CN101490053B - Bicyclic heteroaryl compounds - Google Patents

Abstract

This invention relates to compounds of the general formula (I): in which the variable groups are as defined herein, and to their preparation and use.

Description

Bicyclic heteroaryl compounds

Related application

The application requires the rights and interests of International Application Serial No. PCT/US2007/011136 number (disclosed PCT application number WO2007/133562) of proposition on May 8th, 2007 according to 35U.S.C. § 371, the application requires the right of priority of following application according to 35U.S.C. § 119 (e): the U.S. Provisional Patent Application 60/798472 that on May 8th, 2006 proposed, the U.S. Provisional Patent Application 60/833191 that on July 25th, 2006 proposed, with No. 60/920687, the U.S. Provisional Patent Application that proposed on March 29th, 2007, full content of described each application is here quoted as a reference.

Background of invention

Protein kinase represents an extended familys protein, and it plays an important role with keeping in the control of cell function in the regulation and control of various kinds of cell process.Nonrestrictive this class kinases of listing a part comprises abl, Akt, bcr-abl, Blk, Brk, c-kit, c-met, c-src, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, cRaf1, CSK, EGFR, ErbB2, ErbB3, ErbB4, Erk, Pak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, flt-1, Fps, Frk, Fyn, Hck, IGF-1R, INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, ros, tie, tie2, TRK and Zap70.The disease that unusual protein kinase activity and multiple disease-related, these diseases threaten from no life such as psoriasis are to extremely serious disease cancer for example.

Consider a large amount of protein kinases and many diseases relevant with protein kinase, therefore exist provides the optionally demand of new species compound with increase always, and these compounds can and be used for the treatment of and the protein tyrosine kinase diseases associated thus as kinases inhibitor.

The present invention relates to the new acetylenic heteroaryl compounds of gang and the purposes in treatment cancer, osteopathy, metabolic trouble and inflammatory diseases and other disease thereof.

Summary of the invention

1. the general introduction of invention compound

The compounds of this invention has widely useful biology and pharmacological activity, thereby the method that relates to the purposes of these compounds in pharmaceutical composition and the following disease for the treatment of: metabolic trouble, osteopathy (osteoporosis for example, Paget's disease etc.), inflammation (comprising rheumatoid arthritis and other inflammatory diseases) and cancer (comprise solid tumor and leukemia, especially those are mediated as Src or kdr by one or more kinases, or by kinases Abl and mutant thereof imbalance cancers mediated for example), comprise late case and to the case of one or more other treatment opposing or tolerance.

The compound, its tautomer, single isomer, mixture of isomers or its pharmacy acceptable salt, solvate or the hydrate that comprise formula I:

Wherein:

Ring T represents 5-unit bicyclic heteroaryl ring, and it comprises 1-3 heteroatoms that is selected from O, N, S also randomly by 1-3 R ^tGroup replaces;

Ring A represent the first aryl of 5-or 6-or heteroaryl ring and it is randomly by 1-4 R ^aGroup replaces;

Ring B represent the first aryl of 5-or 6-or heteroaryl ring and it is randomly by 1-5 R ^bGroup replaces;

L ¹Be selected from NR ¹C (O) and C (O) NR ¹

In each case, R ^a, R ^bAnd R ^tBe independently selected from halogen ,-CN ,-NO ₂,-R ⁴,-OR ²,-NR ²R ³,-C (O) YR ²,-OC (O) YR ²,-NR ²C (O) YR ²,-SC (O) YR ²,-NR ²C (=S) YR ²,-OC (=S) YR ²,-C (=S) YR ²,-YC (=NR ³) YR ²,-YP (=O) (YR ⁴) (YR ⁴) ,-Si (R ⁴) ₃,-NR ²SO ₂R ²,-S (O) _rR ²,-SO ₂NR ²R ³With-NR ²SO ₂NR ²R ³, wherein Y be independently chemical bond ,-O-,-S-or-NR ³-;

R ¹, R ²And R ³Be independently selected from H, alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, aryl, heterocyclic radical and heteroaryl;

Perhaps, NR ²R ³Group can be saturated, fractional saturation or the undersaturated ring of 5-or 6-unit, and it optionally is substituted and it contains individual N, O and the S (O) of being selected from of 0-2 _rOther heteroatoms;

In each case, R ⁴Be independently selected from alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, aryl, heterocyclic radical and heteroaryl;

Aforesaid each alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, aryl, heteroaryl and heterocyclic radical randomly are substituted;

M is 0,1,2,3 or 4;

N is 0,1,2 or 3;

P is 0,1,2,3,4 or 5; With

R is 0,1 or 2.

Except as otherwise noted, further describe and exemplified aforesaid definition below, and these definition are applicable to the situation that the back is all.

2. the compound of characteristic type and general use thereof

In The compounds of this invention, ring T randomly is independently selected from R on 1 to 3 annular atoms (it can be carbon and/or heteroatoms) ^tGroup replace.For example, ring T can be selected from, but is not limited to following type:

Wherein n is 0,1,2 or 3.Should understand substituent R ^tSum be no more than valency good for use.Therefore, for example when ring T was pyrrole ring, it was optionally replaced (being that n is 0,1,2 or 3) by 1 to 3 substituting group, yet when ring T was pyrazoles or imidazoles, it was optionally replaced (being that n is 0,1 or 2) by maximum 2 substituting groups.Will also be understood that except as otherwise noted, when ring T is not substituted, then exist hydrogen atom to satisfy required valency.

The example of above-claimed cpd comprises that wherein encircling T is following compound:

As in all compounds of the present invention, for aforesaid classes of compounds and group, ring A and ring B define in the part 1 as described above.

The ring A that replaces is exemplified as:

Ring B represents as described above in the part 1 defined 5 or 6-unit's aryl or heteroaryl ring.

The ring B that replaces is exemplified as:

The special meaningfully compound of the another kind of formula I described in above-mentioned part 1, wherein R ^bBe 5-or 6-unit ring (ring C) one of in the substituting group, this ring can be heteroaryl or heterocyclic radical, and it comprises carbon atom and 1-3 and is independently selected from O, N and S (O) _rHeteroatoms, the ring C on carbon or heteroatoms randomly by 1 to 5 substituent R ^cReplace.

Such is expressed as formula II compound, its tautomer, single isomer, mixture of isomers or its pharmacy acceptable salt, solvate or hydrate:

The wherein variable of aforementioned definitions such as n, m, A, B, T, L ¹, R ¹, R ^t, R ^aAnd R ^bSuch as in the upper section 1 definition; And

In each case, R ^cBe selected from halogen ,=O ,=S ,-CN ,-NO ₂,-R ⁴,-OR ²,-NR ²R ³,-C (O) YR ²,-OC (O) YR ²,-NR ²C (O) YR ²,-Si (R ⁴) ₃,-SC (O) YR ²,-NR ²C (=S) YR ²,-OC (=S) YR ²,-C (=S) YR ²,-YC (=NR ³) YR ²,-YP (=O) (YR ⁴) (YR ⁴) ,-NR ²SO ₂R ²,-S (O) _rR ²,-SO ₂NR ²R ³With-NR ²SO ₂NR ²R ³, wherein Y, r, R ², R ³And R ⁴Such as in the previous section 1 definition; T be 0,1,2,3 or 4 and v be 0,1,2,3,4 or 5.

Randomly by 1-5 R ^cThe example of the ring C system that group replaces includes but not limited to following type:

Wherein v and R ^cAs defined above and substituent R ^cSum be no more than normal valency.

Such concrete non-limiting example comprises following compound:

Wherein illustrated multiple example-[ring A]-[L ¹Encircle B]-[]-[ring C] part.

Significant compound also comprises formula II compound, wherein encircles C and be not replace or by one or more R ^cThe heteroaryl ring that group replaces.Meaningfully wherein encircle this little compounds that C is imidazole ring at present especially.More meaningfully wherein encircle C and have single low alkyl group (as methyl) R ^cThe little compounds of this of group.

Another feature of the present invention relates to the formula I compound described in part 1, wherein R ^bOne of substituting group is-[L ²Encircle D]-[].Such is represented by formula III:

Wherein variable such as n, m, ring T, ring A, ring B, L ₁, R ¹, R ^t, R ^aAnd R ^bSuch as in the previous section 1 definition,

L ²Be selected from (CH ₂) _z, O (CH ₂) _x, NR ³(CH ₂) _x, S (CH ₂) _x(CH ₂) _xNR ³C (O) (CH ₂) _x, and described linking group L ²Can connect with either direction;

Ring D representative comprises carbon atom and individual O, N and the S (O) of being independently selected from of 1-3 _rHeteroatomic 5-or 6-unit heterocycle or heteroaryl ring, and ring D on carbon or heteroatoms randomly by 1-5 R ^dGroup replaces;

In each case, R ^dBe independently selected from halogen ,=O ,=S ,-CN ,-NO ₂,-R ⁴,-OR ²,-NR ²R ³,-Si (R ⁴) ₃,-C (O) YR ²,-OC (O) YR ²,-NR ²C (O) YR ²,-SC (O) YR ²,-NR ²C (=S) YR ²,-OC (=S) YR ²,-C (=S) YR ²,-YC (=NR ³) YR ²,-YP (=O) (YR ²) (YR ²) ,-NR ²SO ₂R ²,-S (O) _rR ²,-SO ₂NR ²R ³With-NR ²SO ₂NR ²R ³, wherein Y, r, R ², R ³And R ⁴Such as in the previous section 1 definition;

W is 0,1,3,4 or 5;

X is 0,1,2 or 3;

Z is 1,2,3 or 4; With

T is 0,1,2,3 or 4.

In the formula III compound-[ring B]-[L ²]-[ring D] non-limiting example of part comprises:

Such concrete non-limiting example comprises following compound:

Significant compound also comprises the formula III compound, and wherein encircling D is heterocycle, piperazine ring for example, its on nitrogen randomly by R ^dReplace and L ²Be-CH ₂R wherein especially meaningfully at present ^dIt is this little compounds of replacement or unsubstituted low alkyl group (that is the alkyl of 1-6 carbon).

Other significant compound also comprises the formula III compound, and wherein encircling D is heteroaryl ring, and it does not replace or by one or more R ^dGroup replaces.

Be used for formula II and the III compound that A and B are aryl that meaningfully wherein encircle especially of the present invention.

Other significant compound is formula II and III compound, wherein encircles T randomly by one or more R ^tGroup replaces, R ^tBe selected from halogen, low alkyl group, alkoxyl group, amino ,-the NH-alkyl ,-C (O) NH ₂,-C (O) O-alkyl ,-C (O) NH-alkyl ,-NHC (O)-alkyl ,-NHC (O)-heterocycle ,-NHC (O) NH-alkyl ,-NHC (O) NH-(CH ₂) _xHeterocycle ,-NHC (NH)-alkyl ,-NHC (NH) NH ₂,-NHC (NH) O-alkyl ,-NH (CH ₂) _x-heteroaryl ,-NH (CH ₂) _x-heterocycle ,-NH (CH ₂) _x-aryl or-(CH ₂) _xC (O) NH ₂, wherein x is the integer of 0-3, and alkyl comprises the alkyl of straight chain (namely not branch or acyclic), side chain and ring-type and is optionally substituted and wherein aryl, heteroaryl, heterocyclic ring randomly are substituted.

This group non-limiting example comprises formula II and III compound, and wherein encircling T is one of the following:

Present significant group comprises formula IIa, IIb, IIc, IIIa, IIIb, IIIc compound:

The wherein variable of aforementioned definitions such as R ^a, R ^b, R ^c, R ^dAnd R ^t, n, m and t be as described above as definition in the part 1, and (R wherein ^d) _0-1Represent 0-1 R ^dGroup.When ring D does not replace, it is evident that for the professional hydrogen atom replaces described Rd group to satisfy required valency.Substituent R ^t, R ^cAnd R ^dQuantity be no more than normal valency.

The little compounds of formula II and III especially meaningfully, it is optional by one or more R wherein encircling T ^tThe imidazoles that replaces.Significant especially compound is R wherein ^tDo not exist or R ^tBe independently selected from the compound of following radicals: halogen, low alkyl group, alkoxyl group, amino ,-the NH-alkyl ,-C (O) NH ₂,-C (O) NH-alkyl ,-NHC (O)-alkyl ,-NHC (O) NH-alkyl ,-NHC (NH)-alkyl ,-NHC (O) CH ₂N (alkyl) ₂,-NHC (NH) NH ₂Or (CH ₂) C (O) NH ₂, wherein alkyl comprises the alkyl of straight chain (namely not branch or acyclic), side chain and ring-type and is optionally substituted.

This group non-limiting example is that the ring T that wherein replaces is the compound of following group:

A significant especially compounds comprises formula IIa, IIb and IIc compound, and wherein m is that 1, t is that 1, v is 1, R ^tDo not exist independently or R ^tBe selected from-C (O) NH ₂,-C (O) NH alkyl, NH ₂, and low alkyl group, as-CH ₃R ^aBe low alkyl group, as-CH ₃R ^bBe sec.-propyl or CF ₃And R ^cDo not exist or methyl.

Significant another little compounds comprises formula III a, IIIb and IIIc compound, and wherein m is that 1, t is 1, R ^tDo not exist independently or be selected from-C (O) NH ₂,-C (O) NH alkyl, NH ₂, and low alkyl group, as-CH ₃R ^aBe low alkyl group, as-CH ₃R ^bBe sec.-propyl or CF ₃And R ^dBe methyl or CH ₂CH ₂OH.

Especially the compound of the present invention of Guan Zhuing comprises the compound with one or more following characteristics:

Molecular weight is less than 1000, preferably less than 750, is more preferably less than 600 mass units (weight that does not comprise any solvation or cocrystallization material does not comprise the weight of any gegenion when for salt); Or

The kinase whose inhibition of antagonism wild-type or sudden change (especially clinical relevant variation) is active, and described kinases especially is the Src family kinase, as Src, Yes, Lyn or Lck; VEGF-R such as VEGF-R1 (Flt-1), VEGF-R2 (kdr) or VEGF-R3; PDGF-R; The kinases that Abl kinases or other are paid close attention to, described inhibition activity is 1 μ M or littler (using acceptable kinase inhibition test determination on any science) for the IC50 value, preferred IC50 value is 500nM or better (better), and best IC50 value is 250nM or better; Or

It is active to resist given kinase whose inhibition, and the IC50 value is lower than at least pays close attention to 1/100 of kinase whose IC50 value to other; Or

The inhibition activity of antagonism Src and kdr is 1 μ M or better to each kinase whose IC50 value; Or

To the cytotoxicity of the cancerous cell line of external maintenance or the restraining effect of growth, or (the especially preferred compound of the present invention that suppresses the K562 cell proliferation of cultivating of the cytotoxicity of acceptable cancer cells heteroplastic transplantation model or growth-inhibiting effect on the use science in zooscopy, measure by comparative studies, the effect of described compound is identical with imatinib mesylate (Gleevec) at least, be preferably the twice at least of imatinib mesylate, and at least 10 times of imatinib mesylate more preferably).

The present invention also provides composition, and it comprises at least a compound or its salt of the present invention, hydrate or other solvate and the acceptable vehicle of at least a pharmacy or additive.Can be to the described composition of required curee's administration to suppress growth, development and/or the transfer of cancer, described cancer comprise solid tumor (as, mammary cancer, colorectal carcinoma, carcinoma of the pancreas, CNS and head and neck cancer etc.) and the leukemia of various ways, comprise other treatment opposing leukemia and other cancer of (comprising imatinib mesylate or the opposing of other kinase inhibitor), described composition is generally used for treating and prevents by one or more kinase mediated diseases or undesirable illness, and described kinases is suppressed by compound of the present invention.

Cancer treatment method of the present invention relates to compound of the present invention to needed human or animal's administration (as monotherapy or with one or more other cancer therapy drugs, one or more improve the combinations such as medicine, radiotherapy of side effect) treatment significant quantity to suppress, to slow down or to reverse growth, development or the diffusion of cancer among the curee, described cancer comprises the cancer of solid tumor or other form, as leukemia.Described administration constitutes treatment or prevention by the method for one or more kinase mediated diseases, and described kinases can be accepted a kind of inhibition in the derivative by compound disclosed in this invention or its pharmacy." administration " compound of the present invention comprises the change thing that gives kind described herein to the curee, or its prodrug or other pharmacy acceptable derivates, uses any appropriate formulation or route of administration as described herein.The described compound one or many of administration in general every month, usually once in a week or repeatedly, for example every day, every other day, 5 days/week etc.What especially pay close attention to now is oral administration and intravenously administrable.

Salt or any other adduct or the derivative of any pharmacologically acceptable salts, ester or this ester of the described compound of word used herein " pharmacy acceptable derivates " expression, when after patient's administration, can providing (directly or indirectly) other formalization compounds as herein described with it, or its meta-bolites or resistates (MW＞300).Therefore the pharmacy acceptable derivates comprises prodrug.Prodrug is the pharmacological activity that the derivative of compound has obvious reduction usually, and prodrug contains other and is easy to the part of removing in vivo and produces parent molecule as pharmacological active substance.The example of prodrug by cracking in vivo produce the ester of concern compound.The prodrug of multiple compound and the material and the method that make parent compound derive to produce prodrug are known, and are applicable to the present invention.

Especially feeling the derivative of preferred parent compound and prodrug and be those can increase the derivative of bioavailability of compound and prodrug (as increasing the optical density that enters blood by oral back) or those with respect to parent compound and increase send (for example brain or lymphsystem) to the biology compartment of paying close attention to respect to parent compound when to the Mammals administration.Preferred prodrug comprises the derivative that has the water-soluble of increase or the present composition by enteron aisle film transport activity material with respect to parent compound.

An importance of the present invention has the curee's method for cancer that needs for treatment, and this method comprises to the composition that contains The compounds of this invention of curee's drug treatment significant quantity.The various cancers that can treat thus are other local description of this paper, and also comprise mention or become cancer to the opposing of other cancer therapy drug, a kind of in described other cancer therapy drug such as imatinib mesylate, Iressa, Te Luokai or the other medicines as herein described.Treatment can be made up with one or more other cancer therapies, and described other therapies comprises operation, radiotherapy (as γ-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy and body radioactivity isotropic substance etc.), endocrinotherapy, biological response modifier (as interferons, interleukin and tumour necrosis factor (TNF)), mistake heating therapy, psychrotherapy, weakens medicine (as antiemetic) and other cancer chemotherapeutic drug of any undesirable action.Other medicines can use the preparation administration, and route of administration and dosage regimen and compound of the present invention are identical or different.

Described other medicines include but not limited to one or more following medicines: anticancer alkylating agent or intercalating agent (as mustargen, Chlorambucil, endoxan, melphalan and ifosfamide); Antimetabolite (as methotrexate); Purine antagonist or pyrimidine antagonist (as 6-mercaptopurine, 5 FU 5 fluorouracil, cytosine arabinoside and gemcitabine); Spindle poison (as vinealeucoblastine(VLB), vincristine(VCR), vinorelbine and taxol); Podophyllotoxin (as Etoposide, irinotecan, Hycamtin); Microbiotic (as Dx, bleomycin and mitomycin); Nitrosoureas (as carmustine, lomustine); Mineral ion (as cis-platinum, carboplatin, oxaliplatin or oxiplatin); Enzyme (as asparaginase); Hormone (as tamoxifen, Leuprolide, flutamide and megestrol); MTOR inhibitor (as sirolimus (rapamycin), Temsirolimus (CCI779), everolimus (RAD001), AP23573 or be disclosed in United States Patent (USP) 7,091, other compound in 213); Proteasome inhibitor (as ten thousand jade-like stones, other proteasome inhibitor (referring to for example WO02/096933), or other NF-kB inhibitor, comprise for example IkK inhibitor); Other kinase inhibitor (as the inhibitor of Src, BRC/Abl, kdr, flt3, aurora-2, glycogen synthase kinase 3 (" GSK-3 "), EGF-R kinases (as Iressa, Te Luokai etc.), VEGF-R kinases, PDGF-R kinases etc.); The acceptor that relates in antibody, soluble receptors or the opposing cancer or other receptor antagonist of hormone (comprise acceptor such as EGFR, ErbB2, VEGFR, PDGFR and IGF-R; With medicine such as Trastuzumab, Avastin, Erbitux etc.); Etc..For up-to-date cancer therapy is described more comprehensively, referring to Http:// www.nci.nih.gov/, the tabulation of the oncology medicine of FDA approval exists Http:// www.fda.gov/cder/cancer/druglistframe.htmAnd The Merck Manual, the 17th edition 1999, full content is incorporated herein by reference.The example of other medicine is as described in other place of this paper, and comprise allopurinol, alemtuzmab, hexamethyl melamine, amifostine, nastrozole, the antibody of antagonism prostate specific membrane antigen is (as MLN-591, MLN591RL and MLN2704), white arsenic, bexarotene, bleomycin, busulfan, capecitabine, Gliadel Wafer, celecoxib, Chlorambucil, the Intra Dose gel, carat Qu Bin, the cytosine arabinoside liposome, daunorubicin liposome, daunorubicin, Rubomycin C, dexrazoxane, Docetaxel, Dx, Elliott ' sB solution, epirubicin, estramustine phosphate, the phosphoric acid Etoposide, Etoposide, Exemestane, fludarabine, 5-FU, fulvestrant, gemcitabine, gemtuzumab-ozogamicin, goserelin acetate, hydroxyurea, idarubicin, idarubicin, darubicin, ifosfamide, imatinib mesylate, irinotecan (or other topoisomerase enzyme inhibitor, comprise antibody such as MLN576 (XR11576)), letrozole, Calciumlevofolinate, the Calciumlevofolinate LEVAMISOLE HCL, the liposome daunorubicin, melphalan, L-PAM, mesna, methotrexate, Methoxsalen, ametycin, mitoxantrone, MLN518 or MLN608 (or other flt-3 receptor tyrosine kinase, the inhibitor of PDFG-R or c-kit), itoxantrone, taxol, pegademase, spray Ta Siding, porfimer sodium, Rituximab

Talcum, tamoxifen, temozolamide, for the Buddhist nun moor former times, VM-26, Hycamtin, toremifene, 2C4 (or disturb other antibody of the signal conduction of HER2-mediation), vitamin A acid, ATRA, valrubicin, vinorelbine or Pamidronate, azoles comes disodium diphosphate or other diphosphate.

The present invention also comprises the preparation of any formula I, II, III, IIa, IIb, IIc, IIIa, IIIb, IIIc compound or any other compound of the present invention.

The present invention comprises that also compound of the present invention or its pharmacy acceptable derivates (comprise leukemia and solid tumor at or chronic cancer acute for the preparation for the treatment of, former or shift, comprise other local described cancer of this paper and comprise cancer to one or more other treatment opposing or tolerance) medicine in purposes.Compound of the present invention is for the preparation of cancer therapy drug.Compound of the present invention also alleviate or the medicine of prevention illness by suppressing for the preparation of being used for by one or more kinases (as Src, kdr, abl etc.).

Other illness of available compounds for treating of the present invention comprises metabolic trouble, inflammatory diseases and osteoporosis and other bone disorders.In these cases, compound of the present invention can as monotherapy or with other medicines for this illness, as the diphosphonate combination medicine-feeding in the disease that osteoporosis or other bone photo close.

The present invention also comprises the composition that contains The compounds of this invention, said composition comprises the compound of any described type or subclass, comprise the compound of above-mentioned any chemical formula etc., the amount of preferred described compound is treatment significant quantity and at least a pharmaceutically acceptable carrier, adjuvant or thinner.

Compound of the present invention is also as characterizing various kinase whose standard substances and reagent, described kinases especially for but be not limited to the kinases of kdr and Src family, and compound of the present invention also is used for these kinases of research in the effect of biology and pathology phenomenon; Be used for research and forward approach to by signal in these kinase mediated cells, with the new kinase inhibitor of comparative assessment; And the multiple cancer that is used for research clone and animal model.

3. definition

When reading this piece file, unless otherwise indicated, all use following information and definition.And unless otherwise indicated, the functional group that occurs all is selecteed independently, reminds the reader by using the slash mark or being coated with coloring grounding sometimes, with twice appearance of simple expression can be identical or different (for example R, R ', R ", or Y, Y ', Y " etc.).

Term " alkyl " refers to comprise straight chain (being non-side chain or non-annularity), side chain, ring-type or encircles the non-aromatic hydrocarbon base more that it is chosen wantonly and is replaced by one or more functional groups.Except as otherwise noted, " alkyl " comprises 1-8, and preferred 1-6 carbon atom.C _1-6Alkyl refers to comprise C ₁, C ₂, C ₃, C ₄, C ₅And C ₆Alkyl.Low alkyl group refers to contain the alkyl of 1-6 carbon atom.The example of alkyl includes, but not limited to methyl, ethyl, n-propyl, sec.-propyl, cyclopropyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, cyclobutyl, amyl group, isopentyl, tert-pentyl, cyclopentyl, hexyl, isohexyl, cyclohexyl etc.Alkyl can be substituted or not be substituted.Exemplary substituted alkyl includes, but not limited to benzyl, the styroyl of methyl fluoride, difluoromethyl, trifluoromethyl, 2-fluoro ethyl, 3-fluoropropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, benzyl, replacement, styroyl of replacement etc.

The subclass of term " alkoxyl group " expression alkyl, wherein alkyl such as above-mentioned definition is by the carbon of quantity shown in the oxo bridge connection.For example, " alkoxyl group " refers to group-O-alkyl, and wherein said alkyl contains 1-8 carbon atom, and it can be straight chain, side chain, ring texture.The example of " alkoxyl group " includes, but not limited to methoxyl group, oxyethyl group, positive propoxy, isopropoxy, tert.-butoxy, n-butoxy, s-pentyloxy etc.

" haloalkyl " comprises the stable hydrocarbon of side chain and straight chain, and this hydrocarbon has one or more carbon that replaced by halogen.The example of haloalkyl includes, but not limited to trifluoromethyl, trichloromethyl, pentafluoroethyl group etc.

Term " thiazolinyl " refers to comprise the hydrocarbon chain of straight chain, side chain or ring texture, and this hydrocarbon chain has one or more undersaturated C-Cs in any stable site of chain or ring.Except as otherwise noted, " thiazolinyl " generally has 2-8, usually 2-6 carbon atom.For example, " thiazolinyl " can refer to third-2-thiazolinyl, but-2-ene base, fourth-3-thiazolinyl, 2-methyl-prop-2-thiazolinyl, own-the 2-thiazolinyl, own-5-thiazolinyl, 2,3-dimethyl butyrate-2-thiazolinyl etc.And thiazolinyl can be substituted or not be substituted.

Term " alkynyl " comprises the hydrocarbon chain of straight or branched structure, and this hydrocarbon chain has one or more carbon-to-carbon triple bonds in any stable site of chain.Except as otherwise noted, " alkynyl " has 2-8, preferred 2-6 carbon.The example of " alkynyl " include, but are not limited to Propargyl, fourth-2-alkynyl, fourth-3-alkynyl, penta-2-alkynyl, 3-methylpent-4-alkynyl, oneself-the 2-alkynyl, oneself-5-alkynyl etc.And alkynyl can be substituted or not be substituted.

Cycloalkyl is the subclass of alkyl, and comprises ring-type or the multi-ring alkyl of any stable 3-13 carbon atom, and any carbon atom all is saturated.The example of these cycloalkyl includes, but not limited to cyclopropyl, norborneol alkyl, [2.2.2] bicyclooctane, [4.4.0] two cyclodecane etc., can choose wantonly to be substituted when as other moieties.Term " cycloalkyl " can exchange with term " carbocylic radical " and use.

Cycloalkenyl group is the subclass of thiazolinyl, and comprises any stable ring-type or multi-ring alkyl, and this alkyl has 3-13 carbon atom, preferred 5-8 carbon atom, and this alkyl contains one or more undersaturated carbon-to-carbon double bonds in any site of ring.The example of these cycloalkenyl groups includes, but not limited to cyclopentenyl, cyclohexenyl etc.

Cycloalkynyl radical is the subclass of alkynyl, and comprises ring-type or the multi-ring alkyl of any stable 5-13 carbon atom, and this alkyl contains one or more carbon-to-carbon triple bonds in any site of ring.When as other thiazolinyl and alkynyl part, cycloalkenyl group and cycloalkynyl radical can be chosen wantonly and be substituted.

" heterocycle " used herein, " heterocyclic radical " or " (heterocyclic) of heterocycle " refer to have 5-14, the non-aromatic ring system of preferred 5-10 annular atoms, and wherein one or more encircle carbon, and preferred 1-4 ring carbon is substituted by the heteroatoms as N, O or S.The heterocyclic radical limiting examples comprises 3-1H-benzimidazolyl-2 radicals-ketone, (1-replacement)-2-oxo-benzoglyoxaline-3-base, the 2-tetrahydrofuran base, the 3-tetrahydrofuran base, the 2-tetrahydro-thienyl, the 3-tetrahydro-thienyl, the 2-morpholinyl, morpholinyl, the 4-morpholinyl, 2-parathiazan base, 3-parathiazan base, 4-parathiazan base, the 1-pyrrolidyl, the 2-pyrrolidyl, the 3-pyrrolidyl, the 1-piperazinyl, the 2-piperazinyl, piperidino, the 2-piperidyl, the 3-piperidyl, the 4-piperidyl, the 4-thiazolidyl, azo cyclopentenyl (diazolonyl), the azo cyclopentenyl that N-replaces, 1-benzopyrrole alkane ketone (1-phthalimidinyl) Ben Bing oxane base (benzoxanyl), the benzopyrrole alkyl, the benzo piperidyl, benzo oxa-cyclopentyl, benzimidazole thiophanate heterocycle amyl group (benzothiolanyl) and benzo thiophene alkyl (benzothianyl).Also comprise following radicals in the scope of term as described herein " heterocycle " or " heterocyclic radical ", wherein non-fragrance contains heteroatomic ring and is fused on one or more fragrance or the non-aromatic ring, as in indolinyl, chromanyl, phenanthridinyl or tetrahydric quinoline group, wherein linking group or tie point contain on the heteroatomic ring at non-fragrance.Term " heterocycle ", " heterocyclic radical " or " heterocycle " no matter saturated or fractional saturation also relate to optional substituted ring.

The term " aryl " that independent use or conduct are used than macoradical (in " aralkyl ", " aralkoxy " or " aryloxy-alkyl ") part refers to have the aromatic group of 6-14 annular atoms, as phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl and 2-anthryl." aryl " ring can contain one or more substituting groups.Term " aryl " can exchange with term " aryl rings " and use." aryl " also comprises the fragrant member ring systems of the many cyclophanes that condense, and wherein aromatic nucleus is fused on one or more rings.The limiting examples of useful aryl rings group comprises phenyl, hydroxy phenyl, halogenophenyl, alkoxyl phenyl, dialkoxy phenyl, tri-alkoxy phenyl, alkylenedioxy group phenyl, naphthyl, phenanthryl, anthryl, phenanthro-(phenanthro) etc., and 1-naphthyl, 2-naphthyl, 1-anthryl and 2-anthryl.Also comprise following radicals in the scope of term used herein " aryl ", wherein aromatic nucleus is fused on one or more non-aromatic rings, and as in indanyl, phenanthridinyl or tetralyl, wherein linking group or tie point are on aromatic nucleus.

Term used herein " heteroaryl " refers to stable heterocyclic radical and has many heteroaromatics group of 5-14 annular atoms.Heteroaryl can be substituted or not replace, and can comprise one or more rings.The example of general hetero-aromatic ring comprises 5-unit monocyclic groups, as thienyl, pyrryl, imidazolyl, pyrazolyl, furyl, isothiazolyl, furazan base, isoxazolyl, thiazolyl etc.; 6-unit monocyclic groups is as pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, triazinyl etc.; With many rings heterocyclic radical group, as benzo [b] thienyl, naphtho-[2,3-b] thienyl, thianthrenyl, isobenzofuran-base, chromenyl, xanthenyl, benzo oxathiene base (phenoxathienyl), the indolizine base, pseudoindoyl, indyl, indazolyl, purine radicals, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolyl, benzothiazole, benzoglyoxaline, tetrahydroquinoline, the cinnolines base, pteridyl, carbazyl, the β-Ka Lin base, phenanthridinyl, acridyl, perimidinyl (perimidinyl), the phenodiazine phenanthryl, phenazinyl, isothiazolyl, phenothiazinyl phenoxazinyl etc. (referring to, as Katritzky, Handbook of HeterocyclicChemistry).The specific example of other of heteroaryl ring comprises the 2-furyl, the 3-furyl, the TMSIM N imidazole base, the 2-imidazolyl, the 4-imidazolyl, the 5-imidazolyl, the 3-isoxazolyl, the 4-isoxazolyl, the 5-isoxazolyl, 2-oxadiazole base, 5-oxadiazole base, the 2-oxazolyl, the 4-oxazolyl, the 5-oxazolyl, the 1-pyrryl, the 2-pyrryl, the 3-pyrryl, the 2-pyridyl, the 3-pyridyl, the 4-pyridyl, the 2-pyrimidyl, the 4-pyrimidyl, the 5-pyrimidyl, the 3-pyridazinyl, the 2-thiazolyl, the 4-thiazolyl, the 5-thiazolyl, the 5-tetrazyl, the 2-triazolyl, the 5-triazolyl, the 2-thienyl, the 3-thienyl, carbazyl, benzimidazolyl-, benzothienyl, benzofuryl, indyl, quinolyl, the benzotriazole base, benzothiazolyl benzoxazolyl, benzimidazolyl-, isoquinolyl, indyl, pseudoindoyl, acridyl or benzoisoxazole base.Heteroaryl also comprises following radicals, and wherein assorted aromatic nucleus is fused on one or more fragrance or the non-aromatic ring, and wherein linking group or tie point are on assorted aromatic nucleus.Example comprises tetrahydroquinoline, tetrahydroisoquinoline and pyrido [3,4-d] pyrimidyl, imidazo [1,2-a] pyrimidyl, imidazo [1,2-a] pyrazinyl, imidazo [1,2-a] pyridyl, imidazo [1,2-c] pyrimidyl, pyrazolo [1,5-a] [1,3,5] triazinyl, pyrazolo [1,5-c] pyrimidyl, imidazo [1,2-b] pyridazinyl, imidazo [1,5-a] pyrimidyl, pyrazolo [1,5-b] [1,2,4] triazine, quinolyl, isoquinolyl, quinoxalinyl, the imidazo-triazine base, pyrrolo-[2,3-d] pyrimidyl, triazolopyrimidinyl, the pyrido-pyrazine base.Term " heteroaryl " also refers to optional substituted ring.Term " heteroaryl " can exchange with term " heteroaryl ring " or term " assorted aromatic base " and use.

Aryl (aryl moiety that comprises aralkyl, aralkoxy or aryloxyalkyl group etc.) or heteroaryl (heteroaryl moieties that comprises heteroaralkyl or heteroaryl alkoxyl group etc.) can contain one or more substituting groups.On the unsaturated carbon atom of aryl or heteroaryl the example of suitable substituents comprise halogen (F, Cl, Br or I), alkyl, thiazolinyl, alkynyl ,-CN ,-R ⁴,-OR ²,-S (O) _rR ²(wherein r is 0,1 or 2 integer) ,-SO ₂NR ²R ³,-NR ²R ³The YR of ,-(CO) ²,-O (CO) YR ²,-NR ²(CO) YR ²,-S (CO) YR ²,-NR ²C (=S) YR ²,-OC (=S) YR ²,-C (=S) YR ², wherein in each case, Y is independently-O-,-S-,-NR ³-or chemical bond; Therefore-(CO) YR ²Comprise-C (=O) R ²,-C (=O) OR ², and-C (=O) NR ²R ³Other substituting group comprises-YC (=NR ³) Y ' R ²,-COCOR ²,-COMCOR ²(wherein M is the alkyl of 1-6 carbon) ,-YP (=O) (YR ⁴) (YR ⁴) (comprise-P (=O) (R ⁴) ₂) ,-Si (R ⁴) ₃,-NO ₂,-NR ²SO ₂R ²With-NR ²SO ₂NR ²R ³In order to further specify, wherein Y is-NR ³Substituting group also comprise-NR ³C (=O) R ²,-NR ³C (=O) NR ²R ³,-NR ³C (=O) OR ², and-NR ³C (=NH) NR ²R ³R ⁴Substituting group is selected from alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, aryl, heteroaryl, heterocyclic radical; R ²And R ³Substituting group is independently selected from hydrogen, alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, aryl, heteroaryl, heterocyclic radical and R in each case ², R ³And R ⁴Substituting group itself can be substituted or not be substituted.R ², R ³And R ⁴On the substituent example that can have comprise amino, alkylamino, dialkyl amido, aminocarboxyl, halogen, alkyl, aryl, heteroaryl, carbocyclic ring, heterocycle, alkyl amino-carbonyl, dialkyl amino carbonyl, alkyl amino carbonyl oxy, dialkyl amido carbonyl oxygen base, nitro, cyano group, carboxyl, alkoxy carbonyl, alkyl-carbonyl, hydroxyl, alkoxyl group, halogen alkoxyl group.Other example comprise OH (for example acyloxy), phenyl, the replacement of protection phenyl ,-the O-phenyl ,-O-(replacement) phenyl ,-benzyl of benzyl, replacement ,-the O-styroyl (namely-OCH ₂CH ₂C ₆H ₅) ,-O-(replacement) styroyl.The R that replaces ², R ³Or R ⁴The non-limiting example of group comprise alkylhalide group and three alkylhalide groups, alkoxyalkyl, halobenzene base ,-the M-heteroaryl ,-the M-heterocycle ,-the M-aryl ,-M-OR ²,-M-SR ²,-M-NR ²R ³,-M-OC (O) NR ²R ³,-M-C (=NR ²) NR ²R ³,-M-C (=NR ²) OR ³,-M-P (O) R ²R ³, Si (R ²) ₃,-M-NR ²C (O) R ³,-M-NR ²C (O) OR ²,-M-C (O) R ²,-M-C (=S) R ²,-M-C (=S) NR ²R ³,-M-C (O) NR ²R ³,-M-C (O) NR ²-M-NR ²R ³,-M-NR ²C (NR ³) NR ²R ³,-M-NR ²C (S) NR ²R ³,-M-S (O) ₂R ³,-M-C (O) R ³,-M-OC (O) R ³,-MC (O) SR ²,-M-S (O) ₂NR ²R ³,-C (O)-M-C (O) R ²,-MCO ₂R ²,-MC (=O) NR ²R ³,-M-C (=NH) NR ²R ³, and-M-OC (=NH) NR ²R ³(wherein M is the alkyl of 1-6 carbon).

Some more specifically example include but not limited to chloromethyl, trichloromethyl, trifluoromethyl, methoxy ethyl, alkoxyl phenyl, halobenzene base ,-CH ₂-aryl ,-CH ₂-heterocycle ,-CH ₂C (O) NH ₂,-C (O) CH ₂N (CH ₃) ₂,-CH ₂CH ₂OH ,-CH ₂OC (O) NH ₂,-CH ₂CH ₂NH ₂,-CH ₂CH ₂CH ₂NEt ₂,-CH ₂OCH ₃,-C (O) NH ₂,-CH ₂CH ₂-heterocycle ,-C (=S) CH ₃,-C (=S) NH ₂,-C (=NH) NH ₂,-C (=NH) OEt ,-C (O) NH-cyclopropyl, C (O) NHCH ₂CH ₂-heterocycle ,-C (O) NHCH ₂CH ₂OCH ₃,-C (O) CH ₂CH ₂NHCH ₃,-CH ₂CH ₂F ,-C (O) CH ₂-heterocycle ,-CH ₂C (O) NHCH ₃,-CH ₂CH ₂P (O) (CH ₃) ₂, Si (CH ₃) ₃Deng.

The heterocyclic radical of alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylhalide group, cycloalkyl, cycloalkenyl group, cycloalkynyl radical or non-aromatic can also contain one and a plurality of substituting group.The example of suitable substituents includes, but are not limited to those listed substituting groups of carbon atom that the front is used for aryl or heteroaryl on these groups, also comprise in addition following substituting group for saturated carbon atom :=O ,=S ,=NH ,=NNR ²R ³,=NNHC (O) R ²,=NNHCO ₂R ², or=NNHSO ₂R ², wherein in each case, R ²And R ³Be hydrogen, alkyl, thiazolinyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, aryl, heteroaryl, heterocyclic radical independently.On the group of aliphatics, assorted aliphatics or heterocycle substituent example comprise amino, alkylamino, dialkyl amido, aminocarboxyl, halogen, alkyl, alkyl amino-carbonyl, dialkyl amino carbonyl, alkyl amino carbonyl oxy, dialkyl amido carbonyl oxygen base, alkoxyl group, nitro ,-CN, carboxyl, alkoxy carbonyl, alkyl-carbonyl ,-OH, halogen alkoxyl group or alkylhalide group.

Example substituting group on the nitrogen (for example in the heterocycle of heteroaryl or non-aromatic) comprises R ⁴,-NR ²R ³,-C (=O) R ²,-C (=O) OR ²,-C (=O) SR ²,-C (=O) NR ²R ³,-C (=NR ²) NR ²R ³,-C (=NR ²) OR ²,-C (=NR ²) R ³,-COCOR ²,-COMCOR ²,-CN ,-SO ₂R ³, S (O) R ³,-P (=O) (YR ²) (YR ²) ,-NR ²SO ₂R ³With-NR ²SO ₂NR ²R ³, wherein in each case, R ⁴Be alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, aryl, heteroaryl and heterocyclic radical; In each case, R ²And R ³Be hydrogen, alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, aryl, heteroaryl and heterocyclic radical independently.

When member ring systems (for example cycloalkyl, heterocyclic radical, aryl or heteroaryl) is being known that the many substituting groups that change in the range of definition replace, should understand substituent sum and be no more than valency good for use under the existence condition.Therefore, for example the phenyl ring (wherein the scope of " p " is 0-5) that is replaced by " p " individual substituting group can have 0-5 substituting group, has 0-4 substituting group and should understand the pyridine ring that is replaced by " p " individual substituting group.The maximum of the group of The compounds of this invention replaces radix and can be easy to determine.

The present invention only is included in substituting group in the stable or chemically available compound and those combinations of variant.Stable compound or chemically available compound are for its preparation and detect sufficiently stable compound.Preferred The compounds of this invention is sufficiently stable, makes that maintenance does not change at least one week basically in the presence of moisture or under other chemical reaction condition when under 40 ℃ or lower temperature.

Some compound of the present invention can exist with tautomeric forms, and the present invention includes the tautomeric forms of all these compounds except as otherwise noted.

Except as otherwise noted, structure as herein described also comprises the stereochemical form of all described structures; That is be R and S configuration for each asymmetric center.Therefore, the corresponding isomer of single three-dimensional chemical isomer and The compounds of this invention and non-corresponding isomer mixture are within the scope of the invention.Therefore, the present invention includes every kind of non-corresponding isomer or corresponding isomer and do not contain other isomer (＞90%, and preferred＞95%, molar ratio does not contain other steric isomer) and these mixture of isomers substantially.

Can obtain concrete optical isomer by ordinary method resolution of racemates mixture, described method is as by forming non-corresponding isomer salt with optically active acid or alkaline purification.The example of the acid that is fit to is tartrate, diacetyl tartrate, dibenzoyl tartaric acid, dimethylbenzene acyl group tartrate and camphorsulfonic acid, by the non-corresponding isomer mixture of Crystallization Separation, separates out optically active alkali then from these salt then.The different methods of separating optical isomeric body comprises that use is for the chiral chromatographic column of the corresponding isomer optimal selection of maximum separation.Other method comprises by making the optically pure acid of compound of the present invention and activity form or optically pure isocyanate reaction, with synthetic covalently bound non-corresponding isomer molecule.Should can separate by ordinary method by synthetic non-corresponding isomer, as chromatography, distillation, crystallization or distillation, hydrolysis obtains the pure compound of corresponding isomer then.

Optically active compound of the present invention can obtain by using active starting material.These isomer can be the form of free acid, free alkali, ester or salt.

Compound of the present invention can exist with radiolabeled form, and namely described compound can comprise one or more nucleidic mass or total mass number and be different from nucleidic mass that occurring in nature exists usually or the atom of total mass number.The radio isotope of hydrogen, carbon, phosphorus, fluorine and chlorine comprises respectively ³H, ¹⁴C, ³²P, ³⁵S, ⁴³F and ³⁶Cl.Contain other radioisotopic compound of the present invention of these radio isotope and/or other atom in scope of the present invention.Tritium namely ³H and carbon-14 are namely ¹⁴The C isotropic substance is easy to preparation for them and detection is especially preferred.

Radiolabeled compound of the present invention can prepare by method known to those skilled in the art usually.Easily, these radiolabeled compounds can just easily be replaced inactive reaction reagent with available radiolabeled reaction reagent by method preparation as herein described.

4. synthetic general introduction

The professional has the known document about heterocycle and other relevant chemical transformation, recovery and purification technique; the information that itself and the following examples are comprised is used in combination; be used for instructing synthesis strategy, protecting group and other raw material and the method for synthesizing, reclaiming and characterizing to The compounds of this invention, described compound comprises the R that contains multiple choices ^t, R ^a, R ^b, R ^c, R ^d, R ^eCompound with ring T, A, B, C and D.

Can use multiple synthetic method to prepare compound as herein described, comprise the described method of following proposal.The professional will understand in these methods can use protecting group." protecting group " is to make reaction selectivity to carry out on other site of a plurality of functional compounds for the part of the potential reaction site chemical reaction of temporary interruption (for example, amine, hydroxyl, sulfydryl, aldehyde etc.).In preferred embodiments, the protecting group selective reaction obtains being fit to the protected material of plan reaction with high yield; Described protecting group should be removed with the high yield selectivity by quick available preferred nontoxic reaction reagent, and described reaction reagent can excessive influence other functional group of the present invention; Protecting group is preferably formed can segregative derivative (more preferably not producing new stereocenter); And protecting group preferably has other minimum function to avoid making other sites of reaction complicated.The kinds of protect base is known in the art with scheme, reagent and the condition of using and remove these protecting groups.Referring to, " Protective Groups in Organic Synthesis " Third Ed.Greene for example, T.W. and Wuts, P.G., Eds., John Wiley ﹠amp; Sons, New York:1999.For other background information of protecting group method (for the protection of with de-protected material, method and scheme) and other synthetic chemistry for the protection of compound described herein transform referring to R.Larock, Comprehensive organic Transformations, VCH Publishers (1989); T.W.Greene and P.G.M.Wuts, Protective Groups in Organic Synthesis, 3rd.Ed., John Wileyand Sons (1999); L.Fieser and M.Fieser, Fieser and Fieser ' s Reagents for OrganicSynthesis, John Wiley and Sons (1994); And L.Paquette, ed., Enrcyclopedia ofReagents for Organic Synthesis, John Wiley and Sons (1995).The full content of these documents is incorporated herein by reference.

And people can the required isotopic reagent of selective enrichment, replaces hydrogen as deuterium, contains these isotopic compounds of the present invention with preparation.Contain the compound that deuterium replaces hydrogen in one or more positions, or contain the isotopic compound of multiple C, N, P and O and comprise in the present invention, and can be used for for example studying metabolism and/or the tissue distribution of these compounds, or speed or the approach of change metabolism, or the other side of biological function.

Compound of the present invention can use the known synthetic method in following method and organic chemical synthesis field, or understands the changing method of these methods synthetic by those skilled in the art.Preferable methods includes, but are not limited to following method.In the solvent that is suitable for used reaction reagent and material and suitable influence conversion, react.The technician in organic synthesis field will understand the functionality that exists in the molecule should be consistent with the conversion of planning.Sometimes need some to judge to change the order of synthesis step or select a kind of special process program to obtain required compound of the present invention.

The method that The compounds of this invention can be summarized to the scheme XVII according to scheme I and by standard method preparation well known by persons skilled in the art.

Shown in scheme I and II, the Sonogashira linked reaction of palladium catalysis is used for " top " ring T and " bottom " [ring A]-[L ¹Encircle B]-[] partly link together.In scheme I, by alkynes class " top " ring T and [ring A]-[L ¹Encircle B]-[] partly carry out described Sonogashira linked reaction, wherein [encircle A]-[L ¹]-[ring B] the reactive behavior base W activation that existed of part; W is that iodine, bromine or other allow the reaction active groups of required linked reaction.Intermediate W-[encircles A]-[L ¹]-[ring B] in variable as defined above, the R that ring A and B randomly are allowed to respectively ^aAnd R ^bGroup replaces.

Scheme I:Sonogashira linked reaction

In scheme II, described optional linked reaction, wherein encircled reactive behavior base W (for example I or the Br) activation that T existed and similarly be coupled to " bottom " alkynes class [ring A]-[L under the palladium catalytic coupling condition ¹Encircle B]-[] on.

Scheme II: optional Sonogashira linked reaction

Sonogashira coupling condition described in scheme I and the II can be applicable to all bicyclic heteroaryl ring T of the present invention and can be used for synthetic all compounds of the present invention.

According to known conversion, the total synthesis method for the preparation of alkynes class ring T part of explanation various exemplary among the scheme III to VI below:

The preparation of the ethynyl imidazoles that scheme III:2-replaces

The preparation of the ethynyl thiazole that scheme IV:2-replaces

The preparation of the amino Yi Que Ji oxazole that replaces of plan V: 2-

The preparation of the Yi Que Ji oxazole that plan V I:2-aminocarboxyl replaces

These methods that those of ordinary skills can be familiar with for the preparation of the alkynes class ring T base of multiple replacement are widely applicable for other monocycle hetero-aromatic ring that does not demonstrate.

The useful intermediates formula W-[ring A of linked reaction described in following plan V II to XI explanation scheme I and the II]-[L ¹]-[ring B] compound synthetic.

Obviously the intermediate of following formula is significant especially:

Because it produces The compounds of this invention with " top " hetero-aromatic ring generation linked reaction.Variable group A, L ¹, and B as defined above and as described hereinly randomly be substituted, W is I or other reaction active groups that allows required linked reaction.

The example of these intermediates comprises following structure:

Wherein variable such as R ^a, R ^b, R ^cAnd R ^dAs defined above.For example, R in some embodiments ^aBe selected from F or alkyl such as Me, in some embodiments R ^bBe selected from Cl, F, Me, the tertiary butyl ,-CF ₃Or-OCF ₃Deng.These and the substituent formula W-[ring A with multiple permission]-L ¹Other compounds of-[ring B] are for the preparation of the defined respective compound of the present invention of multiple structural formula, kind and group disclosed herein.

The exemplary synthetic route of some of reagent and representative intermediate preparation is as follows:

Plan V II has described and has wherein encircled A and B is phenyl, and L ¹Be the W-[ring A of NHC (O)]-[L ¹]-[ring B] exemplary synthetic.

Plan V II

Plan V III has described and wherein encircled B is 2-pyridine and L ¹Be aforementioned intermediate variant synthetic of C (O) NH (being on another direction).

Plan V III

Below scheme IX and X illustrated that wherein encircling A and B is that phenyl, ring C are the W-[ring A of hetero-aromatic ring]-[L ¹]-[ring B] synthetic.These intermediates are for the preparation of formula II compound.

More specifically, scheme IX has described and has wherein encircled the preparation that C is the intermediate of imidazole ring.

Scheme IX

Scheme X has described and has wherein encircled the preparation that C is the intermediate of pyrroles Huo oxazole ring.

Scheme X

Scheme XI has illustrated and has wherein encircled A and B is phenyl, R ^bSubstituting group is [L ²]-[ring D] W-[ring A]-[L ¹]-[ring B] synthetic.These intermediates for the preparation of wherein encircle D be contain one or two heteroatomic 5 or the formula III compound of 6-unit heterocycle.

Scheme XI

In this scheme, ring B goes up substituent R ^bNon-limitative example comprise halogen, for example Cl, low alkyl group, for example sec.-propyl; With the low alkyl group that replaces, for example-CF ₃The non-limitative example of ring D is N, N-dimethyl pyrrolidine, N-(2-hydroxyethyl) piperazine and N methyl piperazine.

Intermediate W-[encircles A]-[L ¹Encircle B]-[], for example those shown in the top various synthetic schemess can use the Sonogashir coupling condition described in the general approach I and alkynes class ring T reaction.

Example of explanation among the scheme XII below, wherein encircling the T part can be after the Sonogashir coupling step, and further derivatize obtains the analogue of the present invention of multiple significant replacement.

Scheme XII

Alternatively, before that describe in addition in general approach II and ring T coupling iodine or bromine activation, intermediate W-[encircles A]-[L ¹]-[ring B] can be under the Sonogashira condition and the TMS acetylene reaction.

Example of explanation among the scheme XIII.

Scheme XIII

In other embodiments, the order that described step can be different is carried out.For example, as shown in scheme XIV, the Sonogashira linked reaction can be used for shack T and ring A, afterwards this part is connected to ring B and/or [ring B]-[L ²]-[ring D] and/or [ring B]-[ring C] on.

Scheme XIV

Encircling A and B therein is phenyl, L ¹Be in the non-limitative example of CONH, the Sonogashira coupling that scheme XV has described alkynes class ring T and 3-iodo-4-tolyl acid (ring A part) produces [ring T]-[ring A] intermediate, and it partly carries out the acid amides linked reaction with the optional ring B that replaces then:

Scheme XV

This method is shown among the scheme XVI, its explanation acetylene class ring T (being 5-ethynyl-1-methyl isophthalic acid H-imidazoles-2-methane amide) and the W-[ring A that replaces] (being 3-iodo-4-tolyl acid) coupling, gained [ring T]-[ring A]-COOH intermediate and H then ₂N-[encircles B]-L2-[encircles C] partly (be that 4-((4-methylpiperazine-1-yl) methyl)-3-(5-trifluoromethylaniline) carries out the acid amides coupling:

Scheme XVI

Alternatively; as scheme XVII explanation; another example in professional's the connection range of choice is that 3-iodo-4-tolyl acid ring A intermediate can carry out the Sonogashira reaction with the trimethyl silane ethyl-acetylene, and it can carry out the Sonogashira linked reaction second time with the ring T of activation after the silylation deprotection then.

Scheme XVII

According to such as foregoing synthetic method, in conjunction with the following examples, the out of Memory that provides herein and ordinary method and raw material, the professional should be able to prepare compound in the four corner disclosed herein.

5. purposes, preparation, administration

Pharmaceutical use; Indication

The invention provides the compound with biological property, these character make these compounds can treat or improve pay close attention to may relate to kinase whose disease, the symptom of these diseases, or by the effect of other kinase mediated physiological event.For example, many compound exhibits of the present invention go out to suppress the tyrosine kinase activity of Src and abl, and other thinks the Tyrosylprotein kinase of growth, development and/or the transfer of regulating cancer.Have been found that many compounds of the present invention have the activity that potent external opposing cancer cell is, described cancer cell is to comprise K-562 leukemia cell.Viewed effect is 10 times of imatinib mesylate in the conventional antiproliferative test of K562 cell.

Therefore these compounds are paid close attention to the treatment cancer, described cancer comprises cancer idiopathic and that shift, comprise solid tumor and lymphoma and leukemia (comprising CML, AML and ALL), and comprise the cancer to other treatment (comprising relating to the administration kinase inhibitor, as the treatment of imatinib mesylate, Te Luokai or Iressa) opposing.

These cancers comprise mammary cancer, cervical cancer, colorectal carcinoma, lung cancer, ovarian cancer, carcinoma of the pancreas, prostate cancer, head and neck cancer, gastrointestinal stromal cancer, and following disease, as melanoma, multiple myeloma, non-hodgkin's (family name) lymphoma, melanoma, cancer of the stomach and leukemia (as marrow, lymphatic, myeloid and lymphoblastic leukemia), comprise the disease to one or more other treatments (comprising imatinib mesylate, Te Luokai or Iressa) opposing.

Opposing may be that (as, the sudden change in kinases such as Src or Abl) causes because the sudden change of cancer amboceptor or effector to multiple anticarcinogen, and this is relevant in conjunction with character, phosphate-binding matter, protein binding character, self adjusting or other character with patient's medicine.For example, in the situation of BCR-Abl (kinases relevant with chronic granulocytic leukemia), opposing to imatinib mesylate has been mapped to multiple BCR/Abl sudden change, described sudden change is relevant with multiple functional consequence, comprise sterically hindered, phosphoric acid that medicine occupies at kinase whose avtive spot in conjunction with P encircle variable change, for around the influence of the structure of the activation ring of avtive spot etc.Referring to people such as for example Shah, 2002, Cancer Cell 2, people such as 117-125 and Azam, 2003, Cell 112, and 831-843 is with the reference of wherein quoting for the representative example of these sudden changes in the Bcr/Abl relevant with drug resistance.Also referring to following reference replenishing for the BCR/Abl background information, its mechanism effect in CML and drug resistance mechanism of production and sudden change: people such as Kurzrock, Philadelphia chromosome-positive leukemias:from basic mechanisms tomolecular therapeutics, Ann Intern Med.2003 May 20; 138 (10): 819-30; People such as O ' Dwyer, Demonstration of Philadelphia chromosome negative abnormal clones inpatients with chronic myelogenous leukemia during major cytogenetic responsesinduced by imatinib mesylate.Leukemia.2003Mar; 17 (3): 481-7; People such as Hochhaus, Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy, Leukemia.2002Nov; 16 (11): 2190-6; People such as O ' Dwyer, The impact ofclonal evolution on response to imatinib mesylate (STI571) in accelerated phaseCML.Blood.2002Sep1; 100 (5): 1628-33; People such as Braziel, Hematopathologic andcytogenetic findings in imatinib mesylate-treated chronic myelogenous leukemia patients:14months ' experience.Blood.2002Jul 15; 100 (2): 435-41; People such as Corbin, Analysis of the structural basis of specificity of inhibition of the Abl kinase bySTI571.J Biol Chem.2002 Aug 30; 277 (35): 32214-9; People such as Wertheim, BCR-ABL-induced adhesion defects are tyrosine kinase-independent.Blood.2002Jun 1; 99 (11): 4122-30; People such as Kantarjian, Hematologic and cytogeneticresponses to imatinib mesylate in chronic myelogenous leukemia, N Engl J Med.2002Feb 28; 346 (9): 645-52.Erratum in:N Engl J Med 2002 Jun 13; 346 (24): 1923; People such as Hochhaus, Roots of clinical resistance to STI-571cancertherapy.Science.2001Sep 21; 293 (5538): 2163; People such as Druker, Activity of aspecific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronicmyeloid leukemia and acute lymphoblastic leukemia with the Philadelphiachromosome.N Engl J Med.2001Apr 5; 344 (14): 1038-42.Erratum in:N Engl JMed 2001 Jul 19; 345 (3): 232; People such as Mauro, Chronic myelogenous leukemia.Curr Opin Oncol.2001 Jan; 13 (1): 3-7.Review; People such as Kolibaba, CRKL bindingto BCR-ABL and BCR-ABL transformation.Leuk Lymphoma.1999 Mar; 33 (1-2): 119-26; People such as Bhat, Interactions of p62 (dok) with p210 (bcr-abl) andBcr-Abl-associated proteins.J Biol Chem.1998 Nov 27; 273 (48): 32360-8; People such as Senechal, Structural requirements for function of the Crkl adapter proteinin fibroblasts and hematopoietic cells.Mol Cell Biol.1998 Sep; 18 (9): 5082-90; Kolibaba et al., Protein tyrosine kinases and cancer.Biochim Biophys Acta.1997Dec 9; 1333 (3): F217-48.Review; People such as Heaney, Direct binding of CRKL toBCR-ABL is not required for BCR-ABL transformation.Blood.1997 Jan 1; 89 (1): 297-306; People such as Hallek, Interaction of the receptor tyrosine kinase p145c-kitwith the p210bcr/abl kinase in myeloid cells.Br J Haematol.1996 Jul; 94 (1): 5-16; People such as Oda, The SH2 domain of ABL is not required forfactor-independent growth induced by BCR-ABL in a murine myeloid cell line.leukemia.1995 Feb; 9 (2): 295-301; People such as Carlesso, Use of a temperature-sensitivemutant to define the biological effects of the p210BCR-ABL tyrosine kinase onproliferation of a factor-dependent murine myeloid cell line.Oncogene.1994Jan; 9 (1): 149-56.

Again, we think compound of the present invention both can monotherapy also can combination treatment, be used for opposing leukemia and other cancer, comprise the cancer of resisting wholly or in part for other anticarcinogen (especially comprising imatinib mesylate and other kinase inhibitor), and especially comprise the leukemia that relates to one or more sudden changes among the BCR/Abl (in the kinases zone or outside), include but not limited to above-mentioned disclosed any.Especially referring to people's such as Azam paper and the reference wherein quoted for the example of the sudden change among the BCR/Abl, described sudden change is included in medicine in conjunction with the sudden change in the cracking, the phosphoric acid sudden change in conjunction with the zone in the sudden change of long α-3 spiral in the sudden change of catalysis α-1 spiral of the sudden change in the P ring, the sudden change that activates the conservative VAVK of sudden change in the ring, kinase beta-3 lamella, little N leaf (lobe), the big C leaf and the C leaf downstream that activation encircles.

Method of pharmacy

Method of the present invention comprises to the compound of the present invention of required curee's drug treatment significant quantity.

" treatment significant quantity " is for effectively to measure for following effects: detectable kill cancer cell or anticancer growth or diffusion; The size of tumour or quantity; Or to other mensuration of cancer level, stage, progress or severity.Definite amount will change according to curee's difference, its ethnic group according to the curee, age and generalized case, and the severity of disease, specific cancer therapy drug, administering mode changes with the combined therapy of other treatment etc.

Compound or contain this compound compositions and can use and effectively kill or suppress any amount and any route of administration administration that tumor growth or other cancer form.

Anticancer compound of the present invention preferably is formulated as the unit dosage that makes things convenient for administration, and dosage is even.Term used herein " unit dosage " refers to the unit of the physical sepn of anticarcinogen that the patient who treats is fit to.Usually, total per daily dose of compound of the present invention and composition will be used according to the reasonably conventional procedure decision of medical judgment by the attending doctor.To depend on multiple factor for any concrete patient or organic particular treatment effective dose level, comprise the disease that to treat; The severity of disease; The usefulness of used particular compound; Used concrete composition; Patient's age, body weight, general health, sex and diet; The approach of administration and scheme; The speed of compound metabolism and/or drainage; The time length for the treatment of; That use in the medicinal composition or with the medicine of The compounds of this invention administration simultaneously; With the known similar factor of field of medicaments.

And, with after required dosage and the pharmaceutically acceptable carrier preparation that is fit to, composition of the present invention can be to people or the administration in the following manner of other animal: in oral, per rectum, parenteral, the brain pond, intravaginal, intraperitoneal, part (as by percutaneous plaster, powder, ointment or drops), hypogloeeis, contain clothes, mouth or nose spraying etc.

The common scope of effective body dose of this compound is 0.01 to 500mg compound/kg patient body weight, and preferred 0.1 to 125mg/kg, and sometimes 1 to 25mg/kg, with single dose or multiple dose administration.Usually, be about 50 to about patient 2000mg/ to the per daily dose scope of this compound of patient's administration of this treatment of needs.Administration can be (or other many days at interval) every day 1 time or repeatedly with the week in the unit, or with interlude.For example, be that this compound of unit (as on every Mondays) can be administered once or indefinite or lasting a few week repeatedly every day with the week, as 4-10 week.Perhaps, administration every day continues several days (as 2-10 days), several days then (as 1-30 days) these compounds of not administration, and indefinite repeats this circulation or repeats given number of times, as 4-10 circulation.For example, compound of the present invention can administration every day, continues 5 days, is interrupted 9 days then, and then administration every day continues 5 days, be interrupted then 9 days, etc., indefinite repeat this circulation or repeat 4-10 time altogether.

Be effective to treat or prevent the amount of the compound of particular disorder or disease will partly depend on the known factor that influences drug dose.And, the external or definite optimal dose scope of in vivo test help of optional use.Can extrapolate from dose-response curve for the general guidance of effective dose obtains, and described curve is from external or animal model test system.The accurate dose level should be definite by attending doctor or other health care personnels, and will depend on following known factor, comprises age, body weight, sex and the general health situation of route of administration, individuality; The character of disease, severity and clinical stage; The use of co-therapy (or not using); Engineered character and the scope of cell among the patient.

When being used for the treatment of or prevent particular disease states or illness administration, the effective dose of The compounds of this invention can change according to following factor: the state of an illness and its severity and the multiple physical factors relevant with the individuality for the treatment of of used particular compound, administering mode, the illness for the treatment of.In many cases, when compound obtains satisfied result during with following dosed administration, described dosage is about 0.01mg/kg-500mg/kg, and preferred 0.1 to 125mg/kg, and more preferably 1 to 25mg/kg.Dosage every day of plan changes according to route of administration.Therefore, parenteral admin dosage is generally 10% to 20% of about oral administration dosage.

When compound of the present invention during as medicinal composition medication a part of, every kind of dose of components in the administration medicinal composition during required treatment.The administration simultaneously of the composition of medicinal composition; Containing the single formulation of two kinds of compositions, or the formulation of separating; The composition of combination also can be in the different time administration during treating, or a kind of composition of administration is as the treatment in advance of another kind of composition.

About compound

Compound of the present invention can exist with the free form that is used for the treatment of, if or suitablely exist with its pharmacologically acceptable salts or other derivative.Term used herein " pharmacologically acceptable salts " refers to be suitable in rational medical determination range contact with the tissue of people or more rudimentary animal and does not have those salt of excessive toxicity, stimulation, anaphylaxis etc., and has suitable rational interests/risk ratio.The pharmacologically acceptable salts of the compound of amine, carboxylic acid, phosphonic acids and other type is well known in the art.For example, S.M.Berge waits the people to describe pharmacologically acceptable salts in detail, J.Pharmaceutical Sciences, and 66:1-19 (1977) is incorporated herein by reference.Separating and can the described salt of in-situ preparing during the purifying The compounds of this invention, or make the free alkali of The compounds of this invention or free acid respectively with suitable acid or alkali reaction.The example of the receivable atoxic acid salt of pharmacy is: the amino salt that forms with mineral acid, described mineral acid example hydrochloric acid, Hydrogen bromide, phosphoric acid, sulfuric acid and perchloric acid; The amino salt that forms with organic acid, described organic acid such as acetic acid, oxalic acid, toxilic acid, tartrate, citric acid, succsinic acid or propanedioic acid; Or by using other method such as the ion-exchange in this area.Other pharmacologically acceptable salts comprises adipic acid salt, alginate, ascorbate salt, aspartate, benzene sulfonate, benzoate, hydrosulfate, borate, butyrates, camphorate, camsilate, Citrate trianion, cyclopentane propionate, digluconate, dodecane sulfonate, esilate, formate, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate (hernisulfate), enanthate, hexanoate, hydriodate, 2-hydroxyl-esilate, lactobionate, lactic acid salt, lauroleate, lauryl sulfate, malate, maleate, malonate, mesylate, the 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectate (pectinate), persulphate, 3-phenylpropionic acid salt, phosphoric acid salt, picrate, Pivalate, propionic salt, stearate, succinate, vitriol, tartrate, thiocyanate-, tosilate, undecylate, valerate etc.Representational an alkali metal salt or alkaline earth salt comprise sodium salt, lithium salts, sylvite, calcium salt, magnesium salts etc.When suitable, pharmacologically acceptable salts also comprises the positively charged ion of nontoxic ammonium salt, quaternary ammonium salt and amine and the salt that gegenion forms, described gegenion such as halide-ions, hydroxide radical, carboxylate radical, sulfate radical, phosphate radical, nitrate radical, low alkyl group sulfonate radical and aryl sulfonic acid root.

And term used herein " the acceptable ester of pharmacy " preferably refers to the ester of hydrolysis in the body, and is included in the ester that decomposes fast in the human body with generation parent compound or its salt.The ester that is fit to comprises that for example, from the ester of the acceptable aliphatic carboxylic acid of pharmacy, described carboxylic acid especially be paraffinic acid, alkenoic acid, naphthenic acid and chain docosandioic acid, wherein each alkyl or alkenyl maximum 6 carbon atoms advantageously partly.The example of concrete ester comprises manthanoate, acetic ester, propionic ester, butyric ester, acrylate and ethyl succinate.Significantly, ester can be formed by hydroxyl or the carboxylic acid group of The compounds of this invention.

And, term used herein " pharmacy acceptable prodrugs " refers to the prodrug of The compounds of this invention, it is in the scope that reasonably medicine is judged, described prodrug is suitable for contacting with the tissue of people and more rudimentary animal and does not have excessive toxicity, stimulation, anaphylaxis etc., has rational interests/risk ratio, and be effectively to its desired purposes, and if suitablely can be the zwitterionic form of The compounds of this invention.Term " prodrug " refers to transform in vivo the compound that (for example by hydrolysis in blood) produces the parent compound of said structure formula.Referring to for example T.Higuchi and V.Stella, Pro-drugs as NovelDelivery Systems, Vol.14 of the A.C.S.Symposium Series, with Edward B.Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Assocn.and Pergamon Press, 1987, all be incorporated herein by reference.

Composition

The composition that provides comprises any compound as herein described (or its prodrug, pharmacologically acceptable salts or other pharmacy acceptable derivates) and one or more pharmaceutically acceptable carriers or vehicle.Optional one or more other therapeutical agents that also comprises of these compositions.Perhaps, compound of the present invention can with one or more other treatment plans (as imatinib mesylate or other kinase inhibitor, Interferon, rabbit, bone marrow transplantation, farnesyl transferase inhibitor, diphosphonate, Thalidomide, cancer vaccine, hormonotherapy, antibody, radiotherapy etc.) combination to required patient's administration.For example, for combination medicine-feeding or other therapeutical agent that is included in the pharmaceutical compositions with The compounds of this invention can be other one or more anticarcinogens.

As described herein, composition of the present invention comprises compound of the present invention and the pharmaceutically acceptable carrier (comprising any He all solvents, thinner or other vehicle, dispersion agent or suspending agent, tensio-active agent, isotonic agent, thickening material or emulsifying agent, sanitas, solid binder, lubricant etc.) that is fit to required concrete formulation used herein.Remington ' s Pharmaceutical Sciences, FifteenthEdition, E.W.Martin (Mack Publishing Co., Easton, Pa., 1975) disclose multiple for the carrier of compounding pharmaceutical composition and the known technology of its preparation.Unless any conventional mounting medium is incompatible with The compounds of this invention, as produce undesirable biological action or the interaction harmful with any other composition generation in the pharmaceutical composition, think that any conventional mounting medium is in the scope of this area.Some examples that can be used as the material of pharmaceutically acceptable carrier include, but not limited to carbohydrate, as lactose, dextrose plus saccharose; Starch is as W-Gum and yam starch; Mierocrystalline cellulose and derivative thereof are as sodium carboxy methyl cellulose, ethyl cellulose and rhodia; The tragakanta of powdered; Fructus Hordei Germinatus; Gelatin; Talcum; Vehicle is as theobroma oil and suppository wax; Oil is as peanut oil, Oleum Gossypii semen; Thistle oil; Sesame oil; Sweet oil; Semen Maydis oil and soya-bean oil; Ethylene glycol; Propylene glycol; Ester is as ethyl oleate and Laurate ethyl; Agar; Buffer reagent is as magnesium hydroxide and aluminium hydroxide; Lalgine; Pyrogen-free water; Isotonic saline solution; Ringer's solution; Ethanol and phosphate buffered saline buffer, and the present invention also can use other nontoxic compatible lubricant, as Sodium Lauryl Sulphate BP/USP and Magnesium Stearate, and tinting material, releasing agent, Drug coating, sweeting agent, seasonings and flavouring agent, sanitas and antioxidant.

Preparation

The present invention also comprises a based composition, and it comprises active compound of the present invention and one or more pharmaceutically acceptable carriers and/or thinner and/or adjuvant (this paper is generically and collectively referred to as " carrier " material), and other activeconstituents optionally.Active compound of the present invention can pass through any suitable administration, preferably with the form of the pharmaceutical composition that is fit to these approach, and with for the effective dosed administration of required treatment.Compound of the present invention and composition can for example pass through the following manner administration, oral, mucous membrane, part, rectum, lung (as by sucking spraying) or parenteral, comprise in the blood vessel, in intravenously, intraperitoneal, subcutaneous, intramuscular, the breastbone and infusion techniques, to contain the dosage unit forms of conventional pharmaceutical acceptable carrier, adjuvant and vehicle.

The compound of pharmaceutical active of the present invention can be processed to prepare to the pharmaceutical agent of patient's (comprising people and other Mammals) administration according to the conventional dose method.

For oral administration, described pharmaceutical composition can be with following form, for example, and tablet, capsule, suspensoid or liquid.Described pharmaceutical composition preferred preparation becomes to contain the dosage unit form of specified quantitative activeconstituents.

The example of these dose units is tablet or capsule.For example, the amount of the activeconstituents that these dose units can contain is about 1-2000mg, and is preferred about 1 to 500mg, is more typically about 5 to 200mg.Can change according to patient's situation and other factors for people or the suitable per daily dose of other Mammals, but can use ordinary method to determine again.

The amount of the compound of administration and use the dosage of compound of the present invention and/or composition therapeuticing disease to depend on multiple factor comprises curee's age, body weight, sex and medical condition, the type of disease, severity, route of administration and the frequency of disease and used particular compound.Therefore, dosage can change in wide range, but can use standard method to determine routinely.Common per daily dose scope is 0.01 to 500mg compound/kg body weight, preferred 0.1 to 125mg/kg body weight, and be 1 to 25mg/kg body weight sometimes.As mentioned above, per daily dose can single administration maybe can be divided into 2,3,4 or more times administration.

For therapeutic purpose, active compound of the present invention usually with one or more adjuvants, vehicle or the carrier combinations of described suitable route of administration.If oral administration, described compound can mix with following substances: the sodium salt of the cellulose ester of lactose, sucrose, starch powder, paraffinic acid, Mierocrystalline cellulose alkyl ester, talcum, stearic acid, Magnesium Stearate, magnesium oxide, phosphoric acid and sulfuric acid and calcium salt, gelatin, kordofan gum, sodium alginate, polyvinylpyrrolidone and/or polyvinyl alcohol, make the tablet or the capsule that are fit to make things convenient for administration then.When active compound was dispersed in the hypromellose, these capsules or tablet can contain controlled release preparation.

For skin conditions, can preferably use the topical formulations of The compounds of this invention to use 2-4 time every day in affected zone.

The preparation that is fit to topical comprises and being fit to by dermal osmosis liquid or semi-liquid preparations (as liniment, lotion, ointment, ointment or paste) and suitable drops for eye, ear or nasal administration.The dosage of the suitable topical of the activeconstituents of The compounds of this invention is 0.1mg to 150mg, and every day, administration was 1-4 time, preferred 1 or 2 time.For topical, activeconstituents can account for preparation 0.001% to 10%w/w, as 1% to 2% weight, though can account for the 10%w/w of preparation, preferably be no more than 5%w/w, and more preferably 0.1% to 1%.

When being mixed with ointment, activeconstituents can use with paraffin or with ointment base that water soluble mixes.Perhaps, activeconstituents can be mixed with ointment with the oil-in-water emulsifiable paste matrix.Optionally, the water of emulsifiable paste matrix for example can comprise the polyvalent alcohol of 30%w/w at least, as propylene glycol, fourth-1,3-glycol, N.F,USP MANNITOL, sorbyl alcohol, glycerine, polyoxyethylene glycol and composition thereof.Topical formulations can wish to comprise that improving activeconstituents is attacked the compound that the zone absorbs or permeates by skin or other.The example of these skin penetration enhancers comprises methyl-sulphoxide and related analogs.

Compound of the present invention also can pass through the transcutaneous device administration.Preferred percutaneous dosing will use the paster of storer and porous-film type or the paster of solid substrate type to realize.In both of these case, delivery of active agents-this active agent enters the permeable tackiness agent of active agent by film continuously from storer or micro-capsule, and this tackiness agent contacts with recipient's skin or mucous membrane.If active agent is by skin absorption, then with the active agent of controlled and predetermined amount of flow to recipient's administration.In the situation of micro-capsule, the function that encapsulated medicine also can skinning.

The oil phase of emulsion of the present invention can constitute in a known manner from principal component.

And this can only contain emulsifying agent mutually, and this can contain the mixture of at least a emulsifying agent and fat or oil or the mixture of at least a emulsifying agent and fat and oil mutually.Preferred hydrophilic emulsifier can be included in the emulsifying agent with the lipophilic emulsifier as stablizer.Preferably not only comprise oil but also comprise fat.The emulsifying agent that contains or do not contain stablizer is formed so-called emulsifying wax, and this wax is formed so-called emulsification ointment base with oil and fat, the oily disperse phase of this matrix formation cream formulation.The emulsifying agent and the emulsion stabilizer that are used for preparation of the present invention comprise polysorbate60, sorbester p17,18/hexadecanol, tetradecyl alcohol, glyceryl monostearate, Sodium Lauryl Sulphate BP/USP, distearin, and these materials use separately or use with wax or other material well known in the art.

Selection for the suitable oil of preparation or fat can be based on realizing required decoration character, because activeconstituents be low-down in most of solubleness that may be used in the oil of pharmaceutical emulsion.Therefore, described emulsion should preferably be product non-grease, non-staining and rinsable, its have suitable denseness with avoid from the pipe or other container spill.Can use straight or branched ,-or dialkyl, as the mixture of dissident's two acid diesters, stearic acid isocetyl fat, propylene glycol two coconut oil fat acid esters, Isopropyl myristate, decyl oleate, Wickenol 111, butyl stearate, palmitinic acid 2-(ethyl hexyl) ester or branched ester.According to required character, these materials can be used singly or in combination.

Perhaps, can use the high-melting-point lipid, as paraffinum molle alba and/or whiteruss or other mineral oil.

Be fit to also comprise eye drops to the preparation of eye topical, wherein activeconstituents dissolves or is suspended in the suitable carrier, especially in the water-containing solvent of activeconstituents.

The concentration of the activeconstituents that exists in these preparations is preferably 0.5 to 20%, advantageously is 0.5 to 10%, and is in particular about 1.5%w/w.

The preparation that is used for parenteral admin can be the form of moisture or water-free isotonic sterile injection solution or suspension.These solution and suspension can use one or more used the preparation of preparation oral administration carriers or thinner preparation from sterilized powder or particle, or by using the preparation of other stable dispersion agent or wetting agent and suspending agent.This compound can be dissolved in the following substances: water, polyoxyethylene glycol, propylene glycol, ethanol, Semen Maydis oil, Oleum Gossypii semen, peanut oil, sesame oil, phenylcarbinol, sodium-chlor, tragacanth gum and/or various damping fluid.

Other adjuvant and medication are that pharmaceutical field is well-known.Activeconstituents can pass through the injectable composition administration, and described composition has suitable carrier, comprises salt solution, glucose or water, or has cyclodextrin (being Captisol), cosolvent solubilizing agent (being propylene glycol) or micella solubilizing agent (being tween 80).

Sterile injectable preparation also can be sterile injectable solution or the suspensoid in nontoxic parenteral acceptable diluent or solvent, for example solution in 1,3 butylene glycol.In acceptable vehicle and solvent, can make water, Ringer's solution and isotonic sodium chlorrde solution.And aseptic expressed oil is easily used as solvent or suspension medium.Any mixed expressed oil be can use for this purpose, synthetic direactive glyceride or two glyceryl ester comprised.And, found lipid acid, as the use of oleic acid in injectable formulation.

For the lung administration, pharmaceutical composition can comprise the inhalation form administration of dried powder aerosol with aerosol or inhalation.

The suppository that is used for rectal administration can be by preparing medicine and the non-stimulated mixed with excipients that is fit to, described vehicle such as theobroma oil and polyoxyethylene glycol, described vehicle is solid at normal temperatures but is liquid under rectal temperature, and therefore will fuse and discharge medicine in rectum.

Can carry out conventional pharmaceutical operation to pharmaceutical composition, as sterilizing and/or can containing conventional adjuvant, as sanitas, stablizer, wetting agent, emulsifying agent, buffer reagent etc.Can further prepare tablet and pill with casing.These compositions also can comprise adjuvant, as wetting agent, sweeting agent, correctives and perfume compound.

Pharmaceutical composition of the present invention comprises compound or its pharmacologically acceptable salts of structural formula as herein described; Other medicines, it is selected from kinase inhibitor (small molecules, polypeptide, antibody etc.), immunosuppressor, carcinostatic agent, antiviral agent, anti-inflammatory agent, anti-mycotic agent, microbiotic or anti-angiogenic hyper-proliferative compound; With any pharmaceutically acceptable carrier, adjuvant or vehicle.

Other composition of the present invention comprises compound or its pharmacologically acceptable salts of structural formula described herein; With pharmaceutically acceptable carrier, adjuvant or vehicle.These compositions can choose wantonly comprise one or more other the treatment reagent, for example comprise kinase inhibitor (small molecules, polypeptide, antibody etc.), immunosuppressor, carcinostatic agent, antiviral agent, anti-inflammatory agent, anti-mycotic agent, microbiotic or anti-angiogenic hyper-proliferative compound.

Term " pharmaceutically acceptable carrier or adjuvant " refers to can be with carrier or the adjuvant of compound of the present invention to patient's administration, and it does not destroy the pharmacological activity of The compounds of this invention, and is nontoxic when with the amount administration of the compound that is enough to the delivery treatments amount.

The pharmaceutically acceptable carrier that can be used for pharmaceutical composition of the present invention, adjuvant and vehicle comprise, but be not limited to ion-exchanger, aluminum oxide, aluminum stearate, Yelkin TTS, self-emulsifying drug delivery system (SEDDS) is as d-atocopherol cetomacrogol 1000 succinate, used tensio-active agent such as tween or other similar polymerization thing delivery matrices in the pharmaceutical dosage form, serum protein such as human serum albumin, buffer substance such as phosphoric acid salt, glycine, Sorbic Acid, potassium sorbate, the partial glyceride mixture of saturated vegetable fatty acid, water, salt or ionogen such as Protamine sulfates (protamine sulfate), Sodium phosphate dibasic, potassium hydrogen phosphate, sodium-chlor, zinc salt, colloid silica, Magnesium Trisilicate, polyvinylpyrrolidone, the material of cellulose base, polyoxyethylene glycol, sodium carboxy methyl cellulose, polyacrylic ester, wax, polyethylene-polyoxypropylene-block polymer, polyoxyethylene glycol and lanolin.Cyclodextrin as u-, P-and y-cyclodextrin, or the derivative of chemical modification such as hydroxyalkyl cyclodextrin, comprises 2 and 3-hydroxypropyl-cyclodextrin, or other soluble derivative also can be advantageously used in sending of the compound that improves structural formula described herein.

Pharmaceutical composition can be with following any oral acceptable forms oral administration, and described formulation includes, but not limited to capsule, tablet, emulsion and aqueous suspensions, dispersion agent and solution.In the situation that is used for oral tablet, normally used carrier comprises lactose and W-Gum.Generally also add lubricant, as Magnesium Stearate.For the oral administration of capsule form, useful thinner comprises lactose and anhydrous W-Gum.When oral administration aqueous suspensions and/or emulsion, can or be dissolved in the oil phase that mixes with emulsifying agent and/or suspending agent the activeconstituents suspendible.

Optionally, can add some sweeting agent, correctives and/or tinting material.

Pharmaceutical composition can comprise the preparation that utilizes liposome or microcapsulary, and its multiple example is known in the art.

Pharmaceutical composition can pass through nose aerosol or inhalation administration.These compositions prepare according to the field of pharmaceutical preparations technique known, and can use following substances to be prepared into solution in salt solution: phenylcarbinol or other sanitas that is fit to, strengthen absorption enhancer, hydrofluoric ether and/or other solubilizing agent or the dispersion agent of bioavailability, the example is well known in the art.

Medicinal composition

Though compound of the present invention can be with independent active medicine administration, they also can with one or more other compound of the present invention or one or more other medicines combination medicine-feedings.When with the medicinal composition administration, medicine can be formulated as independent composition, administration simultaneously, or in different time sequence administrations, or can be used as single composition and give medicine.

Term " combination treatment " refers to that compound of the present invention uses with other medicines, namely in all cases in the dosage regimen of the beneficial effect that drug regimen will be provided, with simultaneously every kind of medicine of mode administration simultaneously basically, and every kind of medicine of administration in a sequential manner.Administration simultaneously comprises especially simultaneously and giving, and as with single tablet, capsule, injection or have other formulation modes of these promoting agent fixed proportions, and sends simultaneously with a plurality of formulations that are respectively independent for every kind of medicine.

Therefore, administration compound of the present invention can with the other therapies combination of prevention well known by persons skilled in the art and treatment cancer, as radiotherapy or cytostatic agent, cytotoxic agent, other carcinostatic agent with improve cancer or the other medicines of the symptom of any drug side effect.

If be formulated as fixing dosage, these combination product have been used the compound of the present invention in acceptable dosage range.When combination preparation is not suitable for, compound of the present invention also can with the administration of other carcinostatic agent or cytotoxic agent order.The invention is not restricted to the order administration; Compound of the present invention can be before other carcinostatic agent of administration or cytotoxic agent, simultaneously or administration afterwards.

Now, comprise surgical resection for the standard care of primary tumo(u)r, optionally, radiotherapy or chemotherapy then, and general vein (IV) administration.Usually chemotherapy regimen comprises DNA alkylating agent, DNA intercalator, CDK inhibitor or microtubule toxic agent.Used chemotherapy dosage just is lower than maximum tolerated dose, and therefore dose limitation toxicity generally includes nausea,vomiting,diarrhea, alopecia, neutrophilic granulocytopenia etc.

Have many antineoplastic agents can be used for commercial using, at clinical evaluation with in preclinical study, select these antineoplastic agents to be used for the treatment of cancer by the medicinal composition chemotherapy.And these antineoplastic agents that some main kinds are arranged, i.e. Tri-Biocin, alkylating agent, antimetabolite, amcinonide, immune substance, interferons medicine and mixed type medicine.

Be used for comprising antimetabolite-type/thymidylic acid synthetic inhibitor antineoplastic agent with the antineoplastic agent of the first kind of compound combination of the present invention.The antimetabolic antineoplastic agent that is fit to can be selected from, but is not limited to the 5-FU-Fibrinogen, acanthifolic acid, amino thiadiazoles, brequinar sodium, carmofur, CibaGeigyCGP-30694, the cyclopentyl cytosine(Cyt), cytosine arabinoside phosphoric acid stearate, the cytosine arabinoside binding substances, gift comes DATHF, Merrel Dow DDFC, dezaguanine, dideoxycytidine, dideoxyguanosine, didox, Yoshitomi DMDC, doxifluridine, Wei Kang (Wellcome) EHNA, Merck EX-015, fazarabine, the Ro 2-9757 deoxynucleoside, fludarabine phosphate, 5 FU 5 fluorouracil, N-(21-furan alkyls) Fluracil, the first pharmacy FO-152, the sec.-propyl tetramethyleneimine, gift comes LY-188011, gift comes LY-264618, methobenzaprim, methotrexate, prestige health MZPES, go the first essence to narrow, NCINSC-127716, NCI NSC-264880, NCI NSC-39661, NCI NSC-612567, Warner-blue Bert PALA, spray Ta Siding, piritrexim, Plicamycin, the PL-AC of Asahi Chemical Industry, military field TAC788, Tioguanine, tiazofurine, Erbamont TIF, trimetrexate, tyrosine kinase inhibitor, roc UFT and uricytin.

Be used for comprising alkylating agent class antineoplastic agent with the antineoplastic agent of second class of compound combination of the present invention.The alkylating agent class antineoplastic agent that is fit to can be selected from but be not limited to the wild justice of salt (Shionogi) 254-S, the aldophosphamide analogue, hexamethyl melamine, Anaxirone, the BBR-2207 of Bao Ling Man (Boehringer Mannheim), hundred lappet west, budotitane, gush CA-102 forever, carboplatin, carmustine, Chinoin-139, Chinoin-153, Chlorambucil, cis-platinum, endoxan, the CL-286558 of cyanamide company (American Cyanamid), Sanofi CY-233, cyplatate, Degussa D 384, SumimotoDACHP (Myr) 2, the phenylbenzene spiromustine, two platinum growth inhibitors, the Erba distamycin derivatives, Chugai DWA-2114R, ITI E09, elmustine, Erbamont FCE-24517, estramustine phosphate sodium, fotemustine, Unimed G M, Chinoin GYKI-17230, hepsulfam, ifosfamide, iproplatin, lomustine, Mafosfamide, mitolactol Japan chemical drug NK-121, NCINSC-264395, NCI NSC-342215, oxaliplatin, Upjohn PCNU, prednimustine, Proter PTT-119, ranomustine, semustine, SmithKline SK﹠amp; F-101772, Yakult HonshaSN-22, spiromustine, limit, field pharmacy TA-077, tauromustine, Temozolomide, teroxirone, four platinum and the close alcohol of front three.

Be used for comprising the antibiotics antineoplastic agent with the antineoplastic agent of the 3rd class of compound combination of the present invention.The antibiotics antineoplastic agent that is fit to can be selected from but be not limited to roc 4181-A, aclarubicin, dactinomycin, actinoplanone, Erbamont ADR-456, the aeroplysinin derivative, aginomoto AN II, aginomoto AN3, Japan Cao Da Anisomycin, anthracycline antibiotics, Azinomycin B-A, bisucaberin, Shi Guibao (Bristol-Myers) BL-6859, execute expensive precious BMY-25067, execute expensive precious BNY-25551, execute expensive precious BNY-26605I and execute expensive precious BNY-27557, execute expensive precious BMY-28438, bleomycin sulfate, bryostatin-1, roc C-1027, the Gary mycin of stopping, chromoximycin, dactinomycin, daunorubicin, consonance fermentation DC-102, consonance fermentation DC-79, consonance fermentation DC-88A, Kyowa Hakko, DC89-Al, consonance fermentation DC92-B, anthracycline B, the wild adopted DOB-41 of salt, Dx, Dx-Fibrinogen, elsamicin-A, epirubicin, erbstatin, esorubicin, Ai Sipeila mycin-Al, Ai Sipeila mycin-Alb, ErbamontFCE21954, rattan pool medicine FK-973, Phosphotrienin, rattan pool medicine FR-900482, slide rhzomorph, gregatin-A, grincamycin, herbimycin, idarubicin, agaricol, kazusamycin, kesarirhodins, consonance fermentation KM-5539, Kirin Brewery KRN-8602, consonance fermentation KT-5432, consonance fermentation KT-5594, consonance fermentation KT-6149, the LL-D49194 of cyanamide company, Meiji Seika Kaisba (Meiji seika) ME 2303, menogaril, mitomycin, mitoxantrone, SmithKline M-TAG, neoenactin, Japan chemical drug NK-313, Japan chemical drug NKT-01, SRI InternationalNSC-357704 oxalysine, oxaunomycin, peplomycin, pilatin, pirarubicin, porothramycin, pyrindanycin A, Tobishi RA-I, rapamycin, rhizomycin, rodorubicin, sibanomicin, siwenmycin, Sumitomo SM5887, Snow Brand SN-706, SnowBrand SN-07, sorangicin-A, sparsomycin, SS Pharmaceutical SS-21020, SSPharmaceutical SS-7313B, SS Pharmaceutical SS-9816B, steffimycin B, roc 4181-2, talisomycin, military field TAN-868A, terpentecin, thrazine, tricrozarin A, Upjohn U-73975, consonance fermentation UCN-10028A, rattan pool medicine WF-3405, Yoshitomi Y-25024 and zorubicin.

Be used for comprising the mixed type anti-tumor agent comprising salmosin with the antineoplastic agent of the 4th class of compound combination of the present invention, comprise the microtubule agent interfering, the topoisomerase II inhibitor, topoisomerase I inhibitor and amcinonide, it is selected from but is not limited to (xcarotene, (X-difluoromethyl-arginine, Acitretin, BiotecAD-5, Kyorin AHC-52, alstonine, amonafide, amphethinile, amsacrine, Angiostat, ankinomycin, anti-vegetation A10, anti-vegetation A2, anti-vegetation A3, anti-vegetation A5, anti-vegetation AS2-1F Henkel APD, the glycine aphidicolin, asparaginase, A Fuluo alcohol, baccharin, batracylin, the human relations of benzene fluorine, benzotript, Ipsen-Beaufour BIM-23015, bisantrene, BristoMyers BNY-40481, Vestar boron-10, bromo fosfamide, prestige health BW-502, prestige health BW-773, caracemide, hydrochloric acid carmethizole, aginomoto CDAF, chlorsulfaquinoxalone, Chemes CHX-2053, Chemex CHX-100, Warner-blue Bert CI-921, WarnerLambert CI-937, Warner-blue Bert CI-941, Warner-blue Bert CI958, clanfenur, claviridenone, ICN compound 1259, ICN compound 4711, Contracan, YakultHonsha CPT-11, crisnatol, curaderm, cytochalasin B, cytosine arabinoside, cytocytin, Merz D-609, toxilic acid DABIS, Dacarbazine, datelliptinium, from generation to generation rather-B, DHE, dihydrolenperone, Goe 1734, distamycin, Toyo Pharmar DM-341, ToyoPharmar DM-75, the first pharmacy DN-9693, Docetaxel elliprabin, the acetic acid elliptinium acetate, Tsumura EPMTC, ebormycine, Ergotamine, Etoposide, etretinate, fenretinide, rattan pool medicine FR-57704t gallium nitrate, genkwadaphnin, Chugai GLA-43, Glaxo GR-63178, grifolan NMF5N, Hexadecylphosphocholine, Green Cross HO-221, homoharringtonine, hydroxyurea, BTG ICRF-187, Thio ALP, isoglutamine, isotretinoin, Otsuka JI-36, Ramot K-477, Otsuak K-76COONa, Kureha Chemical K-AM, MECT CorpKI-8110, the L-623 of cyanamide company, leucoregulin, lonidamine, Lundbeck LU 1121 gifts come LY-186641, NCI (US) MAP, marycin, Merrel Dow MDL-27048, MedcoMEDR-340, merbarone, the merocyanlne derivative, the toluidine acridine, MolecularGenetics MGI136, tender tea leaves naphthalene tincture, Mitonafide, the mitoquidone mopidamol, motretinide, ZenyakuKogyo MST-16, N-(class tretinoin) amino acid, Nisshin Flour Milling N-021, N-acetylize-alanine dehydrogenase, nafazatrom, Taisho NCU-190, the R 17934 derivative, Normosang, NCI NSC-145813, NCI NSC-361456, NCI NSC-604782, NCI NSC-95580, octapeptide Sostatin (ocreotide), Ono ONO-112, oquizanocine, Akzo Org-10172, taxol, water ghost any of several broadleaf plants alkali, Pazelliptine, Warner-blue Bert (Warner-Lambert) PD-111707, Warner-blue Bert PD-115934, Warner-blue Bert PD-131141, Pierre Fabre PE-1001, ICRT peptide D, piroxantrone, polyhaematoporphyrin, polypreic acid, the Efamol porphyrin, third pair of beautiful jade, Procarbazine, proglumide, Invitron PN I, Tobishi RA-700, razoxane, Sapporo Breweries RBS, restraining albumen-P, retelliptine, tretinoin, Rhone-PoulencRP-49532, Rhone-Poulenc RP-56976, SmithKline SK﹠amp; F-104864, Sumitomo SM-108, Kuraray SMANCS, SeaPharm SP10094, brown tongue algae alcohol, the spirocyclopropane derivative, Spirogermanium, Unimed, SS Pharmaceutical SS-554, strypoldinone, Stypoldione, three SUN 0237 that get profit, three SUN 2071 that get profit, superoxide-dismutase, Toyama T-506, ToyamaT-680, taxol, Teijin TEI-0303, moor former times for the Buddhist nun, thaliblastine, Eastman KodakTJB-29, tocotrienol, Hycamtin, Topostin, Teijin TT82, consonance fermentation UCN-01, consonance fermentation UCN-1028, ukrain, Eastman Kodak USB-006, Vinblastine sulphate, vincristine(VCR), vindesine, vinestramide, vinorelbine, vintriptol, vinzolidine, liquor-saturated eggplant lactone and Yamanouchi YM.On the other hand, compound of the present invention also can be used for and other antineoplastic agent combination therapy, and described antineoplastic agent is Acemannan for example, aclarubicin, rIL-2, alemtuzumab, alitretinoin, hexamethyl melamine, amifostine, amino-laevulic acid, amrubicin, amsacrine, anagrelide, Anastrozole, ANCER, ancestim, ARGLABIN, white arsenic, BAM 002 (Novelos), bexarotene, bicalutamide, broxuridine, capecitabine, celmoleukin, cetrorelix, carat Qu Bin, clotrimazole, cytosine arabinoside ocfosfate, DA 3030 (Dong-A), daclizumab, denileukin diftitox, deslorelin, dexrazoxane, Cormelian, Docetaxel, V-1326, the degree ostelin, doxifluridine, Dx, bromocriptine, carmustine, cytosine arabinoside, Fluracil, the HIT diclofenac, interferon alpha, daunorubicin, Dx, vitamin A acid, Ro 14-5243, the Edrecolomab eflornithine, emitefur, epirubicin, erythropoietin β, the phosphoric acid Etoposide, Exemestane, exisulind, fadrozole, filgrastim, finasteride, fludarabine phosphate, formestane, fotemustine, gallium nitrate, gemcitabine, Gemtuzumab Ozogamicin, gimeracil/oteracil/Tegafur combination, glycopine, goserelin, heptan platinum, human chorionic gonadotrophin, the human fetal alpha fetoprotein, Ibandronic acid, idarubicin, (Imiquimod, interferon alpha, interferon alpha, natural interferon alpha-2, Intederon Alpha-2a, Interferon Alpha-2b, interferon alpha-NI, Alferon N, Alfacon-1, interferon alpha, natural interferon β, interferon beta-1a, interferon beta-1b, interferon-gamma, natural interferon γ-1a, gamma interferon 1-b, interleukin--I β, m-iodobenzylguanidine, irinotecan, irsogladine, Lanreotide, LC 9018 (Yakult), leflunomide, lenograstim, the sulfuric acid lentinan, letrozole, the white corpuscle interferon-alpha, Leuprolide, LEVAMISOLE HCL+Fluracil, liarozole, Lip river platinum, lonidamine, lovastatin, masoprocol, melarsoprol, metoclopramide, mifepristone, miltefosine, mirimostim, mismatching double stranded, mitoguazone, mitolactol, mitoxantrone, Sch-39300, nafarelin, naloxone+pentazocine, Neu-up 100, S 254, Nilutamide, Noscapine, novel erythropoiesis stimulating protein, NSC 631570 Sostatins, oprelvekin, osaterone, oxaliplatin, taxol, Pamidronic Acid, pegaspargase, the polyoxyethylene glycol Interferon Alpha-2b, Pentosan Polysulfate Sodium, spray Ta Siding, molten chain bacterium, pirarubicin, rabbit anti-thymocyte polyclonal antibody, the polyoxyethylene glycol Intederon Alpha-2a, porfimer sodium, raloxifene, Raltitrexed, rasburicase, ethylenediamine tetraacetic acid (EDTA) rhenium Re 186, the RII viaminate, Rituximab, romurtide, samariumlexidronam (153Sm), Sargramostim, sizofiran, sobuzoxane, sonermin, Metastron, Suramine, tasonermin, Tazarotene, Tegafur, temoporfin, Temozolomide, moor former times for the Buddhist nun, ten oxidation tetrachloros, Thalidomide, Thymosin-Alpha1, thyrotropin alfa, Hycamtin, toremifene, tositumomab-iodine 131, trastuzumab, Treosulfan, vitamin A acid, Win-24540, trimetrexate, triptorelin, tumor necrosis factor alpha, natural bestatin, the bladder cancer vaccine, Maruyama. vaccine, melanoma lysate vaccine, valrubicin, Visudyne, vinorelbine, VIRULIZIN, Zinostatin stimalamer or Zoledronic acid; Abarelix; AE 941 (Aeterna), ambamustine, antisense oligonucleotide, bcl-2 (Genta), APC 8015 (Dendreon), Cetuximab, Decitabine, glutethimide deaminizes, diaziquone, EL 532 (Elan), EM 800 (Endorecherche), eniluracil, etanidazole, fenretinide I filgrastim SDO1 (Amgen), fulvestrant, Galocitabine, gastrin 17 immunogens, HLA-B7 gene therapy (Vical), rHuGM-CSF, Peremin, ibritumomab tiuxetan, Ilomastat, IM 862 (Cytran), interleukin-iproxifene, LDI 200 (Milkhaus), leridistim, lintuzumab, CA 125MAb (Biomira), cancer MAb (JapanPharmaceutical Development), HER-2 and Fc MAb (Medarex), genes of individuals 105AD7MAb (CRC Technology), genes of individuals CEA MAb (Trilex), LYM iodine 131 MAb (Techniclone), polymorphic epithelium Saliva Orthana-yttrium 90MAb (Antisoma), Marimastat, menogaril, mitumomab, motexafin, gadolinium, MX 6 (Galderma), Nelzarabine, Nolatrexed, P 30 albumen, pegvisomant, pemetrexed, porfiromycin, the prinomastat, RL 0903 (Shire), rubitecan, husky platinum, sodium, sparfosic acid, SRL 172 (SR Pharma), SU 5416 (SUGEN) y SU 6668 (SUGEN), TA 077 (Tanabe), tetrathiomolybdate, thaliblastine, thrombopoietin, the tin ethyl is C.I. Natural Red 8 just, Win-59075, cancer vaccine (Biomira), Melacine (New York University), Melacine (Sloan Kettering Institute), melanoma oncolysate vaccine (New York Medical College), virus melanoma cells lysate vaccine (Royal Newcastle Hospital) or valspodar.

The treatment test kit

In other embodiments, the present invention relates to convenient and effective test kit of implementing the inventive method.Usually, cartridge bag or test kit comprise one or more containers that one or more compositions of pharmaceutical composition of the present invention are housed.These test kits are particularly suitable for the delivery of solids oral dosage form, for example tablet or capsule.Such test kit preferably includes many unitary doses, and also can comprise the card with dosage of demarcating for the purposes of hope.Optionally can provide memory auxiliary, for example with numeral, letter or other mark, or the calendar inset, show the date for the treatment of plan, wherein said dosage is dosage.Randomly, the container of combination should be with the mode note of government bodies' regulation, and to regulate production, purposes or the sale of medicament production, the manufacturer of described note reaction approval is to purposes or the sale of people's administration.

Following representative embodiment comprises that being fit to the present invention implements important out of Memory, example and guidance with its multiple embodiments and equivalent.These embodiment are in order to help to illustrate the present invention, rather than in order to limit the present invention in this scope.In fact, after finishing watching presents (comprising science reference and patent document that following embodiment and this paper quote), except shown in this paper and described, multiple improvement of the present invention and its many other embodiments it will be apparent to those skilled in the art that.These contents of quoting are incorporated herein by reference to help to illustrate the situation of this area.And, to achieve the object of the present invention, described in this manual chemical element and the periodic table of elements (Periodic Table ofthe Elements), the CAS version, chemistry and physics handbook (Handbook of Chemistry and Physics, the 75th edition, interior table (inside cover)) identical.And, vitochemical general rule and particular functional group's part and active as " Organic Chemistry ", Thomas Sorrell, University ScienceBooks, Sausalito:1999 and " Organic Chemistry ", Morrison ﹠amp; Described in the Boyd (3d Ed), the two all is incorporated herein by reference.

Embodiment

Some compounds among the following embodiment are converted into hydrochloride.The general method that generates hydrochloride is as described below:

Adding just that the enough saturated methyl alcohol of HCl (g) makes the final product dissolving in the final product, be cooled to 0 ℃ and kept 0.5-1 hour, filter, is Et with ice-cooled methyl alcohol then ₂O washs solid, and the gained solid is dry in vacuum drier, in most cases obtains tri hydrochloride.

Embodiment 1

3-(1H-pyrazoles-1-methane amide-N-methyl)-4-methyl-N-(4-((4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) phenyl) benzamide

1-(brooethyl)-4-nitro-2-(trifluoromethyl) benzene: under nitrogen, with 2-methyl-5-nitro benzenyl fluoride thing (3.90g, 19mmol), N-bromosuccinimide (NBS, 3.56g, 20mmol), 2,2 '-azo two (2-methyl propionitrile) (AIBN, 94mg, CCl 0.6mmol) ₄(40mL) suspension returning is 16 hours.HPLC shows that about 50% transforms.Add NBS (10mmol) and AIBN (0.6mmol) again, this mixture was refluxed 14 hours again.HPLC shows that about 80% transforms.With reaction mixture cooling, the elimination solid also washs with ethyl acetate.The filtrate that merges is used NaHCO ₃Solution washing, Na ₂SO ₄Drying is filtered, and concentrates vacuum-drying at rotatory evaporator (rotovap).1H NMR shows that the ratio of required product and unreacted 2-methyl-5-nitro benzenyl fluoride thing is 75: 25.This material does not carry out purifying and is directly used in next step.

1-methyl-4-(4-nitro-2-(trifluoromethyl) benzyl) piperazine: in DCM (10mL) solution of thick 1-(brooethyl)-4-nitro-2-(trifluoromethyl) benzene (13.33mmol, 75% is pure), add Et ₃N (1.4mL, 10mmol) and the 1-methylpiperazine (1.1mL, 10mmol).After at room temperature stirring 3 hours, add NaHCO ₃The aqueous solution, this mixture extracts with DCM.The organic layer Na that merges ₂SO ₄Drying is filtered, and concentrates, and the gained residue obtains the 2.21g product through silica gel column chromatography purifying (with 10% methyl alcohol/DCM wash-out), is faint yellow oily.

4-((4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) aniline: with 1-methyl-4-(4-nitro-2-(trifluoromethyl) benzyl) piperazine (1.23g, 4mmol) and sodium bisulfite (7.0g, purity 85%, available from Aldrich, 40mmol) (1: 1,20mL) suspension returning in was 3 hours at acetone and water.During cooling, remove volatile component (mainly being acetone) at rotatory evaporator, and filter the gained mixture.Solid washs fully with ethyl acetate.The filtrate that merges extracts with n-BuOH (4x).The saturated NaHCO of organic layer that merges ₃Solution washing, Na ₂SO ₄Drying is filtered, and concentrates, and the gained residue obtains the 0.71g product through silica gel column chromatography purifying (with 5% methyl alcohol/DCM wash-out, methyl alcohol uses the ammonia saturated in advance), is faint yellow solid.

3-iodo-4-methyl-N-(4-((4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) phenyl) benzamide: (0.48g is 1.7mmol) (by 3-iodo-4-tolyl acid and SOCl with 3-iodo-4-methyl benzoyl chloride ₂Reaction makes (as previously mentioned)) join 4-((4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) aniline (0.47g, 1.7mmol), N, (0.26g is 2.0mmol) and in the solution of DMAP in THF (10mL) of catalytic amount for the N-diisopropyl ethyl amine.After at room temperature stirring 2 hours, water cancellation reaction.Add ethyl acetate and layering.The organic layer that merges is concentrated into dried, and silica gel column chromatography purifying (with 5% methyl alcohol/DCM wash-out, methyl alcohol uses the ammonia saturated in advance) obtains the 0.51g product, and solid is creamy white.

4-methyl-N-[4-(4-methyl-piperazine-1-ylmethyl)-3-trifluoromethyl-phenyl]-3-TMS ethynyl-benzamide: with 3-iodo-4-methyl-N-[4-(4-methyl-piperazine-1-ylmethyl)-3-trifluoromethyl-phenyl]-benzamide (2.59g, 5mmol), Pd[(PPh ₃)] ₄(289mg, 0.25mmol), (71mg 0.375mmol) places the schlenk flask to CuI.This flask is carried out 3 vacuum-be full of again circulation of nitrogen.Add anhydrous N in this mixture, the N-diisopropyl ethyl amine (1.1mL, 6mmol), DMF (5mL) and trimethyl silane ethyl-acetylene (0.92mL, 6.5mmol).At room temperature stirred this solution 24 hours.In reaction mixture, add water and ethyl acetate, extract.The organic layer Na that merges ₂SO ₄Drying is filtered, concentrate at rotatory evaporator then, residue through the silicagel column purifying (with the CH of 5% methyl alcohol ₂Cl ₂Eluant solution, methyl alcohol is saturated in advance with ammonia), obtain required product, be faint yellow solid, productive rate 82% (2.0g).

3-ethynyl-4-methyl-N-[4-(4-methyl-piperazine-1-ylmethyl)-3-trifluoromethyl-phenyl]-benzamide: to 4-methyl-N-[4-(4-methyl-piperazine-1-ylmethyl)-3-trifluoromethyl-phenyl]-3-TMS ethynyl-benzamide (2.0g, the solution of TBAF in THF (1.0M) of adding 5mL in THF 4.1mmol) (15mL) solution.Stir after 1 hour under the room temperature, mixture is at H ₂Distribute between O and the ethyl acetate.The organic layer Na that merges ₂SO ₄Drying is filtered, concentrate at rotatory evaporator then, residue on silicagel column purifying (with the CH of 10% methyl alcohol ₂Cl ₂Eluant solution, methyl alcohol is saturated in advance with ammonia), obtain required product, be faint yellow solid, productive rate 78% (1.33g).

1H-pyrazoles-1-N-methylformamide: to 4-iodine pyrazoles (3g, dry CH 15.5mmol) ₂Cl ₂(20mL) add in the solution chloroformic acid right-nitrophenyl ester (3.43g, CH 17mmol) ₂Cl ₂(30mL) solution, add then TEA (2.5mL, 18.6mmol).This mixture was at room temperature stirred 2 hours.This mixture is with excessive CH then ₂Cl ₂(60mL) dilute and use 10%NaHCO ₃Solution washing.Organic layer Na ₂SO ₄Drying also boils off solvent, and the gained solid is through Et ₂The O recrystallization obtains white solid (5g).Use MeNH ₂Solution (2mL, the THF solution of 2M) is handled products therefrom (1g, THF 2.79mmol) (12mL) solution 10 minutes.The evaporation organic layer is dissolved in DCM with the gained solid and washs with 5%NaOH.Dry organic layer, filtration and with the ether development obtain colourless glossiness sheet product (0.55g).

3-(1H-pyrazoles-1-methane amide-N-methyl)-4-methyl-N-(4-((4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) phenyl) benzamide: with 3-ethynyl-4-methyl-N-[4-(4-methyl-piperazine-1-ylmethyl)-3-trifluoromethyl-phenyl]-benzamide (91mg, 0.22mmol), 1H-pyrazoles-1-N-methylformamide (0.2mmol), Pd[(PPh ₃)] ₄(11.6mg, 0.01mmol), CuI (2.9mg, 0.015mmol) place be stamped sheet rubber (septa) the bottle.Allow this bottle carry out 3 vacuum/be full of circulation of nitrogen.Add anhydrous N in this mixture, and the N-diisopropyl ethyl amine (0.1mL, 0.6mmol) and DMF (1.0mL).Stirred gained solution 24 hours at 80 ℃.After the reaction mixture cooling, add water with ethyl acetate and extract.The organic layer Na that merges ₂SO ₄Dry, filter, concentrate at rotatory evaporator then, residue through the silicagel column purifying (with the CH of 10% methyl alcohol ₂Cl ₂Eluant solution, methyl alcohol is saturated in advance with ammonia), obtain required product, be faint yellow solid, productive rate 56% (63.0mg): MS (M+H) ⁺538.

Embodiment 2:

1-methyl-5-(2-methyl-5-[4-(4-methyl-piperazine-1-ylmethyl)-3-trifluoromethyl-phenyl amino formyl radical]-the phenylacetylene base)-1H-imidazoles-2-methane amide

5-ethynyl-1-methyl isophthalic acid H-imidazoles-2-methane amide: under-78 ℃, to 1-methyl-5-TMS ethynyl-1H-imidazoles (1.78g, hexane solution (the 2.5M that slowly adds n-BuLi in THF 10mmol) (30mL) solution, 4.4mL), and under uniform temp, stirred gained suspension 1 hour.Under-78 ℃, to wherein slowly add isocyanic acid TMS ester (available from Aldrich, purity 85%, 11.76mmol, 1.6mL).After-78 ℃ of restir 30 minutes, remove cooling bath and allow reaction mixture slowly heat up.Add water (2mL) and methyl alcohol (1mL) cancellation reaction, and stir this mixture overnight.Add water again with ethyl acetate and extract.The organic layer Na that merges ₂SO ₄Dry, filtration, concentrated at rotatory evaporator then, residue is through silicagel column purifying (elutriant: the hexane solution of 40-60% ethyl acetate), obtain required product, the solid that is white in color, productive rate 26% (387mg).

1-methyl-5-(2-methyl-5-[4-(4-methyl-piperazine-1-ylmethyl)-3-trifluoromethyl-phenyl amino formyl radical]-the phenylacetylene base)-1H-imidazoles-2-methane amide: with 5-ethynyl-1-methyl isophthalic acid H-imidazoles-2-methane amide (33mg; 0.22mmol), 3-iodo-4-methyl-N-(4-((4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) phenyl) benzamide (103.4mg, 0.2mmol) (as preparation as described in the embodiment 1), Pd[(PPh ₃) ₄] (11.6mg, 5mol%) and CuI (2.9mg, 7.5mmol%) place sheet rubber the bottle.Allow this mixture carry out 3 vacuum/be full of the circulation of nitrogen, add DMF (1.5ml) and N, and the N-diisopropyl ethyl amine (53 μ L, 0.3mmol).At room temperature stirred this mixture 16 hours, the water cancellation should reaction.Add ethyl acetate and other water and be used for extraction.Organic layer drying (the Na that merges ₂SO ₄), filter, concentrate, the gained residue is through silica gel column chromatography purifying (elutriant: the dichloromethane solution of 5% methyl alcohol, methyl alcohol is saturated in advance with ammonia), obtain being the beige solid title compound (65%, 70mg): MS (M+H) ⁺539.

Embodiment 3:

1-methyl-5-(2-methyl-5-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl amino formyl radical]-the phenylacetylene base)-1H-imidazoles-2-methane amide

Use 5-ethynyl-1-methyl isophthalic acid H-imidazoles-2-methane amide and 3-iodo-4-methyl-N-(3-(4-methyl isophthalic acid H-imidazoles-1-yl)-5-(trifluoromethyl) phenyl) benzamide to make title compound according to embodiment 2: MS (M+H) ⁺507.

3-(4-methyl isophthalic acid H-imidazoles-1-yl)-5-(trifluoromethyl) aniline: with 3-bromo-5-(trifluoromethyl) aniline (4.8g, 20mmol), 4-methylimidazole (1.97g, 24mmol), salt of wormwood (3.04g, 22mmol), CuI (0.57g, 3mmol) and oxine (0.44g, 3mmol) suspension in anhydrous DMSO (20mL) places penstock, outgases 10 minutes by be blown into nitrogen in this suspension when stirring.Should manage closely sealing.Heated this mixture 15 hours at 120 ℃ (oil bath temperatures).This mixture is cooled to 45-50 ℃ and add 14%NH ₄OH (20mL) aqueous solution.Allow mixture keep this temperature 1 hour.After being cooled to room temperature, add water and ethyl acetate.The water layer ethyl acetate extraction, the machine layer that is associated with by short silicagel column with remove most green/blue Cu salt.Filtrate concentrates with dried over sodium sulfate and at rotatory evaporator.Crude product ethyl acetate/hexane recrystallization obtains pure faint yellow spicule.Concentrated mother liquor, residue obtains second batch of product with silicagel column purifying (5% ethanol/methylene), is faint yellow spicule.

3-iodo-4-methyl-N-(3-(4-methyl isophthalic acid H-imidazoles-1-yl)-5-(trifluoromethyl) phenyl) benzamide: (2.62g is 10mmol) at SOCl with 3-iodo-4-tolyl acid ₂Refluxed 1 hour (10mL).Remove volatile component at rotatory evaporator, residue be dissolved in the benzene (10mL), be concentrated at rotatory evaporator dried, and then vacuum-drying.The gained acyl chlorides is joined 3-(4-methyl isophthalic acid H-imidazoles-1-yl)-5-(trifluoromethyl) aniline, and (2.46g, 10.2mmol), N, (1.56g is 12mmol) and in the solution of the DMAP of catalytic amount in THF (20mL) for the N-diisopropyl ethyl amine.Stir after 2 hours the cancellation of reaction water under the room temperature.Add ethyl acetate and layering.The organic layer that merges is concentrated into dried, and namely is used for next step without purifying.

Embodiment 4:

5-[5-(3-imidazoles-1-base-5-trifluoromethyl formamyl)-2-methyl-phenylacetylene base]-1-methyl isophthalic acid H-imidazoles-2-methane amide

Use 5-ethynyl-1-methyl isophthalic acid H-imidazoles-2-methane amide and N-(3-(1H-imidazoles-1-yl)-5-(trifluoromethyl) phenyl)-3-iodo-4-methyl benzamide to make above-claimed cpd according to embodiment 2: MS (M+H) ⁺493.

3-(1H-imidazoles-1-yl)-5-(trifluoromethyl) aniline: under argon atmospher, with 3-amino-5-bromo benzenyl fluoride thing (4.0g, 0.0167mol), oxine (0.362g, 0.0025mol), CuI (0.476g, 0.025mol), imidazoles (1.36g, 0.0199mol) and salt of wormwood (2.52g, 0.0183mol) mixture in the DMSO of 17mL (with argon-degassed～10 minute) is 120 ℃ of heating 15 hours down; HPLC represents there is not starting material.Ammonium hydroxide aqueous solution with 14% adds in the mixture of cooling, stirs at ambient temperature 1 hour.Add water (50mL) and ethyl acetate (200mL), water layer extracts with ethyl acetate (3x30mL).The organic layer Na that merges ₂SO ₄Dry and concentrated.Crude product obtains the 2.51g product with flash chromatography on silica gel (using the ethyl acetate/hexane wash-out) purifying.

N-(3-(1H-imidazoles-1-yl)-5-(trifluoromethyl) phenyl)-3-iodo-4-methyl benzamide: (3.07g, 0.0117mol) the middle thionyl chloride (10mL) that adds refluxed 2 hours to 3-iodo-4-tolyl acid.Remove excessive thionyl chloride carefully, gained acyl chlorides vacuum-drying 2 hours.Then residue is dissolved in DCM (anhydrous, 25mL) in and in cooled on ice.Add in the cooling solution 3-(1H-imidazoles-1-yl)-5-(trifluoromethyl) aniline (3.46g, DCM solution 0.0152mol), drip then diisopropyl ethyl amine (8.2mL, 0.047mol).It was stirred 21 hours at ambient temperature.The white solid of filtering separation washes with water and drying obtains the 4.65g product.Other product can be concentrated by filtrate, and flash chromatography on silica gel (using the ethyl acetate/hexane wash-out) purifying obtains.

Embodiment 5:

3-[(2-amino-1,3-thiazoles-5-yl) ethynyl]-4-methyl-N-[3-(4-methyl isophthalic acid H-imidazoles-1-yl)-5-(trifluoromethyl) phenyl] benzamide

The 5-[(TMS) and ethynyl]-1, the 3-thiazol-2-yl } t-butyl carbamate: under nitrogen atmosphere, with (5-bromo-1,3-thiazoles-2-yl) t-butyl carbamate (2.79g, 10mmol), the ethynyl trimethyl silane (1.27g, 13mmol), Pd (PPh ₃) ₄(578mg, 0.5mmol), CuI (143mg, 0.75mmol) and diisopropyl ethyl amine (1.94g, 15mmol) mixture in DMF (10mL) is in 50 ℃ of following heated overnight.After being cooled to envrionment temperature, reaction mixture is concentrated, crude product obtains yellow solid (2.55g, 86%) through flash chromatography on silica gel (with 20% ethyl acetate/hexane wash-out) purifying.

5-[(2-methyl-5-{[3-(4-methyl isophthalic acid H-imidazoles-1-yl)-5-(trifluoromethyl) phenyl] and formamyl } phenyl) ethynyl]-1; the 3-thiazol-2-yl } t-butyl carbamate: under nitrogen atmosphere; will the 5-[(TMS) and ethynyl]-1; the 3-thiazol-2-yl } t-butyl carbamate (166mg; 0.56mmol), 3-iodo-4-methyl-N-(3-(4-methyl isophthalic acid H-imidazoles-1-yl)-5-(trifluoromethyl) phenyl) benzamide (247mg, 0.51mmol), Pd (PPh ₃) ₄(29mg, 0.025mmol), CuI (7.1mg, 0.0375mmol), TBAF (the THF solution of 1.0M, 0.62mL, 0.62mmol) and diisopropyl ethyl amine (0.14mL, 0.78mmol) mixture in the DMF of 3.0mL stirs under envrionment temperature and spends the night.The cancellation of reaction water.Add ethyl acetate and other water and be used for extraction.Organic layer drying (the Na that merges ₂SO ₄), filter, concentrate, the gained residue obtains being the required product (216mg, 73%) of brown solid through flash chromatography on silica gel purifying (with the dichloromethane solution wash-out of 10% methyl alcohol).

3-[(2-amino-1; 3-thiazole-5-yl) ethynyl]-4-methyl-N-[3-(4-methyl isophthalic acid H-imidazoles-1-yl)-5-(trifluoromethyl) phenyl] benzamide: at room temperature stir { 5-[(2-methyl-5-{[3-(4-methyl isophthalic acid H-imidazoles-1-yl)-5-(trifluoromethyl) phenyl] formamyl } phenyl) ethynyl]-1,3-thiazoles-2-yl } TFA/CH of t-butyl carbamate (216mg) ₂Cl ₂(10mL, 1: 1) solution 1 hour.Remove volatile component at rotatory evaporator, residue is at ethyl acetate and NaHCO ₃Distribute between the aqueous solution.Organic layer drying (the Na that merges ₂SO ₄), filter, concentrate, the gained residue obtains being the required product (170mg, 95%) of brown solid: 482m/z (M+H) with flash chromatography on silica gel purifying (with the dichloromethane solution wash-out of 10% methyl alcohol).

Embodiment 6:

3-{[2-(acetylamino)-1,3-thiazoles-5-yl] ethynyl }-4-methyl-N-[3-(4-methyl isophthalic acid H-imidazoles-1-yl)-5-(trifluoromethyl) phenyl] benzamide

With 3-[(2-amino-1,3-thiazoles-5-yl) ethynyl]-4-methyl-N-[3-(4-methyl isophthalic acid H-imidazoles-1-yl)-5-(trifluoromethyl) phenyl] Ac of benzamide (100mg) ₂O (10mL) solution heated 2 hours down at 130 ℃.Behind the cool to room temperature, vacuum is removed volatile component, and residue is at ethyl acetate and NaHCO ₃Distribute between the aqueous solution.Organic layer drying (the Na that merges ₂SO ₄), filter, concentrate, the gained residue obtains being the required product (105mg, 96%) of brown solid: 524m/z (M+H) with flash chromatography on silica gel purifying (with the dichloromethane solution wash-out of 10% methyl alcohol).

Embodiment 7

The 4-[(5-{[3-{2-[(dimethylamino) methyl]-1H-imidazoles-1-yl }-5-(trifluoromethyl) phenyl] formamyl }-the 2-aminomethyl phenyl) ethynyl]-the optional synthetic method of N-methyl isophthalic acid H-pyrazoles-1-methane amide

Title compound can be by 1H-pyrazoles-1-N-methylformamide and N-[3-{2-[(dimethylamino) methyl]-1H-imidazoles-1-yl }-5-(trifluoromethyl) phenyl]-3-ethynyl-4-methyl benzamide is according to synthetic with embodiment 1 described similar method.

1-(1H-imidazoles-2-yl)-N, N-dimethyl methylamine: in the two neck round-bottomed flasks that reflux exchanger and pressure equilibrium feed hopper are installed, add 2-imidazole formaldehyde (6g, methyl alcohol 62.5mmol) (60mL) solution.In this suspension (envrionment temperature), drip dimethylamine (40% aqueous solution, 60mL) solution (20 minutes) fast.After adding, carefully add solid sodium borohydride (7g, 186.8mmol) with gradation in 45 minutes.Each back that adds forms foam, and make internal temperature remain on～50 ℃ and need not exterior cooling.Then this reaction mixture is heated to 65 ℃ and kept 3 hours, be cooled to envrionment temperature then and spend the night.Vacuum concentration reactant, gained residue be dissolved in ethyl acetate (2 * 30mL), with salt solution and CHCl ₃(4 * 100mL) washings.Discard acetic acid ethyl acetate extract.Use NaSO ₄Dry CHCl ₃Extraction liquid, and vacuum concentration obtains the required product of 3.7g, is waxy solid.

3-(2-((dimethylamino) methyl)-1H-imidazoles-1-yl)-5-(trifluoromethyl) aniline: with 3-amino-5-bromo benzenyl fluoride thing (6g, 25mmol) and 1-(1H-imidazoles-2-yl)-N, (3.7g 29.6mmol) is dissolved among the anhydrous DMSO (25mL) N-dimethyl methylamine.To wherein add CuI (0.95g, 7.5mmol), oxine (0.72g, 7.5mmol) and K ₂CO ₃(6.9g, 50mmol).This mixture of vigorous stirring and with the nitrogen degassing 15 minutes.Then flask is installed condenser and 120 ℃ the heating 18 hours.The gained heterogeneous mixture is cooled to room temperature, pours into to 14%NH ₄(3 * 300ml) extract in OH (100mL) aqueous solution and with ethyl acetate.The extraction liquid NaSO that merges ₄Drying, vacuum concentration.Residue with methyl alcohol/DCM (5: 95) wash-out, obtains the required product of 3.5g through silica gel column chromatography, is pale brown look, 285m/z (M+H).

N-(3-(2-((dimethylamino) methyl)-1H-imidazoles-1-yl)-5-(trifluoromethyl) phenyl)-3-iodo-4-methyl benzamide: with 3-iodo-4-methyl benzoyl chloride (2.2g, 7.88mmol) be dissolved among the anhydrous THF (13mL), at～5 ℃ it is added dropwise to 3-(2-((dimethylamino) methyl)-1H-imidazoles-1-yl)-5-(trifluoromethyl) aniline (1.5g then, 5.5mmol), (2.1mL is 11.8mmol) in the solution in THF (30mL) for DIPEA.Gained solution stirs at ambient temperature and spends the night.Solvent removed in vacuo, thick residue is dissolved in CH again ₂Cl ₂In, with the NaOH washing of 1N.Organic layer water and salt water washing then, NaSO ₄Drying, vacuum concentration then.Brown residue is developed with hexane/DCM mixture then, and precipitation obtains the required product of 1.4g, is beige powder: 529m/z (M+H).

The N-[3-{2-[(dimethylamino) methyl]-1H-imidazoles-1-yl }-5-(trifluoromethyl) phenyl]-4-methyl-3-[(TMS) ethynyl] the optional synthetic method of benzamide: with N-(3-(2-((dimethylamino) methyl)-1H-imidazoles-1-yl)-5-(trifluoromethyl) phenyl)-3-iodo-4-methyl benzamide (5mmol), Pd[(PPh ₃)] ₄(289mg, 0.25mmol), (71mg 0.375mmol) places the schlenk flask to CuI.This flask is carried out 3 vacuum-be full of again circulation of nitrogen.Add anhydrous N in this mixture, the N-diisopropyl ethyl amine (1.1mL, 6mmol), DMF (5mL) and trimethyl silane ethyl-acetylene (0.92mL, 6.5mmol).At room temperature stirred this solution 24 hours.In reaction mixture, add water and ethyl acetate, extract.The organic layer Na that merges ₂SO ₄Drying is filtered, concentrate at rotatory evaporator then, residue through the silicagel column purifying (with the CH of 5% methyl alcohol ₂Cl ₂Eluant solution, methyl alcohol is saturated in advance with ammonia) obtain required product.

The N-[3-{2-[(dimethylamino) methyl]-1H-imidazoles-1-yl }-5-(trifluoromethyl) phenyl]-the optional synthetic method of 3-ethynyl-4-methyl benzamide: to the N-[3-{2-[(dimethylamino) methyl]-1H-imidazoles-1-yl }-5-(trifluoromethyl) phenyl]-4-methyl-3-[(TMS) ethynyl] add THF (1.0M) solution of 5mL TBAF in THF (15mL) solution of benzamide (4.1mmol).After at room temperature stirring 1 hour, this mixture is distributed between water and ethyl acetate.Merge organic layer, use Na ₂SO ₄Drying is filtered, concentrate at rotatory evaporator then, residue through the silicagel column purifying (with the CH of 10% methyl alcohol ₂Cl ₂Eluant solution, methyl alcohol is saturated in advance with ammonia) obtain required product.

Embodiment 8

N-{3-chloro-4-[(4-methylpiperazine-1-yl) methyl] phenyl }-4-methyl-3-[(1-methyl isophthalic acid H-imidazoles-5-yl) ethynyl] the optional synthetic method of benzamide:

According to embodiment 2, by 5-ethynyl-1-methyl isophthalic acid H-imidazoles (being made by 1-methyl-5-TMS ethynyl-1H-imidazoles deprotection) and N-(3-chloro-4-((4-methylpiperazine-1-yl) methyl) phenyl)-3-iodo-4-methyl benzamide synthesising title compound.

1-(brooethyl)-2-chloro-4-nitro-benzene: under nitrogen atmosphere, with 2-chloro-4-nitrotoluene (10.0g, 58.3mmol), N-bromosuccinimide (NBS, 10.9g, 61.2mmol) and 2,2 '-azo two (2-methyl propionitrile) (AIBN, 0.29g, 1.75mmol) at 120mL CCl ₄In suspension returning heating 12 hours.Reaction mixture is cooled to envrionment temperature, crosses filter solid and wash with ethyl acetate.The filtrate that merges is used NaHCO ₃Solution washing, Na ₂SO ₄Drying is filtered, and concentrates further vacuum-drying at rotatory evaporator. ¹H NMR shows that the ratio of required product and unreacted 2-chloro-4-nitrotoluene is that 50: 50. these materials are directly used in next step.

1-(2-chloro-4-nitrobenzyl)-4-methylpiperazine: to thick 1-(brooethyl)-2-chloro-4-nitro-benzene (29.1mmol; Purity 50%) add in the DCM solution of 30mL Et3N (4.2mL, 30mmol) and the 1-methylpiperazine (3.4mL, 30mmol).Stir under the envrionment temperature after 3 hours, add NaHCO ₃The aqueous solution also extracts with DCM.The organic layer Na that merges ₂SO ₄Dry, filtration, concentrated, the gained residue obtains the 6.80g product through silica gel column chromatography purifying (with 5% methyl alcohol/DCM wash-out), is dark yellow oily thing.

3-chloro-4-((4-methylpiperazine-1-yl) methyl) aniline: to 1-(2-chloro-4-nitrobenzyl)-4-methylpiperazine (0.96g, methanol 3.6mmol) (4: 1,50mL) add 1.80g (33.7mmol) NH in the solution ₄Cl and 1.47g (26.3mmol) iron powder, this mixture of reflux 2 hours (the HPLC demonstration gets nowhere) under nitrogen atmosphere.To wherein adding the 4mL Glacial acetic acid, again with this mixture reflux 2 hours.Reaction mixture is cooled to envrionment temperature, filters and concentrated filtrate.Residue is at ethyl acetate and saturated NaHCO ₃Distribute between the aqueous solution, the water layer ethyl acetate extraction of separation, the organism that merges with the salt water washing is also used Na ₂SO ₄Dry.After concentrating, crude product (is used 5-7% methyl alcohol/DCM wash-out through the silica gel column chromatography purifying; Silica gel is with 1% triethylamine/DCM passivation), obtain the 0.53g product.

N-{3-chloro-4-[(4-methylpiperazine-1-yl) methyl] phenyl }-4-methyl-3-[(1-methyl isophthalic acid H-imidazoles-5-yl) ethynyl] other optional synthetic method of benzamide:

5-ethynyl-1-methyl isophthalic acid H-imidazoles: add the salt of wormwood of 2.5 equivalents at ambient temperature in the solution of 1-methyl-5-TMS ethynyl-1H-imidazoles (1.39mol) in the methyl alcohol of the ethyl acetate of 10x volume and 1.5x volume, stirred this solution 1 hour.Elimination salt of wormwood, organic liquor water and saturated nacl aqueous solution washing (2 times or more times).Merge water and use ethyl acetate extraction again.Merge organic liquor then, vacuum concentration is to about 0.5L.Precipitablely when concentrating go out solid.Cool off this slurries, for example to-5 ℃ approximately, preservation is spent the night, and filters, and washs with about 0.3L cold ethyl acetate.This solid of vacuum-drying then.

4-methyl-3-[(1-methyl isophthalic acid H-imidazoles-5-yl) ethynyl] phenylformic acid can prepare according to reacting described similar mode with above-mentioned Sonogashira.5-ethynyl-1-methyl isophthalic acid H-imidazoles and 3-iodo-4-tolyl acid are right as coupling.Alternatively, solvent (DMF) can be replaced by ethyl acetate, and alkali (Hunig alkali) can be replaced by triethylamine.Can come separated product by filtering crude product mixture.Filter cake is water washing with solvent such as ethyl acetate successively then, and is then dry in vacuum oven.Further purifying can be by with the slurrying in water of described solid, adds dense HCl and be adjusted to pH3 and realize.After filtering and washing, desciccate in vacuum oven.

N-{3-chloro-4-[(4-methylpiperazine-1-yl) methyl] phenyl }-4-methyl-3-[(1-methyl isophthalic acid H-imidazoles-5-yl) ethynyl] benzamide: with 4-methyl-3-[(1-methyl isophthalic acid H-imidazoles-5-yl) ethynyl] phenylformic acid (18mmol) is dissolved in methylene dichloride (100mL).The 4-methylmorpholine (NMM) that adds 3 equivalents in this solution adds the oxalyl chloride of 1.05 equivalents then.After stirring 30 minutes at ambient temperature, 3-chloro-4-((4-methyl-piperazine-1-yl) methyl) aniline (as above-mentioned prepared) that adds 0.8 equivalent adds the DMAP of 5 moles of % simultaneously.After initial the stirring, reflux this mixture and stirring are spent the night at ambient temperature.After 16 hours, add the described aniline of other 0.2 equivalent, make total amount reach 1 equivalent.And then stirred this mixture 2 hours, water cancellation, layering.Water layer can be used methylene dichloride (2X50mL) extraction, and the extraction liquid of merging washes with water.The dichloromethane layer evaporation that merges then, residue is dissolved in the 100mL ethyl acetate (20mL).After leaving standstill 1 hour, make the product crystallization.Cool off this mixture for example to 0 ℃, filter, solid product washs with cold ethyl acetate.

Embodiment 9

3-[(2-amino-1,3-thiazoles-5-yl) ethynyl]-N-{3-cyclopropyl-4-[(4-methylpiperazine-1-yl) methyl] phenyl }-the optional synthetic method of 4-methyl benzamide:

According to embodiment 2 described similar methods, title compound can be synthetic (according to carrying out nitroreduction with embodiment 8 described similar methods by (5-ethynyl-1,3-thiazoles-2-yl) t-butyl carbamate and N-(3-cyclopropyl-4-((4-methylpiperazine-1-yl) methyl) phenyl)-3-iodo-4-methyl benzamide; 0.25M methanol solution/10% acetic acid).Can be according to the embodiment 5 described t-BOC deprotections that after coupling, carry out.

(5-ethynyl-1, the 3-thiazol-2-yl) the optional synthetic method of t-butyl carbamate: under the envrionment temperature to the 5-[(TMS) ethynyl]-1, the 3-thiazol-2-yl } t-butyl carbamate is (as preparation as described in the embodiment 5,1.39mol) in the solution of the methyl alcohol of the ethyl acetate of 10x volume and 1.5x volume, add the salt of wormwood of 2.5 equivalents, stirred this solution 1 hour.Elimination salt of wormwood, organic liquor water and saturated nacl aqueous solution washing (2 times or more times).Merge water and use ethyl acetate extraction again.Merge organic liquor then, vacuum concentration is to about 0.5L.Concentrate that the back is precipitable to go out solid.Cool off this slurries, for example to-5 ℃ approximately, preservation is spent the night, and filters, and washs with about 0.3L cold ethyl acetate.This solid of vacuum-drying then.

1-(2-cyclopropyl-4-nitrobenzyl)-4-methylpiperazine: under nitrogen atmosphere, with 1-(2-bromo-4-nitrobenzyl)-4-methylpiperazine (0.94g, 3.0mmol), the cyclopropylboronic acid of 0.77g (9.0mmol), 0.067g (0.30mmol) Pd (OAc) ₂, 2.87g (13.5mmol) K ₃PO ₄, and the mixture reflux of 0.168g (0.60mmol) tricyclohexyl phosphine in 18mL toluene (5: 1) 19 hours.Concentrate this reaction mixture, crude product through the silica gel column chromatography purifying (with 5% methyl alcohol/DCM wash-out; Methyl alcohol is saturated in advance with ammonia), obtain the 0.80g product.

Embodiment 10

1-methyl-5-({ 2-methyl-5-[({4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } carbonyl) amino] phenyl } ethynyl)-the optional synthetic method of 1H-imidazoles-2-methane amide:

According to embodiment 2 described similar methods, title compound can be synthetic by 5-ethynyl-1-methyl isophthalic acid H-imidazoles-2-methane amide and N-(3-iodo-4-aminomethyl phenyl)-4-((4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) benzamide.5-ethynyl-1-methyl isophthalic acid H-imidazoles-2-methane amide is according to embodiment 2 preparations.

N-(3-iodo-4-aminomethyl phenyl)-4-((4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) benzamide: to the 4-[(4-methyl isophthalic acid-piperazinyl that contains 1.0g (2.67mmol)) methyl]-3-(trifluoromethyl)-phenylformic acid (CAS#859027-02-4; According to Asaki, T. wait Bioorg.Med.Chem.Lett. (2006), 16,1421-1425 preparation), the 3-iodo-4-monomethylaniline of 0.62g (2.67mmol), N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride (EDAC) of 0.77g (4.0mmol), 0.43g (3.2mmol) ofN-hydroxybenzotriazole monohydrate (HOBtH ₂O) add the DCM of 5mL and the triethylamine of 5mL in the flask.Stirred this solution 3 days under nitrogen atmosphere, envrionment temperature, and concentrated, crude product is through silica gel column chromatography purifying (use 100% eluent ethyl acetate, use 10% methanol/ethyl acetate wash-out then), obtains 0.69 product that is white in color solid.

Embodiment 11:

5-[(5-{[4-{[(3R)-and 3-(dimethylamino) tetramethyleneimine-1-yl] methyl }-3-(trifluoromethyl) phenyl] formamyl }-the 2-aminomethyl phenyl) ethynyl]-the optional synthetic method of 1-methyl isophthalic acid H-imidazoles-2-methane amide

According to embodiment 2 described similar methods, title compound can be synthetic by 5-ethynyl-1-methyl isophthalic acid H-imidazoles-2-methane amide and (R)-N-(4-((3-(dimethylamino) tetramethyleneimine-1-yl) methyl)-3-(trifluoromethyl) phenyl)-3-iodo-4-methyl benzamide.5-ethynyl-1-methyl isophthalic acid H-imidazoles-2-methane amide is according to embodiment 2 preparations.

1-(brooethyl)-4-nitro-2-(trifluoromethyl) benzene: at N ₂Down with 2-methyl-5-nitro benzenyl fluoride thing (3.90g, 19mmol), N-bromosuccinimide (NBS, 3.56g, 20mmol), 2,2 '-azo two (2-methyl propionitrile) (AIBN, 0.094g, CCl 0.6mmol) ₄(40mL) suspension returning is 16 hours.HPLC shows that about 50% transforms.Add NBS (10mmol) and AIBN (0.6mmol) again, with this mixture reflux 14 hours again.HPLC shows that about 80% transforms.Reaction mixture is cooled to room temperature, and the elimination solid also washs with ethyl acetate.The filtrate that merges is used NaHCO ₃Solution washing, Na ₂SO ₄Drying is filtered, and concentrates further vacuum-drying at rotatory evaporator.1H NMR shows that the ratio of required product and unreacted 2-methyl-5-nitro benzenyl fluoride is 75: 25.This material is directly used in next step.

(R)-and N, N-dimethyl-1-(4-nitro-2-(trifluoromethyl) benzyl) tetramethyleneimine-3-amine: in the 40mL DCM solution of thick 1-(brooethyl)-4-nitro-2-(trifluoromethyl) benzene (17.5mmol, purity 75%), add Et ₃N (2.69mL, 19.3mmol) and (R)-(+)-3-(dimethylamino) tetramethyleneimine (2.0g, 17.5mmol).After stirring under nitrogen atmosphere, the envrionment temperature was spent the night, concentrated reaction solution added NaHCO ₃The aqueous solution (100mL), the gained mixture extracts with DCM (4x50mL).The organic layer Na that merges ₂SO ₄Dry, filtration, concentrated, the gained residue obtains the 3.35g product through silica gel column chromatography purifying (with 0-10% methyl alcohol/DCM wash-out), is yellow oily.

(R)-1-(4-amino-2-(trifluoromethyl) benzyl)-N, N-dimethyl pyrrolidine-3-amine: to (R)-N, N-dimethyl-1-(4-nitro-2-(trifluoromethyl) benzyl) tetramethyleneimine-3-amine (1.20g, 3.79mmol) 20mL aqueous ethanol solution in add 0.26g Pd/C (10%Pd loads on the C), this mixture (is used H at the Parr device ₂Fully purge pressure reactor and pressure are controlled all the time at 45psi) vibrated 2-3 hour.Reaction mixture filters by the fritter Celite pad, washs with ethyl acetate.The organism that merges concentrates, and obtains quantitative faint yellow oily thing.This material is directly used in next step.

(R)-N-(4-((3-(dimethylamino) tetramethyleneimine-1-yl) methyl)-3-(trifluoromethyl) phenyl)-3-iodo-4-methyl benzamide: under nitrogen atmosphere, to the cooling (0 ℃) (R)-1-(4-amino-2-(trifluoromethyl) benzyl)-N, add 3-iodo-4-methyl benzoyl chloride (1.17g, 4.17mmol in the 14mL DCM solution of N-dimethyl pyrrolidine-3-amine (3.79mmol); CAS#52107-98-9 is by 3-iodo-4-tolyl acid and SOCl ₂Reaction makes), drip N subsequently, the N-diisopropyl ethyl amine (2.64mL, 15.2mmol).After envrionment temperature stirs 1.5 hours, concentrated reaction mixture, crude product (is used 0-8% methyl alcohol/DCM wash-out through the silica gel column chromatography purifying; Methyl alcohol is saturated in advance with ammonia), obtain the 0.71g product, be deep yellow oily thing.

5-[(5-{[4-{[(3R)-and 3-(dimethylamino) tetramethyleneimine-1-yl] methyl }-3-(trifluoromethyl) phenyl] formamyl }-the 2-aminomethyl phenyl) ethynyl]-the optional synthetic method of 1-methyl isophthalic acid H-imidazoles-2-methane amide: under nitrogen atmosphere, with (R)-N-(4-((3-(dimethylamino) tetramethyleneimine-1-yl) methyl)-3-(trifluoromethyl) phenyl)-3-iodo-4-methyl benzamide of 5-ethynyl pyrimidine (0.34mmol), 0.150g (0.28mmol), the Pd (PPh of 0.016g (0.014mmol) ₃) ₄, the CuI of 0.004g (0.021mmol) and the N of 0.09mL (0.51mmol), the mixture of N-diisopropyl ethyl amine in 3.5mL DMF stirs 3 days (adding the reagent that replenishes equivalent and being heated to 80 ℃ advances reaction to finish) at ambient temperature.Concentrated reaction mixture, crude product (is used 0-10% methyl alcohol/DCM wash-out through the silica gel column chromatography purifying; Methyl alcohol is saturated in advance with ammonia), obtain title compound.

Embodiment 12: the biological assessment of compound

In a plurality of experiments, measured the biologic activity of The compounds of this invention to estimate The compounds of this invention.For example, can test the ability that The compounds of this invention suppresses the protein kinase of various concerns.The compound of some tests demonstrates the activity of strong nmole level to following kinases: Abl, Abl T315I, Src and FGFR.In addition, screened the some of them compound to transfection the antiproliferative activity of BAF3 cell of wild-type Bcr-Abl or Bcr-AblT315I mutant, and demonstrate active between 1-100nM.

Also assessed the tumour cell of described compound to paying close attention to, for example below in greater detail and as shown previously for cytotoxicity or the growth-inhibiting effect of the tumour cell of some representative compounds.For example referring to WO 03/000188, the 115-136 page or leaf, its full content is incorporated herein by reference.

Representative compounds more of the present invention are as follows:

Kinase inhibitory activity

More specifically, filter out compound described herein for kinase inhibiting activity.The kinases that is suitable for following proposal includes, but are not limited to: Abl, Lck, Lyn, Src, Fyn, Syk, Zap-70, Itk, Tec, Btk, EGFR, ErbB2, Kdr, Flt1, Flt-3, Tek, c-Met, InsR and AKT.

Kinases be expressed as with intestinal bacteria (E.coli) or baculovirus (Baculovirus)-High Five expression system in the fusion rotein of gsh S-transferring enzyme (GST) or polyhistidine mark the kinases zone or the total length structure that merge.By the described affinity chromatography of forefathers (people such as Lehr, 1996; People such as Gish, 1995) they are purified near homogeneous.Kinases is measured active with regulatory polypeptide coexpression purifying or partially purified or mix then in some instances.

Kinase activity and inhibition can be by having set up scheme (referring to, people such as Braunwalder for example, 1996) measure.In these examples, will ³³PO ₄Synthetic substrate from from ATP to the bioactivity surface that is connected in microtiter plate many (Glu, Tyr) 4: 1 or many (Arg, Ser) 3: 1 transfer conduct measuring enzymic activity.Incubation is after for some time, measures the amount of the phosphoric acid that shifts by following method, at first uses this plate of 0.5% phosphoric acid washing, adds liquid scintillator, counts in the liquid scintillation detector then.By cause mixing with the substrate that closes that hardens in ³³The compound concentrations of the amount reduction by 50% of P is tried to achieve IC50.

In a method,, be with or without in the presence of the The compounds of this invention kinases of incubation activation with biotinylated peptide substrate (containing tyrosine).After the kinase assay incubation period, add the excessive kinase inhibitor that is used for stopping kinase reaction, and anti--phosphotyrosine antibody (Eu-Ab) and the allophycocyanin-streptavidin (SA-APC) of europium-mark.Biotinylated peptide substrate in the solution (being with or without the tyrosine of phosphorylation) is combined with SA-APC by the biotin-avidin combination.Eu-Ab only is combined with the substrate of the tyrosine with phosphorylation.When solution is excited at 615nm, when the distance of europium and APC is very near (being connected in the same molecular of the peptide substrate of biotinylation and phosphorylation), energy is transferred on the APC from europium.APC sends the fluorescence of 665nm wavelength then.Excite and emission occurs in Wallac Victor ²In the V plate reader, wherein read the fluorescence of this plate, and be recorded in 615 and the absorbancy of 665nm.Handle these data by the Excel sheet processor then, by being the amount of used phosphorylated substrate with fluorescence conversion, and obtain the mensuration compound concentrations that need suppress 50% (IC50) of phosphorylated substrate colour developing (development), calculate the IC50 that measures compound.

Also can use based on phosphoric acid other method to the transfer of peptide or peptide substrate, described substrate comprises independent tyrosine, Serine, Threonine or the Histidine of solution or fixing (being solid phase) form; Their combinations with one another or with the combination of other amino acid.

For example, can use also that flicker is got close to, fluorescence polarization or even matter time resolved fluorescence detect phosphoric acid to the transfer of peptide or polypeptide.Perhaps, can use based on the method for antibody and measure kinase activity, wherein antibody or polypeptide are as the reaction reagent that detects the phosphorylation target polypeptides.

For further background information, as test method, referring to people such as for example Braunwalder, 1996, Anal.Biochem.234 (1): 23; People such as Cleaveland, 1990, Anal Biochem.190 (2): people such as 249Gish (1995) .Protein Eng.8 (6): people (1996) .Gene 169 (2) such as people such as 609Kolb (1998) .Drug Discov.TodaV.3:333Lehr: people such as 27527-87Seethala (1998) .AnalBiochem.255 (2): people such as 257Wu (2000).

Observe compound of the present invention and resist the IC50 value of multiple kinases (comprising Src, Abl and kdr) in the scope of low nmole.

Test based on cell

Also verified some compound of the present invention is for cytotoxic effect and the growth-inhibiting effect of tumour and other cancerous cell line, so The compounds of this invention can be used for treating cancer and other cell breeding disease.Use the anti-tumor activity of measuring these compounds in the body well known by persons skilled in the art with in vitro tests.Usually, in test cell line the primary dcreening operation compound to determine candidate's cancer therapy drug.Determine in these tests based on cell that then the compound with antiproliferative activity can continue to carry out anti-tumor activity and toxicity test in whole organism.In general, quicker and more economical with respect to using whole organic test based on the screening of cell.For realizing purpose of the present invention, term " antitumor " and " anticancer " activity can be exchanged use.

The method based on cell for the mensuration antiproliferative activity is known, and can be used for the feature of compound more of the present invention.Usually, the test of design cell proliferation and cell viability makes it that detectable signal is provided when cell has metabolic activity.Can measure the antiproliferative activity of compound by measuring the reduction when cellular exposure any observable cell metabolic activity behind compound.Method commonly used comprises, for example, measures film integrality (as measuring of cell viability) (repelling as using Trypan Blue) or measures DNA synthetic (as by measuring mixing of BrdU or 3H-thymidine).

Measure the certain methods of cell proliferation and use the reaction reagent that during cell proliferation, is converted into detectable compound.Especially preferred compound is tetrazolium salts, and includes but not limited to MTT (3-(4,5-dimethylthiazole-2-yl)-2,5-phenylbenzene tetrazolium bromide; Sigma-A1drich, St.Louis, MO), (3-(4 for MTS, 5-dimethylthiazole-2-yl)-5-(3-carboxyl p-methoxy-phenyl)-2-(4-sulfo group phenyl)-2H-tetrazolium), XTT (2,3-two (2-methoxyl group-4-nitro-5-sulfo group phenyl)-2H-tetrazolium-5-N-formylaniline (carboxanilide)), INT, NBT and NTV (people Biochim Biophys Acta1451 (1): 73-81 such as Bernas, 1999).Preferred test uses tetrazolium salts by detecting tetrazolium salts to blue first

The product of the enzymatic conversion of derivative detects cell proliferation, and this can pass through spectrophotometric method rapid detection (Mosman.J.Immunol.Methods.65:55-63,1983).

Usually, the preferable methods of mensuration cell proliferation relates to incubation cell in required growth medium (being with or without the compound of measuring).Multiple prokaryotic cell prokaryocyte and eukaryotic growth conditions are known (people Current Protocols in MolecularBiology.Wiley and Sons.1999 such as Ausubel for those of ordinary skills; People Current Protocols in Cell Biology.Wiley such as Bonifacino and Sons.1999 all are incorporated herein by reference).For detecting cell proliferation, tetrazolium salts is joined by in the culturing cell of incubation, making it is detectable product by the viable cell Enzymatic transformation.Handle cell, and the optical density(OD) of mensuration cell is to measure first

The amount of derivative.And, can use the commercially available test kit that comprises reaction reagent, rules, for example available from Promega Corporation (Madison, WI), Sigma-Aldrich (St.Louis, MO), and Trevigen (Gaithersburg, MD).

More particularly, we use CellTiter 96AQueous One Solution cell proliferation test test kit (Promaga Cat#G3581) carry out cell proliferation test now.This test is the colorimetry of measuring the viable cell quantity in propagation or the cell toxicity test.Tetrazolium salts is used in this test, by detecting tetrazolium salts to blue first The product of the Enzymatic transformation of derivative detects cell proliferation, and this can pass through at plate reader Wallac Victor ²Detecting absorbancy in 490nm among the V (PerkinElmer) detects.

Example based on the test of cell is as follows.The cell that is used for test is Ba/F3, it is the former B of muroid (pro-B) clone, and this clone is by total length wild-type Bcr-Abl or Bcr-Abl construct stable transfection with a plurality of kinases territory point mutation (comprising T351I, Y253F, E255K, H396P, M351T etc.) structure.Use parental generation Ba/F3 clone in contrast.From Brian J.Druker (Howard Hughes Medical Institute, Oregon Health and Science University, Portland, Oregon USA) obtains these clone.The Ba/F3 cell of expressing Bcr-Abl or Bcr-Abl mutant maintained contain 200 μ M L-glutaminate, 10%FCS is in PRMI 1640 growth mediums of penicillin (200U/ml) and Streptomycin sulphate (200 μ g/ml).Parental generation Ba/F3 cell is cultivated in the identical substratum that is supplemented with 10ng/ml IL-3.

With parental generation Ba/F3 cell (being supplemented with IL-3) express WT or the Ba/F3 cell of mutant Bcr-Abl in duplicate with 1x10 ⁴Cells/well is inoculated in the 96-orifice plate, contains the described compound of the different concns in substratum in the described 96-orifice plate.At first with described compound dissolution and be diluted in and make 4 times of diluents among the DMSO; Then isopyknic compound and DMSO are transferred in the substratum, transferred in the cell plate again.The final concentration of compound is from 10 μ M to 6nM.The DMSO of same percentage is with comparing.Compound and cell incubation used CellTiter 96AQueous One Solution cell proliferation test test kit to detect the quantity of viable cell according to the test kit explanation after 3 days.Basically, tetrazolium salts is joined to make it in the incubation cultured cells be detectable product by the viable cell Enzymatic transformation.Handle cell, detect the optical density(OD) of cell to detect first

The amount of derivative.From bipartite hole, obtain mean number+/-SD, and with the per-cent report with respect to the contrast absorbancy.Use Micorsoft Excel-match software to calculate IC50 with optimum fit curve.

And, many cell types can be used for for the antiproliferative activity SCREENED COMPOUND, comprise following clone: COLO 205 (colorectal carcinoma), DLD-1 (colorectal carcinoma), HCT-15 (colorectal carcinoma), HT29 (colorectal carcinoma), HEP G2 (liver cancer), K-562 (leukemia), A549 (lung cancer), NCI-H249 (lung cancer), MCF7 (mammary cancer), MDA-MB-231 (mammary cancer), SAOS-2 (osteosarcoma), OVCAR-3 (ovarian cancer), PANC-1 (carcinoma of the pancreas), DU-145 (prostate cancer), PC-3 (prostate cancer), ACHN (kidney), CAKI-1 (kidney), MG-63 (sarcoma).

Though it is mammiferous that described clone is preferably, also can use low eukaryotic cell such as the yeast SCREENED COMPOUND of waiting.Preferred mammal cell line is from people, rat, mouse, rabbit, monkey, hamster and cavy, because be convenient to research and sign from these organic cells.Yet, also can use other cell.

The mammal cell line that is fit to is usually from tumour.For example, following tumor cell type can be the cell source of culturing cell: melanoma, myeloid leukemia, lung cancer, mammary cancer, ovarian cancer, colorectal carcinoma, kidney, prostate cancer, carcinoma of the pancreas and carcinoma of testis, myocardial cell (cardiomyocytes), endotheliocyte, epithelial cell, lymphocyte (T-cell and B cell), mastocyte, eosinophilic granulocyte, the tunica intima cell, liver cell, white corpuscle (comprising single nuclear leukocyte), stem cell is (as hemopoietic stem cell, neural, skin, lung, kidney, liver and flesh stem cell (be used for the screening differentiation and dedifferente the factor)), osteoclast, chondrocyte and other phoirocyte, keratinocyte, melanophore, liver cell, nephrocyte and adipocyte.The limiting examples that is not studied the widely used mammal cell line of person comprises HeLa, NIH/3T3, HT1080, CHO, COS-1,293T, WI-38 and CV1/EBNA-1.

Can use other test cell line that detects the metabolic activity cell according to reporter gene.The limiting examples of reporter gene expression system comprises green fluorescent protein (GFP) and luciferase.Use GFP screens the example of potential antitumor drug, people such as Sandman (Chem Biol.6:541-51; Be incorporated herein by reference) use the HeLa cell detection of the derivable varient that contains GFP to suppress the compound that GFP expressed and suppressed thus cell proliferation.

The compound that has the inhibition of cell proliferation activity by these test cell lines evaluations is tested anti-tumor activity in whole organism then.Preferably, described organism is Mammals.The Mammals system that is used for the better sign of research cancer comprises rodents, as rat and mouse.Usually, in mouse, described mouse initiates lower to the immune response ability of tumour with the tumour transplatation paid close attention to, to reduce the possibility of rejection.These mouse for example comprise, nude mouse (athymia) and SCID (immune deficiency of severe associating) mouse.In this test, can use other genetically modified mouse, as contain oncogene mouse (referring to, for example USP 4,736,866 and USP 5,175,383).For for detection of the summary of the rodents model of antitumor drug and discuss referring to Kerbel (Cancer Metastasis Rev.17:301-304,1998-99).

Usually, the tumour of paying close attention to is implanted in the organism that detects preferred subcutaneous transplantation.The organism that contains tumour is treated with candidate's antineoplastic compound of some dosage.Regularly detect the size of tumour to determine that institute's detection compound is to the effect of tumour.Some tumor types are implanted rather than subcutaneous implantation (as the intraperitoneal site) in other site, and detect survival rate as terminal point.The parameter that detects by the routine screening comprises different tumor models, kinds of tumors and medicine approach, and dosage and scheme.For using mouse to detect the summary of antineoplastic compound referring to people such as Corbett (Invest New Drugs.15:207-218,1997; Be incorporated herein by reference).

Embodiment 8: pharmaceutical composition

Provide the representational pharmaceutical dosage form (activeconstituents is called " compound ") of compound of the present invention to be used for human treatment and prevention:

(a) tablet I mg/ sheet

Compound ... 100

Lactose Ph.Eur ... 182.75

Croscarmellose sodium ... 12.0

Corn starch paste (5%w/v paste) ... 2.25

Magnesium Stearate ... 3.0

(b) tablet II mg/ sheet

Compound ... 50

Lactose Ph.Eur ... 223.75

Croscarmellose sodium ... 6.0

W-Gum ... 15.0

Polyvinylpyrrolidone (Polyvinylpyffolidone) (5%w/v paste) ... 2.25

Magnesium Stearate ... .3.0

(c) tablet III mg/ sheet

Compound ... 1.0

Lactose Ph.Eur ... 93.25

Croscarmellose sodium ... 4.0

Corn starch paste (5%w/v paste) ... 0.75

Magnesium Stearate ... 1.0-76

(d) capsule mg/ capsule

Compound ... 10

Lactose Ph.Eur ... 488.5

Magnesium ... 1.5

(e) injection I (50mg/ml)

Compound ... 5.0%w/v

1M sodium hydroxide solution ... 15.0%v/v

0.1M hydrochloric acid (regulating pH to 7.6)

Poly(oxyethylene glycol) 400 ... 4.5%w/v

Water for injection to 100%

(f) injection II (10mg/ml)

Compound ... 1.0%W/v

Sodium phosphate BP ... 3.6%w/v

0.1M sodium hydroxide solution ... 15.0%v/v

Water for injection to 100%

(g) injection III (1mg/ml is buffered to pH6)

Compound ... 0.1%w/v

Sodium phosphate BP ... 2.26%w/v

Citric acid ... 0.38%w/v

Poly(oxyethylene glycol) 400 ... 3.5%w/v

Water for injection to 100%

(h) aerosol I mg/ml

Compound ... 10.0

Sorbitan trioleate ... 13.5

Trichlorofluoromethane ... 910.0

Refrigerant 12 ... 490.0

(i) aerosol II mg/ml

Compound ... 0.2

Sorbitan trioleate ... 0.27

Trichlorofluoromethane ... 70.0

Refrigerant 12 ... 280.0

Dichloro tetrafluoro ethane ... 1094.0

(j) aerosol III mg/ml

Compound ... 2.5

Sorbitan trioleate ... 3.38

Trichlorofluoromethane ... 67.5

Refrigerant 12 ... 1086.0

Dichloro tetrafluoro ethane ... 191.6

(k) aerosol IV mg/ml

Compound ... 2.5

Soybean lecithin ... 2.7

Trichlorofluoromethane ... 67.5

Refrigerant 12 ... 1086.0

Dichloro tetrafluoro ethane ... 191.6

(1) ointment ml

Compound ... 40mg

Ethanol ... 300 μ l

Water ... 300 μ l

1-agone ... 50 μ l

Propylene glycol ... to 1ml

Attention: these preparations can use the known ordinary method preparation of pharmaceutical field.Optionally, tablet (a)-(c) can use the ordinary method dressing, so that for example cellulose acetate phthalate dressing to be provided.Aerosol (h)-(k) can use with the aerosol dispenser of the metering of standard, and suspension agent, sorbitan trioleate and soybean lecithin can be replaced by other suspension agent, described suspension agent such as dehydrated sorbitol mono-fatty acid ester, NOFABLE SO-992, polysorbate80, poly-olein (polyglycerol oleate) or oleic acid.

Claims (10)

1. the compound of formula II or formula III or its pharmacy acceptable salt:

Formula II

Formula III

Wherein:

Ring T is

Ring A is phenyl;

Ring B is phenyl or pyridyl;

L ¹Be selected from NR ¹C (O) and C (O) NR ¹

R ^a, R ^bAnd R ^tBe independently selected from halogen ,-R ⁴,-NR ²R ³,-C (O) YR ²With-NR ²C (O) YR ², wherein Y be independently chemical bond or-NR ³-;

R ¹, R ²And R ³Be independently selected from H; (C ₁-C ₈) alkyl, it is randomly by NR ²R ³Replace;

R ⁴Be independently selected from (C ₁-C ₈) alkyl, it is randomly replaced by three fluorine atoms; Or

Ring C is imidazolyl;

Ring D is piperazinyl or pyrrolidyl;

R ^cBe (C ₁-C ₈) alkyl, it is randomly by tetramethyleneimine, hydroxyl or NR ²R ³Replace;

R ^dBe (C ₁-C ₈) alkyl, CH ₂CH ₂OH or NR ²R ³

L ²Be (CH ₂) _z

M is 1;

N is 1 or 2;

T is 1;

V is 0 or 1;

W is 1; And

Z is 1.

2. according to the compound of claim 1, wherein encircling A and B is phenyl.

3. according to the compound of claim 1, it is selected from formula IIa and IIc:

Formula IIa

Formula IIc.

4. according to the compound of claim 3, R wherein ^tBe independently selected from-CH ₃, or-C (O) NH ₂, v is that 1, n is that 1, m is that 1, t is 1, R ^aBe-CH ₃, R ^bBe CF ₃And R ^cBe-CH ₃

5. according to the compound of claim 1, wherein encircling D is piperazinyl.

6. according to the compound of claim 5, it is selected from formula III a and IIIc:

Formula III a

Formula III c.

7. according to the compound of claim 6, R wherein ^tBe independently selected from-CH ₃With-C (O) NH ₂, n is that 1, m is that 1, t is 1, R ^aBe methyl, R ^bBe CF ₃, a R ^dBe selected from methyl and CH ₂CH ₂OH.

8. compound, it is selected from:

3-(1H-pyrazoles-1-methane amide-N-methyl)-4-methyl-N-(4-((4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) phenyl) benzamide;

1-methyl-5-(2-methyl-5-[4-(4-methyl-piperazine-1-ylmethyl)-3-trifluoromethyl-phenyl amino formyl radical]-the phenylacetylene base)-1H-imidazoles-2-methane amide;

1-methyl-5-(2-methyl-5-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl amino formyl radical]-the phenylacetylene base)-1H-imidazoles-2-methane amide;

5-[5-(3-imidazoles-1-base-5-trifluoromethyl formamyl)-2-methyl-phenylacetylene base]-1-methyl isophthalic acid H-imidazoles-2-methane amide;

3-[(2-amino-1,3-thiazoles-5-yl) ethynyl]-4-methyl-N-[3-(4-methyl isophthalic acid H-imidazoles-1-yl)-5-(trifluoromethyl) phenyl] benzamide;

3-{[2-(acetylamino)-1,3-thiazoles-5-yl] ethynyl }-4-methyl-N-[3-(4-methyl isophthalic acid H-imidazoles-1-yl)-5-(trifluoromethyl) phenyl] benzamide;

The 4-[(5-{[3-{2-[(dimethylamino) methyl]-1H-imidazoles-1-yl }-5-(trifluoromethyl) phenyl] formamyl }-the 2-aminomethyl phenyl) ethynyl]-N-methyl isophthalic acid H-pyrazoles-1-methane amide;

N-{3-chloro-4-[(4-methylpiperazine-1-yl) methyl] phenyl }-4-methyl-3-[(1-methyl isophthalic acid H-imidazoles-5-yl) ethynyl] benzamide;

3-[(2-amino-1,3-thiazoles-5-yl) ethynyl]-N-{3-cyclopropyl-4-[(4-methylpiperazine-1-yl) methyl] phenyl }-the 4-methyl benzamide;

1-methyl-5-(2-methyl-5-[({4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } carbonyl) amino] phenyl } ethynyl)-1H-imidazoles-2-methane amide; With

5-[(5-{[4-{[(3R)-and 3-(dimethylamino) tetramethyleneimine-1-yl] methyl }-3-(trifluoromethyl) phenyl] formamyl }-the 2-aminomethyl phenyl) ethynyl]-1-methyl isophthalic acid H-imidazoles-2-methane amide;

Or its pharmacy acceptable salt.

9. the purposes in the medicine of each compound or its pharmacy acceptable salt treatment cancer in for the preparation of the Mammals in needs treatments among the claim 1-8.

10. pharmaceutical composition, it comprises among the claim 1-8 each compound or its pharmacy acceptable salt and pharmaceutically acceptable carrier, thinner or vehicle.