinolyl, isoquinolyl, quinazolyl, quinoxalinyl, cinnolines base or naphthyridinyl.Preferred furyl, pyrryl, thienyl, azoles base, different azoles base, imidazolyl, pyrazolyl, azoles base thiazolyl, isothiazolyl, di azoly, thiadiazolyl group, triazolyl, tetrazyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl or 1,3,5-triazenyl and more preferably pyrryl, thienyl, imidazolyl, azoles base or pyridyl.
Suitable contain one or more nitrogen that are selected from, the heteroatomic saturated or unsaturated 5-8 element heterocycle of the part group of oxygen or sulphur comprises, for example tetrahydrofuran base, THP trtrahydropyranyl, 2,3-dihydro-1, the 3-thiazolyl, the 1,3-thiazoles alkyl, pyrrolinyl, pyrrolidyl, morpholinyl, tetrahydrochysene-1,4-thiazinyl, 1-oxo tetrahydro-thienyl, 1,1-dioxo tetrahydrochysene-1,4-thiazinyl, piperidyl, homopiperidinyl, piperazinyl, high piperazinyl, dihydropyridine base, tetrahydro pyridyl, dihydro-pyrimidin base or tetrahydro-pyrimidine base, preferred tetrahydrofuran base, THP trtrahydropyranyl, pyrrolidyl, morpholinyl, piperidyl or piperazinyl, more preferably tetrahydrofuran (THF)-3-base, tetrahydropyran-4-base, tetramethyleneimine-3-base, morpholino, piperidino-(1-position only), piperidin-4-yl or piperazine-1-base.
Suitable wherein R
1The expression radicals R
5S (O)
2O, R wherein
5Expression is by the optional C that replaces of one or more fluorine
1-6The group of alkyl comprises mesyloxy, ethylsulfonyl oxygen base, n-propyl alkylsulfonyl oxygen base; normal-butyl alkylsulfonyl oxygen base, 3-methyl fourth-1-alkylsulfonyl oxygen base, 3; 3-dimethyl butyrate-1-alkylsulfonyl oxygen base, methyl fluoride alkylsulfonyl oxygen base, difluoromethyl alkylsulfonyl oxygen base; trifluoromethyl sulfonyl oxygen base, one, two or three (fluoro ethyl) alkylsulfonyl oxygen base, 3; 3,3-trifluoro propyl-1-alkylsulfonyl oxygen base, or 4; 4,4-trifluoro butyl-1-alkylsulfonyl oxygen base
Suitable wherein R
1The C that expression is replaced by one or more fluorine
1-3Alkoxyl group or the C that is randomly replaced by one or more fluorine
4-6The group of alkoxyl group comprises butoxy, pentyloxy, hexyloxy, fluorine methoxyl group, difluoro-methoxy, trifluoromethoxy, 4,4,4-trifluoro butoxy, 5,5,5-trifluoro pentyloxy and 6,6,6-trifluoro hexyloxy.
Suitable wherein R
1Expression R
5S (O)
2O, R wherein
5The phenyl that the group that expression is randomly represented by 1,2 and 3 Z separately replaces and the group of heteroaryl comprise phenyl sulfonyl oxygen base, thienyl sulphonyl base oxygen base or the pyridyl sulfonyl oxygen base that the group randomly represented by 1,2 and 3 Z replaces.
In the compound of the formula I of a particular group, R
1The C that expression a) is replaced by one or more following groups
1-3Alkoxyl group i) ii) group NR of fluorine
cR
d, R wherein
cAnd R
dRepresent H independently, C
1-6Alkyl or C
1-6Alkoxy carbonyl, condition are R
cAnd R
dOne of be not H or iii) 1,3-dioxolane-2-base; B) R
1The C that expression is randomly replaced by one or more following groups
4-6Alkoxyl group i) ii) group NR of fluorine
cR
d, R wherein
cAnd R
dRepresent H independently, C
1-6Alkyl or C
2-6Alkoxy carbonyl, condition are R
cAnd R
dOne of be not H or iii) 1,3-dioxolane-2-base; C) formula phenyl (CH
2)
pThe group of O-, wherein p be 1,2 or 3 and the group randomly represented by 1,2 or 3 Z of phenyl ring replace; D) R
5S (O)
2O or R
5S (O)
2NH, wherein R
5The C that expression is randomly replaced by one or more fluorine
1-6Alkyl, or R
5Optional phenyl or the heteroaryl that replaces of group that expression is represented by 1,2 or 3 Z respectively; E) formula (R
6)
3The group of Si, wherein R
6Expression C
1-6Alkyl, its identical or different or f) formula R
bThe group of O (CO) O, wherein R
bThe C that expression is randomly replaced by one or more fluorine
1-6Alkyl;
R
aThe expression halogen;
M is 0,1,2 or 3;
R
2The expression halogen;
N is 0,1,2 or 3;
R
3Expression group CONR
7R
8, R wherein
7Expression H and R
8The C that the group that expression is randomly represented by W replaces
3-15Cycloalkyl or R
8Expression group-(CH
2)
tHet, wherein t be 0 and Het represent randomly to be selected from C by 1,2 or 3
1-5The pyridyl that the group of alkyl replaces, this C
1-5Alkyl is independent randomly to be replaced by one or more fluorine; Or
R
3Expression group CONHNR
7R
8, NR wherein
7R
8Expression piperidino-(1-position only) or morpholino; And R
4Expression H, halogen or C
1-6Alkyl, it is randomly replaced by one or more fluorine; Z represents halogen;
Represent C with W
1-6Alkoxy carbonyl.
One group of specific formula I compound is represented by formula IA
R wherein
1Be
A) by the optional C that replaces of one or more fluorine
4-6Alkoxyl group, b) formula phenyl (CH
2)
pThe group of O-, wherein p be 1,2 or 3 and the group randomly represented by 1,2 or 3 Z of this phenyl ring replace c) radicals R
5S (O)
2O or R
5S (O)
2NH, wherein R
5Expression is by the optional C that replaces of one or more fluorine
1-6Alkyl, or R
5Expression phenyl or heteroaryl, its group of randomly being represented by 1,2 or 3 Z separately replaces, and wherein Z defines as above, d) (R
6)
3The group of Si, wherein R
6Expression C
1-6Alkyl its can be identical or different, or e) formula R
bThe group of O (CO) O, wherein R
bExpression
By the optional C that replaces of one or more fluorine
1-6Alkyl;
R
aExpression halogen and m are 0,1 or 2;
R
2aExpression chlorine;
R
2bExpression chlorine;
R
2cExpression H or fluorine;
R
3Expression group CONHNR
7R
8, NR wherein
7R
8Expression piperidino-(1-position only) or morpholino or R
3Expression group CONHR
8, R wherein
8Expression is randomly by C
1-6The C that alkoxy carbonyl replaces
5-7Cycloalkyl or R
8The optional pyridyl that replaces of expression; With
R
4Expression H, C
1-3Alkyl or halogen.
The formula I compound of one particular group represented by formula IA, wherein R
1Be a) by the optional C that replaces of one or more fluorine
4-6Alkoxyl group, b) formula phenyl (CH
2)
pThe group of O-wherein p be 1,2 or 3 and the group randomly represented by 1,2 or 3 Z of this phenyl ring replace c) radicals R
5S (O)
2O or R
5S (O)
2NH, wherein R
5Expression is by the optional C that replaces of one or more fluorine
1-6Alkyl, or R
5Phenyl or heteroaryl that the group that expression is randomly represented by 1,2 or 3 Z separately replaces, d) (R
6)
3The group of Si, wherein R
6Expression C
1-6Alkyl, it can identical or different or e) formula R
bThe group of O (CO) O, wherein R
bExpression is by the optional C that replaces of one or more fluorine
1-6Alkyl;
R
aExpression halogen and m are 0,1 or 2;
R
2aExpression chlorine;
R
2bExpression chlorine;
R
2cExpression H;
R
3Expression group CONHNR
7R
8, NR wherein
7R
8Expression piperidino-(1-position only) or morpholino or R
3Expression group CONHR
8, R wherein
8Expression C
1-6The optional C that replaces of alkoxy carbonyl
5-7Cycloalkyl; With
R
4Expression C
1-3Alkyl or halogen.
The formula I compound of another particular group is represented by formula IB
R wherein
1Be
A) by the optional C that replaces of one or more fluorine
4-6Alkoxyl group, b) formula phenyl (CH
2)
pThe group of O-, wherein p be 1,2 or 3 and the group randomly represented by 1,2 or 3 Z of this phenyl ring replace c) radicals R
5S (O)
2O or R
5S (O)
2NH, wherein R
5Expression is by the optional C that replaces of one or more fluorine
1-6Alkyl, or R
5Expression phenyl or heteroaryl, its group of randomly being represented by 1,2 or 3 Z separately replaces or d) (R
6)
3The group of Si, wherein R
6Expression C
1-6Alkyl its can be identical or different;
B) R
a1 expression halogen or H;
R
A2Expression halogen or H;
R
2aExpression chlorine;
R
2bExpression chlorine;
R
2cExpression halogen or H;
R
3Expression group CONHNR
7R
8, NR wherein
7R
8The expression piperidino-(1-position only); With
R
4Expression C
1-3Alkyl.
In the compound of formula I, the formula IA of a particular group or formula IB, R
1Expression is by the optional C that replaces of one or more fluorine
4-6Alkoxyl group.
In the compound of formula I, the formula IA of another particular group or formula IB, R
1The expression radicals R
5S (O)
2O or R
5S (O)
2NH, wherein R
5Expression is by the optional C that replaces of one or more fluorine
1-6Alkyl, or R
5The optional heteroaryl that replaces of group that expression is represented by 1,2 or 3 Z.R in another group
1The expression radicals R
5S (O)
2O, wherein R
5Expression is by the optional C that replaces of one or more fluorine
1-6Alkyl.
In the compound of formula I, the formula IA of another particular group or formula IB, R
1Expression (R
6)
3The group of Si, wherein R
6Expression C
1-6Alkyl its can be identical or different.
The formula I compound of one particular group is represented by formula IC
R wherein
1Be
A) by the optional C that replaces of one or more fluorine
4-6Alkoxyl group, b) radicals R
5S (O)
2O, wherein R
5Expression is by the optional C that replaces of one or more fluorine
1-6Alkyl;
R
2aExpression chlorine;
R
2bExpression chlorine;
R
3Expression group CONHNR
7R
8, NR wherein
7R
8Expression piperidino-(1-position only) or morpholino; With
R
4Expression C
1-3Alkyl or halogen.
In the formula IC compound of a special group, R
1It is radicals R
5S (O)
2O wherein represents the C that is replaced by one or more fluorine
1-6Alkyl.R more particularly
1It is radicals R
5S (O)
2O, wherein R
5The C that expression is replaced by one or more fluorine
3-6Alkyl.
R
1, R
2, R
3, R
4And R
aOther values in the compound of formula I, formula IA, formula IB or formula IC are as follows.This type of value should be understood and the value that provides in any definition, claims or the context embodiment can be when suitable, adopted.
R
1Expression 4,4,4-trifluoro butoxy; normal-butyl alkylsulfonyl oxygen base; n-propyl alkylsulfonyl oxygen base, 4,4; 4-trifluoro butyl-1-alkylsulfonyl oxygen base; 3,3,3-trifluoro propyl-1-alkylsulfonyl oxygen base; propoxy-carbonyl oxygen base; 2-(1,3-dioxolane-2-yl) oxyethyl group, N-ethyl-2-amino ethoxy; N-tert-butoxycarbonyl-N-ethyl-2-amino ethoxy; 3-methyl fourth-1-alkylsulfonyl oxygen base, 3,3-dimethyl butyrate-1-alkylsulfonyl oxygen base; 5-chloro-2-thienyl sulphonyl base oxygen base, 2-thienyl sulphonyl base oxygen base or 3-pyridyl sulfonyl oxygen base.
R
1The C that expression is replaced by one or more fluorine
4-6Alkoxyl group.R
1Expression 4,4,4-trifluoro butoxy; normal-butyl alkylsulfonyl oxygen base, n-propyl alkylsulfonyl oxygen base, 4; 4,4-trifluoro butyl-1-alkylsulfonyl oxygen base, 3; 3,3-trifluoro propyl-1-alkylsulfonyl oxygen base, propoxy-carbonyl oxygen base; 2-(1; 3-dioxolane-2-yl) oxyethyl group, N-ethyl-2-amino ethoxy, or N-tert-butoxycarbonyl-N-ethyl-2-amino ethoxy.
R
1Expression 4,4,4-trifluoro butoxy, normal-butyl alkylsulfonyl oxygen base, n-propyl alkylsulfonyl oxygen base, 4,4,4-trifluoro butyl-1-alkylsulfonyl oxygen base, 3,3,3-trifluoro propyl-1-alkylsulfonyl oxygen base or propoxy-carbonyl oxygen base.
R
1Expression 4,4,4-trifluoro butoxy, normal-butyl alkylsulfonyl oxygen base or n-propyl alkylsulfonyl oxygen base.
R
2Expression chlorine or fluorine and n are 2 or 3.
R
3Expression N-(piperidines-1-yl) formamyl, 5-(trifluoromethyl) pyridine-2-yl] amino } carbonyl, morpholine-4-base formamyl or N-(1-methoxycarbonyl-1-cyclopentyl) formamyl.
R
4Expression C1-4 alkyl or halogen.R
4Expression methyl or bromine.M be 0 or when m is 1 or 2 R
aThe expression fluorine.
In the compound or its any embodiment of formula I, formula IA, formula IB or the formula IC of another particular group, R
3Expression N-(piperidines-1-yl) formamyl.
" pharmaceutically acceptable salt ", when this type of salt is feasible, comprise pharmacy can accept the bronsted lowry acids and bases bronsted lowry additive salt both.The suitable pharmaceutically acceptable salt of formula I compound is, for example, has the acid salt of the formula I compound of enough alkalescence, for example with inorganic or organic acid acid salt, and hydrochloric acid for example, Hydrogen bromide, sulfuric acid, trifluoroacetic acid, citric acid or toxilic acid; Or, for example have the salt of enough tart formula I compounds, for example basic metal or alkaline earth salt, sodium for example, calcium or magnesium salts, or ammonium salt, or with the salt of organic bases, methylamine for example, dimethylamine, Trimethylamine 99, piperidines, morpholine or three-(2-hydroxyethyl) amine.
In whole specification sheets and appending claims, chemical formula that provides and title should comprise the miscellany of the single enantiomer of all solids and optical isomer and racemic modification and different ratios, if the words that this type of isomer and enantiomer exist, with and pharmaceutically acceptable salt and its solvate, for example hydrate.Isomer can utilize routine techniques to separate, for example chromatogram or fractional crystallization.Enantiomer can be separated by the separation of racemic body, for example by fractional crystallization, fractionation or HPLC.Diastereomer can utilize fractional crystallization, HPLC or flash chromatography to come separately by separating isomerism body compound.Steric isomer can be made under the condition that does not cause racemization or epimerization by the chirality starting raw material by chirality is synthetic in addition, perhaps makes with chiral reagent by derivatize.All steric isomers belong within the scope of the invention.If possible, all tautomers belong in the scope of the present invention.The present invention also comprises and for example contains one or more isotropic substances
14C,
11C or
19The compound of F and be used for pharmacology and metabolism research as compound isotopically labelled.
The present invention also comprises the prodrug of formula I compound, and they are the compounds that are converted into formula I compound in vivo.
Following definition should be applicable to whole specification sheets and appended claims.
Unless otherwise indicated or point out that the straight or branched alkyl represented in term " alkyl ".The example of this alkyl comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, neo-pentyl, tert-pentyl, hexyl and isohexyl.
Preferred alkyl is a methyl, ethyl, propyl group, sec.-propyl, butyl and the tertiary butyl.
Unless otherwise indicated or point out that group O-alkyl represented in term " alkoxyl group ", wherein the alkyl definition is as above.
Unless otherwise indicated or point out that term " halogen " should be meant fluorine, chlorine, bromine or iodine.
Particular compound of the present invention is one or more following compounds:
Butane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] phenylester;
1-(2,4 dichloro benzene base)-4-methyl-5-[4-(4,4,4-trifluoro butoxy) phenyl]-1H-pyrazoles-3-carboxylic acid piperidines-1-base acid amides;
Propane-1-sulfonic acid 4-[2-(2,4-two chloro-phenyl)-4-methyl-5-(piperidines-1-base formamyl) 2H-pyrazole-3-yl]-phenylester;
Propane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(morpholine-4-base formamyl)-2H-pyrazole-3-yl] phenylester;
3,3,3-trifluoro propane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] phenylester;
4,4,4-trifluoro butane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] phenylester;
Propane-1-sulfonic acid-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl]-2,6-difluorophenyl ester;
Propane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] phenylester; Propane-1-sulfonic acid 4-[4-bromo-2-(2,4 dichloro benzene base)-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] phenylester;
1-{[(1-(2,4 dichloro benzene base)-4-methyl-5-{4[(sulfonyl propyl base) oxygen base] phenyl }-the 1H-pyrazole-3-yl) carbonyl] amino } cyclopentane carboxylic acid methyl;
Carbonic acid 4-[2-(2, the 4-chloro-phenyl-)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl]-the phenylester propyl diester;
4-{1-(2,4 dichloro benzene base)-4-methyl-3-[(piperidines-1-base is amino) carbonyl]-1H-pyrazoles-5-yl } phenyl thiophene-2-sulphonate;
4-{1-(2,4 dichloro benzene base)-4-methyl-3-[(piperidines-1-base is amino) carbonyl]-1H-pyrazoles-5-yl } phenylpyridine-3-sulphonate;
[2-(4-{1-(2,4 dichloro benzene base)-4-methyl-3-[(piperidines-1-base is amino) carbonyl]-1H-pyrazoles-5-yl } phenoxy group) ethyl] the ethyl carbamic acid tert-butyl ester;
1-(2,4 dichloro benzene base)-5-{4-[2-(ethylamino) oxyethyl group] phenyl }-4-methyl-N-piperidines-1-base-1H-pyrazole-3-carboxamide;
4-{1-(2,4 dichloro benzene base)-4-methyl-3-[(piperidines-1-base is amino) carbonyl]-1H-pyrazoles-5-yl } phenyl 3-methylbutane-1-sulphonate;
4-{1-(2,4 dichloro benzene base)-4-methyl-3-[(piperidines-1-base is amino) carbonyl]-1H-pyrazoles-5-yl } phenyl 3,3-dimethylbutane-1-sulphonate;
4-[1-(2,4 dichloro benzene base)-4-methyl-3-({ [5-(trifluoromethyl) pyridine-2-yl] amino } carbonyl)-1H-pyrazoles-5-yl] phenyl 3,3,3-trifluoro propane-1-sulphonate;
1-(2,4 dichloro benzene base)-5-{4-[2-(1,3-dioxolane-2-yl) oxyethyl group] phenyl }-4-methyl-N-piperidines-1-base-1H-pyrazole-3-carboxamide;
Propane-1-sulfonic acid 4-[2-(2,4-two chloro-3-fluorophenyls)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] phenylester; With
5-chloro-thiophene-2-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] phenylester;
With and pharmaceutically acceptable salt.
Prepare wherein R
a, R
2, R
3, R
4, m and n define as above and R
1The expression radicals R
5S (O)
2The method of the formula I compound of NH can through type II compound
R wherein
a, R
2, R
3, R
4, m and n define as above, with formula R
5SO
2The sulfonated reagent of L, wherein R
5Definition is as above represented for example chlorine of leavings group with L, at inert solvent for example in the methylene fluoride, alkali for example triethylamine in the presence of, in-25 ℃ to 150 ℃ temperature range, react and make.
R wherein
1The C that expression a) is replaced by one or more fluorine
1-3Alkoxyl group or by the optional C that replaces of one or more fluorine
4-6Alkoxyl group or b) formula phenyl (CH
2)
pThe group of O-wherein p be 1,2 or 3 and the group randomly represented by 1,2 or 3 Z of this phenyl ring replace, or c) radicals R
5S (O)
2The formula I compound of O can be by making the compound of formula III
R wherein
a, R
2, R
3, R
4, m and n definition as above, respectively with a) formula R
9The alkanisation reagent of X, wherein R
9The C that expression is replaced by one or more fluorine
1-3Alkyl or the optional C that is replaced by one or more fluorine
4-6Alkyl and X represent for example chlorine of leavings group, bromine or iodine, at inert solvent for example in the acetone, alkali for example salt of wormwood in the presence of, make at-25 ℃ to 150 ℃ temperature range internal reaction; Or b) with formula R
9The alkanisation reagent of X, wherein R
9Expression phenyl (CH
2)
p-group, wherein p be 1,2 or 3 and the group randomly represented by 1,2 or 3 Z of this phenyl ring replace, represent for example chlorine of leavings group with X, bromine or iodine is at inert solvent for example in the acetone, alkali for example salt of wormwood in the presence of, make at-25 ℃ to 150 ℃ temperature range internal reaction; Or c) with formula R
5SO
2The sulfonated reagent of L, wherein R
5Definition is as above represented for example chlorine of leavings group with L, at inert solvent for example in the difluoro hexane, alkali for example triethylamine in the presence of, make at-25 ℃ to 150 ℃ scope internal reaction.
R wherein
a, R
1, R
2, R
4, m and n define as above and R
3Expression radicals X-Y-NR
7R
8Wherein X is CO, and Y does not exist or represents by C
1-3Optional NH and the R that replaces of alkyl
7And R
8Definition formula I compound as above also can through type IV compound
R wherein
a, R
1, R
2, R
4, m and n define as above and R
1Expression C
1-6Alkyl is with the compound reaction of formula V
R
7R
8YNH
2 V
Y wherein, R
7And R
8Definition as above or its salt, at inert solvent for example in the toluene, Lewis acid for example trimethyl aluminium in the presence of, make at-25 ℃ to 150 ℃ temperature range internal reaction;
The R of formula I
3Expression radicals X-Y-NR
7R
8, wherein X is SO
2, Y does not exist or represents by C
1-3Optional NH and the R that replaces of alkyl
7And R
8Definition compound as above also can through type VI compound
R wherein
a, R
1, R
2, R
4, m and n definition is as above represented leavings group with A, for example halogen such as chlorine, and with the compound of formula V, Y wherein, R
7And R
8Definition as above or its salt inert solvent for example in THF or the methylene fluoride alkali for example salt of wormwood, triethylamine or pyridine in the presence of, make at-25 ℃ to 150 ℃ temperature range internal reaction.
The compound of formula III, IV and VI can prepare by being similar to above-mentioned method.
Some midbody compound is doubly thought new and is constituted integral part of the present invention.It will be understood by those skilled in the art that some functional group need be protected in this reaction process, suitably temporarily transferring deprotection subsequently, referring to " the Protective Groups inOrganic Synthesis " of Greene and Wuts work, the third edition (1999).
Pharmacological property
The general oral administration of compound of the present invention, non-enteron aisle, intravenously, intramuscular, subcutaneous or other injectable approach, in cheek, rectum, vagina, transdermal and/or nose approach and/or through inhalation, adopt in pharmacy and can accept to contain in the formulation form that activeconstituents or its pharmacy can be accepted the pharmaceutical preparation of additive salt.According to the disease that will treat and patient and route of administration, said composition can be with the various dose administration.
The suitable per daily dose of The compounds of this invention in the therapeutic treatment human body is about 0.001-10mg/kg body weight, preferred 0.01-1mg/kg body weight.
Special preferred tablet of oral preparations or capsule, they can be mended by the method known to those skilled in the art duty dosage of active compound in the 0.5mg-500mg scope, for example 1mg, 3mg, 5mg, 10mg, 25mg, 50mg, 100mg and 250mg are provided.
Provide pharmaceutical preparation according to another aspect of the present invention, contain wherein that any compound of the present invention or its pharmacy can be accepted derivative and pharmacy can be accepted assistant agent, thinner and/or carrier.
Pharmacological property
The compound of formula (I) is effectively treated fat or overweight, (for example, promoting loses weight and keep loses weight), the prevention weight increase (for example, cause after the drug-induced or smoking cessation), modulation of appetite and/or satietion, eating disorder (for example gluttony, apocleisis, Bulimia nerovsa and mandatory), habituation is (to medicine, tobacco, alcohol, big nutrition agent of any delicious food or nonessential food), treatment obstacle psychotic disorders is psychosis and/or mood disorder for example, schizophrenia and schizoaffective disorder, the bipolarity obstacle, anxiety, anxiety-depression sexual dysfunction, depression, manic, mandatory idea and behavior disorder, the controlled obstacle of getting excited (for example, Tourette's syndrome), attention disorders such as DD/ADHD, stress and the neuropathic obstacle is for example dull-witted and cognition and/or memory machine dysfunction (for example, amnesia, Alzheimer, the Pi Keshi dementia, aging dementia, vascular dementia, the mild cognitive damage, aging-related cognitive decline and slight aging dementia), psychosis and/or neurodegeneration obstacle (multiple sclerosis for example, Raynaud's syndrome, Parkinson's disease, Hang Ting Dun Shi chorea and Alzheimer), the sheath of emedullating forms relative disease, neural inflammatory diseases (for example, guillain-Barre syndrome).
Compound of the present invention is effectively prevention or treatment dependency and addictive disorders and behavior (for example, alcohol and/or drug abuse, Pathological Gambling, kleptomania) also, and (for example, disturbance of perception is followed or do not followed in abstinence from alcohol to the drug withdrawal disease; It is absurd that alcohol is given up slander; Amphetamine is given up; Cocaine is given up; Nicotine abstinence; Opium is given up; Tranquilizer, soporific or anxiety (anxiolytic) are given up and are followed or do not follow disturbance of perception; It is absurd that tranquilizer, soporific or antianxiety agent are given up slander; The Withrawal symptom that causes with other materials), alcohol and/or drug-induced mental state, anxiety and/or somnopathy and in giving up process, show effect and alcohol and/or medicine so the attitude recurrence.
Described compound also effectively prevents or treats for example dystonia of psychosis dysfunction, and dyskinesia is cathisophobiaed, tremble with tetanic treatment spinal injury, neuropathy, migraine, the insomnia obstacle, somnopathy is (for example, the sleep system confusion, sleep apnea, obstructive sleep apnea, sleep apnea syndrome), the pain obstacle, the cranium wound.
Described compound is effectively treatment immunity also, vascular disease (atherosclerosis for example, arteriosclerosis, stenocardia, rhythm abnormality and arythmia disease (arrythmias), congestive heart failure, coronary artery disease, heart disease, hypertension, prevention and treatment left ventricular hypertrophy, myocardial infarction, transient ischemic attack, peripheral vascular disease, the system inflammation of vascular wash-out, septic is stopped up, apoplexy, cerebral apoplexy, cerebral infarction, cerebral ischaemia, cerebral thrombosis, cerebral embolism, hematencephalon, metabolic disturbance (for example shows the illness that metabolic activity reduces or the percentage of the total free-fat amount of static energy consumption conduct decreases, diabetes, dyslipidemias mass formed by blood stasis, fatty liver, gout, hypercholesterolia mass formed by blood stasis, hyperlipidemia, hypertriglyceridemia, high urea mass formed by blood stasis, the fasting glucose that the glucose tolerance is impaired, impaired, insulin resistance, insulin resistance syndrome, metabolism syndrome, syndrome X, obesity-underventilation syndrome (Pickwickian syndrome), type i diabetes, type ii diabetes, low HDL-and/or high LDL-cholesterol levels, low adiponectin level), reproduction and endocrinopathy (are for example treated the male sex's hypogonadism, treatment infertility or as contraceptive bian, irregular menstruation/menopathy, the polycystic ovary disease, the women and the male sex's property and reproductive dysfunction (erectile dysfunction), the not enough object of GH-, female hirsutism, normal variant is short and small) and with the disease of breathing diseases associated (for example asthma and chronic obstructive disease of lung) and gastro-intestinal system (the propulsive dysfunction of gastrointestinal motility or intestines for example, diarrhoea, vomiting is felt sick, gallbladder disease, gallbladdergallstonecholetithiasis, fat relevant stomach-esophageal reflux, ulcer).
Described compound also effectively as the treatment tetter just, cancer (colon for example, rectum, prostate gland, mammary gland, ovary, uterine endometrium, uterine cervix, gall-bladder, bile duct), cranium smoke pipe knurl, Prader-Willi syndrome, Turner syndrome, Frohlich Cotard, glaucoma, infectious diseases, urethral disease and inflammatory diseases (for example lopsided sacroiliitis, inflammation, the inflammatory sequela of viral encephalitis, osteoarthritis) and the medicine of orthopedic disease s.This compound also have effectiveness do treatment (oesophagus) relax can not medicine.
The invention provides as defined above on the other hand, the compound of formula I is used as medicine.
The compound that the invention provides formula I on the other hand preparation be used for the treatment of or prevention of obesity or overweight medicine in application, (for example, promotion loses weight and maintenance loses weight), the prevention weight increase (for example, drug-induced or the smoking cessation secondary), modulation of appetite and/or satietion, eating disorder (for example gluttony, apocleisis, Bulimia nerovsa and mandatory), and habituation (for medicine, tobacco, alcohol, high nutrition agent of any delicious food or nonessential food), the treatment psychotic disorders is psychosis and/or mood disorder for example, schizophrenia and schizoaffective disorder, the bipolarity obstacle, anxiety, anxiety-depression sexual dysfunction, depression, manic, mandatory idea and behavior disorder, the controlled obstacle of getting excited (for example, Tourette's syndrome), attention disorders such as ADD/ADHD, stress and the neuropathic obstacle is for example dull-witted and cognition and/or memory machine dysfunction (for example, amnesia, Alzheimer, the Pi Keshi dementia, aging dementia, vascular dementia, the mild cognitive damage, aging-related cognitive decline and slight aging dementia), psychosis and/or neurodegeneration obstacle (multiple sclerosis for example, Raynaud's syndrome, Parkinson's disease, Hang Ting Dun Shi chorea and Alzheimer), the sheath of emedullating forms relative disease, neural inflammatory diseases (for example, guillain-Barre syndrome).
The compound that the invention provides formula I on the other hand is used for the treatment of or (for example prevents dependency and addictive disorders and behavior in preparation, alcohol and/or drug abuse, Pathological Gambling, kleptomania), the drug withdrawal disease (for example, give up and follow or do not follow disturbance of perception by alcohol; It is absurd that alcohol is given up slander; Amphetamine is given up; Cocaine is given up; Nicotine abstinence; Opium is given up; Tranquilizer, soporific or antianxiety agent are given up and are followed or do not follow disturbance of perception; It is absurd that tranquilizer, soporific or antianxiety agent are given up slander; The Withrawal symptom that causes with other materials), alcohol and/or drug-induced mental state, anxiety and/or somnopathy follow show effect in the process of giving up and alcohol and/or medicine so the application in the medicine of attitude recurrence.
The compound that the invention provides formula I on the other hand is used for the treatment of or prevents for example dystonia of psychosis dysfunction in preparation, and dyskinesia is cathisophobiaed, tremble with tetanic treatment spinal injury, neuropathy, migraine, the insomnia obstacle, somnopathy is (for example, the sleep system confusion, sleep apnea, obstructive sleep apnea, sleep apnea syndrome), the pain obstacle, the application in the medicine of cranium wound.
The compound that the invention provides formula I on the other hand is used for the treatment of or prevents application in the medicine of following disease in preparation: immunity, vascular disease (atherosclerosis for example, arteriosclerosis, stenocardia, rhythm abnormality, with arythmia disease, congestive heart failure, coronary artery disease, heart disease, hypertension, prevention and treatment left ventricular hypertrophy, myocardial infarction, transient ischemic attack, peripheral vascular disease, the system inflammation of vascular wash-out, septic is stopped up, apoplexy, cerebral apoplexy, cerebral infarction, cerebral ischaemia, cerebral thrombosis, cerebral embolism, hematencephalon, metabolic disturbance (for example shows the illness that metabolic activity reduces or the percentage of the total free-fat amount of static energy consumption conduct decreases, diabetes, dyslipidemias mass formed by blood stasis, fatty liver, gout, hypercholesterolia mass formed by blood stasis, hyperlipidemia, hypertriglyceridemia, high urea mass formed by blood stasis, the fasting glucose that the glucose tolerance is impaired, impaired, insulin resistance, insulin resistance syndrome, metabolism syndrome, syndrome X, obesity-underventilation syndrome (Pickwickian syndrome), type i diabetes, type ii diabetes, low HDL-and/or high LDL-cholesterol levels, low adiponectin level), reproduction and endocrinopathy (are for example treated the male sex's hypogonadism, treatment infertility or as contraceptive bian, irregular menstruation/menopathy, the polycystic ovary disease, the women and the male sex's property and reproductive dysfunction (erectile dysfunction), the damaged object of GH-, female hirsutism, normal variant is short and small) and with breathe diseases associated (for example asthma and chronic obstructive disease of lung) and gastro-intestinal system (the propulsive dysfunction of gastrointestinal motility or intestines for example, diarrhoea, vomiting is felt sick, gallbladder disease, gallbladdergallstonecholetithiasis, fat relevant stomach-esophageal reflux, ulcer).
The compound that the invention provides formula I on the other hand is used for the treatment of or prevents application in the medicine of following disease in preparation: tetter, cancer (colon for example, rectum, prostate gland, mammary gland, ovary, uterine endometrium, uterine cervix, gall-bladder, bile duct), cranium smoke pipe knurl, Prader-Willi syndrome, Turner syndrome, the Frohlich Cotard, glaucoma, infectious diseases, urethral disease and inflammatory diseases (arthritis deformans for example, inflammation, the inflammatory sequela of viral encephalitis, osteoarthritis) and orthopedic disease.
The invention provides a kind of compound of the formula I that uses the pharmacology significant quantity that comprises in aspect another and give patient's prevention that needs it or the method for the treatment of following disease: be fat or overweight, (for example, promotion loses weight and maintenance loses weight), the prevention weight increase (for example, drug-induced or the smoking cessation secondary), modulation of appetite and/or satietion, eating disorder (for example gluttony, apocleisis, Bulimia nerovsa and mandatory), habituation is for medicine, tobacco, alcohol, high nutrition agent of any delicious food or nonessential food), the treatment psychotic disorders is psychosis and/or mood disorder for example, schizophrenia and schizoaffective disorder, the bipolarity obstacle, anxiety, anxiety-depression sexual dysfunction, depression, manic, mandatory idea and behavior disorder, the controlled obstacle of getting excited (for example, Tourette's syndrome), attention disorders such as ADD/ADHD, stress and the neuropathic obstacle is for example dull-witted and cognition and/or memory machine dysfunction (for example, amnesia, Alzheimer, the Pi Keshi dementia, aging dementia, vascular dementia, the mild cognitive damage, aging-related cognitive decline and slight aging dementia), psychosis and/or neurodegeneration obstacle (multiple sclerosis for example, Raynaud's syndrome, Parkinson's disease, Hang Ting Dun Shi chorea and Alzheimer), the sheath of emedullating forms relative disease, neural inflammatory diseases (for example, Guillain-Barr syndrome).
The invention provides a kind of compound of the formula I that uses the pharmacology significant quantity that comprises in aspect another and give patient's prevention that needs it or the method for the treatment of following disease: dependency and addictive disorders and behavior are (for example, alcohol and/or drug abuse, Pathological Gambling, the kleptomania), the drug withdrawal disease (for example, give up and follow or do not follow disturbance of perception by alcohol; It is absurd that alcohol is given up slander; Amphetamine is given up; Cocaine is given up; Nicotine abstinence; Opium is given up; Tranquilizer, soporific or antianxiety agent are given up and are followed or do not follow disturbance of perception; It is absurd that tranquilizer, soporific or antianxiety agent are given up slander; The Withrawal symptom that causes with other materials), alcohol and/or drug-induced mental state, anxiety and/or somnopathy follow show effect in the process of giving up and alcohol and/or medicine so the attitude recurrence.
The invention provides a kind of compound of the formula I that uses the pharmacology significant quantity that comprises in aspect another and give patient's prevention that needs it or the method for the treatment of following disease: the psychosis dysfunction is dystonia for example, and dyskinesia is cathisophobiaed, tremble with tetanic treatment spinal injury, neuropathy, migraine, the insomnia obstacle, somnopathy s is (for example, the sleep system confusion, sleep apnea, obstructive sleep apnea, sleep apnea syndrome), the pain obstacle, the cranium wound.
The invention provides a kind of compound of the formula I that uses the pharmacology significant quantity that comprises in aspect another and give patient's prevention that needs it or the method for the treatment of following disease: immunity, vascular disease (atherosclerosis for example, arteriosclerosis, stenocardia, rhythm abnormality, with arythmia disease, congestive heart failure, coronary artery disease, heart disease, hypertension, prevention and treatment left ventricular hypertrophy, myocardial infarction, transient ischemic attack, peripheral vascular disease, the system inflammation of vascular wash-out, septic is stopped up, apoplexy, cerebral apoplexy, cerebral infarction, cerebral ischaemia, cerebral thrombosis, cerebral embolism, hematencephalon, metabolic disturbance (for example shows the illness that metabolic activity reduces or the percentage of the total free-fat amount of static energy consumption conduct decreases, diabetes, dyslipidemias mass formed by blood stasis, fatty liver, gout, hypercholesterolia mass formed by blood stasis, hyperlipidemia, hypertriglyceridemia, high urea mass formed by blood stasis, the fasting glucose that the glucose tolerance is impaired, impaired, insulin resistance, insulin resistance syndrome, metabolism syndrome, syndrome X, obesity-underventilation syndrome (Pickwickian syndrome), type i diabetes, type ii diabetes, low HDL-and/or high LDL-cholesterol levels, low adiponectin level), reproduction and endocrinopathy (are for example treated the male sex's hypogonadism, treatment infertility or as contraceptive bian, irregular menstruation/menopathy, the polycystic ovary disease, the women and the male sex's property and reproductive dysfunction (erectile dysfunction), the damaged object of GH-, female hirsutism, normal variant is short and small) and with breathe diseases associated (for example asthma and chronic obstructive disease of lung) and gastro-intestinal system (the propulsive dysfunction of gastrointestinal motility or intestines for example, diarrhoea, vomiting is felt sick, gallbladder disease, gallbladdergallstonecholetithiasis, fat relevant stomach-esophageal reflux, ulcer).
The invention provides a kind of compound of the formula I that uses the pharmacology significant quantity that comprises in aspect another and give patient's prevention that needs it or the method for the treatment of following disease: tetter, cancer (colon for example, rectum, prostate gland, mammary gland, ovary, uterine endometrium, uterine cervix, gall-bladder, bile duct), cranium smoke pipe knurl, Prader-Willi syndrome, Turner syndrome, the Frohlich Cotard, glaucoma, infectious diseases, urethral disease and inflammatory diseases (for example lopsided sacroiliitis, inflammation, the inflammatory sequela of viral encephalitis, osteoarthritis) and orthopedic disease.
It is fat or overweight that compound of the present invention is particularly suitable for treatment, (for example, the promotion loses weight and maintenance loses weight), prevention or reverse weight increase (for example, bounce-back, drug-induced or the smoking cessation secondary), modulation of appetite and/or satietion, eating disorder (for example gluttony, apocleisis, Bulimia nerovsa and mandatory), habituation is (for medicine s, tobacco, alcohol, high nutrition agent of any delicious food or nonessential food).
The compound of formula (I) is effectively treated obesity, and psychotic disorders is psychiatric disorders for example, schizophrenia, bipolarity obstacle, anxiety, anxiety-depression sexual dysfunction, depression, cognitive disorder, dysmnesia, mandatory idea and behavior disorder, apocleisis, Bulimia nerovsa, attention disorders such as ADHD, epilepsy and have related disorders and neuropathic obstacle for example dull-witted, neuropathic obstacle (for example multiple sclerosis), Raynaud's syndrome, Parkinson's disease, Hang Ting Dun Shi chorea and Alzheimer.Described compound is effectively treatment immunity, cardiovascular also, reproduction and endocrinopathy, septic shock and with breathe diseases associated and gastro-intestinal system (for example diarrhoea).Described compound is also effectively treated long-term abuse, habituation and/or so attitude recurrence indication, for example medicine (nicotine, ethanol, Cocaine, opiate etc.) dependency and/or medicine (nicotine, ethanol, Cocaine, opiate etc.) Withrawal symptom.Described compound is also eliminated the weight increase of generally following smoking cessation to occur.
The compound that the invention provides the formula I of above-mentioned definition on the other hand is used as medicine.
The compound that the invention provides formula I on the other hand is used for the treatment of or prevents application in the medicine of following disease in preparation: obesity, and psychotic disorders is psychiatric disorders for example, schizophrenia, the bipolarity obstacle, anxiety, anxiety-depression obstacle, depression, cognitive disorder, dysmnesia, obsessional idea and behavior disorder, apocleisis, Bulimia nerovsa, attention disorders like ADHD, epilepsy and related disorders is arranged, the neuropathic obstacle is for example dull-witted, neuropathic obstacle (for example multiple sclerosis), Parkinson's disease, Hang Ting Dun Shi chorea and Alzheimer, immunity, cardiovascular, reproduction and endocrinopathy, septic shock, the illness relevant (for example diarrhoea) with breathing and gastro-intestinal system, with long-term abuse, habituation and/or recurrence indication, for example medicine (nicotine, ethanol, Cocaine, opiate etc.) dependency and/or medicine (nicotine, ethanol, Cocaine, opiate etc.) withdrawal symptom.
The invention provides a kind of method for the treatment of following disease on the other hand: obesity, psychotic disorders be for example schizophrenia and bipolarity obstacle of psychiatric disorders for example, anxiety, the anxiety-depression sexual dysfunction, depression, cognitive disorder, dysmnesia, mandatory idea and behavior disorder, apocleisis, Bulimia nerovsa, attention disorders such as ADHD, epilepsy, with related disorders is arranged, the neuropathic obstacle is for example dull-witted, neuropathic obstacle (for example multiple sclerosis), Parkinson's disease, Hang Ting Dun Shi chorea and Alzheimer, immunity, cardiovascular, reproduction and endocrinopathy, septic shock, with breathing diseases associated and gastro-intestinal system (for example diarrhoea) and long-term abuse, habituation and/or recurrence indication, medicine (nicotine for example, ethanol, Cocaine, opiate etc.) dependency and/or medicine (nicotine, ethanol, Cocaine, opiate etc.) withdrawal symptom, this method comprises that the compound of the formula I that uses the pharmacology significant quantity is to the patient who needs it.
It is fat that compound of the present invention is particularly suitable for treatment, for example rebounds by reducing appetite and body weight, keep to lose weight and prevent.
The weight increase that compound of the present invention can also be used to prevent or reversing drug causes, for example weight increase that causes of antipsychotic (neuroleptic) treatment.Compound of the present invention can also be used to prevent or reverse and the relevant weight increase of giving up smoking.
Conjoint therapy
Compound of the present invention can make up with the therapeutical agent of another effectively treatment obesity, other anti-obesity medicines for example, this drug influence energy expenditure, glycolysis-, glyconeogenesis, glycogenolysis (glucogenolysis), steatolysis, steatogenesis, fat absorbing, fat stores, fatty drainage, hunger and/or satietion and/or sensual desires mechanism, appetite/actuate, ingestion of food or G-I motion.
Compound of the present invention can be further and the effective therapeutic combination of treatment and fat diseases associated of another kind, and this disease for example is a hypertension, hyperlipidemia, hyperlipemia, diabetes, sleep apnea, asthma, heart trouble, atherosclerosis, great vessels and microvascular disease, the liver fat sex change, cancer, joint disease, and gallbladder disease.For example, compound of the present invention can bring high blood pressure down with another kind or reduce LDL: the medicine of HDL ratio or with the medication combined use that causes that LDL-cholesterol cyclical level reduces.Compound of the present invention can also be used for the treatment of and the macroangiopathic complications associated with arterial system with the therapeutical agent combination in suffering from the patient of diabetes.
Compound of the present invention can therapy fat with other treatment and its mutual complication metabolism syndrome and type ii diabetes be united, these comprise biguanides biguanides medicine, Regular Insulin (synthetic insulin analogue) and oral hyperglycemia medicine (these are divided into meals glucose conditioning agent and α-Pu Taotang enzyme inhibitors).
Another aspect of the present invention, the compound of formula I or its pharmaceutically acceptable salt can combine administration with the PPAR conditioning agent.The PPAR conditioning agent includes but not limited to PPAR α and/or gamma agonist, or pharmaceutically acceptable salt, solvate, the solvate of this type of salt or its prodrug.Suitable substance P PAR α and/or gamma agonist, its pharmaceutically acceptable salt, solvate, the solvate of this type of salt or prodrug are well known in the art.
Combination of the present invention in addition can be united with sulfonylurea.The present invention also comprises compound of the present invention and anticholesteremic agent combination.Anticholesteremic agent is meant the inhibitor that includes but not limited to HMG-CoA reductase enzyme (3-hydroxy-3-methyl glutaryl base CoA-reductase) in this application.Suitable HMG-CoA reductase inhibitor is his spit of fland.
Among the present invention, term " anticholesteremic agent " also comprises the chemically modified of HMG-CoA reductase inhibitor, ester for example, and no matter whether prodrug and metabolite have activity or non-activity.
The present invention also comprises compound of the present invention and ileum cholic acid movement system inhibitor (ibat inhibitor) combination.The present invention also comprises compound of the present invention and the combination of cholic acid binding resin.
The present invention also comprises compound of the present invention and cholic acid chelating agent combination, for example cholestipol or Colestyramine or cholestagel.
Provide a kind of combined therapy according to another aspect of the present invention, comprise, randomly can accept diluent or carrier, be selected from following medicine with one or more with pharmacy with formula I compound or its pharmaceutically acceptable salt of significant quantity:
CETP (cholesteryl ester transfer protein) inhibitor;
The cholesterol absorption antagonist;
MTP (microsome transfer protein) inhibitor;
Nicotinic acid derivates comprises slowly-releasing and combined prod;
The plant sterol compound;
Probucol;
Antithrombotics;
Omega-fatty acid;
Another kind of anti-obesity compound, sibutramin for example, PHENTERMINE, orlistat, Bupropion, ephedrine, thyroxine;
Anti-hypertension compound, angiotensin-converting enzyme (ACE) inhibitor for example, angiotensin II receptor antagonists, adrenergic blocking agent, the alpha-1 adrenergic retarding agent, the Beta-3 adrenergic retarding agent, mix mode α/Beta-3 adrenergic retarding agent, Adrenergic agonists, calcium channel blocker, the AT-1 retarding agent, chlorothiazide (saluretic), diuretic(s) or vasodilator;
Denseization of melanocyte hormone (MCH) conditioning agent;
The npy receptor conditioning agent;
The orexin receptor conditioning agent;
Phosphoinositide deopendent protein kinase (PDK) conditioning agent; Or
Nuclear receptor modulators, LXR for example, FXR, RXR, GR, ERR α, β, PPAR α, beta, gamma and ROR α;
Monoamine transmission conditioning agent, selectivity five hydroxytryptamine uptake inhibitor (SSRI) for example, norepinephrine uptake inhibitors (NARI), norepinephrine-five hydroxytryptamine uptake inhibitor (SNRI), oxidase inhibitor (MAOI), three ring thunder thymoleptic (TCA), norepinephrine energy and specificity five hydroxytryptamine energy antidepressant drug (NaSSA);
Antipsychotics, for example Zyprexa and leoponex;
The seretonine receptor conditioning agent;
Leptin/leptin receptor conditioning agent;
The ghrelin/ghrelin receptor modulators;
The DPP-IV inhibitor;
Or its pharmaceutically acceptable salt, solvate, the solvate of described salt or its prodrug randomly can be accepted diluent or carrier while, order or separate administration with pharmacy and be administered to warm-blooded animal, for example need the people of this treatment.
According to another aspect of the present invention, a kind of composition is provided, comprises formula I compound significant quantity, or its pharmaceutically acceptable salt, randomly with pharmacy can accept diluent or carrier and utmost point low calorie diets (VLCD) or low calorie diets (LCD) simultaneously, the order or separate administration.
Another aspect of the present invention thus, provide a kind of in this treatment of needs warm-blooded animal such as human body in the method for treatment obesity and complication thereof, this method comprises to this animal with the solvate that is selected from a kind of compound in described other species compound of built-up section or its pharmaceutically acceptable salt, solvate, described salt of the formula I compound of significant quantity or its pharmaceutically acceptable salt and significant quantity or its prodrug simultaneously, in proper order or separate administration.
So another aspect of the present invention, provide a kind of in this treatment of needs warm-blooded animal such as human body in the method for treatment hyperlipidemia illness, this method comprises to this animal with the solvate that is selected from a kind of compound in described other species compound of built-up section or its pharmaceutically acceptable salt, solvate, described salt of the formula I compound of significant quantity or its pharmaceutically acceptable salt and significant quantity or its prodrug simultaneously, in proper order or separate administration.
Provide a kind of pharmaceutical composition according to another aspect of the present invention, said composition contains compound or its pharmaceutically acceptable salt of formula I, with solvate or its prodrug of a kind of compound in described other species compound of built-up section or its pharmaceutically acceptable salt, solvate, described salt, and pharmacy can be accepted diluent or carrier.
Provide a kind of cover box according to another aspect of the present invention, the solvate or its prodrug that wherein contain the compound of formula I or its pharmaceutically acceptable salt and a kind of compound in described other species compound of built-up section or its pharmaceutically acceptable salt, solvate, described salt.
Provide a kind of cover box according to another aspect of the present invention, wherein contain:
A) in first unit dosage, the compound of formula I, or its pharmaceutically acceptable salt;
B) in second unit dosage, solvate or its prodrug of a kind of compound in described other species compound of built-up section or its pharmaceutically acceptable salt, solvate, described salt; With
C) contain the container of above-mentioned first and second formulations.
Provide a kind of cover box according to another aspect of the present invention, wherein contain:
A) in first unit dosage, the compound of formula I or its pharmaceutically acceptable salt, and pharmacy can be accepted diluent or carrier;
B) in second unit dosage, solvate or its prodrug of a kind of compound in described other species compound of built-up section or its pharmaceutically acceptable salt, solvate, described salt; With
C) contain the container of above-mentioned first and second formulations.
Provide a kind of other compound or the solvate of its pharmaceutically acceptable salt, solvate, described salt or its prodrug described in formula I compound or its pharmaceutically acceptable salt and the built-up section to be used for the treatment of application in the medicine of obesity among warm-blooded animal such as the people and related complication thereof according to another aspect of the present invention in preparation.
Provide a kind of other compound or the solvate of its pharmaceutically acceptable salt, solvate, described salt or its prodrug described in formula I compound or its pharmaceutically acceptable salt and the built-up section to be used for the treatment of application in the medicine of the hyperlipidemia illness among warm-blooded animal such as the people according to another aspect of the present invention in preparation.
Provide a kind of combination therapy according to another aspect of the present invention, comprise formula I compound or its pharmaceutically acceptable salt with significant quantity, randomly can accept diluent or carrier with pharmacy, a kind of solvate or its prodrug with significant quantity at described other compounds of built-up section or its pharmaceutically acceptable salt, solvate, described salt, randomly can accept diluent or carrier together with pharmacy, simultaneously, order or separate administration give the document animal, for example needs the people of this therapeutic treatment.
In addition, compound of the present invention can also with effective treatment and fat (type ii diabetes for example, metabolism syndrome, the dyslipidemias mass formed by blood stasis, the glucose tolerance is impaired, hypertension, coronary heart disease, the non-alcoholic fatty liver disease inflammation, osteoarthritis and some cancer) and psychosis and mental illness diseases associated or treatment of conditions agent combination.
Should understand fat and overweight medical science can be accepted definition.The patient can provide and for example measure weight index (BMI) and identify, it is with the body weight of the kilogram height divided by square metre meter, and defines comparing result with this.
Pharmacological activity
Compound of the present invention is to CB
1The acceptor product of gene has activity resistent.Compound of the present invention to the avidity of maincenter cannabinol alkaloid (cannabinoid) acceptor be according to Devane etc. at Molecular Pharmacology, 1988,34,605 or WO01/70700 or EP 656354 described in those methods measure.This test can be carried out as follows in addition.
With 10 μ g by using CB
1The film of stable gene cells transfected preparation is suspended in the 100mM NaCl of 200 μ l, 5mM MgCl
2, ImM EDTA, 50mM HEPES (pH 7.4), 1mMDTT is among 0.1%BSA and the 10011M GDP.To the agonist that wherein adds EC80 concentration (CP55940), the test compound of desired concn and 0.1 μ Ci[
35S]-GTPyS.This is reflected at carried out under 30 ℃ 45 minutes.With cell harvester sample is transferred on the GF/B filter membrane and with lavation buffer solution subsequently and washed (50mM Tris (pH 7.4), 5mM MgCl
2, 50mMNaCl).Filter membrane cover with scintillator subsequently and calculate keep on the filter membrane [
35S]-amount of GTP γ S.
Measure active (minimum active) or in the presence of EC80 concentration C P55940, measure activity (maximum activity) in the presence of not at all parts.These activity are set to 0% and 100% activity respectively.Under the new part of different concns, calculated activity is the per-cent and the drawing of maximum activity.Data are concentration required when used condition is issued to GTP γ S bonded half maximum restraining effect with following formula y=A+ ((B-A)/l+ ((C/x) UD)) match and IC50 pH-value determination pH.
Compound of the present invention is to CB
1Acceptor (IC50＜1 micromole) has activity.Most preferred has IC50＜200 nmoles.For example the IC50 of embodiment 10 is the 6.4nM that is of 6.0nM and embodiment 11.
Compound of the present invention is considered to selectivity CB
1Antagonist or inverse agonist.Tire, selectivity and side effect tendency may limit hitherto known definite CB that has
1The clinical application of the compound of antagonism/reverse exciting character.In this respect, the clinical preceding assessment of The compounds of this invention in gi tract and/or cardiovascular function model shows that they and representativeness are with reference to CB
1Antagonists/inverse agonists is compared has significant advantage.
Compound of the present invention tire, select performance, bioavailability, plasma half-life, blood brain perviousness, plasma proteins in conjunction with aspect (for example higher free fractional medicine) or the solubleness with representative with reference to CB
1Antagonists/inverse agonists is compared can provide additional superiority.
Compound of the present invention is fat in treatment to be to bring out to lose weight in the obesity mice by self-service diet to be confirmed with the practicality in the related disorders is arranged.Female C57B1/6J mouse arbitrarily obtains high calorie ' self-service ' feed (soft chocolate/cocoa millet cake, chocolate, fatty cheese and Niu Zha sugar) and standard laboratory feed 8-10 week.Tested compound is administered systemically once (iv, ip, sc or po) minimum 5 days subsequently every day, and is the body weight of inositol monitoring mouse with the sky.Fat synchronous assessment is by carrying out at the DEXA of baseline imaging mode and finishing when studying.Gather blood to analyze the variation of fat relevant blood plasma marker thing.
Embodiment
Abbreviation
AcOH acetate
The DCM methylene fluoride
The DMF dimethyl methyl
Acid amides
The DEA diethylamine
DIEA N, the N-diisopropyl ethyl amine
The DMAP 4-dimethylaminopyridine
The EtOAc acetoacetic ester
Et
3The N triethylamine
Ex or EX embodiment
LiHMDS hexamethyl two silicon Lithium Azides
MeOH methyl alcohol
MeCN second eyeball
Rt or RT room temperature
The TEA triethylamine
THF hydrogen furans
The t triplet
The s singlet
The d doublet
The q quartet
The qvint quintet
The m multiplet
The br broad peak
The wide singlet of bs
The multiplet that dm is dual
The wide triplet of bt
The dd double doublet
General implementation method
Mass spectrum is recorded on single four utmost points of ZQ or the single quadrupole mass spectrometer of Micromass LCZ, and inflation auxiliary EFI interface (LC-MS) wherein is installed.
1It is to carry out on VarianMercury 300 or Varian Inova 500 that H NMR measures,
1The H frequency is respectively 300 and 500MHz.Chemical shift is with respect to CDCl
3As the interior ppm meter that is marked with.CDCl
3Be used in the solvent of NMR, unless otherwise indicated.Purifying triggers the classification collector partly preparing HPLC (high efficiency liquid chromatography) and quality, has on Shimadzu QP 8000 single quadrupole mass spectrometers of 19 * 100mmC8 post to carry out.If not explanation, moving phase is second eyeball and damping fluid (0.1M ammonium acetate: second eyeball 95: 5).For the separating isomerism body, adopt Kromasil CN E9344 (250 * 20mm i.d.) post.Heptane: ethyl acetate: DEA is used as moving phase (1ml/min) at 95: 5: 0.1.Fraction collection instructs with UV-detector (330mn).
The typical HPLC-parameter of purity check:
HPLC system: Agilent 1100
Post: Zorbax EclipseXDB-C8150 * 4.6mm
Analysis time: 15 minutes
Flow: 1.5ml/min
Moving phase: A: water, 5%MeOH
B：MeOH
Temperature: 40 ℃
Detector: Uv 240nm
Embodiments of the invention
Embodiment 1
Steps A 1-(4-benzyloxy phenyl) third-1-ketone
The 4-hydroxypropiophenone (15.0g, 0.10mol) be dissolved in acetone (200ml) and salt of wormwood (13.8g, 0.10mol).(17.1g 0.10mol) and with this reaction mixture reflux spends the night to add bromotoluene.Be cooled to this mixture of room temperature after-filtration and concentrate this title compound that obtains 24.0g (100%) on rotatory evaporator, it is a white solid.
Step B 1-(4-benzyloxy phenyl)-2-bromine third-1-ketone
(4.80g 20.0mmol) is suspended in acetate (25ml) and be cooled to 0 ℃ with 1-(4-benzyloxy phenyl) third-1-ketone.(3.20g 20.0mmol) and with this reaction mixture at room temperature stirred 2 hours dripping bromine, and be clarification, yellow solution with this reaction mixture this moment.After the cooling, add entry (100ml) and this product extracted with diethyl ether (2 * 100ml).The organic extract liquid water, sodium bicarbonate and the salt water washing that merge.Dry organic phase (Na
2SO
4), filtration and evaporation obtain this title compound, and it is yellow solid (6.17g, 97%).
Step C 2-[2-(4-benzyloxy phenyl)-2-oxo-ethyl]-3-oxo-ethyl butyrate
The solution of sodium ethylate is that (0.53g 23.0mmol) prepares in the 30ml absolute ethanol by the sodium metal.In this solution, add under 0 ℃ the ethanoyl ethyl acetate (3.00g, 23.0mmol).After 30 minutes, (6.17g is 19.0mmol) at ethanol: toluene (30: the solution 15ml) and this reaction mixture stirred spend the night to add 1-(4-benzyloxy phenyl)-2-bromo-third-1-ketone in this solution.Carry out acidic treatment with 1MHCl,, use the salt water washing, dry (Na with ethyl acetate extraction (3x)
2SO
4), filter and evaporation obtains crude product by purification by flash chromatography (hexane: EtOAc 95: 5-70: 30) obtain this title compound of 5.18g, it is a light yellow oil.
Step D 5-(4-benzyloxy phenyl)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid
The solution of sodium ethylate is that (0.19g 8.26mmol) prepares in the 20ml absolute ethanol by the sodium metal.In this solution, add 2-[2-(4-benzyloxy phenyl)-2-oxo-ethyl]-(2.13g 6.00mmol) and with this reaction mixture at room temperature stirred 30 minutes 3-oxo-ethyl butyrate.((1.19g 7.30mmol) divides at 3ml 24%HCl and Sodium Nitrite (0.52g, 7.50mmol) 0 ℃ of preparation down in 3ml water) and adds for 5 times and holding temperature is lower than 5 ℃ by 2,4 dichloro aniline with the solution of previously prepared 2,4 dichloro benzene basic weight nitrogenize chlorine.Stir under the room temperature and add entry and EtOAc (3x) extraction of this product after 2.5 hours.Organic extract liquid drying (the Na that merges
2SO
4), filter and evaporation.Resistates be dissolved in ethanol (40ml) and add the sodium hydroxide be present in the 10ml water (0.80g, 20.0mmol).The boiling down that refluxes was cooled off this reaction mixture after 2 hours, extracted (3x) with HCl acidifying and this product with EtOAc.After the washing, dry (Na
2SO
4), filtering and concentrate, (hexane: EtOAc 70: 30-50: 50) obtain the title compound of 1.84g (68%), it is a yellow solid to resistates by purification by flash chromatography.
Step e 5-(4-benzyloxy phenyl)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid piperidines-1-base acid amides
With 5-(4-benzyloxy phenyl)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid (1.84g 4.07mmol) is suspended in the methylene dichloride and adds several DMF, add subsequently oxalyl chloride (1.03g, 8.14mmol).With this reaction mixture refluxed 2 hours.After being cooled to room temperature, except that desolvating and thick acyl chlorides being dissolved in methylene dichloride again and being cooled to 0 ℃.Add triethylamine (1.15ml, 8.20mmol), add subsequently the 1-amino piperidine (0.5ml, 4.50mmol).Remove cooling bath and this reaction mixture was at room temperature stirred 2 hours.Add entry and this product dichloromethane extraction (3x).Extract drying (the Na that merges
2SO
4), filter and evaporation.(hexane: EtOAc 80: 20-70: 30) obtain this title compound of 1.13g (52%), it is a solid to flash chromatography.
Step F 1-(2,4 dichloro benzene base)-5-(4-hydroxy phenyl-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid piperidines-1-base acid amides
With 5-(4-benzyloxy phenyl)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid piperidines-1-base acid amides (1.00g, 1.87mmol) be dissolved in 25ml contain 100mg carbon carry palladium (10%Pd) definitely in the ethanol.This reaction is spent the night with balloon hydrogenation.Filter, concentrate and flash chromatography (hexane: EtOAc 50: 50-EtOAc) obtain this title compound of 0.83g (100%), it is a solid.
Step G propane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl) 2H-pyrazole-3-yl-phenylester
1-(2,4 dichloro benzene base)-5-(4-hydroxy phenyl)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid piperidines-1-base acid amides (222mg, 0.50mmol) be dissolved in methylene dichloride (10ml) and adding triethylamine (0.07ml, 0.50mmol).Adding third SULPHURYL CHLORIDE under 0 ℃ (71mg 0.50mmol), removes cooling bath and this reaction and at room temperature stirred 2 hours. add entry and this product dichloromethane extraction, dry (Na
2SO
4), filter and concentrate.Flash chromatography (hexane: EtOAc 70: 30-50: 50) obtain product, with it by hexane: the EtOAc recrystallization obtains this title compound of 135mg (49%), and it is white solid m.p.190 ℃.
1H NMR (CDCl
3): δ 7.66 (1H, broad peak s), 7.44-7.17 (7H, m), 3.25 (2H, t), 2.90 (4H, m), 2.39 (3H, s), 2.09-1.97 (2H, m), 1.78 (4H, m), 1.45 (2H, m), 1.17 (3H, t) MS m/z 573 (M+Na)
Embodiment 2
1-(2,4 dichloro benzene base)-4-methyl-5-[4-(4,4,4-trifluoro butoxy)-phenyl]-1H-pyrazoles-3-carboxylic acid piperidines-1-base acid amides
To derive from Ex 1, the 1-(2 of step F, the 4-dichlorophenyl)-5-(4-hydroxy phenyl)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid piperidines-1-base acid amides (250mg, 0.56mmol) be dissolved in acetone (10ml) and add salt of wormwood (77mg, 0.56mmol), add 1-iodo-4,4 subsequently, 4-trifluoro butane (140mg, 0.56mmol).This reaction mixture seethe with excitement under refluxing spend the night, concentrate and (hexane: EtOAc 70: 30-60: 40) obtain the white solid of 130mg (42%), it uses hexane: EtOAc develops and filtration at 95: 5 by purification by flash chromatography.
1H NMR (CDCl
3): δ 7.63 (1H, broad peak s), 7.43 (1H, m), 7.30 (2H, m), 7.10-7.00 (2H, m), 6.85-6.78 (2H, m), 4.05 (2H, t), 2.90 (4H, m), 2.40-2.19 (SH, s and m), 2.15-1.97 (2H, m), 1.78 (4H, m), 1.45 (2H, m)
MS?m/z?577(M+Na).HPLC：98.4％
Embodiment 3
Butane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl]-phenylester
With Ex1,1-(2,4 dichloro benzene base)-5-(4-hydroxyl-phenyl)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid piperidines of step F preparation-1-base acid amides (350mg, 0.78mmol) be dissolved in methylene dichloride (10ml) and adding triethylamine (0.11ml, 0.78mmol).(0.12g 0.78mmol), removes cooling bath and carries should react under the room temperature to stir and spend the night to add the fourth SULPHURYL CHLORIDE under 0 ℃.Add entry, this product dichloromethane extraction, dry (Na
2SO
4), filter and concentrate.(hexane: EtOAc 70: 30-50: 50) obtain product, it is by hexane: the EtOAc recrystallization obtains this title compound of 200mg (45%) to flash chromatography, and it is a solid.
1H?NMR(CDCl
3)：δ7.48-7.19(8H，m)，3.29(2H，m)，2.96(4H，m)，2.41(3H，s)，2.09-1.97(2H，m)，1.81(4H，m)，1.64-1.50(4H，m)，1.02(3H，t)
Embodiment 4
Propane-1-sulfonic acid 4-r2-(2,4 dichloro benzene base)-4-methyl-5-(morpholine-4-base carbonyl)-2H-pyrazole-3-yl] phenylester
Steps A 5-(4-benzyloxy phenyl)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid morpholine-4-base acid amides
To Ex 1, step D preparation be present in 25ml CH
2Cl
2In 5-(4-benzyloxy phenyl)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid (1.18g 2.6mmol) adds 2 DMF, add subsequently oxalyl chloride (0.44ml, 5.2mmol).This mixture seethed with excitement 2 hours under refluxing, and was cooled to room temperature and was evaporated to dried.Resistates is dissolved in 25ml CH
2Cl
2Be cooled to 0 ℃.(0.73ml, 5.2mmol), (0.28ml 2.9mmol) at room temperature stirred 3 hours with this mixture to add the 1-amino piperidine subsequently to add triethylamine.Add entry (100ml) and this mixture CH
2Cl
2(3 * 50ml) extractions, dry (Na
2SO
4), filter and concentrate.(silica gel, hexane: EtOAc 1: 2 EtOAc) obtain this title compound of 215mg (15%) to flash chromatography, and it is a white solid.
Step B 1-(2,4 dichloro benzene base)-5-(4-hydroxy phenyl)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid morpholine-4-base acid amides
5-(4-benzyloxy phenyl)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid morpholine-(215mg 0.40mmol) is dissolved in 20ml CH to 4-base acid amides
2Cl
2Be cooled to 0 ℃.(78 μ l 0.80mmol) and with this reaction mixture at room temperature stirred 2.5 hours to drip boron tribromide.Add entry (50ml) and this solution and extract (3 * 50ml) with EtOAc.With the organic phase drying (Na that merges
2SO
4), filter and concentrate.(silica gel, hexane: EtOAc 1: 2 EtOAc) obtain this title compound of 180mg (99%) to flash chromatography, and it is a white solid.
Step C propane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(morpholine-4-base formamyl)-2H-pyrazole-3-yl]-phenylester
With 1-(2,4 dichloro benzene base)-5-(4-hydroxy phenyl)-4-methyl-IH-pyrazoles-3-carboxylic acid morpholine-(180mg is 0.40mmol) at 10ml CH for 4-base acid amides
2Cl
2In solution be cooled to 0 ℃.(561,0.40mmol), (45 μ l 0.40mmol) and with this reaction mixture at room temperature stirred 5 hours to add 1-propane SULPHURYL CHLORIDE subsequently to add triethylamine.Add entry and this mixture CH
2Cl
2(3 * 20ml) extractions, dry (Na
2SO
4), filter and concentrate.Flash chromatography (silica gel, hexane: EtOAc 1: 2) obtains this title compound of 82mg (46%), and it is a white solid.
1H?NMR(CDCl
3)：δ7.7(1H，s)，7.5-7.4(1H，m)，7.4-7.1(6H，m)，3.9-3.8(4H，m)，3.3-3.2(2H，m)，3.0-2.9(4H，m)，2.4(3H，s)，2.1-1.9(2H，m)，1.2(3H，t)。
MS?m/z?576(M+Na).HPLC：98.0％。
Embodiment 5
3,3,3-trifluoro propane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] phenylester
Steps A 1-(2,4 dichloro benzene base)-5-(4-hydroxy phenyl)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid piperidines-1-base acid amides
(330mg 0.62mmol) is dissolved in 20ml CH with the basic acid amides of 5-(4-benzyloxy phenyl)-1-(2,4 dichloro benzene the base)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid piperidines-1-of Ex.1 step e preparation
2Cl
2Be cooled to 0 ℃.(120 μ l 1.24mmol) and with this reaction mixture at room temperature stirred 1 hour to drip boron bromide.(3 * 20ml) extract with EtOAc to add entry (50ml) and this solution.Organic phase drying (the Na that merges
2SO
4), filter and concentrate.(silica gel, hexane: EtOAc 1: 3 EtOAc) obtain this title compound of 130mg (47%) to flash chromatography, and it is a white solid.
Step B 3,3,3-trifluoro propane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl phenylester
With 1-(2,4 dichloro benzene base)-5-(4-hydroxy phenyl)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid piperidines-1-base acid amides, (130mg is 0.30mmol) at 10ml CH
2Cl
2In solution be cooled to 0 ℃.Add triethylamine (42 μ l, 0.30mmol), add 3 subsequently, 3, and 3-trifluoro propane-1-SULPHURYL CHLORIDE (59mg, 0.30mmol), (but also can prepare 4 available from Manchester Organics in similar WO 200010968 described modes, 4,4-trifluoro butane-1-SULPHURYL CHLORIDE), and this reaction mixture at room temperature stirred 2 hours.Add entry and this mixture CH
2Cl
2Extraction (3 * 20ml), dry (Na
2SO
4), filter and concentrate.Flash chromatography (silica gel, hexane: EtOAc 7: 3,6: 4) obtains this title compound of 150mg (82%), and it is 160 ℃ of white solid m.p.
1H NMR (CDCl
3): δ 7.7 (1H, broad peak s), 7.5-7.2 (7H, m), 3.6-3.5 (2H, m), 3.0-2.7 (6H, m), 2.4 (3H, s), 1.9-1.7 (4H, m), 1.6-1.4 (2H, m).
MS?m/z?628(M+Na).HPLC：92.5％。
Embodiment 6
4,4,4-trifluoro butane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl (piperidines-1-base formamyl)-2H-pyrazole-3-yl] phenylester
1-(2 with the preparation of Ex 5 steps A, the 4-dichlorophenyl)-5-(4-hydroxy phenyl)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid piperidines-1-base acid amides (0.49g, 1.20mmol) be dissolved in methylene dichloride (20ml), be cooled to 0 ℃ and adding triethylamine (0.67ml, 4.8mmol), add subsequently according to 4,4 of WO 200010968 preparations, 4-trifluoro butane-1-SULPHURYL CHLORIDE (0.38g, 1.80mmol).This reaction mixture at room temperature stirred spend the night.Add entry, this product dichloromethane extraction, dry (Na
2SO
4), filtering and concentrate. (hexane: EtOAc 1: 1-EtOAc), (hexane: EtOAc) obtain this title compound of 0.32g (43%), it is a colorless solid to recrystallization to flash chromatography subsequently.
1H NMR (CDCl
3): δ 7.80 (1H, broad peak s), 7.50-7.19 (7H, m), 3.40 (2H, m), 3.05-2.90 (4H, m), 2.50-2.20 (7H, sand m), 1.92-1.70 (4H, m), 1.57-1.40 (2H, m).
MS?m/z?641(M+Na)HPLC：96.5％
Embodiment 7
Propane-1-sulfonic acid-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl]-2,6-difluorophenyl ester
Steps A 1-(4-benzyloxy-3,5-difluorophenyl)-propane-1-ketone
(5.00g 26.9mmol) is dissolved in and contains salt of wormwood (3.90g is in acetone 28.2mmol) (100ml) with 1-(3,5-two fluoro-4-hydroxy phenyls) propane-1-ketone.(4.82g seethes with excitement under refluxing 28.2mmol) and with this reaction mixture and to spend the night to add bromotoluene.Be cooled to this mixture of room temperature after-filtration and concentrate the title compound that obtains 7.43g (100%) on rotatory evaporator, it is a white solid.
Step B 1-[4-benzyloxy-3, the 5-difluorophenyl)-2-bromine third-1-ketone
(7.43g 26.9mmol) is suspended in acetate (35ml) to 1-(4-benzyloxy-3,5-difluorophenyl) propane-1-ketone.(4.28g, 26.8mmol) and will be under this reaction mixture room temperature stir 2 hours, this moment, this reaction mixture was clarification, yellow solution to dripping bromine.After the cooling, add frozen water (100ml) and this product extracted with diethyl ether (2 * 100ml).The organic extract liquid water, sodium hydrogen carbonate solution and the salt water washing that merge.Dry organic phase (Na
2SO
4), filtration and evaporation obtain the title compound of 9.30g (98%), and it is a light yellow oil.
Step C 2-ethanoyl-4-(4-benzyloxy-3,5-difluorophenyl)-3-methyl-4-ketobutyric acid ethyl ester
The solution of sodium ethylate is that (0.74g 32.0mmol) prepares in the 40ml absolute ethanol by the sodium metal.In this solution, add under 0 ℃ the ethanoyl ethyl acetate (4.16g, 32.0mmol).After 30 minutes, this solution is joined 1-(4-benzyloxy-3,5-difluorophenyl)-2-bromine third-1-ketone, and (9.30g is 26.2mmol) at ethanol: toluene (40: stir in the solution 20ml) and with this reaction mixture and spend the night.With 1M HCl acidic treatment, with ethyl acetate extraction (3x), use the salt water washing, dry (Na
2SO
4), filter and evaporation obtains crude product, (hexane: EtOAc 95: 5-70: 30) obtain the title compound of 6.95g (66%), it be oily by purification by flash chromatography.
Step D 5-(4-benzyloxy-3,5-difluorophenyl)-1-(2,4 dichloro benzene-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid
The solution of sodium ethylate is that (0.53g 22.0mmol) makes in the 60ml absolute ethanol by the sodium metal.(6.95g 17.2mmol) and with this reaction mixture at room temperature stirred 30 minutes to add 2-ethanoyl-4-(4-benzyloxy-3,5-difluorophenyl)-3-methyl-4-ketobutyric acid ethyl ester in this solution.With previously prepared 2,4-dichlorophenyl diazotization chlorine is (by 2, (3.39g, 21.0mmol) solution at 9ml 24%HCl and Sodium Nitrite 1. (48g 21.0mmol) makes under 0 ℃ in 3ml water) divides 5 addings and keeps temperature to be lower than 5 ℃ the 4-dichlorphenamide bulk powder.0 ℃ time stirring after 2 hours this reaction mixture is risen to room temperature and stirring is spent the night.Add entry, this product extracts (3x) with EtOAc.With the organic extract liquid drying (Na that merges
2SO
4), filtration and evaporation obtain the thick ethyl ester of 9.20g, and it is an oil.Resistates (9.20g) is dissolved in ethanol (120ml) and add the sodium hydroxide be present in the 15ml water (2.30g, 57.5mmol).The boiling down that refluxes was cooled off this reaction mixture after 2 hours, used the HCl acidifying, and this product extracts with EtOAc (3x).After the washing, dry (Na
2SO
4), filtering and concentrate, (hexane: EtOAc: AcOH80: 20: 2-hexane: EtOAc: AcOH 50: 50: 2) obtain the 5.46g title compound in (65%, 2 step), it is a solid to resistates by purification by flash chromatography.
Step e 5-(4-benzyloxy-3,5-difluorophenyl)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid piperidines-1-base acid amides
5-(4-benzyloxy-3,5-difluorophenyl)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid (5.46g 11.2mmol) is suspended in the methylene dichloride (60ml) and adds several DMF, add subsequently oxalyl chloride (4.70ml, 55.8mmol).This reaction mixture was seethed with excitement 1.5 hours under refluxing.Be cooled to remove after the room temperature and desolvate, thick acyl chlorides is dissolved in the methylene dichloride again, is cooled to 0 ℃, adds Et
3N (3.10ml, 22.2mmol), adding 1-amino piperidine (1.2ml, 11.2mmol).Remove cooling bath and this reaction mixture at room temperature stirred and spend the night.Add entry and this product dichloromethane extraction (3x), the extract drying (Na of merging
2SO
4), filter and evaporation.(hexane: EtOAc 80: 20-70: 30) obtain the title compound of 1.86g (30%), it is a yellow solid to flash chromatography.
Step F 5-(4-hydroxyl-3,5-difluorophenyl)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrazoles 3-carboxylic acid piperidines-1-base acid amides
(1.86g 3.25mmol) is dissolved in the methylene dichloride of 50ml and is cooled to-78 ℃ 5-(4-benzyloxy-3,5-difluorophenyl)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H pyrazoles-3-carboxylic acid piperidines-1-base acid amides.(0.60ml 6.50mmol) and with this reaction mixture stirred 30 minutes down at 0 ℃ slowly to add BBr3.Add entry and this product CH
2Cl
2Extraction (x3). the organic extract liquid drying (Na of merging
2SO
4), filter and concentrate.Flash chromatography (hexane: EtOAc 50: 50) obtains the title compound of 0.64g (41%), and it is a yellow solid.
Step G propane-1-sulfonic acid-[2-(2,4 dichloro benzene base)-4-methyl-5-(pyridine-1-base formamyl)-2H-pyrazole-3-yl]-2,6-difluorophenyl ester
With 5-(4-hydroxyl-3, the 5-difluorophenyl)-1-(2, the 4-dichlorophenyl)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid piperidines-1-base acid amides (0.64g, 1.32mmol) be dissolved in methylene dichloride (20ml), be cooled to 0 ℃ and triethylamine (0.18ml, 1.32mmol), add subsequently the propane SULPHURYL CHLORIDE (0.19g, 1.31mmol).This reaction mixture at room temperature stirred spend the night.Add entry, this product dichloromethane extraction, dry (Na
2SO
4), filter and concentrate.(hexane: EtOAc 70: 30-50: 50) obtain the title compound of 410mg (53%), it is a light yellow solid to flash chromatography.
1H NMR (CDCl
3): δ 7.66 (1H, broad peak s), 7.60-7.24 (4H, m), 6.97-6.78 (1H, m), 3.50-3.37 (2H, m), 3.02-2.80 (4H, m), 2.40 (3H, s), 2.20-2.00 (2H, m), 1.92-2.72 (4H, m), 1.60-1.40 (2H, m), 1.08 (3H, t).
MS?m/z?609(M+Na).HPLC：97.5％。
Embodiment 8
Propane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] phenylester
Steps A 4-(4-benzyloxy phenyl)-2,4-dioxo ethyl butyrate
(20g 88.4mmol) is dissolved in suspension among ether (150ml) and the THF (50ml) to added 1-(4-benzyloxy phenyl) ethane ketone in the solution of LiHMDS (88ml, 1M is in THF) in ether (50ml) in 1 hour under nitrogen and-78 ℃.The gained mixture-78 ℃ stirred 1 hour down and add subsequently oxalic acid diethyl ester (14.2g, 97.2mmol).The gained mixture slowly rises to room temperature and places subsequently and spend the night.This reaction mixture is precipitated as lithium salts with pentane (90ml) dilution and crude product.The solid of collecting (27.2g) is dry and be directly used in the step down under vacuum.
Step B 5-(4-benzyloxy phenyl)-1-(2,4 dichloro benzene base)-1H-pyrazoles-3-carboxylic acid, ethyl ester
With 4-(4-benzyloxy phenyl)-2,4-dioxo ethyl butyrate (27.2g is the Li salt in last step) be suspended in the ethanol (350ml) and add 2,4 dichloro benzene base hydrazine (17.8g, 83.3mmol).This reaction mixture at room temperature stirred spend the night.Except that desolvating and resistates being dissolved in acetate, the gained mixture refluxed 24 hours down in decompression subsequently.With this reaction mixture with ethyl acetate (1L) dilution and use saturated NaHCO subsequently
3(6 * 250ml) and salt solution (100ml) washing.With organic layer drying (MgSO
4), filter and the concentrated down oil that obtains of decompression.This oil is by purification by flash chromatography (SiO
2, 20%EtOAc is in heptane).This product cut under reduced pressure concentrates and residual substance further obtains white solid (19.6,57% 2 go on foot totally) by recrystallization purifying (ethyl acetate/heptane) subsequently.
1H-NMR(CDCl
3)：δ1.42(t，3H)，4.45(q，2H)，5.03(s，2H)，6.88(d，2H)，7.01(s，1H)，7.11(d，2H)，7.3-7.45(m，8H)。
MS：467(M+1)。
Step C 1-(2,4 dichloro benzene base)-5-(4-hydroxy phenyl)-1H-pyrazoles-3-carboxylic acid, ethyl ester
To 5-(4-benzyloxy phenyl)-1-(2, the 4-dichlorophenyl)-1H-pyrazoles-3-carboxylic acid, ethyl ester (735mg, 1.57mmol) and (CH3) 2S (0.58ml, 7.86mmol) under nitrogen, drip in the solution in methylene dichloride (30ml) BF3-Anaesthetie Ether compound (1.0ml, 7.86mmol).The gained miscellany at room temperature stirs and spends the night.(0.58ml, 7.86mmol) (1.0ml, 7.86mmol), the gained miscellany continues to stir 3 days with BF3-Anaesthetie Ether compound to add more (CH3) 2S.This reaction mixture is diluted to 80ml and water (3 * 30ml) and salt solution (40ml) washing with methylene fluoride.With organic layer drying (MgSO
4), filter and the concentrated down white solid (573mg, 96%) that obtains of decompression.Crude product directly uses.
1H-NMR(CDCl
3)：δ1.41(t，3H)，4.44(q，2H)，6.74(d，2H)，7.00(s，1H)，7.06(d，2H)，7.3-7.45(m，3H).MS：375(M-1)。
Step D 1-(2,4 dichloro benzene base)-5-[4-(propane-1-alkylsulfonyl oxygen base)-phenyl]-1H-pyrazoles-3-carboxylic acid ethyl ester
Under the nitrogen with 1-(2,4 dichloro benzene base)-5-(4-hydroxy phenyl)-1H-pyrazoles-3-carboxylic acid, ethyl ester (510mg, 1.35mmol) be suspended in the methylene dichloride (20ml) and add triethylamine (0.75ml, 5.4mmol).The gained miscellany be cooled to 0 ℃ or its drip 1-propane SULPHURYL CHLORIDE (0.30ml, 2.7mmol).This mixture stirred 1 hour down at 0 ℃.This reaction mixture is diluted to 40ml with methylene dichloride subsequently, uses saturated NaHCO subsequently
3(3 * 20ml) and salt solution (20ml) washing.With organic layer drying (MgSO
4), filter and the concentrated down oil (0.64g, 98%) that obtains of decompression.Crude product need not to be further purified and can use.
1H-NMR(CDCl
3)：δ1.12(t，3H)，1.43(t，3H)，2.01(m，2H)，3.23(m，2H)，4.46(q，2H)，7.07(s，1H)，7.19-7.46(m，7H)。
MS：483(M+1)。
Step e propane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] phenylester
(36mg 0.26mmol) is dissolved in toluene (1.0ml) with the 1-amido piperidine hydrochlorate under the nitrogen atmosphere.(2M is in toluene, 0.17ml) to drip trimethyl aluminium under the room temperature.The gained miscellany at room temperature stirred 40 minutes subsequently.This miscellany joins 1-(2 immediately; 4-two chloro-phenyl)-5-[4-(propane-1-alkylsulfonyl oxygen base) phenyl]-1H-pyrazoles-3-carboxylic acid, ethyl ester (42mg; 0.087mmol) in the stirred solution in DCM (1.0ml), and the gained miscellany is 60 ℃ of following heated overnight.This reaction is by adding the entry quencher and distributing between water (20ml) and DCM (20ml) subsequently.(3 * 10ml) washings, decompression subsequently concentrates down the organic layer water.Resistates is by the reversed-phase HPLC purifying, and the C8 post contains the water (damping fluid: the 0.1M ammonium acetate) of 5-100% second eyeball.This product cut is with the ethyl acetate dilution and wash several with water.The organic layer decompression concentrates down and the lyophilize resistates obtains white solid (26mg, 55%).
1H-NMR(CDCl
3)：1.11(t，3H)，1.43(m，2H)，1.76(m，4H)，2.00(m，2H)，2.85(m，4H)，3.22(m，2H)，7.11(m，1H)，7.20(m，4H)，7.37(m，2H)，7.49(m，1H)。
MS：537(M+1)。
Embodiment 9
Propane-1-sulfonic acid 4-[4-bromo-2-(2,4 dichloro benzene base (piperidines-1-base formamyl)-2H-pyrazole-3-yl] phenylester
Steps A 4-bromo-1-(2,4 dichloro benzene base)-5-[4-(propane-1-alkylsulfonyl oxygen base) phenyl]-1H-pyrazoles-3-carboxylic acid, ethyl ester
With Ex.8; the 1-(2 for preparing among the step D; the 4-dichlorophenyl)-5-[4-(propane-1-alkylsulfonyl oxygen base) phenyl]-1H-pyrazoles-3-carboxylic acid, ethyl ester (597mg; 1.23mmol) be dissolved in methylene dichloride (15ml) and be added in bromine (0.06ml in the methylene dichloride (1ml); 1.23mmol), the gained miscellany at room temperature stirs and spends the night.(0.06ml 1.23mmol) and with this mixture continues to stir 20 hours to add excessive bromine.This reaction mixture is diluted to 80ml with methylene dichloride, uses saturated NaHCO subsequently
3(40ml), 20%Na2S2O5 (40ml), saturated NaHCO
3(2 * 40ml) and salt solution (40ml) washing.With organic layer drying (MgSO
4), filter and the concentrated down orange oil (0.598,73%) that obtains of decompression.Crude product need not to be further purified and can use.
1H-NMR(CDCl
3)：δ1.12(t，3H)，1.44(t，3H)，2.01(m，2H)，3.24(m，2H)，4.48(q，2H)，7.2-7.46(m，7H).MS：561
Step B propane-1-sulfonic acid 4-[4-bromo-2-(2,4 dichloro benzene base)-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] phenylester
This compound is to be similar to the described mode of Ex.8 step e, to pass through 4-bromo-1-(2; the 4-dichlorophenyl)-5-[4-(propane-1-alkylsulfonyl oxygen base) phenyl]-1H-pyrazoles-3-carboxylic acid, ethyl ester and 1-amido piperidine hydrochlorate react and prepare this title compound of 26mg, and it is a white solid.Yield: 25%
1H-NMR (CDCl
3): 1.12 (t, 3H), 1.43 (m, 2H), 1.74 (m, 4H), 2.01 (m, 2H), 2.90 (m, 4H), 3.24 (m, 2H), 7.21-7.45 (m, 7H) MS:615.
Embodiment 10
1-{[(1-(2,4 dichloro benzene base)-4-methyl-5-{4[(sulfonyl propyl base) oxygen base] phenyl }-the 1H-pyrazole-3-yl) carbonyl] amino } cyclopentane carboxylic acid methyl
Steps A 1-aminocyclopentanecarboxylic acid methyl ester hydrochloride
With thionyl chloride (1.5ml) be dissolved in methyl alcohol (15ml) and impouring 1-aminocyclopentanecarboxylic acid (100mg, 0.774mmol).This mixture was refluxed 1 hour.Evaporating solvent obtains this product (107mg, 77%).
1H?NMR(399.964MHz)：δ9.00-8.60(br，3H)，3.79(s，3H)，2.23(s，4H)，2.14-2.00(m，2H)，1.90-1.76(m，2H)。
Step B 1-([5-[4-(benzyloxy) phenyl]-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrazole-3-yl] and carbonyl } amino) cyclopentane carboxylic acid methyl
With Ex.1, the 5-[4-benzyloxy of step D preparation) phenyl]-(59mg, 0.130mmol) solution in DCM (2ml) and the solution of oxalyl chloride (2ml) in DCM (20ml) are mixed for 1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid.Adding 1 DMF and this is reflected under room temperature and the no optical condition and carried out 1 hour.Evaporating solvent adds DCM (2ml) and the acyl chlorides miscellany is joined the 1-aminocyclopentanecarboxylic acid methyl ester hydrochloride that (23mg is 0.130mmol) at DCM (2ml) and K
2CO
3(aqueous solution, 10wt% is 2ml) in the miscellany in.This is reflected at room temperature and carried out 3 hours.Separate each phase and organic phase and wash and use MgSO with water
4Drying obtains product (71mg, 94%).
1H?NMR(399.964MHz)：δ7.43-7.23(m，9H)，7.06-7.00(m，2H)，6.93-6.87(m，2H)，5.02(s，2H)，3.75(s，3H)，2.40-2.30(m，2H)，2.34(s，3H)，2.14-2.04(m，2H)，1.87-1.77(m，4H)。
MS?m/z?578，580，582(M+H)+。
Step C 1-{[1-(2,4 dichloro benzene base)-5-(4-hydroxy phenyl)-4-methyl isophthalic acid H-pyrazole-3-yl] carbonyl } amino) cyclopentane carboxylic acid methyl
With boron trifluoride etherate (156 μ l, 1.23mmol) join 1-({ [5-[4-(benzyloxy) phenyl]-1-(2, the 4-dichlorophenyl)-and 4-methyl isophthalic acid H-pyrazole-3-yl] carbonyl } amino) cyclopentane carboxylic acid methyl (51mg, 0.088mmol) and dimethyl sulphide (90 μ l are 1.23mmol) in the miscellany in DCM (2ml).This is reflected under room temperature and the no optical condition and carried out 46 hours.Add entry and DCM, branch descriscent and organic phase wash and use MgSO with water
4Dry (39mg, 90%).
1H?NMR(399.964MHz)：δ7.60-6.60(m，8H)，3.72(s，3H)，2.43-2.23(m，2H)，2.26(s，3H)，2.15-2.00(m，2H)，1.85-1.75(m，4H)。
MS?m/z?488，490，492(M+H)+。
Step D 1-{[1-(2,4 dichloro benzene base)-4-methyl-5-{4[(sulfonyl propyl base) oxygen base] phenyl)-the 1H-pyrazole-3-yl] carbonyl } amino) cyclopentane carboxylic acid methyl
Under-78 ℃ with TEA (100 μ l) and 1-propane SULPHURYL CHLORIDE (30 μ l, 0.268mmol) join 1-{[1-(2, the 4-dichlorophenyl)-and 5-(4-hydroxy phenyl)-4-methyl isophthalic acid H-pyrazole-3-yl] carbonyl } amino) (39mg is 0.090mmol) in the miscellany in dry DCM (1.5ml) for cyclopentane carboxylic acid methyl.This is reflected at-78 ℃ and Na (gas) time and continues 1.5 hours.Add entry and DCM and make temperature rise to room temperature.Separate each phase and organic phase and wash and use MgSO with water
4Dry.Product by preparation HPLC purifying (Kromasil C8 post, ammonium acetate (aqueous solution, 0.1M): acetonitrile obtains product when 88% acetonitrile) obtains this product, it is near-white powder (17mg, 35%).
1H?NMR(399.964MHz)：δ7.45-7.39(br，1H)，7.32-7.28(m，2H)，7.27-7.19(m，3H)，7.18-7.12(m，2H)，3.76(s，3H)，3.26-3.20(m，2H)，2.40-2.30(m，2H)，2.35(s，3H)，2.15-2.05(m，2H)，2.05-1.95(m，2H)，1-88-1.78(m，4H)，1.12(t，3H)。
HRMS calculated value [C
27H
29Cl
2N
3O
6S+H]+: 594.123. measured value: 594.121.
Embodiment 11
Carbonic acid 4-[2-(2,4-two chloro-phenyl)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl-phenylester propyl diester
Carbonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl-2H-pyrazole-3-yl l-phenylester propyl diester
With Ex 1,1-(2,4-two chloro-phenyl)-5-(4-the hydroxy phenyl)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid piperidines of step F preparation-1-base acid amides (0.44g, 1.00mmol) be dissolved in methylene dichloride (10ml) and add triethylamine (0.28ml, 2.24mmol).0 ℃ adds down propyl chloroformate (0.14ml, 1.24mmol) and should react stirring 40 minutes, concentrated and this product is by purification by flash chromatography (hexane: EtOAc 70: 30-50: 50) obtain the title compound of 345mg (65%).HPLC is further purified the title compound that obtains 239mg by preparation.
1H?NMR(CDCl
3)：δ7.71-7.18(8H，m)，4.24(2H，t)，2.93(4H，m)，2.40(3H，s)，1.78(6H，m)，1.46(2H，m)，1.03(3H，t)
MS?m/z?553(M+Na)
HPLC：94.15
Embodiment 12
4-(2,4 dichloro benzene base)-4-methyl-3-[(piperidines-1-base is amino) carbonyl]-1H-pyrazoles-5-yl } phenyl thiophene-2-sulphonate
Will be at-78 ℃ and N2 (g) time at the thiophene among the DCM (2.5ml)-2-SULPHURYL CHLORIDE (433mg, 2.37mmol) join Ex 1, the 1-(2 of step F preparation, the 4-dichlorophenyl)-5-(4-hydroxy phenyl)-4-methyl-N-piperidines-1-base-1H-pyrazole-3-carboxamide (200mg, 0.45mmol) and TEA (0.5ml is 3.59mmol) in the miscellany in DCM (2.5ml).This is reflected at-78 ℃ and continues 2 hours down, continues 19 hours in room temperature subsequently.Add entry and separate each phase.Organic phase washes and uses MgSO with water
4Dry.This product is further purified by preparation HPLC that (the kromasilC8 post, ammonium acetate (aqueous solution, 0.1M): acetonitrile obtains product when 100% acetonitrile) obtains near-white powder (158mg, 60%).
1H?NMR(399.964MHz)δ7.71-7.67(m，1H)，7.67-7.57(br，1H)，7.50-7.46(m，1H)，7.35(s，1H)，7.25(s，2H)，7.07-7.00(m，3H)，6.98-6.92(m，2H)，2.86-2.76(m，4H)，2.29(s，3H)，1.73-1.65(m，4H)，1.42-1.33(m，2H)。
HRMS calculated value [C
26H
24Cl
2N
4O
4S
2+ H]+: 591.069. measured value: 591.067.
Embodiment 13:
: 4-{1-(2,4 dichloro benzene base)-4-methyl-3-[(piperidines-1-base is amino) carbonyl]-1H-pyrazoles-5-yl } phenylpyridine-3-sulphonate hydrochloride
Steps A: 4-{-(2,4 dichloro benzene base)-4-methyl-3-[(piperidines-1-base is amino) carbonyl]-1H-pyrazoles-5-yl } phenylpyridine-3-sulphonate
Under-78 ℃ and the N2 (gas) with pyridine-3-SULPHURYL CHLORIDE (144mg, 0.67mmol) suspension in DCM (10ml) joins Ex 1, the 1-(2 of step F preparation, the 4-dichlorophenyl)-5-(4-hydroxy phenyl)-4-methyl-N-piperidines-1-base-1H-pyrazole-3-carboxamide (200mg, 0.45mmol) and TEA (0.5ml is 3.59mmol) in the miscellany in DCM (2.5ml).This is reflected at-78 ℃ and continued 1.5 hours down and at room temperature lasting 30 minutes subsequently.Add entry and separate each phase.Organic phase washes and uses MgSO with water
4Dry.This product is further by purification by flash chromatography (SiO
2, toluene: ethyl acetate obtains product when 42% ethyl acetate) and obtain near-white powder (216mg, 82%).
1H?NMR(399.964MHz)δ8.95-8.85(m，2H)，8.10-8.04(m，1H)，7.64(s，1H)，7.50-7.45(m，1H)，7.44-7.40(m，1H)，7.34-7.24(m，2H)，7.09-7.04(m，2H)，7.00-6.95(m，2H)，2.88-2.78(m，4H)，2.33(s，3H)，1.78-1.68(m，4H)，1.46-1.36(m，2H)。
HRMS calculated value [C
27H
25Cl
2N
5O
4S+H]+: 586.108. measured value: 586.111.
Step B:4-{1-(2,4 dichloro benzene base)-4-methyl-3-[(piperidines-1-base is amino) carbonyl]-1H-pyrazoles-5-yl } phenylpyridine-3-sulphonate hydrochloride
With 4-{1-(2, the 4-dichlorophenyl)-4-methyl-3-[(piperidines-1-base is amino) carbonyl]-1H-pyrazoles-5-yl } phenylpyridine-3-sulphonate (150mg, 0.26mmol) be dissolved in the acetic acid solution (10ml) of 0.1M HCl and lyophilize obtains salt, it is white powder (159mg, 99.8%).
Embodiment 14
[2-(4-{1-(2,4 dichloro benzene base)-4-methyl-3-[(piperidines-1-base is amino) carbonyl]-1H-pyrazoles-5-yl } phenoxy group) ethyl] t-butyl carbamate
Steps A: ethyl (2-hydroxyethyl) carboxylamine tertiary butyl ester
Will (3.19g, (1.00g 11.2mmol) and at room temperature reacts 3 hours 14.6mmol) to join 2-(ethylamino) ethanol at the tert-Butyl dicarbonate among the THF (10ml).Decompression evaporating solvent down obtains crude product (2.28g).
1H?NMR(499.961MHz)δ3.71-3.65(br，2H)，3.55-3.35(br，1H)，3.35-3.30(br，2H)，3.30-3.20(br，2H)，1.43(s，9H)，1.07(t，3H)。
Step B:[2-(4-{1-(2,4 dichloro benzene base)-4-methyl-3-[(piperidines-1-base is amino) carbonyl]-pyrazoles-5-yl } phenoxy group) ethyl] the carboxylamine tertiary butyl ester
With Ex 1, the 1-(2 of step F preparation, the 4-dichlorophenyl)-5-(4-hydroxy phenyl)-4-methyl-N-piperidines-1-base-1H-pyrazole-3-carboxamide (151.6mg, 0.34mmol) and ethyl (2-hydroxyethyl) t-butyl carbamate (408.6mg, 1.73mmol) the mixed and reaction under 180 ℃ in the single-unit microwave oven repeatedly with toluene (lml).Total reaction time is 2 hours.Cyano group methylene tri-N-butyl phosphine added before each heating (total amount is 925mg, 3.83mmol).Evaporating solvent and this product are by preparation HPLC purifying (kromasil C8 post, ammonium acetate (aq, 0.1M): acetonitrile obtains product when 100% acetonitrile) and flash chromatography (SiO
2, toluene: ethyl acetate obtains product under 30% ethyl acetate) and obtain near-white powder (125mg, 60%).
1H?NMR(399.964MHz)δ7.62(s，1H).7.37(s，1H)，7.23(s，2H)，7.01-6.95(m，2H)，6.81-6.75(m，2H)，4.05-3.95(br，2H)，3.55-3.45(br，2H)，3.35-3.25(br，2H)，2.86-2.78(br，4H)，2.32(s，3H)，1.75-1.65(m，4H)，1.41(s，9H)，1.45-1.35(m，2H)，1.08(t，3H)。
MS?m/z?616，618，620(M+H)+。
Embodiment 15
1-(2,4 dichloro benzene base)-5-{4-[2-(ethylamino) oxyethyl group] phenyl }-4-methyl-N-piperidines-1-base-1H-pyrazole-3-carboxamide dihydrochloride
Will be at the thionyl chloride (1ml in the methyl alcohol (10ml), 13.71mmol) join and derive from Ex 14, step B [(4-{1-(2 for 2-, the 4-dichlorophenyl)-4-methyl-3-[(piperidines-1-base is amino) carbonyl]-1H-pyrazoles-5-yl } phenoxy group) ethyl] (137mg is 0.22mmol) in the suspension in methyl alcohol (2ml) for the ethyl carbamic acid tertiary butyl ester.2.5 evaporating solvent and this product lyophilize after hour.This compound is by preparation HPLC purifying (kromasil C8 post, ammonium acetate (aqueous solution, 0.1M): acetonitrile obtains product when 72% acetonitrile), lyophilize and be dissolved in the acetic acid solution (15ml) of 0.1M HCl at last and once more lyophilize obtain near-white powder (53mg, 40%).
1H?NMR(399.964MHz)δ7.54-7.47(m，2H)，7.44-7.39(m，1H)，7.19-7.14(m，2H)，7.01-6.96(m，2H)，4.24(t，2H)，3.41(t，2H)，3.18-3.06(m，6H)，2.27(s，3H)，1.87-1.78(m，4H)，1.57-1.48(m，2H)，1.32(t，3H)。
HRMS calculated value [C
26H
31Cl
2N
5O
2+ H]+: 516.193. measured value: 516.195.
Embodiment 16
4-1-(2,4 dichloro benzene base)-4-methyl-3-[(piperidines-1-base is amino) carbonyl]-1H-pyrazoles-5-yl } phenyl 3-methylbutane-1-sulphonate
-78 ℃ and N2 (gas) time will be at (the 84mg of the 3-methylbutane-1-SULPHURYL CHLORIDE among the DCM (2ml), 0.49mmol) join embodiment 1, the 1-(2 of step F preparation, the 4-dichlorophenyl)-5-(4-hydroxy phenyl)-4-methyl-N-piperidines-1-base-1H-pyrazole-3-carboxamide (100mg, 0.23mmol) and TEA (0.5ml is 3.59mmol) in the miscellany in DCM (2ml).This is reflected at-78 ℃ and continues 1 hour down.Add entry and separate each phase.Organic phase washes and uses MgSO with water
4Dry.Further (kromasil C8 post, ammonium acetate (aq, 0.1M): acetonitrile, the product output is in 100% acetonitrile) obtains near-white powder (94mg, 72%) to this product by preparation HPLC purifying.
1H?NMR(399.964MHz)δ7.85-7.45(br，1H)，7.38(s，1H)，7.29-7.25(m，2H)，7.23-7.18(m，2H)，7.16-7.11(m，2H)，3.25-3.18(m，2H)，2.88-2.80(m，4H)，2.33(s，3H)，1.86-1.77(m，2H)，1.76-1.65(m，5H)，1.45-1.34(m，2H)，0.92(d，6H)。
HRMS calculated value [C
27H
32Cl
2N
4O
4S+H]+: 579.160. measured value: 579.159.
Embodiment 17
4-{1-(2,4 dichloro benzene base)-4-methyl-3-[(piperidines-1-base is amino) carbonyl]-1H-pyrazoles-5-yl } phenyl 3,3-dimethylbutane-1-sulphonate
-78 ℃ and N2 (gas) down will be in DCM (2ml) 3,3-dimethylbutane-1-SULPHURYL CHLORIDE (59mg, 0.32mmol) join the 1-(2 of embodiment 1 step F preparation, the 4-dichlorophenyl)-5-(4-hydroxy phenyl)-4-methyl-N-piperidines-1-base-1H-pyrazole-3-carboxamide (103mg, 0.23mmol) and TEA (0.5ml is 3.59mmol) in the miscellany in DCM (2ml).This is reflected at-78 ℃ and continues 1 hour down.Add entry and separate each phase.Organic phase washes and uses MgSO with water
4Dry.Further (kromasil C8 post, ammonium acetate (aq, 0.1M): acetonitrile, the product output is in 100% acetonitrile) obtains near-white powder (94mg, 68%) to this product by preparation HPLC purifying.
1H?NMR(399.964MHz)δ8.20-7.40(br，1H)，7.36(s，1H)，7.28-7.22(m，2H)，7.21-7.16(m，2H)，7.15-7.09(m，2H)，3.20-3.13(m，2H)，2.87-2.80(m，4H)，2.31(s，3H)，1.83-1.76(m，2H)，1.73-1.65(m，4H)，1.43-1.32(m，2H)，0.89(s，9H)。
HRMS calculated value [C
28H
34Cl
2N
4O
4S+H]+: 593.176. measured value: 593.176.
Embodiment 18
4-[1-(2,4 dichloro benzene base)-4-methyl-3-({ [5-(trifluoromethyl) pyridine-2-yl] amino } carbonyl)-1H-pyrazoles-5-yl] phenyl 3,3,3-trifluoro propane-1-sulphonate
Steps A: 5-[4-(benzyloxy) phenyl]-1-(2,4 dichloro benzene base)-4-methyl-N-[5-(5-flumethiazine-2-yl]-the 1H-pyrazole-3-carboxamide
To join 5-[4-(benzyloxy) phenyl of embodiment 1 step D preparation at the oxalyl chloride (1ml) among the DCM (4ml)]-(202mg is 0.45mmol) in the suspension in DCM (4ml) for 1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid.Adding 1 DMF and this is reflected at room temperature and continues 1 hour.Decompression is down removed DCM and excessive oxalyl chloride, is suspended in acyl chlorides among the DCM (4ml) and joins at DCM/K
2CO
3(10%, aq) (1/1,8ml) 5-in (trifluoromethyl) pyridine-2-amine (87.6mg, 0.54mmol).This reaction at room temperature continue 24 hours, added 50mg DMAP and this reaction at room temperature lasting 1 hour subsequently.Separate each phase and organic phase and wash and use MgSO with water
4Dry.This product is further by purification by flash chromatography (SiO
2, toluene) and (108mg, 41%).
1H?NMR(399.964MHz)δ9.66(s，1H)，8.58-8.48(m，2H)，7.95-7.90(m，1H)，7.44-7.14(m，8H)，7.10-7.04(m，2H)，6.94-6.90(m，2H)，5.02(s，2H)，2.42(s，3H)。
MS?m/z?597，599，601(M+H)+。
Step B:1-(2,4 dichloro benzene base)-5-(4-hydroxy phenyl)-4-methyl-N-[5-(5-flumethiazine)-2-yl]-the 1H-pyrazole-3-carboxamide
With 5-[4-(benzyloxy) phenyl]-1-(2, the 4-dichlorophenyl)-4-methyl-N-[5-(trifluoromethyl) pyridine-2-yl]-(108mg 0.18mmol) is suspended in the acetic acid solution (10ml) of 4.1M HBr and at room temperature reacting 6 hours to the 1H-pyrazole-3-carboxamide.Adding ethanol (95%, 75ml) with the evaporating solvent down that reduces pressure.Add methyl alcohol and this product NaHCO
3(1M, aq) neutralization.Evaporating solvent and this mixture is dissolved in DCM and the water.Separate each phase and organic phase and wash and use MgSO with water
4Dry (87mg, 95%).
1H?NMR(399.964MHz)δ9.64(s，1H)，8.58-8.48(m，2H)，7.97-7.91(m，1H)，7.45-7.41(m，1H)，7.32-7.23(m，2H)，7.03-6.98(m，2H)，6.80-6.75(m，2H)，5.50-5.30(br，1H)，2.40(s，3H)。
MS?m/z?507，509，511(M+H)+。
Step C:4-[1-(2,4 dichloro benzene base)-4-methyl-3-({ [5-(trifluoromethyl) pyridine-2-yl] amino } carbonyl)-1H-pyrazoles-5-yl] phenyl
Under-78 ℃ and N2 (gas) with 3,3,3-trifluoro propane-1-sulphonate 3,3,3-trifluoro propane-1-SULPHURYL CHLORIDE (105mg 0.53mmol) joins 1-(2,4 dichloro benzene base)-5-(4-hydroxy phenyl)-4-methyl-N-[5-(trifluoromethyl) pyridine-2-yl]-1H-pyrazoles-3-Carboxylamide (87mg, 0.17mmol) and TEA (0.5ml is 3.59mmol) in the miscellany in DCM (3ml).This is reflected at-78 ℃ and continued 2 hours down and subsequently in ambient temperature overnight.Add entry and separate each phase.Organic phase washes and uses MgSO with water
4Dry.Further (kromasil C8 post, ammonium acetate (aqueous solution, 0.1M): acetonitrile, the product output is in 100% acetonitrile) obtains near-white powder (86mg, 75%) to this product by preparation HPLC purifying.
1H?NMR(399.964MHz)δ9.70(s，1H)，8.57-8.48(m，2H)，7.99-7.92(m，1H)，7.43(s，1H)，7.32(s，2H)，7.28-7.19(m，4H)，3.53-3.44(m，2H)，2.85-2.71(m，2H)，2.42(s，3H)。
HRMS calculated value [C
26H
28Cl
2F
6N
4O
4S+H]+: 667.041. measured value: 667.031.
Embodiment 19
1-(2,4 dichloro benzene base)-5-{4-[2-(1,3-dioxolane-2-yl) oxyethyl group] phenyl }-4-methyl-N-piperidines-1-base-1H-pyrazole-3-carboxamide
With 2-(2-bromotrifluoromethane)-1,3-dioxolane (60mg, 0.33mmol), Ex.1, the 1-(2 of step F preparation, the 4-dichlorophenyl)-5-(4-hydroxy phenyl)-4-methyl-N-piperidines-1-base-1H-pyrazole-3-carboxamide (100mg, 0.22mmol) and salt of wormwood (150mg 1.09mmol) refluxed in acetonitrile (25ml) 15 hours.Evaporating solvent adds entry and DCM, separates each mutually and organic phase washes with water and drying (MgSO
4).Further (kromasil C8 post, ammonium acetate (aqueous solution, 0.1M): acetonitrile, the product output is in 100% acetonitrile) obtains near-white powder (60mg, 49%) to this product by preparation HPLC purifying.
1H?NMR(399.964MHz)δ7.80-7.50(br，1H)，7.36(s，1H)，7.21(s，2H)，7.00-6.94(m，2H)，6.80-6.74(m，2H)，5.02(t，1H)，4.04(t，2H)，3.96-3.78(m，4H)，2.86-2.78(m，4H)，2.30(s，3H)，2.09(q，2H)，1.74-1.65(m，4H)，1.42-1.32(m，2H)。
HRMS calculated value [C
27H
30Cl
2N
4O
4+ H]+: 545.172. measured value: 545.172.
Embodiment 20
Propane-1-sulfonic acid 4-[2-(2,4-two chloro-3-fluorophenyls)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] phenylester
Steps A: 1-(2,4-two chloro-3-fluorophenyls)-5-(4-p-methoxy-phenyl)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid
The solution of sodium ethylate is that (0.18g 7.89mmol) prepares in the 20ml absolute ethanol by the sodium metal.(1.73g 5.92mmol) and with this reaction mixture at room temperature stirred 30 minutes to add 2-ethanoyl-4-(4-methoxyl group-phenyl)-3-methyl-4-oxo-ethyl butyrate in this solution.Previously prepared 2,4-two chloro-3-fluorine diazotization chlorine are (by 2,4-two chloro-3-fluoroanilines (1.30g, 7.22mmol) in 3ml 24%HCl and the solution of Sodium Nitrite (0.51g, 7.39mmol) in 3.5ml water in 0 ℃ of down preparation) divide and add and keep temperature 5 times and be lower than 5 ℃.Stir after 2.5 hours under the room temperature and add entry, EtOAc (3x) extraction of this product.With the organic extract liquid drying (Na that merges
2SO
4), filter and evaporation.Resistates be dissolved in ethanol (40ml) and be added in sodium hydroxide in the 5ml water (1.00g, 25.0mmol).Boiling with this reaction mixture cooling, extracted with EtOAc (3x) with HCl acidifying and this product after 2 hours under refluxing.After the washing, dry (Na
2SO
4), filtering and concentrate, (hexane: EtOAc 70: 30-50: 50) obtain the title compound of 1.37g (31%), it is light brown solid to resistates by purification by flash chromatography.
Step B:1-(2,4-two chloro-3-fluoro-phenyl)-5-(4-methoxyl group-phenyl)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid piperidines-1-base acid amides
With 1-(2,4-two chloro-3-fluoro-phenyl)-5-(4-methoxyl group-phenyl)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid (1.37g 3.43mmol) is suspended in the methylene dichloride (20ml) and adds several DMF, add subsequently oxalyl chloride (0.87g, 6.86mmol).With this reaction mixture refluxed 2 hours.Be cooled to remove after the room temperature and desolvate and should be dissolved in methylene dichloride (20ml) again by thick acyl chlorides, be cooled to 0 ℃, adding Et
3N (0.96ml, 6.94mmol), add subsequently the 1-amino piperidine (0.37ml, 3.62mmol).Remove cooling bath and with this reaction mixture in stirred overnight at room temperature.Add entry and this product with dichloromethane extraction (3x), with the extract drying (Na that merges
2SO
4), filtering and evaporation. flash chromatography (hexane: EtOAc 50: 50) obtains the title compound of 0.79g (48%), and it is light brown solid.
Step C:1-(2,4-two chloro-3-fluoro-phenyl)-5-(4-hydroxyl-phenyl)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid piperidines-1-base acid amides
(0.79g 1.66mmol) is dissolved in the methylene fluoride of 40ml with 1-(2,4-two chloro-3-fluoro-phenyl)-5-(4-methoxyl group-phenyl)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid piperidines-1-base acid amides under 0 ℃.(0.32ml 3.31mmol), removes and continues under cooling bath and the room temperature to stir 2 hours, afterwards impouring ice-water and extract with DCM (x3) to add boron bromide.With the extraction liquid drying (Na that merges
2SO
4), filter and concentrate.Flash chromatography (EtOAc) obtains the title compound of 0.36g (47%), and it is a colorless solid.
Step D: propane-1-sulfonic acid 4-[2-(2,4-two chloro-3-fluoro-phenyl)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl]-phenylester
To 1-(2,4-two chloro-3-fluoro-phenyl)-5-(4-hydroxyl-phenyl)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid piperidines-1-base acid amides (0.36g, 0.78mmol) (0.22ml 1.56mmol) and with this reaction mixture is cooled to 0 ℃ to add triethylamine in the solution in methylene dichloride (10ml).(0.22g 1.56mmol), removes cooling bath and this reaction mixture was stirred 2 hours under rt to add 1-propane SULPHURYL CHLORIDE.Add entry, this product extracts with DCM (x2), and the organic extract liquid of merging washes with water, dry (Na
2SO
4), filter and concentrate.(hexane: the EtOAc gradient) obtain the title compound of 100mg (23%), it is a colorless solid to flash chromatography.HPLC 80% purity.Preparation HPLC obtains this title compound of 40mg.
1H?NMR(CDCl
3)：δ7.50-7.20(7H，m)，3.57-3.23(6H，m)，2.37(3H，s)，2.10-1.80(6H，m)，1.70-1.50(2H，m)，1.10(3H，t)
MS：591(M+Na)HPLC：97.1％
Embodiment 21
5-chlorothiophene-2-sulfonic acid 4-[2-(2,4 difluorobenzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] phenylester
Under the nitrogen atmosphere with Ex 1, the 1-(2 of step F preparation, 4-two chloro-phenyl)-(100mg 0.22mmol) is dissolved in dry methylene chloride (3ml) and adding triethylamine (0.09ml) to 5-(4-hydroxyl-phenyl)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid piperidines-1-base acid amides.Add the 5-chlorothiophene-2-SULPHURYL CHLORIDE be dissolved in the dry methylene chloride (2ml) (0.54mg, 0.24mmol).This reaction mixture is at room temperature stirred weekend.This reaction mixture is diluted to 20ml and water (2 * 5ml) and salt solution (5ml) washing subsequently with methylene fluoride.The organic layer decompression concentrates down and obtains oil.Crude product passes through the reversed-phase HPLC purifying, Kromasil C8, and 5-100%MeCN is in the water that contains the 0.1M ammonium acetate.This product cut under reduced pressure concentrates and resistates is dissolved in methylene dichloride and water and salt water washing.Organic layer drying (MgSO
4), filtration and decompression concentrate down and obtain this title compound, and it is a yellow solid.
1H-NMR(CDCl
3)：δ1.42-1.50(m，2H)，1.73-1.81(m，4H)，2.39(s，3H)，2.84-2.92(m，4H)，6.95(d，1H)，7.04-7.14(m，4H)，7.30-7.36(m，3H)，7.44(d，1H)，7.63(s，1H)。
MS:625 (M+1) .HPLC:＞99% purity.
Claims (14)
1. the compound of formula (I)
And pharmaceutically acceptable salt, wherein
R
1The C that expression a) is replaced by one or more following groups
1-3Alkoxyl group i) ii) group NR of fluorine
cR
d, R wherein
cAnd R
dRepresent H independently, C
1-6Alkyl or C
1-6Alkoxy carbonyl, condition are R
cAnd R
dOne of be not H or iii) 1,3-dioxolane-2-base; B) R
1The C that expression is randomly replaced by one or more following groups
4-6Alkoxyl group i) ii) group NR of fluorine
cR
d, R wherein
cAnd R
dRepresent H independently, C
1-6Alkyl or C
2-6Alkoxy carbonyl, condition are R
cAnd R
dOne of be not H or iii) 1,3-dioxolane-2-base; C) formula phenyl (CH
2)
pThe group of O-, wherein p be 1,2 or 3 and the group randomly represented by 1,2 or 3 Z of phenyl ring replace; D) R
5S (O)
2O or R
5S (O)
2NH, wherein R
5The C that expression is randomly replaced by one or more fluorine
1-6Alkyl, or R
5Optional phenyl or the heteroaryl that replaces of group that expression is represented by 1,2 or 3 Z respectively; E) formula (R
6)
3The group of Si, wherein R
6Expression C
1-6Alkyl, its identical or different or f) formula R
bThe group of O (CO) O, wherein R
bThe C that expression is randomly replaced by one or more fluorine
1-6Alkyl;
R
aThe expression halogen, C
1-3Alkyl or C
1-3Alkoxyl group;
M is 0,1,2 or 3;
R
2Expression C
1-3Alkyl, C
1-3Alkoxyl group, hydroxyl, nitro, cyano group or halogen;
N is 0,1,2 or 3;
R
3Expression is radicals X-Y-NR a)
7R
8, wherein X is CO or SO
2, Y does not exist or represents randomly by C
1-3The NH that alkyl replaces; And R
7And R
8Expression independently: chosen wantonly the C that replaces by the group that 1,2 or 3 W represents
1-6Alkyl;
Randomly the group of being represented by 1,2 or 3 W is chosen the (C that replaces wantonly
3-15Cycloalkyl) C
1-3Alkylidene group;
-(CH
2)
r(phenyl)
s, wherein r is 0,1,2,3 or 4, and s is 1 otherwise s is 1 or 2 when r is 0
And the independent group of randomly being represented by 1,2 or 3 Z of phenyl replaces;
Contain a nitrogen and randomly contain one of following saturated 5-8 element heterocycle group: oxygen, sulphur or additional nitrogen, wherein this heterocyclic group is randomly by one or more C
1-3Alkyl, hydroxyl or benzyl replace;
-(CH
2)
tHet, wherein t is 0,1,2,3 or 4 and this alkylidene chain randomly by one or more C
1-3Alkyl replaces and Het represents randomly to be selected from C by 1,2 or 3
1-5Alkyl, C
1-5The aromatic heterocycle that alkoxy or halogen replaces, wherein this alkyl and alkoxyl group are independent is randomly replaced by one or more fluorine;
Or R
7Expression H and R
8Definition as above;
Or R
7And R
8Represent saturated or the unsaturated 5-8 element heterocycle of part group with the nitrogen-atoms that it connected, this heterocyclic group contains a nitrogen and randomly contains one of following: oxygen, sulphur or additional nitrogen; Wherein this heterocyclic group is randomly by one or more C
1-3Alkyl, hydroxyl, fluorine or benzyl replace;
Or b) azoles base, different azoles base, thiazolyl, isothiazolyl, the di azoly, thiadiazolyl group, pyrryl, pyrazolyl, imidazolyl, triazolyl, tetrazyl, thienyl, furyl or azoles quinoline base are randomly replaced by 1,2 or 3 group Z separately;
R
4Expression H, halogen, hydroxyl, cyano group, C
1-6Alkyl, C
1-6Alkoxyl group or C
1-6Alkoxy C
1-6Alkylidene group wherein contains maximum 6 carbon atoms, and each group is randomly replaced by one or more fluorine or cyano group;
Z represents C
1-3Alkyl, C
1-3Alkoxyl group, hydroxyl, halogen, trifluoromethyl, trifluoromethylthio, difluoro-methoxy, trifluoromethoxy, trifluoromethyl sulfonyl, nitro, amino, one or two C
1-3Alkylamino, C
1-3Alkyl sulphonyl, C
1-3Alkoxy carbonyl, carboxyl, cyano group, formamyl, one or two C
1-3Alkyl-carbamoyl and ethanoyl; With
W represents hydroxyl, fluorine, C
1-3Alkyl, C
1-3Alkoxyl group, amino, one or two C
1-3Alkylamino, C
1-6Alkoxy carbonyl or heterocyclic amine are selected from morpholinyl, pyrrolidyl, and piperidyl or piperazinyl, wherein heterocyclic amine is randomly by C
1-3Alkyl or hydroxyl replace; But do not comprise [the 2-[4-[3-[(ethylmethylamino) carbonyl]-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group] ethyl] carboxylamine 1,1-dimethyl ethyl ester and [2-[4-[1-(4-p-methoxy-phenyl)-3-(piperidino carbonyl)-1H-pyrazoles-5-yl] phenoxy group] ethyl] carboxylamine 1,1-dimethyl ethyl ester.
2. the compound of claim 1, wherein R
3The group that expression as above-mentioned paragraph a) define.
3. the compound of claim 1 is shown in IA
R wherein
1Be
A) by the optional C that replaces of one or more fluorine
4-6Alkoxyl group, b) formula phenyl (CH
2)
pThe group of O-, wherein p be 1,2 or 3 and the group randomly represented by 1,2 or 3 Z of this phenyl ring replace c) radicals R
5S (O)
2O or R
5S (O)
2NH, wherein R
5Expression is by the optional C that replaces of one or more fluorine
1-6Alkyl, or R
5Expression phenyl or heteroaryl, its group of randomly being represented by 1,2 or 3 Z separately replaces, and wherein Z defines as above, d) (R
6)
3The group of Si, wherein R
6Expression C
1-6Alkyl its can be identical or different, or e) formula R
bThe group of O (CO) O, wherein R
bExpression is by the optional C that replaces of one or more fluorine
1-6Alkyl;
R
aExpression halogen and m are 0,1 or 2;
R
2aExpression chlorine;
R
2bExpression chlorine;
R
2cExpression H or fluorine;
R
3Expression group CONHNR
7R
8, NR wherein
7R
8Expression piperidino-(1-position only) or morpholino or R
3Expression group CONHR
8, R wherein
8Expression is randomly by C
1-6The C that alkoxy carbonyl replaces
5-7Cycloalkyl or R
8The optional pyridyl that replaces of expression; With
R
4Expression H, C
1-3Alkyl or halogen.
4. the compound of claim 1 is shown in IB
R wherein
1Be
A) by the optional C that replaces of one or more fluorine
4-6Alkoxyl group, b) formula phenyl (CH
2)
pThe group of O-, wherein p be 1,2 or 3 and the group randomly represented by 1,2 or 3 Z of this phenyl ring replace c) radicals R
5S (O)
2O or R
5S (O)
2NH, wherein R
5Expression is by the optional C that replaces of one or more fluorine
1-6Alkyl, or R
5Expression phenyl or heteroaryl, its group of randomly being represented by 1,2 or 3 Z separately replaces or d) (R
6)
3The group of Si, wherein R
6Expression C
1-6Alkyl its can be identical or different;
B) R
a1 expression halogen or H;
R
A2Expression halogen or H;
R
2aExpression chlorine;
R
2bExpression chlorine;
R
2cExpression halogen or H;
R
3Expression group CONHNR
7R
8, NR wherein
7R
8The expression piperidino-(1-position only); With
R
4Expression C
1-3Alkyl.
5. the compound of claim 1 is shown in IC
R wherein
1Be
A) by the optional C that replaces of one or more fluorine
4-6Alkoxyl group, b) radicals R
5S (O)
2O, wherein R
5Expression is by the optional C that replaces of one or more fluorine
1-6Alkyl;
R
2aExpression chlorine;
R
2bExpression chlorine;
R
3Expression group CONHNR
7R
8, NR wherein
7R
8Expression piperidino-(1-position only) or morpholino; With
R
4Expression C
1-3Alkyl or halogen.
6. aforesaid right requires each described compound, wherein R
1It is radicals R
5S (O)
2O, wherein R
5Expression is by the optional C that replaces of one or more fluorine
1-6Alkyl.
7. each described compound, wherein R of claim 1-5
1The C that is replaced by one or more fluorine
4-6Alkoxyl group.
8. be selected from one or more following compounds:
Butane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] phenylester;
1-(2,4 dichloro benzene base)-4-methyl-5-[4-(4,4,4-trifluoro butoxy) phenyl]-1H-pyrazoles-3-carboxylic acid piperidines-1-base acid amides;
Propane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl) 2H-pyrazole-3-yl] phenylester;
Propane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(morpholine-4-base formamyl)-2H-pyrazole-3-yl] phenylester;
3,3,3-trifluoro propane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] phenylester;
4,4,4-trifluoro butane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] phenylester;
Propane-1-sulfonic acid-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl]-2,6-difluorophenyl ester;
Propane-1-sulfonic acid 4-[2-(2,4 dichloro benzene base)-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] phenylester;
Propane-1-sulfonic acid 4-[4-bromo-2-(2,4 dichloro benzene base)-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] phenylester;
1-{[(1-(2,4 dichloro benzene base)-4-methyl-5-{4[(sulfonyl propyl base) oxy] phenyl }-the 1H-pyrazole-3-yl) carbonyl] amino } cyclopentane carboxylic acid methyl;
Carbonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl]-the phenylester propyl diester;
4-{1-(2,4 dichloro benzene base)-4-methyl-3-[(piperidines-1-base is amino) carbonyl]-1H-pyrazoles-5-yl } phenyl thiophene-2-sulphonate;
4-{1-(2,4 dichloro benzene base)-4-methyl-3-[(piperidines-1-base is amino) carbonyl]-1H-pyrazoles-5-yl } phenylpyridine-3-sulphonate;
[2-(4-{1-(2,4 dichloro benzene base)-4-methyl-3-[(piperidines-1-base is amino) carbonyl]-1H-pyrazoles-5-yl } phenoxy group) ethyl] the ethyl carbamic acid tertiary butyl ester;
1-(2,4 dichloro benzene base)-5-{4-[2-(ethylamino) oxyethyl group] phenyl }-4-methyl-N-piperidines-1-base-1H-pyrazole-3-carboxamide;
4-{1-(2,4 dichloro benzene base)-4-methyl-3-[(piperidines-1-base is amino) carbonyl]-1H-pyrazoles-5-yl } phenyl 3-methylbutane-1-sulphonate;
4-{1-(2,4 dichloro benzene base)-4-methyl-3-[(piperidines-1-base is amino) carbonyl]-1H-pyrazoles-5-yl } phenyl 3,3-dimethylbutane-1-sulphonate;
4-[1-(2,4 dichloro benzene base)-4-methyl-3-({ [5-(trifluoromethyl) pyridine-2-yl] amino } carbonyl)-1H-pyrazoles-5-yl] phenyl 3,3,3-trifluoro propane-1-sulphonate;
1-(2,4 dichloro benzene base)-5-{4-[2-(1,3-dioxolane-2-yl) oxyethyl group] phenyl }-4-methyl-N-piperidines-1-base-1H-pyrazole-3-carboxamide;
Propane-1-sulfonic acid 4-[2-(2,4-two chloro-3-fluorophenyls)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] phenylester;
5-chloro-thiophene-2-sulfonic acid 4-[2-(2,4 dichloro benzene base)-4-methyl-5-(piperidines-1-base formamyl)-2H-pyrazole-3-yl] phenylester;
And pharmaceutically acceptable salt.
9. each described formula I compound of claim 1-8 is as medicine.
10. a pharmaceutical preparation wherein contains each described formula I compound of claim 1-8 and pharmacy and can accept assistant agent, diluent or carrier.
11. each described formula I compound of claim 1-8 is used for the treatment of or prevents application in the medicine of following disease in preparation: obesity, psychotic disorders is psychiatric disorders for example, schizophrenia and bipolarity obstacle, anxiety, anxiety-depression obstacle, depression, cognitive disorder, dysmnesia, obsessional idea and behavior disorder, apocleisis, Bulimia nerovsa, attention disorders, epilepsy and related disorders arranged, with the neuropathic obstacle, Parkinson's disease, Hang Ting Dun Shi chorea and Alzheimer, immunity, cardiovascular, reproduction and endocrinopathy, septic shock is with breathing diseases associated and gastro-intestinal system, with long-term abuse, habituation and/or recurrence indication.
12. a treatment is fat, psychotic disorders, psychiatric disorders, schizophrenia and bipolarity obstacle, anxiety, the anxiety-depression sexual dysfunction, depressed, cognitive disorder, dysmnesia, mandatory idea and behavior disorder, apocleisis, Bulimia nerovsa, attention disorders, epilepsy and related disorders arranged, the neuropathic obstacle, Parkinson's disease, Hang Ting Dun Shi chorea and Alzheimer, immunity, cardiovascular, reproduction and endocrinopathy, septic shock, with breathing and gastrointestinal system diseases associated and long-term abuse, the method of habituation and/or recurrence indication, this method comprise that each described formula I compound of claim 1-8 of using the pharmacology significant quantity is to the patient who needs it.
13. each described compound of claim 1-8 is used for the treatment of obesity.
14. the method for a preparation I compound, wherein R
1The C that expression a) is replaced by one or more fluorine
1-3Alkoxyl group or by the optional C that replaces of one or more fluorine
4-6Alkoxyl group or b) formula phenyl (CH
2)
pThe group of O-, wherein p be 1,2 or 3 and the group randomly represented by 1,2 or 3 Z of this phenyl ring replace, or c) radicals R
5S (O)
2O comprises the compound that makes formula III
R wherein
a, R
2, R
3, R
4, m and n definition as above, respectively with respectively with
A) formula R
9The alkanisation reagent of X, wherein R
9The C that expression is replaced by one or more fluorine
1-3Alkyl or the optional C that is replaced by one or more fluorine
4-6Alkyl and X represent leavings group, in inert solvent in the presence of alkali in-25 ℃ to 150 ℃ temperature range internal reaction; Or
B) with formula R
9The alkanisation reagent of X, wherein R
9Expression phenyl (CH
2)
p-group, wherein p is 1,2 or 3 and the group randomly represented by 1,2 or 3 Z of this phenyl ring replaces and X represents leavings group, in inert solvent in the presence of alkali in-25 ℃ to 150 ℃ temperature range internal reaction; Or
C) with formula R
5SO
2The sulfonated reagent of L, wherein R
5The definition as above represent leavings group with L, in inert solvent in the presence of alkali in-25 ℃ to 150 ℃ scope internal reaction.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0403779A GB0403779D0 (en) | 2004-02-20 | 2004-02-20 | Therapeutic agents |
| GB0403779.2 | 2004-02-20 | ||
| GB0420780A GB0420780D0 (en) | 2004-09-18 | 2004-09-18 | Therapeutic agents |
| GB0420780.9 | 2004-09-18 | ||
| PCT/GB2005/000534 WO2005080343A2 (en) | 2004-02-20 | 2005-02-16 | 3-substituted 1,5-diphenylpyrazole derivatives useful as cb1 modulators |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1918129A true CN1918129A (en) | 2007-02-21 |
| CN1918129B CN1918129B (en) | 2011-06-15 |
Family
ID=32040067
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2005800049765A Expired - Fee Related CN1918129B (en) | 2004-02-20 | 2005-02-16 | Therapeutic agent |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN1918129B (en) |
| GB (1) | GB0403779D0 (en) |
| ZA (1) | ZA200606563B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2024092205A1 (en) * | 2022-10-27 | 2024-05-02 | The Trustees Of Indiana University | Inhibition of ship1 as a therapeutic strategy for the treatment of alzheimer's disease |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2714057B1 (en) * | 1993-12-17 | 1996-03-08 | Sanofi Elf | New derivatives of 3-pyrazolecarboxamide, process for their preparation and pharmaceutical compositions containing them. |
-
2004
- 2004-02-20 GB GB0403779A patent/GB0403779D0/en not_active Ceased
-
2005
- 2005-02-16 CN CN2005800049765A patent/CN1918129B/en not_active Expired - Fee Related
-
2006
- 2006-08-07 ZA ZA200606563A patent/ZA200606563B/en unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2024092205A1 (en) * | 2022-10-27 | 2024-05-02 | The Trustees Of Indiana University | Inhibition of ship1 as a therapeutic strategy for the treatment of alzheimer's disease |
Also Published As
| Publication number | Publication date |
|---|---|
| GB0403779D0 (en) | 2004-03-24 |
| CN1918129B (en) | 2011-06-15 |
| ZA200606563B (en) | 2008-10-29 |
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