CN101654452A - Heterocyclic compounds and methods of use. - Google Patents

Abstract

Heterocyclic compounds derived from benzotriazine, triazines, triazoles and oxadiazoles are disclosed. The methods of synthesis and of use of such heterocyclic compounds are also provided.

Description

The heterogeneous ring compound and methods for using them

The application divides an application, and the applying date of original application is that August 24, application number in 2005 are that 200580035918.9 (PCT/US2005/030614), denomination of invention are " heterogeneous ring compound and methods for using them ".

The cross reference of related application

[0001] the application requires under 35 U.S.C. § 119 (e) in the U.S. Patent Application Serial 60/604 of submission on August 25th, 2004,298 and the U.S. Patent Application Serial 60/696 submitted on July 1st, 2005,168 benefit of priority is incorporated this paper into as a reference at this full content with above-mentioned application.

Technical field

[0002] relate generally to of the present invention uses the various illnesss of compounds for treating, disease and pathological state, relates more specifically to use various heterogeneous ring compounds to be used for the treatment of purpose.

Background technology

[0003] kinases is the cell protein extended familys that relate in the cascade signal transduction, and growth and death, existence, migration, differentiation, genetic expression, metabolism, protein synthesis and the regulation and control of cell cycle of cell in described cascade signal transduction process control.The general mechanism of transmitting these signals is the reversible phosphorylation, and it induces these enzyme occurred conformations to change and changed their 26S Proteasome Structure and Functions.Whole kinase gene groups of having found have so far contained range protein and the isoform thereof more than 500 kinds.The different branches of this genome tree have been characterized as being the group of phosphorylation serine/threonine residue specifically or phosphorylated tyrosine.Some kinases shows dual specificity, and the substrate phosphorylation that can either carry out tyrosine can carry out the substrate phosphorylation of serine/threonine again.Can be according to their positions in cell with its further differentiation.The transmembrane receptor protein kinases shows ectodomain, can binding partner.These part combining mechanisms cause the activation of kinase catalytic structural domain, thereby have started the cascade signal of function in the control born of the same parents.The example of receptor protein kinase is somatomedin such as EGF, FGF, PDGF and IGF.Non-receptor protein kinase then can be found to nuclear many cells in the cell internal membrane of cell.An example of non-receptor protein kinase is a mitogen-activated protein kinase (MAPK) of regulating path important in the cell signaling, described signal conduction is to pass through somatomedin, for example VEGF or hormone start on cell outer surface, and extend to nucleus by transcriptional factors.These nfs and then in the regulate process of cell cycle process and final cell proliferation and differentiation, controlling genetic expression again.

[0004] nearly all cancer cells functional character such as immortalization, somatomedin self propagation, the insensitivity to growth inhibitory signal, transfer, blood vessel attract MAPK cell signaling path because it has influence on, escape apoptosis and other functional character, thereby are important for drug targeting.The inappropriate activation that causes by this molecule that suddenlys change and all human cancers nearly 30% relevant.Generally speaking, the inhibition of imbalance kinases (disregulatedkinases) such as Ras, PI3K and Raf is a kind of important channel of the novel therapeutic means of exploitation cancer and other disease.A kind of approach is that exploitation can be bonded to kinase catalytic structural domain or adjusted and controlled territory so that regulate the small molecules of protein kinase function.In this regard, importantly develop the molecule that suppresses the specific signal conduction path and have practical treatment effectiveness with high selectivity.Although obtaining significant progress aspect the various compounds that are used for the treatment of cancer and diseases associated with inflammation of exploitation, but still have the demand to the specificity chemical structure that can regulate protein kinase, the functional disorder of described protein kinase has related to these diseases.

Summary of the invention

[0005] the invention provides the compound that influences the MAPK path.Compound of the present invention for example can be used for treating under the situation of multiple human diseases such as cancer in the adjusting that shows the MAPK path as pharmaceutical cpd, is useful.

[0006], provide compound, perhaps their N-oxide compound, N, N '-dioxide, N, N ', N with structure (A) according to one embodiment of the present invention "-trioxide or pharmacology on acceptable salt:

Wherein Y can not exist or can be one of following part (moieties):

[0007], provide compound, perhaps their N-oxide compound, N, N '-dioxide, N, N ', N with structure (B) according to another embodiment of the present invention "-trioxide or pharmacology on acceptable salt:

Wherein X can not exist or can be NH; And Y can not exist or can be one of following part (moieties);

[0008] in compound with structure (B), Z ₁, Z ₂And Z ₃Each can be N, N=CH, CH, O, S or N-R independently ⁴, R wherein ⁴Be hydrogen or low-carbon alkyl, further condition is Z ₁, Z ₂And Z ₃In at least one is not CH.

[0009] in compound with structure (A), substituent R ₁Can be aryl, heterocycle, heteroaryl, the heterocycle of replacement and the heteroaryl of replacement of aryl, replacement.For example, R ₁Can be one of following: C ₆-C ₁₂Aryl; C ₃-C ₁₂Heteroaryl, it has 1-3 heteroatoms such as N, S and O; The C that replaces ₃-C ₁₀Cycloalkyl, it has 0-3 heteroatoms such as N, S and O; The C that replaces ₆-C ₁₂Aryl; The C that replaces ₃-C ₁₂Heteroaryl, it has 1-3 heteroatoms such as N, S and O; C ₇-C ₂₄Aralkyl; C ₇-C ₂₄Alkylaryl; The C that replaces ₇-C ₂₄Aralkyl; With the C that replaces ₇-C ₂₄Alkaryl.

[0010] in compound with structure (B), substituent R ₁Be independent of the substituent R that occurs in the structure (A) ₁, can be the C that does not replace or replace ₃-C ₁₂Heteroaryl, it has 1-3 heteroatoms such as N, S or O.The substituent R that can in compound, occur with structure (B) ₁The pyridyl that can comprise replacement.Substituting group in the pyridyl of described replacement can comprise amido part, aminoalkyl group (for example aminomethyl) or carboxylic group or carboxylate salt/ester group.The amido part that is connected in described pyridyl can be substituted by connecting substituting group on the nitrogen in described amido part again, and described substituting group is selected from alkyl (for example methyl), alkyl aminoalkyl (for example diethylin alkyl), pyridyl, alkyl pyrrolidine, alkyl morpholine and alkylpiperazine group.

[0011] the described substituent R that can in compound, occur with structure (A) or structure (B) ₁Some examples can be selected from one of lower section (moieties):

Wherein n is selected from 0,1,2 and 3 integer.

[0012] in having structure (A) or compound (B), R ₂Can be any one in following independently: hydrogen, halogen, C ₁-C ₁₈Alkyl (for example methyl) ,-OH ,-NO ₂,-CN, C ₁-C ₁₈Alkoxyl group (for example methoxyl group) ,-NHSO ₂R ⁵,-SO ₂NHR ⁵,-NHCOR ⁵,-NH ₂,-NR ⁵R ⁶,-S (O) R ⁵,-S (O) ₂R ⁵,-CO ₂R ⁵,-CONR ⁵R ⁶, R wherein ⁵And R ⁶Be independently selected from hydrogen, C ₁-C ₁₂The C of alkyl and replacement ₁-C ₁₂Alkyl.

[0013] in compound with structure (A), substituent R ₃Can be aryl, heterocycle, heteroaryl, the heterocycle of replacement and the heteroaryl of replacement of aryl, replacement.For example, R ₃Can be one of following: C ₆-C ₁₂Aryl; C ₃-C ₁₂Heteroaryl, it has 1-3 heteroatoms such as N, S and O; The C that replaces ₃-C ₁₀Cycloalkyl, it has 0-3 heteroatoms such as N, S and O; The C that replaces ₆-C ₁₂Aryl; The C that replaces ₃-C ₁₂Heteroaryl, it has 1-3 heteroatoms such as N, S and O; C ₇-C ₂₄Aralkyl; C ₇-C ₂₄Alkylaryl; The C that replaces ₇-C ₂₄Aralkyl; With the C that replaces ₇-C ₂₄Alkaryl.

[0014] in compound with structure (B), substituent R ₃Be independent of the substituent R that structure (A) occurs ₃, can be hydrogen, C ₁-C ₁₈The C of alkyl, replacement ₁-C ₁₈Alkyl, C ₁-C ₁₂The C of cycloalkyl, replacement ₁-C ₁₂Cycloalkyl, has the C of the replacement of 0-3 heteroatoms such as N, S or O ₃-C ₁₀Cycloalkyl, aryl are such as C ₆-C ₁₂The aryl of aryl, replacement is such as the C that replaces ₆-C ₁₂The heterocycle of aryl, heterocycle, replacement, heteroaryl are such as the C with 1-3 heteroatoms such as N, S or O ₃-C ₁₂The heteroaryl of heteroaryl, replacement is such as the C of the replacement with 1-3 heteroatoms such as N, S or O ₃-C ₁₂Heteroaryl, C ₇-C ₂₄The C of aralkyl, replacement ₇-C ₂₄Aralkyl, C ₇-C ₂₄The C of alkylaryl and replacement ₇-C ₂₄Alkaryl.Operable substituent R ₃Some specific exampless comprise tert-butyl-phenyl, Trifluoromethoxyphen-l, p-methoxy-phenyl, dimethylaminophenyl, aminophenyl, trifluoro ethoxy phenyl, trifluoromethoxy chloro-phenyl-, trifluoro-methoxyl bromobenzene base, trifluoro ethoxy chloro-phenyl-, chloro-phenyl-, dichlorophenyl, trifluoromethyl, trifluoromethyl chloro-phenyl-, chloromethane phenyl, phenyl acetanilide,Phenacetylaniline, N, N-alkyl-benzamide, isopropyl phenyl, alkoxyl phenyl, dialkoxy phenyl or acetyl phenyl.

[0015] briefly, the described substituent R that can in compound, occur with structure (A) or structure (B) ₃Some examples can be selected from one of following part (moieties):

[0016] according to another embodiment of the present invention, compound as phentriazine derivative is provided, described compound comprises the phentriazine part, second substituting group that it has first substituting group of at least one phenyl ring that is connected in phentriazine and is connected in the triazine ring of phentriazine, wherein said first substituting group comprises the pyridyl of replacement, and described second substituting group comprises the amide group of secondary amino group, replacement or the sulfonamido of replacement.

[0017] according to another embodiment of the invention; the compound that comprises the benzenesulfonamide derivative part (benzene-derived moiety) that bridges at heterocyclic moiety is provided; wherein said benzenesulfonamide derivative partly comprises the benzene molecular that replaces with alkylsulfonyl group or pyridyl group; the logical peroxide bridge of described pyridyl group is connected in described benzene molecular, and described heterocyclic moiety comprises triazole, oxadiazole, oxazole, pyrazoles, imidazoles, thiadiazoles and triazine.

[0018] according to another embodiment of the invention, goods are provided, described goods comprise wrapping material and the pharmaceutical composition that is included in these wrapping material, and wherein said wrapping material comprise label, and it has shown that this pharmaceutical composition can be used to treat the illness relevant with cancer.Described pharmaceutical composition can comprise structure (A) and (B) in illustrated at least a compound or their any combination.

[0019] according to another embodiment, sanatory method comprises compound from significant quantity to the object of needs treatments that use, and wherein said compound is in structure (A) and (B) or in their any combination illustrated.

[0020] on the one hand, described illness for example is cancer, illness in eye, inflammation, psoriatic or virus infection.More specifically, described cancer is esophagus/gastrointestinal cancer, colorectal carcinoma, liver cancer, skin carcinoma, mammary cancer, ovarian cancer, prostate cancer, lymphoma, leukemia, kidney, lung cancer, flesh cancer, osteocarcinoma, bladder cancer or the cancer of the brain.

[0021] according to another embodiment, a kind of pharmaceutical composition is provided, structure (A) and (B) or at least a compound of illustrating in their any combination on pharmacology in the acceptable carrier.

Description of drawings

[0022] Fig. 1 represents the result that the Raf1 of The compounds of this invention directly tests.

[0023] Fig. 2 represents the result of the XTT cell viability test of The compounds of this invention.

Detailed Description Of The Invention

[0024] the present invention relates to heterocyclic compound, such as the heterocyclic compound that is derived from phentriazine, triazine, triazole, oxadiazole, imidazoles and thiadiazoles, and described heterocyclic compound is used for the treatment of the purpose application.

[0025] following term and definition are employed, and as used among the application, they generally meet the terminology that international applications and pure chemical combined meeting (IUPAC) are recommended.

[0026] term " heterocycle " when being used for describing aromatic rings, means that described aromatic rings comprises at least one hetero atom. Abbreviation " Het " is used to indicate heterocycle structure sometimes.

[0027] " " hetero atom " is defined as comprising any atom except carbon atom, for example N, O or S to term.

[0028] term " aromatics " or " aryl " are defined as comprising the cyclic conjugated molecular entity with stability, because the delocalization effect, its stability is significantly greater than the localization structure of supposing, such as Kai Kule (Kekul é) structure.

[0029] term " heterocycle " when not being used to describe aromatic rings, is defined as comprising ring-type (namely the containing ring) group of non-aromatic group, and described cyclic group is to form to about 14 carbon atoms and at least one above-mentioned hetero atom by 3.

[0030] term " heterocycle of replacement " is defined as comprising the heterocyclic group of fragrance or non-aromatic structure, and it is further with one or more above-mentioned substituting groups.

[0031] term " alkyl " is defined as comprising unit price straight or branched alkyl, it has 1 to about 12 carbon atoms, for example methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, n-pentyl (being also referred to as n-amyl), n-hexyl and similar group. Abbreviation " Me " and " Et " be represent methylidene and ethyl respectively.

[0032] term " aralkyl " refers to that described aryl or heteroaryl are as defined herein by aryl or the heteroaryl of the connection of C1-C6 alkyl joint. The example of " aralkyl " includes, but not limited to benzyl, phenyl propyl, 2-pyridylmethyl, 3-isoxazolyl methyl, 2-imidazole radicals ethyl.

[0033] term " methoxyl group " is defined as group-OCH₃。

[0034] term " halogen " is defined as comprising the atom of fluorine, chlorine, bromine or iodine.

[0035] term " carboxyl " or " carboxylic group " are defined as having the acid moieties of structure-COOH.

[0036] term " amino " or " amino group " are defined as comprising-NRR ' part, wherein R and R ' are hydrogen (" primary amino radicals "), perhaps they one of be organic group (" secondary amino group "), perhaps they all are organic group (" uncle amino ").

[0037] term " aminoalkyl " or " aminoalkyl group " are defined as comprising-R-N (R ' R ") part, and wherein R is organic group, R ' and R " each naturally hydrogen or organic group. If R ' and R " in be organic group one of at least, then described part namely is defined as " alkyl aminoalkyl " or " alkyl aminoalkyl group ".

[0038] term " sulfonyl " or " sulfonyl group " are defined as comprising the part that comprises structure (S), and wherein R is organic group:

[0039] term " sulfonamido " or " sulfonamido group " are defined as comprising the part that comprises structure (Sa), and wherein R is organic group:

[0040] term " acid amides " or " acylamino-" or " amide group " or " acylamino-group " are defined as comprising and comprise the part that at least one is connected in the carboxyl groups＞C=O of nitrogen. Term " acid amides of replacement " is defined as comprising the part that comprises structure RNH-CO-, and wherein R is organic group.

[0041] term " phenyl " is defined as comprising the part with structure (Ph):

[0042] term " tolyl (toluyl) " is defined as comprising the part with structure (TI):

[0043] term " heteroaryl " is defined as comprising aromatic ring, wherein said ring structure is to form to about 14 carbon atoms and at least one above-mentioned hetero atom by 3, and term " heteroaryl of replacement " refers to further with one or more above-mentioned substituent heteroaryl groups.

[0044] term " triazine " is defined as comprising the part that contains fragrant hexa-member heterocycle, and described hexa-member heterocycle contains 3 nitrogen-atoms in this ring. Shown in two following array structures of example (Tr) of this type of heterocycle:

[0045] term " phentriazine " is defined as comprising the part that contains heterocycle structure, and wherein triazine ring and phenyl ring condense, shown in structure (BTr):

【0046】

[0047] term " N-oxide ", " N, N '-dioxide " and " N, N ', N "-trioxide " be defined as comprising nitrogenous heterocyclic moiety, wherein at least one nitrogen-atoms and oxygen link to form structure N → O. Described heterocyclic moiety can be any nitrogen heterocyclic ring, such as phentriazine, triazine, pyridine, pyrimidine etc. For example, be in the situation of phentriazine at described heterocycle structure, some N-oxides or dioxide can be described to lower array structure:

[0048] term " pteridine (pteridine) " is defined as comprising that the part that contains heterocycle structure, described heterocycle structure contain two condensed six-rings, and each ring contains two nitrogen-atoms, shown in structure (PTr):

[0049] term " pyridazine " is defined as comprising and contains 6 yuan of heterocyclic parts of fragrance, and described fragrant 6 yuan of heterocycles contain two ortho position nitrogen-atoms in ring, shown in structure (PAz):

[0050] term " pyrimidine " is defined as comprising and contains 6 yuan of heterocyclic parts of fragrance, and described fragrant 6 yuan of heterocycles contain position nitrogen-atoms between two in ring, shown in structure (PRm):

[0051] term " thiadiazoles " is defined as comprising the 5 yuan of heterocyclic parts of fragrance that contain based on thiophene, and it contains two nitrogen-atoms and a sulphur atom, shown in structure (TDa):

[0052] term " pyridyl " is defined as comprising the part that contains derived from the group of pyridine.A kind of structure of pyridyl is shown in structure (Py):

[0053] term " alkyl pyrrolidine " is defined as comprising the part that contains derived from the group of tetramethyleneimine (a kind of 5 yuan of saturated heterocyclics that contain a nitrogen-atoms), and wherein alkylidene group R is connected on the nitrogen-atoms of pyrrolidine ring.A kind of structure of alkyl pyrrolidine is shown in structure (APy):

[0054] term " alkyl morpholine " is defined as comprising the part that contains derived from the group of morpholine (a kind of 6 yuan of saturated heterocyclics that contain a nitrogen-atoms and a Sauerstoffatom), and wherein alkylidene group R is connected on the nitrogen-atoms of morpholine ring.A kind of structure of alkyl morpholine is shown in structure (AMr):

[0055] term " alkylpiperazine " is defined as comprising the part that contains derived from the group of piperazine (a kind of 6 yuan of saturated heterocyclics that contain two nitrogen-atoms), and wherein alkylidene group R is connected on the nitrogen-atoms of piperazine ring.A kind of structure of alkylpiperazine is shown in structure (APi):

[0056] term “ isoxazole " be defined as comprising and contain 5 yuan of heterocyclic parts of fragrance, described fragrant 5 yuan of heterocycles contain a nitrogen-atoms and a Sauerstoffatom, shown in structure (ISo):

[0057] term " hydrophobic " be defined as not containing strong polar group such as-OH ,-COOH ,-NH ₂The group of ,-NH-CO-, halogen or similar group or structure.

[0058] term " kinases " is defined as comprising that catalysis is added into phosphate group any enzyme of residue of protein; For example, Serine and threonine kinase enzyme catalysis are added into Serine and threonine residues with phosphate group.

[0059] term " significant quantity in the treatment " is defined as the amount of compound or pharmaceutical composition, it will cause tissue that researchist, animal doctor, doctor or other clinical positions person look for, system, animal or human's biology or medical response, for example recover or keep the damage or the infringement of blood vessel stable state or prevention blood vessel stable state; The ameliorate tumor burden; Reduce sickness rate and/or lethality rate.

[0060] term " acceptable on the pharmacology " is defined as a kind of carrier, no matter thinner or vehicle, all with the prescription in other composition compatible and harmless to its recipient.

[0061] term administering compound (administration of a compound) " or " administered compound (administrating a compound) " be defined as comprising the behavior that compound of the present invention or pharmaceutical composition is offered the object of needs treatment.

[0062] according to the embodiment of the present invention, provide two types heterogeneous ring compound to be used for the treatment of multiple disease, illness and symptom, comprised cancer.Heterogeneous ring compound of the present invention can suppress kinases such as any kinase whose activity in the MAPK signal path.

[0063] according to the embodiment of the present invention, provide the compound of the first kind to be used for the treatment of multiple disease, illness and symptom, comprised cancer.The compound of the described first kind can comprise the derivative of phentriazine.The derivative of operable phentriazine can comprise the compound that contains the phentriazine part, the substituting group that described phentriazine partly has at least one phenyl ring that is connected in phentriazine is connected in the substituting group of the triazine ring of phentriazine with at least one, and their N-oxide compound, N, N '-dioxide, N, N ', N "-trioxide or pharmacology on acceptable salt.

[0064] substituting group that is connected in the phenyl ring of phentriazine can comprise the pyridyl group of replacement.Substituting group in the pyridyl group that replaces can comprise amido part, aminoalkyl group (for example aminomethyl) or carboxylic group or carboxylate salt/ester group.The amido part that is connected in described pyridyl group can be substituted by connecting substituting group on the nitrogen in described amido part again, and described substituting group is selected from alkyl (for example methyl), alkyl aminoalkyl (for example diethylin alkyl), pyridyl, alkyl pyrrolidine, alkyl morpholine and alkylpiperazine group.

[0065] alternatively, the phenyl ring of described first kind compound can comprise and is positioned at this and encircles second substituting group on any available position, for example methyl, halogen or methoxyl group.Operable some specific exampless that contain the phenyl ring part comprise tert-butyl-phenyl, Trifluoromethoxyphen-l, p-methoxy-phenyl, dimethylamino, dimethylaminophenyl, aminophenyl, trifluoro ethoxy phenyl, trifluoromethoxy chloro-phenyl-, trifluoro-methoxyl bromobenzene base, trifluoro ethoxy chloro-phenyl-, chloro-phenyl-, dichlorophenyl, trifluoromethyl, trifluoromethyl chloro-phenyl-, chloromethane phenyl, phenyl acetanilide,Phenacetylaniline, N, N-alkyl-benzamide, isopropyl phenyl, alkoxyl phenyl, dialkoxy phenyl or acetyl phenyl.

[0066] substituting group that is connected in the triazine ring of phentriazine in the first kind compound can comprise the amide group of secondary amino group, replacement or the sulfonamido group of replacement; Each of these groups can further contain the part derived from benzene, thiophene Huo isoxazole.If being connected in the substituting group of the triazine ring of phentriazine in the first kind compound is secondary amino group, then described part derived from benzene, thiophene Huo isoxazole can be connected on the nitrogen of described secondary amino group.If the substituting group in the triazine ring is the amide group of replacement or the sulfonamido group of replacement, then described part derived from benzene, thiophene Huo isoxazole can be connected by acetyl group or sulfonyl group respectively.Part derived from benzene, thiophene or isoxazole may further include alkyl, for example tert-butyl-phenyl, chloro-phenyl-, dichlorophenyl, trifluoromethyl, trifluoromethyl chloro-phenyl-and chloromethane phenyl.

[0067] compound of the described first kind can be described to have the compound of formula (A), and their N-oxide compound, N, N '-dioxide, N, N ', N "-trioxide or pharmacology on acceptable salt.(A) is as follows for described formula:

Wherein Y can not exist or can be one of following part (moieties):

[0068] in structure (A), R ₁Can be aryl, heterocycle, heteroaryl, the heterocycle of replacement and the heteroaryl of replacement of aryl, replacement, such as C ₆-C ₁₂Aryl; C ₃-C ₁₂Heteroaryl, it has 1-3 heteroatoms such as N, S and O; The C that replaces ₃-C ₁₀Cycloalkyl, it has 0-3 heteroatoms such as N, S and O; The C that replaces ₆-C ₁₂Aryl; The C that replaces ₃-C ₁₂Heteroaryl, it has 1-3 heteroatoms such as N, S and O; C ₇-C ₂₄Aralkyl; C ₇-C ₂₄Alkylaryl; The C that replaces ₇-C ₂₄Aralkyl; With the C that replaces ₇-C ₂₄Alkaryl.Particularly, R ₁Can be any in the following part:

Wherein n is selected from 0,1,2 and 3 integer.

[0069] in structure (A), substituent R ₂One of can be following: hydrogen, halogen, C ₁-C ₁₈Alkyl (for example methyl) ,-OH ,-NO ₂,-CN, C ₁-C ₁₈Alkoxyl group (for example methoxyl group) ,-NHSO ₂R ⁵,-SO ₂NHR ⁵,-NHCOR ⁵,-NH ₂,-NR ⁵R ⁶,-S (O) R ⁵,-S (O) ₂R ⁵,-CO ₂R ⁵,-CONR ⁵R ⁶, R wherein ⁵And R ⁶Be independently selected from hydrogen, C ₁-C ₁₂The C of alkyl and replacement ₁-C ₁₂Alkyl.

[0070] in structure (A), radicals R ₃Can be aryl, heterocycle, heteroaryl, the heterocycle of replacement and the heteroaryl of replacement of aryl, replacement.For example, R ₃Can be one of following: C ₆-C ₁₂Aryl; C ₃-C ₁₂Heteroaryl, it has 1-3 heteroatoms such as N, S and O; The C that replaces ₃-C ₁₀Cycloalkyl, it has 0-3 heteroatoms such as N, S and O; The C that replaces ₆-C ₁₂Aryl; The C that replaces ₃-C ₁₂Heteroaryl, it has 1-3 heteroatoms such as N, S and O; C ₇-C ₂₄Aralkyl; C ₇-C ₂₄Alkylaryl; The C that replaces ₇-C ₂₄Aralkyl; With the C that replaces ₇-C ₂₄Alkaryl.Particularly, substituent R ₃Can be one of following part:

[0071] some general examples of the described compound of formula (A) comprise have formula (I) compound, have formula (II) compound, have the compound of formula (III) or have the compound of formula (IV):

[0072] some limiting examples of the described particular compound of operable formula (A) comprise the compound of (1)-(33) that have formula:

[0073] phentriazine derivative above-described and that set forth with formula (A) can prepare shown in scheme I:

[0074] in order to prepare intermediate product A, wherein R ₁Be 2-pyridine carboxamide for example, the synthetic route shown in can operational version II:

[0075] as seen at scheme II, intermediate product A synthetic needs to use 4-chloro-2-pyridine carboxamide 4, and it can be synthetic in advance individually shown in scheme III:

Formula (IV) phentriazine derivative described and that set forth with formula (A) can prepare shown in scheme IV:

[0076] according to the embodiment of the present invention, provide the compound of second type to be used for the treatment of multiple disease, illness and symptom, comprised cancer.The compound of described second type can comprise the benzenesulfonamide derivative part of bridging in heterocyclic moiety, or acceptable salt on their pharmacology.Bridge between described benzenesulfonamide derivative part and the heterocyclic moiety can comprise singly-bound or nitrogen-atoms.If described heterocyclic moiety contains at least one nitrogen-atoms, then this second type compound can be N-oxide compound or N, N '-dioxide or N, N ', N "-trioxide.

[0077] whether described compound can be N-oxide compound or N, N '-dioxide or N, N ', N "-trioxide, be decided by nitrogen-atoms number contained in the heterocyclic moiety.For example, if heterocyclic moiety only contains a nitrogen, then this second type compound can be the N-oxide compound.If heterocyclic moiety contains two nitrogen-atoms, then this second type compound can be N-oxide compound or N, N '-dioxide.If heterocyclic moiety contains three nitrogen-atoms, then this second type compound can be N-oxide compound, N, N '-dioxide, N, N ', N "-any in the trioxide.

[0078] described benzenesulfonamide derivative part can comprise that substituting group such as logical peroxide bridge is connected in the pyridyl group of benzene molecular, perhaps sulfonyl group.The pyridyl group that is connected in benzene molecular can further be replaced.Substituting group in the pyridyl group can comprise the same section (moieties) that is used for first kind compound of the present invention as mentioned above.The sulfonyl group that is connected in benzene molecular also can further be substituted.Substituting group in the sulfonyl group can comprise the above-mentioned pyridyl group that is used for the replacement of first kind compound of the present invention.

[0079] alternatively, the benzenesulfonamide derivative of described second type compound part can contain second substituting group, for example methyl, halogen or methoxyl group, and it can be positioned at any position of phenyl ring.Some exemplary benzenesulfonamide derivative parts that can be included in second type compound can comprise tert-butyl-phenyl, Trifluoromethoxyphen-l, p-methoxy-phenyl, dimethylamino, dimethylaminophenyl, aminophenyl, trifluoro ethoxy phenyl, trifluoromethoxy chloro-phenyl-, trifluoro-methoxyl bromobenzene base, trifluoro ethoxy chloro-phenyl-, chloro-phenyl-, dichlorophenyl, trifluoromethyl, trifluoromethyl chloro-phenyl-, chloromethane phenyl, phenyl acetanilide,Phenacetylaniline, N, N-alkyl-benzamide, isopropyl phenyl, alkoxyl phenyl, dialkoxy phenyl, acetyl phenyl.

[0080] compound of described second type comprises the have formula heterogeneous ring compound of (B), perhaps their N-oxide compound, N, N '-dioxide, N, N '; N " acceptable salt on-trioxide or the pharmacology, they can suppress kinases such as any kinase whose activity in the MAPK signal path.Described formula (B) can be expressed as followsin:

[0081] in structure (B), Z ₁, Z ₂And Z ₃In each can be N, CH, N=CH, O, S or N-R independently ⁴, R wherein ⁴Be hydrogen or low-carbon alkyl, condition is Z ₁, Z ₂And Z ₃In be not CH one of at least; X can not exist or NH; Y can not exist or can be one of following part:

[0082] further, in structure (B), substituent R ₁, R ₂And R ₃Can be as follows:

[0083] R ₁Can be the C that does not replace or replace ₃-C ₁₂Heteroaryl, it has 1-3 heteroatoms such as N, S or O;

[0084] R ₂Can be any one in following: hydrogen, halogen, C ₁-C ₁₈Alkyl (for example methyl) ,-OH ,-NO ₂,-CN, C ₁-C ₁₈Alkoxyl group (for example methoxyl group) ,-NHSO ₂R ⁵,-SO ₂NHR ⁵,-NHCOR ⁵,-NH ₂-NR ⁵R ⁶,-S (O) R ⁵,-S (O) ₂R ⁵,-CO ₂R ⁵,-CONR ⁵R ⁶, R wherein ⁵And R ⁶Be independently selected from hydrogen, C ₁-C ₁₈The C of alkyl and replacement ₁-C ₁₂Alkyl; And

[0085] R ₃Can be hydrogen, C ₁-C ₁₈The C of alkyl, replacement ₁-C ₁₂Alkyl, C ₁-C ₁₂The C of cycloalkyl, replacement ₁-C ₁₂The C of cycloalkyl, replacement ₃-C ₁₀Cycloalkyl, it has 0-3 heteroatoms such as N, S or O, aryl such as C ₆-C ₁₂The aryl of aryl, replacement is such as the C that replaces ₆-C ₁₂The heterocycle of aryl, heterocycle, replacement, heteroaryl are such as C ₃-C ₁₂Heteroaryl, its heteroaryl with 1-3 heteroatoms such as N, S or O, replacement is such as the C that replaces ₃-C ₁₂Heteroaryl, it has 1-3 heteroatoms such as N, S or O, C ₇-C ₂₄The C of aralkyl, replacement ₇-C ₂₄Aralkyl, C ₇-C ₂₄The C of alkylaryl and replacement ₇-C ₂₄Alkaryl.

[0086] substituent R ₁Can comprise the pyridyl of replacement or the pyrimidyl group of replacement.Substituting group in the pyrimidyl group of the pyridyl of described replacement or replacement can comprise amido part, aminoalkyl group (for example amino methyl) or carboxylic group or carboxylate salt/ester group.The amido part that is connected in described pyridyl/pyrimidyl group can be substituted by connecting substituting group on the nitrogen in described amido part again, and described substituting group is selected from alkyl (for example methyl), alkyl aminoalkyl (for example diethylin alkyl), pyridyl, alkyl pyrrolidine, alkyl morpholine and alkylpiperazine group.

[0087] particularly, can be used in R in the compound with structure (B) ₁Limiting examples comprise any following part:

Wherein n is selected from 0,1,2 and 3 integer.

[0088] can be used in R in the compound with structure (B) ₃Some concrete limiting examples comprise tert-butyl-phenyl, Trifluoromethoxyphen-l, p-methoxy-phenyl, dimethylaminophenyl, aminophenyl, trifluoro ethoxy phenyl, trifluoromethoxy chloro-phenyl-, trifluoro-methoxyl bromobenzene base, trifluoro ethoxy chloro-phenyl-, chloro-phenyl-, dichlorophenyl, trifluoromethyl, trifluoromethyl chloro-phenyl-, chloromethane phenyl, phenyl acetanilide,Phenacetylaniline, N, N-alkyl-benzamide, isopropyl phenyl, alkoxyl phenyl, dialkoxy phenyl and acetyl phenyl.These parts and still can be used as substituent R ₃Other parts (moieties) can be illustrated as follows:

Wherein n is selected from 0,1,2 and 3 integer, and R ' is hydrogen, C ₁-C ₁₈The C of alkyl or replacement ₁-C ₁₈Alkyl.

[0089] some general examples of the described compound of formula (B) comprise the have formula compound of (V)-(XXVIII):

[0090] 1,2, under the situation of 4-triazole, there are three kinds of tautomeric structures, as follows:

[0091] which kind of tautomeric structure is preponderated and is decided by substituting group and reaction conditions on the triazole part.As known to persons of ordinary skill in the art, usually, 1H-1,2, the 4-triazole is modal tautomeric form, if particularly amino substituting group is connected to this ring when going up.Although whole three kinds of tautomeric structures all can occur, for the sake of simplicity and for its direct analogue such as containing 1,3, the example of 4-oxadiazole part compares, have 1,2, all categories structure of 4-triazole part and all examples in this article with a kind of tautomeric form 4H-1 for example, 2, the 4-triazole is represented.For the sake of simplicity, only use the 4H-tautomeric form to describe described structure and do not mean that example shown below (30)-(74) compound all is to exist with this concrete tautomeric form.

[0092] some examples of the described particular compound of formula (B) comprise the compound of (34)-(83) that have formula:

[0093] 1,2 of the suitable replacement of above-mentioned (V) class of using formula (B) elaboration, the 4-triazole can use one of some kinds of reaction scheme to be synthesized, for example shown in following plan V, VI and VII.According to the availability and the easy degree of synthetic of desired replacement, parent material, can select appropriate means.

[0094] 1,2 of above-mentioned (VI) class, the 4-triazole can be shown in plan V III or by being prepared as generalized optional route among the scheme IX.

[0095] (VIII) the 2-amino-1,3 of the suitable replacement of class, the 4-oxadiazole can use one of some kinds of reaction scheme to be synthesized, for example, shown in scheme X, XI and XII.

[0096] (IX) the 2-amino-1,3 of the suitable replacement of class, the 4-oxadiazole can use one of some kinds of reaction scheme to be synthesized, for example, shown in scheme XIII and XIV.

[0097] (XI) the 2-amino-1,3 of the suitable replacement of class, the 4-thiadiazoles can be prepared by generalized method among the scheme XV.

[0098] (XII) the 2-amino-1,3 of the suitable replacement of class, the 4-thiadiazoles can be prepared by generalized method among the scheme XVI.

[0099] (XXIII)-(XXV) the 3-amino-1,2 of the suitable replacement of class, the 4-triazine can be prepared by generalized method among the scheme XVII.

(XXVI)-(XXVIII) the 3-amino-1,2 of the suitable replacement of class, the 4-triazine can be prepared by generalized method among the scheme XVIII.

[0100] Compounds and methods for of the present invention, no matter using separately or the time with other medicament (for example chemotherapeutic of the following stated or protein for treatment agent) combined administration, all be useful aspect the treatment various disease conditions, described illness comprises, but be not limited to, for example cancer, illness in eye, inflammation, psoriatic and virus infection.Treatable cancer kind includes, but not limited to esophagus/gastrointestinal cancer, colorectal carcinoma, liver cancer, skin carcinoma, mammary cancer, ovarian cancer, prostate cancer, lymphoma, leukemia, kidney, lung cancer, flesh cancer, osteocarcinoma, bladder cancer or the cancer of the brain.

[0101] embodiments of the present invention also provide goods, and it can comprise wrapping material and the pharmaceutical composition that is contained in these wrapping material.Wrapping material can comprise label, and it indicates this pharmaceutical composition can be used to top described one or more treatment of conditions.

[0102] described pharmaceutical composition can comprise compound of the present invention.Except that compound of the present invention, this medicine can also comprise other therapeutical agent, and can be according to the known technology of medicine formulation art, for example pass through to use traditional solid or liquid vehicle or thinner, and the medicated premix of the method for application type that is suitable for expecting (for example vehicle, tackiness agent, sanitas, stablizer, seasonings etc.) is prepared.

[0103] therefore, in one embodiment, the invention provides pharmaceutical composition, comprise therapeutical agent and compound of the present invention.This compound is to exist for the effective concentration of treatment cancer.

[0104] can be formulated into natural form or salt form be therapeutic composition to compound of the present invention.Acceptable non-toxic salt comprises base addition salt (forming with free carboxy or other anionic group) on the pharmacology, its can be derived from mineral alkali such as, for example sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide or ironic hydroxide, and organic bases such as Isopropylamine, Trimethylamine 99,2-ethylamino-ethanol, Histidine, PROCAINE HCL, PHARMA GRADE and similar organic bases.This type of salt also can form acid salt with any free cations group, and generally can with mineral acid such as, for example hydrochloric acid, sulfuric acid or phosphoric acid, perhaps organic acid such as acetate, citric acid, tosic acid, methylsulfonic acid, oxalic acid, tartrate, amygdalic acid and similarly organic acid formation.

[0105] salt of the present invention can comprise the amine salt that the protonation by amino group and mineral acid forms, all example hydrochloric acids of described mineral acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, phosphoric acid and similar mineral acid.Salt of the present invention also can comprise the amine salt that the protonation by amino group and appropriate organic forms, described organic acid such as tosic acid, acetate, methylsulfonic acid and similar organic acid.Other vehicle that is considered in the present invention's practice is the available vehicle of those of ordinary skills, for example at the United StatesPharmacopeia Vol.XXII and National Formulary Vol.XVII, U.S.PharmacopeiaConvention, Inc., Rockville, those vehicle that can find among the MD (1989), the associated viscera of the document is incorporated this paper into as a reference at this.In addition, the polymorphic form of The compounds of this invention is included among the present invention.

[0106] pharmaceutical composition of the present invention can be to contain the dosage unit preparations form of acceptable carrier on the atoxic pharmacology or thinner, be applied by any suitable mode, for example oral, such as form with tablet, capsule, particle or pulvis; Take in the hypogloeeis; Orally administer; Parenteral is taken, such as by in subcutaneous, intravenously, intramuscular, the sheath or intracisternal injection or infusion techniques (for example, as the injectable water of sterilization or non-aqueous solution or suspension); Intranasal is taken, such as passing through to suck spray; Topical application is such as with emulsion or ointment form; Perhaps rectal administration is such as the form with suppository.This compound can, for example be applied with the form that is suitable for discharging immediately or postpone to discharge.Comprise the suitable pharmaceutical compositions of The compounds of this invention by use, can realize discharging immediately or postpone and discharge, perhaps postponing to use device under the situation about discharging especially such as hypodermic implant or osmotic pump.The compounds of this invention also can be used by liposome.

[0107] except that primate such as the mankind, various other lactations also can be treated according to method of the present invention.For example, treatable Mammals includes, but not limited to ox, sheep, goat, horse, dog, cat, cavy, rat or other Bovidae, sheep section, equine, Canidae, cat family, rodents or murine.But present method also can be used in other species such as birds (for example chicken).

[0108] is used to use the pharmaceutical composition of the compound of this embodiment,, can be easily exists, and prepared by the known any method of pharmacy field with the form of dose unit no matter use separately or during with other therapeutical agent combined administration.All methods comprise that the carrier that makes activeconstituents and constitute one or more ancillary components is linked together.Generally speaking, pharmaceutical composition is by evenly closely activeconstituents being incorporated among liquid vehicle or pulverizing solid carrier or both, then if necessary, is required preparation and being prepared with product machine-shaping.In this pharmaceutical composition, the amount that active target compound is comprised is enough to the process of disease or symptom are produced required effect.The pharmaceutical composition that contains activeconstituents can be to be suitable for oral form, for example tablet, spray, lozenge, water quality or oleagenous suspension, dispersible pulvis or particle, emulsion, hard or soft capsule or syrup or elixir.

[0109] being intended to be used for oral composition can make the known any method in field according to pharmaceutical composition and prepared, and this based composition can comprise one or more reagent, it is selected from sweeting agent, seasonings, tinting material and sanitas, so that good to eat preparation outstanding in the pharmacy is provided.The activeconstituents that tablet comprises be present in atoxic pharmacy in the mixture of acceptable vehicle, described vehicle is suitable for tablet processing.These vehicle can be, for example inert diluent such as lime carbonate, yellow soda ash, lactose, calcium phosphate or sodium phosphate; Granulating agent and disintegrating agent, for example W-Gum or alginic acid; Tackiness agent, for example starch, gelatin or Sudan Gum-arabic, and lubricant, for example Magnesium Stearate, stearic acid or talcum.Described tablet can be do not wrap quilt or can be by known technology bag quilt, postponing its disintegration and absorption in gi tract, thereby in one long period, provide persistent effect.For example, can use time-delay material such as glyceryl monostearate or distearin.They also can be coated to be formed for the osmotic therapeutic tablets that controllability discharges.

[0110] being used for oral preparation also can exist with the form of hard gelatin capsule, wherein activeconstituents and inert solid diluent, for example lime carbonate, calcium phosphate or kaolin mix mutually, perhaps the form with soft capsule exists, wherein activeconstituents and water medium or oily medium, for example peanut oil, whiteruss or the mixing of olive oil phase.

[0111] aq suspension comprises and the vehicle that is suitable for processing aq suspension blended active substance mutually.This type of vehicle is a suspension agent, for example Xylo-Mucine, methylcellulose gum, Vltra tears, sodiun alginate, polyvinylpyrrolidone, tragacanth gum and Sudan Gum-arabic; Dispersion agent or wetting agent can be naturally occurring phosphatide, Yelkin TTS for example, the perhaps polycondensation product of oxyalkylene and lipid acid, the polycondensation product of polyoxyethylene stearic acid ester or oxyethane and long chain aliphatic alcohol for example, Shi seven ethylene oxy Ji Whale ceryl alcohols for example, perhaps oxyethane with come from the polycondensation product of the part ester class of lipid acid and hexitol, octadecanoic acid ester of polyethylene glycol for example, perhaps oxyethane with come from the polycondensation product of the part ester class of lipid acid and hexitan, polyethylene sorbitanic monoleate for example.As solubilizing agent same useful for example be polyoxyethylene glycol.Aq suspension also can comprise one or more sanitass, for example ethyl p-hydroxybenzoate or P-hydroxybenzoic acid n-propyl, one or more tinting materials, one or more seasoningss and one or more sweeting agents such as sucrose or asccharin.

[0112] oleagenous suspension can be by being suspended in vegetables oil with activeconstituents, and for example peanut oil, sweet oil, sesame oil or cocounut oil perhaps are suspended in mineral oil such as whiteruss and are carried out preparation.Oleagenous suspension can comprise thickening material, for example beeswax, paraffinum durum or cetyl alcohol.Can add such as top those illustrated sweeting agents and seasonings so that good to eat oral preparations to be provided.These compositions can be preserved by adding antioxidant such as xitix.

[0113] being adapted to pass through the dispersible powder that adds water and make water quality suspension and particle provides and dispersion agent or wetting agent, suspension agent and one or more sanitass blended activeconstituents mutually.Suitable dispersion agent or wetting agent and suspension agent are illustrated by above mentioned those materials.Other vehicle, for example sweeting agent, seasonings and tinting material also can exist.

[0114] syrup and elixir can with sweeting agent, for example glycerol, propylene glycol, sorbyl alcohol or sucrose are prepared together.This type of preparation also can contain negative catalyst, sanitas and seasonings and tinting material.

[0115] described pharmaceutical composition can be the injectable water quality suspension of sterilization or the form of oleagenous suspension.According to known technology, this suspension can use those the suitable dispersion agents mentioned or wetting agent and suspension agent to be prepared in the above.The injectable formulation of described sterilization also can be the injection solution or the suspension of sterilization, it is present in parenteral acceptable diluent or solvent or cosolvent or complex reagent or dispersion agent or vehicle or their combination, 1,3 butylene glycol for example, polyoxyethylene glycol, polypropylene glycol, ethanol or other alcohols, polyvidone (povidones), the TWEEN tensio-active agent of various brands, sodium lauryl sulphate, Sodium desoxycholate, N,N-DIMETHYLACETAMIDE, polysorbate, poloxamer (poloxamer), cyclodextrin, lipid, with vehicle such as inorganic salt (for example sodium-chlor), buffer reagent (Trisodium Citrate for example, sodium phosphate) and carbohydrate (for example sucrose and glucose).Acceptable carrier that can be used and solvent are water, glucose solution, Ringer's solution and isotonic sodium chlorrde solution.In addition, aseptic fixed oil is used as solvent or suspension medium routinely.For this purpose, any temperature that comprises synthetic glycerine monoesters or triglyceride is closed fixed oil and can be used.In addition, lipid acid can be used in the injectable formulation such as oleic acid.

[0116] according to the symptom of being treated, these pharmaceutical compositions can be by preparation and general or topical application.Preparation and application technique can be found in " Remington ' s Pharmaceutical Sciences " (MackPublishing Co, the Easton Pa.) of latest edition.Suitable way can, for example, comprise oral administration with or mucosal administration; And parenteral carries, and comprises in intramuscular, subcutaneous, the marrow, sheath is interior, indoor, intravenously, intraperitoneal or intranasal administration.For injection, pharmaceutical composition of the present invention can be at the aqueous solution, preferably prepares in such as Hank ' s solution, ringer's solution or physiological buffer salt solution at the physiological compatibility damping fluid.Use for tissue or cell, be suitable for and be used in the described preparation by the permeate agent of the concrete barrier that be permeated.This type of permeate agent generally is known in the art.Be used for the aqueous solution that pharmaceutical preparation that parenteral uses comprises the active compound of water-soluble form.In addition, the suspension of active compound can be made into suitable oily injectable suspensions.Suitable lipophilic solvent or carrier comprise fatty oil such as sesame oil or synthetic fatty acid ester such as ethyl oleate or triglyceride level or liposome.The water quality injectable suspensions can comprise the material that increases suspension viscosity, such as Xylo-Mucine, sorbyl alcohol or dextran.Randomly, described suspension also can comprise suitable stabilizers or increase described compound dissolution degree so that the reagent of preparation height concentrated solution.

[0117] for the rectal administration medicine, compound of the present invention also can be used with the form of suppository.These compositions can be made by medicine and suitable non-irritating excipient are mixed mutually, and described non-irritating excipient is solid under ordinary temp, but are liquid in rectal temperature, discharge described medicine thereby therefore will melt in rectum.This type of material is theobroma oil and polyoxyethylene glycol.

[0118] uses for the part, can use emulsion, ointment, gel, solution or the suspension etc. that contain The compounds of this invention.(for this purposes, topical application will comprise collutory and gargle).

[0119] in one embodiment, The compounds of this invention and anti-inflammatory agent, antihistaminic, chemotherapeutic, immunomodulator, therapeutic antibodies or kinases inhibitor, for example the tyrosine kinase inhibitor combined administration is in the object of this type of treatment of needs.Be not to want restriction, chemotherapeutic comprises metabolic antagonist, and such as methotrexate, the DNA linking agent is such as cis-platinum (cisplatin)/carboplatin (carboplatin); Alkylating agent is such as canbusil; The topoisomerase I inhibitor is such as gengshengmeisu; Microtubule inhibitor such as taxol (handkerchief nit west (paclitaxol)), and analogue.Other chemotherapeutic comprises, for example, vinca alkaloids, mitomycin type microbiotic, bleomycin type microbiotic, antifol, colchicine, Omaine, etoposide, Taxan, anthracycline antibiotics, Zorubicin, daunorubicin, carminomycin, pidorubicin, idarubicin, mitoxantrone (mithoxanthrone), 4-dimethoxy-daunorubicin, 11-deoxidation daunorubicin, 13-deoxidation daunorubicin, doxorubicin hydrochloride-14-benzoic ether, doxorubicin hydrochloride-14-octanoate, doxorubicin hydrochloride-14-naphthylacetic acid ester, amsacrine (amsacrine), carmustine (carmustine), endoxan, cytosine arabinoside (cytarabine), etoposide (etoposide), lovastatin (lovastatin), L-sarcolysin, topotecan (topetecan), oxalaplatin, Chlorambucil, methotrexate, lomustine (lomustine), Tioguanine, asparaginase, vincaleucoblastine, vindesine, tamoxifen (tamoxifen) or mustargen.Be not to want restriction, therapeutic antibodies comprises the proteic antibody at HER2, such as Herceptin (trastuzumab); At the antibody of somatomedin or growth factor receptors, such as rhuMAb-VEGF (bevacizumab), it is defined as target with vascular endothelial growth factor, and OSI-774, and it is defined as target with Urogastron; With the antibody of integrin receptor as target, such as Vitaxin (being also referred to as MEDI-522), and analogue.The carcinostatic agent kind that is applicable to the compositions and methods of the invention comprises, but be not limited to: 1) alkaloid, comprise microtubule inhibition (vincristin for example, vincaleucoblastine and vindesine etc.), microtubule stabilizer (for example handkerchief nit west [taxol], Docetaxel, taxotere (Taxotere) etc.), with chromatin function inhibition, comprise topoisomerase enzyme inhibitor, such as Etoposide (for example semi-synthetic derivative teniposide (Teniposide) [VM-26] of etoposide [VP-16] and podophyllotoxin etc.) with the topoisomerase I is the reagent (for example camptothecine and irinotecan (Isirinotecan) [CPT-11] etc.) of target; 2) covalency DNA binding reagents [alkylating agent], comprise mustargen (for example mustargen, Chlorambucil, endoxan, ifosfamide, busulfan (Busulfan) [busulfan (Myleran)] etc.), nitrosourea (for example carmustine, lomustine, semustine (Semustine) etc.) and other alkylating agent (for example Dacarbazine (Dacarbazine), methylol melamine, thiotepa (Thiotepa) and Mitocycin etc.); 3) non-covalent DNA binding reagents [antitumor antibiotics], comprise nucleic acid inhibitor (for example gengshengmeisu [dactinomycin] etc.), anthracycline drug (for example daunorubicin [Daunomycin and Cerubidine], Zorubicin (Doxorubicin) [doxorubicin hydrochloride (Adriamycin)], idarubicin (Idarubicin) [Yi Da mycin (Idamycin)] etc.), amerantrone (anthracycline drug analogue for example, such as [mitoxantrone] etc.), bleomycin (bleomycin sulfate) etc., and Plicamycin (Plicamycin (Mithramycin)) etc.; 4) metabolic antagonist, comprise antifol (methotrexate (Methotrexate) for example, methotrexate (Folex), methotrexate sodium (Mexate) etc.), purine metabolic antagonist (Ismipur [6-MP, Purinethol] for example, 6-Tioguanine [6-TG], azathioprine (Azathioprine), acycloguanosine (Acyclovir), ganciclovir (Ganciclovir), chlorine Desoxyadenosine (Chlorodeoxyadenosine), 2-chlorodeoxyadenosine (2-ChlorodeoxyAdenosine) [CdA], with 2 '-deoxycoformycin (2 '-Deoxycoformycin) [pentostatin (Pentostatin)] etc.), pyrimidine antagonistic (fluorine pyrimidine [5 FU 5 fluorouracil (Adrucil) for example for example, floxuridine (FdUrd) is (Floxuridine)] etc.) and cytarabin (for example cytosine arabinoside [ara-C] and fludarabine (Fludarabine) etc.); 5) enzyme comprises the altheine enzyme; 6) hormone, comprise glucocorticosteroid, such as estrogen antagonist (for example tamoxifen etc.), on-steroidal androgen antagonist (for example flutamide (Flutamide) etc.) and aromatase enzyme inhibition (for example anastrozole (anastrozole) [Arimidex (Arimidex)] etc.); 7) platinic compound (for example cis-platinum (cisplatin)/carboplatin (carboplatin) etc.); 8) with link coupled monoclonal antibodies such as cancer therapy drug, toxin and/or radionuclides; 9) biological respinse modifier (for example Interferon, rabbit [for example IFN-α etc.] and interleukin [for example IL-2 etc.] etc.); 10) adoptive immunotherapy; 11) hemopoieticgrowth factor; 12) reagent of inducing tumor cell differentiation (for example Vitamin-A Acid etc.); 13) gene therapy technology; 14) antisense therapy technology; 15) tumor vaccine; 16) at the treatment (for example Batimistat etc.) of metastases; With 17) angiogenesis inhibitor.

[0120] pharmaceutical composition of the present invention and method may further include other compound that therapeutic activity is arranged as mentioned in this article, and it is applied to the treatment of above-mentioned pathological symptom usually.The example of other therapeutical agent comprises as follows: ciclosporin (for example Ciclosporin A), CTLA4-Ig, antibody is such as ICAM-3, anti--the IL-2 acceptor (anti--Tac), anti--CD45RB, anti--CD2, anti--CD3 (OKT-3), anti--CD4, anti--CD80, anti--CD86, stop interactional reagent between CD40 and the gp39, such as CD40 and/or gp39 (being CD154) specific antibody, fusion rotein by CD40 and gp39 (CD40Ig and CD8gp39) structure, inhibitor, such as nuclear transposition inhibitor, NF-κ B depressant of functions such as Gusperimus (deoxyspergualin (DSG)), cholesteral biosynthesis inhibitor such as HMG CoA reductase inhibitor (lovastatin (lovastatin) and simvastatin (simvastatin)), on-steroidal anti-inflammatory agent (NSAIDs) such as Ibuprofen BP/EP and cyclooxygenase inhibitors are such as rofecoxib, steroid such as prednisone (prednisone) or dexamethasone (dexamethasone), gold compound, antiproliferative is such as Rheumatrex, FK506 (Ta Keluomu (tacrolimus, Prograf)), mycophenolic acid morpholine ethyl ester (mycophenolate mofetil), cytotoxicity medicine such as azathioprine (Azathioprine) and endoxan, TNF-a inhibitor such as tenidap (tenidap), anti-TNF antibody or soluble TNF acceptor and rapamycin (rapamycin) (sirolimus (sirolimus) or Lei Paming (Rapamune)), perhaps their derivative.

[0121] can comprise protein for treatment agent such as cytokine, immunomodulator and antibody with other reagent of The compounds of this invention combined administration.As used herein, term " cytokine " " comprise chemokine, interleukin-, lymphokine, monokine, G CFS and receptor associated protein(RAP) and their functional fragment.As used herein, term " functional fragment " refers to have biological function or active polypeptide or peptide, described biological function or active in determining that functional experiment is identified.

[0122] described cytokine comprises endothelial mononuclear cell activating polypeptide II (EMAP-II), granulosa cell-scavenger cell-CSF (GM-CSF), granulosa cell-CSF (G-CSF), scavenger cell-CSF (M-CSF), IL-I, IL-2, IL-3, IL-4, IL-5, IL-6, IL-12 and IL-13, Interferon, rabbit and similar cytokine, and it changes relevant with concrete biology, morphology or the phenotype of cell or cell mechanism.

[0123] when other therapeutical agent and compound of the present invention are used in combination, they can be with for example mentioned amount or as be carried out use by the otherwise determined amount of those of ordinary skills in thePhysician Desk Reference (PDR).

[0124] relate in the process of symptom of cell proliferation in treatment or prevention, the proper dosage level generally can be every day per kilogram weight in patients about 0.01 to about 1000mg, it can be applied with single dose or multiple doses mode.For example, dosage level can be that every day about 0.01 is to about 250mg/kg; Narrower ground, every day about 0.5 is to about 100mg/kg.The proper dosage level can be every day about 0.01 to about 250mg/kg, every day about 0.05 is to about 100mg/kg, perhaps every day about 0.1 is to about 50mg/kg, perhaps every day about 1.0mg/kg.For example, in this scope, this dosage can be every day about 0.05 to about 0.5mg/kg, perhaps every day about 0.5, perhaps every day about 5 was to about 50mg/kg to about 5mg/kg.For oral, described composition can provide with tablet form, described tablet contains about 1.0 to about 1, the 000mg activeconstituents, for example about 1.0, about 5.0, about 10.0, about 15.0, about 20.0, about 25.0, about 50.0, about 75.0, about 100.0, about 150.0, about 200.0, about 250.0, about 300.0, about 400.0, about 500.0, about 600.0, about 750.0, about 800.0, about 900.0 and about 1,000.0mg activeconstituents, be used to the patient that will be treated that dose titration scheme according to symptom is provided.Described compound can be according to every day 1 to 4 time, such as once a day or twice instructions about how to take medicine use.Before carrying out next course of treatment, can withdrawal for some time.

[0125] still, be to be understood that, for any particular patient, concrete dosage level and administration frequency all can change, and be decided by various factors, comprise the activity of used particular compound, the metabolic stability of this compound and length, age, body weight, general health, sex, diet, medicining mode and time, row's medicine speed, drug regimen, the severity of concrete symptom and the treatment that the patient is accepting of effect.

[0126] compound of the present invention can use separately, and perhaps be used for the treatment of tumor treatment antibody or the chemistry with significant quantity is connected in tumor tissues targeting antibodies (perhaps its therapeutic fragment), chemotherapeutic or immunotoxicity agent and is used in combination.The illustrative examples that can be used for the chemotherapeutic of this purpose comprises Zorubicin, Docetaxel or taxol.Should further understand, the present invention includes the combination treatment that comprises The compounds of this invention, it includes but not limited to blood vessel stable state agent (vasculostatic agents), such as tyrosine kinase inhibitor, Serine or threonine kinase enzyme inhibitors, Src-family's group inhibitor for example, and any chemotherapeutic or therapeutic antibodies.

[0127] the present invention also provides the filler test that carries out with suitable cell method, any kinases in the described cell expressing MAPK path.This type of cell comprises from Mammals, yeast, fruit bat or colibacillary cell.For example, Raf polypeptide or any kinases such as the MEK in Raf downstream or the cell of ERK1/2 will be expressed, perhaps the cell that Raf polypeptide or MAPK path polypeptide are made response contacts with test-compound, to observe in conjunction with situation or to the stimulation situation or the inhibition situation of functional response.In order to determine the activity of Raf polypeptide or MAPK path polypeptide, the cell that will contact with candidate compound compares with the same cell that does not contact.

[0128] the present invention expection by using MAPK path polypeptide amount of suppression compounds for treating and/or improve this type of disease.Under the situation of any concrete principle of the function of not wishing to be subject to MAPK path polypeptide, believe that the useful inhibitor of MAPK path polypeptide function is those compounds that suppress the kinase activity of MAPK path polypeptide.Other inhibition position is certainly possibly owing to its position in the signal transduction cascade.Interactional inhibitor between Raf polypeptide or MAPK path polypeptide and other factor for example between the protein-protein may cause developing the medicament of regulating Raf polypeptide or MAPK path polypeptide active.

[0129] be an approach that developing drugs very likely is interfered with proteic allosteric site as target.Further, the traditional method that suppresses various protein kinases comprises the ATP combining site as target.The present invention is intended to be limited by any concrete restraining effect mechanism.Testing method of the present invention can detect candidate compound in conjunction with situation, be the mark that interrelates with candidate compound by directly or indirectly wherein, perhaps detect in the experiment of competition effect of thing comprising competing with mark to the adhesion situation of the cell that has Raf polypeptide or MAPK path polypeptide.Further, these analyze the detection system that experiment can utilize the cell that is suitable for having Raf polypeptide or MAPK path polypeptide, test out whether candidate compound can produce because the signal that activation generated of MAPK path polypeptide.The inhibitor of activation generally is to test existing under the condition of known agonist, and to because the existence of candidate compound and the influence that activation produced of this agonist is observed.The standard method of carrying out this type of filler test is known in the art, and in following examples illustrated (for example direct method and raf1-MEK1 method of testing or MAPK path cell tests method).

[0130] the following example is provided in order to further illustrating advantages and features of the invention, but is not to be intended to limit scope of the present invention.

Embodiment 1 general method

[0131] embodiment 1 has described the general synthesis program that is used to prepare compound described in the subsequent embodiment.All solvents are used without being further purified.Unless otherwise mentioned, reaction can be carried out under the condition of inert-free gas environment usually.The yield of being reported is based on not optimized conditions and single test calculating.Yield can be by changing reaction conditions, such as solvent, use alkali or acid, temperature, use catalyzer and reaction times to be optimized.At Emrys ^TMUse initiation module (Biotage/Personalchemistry) in the Process pipe (2-5mL) and carry out microwave reaction.All ¹H NMR moves on 500MHz Bruker NMR or BrukerAvance 400MHz NMR.Chemical shift is that unit is reported with delta (δ), i.e. per 1,000,000 umber (ppm) under the downfield of tetramethylsilane.Coupling constant is that unit is reported with hertz (Hz).Waters LC/MS system is used to identity and purity check.This system comprises 2795 separation modules, 996 photodiode array detectors and ZQ2000 mass spectrograph.Zorbax SB post (150x4.6mm 3.5 μ, Agilent Technologies) is used to LC.Column temperature is 40 ℃.Use gradient elution to separate with acetonitrile (0.05%TFA (B)) as moving phase compound water (0.05%TFA (A)).Flow velocity is 1mL/min.The gradient program of using in sepn process is 0-15 minute: 5-60%B; 15-15.5 minute: 60-100%B; 15.5-17 minute: 100%B.

Synthesizing of embodiment 2 3-amino-benzos [1,2,4] triazine-7-alcohol-1-oxide compound

[0132] 7.7g (0.05 mole) 4-amino-3-nitro phenol is dissolved in the 20mL glacial acetic acid, and in being furnished with the 500mL round-bottomed flask of long condenser, the shiny red solution that is produced is heated to about 100 ℃.The 20mL concentrated hydrochloric acid solution that in this solution, adds the cyanamide that contains 16.81g (8.0 equivalents, 0.4 mole).Approximately 5-10 minute, reaction mixture began violent boiling, therefore removed heating unit and under no heating condition its stirring was calmed down until boiling.Again application of heat device and with reaction mixture refluxed 48 hours then.Add 150mL30%NaOH subsequently and the dark red solution that is produced was refluxed 3 hours again.Then it is cooled to room temperature and forms dark red mill base.Red precipitate is filtered, heavily be dissolved in the 200mL water, and add 1N HCl while stirring in batches and reach 5-4 until pH.This solution colour becomes pale yellowly by dark red, and forms light yellow meticulous precipitation.With this sedimentation and filtration, with 50mL water washing twice,, finally use 50mL ether washed twice with 50mL acetonitrile washed twice, and vacuum-drying, obtain 4.6g glassy yellow solid.Yield: 51.7%.

【0133】 ¹H?NMR(DMSO-d ₆)：δ6.96(s，2H)，7.35-7.38(m，2H)，7.45-7.47(m，1H)，10.36(s，1H)。

Synthesizing of embodiment 3 3-amino-benzos [1,2,4] triazine-7-alcohol

[0134] with 4.6g (25.82 mmole) 3-amino-benzo [1,2,4] triazine-7-alcohol-1-oxide dissolution in 1: 1 mixture of 200mL dimethyl formamide and methyl alcohol.0.5g 10%Pd/C is added in this solution, and hydrogen was charged in the solution 3 hours.9: 1 mixtures of use methylene chloride are as eluent and use ultraviolet lamp, by TLC monitoring reaction process.Starting material are highly fluorescigenic under ultraviolet ray, and product then is not.After reaction is finished, the dark solution that is produced is filtered by short silicagel pad, and vacuum is removed solvent, generation burgundy solid.40mL ethyl acetate and 40mL methyl alcohol are added in this solid, and the suspension that is produced is heated to about 10 minutes of backflow.Make this suspension be cooled to room temperature then.Solid filtering is collected, with 40mL acetate ethyl ketone, the washing of 40mL ether, and vacuum-drying, the product of generation 3.2g green solid form.Yield: 76%.

【0135】 ¹H?NMR(DMSO-d ₆)：δ7.18(s，1H)，7.36(d，J＝2.6Hz，1H)，7.40-7.42(dd，J ₁＝9.1Hz，J ₂＝2.6Hz，1H)，7.45-7.46(d，J＝9.1Hz，1H)。

Synthesizing of embodiment 4 4-chloro-pyridine-2-carboxylic acids methyl ester hydrochlorides

[0136] with the anhydrous N of 2.4mL (0.031 mole, 0.16 equivalent), dinethylformamide is added dropwise in 40-50 ℃ temperature range in the thionyl chloride of 72mL (1.23 moles, 5.0 equivalents) under argon gas covers.Under this temperature,, slowly add 24.0g (0.195 mole, 1.0 equivalents) pyridine carboxylic acid then with solution stirring 10 minutes in batches.Reaction mixture was heated 30 hours at 70-75 ℃ under argon gas with reflux exchanger.Observe SO ₂The release of gas.The color of reaction mixture becomes the tangerine look by green, becomes purple then in 2 hours later on, produces the tangerine look solution that has yellow mercury oxide subsequently.It is cooled to room temperature and adds the 150mL dry toluene.This suspension is concentrated into altogether approximately 50mL on Rotary Evaporators.This process is repeated 3 times.

[0137] the tangerine look suspension that produces is cooled to-20 ℃ and add 200mL methyl alcohol.Reaction mixture placed under the room temperature stirred 18 hours.Then this clear yellow solution is changed in the round-bottomed flask, and solvent removed in vacuo.The yellow solid that produces is dissolved in the 50mL methyl alcohol by being heated to 50 ℃, in case cooling just adds the 300mL ether.This solution was left standstill 18 hours at 0 ℃.The white precipitate that forms is filtered collection,, produce 29.05g white fine hair shape solid product with ether thorough washing and vacuum-drying.Yield: 71.5%.

【0138】 ¹H?NMR(DMSO-d ₆)：δ3.88(s，3H)，7.81-7.83(dd，J ₁＝1.9Hz，J ₂＝5.4Hz，1H)，8.06-8.07(d，J＝1.9Hz，1H)，8.68-8.69(d，J＝5.4Hz，1H)。

Synthesizing of embodiment 5 4-chloro-pyridine-2-carboxylic acids methyl nitrosoureas

[0139] methanol suspension with 15mL 17.8g (0.103 mole, 1 equivalent) hydrochloric acid 4-chloro-pyridine-2-carboxylic acids methyl esters is cooled to 0 ℃, and with the tetrahydrofuran solution of 2.0M methylamine so that the speed that internal temperature remains on below 5 ℃ slowly handle.Reaction mixture was stirred 2 hours at 0 ℃, make it rise to room temperature then lentamente and stirred 18 hours.Solvent removed in vacuo adds about 200mL ethyl acetate and filters the suspension that is produced.With the washing precipitation of 100mL ethyl acetate.With the ethyl acetate solution that merges 100mL salt water washing 3 times, and dry on sodium sulfate.Solvent removed in vacuo produces 14.16g tangerine look oily product.Yield: 80.5%.

【0140】 ¹H?NMR(DMSO-d ₆)：δ2.81-2.82(d，J＝4.8Hz，3H)，7.73-7.75(dd，J ₁＝2.1Hz，J ₂＝5.4Hz，1H)，8.00-8.01(d，J＝2.1Hz，1H)，8.60-8.61(d，J＝5.4Hz，1H)，8.84(q，J＝4.8Hz，1H)。

Synthesizing of embodiment 6 4-(3-amino-benzo [1,2,4] triazine-7-base oxygen base)-pyridine-2-carboxylic acids methyl nitrosourea

[0141] 3-amino-benzo [1,2, the 4] triazine-7-alcohol with 3.2g (19.73 mmole) is dissolved in the 80mL anhydrous dimethyl formamide under argon gas.The solid potassium tert-butoxide of 2.44g (21.71 mmoles, 1.1 equivalents) is added in this solution.With the scarlet mixture heating up that produces to about 100 ℃ and under this temperature, stirred 15 minutes.The anhydrous dimethyl formamide solution that adds 10mL 3.7g (21.71 mmoles, 1.1 equivalents) 4-chloro-pyridine-2-carboxylic acids methane amide adds the anhydrous K of 3.28g (23.68 mmoles, 1.2 equivalents) subsequently ₂CO ₃This reaction mixture was heated 30 hours at 140 ℃.By LC/MS monitoring reaction process.Make it be cooled to room temperature then.The dark brown mill base that produces is poured in 500mL water and the 100mL ethyl acetate.The sedimentation and filtration that forms is collected,, produced 3.22g dark yellow solid product with 50mL water, 50mL methyl alcohol, the washing of 50mL ether and vacuum-drying.Filtrate is used 100mL ethyl acetate extraction 4 times.With extract 100mL water washing 3 times that merge, use salt water washing 3 times then and drying on anhydrous sodium sulphate.Solvent removed in vacuo produces the product of extra 1.2g yellow solid form.Yield: be 75% after the merging.

【0142】 ¹H?NMR(DMSO-d ₆)：δ2.78-2.79(d，J＝4.8Hz，3H)，7.25-7.27(dd，J ₁＝2.6Hz，J ₂＝5.6Hz，1H)，7.50-7.51(d，J＝2.6Hz，1H)，7.66-7.68(d，J＝9.2Hz，1H)，7.71-7.73(dd，J ₁＝2.7Hz，J ₂＝9.2Hz，1H)，7.71(s，2H)，8.03-8.05(d，J＝2.7Hz，1H)，8.54-8.55(d，J＝5.6Hz，1H)，8.78-8.80(q，J＝4.8Hz，1H)。

Embodiment 7 4-[3-(4-chloro-3-trifluoromethyl-phenyl amino)-benzo [1,2,4] triazine-7-base oxygen base]-pyridine-2-carboxylic acids methyl nitrosourea trifluoroacetate synthetic

[0143] under argon atmospher, in the bottle that the 2mL anhydrous dimethyl formamide is housed, adds 15.4mg (0.0168 mmole by this particular order, 0.05 three (dibenzyllideneatone), two palladiums (0) equivalent), 21.0mg (0.033 mmole, 0.1 BINAP equivalent), 220.0mg (0.675 mmole, 2.0 Carbon Dioxide caesium equivalent), 175.1mg (0.675 mmole, 2.0 5-bromo-2-chlorobenzotrifluoride equivalent) and 100mg (0.337 mmole, 1.0 (3-amino-the benzo [1 of 4-equivalent), 2,4] triazine-7-base oxygen base)-the pyridine-3-carboxylic acid methyl nitrosourea.Fed argon gas 5 minutes to mixture.Cover bottle cap then, and under argon atmospher, reaction mixture is heated to 120 ℃ and stirred 18 hours.This moment, LC/MS showed that about 40% changes product into.Pointed as in the previous examples, the long reaction times has caused the formation and the part degraded of by product.Therefore, reaction mixture is cooled to room temperature, filters, and carry out purifying with the acetonitrile/water mixture that contains 0.1%TFA by anti-phase preparation HPLC by 0.3 μ m syringe filter.

【0144】ESI-MS：[M+H] ⁺，475，477. ¹H?NMR(DMSO-d6)：δ2.79-2.90(d，J＝4.8Hz，3H)，7.31-7.33(dd，J ₁＝2.4Hz，J ₂＝5.4Hz，1H)，7.55-7.55(d，J＝2.4Hz，1H)，7.73-7.75(d，J＝8.9Hz，1H)，7.89-7.91(dd，J ₁＝2.5Hz，J ₂＝9.2Hz，1H)，7.94-7.95(d，J＝9.2Hz，1H)，8.24(d，J＝2.5Hz，2H)，8.25-8.27(dd，J ₁＝2.6Hz，J ₂＝8.9Hz，1H)，8.55(d，J＝2.6Hz，1H)，8.60(d，J＝5.4Hz，1H)，8.81-8.82(q，J＝4.8Hz，1H)，11.36(s，1H)。

Embodiment 8 4-[3-(4-chloro-phenyl amino)-benzo [1,2,4] triazine-7-base oxygen base]-pyridine 2-carboxylic acid methyl acid amides trifluoroacetate synthetic

[0145] under argon gas, in the bottle that the 2mL anhydrous dimethyl formamide is housed, adds 15.4mg (0.0168 mmole by this particular order, 0.05 three (dibenzyllideneatone), two palladiums (O) equivalent), 21.0mg (0.033 mmole, 0.1 BINAP equivalent), 220.0mg (0.675 mmole, 2.0 Carbon Dioxide caesium equivalent), 161.0mg (0.675 mmole, 2.0 1-chloro-4-iodobenzene equivalent) and 100mg (0.337 mmole, 1.0 (3-amino-the benzo [1 of 4-equivalent), 2,4] triazine-7-base oxygen base)-the pyridine-3-carboxylic acid methyl nitrosourea.Fed argon gas 5 minutes to mixture.Cover bottle cap then, and under argon gas, reaction mixture is heated to 120 ℃ and stirred 18 hours.This moment, LC/MS showed that about 30% changes product into.Viewed as in the previous examples, the long reaction times has caused the formation and the part degraded of by product.Therefore, reaction mixture is cooled to room temperature, filters, and carry out purifying with the acetonitrile/water mixture that contains 0.1%TFA by anti-phase preparation HPLC by 0.22 μ m syringe filter.

【0146】ESI-MS：[M+H] ⁺，407，409. ¹H?NMR(DMSO-d ₆)：δ2.79-2.80(d，J＝4.88Hz，3H)，7.30-7.32(dd，J ₁＝2.6Hz，J ₂＝5.6Hz，1H)，7.44-7.46(d，J＝6.8Hz，2H)，7.54-7.55(d，J＝2.6Hz，1H)，7.84-7.87(dd，J ₁＝2.6Hz，J ₂＝9.05Hz，1H)，7.92-7.94(d，J＝9.05Hz，1H)，8.00-8.01(d，J＝6.8Hz，2H)，8.19-8.20(d，J＝2.6Hz，1H)，8.58-8.59(d，J＝5.6Hz，1H)，8.81-8.82(q，J＝4.88Hz，1H)，11.08(s，1H)。

Embodiment 9 4-[3-(3-trifluoromethyl-phenylsulfonamido)-benzo [1,2,4] triazine-7-base oxygen base]-pyridine-2-carboxylic acids methyl nitrosourea trifluoroacetate synthetic

[0147] 4-(3-amino-benzo [1,2,4] triazine-7-base oxygen the base)-pyridine-3-carboxylic acid methyl nitrosourea with 100mg (0.337 mmole, 1.0 equivalents) is dissolved in the 2mL anhydrous dimethyl formamide, and is heated to about 100 ℃.The solid potassium tert-butoxide of 45.4mg (0.405 mmole, 1.2 equivalents) is added in this solution.The dark red solution that produces was stirred 30 minutes at 100 ℃, make it be cooled to room temperature then.By syringe 3-trifluoromethyl-benzene sulfonyl chloride of 100mg (0.405 mmole, 1.2 equivalents) is added this mixture.It was at room temperature stirred 2 hours.Reaction mixture is filtered by 0.22 μ m syringe filter, and carry out purifying with the acetonitrile/water mixture that contains 0.1%TFA by anti-phase preparation HPLC.

【0148】ESI-MS：[M+H] ⁺，505，506，507. ¹H?NMR(DMSO-d ₆)：δ2.78-2.79(d，J＝4.8Hz，3H)，7.29-7.31(dd，J ₁＝2.6Hz，J ₂＝5.7Hz，1H)，7.56(d，J＝2.6Hz，1H)，7.87-7.90(t，J＝7.8Hz，1H)，7.93-7.94(d，J＝9.2Hz，1H)，7.97-7.99(dd，J ₁＝2.6Hz，J ₂＝9.2Hz，1H)，8.06-8.08(d，J＝7.8Hz，1H)，8.21(d，J＝2.5Hz，1H)，8.43-8.46(m，2H)，8.57-8.58(d，J＝5.7Hz，1H)，8.80-8.81(q，J＝4.8Hz，1H)。

Embodiment 10 4-[3-(3-trifluoromethyl-benzamido)-benzo [1,2,4] triazine-7-base oxygen base]-pyridine-2-carboxylic acids methyl nitrosourea trifluoroacetate synthetic

[0149] 4-(3-amino-benzo [1,2,4] triazine-7-base oxygen the base)-pyridine-3-carboxylic acid methyl nitrosourea with 100mg (0.337 mmole, 1.0 equivalents) is dissolved in the 2mL anhydrous dimethyl formamide, and is heated to about 100 ℃.The solid potassium tert-butoxide (t-BuOK) of 45.4mg (0.405 mmole, 1.2 equivalents) is added in this solution.The dark red solution that produces was stirred 30 minutes at 100 ℃, make it be cooled to room temperature then.By syringe 3-trifluoromethyl-Benzoyl chloride of 84.5mg (0.405 mmole, 1.2 equivalents) is added this mixture.It was at room temperature stirred 2 hours.Reaction mixture is filtered by 0.22 μ m syringe filter, and carry out purifying with the acetonitrile/water mixture that contains 0.1%TFA by anti-phase preparation HPLC.

【0150】ESI-MS：[M+H] ⁺，469，470. ¹H?NMR(DMSO-d ₆)：δ2.80-2.81(d，J＝4.88Hz，3H)，7.37-7.39(dd，J ₁＝2.6Hz，J ₂＝5.7Hz，1H)，7.64(d，J＝2.6Hz，1H)，7.81-7.84(t，J＝7.8Hz，1H)，8.03-8.06(m，2H)，8.15-8.17(d，J＝9.2Hz，1H)，8.33-8.34(d，J＝2.6Hz，1H)，8.36-8.38(d，J＝8.0Hz，1H)，8.45(s，1H)，8.62-8.63(d，J＝5.7Hz，1H)，8.84-8.85(q，J＝4.88Hz，1H)，12.29(s，1H)。

Embodiment 11 4-[4-(trifluoromethoxy-benzamido)-benzo [1,2,4] triazine-7-base oxygen base]-pyridine-2-carboxylic acids methyl nitrosourea trifluoroacetate synthetic

[0151] 4-(3-amino-benzo [1,2,4] triazine-7-base oxygen the base)-pyridine-3-carboxylic acid methyl nitrosourea with 100mg (0.337 mmole, 1.0 equivalents) is dissolved in the 2mL dry DMF, and is heated to about 100 ℃.The solid t-BuOK of 45.4mg (0.405 mmole, 1.2 equivalents) is added in this solution.The dark red solution that produces was stirred 30 minutes at 100 ℃, make it be cooled to room temperature then.By syringe 4-trifluoromethoxy-Benzoyl chloride of 64 μ L (91.0mg, 0.405 mmole, 1.2 equivalents) is added this mixture.It was at room temperature stirred 2 hours.Reaction mixture is filtered by 0.22 μ syringe filter, and carry out purifying with the acetonitrile/water mixture that contains 0.1%TFA as solvent systems by anti-phase preparation HPLC.

【0152】ESI-MS：[M+H] ⁺，485，486. ¹H?NMR(DMSO-d ₆)：δ2.80-2.81(d，J＝4.8Hz，3H)，7.37-7.38(dd，J ₁＝2.6Hz，J ₂＝5.6Hz，1H)，7.55-7.57(d，J＝8.8Hz，2H)，7.63-7.64(d，J＝2.6Hz，1H)，8.03-8.05(dd，J ₁＝2.7Hz，J ₂＝9.1Hz，1H)，8.14-8.15(d，J＝9.1Hz，1H)，8.20-8.22(d，J＝8.8Hz，2H)，8.32-8.33(d，J＝2.7Hz，1H)，8.83-8.84(q，J＝4.8Hz，1H)，12.12(s，1H)。

Embodiment 12 4-[3-(trifluoromethoxy-benzamido)-benzo [1,2,4] triazine-7-base oxygen base]-pyridine-2-carboxylic acids methyl nitrosourea trifluoroacetate synthetic

[0153] 4-(3-amino-benzo [1,2,4] triazine-7-base oxygen the base)-pyridine-3-carboxylic acid methyl nitrosourea with 100mg (0.337 mmole, 1.0 equivalents) is dissolved in the 2mL dry DMF, and is heated to about 100 ℃.The solid t-BuOK of 45.4mg (0.405 mmole, 1.2 equivalents) is added in this solution.The dark red solution that produces was stirred 30 minutes at 100 ℃, make it be cooled to room temperature then.By syringe 3-trifluoromethoxy-Benzoyl chloride of 64 μ L (91.0mg, 0.405 mmole, 1.2 equivalents) is added this mixture.It was at room temperature stirred 2 hours.Reaction mixture is filtered by 0.22 μ syringe filter, and carry out purifying with the acetonitrile/water mixture that contains 0.1%TFA as solvent systems by anti-phase preparation HPLC.

【0154】ESI-MS：[M+H] ⁺，485，486. ¹H?NMR(DMSO-d ₆)：δ2.80-2.81(d，J＝4.8Hz，3H)，7.37-7.39(dd，J ₁＝2.5Hz，J ₂＝5.6Hz，1H)，7.63-7.64(d，J＝2.6Hz，1H)，7.67-7.74(m，2H)，8.03-8.05(dd，J ₁＝2.8Hz，J ₂＝9.36Hz，1H)，8.05(m，1H)，8.12-8.14(m，1H)，8.14-8.16(d，J＝9.36Hz，1H)，8.33(d，J＝2.8Hz，1H)，8.62-8.63(d，J＝5.7Hz，1H)，8.83-8.84(q，J＝4.8Hz，1H)，12.21(s，1H)。

Embodiment 13 4-[3-(chloro-phenylsulfonamido)-benzo [1,2,4] triazine-7-base oxygen base]-pyridine-2-carboxylic acids methyl nitrosourea trifluoroacetate synthetic

[0155] 4-(3-amino-benzo [1,2,4] triazine-7-base oxygen the base)-pyridine-3-carboxylic acid methyl nitrosourea with 100mg (0.337 mmole, 1.0 equivalents) is dissolved in the 2mL dry DMF, and is heated to about 100 ℃.The solid potassium tert-butoxide of 45.4mg (0.405 mmole, 1.2 equivalents) is added in this solution.The dark red solution that produces was stirred 30 minutes at 100 ℃, make it be cooled to room temperature then.By syringe the 3-chlorobenzene sulfonyl chloride of 85.8mg (0.405 mmole, 1.2 equivalents) is added this mixture.It was at room temperature stirred 2 hours.Reaction mixture is filtered by 0.22 μ m syringe filter, and carry out purifying with the acetonitrile/water mixture that contains 0.1%TFA by anti-phase preparation HPLC.

【0156】ESI-MS：[M+H] ⁺，471，473，474. ¹H?NMR(DMSO-d ₆)：δ2.78-2.79(d，J＝4.9Hz，3H)，7.30-7.32(dd，J ₁＝2.6Hz，J ₂＝5.6Hz，1H)，7.57(d，J＝2.6Hz，1H)，7.65-7.68(t，J＝9.0Hz，1H)，7.75-7.77(m，1H)，7.98-7.99(m，2H)，8.10-8.12(d，J＝7.8Hz，1H)，8.15(t，J＝1.8Hz，1H)，8.22(d，J＝2.5Hz，1H)，8.57-8.58(d，J＝5.4Hz，1H)，8.80-8.83(q，J＝4.9Hz，1H)。

Embodiment 14 4-[2-(trifluoromethyl-phenylsulfonamido)-benzo [1,2,4] triazine-7-base oxygen base]-pyridine-2-carboxylic acids methyl nitrosourea trifluoroacetate synthetic

[0157] 4-(3-amino-benzo [1,2,4] triazine-7-base oxygen the base)-pyridine-3-carboxylic acid methyl nitrosourea with 100mg (0.337 mmole, 1.0 equivalents) is dissolved in the 2mL dry DMF, and is heated to about 100 ℃.The solid potassium tert-butoxide of 45.4mg (0.405 mmole, 1.2 equivalents) is added in this solution.The dark red solution that produces was stirred 30 minutes at 100 ℃, make it be cooled to room temperature then.By syringe the 2-trifluoromethyl benzene sulfonyl chloride of 100mg (0.405 mmole, 1.2 equivalents) is added this mixture.It was at room temperature stirred 2 hours.Reaction mixture is filtered by 0.22 μ syringe filter, and the anti-phase preparation HPLC that contains the acetonitrile/water mixture of 0.1%TFA by use carries out purifying.

【0158】ESI-MS：[M+H] ⁺，505，506，507. ¹H?NMR(DMSO-d ₆)：δ2.78-2.79(d，J＝4.8Hz，3H)，7.29-7.31(dd，J ₁＝2.6Hz，J ₂＝5.7Hz，1H)，7.56(d，J＝2.6Hz，1H)，7.87-7.99(m，5H)，8.21(d，J＝2.6Hz，1H)，8.56-8.58(d，1H)，8.59-8.60(d，J＝8.0Hz，1H)，8.80-8.81(q，J＝4.8Hz，1H)。

Embodiment 15 4-[2-chloro-5-(trifluoromethyl-phenylsulfonamido)-benzo [1,2,4] triazines-7-base oxygen base]-pyridine-2-carboxylic acids methyl nitrosourea trifluoroacetate synthetic

[0159] used experimental technique is with identical described in the embodiment 9.

【0160】ESI-MS：[M+H] ⁺，539，541，542. ¹H?NMR(DMSO-d ₆)：δ(ppm)2.78-2.79(d，J＝4.9Hz，3H)，7.27-7.29(dd，J ₁＝2.6Hz，J ₂＝5.7Hz，1H)，7.55(d，J＝2.6Hz，1H)，7.63-7.65(d，J＝9.1Hz，1H)，7.86-7.88(d，J＝8.4Hz，1H)，7.91-7.94(dd，J ₁＝2.6Hz，J ₂＝9.1Hz，1H)，8.04-8.06(dd，J ₁＝2.0Hz，J ₂＝8.4Hz，1H)，8.17-8.18(d，J＝2.6Hz，1H)，8.56-8.57(d，J＝5.7Hz，1H)，8.60-8.61(d，J＝2.0Hz，1H)，8.80-8.81(q，J＝4.9Hz，1H)。

Embodiment 16 4-[3-chloro-6-methoxyl group-phenylsulfonamido)-benzo [1,2,4] triazine-7-base oxygen base]-pyridine-2-carboxylic acids methyl nitrosourea trifluoroacetate synthetic

[0161] used experimental technique is with identical described in the embodiment 9.

【0162】ESI-MS：[M+H] ⁺，501，503，504. ¹H?NMR(DMSO-d ₆)：δ(ppm)2.78-2.79(d，J＝4.9Hz，3H)，3.85(s，3H)，7.20-7.22(d，J＝8.9Hz，1H)，7.29-7.31(dd，J ₁＝2.6Hz，J ₂＝5.7Hz，1H)，7.55(d，J＝2.6Hz，1H)，7.67-7.70(dd，J ₁＝2.8Hz，J ₂＝8.9Hz，1H)，7.80-7.81(d，J＝9.2Hz，1H)，7.92-7.95(dd，J ₁＝2.8Hz，J ₂＝9.2Hz，1H)，8.05-8.06(d，J＝2.8Hz，1H)，8.19-8.20(d，J＝2.6Hz，1H)，8.57-8.58(d，J＝5.6Hz，1H)，8.80-8.81(q，J＝4.9Hz，1H)，13.00(br.s.1H)。

Embodiment 17 4-[3-(5-chloro-thiophene-2-sulfonamido)-benzo [1,2,4] triazine-7-base oxygen base]-pyridine-2-carboxylic acids methyl nitrosourea trifluoroacetate synthetic

[0163] used experimental technique is with identical described in the embodiment 9.

【0164】ESI-MS：[M+H] ⁺，477，479. ¹H?NMR(DMSO-d ₆)：δ(ppm)2.79-2.80(d，J＝4.8Hz，3H)，7.26-7.27(d，J＝4.1Hz，1H)，7.32-7.34(dd，J ₁＝2.6Hz，J ₂＝5.6Hz，1H)，7.59(d，J＝2.6Hz，1H)，7.88-7.89(d，J＝4.1Hz，1H)，7.99-8.02(dd，J ₁＝2.7Hz，J ₂＝9.1Hz，1H)，8.12-8.14(d，J＝9.1Hz，1H)，8.26(d，J＝2.7Hz，1H)，8.59(d，J＝5.6Hz，1H)，8.82-8.83(q，J＝4.8Hz，1H)，13.00(br.s.1H)。

Embodiment 18 4-[2-chloro-3-trifluoromethyl-benzamidos)-benzo [1,2,4] triazine-7-base oxygen base]-pyridine-2-carboxylic acids methyl nitrosourea trifluoroacetate synthetic

[0165] used experimental technique is with identical described in the embodiment 10.

【0166】ESI-MS：[M+H] ⁺，503，505，506. ¹H?NMR(DMSO-d ₆)：δ(ppm)2.80-2.81(d，J＝4.8Hz，3H)，7.36-7.37(dd，J ₁＝2.6Hz，J ₂＝5.6Hz，1H)，7.61(d，J＝2.6Hz，1H)，7.82-7.83(d，J＝8.4Hz，1H)，7.90-7.92(dd，J ₁＝2.1Hz，J ₂＝8.4Hz，1H)，8.00-8.03(m，2H)，8.09(m，1H)，8.29(m，1H)，8.61-8.62(d，J＝5.6Hz，1H)，8.83-8.84(q，J＝4.8Hz，1H)，12.41(s，1H)。

Embodiment 19 4-[2-chloro-3-trifluoromethyl-benzamidos)-benzo [1,2,4] triazine-7-base oxygen base]-pyridine-2-carboxylic acids methyl nitrosourea trifluoroacetate synthetic

[0167] used experimental technique is with identical described in the embodiment 10.

【0168】ESI-MS：[M+H] ⁺，435，437. ¹H?NMR(DMSO-d ₆)：δ(ppm)2.80-2.81(d，J＝4.8Hz，3H)，7.37-7.39(dd，J ₁＝2.6Hz，J ₂＝5.6Hz，1H)，7.59-7.62(t，J＝7.8Hz，1H)，7.63-7.64(d，J＝2.6Hz，1H)，7.72-7.74(m，1H)，8.03-8.05(m，2H)，8.13(m，1H)，8.15(d，J＝9.1Hz，1H)，8.33(d，J＝2.6Hz，1H)，8.62-8.63(d，J＝5.6Hz，1H)，8.83-8.84(q，J＝4.8Hz，1H)，12.12(s，1H)。

Embodiment 20 4-[2,4-two chloro-benzamidos)-benzo [1,2,4] triazine-7-base oxygen base]-pyridine-2-carboxylic acids methyl nitrosourea trifluoroacetate synthetic

[0169] used experimental technique is with identical described in the embodiment 10.

【0170】ESI-MS：[M+H] ⁺，469，471，472. ¹H?NMR(DMSO-d ₆)：δ(ppm)2.80-2.81(d，J＝4.8Hz，3H)，7.35-7.37(dd，J ₁＝2.6Hz，J ₂＝5.6Hz，1H)，7.55-7.57(dd，J ₁＝1.9Hz，J ₂＝8.3Hz，1H)，7.61(d，J＝2.6Hz，1H)，7.68-7.69(d，J＝8.3Hz，1H)，7.76-7.77(d，J＝1.9Hz，1H)，8.01(m，2H)，8.28-8.29(m，1H)，8.61(d，J＝5.6Hz，1H)，8.83-8.84(q，J＝4.8Hz，1H)，12.28(s，1H)。

Embodiment 21 4-[2-fluoro-3-chloro-5-trifluoromethyl-benzamidos)-benzo [1,2,4] triazine-7-base oxygen base]-pyridine-2-carboxylic acids methyl nitrosourea trifluoroacetate synthetic

[0171] used experimental technique is with identical described in the embodiment 10.

【0172】ESI-MS：[M+H] ⁺，521，523，524. ¹H?NMR(DMSO-d ₆)：δ(ppm)2.80-2.81(d，J＝4.8Hz，3H)，7.36-7.38(dd，J ₁＝2.6Hz，J ₂＝5.6Hz，1H)，7.62(d，J＝2.6Hz，1H)，8.02-8.05(dd，J ₁＝2.6Hz，J ₂＝9.2Hz，1H)，8.07-8.09(d，J＝9.2Hz，1H)，8.14-8.15(dd，1H)，8.31-8.32(d，J＝2.6Hz，1H)，8.33-8.34(dd，J ₁＝2.1Hz，J ₂＝6.4Hz，1H)，8.62(d，J＝5.6Hz，1H)，8.83-8.84(q，J＝4.8Hz，1H)，12.45(s，1H)。

Embodiment 22 4-[3-(4-chloro-3-trifluoromethyl-benzamido)-benzo [1,2,4] triazine-7-base oxygen base]-pyridine-2-carboxylic acids methyl nitrosourea trifluoroacetate synthetic

[0173] used experimental technique is with identical described in the embodiment 10.

【0174】ESI-MS：[M+H] ⁺，503，505，506. ¹H?NMR(DMSO-d ₆)：δ(ppm)2.80-2.81(d，J＝4.8Hz，3H)，7.37-7.39(dd，J ₁＝2.6Hz，J ₂＝5.6Hz，1H)，7.63-7.64(d，J＝2.6Hz，1H)，7.95-7.97(d，J＝8.4Hz，1H)，8.04-8.06(dd，J ₁＝2.7Hz，J ₂＝9.3Hz，1H)，8.15-8.17(d，J＝9.3Hz，1H)，8.33-8.34(d，J＝2.7Hz，1H)，8.34-8.36(dd，J ₁＝2.1Hz，J ₂＝8.4Hz，1H)，8.54-8.56(d，J＝2.1Hz，1H)，8.62-8.63(d，J＝5.6Hz，1H)，8.83-8.84(q，J＝4.8Hz，1H)，12.35(s，1H)。

Embodiment 23 4-[3-(2-chloro-3-trifluoromethyl-benzamido)-benzo [1,2,4] triazine-7-base oxygen base]-pyridine-2-carboxylic acids methyl nitrosourea trifluoroacetate synthetic

[0175] used experimental technique is with identical described in the embodiment 10.

【0176】ESI-MS：[M+H] ⁺，503，505，506. ¹H?NMR(DMSO-d ₆)：δ(ppm)2.80-2.81(d，J＝4.8Hz，3H)，7.35-7.36(dd，J ₁＝2.6Hz，J ₂＝5.5Hz，1H)，7.60-7.61(d，J＝2.6Hz，1H)，7.66-7.69(t，J＝7.8Hz，1H)，7.92-7.94(m，2H)，7.99-8.02(m，2H)，8.29(d，J＝2.8Hz，1H)，8.61-8.62(d，J＝5.6Hz，1H)，8.83-8.84(q，J＝4.8Hz，1H)，12.43(s，1H)。

Embodiment 24 4-[3-(3-trifluoromethoxy-benzamido)-benzo [1,2,4] triazine-7-base oxygen base]-pyridine-2-carboxylic acids methyl nitrosourea trifluoroacetate synthetic

[0177] used experimental technique is with identical described in the embodiment 10.

【0178】ESI-MS：[M+H] ⁺，485，486，487. ¹H?NMR(DMSO-d ₆)：δ(ppm)2.80-2.81(d，J＝4.8Hz，3H)，7.35-7.37(dd，J ₁＝2.6Hz，J ₂＝5.6Hz，1H)，7.48-7.50(d，J＝8.3Hz，1H)，7.53-7.56(dt，J ₁＝0.9Hz，J ₂＝7.6Hz，1H)，7.62(d，J＝2.6Hz，1H)，7.66-7.68(dt，J ₁＝1.7Hz，J ₂＝8.0Hz，1H)，7.78-7.79(dt，J ₁＝1.7Hz，J ₂＝7.6Hz，1H)，7.99-8.02(m，2H)，8.29(d，J＝2.6Hz，1H)，8.61(d，J＝5.6Hz，1H)，8.83-8.84(q，J＝4.8Hz，1H)，12.22(s，1H)。

Embodiment 25 4-{3-[(5-methyl-isoxazoles-3-carbonyl)-amino]-benzo [1,2,4] triazine-7-base oxygen base]-pyridine-2-carboxylic acids methyl nitrosourea trifluoroacetate synthetic

[0179] used experimental technique is with identical described in the embodiment 10. ¹H?NMR(DMSO-d ₆)：δ(ppm)2.53(s，3H)，2.80-2.81(d，J＝4.8Hz，3H)，6.79(s，1H)，7.37-7.38(dd，J ₁＝2.5Hz，J ₂＝5.5Hz，1H)，7.63-7.64(d，J＝2.4Hz，1H)，8.04-8.06(dd，J ₁＝2.5Hz，J ₂＝9.2Hz，1H)，8.15-8.17(d，J＝9.2Hz，1H)，8.32-8.33(d，J＝2.5Hz，1H)，8.61-8.62(d，J＝5.5Hz，1H)，8.83-8.84(q，J＝4.8Hz，1H)，12.04(s，1H)。

The kinase whose inhibiting external test of 26 couples of Raf of embodiment

[0180] ability of the kinase activity of formula of the present invention (A) compound inhibition Raf1 is assessed with two kinds of methods: direct assay method and Raf1-MEK1 assay method.In direct assay method, in the 96-orifice plate, pass through recombinant human raf1 (29.4U/ hole, Upstate, Lake Placid, NY), ATP (3 μ M), myelin basic protein substrate (MBP, 1mg/ml, Upstate, Lake Placid, NY) and test agent (concentration range be about 1nM/l to about 10 μ M) combined, under the situation that has the kinase reaction damping fluid, carry out kinase reaction.The Raf1-MEK1 assay method use the raf1 in 2.9U/ hole and the inactivation MEK1 in 0.25uG/ hole (MEK1, inactivation, Upstate, LakePlacid, NY) and 3uM ATP., use based on the assay method (KinaseGlo, Promega Corp.) of luciferase residue ATP is measured, after 60 minutes 30 ℃ of reactions as the tolerance of kinase activity.To average and be used for determining the IC of test compounds from the data in four holes then ₅₀Value (Prism software package, GraphPad Software, San Diego CA).

[0181] test result is as follows: a kind of known Raf inhibitor, compd A, the IC that shows ₅₀Be 16nM; A kind of known Raf inhibitor, compd B, the IC that shows ₅₀Be 43nM; The compounds of this invention C, the IC that shows ₅₀Be 76nM.The The compounds of this invention of other of Fig. 1 illustrated, the IC that they show ₅₀Below 100 μ M.

In embodiment 27 test cell lines to the inhibiting mensuration of MAPK path

[0182] western blot analysis: the former generation Human umbilical vein endothelial cells (HUVECs) that will go down to posterity in early days is kept at and contains SingleQuots (Cambrex, East Rutherford, NJ), among the EGM-2 of 10%FBS, 10mM HEPES and 50 μ g/ml gentamicins.Before handling this cell with inhibitor, by replace the complete culture solution that contains serum with the nutrient solution of serum-free and no SingleQuot so that HUVECs hunger 18 hours.With the cell after this hunger with inhibitor (0-20 μ M) pre-treatment 60 minutes under multiple concentration.Then (Peprotech, Rocky Hill NJ) handled 6 minutes, and immediately with ice-cold PBS cleaning cell with 50ng/mlVEGF or FGF with this HUVECs.With cell with ice-cold RIPA damping fluid cracking, this damping fluid contains 100mM Tris pH7.5,150mMNaCl, 1mM EDTA, 1% Septochol, 1%Triton X-100,0.1%SDS, 2mM PMSF, a Complete-Mini proteinase inhibitor (Complete-Mini protease inhibitor) tablet (Roche, Indianapolis, IN; Every 7ml lysis buffer a slice) and inhibitors of phosphatases NaF (500mM) and ortho-vanadate (1mM).Cell is scraped, shift lysate and, centrifugal 10 minutes of 000g 15.Supernatant is changed in the new pipe also with BCA protein reagent (Pierce, Rockford, IL) mensuration protein concentration.The cell lysate that will contain 20 μ g total proteins separates with 10%SDS-PAGE, it is transferred on the nitrocellulose, and seals in containing the TBST liquid of 5% milk.As an anti-anti-phosphorylation ERK Thr202/Tyr204 (Cell Signaling, Beverly, MA), anti-phosphorylation MEK Ser217/221 (Cell Signaling) and c-Raf (BD BioscencesPharmingen, San Diego, CA) with the goat anti-mouse of horseradish peroxidase or goat antirabbit two anti-detections, and (as seen Rochester NY) makes band to use SuperSignal West Pico chemical illuminating reagent system (Pierce) and Kodak's X-ray film.

[0183] when testing in this experiment, Bay 43-9006 (Raf/FGF inhibitor) shows the expression that has reduced p-MEK and p-ERK, IC ₅₀Be 200 to 300nM.U0126 (mek inhibitor) shows and has reduced p-Erk level, IC ₅₀Be 200 to 300nM, and the p-MEK level is unaffected.The result is illustrated in the table 1.As can be seen, compound of the present invention shows the reduction of p-MEK and p-ERK level, has the IC of 400nM to 20 μ M ₅₀

Embodiment 28 cell viability analyses

[0184] XTT analyzes: HUVECs is inoculated in the tissue culture treated 96-orifice plate of handling through type i collagen albumen with 10,000 cells/well, and in aforesaid complete EGM-2 nutrient solution grow overnight.Morning next day is with DMSO serial dilution inhibitor and with in 1% the DMSO final concentration adding cell.(Sigma, St.Louis MO) measure cell viability with the XTT assay method after 24-48 hour.Also take a picture with the morphology difference of more viewed XTT trend for cell.(Prism Software package, GraphPadSoftware, San Diego CA) determines IC with quantitation software ₅₀Value.Some kinds of inhibitor have stoped cell proliferation, and apoptosis-induced when being lower than the concentration of 1 μ M, and the triplicate experiment is to confirm observations.Compound of the present invention shows the IC of 100nM to 40 μ M in this experiment ₅₀(table 1).

Table 1. embodiment 26,27 and 28 test result

Synthesizing of embodiment 29S-methyl N-[4-chloro-3-(trifluoromethyl)-phenyl] isothiourea hydriodide

[0185] 4-chloro-3-trifluoromethyl-phenylthiourea (5.0g, 19.63 mmoles) is dissolved among the anhydrous MeOH of about 80mL, and adds methyl-iodide (2.93g, 20.61 mmoles) by syringe.With reaction mixture refluxed 12 hours.Then it is cooled to room temperature and solvent removed in vacuo, obtains water white oil (7.85g), it is used to next step without being further purified.

[0186] according to the method for this embodiment, prepares S-methyl N-[4-Trifluoromethoxyphen-l] isothiourea hydriodide, S-methyl N-[4-hydroxyl-phenyl] isothiourea hydriodide, S-methyl N-[3-hydroxyl-phenyl] isothiourea hydriodide and S-methyl N-[3-(trifluoromethyl) phenyl] isothiourea hydriodide.

[0187] 1,2, under the situation of 4-triazole, three kinds of tautomeric structures can appear, as follows:

[0188] even may there be whole three kinds of tautomeric structures, for the sake of simplicity and for analogue direct with it such as containing 1,3, the example of 4-oxadiazole part compares, and has 1,2, the all categories structure of 4-triazole part and all examples by with a kind of tautomeric form, such as using 4H-1,2, the 4-triazole is represented.Dominant tautomeric structure is decided by substituting group and the reaction conditions on the triazole part.As shown in document, 1H-1,2, the normally modal tautomeric form of 4-triazole is if particularly amino substituting group is connected to this ring when going up.For the sake of simplicity, only use the 4H-tautomeric form to describe this structure and do not mean that following examples compound must exist with this concrete tautomeric form.Use this method, the IUPAC title of following examples only is provided with the 4-H tautomeric form, but should be appreciated that substituent numbering may be different with the numbering that is provided when explaining accurately tautomeric structure.

Embodiment 304-[5-(4-chloro-3-trifluoromethyl-phenyl amino)-4H[1,2,4] triazole-3-yl]-phenol synthetic

[0189] 4-hydroxybenzoyl hydrazine (3.0g, 19.66 mmoles) and S-methyl N-[4-chloro-3-(trifluoromethyl) phenyl] isothiourea hydriodide (7.8g, 19.66 mmoles) are suspended in the 100mL anhydrous pyridine.Under Ar gas with reaction mixture refluxed 18 hours.Then it is cooled to room temperature and vacuum and removes pyridine.The yellow oil that produces is dissolved in the amount of ethyl acetate again, is loaded on the short silicagel pad and with 5: 1 hexane/ethyl acetate wash-outs, then with 100% eluent ethyl acetate with the collection product.Use ISCO system (80g prepacked column, the hexane with containing 20% to 50%EtOAc gradient move 25 minutes), with this product by silica gel column chromatography second time purifying once more.Solvent removed in vacuo obtains this title product, is white solid (2.83g).Yield 40.4%.

【0190】ESI-MS：[M+H] ⁺355.1，356.8， ¹H?NMR(DMSO-d ₆)：δ6.89-6.91(d，J＝8.7Hz，2H)，7.53-7.55(d，J＝8.8Hz，1H)，7.70-7.72(dd，J ₁＝8.8Hz，J ₂＝2.6Hz，1H)，7.77-7.79(d，J＝8.7Hz，2H)，8.24-8.25(d，J＝2.6Hz，1H)，9.81(s，1H)，9.98(s，1H)，13.62(s，1H)。

Embodiment 31 4-{4-[5-(4-chloro-3-trifluoromethyl-phenyl amino)-4H-[1,2,4] triazole-3-yl]-phenoxy group }-pyridine-2-carboxylic acids methyl nitrosourea trifluoroacetate synthetic

【0191】ESI-MS：[M+H] ⁺，490，491. ¹H?NMR(DMSO-d ₆)：δ2.78-2.79(d，J＝4.8Hz，3H)，7.24-7.25(m，1H)，7.40-7.42(d，J＝8.7Hz，2H)，7.48(s，1H)，7.56-7.58(d，J＝8.8Hz，1H)，7.79-7.82(dd，J ₁＝2.6Hz，J ₂＝8.8Hz，1H)，8.07-8.09(d，J＝8.7Hz，2H)，8.24-8.25(d，J＝2.6Hz，1H)，8.55-8.56(m，1H)，8.80-8.81(m，1H)，9.95(s，1H)。

Embodiment 32 (4-chloro-3-trifluoromethyl-phenyl)-5-[4-(pyridin-3-yl oxygen base)-phenyl]-4H-[1,2,4] triazole-3-yl }-amine trifluoroacetate synthetic

[0192] with 4-[5-(4-chloro-3-trifluoromethyl-phenyl amino)-4H[1,2,4] triazole-3-yl]-phenol (127.8mg, 0.36 mmole) is dissolved in the 3mL dry DMF in 5mL microwave tube (Personal Chemistry).Add two (trimethyl silyl) acid amides potassium (144.0mg, 0.72 mmole) of solid, reaction mixture is heated to 80 ℃ and stirred 15 minutes, add 3-bromopyridine (68.3mg, 0.432 mmole) then, add anhydrous K subsequently ₂CO ₃(50.0mg, 0.36 mmole).Cover bottle cap then and 250 ℃ of microwave heatings 30 minutes.Then reaction mixture is diluted with about 1mL MeOH, filter, and carry out purifying with the acetonitrile/water system that contains 0.01%TFA by anti-phase preparation HPLC by 0.22 μ m syringe filter.This product is with tfa salt form separated (15.1mg).

【0193】ESI-MS：[M+H] ⁺，432，433. ¹H?NMR(DMSO-d ₆)：δ7.19-7.21(d，J＝8.8Hz，2H)，7.49-7.51(dd，J ₁＝4.5Hz，J ₂＝8.6Hz，1H)，7.53-7.55(d，J＝8.8Hz，1H)，7.58-7.60(m，1H)，7.74-7.76(m，1H)，7.95-7.98(d，J＝8.8Hz，2H)，8.21-8.21(d，J＝2.6Hz，1H)，8.44(m，1H)，8.48(m，1H)，9.88(s，1H)。

Synthesizing of embodiment 33 4-(pyridin-3-yl oxygen base) methyl benzoate

[0194] under argon gas, 3-pyridone (6.17g, 64.87 mmoles) is dissolved in the 100mL dry DMF.Add solid K ₂CO ₃(8.96g, 64.87 mmoles) add pure 4-fluorophenyl carbamate (10.0g, 64.87 mmoles) subsequently.Reaction mixture was heated 10 hours at 135 ℃.Confirm not exist starting material by LC/MS.Reaction mixture is cooled to room temperature and pours in about 500mL water.The solution that produces (in extraction process, is added a spot of MeOH, Et 3 times with about 150mL EtOAc extraction ₂O and salt solution help this sepn process).With the saturated NaHCO of EtOAc layer that merges ₃Washed twice is with the salt solution washed twice and in anhydrous Na ₂SO ₄Last dry.Solvent removed in vacuo obtains scarlet oil, and the EtOAc/ hexanes mixtures of using 1: 1 is purified by silica gel chromatography as eluent, obtains this title product (4.8g, 32.3% yield) of yellow solid form.

【0195】ESI-MS：[M+H] ⁺，230，231. ¹H?NMR(DMSO-d ₆)：δ3.83(s，3H)，7.09-7.12(d，J＝8.8Hz，2H)，7.48-7.51(dd，J ₁＝8.4Hz，J ₂＝4.9Hz，1H)，7.58-7.61(dq，J ₁＝8.4Hz，J ₂＝1.4Hz，1H)，7.96-7.99(d，J＝8.8Hz，2H)，8.46-8.47(m，2H)。

Synthesizing of embodiment 34 4-(pyridin-3-yl oxygen base) benzoyl hydrazine

[0196] 4-(pyridin-3-yl oxygen base) methyl benzoate (4.8g, 20.94 mmoles) is dissolved among about 150mLEtOH, and by syringe add anhydrous hydrazine (4.08g, 4.0mL).The yellow solution that produces was refluxed 24 hours.Solvent removed in vacuo obtains this title product (4.8g, 100% yield) then, is yellow viscous oil, and it slowly solidifies.

【0197】ESI-MS：[M+H] ⁺，230，231. ¹H?NMR(DMSO-d ₆)：δ4.13(br?s.，2H)，7.06-7.09(d，J＝8.7Hz，2H)，7.45-7.47(dd，J ₁＝8.4Hz，J ₂＝4.9Hz，1H)，7.51-7.54(dq，J ₁＝8.4Hz，J ₂＝1.4Hz，1H)，7.85-7.88(d，J＝8.8Hz，2H)，8.42-8.43(m，2H)，9.74(s，1H)。

Embodiment 35 (4-chloro-3-trifluoromethyl-phenyl)-5-[4-(pyridin-3-yl oxygen base)-phenyl]-4H-[1,2,4] triazole-3-yl }-amine synthetic

[0198] 4-(pyridin-3-yl oxygen base) benzoyl hydrazine (2.33g, 10.2 mmoles) is dissolved in about 70mL anhydrous pyridine, and adds S-methyl N-[4-chloro-3-(trifluoromethyl) phenyl] isothiourea hydriodide (4.04g, 10.2 mmoles).Reaction mixture was refluxed 18 hours under argon gas.Vacuum is removed pyridine, and uses EtOAc as eluent, and the residue that produces is carried out purifying by silica gel chromatography, obtains this title product (0.56g), is white solid.

【0199】ESI-MS：[M+H] ⁺，432，433. ¹H?NMR(DMSO-d ₆)：δ7.20-7.23(d，J＝8.8Hz，2H)，7.46-7.49(dd，J ₁＝8.4Hz，J ₂＝4.5Hz，1H)，7.54-7.57(m，2H)，7.75-7.77(dd，J ₁＝8.8Hz，J ₂＝2.6Hz，1H)，7.97-7.99(d，J＝8.8Hz，2H)，8.23-8.24(d，J＝2.6Hz，1H)，8.43(m，1H)，8.46(d，J＝2.6Hz，1H)，9.88(s，1H)，13.91(s，1H)。

Embodiment 36 6-{4-[5-(4-chloro-3-trifluoromethyl-phenyl amino)-4H-[1,2,4] triazole-3-yl]-phenoxy group }-pyrimidine-2,4-diamines synthetic

[0200] with 4-[5-(4-chloro-3-trifluoromethyl-phenyl amino)-4H[1,2,4] triazole-3-yl] phenol (1.3g, 3.66 mmoles) is dissolved in the no Shui diox of 18mL in 10-20mL microwave tube (Personal Chemistry).Add solid Cs ₂CO ₃(1.19g, 3.66 mmoles, 1.0 equivalents) and with reaction mixture 80 ℃ of heated and stirred 10 minutes, add 4-chloro-2 then, 4-di-amino-pyrimidine (0.530g, 3.66 mmoles).Cover bottle cap and 200 ℃ of microwave heatings 25 minutes.Then reaction mixture is diluted with about 10mLMeOH, change in the round-bottomed flask and the extremely about 20mL of vacuum concentration.The red solution that produces is loaded on the short silicagel pad, and wash-out is to remove unreacted starting material for the first time with 100% ethyl acetate, usefulness contains the EtOAc eluted product of 20%MeOH then.Product is further purified by ISCO system (80g prepacked column, 40 minutes methods are with the ethyl acetate that contains 0% to 10%MeOH gradient).Solvent removed in vacuo obtains this title product, is pale solid (0.785g).Yield 46.3%.

【0201】ESI-MS：[M+H] ⁺，463，464，465. ¹H?NMR(DMSO-d ₆)：δ5.15(s，1H)，6.03(s，2H)，6.31(s，2H)，7.25-7.27(d，J＝8.6Hz，2H)，7.55-7.57(d，J＝8.8Hz，1H)，7.77-7.78(m，1H)，7.96-7.97(d，J＝8.8Hz，2H)，8.25-8.26(d，J＝2.6Hz，1H)，9.91(s，1H)，13.91(s，1H)。Analyze. calculated value (C ₁₉H ₁₄ClF ₃N ₈O x 0.4EtOAc): C, 49.68; H, 3.48; N, 22.50, observed value: C, 49.61; H, 3.55; N, 22.90.

Embodiment 37 6-{4-[5-(4-chloro-3-trifluoromethyl-phenyl amino)-4H-[1,2,4] triazole-3-yl]-phenoxy group }-pyrimidine-2,4-diamines mesylate synthetic

[0202] with 6-{4-[5-(4-chloro-3-trifluoromethyl-phenyl amino)-4H-[1,2,4] triazole-3-yl]-phenoxy group }-pyrimidine-2,4-diamines x 0.4EtOAc mixture (470.0mg, 0.943 mmole) be dissolved in about 50mL anhydrous methanol, and adding methylsulfonic acid (0.0612mL, 0.943 mmole, 1 equivalent).With the solution stirring that produces 30 minutes.Solvent removed in vacuo, and the light yellow foam that will produce 70 ℃ under the high vacuum condition dry 3 hours, obtain this title compound, be pale solid (527.3mg).Yield 100%.

【0203】ESI-MS：[M+H] ⁺，463，464. ¹H?NMR(DMSO-d ₆)：δ2.36(s，3H)，5.40(s，1H)，7.39-7.40(d，J＝8.6Hz，2H)，7.57-7.58(d，J＝8.8Hz，1H)，7.78(m，1H)，7.80(br.s.，4H)，8.02-8.03(d，J＝8.8Hz，2H)，8.25-8.26(d，J＝2.6Hz，1H)，9.94(s，1H)，13.98(br..s.1H)。Analyze. calculated value (C ₁₉H ₁₄ClF ₃N ₈O x 1CH ₃SO ₃H): C, 42.98; H, 3.25; N, 20.05, observed value: C, 42.93; H, 3.62; N, 20.12.

Embodiment 38 4-[(2,6-di-amino-pyrimidine-4-yl) oxygen base] methyl benzoate synthetic

[0204] 4-methyl hydroxybenzoate (1.52g, 10.0 mmoles) is dissolved in the no Shui diox of 18mL in 10-20mL microwave tube (Personal Chemistry), and with solid Cs ₂CO ₃Add this solution.This suspension was at room temperature stirred 10 minutes, add 4-chloro-2 then, 6-di-amino-pyrimidine (1.45g, 10.0 mmoles).Cover bottle cap and 200 ℃ of microwave heatings 40 minutes.Add MeOH then, dissolve formed suspension, produce limpid amber solution.Solution is changed over to round-bottomed flask and is concentrated into about 20mL.As eluent, this solution is carried out purifying by silica gel chromatography with 100% ethyl acetate.Again from 4: 1 EtOAc/MeOH mixture of about 50mL with the product recrystallization.Product is filtered, with 40mL EtOAc washing, with the anhydrous Et of 40mL ₂O washing and vacuum-drying obtain this title product, are white solid (0.812g).Yield 31.2%.

【0205】ESI-MS：[M+H] ⁺，261.01. ¹H?NMR(DMSO-d ₆)：δ3.84(s，3H)，5.19(s，1H)，6.06(br.s，2H)，6.37(br.s，2H)，7.19-7.21(d，J＝8.7Hz，2H)，7.95-7.97(d，J＝8.7Hz，2H)。 ¹³C?NMR(DMSO-d ₆)52.1，78.3，121.0，125.3，130.9，157.8，163.2，165.7，166.6，169.2。

Embodiment 39 4-[(2,6-di-amino-pyrimidine-4-yl) oxygen base] benzoyl hydrazine synthetic

[0206] oxygen base with 4-[(2,6-di-amino-pyrimidine-4-yl)] methyl benzoate (2.74g, 10.52 mmoles) is suspended in about 180mL anhydrous methanol, and anhydrous hydrazine (1.021g, 1.0mL, 31.85 mmoles, 3.03 equivalents) added this suspension.With reaction mixture refluxed 3 hours, distill MeOH then very lentamente and reach about 30mL until cumulative volume.This solution was at room temperature placed 48 hours.Slowly crystallization goes out white precipitate.With its collection, with the 40mLEtOAc washing, with the anhydrous Et of 40mL ₂O washing and vacuum-drying obtain this title product, are meticulous white powder (2.02g).Yield 73.7%.

【0207】ESI-MS：[M+H] ⁺，261.12. ¹H?NMR(DMSO-d ₆)：δ4.54(br.s.，2H)，5.13(s，1H)，6.01(br.s，2H)，6.30(br.s，2H)，7.13-7.14(d，J＝8.7Hz，2H)，7.83-7.84(d，J＝8.7Hz，2H)，9.75(s，1H)。 ¹³C?NMR(DMSO-d ₆)77.9，120.9，128.5，129.3，155.8，163.3，165.4，166.6，169.7。

Embodiment 40 6-{4-[5-(4-chloro-3-trifluoromethyl-phenyl amino)-4H-[1,2,4] triazole-3-yl]-phenoxy group }-pyrimidine-2,4-diamines synthetic

[0208] oxygen base with 4-[(2,6-di-amino-pyrimidine-4-yl)] benzoyl hydrazine (1.48g, 5.68 mmoles) and S-methyl N-[4-chloro-3-(trifluoromethyl) phenyl] isothiourea hydriodide (2.33g, 5.89 mmoles) be suspended in the 30mL anhydrous pyridine.Under Ar atmosphere with reaction mixture refluxed 18 hours.The yellow solution that forms is cooled to room temperature and vacuum removal pyridine.The yellow spumescence solid that produces is dissolved among 5: 1 the EtOAc/MeOH of 50mL again; Add about 15g silica gel and solvent removed in vacuo.The silica gel that will the be soaked into ISCO post of packing into, and with the ISCO system (the 80g prepacked column is with the solvent orange 2 A that contains 0% to 10% solvent B gradient [solvent orange 2 A-contain 4mL MeOH, 4mL Et ₃The 4LCH of N ₂Cl ₂Solvent B-contains 4mLEt ₃The 4LMeOH of N], move 50 minutes) purified product.Solvent removed in vacuo obtains this title product, is white solid (1.33g).Yield 50.5%.

【0209】ESI-MS：[M+H] ⁺，463，464. ¹H?NMR(DMSO-d ₆)：δ5.15(s，1H)，6.03(s，2H)，6.31(s，2H)，7.25-7.27(d，J＝8.6Hz，2H)，7.55-7.57(d，J＝8.8Hz，1H)，7.77-7.78(m，1H)，7.96-7.97(d，J＝8.8Hz，2H)，8.25-8.26(d，J＝2.6Hz，1H)，9.91(s，1H)，13.91(s，1H)。Analyze. calculated value (C ₁₉H ₁₄ClF ₃N ₈O x 0.4EtOAc): C, 49.68; H, 3.48; N, 22.50, observed value: C, 49.61; H, 3.55; N, 22.90.

Embodiment 41 6-{4-[5-(4-chloro-3-trifluoromethyl-phenyl amino)-4H-[1,2,4] triazole-3-yl]-phenoxy group }-pyridazine-3-base amine trifluoroacetate synthetic

[0210] with 4-[5-(4-chloro-3-trifluoromethyl-phenyl amino)-4H[1,2,4] triazole-3-yl]-phenol (120.0mg, 0.338 mmole) is dissolved in the 3mL dry DMF in 5mL microwave tube (Personal Chemistry).Add two (trimethyl silyl) acid amides potassium (81.0mg, 0.406 mmole) of solid, reaction mixture 80 ℃ of heated and stirred 15 minutes, is added 3-amino-6-chloro-pyridazine (48.2mg, 0.372 mmole) then, add anhydrous K subsequently ₂CO ₃(46.7mg, 0.338 mmole).Cover bottle cap then and 200 ℃ of microwave heatings 30 minutes.After reaction is finished, reaction mixture is diluted with about 1mL MeOH, filter, and carry out purifying with the acetonitrile/water system that contains 0.01%TFA by anti-phase preparation HPLC by 0.22 μ m syringe filter.This product is with tfa salt form separated (18.2mg).

【0211】ESI-MS：[M+H] ⁺，448，449. ¹H?NMR(DMSO-d ₆)：δ7.42-7.43(d，J＝8.7Hz，2H)，7.54-7.56(d，J＝9.7Hz，1H)，7.56-7.58(d，J＝8.8Hz，1H)，7.76-7.79(m，1H)，7.78-7.80(d，J＝9.7Hz，1H)，8.01-8.04(d，J＝8.8Hz，2H)，8.25-8.26(d，J＝2.6Hz，1H)，8.49(br.s.，2H)，9.94(s，1H)。

Embodiment 42 4-[5-(4-trifluoromethoxy-phenyl amino)-4H-[1,2,4] triazole-3-yl]-phenol synthetic

[0212] 4-hydroxybenzoyl hydrazine (0.643g, 4.23 mmoles) and S-methyl N-[4-(trifluoromethoxy) phenyl] isothiourea hydriodide (1.6g, 4.23 mmoles) are suspended in the 10mL anhydrous pyridine.With reaction mixture refluxed 24 hours, its color was become orange red by yellow during this period.Then it is cooled to room temperature and is stirring and pouring in the 150mL frozen water.The white solid that forms is collected, and water thoroughly cleans and at air drying.Use the Isco post, use the hexane that contains 10% to 100% gradient ethyl acetate by silica gel chromatography the residue purifying that produces.Solvent removed in vacuo obtains this title product, is pink solid (575.2mg).Yield 40.4%.

【0213】ESI-MS：[M+H] ⁺337，338. ¹H?NMR(DMSO-d ₆)：δ6.85-6.87(d，J＝8.0Hz，2H)，7.19-7.20(d，J＝8.0Hz，2H)，7.61-7.63(d，J＝8.7Hz，2H)，7.75-7.77(d，J＝8.7Hz，2H)，9.39(s，1H)，9.92(s，1H)，13.42(s，1H)。

Embodiment 43 4-{4-[5-(4-trifluoromethoxy-phenyl amino)-4H-[1,2,4] triazole-3-yl]-phenoxy group }-pyridine-2-carboxylic acids methyl nitrosourea trifluoroacetate synthetic

[0214] with 4-[5-(4-trifluoromethoxy-phenyl amino)-4H[1,2,4] triazole-3-yl]-phenol (66.4mg, 0.197 mmole) is dissolved in the 2mL dry DMF in 5mL microwave tube (Personal Chemistry).Add two (trimethyl silyl) acid amides potassium (39.4mg, 0.197 mmole) of solid, reaction mixture 80 ℃ of heated and stirred 15 minutes, is added 4-chloro-2-pyridine carboxamide (33.7mg, 0.197 mmole) then, add anhydrous K subsequently ₂CO ₃(27.3mg, 0.197 mmole).Cover bottle cap then and 200 ℃ of microwave heatings 15 minutes.Then reaction mixture is diluted with about 1mL MeOH, filter, and carry out purifying with the acetonitrile/water system that contains 0.01%TFA by anti-phase preparation HPLC by 0.22 μ m syringe filter.This product is with tfa salt form separated (46.6mg).

【0215】ESI-MS：[MH-H] ⁺471，472. ¹H?NMR(DMSO-d ₆)：δ2.78-2.79(d，J＝4.8Hz，3H)，7.23-7.25(dd，J ₁＝5.6Hz，J ₂＝2.6Hz，1H)，7.25-7.27(d，J＝8.6Hz，2H)，7.38-7.40(d，J＝8.6Hz，2H)，7.47-7.47(d，J＝2.6Hz，1H)，7.66-7.70(d，J＝8.7Hz，2H)，8.08-8.11(d，J＝8.7Hz，2H)，8.55-8.56(d，J＝5.6Hz，1H)，8.79-8.82(t，J＝4.8Hz，1H)，9.58(s，1H)。

Embodiment 44{5-[4-(pyridin-4-yl oxygen base)-phenyl]-4H-[1,2,4] triazole-3-yl }-(4-trifluoromethoxy-phenyl)-amine trifluoroacetate synthetic

[0216] with 4-[5-(4-trifluoromethoxy-phenyl amino)-4H[1,2,4] triazole-3-yl]-phenol (106.0mg, 0.315 mmole) is dissolved in the 2mL dry DMF in 5mL microwave tube (Personal Chemistry).Add two (trimethyl silyl) acid amides potassium (157.2mg, 0.788 mmole) of solid, reaction mixture 80 ℃ of heated and stirred 15 minutes, is added 4-chloropyridine hydrochloric acid (56.7mg, 0.378 mmole) then, add anhydrous K subsequently ₂CO ₃(44.0mg, 0.315 mmole).Cover bottle cap then and 250 ℃ of microwave heatings 20 minutes.Then reaction mixture is diluted with about 1mL MeOH, filter, and carry out purifying with the acetonitrile/water system that contains 0.01%TFA by anti-phase preparation HPLC by 0.22 μ m syringe filter.This product is with tfa salt form separated (66.5mg pale solid).

【0217】ESI-MS：[M+H] ⁺，415，416. ¹H?NMR(DMSO-d ₆)：δ7.26-7.27(d，J＝8.7Hz，2H)，7.46-7.48(m，2H)，7.46-7.48(d，J＝7.1Hz，2H)，7.67-7.70(d，J＝8.7Hz，2H)，8.13-8.16(d，J＝8.7Hz，2H)，8.77-8.78(d，J＝7.1Hz，2H)，9.64(s，1H)。

Embodiment 45 6-{4-[5-(4-trifluoromethoxy-phenyl amino)-4H-[1,2,4] triazole-3-yl]-phenoxy group }-pyridazine-3-base amine trifluoroacetate synthetic

[0218] with 4-[5-(4-trifluoromethoxy-phenyl amino)-4H[1,2,4] triazole-3-yl]-phenol (112.0mg, 0.33 mmole) is dissolved in the 2mL dry DMF in 5mL microwave tube (Personal Chemistry).Add two (trimethyl silyl) acid amides potassium (132.8mg, 0.66 mmole) of solid, reaction mixture 80 ℃ of heated and stirred 15 minutes, is added 3-amino-6-chlorine pyridazine (47.4mg, 0.366 mmole) then, add anhydrous K subsequently ₂CO ₃(46.0mg, 0.33 mmole).Cover bottle cap then and 250 ℃ of microwave heatings 15 minutes.Then reaction mixture is diluted with about 1mL MeOH, filter, and carry out purifying with the acetonitrile/water system that contains 0.01%TFA by anti-phase preparation HPLC by 0.22 μ m syringe filter.This product is with tfa salt form separated (the brown crystalline solid of 52.1mg).

【0219】ESI-MS：[M+H] ⁺，431. ¹H?NMR(DMSO-d ₆)：δ7.25-7.26(d，J＝8.7Hz，2H)，7.39-7.41(d，J＝8.7Hz，2H)，7.52-7.54(d，J＝9.7Hz，1H)，7.67-7.68(d，J＝8.7Hz，2H)，7.76-7.78(d，J＝9.7Hz，1H)，8.03-8.06(d，J＝8.7Hz，2H)，9.58(s，1H)。

Embodiment 46 6-{4-[5-(4-trifluoromethoxy-phenyl amino)-4H-[1,2,4] triazole-3-yl]-phenoxy group }-pyrimidine-2,4-diamines trifluoroacetate synthetic

[0220] with 4-[5-(4-trifluoromethoxy-phenyl amino)-4H[1,2,4] triazole-3-yl]-phenol (112.0mg, 0.33 mmole) is dissolved in the 2mL dry DMF in 5mL microwave tube (Personal Chemistry).Add two (trimethyl silyl) acid amides potassium (132.8mg, 0.66 mmole) of solid, reaction mixture 80 ℃ of heated and stirred 15 minutes, is added 4-chloro-2 then, 6-diamino-pyrimidine (53.0mg, 0.366 mmole) adds anhydrous K subsequently ₂CO ₃(46.0mg, 0.33 mmole).Cover bottle cap then and 250 ℃ of microwave heatings 15 minutes.Then reaction mixture is diluted with about 1mLMeOH, filter, and carry out purifying with the acetonitrile/water system that contains 0.01%TFA by anti-phase preparation HPLC by 0.22 μ m syringe filter.This product is with tfa salt form separated (51.1mg light brown solid).

【0221】ESI-MS：[M+H] ⁺，445，446. ¹H?NMR(DMSO-d ₆)：δ5.36(s，1H)，7.25-7.27(br.d，J＝8.0Hz，2H)，7.35-7.36(br.d，J＝8.0Hz，2H)，7.67-7.68(d，J＝8.7Hz，2H)，7.67(br.s.，4H)，8.02-8.04(d，J＝8.7Hz，2H)，9.57(br.s，1H)。

Embodiment 47 4-(5-{[3-(trifluoromethyl) phenyl] amino }-4H-1,2,4-triazole-3-yl)-phenol synthetic

[0222] under argon gas, S-methyl N-[3-(trifluoromethyl) phenyl] isothiourea hydriodide (9.09g, 25.11 mmoles) and 4-hydroxybenzoyl hydrazine (3.82g, 25.11 mmoles) are suspended in about 50mL anhydrous pyridine.This mixture was refluxed 12 hours under argon gas.Then this deep yellow solution is cooled to room temperature, and vacuum is removed pyridine.The reddish yellow solid that produces is dissolved in 4: 1 the EtOAc/MeOH mixture of about 50mL again, adds about 20g silica gel, and solvent removed in vacuo.The silica gel that will be soaked into is packed in the 25g ISCO sample hose, and with ISCO system (solid process, the 80g post was with the hexane that contains 0% to 50%EtOAc gradient, 45 minutes) purified product.Solvent removed in vacuo obtains this title product, is white solid (3.83g).Yield 47.6%.

【0223】ESI-MS：[M+H] ⁺，321.09. ¹H?NMR(DMSO-d ₆)：δ6.89-6.90(d，J＝8.6Hz，2H)，7.09-7.11(d，J＝7.3Hz，1H)，7.42-7.46(t，J＝7.9Hz，1H)，7.73-7.74(d，J＝7.0Hz，1H)，7.77-7.79(d，J＝8.6Hz，2H)，8.09(s，1H)，9.65(s，1H)，9.97(br.s.，1H)。

Embodiment 48 6-[4-(5-{[3-(trifluoromethyl) phenyl] amino }-4H-[1,2,4] triazole-3-yl]-phenoxy group }-pyrimidine-2,4-diamines synthetic

[0224] with 4-(5-{[3-(trifluoromethyl) phenyl] amino }-4H-1,2,4-triazole-3-yl) phenol (160mg, 0.5 mmole) is dissolved in the no Shui diox of 3mL in 2-5mL microwave tube (Personal Chemistry).Add solid Cs ₂CO ₃(163.0mg, 0.5 mmole) adds 4-chloro-2 subsequently, 6-di-amino-pyrimidine (79.5mg, 0.55 mmole).Cover bottle cap then and 200 ℃ of microwave heatings 20 minutes.Add about 3mLMeOH then to dissolve formed suspension, this solution is changed in the round-bottomed flask, and solvent removed in vacuo.Residue is dissolved among the 3mL DMF again, filters, and carry out purifying with the acetonitrile/water system that contains 0.01%TFA by anti-phase preparation HPLC by 0.22 μ m syringe filter.

[0225] part that will contain product is collected, and at EtOAc and saturated NaHCO ₃Distribute between the aqueous solution.With ethyl acetate layer salt water washing, dry and filtration on anhydrous sodium sulphate.Solvent removed in vacuo obtains this title compound, is pale solid (92.2mg).

【0226】ESI-MS：[M+H] ⁺，429.08. ¹H?NMR(DMSO-d ₆)：δ5.15(s，1H)，6.02(s，2H)，6.30(s，2H)，7.12(m，1H)，7.25-7.27(d，J＝7.4Hz，2H)，7.45-7.47(m，1H)，7.75-7.76(m，1H)，7.95-7.97(d，J＝8.6Hz，2H)，8.10(s，1H)，9.73(s，1H)，13.84(s，1H)。

Embodiment 49 5-[4-(pyrimidine-5-base oxygen base) phenyl]-N-[3-(trifluoromethyl) phenyl]-4H-1,2,4-triazole-3-amine synthetic

[0227] with 4-(5-{[3-(trifluoromethyl) phenyl] amino }-4H-1,2,4-triazole-3-yl)-phenol (100nmg, 0.31 mmole) is dissolved in the no Shui diox of 3mL in 2-5mL microwave tube (Personal Chemistry).Add solid Cs ₂CO ₃(203.4mg, 0.62 mmole) adds 5-bromo pyrimi piperidine (100mg, 0.62 mmole) subsequently.Add the 1mL dry DMF then, cover bottle cap and 250 ℃ of microwave heatings 30 minutes.Add about 3mL MeOH then to dissolve formed suspension, this solution is changed in the round-bottomed flask, and solvent removed in vacuo.Residue is dissolved among the 3mL DMF again, filters, and carry out purifying with the acetonitrile/water system that contains 0.01%TFA by anti-phase preparation HPLC by 0.22 μ m syringe filter.The part that will contain product is collected, and at EtOAc and saturated NaHCO ₃Distribute between the aqueous solution.With ethyl acetate layer salt water washing, dry and filtration on anhydrous sodium sulphate.Solvent removed in vacuo obtains this title compound, is light brown spumescence solid (34.7mg).

【0228】ESI-MS：[M+H] ⁺，399.06. ¹H?NMR(DMSO-d ₆)：δ7.12(m，1H)，7.30-7.32(d，J＝7.4Hz，2H)，7.46(m，1H)，7.76(m，1H)，8.00-8.02(d，J＝8.6Hz，2H)，8.09(s，1H)，8.73(s，2H)，9.06(s，1H)，9.73(s，1H)，13.95(s，1H)。

Embodiment 50 5-[4-(pyridin-3-yl oxygen base) phenyl]-N-[3-(trifluoromethyl) phenyl]-4H-[1,2,4]-triazole-3-amine synthetic

[0229] with 4-(5-{[3-(trifluoromethyl) phenyl] amino }-4H-1,2,4-triazole-3-yl)-phenol (100mg, 0.31 mmole) is dissolved in the 2mL dry DMF in 2-5mL microwave tube (Personal Chemistry).Add solid Cs ₂CO ₃(203.4mg, 0.62 mmole) adds 3-bromopyridine (74.0mg, 0.468 mmole) subsequently.Cover bottle cap and 250 ℃ of microwave heatings 30 minutes.Add about 1mL MeOH then to dissolve formed suspension.The red tan solution that produces is filtered by 0.22 μ m syringe filter, and carry out purifying with the acetonitrile/water system that contains 0.01%TFA by anti-phase preparation HPLC.The part that will contain product is collected, and at EtOAc and saturated NaHCO ₃Distribute between the aqueous solution.With ethyl acetate layer salt water washing, dry and filtration on anhydrous sodium sulphate.Solvent removed in vacuo obtains this title compound, is yellow solid (22.4mg).

【0230】ESI-MS：[M+H] ⁺，398.11. ¹HNMR(DMSO-d ₆)：δ7.09(d，J＝7.6Hz，1H)，7.20-7.22(d，J＝8.6Hz，2H)，7.46-7.48(m，2H)，7.52-7.54(m，1H)，7.75-7.76(d，J＝8.2Hz，1H)，7.99-8.02(d，J＝8.6Hz，2H)，8.09(s，1H)，8.42-8.43(d，J＝4.5Hz，1H)，8.45-8.46(d，J＝2.6Hz，1H)，9.73(s，1H)，13.85(s，1H)。

Embodiment 51 4-methoxyl group-6-[4-(5-{[3-(trifluoromethyl) phenyl] amino }-4H-1,2,4-triazole-3-yl) phenoxy group] pyrimidine-2-amine synthetic

[0231] with 4-(5-{[3-(trifluoromethyl) phenyl] amino }-4H-1,2,4-triazole-3-yl)-phenol (100mg, 0.31 mmole) is dissolved in the no Shui diox of 3mL in 2-5mL microwave tube (Personal Chemistry).Add solid Cs ₂CO ₃(101.7mg, 0.31 mmole) adds 2-amino-4-chloro-6-methoxy pyrimidine (55.0mg, 0.34 mmole) subsequently.Cover bottle cap and 200 ℃ of microwave heatings 15 minutes.Add about 3mL MeOH then to dissolve formed suspension.The red tan solution that produces is changed in the round-bottomed flask, and solvent removed in vacuo.Residue is dissolved among the 3mL DMF again, filters, and carry out purifying with the acetonitrile/water system that contains 0.01%TFA by anti-phase preparation HPLC by 0.22 μ m syringe filter.The part that will contain product is collected, and at EtOAc and saturated NaHCO ₃Distribute between the aqueous solution.With ethyl acetate layer salt water washing, dry and filtration on anhydrous sodium sulphate.Solvent removed in vacuo obtains this title compound, is pale solid (55.6mg).

【0232】ESI-MS：[M+H] ⁺，443.87. ¹H?NMR(DMSO-d ₆)：δ3.80(s，3H)，5.53(s，1H)，6.70(s，2H)，7.11-7.12(d，J＝7.4Hz，1H)，7.30-7.32(d，J＝8.4Hz，2H)，7.44-7.47(t，J＝7.6Hz，1H)，7.74-7.76(d，J＝8.4Hz，1H)，7.97-7.98(d，J＝8.4Hz，2H)，8.10(s，1H)，9.73(s，1H)，13.88(s，1H)。

Embodiment 52 6-[4-(5-{[3-(trifluoromethyl) phenyl] amino }-4H-[1,2,4]-triazole-3-yl) phenoxy group]-pyrimidine-4-amine synthetic

[0233] with 4-(5-{[3-(trifluoromethyl) phenyl] amino }-4H-1,2,4-triazole-3-yl)-phenol (100mg, 0.31 mmole) is dissolved in the no Shui diox of 3mL in 2-5mL microwave tube (Personal Chemistry).Add solid Cs ₂CO ₃(101.7mg, 0.31 mmole) adds 4-amino-6-chloro-pyrimidine (48.5mg, 0.37 mmole) subsequently.Cover bottle cap and 200 ℃ of microwave heatings 5 minutes.Add about 3mL MeOH then to dissolve formed suspension.The red tan solution that produces is changed in the round-bottomed flask, and solvent removed in vacuo.Residue is dissolved among the 3mL DMF again, filters, and carry out purifying with the acetonitrile/water system that contains 0.01%TFA by anti-phase preparation HPLC by 0.22 μ m syringe filter.The part that will contain product is collected, and at EtOAc and saturated NaHCO ₃Distribute between the aqueous solution.With ethyl acetate layer salt water washing, dry and filtration on anhydrous sodium sulphate.Solvent removed in vacuo obtains this title compound, is white solid (76.6mg).

【0234】ESI-MS：[M+H] ⁺，461.0. ¹H?NMR(DMSO-d ₆)：δ2.31(s，3H)，5.49(s，1H)，6.93(s，2H)，7.14(m，1H)，7.33-7.35(d，J＝7.5Hz，2H)，7.45-7.48(t，J＝7.6Hz，1H)，7.75(m，1H)，8.00-8.02(d，J＝8.6Hz，2H)，8.10(s，1H)，9.75(s，1H)，13.88(s，1H)。

Embodiment 53 2-(methylthio group)-6-[4-(5-{[3-(trifluoromethyl) phenyl] amino }-4H-1,2,4-triazole-3-yl)-phenoxy group]-pyrimidine-4-amine synthetic

[0235] with 4-(5-{[3-(trifluoromethyl) phenyl] amino }-4H-1,2,4-triazole-3-yl)-phenol (100mg, 0.31 mmole) is dissolved in the no Shui diox of 3mL in 2-5mL microwave tube (Personal Chemistry).Add solid Cs ₂CO ₃(101.7mg, 0.31 mmole) adds 4-amino-6-chloro-2-(methylthio group)-pyrimidine (60.3mg, 0.34 mmole) subsequently.Cover bottle cap and 200 ℃ of microwave heatings 10 minutes.Add about 3mLMeOH then to dissolve formed suspension.The red tan solution that produces is changed in the round-bottomed flask, and solvent removed in vacuo.Residue is dissolved among the 3mL DMF again, filters, and carry out purifying with the acetonitrile/water system that contains 0.01%TFA by anti-phase preparation HPLC by 0.22 μ m syringe filter.The part that will contain product is collected, and at EtOAc and saturated NaHCO ₃Distribute between the aqueous solution.With ethyl acetate layer salt water washing, dry and filtration on anhydrous sodium sulphate.Solvent removed in vacuo obtains this title compound, is white solid (39.5mg).

【0236】ESI-MS：[M+H] ⁺，461.0. ¹H?NMR(DMSO-d ₆)：δ3.80(s，3H)，5.53(s，1H)，6.70(s，2H)，6.30(s，2H)，(d，J＝8.6Hz，2H)。

Embodiment 54 4-[5-(4-trifluoromethoxy-phenyl)-4H-[1,2,4]-triazole-3-base is amino]-phenol synthetic

[0237] 4-trifluoromethoxy benzoyl hydrazine (1.1g, 5.0 mmoles) and S-methyl N-[4-hydroxyl-phenyl] isothiourea hydriodide (1.55g, 5.0 mmoles) are suspended in the 10mL anhydrous pyridine.With reaction mixture refluxed 24 hours, its color was become orange red by yellow during this period.Then it is cooled to room temperature and is stirring and pouring in the 150mL frozen water.Water layer is decanted, and the residue that produces is carried out purifying by silica gel chromatography with 1: 1 ethyl acetate/hexane mixture.Solvent removed in vacuo obtains this title product, is powder gray solid (684.0mg).40.6% yield.

【0238】ESI-MS：[M+H] ⁺，337，338. ¹H?NMR(DMSO-d ₆)：δ7.68-6.71(d，J＝8.8Hz，2H)，7.32-7.35(d，J＝8.8Hz，2H)，7.47-7.49(d，J＝8.8Hz，2H)，8.04-8.07(d，J＝8.8Hz，2H)，9.05(br.s，1H)。

Embodiment 55 4-{4-[5-(4-trifluoromethoxy-phenyl)-4H-[1,2,4] triazole-3-base is amino]-phenoxy group }-pyridine-2-carboxylic acids methyl nitrosourea trifluoroacetate synthetic

[0239] with 4-[5-(4-trifluoromethoxy-phenyl)-4H[1,2,4] triazole-3-base is amino]-phenol (134.5mg, 0.4 mmole) is dissolved in the 2mL dry DMF in 5mL microwave tube (Personal Chemistry).Add two (trimethyl silyl) acid amides potassium (120.0mg, 0.6 mmole) of solid, reaction mixture 80 ℃ of heated and stirred 15 minutes, is added 4-chloro-2-pyridine-2-carboxamide (68.2mg, 0.4 mmole) then, add anhydrous K subsequently ₂CO ₃(62.0mg, 0.44 mmole).Cover bottle cap then and 150 ℃ of microwave heatings 30 minutes.Then reaction mixture is diluted with about 1mL MeOH, filter, and carry out purifying with the acetonitrile/water system that contains 0.01%TFA by anti-phase preparation HPLC by 0.22 μ m syringe filter.This product is with tfa salt form separated (31.7mg white solid).

【0240】ESI-MS：[M+H] ⁺?471，472. ¹H?NMR(DMSO-d ₆)：δ2.77-2.78(d，J＝4.8Hz，3H)，7.13-7.15(d，J＝8.3Hz，2H)，7.13(m，1H)，7.40(br.s，1H)，7.51-7.53(d，J＝8.3Hz，2H)，7.70-7.73(d，J＝8.8Hz，2H)，8.09-8.11(d，J＝8.8Hz，2H)，8.48-8.49(d，J＝5.3Hz，1H)，8.77-8.78(q，J＝4.8Hz，1H)，9.56(s，1H)。

Embodiment 56 3-[5-(4-chloro-3-trifluoromethyl-phenyl amino)-4H[1,2,4]-triazole-3-yl]-phenol synthetic

[0241] 3-hydroxybenzoyl hydrazine (2.98g, 19.58 mmoles) and S-methyl N-[4-chloro-3-(trifluoromethyl) phenyl] isothiourea hydriodide (7.78g, 19.63 mmoles) are suspended in the 40mL anhydrous pyridine.With reaction mixture refluxed 18 hours, its color became scarlet by yellow during this period.Then it is cooled to room temperature and is stirring and pouring in the 250mL frozen water.Water layer is decanted, and oily residue is carried out purifying by silica gel chromatography on the Isco post with the hexane that contains 0=＞50% gradient ethyl acetate.Solvent removed in vacuo obtains this title product, is white solid (2.176g).31.3% yield.

【0242】ESI-MS：[M+H] ⁺355.1，356.8， ¹H?NMR(DMSO-d ₆)：δ6.88-6.90(dq，J ₁＝7.9Hz，J ₂＝0.9Hz，1H)，7.31-7.34(t，J＝7.9Hz，1H)，7.35-7.39(m，2H)，7.54-7.56(d，J＝8.8Hz，1H)，7.74-7.76(dd，J ₁＝8.8Hz，J ₂＝2.7Hz，1H)，8.23-8.24(d，J＝2.7Hz，1H)，9.79(s，1H)，9.87(s，1H)，13.86(s，1H)。

Embodiment 57 4-{3-[5-(4-chloro-3-trifluoromethyl-phenyl amino)-4H-[1,2,4] triazole-3-yl]-phenoxy group }-pyridine-2-carboxylic acids methyl nitrosourea trifluoroacetate synthetic

[0243] with 3-[5-(4-chloro-3-trifluoromethyl-phenyl amino)-4H[1,2,4] triazole-3-yl]-phenol (100mg, 0.282 mmole) is dissolved in the 2mL dry DMF in 5mL microwave tube (Personal Chemistry).Add two (trimethyl silyl) acid amides potassium (140.6mg, 0.705 mmole) of solid, reaction mixture 80 ℃ of heated and stirred 15 minutes, is added 4-chloro-2-pyridine-2-carboxamide (52.9mg, 0.31 mmole) then, add anhydrous K subsequently ₂CO ₃(19.5mg, 0.141 mmole).Cover bottle cap then and 250 ℃ of microwave heatings 20 minutes.Then reaction mixture is diluted with about 1mL MeOH, filter, and carry out purifying with the acetonitrile/water system that contains 0.01%TFA by anti-phase preparation HPLC by 0.22 μ m syringe filter.This product is with tfa salt form separated (25.0mg white solid).

【0244】ESI-MS：[M+H] ⁺489，490，491. ¹H?NMR(DMSO-d ₆)：δ2.78-2.79(d，J＝4.8Hz，3H)，7.25-7.26(dd，J ₁＝2.5Hz，J ₂＝5.5Hz，1H)，7.38(m，1H)，7.48-7.49(d，J＝2.5Hz，1H)，7.55-7.57(d，J＝8.8Hz，1H)，7.67-7.70(t，J＝7.8Hz，1H)，7.73(br.s.，1H)，7.78(br.s.，1H)，7.91-7.93(d，J＝7.8Hz，1H)，8.20-8.21(d，J＝2.6Hz，1H)，8.56-8.57(d，J＝5.5Hz，1H)，8.80-8.81(q，J＝4.8Hz，1H)，9.93(s，1H)。

Embodiment 58 6-{3-[5-(4-chloro-3-trifluoromethyl-phenyl amino)-4H-[1,2,4] triazole-3-yl]-phenoxy group }-pyrimidine-2,4-diamines trifluoroacetate synthetic

[0245] with 3-[5-(4-chloro-3-trifluoromethyl-phenyl amino)-4H[1,2,4] triazole-3-yl]-phenol (100mg, 0.282 mmole) is dissolved in the 2mL dry DMF in 5mL microwave tube (Personal Chemistry).Add two (trimethyl silyl) acid amides potassium (140.6mg, 0.705 mmole) of solid, reaction mixture 80 ℃ of heated and stirred 15 minutes, is added 4-chloro-2 then, 6-diamino-pyrimidine (44.8mg, 0.31 mmole) adds anhydrous K subsequently ₂CO ₃(19.5mg, 0.141 mmole).Cover bottle cap then and 250 ℃ of microwave heatings 20 minutes.Then reaction mixture is diluted with about 1mL MeOH, filter, and carry out purifying with the acetonitrile/water system that contains 0.01%TFA by anti-phase preparation HPLC by 0.22 μ m syringe filter.This product is with tfa salt form separated (37.8mg light brown solid).

【0246】ESI-MS：[M+H] ⁺464，465. ¹H?NMR(DMSO-d ₆)：δ5.40(s，1H)，7.33-7.35(d，J＝7.6Hz，1H)，7.57-7.59(d，J＝8.8Hz，1H)，7.62-7.65(t，J＝7.8Hz，1H)，7.73(br.s.，1H)，7.80(br.m.，1H)，7.88-7.89(d，J＝7.8Hz，1H)，8.21-8.22(d，J＝2.6Hz，1H)，9.96(s，1H)。

Embodiment 59 (4-chloro-3-trifluoromethyl-phenyl)-5-[3-(pyridin-4-yl oxygen base)-phenyl]-4H-[1,2,4] triazole-3-yl }-amine trifluoroacetate synthetic

[0247] with 3-[5-(4-chloro-3-trifluoromethyl-phenyl amino)-4H[1,2,4] triazole-3-yl]-phenol (100mg, 0.282 mmole) is dissolved in the 2mL dry DMF in the 5mL microwave tube.Add two (trimethyl silyl) acid amides potassium (140.6mg, 0.705 mmole) of solid, reaction mixture 80 ℃ of heated and stirred 15 minutes, is added 4-chloro-pyridine hydrochloric acid (46.5mg, 0.31 mmole) then, add anhydrous K subsequently ₂CO ₃(19.5mg, 0.141 mmole).Cover bottle cap then and 250 ℃ of microwave heatings 20 minutes.Then reaction mixture is diluted with about 1mL MeOH, filter, and carry out purifying with the acetonitrile/water system that contains 0.01%TFA by anti-phase preparation HPLC by 0.22 μ m syringe filter.This product is with tfa salt form separated (34.6mg light brown solid).

【0248】ESI-MS：[M+H] ⁺?432，433. ¹H?NMR(DMSO-d ₆)：δ7.43-7.45(br.s.1H)，7.46-7.47(d，J＝7.0Hz，2H)，7.56-7.58(d，J＝8.8Hz，1H)，7.72-7.75(t，J＝7.8Hz，1H)，7.80(br.s.，1H)，7.81(br.s，1H)，7.98-8.00(d，J＝7.8Hz，1H)，8.21-8.22(d，J＝2.6Hz，1H)，8.76-8.78(d，J＝7.0Hz，1H)，9.98(s，1H)。

Embodiment 60 6-{3-[5-(4-chloro-3-trifluoromethyl-phenyl amino)-4H-[1,2,4] triazole-3-yl]-phenoxy group }-pyridazine-3-base amine trifluoroacetate synthetic

[0249] with 3-[5-(4-chloro-3-trifluoromethyl-phenyl amino)-4H[1,2,4] triazole-3-yl]-phenol (100mg, 0.282 mmole) is dissolved in the 2mL dry DMF in the 5mL microwave tube.Add two (trimethyl silyl) acid amides potassium (140.6mg, 0.705 mmole) of solid, reaction mixture 80 ℃ of heated and stirred 15 minutes, is added 3-amino-6-chloro-pyridazine (40.2mg, 0.31 mmole) then, add anhydrous K subsequently ₂CO ₃(19.5mg, 0.141 mmole).Cover bottle cap then and 250 ℃ of microwave heatings 20 minutes.Then reaction mixture is diluted with about 1mL MeOH, filter, and carry out purifying with the acetonitrile/water system that contains 0.01%TFA by anti-phase preparation HPLC by 0.22 μ m syringe filter.This product is with tfa salt form separated (35.5mg light brown solid).

【0250】ESI-MS：[M+H] ⁺448，449. ¹H?NMR(DMSO-d ₆)：δ7.38-7.39(br.s.1H)，7.55-7.57(d，J＝9.6Hz，1H)，7.57-7.58(d，J＝8.6Hz，1H)，7.62-7.65(t，J＝7.8Hz，1H)，7.78(br.s.，1H)，7.80(br.s，1H)，7.82-7.84(d，J＝9.6Hz，1H)，7.86-7.88(d，J＝7.8Hz，1H)，8.22-8.23(d，J＝2.6Hz，1H)，8.52(br.s，2H)，9.94(s，1H)。

Embodiment 61 4-(5-{[4-chloro-3-(trifluoromethyl)-phenyl] amino }-1,3,4-oxadiazole-2-yl) phenol synthetic

[0251] with titanium dioxide mercury (II) (yellow) (4.55g, 21.0 mmoles) at the argon gas low suspension in the anhydrous MeOH of 60mL.Form bright orange suspension.In this suspension, add 4-hydroxybenzoyl hydrazine (3.20g, 21.0 mmoles) and 4-chloro-3-trifluoromethyl-phenyl lsothiocyanates (5.0g, 21.0 mmoles).With reaction mixture refluxed 2 hours.Solvent removed in vacuo.Black residue is dissolved among the 100mL EtOAc again, and the black suspension that produces is filtered by short silicagel pad.Filtrate is mixed with the dried silica gel of 10g and solvent removed in vacuo.The silica gel that will be soaked into is contained on the silicagel column, and with starting from 50: 50 ratios and ending at the hexane of 0: 100 ratio: the ethyl acetate mixture gradient is separated product.The part that all contains product is merged; Solvent removed in vacuo obtains gray solid.This solid is heated in 4: 1 EtOAc/MeOH mixture of 50mL.Formed suspension is cooled to room temperature and filtration, obtains this title product, be white crystalline solid (4.54g, 60.7% yield).

【0252】ESI-MS：[M+H] ⁺356.0. ¹H?NMR(DMSO-d ₆)：δ6.92-6.95(d，J＝8.8Hz，2H)，7.69-7.70(d，J＝8.8Hz，1H)，7.71-7.73(d，J＝8.8Hz，2H)，7.82-7.84(dd，J ₁＝8.8Hz，J ₂＝2.6Hz，1H)，8.16-8.17(d，J＝2.6Hz，1H)，10.21(br?s.，1H)，11.11(br?s.，1H)。

Embodiment 62 6-[4-(5-{[4-chloro-3-trifluoromethyl-phenyl] amino }-1,3,4-oxadiazole-2-yl)-phenoxy group]-pyrimidine-2,4-diamines synthetic

[0253] with 4-(5-{[4-chloro-3-(trifluoromethyl)-phenyl] amino-1,3,4-oxadiazole-2-yl)-phenol (1.067g, 3.0 mmoles) is dissolved under argon gas in about 70mL dry DMF.Add two (trimethyl silyl) acid amides potassium (0.718g, 3.6 mmoles) of solid, and the yellow solution that produces was heated 1.5 hours at 70 ℃.Add solid K then ₂CO ₃(0.414g, 3.0 mmoles) add 2 subsequently, 6-diamino-4-chloro-pyrimidine (0.520g, 3.6 mmoles).Reaction mixture was refluxed 30 hours under argon gas.Then it is cooled to room temperature and pours in about 500mL water.With 100mLEtOAc this aqueous mixture is extracted 5 times.With the EtOAc extraction liquid that merges 100mL salt water washing 3 times, and in anhydrous Na ₂SO ₄Last dry.Solvent removed in vacuo obtains the reddish yellow residue, is purified by silica gel chromatography as eluent with EtOAc.The part that will contain product is collected, and solvent removed in vacuo obtains product, is the reddish yellow solid.From 10mL EtOAc,, collect,, obtain this title compound (0.527g, 38% yield), be the light brown solid with ether thorough washing and vacuum-drying with this solid recrystallization.

【0254】ESI-MS：[M+H] ⁺464，465. ¹H?NMR(DMSO-d ₆)：δ5.20(s，1H)，6.05(br?s.，2H)，6.34(br.s.，2H)，7.27-7.30(d，J＝8.7Hz，2H)，7.71-7.72(d，J＝8.8Hz，1H)，7.84-7.88(dd，J ₁＝8.8Hz，J ₂＝2.6Hz，1H)，7.89-7.91(d，J＝8.7Hz，2H)，8.18-8.19(d，J＝2.6Hz，1H)，11.26(s，1H)。Analyze. calculated value C ₁₉H ₁₃ClF ₃N ₇O ₂: C, 49.20; H, 2.83; N, 21.14, observed value: C, 49.08; H, 3.21; N, 20.95.

Embodiment 63 6-[4-(5-{[4-chloro-3-trifluoromethyl-phenyl] amino }-1,3,4-oxadiazole-2-yl)-phenoxy group]-pyrimidine-2,4-diamines trifluoroacetate synthetic

[0255] with 4-(5-{[4-chloro-3-(trifluoromethyl)-phenyl] amino-1,3,4-oxadiazole-2-yl)-phenol (100mg, 0.281 mmole) is dissolved in the 2.5mL dry DMF in the 5mL microwave tube.Add two (trimethyl silyl) acid amides potassium (140.6mg, 0.703 mmole) of solid, reaction mixture 80 ℃ of heated and stirred 15 minutes, is added 6-chloro-2 then, 4-diamino-pyrimidine (81.3mg, 0.562 mmole) adds anhydrous K subsequently ₂CO ₃(19.5mg, 0.141 mmole).Cover bottle cap then and 200 ℃ of microwave heatings 15 minutes.Then reaction mixture is diluted with about 1mL MeOH, filter, and carry out purifying with the acetonitrile/water system that contains 0.01%TFA by anti-phase preparation HPLC by 0.22 μ m syringe filter.This product is with tfa salt form separated (75.8mg light brown solid).

【0256】ESI-MS：[M+H] ⁺464，465. ¹H?NMR(DMSO-d ₆)：δ5.41(s，1H)，7.39-7.42(d，J＝8.7Hz，2H)，7.63(br?s.，4H)，7.72-7.74(d，J＝8.8Hz，1H)，7.85-7.87(dd，J ₁＝8.8Hz，J ₂＝2.7Hz，1H)，7.95-7.97(d，J＝8.7Hz，2H)，8.20(d，J＝2.7Hz，1H)，11.29(s，1H)。

Embodiment 64N-[4-chloro-3-(trifluoromethyl) phenyl]-5-[4-(pyridin-3-yl oxygen base) phenyl]-1,3,4-oxadiazole-2-amine trifluoroacetate synthetic

[0257] with 4-(5-{[4-chloro-3-(trifluoromethyl)-phenyl] amino-1,3,4-oxadiazole-2-yl)-phenol (100mg, 0.281 mmole) is dissolved under argon gas in about 2mL dry DMF.Add two (trimethyl silyl) acid amides potassium (140.2mg, 0.702 mmole) of solid, the yellow solution that produces was heated 15 minutes at 80 ℃.Add solid K then ₂CO ₃(19.4mg, 0.140 mmole) adds 3-bromopyridine (89.0mg, 0.562 mmole) subsequently.With reaction mixture 250 ℃ of microwave heatings 10 minutes.With its usefulness 1mL MeOH dilution, filtration and the acetonitrile/water system that contains the 0.1%TFA gradient by anti-phase preparative scale chromatography usefulness carry out purifying then.Collection has the main peak of product quality; Solvent removed in vacuo obtains this title product, is brown oil (20.6mg).

【0258】ESI-MS：[M+H] ⁺433.5，434.3. ¹H?NMR(DMSO-d ₆)：δ7.24-7.26(d，J＝8.8Hz，2H)，7.57-7.59(dd，J ₁＝8.4Hz，J ₂＝4.7Hz，1H)，7.68-7.71(dq，J ₁＝8.4Hz，J ₂＝1.4Hz，1H)，7.71-7.73(d，J＝8.8Hz，1H)，7.84-7.86(dd，J ₁＝8.8Hz，J ₂＝2.7Hz，1H)，7.92-7.94(d，J＝8.8Hz，2H)，8.17-8.18(d，J＝2.7Hz，1H)，8.50(br?d，J＝4.0Hz，1H)，8.54(br?s，1H)，11.24(s，1H)。

Embodiment 65N-[4-chloro-3-(trifluoromethyl) phenyl]-5-[4-(pyridin-4-yl oxygen base) phenyl]-1,3,4-oxadiazole-2-amine trifluoroacetate synthetic

[0259] with 4-(5-{[4-chloro-3-(trifluoromethyl)-phenyl] amino-1,3,4-oxadiazole-2-yl)-phenol (100mg, 0.281 mmole) is dissolved under argon gas in about 2mL dry DMF.Add two (trimethyl silyl) acid amides potassium (225mg, 1.12 mmoles) of solid, the yellow solution that produces was heated 15 minutes at 80 ℃.Add solid K then ₂CO ₃(38.8mg, 0.281 mmole) adds 4-chloropyridine hydrochloric acid (84.3mg, 0.562 mmole) subsequently.With reaction mixture 200 ℃ of microwave heatings 25 minutes (Initiator, Biotage).Then it is diluted with 1mL MeOH, filter, and carry out purifying with the acetonitrile/water gradient that contains 0.1%TFA by anti-phase preparative scale chromatography by 0.22 μ m syringe filter.Collection has the main peak of product quality; Solvent removed in vacuo obtains this title product, is white fine hair shape solid (85.6mg).

【0260】ESI-MS：[M+H] ⁺435.3. ¹H?NMR(DMSO-d ₆)：δ7.37-7.38(d，J＝4.8Hz，2H)，7.48-7.50(d，J＝8.8Hz，2H)，7.72-7.74(d，J＝8.8Hz，1H)，7.85-7.88(dd，J ₁＝8.8Hz，J ₂＝2.7Hz，1H)，8.03-8.06(d，J＝8.8Hz，1H)，8.19-8.20(d，J＝2.7Hz，1H)，8.74(br?s.，2H)，11.31(s，1H)。

Embodiment 66N-[4-chloro-3-(trifluoromethyl) phenyl]-5-[4-(pyrimidine-5-base oxygen base) phenyl]-1,3,4-oxadiazole-2-amine trifluoroacetate synthetic

[0261] with 4-(5-{[4-chloro-3-(trifluoromethyl)-phenyl] amino-1,3,4-oxadiazole-2-yl)-phenol (100mg, 0.281 mmole) is dissolved under argon gas in about 2mL dry DMF.Add two (trimethyl silyl) acid amides potassium (140.2mg, 0.702 mmole) of solid, the yellow solution that produces was heated 15 minutes at 80 ℃.Add solid K then ₂CO ₃(19.4mg, 0.140 mmole) adds 3-bromo pyrimi piperidine (89.4mg, 0.562 mmole) subsequently.With reaction mixture 200 ℃ of microwave heatings 15 minutes.Then it is diluted with 1mLMeOH, filter, and carry out purifying with the acetonitrile/water gradient that contains 0.1%TFA by anti-phase preparative scale chromatography by 0.22 μ m syringe filter.Collection has the main peak of product quality; Solvent removed in vacuo obtains this title product, is white fine hair shape solid (73.0mg white crystalline solid).

【0262】ESI-MS：[M+H] ⁺434.3，435.3. ¹H?NMR(DMSO-d ₆)：δ7.31-7.33(d，J＝8.8Hz，2H)，7.71-7.73(d，J＝8.8Hz，1H)，7.84-7.86(dd，J ₁＝8.8Hz，J ₂＝2.7Hz，1H)，7.93-7.95(d，J＝8.8Hz，2H)，8.17-8.18(d，J＝2.7Hz，1H)，8.77(s，2H)，9.09(s，1H)，11.25(s，1H)。

Embodiment 67 4-[4-(5-{[4-chloro-3-(trifluoromethyl) phenyl] amino }-1,3,4-oxadiazole-2-yl) phenoxy group]-N-picoline-2-methane amide trifluoroacetate synthetic

[0263] with 4-(5-{[4-chloro-3-(trifluoromethyl)-phenyl] amino-1,3,4-oxadiazole-2-yl)-phenol (100mg, 0.281 mmole) is dissolved under argon gas in about 2mL dry DMF.Add two (trimethyl silyl) acid amides potassium (140.2mg, 0.702 mmole) of solid, the yellow solution that produces was heated 15 minutes at 80 ℃.Add solid K then ₂CO ₃(19.4mg, 0.140 mmole) adds 4-chloro-2-pyridine-2-carboxamide (52.7mg, 0.309 mmole) subsequently.With reaction mixture 200 ℃ of microwave heatings 15 minutes.Then it is diluted with 1mL MeOH, filter, and carry out purifying with the acetonitrile/water gradient that contains 0.1%TFA by anti-phase preparative scale chromatography by 0.22 μ m syringe filter.Collection has the main peak of product quality; Solvent removed in vacuo obtains this title product, is white solid (67.5mg).

【0264】ESI-MS：[M+H] ⁺490.4，491.3. ¹H?NMR(DMSO-d ₆)：δ2.79-2.80(d，J＝4.9Hz，3H)，7.26-7.28(dd，J ₁＝5.6Hz，J ₂＝2.6Hz，1H)，7.43-7.44(d，J＝6.8Hz，2H)，7.49(d，J＝2.6Hz，1H)，7.72-7.74(d，J＝8.8Hz，1H)，7.85-7.86(dd，J ₁＝8.8Hz，J ₂＝2.6Hz，1H)，8.01-8.03(d，J＝6.8Hz，2H)，8.19(d，J＝2.6Hz，1H)，8.57-8.58(d，J＝5.7Hz，1H)，8.79-8.81(q，J＝4.9Hz，1H)，11.28(s，1H)。

Embodiment 68 4-[5-(4-chloro-3-(trifluoromethyl)-phenyl)-4H-1,2,4-triazole-3-base is amino] phenol synthetic

[0265] 4-chloro-3-trifluoromethyl benzoyl hydrazine (2.89g, 12.1 mmoles) and S-methyl N-(4-hydroxy phenyl) isothiourea hydriodide (3.75g, 12.1 mmoles) are suspended in the 40mL anhydrous pyridine.With reaction mixture refluxed 18 hours, its color became scarlet by yellow during this period.Then it is cooled to room temperature and is stirring and pouring in the 250mL frozen water.The aqueous solution is decanted, and oily residue is carried out purifying by silica gel chromatography with 1: 1 ethyl acetate/hexane mixture.Solvent removed in vacuo obtains this title product, is white solid (1.95g).Yield 45.5%.

Embodiment 69 6-[4-({ 5-[4-chloro-3-(trifluoromethyl) phenyl-4H-1,2,4-triazole-3-yl } amino) phenoxy group] pyrimidine-2,4-diamines trifluoroacetate synthetic

[0266] with 4-[5-(4-chloro-3-(trifluoromethyl)-phenyl)-4H-1,2,4-triazole-3-base is amino] phenol (100mg, 0.282 mmole) is dissolved in the 2mL dry DMF.Add two (trimethyl silyl) acid amides potassium (140.6mg, 0.705 mmole) of solid, the solution that produces was heated 15 minutes at 80 ℃.Add solid K then ₂CO ₃(20mg, 0.141 mmole) adds 4-chloro-2 subsequently, 6-diamino-pyrimidine (61.1mg, 0.422 mmole).With reaction mixture 200 ℃ of microwave heatings 20 minutes.Then it is diluted with 1mLMeOH, filter, and carry out purifying with the acetonitrile/water gradient that contains 0.1%TFA by anti-phase preparative scale chromatography by 0.22 μ m syringe filter.Collection has the main peak of product quality, and solvent removed in vacuo obtains the trifluoroacetate of product, is white solid (28.6mg).

【0267】ESI-MS：[M+H] ⁺463.4，464.4. ¹H?NMR(DMSO-d ₆)：δ5.24(s，1H)，7.14-7.16(d，J＝8.8Hz，2H)，7.65-7.66(d，J＝8.8Hz，2H)，7.81(brs.，4H)，7.88-7.90(d，J＝8.4Hz，1H)，8.23-8.25(dd，J ₁＝8.4Hz，J ₂＝1.7Hz，1H)，8.37(s，1H)，9.66(br?s.，1H)。

Embodiment 70 5-[4-chloro-3-(trifluoromethyl) phenyl]-N-[4-(pyridin-4-yl oxygen base) phenyl]-4H-1,2,4-triazole-3-amine trifluoroacetate synthetic

[0268] with 4-[5-(4-chloro-3-(trifluoromethyl)-phenyl)-4H-1,2,4-triazole-3-base is amino] phenol (100mg, 0.282 mmole) is dissolved in the 2mL dry DMF.Add two (trimethyl silyl) acid amides potassium (196.2mg, 0.983 mmole) of solid, the solution that produces was heated 15 minutes at 80 ℃.Add solid K then ₂CO ₃(20mg, 0.141 mmole) adds 4-chloropyridine hydrochloric acid (63.2mg, 0.421 mmole) subsequently.With reaction mixture 220 ℃ of microwave heatings 30 minutes.Then it is diluted with 1mL MeOH, filter, and carry out purifying with the acetonitrile/water gradient that contains 0.1%TFA by anti-phase preparative scale chromatography by 0.22 μ m syringe filter.Collection has the main peak of product quality, and solvent removed in vacuo obtains the trifluoroacetate of product, is light brown solid (23.5mg).

【0269】ESI-MS：[M+H] ⁺432，433. ¹H?NMR(DMSO-d ₆)：δ7.23-7.25(d，J＝8.8Hz，2H)，7.39-7.40(d，J＝7.2Hz，2H)，7.74-7.77(d，J＝8.8Hz，2H)，7.89-7.90(m，1H)，8.24-8.26(dd，J ₁＝8.4Hz，J ₂＝2.0Hz，1H)，8.38(s，1H)，8.73-8.74(d，J＝7.2Hz，2H)，9.75(br?s.，1H)。

Embodiment 71 5-[4-chloro-3-(trifluoromethyl) phenyl]-N-[4-(pyrimidine-5-base oxygen base) phenyl]-4H-1,2,4-triazole-3-amine trifluoroacetate synthetic

[0270] with 4-[5-(4-chloro-3-(trifluoromethyl)-phenyl)-4H-1,2,4-triazole-3-base is amino] phenol (100mg, 0.282 mmole) is dissolved in the 2mL dry DMF.Add two (trimethyl silyl) acid amides potassium (84.1mg, 0.421 mmole) of solid, the solution that produces was heated 15 minutes at 80 ℃.Add solid K then ₂CO ₃(20mg, 0.141 mmole) adds 5-bromo pyrimi piperidine (67.0mg, 0.421 mmole) subsequently.With reaction mixture 220 ℃ of microwave heatings 20 minutes.Then it is diluted with 1mL MeOH, filter, and carry out purifying with the acetonitrile/water gradient that contains 0.1%TFA by anti-phase preparative scale chromatography by 0.22 μ m syringe filter.Collection has the main peak of product quality, and solvent removed in vacuo obtains the trifluoroacetate of product, is light brown solid (25.0mg).

【0271】ESI-MS：[M+H] ⁺432.9，435. ¹H?NMR(DMSO-d ₆)：δ7.14-7.16(d，J＝8.9Hz，2H)，7.63-7.67(d，J＝8.9Hz，2H)，7.87-7.89(d，J＝8.4Hz，1H)，8.22-8.24(dd，J ₁＝8.4Hz，J ₂＝2.0Hz，1H)，8.36(s，1H)，8.54(s，2H)，8.93(s，1H)，9.57(br?s.，1H)。

Embodiment 72 6-[4-({ 5-[4-chloro-3-(trifluoromethyl) phenyl-4H-1,2,4-triazole-3-yl } amino) phenoxy group] pyridazine-3-amine trifluoroacetate synthetic

[0272] with 4-[5-(4-chloro-3-(trifluoromethyl)-phenyl)-4H-1,2,4-triazole-3-base is amino] phenol (100mg, 0.282 mmole) is dissolved in the 2mL dry DMF.Add two (trimethyl silyl) acid amides potassium (140.6mg, 0.705 mmole) of solid, the solution that produces was heated 15 minutes at 80 ℃.Add solid K then ₂CO ₃(20mg, 0.141 mmole) adds 3-amino-6-chlorine pyridazine (54.6mg, 0.421 mmole) subsequently.With reaction mixture 220 ℃ of microwave heatings 40 minutes.Then it is diluted with 1mL MeOH, filter, and carry out purifying with the acetonitrile/water gradient that contains 0.1%TFA by anti-phase preparative scale chromatography by 0.22 μ m syringe filter.Collection has the main peak of product quality, and solvent removed in vacuo obtains the trifluoroacetate of product, is light brown solid (23.1mg).

【0273】ESI-MS：[M+H] ⁺448，449. ¹H?NMR(DMSO-d ₆)：δ7.16-7.18(d，J＝8.9Hz，2H)，7.51-7.53(d，J＝9.7Hz，1H)，7.62-7.66(d，J＝8.9Hz，2H)，7.73-7.75(d，J＝9.7Hz，1H)，7.88(d，J＝8.4Hz，1H)，8.23-8.25(dd，J ₁＝8.4Hz，J ₂＝2.0Hz，1H)，8.36(s，1H)，8.48(br?s.，2H)，9.62(br?s.，1H)。

Embodiment 73 4-[4-(5-[4-chloro-3-(trifluoromethyl) phenyl]-4H-1,2,4-triazole-3-yl } amino) phenoxy group]-N-picoline-2-methane amide trifluoroacetate synthetic

[0274] with 4-[5-(4-chloro-3-(trifluoromethyl)-phenyl)-4H-1,2,4-triazole-3-base is amino] phenol (100mg, 0.282 mmole) is dissolved in the 2mL dry DMF.Add two (trimethyl silyl) acid amides potassium (140.6mg, 0.705 mmole) of solid, the solution that produces was heated 15 minutes at 80 ℃.Add solid K then ₂CO ₃(20mg, 0.141 mmole) adds 4-chloro-2-pyridine-2-carboxamide (71.9mg, 0.421 mmole) subsequently.With reaction mixture 220 ℃ of microwave heatings 20 minutes.Then it is diluted with 1mL MeOH, filter, and carry out purifying with the acetonitrile/water gradient that contains 0.1%TFA by anti-phase preparative scale chromatography by 0.22 μ m syringe filter.Collection has the main peak of product quality, and solvent removed in vacuo obtains the trifluoroacetate of product, is yellow solid (25.4mg).

【0275】ESI-MS：[M+H] ⁺489，490. ¹H?NMR(DMSO-d ₆)：δ2.77-2.78(d，J＝4.8Hz，3H)，7.14-7.15(dd，J ₁＝5.6Hz，J ₂＝2.5Hz，1H)，7.15-7.17(d，J＝9.0Hz，2H)，7.40(d，J＝2.5Hz，1H)，7.68-7.71(d，J＝9.0Hz，2H)，7.87-7.89(d，J＝8.4Hz，1H)，8.23-8.25(dd，J ₁＝8.4Hz，J ₂＝2.0Hz，1H)，8.37(s，1H)，8.49-8.50(d，J＝5.6Hz，1H)，8.75-8.78(q，J＝4.8Hz，1H)，9.65(br?s.，1H)。

Embodiment 74 5-[4-chloro-3-(trifluoromethyl) phenyl]-N-[4-(pyridin-3-yl oxygen base) phenyl]-4H-1,2,4-triazole-3-amine trifluoroacetate synthetic

[0276] with 4-[5-(4-chloro-3-(trifluoromethyl)-phenyl)-4H-1,2,4-triazole-3-base is amino] phenol (200mg, 0.562 mmole) is dissolved in the 2mL dry DMF.Add two (trimethyl silyl) acid amides potassium (280.3mg, 1.405 mmoles) of solid, the solution that produces was heated 15 minutes at 80 ℃.Add solid K then ₂CO ₃(40mg, 0.282 mmole) adds 3-bromopyridine (177.6mg, 1.12 mmoles) subsequently.With reaction mixture 250 ℃ of microwave heatings 20 minutes.Then it is diluted with 1mL MeOH, filter, and carry out purifying with the acetonitrile/water gradient that contains 0.1%TFA by anti-phase preparative scale chromatography by 0.22 μ m syringe filter.Collection has the main peak of product quality, and solvent removed in vacuo obtains the trifluoroacetate of product, is yellow solid (17.0mg).

【0277】ESI-MS：[M+H] ⁺432，433. ¹H?NMR(DMSO-d ₆)：δ7.09-7.11(d，J＝9.0Hz，2H)，7.50-7.52(m，2H)，7.63-7.66(d，J＝9.0Hz，2H)，7.87-7.89(d，J＝8.4Hz，1H)，8.22-8.25(dd，J ₁＝8.4Hz，J ₂＝2.0Hz，1H)，8.37-8.38(m，2H)，8.43(m，1H)，9.56(brs.，1H)。

Embodiment 75 4-(5-{[3-(trifluoromethyl) phenyl] amino }-1,3,4-oxadiazole-2-yl) phenol synthetic

[0278] yellow precipitate (II) (5.33g, 24.60 mmoles) is suspended in about 70mL anhydrous methanol.In this bright orange suspension, add 4-hydroxybenzoyl hydrazine (3.74g, 24.60 mmoles), add 3-trifluoromethyl lsothiocyanates (5.0g, 24.60 mmoles) subsequently.With reaction mixture refluxed 2 hours.The color of reaction mixture becomes pitch-dark and forms black precipitate.Then it is cooled to room temperature and passes through short Celite pad filtration, then by short silicagel pad filtration.With final vacuum remove methyl alcohol and from about 100mL EtOAc with the gray precipitate recrystallization that produces.The white crystalline solid that forms is filtered,, obtain this title product, be white crystals (7.182g) with a small amount of EtOAc washing and vacuum-drying.Yield 71.3%.

【0279】ESI-MS：[M+H] ⁺322.0. ¹H?NMR(DMSO-d ₆)：δ6.92-6.95(d，J＝8.7Hz，2H)，7.33-7.35(d，J＝8.3Hz，1H)，7.57-7.60(t，J＝8.0Hz，1H)，7.72-7.75(d，J＝8.7Hz，2H)，7.80-7.82(dd，J ₁＝8.0Hz，J ₂＝1.8Hz，1H)，8.06(s，1H)，10.21(s，1H)，10.99(brs.，1H)。 ¹³C?NMR(DMSO-d ₆)112.9，114.5，116.1，117.9，120.6，127.6，129.7，130.0，130.3，139.6，158.3，158.9，160.1。

Embodiment 76 6-[4-(5-{[3-(trifluoromethyl) phenyl] amino }-1,3,4-oxadiazole-2-yl) phenoxy group] pyrimidine-2,4-diamines synthetic

[0280] with 4-(5-{[3-(trifluoromethyl)-phenyl] amino-1,3,4-oxadiazole-2-yl)-phenol (160.6mg, 0.5 mmole) is dissolved in the 3mL dry DMF in 2-5mL microwave tube (Personal Chemistry).Add two (trimethyl silyl) acid amides potassium (119.7mg, 0.6 mmole) of solid, and with reaction mixture 80 ℃ of heated and stirred 10 minutes, add 6-chloro-2 then, 4-diamino-pyrimidine (86.7mg, 0.6 mmole) adds anhydrous K subsequently ₂CO ₃(69.1mg, 0.5 mmole).Cover bottle cap then and 200 ℃ of microwave heatings 20 minutes.Then reaction mixture is diluted with about 1mL MeOH, filter, and carry out purifying with the acetonitrile/water system that contains 0.01%TFA by anti-phase preparation HPLC by 0.22 μ m syringe filter.The part that will contain product is collected, and at approximately 40mL EtOAc and the approximately saturated NaHCO of 40mL ₃Between distribute.With the salt water washing of EtOAc layer, in anhydrous Na ₂SO ₄Last dry and filtration.Solvent removed in vacuo obtains this title product, is light brown solid (87.0mg).Yield 37.7%.

【0281】ESI-MS：[M+H] ⁺430.29. ¹H?NMR(DMSO-d ₆)：δ5.19(s，1H)，6.04(s，2H)，6.33(s，2H)，7.27-7.30(d，J＝8.7Hz，2H)，7.36-7.37(d，J＝7.9Hz，1H)，7.59-7.63(t，J＝8.0Hz，1H)，7.82-7.83(dd，J ₁＝8.0Hz，J ₂＝1.8Hz，1H)，7.89-7.92(d，J＝8.7Hz，2H)，8.08(s，1H).11.11(s，1H)。

Embodiment 77 5-[4-(pyrimidine-5-base oxygen base) phenyl]-N-[3-(trifluoromethyl) phenyl]-1,3,4-oxadiazole-2-amine synthetic

[0282] with 4-(5-{[3-(trifluoromethyl)-phenyl] amino-1,3,4-oxadiazole-2-yl)-phenol (160.6mg, 0.5 mmole) is dissolved in the 3mL dry DMF in 2-5mL microwave tube (Personal Chemistry).Add two (trimethyl silyl) acid amides potassium (149.6mg, 0.75 mmole) of solid, and with reaction mixture 80 ℃ of heated and stirred 10 minutes, add 5-bromo pyrimi piperidine (119.2mg, 0.75 mmole) then, add anhydrous K subsequently ₂CO ₃(69.1mg, 0.5 mmole).Cover bottle cap then and 200 ℃ of microwave heatings 20 minutes.Then reaction mixture is diluted with about 1mL MeOH, filter, and carry out purifying with the acetonitrile/water system that contains 0.01%TFA by anti-phase preparation HPLC by 0.22 μ m syringe filter.The part that will contain product is collected, and at approximately 40mLEtOAc and the approximately saturated NaHCO of 40mL ₃Between distribute.With the salt water washing of EtOAc layer, in anhydrous Na ₂SO ₄Last dry and filtration.Solvent removed in vacuo obtains this title product, is light brown solid (81.5mg).Yield 43.5%.

【0283】ESI-MS：[M+H] ⁺400.16. ¹HNMR(DMSO-d ₆)：δ7.31-7.33(d，J＝8.7Hz，2H)，7.35-7.37(d，J＝7.9Hz，1H)，7.59-7.62(t，J＝8.0Hz，1H)，7.81-7.83(dd，J ₁＝8.0Hz，J ₂＝1.8Hz，1H)，7.93-7.95(d，J＝8.7Hz，2H)，8.07(s，1H)，8.76(s，2H)，9.08(s，1H)，11.11(s，1H)。

Embodiment 78 4-{5-[(4-chloro-phenyl-s) amino]-1,3,4-oxadiazole-2-yl } phenol synthetic

[0284] yellow precipitate (II) (6.38g, 29.47 mmoles) is suspended in about 70mL anhydrous methanol.4-hydroxybenzoyl hydrazine (4.48g, 29.47 mmoles) is added in this bright orange suspension, add 4-chloro-phenyl-lsothiocyanates (5.0g, 29.47 mmoles) subsequently.With reaction mixture refluxed 2 hours.The color of reaction mixture becomes pitch-dark and forms black precipitate.Then it is cooled to room temperature and passes through short Celite pad filtration, then by short silicagel pad filtration.With final vacuum remove methyl alcohol and from about 40mL EtOAc with the gray precipitate recrystallization that produces.The white crystals that forms is filtered,, obtain this title product, be white powder with a small amount of EtOAc washing and vacuum-drying.

【0285】ESI-MS：[M+H] ⁺287.94. ¹H?NMR(DMSO-d ₆)：δ6.91-6.94(d，J＝8.7Hz，2H)，7.39-7.41(d，J＝8.9Hz，2H)，7.61-7.63(d，J＝8.9Hz，2H)，7.71-7.74(d，J＝8.7Hz，2H)，10.19(s，1H)，10.73(s，1H)。 ¹³C?NMR(DMSO-d ₆)114.6，116.1，118.5，125.3，127.5，128.9，137.8，158.1，159.1，160.0。

Embodiment 79 6-(4-{5-[(4-chloro-phenyl-) amino]-1,3,4-oxadiazole-2-yl } phenoxy group) pyrimidine-2,4-diamines synthetic

[0286] with the 4-{5-[(4-chloro-phenyl-) amino]-1,3,4-oxadiazole-2-yl } phenol (144.0mg, 0.5 mmole) is dissolved in the 3mL dry DMF in 2-5mL microwave tube (Personal Chemistry).Add two (trimethyl silyl) acid amides potassium (100.0mg, 0.5 mmole) of solid, and with reaction mixture 80 ℃ of heated and stirred 10 minutes, add 6-chloro-2 then, 4-diamino-pyrimidine (72.3mg, 0.5 mmole) adds anhydrous K subsequently ₂CO ₃(34.5mg, 0.25 mmole).Cover bottle cap then and 200 ℃ of microwave heatings 15 minutes.Then reaction mixture is diluted with about 1mL MeOH, filter, and carry out purifying with the acetonitrile/water system that contains 0.01%TFA by anti-phase preparation HPLC by 0.22 μ m syringe filter.The part that will contain product is collected, and at approximately 40mL EtOAc and the approximately saturated NaHCO of 40mL ₃Between distribute.With the salt water washing of EtOAc layer, in anhydrous Na ₂SO ₄Last dry and filtration.Solvent removed in vacuo obtains this title product, is light brown solid (24.5mg).

【0287】ESI-MS：[M+H] ⁺396.25. ¹H?NMR(DMSO-d ₆)：δ5.19(s，1H)，6.04(s，2H)，6.33(s，2H)，7.26-7.29(d，J＝8.7Hz，2H)，7.41-7.43(d，J＝8.9Hz，2H)，7.63-7.65(d，J＝8.9Hz，2H)，7.88-7.90(d，J＝8.7Hz，2H)，10.85(s，1H)。

Embodiment 80 5-[4-(pyrimidine-5-base oxygen base) phenyl]-N-[4-chloro-phenyl]-1,3,4-oxadiazole-2-amine synthetic

[0288] with the 4-{5-[(4-chloro-phenyl-) amino]-1,3,4-oxadiazole-2-yl } phenol (144.0mg, 0.5 mmole) is dissolved in the 3mL dry DMF in 2-5mL microwave tube (Personal Chemistry).Add two (trimethyl silyl) acid amides potassium (100.0mg, 0.5 mmole) of solid, and with reaction mixture 80 ℃ of heated and stirred 10 minutes, add 5-bromo pyrimi piperidine (79.5mg, 0.5 mmole) then, add anhydrous K subsequently ₂CO ₃(34.5mg, 0.25 mmole).Cover bottle cap then and 200 ℃ of microwave heatings 15 minutes.Then reaction mixture is diluted with about 1mL MeOH, filter, and carry out purifying with the acetonitrile/water system that contains 0.01%TFA by anti-phase preparation HPLC by 0.22 μ m syringe filter.The part that will contain product is collected, and at approximately 40mL EtOAc and the approximately saturated NaHCO of 40mL ₃Between distribute.With the salt water washing of EtOAc layer, in anhydrous Na ₂SO ₄Last dry and filtration.Solvent removed in vacuo obtains this title product, is light brown solid (61.6mg).

【0289】ESI-MS：[M+H] ⁺366.24. ¹H?NMR(DMSO-d ₆)：δ7.30-7.32(d，J＝8.7Hz，2H)，7.41-7.43(d，J＝8.9Hz，2H)，7.63-7.65(d，J＝8.9Hz，2H)，7.92-7.94(d，J＝8.7Hz，2H)，8.76(s，2H)，9.08(s，1H)，10.85(s，1H)。

Embodiment 81 4-(5-{[2-chloro-5-(trifluoromethyl) phenyl] amino }-1,3,4-oxadiazole-2-yl) phenol synthetic

[0290] yellow precipitate (II) (1.82g, 8.41 mmoles) is suspended in about 50mL anhydrous methanol.4-hydroxybenzoyl hydrazine (1.28g, 8.41 mmoles) is added in this bright orange suspension, add 2-chloro-5-trifluoromethyl-phenyl lsothiocyanates (2.0g, 8.41 mmoles) subsequently.With reaction mixture refluxed 2 hours.The color of reaction mixture becomes pitch-dark and forms black precipitate.Then it is cooled to room temperature and passes through short Celite pad filtration, then by short silicagel pad filtration.With final vacuum remove methyl alcohol and from about 20mL EtOAc with the gray solid recrystallization that produces.The white precipitate that forms is filtered, use anhydrous Et ₂O washing and vacuum-drying obtain this title product, are white solid (2.638g).Yield 88.1%.

【0291】ESI-MS：[M+H] ⁺356.22. ¹H?NMR(DMSO-d ₆)：δ6.93-6.96(d，J＝8.7Hz，2H)，7.41-7.43(dd，J ₁＝8.3Hz，J ₂＝1.7Hz，1H)，7.72-7.75(m，3H)，8.61(s，1H)，10.23(s，1H)，10.30(s，1H)。

Embodiment 82 6-(4-{5-[(2-chloro-5-trifluoromethyl-phenyl) amino]-1,3,4-oxadiazole-2-yl } phenoxy group) pyrimidine-2,4-diamines synthetic

[0292] with 4-(5-{[2-chloro-5-(trifluoromethyl) phenyl] amino-1,3,4-oxadiazole-2-yl) phenol (177.85mg, 0.5 mmole) is dissolved in the 3mL dry DMF in 2-5mL microwave tube (Personal Chemistry).Add two (trimethyl silyl) acid amides potassium (200.0mg, 1.0 mmoles) of solid, and with reaction mixture 80 ℃ of heated and stirred 10 minutes, add 6-chloro-2 then, 4-=amino-pyrimidine (86.7mg, 0.6 mmole) adds anhydrous K subsequently ₂CO ₃(69.1mg, 0.5 mmole).Cover bottle cap then and 180 ℃ of microwave heatings 30 minutes.Then reaction mixture is diluted with about 1mL MeOH, filter, and carry out purifying with the acetonitrile/water system that contains 0.01%TFA by anti-phase preparation HPLC by 0.22 μ m syringe filter.The part that will contain product is collected, and at approximately 50mL EtOAc and the approximately saturated NaHCO of 50mL ₃Distribute between the aqueous solution.With the salt water washing of EtOAc layer, in anhydrous Na ₂SO ₄Last dry and filtration.Solvent removed in vacuo obtains this title product, is pale solid (131.1mg).Yield 56.5%.

【0293】ESI-MS：[M+H] ⁺464.21. ¹H?NMR(DMSO-d ₆)：δ5.20(s，1H)，6.05(s，2H)，6.34(s，2H)，7.28-7.31(d，J＝8.7Hz，2H)，7.46-7.48(dd，J ₁＝8.3Hz，J ₂＝1.8Hz，1H)，7.76-7.78(d，J＝8.3Hz，1H)，7.90-7.92(d，J＝8.7Hz，2H)，8.62(s，1H)，10.47(s，1H)。

Embodiment 83 5-[4-(pyrimidine-5-base oxygen base) phenyl]-N-[2-chloro-5-(trifluoromethyl)-phenyl]-1,3,4-oxadiazole-2-amine synthetic

[0294] with 4-(5-{[2-chloro-5-(trifluoromethyl) phenyl] amino-1,3,4-oxadiazole-2-yl) phenol (177.85mg, 0.5 mmole) is dissolved in the 3mL dry DMF in 2-5mL microwave tube (Personal Chemistry).Add two (trimethyl silyl) acid amides potassium (200.0mg, 1.0 mmoles) of solid, and with reaction mixture 80 ℃ of heated and stirred 10 minutes, add 5-bromo pyrimi piperidine (95.4mg, 0.6 mmole) then, add anhydrous K subsequently ₂CO ₃(69.1mg, 0.5 mmole).Cover bottle cap then and 180 ℃ of microwave heatings 40 minutes.Then reaction mixture is diluted with about 1mL MeOH, filter, and carry out purifying with the acetonitrile/water system that contains 0.01%TFA by anti-phase preparation HPLC by 0.22 μ m syringe filter.The part that will contain product is collected, and at approximately 50mL EtOAc and the approximately saturated NaHCO of 50mL ₃Distribute between the aqueous solution.With the salt water washing of EtOAc layer, in anhydrous Na ₂SO ₄Last dry and filtration.Solvent removed in vacuo obtains this title product, is light brown solid (129.1mg).Yield 59.5%.

【0295】ESI-MS：[M+H] ⁺434.20. ¹H?NMR(DMSO-d ₆)：δ7.32-7.35(d，J＝8.7Hz，2H)，7.46-7.48(dd，J ₁＝8.3Hz，J ₂＝1.8Hz，1H)，7.76-7.78(d，J＝8.3Hz，1H)，7.94-7.96(d，J＝8.7Hz，2H)，8.61(s，1H)，8.77(s，2H)，9.09(s，1H)，10.47(s，1H)。

Embodiment 84 4-{5-[(3-chloro-phenyl-s) amino]-1,3,4-oxadiazole-2-yl } phenol synthetic

[0296] yellow precipitate (II) (6.38g, 29.47 mmoles) is suspended in about 100mL anhydrous methanol.4-hydroxybenzoyl hydrazine (4.48g, 29.47 mmoles) is added in this bright orange suspension, add 3-chloro-phenyl-lsothiocyanates (5.0g, 29.47 mmoles) subsequently.With reaction mixture refluxed 2 hours.The color of reaction mixture becomes pitch-dark and forms black precipitate.Then it is cooled to room temperature and passes through short Celite pad filtration.With the EtOAc that contains 0% to 20% methyl alcohol gradient it is carried out purifying by silica gel chromatography then.Solvent removed in vacuo and from about 50mLEtOAc with the gray precipitate recrystallization that produces.The white crystalline solid that forms is filtered, with a small amount of EtOAc and anhydrous Et ₂O washing, and vacuum-drying obtain this title product, are white powder (7.606g).Yield 89.7%.

【0297】ESI-MS：[M+H] ⁺288.26. ¹H?NMR(DMSO-d ₆)：δ6.92-6.94(d，J＝8.7Hz，2H)，7.00-7.02(dd，J ₁＝7.9Hz，J ₂＝1.8Hz，1H)，7.33-7.36(t，J＝8.1Hz，1H)，7.47-7.49(dd，J ₁＝8.1Hz，J ₂＝1.8Hz，1H)，7.72-7.74(d，J＝8.7Hz，2H)，7.76-7.78(t，J＝2.1Hz，1H)，10.19(s，1H)，10.81(s，1H)。 ¹³C?NMR(DMSO-d ₆)114.6，115.5，116.1，116.4，121.3，127.6，130.6，133.5，140.3，158.3，159.0，160.1。

Embodiment 85 6-(4-{5-[(3-chloro-phenyl-) amino]-1,3,4-oxadiazole-2-yl } phenoxy group) pyrimidine-2,4-diamines synthetic

[0298] with the 4-{5-[(3-chloro-phenyl-) amino]-1,3,4-oxadiazole-2-yl } phenol (143.8mg, 0.5 mmole) is dissolved in the 3mL dry DMF in 2-5mL microwave tube (Personal Chemistry).Add two (trimethyl silyl) acid amides potassium (200.0mg, 1.0 mmoles) of solid, and with reaction mixture 80 ℃ of heated and stirred 10 minutes, add 6-chloro-2 then, 4-diamino-pyrimidine (86.7mg, 0.6 mmole) adds anhydrous K subsequently ₂CO ₃(69.1mg, 0.5 mmole).Cover bottle cap then and 180 ℃ of microwave heatings 40 minutes.Then reaction mixture is diluted with about 1mLMeOH, filter, and carry out purifying with the acetonitrile/water system that contains 0.01%TFA by anti-phase preparation HPLC by 0.22 μ m syringe filter.The part that will contain product is collected, and at approximately 50mL EtOAc and the approximately saturated NaHCO of 50mL ₃Distribute between the aqueous solution.With the salt water washing of EtOAc layer, in anhydrous Na ₂SO ₄Last dry and filtration.Solvent removed in vacuo obtains this title product, is light yellow solid (62.0mg).Yield 31.3%.

【0299】ESI-MS：[M+H] ⁺396.22. ¹H?NMR(DMSO-d ₆)：δ5.19(s，1H)，6.04(s，2H)，6.33(s，2H)，7.06-7.08(m，1H)，7.27-7.29(d，J＝8.7Hz，2H)，7.37-7.41(t，J＝8.1Hz，1H)，7.50-7.52(dd，J ₁＝8.1Hz，J ₂＝1.8Hz，1H)，7.78-7.79(t，J＝2.1Hz，1H)，7.89-7.90(d，J＝8.7Hz，2H)，10.95(s，1H)。

Embodiment 86 5-[4-(pyrimidine-5-base oxygen base) phenyl]-N-[3-chloro-phenyl]-1,3,4-oxadiazole-2-amine synthetic

[0300] with the 4-{5-[(3-chloro-phenyl-) amino]-1,3,4-oxadiazole-2-yl } phenol (143.8mg, 0.5 mmole) is dissolved in the 3mL dry DMF in 2-5mL microwave tube (Personal Chemistry).Add two (trimethyl silyl) acid amides potassium (200.0mg, 1.0 mmoles) of solid, and with reaction mixture 80 ℃ of heated and stirred 10 minutes, add 5-bromo pyrimi piperidine (95.4mg, 0.6 mmole) then, add anhydrous K subsequently ₂CO ₃(69.1mg, 0.5 mmole).Cover bottle cap then and 180 ℃ of microwave heatings 30 minutes.Then reaction mixture is diluted with about 1mL MeOH, filter, and carry out purifying with the acetonitrile/water system that contains 0.01%TFA by anti-phase preparation HPLC by 0.22 μ m syringe filter.The part that will contain product is collected, and at approximately 50mL EtOAc and the approximately saturated NaHCO of 50mL ₃Distribute between the aqueous solution.With the salt water washing of EtOAc layer, in anhydrous Na ₂SO ₄Last dry and filtration.Solvent removed in vacuo obtains this title product, is light yellow solid (74.7mg).Yield 40.8%.

【0301】ESI-MS：[M+H] ⁺366.23. ¹H?NMR(DMSO-d ₆)：δ7.06-7.08(m，1H)，7.31-7.33(d，J＝8.7Hz，2H)，7.37-7.41(t，J＝8.1Hz，1H)，7.50-7.52(dd，J ₁＝8.1Hz，J ₂＝1.8Hz，1H)，7.77-7.79(t，J＝2.0Hz，1H)，7.93-7.94(d，J＝8.7Hz，2H)，8.77(s，2H)，9.09(s，1H)，10.96(s，1H)。

Embodiment 87 5-[4-(pyridin-3-yl oxygen base) phenyl]-1,3,4-oxadiazole-2-amine hydrobromate synthetic

[0302] 4-(pyridin-3-yl oxygen base) benzo hydrazides (3.7g, 16.14 mmoles) is dissolved among the anhydrous THF of 100mL, and adds the cyanogen bromide (5.38mL, 16.14 mmoles) of 3.0M by syringe.Stirred 5-10 minute, the orange precipitation begins to form.With reaction mixture refluxed 1 hour.Then it is cooled to room temperature and filtration.The orange of collecting is precipitated with about 100mL THF, about 100mL EtOAc, anhydrous Et ₂O washing and vacuum-drying obtain this title product, are orange solid (4.40g).Yield 81.4%.

【0303】ESI-MS：[M+H] ⁺255.05. ¹H?NMR(DMSO-d ₆)：δ7.27-7.29(d，J＝8.8Hz，2H)，7.75-7.78(dd，J ₁＝8.5Hz，J ₂＝5.0Hz，1H)，7.85-7.87(d，J＝8.8Hz，2H)，7.92-7.94(m，1H)，8.59-8.60(dd，J ₁＝5.0Hz，J ₂＝1.0Hz，1H)，8.69-8.70(d，J＝2.7Hz，1H)。

Embodiment 88N-{5-[4-(pyridin-3-yl oxygen base) phenyl]-1,3,4-oxadiazole-2-yl }-4-(trifluoromethoxy) benzamide synthetic

[0304] with 5-[4-(pyridin-3-yl oxygen base) phenyl]-1,3,4-oxadiazole-2-amine hydrobromate (167.5mg, 0.5 mmole) is suspended in the 2mL anhydrous pyridine.4-trifluoromethoxy Benzoyl chloride (167.2mg, 117 μ L, 0.75 mmole) is directly added in this solution.Reaction mixture forms the orange solution that has small amount of precipitate.It was stirred 6 hours.With about 1mLMeOH it is diluted then, filter, and carry out purifying with the acetonitrile/water mixture that contains 0.01%TFA by anti-phase preparation HPLC by 0.22 μ m syringe filter.The part that will contain product merges, and at approximately 40mL EtOAc and the approximately saturated NaHCO of 40mL ₃Distribute between the aqueous solution.With the salt water washing of EtOAc layer, in anhydrous Na ₂SO ₄Last dry and filtration.Solvent removed in vacuo obtains this title product, is yellow solid (89.0mg).Yield 40.2%.

【0305】ESI-MS：[M+H] ⁺442.82. ¹H?NMR(DMSO-d ₆)：δ7.20-7.22(d，J＝8.8Hz，2H)，7.44-7.46(d，J＝8.6Hz，2H)，7.48-7.51(dd，J ₁＝8.4Hz，J ₂＝4.6Hz，1H)，7.59-7.62(ddd，J ₁＝8.4Hz，J ₂＝2.8Hz，J ₃＝1.2Hz，1H)，7.94-7.96(d，J＝8.8Hz，2H)，8.17-8.19(d，J＝8.6Hz，2H)，8.45-8.46(dd，J ₁＝4.6Hz，J ₂＝1.2Hz，1H)，8.48-8.49(d，J＝2.8Hz，1H)。

Embodiment 89N-{5-[4-(pyridin-3-yl oxygen base) phenyl]-1,3,4-oxadiazole-2-yl }-3-(trifluoromethyl) benzamide synthetic

[0306] with 5-[4-(pyridin-3-yl oxygen base) phenyl]-1,3,4-oxadiazole-2-amine hydrobromate (167.5mg, 0.5 mmole) is suspended in the 2mL anhydrous pyridine.3-trifluoromethyl benzoyl chloride (156.4mg, 0.75 mmole) is added in this solution.Reaction mixture forms the orange solution that has a small amount of white precipitate.It was stirred 3 hours.With about 1mLMeOH dilution, filter by 0.22 μ m syringe filter, and carry out purifying with the acetonitrile/water mixture that contains 0.01%TFA then by anti-phase preparation HPLC.The part that will contain product merges, and at approximately 40mL EtOAc and the approximately saturated NaHCO of 40mL ₃Distribute between the aqueous solution.With the salt water washing of EtOAc layer, dry and filtration on anhydrous sodium sulphate.Solvent removed in vacuo obtains this title product, is yellow solid (50.0mg).Yield 23.4%.

【0307】ESI-MS：[M+H] ⁺426.94. ¹H?NMR(DMSO-d ₆)：δ7.21-7.23(d，J＝8.8Hz，2H)，7.49-7.51(dd，J ₁＝8.4Hz，J ₂＝4.6Hz，1H)，7.60-7.62(ddd，J ₁＝8.4Hz，J ₂＝2.8Hz，J ₃＝1.2Hz，1H)，7.75-7.76(t，J＝7.7Hz，1H)，7.95-7.98(m，3H)，8.33-8.34(d，J＝7.7Hz，1H)，8.39(s，1H)，8.46-8.47(dd，J ₁＝4.6Hz，J ₂＝1.2Hz，1H)，8.48-8.49(d，J＝2.8Hz，1H)。

Embodiment 90 4-bromo-N-{5-[4-(pyridin-3-yl oxygen base) phenyl]-1,3,4-oxadiazole-2-yl }-benzamide synthetic

[0308] with 5-[4-(pyridin-3-yl oxygen base) phenyl]-1,3,4-oxadiazole-2-amine hydrobromate (167.5mg, 0.5 mmole) is suspended in the 2mL anhydrous pyridine.4-bromo-benzoyl chloride (164.6mg, 0.75 mmole) is added in this solution.Reaction mixture forms the orange solution that has a small amount of white precipitate.It was stirred 3 hours.With about 1mL MeOH dilution, filter by 0.22 μ m syringe filter, and carry out purifying with the acetonitrile/water mixture that contains 0.01%TFA then by anti-phase preparation HPLC.The part that will contain product merges, and at approximately 40mL EtOAc and the approximately saturated NaHCO of 40mL ₃Distribute between the aqueous solution.With the salt water washing of EtOAc layer, dry and filtration on anhydrous sodium sulphate.Solvent removed in vacuo obtains this title product, is yellow solid (46.5mg).Yield 21.2%.

【0309】ESI-MS：[M+H] ⁺438.84. ¹H?NMR(DMSO-d ₆)：δ7.20-7.22(d，J＝8.8Hz，2H)，7.49-7.51(dd，J ₁＝8.4Hz，J ₂＝4.6Hz，1H)，7.60-7.62(ddd，J ₁＝8.4Hz，J ₂＝2.8Hz，J ₃＝1.2Hz，1H)，7.68-7.70(d，J＝8.4Hz，2H)，7.95-7.97(d，J＝8.8Hz，2H)，8.00-8.02(d，J＝8.4Hz，2H)，8.45-8.46(dd，J ₁＝4.6Hz，J ₂＝1.2Hz，1H)，8.48-8.49(d，J＝2.8Hz，1H)。

Embodiment 91N-{5-[4-(pyridin-3-yl oxygen base) phenyl]-1,3,4-oxadiazole-2-yl }-3-(trifluoromethoxy)-benzamide synthetic

[0310] with 5-[4-(pyridin-3-yl oxygen base) phenyl]-1,3,4-oxadiazole-2-amine hydrobromate (167.5mg, 0.5 mmole) is suspended in the 2mL anhydrous pyridine.(117 μ L) directly adds in this solution with pure 3-trifluoromethoxy Benzoyl chloride.Reaction mixture forms the orange solution that has a small amount of white precipitate.It was stirred 3 hours.With about 1mLMeOH it is diluted then, filter, and carry out purifying with the acetonitrile/water mixture that contains 0.01%TFA by anti-phase preparation HPLC by 0.22 μ m syringe filter.The part that will contain product merges, and at approximately 40mL EtOAc and the approximately saturated NaHCO of 40mL ₃Distribute between the aqueous solution.With the salt water washing of EtOAc layer, dry and filtration on anhydrous sodium sulphate.Solvent removed in vacuo obtains this title product, is yellow solid (38.8mg).Yield 17.5%.

【0311】ESI-MS：[M+H] ⁺442.85. ¹H?NMR(DMSO-d ₆)：δ7.22-7.24(d，J＝8.8Hz，2H)，7.49-7.51(dd，J ₁＝8.4Hz，J ₂＝4.6Hz，1H)，7.60-7.62(ddd，J ₁＝8.4Hz，J ₂＝2.8Hz，J ₃＝1.2Hz，1H)，7.61-7.63(m，1H)，7.68.-7.71(t，J＝7.7Hz，1H)，7.97-7.98(m，3H)，8.08-8.10(d，J＝7.7Hz，1H)，8.46-8.47(dd，J ₁＝4.6Hz，J ₂＝1.2Hz，1H)，8.48-8.49(d，J＝2.8Hz，1H)。

Embodiment 92 4-methoxyl group-N-{5-[4-(pyridin-3-yl oxygen base) phenyl]-1,3,4-oxadiazole-2-yl }-3-(trifluoromethyl)-benzamide synthetic

[0312] with 5-[4-(pyridin-3-yl oxygen base) phenyl]-1,3,4-oxadiazole-2-amine hydrobromate (167.5mg, 0.5 mmole) is suspended in the 2mL anhydrous pyridine.Pure 4-methoxyl group-3-trifluoromethyl benzoyl chloride (179.0mg, 0.75 mmole) is directly added in this solution.Reaction mixture forms the orange solution that has a small amount of white precipitate.It was stirred 3 hours.With about 1mL MeOH it is diluted then, filter, and carry out purifying with the acetonitrile/water mixture that contains 0.01%TFA by anti-phase preparation HPLC by 0.22 μ m syringe filter.The part that will contain product merges, and at approximately 40mL EtOAc and the approximately saturated NaHCO of 40mL ₃Distribute between the aqueous solution.With the salt water washing of EtOAc layer, dry and filtration on anhydrous sodium sulphate.Solvent removed in vacuo obtains this title product, is yellow solid (37.0mg).Yield 16.2%.

【0313】ESI-MS：[M+H] ⁺456.85. ¹H?NMR(DMSO-d ₆)：δ3.97(s，3H)，7.21-7.23(d，J＝8.8Hz，2H)，7.38-7.40(d，J＝9.1Hz，1H)，7.49-7.51(dd，J ₁＝8.4Hz，J ₂＝4.6Hz，1H)，7.60-7.62(ddd，J ₁＝8.4Hz，J ₂＝2.8Hz，J ₃＝1.2Hz，1H)，7.95-7.97(d，J＝8.8Hz，2H)，8.34-8.35(m，2H)，8.46-8.47(dd，J ₁＝4.6Hz，J ₂＝1.2Hz，1H)，8.48-8.49(d，J＝2.8Hz，1H)。

Embodiment 93 2,2-two fluoro-N-{5-[4-(pyridin-3-yl oxygen base) phenyl]-1,3,4-oxadiazole-2-yl }-1, dioxolane between the 3-benzo-5-carboxylic acid amides synthetic

[0314] with 5-[4-(pyridin-3-yl oxygen base) phenyl]-1,3,4-oxadiazole-2-amine hydrobromate (167.5mg, 0.5 mmole) is suspended in the 2mL anhydrous pyridine.With pure 2,2-two fluoro-1, dioxolane between the 3-benzo-5-formyl chloride (165.4mg, 0.75 mmole) directly adds in this solution.Reaction mixture forms the orange solution that has a small amount of white precipitate.It was stirred 3 hours.With about 1mL MeOH it is diluted then, filter, and carry out purifying with the acetonitrile/water mixture that contains 0.01%TFA by anti-phase preparation HPLC by 0.22 μ m syringe filter.The part that will contain product merges, and at approximately 40mL EtOAc and the approximately saturated NaHCO of 40mL ₃Distribute between the aqueous solution.With the salt water washing of EtOAc layer, dry and filtration on anhydrous sodium sulphate.Solvent removed in vacuo obtains this title product, is yellow solid (27.0mg).Yield 12.3%.

【0315】ESI-MS：[M+H] ⁺456.85. ¹H?NMR(DMSO-d ₆)：δ7.19-7.21(d，J＝8.8Hz，2H)，7.47-7.51(m，2H)，7.58-7.60(ddd，J ₁＝8.4Hz，J ₂＝2.8Hz，J ₃＝1.2Hz，1H)，7.93-7.95(d，J＝8.8Hz，2H)，7.99-8.01(m，2H)，8.45-8.46(dd，J ₁＝4.6Hz，J ₂＝1.2Hz，1H)，8.48-8.49(d，J＝2.8Hz，1H)。

Embodiment 94 3-chloro-2-fluoro-N-{5-[4-(pyridin-3-yl oxygen base) phenyl]-1,3,4-oxadiazole-2-yl }-5-(trifluoromethyl)-benzamide synthetic

[0316] with 5-[4-(pyridin-3-yl oxygen base) phenyl]-1,3,4-oxadiazole-2-amine hydrobromate (167.5mg, 0.5 mmole) is suspended in the 2mL anhydrous pyridine.Pure 3-chloro-2-fluoro-5-trifluoromethyl benzoyl chloride (250 μ L) is directly added in this solution.Reaction mixture forms the red solution that has a small amount of white precipitate.It was stirred 18 hours.With about 1mL MeOH it is diluted then, filter, and carry out purifying with the acetonitrile/water mixture that contains 0.01%TFA by anti-phase preparation HPLC by 0.22 μ m syringe filter.The part that will contain product merges, and at approximately 40mL EtOAc and the approximately saturated NaHCO of 40mL ₃Distribute between the aqueous solution.With the salt water washing of EtOAc layer, dry and filtration on anhydrous sodium sulphate.Solvent removed in vacuo obtains this title product, is yellow solid (83.4mg).Yield 34.8%.

【0317】ESI-MS：[M+H] ⁺480.71. ¹H?NMR(DMSO-d ₆)：δ7.18-7.20(d，J＝8.8Hz，2H)，7.47-7.50(dd，J ₁＝8.4Hz，J ₂＝4.6Hz，1H)，7.58-7.60(ddd，J ₁＝8.4Hz，J ₂＝2.8Hz，J ₃＝1.2Hz，1H)，7.92-7.94(d，J＝8.8Hz，2H)，8.13-8.16(m，2H)，8.44-8.45(dd，J ₁＝4.6Hz，J ₂＝1.2Hz，1H)，8.47-8.48(d，J＝2.8Hz，1H)。

Embodiment 95 4-fluoro-N-{5-[4-(pyridin-3-yl oxygen base) phenyl]-1,3,4-oxadiazole-2-yl }-3-(trifluoromethyl)-benzamide synthetic

[0318] with 5-[4-(pyridin-3-yl oxygen base) phenyl]-1,3,4-oxadiazole-2-amine hydrobromate (167.5mg, 0.5 mmole) is suspended in the 2mL anhydrous pyridine.Pure 4-fluoro-3-trifluoromethyl benzoyl chloride (200 μ L) is directly added in this solution.It was stirred 18 hours.Reaction mixture forms the red solution that has yellow mercury oxide.With about 1mL MeOH it is diluted then, filter, and carry out purifying with the acetonitrile/water mixture that contains 0.01%TFA by anti-phase preparation HPLC by 0.22 μ m syringe filter.The part that will contain product merges, and at approximately 40mLEtOAc and the approximately saturated NaHCO of 40mL ₃Distribute between the aqueous solution.With the salt water washing of EtOAc layer, dry and filtration on anhydrous sodium sulphate.Solvent removed in vacuo obtains this title product, is yellow solid (105.1mg).Yield 47.3%.

【0319】ESI-MS：[M+H] ⁺444.79. ¹HNMR(DMSO-d ₆)：δ7.18-7.20(d，J＝8.8Hz，2H)，7.47-7.50(dd，J ₁＝8.4Hz，J ₂＝4.6Hz，1H)，7.53-7.60(m，2H)，7.93-7.94(d，J＝8.8Hz，2H)，8.40-8.43(m，1H)，8.43-8.45(dd，J ₁＝4.6Hz，J ₂＝1.2Hz，1H)，8.47-8.48(d，J＝2.8Hz，1H)。

Embodiment 96N-{5-[4-(pyridin-3-yl oxygen base) phenyl]-1,3,4-oxadiazole-2-yl }-2-(trifluoromethoxy)-benzamide synthetic

[0320] with 5-[4-(pyridin-3-yl oxygen base) phenyl]-1,3,4-oxadiazole-2-amine hydrobromate (167.5mg, 0.5 mmole) is suspended in the 2mL anhydrous pyridine.(100 μ L) directly adds in this solution with pure 2-trifluoromethoxy Benzoyl chloride.It was stirred 18 hours.Reaction mixture forms the orange solution that has yellow mercury oxide.With about 1mL MeOH it is diluted then, filter, and carry out purifying with the acetonitrile/water mixture that contains 0.01%TFA by anti-phase preparation HPLC by 0.22 μ m syringe filter.The part that will contain product merges, and at approximately 40mLEtOAc and the approximately saturated NaHCO of 40mL ₃Distribute between the aqueous solution.With the salt water washing of EtOAc layer, dry and filtration on anhydrous sodium sulphate.Solvent removed in vacuo obtains this title product, is glassy yellow solid (20.2mg).Yield 9.1%.

【0321】ESI-MS：[M+H] ⁺443.04. ¹H?NMR(DMSO-d ₆)：δ7.22-7.24(d，J＝8.8Hz，2H)，7.48-7.54(m，4H)，7.60-7.63(ddd，J ₁＝8.4Hz，J ₂＝2.8Hz，J ₃＝1.2Hz，1H)，7.69-7.71(t，J＝7.8Hz，1H)，7.80-7.81(d，J＝7.5Hz，1H)，7.94-7.96(d，J＝8.8Hz，2H)，8.47-8.49(m，2H)。

Synthesizing of embodiment 97N-amino-N '-(4-chloro-3-trifluoromethyl-phenyl-guanidine) hydriodide

[0322] mixture with 2.54g 4-chloro-3-trifluoromethyl-phenylthiourea, 0.62mL methyl iodide refluxes 1 hour so that 1-[4-chloro-3-(trifluoromethyl) phenyl to be provided in the anhydrous EtOH of 50mL]-S-methyl-isothiourea hydriodide.Then it is cooled to room temperature and uses the hydrazine of 0.35g 98% to handle, mild heat calms down until the violent release of original M eSH under stirring, and then refluxes 1 hour.

Embodiment 98 4-(3-{[4-chloro-3-(trifluoromethyl) phenyl] amino }-1,2,4-triazine-5-yl) phenol synthetic

[0323] N-amino-N '-[4-chloro-3-(trifluoromethyl) phenyl]-guanidine hydriodide and the normal 4-hydroxyl of the about 1.0-1.5-phenyl oxalic dialdehyde in 1: 1 methanol/water mixture can be carried out reacting to produce this title product.This product can perhaps be separated by silica gel column chromatography by precipitation or by with a large amount of solvents such as ethyl acetate, methylene dichloride or extracted with diethyl ether.

Embodiment 99 4-[4-(3-{[4-chloro-3-(trifluoromethyl) phenyl] amino }-[1,2,4] triazine-5-yl) phenoxy group]-N-picoline-2-carboxylic acid amides synthetic

[0324] 4-of 7.23g (19.73 mmole) (3-{[4-chloro-3-(trifluoromethyl)-phenyl] amino-1,2,4-triazine-5-yl) phenol can be dissolved in the 80mL dry DMF under argon gas.2.44g the solid potassium tert-butoxide of (21.71 mmoles, 1.1 equivalents) can be added in this solution.The mixture that is produced can be heated to about 100 ℃ and stirred 15 minutes in this temperature.Can add 10mL then and contain the anhydrous DMF solution of the 4-chloro-pyridine-2-carboxylic acids methyl nitrosourea of 3.7g (21.71 mmoles, 1.1 equivalents), add the anhydrous K of 3.28g (23.68 mmoles, 1.2 equivalents) subsequently ₂CO ₃Can be with reaction mixture 140 ℃ of heating 30 hours.This reaction process can be monitored by LC/MS.It can be cooled to room temperature then.The mixture that is produced can be introduced in 500mL water and the 100mL ethyl acetate.The waterbearing stratum can be extracted with a large amount of solvents such as ethyl acetate, methylene dichloride or ether.Extraction liquid after the merging can be used the salt water washing and drying on anhydrous sodium sulphate then with 100mL water washing 3 times.Can solvent removed in vacuo, produce rough 4-[4-(3-phenyl amino-[1,2,4] triazine-6-yl)-phenoxy group]-the pyridine-2-carboxylic acids methyl nitrosourea.Then can be with product with silica gel column chromatography purifying in addition.Those of ordinary skill in the art can determine which kind of solvent systems can be used as the eluent in the chromatographic purification process.

Synthesizing of embodiment 100 4-(3-ethylmercapto group-[1,2,4] triazine-5-yl)-phenol

[0325] can be with the normal 4-hydroxy phenyl of 1.0-1.5 oxalic dialdehyde with containing 1.0-2.0 equivalent K ₂CO ₃1: 1 methanol/water mixture in 1-amino-S-ethyl isothiourea hydrobromide react to produce 4-(3-ethylmercapto group-[1,2,4] triazine-5-yl)-phenol.This product can perhaps be separated by silica gel column chromatography by big metering method well known by persons skilled in the art such as precipitation or with a large amount of solvents such as ethyl acetate, methylene dichloride or extracted with diethyl ether.

Synthesizing of embodiment 101 4-(3-amino-[1,2,4] triazine-5-yl)-phenol

[0326] can be with 1.0 normal 4-(3-ethylmercapto group-[1,2,4] triazine-6-yl)-phenol Yu in the diox the normal ammonia of 1-5 react so that 4-(3-amino-[1,2,4] triazine-5-yl)-phenol to be provided.This product can perhaps be separated by silica gel column chromatography by big metering method well known by persons skilled in the art such as precipitation or with a large amount of solvents such as ethyl acetate, methylene dichloride or extracted with diethyl ether.

Embodiment 102 4-[4-(3-amino-[1,2,4] triazine-5-yl)-phenoxy group]-N-picoline-2-carboxylic acid amides synthetic

[0327] 4-of 3.71g (19.73 mmole) (3-amino-[1,2,4] triazine-5-yl)-phenol can be dissolved in the 80mL dry DMF under argon gas.2.44g the solid potassium tert-butoxide of (21.71 mmoles, 1.1 equivalents) can be added in this solution.The mixture that is produced can be heated to about 100 ℃ and stirred 15 minutes in this temperature.Can add 10mL then and contain the anhydrous DMF solution of the 4-chloro-pyridine-2-carboxylic acids methyl nitrosourea of 3.7g (21.71 mmoles, 1.1 equivalents), add the anhydrous K of 3.28g (23.68 mmoles, 1.2 equivalents) subsequently ₂CO ₃Reaction mixture was heated 30 hours at 140 ℃.The process of this reaction can be monitored by LC/MS.It can be cooled to room temperature then.The mixture that is produced can be introduced in 500mL water and the 100mL ethyl acetate.The waterbearing stratum can be extracted with a large amount of solvents such as ethyl acetate, methylene dichloride or ether.Extraction liquid after the merging can be used the salt water washing and drying on anhydrous sodium sulphate then with 100mL water washing 3 times.Can solvent removed in vacuo to produce rough 4-[4-(3-amino-[1,2,4] triazine-5-yl)-phenoxy group]-N-picoline-2-carboxylic acid amides.Then can be with product with silica gel column chromatography purifying in addition.Those of ordinary skill in the art can determine which kind of solvent systems can be used as the eluent in the chromatographic purification process.

Embodiment 103 4-[4-(3-{[4-chloro-3-(trifluoromethyl) benzoyl] amino }-[1,2,4] triazine-5-yl)-phenoxy group]-N-picoline-2-carboxylic acid amides synthetic

[0328] 4-[4-of 108.6mg (0.337 mmole, 1.0 equivalents) (3-amino-[1,2,4] triazine-5-yl)-phenoxy group]-N-picoline-2-carboxylic acid amides can be dissolved in the 2mL dry DMF and be heated to about 100 ℃.45.4mg the solid potassium tert-butoxide of (0.405 mmole, 1.2 equivalents) can be added in this solution, adds the 4-chloro-3-trifluoromethyl benzoyl chloride of 0.405 mmole (1.2 equivalent) subsequently.It was at room temperature stirred 1-2 hour.This product can perhaps by silica gel column chromatography, perhaps be separated by anti-phase preparation HPLC chromatogram by big metering method well known by persons skilled in the art such as precipitation or by with a large amount of solvents such as ethyl acetate, methylene dichloride or extracted with diethyl ether.

Embodiment 104 4-{4-[3-({ [4-chloro-3-(trifluoromethyl) phenyl] alkylsulfonyl } amino)-[1,2,4] triazine-5-yl]-phenoxy group }-N-picoline-2-carboxylic acid amides synthetic

[0329] 4-[4-of 108.6mg (0.337 mmole, 1.0 equivalents) (3-amino-[1,2,4] triazine-5-yl)-phenoxy group]-N-picoline-2-carboxylic acid amides can be dissolved in the 2mL anhydrous pyridine and be heated to about 100 ℃.The 4-chloro-3-trifluoromethyl benzene sulfonyl chloride that can add 0.405 mmole (1.2 equivalent).Reaction mixture was at room temperature stirred 1-2 hour.This product can perhaps by silica gel column chromatography, perhaps be separated by anti-phase preparation HPLC chromatogram by big metering method well known by persons skilled in the art such as precipitation or by with a large amount of solvents such as ethyl acetate, methylene dichloride or extracted with diethyl ether.

In embodiment 105 test cell lines to the inhibiting test of MAPK path

[0330] tested some compounds of describing with formula (B) restraining effect in cell experiment to the MAPK path.Western blot analysis: the former generation Human umbilical vein endothelial cells (HUVECs) that will go down to posterity in early days be kept at contain SingleQuots (Cambrex, East Rutherford, NJ), among the EGM-2 of 10%FBS, 10mM HEPES and 50 μ g/ml gentamicins.Before handling this cell, made HUVECs hungry 18 hours by replacing the complete culture solution that contains serum with the nutrient solution of serum-free and no SingleQuot with inhibitor.With the cell after this hunger with inhibitor (0-20 μ M) pre-treatment 60 minutes under multiple concentration.Then (Peprotech, Rocky Hill NJ) handled 6 minutes, and immediately with ice-cold PBS cleaning cell with 50ng/mlVEGF or FGF with this HUVECs.With cell with ice-cold RIPA damping fluid cracking, this damping fluid contains 100mM Tris pH 7.5,150mMNaCl, 1mM EDTA, 1% Septochol, 1%Triton X-100,0.1%SDS, 2mM PMSF, a Complete-Mini proteinase inhibitor (Complete-Mini protease inhibitor) tablet (Roche, Indianapolis, IN; Every 7ml lysis buffer a slice) and inhibitors of phosphatases NaF (500mM) and ortho-vanadate (1mM).Cell is scraped, shift lysate and, centrifugal 10 minutes of 000g 15.Supernatant is changed in the new pipe also with BCA protein reagent (Pierce, Rockford, IL) mensuration protein concentration.The cell lysate that will contain 20 μ g total proteins separates with 10%SDS-PAGE, it is transferred on the nitrocellulose, and seals in containing the TBST liquid of 5% milk.As an anti-anti-phosphorylation ERK Thr202/Tyr204 (Cell Signaling, Beverly, MA), anti-phosphorylation MEK Ser217/221 (Cell Signaling) and c-Raf (BD BioscencesPharmingen, San Diego, CA) with the goat anti-mouse of horseradish peroxidase or goat antirabbit two anti-detections, and (as seen Rochester NY) makes band to use SuperSignal West Pico chemical illuminating reagent system (Pierce) and Kodak's X-ray film.

[0331] when testing in this experiment, Bay 43-9006 (Raf/FGF inhibitor) shows the reduction of p-MEK and p-ERK expression, has 200 to 300nM IC ₅₀The reduction that U0126 (mek inhibitor) shows the p-Erk level has 200 to 300nM IC ₅₀, and the p-MEK level is unaffected.The result is illustrated in the table 1.As can be seen, compound of the present invention shows the reduction of p-MEK and p-ERK level, has the IC of 400nM to 20 μ M ₅₀

Embodiment 106 cell viability analyses

[0332] tested the effect of some compound pair cell vigor of describing with formula (B).XTT analyzes: HUVECs is inoculated in tissue culture treated 96 orifice plates of handling through type i collagen albumen with 10,000 cells/well, and in aforesaid complete EGM-2 nutrient solution grow overnight.Morning next day is with the described inhibitor of DMSO serial dilution and with in 1% the DMSO final concentration adding cell.(Sigma, St.Louis MO) measure cell viability with the XTT assay method after 72 hours.Also be the take a picture morphology difference of the XTT trend that arrives with comparative observation of cell.(Prism Software package, GraphPad Software, San Diego CA) determines IC with quantitation software ₅₀Value.Some kinds of inhibitor have stoped cell proliferation, and apoptosis-induced when being lower than the concentration of 1 μ M, and repeated experiments three times is to determine observations.Compound of the present invention shows the IC of 100nM to 40 μ M in this experiment ₅₀(table 2).

Table 2. embodiment 105 and 106 test result

Embodiment

Western blotting

Restraining effect to HUVEC cell proliferation

		????(IC50)
			4-{4-[5-(4-chloro-3-trifluoromethyl-phenyl amino)-4H-[1,2,4] triazole-3-yl]-phenoxy group)-pyridine-2-carboxylic acid methyl acid amides	Activity is arranged during 10 μ M	????2.85μM
4-{4-[5-(4-trifluoro methoxy China ink-phenyl)-4H-[1,2,4] triazole-3-base amino]-phenoxy group }-the pyridine-2-carboxylic acids methyl nitrosourea	Non-activity	????2.2μM
			(4-chloro-3-trifluoromethyl-phenyl)-5-[4-(pyridin-3-yl oxygen base)-phenyl]-4H-[1,2,4] triazole-3-yl }-amine	Activity is arranged during 5 μ M	????1.81μM
4-{4-[5-(4-trifluoromethoxy-phenyl amino)-4H-[1,2,4] triazole-3-yl]-phenoxy group)-pyridine-2-carboxylic acid methyl acid amides	Non-activity	????＞40μM
			5-[4-(pyridin-4-yl oxygen base)-phenyl]-4H-[1,2,4] triazole-3-yl }-(4-trifluoromethoxy-phenyl)-amine	Non-activity	????＞40μM
6-{4-[5-(4-trifluoromethoxy-phenyl amino)-4H-[1,2,4] triazole-3-yl]-phenoxy group }-pyridazine-3-base amine	Non-activity	????＞20μM
			6-{4-[5-(4-trifluoromethoxy-phenyl amino)-4H-[1,2,4] triazole-3-yl]-phenoxy group)-pyrimidine-2, the 4-diamines	Non-activity	????6.0μM
6-[4-({ 5-[4-(trifluoromethoxy)-phenyl-4H-1,2,4-triazole-3-yl } amino) phenoxy group]-pyrimidine-2, the 4-diamines	Non-activity	????6.58μM
			6-(4-[5-(4-chloro-3-trifluoromethyl-phenyl amino)-4H-[1,2,4] triazole-3-yl]-phenoxy group }-pyrimidine-2, the 4-diamines	Activity is arranged during 5 μ M	????0.089μM
6-(4-[5-(4-chloro-3-trifluoromethyl-phenyl amino)-4H-[1,2,4] triazole-3-yl]-phenoxy group)-the basic amine of pyridazine-3	Non-activity	????1.79μM
			4-{3-[5-(4-chloro-3-trifluoromethyl-phenyl amino)-4H-[1,2,4] triazole d-yl]-phenoxy group)-pyridine-2-carboxylic acid methyl acid amides	Non-activity	????＞20μM
6-{3-[5-(4-chloro-3-trifluoromethyl-phenyl amino)-4H-[1,2,4] triazole-3-yl]-phenoxy group)-pyrimidine-2, the 4-diamines	Activity is arranged during 5 μ M	????0.404μM
			(4-chloro-3-trifluoromethyl-phenyl)-5-[3-(pyridine 4-base oxygen base)-phenyl]-4H-[1,2,4] triazole-3-yl }-amine	Activity is arranged during 5 μ M	????1.79μM

6-{3-[5-(4-chloro-3-trifluoromethyl-phenyl amino)-4H-[1,2,4] triazole-3-yl]-phenoxy group }-pyridazine-3-base amine	Non-activity	??＞10μM
			6-[4-(5-[4-chloro-3-trifluoromethyl-phenyl] and amino }-1,3,4-oxadiazole-2-yl)-phenoxy group]-pyrimidine-2, the 4-diamines	Activity is arranged during 5 μ M	??1.57μM
N-[4-chloro-3-(trifluoromethyl) phenyl]-5-[4-(pyridine-3-base oxygen base)-phenyl]-1,3,4-oxadiazole-2-amine	Activity is arranged during 5 μ M	??1.72μM
			N-[4-chloro-3-(trifluoromethyl) phenyl]-5-[4-(pyridine-4-base oxygen base)-phenyl]-1,3,4-oxadiazole-2-amine	Activity is arranged during 5 μ M	??8.6μM
N-[4-chloro-3-(trifluoromethyl) phenyl]-5-[4-(pyridine-5-base oxygen base)-phenyl]-1,3,4-oxadiazole-2-amine	Activity is arranged during 5 μ M	??9.65μM
			4-[4-(5-[4-chloro-3-(trifluoromethoxy)-phenyl] and amino }-1,3,4-oxadiazole-2-yl)-phenoxy group]-N-picoline-2-carboxylic acid amides	Activity is arranged during 5 μ M	??5.6μM
6-[4-(5-[4-chloro-3-(trifluoromethyl) phenyl-4H-1,2,4-triazole-3-yl] amino]-phenoxy group]-pyrimidine-2, the 4-diamines	Activity is arranged during 5 μ M	??9.57μM
			5-[4-chloro-3-(trifluoromethyl) phenyl]-N-[4-(pyridine-4-base oxygen base) phenyl]-4H-1,2,4-triazole-3-amine	Non-activity	??＞40μM
5-[4-chloro-3-(trifluoromethyl) phenyl]-N-[4-(pyrimidine-5-base oxygen base) phenyl]-4H-1,2,4-triazole-3-amine	Activity is arranged during 5 μ M	??＞10μM
			6-[4-(5-[4-chloro-3-(trifluoromethyl) phenyl]-4H-1,2,4-triazole-3-yl } amino) phenoxy group]-pyridazine-3-amine	Activity is arranged during 5 μ M	??＞40μM
4-[4-(5-[4-chloro-3-(trifluoromethyl) phenyl-4H-1,2,4-triazole-3-yl] and amino } phenoxy group)-N-picoline-2-carboxylic acid amides	Non-activity	??＞40μM
			5-[4-chloro-3-(trifluoromethyl) phenyl]-N-[4-(pyridine-3-base oxygen base) phenyl]-4H-1,2,4-triazole-3-amine	Activity is arranged during 5 μ M	??＞40μM
6-[4-(5-{[3-(trifluoromethyl) phenyl] amino }-1,3,4-oxadiazole-2-yl) phenoxy group] pyrimidine-2, the 4-diamines	Activity is arranged during 5 μ M	??＞10μM
			5-[4-(pyrimidine-5-base oxygen base) phenyl]-N-[3-(trifluoromethyl) phenyl]-1,3,4-oxadiazole-2-amine	Activity is arranged during 5 μ M	??＞10μM
6-(4-{5-[(4-chloro-phenyl-) amino]-1,3,4-oxadiazole-2-	Activity is arranged during 5 μ M	??2.6μM

Base } phenoxy group) pyrimidine-2, the 4-diamines
			5-[4-(pyrimidine-5-base oxygen base) phenyl]-N-[4-chloro-phenyl]-1,3,4-oxadiazole-2-amine	Activity is arranged during 5 μ M	??＞20μM
6-(4-{5-[(2-chloro-5-trifluoromethyl-phenyl) amino]-1,3,4-oxadiazole-2-yl } phenoxy group) pyrimidine-2, the 4-diamines	Non-activity	??～20μM
			5-[4-(pyrimidine-5-base oxygen base) phenyl]-N-[2-chloro-5-(trifluoromethyl)-phenyl]-1,3,4-oxadiazole-2-amine	Non-activity	??～20μM
6-(4-{5-[(3-chloro-phenyl-) amino]-1,3,4-oxadiazole-2-yl } phenoxy group) pyrimidine-2, the 4-diamines	Activity is arranged during 5 μ M	??～20μM
			5-[4-(pyrimidine-5-base oxygen base) phenyl]-N-[2-chloro-phenyl]-1,3,4-oxadiazole-2-amine	Activity is arranged during 5 μ M	??～20μM
5-[4-(pyridin-3-yl oxygen base) phenyl]-N-[4-chloro-phenyl]-1,3,4-oxadiazole-2-amine	Activity is arranged during 10 μ M	??9.6μM
			5-[4-(pyridin-3-yl oxygen base) phenyl]-N-[3-trifluoromethyl-phenyl]-1,3,4-oxadiazole-2-amine	Activity is arranged during 10 μ M	??＞20μM
5-[4-(pyridin-3-yl oxygen base) phenyl]-1,3,4-oxadiazole-2-amine	Non-activity during 10 μ M	??＞40μM
			N-{5-[4-(pyridin-3-yl oxygen base) phenyl]-1,3,4-oxadiazole-2-yl }-4-(trifluoromethoxy)-benzamide	Non-activity during 10 μ M	??＞40μM
N-{5-[4-(pyridin-3-yl oxygen base) phenyl]-1,3,4-oxadiazole-2-yl }-3-(trifluoromethyl)-benzamide	Activity is arranged during 10 μ M	??＞40μM
			4-bromo-N-{5-[4-(pyridin-3-yl oxygen base) phenyl]-1,3,4-oxadiazole-2-yl }-benzamide	Non-activity during 10 μ M	??＞40μM
N-{5-[4-(pyridin-3-yl oxygen base) phenyl]-1,3,4-oxadiazole-2-yl }-3-(trifluoromethoxy)-benzamide	Non-activity during 10 μ M	??＞40μM
			4-methoxyl group-N-{5-[4-(pyridin-3-yl oxygen base) phenyl]-1,3,4-oxadiazole-2-yl }-3-(trifluoromethyl)-benzamide	Activity is arranged during 10 μ M	??＞40μM
2,2-two fluoro-N-{5-[4-(pyridin-3-yl oxygen base) phenyl]-1,3,4-oxadiazole-2-yl }-1, dioxolane between the 3-benzo-5-carboxylic acid amides	Non-activity during 10 μ M	??＞40μM
			3-chloro-2-fluoro-N-{5-[4-(pyridin-3-yl oxygen base) phenyl]-1,3,4-oxadiazole-2-yl }-5-(trifluoromethyl)-benzamide	Non-activity during 10 μ M	??＞40μM

4-fluoro-N-{5-[4-(pyridin-3-yl oxygen base) phenyl]-1,3,4-oxadiazole-2-yl }-3-(trifluoromethyl)-benzamide	Activity is arranged during 10 μ M	??～20μM
			N-{5-[4-(pyridin-3-yl oxygen base) phenyl]-1,3,4-oxadiazole-2-yl }-2-(trifluoromethoxy)-benzamide	Non-activity during 10 μ M	??～20μM

[0333] although the present invention is carried out description with reference to above embodiment, should be appreciated that to comprise numerous modifications and variations within the spirit and scope of the present invention.Therefore the present invention is limited by claims only.

Claims (26)

1. a compound has structure (B) or N-oxide compound, N, N '-dioxide, N, N ', N "-trioxide or their pharmacy on acceptable salt:

Wherein:

Z ₁, Z ₂And Z ₃Each be to be independently selected from N, CH, N=CH, O, S and N-R ⁴, R wherein ⁴Be hydrogen or low-carbon alkyl, condition is Z at least ₁, Z ₂And Z ₃In one of be not CH;

X does not exist or NH; And

Y does not exist or is selected from following part:

R ₁Be to have 1-3 heteroatomic the replacement or replacement C ₃-C ₁₂Heteroaryl;

R ₂Be selected from hydrogen, halogen, C ₁-C ₁₈Alkyl ,-OH ,-NO ₂,-CN, C ₁-C ₁₈Alkoxyl group ,-NHSO ₂R ⁵,-SO ₂NHR ⁵,-NHCOR ⁵,-NH ₂,-NR ⁵R ⁶,-S (O) R ⁵,-S (O) ₂R ⁵,-CO ₂R ⁵,-CONR ⁵R ⁶, R wherein ⁵And R ⁶Be independently selected from hydrogen, C ₁-C ₁₈Alkyl and replacement C ₁-C ₁₂Alkyl; And

R ₃Be selected from C ₁-C ₁₈Alkyl, replacement C ₁-C ₁₂Alkyl, C ₁-C ₁₂Cycloalkyl, replacement C ₁-C ₁₂Cycloalkyl, has 0-3 heteroatomic replacement C ₃-C ₁₀Cycloalkyl, C ₆-C ₁₂Aryl, replacement C ₆-C ₁₂Aryl, heterocycle, substituted heterocycle, has 1-3 heteroatomic C ₃-C ₁₂Heteroaryl, has 1-3 heteroatomic replacement C ₃-C ₁₂Heteroaryl, C ₇-C ₂₄Aralkyl, replacement C ₇-C ₂₄Aralkyl, C ₇-C ₂₄Alkylaryl and replacement C ₇-C ₂₄Alkaryl.

2. the described compound of claim 1, wherein R ₁Be selected from:

R ₃Be selected from:

N is selected from 0,1,2 and 3 integer, and

R ' is selected from hydrogen, C ₁-C ₁₈Alkyl and replacement C ₁-C ₁₂Alkyl.

3. the described compound of claim 1, the described compound that wherein has structure (B) are selected from the compound of (17)-(35) that have molecular formula:

4. the described compound of claim 3, wherein said compound has described molecular formula:

5. the described compound of claim 3, wherein said compound has described molecular formula:

6. the described compound of claim 3, wherein said compound has described molecular formula:

7. the described compound of claim 3, wherein said compound has described molecular formula:

8. the described compound of claim 3, wherein said compound has described molecular formula:

9. the described compound of claim 3, wherein said compound has described molecular formula:

10. the described compound of claim 3, wherein said compound has described molecular formula:

11. the described compound of claim 3, wherein said compound has described molecular formula:

12. the described compound of claim 3, wherein said compound has described molecular formula:

13. the described compound of claim 3, wherein said compound has described molecular formula:

14. the described compound of claim 3, wherein said compound has described molecular formula:

15. the described compound of claim 3, wherein said compound has described molecular formula:

16. the described compound of claim 3, wherein said compound has described molecular formula:

17. the described compound of claim 3, wherein said compound has described molecular formula:

18. the described compound of claim 3, wherein said compound has described molecular formula:

19. the described compound of claim 3, wherein said compound has described molecular formula:

20. the described compound of claim 3, wherein said compound has described molecular formula:

21. the described compound of claim 3, wherein said compound has described molecular formula:

22. the described compound of claim 3, wherein said compound has described molecular formula:

23. a pharmaceutical composition, it comprises the compound as illustrating in the claim 1 in acceptable carrier in pharmacy.

24. the described compound of claim 1, wherein Y is

25. the compound that is expressed from the next:

Or acceptable salt or N-oxide compound in its pharmacy.

26. a composition, it comprises acceptable vehicle in described compound of claim 25 and the pharmacy.

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