CN1177959A - Novel compounds - Google Patents

Abstract

This invention relates to 1-cycloalkyl, 4, 5-trisubstituted imidazole compounds, process for the preparation thereof, the use thereof in treating cytokine mediated diseases and pharmaceutical compositions for the use in such therapy.

Description

New compound

The present invention relates to one group of new imidazolium compounds, its preparation method, its in the cytokine mediated disease of treatment application and be used for the pharmaceutical composition of this treatment.

Background of invention

Interleukin-(IL-1) and tumour necrosis factor (TNF) are the biological substances by various cells such as monocyte or scavenger cell generation.Prove that the IL-1 adjusting is various to be considered to important biological (for example, seeing people such as Dinarello, Rev.Infect.Disease, 6,51 (1984)) in immunomodulatory and other physiological situation such as inflammation.A large amount of known IL-1 biological activitys comprise the activation t helper cell, induce fever, stimulate prostaglandin(PG) or collagenase to produce, and the neutrophil chemotaxis is induced acute phase protein and suppressed the blood plasma iron level.

A lot of morbid states are arranged, wherein, the IL-1 that produces excessive or non-regulated quantity with increase the weight of and/or cause that this disease is relevant.These morbid states comprise rheumatoid arthritis, osteoarthritis, endotoxemia and/or toxic shock syndrome, other acute or chronic inflammatory disease state Inflammatory response or inflammatory bowel disease inflammatory reaction as being caused by intracellular toxin; Tuberculosis, atherosclerosis, myodegeneration, emaciation, arthritic psoriasis, Josef Reiter sick syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella arthritis and acute synovitis.Up-to-date sign shows that IL-1 is active relevant with diabetes and pancreatic beta cell.

Dmarello, J.Clinical Immunology, 5 (5), commented on several biological activitys among the 287-297 (1985) owing to IL-1.Should be noted that these active parts are described as the IL-1 indirect action by other people.

Produce excessive or non-regulated quantity TNF and mediation or increase the weight of a large amount of diseases relevant, described disease comprises rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, urarthritis and other arthritis disease; Sepsis, septic shock, apoplexy, endotoxin shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, sarcoidosis of lung (sarcoisosis), bone absorpting disease, reperfusion injury, graft-vs-host reaction, homograft rejecting reaction, infect the fever and the myalgia that cause as influenza, the emaciation of secondary infection or malignant tumour, emaciation, the emaciation of secondary acquired immune deficiency syndrome (AIDS) (AIDS), AIDS, ARC (syndrome relevant) with AIDS, keloid forms, and scar tissue forms, Crohn disease, ulcerative colitis or pyresis.

AIDS is caused by T lymphocyte infected person immunodeficiency virus (HIV).At least three kinds of HIV have been identified, i.e. HIV-1, HIV-2 and HIV-3.As the result that HIV infects, the cell-mediated immunity of T sustains damage and infected individual serious opportunistic infection and/or the unusual knurl of occurring.HIV enters the T lymphocyte needs the effect of T lymphocyte activator.Behind the t cell activation, other virus is as HIV-1, and HIV-2 infects T lymphocyte and this t cell activation effect to be mediated or keep the expression of this virus protein and/or duplicate.In case activated T lymphocyte has infected HIV virus, the T lymphocyte must continue to remain on state of activation, so that HIV genetic expression and/or HIV duplicate.Monokine particularly TNF is relevant with the HIV protein expression and/or the virus replication of activated T cells mediation, and it plays a role by keeping the T lymphocyte activator.Therefore, for example, disturb the monokine activity to help the restricted T cells activated to keep by the generation that suppresses monokine, particularly TNF in the HIV infected individuals, and delaying the process that the HIV viral communication is given non-infected cells thus, this slows down or eliminates the process that is infected the immunodeficiency disease that causes by HIV.Monocyte, scavenger cell and relevant cell, as Kupffer Cell and neurogliocyte also with keep HIV and infect relevant.The same with the T cell, these cells are states of activation that the level of the target of virus replication and virus replication depends on cell.(seeing people such as Rosenberg, The Immunopathogenesis of HIV Infection, Advances inImmunology, Vol.57, (1989)).Show, in monocyte and/or scavenger cell, monokine such as TNF activation HIV duplicate and (see people such as Poli, Proc.Natl.Acad.Sci., 87:782-784 (1990)), thus, suppress monokine generation or activity and help to limit as above HIV process about being stated in the T cell.

Owing to similar reason, TNF also with other virus, as scavenger cell virus (CMV), the various effects of influenza virus and herpesvirus infection are relevant.

Interleukin 8 (IL-8) is identification and chemokine at first qualitatively in 1987.IL-8 comprises monocyte by several cells, inoblast, and endotheliocyte and keratinocyte produce.By IL-1, the inducing of TNF or lipopolysaccharides (LPS), endotheliocyte produces IL-8.Show that people IL-8 is to mouse, cavy, the neutrophil of rat and rabbit plays a role.IL-8 has a lot of different titles, as neutrophil attractive substance/activator-1 (NAP-1), and chemotactic factor for neutrophil (MDNCF), neutrophil incitant (NAF) and T cell lymphocyte chemokine that monocyte produces.

External, IL-8 promotes a lot of functions.Show that it has neutrophil, the chemical attractants of T lymphocyte and basophilic cell (chemoattractant) characteristic.In addition, it is induced from the basophilic cell release histamine of normal and atopic individuals and from neutrophil and discharges N,O-Diacetylmuramidase (1ysozomal enzyme) and cause breathing break (respiratory burst).Show that also IL-8 also increases Mac-1 (CD11b/CD18) does not have the protein de novo synthesis at the neutrophil surface expression, this may be because the adhesion of neutrophil and vascular endothelial cell increases.It is feature that a lot of diseases are soaked into a large amount of neutrophils.It will be favourable utilizing the compounds for treating and IL-8 (it is responsible for the chemotactic of neutrophil to the inflammatory position) the generation increase diseases associated that suppress the IL-8 generation.

The cytokine that IL-1 and TNF influence various kinds of cell and tissue and these cytokines and the generation of other white corpuscle is the important and crucial inflammatory mediator of multiple disease.Suppressing these cytokines is good to controlling, alleviating and delay a lot of diseases.

In this area, still need methods of treatment and compound, wherein said compound is the cell factor inhibiting anti-inflammatory agent thing, promptly can suppress cytokine, as IL-1, IL-6, the compound of IL-8 and TNF.

Brief summary of the invention

The present invention relates to new formula (I) compound, and the pharmaceutical composition that contains formula (I) compound and pharmaceutically acceptable diluent or carrier.

The present invention also relates to need to suppress the mammalian cytokine and the method for the treatment of cytokine mediated disease of this effect, it comprises to the formula of described administration significant quantity (I) compound.

The invention particularly relates to inhibition needs the method for the Mammals IL-1 generation of this effect, and it comprises to the formula of described administration significant quantity (I) compound.

The invention particularly relates to inhibition needs the method for the Mammals IL-8 generation of this effect, and it comprises to the formula of described administration significant quantity (I) compound.

The invention particularly relates to inhibition needs the method for the Mammals TNF generation of this effect, and it comprises to the formula of described administration significant quantity (I) compound.

Therefore, the invention provides formula (I) compound or pharmaceutically acceptable salt thereof: Wherein

R ₁Be the 4-pyridyl, pyrimidyl, quinolyl, isoquinolyl, quinazoline-4-base, 1-imidazolyl or 1-benzimidazolyl-, described aromatic ring replaces by one or two substituting group is optional, and each substituting group is independently selected from C _1-4Alkyl, halogen, hydroxyl, C _1-4Alkoxyl group, C _1-4Alkylthio, C _1-4Alkyl sulphinyl, CH ₂OR ₁₂, amino, one or two-C _1-6The amino that alkyl replaces, N (R ₁₀) C (O) R _cOr the N-heterocyclic ring, this ring contains another for 5-7 unit encircles and can choose wantonly and is selected from oxygen, sulphur or NR ₁₅Other heteroatoms;

R ₄Be phenyl, naphthalene-1-base or naphthalene-2-base, or heteroaryl, it can replace by one or two substituting group is optional, each substituting group can independently be selected, and for the 4-phenyl, 4-naphthalene-1-base, 5-naphthalene-2-base or 6-naphthalene-2-base, substituting group can be halogen, cyano group, nitro ,-C (Z) NR ₇R ₁₇,-C (Z) OR ₁₆,-(CR ₁₀R ₂₀) _vCOR ₁₂,-SR ₅,-SOR ₅,-OR ₁₂, the C that halogen replaces _1-4Alkyl ,-C _1-4Alkyl ,-ZC (Z) R ₁₂,-NR ₁₀C (Z) R ₁₆, or-(CR ₁₀R ₂₀) _vNR ₁₀R ₂₀, and for the replacement at other position, substituting group can be halogen, cyano group ,-C (Z) NR ₁₃R ₁₄,-C (Z) OR ₃,-(CR ₁₀R ₂₀) _{M "}COR ₃,-S (O) _mR ₃,-OR ₃, the C that halogen replaces _1-4Alkyl ,-C _1-4Alkyl ,-(CR ₁₀R ₂₀) _{M "}NR ₁₀C (Z) R ₃,-NR ₁₀S (O) _{M '}R ₈,-NR ₁₀S (O) _{M '}NR ₇R ₁₇,-ZC (Z) R ₃, or-(CR ₁₀R ₂₀) _{M "}NR ₁₃R ₁₄

V is 0, or integer 1 or 2;

M is 0, or integer 1 or 2;

M ' is integer 1 or 2;

M " be 0, or integer 1-5;

R _cBe hydrogen, C _1-6Alkyl, C _3-7Cycloalkyl, aryl, aryl C _1-4Alkyl, heteroaryl, heteroaryl C _1-4Alkyl, heterocyclic radical, or heterocyclic radical C _1-4Alkyl C _1-4Alkyl;

R ₂Be the optional C that replaces _3-7Cycloalkyl, or C _3-7Cycloalkyl C _1-10Alkyl;

R ₃Be heterocyclic radical, heterocyclic radical C _1-10Alkyl or R ₈

R ₅Be hydrogen, C _1-4Alkyl, C _2-4Alkenyl, C _2-4Alkynyl group, or NR ₇R ₁₇, remove-SR ₅Part is-SNR ₇R ₁₇And-SOR ₅For outside-the SOH;

R ₇And R ₁₇Be selected from hydrogen or C independently of one another _1-4Alkyl or R ₇And R ₁₇Form 5-7 unit heterocycle with the nitrogen-atoms that they connected, this ring can be chosen wantonly and contain another and be selected from oxygen, sulphur or NR ₁₅Heteroatoms.

R ₈Be C _1-10Alkyl, the C that halogen replaces _1-10Alkyl, C _2-10Alkenyl, C _2-10Alkynyl group, C _3-7Cycloalkyl, C _5-7Cycloalkenyl group, aryl, aryl C _1-10Alkyl, heteroaryl, heteroaryl C _1-10Alkyl, (CR ₁₀R ₂₀) _nOR ₁₁, (CR ₁₀R ₂₀) _nS (O) _mR ₁₈, (CR ₁₀R ₂₀) _nNHS (O) ₂R ₁₈, (CR ₁₀R ₂₀) _nNR ₁₃R ₁₄Wherein, aryl, arylalkyl, heteroaryl, heteroarylalkyl can be optionally substituted;

N is the integer of 1-10;

R ₉Be hydrogen ,-C (Z) R ₁₁, the optional C that replaces _1-10Alkyl, S (O) ₂R ₁₈, optional aryl that replaces or the optional aryl C that replaces _1-4Alkyl;

R ₁₀And R ₂₀Be selected from hydrogen or C independently of one another _1-4Alkyl;

R ₁₁Be hydrogen or R ₁₈

R ₁₂Be hydrogen or R ₁₆

R ₁₃And R ₁₄Be selected from hydrogen or the optional C that replaces independently of one another _1-4Alkyl, optional aryl that replaces or the optional aryl C that replaces _1-4Alkyl perhaps forms 5-7 unit heterocycle with the nitrogen-atoms that they connected, and this ring can be chosen wantonly and contain another and be selected from oxygen, sulphur or NR ₉Heteroatoms;

R ₁₅Be hydrogen, C _1-4Alkyl or C (Z)-C _1-4Alkyl;

R ₁₆Be C _1-4Alkyl, the C that halogen replaces _1-4Alkyl, or C _3-7Cycloalkyl;

R ₁₈Be C _1-10Alkyl, C _3-7Cycloalkyl, heterocyclic radical, aryl, aryl C _1-10Alkyl; Heterocyclic radical, heterocyclic radical C _1-10Alkyl, heteroaryl or heteroarylalkyl.

The detailed description of the invention

New formula (I) compound also can be used for the treatment of needs and suppress the Mammals except that the people that cytokine produces.Especially, in animal, need treatment and preventative-therapeutic, comprise those morbid states of mentioning during this paper methods of treatment partly by cytokine mediated disease, but especially refer to virus infection.These viral examples include, but are not limited to lentivirus and infect, infectious anemia virus as horse, the arthritis virus of sheep, visna virus, or maedi virus or retroviral infection, for example include, but are not limited to feline immunodeficiency virus (FIV), bovine immunodeficiency virus, or dog immunodeficiency virus or other retroviral infection.

In formula (I), suitable R ₁Part comprises the 4-pyridyl, the 4-pyrimidyl, and the 4-quinolyl, the 6-isoquinolyl, the 4-quinazolyl, 1-imidazolyl and 1-benzimidazolyl-, 4-pyridyl wherein, 4-pyrimidyl and 4-quinolyl are preferred.More preferably optional 4-pyrimidyl that replaces or the optional 4-pyridyl part that replaces, and the most preferably optional 4-pyrimidyl that replaces.

Suitable assorted R ₁The aromatic ring substituting group is the C1-4 alkyl, halogen, OH, C _1-4Alkoxyl group, C _1-4Alkylthio, C _1-4Alkyl sulphinyl, CH ₂OR ₁₂, amino, one or two-C _1-6The amino that alkyl replaces, N (R ₁₀) C (O) R _c, or the N-heterocyclic ring, this heterocycle is 5-7 unit ring and optional comprising to be selected from oxygen, sulphur or NR ₁₅Another heteroatoms.Preferred all R ₁The part substituting group is C _1-4Alkyl, particularly methyl, amino and one or two-C _1-6The amino that alkyl replaces, preferably, wherein amino is monobasic, more preferably by methyl substituted.One or two-C _1-6Alkyl replaces in the part, and alkyl can replace for halogen, replaces as trifluoro, i.e. trifluoromethyl or trifluoroethyl.

Work as R ₁Optional substituting group is N (R ₁₀) C (O) R _c, wherein, R _cBe hydrogen, C _1-6Alkyl, C _3-7Cycloalkyl, aryl, aryl C _1-4Alkyl, heteroaryl or heteroaryl C _1-4Alkyl, heterocyclic radical or heterocyclic radical C _1-4Alkyl C _1-4Alkyl, R _cBe preferably C _1-6Alkyl; R preferably ₁₀Be hydrogen.Known, R _cPart, particularly C _1-6Alkyl can replace 1-3 time or not replace as the fluorine with trifluoromethyl or trifluoroethyl form preferably by halogen.

Preferred R ₁Substituting group is amino or by a C _1-6The amino that alkyl replaces.R on the 4-pyridine derivate ₁Substituent preferred substitution in ring position is the 2-position, as 2-methyl-4-pyridyl.Preferred substitution in ring position on the 4-pyrimidine ring also is the 2-position, as 2-methylpyrimidine base, and 2-amino-pyrimidyl or 2-methylamino pyrimidyl.

Aptly, R ₄Be phenyl, naphthalene-1-base or naphthalene-2-base, or heteroaryl, it can replace by one or two substituting group is optional.More preferably, R ₄Be benzene or naphthalene nucleus.For R ₄, work as R ₄Be the 4-phenyl, 4-naphthalene-1-base, when 5-naphthalene-2-base or 6-naphthalene-2-was basic, suitable substituting group was one or two substituting group, wherein, each substituting group is independently selected from halogen ,-SR ₅,-SOR ₅,-OR ₁₂, CF ₃, or-(CR ₁₀R ₂₀) _vNR ₁₀R ₂₀, and for other replacement on these rings, preferred substituted is a halogen ,-S (O) _mR ₃,-OR ₃, CF ₃,-(CR ₁₀R ₂₀) _{M "}NR ₁₃R ₁₄,-NR ₁₀C (Z) R ₃With-NR ₁₀S (O) _{M '}R ₈Preferred substituents on the 4-position of phenyl and naphthalene-1-base and at naphthalene-2-base 5 comprises halogen, particularly fluorine and chlorine, and-SR ₅With-SOR ₅, wherein, preferably, R ₅Be C _1-2Alkyl, more preferably methyl; Wherein fluorine and chlorine are preferred and and preferred especially fluorine.Preferred substituents in the 3-position of phenyl and naphthalene-1-base comprises: halogen, particularly fluorine and chlorine;-OR ₃, C particularly _1-4Alkoxyl group; CF ₃, NR ₁₀R ₂₀, as amino;-NR ₁₀C (Z) R ₃, particularly-NHCO (C _1-10Alkyl);-NR ₁₀S (O) _{M '}R ₈, particularly-NHSO ₂(C _1-10Alkyl), and-SR ₃With-SOR ₃, wherein, preferably, R ₃Be C _1-2Alkyl, more preferably methyl.When phenyl ring is two when replacing, preferably, substituting group is two independently halogen parts, as fluorine and chlorine, is preferably dichloro and more preferably 3, the 4-position.Also preferably the 3-position-OR ₃With-ZC (Z) R ₃Part, R ₃Also can comprise hydrogen.

Preferably, R ₄Part is the optional phenyl moiety that replaces.More preferably, R ₄For phenyl or replace by fluorine in the 4-position and/or in the 3-position by fluorine, chlorine, C _1-4Alkoxyl group, the phenyl that methanesulfonamido or kharophen replace, perhaps R ₄For at 3,4 independently by chlorine or fluorine, more preferably by the dibasic phenyl of chlorine.Most preferably, R ₄Be the 4-fluorophenyl.

In formula (I), Z is suitably oxygen.

Aptly, R ₂Be the optional C that replaces _3-7Cycloalkyl, or the optional C that replaces _3-7Cycloalkyl C _1-10Alkyl.Preferably, R ₂Be C _3-7Cycloalkyl, wherein, preferably, cycloalkyl is C _4-7Ring, more preferably C ₄Ring or C ₆Ring, most preferably C ₆Ring, this ring can be optional the replacements.

C _3-7Cycloalkyl ring can be replaced 1-3 time by following substituting group, and described substituting group is independently selected from halogen, as fluorine, and chlorine, bromine or iodine; Hydroxyl; C _1-10Alkoxyl group is as methoxy or ethoxy; S (O) _mAlkyl, wherein m is 0,1 or 2, for example methylthio group, methanesulfinyl or methylsulfonyl; S (O) _mAryl; Cyano group; Nitro; Amino; One and dibasic amino, as NR ₇R ₁₇, wherein, R ₇And R ₁₇Suc as formula the definition in (I); Perhaps R wherein ₇R ₁₇Can form 5-7 unit ring with the nitrogen-atoms that they connected, this ring can be chosen wantonly and contain another and be selected from oxygen, sulphur or NR ₁₅Heteroatoms (and R ₁₅Suc as formula the definition in (I)); N (R ₁₀) C (O) X (R wherein ₁₀Suc as formula the definition in (I), and X ₁Be C _1-4Alkyl, aryl or aryl C _1-4Alkyl); N (R ₁₀) C (O) aryl; C _1-10Alkyl, as methyl, ethyl, propyl group, sec.-propyl, or the tertiary butyl; The optional alkyl that replaces, wherein, substituting group is that halogen is (as CF ₃), hydroxyl, nitro, cyano group, amino, one and dibasic amino, as NR ₇R ₁₇Base, S (O) _mAlkyl and S (O) _mAryl, wherein m is 0,1, or 2; The optional C that replaces _1-10Alkylidene group is as ethylidene or propylidene; The optional C that replaces _1-10Alkynes is as acetylene or 1-proyl; C (O) OR ₁₁(wherein, R ₁₁Suc as formula the definition in (I)), as free acid or methyl ester derivation; R _aBase;-C (O) H;=O;=N-OR ₁₁-N (H)-OH (or its alkyl or aryl derivative that partly replaces at nitrogen or oxime);-N (OR _b)-C (O)-R ₆Oxyethane; The optional aryl that replaces is as phenyl; The optional aryl C that replaces _1-4Alkyl is as benzyl or styroyl; Optional heterocyclic radical or the heterocycle C that replaces _1-4Alkyl, and further, these aryl, arylalkyl, heterocyclic radical and Heterocyclylalkyl part can be replaced 1-2 time or do not replaced, described group such as halogen, hydroxyl, C by following groups _1-10Alkoxyl group, S (O) _mAlkyl, cyano group, nitro, amino, one and dibasic amino, as NR ₇R ₁₇Base, alkyl, the alkyl that halogen replaces.

Aptly, R _aBe formula-O-(CH ₂) _s1 of-O-, the 3-alkylene dioxo base, wherein, s is 1-3, preferably s is 2, obtains 1,3-ethylenedioxy part.

Aptly, R _bBe hydrogen, pharmaceutically acceptable positively charged ion, aroyl or C _1-10Alkanoyl.

Aptly, R ₆Be NR ₁₉R ₂₁Alkyl _1-6The alkyl that halogen replaces _1-6The alkyl that hydroxyl replaces _1-6Alkenyl _2-6By halogen, alkyl _1-6, the alkyl that halogen replaces _1-6, hydroxyl, or alkoxyl group _1-6Optional aryl or the heteroaryl that replaces.

Aptly, R ₁₉Be H or alkyl _1-6

Aptly, R ₂₁Be H, alkyl _1-6, aryl, benzyl, heteroaryl, by the alkyl that halogen or hydroxyl replace, by the phenyl that a following group replaces, described group is selected from halogen, cyano group, alkyl _1-2, alkoxyl group _1-6, the alkyl that halogen replaces _1-6, alkylthio, alkyl sulphonyl, or alkyl sulphinyl; Perhaps R ₁₉And R ₂₁Can form 5-7 unit ring with the nitrogen-atoms that they connected, described annular atoms can be by being selected from oxygen, and the heteroatoms of sulphur or nitrogen is optional to be substituted.This ring can be saturated or can comprise an above unsaturated link(age).Preferably, R ₆Be NR ₁₉R ₂₁And R ₁₉And R ₂₁Be preferably hydrogen.

Work as R ₂Part is by NR ₇R ₁₇Base, or NR ₇R ₁₇C _1-10Alkyl replaces and R wherein ₇And R ₁₇During partly suc as formula the definition in (I), preferably, substituting group is amino, aminoalkyl group, or the optional pyrrolidyl part that replaces.

Replacement on the preferred cyclohexyl ring is in the 4-position, and particularly working as described ring is C ₆The time.

When cyclohexyl ring is two replacements, preferably, replace in the 4-position, as:

Wherein, R ^{1 '}And R ^{2 '}Be above-mentioned relevant R independently ₂The substituting group of optional replacement.Preferably, R ^{1 '}And R ^{2 '}Be hydrogen, hydroxyl, alkyl, the alkyl of replacement, the optional alkynyl group that replaces, aryl, arylalkyl, NR ₇R ₁₇And N (R ₁₀) C (O) R ₁₁Aptly, alkyl is C _1-4Alkyl, as methyl, ethyl or sec.-propyl; NR ₇R ₁₇And NR ₇R ₁₇Alkyl, as amino, methylamino, amino methyl, amino-ethyl, the alkyl of replacement such as cyano group alkyl, cyano ethyl, nitro-ethyl, pyrrolidyl; The optional alkynyl group that replaces is as proyl or ethynyl; Aryl such as phenyl, arylalkyl is as benzyl; Perhaps R ^{1 '}And R ²＇ is a ketone.

Except that other explanation, this paper " optional replacement " is meant following groups, as halogen, and as fluorine, chlorine, bromine or iodine; Hydroxyl; The C that hydroxyl replaces _1-10Alkyl; C _1-10Alkoxyl group is as methoxy or ethoxy; S (O) _mAlkyl, wherein, m is 0,1 or 2, as methylthio group, methylsulfinyl or methyl sulphonyl; Amino, the amino of one and two-replacement is as NR ₇R ₁₇Base; Perhaps, NR wherein ₇R ₁₇Can form 5-7 unit ring with the nitrogen-atoms that they connected, this ring can be chosen wantonly and contain the heteroatoms that another is selected from O/S/N; C _1-10Alkyl, cycloalkyl, or cycloalkylalkyl, as methyl, ethyl, propyl group, sec.-propyl, the tertiary butyl etc. and cyclopropyl methyl; The C that halogen replaces _1-10Alkyl is as CF ₃The optional aryl that replaces, as phenyl, or the optional arylalkyl that replaces, as benzyl or styroyl, wherein, these aryl moieties also can be replaced 1-2 time by following groups, described group such as halogen; Hydroxyl; The alkyl that hydroxyl replaces; C _1-10Alkoxyl group; S (O) _mAlkyl; Amino, the amino of one and two-replacement is as NR ₇R ₁₇Base; Alkyl, or CF ₃

In preferred one group of formula (I) compound, R ₁Be the 4-pyridyl, 2-alkyl-4-pyridyl, 4-pyrimidyl, 2-amino-4-pyrimidyl or 2-methylamino-4-pyrimidyl; R ₂Be the optional C that replaces ₄Or C ₆Cycloalkyl and R ₄Be phenyl or the optional phenyl that replaces.In preferred one group, R ₄Replace 1 or 2 time phenyl, described group such as fluorine, chlorine, C for phenyl or by following groups _1-4Alkoxyl group ,-S (O) _mAlkyl, methanesulfonamido or kharophen; R ₂Be the cyclohexyl that replaces by following groups, described group such as methyl, phenyl, benzyl, amino, ethanamide, amino methyl, amino-ethyl, cyano methyl, cyano ethyl, hydroxyl, nitro-ethyl, pyrrolidyl, ethynyl, 1-proyl ,=O, O-(CH ₂) ₂O-,=NOR ₁₁, wherein, R ₁₁Be hydrogen, alkyl or aryl, NHOH, or N (OH)-C (O)-NH ₂And R ₁The optional 4-pyrimidyl part that replaces of amino or methylamino of serving as reasons; Perhaps R ₁Be 4-pyridyl by the optional replacement of methyl.

Suitable pharmacologically acceptable salt is well known by persons skilled in the art and comprises mineral acid and the organic acid subsalt, described sour example hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, methylsulfonic acid, ethyl sulfonic acid, acetic acid, oxysuccinic acid, tartrate, Citric Acid, lactic acid, oxalic acid, succsinic acid, fumaric acid, toxilic acid, phenylformic acid, Whitfield's ointment, toluylic acid and amygdalic acid.In addition, if comprise carboxy moiety in the substituting group group, the pharmacologically acceptable salt of formula (I) compound also can be by forming with pharmaceutically acceptable cation sites so.Suitable pharmaceutically acceptable positively charged ion is to well known to a person skilled in the art and comprise basic metal, alkaline-earth metal, ammonium and quaternary ammonium cation.

The employed following term of this paper refers to:

" halogen " or " halogen " comprises halogen: chlorine, fluorine, bromine and iodine.

" C _1-10Alkyl " or " alkyl ", except that other explanation, referring to the straight or branched group of 1-10 carbon atom, it includes, but are not limited to methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-, the tertiary butyl, n-pentyl, or the like.

Term as used herein " cycloalkyl " finger ring shape group, preferred 3-8 carbon atom includes, but are not limited to cyclopropyl, cyclopentyl, cyclohexyl, or the like.

Term as used herein " cycloalkenyl group " finger ring shape group, preferred 5-8 carbon atom, it has a two key at least, includes, but are not limited to cyclopentenyl, cyclohexenyl, or the like.

Term as used herein " alkenyl " except that other explanation, refers to have the straight or branched group of 2-10 carbon atom, and it includes, but are not limited to vinyl, 1-propenyl, 2-propenyl, 2-methyl isophthalic acid-propenyl, 1-butylene base, crotyl or the like.

" aryl " refers to phenyl and naphthyl;

" heteroaryl " (or any array configuration own, as " heteroaryloxy ", or " heteroarylalkyl ") referring to 5-10 unit aromatic ring, wherein one or more rings comprise one or more N of being selected from, the heteroatoms of O or S, it includes, but are not limited to the pyrroles, pyrazoles, furans, thiophene, quinoline, isoquinoline 99.9, quinazoline, pyridine, pyrimidine oxazole, thiazole, thiadiazoles, triazole, imidazoles, or benzoglyoxaline.

" heterocycle " (or any array configuration own, as " heterocyclic radical alkyl ") refer to saturated or the undersaturated 4-10 of part unit ring, wherein one or more rings comprise one or more N of being selected from, the heteroatoms of O or S, it includes, but are not limited to tetramethyleneimine, piperidines, piperazine, morpholine, tetrahydropyrans, or imidazolidine.

Term as used herein " aralkyl " or " heteroarylalkyl " or " Heterocyclylalkyl " except that other explanation, refer to the aryl with above-mentioned definition, the C as defined above that heteroaryl or heterocyclic radical partly connect _1-4Alkyl.

" sulfinyl " refers to the oxide S (O) of corresponding sulfide, and term " sulphur " refers to sulfide, and term " alkylsulfonyl " refers to the S (O) of complete oxidation ₂Part.

" aroyl " refers to C (O) Ar, and wherein Ar is a phenyl, naphthyl, or the arylalkyl derivative of above-mentioned definition, and this group includes, but are not limited to benzyl and styroyl.

" alkyloyl " refers to C (O) C _1-10Alkyl, wherein, alkyl as above defines.

Known, The compounds of this invention can comprise one or more unsymmetrical carbons and can exist with racemize and optical activity form.All these compounds are included in the scope of the invention.

Formula (I) examples for compounds comprises:

5-(2-amino-4-pyrimidyl)-4-(4-fluoro phenyl)-1-(4-(1,3-dioxy cyclopentyl) cyclohexyl)-imidazoles;

5-(2-amino-4-pyrimidyl)-4-(4-fluoro phenyl)-1-(4-ketone cyclohexyl)-imidazoles;

5-(2-amino-4-pyrimidyl)-4-(4-fluoro phenyl)-1-(4-cyclohexyl oxime)-imidazoles;

5-(2-amino-4-pyrimidyl)-4-(4-fluoro phenyl)-1-(4-cyclohexyl azanol)-imidazoles;

5-(2-amino-4-pyrimidyl)-4-(4-fluoro phenyl)-1-(trans-the 4-hydroxyurea)-imidazoles;

5-(2-amino-4-pyrimidyl)-4-(4-fluoro phenyl)-1-(cis-4-hydroxyurea)-imidazoles;

5-(2-amino-4-pyrimidyl)-4-(4-fluoro phenyl)-1-(4-hydroxy-cyclohexyl)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-ketone cyclohexyl)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(trans-the 4-hydroxy-cyclohexyl)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(cis-4-hydroxy-cyclohexyl)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-(cis-pyrrolidyl) cyclohexyl)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-(anti-form-1-pyrrolidyl) cyclohexyl)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-ethynyl-4-hydroxy-cyclohexyl)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-(1-proyl)-4-hydroxy-cyclohexyl)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-amino-4-methyl-cyclohexyl base)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-acetylaminohydroxyphenylarsonic acid 4-methyl-cyclohexyl base)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-hydroxy-4-methyl-cyclohexyl)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-Oxyranyle cyclohexyl)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-cyano methyl-4-hydroxy-cyclohexyl)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-hydroxy-4-hydroxymethyl ylmethyl cyclohexyl)-imidazoles;

5-(4-(2-amino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-hydroxyl-4-(1-proyl) cyclohexyl)-imidazoles;

5-(4-(2-amino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-hydroxy-4-methyl-cyclohexyl)-imidazoles.

Other compound in formula (I) scope comprises:

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-hydroxyl-4-sec.-propyl-cyclohexyl)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-hydroxy-4-phenyl-cyclohexyl)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-hydroxyl-4-benzyl-cyclohexyl)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-hydroxyl-4-cyano methyl cyclohexyl)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-hydroxyl-4-(2-cyano ethyl) cyclohexyl)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-hydroxyl-4 (2-ethyl) cyclohexyl)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-hydroxyl-(2-nitro-ethyl) cyclohexyl)-imidazoles;

5-(4 (2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-hydroxymethyl-4-amino-cyclohexyl)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-hydroxyl-4-amino-cyclohexyl)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-amino-cyclohexyl)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-2-hydroxy-4-methylthio-cyclohexyl)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-hydroxy-4-hydroxymethyl methylcyclohexyl)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-hydroxyl-4-amino methyl-cyclohexyl)-imidazoles;

5-(4-(2-amino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-amino-4-methyl-cyclohexyl base)-imidazoles;

5-(4-(2-amino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-hydroxy-4-methyl-cyclohexyl)-imidazoles;

5-(4-(2-amino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-epoxy ethyl-cyclohexyl)-imidazoles.

Exemplary other formula (I) compound that this paper comprised comprises the 2-methylamino-4-pyrimidinyl derivatives of above-mentioned 2-aminopyrimidine-4-based compound and the 2-amino-4-pyrimidinyl derivatives of above-mentioned 2-methylamino pyrimidine-4-based compound of not describing in detail.

Can come acquisition formula (I) compound by using synthetic method, wherein some illustrates in this paper reaction scheme I-XI.The synthetic method that is provided in these reaction schemes can be used for preparation and has various different R ₁, R ₂, and R ₄The formula of group (I) compound is by using any substituting group of suitable protection, with the consistency of formula (I) compound reaction acquisition with reaction that this paper mentions.Carry out deprotection subsequently, obtain common disclosed compound.Behind synthetic imidazole ring, can use functional group well known in the art change standard technique and prepare other formula (I) compound.

For example: by at CH ₃Among the OH, general-CO ₂CH ₃And HNR ₁₃R ₁₄With or not with the catalytic metal prussiate, for example NaCN heats together, obtains-C (O) NR ₁₃R ₁₄For example, in pyridine, from-OH and Cl (O) R ₃In obtain-OC (O) R ₃From-NHR ₁₀With obtain in alkyl lsothiocyanates or the thiocyanic acid-NR ₁₀-C (S) NR ₁₃R ₁₄From-NHR ₆With obtain NR in the alkyl chloroformate ₆C (O) OR ₆By using isocyanic acid, for example, HN=C=O or R ₁₀N=C=O handles, from-NHR ₁₀Obtain-NR ₁₀C (O) NR ₁₃R ₁₄By in pyridine, with ClC (O) R ₃Handle, from-NHR ₁₀In obtain-NR ₁₀-C (O) R ₈By in ethanol, heating, from-C (NR ₁₃R ₁₄) SR ₃And H ₃NR ₃ ⁺OAc ^-In obtain-C (=NR ₁₀) NR ₁₃R ₁₄At inert solvent, for example in the acetone, from-C (S) NR ₁₃R ₁₄And R ₆Obtain among-the I-C (NR ₁₃R ₁₄) SR ₃From-C (S) NH ₂And HNR ₁₃R ₁₄In obtain-C (S) NR ₁₃R ₁₄(R wherein ₁₃And R ₁₄Not hydrogen); By in dehydrated alcohol, heating, from-C (=NR ₁₃R ₁₄)-SR ₃And NH ₂Obtain among the CN-C (=NCN)-NR ₁₃R ₁₄, perhaps by in EtOH, handle with BrCN and NaOEt, from-C (=NH)-NR ₁₃R ₁₄In obtain; By using (R ₈S) ₂C=NCN handles, from-NHR ₁₀In obtain-NR ₁₀-C (=NCN) SR ₈By using ClSO ₂R ₃Processing is also heated in pyridine, from-NHR ₁₀In obtain-NR ₁₀SO ₂R ₃By using Lawesson ' s reagent (2,4-two (4-p-methoxy-phenyl)-1,3,2,4-dithia two phospha cyclohexanes-2,4-disulphide) to handle, from-NR ₁₀C (O) R ₈Obtain-NR ₁₀C (S) R ₃By-NHR ₆Obtain-NR with trifluoromethanesulfanhydride anhydride and alkali ₁₀SO ₂CF ₃, R wherein ₃, R ₆, R ₁₀, R ₁₃And R ₁₄Definition as this paper formula (I).

The present invention provides the compound of the formula (II) with following array structure on the other hand:

Wherein p is 0, or 2; R ₄Suc as formula the definition of (I) and Ar is the aryl of optional replacement defined herein.Aptly, Ar is by C _1-4Alkyl, C _1-4The optional phenyl that replaces of alkoxy or halogen.Preferably, Ar is phenyl or 4-aminomethyl phenyl, i.e. tolylsulfonyl radical derivative.Formula (II) it is believed that it is new, precondition be when Ar be tosyl group, and p is 0 or 2, R4 is not unsubstituted phenyl so.

R ₁, R ₂And R ₄The precursor of base can be and R ₁, R ₂And R ₄The group that base is different, they can pass through the change technology change of standard functional group.For example, by with the reactant salt of suitable trinitride, can be with formula (I) compound, wherein R ₂C for the halogen replacement _1-10Alkyl is converted into corresponding C _1-10Alkyl N ₃Derivative, and after this, if desired, reducible is corresponding C _1-10Alkyl NH ₂Compound, this compound conversely can with R ₁₈S (O) ₂The X reaction, wherein, X is halogen (for example, chlorine), obtains corresponding C _1-10Alkyl NHS (O) ₂R ₁₈Compound.

Perhaps, formula (I) compound, wherein R ₂C for the halogen replacement _1-10Alkyl, can with amine R ₁₃R ₁₄The NH reaction obtains corresponding C _1-10Alkyl NR ₁₃R ₁₄Compound, perhaps, can with R ₁₈An alkali metal salt reaction of SH obtains corresponding C _1-10Alkyl SR ₁₈Compound.

Reaction scheme I

Reference reaction route I can be by reacting formula (II) compound and formula (III) compound to preparation formula (I) compound aptly, and wherein, p is 0 or 2, R ₁, R ₂And R ₄As the definition of this paper formula (I), perhaps be R ₁, R ₂And R ₄The precursor of base, and Ar is the optional phenyl that replaces, and after this, if desired, can be with R ₁, R ₂And R ₄The precursor conversion of base is R ₁, R ₂And R ₄Base.Known, R ₂NH ₂With R ₁The CHO reaction forms imines, the R in formula (III) ₂Part comprises reactive functionality, and as primary amine, secondary amine during functional group in alcohol or the mercaptan compound, must suitably protect these groups.Suitable protecting group can be in " protecting group in the organic synthesis ", Greene TW, and Wiley-Interscience, New York finds that it is for reference to be introduced into this paper in 1981.For example, work as R ₂Be heterocycle, as piperidine ring during as substituting group, with group such as t-Boc, CO ₂R ₁₈, or the arylalkyl that replaces part protects nitrogen.

Aptly, in envrionment temperature or under cooling (for example-50 ℃-10 ℃) or heating condition, at suitable inert solvent such as methylene dichloride, DMF, tetrahydrofuran (THF), toluene, acetonitrile, or in the glycol dimethyl ether, at suitable alkali as 1,8-diazabicylo (5.4.0) 11 carbon-7-alkene (DBU), perhaps guanidine alkali is as 1,5,7-three aza-bicyclos (5.4.0) last of the ten Heavenly stems-5-alkene (TBD) reacts under existing.Find that the intermediate of formula (II) is highly stable and can store for a long time.Preferably, p is 2.

With formula (II) compound, p=2 wherein is with formula (III) compound reaction-reaction scheme I, formula (I) compound that productive rate is higher when obtaining than p=0.In addition, consider from environment and economic aspect, formula (II) compound, wherein the reaction of p=2 has more attractive.When p=0, preferred solvent is a methylene dichloride, with comparing that use this paper further describes at commercial attractive synthetic (p=2), for scale operation, from the angle of economy, it is not attractive, and preferred alkali, TBD also is expensive, and produces some byproduct and impurity.

Notice that reaction scheme I utilizes the aryl sulphomethyl isocyanide negatively charged ion (p=0) that replaces to carry out 1,3-dipole cycloaddition with imines.Especially, this reaction needed highly basic carries out deprotection as amine alkali.Although can use trimethyl carbinol Li ⁺Or Na ⁺, perhaps hexamethyl dimethylamino silane ammonification potassium, but preferably use commercially beneficial TBD.When methylene dichloride is preferred solvent, can use other halogenated solvent, as chloroform or tetracol phenixin; Ether, as THF, DME, DMF, ether, t-butyl methyl ether; And acetonitrile, toluene or its mixture.For R ₁Base is the reaction of pyrimidine, can preferably at about 0 ℃-23 ℃, more preferably at about 0 ℃-10 ℃, and most preferably carry out this reaction under about 4 ℃ at approximately-20 ℃-40 ℃.For R ₁Base is the compound of pyridine, and known change comprises that the reaction conditions of temperature and solvent is essential, as temperature being reduced to-50 ℃ or solvent changed into THF.

In other method, can pass through the derivative of formula (IX) compound that will be suitable:

T wherein ₁Be hydrogen and T ₄Be R ₄, perhaps T ₁Be R ₁And T ₄Be H, wherein R ₁, R ₂And R ₄As above definition; Come preparation formula (I) compound with the appropriate derivative coupling; (i) work as T ₁During for hydrogen, under the ring coupling condition, with hetero-aromatic ring R ₁The reaction of H appropriate derivative, thus, with hetero-aromatic ring R ₁Be coupled on the 5-position of imidazole ring; (ii) work as T ₄During for hydrogen, under the ring coupling condition, with aromatic ring R ₄The reaction of H appropriate derivative, thus, with aromatic ring R ₄Be coupled on the 4-position of imidazole ring.

This aryl/hetaryl linked reaction is well known to a person skilled in the art.Usually, in the presence of suitable catalyzer, with the negatively charged ion of the synthetic normal a kind of component of organo-metallic and the derivatives reactivity coupling of second kind of component.Negatively charged ion can be formed by formula (IX) imidazoles (under this state, providing derivatives reactivity by the aryl/hetaryl compound) or aryl/hetaryl compound (under this state, providing derivatives reactivity by imidazoles).Therefore, formula (IX) compound or aryl/hetaryl ring appropriate derivative comprise Organometallic derivatives such as organic-magnesium, organic zinc, organic stannane and boric acid derivatives and suitable derivatives reactivity comprise bromine, iodine, fluorinated sulfonate and trifluoromethanesulfonic acid salt derivative.Suitable method is described in WO91/19497, and it is for reference to be introduced into this paper.

According to people Tetrahedron Letters such as Kumada, 22, method in 5319 (1981), can be at the ring coupling catalyst, exist down as palladium (0) or palladium (II) catalyzer, the organic-magnesium that formula (IX) compound is suitable and halogen, fluoro sulphonate or the triflate derivatives reaction of organic zinc derivative and heteroaryl or aryl rings.This suitable catalyzer comprises at lithium chloride and alkali, four under existing or do not exist as triethylamine-(triphenylphosphine) palladium and PdCl ₂[1,4-two-(diphenylphosphino)-butane].In addition, at J.Org.Chem, the method in 1982,47,4319 also can be used nickel (II) catalyzer, as Ni (II) Cl according to people such as Pridgen ₂(1, the 2-diphenylphosphino) ethane comes the coupling aromatic ring.Suitable reaction solvent comprises hexametapol.When hetero-aromatic ring was the 4-pyridyl, appropriate derivative comprised the fluoro sulphonate and the triflate of 4-bromo-and 4-iodo-pyridine and 4-pyridone.Similarly, when aromatic ring was phenyl, appropriate derivative comprised bromo, fluoro sulphonate, triflate and preferred iodo derivative.Can be by handling with alkyl lithium compounds that formula (IX) compound or its bromo derivative obtain corresponding lithium agent and respectively by taking off organic-magnesium and the organic zinc derivative that proton and trans-metallation obtain suiting.Available excessive magnesium halide or zinc halide are handled this lithium intermediate, obtain corresponding organometallic reagent.

According to Stille, J.Amer.Chem.Soc, 1987,109,5478, United States Patent (USP) 4,719,218 and 5,002, the method described in 942, can be at inert solvent such as tetrahydrofuran (THF), preferably in the tetrahydrofuran (THF) that comprises 10% hexamethylphosphoramide, at suitable coupling catalyst such as palladium (0) catalyzer, for example four-(triphenylphosphine) palladiums exist down, perhaps in inert solvent such as dimethyl formamide, at lithium chloride, in the presence of alkali such as triethylamine, use palladium (II) catalyzer not essentially, bromide with aryl or heteroaryl ring, the fluoro sulphonate, triflate, perhaps preferred iodide come the trialkyltin derivative of processing formula (IX) compound.Can pass through at ether solvents, in tetrahydrofuran (THF), use the lithiumation agent, as s-butyl lithium or n-Butyl Lithium with corresponding formula (IX) compound metalization, perhaps by handle the bromo derivative of corresponding formula (IX) compound with lithium alkylide, then, handle with trialkyltin halogenide more respectively, obtain the trialkyltin derivative.Perhaps, can be under above-mentioned similar condition, catalyzer as four-(triphenylphosphine) palladiums in the presence of, the bromo derivative that comes processing formula (IX) compound with suitable heteroaryl or aryl trialkyl tin compound.

Also can use boric acid derivatives.Therefore, can be in solvent such as glycol dimethyl ether, under reflux state, palladium catalyst as four-(triphenylphosphine) palladium or PdCl ₂[1,4-two-(diphenylphosphino)-butane] and suitable alkali such as sodium bicarbonate exist down, with formula (IX) compound appropriate derivative, as bromo, iodo, triflate or fluoro sulfonate derivatives and heteroaryl-or aryl-acid reaction (see Fisher and Haviniga, Rec.Trav.Chim.Pays Bas, 84,439,1965, Snieckus, V., Tetrahedron Lett., 29,2135,1988 and Terashimia, M., Chem.Pharm.Bull., 11,4755,1985).Also can use non-water condition, for example solvent such as DMF, under about 100 ℃ temperature, the condition in the presence of Pd (II) catalyzer (seeing people such as Thompson W J, J Org Chem, 49,5237,1984).Can be according to standard method, by using trialkylboron acid esters such as triethyl, triisopropyl or tri butyl boron acid esters are handled magnesium or the lithium derivative prepares suitable boric acid derivatives.

In this linked reaction, the known functional group that exists in formula (IX) compound that must be noted that.Therefore amino usually and sulphur substituting group should be unoxidized or protection.

Formula (IX) compound is imidazoles and can obtains by any method of relevant preparation formula (I) compound described herein.Especially, can be at inert solvent such as halogenated hydrocarbon solvent, for example in the chloroform, under the temperature that suitably raises, and if desired, in the presence of suitable condensing agent such as alkali, with α-Lu Daitong or other active ketone R that suits ₄COCH ₂Hal is (for T ₁Formula (IX) compound for hydrogen) or R ₁COCH ₂Hal is (for T ₄Formula (IX) compound for hydrogen) with formula R ₂The amidine of NH-C=NH, wherein R ₂Suc as formula the definition in (I), or its reactant salt.The preparation of suitable halogenated ketone has been described in WO91/19497.Suitable active ester comprises strong organic acid, as low alkyl group sulfonic acid or aryl sulfonic acid, and the ester of methylsulfonic acid or tosic acid for example.Preferably, use the salt of amidine, suitable is its hydrochloride, by using biphasic system, wherein active ester is in inert organic solvents such as chloroform, and salt is at aqueous phase, described water under agitation adds the aqueous bases of 2 molar weights lentamente, the salt of described amidine can be converted on the spot free amidine.Amidine by standard method can obtain suiting for example, sees Gaigipai R, Tetrahedon letters, 190,31,1989.

Also can be according to United States Patent (USP) 4,803,279; United States Patent (USP) 4,719,218 and United States Patent (USP) 5; method described in 002,942 is come preparation formula (I) compound, and this method comprises; with formula (IX) compound, wherein T1 is a hydrogen, with N-acyl group heteroaryl reactant salt; obtain intermediate, wherein, hetero-aromatic ring be connected on the imidazole ring and with its 1; the form of 4-dihydro derivative exists, and then, this intermediate can be carried out oxidation-deacylation (reaction scheme II).Heteroaryl salt, for example pyridinium salt can form on the spot, perhaps more preferably; the carbonyl halide that can pass through to replace is (as acyl halide; aroyl halogen, halo formic acid alkyl aryl, perhaps; preferred halo alkyl formate; as the ethanoyl bromine, benzoyl chlorine, benzyl chloroformate; perhaps, preferred Vinyl chloroformate) be added to formula (IX) compound at heteroaryl compound R ₁H or preparation on the spot in the solution of inert solvent that adds heteroaryl compound such as methylene dichloride.Suitable deacylated tRNA and oxidizing condition be at United States Patent (USP) 4,803, describes in 279,4,719,218 and 5,002,942, introduces the document for reference in full.Suitable oxidation system is included under the reflux state, at inert solvent or solvent mixture, as naphthalane, naphthalane and diglyme, to cymene, dimethylbenzene or 1,3, the sulphur in the 5-Three methyl Benzene, perhaps preferred potassium tert.-butoxide in the trimethyl carbinol and dry air or oxygen.

Reaction scheme II

In further method, shown in the following reaction scheme III, can or handle formula (X) compound by cyclizing agent such as phosphoryl chloride or phosphorus pentachloride and come preparation formula (I) compound (to see Engel and Steglich by thermal treatment, Liebigs Ann Chem, 1978,1916 and people such as Strzybny, J.OrgChem, 1963,28,3381).For example, can use the active formate derivative, as corresponding acid anhydride, with corresponding α-ketone-amine acidylate, then with R by under the standard acylation condition ₂NH ₂Form imines and come preparation formula (X) compound.Can be by parent ketone oxalyl amination (oxamination) and reduction being obtained keto-amine and conversely, can be by will be by aryl (heteroaryl) acetic ester and R ₁The 'beta '-ketoester decarboxylation that the condensation of COX component obtains prepares needed ketone.

Reaction scheme III

In following reaction scheme IV, two approach that (2) are different are arranged, utilize ketone (formula XI) to come preparation formula (I) compound.By with the negatively charged ion of alkyl heterocycle such as 4-methyl-quinoline (by using lithium alkylide, handle as n-Butyl Lithium and to prepare) be added to N-alkyl-O-alkoxy benzamides, ester, or prepare heterocyclic ketone (XI) in other any reactive derivative suitable, the identical state of oxidation.Perhaps, negatively charged ion and phenyl aldehyde condensation can be obtained alcohol, then pure oxidation be obtained ketone (XI)

Reaction scheme IV

In other method, can be prepared as follows formula (I) compound that N-replaces, this method comprises usefulness:

(a), the nitrile of formula (XIII):

R ₄CN (XIII) is R wherein ₄Definition as mentioned in the above, perhaps

(b), the acyl halide of excessive formula (XIV), for example chloride of acid:

R ₄COHal (XIV) is R wherein ₄Definition as mentioned in the above and Hal are halogen, or corresponding acid anhydrides is handled the negatively charged ion of formula (XII) acid amides:

R ₁CH ₂NR ₂COH (XII) is R wherein ₁And R ₂Definition as mentioned in the above obtains the intermediate of two acidylates, then with this intermediate with the compound that can produce ammonia, handle as amine acetate.

Reaction scheme V

The change of this method has been described at above-mentioned reaction scheme V.With primary amine (R ₂NH ₂) use formula R ₁CH ₂The halogenated methyl heterogeneous ring compound of X is handled, and obtains secondary amine, then according to standard method, this secondary amine is converted into acid amides.Perhaps, can be as the described method of reaction scheme V, by using R ₁CH ₂X prepares acid amides with the methane amide alkylation.With this acid amides with strong amide alkali; take off proton as di-isopropyl lithamide or two (trimethyl silyl) ammonification sodium, then, add excessive aroyl chloride; obtain two-acylated compounds, this compound turns to formula (I) imidazolium compounds by heating ring in containing the acetate of ammonium acetate.Perhaps, the negatively charged ion of acid amides and the aryl nitrile reaction of replacement directly can be obtained formula (I) imidazoles.

Following description and reaction scheme further specify method described in the above-mentioned reaction scheme I.Can improve the various pyrimidine aldehyde derivatives 6,7 and 8 that prepare described in the reaction scheme VI hereinafter by the method (Chem.Ber, 1964,97,3407) that will be incorporated herein people such as Bredereck for reference.Then this paper further describe synthetic in, with these pyrimidine aldehyde as intermediate.Unprotected amino-aldehyde derivative, for example 8 some instability of possibility.Shown in reaction scheme VI, utilize the acetate decomposition method, aldehyde 7 is come out with the isolated in form of acetamide derivative, (by intermediate 4, compound 3 being converted into 7) and the more stable compound of generation are used at cycloaddition reaction preparation formula (I) compound.

Should react, can use general acetate decomposition condition and this acetate decomposition condition is well known to a person skilled in the art.For example, at the suitable reaction conditions of embodiment 83 illustrated.In more detail, this reaction utilizes in the presence of the vitriol oil of catalytic amount, 2-aminopyrimidine dialkoxy acetal is heated with diacetyl oxide, simultaneously with the amine acetylize and make an alkoxyl group be converted into acetoxyl group.By alkoxide and corresponding alcoholic solvent with catalytic amount, for example, sodium methylate and methyl alcohol are deacetylated, and the compound that obtains is converted into aldehyde.Perhaps, can by earlier with diacetyl oxide with the amine acetylize, influence alkoxyl group and be converted into acetoxyl group and obtain higher productive rate by adding the vitriol oil then. Reaction scheme VI

At first reported the reaction of imines and tosyl group methyl carbylamine by van Leusen (people such as van Leusen, J.Org.Chem.1977,42,1153.).The condition of being reported is as follows: tert-butylamine (tBuNH ₂)/glycol dimethyl ether (DME), K ₂CO ₃/ MeOH, and NaH/DME.When testing these conditions again, find that each condition all produces very low productive rate.The second approach is also carrying out, and this approach comprises that amine transforms generation tertiary butyl imines, again with this tertiary butyl imines and carbylamine reaction, produces the 1-tBu imidazoles.Use any primary amine as alkali, this reaction all can take place similarly.Can use secondary amine, although it is not preferred, secondary amine also may decompose isocyanides lentamente.Similarly, reaction needed about 3 normal amine are finished, and obtain about 50% isolated yield.Be obstructed secondary amine (diisopropylamine) although suit, and its productive rate is very low and be not effectively usually.Under certain test conditions, use tertiary amine and aromatic amine, do not react as pyridine and triethylamine, more alkaline amine, as DBU, and 4-dimethylaminopyridine (DMAP), though sluggish, can produce certain productive rate and therefore be applicable to this paper.

Following reaction scheme VII and VIII are described, formula VI pyrimidine aldehyde and primary amine condensation can be produced imines, it is separated aptly or in the presence of various suitable alkali and solvent described herein, with needed isocyanides situ reaction, obtain 5-(4-pyrimidyl)-imidazoles, wherein R ₂And R ₄As this paper about the definition in formula (I) compound.

The preferred method that shows a kind of preparation formula (I) compound hereinafter among the reaction scheme VII.Preparation and the normally unmanageable tar of isolating imines in not discrete step.And black is also often brought in the final product.The productive rate of preparation imines changes, and in its preparation, using from the environment protection aspect usually is unfavorable solvent, as CH ₂Cl ₂

This reaction, wherein p=2 needs suitable alkali to carry out.A kind of highly basic of this reaction needed, it is enough to isocyanides is taken off proton.Suitable alkali comprises amine, carbonate, hydride, perhaps alkyl or aryl lithium reagent; Or its mixture.Alkali comprises, but is not restricted to salt of wormwood, yellow soda ash, and primary amine and secondary amine, as tert-butylamine, diisopropylamine, morpholine, piperidines, tetramethyleneimine and other non-nucleophilicity alkali, as DBU, DMAP and 1,4-diazabicylo [2,2,2] octanes (DABCO).

The employed The suitable solvent of this paper comprises, but is not restricted to N, dinethylformamide (DMF), and MeCN, halogenated solvent, as methylene dichloride or chloroform, tetrahydrofuran (THF) (THF), methyl-sulphoxide (DMSO), alcohol, as methyl alcohol or ethanol, benzene, toluene, DME, or EtOAc.Preferably, solvent is DMF, DME, THF, or MeCN, more preferably DMF.Usually by adding entry and product being filtered into the separation that purified compound is finished product.

Reaction scheme VII

Although for scale operation is inconvenient, but still need replace TERTIARY BUTYL AMINE to be added in the isocyanides with NaH, simultaneously, temperature of reaction may be lower than 25 ℃ (in THF).In addition, it is reported that under-50 ℃, BuLi is the effective alkali that is used for tosyl group benzyl isocyanides is taken off proton.(DiSanto，R.；Costi，R.；Massa，S.；Artico，M.Synth.Commun.1995，25，795)。

According to preferred bases, can use all temps.For example, when using tBuNH ₂/ DME and K ₂CO ₃/ MeOH, K ₂CO ₃During/DMF, surpassing under 40 ℃ the temperature, it is about 20% that productive rate can be reduced to, but 0 ℃ to 25 ℃ reaction down, productive rate does not have too big difference.Therefore, will be lower than 0 ℃ and surpass 80 ℃ temperature range and also regard as within the scope of the present invention.Preferably, temperature range is at about 0 ℃-25 ℃.Room temperature mentioned in this article is meant 25 ℃, but known this temperature can change between 20 ℃-30 ℃.

Shown in the following reaction scheme VIII, preferably, imines forms in solvent on the spot.This preferred synthetic method is the synthetic method that exists with one pot of (one-pot) synthesized form.Aptly, when the salt that uses primary amine in an embodiment, during as dihydrochloride, before adding isocyanides, alkali can further be comprised in the reactant, as salt of wormwood.In addition, as described below, piperidines nitrogen can be protected with protecting group.Reaction conditions, as solvent, alkali, temperature or the like is similar with the condition of relevant segregation imines described in the above-mentioned reaction scheme VII.It will be recognized by those skilled in the art that in some cases the formation on the spot of imines may need dehydration conditions, the latter may need acid catalyst.

Reaction scheme VIII

Shown among the reaction scheme VIIIa hereinafter is the other method of preparation formula (I) compound.Difficulty for fear of relevant with separating pyrimidine aldehyde 8 as described herein, must be hydrolyzed to aldehyde 8 with acetal 3.Subsequently, available primary amine, ethyl acetate, and NaHCO ₃Handle formed aldehyde 8, form corresponding imines on the spot, this imines is extracted in the ethyl acetate.Add isocyanides, carbonate bases and DMF make 5-(4-pyrimidyl)-imidazolium compounds form, wherein R ₂And R ₄As the definition of this paper about formula (I) compound.

Although known response route VII, VIII and VIII (a) use R ₂The piperidine ring of position illustrates, but this only is to be used for illustration purpose, and should utilize any suitable R defined herein ₂

Reaction scheme VIIIa

The method of preferred synthesis type (I) compound also provides for example by using the 2-methylthiopyrimidine aldehyde derivatives of partly describing at embodiment, with S (O) m moieties introducing pyrimidine (R ₁Base) the suitable and reliable method on.

In following reaction scheme IX, although compound 1 (X=S methyl) is a final product, also can be used as precursor compound, be used to prepare other formula (I) compound as mentioned above.In this particular case, be the methylsulfinyl part with the methylthio group partial oxidation, can further this part be modified to the amino of replacement in addition.

Reaction scheme IX

Shown in reaction scheme X, another embodiment of the present invention is that 2-methylthio group-pyrimidine acetal is hydrolyzed to 2-methylthiopyrimidine aldehyde.Use various reaction conditionss,, acetal is hydrolyzed to aldehyde can not obtains gratifying productive rate, resulting productive rate＜13% as formic acid.Preferred synthetic method relates under heating condition, uses the solvent orange 2 A cOH (fresh) and the vitriol oil, the sulfuric acid of preferred catalytic amount.Heating condition comprises that temperature is about 60 ℃-85 ℃, 70 ℃-80 ℃ of preferably approximatelies, and higher temperature makes the reaction mixture blackening.After reaction is finished, be cooled to mixture under about room temperature and remove acetate.Other method relates under 40 ℃, in 3NHCl, with acetal heating 18 hours, cools off, and the solution of bicarbonate neutralizes is extracted among the EtOAc.

Reaction scheme X

Prepare final formula (I) 2-aminopyrimidine-4-base imidazolium compounds by a kind of in following three kinds of methods, and the compound that similarly contains pyridine: 1), directly and carbylamine reaction with 2-aminopyrimidine imines; 2), with 2-kharophen pyrimidine imines and isocyanides condensation, remove kharophen then; With 3), 2-methylthiopyrimidine derivative is oxidized to corresponding sulfoxide, replace with needed amine then.

For example, although for R ₂The position is with the optional piperidines part that replaces or for R ₄, assign to describe the reaction scheme of this paper with 4-fluorobenzene base portion, if but can on primary amine, prepare any suitable R ₂Part or R ₄Part can add in this mode.Similarly, any suitable R ₄Can add by the isocyanides approach.

Can come preparation feedback route I Chinese style (II) compound by the same methods of people's document such as above-mentioned van Leusen.For example, can come preparation formula (II) compound, Ar wherein, R by formula (IV) compound-reaction scheme I is dewatered ₄With p as herein definition.

Suitable dewatering agent is included in suitable alkali, as triethylamine or diisopropylethylamine, or similar alkali, as the phosphoryl chloride under the pyridine existence, oxalyl chloride, thionyl chloride, phosgene, or toluene sulfonyl chloride.The suitable solvent is a dimethoxy ether, tetrahydrofuran (THF), or halogenated solvent, preferred THF.When temperature of reaction remained on-10 ℃-0 ℃, reaction was the most effective.At a lower temperature, reaction not exclusively and under comparatively high temps, solution blackening and productive rate descend.

Can be by removing water or not removing under the condition of water, with formula V compound-reaction scheme I, R ₄CHO (R wherein ₄As defined herein) with ArS (O) _pH and formamide are come preparation formula (IV) compound-reaction scheme I, preferably, under dehydration conditions, in the temperature of room temperature or rising, for example under 30 ℃-150 ℃, usually acid catalyst exist or not in the presence of, under refluxing, react.Perhaps, can use trimethylsilyl chloride to replace acid catalyst.The example of acid catalyst comprises camphor-10-sulfonic acid, formic acid, tosic acid, hydrogenchloride or sulfuric acid.

The best approach of preparation formula (IIa) isocyanides illustrates among the reaction scheme XI hereinafter.

Reaction scheme XI

Can pass through aldehyde 1-reaction scheme XI-and acid, as tosic acid, formic acid or camphorsulfonic acid; With methane amide and to toluenesulfinic acid (under about 60 ℃ reaction conditions reaction about 24 hours) heating finish and replace the conversion of aldehyde to tosyl group benzyl methane amide.Preferably, do not use solvent.When using solvent, as DMF, DMSO, toluene, when acetonitrile or excessive methane amide, reaction obtains lower productive rate (＜30%).When temperature is lower than 60 ℃, the required product that obtains seldom, and when temperature surpassed 60 ℃, the product that can obtain decomposing perhaps obtained benzyl diformamide 2-reaction scheme XI.In the described embodiment 23 of people WO95/02591 such as Adams (a), synthesized 4-fluoro phenyl-tosyl group methylformamide, formula (IV) compound-reaction scheme I, wherein, p=2.The difference of this method and described herein method is following reaction conditions, use the sodium salt of toluenesulfinic acid, this reaction is compared with the non-water condition of use with use-sulfinic acid described herein, causes unsettled heat release, low-yield and the low repeatability of producing.

The condition of α-(the p-toluenesulfonyl)-4-fluoro benzyl isocyanides of people described in WO95/02591 embodiment 23 (b) such as preparation Adams is to extract product with MeCl and DME as solvent.The present invention is by using cheap solvent, extracts as THF and EtOAc and improves this method.By with alcohol, as 1-propyl alcohol recrystallization, obtain higher productive rate, although other alcohol, as methyl alcohol, ethanol and butanols also suit.By using the chromatography technology, be further purified with dangerous solvents more earlier the compound partial purification.

Another embodiment of the present invention be by with two methane amide intermediate 2-reaction scheme XI-with toluenesulfinic acid is reacted to synthesize tosyl group benzyl benzamide compound.In this optimization approach, by in The suitable solvent, using acid catalysis, aldehyde and methane amide heated finish from the two methane amides of aldehyde preparation.The suitable solvent is a toluene, acetonitrile, DMF and DMSO or its mixture.Acid catalyst is well known by persons skilled in the art and includes, but are not limited to hydrogenchloride, tosic acid, camphorsulfonic acid and other anhydrous acid.This reaction can be carried out in the temperature range that preferably approximately is 50 ℃ about 4-5 hour at about 25 ℃-110 ℃, and the longer reaction times also suits.Visible product decomposes and lower productive rate in (＞70 ℃) and longer reaction times under higher temperature.Finishing the conversion of product need remove water usually from reaction mixture.

The condition that preferably two carboxamides derivatives is converted into tosyl group benzyl methane amide is by in The suitable solvent, two methane amides and acid catalyst and tosic acid is reacted realize.Employed solvent includes, but are not limited to toluene and acetonitrile or its mixture in this reaction.These solvents and DMF, or other mixture of DMSO also can use, but may produce lower productive rate.Temperature can change in about 30 ℃ of-100 ℃ of scopes.Being lower than 40 ℃ is not preferred with the temperature that is higher than 60 ℃, because productive rate and speed of response reduce.Preferably, temperature range is at about 40 ℃-60 ℃, most preferably about 50 ℃.Best Times is 4-5 hour, although the reaction times can also be longer.Preferably, employed acid includes, but are not limited to toluenesulphonic acids, camphorsulfonic acid and hydrogenchloride and other anhydrous acid.Most preferably, in 1: 1 toluene and acetonitrile, two methane amides are heated with tosic acid and hydrogenchloride.

Another embodiment of the present invention is the preferred route of synthesis of synthetic tosyl group benzyl benzamide compound, and it is finished by using one pot of method.This method at first is converted into aldehyde two carboxamides derivatives and subsequently two carboxamides derivatives and toluenesulphonic acids is reacted.This method is merged into single, effective means with top condition.In the method, can obtain high yield,＞90% aryl benzyl methane amide.

Preferred reaction conditions is at preferred solvent toluene: in the acetonitrile, preferably, this solvent ratio is 1: 1, uses catalyzer, as trimethylsilyl chloride (TMSCl).Reagent such as TMSCl are preferred, and also producing hydrogenchloride simultaneously comes catalyzed reaction with the water reaction that wherein produces for it.Also preferably use hydrogenchloride and tosic acid.1), use the dewatering agent that hydrogenchloride also is provided, as TMSCl therefore, employed three the suitable reaction conditionss of this paper comprise:; Or by 2), use suitable dewatering agent and suitable acid source, for example include, but are not limited to camphorsulfonic acid, hydrogenchloride or tosic acid; With 3), other dehydration conditions, remove water and use acid catalyst and tosic acid as azeotropic.

Also can be by in the presence of highly basic, with formula (VI) compound-reaction scheme I-R ₄CH ₂NC and formula (VII) compound-reaction scheme I-ArSO ₂L ₁Reaction, wherein R ₄With Ar as herein definition and L ₁Be leavings group such as halogen, for example fluorine comes preparation formula (II) compound, and wherein p is 2.Suitable highly basic includes, but are not limited to lithium alkylide such as butyllithium or di-isopropyl lithamide people such as (, Tetrahedron Letters, No.23,2367-68 (1972)) Van Leusen.

Can come preparation formula (VI) compound-reaction scheme I by following method, described method comprises formula (VIII) compound-reaction scheme I-R ₄CH ₂NH ₂With alkyl formate (for example ethyl formate) reaction, obtain midbody acid amide, by the alkali that is suiting, exist down as triethylamine,, as include, but are not limited to oxalyl chloride this acid amides and known dewatering agent, phosphoryl chloride or toluene sulfonyl chloride reaction are converted into the isocyanides that needs.

Perhaps, can in moisture methylene dichloride,, formula (VIII) compound-reaction scheme I-be converted into formula (VI) compound-reaction scheme I by in the presence of phase reforming catalyst with chloroform and sodium hydroxide reaction.

Can pass through formula R ₁CHO compound and primary amine R ₂NH ₂Reaction comes preparation formula (III) compound-reaction scheme I.

The aminocompound of formula (VIII)-reaction scheme I-is known or can be by use standard functional group change method that from corresponding alcohol, oxime or acid amides prepare.

In following reaction scheme XII, compound 5-reaction scheme 12-is shown among the embodiment 2 of embodiment part, and compound 6-reaction scheme 1 2-is shown among the embodiment 4; Compound 7-reaction scheme 12-is shown among the embodiment 5; Compound 8-reaction scheme 12-is shown among the embodiment 6; And compound 9-reaction scheme 12-is shown among the embodiment 7. Condition: a) i, NH ₂OHHCl, Na ₂CO ₃, H ₂O; Ni in ii, the Ruan, H ₂B) 2-aminopyrimidine base-4-formaldehyde, CH ₂Cl ₂C), 4-fluorophenyl-toluene thiomethyl isocyanides, TBD, CH ₂Cl ₂D) i, HCl, H ₂O; Ii, Na ₂CO ₃, H ₂O; E), NH ₂OHHCl, Na ₂CO ₃, H ₂O; F), NaCNBH ₃, MeOH; G), KNCO, DMF, H ₂O, HOAC.

Reaction scheme XII

Can be according to the conventional reduction amination method, as at H ₂Among the O, form oxime, then under standard conditions, as at H with azanol ₂Under the environment,, oxime is reduced to the method for amine, naphthenone such as 1-reaction scheme XII-(from Aldrich Chemical Co., Milwaukee, Wi obtains) are converted into cycloalkanes amine such as 2-reaction scheme XII with Ni catalytic hydrogenation in Ruan.Can be in the non-hydroxyl organic solvent, the cycloalkanes amine that obtains such as 2-reaction scheme XII-and aryl aldehyde such as 2-aminopyrimidine base-4-formaldehyde reaction are obtained imines such as 3-reaction scheme XII.According to the aldehyde activation is the degree of imines, need or do not need acid catalyst (as toluenesulphonic acids) and dehydration conditions (removing water) as azeotropic in backflow benzene.Can pass through at alkali, as 1,5,7-three azabicyclics [4.4.0]-last of the ten Heavenly stems-5-alkene (TBD) existence is following, at organic solvent, as CH ₂Cl ₂In with isocyanides, as 4-fluorophenyl-tolyl thiomethyl carbylamine reaction,, be converted into 1 of cycloalkylalkylization the 4-diaryl imidazole as 3-reaction scheme XII-with imines.In the method, 3-reaction scheme XII-is converted into 5-reaction scheme XII.With the imidazoles that the cycloalkyl ketal replaces, with aqueous acid (as the HCl aqueous solution) hydrolysis, use alkali then (as Na as 5-reaction scheme XII- ₂CO ₃The aqueous solution) neutralization obtains ketone such as 6-reaction scheme XII.At H ₂Among the O, 6-reaction scheme XII-is converted into oxime 7-reaction scheme XII with azanol.By in methyl alcohol,, 7-reaction scheme XII-is converted into azanol 8-reaction scheme XII with the sodium cyanoborohydride reduction.Method according to people such as Adams (WO91/1467 announced on October 3rd, 1991) is converted into hydroxyurea 9-reaction scheme XII with 8-reaction scheme X-.

Reaction scheme XIII

In above-mentioned reaction scheme, can be by using suitable reductive agent, as NaBH ₄13-also prepared pure 10-reaction scheme 13 originally with ketone 6-reaction scheme.

In following formula XI, R ₁Can be the optional alkyl that replaces, aryl or heterocyclic radical and R ₂Be OH, NH ₂Or SH, perhaps R ₁And R ₂Form C together _3-7Cycloalkyl ring is as tetramethyleneimine or piperidine ring.Some representational this examples for compounds has been described in following reaction scheme XIV.

Reaction scheme XIV

Can be with ketone 1 and organometallic reagent (R ₁M) reaction obtains corresponding alcohol 2 (wherein, R ₁Can be the alkyl of hydrogen or any optional replacement, aryl, arylalkyl, heterocyclic radical, parts such as heterocyclic radical alkyl).Well known to a person skilled in the art traditional Ritter reaction by use, alcohol 2 can be converted into neo-pentyl amine 3.Can be with amine 3 acidylates or sulfonylation.Available reagent such as dimethyl sulfonium methylide and dimethyl sulfoxonium methylide are converted into volution oxidative ethane 4 with ketone 1.Available excessive nucleophilic reagent, as oxyhydroxide, thiolate, amine, organometallic reagent (organic copper hydrochlorate or organoaluminum reagent etc. as is well known) is opened the ring of oxyethane 4.

Reaction scheme XIV

Also can ketone 1-reaction scheme XV-be carried out reductive amination, obtain amine 6-reaction scheme XV with primary amine or secondary amine.

R ₁And R ₂Can be any alkyl or aryl, R ₁And R ₂Also can be the integral part of ring

Reaction scheme XV

The suitable protecting group that is used for hydroxyl and imidazoles nitrogen is well known in the art and at a lot of documents, for example " protecting group in the organic synthesis ", Greene T W, Wiley-Interscience, NewYork describes in 1981.The example of suitable hydroxyl protecting group comprises silyl ether, as tertiary butyl dimethyl or tert-butyl diphenyl, with alkyl oxide, has the alkyl chain (CR of variable key as connection ₁₀R ₂₀) _nMethyl.The example of suitable imidazoles nitrogen-protecting group comprises THP trtrahydropyranyl.

In known manner, for example, by in the presence of The suitable solvent, the acid treatment with sufficient quantity obtains formula (I) compound pharmaceutically acceptable acid additive salt.

Methods of treatment

Can utilize formula (I) compound or pharmaceutically acceptable salt thereof to prepare and be used for medicine preventative or therapeutic treatment people or any disease of other Mammals, described disease is by described mammiferous cell, as includes, but are not limited to monocyte and/or scavenger cell and produce the cytokine of excessive or non-regulated quantity and increase the weight of or cause.

Formula (I) compound can suppress preceding inflammatory cytokine, as IL-1, during therefore IL-6, IL-8 and TNF also are used for the treatment of.IL-1, IL-6, IL-8 and TNF influence various cells and tissue and these cytokines and other white corpuscle deutero-cytokine be various diseases important with inflammatory mediator key.Suppressing these preceding inflammatory cytokines is useful controlling, alleviating and alleviate in a lot of diseases.

Formula (I) compound can suppress derivable preceding inflammatory protein, and as COX-2, it also has a lot of other titles, as prostaglandin(PG) endogenous superoxide synthetic enzyme-2 (PGHS-2) and in therefore being used for the treatment of.Produce these preceding inflammatory lipid mediums of cyclooxygenase (CO) approach by derivable COX-2 enzyme.Therefore, regulate COX-2 (its participate in medicine give birth to tetraenoic acid produce product) various cells of influence and tissue such as prostaglandin(PG), thus COX-2 be various diseases important with inflammatory mediator key.The expression of COX-1 is not subjected to the influence of formula (I) compound.This selectivity suppresses COX-2 and can alleviate or do not injure and suppress relevant the causing the ulcer tendency and so suppress the essential prostaglandin(PG) of cytoprotection of COX-1.Therefore, suppressing these these pre-inflammatory mediators is useful controlling, alleviating and alleviate in a lot of morbid states.The most significantly, these inflammatory mediators, particularly prostaglandin(PG) and pain, as with pain receptor sensitization, or edema is relevant.Therefore, this respect treatment of pain comprises the treatment of neuromuscular pain, headache, cancer pain and arthritis ache.By suppressing the synthetic of COX-2 enzyme, formula (I) compound or pharmaceutically acceptable salt thereof is used for people or other mammiferous prevention or treatment.

Therefore, the invention provides and suppress COX-2 synthetic method, it comprises formula (I) compound or pharmaceutically acceptable salt thereof that gives significant quantity.The present invention also provides by what suppress the COX-2 enzyme and synthesizes to come prophylactic treatment people or mammiferous method.

Therefore, the invention provides the method for the cytokine mediated disease of treatment, it comprises formula (I) compound or pharmaceutically acceptable salt thereof that gives interference cell factor significant quantity.

Especially, formula (I) compound or pharmaceutically acceptable salt thereof can be used for prevention or treatment people or other mammiferous any disease, wherein, described disease is by described mammiferous cell, as including, but are not limited to the IL-1 that monocyte and/or scavenger cell produce excessive or non-regulated quantity, IL-8 or TNF increase the weight of.

Therefore, on the other hand, the present invention relates to suppress the method that the described inhibiting Mammals IL-1 of needs produces, it comprises formula (I) compound or pharmaceutically acceptable salt thereof that gives described Mammals significant quantity.

A lot of morbid states are arranged, wherein, produce excessive or non-regulated quantity IL-1 and increase the weight of and/or cause that this disease is relevant.These morbid states comprise rheumatoid arthritis, osteoarthritis, and apoplexy, endotoxemia and/or toxic shock syndrome, other acute or chronic inflammatory disease state is as Inflammatory response or inflammatory bowel disease by endotoxin induced; Tuberculosis, atherosclerosis, myodegeneration, multiple sclerosis disease, emaciation, bone resorption, arthritic psoriasis, Josef Reiter sick syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella arthritis and acute synovitis.Up-to-date sign shows, IL-1 activity and diabetes, and pancreatic beta cell is relevant with presenile dementia.

On the other hand, the present invention relates to suppress the method that the described inhibiting Mammals TNF of needs produces, it comprises formula (I) compound or pharmaceutically acceptable salt thereof that gives described Mammals significant quantity.

Produce excessive or non-regulated quantity TNF and mediation or increase the weight of a large amount of diseases relevant, described disease comprises rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, urarthritis and other arthritis disease, Sepsis, septic shock, endotoxin shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, apoplexy, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, sarcoidosis of lung (sarcoisosis), bone absorpting disease is as osteoporosis, reperfusion injury, graft-vs-host reaction, homograft rejecting reaction infects the fever and the myalgia that cause as influenza, the emaciation of secondary infection or malignant tumour, the emaciation of secondary acquired immune deficiency syndrome (AIDS) (AIDS), AIDS, ARC (syndrome relevant) with AIDS, keloid forms, scar tissue forms, Crohn disease, ulcerative colitis and pyresis.

Formula (I) compound also is used for the treatment of virus infection, and wherein, the rise that described virus causes TNF (upregulation) is generation responsive or that will excite TNF in the body.The virus that this paper will treat is those producing the virus of TNF as result of infection, or those are to the virus of restraining effect sensitivity, and described restraining effect for example comprises that the compound by the inhibition TNF of formula (I) directly or indirectly suppresses to duplicate.This virus includes, but are not limited to HIV-1, HIV-2 and HIV-3, and scavenger cell virus (CMV), influenza, adenovirus and simplexvirus group, as include, but are not limited to zoster and herpes simplex.Therefore, on the other hand, the present invention relates to the mammiferous method that treatment is subjected to human immunodeficiency virus (HIV) invasion and attack, it comprises formula (I) compound or pharmaceutically acceptable salt thereof that gives the effective TNF amount of suppression of this Mammals.

Formula (I) compound also can be used for needs and suppress the mammiferous treatment except that the people that TNF produces.In animal, be used for the treatment of the disease that mediates with preventative-therapeutic TNF and comprise above-mentioned morbid state, but especially refer to virus infection.These viral examples include, but are not limited to lentivirus and infect, infectious anemia virus as horse, the arthritis virus of sheep, visna virus, or maedi virus or retroviral infection, include, but are not limited to feline immunodeficiency virus (FIV) as these viral examples, bovine immunodeficiency virus, or dog immunodeficiency virus or other retroviral infection.

Typically, formula (I) compound also can treat or prevent by producing excessive cytokine, as the morbid state that mediates or increase the weight of by IL-1 or TNF respectively, and as sacroiliitis, eczema, psoriasis and other inflammatory dermatosis are as sunburn; The ophthalmia disease comprises conjunctivitis; Pyresis, the disease of pain and other and inflammation-related.

Show that formula (I) compound can suppress IL-8 (interleukin 8, generation NAP).Therefore, on the other hand, the present invention relates to suppress the method that the described inhibiting Mammals IL-8 of needs produces, it comprises formula (I) compound or pharmaceutically acceptable salt thereof that gives described Mammals significant quantity.

A lot of morbid states are arranged, wherein, produce excessive or non-regulated quantity IL-8 and increase the weight of and/or cause that this disease is relevant.The characteristics of these diseases are that a large amount of neutrophils soak into, as psoriasis, and inflammatory bowel disease, asthma, heart and kidney reperfusion injury, grownup's respiratory distress syndrome (ivrds), thrombosis and glomerulonephritis.All these diseases are all relevant with IL-8 generation increase, and wherein, IL-8 is relevant to the chemotactic at inflammatory position with neutrophil.Opposite with other inflammatory cytokine (IL-1, TNF and IL-6), IL-8 has unique promotion neutrophil chemotactic and activated characteristic.Therefore, suppress IL-8 and produce the infiltration that will cause directly reducing neutrophil.

With enough inhibition cytokine, particularly IL-1, IL-6, IL-8 or TNF produce, and make it be adjusted to normal value, perhaps, make it be adjusted to amount giving construction (I) compound that is lower than normal value in some cases, improve thus or the preventing disease state.For example, in the present invention, IL-1, IL-6, the outlier of IL-8 or TNF comprises: (i), free (not combining) IL-1 with cell, and IL-6, the level of IL-8 or TNF is more than or equal to 1pg/ml; (ii), any and cell bonded IL-1, IL-6, IL-8 or TNF; Or (iii), in cell or tissue, exist to surpass the IL-1 of basal level, IL-6, IL-8 or TNF mRNA wherein produce IL-1, IL-6, IL-8 or TNF respectively.

Formula (I) compound is a cytokine, IL-1 particularly, and IL-6, the inhibitor of IL-8 and TNF, during this discovery was based on and measures in the body described herein, formula (I) compound was to IL-1, and the effect that IL-6 and TNF produce is made.

Term as used herein " suppresses the generation of IL-1 (IL-6, IL-8 or TNF) " and is meant:

A), by suppressing all cells in the body, include, but are not limited to monocyte or scavenger cell and discharge cytokine, (IL-1, IL-6, IL-8 or TNF) is reduced to normal value or is lower than normal value with cytokine excessive in the human body;

B), on gene level, (IL-1, IL-6, IL-8 or TNF) is lowered to normal value or is lower than normal value with cytokine excessive in the human body;

C), directly suppress the synthetic of cytokine (IL-1, IL-6, IL-8 or TNF), (IL-1, IL-6, IL-8 or TNF) is lowered to normal value or is lower than normal value with cytokine excessive in the human body by the back translation activities; Perhaps

D), on translation skill, (IL-1, IL-6, IL-8 or TNF) is lowered to normal value or is lower than normal value with cytokine excessive in the human body;

Term as used herein " disease or the morbid state of TNF mediation " is meant a kind of like this or all morbid states, wherein TNF is by generation TNF itself or by causing another kind of monokine, as including, but are not limited to IL-1, L-6 or IL-8 discharge and play a role.Therefore, a kind of disease, if wherein for example IL-1 be main ingredient, the disease states mediated by TNF is then thought in and its generation or to play a role be to be strengthened or produced (secreted) by TNF.

Term as used herein " cytokine " is meant and anyly influences the secrete polypeptide of cell function and be the molecule of regulating cell-cell interaction in immunity, inflammation or hematopoiesis reaction.Cytokine includes, but are not limited to monokine and lymphokine, and no matter which cell they are produces.For example, usually, monokine is meant by monocyte, produces and the excretory factor as scavenger cell and/or monocyte.Yet much other cell also produces monokine, as natural killer cell, and inoblast, basophilic cell, neutrophil(e) cell, endotheliocyte, cerebral astrocytic, marrow stromal cell, epidermal keratinocytes and B-lymphocyte.Usually, lymphokine is meant the factor that is produced by lymphocyte.The example of cytokine includes, but are not limited to interleukin 1 (IL-1), interleukin-6 (IL-6), interleukin 8 (IL-8), tumor necrosis factor-alpha (TNF-α) and tumour necrosis factor-β (TNF-β).

Term as used herein " cytokine interference volume " or " cytokine amount of suppression " are meant, prevent or treat when giving patient's formula (I) compound by producing that excessive or non-regulated quantity cytokine increases the weight of or during the disease that causes, the significant quantity of needed formula (I) compound when the cells in vivo factor is reduced to normal value or is lower than normal value.

The cytokine of indication was and following process related cytokine during term as used herein " suppressed cytokine; be used for the treatment of the patient that HIV-infects ": (a), start and/or keep the HIV genetic expression of t cell activation and/or activated T cells mediation and/or duplicate and/or (b), any and cytokine mediated relevant problem of disease, as emaciation or myodegeneration.

Because TNF-β (also claiming lymphotoxin) and TNF-α (also claiming cachectin) have close structural homology and owing to they all cause similar biologically and combine with identical cell receptor, therefore, TNF-α and TNF-β can be suppressed by The compounds of this invention and therefore be referred to as " TNF " at this paper, except that other explanation.

Recently, the newcomer of map kinase family perhaps claims CSBP, p38, or RK is determined independently by several families laboratory.When in different cell systems, use the wide spectrum stimulator, during as the physics and chemistry stress stimulation with lipopolysaccharides or preceding inflammatory cytokine such as interleukin 1 and tumour necrosis factor processing, find can activate this new protein kinase by the binary phosphorylation.Prove that cytokine biosynthesis inhibitor of the present invention, formula (I) compound are CSBP/p38/RK kinase activity inhibitor effectively and optionally.These inhibitor assist to determine the related signal pathway that sends in the Inflammatory response.Especially, for the first time clear and definite signal transduction pathway is described as lipopolysaccharides in the scavenger cell in the aborning effect of cytokine.

Subsequently, cytokine inhibitor is tested at the animal model that much is used for measuring anti-inflammatory activity.Selected model system is to the cyclooxygenase-2 inhibitors relative insensitivity, so that find the unique activity of cytokine inhibitor.Aspect this in body in the research, this inhibitor shows tangible activity a lot.It should be noted that most its effectiveness in the endotoxin shock model of collagen protein inductive arthritis model and inhibition TNF generation.In one research of back, the reduction of Plasma TNF and existence and exempt from the death relevant and be correlated with interior toxicity.In mouse fetus long bone bone organ culture system, the effectiveness that compound suppresses bone resorption also is important.People such as Griswold, (1988) Arthritis Rheum.31:1406-1412; People such as Badger, (1989) Circ.Shock 27,51-61; People such as Votta, (1994) in vitro.Bone 15,533-538; People such as Lee, (1993) .B Ann.N.Y.Acad.Sci, 696,149-170.

For use formula (I) compound or pharmaceutically acceptable salt thereof in treatment,, usually it is formulated as pharmaceutical composition according to the standard pharmaceutical convention.Therefore, the present invention also relates to comprise the pharmaceutical composition of effective, nontoxic amount formula (I) compound and pharmaceutically acceptable carrier or thinner.

Usually, formula (I) compound, its pharmacologically acceptable salt and the pharmaceutical composition that comprises them thereof can give by normally used any approach in the administering mode, for example, and oral, local, non-enteron aisle or inhalation.Formula (I) compound can give with regular dosage form, and described regular dosage form can prepare by formula (I) compound is combined with the standard drug carrier according to ordinary method.Formula (I) compound also can be united with routine dose and known, second kind of therapeutical active compound and given.These methods also relate to becomes needed preparation with suitable component mixing, granulation and compressing tablet or dissolving.Known, the form of pharmaceutically acceptable carrier or thinner and characteristics receptor 1 activity component and merge amount, route of administration and the domination of other known variables of component.Other component should be compatible in carrier and the preparation, and on this meaning, carrier must be " acceptable " and be harmless to the user.

For example, employed pharmaceutical carrier can be solid or liquid.The example of solid carrier is a lactose, terra alba, sucrose, talcum powder, gelatin, agar, pectin, gum arabic, Magnesium Stearate, stearic acid or the like.The example of liquid vehicle is a syrup, peanut oil, sweet oil, water or the like.Similarly, carrier or thinner can comprise time lag material well known in the art, as the mixture of single glyceryl monostearate or distearin or itself and wax.

Can use various medicament forms.Therefore, if use solid carrier, preparation can be a tablet, is placed on capsule in the gelatine capsule, perhaps lozenge or dragee with powder or short grained form.The amount of solid preparation can extensively change, but preferably approximately is 25mg-1g.When using liquid vehicle, dosage form is a syrup, emulsion, and Gelseal, the sterilization injectable liquids is as peace bottle or non-aqueous liquid suspension.

Formula (I) compound can pass through topical, promptly gives by non-whole body administering mode.This comprises by applications, and formula (I) compound is applied to the part or the vestibule of mouth diease and this compound is instilled into ear, in eye and the nose, makes compound can not enter blood flow significantly like this.On the contrary, the whole body administration is meant oral, intravenously administrable, intraperitoneal administration and intramuscular administration.

The preparation that is suitable for topical comprises and is suitable for liquid or the semi-liquid preparations that transdermal reaches inflammation part, as liniment, and lotion, creme, ointment or paste and be suitable for eye, the drops of ear and nasal administration.For topical, active ingredient can account for the 0.001%-10% of the weight of preparation, for example 1%-2%w/w.Yet active ingredient can account for 10% of weight of formulation, but preferably is less than 5%w/w, more preferably 0.1%-1%w/w.

According to the present invention, lotion comprises the lotion that is suitable for skin or eye application.Eye wass can comprise the optional sterile water solution that comprises sterilant and can be according to similar preparation eye drops method preparation.The lotion or the liniment that are used for skin also can comprise the reagent that quickens drying and cooling skin, as ethanol or acetone, and/or wetting Agent for Printing Inks, as glycerine or oily as Viscotrol C or peanut oil.

According to the present invention, emulsion, ointment or paste are the semi-solid preparations that is suitable for the active ingredient of external application.They can be by under assisting at suitable machine, will fully separate or the active ingredient of powder type, separately or with the form of the aqueous solution or the suspension in water-based or non-aqueous liquid, mixes with greasing base or non-greasing base and to prepare.Matrix can comprise hydrocarbon such as hard, soft or whiteruss, glycerine, beeswax, metallic soap; Glue; Naturally occurring oil is as almond, corn, peanut, castor-oil plant or sweet oil; Lanolin or derivatives thereof or lipid acid are as stearic acid or oleic acid and alcohol, as the mixture or the tight gel of propylene glycol.Can comprise any suitable tensio-active agent in the preparation, as negatively charged ion, positively charged ion or nonionogenic tenside, as sorbitan ester or its polyoxyethylene deriv.Also can comprise suspension agent, as natural gum, derivatived cellulose or inorganic substance are as silicaceous silica and other component such as lanolin.

According to the present invention, drops can comprise sterilization water-based or oily solution or suspension and can be by solubilization of active ingredient is being contained sterilant and/or mycocide and/or any other suitable sanitas, and preferably comprises in the suitable aqueous solution of tensio-active agent and prepare.Then, can filter, transfer in the suitable container, handle or under 98-100 ℃, keep to sterilize half an hour and clarify the solution that obtains with this container sealing and by autoclave again by the solution that will obtain.Perhaps, can this solution be filtered and transfer to this solution of sterilizing in the container by under aseptic condition.The sterilant that is suitable for comprising in the drops and the example of mycocide are nitric acid or Phenylmercuric Acetate (0.002%), and benzyl chloride alkanamine (0.01%) and acetic acid are washed must Qin's (0.01%).The The suitable solvent that is used to prepare preferred solution comprises glycerine, the pure and mild propylene glycol of dilution.

Formula (I) compound can pass through parenterai administration, promptly by intravenously, and intramuscular, subcutaneous, in the nose, internal rectum, intravaginal or intraperitoneal administration.Usually, the subcutaneous and intramuscular administration form in the parenterai administration is preferred.The suitable formulation that is applicable to this kind administering mode can prepare by routine techniques.Formula (I) compound also can pass through inhalation, i.e. interior the or oral cavity inhalation by nose.Be applicable to the suitable formulation of this kind administering mode,, can prepare by routine techniques as aerosol or the sucker according to dosage supplied with.

For all methods disclosed herein, use formula (I) compound, preferably, every day, oral dosage was approximately the 0.1-80mg/kg body weight, and preferably approximately is the 0.2-30mg/kg body weight, more preferably is approximately 0.5-15mg.Every day, parenterai administration dosage was approximately the 0.1-80mg/kg body weight, and preferably approximately is 0.2-30mg/kg, and more preferably was approximately 0.5-15mg/kg.Preferably, every day, topical dosage was 0.1mg-150mg/kg, divided to give for 1-4 time, preferred every day 2-3 time.Preferably, every day, inhalation dose was approximately 0.01-1mg/kg.Those skilled in the art are also known, nature and extent according to the treatment disease, form of administration, approach and position and the particular patient of being treated are determined optimal dose and each spacing of doses of formula (I) compound or pharmaceutically acceptable salt thereof, and can determine this optimum value by routine techniques.Those skilled in the art are also known, can determine the optimal treatment approach by the normally used treatment approach of those skilled in the art determination test, i.e. the dosage number of times of the formula that gave every day (I) compound or pharmaceutically acceptable salt thereof.

By describing the present invention with reference to following biology embodiment, described embodiment only is used for explanation and does not limit the scope of the invention.

Biology embodiment

Determine that by following in vitro tests The compounds of this invention suppresses effect of cytokines:

Interleukin 1 (IL-1):

According to people such as Colotta, J Immunol, the method in 132,936 (1984) from the fresh blood goods that the volunteer provides, is perhaps separated the human peripheral blood mononuclear cell and purifying comes out from blood bank's buffy coat.With these monocytes (1 * 10 ⁶) be placed in 24 orifice plates with the concentration in 1,000,000/ml/ of 1-2 hole.Allow cell adhesion 2 hours, by washing lightly, remove not adherent cell then.Then, adding lipopolysaccharides (50ng/ml) before, test compound is being added to keeps 1 hour in the cell, and under 37 ℃, culture was hatched 24 hours again.After cultivate finishing, remove the supernatant liquor of substratum and with cell and all fragment clarifications.Then according to people's such as Simon method, J.Immunol.Methods, 84,85, people's such as (1985) (, consistent) or Lee method with the A23187 ionophore according to the ability that IL-1 stimulates clone (EL-4) the secretion IL-2 of interleukin II generation, J.Immuol Therapy, 6 (1), 1-12 (1990) (ELISA mensuration) measures the IL-1 biological activity of medium supernatant immediately.

Tumour necrosis factor (TNF):

According to Colotta, people such as R., J Immunol, the method in 132 (2), 936 (1984) from blood bank's buffy coat, is perhaps separated the human peripheral blood mononuclear cell and purifying comes out from the plateletpheresis residue.With these monocytes with 1 * 10 ⁶The density in individual cell/ml matrix/hole is placed in the 24 hole porous plates.Allow cell adhesion 1 hour, aspirate supernatant liquor then and add contain 1% foetal calf serum add penicillin and Streptomycin sulphate (the fresh matrix of 10 units/ml) (and 1ml, RPMI-1640, Whitaker Biomedical Products, Whitaker, CA).The test compound of 1nM-10mM dosage range exist or not in the presence of (with compound dissolution in dimethyl sulfoxide (DMSO)/ethanol, making that the ultimate density of solvent is 0.5% dimethyl sulfoxide (DMSO)/0.5% ethanol in the substratum), with cell constant temperature culture 45 minutes.Add bacteria lipopolysaccharide (the E.coli 055:B5[LPS that obtains by Sigma Chemicals Co.]) (100ng/ml is in the salt solution of 10ml phosphate buffered) then and with culture under 37 ℃, containing 5%CO ₂Incubator in constant temperature culture 16-18 hour.After cultivate finishing, the supernatant liquor of substratum removed from cell and centrifugal under the 3000rpm rotating speed, so that remove cell debris.Then described in WO92/10190 and according to people such as Becker, J.Immunol, the method in 1991,147,4307 with radioimmunoassay or ELISA assay method, is measured the TNF biological activity of supernatant liquor.

As if aspect the inhibition of mediation arachidonic acid metabolism, the inhibition of IL-1 and TNF is active inconsistent with the character of formula (I) compound.And, by nonsteroidal anti-inflammatory drug and effectively cyclooxygenase and/or lipoxygenase suppress activity and suppress that prostaglandin(PG) produces and/or leukotrienes synthetic ability is not to mean, compound also must suppress the generation of TNF or IL-1 under non-toxic dose.

Interleukin 8 (II-8):

(Cell Systems, Kirland Wa) are kept in the substratum, the CS-HBGF that described culture medium supplemented is made up of aFGF and heparin 15% foetal calf serum and 1% with initial stage people umbilical cord endotheliocyte (HUVEC).With 20 times of cell dilutions, put into coated 96 orifice plates of (250 μ 1) gelatin (gelating) then.Before use, change fresh substratum (200 μ l).Then buffer reagent or test compound (25 μ l, concentration is 1-10 μ M) are added in each hole in every group four hole and in 37 ℃ of humidification incubators, at 5%CO ₂Constant temperature culture is 6 hours under the environment.After cultivating end, remove supernatant liquor and use R﹠amp; D Systems (Minneapolis, IL-8ELISA kit measurement IL-8 concentration MN).According to typical curve, all data are all represented with the mean value (ng/ml) of a plurality of samples.If desired, obtain IC by non-linear regression ₅₀

The test of cytokine binding proteins specific

Utilize the radioactivity competition to provide the height multiple to elementary screening at structure-activity research in conjunction with test.This mensuration provides a lot of benefits that routine biochemistry is measured that surpass, and it utilizes new isolating person monocytic cell as the cytokine source and utilize ELISA to measure to determine its quantity.Except being the easier mensuration, confirm that extensively this is consistent with the height as a result of biochemical measurement in conjunction with measuring.Utilization obtains solubility kytoplasm part by the THP.1 cell and radiolabeled compound carries out the cytokine inhibitor of specificity and repeatability in conjunction with mensuration.The patent application USSN08/123175 that people such as Lee submitted in September, 1993 is among the USSN; The PCT94/10529 that people such as Lee submitted in September, 1994, with people such as Lee at nature 300, n (72), among the 739-746 (Dec.1994) above-mentioned screening of medicaments has been described so as to determine to interact with cytokine binding proteins specific (hereinafter claiming CSBP) and with the method for its bonded compound, this paper is incorporated herein by reference above-mentioned open source literature.Yet, in this article, conjugated proteinly in solution, can be isolated form, or fixed, perhaps can be expressed in the recombinant host cell surface by gene engineering method, as in the phage indicating system as expressing fusion protein.Perhaps, all comprise the full cell of CSBP or the kytoplasm fraction all can be used in the screening.Do not consider protein-bonded form, be enough to form under the condition of compound/conjugated protein mixture, chemical compound lot is contacted and detect the compound that can form, strengthen or disturb described mixture with conjugated protein.

In the final compound of representational formula (I), embodiment 4,7,8, and 10-21 demonstrates the positive activity that suppresses in this mensuration.

The mensuration of prostaglandin(PG) endoperoxides synthetic enzyme-2 (PGHS-2):

Following test has been described and has been used for the proteic inhibiting method of people PGHS-2 that mensuration formula (I) compound is expressed the person monocytic cell who stimulates at LPS.

Method:

By Ficoll and Percoll gradient centrifugation, the human peripheral blood mononuclear cell is separated from buffy coat.With cell with 2 * 10 ⁶The concentration in strain/hole is added in 24 orifice plates and allows them be supplemented with 1% people AB serum, and the 20mM L-glutaminate adhered to 1 hour among the RPMI of penicillin-Streptomycin sulphate and 10mMHEPES.Add the compound of various concentration and under 37 ℃, hatched 10 minutes.Add the LPS (causing expression of enzymes) in 50ng/ hole and 37 ℃ of following overnight incubation.Remove supernatant liquor and cell is washed once in cold PBS.With cytolysis at 100 μ l refrigerative cytolysis buffer reagent (50mM Tris/HCl pH7.5,150mM NaCl, 1%NP40,0.5% Sodium desoxycholates, 0.1%SDS, 300ug/ml DNAse, 0.1%TRITON X-100,1mMPMSF, 1mM leupeptin, 1mM Pepstatin) in.With solute centrifugal (10,000Xg is 10 minutes, under 4 ℃), removes fragment, and solvable fraction is carried out SDS PAGE. analyze (12% gel).By electrophoresis method, under 60 volts,, the protein transduction that is separated on the gel is moved on on the nitrocellulose membrane with 2 hours time.This film was dialysed 1 hour in containing the PBS/0.1% polysorbas20 of 5% skim-milk.After in PBS/ temperature buffer reagent, washing 3 times, this film with the anti-PGHS-2 serum of specificity of dilution in 1: 2000 or the anti-PGHs-1 serum of dilution in 1: 1 000, was hatched in containing the PBS/ tween of 1%BSA 1 hour and constantly jolting.This film is washed 3 times in the PBS/ tween, then with dilution in 1: 3000, donkey serum that horseradish peroxidase is puted together, anti-rabbit Ig (Amersham), in containing the PBS/ tween of 1%BSA, hatched 1 hour and constantly jolting.Then this film is washed 3 times in the PBS/ tween and utilize ECL immune detection system (Amersham) to measure the expression level of prostaglandin endoperoxides synthetic enzyme-2.

The result:

Following compounds has been carried out test and has been found that they are active (suppress LPS induce the effectiveness of PGHS-2 protein expression similar with the effectiveness of above-mentioned inhibition cytokine generation):

6-(4-fluoro phenyl)-2,3-dihydro-5-(4-pyridyl) imidazo (2,1-b) thiazole and dexamethasone.

There are several compounds to carry out testing and finding that they are inactive (maximum concentration to 10 μ M): 2-(4-methylsulfinyl phenyl)-3-(4-pyridyl)-6, the 7-dihydro-(5H)-pyrrolo-(1,2-a) imidazoles Rolipram; Azoxodone and NDGA.

In similarly testing, find that the none test compound can suppress PGHS-1 or cPLA ₂Protein level.

Synthetic embodiment

Describe the present invention by reference the following example, described embodiment only is illustrative, does not limit the scope of the invention.Except that other explanation, all temperature all are degree centigrade that all solvents all are that the highest suitable purity and all reactions all is under anhydrous condition, carry out under argon atmospher.

In an embodiment, all temperature all be degree centigrade (℃).Except that other explanation, on the VGZab mass spectrograph, utilize fast atom bombardment to carry out mass spectroscopy.At 250MHz, utilize BrukerAM 250 or Am400 spectrometer record ¹H-NMR (hereinafter " NMR ") spectrum.Multiplicity is meant: s=is unimodal, and d=is bimodal, t=three peaks, q=quartet, m=multiplet and br finger beam peak-to-peak signal.Sat refers to saturated solution, and eq refers to the molar equivalent ratio of the relative initial action thing of reagent.Carrying out the flash chromatography method on Merck silica gel 60 (230-400 order) measures.

Embodiment 1

1-(3-(4-morpholinyl)-propyl group-4-(4-fluoro phenyl)-5-(4-pyridyl) imidazoles

A), 4-fluoro phenyl-tolyl thiomethyl methane amide:

With right-fluorobenzaldehyde (1 3.1 milliliters (hereinafter claiming ml), 122 mmoles (hereinafter claiming mmol)), thiocresol (16.64 grams (hereinafter claiming g), 122mmol), methane amide (15.0ml, 445mmol), and the solution of toluene (300ml) merges and is heated to refluxing toluene, kept 18 hours, azeotropic is removed H simultaneously ₂O.The refrigerative reactant is used EtOAc (500ml) dilution and used saturated Na ₂CO ₃The aqueous solution (3 * 100ml), the saturated NaCl aqueous solution (100ml) washing, dry (NaSO ₄), and concentrate.Residue is handled with sherwood oil, filtered and vacuum-drying, obtain the white solid (85%) of 28.50g title compound, fusing point (hereinafter claiming mp)=119-120 ℃.

B), 4-fluoro phenyl-tolyl thiomethyl isocyanides:

Will be at CH ₂Cl ₂(25g 91mmol) is cooled to-30 ℃ and under mechanical stirring to embodiment 1 (a) compound (300ml), drips POCl ₃(11ml 110mmol), drips Et then ₃(45ml 320mmol), keeps temperature to be lower than-30 ℃ to N simultaneously.Stirred 30 minutes down and stirred 2 hours down at-30 ℃, use CH at 5 ℃ ₂Cl ₂(300ml) dilute and use 5%Na ₂CO ₃The aqueous solution (3 * 100ml) washings, dry (Na ₂SO ₄) and be concentrated into 500ml.With this solution by sintering in big glass funnel, 12 * 16cm contains CH ₂Cl ₂The silica gel tube filter, obtain light brown, the wax sample solid of 12.5g (53%) purifying isocyanides.IR(CH ₂Cl ₂)2130cm ^-1。

C), Pyridine-4-Carboxaldehyde (4-morpholinyl third-3-yl) imines:

With Pyridine-4-Carboxaldehyde (2.14g, 20mmol), 4-(3-aminopropyl) morpholine (2.88g, 20mmol), toluene (50ml) and MgSO ₄(2g) merge and under argon environment, stirred 18 hours.With MgSO ₄Filter out and filtrate concentrated, with residue at CH ₂Cl ₂In reconcentration, obtain the yellow oil of 4.52g (97%) title compound, according to ¹H NMR finds, comprises in this oily matter and be less than 5% aldehyde.

¹H?NMR

(CD ₃Cl)：d8.69(d，J＝4.5Hz，2H)，8.28(s，1H)，7.58(d，J＝4.5Hz，2H)，3.84(m，

6H)，2.44(m，6H)，1.91(m，2H).

D), 1-(3-(4-morpholinyl) propyl group)-4-(4-fluoro phenyl)-5-(4-pyridyl) imidazoles:

With embodiment 1 (b) compound (1.14g, 5.5mmol) and embodiment 1 (c) compound (1.17g, 5.0mmol) and CH ₂Cl ₂(10ml) be cooled to 5 ℃.Add 1,5, above claim TBD 7-three azabicyclics (4,4,0) last of the ten Heavenly stems-5-alkene, (0.71g 5.0mmol) and with reactant kept 16 hours down at 5 ℃, with EtOAc (80ml) dilution and use saturated Na ₂CO ₃The aqueous solution (2 * 15ml) washings.(3 * 15ml) extract, and EtOAc is used in acid mutually, and (2 * 25ml) washings are with EtOAc (25ml) layering and by adding solid K with 1NHCl with EtOAc ₂CO ₃Alkalize until pH8.0, add 10%NaOH then until pH10.Separate two-phase and (3 * 25ml) extract with EtOAc with water.With extracting solution drying (K ₂CO ₃) and concentrate, with residue crystallization in acetone/hexane, obtain 0.94g (51%) title compound.mp＝149-150°。

Embodiment 25-(2-amino-4-pyrimidyl)-4-(4-fluoro phenyl)-1-(4-(1,3-dioxy cyclopentyl) cyclohexyl) imidazoles

A), 1-amino-4-(1,3-dioxy cyclopentyl) hexanaphthene

With 1,4-cyclohexanedione list ethylidene contract carbonyl (15.6g, 0.10mol), H ₂O (170ml) and Na ₂CO ₃(27.8g) merging also, gradation adds NH ₂OHHCl (27.8g, O.40mol).Resulting mixture was stirred 30 minutes.Extract dry (Na with EtOAc ₂SO ₄) and concentrate, obtain 17.1g (100%) 4-(1,3-dioxy cyclopentyl) cyclohexanone-oxime.

At 50psiH ₂Down, (6.0g, 35mmol), (about 3ml is at pH7.0H for Ni in Ruan with this oxime ₂Suspension among the O) and EtOH (anhydrous) merges and jolting 16 hours.Catalyzer is filtered out, filtrate is concentrated and distillation, obtain 2.4g (60%) title compound (bp=68 ℃, 0.18mm).

B), 2-aminopyrimidine-4-formaldehyde (4-ethylidene ketal-1-cyclohexyl) imines

Except solvent is CH ₂Cl ₂Do not need siccative (MgSO ₄) outside, the product that step 2 (a) is obtained according to the method for 1 (c) and the product reaction of embodiment 3 (b) preparation obtain the faint yellow oily thing of title compound.

C), 5-(2-amino-4-pyrimidyl)-4-(4-fluoro phenyl)-1-(4-dioxy cyclohexyl) imidazoles

Except using compound that a step obtains as the imines, the method according to the foregoing description 1 (d) obtains title compound.ESI mass spectrum MH ⁺=396.

Embodiment 3

2-aminopyrimidine-4-formaldehyde

A), 2-aminopyrimidine-4-formaldehyde dimethyl carbonyl that contracts

The dimethyl formamide dimethyl contracted, and (55ml, 0.41mol), the pyruvic aldehyde dimethyl contracts, and (50ml 0.41mol) merges and is heated to 100 ° and kept about 18 hours carbonyl carbonyl.Vacuum is removed methyl alcohol, obtains oily matter.

With NaOH (18g, H 0.45mol) ₂O (50ml) solution is added to guanidine HCl (43g, H 0.45mol) ₂In O (100ml) solution, and the solution that obtains is added in the above-mentioned oily matter.The mixture that obtains was stirred 48 hours down at 23 °.Filtration obtains 25g (50%) title compound.

B), 2-aminopyrimidine-4-formaldehyde

The compound that previous step is obtained suddenly (1.69g, 10mmol) and 3NHCl (7.3ml 22mmol) merges and is heated to 48 ° and kept 14 hours, and cooling adds NaHCO with EtOAC (50ml) layering and by gradation ₃(2.1g, 25mmol) neutralization.(5 * 50ml) extract and with extracting solution drying (Na with EtOAC with water ₂SO ₄), concentrate and obtain 0.793g (64%) title compound.

Embodiment 45-(2-amino-4-pyrimidyl)-4-(4-fluoro phenyl)-1-(4-ketone cyclohexyl) imidazoles

With the product of embodiment 2 (1.27g, 3.22mmol) and 3NHCl (12.4ml) merge and stirred 16 hours down at 23 °, with 10% Na ₂CO ₃The aqueous solution (50ml) merges and extracts with EtOAC.With extracting solution drying (Na ₂SO ₄), concentrate and flash chromatagraphy (0-4%MeOH), obtain the white solid of 0.72g (64%) title compound.ESI mass spectrum MH ⁺=352.

Embodiment 55-(2-amino-4-pyrimidyl)-4-(4-fluoro phenyl)-1-(4-cyclohexyl oxime) imidazoles

With the product of embodiment 4 (351g, 1.0mmol), NH ₂OHHCl (278mg, 4.0mmol), H ₂O (6ml) and CH ₃OH (2ml) merges, and gradation adds Na ₂CO ₃The aqueous solution (278g, 2.6mmol).Mixture was stirred 24 hours, add NaHCO ₃The aqueous solution and with mixture CH ₂Cl ₂Extract, concentrate and use the 0-8%MeOH flash chromatagraphy, obtain 0.248g (67%) title compound.

Embodiment 65-(2-amino-4-pyrimidyl)-4-(4-fluoro phenyl)-1-(4-cyclohexyl azanol) imidazoles

With the product of embodiment 5 (250mg, 0.68mmol), NaCNBH ₃(42mg, 0.68mmol) and MeOH (2.5ml) merge.Add HCl methanol solution (several) (pH＜3) and mixture was stirred 1 hour, dilute and extract with EtOAC with the 10%NaOH aqueous solution.With extract drying (Na ₂SO ₄), concentrate and flash chromatagraphy (0-8%MeOH/CH ₂Cl ₂), obtain 1 60mg (64%).ESI mass spectrum MH ⁺=369.

Embodiment 75-(2-amino-4-pyrimidyl)-4-(4-fluoro phenyl)-1-(trans-the 4-hydroxyurea) imidazoles and 5-(2-amino-4-pyrimidyl)-4-(4-fluoro phenyl)-1-(cis-4-hydroxyurea) imidazoles

According to people's such as Adames method (WO91/14674, on October 3rd, 1991 is open), the product reaction with embodiment 6 obtains cis and trans cyclohexyl hydroxyurea mixture of isomers.Use CH ₂Cl ₂Develop this mixture, optionally dissolve cis-isomeride (based on nmr).With solid filtering.Filtrate is concentrated, obtain 5-(2-amino-4-pyrimidyl)-4-(4-fluoro phenyl)-1-(cis-4-hydroxyurea) imidazoles SB223768, it comprises about 20% trans-isomer(ide) (based on nmr).Mp=185-245 (decomposition).

Above-mentioned solid is dissolved in CH again ₂Cl ₂Also concentrate among/the MeOH until beginning to occur precipitation.Filtration obtains pure 5-(2-amino-4-pyrimidyl)-4-(4-fluoro phenyl)-1-(trans-the 4-hydroxyurea) imidazoles.mp＝188-190°。

Embodiment 85-(2-amino-4-pyrimidyl)-4-(4-fluoro phenyl)-1-(trans-the 4-hydroxy-cyclohexyl) imidazoles

(0.61g is 1.74mmol) with at CH with the product of embodiment 4 ₃1MNaBH among the OH ₄At CH ₃OH/THF (1: 1, merge in 7ml) and stirred 10 minutes, with reactant impouring 10%Na ₂CO ₃In the aqueous solution (25ml), (4 * 50ml) extract and dry (Na with EtOAC ₂SO ₄).Flash chromatagraphy (0-8%CH ₃OH/CH ₂Cl ₂), obtain 0.52g (85%) title compound.

Can prepare following compounds according to reaction scheme with the similar method of aforesaid method and this paper:

Embodiment 95-(2-amino-4-pyrimidyl)-4-(4-fluoro phenyl)-1-(4-aminocyclohexyl) imidazoles.

Embodiment 105-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-ketone cyclohexyl) imidazoles

A), 2-N-methylamino pyrimidine-4-formaldehyde

As described in embodiment 3, HCl prepares title compound with methylguanidine.

¹HNMR(CDCl ₃，400MHz)：δ9.95(s，1H)，8.88(d，1H)，7.50(，1H)，

3.54(s，3H)，2.54(s，3H).

B), 2-N-methylamino pyrimidine-4-formaldehyde-(4-ethylidene contract carbonyl-1-cyclohexyl) imines

(.8g, 5.8mmol) (8g 5.1mmol) stirred 18 hours in DMF (12ml) with embodiment 2 (a) compound with embodiment 10 (a) compound.Vacuum concentration obtains the yellow oil of title compound.

¹HNMR(400MHz，CDCl ₃)：δ

8.34(d，1H)，8.15(s，1H)，7.13(d，1H)，5.25(d，1H)，3.39(m，1H)，3.03(d，3H)，1.90

(m，7H)，1.79(m，2H)，1.65(m，2H).

C), 4-fluoro phenyl-tosyl group methylformamide

Dense HCl (15ml) is added drop-wise to SPTS salt (30g) in the suspension of water (100ml) and t-butyl methyl ether (50ml).Stir after 15 minutes, remove organic phase and extract water with t-butyl methyl ether.Merge organic phase, dry (Na ₂SO ₄), and be concentrated into dried.Add hexane and, obtain free acid (22.06g) the solid filtering that obtains.With this free acid (140.6mmol) and p-Fluorobenzenecarboxaldehyde (22ml, 206mmol), methane amide (20ml, 503mmol) and camphorsulfonic acid (4g 17.3mmol) merges and 60 ℃ of stirrings 18 hours down.The solid that obtains is smashed and stirred with methyl alcohol (35ml) and hexane (82ml).Mixture is filtered.Bulk is smashed and the solid that obtains was fully stirred 5 hours in methyl alcohol/hexane (200ml, 1: 3).With suspension filtered, obtain title compound (27.08g, 62.7% productive rate).

¹H?NMR(400?MHz，CDCl ₃)：δ

8.13(s，1H)，7.71(d，2H)，7.43(dd，2H)，7.32?(d，2H)，7.08(t，2H)，6.35(d，1H)，2.45

(s，3H).

D), 4-toluene fluoride alkylsulfonyl methyl carbylamine

(2.01g 6.52mmol) is cooled to-10 ℃ at the mixture of ethylene glycol dimethyl ether (DME) in (32ml) to the compound that embodiment 10 (c) is obtained.Dropping is dissolved in the POCl among the DME (3ml) ₃(1.52ml 16.30mmol), keeps internal temperature to be lower than-5 ℃.After stirring 1 hour under-5 ℃, with reactant H ₂O quenches and product is extracted with EtOAC, uses saturated NaHCO then ₃Washing.With organic phase drying (Na ₂SO ₄) and concentrate.Residue is developed and filtered with sherwood oil, obtain the orange-brown solid of title compound (1.70g, 90% productive rate).IR(CH ₂Cl ₂)2135cm ^-1。

E), 5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-(1,3-dioxy cyclopentyl) cyclohexyl) imidazoles

Under 0 ℃, the compound that embodiment 10 (b) is obtained (1.6g, 5.84mmol) compound that obtains with embodiment 10 (d) (2g, 6.9mmol) and Powdered K ₂CO ₃(1.2g 8.7mmol) merges 3 hours in DME (12ml).Mixture was warming up to room temperature and restir 18 hours lentamente.Add EtOAC and, concentrate and be dissolved in H the mixture filtration ₂Among the O/EtOAC.The yellow solid that obtains is filtered and, use 5%MeOH/CH by flash chromatagraphy (silica gel) purifying ₂Cl ₂Wash-out obtains title compound (.5Og, 29% productive rate)

¹HNMR(400MHz，

CDCl ₃)：δ8.16(d，1H)，7.78(s，1H)，7.45(q，2H)，6.99(t，2H)，6.40(d，1H)，5.70(m，

1H)，4.74(m，1H)，3.99(s，4H)，3.05(d，3H)，2.20(M，2H)，2.04(q，2H)，1.89(dd，2H)，

1.68(m，3H).

F), 5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-ketone cyclohexyl) imidazoles

Except with embodiment 10 (e) compound (.50g .22mmol) outside, according to the method for embodiment 4, obtain title compound (.37g, 78% productive rate).

.mp232.5

-233.5℃. ¹HNMR(400MHz，CDCl ₃)：δ7.97(d，1H)，7.69(s，1H)，6.89(t，2H)，

6.24(d，1H)，5.08(m.1H)，3.25(s，1H)，2.91(d，3H)，2.39(d，5H)，2.08(m，2H)，1.92

(m，1H).

Embodiment 115-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(trans-4-hydroxyl cyclohexyl) imidazoles

Except (.49g is 1.34mmol) and from EtOH/H with implementing 11 (f) compound ₂Among the O outside the recrystallization, prepare title compound, obtain white crystals (.38g, 77% productive rate) according to the method for embodiment 8.

mp230-231℃. ¹HNMR(400

MHz，CDCl ₃)：δ8.08(m，1H)，7.70(s，1H)，7.37(q，2H)，6.98(t，2H)，6.32(d，1H)，

4.67(m，1H)，3.67(m，1H)，3.00(s，3H)，2.18(m，2H)，2.07(m，2H)，1.75(m，2H)，1.37

(m，2H).

With with the similar method of embodiment 11 methods, obtain cis-isomeride: 5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(cis-4-hydroxy-cyclohexyl) imidazoles.

Embodiment 125-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-(cis-pyrrolidyl) cyclohexyl) imidazoles and 5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-(anti-form-1-pyrrolidyl) cyclohexyl) imidazoles

The ethanolic soln (.25ml) of 5%HCl is added to tetramethyleneimine, and (.3ml is 3.6mmol) in the solution of MeOH (3ml).Add embodiment 10 (f) compound (.50g, 1.26mmol), add again sodium cyanoborohydride (.50g, 1.30mmol).Stir after 2 days, mixture is concentrated and residue is suspended in H ₂In O and the salt solution, extract with EtOAC then.With organic phase drying (Na ₂SO ₄) and concentrate.Product by flash chromatagraphy (silica gel) purifying, is used 5-20%MeOH/CH ₂Cl ₂Wash-out, cis-isomeride at first elutes from pillar, obtains title compound 5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-(cis-pyrrolidyl) cyclohexyl) imidazoles.

mp192-193℃， ¹HNMR(400MHz，CDCl ₃)：δ

8.04(s，1H)，7.95(s，1H)，7.35(q，2H)，6.95(t，2H)，6.30(d，1H)，4.59(s，1H)，3.40(m，

1H), 2.97 (s, 3H), 2.58 (s, 4H), 2.13 (q, 2H), 2.00 (d, 2H), 1.84 (m, 6H), 1.50 (t, 2H), and 5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-(trans-pyrrolidyl) cyclohexyl) imidazoles

mp155-156℃， ¹HNMR(400MHz，CDCl ₃)：δ8.03(d，1H).

7.69(s，1H)，7.35(q，2H)，6.95(t，2H)，6.28(d，1H)，4.61(t，1H)，3.12(s，1H)，2.96(s，

3H)，2.58(s，4H).2.25-2.05(m，4H)，1.78(s，4H)，1.70(m，2H)，1.35(t，2H).

Embodiment 135-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-ethynyl-4-hydroxy-cyclohexyl) imidazoles

(.50g 1.37mmol) is suspended among the anhydrous THF (5ml) and is cooled to-78 ℃ with embodiment 10 (f) compound.Add bromination ethynyl magnesium (13.4ml, 6.17mmol, the THF liquid of .5M) and mixture was stirred 2 hours.With the saturated NH of reactant ₄Cl handles and product is extracted with EtOAC.With organic phase drying (Na ₂SO ₄) and concentrate.Product by cis chromatography purifying, is used 2%MeOH/CH ₂Cl ₂Wash-out obtains title compound.

mp233.5-234.5℃. ¹HNMR(400MHz，CDCl ₃)：δ8.08(d，1H)，7.77(s，

1H)，7.38(q，2H)，6.97(t，2H)，6.31(d，1H)，4.68(s，1H)，2.76(s，3H)，2.62(s，1H)，

2.10(m，6H).1.63(q，2H).

Embodiment 145-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-amino-4-methylcyclohexyl) imidazoles

A), 5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-hydroxy-4-methyl cyclohexyl) imidazoles

Except with the methylmagnesium-bromide,, obtain the title compound (76% productive rate) of 1: 1 mixture of cis and trans-isomer(ide) according to the method for embodiment 13.

¹HNMR(400MHz，CDCl ₃)：δ8.13(s，1H)，7.79(s，.5H)，7.72(s，5H)，7.43(m，2H)，6.96(m，2H)，6.38(m，1H)，5.45(m，1H)，4.68(m，.5H)，452(m，5H)，3.00(d，3H)，2.30-1.40(m，8H)，1.36(s，1.5H)，1.25(s，1.5H).

B), 5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-amino-4-methylcyclohexyl) imidazoles

The compound that embodiment 14 (a) is obtained (.28g .75mmol), sodium cyanide (.03g) and H ₂SO ₄(.5ml) stirred 18 hours.Use H ₂O dilution and add 50%NaOH after, mixture was refluxed 4 hours, then cooling and extract with EtOAC.Water is extracted with the 50%NaOH alkalization and with EtOAC.With organic phase drying (Na ₂SO ₄) and concentrate.Residue by flash chromatagraphy (silica gel) purifying, is used MeOH/CH ₂Cl ₂/ H ₂O (20: 80: 2) wash-out obtains title compound.mp186-192℃。

Embodiment 155-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-acetylaminohydroxyphenylarsonic acid 4-methylcyclohexyl) imidazoles

With embodiment 14 (b) compound (.02g .05mmol) and DMAP (.0012g .01mmol) is cooled to 0 ℃ in pyridine (1ml).Add diacetyl oxide (.009ml) and mixture is warming up to room temperature.Stir after 18 hours, with mixture H ₂O dilutes and product is extracted with EtOAC.With organic phase drying (Na ₂SO ₄) and concentrate.Cis chromatography (silica gel) is used 0-5%MeOH/CH ₂Cl ₂Wash-out obtains title compound (.19g, 90% productive rate).

mp175-176℃. ¹HNMR(400MHz，CDCl ₃)：δ8.14(d，1H)，7.77(s，1H)，7.43(q，

2H)，7.00(t，2H)，6.40(d，1H)，4.58(m，1H)，3.03(d，3H)，2.41(d，2H)，2.09(m，2H)，

2.02(s，3H)，1.82(m，2H)，1.40(c，3H)，1.37(m，2H).

Can prepare following compounds with the similar method of the foregoing description 1-15:

Embodiment 165-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-hydroxy-4-methyl cyclohexyl) imidazoles; Mp160-161 ℃.

Embodiment 175-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-Oxyranyle cyclohexyl) imidazoles; Mp229-230 ℃.

Embodiment 185-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-cyano methyl-4-hydroxy-cyclohexyl) imidazoles

A), 4-fluoro phenyl-tosyl group methylformamide

Methyl tertiary butyl ether (50ml) is added to SPTS salt (30g) at H ₂In the suspension of O (100ml), drip concentrated hydrochloric acid (15ml) then.Stir after 5 minutes, remove organic phase and water is extracted with methyl tertiary butyl ether.With organic phase drying (Na ₂SO ₄) and be concentrated into dried.Add hexane and free acid is filtered.

Will to toluenesulfinic acid (22g, 140.6mmol), right-fluorobenzaldehyde (22ml, 206mmol), methane amide (20ml, 503mmol) and camphorsulfonic acid (4g 17.3mmol) merges and stirred 18 hours down at 60 ℃.The solid that obtains smashed and stir, filter then with the mixture of MeOH (35ml) and hexane (82ml).With solid suspension the MeOH/ hexane (1: 3,200ml) in and fully stir until smashing remaining bulk.Filtration obtains title compound (27g, 62% productive rate).

¹HNMR(400MHz，CDCl ₃)：δ8.13(s，1H)，7.71(d，2H)，

7.43(dd，2H)，7.32(d，2H)，7.08(t，2H)，6.34(d，1H)，2.45(s，3H).

B), 4-fluoro phenyl-tosyl group methyl carbylamine

Will (2.01g 6.25mmol) be cooled to-10 ℃ at the above-claimed cpd among the DME (32ml).Add POCl ₃(1.52ml, 16.3mmol), drip then triethylamine in DME (3ml) (4.6ml, 32.6mmol) and keep internal temperature to be lower than-5 ℃.With 1 hour time, mixture is heated up gradually, use H ₂O handles and extracts with EtOAC.With the saturated NaHCO of organic phase ₃Solution washing, dry (Na ₂SO ₄), and concentrate.The residue that obtains is developed and filtered with sherwood oil, obtain title compound (1.7g, 90% productive rate).

¹HNMR(CDCl ₃)：δ7.63(d，2H)，7.33(m，4H)，

7.10(t，2H)，5.60(s，1H)，2.50(s，3H)

C), 1-amino-4-(1,3-dioxy cyclopentyl) hexanaphthene

With Na ₂CO ₃(49.2g 547mmol) is added drop-wise to 1,4-cyclohexanedione list ethylidene contract carbonyl (27.6g, 177mmol) and oxammonium hydrochloride (49.2g is 708mmol) at H ₂In the mixture of O (250ml).Stir after 1 hour, mixture is extracted with EtOAC.With organic phase drying (Na ₂SO ₄) and concentrate, obtain 4-(1,3-dioxy cyclopentyl)-cyclohexanone-oxime (27.5g, 90% productive rate).

With this oxime (27.5g, 161mmol), Ni in Ruan (the approximately EtOH suspension of 13.5ml) and EtOH (200ml) merging and at 50psiH ₂Following jolting 4 hours.Catalyzer is filtered out and filtrate is concentrated, obtain the colorless oil (23.6g, 93% productive rate) of title compound.

¹HNMR(CDCl ₃)：δ2.64(m，1H)，1.75-1.25(m，12H).

D), 2-N-methylamino pyrimidine-4-formaldehyde dimethyl carbonyl that contracts

The pyruvic aldehyde dimethyl contracted, and (277ml, 2.3mol) and N, the dinethylformamide dimethyl contracts, and (304ml 2.3mol) stirred 18 hours down at 100 ℃ carbonyl carbonyl together.With mixture cooling and concentrated.

This crude product is added in the solution of well-beaten methylguanidine hydrochloride (112g) and NaOEt (74g), and the mixture that obtains was refluxed 24 hours, cool off then and concentrate.The residue that obtains is developed with hot EtOAC and filtered on diatomite.Filtrate is concentrated, obtain the title compound brown oil. ¹HNMR(CDCl ₃)：δ8.33(d，lH)，6.75(d，1H)，5.10(s，1H)，3.40(s，6H)，3.00(s，3H).

E), 2-N-methylamino pyrimidine-4-formaldehyde

(10.04g, 55mmol) mixture in 3NHCl (45ml) stirred 24 hours down at 47 ℃ the compound that above-mentioned steps is obtained.After the cooling, add EtOAC, add solid NaHCO then ₃(4 * 100ml) extract with EtOAC with water.Organic phase is merged dry (Na ₂SO ₄) and concentrate, obtain the yellow foam thing of title compound. ¹HNMR(CDCl ₃)：δ9.88(s，1H)，7.13(d，1H)，7.01(d，1H)，2.05(s，3H).

F), 2-N-methylamino-4-formaldehyde (4-ethylidene contract carbonyl cyclohexyl) imines

(9.5g, 6.9mmol) (10.8g, mixture 6.9mmol) stirred 18 hours in DMF (150ml) compound that above-mentioned steps is obtained with middle 1-amino-4-(1, the 3-dioxy cyclopentyl) hexanaphthene for preparing of embodiment 18 (e).Title compound needn't can use by any purifying. ¹H?NMR(CDCl ₃)：δ8.34(d，1H)，8.15(s，1H)，7.13(d，

1H)，5.25(d，1H)，3.39(m，1H)，3.03(d，3H)，1.90(m，7H0，1.79(m，2H)，1.65

(m，2H).

G), 5-(4-(2-N-methylamino pyrimidyl)-4-(4-fluoro phenyl)-1-(4-ethylidene contract carbonyl cyclohexyl) imidazoles

With the 4-fluoro phenyl-tosyl group methyl carbylamine of embodiment 1 (b) preparation (20g, 69mmol) and K ₂CO ₃(12g 87mmol) is added to being cooled in the crude product that the foregoing description of 0 ℃ obtains in DMF.This mixture was stirred 3 hours down at 0 ℃.Be warming up to room temperature then gradually and stirred 18 hours.Add EtOAC and, wash solid with EtOAC with the mixture filtration.With H ₂O is added in the filtrate, and organic phase is separated, dry (Na ₂SO ₄) and concentrate.Residue is passed through flash chromatagraphy (silica gel, 2%MeOH/CH ₂Cl ₂) purifying, obtain the yellow solid (10.7g, 38% productive rate) of title compound.

¹HNMR(CDCl ₃)：δ8.16(d，1H)，7.78(s，1H)，7.45(q，2H)，6.99(t，2H)，6.40(d，

1H)，5.70(m，1H)，4.74(m，1H)，3.99(s，4H)，3.05(d，3H)，2.20(m，2H)，2.04(dq，

2H)，1.89(dd，2H)，1.68(m，2H).

H), 5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-oxo cyclohexyl) imidazoles

(10.73g, 26.23mmol) mixture in 3NHCl (150ml) stirred 36 hours the compound that above-mentioned steps is obtained, and used saturated Na then ₂CO ₃Neutralization is also filtered.Solid is washed with water and mixture aqueous solution is extracted with EtOAC.With organic phase drying (Na ₂SO ₄) and concentrate, obtain mp232.5-233.5 ℃ of the faint yellow solid (7.9g, 77% productive rate) of title compound.

I), 5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-Oxyranyle cyclohexyl) imidazoles

(0.39g 1.78mmol) is added to sodium hydride (0.07g, 1.18mmol, 60% mineral oil suspension) in the suspension of DMSO (1.2ml) with trimethylammonium sulfur oxide iodide.Mixture is stirred to come out until no longer including gas release.Will (0.50g 1.4mmol) be added in this mixture at the compound of the above-mentioned steps among the anhydrous THF (5ml).The mixture that obtains was stirred 4 hours, then impouring H ₂Also filter among the O.The solid that obtains is developed with acetone/hexane, obtained title compound (.4117g, 77% productive rate).mp229-230℃。

I), 5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-cyano methyl-4-hydroxy-cyclohexyl) imidazoles

(2ml, 1M is in toluene) is added to the above-mentioned steps compound in the solution of anhydrous THF (10ml) with the cyaniding diethyl aluminum.After stirring 1 hour under 70 ℃, handle and decantation with the mixture cooling and with 10%NaOH.With organic phase decantation and concentrated.Residue is passed through flash chromatagraphy (silica gel, 5%MeOH/CH ₂Cl ₂) purifying and with product at EtOH/H ₂Recrystallization among the O obtains the white crystals of title compound.mp152-154℃。

Embodiment 195-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-hydroxy-4-hydroxymethyl ylmethyl cyclohexyl) imidazoles

A), with the compound of embodiment 18 (i) (0.084g .22mmol) and the solution stirring of 88% formic acid (3ml) 1 hour.Mixture is concentrated and residue is dissolved among the MeOH.Add excessive Et ₃N also stirs mixture 24 hours.Mixture concentrated and by flash chromatagraphy (silica gel, 2-10%MeOH/CH ₂Cl ₂) purifying.The white solid that obtains is developed with acetone/hexane, obtained the title compound (0.047g, 53% productive rate) of cis and trans-isomer(ide) mixture.mp125-130℃。

Embodiment 205-(4-(2-amino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-hydroxyl-4-(1-proyl) cyclohexyl) imidazoles

A), 2-amino-4-formaldehyde (4-ethylidene contract carbonyl cyclohexyl) imines

According to the method among the embodiment 18 (c),, obtain title compound by replacing 2-aminopyrimidine-4-formaldehyde (preparation in embodiment 3).

¹HNMR(CDCl ₃)：δ8.36(d，1H)，8.16(s，1H)，7.21(d，1H)，5，13(m，

1H)，3.98(s，4H)，2.00-1.40(m，8H).

B), 5-(4-(2-amino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-ethylidene contract carbonyl cyclohexyl) imidazoles

According to the method for embodiment 18 (g), the compound by using above-mentioned steps to obtain obtains title compound.

¹HNMR(CDCl ₃)：δ8.29(d，1H)，7.77

(s，1H)，7.45(q，2H)，7.00(t，2H)，6.50(d，1H)，5.12(s，2H)，4.63(m，1H)，4.00(s，

4H)，2.17(m，2H)，2.05(m，2H)，1.90(m，2H)，1.73(m，2H).

C), 5-(4-(2-amino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-oxo cyclohexyl) imidazoles

Except the compound that obtains with above-mentioned steps,, obtain the white solid of title compound according to the method for embodiment 1 (h).

¹HNMR(CDCl ₃)：δ

8.02(d，1H)，7.74(s，1H)，7?32(q，2H)，6.94(t，2H)，6.28(d，1H)，5.10(m，1H)，

2.93(s，3H)，2.44(m，6H)，2.12(m，2H).

D), 5-(amino) pyrimidyl)-and 4-(4-fluoro phenyl)-1-(4-hydroxyl-2-propine) cyclohexyl) imidazoles

Under-78 ℃, (15ml, the THF solution of 1M obtains by following method, is about to propine gas (4g) and feeds among the anhydrous THF (75ml), adds methylmagnesium-bromide (26ml, 78mmol, the Et of 3M then with bromination proyl magnesium ₂O liquid) and with mixture stir till no gas sends) (0.49g is in anhydrous THF (30ml) suspension 1.4mmol) to be added to the compound that above-mentioned steps obtains.The mixture that obtains is warming up to room temperature gradually.Use saturated NH ₄The Cl aqueous solution extracts mixture after handling with EtOAC.With organic phase drying (Na ₂SO ₄) and concentrate.The residue that obtains is passed through cis chromatography (silica gel, 5%MeOH/CH ₂Cl ₂) purifying, obtain the white solid of title compound (0.068g, 12% productive rate), mp231-232 ℃.

Embodiment 215-(4-(2-amino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-hydroxy-4-methyl cyclohexyl) imidazoles

A), 5-(4-(2-amino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-Oxyranyle cyclohexyl) imidazoles

According to the method among the embodiment 18 (i), except 5-(4-(2-amino) pyrimidyl)-4-(4-fluoro phenyl)-1-(the 4-oxo cyclohexyl) imidazoles that uses embodiment 20 (c) preparation, obtain the white solid of title compound. ¹H?NMR(CDCl ₃)：

δ8.11(d，1H)，7.78(s，1H)，7.38(q，2H)，6.99(t，2H)，6.43(d，1H)，4.65(m，1H)，

2.71(s，2H)，2.26(m，2H)，2.03(m，4H)，1.39(m，2H).

B), 5-((4-(2-amino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-hydroxy-4-methyl cyclohexyl) imidazoles

Lithium aluminium hydride (5ml, 5mmol, the THF liquid of 1M) is added to the compound that above-mentioned steps obtains, and (1.24g is in the suspension of anhydrous THF (40ml) 3.39mmol).The mixture that obtains was refluxed 1 hour, also use solid NaHCO then among the impouring 3N HCl (200ml) ₃Alkalization.After the EtOAC extraction, with organic phase drying (Na ₂SO ₄) and concentrate.The residue that obtains is passed through flash chromatagraphy (silica gel, 5%MeOH/CH ₂Cl ₂) purifying, then at EtOH/H ₂Crystallization among the O obtains the white solid (0.06g, 4.8% productive rate) of title compound.mp110-111℃。

In the similar method of embodiment 1-18, can obtain following compounds:

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-hydroxyl-4-isopropylcyclohexyl-) imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-hydroxy-4-phenyl cyclohexyl) imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-hydroxyl-4-benzyl rings hexyl) imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-hydroxyl-4-cyano methyl cyclohexyl) imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-hydroxyl-4-(2-cyano ethyl) cyclohexyl) imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-hydroxyl-4-(2-amino-ethyl) cyclohexyl) imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-hydroxyl-4-(2-nitro-ethyl) cyclohexyl) imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-hydroxymethyl-4-aminocyclohexyl) imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-hydroxyl-4-aminocyclohexyl) imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-aminocyclohexyl) imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-2-hydroxy-4-methylthio cyclohexyl) imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-hydroxy-4-hydroxymethyl ylmethyl cyclohexyl) imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-hydroxyl-4-amino methyl cyclohexyl) imidazoles;

5-(4-(2-amino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-amino-4-methylcyclohexyl) imidazoles;

5-(4-(2-amino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-hydroxy-4-methyl cyclohexyl) imidazoles;

5-(4-(2-amino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-Oxyranyle cyclohexyl) imidazoles.

Above-mentioned specification sheets fully discloses the present invention, comprises its embodiment preferred.Modification and change to the open embodiment of this paper all are included in the following claim scope.Known, needn't further specify, those skilled in the art are by using above-mentioned specification sheets, but maximum range utilize the present invention.Therefore, this paper embodiment only is the illustrative scope of the invention that do not limit in any form.Following pyridine justice embodiment of the present invention is wherein carried out claim to exclusiveness or privilege.

Claims (34)

1, formula (I) compound or pharmaceutically acceptable salt thereof: R wherein ₁Be the 4-pyridyl, pyrimidyl, quinolyl, isoquinolyl, quinazoline-4-base, 1-imidazolyl or 1-benzimidazolyl-, described ring can replace by one or two substituting group is optional, and described substituting group is independently selected from C _1-4Alkyl, halogen, hydroxyl, C _1-4Alkoxyl group, C _1-4Alkylthio, C _1-4Alkyl sulphinyl, CH ₂OR ₁₂, amino, one or two-C _1-6The amino that alkyl replaces, N (R ₁₀) C (O) R _cOr the N-heterocyclic radical, this heterocycle is a 5-7 unit ring, and can choose wantonly and contain another and be selected from oxygen, sulphur or NR ₁₅Heteroatoms;

R ₄Be phenyl, naphthalene-1-base or naphthalene-2-base, or heteroaryl, it can replace by one or two substituting group is optional, each substituting group can independently be selected, and for the 4-phenyl, 4-naphthalene-1-base, 5-naphthalene-2-base or 6-naphthalene-2-base, substituting group can be halogen, cyano group, nitro ,-C (Z) NR ₇R ₁₇,-C (Z) OR ₁₆,-(CR ₁₀R ₂₀) _vCOR ₁₂,-SR ₅,-SOR ₅,-OR ₁₂, the C that halogen replaces _1-4Alkyl, C _1-4Alkyl ,-ZC (Z) R ₁₂,-NR ₁₀C (Z) R ₁₆, or-(CR ₁₀R ₂₀) _vNR ₁₀R ₂₀, and for the replacement at other position, substituting group can be halogen, cyano group ,-C (Z) NR ₁₃R ₁₄,-C (Z) OR ₃,-(CR ₁₀R ₂₀) _{M "}COR ₃,-S (O) _mR ₃,-OR ₃, the C that halogen replaces _1-4Alkyl ,-C _1-4Alkyl ,-(CR ₁₀R ₂₀) _{M "}NR ₁₀C (Z) R ₃,-NR ₁₀S (O) _{M '}R ₈,-NR ₁₀S (O) _{M '}NR ₇R ₁₇,-ZC (Z) R ₃, or-(CR ₁₀R ₂₀) _{M "}NR ₁₃R ₁₄

V is 0, or integer 1 or 2;

M is 0, or integer 1 or 2;

M ' is integer 1 or 2;

M " be 0, or integer 1-5;

R _cBe hydrogen, C _1-6Alkyl, C _3-7Cycloalkyl, aryl, aryl C _1-4Alkyl, heteroaryl, heteroaryl C _1-4Alkyl, heterocyclic radical, or heterocyclic radical C _1-4Alkyl C _1-4Alkyl;

R ₂Be the optional C that replaces _3-7Cycloalkyl, or C _3-7Cycloalkyl C _1-10Alkyl;

R ₃Be heterocyclic radical, heterocyclic radical C _1-10Alkyl or R ₈

R ₅Be hydrogen, C _1-4Alkyl, C _2-4Alkenyl, C _2-4Alkynyl group, or NR ₇R ₁₇, remove-SR ₅Part is-SNR ₇R ₁₇And-SOR ₅For outside-the SOH;

R ₇And R ₁₇Be selected from hydrogen independently of one another, or C _1-4Alkyl or R ₇And R ₁₇Form 5-7 unit heterocycle with the nitrogen-atoms that they connected, this ring can be chosen wantonly and contain another and be selected from oxygen, sulphur or NR ₁₅Heteroatoms.

R ₈Be C _1-10Alkyl, the C that halogen replaces _1-10Alkyl, C _2-10Alkenyl, C _2-10Alkynyl group, C _3-7Cycloalkyl, C _5-7Cycloalkenyl group, aryl, aryl C _1-10Alkyl, heteroaryl, heteroaryl C _1-10Alkyl, (CR ₁₀R ₂₀) _nOR ₁₁, (CR ₁₀R ₂₀) _nS (O) _mR ₁₈, (CR ₁₀R ₂₀) _nNHS (O) ₂R ₁₈, (CR ₁₀R ₂₀) _nNR ₁₃R ₁₄Wherein, aryl, arylalkyl, heteroaryl, heteroarylalkyl can be optionally substituted;

N is the integer of 1-10;

R ₉Be hydrogen ,-C (Z) R ₁₁, the optional C that replaces _1-10Alkyl, S (O) ₂R ₁₈, optional aryl that replaces or the optional aryl C that replaces _1-4Alkyl;

R ₁₀And R ₂₀Be selected from hydrogen or C independently of one another _1-4Alkyl;

R ₁₁Be hydrogen or R ₁₈

R ₁₂Be hydrogen or R ₁₆

R ₁₃And R ₁₄Be selected from hydrogen or the optional C that replaces independently of one another _1-4Alkyl, optional aryl that replaces or the optional aryl C that replaces _1-4Alkyl perhaps forms 5-7 unit heterocycle with the nitrogen-atoms that they connected, and this ring can be chosen wantonly and contain another and be selected from oxygen, sulphur or NR ₉Heteroatoms;

R ₁₅Be hydrogen, C _1-4Alkyl or C (Z)-C _1-4Alkyl;

R ₁₆Be C _1-4Alkyl, the C that halogen replaces _1-4Alkyl, or C _3-7Cycloalkyl;

R ₁₈Be C _1-10Alkyl, C _3-7Cycloalkyl, heterocyclic radical, aryl, aryl C _1-10Alkyl; Heterocyclic radical, heterocyclic radical C _1-10Alkyl, heteroaryl or heteroarylalkyl.

2, according to the compound of claim 1, R wherein ₁Be optional 4-pyridyl or the 4-pyrimidyl that replaces.

3, according to the compound of claim 2, wherein Ren Xuan substituting group is methyl, amino or methylamino.

4, according to the compound of claim 2, R wherein ₄Be the optional phenyl that replaces.

5, according to the compound of claim 4, wherein phenyl is by halogen ,-SR ₅,-S (O) R ₅,-OR ₁₂, the C that halogen replaces _1-4Alkyl or C _1-4Alkyl replaces one or many.

6, according to the compound of claim 1, R wherein ₂Be selected from the optional C that replaces ₄-C ₇Cycloalkyl.

7, according to the compound of claim 6, R wherein ₂Be selected from the optional C that replaces ₄Or C ₆Cycloalkyl or C ₄Or C ₆Cycloalkyl C _1-4Alkyl.

8, according to the compound of claim 6, wherein cycloalkyl ring can be replaced 1-3 time independently by following groups, and described group is a halogen; Hydroxyl; C _1-10Alkoxyl group; S (O) _mC _1-10Alkyl, wherein m is 0,1, or 2; Amino; Cyano group; Nitro; NR ₇R ₁₇Base; C _1-10Alkyl; The alkyl that replaces, wherein substituting group is selected from halogen, hydroxyl, nitro, cyano group NR ₇R ₁₇, S (O) _mC _1-4Alkyl, C (O) OR ₁₁-O-(CH ₂) _sO-, and s is 1-3;-C (O) H;=O;=N-OR ₁₁-N (R ₁₀)-OH;-N (OR _b)-C (O)-R ₆The optional aryl that replaces; Or the optional arylalkyl that replaces; N (R ₁₀) C (O) X ₁C (O) OR ₁₁The optional alkylidene group that replaces; Or the optional C that replaces _1-10Alkynyl group;

R wherein _bBe hydrogen, pharmaceutically acceptable positively charged ion, aroyl or C _1-10Alkanoyl;

R ₆Be NR ₁₉R ₂₁Alkyl _1-6The alkyl that halogen replaces _1-6The alkyl that hydroxyl replaces _1-6Alkenyl _2-6By halogen, alkyl _1-6, the alkyl that halogen replaces _1-6, hydroxyl, or alkoxyl group _1-6Optional aryl or the heteroaryl that replaces;

R ₁₉Be H or alkyl _1-6And

R ₂₁Be H, alkyl _1-6, aryl, benzyl, heteroaryl, the alkyl that replaces by halogen or hydroxyl, or the phenyl that replaces by a following group, described group is selected from halogen, cyano group, alkyl _1-12, alkoxyl group _1-6, the alkyl that halogen replaces _1-6, alkylthio, alkyl sulphonyl, or alkyl sulphinyl; Perhaps R ₁₉And R ₂₁Can form 5-7 unit ring with the nitrogen-atoms that they connected, its annular atoms can be by being selected from oxygen, and a heteroatoms of sulphur or nitrogen is optional to be substituted; And

X ₁Be C _1-4Alkyl, aryl or aryl C _1-4Alkyl; N (R ₁₀) C (O) aryl.

9, compound according to Claim 8, wherein Ren Xuan substituting group is a hydroxyl, aryl, arylalkyl, alkyl, alkynyl group, NR ₇R ₁₇, NR ₇R ₁₇C _1-6Alkyl ,=O ,=NOR ₁₁,-NH (OH) ,-N (OH)-C (O)-NH ₂, the cyano group alkyl, 4-nitro alkyl, or-O-(CH ₂) ₂O-.

10, according to the compound of claim 1, this compound is:

5-(2-amino-4-pyrimidyl)-4-(4-fluoro phenyl)-1-(4-(1,3-dioxy cyclopentyl) cyclohexyl)-imidazoles;

5-(2-amino-4-pyrimidyl)-4-(4-fluoro phenyl)-1-(4-ketone cyclohexyl)-imidazoles;

5-(2-amino-4-pyrimidyl)-4-(4-fluoro phenyl)-1-(4-cyclohexyl oxime)-imidazoles;

5-(2-amino-4-pyrimidyl)-4-(4-fluoro phenyl)-1-(4-cyclohexyl azanol)-imidazoles;

5-(2-amino-4-pyrimidyl)-4-(4-fluoro phenyl)-1-(trans-the 4-hydroxyurea)-imidazoles;

5-(2-amino-4-pyrimidyl)-4-(4-fluoro phenyl)-1-(cis-4-hydroxyurea)-imidazoles;

5-(2-amino-4-pyrimidyl)-4-(4-fluoro phenyl)-1-(4-hydroxy-cyclohexyl)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-ketone cyclohexyl)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(trans-the 4-hydroxy-cyclohexyl)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(cis-4-hydroxy-cyclohexyl)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-(cis-pyrrolidyl) cyclohexyl)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-(anti-form-1-pyrrolidyl) cyclohexyl)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-ethynyl-4-hydroxy-cyclohexyl)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-(1-proyl)-4-hydroxy-cyclohexyl)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-amino-4-methyl-cyclohexyl base)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-acetylaminohydroxyphenylarsonic acid 4-methyl-cyclohexyl base)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-hydroxy-4-methyl-cyclohexyl)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-Oxyranyle cyclohexyl)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-cyano methyl-4-hydroxy-cyclohexyl)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-hydroxy-4-hydroxymethyl ylmethyl cyclohexyl)-imidazoles;

5-(4-(2-amino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-hydroxyl-4-(1-proyl) cyclohexyl)-imidazoles;

5-(4-(2-amino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-hydroxy-4-methyl-cyclohexyl)-imidazoles; Or its pharmacologically acceptable salt.

11, a kind of pharmaceutical composition, it contains the described compound of arbitrary claim and pharmaceutically acceptable carrier or thinner among the claim 1-10.

12, a kind of Mammals for the treatment of the described therapeutic action of needs suffers from the method for cytokine mediated disease, and it comprises the described formula of arbitrary claim (I) compound among the claim 1-10 that gives described Mammals significant quantity.

13, according to the method for claim 11, wherein said Mammals suffers from cytokine mediated disease, is selected from rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, urarthritis and other arthritis disease; Sepsis, septic shock, endotoxin shock, gram negative sepsis, toxic shock syndrome, apoplexy, asthma, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, sarcoidosis of lung, bone absorpting disease, osteoporosis, reperfusion injury, graft-vs-host reaction, homograft rejecting reaction, Crohn disease, ulcerative colitis or pyresis.

14, according to the method for claim 12, wherein said morbid state is by IL-1, IL-6, IL-8, or TNF mediation.

15, according to the method for claim 13, wherein said cytokine mediated morbid state is asthma, osteoporosis or sacroiliitis.

16, a kind of method for the treatment of the inflammation in mammals that needs described therapeutic action, it comprises the described formula of arbitrary claim (I) compound among the claim 1-10 that gives described Mammals significant quantity.

17, a kind of method for the treatment of the Mammals sclerotin osteoporosis that needs described therapeutic action, it comprises the described formula of arbitrary claim (I) compound among the claim 1-10 that gives described Mammals significant quantity.

18, a kind of method for the treatment of the kinase mediated disease of the CSBP/RK/p38 that Mammals suffers from that needs described therapeutic action, it comprises the described formula of arbitrary claim (I) compound among the claim 1-10 that gives described Mammals significant quantity.

19, according to the method for claim 18, the disease that CSBP/RK/p38 that wherein said Mammals suffers from is kinase mediated is selected from rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, urarthritis and other arthritis disease; Sepsis, septic shock, endotoxin shock, gram negative sepsis, toxic shock syndrome, asthma, adult respiratory distress syndrome, apoplexy, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, sarcoidosis of lung, bone absorpting disease, osteoporosis, reperfusion injury, graft-vs-host reaction, homograft rejecting reaction, Crohn disease, ulcerative colitis or pyresis.

20, a kind of preparation is as the method for the defined formula of claim 1 (I) compound, and it comprises formula (II) compound:

With formula (III) compound:

Wherein p is 0 or 2; With the highly basic reaction that is enough to the isocyanides of formula (II) is partly taken off proton;

And R ₁, R ₂And R ₄As defining in the claim 1 or being R ₁, R ₂And R ₄Precursor and Ar be the optional phenyl that replaces, and after this, if desired, with R ₁, R ₂And R ₄Precursor conversion is R ₁, R ₂And R ₄Base.

19, according to the method for claim 18, wherein when p=0, reaction utilizes TBD as alkali.

20, according to the method for claim 18, wherein when p=2, employed alkali is amine in the reaction, carbonate, hydride, perhaps alkyl or aryl lithium reagent.

21, according to the method for claim 18, wherein, before reacting, formula (II) imines is separated with formula (II).

22, according to the method for claim 18, wherein, before reacting, form imines on the spot with formula (II).

23, according to the method for claim 22, wherein pass through formula R ₄CHO aldehyde, wherein R ₄Suc as formula (I) definition, with formula R ₂NH ₂Primary amine reaction, wherein R ₂Suc as formula (I) definition, form imines on the spot.

24, according to the method for claim 22, wherein utilize dehydration conditions, form imines on the spot.

25, according to the method for claim 23, wherein solvent is N, dinethylformamide (DMF), halogenated solvent, tetrahydrofuran (THF) (THF), dimethyl sulfoxide (DMSO) (DMSO), alcohol, benzene, or toluene, or DME.

26, according to the method for claim 23, aldehyde R wherein ₄CHO is a following formula pyrimidine aldehyde: Wherein X is NHR _aAnd X ₁As R in claim 1 formula (I) ₁On the part, optional substituent definition, obtain formula (I) compound or pharmaceutically acceptable salt thereof.

27, according to the method for claim 23, primary amine R wherein ₂NH ₂Be C _3-7Cycloalkyl amine, C _3-7Cycloalkyl C _1-10Alkylamine, all amine can be chosen wantonly and be substituted.

28, according to the method for claim 27, R wherein ₂R in the part ₂Be the 4-hydroxy-cyclohexyl, 4-hydroxy-cyclohexyl, 4-ketone cyclohexyl, 4-Oxyranyle cyclohexyl, 4-methyl-4-hydroxy-cyclohexyl, 4-sec.-propyl-4-hydroxy-cyclohexyl, 4-pyrrolidyl-cyclohexyl, 4-methyl-4-aminocyclohexyl, 4-methyl-4-kharophen cyclohexyl, 4-phenyl-4-hydroxy-cyclohexyl, 4-benzyl-4-hydroxy-cyclohexyl, 1-propenyl-4-hydroxyl, 4-hydroxyl-4-amino-cyclohexyl, 4-amino methyl-4-hydroxy-cyclohexyl or 4-(1,3-dioxy cyclopentyl) cyclohexyl.

29, the method for claim 23, its Chinese style (I) compound is:

5-(2-amino-4-pyrimidyl)-4-(4-fluoro phenyl)-1-(4-ketone cyclohexyl)-imidazoles;

5-(2-amino-4-pyrimidyl)-4-(4-fluoro phenyl)-1-(4-cyclohexyl oxime)-imidazoles;

5-(2-amino-4-pyrimidyl)-4-(4-fluoro phenyl)-1-(4-cyclohexyl azanol)-imidazoles;

5-(2-amino-4-pyrimidyl)-4-(4-fluoro phenyl)-1-(trans-the 4-hydroxyurea)-imidazoles;

5-(2-amino-4-pyrimidyl)-4-(4-fluoro phenyl)-1-(cis-4-hydroxyurea)-imidazoles;

5-(2-amino-4-pyrimidyl)-4-(4-fluoro phenyl)-1-(4-hydroxy-cyclohexyl)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-ketone cyclohexyl)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(trans-the 4-hydroxy-cyclohexyl)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(cis-4-hydroxy-cyclohexyl)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-(cis-pyrrolidyl) cyclohexyl)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-(anti-form-1-pyrrolidyl) cyclohexyl)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-ethynyl-4-hydroxy-cyclohexyl)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-(1-proyl)-4-hydroxy-cyclohexyl)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-amino-4-methyl-cyclohexyl base)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-acetylaminohydroxyphenylarsonic acid 4-methyl-cyclohexyl base)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-hydroxy-4-methyl-cyclohexyl)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-Oxyranyle cyclohexyl)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-cyano methyl-4-hydroxy-cyclohexyl)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-hydroxy-4-hydroxymethyl ylmethyl cyclohexyl)-imidazoles;

5-(4-(2-amino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4 hydroxyls-4-(1-proyl) cyclohexyl)-imidazoles;

5-(4-(2-amino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-hydroxy-4-methyl-cyclohexyl)-imidazoles;

Or its pharmacologically acceptable salt.

30, a kind of inhibition needs described inhibiting Mammals prostaglandin endoperoxides synthetic enzyme-2 (PGHS-2) synthetic method, and it comprises claim 1 Chinese style (I) compound that gives described Mammals significant quantity.

31,, wherein suppress PGHS-2 and be used for preventative or the therapeutic treatment oedema, fever, oxypathy, neuromuscular pain, headache, cancer pain, or arthritis ache according to the method for claim 30.

32, according to the method for claim 30, wherein compound is:

5-(2-amino-4-pyrimidyl)-4-(4-fluoro phenyl)-1-(4-(1,3-dioxy cyclopentyl) cyclohexyl)-imidazoles;

5-(2-amino-4-pyrimidyl)-4-(4-fluoro phenyl)-1-(4-ketone cyclohexyl)-imidazoles;

5-(2-amino-4-pyrimidyl)-4-(4-fluoro phenyl)-1-(4-cyclohexyl oxime)-imidazoles;

5-(2-amino-4-pyrimidyl)-4-(4-fluoro phenyl)-1-(4-cyclohexyl azanol)-imidazoles;

5-(2-amino-4-pyrimidyl)-4-(4-fluoro phenyl)-1-(trans-the 4-hydroxyurea)-imidazoles;

5-(2-amino-4-pyrimidyl)-4-(4-fluoro phenyl)-1-(cis-4-hydroxyurea)-imidazoles;

5-(2-amino-4-pyrimidyl)-4-(4-fluoro phenyl)-1-(4-hydroxy-cyclohexyl)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-ketone cyclohexyl)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(trans-the 4-hydroxy-cyclohexyl)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(cis-4-hydroxy-cyclohexyl)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-(cis-pyrrolidyl) cyclohexyl)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-(anti-form-1-pyrrolidyl) cyclohexyl)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-ethynyl-4-hydroxy-cyclohexyl)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-(1-proyl)-4-hydroxy-cyclohexyl)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-amino-4-methyl-cyclohexyl base)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-acetylaminohydroxyphenylarsonic acid 4-methyl-cyclohexyl base)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-hydroxy-4-methyl-cyclohexyl)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-Oxyranyle cyclohexyl)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-hydroxy-4-hydroxymethyl ylmethyl cyclohexyl)-imidazoles;

5-(4-(2-N-methylamino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-hydroxyl-4-cyano methyl cyclohexyl)-imidazoles;

5-(4-(2-amino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-hydroxyl-4-(1-proyl) cyclohexyl)-imidazoles;

5-(4-(2-amino) pyrimidyl)-4-(4-fluoro phenyl)-1-(4-hydroxy-4-methyl-cyclohexyl)-imidazoles; Or its pharmacologically acceptable salt.