CN100448869C - Anilinopyrazole derivatives for the treatment of diabetes - Google Patents
Anilinopyrazole derivatives for the treatment of diabetes Download PDFInfo
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- CN100448869C CN100448869C CNB2003801043536A CN200380104353A CN100448869C CN 100448869 C CN100448869 C CN 100448869C CN B2003801043536 A CNB2003801043536 A CN B2003801043536A CN 200380104353 A CN200380104353 A CN 200380104353A CN 100448869 C CN100448869 C CN 100448869C
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Abstract
The present invention relates to anilinopyrazole compounds, pharmaceutical compositions, and methods for treating diabetes and related diseases.
Description
It is that the sequence number of 60/429,917 U.S. Provisional Application and application on August 27th, 2003 is the interests of 60/498,214 U.S. Provisional Application that the application requires the sequence number of on November 27th, 2002 application, and its content is hereby incorporated by reference with its integral form.
Technical field
The present invention relates to anilino pyrazole compound, pharmaceutical composition, and the method that is used for the treatment of diabetes and relative disease.
Background technology
Diabetes are characterised in that, in the diabetic subject, raise by glucose level, make that the glucose metabolism ability wherein occurring weakens.According to the defective difference, diabetes are divided into two kinds of main types.When the patient lacked the beta cell that produces Regular Insulin in its pancreas part, type i diabetes or insulin-dependent diabetes mellitus (IDDM) will appear.When the patient beta cell function and insulin action occurred weakening and changes, type ii diabetes or non insulin dependent diabetes (NIDDM) will take place.
At present treatment type i diabetes patient's method is exactly an insulin injection, and most of type ii diabetes patient utilizes the reagent that can stimulate the beta cell function or utilize can strengthen the patient reagent of Regular Insulin structure sensitive properties is treated.The medicament that is used for the treatment of type ii diabetes now comprises: alpha-glucosidase inhibitor, insulin sensitivity agent, insulin secretagogue and metformin.
As time goes by, almost there is half type ii diabetes patient all can lose response to these reagent.After the suitable controlling blood sugar failure of diet, exercise and oral pharmaceutical, people have set up insulinogenic therapeutic method.The defective of insulinogenic therapeutic method is to carry out medicine injection, exist the potential hypoglycemia and body weight increases once more.
Because present methods of treatment exists problem, people need the method for new treatment type ii diabetes.Especially, new methods of treatment need keep normally (glucose relies on) insulin secretion.This kind new medicine thing must have following feature: the glucose dependency (that is, compound only just stimulates insulin secretion when the glucose level rising occurring) that promotes insulin secretion; Low first with the secondary failure rate; And preservation islet function.
The INS-1 cell is the model of pancreatic insulin secretion.When keeping in having beta-mercaptoethanol, these cells can keep the feature of many pancreatics on the spot.Cell can be according to EC
50Be the relevant glucose concn excreting insulin (Hohmeier, etal., Diabetes 49:424,2002) of the physiology of 6mM glucose.
These cells also can be according to multiple known secretogogue excreting insulin, and described secretogogue comprises the reagent that can promote ring AMP, the nutritive ingredient except that glucose and Repone K in the cell.This feature of INS-1 cell further illustrates these cells and has kept many transmission signal paths that relate to the insulin secretion response, therefore is suitable for differentiating that these paths are had the compound that is used as.Thus, the INS-1 cell can be used as and is used to differentiate and can has the instrument that stimulates insulin secretion under the condition of glucose and therefore can be used for treating the compound of diabetes and relative disease.
Detailed Description Of The Invention
The invention provides formula (I) anilino pyrazole derivatives and pharmacologically acceptable salt thereof,
Wherein
R is H or (C
1-C
6) alkyl;
R
1Be H,
(C
1-C
6) alkyl, this group randomly is selected from (C
1-C
4) alkoxyl group, the phenyl that is randomly replaced by halogen and [three (C
1-C
4) alkyl] substituting group of silyl replaces,
(C
3-C
6) alkenyl,
(C
3-C
6) alkynyl,
(C
3-C
6) cycloalkyl, this group randomly is selected from (C
1-C
3) alkyl, CF
3Replace with two substituting groups of as many as of halogen,
(C
1-C
3) haloalkyl, or
Phenyl, this group randomly is selected from
Halogen,
(C
1-C
6) alkyl, this group is randomly by (a C
1-C
4) the alkoxyl group replacement,
(C
1-C
6) alkoxyl group,
(C
1-C
3) haloalkyl,
(C
1-C
3) halogenated alkoxy,
NR
8R
8，
Cyano group and
(C
1-C
6) four substituting groups of as many as of alkylthio replace;
R
2Be H,
Halogen,
(C
1-C
6) alkyl, this group is randomly by (a C
1-C
4) the alkoxyl group replacement,
(C
3-C
6) cycloalkyl, this group randomly is selected from (C
1-C
3) two substituting groups of as many as of alkyl and halogen replace,
(C
1-C
3) haloalkyl,
Pyridyl, this group is selected from (C arbitrarily
1-C
6) alkoxyl group, (C
1-C
6) alkylthio, halogen and randomly by (a C
1-C
4) (the C of alkoxyl group
1-C
6) two substituting groups of as many as of alkyl replace,
Pyrimidyl,
Phenyl, this group randomly is selected from
(C
1-C
6) alkyl, this group is randomly by (a C
1-C
4) the alkoxyl group replacement,
(C
1-C
6) alkoxyl group,
Hydroxyl,
NR
8R
8，
Cyano group,
(C
1-C
6) alkylthio,
Halogen,
CO
2R
8，
(C
1-C
3) halogenated alkoxy,
(C
1-C
4) acyl group and
Four substituting groups of the as many as of benzoyl replace this group,
Or
Tetralyl, 2,3-indanyl, benzo dioxolyl or benzodioxan base can randomly be selected from (C separately
1-C
6) alkoxyl group, (C
1-C
6) alkylthio, halogen and randomly by (a C
1-C
4) (the C that replaces of alkoxyl group
1-C
6) two substituting groups of as many as of alkyl replace,
Or
Work as R
1And R
2Be (C
1-C
6) during alkyl, they can form 5-or 6-unit carbocyclic ring together with coupled C atom,
Or
R
1And R
2Can form that 6-unit contains the N atom with coupled C atom together and on N randomly by (C
1-C
3) heterocycle that replaces of alkyl;
R
3Be (C
1-C
6) alkyl,
(C
3-C
6) cycloalkyl,
Benzyl, this group randomly is selected from its aryl
(C
1-C
6) alkyl, this group is randomly by (a C
1-C
4) the alkoxyl group replacement,
Halogen,
(C
1-C
3) haloalkyl,
(C
1-C
6) alkoxyl group,
(C
1-C
3) halogenated alkoxy,
NR
8R
8，
Cyano group,
(C
1-C
6) alkylthio and
SO
2(C
1-C
3) four substituting groups of as many as of alkyl replace,
(C
2-C
3) haloalkyl, or
Phenyl, this group randomly is selected from
(C
1-C
6) alkyl, this group is randomly by (a C
1-C
4) the alkoxyl group replacement,
Halogen,
(C
1-C
3) haloalkyl,
(C
1-C
6) alkoxyl group,
(C
1-C
3) halogenated alkoxy,
NR
8R
8，
Cyano group,
(C
1-C
6) alkylthio and
SO
2(C
1-C
3) four substituting groups of as many as of alkyl replace;
R
4Be (C
1-C
6) alkyl, this group is randomly by (a C
1-C
4) the alkoxyl group replacement, (C
1-C
6) alkoxyl group,
(C
1-C
6) alkylthio,
(C
1-C
3) haloalkyl,
(C
1-C
3) halogenated alkoxy,
Halogen,
NR
8R
8，
Pyrimidyl
Pyridyl,
Imidazolyl, or
Phenyl, this group randomly is selected from
Halogen,
(C
1-C
6) alkyl, this group is randomly by (a C
1-C
4) the alkoxyl group replacement,
(C
1-C
6) alkoxyl group,
(C
1-C
3) haloalkyl,
(C
1-C
3) halogenated alkoxy,
NR
8R
8，
Cyano group,
(C
1-C
6) four substituting groups of as many as of alkylthio replace;
N=0,1,2 or 3;
X is CO
2R
8, CONR
5R
6, SO
2NHR
7Or randomly by (C
1-C
6) alkyl replacement De oxadiazole base;
R
5Be H,
(C
1-C
6) alkyl,
(C
2-C
6) alkyl, this group is by OR
6Replace,
Benzyl, this group randomly is selected from its aromatic ring
Halogen,
(C
1-C
6) alkyl, this group is randomly by (a C
1-C
4) the alkoxyl group replacement,
(C
1-C
6) alkoxyl group,
(C
1-C
3) haloalkyl,
(C
1-C
3) halogenated alkoxy,
NR
8R
8，
Cyano group and
(C
1-C
6) four substituting groups of as many as of alkylthio replace,
Phenyl, this group randomly by
(C
1-C
6) alkyl, this group is randomly by (a C
1-C
4) the alkoxyl group replacement,
Halogen,
(C
1-C
6) alkoxyl group,
(C
1-C
3) haloalkyl,
(C
1-C
3) halogenated alkoxy,
NR
8R
8，
Cyano group and
(C
1-C
6) four substituting groups of as many as of alkylthio replace, pyridyl, this group randomly is selected from
Halogen,
(C
1-C
6) alkyl, this group is randomly by (a C
1-C
4) the alkoxyl group replacement,
(C
1-C
6) alkoxyl group,
(C
1-C
3) haloalkyl,
(C
1-C
3) halogenated alkoxy,
NR
8R
8，
Cyano group and
(C
1-C
6) four substituting groups of as many as of alkylthio replace,
SO
2-phenyl, described phenyl randomly is selected from
Halogen,
(C
1-C
6) alkyl, this group is randomly by (a C
1-C
4) the alkoxyl group replacement,
(C
1-C
6) alkoxyl group,
(C
1-C
3) haloalkyl,
(C
1-C
3) halogenated alkoxy,
NR
8R
8，
Cyano group and
(C
1-C
6) four substituting groups of as many as of alkylthio replace;
R
6Be H or (C
1-C
6) alkyl; Or
R
5With R
6Form piperidines, morpholine, thiomorpholine or piperazine ring together with coupled N atom, described piperazine is quilt (C on its N atom randomly
1-C
3) the alkyl replacement;
R
7Be H or methyl;
R
8Be H,
(C
1-C
6) alkyl,
Benzyl, this group randomly is selected from its aromatic ring
Halogen,
(C
1-C
6) alkyl, this group is randomly by (a C
1-C
4) the alkoxyl group replacement,
(C
1-C
3) alkoxyl group,
(C
1-C
3) haloalkyl,
(C
1-C
3) halogenated alkoxy,
Cyano group and
(C
1-C
6) four substituting groups of as many as of alkylthio replace,
Or
Phenyl, this group randomly is selected from
(C
1-C
6) alkyl, this group is randomly by (a C
1-C
4) the alkoxyl group replacement,
Halogen,
(C
1-C
6) alkoxyl group,
(C
1-C
3) haloalkyl,
(C
1-C
3) halogenated alkoxy,
Cyano group and
(C
1-C
6) four substituting groups of as many as of alkylthio replace;
Condition is: as R and R
2For H and X are CO
2During H, R
1Be not H, methyl or ethyl, and further condition is: formula (I) compound is not
Above the term of Que Dinging all has following meanings:
Term " halogen " is meant F, Br, Cl and I.
Term " (C
1-C
3) alkyl ", " (C
1-C
6) alkyl " and " (C
2-C
6) alkyl " and be meant respectively contain about 1 to about 3 C atoms, about 1 to about 6 C atoms and about 2 straight or branched saturated hydrocarbyls to about 6 C atoms.This class group is including, but not limited to methyl, ethyl, n-propyl, sec.-propyl, butyl, isobutyl-, amyl group, hexyl etc.
Term " (C
3-C
6) alkenyl " be meant and contain two keys and the about 3 straight or branched unsaturated alkyls to about 6 C atoms.Between can be in chain possible two carbon atoms of two keys.This class group comprises allyl group, pseudoallyl, crotyl, 2-ethyl-crotyl, 1-hexenyl etc.
Term " (C
3-C
6) alkynyl " be meant and contain a triple bond and the about 3 straight or branched unsaturated alkyls to about 6 C atoms.Between can be in chain possible two carbon atoms of triple bond.This class group comprises propargyl, 2-butyne base, 1-methyl-2-butyne base, 3-hexin base etc.
Term " (C
3-C
6) cycloalkyl " comprise cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
Term " (C
1-C
3) alkoxyl group ", " (C
1-C
4) alkoxyl group " and " (C
1-C
6) alkoxyl group " and be meant respectively contain about 1 to about 3 C atoms, about 1 to about 4 C atoms and about 1 straight or branched saturated hydrocarbyl to about 6 C atoms, described group links to each other with an O atom.The O atom is for making the atom that alkoxy substituent links to each other with the rest part of molecule by this atom.This class group is including, but not limited to methoxyl group, oxyethyl group, positive propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy etc.
Term " (C
1-C
3) halogenated alkoxy " and " (C
2-C
3) halogenated alkoxy " be meant (C respectively
1-C
3) alkoxy base or (C
2-C
3) alkoxy base, it is replaced by halogen atom on C.This class group comprises trifluoromethoxy, difluoro-methoxy, 2,2-difluoroethoxy, 2,2,2-trifluoro ethoxy, 2-chloroethoxy, 3-chlorine propoxy-, 1-fluoro-2,2 ,-two chloroethoxies etc.
Term " (C
1-C
3) haloalkyl " and " (C
2-C
3) haloalkyl " be meant (C respectively
1-C
3) alkyl group or (C
2-C
3) alkyl group, it is replaced by halogen atom on C.This class group comprises trifluoromethyl, two fluoro ethyls, 1-fluoro-2,2-Dichloroethyl, 3-chloropropyl, 4-bromine hexyl etc.
Term " [three (C
1-C
4) the alkyl silyl] " be meant and have three (C
1-C
4) the Si group of alkyl substituent, each substituting group is selected independently.The Si atom is for making the atom that this group links to each other with the rest part of molecule by this atom.This class group is including, but not limited to trimethyl silyl, the tertiary butyl-dimetylsilyl etc.
Formula C (O) is meant that C atom wherein has two key oxygen (oxygen-containing substituents) and wherein keeping the group of two other bonding positions, has promptly represented the following formula group:
Term " (C
1-C
4) acyl group " C that is meant at C (O) group goes up substituted (C
1-C
4) alkyl group.The C atom of C (O) is for making the atom that this substituting group links to each other with the rest part of molecule by this atom.This class group is including, but not limited to ethanoyl (CH
3C (O)-), positive propionyl (CH
3CH
2C (O)-), isobutyryl [(CH
3)
2CHC (O)-] etc.
Term " NR
8R
8" be meant two R that link to each other with the N atom
8Group is selected independently of one another, each other can be identical, and also can be different.
Term " (C
1-C
3) alkylthio " and " (C
1-C
6) alkylthio " be meant respectively and contain about 1 that described group is connected with a S atom to about 3 C atoms or about 1 straight or branched saturated hydrocarbyl to about 6 C atoms.The S atom is for making the atom that this alkylthio substituting group links to each other with the rest part of molecule by this atom.This class group is including, but not limited to methylthio group, ethylmercapto group, positive rosickyite base, iprotiazem base etc.
Term " SO
2(C
1-C
3) alkyl " be meant and contain the about 1 straight or branched saturated hydrocarbyl to about 3 C atoms, described group and SO
2S atom in the group links to each other.SO
2Sulphur atom in the group should (C for making by this atom
1-C
3) atom that links to each other with the rest part of molecule of alkyl substituent.This class group comprises methylsulfonyl, ethylsulfonyl, positive third alkylsulfonyl and different third alkylsulfonyl etc.
Term " 6-unit carbocyclic ring " is meant and comprises the unsaturated ring of part that condenses the C atom that forms the tetrahydrochysene indazole ring system with the pyrazoles ring.This ring is quilt (C on any possible position randomly
1-C
6) the alkyl group replacement, can contain about 6 the C atoms of accumulative total at the most.
Term " contains the N atom and quilt (C on N
1-C
6) the 6-unit heterocycle that replaces of alkyl " be meant to condense with the pyrazoles ring and form also [4,3-c] pyridine or the tetrahydro-pyrazole heterocycle of [3,4-c] pyridine bicyclic ring system also of tetrahydro-pyrazole.Shown in hereinafter, the N atom in the tetrahydropyridine heterocycle can be positioned on the 5-or 6-position of bicyclic ring system.The N atom can be randomly by (C
1-C
3) alkyl replaces and (hereinafter to be expressed as R in the explanation
Opt sub).
Tetrahydro-pyrazole is [4,3-c] pyridine tetrahydro-pyrazole [3,4-c] pyridine also also
Term " tetralyl ", " 2, the 3-indanyl ", " benzodioxan base " or " benzo dioxolyl " are meant the following formula bicyclic groups respectively:
Group may link to each other with the rest part of molecule on the carbon any of phenyl ring.When group was optional substituting group, substituting group can connect on any possible carbon atom.
Term " replacement arbitrarily " is meant that the part of being modified can have 0 substituting group to specified at least maximum quantity.As long as be substituted in chemically possibility and chemically stable, the replaceable any H atom modified in the part of each substituting group.When containing two or more substituting group on any part, each substituting group can be selected independently with any other substituting group, and therefore can be identical or different.
The other form of new compound
The compounds of this invention also comprises (a) its steric isomer, (b) its pharmacologically acceptable salt, (c) its tautomer, (d), and it is protected acid and conjugate acid and (e) its prodrug.
The steric isomer of these compounds is including, but not limited to enantiomorph, diastereomer, racemic mixture and combination thereof.This class steric isomer can prepare and separate by ordinary method, as the isomer that passes through to react the enantiomorph starting raw material or pass through to separate The compounds of this invention.Isomer can comprise geometrical isomer.The example of geometrical isomer is including, but not limited to crossing the cis-isomeride or the trans-isomer(ide) of two keys.Other isomer of The compounds of this invention also is desired.Isomer can be with pure form or to be used as above-mentioned inhibitor with other mixture of isomers form.
The pharmacologically acceptable salt of The compounds of this invention comprises the salt that is usually used in generating an alkali metal salt or generates the additive salt of free acid or free alkali.The character of salt needs only pharmaceutically acceptable without limits.Suitable pharmaceutically acceptable acid additive salt can be by mineral acid or organic acid preparation.This class representative examples of mineral pigments is hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, nitric acid, carbonic acid, sulfuric acid and phosphoric acid.Suitable organic acid can be selected from aliphatic acid, cycloaliphatic acids, aromatic acid, heterocyclic acids, carboxylic acid and organic acid sulfonic acid.Organic and sulfo group class organic acid example is including, but not limited to formic acid, acetate, propionic acid, succsinic acid, oxyacetic acid, glyconic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, xitix, glucuronic acid, toxilic acid, fumaric acid, pyruvic acid, aspartic acid, L-glutamic acid, phenylformic acid, benzaminic acid, methylsulfonic acid, Whitfield's ointment, the 4-hydroxy-benzoic acid, phenylacetic acid, amygdalic acid, embellic acid, methylsulfonic acid, ethyl sulfonic acid, Phenylsulfonic acid, pantothenic acid, the 2-ethylenehydrinsulfonic acid, toluenesulphonic acids, sulfanilic acid, the cyclohexyl thionamic acid, stearic acid, alginic acid, the N-hydroxybutyric acid, Whitfield's ointment, tetrahydroxyadipic acid and galacturonic acid and combination thereof.
The tautomer of The compounds of this invention is included in the scope of the present invention.Thus, for example carbonyl comprises its hydroxyl tautomer.
Protected acid including, but not limited to ester, hydroxylamino derivative, acid amides and sulphonamide.
The present invention includes prodrug and prodrug salt.In order to improve the performance of parent compound, generate prodrug and be known in the art; This class performance comprise solvability, absorptivity biologically stable and time of releasing (referring to as " Pharmaceutical Dosage Form and Drug DeliverySystems " (Sixth Edition), edited by Ansel et al., publ.byWilliams ﹠amp; Wilkins, pgs.27-29, (1995), the document is hereby incorporated by reference).Prodrug commonly used is designed to draw the advantage of most prodrug biotransformation reactions, also is considered within the scope of the present invention.Most prodrug biotransformation reactions comprise that N-dealkylation, O-dealkylation, aliphatic hydroxide radical reaction, aromatic hydroxy reaction, N-oxidizing reaction, S-oxidizing reaction, the reaction that deaminizes, hydrolysis reaction, glucose reaction of guanosine, sulfonation reaction and acetylization reaction are (referring to as Goodman and Gilman ' s The Pharmacological Basis ofTherapeutics (Ninth Edition); editormolinoff et al.; publ.byMcGraw-Hill; pages 11-13; (1996), the document is hereby incorporated by reference).
Comprehensively the enumerating of the shortenings that the organic chemist of ordinary skill uses appears at respectively rolls up in organic chemistry magazine downpayment; This enumerating typically appears in the form that gauge outfit enumerates for the shortenings standard.Being included in the shortenings that the organic chemist of shortenings in described the enumerating and ordinary skill uses is hereby incorporated by reference.
For purpose of the present invention, chemical element is determined in the periodic table of chemical element, CASversion, Handbook of Chemistry and Physics, 67th Ed., 1986-87.
General preparation method
Usually, being used for compound of the present invention can be by standard method well known in the art preparation, utilizes starting raw material commercially available or that generate according to synthetic route, according to the chemical process of routine, by known similar approach or by method preparation described herein.Following preparation method is used to help the reader to synthesize The compounds of this invention.
Reaction process A has illustrated the general method of preparation formula (Ia) [wherein R is the formula (I) of H] compound.With formula (III) amino-pyrazol, utilize the Ullmann type condition (venus crystals in DMF (II), heating is 16 hours in airtight test tube), with formula (IV) 2-bromine or 2-iodo-benzoic acid, benzoic ether, benzoic amide or benzsulfamide coupling, or utilize Buchwald type condition (cesium carbonate, BINAP in dry toluene and Pd
2(dba)
3, under argon gas, be heated to 110 ℃ 16 hours), with formula (IV) 2-bromo-benzoate, benzoic ether, benzoic amide or benzsulfamide coupling.
Reaction process A
Reaction process B has illustrated formula (Ib) compound changed into and has contained at least one R
4The general method of substituent other formula (Ia) compound, by Suzuki coupling condition [as, palladium catalyst, for example Pd (dppf) Cl
2And boric acid (V)] following reaction Halogen (Ib).
Reaction process B
Reaction process C has described by formula (Id) compound [R wherein
2Formula (I) for bromine or iodine] general method of preparation formula (Ia) compound.In this flow process, bromine or iodine is introduced in formula (Ic) compound [R wherein
2Formula (I) for H], gained formula (Id) compound allows and boric acid R
2B (OH)
2Experience Suzuki reaction conditions.
Reaction process C
By association reaction flow process A, B and C, can prepare and contain various R
2And R
4Substituent formula (Ia) compound is shown in reaction process D1.For example, coupling type (Iva) dibromobenzoic acid, dibromobenzoic acid ester or dibromobenzene sulphonamide and formula (IIIa) pyrazoles can obtain intermediate formula (Ie).(Ie) Suzuki with boric acid derivatives reacts, and can obtain (If), and bromination or iodate again can obtain (Id).At last, by another Suzuki reaction, (Id) can be transformed an accepted way of doing sth (Ia) compound.
Reaction process D1
Shown in reaction process D2, by formula (If) compound, respectively by with NIS iodate, or and Selectfluor
Fluoridize, can make wherein R
2Other formula (I) compound for iodine (formula (Ig)) or fluorine (formula (Ih)).
Reaction process D2
R wherein
4Be amino group NR
5R
6Or the formula of imidazoles (I) compound can make by the particular sequence shown in the reaction process E.
Reaction process E
In this sequence, the 4-fluorin radical in the phenyl ring can be by R in nucleophilic aromatic substitution reaction
4Group substitutes, wherein R
4=NR
5R
6Or imidazolyl.Be reflected at and have alkali such as LiNMe
2Or K
2CO
3Condition under carry out.
Wherein X is C (O) NR
5R
6Formula (I) compound of Huo oxadiazole base can make by the route shown in the reaction process F.
Reaction process F
Usually in slight alkaline aqueous solution, with formula (Im) ester cpds hydrolysis accepted way of doing sth (In) acid compound.Then, by with amine R
5R
6NH and coupler or with the benzsulfamide ArSO of any replacement
2NH
2With the coupler reaction, formula (In) compound is transformed an accepted way of doing sth (Io) acid amides, obtain formula (Ip) acyl group sulphonamide.By with by alkali such as the promoted N-hydroxyl-ethanamidine of triethylamine and coupler such as HOAT and EDCI reaction, also formula (In) compound can be transformed an accepted way of doing sth (Iq) compound.When formula (VI) compound being stood cyclodehydration reaction conditions (as (methoxycarbonyl sulfamyl)-triethyl ammonium oxyhydroxide (Burgess reagent)), but production (Iq) oxadiazole ring.
Reaction process G has described and has prepared wherein X=SO
2NHR
7And R
7General preparation method for formula (I) compound of H.
Reaction process G
According to method preparation formula (Ir) N that reaction process A describes, N-dibenzyl sulfonamide compounds utilizes sulfuric acid to carry out debenzylating reaction, obtains formula (Is) compound.
Reaction process H
The standard conditions of utilization shown in reaction process H, by the N-alkylation accordingly wherein R be H formula (I) compound, can making wherein, R is (C
1-C
6) formula (I) compound of alkyl.This class condition comprises alkylating reagent (as methyl iodide) and alkali (as sodium hydroxide), is reflected among inert solvent such as the DMF and carries out.
Intermediate is synthetic
Intermediate can be commercial, or by standard method well known in the art and/or following a kind of similar method preparation.
The 5-amino-pyrazol
Formula (III) 5-amino-pyrazol starting raw material can be commercial, or prepare by the method shown in following reaction process I, J or the K.
Reaction process I
In reaction process I, arbitrarily the acetonitrile that replaces and formula (VII) suitably replaces ester and alkali carries out condensation obtains formula (VIII) cyano group ketone.If necessary, R wherein
1For formula (VII) ester of substituted-phenyl can be by corresponding formula R arbitrarily
1-Br bromo compound, by as with BuLi and CO
2Reaction production R
1-COOH acid, the method for a resterification accepted way of doing sth (VII) makes formula (VII) ester.Then formula (VIII) compound and formula (II) are replaced hydrazine reaction, obtain required formula (III) amino-pyrazol.If commercial cyano group ketone (VIII) then can save first step.
Reaction process J
In reaction process J, acetonitrile is condensed into enamino nitrile (IX), then with hydrazine (II) reaction, generate (IIIa) [R wherein
2=H].
Reaction process K
R
20Be H, (C
1-C
4) alkyl
*Suitable boric acid ester comprises
R
2B (OR ')
2, wherein R ' is a low alkyl group, or two R ' groups formation rings, as
And the trimerization boric acid ester, as
How reaction process K has illustrated by bromination reaction and Suzuki or Stille coupled reaction and has introduced R outside the dehydrogenation
2Group changes into formula (IIIa) amino-pyrazol other formula (III) amino-pyrazol.Stille reaction product (IIIc) also can be by reducing an accepted way of doing sth (IIId) saturated compound as hydrogenation.
The embodiment of preparation amino-pyrazol is illustrated in the description of mesosome B-M hereinafter.
Hydrazine
Formula (II) hydrazine starting raw material can be commercial, or at phenyl hydrazine (R
3=optional the phenyl that replaces) under the situation, can be by the preparation of the method shown in the reaction process L.
Reaction process L
R
Spt sub=substituting group arbitrarily, (IIa), [(II), R
3=any phenyl that replaces
Substituted aniline can be converted into the diazonium salt intermediate, then utilizes tin chloride (II) as reductive agent, with its reduction again.
The example of preparation aryl hydrazine is shown in the description of intermediate A hereinafter.
2-bromo-benzoic acid derivative
The 2-bromo-benzoic acid derivative that is used for 5-amino-pyrazol coupled reaction can be commercial, or direct method well known in the art preparation.A kind of example of this class preparation is shown in the description of mesosome N hereinafter.
Specific embodiment of the present invention
Hereinafter specific embodiment is used to illustrate the present invention as described herein, but is used for by any way anything but limiting the scope of the invention.
Shortenings and abbreviation
When following shortenings was used for the open text of the present invention, they had following meanings:
Abs: absolute
Ac: ethanoyl
AcOH: acetate
Amu: awu
Aq: hydration
BINAP:2,2 '-two (diphenylphosphino)-1,1 '-dinaphthyl
Bn: benzyl
Boc: tert-butoxycarbonyl
BTMAICl
2: two chloriodic acid benzyltrimethylammon.um
Bu: butyl
CDCl
3: inferior chloroform
CDI: carbonyl dimidazoles
Celte
: the brand of diatomite filtration agent, the registered trademark of Celite company
CI-MS: chemical ionization mass spectrometry
Conc: concentrate
D: doublet
DCM: methylene dichloride
Dd: the doublet of doublet
Ddd: the doublet of the doublet of doublet
DMAP:4-(N, N-dimethyl) aminopyridine
DMF:N, dinethylformamide
DMSO: dimethyl sulfoxide (DMSO)
DMSO-d
6: dimethyl sulfoxide (DMSO)-d
6
DOWEX
66:Dowex oxyhydroxide, weakly-basic anion, macroporosity, 25-50 order
Dppf:1,1 '-two (diphenylphosphino) ferrocene
EDCI:1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride
EI: electron bombardment ionization
EI-MS: electron bombardment mass spectrum
Equiv: equivalent
ES-MS: EFI mass spectrum
Et: ethyl
Et
2O: Anaesthetie Ether
Et
3N: triethylamine
EtOAc: ethyl acetate
EtOH: ethanol
G: gram
GC-MS: gas chromatogram purifying mass spectrum
H: hour
Hex: hexane
1H NMR: proton magnetic resonance (PMR)
HOAT:1-hydroxyl-7-azepine-benzotriazole
The HOBT:1-hydroxybenzotriazole
HPLC: high efficiency liquid chromatography
HPLC ES-MS: high efficiency liquid chromatography-EFI mass spectrum
KotBu: potassium tert.-butoxide
L: rise
LC-MS: liquid chromatography/mass spectrometry
LDA: LDA
M: multiplet
M: mole
Ml: milliliter
M/z: unit charge quality
Me: methyl
MeCN: acetonitrile
MeOH: methyl alcohol
Mg: milligram
MHz: megahertz
Min: minute
Mmol: mmole
Mol: mole
Mp: fusing point
MS: mass spectrum
N: routine
NaOAc: sodium acetate
The NBS:N-bromo-succinimide
NIS:N-iodo succinimide
The NMM:4-methylmorpholine
NMR: nucleus magnetic resonance
Pd
2(dba)
3: three (dibenzalacetones), two palladiums (0)
Pd (OAc)
2: acid chloride
Pd (PPh
3)
4: tetrakis triphenylphosphine palladium (0)
Pd/C: palladium/carbon
Pd (dppf) Cl
2: [1,1 '-two (diphenylphosphino) ferrocene] dichloro palladium (II)
Ph: phenyl
Ppm: 1,000,000/umber
Pr: propyl group
Psi: poundage per square inch
Q: quartet
Qt: quartet
R
f: the TLC retention factors
Rt: room temperature
RT: retention time (HPLC)
S: unimodal
TBAF: tetrabutylammonium chloride
TBDMS: t-butyldimethylsilyl
TBDMSCI: tert-butyldimethylsilyl chloride
TBS: t-butyldimethylsilyl
TFA: trifluoroacetic acid
THF: tetrahydrofuran (THF)
TLC: thin-layer chromatography
TMS: tetramethyl-silicomethane
V/v: the volume in the per unit volume
Vol: volume
Weight in the w/w per unit weight
General experimental technique
By syringe or conduit, shift liquid and solution, and be incorporated in the reaction vessel by rubber septum to air and moisture sensitivity.Under the condition that is not further purified, use business level reagent and solvent.Term " concentrating under reduced pressure " is meant and is approximately using the Buchi rotatory evaporator under the 15mm Hg post.All temperature all with uncorrected centigradetemperature (℃) report.Thin-layer chromatography (TLC) carries out on EM Science precoating glass back of the body silica gel 60A F-254250 μ m plate.Utilize 32-63 micron 60A silica gel to carry on the back medicine box in advance, in Biotage system, carry out column chromatography (flash chromatography) purifying.Utilize Gilson 215 to be, typically use YMC Pro-C18 AS-342 (150 * 20mm I.D.) post, finish and utilize preparation property reversed-phase HPLC chromatogram purification.Typically, employed moving phase is H
2The mixture of O (A) and MeCN (B).Water can be blended, or does not contain 0.1%TFA.Typical gradient is:
| Time [min] | A：％ | B：％ | Flow velocity [mL/min] |
| 0.60 | 90.0 | 10.0 | 1.0 |
| 11.00 | 0.0 | 100.0 | 1.0 |
| 14.00 | 0.0 | 100.0 | 1.0 |
| 15.02 | 100.0 | 0.0 | 1.0 |
Electron bombardment mass spectrum (EI-MS) obtains by Hewlett Packard 5989A mass spectrograph, and this mass spectrograph is equipped with and contains J﹠amp; W DB-5 post (0.25 μ M coating; Hewlett Packard 5890 gas chromatographs of 30m * 0.25mm).Ion source remains on 25 ℃, 2 seconds/scanning place, by the 50-800amu scanning optical spectrum.
Utilize following manner to obtain high pressure liquid chromatography/EFI mass spectrum (LC-MS):
(A) Hewlett-Packard 1100HPLC is equipped with four-stage pump, at the 254nm place wavelength variable detector assembly is installed, and (2 * 23mm 120A), contains the ionized Finnigan LCQ of EFI ion trap mass spectrometer to YMC pro C-18 post.According to ion source quantity, utilize the variable ion time, by the 120-1200amu scanning optical spectrum.Elutriant is water/0.018%TFA in acetonitrile/0.02%TFA and the B:2% acetonitrile in the A:2% water.In 3.5 minutes, by 10% to 95%B gradient elution, flow velocity is 1.0ml/min, begins to keep 0.5 minute, keeps 0.5 minute when 95%B at last.Total operating time is 6.5 minutes.
Perhaps
(B) Gilson HPLC system is equipped with two Gilson 306 pumps, Gilson 215 self-actuated samplers, the Gilson diode is arranged detector, (2 * 23mm 120A), and contains the single quadruple mass spectrograph of the ionized Micromass LCZ of z-spraying EFI to YMC pro C-18 post.In 1.5 seconds kinds, by the 120-800amu scanning optical spectrum.Obtain ELSD (evaporat light scattering detector) data by similar signalling channel.Elutriant is water/0.018%TFA in acetonitrile/0.02%TFA and the B:2% acetonitrile in the A:2% water.In 3.5 minutes, by 10% to 90%B gradient elution, flow velocity is 1.5ml/min, begins to keep 0.5 minute, keeps 0.5 minute when 90%B at last.Total operating time is 4.8 minutes.Extra switch-valve is used for post switch and regeneration.
On 300/400MHz Varian Mercury-plus spectrograph, measure conventional one-dimensional NMR spectrum.Sample dissolution in the heavy hydrogen solvent that is obtained by Cambridge Isotope Labs, is moved to it in 5mm ID Wilmad NMR test tube.Obtain spectrum at the 293K place.On the ppm scale, write down chemical shift, as the reference of appropriate solvent signal, for example, for 1H spectrum: 2.49ppm (DMSO-d
6), 1.93ppm (CD
3CN), 3.30ppm (CD
3OD), 5.32ppm (CD
2Cl
2) and 7.26ppm (CDCl
3); For 13C spectrum: 39.5ppm (DMSO-d
6), 1.3ppm (CD
3CN), 49.0ppm (CD
3OD), 53.8ppm (CD
2Cl
2) and 77.0ppm (CDCl
3).
Synthetic intermediate
Hydrazine
Intermediate A
Preparation (2, the 6-3,5-dimethylphenyl) hydrazonium salt hydrochlorate
Under agitation condition, to 2, (5.0g slowly adds NaNO2 (2.85g, water 41.3mmol) (22.5ml) cold (0 ℃) solution to the 6-xylidine in 50% hydration HCl (45ml) cold (0 ℃) solution 41.3mmol).Strict controlled temperature in reinforced process does not allow above 5 ℃.After reinforced the finishing, under uniform temp, stir the bright orange solution 20 minutes that contains the diazonium salt intermediate.Under 0 ℃, in～5 minutes, in reaction mixture, add SnCl
2(11.0g, dense HCl (30ml) solution 57.8mmol).Reaction mixture is warmed to room temperature, stirred 6 hours.Filter collecting precipitation, utilize a small amount of cold water washing.Vacuum-drying obtains title compound, is white amorphous solid (7.00g, 98%).Product can be used for next step under not being further purified.ES-MS m/z 137.0(MH
+)；HPLC RT(min)1.09。
The 5-amino-pyrazol
Intermediate B
Preparation 3-cyclopentyl-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-amine
Step 1: preparation 3-cyclopentyl-3-oxypropionitrile
Under 70 ℃, to NaH (2.75g, drip in THF 68.7mmol) (15ml) suspension pentamethylene methyl esters (8.00g, 62.4mmol) and anhydrous acetonitrile (3.91ml, THF 74.9mmol) (5ml) solution.Mixture stirred 16 hours down at 70 ℃-72 ℃, was cooled to room temperature, utilized ethyl acetate and hydration HCl dilution.Utilize water and salt water washing organic layer, dry (MgSO
4).Remove and desolvate, obtain 3-cyclopentyl-3-oxypropionitrile, this product can need not to be further purified use down.
Step 2: preparation 3-cyclopentyl-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-amine
With (2-aminomethyl phenyl) hydrazonium salt hydrochlorate (2.00g, 14.6mmol) and the thick 3-cyclopentyl-3-oxypropionitrile that obtains suddenly by previous step (2.32g ,～14.6mmol) toluene (6ml) solution can flow heating 16 hours.Solvent is removed in decompression, obtains residue, this residue of silica gel chromatography purifying, utilize hexane/EtOAc (3: 1, v/v) as elutriant.Concentrating under reduced pressure obtains 3-cyclopentyl-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-amine, is bright orange solid (2.19g, 62%).
ES-MSm/z241.9(MH
+)；HPLC RT(min)1.69.
1H NMR(400MHz，CDCl
3)δ1.58-1.82(m，6H)，2.00-2.16(m，2H)，2.17-2.21(s，3H)，2.93-3.11(m，1H)，3.42-3.58(s，2H)，5.41-5.46(s，1H)，7.20-7.28(m，2H)7.29-7.37(m，2H).
Intermediate C
The preparation 3-tertiary butyl-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-amine
With 4,4-dimethyl-3-oxypropionitrile (36.7g, 0.29mol), (2-aminomethyl phenyl) hydrazonium salt hydrochlorate (47.7g, 0.29mol) and Glacial acetic acid (7.03g, 6.7ml 0.12mol) are dissolved in the dehydrated alcohol (585ml), can flow the heating 18 hours.After the removal of solvent under reduced pressure, add EtOAc and water (each 500ml), carefully add then sodium bicarbonate (42g, 0.50mol).After adding hexane (500ml), separate organic phase, utilize salt solution (500ml) washing, at Na
2SO
4Last dry.Then on the embed type glass funnel, by silicagel pad (500g) filtering mixt.Utilize hexane/EtOAc (1: 1, v/v) wash this pad, concentrating under reduced pressure filtrate.(9: 1, v/v) grinding gained solid filtered, and washs and vacuum-drying, obtains colorless solid (61.5g, 93%) to utilize hexane/EtOAc.
1H NMR(400MHz，CD
2Cl
2)δ1.29(s，9H)，2.12(s，3H)，3.56(br，2H)，5.48(s，1H)，7.28(m，2H)，7.31(m，2H).
Intermediate D
Preparation 3-(4-fluorophenyl)-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-amine
Step 1: preparation 3-amino-3-(4-fluorophenyl) vinyl cyanide
To the 4-fluorobenzonitrile (5.00g, 41.3mmol) and acetonitrile (4.35ml, add in toluene 82.5mmol) (100ml) solution potassium tert.-butoxide (13.9g, 124mmol).Stirred the mixture 24 hours, and by slowly adding sodium bicarbonate aqueous solution, made the reaction quenching then.(3 * 50ml) extract gained suspension to utilize methylene dichloride.Utilize water washing organic solution, dry (Na
2SO
4), concentrating under reduced pressure.Utilize EtOH/Et
2O grinds residue, obtains 3-amino-3-(4-fluorophenyl) vinyl cyanide (6.20g, 93%), is white solid.
1H NMR (300MHz, acetone-d
6)
δ4.23(s，1H)，6.20(s，2H)，7.22(ddd，2H)，7.71(m，2H).
Step 2: preparation 3-(4-fluorophenyl)-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-amine
To 3-amino-3-(4-fluorophenyl) vinyl cyanide (600mg, add in 1N HCl (6ml) solution 3.70mmol) (2-aminomethyl phenyl) hydrazonium salt hydrochlorate (558mg, 3.51mmol).Back flow reaction 16 hours is cooled to room temperature then.By slowly adding 1N aqueous sodium hydroxide solution alkalization gained mixture to pH 12.Filter collecting precipitation, then by EtOH/Et
2The O recrystallization obtains intermediate (800mg, 81%), is bright orange solid.
1H NMR(400MHz，CD
2Cl
2)δ2.20(s，3H)，2.14
(br s，2H)，5.91(s，1H)，7.06(t，2H)，7.36(d，4H)，7.75(m，2H).
This product can use under the condition that be further purified need not.
Intermediate E
Preparation 3-(4-fluoro-2-aminomethyl phenyl)-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-amine
Step 1: preparation 4-fluoro-2-tolyl acid
To 2-bromo-5-toluene fluoride (10.0g, drip in Anaesthetie Ether 52.9mmol) (100ml) cold (78 ℃) solution n-Butyl Lithium (1.6M, in hexane, 21.2ml, 52.9mmol).Stirred the mixture 5 minutes, and slowly be warmed to 0 ℃.(100g 2.27mol), allows to be warmed to room temperature in 16 hours under agitation slowly to add dry ice in mixture.Regulate mixture to pH=2, (3 * 20ml) extract to utilize ethyl acetate.Concentrate organic phase, the yellow residue of gained is suspended in the water (100ml).Utilize 2N NaOH to regulate suspension, utilize the Anaesthetie Ether washing to pH=12.Utilize 2N HCl acidifying water to pH=2 then, (3 * 50ml) extract to utilize Anaesthetie Ether.Utilize the organic extracting solution of water washing, dry (MgSO
4), concentrating under reduced pressure obtains product (5.0mg, 61%), is white solid.
1H NMR(400
MHz，DMSO-d
6)δ2.53(s，3H)，7.06-7.17(m，2H)，7.87(dd，1H)，12.85(s，1H).
Step 2: preparation 4-fluoro-2-methyl-toluate
In pressurized vessel, to 4-fluoro-2-tolyl acid (4.0g, add in THF 26.0mmol) (30ml) solution cesium carbonate (8.45mg, 26.0mmol) and methyl iodide (2.0M, in t-butyl methyl ether, 13.0ml, 26.0mmol).Sealed vessel was 70 ℃ of following stirring reactions 16 hours.After being cooled to room temperature, utilize saturated sodium bicarbonate (10ml) and water (50ml) to make the reaction quenching.(3 * 50ml) extract water layer, dry then (Na to utilize methylene dichloride
2SO
4) organic phase, concentrating under reduced pressure obtains crude product.Utilize acetone and hexane to grind this product, obtain pure products (3.8g, 87%), be white solid.
1H NMR (400MHz, acetone-d
6) δ 2.60 (s, 3H), 3.86 (s, 3H), 7.05-7.12 (m, 2H), 7.96 (s, 1H); ES-MS m/z188.2 (MH
+); HPLC RT (min) 3.20.
Step 3: preparation 3-(4-fluoro-2-aminomethyl phenyl)-3-oxypropionitrile
The sodium hydride of crossing to hexane wash (60% oily dispersion liquid, 995mg, drip in suspension 24.9mmol) 4-fluoro-2-methyl-toluate (3.8g, 22.6mmol) and anhydrous acetonitrile (2.4ml, THF solution (20ml) 45.2mmol).70 ℃ of following stirring reactions 16 hours, be cooled to room temperature then.Utilize ethyl acetate (20ml) and 1N HCl (10ml) dilution gained mixture, layering.Utilize water (3 * 20ml) and salt solution (20ml) washing organic phase, dry (Na
2SO
4), concentrating under reduced pressure obtains the 4.0g yellow oil, and this product can be used for next step under need not to be further purified.
ES-MS m/z178.2(MH
+)；HPLC RT(min)2.22.
Step 4: preparation 3-(4-fluoro-2-aminomethyl phenyl)-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-
Amine
To 3-(4-fluoro-2-aminomethyl phenyl)-3-oxypropionitrile (2.0g, add in toluene 11.3mmol) (10ml) solution (2-aminomethyl phenyl) hydrazonium salt hydrochlorate (2.15g, 13.5mmol).Be reflected at 110 ℃ and stirred 16 hours down, be cooled to room temperature then.Concentrating under reduced pressure, fast silica gel chromatogram purifying residue (2: 1-1: the 1=hexane: ethyl acetate), obtain product, be yellow oil (500mg, 16%).
1HNMR(400MHz，DMSO-d
6)δ2.12(s，3H)，2.44(s，3H)，5.74(s，1H)，7.02-7.14(m，2H)，7.34-7.43(m，4H)，7.52(dd，1H)；ES-MS m/z 282.4(MH
+)；HPLC RT(min)3.36.
Intermediate F
Preparation 3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-amine
(2.00g, (3.67g is in 1M hydrochloric acid (20ml) solution 23.1mmol) 24.4mmol) to join (2-aminomethyl phenyl) the hydrazonium salt hydrochlorate that is stirring with 3-aminobutene nitrile.Heating (100 ℃) reaction 18 hours is cooled to room temperature then.Utilize 1M aqueous sodium hydroxide solution regulator solution pH＞12.(3 * 20ml) extract mixture, and the organic extraction that utilizes the salt water washing to merge then is dry on anhydrous magnesium sulfate, filters and vacuum concentration to utilize methylene dichloride.Fast silica gel chromatogram purifying residue utilizes 25-50% ethyl acetate/hexane wash-out, obtains 3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-amine (3.97g, 87%), is orange oily matter.
1H NMR (300MHz, acetone-d
6) δ 7.29 (m, 4H), 5.32 (s, 1H), 2.12 (s, 3H), 2.08 (s, 3H); ES-MS m/z 188.2 (MH
+), HPLC RT (min) 0.79.
Intermediate G
Preparation 2-(2-aminomethyl phenyl)-4,5,6,7-tetrahydrochysene-2H-imidazoles-3-amine
(464mg, (300mg, 2.44mmol), mixture heats down at 60 ℃, and stirs 16 hours to add 2-oxo cyclohexanenitrile in ethanol 2.92mmol) (2ml) solution to (2-aminomethyl phenyl) hydrazonium salt hydrochlorate.Then flask is cooled to room temperature, evaporating solvent obtains solid.Thick residue 2-(2-aminomethyl phenyl)-4,5,6,7-tetrahydrochysene-2H-imidazoles-3-amine hydrochlorate (449mg, 70%) can be used for next step under need not to be further purified.
ES-MS m/z228.2(MH
+)；HPLCRT(min)1.22.
Intermediate H
Preparation 4-(4-fluorophenyl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-amine
Step 1: preparation 4-bromo-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-amine
(intermediate F, 7.78g add bromine (6.64g, acetate 41.6mmol) (10ml) solution in acetate 41.7mmol) (90ml) solution to 3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-amine.Stirred reaction mixture 30 minutes.In reaction mixture, add entry, utilize cold KOH solution (1N) alkalization mixture.Collect white solid 4-bromo-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-amine, under need not to be further purified, be used for next step.
Step 2: preparation 4-(4-fluorophenyl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-
Amine
With 4-bromo-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-amine (2g, 7.52mmol), 4-fluorophenyl boric acid (2.10g, 11.3mmol) and Pd (PPh
3)
4(434mg 0.38mmol) is dissolved among the DMF (20ml), adds Na
2CO
3(saturated aqueous solution, 18ml).Mixture was outgased 10 minutes, heated 2 hours down at 110 ℃ then.Diluted reaction mixture leaches solid.Solvent evaporated under reduced pressure, fast silica gel chromatogram purifying residue utilizes 10 to 40% ethyl acetate (in hexane) wash-outs, obtains 1.2g (purity 90%, 51%) title compound.
1H NMR
(300MHz，CD
2Cl
2)δ7.25-7.34(m，6H)，7.08(t，2H)，3.62(s，2H)，220(s，3H)，2.14(s，3H)，
Intermediate compound I
Preparation (the 4-bromo-3-tertiary butyl-1-methyl isophthalic acid H-pyrazoles-5-yl) t-butyl carbamate
Step 1: the preparation 4-bromo-3-tertiary butyl-1-methyl isophthalic acid H-pyrazoles-5-amine
(10g adds bromine (10.4g, acetate 65.26mmol) (10ml) solution in acetate 65.3mmol) (90ml) solution to the 3-tertiary butyl-1-methyl isophthalic acid H-pyrazoles-5-amine.At room temperature stirred solution is 30 minutes, adds entry (100ml) then.Utilize KOH (the ice-cold solution of 1.0M) quaternization mixture to pH9.Filter and collect the gained brown solid, the fast silica gel chromatogram purifying utilizes 10 to 30% ethyl acetate (in hexane) wash-outs, obtains 13.2g (87%) title compound (white solid).
Step 2: preparation (the 4-bromo-3-tertiary butyl-1-methyl isophthalic acid H-pyrazoles-5-yl) carboxylamine uncle
Butyl ester
With step 1 product (2g, 8.62mmol), tert-Butyl dicarbonate (2.82g, 12.92mmol) and DMAP (105mg 0.86mmol) is dissolved among the DCM (40ml), stirs 16 hours.(10% aqueous solution 100ml), continues to stir 4 hours again to add salt of wormwood in reaction mixture.Separate organic layer, concentrating under reduced pressure.Fast silica gel chromatogram purifying residue utilizes 5 to 20% ethyl acetate (in hexane) wash-outs, obtains 2.3g (80%) title compound.
1H NMR(300MHz，CD
2Cl
2)δ3.55(s，3H)，1.37(s，9H)，1.31(s，9H).
Intermediate J
The preparation 4-bromo-3-tertiary butyl-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-amine
To the 3-tertiary butyl-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-amine (1.00g, dripping bromine in acetate 4.36mmol) (10ml) solution (662mg, 0.21ml, 4.14mmol).Stirred reaction mixture 5 minutes utilizes water (50ml) dilution then, is settled out solid.Solid collected by filtration is dissolved in it among EtOAc (50ml).Utilize saturated NaHCO
3With salt water washing EtOAc solution, dry (Na
2SO
4), concentrating under reduced pressure obtains product (935mg, 70%), is white solid.
1H NMR(300MHz，DMSO-d
6)δ1.32(s，9H)，2.04(8，3H)5.02(s，2H)，7.20-7.38(m，4H).ES-MS m/z308.6(MH
+)；HPLC RT(min)3.15.
Intermediate K
The preparation 3-tertiary butyl-4-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-amine
To the 4-bromo-3-tertiary butyl-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-amine (intermediate J, 800mg, 2.60mmol) DMF (5ml) solution in add trimethylboroxin (0.73ml, 5.19mmol), [1,1 '-two (diphenylphosphino)-butane] palladium chloride (II) (157mg, 0.26mmol) and salt of wormwood (1.08g, 7.79mmol).155 ℃ of following stirred reaction mixtures 18 hours.After the cooling, utilize water (100ml) diluted reaction mixture, (3 * 25ml) extract to utilize EtOAc.The organic layer that utilizes the salt water washing to merge, dry (Na
2SO
4), filter and concentrating under reduced pressure.Fast silica gel chromatogram purifying residue, (1: 9, v/v) wash-out obtained product (243mg, 38%), is white solid to utilize hexane/EtOAc.
1H NMR(300MHz，DMSO-d
6)δ1.24(s，9H)，1.97(s，3H)，2.03(s，3H)，4.48(s，2H)7.14-7.32(m，4H).ES-MS m/z244.2(MH
+)；HPLC RT(min)1.17.
Intermediate L
The preparation 3-tertiary butyl-1-methyl-4-pyridin-3-yl-1H-pyrazoles-5-amine
With (the 4-bromo-3-tertiary butyl-1-methyl isophthalic acid H-pyrazoles-5-yl) t-butyl carbamate (intermediate compound I, 1.7g, 5.12mmol), pyridine-3-boric acid (1.26g, 10.23mmol) and Pd (PPh
3)
4(295mg 0.26mmol) is dissolved in the ethanol (25ml), adds Na
2CO
3(the 2M aqueous solution, 25ml).Mixture was outgased 10 minutes.Then reaction mixture is heated to 80 ℃ 16 hours.Utilize ethyl acetate diluted mixture thing, leach solid, utilize TFA (5ml) to handle filtrate.Stirred the mixture 30 minutes, afterwards concentrating under reduced pressure.Crude product is dissolved in the methyl alcohol, passes through C
8-silica gel plug filters.The HPLC purifying is because 5 to 60% acetonitrile gradient wash-outs in the water obtain 300mg (25%) title compound.
1H NMR(300
MHz，CD
3CD)δ8.73(d，1H)，8.64(s，1H)，8.14(d，1H)，7.81(dd，1H)，3.73(s，3H).1.20(s，9H).ES-MS m/z 231.2(MH
+)；HPLC RT(min)0.23.
Intermediate M
Preparation 4-ethyl-3-(4-fluorophenyl)-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-amine
Step 1: preparation 3-(4-fluorophenyl)-1-(2-aminomethyl phenyl)-4-vinyl-1H-pyrazoles
-5-amine
To 4-bromo-3-(4-fluorophenyl)-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-amine (200mg, 0.58mmol) toluene (10ml) solution in add tributylvinyl tin (0.33ml, 366mg, 1.16mmol) and tetrakis triphenylphosphine palladium (O) (66mg, 0.06mmol).The reflux reaction mixture stirred 16 hours.After being cooled to room temperature, the concentrating under reduced pressure mixture.Residue is dissolved among the EtOAc (100ml), utilizes salt solution (50ml) washing, dry (Na
2SO
4), filter and concentrating under reduced pressure.Fast silica gel chromatogram purifying residue utilizes 10%EtOAc/ hexane wash-out, obtains 3-(4-fluorophenyl)-1-(2-aminomethyl phenyl)-4-vinyl-1H-pyrazoles-5-amine (87mg, 51%).
1H NMR(300MHz，DMSO-d
6)δ2.12(s，3H)，4.96(dd，1H)5.21(dd，1H)，5.26(s，2H)，6.55(dd，1H)，7.18-7.56(m，8H).ES-MS m/z 294.2(MH
+)；HPLC RT(min)3.54.
Step 2: preparation 4-ethyl-3-(4-fluorophenyl)-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-
Amine
To the wet palladium/carbon in EtOH (5ml) (10wt%, be incorporated in 10mg) 3-(4-fluorophenyl)-1-(2-aminomethyl phenyl)-4-vinyl-1H-pyrazoles-5-amine among the EtOH (5ml) (87mg, 0.30mmol).At H
2Under the atmosphere (55psi), hybrid reaction is 16 hours on the Parr mixing tank.By the diatomite filtration palladium catalyst, utilize EtOH (3 * 20ml) flushings.Decompression concentrated solution obtains containing the title compound (68mg, 77%) of trace impurity.This product can be used for next reactions steps under the condition that need not to be further purified.
ES-MS m/z 296.2(MH
+)；HPLC RT(min)2.65.
2-bromo-benzoic acid derivative
Intermediate N
Preparation 2-bromo-5-(difluoro-methoxy) methyl benzoate
Step 1: preparation 2-bromo-5-methyl hydroxybenzoate
Under argon gas atmosphere, (2.00g adds AlCl in methylene dichloride 8.16mmol) (15ml) cold (ice-water bath) solution to 2-bromo-5-methoxyl methyl benzoate
3(5.44g 40.8mmol), utilizes ice-water bath to keep temperature of reaction to be lower than 10 ℃.Stirred fulvescent suspension 10 minutes, (3.02ml, 40.8mmol), rate of addition keeps temperature of reaction to be lower than 5 ℃ to drip EtSH then.After stirring 2.5 hours under 10 ℃, under agitation condition, reaction mixture is slowly injected the chela frozen water.Separate organic layer, utilize DCM to extract water layer, utilize the water washing organic layer, at MgSO
4Last dry, filter and concentrating under reduced pressure, obtain glassy yellow oily matter, this product can need not to be used for next step under the condition that is further purified.
Step 2: preparation 2-bromo-5-(difluoro-methoxy) methyl benzoate
(5.63mmol, (11.3mmol, 3.67g) (6.75mmol, 0.71ml), reaction mixture stirred 16 hours down at 90 ℃ with chlorine difluoroacetic acid methyl esters to add cesium carbonate in DMF 1.30g) (8ml) solution to 2-bromo-5-methyl hydroxybenzoate.After being cooled to room temperature, utilize the ethyl acetate dilution, filtering mixt, concentrating under reduced pressure.Silica gel chromatography purifying residue, (9: 1, v/v) wash-out obtained product, is glassy yellow oily matter (560mg, 35%) to utilize hexane/EtOAc.GC-MS m/z：280(MH
+)。
The second month in a season and teritary amide
Except the amine that is used for embodiment 315, other amine precursor that is used for all acid amides formation reaction is all commercially available.Its synthetic method is described in the following part.
Intermediate O
Preparation (2-{4-methoxyl group-3-[(4-methylpiperazine-1-yl) alkylsulfonyl] phenyl } ethyl) the amine dihydrochloride
Step 1: preparation 2,2,2-three fluoro-N-[2-(4-p-methoxy-phenyl) ethyl] ethanamide
Under 0 ℃, to 4-anisole ethylamine (2.5g, CH 16.5mmol)
2Cl
2(45ml) CH of adding trifluoroacetic anhydride in the solution
2Cl
2(5ml) solution.Reaction mixture stirred 30 minutes down at 0 ℃, at room temperature stirred then 1 hour.Add NH
4The Cl aqueous solution, phase-splitting utilizes CH
2Cl
2Extract water.Dry (Na
2SO
4) organic phase that merges, filter and concentrating under reduced pressure.By Et
2O/ hexane recrystallization gained solid obtains product, is light brown solid (2.36g, 58%).
1H NMR(400 MHz，CDCl
3)，δ2.82(t，2H)，3.62(q，2H)，3.81(s，3H)，6.19-6.30(broad，1H)，6.87(d，2H)，7.10(d，2H)；GC-MS m/z 247(M
+)，1RT(min)12.22.
Step 2: preparation 2,2,2-three fluoro-N-(2-{4-methoxyl group-3-[(4-methylpiperazine-1-
Base) alkylsulfonyl] phenyl } ethyl) ethanamide
At 0 time, in N
2Down, to filling 2,2,2-three fluoro-N-[2-(4-p-methoxy-phenyl) ethyl] (1.00g adds chlorsulfonic acid (4ml) to ethanamide in flask 4.05mmol).After 30 minutes, temperature is risen to room temperature, continue again to stir 90 minutes.Reaction mixture is added drop-wise to CH
2Cl
2With in the mixture of ice bath refrigerative frozen water [vigorous reaction when contacting] with water.Phase-splitting utilizes CH
2Cl
2Extract water.Dry (Na
2SO
4) organic phase that merges, filter and concentrating under reduced pressure.
Under 0 ℃, in N
2The gained SULPHURYL CHLORIDE is dissolved in CH down,
2Cl
2(30ml), add Et
3N (1.29ml, 8.10mmol) and the 1-methylpiperazine (0.674ml, 6.08mmol).Solution is warmed to room temperature and stirred 14 hours.Concentrated reaction mixture then, the fast silica gel chromatogram purifying, (4: 1, v/v) wash-out obtained title compound, is yellow oil (1.26g, 75%) to utilize EtOAc/MeOH.
1H NMR(400MHz，CDCl
3).δ2.13(s，3H)，2.48(broad t，4H)，2.87(t，2H)，3.27(broad t，4H )，3.56(q，2H)，3.88(s，3H)，6.70-6.77(broad s，1H)，6.94(d，1H)，7.33(dd，1H)，7.69(dd，1H)；ES-MSm/z 410.3((MH)
+)，432.1((M+Na)
+)840.7((2M+Na)
+)HPLC RT(min)1.19.
Step 3: preparation (2-{4-methoxyl group-3-[(4-methylpiperazine-1-yl) alkylsulfonyl] phenyl }
Ethyl) amine dihydrochloride
To 2,2,2-three fluoro-N-(2-{4-methoxyl group-3-[(4-methylpiperazine-1-yl) alkylsulfonyl]-phenyl } ethyl) ethanamide (obtaining) (1.25g, MeOH 3.05mmol) (30ml) and H by step 2
2Add K in the solution of O (8ml)
2CO
3(2.11g, 15.3mmol), 60 times stirred solutions 2 hours.After being cooled to room temperature, reduction vaporization MeOH.Utilize CH
2Cl
2(6 * 50ml) extract remaining hydration mixture, dry (Na
2SO
4) organic phase that merges, filter and concentrating under reduced pressure.Residue is dissolved among the MeOH, is incorporated in 4 equivalent 1N HCl among the MeOH, make it generate white precipitate.Solvent evaporated under reduced pressure is by MeOH/Et
2O recrystallization gained solid obtains title compound [assuming two-HCl salt], is white solid (457mg, 48%).
1HNMR(400MHz，CD
3OD)δ2.29(s，3H)，2.48(broad t，4H)，2.78(dd，2H)，2.87-2.92(m，2H)，3.23(broad t，4H)，3.91(s，3H)7.16(d，1H)，7.47(dd，1H)，7.68(d，1H)；ES-MS m/z(MH
+)314.2，HPLC RT(min)0.70.
Embodiment 1
The preparation 2-[(3-tertiary butyl-1-methyl isophthalic acid H-pyrazoles-5-yl) amino]-the 5-methoxybenzoic acid
In airtight test tube, heating (150 ℃) 2-bromo-5-methoxybenzoic acid (2.26g in DMF (20ml), 9.79mmol), salt of wormwood (1.49g, 10.8mmol), the 5-amino-3-tertiary butyl-1-methylpyrazole (1.50g, 9.79mmol) and venus crystals (II) (35mg, mixture 0.20mmol) 16 hours.After the cooling, utilize water (10ml) diluted reaction mixture, utilize acetate to be acidified to pH=4.(3 * 20ml) extract this mixture, and (organic extracting solution that 2 * 30ml) washings merge is at Na to utilize water then to utilize methylene dichloride
2SO
4Last dry, filter and concentrating under reduced pressure.HPLC purifying residue (YMC propack C18 post, 150 * 20mm ID, 30%-80% acetonitrile/water gradient elution) obtains title compound (973mg, 31%), is light yellow solid.
1H NMR(300MHz，DMSO-d
6)δ13.22(brs，1H)，9.24(br s，1H)，7.38(d，1H)，7.10(dd，1H)，6.80(d，1H)，5.95(s，1H)，3.70(s，3H)，3.55(s，3H)，1.21(s，9H)：ES-MS m/z 304.2(MH
+)，HPLC RT(min)2.58.
Embodiment 2
Preparation 2-{[3-(4-chloro-phenyl-)-1-methyl isophthalic acid H-pyrazoles-5-yl] amino }-4,5-dimethoxybenzoic acid trifluoroacetate
In airtight test tube, heating (150 ℃) 2-bromo-5-methoxybenzoic acid (105mg in DMF (2ml), 0.40mmol), salt of wormwood (61mg, 0.44mmol), 5-amino-3-(4-chloro-phenyl-)-1-methylpyrazole (84mg, 0.40mmol) and venus crystals (II) (2mg, mixture 0.01mmol) 16 hours.After the cooling, utilize water (2ml) diluted reaction mixture, utilize acetate to be acidified to pH=4.(3 * 5ml) extract this mixture, and (organic extracting solution that 2 * 5ml) washings merge is at Na to utilize water then to utilize methylene dichloride
2SO
4Last dry, filter and concentrating under reduced pressure.(10%-95% acetonitrile/TFA (0.1%) is in water/TFA (0.1%) gradient elution for HPLC:YMC propack C18 post, 100 * 20mm ID for HPLC-MS purifying residue; MS:120-1000amu is in the single quartet of Micromass LCZ, EFI ionization), obtain title compound (28mg, 14%), be white solid.
1H NMR(300MHz，DMSO-d
6)δ9.78(s，1H)，7.82(ddd，2H)，7.42(ddd，2H)，7.36(s，1H)，6.74(s，1H)，6.56(s，1H)，3.74(s，3H)，3.71(s，6H)；ES-MS m/z 388.2(MH
+)，HPLC RT(min)2.58.
Embodiment 3
Preparation 2-{[3-(4-fluorophenyl)-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid
To 3-(4-fluorophenyl)-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-amine (intermediate D, 100mg, add in DMF 0.37mmol) (3ml) solution 2-iodo-benzoic acid (93mg, 0.37mmol), salt of wormwood (62mg, 0.45mmol) and venus crystals (II) (3mg, 0.01mmol).Mixture stirred 18 hours down at 150 ℃, was cooled to room temperature then.Utilize the Glacial acetic acid regulator solution to pH 4.(3 * 5ml) extract mixing, the organic extracting solution that utilizes the salt water washing to merge, dry (MgSO to utilize methylene dichloride
4), filter and concentrating under reduced pressure.(the 45-90% acetonitrile Yu Shuizhong), obtains title compound (17mg, 12%) to HPLC purifying residue, is the glassy yellow solid.
1H NMR(400MHz，DMSO-d
6)δ2.08(s，3H)，6.85(ddd，1H)，6.93(s，1H)，7.24(ddd，2H)，7.42(m，6H)，7.84(dd，1H)，7.92(ddd，2H)，10.02(s，1H)，13.23(s，1H)；ES-MS m/z 388.2(MH
+)；HPLC RT(min)3.47.
Embodiment 4
The preparation 2-{[3-tertiary butyl-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid
To the 3-tertiary butyl-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-amine (intermediate C, 1.00g, add in DMF 4.36mmol) (20ml) solution 2-bromo-5-methoxybenzoic acid (1.01g, 4.36mmol), salt of wormwood (723mg, 5.23mmol) and venus crystals (II) (32mg, 0.17mmol).Mixture stirred 18 hours down at 150 ℃, was cooled to room temperature then.Utilize the Glacial acetic acid regulator solution to pH4.(3 * 5ml) extract mixing, the organic extracting solution that utilizes the salt water washing to merge, dry (MgSO to utilize methylene dichloride
4), filter and concentrating under reduced pressure.(the 45-90% acetonitrile Yu Shuizhong), obtains title compound (500mg, 33%) to HPLC purifying residue, is the glassy yellow solid.
1H NMR(400MHz，DMSO-d
6)δ1.29(s，9H)，1.98(s，3H)，3.69(s，3H)，6.19(s，1H)，7.14(dd，1H)，7.26-7.37(m，6H)，9.49(s，1H)，13.25(s，1H)；ES-MSm/z 380.3(MH
+)；HPLC RT(min)3.18.
The similar approach of utilizing embodiment 1-4 to describe, synthetic following analogue.As described in Example 2, embodiment 7 and 28 products that obtain are salt.
In table 1a, R
4Group position such as following.
Table 1a
* remarks: the source that is used for the amino-pyrazol of coupled reaction: c=commercial; H, I, J, K=use above reaction process H, I, the described method preparation of J or K.
Table 1b
| The embodiment sequence number | The IUPAC name |
| 5 | 2-[(1-ethyl-1H-pyrazoles-5-yl) amino] phenylformic acid |
| 6 | 2-[(1-phenyl-1H-pyrazoles-5-yl) amino-5-(methylthio group)] phenylformic acid |
| 7 | 2-[(1,3-dimethyl-1H-pyrazoles-5-yl) amino]-4-fluorobenzoic acid trifluoroacetate |
| 8 | 2-[(1,3-dimethyl-1H-pyrazoles-5-yl) amino]-3-(trifluoromethyl) phenylformic acid |
| 9 | 2-[(1-benzyl-3-methyl isophthalic acid H-pyrazoles-5-yl) amino]-the 4-fluorobenzoic acid |
| 10 | 5-methoxyl group-2-[(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-yl) amino] phenylformic acid |
| 11 | The 2-[(3-tertiary butyl-1-methyl isophthalic acid H-pyrazoles-5-yl) amino] phenylformic acid |
| 12 | The 2-[(3-tertiary butyl-1-methyl isophthalic acid H-pyrazoles-5-yl) amino]-5-(methylthio group) phenylformic acid |
| 13 | The 2-[(3-tertiary butyl-1-ethyl-1H-pyrazoles-5-yl) amino]-4, the 5-dimethoxybenzoic acid |
| 14 | The 2-{[3-tertiary butyl-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 15 | The 2-{[3-tertiary butyl-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-4, the 5-dimethoxybenzoic acid |
| 16 | 2-([the 3-tertiary butyl-1-(2, the 4-3,5-dimethylphenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 17 | The 2-{[3-tertiary butyl-1-(2-ethylphenyl)-1H-pyrazoles-5-yl] amino }-4, the 5-dimethoxybenzoic acid |
| 18 | The 2-{[3-tertiary butyl-1-(2-ethylphenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 19 | The 2-{[3-tertiary butyl-1-(2-ethylphenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| The embodiment sequence number | The IUPAC name |
| 20 | The 2-{[3-tertiary butyl-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 6-fluorobenzoic acid |
| 21 | The 2-{[3-tertiary butyl-1-(2, the 5-3,5-dimethylphenyl)-1H-pyrazoles-5-yl] amino }-the 4-fluorobenzoic acid |
| 22 | The 2-{[3-tertiary butyl-1-(2, the 5-3,5-dimethylphenyl)-1H-pyrazoles-5-yl] amino }-the 5-fluorobenzoic acid |
| 23 | The 2-{[3-tertiary butyl-1-(2, the 5-3,5-dimethylphenyl)-1H-pyrazoles-5-yl] amino }-the 6-fluorobenzoic acid |
| 24 | The 2-{[3-tertiary butyl-1-(2, the 5-3,5-dimethylphenyl)-1H-pyrazoles-5-yl] amino }-the 4-tolyl acid |
| 25 | The 2-{[3-tertiary butyl-1-(2, the 5-3,5-dimethylphenyl)-1H-pyrazoles-5-yl] amino }-the 5-tolyl acid |
| 26 | The 2-{[3-tertiary butyl-1-(4-chloro-phenyl-)-1H-pyrazoles-5-yl] amino }-4, the 5-dimethoxybenzoic acid |
| 27 | The 2-{[3-tertiary butyl-1-(2-p-methoxy-phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 28 | 4,5-dimethoxy-2-[(1-methyl-3-phenyl-1H-pyrazoles-5-yl) amino] the phenylformic acid trifluoroacetate |
| 29 | 2-[(1,3-phenylbenzene-1H-pyrazoles-5-yl) amino]-the 5-methoxybenzoic acid |
| 30 | 2-{[1-(2 aminomethyl phenyl)-3-phenyl-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 31 | 4,5-dimethoxy-2-{[1-(2-aminomethyl phenyl)-3-phenyl-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 32 | 5-methoxyl group-2-{[1-(2-aminomethyl phenyl)-3-phenyl-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 33 | 2-{[1-(2, the 5-3,5-dimethylphenyl)-3-phenyl-1H-pyrazoles-5-yl] amino }-the 4-fluorobenzoic acid |
| The embodiment sequence number | The IUPAC name |
| 34 | 2-{[1-(2, the 5-3,5-dimethylphenyl)-3-phenyl-1H-pyrazoles-5-yl] amino }-the 6-fluorobenzoic acid |
| 35 | 2-{[1-(2, the 5-3,5-dimethylphenyl)-3-phenyl-1H-pyrazoles-5-yl] amino }-the 4-tolyl acid |
| 36 | 2-{[1-(2, the 5-3,5-dimethylphenyl)-3-phenyl-1H-pyrazoles-5-yl] amino }-the 5-tolyl acid |
| 37 | 2-{[1-(2, the 5-3,5-dimethylphenyl)-3-phenyl-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 38 | 2-{[1-(2, the 5-3,5-dimethylphenyl)-3-phenyl-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 39 | 2-{[1-(2, the 5-3,5-dimethylphenyl)-3-phenyl-1H-pyrazoles-5-yl] amino }-4, the 5-dimethoxybenzoic acid |
| 40 | 4-fluoro-2-{[1-(2-aminomethyl phenyl)-3-phenyl-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 41 | 2-fluoro-6-{[1-(2-aminomethyl phenyl)-3-phenyl-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 42 | 4-chloro-2-{[1-(2-aminomethyl phenyl)-3-phenyl-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 43 | 5-methyl-2-{[1-(2-aminomethyl phenyl)-3-phenyl-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 44 | 2-{[1-(2-ethylphenyl)-3-phenyl-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 45 | 2-{[1-(2-ethylphenyl)-3-phenyl-1H-pyrazoles-5-yl] amino }-4, the 5-dimethoxybenzoic acid |
| 46 | 2-{[3-(4-fluorophenyl)-1-phenyl-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 47 | 2-{[3-(4-fluorophenyl)-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| The embodiment sequence number | The IUPAC name |
| 48 | 2-{[3-(4-p-methoxy-phenyl)-1-(4-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 49 | 2-{[1-(2-aminomethyl phenyl)-3-(4-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 50 | 5-methoxyl group-2-{[1-(2-aminomethyl phenyl)-3-(4-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 51 | 4,5-dimethoxy-2-{[1-(2-aminomethyl phenyl)-3-(4-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 52 | 2-{[3-(4-p-methoxy-phenyl)-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino) phenylformic acid |
| 53 | 5-methoxyl group-2-{[3-(4-p-methoxy-phenyl)-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 54 | 2-{[3-(4-chloro-phenyl-)-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-4, the 5-dimethoxybenzoic acid |
| 55 | 2-{[1,3-bis (2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 56 | 4-fluoro-2-{[3-(4-fluorophenyl)-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 57 | 2-fluoro-6-{[3-(4-fluorophenyl)-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 58 | 2-{[3-(4-fluorophenyl)-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 4-tolyl acid |
| 59 | 2-{[3-(4-fluorophenyl)-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-tolyl acid |
| 60 | 2-{[1,3-bis (2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 61 | 4-fluoro-2-{[1-(2-aminomethyl phenyl)-3-(4-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid |
| The embodiment sequence number | The IUPAC name |
| 62 | 2-fluoro-6-{[1-(2-aminomethyl phenyl)-3-(4-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 63 | 4-chloro-2-{[1-(2-aminomethyl phenyl)-3-(4-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 64 | 4-methyl-2-{[1-(2-aminomethyl phenyl)-3-(4-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 65 | 5-methyl-2-{[1-(2-aminomethyl phenyl)-3-(4-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 66 | 2-{[1-(2, the 5-3,5-dimethylphenyl)-3-(4-fluorophenyl)-1H-pyrazoles-5-yl] amino }-the 4-fluorobenzoic acid |
| 67 | 2-{[1-(2, the 5-3,5-dimethylphenyl)-3-(4-fluorophenyl)-1H-pyrazoles-5-yl] amino }-the 4-fluorobenzoic acid |
| 68 | 2-{[1-(2, the 5-3,5-dimethylphenyl)-3-(4-fluorophenyl)-1H-pyrazoles-5-yl] amino }-the 6-fluorobenzoic acid |
| 69 | 2-{[1-(2, the 5-3,5-dimethylphenyl)-3-(4-fluorophenyl)-1H-pyrazoles-5-yl] amino }-the 4-tolyl acid |
| 70 | 2-{[1-(2, the 5-3,5-dimethylphenyl)-3-(4-fluorophenyl)-1H-pyrazoles-5-yl] amino }-the 5-tolyl acid |
| 71 | 2-{[1-(2, the 5-3,5-dimethylphenyl)-3-(4-fluorophenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 72 | 2-{[1-(2, the 5-3,5-dimethylphenyl)-3-(4-fluorophenyl)-1H-pyrazoles-5-yl] amino }-4, the 5-dimethoxybenzoic acid |
| 73 | 2-{[1-(2-aminomethyl phenyl)-3-(3-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 74 | 5-methoxyl group-2-{[1-(2-aminomethyl phenyl)-3-(3-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 75 | 2-fluoro-6-{[4-(4-fluorophenyl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid |
| The embodiment sequence number | The IUPAC name |
| 76 | The 2-{[3-tertiary butyl-1-(5-fluoro-2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 6-fluorobenzoic acid |
| 77 | The 2-{[3-tertiary butyl-1-(5-fluoro-2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 4-fluorobenzoic acid |
| 78 | The 2-{[3-tertiary butyl-1-(2-p-methoxy-phenyl)-1H-pyrazoles-5-yl] amino }-the 4-fluorobenzoic acid |
| 79 | The 2-{[3-tertiary butyl-1-(2-p-methoxy-phenyl)-1H-pyrazoles-5-yl] amino }-the 5-tolyl acid |
| 80 | 2-(the 3-tertiary butyl-1-[2-(methylthio group) phenyl]-1H-pyrazoles-5-yl } amino)-the 5-methoxybenzoic acid |
| 81 | The 2-{[3-tertiary butyl-1-(2-ethoxyl phenenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 82 | The 2-{[3-tertiary butyl-1-(2-ethoxyl phenenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 83 | The 2-{[3-tertiary butyl-1-(2-ethoxyl phenenyl)-1H-pyrazoles-5-yl] amino }-the 5-tolyl acid |
| 84 | The 2-{[3-tertiary butyl-1-(2-chloro-phenyl-)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 85 | The 2-{[3-tertiary butyl-1-(2-chloro-phenyl-)-1H-pyrazoles-5-yl] amino }-the 4-fluorobenzoic acid |
| 86 | 2-{[3-(4-fluoro-2-aminomethyl phenyl)-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 87 | 2-{[3-(4-fluoro-2-aminomethyl phenyl)-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 88 | 2-{[1-(5-fluoro-2-aminomethyl phenyl)-3-phenyl-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 89 | 2-{[1-(2-ethylphenyl)-3-(4-fluorophenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid |
| The embodiment sequence number | The IUPAC name |
| 90 | 4-fluoro-2-{[3-(4-fluorophenyl)-1-(2-p-methoxy-phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 91 | 2-{[1-(2-ethylphenyl)-3-(4-fluorophenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 92 | 2-{[3-(4-fluorophenyl)-1-(2-p-methoxy-phenyl)-1H-pyrazoles-5-yl] amino }-4, the 5-dimethoxybenzoic acid |
| 93 | 2-{[1-(5-fluoro-2-aminomethyl phenyl)-3-(4-fluorophenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 94 | 2-{[3-(4-fluorophenyl)-1-(2-p-methoxy-phenyl)-1H-pyrazoles-5-yl] amino }-the 5-tolyl acid |
| 95 | 2-{[1-(5-fluoro-2-aminomethyl phenyl)-3-(4-fluorophenyl)-1H-pyrazoles-5-yl] amino }-the 5-tolyl acid |
| 96 | 2-{[3-(4-fluorophenyl)-1-(2-p-methoxy-phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 97 | 4-fluoro-2-{[3-(3-p-methoxy-phenyl)-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 98 | 4,5-dimethoxy-2-{[3-(3-p-methoxy-phenyl)-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 99 | 2-{[3-(3-p-methoxy-phenyl)-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 100 | 5-methoxyl group-2-{[3-(3-p-methoxy-phenyl)-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 101 | 2-{[3-(3-p-methoxy-phenyl)-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-tolyl acid |
| 102 | 5-chloro-2-{[3-methyl isophthalic acid-(2-aminomethyl phenyl)-4-pyridin-3-yl-1H-pyrazoles-5-yl] amino } the phenylformic acid trifluoroacetate |
| 103 | The 2-{[3-tertiary butyl-4-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid |
| The embodiment sequence number | The IUPAC name |
| 104 | The 2-{[3-tertiary butyl-4-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 105 | 2-{[3-(4-fluorophenyl)-4-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino)-the 5-methoxybenzoic acid |
| 106 | The 2-{[3-tertiary butyl-1-(2-p-methoxy-phenyl)-4-methyl isophthalic acid H-pyrazoles-5-yl] amino } phenylformic acid |
| 107 | The 2-{[3-tertiary butyl-1-(2-p-methoxy-phenyl)-4-methyl isophthalic acid H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
Embodiment 108
Preparation 2-{[3-cyclopentyl-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } methyl benzoate
Under argon gas atmosphere, with 3-cyclopentyl-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-amine (intermediate B, 400mg, 1.66mmol), 2-methyl-bromobenzoate (297mg, 1.38mmol), cesium carbonate (630mg, 1.93mmol), BINAP (87mg, 0.14mmol) and Pd
2(dba)
3(72mg, the mixture heating up to 110 of dry toluene 0.07mmol) (4ml) ℃ 16 hours reaction mixture are utilized the ethyl acetate dilution to room temperature, filter and concentrating under reduced pressure.Silica gel chromatography purifying residue, (1: 8, v/v) wash-out obtained product, is glassy yellow oily matter (303mg, 58%) to utilize the EtOAc/ hexane.ES-MSm/z 376.3(MH
+)；HPLCRT(min)3.94。
Embodiment 109
Preparation 2-{[3-cyclopentyl-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid
To 2-{[3-cyclopentyl-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } (0.59mmol adds the THF (5.4ml) and the 1N NaOH aqueous solution (1.8ml) to methyl benzoate in the solution of MeOH 220mg) (1.8ml).Mixture at room temperature stirred 21 hours.Organic solvent is removed in decompression, utilizes water dilution residue, and (2 * 5ml) extract the aqueous solution to utilize Anaesthetie Ether.Utilize 1N HCl solution acidifying water layer to pH=1 to 2.(3 * 5ml) extract mixture to utilize ethyl acetate.After the removal of solvent under reduced pressure, obtain product, be white solid (169mg, 79%).
1H NMR(400MHz，DMSO-d
6)δ1.58-1.62(m，2H)，1.65-1.78(m，4H)，1.90-2.01(m，2H)，2.06(s，3H)，2.99-3.10(m，1H)，6.23(s，1H)，6.80(t，1H)，7.20-7.30(m，3H)，7.30-7.40(m，2H)，7.42-7.51(m，1H)，7.81(d，1H)，9.84(s，1H)，13.14(s，1H).ES-MS m/z 362.3(MH
+)，HPLC RT(min)3.39.
The method of utilizing the foregoing description 109 to describe prepares following analogue.
In table 2a, R
4The group position is as follows.
Table 2a
* remarks: the source that is used for the amino-pyrazol of coupled reaction: c=commercial; I=uses the above described method preparation of reaction process I.
Table 2b
| The embodiment sequence number | The IUPAC name |
| 110 | The 2-[(3-tertiary butyl-1-methyl isophthalic acid H-pyrazoles-5-yl) amino]-the 5-tolyl acid |
| 111 | The 2-[(3-tertiary butyl-1-phenyl-1H-pyrazoles-5-yl) amino]-the 5-methoxybenzoic acid |
| 112 | The 2-{[3-tertiary butyl-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-fluorobenzoic acid |
| The embodiment sequence number | The IUPAC name |
| 113 | The 2-{[3-tertiary butyl-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-tolyl acid |
| 114 | The 2-{[3-tertiary butyl-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 4-tolyl acid |
| 115 | 2-(the 3-tertiary butyl-1-[2-(trifluoromethyl) phenyl]-1H-pyrazoles-5-yl } amino)-the 5-methoxybenzoic acid |
| 116 | The 2-{[3-tertiary butyl-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-5-(difluoro-methoxy) phenylformic acid |
| 117 | The 2-{[3-tertiary butyl-1-(2, the 5-3,5-dimethylphenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 118 | The 2-{[3-tertiary butyl-1-(2, the 5-3,5-dimethylphenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 119 | The 2-{[3-tertiary butyl-1-(5-fluoro-2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 120 | The 2-{[3-tertiary butyl-1-(5-fluoro-2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 121 | The 2-{[3-tertiary butyl-1-(2, the 3-3,5-dimethylphenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 122 | The 2-{[3-tertiary butyl-1-(2, the 6-3,5-dimethylphenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 123 | 2-{[3-cyclopentyl-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 124 | 2-{[3-cyclopentyl-1-(2, the 5-3,5-dimethylphenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 125 | 5-methoxyl group-2-[(2-phenyl-4,5,6,7-tetrahydrochysene-2H-imidazo-3-yl) amino] phenylformic acid |
| 126 | 5-methoxyl group-2-[(3-methyl isophthalic acid, 4-phenylbenzene-1H-pyrazoles-5-yl) amino] phenylformic acid |
| The embodiment sequence number | The IUPAC name |
| 127 | 2-{[1-(2, the 5-3,5-dimethylphenyl)-3-(1-methyl cyclopropyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 128 | 2-([1-(2, the 5-3,5-dimethylphenyl)-3-(1-methyl cyclopropyl)-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 129 | 2-{[1-(2, the 6-3,5-dimethylphenyl)-3-sec.-propyl-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 130 | 2-{[3-isobutyl--1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 131 | 2-{[3-cyclohexyl-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 132 | 2-{[3-cyclohexyl-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 133 | 5-methoxyl group-2-{[1-methyl-4-phenyl-3-(trifluoromethyl)-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 134 | 5-methoxyl group-2-{[1-(2-aminomethyl phenyl)-4-phenyl-3-(trifluoromethyl)-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 135 | 2-{[1-(2, the 5-3,5-dimethylphenyl)-4-phenyl-3-(trifluoromethyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 136 | The 2-{[3-tertiary butyl-1-(2-methoxyl group-5-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 137 | The 2-{[3-tertiary butyl-1-(2, the 3-3,5-dimethylphenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 138 | The 2-{[3-tertiary butyl-1-(5-chloro-2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 139 | The 2-{[3-tertiary butyl-1-(2-methoxyl group-6-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 140 | The 2-{[3-tertiary butyl-1-(5-methoxyl group-2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| The embodiment sequence number | The IUPAC name |
| 141 | The 2-{[3-tertiary butyl-1-(2-methoxyl group-6-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 142 | The 2-{[3-tertiary butyl-1-(5-chloro-2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 143 | The 2-{[3-tertiary butyl-1-(2, the 6-3,5-dimethylphenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 144 | 2-{[1-(4-chloro-2-aminomethyl phenyl)-3-methyl-4-phenyl-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 145 | 5-methoxyl group-2-(3-methyl-4-phenyl-1-[2-(trifluoromethyl) phenyl]-1H-pyrazoles-5-yl } amino } phenylformic acid |
| 146 | 2-{[1-(2-p-methoxy-phenyl)-3-methyl-4-phenyl-1H-pyrazoles-5-yl] amino }-the 5-tolyl acid |
| 147 | 2-{[1-(2, the 5-3,5-dimethylphenyl)-3-methyl-4-phenyl-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 148 | 2-{[1-(5-fluoro-2-aminomethyl phenyl)-3-methyl-4-phenyl-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 149 | 2-{[1-(2-chloro-phenyl-)-3-methyl-4-phenyl-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 150 | 2-{[1-(2, the 6-3,5-dimethylphenyl)-3-isobutyl--1H-pyrazoles-5-yl] amino } phenylformic acid |
| 151 | 2-{[1-(2, the 6-3,5-dimethylphenyl)-3-(1-methyl cyclopropyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 152 | 2-{[1-(2, the 6-3,5-dimethylphenyl)-3-isobutyl--1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 153 | 2-{[1-(2, the 6-3,5-dimethylphenyl)-3-(1-methyl cyclopropyl)-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 154 | 2-{[1-(2, the 6-3,5-dimethylphenyl)-3-(3,3, the 3-trifluoro propyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
Embodiment 155
The preparation 2-[(3-tertiary butyl-1-methyl isophthalic acid H-pyrazoles-5-yl) amino]-the 5-methoxyl methyl benzoate
In 100ml oven dried flask, add the 5-amino-3-tertiary butyl-1-methylpyrazole (2.00g, 13.1mmol), 2-bromo-5-methoxyl methyl benzoate (2.67g, 10.9mmol), cesium carbonate (4.96g, 15.2mmol), Pd
2(dba)
3(337mg, 0.33mmol), BINAP (338mg, 0.54mmol) and toluene (35ml).With the reaction mixture degassing, place N
2Under the atmosphere, stirred 16 hours at 110 ℃ then.Reaction mixture adds ethyl acetate (30ml) to room temperature.Filtering mixt utilizes EtOAc (10ml) washing leaching cake, concentrating under reduced pressure filtrate.Fast silica gel chromatogram purifying residue (elutriant: 10 to 30%EtOAc hexane solution), obtain title compound, be glassy yellow oily matter (1.34g, 38%).
1H NMR(400MHz，CDCl
3)δ1.28(s，9H)，3.63(s，3H)，3.78(s，3H)，3.94(s，3H)，5.97(s，1H)，6.82(d，1H)，7.10(dd，1H)，7.47(d，1H).
Embodiment 156
The preparation 2-[(4-bromo-3-tertiary butyl-1-methyl isophthalic acid H-pyrazoles-5-yl) amino]-the 5-methoxyl methyl benzoate
(embodiment 155, and 1.34g drips Br in acetate 4.22mmol) (27ml) solution to 2-(the 5-tertiary butyl-2-methyl-2H-pyrazole-3-yl amino)-5-methoxyl group-methyl benzoate
2(6.74g, acetate 4.22mmol) (5ml) solution.Stirring reaction 5 minutes adds entry (100ml) then.Utilize EtOAc to extract water, the organic layer that utilizes water washing to merge utilizes NaHCO then
3(10% aqueous solution) washing 10 times.Dry organic layer (Na
2SO
4), filter and concentrating under reduced pressure.Fast silica gel chromatogram purifying residue (elutriant: 5 to 10%EtOAc hexane solutions), obtain title compound, be glassy yellow solid (1.49g, 89%).
1H NMR(400MHz，CDCl
3)δ1.40(s，9H)，3.66(s，3H)，3.78(s，3H)，4.05(s，3H)，6.32(d，1H)，7.06(dd，1H)，7,48(d，1H).
Embodiment 157
The preparation 2-{[3-tertiary butyl-4-(4-p-methoxy-phenyl)-1-methyl isophthalic acid H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid
To 2-(the 4-bromo-5-tertiary butyl-2-methyl-2H-pyrazole-3-yl amino)-5-methoxyl methyl benzoate (embodiment 96,100mg, 0.25mmol), 4-anisole ylboronic acid (153.4mg, 1.01mmol), PdCl
2(dppf) CH
2Cl
2(18.46mg, toluene 0.03mmol) (6.1ml) He add in the solution of diox (1.22ml) the 2M aqueous sodium carbonate (1.22ml, 2.44mmol).In reaction mixture, fed Ar 15 minutes, then 75 ℃ of following stirring reactions 18 hours.Then reaction mixture is cooled to room temperature, filters by silica gel plug.Concentrating under reduced pressure filtrate is dissolved in residue in the mixture of THF (4ml), MeOH (2ml) and water (4ml).(60mg, 2.52mmol), mixture at room temperature stirred 18 hours to add lithium hydroxide.Concentrated reaction mixture, preparation property HPLC purifying residue obtains title compound (27.9mg, 27%), is white solid.
1H NMR(400MHz，CDCl
3)δ1.21(s，9H)，3.61(s，3H)，3.74(s，6H)，6.41(d，1H)，6.70(d，2H)，7.04(dd，1H)，7.09(d，2H)，7.39(d，1H).ES-MS m/z 410.2(MH
+)；HPLC RT(min)3.66.
The analogue that utilizes the synthetic table of aforesaid method 3a to enumerate.Embodiment 162,163,173,182,183,186 and 187 products that obtain are trifluoroacetate.
In table 3a, R
4Group position such as following.
Table 3a
* remarks: the source that is used for the amino-pyrazol of coupled reaction: c=is commercial; I and J=use above reaction process I and the described method preparation of J.
Table 3b
| The embodiment sequence number | The IUPAC name |
| 158 | 2-[(1,4-phenylbenzene-1H-pyrazoles-5-yl) amino]-the 5-methoxybenzoic acid |
| 159 | 5-methoxyl group-2-{[4-(4-p-methoxy-phenyl)-1-phenyl-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 160 | 2-{[4-(2,4 difluorobenzene base)-1-phenyl-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 161 | 2-{[4-(4-acetylphenyl)-1-phenyl-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 162 | 5-methoxyl group-2-[(1-phenyl-4-pyridin-4-yl-1H-pyrazoles-5-yl) amino] the phenylformic acid trifluoroacetate |
| 163 | 5-methoxyl group-2-[(1-phenyl-4-pyridin-3-yl-1H-pyrazoles-5-yl) amino] the phenylformic acid trifluoroacetate |
| 164 | 5-methoxyl group-2-{[3-methyl isophthalic acid-(2-aminomethyl phenyl)-4-phenyl-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 165 | 2-{[4-(4-fluorophenyl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 166 | 5-methoxyl group-2-{[3-methyl isophthalic acid-(2-aminomethyl phenyl)-4-(4-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 167 | 5-methoxyl group-2-{[4-(4-p-methoxy-phenyl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 168 | 2-{[4-(4-chloro-phenyl-)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| The embodiment sequence number | The IUPAC name |
| 169 | 2-{[4-(2,4 difluorobenzene base)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 170 | 2-{[4-(3-fluoro-4-p-methoxy-phenyl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 171 | 2-{[4-(4-acetylphenyl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 172 | 5-methoxyl group-2-(3-methyl isophthalic acid-(2-aminomethyl phenyl)-4-[4-(trifluoromethoxy) phenyl]-1H-pyrazoles-5-yl } amino) phenylformic acid |
| 173 | 5-methoxyl group-2-{[3-methyl isophthalic acid-(2-aminomethyl phenyl)-4-pyridin-4-yl-1H-pyrazoles-5-yl] amino } the phenylformic acid trifluoroacetate |
| 174 | 5-methoxyl group-2-{[3-methyl isophthalic acid-(2-aminomethyl phenyl)-4-pyridin-3-yl-1H-pyrazoles-5-yl] amino } the phenylformic acid trifluoroacetate |
| 175 | 5-methoxyl group-2-{[4-(6-methoxypyridine-3-yl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 176 | 5-fluoro-2-{[3-methyl isophthalic acid-(2-aminomethyl phenyl)-4-pyridine-3-base-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 177 | 2-{[4-(3-chloro-phenyl-)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 178 | 2-{[4-(2-chloro-phenyl-)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 179 | 2-{[4-(4-fluoro-2-aminomethyl phenyl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 180 | 2-{[4-(4-fluoro-3-aminomethyl phenyl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| The embodiment sequence number | The IUPAC name |
| 181 | 2-{[4-(4-ethoxyl phenenyl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 182 | The 2-{[3-tertiary butyl-4-(4-chloro-phenyl-)-1-methyl isophthalic acid H-pyrazoles-5-yl] amino }-5-methoxybenzoic acid trifluoroacetate |
| 183 | The 2-[(3-tertiary butyl-1-methyl-4-phenyl-1H-pyrazoles-5-yl) amino]-5-methoxybenzoic acid trifluoro-acetate |
| 184 | The 2-{[3-tertiary butyl-1-methyl-4-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 185 | The 2-{[3-tertiary butyl-4-(6-methoxypyridine-3-yl)-1-methyl isophthalic acid H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 186 | The 2-[(3-tertiary butyl-1-methyl-4-pyridin-4-yl-1H-pyrazoles-5-yl) amino]-5-methoxybenzoic acid trifluoroacetate |
| 187 | The 2-[(3-tertiary butyl-1-methyl-4-pyridin-3-yl-1H-pyrazoles-5-yl) amino]-5-methoxybenzoic acid trifluoroacetate |
| 188 | The 2-{[3-tertiary butyl-4-(3-p-methoxy-phenyl)-1-methyl isophthalic acid H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 189 | The 2-{[3-tertiary butyl-4-(2-fluorophenyl)-1-methyl isophthalic acid H-pyrazoles-5-yl] amino }-the 5-tolyl acid |
| 190 | The 2-[(3-tertiary butyl-1-methyl-4-phenyl-1H-pyrazoles-5-yl) amino]-the 5-tolyl acid |
| 191 | The 2-{[3-tertiary butyl-1-methyl-4-(4-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 192 | The 2-{[3-tertiary butyl-4-(4-fluorophenyl)-1-methyl isophthalic acid H-pyrazoles-5-yl] amino }-the 5-tolyl acid |
| 193 | The 2-{[3-tertiary butyl-4-(4-fluorophenyl)-1-methyl isophthalic acid H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 194 | The 2-[(3-tertiary butyl-1-methyl-4-pyridin-4-yl-1H-pyrazoles-5-yl) amino]-the 5-tolyl acid |
| The embodiment sequence number | The IUPAC name |
| 195 | 2-{[4-(4-fluorophenyl)-1-(2-aminomethyl phenyl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 196 | 2-{[1-(2, the 5-3,5-dimethylphenyl)-3-ethyl-4-(4-fluorophenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 197 | 5-methoxyl group-2-{[1-(2-aminomethyl phenyl)-4-pyridin-4-yl-3-(trifluoromethyl)-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 198 | 5-methoxyl group-2-{[4-(4-p-methoxy-phenyl)-1-(2-aminomethyl phenyl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 199 | 2-{[3-ethyl-4-(4-fluorophenyl)-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 200 | 2-{[3-ethyl-1-(2-aminomethyl phenyl)-4-phenyl-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 201 | 2-{[1-(2, the 5-3,5-dimethylphenyl)-3-ethyl-4-phenyl-I H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 202 | 2-{[3-ethyl-4-(6-methoxypyridine-3-yl)-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 203 | 2-{[3-ethyl-1-(2-aminomethyl phenyl)-4-pyridin-4-yl-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 204 | 2-{[3-ethyl-4-(4-p-methoxy-phenyl)-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 205 | 2-{[1-(2, the 5-3,5-dimethylphenyl)-3-ethyl-4-pyridine-4-base-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 206 | 2-{[1-(2, the 5-3,5-dimethylphenyl)-3-ethyl-4-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 207 | 2-{[4-(4-benzoyl phenyl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| The embodiment sequence number | The IUPAC name |
| 208 | 2-{[4-(4-fluorophenyl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-tolyl acid |
| 209 | 2-{[4-(2-isopropyl phenyl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-tolyl acid |
| 210 | 5-methyl-2-{[3-methyl isophthalic acid-(2-aminomethyl phenyl)-4-(4-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 211 | 5-methyl-2-{[3-methyl isophthalic acid-(2-aminomethyl phenyl)-4-(2-propoxy-phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 212 | 2-{[4-(2-butoxy phenyl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-tolyl acid |
| 213 | 2-{[4-(3-fluoro-4-p-methoxy-phenyl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-tolyl acid |
| 214 | 5-methoxyl group-2-{[3-methyl isophthalic acid-(2-aminomethyl phenyl)-4-(3-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 215 | 2-{[4-(2-p-methoxy-phenyl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-tolyl acid |
| 216 | 2-{[4-(3-fluorophenyl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 217 | 2-{[4-(2-isopropyl phenyl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 218 | 2-{[4-(4-p-methoxy-phenyl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-tolyl acid |
| 219 | 2-{[4-(2-fluorophenyl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 220 | 2-{[4-(2-ethoxyl phenenyl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-tolyl acid |
| 221 | 5-methoxyl group-2-{[4-(2-p-methoxy-phenyl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid |
| The embodiment sequence number | The IUPAC name |
| 222 | 5-methoxyl group-2-{[4-(3-p-methoxy-phenyl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 223 | 5-methyl-2-{[3-methyl isophthalic acid-(2-aminomethyl phenyl)-4-pyridine-3-base-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 224 | 2-{[4-(2-ethoxyl phenenyl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 225 | 2-{[4-(2,4 dichloro benzene base)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 226 | 2-{[4-(2-ethylphenyl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 227 | 2-{[4-(5-chloro-2-p-methoxy-phenyl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 228 | 5-methoxyl group-2-{[3-methyl isophthalic acid-(2-aminomethyl phenyl)-4-(2-propoxy-phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 229 | 5-methoxyl group-2-{[1-(2-p-methoxy-phenyl)-3-methyl-4-phenyl-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 230 | 2-{[4-(2,2-two fluoro-1,3-benzo dioxole-4-yl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 231 | 2-{[4-(5-fluoro-2-p-methoxy-phenyl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 232 | 2-{[4-(2, the 4-Dimethoxyphenyl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid |
| 233 | 5-methoxyl group-2-(3-methyl isophthalic acid-(2-aminomethyl phenyl)-4-[2-(methylthio group) phenyl]-1H-pyrazoles-5-yl } amino) phenylformic acid |
Embodiment 234
The preparation 5-bromo-2-{[3-tertiary butyl-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } methyl benzoate
In dry 25ml flask, introduce the 3-tertiary butyl-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-amine (intermediate C, 220mg, 0.96mmol), 2, the 5-methyl-dibromobenzoate (235mg, 0.80mmol), Pd
2(dba)
3(36.6mg, 0.04mmol), BINAP (49.8mg, 0.08mmol) and Cs
2CO
3(365mg, 1.12mmol).Make the flask degassing by adding toluene (1ml), say mixture heating up to 110 then ℃ 20 hours.Cooling mixture utilizes the ethyl acetate dilution to room temperature.Leach solid, removal of solvent under reduced pressure.With residue be dissolved in methyl alcohol/THF (4: 1, v/v), pass through C
2-silica gel plug filters.The HPLC purifying utilizes 10% to 90% acetonitrile/water gradient elution, obtains 110mg (31%) title compound.
1H NMR(300 MHz，CD
2Cl
2)δ9.21(s，1H)，7.41(d，1H)，7.20-7.30(m，5H)，7.10(d，1H)，6.09(s，1H)，3.72(s，3H)，2.04(s，3H)，1.30(s，9H)，ES-MS m/z 444.1(MH
+)；NPLC RT(min)4.30.
Embodiment 235
The preparation 2-{[3-tertiary butyl-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-5-ethyl benzoate methyl esters
To the 5-bromo-2-{[3-tertiary butyl-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino methyl benzoate (embodiment 234,1.15g, 4.13mmol), ethyl-boron dihydroxide (1.16g, 15.7mmol) and Pd (dppf) Cl
2CH
2Cl
2(114mg, (20ml) is with diox (5ml) to add toluene in mixture 0.16mmol).Degassing gained solution is 30 minutes under nitrogen atmosphere, then add sodium bicarbonate (the 2M aqueous solution, 15ml).With mixture heating up to 85 ℃ 16 hours.Permission is cooled to room temperature with reaction mixture.Removal of solvent under reduced pressure, fast silica gel chromatogram purifying residue utilizes 0 to 10% ethyl acetate/hexane wash-out, obtains 606mg (61%) title compound.
1H NMR(300MHz，CD
2Cl
2)δ9.17(s，1H)，7.68(s，1H)，7.22-7.33(m，6H)，6.08(s，1H)，3.70(s，3H)，2.51(q，2H)，2.05(s，3H)，1.30(s，9H)，1.14(t，3H).ES-MS m/z 392.2(MH
+)；HPLC RT(min)4.62.
Embodiment 236
The preparation 2-{[3-tertiary butyl-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-ethyl benzoate
To the 2-{[3-tertiary butyl-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-(embodiment 235 for 5-ethyl benzoate methyl esters, 115mg, 0.29mmol) methyl alcohol (1ml) and the solution of THF (1ml) mixture in add lithium hydroxide monohydrate (123mg, 2.94mmol) water (2ml) solution, heated mixt to 40 ℃ 1 hour.Reaction mixture is cooled to room temperature, utilizes 0.5NHCl solution regulator solution pH to 5.Removal of solvent under reduced pressure is carried out the HPLC purifying with residue, utilizes 10% to 90% acetonitrile/water gradient elution, obtains 109.6mg (99%) title compound.
1H NMR(300MH
z，CD
2Cl
2)δ9.28(s，1H)，7.76(s，1H)，7.26-7.37(m，6H)，6.15(s，1H)，2.60(q，2H)，2.08(s，3H)，1.37(s，9H)，1.23(t，3H).ES-MS m/z 378.3(MH
+)；HPLC RT(min)3.64.
The synthetic following analogue of the method for utilizing the foregoing description 236 to describe.
Table 4a
* remarks: the source that is used for the amino-pyrazol of coupled reaction: c=is commercial; J=uses the above described method preparation of reaction process J.
Table 4b
| The embodiment sequence number | The IUPAC name |
| 237 | 5-ethyl-2-{[1-(2-aminomethyl phenyl)-3-phenyl-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 238 | 5-ethyl-2-{[3-(4-fluorophenyl)-1-(2-rh ethylphenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 239 | 5-ethyl-2-([1-(2-aminomethyl phenyl)-3-(4-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid |
| 240 | 2-{[1-(2, the 5-3,5-dimethylphenyl)-3-phenyl-1H-pyrazoles-5-yl] amino }-the 5-ethyl benzoate |
| 241 | 2-([1-(2, the 5-3,5-dimethylphenyl)-3-(4-fluorophenyl)-1H-pyrazoles-5-yl] amino }-the 5-ethyl benzoate |
Embodiment 242
Preparation 2-([the 3-tertiary butyl-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 4-chloro benzoic ether
According to the method that embodiment 234 describes, utilize intermediate C and 2-bromo-4-chloro benzoic ether as starting raw material, prepare this compound.
1HNMR(300MHz，CD
2Cl
2)δ9.33(s，1H)，7.84(d，1H)，7.20-7.30(m，4H)，7.15(s，1H)，6.68(d，1H)，6.13(s，1H)，3.72(s，3H)，2.06(s，3H)，1.31(s，9H).ES-MS m/z398.3(MH)
+；HPLC RT(min)4.27.
Embodiment 243
The preparation 2-{[3-tertiary butyl-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-4-ethyl benzoate methyl esters
To the 2-{[3-tertiary butyl-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino-the 4-chloro benzoic ether (embodiment 242,50mg, 0.13mmol), ethyl-boron dihydroxide (18.56mg, 0.26mmol), Pd
2(dba)
3(5.8mg, 0.006mmol), three (tertiary butyl) phosphine (2.54mg, 0.013mmol) and Repone K (14.6mg adds diox (1ml) in mixture 0.25mmol).Gained solution outgased 30 minutes under argon gas, be heated to then 110 ℃ 16 hours.Reaction mixture is cooled to room temperature.Utilize the ethyl acetate dilution, filter by silica gel plug.Removal of solvent under reduced pressure, HPLC purifying crude product utilizes 30 to 100% acetonitrile/water gradient elutions, obtains 39.8mg (81%) title compound.
1H NMR(300MHz，CD
2Cl
2)δ9.23(s，1H)，7.74(d，1H)，7.23-7.29(m，4H)，7.03(s，1H)，6.57(d，1H)，6.09(s，1H)，3.69(s，3H)，2.55(q，2H)，2.06(s，3H)，1.30(s，9H)，1.15(t，3H).ES-MS m/z 392.2(MH
+)；HPLC RT(min)4.65.
Embodiment 244
The preparation 2-{[3-tertiary butyl-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 4-ethyl benzoate
The method for hydrolysis that utilizes embodiment 243 to describe prepares this compound.
1H NMR(300MH
z，CD
2Cl
2)δ9.45(s，1H)，7.81(d，1H)，7.20-7.35(m，4H)，7.09(s，1H)，6.68(d，1H)，6.13(s，1H)，2.61(q，2H)，2.03(s，3H)，1.33(s，9H)，1.19(t，3H)，ES-MS m/z 378.2(MH
+)；HPLC RT(min)4.12.
Embodiment 245
The preparation 2-[(3-tertiary butyl-1-methyl isophthalic acid H-pyrazoles-5-yl) amino]-4-pyrimidine-5-yl benzoic acid
The method of utilizing embodiment 244 to describe prepares title compound similarly.ES-MS m/z352.2(MH
+)；HPLC RT(min)2.94。
Embodiment 246
The preparation 2-[(3-tertiary butyl-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl) amino]-the 4-fluorophenyl carbamate
In exsiccant 25ml flask, introduce the 3-tertiary butyl-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-amine (intermediate C, 110mg, 0.48mmol), 2-bromo-4-fluorophenyl carbamate (93.1mg, 0.40mmol), Pd
2(dba)
3(18.3mg, 0.02mmol), BINAP (24.9mg, 0.04mmol) and Cs
2CO
3(182mg, 0.56mmol).By adding toluene (1ml), make the flask degassing, with mixture heating up to 110 ℃ 20 hours.Cooling mixture utilizes the ethyl acetate dilution to room temperature then.Leach solid, removal of solvent under reduced pressure.With residue be dissolved in methyl alcohol/THF (4: 1, v/v) in, filter by the C1-silica gel plug.The HPLC purifying utilizes 30% to 90% acetonitrile/water gradient elution, obtains 136.2mg (89%) title compound.
1HNMR(300MHz，CD
2Cl
2)δ9.42(s，1H)，7.85(dd，1H)，7.21-7.30(m，4H)，6.86(dd，1H)，6.44(dt，1H)，6.11(s，1H)，3.70(s，3H)，2.04(s，3H)，1.30(s，9H).ES-MS m/z 381.9(MH
+)；HPLCRT(min)4.50.
Embodiment 247
The preparation 2-{[3-tertiary butyl-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-4-(1H-imidazoles-1-yl) phenylformic acid
To the 2-{[3-tertiary butyl-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-(embodiment 246 for the 4-fluorophenyl carbamate, 50mg, 0.13mmol), imidazoles (17.8mg, 0.26mmol) and salt of wormwood (90.6mg adds DMF (1ml) in mixture 0.66mmol).Mixture heated 16 hours down at 110 ℃ then.Permission is cooled to room temperature with reaction mixture.Removal of solvent under reduced pressure, HPLC purifying residue utilizes 10 to 80% acetonitrile/water gradient elutions, obtains 13.8mg (25%) title compound
1H NMR(300MHz，CD
3OD)δ9.48(t，1H)，8.15(d，1H)，8.07(t，1H)，7.76(t，1H)，7.52(d，1H)，7.28-7.42(m，4H)，7.10(dd，1H)，6.48(s，1H)，2.06(s，3H)，1.35(s，9H).ES-MS m/z 416.2(MH
+)；HPLC RT(min)2.21.
Embodiment 248
The preparation 2-{[3-tertiary butyl-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 4-fluorobenzoic acid
The method for hydrolysis that utilizes embodiment 246 to describe prepares this compound.
1H NMR(300MHz，CD
2Cl
2)δ9.49(s，1H)，7.89(dd，1H)，7.19-7.32(m，4H)，6.91(dd，1H)，6.47(dt，1H)，6.13(s，1H)，2.01(s，3H)，1.31(s，9H).ES-MSm/z 368.1(MH
+)；HPLC RT(min)4.01.
Embodiment 249
The preparation 2-{[3-tertiary butyl-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-4-(dimethylamino) phenylformic acid
Under nitrogen atmosphere, under-40 ℃, to the 2-{[3-tertiary butyl-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-(embodiment 248, and 35mg adds LiNMe in THF 0.09mmol) (1ml) solution for the 4-fluorobenzoic acid
2(0.19ml, 1M is in hexane).At room temperature stirred the mixture then 30 minutes, and in 4 hours, be warmed to room temperature gradually.Regulator solution pH to pH5 utilizes ethyl acetate extraction.Utilize salt water washing organic layer, at Na
2SO
4Last dry, concentrating under reduced pressure.HPLC purifying crude product utilizes 10 to 80% acetonitrile/water gradient elutions, obtains 5.7mg (15%) title compound.
1HNMR(300 MHz，CD
2Cl
2)δ9.55(s，1H)，7.73(d，1H)，7.22-7.35(m，4H)，6.44(d，1H)，6.18(dd，1H)，6.15(s，1H)，3.00(s，6H)，2.04(s，3H)，1.32(s，9H).ES-MS m/z 393.2(MH
+)；HPLCRT(min)2.84.
At Suzuki reaction, bromination reaction (R
2), carry out Buchwald type coupled reaction, the embodiment compound shown in the preparation table 5a after the 2nd Suzuki reaction and the posthydrolysis.All reactions steps are described in the aforementioned embodiment.
Table 5a
Table 5b
| The embodiment sequence number | The IUPAC name |
| 250 | The 2-{[3-tertiary butyl-4-(3-p-methoxy-phenyl)-1-methyl isophthalic acid H-pyrazoles-5-yl] amino }-the 5-ethyl benzoate |
| 251 | The 2-{[3-tertiary butyl-4-(4-p-methoxy-phenyl)-1-methyl isophthalic acid H-pyrazoles-5-yl] amino }-the 5-ethyl benzoate |
| 252 | The 2-[(3-tertiary butyl-1-methyl-4-phenyl-1H-pyrazoles-5-yl) amino]-the 5-ethyl benzoate |
| 253 | The 2-[(3-tertiary butyl-1-methyl-4-pyrimidine-5-base-1H-pyrazoles-5-yl) amino]-the 5-ethyl benzoate |
| 254 | The 2-{[3-tertiary butyl-1-methyl-4-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-ethyl benzoate |
| 255 | The 2-[(3-tertiary butyl-1-methyl-4-pyridin-4-yl-1H-pyrazoles-5-yl) amino]-5-ethyl benzoate trifluoroacetate |
The following example has been represented carboxylicesters, and it can make by utilizing Ullmann-type coupled reaction and then carrying out step of esterification.
Embodiment 256
Preparation 5-methoxyl group-2-[(1-phenyl-1H-pyrazoles-5-yl) amino] isopropyl benzoate
Step 1: amino preparation 5-methoxyl group-2-[(1-phenyl-1H-pyrazoles-5-yl)] phenylformic acid
In airtight test tube, heating (150 ℃) 2-bromo-5-methoxybenzoic acid (1.31g, 5.7mmol), salt of wormwood (859mg, 6.2mmol), 5-amino-1-phenyl-pyrazole (900mg, 5.7mmol) and venus crystals (II) (21mg, DMF 0.11mmol) (12ml) mixture 16 hours.After the cooling, utilize water (5ml) diluted reaction mixture, utilize acetate to be acidified to pH 4.(3 * 10ml) extract mixture, and (organic extracting solution that 2 * 10ml) washings merge is at Na to utilize water then to utilize methylene dichloride
2SO
4Last dry, filter and concentrating under reduced pressure.HPLC purifying residue (YMC propack C18 post, 150 * 20mm ID, 30%-80% acetonitrile/water elutriant) obtains 5-methoxyl group-2-[(1-phenyl-1H-pyrazoles-5-yl) amino] phenylformic acid (450mg, 26%), be light yellow solid.
1HNMR(300MHz，DMSO-d
6)δ13.33(brs，1H)，9.62(brs，1H)，7.64(d，1H)，7.34-7.58(m，6H)，7.00-7.11(m，2H)，6.30(d，1H)，3.69(s，3H)；ES-MS m/z 310.1(MH
+)；HPLC RT(min)2.74.
Step 2: amino preparation 5-methoxyl group-2-[(1-phenyl-1H-pyrazoles-5-yl)] phenylformic acid
Isopropyl ester
With cesium carbonate (105mg, 0.19mmol) and 2-iodopropane (18mg 0.11mmol) joins intermediate 5-methoxyl group-2-[(1-phenyl-1H-pyrazoles-5-yl) amino] (30mg is in DMF 0.10mmol) (4ml) solution for phenylformic acid.Mixture at room temperature stirred 16 hours.Utilize water (5ml) to make the reaction quenching, (3 * 5ml) extract to utilize methylene dichloride then.The organic layer that utilizes water (5ml) washing to merge is at Na
2SO
4Last dry, filter and concentrating under reduced pressure.HPLC purifying residue (YMC propack C18 post, 150 * 20mmID, 30%-80% acetonitrile/water elutriant) obtains required product, is white solid (20mg, 59%).
1H NMR(300MHz，DMSO-d
6)δ9.07(s，1H)，7.65(d，1H)，6.96-7.56(m，9H)，6.29(dd，1H)，5.06(q，1H)，3.69(s，3H)，1.24(d，6H)；ES-MS m/z 352.1(MH
+)；HPLC RT(min)3.53.
Utilize above-described method to prepare following analogue.The amino-pyrazol that is used for coupled reaction is commercial commodity.
Table 6a
| The embodiment sequence number | R 6 | LC-MS RT(min) | LC-MS [M+H] + |
| 257 | Bn | 3.68 | 400.1 |
| 258 | Me | 3.15 | 324.1 |
| 259 | Et | 3.31 | 338.3 |
| 260 | i-Bu | 3.75 | 366.2 |
| 261 | 4-MeOBn | 3.68 | 430.1 |
Table 6b
| The embodiment sequence number | The IUPAC name |
| 257 | 5-methoxyl group-2-[(1-phenyl-1H-pyrazoles-5-yl) amino] peruscabin |
| 258 | 5-methoxyl group-2-[(1-phenyl-1H-pyrazoles-5-yl) amino] methyl benzoate |
| 259 | 5-methoxyl group-2-[(1-phenyl-1H-pyrazoles-5-yl) amino] ethyl benzoate |
| 260 | 5-methoxyl group-2-[(1-phenyl-1H-pyrazoles-5-yl) amino] isobutyl benzoate |
| 261 | 4-methoxy-benzyl 5-methoxyl group-2-[(1-phenyl-1H-pyrazoles-5-yl) amino] benzoic ether |
The method of utilizing embodiment 108 to describe, synthetic following compounds.
In table 7a, R
4Group position such as following.
Table 7a
* remarks: the source that is used for the amino-pyrazol of coupled reaction: c=is commercial; I=uses the above described method preparation of reaction process I.
Table 7b
| The embodiment sequence number | The IUPAC name |
| 262 | 5-methoxyl group-2-{[1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] amino } methyl benzoate |
| 263 | 2-{[1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] amino } methyl benzoate |
| 264 | 5-methoxyl group-2-[(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-yl) amino] methyl benzoate |
| 265 | The 2-{[3-tertiary butyl-1-(2,2, the 2-trifluoroethyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxyl methyl benzoate |
| 266 | The 2-[(3-tertiary butyl-1-methyl isophthalic acid H-pyrazoles-5-yl) amino]-the 5-methyl-toluate |
| 267 | The 2-[(3-tertiary butyl-1-methyl isophthalic acid H-pyrazoles-5-yl) amino]-the 3-methyl-toluate |
| 268 | 2-[(3-cyclopropyl-1-phenyl-1H-pyrazoles-5-yl) amino]-the 5-methoxyl methyl benzoate |
| 269 | 2-[(3,4-dimethyl-1-phenyl-1H-pyrazoles-5-yl) amino]-the 5-methoxyl methyl benzoate |
| 270 | 5-methoxyl group-2-[(5-methyl-2-phenyl-4,5,6,7-tetrahydrochysene-2H-pyrazolo [4,3-c] pyridin-3-yl) amino] methyl benzoate |
| 271 | 2-[(5-methyl-2-phenyl-4,5,6,7-tetrahydrochysene-2H-pyrazolo [4,3-c] pyridin-3-yl) amino] methyl benzoate |
| 272 | 2-{[3-cyclohexyl-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxyl methyl benzoate |
| 273 | 2-{[3-isobutyl--1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxyl methyl benzoate |
| 274 | The 2-{[3-tertiary butyl-1-(5-methoxyl group-2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxyl methyl benzoate |
| 275 | The 2-{[3-tertiary butyl-1-(2, the 6-3,5-dimethylphenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxyl methyl benzoate |
The similar approach of utilizing embodiment 243 to describe is according to embodiment 242 similar modes, by the synthetic following analogue of C1 precursor.The boric acid that uses is commercial commodity.
Table 8a
Table 8b
| The embodiment sequence number | The IUPAC name |
| 276 | The 3-[(3-tertiary butyl-1-methyl isophthalic acid H-pyrazoles-5-yl) amino]-3 '-fluorine biphenyl-4-carboxylic acid methyl esters |
| 277 | The 3-[(3-tertiary butyl-1-methyl isophthalic acid H-pyrazoles-5-yl) amino]-4 '-fluorine biphenyl-4-carboxylic acid methyl esters |
| 278 | The 2-[(3-tertiary butyl-1-methyl isophthalic acid H-pyrazoles-5-yl) amino]-4-pyrimidine-5-methyl benzoate |
The following example is represented carboxylic acid amide, and they can utilize Ullmann-type coupled reaction to make.
Embodiment 279
Preparation 2-{[3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } benzamide
In airtight test tube, heating (150 ℃) 3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-amine (intermediate F, 1.00g, 5.3mmol), 2-brombenzamide (1.07g, 5.3mmol), salt of wormwood (0.89g, 6.4mmol) and venus crystals (II) (39mg, DMF 0.2mmol) (20ml) mixture 18 hours.Behind the cooling solution, utilize Glacial acetic acid regulator solution pH=4.Methylene dichloride (3 * 20ml) abstraction reaction mixtures, the organic extracting solution that utilizes the salt water washing to merge then, dry on sal epsom, filter and vacuum concentration.Fast silica gel chromatogram purifying residue utilizes 33-50% ethyl acetate/hexane wash-out, obtains yellow solid, utilize the Anaesthetie Ether washing, obtain 2-{[3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } benzamide (350mg, 21%), be white solid.
1H NMR(300MHz，DMSO-d
6)δ10.48(s，1H)，8.01(s，1H)，7.67(dd，1H)，7.32(m，7H)，8.77(ddd，1H)，6.08(s，1H)，2.19(s，3H)，2.00(s，3H)；ES-MS m/z 307.1(MH
+)；HPLC RT(min)2.41.
The method of utilizing embodiment 279 to describe makes following analogue.
In table 9a, R
4The group position is as follows.
Table 9a
* remarks: the source that is used for the amino-pyrazol of coupled reaction: c=is commercial; J=uses the above described method preparation of reaction process J.
Table 9b
| The embodiment sequence number | The IUPAC name |
| 280 | 2-{[3-methyl isophthalic acid--(4-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } benzamide |
| 281 | 5-methoxyl group-2-{[3-methyl isophthalic acid-(4-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } benzamide |
| 282 | 2-{[1-(4-chloro-phenyl-)-3-methyl isophthalic acid H-pyrazoles-5-yl] amino } benzamide |
| 283 | 2-{[1-(4-p-methoxy-phenyl)-3-methyl isophthalic acid H-pyrazoles-5-yl] amino } benzamide |
The following example is represented carboxylic acid 1
0Acid amides, they are made by its corresponding carboxylic acid of Ullmann-type coupled reaction deutero-.
Embodiment 284
The preparation 2-{[3-tertiary butyl-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxy benzamide
To the 2-{[3-tertiary butyl-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-5-methoxybenzoic acid (embodiment 4) (130mg, 0.34mmol) DMF (5ml) solution in add ammonium chloride (22mg, 0.41mmol), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (79mg, 0.41mmol), HOBT hydrate (56mg, 0.41mmol) and triethylamine (0.17ml, 1.20mmol).Stirred reaction mixture 16 hours, concentrating under reduced pressure then.HPLC purifying residue (45-90% acetonitrile/water) obtains product (63mg, 49%), is white solid.
1H NMR(400MHz，DMSO-d
s)δ1.26(s，9H)，1.97(s，3H)，3.71(s，3H)，6.03(s，1H)，7.04(dd，1H)，7.24-7.37(m，6H)，7.44(s，1H)，8.05(s，1H)，10.01(s，1H)；ES-MS m/z379.3(MH
+)；HPLC RT(min)2.83.
The method of utilizing the foregoing description 284 to describe, the analogue shown in synthetic table 10a, 10b, 11a and the 11b.
In table 10a, R
4The group position is as follows.
Table 10a
* remarks: the source that is used for the amino-pyrazol of coupled reaction: c=is commercial; I and J=use above reaction process I and the described method preparation of J.
Table 10b
| The embodiment sequence number | The IUPAC name |
| 285 | 5-methoxyl group-2-({ 3-methyl isophthalic acid-[4-(methylsulfonyl) phenyl]-1H-pyrazoles-5-yl } amino) benzamide |
| 286 | 5-methoxyl group-2-{[3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } benzamide |
| 287 | The 2-[(3-tertiary butyl-1-sec.-propyl-1H-pyrazoles-5-yl) amino]-4,5-dimethoxy benzamide |
| 288 | The 2-{[3-tertiary butyl-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-4,5-dimethoxy benzamide |
| The embodiment sequence number | The IUPAC name |
| 289 | The 2-{[3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } benzamide |
| 290 | The 2-{[3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxy benzamide |
| 291 | The 2-{[3-tertiary butyl-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } benzamide |
| 292 | The 2-{[3-tertiary butyl-1-(2, the 4-3,5-dimethylphenyl)-1H-pyrazoles-5-yl] amino } benzamide |
| 293 | The 2-{[3-tertiary butyl-1-(3-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } benzamide |
| 294 | The 2-{[3-tertiary butyl-1-(2-ethylphenyl)-1H-pyrazoles-5-yl] amino }-4,5-dimethoxy benzamide |
| 295 | The 2-{[3-tertiary butyl-1-(2, the 4-3,5-dimethylphenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxy benzamide |
| 296 | The 2-{[3-tertiary butyl-1-(2, the 4-3,5-dimethylphenyl)-1H-pyrazoles-5-yl] amino }-4,5-dimethoxy benzamide |
| 297 | 2-[(1,3-phenylbenzene-1H-pyrazoles-5-yl) amino]-the 5-methoxy benzamide |
| 298 | 2-{[1-(2-aminomethyl phenyl)-3-phenyl-1H-pyrazoles-5-yl] amino } benzamide |
| 299 | 2-{[1-(2, the 4-3,5-dimethylphenyl)-3-(4-fluorophenyl)-1H-pyrazoles-5-yl] amino } benzamide |
| 300 | The 2-{[3-tertiary butyl-1-(2, the 6-3,5-dimethylphenyl)-1H-pyrazoles-5-yl] amino } benzamide |
The following example is represented primary amide, the serial of methods deutero-that it is made up of Buchwald-type coupled reaction, hydrolysis and acid amides formation reaction.
In table 10a, R
4The group position is as follows.
Table 11a
* remarks: the source that is used for the amino-pyrazol of coupled reaction: c=is commercial; I=uses the above described method preparation of reaction process I.
Table 11b
| The embodiment sequence number | The IUPAC name |
| 301 | 5-methoxyl group-2-{[1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] amino } benzamide |
| 302 | The 2-[(1-benzyl-3-tertiary butyl-1H-pyrazoles-5-yl) amino] benzamide |
| 303 | The 2-{[3-tertiary butyl-1-(2, the 5-3,5-dimethylphenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxy benzamide |
| 304 | The 2-[(3-tertiary butyl-1-phenyl-1H-pyrazoles-5-yl) amino] benzamide |
| The embodiment sequence number | The IUPAC name |
| 305 | The 2-[(3-tertiary butyl-phenyl-1H-pyrazoles-5-yl) amino]-the 5-methoxy benzamide |
| 306 | The 2-{[3-tertiary butyl-1-(4-chloro-2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } benzamide |
| 307 | 2-{[1-(2-aminomethyl phenyl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl] amino } benzamide |
The following example is represented the second month in a season and teritary amide, and its method of being made up of Ullmann-type coupled reaction and the acid amides formation reaction of following makes.
Embodiment 308
Preparation N-benzyl-5-methoxyl group-2-[(1-phenyl-1H-pyrazoles-5-yl) amino] benzamide
With 5-methoxyl group-2-[(1-phenyl-1H-pyrazoles-5-yl) amino] (the Ullmann reaction of being described by embodiment 1 makes phenylformic acid, 42.0mg, 0.14mmol), benzylamine hydrochloride (23.4mg, 0.16mmol), EDCI (31.2mg, 0.16mmol), HOBT (22.0mg, 0.16mmol) and triethylamine (0.066ml, DMF 0.48mmol) (3ml) mixture at room temperature stirred 16 hours.Utilize water (20ml) to make the reaction quenching, utilize ethyl acetate (10ml) to extract.Utilize salt water washing organic layer, at Na
2SO
4Last dry, filter and concentrating under reduced pressure.Fast silica gel chromatogram purifying residue utilizes 20% ethyl acetate/hexane wash-out, obtains title compound (16.1mg, 30%), is white solid.
1H NMR(300MHz，DMSO-d
s)δ9.72(s，1H)，9.14(t，1H)，7.57(d，1H)，7.38-7.51(m，4H)，7.16-7.36(m，7H)，6.967.06(m，2H)，6.15(s，1H)，4.37(d，2H)，3.70(s，3H)；ES-MS m/z399.1(MH
+)，HPLC RT(min)3.72.
The method of utilizing the foregoing description 308 to describe, the analogue shown in synthetic table 12a, 12b, 13a and the 13b.
In table 12a, R
4The group position is as follows.
Table 12a
| The embodiment sequence number | R 1 | R 3 | R 4 | R 5 | R 6 | LC-MS RT(min) | LC-MS [M+H] + | Remarks ＊ |
| 309 | H | Ph | 5-OMe | Et | Et | 3.24 | 365.1 | c |
| 310 | H | Ph | 5-SMe | Me | H | 2.82 | 339.1 | c |
| 311 | H | Ph | 5-SMe | Et | H | 3.02 | 353.1 | c |
| 312 | H | Ph | 5-SMe | i-Pr | H | 3.19 | 367.1 | c |
| 313 | H | Ph | 5-SMe | Et | Et | 3.00 | 381.1 | c |
* remarks: the source that is used for the amino-pyrazol of coupled reaction: c=is commercial.
Table 12b
| The embodiment sequence number | The IUPAC name |
| 309 | N, N-diethyl-5-methoxyl group-2-[(1-phenyl-1H-pyrazoles-5-yl) amino] benzamide |
| 310 | N-methyl-5-(methylthio group)-2-[(1-phenyl-1H-pyrazoles-5-yl) amino] benzamide |
| 311 | N-ethyl-5-(methylthio group)-2-[(1-phenyl-1H-pyrazoles-5-yl) amino] benzamide |
| 312 | N-sec.-propyl-5-(methylthio group)-2-[(1-phenyl-1H-pyrazoles-5-yl) amino] benzamide |
| 313 | N, N-diethyl-5-(methylthio group)-2-[(1-phenyl-1H-pyrazoles-5-yl) amino] benzamide |
| 314 | N-[4-(methylthio group)-2-(piperidines-1-base carbonyl) phenyl]-1-phenyl-1H-pyrazoles-5-amine |
| 315 | N-(2-{3-methoxyl group-4-[(4-methylpiperazine-1-yl) alkylsulfonyl] phenyl } ethyl }-5-(methylthio group)-2-[(1-phenyl-1H-pyrazoles-5-yl) amino] benzamide |
| 316 | N-sec.-propyl-2-{[3-methyl isophthalic acid-(4-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } benzamide |
| The embodiment sequence number | The IUPAC name |
| 317 | 2-{[3-methyl isophthalic acid-(4-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the N-phenylbenzamaide |
| 318 | 5-methoxyl group-N-methyl-2-{[3-methyl isophthalic acid-(4-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } benzamide |
| 319 | N-ethyl-5-methoxyl group-2-{[3-methyl isophthalic acid-(4-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } benzamide |
| 320 | N-sec.-propyl-5-methoxyl group-2-{[3-methyl isophthalic acid-(4-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } benzamide |
| 321 | 5-methoxyl group-2-{[3-methyl isophthalic acid-(4-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the N-phenylbenzamaide |
| 322 | 2-{[3-methyl isophthalic acid-(4-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-N-(2-aminomethyl phenyl) benzamide |
| 323 | N-(2-fluorophenyl)-2-{[3-methyl isophthalic acid-(4-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } benzamide |
| 324 | 2-{[3-methyl isophthalic acid-(4-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-N-pyridin-4-yl benzamide |
| 325 | 2-{[3-methyl isophthalic acid-(4-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-N-pyridin-3-yl benzamide |
The following example is represented the second month in a season and teritary amide, and its method of being made up of coupled reaction hydrolysis of Buchwald-type and the acid amides formation reaction followed makes.
Table 13a
| The embodiment sequence number | R 1 | R 3 | R 5 | R 6 | LC-MS RT(min) | LC-MS [M+H] + |
| 326 | Me | Ph | Pr | H | 2.80 | 365.1 |
| 327 | Ph | Ph | (CH 2) 2OH | H | 3.56 | 429.2 |
Table 13b
| The embodiment sequence number | The IUPAC name |
| 326 | N-sec.-propyl-5-methoxyl group-2-[(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-yl) amino] benzamide |
| 327 | 2-[(1,3-phenylbenzene-1H-pyrazoles-5-yl) amino]-N-(2-hydroxyethyl)-5-methoxy benzamide |
The following example is represented N-acyl group sulfamide compound, and it is for utilizing sulphonamide, is derived and is got by the coupling of carboxylic acid precursor.
Embodiment 328
Preparation 2-[(1,3-phenylbenzene-1H-pyrazoles-5-yl) amino]-5-methoxyl group-N-[(2-aminomethyl phenyl) alkylsulfonyl] benzamide
To 2-[(1,3-phenylbenzene-1H-pyrazoles-5-yl) amino]-5-methoxybenzoic acid (embodiment 29) (100mg, 0.26mmol) methylene dichloride (3ml) solution in add orthotoluene sulfonamide (53.3mg, 0.31mmol), EDCI (99.47mg, 0.52mmol), DMAP (63.40mg, 0.52mmol) and triethylamine (0.127ml, 0.91mmol).Reaction mixture stirred 2 hours, utilized the dilution of methylene dichloride (10ml) and water (20ml) then.Separate organic phase, utilize the salt water washing then, dry (Na
2SO
4), filter and concentrating under reduced pressure.Silica gel chromatography purifying residue utilizes 90%EtOAc/ hexane wash-out, obtains product (13.9mg, 10.0%), is white solid.
1H NMR(300MHz，DMSO-d
6)δ2.56(s，3H)，3.74(s，3H)6.67(s，1H)，7.03(dd，2H)，7.26-7.60(m，14H)，7.84(dd，2H)，7.94(d，1H)，ES-MS m/z 539.1(MH
+)；HPLC RT(min)3.71.
Utilize embodiment 328 identical methods to synthesize following compounds.
Table 14a
Table 14b
| The embodiment sequence number | The IUPAC name |
| 329 | 2-[(1,3-phenylbenzene-1H-pyrazoles-5-yl) amino]-N-[(3-fluorophenyl) alkylsulfonyl]-5-methoxy benzamide |
| 330 | 2-[(1,3-phenylbenzene-1H-pyrazoles-5-yl) amino]-N-[(2-fluorophenyl) alkylsulfonyl]-5-methoxy benzamide |
The following example Biao Shi oxadiazole compounds, it is partly derived by hydroxy-acid group Zhuanization Cheng oxadiazole and gets.
Embodiment 331
Preparation N-[4-methoxyl group-2-(3-methyl isophthalic acid, 2,4-oxadiazole-5-yl) phenyl]-3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-amine
Step 1: preparation N-hydroxyl-ethanamidine
To azanol (2.21g, add in water 67mmol) (5ml) solution acetonitrile (3.5ml, 2.75g, 67mmol).Drip ethanol, until obtaining clear solution.Mixture is cooled to 0 ℃, and the adding sodium ethylate (21.7g 21% ethanolic soln, 67mmol).After reinforced the finishing, reaction mixture is warmed to 35 ℃, under this temperature, stirred 3 days.Reaction mixture is cooled to room temperature, and filtering separation solid residue (NaCl) utilizes the acetonitrile washing.Merging filtrate and washings, the vacuum-evaporation partial solvent adds dense HCl, is approximately 1.0 until pH.Evaporating solvent is until yellow residue occurring.Residue is dissolved among the hot EtOH, by adding the Anaesthetie Ether redeposition.Leach the needle-like crystal that in solution, occurs.Preserve filtrate, be placed on a couple of days in the refrigerating chamber, obtain product for the second time.Obtain product (1.12g, 15%) with the clear crystal form.
1HNMR (400MHz, DMSO-d
6). δ 2.09 (s, 3H), 8.45 (br, s, 1H), 10.64-10. (br, 1H), 12.2-12.5 (br, 1H).
Step 2: preparation N-[(1Z)-N-hydroxyl second imino-]-5-methoxyl group-2-[(3-methyl-
1-phenyl-1H-pyrazoles-5-yl) amino] benzamide
Under-20 ℃, to 2-[(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-yl) amino] phenylformic acid (400mg, 1.04mmol) (be similar to embodiment 108 and 109, make according to Buchwald-type coupled reaction and hydrolysis reaction), HOAT (186mg, 1.39mmol) and EDCI (263mg, 1.39mmol) DMF (7ml) mixture in add triethylamine (0.45ml, 3.25mmol).After stirring 15 minutes under this temperature, (305mg, 2.78mmol), temperature slowly rises to room temperature to add N-hydroxyl-ethanamidine.Continue to stir 16 hours, vacuum evaporating solvent is distributed in residue between water and the EtOAc.Layering utilizes EtOAc to extract water layer.Utilize 5% citric acid, saturated Na
2CO
3The aqueous solution and salt solution wash the organic layer of merging in proper order, dry (MgSO
4), filter and concentrate, obtain the thick solid of 147mg.This solid can be used for next step under not being further purified.ES-MS m/z 380.1(MH
+)；HPLC RT(min)2.53。
Step 3: preparation N-[4-methoxyl group-2-(3-methyl isophthalic acid, 2,4-oxadiazoles-5-yl) phenyl]-3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-amine
To thick N-[(1Z)-N-hydroxyl second imino-]-2-[(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-yl) amino] benzamide (257mg; 0.41mmol) THF (3ml) solution in add (methoxycarbonyl sulfamyl) triethyl ammonium hydroxide (Burgess reagent) (145mg, 0.61mmol).Utilize the argon cleaning flask, under argon gas, refluxed 3 hours.Reaction mixture is cooled to room temperature, filters by little silica gel plug, utilizes EtOAc washing silica gel plug.Concentrating under reduced pressure filtrate, by preparation property TLC purifying residue, (1: 2, v/v) wash-out obtained title product, is solid (5.5mg, total recovery 4%) to utilize the EtOAc/ hexane on silica gel.
1H NMR(400MHz，CD
3CH).δ2.30(s，3H)，2.32(s，3H)，3.82(s，3H)，6.16(s，1H)，7.09(dd，1H)，721(d，1H)，7.38-7.42(m，1H)，7.42-7.50(m，3H)，7.50-7.58(m，2H)，9.46(br，s，1H).ES-MS m/z 362.2(MH
+)；HPLC RT(min)3.28.
Embodiment 332
Preparation N-[4-methoxyl group-2-(5-methyl isophthalic acid, 2,4-oxadiazoles-3-yl) phenyl]-1-phenyl-1H-pyrazoles-5-amine
The method of utilizing embodiment 331 to describe,, prepare title compound similarly.ES-MS m/z348.3(MH
+)；HPLC RT(min)3.25。
The following example is represented sulfamide compound, and it is prepared by following method: dibenzyl sulphonamide precursor and 5-amino-pyrazol that coupling is suitable then make two benzyl group deprotections.
Embodiment 333
The preparation 2-{[3-tertiary butyl-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino) benzsulfamide
Step 1: preparation N, N-dibenzyl-2-bromobenzene sulphonamide
With the 2-bromobenzene sulfonyl chloride (1.0g, 3.91mmol) and triethylamine (455mg, 0.63ml 4.5mmol) are dissolved among the THF (15ml), and mixture is cooled to 10 ℃, drips dibenzylamine 849mg then, 0.83ml, 4.3mmol).Remove cooling bath, reaction mixture at room temperature stirred 10 hours, and then stirred 6 hours down at 60 ℃.After being cooled to room temperature, removal of solvent under reduced pressure adds ethyl acetate.Utilize 1N HCl, water, semi-saturation Na
2CO
3The aqueous solution, water and salt solution wash organic layer in proper order.Utilizing Na
2SO
4After the dry also filtration, removal of solvent under reduced pressure obtains title compound, is canescence crystal (1.44g, 88%).
1H NMR(400MHz，CDCl
3)δ4.42(s，4H)，7.08(m，4H)，7.27(m，6H)，7.41(m，2H)，7.78(d，1H)，8.19(d，1H).
Step 2: preparation N, the N-dibenzyl-2-{[3-tertiary butyl-1-(2-aminomethyl phenyl)-1H-pyrrole
Azoles-5-yl] amino } benzsulfamide
Under nitrogen atmosphere, with N, N-dibenzyl-2-bromobenzene sulphonamide (obtain by step 1,333mg, 0.80mmol), the 3-tertiary butyl-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-amine (intermediate C), cesium carbonate (365mg, 1.12mmol), Pd
2(dba)
3(41.4mg, 0.04mmol) and BINAP (49.8mg 0.08mmol) is dissolved in the toluene (7ml), at 110 ℃ of following heating flasks 20 hours.Reaction mixture is to room temperature, the solids removed by filtration residue.Removal of solvent under reduced pressure, by fast silica gel chromatogram purifying residue, (1: 12, v/v) wash-out obtained title compound, is thick oily matter (348mg, 77%) to utilize the EtOAc/ hexane.
1H NMR(400MHz，CDCl
3)δ1.40(s，9H)，2.03(s，3H)，3.99(s，4H)，6.10(s，1H)，6.88(m，4H)，7.07(m，1H)，7.10-7.27(m，10H)，7.38(d，1H)，7.47(t，1H)，7.71(s，1H)，7.77(d，1H).ES-MS m/z 565.4(MH)
+；HPLCRT(min)4.37.
The step 3. preparation 2-{[3-tertiary butyl-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }
Benzsulfamide
With N, the N-dibenzyl-2-{[3-tertiary butyl-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } (obtained by step 2,240mg 0.42mmol) joins dense H to benzsulfamide
2SO
4(3ml), vigorous stirring mixture 20 minutes.Mixture is injected in the ice, adds concentrated NaOH solution, be about 7.5 until pH.Utilize 2 * EtOAc to extract water layer, utilize Na
2SO
4The dry organic layer that merges filters and concentrating under reduced pressure.The fast silica gel chromatogram purifying, (1: 3, v/v) wash-out obtained title compound, is white solid (104mg, 64%) to utilize the EtOAc/ hexane.
1H NMR(400MHz，CD
2Cl
2)δ1.39(s，9H)，2.09(s，3H)，4.50(br，2H)，6.20(s，1H)，7.94(t，1H)，7.23(m，4H)，7.34(m，2H)，7.45(t，1H)，7.73(d，1H)，ES-MS m/z 385.2(MH
+)HPLC RT(min)3.11.
Embodiment 334
Preparation 2-{[1-(2-aminomethyl phenyl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl] amino } benzsulfamide
The method of utilizing embodiment 333 to describe prepares title compound similarly.ES-MS m/z397.1(MH
+)；HPLC RT(min)3.18。
Embodiment 335
Preparation 2-{[4-iodo-1-(2-aminomethyl phenyl)-3-(4-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-tolyl acid
To 5-methyl-2-{[1-(2-aminomethyl phenyl)-3-(4-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid (embodiment 65) (49.5mg, 0.13mmol) AcOH/DCM (1: 1, v/v) (2ml) add NIS (28mg, DCM 0.13mmol) (1ml) solution in the solution.At room temperature stirring reaction is 3 hours.In reaction mixture, add entry (1ml).Utilize DCM (2ml) to extract water layer, the organic layer that utilizes S-WAT and salt water washing to merge, concentrating under reduced pressure.Crude product is carried out the HPLC purifying, utilize 30% to 95% acetonitrile/water gradient elution, obtain 9.1mg (14%) title compound.
1H NMR(300MHz，CD
2Cl
2)δ8.88(s，1H)，7.85(d，2H)，7.74(s，1H)，7.18-7.32(m，7H)，6.58(d，1H)，2.41(s，3H)，2 25(s，3H)，221(s，3H).ES-MS m/z 524.1(MH
+)；HPLC RT(min)4.35.
Embodiment 336
The preparation 2-{[3-tertiary butyl-4-fluoro-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid
To the 2-{[3-tertiary butyl-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-5-methoxybenzoic acid (embodiment 4) (49mg, CH 0.13mmol)
3Add [(1-(chloromethyl)-4-fluoro-1,4-phenodiazine father-in-law two ring [2.2.2] octanes two (a tetrafluoro borate)) (SELECTFLUOR in CN (1ml) solution
) (46mg, 0.13mmol), mixture at room temperature stirred 16 hours.Leach solid, filtrate is carried out the HPLC purifying, utilize 10% to 90% acetonitrile/water gradient elution, obtain 4mg (8%) title compound.
1H NMR(300MHz，CD
2Cl
2)δ8.62(s，1H)，7.40(d，1H)，7.16-7.35(m，4H)，7.05(dd，1H)，7.76(dd，1H)，3.75(s，3H)，2.12(s，3H)，1.40(s，9H).ES-MS m/z 398.2(MH
+)；HPLC RT(min)4.06.
Embodiment 337
Preparation 5-methoxyl group-2-{ methyl [3-methyl isophthalic acid-(2-aminomethyl phenyl)-4-phenyl-1H-pyrazoles-5-yl] amino } methyl benzoate
Step 1: preparation 5-methoxyl group-2-{ methyl [3-methyl (2-aminomethyl phenyl)-4-phenyl-
1H-pyrazoles-5-yl] amino } methyl benzoate
At room temperature, to NaH (60%, be scattered in the mineral oil; 0.28g, Dropwise 5-methoxyl group-2-{[3-methyl isophthalic acid in DMF 7mmol) (10ml) suspension-(2-aminomethyl phenyl)-4-phenyl-1H-pyrazoles-5-yl] and amino } methyl benzoate (1.495g, DMF 3.5mmol) (15ml).Stirred the mixture 0.5 hour, add then methyl iodide (0.88ml, 14mmol).At room temperature stirred reaction mixture is 1 hour.Carefully add entry (100ml), utilize ethyl acetate (25ml * 3) to extract mixture.The organic phase of utilizing saturated sodium bicarbonate aqueous solution (50ml) washing to merge, dry (Na
2SO
4), filter and concentrating under reduced pressure.Fast silica gel chromatogram purifying residue (EtOAc/ hexane 1: 12) obtains title compound (1.18g, 68%), is light yellow solid.
1H NMR (400MHz, acetone-d
6) δ 2.1 (s, 3H), 2.3 (s, 3H), 2.9 (s, 3H), 3.65 (s, 3H), 3.7 (s, 3H), 6.87-6.92 (m, 2H), 6.94-6.98 (m, 1H), 7.03-7.09 (m, 1H), 7.15-7.27 (m, 4H), 7.30-7.36 (m, 2H), 7.39-7.43 (m, 2H) .ES-MS m/z 442.3 (MH
+); HPLC RT (min) 3.96.
Step 2: preparation 5-methoxyl group-2-{ methyl [3-methyl isophthalic acid-(2-aminomethyl phenyl)-4-phenyl
-1H-pyrazoles-5-yl] amino } phenylformic acid
To step 1 compound (60mg, add in the solution of THF 0.129mmol) (4ml), water (4ml) and MeOH (2ml) mixture LiOH (32mg, 1.32mmol).Vigorous stirring reaction mixture 24 hours, concentrating under reduced pressure utilizes water (10ml) dilution afterwards.Utilize the 1NHCl souring soln to be about 1 to pH, utilize CH
2Cl
2(3 * 20ml) extract.Dry (Na
2SO
4) organic phase that merges, filter and concentrating under reduced pressure.Preparation property HPLC purifying residue obtains title compound (32mg, 58%), is white solid.
1H NMR (400MHz, acetone-d
6) δ 2.12 (s, 3H), 2.23 (s, 3H), 2.9 (s, 3H), 3.74 (s, 3H), 6.87-6.90 (m, 2H), 6.92-6.98 (m, 1H), 7.03-7.11 (m, 1H), 7.16-7.27 (m, 4H), 7.30-7.36 (m, 2H), 7.40-7.45 (m, 2H); ES-MS m/z428.3 (MH
+); HPLC RT (min) 3.54.
Embodiment 338
The preparation 2-{[3-tertiary butyl-1-(2, the 6-3,5-dimethylphenyl)-1H-pyrazoles-5-yl] (methyl) amino }-the 5-methoxybenzoic acid
The method of utilizing embodiment 337 to describe prepares this compound.
1H NMR(400MHz，CD
3OD)δ1.40(s，9H)，1.95(s，6H)，3.26(s，3H)，3.74(s，3H)，6.81(dd，1H)，6.93(m，4H)，7.13(m，1H)，7.26(d，1H).ES-MS m/z 408.3(MH
+)；HPLC RT(min)2.65.
Utilize embodiment 108 and 109 methods of describing, the preparation following compounds.The amino-pyrazol that is used for coupled reaction can be made by commercial carboxylate methyl ester or ethyl ester by the method for intermediate B description.
Table 15
The compounds of this invention can be used for treating diabetes, comprises I type and type ii diabetes (non insulin dependent diabetes).This treatment also can delay the outbreak and the diabetic complication of diabetes.This compound can be used for preventing to have the chemical sproof main body of weakening glucose from the type ii diabetes development.In the methods of the invention, can utilize other disease or the focus of The compounds of this invention treatment or prevention to comprise: the ripe outbreak of youngster diabetes (MODY) (Herman, et al., Diabetes 43:40,1994); The potential autoimmune diabetes of grownup (LADA) (Zimmet, etal., Diabetes Med.11:299,1994) weaken glucose resistance (IGT) (Expert Committee on Classification of DiabetesMellitus, Diabetes Care 22 (Supp.1): S5,1999); Weaken fasting glucose (IFG) (Charles, et al., Diabetes 40:796,1991); Gestational diabetes mellitus (Metzger, Diabetes, 40:197,1991); And metabolic syndrome X.
The compounds of this invention also has effect in the following disease of treatment, as obesity class disease, atheromatosis, hyperlipidemia, hypercholesteremia, low HDL levels, hypertension, cardiovascular disorder (comprising arteriosclerosis, coronary heart disease, coronary artery disease and hypertension), cerebrovascular disease and periphery vascular disease.
The compounds of this invention also can be used for treating and as produce lipoid and assemble the cytodifferentiation of cell, regulate insulin sensitivity and the relevant physiology disease of glucose level, they can comprise, as improper pancreas beta cell function; The insulin secretion tumour and/or since insulin autoantibody, insulin receptor autoantibody or stimulate that the autoantibody of beta cell causes from immune hypoglycemia; Can form the scavenger cell differentiation of atherosclerotic plaque; Inflammatory responses; Carcinogenesis; Hyperplasia disease; Adipocyte genetic expression; The adipocyte differentiation; Pancreas beta cell amount reduces; Insulin secretion; Tissue is to the susceptibility of Regular Insulin; The growth of liposarcoma cell; Polycystic ovarian disease; Chronic anovulation; Androgen is too much; Progesterone generates; Steroid generates; Cellular oxidation reducing power and oxidative pressure; Nitric oxide synthase (NOS) generates; Gamma glutamyl transpeptidase, katalaze enzyme, plasma triglyceride, HDL and the increase of LDL cholesterol levels etc.
The compounds of this invention also can be used for treating the second reason diabetes (Expert Committeeon Classification of Diabetes Mellitus, Diabetes Care 22 (Supp.1): S5,1999).This class second reason comprises that glucocorticoid is excessive, tethelin is excessive, pheochromocytoma and drug-induced diabetes.Medicine can and be used for the medicine that HIV infects including, but not limited to pyriminil, nicotinic acid, glucocorticoid, Phenytoin Sodium Salt, Triiodothyronine, beta-adrenaline agent, alpha-interferon.
The compounds of this invention can use separately or be used in combination with other treatment and/or treatment diabetes and the relative disease field known compound of those of ordinary skill.In addition, method described herein and compound can partly or entirely be used in combination with treatment.
The compounds of this invention also can be used in combination with other known healing potion of treatment diabetes, and described healing potion comprises: PPAR agonist, sulphur urea medicine, non-sulphur urea secretogogue, alpha-glucosidase inhibitor, insulin sensitivity agent, insulin secretagogue, the output of reduction hepatic glucose compound, Regular Insulin and anti-obesity medicine.This class medicine can be before taking The compounds of this invention, simultaneously or take afterwards.Regular Insulin comprises long-acting or fugitive form and insulin preparation.The PPAR agonist comprises any PPAR subclass agonist or its combination.For example the PPAR agonist can comprise PPAR-α, PPAR-γ, PPAR-δ or two or three subclass PPAR combination.The PPAR agonist comprises as Rosiglitazone and pioglitazone.Sulphur urea cartridge bag is drawn together as Glyburide, glimepiride, P-607 and Glipizide.When taking with The compounds of this invention, the alpha-glucosidase inhibitor that is used for the treatment of diabetes comprises acarbose, miglitol and voglibose.The insulin sensitivity agent that can be used for treating diabetes comprises thiazolidinediones and non-thiazolidinediones.When taking with The compounds of this invention, the reduction hepatic glucose output compound that is used for the treatment of diabetes comprises metformin, as glucophage and glucophage XR.When taking with The compounds of this invention, the insulin secretagogue that is used for the treatment of diabetes comprises sulphur urea and non-sulphur urea medicine: GLP-1, GIP, secretin, nateglinide, meglitinide, repaglinide, Glyburide, glimepiride, P-607, Glipizide.GLP-1 comprises the GLP-1 derivative of transformation period than this height of GLP-1, for example GLP-1 derivative of fatty acid and exendin.In one embodiment of the invention, The compounds of this invention can use with insulin secretagogue, thereby strengthens the susceptibility of pancreas beta cell to insulin secretagogue.
The compounds of this invention also can combine with the anti-obesity medicine and be used for the inventive method.The anti-obesity medicine comprises beta-3 agonist, CB-1 antagonist, appetite down (as sibutramine (Meridia)) and lipase inhibitor (as orlistat (Xenical)).
The compounds of this invention also can combine with the medicine that is usually used in diabetic subject's lipoid dyscrasias and be used for the inventive method.This class medicine is including, but not limited to HMG-CoA reductase inhibitor, nicotinic acid, bile acid chelating agent and fiber acid derivative.The compounds of this invention also can combine with hypotensive agent (as β-3 retarding agent and ACE inhibitor) and be used for the inventive method.
This class assisting therapy medicament can be with any combination medicine-feeding of two or more medicines, as The compounds of this invention and Regular Insulin stablizer and anti-obesity medicine combination medicine-feeding.This class adjuvant therapy medicaments can be as indicated above, with the pharmaceutical compositions administration.
The employed various term definitions of this class are as follows.
When introducing the key element of the present invention or its preferred embodiment, definite article, indefinite article or " described " are meant to have one or more key elements.Term " comprises ", " comprising " and " containing " among being meant and being contained in, and means that can there be the key element outside the listed key element in they.
Term " main body " comprises Mammals (as humans and animals).
Term " treatment " comprises any process, behavior, application, disposal etc., comprising the relief that is medically treated of the mankind's main body, thereby makes the main body focus improve directly or indirectly, or slows down the progress of main body focus or disease.
Term " combined treatment " or " assisting therapy " are meant in order to treat diabetes focus and/or disease, take two or more therapeutical agents.This administration comprises with simultaneously auxiliary two or more therapeutical agents of administration of mode basically, as in single capsule, comprising the activeconstituents of fixed proportion, and perhaps in multiple mode, each self-contained inhibitor in capsule independently.In addition, this class administration comprises and uses various types of therapeutical agents in a continuous manner.
Phrase " treatment effectively " is meant and can reaches the purpose of improving diabetes focus or disease seriousness, avoid simultaneously or minimize with to the relevant side effect of treatment plan, the amount of the various medicaments of being taken.
Term " pharmaceutically acceptable " is meant that the main body composition that is used for pharmaceutical preparation is suitable.
Based on being used to measure the known method that the definite disease treatment of above-mentioned Mammals is renderd a service, and, can easily determine to handle the The compounds of this invention effective dose of various indication actions by these results and the result who is used for the treatment of the known drug of this class disease are compared.The amount for the treatment of the activeconstituents (as compound) that one of this class disease taken can broadly change according to following consideration: employed specific compound and dose unit, administering mode, treatment cycle, patients receiving treatment's age and sex, and the nature and extent of the disease of receiving treatment.
Total weight range of delivery of active ingredients is generally approximately changing between the extremely about 200mg/kg body weight of 0.0001mg/kg, and preferably approximately 0.01mg/kg is to about 200mg/kg.Unitary dose can contain about 0.05mg to about 1500mg activeconstituents, the one or many of can taking medicine every day.By injection, comprise quiet in, the injection of intramuscular, subcutaneous and non-enteron aisle, and use the day dosage of the technology of inculcating to can be about 0.01 to about 200mg/kg.The per daily dose of rectal administration method can be about 0.01 to 200mg/kg TBW.The day maintenance dose of percutaneous dosing can be about 0.01 to 200mg/kg.
Certainly, the character of the illness that will determine according to the clinician of each patient's specific predose and successive doses and seriousness, employed specific compound activity, patient age, patient's diet, administration time, administration route, drug excretion speed, drug regimen etc. change.The required treatment pattern and the dosage situation of The compounds of this invention can be utilized conventional therapeutic test, determine by those skilled in the art.
Take the suitable drugs composite preparation by the patient to needs treatments, The compounds of this invention can be used for the pharmacological effect that reaches required.For the purposes of the present invention, the patient can be the Mammals that needs specific focus of treatment or disease, comprises the mankind.Thus, the present invention includes pharmaceutical composition, it comprises the compound of pharmaceutically acceptable carrier and treatment significant quantity.Pharmaceutically acceptable carrier can be with the corresponding to concentration of activeconstituents effective active under, any carrier nontoxic and harmless relatively to the patient is so any side effect of carrier all can not damage the useful effect of activeconstituents.The treatment significant quantity of compound is meant the amount that specific focus to be treated is born results or has an effect.Compound described herein can utilize the administration of any effective routine dose unit form with pharmaceutically acceptable carrier, and described dosage unit form comprises the preparation that the gentle slow release of release is immediately put, and the administration route can be oral, non-enteron aisle, part etc.
For oral administration, compound can be made solid or liquid preparation, and as capsule, pill, tablet, tablet, lozenge, suck agent, pulvis, solution, suspension or emulsion, they can prepare according to production field of medicinal compositions known method.The solid unit dosage form can be general hard or soft gelatin class capsule, and it comprises tensio-active agent, lubricant and natural instincts filler (as lactose, sucrose, calcium phosphate and W-Gum).
In another embodiment, The compounds of this invention can be made the tablet form that contains the conventional tablet base, described tablet base as with following auxiliary agent bonded lactose, sucrose and W-Gum: tackiness agent, as gum arabic, W-Gum or gelatin; After administration, help to decompose the disintegrating agent with solution tablet, as potato starch, alginic acid, W-Gum and guar gum; Be used for improving flowing and prevention tablet material and tablet mould and of tablet and powder towards the adherent lubricant, as talcum, stearic acid or Magnesium Stearate, calcium or zinc; Dyestuff; Tinting material; And the flavouring agent that is used for strengthening the tablet aesthetic quality and it more can be accepted by the patient.
The proper excipient that is used for liquid oral dosage form comprises thinner, and as water and alcohols (as ethanol, phenylcarbinol and polyoxyethylene glycol), it can add or not add pharmaceutically acceptable tensio-active agent, suspension agent or emulsifying agent.Various other materials can exist with coating or other form of improving the unitary physicals of dosage.For tablet of the present invention, pill or capsule, can apply shellac, sugar or the two all applies.
Dispersible powder and particle are applicable to preparation hydration suspension.They can provide and dispersion agent or wetting agent, suspension agent and one or more sanitass blended activeconstituents mutually.The suitable dispersion or the example of wetting agent and suspension agent are as indicated above.Other vehicle, sweeting agent described above, flavouring agent and tinting material also can exist.
Pharmaceutical composition of the present invention also can be an O/w emulsion.Oil phase can be a vegetables oil, as liquid olefin or vegetable oil mixt.Examples of suitable emulsifiers can be (1) natural gum, have a liking for glue as gum arabic and Huang, (2) natural phospholipid, as soybean and Yelkin TTS, (3) by lipid acid and hexitol acid anhydrides deutero-ester or partial ester, and the condensation product of (4) described partial ester and oxyethane, as polyoxyethylene sorbitanic monoleate.Emulsion also can comprise sweeting agent and flavouring agent.
Oily suspension can be by being suspended in activeconstituents the method preparation in the vegetables oil, described vegetables oil such as peanut oil, sweet oil, Viscotrol C or theobroma oil; Perhaps by activeconstituents being suspended in the method preparation in the mineral oil, described mineral oil such as liquid olefin.Oily suspension can comprise thickening material, as beeswax, hard alkene or hexadecyl alcohol.Suspension also can comprise one or more sanitass, as benzene to hydroxyl ethyl formate or n-propyl; One or more tinting materials; One or more flavouring agents; And one or more sweeting agents, as sucrose or asccharin.
Syrup or elixir also can be made into and comprise sweeting agent, as glycerol, propylene glycol, sorbyl alcohol or sucrose.This class preparation also can comprise negative catalyst, sanitas, flavouring agent and tinting material
The compounds of this invention also can be with the injection type of compound, by non-enteron aisle, as in subcutaneous, quiet, intramuscular or intraperitoneal administration, described injection type comprises with pharmaceutically acceptable carrier blended physiology can accept thinner.Described thinner can be sterile liquid or liquid mixture, as water, salt solution, DEXTROSE MONOHYDRATE and relevant sugar solution; Alcohols is as ethanol, Virahol or cetyl alcohol; Glycols is as propylene glycol or polyoxyethylene glycol; Glycerol ketals, as 2,2-dimethyl-1,1-dioxolane-4-methyl alcohol; Ethers is as poly-(ethylene glycol) 400; Oils; Lipid acid; Fatty acid ester or glyceryl ester; Or add or do not add pharmaceutically acceptable tensio-active agent (as after the soap class or washing composition), the acetylize glycerin fatty acid ester of suspension agent (as colloid, carbomer, methylcellulose gum Vltra tears or carboxymethyl cellulose) or emulsifying agent or other pharmaceutically acceptable auxiliary agent.
The illustrative example that can be used for the oils of parenteral formulation of the present invention is oil, animal oil, vegetables oil or synthetic class oil, for example peanut oil, soya-bean oil, Viscotrol C, Oleum Gossypii semen, Semen Maydis oil, sweet oil, vaseline and mineral oil.Suitable lipid acid comprises oleic acid, stearic acid and Unimac 5680.Suitable fatty acid ester is, as ethyl oleate and isopropyl myristate.Suitable soap class comprises fatty an alkali metal salt, ammonium salt and triethanolamine salt.Suitable washing composition comprises cationic detergent, as dimethyl dialkyl ammonium halide, alkyl pyridine halide salts and alkylamine acetate; Anionic detergent, as alkyl, aryl and alkene sulfonate, alkyl, alkene, ether and single glycerate vitriol, and sulfosuccinate; Nonionic detergent is as fatty amine oxide, fatty acid alkyl amide and polyoxyethylene polypropylene copolymer; And ampholytic detergent, as alkyl-β-An Jibingsuan ester and 2-alkyl imidazole alkane quaternary ammonium salt, and their mixture.
The non-enteron aisle composition of the present invention can typically comprise about 0.5% to about 25% (weight) activeconstituents in its solution.Also can advantageously use sanitas and buffer reagent.In order to minimize or eliminate the pain of injection position, hydrophilic-plain fat balance (HLB) that this based composition can comprise is about 12 to about 17 nonionogenic tenside.Amount of surfactant in this class preparation is about 5% to about 15% (weight).Tensio-active agent can be the single composition with above-mentioned HLB, perhaps can be two or more mixture of ingredients with above-mentioned HLB.
The illustrative polyethylene sorbitan fatty acid ester that is embodied as that is used for the tensio-active agent of parenteral formulation, the adduct of the hydrophobic alkali that forms as sorbitanic monoleate and oxyethane and by condensed epoxy propane and propylene glycol.
Pharmaceutical composition can exist with the aseptic injection water form of suspension.This class suspension can utilize suitable dispersion or wetting agent and suspension agent, is made by known method.Described suspension agent such as Xylo-Mucine, methylcellulose gum, hydroxypropyl methyl-Mierocrystalline cellulose, sodiun alginate, polyvinylpyrrolidone Huang are had a liking for glue and gum arabic; Described dispersion or wetting agent can be naturally occurring phosphatide, Yelkin TTS for example, the condensation product of oxirane and lipid acid, as polyoxyethylene 8 stearate salt, the condensation product of oxirane and long chain aliphatic alcohol is as heptadecaethylene oxycetanol, oxyethane with by the condensation product of lipid acid and hexitol deutero-partial ester, as octadecanoic acid ester of polyethylene glycol, or oxyethane and by lipid acid and hexitol acid anhydrides deutero-condensation product, as polyoxyethylene sorbitanic monoleate.
Aseptic injection preparation also can be aseptic injectable solution or the suspension in non-enteron aisle acceptable diluent of nontoxicity or the solvent.Spendable thinner and solvent are, as water, Ringer solution and isotonic sodium chlorrde solution.In addition, aseptic stable oils can be used as solvent or suspension medium easily.For this reason, the stable oils of any gentleness be can use, synthetic glycerine list or diester comprised.In addition, can be used for preparing in the injection as oleic fatty acid.
The present composition also can be used for the suppository form administration of medicine rectal administration.These compositions can prepare by following method: medicine (as compound) is mixed with the non-irritating excipient that suits, described vehicle is a solid under general temperature, and be liquid under rectal temperature, this vehicle can dissolve in rectum and discharge medicine thus.This class material can be as theobroma oil and polyoxyethylene glycol.
The another kind of preparation that is used for the inventive method adopts through skin transfer device (" sticking patch ").This class can be used for providing The compounds of this invention continuous or discontinuous inculcating with the manipulated variable form through the skin sticking patch.Be used to transmit pharmaceutical preparation through the manufacturing of skin sticking patch and use and be known in the art (referring to U.S. Pat 5,023,252, this document is hereby incorporated by reference).The pharmaceutical preparation that this class sticking patch can be made into continuously, pulses or transmits as required.
People need or are necessary by the mechanical transfer device pharmaceutical composition to be incorporated in patient's body.The mechanical transfer device of making and being used to transmit pharmaceutical preparation is known in the art.For example, the direct technology of the direct administration of brain is related generally to the useful for drug delivery conduit is inserted in patient's the ventricular system, thus the bypass blood brain barrier.A class portable transfer system that is used for medicament is passed to health particular anatomical zone is described in U.S. Pat 5,011, and in 472, this document is hereby incorporated by reference.
The present composition also can comprise the pharmaceutically acceptable compound composition of other routine according to necessity or needs, generally is meant carrier or thinner.Any composition of the present invention can be by adding antioxidant such as xitix or preserving by other suitable sanitas.Can use the ordinary method of the composition of the suitable dosage form of preparation.
The common drug composition that can be used for forming the appropriate dosage forms of required administration route comprises: souring agent, as, but be not limited to acetate, citric acid, fumaric acid, hydrochloric acid, nitric acid; Basifier, as.But be not limited to ammonia solution, volatile salt, diethanolamine, monoethanolamine, potassium hydroxide, Sodium Tetraborate, yellow soda ash, sodium hydroxide, trolamine.
The other medicines composition including, but not limited to, as sorbent material, as Solka-floc and activated carbon; Aerosol propellants is as carbonic acid gas, CCl
2F
2, F
2ClC-CClF
2And CClF
3The air displacement agent is as nitrogen and argon gas; Antimycotic preservative is as phenylformic acid, butyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, methyl p-hydroxybenzoate, propylparaben, Sodium Benzoate; The antibacterium sanitas spreads as chlorination benzalkonium, benzethonium chloride, phenylcarbinol, cetylpyridinium chloride salt, butylene-chlorohydrin, phenol, phenylethyl alcohol, phenyl Silver Nitrate and thiophene mercury; Antioxidant is as xitix, ascorbigen palmitate butylated hydroxyanisol, Yoshinox BHT, Hypophosporous Acid, 50, monothio glycerol, Tenox PG, sodium ascorbate, Sodium Metabisulphate 65, sodium sulfoxylate formaldehyde, sodium metabisulfite; Jointing material is as block polymer, natural and synthetic rubber, polyacrylic ester, urethane, silicone resin and styrene-butadiene copolymer; Buffer reagent is as potassium metaphosphate, single alkali formula potassiumphosphate, sodium acetate, Citric Acid, usp, Anhydrous Powder sodium and Trisodium Citrate monohydrate; Support agent is as chloride injection agent of syrup acacia, syrupus aromaticus, aromatic elixir, cherry syrup, cocoa syrup, orange syrup, syrup, Semen Maydis oil, mineral oil, peanut oil, Viscotrol C, inhibition bacterium and the water injection of inhibition bacterium; Sequestrant is as disodium ethylene diamine tetraacetate and ethylenediamine tetraacetic acid (EDTA); Tinting material is as FD﹠amp; No. 3 red, FD﹠amp of C; No. 20 red, FD﹠amp of C; No. 6 Huangs of C, FD﹠amp; No. 2 orchids of C, D﹠amp; No. 5 green, D﹠amp of C; No. 5 oranges of C, D﹠amp; No. 8, C is red, caramel and red iron oxide; Finings is as wilkinite; Emulsifying agent, but be not limited to as gum arabic, hexadecyl tight gel, hexadecyl alcohol, glycerol monostearate, Yelkin TTS, sorbitanic monoleate, polyethylene 50 stearates; Form capsule, as gelatin and Cellacefate ester; Flavouring agent is as oleum anisi, Oleum Cinnamomi, cocoa powder, menthol, mandarin oil, Fructus Piperis peppermint oil and vanillin food grade,1000.000000ine mesh; Wetting agent is as glycerol, propylene glycol and sorbyl alcohol; Abrasive is as mineral oil and glycerine; Oils is as Peanut oil, mineral oil, sweet oil, peanut oil, Viscotrol C, hydrophilic ointment and vegetables oil; The ointment base is as lanolin, hydrophilic ointment, polyoxyethylene glycol ointment, vaseline, hydrophilic petrolatum, white ointment, yellow ointment and rose water ointment; Penetration enhancers (through the skin transmission) is as monohydroxy or polyhydroxy-alcohol, saturated or unsaturated fatty alcohol, saturated or unsaturated fatty acids ester, saturated or unsaturated dicarboxylic acid, essential oils, phosphatidyl derivant, kephalin, terpenes, acid amides, ether, ketone and urea; Softening agent is as diethyl phthalate and glycerol; Solvent is as alcohol, Semen Maydis oil, Oleum Gossypii semen, glycerol, Virahol, mineral oil, oleic acid, peanut oil, pure water, water for injection, Injectable sterile water and wash water; Stiffening agent is as hexadecanol, spermaceti ester type waxes, Microcrystalline Wax, alkene, Solsperse 2000, Chinese wax and yellow wax; The suppository base is as theobroma oil and polyoxyethylene glycol (mixture); Tensio-active agent is as chlorination benzalkonium, nonoxynol 10, oxtoxynol 9, polysorbate80, Sodium Lauryl Sulphate BP/USP and sorbitanic monopalmitate; Suspension agent is had a liking for glue and veegum as agar, wilkinite carbomer, Xylo-Mucine, Natvosol, hydroxypropylcellulose, Vltra tears, kaolin, methylcellulose gum, Huang; Sweeting agent is as l-asparagine phenylalanine methyl ester, glucose, glycerol, N.F,USP MANNITOL, propylene glycol, soluble saccharin, sorbyl alcohol and sucrose; The tablet antiadhesives is as Magnesium Stearate and talcum; The tablet wedding agent is as the starch of gum arabic, alginic acid, Xylo-Mucine compression sugar, ethyl cellulose, gelatin, Liquid Glucose, methylcellulose gum, pyrrolidone, preformation gel; Tablet and capsule thinner are as Bibasic Calcium Phosphate, kaolin, lactose, N.F,USP MANNITOL, Microcrystalline Cellulose, Solka-floc, precipitated chalk, yellow soda ash, sodium phosphate, sorbyl alcohol and starch; The tablet coating agent is as Liquid Glucose, Natvosol, hydroxypropylcellulose, Vltra tears, methylcellulose gum, ethyl cellulose, Cellacefate ester and shellac; Tablet is with directly compression agent, as Bibasic Calcium Phosphate; The tablet disintegrating agent is as alginic acid, calcium carboxymethylcellulose, Microcrystalline Cellulose, polacrillin potassium, sodium alginate, Explotab and starch; The tablet releasing agent is as colloid silica gel, W-Gum and talcum; Tablet lubricants is as calcium stearate, Magnesium Stearate, mineral oil, stearic acid and Zinic stearas; Tablets/capsules agent opacifying agent is as titanium dioxide; The tablet rumbling compound is as carnuba wax and Chinese wax; Thickening material is as beeswax, hexadecanol and alkene; Toughener is as glucose and sodium-chlor; Viscosity increasing agent moistens native carbomer, Xylo-Mucine, methylcellulose gum, pyrrolidone, sodium alginate and Huang as alginic acid, pump and has a liking for glue; And moistening agent, as heptadecaethylene oxycetanol, Yelkin TTS, polyethylene sorbitan monooleate, octadecanoic acid ester of polyethylene glycol and polyoxyethylene stearic acid ester.
Compound described herein can be individually dosed or not be caused one or more medicaments of unacceptable side-effects to be used in combination with other.For example, The compounds of this invention can with known anti-obesity medicine, or with medicine and hybrid medicine or its built up section administration of known anti-diabetic or other order.
In research and diagnosis, compound described herein also can free alkali or composition forms use, or can be used as and analyze reference standard etc.Therefore, the present invention includes composition, it comprises inert support and definite significant quantity compound or its salt or the ester of method described herein.Described inert support can be not with the interactional any material of contained compound, described inert material provides carrier, transfer mode, large and trace material etc. for contained compound.The significant quantity of compound is meant the amount that can bear results or have an effect pending particular procedure.
Be suitable for subcutaneous, quiet in, the preparation of administration such as intramuscular, appropriate drug carrier and medicine form and the method for administration can obtain by means commonly known in the art (referring to, as Remington ' sPharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 20
ThEdition, 2000).
The following example will be used for disclosing the present invention and describe, but be not to be used for limiting the scope of the invention by any way.
Capsule preparations
Capsule preparations can prepare by following manner:
| The compounds of this invention | 10mg |
| Starch | 109mg |
| Magnesium Stearate | 1mg |
Mentioned component is mixed,, insert in the hard gelatin capsule by the sieve of suitable order number.Tablet formulation
Tablet can prepare by following manner:
| The compounds of this invention | 25mg |
| Microcrystalline Cellulose | 200mg |
| Colloidal silicon dioxide | 10mg |
| Stearic acid | 5.0mg |
Mentioned component is mixed, be pressed into sheet.In order to strengthen planeness, improve grace and stability or to postpone absorption, can use suitable hydration or non-hydrated coating.
Aseptic IV solution
Utilize sterile water for injection, the mg/ml solution of preparation The compounds of this invention if desired, can be regulated pH.When administration, utilize aseptic 5% glucose to dilute this solution, inculcate form administration with IV.
Intramuscular suspension
Intramuscular suspension can prepare by following manner:
| The compounds of this invention | 50μg/ml |
| Xylo-Mucine | 5mg/ml |
| TWEEN 80 | 4mg/ml |
| Sodium-chlor | 9mg/ml |
| Phenylcarbinol | 9mg/ml |
This suspension passes through intramuscular administration.
Hard shell capsule
Two hard roulade capsules in standard are inserted Powdered activeconstituents, 150mg lactose, 50mg Mierocrystalline cellulose and 6mg Magnesium Stearate separately, prepare a large amount of dosage unit capsules.
Gelseal
Be prepared in digestible oil,, it be injected in the molten gelatin by the malleation piston pump, form the Gelseal that contains above-mentioned activeconstituents as after soya-bean oil, the Oleum Gossypii semen or the mixture of active principles in the sweet oil.The flushing capsule is also dry.Activeconstituents may be dissolved in the mixture of polyoxyethylene glycol and sorbyl alcohol, makes the pharmaceutical composition miscible with water.
Immediate-release tablet formulations/capsule
These preparations are to make solid oral dosage forms by conventional and novel method.These unitary doses can be used for dissolving immediately and transmit oral administration under the condition of water of medicine not existing.Activeconstituents mixes in the liquid that contains sugar, gelatin, colloid and sweeting agent.These liquid can become solid tablet or capsule sheet by lyophilize with the solids extraction technical cure.Medical compounds can be under the condition that does not have water, promptly releases the compacting of porous medium effervesce composition with visco-elasticity and thermoplasticity sugar and polymkeric substance or with can producing.
For those of ordinary skills, changes and improvements the present invention is conspicuous under the prerequisite of not leaving the present invention's scope of the invention spiritual or described here.
Biological assessment
In order to understand the present invention better, the following example has been proposed here.These embodiment only are used for disclosing the present invention, rather than are used for limiting the scope of the invention by any way.Above-mentioned all publications are all incorporated by reference with its integral form.
By well known in the art in vitro, measure in the external and body, can finish the active real example of The compounds of this invention.For example in order to confirm to treat diabetes and relative disease, as syndrome X, weaken the glucose resistance, weaken the effectiveness of the pharmaceutical preparation of fasting glucose and hyperinsulinemia, can use following mensuration.
External test
By INS-1 emiocytosis Regular Insulin
Isolate INS-1 cell (Asfari, et al., Endocrinology 130:167,1992) from the rat Langerhans islet knurl of X-ray induction.In Biocoat CollagenlCellware 96 orifice plates, with every hole 30,000 cell inoculation INS-1 cell and hatched 4-5 days.Utilization is adjusted to the complete medium (RPMI 1640,10% fetal bovine serum, 100 μ g/ml penicillin/streptomycin, 0.5mM Sodium.alpha.-ketopropionate, 10mM HEPES, and 50 μ M beta-mercaptoethanols) of 3mM glucose and handled cell 2 days.Handle two days later, utilize Krebs-Ringer hydrocarbonate-HEPES (KRBH) flushing cell that contains 3mM glucose.In same buffer, hatched then 30 minutes.Under the condition that has desired concn glucose and compound, hatched again 2 hours.Collect supernatant liquor.
In order to determine the amount of excreting insulin, with supernatant liquor and anti-insulin antibody and trace in the phosphate buffered saline (PBS) that contains 0.5% bovine serum albumin
125I-Regular Insulin mixes.Add the a-protein grain pearl that is coated with SPA (flicker is near measuring).Orifice plate was hatched 5-20 hour, in scintillometer, count, thereby measure insulin level.Compound activity under the given concentration is expressed as the multiple that stimulates insulin secretion with respect to control group.
Found that The compounds of this invention (measuring under the 10 μ M) has activity in INS-1 measures.
By dispersive Islet cells excreting insulin
According to following method, measure insulin secretion by the dispersive Islet cells of a large amount of The compounds of this invention media.(200-250g) isolates the Langerhans pancreas islet by male Sprague-Dawley rat, utilizes the collagenase classification.Utilize Regular Insulin to handle the dispersive islet cells, be seeded in the 96V-bottom outlet plate, make bead.Cell is saturated and do not comprise overnight incubation in the substratum of The compounds of this invention.With substratum ventilation, under 37 ℃, utilize the Krebs-Ringer-HEPES damping fluid preincubate cell 30 minutes that contains 3mM glucose.Remove and take damping fluid in advance, under 37 ℃, utilize the Krebs-Ringer-HEPES damping fluid that comprises or do not comprise containing of The compounds of this invention of suitable glucose concn (as 8mM) to hatch appropriate time again.In some research, also comprise GLP-1 or forskolin.Remove the part supernatant liquor, measure its insulin content by SPA.The result is expressed as " control group multiple " (FOC).
Measure in the body
Compound is to the chemical sproof effect of glucose in the rat peritoneum
The test The compounds of this invention is by the activity in vivo of oral administration in rat.The rat at one night of fasting is given contrast and the compound with oral dosage.Measure basic glucose level after 3 hours, through peritonaeum rat is given and used 2g/kg glucose.15, measure glucose level again after 30 and 60 minutes.With respect to the carrier behind the IPGTT (intraperitoneal glucose drug-resistant test), representational the present invention has reduced glucose level significantly.
Differentiate the target thing
Be used to differentiate that formula of the present invention (I) compound biological targets can be used for also differentiating that to formula (I) compound of thing the relevant biological targets that influences the insulin secretion function response of compound is to thing (as nucleic acid, peptide, polypeptide, protein, carbohydrate, lipoid or other molecule).Target thing or protein molecule that this class is regulated by The compounds of this invention can be differentiated by several modes.
For example, a kind of method of this class target discriminating can be finished by optics avidity labeling technique well known in the art.In this method, preparation comprises formula (I) compound of optical activity group (as benzoyl phenyl group), utilizes radio isotope (as tritium) mark again.As embodiment, can be used for the radio-labeling derivative of suitable formula (I) compound of this experiment for the benzophenone analogue of embodiment 207 descriptions.The method for preparing this compounds is a starting raw material with formula (X) compound wherein shown in following reaction process M.Chloride starting raw material can prepare according to the similar approach that embodiment 142 describes.In mode progressively, this starting raw material benzoyl radical functino, and allow experience tritium-halogen conversion reaction, thus the formula of providing (XIII) detection of compound.The method of replacing the chlorine atom by tritium is a technology well known in the art, its can under the condition that does not influence benzophenone part ketone groups globality, finish (as, Mesange, et al.Bioconj.Chem.13:766-772,2002; Held, et al., Labelled Compd.Radiopharm.39:501-508,1997; Kaspersen, et al., Rec.Trav.Chim.Pays-Bas112:191-199,1993; Hergert, etal., Pharmazie 38:28-29,1983).
Then, permission will contain molecular detection and pancreas beta cell lysate uniform mixture (or any biological sample of suspicious target thing, as by biological organism (as the people) or by biological organism constituent (as cell, biological tissue or body fluid), cell line or tissue culture sample, or sample can be derived from the patient who includes but not limited to its tissue or cell) contact, hatch the time that is enough to make molecular detection and the effect of targeting proteins matter, utilize this mixture of rayed of molecular detection optical active group wavelength then.Then utilize the standard method purifying owing to irradiation forms covalently bound protein and molecular detection, the radioactivity of impelling molecular detection/target thing mixture is as its isolating a kind of mode from remaining lysate mixture.Then, utilize method well known in the art (referring to, as Dorman, et al., Tibtech.18:64-77,2000), differentiate protein purification (molecular detection/target thing mixture).
Reaction process M
With formula (I) compound be used for another kind of method that characterization of biological influences insulin secretion function response targeting for be called medicine " fold " experiment (referring to, as Graves, et al., Rec.Prog.Horm.Res.58:1-24,2003).Contain formula (I) compound that is applicable to chemical coupling response function group (as carboxyl, amino, alcohol groups) and can carry out coupled reaction with the commercial polymkeric substance (resin) that contains suitable active linking group.For example, the polymkeric substance pearl thing that contains amino linking group can generate acid amides with the reaction of the formula of X=COOH (I) compound wherein, and described acid amides combines with polymkeric substance pearl thing, can maintain static thus.The polymkeric substance pearl thing that contains the formula of maintaining static (I) compound can be by the temptation of following manner as suitable Pancreatico-cathepsis product: polymkeric substance pearl thing is contacted with lysate, hatching is enough to make targeting proteins matter to generate the mixture that contains this polymkeric substance, to not have the bonded protein material from polymkeric substance, to remove, bonded protein will be split off from polymkeric substance.Thus, utilize technology well known in the art, by mass spectroscopy, can identify interested protein purification target thing (referring to, as Kim, etal., Biochem.Mol.Biol.36:299-304,2003.
All publications and patent documentation described in the above-mentioned specification sheets are hereby incorporated by reference.Under the prerequisite of not leaving the scope of the invention and spirit, the various improvement of the invention described above composition and method and change all are conspicuous to those skilled in the art.Although the present invention combines description with specific embodiment, should be appreciated that the present invention for required protection should only not only limit to this class particular.
Really, carry out the scope that above-mentioned pattern of the present invention all should belong to following claim for molecular biology or those of ordinary skill in the related art are conspicuous.These those skilled in the art can utilize the technology that is no more than normal experiment, and understanding maybe can be confirmed the technology that many and of the present invention particular are equal to.These equivalent technologies should be included in the following claim scope.
Claims (29)
1. formula (I) compound and pharmacologically acceptable salt thereof,
Wherein
R is H or (C
1-C
6) alkyl;
R
1Be H,
(C
1-C
6) alkyl, this group randomly is selected from (C
1-C
4) alkoxyl group, the phenyl that is randomly replaced by halogen and [three (C
1-C
4) alkyl] substituting group of silyl replaces,
(C
3-C
6) alkenyl,
(C
3-C
6) alkynyl,
(C
3-C
6) cycloalkyl, this group randomly is selected from (C
1-C
3) alkyl, CF
3Replace with two substituting groups of as many as of halogen,
(C
1-C
3) haloalkyl, or
Phenyl, this group randomly is selected from
Halogen,
(C
1-C
6) alkyl, this group is randomly by (a C
1-C
4) the alkoxyl group replacement,
(C
1-C
6) alkoxyl group,
(C
1-C
3) haloalkyl,
(C
1-C
3) halogenated alkoxy,
NR
8R
8，
Cyano group and
(C
1-C
6) four substituting groups of as many as of alkylthio replace;
R
2Be H,
Halogen,
(C
1-C
6) alkyl, this group is randomly by (a C
1-C
4) the alkoxyl group replacement,
(C
3-C
6) cycloalkyl, this group randomly is selected from (C
1-C
3) two substituting groups of as many as of alkyl and halogen replace,
(C
1-C
3) haloalkyl,
Pyridyl, this group is optional to be selected from (C
1-C
6) alkoxyl group, (C
1-C
6) alkylthio, halogen and randomly by (a C
1-C
4) (the C that replaces of alkoxyl group
1-C
6) two substituting groups of as many as of alkyl replace,
Pyrimidyl,
Phenyl, this group randomly is selected from
(C
1-C
6) alkyl, this group is randomly by (a C
1-C
4) the alkoxyl group replacement,
(C
1-C
6) alkoxyl group,
Hydroxyl,
NR
8R
8，
Cyano group,
(C
1-C
6) alkylthio,
Halogen,
CO
2R
8，
(C
1-C
3) halogenated alkoxy,
(C
1-C
4) acyl group and
Four substituting groups of the as many as of benzoyl replace this group,
Or
Tetralyl, 2,3-indanyl, benzo dioxolyl or benzodioxan base can randomly be selected from (C separately
1-C
6) alkoxyl group, (C
1-C
6) alkylthio, halogen and randomly by (a C
1-C
4) (the C that replaces of alkoxyl group
1-C
6) two substituting groups of as many as of alkyl replace,
Or
Work as R
1And R
2Be (C
1-C
6) during alkyl, they can form 5-or 6-unit carbocyclic ring together with coupled C atom,
Or
R
1And R
2Can form that 6-unit contains the N atom with coupled C atom together and on N randomly by (C
1-C
3) heterocycle that replaces of alkyl;
R
3Be (C
1-C
6) alkyl,
(C
3-C
6) cycloalkyl,
Benzyl, this group randomly is selected from its aryl
(C
1-C
6) alkyl, this group is randomly by (a C
1-C
4) the alkoxyl group replacement, halogen,
(C
1-C
3) haloalkyl,
(C
1-C
6) alkoxyl group,
(C
1-C
3) halogenated alkoxy,
NR
8R
8，
Cyano group,
(C
1-C
6) alkylthio and
SO
2(C
1-C
3) four substituting groups of as many as of alkyl replace,
(C
2-C
3) haloalkyl, or
Phenyl, this group randomly is selected from
(C
1-C
6) alkyl, this group is randomly by (a C
1-C
4) the alkoxyl group replacement,
Halogen,
(C
1-C
3) haloalkyl,
(C
1-C
6) alkoxyl group,
(C
1-C
3) halogenated alkoxy,
NR
8R
8，
Cyano group,
(C
1-C
6) alkylthio and
SO
2(C
1-C
3) four substituting groups of as many as of alkyl replace;
R
4Be (C
1-C
6) alkyl, this group is randomly by (a C
1-C
4) the alkoxyl group replacement,
(C
1-C
6) alkoxyl group,
(C
1-C
6) alkylthio,
(C
1-C
3) haloalkyl,
(C
1-C
3) halogenated alkoxy,
Halogen,
NR
8R
8，
Pyrimidyl
Pyridyl,
Imidazolyl, or
Phenyl, this group randomly is selected from
Halogen,
(C
1-C
6) alkyl, this group is randomly by (a C
1-C
4) the alkoxyl group replacement,
(C
1-C
6) alkoxyl group,
(C
1-C
3) haloalkyl,
(C
1-C
3) halogenated alkoxy,
NR
8R
8，
Cyano group
(C
1-C
6) four substituting groups of as many as of alkylthio replace;
N=0,1,2 or 3;
X is CO
2R
8, CONR
5R
6, SO
2NHR
7Or randomly by (C
1-C
6) alkyl replacement De oxadiazole base;
R
5Be H,
(C
1-C
6) alkyl,
(C
2-C
6) alkyl, this group is by OR
6Replace,
Benzyl, this group randomly is selected from its aromatic ring
Halogen,
(C
1-C
6) alkyl, this group is randomly by (a C
1-C
4) the alkoxyl group replacement,
(C
1-C
6) alkoxyl group,
(C
1-C
3) haloalkyl,
(C
1-C
3) halogenated alkoxy,
NR
8R
8，
Cyano group and
(C
1-C
6) four substituting groups of as many as of alkylthio replace,
Phenyl, this group randomly by
(C
1-C
6) alkyl, this group is randomly by (a C
1-C
4) the alkoxyl group replacement,
Halogen,
(C
1-C
6) alkoxyl group,
(C
1-C
3) haloalkyl,
(C
1-C
3) halogenated alkoxy,
NR
8R
8，
Cyano group and
(C
1-C
6) four substituting groups of as many as of alkylthio replace,
Pyridyl, this group randomly is selected from
Halogen,
(C
1-C
6) alkyl, this group is randomly by (a C
1-C
4) the alkoxyl group replacement,
(C
1-C
6) alkoxyl group,
(C
1-C
3) halogenated alkoxy,
NR
8R
8，
Cyano group and
(C
1-C
6) four substituting groups of as many as of alkylthio replace,
SO
2-phenyl, described phenyl randomly is selected from
Halogen,
(C
1-C
6) alkyl, this group is randomly by (a C
1-C
4) the alkoxyl group replacement,
(C
1-C
6) alkoxyl group,
(C
1-C
3) haloalkyl,
(C
1-C
3) halogenated alkoxy,
NR
8R
8，
Cyano group and
(C
1-C
6) four substituting groups of as many as of alkylthio replace;
R
6Be H or (C
1-C
6) alkyl; Or
R
5With R
6Form piperidines, morpholine, thiomorpholine or piperazine ring together with coupled N atom,
Described piperazine is quilt (C on its N atom randomly
1-C
3) the alkyl replacement;
R
7Be H or methyl;
R
8Be H,
Or
(C
1-C
6) alkyl,
Condition is: as R and R
2For H and X are CO
2During H, R
1Be not H, methyl or ethyl, and further condition is: formula (I) compound is not
With further condition be:
Formula (I) compound is not N-(1, a 3-dimethyl pyrazole-5-yl) methyl o-aminobenzoate; N-(3-methyl isophthalic acid-propyl group pyrazoles-5-yl) methyl o-aminobenzoate, N-(1,3-dimethyl pyrazole-5-yl) methyl o-aminobenzoate; 5-chloro-N-(1,3-dimethyl pyrazole-5-yl) methyl o-aminobenzoate; 5-chloro-N-(3-ethyl-1-methylpyrazole-5-yl) methyl o-aminobenzoate; 5-fluoro-N-(1,3-dimethyl pyrazole-5-yl) methyl o-aminobenzoate; N-(1,3-dimethyl pyrazole-5-yl)-5-methoxyl group methyl o-aminobenzoate; N-(1,3-dimethyl pyrazole-5-yl)-5-(methylthio group) methyl o-aminobenzoate; 4-chloro-N-(1,3-dimethyl pyrazole-5-yl) methyl o-aminobenzoate; Or N-(1,3-dimethyl pyrazole-5-yl)-4-methoxyl group methyl o-aminobenzoate.
2. according to the compound of claim 1, wherein
R
1Be phenyl, this group randomly is selected from
Halogen,
(C
1-C
6) alkyl, this group is randomly by (a C
1-C
4) the alkoxyl group replacement,
(C
1-C
6) alkoxyl group,
(C
1-C
3) haloalkyl,
(C
1-C
3) halogenated alkoxy,
NR
8R
8，
Cyano group and
(C
1-C
6) four substituting groups of as many as of alkylthio replace;
And
R, R
2, R
3, R
4, R
5, R
6, R
7, R
8, X and n such as claim 1 definition.
3. according to the compound of claim 1, wherein
R
2Be pyridyl, this group is optional to be selected from (C
1-C
6) alkoxyl group, (C
1-C
6) alkylthio, halogen and randomly by (a C
1-C
4) (the C that replaces of alkoxyl group
1-C
6) two substituting groups of as many as of alkyl replace,
Or
Phenyl, this group randomly is selected from
(C
1-C
6) alkyl, this group is randomly by (a C
1-C
4) the alkoxyl group replacement,
(C
1-C
6) alkoxyl group,
Hydroxyl,
NR
8R
8，
Cyano group,
(C
1-C
6) alkylthio,
Halogen,
CO
2R
8，
(C
1-C
3) halogenated alkoxy,
(C
1-C
4) acyl group and
Four substituting groups of the as many as of benzoyl replace this group,
And
R, R
1, R
3, R
4, R
5, R
6, R
7, R
8, X and n such as claim 1 definition.
4. according to the compound of claim 1, wherein
X＝CO
2R
8；
And
R, R
1, R
2, R
3, R
4, R
8With n such as claim 1 definition.
5. according to the compound of claim 1, wherein
R
1Be phenyl, this group randomly is selected from
Halogen,
(C
1-C
6) alkyl, this group is randomly by (a C
1-C
4) the alkoxyl group replacement,
(C
1-C
6) alkoxyl group,
(C
1-C
3) haloalkyl,
(C
1-C
3) halogenated alkoxy,
NR
8R
8，
Cyano group and
(C
1-C
6) four substituting groups of as many as of alkylthio replace;
R
2Be H,
Halogen,
(C
1-C
6) alkyl, this group is randomly by (a C
1-C
4) the alkoxyl group replacement,
(C
3-C
6) cycloalkyl, this group randomly is selected from (C
1-C
3) two substituting groups of as many as of alkyl and halogen replace, or
(C
1-C
3) haloalkyl,
And
R, R
3, R
4, R
5, R
6, R
7, R
8, X and n such as claim 1 definition.
6. according to the compound of claim 1, wherein
R
1Be H,
(C
1-C
6) alkyl, this group randomly is selected from (C
1-C
4) alkoxyl group, the phenyl that is randomly replaced by halogen and [three (C
1-C
4) alkyl] substituting group of silyl replaces,
(C
3-C
6) alkenyl,
(C
3-C
6) alkynyl,
(C
3-C
6) cycloalkyl, this group randomly is selected from (C
1-C
3) alkyl, CF
3Replace with two substituting groups of as many as of halogen, or
(C
1-C
3) haloalkyl;
R
2Be H,
Halogen,
(C
1-C
6) alkyl, this group is randomly by (a C
1-C
4) the alkoxyl group replacement,
(C
3-C
6) cycloalkyl, this group randomly is selected from (C
1-C
3) two substituting groups of as many as of alkyl and halogen replace,
(C
1-C
3) haloalkyl,
And
R, R
3, R
4, R
5, R
6, R
7, R
8, X and n such as claim 1 definition.
7. according to the compound of claim 1, wherein
R
1Be H,
(C
1-C
6) alkyl, this group randomly is selected from (C
1-C
4) alkoxyl group, the phenyl that is randomly replaced by halogen and [three (C
1-C
4) alkyl] substituting group of silyl replaces,
(C
3-C
6) alkenyl,
(C
3-C
6) alkynyl,
(C
3-C
6) cycloalkyl, this group randomly is selected from (C
1-C
3) alkyl, CF
3Replace with two substituting groups of as many as of halogen, or
(C
1-C
3) haloalkyl;
R
2Be pyridyl, this group is optional to be selected from (C
1-C
6) alkoxyl group, (C
1-C
6) alkylthio, halogen and randomly by (a C
1-C
4) (the C that replaces of alkoxyl group
1-C
6) two substituting groups of as many as of alkyl replace, or
Phenyl, this group randomly is selected from
(C
1-C
6) alkyl, this group is randomly by (a C
1-C
4) the alkoxyl group replacement,
(C
1-C
6) alkoxyl group,
Hydroxyl,
NR
8R
8，
Cyano group,
(C
1-C
6) alkylthio,
Halogen,
CO
2R
8，
(C
1-C
3) halogenated alkoxy,
(C
1-C
4) acyl group and
Four substituting groups of the as many as of benzoyl replace this group,
And
R, R
3, R
4, R
5, R
6, R
7, R
8, X and n such as claim 1 definition.
8. according to the compound of claim 1, wherein
R
1Be phenyl, this group randomly is selected from
Halogen,
(C
1-C
6) alkyl, this group is randomly by (a C
1-C
4) the alkoxyl group replacement,
(C
1-C
6) alkoxyl group,
(C
1-C
3) haloalkyl,
(C
1-C
3) halogenated alkoxy,
NR
8R
8，
Cyano group and
(C
1-C
6) four substituting groups of as many as of alkylthio replace;
R
2Be H,
Halogen,
(C
1-C
6) alkyl, this group is randomly by (a C
1-C
4) the alkoxyl group replacement,
(C
3-C
6) cycloalkyl, this group randomly is selected from (C
1-C
3) two substituting groups of as many as of alkyl and halogen replace,
(C
1-C
3) haloalkyl;
X is CO
2R
8
And
R, R
3, R
4, R
8With n such as claim 1 definition.
9. according to the compound of claim 1, wherein
R
1Be H,
(C
1-C
6) alkyl, this group randomly is selected from (C
1-C
4) alkoxyl group, the phenyl that is randomly replaced by halogen and [three (C
1-C
4) alkyl] substituting group of silyl replaces,
(C
3-C
6) alkenyl,
(C
3-C
6) alkynyl,
(C
3-C
6) cycloalkyl, this group randomly is selected from (C
1-C
3) alkyl, CF
3Replace with two substituting groups of as many as of halogen, or
(C
1-C
3) haloalkyl;
R
2Be H,
Halogen,
(C
1-C
6) alkyl, this group is randomly by (a C
1-C
4) the alkoxyl group replacement,
(C
3-C
6) cycloalkyl, this group randomly is selected from (C
1-C
3) two substituting groups of as many as of alkyl and halogen replace,
(C
1-C
3) haloalkyl;
X is CO
2R
8
And
R, R
3, R
4, R
8With n such as claim 1 definition.
10. according to the compound of claim 1, wherein
R
1Be H,
(C
1-C
6) alkyl, this group randomly is selected from (C
1-C
4) alkoxyl group, the phenyl that is randomly replaced by halogen and [three (C
1-C
4) alkyl] substituting group of silyl replaces,
(C
3-C
6) alkenyl,
(C
3-C
6) alkynyl,
(C
3-C
6) cycloalkyl, this group randomly is selected from (C
1-C
3) alkyl, CF
3Replace with two substituting groups of as many as of halogen, or
(C
1-C
3) haloalkyl;
R
2Be pyridyl, this group is selected from (C arbitrarily
1-C
6) alkoxyl group, (C
1-C
6) alkylthio, halogen and randomly by (a C
1-C
4) (the C that replaces of alkoxyl group
1-C
6) two substituting groups of as many as of alkyl replace, or
Phenyl, this group randomly is selected from
(C
1-C
6) alkyl, this group is randomly by (a C
1-C
4) the alkoxyl group replacement,
(C
1-C
6) alkoxyl group,
Hydroxyl,
NR
8R
8，
Cyano group,
(C
1-C
6) alkylthio,
Halogen,
CO
2R
8，
(C
1-C
3) halogenated alkoxy,
(C
1-C
4) acyl group and
Four substituting groups of the as many as of benzoyl replace this group;
X is CO
2R
8
And
R, R
3, R
4, R
8With n such as claim 1 definition.
11. according to the compound of claim 1, wherein
R is H;
R
1Be H,
(C
1-C
6) alkyl, this group randomly is selected from (C
1-C
4) alkoxyl group, the phenyl that is randomly replaced by halogen and [three (C
1-C
4) alkyl] substituting group of silyl replaces (C
3-C
6) cycloalkyl, this group randomly is selected from (C
1-C
3) alkyl, CF
3Replace with two substituting groups of as many as of halogen,
(C
1-C
3) haloalkyl, or
Phenyl, this group randomly is selected from
Halogen,
(C
1-C
6) alkyl, this group is randomly by (a C
1-C
4) the alkoxyl group replacement,
(C
1-C
6) alkoxyl group,
(C
1-C
3) haloalkyl,
(C
1-C
3) halogenated alkoxy,
NR
8R
8，
Cyano group and
(C
1-C
6) four substituting groups of as many as of alkylthio replace;
R
2Be H,
(C
1-C
6) alkyl, this group is randomly by (a C
1-C
4) the alkoxyl group replacement,
Pyridyl, this group is optional to be selected from (C
1-C
6) alkoxyl group, (C
1-C
6) alkylthio, halogen and randomly by (a C
1-C
4) (the C that replaces of alkoxyl group
1-C
6) two substituting groups of as many as of alkyl replace, or
Phenyl, this group randomly is selected from
(C
1-C
6) alkyl, this group is randomly by (a C
1-C
4) the alkoxyl group replacement,
(C
1-C
6) alkoxyl group,
Hydroxyl,
NR
8R
8，
Cyano group,
(C
1-C
6) alkylthio,
Halogen,
CO
2R
8，
(C
1-C
3) halogenated alkoxy,
(C
1-C
4) acyl group and
Four substituting groups of the as many as of benzoyl replace this group,
R
3Be (C
1-C
6) alkyl,
(C
3-C
6) cycloalkyl, or
Phenyl, this group randomly is selected from
(C
1-C
6) alkyl, this group is randomly by (a C
1-C
4) the alkoxyl group replacement,
Halogen,
(C
1-C
3) haloalkyl,
(C
1-C
6) alkoxyl group,
(C
1-C
3) halogenated alkoxy,
NR
8R
8，
Cyano group,
(C
1-C
6) alkylthio and
SO
2(C
1-C
3) four substituting groups of as many as of alkyl replace;
R
4Be (C
1-C
6) alkyl, this group is randomly by (a C
1-C
4) the alkoxyl group replacement,
(C
1-C
6) alkoxyl group,
Halogen,
Phenyl, this group randomly is selected from
Halogen,
(C
1-C
6) alkyl, this group is randomly by (a C
1-C
4) the alkoxyl group replacement,
(C
1-C
6) alkoxyl group,
(C
1-C
3) haloalkyl,
(C
1-C
3) halogenated alkoxy,
NR
8R
8，
Cyano group
(C
1-C
6) four substituting groups of as many as of alkylthio replace;
N=0,1,2 or 3;
X is CO
2R
8
And
R
8Be H,
(C
1-C
6) alkyl,
Benzyl, this group randomly is selected from its aromatic ring
Halogen,
(C
1-C
6) alkyl, this group is randomly by (a C
1-C
4) the alkoxyl group replacement,
(C
1-C
3) alkoxyl group,
(C
1-C
3) haloalkyl,
(C
1-C
3) halogenated alkoxy,
Cyano group and
(C
1-C
6) four substituting groups of as many as of alkylthio replace, or
Phenyl, this group randomly is selected from
(C
1-C
6) alkyl, this group is randomly by (a C
1-C
4) the alkoxyl group replacement,
Halogen,
(C
1-C
6) alkoxyl group,
(C
1-C
3) haloalkyl,
(C
1-C
3) halogenated alkoxy,
Cyano group and
(C
1-C
6) four substituting groups of as many as of alkylthio replace.
12. according to the compound of claim 1, wherein
R is H;
R
1Be H,
(C
1-C
6) alkyl, this group randomly is selected from (C
1-C
4) alkoxyl group, randomly replaced by halogen
Phenyl and [three (C
1-C
4) alkyl] substituting group of silyl replaces, or phenyl, this group randomly is selected from
Halogen,
(C
1-C
6) alkyl, this group is randomly by (a C
1-C
4) the alkoxyl group replacement,
(C
1-C
6) alkoxyl group,
(C
1-C
3) haloalkyl,
(C
1-C
3) halogenated alkoxy,
NR
8R
8，
Cyano group and
(C
1-C
6) four substituting groups of as many as of alkylthio replace;
R
2Be H,
Halogen, or
(C
1-C
6) alkyl, this group is randomly by (a C
1-C
4) the alkoxyl group replacement; R
3Be (C
1-C
6) alkyl, or
Phenyl, this group randomly is selected from
(C
1-C
6) alkyl, this group is randomly by (a C
1-C
4) the alkoxyl group replacement,
Halogen,
(C
1-C
3) haloalkyl,
(C
1-C
6) alkoxyl group,
(C
1-C
3) halogenated alkoxy,
NR
8R
8，
Cyano group,
(C
1-C
6) alkylthio and
SO
2(C
1-C
3) four substituting groups of as many as of alkyl replace;
R
4Be (C
1-C
6) alkyl, this group is randomly by (a C
1-C
4) the alkoxyl group replacement,
(C
1-C
6) alkoxyl group,
(C
1-C
6) alkylthio,
(C
1-C
3) haloalkyl,
(C
1-C
3) halogenated alkoxy,
Halogen;
N=0,1,2 or 3;
X is CONR
5R
6
R
5Be H,
(C
1-C
6) alkyl,
(C
2-C
6) alkyl, this group is by OR
6Replace,
Benzyl, this group randomly is selected from its aromatic ring
Halogen,
(C
1-C
6) alkyl, this group is randomly by (a C
1-C
4) the alkoxyl group replacement,
(C
1-C
6) alkoxyl group,
(C
1-C
3) haloalkyl,
(C
1-C
3) halogenated alkoxy,
NR
8R
8，
Cyano group and
(C
1-C
6) four substituting groups of as many as of alkylthio replace,
Phenyl, this group randomly by
(C
1-C
6) alkyl, this group is randomly by (a C
1-C
4) the alkoxyl group replacement,
Halogen,
(C
1-C
6) alkoxyl group,
(C
1-C
3) haloalkyl,
(C
1-C
3) halogenated alkoxy,
NR
8R
8，
Cyano group and
(C
1-C
6) four substituting groups of as many as of alkylthio replace,
Pyridyl, this group randomly is selected from
Halogen,
(C
1-C
6) alkyl, this group is randomly by (a C
1-C
4) the alkoxyl group replacement,
(C
1-C
6) alkoxyl group,
(C
1-C
3) halogenated alkoxy,
NR
8R
8，
Cyano group and
(C
1-C
6) four substituting groups of as many as of alkylthio replace,
Or
SO
2-phenyl, described phenyl randomly is selected from
Halogen,
(C
1-C
6) alkyl, this group is randomly by (a C
1-C
4) the alkoxyl group replacement,
(C
1-C
6) alkoxyl group,
(C
1-C
3) haloalkyl,
(C
1-C
3) halogenated alkoxy,
NR
8R
8，
Cyano group and
(C
1-C
6) four substituting groups of as many as of alkylthio replace;
R
6Be H or (C
1-C
6) alkyl; Or
R
5With R
6Form piperidines, morpholine, thiomorpholine or piperazine ring together with coupled N atom,
Described piperazine is quilt (C on its N atom randomly
1-C
3) the alkyl replacement;
R
8Be H,
(C
1-C
6) alkyl,
Benzyl, this group randomly is selected from its aromatic ring
Halogen,
(C
1-C
6) alkyl, this group is randomly by (a C
1-C
4) the alkoxyl group replacement,
(C
1-C
3) alkoxyl group,
(C
1-C
3) haloalkyl,
(C
1-C
3) halogenated alkoxy,
Cyano group and
(C
1-C
6) four substituting groups of as many as of alkylthio replace,
Or
Phenyl, this group randomly is selected from
(C
1-C
6) alkyl, this group is randomly by (a C
1-C
4) the alkoxyl group replacement,
Halogen,
(C
1-C
6) alkoxyl group,
(C
1-C
3) haloalkyl,
(C
1-C
3) halogenated alkoxy,
Cyano group and
(C
1-C
6) four substituting groups of as many as of alkylthio replace.
13. according to the compound of claim 1, this compound is selected from:
The 2-[(3-tertiary butyl-1-methyl isophthalic acid H-pyrazoles-5-yl) amino]-the 5-methoxybenzoic acid;
2-{[3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } benzamide;
2-{[3-(4-fluorophenyl)-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid;
The 2-{[3-tertiary butyl-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid;
The 2-{[3-tertiary butyl-1-(2-p-methoxy-phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid;
2-[(1,3-phenylbenzene-1H-pyrazoles-5-yl) amino]-the 5-methoxybenzoic acid;
2-fluoro-6-{[3-(4-fluorophenyl)-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid;
2-fluoro-6-{[1-(2-aminomethyl phenyl)-3-(4-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid;
The 2-{[3-tertiary butyl-1-(5-fluoro-2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 6-fluorobenzoic acid;
2-(the 3-tertiary butyl-1-[2-(methylthio group) phenyl]-1H-pyrazoles-5-yl } amino)-the 5-methoxybenzoic acid;
The 2-{[3-tertiary butyl-1-(2-ethoxyl phenenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid;
The 2-{[3-tertiary butyl-1-(2-ethoxyl phenenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid;
2-{[3-(3-p-methoxy-phenyl)-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid;
5-methoxyl group-2-{[3-(3-p-methoxy-phenyl)-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid;
2-{[3-(3-p-methoxy-phenyl)-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-tolyl acid;
The 2-{[3-tertiary butyl-1-(2-p-methoxy-phenyl)-4-methyl isophthalic acid H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid;
The 2-[(3-tertiary butyl-1-phenyl-1H-pyrazoles-5-yl) amino]-the 5-methoxybenzoic acid;
The 2-{[3-tertiary butyl-1-(5-fluoro-2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid;
The 2-{[3-tertiary butyl-1-(2, the 6-3,5-dimethylphenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid;
The 2-{[3-tertiary butyl-1-(2-methoxyl group-5-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid;
The 2-{[3-tertiary butyl-1-(2, the 3-3,5-dimethylphenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid;
The 2-{[3-tertiary butyl-1-(2-methoxyl group-6-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid;
The 2-{[3-tertiary butyl-1-(2, the 6-3,5-dimethylphenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid;
2-{[1-(2, the 6-3,5-dimethylphenyl)-3-(1-methyl cyclopropyl)-1H-pyrazoles-5-yl] amino } phenylformic acid;
2-{[1-(2, the 6-3,5-dimethylphenyl)-3-(3,3, the 3-trifluoro propyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid;
5-methoxyl group-2-{[3-methyl isophthalic acid-(2-aminomethyl phenyl)-4-phenyl-1H-pyrazoles-5-yl] amino } phenylformic acid;
5-methoxyl group-2-{[4-(6-methoxypyridine-3-yl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid;
5-methoxyl group-2-{[1-(2-aminomethyl phenyl)-4-pyridin-4-yl-3-(trifluoromethyl)-1H-pyrazoles-5-yl] amino } phenylformic acid;
5-methoxyl group-2-{[4-(4-p-methoxy-phenyl)-1-(2-aminomethyl phenyl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl] amino) phenylformic acid;
2-{[3-ethyl-4-(6-methoxypyridine-3-yl)-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid;
2-{[4-(2-fluorophenyl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid;
5-methoxyl group-2-{[1-(2-p-methoxy-phenyl)-3-methyl-4-phenyl-1H-pyrazoles-5-yl] amino } phenylformic acid; And
2-{[4-(2, the 4-Dimethoxyphenyl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid.
14. a pharmaceutical composition, this pharmaceutical composition comprise claim 1 compound or pharmacologically acceptable salt with pharmaceutically acceptable carrier bonded treatment significant quantity.
15. the compound of claim 1 and following compound be used to prepare treat and/or prevent diabetes and with the purposes of the medicine of diabetes relative disease: N-(1,3-dimethyl pyrazole-5-yl) methyl o-aminobenzoate monohydrochloride; N-(3-methyl isophthalic acid-propyl group pyrazoles-5-yl) methyl o-aminobenzoate, N-(1,3-dimethyl pyrazole-5-yl) methyl o-aminobenzoate; 5-chloro-N-(1,3-dimethyl pyrazole-5-yl) methyl o-aminobenzoate; 5-chloro-N-(3-ethyl-1-methylpyrazole-5-yl) methyl o-aminobenzoate monohydrochloride; 5-fluoro-N-(1,3-dimethyl pyrazole-5-yl) methyl o-aminobenzoate monohydrochloride; N-(1,3-dimethyl pyrazole-5-yl)-5-methoxyl group methyl o-aminobenzoate; N-(1,3-dimethyl pyrazole-5-yl)-5-(methylthio group) methyl o-aminobenzoate monohydrochloride; 4-chloro-N-(1,3-dimethyl pyrazole-5-yl) methyl o-aminobenzoate; Or N-(1,3-dimethyl pyrazole-5-yl)-4-methoxyl group methyl o-aminobenzoate.
16. according to the purposes of claim 15, described diabetes are selected from type i diabetes, type ii diabetes, young adult's ripening stage show effect diabetes, the potential autoimmune diabetes of grownup and gestational diabetes.
17. the compound of claim 1 and following compound are used to prepare the purposes of the medicine for the treatment of syndrome X: N-(1,3-dimethyl pyrazole-5-yl) methyl o-aminobenzoate monohydrochloride; N-(3-methyl isophthalic acid-propyl group pyrazoles-5-yl) methyl o-aminobenzoate, N-(1,3-dimethyl pyrazole-5-yl) methyl o-aminobenzoate; 5-chloro-N-(1,3-dimethyl pyrazole-5-yl) methyl o-aminobenzoate; 5-chloro-N-(3-ethyl-1-methylpyrazole-5-yl) methyl o-aminobenzoate monohydrochloride; 5-fluoro-N-(1,3-dimethyl pyrazole-5-yl) methyl o-aminobenzoate monohydrochloride; N-(1,3-dimethyl pyrazole-5-yl)-5-methoxyl group methyl o-aminobenzoate; N-(1,3-dimethyl pyrazole-5-yl)-5-(methylthio group) methyl o-aminobenzoate monohydrochloride; 4-chloro-N-(1,3-dimethyl pyrazole-5-yl) methyl o-aminobenzoate; Or N-(1,3-dimethyl pyrazole-5-yl)-4-methoxyl group methyl o-aminobenzoate.
18. according to the purposes of claim 15, wherein said and diabetes relative disease is selected from hyperglycemia, hyperinsulinemia, weakening glucose resistance, weakens fasting glucose, lipidosis disease, high triglyceride disease and insulin resistant.
19. the compound of claim 1 and following compound are used to prepare the purposes of the medicine of treatment of obesity: N-(1,3-dimethyl pyrazole-5-yl) methyl o-aminobenzoate monohydrochloride; N-(3-methyl isophthalic acid-propyl group pyrazoles-5-yl) methyl o-aminobenzoate, N-(1,3-dimethyl pyrazole-5-yl) methyl o-aminobenzoate; 5-chloro-N-(1,3-dimethyl pyrazole-5-yl) methyl o-aminobenzoate; 5-chloro-N-(3-ethyl-1-methylpyrazole-5-yl) methyl o-aminobenzoate monohydrochloride; 5-fluoro-N-(1,3-dimethyl pyrazole-5-yl) methyl o-aminobenzoate monohydrochloride; N-(1,3-dimethyl pyrazole-5-yl)-5-methoxyl group methyl o-aminobenzoate; N-(1,3-dimethyl pyrazole-5-yl)-5-(methylthio group) methyl o-aminobenzoate monohydrochloride; 4-chloro-N-(1,3-dimethyl pyrazole-5-yl) methyl o-aminobenzoate; Or N-(1,3-dimethyl pyrazole-5-yl)-4-methoxyl group methyl o-aminobenzoate.
20. the compound of claim 1 and following compound are used to prepare the purposes of the medicine for the treatment of cardiovascular disorder: N-(1,3-dimethyl pyrazole-5-yl) methyl o-aminobenzoate monohydrochloride; N-(3-methyl isophthalic acid-propyl group pyrazoles-5-yl) methyl o-aminobenzoate, N-(1,3-dimethyl pyrazole-5-yl) methyl o-aminobenzoate; 5-chloro-N-(1,3-dimethyl pyrazole-5-yl) methyl o-aminobenzoate; 5-chloro-N-(3-ethyl-1-methylpyrazole-5-yl) methyl o-aminobenzoate monohydrochloride; 5-fluoro-N-(1,3-dimethyl pyrazole-5-yl) methyl o-aminobenzoate monohydrochloride; N-(1,3-dimethyl pyrazole-5-yl)-5-methoxyl group methyl o-aminobenzoate; N-(1,3-dimethyl pyrazole-5-yl)-5-(methylthio group) methyl o-aminobenzoate monohydrochloride; 4-chloro-N-(1,3-dimethyl pyrazole-5-yl) methyl o-aminobenzoate; Or N-(1,3-dimethyl pyrazole-5-yl)-4-methoxyl group methyl o-aminobenzoate.
21. the compound of claim 1 and following compound be used to prepare treatment and/or or the purposes of preventing the medicine of the second reason diabetes: N-(1,3-dimethyl pyrazole-5-yl) methyl o-aminobenzoate monohydrochloride; N-(3-methyl isophthalic acid-propyl group pyrazoles-5-yl) methyl o-aminobenzoate, N-(1,3-dimethyl pyrazole-5-yl) methyl o-aminobenzoate; 5-chloro-N-(1,3-dimethyl pyrazole-5-yl) methyl o-aminobenzoate; 5-chloro-N-(3-ethyl-1-methylpyrazole-5-yl) methyl o-aminobenzoate monohydrochloride; 5-fluoro-N-(1,3-dimethyl pyrazole-5-yl) methyl o-aminobenzoate monohydrochloride; N-(1,3-dimethyl pyrazole-5-yl)-5-methoxyl group methyl o-aminobenzoate; N-(1,3-dimethyl pyrazole-5-yl)-5-(methylthio group) methyl o-aminobenzoate monohydrochloride; 4-chloro-N-(1,3-dimethyl pyrazole-5-yl) methyl o-aminobenzoate; Or N-(1,3-dimethyl pyrazole-5-yl)-4-methoxyl group methyl o-aminobenzoate.
22. according to the purposes of claim 21, wherein said second reason is selected from that sugared corticoid is excessive, tethelin is excessive, pheochromocytoma and drug-induced diabetes.
23. the compound of claim 1 and following compound are used to prepare the purposes of medicine: N-(1,3-dimethyl pyrazole-5-yl) methyl o-aminobenzoate monohydrochloride; N-(3-methyl isophthalic acid-propyl group pyrazoles-5-yl) methyl o-aminobenzoate, N-(1,3-dimethyl pyrazole-5-yl) methyl o-aminobenzoate; 5-chloro-N-(1,3-dimethyl pyrazole-5-yl) methyl o-aminobenzoate; 5-chloro-N-(3-ethyl-1-methylpyrazole-5-yl) methyl o-aminobenzoate monohydrochloride; 5-fluoro-N-(1,3-dimethyl pyrazole-5-yl) methyl o-aminobenzoate monohydrochloride; N-(1,3-dimethyl pyrazole-5-yl)-5-methoxyl group methyl o-aminobenzoate; N-(1,3-dimethyl pyrazole-5-yl)-5-(methylthio group) methyl o-aminobenzoate monohydrochloride; 4-chloro-N-(1,3-dimethyl pyrazole-5-yl) methyl o-aminobenzoate; Or N-(1,3-dimethyl pyrazole-5-yl)-4-methoxyl group methyl o-aminobenzoate, this medicine is taken claim 1 compound and following compound and is stimulated described main body insulin secretion the main body of needs treatments.
24. comprise the medicine of at least a and at least a pharmaceutically acceptable safety of medicine carrier or vehicle bonded claim 1 compound.
25. be used for the treatment of and/or claim 24 medicine of prevent diabetes, wherein said compound exists with significant quantity.
26. a method of differentiating the biological targeting thing, the method comprising the steps of:
Claim 1 compound and following compound are contacted with biological sample: N-(1,3-dimethyl pyrazole-5-yl) methyl o-aminobenzoate monohydrochloride; N-(3-methyl isophthalic acid-propyl group pyrazoles-5-yl) methyl o-aminobenzoate, N-(1,3-dimethyl pyrazole-5-yl) methyl o-aminobenzoate; 5-chloro-N-(1,3-dimethyl pyrazole-5-yl) methyl o-aminobenzoate; 5-chloro-N-(3-ethyl-1-methylpyrazole-5-yl) methyl o-aminobenzoate monohydrochloride; 5-fluoro-N-(1,3-dimethyl pyrazole-5-yl) methyl o-aminobenzoate monohydrochloride; N-(1,3-dimethyl pyrazole-5-yl)-5-methoxyl group methyl o-aminobenzoate; N-(1,3-dimethyl pyrazole-5-yl)-5-(methylthio group) methyl o-aminobenzoate monohydrochloride; 4-chloro-N-(1,3-dimethyl pyrazole-5-yl) methyl o-aminobenzoate; Or N-(1,3-dimethyl pyrazole-5-yl)-4-methoxyl group methyl o-aminobenzoate;
Form mixture with described compound and described biological targeting thing;
Separate this compound-target thing mixture; And
Differentiate the target thing.
27. according to the method for claim 26, wherein biological sample is the pancreas beta cell.
28. according to the method for claim 26, wherein said compound utilizes photosensitive group and/or radioisotope mark.
29. according to the method for claim 26, wherein said compound and polymkeric substance coupling.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US42991702P | 2002-11-27 | 2002-11-27 | |
| US60/429,917 | 2002-11-27 | ||
| US60/498,214 | 2003-08-27 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1717401A CN1717401A (en) | 2006-01-04 |
| CN100448869C true CN100448869C (en) | 2009-01-07 |
Family
ID=35822519
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2003801043536A Expired - Fee Related CN100448869C (en) | 2002-11-27 | 2003-11-25 | Anilinopyrazole derivatives for the treatment of diabetes |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN100448869C (en) |
| GT (1) | GT200300260A (en) |
| ZA (1) | ZA200505055B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010034657A1 (en) * | 2008-09-25 | 2010-04-01 | F. Hoffmann-La Roche Ag | 3-amino-indazole or 3-amino-4,5,6,7-tetrahydro-indazole derivatives |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3790576A (en) * | 1972-03-20 | 1974-02-05 | Parke Davis & Co | 9 substituted 4,9-dihydro-1,3,4,4-tetraalkyl-1h-pyrazolo(3,4-b)quinolines |
| WO1999064407A1 (en) * | 1997-05-13 | 1999-12-16 | Merck Patent Gmbh | α-(1-PIPERAZINYL)ACETAMIDO ARENECARBOXYLIC ACID DERIVATIVES AS ANTIDIABETIC AGENTS |
-
2003
- 2003-11-25 CN CNB2003801043536A patent/CN100448869C/en not_active Expired - Fee Related
- 2003-11-27 GT GT200300260A patent/GT200300260A/en unknown
-
2005
- 2005-06-22 ZA ZA200505055A patent/ZA200505055B/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3790576A (en) * | 1972-03-20 | 1974-02-05 | Parke Davis & Co | 9 substituted 4,9-dihydro-1,3,4,4-tetraalkyl-1h-pyrazolo(3,4-b)quinolines |
| WO1999064407A1 (en) * | 1997-05-13 | 1999-12-16 | Merck Patent Gmbh | α-(1-PIPERAZINYL)ACETAMIDO ARENECARBOXYLIC ACID DERIVATIVES AS ANTIDIABETIC AGENTS |
Also Published As
| Publication number | Publication date |
|---|---|
| GT200300260A (en) | 2004-06-23 |
| CN1717401A (en) | 2006-01-04 |
| ZA200505055B (en) | 2006-09-27 |
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