CN103906736A

CN103906736A - Substituted pyrazolyl-based carboxamide and urea derivatives bearing a phenyl moiety substituted with an N-containing group as vanilloid receptor ligands

Info

Publication number: CN103906736A
Application number: CN201280055195.9A
Authority: CN
Inventors: R.弗兰克-福尔蒂恩; T.克里斯托弗; N.达曼; B.莱施; G.巴伦贝格; D.J.绍恩德斯; H.施托克豪森; 金勇洙; 金明燮; 李智雨
Original assignee: Gruenenthal GmbH
Current assignee: Gruenenthal GmbH
Priority date: 2011-11-09
Filing date: 2012-11-08
Publication date: 2014-07-02
Also published as: AU2012334066A1; TW201326134A; AR088701A1; KR20140096351A; IN2014KN00847A; WO2013068462A1; HK1202116A1; JP2014532742A; EP2776399A1; MX2014005611A; BR112014010957A2; CA2854935A1

Abstract

The invention relates to substituted pyrazolyl-based carboxamide and urea derivatives of formula (R) bearing a phenyl moiety substituted with an N-containing group as vanilloid receptor ligands, to pharmaceutical compositions containing these compounds and also to these compounds for use in the treatment and/or prophylaxis of pain and further diseases and/or disorders.

Description

As having by substituted carboxylic acid amides and the urea derivatives based on pyrazolyl of the phenyl group replacing containing N-group of vanilloid receptor part

Invention field

The present invention relates to thering is carboxylic acid amides and urea derivatives, the pharmaceutical composition that contain these compounds of phenyl group substituted being replaced containing N-group based on pyrazolyl and being used for the treatment of and/or these compounds of prevent irritation and Other diseases and/or illness as vanilloid receptor part.

Background of invention

Pain therapy, especially neuropathic pain, very important in medical circle.All need effectively to treat the method for pain all over the world.To chronic and non-chronic pain state give patient pay close attention to and goal-oriented treatment have active demand, this is considered to successfully and effectively treat the mode of patient's pain, it is also documented in many scientific researches, and these Recent Researchs appear at application anodyne field or in the fundamental research of nociception.

Vanilloid receptor hypotype 1 (VR1/TRPV1), conventionally also referred to as capsaicin receptor, is a suitable starting point for the treatment of pain, is especially selected from the pain of acute pain, chronic pain, neuropathic pain and visceral pain.Especially, this receptor can for example, by class Vanillin (capsaicine), heat and proton excitation, and is playing the part of core roles forming in pain.In addition, this receptor is also very important to much other physiology and pathophysiological process, and be for example, in many other illnesss for the treatment of, suitable targets when migraine, dysthymia disorders, neurodegenerative disorders, cognitive illness, anxiety state, epilepsy, cough, diarrhoea, pruritus, inflammation, disorder of circulatory system, diet illness, pharmacological dependence, drug abuse and the urinary incontinence.

Compound vanilloid receptor hypotype 1 (VR1/TRPV1) to affinity can be learnt from for example WO 2010/127855-A2 and WO 2010/127856-A2.

Also need other compound, need to this other compound not only to the tool affinity of vanilloid receptor 1 (VR1/TRPV1 acceptor) own ( effect, curative effect), also to have similarly or better properties.

Therefore, improve the metabolic stability of this compound, solubleness or transmissibility in aqueous medium is favourable.These factors are of value to oral administration biaavailability, maybe can change the character of PK/PD (pharmacokinetics/pharmacodynamics); For example, it can cause the more favourable effect time limit.

With participate in the absorption of pharmaceutical composition and the transport molecule of excretion and there is the faint or non-existent interaction minimum evidence that also can be regarded as that bioavailability improves and pharmaceutical composition interacts.In addition, also should be low as far as possible with the interaction that participates in the decomposition of pharmaceutical composition and the enzyme of excretion, therefore this type of test result is also advised the minimum interaction of pharmaceutical composition or is supposed to without interacting completely.

Therefore, the object of this invention is to provide compounds, be preferably better than the compound of prior art.This compound should be particularly suitable as the pharmacological component in pharmaceutical composition, is preferably used in and is used for the treatment of and/or prevents at least partly by the illness of vanilloid receptor 1 (VR1/TRPV1 acceptor) mediation or the pharmaceutical composition of disease.

This object is reached by theme as herein described.

Be surprised to find that, the substitution compound of general formula (R) as follows presents the extremely strong affinity of vanilloid receptor hypotype 1 (VR1/TRPV1), is therefore particularly suitable for preventing and/or treating the illness or the disease that are mediated by vanilloid receptor 1 (VR1/TRPV1) at least partly.

Specially suitable is the substitution compound of general formula (R) as follows, and except to the activity of VR1-acceptor, it shows one or more other favourable character, and for example, suitable effect, suitable curative effect, body temperature and/or hot threshold of pain do not raise; Suitable solubleness in biology associated media, for example aqueous medium, particularly on physiology for example, for example, in the aqueous medium of acceptable pH value, in buffering system, in phosphatebuffer buffer system; Suitable metabolic stability and diversity (for example, the enough stability of for example, oxidation capacity to liver enzyme (Cytochrome P450 (CYP) enzyme) and about by enough diversity of these enzymes metabolism elimination aspects); Etc..

Therefore the present invention relates to the substitution compound of general formula (R),

Figure 2012800551959100002DEST_PATH_IMAGE001

Wherein

R ¹⁰¹, R ¹⁰²and R ¹⁰³be independently from each other H, F, Cl, Br, CFH ₂, CF ₂h, CF ₃, CN, CH ₂-OH, CH ₂cH ₂-OH, CH ₂-OCH ₃, CH ₂cH ₂-OCH ₃, OCFH ₂, OCF ₂h, OCF ₃, OH, NH ₂, C _1-4alkyl, O-C _1-4alkyl, NH-C _1-4alkyl and N (C _1-4alkyl) ₂, wherein C _1-4alkyl is unsubstituted in each case,

R ²represent CF ₃, unsubstituted C _1-4alkyl or unsubstituted C _3-6cycloalkyl,

R ⁷and R ⁹be independently from each other H, F, Cl, Br, CFH ₂, CF ₂h, CF ₃, CN, OH, OCF ₃, C _1-4alkyl and O-C _1-4alkyl, wherein C _1-4alkyl is unsubstituted in each case,

A represents N, CH or C (CH ₃),

Q represents 0,1 or 2,

R ¹¹²represent H or C _1-4alkyl, it is unsubstituted or is selected from F, Cl, Br, OH ,=O and OCH by 1,2 or 3 ₃substituting group monosubstituted, two replace or three replace,

R ¹¹³represent H, S (=O) ₂-NH ₂, C _1-4alkyl or S (=O) ₂-C _1-4alkyl, wherein C _1-4alkyl is unsubstituted in each case or is selected from F, Cl, Br, OH ,=O and OCH by 1,2 or 3 ₃substituting group monosubstituted, two replace or three replace,

Or-condition be q ≠ 0-

R ¹¹²and R ¹¹³form 3 to 6 yuan of heterocyclic radicals together with the nitrogen-atoms connecting, it is unsubstituted or is independently from each other F, Cl, Br, CN, CF by 1,2 or 3 ₃, CH ₃, CH ₂cH ₃, CH (CH ₃) ₂, the tertiary butyl, cyclopropyl, OH ,=O, OCH ₃, OCF ₃, NH ₂, NH (CH ₃) and N (CH ₃) ₂substituting group monosubstituted, two replace or three replace,

The form of the optional mixture with single stereoisomers or steric isomer, with the form of acceptable solvate on acceptable salt and/or physiology on free cpds and/or its physiology.

Describe in detail

In the sense of the present invention, term " single stereoisomers " preferably represents indivedual enantiomers or diastereomer.In the sense of the present invention, term " mixture of steric isomer " refers to the enantiomer of racemic modification and any blending ratio and/or the mixture of diastereomer.

In the sense of the present invention, term " acceptable salt on physiology " preferably comprises the salt of acceptable acid at least one the compounds of this invention and at least one physiology or alkali.

In the sense of the present invention, on at least one the compounds of this invention and at least one physiology, on the physiology of acceptable acid, acceptable salt preferably refers at least one the compounds of this invention and at least one inorganic or organic acid salt, described inorganic or organic acid be acceptable on physiology-during especially for the mankind and/or other Mammals.On physiology, the example of acceptable acid is: hydrochloric acid, Hydrogen bromide, sulfuric acid, methylsulfonic acid, tosic acid, carbonic acid, formic acid, acetic acid, oxalic acid, succsinic acid, tartrate, amygdalic acid, fumaric acid, toxilic acid, lactic acid, citric acid, L-glutamic acid, saccharic acid, monomethyl sebacic acid, 5-oxo proline(Pro), hexane-1-sulfonic acid, nicotinic acid, 2,3 or PABA, 2; 4,6-trimethylbenzoic acid, alpha-lipoic acid, acetyl-glycine, urobenzoic acid, phosphoric acid, Aspartic Acid.Citric acid and hydrochloric acid are particularly preferred.Therefore, hydrochloride and Citrate trianion are particularly preferred salt.

In the sense of the present invention, on at least one the compounds of this invention and at least one physiology, on the physiology of acceptable alkali, acceptable salt preferably refers to the salt of at least one the compounds of this invention as negatively charged ion and at least one preferred inorganic cation, and described inorganic cation is that the – that can accept on physiology is during especially for the mankind and/or other Mammals.Be particularly preferably the salt of alkali and alkaline earth metal ions, but also can be ammonium salt [NH _xr _4-x] ⁺, wherein x=0,1,2,3 or 4 and R represent side chain or non-side chain C _1-4alkyl residue, particularly (single-) or (two) sodium, (single-) or (two) potassium, magnesium or calcium salt.

In the sense of the present invention, term " alkyl " and " C _1-4alkyl " preferably comprise non-annularity representative examples of saturated aliphatic hydrocarbon residue; its can be respectively side chain or non-side chain and can be unsubstituted can be maybe single-or polysubstituted, for example single-, two-or trisubstituted, and it contains 1 to 4; i.e. 1,2,3 or 4 carbon atom, i.e. C _1-4aliphatic residue, i.e. C _1-4alkyl.Preferred C _1-4alkyl residue is selected from methyl, ethyl, n-propyl, 2-propyl group, normal-butyl, isobutyl-, sec-butyl and the tertiary butyl.

In the sense of the present invention, with term " alkyl " and " C _1-4alkyl " relevant term " mono-substituted " or " polysubstituted " for example two-or three-replace; with regard to corresponding residue or group; refer to that one or more hydrogen atoms are replaced or replace more by least one substituting group list independently of one another separately, for example, two replace or three replace.Term " polysubstituted " for example two-or three-replace, with regard to polysubstituted residue and group for example two-or three-residue and group that replace with regard to, comprise that these residues and group are polysubstituted on similar and different atom, for example three replacements in identical carbon atoms, as CF ₃or CH ₂cF ₃situation or polysubstituted at difference, as CH (OH)-CH ₂cH ₂-CHCl ₂situation.Polysubstitutedly use identical or different substituting group to carry out.

For object of the present invention, term " cycloalkyl " and " C _3-6cycloalkyl " preferably represent cycloaliphatic (alicyclic) hydrocarbon that contains 3,4,5 or 6 carbon atoms, i.e. C _3-6-cycloaliphatic residue, wherein said hydrocarbon is saturated, and its can be unsubstituted can be maybe single-or polysubstituted, for example single-, two-or trisubstituted.Described cycloalkyl can be bonded to higher level's universal architecture separately via any required and possible ring members of cycloalkyl residues.Preferably, cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, is more preferably selected from cyclopropyl and cyclobutyl.Particularly preferred cycloalkyl is cyclopropyl.

In the sense of the present invention, term " heterocyclic radical " and " 3 to 6 yuan of heterocyclic radicals " preferably comprise and have 3 to 6, the i.e. aliphatics saturated heterocyclic alkyl of 3,4,5 or 6 ring memberses, i.e. 3 to 6 yuan of heterocyclic radicals, wherein at least one, also can be independently from each other O, S, S (=O), S (=O) for two or three carbon atoms suitably time separately ₂, N, NH and N (C _1-8alkyl) heteroatoms or heteroatom group replace, wherein ring members can be unsubstituted can be maybe single-or polysubstituted, for example single-, two-or trisubstituted.Therefore, heterocyclic radical is heterocycle aliphatic residue.Heterocyclic radical of the present invention is by radicals R ¹¹²and R ¹¹³form together with the nitrogen-atoms connecting, contain at least one N as ring members.The heterocyclic residues of the group that comprises azelidinyl, nitrogen heterocyclic propyl group, dithiolane base, pyrrolin base, dihydropyridine base, imidazolidyl, isoxazole alkyl, morpholinyl, pyrrolidyl, piperazinyl, 4-methylpiperazine base, piperidyl, pyrazolidyl, Pyrrolidine base, tetrahydro pyridyl, thiazolidyl and thio-morpholinyl is preferred.

In the sense of the present invention, with term " cycloalkyl ", " C _3-6cycloalkyl ", " heterocyclic radical " term " mono-substituted " relevant with " 3 to 6 yuan of heterocyclic radicals " or " polysubstituted " for example two-or three-replace; with regard to corresponding residue or group; refer to that one or more hydrogen atoms are replaced or replace more by least one substituting group list independently of one another separately, for example, two replace or three replace.Term " polysubstituted " for example two-or three-replace, with regard to polysubstituted residue and group for example two-or three-residue and group that replace with regard to, comprise that these residues and group are polysubstituted on similar and different atom, for example two replacements in identical carbon atoms, as 1, the situation of 1-difluoro cyclohexyl or replace the situation of 3-fluorine cyclohexyl as chloro-in 1-at difference two.Polysubstitutedly use identical or different substituting group to carry out.

Within the scope of the invention, the symbol using in formula

Represent being connected of corresponding residue and higher level's universal architecture separately.

In the preferred embodiment of the compounds of this invention

R ¹⁰¹, R ¹⁰²and R ¹⁰³be independently from each other H, F, Cl, Br, CFH ₂, CF ₂h, CF ₃, CN, CH ₂-OH, CH ₂-OCH ₃, OCF ₃, OH, CH ₃, CH ₂cH ₃, CH (CH ₃) ₂, O-CH ₃, O-CH ₂cH ₃, NH ₂, NH (CH ₃) and N (CH ₃) ₂.

Preferably,

R ¹⁰¹, R ¹⁰²and R ¹⁰³be independently from each other H, F, Cl, Br, CFH ₂, CF ₂h, CF ₃, CN, CH ₂-OH, CH ₂-OCH ₃, OCF ₃, OH, CH ₃, O-CH ₃, O-CH ₂cH ₃, NH ₂, NH (CH ₃) and N (CH ₃) ₂.

More preferably,

R ¹⁰¹, R ¹⁰²and R ¹⁰³be independently from each other H, F, Cl, CFH ₂, CF ₂h, CF ₃, CN, CH ₂-OCH ₃, OCF ₃, CH ₃, O-CH ₃, O-CH ₂cH ₃and N (CH ₃) ₂.

Again more preferably,

R ¹⁰¹, R ¹⁰²and R ¹⁰³be independently from each other H, F, Cl, CFH ₂, CF ₂h, CF ₃, OCF ₃, CH ₃, O-CH ₃and O-CH ₂cH ₃.

Still more preferably,

R ¹⁰¹, R ¹⁰²and R ¹⁰³be independently from each other H, F, Cl, CF ₃, OCF ₃, CH ₃and O-CH ₃.

Especially,

R ¹⁰¹, R ¹⁰²and R ¹⁰³be independently from each other H, F, Cl, CF ₃and O-CH ₃.

More particularly preferred again

R ¹⁰¹, R ¹⁰²and R ¹⁰³be independently from each other H, F, Cl and O-CH ₃.

In the preferred embodiment of the compounds of this invention, R ¹⁰¹, R ¹⁰²and R ¹⁰³in at least one ≠ H.

In another preferred embodiment of the compounds of this invention, R ¹⁰¹, R ¹⁰²and R ¹⁰³in one or two, preferably R ¹⁰²and/or R ¹⁰³, represent H.

In another preferred embodiment of the compounds of this invention, R ¹⁰¹, R ¹⁰²and R ¹⁰³in one represent H, preferably R ¹⁰³represent H.

In another preferred embodiment of the compounds of this invention

R ¹⁰¹and R ¹⁰²be independently from each other H, F, Cl, Br, CFH ₂, CF ₂h, CF ₃, CN, CH ₂-OH, CH ₂-OCH ₃, OCF ₃, OH, CH ₃, CH ₂cH ₃, CH (CH ₃) ₂, O-CH ₃, O-CH ₂cH ₃, NH ₂, NH (CH ₃) and N (CH ₃) ₂,

And R ¹⁰³represent H.

Preferably,

R ¹⁰¹and R ¹⁰²be independently from each other H, F, Cl, Br, CFH ₂, CF ₂h, CF ₃, CN, CH ₂-OH, CH ₂-OCH ₃, OCF ₃, OH, CH ₃, O-CH ₃, O-CH ₂cH ₃, NH ₂, NH (CH ₃) and N (CH ₃) ₂, be more preferably independently from each other H, F, Cl, CFH ₂, CF ₂h, CF ₃, CN, CH ₂-OCH ₃, OCF ₃, CH ₃, O-CH ₃, O-CH ₂cH ₃and N (CH ₃) ₂, be more preferably independently from each other again H, F, Cl, CFH ₂, CF ₂h, CF ₃, OCF ₃, CH ₃, O-CH ₃and O-CH ₂cH ₃, be still more preferably independently from each other H, F, Cl, CF ₃, OCF ₃, CH ₃and O-CH ₃, be independently from each other especially H, F, Cl, CF ₃and O-CH ₃, be more particularly preferably independently from each other again H, F, Cl and O-CH ₃,

And R ¹⁰³represent H.

In another preferred embodiment of the compounds of this invention

R ¹⁰¹be selected from F, Cl, Br, CFH ₂, CF ₂h, CF ₃, CN, CH ₂-OH, CH ₂-OCH ₃, OCF ₃, OH, CH ₃, CH ₂cH ₃, CH (CH ₃) ₂, O-CH ₃, O-CH ₂cH ₃, NH ₂, NH (CH ₃) and N (CH ₃) ₂,

And R ¹⁰²and R ¹⁰³all represent H.

Preferably,

R ¹⁰¹be selected from F, Cl, Br, CFH ₂, CF ₂h, CF ₃, CN, CH ₂-OH, CH ₂-OCH ₃, OCF ₃, OH, CH ₃, O-CH ₃, O-CH ₂cH ₃, NH ₂, NH (CH ₃) and N (CH ₃) ₂, be more preferably selected from F, Cl, CFH ₂, CF ₂h, CF ₃, CN, CH ₂-OCH ₃, OCF ₃, CH ₃, O-CH ₃, O-CH ₂cH ₃and N (CH ₃) ₂, be more preferably selected from again F, Cl, CFH ₂, CF ₂h, CF ₃, OCF ₃, CH ₃, O-CH ₃and O-CH ₂cH ₃, be still more preferably selected from F, Cl, CF ₃, OCF ₃, CH ₃and O-CH ₃, be selected from especially F, Cl, CF ₃and O-CH ₃, be more particularly preferably selected from again F, Cl and O-CH ₃,

And R ¹⁰²and R ¹⁰³all represent H.

In another preferred embodiment of the compounds of this invention

R ¹⁰²be selected from F, Cl, Br, CFH ₂, CF ₂h, CF ₃, CN, CH ₂-OH, CH ₂-OCH ₃, OCF ₃, OH, CH ₃, CH ₂cH ₃, CH (CH ₃) ₂, O-CH ₃, O-CH ₂cH ₃, NH ₂, NH (CH ₃) and N (CH ₃) ₂,

And R ¹⁰¹and R ¹⁰³all represent H.

Preferably,

R ¹⁰²be selected from F, Cl, Br, CFH ₂, CF ₂h, CF ₃, CN, CH ₂-OH, CH ₂-OCH ₃, OCF ₃, OH, CH ₃, O-CH ₃, O-CH ₂cH ₃, NH ₂, NH (CH ₃) and N (CH ₃) ₂, be more preferably selected from F, Cl, CFH ₂, CF ₂h, CF ₃, CN, CH ₂-OCH ₃, OCF ₃, CH ₃, O-CH ₃, O-CH ₂cH ₃and N (CH ₃) ₂, be more preferably selected from again F, Cl, CFH ₂, CF ₂h, CF ₃, OCF ₃, CH ₃, O-CH ₃and O-CH ₂cH ₃, be still more preferably selected from F, Cl, CF ₃, OCF ₃, CH ₃and O-CH ₃, be selected from especially F, Cl, CF ₃and O-CH ₃, be more particularly preferably selected from again F, Cl and O-CH ₃,

And R ¹⁰¹and R ¹⁰³all represent H.

In the further preferred embodiment again of the compounds of this invention

R ¹⁰²be selected from H, F, Cl, Br, CFH ₂, CF ₂h, CF ₃, CN, CH ₂-OH, CH ₂-OCH ₃, OCF ₃, OH, CH ₃, CH ₂cH ₃, CH (CH ₃) ₂, O-CH ₃, O-CH ₂cH ₃, NH ₂, NH (CH ₃) and N (CH ₃) ₂,

And R ¹⁰³represent H.

Preferably,

R ¹⁰²be selected from H, F, Cl, Br, CFH ₂, CF ₂h, CF ₃, CN, CH ₂-OH, CH ₂-OCH ₃, OCF ₃, OH, CH ₃, O-CH ₃, O-CH ₂cH ₃, NH ₂, NH (CH ₃) and N (CH ₃) ₂, be more preferably selected from H, F, Cl, CFH ₂, CF ₂h, CF ₃, CN, CH ₂-OCH ₃, OCF ₃, CH ₃, O-CH ₃, O-CH ₂cH ₃and N (CH ₃) ₂, be more preferably selected from again H, F, Cl, CFH ₂, CF ₂h, CF ₃, OCF ₃, CH ₃, O-CH ₃and O-CH ₂cH ₃, be still more preferably selected from H, F, Cl, CF ₃, OCF ₃, CH ₃and O-CH ₃, be selected from especially H, F, Cl, CF ₃and O-CH ₃, be more particularly preferably selected from again H, F, Cl and O-CH ₃,

And R ¹⁰³represent H.

In the further preferred embodiment again of the compounds of this invention

R ¹⁰¹be selected from F, Br, CFH ₂, CF ₂h, CF ₃, CN, CH ₂-OH, CH ₂-OCH ₃, OCF ₃, OH, CH ₃, O-CH ₃, O-CH ₂cH ₃, NH ₂, NH (CH ₃) and N (CH ₃) ₂, be more preferably selected from F, CFH ₂, CF ₂h, CF ₃, CN, CH ₂-OCH ₃, OCF ₃, CH ₃, O-CH ₃, O-CH ₂cH ₃and N (CH ₃) ₂, be more preferably selected from again F, CFH ₂, CF ₂h, CF ₃, OCF ₃, CH ₃, O-CH ₃and O-CH ₂cH ₃, be still more preferably selected from F, CF ₃, OCF ₃, CH ₃and O-CH ₃, be selected from especially F, CF ₃and O-CH ₃, be more particularly preferably selected from again F and O-CH ₃,

And R ¹⁰²and R ¹⁰³all represent H.

In the still further preferred embodiment of the compounds of this invention

R ¹⁰¹be selected from F, Br, CFH ₂, CF ₂h, CF ₃, CN, CH ₂-OH, CH ₂-OCH ₃, OCF ₃, OH, CH ₃, CH ₂cH ₃, CH (CH ₃) ₂, O-CH ₃, O-CH ₂cH ₃, NH ₂, NH (CH ₃) and N (CH ₃) ₂,

And R ¹⁰³represent H.

Preferably,

In another particularly preferred embodiment of the present invention, part-structure (RS2)

Figure 2012800551959100002DEST_PATH_IMAGE003

Be selected from

Particularly represent 0,1 or 2 as q, and A is while representing N.

More particularly preferred again, part-structure (RS2)

Figure 2012800551959100002DEST_PATH_IMAGE005

Be selected from

Particularly represent 0,1 or 2 as q, and A is while representing N.

Most preferred, part-structure (RS2)

Be selected from

Particularly represent 0,1 or 2 as q, and A is while representing N,

Be preferably selected from

Particularly represent 0,1 or 2 as q, and A is while representing N.

Be selected from

Particularly work as q and represent 1 or 2, and A represents CH or C (CH ₃) time.

More particularly preferred again, part-structure (RS2)

Be selected from

Most preferred, part-structure (RS2)

Be selected from

Particularly work as q and represent 1 or 2, and A represents CH or C (CH ₃) time,

Be preferably selected from

In another preferred embodiment of the compounds of this invention

R ²represent CF ₃, methyl, ethyl, n-propyl, 2-propyl group, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

Preferably,

R ²represent CF ₃, 2-propyl group, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, cyclopropyl or cyclobutyl.

More preferably,

R ²represent CF ₃, the tertiary butyl or cyclopropyl.

In the particularly preferred embodiment of the compounds of this invention, R ²represent CF ₃.

In another particularly preferred embodiment of the compounds of this invention, R ²represent the tertiary butyl.

In another particularly preferred embodiment of the compounds of this invention, R ²represent cyclopropyl.

In the further preferred embodiment of the compounds of this invention

R ⁷and R ⁹be independently from each other H, F, Cl, Br, CF ₃, CN, OH, OCF ₃, CH ₃, CH ₂cH ₃, CH (CH ₃) ₂, O-CH ₃and O-CH ₂cH ₃.

Preferably,

R ⁷and R ⁹be independently from each other H, F, Cl, CF ₃, CN, OH, OCF ₃, CH ₃, O-CH ₃and O-CH ₂cH ₃.

More preferably,

R ⁷and R ⁹be independently from each other H, F, Cl, CF ₃, O-CH ₃and O-CH ₂cH ₃.

Again more preferably,

R ⁷and R ⁹be independently from each other H, F, Cl and O-CH ₃, be still more preferably independently from each other H, F and Cl.

In the further preferred embodiment again of the compounds of this invention, R ⁷and R ⁹in at least one ≠ H.

In the further preferred embodiment of the compounds of this invention, R ⁹represent H.

In another preferred embodiment of the compounds of this invention

R ⁷be selected from F, Cl, Br, CF ₃, CN, OH, OCF ₃, CH ₃, CH ₂cH ₃, CH (CH ₃) ₂, O-CH ₃and O-CH ₂cH ₃, be preferably selected from F, Cl, CF ₃, CN, OH, OCF ₃, CH ₃, O-CH ₃and O-CH ₂cH ₃, be more preferably selected from F, Cl, CF ₃, O-CH ₃and O-CH ₂cH ₃, be more preferably selected from again F, Cl and O-CH ₃, be still more preferably selected from F and Cl,

And R ⁹represent H.

In another preferred embodiment of the compounds of this invention

A represents N or C (CH ₃).

In the particularly preferred embodiment of the compounds of this invention, A represents N.

In another particularly preferred embodiment of the compounds of this invention, A represents C (CH ₃).

In another preferred embodiment of the compounds of this invention

Q represents 1 or 2, preferably 1.

In the further preferred embodiment of the compounds of this invention,

A represents N, and

R ¹¹²represent H or C _1-4alkyl, it is unsubstituted or is selected from F, Cl, Br, OH ,=O and OCH by 1,2 or 3 ₃substituting group monosubstituted, two replace or three replace;

Preferably represent H or C _1-4alkyl, it is unsubstituted; And

R ¹¹³represent H, S (=O) ₂-NH ₂, C _1-4alkyl or S (=O) ₂-C _1-4alkyl, wherein C _1-4alkyl is unsubstituted in each case or is selected from F, Cl, Br, OH ,=O and OCH by 1,2 or 3 ₃substituting group monosubstituted, two replace or three replace;

Preferably represent H, S (=O) ₂-NH ₂, C _1-4alkyl or S (=O) ₂-C _1-4alkyl, wherein C _1-4alkyl is unsubstituted in each case;

Or-condition is q ≠ 0 –

R ¹¹²and R ¹¹³form 3 to 6 yuan of heterocyclic radicals together with the nitrogen-atoms connecting, it is unsubstituted or is independently from each other F, Cl, Br, CN, CF by 1,2 or 3 ₃, CH ₃, CH ₂cH ₃, CH (CH ₃) ₂, the tertiary butyl, cyclopropyl, OH ,=O, OCH ₃, OCF ₃, NH ₂, NH (CH ₃) and N (CH ₃) ₂substituting group monosubstituted, two replace or three replace;

Preferably form 3 to 6 yuan of heterocyclic radicals together with the nitrogen-atoms connecting, it is unsubstituted;

Or

A represents CH or C (CH ₃), and

Preferably represent H or C _1-4alkyl, it is unsubstituted; And

R ¹¹³represent H, S (=O) ₂-NH ₂, C _1-4alkyl, it is unsubstituted or is selected from F, Cl, Br, OH ,=O and OCH by 1,2 or 3 ₃substituting group monosubstituted, two replace or three replace;

Preferably H, S (=O) ₂-NH ₂or C _1-4alkyl, it is unsubstituted;

Or-condition is q ≠ 0 –

Preferably form 3 to 6 yuan of heterocyclic radicals together with the nitrogen-atoms connecting, it is unsubstituted.

In another preferred embodiment of the compounds of this invention

Q represents 0,1 or 2, preferably 1 or 2, more preferably 1,

A represents N,

R ¹⁰¹be selected from H, F, Cl, Br, CFH ₂, CF ₂h, CF ₃, CN, CH ₂-OH, CH ₂-OCH ₃, OCF ₃, OH, CH ₃, CH ₂cH ₃, CH (CH ₃) ₂, O-CH ₃, O-CH ₂cH ₃, NH ₂, NH (CH ₃) and N (CH ₃) ₂; Be preferably selected from H, F, Cl, CFH ₂, CF ₂h, CF ₃, CN, CH ₂-OCH ₃, OCF ₃, CH ₃, O-CH ₃, O-CH ₂cH ₃and N (CH ₃) ₂; More preferably be selected from H, F, Cl, CFH ₂, CF ₂h, CF ₃, OCF ₃, CH ₃, O-CH ₃and O-CH ₂cH ₃; More preferably be selected from again H, F, Cl, CF ₃, OCF ₃, CH ₃and O-CH ₃; Still more preferably be selected from H, F, Cl, CF ₃and O-CH ₃; Be selected from especially H, F, Cl and O-CH ₃; Most preferably represent F or Cl;

With

R ¹⁰²and R ¹⁰³be independently from each other H, F, Cl, Br, CFH ₂, CF ₂h, CF ₃, CN, CH ₂-OH, CH ₂-OCH ₃, OCF ₃, OH, CH ₃, CH ₂cH ₃, CH (CH ₃) ₂, O-CH ₃, O-CH ₂cH ₃, NH ₂, NH (CH ₃) and N (CH ₃) ₂; Preferably be independently from each other H, F, Cl, CFH ₂, CF ₂h, CF ₃, CN, CH ₂-OCH ₃, OCF ₃, CH ₃, O-CH ₃, O-CH ₂cH ₃and N (CH ₃) ₂; More preferably be independently from each other H, F, Cl, CFH ₂, CF ₂h, CF ₃, OCF ₃, CH ₃, O-CH ₃and O-CH ₂cH ₃; More preferably be independently from each other again H, F, Cl, CF ₃, OCF ₃, CH ₃and O-CH ₃; Still more preferably be independently from each other H, F, Cl, CF ₃and O-CH ₃; Be independently from each other especially H, F, Cl and O-CH ₃; Most preferably represent independently of one another F or Cl;

Or

Q represents 1 or 2, preferably 1,

A represents CH or C (CH ₃), preferably C (CH ₃),

R ¹⁰¹be selected from H, F, Br, CFH ₂, CF ₂h, CF ₃, CN, CH ₂-OH, CH ₂-OCH ₃, OCF ₃, OH, CH ₃, CH ₂cH ₃, CH (CH ₃) ₂, O-CH ₃, O-CH ₂cH ₃, NH ₂, NH (CH ₃) and N (CH ₃) ₂; Be preferably selected from H, F, CFH ₂, CF ₂h, CF ₃, CN, CH ₂-OCH ₃, OCF ₃, CH ₃, O-CH ₃, O-CH ₂cH ₃and N (CH ₃) ₂; More preferably be selected from H, F, CFH ₂, CF ₂h, CF ₃, OCF ₃, CH ₃, O-CH ₃and O-CH ₂cH ₃; More preferably be selected from again H, F, CF ₃, OCF ₃, CH ₃and O-CH ₃; Still more preferably be selected from H, F, CF ₃and O-CH ₃; Be selected from especially H, F and O-CH ₃; Most preferably represent F;

And

R ¹⁰²and R ¹⁰³be independently from each other H, F, Cl, Br, CFH ₂, CF ₂h, CF ₃, CN, CH ₂-OH, CH ₂-OCH ₃, OCF ₃, OH, CH ₃, CH ₂cH ₃, CH (CH ₃) ₂, O-CH ₃, O-CH ₂cH ₃, NH ₂, NH (CH ₃) and N (CH ₃) ₂; Preferably be independently from each other H, F, Cl, CFH ₂, CF ₂h, CF ₃, CN, CH ₂-OCH ₃, OCF ₃, CH ₃, O-CH ₃, O-CH ₂cH ₃and N (CH ₃) ₂; More preferably be independently from each other H, F, Cl, CFH ₂, CF ₂h, CF ₃, OCF ₃, CH ₃, O-CH ₃and O-CH ₂cH ₃; More preferably be independently from each other again H, F, Cl, CF ₃, OCF ₃, CH ₃and O-CH ₃; Still more preferably be independently from each other H, F, Cl, CF ₃and O-CH ₃; Be independently from each other especially H, F, Cl and O-CH ₃; Most preferably represent independently of one another F or Cl.

In the further preferred embodiment of the compounds of this invention, part-structure (RS1)

Represent part-structure (PR1)

Wherein

R ¹¹⁴represent NH ₂or unsubstituted C _1-4alkyl; Preferably represent NH ₂, CH ₃or CH ₂cH ₃, more preferably represent NH ₂or CH ₃, special representative CH ₃,

Or

Represent part-structure (PR2-a) or (PR2-b)

The wherein C in part-structure (PR2-b) _1-4alkyl be unsubstituted quilt=O or OH monosubstituted, preferably unsubstituted, and the C in part-structure (PR2-b) wherein _1-4alkyl is preferably selected from methyl and ethyl,

Or

Represent one of following part-structure

Preferably, part-structure (RS1)

Represent part-structure (PR1)

Wherein

R ¹¹⁴represent NH ₂or unsubstituted C _1-4alkyl; Preferably represent NH ₂, CH ₃or CH ₂cH ₃, more preferably represent NH ₂or CH ₃, special representative CH ₃.

In particularly preferred embodiment of the present invention,

A represent N and

R ¹⁰¹be selected from H, F, Cl, Br, CFH ₂, CF ₂h, CF ₃, CN, CH ₂-OH, CH ₂-OCH ₃, OCF ₃, OH, CH ₃, CH ₂cH ₃, CH (CH ₃) ₂, O-CH ₃, O-CH ₂cH ₃, NH ₂, NH (CH ₃) and N (CH ₃) ₂, and

R ¹⁰²and R ¹⁰³be independently from each other H, F, Cl, Br, CFH ₂, CF ₂h, CF ₃, CN, CH ₂-OH, CH ₂-OCH ₃, OCF ₃, OH, CH ₃, CH ₂cH ₃, CH (CH ₃) ₂, O-CH ₃, O-CH ₂cH ₃, NH ₂, NH (CH ₃) and N (CH ₃) ₂,

Preferably, R wherein ¹⁰¹, R ¹⁰²and R ¹⁰³in at least one ≠ H,

Or

A represents CH or C (CH ₃), preferably C (CH ₃), and

R ¹⁰¹be selected from H, F, Br, CFH ₂, CF ₂h, CF ₃, CN, CH ₂-OH, CH ₂-OCH ₃, OCF ₃, OH, CH ₃, CH ₂cH ₃, CH (CH ₃) ₂, O-CH ₃, O-CH ₂cH ₃, NH ₂, NH (CH ₃) and N (CH ₃) ₂, and

R ¹⁰²and R ¹⁰³be independently from each other H, F, Cl, Br, CFH ₂, CF ₂h, CF ₃, CN, CH ₂-OH, CH ₂-OCH ₃, OCF ₃, OH, CH ₃, CH ₂cH ₃, CH (CH ₃) ₂, O-CH ₃, O-CH ₂cH ₃, NH ₂, NH (CH ₃) and N (CH ₃) ₂;

Preferably, R wherein ¹⁰¹, R ¹⁰²and R ¹⁰³in at least one ≠ H,

R ²represent CF ₃, the tertiary butyl or cyclopropyl,

R ⁷and R ⁹be independently from each other H, F, Cl, Br, CF ₃, CN, OH, OCF ₃, CH ₃, CH ₂cH ₃, CH (CH ₃) ₂, O-CH ₃and O-CH ₂cH ₃,

Preferably, R wherein ⁷and R ⁹in at least one ≠ H,

Part-structure (RS1)

Represent part-structure (PR1)

Wherein

R ¹¹⁴represent NH ₂, CH ₃or CH ₂cH ₃.

In another particularly preferred embodiment of the present invention,

Preferably, R wherein ¹⁰¹, R ¹⁰²and R ¹⁰³in at least one ≠ H,

R ²represent CF ₃, the tertiary butyl or cyclopropyl,

Preferably, R wherein ⁷and R ⁹in at least one ≠ H,

A represents N, and

R ¹¹²represent H or C _1-4alkyl, it is unsubstituted, preferably represents H, CH ₃or CH ₂cH ₃, more preferably represent H or CH ₃, represent especially H,

R ¹¹³represent H, S (=O) ₂-NH ₂, C _1-4alkyl or S (=O) ₂-C _1-4alkyl, wherein C _1-4alkyl is unsubstituted in each case, preferably represents S (=O) ₂-NH ₂or unsubstituted S (=O) ₂-C _1-4alkyl, more preferably represents S (=O) ₂-NH ₂, S (=O) ₂-CH ₃or S (=O) ₂-CH ₂cH ₃, more preferably represent again S (=O) ₂-NH ₂or S (=O) ₂-CH ₃, special representative S (=O) ₂-CH ₃,

Or

A represents CH or C (CH ₃), preferably C (CH ₃),

R ¹¹³represent H, S (=O) ₂-NH ₂or C _1-4alkyl, it is unsubstituted, preferably represents S (=O) ₂-NH ₂.

The preferred embodiment of the compounds of this invention of general formula (R) has general formula (R0-a) and/or (R0-b):

Wherein specific group, variable have the described herein implication relevant to the compounds of this invention and preferred embodiment thereof with indicator (indices).

The further preferred embodiment of the compounds of this invention of general formula (R) has general formula (R1-a), (R1-a-1) and/or (R1-a-2):

Wherein specific group, variable have the described herein implication relevant to the compounds of this invention and preferred embodiment thereof with indicator.

In addition, the preferred embodiment of the compounds of this invention of general formula (R) has general formula (R1-b), (R1-b-1) and/or (R1-b-2):

In addition, the preferred embodiment of the compounds of this invention of general formula (R) has general formula (R1-c), (R1-c-1) and/or (R1-c-2):

The compounds of this invention of general formula (R) again further preferred embodiment there is general formula (R1-d), (R1-d-1) and/or (R1-d-2):

The further preferred embodiment of the compounds of this invention of general formula (R) has general formula (R1-e), (R1-e-1) and/or (R1-e-2):

In addition, the preferred embodiment of the compounds of this invention of general formula (R) has general formula (R1-f), (R1-f-1) and/or (R1-f-2):

In particularly preferred embodiment of the present invention, the radicals R in general formula (R), (R1-a), (R1-a-1), (R1-b), (R1-b-1), (R1-c), (R1-c-1), (R1-d) and/or (R1-d-1) compound ¹⁰¹represent F, Cl, CF ₃or O-CH ₃, preferably F or Cl, most preferably Cl – preferably works as R ¹⁰³for H and R ¹⁰²represent H, F, Cl, CF ₃or OCH ₃time, more preferably work as R ¹⁰³for H and R ¹⁰²while representing H, F or Cl, more preferably work as again R ¹⁰²and R ¹⁰³while all representing H, and remaining special groups, variable and indicator have the described herein implication relevant to the compounds of this invention and preferred embodiment thereof.

In particularly preferred embodiment of the present invention, the radicals R in general formula (R), (R1-a), (R1-a-2), (R1-b), (R1-b-2), (R1-c), (R1-c-2), (R1-d) and/or (R1-d-2) compound ¹⁰¹represent F, CF ₃or O-CH ₃, preferably F or OCH ₃, most preferably F – preferably works as R ¹⁰³for H and R ¹⁰²represent H, F, Cl, CF ₃or OCH ₃time, more preferably work as R ¹⁰³for H and R ¹⁰²while representing H, F or Cl, more preferably work as again R ¹⁰²and R ¹⁰³while all representing H, and remaining special groups, variable and indicator have the described herein implication relevant to the compounds of this invention and preferred embodiment thereof.

In further particularly preferred embodiment of the present invention, the radicals R in general formula (R1-e), (R1-e-1), (R1-e-2), (R1-f), (R1-f-1) and/or (R1-f-2) compound ¹⁰¹represent F, Cl, CF ₃or O-CH ₃, preferably F or Cl, most preferably Cl – preferably works as R ¹⁰³for H and R ¹⁰²represent H, F, Cl, CF ₃or OCH ₃time, more preferably work as R ¹⁰³for H and R ¹⁰²while representing H, F or Cl, more preferably work as again R ¹⁰²and R ¹⁰³while all representing H, and remaining special groups, variable and indicator have the described herein implication relevant to the compounds of this invention and preferred embodiment thereof.

Be particularly preferably and be selected from following the compounds of this invention:

B1 N-[[2-(3-chloro-phenyl-)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl] the fluoro-4-of-2-[3-(methanesulfonamido-methyl)-phenyl]-propionic acid amide;

B2 N-[[2-(the fluoro-phenyl of the chloro-4-of 3-)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl] the fluoro-4-of-2-[3-(methanesulfonamido-methyl)-phenyl]-propionic acid amide;

The B3 N-[[5-tertiary butyl-2-(the fluoro-phenyl of the chloro-4-of 3-)-2H-pyrazole-3-yl]-methyl] the fluoro-4-of-2-[3-(methanesulfonamido-methyl)-phenyl]-propionic acid amide;

B4 N-[[2-(3-chloro-phenyl-)-5-cyclopropyl-2H-pyrazole-3-yl]-methyl] the fluoro-4-of-2-[3-(methanesulfonamido-methyl)-phenyl]-propionic acid amide;

B5 N-[[2-(3-chloro-phenyl-)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl]-2-[4-(methanesulfonamido-methyl)-phenyl]-propionic acid amide;

The B6 N-[[5-tertiary butyl-2-(3-chloro-phenyl-)-2H-pyrazole-3-yl]-methyl]-2-[4-(methanesulfonamido-methyl)-phenyl]-propionic acid amide;

The fluoro-4-of B7 2-[3-(methanesulfonamido-methyl)-phenyl]-N-[[2-(3-fluorophenyl)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl]-propionic acid amide;

The fluoro-4-of B8 2-[3-(methanesulfonamido-methyl)-phenyl]-N-[[5-(trifluoromethyl)-2-[3-(trifluoromethyl) phenyl]-2H-pyrazole-3-yl]-methyl]-propionic acid amide;

The B9 N-[[5-tertiary butyl-2-(3-fluorophenyl)-2H-pyrazole-3-yl]-methyl] the fluoro-4-of-2-[3-(methanesulfonamido-methyl)-phenyl]-propionic acid amide;

The B10 N-[[5-tertiary butyl-2-(the fluoro-phenyl of 3,4-bis-)-2H-pyrazole-3-yl]-methyl] the fluoro-4-of-2-[3-(methanesulfonamido-methyl)-phenyl]-propionic acid amide;

The B11 1-[[5-tertiary butyl-2-(3-chloro-phenyl-)-2H-pyrazole-3-yl]-methyl]-3-[4-(methanesulfonamido-methyl)-3-methoxyl group-phenyl]-urea;

B12 1-[[2-(3-chloro-phenyl-)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl]-3-[4-(methanesulfonamido-methyl)-3-methoxyl group-phenyl]-urea;

The B13 N-[[5-tertiary butyl-2-(3-chloro-phenyl-)-2H-pyrazole-3-yl]-methyl] the chloro-4-of-2-[3-(methanesulfonamido-methyl)-phenyl]-propionic acid amide;

B14 1-[[2-(3-chloro-phenyl-)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl]-3-[4-(methylamino-methyl)-phenyl]-urea;

The fluoro-4-of B15 2-[3-(methanesulfonamido-methyl)-phenyl]-N-[[2-(3-p-methoxy-phenyl)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl]-propionic acid amide;

The B16 N-[[5-tertiary butyl-2-(3-chloro-phenyl-)-2H-pyrazole-3-yl]-methyl]-2-[4-[[(ethylsulfonyl) amino]-methyl] the fluoro-phenyl of-3-]-propionic acid amide;

B17 N-[[2-(3-chloro-phenyl-)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl]-2-[4-[[(ethylsulfonyl) amino]-methyl] the fluoro-phenyl of-3-]-propionic acid amide;

B18 N-[[2-(4-chloro-phenyl-)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl] the fluoro-4-of-2-[3-(methanesulfonamido-methyl)-phenyl]-propionic acid amide;

B19 N-[[2-(the fluoro-phenyl of 3,4-bis-)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl] the fluoro-4-of-2-[3-(methanesulfonamido-methyl)-phenyl]-propionic acid amide;

The B20 N-[[5-tertiary butyl-2-(4-chloro-phenyl-)-2H-pyrazole-3-yl]-methyl] the fluoro-4-of-2-[3-(methanesulfonamido-methyl)-phenyl]-propionic acid amide;

The B21 N-[[5-tertiary butyl-2-(4-fluorophenyl)-2H-pyrazole-3-yl]-methyl] the fluoro-4-of-2-[3-(methanesulfonamido-methyl)-phenyl]-propionic acid amide;

The chloro-4-of B22 2-[3-(methanesulfonamido-methyl)-phenyl]-N-[[2-(3-chloro-phenyl-)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl]-propionic acid amide;

B23 N-[[2-(3-chloro-phenyl-)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl] the fluoro-4-of-2-[3-(methanesulfonamido-methyl)-phenyl]-ethanamide;

B24 1-[[2-(3-chloro-phenyl-)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl] the fluoro-phenyl of-3-[4-(ethylamino-methyl)-3-]-urea;

The B25 1-[[5-tertiary butyl-2-(3-chloro-phenyl-)-2H-pyrazole-3-yl]-methyl] the fluoro-phenyl of-3-[4-(ethylamino-methyl)-3-]-urea;

The B26 N-[[5-tertiary butyl-2-(3-chloro-phenyl-)-2H-pyrazole-3-yl]-methyl] the fluoro-4-of-2-[3-(methanesulfonamido-methyl)-phenyl]-ethanamide;

B27 1-[[2-(3-chloro-phenyl-)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl]-3-[3, the fluoro-4-of 5-bis-(methanesulfonamido-methyl)-phenyl]-urea;

The B28 1-[[5-tertiary butyl-2-(3-chloro-phenyl-)-2H-pyrazole-3-yl]-methyl]-3-[4-(methanesulfonamido-methyl)-phenyl]-urea;

B29 N-[[2-(3-chloro-phenyl-)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl] the fluoro-4-[(methyl-methylsulfonyl-amino of-2-[3-)-methyl]-phenyl]-propionic acid amide;

The B30 N-[[5-tertiary butyl-2-(3-chloro-phenyl-)-2H-pyrazole-3-yl]-methyl] the fluoro-4-[(methyl-methylsulfonyl-amino of-2-[3-)-methyl]-phenyl]-propionic acid amide;

The B31 1-[[5-tertiary butyl-2-(3-chloro-phenyl-)-2H-pyrazole-3-yl]-methyl] the fluoro-4-of-3-[3-(methanesulfonamido-methyl)-phenyl]-urea;

The B32 1-[[5-tertiary butyl-2-(3-chloro-phenyl-)-2H-pyrazole-3-yl]-methyl]-3-[3, the fluoro-4-of 5-bis-(methanesulfonamido-methyl)-phenyl]-urea;

B33 N-[[4-[[[2-(3-chloro-phenyl-)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl-formamyl] amino] the fluoro-phenyl of-2-]-methyl]-ethanamide;

The B34 N-[[4-[[[5-tertiary butyl-2-(3-chloro-phenyl-)-2H-pyrazole-3-yl]-methyl-formamyl] amino] the fluoro-phenyl of-2-]-methyl]-ethanamide;

B35 1-[[2-(3-chloro-phenyl-)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl]-3-[4-[(sulfamyl amino)-methyl]-phenyl]-urea;

The B36 1-[[5-tertiary butyl-2-(3-chloro-phenyl-)-2H-pyrazole-3-yl]-methyl]-3-[4-[(sulfamyl amino)-methyl]-phenyl]-urea;

The fluoro-4-of B37 2-[3-(methanesulfonamido-methyl)-phenyl]-N-[[2-(3-fluorophenyl)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl]-ethanamide;

B38 1-[[2-(3-chloro-phenyl-)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl] the fluoro-phenyl of-3-[4-(dimethylaminomethyl)-3-]-urea;

The fluoro-phenyl of B39 1-[4-(amino methyl)-3-]-3-[[2-(3-chloro-phenyl-)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl]-urea;

The fluoro-phenyl of B40 1-[4-(amino methyl)-3-]-3-[[5-the tertiary butyl-2-(3-chloro-phenyl-)-2H-pyrazole-3-yl]-methyl]-urea;

B41 1-[[2-(3-chloro-phenyl-)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl] the fluoro-4-[(sulfamyl of-3-[3-amino)-methyl]-phenyl]-urea;

The fluoro-phenyl of B42 2-[4-(amino methyl)-3-]-N-[[2-(3-chloro-phenyl-)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl]-propionic acid amide;

The B43 N-[[5-tertiary butyl-2-[3-(trifluoromethyl) phenyl]-2H-pyrazole-3-yl]-methyl] the fluoro-4-of-2-[3-(methanesulfonamido-methyl)-phenyl]-propionic acid amide;

B44 1-[[2-(3-fluorophenyl)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl]-3-[4-(methanesulfonamido-methyl)-phenyl]-urea;

The B45 1-[[5-tertiary butyl-2-(3-fluorophenyl)-2H-pyrazole-3-yl]-methyl]-3-[4-(methanesulfonamido-methyl)-phenyl]-urea;

The B46 1-[[5-tertiary butyl-2-(3-chloro-phenyl-)-2H-pyrazole-3-yl]-methyl] the fluoro-4-[(sulfamyl of-3-[3-amino)-methyl]-phenyl]-urea;

The fluoro-phenyl of B47 2-[4-(amino methyl)-3-]-N-[[5-the tertiary butyl-2-(3-chloro-phenyl-)-2H-pyrazole-3-yl]-methyl]-propionic acid amide;

The fluoro-4-of B48 1-[3-(methanesulfonamido-methyl)-phenyl]-3-[[2-(3-fluorophenyl)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl]-urea;

B49 1-[[2-(the fluoro-phenyl of 3,4-bis-)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl] the fluoro-4-of-3-[3-(methanesulfonamido-methyl)-phenyl]-urea;

The B50 1-[[5-tertiary butyl-2-(3-fluorophenyl)-2H-pyrazole-3-yl]-methyl] the fluoro-4-of-3-[3-(methanesulfonamido-methyl)-phenyl]-urea;

The B51 1-[[5-tertiary butyl-2-(the fluoro-phenyl of the chloro-4-of 3-)-2H-pyrazole-3-yl]-methyl] the fluoro-4-of-3-[3-(methanesulfonamido-methyl)-phenyl]-urea;

B52 1-[[2-(3-chloro-phenyl-)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl] the fluoro-4-of-3-[3-(methanesulfonamido-methyl)-phenyl]-urea;

The B53 1-[[5-tertiary butyl-2-(4-fluorophenyl)-2H-pyrazole-3-yl]-methyl] the fluoro-4-of-3-[3-(methanesulfonamido-methyl)-phenyl]-urea;

The B54 1-[[5-tertiary butyl-2-[3-(trifluoromethyl) phenyl]-2H-pyrazole-3-yl]-methyl] the fluoro-4-of-3-[3-(methanesulfonamido-methyl)-phenyl]-urea;

The fluoro-4-of B55 1-[3-(methanesulfonamido-methyl)-phenyl]-3-[[5-(trifluoromethyl)-2-[3-(trifluoromethyl) phenyl]-2H-pyrazole-3-yl]-methyl]-urea;

The B56 1-[[5-tertiary butyl-2-(3-fluorophenyl)-2H-pyrazole-3-yl]-methyl]-3-[4-[(sulfamyl amino)-methyl]-phenyl]-urea;

B57 1-[[2-(the fluoro-phenyl of 3,4-bis-)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl]-3-[4-[(sulfamyl amino)-methyl]-phenyl]-urea;

The fluoro-4-of B58 1-[3-(methanesulfonamido-methyl)-phenyl]-3-[[2-(3-p-methoxy-phenyl)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl]-urea;

The B59 1-[[5-tertiary butyl-2-(3-fluorophenyl)-2H-pyrazole-3-yl]-methyl] the fluoro-4-[(sulfamyl of-3-[3-amino)-methyl]-phenyl]-urea;

B60 1-[[2-(3-fluorophenyl)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl] the fluoro-4-[(sulfamyl of-3-[3-amino)-methyl]-phenyl]-urea;

B61 1-[[2-(3-chloro-phenyl-)-5-cyclopropyl-2H-pyrazole-3-yl]-methyl] the fluoro-4-[(sulfamyl of-3-[3-amino)-methyl]-phenyl]-urea;

B62 1-[[2-(the fluoro-phenyl of 3,4-bis-)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl] the fluoro-4-[(sulfamyl of-3-[3-amino)-methyl]-phenyl]-urea;

The B63 N-[[5-tertiary butyl-2-(3-chloro-phenyl-)-2H-pyrazole-3-yl]-methyl] the fluoro-4-of-2-[3-(methylamino-methyl)-phenyl]-propionic acid amide;

The B64 N-[[5-tertiary butyl-2-(3-chloro-phenyl-)-2H-pyrazole-3-yl]-methyl] the fluoro-phenyl of-2-[4-(dimethylaminomethyl)-3-]-propionic acid amide;

B65 N-[[2-(3-chloro-phenyl-)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl] the fluoro-phenyl of-2-[4-(dimethylaminomethyl)-3-]-propionic acid amide;

The fluoro-phenyl of B66 2-[4-(acetylamino-methyl)-3-]-N-[[2-(3-chloro-phenyl-)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl]-propionic acid amide;

The fluoro-phenyl of B67 2-[4-(acetylamino-methyl)-3-]-N-[[5-the tertiary butyl-2-(3-chloro-phenyl-)-2H-pyrazole-3-yl]-methyl]-propionic acid amide;

The fluoro-4-of B68 2-[3-(methanesulfonamido-methyl)-phenyl]-N-[[2-(tolyl)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl]-propionic acid amide;

The B69 1-[[5-tertiary butyl-2-(the fluoro-phenyl of 3,4-bis-)-2H-pyrazole-3-yl]-methyl] the fluoro-4-[(sulfamyl of-3-[3-amino)-methyl]-phenyl]-urea;

B70 1-[[2-(the fluoro-phenyl of the chloro-4-of 3-)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl] the fluoro-4-[(sulfamyl of-3-[3-amino)-methyl]-phenyl]-urea;

The fluoro-4-[(sulfamyl of B71 1-[3-amino)-methyl]-phenyl]-3-[[2-(3-p-methoxy-phenyl)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl]-urea;

The B72 1-[[5-tertiary butyl-2-(the fluoro-phenyl of 3,4-bis-)-2H-pyrazole-3-yl]-methyl] the fluoro-4-of-3-[3-(methanesulfonamido-methyl)-phenyl]-urea;

The fluoro-4-of B73 1-[3-(methanesulfonamido-methyl)-phenyl]-3-[[2-(3-sec.-propyl-phenyl)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl]-urea;

The B74 1-[[5-tertiary butyl-2-(the fluoro-phenyl of 3,4-bis-)-2H-pyrazole-3-yl]-methyl]-3-[4-[(sulfamyl amino)-methyl]-phenyl]-urea;

B75 1-[[2-(3-chloro-phenyl-)-5-cyclopropyl-2H-pyrazole-3-yl]-methyl]-3-[4-[(sulfamyl amino)-methyl]-phenyl]-urea;

B76 N-[[2-(3-chloro-phenyl-)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl]-2-[4-(methanesulfonamido-methyl)-3-methoxyl group-phenyl]-propionic acid amide;

B77 1-[[2-(3-fluorophenyl)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl]-3-[4-[(sulfamyl amino)-methyl]-phenyl]-urea;

B78 1-[[2-(the fluoro-phenyl of the chloro-4-of 3-)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl]-3-[4-[(sulfamyl amino)-methyl]-phenyl]-urea;

B79 1-[[2-(3-sec.-propyl-phenyl)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl]-3-[4-[(sulfamyl amino)-methyl]-phenyl]-urea;

The fluoro-4-[(sulfamyl of B80 1-[3-amino)-methyl]-phenyl]-3-[[2-(3-sec.-propyl-phenyl)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl]-urea;

B81 1-[[2-(3-chloro-phenyl-)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl]-3-[4-(methanesulfonamido-methyl)-phenyl]-urea;

The fluoro-4-of B82 2-[3-(methanesulfonamido-methyl)-phenyl]-N-[[2-(3-sec.-propyl-phenyl)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl]-propionic acid amide;

B83 1-[[2-(3-sec.-propyl-phenyl)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl]-3-[4-(methanesulfonamido-methyl)-phenyl]-urea;

B84 1-[[2-(3-chloro-phenyl-)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl]-3-[4-[[(ethylsulfonyl) amino]-methyl]-phenyl]-urea;

The B85 1-[[5-tertiary butyl-2-(3-chloro-phenyl-)-2H-pyrazole-3-yl]-methyl]-3-[4-[[(ethylsulfonyl) amino]-methyl]-phenyl]-urea;

B86 1-[4-(methanesulfonamido-methyl)-3-methoxyl group-phenyl]-3-[[2-(tolyl)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl]-urea;

The fluoro-4-of B87 1-[3-(methanesulfonamido-methyl)-phenyl]-3-[[2-(tolyl)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl]-urea;

The B88 N-[[5-tertiary butyl-2-(tolyl)-2H-pyrazole-3-yl]-methyl] the fluoro-4-of-2-[3-(methanesulfonamido-methyl)-phenyl]-propionic acid amide;

B89 1-[4-(methanesulfonamido-methyl)-phenyl]-3-[[2-(tolyl)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl]-urea;

The B90 1-[[5-tertiary butyl-2-(tolyl)-2H-pyrazole-3-yl]-methyl]-3-[4-(methanesulfonamido-methyl)-phenyl]-urea;

B91 1-[4-[[(ethylsulfonyl) amino]-methyl]-phenyl]-3-[[2-(tolyl)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl]-urea;

The B92 1-[[5-tertiary butyl-2-(tolyl)-2H-pyrazole-3-yl]-methyl]-3-[4-[[(ethylsulfonyl) amino]-methyl]-phenyl]-urea;

The B93 N-[[5-tertiary butyl-2-(3-chloro-phenyl-)-2H-pyrazole-3-yl]-methyl] the fluoro-4-[(sulfamyl of-2-[3-amino)-methyl]-phenyl]-propionic acid amide;

The fluoro-4-[(sulfamyl of B94 2-[3-amino)-methyl]-phenyl]-N-[[2-(3-sec.-propyl-phenyl)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl]-propionic acid amide;

B95 N-[[2-(3-chloro-phenyl-)-5-cyclopropyl-2H-pyrazole-3-yl]-methyl] the fluoro-4-[(sulfamyl of-2-[3-amino)-methyl]-phenyl]-propionic acid amide;

The B96 N-[[5-tertiary butyl-2-(the fluoro-phenyl of the chloro-4-of 3-)-2H-pyrazole-3-yl]-methyl] the fluoro-4-[(sulfamyl of-2-[3-amino)-methyl]-phenyl]-propionic acid amide;

B97 N-[[2-(3-chloro-phenyl-)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl] the fluoro-4-[(sulfamyl of-2-[3-amino)-methyl]-phenyl]-propionic acid amide;

The B98 N-[[5-tertiary butyl-2-(3-chloro-phenyl-)-2H-pyrazole-3-yl]-methyl]-2-[4-(methanesulfonamido-methyl)-3-methoxyl group-phenyl]-propionic acid amide;

B99 1-[[2-(3-chloro-phenyl-)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl]-3-[4-(pyrrolidin-1-yl-methyl)-phenyl]-urea;

B100 1-[[2-(3-chloro-phenyl-)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl] the fluoro-4-of-3-[3-(piperidin-1-yl-methyl)-phenyl]-urea;

The B101 1-[[5-tertiary butyl-2-(3-chloro-phenyl-)-2H-pyrazole-3-yl]-methyl] the fluoro-4-of-3-[3-(pyrrolidin-1-yl-methyl)-phenyl]-urea;

B102 N-[[2-(3-chloro-phenyl-)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl]-2-[4-[(sulfamyl amino)-methyl]-phenyl]-propionic acid amide;

The B103 N-[[5-tertiary butyl-2-(3-chloro-phenyl-)-2H-pyrazole-3-yl]-methyl]-2-[4-[(sulfamyl amino)-methyl]-phenyl]-propionic acid amide;

B104 N-[[2-(3-fluorophenyl)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl]-2-[4-(methanesulfonamido-methyl)-phenyl]-propionic acid amide;

B105 1-[[2-(3-fluorophenyl)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl]-3-[4-(methanesulfonamido-methyl)-3-methoxyl group-phenyl]-urea;

B106 N-[[2-(3-chloro-phenyl-)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl]-2-[4-(methanesulfonamido-methyl)-3-methyl-phenyl]-propionic acid amide; With

The B107 N-[[5-tertiary butyl-2-(3-chloro-phenyl-)-2H-pyrazole-3-yl]-methyl]-2-[4-(methanesulfonamido-methyl)-3-methyl-phenyl]-propionic acid amide;

The form of the optional mixture with single stereoisomers or steric isomer, with the form of acceptable salt on free cpds and/or its physiology.

In addition, preferably in the FLIPR test that uses CHO K1 cell, can cause replacing the compound of the present invention of 50% capsaicine, capsaicine exists with the concentration of 100 nM, CHO K1 cell is the cell with mankind VR1 gene transfection, concentration is less than 2,000 nM, is preferably less than 1,000 nM, particularly preferably be less than 300 nM, be the most particularly preferably less than 100 nM, be even more preferably and be less than 75 nM, preferably be less than in addition 50 nM, be most preferably less than 10 nM.

In the method, read in plate instrument (FLIPR, Molecular Devices, Sunnyvale, USA), by means of Ca at fluorescence imaging ²⁺-sensitive dye (Fluo-4 type, Molecular Probes Europe BV, Leiden, the Netherlands) is quantitative Ca in FLIPR test ²⁺flow, as described below.

Substitution compound of the present invention and corresponding steric isomer and separately corresponding acid, alkali, salt and solvate are safe in toxicology, and are therefore suitable as the medical active component in pharmaceutical composition.

Therefore the present invention further relates to pharmaceutical composition, it contains at least one compound of the present invention, if suitable, in each case, compound is its a kind of pure stereoisomers form, especially enantiomer or diastereomer, the form of mixtures of the steric isomer of its racemic modification or any needed blending ratio, especially the mixture of enantiomer and/or diastereomer, or be respectively corresponding salt form, or the corresponding solvate forms of difference, if suitable, pharmaceutical composition also contains the auxiliary agent of one or more pharmaceutically compatible.

These pharmaceutical compositions of the present invention are especially applicable to regulating vanilloid receptor 1-(VR1/TRPV1), be preferred for suppressing vanilloid receptor 1-(VR1/TRPV1), and/or, be used for stimulating vanilloid receptor 1-(VR1/TRPV1),, they produce excitement or antagonistic effect.

Equally, preferably, pharmaceutical composition of the present invention is suitable for preventing and/or treating the illness or the disease that are mediated by vanilloid receptor 1 at least in part.

Pharmaceutical composition of the present invention is suitable for being grown up and children, comprises child and baby.

Pharmaceutical composition of the present invention can be liquid, semisolid or solid medicinal form, for example, injection solution, drops, juice agent, syrup, sprays, suspensoid, tablet, paster, capsule, plaster, suppository, ointment, ointment, lotion, gelifying agent, emulsion, aerosol form or with many particle form, for example, piller or particle form, if suitable, can be pressed into tablet, be poured in capsule, or float on a liquid, and also in statu quo administration.

Except at least one substitution compound of the present invention, if suitable, this compound can be its a kind of pure stereoisomers form, especially enantiomer or diastereomer, the form of mixtures of the steric isomer of its racemic modification or any needed blending ratio, especially the mixture of enantiomer or diastereomer, if or suitable, it can be corresponding salt form, or be respectively corresponding solvate forms, pharmaceutical composition of the present invention also contains the medicinal auxiliary agent of other physical compatibility conventionally, for example, it is selected from vehicle, filler, solvent, thinner, surfactant, dyestuff, sanitas, disintegrating agent (blasting agents), help sliding additive (slip additives), lubricant, aromatoising substance and tackiness agent.

The auxiliary agent of physical compatibility with and the selection of usage quantity depends on whether pharmaceutical composition oral, subcutaneous, in parenteral, intravenously, intraperitoneal, intracutaneous, intramuscular, nose, in oral cavity, rectum or local use, for example, be applied to infection place of skin, mucous membrane and eyes.The preparation of tablet, lozenge, capsule, granule, piller, drops, juice agent and syrup form is preferably suitable for orally using; The dry preparation of solution, suspensoid, easy preparation again and sprays are preferably suitable for parenteral, part and suck using.The substitution compound of the present invention using in pharmaceutical composition of the present invention, is present in container with solubilized form or plaster form, if suitable, adds the medicament that promotes skin infiltration, is suitable to use preparation through skin.Oral or use suitable dosage form also can discharge corresponding substitution compound of the present invention with delayed mode through skin.

Pharmaceutical composition of the present invention can utilize conventional means known in the art, equipment, Method and process to prepare, for example, " Remington ' s Pharmaceutical Sciences ", A.R. Gennaro (editor), the 17th edition, Mack Publishing Company, Easton, Pa, 1985 described those, especially the 8th part, the 76th to 93 chapters described those.Be incorporated herein corresponding specification sheets by the mode of quoting as proof thus, and form a part of this disclosure.The quantity that gives each substitution compound of patient's corresponding above-mentioned general formula I of the present invention can be different, for example, depend on patient's body weight or the age, and the severity of the type of using, indication and illness.Every kg of patient body weight, the usage quantity of at least one this compound of the present invention is 0.001 to 100 mg/kg normally, preferably 0.05 to 75 mg/kg, particularly preferably 0.05 to 50 mg.

Pharmaceutical composition of the present invention is preferably suitable for treating and/or preventing one or more and is selected from following illness and/or disease: pain, and preferably, pain is selected from acute pain, chronic pain, neuropathic pain, visceral pain and arthralgia; Hyperpathia; Touch pain; Cusalgia; Migraine; Dysthymia disorders; Neuropathy; Axonal injury; Neurodegenerative disease, is preferably selected from multiple sclerosis, alzheimer's disease, Parkinson's disease and Heng Tingdunshi chorea; Cognition dysfunction, preferred cognitive miss status, particularly preferably disturbance of memory; Epilepsy; Respiratory system disease, is preferably selected from asthma, bronchitis and pneumonia; Cough; The urinary incontinence; Bladder hyperactivity hyperkinesia (OAB); GI illness and/or damage; Duodenal ulcer; Stomach ulcer; Irritable bowel syndrome; Apoplexy; Eye irritation; Skin irritation; Neurodermatosis; Anaphylaxis dermatosis; Psoriasis; Vitiligo; Herpes simplex; Inflammation, the preferably inflammation of intestines, eyes, bladder, skin or nasal mucosa; Diarrhoea; Itch; Osteoporosis; Sacroiliitis; Osteoarthritis; Rheumatism; Eating disorder, is preferably selected from exessive appetite, cachexia, apositia and obesity; Drug dependence; Drug abuse; The Withrawal symptom of drug dependence; There is the tolerance to medicine, preferably to natural or synthetic opioid; Drug dependence; Drug abuse; The Withrawal symptom of drug dependence; Alcohol dependence; The Withrawal symptom of alcohol abuse and alcohol dependence; Diuresis; Natruresis suppresses; Affect cardiovascular systems; Insomnia aggravation; Treat wound and/or burn; Treatment cuts off neural; Increase sexual desire; Adjustment movement behavior; Anxiety disorder; Toponarcosis and/or suppress undesirable side effect, preferably, be selected from and give vanilloid receptor 1 (VR1/TRPV1 acceptor) hyperpyrexia, hypertension and bronchoconstriction that agonist causes, this agonist is preferably selected from capsaicine, Root and stem of Cholla toxin (resiniferatoxin), olvanil (olvanil), arvanil, SDZ-249665, SDZ-249482, nuvanil and capsavanil.

Particularly preferably, pharmaceutical composition of the present invention is suitable for treating and/or preventing one or more and is selected from following illness and/or disease: pain, and preferably, pain is selected from acute pain, chronic pain, neuropathic pain, visceral pain and arthralgia; Migraine; Dysthymia disorders; Neurodegenerative disease, is preferably selected from multiple sclerosis, alzheimer's disease, Parkinson's disease and Heng Tingdunshi chorea; Cognition dysfunction, preferred cognitive miss status, particularly preferably disturbance of memory; Inflammation, preferably, the inflammation of intestines, eyes, bladder, skin or nasal mucosa; The urinary incontinence; Bladder hyperactivity hyperkinesia (OAB); Drug dependence; Drug abuse; The Withrawal symptom of drug dependence; Be there is to tolerance in medicine, preferably, tolerance is appearred in natural or synthetic opioid; Drug dependence; Drug abuse; The Withrawal symptom of drug dependence; Alcohol dependence; The Withrawal symptom of alcohol abuse and alcohol dependence.

The most particularly preferably, pharmaceutical composition of the present invention is suitable for treating and/or preventing pain, and preferably, pain is selected from acute pain, chronic pain, neuropathic pain and visceral pain.

In addition, the present invention relates to substitution compound of the present invention, if suitable, also relate to substitution compound of the present invention and one or more pharmaceutically acceptable auxiliary agent, it regulates for vanilloid receptor 1-(VR1/TRPV1), preferably, stimulate for vanilloid receptor 1-(VR1/TRPV1) inhibition and/or vanilloid receptor 1-(VR1/TRPV1).

Therefore, the invention still further relates to substitution compound of the present invention, if suitable, also relate to substitution compound of the present invention and one or more pharmaceutically acceptable auxiliary agent, it is for preventing and/or treating the illness and/or the disease that are mediated by vanilloid receptor 1 at least in part.

Especially, therefore the present invention also relates to substitution compound of the present invention, if suitable, also relate to substitution compound of the present invention and one or more pharmaceutically acceptable auxiliary agent, it is selected from following illness and/or disease for preventing and/or treating: pain, preferably, pain is selected from acute pain, chronic pain, neuropathic pain, visceral pain and arthralgia; Hyperpathia; Touch pain; Cusalgia; Migraine; Dysthymia disorders; Neuropathy; Axonal injury; Neurodegenerative disease, is preferably selected from multiple sclerosis, alzheimer's disease, Parkinson's disease and Heng Tingdunshi chorea; Cognition dysfunction, preferred cognitive miss status, particularly preferably disturbance of memory; Epilepsy; Respiratory system disease, is preferably selected from asthma, bronchitis and pneumonia; Cough; The urinary incontinence; Bladder hyperactivity hyperkinesia (OAB); GI illness and/or damage; Duodenal ulcer; Stomach ulcer; Irritable bowel syndrome; Apoplexy; Eye irritation; Skin irritation; Neurodermatosis; Anaphylaxis dermatosis; Psoriasis; Vitiligo; Herpes simplex; Inflammation, the preferably inflammation of intestines, eyes, bladder, skin or nasal mucosa; Diarrhoea; Itch; Osteoporosis; Sacroiliitis; Osteoarthritis; Rheumatism; Eating disorder, is preferably selected from exessive appetite, cachexia, apositia and obesity; Drug dependence; Drug abuse; The Withrawal symptom of drug dependence; There is the tolerance to medicine, preferably to natural or synthetic opioid; Drug dependence; Drug abuse; The Withrawal symptom of drug dependence; Alcohol dependence; The Withrawal symptom of alcohol abuse and alcohol dependence; Diuresis; Natruresis suppresses; Affect cardiovascular systems; Insomnia aggravation; Treat wound and/or burn; Treatment cuts off neural; Increase sexual desire; Adjustment movement behavior; Anxiety disorder; Toponarcosis and/or suppress undesirable side effect, preferably, be selected from and give vanilloid receptor 1 (VR1/TRPV1 acceptor) hyperpyrexia, hypertension and bronchoconstriction that agonist causes, this agonist is preferably selected from capsaicine, Root and stem of Cholla toxin (resiniferatoxin), olvanil (olvanil), arvanil, SDZ-249665, SDZ-249482, nuvanil and capsavanil.

Particularly preferably be most substitution compound of the present invention, if suitable, also relate to substitution compound of the present invention and one or more pharmaceutically acceptable auxiliary agent, it is for preventing and/or treating pain, preferably, pain is selected from acute pain, chronic pain, neuropathic pain and visceral pain.

The invention further relates to purposes and (if suitable) at least one substitution compound of the present invention and the purposes of one or more pharmaceutically acceptable auxiliary agent for the preparation of pharmaceutical composition of at least one substitution compound of the present invention, this pharmaceutical composition regulates for vanilloid receptor 1-(VR1/TRPV1), preferably, suppress and/or stimulate for vanilloid receptor 1-(VR1/TRPV1) for vanilloid receptor 1-(VR1/TRPV1), be further used for preventing and/or treating the illness and/or the disease that are mediated by vanilloid receptor 1 at least in part, for example, be selected from following illness and/or disease: pain, preferably, pain is selected from acute pain, chronic pain, neuropathic pain, visceral pain and arthralgia, hyperpathia, touch pain, cusalgia, migraine, dysthymia disorders, neuropathy, axonal injury, neurodegenerative disease, is preferably selected from multiple sclerosis, alzheimer's disease, Parkinson's disease and Heng Tingdunshi chorea, cognition dysfunction, preferred cognitive miss status, particularly preferably disturbance of memory, epilepsy, respiratory system disease, is preferably selected from asthma, bronchitis and pneumonia, cough, the urinary incontinence, bladder hyperactivity hyperkinesia (OAB), GI illness and/or damage, duodenal ulcer, stomach ulcer, irritable bowel syndrome, apoplexy, eye irritation, skin irritation, neurodermatosis, anaphylaxis dermatosis, psoriasis, vitiligo, herpes simplex, inflammation, the preferably inflammation of intestines, eyes, bladder, skin or nasal mucosa, diarrhoea, itch, osteoporosis, sacroiliitis, osteoarthritis, rheumatism, eating disorder, is preferably selected from exessive appetite, cachexia, apositia and obesity, drug dependence, drug abuse, the Withrawal symptom of drug dependence, there is the tolerance to medicine, preferably to natural or synthetic opioid, drug dependence, Drug abuse, the Withrawal symptom of drug dependence, alcohol dependence, the Withrawal symptom of alcohol abuse and alcohol dependence, diuresis, natruresis suppresses, affect cardiovascular systems, insomnia aggravation, treat wound and/or burn, treatment cuts off neural, increase sexual desire, adjustment movement behavior, anxiety disorder, toponarcosis and/or suppress undesirable side effect, preferably, be selected from and give vanilloid receptor 1 (VR1/TRPV1 acceptor) hyperpyrexia, hypertension and bronchoconstriction that agonist causes, this agonist is preferably selected from capsaicine, Root and stem of Cholla toxin (resiniferatoxin), olvanil (olvanil), arvanil, SDZ-249665, SDZ-249482, nuvanil and capsavanil.

Another aspect of the present invention is the method that regulates vanilloid receptor 1-(VR1/TRPV1), preferably, suppress vanilloid receptor 1-(VR1/TRPV1) and/or stimulate vanilloid receptor 1-(VR1/TRPV1), further relate to the method that treats and/or prevents the mammiferous illness being mediated by vanilloid receptor 1 at least in part and/or disease, preferably, be selected from following illness and/or disease: pain, preferably, pain is selected from acute pain, chronic pain, neuropathic pain, visceral pain and arthralgia; Hyperpathia; Touch pain; Cusalgia; Migraine; Dysthymia disorders; Neuropathy; Axonal injury; Neurodegenerative disease, is preferably selected from multiple sclerosis, alzheimer's disease, Parkinson's disease and Heng Tingdunshi chorea; Cognition dysfunction, preferred cognitive miss status, particularly preferably disturbance of memory; Epilepsy; Respiratory system disease, is preferably selected from asthma, bronchitis and pneumonia; Cough; The urinary incontinence; Bladder hyperactivity hyperkinesia (OAB); GI illness and/or damage; Duodenal ulcer; Stomach ulcer; Irritable bowel syndrome; Apoplexy; Eye irritation; Skin irritation; Neurodermatosis; Anaphylaxis dermatosis; Psoriasis; Vitiligo; Herpes simplex; Inflammation, the preferably inflammation of intestines, eyes, bladder, skin or nasal mucosa; Diarrhoea; Itch; Osteoporosis; Sacroiliitis; Osteoarthritis; Rheumatism; Eating disorder, is preferably selected from exessive appetite, cachexia, apositia and obesity; Drug dependence; Drug abuse; The Withrawal symptom of drug dependence; There is the tolerance to medicine, preferably to natural or synthetic opioid; Drug dependence; Drug abuse; The Withrawal symptom of drug dependence; Alcohol dependence; The Withrawal symptom of alcohol abuse and alcohol dependence; Diuresis; Natruresis suppresses; Affect cardiovascular systems; Insomnia aggravation; Treat wound and/or burn; Treatment cuts off neural; Increase sexual desire; Adjustment movement behavior; Anxiety disorder; Toponarcosis and/or suppress undesirable side effect, preferably, be selected from and give vanilloid receptor 1 (VR1/TRPV1 acceptor) hyperpyrexia, hypertension and bronchoconstriction that agonist causes, this agonist is preferably selected from capsaicine, Root and stem of Cholla toxin (resiniferatoxin), olvanil (olvanil), arvanil, SDZ-249665, SDZ-249482, nuvanil and capsavanil, and the method comprises: at least one substitution compound of the present invention that gives Mammals significant quantity.

For example; can be with Bennett or Chung model (Bennett; and Xie G.J.; Y.K.; A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man; Pain 1988,33 (1), 87-107; Kim, and Chung S.H., J.M., An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat, Pain 1992,50 (3), 355-363), tail (for example flicks experiment, according to D'Amour and Smith (J. Pharm. Exp. Ther. 72,74 79 (1941)) or gate-Papacostas' tests (for example,, according to the people's such as D. Dubuisson Pain 1977,4,161-174), prove the effect for pain.

The invention still further relates to the method for preparing substitution compound of the present invention.

Especially, the compounds of this invention can be prepared by following method, according to the method, and at least one general formula (R-II) compound,

Wherein R ¹⁰¹, R ¹⁰², R ¹⁰³and R ²there is one of aforementioned implication, in reaction medium, suitably time, under at least one suitable coupling agent exists, suitably time, under at least one alkali exists, react with general formula (R-III) compound of D=OH or Hal,

Wherein Hal represents halogen, preferably Br or Cl, and R ⁷, R ⁹, R ¹¹², R ¹¹³there is separately one of aforementioned implication with q and A represents CH or C (CH ₃), in reaction medium, suitably time under at least one suitable coupling agent exists, suitably time under at least one alkali exists, to form general formula (R) compound,

Wherein A represents CH or C (CH ₃) and R ¹⁰¹, R ¹⁰², R ¹⁰³and R ²and R ⁷, R ⁹, R ¹¹², R ¹¹³there is one of aforementioned implication with q;

Or at least one general formula (R-II) compound,

Wherein R ¹⁰¹, R ¹⁰², R ¹⁰³and R ²have one of aforementioned implication, in reaction medium, under phenyl chloroformate exists, suitably time, under at least one alkali and/or the existence of at least one coupling agent, reaction forms general formula (R-IV) compound,

Wherein R ¹⁰¹, R ¹⁰², R ¹⁰³and R ²there is one of aforementioned implication, and described in suitably time, compound is purified and/or separate, and general formula (R-IV) compound reacts with general formula (R-V) compound,

Wherein R ⁷, R ⁹, R ¹¹², R ¹¹³there is one of aforementioned implication with q, and A represents N, in reaction medium, suitably time under at least one suitable coupling agent exists, suitably time under at least one alkali exists, to form general formula (R) compound,

Wherein A represents N and R ¹⁰¹, R ¹⁰², R ¹⁰³and R ²and R ⁷, R ⁹, R ¹¹², R ¹¹³there is one of aforementioned implication with q.

Above-mentioned general formula (R-II) compound and the carboxylic acid (particularly D=OH) of above-mentioned general formula (R-III) react to form the reaction of above-mentioned general formula (R) compound, preferably carry out being selected from following reaction medium: ether, tetrahydrofuran (THF), acetonitrile, methyl alcohol, ethanol, (1,2)-ethylene dichloride, dimethyl formamide, methylene dichloride and corresponding mixture if suitable, react under the existence of at least one coupling agent, and preferably, coupling agent is selected from: 1-benzotriazole base oxygen base-tri--(dimethylamino)-phosphorus hexafluorophosphate (BOP), dicyclohexylcarbodiimide (DCC), N'-(3-dimethylaminopropyl)-N-ethyl carbodiimide (EDCI), DIC, 1,1'-N,N'-carbonyldiimidazole (CDI), N-[(dimethylamino)-1H-1,2,3-triazolo [4,5-b] pyrido-1-base-methylene radical]-N-methyl first ammonium hexafluorophosphate N-oxide compound (HATU), O-(benzotriazole-1-yl)-N, N, N', N'-tetramethyl-urea hexafluorophosphate (HBTU), O-(benzotriazole-1-yl)-N, N, N', N'-tetramethyl-urea a tetrafluoro borate (TBTU), N-hydroxybenzotriazole (HOBt) and 1-hydroxyl-7-azepine benzotriazole (HOAt) if suitable, react under the existence of at least one organic bases, and preferably, organic bases is selected from triethylamine, pyridine, dimethyl aminopyridine, N-methylmorpholine and diisopropylethylamine preferably, react at the temperature of-70 DEG C to 100 DEG C.

Or, above-mentioned general formula (R-II) compound and above-mentioned general formula (R-III) (D=Hal, wherein Hal represents that halogen is as leavings group, preferably chlorine or bromine atom) carboxylic acid halide form the reaction of above-mentioned general formula (R) compound, in reaction medium, carry out, preferably, reaction medium is selected from: ether, tetrahydrofuran (THF), acetonitrile, methyl alcohol, ethanol, dimethyl formamide, methylene dichloride and corresponding mixture, if suitable, under the existence of organic or inorganic alkali, react, preferably, alkali is selected from triethylamine, dimethyl aminopyridine, pyridine and diisopropylamine, at the temperature of-70 DEG C to 100 DEG C, react.

The compound that above-mentioned formula (R-II), (R-III), (R-IV) and compound (R-V) are respectively purchased naturally, and/or, ordinary method preparation well known by persons skilled in the art can be used.Especially, for example, WO 2010/127855-A2 and WO 2010/127856-A2 disclose the method for preparing these compounds.The corresponding part of these reference is considered as to a part of this disclosure herein.

Can for the synthesis of the compounds of this invention carry out under can the each comfortable those skilled in the art familiar normal condition that responds, for example, pressure or add the order of component.If suitable, by carrying out simple trial test, those skilled in the art can determine the optimum program under corresponding condition.If necessary and/or require, can use ordinary method well known by persons skilled in the art, by the intermediate that uses separately reaction described above to obtain with final product purifying and/or separate.For example, suitable purification process is extracting method and chromatographic process, for example, and column chromatography or preparative chromatography.Can be for the synthesis of all processing steps of the reaction sequence of the compounds of this invention, and corresponding purifying and/or the separation of intermediate or final product, can partially or completely in inert atmosphere, carry out, preferably, under nitrogen atmosphere.

Substitution compound of the present invention can its free alkali form, and with the form of acceptable salt on corresponding salt, particularly physiology, and further with the isolated in form of for example hydrate of solvate.

The free alkali of corresponding substitution compound of the present invention can change corresponding salt into, preferably, acceptable salt on physiology, for example, by with inorganic or organic acid reaction, preferably, with following acid-respons: hydrochloric acid, Hydrogen bromide, sulfuric acid, methylsulfonic acid, tosic acid, carbonic acid, formic acid, acetic acid, oxalic acid, succsinic acid, tartrate, amygdalic acid, fumaric acid, toxilic acid, lactic acid, citric acid, L-glutamic acid, saccharic acid (saccharic acid), monomethyl sebacic acid (monomethylsebacic acid), 5-oxo proline(Pro) (5-oxoproline), hexane-1-sulfonic acid, nicotinic acid, 2, 3 or PABA, 2, 4, 6-trimethylbenzoic acid, alpha-lipoic acid, acetyl glycine, urobenzoic acid, phosphoric acid and/or aspartic acid.Use free acid, or the salt of sugared adducts (salt of a sugar additive), for example, asccharin, hexamethylene (base) sulfamate (cyclamate) or acesulfame potassium (acesulphame), the free alkali of each substitution compound of the present invention and corresponding steric isomer also can change acceptable salt on corresponding physiology into.

Correspondingly, by with suitable alkali reaction, substitution compound of the present invention can change acceptable salt on corresponding physiology into as the free acid of substitution compound of the present invention.Example comprises an alkali metal salt, alkaline earth salt or ammonium salt [NH _xr _4-x] ⁺, wherein x=0,1,2,3 or 4, R represent the C of side chain or non-side chain _1-4alkyl residue.

If suitable, substitution compound of the present invention and corresponding steric isomer, for example, the salt of corresponding acid, corresponding alkali or these compounds, also can use ordinary method well known by persons skilled in the art, obtains with their solvate forms, preferably, their hydrate forms.

If after preparation, obtain the substitution compound of the present invention of the form of mixtures of steric isomer, preferably their racemic modification form, or other form of mixtures of their various enantiomers and/or diastereomer, they can be separated, if suitable, use ordinary method well known by persons skilled in the art to separate.Example comprises: chromatography separating method, especially normal pressure or high pressure liquid chromatography method, preferably MPLC and HPLC method, and fractional crystallization method.These methods make each enantiomer disconnected from each other, for example, by means of chiral stationary phase HPLC, or the diastereoisomeric salt that crystallization forms together with chiral acid, described chiral acid for example (+)-tartrate, (-)-tartrate or (+)-10-camphorsulfonic acid.

The chemicals and the reactive component that in reaction as described below and scheme, use are available commercially, or in each case, can prepare by ordinary method well known by persons skilled in the art.

general reaction scheme 1 (scheme 1):

In step j01, can be by the familiar method of those skilled in the art by acyl halide J-0, wherein Hal preferably represents Cl or Br, uses methyl alcohol to carry out esterification to form compound J-I.

In step j02, can pass through method known to those skilled in the art, for example use acetonitrile CH ₃-CN, under alkali exists, is converted into oxoalkyl group nitrile J-II by methyl trimethylacetate J-I suitably time.

In step j03, can pass through method known to those skilled in the art, for example use hydrazine hydrate, adopt cyclic action, compound J-II is converted into the pyrazolyl derivative J-III of amino-replacement.

In step j04, can pass through method known to those skilled in the art, for example use nitrite, first aminocompound J-III is converted into diazonium salt, and can uses prussiate, suitably time under coupling agent exists, except denitrification, diazonium salt is converted into the pyrazolyl derivative J-IV of cyano group-replacement.

In step j05, can pass through method known to those skilled in the art, for example use the halogenide of part-structure (RS2), be Hal-(RS2), suitably time, under alkali and/or coupling agent existence, wherein Hal is preferably Cl, Br or I, or uses boric acid B (OH) ₂(RS2) or corresponding boric acid ester, suitably time, under coupling agent and/or alkali exist, in N position, compound J-IV is replaced, and can obtain in this way compound J-V.

Or the second route of synthesis is also applicable to prepare compound J-V, wherein, in step k01, first by method known to those skilled in the art, for example, use suitable hydroborating reagent, for example metal hydride, by ester K-0 reduction, to form aldehyde K-I.

Then in step k02, can make aldehyde K-I and hydrazine K-V (can pass through method known to those skilled in the art, from primary amine K-IV, obtain) reaction in step k05, by method known to those skilled in the art, except anhydrating, to form hydrazine K-II.

In step k03, can pass through method known to those skilled in the art, for example use chlorination reagent, for example NCS, keeping, two keys are complete lower to hydrazine K-II halogenation, preferably chlorination, and can obtain in this way compound K-III.

In step k04, can pass through method known to those skilled in the art, for example use the nitrile of halogen-replacement, adopt cyclic action, hydrazone acyl halide K-III is converted into the compound J-V of cyano group-replacement.

In step j06, can pass through method known to those skilled in the art, for example use for example palladium/activated carbon of suitable catalyzer or use suitable hydroborating reagent, by compound J-V hydrogenation, and can obtain in this way compound (R-II).

In step j07, can pass through method known to those skilled in the art, for example use phenyl chloroformate, suitably time, under coupling agent and/or alkali existence, compound (R-II) is converted into compound (R-IV).Except use phenyl chloroformate disclosed herein is prepared the method for unsymmetrical urea, suitably time, also there is the familiar method of other those skilled in the art, based on using active carbonic acid derivative or isocyanic ester.

In step j08, amine (R-V) can be converted into carbamide compound (R) (wherein A=N).This can, by the familiar method of those skilled in the art, under alkali exists, react with (R-IV) suitably time.

In step j09, amine (R-II) can be converted into acid amides (R) (wherein A=CH or C (CH ₃)).For example; this can be by the familiar method of those skilled in the art; by with acyl halide; preferably the muriate of the formula (R-III) of D=Hal has reacted; suitably time under alkali exists or by completing with the acid-respons of the formula (R-III) of D=OH; suitably time, under suitable coupling agent exists, for example HATU or CDI, add alkali suitably time.In addition, can, by the familiar method of those skilled in the art, suitably time, under alkali exists, by reacting with compound (R-IIIa), amine (R-II) be converted into acid amides (R) (wherein A=CH or C (CH ₃)).

Can further prepare general formula (R) compound, wherein A=N according to the reaction sequence of general reaction scheme 2.

general reaction scheme 2 (scheme 2)

In step v1, can pass through method known to those skilled in the art, for example use phenyl chloroformate, suitably time, under coupling agent and/or alkali existence, compound (R-V) is converted into compound (R-Va).Except use phenyl chloroformate disclosed herein is prepared the method for unsymmetrical urea, suitably time, also there is the familiar method of other those skilled in the art, based on using active carbonic acid derivative or isocyanic ester.

In step v2, amine (R-II) can be converted into carbamide compound (R) (wherein A=N).This can, by the familiar method of those skilled in the art, under alkali exists, react with (R-Va) suitably time.

Can be from organic chemistry standard operation, for example, J. March, Advanced Organic Chemistry (Advanced Organic Chemistry), Wiley & Sons, the 6th edition, 2007; F. A. Carey, R. J. Sundberg, Advanced Organic Chemistry (Advanced Organic Chemistry), part A and B, Springer, the 5th edition, 2007; Team of authors, methodology of organic synthesis general introduction (Compendium of Organic Synthetic Methods), Wiley & Sons infers the method for carrying out reactions steps j01 to j09 and k01 to k05 and v1 and v2 that those skilled in the art are familiar with.In addition, other method and reference can be published in frequently-used data storehouse, for example, and the Reaxys database of Elsevier, Amsterdam, the SciFinder database of NL or American Chemical Society, Washington, US.

Embodiment

The following example is further set forth the present invention but be may not be interpreted as limiting its scope.

Symbol " equivalent " (" eq. " or " eq " or " equiv. " or " equiv ") refers to molar equivalent, " RT " or " rt " refers to room temperature (23 ± 7 DEG C), the concentration that " M " unit of referring to is mol/l, " aq. " refers to the aqueous solution, " sat. " refers to saturated, " sol. " refers to solution, and " conc. " refers to dense.

Other abbreviations:

D days

AcOH acetic acid

BH ₃s (CH ₃) ₂borine-dimethyl sulfide mixture (BH ₃-DMS)

Brine saturated sodium-chloride water solution

N-BuLi n-Butyl Lithium

CC silica gel column chromatography

DBU 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene

DCM methylene dichloride

DIPEA diisopropylethylamine

DMA dimethylamine

DMAP 4-dimethylaminopyridine

DMF DMF

EDC N-(3-dimethylaminopropyl)-N '-ethyl carbodiimide

EDCI N-ethyl-N '-(3-dimethylaminopropyl) carbodiimide hydrochloride

Ether ether

EtOAc ethyl acetate

EtOH ethanol

H hour

GC gas-chromatography

HBTU O-(benzotriazole-1-yl)-N, N, N ', N '-tetramethyl-urea hexafluorophosphate

HOBt N-hydroxybenzotriazole

H ₂o water

M/z mass-to-charge ratio

MeOH methyl alcohol

MeCN acetonitrile

Min or min. minute

MS mass spectrum

NBS N-bromosuccinamide

TEA triethylamine

NMP METHYLPYRROLIDONE

Pd/C palladium carbon

Pd ₂(dba) ₃three (dibenzalacetone) two palladiums (0)

Pd (PPh ₃) ₄tetrakis triphenylphosphine palladium (0)

TBTU O-(benzotriazole-1-yl)-N, N, N ', N '-tetramethyl-urea a tetrafluoro borate

TLC thin-layer chromatography

TFA trifluoroacetic acid

THF tetrahydrofuran (THF)

V/v volume/volume

W/w w/w

The productive rate right and wrong of prepared compound are optimized.

All temperature are uncorrected.

All starting raw materials of clearly not describing can be purchased (supplier's details, for example, Acros, Avocado, Aldrich, Apollo, Bachem, Fluka, Fluor Chem, Lancaster, Manchester Organics, MatrixScientific, Maybridge, Merck, Rovathin, Sigma, TCI, Oakwood, etc., can be respectively at for example Symyx Available Chemicals Database of MDL, San Ramon, US or SciFinder Database of the ACS, Washington DC, in US, find), or its synthetic method is described exactly (for example in technical literature, experiment instruction principle can be respectively at Reaxys Database of Elsevier, Amsterdam, NL or SciFinder Database of the ACS, Washington DC, in US, obtain), maybe can prepare by ordinary method well known by persons skilled in the art.

Stationary phase for column chromatography is E. Merck, the silica gel 60 (0.04-0.063 mm) of Darmstadt.

Illustrate the blending ratio of chromatogram solvent used or elutriant with v/v.

Utilize ¹h-NMR spectrum characterizes all intermediate products and embodiment compound analytically.In addition, for all embodiment compounds and the intermediate product of selection, carry out mass spectrum inspection (MS, [M+H] ⁺m/z).

Synthesizing of selected intermediate product:

1. synthetic (the step j01-j06) of (the 3-tertiary butyl-1-(3-chloro-phenyl-)-1H-pyrazoles-5-yl) methylamine

Step j01: (1 eq., 60 g) drop in methanol solution (120 mL) and mixture is at room temperature stirred to 1 h at 0 DEG C in 30 min by trimethyl-acetyl chloride (J-0).Add after water (120 mL), the organic phase that water (120 mL) washing separates, also uses methylene dichloride (150 mL) condistillation through dried over sodium sulfate.(57 g) can 99% purity to obtain product liquid J-I.

Step j02: (1.2 equivalents, 4.6 g) are dissolved in Isosorbide-5-Nitrae-dioxs (120 mL) and by mixture stirred for several minute by NaH (50% in paraffin oil).(1.2 equivalents, 4.2 g) and by mixture stir 30 min again in 15 min, to drip acetonitrile.(1 equivalent, 10 g) and by reaction mixture refluxed 3 h in 15 min, to drip methyl trimethylacetate (J-I).After having reacted, reaction mixture is placed in to frozen water, and (200 g), is acidified to pH 4.5 and uses methylene dichloride (12 x 250 mL) extraction.The organic phase merging is through dried over sodium sulfate, and distillation after recrystallization, can obtain 5 g products (J-II) (51% productive rate) from normal hexane (100 mL), is brown solid material.

Step j03: by 4,4-dimethyl-3-oxo valeronitrile (J-II) (1 equivalent, 5 g) are at room temperature dissolved in ethanol (100 mL), (2 equivalents, 4.42 g) mix and 3 h that reflux with hydrazine hydrate.To remove the residue obtaining after ethanol water-soluble (100 mL) by distillation and use ethyl acetate (300 mL) extraction.The organic phase merging, through dried over sodium sulfate, except desolventizing, after recrystallization, obtains product (J-III) (5 g, 89% productive rate) under vacuum from normal hexane (200 mL), is incarnadine solid.

Step j04: by the 3-tertiary butyl-1H-pyrazoles-5-amine (J-III) (1 equivalent, 40 g) be dissolved in rare HCl (120 mL HCl are in 120 mL water) and at 0-5 DEG C through 30 min times dropwise with NaNO ₂(1.03 equivalents, 25 g are in 100 mL) mix.Stir after 30 minutes reaction mixture Na ₂cO ₃neutralization.Will by with KCN (2.4 equivalents, 48 g), (1.12 equivalents, 31 g) during diazonium salt that reaction obtains drops to reaction mixture in 30 min and mixture is stirred at 75 DEG C again to 30 min for water (120 mL) and CuCN.After having reacted, ethyl acetate for reaction mixture (3 x 500 mL) extraction, the organic phase of merging is removed desolventizing through dried over sodium sulfate and under vacuum.Residue obtains white solid (J-IV) (6.5 g, 15%) by column chromatography (silica gel: 100-200 mesh sieve, elutriant: 20% ethyl acetate/normal hexane) purifying.

Step j05 ( method 1):

The 3-tertiary butyl-1H-pyrazoles-5-formonitrile HCN (J-IV) (10 mmol) is joined under the mild stirring of chamber in dimethyl formamide (20 mL) suspension of NaH (60%) (12.5 mmol).Stir after 15 minutes, iodo-1-3-chlorobenzene (37.5 mmol) is at room temperature dropped in this reaction mixture.At 100 DEG C, stir after 30 min, reaction mixture mixes with water (150 mL) and uses methylene dichloride (3 x 75 mL) to extract.Merge organic extract water (100 mL) and saturated NaCl solution (100 mL) wash and through dried over mgso.Under vacuum, except after desolventizing, residue is by column chromatography (silica gel: 100-200 mesh sieve, elutriant: the various mixtures of ethyl acetate and hexanaphthene are as mobile solvent) purifying and obtain product J-V.

Step j05 ( method 2):

By the 3-tertiary butyl-1H-pyrazoles-5-formonitrile HCN (J-IV) (10 mmol), boric acid B (OH) ₂the mixture of (3-chloro-phenyl-) or corresponding boric acid ester (20 mmol) and venus crystals (II) (15 mmol) is placed in methylene dichloride (200 mL), under stirring and room temperature, mixes and mixture is stirred to 16 h with pyridine (20 mmol).Under vacuum, except after desolventizing, the residue obtaining is by column chromatography (silica gel: 100-200 mesh sieve, elutriant: the various mixtures of ethyl acetate and hexanaphthene are as mobile solvent) purifying and obtain in this way product J-V.

Step j06:( method 1):

J-V and palladium carbon (10%, 500 mg) and dense HCl (3 mL) are dissolved in together to methyl alcohol (30 mL) and are at room temperature exposed to nitrogen atmosphere 6 h.Reaction mixture is through diatomite filtration filtrate is concentrated under vacuum.Residue is by flash chromatography (silica gel: 100-200 mesh sieve, elutriant: ethyl acetate) purifying and obtain in this way product (U-II).

Step j06:( method 2):

J-V is dissolved in to tetrahydrofuran (THF) (10 mL) and adds wherein BH ₃s (CH ₃) ₂(2.0 M in tetrahydrofuran (THF), 3 mL, 3 equivalents).By reaction mixture reflux 8 h, add wherein the 2 N HCl aqueous solution (2 N) and reaction mixture is refluxed 30 minutes again.Reaction mixture mixes with the NaOH aqueous solution (2N) and washs by ethyl acetate.The organic phase merging is with saturated NaCl solution washing and through dried over mgso.Under vacuum, except desolventizing, residue is by column chromatography (silica gel: 100-200 mesh sieve, elutriant: the various mixtures of methylene dichloride and methyl alcohol are as mobile solvent) purifying and obtain in this way product (U-II).

Following other intermediate product is/can use in a similar manner that 1. described methods are synthetic above:

(the 3-tertiary butyl-1-(4-chloro-phenyl-)-1H-pyrazoles-5-yl) methylamine
	(the 3-tertiary butyl-1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl) methylamine
(the 3-tertiary butyl-1-(3-fluorophenyl)-1H-pyrazoles-5-yl) methylamine
	(the 3-tertiary butyl-1-(4-fluorophenyl)-1H-pyrazoles-5-yl) methylamine
(the 3-tertiary butyl-1-(3,4-difluorophenyl)-1H-pyrazoles-5-yl) methylamine
	(the 3-tertiary butyl-1-(3-aminomethyl phenyl)-1H-pyrazoles-5-yl) methylamine
(the 3-tertiary butyl-1-(3-trifluoromethyl-phenyl)-1H-pyrazoles-5-yl) methylamine

2. synthesizing of 1-(3-chloro-phenyl-)-3-(trifluoromethyl)-1H-pyrazoles-5-base-methylamine (step k01-k05 and j06)

Step k01: LAlH (lithium aluminum hydride) (0.25 equivalent, 0.7g) is dissolved in to dry diethyl ether (30 mL) under protective gas atmosphere and at room temperature stirs 2 h.The suspension obtaining is dissolved in to ether (20 mL).By 2,2,2-Trifluoroacetic Acid Ethyl Ester (K-0), (1 equivalent, 10 g) are dissolved in dry diethyl ether (20 mL) and drop in suspension through 1 h time at-78 DEG C.Then mixture is stirred at-78 DEG C again to 2 h.Then drip ethanol (95%) (2.5 mL), by reaction mixture be heated to room temperature and with dense H ₂sO ₄(7.5 mL) is placed in frozen water (30 mL) together.Separate organic phase and concentrate under vacuum, immediately reaction product K-I being imported to next reactions steps k02.

Step k05: (1 equivalent, 50 g) are dissolved in dense HCl (300 mL) and stir 10 min at-5 to 0 DEG C by 3-chloroaniline (K-IV).Drip NaNO through 3 h times ₂(1.2 equivalents, 32.4 g), water (30 mL), SnCl ₂2H ₂(2.2 equivalents, 70.6 g) and the mixture of dense HCl (100 mL), simultaneously holding temperature for O.At-5 to 0 DEG C, stir again after 2 h, use NaOH solution that reaction mixture is adjusted into pH 9 and uses ethyl acetate (250 mL) extraction.The organic phase merging is removed desolventizing through dried over mgso and under vacuum.By column chromatography (silica gel: 100-200 mesh sieve, elutriant: 8% ethyl acetate/normal hexane) purifying, obtain 40 g (72%) (3-chloro-phenyl-) hydrazines (K-IV), be brown oil.

Step k02: (1 equivalent, 20 g) are placed in ethanol (200 mL) 5 h that reflux by the aldehyde being obtained by k01 (K-I) (2 equivalents, 300 mL) and (3-chloro-phenyl-) hydrazine (K-IV).Under vacuum, except desolventizing, residue is by column chromatography (silica gel: 100-200 mesh sieve, elutriant: normal hexane) purifying and obtain product (25 g, 72%) K-II, is brown oil.

Step k03: (1 equivalent, 25 g) are dissolved in dimethyl formamide (125 mL) by hydrazine K-II.At room temperature in 15 min portion-wise addition N-chlorosuccinimide (1.3 equivalents, 19.5 g) and by mixture stir 3 h.Remove dimethyl formamide and residue is dissolved in to ethyl acetate by distillation.Under vacuum, remove ethyl acetate, the residue obtaining is by column chromatography (silica gel: 100-200 mesh sieve, elutriant: normal hexane) purifying and obtain product K-III (26.5 g, 92%), is pink oily matter.

Step k04: (1 equivalent, 10 g) are at room temperature dissolved in toluene (150 mL) and mix with 2-chloroacrylonitrile (2 equivalents, 6.1 mL) and triethylamine (2 equivalents, 10.7 mL) by hydrazone acyl chlorides K-III.This reaction mixture is stirred at 80 DEG C to 20 h.Then water (200 mL) dilution mixture separation of phases.Organic phase is removed desolventizing through dried over mgso and under vacuum.Residue is by column chromatography (silica gel: 100-200 mesh sieve, elutriant: 5% ethyl acetate/normal hexane) purifying and obtain product (5.5 g, 52%), is white solid J-V.

Step j06 ( method 3):

By nitrile J-V, (1 equivalent, 1 g) is dissolved in methanol ammonia solution (150 mL, 1:1) hydrogenation in H-cube (10 bar, 80 DEG C, 1 mL/min, 0.25 mol/L).Under vacuum, except after desolventizing, can obtain (1-(3-chloro-phenyl-)-3-(trifluoromethyl)-1H-pyrazoles-5-yl) methylamine (II), be white solid (0.92 g, 91%).

Following other intermediate product is/can use in a similar manner that 2. described methods are synthetic above:

(1-(3-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl) methylamine
	(1-(the chloro-4-fluorophenyl of 3-)-3-(trifluoromethyl)-1H-pyrazoles-5-yl) methylamine
(1-(3-p-methoxy-phenyl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl) methylamine
	(1-(4-chloro-phenyl-)-3-(trifluoromethyl)-1H-pyrazoles-5-yl) methylamine
(1-(3,4-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl) methylamine
	(1-(3-trifluoromethyl-phenyl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl) methylamine
(1-(3-aminomethyl phenyl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl) methylamine
	(1-(3-isopropyl phenyl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl) methylamine

3. the preparation of (the 3-tertiary butyl-1-(3-chloro-phenyl-)-1H-pyrazoles-5-yl) methyl carbamic acid methyl phenyl ester

Step a: to (the 3-tertiary butyl-1-(3-chloro-phenyl-)-1H-pyrazoles-5-yl) methylamine (5 g, 18 mmol) dimethyl formamide (25 mL) solution in, add salt of wormwood (9.16 g, 66 mmol, 3.5 eq) and content is cooled to 0 DEG C.Then dripped phenyl chloroformate (3.28 g (2.65 mL), 20 mmol, 1.1 equivalents) and total reaction mixture is stirred 15 minutes at 0 DEG C again through 15 minutes.By TLC (hexane solution of 20% ethyl acetate) monitoring extent of reaction.Once react, filter reaction content, dilute filtrate with cold water (100 mL) and also use ethyl acetate (3 × 25 mL) extraction product.Salt brine solution for organic layer (100 mL) washing merging, through dried over sodium sulfate under reduced pressure concentrated.The crude product obtaining, by column chromatography (silica gel: 100-200 mesh sieve, elutriant: the hexane solution of 10% ethyl acetate) purifying, obtains required product, is white solid (3.2 g, 45%).

4. the preparation of (1-(3-chloro-phenyl-)-3-cyclopropyl-1H-pyrazoles-5-yl) methylamine hydrochloride

Step a :at room temperature, to alcohol sodium solution (by by sodium (1 g, 8.2 mmol, 1.2 equivalents) be dissolved in ethanol (30 mL) and freshly prepd) in, add oxalic acid diethyl ester (0.92 mL, 6.85 mmol, 1 equivalent), then at 0 DEG C, drip Cyclopropyl Methyl Ketone (0.74 mL, 7.5 mmol, 1.1 equivalents).Reaction mixture is slowly risen to room temperature and stirs 3 h.Add ice cold water (10 mL) vapourisation under reduced pressure ethanol.Diluting residual water layer with the 2 N HCl aqueous solution (15mL) also extracts with ether (2 × 25 mL).Organic layer, with salt brine solution washing and through dried over sodium sulfate, filters and concentrates, and obtains light brown liquid (400 mg, 31%).

Step b :at room temperature, to step-a product (200 mg, 0.543 mmol, 1 equivalent) ethanol (8 mL) solution in, add methoxamine hydrochloride (30% aqueous solution, 0.4 mL, 0.651 mmol, 1.2 equivalents) and reaction mixture is stirred to 1 h.Vapourisation under reduced pressure ethanol also extracts residual water layer by ethyl acetate (15 mL).Organic layer water (10 mL), salt brine solution (10 mL) washing, through dried over sodium sulfate, filter and under reduced pressure concentrate, and obtains weak yellow liquid (180 mg, 78%).

Step c :by step-b product (1.1 g, 5.164 mmol, 1 equivalent) and 3-chloro-phenyl-hydrazonium salt hydrochlorate (1.84 g, 10.27 mmol, 2 equivalents) mixture be dissolved in acetic acid (20 mL), 2-methyl cellosolve (10 mL) and reaction mixture heated at 105 DEG C to 3 h.Evaporating solvent is also used ethyl acetate (60 mL) extraction leftover.Organic layer water (10 mL), salt brine solution (10 mL) washing, through dried over sodium sulfate, filter and under reduced pressure concentrate, and obtains residue.By column chromatography (silica gel: 100-200 mesh sieve; Elutriant: ethyl acetate-sherwood oil (4:96)) purifying, obtain light brown semisolid (1.15g, 77%).

Steps d :at 0 DEG C, to step-c product (2.5 g, 8.62 mmol, 1 eq) tetrahydrofuran (THF) (15 mL) – methyl alcohol are (in 9 mL) – water (3 mL) solution, add lithium hydroxide (1.08 g, 25.71 mmol, 3 equivalents) and reaction mixture is at room temperature stirred to 2 h.Evaporating solvent and with the 2 N HCl aqueous solution (1.2 mL) by the pH regulator of residue extremely ~ 3.Extract acid water layer by ethyl acetate (2 × 60 mL); The organic layer water (10 mL), salt brine solution (10 mL) washing that merge, through dried over sodium sulfate, filter and under reduced pressure concentrate, and obtains pale solid (1.4 g, 62%).

Step e :at 0 DEG C, to step-d product (1.4 g, 5.34 mmol, 1 equivalent) Isosorbide-5-Nitrae-dioxs (30 mL) solution in, add pyridine (0.25 mL, 3.2 mmol, 0.6 equivalent) and tert-Butyl dicarbonate (1.4 mL, 6.37 mmol, 1.2 equivalents) the mixture obtaining is stirred 30 minutes at the same temperature.At 0 DEG C, add bicarbonate of ammonia (0.84 g, 10.63 mmol, 2 equivalents) and reaction mixture is at room temperature stirred and spent the night.Water (10 mL) diluted reaction mixture is also used ethyl acetate (2 × 30 mL) aqueous layer extracted.2N HCl (20 mL), water (10 mL), salt brine solution (10 mL) washing for organic layer, through dried over sodium sulfate, filter and under reduced pressure concentrate, and obtains residue.By column chromatography (silica gel: 100-200 mesh sieve; Elutriant: ethyl acetate-sherwood oil (16:84)) purifying, obtain white solid (1 g, 72%).

Step f :at 0 DEG C, in tetrahydrofuran (THF) (25 mL) solution of step-e product (2 g, 7.66 mmol, 1 equivalent), add BH ₃.DMS (1.44 mL, 15.32 mmol, 2 equivalents) reaction mixture is heated at 70 DEG C to 3 h.Reaction mixture is cooled to 0 DEG C, adds methyl alcohol (15 mL), and reaction mixture is heated to 1 h under refluxing.Make reaction mixture reach room temperature vapourisation under reduced pressure solvent.Residue is dissolved in ether (15 mL), is cooled to 0 DEG C and add Isosorbide-5-Nitrae-dioxs (3 mL) solution (pH of reaction mixture for ~ 4) of HCl.The solid of filtering-depositing is also used ether (5 mL, three times) washing, obtains hydrochloride compound, is white solid (600 mg, 28%).

Synthesizing of embodiment compound:

1. acid amides (A=CH or C (CH ₃ )) preparation

The amine of general formula (R-II) and the carboxylic acid derivative of the carboxylic acid of general formula or general formula (R-III) react to form the general remark of general formula (R) compound, wherein A=CH or C (CH ₃) (acid amides), as scheme 1 (step j09).

1.1 method A:

The amine (1.2 equivalent) of the acid of general formula (R-III) (1 equivalent), general formula (R-II) and EDCI (1.2 equivalent) are stirred 12 hours under RT in DMF (10 mmol acid/20 mL), add wherein subsequently water.With EtOAc re-extract reaction mixture, water is saturated with NaCl, extracts subsequently with EtOAc again.1 N HCl and the salt water washing for organic phase merging, removes desolventizing through dried over mgso and under vacuum.Residue is by flash chromatography (SiO ₂, the EtOAc/ hexane of different ratios, for example 1:2) and purifying obtain in this way product (R).

1.2 method B:

The amine (1.1 equivalent) of the acid of general formula (R-III) (1 equivalent) and general formula (R-II) is dissolved in to methylene dichloride (acid of 1 mmol is in 6 mL) and mixes with EDCI (1.5 equivalent), HOBt (1.4 equivalent) and triethylamine (3 equivalent) at 0 DEG C.Reaction mixture is at room temperature stirred to 20 h, and crude product is by column chromatography (SiO ₂, the normal hexane/EtOAc of different ratios, for example 2:1) and purifying obtain in this way (R).

1.3 method C:

First the acid of general formula (R-III) (1 equivalent) is mixed with chlorizating agent; preferably mix with thionyl chloride, the mixture obtaining in this way boiling under refluxing is also converted into corresponding chloride of acid by acid (R-III) in this way.The amine of general formula (R-II) (1.1 equivalent) is dissolved in to methylene dichloride (acid of 1 mmol is in 6 mL) and mixes with triethylamine (3 equivalent) at 0 DEG C.Reaction mixture is at room temperature stirred to 20 h, and crude product is by column chromatography (SiO ₂, the normal hexane/EtOAc of different ratios, for example 2:1) and purifying obtain in this way (R).

1.4 method D:

Phenyl ester (R-IIIa) (1 equivalent) and corresponding amine (R-II) (1.1 equivalent) are dissolved in to THF (reaction mixture of 10 mmol is in 120 mL), and adding after DBU (1.5 equivalent), at room temperature stir 16 h.Under vacuum, except after desolventizing, the residue obtaining is by flash chromatography (SiO ₂, the EtOAc/ hexane of different ratios, for example 1:1) and purifying obtain in this way (R).

Use one of aforesaid method to obtain embodiment compound B-11-B10, B13, B15-B23, B26, B29-B30, B37, B42-B43, B47, B63-B68, B76, B82, B88, B93-B98 and B102-B104 and B106-B107.

2. the preparation of urea (A=N)

General formula (R-II) or amine (R-V) react to form formula (R-IV) or (R-Va) compound (scheme 1 with phenyl chloroformate, step j07 and scheme 2, step v1), formula (R-IV) compound reacts (scheme 1 with the amine of general formula (R-V) subsequently, step j08) or formula (R-Va) compound react (scheme 2 with the amine of general formula (R-II), step v2) to form the general remark of general formula (R) compound, wherein A=N:

Step j07/ step v1: general formula (R-II) or amine (R-V) (1 equivalent) are placed in to methylene dichloride (10 mmol amine are at 70 mL), at room temperature add wherein phenyl chloroformate (1.1 equivalent) and mixture is stirred to 30 min.Under vacuum, except after desolventizing, residue is by flash chromatography (SiO ₂, the ether/hexane of different ratios, for example 1:2) and purifying obtain in this way (R-IV) or (R-Va).

Step j08/ step v2: by the phenyl carbamate obtaining (R-IV) or (R-Va) (1 equivalent) and corresponding amine (R-V) or (R-II) (1.1 equivalent) be dissolved in THF (reaction mixture of 10 mmol is in 120 mL) and adding after DBU (1.5 equivalent), at room temperature stir 16 h.Under vacuum, except after desolventizing, the residue obtaining is by flash chromatography (SiO ₂, the EtOAc/ hexane of different ratios, for example 1:1) and purifying obtain in this way (R).

Use one of aforesaid method to obtain embodiment compound B-11 1-B12, B15, B24-B25, B27-B28, B31-B36, B38-B41, B44-B46, B48-B62, B69-B75, B77-B81, B83-B87, B89-B92 and B99-B101 and B105.

Synthesizing in detail of selected embodiment compound

Synthesizing of Embodiment B 5: N-[[2-(3-chloro-phenyl-)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl]-2-[4-(methanesulfonamido-methyl)-phenyl]-propionic acid amide

Step 1: at 0 DEG C, add methylsulfonyl chloride (0.4 mL, 5.106 mmol) in the pyridine solution of (4-bromophenyl) methylamine (500 mg, 2.687 mmol) stirring.Reaction mixture is stirred to 1 h, then dilute with methylene dichloride.Mixture washes with water.Dry (MgSO ₄) organic layer filtration.Under vacuum, remove desolventizing.Crude product is by CC purifying.Obtain N-(4-bromobenzyl) Toluidrin (675 mg) (95% productive rate).

Step 2: to N-(4-bromobenzyl) Toluidrin (675 mg that stir, 2.555 mmol) DMF solution in add 2-chloropropionate (0.42 mL), manganese (280 mg) and (2,2 '-dipyridyl) nickel (II)-dibromide (NiBr ₂bipy) (67 mg, 0.17885mmol).Add TFA (1-2 drips).Reaction mixture is stirred at 60 DEG C to 36 h.Be cooled to after room temperature, mixture is hydrolyzed and uses extracted with diethyl ether by 1N HCl.Dry (MgSO ₄) organic layer filtration.Under vacuum, remove desolventizing.Crude product is by CC purifying.Obtain 2-(4-(methanesulfonamido methyl) phenyl) ethyl propionate (325 mg).

Step 3: to 2-(4-(methanesulfonamido methyl) phenyl) ethyl propionate (325 mg that stir, 1.139 mmol) THF and the cosolvent solution of water (1:1) in add sodium hydroxide (114 mg, 2.8475 mmol).By reaction mixture refluxed 16 h, be then cooled to room temperature, be acidified to pH 3-4 with AcOH.Residue is dissolved in EtOAc water and salt water washing.Dry (MgSO ₄) organic layer filtration.Under vacuum, remove desolventizing.Crude product is by CC purifying.Obtain 2-(4-(methanesulfonamido methyl) phenyl) propionic acid (74 mg) with 25% productive rate.

Step 4: to 2-(4-(methanesulfonamido methyl) phenyl) propionic acid (37 mg that stir, 0.144 mmol) and (1-(3-chloro-phenyl-)-3-(trifluoromethyl)-1H-pyrazoles-5-yl) methylamine (44 mg, 0.158 mmol) acetonitrile solution in add EDC (41 mg, 0.216 mmol), HOBt (29 mg, 0.216 mmol) and triethylamine (0.05 mL, 0.36 mmol).Reaction mixture is at room temperature stirred to 15 h.Residue is dissolved in EtOAc water and salt water washing.Dry (MgSO ₄) organic layer filtration.Under vacuum, remove desolventizing.Crude product is by CC purifying.Obtain embodiment compd B 5 (62 mg) with 84% productive rate.

Synthesizing of Embodiment B 17: N-[[2-(3-chloro-phenyl-)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl]-2-[4-[[(ethylsulfonyl) amino]-methyl] the fluoro-phenyl of-3-]-propionic acid amide

Step 1: at 0 DEG C, bromo-4-2-flunamine (924 mg, 4.53 mmol) is dissolved in to pyrido ethanesulfonyl chloride (0.82 mL, 8.60 mmol) is joined in this solution.Mixture is stirred at 0 DEG C to 1 h.Then, also extract by ethyl acetate (EtOAc) with 1N HCl cancellation mixture.Dry (MgSO ₄), evaporation of acetic acid ethyl ester subsequently, residue, by CC (elutriant EtOAc/ normal hexane) purifying, obtains N-(the bromo-2-luorobenzyl of the 4-) ethyl sulfonamide (1.06 g, 79%) of pure form.

Step 2: in the DMF solution of N-(the bromo-2-luorobenzyl of 4-) ethyl sulfonamide (305 mg, 1.03 mmol), add manganese (113 mg, 2.06 mmol), NiBr ₂bipy (27 mg, 0.07 mmol), 2-chloropropionate (0.17 ml, 1.34 mmol), then add TFA (0.002 ml, 0.028 mmol).Mixture is stirred 1 day at 65 DEG C.Reaction mixture, by dense HCl (7-drips) cancellation, is then used extracted with diethyl ether, dry (MgSO ₄) and vaporising under vacuum solvent.Residue is by CC (EtOAc/ normal hexane) purifying.Obtain 2-(4-(ethyl sulfonamido the methyl)-3-fluorophenyl) ethyl propionate (65 mg, 20%) of pure form.

Step 3: in the DMF solution of 2-(4-(ethyl sulfonamido methyl)-3-fluorophenyl) ethyl propionate (305 mg, 1.03 mmol), add manganese (113 mg, 2.06 mmol), NiBr ₂bipy (27 mg, 0.07 mmol), 2-chloropropionate (0.17 mL, 1.34 mmol), then add TFA (0.002 mL, 0.028 mmol).Mixture is stirred 1 day at 65 DEG C.Reaction mixture, by dense HCl (7-drips) cancellation, is then used extracted with diethyl ether, dry (MgSO ₄) and vaporising under vacuum solvent.Residue is by CC (EtOAc/ normal hexane) purifying.Obtain 2-(4-(ethyl-sulfonamido methyl)-3-fluorophenyl) propionic acid (65 mg, 20%) of pure form.

Step 4: by 2-(4-(ethyl-sulfonamido methyl)-3-fluorophenyl) propionic acid (60 mg, 0.207 mmol) and (1-(3-chloro-phenyl-)-3-(trifluoromethyl)-1H-pyrazoles-5-yl) methylamine (63 mg, 0.228 mmol) dissolve and be blended in 1, in 4-diox, then add HOBt (42 mg, 0.310 mmol), EDC (60 mg, 0.313 mmol) and TEA (0.07 mL, 0.518 mmol).Reaction mixture is stirred and spent the night, then go out by shrend and extract with EtOAc.Dry (MgSO ₄), evaporation of acetic acid ethyl ester subsequently, residue, by CC (EtOAc/ normal hexane) purifying, obtains the Embodiment B 17 (104 mg, 92%) of pure form.

Synthesizing of Embodiment B 22: the chloro-4-of 2-[3-(methanesulfonamido-methyl)-phenyl]-N-[[2-(3-chloro-phenyl-)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl]-propionic acid amide

Step 1: add sulfuric acid (0.3 mL) in methyl alcohol (35 mL) solution of 1 (3 g, 16.078 mmol) that stir.By reaction mixture refluxed 15 h and be cooled to room temperature.Evaporating solvent.Residue is dissolved in EtOAc and uses NaHCO ₃saturated solution extraction.Dry (MgSO ₄) organic layer filtration.Under vacuum, remove desolventizing.Crude product is by CC purifying.(3.557 g) to obtain 2 with 99% productive rate.

Step 2: at 0 DEG C, in the dichloromethane solution of 2 (3.557 g, 17.73 mmol) that stir and TEA (2.5 mL, 17.73 mmol), drip trifluoromethanesulfanhydride anhydride (3 mL, 17.73 mmol).Reaction mixture is stirred to 2 h.Residue CH ₂cl ₂extraction water and salt water washing.Dry (MgSO ₄) organic layer filtration.Under vacuum, remove desolventizing.Crude product is by CC purifying.(5.15 g) to obtain 3 with 87% productive rate.

Step 3: add zinc cyanide (II) (1.6 g, 13.681 mmol) and Pd (PPh in the DMF solution of 3 (4.419 g, 13.283 mmol) that stir ₃) ₄(1.5 g, 1.3283 mmol).Reaction mixture is stirred 34 hours at 80 DEG C, be then cooled to room temperature and dilute with EtOAc.Use Celite pad filtering mixt.With EtOAc dilution filtrate and use NaHCO ₃saturated solution extraction.Dry (MgSO ₄) organic layer filtration.Under vacuum, remove desolventizing.Crude product is by column chromatography purifying.(1.044 g) to obtain 4 with 37% productive rate.

Step 4: at 0 DEG C, to add in the DMF solution of 4 (931 mg, 4.441 mmol) stirring sodium hydride (60 wt.-% in mineral oil, 178 mg, 4.441 mmol) and methyl iodide (0.3 ml, 4.441 mmol).Reaction mixture is stirred 1 hour at 0 DEG C to then dilute with water.Residue is dissolved in EtOAc water and salt water washing.Dry (MgSO ₄) organic layer filtration.Under vacuum, remove desolventizing.Crude product is by column chromatography purifying.Obtain 5 (642 mg) with 65% productive rate.

Step 5: add sodium hydroxide (287 mg, 7.175 mmol) in the THF of 5 (642 mg, 2.870 mmol) stirring and water (1:1) cosolvent solution.Reaction mixture is at room temperature stirred 15 hours, be then acidified to pH 3-4 with AcOH.Residue is dissolved in EtOAc water and salt water washing.Dry (MgSO ₄) organic layer filtration.Under vacuum, remove desolventizing.Crude product is by column chromatography purifying.Obtain 6 (665 mg) with 99% productive rate.

Step 6: to 6 (224 mg that stir, 1.069 mmol) and 7 (324 mg, 1.175 mmol) acetonitrile solution in add EDC (307 mg, 1.064 mmol), HOBt (217 mg, 1.064 mmol) and triethylamine (0.4 mL, 2.673 mmol).Reaction mixture is at room temperature stirred 15 hours.With EtOAc dilution mixture water and salt water washing.Dry (MgSO ₄) organic layer filtration.Under vacuum, remove desolventizing.Crude product is by column chromatography purifying.Obtain 8 (366 mg) with 78% productive rate.

Step 7: to being cooled in the methanol solution of 8 (366 mg, 1.460 mmol) of stirring of 0 DEG C, add Boc ₂o (342 mg, 1.566 mmol) and NiCl ₂6H ₂o (19 mg, 0.0783 mmol).Then be divided into aliquot and add NaBH ₄(207 mg, 5.481 mmol).Exothermic heat of reaction is also bubbled.The reaction mixture obtaining is risen to room temperature and stir 1 hour.Diethylenetriamine (DETA) (0.09 mL, 0.783 mmol) is added in mixture.Mixture is stirred 1 hour.Evaporating solvent.Residue is dissolved in EtOAc and uses NaHCO ₃saturated solution extraction.Dry (MgSO ₄) organic layer filtration.Under vacuum, remove desolventizing.Crude product is by column chromatography purifying.Obtain 9 (227 mg) with 50% productive rate.

Step 8: to being cooled in methylene dichloride (4 mL) solution of 9 (227 mg, 0.397 mmol) of stirring of 0 DEG C, add trifluoroacetic acid (2 mL).The reaction mixture obtaining stirred at 0 DEG C 1 hour and at room temperature stir 1 hour, then using NaHCO ₃the aqueous solution alkalizes to pH 8-9.Use Celite pad filtering mixt.Filtrate is dissolved in methylene dichloride and uses NaHCO ₃saturated solution extraction.Dry (MgSO ₄) organic layer filtration.Under vacuum, remove desolventizing.Crude product is by column chromatography purifying.Obtain 10 (116 mg) with 62% productive rate.

Step 9: add methylsulfonyl chloride (116 mg) to being cooled in the pyridine solution of 10 (116 mg, 0.246 mmol) of stirring of 0 DEG C.The reaction mixture obtaining is at room temperature stirred 15 hours.Mixture is dissolved in methylene dichloride and uses 1N HCl washing.Dry (MgSO ₄) organic layer filtration.Under vacuum, remove desolventizing.Crude product is by column chromatography purifying.Obtain 11 (108 mg) with 80% productive rate.

Synthesizing of Embodiment B 28: the 1-[[5-tertiary butyl-2-(3-chloro-phenyl-)-2H-pyrazole-3-yl]-methyl]-3-[4-(methanesulfonamido-methyl)-phenyl]-urea

Step 1: add triethylamine (0.3 ml, 2.147 mmol) in the dichloromethane solution of 1 (299 mg, 1.952 mmol) that stir.At 0 DEG C, drip methylsulfonyl chloride (0.18 ml, 2.343 mmol).Reaction mixture is heated to 80 DEG C and stir 4 hours, is then cooled to room temperature, and dilute with methylene dichloride.Mixture washes with water.Dry (MgSO ₄) organic layer filtration.Under vacuum, remove desolventizing.Crude product is by column chromatography purifying.Obtain 2 (333 mg) with 74% productive rate.

Step 2: add potassium phthalimide (293 mg, 1.584 mmol) in the DMF solution of 2 (333 mg, 1.440 mmol) that stir.Reaction mixture is stirred 16 hours.Mixture is dissolved in EtOAc, water and salt water washing.Dry (MgSO ₄) organic layer filtration.Under vacuum, remove desolventizing.Crude product is by column chromatography purifying.Obtaining 3 (535 mg), is crude product.

Step 3: add hydrazine monohydrate (246 mg, 3.089 mmol) and tosic acid monohydrate (15 mg, 0.0772 mmol) in the THF solution of 3 (218 mg, 0.772 mmol) that stir.Reaction mixture is stirred 4 hours at 80 DEG C, be then cooled to room temperature, and dilute with EtOAc.Mixture water and salt water washing.Dry (MgSO ₄) organic layer filtration.Under vacuum, remove desolventizing.Crude product is by column chromatography purifying.Obtain 4 (46 mg) with 39% productive rate.

Step 4: to being cooled in the pyridine solution of 4 (46 mg, 0.302 mmol) of stirring of 0 DEG C, add methylsulfonyl chloride (46 mg).The reaction mixture obtaining is at room temperature stirred 1 hour.Mixture is dissolved in methylene dichloride and uses 1N HCl washing.Dry (MgSO ₄) organic layer filtration.Under vacuum, remove desolventizing.Crude product is by column chromatography purifying.Obtain 5 (43 mg) with 62% productive rate.

Step 5: add 10% palladium carbon (5 mg) in the EtOAc solution of 5 (43 mg, 0.188 mmol) that stir.Mixture H ₂(gas) balloon inflation.The mixture obtaining is stirred 3 hours, then through diatomite filtration.Under vacuum, remove desolventizing.Crude product is by column chromatography purifying.Obtain 6 (41 mg) with 99% productive rate.

Step 6: add phenyl chloroformate (34 mg, 0.2142 mmol) and pyridine (0.02 mL, 0.2448 mmol) in the tetrahydrofuran (THF) of 6 (41 mg, 0.204 mmol) stirring and the solution of acetonitrile as cosolvent.Reaction mixture is at room temperature stirred 3 hours.With EtOAc dilution mixture water and salt water washing.Dry (MgSO ₄) organic layer filtration.Under vacuum, remove desolventizing.Crude product is by column chromatography purifying.Obtain 7 (54 mg) with 83% productive rate.

Step 7: add DMAP (11 mg, 0.087 mmol) in the acetonitrile solution of 7 (28 mg, 0.087 mmol) that stir and 8 (23 mg, 0.087 mmol).Reaction mixture is stirred 15 hours at 50 DEG C.With EtOAc dilution mixture water and salt water washing.Dry (MgSO ₄) organic layer filtration.Under vacuum, remove desolventizing.Crude product is by column chromatography purifying.Obtain 9 (embodiment compd B 28) (32 mg) with 75% productive rate.

Synthesizing of Embodiment B 29: N-[[2-(3-chloro-phenyl-)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl] the fluoro-4-[(methyl-methylsulfonyl-amino of-2-[3-)-methyl]-phenyl]-propionic acid amide

Step 1: (the bromo-2-fluorophenyl of the 4-) methylamine being commercially available is stirred and drip at 0 DEG C methylsulfonyl chloride (1.9 eq.) in pyridine.Reaction mixture is at room temperature stirred to 1 h.Reaction extracts with 1N HCl cancellation and with EtOAc.Organic layer is through MgSO ₄dry also evaporating solvent.Crude product is by column chromatography purifying and obtain 1.

Step 2: compound 1 is dissolved in to dry DMF and is full of N ₂.The 2-chloropropionate (1.3 eq.) that dropping is commercially available, adds manganese (2 eq.), NiBr subsequently ₂bipy (0.1 equiv.) and TFA (0.026 eq.).Reaction mixture refluxed is spent the night.Reaction mixture is risen to envrionment temperature.React and use extracted with diethyl ether organic layer with 1N HCl cancellation.The organic layer of extraction is through MgSO ₄dry, and be condensed into compound 2, it does not need to be further purified for next step.

Step 3: crude compound 2 is stirred at 0 DEG C in acetone, and add K ₂cO ₃(1.5 eq.).Drip methyl iodide (3 eq.) by reaction mixture refluxed.After 15 h, water cancellation reaction mixture also extracts with EtOAc.Organic layer is through MgSO ₄be dried and concentrate.Crude product is by column chromatography purifying and obtain required product 3.

Step 4: add NaOH (2.5 equiv.) and the mixture obtaining is at room temperature stirred in the THF of compound 3 and water (1:1) solution.After 15 hours, it is 2-3 that reaction mixture is acidified to pH with AcOH.With DCM and water extraction mixture.Organic layer washes with water, dry (MgSO ₄) and concentrated under vacuum.Product is by column chromatography purifying and obtain required product 4.

Step 5: add EDC (1.5 eq.), HOBt (1.5 eq.) and (1-(3-chloro-phenyl-)-3-(trifluoromethyl)-1H-pyrazoles-5-yl) methylamine (1 eq.) and drip TEA (2.5 eq.) in Isosorbide-5-Nitrae-dioxane solutions of carboxylic acid (4).Reaction mixture is at room temperature stirred and spent the night.Water is joined in reaction mixture and be extracted with ethyl acetate mixture.The organic layer of extraction is through MgSO ₄dry.Evaporating solvent, by column chromatography (EtOAc/ normal hexane) purifying, obtains embodiment compd B 29 subsequently.

Synthesizing of Embodiment B 31: the 1-[[5-tertiary butyl-2-(3-chloro-phenyl-)-2H-pyrazole-3-yl]-methyl] the fluoro-4-of-3-[3-(methanesulfonamido-methyl)-phenyl]-urea

Step 1: add Benzoyl Peroxide (497 mg, 1.2847 mmol) and N-bromosuccinimide (2.972 g, 16.701 mmol) in the carbon tetrachloride solution of 1 (1.993 g, 12.847 mmol) that stir.By reaction mixture refluxed 18 h, be then cooled to room temperature.Dilute mixture, then water and salt water washing with EtOAc.Dry (MgSO ₄) organic layer filtration.Under vacuum, remove desolventizing.Crude product is by column chromatography purifying.Obtain 2 (780 mg) with 26% productive rate.

Step 2: add potassium phthalimide (1.235 g, 6.666 mmol) in the DMF solution of 2 (780 mg, 3.333 mmol) that stir.Reaction mixture is stirred to 18 h.Mixture is dissolved in EtOAc, water and salt water washing.Dry (MgSO ₄) organic layer filtration.Under vacuum, remove desolventizing.Crude product is by column chromatography purifying.(1.034 g), is crude product to obtain 3.

Step 3: add hydrazine monohydrate (1.104 g, 13.776 mmol) and tosic acid monohydrate (66 mg, 0.3444 mmol) in the THF solution of 3 (1.034 g, 3.444 mmol) that stir.By reaction mixture refluxed 6 hours, be then cooled to room temperature, and dilute with EtOAc.Mixture water and salt water washing.Dry (MgSO ₄) organic layer filtration.Under vacuum, remove desolventizing.Crude product is by column chromatography purifying.Obtain 4 (329 mg) with 56% productive rate.

Step 4: to being cooled in the pyridine solution of 4 (131 mg, 0.770 mmol) of stirring of 0 DEG C, add methylsulfonyl chloride (131 mg).The reaction mixture obtaining is at room temperature stirred 1 hour.Diluting mixture with methylene dichloride also washs with 1N HCl.Dry (MgSO ₄) organic layer filtration.Under vacuum, remove desolventizing.Crude product is by column chromatography purifying.Obtain 5 (173 mg) with 91% productive rate.

Step 5: add 10% palladium carbon (20 mg) in the tetrahydrofuran (THF) of 5 (187 mg, 0.753 mmol) stirring and the solution of ethanol as cosolvent.Mixture H ₂(gas) balloon inflation.The mixture obtaining is stirred 15 hours, then use diatomite filtration.Under vacuum, remove desolventizing.Crude product is by column chromatography purifying.Obtain 6 (135 mg) with 82% productive rate.

Step 6: to 6 (135 mg that stir, 0.618 mmol) tetrahydrofuran (THF) and the solution of acetonitrile as cosolvent in add phenyl chloroformate (0.08 mL, 0.6489 mmol) and pyridine (0.06 mL, 0.7416 mmol).Reaction mixture is at room temperature stirred 1 hour.With EtOAc dilution mixture water and salt water washing.Dry (MgSO ₄) organic layer filtration.Under vacuum, remove desolventizing.Crude product is by column chromatography purifying.Obtain 7 (140 mg) with 67% productive rate.

Step 7: add DMAP (17 mg, 0.136 mmol) in the acetonitrile solution of 7 (46 mg, 0.136 mmol) that stir and 8 (36 mg, 0.136 mmol).Reaction mixture is stirred 15 hours at 50 DEG C.With EtOAc dilution mixture water and salt water washing.Dry (MgSO ₄) organic layer filtration.Under vacuum, remove desolventizing.Crude product is by column chromatography purifying.Obtain 9 (72 mg) with 99% productive rate.

Synthesizing of Embodiment B 35: 1-[[2-(3-chloro-phenyl-)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl]-3-[4-[(sulfamyl amino)-methyl]-phenyl]-urea

Step 1: NBS (1.51 g, 8.509 mmol) is joined in the carbon tetrachloride solution of 4-nitro-toluene 1 (1.2 g, 7.735 mmol).70% Benzoyl Peroxide (120 mg) is at room temperature joined in mixture.Mixture is refluxed.After 24 h, with ethyl acetate (EtOAc) extraction mixture.Dry (MgSO ₄), evaporation of acetic acid ethyl ester subsequently, residue, by column chromatography (EtOAc/ normal hexane) purifying, obtains the compound 2 of pure form with 61% productive rate.

Step 2: in the DMF solution of compound 2 (1.1 g, 4.69 mmol), add potassium phthalimide (1.9 g, 10.314 mmol).Mixture is stirred and spent the night, then with EtOAc extraction, and by salt water washing.Dry (MgSO ₄), evaporation of acetic acid ethyl ester subsequently, residue, by column chromatography (EtOAc/ normal hexane) purifying, obtains the compound 3 of pure form with 99% productive rate.

Step 3: in the THF solution of compound 3 (1.6 g, 5.33 mmol), add hydrazine monohydrate (4 eq).Mixture is refluxed 6 hours and is cooled to RT.Mixture with saleratus process to pH be 12 ~ 13.With EtOAc extraction mixture and by salt water washing.Dry (MgSO ₄), evaporation of acetic acid ethyl ester subsequently, residue, by column chromatography (EtOAc/ normal hexane) purifying, obtains the compound 4 (592 mg) of pure form with 65% productive rate.

Step 4: Sulfuryl chloride isocyanate (0.063 mL) and t-BuOH (0.07 mL) are mixed in DCM.After 10 minutes, at 50 DEG C, add the DCM solution of compound 4 (100 mg, 0.657 mmol).Stir after 30 min, mixture is cooled to room temperature, then add TEA (0.11 mL) and mixture is stirred 3 hours, then with EtOAc extraction, and by salt water washing.Dry (MgSO ₄), evaporation of acetic acid ethyl ester subsequently, residue, by column chromatography (EtOAc/ normal hexane) purifying, obtains the compound 5 (112 mg) of pure form with 51% productive rate.

Step 5: 10% palladium carbon (7 mg) is added in the ethanol of compound 5 (65 mg) and THF solution and mixture is full of to H ₂(g).Reaction mixture is stirred after 6 h, use diatomite filtration mixture vaporising under vacuum solvent, obtain the compound 6 (98 mg) of pure form with 58% productive rate.

Step 6: compound 6 (86 mg, 0.285 mmol) is dissolved in to THF/ acetonitrile.Add pyridine (0.03 mL, 0.342 mmol), then at 0 DEG C, add phenyl chloroformate (0.04 ml, 0.300 mmol).Mixture stirred at 0 DEG C to 30 min and be heated to room temperature, then stirring 30 min.Afterwards, it extracted with EtOAc and pass through salt water washing.Dry (MgSO ₄), evaporation of acetic acid ethyl ester subsequently, residue, by column chromatography (EtOAc/ normal hexane) purifying, obtains the compound 7 (59 mg) of pure form with 49% productive rate.

Step 7: compound 7 (58 mg, 0.138 mmol) is dissolved in to MeCN.Compound 8 (38 mg, 0.138 mmol) and DMAP (16 mg) are joined in solution.Reaction mixture is stirred and spent the night at 50 DEG C.With EtOAc extraction mixture and by salt water washing.Dry (MgSO ₄), evaporation of acetic acid ethyl ester subsequently, residue, by column chromatography (EtOAc/ normal hexane) purifying, obtains the compound 9 (60 mg) of pure form with 50% productive rate.

Step 8: at 0 DEG C, in DCM (6 mL) solution of compound 9 (80 mg, 0.133 mmol), add TFA (2 mL).Mixture is stirred to 30 min and at room temperature stirs 2 hours again.It is 7-8 that mixture is neutralized to pH with sodium bicarbonate, then extracts with EtOAc and passes through salt water washing.Dry (MgSO ₄), evaporation of acetic acid ethyl ester subsequently, residue, by column chromatography (EtOAc/ normal hexane) purifying, obtains the compound 10 (50 mg) of pure form with 75% productive rate.

Synthesizing of Embodiment B 40: the fluoro-phenyl of 1-[4-(amino methyl)-3-]-3-[[5-the tertiary butyl-2-(3-chloro-phenyl-)-2H-pyrazole-3-yl]-methyl]-urea

Step 1-3 is as the synthetic described execution of embodiment B31.

Step 4: compound 4 (100 mg, 0.588 mmol) is dissolved in to DCM.At 0 DEG C, by Boc ₂o (154 mg, 0.705 mmol) joins in solution.Stir after 30 min, mixture is heated to room temperature, then add TEA (0.13 ml) and mixture is stirred and spent the night.Then it extracted with EtOAc and pass through salt water washing.Dry (MgSO ₄), evaporation of acetic acid ethyl ester subsequently, residue, by column chromatography (EtOAc/ normal hexane) purifying, obtains the compound 5 (136 mg) of pure form with 86% productive rate.

Step 5: 10% palladium carbon (20 mg) is joined in the ethanol of compound 5 (136 mg) and THF solution and mixture is full of to H ₂(g).Reaction mixture is stirred after 6 h, use diatomite filtration mixture vaporising under vacuum solvent.Obtain compound 6 (103 mg) with 85%.

Step 6: compound 6 (103 mg, 0.429 mmol) is dissolved in to THF/MeCN.Add pyridine (0.04 mL, 0.515 mmol), then at 0 DEG C, add phenyl chloroformate (0.06 mL, 0.450 mmol).Mixture stirred at 0 DEG C to 30 min and be heated to room temperature, and then stirring 30 min.Afterwards, it extracted with EtOAc and pass through salt water washing.Dry (MgSO ₄), evaporation of acetic acid ethyl ester subsequently, residue, by column chromatography (EtOAc/ normal hexane) purifying, obtains the compound 7 (116 mg) of pure form with 75% productive rate.

Step 7: compound 7 (70 mg, 0.194 mmol) is dissolved in to MeCN.Compound 8 (52 mg, 0.137 mmol) and DMAP (24 mg) are joined in solution.Reaction mixture is stirred and spent the night at 50 DEG C.With EtOAc extraction mixture and by salt water washing.Dry (MgSO ₄), evaporation of acetic acid ethyl ester subsequently, residue, by column chromatography (EtOAc/ normal hexane) purifying, obtains the compound 9 (100 mg) of pure form with 97% productive rate.

Step 8: at 0 DEG C, in DCM (6 mL) solution of compound 9 (100 mg, 0.189 mmol), add TFA (2 mL), mixture is stirred to 30 min and at room temperature stirs 2 h again.It is 7-8 that mixture is neutralized to pH with sodium bicarbonate, then extracts with EtOAc and passes through salt water washing.Dry (MgSO ₄), evaporation of acetic acid ethyl ester subsequently, residue, by column chromatography (EtOAc/ normal hexane) purifying, obtains the compound 10 (60 mg) of pure form with 74% productive rate.

Synthesizing of Embodiment B 46: the 1-[[5-tertiary butyl-2-(3-chloro-phenyl-)-2H-pyrazole-3-yl]-methyl] the fluoro-4-[(sulfamyl of-3-[3-amino)-methyl]-phenyl]-urea

Step 1-3 is as the synthetic described execution of embodiment B31.

Step 4: Sulfuryl chloride isocyanate (0.1 mL) and t-BuOH (0.12 mL) are mixed in DCM.After 10 minutes, at 50 DEG C, add the DCM solution of compound 4 (200 mg, 1.176 mmol).Stir after 30 min, mixture is cooled to room temperature, then add TEA (0.11 mL) and mixture is stirred 3 hours, then extract with EtOAc and pass through salt water washing.Dry (MgSO ₄), evaporation of acetic acid ethyl ester subsequently, residue, by column chromatography (EtOAc/ normal hexane) purifying, obtains the compound 5 (139 mg) of pure form with 23% productive rate.

Step 5: 10% palladium carbon (42 mg) is joined in the ethanol of compound 5 (135 mg) and THF solution and mixture is full of to H ₂(g).Reaction mixture is stirred after 6 h, use diatomite filtration mixture vaporising under vacuum solvent, obtain the compound 6 (127 mg) of pure form with 99% productive rate.

Step 6: compound 6 (127 mg, 0.398 mmol) is dissolved in to THF/ acetonitrile.At 0 DEG C, add pyridine (0.04 ml, 0.478 mmol) and then add phenyl chloroformate (0.05 mL, 0.418 mmol).Mixture stirred at 0 DEG C to 30 min and be heated to room temperature, then stirring 30 min.Afterwards, it extracted with EtOAc and pass through salt water washing.Dry (MgSO ₄), evaporation of acetic acid ethyl ester subsequently, residue, by column chromatography (EtOAc/ normal hexane) purifying, obtains the compound 7 (160 mg) of pure form with 91% productive rate.

Step 7: compound 7 (50 mg, 0.114 mmol) is dissolved in to MeCN.Compound 8 (30 mg, 0.114 mmol) and DMAP (14 mg) are joined in solution.Reaction mixture is stirred and spent the night at 50 DEG C.With EtOAc extraction mixture and by salt water washing.Dry (MgSO ₄), evaporation of acetic acid ethyl ester subsequently, residue, by column chromatography (EtOAc/ normal hexane) purifying, obtains the compound 9 (45 mg) of pure form with 65% productive rate.

Step 8: at 0 DEG C, in DCM (6 mL) solution of compound 9 (45 mg, 0.074 mmol), add TFA (2 mL).Mixture is stirred to 30 min and at room temperature stirs 2 h again.It is 7-8 that mixture is neutralized to pH with sodium bicarbonate, then with EtOAc extraction, and by salt water washing.Dry (MgSO ₄), evaporation of acetic acid ethyl ester subsequently, residue, by column chromatography (EtOAc/ normal hexane) purifying, obtains the compound 10 (28 mg) of pure form with 74% productive rate.

Synthesizing of Embodiment B 63: the N-[[5-tertiary butyl-2-(3-chloro-phenyl-)-2H-pyrazole-3-yl]-methyl] the fluoro-4-of-2-[3-(methylamino-methyl)-phenyl]-propionic acid amide

Step 1: add sulfuric acid (0.3 mL) in the methanol solution of 2-(the fluoro-4-nitro-phenyl of the 3-)-propionic acid stirring.By reaction mixture refluxed 15 h and be cooled to room temperature.Evaporating solvent.Residue is dissolved in EtOAc and uses NaHCO ₃saturated solution extraction.Dry (MgSO ₄) organic layer filtration.Under vacuum, remove desolventizing.Crude product is by CC purifying.Obtain 1.

Step 2: 10% palladium carbon is joined in the ethanol of ethyl ester (1) and THF solution and mixture is full of to H ₂(g).Reaction mixture is stirred after 6 h, use diatomite filtration mixture and by column chromatography purifying, obtain 2.

Step 3: by p-TsOH.H ₂the CH of O (3 equiv.) ₃cN solution joins the CH of 2 (1 eq.) ₃in CN solution.The suspension obtaining is cooled to 15 DEG C of 10 – and progressively adds wherein NaNO ₂the H of (2 eq.) and KI (2.5 eq.) ₂o solution.Reaction mixture is stirred to 10 min, then rise again to 20 DEG C and stir until starting raw material exhausts.After 4 hours, add water, NaHCO ₃(until pH=9-10) is also extracted with ethyl acetate.Organic layer washes with water, dry (MgSO ₄) and concentrated under vacuum.Residue, by CC purifying, obtains 3.

Step 4: by compound 3, Pd ₂(dba) ₃, dppf, Zn powder, Zn (CN) ₂be placed in and be full of N ₂round-bottomed flask in and drip DMA (0.02 equiv.) by syringe.Reaction mixture stirred 15 hours at 120 DEG C and be cooled to room temperature, extracting and use subsequently 2N NH with EtOAc ₄oH solution washing.Organic layer washes with water, dry (Na ₂sO ₄) and concentrated under vacuum.Residue, by CC purifying, obtains required product 4.

Step 5: add NaOH (2.5 equiv.) and mixture is at room temperature stirred in the THF of compound 4 and water (1:1) solution.After 15 hours, reaction mixture passes through AcOH acidifying until pH=2-3.With DCM and water extraction mixture.Organic layer washes with water, dry (MgSO ₄) and concentrated under vacuum.Product is by CC (elutriant DCM:MeOH 10:1) purifying and obtain required product 5.

Step 6: EDC (1.5 equiv), HOBt (1.5 equiv) and (the 3-tertiary butyl-1-(3-chloro-phenyl-)-1H-pyrazoles-5-yl) methylamine (1 eq.) are joined in the solution of (5), then drip TEA (2.5 mL).Reaction mixture is at room temperature stirred and spent the night.Water cancellation is reacted and is extracted with ethyl acetate.The organic layer of extraction passes through MgSO ₄dry.After solvent evaporation, residue is by column chromatography (elutriant EtOAc: normal hexane) purifying and obtain 6.

Step 7: nickelous chloride (II) hexahydrate (1 eq.) and compound 6 are stirred to 15 minutes with activation in dehydrated alcohol.Add sodium borohydride (7 eq.) and mixture is stirred to 2 h.Diatomite is joined in reaction, use diatomaceous strainer filtration is housed, and use washing with alcohol.After residue is concentrated, purifying, obtains 7.

Step 8: sodium methylate (1M is in methyl alcohol) is joined in the methanol solution of compound 7, add subsequently paraformaldehyde (5 eq.).By reaction mixture refluxed 1.5 h, be then cooled to 0 DEG C with ice bath.Add modestly sodium borohydride (6 equiv.).By reflux again 1 h cooling of mixture.With DCM extraction mixture and wash with water.After evaporating solvent, mixture, by column chromatography (DCM:MeOH=4:1) purifying, obtains embodiment compound B-26 3.

Synthesizing of Embodiment B 64: the N-[[5-tertiary butyl-2-(3-chloro-phenyl-)-2H-pyrazole-3-yl]-methyl] the fluoro-phenyl of-2-[4-(dimethylaminomethyl)-3-]-propionic acid amide

Step 1-7 is as the synthetic described execution of embodiment B63.

Step 8: sodium cyanoborohydride is joined in the acetic acid solution of compound 7 and paraformaldehyde.Reaction mixture is at room temperature stirred 15 hours and fallen on ice.With sodium bicarbonate adjusting pH to 9.With EtOAc extraction mixture and through dried over sodium sulfate.After evaporating solvent, mixture, by column chromatography purifying, obtains required product embodiment compound B-26 4.

Synthesizing of Embodiment B 86: 1-[4-(methanesulfonamido-methyl)-3-methoxyl group-phenyl]-3-[[2-(tolyl)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl]-urea

Step 1: at room temperature, to 1 (300 mg that stir, 1.683 mmol) THF solution in add borine dimethyl sulphide ether complexes (borane methyl sulfide complex) (2M is in THF) (1.4 mL, 2.83 mmol).Reaction mixture is stirred at 66 DEG C to 16 h, be then cooled to room temperature.With EtOAc dilution residue water and salt water washing.Dry (MgSO ₄) organic layer filtration.Under vacuum, remove desolventizing.Crude product is by column chromatography purifying.Obtain 2 (270 mg) with 68% productive rate.

Step 2: at 0 DEG C, add methylsulfonyl chloride in the pyridine solution of 2 (190 mg, 1.04 mmol) that stir.Reaction mixture is at room temperature stirred to 1 h.Mixture is by 1N HCl cancellation.With DCM dilution residue water and salt water washing.Dry (MgSO ₄) organic layer filtration.Under vacuum, remove desolventizing.Crude product is by column chromatography purifying.Obtain 3 (205 mg) with 76% productive rate.

Step 3: add 10% palladium carbon (21 mg) in the tetrahydrofuran (THF) of 3 (205 mg, 0.79 mmol) stirring and the solution of ethanol as cosolvent.Mixture H ₂(gas) balloon inflation.The mixture obtaining is stirred to 16 h, then use diatomite filtration.Under vacuum, remove filtrate.Under vacuum, remove filtrate.Crude product is by column chromatography purifying.Obtain 4 (190 mg) with 99% productive rate.

Step 4: to THF (6 mL) and the CH of 4 (190 mg, 0.83 mmol) that stir ₃in the solution of CN (8 mL) as cosolvent, add phenyl chloroformate (0.11 mL, 0.866 mmol) and pyridine (0.08 mL, 0.99 mmol).Reaction mixture is at room temperature stirred to 3 h.Residue is dissolved in EtOAc water and salt water washing.Dry (MgSO ₄) organic layer filtration.Under vacuum, remove desolventizing.Crude product is by column chromatography purifying.Obtain 5 (238 mg) with 82% productive rate.

Step 5: add DMAP (28 mg, 0.225 mmol) in the MeCN solution and 6 (57 mg, 0.225 mmol) of 5 (79 mg, 0.225 mmol) that stir.Reaction mixture is stirred 16 hours at 50 DEG C.Residue is dissolved in EtOAc water and salt water washing.Dry (MgSO ₄) organic layer filtration.Under vacuum, remove desolventizing.Crude product is by column chromatography purifying.Obtain 7 (104 mg) with 90% productive rate.

Synthesizing of Embodiment B 95: N-[[2-(3-chloro-phenyl-)-5-cyclopropyl-2H-pyrazole-3-yl]-methyl] the fluoro-4-[(sulfamyl of-2-[3-amino)-methyl]-phenyl]-propionic acid amide

Step 1-5 is as the synthetic described execution of embodiment B63.

Step 6: EDC (1.5 equiv), HOBt (1.5 equiv) and (1-(3-chloro-phenyl-)-3-cyclopropyl-1H-pyrazoles-5-yl) methylamine (1 eq.) are joined in the solution of (5), then drip TEA (2.5 mL).Reaction mixture is at room temperature stirred and spent the night.Water cancellation is reacted and is extracted with ethyl acetate.The organic layer of extraction is through MgSO ₄dry.After solvent evaporation, residue is by column chromatography (elutriant EtOAc/ normal hexane) purifying and obtain 6.

Step 7: nickelous chloride (II) hexahydrate (1 eq.) and compound 6 are stirred to 15 minutes with activation in dehydrated alcohol.Add sodium borohydride (7 eq.) and mixture is stirred 2 hours.Diatomite is joined in reaction, use diatomaceous strainer filtration is housed, and use washing with alcohol.After residue is concentrated, purifying, obtains 7.

Step 8: compound 7 and compound 8 are dissolved in to DCM.Drip TEA (0.1 eq.).Reaction mixture is at room temperature stirred to 15 h water cancellation.With DCM extraction organic layer concentrated.After CC purifying, obtain compound 9.

Step 9: TFA (12 mL) is joined in the solution of DCM solution of compound 9 and reaction mixture is at room temperature stirred to 4 h.Water is joined to the mixture of also using DCM extracting and separating in mixture.After residue is concentrated, by CC purifying and obtain compound 10 (Embodiment B 95).

Step 10: 1 eq. CSI (Sulfuryl chloride isocyanate) is dropped in the cold soln of anhydrous DCM of the trimethyl carbinol (1 eq.).Then add DMAP (2 eq.).Mixture is at room temperature stirred to 3 h.With DCM extraction organic layer and wash with water.After column chromatography, obtain colourless powder (compound 8).

Synthesizing of Embodiment B 97: N-[[2-(3-chloro-phenyl-)-5-(trifluoromethyl)-2H-pyrazole-3-yl]-methyl] the fluoro-4-[(sulfamyl of-2-[3-amino)-methyl]-phenyl]-propionic acid amide

Step 1-5 is as the synthetic described execution of embodiment B95.

Step 6: EDC (1.5 equiv), HOBt (1.5 equiv) and (1-(3-chloro-phenyl-)-3-(trifluoromethyl)-1H-pyrazoles-5-yl) methylamine (1 eq.) are joined in the solution of (5), then drip TEA (2.5 mL).Reaction mixture is at room temperature stirred and spent the night.Water cancellation is reacted and is extracted with ethyl acetate.The organic layer of extraction is through MgSO ₄dry.After solvent evaporation, residue is by column chromatography (elutriant EtOAc/ normal hexane) purifying and obtain 6.

Step 7-10 is as the synthetic described execution of embodiment B95.

The NMR feature of Embodiment B 97 (compound 10):

The mass-spectrometric data of the following example compound is incorporated in below (table 1) in the mode of example:

Table 1

Pharmacological method

I. the function test of vanilloid receptor 1 (VRI/TRPV1 acceptor) being carried out

Use following test, can measure excitement or the antagonistic effect of the vanilloid receptor 1 (VR1/TRPV1) of checked material to rat species.In this test, read in plate instrument (FLIPR, Molecular Devices, Sunnyvale, USA), by means of Ca at fluorescence imaging ²⁺-sensitive dye (Fluo-4 type, Molecular Probes Europe BV, Leiden, the Netherlands) is quantitatively by the Ca of receptor channel ²⁺flow.

Method:

Perfect medium: 50 mL HAMS F12 nutrient substance mixture (Gibco Invitrogen GmbH, Karlsruhe, Germany), it contains 10% (by volume) FCS (foetal calf serum, Gibco Invitrogen GmbH, Karlsruhe, Germany, heated and inactivated); 2mM L-glutaminate (Sigma, Munich, Germany); 1% (calculating by weight) AA solution (microbiotic/antifungal solution, PAA, Pasching, Austria) and 25 ng/mL NGF substratum (2.5 S, Gibco Invitrogen GmbH, Karlsruhe, Germany).

Tissue Culture Plate: will be coated with black 96 orifice plates (the 96 hole black/transparent panels of stain with the poly-D-Lys of clear bottom, BD Biosciences, Heidelberg, Germany) other coat Fibronectin (Gibco Invitrogen GmbH, Karlsruhe, Germany), PBS for ln (is not contained to the PBS of Ca-Mg, Gibco Invitrogen GmbH, Karlsruhe, Germany) be diluted to the concentration of 100 μ g/mL.Taking-up contains the aliquot sample that concentration is the ln of 100 μ g/mL, and-20 DEG C of preservations.By this aliquot sample with the ratio of 1:10 with PBS by ln concentration dilution to 10 μ g/mL, and respectively 50 these solution of μ L are transferred in the recess of Tissue Culture Plate.By Tissue Culture Plate, 37 DEG C of cultivations at least two hours, suction filtration took out excessive solution, and by each recess PBS washed twice.Preserve together with the excessive PBS not taking out being coated with the Tissue Culture Plate of stain, until just before adding cell.

Prepare cell:

From cut the rat of head, take out backbone, and be put into immediately (Hank's buffered saline solution in cold HBSS damping fluid, Gibco Invitrogen GmbH, Karlsruhe, Germany), be placed on the damping fluid in ice bath, with 1% (by volume, volume percent) AA solution (microbiotic/antifungal solution, PAA, Pasching, Austria) mix.Backbone is longitudinally cut, and take out with together with manadesma in canalis spinalis.Subsequently, take out spinal ganglion (DRG), and be again kept in the cold HBSS damping fluid mixing with 1% (by volume) AA solution.In each case, DRG (from wherein having taken out all residual blood and spinal nerves) is transferred in the II Collagenase Type (PAA, Pasching, Austria) that 500 μ L are cold, and cultivates 35 minutes at 37 DEG C.Add 2.5% (by volume) trypsin PAA, Pasching, Austria) afterwards, continue to cultivate 10 minutes at 37 DEG C.After cultivation completes, sucking-off enzyme solution carefully, and 500 μ L perfect mediums are joined in each remaining DRG.By the DRG several times that suspend respectively, use syringe, extract by sleeve pipe No. 1, No. 12 and No. 16, and be transferred in 50 mL Falcon test tubes, in test tube, be filled to many 15 mL perfect mediums.The inclusion of each Falcon test tube is filtered by 70 μ m Falcon filtering elements respectively, and under 1,200 rpm and room temperature centrifugal 10 minutes.The granule obtaining is dissolved in respectively in 250 μ L perfect mediums, and measures cell count.

Cell number in suspension is set in to every milliliter of 3 x 10 ⁵individual, in each case, 150 these suspension of μ L are joined in the recess of Tissue Culture Plate of painting stain as described above.In incubator, at 5% (by volume) CO ₂under 95% relative humidity, plate is placed two to three days at 37 DEG C.Subsequently, at 37 DEG C, be used in HBSS damping fluid (Hank's buffered saline solution, Gibco Invitrogen GmbH, Karlsruhe, Germany) 2 μ M Fluo-4 in and 0.01% (by volume) Pluronic F127 (Molecular Probes Europe BV, Leiden, the Netherlands) load cell 30 minutes, with HBSS damping fluid washing 3 times, after at room temperature further cultivating 15 minutes, in FLIPR test for measuring Ca ²⁺.In this case, in the front and back that add material, measure Ca ²⁺dependency fluorescence (λ ex=488 nm, λ em=540 nm).Undertaken quantitatively by measuring the high fluorescent (FC, fluorescence counting) of passing in time.

FLIPR test:

FLIPR scheme comprises and adds two kinds of materials.First, the compound (10 μ M) that will check is drawn on cell, and by Ca ²⁺flow (Ca ²⁺influx) compare with contrast (capsaicine 10 μ M).Add 10 μ M capsaicines (CP) afterwards, provide based on Ca ²⁺signal activate with % the result representing.After cultivating 5 minutes, use 100 nM capsaicines, and measure Ca ²⁺flow.

The agonist of desensibilization and antagonist cause suppressing Ca ²⁺flow.The inhibition that maximum possible is reached is compared with 10 μ M capsicums flat (capsazepine), calculates % and suppresses.

Carry out three analyses (n=3), and at least in 3 independent experiments (N=4), repeat.

Initial from the caused replacement percentage of compound to be tested of the general formula I of different concns, calculate the IC that causes 50% capsaicine displacement ₅₀inhibition concentration.Utilize Cheng-Prusoff equation (Cheng, Prusoff; Biochem. Pharmacol. 22,3099-3108,1973) transform, obtain the K of substances _ivalue.

II. the function test of vanilloid receptor 1 (VRI/TRPV1 acceptor) being carried out

Use following test, can also measure excitement or the antagonistic effect of checked material to vanilloid receptor 1 (VR1).In this test, read in plate instrument (FLIPR, Molecular Devices, Sunnyvale, USA), by means of Ca at fluorescence imaging ²⁺-sensitive dye (Fluo-4 type, Molecular Probes Europe BV, Leiden, the Netherlands) is quantitatively by the Ca of passage ²⁺flow.

Method:

VR1 stable gene ground transfection for Chinese hamster ovary cell (CHO K1 cell, European cell cultures preservation center (European Collection of Cell Cultures, ECACC), United Kingdom).For function test, these cells are placed in the density of 25,000 cells/well on 96 orifice plates of the black with clear bottom (BD Biosciences, Heidelberg, Germany) of poly--D-Lys coating.By cell at 37 DEG C and 5% CO ₂under in substratum (HAM ' S F12 nutrient substance mixture, 10% FCS (foetal calf serum) by volume, 18 μ g/mL L-PROLINEs) overnight incubation.Next day, by cell at 37 DEG C with Fluo-4 (Fluo-4 2 μ M, 0.01% Pluronic F127 by volume, Molecular Probes, in HBSS (Hank ' s buffer salt solution), Gibco Invitrogen GmbH, Karlsruhe, Germany) cultivate 30 minutes.Subsequently, by plate washing three times, under RT, further cultivate afterwards 15 minutes for Ca in FLIPR test with HBSS damping fluid ²⁺measurement.Before material to be tested adds and measure afterwards Ca ²⁺dependency fluorescence (λ ex wavelength=488 nm, λ em=540 nm).Quantitatively undertaken by measuring time dependent hyperfluorescenceZeng Yongminggaoyingguang intensity (FC, fluorescence counting).

FLIPR test:

FLIPR scheme comprises and adds two kinds of materials.First, the compound (10 μ M) that will check is drawn on cell, and by Ca ²⁺flow (Ca ²⁺influx) compare (after adding 10 μ M capsaicines, based on Ca with contrast (capsaicine 10 μ M) ²⁺the % activation of signal).After cultivating 5 minutes, use 100 nM capsaicines, and measure Ca ²⁺flow.

Pharmacology data:

The compounds of this invention is to the affinity of vanilloid receptor 1 (VR1/TRPV1 acceptor) (pharmacological method I or II) mensuration as described above.

The compounds of this invention demonstrates extremely strong affinity (table 2) to VR1/TRPV1 acceptor.

Following abbreviation in table 2 has following meaning:

Cap=capsaicine

AG=agonist

Value representation after "@" symbol has been measured respectively the concentration of inhibition (representing with per-cent).

Table 2

Claims

1. the substitution compound of general formula (R),

Figure 2012800551959100001DEST_PATH_IMAGE002

Wherein

A represents N, CH or C (CH ₃),

Q represents 0,1 or 2,

Or-condition be q ≠ 0-

2. according to the compound of claim 1, it is characterized in that

R ²represent CF ₃, the tertiary butyl or cyclopropyl.

3. according to the compound of claim 1 or 2, it is characterized in that

4. according to the compound of any one in aforementioned claim, it is characterized in that

A represents N,

Or-condition is q ≠ 0 –

Or

A represents CH or C (CH ₃),

R ¹¹³represent H, S (=O) ₂-NH ₂, C _1-4alkyl, it is unsubstituted or is selected from F, Cl, Br, OH ,=O and OCH by 1,2 or 3 ₃substituting group monosubstituted, two replace or three replace,

Or-condition is q ≠ 0 –

R ¹¹²and R ¹¹³form 3 to 6 yuan of heterocyclic radicals together with the nitrogen-atoms connecting, it is unsubstituted or is independently from each other F, Cl, Br, CN, CF by 1,2 or 3 ₃, CH ₃, CH ₂cH ₃, CH (CH ₃) ₂, the tertiary butyl, cyclopropyl, OH ,=O, OCH ₃, OCF ₃, NH ₂, NH (CH ₃) and N (CH ₃) ₂substituting group monosubstituted, two replace or three replace.

5. according to the compound of any one in aforementioned claim, it is characterized in that

Q represents 0,1 or 2,

A represents N,

Or

Q represents 1 or 2,

A represents CH or C (CH ₃),

R ¹⁰²and R ¹⁰³be independently from each other H, F, Cl, Br, CFH ₂, CF ₂h, CF ₃, CN, CH ₂-OH, CH ₂-OCH ₃, OCF ₃, OH, CH ₃, CH ₂cH ₃, CH (CH ₃) ₂, O-CH ₃, O-CH ₂cH ₃, NH ₂, NH (CH ₃) and N (CH ₃) ₂.

6. according to the compound of any one in aforementioned claim, it is characterized in that

R ¹⁰¹, R ¹⁰²and R ¹⁰³in at least one ≠ H.

7. according to the compound of any one in aforementioned claim, it is characterized in that

8. according to the compound of any one in aforementioned claim, it is characterized in that

R ⁷and R ⁹in at least one ≠ H.

9. according to the compound of any one in claim 1-3 and 5-8, it is characterized in that part-structure (RS1)

Figure 2012800551959100001DEST_PATH_IMAGE004

Represent part-structure (PR1)

Figure 2012800551959100001DEST_PATH_IMAGE006

Wherein

R ¹¹⁴represent NH ₂or unsubstituted C _1-4alkyl.

10. according to the compound of any one in claim 1-3 and 5-9, it is characterized in that part-structure (RS1)

Figure 2012800551959100001DEST_PATH_IMAGE008

Represent part-structure (PR1)

Figure 2012800551959100001DEST_PATH_IMAGE010

Wherein

R ¹¹⁴represent NH ₂, CH ₃or CH ₂cH ₃.

11. according to the compound of any one in aforementioned claim, it is characterized in that

A represents N or C (CH ₃).

12. according to the compound of any one in claim 1-5,7,9 and 10, it is characterized in that

A represent N and

Or

A represents CH or C (CH ₃) and

R ²represent CF ₃, the tertiary butyl or cyclopropyl,

Part-structure (RS1)

Represent part-structure (PR1)

Figure 2012800551959100001DEST_PATH_IMAGE014

Wherein

R ¹¹⁴represent NH ₂, CH ₃or CH ₂cH ₃.

13. according to the compound of any one in aforementioned claim, and it is selected from

14. pharmaceutical compositions, it comprises at least one according to the substitution compound of any one in claim 1 to 13.

15. according to the substitution compound of any one in claim 1 to 13, be used for the treatment of and/or prevent one or more to be selected from following disease and/or illness: pain, preferably, pain is selected from acute pain, chronic pain, neuropathic pain, visceral pain and arthralgia; Hyperpathia; Touch pain; Cusalgia; Migraine; Dysthymia disorders; Neuropathy; Axonal injury; Neurodegenerative disease, is preferably selected from multiple sclerosis, alzheimer's disease, Parkinson's disease and Heng Tingdunshi chorea; Cognition dysfunction, preferred cognitive miss status, particularly preferably disturbance of memory; Epilepsy; Respiratory system disease, is preferably selected from asthma, bronchitis and pneumonia; Cough; The urinary incontinence; Bladder hyperactivity hyperkinesia (OAB); GI illness and/or damage; Duodenal ulcer; Stomach ulcer; Irritable bowel syndrome; Apoplexy; Eye irritation; Skin irritation; Neurodermatosis; Anaphylaxis dermatosis; Psoriasis; Vitiligo; Herpes simplex; Inflammation, the preferably inflammation of intestines, eyes, bladder, skin or nasal mucosa; Diarrhoea; Itch; Osteoporosis; Sacroiliitis; Osteoarthritis; Rheumatism; Eating disorder, is preferably selected from exessive appetite, cachexia, apositia and obesity; Drug dependence; Drug abuse; The Withrawal symptom of drug dependence; There is the tolerance to medicine, preferably to natural or synthetic opioid; Drug dependence; Drug abuse; The Withrawal symptom of drug dependence; Alcohol dependence; The Withrawal symptom of alcohol abuse and alcohol dependence; Diuresis; Natruresis suppresses; Affect cardiovascular systems; Insomnia aggravation; Treat wound and/or burn; Treatment cuts off neural; Increase sexual desire; Adjustment movement behavior; Anxiety disorder; Toponarcosis and/or suppress undesirable side effect, preferably, be selected from and give vanilloid receptor 1 (VR1/TRPV1 acceptor) hyperpyrexia, hypertension and bronchoconstriction that agonist causes, this agonist is preferably selected from capsaicine, Root and stem of Cholla toxin, olvanil, arvanil, SDZ-249665, SDZ-249482, nuvanil and capsavanil.