CN101558070A - Triazolo-pyridazine protein kinase modulators - Google Patents

Triazolo-pyridazine protein kinase modulators Download PDF

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CN101558070A
CN101558070A CNA2007800385271A CN200780038527A CN101558070A CN 101558070 A CN101558070 A CN 101558070A CN A2007800385271 A CNA2007800385271 A CN A2007800385271A CN 200780038527 A CN200780038527 A CN 200780038527A CN 101558070 A CN101558070 A CN 101558070A
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replace
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C·R·史密斯
P·布诺
E·A·杰斐逊
P·S·李
E·托雷斯
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SGX Pharmaceuticals Inc
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Abstract

The present disclosure relates to tirazalopyridazine protein kinase modulators and methods of using these compounds to treat diseases mediated by kinase activity.

Description

Triazolo-pyridazine protein kinase modulators
The cross reference of related application
[0001] the application requires the U.S. temporary patent application series number 60/862 that is entitled as " triazolo-pyridazine protein kinase modulators " respectively on October 23rd, 2006, on January 4th, 2007 and submission on April 24th, 2007,552,60/883,468 and 60/913,752 rights and interests.Require to submit to the right of priority of day thus, the content of these applications is attached to herein by reference in full.
Background of invention
[0002] the mammalian proteins kinases is the important conditioning agent of cell function.Because the dysfunction of protein kinase activity and disease and disorderly relevant, protein kinase is the target of drug development.Family tyrosine kinase, and especially the subgroup of receptor tyrosine kinase has been proved to be enrichment in cancer, thereby be estimated as the target of cancer.Receptor tyrosine kinase (RTKs) fully has been accredited as EGFR, HER2, KIT and KDR plays the clearly albumen of affirmation in cancer.The medicine of these RTKs of target such as Gleevec, Iressa and Tarceva has been approved for some cancer of treatment.Other RTKs then fully identifies, but also with related to cancer.For example, the inhibitor of new Notes of Key Data TRKC, ROS, CSF1R/FMS and ALK can be used for treating cancer.MET and RON are two attracting especially RTK targets that are used to develop the new drug for the treatment of cancer.
[0003] pHGF (HGF) is also referred to as and sends out the factor (scatter factor), is multi-functional somatomedin, and it promotes to shift and tumor development by inducing mitogenesis and cell migration.And HGF invades through the irritation cell migration with by various signal transduction paths and promotes to shift.In order to produce cytosis, HGF must be incorporated into its acceptor c-Met, a kind of receptor tyrosine kinase.C-Met, a kind of heterodimer albumen (Maggiora etc. that contain the wide expression of 50 kilodaltons (kDa) α-subunit and 145kDa beta subunit, J.Cell Physiol., 173:183-186,1997) overexpression in people's cancer of significant percentage, and at primary tumor and between shifting excessively during amplification.The related various cancers of c-Met overexpression therein include, but are not limited to adenocarcinoma of stomach, kidney, small cell lung cancer, colorectal carcinoma, prostate cancer, the cancer of the brain, liver cancer, carcinoma of the pancreas and mammary cancer.C-Met also relates to atherosclerosis and pulmonary fibrosis.
[0004] MET is accredited as transfering DNA first and resets (TPR-MET) (Cooper etc. 1984) in the human osteosarcoma cell line with N-methyl-N '-nitro-nitroso-guanidine treatment.The MET receptor tyrosine kinase (is also referred to as hepatocyte growth factor receptor, HGFR, MET or c-Met), and its part pHGF (" HGF ") has a lot of biologic activity, comprise stimulate proliferation, survive, differentiation and form takes place, (branching tubulogenesis), cell migration and invasive growth take place branch vessel.On pathology, MET relates to growth, invasion and attack and the transfer of many multi-form cancers, comprises kidney, cancer of the stomach, lung cancer, ovarian cancer, liver cancer and mammary cancer.Shift and distribute the somatic activated mutant of having found in cancer such as the Papillary Renal Cell Carcinoma among the MET at human cancer.Evidence suggests that also the MET signal transduction path can play an important role in the opposing cancer therapy.For example, in the patients with lung cancer of having found to recur behind the initial reaction of MET gene pairs EGFR inhibitor such as Gefitinib and Tarceva amplification is arranged.Except cancer, evidence suggests that MET suppresses to have the various indications of treatment and comprises: listeria spp invades, osteolysis, malaria infection, diabetic retinopathy, psoriatic and the arthritic value relevant with multiple myeloma.The sudden change of MET encoding sequence is uncommon relatively in people's cancer.Yet, based on precedent in the selection that suddenlys change with the sudden change of the BCR-ABL among the chronic lymphocytic leukemia patient of treatment with imatinib with the EGFR among the cancer patients of Tarceva and Gefitinib treatment, if the MET inhibitor is widely used in cancer, estimate that these and/or the possible chemical sproof other MET sudden change of generation will become more prevalent.Therefore, the medicine that suppresses some sudden change in these MET sudden change effectively can become extremely important in the cancer therapy in future.
[0005] MET and one group of 5 kinds of receptor tyrosine kinase are closely related, and these kinases are not well studied as MET itself.These kinases comprise Tyro3/Sky, MER, AXL, RYK and RON.Tyrosylprotein kinase RON is the acceptor of macrophage stimulating protein and closely related with MET, belongs to the MET family of receptor tyrosine kinase.As MET, RON relates to growth, invasion and attack and the transfer of several multi-form cancers, comprises colorectal carcinoma and bladder cancer.Evidence suggests that also the AXL of imbalance and MER can play an important role in cancer.MER has the active consistent characteristic of many and oncogene.T-cell lymphocytoblast leukemia/lymphadenomatous symptom appears being similar in the transgenic mice of expressing MER in hematopoietic lineage, and MER expresses in the acute lymphocytoblast leukemia of most of T cells (T-ALL) patient.Research in mouse model prompting, as if it is important that AXL regulates the growth that the hyperamization pipe generates the mammary cancer of (angiogenic) and tumorigenesis process to AXL wherein.To the other research prompting of human cancer cell, AXL relates to NSCLC to be shifted and resistance.Though the normal and pathology effect of Tyro3/Sky is known little about it, this receptor tyrosine kinase is shared some characteristic and function with its correlative of fully studying (relatives), but and the also important effect of final certification tool in cancer.RYK also expresses in some cancer, but it is atypical orphan receptor Tyrosylprotein kinase, and it lacks detectable kinase activity, thereby it it be not immediately clear as the easy processing of the target of small molecules cancer therapy.
[0006] because kinases and numerous disease and illness such as related to cancer need the new and kinases inhibitor that effectively can be used for the treatment of of exploitation.The present invention satisfies these and other the needs of this area.Though this paper clearly mentions some protein kinase, the invention is not restricted to these kinase whose inhibitor, and in its scope, comprise relevant kinases inhibitor, and the inhibitor of homologous protein.
The invention summary
[0007] found that triazolopyridazine compounds, their of the present disclosure can be used for regulating kinase activity and treats the disease that mediates by kinase activity.Particularly, compound of the present disclosure can be used for regulating and/or suppressing Tyrosylprotein kinase, comprises MET.And compound of the present disclosure can be used for reducing or suppressing the kinase activity of the MET among cell or the curee, and is used for regulating the expression of MET cell or curee.Disclosed compound also is used in patient's prevention or treatment cell proliferation disorders and/or the disorder relevant with MET.Describe disclosed Triazolopyridazines kinase modulator below in detail.In addition, the inhibition activity of the compound openly selected of this paper.
[0008] in one aspect, the disclosure provides the compound with formula I:
Figure A20078003852700781
Or its enantiomorph, diastereomer, racemic modification or pharmacy acceptable salt or solvate,
Wherein:
[0009] A independently is that replace or unsubstituted aryl or replacement or unsubstituted heteroaryl;
[0010] Q independently is that replace or unsubstituted alkyl, replacement or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl, replacement or unsubstituted-O-aryl, replacement or unsubstituted arylalkyl, replacement or unsubstituted heteroaryl, replacement or unsubstituted-O-heteroaryl, that perhaps replace or unsubstituted heteroarylalkyl, wherein Q is optional by 1-3 R 22Replace independently;
[0011] T is CH independently 2, CH (halogen), C (halogen) 2, CH ((C 1-C 6) alkyl) or C ((C 1-C 6) alkyl) 2
[0012] X is N or CR 2
[0013] R 1And R 2Optional separately be independently hydrogen, halogen, nitro, cyano group, hydroxyl, replacement or unsubstituted alkyl, perfluoroalkyl ,-(CH 2) jCN ,-(CH 2) jOR 3,-(CH 2) jC (O) R 3,-(CH 2) jC (O) OR 3,-(CH 2) jNR 4R 5,-(CH 2) jC (O) NR 4R 5,-(CH 2) jOC (O) NR 4R 5,-(CH 2) jNR 6C (O) R 3,-(CH 2) jNR 6C (O) OR 3,-(CH 2) jNR 6C (O) NR 4R 5,-(CH 2) jS (O) mR 7,-(CH 2) jNR 6S (O) 2R 7,-(CH 2) jS (O) 2NR 4R 5, wherein each j is the integer of 0-6 independently; With m be the integer of 0-2 independently; Or
[0014] R 1And R 2That form to replace or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl, perhaps that replace or unsubstituted heteroaryl;
[0015] R 3, R 4, R 5, R 6And R 7Be hydrogen, replacement or unsubstituted alkyl, replacement independently of one another or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl, replacement or unsubstituted-O-aryl, replacement or unsubstituted arylalkyl, replacement or unsubstituted heteroaryl, replacement or unsubstituted-O-heteroaryl, that perhaps replace or unsubstituted heteroarylalkyl, or
[0016] R 3, R 6And R 7As mentioned above, and R 4And R 5N atom with they connect forms that replace or unsubstituted Heterocyclylalkyl, perhaps that replace or unsubstituted heteroaryl;
[0017] R 22Be hydrogen, halogen, nitro, cyano group, hydroxyl, replacement or unsubstituted alkyl, replacement independently or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl, replacement or unsubstituted-O-aryl, replacement or unsubstituted arylalkyl, replacement or unsubstituted heteroaryl, replacement or unsubstituted-O-heteroaryl, replacement or unsubstituted heteroarylalkyl ,-(CH 2) jCN ,-(CH 2) jOR 23,-(CH 2) jC (O) R 23,-(CH 2) jC (O) OR 23,-(CH 2) jNR 24R 25,-(CH 2) jC (O) NR 24R 25,-(CH 2) jOC (O) NR 24R 25,-(CH 2) jNR 26C (O) R 23,-(CH 2) jNR 26C (O) OR 23,-(CH 2) jNR 26C (O) NR 24R 25,-(CH 2) jS (O) mR 27,-(CH 2) jS (O) 2NR 24R 25Or-(CH 2) jNR 26S (O) 2R 27, wherein each j is the integer of 0-6 independently, and each m is the integer of 0-2 independently;
[0018] R 23, R 24, R 25, R 26And R 27Be hydrogen, replacement or unsubstituted alkyl, replacement independently of one another or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl, replacement or unsubstituted-O-aryl, replacement or unsubstituted arylalkyl, replacement or unsubstituted heteroaryl, replacement or unsubstituted-O-heteroaryl, that perhaps replace or unsubstituted heteroarylalkyl, or
[0019] R 23, R 26And R 27As mentioned above, and R 24And R 25N atom with they connect forms that replace or unsubstituted Heterocyclylalkyl, perhaps that replace or unsubstituted heteroaryl;
[0020] R 28' and R 28" be hydrogen, halogen, nitro, cyano group, hydroxyl, replacement or unsubstituted alkyl, replacement independently of one another or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted alkoxyl group, amino, an amino alkyl or amino dialkyl group;
[0021] R 35Be key, hydrogen, halogen, nitro, cyano group, hydroxyl, replacement or unsubstituted alkyl, replacement independently or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl, replacement or unsubstituted arylalkyl, replacement or unsubstituted heteroaryl, replacement or unsubstituted heteroarylalkyl ,-(CH 2) jCN ,-(CH 2) jOR 30,-(CH 2) jC (O) R 30,-(CH 2) jC (O) OR 30,-(CH 2) jNR 31R 32,-(CH 2) jC (O) NR 31R 32,-(CH 2) jOC (O) NR 31R 32,-(CH 2) jNR 33C (O) R 30,-(CH 2) jNR 33C (O) OR 30,-(CH 2) jN 33C (O) NR 31R 32,-(CH 2) jS (O) mR 34,-(CH 2) jS (O) 2NR 31R 32Or-(CH 2) jNR 33S (O) 2R 34, wherein each j is that integer and the m of 0-6 is the integer of 0-2 independently independently;
[0022] z is the integer of 0-3 independently;
[0023] R 30, R 31, R 32, R 33And R 34Be hydrogen, replacement or unsubstituted alkyl, replacement independently of one another or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl, replacement or unsubstituted-O-aryl, replacement or unsubstituted arylalkyl, replacement or unsubstituted heteroaryl, replacement or unsubstituted-O-heteroaryl, that perhaps replace or unsubstituted heteroarylalkyl, or
[0024] R 30, R 33And R 34As mentioned above, and R 31And R 32N atom with they connect forms that replace or unsubstituted Heterocyclylalkyl, perhaps that replace or unsubstituted heteroaryl; With
[0025] R wherein 1, R 2, R 3, R 4, R 5, R 6, R 7, R 22, R 23, R 24, R 25, R 26, R 27, R 28', R 28", R 30, R 31, R 32, R 33, R 34And R 35Optionally separately replaced independently by 1-3 group, each group be independently selected from hydrogen, halogen, hydroxyl, amino, an amino alkyl, amino dialkyl group, cyano group, nitro, difluoromethyl, trifluoromethyl, oxo, alkyl ,-the O-alkyl and-the S-alkyl.
[0026] in other embodiments, the disclosure relates to the method for regulating protein kinase activity; The medicinal compositions of treatment method for cancer and the formula of use I compound.
The accompanying drawing summary
[0027] Fig. 1 explanation gives compound 30 effects to the inhibition of GTL 16 tumor growths in continuous 14 days by every day twice oral (PO) with by intravenous injection (IP).
[0028] Fig. 2 explanation gives the compound effect that 30 pairs of GTL 16 tumor growths suppress by oral and intraperitoneal (intraperitoneally)
[0029] Fig. 3 explanation gives the effect of 30 pairs of GTL 16 tumor growths of compound by oral and intraperitoneal.
[0030] Fig. 4 explanation gives the influence of 124 couples of tumour MET of compound phosphorylation of acute dose (acute dose) by oral (PO).
[0031] Fig. 5 explanation gives the influence of 87 couples of tumour MET of compound phosphorylation of acute dose by oral (PO).
[0032] Fig. 6 explanation gives 14.5 days, to the influence of mean tumour volume continuously by giving compound 124 every day (Q12H) twice oral (PO).
[0033] Fig. 7 explanation is by orally give compound 124, the tumor growth of GTL 16 tumours of nude mice suppressed the effect of (TGI).
Detailed Description Of The Invention
Definition
[0034] abbreviation used herein has its meaning commonly used in the chemistry and biology field.
[0035] when passing through its conventional chemical formula, while writing from left to right the substituting group of regulation, they similarly comprise because writing from right to left the chemically identical substituting group of structure, as ,-CH2O-is equal to-OCH2-。
[0036] term " alkyl ", itself or as another substituent part, except as otherwise noted, mean straight chain (namely not branch) or side chain, or cyclic hydrocarbon group, or its combination, it can be fully saturated, single-or polyunsaturated, and can comprise divalence and multivalence group, the carbon number with appointment (is C1-C 10Refer to 1-10 carbon). The example of saturated alkyl includes, but are not limited to group such as methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, isobutyl group. Sec-butyl, cyclohexyl, (cyclohexyl) methyl, cyclopropyl methyl, for example, the homologue of n-pentyl, n-hexyl, n-heptyl, n-octyl and isomers etc. Undersaturated alkyl is the alkyl with one or more pairs of keys or triple bond. The example of undersaturated alkyl comprises, but be not limited to vinyl, 2-acrylic, cyclobutenyl, 2-isopentene group, 2-(butadienyl), 2,4-pentadienyl, 3-(1, the 4-pentadienyl), acetenyl, 1-and 3-propinyl, 3-butynyl, and higher homologue and isomers. The alkyl that is limited to alkyl is called " high alkyl (homoalkyl) ".
[0037] term " alkylidene " itself or as another substituent part, mean the divalent group derived from alkyl, and the example is, but is not limited to-CH2CH 2CH 2CH 2-. Typically, alkyl (or alkylidene) group should have 1-24 carbon atom, and the disclosure preferably has those groups of 10 or carbon atom still less. " low alkyl group " or " low-grade alkylidene " is short-chain alkyl or alkylidene, generally has 8 or carbon atom still less.
[0038] term " assorted alkyl ", itself or with the combination of another term, except as otherwise noted, mean to be selected from by at least one carbon atom and at least one the stable straight or branched that the hetero atom of O, N, P, Si and S forms, or cyclic hydrocarbon group, or its combination, and wherein nitrogen and sulphur atom can be chosen wantonly oxidized and nitrogen heteroatom can be chosen wantonly by quaternary ammoniated. Hetero atom O, N, P, S and Si can be positioned on the position of any interior location of assorted alkyl or the remainder that alkyl is connected in this molecule. Example includes, but are not limited to-CH2-CH 2-O-CH 3、-CH 2-CH 2-NH-CH 3、 -CH 2-CH 2-N(CH 3)-CH 3、-CH 2-S-CH 2-CH 3、-CH 2-CH 2、-S(O)-CH 3、 -CH 2-CH 2-S(O) 2-CH 3、-CH＝CH-O-CH 3、-Si(CH 3) 3、-CH 2-CH＝N-OCH 3、 -CH＝CH-N(CH 3)-CH 3、O-CH 3、-O-CH 2-CH 3With-CN. Two hetero atoms can be adjacent at the most, for example, and-CH2-NH-OCH 3With-CH2-O-Si(CH 3) 3. Similarly, term " assorted alkylidene " itself or as another substituent part, mean divalent group derived from assorted alkyl, example is, but is not limited to-CH2-CH 2-S-CH 2-CH 2-and-CH2-S-CH 2-CH 2-NH-CH 2-. For assorted alkylidene, hetero atom also can occupy chain one or both ends as, alkylidene oxo (alkyleneoxo), alkylidene dioxygen generation (alkylenedioxo), alkylidene amino, alkylidene diaminourea etc.). Further also that for alkylidene and assorted alkylidene linking group, the direction of the structural formula of the linking group of wherein writing does not hint the orientation of linking group. For example, formula-C (O) OR '-expression-C (O) OR1-and-R1OC (O)-both. As above-mentioned, assorted alkyl group used herein comprises by hetero atom, as-C (O) R ' ,-C (O) NR ' ,-NR ' R " ,-OR ' ,-SR and/or-SO2R ' is connected in those groups of molecule remainder. When describing " assorted alkyl ", special assorted alkyl is then described in back, as-NR ' R " while waiting, should be appreciated that the assorted alkyl of term and-NR ' R is " unnecessary or mutually repel anything but. But special assorted alkyl clearly is described as being coupled with. Therefore, term " assorted alkyl " should not be interpreted as getting rid of special assorted alkyl at this paper, as-NR ' R " etc.
[0039] " carbalkoxy (alkylesteryl) " used herein refers to have formula R '-C (O) O-R " part, wherein R ' is alkylidene part and R " is the alkyl part.
[0040] term " cycloalkyl " and " heterocycle alkyl ", itself or during with other term combination, except as otherwise noted, the ring-type variant of expression " alkyl " and " assorted alkyl " respectively. In addition, for the heterocycle alkyl, hetero atom can occupy heterocycle and be connected in the position of the remainder of molecule. The example of cycloalkyl includes, but are not limited to cyclopenta, cyclohexyl, 1-cyclohexenyl group, 3-cyclohexenyl group, suberyl etc. The example of heterocycle alkyl comprises, but be not limited to 1-(1,2,5,6-tetrahydropyridine base), 1-piperidyl, 2-piperidyl, 3-piperidyl, 4-morpholinyl, morpholinyl, oxolane-2-base, oxolane-3-base, thiophane-2-base, thiophane-3-base, 1-piperazinyl, 2-piperazinyl etc. The divalent derivative of term " inferior cycloalkyl " and " inferior heterocycle alkyl " difference finger ring alkyl and heterocycle alkyl.
[0041] term " cycloalkyl " or " cycloalkyl-alkyl " also refer to be connected in by unsubstituted alkylidene the 3-7 unit cycloalkyl of the remainder of molecule. The carbon atom of given number is described (as C1-C 10Cycloalkyl-alkyl) refer to the number of the carbon atom in alkylidene.
[0042] term " heterocycle alkyl " or " heterocycle alkyl alkyl " also refer to be connected in by unsubstituted alkylidene the 3-7 unit heterocycle alkyl of the remainder of molecule. The carbon atom of given number is described (as C1-C 10Assorted-cycloalkyl-alkyl) refer to the number of the carbon atom in alkylidene.
[0043] term " halo " or " halogen " itself or as another substituent part, except as otherwise noted, mean fluorine, chlorine, bromine or iodine atom. In addition, term is intended to comprise a haloalkyl and multi-haloalkyl as " haloalkyl ". For example, term " halo (C1-C 4) alkyl " is intended to include, but are not limited to trifluoromethyl, 2,2,2-trifluoroethyl, 4-chloro butyl, 3-bromo propyl group etc.
[0044] term " aryl ", except as otherwise noted, mean polyunsaturated, aromatic hydrocarbon substituting group, and it can be monocycle or many rings (preferred 1-3 ring), and described ring can condense together or through covalently bound. term " heteroaryl " refers to contain 1-4 heteroatomic aryl (or ring) that is selected from N, O and S, and wherein optional oxidized the and nitrogen-atoms of nitrogen and sulphur atom can be chosen wantonly by quaternary ammoniated. heteroaryl can be connected in by carbon or hetero atom the remainder of molecule. the limiting examples of aryl and heteroaryl comprises phenyl, the 1-naphthyl, the 2-naphthyl, the 4-xenyl, the 1-pyrrole radicals, the 2-pyrrole radicals, the 3-pyrrole radicals, the 3-pyrazolyl, the 2-imidazole radicals, the 4-imidazole radicals, pyrazinyl, the 2-oxazolyl, the 4-oxazolyl, 2-phenyl-4-oxazolyl, the 5-oxazolyl, the 3-isoxazolyl, the 4-isoxazolyl, the 5-isoxazolyl, the 2-thiazolyl, the 4-thiazolyl, the 5-thiazolyl, the 2-furyl, the 3-furyl, the 2-thienyl, the 3-thienyl, the 2-pyridine radicals, the 3-pyridine radicals, the 4-pyridine radicals, the 2-pyrimidine radicals, the 4-pyrimidine radicals, the 5-benzothiazolyl, purine radicals, the 2-benzimidazolyl, the 5-indyl, the 1-isoquinolyl, the 5-isoquinolyl, the 2-quinoxalinyl, the 5-quinoxalinyl, 3-quinolyl and 6-quinolyl. the substituting group that is used for each described aryl and heteroaryl loop systems is selected from following acceptable substituting group. term " arlydene " and " inferior heteroaryl " refer to respectively the divalent derivative of aryl and heteroaryl.
[0045] for simplicity's sake, term " aryl " while being used in combination, comprises aryl and heteroaryl ring as defined above with other term (as aryl oxide generation (aryloxo), aryl sulfo-(arylthioxo), aryl alkyl). Therefore, term " aryl alkyl " be intended to comprise aryl wherein be connected in those groups of alkyl (as, benzyl, phenethyl, pyridine radicals methyl etc.), comprise wherein carbon atom (as, those alkyl that methylene) by for example oxygen atom, substituted (as, phenoxymethyl, 2-pyridine radicals oxygen ylmethyl, 3-(1-naphthoxy) propyl group etc.). Yet term used herein " halogenated aryl " only is intended to cover the aryl that is replaced by one or more halogens.
[0046] term used herein " oxo " means two keys and is connected in the oxygen of carbon atom.
[0047] above-mentioned each term (as, " alkyl ", " assorted alkyl ", " cycloalkyl and " heterocycle alkyl ", " aryl ", " heteroaryl " and their divalent group derivative) is intended to comprise replacement and unsubstituted two kinds of forms of specifying group. The preferred substituting group of each type group below is provided.
[0048] be used for alkyl, assorted alkyl, cycloalkyl, the derivative group of heterocycle alkyl monovalence and divalence (comprises and is commonly referred to alkylidene, alkenyl, assorted alkylidene, the heterochain thiazolinyl, alkynyl, cycloalkyl, the heterocycle alkyl, those groups of cycloalkenyl and heterocycle thiazolinyl) substituting group can be selected from following group (but being not limited to) :-OR ' for one or more,=O,=NR ',=N-OR ',-NR ' R ",-SR ',-halogen,-SiR ' R " R ' ",-OC (O) R ',-C (O) R ',-CO2R′、-C(O)NR′R″、 -OC(O)NR′R″、-NR″C(O)R′、-NR′-C(O)NR″R′″、-NR″C(O)OR′、 -NR-C(NR′R″)＝NR′″、-S(O)R′、-S(O) 2R′、-S(O) 2NR′R″、-NRSO 2R ' ,-CN and-NO2, the scope of substituent number is 0 to (2m '+1), wherein m ' is the sum of the carbon atom in such group. That R ', R ", R ' " and R " " preferably refer to hydrogen, replacement separately independently or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted heterocycle alkyl, replacement or unsubstituted aryl (as, the aryl that is replaced by 1-3 halogen), replace or unsubstituted alkyl, alkoxyl or thio alkoxy, or aryl alkyl. For example, when compound of the present disclosure comprised more than one R group, each R group was selected independently, as each R ', R ", R ' " the same with R " " group (when more than one, these groups exist). " while being connected in identical nitrogen-atoms, they can be combined with this nitrogen-atoms and form 4-, 5-, 6-or 7-ring as R ' and R. For example ,-NR ' R " is intended to include, but are not limited to 1-pyrrolidinyl and 4-morpholinyl. , to substituent discussion, it should be appreciated by those skilled in the art that term " alkyl " is intended to comprise the group of the carbon atom that contains the group that is connected in non-hydrogen group from above, as haloalkyl (as ,-CF3With-CH2CF 3) and acyl group (as ,-C (O) CH3、-C(O)CF 3、 -C(O)CH 2OCH 3Deng).
[0049] be similar to the substituting group that above alkyl is described, the exemplary substituting group of aryl and heteroaryl (and their divalent derivative) for change and be selected from, for example: halogen ,-OR ' ,-NR ' R " ,-SR ' ,-halogen ,-SiR " R " R ' " ,-OC (O) R ' ,-C (O) R ' ,-CO2R′、 -C(O)NR′R″、-OC(O)NR′R″、-NR″C(O)R′、-NR′-C(O)NR″R′″ -NR″C(O)OR′、-NR-C(NR′R″R R′″)＝NR″″、-NR-C(NR′R″)＝NR′″、 -S(O)R′、-S(O) 2R′、-S(O) 2NR′R″、-NRSO 2R ' ,-CN and-NO2、-R′、-N 3、 -CH(Ph) 2, fluoro (C1-C 4) alkoxyl (alkoxo) and fluoro (C1-C 4) alkyl, substituent number range 0 between the sum of the open valency on aromatic ring system; And wherein that preferably be independently selected from assorted alkyl alkyl hydrogen, replacement or unsubstituted, replacement or unsubstituted, replacement or unsubstituted cycloalkyl, replacement or the unsubstituted heterocycle alkyl of R ', R ", R ' " and R " ", replacement or unsubstituted aryl and replacement or unsubstituted heteroaryl. For example, when compound of the present disclosure comprised more than one R group, each R group was selected independently, as each R ', R ", R ' " the same with R " " group (when more than one, these groups exist).
[0050] two substituting groups on the adjacent atom of aryl or heteroaryl ring optionally form formula-T-C (O)-(CRR ')qThe ring of-U-, wherein T and U be independently-NR-,-O-,-CRR '-or singly-bound, and q is the integer of 0-3. Perhaps, two substituting groups on the adjacent atom of aryl or heteroaryl ring are optionally by formula-A-(CH2) rThe substituting group of-B-substitutes, wherein A and B be independently-CRR '-,-O-,-NR-,-S-,-S (O)-,-S (O)2-、-S(O) 2NR '-or singly-bound, and r is the integer of 1-4. A singly-bound of the new ring that so forms is optionally substituted by two keys. Perhaps, two substituting groups on the adjacent atom of aryl or heteroaryl ring can be chosen wantonly by formula-(CRR ')s-X′-(C″R′″) d-substituting group replace, wherein s and d are the integer of 0-3 independently, and X ' be-O-,-NR '-,-S-,-S (O)-,-S (O)2-or-S (O)2NR '-. That substituting group R, R ', R " and R ' " preferably are independently selected from alkyl hydrogen, replacement or unsubstituted, replacement or unsubstituted cycloalkyl, replacement or unsubstituted heterocycle alkyl, replacement or unsubstituted aryl and replacement or unsubstituted heteroaryl.
[0051] as used herein, term " hetero atom " or " ring hetero atom " are intended to comprise oxygen (O), nitrogen (N), sulphur (S), phosphorus (P) and silicon (Si).
[0052] compound of the present disclosure can be used as the salt existence. the disclosure comprises such salt. the example of applicable salt form comprises that hydrochloride, hydrobromate, sulfate, mesylate, nitrate, maleate, acetate, citrate, fumarate, tartrate are (as (+)-tartrate, (-)-tartrate or its mixture, comprise racemic mixture), succinate, benzoate and the salt that becomes with amino acid such as glutamic acid. these salt can prepare by method known to those skilled in the art. also comprise base addition salts such as sodium, potassium, calcium, ammonium, organic amino or magnesium salts, or similar salt. when compound of the present disclosure contained relatively alkaline functional group, sour addition salts can contact by the such compound that makes neutral form (no matter being when solvent-free or in suitable atent solvent) to be obtained with enough required acid. the example of acceptable sour addition salts comprises derived from the inorganic acid example hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, one hydrogen carbonic acid (monohydrogencarbonic), phosphoric acid, one hydrogen phosphoric acid, dihydrogen phosphoric acid (dihydrogenphosphoric), sulfuric acid, one hydrosulphuric acid, those salt of hydroiodic acid or phosphorous acid etc., and by organic acid such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, butanedioic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzene sulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, the salt that methanesulfonic acid etc. are derivative. also comprise amino acid whose salt such as arginine salt etc., and the salt that is formed by organic acid such as glucuronic acid or galacturonic acid etc. some special disclosure compound not only contains basic functionality but also contain acid functional group, and this makes described compound to be converted into or base addition salts or sour addition salts.
[0053] the neutral form of described compound preferably generates by making salt with alkali or acid contact and separating in a usual manner parent compound. The parent form of compound is different from various salt forms in (as the solubility in polar solvent) aspect some physical characteristic.
[0054] some compound of the present disclosure can non-solvated form and the solvation form exist, comprise hydrated form. In general, the solvation form is equivalent to non-solvated form and is included in the scope of the present disclosure. Some compound of the present disclosure can polymorphic or the existence of amorphous form. In general, all physics forms to the application of disclosure expection be all equivalence and be intended to be included in disclosure scope.
[0055] some compound of the present disclosure has asymmetric carbon atom (optical centre) or two key; Enantiomer, racemic modification, diastereomer, dynamic isomer, geometric isomer, stereoisomer form can be according to the absolute stereo chemistry, be accredited as (R)-or (S)-, or to amino acid be accredited as (D)-or (L)-, and each isomers is included in disclosure scope. Compound of the present disclosure does not comprise known in the art very unstable so that can not synthesize and/or indissociable those compounds. The disclosure is intended to comprise the compound of racemic form and optical voidness form. Optical activity (R)-and (S)-, or (D)-can adopt chiral synthon or chiral reagent preparation with (L)-isomers, or adopt routine techniques to split. When compound described herein contains ethylene linkage or how much asymmetric other centers, except as otherwise noted, should refer to that compound comprises E and two kinds of geometric isomers of Z.
[0056] term used herein " tautomer " refers to that the balanced existence of two or more constitutional isomers and a kind of isomeric forms easily are converted into the tautomer of another kind of isomeric forms.
[0057] some compound of the present disclosure can tautomeric form exist, and this should be conspicuous for a person skilled in the art, and this type of all tautomeric form of described compound is included in the disclosure scope.
[0058] unless otherwise indicated, structure as herein described is also intended to comprise all stereochemical forms of this structure; Be the R and the S configuration of each asymmetric center.Therefore, the scope of the present disclosure comprises the enantiomorph of single three-dimensional chemical isomer and The compounds of this invention and the mixture of diastereomer.
[0059] unless otherwise indicated, structure as herein described is also intended to comprise that difference only is to exist the compound that is rich in one or more isotopic atoms.For example, the scope of the present disclosure comprises having this structure, but hydrogen is by deuterium or tritium metathetical compound, or carbon is rich in 13C-or 14The carbon metathetical compound of C-.
[0060] compound of the present disclosure also can have the non-natural characteristic of the atom isotope of the one or more atoms that constitute such compound.For example, described compound can be used radio isotope, for example tritium ( 3H), iodine-125 ( 125I) or carbon-14 ( 14C) carry out radio-labeled.No matter whether all isotopic variations of disclosure compound have radioactivity, includes in disclosure scope.
[0061] term " pharmacy acceptable salt " is intended to comprise the salt of active compound, and it prepares with avirulent relatively acid or alkali, and this depends on the special substituent part of finding on the compound as herein described.When compound of the present disclosure contains relative acidic functionality, contact with the required alkali (no matter being when solvent-free or in suitable inert solvent) of capacity by the neutral form that makes such compound, can obtain base addition salt.The example of pharmaceutically acceptable base addition salt comprises sodium, potassium, calcium, ammonium, organic amino or magnesium salts, or similar salt.When compound of the present disclosure contains alkaline relatively functional group, contact with the required acid (no matter being when solvent-free or in suitable inert solvent) of capacity by the neutral form that makes such compound, can obtain acid salt.The example of pharmaceutically-acceptable acid addition comprises those acid salt derived from mineral acid example hydrochloric acid, Hydrogen bromide, nitric acid, carbonic acid, a hydrogen carbonic acid, phosphoric acid, a hydrogen phosphoric acid, dihydrogen phosphoric acid, sulfuric acid, a hydrosulphuric acid, hydroiodic acid HI or phosphorous acid etc., and derived from the salt of avirulent relatively organic acid such as acetate, propionic acid, isopropylformic acid, toxilic acid, propanedioic acid, phenylformic acid, succsinic acid, suberic acid, fumaric acid, lactic acid, amygdalic acid, phthalic acid, Phenylsulfonic acid, right-toluenesulphonic acids, citric acid, tartrate, methylsulfonic acid etc.Also comprise amino acid whose salt such as arginic acid salt etc., and the salt of organic acid such as glucuronic acid or galacturonic acid etc. for example see, Berge etc., " pharmaceutical salts ", pharmaceutical science magazine (the medicinal Science of Journal of), 1977,66,1-19).Some special disclosure compound not only contains basic functionality but also contain acidic functionality, and this makes described compound to be converted into or base addition salt or acid salt.
[0062] except salt form, the disclosure also is related to the compound of prodrug forms.The prodrug of compound as herein described experiences chemical transformation easily so that those compounds of disclosure compound to be provided under physiological conditions.In addition, prodrug can be by being converted into compound of the present disclosure through chemistry or biochemical method under stripped (ex vivo) environment.For example, when prodrug and suitable enzyme or chemical reagent place transdermal patch storage storehouse, can slowly be converted into compound of the present disclosure.
[0063] term " ", " one " or " one " are when when this paper is used to substituent group is described.Mean at least one.For example, when compound was replaced by " one " alkyl or aryl, this compound is optional to be replaced by at least one alkyl and/or at least one aryl.In addition, when one of them part was replaced by a R substituting group, this group can be called as " R-replaces ".When a part was the R-replacement, this part is replaced by at least one R substituting group and each R substituting group is chosen wantonly to different.
[0064] description of compound of the present disclosure is subjected to the restriction of chemical bond well known by persons skilled in the art.Therefore, one of them group can be replaced by the substituting group of one or more numbers, select such substituting group, so as to meet the principle of chemical bond and obtain and non-natural unstable compounds and/or those of ordinary skills should be known under envrionment conditions such as water-based, neutrality, physiological conditions the compound of potentially unstable.
[0065] term " treatment " or " processing " comprises preventing disease when relating to disease.
[0066] symbol
Figure A20078003852700891
The tie point of the rest part of expression group and molecule.
Triazolo-pyridazine protein kinase modulators
[0067] in one aspect, the disclosure relates to the compound with formula I:
Figure A20078003852700892
Or its enantiomorph, diastereomer, racemic modification or pharmacy acceptable salt or solvate,
Wherein:
[0068] A independently is that replace or unsubstituted aryl or replacement or unsubstituted heteroaryl;
[0069] Q independently is that replace or unsubstituted alkyl, replacement or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl, replacement or unsubstituted-O-aryl, replacement or unsubstituted arylalkyl, replacement or unsubstituted heteroaryl, replacement or unsubstituted-O-heteroaryl, that perhaps replace or unsubstituted heteroarylalkyl, wherein Q is optional by 1-3 R 22Replace independently;
[0070] T is CH independently 2, CH (halogen), C (halogen) 2, CH ((C 1-C 6) alkyl) or C ((C 1-C 6) alkyl) 2
[0071] X is N or CR 2
[0072] R 1And R 2Optional separately be independently hydrogen, halogen, nitro, cyano group, hydroxyl, replacement or unsubstituted alkyl, perfluoroalkyl ,-(CH 2) jCN ,-(CH 2) jOR 3,-(CH 2) jC (O) R 3,-(CH 2) jC (O) OR 3,-(CH 2) jNR 4R 5,-(CH 2) jC (O) NR 4R 5,-(CH 2) jOC (O) NR 4R 5,-(CH 2) jNR 6C (O) R 3,-(CH 2) jNR 6C (O) OR 3,-(CH 2) jNR 6C (O) NR 4R 5,-(CH 2) jS (O) mR 7,-(CH 2) jNR 6S (O) 2R 7,-(CH 2) jS (O) 2NR 4R 5, wherein each j is the integer of 0-6 independently; With m be the integer of 0-2 independently; Or
[0073] R 1And R 2That form to replace or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl, perhaps that replace or unsubstituted heteroaryl;
[0074] R 3, R 4, R 5, R 6And R 7Be hydrogen, replacement or unsubstituted alkyl, replacement independently of one another or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl, replacement or unsubstituted-O-aryl, replacement or unsubstituted arylalkyl, replacement or unsubstituted heteroaryl, replacement or unsubstituted-O-heteroaryl, that perhaps replace or unsubstituted heteroarylalkyl, or
[0075] R 3, R 6And R 7As mentioned above, and R 4And R 5N atom with they connect forms that replace or unsubstituted Heterocyclylalkyl, perhaps that replace or unsubstituted heteroaryl;
[0076] R 22Be hydrogen, halogen, nitro, cyano group, hydroxyl, replacement or unsubstituted alkyl, replacement independently or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl, replacement or unsubstituted-O-aryl, replacement or unsubstituted arylalkyl, replacement or unsubstituted heteroaryl, replacement or unsubstituted-O-heteroaryl, replacement or unsubstituted heteroarylalkyl ,-(CH 2) jCN ,-(CH 2) jOR 23,-(CH 2) jC (O) R 23,-(CH 2) jC (O) OR 23,-(CH 2) jNR 24R 25,-(CH 2) jC (O) NR 24R 25,-(CH 2) jOC (O) NR 24R 25,-(CH 2) jNR 26C (O) R 23,-(CH 2) jNR 26C (O) OR 23,-(CH 2) jNR 26C (O) NR 24R 25,-(CH 2) jS (O) mR 27,-(CH 2) jS (O) 2NR 24R 25Or-(CH 2) jNR 26S (O) 2R 27, wherein each j is the integer of 0-6 independently, and each m is the integer of 0-2 independently;
[0077] R 23, R 24, R 25, R 26And R 27Be hydrogen, replacement or unsubstituted alkyl, replacement independently of one another or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl, replacement or unsubstituted-O-aryl, replacement or unsubstituted arylalkyl, replacement or unsubstituted heteroaryl, replacement or unsubstituted-O-heteroaryl, that perhaps replace or unsubstituted heteroarylalkyl, or
[0078] R 23, R 26And R 27As mentioned above, and R 24And R 25N atom with they connect forms that replace or unsubstituted Heterocyclylalkyl, perhaps that replace or unsubstituted heteroaryl;
[0079] R 28' and R 28" be hydrogen, halogen, nitro, cyano group, hydroxyl, replacement or unsubstituted alkyl, replacement independently of one another or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted alkoxyl group, amino, an amino alkyl or amino dialkyl group;
[0080] R 35Be key, hydrogen, halogen, nitro, cyano group, hydroxyl, replacement or unsubstituted alkyl, replacement independently or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl, replacement or unsubstituted arylalkyl, replacement or unsubstituted heteroaryl, replacement or unsubstituted heteroarylalkyl ,-(CH 2) jCN ,-(CH 2) jOR 30,-(CH 2) jC (O) R 30,-(CH 2) jC (O) OR 30,-(CH 2) jNR 31R 32,-(CH 2) jC (O) NR 31R 32,-(CH 2) jOC (O) NR 31R 32,-(CH 2) jNR 33C (O) R 30,-(CH 2) jNR 33C (O) OR 30,-(CH 2) jN 33C (O) NR 31R 32,-(CH 2) jS (O) mR 34,-(CH 2) jS (O) 2NR 31R 32, or-(CH 2) jNR 33S (O) 2R 34, wherein each j is that integer and the m of 0-6 is the integer of 0-2 independently independently;
[0081] z is the integer of 0-3 independently;
[0082] R 30, R 31, R 32, R 33And R 34Be hydrogen, replacement or unsubstituted alkyl, replacement independently of one another or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl, replacement or unsubstituted-O-aryl, replacement or unsubstituted arylalkyl, replacement or unsubstituted heteroaryl, replacement or unsubstituted-O-heteroaryl, that perhaps replace or unsubstituted heteroarylalkyl, or
[0083] R 30, R 33And R 34As mentioned above, and R 31And R 32N atom with they connect forms that replace or unsubstituted Heterocyclylalkyl, perhaps that replace or unsubstituted heteroaryl; With
[0084] R wherein 1, R 2, R 3, R 4, R 5, R 6, R 7, R 22, R 23, R 24, R 25, R 26, R 27, R 28', R 28", R 30, R 31, R 32, R 33, R 34And R 35Optionally separately replaced independently by 1-3 group, each group be independently selected from hydrogen, halogen, hydroxyl, amino, an amino alkyl, amino dialkyl group, cyano group, nitro, difluoromethyl, trifluoromethyl, oxo, alkyl ,-the O-alkyl and-the S-alkyl.
[0085] on the other hand, the disclosure provides the compound with formula I, wherein:
[0086] A independently is that replace or unsubstituted phenyl, that replace or unsubstituted naphthyl, that replace or unsubstituted biphenyl group, that replace or unsubstituted pyrryl, that replace or unsubstituted furyl, that replace or unsubstituted thienyl, that replace or do not replace the De oxazolyl, that replace or unsubstituted thiazolyl, that replace or unsubstituted imidazolyl, that replace or unsubstituted pyrazolyl, that replace or unsubstituted pyridine base, that replace or unsubstituted isoxazolyl, that replace or unsubstituted isothiazolyl, that replace or unsubstituted triazolyl, that replace or unsubstituted pyrazinyl, that replace or unsubstituted pyridine base, that replace or unsubstituted pyrimidyl, that replace or unsubstituted benzothiazolyl, that replace or unsubstituted purine radicals, that replace or unsubstituted benzimidazolyl-, that replace or unsubstituted indyl, that replace or unsubstituted isoquinolyl, that replace or unsubstituted quinoxalinyl, that replace or unsubstituted quinolines base, that replace or unsubstituted benzoxazolyl, that replace or unsubstituted [1,5] phthalazinyl, that replace or unsubstituted pyridine also [3,2-d] pyrimidyl, that replace or unsubstituted [1,7] phthalazinyl, that replace or unsubstituted 1H-pyrrolo-[2,3-b] pyridyl, that replace or unsubstituted pyrazolo [4,3-b] pyridyl, that replace or unsubstituted pyrrolo-[2,3-b] pyridyl, that replace or unsubstituted thieno-[2,3-b] pyridyl, that replace or unsubstituted thiazole also [5,4-b] pyridyl, that replace or unsubstituted pyridine base-2-ketone, that replace or unsubstituted imidazo [1,2-b] pyridazinyl, that replace or unsubstituted pyrazolo [1,5-a] pyrimidyl, that replace or unsubstituted pyridazinyl-3-ketone, that replace or unsubstituted imidazo [2,1-b] [1,3,4] thiadiazolyl group (thiaciazolyl), that replace or unsubstituted imidazo [2,1-b] thiazolyl, that perhaps replace or unsubstituted imidazo [4,5-b] pyridyl;
[0087] Q is hydrogen independently, halogen, that replace or unsubstituted alkyl, perfluoroalkyl, amino, that replace an or unsubstituted amino alkyl, that replace or unsubstituted amino dialkyl group, that replace or unsubstituted phenyl, that replace or unsubstituted phenoxy, that replace or unsubstituted piperidyl, that replace or unsubstituted piperazinyl, that replace or unsubstituted pyrrolidyl, that replace or unsubstituted morpholinyl, that replace or unsubstituted pyrryl, that replace or unsubstituted furyl, that replace or unsubstituted thienyl, that replace or do not replace the De oxazolyl, that replace or unsubstituted thiazolyl, that replace or unsubstituted imidazolyl, that replace or unsubstituted pyrazolyl, that replace or unsubstituted pyridine base, that replace or unsubstituted-O-pyridyl, that replace or unsubstituted isoxazolyl, that replace or unsubstituted isothiazolyl, perhaps that replace or unsubstituted triazolyl;
[0088] R 1And R 2Optional separately be independently hydrogen, halogen, nitro, cyano group, hydroxyl, replacement or unsubstituted alkyl, perfluoroalkyl ,-(CH 2) jCN ,-(CH 2) jOR 3,-(CH 2) jC (O) R 3,-(CH 2) jC (O) OR 3,-(CH 2) jNR 4R 5,-(CH 2) jC (O) NR 4R 5,-(CH 2) jOC (O) NR 4R 5,-(CH 2) jNR 6C (O) R 3,-(CH 2) jNR 6C (O) OR 3,-(CH 2) jNR 6C (O) NR 4R 5,-(CH 2) jS (O) mR 7,-(CH 2) jNR 6S (O) 2R 7,-(CH 2) jS (O) 2NR 4R 5
[0089] R 22Be hydrogen independently, halogen, nitro, cyano group, hydroxyl, that replace or unsubstituted alkyl, that replace or unsubstituted cycloalkyl, perfluoroalkyl, that replace or unsubstituted assorted alkyl, that replace or unsubstituted Heterocyclylalkyl, that replace or unsubstituted phenyl, that replace or unsubstituted naphthyl, that replace or unsubstituted biphenyl group, that replace or unsubstituted pyrryl, that replace or unsubstituted imidazolyl, that replace or unsubstituted pyrazolyl, that replace or unsubstituted furyl, that replace or unsubstituted thienyl, that replace or do not replace the De oxazolyl, that replace or unsubstituted isoxazolyl, that replace or unsubstituted thiazolyl, that replace or unsubstituted pyridine base, that replace or unsubstituted pyrazinyl, that replace or unsubstituted pyrimidyl, that replace or unsubstituted benzothiazolyl, that replace or unsubstituted purine radicals, that replace or unsubstituted benzimidazolyl-, that replace or unsubstituted indyl, that replace or unsubstituted isoquinolyl, that replace or unsubstituted quinoxalinyl, that replace or unsubstituted quinolines base, that replace or unsubstituted benzoxazolyl, that replace or unsubstituted [1,5] phthalazinyl, that replace or unsubstituted pyridine also [3,2-d] pyrimidyl, that replace or unsubstituted [1,7] phthalazinyl, that replace or unsubstituted 1H-pyrrolo-[2,3-b] pyridyl, that replace or unsubstituted pyrazolo [4,3-b] pyridyl, that replace or unsubstituted pyrrolo-[2,3-b] pyridyl, that replace or unsubstituted thieno-[2,3-b] pyridyl, that replace or unsubstituted thiazole also [5,4-b] pyridyl, that replace or unsubstituted pyridine base-2-ketone, that replace or unsubstituted imidazo [1,2-b] pyridazinyl, that replace or unsubstituted pyrazolo [1,5-a] pyrimidyl, that replace or unsubstituted pyridazinyl-3-ketone, that replace or unsubstituted imidazo [2,1-b] [1,3,4] thiadiazolyl group, that replace or unsubstituted imidazo [2,1-b] thiazolyl, that perhaps replace or unsubstituted imidazo [4,5-b] pyridyl,-(CH 2) jCN ,-(CH 2) jOR 23,-(CH 2) jC (O) R 23,-(CH 2) jC (O) OR 23,-(CH 2) jNR 24R 25, (CH 2) jC (O) NR 24R 25,-(CH 2) jOC (O) NR 24R 25,-(CH 2) jNR 26C (O) R 23,-(CH 2) jNR 26C (O) OR 23,-(CH 2) jNR 26C (O) NR 24R 25,-(CH 2) jS (O) mR 27,-(CH 2) jS (O) 2NR 24R 25Or-(CH 2) jNR 26S (O) 2R 27
[0090] R 28' and R 28" be independently of one another hydrogen, halogen, cyano group, hydroxyl, replacement or unsubstituted alkyl, or perfluoroalkyl; With
[0091] R 35Be hydrogen independently, halogen, nitro, cyano group, hydroxyl, that replace or unsubstituted alkyl, that replace or unsubstituted cycloalkyl, perfluoroalkyl, that replace or unsubstituted assorted alkyl, that replace or unsubstituted Heterocyclylalkyl, that replace or unsubstituted azetidinyl, that replace or unsubstituted phenyl, that replace or unsubstituted naphthyl, that replace or unsubstituted biphenyl group, that replace or unsubstituted pyrryl, that replace or unsubstituted imidazolyl, that replace or unsubstituted pyrazolyl, that replace or unsubstituted furyl, that replace or unsubstituted thienyl, that replace or do not replace the De oxazolyl, that replace or unsubstituted isoxazolyl, that replace or unsubstituted thiazolyl, that replace or unsubstituted pyridine base, that replace or unsubstituted pyrazinyl, that replace or unsubstituted pyrimidyl, that replace or unsubstituted benzothiazolyl, that replace or unsubstituted purine radicals, that replace or unsubstituted benzimidazolyl-, that replace or unsubstituted indyl, that replace or unsubstituted isoquinolyl, that replace or unsubstituted quinoxalinyl, that replace or unsubstituted quinolines base, that replace or unsubstituted benzoxazolyl, that replace or unsubstituted [1,5] phthalazinyl, that replace or unsubstituted pyridine also [3,2-d] pyrimidyl, that replace or unsubstituted [1,7] phthalazinyl, that replace or unsubstituted 1H-pyrrolo-[2,3-b] pyridyl, that replace or unsubstituted pyrazolo [4,3-b] pyridyl, that replace or unsubstituted pyrrolo-[2,3-b] pyridyl, that replace or unsubstituted thieno-[2,3-b] pyridyl, that replace or unsubstituted thiazole also [5,4-b] pyridyl, that replace or unsubstituted pyridine base-2-ketone, that replace or unsubstituted imidazo [1,2-b] pyridazinyl, that replace or unsubstituted pyrazolo [1,5-a] pyrimidyl, that replace or unsubstituted pyridazinyl-3-ketone, that replace or unsubstituted imidazo [2,1-b] [1,3,4] thiadiazolyl group, that replace or unsubstituted imidazo [2,1-b] thiazolyl, that perhaps replace or unsubstituted imidazo [4,5-b] pyridyl,-(CH 2) jCN ,-(CH 2) jOR 30,-(CH 2) jC (O) R 30,-(CH 2) jC (O) OR 30,-(CH 2) jNR 31R 32,-(CH 2) jC (O) NR 31R 32,-(CH 2) jOC (O) NR 31R 32,-(CH 2) jNR 33C (O) R 30,-(CH 2) jNR 33C (O) OR 30,-(CH 2) jNR 33C (O) NR 31R 32,-(CH 2) jS (O) mR 34,-(CH 2) jS (O) 2NR 31R 32Or-(CH 2) jNR 33S (O) 2R 34
[0092] on the other hand, the disclosure provides the compound with formula I, wherein:
[0093] A independently is that replace or unsubstituted phenyl, that replace or unsubstituted naphthyl, that replace or unsubstituted biphenyl group, that replace or unsubstituted pyrryl, that replace or unsubstituted furyl, that replace or unsubstituted thienyl, that replace or do not replace the De oxazolyl, that replace or unsubstituted thiazolyl, that replace or unsubstituted imidazolyl, that replace or unsubstituted pyrazolyl, that replace or unsubstituted pyridine base, that replace or unsubstituted isoxazolyl, that replace or unsubstituted isothiazolyl, that replace or unsubstituted triazolyl, that replace or unsubstituted pyrazinyl, that replace or unsubstituted pyridine base, that replace or unsubstituted pyrimidyl, that replace or unsubstituted benzothiazolyl, that replace or unsubstituted purine radicals, that replace or unsubstituted benzimidazolyl-, that replace or unsubstituted indyl, that replace or unsubstituted isoquinolyl, that replace or unsubstituted quinoxalinyl, replace or the unsubstituted quinolines base;
[0094] Q is hydrogen independently, halogen, that replace or unsubstituted alkyl, perfluoroalkyl, amino, that replace an or unsubstituted amino alkyl, that replace or unsubstituted amino dialkyl group, that replace or unsubstituted phenyl, that replace or unsubstituted phenoxy, that replace or unsubstituted piperidyl, that replace or unsubstituted piperazinyl, that replace or unsubstituted pyrrolidyl, that replace or unsubstituted morpholinyl, that replace or unsubstituted pyrryl, that replace or unsubstituted furyl, that replace or unsubstituted thienyl, that replace or do not replace the De oxazolyl, that replace or unsubstituted thiazolyl, that replace or unsubstituted imidazolyl, that replace or unsubstituted pyrazolyl, that replace or unsubstituted pyridine base, perhaps that replace or unsubstituted-O-pyridyl;
[0095] R 1And R 2Be independently of one another hydrogen, halogen, nitro, cyano group, hydroxyl, replacement or unsubstituted alkyl, or perfluoroalkyl;
[0096] X is CR 2
[0097] R 22Be hydrogen, halogen, nitro, cyano group, hydroxyl, replacement or unsubstituted alkyl, replacement independently or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted Heterocyclylalkyl ,-(CH 2) jCN ,-(CH 2) jOR 23,-(CH 2) jC (O) R 23,-(CH 2) jC (O) OR 23,-(CH 2) jNR 24R 25,-(CH 2) jC (O) NR 24R 25,-(CH 2) jOC (O) NR 24R 25,-(CH 2) jNR 26C (O) R 23,-(CH 2) jNR 26C (O) OR 23,-(CH 2) jNR 26C (O) NR 24R 25,-(CH 2) jS (O) mR 27,-(CH 2) jS (O) 2NR 24R 25Or-(CH 2) jNR 26S (O) 2R 27
[0098] R 28' and R 28" be hydrogen, halogen, hydroxyl, alkyl or perfluoroalkyl independently of one another; With
[0099] R 35Be hydrogen, halogen, nitro, cyano group, hydroxyl, replacement or unsubstituted alkyl, replacement independently or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted Heterocyclylalkyl ,-(CH 2) jCN ,-(CH 2) jOR 30,-(CH 2) jC (O) R 30,-(CH 2) jC (O) OR 30,-(CH 2) jNR 31R 32,-(CH 2) jC (O) NR 31R 32,-(CH 2) jOC (O) NR 31R 32,-(CH 2) jNR 33C (O) R 30,-(CH 2) jNR 33C (O) OR 30,-(CH 2) jN 33C (O) NR 31R 32,-(CH 2) jS (O) mR 34,-(CH 2) jS (O) 2NR 31R 32,-(CH 2) jNR 33S (O) 2R 34,
Figure A20078003852700971
[0100] on the other hand, the disclosure provides the compound with formula I, wherein:
[0101] A is independently:
Figure A20078003852700972
[0102] Q be independently hydrogen, chloro, replacement or unsubstituted alkyl, perfluoroalkyl ,-NH 2,-NH (C 1-C 6) alkyl or-N[(C 1-C 6) alkyl] 2,
Figure A20078003852700981
Wherein each alkyl is optional by 1-3 R 22Group replace independently and wherein w be the integer of 0-3 independently; Two R wherein 22Group and-O (CH 2CH 2) the optional ring texture that forms of O-;
[0103] R 1And R 2Be hydrogen independently of one another;
[0104] R 22Be independently-H ,-F, Cl, Br, I ,-(C 1-C 6) alkyl ,-(CH 2) jCN ,-(CH 2) jO (C 1-C 6) alkyl ,-(CH 2) jOH ,-(CH 2) jC (O) (C 1-C 6) alkyl ,-(CH 2) jNH 2,-(CH 2) jNH (C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) 2,-(CH 2) jC (O) NH 2,-(CH 2) jC (O) NH (C 1-C 6) alkyl ,-C (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jNHC (O) (C 1-C 6) alkyl ,-(CH 2) jNHSO 2(C 1-C 6) alkyl ,-(CH 2) jNHSO 2(C 1-C 6) alkyl ,-(CH 2) jSO 2CH 3,-(CH 2) jSO 2NH 2,-(CH 2) jSO 2NH (C 1-C 6)-alkyl ,-(CH 2) jSO 2N ((C 1-C 6) alkyl) 2,-(CH 2) jSO 2NH (C 1-C 6) alkyl (OH), phenyl,
[0105] R 28' and R 28" be hydrogen, halogen, hydroxyl, (C independently of one another 1-C 6) alkyl or trifluoromethyl; With
[0106] R 35Be hydrogen, halogen, nitro, cyano group, hydroxyl, (C independently 1-C 6) alkyl, ring (C 3-C 10) alkyl, perfluor (C 1-C 6) alkyl ,-(CH 2) jCN ,-(CH 2) jO (C 1-C 6) alkyl ,-(CH 2) jC (O) (C 1-C 6) alkyl ,-(CH 2) jC (O) O (C 1-C 6) alkyl ,-(CH 2) jNH 2,-(CH 2) jNH (C 1-C 6) alkyl) ,-(CH 2) jN ((C 1-C 6) alkyl) 2,-(CH 2) jC (O) NH 2,-(CH 2) jC (O) NH (C 1-C 6) alkyl) ,-(CH 2) jC (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jOC (O) NH 2,-(CH 2) jOC (O) NH (C 1-C 6) alkyl) ,-(CH 2) jOC (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jNHC (O) (C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) C (O) (C 1-C 6) alkyl ,-(CH 2) jNHC (O) O (C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) C (O) O (C 1-C 6) alkyl ,-(CH 2) jNHC (O) NH 2, (CH 2) jNHC (O) NH (C 1-C 6) alkyl) ,-(CH 2) jNHC (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jN ((C 1-C 6) alkyl) C (O) NH (C 1-C 6) alkyl) ,-(CH 2) jN ((C 1-C 6) alkyl) C (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jS (O) m(C 1-C 6) alkyl ,-(CH 2) jS (O) 2NH 2,-(CH 2) jS (O) 2NH (C 1-C 6) alkyl) ,-(CH 2) jS (O) 2N ((C 1-C 6) alkyl) 2,-(CH 2) jNHS (O) 2(C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) S (O) 2(C 1-C 6) alkyl,
Figure A20078003852700991
[0107] on the other hand, the disclosure provides the compound with formula I, wherein:
[0108] A is independently:
Figure A20078003852700992
[0109] Q is (C independently 1-C 6) alkyl, perfluoroalkyl ,-NH 2,-NH (C 1-C 6) alkyl ,-N[(C 1-C 6) alkyl] 2,
Figure A20078003852700993
[0110] R 28' and R 28" be hydrogen, halogen, (C independently of one another 1-C 6) alkyl or trifluoromethyl; With
[0111] R 35Be independently hydrogen, halogen, cyano group, hydroxyl ,-(C 1-C 6) alkyl ,-(CH 2) jCN ,-(CH 2) jO (C 1-C 6) alkyl ,-(CH 2) jOH ,-(CH 2) jC (O) (C 1-C 6) alkyl ,-(CH 2) jC (O) OH ,-(CH 2) jNH 2,-(CH 2) jNH (C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) 2,-(CH 2) jC (O) NH 2,-(CH 2) jC (O) NH (C 1-C 6) alkyl ,-C (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jNHC (O) (C 1-C 6) alkyl ,-(CH 2) jNHSO 2(C 1-C 6) alkyl ,-(CH 2) jNHSO 2(C 1-C 6) alkyl ,-(CH 2) jSO 2CH 3,-(CH 2) jSO 2NH 2,-(CH 2) jSO 2NH (C 1-C 6)-alkyl ,-(CH 2) jSO 2N ((C 1-C 6) alkyl) 2,-(CH 2) jSO 2NH (C 1-C 6) alkyl (OH), phenyl,
Figure A20078003852701001
[0112] on the other hand, the disclosure provides the compound with formula II:
Figure A20078003852701002
Wherein:
[0113] A independently is that replace or unsubstituted phenyl, that replace or unsubstituted naphthyl, that replace or unsubstituted biphenyl group, that replace or unsubstituted pyrryl, that replace or unsubstituted furyl, that replace or unsubstituted thienyl, that replace or do not replace the De oxazolyl, that replace or unsubstituted thiazolyl, that replace or unsubstituted imidazolyl, that replace or unsubstituted pyrazolyl, that replace or unsubstituted pyridine base, that replace or unsubstituted isoxazolyl, that replace or unsubstituted isothiazolyl, that replace or unsubstituted triazolyl, that replace or unsubstituted pyrazinyl, that replace or unsubstituted pyridine base, that replace or unsubstituted pyrimidyl, that replace or unsubstituted benzothiazolyl, that replace or unsubstituted purine radicals, that replace or unsubstituted benzimidazolyl-, that replace or unsubstituted indyl, that replace or unsubstituted isoquinolyl, that replace or unsubstituted quinoxalinyl, that replace or unsubstituted quinolines base, that replace or unsubstituted benzoxazolyl, that replace or unsubstituted [1,5] phthalazinyl, that replace or unsubstituted pyridine also [3,2-d] pyrimidyl, that replace or unsubstituted [1,7] phthalazinyl, that replace or unsubstituted 1H-pyrrolo-[2,3-b] pyridyl, that replace or unsubstituted pyrazolo [4,3-b] pyridyl, that replace or unsubstituted pyrrolo-[2,3-b] pyridyl, that replace or unsubstituted thieno-[2,3-b] pyridyl, that replace or unsubstituted thiazole also [5,4-b] pyridyl, that replace or unsubstituted pyridine base-2-ketone, that replace or unsubstituted imidazo [1,2-b] pyridazinyl, that replace or unsubstituted pyrazolo [1,5-a] pyrimidyl, that replace or unsubstituted pyridazinyl-3-ketone, that replace or unsubstituted imidazo [2,1-b] [1,3,4] thiadiazolyl group, that replace or unsubstituted imidazo [2,1-b] thiazolyl, that perhaps replace or unsubstituted imidazo [4,5-b] pyridyl;
[0114] Q is hydrogen independently, halogen, that replace or unsubstituted alkyl, perfluoroalkyl, amino, that replace an or unsubstituted amino alkyl, that replace or unsubstituted amino dialkyl group, that replace or unsubstituted phenyl, that replace or unsubstituted phenoxy, that replace or unsubstituted piperidyl, that replace or unsubstituted piperazinyl, that replace or unsubstituted pyrrolidyl, that replace or unsubstituted morpholinyl, that replace or unsubstituted pyrryl, that replace or unsubstituted furyl, that replace or unsubstituted thienyl, that replace or do not replace the De oxazolyl, that replace or unsubstituted thiazolyl, that replace or unsubstituted imidazolyl, that replace or unsubstituted pyrazolyl, that replace or unsubstituted pyridine base, that replace or unsubstituted-O-pyridyl, that replace or unsubstituted isoxazolyl, that replace or unsubstituted isothiazolyl, perhaps that replace or unsubstituted triazolyl;
[0115] R 22Be hydrogen independently, halogen, nitro, cyano group, hydroxyl, that replace or unsubstituted alkyl, that replace or unsubstituted cycloalkyl, perfluoroalkyl, that replace or unsubstituted assorted alkyl, that replace or unsubstituted Heterocyclylalkyl, that replace or unsubstituted phenyl, that replace or unsubstituted naphthyl, that replace or unsubstituted biphenyl group, that replace or unsubstituted pyrryl, that replace or unsubstituted imidazolyl, that replace or unsubstituted pyrazolyl, that replace or unsubstituted furyl, that replace or unsubstituted thienyl, that replace or do not replace the De oxazolyl, that replace or unsubstituted isoxazolyl, that replace or unsubstituted thiazolyl, that replace or unsubstituted pyridine base, that replace or unsubstituted pyrazinyl, that replace or unsubstituted pyrimidyl, that replace or unsubstituted benzothiazolyl, that replace or unsubstituted purine radicals, that replace or unsubstituted benzimidazolyl-, that replace or unsubstituted indyl, that replace or unsubstituted isoquinolyl, that replace or unsubstituted quinoxalinyl, that replace or unsubstituted quinolines base, that replace or unsubstituted benzoxazolyl, that replace or unsubstituted [1,5] phthalazinyl, that replace or unsubstituted pyridine also [3,2-d] pyrimidyl, that replace or unsubstituted [1,7] phthalazinyl, that replace or unsubstituted 1H-pyrrolo-[2,3-b] pyridyl, that replace or unsubstituted pyrazolo [4,3-b] pyridyl, that replace or unsubstituted pyrrolo-[2,3-b] pyridyl, that replace or unsubstituted thieno-[2,3-b] pyridyl, that replace or unsubstituted thiazole also [5,4-b] pyridyl, that replace or unsubstituted pyridine base-2-ketone, that replace or unsubstituted imidazo [1,2-b] pyridazinyl, that replace or unsubstituted pyrazolo [1,5-a] pyrimidyl, that replace or unsubstituted pyridazinyl-3-ketone, that replace or unsubstituted imidazo [2,1-b] [1,3,4] thiadiazolyl group, that replace or unsubstituted imidazo [2,1-b] thiazolyl, that perhaps replace or unsubstituted imidazo [4,5-b] pyridyl,-(CH 2) jCN ,-(CH 2) jOR 23,-(CH 2) jC (O) R 23,-(CH 2) jC (O) OR 23,-(CH 2) jNR 24R 25,-(CH 2) jC (O) NR 24R 25,-(CH 2) jOC (O) NR 24R 25,-(CH 2) jNR 26C (O) R 23,-(CH 2) jNR 26C (O) OR 23,-(CH 2) jNR 26C (O) NR 24R 25,-(CH 2) jS (O) mR 27,-(CH 2) jS (O) 2NR 24R 25Or-(CH 2) jNR 26S (O) 2R 27
[0116] R 28' and R 28" be independently of one another hydrogen, halogen, cyano group, hydroxyl, replacement or unsubstituted alkyl, or perfluoroalkyl; With
[0117] R 35Be hydrogen independently, halogen, nitro, cyano group, hydroxyl, that replace or unsubstituted alkyl, that replace or unsubstituted cycloalkyl, perfluoroalkyl, that replace or unsubstituted assorted alkyl, that replace or unsubstituted Heterocyclylalkyl, that replace or unsubstituted azetidinyl, that replace or unsubstituted phenyl, that replace or unsubstituted naphthyl, that replace or unsubstituted biphenyl group, that replace or unsubstituted pyrryl, that replace or unsubstituted imidazolyl, that replace or unsubstituted pyrazolyl, that replace or unsubstituted furyl, that replace or unsubstituted thienyl, that replace or do not replace the De oxazolyl, that replace or unsubstituted isoxazolyl, that replace or unsubstituted thiazolyl, that replace or unsubstituted pyridine base, that replace or unsubstituted pyrazinyl, that replace or unsubstituted pyrimidyl, that replace or unsubstituted benzothiazolyl, that replace or unsubstituted purine radicals, that replace or unsubstituted benzimidazolyl-, that replace or unsubstituted indyl, that replace or unsubstituted isoquinolyl, that replace or unsubstituted quinoxalinyl, that replace or unsubstituted quinolines base, that replace or unsubstituted benzoxazolyl, that replace or unsubstituted [1,5] phthalazinyl, that replace or unsubstituted pyridine also [3,2-d] pyrimidyl, that replace or unsubstituted [1,7] phthalazinyl, that replace or unsubstituted 1H-pyrrolo-[2,3-b] pyridyl, that replace or unsubstituted pyrazolo [4,3-b] pyridyl, that replace or unsubstituted pyrrolo-[2,3-b] pyridyl, that replace or unsubstituted thieno-[2,3-b] pyridyl, that replace or unsubstituted thiazole also [5,4-b] pyridyl, that replace or unsubstituted pyridine base-2-ketone, that replace or unsubstituted imidazo [1,2-b] pyridazinyl, that replace or unsubstituted pyrazolo [1,5-a] pyrimidyl, that replace or unsubstituted pyridazinyl-3-ketone, that replace or unsubstituted imidazo [2,1-b] [1,3,4] thiadiazolyl group, that replace or unsubstituted imidazo [2,1-b] thiazolyl, that perhaps replace or unsubstituted imidazo [4,5-b] pyridyl,-(CH 2) jCN ,-(CH 2) jOR 30,-(CH 2) jC (O) R 30,-(CH 2) jC (O) OR 30,-(CH 2) jNR 31R 32,-(CH 2) jC (O) NR 31R 32,-(CH 2) jOC (O) NR 31R 32,-(CH 2) jNR 33C (O) R 30,-(CH 2) jNR 33C (O) OR 30,-(CH 2) jNR 33C (O) NR 31R 32,-(CH 2) jS (O) mR 34,-(CH 2) jS (O) 2NR 31R 32Or-(CH 2) jNR 33S (O) 2R 34
[0118] on the other hand, the disclosure provides the compound with formula II, wherein:
[0119] A independently is that replace or unsubstituted phenyl, that replace or unsubstituted naphthyl, that replace or unsubstituted biphenyl group, that replace or unsubstituted pyrryl, that replace or unsubstituted furyl, that replace or unsubstituted thienyl, that replace or do not replace the De oxazolyl, that replace or unsubstituted thiazolyl, that replace or unsubstituted imidazolyl, that replace or unsubstituted pyrazolyl, that replace or unsubstituted pyridine base, that replace or unsubstituted isoxazolyl, that replace or unsubstituted isothiazolyl, that replace or unsubstituted triazolyl, that replace or unsubstituted pyrazinyl, that replace or unsubstituted pyridine base, that replace or unsubstituted pyrimidyl, that replace or unsubstituted benzothiazolyl, that replace or unsubstituted purine radicals, that replace or unsubstituted benzimidazolyl-, that replace or unsubstituted indyl, that replace or unsubstituted isoquinolyl, that replace or unsubstituted quinoxalinyl, replace or the unsubstituted quinolines base;
[0120] Q is hydrogen independently, halogen, that replace or unsubstituted alkyl, perfluoroalkyl, amino, that replace an or unsubstituted amino alkyl, that replace or unsubstituted amino dialkyl group, that replace or unsubstituted phenyl, that replace or unsubstituted phenoxy, that replace or unsubstituted piperidyl, that replace or unsubstituted piperazinyl, that replace or unsubstituted pyrrolidyl, that replace or unsubstituted morpholinyl, that replace or unsubstituted pyrryl, that replace or unsubstituted furyl, that replace or unsubstituted thienyl, that replace or do not replace the De oxazolyl, that replace or unsubstituted thiazolyl, that replace or unsubstituted imidazolyl, that replace or unsubstituted pyrazolyl, that replace or unsubstituted pyridine base, perhaps that replace or unsubstituted-O-pyridyl;
[0121] R 22Be hydrogen, halogen, nitro, cyano group, hydroxyl, replacement or unsubstituted alkyl, replacement independently or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted Heterocyclylalkyl ,-(CH 2) jCN ,-(CH 2) jOR 23,-(CH 2) jC (O) R 23,-(CH 2) jC (O) OR 23,-(CH 2) jNR 24R 25,-(CH 2) jC (O) NR 24R 25,-(CH 2) jOC (O) NR 24R 25,-(CH 2) jNR 26C (O) R 23,-(CH 2) jNR 26C (O) OR 23,-(CH 2) jNR 26C (O) NR 24R 25,-(CH 2) jS (O) mR 27,-(CH 2) jS (O) 2NR 24R 25Or-(CH 2) jNR 26S (O) 2R 27
[0122] R 28' and R 28" be hydrogen, halogen, hydroxyl, alkyl independently of one another, or perfluoroalkyl; With
[0123] R 35Be hydrogen, halogen, nitro, cyano group, hydroxyl, replacement or unsubstituted alkyl, replacement independently or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted Heterocyclylalkyl ,-(CH 2) jCN ,-(CH 2) jOR 30,-(CH 2) jC (O) R 30,-(CH 2) jC (O) OR 30,-(CH 2) jNR 31R 32,-(CH 2) jC (O) NR 31R 32,-(CH 2) jOC (O) NR 31R 32,-(CH 2) jNR 33C (O) R 30,-(CH 2) jNR 33C (O) OR 30,-(CH 2) jN 33C (O) NR 31R 32,-(CH 2) jS (O) mR 34,-(CH 2) jS (O) 2NR 31R 32,-(CH 2) jNR 33S (O) 2R 34,
Figure A20078003852701051
[0124] on the other hand, the disclosure provides the compound with formula II, wherein:
[0125] A is independently:
Figure A20078003852701052
[0126] Q be independently hydrogen, chloro, replacement or unsubstituted alkyl, perfluoroalkyl ,-NH 2,-NH (C 1-C 6) alkyl or-N[(C 1-C 6) alkyl] 2,
Figure A20078003852701061
Wherein each alkyl is optional by 1-3 R 22Group replace independently and wherein w be the integer of 0-3 independently; Two R wherein 22Group and-O (CH 2CH 2) the optional ring texture that forms of O-;
[0127] R 22Be independently-H ,-F, Cl, Br, I ,-(C 1-C 6) alkyl ,-(CH 2) jCN ,-(CH 2) jO (C 1-C 6) alkyl ,-(CH 2) jOH ,-(CH 2) jC (O) (C 1-C 6) alkyl ,-(CH 2) jNH 2,-(CH 2) jNH (C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) 2,-(CH 2) jC (O) NH 2,-(CH 2) jC (O) NH (C 1-C 6) alkyl ,-C (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jNHC (O) (C 1-C 6) alkyl ,-(CH 2) jNHSO 2(C 1-C 6) alkyl ,-(CH 2) jNHSO 2(C 1-C 6) alkyl ,-(CH 2) jSO 2CH 3,-(CH 2) jSO 2NH 2,-(CH 2) jSO 2NH (C 1-C 6) alkyl ,-(CH 2) jSO 2((C 1-C 6) alkyl) 2,-(CH 2) jSO 2NH (C 1-C 6) alkyl (OH), phenyl,
Figure A20078003852701062
[0128] R 28' and R 28" be hydrogen, halogen, hydroxyl, (C independently of one another 1-C 6) alkyl or trifluoromethyl; With
[0129] R 35Be hydrogen, halogen, nitro, cyano group, hydroxyl, (C independently 1-C 6) alkyl, ring (C 3-C 10) alkyl, perfluor (C 1-C 6) alkyl ,-(CH 2) jCN ,-(CH 2) jO (C 1-C 6) alkyl ,-(CH 2) jC (O) (C 1-C 6) alkyl ,-(CH 2) jC (O) O (C 1-C 6) alkyl ,-(CH 2) jNH 2,-(CH 2) jNH (C 1-C 6) alkyl) ,-(CH 2) jN ((C 1-C 6) alkyl) 2,-(CH 2) jC (O) NH 2,-(CH 2) jC (O) NH (C 1-C 6) alkyl) ,-(CH 2) jC (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jOC (O) NH 2,-(CH 2) jOC (O) NH (C 1-C 6) alkyl) ,-(CH 2) jOC (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jNHC (O) (C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) C (O) (C 1-C 6) alkyl ,-(CH 2) jNHC (O) O (C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) C (O) O (C 1-C 6) alkyl ,-(CH 2) jNHC (O) NH 2, (CH 2) jNHC (O) NH (C 1-C 6) alkyl) ,-(CH 2) jNHC (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jN ((C 1-C 6) alkyl) C (O) NH (C 1-C 6) alkyl) ,-(CH 2) jN ((C 1-C 6) alkyl) C (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jS (O) m(C 1-C 6) alkyl ,-(CH 2) jS (O) 2NH 2,-(CH 2) jS (O) 2NH (C 1-C 6) alkyl) ,-(CH 2) jS (O) 2N ((C 1-C 6) alkyl) 2,-(CH 2) jNHS (O) 2(C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) S (O) 2(C 1-C 6) alkyl,
Figure A20078003852701071
[0130] on the other hand, the disclosure provides the compound with formula II, wherein:
[0131] A is independently:
[0132] Q is (C independently 1-C 6) alkyl, perfluoroalkyl ,-NH 2,-NH (C 1-C 6) alkyl ,-N[(C 1-C 6) alkyl] 2,
[0133] R 28' and R 28" be hydrogen, halogen, (C independently of one another 1-C 6) alkyl or trifluoromethyl; With
[0134] R 35Be independently hydrogen, halogen, cyano group, hydroxyl ,-(C 1-C 6) alkyl;-(CH 2) jCN ,-(CH 2) jO (C 1-C 6) alkyl ,-(CH 2) jOH ,-(CH 2) jC (O) (C 1-C 6) alkyl ,-(CH 2) jC (O) OH ,-(CH 2) jNH 2,-(CH 2) jNH (C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) 2,-(CH 2) jC (O) NH 2,-(CH 2) jC (O) NH (C 1-C 6) alkyl ,-C (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jNHC (O) (C 1-C 6) alkyl ,-(CH 2) jNHSO 2(C 1-C 6) alkyl ,-(CH 2) jNHSO 2(C 1-C 6) alkyl ,-(CH 2) jSO 2CH 3,-(CH 2) jSO 2NH 2,-(CH 2) jSO 2NH (C 1-C 6)-alkyl ,-(CH 2) jSO 2N ((C 1-C 6) alkyl) 2,-(CH 2) jSO 2NH (C 1-C 6) alkyl (OH), phenyl,
Figure A20078003852701081
[0135] on the other hand, the disclosure provides the compound with formula III:
Figure A20078003852701082
Wherein:
[0136] Q is hydrogen independently, halogen, that replace or unsubstituted alkyl, perfluoroalkyl, amino, that replace an or unsubstituted amino alkyl, that replace or unsubstituted amino dialkyl group, that replace or unsubstituted phenyl, that replace or unsubstituted phenoxy, that replace or unsubstituted piperidyl, that replace or unsubstituted piperazinyl, that replace or unsubstituted pyrrolidyl, that replace or unsubstituted morpholinyl, that replace or unsubstituted pyrryl, that replace or unsubstituted furyl, that replace or unsubstituted thienyl, that replace or do not replace the De oxazolyl, that replace or unsubstituted thiazolyl, that replace or unsubstituted imidazolyl, that replace or unsubstituted pyrazolyl, that replace or unsubstituted pyridine base, that replace or unsubstituted-O-pyridyl, that replace or unsubstituted isoxazolyl, that replace or unsubstituted isothiazolyl, perhaps that replace or unsubstituted triazolyl;
[0137] R 22Be hydrogen independently, halogen, nitro, cyano group, hydroxyl, that replace or unsubstituted alkyl, that replace or unsubstituted cycloalkyl, perfluoroalkyl, that replace or unsubstituted assorted alkyl, that replace or unsubstituted Heterocyclylalkyl, that replace or unsubstituted phenyl, that replace or unsubstituted naphthyl, that replace or unsubstituted biphenyl group, that replace or unsubstituted pyrryl, that replace or unsubstituted imidazolyl, that replace or unsubstituted pyrazolyl, that replace or unsubstituted furyl, that replace or unsubstituted thienyl, that replace or do not replace the De oxazolyl, that replace or unsubstituted isoxazolyl, that replace or unsubstituted thiazolyl, that replace or unsubstituted pyridine base, that replace or unsubstituted pyrazinyl, that replace or unsubstituted pyrimidyl, that replace or unsubstituted benzothiazolyl, that replace or unsubstituted purine radicals, that replace or unsubstituted benzimidazolyl-, that replace or unsubstituted indyl, that replace or unsubstituted isoquinolyl, that replace or unsubstituted quinoxalinyl, that replace or unsubstituted quinolines base, that replace or unsubstituted benzoxazolyl, that replace or unsubstituted [1,5] phthalazinyl, that replace or unsubstituted pyridine also [3,2-d] pyrimidyl, that replace or unsubstituted [1,7] phthalazinyl, that replace or unsubstituted 1H-pyrrolo-[2,3-b] pyridyl, that replace or unsubstituted pyrazolo [4,3-b] pyridyl, that replace or unsubstituted pyrrolo-[2,3-b] pyridyl, that replace or unsubstituted thieno-[2,3-b] pyridyl, that replace or unsubstituted thiazole also [5,4-b] pyridyl, that replace or unsubstituted pyridine base-2-ketone, that replace or unsubstituted imidazo [1,2-b] pyridazinyl, that replace or unsubstituted pyrazolo [1,5-a] pyrimidyl, that replace or unsubstituted pyridazinyl-3-ketone, that replace or unsubstituted imidazo [2,1-b] [1,3,4] thiadiazolyl group, that replace or unsubstituted imidazo [2,1-b] thiazolyl, that perhaps replace or unsubstituted imidazo [4,5-b] pyridyl,-(CH 2) jCN ,-(CH 2) jOR 23,-(CH 2) jC (O) R 23,-(CH 2) jC (O) OR 23,-(CH 2) jNR 24R 25,-(CH 2) jC (O) NR 24R 25,-(CH 2) jOC (O) NR 24R 25,-(CH 2) jNR 26C (O) R 23,-(CH 2) jNR 26C (O) OR 23,-(CH 2) jNR 26C (O) NR 24R 25,-(CH 2) jS (O) mR 27,-(CH 2) jS (O) 2NR 24R 25Or-(CH 2) jNR 26S (O) 2R 27
[0138] R 28' and R 28" be hydrogen, halogen, hydroxyl, alkyl or perfluoroalkyl independently of one another; With
[0139] R 35Be hydrogen independently, halogen, nitro, cyano group, hydroxyl, that replace or unsubstituted alkyl, that replace or unsubstituted cycloalkyl, perfluoroalkyl, that replace or unsubstituted assorted alkyl, that replace or unsubstituted Heterocyclylalkyl, that replace or unsubstituted azetidinyl, that replace or unsubstituted phenyl, that replace or unsubstituted naphthyl, that replace or unsubstituted biphenyl group, that replace or unsubstituted pyrryl, that replace or unsubstituted imidazolyl, that replace or unsubstituted pyrazolyl, that replace or unsubstituted furyl, that replace or unsubstituted thienyl, that replace or do not replace the De oxazolyl, that replace or unsubstituted isoxazolyl, that replace or unsubstituted thiazolyl, that replace or unsubstituted pyridine base, that replace or unsubstituted pyrazinyl, that replace or unsubstituted pyrimidyl, that replace or unsubstituted benzothiazolyl, that replace or unsubstituted purine radicals, that replace or unsubstituted benzimidazolyl-, that replace or unsubstituted indyl, that replace or unsubstituted isoquinolyl, that replace or unsubstituted quinoxalinyl, that replace or unsubstituted quinolines base, that replace or unsubstituted benzoxazolyl, that replace or unsubstituted [1,5] phthalazinyl, that replace or unsubstituted pyridine also [3,2-d] pyrimidyl, that replace or unsubstituted [1,7] phthalazinyl, that replace or unsubstituted 1H-pyrrolo-[2,3-b] pyridyl, that replace or unsubstituted pyrazolo [4,3-b] pyridyl, that replace or unsubstituted pyrrolo-[2,3-b] pyridyl, that replace or unsubstituted thieno-[2,3-b] pyridyl, that replace or unsubstituted thiazole also [5,4-b] pyridyl, that replace or unsubstituted pyridine base-2-ketone, that replace or unsubstituted imidazo [1,2-b] pyridazinyl, that replace or unsubstituted pyrazolo [1,5-a] pyrimidyl, that replace or unsubstituted pyridazinyl-3-ketone, that replace or unsubstituted imidazo [2,1-b] [1,3,4] thiadiazolyl group, that replace or unsubstituted imidazo [2,1-b] thiazolyl, that perhaps replace or unsubstituted imidazo [4,5-b] pyridyl,-(CH 2) jCN ,-(CH 2) jOR 30,-(CH 2) jC (O) R 30,-(CH 2) jC (O) OR 30,-(CH 2) jNR 31R 32,-(CH 2) jC (O) NR 31R 32,-(CH 2) jOC (O) NR 31R 32,-(CH 2) jNR 33C (O) R 30,-(CH 2) jNR 33C (O) OR 30,-(CH 2) jNR 33C (O) NR 31R 32,-(CH 2) jS (O) mR 34,-(CH 2) jS (O) 2NR 31R 32Or-(CH 2) jNR 33S (O) 2R 34
[0140] on the other hand, the disclosure provides the compound with formula III, wherein:
[0141] Q is hydrogen independently, halogen, that replace or unsubstituted alkyl, perfluoroalkyl, amino, that replace an or unsubstituted amino alkyl, that replace or unsubstituted amino dialkyl group, that replace or unsubstituted phenyl, that replace or unsubstituted phenoxy, that replace or unsubstituted piperidyl, that replace or unsubstituted piperazinyl, that replace or unsubstituted pyrrolidyl, that replace or unsubstituted morpholinyl, that replace or unsubstituted pyrryl, that replace or unsubstituted furyl, that replace or unsubstituted thienyl, that replace or do not replace the De oxazolyl, that replace or unsubstituted thiazolyl, that replace or unsubstituted imidazolyl, that replace or unsubstituted pyrazolyl, that replace or unsubstituted pyridine base, perhaps that replace or unsubstituted-O-pyridyl;
[0142] R 22Be hydrogen, halogen, nitro, cyano group, hydroxyl, replacement or unsubstituted alkyl, replacement independently or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted Heterocyclylalkyl ,-(CH 2) jCN ,-(CH 2) jOR 23,-(CH 2) jC (O) R 23,-(CH 2) jC (O) OR 23,-(CH 2) jNR 24R 25,-(CH 2) jC (O) NR 24R 25,-(CH 2) jOC (O) NR 24R 25,-(CH 2) jNR 26C (O) R 23,-(CH 2) jNR 26C (O) OR 23,-(CH 2) jNR 26C (O) NR 24R 25,-(CH 2) jS (O) mR 27,-(CH 2) jS (O) 2NR 24R 25Or-(CH 2) jNR 26S (O) 2R 27
[0143] R 28' and R 28" be hydrogen, halogen, hydroxyl, alkyl or perfluoroalkyl independently of one another; With
[0144] R 35Be hydrogen, halogen, nitro, cyano group, hydroxyl, replacement or unsubstituted alkyl, replacement independently or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted Heterocyclylalkyl ,-(CH 2) jCN ,-(CH 2) jOR 30,-(CH 2) jC (O) R 30,-(CH 2) jC (O) OR 30,-(CH 2) jNR 31R 32,-(CH 2) jC (O) NR 31R 32,-(CH 2) jOC (O) NR 31R 32,-(CH 2) jNR 33C (O) R 30,-(CH 2) jNR 33C (O) OR 30,-(CH 2) jN 33C (O) NR 31R 32,-(CH 2) jS (O) mR 34,-(CH 2) jS (O) 2NR 31R 32,-(CH 2) jNR 33S (O) 2R 34,
Figure A20078003852701121
[0145] on the other hand, the disclosure provides the compound with formula III, wherein:
[0146] Q be independently hydrogen, chloro, replacement or unsubstituted alkyl, perfluoroalkyl ,-NH 2,-NH (C 1-C 6) alkyl, or-N[(C 1-C 6) alkyl] 2,
Figure A20078003852701122
Wherein each alkyl is optional by 1-3 R 22Group replace independently and wherein w be the integer of 0-3 independently; Two R wherein 22Group and-O (CH 2CH 2) the optional ring texture that forms of O-;
[0147] R 22Be independently-H ,-F, Cl, Br, I ,-(C 1-C 6) alkyl ,-(CH 2) jCN ,-(CH 2) jO (C 1-C 6) alkyl ,-(CH 2) jOH ,-(CH 2) jC (O) (C 1-C 6) alkyl ,-(CH 2) jNH 2,-(CH 2) jNH (C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) 2,-(CH 2) jC (O) NH 2,-(CH 2) jC (O) NH (C 1-C 6) alkyl ,-C (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jNHC (O) (C 1-C 6) alkyl ,-(CH 2) jNHSO 2(C 1-C 6) alkyl ,-(CH 2) jNHSO 2(C 1-C 6) alkyl ,-(CH 2) jSO 2CH 3,-(CH 2) jSO 2NH 2,-(CH 2) jSO 2NH (C 1-C 6)-alkyl ,-(CH 2) jSO 2N ((C 1-C 6) alkyl) 2,-(CH 2) jSO 2NH (C 1-C 6) alkyl (OH), phenyl,
Figure A20078003852701131
[0148] R 28' and R 28" be hydrogen, halogen, hydroxyl, (C independently of one another 1-C 6) alkyl or trifluoromethyl; With
[0149] R 35Be hydrogen, halogen, nitro, cyano group, hydroxyl, (C independently 1-C 6) alkyl, ring (C 3-C 10) alkyl, perfluor (C 1-C 6) alkyl ,-(CH 2) jCN ,-(CH 2) jO (C 1-C 6) alkyl ,-(CH 2) jC (O) (C 1-C 6) alkyl ,-(CH 2) jC (O) O (C 1-C 6) alkyl ,-(CH 2) jNH 2,-(CH 2) jNH (C 1-C 6) alkyl) ,-(CH 2) jN ((C 1-C 6) alkyl) 2,-(CH 2) jC (O) NH 2,-(CH 2) jC (O) NH (C 1-C 6) alkyl) ,-(CH 2) jC (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jOC (O) NH 2,-(CH 2) jOC (O) NH (C 1-C 6) alkyl) ,-(CH 2) jOC (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jNHC (O) (C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) C (O) (C 1-C 6) alkyl ,-(CH 2) jNHC (O) O (C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) C (O) O (C 1-C 6) alkyl ,-(CH 2) jNHC (O) NH 2, (CH 2) jNHC (O) NH (C 1-C 6) alkyl) ,-(CH 2) jNHC (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jN ((C 1-C 6) alkyl) C (O) NH (C 1-C 6) alkyl) ,-(CH 2) jN ((C 1-C 6) alkyl) C (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jS (O) m(C 1-C 6) alkyl ,-(CH 2) jS (O) 2NH 2,-(CH 2) jS (O) 2NH (C 1-C 6) alkyl) ,-(CH 2) jS (O) 2N ((C 1-C 6) alkyl) 2,-(CH 2) jNHS (O) 2(C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) S (O) 2(C 1-C 6) alkyl,
Figure A20078003852701132
[0150] on the other hand, the disclosure provides the compound with formula III, wherein:
[0151] Q is (C independently 1-C 6) alkyl, perfluoroalkyl ,-NH 2,-NH (C 1-C 6) alkyl ,-N[(C 1-C 6) alkyl] 2,
Figure A20078003852701141
[0152] R 28' and R 28" be hydrogen, halogen, (C independently of one another 1-C 6) alkyl or trifluoromethyl; With
[0153] R 35Be independently hydrogen, halogen, cyano group, hydroxyl ,-(C 1-C 6) alkyl ,-(CH 2) jCN ,-(CH 2) jO (C 1-C 6) alkyl ,-(CH 2) jOH ,-(CH 2) jC (O) (C 1-C 6) alkyl ,-(CH 2) jC (O) OH ,-(CH 2) jNH 2,-(CH 2) jNH (C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) 2,-(CH 2) jC (O) NH 2,-(CH 2) jC (O) NH (C 1-C 6) alkyl ,-C (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jNHC (O) (C 1-C 6) alkyl ,-(CH 2) jNHSO 2(C 1-C 6) alkyl ,-(CH 2) jNHSO 2(C 1-C 6) alkyl ,-(CH 2) jSO 2CH 3,-(CH 2) jSO 2NH 2,-(CH 2) jSO 2NH (C 1-C 6)-alkyl ,-(CH 2) jSO 2N ((C 1-C 6) alkyl) 2,-(CH 2) jSO 2NH (C 1-C 6) alkyl (OH), phenyl,
Figure A20078003852701142
[0154] on the other hand, the disclosure provides the compound with formula III, wherein:
[0155] Q is (C independently 1-C 6) alkyl;
[0156] T is CH 2
[0157] R 28' and R 28" be hydrogen independently of one another; With
[0158] R 35For-(C 1-C 6) alkyl.
[0159] on the other hand, the disclosure provides the compound with following formula:
Figure A20078003852701151
Figure A20078003852701161
Figure A20078003852701171
Figure A20078003852701181
Figure A20078003852701191
Figure A20078003852701201
[0160] on the other hand, the disclosure provides the compound with following formula:
Figure A20078003852701202
Figure A20078003852701211
[0161] on the other hand, the disclosure provides the method for regulating protein kinase activity, and it comprises makes protein kinase contact with formula I compound.
[0162] on the other hand, the disclosure provides the method for regulating protein kinase activity, it comprises makes protein kinase contact with formula I compound, and wherein said protein kinase is Ron receptor tyrosine kinase, Met receptor tyrosine kinase, ALK receptor tyrosine kinase, MER receptor tyrosine kinase, Tyro3/Sky receptor tyrosine kinase, axl receptor Tyrosylprotein kinase, TRKC receptor tyrosine kinase, ROS receptor tyrosine kinase, CSFIR/FMS receptor tyrosine kinase, BRAF kinases or Raf1 kinases.
[0163] on the other hand, the disclosure provides the method for regulating protein kinase activity, and it comprises makes protein kinase contact with formula I compound, and wherein said protein kinase is the Met receptor tyrosine kinase.
[0164] on the other hand, the disclosure is provided among the patient who needs this kind treatment and treats method for cancer, and described method comprises the formula I compound that gives described patient treatment significant quantity.
[0165] on the other hand, the disclosure is provided among the patient who needs this kind treatment and treats method for cancer, described method comprises the formula I compound that gives described patient treatment significant quantity, and wherein said cancer is a mammary cancer, lung cancer, melanoma, colorectal carcinoma, bladder cancer, ovarian cancer, prostate cancer, kidney, squamous cell carcinoma, glioblastoma, carcinoma of the pancreas, leiomyosarcoma, multiple myeloma, Papillary Renal Cell Carcinoma, cancer of the stomach, liver cancer, head and neck cancer, melanoma or leukemia are (as myelomatosis, chronic lymphocytic leukemia, acute lymphocytoblast leukemia, chronic lymphocytoblast leukemia, Hokdkin disease and other leukemia and hematology cancer).
[0166] on the other hand, the disclosure provides the medicinal compositions of the formula I compound that is included in the pharmaceutically acceptable vehicle.
[0167] on the other hand, the disclosure is provided at the method for preventing and/or suppress the proliferative cell transfer among the patient who needs this kind treatment, and this method is to be undertaken by the formula I compound that gives described patient treatment significant quantity.
[0168] on the other hand, the disclosure is provided at the method for preventing and/or suppress the proliferative cell transfer among the patient who needs this kind treatment, and this method is to be undertaken by the medicinal compositions that gives the formula I compound in the pharmaceutically acceptable vehicle of being included in of described patient treatment significant quantity.
[0169] on the other hand, the disclosure provides the method for preparation I compound,
Figure A20078003852701231
[0170] a) it is included in and makes the cyclodehydration of formula IV compound under acidity or the dehydration conditions.
[0171] on the other hand, the disclosure provides by making the formula IV compound method that cyclodehydration comes preparation I compound under acidity or dehydration conditions, and wherein said acidic conditions is acetate, POCl 3Or trifluoromethanesulfonic acid.
[0172] on the other hand, the disclosure provides the method for preparation I compound:
Figure A20078003852701241
[0173] a) it comprises and makes formula V compound and the coupling in solvent of formula VI compound, and wherein LG is halogen or trifluoromethanesulfonic acid ester group.
[0174] on the other hand, the disclosure provides by the method that makes formula V compound and the coupling in solvent of formula VI compound come preparation I compound, and wherein LG is halogen or trifluoromethanesulfonic acid ester group.
[0175] on the other hand, the disclosure provides by the method that makes formula V compound and the coupling in solvent of formula VI compound come preparation I compound, and wherein said solvent is an alcohol.
[0176] on the other hand, the disclosure provides the method for preparation I compound, said method comprising the steps of:
Figure A20078003852701242
[0177] a) make formula VII and formula VIII compound condensation, wherein R ' is C 1-C 6Alkyl.
[0178] on the other hand, the disclosure provides the compound with formula IX:
Figure A20078003852701243
Or its enantiomorph, diastereomer, racemic modification or pharmacy acceptable salt or solvate,
Wherein:
[0179] A independently is that replace or unsubstituted aryl or replacement or unsubstituted heteroaryl;
[0180] Q be hydrogen, amino, halogen, replacement or unsubstituted alkyl, replacement independently or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl, replacement or unsubstituted-O-aryl, replacement or unsubstituted arylalkyl, replacement or unsubstituted-O-heteroaryl, that perhaps replace or unsubstituted heteroarylalkyl, wherein Q is optional by 1-3 R 22Replace independently;
[0181] T is CH (halogen), C (halogen) independently 2
[0182] X is N or CR 2
[0183] R 1And R 2Optional separately be independently hydrogen, halogen, nitro, cyano group, hydroxyl, replacement or unsubstituted alkyl, perfluoroalkyl ,-(CH 2) jCN ,-(CH 2) jOR 3,-(CH 2) jC (O) R 3,-(CH 2) jC (O) OR 3,-(CH 2) jNR 4R 5,-(CH 2) jC (O) NR 4R 5,-(CH 2) jOC (O) NR 4R 5,-(CH 2) jNR 6C (O) R 3,-(CH 2) jNR 6C (O) OR 3,-(CH 2) jNR 6C (O) NR 4R 5,-(CH 2) jS (O) mR 7,-(CH 2) jNR 6S (O) 2R 7,-(CH 2) jS (O) 2NR 4R 5, wherein each j is the integer of 0-6 independently; With m be the integer of 0-2 independently; Or
[0184] R 1And R 2That form to replace or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl, perhaps that replace or unsubstituted heteroaryl;
[0185] R 3, R 4, R 5, R 6And R 7Be hydrogen, replacement or unsubstituted alkyl, replacement independently of one another or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl, replacement or unsubstituted-O-aryl, replacement or unsubstituted arylalkyl, replacement or unsubstituted heteroaryl, replacement or unsubstituted-O-heteroaryl, that perhaps replace or unsubstituted heteroarylalkyl, or
[0186] R 3, R 6And R 7As mentioned above, and R 4And R 5N atom with they connect forms that replace or unsubstituted Heterocyclylalkyl, perhaps that replace or unsubstituted heteroaryl;
[0187] R 22Be hydrogen, halogen, nitro, cyano group, hydroxyl, replacement or unsubstituted alkyl, replacement independently or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl, replacement or unsubstituted-O-aryl, replacement or unsubstituted arylalkyl, replacement or unsubstituted heteroaryl, replacement or unsubstituted-O-heteroaryl, replacement or unsubstituted heteroarylalkyl ,-(CH 2) jCN ,-(CH 2) jOR 23,-(CH 2) jC (O) R 23,-(CH 2) jC (O) OR 23,-(CH 2) jNR 24R 25,-(CH 2) jC (O) NR 24R 25,-(CH 2) jOC (O) NR 24R 25,-(CH 2) jNR 26C (O) R 23,-(CH 2) jNR 26C (O) OR 23,-(CH 2) jNR 26C (O) NR 24R 25,-(CH 2) jS (O) mR 27,-(CH 2) jS (O) 2NR 24R 25Or-(CH 2) jNR 26S (O) 2R 27, wherein each j is the integer of 0-6 independently, and each m is the integer of 0-2 independently;
[0188] R 23, R 24, R 25, R 26And R 27Be hydrogen, replacement or unsubstituted alkyl, replacement independently of one another or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl, replacement or unsubstituted-O-aryl, replacement or unsubstituted arylalkyl, replacement or unsubstituted heteroaryl, replacement or unsubstituted-O-heteroaryl, that perhaps replace or unsubstituted heteroarylalkyl, or
[0189] R 23, R 26And R 27As mentioned above, and R 24And R 25N atom with they connect forms that replace or unsubstituted Heterocyclylalkyl, perhaps that replace or unsubstituted heteroaryl;
[0190] R 28' and R 28" be hydrogen, halogen, nitro, cyano group, hydroxyl, replacement or unsubstituted alkyl, replacement independently of one another or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted alkoxyl group, amino, an amino alkyl, or amino dialkyl group;
[0191] R 35Be covalent linkage, hydrogen, halogen, nitro, cyano group, hydroxyl, replacement or unsubstituted alkyl, replacement independently or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl, replacement or unsubstituted arylalkyl, replacement or unsubstituted heteroaryl, replacement or unsubstituted heteroarylalkyl ,-(CH 2) jCN ,-(CH 2) jOR 30,-(CH 2) jC (O) R 30,-(CH 2) jC (O) OR 30,-(CH 2) jNR 31R 32,-(CH 2) jC (O) NR 31R 32,-(CH 2) jOC (O) NR 31R 32,-(CH 2) jNR 33C (O) R 30,-(CH 2) jNR 33C (O) OR 30,-(CH 2) jN 33C (O) NR 31R 32,-(CH 2) jS (O) mR 34,-(CH 2) jS (O) 2NR 31R 32Or-(CH 2) jNR 33S (O) 2R 34, wherein each j is that integer and the m of 0-6 is the integer of 0-2 independently independently;
[0192] z is the integer of 0-3 independently;
[0193] R 30, R 31, R 32, R 33And R 34Be hydrogen, replacement or unsubstituted alkyl, replacement independently of one another or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl, replacement or unsubstituted-O-aryl, replacement or unsubstituted arylalkyl, replacement or unsubstituted heteroaryl, replacement or unsubstituted-O-heteroaryl, that perhaps replace or unsubstituted heteroarylalkyl, or
[0194] R 30, R 33And R 34As mentioned above, and R 31And R 32N atom with they connect forms that replace or unsubstituted Heterocyclylalkyl, perhaps that replace or unsubstituted heteroaryl; With
[0195] R wherein 1, R 2, R 3, R 4, R 5, R 6, R 7, R 22, R 23, R 24, R 25, R 26, R 27, R 28', R 28", R 30, R 31, R 32, R 33, R 34And R 35Optionally separately replaced independently by 1-3 group, each group be independently selected from hydrogen, halogen, hydroxyl, amino, an amino alkyl, amino dialkyl group, cyano group, nitro, difluoromethyl, trifluoromethyl, oxo, alkyl ,-the O-alkyl and-the S-alkyl.
[0196] on the other hand, the disclosure provides the compound with formula IX, wherein:
[0197] A independently is that replace or unsubstituted phenyl, that replace or unsubstituted naphthyl, that replace or unsubstituted biphenyl group, that replace or unsubstituted pyrryl, that replace or unsubstituted furyl, that replace or unsubstituted thienyl, that replace or do not replace the De oxazolyl, that replace or unsubstituted thiazolyl, that replace or unsubstituted imidazolyl, that replace or unsubstituted pyrazolyl, that replace or unsubstituted pyridine base, that replace or unsubstituted isoxazolyl, that replace or unsubstituted isothiazolyl, that replace or unsubstituted triazolyl, that replace or unsubstituted pyrazinyl, that replace or unsubstituted pyrimidyl, that replace or unsubstituted benzothiazolyl, that replace or unsubstituted purine radicals, that replace or unsubstituted benzimidazolyl-, that replace or unsubstituted indyl, that replace or unsubstituted isoquinolyl, that replace or unsubstituted quinoxalinyl, that replace or unsubstituted quinolines base, that replace or unsubstituted benzoxazolyl, that replace or unsubstituted [1,5] phthalazinyl, that replace or unsubstituted pyridine also [3,2-d] pyrimidyl, that replace or unsubstituted [1,7] phthalazinyl, that replace or unsubstituted 1H-pyrrolo-[2,3-b] pyridyl, that replace or unsubstituted pyrazolo [4,3-b] pyridyl, that replace or unsubstituted pyrrolo-[2,3-b] pyridyl, that replace or unsubstituted thieno-[2,3-b] pyridyl, that replace or unsubstituted thiazole also [5,4-b] pyridyl, that replace or unsubstituted pyridine base-2-ketone, that replace or unsubstituted imidazo [1,2-b] pyridazinyl, that replace or unsubstituted pyrazolo [1,5-a] pyrimidyl, that replace or unsubstituted pyridazinyl-3-ketone, that replace or unsubstituted imidazo [2,1-b] [1,3,4] thiadiazolyl group, that replace or unsubstituted imidazo [2,1-b] thiazolyl, that perhaps replace or unsubstituted imidazo [4,5-b] pyridyl;
[0198] Q be hydrogen, halogen, replacement or unsubstituted alkyl, perfluoroalkyl, amino, replacement independently or a unsubstituted amino alkyl, replacement or unsubstituted amino dialkyl group, replacement or unsubstituted phenyl, replacement or unsubstituted phenoxy, replacement or unsubstituted piperidyl, replacement or unsubstituted piperazinyl, replacement or unsubstituted pyrrolidyl, replacement or unsubstituted morpholinyl, replacement or unsubstituted-O-pyridyl;
[0199] R 1And R 2Optional separately be independently hydrogen, halogen, nitro, cyano group, hydroxyl, replacement or unsubstituted alkyl, perfluoroalkyl ,-(CH 2) jCN ,-(CH 2) jOR 3,-(CH 2) jC (O) R 3,-(CH 2) jC (O) OR 3,-(CH 2) jNR 4R 5,-(CH 2) jC (O) NR 4R 5,-(CH 2) jOC (O) NR 4R 5,-(CH 2) jNR 6C (O) R 3,-(CH 2) jNR 6C (O) OR 3,-(CH 2) jNR 6C (O) NR 4R 5,-(CH 2) jS (O) mR 7,-(CH 2) jNR 6S (O) 2R 7,-(CH 2) jS (O) 2NR 4R 5
[0200] R 22Be hydrogen independently, halogen, nitro, cyano group, hydroxyl, that replace or unsubstituted alkyl, that replace or unsubstituted cycloalkyl, perfluoroalkyl, that replace or unsubstituted assorted alkyl, that replace or unsubstituted Heterocyclylalkyl, that replace or unsubstituted phenyl, that replace or unsubstituted naphthyl, that replace or unsubstituted biphenyl group, that replace or unsubstituted pyrryl, that replace or unsubstituted imidazolyl, that replace or unsubstituted pyrazolyl, that replace or unsubstituted furyl, that replace or unsubstituted thienyl, that replace or do not replace the De oxazolyl, that replace or unsubstituted isoxazolyl, that replace or unsubstituted thiazolyl, that replace or unsubstituted pyridine base, that replace or unsubstituted pyrazinyl, that replace or unsubstituted pyrimidyl, that replace or unsubstituted benzothiazolyl, that replace or unsubstituted purine radicals, that replace or unsubstituted benzimidazolyl-, that replace or unsubstituted indyl, that replace or unsubstituted isoquinolyl, that replace or unsubstituted quinoxalinyl, that replace or unsubstituted quinolines base, that replace or unsubstituted benzoxazolyl, that replace or unsubstituted [1,5] phthalazinyl, that replace or unsubstituted pyridine also [3,2-d] pyrimidyl, that replace or unsubstituted [1,7] phthalazinyl, that replace or unsubstituted 1H-pyrrolo-[2,3-b] pyridyl, that replace or unsubstituted pyrazolo [4,3-b] pyridyl, that replace or unsubstituted pyrrolo-[2,3-b] pyridyl, that replace or unsubstituted thieno-[2,3-b] pyridyl, that replace or unsubstituted thiazole also [5,4-b] pyridyl, that replace or unsubstituted pyridine base-2-ketone, that replace or unsubstituted imidazo [1,2-b] pyridazinyl, that replace or unsubstituted pyrazolo [1,5-a] pyrimidyl, that replace or unsubstituted pyridazinyl-3-ketone, that replace or unsubstituted imidazo [2,1-b] [1,3,4] thiadiazolyl group, that replace or unsubstituted imidazo [2,1-b] thiazolyl, that perhaps replace or unsubstituted imidazo [4,5-b] pyridyl,-(CH 2) jCN ,-(CH 2) jOR 23,-(CH 2) jC (O) R 23,-(CH 2) jC (O) OR 23,-(CH 2) jNR 24R 25,-(CH 2) jC (O) NR 24R 25,-(CH 2) jOC (O) NR 24R 25,-(CH 2) jNR 26C (O) R 23,-(CH 2) jNR 26C (O) OR 23,-(CH 2) jNR 26C (O) NR 24R 25,-(CH 2) jS (O) mR 27,-(CH 2) jS (O) 2NR 24R 25Or-(CH 2) jNR 26S (O) 2R 27
[0201] R 28' and R 28" be independently of one another hydrogen, halogen, cyano group, hydroxyl, replacement or unsubstituted alkyl, or perfluoroalkyl; With
[0202] R 35Be hydrogen independently, halogen, nitro, cyano group, hydroxyl, replace or unsubstituted alkyl, that replace or unsubstituted cycloalkyl, perfluoroalkyl, that replace or unsubstituted assorted alkyl, that replace or unsubstituted Heterocyclylalkyl, that replace or unsubstituted azetidinyl, that replace or unsubstituted phenyl, that replace or unsubstituted naphthyl, that replace or unsubstituted biphenyl group, that replace or unsubstituted pyrryl, that replace or unsubstituted imidazolyl, that replace or unsubstituted pyrazolyl, that replace or unsubstituted furyl, that replace or unsubstituted thienyl, that replace or do not replace the De oxazolyl, that replace or unsubstituted isoxazolyl, that replace or unsubstituted thiazolyl, that replace or unsubstituted pyridine base, that replace or unsubstituted pyrazinyl, that replace or unsubstituted pyrimidyl, that replace or unsubstituted benzothiazolyl, that replace or unsubstituted purine radicals, that replace or unsubstituted benzimidazolyl-, that replace or unsubstituted indyl, that replace or unsubstituted isoquinolyl, that replace or unsubstituted quinoxalinyl, that replace or unsubstituted quinolines base, that replace or unsubstituted benzoxazolyl, that replace or unsubstituted [1,5] phthalazinyl, that replace or unsubstituted pyridine also [3,2-d] pyrimidyl, that replace or unsubstituted [1,7] phthalazinyl, that replace or unsubstituted 1H-pyrrolo-[2,3-b] pyridyl, that replace or unsubstituted pyrazolo [4,3-b] pyridyl, that replace or unsubstituted pyrrolo-[2,3-b] pyridyl, that replace or unsubstituted thieno-[2,3-b] pyridyl, that replace or unsubstituted thiazole also [5,4-b] pyridyl, that replace or unsubstituted pyridine base-2-ketone, that replace or unsubstituted imidazo [1,2-b] pyridazinyl, that replace or unsubstituted pyrazolo [1,5-a] pyrimidyl, that replace or unsubstituted pyridazinyl-3-ketone, that replace or unsubstituted imidazo [2,1-b] [1,3,4] thiadiazolyl group, that replace or unsubstituted imidazo [2,1-b] thiazolyl, that perhaps replace or unsubstituted imidazo [4,5-b] pyridyl,-(CH 2) jCN ,-(CH 2) jOR 30,-(CH 2) jC (O) R 30,-(CH 2) jC (O) OR 30,-(CH 2) jNR 31R 32,-(CH 2) jC (O) NR 31R 32,-(CH 2) jOC (O) NR 31R 32,-(CH 2) jNR 33C (O) R 30,-(CH 2) jNR 33C (O) OR 30,-(CH 2) jNR 33C (O) NR 31R 32,-(CH 2) jS (O) mR 34,-(CH 2) jS (O) 2NR 31R 32Or-(CH 2) jNR 33S (O) 2R 34
[0203] on the other hand, the disclosure provides the compound with formula IX, wherein:
[0204] A independently is that replace or unsubstituted phenyl, that replace or unsubstituted naphthyl, that replace or unsubstituted biphenyl group, that replace or unsubstituted pyrryl, that replace or unsubstituted furyl, that replace or unsubstituted thienyl, that replace or do not replace the De oxazolyl, that replace or unsubstituted thiazolyl, that replace or unsubstituted imidazolyl, that replace or unsubstituted pyrazolyl, that replace or unsubstituted pyridine base, that replace or unsubstituted isoxazolyl, that replace or unsubstituted isothiazolyl, that replace or unsubstituted triazolyl, that replace or unsubstituted pyrazinyl, that replace or unsubstituted pyrimidyl, that replace or unsubstituted benzothiazolyl, that replace or unsubstituted purine radicals, that replace or unsubstituted benzimidazolyl-, that replace or unsubstituted indyl, that replace or unsubstituted isoquinolyl, that replace or unsubstituted quinoxalinyl, replace or the unsubstituted quinolines base;
[0205] Q is hydrogen, halogen, replacement or unsubstituted alkyl, perfluoroalkyl, amino, replacement or a unsubstituted amino alkyl, replacement or unsubstituted amino dialkyl group, replacement or unsubstituted phenyl, replacement or unsubstituted phenoxy, replacement or unsubstituted piperidyl, replacement or unsubstituted piperazinyl, replacement or unsubstituted pyrrolidyl, replacement or unsubstituted morpholinyl independently, perhaps that replace or unsubstituted-O-pyridyl;
[0206] R 1And R 2Be independently of one another hydrogen, halogen, nitro, cyano group, hydroxyl, replacement or unsubstituted alkyl, or perfluoroalkyl;
[0207] X is CR 2
[0208] R 22Be hydrogen, halogen, nitro, cyano group, hydroxyl, replacement or unsubstituted alkyl, replacement independently or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted Heterocyclylalkyl ,-(CH 2) jCN ,-(CH 2) jOR 23,-(CH 2) jC (O) R 23,-(CH 2) jC (O) OR 23,-(CH 2) jNR 24R 25,-(CH 2) jC (O) NR 24R 25,-(CH 2) jOC (O) NR 24R 25,-(CH 2) jNR 26C (O) R 23,-(CH 2) jNR 26C (O) OR 23,-(CH 2) jNR 26C (O) NR 24R 25,-(CH 2) jS (O) mR 27,-(CH 2) jS (O) 2NR 24R 25Or-(CH 2) jNR 26S (O) 2R 27
[0209] R 28' and R 28" be hydrogen, halogen, hydroxyl, alkyl or perfluoroalkyl independently of one another; With
[0210] R 35Be hydrogen, halogen, nitro, cyano group, hydroxyl, replacement or unsubstituted alkyl, replacement independently or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted Heterocyclylalkyl ,-(CH 2) jCN ,-(CH 2) jOR 30,-(CH 2) jC (O) R 30,-(CH 2) jC (O) OR 30,-(CH 2) jNR 31R 32,-(CH 2) jC (O) NR 31R 32,-(CH 2) jOC (O) NR 31R 32,-(CH 2) jNR 33C (O) R 30,-(CH 2) jNR 33C (O) OR 30,-(CH 2) jN 33C (O) NR 31R 32,-(CH 2) jS (O) mR 34,-(CH 2) jS (O) 2NR 31R 32,-(CH 2) jNR 33S (O) 2R 34,
[0211] on the other hand, the disclosure provides the compound with formula IX, wherein:
[0212] A is independently:
Figure A20078003852701321
[0213] Q be independently hydrogen, chloro, replacement or unsubstituted alkyl, perfluoroalkyl ,-NH 2,-NH (C 1-C 6) alkyl or-N[(C 1-C 6) alkyl] 2,
Wherein each alkyl is optional by 1-3 R 22Group replace independently and wherein w be the integer of 0-3 independently; Two R wherein 22Group and-O (CH 2CH 2) the optional ring texture that forms of O-;
[0214] R 1And R 2Be hydrogen independently of one another;
[0215] R 22Be independently-H ,-F, Cl, Br, I ,-(C 1-C 6) alkyl ,-(CH 2) jCN ,-(CH 2) jO (C 1-C 6) alkyl ,-(CH 2) jOH ,-(CH 2) jC (O) (C 1-C 6) alkyl ,-(CH 2) jNH 2,-(CH 2) jNH (C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) 2,-(CH 2) jC (O) NH 2,-(CH 2) jC (O) NH (C 1-C 6) alkyl ,-C (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jNHC (O) (C 1-C 6) alkyl ,-(CH 2) jNHSO 2(C 1-C 6) alkyl ,-(CH 2) jNHSO 2(C 1-C 6) alkyl ,-(CH 2) jSO 2CH 3,-(CH 2) jSO 2NH 2,-(CH 2) jSO 2NH (C 1-C 6)-alkyl ,-(CH 2) jSO 2N ((C 1-C 6) alkyl) 2,-(CH 2) jSO 2NH (C 1-C 6) alkyl (OH), phenyl,
Figure A20078003852701331
[0216] R 28' and R 28" be hydrogen, halogen, hydroxyl, (C independently of one another 1-C 6) alkyl or trifluoromethyl; With
[0217] R 35Be hydrogen, halogen, nitro, cyano group, hydroxyl, (C independently 1-C 6) alkyl, ring (C 3-C 10) alkyl, perfluor (C 1-C 6) alkyl ,-(CH 2) jCN ,-(CH 2) jO (C 1-C 6) alkyl ,-(CH 2) jC (O) (C 1-C 6) alkyl ,-(CH 2) jC (O) O (C 1-C 6) alkyl ,-(CH 2) jNH 2,-(CH 2) jNH (C 1-C 6) alkyl) ,-(CH 2) jN ((C 1-C 6) alkyl) 2,-(CH 2) jC (O) NH 2,-(CH 2) jC (O) NH (C 1-C 6) alkyl) ,-(CH 2) jC (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jOC (O) NH 2,-(CH 2) jOC (O) NH (C 1-C 6) alkyl) ,-(CH 2) jOC (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jNHC (O) (C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) C (O) (C 1-C 6) alkyl ,-(CH 2) jNHC (O) O (C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) C (O) O (C 1-C 6) alkyl ,-(CH 2) jNHC (O) NH 2,-(CH 2) jNHC (O) NH (C 1-C 6) alkyl) ,-(CH 2) jNHC (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jN ((C 1-C 6) alkyl) C (O) NH (C 1-C 6) alkyl) ,-(CH 2) jN ((C 1-C 6) alkyl) C (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jS (O) m(C 1-C 6) alkyl ,-(CH 2) jS (O) 2NH 2,-(CH 2) jS (O) 2NH (C 1-C 6) alkyl) ,-(CH 2) jS (O) 2N ((C 1-C 6) alkyl) 2,-(CH 2) jNHS (O) 2(C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) S (O) 2(C 1-C 6) alkyl,
Figure A20078003852701341
[0218] on the other hand, the disclosure provides the compound with formula IX, wherein:
[0219] A is independently:
Figure A20078003852701342
[0220] Q is (C independently 1-C 6) alkyl, perfluoroalkyl ,-NH 2,-NH (C 1-C 6) alkyl ,-N[(C 1-C 6) alkyl] 2
[0221] R 28And R 28" be hydrogen, halogen, (C independently of one another 1-C 6) alkyl or trifluoromethyl; With
[0222] R 35Be independently hydrogen, halogen, cyano group, hydroxyl ,-(C 1-C 6) alkyl;-(CH 2) jCN ,-(CH 2) jO (C 1-C 6) alkyl ,-(CH 2) jOH ,-(CH 2) jC (O) (C 1-C 6) alkyl ,-(CH 2) jC (O) OH ,-(CH 2) jNH 2,-(CH 2) jNH (C 1-C 6) alkyl ,-(CH 2) jN ((C -C 6) alkyl) 2,-(CH 2) jC (O) NH 2,-(CH 2) jC (O) NH (C 1-C 6) alkyl ,-C (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jNHC (O) (C 1-C 6) alkyl ,-(CH 2) jNHSO 2(C 1-C 6) alkyl ,-(CH 2) jNHSO 2(C 1-C 6) alkyl ,-(CH 2) jSO 2CH 3,-(CH 2) jSO 2NH 2,-(CH 2) jSO 2NH (C 1-C 6)-alkyl ,-(CH 2) jSO 2N ((C 1-C 6) alkyl) 2,-(CH 2) jSO 2NH (C 1-C 6) alkyl (OH), phenyl,
Figure A20078003852701351
[0223] on the other hand, the disclosure provides the compound with formula X:
Wherein:
[0224] T is CH (halogen), C (halogen) independently 2
[0225] A independently is that replace or unsubstituted phenyl, that replace or unsubstituted naphthyl, that replace or unsubstituted biphenyl group, that replace or unsubstituted pyrryl, that replace or unsubstituted furyl, that replace or unsubstituted thienyl, that replace or do not replace the De oxazolyl, that replace or unsubstituted thiazolyl, that replace or unsubstituted imidazolyl, that replace or unsubstituted pyrazolyl, that replace or unsubstituted pyridine base, that replace or unsubstituted isoxazolyl, that replace or unsubstituted isothiazolyl, that replace or unsubstituted triazolyl, that replace or unsubstituted pyrazinyl, that replace or unsubstituted pyrimidyl, that replace or unsubstituted benzothiazolyl, that replace or unsubstituted purine radicals, that replace or unsubstituted benzimidazolyl-, that replace or unsubstituted indyl, that replace or unsubstituted isoquinolyl, that replace or unsubstituted quinoxalinyl, that replace or unsubstituted quinolines base, that replace or unsubstituted benzoxazolyl, that replace or unsubstituted [1,5] phthalazinyl, that replace or unsubstituted pyridine also [3,2-d] pyrimidyl, that replace or unsubstituted [1,7] phthalazinyl, that replace or unsubstituted 1H-pyrrolo-[2,3-b] pyridyl, that replace or unsubstituted pyrazolo [4,3-b] pyridyl, that replace or unsubstituted pyrrolo-[2,3-b] pyridyl, that replace or unsubstituted thieno-[2,3-b] pyridyl, that replace or unsubstituted thiazole also [5,4-b] pyridyl, that replace or unsubstituted pyridine base-2-ketone, that replace or unsubstituted imidazo [1,2-b] pyridazinyl, that replace or unsubstituted pyrazolo [1,5-a] pyrimidyl, that replace or unsubstituted pyridazinyl-3-ketone, that replace or unsubstituted imidazo [2,1-b] [1,3,4] thiadiazolyl group, that replace or unsubstituted imidazo [2,1-b] thiazolyl, that perhaps replace or unsubstituted imidazo [4,5-b] pyridyl;
[0226] Q be hydrogen, halogen, replacement or unsubstituted alkyl, perfluoroalkyl, amino, replacement independently or a unsubstituted amino alkyl, replacement or unsubstituted amino dialkyl group, replacement or unsubstituted phenyl, replacement or unsubstituted phenoxy, replacement or unsubstituted piperidyl, replacement or unsubstituted piperazinyl, replacement or unsubstituted pyrrolidyl, replacement or unsubstituted morpholinyl, replacement or unsubstituted-O-pyridyl;
[0227] R 22Be hydrogen independently, halogen, nitro, cyano group, hydroxyl, that replace or unsubstituted alkyl, that replace or unsubstituted cycloalkyl, perfluoroalkyl, that replace or unsubstituted assorted alkyl, that replace or unsubstituted Heterocyclylalkyl, that replace or unsubstituted phenyl, that replace or unsubstituted naphthyl, that replace or unsubstituted biphenyl group, that replace or unsubstituted pyrryl, that replace or unsubstituted imidazolyl, that replace or unsubstituted pyrazolyl, that replace or unsubstituted furyl, that replace or unsubstituted thienyl, that replace or do not replace the De oxazolyl, that replace or unsubstituted isoxazolyl, that replace or unsubstituted thiazolyl, that replace or unsubstituted pyridine base, that replace or unsubstituted pyrazinyl, that replace or unsubstituted pyrimidyl, that replace or unsubstituted benzothiazolyl, that replace or unsubstituted purine radicals, that replace or unsubstituted benzimidazolyl-, that replace or unsubstituted indyl, that replace or unsubstituted isoquinolyl, that replace or unsubstituted quinoxalinyl, that replace or unsubstituted quinolines base, that replace or unsubstituted benzoxazolyl, that replace or unsubstituted [1,5] phthalazinyl, that replace or unsubstituted pyridine also [3,2-d] pyrimidyl, that replace or unsubstituted [1,7] phthalazinyl, that replace or unsubstituted 1H-pyrrolo-[2,3-b] pyridyl, that replace or unsubstituted pyrazolo [4,3-b] pyridyl, that replace or unsubstituted pyrrolo-[2,3-b] pyridyl, that replace or unsubstituted thieno-[2,3-b] pyridyl, that replace or unsubstituted thiazole also [5,4-b] pyridyl, that replace or unsubstituted pyridine base-2-ketone, that replace or unsubstituted imidazo [1,2-b] pyridazinyl, that replace or unsubstituted pyrazolo [1,5-a] pyrimidyl, that replace or unsubstituted pyridazinyl-3-ketone, that replace or unsubstituted imidazo [2,1-b] [1,3,4] thiadiazolyl group, that replace or unsubstituted imidazo [2,1-b] thiazolyl, that perhaps replace or unsubstituted imidazo [4,5-b] pyridyl,-(CH 2) jCN ,-(CH 2) jOR 23,-(CH 2) jC (O) R 23,-(CH 2) jC (O) OR 23,-(CH 2) jNR 24R 25, (CH 2) jC (O) NR 24R 25,-(CH 2) jOC (O) NR 24R 25,-(CH 2) jNR 26C (O) R 23,-(CH 2) jNR 26C (O) OR 23,-(CH 2) jNR 26C (O) NR 24R 25,-(CH 2) jS (O) mR 27,-(CH 2) jS (O) 2NR 24R 25Or-(CH 2) jNR 26S (O) 2R 27
[0228] R 28' and R 28" be independently of one another hydrogen, halogen, cyano group, hydroxyl, replacement or unsubstituted alkyl, or perfluoroalkyl; With
[0229] R 35Be hydrogen independently, halogen, nitro, cyano group, hydroxyl, that replace or unsubstituted alkyl, that replace or unsubstituted cycloalkyl, perfluoroalkyl, that replace or unsubstituted assorted alkyl, that replace or unsubstituted Heterocyclylalkyl, that replace or unsubstituted azetidinyl, that replace or unsubstituted phenyl, that replace or unsubstituted naphthyl, that replace or unsubstituted biphenyl group, that replace or unsubstituted pyrryl, that replace or unsubstituted imidazolyl, that replace or unsubstituted pyrazolyl, that replace or unsubstituted furyl, that replace or unsubstituted thienyl, that replace or do not replace the De oxazolyl, that replace or unsubstituted isoxazolyl, that replace or unsubstituted thiazolyl, that replace or unsubstituted pyridine base, that replace or unsubstituted pyrazinyl, that replace or unsubstituted pyrimidyl, that replace or unsubstituted benzothiazolyl, that replace or unsubstituted purine radicals, that replace or unsubstituted benzimidazolyl-, that replace or unsubstituted indyl, that replace or unsubstituted isoquinolyl, that replace or unsubstituted quinoxalinyl, that replace or unsubstituted quinolines base, that replace or unsubstituted benzoxazolyl, that replace or unsubstituted [1,5] phthalazinyl, that replace or unsubstituted pyridine also [3,2-d] pyrimidyl, that replace or unsubstituted [1,7] phthalazinyl, that replace or unsubstituted 1H-pyrrolo-[2,3-b] pyridyl, that replace or unsubstituted pyrazolo [4,3-b] pyridyl, that replace or unsubstituted pyrrolo-[2,3-b] pyridyl, that replace or unsubstituted thieno-[2,3-b] pyridyl, that replace or unsubstituted thiazole also [5,4-b] pyridyl, that replace or unsubstituted pyridine base-2-ketone, that replace or unsubstituted imidazo [1,2-b] pyridazinyl, that replace or unsubstituted pyrazolo [1,5-a] pyrimidyl, that replace or unsubstituted pyridazinyl-3-ketone, that replace or unsubstituted imidazo [2,1-b] [1,3,4] thiadiazolyl group (thia-ciazolyl), that replace or unsubstituted imidazo [2,1-b] thiazolyl, that perhaps replace or unsubstituted imidazo [4,5-b] pyridyl,-(CH 2) jCN ,-(CH 2) jOR 30,-(CH 2) jC (O) R 30,-(CH 2) jC (O) OR 30,-(CH 2) jNR 31R 32,-(CH 2) jC (O) NR 31R 32,-(CH 2) jOC (O) NR 31R 32,-(CH 2) jNR 33C (O) R 30,-(CH 2) jNR 33C (O) OR 30,-(CH 2) jNR 33C (O) NR 31R 32,-(CH 2) jS (O) mR 34,-(CH 2) jS (O) 2NR 31R 32Or-(CH 2) jNR 33S (O) 2R 34
[0230] on the other hand, the disclosure provides the compound with formula X, wherein:
[0231] A independently is that replace or unsubstituted phenyl, that replace or unsubstituted naphthyl, that replace or unsubstituted biphenyl group, that replace or unsubstituted pyrryl, that replace or unsubstituted furyl, that replace or unsubstituted thienyl, that replace or do not replace the De oxazolyl, that replace or unsubstituted thiazolyl, that replace or unsubstituted imidazolyl, that replace or unsubstituted pyrazolyl, that replace or unsubstituted pyridine base, that replace or unsubstituted isoxazolyl, that replace or unsubstituted isothiazolyl, that replace or unsubstituted triazolyl, that replace or unsubstituted pyrazinyl, that replace or unsubstituted pyrimidyl, that replace or unsubstituted benzothiazolyl, that replace or unsubstituted purine radicals, that replace or unsubstituted benzimidazolyl-, that replace or unsubstituted indyl, that replace or unsubstituted isoquinolyl, that replace or unsubstituted quinoxalinyl, replace or the unsubstituted quinolines base;
[0232] Q is hydrogen, halogen, replacement or unsubstituted alkyl, perfluoroalkyl, amino, replacement or a unsubstituted amino alkyl, replacement or unsubstituted amino dialkyl group, replacement or unsubstituted phenyl, replacement or unsubstituted phenoxy, replacement or unsubstituted piperidyl, replacement or unsubstituted piperazinyl, replacement or unsubstituted pyrrolidyl, replacement or unsubstituted morpholinyl independently, perhaps that replace or unsubstituted-O-pyridyl;
[0233] R 22Be hydrogen, halogen, nitro, cyano group, hydroxyl, replacement or unsubstituted alkyl, replacement independently or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted Heterocyclylalkyl ,-(CH 2) jCN ,-(CH 2) jOR 23,-(CH 2) jC (O) R 23,-(CH 2) jC (O) OR 23,-(CH 2) jNR 24R 25,-(CH 2) jC (O) NR 24R 25,-(CH 2) jOC (O) NR 24R 25,-(CH 2) jNR 26C (O) R 23,-(CH 2) jNR 26C (O) OR 23,-(CH 2) jNR 26C (O) NR 24R 25,-(CH 2) jS (O) mR 27,-(CH 2) jS (O) 2NR 24R 25Or-(CH 2) jNR 26S (O) 2R 27
[0234] R 28' and R 28" be hydrogen, halogen, hydroxyl, alkyl or perfluoroalkyl independently of one another; With
[0235] R 35Be hydrogen, halogen, nitro, cyano group, hydroxyl, replacement or unsubstituted alkyl, replacement independently or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted Heterocyclylalkyl ,-(CH 2) jCN ,-(CH 2) jOR 30,-(CH 2) jC (O) R 30,-(CH 2) jC (O) OR 30,-(CH 2) jNR 31R 32,-(CH 2) jC (O) NR 31R 32,-(CH 2) jOC (O) NR 31R 32,-(CH 2) jNR 33C (O) R 30,-(CH 2) jNR 33C (O) OR 30,-(CH 2) jN 33C (O) NR 31R 32,-(CH 2) jS (O) mR 34,-(CH 2) jS (O) 2NR 31R 32,-(CH 2) jNR 33S (O) 2R 34,
Figure A20078003852701391
[0236] on the other hand, the disclosure provides the compound with formula X, wherein:
[0237] A is independently:
Figure A20078003852701392
Figure A20078003852701401
[0238] Q be independently hydrogen, chloro, replacement or unsubstituted alkyl, perfluoroalkyl ,-NH 2,-NH (C 1-C 6) alkyl or-N[(C 1-C 6) alkyl] 2,
Wherein each alkyl is optional by 1-3 R 22Group replace independently and wherein w be the integer of 0-3 independently; Two R wherein 22Group and-O (CH 2CH 2) the optional ring texture that forms of O-;
[0239] R 22Be independently-H ,-F, Cl, Br, I ,-(C 1-C 6) alkyl ,-(CH 2) jCN ,-(CH 2) jO (C 1-C 6) alkyl ,-(CH 2) jOH ,-(CH 2) jC (O) (C 1-C 6) alkyl ,-(CH 2) jNH 2,-(CH 2) jNH (C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) 2,-(CH 2) jC (O) NH 2,-(CH 2) jC (O) NH (C 1-C 6) alkyl ,-C (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jNHC (O) (C 1-C 6) alkyl ,-(CH 2) jNHSO 2(C 1-C 6) alkyl ,-(CH 2) jNHSO 2(C 1-C 6) alkyl ,-(CH 2) jSO 2CH 3,-(CH 2) jSO 2NH 2,-(CH 2) jSO 2NH (C 1-C 6)-alkyl ,-(CH 2) jSO 2N ((C 1-C 6) alkyl) 2,-(CH 2) jSO 2NH (C 1-C 6) alkyl (OH), phenyl,
Figure A20078003852701411
[0240] R 28' and R 28" be hydrogen, halogen, hydroxyl, (C independently of one another 1-C 6) alkyl or trifluoromethyl; With
[0241] R 35Be hydrogen, halogen, nitro, cyano group, hydroxyl, (C independently 1-C 6) alkyl, ring (C 3-C 10) alkyl, perfluor (C 1-C 6) alkyl ,-(CH 2) jCN ,-(CH 2) jO (C 1-C 6) alkyl ,-(CH 2) jC (O) (C 1-C 6) alkyl ,-(CH 2) jC (O) O (C 1-C 6) alkyl ,-(CH 2) jNH 2,-(CH 2) jNH (C 1-C 6) alkyl) ,-(CH 2) jN ((C 1-C 6) alkyl) 2,-(CH 2) jC (O) NH 2,-(CH 2) jC (O) NH (C 1-C 6) alkyl) ,-(CH 2) jC (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jOC (O) NH 2,-(CH 2) jOC (O) NH (C 1-C 6) alkyl) ,-(CH 2) jOC (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jNHC (O) (C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) C (O) (C 1-C 6) alkyl ,-(CH 2) jNHC (O) O (C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) C (O) O (C 1-C 6) alkyl ,-(CH 2) jNHC (O) NH 2,-(CH 2) jNHC (O) NH (C 1-C 6) alkyl) ,-(CH 2) jNHC (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jN ((C 1-C 6) alkyl) C (O) NH (C 1-C 6) alkyl) ,-(CH 2) jN ((C 1-C 6) alkyl) C (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jS (O) m(C 1-C 6) alkyl ,-(CH 2) jS (O) 2NH 2,-(CH 2) jS (O) 2NH (C 1-C 6) alkyl) ,-(CH 2) jS (O) 2N ((C 1-C 6) alkyl) 2,-(CH 2) jNHS (O) 2(C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) S (O) 2(C 1-C 6) alkyl,
Figure A20078003852701412
[0242] on the other hand, the disclosure provides the compound with formula X, wherein:
[0243] A is independently:
Figure A20078003852701421
[0244] Q is (C independently 1-C 6) alkyl, perfluoroalkyl ,-NH 2,-NH (C 1-C 6) alkyl ,-N[(C 1-C 6) alkyl] 2
[0245] R 28' and R 28" be hydrogen, halogen, (C independently of one another 1-C 6) alkyl or trifluoromethyl; With
[0246] R 35Be independently hydrogen, halogen, cyano group, hydroxyl ,-(C 1-C 6) alkyl ,-(CH 2) jCN ,-(CH 2) jO (C 1-C 6) alkyl ,-(CH 2) jOH ,-(CH 2) jC (O) (C 1-C 6) alkyl ,-(CH 2) jC (O) OH ,-(CH 2) jNH 2,-(CH 2) jNH (C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) 2,-(CH 2) jC (O) NH 2,-(CH 2) jC (O) NH (C 1-C 6) alkyl ,-C (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jNHC (O) (C 1-C 6) alkyl ,-(CH 2) jNHSO 2(C 1-C 6) alkyl ,-(CH 2) jNHSO 2(C 1-C 6) alkyl ,-(CH 2) jSO 2CH 3,-(CH 2) jSO 2NH 2,-(CH 2) jSO 2NH (C 1-C 6)-alkyl ,-(CH 2) jSO 2N ((C 1-C 6) alkyl) 2,-(CH 2) jSO 2NH (C 1-C 6) alkyl (OH), phenyl,
Figure A20078003852701422
[0247] on the other hand, the disclosure provides the compound with formula XI:
Figure A20078003852701431
Wherein:
[0248] T is CH (halogen), C (halogen) independently 2
[0249] Q be hydrogen, halogen, replacement or unsubstituted alkyl, perfluoroalkyl, amino, replacement independently or a unsubstituted amino alkyl, replacement or unsubstituted amino dialkyl group, replacement or unsubstituted phenyl, replacement or unsubstituted phenoxy, replacement or unsubstituted piperidyl, replacement or unsubstituted piperazinyl, replacement or unsubstituted pyrrolidyl, replacement or unsubstituted morpholinyl, replacement or unsubstituted-O-pyridyl;
[0250] R 22Be hydrogen independently, halogen, nitro, cyano group, hydroxyl, that replace or unsubstituted alkyl, that replace or unsubstituted cycloalkyl, perfluoroalkyl, that replace or unsubstituted assorted alkyl, that replace or unsubstituted Heterocyclylalkyl, that replace or unsubstituted phenyl, that replace or unsubstituted naphthyl, that replace or unsubstituted biphenyl group, that replace or unsubstituted pyrryl, that replace or unsubstituted imidazolyl, that replace or unsubstituted pyrazolyl, that replace or unsubstituted furyl, that replace or unsubstituted thienyl, that replace or do not replace the De oxazolyl, that replace or unsubstituted isoxazolyl, that replace or unsubstituted thiazolyl, that replace or unsubstituted pyridine base, that replace or unsubstituted pyrazinyl, that replace or unsubstituted pyrimidyl, that replace or unsubstituted benzothiazolyl, that replace or unsubstituted purine radicals, that replace or unsubstituted benzimidazolyl-, that replace or unsubstituted indyl, that replace or unsubstituted isoquinolyl, that replace or unsubstituted quinoxalinyl, that replace or unsubstituted quinolines base, that replace or unsubstituted benzoxazolyl, that replace or unsubstituted [1,5] phthalazinyl, that replace or unsubstituted pyridine also [3,2-d] pyrimidyl, that replace or unsubstituted [1,7] phthalazinyl, that replace or unsubstituted 1H-pyrrolo-[2,3-b] pyridyl, that replace or unsubstituted pyrazolo [4,3-b] pyridyl, that replace or unsubstituted pyrrolo-[2,3-b] pyridyl, that replace or unsubstituted thieno-[2,3-b] pyridyl, that replace or unsubstituted thiazole also [5,4-b] pyridyl, that replace or unsubstituted pyridine base-2-ketone, that replace or unsubstituted imidazo [1,2-b] pyridazinyl, that replace or unsubstituted pyrazolo [1,5-a] pyrimidyl, that replace or unsubstituted pyridazinyl-3-ketone, that replace or unsubstituted imidazo [2,1-b] [1,3,4] thiadiazolyl group, that replace or unsubstituted imidazo [2,1-b] thiazolyl, that perhaps replace or unsubstituted imidazo [4,5-b] pyridyl,-(CH 2) jCN ,-(CH 2) jOR 23,-(CH 2) jC (O) R 23,-(CH 2) jC (O) OR 23,-(CH 2) jNR 24R 25,-(CH 2) jC (O) NR 24R 25,-(CH 2) jOC (O) NR 24R 25,-(CH 2) jNR 26C (O) R 23,-(CH 2) jNR 26C (O) OR 23,-(CH 2) jNR 26C (O) NR 24R 25,-(CH 2) jS (O) mR 27,-(CH 2) jS (O) 2NR 24R 25Or-(CH 2) jNR 26S (O) 2R 27
[0251] R 28' and R 28" be hydrogen, halogen, hydroxyl, alkyl or perfluoroalkyl independently of one another; With
[0252] R 35Be hydrogen independently, halogen, nitro, cyano group, hydroxyl, that replace or unsubstituted alkyl, that replace or unsubstituted cycloalkyl, perfluoroalkyl, that replace or unsubstituted assorted alkyl, that replace or unsubstituted Heterocyclylalkyl, that replace or unsubstituted azetidinyl, that replace or unsubstituted phenyl, that replace or unsubstituted naphthyl, that replace or unsubstituted biphenyl group, that replace or unsubstituted pyrryl, that replace or unsubstituted imidazolyl, that replace or unsubstituted pyrazolyl, that replace or unsubstituted furyl, that replace or unsubstituted thienyl, that replace or do not replace the De oxazolyl, that replace or unsubstituted isoxazolyl, that replace or unsubstituted thiazolyl, that replace or unsubstituted pyridine base, that replace or unsubstituted pyrazinyl, that replace or unsubstituted pyrimidyl, that replace or unsubstituted benzothiazolyl, that replace or unsubstituted purine radicals, that replace or unsubstituted benzimidazolyl-, that replace or unsubstituted indyl, that replace or unsubstituted isoquinolyl, that replace or unsubstituted quinoxalinyl, that replace or unsubstituted quinolines base, that replace or unsubstituted benzoxazolyl, that replace or unsubstituted [1,5] phthalazinyl, that replace or unsubstituted pyridine also [3,2-d] pyrimidyl, that replace or unsubstituted [1,7] phthalazinyl, that replace or unsubstituted 1H-pyrrolo-[2,3-b] pyridyl, that replace or unsubstituted pyrazolo [4,3-b] pyridyl, that replace or unsubstituted pyrrolo-[2,3-b] pyridyl, that replace or unsubstituted thieno-[2,3-b] pyridyl, that replace or unsubstituted thiazole also [5,4-b] pyridyl, that replace or unsubstituted pyridine base-2-ketone, that replace or unsubstituted imidazo [1,2-b] pyridazinyl, that replace or unsubstituted pyrazolo [1,5-a] pyrimidyl, that replace or unsubstituted pyridazinyl-3-ketone, that replace or unsubstituted imidazo [2,1-b] [1,3,4] thiadiazolyl group, that replace or unsubstituted imidazo [2,1-b] thiazolyl, replace or unsubstituted imidazo [4,5-b] pyridyl,-(CH 2) jCN ,-(CH 2) jOR 30,-(CH 2) jC (O) R 30,-(CH 2) jC (O) OR 30,-(CH 2) jNR 3IR 32,-(CH 2) jC (O) NR 31R 32,-(CH 2) jOC (O) NR 31R 32,-(CH 2) jNR 33C (O) R 30,-(CH 2) jNR 33C (O) OR 30,-(CH 2) jNR 33C (O) NR 31R 32,-(CH 2) jS (O) mR 34,-(CH 2) jS (O) 2NR 31R 32Or-(CH 2) jNR 33S (O) 2R 34
[0253] on the other hand, the disclosure provides the compound with formula XI, wherein:
[0254] Q is hydrogen, halogen, replacement or unsubstituted alkyl, perfluoroalkyl, amino, replacement or a unsubstituted amino alkyl, replacement or unsubstituted amino dialkyl group, replacement or unsubstituted phenyl, replacement or unsubstituted phenoxy, replacement or unsubstituted piperidyl, replacement or unsubstituted piperazinyl, replacement or unsubstituted pyrrolidyl, replacement or unsubstituted morpholinyl independently, perhaps that replace or unsubstituted-O-pyridyl;
[0255] R 22Be hydrogen, halogen, nitro, cyano group, hydroxyl, replacement or unsubstituted alkyl, replacement independently or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted Heterocyclylalkyl ,-(CH 2) jCN ,-(CH 2) jOR 23,-(CH 2) jC (O) R 23,-(CH 2) jC (O) OR 23,-(CH 2) jNR 24R 25,-(CH 2) jC (O) NR 24R 25,-(CH 2) jOC (O) NR 24R 25,-(CH 2) jNR 26C (O) R 23,-(CH 2) jNR 26C (O) OR 23,-(CH 2) jNR 26C (O) NR 24R 25,-(CH 2) jS (O) mR 27,-(CH 2) jS (O) 2NR 24R 25Or-(CH 2) jNR 26S (O) 2R 27
[0256] R 28' and R 28" be hydrogen, halogen, hydroxyl, alkyl or perfluoroalkyl independently of one another; With
[0257] R 35Be hydrogen, halogen, nitro, cyano group, hydroxyl, replacement or unsubstituted alkyl, replacement independently or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted Heterocyclylalkyl ,-(CH 2) jCN ,-(CH 2) jOR 30,-(CH 2) jC (O) R 30,-(CH 2) jC (O) OR 30,-(CH 2) jNR 31R 32,-(CH 2) jC (O) NR 31R 32,-(CH 2) jOC (O) NR 31R 32,-(CH 2) jNR 33C (O) R 30,-(CH 2) jNR 33C (O) OR 30,-(CH 2) jN 33C (O) NR 31R 32,-(CH 2) jS (O) mR 34,-(CH 2) jS (O) 2NR 31R 32,-(CH 2) jNR 33S (O) 2R 34,
Figure A20078003852701461
[0258] on the other hand, the disclosure provides the compound with formula XI, wherein:
[0259] Q be independently hydrogen, chloro, replacement or unsubstituted alkyl, perfluoroalkyl ,-NH 2,-NH (C 1-C 6) alkyl or-N[(C 1-C 6) alkyl] 2,
Wherein each alkyl is optional by 1-3 R 22Group replace independently and wherein w be the integer of 0-3 independently; Two R wherein 22Group and-O (CH 2CH 2) the optional ring texture that forms of O-;
[0260] R 22Be independently-H ,-F, Cl, Br, I ,-(C 1-C 6) alkyl ,-(CH 2) jCN ,-(CH 2) jO (C 1-C 6) alkyl ,-(CH 2) jOH ,-(CH 2) jC (O) (C 1-C 6) alkyl ,-(CH 2) jNH 2,-(CH 2) jNH (C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) 2,-(CH 2) jC (O) NH 2,-(CH 2) jC (O) NH (C 1-C 6) alkyl ,-C (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jNHC (O) (C 1-C 6) alkyl ,-(CH 2) jNHSO 2(C 1-C 6) alkyl ,-(CH 2) jNHSO 2(C 1-C 6) alkyl ,-(CH 2) jSO 2CH 3,-(CH 2) jSO 2NH 2,-(CH 2) jSO 2NH (C 1-C 6) alkyl ,-(CH 2) jSO 2N ((C 1-C 6) alkyl) 2,-(CH 2) jSO 2NH (C 1-C 6) alkyl (OH), phenyl,
Figure A20078003852701471
[0261] R 28' and R 28" be hydrogen, halogen, hydroxyl, (C independently of one another 1-C 6) alkyl or trifluoromethyl; With
[0262] R 35Be hydrogen, halogen, nitro, cyano group, hydroxyl, (C independently 1-C 6) alkyl, ring (C 3-C 10) alkyl, perfluor (C 1-C 6) alkyl.-(CH 2) jCN ,-(CH 2) jO (C 1-C 6) alkyl ,-(CH 2) jC (O) (C 1-C 6) alkyl ,-(CH 2) jC (O) O (C 1-C 6) alkyl ,-(CH 2) jNH 2,-(CH 2) jNH (C 1-C 6) alkyl) ,-(CH 2) jN ((C 1-C 6) alkyl) 2,-(CH 2) jC (O) NH 2,-(CH 2) jC (O) NH (C 1-C 6) alkyl) ,-(CH 2) jC (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jOC (O) NH 2,-(CH 2) jOC (O) NH (C 1-C 6) alkyl) ,-(CH 2) jOC (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jNHC (O) (C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) C (O) (C 1-C 6) alkyl ,-(CH 2) jNHC (O) O (C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) C (O) O (C 1-C 6) alkyl ,-(CH 2) jNHC (O) NH 2, (CH 2) jNHC (O) NH (C 1-C 6) alkyl) ,-(CH 2) jNHC (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jN ((C 1-C 6) alkyl) C (O) NH (C 1-C 6) alkyl) ,-(CH 2) jN ((C 1-C 6) alkyl) C (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jS (O) m(C 1-C 6) alkyl ,-(CH 2) jS (O) 2NH 2,-(CH 2) jS (O) 2NH (C 1-C 6) alkyl) ,-(CH 2) jS (O) 2N ((C 1-C 6) alkyl) 2,-(CH 2) jNHS (O) 2(C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) S (O) 2(C 1-C 6) alkyl,
Figure A20078003852701472
[0263] on the other hand, the disclosure provides the compound with formula XI, wherein:
[0264] Q is (C independently 1-C 6) alkyl, perfluoroalkyl ,-NH 2,-NH (C 1-C 6) alkyl ,-N[(C 1-C 6) alkyl] 2
[0265] R 28' and R 28" be hydrogen, halogen, (C independently of one another 1-C 6) alkyl or trifluoromethyl; With
[0266] R 35Be independently hydrogen, halogen, cyano group, hydroxyl ,-(C 1-C 6) alkyl;-(CH 2) jCN ,-(CH 2) jO (C 1-C 6) alkyl ,-(CH 2) jOH ,-(CH 2) jC (O) (C 1-C 6) alkyl ,-(CH 2) jC (O) OH ,-(CH 2) jNH 2,-(CH 2) jNH (C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) 2,-(CH 2) jC (O) NH 2,-(CH 2) jC (O) NH (C 1-C 6) alkyl ,-C (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jNHC (O) (C 1-C 6) alkyl ,-(CH 2) jNHSO 2(C 1-C 6) alkyl ,-(CH 2) jNHSO 2(C 1-C 6) alkyl ,-(CH 2) jSO 2CH 3,-(CH 2) jSO 2NH 2,-(CH 2) jSO 2NH (C 1-C 6)-alkyl ,-(CH 2) jSO 2N ((C 1-C 6) alkyl) 2,-(CH 2) jSO 2NH (C 1-C 6) alkyl (OH), phenyl,
Figure A20078003852701481
[0267] on the other hand, the disclosure provides the compound with formula XII:
Figure A20078003852701482
Wherein:
[0268] Q is (C independently 1-C 6) alkyl;
[0269] T is CHF or CF 2With
[0270] R 35For-(C 1-C 6) alkyl.
[0271] on the other hand, the disclosure provides and is selected from following compound:
Figure A20078003852701491
Figure A20078003852701521
[0272] on the other hand, the disclosure provides the compound with following formula:
Figure A20078003852701541
[0273] on the other hand, the disclosure provides the compound with following formula:
Figure A20078003852701571
Figure A20078003852701581
Figure A20078003852701591
[0274] on the other hand, the disclosure provides the compound with following formula:
Figure A20078003852701611
Figure A20078003852701621
Figure A20078003852701631
[0275] on the other hand, the disclosure provides the method for regulating protein kinase activity, and it comprises makes described protein kinase contact with any compound of the present disclosure.
[0276] on the other hand, the disclosure provides the method for regulating protein kinase activity, it comprises makes described protein kinase contact with any compound of the present disclosure, and wherein said protein kinase is Ron receptor tyrosine kinase, Met receptor tyrosine kinase, ALK receptor tyrosine kinase, MER receptor tyrosine kinase, Tyro3/Sky receptor tyrosine kinase, axl receptor Tyrosylprotein kinase, TRKC receptor tyrosine kinase, ROS receptor tyrosine kinase, CSF1R/FMS receptor tyrosine kinase, BRAF kinases or Raf1 kinases.
[0277] on the other hand, the disclosure provides the method for regulating protein kinase activity, and it comprises makes described protein kinase contact with any compound of the present disclosure, and wherein said protein kinase is the Met receptor tyrosine kinase.
[0278] on the other hand, the disclosure is provided among the patient who needs this kind treatment and treats method for cancer, and it comprises the compound any of the present disclosure that gives described patient treatment significant quantity.
[0279] on the other hand, the disclosure provides medicinal compositions, and it contains any compound of the present disclosure and pharmaceutically acceptable vehicle.
[0280] on the other hand, the disclosure provides the method for any compound of the present disclosure of preparation, and it passes through:
Figure A20078003852701641
A) compd A-48 cyclodehydration under acidity or dehydration conditions is carried out.
[0281] on the other hand, the disclosure provides the method for any compound of the present disclosure of preparation, and it passes through a) to make compd A-48 cyclodehydration under acidity or dehydration conditions to carry out, and wherein said acidic conditions is acetate, POCl 3Or trifluoromethanesulfonic acid.
[0282] on the other hand, the disclosure provides the method for any compound of the present disclosure of preparation, and it passes through:
Figure A20078003852701642
A) formula A-50 compound and the coupling in solvent of formula B-50 compound are prepared, wherein LG is halogen or trifluoromethanesulfonic acid ester group.
[0283] on the other hand, the disclosure provides the method for any compound of the present disclosure of preparation, and it passes through a) to make formula A-50 compound and the coupling in solvent of formula B-50 compound to prepare, and wherein LG is that halogen or trifluoromethanesulfonic acid ester group and wherein said solvent are for pure.
[0284] on the other hand, the disclosure provides the method for any compound of the present disclosure of preparation, and it passes through:
Figure A20078003852701651
A) make formula A-52 compound and formula B-52 compound condensation, wherein R ' is C 1-C 6Alkyl.
Exemplary synthetic
[0285] compound of the present disclosure prepares by the suitable combined method of the synthetic method generally known.The technology that is used for synthetic compound of the present disclosure is conspicuous for those skilled in the relevant art and is understandable.Provide following discussion to be used to prepare the utilizable the whole bag of tricks of compound of the present disclosure so that some to be described.Yet, the scope or the reaction sequence of not planning to be used to prepare the reaction of compound of the present disclosure with described discussion restriction.Compound of the present disclosure can be by disclosed step and technology in the part of embodiment hereinafter, and by known organic synthesis technology preparation.
Blocking group
[0286] adopts the general known one or more blocking groups of the field of chemical synthesis, can synthesize compound of the present disclosure.Term " blocking group " refers to such chemical part, and some of its shielding compound or all reactive parts also prevent such subparticipation chemical reaction, are removed until blocking group, for example, at Greene, etc., the blocking group of organic synthesis, the 3rd plate .JohnWiley ﹠amp; Those parts of listing and describe among the Sons (1999).When using different blocking groups, it may be favourable that each (different) blocking group is removed by different modes.The blocking group that diverse on the whole reaction conditions separates down makes that the mode of removing of such blocking group is variant.For example, blocking group can be removed by acid, alkali and hydrogenolysis.Group such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are sour unsettled and can be used to protect carboxyl and hydroxyl reactive part in the presence of the amino with the Cbz radical protection; the Cbz group can be removed by hydrogenolysis, and the Fmoc group is to alkali labile.Carboxylic acid and hydroxyl reactive part can be in that (it be all stablized bronsted lowry acids and bases bronsted lowry with sour unsettled group such as carboxylamine tertiary butyl ester or with carbamate groups; but can remove through hydrolysis) amine of protection exists down; with alkali labile group (as, but be not limited to methyl, ethyl and ethanoyl) shielding.
[0287] carboxylic acid and the hydroxyl reactive part removable blocking group of also available hydrolysis such as benzyl protection, and can protect with unsettled group of amine groups available bases such as the Fmoc that acid forms hydrogen bond.The available oxidation of carboxylic acid reaction part-removable blocking group is as 2, and the 4-dimethoxy-benzyl is protected, and coexistence is amino available to the unsettled silyl carbamate protection of fluorochemical.
[0288] allyl group protection (blocking) group acid-and alkali-blocking group in the presence of be useful because the former is stable and can removes by metal or pi-acid catalyst subsequently.For example, the carboxylic acid of allyl group-protection can be sloughed protection with the catalytic reaction of palladium (0) in the presence of the unsettled carboxylamine tertiary butyl ester of acid or alkali-unsettled acetic ester amine protecting group group.The blocking group of another kind of form is that compound or intermediate can add resin thereon.As long as group is connected in resin, then functional group is protected and do not react.In case functional group disengages from resin, then this functional group can participate in reaction.
[0289] typically shielding or blocking group comprise, for example:
Figure A20078003852701661
Suppress kinase whose method
[0290] on the other hand, the disclosure relates to the method that adopts Triazolopyridazines kinase modulator of the present disclosure to regulate protein kinase activity.Term used herein " regulate kinase activity " means when protein kinase contacts with Triazolopyridazines kinase modulator of the present disclosure, and its activity is with respect to active increase or reduction when the no Triazolopyridazines kinase modulator.Therefore, the disclosure relates to by making protein kinase contact the method for regulating protein kinase activity with Triazolopyridazines kinase modulator of the present disclosure.
[0291] in an exemplary, the Triazolopyridazines kinase modulator suppresses kinase activity.The term that relates to kinase activity used herein " inhibition " means when protein kinase contacts with Triazolopyridazines kinase modulator of the present disclosure, and its activity reduces with respect to the activity when the no Triazolopyridazines kinase modulator.Therefore, the disclosure also relates to by protein kinase is contacted and the method for arrestin kinase activity with Triazolopyridazines kinase modulator of the present disclosure.
[0292] in certain embodiments, described protein kinase is a protein tyrosine kinase.Protein tyrosine kinase refers to the enzyme of the phosphorylation of tyrosine residues in the catalytic protein and phosphate donor (as nucleotide phosphodiesterase salt donor such as ATP) as used herein.Protein tyrosine kinase comprises, for example, Abelson Tyrosylprotein kinase (" Abl ") (as c-Abl and v-Abl), Ron receptor tyrosine kinase (" RON "), Met receptor tyrosine kinase (" MET "), Fms-sample Tyrosylprotein kinase (" FLT ") (as FLT3), src-family Tyrosylprotein kinase (as lynCSK), and p21-activated kinases-4 (" PAK "), FLT3, aurora (aurora)-A kinases, B-lymph sample Tyrosylprotein kinase (" BIk "), cyclin-dependant kinase (" CDK ") (as CDK1 and CDK5), src-family associated protein Tyrosylprotein kinase (as the Fyn kinases), glycogen synthase kinase (" GSK ") (as GSK3 α and GSK3 β), lymphocyte protein Tyrosylprotein kinase (" Lck "), the ribosome S 6 kinases is (as Rsk1, Rsk2 and Rsk3), sperm Tyrosylprotein kinase (as Yes), and demonstrate the hypotype and the homologue of tyrosine kinase activity.
[0293] in certain embodiments, described protein kinase is the Met receptor tyrosine kinase.
[0294] in another embodiment, described kinases is the mutant kinases, as mutant MET.Useful mutant MET kinases comprises, for example, MET kinases with sudden change, comprise in cell intracellular domain or the membrane spaning domain, or insertion in the endochylema structural domain and disappearance, comprise the sudden change that one or more is following: Ser1058Pro, Val1110Ile, His1112Tyr, His1124Asp, Met1149Thr, Val1206Leu or Met1268Thr.
[0295] the MET kinases comprises, for example, MET kinases with sudden change, comprise in the cell or membrane spaning domain in, or insertion in the endochylema structural domain and disappearance, comprise the sudden change that one or more is following: Ser1058Pro, Val1110Ile, His1112Tyr, His1124Asp, Met1149Thr, Val1206Leu or Met1268Thr.
[0296] in certain embodiments, described kinases is and known kinase homologous (this paper is also referred to as " homology kinases ").The compound and the composition that are used to suppress the kinase whose biologic activity of homology can be through for example binding assay preliminary screening.The homology enzyme comprises the aminoacid sequence of equal length, promptly at least 50%, at least 60%, at least 70%, at least 80% or at least 90% is identical with the kinase whose aminoacid sequence of known total length, or have 70%, 80% or 90% homology with the known kinase active structure domain.Homology for example can be used, the PSI blast search, and such as but not limited at Altschul, etc., those mensuration of describing among the Nuc.Acids Rec.25:3389-3402 (1997).In certain embodiments, in this was analyzed, at least 50% or at least 70% described sequence can be mated (aligned).Other instrument that is used to carry out sequences match comprises, for example, DbClustal and ESPript, it can be used for producing the PostScript pattern (version) of sequences match.See Thompson etc., Nucleic Acids Research, 28:2919-26,2000; Gouet, etc., Bioinformatics, 15:305-08 (1999).Homologue can for example have and FLT3, Abl, or another known kinase, or FLT3, Abl, or any functional domain at least 100 amino acid whose 1x10 relatively of another known kinase -6BLAST E-value (Altschul etc., Nucleic Acids Res., 25:3389-402 (1997).
[0297] by the avtive spot binding pocket (pockets) of described enzyme and the avtive spot binding pocket of known kinase are compared, also can measure homology.For example, in the homology enzyme, at least 50%, 60%, 70%, 80% or 90% amino acid of molecule or homologue has in size and has about at the most 1.5
Figure A20078003852701681
About 1.25
Figure A20078003852701682
About 1 About 0.75
Figure A20078003852701684
About 0.5
Figure A20078003852701685
And/or about 0.25
Figure A20078003852701686
The amino acid structure matching of the comparable structural domain of kinase domain of root-mean-square deviation of alpha-carbon atom.
[0298] compound of the present disclosure and composition are used to suppress kinase activity, and also are used to suppress other enzyme in conjunction with ATP.Therefore they are used for the treatment of by suppressing disease and the disorder that such ATP-desmoenzyme activity can be alleviated.The method of measuring such ATP desmoenzyme comprises those methods well known by persons skilled in the art, those methods that this paper is discussed in relating to screening homology enzyme, and by using database PROSITE, the mark, sequence pattern, the motif that wherein contain protein family or structural domain, or the enzyme that distributes can be identified.
[0299] compound of the present disclosure, and their also useful as kinase-wedding agent of derivative.As wedding agent, such compound and derivative can be combined into stabilized resins and be used for the constraint substrate (tethered substrate) that the avidity chromatography is used.Compound of the present disclosure, and their derivative also can be modified (as, labelled with radioisotope or affinity labelling etc.) so that in the research of characterized, structure and/or the function of enzyme or polypeptide, use them.
[0300] in an exemplary, Triazolopyridazines kinase modulator of the present disclosure is a kinase inhibitor.In certain embodiments, kinase inhibitor has and is lower than 1 micromolar inhibition constant (K i) IC 50In another embodiment, kinase inhibitor has and is lower than 500 micromolar IC 50Or inhibition constant (K i).In another embodiment, kinase inhibitor has and is lower than 10 micromolar IC 50Or K iIn another embodiment, kinase inhibitor has and is lower than 1 micromolar IC 50Or K iIn another embodiment, kinase inhibitor has the IC that is lower than 500 nmoles 50Or K iIn another embodiment, kinase inhibitor has and is lower than 10 nmole IC 50Or K iIn another embodiment, kinase inhibitor has and is lower than 1 nmole IC 50Or K i
Methods of treatment
[0301] on the other hand, the disclosure relates to the method for the treatment of by the disease (disease of kinases-mediation or disorder) of kinase activity mediation in organism (as Mammals, as the people)." kinases-mediation " or " kinases-relevant " disease means disease wherein or symptom by suppressing the disease that kinase activity (as signal conduction, the mediation of kinases involved in diseases process wherein, regulate or regulation and control) can be alleviated." disease " means the symptom of disease or disease.
[0302] example of the disease that kinases is relevant comprises cancer (as leukemia, tumour and metastases), transformation reactions, asthma, inflammation (as airway inflammatory disease), obstructive airway diseases, autoimmune disorder, metabolic disease, infection (as bacterium, virus, yeast, fungi infestation), CNS disease, cerebral tumor, deformability nervous system disease, with vasculogenesis, neovascularization and blood vessel relevant cardiovascular disorder and disease takes place.In an exemplary, described compound is used for the treatment of cancer, comprises that leukemia and other relate to disease or disorder, myeloproliferative diseases, blood disease, asthma, inflammatory diseases or the diabetes of abnormal cell proliferation.
[0303] example more specifically with the cancer of compounds for treating of the present disclosure comprises mammary cancer, lung cancer, melanoma, colorectal carcinoma, bladder cancer, ovarian cancer, prostate cancer, kidney, squamous cell carcinoma, glioblastoma, carcinoma of the pancreas, leiomyosarcoma, multiple myeloma, Papillary Renal Cell Carcinoma, cancer of the stomach, liver cancer, head and neck cancer, melanoma and leukemia are (as myelomatosis, chronic lymphocytic leukemia, acute lymphocytoblast leukemia, chronic lymphocytoblast leukemia, Hokdkin disease and other leukemia and hematology cancer).
[0304] disease or other the disorderly specific examples by the compound of the present disclosure that is used for the treatment of or prevents or combination treatment comprises; but (for example be not limited to transplant rejection; kidney; liver; the heart; lung; islet cells; pancreas; marrow; cornea; small intestine; skin allotransplantation or xenotransplantation and other transplanting); transplant versus-host disease; paddy sacroiliitis; rheumatoid arthritis; multiple sclerosis; diabetes; diabetic retinopathy; inflammatory bowel disease (for example; Crohn disease; ulcerative colitis and other intestinal tract disease); ephrosis; emaciation; septic shock; lupus; myasthenia gravis; psoriatic; dermatitis; wet disease; stearrhea; Alzheimer; Parkinson's disease; the stem cell protection of chemotherapeutic period; be used for from the stripped selection of body or allogene bone marrow transplantation or the cleaning (purging) of exsomatizing; ophthalmic diseases; retinopathy (for example; macular degeneration; diabetic retinopathy and other retinopathy); keratopathy; glaucoma; infect (bacterium for example; virus or fungi infestation); heart disease includes but not limited to restenosis.
Conjoint therapy
[0305] on the other hand, the disclosure is provided at and is used for the treatment of among the curee or the conjoint therapy of cell proliferation disorders that inhibition is relevant with c-Met or disorderly morbidity.Described conjoint therapy comprises the formula I compound that gives curee treatment or prevention significant quantity, and one or more other anti--cell proliferation therapy, comprises chemotherapy, radiotherapy, gene therapy and immunotherapy.
[0306] on the other hand, compound of the present disclosure can be united with chemotherapy and given.As used herein, the therapy of chemotherapy reference and chemotherapeutics.Various chemotherapeutics can be used for combinational therapeutic methods disclosed herein.The chemotherapeutics of conceiving as example includes, but are not limited to: platinic compound (as, cis-platinum, NSC-241240, Oxalipratin); Taxane compounds (as, taxol, docetaxel); Comptothecin compounds (irinotecan, Hycamtin); Vinca alkaloids (as, vincristine(VCR), vincaleucoblastine, vinorelbine); The Anti-tumor nucleoside derivates (as, 5 FU 5 fluorouracil, folinic acid, gemcitabine, capecitabine); Alkylating agent (as, endoxan, carmustine, lomustine, plug are for group); Epipodophyllotoxin/podophyllotoxin (as Etoposide, teniposide); Aromatase inhibitor (as, Anastrozole, letrozole, Exemestane); The anti-estrogen compound (as, tamoxifen, fulvestrant), antifol (as, pemetrexed (premetrexed) disodium); The demethyl agent (as, azacitidine); Biotechnological formulation (biologics) (as, gemtuzumab, Cetuximab, Rituximab, training trastuzumab, trastuzumab, rhuMAb-VEGF, Tarceva); Microbiotic/anthracyclines (as idarubicin, dactinomycin, bleomycin, daunorubicin, Dx, ametycin, actinomycin, carminomycin, daunomycin); Antimetabolite (as, clofazimine, aminopterin, cytosine arabinoside, aminopterin); Tubulin-wedding agent (as combretastatin, colchicine, R 17934); Topoisomerase enzyme inhibitor (as, camptothecine); Differentiation agent (as, tretinoin, vitamins D and tretinoin); Tretinoin metabolic defence agent (RAMBA) (as, isotretinoin); Kinase inhibitor (as, flavopiridol (flavoperidol), imatinib mesylate, Gefitinib, Tarceva, Sutent, lapatinibditosylate, Xarelto, Tan Luomosi, Dasatinib); Farnesyl tranfering enzyme inhibitor (as, Zarnestra); Histone deacetylase inhibitors; Ubiquitin protein enzyme body approach restrainer (as, Velcade, bent shellfish are for fixed).
[0307] other useful medicine comprises verapamil, is found to be useful on antineoplastic agent combination and to set up accepted chemotherapeutics is had the chemosensitivity of drug-fast tumour cell and strengthens the calcium antagonist of the effect of such compound in the malignant tumour of medicine-sensitivity.See Simpson W G, the chemotherapy of calcium channel blocker verapamil and cancer.Cell Calcium.December 1985；6(6)：449-67。In addition, be supposed to be used for emerging chemotherapeutics with compound combination of the present disclosure in addition.
[0308] on the other hand, the disclosure provides and can unite administered compound with radiotherapy.As used herein, " radiotherapy " refers to comprise that the patient who makes needs is exposed to the therapy of radiation.Such therapy is well known by persons skilled in the art.Radiotherapeutic suitable scheme will be similar to those schemes that have been used for clinical treatment.Wherein radiotherapy is used alone or unites use with other chemotherapy.
[0309] on the other hand, the disclosure provides and can unite administered compound with gene therapy.As used herein, " gene therapy " refers to that target relates to the therapy of the special gene of tumor development.Possible gene therapy strategy comprises resetting of defective cancer-suppressor gene, cell transduction or use corresponding to be used for somatomedin and acceptor gene thereof the coding the antisense DNA transfection, based on the strategy of RNA such as ribozyme, RNA attractant insecticide, antisense messenger RNAs and siRNA (siRNA) molecule and so-called ' suicide gene '.
[0310] in others, the disclosure provides and can unite administered compound with immunotherapy.As used herein, " immunotherapy " refers to by such albumen there being specific antibody target relate to the special proteic therapy of tumor development.For example, the monoclonal antibody at vascular endothelial growth factor has been used for the treatment of cancer.
[0311] when except compound of the present disclosure, when also using second kind of medicine, these two kinds of medicines can be simultaneously (as separately or with single composition) with or the roughly the same time, perhaps the arbitrary order by the administration progress chart that separates gives sequentially.Under one situation of back, these two kinds of compounds will give over a period to come, and the amount that gives and administering mode answer sufficient to guarantee to reach favourable or synergy.Should be appreciated that preferred medication and order and will depend on compound of the present invention the dosage separately of each component of composite reagent and unite the concrete chemotherapeutics that gives, their route of administration, concrete tumour to be treated and the special host who receives treatment.
[0312] as what it should be understood by one skilled in the art that, the proper dosage of chemotherapeutics will generally be similar to or be lower than already used dosage in clinical treatment, and wherein chemotherapeutics is given separately or unite with other chemotherapeutics to give.
[0313] best approach of administration and order and dosage and dosage regimen can be adopted ordinary method and easily determined with reference to this paper proposes information by those skilled in the art.
[0314] only as an example, platinic compound is advantageously with every square metre of (mg/m of the per 1-500mg course of treatment 2) dosage of body surface area gives, 50-400mg/m for example 2, particularly for cis-platinum with about 75mg/m 2Dosage and for NSC-241240 with about 300mg/m 2Dosage give.Cis-platinum is oral not to be absorbed, therefore must be by intravenously, subcutaneous, tumour interior (intratumorally) or peritoneal injection transmission.
[0315] only as an example, taxane compounds is advantageously with every square metre of 50-400mg (mg/m 2) body surface area, for example 75-250mg/m 2Dosage give, particularly for taxol with per course of treatment of about 175-250mg/m 2Dosage and for docetaxel with about 75-150mg/m 2Dosage give.
[0316] only as an example, Comptothecin compounds is advantageously with every square metre of 0.1-400mg (mg/m 2) body surface area, for example 1-300mg/m 2Dosage give, particularly for irinotecan with per course of treatment of about 100-350mg/m 2Dosage and for Hycamtin with about 1-2mg/m 2Dosage give.
[0317] only as an example, vinca alkaloids can be advantageously with every square metre of 2-30mg (mg/m 2) dosage of body surface area gives, particularly for vincaleucoblastine with per course of treatment of about 3-12mg/m 2Dosage, for vincristine(VCR) with about 1-2mg/m 2Dosage, and for the about 10-30mg/m of vinorelbine 2Dosage give.
[0318] only as an example, the Anti-tumor nucleoside derivates can be advantageously with every square metre of 200-2500mg (mg/m 2) body surface area, for example 700-1500mg/m 2Dosage give.5 FU 5 fluorouracil (5-FU) is usually with 200-500mg/m 2The dosage range of (preferred 3-15mg/kg/ days) gives and uses through vein.Gemcitabine is advantageously with per course of treatment of about 800-1200mg/m 2Dosage give with capecitabine advantageously with about 1000-2500mg/m 2Dosage give.
[0319] only as an example, alkylating agent can be advantageously with every square metre of 100-500mg (mg/m 2) body surface area, for example 120-200mg/m 2Dosage give, particularly for endoxan with per course of treatment of about 100-500mg/m 2Dosage give, give for the dosage of Chlorambucil with about 0.1-0.2mg/kg body weight, for carmustine with about 150-200mg/m 2Dosage give and for lomustine with about 100-150mg/m 2Dosage give.
[0320] only as an example, podophyllotoxin derivative can be advantageously with every square metre of 30-300mg (mg/m2) body surface area, for example 50-250mg/m 2Dosage give, particularly for Etoposide with per course of treatment of about 35-100mg/m 2Dosage give and for teniposide with about 50-250mg/m 2Dosage give.
[0321] only as an example, the anthracycline derivative can be advantageously with every square metre of 10-75mg (mg/m 2) body surface area, for example 15-60mg/m 2Dosage give, particularly for Dx with per course of treatment of about 40-75mg/m 2Dosage give, for daunorubicin with about 25-45mg/m 2Dosage give and for idarubicin with about 10-15mg/m 2The dosage of per course of treatment gives.
[0322] only as an example, according to specific medicine and disease to be treated, the anti-estrogen compound can be advantageously with every day about 1-100mg dosage give.Tamoxifen advantageously gives with the oral dose of 5-50mg, and preferred 10-20mg continues this therapy time enough every day twice, to reach and to keep result of treatment.Tamoxifen advantageously gives with the oral dose of about 60mg, once a day, continues this therapy time enough, to reach and to keep result of treatment.Anastrozole advantageously gives with the oral dose of about 1mg, once a day.Droloxifene advantageously gives with the oral dose of about 20-100mg, once a day.Raloxifene advantageously gives with the oral dose of about 60mg, once a day.Exemestane advantageously gives with the oral dose of about 25mg, once a day.
[0323] only as an example, biotechnological formulation can be advantageously with every square metre of (mg/m of about 1-5mg 2) dosage of body surface area, or dosage known in the art gives, if different.For example, trastuzumab is advantageously with per course of treatment of 1-5mg/m 2Dosage give 2-4mg/m particularly 2Dosage give.
[0324] can give one, two or more dosage per course of treatment, can repeat in for example per 7,14,21 or 28 days.
[0325] but compound whole body of the present disclosure gives the patient, for example, give through intravenously, oral, subcutaneous, intramuscular, intracutaneous or parenteral.But compound of the present invention is the topical administration patient also.The limiting examples of localized delivery system comprises uses (intraluminal) medical apparatus in the chamber, and it comprises that intravascular drug transmits conduit, lead, medicinal support (stents) and inner cavity surface place mat agent (endoluminal paving).
[0326] compound of the present disclosure also can be united with targeted drug and given the curee, to reach the high partial concn of compound at targeting moiety.In addition, compound of the present invention can be configured to and keep medicine or medicament and contact the snap-out release in the period from a few hours to several weeks or the preparation that slowly discharges with target tissue.
Medicinal compositions and administration
[0327] on the other hand, the disclosure relates to medicinal compositions, and comprises the Triazolopyridazines kinase modulator with pharmaceutically acceptable mixed with excipients.Those skilled in the art will recognize that medicinal compositions comprises the pharmacy acceptable salt of aforesaid Triazolopyridazines kinase modulator.
[0328] on treatment and/or diagnostic use, compound of the present disclosure can be formulated as and be used for various administering modes, comprises the preparation of whole body and surface or topical.Technology and preparation generally can be at Remington: pharmaceutical science with put into practice (The Science and Practice of Pharmacy) (20 ThEd.) Lippincott, Williams ﹠amp; Find among the Wilkins (2000).
[0329] according to another aspect, the disclosure provides medicinal compositions, and it comprises formula I compound and pharmaceutically acceptable carrier, auxiliary or solvent.The amount of the compound in the composition of the present disclosure is can the kinase whose amount of detected effective arrestin, particularly suppress in the biological sample or the patient in the amount of c-Met.
[0330] as used herein, term " c-Met " and " cMet ", " MET ", " Met " or other title synonym well known by persons skilled in the art.In one aspect, composition of the present disclosure is configured to the patient's who needs such composition composition.On the other hand, composition of the present disclosure is configured to and is used for the orally give patient.
[0331] in dosage range widely, be effective according to compound of the present disclosure.For example, in when adult treatment, dosage is from every day 0.01 to 10,000mg, from 0.5 to 1000mg, from 1 to 500mg, and every day be the example of adoptable dosage from 5 to 100mg.Accurate dose will depend on route of administration, give the formulation of compound, patient to be treated, the body weight of curer, and depend on attending doctor's preference and experience.
[0332] pharmacy acceptable salt is generally that those of ordinary skills know, and can comprise, such as but not limited to, acetate, benzene sulfonate, benzene sulfonate (besylate), benzoate, supercarbonate, bitartrate, bromide, Ca-EDTA, camsilate (carnsylate), carbonate, Citrate trianion, edetate, ethanedisulphonate (edisylate), clothing holder hydrochlorate (estolate), esilate, fumarate, gluceptate (gluceptate), gluconate, glutaminate, the glycolyl arsanilate, Sucrets hydrochlorate (hexylresorcinate), Hai Baming salt (hydrabamine), hydrobromate, hydrochloride, Hydroxynaphthoate, iodide, isethionate (isethionate), lactic acid salt, Lactobionate, malate, maleate, mandelate, mesylate, mucate, naphthalenesulfonate, nitrate, pamoate (embonate), pantothenate, phosphoric acid salt/diphosphate, polygalacturonic acid, salicylate, stearate, subacetate, succinate, vitriol, tannate, tartrate or-chloro theophylline salt.Other pharmacy acceptable salt can be at for example Remington: pharmaceutical science with put into practice (The Science and Practice of Pharmacy) (20 ThEd.) Lippincott, Williams ﹠amp; Find among the Wilkins (2000).The salt of preferred pharmaceutical compositions comprises, for example, acetate, benzoate, bromide, carbonate, Citrate trianion, gluconate, hydrobromate, hydrochloride, maleate, mesylate, naphthalenesulfonate, pamoate (embonate), phosphoric acid salt, salicylate, succinate, vitriol or tartrate.
[0333] depend on special illness to be treated, but such medicine can be formulated as liquid or solid formulation and whole body or topical administration.Described medicine can be for example with timing well known by persons skilled in the art-or slowly-low form transmission that discharges.The technology of preparation and administration can be at Remington: pharmaceutical science with put into practice (The Science and Practice of Pharmacy) (20 ThEd.) Lippincott, Williams ﹠amp; Find among the Wilkins (2000).That suitable route of administration can comprise is oral, under the cheek, the sprays through sucking, hypogloeeis, rectum, transdermal, vagina, through mucous membrane, nasal cavity or enterally administering; Parenteral transmits, comprise intramuscular, subcutaneous, intramedullary injection, and in the sheath, directly in the ventricle, in the intravenously, intraarticular, breastbone, in the Synovial cavity, in the liver, in the intralesional (intralesional), encephalic, intraperitoneal, nose, or intraocular injection or other transfer mode.
[0334] for injection, medicine of the present disclosure can be at the aqueous solution, as damping fluid that can be adaptive on physiology such as Hank ' s solution, Ringer ' s solution, or preparation and being diluted in wherein in the normal saline buffer solution.For such mucosal, the suitable permeate agent that penetrates barrier can be used in the preparation.Such permeate agent is generally known in the art.
[0335] adopt pharmaceutically acceptable inert support, compound disclosed herein is formulated as the formulation that is fit to the whole body administration according to practice of the present disclosure, this is in disclosure scope.Correct select carrier and suitable pharmacy practice, composition of the present disclosure particularly is formulated as those compositions of solution, can give as intravenous injection through parenteral.Adopt pharmaceutically acceptable carrier well known in the art, described compound easily can be formulated as the formulation that is fit to oral administration.Such carrier can make compound of the present disclosure be formulated as tablet through patient's orally ingestible to be treated, pill, capsule, liquid agent, gelifying agent, syrup, slurry agent (slurries), suspensoid etc.
[0336] transmits for intranasal or suction, medicine of the present disclosure also can be prepared by method known to those skilled in the art, and can comprise, for example, but be not limited to dissolve, example such as salt solution, sanitas such as benzylalcohol, absorption enhancer and the fluorohydrocarbon of dilution or dispersed substance.
[0337] is suitable for medicinal compositions of the present disclosure and comprises and wherein contain effective amount of actives, to reach the composition of its predetermined purpose.The mensuration of significant quantity fully in those skilled in the art's limit of power, especially according to this paper in detail openly the time all the more so.
[0338] except activeconstituents, these medicinal compositionss also can contain suitable pharmaceutically acceptable carrier (comprising vehicle and auxiliary), and it helps active compound is processed into pharmaceutically useful preparation.The preparation that is formulated as oral administration can be tablet, dragee, capsule or solution.
[0339] by active compound is mixed with solid excipient, choose wantonly and grind the mixture that obtains, and the processing granular mixture, add suitable auxiliary if desired subsequently, obtain tablet or dragee core, the medicinal preparations that can obtain to orally use.Suitable vehicle, particularly weighting agent such as sugar comprise lactose, sucrose, N.F,USP MANNITOL or sorbyl alcohol; Cellulose preparation, for example, W-Gum, wheat starch, rice starch, yam starch, gelatin, tragacanth gum, methylcellulose gum, hydroxypropyl methyl-Mierocrystalline cellulose, carboxyl methyl-sodium cellulosate (CMC) and/or polyvinylpyrrolidone (PVP: polyvinyl pyrrolidone).If desired, can add disintegrating agent such as cross-linked polyvinylpyrrolidone, agar or alginic acid or its salt such as sodiun alginate.
[0340] dragee is endorsed and is had suitable dressing.For this purpose, can use dense sugar soln, it can randomly contain gum arabic, talcum powder, polyvinylpyrrolidone, carbopol gel, polyoxyethylene glycol (PEG) and/or titanium dioxide, lacquer solution and appropriate organic solvent or solvent mixture.Dyestuff or pigment can be joined in tablet or the dragee coatings, to distinguish or to differentiate the combination of different active compound doses.
[0341] medicinal preparations that can orally use comprises by what gelatin made and pushes-cooperate (push-fit) formula capsule, and the sealing soft capsule that is made by gelatin and softening agent such as glycerine or sorbyl alcohol.Push-the formula capsule can contain and weighting agent such as lactose, tackiness agent such as starch and/or lubricant such as talcum powder or Magnesium Stearate, and optional stablizer blended activeconstituents.In soft capsule, active compound is dissolvable in water or is suspended in suitable liquid, in fatty oil, whiteruss or liquid macrogol (PEGs).In addition, can add stablizer.
[0342] according to specific illness or the morbid state that will treat or prevent, the other therapeutical agent that is given usually with treatment or prevention illness can give with inhibitor of the present disclosure.For example, chemotherapeutics or other anti--multiplication agent can with inhibitor combination therapy proliferative disease of the present disclosure and cancer.The example of known chemotherapeutics includes, but are not limited to Zorubicin, dexamethasone, vincristine(VCR), endoxan, Fluracil, Hycamtin, taxol (taxol), Interferon, rabbit and platinum derivatives.
[0343] also can include, but are not limited to resist-scorching medicine such as corticosteroids, tnf blockers, IL-I RA, azathioprine, endoxan and sulfasalazine with other example that inhibitor of the present disclosure is united the medicine of use; Immunomodulator and immunosuppressor such as S-Neoral, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, endoxan, azathioprine and sulfasalazine; Neurotrophic factor such as acetyl cholinesterase enzyme inhibitors, MAO inhibitor, interferons, anti--convulsant, ionic channel retarding agent, Riluzole and anti--Parkinson's disease medicine; The medicine such as beta-Blocking agent, ACE inhibitor, diuretic(s), nitrate, calcium channel blocker and the statins that are used for the treatment of cardiovascular disorder; The medicine such as corticosteroids, Colestyramine, interferons and the anti--viral agent that are used for the treatment of hepatopathy; Be used for the treatment of the medicine of washing lotion disorder such as corticosteroids, anti--leukemia medicine and somatomedin; The medicine such as Regular Insulin, insulin analog, α glucosidase inhibitor, biguanides and the euglycemic agent that are used for the treatment of diabetes; With medicine that is used for the treatment of immune deficiency disorder such as gamma Globulin.
[0344] these other medicines part of can be used as a plurality of dosages is separated with the composition that contains inhibitor and is given.Perhaps, these medicines can be the part of single formulation, are mixed together in the single composition with described inhibitor.
[0345] disclosure is not limited to the scope of the embodiment that exemplified, and it is intended to the exemplary illustration as single aspect of the present disclosure.Really, except those embodiments described herein, those skilled in the art can understand various modification of the present disclosure from aforementioned.Such modification is intended to fall in the disclosure scope.In addition, any one of any embodiment of the present disclosure or a plurality of feature can combine with any one or a plurality of further feature of any other embodiment, and do not deviate from the scope of the present disclosure.For example, the Triazolopyridazines kinase modulator of describing at Triazolopyridazines kinase modulator chapters and sections is equally applicable to kinase whose methods of treatment described herein and inhibition method.The reference that the application quotes in full be the art technology level example and be attached to herein to be used for all purposes, no matter and whether incorporated herein especially by quoting in full at preamble.
Measure
[0346] can easily measure compound of the present disclosure, regulate the ability of protein kinase, bindin kinase and/or growth of prevention cell or propagation to determine them.Some example of useful assay method proposes hereinafter.
Kinase inhibition and combination are measured
[0347] various kinase whose inhibition are measured by the known method of those of ordinary skills, as the whole bag of tricks that proposes hereinafter, and those methods of in up-to-date kinases simulated determination scheme (UpstateKinaseProfiler Assay Protocols) (in June, 2003 publication), being discussed.
[0348] for example, when carrying out external test, usually that kinase dilution is extremely suitable concentration is to form kinase solution.Kinase substrate and phosphate donor such as ATP are added in the kinase solution.Described kinases makes phosphate transfection move to kinase substrate, forms phosphorylated substrate.The formation of phosphorylated substrate can be by any suitable manner, as radioactivity (as [γ- 32P-ATP]), or use detectable secondary antibodies (as ELISA) directly to detect.Perhaps, the formation of phosphorylated substrate can be adopted any suitable technique, as detecting ATP concentration (as kinases-Glo
Figure A20078003852701791
Mensuration system (Promega)) detects.Kinase inhibitor detects the formation of phosphorylated substrate and identifies by in the existence of test compounds (seeing following embodiment part) with not.
[0349] kinase whose ability also can adopt method well known in the art to measure in the described compound inhibition cell.For example, containing kinase whose cell can contact with the kinase whose activator of activation (as somatomedin).The amount of the endocellular phosphorus acidifying substrate that forms in the existence of test compounds and not can be measured by dissolved cell and by the existence of any suitable method (as ELISA) detection phosphorylated substrate.When the amount of the phosphorylated substrate that produces in the presence of test compounds reduced with respect to the amount of the phosphorylated substrate that produces under not having test compounds, expression had kinase inhibitory activity.More detailed cell kinase assay method is discussed in following embodiment part.
[0350] combines with kinase whose for measuring compound, can adopt any known any method of those of ordinary skills.For example, can use by Discoverx (Fremont, CA), ED-Staurosporine NSIP TMEnzyme is in conjunction with measuring the assay kit that test kit manufacturer (Enzyme BindingAssay Kit) (seeing the U.S. patent No. 5,643,734) produces.Kinase activity also can be measured described in 950 as the U.S. patent 6,589 of authorizing on July 8th, 2003.
[0351] by as at for example Antonysamy etc., the albumen crystallography screening described in the PCT publication No. WO03087816A1 (it is attached to herein to be used for all purposes by quoting in full), suitable kinase inhibitor can be selected from compound of the present disclosure.
[0352] machine screens compound of the present disclosure as calculated, to measure and to check their combinations and/or suppress various kinase whose abilities.Can carry out computer screening to the structure of compound of the present disclosure, with determine they in each site in conjunction with kinase whose ability.Such compound can attempted aspect the pharmaceutical chemistry of identifying the inhibitor that for example has potential treatment meaning as target or guiding (Travis, Science, 262:1374,1993).The three-dimensional structure of such compound can be superimposed on kinases or its avtive spot or binding pocket three-dimensional apparent, whether spatially meet so apparently to estimate described compound, thereby be fit to described albumen.In such screening, such entity or compound meet binding pocket quality can or by shape complementarity, perhaps judge (Meng, etc., J.Comp.Chem.13:505-24,1992) by the interaction energy of estimation.
[0353] screening according to compound of the present disclosure of combination and/or adjusting kinases (as suppressing or the activation kinases) generally comprises the consideration of two factors.The first, compound must be can with kinases on the physics and structure on or with covalency or with the non covalent bond bonded.For example, the interaction of covalency can be important for the proteic irreversible or suicide inhibitor of design.In the combining of kinases and described compound, the interactional importance of non-covalent molecule comprises hydrogen bond, ionic interaction, Van der Waals bonding (van der Waals) and hydrophobic interaction.The second, described compound must can be taked configuration relevant with binding pocket and orientation, and this makes it combine with kinases.Though some part of compound is not participated in this and kinase whose the combination directly, but these parts still can influence the whole configuration and the remarkably influenced effect of molecule.The prerequisite of conformation comprises and the chemical group all or that the part binding pocket is relevant or the whole three-dimensional structure and the orientation of compound, or comprises directly and the spacing between the functional group of the compound of several chemical groups of kinase interactions.
[0354] stop described herein (Docking) program, for example, DOCK or GOLD are used to identify the compound in conjunction with avtive spot and/or binding pocket.Can be at the more than one binding pocket of protein structure, or, consider that the different molecule dynamic configuration of albumen comes SCREENED COMPOUND to identical proteic more than one coupling.The scoring of available regulation is identified and is met described proteic compound (Charifson, P.S. etc., J.Med.Chem.42:5100-9 (1999)) most then.The data that obtain from more than one protein molecular structure also can equal the method scoring that on May 3rd, 2002, U.S. application for a patent for invention that submit to, that be entitled as " computer system and method (Computer Systems and Methods for Virtual Screening of Compounds) that is used for effective screening of compound " was described according to Klingler.Compound with optimum matching then can obtain from the producer of chemical libraries or synthesize, and is used in conjunction with measuring and biological assay.
[0355] computer modeling technique can be used for the evaluating chemical compound to kinase whose potential adjusting or in conjunction with effect.If computer simulation indicates strong interaction, but synthetic molecules and test it then in conjunction with its active ability of kinases and influence (by suppressing or activating).
[0356] regulates or other can pass through series of steps (wherein chemical group or fragment screened and select) they and each binding pocket or kinase whose other regional bonded ability of machine evaluation as calculated in conjunction with kinase whose compound.This method can be by for example, and the visual inspection of screening on computers based on the avtive spot of described kinases coordinate begins.Fragment of Xuan Zeing or chemical group can be with various orientation positions or stop (Blaney in kinase whose each binding pocket then, J.M and Dixon, J.S., drug development and design prospect (Perspectives in Drug Discovery and Design), 1:301,1993).Manual stop (docking) can adopt software such as Insight II (Accelrys, SanDiego, CA) MOE (Chemical Computing Group, Inc., Montreal, Quebec Canada) finishes; And SYBYL (Tripos, Inc., St.Louis, MO, 1992), then be energy minimization and/or have the molecular dynamics in the standard molecule machinery field of force, as CHARMM (Brooks, Deng, J.Comp.Chem.4:187-217,1983), AMBER (Weiner, Deng, J.Am.Chem.Soc.106:765-84,1984) and C 2MMFF (Merck Molecular ForceField (Merck field of force of molecule); Accelrys, San Diego, CA).More automatic stop can realize that described program has for example DOCK (Kuntz etc., J.MoI.Biol, 161:269-88,1982 by adopting following program; DOCK obtains from the University of California in San Francisco, California); AUTODOCK (Goodsell ﹠amp; Olsen, albumen: structure, function and genetics (Proteins:Structure, Function, and Genetics) 8:195-202,1990; AUTODOCK derive from California La Jolla Scripps institute (Scripps Research Institute, La Jolla, CA); GOLD (Cambridge Crystallographic Data Centre (CCDC); Jones etc., J.MoI.Biol.245:43-53,1995); And FLEXX (Tripos, St.Louis, MO; Rarey, M., etc., J.MoI.Biol.261:470-89,1996).Other suitable procedure for example is described in, Halperin etc.
[0357] during selecting compound by above method, compound can be tested and optimization by computer evaluation in conjunction with kinase whose efficient.For example, when natural substrate is combined, be designed or select compound as kinase inhibitor performance function can occupy not and the volume eclipsed volume that is occupied by the avtive spot residue, yet, one of skill in the art will recognize that some allow that main chain and side chain reset flexibility.In addition, those of ordinary skill can design detectable based on combination, for example causes the compound of the albumen rearrangement of induced-fit (induced fit).Effectively kinase inhibitor can show on the energy between its combination and the free state relatively little difference promptly, its must have little in conjunction with the sex change energy and/or in conjunction with the time low conformation strain).Therefore, great majority effectively kinase inhibitor should be designed to, and for example are not more than 10kcal/mol, are not more than 7kcal/mol, be not more than 5kcal/mol or be not more than 2kcal/mol in conjunction with the sex change energy.Kinase inhibitor can be with more than one conformation and protein-interacting of identical total binding energy.In these examples, bonded sex change energy begins to become the energy of free cpds and average energy poor of observed conformation when inhibitor is incorporated into enzyme.
[0358] the special computers software of assessing compound sex change energy and electrostatic interaction is that this area is obtainable.For the example of the program of this type of Application Design comprises: Gaussian 94, revised edition C (Frisch, Gaussian, Inc., Pittsburgh, PA.
Figure A20078003852701831
1995); AMBER, the 7th edition. (Kollman, University of California, San Francisco (University of California at SanFrancisco), 2002); QUANTA/CHARMM (Accelrys, Inc., San Diego, California (San Diego, CA),
Figure A20078003852701833
1995); Insight II/Discover (Accelrys, Inc., SanDiego, CA,
Figure A20078003852701834
1995); DelPhi (Accelrys, Inc., San Diego, California (San Diego, CA),
Figure A20078003852701835
1995); And AMSOL (the state university in Minnesota (University of Minnesota)) (quantum chemistry programme-controlled exchange (Quantum Chemistry Program Exchange), Indiana State University (Indiana University)).These programs can be for example, the workstation that uses a computer, and as known in the art, for example LINUX, SGI or sun station are implemented.Other hardware system and software package should be well known by persons skilled in the art.
[0359] those of ordinary skills can adopt methods known in the art and method disclosed herein to express kinase protein.Kinase polypeptide natural and sudden change described herein can all or part of employing technology well known in the art and chemically syntheticly (see, as, Creighton, albumen: structure and molecular principle (Proteins:Structures and Molecular Principles), W.H.Freeman ﹠amp; Co., NY, 1983).
[0360] gene expression system can be used for the polypeptide of synthesis of natural and sudden change.Can build the polypeptid coding sequence and suitable the transcribing/translate the expression vector of control signal that contain natural and sudden change, it is well known by persons skilled in the art.These methods comprise reorganization/gene recombination in vitro recombination body dna technique, synthetic technology and the body.See, for example at Sambrook etc., molecular cloning: laboratory manual (Molecular Cloning:A Laboratory Manual), Cold Spring HarborLaboratory, NY, 2001, with Ausubel etc., molecular biology general purpose discipline (CurrentProtocols in Molecular Biology), Greene Publishing Associates and WileyInterscience, NY, the technology of describing in 1989.
[0361] host-expression vector system can be used for expressing kinases.These include, but are not limited to microorganism as with recombinant phage dna, plasmid DNA or contain the bacterium that the cosmid DNA expression vector of encoding sequence is transformed; Yeast with the recombinant yeast expression vector transformation that contains encoding sequence; The insect cell system that infects with the recombinant virus expression vector that contains encoding sequence (as, baculovirus); Recombinant virus expression vector (as, cauliflower mosaic virus, CaMV; Tobacco mosaic virus (TMV), TMV) infect or with the vegetable cell system of the plasmid recombinant expression vector that contains encoding sequence (as, Ti-plasmids) transfection; Or zooblast system.Described albumen also can be expressed in the people's gene therapy system, comprises, for example expresses described albumen with proteic amount in the individuality that increases, or the engineered treatment albumen of expressing gene.The Expression element of these systems is different aspect their intensity and specificity.
[0362] DNA between specially designed carrier permissive host such as bacterium-yeast or the bacterium-zooblast is toward renaturation (shuttling).The appropriate structures expression vector can contain: be used for the copy source of the self-replicating of host cell, one or more selectable markers, the useful limit of minority cut the enzyme site, be used for height duplicates several current potentials and active promotor.Promotor is defined as guiding RNA polymerase to be incorporated into DNA and starts RNA synthetic dna sequence dna.Strong promoter is the promotor that mRNAs is started with high frequency.
[0363] expression vector also can comprise the element that various influences are transcribed and translated, and comprises for example formation type and inducible promoter.These elements usually are that host and/or carrier are dependent.For example, when in bacterial system, cloning, can use pL, plac, ptrp, the ptac (ptrp-lac hybrid promoters) etc. of inducible promoter such as T7 promotor, phage; When in insect cell system, cloning, can use promotor such as baculovirus polyhedrin body protein promotor; When in the vegetable cell system, cloning, can use genomic promotor (as, heat-shocked promotor derived from vegetable cell; The promotor that is used for the little subunit of RUBISCO; Be used for the protein-bonded promotor of chlorophyll a/b) maybe can use promotor (as, the 35SRNA promotor of CaMV derived from plant virus; TMV coating protein promotor); When in mammal cell line system, cloning, can use mammalian promoter (as, metallothionein promoter) or mammalian disease virus promoter (as, gland virus stage starting; Vaccinia virus 7.5K promotor; The SV40 promotor; The bovine papilloma virus promotor; And E Positan-Ba Er (Epstein-Barr) viral promotors).
[0364] the whole bag of tricks can be used for carrier is introduced in the host cell, and for example, conversion, transfection, infection, protoplastis merge and the fax hole.The cell that contains expression vector is also analyzed respectively through clonal reproduction, whether produces suitable polypeptide to determine them.Various systems of selection comprise, for example, antibiotics resistance can be used for identifying transformed host cells.The evaluation of expression host cell clone's polypeptide can be undertaken by several modes, includes but not limited to and the anti--immunological response of kinase antibody and existence of host cell-related activity.
[0365] expression of cDNA also can adopt the synthetic mRNA of produced in vitro to carry out.Synthetic mRNA can translate in various cells-free system effectively, includes but not limited to wheat germ extract and skein cell extract, and translates in cell-based system effectively, includes but not limited to enter the frog's egg parent cell through microinjection.
[0366] for measuring the active and/or proteic cDNA sequence that produces optimum level, makes up the cDNA molecule of modifying.The limiting examples of the cDNA that modifies is that codon is used the position that has been optimised among the cDNA of host cell (wherein cDNA will be expressed in wherein).Host cell transforms and measures kinase RNA and/or proteic level with the cDNA molecule.
[0367] the kinase protein level in the host cell is quantitative by the whole bag of tricks such as immune avidity and/or ligand affinity technology, and kinases-specificity avidity pearl or specific antibody are used to separate 35S-methionine(Met) mark or unlabelled albumen.Albumen mark or unlabelled is analyzed through SDS-PAGE.Unlabelled albumen is by Western blotting, ELISA or adopt the RIA of specific antibody to detect.
[0368] according to the kinase expression in the recombinant host cell, recyclable polypeptide is to provide the albumen of activity form.Several purification process are available and are suitable for using.The recombinant chou kinases can be by the various combination of fractionation known in the art or chromatographic step or is used independently, from cellular lysate or from conditioned medium purifying.
[0369] in addition, by adopting immunity-avidity post that the new raw albumen of total length or the specific mono-clonal of its polypeptide fragment or monoclonal antibody are made, can separate the recombinant chou kinases from other cell protein.Also can adopt other purification technique known in the art based on avidity.
[0370] or, polypeptide can with folded form not, with activity form from host cell, as from the inclusion body of bacterium, reclaiming.The albumen that reclaims with this form can use denaturing agent (as the guanidinesalt hydrochlorate) solubilising, adopts method known to those skilled in the art (as dialysis) to be folded into activity form more then.
The cell growth measurement
[0371] various cell growth measurement methods are that the field is known and be used to identify that triazolopyridazine compounds, their (i.e. " test compounds ") suppresses the ability of (as reducing) cell growth and/or propagation.
[0372] for example, the growth of known various cells and/or propagation need the specificity kinases.Can estimate the ability of this type of growth of cell in the presence of test compounds and the growth during with no test compounds compares, thus the antiproliferative properties of characterization test compound.Such common method is that measuring mark (as tritiate) thymus pyrimidine is attached to the degree among the DNA of somatoblast.Perhaps, the inhibition of cell proliferation can be estimated by the cell total metabolism activity that mensuration has a surrogate markers relevant with cell count.Cell can be handled with the metabolism indicator in the existence of test compounds with not.Viable cell makes metabolism indicator generation metabolism, forms detectable meta-bolites thus.When detectable meta-bolites level in the presence of the test compounds with respect to test compounds not in the presence of when decreasing, growth of expression cell and/or propagation are suppressed.Exemplary metabolism indicator comprises, for example tetrazolium salts and AlamorBlue
Figure A20078003852701861
(seeing following examples part).
[0373] the kinase whose cut assay method (scratch assay) that is determined as of irritation cell migration.Use this assay method to estimate kinase inhibitor by simulation game such as wound healing.In a variation of this assay method that is used for testing the MET inhibitor, on Tissue Culture Plate, form the monolayer cell that merges.After monolayer cell forms, on monolayer cell, cause the wire wound, form cell-free passage thus by machinery scratch monolayer cell.For the cell growth, add the required somatomedin of kinases in the existence of test compounds with not.Test compounds have closing the indication test compounds and can not suppressing kinases of lower channel, thereby make cell migration and growth and closes passage.On the contrary, the existence of passage indication test compounds suppresses kinases after adding test compounds, prevents the cell growth thus.The selection of suitable cell, growth conditions and somatomedin (is seen following examples part) fully in those skilled in the art's limit of power.
Embodiment
[0374] provide following examples to illustrate but not the present invention of requirement for restriction protection.The preparation of embodiment of the present invention is described in following examples.It will be understood by those skilled in the art that the chemical reaction and the synthetic method that provide can be modified to prepare many other compounds of the present invention.When not exemplifying out compound of the present invention, one of skill in the art will recognize that these compounds can pass through to modify the synthetic method that this paper proposes, and adopt synthetic method preparation known in the art.
Universal method A
General reaction process 1
[0375] general formula (XII) and (XI) compound, wherein Q, R 1, X, T and U describe in this article, can be according to general reaction process 1 preparation.Formula (I) and (II) compound or for being commercially available perhaps adopt standard chemical reaction and conversion well known by persons skilled in the art by commercially available compound.
[0376] formula (III) compound can pass through process steps (i) by general formula (I) compound and general formula (II) compound, and it comprises the catalytic C-C key coupled reaction between halogenated material and the metallics.The array (array) of catalytic C-C key coupled reaction is that those skilled in the art are adoptable, as Suzuki-Miyaura condition (M=boron; Miyaura, N.; Suzuki, A.Chem.Rev.1995,95,2457), Stille condition (M=tin; Stille, J.W.J.Org.Chem.1990,55,3019), or Negishi condition (M=zinc, aluminium; Negishi, E.Chem.Rev.1996,96,365).Typical Suzuki-Miyaura condition comprises 1 equivalent (I), 1-1.5 equivalent (II), 1-10mol% palladium catalyst, as Pd (dppf) Cl 2, Pd (PPh 3) 2Cl 2Or Pd (PPh 3) 4, and excessive alkali such as yellow soda ash or salt of wormwood at solvent as 1,2-glycol dimethyl ether or 1, the aqueous solution in the 4-dioxane.
[0377] formula (IV) and (V) compound can be by process steps (ii) respectively by formula (I) and (III) compound, it comprise with hydrazine in suitable solvent, heat or microwave condition under substitution reaction.Typical condition need make 1 normal aryl halide (I) or (III) and 10 normal hydrazines in ethanol, keep a few hours in 80 ℃.
[0378] formula (VIII) and (IX) compound can be by process steps (iii) respectively by formula (IV) and (V) compound, it is included in existence following and the carboxylic acid (VI) or acyl chlorides (VII) the formation amido linkage of suitable coupler, as carboxylic acid (VI) is used 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyl-urea hexafluorophosphate (HBTU) or for acyl chlorides (VII) then at suitable organic removing alkali (scavenging base), as carrying out under the existence of triethylamine or N-methylmorpholine, and two kinds of conversions all occur in suitable solvent such as methylene dichloride or the dimethyl formamide.The array that amido linkage forms reaction be that those skilled in the art are available, as John Jones ' amino acid and peptide synthetic (Amino Acid and Peptide Synthesis) ' (publish and comprise wherein reference) by Oxford Science Press (OxfordScience Publications) in those arrays of description.
[0379] formula (X) and (XI) compound can be by process steps (iv) respectively by formula (VIII) and (IX) compound, it is included in acidic conditions or at typical dehydrated condition such as POCl 3Or the cyclodehydration under the existence of trifluoromethanesulfanhydride anhydride (cyclodehyration) reaction is to form the Triazolopyridazines loop systems.Typical condition need with formula (VIII) or (IX) compound in acetate, heat a few hours.
[0380] formula (XI) compound can pass through process steps (i), and by general formula (X) compound and general formula (II) compound, it comprises the catalytic C-C key coupled reaction between halogenated material and the metallics.The array of catalytic C-C key coupled reaction is that those skilled in the art are adoptable, as Suzuki-Miyaura condition (M=boron; Miyaura, N.; Suzuki, A.Chem.Rev.1995,95,2457), Stille condition (M=tin; Stille, J.W.J Org.Chem.1990,55,3019) or Negishi condition (M=zinc, aluminium; Negishi, E.Chem.Rev.1996,96,365).Typical Suzuki-Miyaura condition comprises the palladium catalyst of 1 equivalent (X), 1-1.5 equivalent (II), 1-10mol%, as Pd (dppf) Cl 2, Pd (PPh 3) 2Cl 2Or Pd (Ph 3) 4, and excessive alkali such as yellow soda ash or salt of wormwood at solvent as 1,2-glycol dimethyl ether or 1, the aqueous solution in the 4-dioxane.
[0381] formula (XII) compound can pass through process steps (v) by general formula (X) compound, it is included in the suitable solvent, under heating or microwave condition, with nucleophilic reagent as one or two-replacement(metathesis)reaction of the amine, alcohol or the phenol that replace.Typical condition need be in DMSO excessive amine and heat a few hours or at alkali such as Cs 2CO 3Or K 2CO 3Exist down, alcohol or phenol are heated a few hours in DMSO.
Universal method B
General reaction process 2
[0382] general formula (VI) and (VII) compound, wherein Q, R 1, X, U and T describe in this article, can be according to general reaction process 2 preparations.Formula (I) and (II) compound or for being commercially available perhaps adopt standard chemical reaction and conversion well known by persons skilled in the art, by commercially available compound
[0383] formula (III) compound can be according to general reaction process 1, the method preparation of describing in the process steps (i).
[0384] general formula (IV) compound can be according to the method preparation of describing in the general reaction process 6.
[0385] formula V is with (VI) compound can be by process steps (ii), respectively by formula (IV) and (I) compound or (III) compound, it is included in 2 coupling part (Albright of heating equimolar amount in suitable solvent such as the 1-butanols, J.D. etc., J Med Chem., 1981,24,592-600).
[0386] formula (VII) compound can be according to general reaction process 1, process steps (the method preparation of describing v).
[0387] formula (VI) compound can be by process steps (ii), and according at general reaction process 1, the method for describing in the process steps (i) is by formula V and (II) compound.
Universal method C
General reaction process 3
Figure A20078003852701921
[0388] logical formula V compound, wherein Q, R 1, X, R 28 ', R 28 ", A and (R 35) z describes in this article, can be according to general reaction process 3 preparations.Formula (I) compound synthetic described in this article or for what be commercially available, perhaps adopts standard chemical reaction and conversion well known by persons skilled in the art, by commercially available compound.
[0389] the formula V compound can pass through process steps (i) by general formula (I) compound and general formula (H) compound, and it comprises the catalytic C-C key coupled reaction between halogenated material and the metallics.The array of catalytic C-C key coupled reaction is that those skilled in the art are adoptable, as Suzuki-Miyaura condition (M=boron; Miyaura, N.; Suzuki, A.Chem.Rev.1995,95,2457), Stille condition (M=tin; Stille, J.W.J Org.Chem.1990,55,3019), or Negishi condition (M=zinc, aluminium; Negishi, E.Chem.Rev.1996,96,365).Typical Suzuki-Miyaura condition comprises the palladium catalyst of 1 equivalent (I), 1-1.5 equivalent (II), 1-10mol%, as Pd (dppf) Cl 2, Pd (PPh 3) 2Cl 2Or Pd (Ph 3) 4, and excessive alkali as yellow soda ash or salt of wormwood at solvent as 1,2-glycol dimethyl ether or 1, the aqueous solution in the 4-dioxane.Perhaps, the coupling part can be reverse (reversed), its formula of (I) compound, for example at highly basic, as n-Butyl Lithium, tert-butyl lithium, or the di-isopropyl lithamide, and experience metal-halogen exchange reaction under the existence of required metal, general formula (III) compound is provided.As above-mentioned, carry out coupled reaction subsequently, obtain the formula V compound with general formula (II) compound.
Universal method D
General reaction process 4
Figure A20078003852701931
[0390] general formula (VI) compound, wherein Q, R 1, X, T, R 28 ', R 28 ", A and (R 35) z describes in this article, can be according to general reaction process 4 preparations.Formula (III) compound or for being commercially available perhaps adopts standard chemical reaction and conversion well known by persons skilled in the art (Pinner synthesizes), by commercially available compound.Formula (I) compound and (II) can prepare according to the method for this paper general introduction (universal method A, general reaction process 1, process steps (i) and (ii)).
[0391] formula (IV) and (VI) compound can pass through process steps (i) respectively by general formula (III) and (I) compound or (II) preparation, it comprise make imido-ester (imidate) (III) with pyridazine (pyrdiazine) hydrazine (I) or (II) condensation, form Triazolopyridazines by heating a few hours in suitable solvent.
[0392] formula (VI) compound can be by process steps (ii), and according at general reaction process 1, the method for describing in the process steps (i) is by formula V compound and (IV) preparation.
Universal method E
General reaction process 5
Figure A20078003852701941
[0393] general formula (VI) compound, wherein R 28 'And R 28 "Describe in this article, can be according to general reaction process 5 preparations.Formula (I) compound or for being commercially available perhaps adopts standard chemical reaction and conversion well known by persons skilled in the art, by commercially available compound.
[0394] formula (II) compound can pass through process (i), by formula (I) compound, described process is described in below with reference to document: Cohn, the Skraup synthetic of Essie White. quinoline is modified (Modification of the Skraup synthesis of quinoline).Journal of the American Chemical Society (Journal of the American Cemical Society) (1930), 52 3685-8; Bradford, L.; Elliott, T.J.; Rowe, the Skraup reaction (Skraupreaction with meta substituted anilines) of the aniline of a F.M. and a replacement. chemical association magazine (Journal of theCemical Society) (1947), 437-45; Palmer, M.H.Skraup reacts (The Skraupreaction).The formation of the quinoline that 5-and 7-replace (forming of 5-and 7-substitutedquinolines). chemical association magazine (Journal of the Chemical Society) (1962), 3645-52.
[0395] formula (IV) compound can be by process steps (ii) by general formula (II) compound and general formula (III) compound, it comprises the catalytic C-C key coupled reaction between halogenated material and the metallics, under the situation of using zinc, adopt Negishi condition (M=zinc, aluminium; Negishi, E.Chem.Rev.1996,96,365).By process steps (iii), under alkalescence or acidic conditions, carry out follow-up ester hydrolysis then, preparation (VII) compound.
[0396] formula (VI) compound can be by process steps (iv) by general formula (II) compound and logical formula V compound, and it is included under the existence of suitable metal such as CuBr and suitable alkali such as sodium hydride, adds the malonic ester class.
Universal method F
General reaction process 6
Figure A20078003852701961
[0397] logical formula V and general formula (VI) compound, wherein T, A, (R 35) z, R 28 'And R 28 "Describe in this article, can be according to general reaction process 6 preparations.Formula (I) compound or for being commercially available, perhaps adopt standard chemical reaction and conversion well known by persons skilled in the art, by commercially available compound, or according to method of describing in universal method E, the general reaction process 5 and method described herein preparation.
[0398] general formula (II) compound can pass through process steps (i), and by the compound of general formula (I), it comprises esterification procedure well known by persons skilled in the art, handles as heating a few hours in acidic methanol or with diazomethane.
[0399] formula (III) compound can be by process steps (ii) by general formula (II) compound, it is included in halogen source, as bromine, iodine, N-bromo or N-iodosuccinimide, or under the existence of tetrabutyl tribromide ammonium, in suitable solvent, under the temperature of-20 ℃ to 200 ℃ variations, carry out bromination reaction.Typical condition comprises keeps a few hours 1 equivalent compound (I) and 1-5 equivalent bromine in 100 ℃ in toluylic acid.
[0400] formula (IV) compound can be by process steps (iii) by general formula (III) compound, and it comprises the common known saponification reaction of those skilled in the art.Typical condition is included under the existence of hydroxide aqueous solution compound (III) stirred for several hour.
[0401] formula (VI) compound can pass through process steps (v) by general formula (III) or general formula (II) compound, it comprise and hydrazine in suitable solvent the heating or microwave condition under substitution reaction.Typical condition needs 1 equivalent ester (III) and 10 equivalent hydrazines to keep a few hours in 80 ℃ in ethanol.
[0402] the formula V compound can be by process steps (iv) by general formula (IV) compound or general formula (III) and (VII) compound, and it comprises the catalytic C-C key coupled reaction between halogenated material and the metallics.The array of catalytic C-C key coupled reaction is that those skilled in the art are adoptable, as Suzuki-Miyaura condition (M=boron; Miyaura, N.; Suzuki, A.Chem.Rev.1995,95,2457), Stille condition (M=tin; Stille, J.W.J.Org.Chem.1990,55,3019) or Negishi condition (M=zinc, aluminium; Negishi, E.Chem.Rev.1996,96,365).Typical Suzuki-Miyaura condition comprises the palladium catalyst of 1 equivalent (I), 1-1.5 equivalent (II), 1-10mol%, as Pd (dppf) Cl 2, Pd (PPh 3) 2Cl 2Or Pd (Ph 3) 4, and excessive alkali such as yellow soda ash or salt of wormwood at solvent as 1,2-glycol dimethyl ether or 1, the aqueous solution in the 4-dioxane.
Universal method G
General reaction process 7
Figure A20078003852701981
[0403] general formula (IV), (V) and (VII) compound, wherein T, A, (R 35) z, R 28 'And R 28 "Describe in this article, according to general reaction process 7 preparations.Formula (I) compound or for being commercially available perhaps adopts standard chemical reaction and conversion well known by persons skilled in the art, by commercially available compound.
[0404] formula (II) compound can pass through process steps (i) by general formula (I) compound; it is included in halogen source; as bromine, iodine, N-bromo or N-iodosuccinimide; or under the existence of tetrabutyl tribromide ammonium and group initiator such as benzoyl peroxide; in suitable solvent, in the free radical halogenating reaction under-20 ℃ to 100 ℃ transformation temperature.Typical condition comprises to be refluxed 1 equivalent compound (I) and 1-5 equivalent N-bromosuccinimide and makes the benzoyl peroxide of 3mol% keep a few hours in tetracol phenixin.
[0405] formula (III) compound can be by process steps (ii) by general formula (II) compound, and it is included in the mineral alkali existence down, in suitable solvent, carries out nucleophilic substitution with prussiate.Typical condition is included under the room temperature 1 equivalent compound (II), 1 equivalent sodium cyanide and 1 equivalent KHCO in dimethyl formamide 3
[0406] the formula V compound can be by process steps (iv) by general formula (III) compound, and it comprises according to Kotoris, Christopher C; Chen, Mei-Jin; Taylor, Scott D. prepares benzylic α by the electric fluorination of parent, α-difluoro nitrile ,-tetrazolium and-sulphonate (Preparation ofBenzylic α, α-Difluoro nitriles ,-tetrazoles, and-sulfonates via ElectrophilicFluorination via Electrophilic Fluorination). organic chemistry magazine (Journal ofOrganic Chemistry (1998), 63 (22), the method for describing among the 8052-8057 (great change is not arranged) is fluoridized.
[0407] formula (IV) compound can be by process steps (iii) by general formula (III) compound, and it comprises that the negatively charged ion (forming with suitable highly basic) of compound (III) and the C-C key between any alkylating agent form.Typical condition is included in-78 ℃ of 1.5-2.5 equivalent tert-butyl lithium, 1 equivalent compound (III) and the normal alkylating agent of 1.2-2.4 such as methyl (metyl) iodine in tetrahydrofuran (THF).
[0408] formula (VII) compound can pass through process steps (v) by general formula (VI) compound, its be included in or acidity or alkaline condition under, by the heating nitrile compound (VI) be hydrolyzed.Typical condition was included in the microwave oven compound (VI) of heating in concentrated hydrochloric acid several minutes.
Universal method H
General reaction process 8
[0409] general formula (VI) compound, wherein Q, R 1, T, (R 35) z, R 28 'And R 28 "Describe in this article, can be according to general reaction process 8 preparations.Formula (I) compound or according to method (the general reaction process 6) system that is used for synthetic general formula (VI) compound described herein, perhaps for be commercially available or adopt standard chemical reaction and conversion well known by persons skilled in the art by commercially available compound.
[0410] formula (II) compound can pass through process steps (i) by general formula (I) compound, and it is included under the existence of cyanogen bromide, forms amino-1,3,4-oxadiazole in the presence of the suitable alkali in polar organic solvent.Typical condition is included in and makes compound (I), excessive a little cyanogen bromide and excessive cyanogen bromide potassium chemical combination in methyl alcohol under the room temperature.
[0411] formula (III) compound can be by process steps (ii) by general formula (II) compound, and it is included under the temperature of rising, and in the presence of hydrazine, by amino-1,3, the 4-oxadiazole forms diaminostilbene, 3,4-triazole.Typical condition is included under 170 ℃ and 2 normal atmosphere (crust), heating compound in the mixture of hydrazine hydrate and water (II) 1 hour.
[0412] the formula V compound can be by process steps (iii) by general formula (III) compound, and it comprises by making compound (III) and (VI) reaction of compound chemical combination formation triazine in the mixture of acetate and water.Typical condition is included under the room temperature, and 1 equivalent compound (III) and excessive compound (IV) are merged in acetate and water.
[0413] formula (VI) compound can be by process steps (iv) by logical formula V compound and (VII) compound, and it comprises the catalytic C-C key coupled reaction between halogenated material and the metallics.The array of catalytic C-C key coupled reaction is that those skilled in the art are adoptable, as Suzuki-Miyaura condition (M=boron; Miyaura, N.; Suzuki, A.Chem.Rev.1995,95,2457), Stille condition (M=tin; Stille, J.W.J.Org.Chem.1990,55,3019) or Negishi condition (M=zinc, aluminium; Negishi, E.Chem.Rev.1996,96,365).Typical Suzuki-Miyaura condition comprises the palladium catalyst of 1 equivalent (V), 1-1.5 equivalent (VII), 1-10mol%, as Pd (dppf) Cl 2, Pd (PPh 3) 2Cl 2Or Pd (Ph 3) 4, and excessive alkali such as yellow soda ash or salt of wormwood at solvent as 1,2-glycol dimethyl ether or 1, the aqueous solution in the 4-dioxane.
Synthesizing of intermediate
Intermediate 1:(2-methyl-quinoline-6-yl)-acetate
Step 1:(2-methyl-quinoline-6-yl)-the acetate ethyl ester
[0414] under nitrogen atmosphere, 6-bromo-quinaldine red (500mg packs in vial, 2.25mmol), hypoboric acid two pinacol esters (bis (pinacolato) diboron) (1.14g, 4.5mmol), dichloro [1,1 '-two (diphenylphosphino)-ferrocene] palladium (II) methylene dichloride adducts (92mg, 0.112mmol), sodium acetate (547mg, 6.75mmol) and dimethyl formamide (10mL).This reaction mixture in 100 ℃ of heating 18 hours, is allocated between ethyl acetate and the water then.With salt water washing organic layer twice,, filter, and be absorbed on the silica gel through dried over sodium sulfate.Purifying on silica gel uses the gradient liquid of 0-8% methyl alcohol in methylene dichloride, obtains the dark oily matter of 432mg.Make this oily matter be dissolved in tetrahydrofuran (THF) (5mL) and under nitrogen atmosphere, join contain acid chloride (II) (7mg, 0.03mmol), three-1-naphthyl phosphine (37mg, 0.09mmol) and Tripotassium phosphate (1g is in container 5mmol).(167mg 1mmol), stirred reaction mixture 18 hours in backflow to add the 2-bromoethyl acetate then.Add entry, mixture extracts with ethyl acetate (3x).The organic layer that merges filters, and absorbs on the silica gel through dried over sodium sulfate.Purifying on silica gel, the gradient liquid of ethyl acetate in hexane of use 0-80% obtains the 105mg product, is yellow oil. 1H NMR 500MHz(DMSO)δ1.19(t，3H)，2.65(s，3H)，3.85(s，2H)，4.10(q，2H)，7.40(d，1H)，7.61(dd，1H)，7.78(d，1H)，7.86(d，1H)，8.20(d，1H)；MS(m/z)230[M+H +] +。
Step 2:(2-methyl-quinoline-6-yl)-acetate
[0415] to (2-methyl-quinoline-6-yl)-acetate ethyl ester (100mg, add in methyl alcohol 0.436mmol) (2mL) solution 4M lithium hydroxide aqueous solution (0.55mL, 2.18mmol).Reaction mixture was stirred under room temperature 14 hours, then vacuum concentration it, dilute with water, and to handle until pH with the 1N aqueous hydrochloric acid be 5.Filter through dried over sodium sulfate with ethyl acetate extraction (3x), the organic layer of merging in the waterbearing stratum, and vacuum concentration, and 19mg is provided product, is the oldlace solid. 1H NMR 500MHz(DMSO)δ2.65(s，3H)，3.76(s，2H)，7.40(d，1H)，7.60(dd，1H)，7.77(d，1H)，7.86(d，1H)，8.20(d，1H)；MS(m/z)202[M+H +] +。
Intermediate 2:3-quinoline-6-base-propionic acid
Figure A20078003852702021
Step 1:3-quinoline-6-base-vinylformic acid ethyl ester
[0416] under nitrogen atmosphere, and the 6-bromo-quinoline of in vial, packing into (1g, 4.8mmol) and dimethyl formamide (15mL), then add ethyl propenoate (2.1mL, 19.2mmol), triethylamine (6.7mL, 48mmol) and acid chloride (II) (32mg, 0.142mmol).This reaction mixture was stirred 5 hours in 100 ℃, then through the mixture and the vacuum concentrated filtrate of diatomite filtration heat.Residue is allocated between water and the ethyl acetate.Organic layer washs with saturated aqueous ammonium chloride solution, saturated sodium bicarbonate aqueous solution, uses the salt water washing then.Then organic layer is absorbed on the silica gel.Purifying on silica gel, the gradient liquid of ethyl acetate in hexane of use 10-80% obtains the 952mg product, is yellow oil. 1H NMR 500MHz(DMSO)δ1.28(t，3H)，4.20(q，2H)，6.82(d，1H)，7.58(d，1H)，7.84(d，1H)，8.01(d，1H)，8.16(dd，1H)，8.30(d，1H)，8.37(dd，1H)，8.93(dd，1H)；MS(m/z)228[M+H +] +。
Step 2:3-quinoline-6-base-propionic acid ethyl ester
[0417] with 3-quinoline-6-base-vinylformic acid ethyl ester (200mg, 0.881mmol) and 10%wtPd/C (93mg, 0.088mmol) mixture in methyl alcohol (3mL) stirred 3 hours under room temperature, nitrogen atmosphere.By this mixture of diatomite filtration filtrate is absorbed on the silica gel.Purifying on silica gel, the gradient liquid of ethyl acetate in hexane of use 0-65% obtains the 100mg product, is clarification oily matter. 1H NMR 500MHz(DMSO)δ1.13(t，3H)，2.74(t，2H)，3.05(t，2H)，4.04(q，2H)，7.50(dd，1H)，7.67(dd，1H)，7.78(d，1H)，7.94(d，1H)，8.29(dd，1H)，8.84(dd，1H)；MS(m/z)230[M+H +] +。
Step 3:3-quinoline-6-base-propionic acid
[0418] to 3-quinoline-6-base-propionic acid ethyl ester (100mg, 0.437mmol) in the solution of methyl alcohol (2mL), add the 4M lithium hydroxide aqueous solution (0.55mL, 2.18mmol).Reaction mixture was stirred under room temperature 3 hours, then vacuum concentration it, dilute with water, and to handle until pH with the 1N aqueous hydrochloric acid be 5.Filter through dried over sodium sulfate with ethyl acetate extraction (3x), the organic layer of merging in the waterbearing stratum, and vacuum concentration, and 18mg is provided product, is white solid. 1H NMR 500MHz(DMSO)δ2.67(t，2H)，3.02(t，2H)，7.50(dd，1H)，7.67(dd，1H)，7.78(d，1H)，7.94(d，1H)，8.29(dd，1H)，8.84(dd，1H)；MS(m/z)202[M+H +] +。
Intermediate 3: trans 2-quinoline-6-base-cyclopropane-carboxylic acid
Figure A20078003852702031
Step 1: trans 2-quinoline-6-base-cyclopropane-carboxylic acid ethyl ester
[0419] under nitrogen atmosphere, to sodium hydride (71mg, 1.76mmol) add in the suspension in DMSO (3mL) trimethylammonium sulfoxonium muriate (261mg, 2.03mmol).After stirring 30 minutes under the room temperature, be added dropwise to 3-quinoline-6-base-vinylformic acid ethyl ester (200mg, DMSO 0.881mmol) (2mL) solution.Reaction mixture is stirred 2.5 hours also with saturated aqueous ammonium chloride solution quencher under room temperature.Mixture is with ethyl acetate extraction (2x), and the organic layer of merging is with salt water washing (3x) and be absorbed on the silica gel.Purifying on silica gel, the gradient liquid of ethyl acetate in hexane of use 0-80% obtains the 126mg product, is white solid. 1H NMR 500MHz(DMSO)δ1.22(t，3H)，1.55(m，2H)，2.10(m，1H)，2.64(m，1H)，4.13(q，2H)，7.50(dd，1H)，7.58(dd，1H)，7.80(d，1H)，7.93(d，1H)，8.26(dd，1H)，8.84(dd，1H)；MS(m/z)242[M+H +] +。
Step 2: trans 2-quinoline-6-base-cyclopropane-carboxylic acid
[0420] to trans 2-quinoline-6-base-cyclopropane-carboxylic acid ethyl ester (125mg, add in methyl alcohol 0.523mmol) (2mL) solution 4M lithium hydroxide aqueous solution (0.65mL, 2.62mmol).With reaction mixture in stirring at room 3 hours, then vacuum concentration it, dilute with water, and to handle until pH with the 1N aqueous hydrochloric acid be 4-5.Filter the throw out that produces, wash with water and vacuum-drying, 102mg is provided product, be white solid. 1H NMR 500MHz(DMSO)δ1.50(m，2H)，1.96(m，1H)，2.60(m，1H)，7.50(dd，1H)，7.57(dd，1H)，7.78(d，1H)，7.93(d，1H)，8.26(dd，1H)，8.83(dd，1H)；MS(m/z)214[M+H +] +。
Intermediate 4: quinoxalin-6-yl-acetate
Figure A20078003852702041
Step 1: quinoxalin-6-yl-acetate ethyl ester
[0421] under nitrogen atmosphere, in vial, pack into benzopyrazines-6-borate hydrochlorate (500mg, 2.38mmol), acid chloride (II) (16mg, 0.071mmol), three-1-naphthyl phosphine (88mg, 0.214mmol), Tripotassium phosphate (2.52g, 11.9mmol) and tetrahydrofuran (THF) (10mL).(0.315mL 2.85mmol) and with reaction mixture stirred in backflow 6 hours to add the 2-bromoethyl acetate then.Add entry, mixture is with ethyl acetate extraction (3x). and the organic layer of merging is absorbed on the silica gel.Purifying on silica gel, the gradient liquid of ethyl acetate in hexane of use 0-100% obtains the 96mg product, is deep yellow oily thing. 1H NMR 500MHz(DMSO)δ1.20(t，3H)，3.99(s，2H)，4.11(q，2H)，7.79(dd，1H)，8.01(d，1H)，8.06(d，1H)，8.94(d，2H)；MS(m/z)217[M+H +] +。
Step 2: quinoxalin-6-yl-acetate
[0422] to quinoxalin-6-yl-acetate ethyl ester (95mg, add in methyl alcohol 0.44mmol) (2mL) solution 4M lithium hydroxide aqueous solution (0.55mL, 2.2mmol).Reaction mixture was stirred under room temperature 17 hours, then vacuum concentration it, dilute with water and with ether extraction (3x).Handle until pH with the 1N aqueous hydrochloric acid in the waterbearing stratum is 2, with ethyl acetate extraction (3x).The organic layer that merges filters through dried over sodium sulfate, and vacuum concentration, and 64mg is provided product, is beige solid. 1H NMR 500MHz(DMSO)δ3.90(s，2H)，7.78(dd，1H)，7.99(d，1H)，8.06(d，1H)，8.93(dd，2H)；MS(m/z)189[M+H +] +。
Intermediate 5: benzothiazole-6-base-acetate
Figure A20078003852702051
Step 1:(2-amino-benzothiazole-6-yl)-acetate
[0423] make (4-amino-phenyl)-acetate (20g, 132.5mmol) and NH 4(20g 263.2mmol) is dissolved in 300ml acetate and make this mixture be cooled to 15 ℃ to SCN, uses Br 2(21.2g 6.8ml) handles in acetate (10ml) and makes temperature be no more than 15 ℃, stirs this reactant 4 hours then under room temperature.Filter this mixture and make filter cake soluble in water again, regulate pH=5.Filtering precipitate and drying obtain 2-amino-benzothiazole-6-yl)-acetate, be pale yellow powder (24g, 87.1%).
Step 2: benzothiazole-6-base-acetate
[0424] make 2-amino-benzothiazole-6-yl)-(20g 96.2mmol) is dissolved in 1 to acetate, 4-dioxane (750mL).Under room temperature, be added dropwise to Isopentyl nitrite (22.4g, 192.4mmol).Under nitrogen atmosphere, this mixture backflow was stirred 2 hours down.After reaction is finished, solvent removed in vacuo, residue need not be further purified and be used for next step.
Intermediate 5 and intermediate 6: benzothiazole-6-base-acetate and (2-chloro-benzothiazole-6-yl)-acetate
Figure A20078003852702061
[0425] under nitrogen atmosphere, to (2-amino-benzothiazole-6-yl)-acetate dihydrochloride (150mg, be added dropwise in dimethyl formamide 0.533mmol) (3mL) solution nitrous acid tertiary butyl ester (0.076mL, 0.64mmol).In 50 ℃ of stirrings 1.5 hours, it is concentrated also vacuum-drying was (2: 3) mixture of benzothiazole-6-base-acetate and (2-chloro-benzothiazole-6-yl)-acetate with this reaction mixture.This mixture can be used for coupling/cyclisation step as former state described in the method Y.
Intermediate 7:4-(6-phenyl-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-benzene-1, the 2-diamines
Figure A20078003852702062
Step 1:4-amino-phenylacetic acid methyl ester
[0426] (5g 33mmol) is added dropwise to the vitriol oil (2mL) in the suspension in methyl alcohol (20mL) to 4-amino-phenylacetic acid.Reaction mixture was stirred in backflow 1.5 hours, then vacuum concentration.Residue is allocated between 1M wet chemical and the ether.Organic layer 1M wet chemical, water washing is then through dried over sodium sulfate and filtration.Concentrated filtrate and vacuum-drying obtain the 4.65g product, are deep yellow oily thing. 1H NMR 500MHz(DMSO)δ3.43(s，2H)，3.57(s，3H)，4.97(s，2H)，6.49(d，2H)，6.88(d，2H)；MS(m/z)166[M+H +] +。
Step 2:(4-acetylamino-3-nitro-phenyl)-the acetate methyl ester
[0427] (3g, acetic anhydride 18.2mmol) (16mL) solution stirred under room temperature 30 minutes with 4-amino-phenylacetic acid methyl ester.This reaction mixture is cooled to 0 ℃ of temperature and is added dropwise to nitrosonitric acid (2.3mL).Remove cryostat and reaction mixture was stirred other 20 minutes, then in the impouring frozen water.The yellow mercury oxide that filter to produce washes with water and in 50 ℃ of vacuum-dryings, obtains the 3.7g product. 1H NMR 500MHz(DMSO)δ2.05(s，3H)，3.63(s，3H)，3.81(s，2H)，7.54(d，1H)，7.58(dd，1H)，7.87(d，1H)，10.2(s，1H)。
Step 3:(4-amino-3-nitro-phenyl)-acetic acid hydrochloride
[0428] with (4-acetylamino-3-nitro-phenyl)-acetate methyl ester (1.3g, 6N aqueous hydrochloric acid (10mL) solution 5.15mmol) stirred in backflow 1.5 hours, vacuum concentration is to doing then.Grind residue with ether, filter, obtain the 978mg product, be dark orange/yellow solid with ether washing and vacuum-drying. 1H NMR 500MHz(DMSO)δ3.49(s，2H)，6.98(d，1H)，7.30(dd，1H)，7.86(d，1H)；MS(m/z)197[M+H +] +。
Step 4:2-nitro-4-(6-phenyl-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-phenyl amine
[0429] can prepare title compound according to the program of describing among the method D, be yellow solid (91mg, 0.263mmol, 23% yield). 1HNMR(DMSO)δ4.50(s，2H)，6.97(d，1H)，7.43(s，2H)，7.45(dd，1H)，7.60(m，3H)，7.95(d，1H)，8.14(m，3H)，8.42(d，1H)；MS(m/z)347(M+H)。
Step 5:4-(6-phenyl-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-benzene-1, the 2-diamines
[0430] with 2-nitro-4-(6-phenyl-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-phenyl amine (89mg, 0.257mmol) and 10%wt Pd/C (27mg, 0.026mmol) mixture in methyl alcohol (4mL), tetrahydrofuran (THF) (2mL) and dimethyl formamide (2mL) stirred 4 hours under room temperature, nitrogen atmosphere.By the diatomite filtration catalyzer, concentrated filtrate and vacuum-drying provide 81m product, are beige solid. 1HNMR(DMSO)δ4.30(s，2H)，4.32(s，2H)，4.43(s，2H)，6.43(m，2H)，6.50(s，1H)，7.60(m，3H)，7.93(d，1H)，8.11(m，2H)，8.39(d，1H)；MS(m/z)317[M+H +] +。
Intermediate 8: quinoline-6-base-acetonitrile
Figure A20078003852702071
[0431] with the 6-toluquinoline (21.48g, 150mmol) and N-bromosuccinimide (27.6g is 155mmol) at CCl 4Suspension (430mL) is heated to backflow.In case obtain to reflux, and disposable adding benzoyl peroxide (1.4g, 5.1mmol).This mixture was stirred in backflow other 2 hours.After this moment, with making this mixture be cooled to room temperature in 3 hours and by removing by filter the precipitation of formation.With the 5%NaOH aqueous solution (2x150mL), water (200mL) wash filtrate, dry (Na 2SO 4) and through rapid column chromatography purifying (SiO 2, hexane/ethyl acetate 100: 0-35/65).The flow point that contains required bromo compound dilutes with dimethyl formamide (400mL), and this mixture of vacuum concentration is to remove hexane and ethyl acetate.In this mixture, add KHCO then 3(15g, 150mmol), then add sodium cyanide (7.34g, 150mmol).This mixture was stirred under room temperature 2 hours and stirred other 2 hours in 40 ℃.After this, this mixture of vacuum concentration is with residue impouring 5%KHCO 3Also use ethyl acetate extraction (3x200mL) in the aqueous solution (600mL).The organic extraction that merges salt water washing (100mL), dry (Na 2SO 4) and concentrate in the silica gel.Through rapid column chromatography purifying (SiO 2, hexane: ethyl acetate 80/20-30/70) reclaim title compound, be white solid (4.8g, 28.6mmol, 20% yield). 1H NMR 500MHz(DMSO-d6)；δ4.28(2H，s)，7.56(1H，dd)，7.11(1H，dd)，7.97(1H，d)，8.01(1H，d)，8.40(1H，dd)，8.92(1H，dd)；MS(m/z)169[M+H +] +。
Intermediate 9:2-methyl-2-quinoline-6-base-propionic salt hydrochlorate
Figure A20078003852702081
Step 1:2-methyl-2-quinoline-6-base-propionitrile
[0432] with quinoline-6-base-acetonitrile (intermediate 8) (200mg, tetrahydrofuran (THF) 1.2mmol) (12mL) solution is cooled to-78 ℃, to wherein adding methyl-iodide (2.5mmol, 157 μ l), then add potassium tert.-butoxide (2.5mmol, 280mg).Make this mixture be cooled to ambient temperature overnight.After this, this mixture of vacuum concentration and be dissolved in NaHCO 3The aqueous solution (30mL) extracts with methylene dichloride (3x30mL).Dry (Na 2SO 4) organic extraction that merges and concentrating in the silica gel.Through rapid column chromatography purifying (SiO 2, hexane: ethyl acetate 90/10-50/50) reclaim title compound, be clear colorless oil shape thing (214mg, 91% yield). 1H NMR 500MHz(DMSO-d6)δ1.80(6H，s)，7.58(1H，dd)，7.94(1H，dd)，8.08(1H，d)，8.11(1H，d)，8.45(1H，dd)，8.93(1H，dd)；MS(m/z)197[M+H +] +。
Step 2:2-methyl-2-quinoline-6-base-propionic salt hydrochlorate
[0433] to 2-methyl-2-quinoline-6-base-propionitrile (760mg, 3.88mmol) add in the mixture in water (3mL) concentrated hydrochloric acid (7mL) and in 160 ℃ of microwave ovens the heating 5 minutes.After this, this mixture of vacuum concentration, residue component distillation (3x5mL) from toluene reclaims title compound, is white solid (949mg, 3.77mmol, 97% yield). 1H NMR 500MHz(D 2O)δ1.54(6H，s)，7.89(1H，dd)，8.03-7.96(2H，m)，8.11(1H，d)，8.95-8.85(2H，m).
Intermediate 10:2-quinoline-6-base-propionic acid
Figure A20078003852702091
Step 1: quinoline-6-base-acetate methyl ester
[0434] (10g 53.0mmol) adds the dense H of 2.5ml in the stirred solution of 100ml methyl alcohol to quinoline-6-base-acetate 2SO 4, with this mixture heating up to refluxing 3 hours.Concentrated reaction mixture obtains brown residue, and it with the dilution of 100ml methylene dichloride, is used sat.aq.NaHCO 3With the salt water washing, organic layer is through anhydrous Na then 2SO 4Dry and the concentrated title compound that reclaims is brown oil (7.9g, 73.6%).
Step 2:2-quinoline-6-base-propionic acid methyl ester
[0435] under nitrogen atmosphere, (1.6M 50.9ml) joins diisopropylamine (5.32g, 52.6mmol) stirring 30 minutes at anhydrous tetrahydro furan (100ml) in-40 ℃ of refrigerative stirred solutions and with mixture with the hexane solution of n-Butyl Lithium.Make reaction mixture be cooled to-78 ℃, (7.9g is 39.3mmol) at 10ml tetrahydrofuran (THF) and HMPA (10.0g, 55.8mmol) solution in to add quinoline-6-base-acetate methyl ester in this solution.This mixture in-78 ℃ of stirrings 1 hour, was stirred 30 minutes in-30 ℃ then.In-78 ℃, add methyl-iodide (8.0g, 56.3mmol) solution in anhydrous tetrahydro furan and mixture stirred 1.5 hours in-78 ℃ to this reaction mixture.Make this reaction mixture slowly be warming up to room temperature and also use saturated NH 4The Cl aqueous solution (100ml) and water (80ml) dilution.Mixture extracts with t-butyl methyl ether, and the organic layer water of merging and salt water washing are through anhydrous sodium sulfate drying and the concentrated brown oil that obtains, it is through purification by silica gel column chromatography, with sherwood oil and ethyl acetate (20: 1) wash-out, obtain light yellow oil (7.7g, 91.1%). 1H NMR and LC-MS analyze and show that title compound is mixed with 10%2-methyl-2-quinoline-6-base-propionic acid methyl ester.
Step 3:2-quinoline-6-base-propionic acid
[0436] will contain 10%2-methyl-2-quinoline-6-base-propionic acid methyl ester (7.7g, 35.8mmol) and 2-quinoline-6-base-propionic acid methyl ester of 2N aq.NaOH (27ml) be heated to and refluxed 4 hours, until the reaction mixture clarification that becomes.After being cooled to room temperature, mixture is acidified to pH 4-5 with dichloromethane extraction and waterbearing stratum with concentrated hydrochloric acid.Adding ethyl acetate (30ml) also stirred 10 minutes, and the solid that removes by filter generation obtains product, and its recrystallization from methyl alcohol is reclaimed title compound (5.3g, 73.7%) twice: 1H NMR 300MHz (DMSO-d6) δ 12.43 (s, 1H), 8.86 (d, 1H), 8.33 (d, 1H), 7.99-7.86 (m, 2H), 7.72-7.49 (m, 2H), 3.92 (q, 1H), 1.48 (d, 3H) .ES MS m/z:200[M-H +], 400 (dimer).
Intermediate 11:(5,7-two fluoro-quinoline-6-yl)-acetate
Figure A20078003852702101
Step 1:6-bromo-5,7-two fluoro-quinoline
[0437] with 4-bromo-3, and 5-two fluoro-phenyl amine (6.0g, 28.8mmole), the mixture mild heat of ferrous sulfate (1.82g), glycerine (8.6mL), oil of mirbane (1.79mL) and the 5.0ml vitriol oil (5mL).Behind the vigorous reaction, this mixture heating up is extremely refluxed through 5 hours for the first time.Oil of mirbane is removed in vacuum distilling.Aqueous solution glacial acetic acid acidifying, and separate the dark-brown throw out, it through flash chromatography purifying (silica gel, petrol ether/ethyl acetate=12/1), is reclaimed title compound, be white solid (3.5g, 49.8%).
Step 2:2-(5,7-two fluoro-quinoline-6-yl)-diethyl malonate
[0438] in 60 ℃, ((60% in mineral oil, and 2.32g is 58.0mmol) 1, in the mixture in the 4-dioxane (29mL) 58.0mmol) to be added dropwise to sodium hydride for 9.28g, 8.8mL with malonic ester.Add then CuBr (4.176g, 29.0mmol) and 6-bromo-5,7-two fluoro-quinoline (7.07g, 29.0mmol) and with this mixture heating up to refluxing 16 hours.After this, at the ice-cooled concentrated hydrochloric acid that adds down, add t-butyl methyl ether and water then.Isolating organic layer washs in proper order with (10%) hydrochloric acid and water.Through dried over sodium sulfate and concentrated.Residue obtains title compound (3.13g, 35.4%) through column chromatography purification.
Step 3:(5,7-two fluoro-quinoline-6-yl)-acetate
[0439] 2-(5,7-two fluoro-quinoline-6-yl)-(2.48g adds the ethanol (77mL) and the 10%NaOH aqueous solution (103.2mL) to diethyl malonate in round-bottomed flask 7.68mmol) to containing.This solution was refluxed 3 hours.After this, decompression is removed ethanol and is formed yellow suspension and add tetrahydrofuran (THF) (50mL), obtains clear yellow solution, is placed in the ice bath and stirring.6N hydrochloric acid (50ml) is slowly joined in this solution to reach pH 1.Light orange solution was refluxed other one hour, and form two-layer this moment.Collect top tetrahydrofuran (THF) layer and use the dichloromethane extraction aqueous solution.Organic layer is with the salt water washing and through anhydrous sodium sulfate drying.Filter this solution then, concentrated filtrate obtains title compound (1.20g, 70.1%). 1H NMR(300MHz，DMSO-d6)δ12.82(s，1H)，8.98～9.00(m，1H)，8.47～8.50(d，1H)，7.61～7.74(m，2H)，3.86(s，2H)。ES-MS m/z：224.2(M ++1)。
Intermediate 12:(7-fluoro-quinoline-6-yl)-acetate
Step 1:6-bromo-7-fluoro-quinoline
[0440] with 4-bromo-3-fluoro-phenyl amine (2.85g, 15m mole), ferrous sulfate (0.95g), glycerine (5.658g, 4.5ml), oil of mirbane (1.125g, 0.93ml) and the mixture mild heat of the vitriol oil (2.61mL).Behind first time vigorous reaction, with this mixture heating up to refluxing 7 hours.Vacuum-evaporation oil of mirbane.Aqueous solution is with the glacial acetic acid acidifying and separate the dark-brown throw out, and it through flash chromatography purifying (silica gel, petrol ether/ethyl acetate=8/1), is reclaimed title compound, is white crystals (1.44g, 42.5%).
Step 2:(7-fluoro-quinoline-6-yl)-ra-butyl acetate
[0441] to 6-bromo-7-fluoro-quinoline (1.04g, 4.6mmole) tetrahydrofuran (THF) (1mL) solution in add tertiary butyl bromination zinc acetate (tert-butylzincbromide acetate) (20mL, 10.4M in tetrahydrofuran (THF)) solution, then add Pd (PPh 3) 4(0.58g, 0.5mmole).This mixture was heated 35 minutes in 120 ℃ in microwave reactor.Reaction mixture is with (60mL) quencher of saturated ammonium chloride and use ethyl acetate extraction.Organic layer is through anhydrous Na 2SO 4Drying is filtered and is concentrated.Residue obtains title compound (0.75g, 63%) through column chromatography purification.
Step 3:(7-fluoro-quinoline-6-yl)-acetate
[0442] mixture with (7-fluoro-quinoline-6-yl)-ra-butyl acetate (3.67g) and 4N aqueous sodium hydroxide solution (14.8mL) heated 3 hours in 90 ℃.This solution ethyl acetate extraction.The waterbearing stratum is adjusted to acid pH with acetate, filters and drying, obtains title compound (2.3g, 79.8%). 1H NMR(300MHz，DMSO-d6)δ12.52(1H，s)，8.88～8.90(d，1H)，8.34～8.38(d，1H)，7.97～7.99(d，1H)，7.73～7.76(d，1H)，7.50～7.54(m，1H)，3.85(s，2H)。ES-MS m/z：206.2(M+1)。
Intermediate 13:(7-methyl-quinoline-6-yl)-acetate
Figure A20078003852702121
Step 1:6-bromo-7-methyl-quinoline
[0443] with 4-bromo-3-methyl-phenyl amine, 6.6g ferrous sulfate, the 40.8g propane-1,2 of 20g, the mixture mild heat of 3-triol, 8.12g oil of mirbane and the 23ml vitriol oil.Behind first time vigorous reaction, this mixture heating up to the 3h that refluxes, is evaporated then to remove excessive oil of mirbane.In this solution, add saturated NaHCO 3So that pH is 8, filters this solution and use dichloromethane extraction.The combined dichloromethane layer is through Na 2SO 4Dry and concentrated.Solid obtains yellow solid through the rapid column chromatography purifying, and it is used petroleum ether, reclaims title compound (7.5g, 65%). 1H NMR(CDCl 3，300MHz)δ8.89(m，1H)，8.04(m，2H)，7.96(s，1H)，7.36(m，1H)，2.60(s，3H)。
Step 2:(7-methyl-quinoline-6-yl)-ra-butyl acetate
[0444] Pd (PPh of adding 20ml tertiary butyl bromination zinc acetate and 0.58g in the 6-of 1.02g bromo-7-methyl-quinoline 3) 4Solution.This mixture was placed microwave reactor 30 minutes, to reach 120 ℃ temperature (repeating 3 times).Reclaim title compound (3.2g, 68%) through the rapid column chromatography purifying. 1H NMR(CDCl 3，300MHz)δ8.84(m，1H)，8.07(m，1H)，7.89(s，1H)，7.63(s，1H)，7.31(m，1H)，3.72(s，2H)，2.51(s，3H)，1.46(s，9H)。
Step 3:(7-methyl-quinoline-6-yl)-acetate
[0445] aqueous solution (4N) of (7-methyl-quinoline-6-yl)-ra-butyl acetate in 25ml NaOH with 3.2g is heated to backflow 4 hours.With this mixture with ethyl acetate washing and add concentrated hydrochloric acid so that pH is 7.Form white solid, it is also dry after filtration, reclaims title compound (1.5g, 71.1%). 1H NMR(DMSO-d6，300MHz)δ12.46(s，1H)，8.82(m，1H)，8.26(m，1H)，7.82(s，1H)，7.77(s，1H)，7.44(m，1H)，3.80(s，2H)，2.44(s，3H)ES-MS m/z：202(M ++H)。
Intermediate 14: fluoro-quinoline-6-base-acetic acid hydrochloride
Figure A20078003852702131
Step 1: fluoro-quinoline-6-base-acetonitrile
[0446] with quinoline-6-base-acetonitrile (1.06g, tetrahydrofuran (THF) 6.3mmol) (40mL) solution is cooled to-78 ℃, with 10 fens clockwise wherein with the mode that drips add tert-butyl lithium (0.8M in pentane, 7.6mmol, 7.9mL).After adding is finished, this mixture in-78 ℃ of stirrings 30 minutes, is added N-fluoro two (benzenesulfonyl)-amine (1.5eq., 9.45mmol, tetrahydrofuran (THF) 3.0g) (10mL) solution then.In-78 ℃ reaction mixture was stirred 2 hours, add entry then, then add NaHCO 3The aqueous solution.Mixture dichloromethane extraction (3x80mL), dry (Na 2SO 4) and on silica gel vacuum concentration, through rapid column chromatography purifying (SiO 2, hexane: ethyl acetate 100/0-50/50) reclaim title compound, be red solid (520mg, 2.8mmol, 44%). 1H NMR 500MHz(DMSO-d6)δ6.05(1H，d)，7.66(1H，dd)，7.95(1H，dd)，8.19(1H，d)，8.32(IH，t)，8.55(1H，d)，9.03(1H，dd)；MS(m/z)187[M+H +] +。
Step 2: fluoro-quinoline-6-base-acetic acid hydrochloride
[0447] make fluoro-quinoline-6-base-acetonitrile (370mg, 2.0mmol) be dissolved in concentrated hydrochloric acid (4mL) and in 145 ℃ of microwave ovens the heating 8 minutes.After this, this mixture of vacuum concentration reclaims title compound with quantitative yield, is white solid. 1H NMR 500MHz(D 2O)δ6.05(1H，d)，7.99-6.93(1H，m)，8.14-8.05(2H，m)，8.26(1H，s)，9.05-8.95(2H，m)。MS(m/z)204[M-H +]″.
Intermediate 15:[6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-pyridazine-3-yl]-hydrazine
Figure A20078003852702141
Step 1 method 1.1:3-chloro-6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-pyridazine
[0448] under nitrogen, with 3,6-dichloro-pyridazine (5.37g, 33.5mmol), 1-methyl-4-pyrazoles boric acid pinacol ester (5g, 24.0mmol) and cesium carbonate (23.44g, 72mmol) 1, the mixture in 4-dioxane (150mL) and the water (750mL) feeds the nitrogen degassing 15 minutes by bubbling.(1g, 1.37mmol), bubbling fed nitrogen other 10 minutes in this mixture to add dichloro [1,1 '-two (diphenylphosphino) ferrocene] palladium (II) methylene dichloride adducts then.This reaction mixture in 80 ℃ of stirrings 2.5 hours, is cooled to room temperature and vacuum concentration then.Residue is allocated between 1N wet chemical and the ethyl acetate.Organic layer is with 1N wet chemical and salt water washing, and through dried over sodium sulfate, filtration also absorbs so that purifying on silica gel.Through the flash chromatography on silica gel purifying, use the gradient liquid of 0-50% ethyl acetate/hexane, obtain the 2.8g title compound, be white solid (60% yield); MS (m/z) 195[M+H +] +
Step 1 method 1.2:3-chloro-6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-pyridazine
[0449] under nitrogen, with 3,6-dichloro-pyridazine (20.1g, 135mmol), 1-methyl-4-pyrazoles boric acid pinacol ester (25.46g, 122mmol) and salt of wormwood (50.7g, 367mmol) 1, the mixture in 4-dioxane (500mL) and the water (200mL) feeds the nitrogen degassing 15 minutes by bubbling.Add then dichloro two (triphenyl phosphine) palladium (II) (1.2%, 1g, 1.4mmol), bubbling fed nitrogen other 10 minutes in this mixture.This reaction mixture in 90 ℃ of stirrings 3 hours, is cooled to room temperature and vacuum concentration then, to remove major part 1,4-dioxane.Make residue be allocated between 1N wet chemical (400mL) and the ethyl acetate (400mL) and separate each phase.Extract with ethyl acetate (2x300mL) and methylene dichloride (300mL) in the waterbearing stratum.The organic layer salt water washing that merges through dried over sodium sulfate, is filtered and vacuum concentration.Residue is stirred in ether (150mL), filter orange throw out and dried recovered title compound (12.76g, 65.6mmol, 54% yield).Concentrated filtrate and through the flash chromatography on silica gel purifying on silica gel uses the elutriant of 0-50% ethyl acetate/hexane, reclaims starting raw material 3, and the 6-dichloro-pyridazine is white solid (9.9g, 66.4mmol, 49% yield).
Step 2:[6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-pyridazine-3-yl]-hydrazine
[0450] to 3-chloro-6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-pyridazine (1.0g, 4.81mmol) in ethanol, add in the suspension of (20mL) the hydrazine monohydrate (2.33mL, 48mmol).This reaction mixture in 80 ℃ of stirring 3.5h, is cooled to room temperature and vacuum concentration.Residue grinds with the 1N wet chemical, filters, and washes with water and vacuum-drying, and 2g is provided title compound, is beige solid (670mg, 73% yield): 1H NMR (DMSO-d6) δ 3.92 (s, 3H), 4.28 (s, 1H) 7.02 (d, 1H), 7.59 (d, 1H), 7.84 (s, 1H), 7.90 (s, 1H), 8.19 (d, 1H); MS (m/z) 191[M+H +] +
Intermediate 16:2-benzothiazole-6-base-propionic acid
Figure A20078003852702151
Step 1: benzothiazole-6-base-acetate methyl ester
[0451] in 0 ℃, N 2Down, with SOCl 2(13.5g, (20.0g is 103.6mmol) in the stirred solution in 150ml methyl alcohol 114.0mmol) to be added dropwise to benzothiazole-6-base-acetate.After stirring 2 hours under the room temperature, evaporating solvent, residue grinds with ethyl acetate (150ml).Mixture washs with saturated sodium carbonate solution (100mlx3) and salt solution (100ml), then vacuum concentration.Residue with ethyl acetate/petroleum ether (1: 5) wash-out, reclaims title compound through column chromatography purification, is light yellow oil (15.0g, 71.5%).
Step 2:2-benzothiazole-6-base-propionic acid methyl ester
[0452] under nitrogen atmosphere, (2.5M in hexane, 27.0ml) solution joins diisopropylamine (7.08g, being cooled in-30 ℃ the stirred solution of anhydrous tetrahydro furan 70.0mmol) (150ml) with n-BuLi.This mixture was stirred 30 minutes, make this reaction mixture be cooled to-78 ℃.(10.4g is 50.0mmol) at 10ml tetrahydrofuran (THF) and hexamethylphosphoramide (13.5g, 75.0mmol) solution in to add benzothiazole-6-base-acetate methyl ester in this solution.This mixture in-78 ℃ of stirrings 2 hours, is added methyl-iodide (10.2g, anhydrous tetrahydrofuran solutions 72.0mmol) in-78 ℃ then.In-78 ℃ this mixture was stirred other 2 hours.Make reaction mixture slowly be warming up to room temperature also with saturated NH 4The Cl aqueous solution (200ml) dilution.Mixture is with the organic layer water and the salt water washing of ethyl acetate extraction (x2) and merging, through anhydrous sodium sulfate drying and the concentrated brown oil that obtains.This oily matter with sherwood oil and ethyl acetate (10: 1) wash-out, reclaims title compound through the rapid column chromatography purifying, is light yellow oil (4.5g, 40.5%).
Step 5:2-benzothiazole-6-base-propionic acid
[0453] (6.6g, 30.0mmol) mixture with the 2N NaOH aqueous solution (23.0ml) heated 1 hour under refluxing, and became dark red solution until reaction mixture with 2-[4-morpholinodithio-6-base-propionic acid methyl ester.Make mixture be cooled to room temperature then, mixture is acidified to pH4-5 with dichloromethane extraction (x2) and waterbearing stratum with concentrated hydrochloric acid.Remove by filter the solid of generation, obtain crude product,, it to be stirred in ethyl acetate, filtration and vacuum-drying provide title compound (4.3g, 69.2%), are pale solid.(300MHz，DMSO-d6)：δ12.41(s，1H)，9.35(s，1H)，8.09～8.08(d，J＝1.5Hz，2H)，8.05～8.02(d，J＝8.7Hz 2H)，7.48～7.45(dd，J＝I.5Hz，8.7Hz，1H)，3.89(q，1H)，1.45(d，3H)。MS m/z 208(M ++1)。
Intermediate 17:(8-methyl-quinoline-6-yl)-acetate
Figure A20078003852702161
Step 1:6-bromo-8-methyl-quinoline
[0454] with the mixture mild heat of 4-bromo-2-aminotoluene, 3.3g ferrous sulfate, 20.4g glycerine, 4.06g oil of mirbane and the 11.5ml vitriol oil of 10g.Behind first time vigorous reaction,, evaporate then to remove t oil of mirbane with the boiling 3 hours under refluxing of this mixture.This solution is added std.aq.NaHCO 3In and use dichloromethane extraction, through Na 2SO 4Dry and concentrated, obtain solid.This solid reclaims title compound (9.5g, 80%) through the rapid column chromatography purifying. 1H NMR(CDCl 3，300MHz)δ8.92(m，1H)，8.01(m，1H)，7.81(d，1H)，7.66(m，1H)，7.43(m，1H)，2.79(s，3H)。
Step 2:(8-methyl-quinoline-6-yl)-ra-butyl acetate
[0455] at N 2In 20ml tetrahydrofuran (THF) and 0.5ml (3.9mmol) chloro trimethyl silane, add (5.2g, 80mmol) zinc powder down.This mixture was stirred under room temperature 20 minutes.Be added dropwise to (5.9ml, 40mmol) the 50ml tetrahydrofuran solution of 2-tert-butylbromo acetate.This mixture was stirred 20 minutes in 42 ℃-45 ℃.Make it be cooled to 25 ℃, obtain the 0.52M solution of 76ml tertiary butyl reformatsky reagent.In the 6-of 1.039g bromo-8-methyl-quinoline, add the solution of the 20ml Reformatsky reagent of previous preparation, then add 0.541gPd (PPh 3) 4This mixture was placed microwave reactor 30 minutes, to reach 120 ℃ temperature.Repeat above step more other 4 times.With the reaction mixture merging of merging and through column chromatography purification, reclaim title compound (3.5g, 49%). 1H NMR(CDCl 3，300MHz)δ8.92(m，1H)，8.11(m，1H)，7.54(s，1H)，7.50(s，1H)，7.40(s，1H)，3.67(s，2H)，2.81(s，3H)，1.46(s，9H)。
Step 3:(8-methyl-quinoline-6-yl)-acetate
[0456] (4N is heated in aq.) and refluxed 3 hours at 18ml NaOH with 3.5g (8-methyl-quinoline-6-yl)-ra-butyl acetate.Mixture with ethyl acetate washing and water layer with the 1N hcl acidifying to pH 4-5 and use dichloromethane extraction.Evaporating solvent, the solid that obtains wash with water and vacuum-drying, reclaim title compound, are pale solid (1.3g, 48%). 1H NMR(DMSO-d6，300MHz)δ12.42(s，1H)，8.90(m，1H)，8.30(m，1H)，7.66(s，1H)，7.54(m，2H)，3.74(s，2H)，2.70(s，3H)。
Intermediate 18:(8-fluoro-quinoline-6-yl)-acetate
Step 1:6-bromo-8-fluoro-quinoline
[0457] with 4-bromo-2-fluoro aniline (12.825g, 67.5mmol), the mixture mild heat of 4.275g ferrous sulfate, 25.46g (20.2ml) glycerine, 5.067g (4.2ml) oil of mirbane and the 11.79ml vitriol oil.Behind first time vigorous reaction, with this mixture boiling 7 hours.Oil of mirbane is removed through vacuum.Add entry.Aqueous solution glacial acetic acid acidifying separates the dark-brown throw out, and it through flash chromatography purifying (silica gel, petrol ether/ethyl acetate=12/1), is reclaimed title compound, is solid (9.72g, 63.7%).
Step 2:(8-fluoro-quinoline-6-yl)-ra-butyl acetate
[0458] at N 2In 20ml tetrahydrofuran (THF) and 0.5ml (3.9mmol) chloro trimethyl silane, join 5.2g (80m mole) zinc powder down.This mixture was stirred under room temperature 20 minutes.Be added dropwise to the solution of 5.9ml (40mmol) 2-tert-butylbromo acetate in the 50ml tetrahydrofuran (THF).This mixture was stirred 20 minutes in 42 ℃-45 ℃.Make it be cooled to 25 ℃, obtain the solution of 76ml 0.52M tertiary butyl reformatsky reagent.(1.04g, (20ml, solution 10.4mmol) then add Pd (PPh to add above zincon in 1ml tetrahydrofuran solution 4.6mmol) to 6-bromo-8-fluoro-quinoline 3) 4(0.58g, 0.5m mole).This mixture was placed microwave reactor 35 minutes, to reach 120 ℃ temperature.Then, use sat.aq.NH 4Cl (60ml) quencher reaction, the mixture ethyl acetate extraction.Organic layer is through anhydrous Na 2SO 4Drying is filtered and is concentrated.Residue obtains title compound (0.78g, 65%) through column chromatography purification.
Step 3:(8-fluoro-quinoline-6-yl)-acetate
[0459] 0.5g (8-fluoro-quinoline-6-yl)-ra-butyl acetate and 2.0ml 4N aqueous sodium hydroxide solution were heated 3 hours in 90 ℃.After the cooling, the reaction mixture ethyl acetate extraction.Make the waterbearing stratum slightly be acid with acetate, filter, obtain title compound, be pale solid (0.24g, 61%). 1H NMR(300MHz，DMSO-d6)δ8.91～8.93(m，1H)，8.37-8.40(m，1H)，7.51～7.69(m，3H)，3.80(s，2H)；ES-MS m/z：206.2(M ++1)。
Intermediate 19:(3-bromo-quinoline-6-yl)-the acetate methyl ester
Figure A20078003852702181
[0460] to quinoline-6-base-acetate (step 1, intermediate 11) (21.6g, 107mmol) in the stirred solution of 150ml tetracol phenixin, add bromine (34.4g, 215mmol) and be heated to and refluxed 4 hours.Then with reaction mixture with the dilution of 17.0g pyridine, and under refluxing other 2 hours of restir.After being cooled to room temperature, this mixture is allocated between methylene dichloride and the saturated sodium bicarbonate aqueous solution.Organic layer washes with water, uses the salt water washing then, and through dried over mgso, reduction vaporization obtains brown residue then.Residue is through column chromatography purification, uses sherwood oil (60～90 ℃), uses 30/1 mixed solvent of sherwood oil and ethyl acetate then, obtains title compound (13.6g, 45.3%), is white crystalline solid.(300MHz，DMSO-d6)：8.89(d，1H)，8.27(d，1H)，8.06(d，1H)，7.67～7.64(m，2H)，3.82(s，2H)，3.72(s，3H)。ES-MS m/z：280(M+H +).360(M+H +).
Intermediate 20:(3-bromo-quinoline-6-yl)-acetate
Figure A20078003852702191
[0461] with (3-bromo-quinoline-6-yl)-acetate methyl ester (14.8g, 52.8mmol) and the 2N NaOH aqueous solution (80ml, mixture 160mmol) heating 1.5 hours under refluxing is until the reaction mixture clarification that becomes.After being cooled to room temperature, the reaction mixture washed with dichloromethane, water layer is acidified to pH 4 with concentrated hydrochloric acid then.Remove by filter the white depositions that stirs in the methyl alcohol that refluxes, filtration and vacuum-drying obtain the product title compound, are white solid (10.3g, 73.5%).(300MHz，DMSO-d6)：12.52(b，1H)，8.91(d，1H)，8.69(d，1H)，7.99(d，1H))，7.82～7.70(m，2H)，3.80(s，2H)。ES-MS m/z：266(M+H +)。Intermediate 21:1-ethyl-4-(4,4,5, assorted penta ring (the dioxaborolan)-2-yl of 5-tetramethyl--[1,3,2] two oxa-boron)-1H-pyrazoles
Figure A20078003852702192
[0462] according at heterocyclic chemistry magazine (Journal of Heterocyclic Chemistry), (2004), 41 (6), the method preparation of describing among the 931-939.
Intermediate 22:(1H-pyrrolo-[2,3-b] pyridin-3-yl)-acetate
Figure A20078003852702193
[0463] basis is in Journal of the American Chemical Society (Journal of the American ChemicalSociety) (1956), and the method for describing among 78 1247-51 prepares.
Intermediate 23:(6-methyl-pyridazine-3-yl)-hydrazine
[0464] according in Australian The Chemicals (Australian Journal of Chemistry) (1977), 30 (10), the method preparation of describing among the 2319-22.
Intermediate 24:3-(6-diazanyl-pyridazine-3-yl)-benzonitrile
Figure A20078003852702202
Step 1:3-(6-chloro-pyridazine-3-yl)-benzonitrile
[0465] nitrogen bubble is fed 3-cyano-phenyl boric acid (90.0g, 612mmol), 3,6-dichloro-pyridazine (1.2eq, 109.4g, 735mmol), salt of wormwood (3.0eq, 253.5g, 1.836mol) 1, in the mixture in 4-dioxane (900mL) and the water (360mL) 15 minutes.After this, and adding dichloro [1,1 '-two (diphenylphosphino) ferrocene] palladium (II) methylene dichloride adducts (0.06eq, 26.8g, 36.7mmol).Fed nitrogen other 10 minutes at bubbling, then with this mixture heating up to 90 ℃ through 3 hours.Cooling reactant and vacuum are removed major part 1,4-dioxane.Make this mixture be dissolved in methylene dichloride and wash with water 3 times.Concentrate organic layer, residue reclaims title compound (60g, 45.5% yield) through column chromatography purification, is white solid. 1H NMR(300MHz，DMSO-d6)：δ8.58～8.59(m，1H)，8.44-8.52(m，2H)，8.09-8.12(d，1H)，8.02～8.05(d，1H)，7.76～7.81(m，1H)；MS(m/z)216.1(M ++1)。
Step 2:3-(6-diazanyl-pyridazine-3-yl)-benzonitrile
[0466] (75.6g, 900mL anhydrous pyridine solution 350mmol) cool off in ice bath and add the 119.2mL hydrazine hydrate with 3-(6-chloro-pyridazine-3-yl)-benzonitrile.Continue cooling and be lower than 30 ℃, at this moment the separating yellow spicule with holding temperature.Then ℃ stirring of this mixture heating up to 65 is spent the night, concentrate this mixture then, residue water and methanol wash reclaim title compound (60g, 81%), are yellow solid. 1H NMR(300MHz，DMSO-d6)：δ8.38-8.39(m，1H)，8.32～8.35(m，1H)，8.24(s，1H)，7.97～8.00(d，1H)，7.82～7.85(m，1H)，7.64～7.69(m，1H)，7.09～7.12(d，1H)，4.39(s，2H)；MS(m/z)212.1[M ++1]。
Intermediate 25:1-{2-[4-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron mix penta ring-2-yl)-pyrazol-1-yl]-ethyl }-piperidines
[0467] in 5ml microwave bottle, adds the 2ml dimethyl formamide with the 4-of dissolving 150mgs (0.773mmols) (4,4,5,5-tetramethyl--[1,2,3] two oxa-boron mix penta ring-2-yl)-1H-pyrazoles.After adding 1-(2-chloro-ethyl)-piperidines of 2eq. (1.546mmols), with this reaction mixture in microwave oven in 190 ℃ of heating (Personel Chemistry, Emrys Optimizer) a hour.Then water (5mL) is joined in the reaction mixture, with ethyl acetate extraction (2x3mL).Merge organic layer and through dried over sodium sulfate.Solvent removed in vacuo reclaims title compound, and it need not be further purified and be used for next step.
Intermediate 26:2-fluoro-4-(6-diazanyl-pyridazine-3-yl)-N-methyl-benzamide
Figure A20078003852702212
Step 1:4-(6-chloro-pyridazine-3-yl)-2-fluoro-N-methyl-benzamide
[0468] nitrogen bubble is fed 4-boric acid-2-fluoro-N-methyl-benzamide (50g, 254mmol), 3,6-dichloro-pyridazine (1.02eq, 38.6g, 259mmol), salt of wormwood (3.0eq, 105.2g, 761mmol) 1, in the mixture in 4-dioxane (500mL) and the water (200mL) 15 minutes.After this, and adding dichloro [1,1 '-two (diphenylphosphino) ferrocene] palladium (II) methylene dichloride adducts (0.06eq, 15.0mmol, 11.0g).Bubbling fed nitrogen other 10 minutes again, then with this mixture heating up to 90 ℃ through 3 hours.Cooling and vacuum are removed most of dioxane.Make this mixture be dissolved in methylene dichloride and wash with water 3 times.Concentrate organic layer, residue reclaims title compound (27.1g, 40% yield) through column chromatography purification, is white solid. 1HNMR(300MHz，CDCl 3)：δ(ppm)：δ8.24～8.30(m，1H)，7.96-8.01(m，1H)，7.83～7.87(m，2H)，7.61～7.64(d，1H)，6.80～6.84(m，1H)3.06～3.08(m，3H)；MS(m/z)：266.1[M ++1]
Step 2:2-fluoro-4-(6-diazanyl-pyridazine-3-yl)-N-methyl-benzamide
[0469] 4-(6-chloro-pyridazine-3-the yl)-2-fluoro-N-methyl-solution of benzamide 34g (128mmol) in the 500mL anhydrous pyridine is cooled off in ice bath and add the 43.5mL hydrazine hydrate.Continue cooling and be lower than 30 ℃, at this moment the separating yellow spicule with holding temperature.Then with this mixture heating up to 65 ℃ and stir and spend the night.Filter this solid of this mixture and water and methanol wash, reclaim title compound (28.8g, 84% yield), be light yellow solid. 1H NMR(300MHz，DMSO-d6)：δ(ppm)：8.27(s，2H)，7.96～7.99(d，1H)，7.86～7.92(m，2H)，7.69～7.75(m，1H)，7.09～7.12(d，1H)，4.42(s，2H)，2.78～2.80(d，3H)；MS(m/z)：262.1[M ++1]。
Intermediate 27:(3-bromo-quinoline-6-yl)-the acetate methyl ester
Figure A20078003852702221
[0470] to quinoline-6-base-acetate (21.6g, 107mmol) add in the stirred solution in the 150ml tetracol phenixin bromine (34.4g, 215mmol) and be heated to and refluxed 4 hours.Use 17.0g pyridine diluted reaction mixture then, and further stir 2 hours until backflow.After being cooled to room temperature, this mixture is allocated between methylene dichloride and the saturated sodium bicarbonate aqueous solution.Organic layer water and salt solution elder generation after scouring, through dried over mgso, reduction vaporization obtains brown residue then.Residue is through column chromatography purification, uses sherwood oil (60～90 ℃), uses 30/1 mixed solvent of sherwood oil and ethyl acetate to obtain title compound (13.6g, 45%) then, is white crystalline solid.(300MHz，DMSO-d6)：8.89(d，1H)，8.27(d，1H)，8.06(d，1H)，7.67～7.64(m，2H)，3.82(s，2H)，3.72(s，3H)。ES-MS m/z：280(M+H ÷).
Intermediate 28:(3-bromo-quinoline-6-yl)-acetic acid hydrazides
Figure A20078003852702222
[0471] to (3-bromo-quinoline-6-yl)-acetate (5g, 18.9mmol) add in the mixture in methyl alcohol (100mL) vitriol oil (1mL) and with mixture heating up to refluxing 16 hours.Remove thermal source and add sodium sulfate (20g), filtering mixt.In filtrate, add hydrazine monohydrate (3.2mL) then, with this mixture heating up to refluxing other 16 hours.Make this mixture be cooled to room temperature then, add entry (60mL) then, the throw out of formation is collected and drying by filtering, and reclaims title compound, is white solid (4.72g, 16.9mmol, 90% yield). 1H-NMR 500MHz(DMSO-d6)3.57(2H，s)，4.26(2H，d)，7.72(1H，dd)，7.80(1H，d)，7.97(1H，d)，8.69(1H，d)，8.90(1H，d)，9.35(1H，bs)。ES-MS m/z：280(M+H +)。
Intermediate 29:(3-bromo-quinoline-6-yl)-acetate
Figure A20078003852702231
[0472] with (3-bromo-quinoline-6-yl)-acetate methyl ester (14.8g, 52.8mmol) and the 2N NaOH aqueous solution (80ml, mixture 160mmol) heating 1.5 hours under refluxing is until the reaction mixture clarification that becomes.After being cooled to room temperature, the reaction mixture washed with dichloromethane, water layer is acidified to pH 4 with concentrated hydrochloric acid then.Remove by filter white depositions, in the methyl alcohol that refluxes, stir, filter and vacuum-drying, obtain the product title compound, be white solid (10.3g, 74%).(300MHz，DMSO-d6)：12.52(b，1H)，8.91(d，1H)，8.69(d，1H)，7.99(d，1H))，7.82～7.70(m，2H)，3.80(s，2H)。ES-MS m/z：266(M+H +)。
Intermediate 30:[3-(1-methyl isophthalic acid H-pyrazoles-4-yl)-quinoline-6-yl]-acetate
Figure A20078003852702232
[0473] in 20mL microwave bottle, add (3-bromo-quinoline-6-yl)-acetate (1g, 3.77mmol), 1-methyl-4-pyrazoles boric acid pinacol ester and 1,4-dioxane (10mL).Bubbling fed nitrogen 10 minutes in mixture.(1.56g, 11.3mmol) and water (5mL), bubbling fed nitrogen other 3 minutes in mixture again to add salt of wormwood then.After this, (138mg, 0.19mmol), sealed vial also heated for 1250 seconds in 130 ℃ in microwave oven to add dichloro two (triphenyl phosphine) palladium.Then by this mixture of diatomite filtration, with its water and saturated sodium bicarbonate aqueous solution washing.Vacuum is removed 1 in the solution, 4-dioxane, washed with dichloromethane 3 times of remaining aqueous solution.With 4M hydrochloric acid water layer is acidified to pH 6, throw out is collected and drying by filtering, and obtains title compound, is pale solid.(500MHz，DMSO-d6)：ES-MS m/z：268(M+H +)。
Intermediate 31:[3-(1-methyl isophthalic acid H-pyrazoles-4-yl)-quinoline-6-yl]-the acetate methyl ester
[0474] in 0 ℃, to [3-(1-methyl isophthalic acid H-pyrazoles-4-yl)-quinoline-6-yl]-acetate (2.4g, 8.6mmols) and in the solution of methyl alcohol (12mL) with the dropping mode add thionyl chloride (2eq., 17.2mmols).Then this reaction mixture is heated to 60 ℃ one hour.Solvent removed in vacuo need not be further purified and is used for next step.MS m/z；282(M+H +)。
Intermediate 32:[3-(1-methyl isophthalic acid H-pyrazoles-4-yl)-quinoline-6-yl]-acetic acid hydrazides
Figure A20078003852702242
[0475] methyl alcohol (75mL) solution with [3-(1-methyl isophthalic acid H-pyrazoles-4-yl)-quinoline-6-yl]-acetate methyl ester (8.6mmols) and hydrazine (80.6mmols) heated 1 hour in 55 ℃, add for the second time hydrazine (80.6mmol) then, this reactant was heated other 16 hours in 55 ℃.After this, make this mixture be cooled to 0 ℃, the throw out that obtains is collected by filtering, and with cold methanol washing and dried recovered title compound, is white solid (1.74g, 70%). 1H NMR 500MHz(DMSO-d6)：ES-MS m/z：282(M+H +)。
Intermediate 33:(3-bromo-5,7-two fluoro-quinoline-6-yl)-the acetate methyl ester
Figure A20078003852702251
[0476] (18.6g adds dense H in methyl alcohol 83.4mmol) (200mL) solution to (5,7-two fluoro-quinoline-6-yl)-acetate 2SO 4(4.7mL, 87.0mmol).Concentrated reaction mixture obtains brown residue, and it with the dilution of 200ml ethyl acetate, is used sat.aq.NaHCO 3With the salt water washing, then through anhydrous Na 2SO 4Dry organic layer also concentrates and obtains (7-fluoro-quinoline-6-yl)-acetate methyl ester, is yellow solid (17.7g, yield: 89.8%).
Intermediate 34:(5,7-two fluoro-quinoline-6-yl)-Acetyl Chloride 98Min.:
Figure A20078003852702252
[0477] (1g 4.48mmol) joins in the round-bottomed flask of oven drying and is suspended in the methylene dichloride (18ml) with (5,7-two fluoro-quinoline-6-yl)-acetate.Be maintained at this suspension under the nitrogen atmosphere and be cooled to 0 ℃.(470uL 5.38mmol), connects and sees the dimethyl formamide that adds catalytic amount slowly to add oxalyl chloride then.Make this solution be warming up to room temperature through 2 hours.Then this solution of vacuum concentration and with toluene through azeotropic distillation drying, obtain title compound, the ES-MS m/z:238 (M+H of methyl ester +).
Intermediate 35:(3-bromo-5,7-two fluoro-quinoline-6-yl)-acetate
Figure A20078003852702253
Step 1: preparation (3-bromo-5,7-two fluoro-quinoline-6-yl)-acetate methyl ester
[0478] to (5,7-two fluoro-quinoline-6-yl)-acetate methyl ester (35.3g, 148.9mmol) and pyridine (24mL, 298mmol) in the mixture in the 300mL tetracol phenixin with the dropping mode add bromine (15.3mL, 298mmol).This mixture heating up to refluxing 2 hours, is cooled to envrionment temperature then.Discard the liquid in the flask and use NaHCO 3And water washing.Dark solid NaHCO at the bottom of the flask 3Handle with methylene dichloride.The organic layer that merges washes with water, dry (Na 2SO 4) and be evaporated to dried.Crude product with petrol ether/ethyl acetate (40/1～3/1) wash-out, reclaims 31.5g (67% yield) title compound through the rapid column chromatography purifying, is crystalline solid. 1HNMR(DMSO-d6)：δ8.92(d，1H)，8.50(d，1H)，7.57～7.61(m，1H)，3.91(s，2H)，3.75(s，3H)。
Step 2: preparation (3-bromo-5,7-two fluoro-quinoline-6-yl)-acetate
[0479] (10.0g, 31.6mmol) suspension in the NaOH of the 48mL aqueous solution (2N) is heated to and refluxed 2 hours, is cooled to room temperature then with (3-bromo-5,7-two fluoro-quinoline-6-yl)-acetate methyl ester.Use the 5N hcl acidifying to pH 4 with this mixture of washed with dichloromethane (50mLx2) and water.Collect white depositions by filtering, wash with water and drying.Obtain the 9.6g title compound with 100% yield, be white powder. 1H NMR(DMSO-d6)：δ12.87(s，1H)，9.05(s，1H)，8.76(s，1H)，7.75-7.79(d，1H)，3.87(s，2H).LC-MS：303(M ++1)。
Intermediate 36:[5,7-two fluoro-3-(1-methyl isophthalic acid H-pyrazoles-4-yl)-quinoline-6-yl]-the acetate methyl ester
Figure A20078003852702261
[0480] in 20mL microwave bottle, adds (3-bromo-2,4-two fluoro-quinoline-6-yl)-acetate methyl ester (1g, 3.16mmol), 1-methyl-4-(4,4,5,5-tetramethyl--[1,3,2] the assorted penta ring-2-yl of two oxa-boron)-and the 1H-pyrazoles (1.2eq.3.79mmol, 788mg) with 1,4-dioxane (10mL).Bubbling feeds nitrogen in spicule, adds salt of wormwood (3eq.9.49mmol) and water (5mL) then and bubbling feeding nitrogen 3 minutes in this mixture.(138mg 0.19mmol) and with mixture heated for 1250 seconds in 130 ℃ to add dichloro two (triphenyl phosphine)-palladium.By this mixture of diatomite filtration and water and saturated sodium bicarbonate aqueous solution washing.Vacuum removes 1 then, 4-dioxane, water layer dichloromethane extraction 3 times.Organic layer is through dried over sodium sulfate and solvent removed in vacuo.
[0481] crude product is filled on the silica gel, purifying on isco uses methylene dichloride then, and methyl alcohol gradient liquid (methyl alcohol 0-10%) obtains the light yellow material of 508mg, 50% yield.MS：m/z318.0(M+H +)。
Intermediate 37:[5,7-two fluoro-3-(1-methyl isophthalic acid H-pyrazoles-4-yl)-quinoline-6-yl]-acetic acid hydrazides
Figure A20078003852702271
[0482] in the 40ml bottle, add methyl alcohol (12mL), [5,7-two fluoro-3-(1-methyl isophthalic acid H-pyrazoles-4-yl)-quinoline-6-yl]-acetate methyl ester (508mg, 1.6mmol) and anhydrous hydrazine (4eq., 6.4mmols).In 55 ℃ after 1 hour, add second part of hydrazine (4eq., 6.4mmol) and with reactant in other 1 hour of 55 ℃ of heating.Make this reaction mixture be cooled to room temperature, filter, wash with cold methanol.Desciccate reclaims title compound, is white solid (425mg, 83% yield).MS：m/z 318.0(M+H +)。
Intermediate 38:(7-fluoro-quinoline-6-yl)-the acetate methyl ester
Figure A20078003852702272
[0483] (13.4g adds dense H in methyl alcohol 65.36mmol) (140mL) solution to (7-fluoro-quinoline-6-yl)-acetate 2SO 4(3.5mL, 68.63mmol).Concentrated reaction mixture obtains brown residue, and it with the dilution of 100ml ethyl acetate, is used sat.aq.NaHCO 3With the salt water washing, organic layer is through anhydrous Na then 2SO 4Drying, and concentrate and to obtain (7-fluoro-quinoline-6-yl)-acetate methyl ester, be yellow solid (14.Og, yield: 98%).
Intermediate 39:(3-bromo-7-fluoro-quinoline-6-yl)-acetate
Figure A20078003852702273
Step 1: preparation (3-bromo-7-fluoro-quinoline-6-yl)-acetate methyl ester
[0484] to (7-fluoro-quinoline-6-yl)-acetate methyl ester (14.0g, 63.9mmol) and pyridine (10.4mL, 127.8mmol) in the mixture of 200mL tetracol phenixin with the dropping mode add bromine (6.6mL, 127.8mmol).This mixture heating up to refluxing 2 hours, is cooled to envrionment temperature then.Discard the liquid in the flask and use NaHCO 3And water washing.Dark solid NaHCO at the bottom of the flask 3Handle with methylene dichloride.The organic layer that merges washes with water, dry (Na 2SO 4) and be evaporated to dried.Crude product with petrol ether/ethyl acetate (40/1～3/1) wash-out, reclaims 13.9g (75% yield) title compound through the rapid column chromatography purifying, is crystalline solid. 1HNMR(DMSO-d6)：δ8.89(s，1H)，8.27(m，1H)，7.66～7.74(m，2H)，3.87(s，2H)，3.74(s，3H)。
Step 2: preparation (3-bromo-7-fluoro-quinoline-6-yl)-acetate
[0485] (13.9g, 46.6mmol) suspension in the 72mL NaOH aqueous solution (2N) is heated to and refluxed 2 hours, is cooled to room temperature then with (3-bromo-7-fluoro-quinoline-6-yl)-acetate methyl ester.Mixture uses the 5N hcl acidifying to pH 4 with washed with dichloromethane (50mLx2) and water.Collect white depositions by filtering, wash with water and drying.Obtain the 11.0g title compound with 83.3% yield, be white powder. 1H NMR(DMSO-dó)：δ12.64(s，1H)，8.94～8.95(d，1H)，8.72～8.72(m，1H)，7.94～7.97(d，1H)，7.77～7.81(d，1H)，3.85(s，2H).LC-MS：283.9(M ++1)。
Intermediate 40:[7-fluoro-3-(1-methyl isophthalic acid H-pyrazoles-4-yl)-quinoline-6-yl]-acetate
Figure A20078003852702281
[0486] nitrogen bubble is fed (3-bromo-7-fluoro-quinoline-6-yl)-acetate (5g, 17.7mmol), 1-methyl-4-pyrazoles boric acid pinacol ester (3.86g, 18.6mmol), salt of wormwood (7.3g.53mmol) is 1, the suspension in 4-dioxane (50mL) and the water (20mL) 10 minutes.After this, add dichloro two (triphenyl phosphine) palladium (II) (248mg, 0.35mmol) and with this mixture heating up to refluxing 3 hours.Moisturely remove, wash with 2N wet chemical (15mL) dilution and with ethyl acetate (2x30mL) by transfer pipet.To contain water with concentrated hydrochloric acid then and be acidified to pH 3.The throw out of formation is collected by filtering, and washes with water and drying, reclaims title compound, is white solid (4.2g, 14.7mmol, 83% yield). 1H NMR 500MHz(DMSO-d6)：δ3.84(2H，s)，3.92(3H，s)，7.71(1H，d)，7.90(1H，d)，8.10(1H，s)，8.39(1H，s)，8.47(1H，d)，9.18(1H，d)。ES-MS m/z：286(M+H +)。
Intermediate 41:[7-fluoro-3-(1-methyl isophthalic acid H-pyrazoles-4-yl)-quinoline-6-yl]-acetic acid hydrazides
Figure A20078003852702291
[0487] to [7-fluoro-3-(1-methyl isophthalic acid H-pyrazoles-4-yl)-quinoline-6-yl]-acetate (4g, 14.0mmol) add in the mixture in methyl alcohol (80mL) vitriol oil (0.8mL) and with mixture heating up to refluxing 16 hours.Remove thermal source and add sodium sulfate (20g), filter this mixture.In filtrate, add hydrazine monohydrate (3.2mL) then and with mixture heating up to refluxing other 16 hours.Make mixture be cooled to room temperature then, add entry (60mL) then, the throw out of formation is collected and drying by filtering, and reclaims title compound, is light gray solid (3.51g, 11.7mmol, 84% yield). 1H-NMR 500MHz(DMSO-d6)3.63(2H，s)，3.91(3H，s)，4.28(2H，d)，7.69(1H，d)，7.88(1H，d)，8.09(1H，s)，8.38(1H，s)，8.47(1H，d)，9.16(1H，d)，9.32(1H，bs)。ES-MS m/z：300(M+H +).
Intermediate 42:3-chloro-6-iodo-pyridazine
Figure A20078003852702292
[0488] add 2.5g 3 in the 40mL bottle, 6-dichloro-pyridazine (16.9mmol) then adds 12.5mL hydroiodic acid HI and 3.75g potassiumiodide.Reaction mixture is heated to 40 ℃ through 3 hours, is cooled to room temperature then.This reaction mixture impouring is contained in the ice of 10M NaOH, and the throw out of formation is collected and drying by filtering, and reclaims title compound (2.36g, 60%).MS：m/z340.9
Intermediate 43:3-chloro-6-trifluoromethyl-pyridazine
Figure A20078003852702293
[0489] under nitrogen, in the 200ml round-bottomed flask, 1 gram (4.16mmol) 3-chloro-6-iodo-pyridazine and 1.5eq cupric iodide (6.24mmol), 2eq. (8.32mmol) Potassium monofluoride and 2eq. (8.32mmol) two chloro-fluoro-acetate methyl ester are merged in the 75ml dimethyl formamide.With this reaction mixture be heated to 115 ℃ 16 hours.Solvent removed in vacuo and solids constituent is assigned between methylene dichloride and the water (150ml).The emulsion that forms by diatomite filtration and organic layer through dried over sodium sulfate.Fill in organic layer on the silica gel and through silica gel purification,, reclaim title compound (150mg, 20%) MS:m/z 183.1 with the hexane solution wash-out of 0% ethyl acetate-50% ethyl acetate.
Intermediate 44:4-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron mix penta ring-2-yl)-1-(2-TMS-ethoxyl methyl)-1H-pyrazoles
Figure A20078003852702301
[0490] title compound passes through by Guzi, Timothy J.; Paruch, Kamil; Dwyer, Michael P.; Labroli, Marc; Keertikar, Kartik M. is as preparation (the Preparation of novelpyrazolopyrimidines as cyclin dependent kinase inhibitors) .U.S.Pat.Appl.Publ. (2007) of the new pyrazolopyrimidine of cell cycle protein dependent kinase inhibitor, 144pp., method (the not doing great change) preparation that US2007072881 describes.
Intermediate 45:4-[4-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron mix penta ring-2-yl)-pyrazol-1-yl]-piperidines-1-carboxylic acid tertiary butyl ester
Figure A20078003852702302
[0491] title compound passes through by Cui, Jingrong Jean; Funk, Lee Andrew; Jia, Lei; Kung, Pei-Pei; Meng, Jerry Jialun; Nambu, Mitchell David; Pairish, Mason Alan; Shen, Hong; Tran-Dube, Michelle Bich. is used to resist the preparation of aminoheteroaryl compounds of pyrazoles-replacements of cancer and other abnormal cell growth disorder, and ((Preparation of pyrazole-substitutedaminoheteroaryl compounds as c-Met protein kinase inhibitors for useagainst cancer and other abnormal cell growth disorders) .PCT Int.Appl. (2006), the method (not doing great change) that 185pp.WO2006021881 describes prepares as the c-Met kinases inhibitor.
Intermediate 46:1-(2-methoxyl group-ethyl)-4-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron mix penta ring-2-yl)-1H-pyrazoles
Figure A20078003852702311
[0492] title compound passes through by Ivachtchenko, Alexandre V.; Kravchenko, Dmitry V.; Zheludeva, Valentina I.; Pershin, Dmitry is alkyl-1H-pyrazoles-5-base-and synthetic (the Synthesis of pinacol esters of1-alkyl-1H-pyrazol-5-yl-and 1-alkyl-1H-pyrazol-4-ylboronic acids) of 1-alkyl-1H-pyrazoles-4-ylboronic acid G.1-. heterocyclic chemistry magazine (Journal of Heterocyclic Chemistry) (2004), 41 (6), method (the not doing great change) preparation that 931-939 describes.
Intermediate 47:1-[4-(4,4,5-trimethylammonium-[1,3,2] two oxa-boron mix penta ring-2-yl)-pyrazol-1-yl]-Ding-2-ketone
[0493] (1g, 1equiv 5.15mmol) are dissolved in dimethyl formamide (15mL), then add Cs to make pyrazoles-4-boric acid pinacol ester 2CO 3(0.86g, 1.5equiv, 7.73mmol) and 1-bromo-2-butanone (1.1equiv, 5.67mmol, 0.86g).With this mixture in 90 ℃ of heated overnight.With ethyl acetate extraction reactant and water (3x) and salt solution (3x) washing.With the filtrate vacuum concentration to silica gel and through flash chromatography purifying (SiO 2, CH 2Cl 2: CH 3OH 100: 0-80: 20), reclaim title compound (0.19g, 14% yield). 1H NMR 500MHz(DMSO)δ0.97(3H，t)1.26(12H，s)，2.50(2H，q)，4.71(2H，s)，7.65(1H，s)，8.04(1H，s)。MSm/z 265(M+H +) +。
Intermediate 48:3-[4-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron mix penta ring-2-yl)-pyrazol-1-yl]-propionitrile
Figure A20078003852702321
[0494] (Ig, 1equiv 5.15mmol) are dissolved in dimethyl formamide (15mL), then add Cs to make pyrazoles-4-boric acid pinacol ester 2CO 3(0.86g, 1.5equiv, 7.73mmol) and 3-chloro propionitrile (1.1equiv, 5.67mmol, 0.44mL).With this mixture in 90 ℃ of heated overnight.With ethyl acetate diluting reaction thing and water (3x) and salt solution (3x) washing.With the organic phase vacuum concentration to silica gel and through flash chromatography purifying (SiO 2, CH 2Cl 2: CH 3OH 100: 0-90: 10), reclaim title compound (0.11g, 9%). 1H NMR(500MHz，DMSO)：δ1.26(12H，s)，3.07(2H，t)，4.40(2H，t)，7.65(1H，s)，8.04(1H，s)。MS m/z 248(M+H +) +。
Intermediate 49:3-(4-bromo-pyrazol-1-yl)-azetidine-1-carboxylic acid tertiary butyl ester;
Intermediate 50:3-(4-bromo-pyrazol-1-yl methyl)-azetidine-1-carboxylic acid tertiary butyl ester; With
Intermediate 51:2-(4-bromo-pyrazol-1-yl)-ethanol
Figure A20078003852702322
[0495] intermediate 49,50,51 passes through by Cui, Jingrong Jean; Funk, Lee Andrew; Jia, Lei; Kung, Pei-Pei; Meng, Jerry Jialun; Nambu, Mitchell David; Pairish, Mason Alan; Shen, Hong; Tran-Dube, Michelle Bich. is used to resist preparation (Preparation of pyrazole-substitutedaminoheteroaryl compounds as c-Met protein kinase inhibitors for useagainst cancer and other abnormal cell growth disorders) the .PCT Int.Appl. (2006) of aminoheteroaryl compounds of pyrazoles-replacements of cancer and other abnormal cell growth disorder as the c-Met kinases inhibitor, the method (not doing great change) that 185pp.WO2006021881 describes prepares.
Intermediate 53:1-ethyl-4-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron mix penta ring-2-yl)-1H-pyrazoles
[0496] title compound is according to Ivachtchenko, Alexandre V.; Kravchenko, Dmitry V.; Zheludeva, Valentina I; Pershin, Dmitry is alkyl-1H-pyrazoles-5-base-and synthetic (the Synthesis of pinacol esters of1-alkyl-1H-pyrazol-5-yl-and 1-alkyl-1H-pyrazol-4-ylboronic acids) of 1-alkyl-1H-pyrazoles-4-ylboronic acid G.1-. heterocyclic chemistry magazine (Journal of Heterocyclic Chemistry) (2004), 41 (6), method (the not doing great change) preparation that 931-939 describes.
Intermediate 54:1-(4-iodo-pyrazol-1-yl)-cyclobutane-carboxylic acid ethyl ester
[0497] to the iodine pyrazoles (2.93g, add in dimethyl formamide 15.09mmol) (25mL) solution NaH (60% in oil, 724mg, 30.18mmol), simultaneously bubbling feeds nitrogen and mixture was stirred 30 minutes under nitrogen in this solution.(1.95mL, solution 12.07mmol) also spends the night solution stirring slowly to add 1-bromo-cyclobutane-carboxylic acid ethyl ester.Ethyl acetate is joined in the reactant to extract product.Ethyl acetate layer water (3x) and salt solution (3x) washing and through dried over sodium sulfate.With the filtrate vacuum concentration to silica gel and through flash chromatography purifying (SiO 2, hexane: ethyl acetate 100: 0-75: 25) reclaim title compound (0.71g, 15% yield). 1H NMR(DMSO)：δ1.15(t，3H)，1.90-2.04(m，2H)，2.69-2.77(m，2H)，4.10(q，2H)，7.59(s，1H)，8.13(s，1H)。MS m/z＝321(M+H +) +。
Intermediate 55:3-chloro-6-vinyl-pyridazine
Figure A20078003852702333
[0498] with 3, and the 6-dichloro-pyridazine (6g, 40.3mmol), vinyl boric acid pinacol ester (6.21g, 6.83mL, 40.3mmol), (120mmol, 16.7g), 1, the mixture of 4-dioxane (60mL) and water (24mL) was with the nitrogen degassing 15 minutes for salt of wormwood.Add then dichloro [1,1 '-two (diphenylphosphino) ferrocene] palladium (II) methylene dichloride adducts (0.4mmol, 292mg) and with mixture heating up to 80 ℃ through 4 hours.Remove by transfer pipet then and contain water, organic phase is concentrated in the silica gel, through rapid column chromatography purifying (SiO 2, hexane: ethyl acetate 100: 0-60: 40), reclaim title compound, be white solid (5.2g, 92% yield). 1H NMR(CDCl 3)：δ5.75(1H，d)，6.25(1H，d)，7.05(1H，dd)，7.49(1H，d)，7.59(1H，d)。MSm/z＝141(M+H +) +。
Intermediate 56:3-chloro-6-ethyl-pyridazine
Figure A20078003852702341
[0499] under room temperature, nitrogen atmosphere, with 3-chloro-6-vinyl-pyridazine (1g, 7.09mmol), (10%wt, 200mg) the mixture vigorous stirring in ethyl acetate (14mL) is 4 hours for palladium on carbon.Filter this mixture by Celite pad then and filtrate is concentrated in the silica gel, through rapid column chromatography purifying (SiO 2, hexane: ethyl acetate 90: 10-50: 50), reclaim title compound, be white solid (627mg, 63% yield). 1H NMR(CDCl 3)：δ1.27(3H，t)，2.93(2H，q)，7.72(1H，d)，7.83(1H，d)。MS m/z＝143(M+H +) +。
Intermediate 57:[5-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-pyrrolo-[2,3-b] pyridin-3-yl]-acetic acid hydrazides
Figure A20078003852702342
Step 1:5-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-pyrrolo-[2,3-b] pyridine
[0500] with 5-bromo-1H-pyrrolo-[2,3-b] pyridine (1.0g, 5.05mmol), 1-methyl-4-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron mix penta ring-2-yl)-1H-pyrazoles (1.17g.5.55mmol) and Pd (dppf) 2Cl 2(37mg 0.045mmol) places and uses N 2In the round-bottomed flask of filling.Join DMA (6mL) in the reaction vessel and bubbling feeding N in solution 210 minutes.Make K 2CO 3(bubbling feeds N for 978mg, 7.07mmol) water-soluble (6mL) 2And join in the reaction vessel, be lower than room temperature with ice/water-bath holding temperature simultaneously.To being equipped with vigeruex post and N 2Bubbling feeds other N in the reaction vessel of pipe 2Through 10 minutes and be heated to 75 ℃ and spend the night.Reaction is not finished as yet; Therefore, with other 1-methyl-4-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron mix penta ring-2-yl)-1H-pyrazoles (1.0g) and Pd (dppf) 2Cl 2(124mg) join in the reactant.This solution was heated other 4 hours.After this period, water (12mL) joined in the reaction vessel and with solution in 60 ℃ of heating 1 hour.This solution is transferred in the separating funnel that contains methylene dichloride (300mL) and with the waterbearing stratum separates.Organic layer is through Na 2SO 4Drying concentrates on silica gel and through flash chromatography purifying (0-10% ethanol/methylene gradient liquid), obtains title compound (780mg, 78% yield).MS m/z＝199[M+H +] +
Step 2:[5-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-pyrrolo-[2,3-b] pyridin-3-yl]-acetate
[0501] with 5-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-pyrrolo-[2,3-b] pyridine (780mg, 3.94mmol) and Eschenmoser ' s salt (1.46g is 7.88mmol) at acetonitrile: merge in the acetate (19: 1, be respectively 12.3ml and 700uL) and in 40 ℃ of heating 5 hours.Then add 4N potassium hydroxide until pH＞9.This solution is transferred to separating funnel also with a large amount of ethyl acetate extraction.Organic layer is through Na 2SO 4Dry and concentrated.Then will the methyl-iodide in the ethanol (11mL) (246uL, 3.94mmol) join in the rough gramine and with solution in stirred overnight at room temperature.This solution of vacuum concentration also is dissolved in dimethyl formamide (10mL) and the water (2mL) again.Be heated to then 70 ℃ 3 hours.Reactant is risen again to room temperature, be transferred in the separating funnel that contains ethyl acetate (250mL) and wash (2x200mL) with water.The merging waterbearing stratum is also returned with ethyl acetate (200mL) and is carried.Organic layer is through Na 2SO 4Dry and concentrated, obtain thick [5-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-pyrrolo-[2,3-b] pyridin-3-yl]-acetonitrile.This material is dissolved in methyl alcohol (6mL) and the 4N potassium hydroxide (8mL) and then in 90 ℃ of heated overnight.Then solution is formed until throw out with 1N hydrochloric acid (aq) acidifying.Filtering precipitate and washing with water obtains crude product then.This product obtains title compound (284mg, 28%) through flash chromatography purifying (0-15% ethanol/methylene gradient liquid).MS m/z＝257[M+H +] +
Step 3:[5-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-pyrrolo-[2,3-b] pyridin-3-yl]-the acetate methyl ester
[0502] (200mg 0.78mmol) is suspended in the methyl alcohol (4mL) with [5-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-pyrrolo-[2,3-b] pyridin-3-yl]-acetate.Then, add sulfuric acid (125uL) and also this solution is heated to backflow 2 hours.This solution of vacuum concentration also makes thick material be dissolved in methylene dichloride, is transferred to separating funnel and uses sat.NaHCO 3(aq) washing.Organic layer is through Na 2SO 4Dry and concentrate, crude product is through flash chromatography purifying (0-10% ethanol/methylene gradient liquid), obtains title compound (148mg, 70% yield).MS m/z＝271[M+H +] +
Step 4:[5-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-pyrrolo-[2,3-b] pyridin-3-yl]-acetic acid hydrazides
[0503] make 5-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-pyrrolo-[2,3-b] pyridin-3-yl]-(148mg 0.55mmol) is dissolved in ethanol (3.0mL) and the hydrazine hydrate (500uL) the acetate methyl ester.This solution is heated to backflow 1 hour.Stopped reaction also rises again to room temperature solution.Crystallized product also removes by filter, and obtains title compound (92mg, 63% yield).MS m/z＝271[M+H +] +；(DMSO-d6)3.88(3H，s)，4.21(2H，bs)，7.27(1H，s)，7.85(1H，s)，8.10(2H，s)，8.42(1H，d)，9.17(1H，s)，11.37(1H，s)
Intermediate 58:[6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-pyrrolo-[3,2-b] pyridine-1-yl]-acetic acid hydrazides
Figure A20078003852702361
Step 1:6-bromo-1H-pyrrolo-[3,2-b] pyridine
[0504] to 5-bromo-2-methyl-3-nitro-pyridine (1.58g, 7.28mmol) add in dimethyl formamide (10mL) solution of [according to WO2006/103449 preparation] the dimethyl formamide dimethyl acetal (1.65mL, 12.37mmol).This reaction mixture in 100 ℃ of stirrings 1 hour, is cooled to room temperature and vacuum concentration then.Make residue be dissolved in the toluylic acid (25mL) and add iron powder (3.25g, 58.24mmol).In 100 ℃ of stirrings 21 hours, make it be cooled to room temperature then reaction mixture.Add methyl alcohol (25mL), filtering suspension liquid is also used methanol wash.Filtrate is through vacuum concentration.Residue is allocated between the saturated sodium bicarbonate aqueous solution and ethyl acetate.Separate organic layer,, filter, and absorb on the silica gel through dried over sodium sulfate.On silica gel,, use the gradient liquid of 0-70% ethyl acetate/hexane, obtain the 869mg title compound, be ivory white solid (60% yield) through the flash chromatography purifying: 1H NMR (DMSO-d6): δ 6.77 (s, 1H), 7.68 (s, 1H), 8.00 (s, 1H), 8.36 (s, 1H), 11.46 (wide s, 1H); MS (m/z) 197,199[M+H +] +
Step 2:6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-pyrrolo-[3,2-b] pyridine
[0505] to N 2Add in the microwave bottle of purge 6-bromo-1H-pyrrolo-[3,2-b] pyridine (327mg, 1.65mmol) and be dissolved in DMA (2mL).Feed N to this solution bubbling 2Through 5 minutes.Then, (516mg 2.48mmol) joins in this solution, feeds N to bubbling wherein with 1-methyl-4-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron mix penta ring-2-yl)-1H-pyrazoles 2Other 5 minutes.Make K 2CO 3(320mg, 2.31mmol) water-soluble (2ml) and in this solution bubbling feed N 2Through 5 minutes.Join aqueous solution in the reaction vessel and in this solution once more bubbling feed N 2At last with Pd (dppf) 2Cl 2(81mg 0.10mmol) joins in the solution, and bubbling feeds N 2, the sealing and in 130 ℃ of microwave heatings 15 minutes.Then with reactant transfer to the separating funnel that contains methylene dichloride (75mL) and wash (2x75mL) with water.Extraction (75mL) is returned with methylene dichloride in the waterbearing stratum.Merge organic layer, through Na 2SO 4Dry also vacuum concentration.Thick material obtains title compound (200mg, 61% yield) through flash chromatography purifying (0-80% acetonitrile/dichloromethane gradient liquid).MS m/z＝199[M+H +] +。
Step 3:[6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-pyrrolo-[3,2-b] pyridine-1-yl]-the acetate ethyl ester:
[0506] at a N 2In the round-bottomed flask of purge, make sodium hydride, 60%, (41mg 1.01mmol) is suspended in the dimethyl formamide (2.5mL).This solution is maintained at N 2Down and be cooled to 0 ℃ through 10 minutes.Then, (200mg 1.01mmol) is dissolved in dimethyl formamide (2.5mL) and being added dropwise in the refrigerative solution to make 6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-pyrrolo-[3,2-b] pyridine.This solution was stirred other 10 minutes in 0 ℃.At last, (123uL 1.11mmol) slowly joins in this reaction vessel with bromo-acetate ethyl ester.Make this reactant balance, rise again, stirred simultaneously 2 hours to room temperature.At last solution is transferred in the separating funnel that contains methylene dichloride (75mL) and washes (2x75mL) with water.Organic layer is through Na 2SO 4Drying concentrates and through flash chromatography purifying (0-10% ethanol/methylene step gradient liquid), obtains title compound (122mg, 43% yield).MS m/z＝285[M+H +] +
Step 4:[6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-pyrrolo-[3,2-b] pyridine-1-yl]-acetic acid hydrazides:
Make [0507] that [6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-pyrrolo-[3,2-b] pyridine-1-yl]-(122mg 0.42mmol) is dissolved in ethanol (1mL) and the hydrazine hydrate (500uL) the acetate ethyl ester.This solution is heated to backflow 1 hour.Then this solution of vacuum concentration also is dissolved in a small amount of hot methanol again.Crystallized product is also collected after filtration, obtains title compound (114.8mg, 99% yield).MSm/z＝271[M+H +] +
Intermediate 59:5-(3-bromo-quinoline-6-ylmethyl)-[1,2,4] triazole-3, the 4-diamines
Figure A20078003852702381
Step 1:5-(3-bromo-quinoline-6-ylmethyl)-[1,3,4] oxadiazoles-2-base amine
[0508] under room temperature, with (3-bromo-quinoline-6-yl)-acetic acid hydrazides (according to method described herein preparation) (4.12g, 14.7mmol), cyanogen bromide (1.1eq., 16.2mmol, 1.7g) and KHCO 3(1.25eq., 18.3mmol, mixture 1.83g) stirred 18 hours in methyl alcohol (30mL).Water (40mL) dilutes and collects this solid by filtering then, washs also dried recovered title compound with cold methanol, is pale solid (4.02g, 13.2mmol, 90%). 1H NMR(DMSO-d6)：δ4.27(2H，s)，6.94(s，2H)，7.71(dd，1H)，7.86(d，1H)，8.02(d，1H)，8.73(d，1H)；8.93(d，1H)；MS(m/z)305[M+H +] +。
Step 2:5-(3-bromo-quinoline-6-ylmethyl)-[1,2,4] triazole-3, the 4-diamines
[0509] with 5-(3-bromo-quinoline-6-ylmethyl)-[1,3,4] oxadiazoles-2-base amine (and 3.53g, 11.6mmol), the mixture of hydrazine hydrate (30mL) and water (15mL) clings under the normal atmosphere in 170 ℃ and 2 in the microwave bottle and heated 1 hour.After the cooling, the solid by filtration of formation is collected, and with cold methanol washing and dried recovered title compound, is solid (1.79g, 5.6mmol, 49%).
1H NMR(OMSO-d6)：δ4.13(2H，s)，5.46(s，2H)，5.56(s，2H)，7.23(d，1H)，7.81(s，1H)，7.98(d，1H)，8.71(d，1H)；8.91(d，1H)；MS(m/z)319[M+H +] +。
Intermediate 60:(3-bromo-5,7-two fluoro-quinoline-6-yl)-acetic acid hydrazides
Figure A20078003852702391
[0510] in 0 ℃, N 2Down, with SOCl 2(394mg, (500mg is 1.65mmol) in the stirred solution in 12ml methyl alcohol 3.31mmol) to be added dropwise to (3-bromo-5,7-two fluoro-quinoline-6-yl)-acetate.After stirring 2 hours under the room temperature, evaporating solvent, rough (3-bromo-5,7-two fluoro-quinoline-6-yl)-acetate methyl ester is directly used in next step.To (3-bromo-5,7-two fluoro-quinoline-6-yl)-acetate methyl ester (2.29g, add in the mixture of methyl alcohol 7.22mmol) (100mL) anhydrous hydrazine (2.31g, 72.2mmol).This mixture was heated 4 hours in 55 ℃.Heating other anhydrous hydrazine (1.16g, 36.1) also stirs this mixture 2 hours in 55 ℃.Make reaction mixture be cooled to room temperature, obtain white solid.Filter white solid,, obtain 2.1g title compound (92% yield) with the cold methanol washing.MS：m/z 318[M+H +]。 1H NMR(500MHz.DMSO-d 6)：δ1.99(2H，s)，4.25(2H，bs)，7.72(1H，d)，8.74(1H，s)，9.03(1H，s)，9.35(1H，s)。
Intermediate 61:(3-bromo-5-fluoro-quinoline-6-yl)-acetate
Step 1:6-bromo-5-fluoro-quinoline
[0511] with 4-bromo-3-fluoro-phenyl amine (100g, 526mmol), the mixture mild heat of ferrous sulfate (30g), glycerine (200g), oil of mirbane (40g) and the vitriol oil (100mL).Behind first time vigorous reaction, with this mixture heating up to refluxing 5 hours.Vacuum-evaporation oil of mirbane.Aqueous solution is with the glacial acetic acid acidifying and separate the dark-brown throw out, with it through flash chromatography purifying (silica gel, petrol ether/ethyl acetate=12/1), reclaim the mixture of 6-bromo-5-fluoro-quinoline and 6-bromo-7-fluoro-quinoline, be white solid (80g, 68%), this mixture is heated to backflow in sherwood oil.Make this solution be cooled to room temperature, filter and drying, reclaim 6-bromo-7-fluoro-quinoline, be white solid.In this solution, add HCl/MeOH, from this solution, precipitate white solid.Cross filter solid and alkalization.Filtration is collected the throw out and the drying that obtain and is obtained 6-bromo-5-fluoro-quinoline, is solid. 1H-NMR(DMSO-d 6，300MHz)：9.0(d，1H)，8.5(d，1H)，8.0(m，1H)，7.8(d，1H)，7.7(m，1H)；MS：m/z 228[M+H +] +。
Step 2:(5-fluoro-quinoline-6-yl)-ra-butyl acetate
[0512] (1.0g adds tertiary butyl bromination zinc acetate solution (10.4M is in tetrahydrofuran (THF) for 9mmol, 20mL) in tetrahydrofuran (THF) 4.5mmol) (1mL) solution, then add Pd (PPh to 6-bromo-5-fluoro-quinoline 3) 4(0.52g, 0.45mmol).With this mixture in microwave reactor 120 ℃ the heating 30 minutes.With saturated ammonium chloride (60mL) quencher reaction mixture and use ethyl acetate extraction.Organic layer is through anhydrous Na 2SO 4Drying is filtered and is concentrated.Residue obtains title compound (0.83g, 71%) through column chromatography purification. 1H-NMR(CDCl 3，300MHz)：8.9(d，1H)，8.4(d，1H)，7.8(d，1H)，7.6(m，1H)，7.5(m，1H)，3.7(d，2H)，1.4(s，9H)。
Step 3:(5-fluoro-quinoline-6-yl)-the acetate methyl ester
[0513] (5g 19mmol) is heated to backflow 4 hours in the 25mlNaOH aqueous solution (4N) with (5-fluoro-quinoline-6-yl)-ra-butyl acetate.Mixture is acidified to pH 5 with ethyl acetate washing and waterbearing stratum with dense HCl.The throw out that collection obtains washes also vacuum-drying with water to reclaim (5-fluoro-quinoline-6-yl)-acetate.In this solid, add dense H 2SO 4(1.2ml) and MeOH (20ml) and solution is heated to refluxed 6 hours.After the cooling, solvent removed in vacuo, residue reclaims title compound (2.0g 48%) through the rapid column chromatography purifying.
Step 4:(3-bromo-5-fluoro-quinoline-6-yl)-the acetate methyl ester
[0514] in 5 ℃, (2.0g is 9mmol) at CCl to (5-fluoro-quinoline-6-yl)-acetate methyl ester 4(20ml) and pyridine (1.48ml, be added dropwise in solution 18mmol) bromine (0.9ml, 18mmol).This solution is heated to backflow 20 minutes.After the cooling, reaction sat.aq.NaHCO 3Quencher, mixture also concentrates with dichloromethane extraction.Residue reclaims title compound (1.8g, 66%) through the rapid column chromatography purifying. 1H-NMR (CDCl 3, 300MHz): 8.9 (d, 1H), 8.5 (d, 1H), 7.8 (d, 1H), 7.6 (m, 1H), 3.9 (d, 2H), 3.7 (s, 3H).
Step 5:(3-bromo-5-fluoro-quinoline-6-yl)-acetate
[0515] with 3-bromo-5-fluoro-quinoline-6-yl)-acetate methyl ester (1.2g) is heated in the 10ml NaOH aqueous solution (4N) and refluxed 4 hours.This mixture is acidified to pH 5 with the ethyl acetate washing and with dense HCl with the waterbearing stratum.The throw out that collection obtains washes with water and vacuum-drying, reclaims title compound (838mg 74%). 1H-NMR(DMSO-d 6，300MHz)：12.6(s，1H)，9.0(d，1H)，8.7(d，1H)，7.9(d，1H)，7.8(m，1H)，3.9(d，2H)。MS：283，285(M+1)。
Intermediate 62:(3-bromo-5-fluoro-quinoline-6-yl)-acetic acid hydrazides
[0516] with (3-bromo-5-fluoro-quinoline-6-yl)-acetate (800mg, 2.7mmol) and hydrazine hydrate (98%, 2mL) solution in methyl alcohol (15mL) is heated to and refluxed 1 hour.Solvent removed in vacuo obtains white solid, and it with methanol wash and dry, is reclaimed title compound (750mg, 94%), is white solid. 1H-NMR(DMSO-d6，300MHz)：9.34(s，1H)，8.996-9.00(d，1H)，8.72-8.73(d，1H)，7.85-7.88(d，1H)，7.73-7.79(m，1H)，4.26-4.27(d，2H)，3.64-3.66(d，2H)；MS：m/z 299[M+H +] +。
Intermediate 63:2-quinoline-6-base-propionic acid hydrazides
[0517] with 2-quinoline-6-base-propionic acid (5.6g, 26.1mmol), hydrazine hydrate (1.6mL) and methyl alcohol (150mL) merges and be heated to and refluxed 72 hours.After this, this mixture of vacuum concentration and be allocated in NaHCO 3(200mL) and between the methylene dichloride (150mL).Contain water dichloromethane extraction (2x150mL), dry (Na 2SO 4) organic extraction and the vacuum concentration that merge, reclaim title compound, be white solid (4.6g, 21.4mmol, 82%). 1H-NMR(DMSO-d6，500MHz)：9.30(1H，bs)，8.85(1H，dd)，8.33(1H，dd)，7.95(1H，d)，7.86(1H，d)，7.74(1H，dd)，7.51(1H，dd)，4.22(3H，s)，3.74(IH，q)，1.44(3H；MS：m/z 216[M+H +] +。
The method that is used for synthetic embodiment
Method A
Compound 21:(R, S)-3-[3-(1-quinoline-6-base-ethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-yl]-benzonitrile
Figure A20078003852702421
[0518] to water (1mL) and 1, add (R in (bubbling fed nitrogen 15 minutes) mixture of the degassing of 4-dioxane (3mL), 5)-6-[1-(6-chloro-[1,2,4] triazolo [4,3-b)] pyridazine-3-yl)-ethyl]-quinoline (100mg, 0.32mmol, 1.0equiv.), 3-cyano-phenyl boric acid (52mg, 0.35mmol, 1.1equiv.), salt of wormwood (2equiv., 0.64mmol, 89mg) and dichloro [1,1 '-two (diphenylphosphino)-ferrocene] palladium (II) methylene dichloride adducts (15mg, 0.07equiv).Heated 20 minutes in 130 ℃ with microwave tubule jam-pack and in microwave reactor.After this, this mixture is concentrated in the silica gel,, uses methylene dichloride: methyl alcohol 100: 0-90: 10 wash-outs through the rapid column chromatography purifying.(triggered) reversed-phase HPLC (5-95%CH that makes residue be dissolved in dimethyl formamide (1mL) and trigger through quality 3CN is at H 2Among the O) purifying, reclaim title compound, be white solid (71mg, 0.19mmol, 59% yield).Analytical data shown in the table 1.The Separation of Enantiomers of in method B, describing.
Method B
Compound 99:(S)-3-[3-(1-quinoline-6-base-ethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-yl]-benzonitrile and compound 100:I-3-[3-(1-quinoline-6-base-ethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-yl]-benzonitrile
Figure A20078003852702422
Embodiment 99 embodiment 100
[0519] makes 3-[3-(1-quinoline-6-base-ethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-yl]-benzonitrile (1.2g) is dissolved in isopropyl alcohol (10g/L) and by carry out chirality HPLC on Chiralpak AS 20 μ M (8cm id x 25cm L) post, with 50% methanol/ethanol (25 ℃), 150g/min, the 325nM wash-out comes enantiomer separation, reclaim embodiment 126 (0.56g, ee＞99.9%) and embodiment 127 (0.56g, ee 97%).On AS-H 4.6mm ID x 250mm S/NASHSAEE001-409291 post, carry out analytical procedure, with 50% methanol/ethanol (25 ℃), 1mL/min, 225nM wash-out.Compound 99 retention time 4.6 minutes and compound 100 retention time 5.8 minutes.Analytical data shown in the table 1.
Method C
Compound 156:3-(1-methyl isophthalic acid H-pyrazoles-4-yl)-6-(6-vinyl-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-quinoline
Figure A20078003852702431
[0520] to water (1mL) and 1, add 6-(6-chloro-[1 in (bubbling fed nitrogen 15 minutes) mixture of the degassing of 4-dioxane (2mL), 2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-3-(1-methyl isophthalic acid H-pyrazoles-4-yl)-quinoline (117mg, 0.31mmol), vinyl boric acid pinacol ester (59 μ l, 0.35mmol), salt of wormwood (0.93mmol, 128mg) and dichloro [1,1 '-two (diphenylphosphino)-ferrocene] and palladium (II) methylene dichloride adducts (15mg, 0.02mmol).Heated for 1500 seconds with microwave tubule jam-pack and in microwave reactor (Personel Chemistry, Emrys Optimizer) in 135 ℃.After this, on silica gel, concentrate organic phase,, be used in the 0-10% methanol-eluted fractions in the methylene dichloride, obtain title compound (22mgs, 19% yield), be white solid through the rapid column chromatography purifying.Analytical data shown in the table 2.
Method D
Compound 15:6-(6-chloro-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-quinoline
[0521] under room temperature, to (6-chloro-pyridazine-3-yl)-hydrazine (1,62g, 11.2mmol) and 6-quinoline acetate (2.1g, 11.2mmol) in the suspension of methylene dichloride (150mL), add dicyclohexylcarbodiimide (2.3g, 11.2mmol).After stirring 4.5 hours under the room temperature, remove by filter the throw out of formation, with washed with dichloromethane and vacuum-drying, reclaim quinoline-6-base-acetate N '-(6-chloro-pyridazine-3-yl)-hydrazides, it also contains dicyclohexylurea (DCU).Then this mixture is dissolved in acetate (250mL) and in 50 ℃ the heating 4 hours.After this, with this mixture vacuum concentration to silica gel, through rapid column chromatography purifying (SiO 2, CH 2Cl 2: CH 3OH 100: 0-97: 3) reclaim title compound, be white solid (3.35g, 11.1mmol, 99% yield).Analytical data shown in the table 1.
Method E
Compound 38:2-methyl-6-(6-phenyl-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-quinoline
Figure A20078003852702442
[0522] (6-phenyl-pyridazine-3-yl)-hydrazine dihydrochloride (20mg packs in a bottle, 0.077mmol), (2-methyl-quinoline-6-yl)-acetate (17mg, 0.085mmol), N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride (22mg, 0.115mmol), I-hydroxybenzotriazole hydrate (11mg, 0.077mmol), salt of wormwood (32mg, 0.231mmol) and N, dinethylformamide (0.7mL).Reaction mixture was stirred under room temperature 14 hours.After this, this mixture of vacuum concentration.(1mL) joins in the residue with acetate, in 55 ℃ the reaction mixture that obtains stirred 5 hours.After this, this mixture of vacuum concentration and being allocated between 1M wet chemical and the ethyl acetate.With 1M wet chemical washing organic layer, use the salt water washing then, and directly be absorbed on the silica gel.Use the 0-8% gradient liquid of methyl alcohol in ethyl acetate, purifying on silica gel obtains title compound (8.7mg, 0.024mmol, 32% yield), is light yellow solid.Analytical data shown in the table 1.
Method F
Compound 103; (S)-3-[3-(1-benzothiazole-6-base-ethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-yl]-benzonitrile and compound 104; I-3-[3-(1-benzothiazole-6-base-ethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-yl]-benzonitrile
Embodiment 103 embodiment 104
[0523] makes 3-[3-(1-benzothiazole-6-base-ethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-yl]-benzonitrile (5.27g) is dissolved in methylene dichloride (200mL) and goes up enantiomer separation in Berger supercritical liq multigram II system (Berger super critical fluid multigram II system).On Chiralcel OD-H (2x15cm) post, separate, with 40% methyl alcohol/CO 2(100 crust), 50mL/min, the 220nM wash-out reclaims embodiment 103 (2.1g, retention time 5.31 minutes, ee＞99%) and embodiment 104 (2.2g, retention time 6.30, ee＞99%).
Method G
Compound 108:6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-3-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-[1,2,4] triazolo [4,3-b] pyridazine
Figure A20078003852702452
[0524] in the 20ml bottle, adds (the 1H-pyrrolo-[2 of 52mgs (0.295mmol), 3-b] pyridin-3-yl)-O-(7-azepine benzo triazol-1-yl)-N of acetate, 1.2eq. (0.354mmol), N, N, N '-tetramethyl-urea hexafluoro-phosphoric acid salt, 1.5eq. (0.443mmol) [6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-pyridazine-3-yl]-hydrazine and 4eq. (1.18mmol) N, the N-diisopropylethylamine also is dissolved in 4mls dimethyl-methane amide.This reaction mixture was stirred under room temperature 18 hours.After this, vacuum is removed dimethyl formamide, joins acetate (4mls) in the residue and be heated to 60 ℃ to continue 4 hours.Solvent removed in vacuo, by the preparation HPLC purifying, use methylene dichloride: 95: 5 wash-outs of methyl alcohol, reclaim title compound (3mgs, 3% yield), be pale solid.Analytical data shown in the table 1.
Method H
Compound 7:6-[6-(3,4-two fluoro-phenoxy groups)-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl]-quinoline
[0525] with 6-(6-chloro-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-quinoline (60mg, 0.203mmol, 1.0equiv.), 3, the 4-fluorophenol (0.223mmol, 1.1equiv.), Cs 2CO 3(86mg, 0.264mmol, 1.3equiv) and the solution of methyl-sulphoxide (1mL) in microwave tube, mix and jam-pack.(Personel Chemistry is EmrysOptimizer) in 70 ℃ of reactions 10 minutes in microwave reactor with the microwave tube content.Through rotary evaporation remove desolvate and crude product through rapid column chromatography purifying (SiO 2, CH 2Cl 2: CH 3OH 100: 0-80: 20), reclaim title compound, be white solid (27.2mg, 0.07mmol, 34% yield).Analytical data shown in the table 1.
Method I
Compound 140:6-(6-methoxyl group-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-3-(1-methyl isophthalic acid H-pyrazoles-4-yl)-quinoline
Figure A20078003852702462
[0526] in 5ml microwave bottle, adds 1ml methyl alcohol, then add 15mg salt of wormwood and 25mg (.067mmol) 6-(6-chloro-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline.This reaction mixture was heated for 3800 seconds in 130 ℃ of microwave ovens.Filter reaction mixture and through the preparation HPLC purifying reclaims title compound (11.6mg, 47%) then.Analytical data shown in the table 2.
Method J
Compound 45:3-(3H-benzoglyoxaline-5-ylmethyl)-6-phenyl-[1,2,4] triazolo [4,3-6] pyridazine
[0527] with 4-(6-phenyl-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-benzene-1, (20mg, 0.063mmol) suspension in formic acid (0.5mL) stirred 5 hours in 100 ℃ the 2-diamines.Making this reaction mixture be cooled to room temperature also filters by 0.45 micron filter.Vacuum concentrated filtrate.(5 microns, 19x150mm) upward through the preparation HPLC purifying, the gradient liquid of use formic acid buffered acetonitrile in water reclaims title compound to residue, is pale solid (15mg, 0.046mmol, 73% yield) at Xbridge prep Cl 8 posts.Analytical data shown in the table 1.
Method K
Compound 68:3-(3-methyl-3H-benzoglyoxaline-5-ylmethyl)-6-phenyl-[1,2,4] triazolo [4,3-b] pyridazine
Figure A20078003852702472
[0528] under nitrogen atmosphere, in 0 ℃ to sodium hydride (60%wt, 9mg, 0.221mmol) be added dropwise to 3-(3H-benzoglyoxaline-5-ylmethyl)-6-phenyl-[1 in the suspension in dimethyl formamide (0.5mL), 2,4] triazolo [4,3-b] pyridazine (60mg, dimethyl formamide 0.184mmol) (0.5mL) solution.This reaction mixture was stirred 15 minutes in 0 ℃, add then methyl-iodide (0.014mL, 0.221mmol).Make temperature reach room temperature, simultaneously this reactant was stirred 3.5 hours.In the quencher reaction carefully of 0 ℃ of water.Mixture also absorbs on the silica gel with ethyl acetate extraction (3x), merging organic layer.Purifying on silica gel, use the gradient liquid of 0-8% ethanol/methylene, obtain 15mg 3-(3-methyl-3H-benzoglyoxaline-5-ylmethyl)-6-phenyl-[1,2,4] triazolo [4,3-b] pyridazine and 3-(1-methyl isophthalic acid H-benzoglyoxaline-5-ylmethyl)-6-phenyl-[1,2,4] (1: 1) mixture of triazolo [4,3-b] pyridazine is pale solid (24% yield): 1H NMR (DMSO-d 6): δ d 3.71 (s, 3H), 3.72 (s, 3H), 4.63 (s, 2H), 4.65 (s, 2H), 7.19 (dd, 1H), 7.25 (dd, 1H), 7.42 (d, 1H), 7.50 (d, 1H), 7.53 (m, 6H), 7.56 (d, 1H), 7.59 (d, 1H), 7.85 (d, 1H), 7.87 (d, 1H), 8.06 (m, 6H), 8.33 (d, 1H), 8.35 (d, 1H); MS (m/z) 341[M+H +] +
Method L compound 124:3-(1-methyl isophthalic acid H-pyrazoles-4-yl)-6-(6-methyl-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-quinoline
Figure A20078003852702481
[0529] with 3-bromo-6-(6-methyl-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-quinoline (50mg, 0.141mmol is 1.0equiv.) 1, solution in the 4-dioxane (1mL) outgases and joins with nitrogen and contains 1-methyl-4-(4,4,5,5-tetramethyl--[1,3,2] the assorted penta ring-2-yl of two oxa-boron)-(0.177mmol, 1.25equiv. is in microwave tube 37mg) for the 1H-pyrazoles.(39mg) solution through the degassing in water (0.5mL) joins in the microwave tube for 0.282mmol, 2equiv. with salt of wormwood, then add dichloro [1,1 '-two (diphenylphosphino) ferrocene] and palladium (II) methylene dichloride adducts (5mg, 0.0071mmol, 0.05equiv).Reacted 30 minutes in 100 ℃ with this microwave tube jam-pack and in microwave reactor.This reaction mixture is allocated between methylene dichloride and the water, and the rapid steamer layer, residue directly is absorbed on the silica gel.Purifying on silica gel uses the 0-10% gradient liquid of methyl alcohol in methylene dichloride, then grinds with methyl alcohol, obtains title compound (1.8mg, 0.005mmol, 4% yield), is white solid.Analytical data shown in the table 2.
Method M
Compound 111:6-(6-chloro-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-5,7-two fluoro-quinoline
Figure A20078003852702491
[0530] with (6-chloro-pyridazine-3-yl)-hydrazine (531mg, 3.67mmol) join in the round-bottomed flask of oven drying and be dissolved in dimethyl formamide (7mL) and triethylamine (1.54ml, 11.01mmol) in.This solution is cooled to 0 ℃.(887mg 3.67mmol) is dissolved in dimethyl formamide (8mL) and being added dropwise in the reaction mixture to make (5,7-two fluoro-quinoline-6-yl)-Acetyl Chloride 98Min..After finishing, reaction promptly adds acyl chlorides.This solution for vacuum concentration to doing, is obtained (5,7-two fluoro-quinoline-6-yl)-acetate N '-(6-chloro-pyridazine-3-yl)-hydrazides.LCMS[M+H +]＝350.0。(1.28g 3.67mmol) is suspended in the acetate (30mL) and with solution and is heated to 60 ℃ through 16 hours to make (5,7-two fluoro-quinoline-6-yl)-acetate N '-(6-chloro-pyridazine-3-yl)-hydrazides.Vacuum concentrated mixture makes residue be dissolved in methylene dichloride (125ml) also with saturated NaHCO then 3(100ml) and salt solution (100ml) washing.Organic layer is through Na 2SO 4Dry also vacuum concentration.The solid that obtains grinds with methyl alcohol, by filtering quantitative collection title compound and dry.Analytical data shown in the table 1.
Method N
Compound 152:6-(6-chloro-[1,2,4] triazolo [4,3-b] pyridazine-3-is a methyl)-3-(1-methyl isophthalic acid H-pyrazoles-4-yl)-quinoline
Figure A20078003852702492
[0531] in 0 ℃, (530mg 1.98mmol) adds oxalyl chloride (1.2eq) and 1 dimethyl formamide in the mixture in methylene dichloride (2mL) to [3-(1-methyl isophthalic acid H-pyrazoles-4-yl)-quinoline-6-yl]-acetate.This reaction mixture was stirred 1 hour.The aliquots containig that takes a morsel also is dissolved in methyl alcohol with the preparation methyl ester, and verify on LCMS: m/z 382.1.Solvent removed in vacuo then adds methylene dichloride, and it is removed through vacuum.And add the toluene of removing through vacuum, and reclaim [3-(1-methyl isophthalic acid H-pyrazoles-4-yl)-quinoline-6-yl]-Acetyl Chloride 98Min. with 88% yield, be yellow solid.
[0532] (190mg 1.315mmol) is dissolved in dimethyl formamide, then adds triethylamine (3eq) to make (6-chloro-pyridazine-3-yl)-hydrazine.This mixture was stirred 5 minutes.This mixture becomes deep green, is cooled to 0 ℃ then.(this reaction mixture becomes deep yellow to Acetyl Chloride 98Min. for 375mg, dimethyl formamide solution 1.315mmol), and stirs 1 hour to be added dropwise to [3-(1-methyl isophthalic acid H-pyrazoles-4-yl)-quinoline-6-yl].After this, concentrate this mixture, be dissolved in acetate (10mL) then and stirred 16 hours in 60 ℃ to doing.Solvent removed in vacuo is allocated between ethyl acetate and the water and with further extraction of ethyl acetate residue and contains water.The organism that merges is through rapid column chromatography purifying (SiO 2, CH 2Cl 2, methyl alcohol gradient liquid 0-10%), reclaim title compound (217mg, 42% yield).Analytical data shown in the table 2.
Method O
Compound 145:5,7-two fluoro-3-(1-methyl isophthalic acid H-pyrazoles-4-yl)-6-(6-methyl-[1,2,4] triazolo [4,3b] pyridazine-3-ylmethyl)-quinoline
Figure A20078003852702501
[0533] in the 40ml bottle, add 1-butanols (10ml), [2,4-two fluoro-3-(1-methyl isophthalic acid H-pyrazoles-4-yl)-quinoline-6-yl]-acetic acid hydrazides (425mg, 1.34mmol) and 3-chloro-6-methyl pyridazine (172mg, 1.34mmol).This mixture was heated 24 hours in 120 ℃.Solvent removed in vacuo stirs residue in ethanol, filter then and obtain the thick material of 200mgs.Through rapid column chromatography purifying (SiO 2, methylene chloride 0-10%), reclaim the 182mgs pure substance with 35% yield.Analytical data shown in the table 2.
Method P
Compound 123:3-(1-methyl isophthalic acid H-pyrazoles-4-yl)-6-(6-trifluoromethyl-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-quinoline
Figure A20078003852702511
[0534] with 1-butanols (2mL), 3-chloro-6-trifluoromethyl-pyridazine (0.13mmol, 25mg), (0.13mmol, mixture 40mg) was in 120 ℃ of heating 18 hours for [3-(1-methyl isophthalic acid H-pyrazoles-4-yl)-quinoline-6-yl]-acetic acid hydrazides.By blasting nitrogen, brown residue is dissolved in 1ml dimethyl formamide and the 1ml methyl alcohol and through the preparation HPLC purifying then, reclaims title compound (15.8mg, 0.04mmol, 29%) except that desolvating.Analytical data shown in the table 2.
Method Q
Compound 159: dimethyl-3-[3-(1-methyl isophthalic acid H-pyrazoles-4-yl)-quinoline-6-ylmethyl]-[1,2,4] triazolo [4,3-b] pyridazine-6-yl }-amine
[0535] aqueous solution of adding 1ml dimethyl amine 40% in 5ml microwave bottle, then add 300 μ DMSO, with dissolving 25mg (0.067mmol) 6-(6-chloro-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline.This reactant was heated for 2000 seconds in 130 ℃ in microwave oven.Filter reaction mixture then through the preparation HPLC purifying, reclaims title compound (7.7mg, 30% yield).Analytical data shown in the table 2.
Method R
Compound 144:2-{4-[6-(6-methyl-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-quinoline-3-yl]-pyrazol-1-yl }-ethanol
Figure A20078003852702513
[0536] in microwave container, adds 3-bromo-6-(6-methyl-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-quinoline (80mg, 0.23mmol, 1equiv), two (tetramethyl ethylene ketone) borine (69mg, 0.27mmol, 1.2equiv), potassium acetate (66mg, 0.67mmol, 3.0equiv), then add N,N-DIMETHYLACETAMIDE (0.8mL).Make this solution degassing 10 minutes and add dichloro [1,1 '-two (diphenylphosphino) ferrocene] palladium (II) methylene dichloride adducts (7mg, 0.01mmol, 0.048equiv).Reacted 1 hour in 120 ℃ with the microwave container jam-pack and in microwave reactor.The cooled microwave container, (0.18mmol 0.8equiv), then adds 2M aqueous sodium carbonate (0.6mL) to add 2-(4-bromo-the pyrazol-1-yl)-ethanol that is dissolved in the N,N-DIMETHYLACETAMIDE (0.6mL) then.Make this solution degassing 10 minutes and add dichloro [1,1 '-two (diphenylphosphino) ferrocene] palladium (II) methylene dichloride adducts (7mg, 0.01mmol, 0.048equiv).Reacted 2 hours in 120 ℃ with the microwave container jam-pack and in microwave reactor.After the cooling, add Na 2SO 4(3g) and with this mixture of dilution in acetonitrile, filter by Celite pad.Concentrated filtrate and warp or flash chromatography (SiO on silica gel 2, CH 2Cl 2: CH 320) or the preparation HPLC purifying OH 100: 0-80:, reclaim title compound.Analytical data shown in the table 2.
Method S
Compound 110:6-(6-methyl-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-quinoline-3-formonitrile HCN
[0537] title compound is according to Chobanian, H.R.; Fors, B.P.; Lin, L.S.Tet Lett.47,2006, method (the not doing great change) preparation that 3303-3305 describes.Analytical data shown in the table 1.
Method T
Compound 157:6-(6-ethyl-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-3-(1-methyl isophthalic acid H-pyrazoles-4-yl)-quinoline
Figure A20078003852702531
[0538] at N 2 (g)Under the atmosphere, to 3-(1-methyl isophthalic acid H-pyrazoles-4-yl)-6-(6-vinyl-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-(22mg 0.06mmol) adds 10% palladium on carbon (20mg) to quinoline in the solution in methylene dichloride (5mL) and methyl alcohol (0.5mL), use H 2 (g)Replace nitrogen.After the vigorous stirring 3 hours, filter this mixture, through rapid column chromatography purifying (SiO by Celite pad 2, CH 2Cl 2, methyl alcohol 0-10%), reclaim title compound, be white solid (17mg, 77%).Analytical data shown in the table 2.
Method U
Compound 142:3-(1H-imidazol-4 yl)-6-(6-methyl-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-quinoline
Figure A20078003852702532
[0539] to 4-bromo-1-trityl-1H-imidazoles (103mg, 0.24mmol, add in tetrahydrofuran (THF) 1.0equiv) (1mL) solution ethylmagnesium bromide (3M in ether, 0.094mL, 0.28mmol, 1.2equiv) and will react stirring 90 minutes.Add ZnCl then 2(38mg, 0.28mmol is 1.2equiv) and with other 90 minutes of solution stirring.(0.10equiv) (100mg, 0.28mmol 1.2equiv) and with solution heated 18 hours in 70 ℃ with 3-bromo-6-(6-methyl-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-quinoline for 2mg, 0.024mmol to add four (triphenyl phosphine) palladium.Solvent removed in vacuo is absorbed in the silica gel residue, through flash chromatography purifying (SiO 2, CH 2Cl 2: CH 3OH 100: 0-80: 20), reclaim 6-(6-methyl-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-3-(3-trityl-3H-imidazol-4 yl)-quinoline.By being stirred, this compound removed trityl in 3 hours in methyl alcohol salt manufacturing acid (0.5N).Vacuum is removed volatile matter, and residue is stirred in ethanol, collects and drying by filtering, and reclaims title compound (5.6mg, 8% yield).Analytical data shown in the table 2.
Method V
Compound 132:3-imidazoles-1-base-6-(6-methyl-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-quinoline
Figure A20078003852702541
[0540] in the reaction bottle, adds 3-bromo-6-(6-methyl-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-quinoline (71mg, 0.2mmol, 1.0equiv), CuI (7mg, 0.04mmol, 0.008equiv), the L-proline(Pro) (9mg, 0.08mmol, 0.4equiv) and K 2CO 3(83mg, 0.60mmol, 3.0equiv).Fill with this system pump down and with nitrogen (3x).Add imidazoles (27mg, 0.4mmol, 2.0equiv) the solution in DMSO (1mL) then through the degassing.This reactant was heated 18 hours in 120 ℃.Solvent removed in vacuo makes residue be absorbed in the silica gel and through flash chromatography purifying (SiO 2, CH 2Cl 2: CH 3OH 100: 0-90: 10) reclaim title compound (15mg, 22% yield).Analytical data shown in the table 2.
Method W
Compound 125:6-(6-methyl-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-3-(1H-pyrazoles-4-yl)-quinoline
Figure A20078003852702542
[0541] in the microwave bottle, adds 3-bromo-6-(6-methyl-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-quinoline (100mg, 0.28mmol, 1equiv), 4-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron penta ring-2-yl of mixing)-1-(2-TMS-ethoxyl methyl)-1H-pyrazoles (113mg, 0.35mmol, 1.25equiv), K 2CO 3(78mg, 0.566mmol 2.0equiv), then add 1,4-dioxane (3mL) and water (1.5mL).
[0542] with this solution with the nitrogen degassing 10 minutes, add then dichloro [1,1 '-two (diphenylphosphino) ferrocene] palladium (II) methylene dichloride adducts (10mg, 0.014mmol, 0.05equiv).Heated 30 minutes in 130 ℃ with the microwave container jam-pack and in microwave reactor.Cooling mixture and be allocated in methylene dichloride and water between.Make organic phase be absorbed in the silica gel and through flash chromatography purifying (SiO 2, CH 2Cl 2: CH 3OH 100: 0-80: 20), obtain 6-(6-methyl-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-3-[1-(2-TMS-ethoxyl methyl)-1H-pyrazoles-4-yl]-quinoline (106mg, 80% yield).Then this solid is joined in the solution of dimethyl formamide of 20% quadrol and stirred 3 hours.Remove and desolvate, residue grinds with ethanol, obtains title compound (65mg, 85% yield).Analytical data shown in the table 2.
Method X
Compound 27:6-[(6-chloro-[1,2,4] triazolo [4,3-b] pyridazine-3-yl)-fluoro-2-methyl-]-quinoline
Step 3:6-[(6-chloro-[1,2,4] triazolo [4,3-b] pyridazine-3-yl)-fluoro-2-methyl-]-quinoline [0543] is under room temperature, to (6-chloro-pyridazine-3-yl)-hydrazine (233mg, 1.6mmol) (3.90mg is 1.6mmol) at methylene dichloride (22mL) and pyridine (1.6mmol with 6-fluoro-quinoline-6-base-acetic acid hydrochloride, add in suspension 126mg) dicyclohexylcarbodiimide (333mg, 1.6mmol).After stirring 18 hours under the room temperature, remove by filter the throw out of formation, with washed with dichloromethane and vacuum-drying, be dissolved in then in the acetate (15mL) and and heated 6 hours in 55 ℃.After this, with this mixture vacuum concentration to silica gel, through rapid column chromatography purifying (SiO 2, CH 2Cl 2: CH 3OH 100: 0-90: 10), reclaim title compound, be yellow foam (138mg, 0.44mmol, 28% yield).Analytical data shown in the table 1.
Method Y
Compound 17:3-benzothiazole-6-ylmethyl-6-chloro-[1,2,4] triazolo [4,3-b] pyridazine
Figure A20078003852702561
[0544] (44g, 228mmoles) (36.2g 251mmoles) is dissolved in the mixture of anhydrous dimethyl formamide (40mL) and anhydrous methylene chloride (600ml) with (6-chloro-pyridazine-3-yl)-hydrazine to make benzothiazole-6-base-acetate.Mixture is under the nitrogen and with ice bath is cooled to 0 ℃, then with N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride (65.5g, 342mmoles), hydroxy benzotriazole hydrate (38.4g, 251mmoles) and salt of wormwood (157g 1.14moles) adds in this mixture.Mixture was stirred 4 hours and in stirred overnight at room temperature in 5 ℃.TLC shows that SM disappears.Filter this mixture and use salt water washing (400mL x 2) filtrate.Organic phase is through anhydrous Na 2SO 4Drying concentrates and obtains brown oil.Make oily matter be dissolved in acetate (750mL) and stirred 4 hours in 50 ℃.After this, solvent removed in vacuo, residue is used eluent ethyl acetate through the silicagel column purifying, obtains crude product (20g).Make crude product recrystallization from ethyl acetate and sherwood oil, obtain title compound (15g).Analytical data shown in the table 1.
Method Z
Compound 149:2-{4-[6-(6-methyl-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-quinoline-3-yl]-pyrazol-1-yl }-ethanamide
[0545] makes 6-(6-methyl-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-(65mg, 0.19mmol 1equiv) are dissolved in dimethyl formamide (0.5mL) to 3-(1H-pyrazoles-4-yl)-quinoline, (60% in oil to add NaH, 1.2equiv, 0.228mmol, 9mg), this solution was stirred 30 minutes under nitrogen, (26mg, 0.19mmol 1equiv) and with this solution heated 18 hours in 90 ℃ to add 2-bromo ethanamide then.Extract this product in the methylene dichloride and wash with water.
Organic phase is concentrated into dried, obtains title compound (40mg, 52% yield).Analytical data shown in the table 2.
Method AA
Compound 109:6-(6-cyclopropyl-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-quinoline
Figure A20078003852702571
Step 1: preparation cyclopropyl bromination magnesium:
[0546] tetrahydrofuran (THF) (2mL) solution with Cyclopropyl Bromide (192 μ L) joins in the magnesium powder (40mg), then adds iodine monocrystalline (single iodine crystal).This mixture heating was also stirred 15 minutes.
Step 2: preparation 6-(6-cyclopropyl-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-quinoline
[0547] with 6-(6-chloro-[1; 2; 4] triazolo [4,3-b] pyridazine-3-ylmethyl)-quinoline (240mg), Acetyl Acetone acid (acetonate), iron (III) (12mg) mixture in tetrahydrofuran (THF) (5mL) feed the nitrogen degassing 10 minutes by bubbling.The tetrahydrofuran solution of the cyclopropyl bromination magnesium that will prepare in step 1 then joins in the reaction mixture and in 50 ℃ and stirred 18 hours.Make this mixture be cooled to room temperature, make by adding 1N hydrochloric acid (20mL) then to be acidified to pH 1.Vacuum is removed tetrahydrofuran (THF) and is passed through to add NaHCO 3The aqueous solution neutralizes, and this contains water, uses ethyl acetate (x3) to extract then, dry (Na 2SO 4) and be concentrated into dried.Make residue be dissolved in piperidines (1mL) and in microwave oven in 120 ℃ the heating 25 minutes to consume remaining 6-(6-chloro-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-quinoline.By preparation HPLC purifying title compound, reclaim title compound (4mg, 10%) then.Analytical data shown in the table 1.
Method BB
Compound 166:6-(6-ethyl-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-5,7-two fluoro-3-(1-methyl isophthalic acid H-pyrazoles-4-yl)-quinoline
Figure A20078003852702581
[0548] to 3-bromo-6-(6-ethyl-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-5,7-two fluoro-quinoline (86mg, 0.2mmol), 1-methyl-4-(4,4,5,5-tetramethyl--[1,3,2] the assorted penta ring-2-yl of two oxa-boron)-1H-pyrazoles (0.21mmol, 44mg) and cesium carbonate (0.6mmol＜, reflux in the mixture in the 4-dioxane (2mL) and add down [2-[(D-N) methyl 195mg) 1] phenyl-c] (tricyclohexyl phosphine) trifluoroacetic acid base (acetato)-O-(SP-4-3)-palladium (Bedford, R.B.; Cazin, C.S.J.; Coles, S.J.; Gelbrich, T.; Horton, P.N.; Hursthouse, M.B.; Light, M.E. organo-metallic (Organometallics) 2003,22,987) (0.5mol%, 0.1 μ mol, 0.1mg).After 30 minutes, by silicagel pad filter reaction mixture (2g), the usefulness methylene chloride (17/3,12mL) wash-out.Concentrated filtrate on silica gel is through rapid column chromatography purifying (SiO 2, CH 2Cl 2: CH 3OH 100: 0-90: 10) reclaim title compound, be pale solid (52mg, 60% yield).Analytical data shown in the table 2.
Method CC
Compound 175:1-(3-{4-[6-(6-methyl-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-quinoline-3-yl]-pyrazol-1-yl }-azetidine-1-yl)-ethyl ketone
[0549] to the 3-in methylene dichloride (1mL) (1-azetidine-3-base-1H-pyrazoles-4-yl)-6-(6-methyl-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-quinoline (25mg, 0.063mmol) the middle triethylamine (9.7uL that adds, 0.069mmol), then add Acetyl Chloride 98Min. (5.0uL, 0.069mmol).This mixture stirred under room temperature spend the night.The dilute with water reactant also extracts product in the methylene dichloride.The dilute with water reactant extracts product in the methylene dichloride and washes with water.Filtrate is concentrated in vacuo in the silica gel, through flash chromatography purifying (SiO 2, CH 2Cl 2: CH 3OH 100: 0-90: 10), reclaim title compound (4.20mg, 15% yield).Analytical data shown in the table 2.
Method DD
Compound 171:3-[1-(1-ethyl-azetidine-3-yl)-1H-pyrazoles-4-yl]-6-(6-methyl-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-quinoline
[0550] to the 3-in methylene dichloride (3mL) (1-azetidine-3-base-1H-pyrazoles-4-yl)-6-(6-methyl-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-quinoline (50mg, 0.126mmol) middle adding acetaldehyde (15uL, 0.505mmol).This solution was stirred under room temperature 15 minutes, add sodium triacetoxy borohydride (67mg, 0.136) then.After 1 hour, dilute this solution and use sodium bicarbonate (1.5mL) washing with methylene dichloride (1.5mL).Further extract with methylene dichloride (1.5mL) in the waterbearing stratum.The dichloromethane layer that merges is with salt water washing (3mL) and through Na 2SO 4Dry.Filtrate is concentrated in vacuo in the silica gel, through flash chromatography purifying (SiO 2, CH 2Cl 2: CH 3OH 100: 0-90: 10), reclaim title compound (4.8mg, 9% yield).Analytical data shown in the table 2.
Method EE
Compound 172:3-[1-(1-methylsulfonyl-azetidine-3-ylmethyl)-1H-pyrazoles-4-yl]-6-(6-methyl-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-quinoline
Figure A20078003852702592
[0551] to (1-azetidine-3-ylmethyl-1H-pyrazoles-4-yl)-6-(6-methyl-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-quinoline (22mg, 0.054mmol) methylene dichloride (1mL) solution in add triethylamine (7.5uL 0.054mmol), then add methane sulfonyl chloride (4.0uL, 0.054mmol) and dimethyl aminopyridine (6.6mg, 0.054mmol).This mixture stirred under room temperature spend the night.The dilute with water reactant also extracts product in the methylene dichloride.The dilute with water reactant also extracts in the methylene dichloride, washes with water.Filtrate is concentrated in vacuo in the silica gel, through flash chromatography purifying (SiO 2, CH 2Cl 2: CH 3OH 100: 0-90: 10), reclaim title compound (5.4mg, 21% yield).Analytical data shown in the table 2.
Method FF
Compound 177:6-methyl-3-[5-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl]-[1,2,4] triazolo [4,3-b] pyridazine
Figure A20078003852702601
[0552] (60mg, 0.22mmol) (35mg 0.27mmol) just is being suspended in-butanols in (1mL) with 3-chloro-6-methyl-pyridazine to make [5-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-pyrrolo-[2,3-b] pyridin-3-yl]-acetic acid hydrazides.This suspension was heated 1 hour in 200 ℃ in microwave oven.Then, this solution is transferred in the separating funnel that contains methylene dichloride (20mL).With saturated NaHCO 3(aq) (30ml) wash this solution.Distribute organic layer, through Na 2SO 4Dry also vacuum concentration.Thick material is dry and be filled in the silica gel, through flash chromatography purifying (0-10% ethanol/methylene gradient liquid), obtain product, 6-methyl-3-[6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-pyrrolo-[3,2-b] pyridine-1-ylmethyl]-[1,2,4] triazolo [4,3-b] pyridazine (24.3mg, 32% yield), make its crystallization in minimum methyl alcohol then.Analytical data shown in the table 2.
Method GG
Compound 176:3-{4-[6-(6-methyl-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-quinoline-3-yl]-the pyrazol-1-yl methyl }-azetidine-1-carboxylic acid tertiary butyl ester
Figure A20078003852702611
[0553] in microwave container, adds 3-bromo-6-(6-methyl-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-quinoline (476mg, 1.35mmol, 1equiv), 3-[4-(4,4,5,5-tetramethyl--[1,3] dioxolane-2-yl)-the pyrazol-1-yl methyl]-azetidine-1-carboxylic acid tertiary butyl ester (1.2g, 3.37mmol, 2.5equiv), K 2CO 3(393mg, 2.84mmol 2.0equiv), connect and see adding dioxane (12mL) and water (6mL).With this solution with the nitrogen degassing 10 minutes, add then dichloro [1,1 '-two (diphenylphosphino) ferrocene] palladium (II) methylene dichloride adducts (44mg, 0.06mmol, 0.05equiv).Reacted 30 minutes in 130 ℃ with the microwave container jam-pack and in microwave reactor.Cooling mixture extracts this mixture in the methylene dichloride then and washes with water.Vacuum is removed volatile matter, makes residue be absorbed in the silica gel and through flash chromatography purifying (SiO 2, CH 2Cl 2: CH 3OH 100: 0-80: 20), obtain 3-{4-[6-(6-methyl-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-quinoline-3-yl]-the pyrazol-1-yl methyl }-azetidine-1-carboxylic acid tertiary butyl ester (189mg, 28% yield).Analytical data shown in the table 2.
Method HH
Compound 155:3-(1-azetidine-3-ylmethyl-1H-pyrazoles-4-yl)-6-(6-methyl-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-quinoline
Figure A20078003852702612
[0554] to 3-{4-[6-(6-methyl-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-quinoline-3-yl]-the pyrazol-1-yl methyl }-the middle 6mLTFA that adds of azetidine-1-carboxylic acid tertiary butyl ester (189mg): methylene dichloride/1: 1 solution.This mixture was stirred 2 hours.Remove volatile matter through rotary evaporation, add then methyl alcohol (6mL) and MP-carbonate (400mg, 3.18mmol/g).Filter resin, vacuum is removed volatile matter, obtains 3-(1-azetidine-3-ylmethyl-1H-pyrazoles-4-yl)-6-(6-methyl-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-quinoline with quantitative yield.Analytical data shown in the table 2.
Method II
Compound 179:3-(1-methyl isophthalic acid H-pyrazoles-4-yl)-6-[1,2,4] triazolo [4,3-b] [1,2,4] triazine-3-ylmethyl-quinoline
Figure A20078003852702621
[0555] to 3-bromo-6-[1,2,4] triazolo [4,3-b] [1,2,4] triazine-3-ylmethyl-quinoline (69mg, 0.204mmol), 1-methyl-4-pyrazoles boric acid pinacol ester (51mg, 0.25mmol), salt of wormwood (56mg.0.41mml), 1, bubbling fed nitrogen 10 minutes in the mixture of 4-dioxane (2mL) and water (ImL).After this, (8mg, 5mol%), sealed vial also heated for 1500 seconds in 135 ℃ in microwave oven to add dichloro two (triphenyl phosphine) palladium.Dilute this mixture with methylene dichloride and salt solution, organic phase is concentrated in the silica gel and then through rapid column chromatography (SiO 24g, methylene dichloride/CH 3OH 0-10%), reclaims title compound, be white solid (11mg, 16%).Analytical data shown in the table 2.
Method JJ
Compound 117:3-bromo-6-[1,2,4] triazolo [4,3-b] [1,2,4] triazine-3-ylmethyl-quinoline
Figure A20078003852702622
[0556] with 5-(3-bromo-quinoline-6-ylmethyl)-[1,2,4] triazole-3, the 4-diamines (977mg, 3mmol), oxalic dialdehyde (40% the aqueous solution, 5mL), the mixture of acetate (10mL) and water (2mL) stirred under room temperature 18 hours.After this, filter this mixture, concentrated filtrate and on silica gel through rapid column chromatography (SiO 212g, methylene dichloride/CH 3OH 0-10%), reclaims title compound, is white solid (298mg, 29%).Analytical data shown in the table 1.
Method KK
Compound 118: 6-(6-methyl-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-3-ethene yl-quinoline
Figure A20078003852702631
[0557] in microwave container, add 3-bromo-6-(6-methyl-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-quinoline (500mg, 1.41mmol, 1equiv), vinyl boric acid (299uL, 1.76mmol, 1.25equiv), K 2CO 3(390mg, 2.82mmol 2.0equiv), then add 1,4-dioxane (10mL) and water (5mL).With this solution with the nitrogen degassing 10 minutes, add then dichloro [1,1 '-two (diphenylphosphino) ferrocene] palladium (II) methylene dichloride adducts (51mg, 0.07mmol, 0.05equiv).Reacted 30 minutes in 130 ℃ with the microwave container jam-pack and in microwave reactor.The cooled microwave container extracts this mixture in the methylene dichloride then and washes with water.Vacuum is removed volatile matter, makes residue be absorbed in the silica gel and through flash chromatography purifying (SiO 2, CH 2Cl 2: CH 3OH 100: 0-80: 20) obtain title compound, be brown oil (35% yield).Analytical data shown in the table 1.
Method LL
Compound 116:3-ethyl-6-(6-methyl-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-quinoline
Figure A20078003852702632
[0558] under nitrogen atmosphere, with 6-(6-methyl-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-3-ethene yl-quinoline (20mg, 0.0664mmol) and palladium on carbon (10%wt, 20mg) vigorous stirring 4 hours under room temperature of the mixture in (1.5mL) in ethanol.Filter this mixture by Celite pad then, concentrated filtrate obtains title compound (15mg, 75% yield).Analytical data shown in the table 1.
Method MM
Compound 119:3-bromo-6-[1-(6-methyl-[1,2,4] triazolo [4,3-b] pyridazine-3-yl)-ethyl]-quinoline
Figure A20078003852702641
[0559] (500mg, (299mg is 2.32mmol) in the stirred solution in propyl carbinol 2.32mmol) to join 3-chloro-6-methyl pyridazine with 2-quinoline-6-base-propionic acid hydrazides (intermediate 63).With this reaction mixture in 120 ℃ of heated overnight.Vacuum is removed volatile matter, and residue is absorbed in the silica gel, through flash chromatography purifying (SiO 2, CH 2Cl 2: CH 3OH 100: 0-90: 10), obtain 6-[1-(6-methyl-[1,2,4] triazolo [4,3-b] pyridazine-3-yl)-ethyl]-quinoline (356mg, 53% yield).To 6-[1-(6-methyl-[1,2,4] triazolo [4,3-b] pyridazine-3-yl)-ethyl]-(356mg is added dropwise to bromine (1.73uL, acetate 3.69mmol) (3mL) solution in 1.23mmol) to quinoline.This reactant was heated 2 hours in 100 ℃.Make reaction mixture be cooled to room temperature, solvent removed in vacuo.Add the aqueous solution (10mL) of 10%NaSH, product is used in 10% methanol extraction in the methylene dichloride.Organic phase is washed with 5% sodium sulfite aqueous solution.Then with the filtrate vacuum concentration to silica gel, through flash chromatography purifying (SiO 2, CH 2Cl 2: CH 3OH 100: 0-90: 10), reclaim title compound (168mg, 37% yield).Analytical data shown in the table 1.
Method NN
Embodiment 3-[1-(1-methyl-azetidine-3-yl)-1H-pyrazoles-4-yl]-6-(6-methyl-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-quinoline
Figure A20078003852702651
[0560] to the 3-in methylene dichloride (9mL) (1-azetidine-3-base-1H-pyrazoles-4-yl)-6-(6-methyl-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-quinoline (194mg, 0.4898mmol) middle adding formaldehyde (37% in water, 1.959mmol, 147uL).This solution was stirred under room temperature 15 minutes, add then sodium triacetoxy borohydride (260mg, 1.22mmol).After 1 hour, dilute this solution and use sodium bicarbonate (6mL) washing with methylene dichloride (6mL).Further extract with methylene dichloride (6mL) in the waterbearing stratum.The dichloromethane layer that merges is with salt water washing (12mL) and through Na 2SO 4Dry.Filtrate is concentrated in vacuo in the silica gel, through flash chromatography purifying (SiO 2, CH 2Cl 2: CH 3OH: NH 4OH, 95: 4.995: 0.005-80: 19.98: 0.02), reclaim title compound (69mg, 35% yield).Analytical data shown in the table 2.
[0561] structure, name, physics and biological data and method are further described in the following table 1 with tabulated form.
Table 1
Figure A20078003852702652
Figure A20078003852702661
Figure A20078003852702681
Figure A20078003852702691
Figure A20078003852702701
Figure A20078003852702711
Figure A20078003852702721
Figure A20078003852702731
Figure A20078003852702741
Figure A20078003852702751
Figure A20078003852702761
Figure A20078003852702771
Figure A20078003852702781
Wherein:
I c-MET IC 50≤100nM；
II 100nM＜c-MET IC 50≤1μM；
III 1 μ M＜c-MET IC 50≤ 10 μ M; With
IV 10μM＜c-MET IC 50≤50μM。
[0562] structure, name, physics and biological data and method are further described in the following table 2 with tabulated form.
Table 2
Figure A20078003852702791
Figure A20078003852702811
Figure A20078003852702821
Figure A20078003852702831
Figure A20078003852702841
Figure A20078003852702851
Figure A20078003852702861
Figure A20078003852702871
Figure A20078003852702881
Wherein:
I c-MET IC 50＜100nM；
II 100nM＜c-MET IC 50＜1μM；
III 1 μ M＜c-MET IC 50＜10 μ M; With
IV 10μM＜c-MET IC 50＜50μM。
Biology is measured
[0563] kinase assay well known by persons skilled in the art can be used for measuring the inhibition activity of compound of the present disclosure and composition.Kinase assays includes, but are not limited to following examples.
[0564] the equation evaluation below garbled data adopts: Z '=1-[3* (σ ++ σ -)/| μ +-μ -|] (Zhang, etc., 1999 J Biomol Screening, 4 (2) 67-73), wherein μ represents that average and σ represent standard error.Subscript refers to the positive or negative contrast.For the Z ' score value of powerful (robust) screening assay should 〉=0.50.Typical threshold value=μ +-3* σ +Any value that is not less than threshold value is designated as " hitting (hit) ".
MET fluorescence-Ji enzyme assay
[0565] material: (SigmaCat#A-3377, FW=551), the HEPES damping fluid, pH 7.5, bovine serum albumin (BSA) (Roche 92423420), MgCl for Poly Glu-Tyr (4: 1) substrate (Sigma Cat#P-0275), ATP 2, Staurosporine (streptomycete (Streptomyces sp.) SigmaCat#85660-1MG), the flat assay plate in white Costar 384-hole (VWRCat#29444-088).MET kinases (seeing below), kinases-Glo TM(PromegaCat#V6712).
[0566] storing solution: the 10mg/ml in water gathers Glu-Tyr (being stored in-20 ℃); The 100mMHEPES damping fluid, pH 7.5 (5ml 1M storing solution+45ml miliQH 2O); (5.51mg/ml is at dH for 10mM ATP 2Among the O) be stored in-20 ℃ and (50 μ l be diluted in 10mlmiliQH altogether 2Among the O, every day=50 μ M ATP active redundancy liquid); 1%BSA (1g BSA is in 100ml 0.1M HEPES, and pH 7.5, is stored in-20 ℃), 100mM MgCl 2200 μ M Staurosporines, 2X kinases-Glo TMReagent (prepared fresh or be stored in-20 ℃).
[0567] (20 μ l kinase reactions, 40 μ l detection reaction) is set in the standard test of 384-hole form plate: 10mM MgCl 20.3mg/ml poly-Glu-Tyr; 0.1%BSA; 1 μ l test compounds (in DMSO); 0.4 μ g/ml MET kinases; 10 μ M ATP; 100mM HEPES damping fluid.Positive control contains the DMSO that has or not test compounds.Negative control contains 10 μ M Staurosporines.Start kinase reaction at time t=0 by adding ATP.In 21 ℃ of incubation kinase reaction things 60 minutes, then with 20 μ l kinases-Glo TMReagent joins in each hole with the quencher kinase reaction and starts fluorescent reaction.After 20 minutes,, on culture plate-readout meter photometer, detect fluorescence in 21 ℃ of incubations.
AurA fluorescence-Ji enzymatic determination
[0568] material: Kemptide peptide substrates=LRRASLG (Biopeptide, San Diego, CA), ATP (Sigma Cat#A-3377, FW=551), the HEPES damping fluid, pH 7.5,10%Brij 35 (Calbiochem Cat#203728), MgCl 2, Staurosporine (streptomycete .SigmaCat#85660-1MG), the flat assay plate in white Costar 384-hole (VWRCat#29444-088), autophosphorylation AurA kinases (seeing below), kinases-Glo TM(PromegaCat#V6712).
[0569] storing solution: 10mM Kemptide peptide (7.72mg/ml is in water) is stored in-20 ℃; 100mM HEPES damping fluid+0.015%Brij 35, pH 7.5 (5ml 1MHEPES storing solution+75 μ L 10%Brij 35+45ml miliQH 2O); (5.51mg/ml is at dH for 10mM ATP 2Among the O) be stored in-20 ℃ and (50 μ l be diluted in 10mlmiliQH altogether 2Among the O, every day=50 μ M ATP active redundancy liquid); 100mM MgCl 2200 μ M Staurosporines, 2X kinases-Glo TMReagent (prepared fresh or be stored in-20 ℃).
[0570] AurA autophosphorylation reaction: with ATP and MgCl 2Join among the 1-5mg/ml AurA, make ultimate density be respectively 10mM and 100mM.Autophosphorylation is reacted on 21 ℃ of incubation 2-3 hours.By add EDTA to ultimate density 50mM with stopped reaction and with the liquid N of sample 2Quick freezing also is stored in-80 ℃.
[0571] (20 μ l kinase reaction things, 40 μ l detecting reactants) is set in the standard test of 384-hole form plate: 10mM MgCl 20.2mM Kemptide peptide; 1 μ l test compounds (in DMSO); 0.3 μ g/ml autophosphorylation AurA kinases; 10 μ M ATP; 100mM HEPES+0.015%Brij damping fluid.Positive control contains the DMSO that has or not test compounds.Negative control contains 5 μ M Staurosporines.Start kinase reaction at time t=0 by adding ATP.In 21 ℃ of incubation kinase reaction things 45 minutes, then with 20 μ l kinases-Glo TMReagent joins in each hole with the quencher kinase reaction and starts fluorescent reaction.After 20 minutes,, on culture plate-readout meter photometer, detect fluorescence in 21 ℃ of incubations.
The purifying of Met:
[0572] cell precipitation by half generation in the 12L Sf9 insect cell culture of the kinase domain of expressing human Met is suspended in and contains 50mM Tris-HCl pH 7.7 and 250mMNaCl, in the damping fluid of the primary culture of the about 40ml/1L of volume.The no EDTA-proteinase inhibitor mixture (Cat#1873580) of 1 RocheComplete is added in every 1L primary culture.In 4 ℃ this suspension was stirred 1 hour.In 4 ℃, by with 39,800xg removed chip in centrifugal 30 minutes.With in the supernatant liquor impouring 500ml beaker and add Qiagen Ni-NTA Agarose (agarose) soup compound (Cat#30250) of 10ml 50%, this soup compound is pre-equilibration and stirred 30 minutes in 4 ℃ in 50mM Tris-HCl pH7.8,50mM NaCl, 10% glycerine, 10mM imidazoles and 10mM methionine(Met).The sample impouring dripped in the post and wash in 4 ℃ then with 50mM Tris-HCl pH 7.8,500mMNaCl, 10% glycerine, 10mM imidazoles and the 10mM methionine(Met) of 10 column volumes.Use the step gradient liquid eluted protein of two column volumes, each column volume contains the successive same buffer of 50mM, 200mM and 500mM imidazoles.Adopt the every 1mg protein cleavage 6x of 40 TEV of unit proteolytic enzyme (Invitrogen Cat#10127017) histidine marker to spend the night, simultaneously in 4 ℃ of dialysis in 50mM Tris-HCl pH 7.8,500mM NaCl, 10% glycerine, 10mM imidazoles and 10mM methionine(Met).Sample is passed through with the nickel filling and at 50mM Tris-HCl pH 7.8,500mM NaCl, 10% glycerine, 10mM imidazoles and 10mM methionine(Met) equilibrated Pharmacia 5ml IMAC post (Cat#17-0409-01) are to remove 6x histidine marker.Make isolating albumen be incorporated into the nickel post and use step gradient liquid wash-out with low-affinity.Step gradient liquid is successively used 15% and 80% B-side (A-side=50mM Tris-HCl pH 7.8,500mMNaCl, 10% glycerine, 10mM imidazoles and 10mM methionine(Met); B-side=50mM Tris-HClpH 7.8,500mM NaCl, 10% glycerine, 500mM imidazoles and 10mM methionine(Met)) operation, each 4 column volumes.Met albumen is at first step wash-out (15%), and uncracked Met and cracked histidine marker wash-out in 80% flow point.Behind SDS-PAGE gel analysis alleged occurrence cracked Met, merge 15% flow point; By equilibrated Amersham BiosciencesHiLoad 16/60 Superdex 200 preparation scale (prep grade) in 50mM Tris-HCl pH 8.5,150mM NaCl, 10% glycerine and 5mM DTT (Cat#17-1069-01) gel permeation chromatography carry out further purifying.Merge the flow point that cleans most and pass through at AmiconUltra-15 10 centrifugal being concentrated into～10.4mg/ml in the 000Da MWCO centrifugal filter unit (Cat#UFC901024).
Raji cell assay Raji
[0573] the HCT116 cell is maintained 37 ℃ and 5%CO 2In the 5a substratum of McCoy ' s in, this culture medium supplemented has 10% foetal calf serum (FBS) 2mM L-glutaminate and 100 unit penicillin/100 μ g Streptomycin sulphates.
Cell survival is measured
[0574] according to following assay method, with duplicate mode test compounds.96-hole XTT measures: make cell be 37 ℃, 5%CO 2Under the flat culture plate in 96-hole in the growth medium that contains various concentration compounds (in duplicate) in the growth 72 hours.The initiator cell number is that every hole of 5000 cells and volume are 120 μ l.After cultivating end in 72-hour, with the mixture of 40 μ l XTT marks (sodium 3 '-[1-(phenyl amino carbonyl)-3,4-tetrazolium]-two (4-methoxyl group-6-nitro) benzenesulfonic acid hydrate and electronics-coupling reagent: PMS (50: 1 solution of N-methyldiphenyl and pyrazine Methylsulfate) joins in every hole of culture plate.After other 2-6 hour, measure in 650nm with spectrophotometer.
[0575] histone-H3 phosphorylation is measured: with the HCT116 cell with every 60x15mm culture dish (Falcon) 1x10 ΛThe density of 6 cells is tiled in the 3mL growth medium (McCoy ' s5A substratum, 10%FBS, 1%pen-strep) and overnight incubation (37 ℃ of 5%CO2).Added compound in second day and cultivated 1 hour (37 ℃ of 5%CO2) after .1 hour, with 1X PBS washed cell 1 time, direct molten born of the same parents and be transferred in the 1.7mL eppendorf pipe and place on ice in the culture plate that contains the molten born of the same parents' damping fluid of 100 μ L (125mM Tris HCl pH 6.8 and 2xSDS fill damping fluid) then.Sample ultrasonic handled about 5 seconds and place 95 ℃ of heat block last 3 minutes.After the heating, this sample is loaded into NuPage 4-12%Bis-Tris Gel (Invitrogen), then electrophoretic transfer is to 0.45 μ m Nitrocellulose film (Invitrogen).After the transfer, in room temperature, jolt down gently, film is placed the damping fluid 1 hour of the Qiagen protection that contains 0.1%Tween.To resist-phosphoric acid-histone H 3 (Ser10) antibody (Upstate#06-570) to be 1: 250 and to join in the blotting membrane (blots) and under room temperature, cultivated 1 hour in protection damping fluid dilution.Use 1X PBS+0.1%Tween20 (polysorbas20) washing blotting membrane 3 times then.(JacksonImmunoResearch Laboratories Inc.#111-035-003), added with 1 hour under room temperature then by 1: 3000 dilution sheep-anti-rabbit HRP secondary antibodies in the protection damping fluid.Wash blotting membrane 3 times with 1X PBS+0.1%Tween20, range estimation is by using SuperSignal West Pico Chemiluminescent Substrate (pik chemical luminous substrate) chemoluminescence (Pierce#34078) then.
Embodiment 25:GTL16 tumour heteroplastic transplantation model
Material and method
Female nude mouse when [0576] beginning one's study (nu/nu derives from Harlan) is 6-8 age in week, and weight range is at 18-22g.Described animal can be free near food and water during whole research.Mouse is housed in the little isolation cage of static (static microisolator caging) of keeping 70-74 and 40-60% humidity, at α-dri
Figure A20078003852702921
Bed-o-cobs
Figure A20078003852702922
Shine on the laboratory animal liner (LaboratoryAnimal Bedding), keep light circulation in 12-hour.NIH guide (NIH Guide for the Care and Use ofLaboratory Animals) according to laboratory animal management and use carries out all programs, and all schemes all obtain authorization (the Internal Animal Care and Use Committee (IACUC) of the domestic protection of animal and the council of use.
[0577] western blot analysis and pharmacodynamics marker are quantitative: adopt Tissuelyser (Qiagen), with tumour homogenization in the RIPA of 2X volume damping fluid (Upstate) (adding proteinase inhibitor (Sigma)) of each about 100mg.The lysate of every part 80 μ g is stood SDS-PAGE, then carry out western blot analysis, adopt Typhoon camera system (GE Life Sciences) to carry out quantitatively to it then to detect phosphoric acid-Met (cell signaling (Cell Signaling)).
Tumour transplatation
[0578] begins xenotransplantation by the GTL-16 tumour cell of cultivating and keeping through domestic cytobiology department (internal Cell Biology Department).Each test mouse 4x10 in the RPMI substratum that is suspended in 100 μ L serum-frees that gets an injection under the skin 6Individual cell.Work as the average tumor size at the 5th day and reach about 150mm 3The time, tumour is randomized into each treatment group.Each dosage group comprises n=5 mouse.Gross tumor volume adopts following formula to calculate: gross tumor volume=(w 2Xl)/2, wherein w=tumour width and l=length of tumor (in mm).Tumor weight can be estimated according to the hypothesis that 1mg is equivalent to the 1mm gross tumor volume.
Tumor growth suppresses (TGI) and analyzes
[0579] calculate TGI by the difference of the mouse mean tumour volume of vehicle treated and pharmacological agent, it is represented with percentage.
Figure A20078003852702931
[0580] MTV is defined as the mean tumour volume (MTV) of number of animals, n, research that day remainder.
The result
[0581] Fig. 1 shows that compound 30 oral administration give (PO) 3mg/kg, twice on the one (BID) and give twice on the one (BID), 14 days effect of successive administration with 50mg/kg by intravenous injection (IP).IP dosage produces the restraining effect of the remarkable meaning of statistics to the GTL16 growth of tumor of subcutaneous growth in nude mouse.At the 5th day begin treatment.In the last day of treatment, with the mean tumour volume of vehicle treated group relatively, 3mg/kg PO and 50mg/kg IP administration reduce mean tumour volume 27% (p＜.2743) and 89% (p＜.0036) respectively.
[0582] Fig. 2 shows that tumor growth that oral and intraperitoneal gives GTL 16 tumours of 30 pairs of nude mices of compound suppresses the effect of (TGI).The 5th day beginning of all treatments after tumour cell is implanted.When 14-days dosage regimens finish,, be expressed as the percentage of mean tumour volume of the control group of vehicle treated by the final TGI% of difference calculating of the mean tumour volume of the mouse of the mouse of vehicle treated and medicine-treatment.
[0583] Fig. 3 shows that oral and intraperitoneal gives the effect of 30 pairs of GTL16 growth of tumor of compound.To female nude mouse right side subcutaneous vaccination 4x10 6 Individual GTL 16 cells are to transmit volume 100 μ L.Made tumor growth 5 days.Give mouse with the 3.0mg/kg oral dose with 50.0mg/kg dosage intraperitoneal, every day twice, continuous 14 days.In that day that research finishes, complete immediately tumor resection is also weighed, and final tumour weight in wet base (milligram) is as initial effect terminal point.
[0584] effect that Fig. 4 shows with 1,3,10,30mg/kg gives compound 124 as acute dose oral (PO).When reaching the about 650mm of mean tumour volume in the 13rd day tumour 3The Shi Jinhang treatment.After dosage gives, killed mouse (n=3) in T=15 minute, 2 hours, 6 hours, 12 hours.With tumour homogenize and add proteinase inhibitor in the RIPA damping fluid.Make 80 μ g lysates experience SDS-PAGE, follow through western blot analysis to detect phosphoric acid-Met and to adopt the Typhoon camera system quantitative.
[0585] effect that Fig. 5 shows with 0.3,1,3,10mg/kg gives compound 87 as acute dose oral (PO).When reaching the about 650mm of mean tumour volume in the 13rd day tumour 3The Shi Jinhang treatment.After dosage gives, killed mouse (n=3) in 1 hour, 2 hours, 6 hours, 12 hours.With tumour homogenize and add proteinase inhibitor in the RIPA damping fluid.Make 80 μ g lysates experience SDS-PAGE, follow through western blot analysis to detect phosphoric acid-Met and to adopt the Typhoon camera system quantitative.
[0586] Fig. 6 show with 1,3,10 and 30mg/kg (twice on the one (Q12H), continuous 14.5 days) oral (PO) give the effect of compound 124.At the 6th day begin treatment.In the last day of treatment, with the mean tumour volume of vehicle treated group relatively, give 1,3,10, the dosage of 30mg/kgPO Q12H reduces mean tumour volume 32% (p=.0079), 55% respectively (p＜.0001), 72% (p＜.0001) and 79% (p＜.0001).
[0587] Fig. 7 shows that the tumor growth of GTL 16 tumours of 124 pairs of nude mices of orally give compound suppresses the effect of (TGI).The 6th day beginning of all treatments after tumour cell is implanted.When 14.5-days dosage regimens finish,, be expressed as the percentage of mean tumour volume of the control group of vehicle treated by the final TGI% of difference calculating of the mean tumour volume of the mouse of the mouse of vehicle treated and medicine-treatment.
Abbreviation
The PO oral administration;
Per 12 hours of Q12H
Per 24 hours of Q24H
RPMI Roswell Park Memorial Institute
NIH national health institute
The IACUC protection of animal and the use council
The MTV mean tumour volume
The PD pharmacodynamics
[0588] should be appreciated that embodiment described herein and embodiment only are following illustrational purposes, the various modifications of its covering or change will to those skilled in the art the enlightenment effect is arranged and should be included in the application's spirit and the scope of claim scope and appended claims in.All applications, patent and the patent application that this paper quotes is attached to herein by reference in full.

Claims (55)

1. a formula (I) compound:
Figure A2007800385270002C1
Or its enantiomorph, diastereomer, racemic modification or pharmacy acceptable salt or solvate, wherein:
A is independently for replacing or unsubstituted aryl or replacement or unsubstituted heteroaryl;
Q is hydrogen, halogen, amino, replacement or unsubstituted alkyl, replacement or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl, replacement or unsubstituted-O-aryl, replacement or unsubstituted arylalkyl, replacement or unsubstituted heteroaryl, replacement or unsubstituted-O-heteroaryl independently, perhaps replace or unsubstituted heteroarylalkyl, wherein Q is optional by 1-3 R 22Replace independently;
T is CH independently 2, CH (halogen), C (halogen) 2, CH ((C 1-C 6) alkyl) or C ((C 1-C 6) alkyl) 2
X is N or CR 2
R 1And R 2Optional separately be independently hydrogen, halogen, nitro, cyano group, hydroxyl, replacement or unsubstituted alkyl, perfluoroalkyl ,-(CH 2) jCN ,-(CH 2) jOR 3,-(CH 2) jC (O) R 3,-(CH 2) jC (O) OR 3,-(CH 2) jNR 4R 5,-(CH 2) jC (O) NR 4R 5,-(CH 2) jOC (O) NR 4R 5,-(CH 2) jNR 6C (O) R 3,-(CH 2) jNR 6C (O) OR 3,-(CH 2) jNR 6C (O) NR 4R 5,-(CH 2) jS (O) mR 7,-(CH 2) jNR 6S (O) 2R 7,-(CH 2) jS (O) 2NR 4R 5, wherein each j is the integer of 0-6 independently; With m be the integer of 0-2 independently; Or
R 1And R 2Form replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl, perhaps replace or unsubstituted heteroaryl;
R 3, R 4, R 5, R 6And R 7Be hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl, replacement or unsubstituted-O-aryl, replacement or unsubstituted arylalkyl, replacement or unsubstituted heteroaryl, replacement or unsubstituted-O-heteroaryl independently of one another, perhaps replace or unsubstituted heteroarylalkyl, or
R 3, R 6And R 7As mentioned above, and R 4And R 5N atom with they connect forms replacement or unsubstituted Heterocyclylalkyl, perhaps replaces or unsubstituted heteroaryl;
R 22Be independently hydrogen, halogen, nitro, cyano group, hydroxyl, replacement or unsubstituted alkyl, replacement or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl, replacement or unsubstituted-O-aryl, replacement or unsubstituted arylalkyl, replacement or unsubstituted heteroaryl, replacement or unsubstituted-O-heteroaryl, replacement or unsubstituted heteroarylalkyl ,-(CH 2) jCN ,-(CH 2) jOR 23,-(CH 2) jC (O) R 23,-(CH 2) jC (O) OR 23,-(CH 2) jNR 24R 25,-(CH 2) jC (O) NR 24R 25,-(CH 2) jOC (O) NR 24R 25,-(CH 2) jNR 26C (O) R 23,-(CH 2) jNR 26C (O) OR 23,-(CH 2) jNR 26C (O) NR 24R 25,-(CH 2) jS (O) mR 27,-(CH 2) jS (O) 2NR 24R 25, or-(CH 2) jNR 26S (O) 2R 27, wherein each j is the integer of 0-6 independently, and each m is the integer of 0-2 independently;
R 23, R 24, R 25, R 26And R 27Be hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl, replacement or unsubstituted-O-aryl, replacement or unsubstituted arylalkyl, replacement or unsubstituted heteroaryl, replacement or unsubstituted-O-heteroaryl independently of one another, perhaps replace or unsubstituted heteroarylalkyl, or
R 23, R 26And R 27As mentioned above, and R 24And R 25N atom with they connect forms replacement or unsubstituted Heterocyclylalkyl, perhaps replaces or unsubstituted heteroaryl;
R 28' and R 28" be hydrogen, halogen, nitro, cyano group, hydroxyl, replacement or unsubstituted alkyl, replacement or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted alkoxyl group, amino, an amino alkyl or amino dialkyl group independently of one another;
R 35Be independently key, hydrogen, halogen, nitro, cyano group, hydroxyl, replacement or unsubstituted alkyl, replacement or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl, replacement or unsubstituted arylalkyl, replacement or unsubstituted heteroaryl, replacement or unsubstituted heteroarylalkyl ,-(CH 2) jCN ,-(CH 2) jOR 30,-(CH 2) jC (O) R 30,-(CH 2) jC (O) OR 30,-(CH 2) jNR 31R 32,-(CH 2) jC (O) NR 31R 32,-(CH 2) jOC (O) NR 31R 32,-(CH 2) jNR 33C (O) R 30,-(CH 2) jNR 33C (O) OR 30,-(CH 2) jN 33C (O) NR 31R 32,-(CH 2) jS (O) mR 34,-(CH 2) jS (O) 2NR 31R 32Or-(CH 2) jNR 33S (O) 2R 34, wherein each j is that integer and the m of 0-6 is the integer of 0-2 independently independently;
Z is the integer of 0-3 independently;
R 30, R 31, R 32, R 33And R 34Be hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl, replacement or unsubstituted-O-aryl, replacement or unsubstituted arylalkyl, replacement or unsubstituted heteroaryl, replacement or unsubstituted-O-heteroaryl independently of one another, perhaps replace or unsubstituted heteroarylalkyl, or
R 30, R 33And R 34As mentioned above, and R 31And R 32N atom with they connect forms replacement or unsubstituted Heterocyclylalkyl, perhaps replaces or unsubstituted heteroaryl; With
R wherein 1, R 2, R 3, R 4, R 5, R 6, R 7, R 22, R 23, R 24, R 25, R 26, R 27, R 28', R 28", R 30, R 31, R 32, R 33, R 34And R 35Optionally separately replaced independently by 1-3 group, each group be independently selected from hydrogen, halogen, hydroxyl, amino, an amino alkyl, amino dialkyl group, cyano group, nitro, difluoromethyl, trifluoromethyl, oxo, alkyl ,-the O-alkyl and-the S-alkyl.
2. the compound of claim 1, wherein:
A independently is replacement or unsubstituted phenyl, replacement or unsubstituted naphthyl, replacement or unsubstituted biphenyl group, replacement or unsubstituted pyrryl, replacement or unsubstituted furyl, replacement or unsubstituted thienyl,
Replace or do not replace the De oxazolyl, replace or unsubstituted thiazolyl, replace or unsubstituted imidazolyl, replace or unsubstituted pyrazolyl, replace or the unsubstituted pyridine base, replace or unsubstituted isoxazolyl, replace or unsubstituted isothiazolyl, replace or unsubstituted triazolyl, replace or unsubstituted pyrazinyl, replace or unsubstituted pyrimidyl, replace or unsubstituted benzothiazolyl, replace or unsubstituted purine radicals, replace or unsubstituted benzimidazolyl-, replace or unsubstituted indyl, replace or unsubstituted isoquinolyl, replace or unsubstituted quinoxalinyl, replace or the unsubstituted quinolines base, replace or unsubstituted benzoxazolyl, replacement or unsubstituted [1,5] phthalazinyl, replace or unsubstituted pyridine also [3,2-d] pyrimidyl, replacement or unsubstituted [1,7] phthalazinyl, replace or unsubstituted 1H-pyrrolo-[2,3-b] pyridyl, replace or unsubstituted pyrazolo [4,3-b] pyridyl, replace or unsubstituted pyrrolo-[2,3-b] pyridyl, replace or unsubstituted thieno-[2,3-b] pyridyl, replace or unsubstituted thiazole also [5,4-6] pyridyl, replace or unsubstituted pyridine base-2-ketone, replace or unsubstituted imidazo [1,2-b] pyridazinyl, replace or unsubstituted pyrazolo [1,5-a] pyrimidyl, replace or unsubstituted pyridazinyl-3-ketone, replace or unsubstituted imidazo [2,1-b] [1,3,4] thiadiazolyl group, replace or unsubstituted imidazo [2,1-b] thiazolyl, perhaps replace or unsubstituted imidazo [4,5-b] pyridyl;
Q is hydrogen independently, halogen, replace or unsubstituted alkyl, perfluoroalkyl, amino, replace or a unsubstituted amino alkyl, replace or unsubstituted amino dialkyl group, replace or unsubstituted phenyl, replace or unsubstituted phenoxy, replace or unsubstituted piperidyl, replace or unsubstituted piperazinyl, replace or unsubstituted pyrrolidyl, replace or unsubstituted morpholinyl, replace or unsubstituted pyrryl, replace or unsubstituted furyl, replace or unsubstituted thienyl, replace or do not replace the De oxazolyl, replace or unsubstituted thiazolyl, replace or unsubstituted imidazolyl, replace or unsubstituted pyrazolyl, replace or the unsubstituted pyridine base, replace or unsubstituted-O-pyridyl, replace or unsubstituted isoxazolyl, replace or unsubstituted isothiazolyl, perhaps replace or unsubstituted triazolyl;
R 1And R 2Optional separately be independently hydrogen, halogen, nitro, cyano group, hydroxyl, replacement or unsubstituted alkyl, perfluoroalkyl ,-(CH 2) jCN ,-(CH 2) jOR 3,-(CH 2) jC (O) R 3,-(CH 2) jC (O) OR 3,-(CH 2) jNR 4R 5,-(CH 2) jC (O) NR 4R 5,-(CH 2) jOC (O) NR 4R 5,-(CH 2) jNR 6C (O) R 3,-(CH 2) jNR 6C (O) OR 3,-(CH 2) jNR 6C (O) NR 4R 5,-(CH 2) jS (O) mR 7,-(CH 2) jNR 6S (O) 2R 7,-(CH 2) jS (O) 2NR 4R 5
R 22Be hydrogen independently, halogen, nitro, cyano group, hydroxyl, replace or unsubstituted alkyl, replace or unsubstituted cycloalkyl, perfluoroalkyl, replace or unsubstituted assorted alkyl, replace or unsubstituted Heterocyclylalkyl, replace or unsubstituted phenyl, replace or unsubstituted naphthyl, replace or unsubstituted biphenyl group, replace or unsubstituted pyrryl, replace or unsubstituted imidazolyl, replace or unsubstituted pyrazolyl, replace or unsubstituted furyl, replace or unsubstituted thienyl, replace or do not replace the De oxazolyl, replace or unsubstituted isoxazolyl, replace or unsubstituted thiazolyl, replace or the unsubstituted pyridine base, replace or unsubstituted pyrazinyl, replace or unsubstituted pyrimidyl, replace or unsubstituted benzothiazolyl, replace or unsubstituted purine radicals, replace or unsubstituted benzimidazolyl-, replace or unsubstituted indyl, replace or unsubstituted isoquinolyl, replace or unsubstituted quinoxalinyl, replace or the unsubstituted quinolines base, replace or unsubstituted benzoxazolyl, replacement or unsubstituted [1,5] phthalazinyl, replace or unsubstituted pyridine also [3,2-d] pyrimidyl, replacement or unsubstituted [1,7] phthalazinyl, replace or unsubstituted 1H-pyrrolo-[2,3-b] pyridyl, replace or unsubstituted pyrazolo [4,3-b] pyridyl, replace or unsubstituted pyrrolo-[2,3-b] pyridyl, replace or unsubstituted thieno-[2,3-b] pyridyl, replace or unsubstituted thiazole also [5,4-b] pyridyl, replace or unsubstituted pyridine base-2-ketone, replace or unsubstituted imidazo [1,2-b] pyridazinyl, replace or unsubstituted pyrazolo [1,5-a] pyrimidyl, replace or unsubstituted pyridazinyl-3-ketone, replace or unsubstituted imidazo [2,1-b] [1,3,4] thiadiazolyl group, replace or unsubstituted imidazo [2,1-b] thiazolyl, perhaps replace or unsubstituted imidazo [4,5-b] pyridyl,-(CH 2) jCN ,-(CH 2) jOR 23,-(CH 2) jC (O) R 23,-(CH 2) jC (O) OR 23,-(CH 2) jNR 24R 25,-(CH 2) jC (O) NR 24R 25,-(CH 2) jOC (O) NR 24R 25,-(CH 2) jNR 26C (O) R 23,-(CH 2) jNR 26C (O) OR 23,-(CH 2) jNR 26C (O) NR 24R 25,-(CH 2) jS (O) mR 27,-(CH 2) jS (O) 2NR 24R 25Or-(CH 2) jNR 26S (O) 2R 27
R 28' and R 28" be hydrogen, halogen, cyano group, hydroxyl, replacement or unsubstituted alkyl independently of one another, or perfluoroalkyl; With
R 35Be hydrogen independently, halogen, nitro, cyano group, hydroxyl, replace or unsubstituted alkyl, replace or unsubstituted cycloalkyl, perfluoroalkyl, replace or unsubstituted assorted alkyl, replace or unsubstituted Heterocyclylalkyl, replace or unsubstituted azetidinyl, replace or unsubstituted phenyl, replace or unsubstituted naphthyl, replace or unsubstituted biphenyl group, replace or unsubstituted pyrryl, replace or unsubstituted imidazolyl, replace or unsubstituted pyrazolyl, replace or unsubstituted furyl, replace or unsubstituted thienyl, replace or do not replace the De oxazolyl, replace or unsubstituted isoxazolyl, replace or unsubstituted thiazolyl, replace or the unsubstituted pyridine base, replace or unsubstituted pyrazinyl, replace or unsubstituted pyrimidyl, replace or unsubstituted benzothiazolyl, replace or unsubstituted purine radicals, replace or unsubstituted benzimidazolyl-, replace or unsubstituted indyl, replace or unsubstituted isoquinolyl, replace or unsubstituted quinoxalinyl, replace or the unsubstituted quinolines base, replace or unsubstituted benzoxazolyl, replacement or unsubstituted [1,5] phthalazinyl, replace or unsubstituted pyridine also [3,2-d] pyrimidyl, replacement or unsubstituted [1,7] phthalazinyl, replace or unsubstituted 1H-pyrrolo-[2,3-b] pyridyl, replace or unsubstituted pyrazolo [4,3-b] pyridyl, replace or unsubstituted pyrrolo-[2,3-b] pyridyl, replace or unsubstituted thieno-[2,3-b] pyridyl, replace or unsubstituted thiazole also [5,4-b] pyridyl, replace or unsubstituted pyridine base-2-ketone, replace or unsubstituted imidazo [1,2-b] pyridazinyl, replace or unsubstituted pyrazolo [1,5-a] pyrimidyl, replace or unsubstituted pyridazinyl-3-ketone, replace or unsubstituted imidazo [2,1-b] [1,3,4] thiadiazolyl group, replace or unsubstituted imidazo [2,1-b] thiazolyl, perhaps replace or unsubstituted imidazo [4,5-b] pyridyl,-(CH 2) jCN ,-(CH 2) jOR 30,-(CH 2) jC (O) R 30,-(CH 2) jC (O) OR 30,-(CH 2) jNR 31R 32,-(CH 2) jC (O) NR 31R 32,-(CH 2) jOC (O) NR 31R 32,-(CH 2) jNR 33C (O) R 30,-(CH 2) jNR 33C (O) OR 30,-(CH 2) jNR 33C (O) NR 31R 32,-(CH 2) jS (O) mR 34,-(CH 2) jS (O) 2NR 31R 32Or-(CH 2) jNR 33S (O) 2R 34
3. the compound of claim 2, wherein:
A is independently for replacing or unsubstituted phenyl, replace or unsubstituted naphthyl, replace or unsubstituted biphenyl group, replace or unsubstituted pyrryl, replace or unsubstituted furyl, replace or unsubstituted thienyl, replace or do not replace the De oxazolyl, replace or unsubstituted thiazolyl, replace or unsubstituted imidazolyl, replace or unsubstituted pyrazolyl, replace or the unsubstituted pyridine base, replace or unsubstituted isoxazolyl, replace or unsubstituted isothiazolyl, replace or unsubstituted triazolyl, replace or unsubstituted pyrazinyl, replace or unsubstituted pyrimidyl, replace or unsubstituted benzothiazolyl, replace or unsubstituted purine radicals, replace or unsubstituted benzimidazolyl-, replace or unsubstituted indyl, replace or unsubstituted isoquinolyl, replace or unsubstituted quinoxalinyl, perhaps replace or the unsubstituted quinolines base;
Q is hydrogen independently, halogen, replace or unsubstituted alkyl, perfluoroalkyl, amino, replace or a unsubstituted amino alkyl, replace or unsubstituted amino dialkyl group, replace or unsubstituted phenyl, replace or unsubstituted phenoxy, replace or unsubstituted piperidyl, replace or unsubstituted piperazinyl, replace or unsubstituted pyrrolidyl, replace or unsubstituted morpholinyl, replace or unsubstituted pyrryl, replace or unsubstituted furyl, replace or unsubstituted thienyl, replace or do not replace the De oxazolyl, replace or unsubstituted thiazolyl, replace or unsubstituted imidazolyl, replace or unsubstituted pyrazolyl, replace or the unsubstituted pyridine base, perhaps replace or unsubstituted-O-pyridyl;
R 1And R 2Be hydrogen, halogen, nitro, cyano group, hydroxyl, replacement or unsubstituted alkyl independently of one another, or perfluoroalkyl;
X is CR 2
R 22Be independently hydrogen, halogen, nitro, cyano group, hydroxyl, replacement or unsubstituted alkyl, replacement or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted Heterocyclylalkyl ,-(CH 2) jCN ,-(CH 2) jOR 23,-(CH 2) jC (O) R 23,-(CH 2) jC (O) OR 23,-(CH 2) jNR 24R 25,-(CH 2) jC (O) NR 24R 25,-(CH 2) jOC (O) NR 24R 25,-(CH 2) jNR 26C (O) R 23,-(CH 2) jNR 26C (O) OR 23,-(CH 2) jNR 26C (O) NR 24R 25,-(CH 2) jS (O) mR 27,-(CH 2) jS (O) 2NR 24R 25Or-(CH 2) jNR 26S (O) 2R 27
R 28' and R 28" be hydrogen, halogen, hydroxyl, alkyl or perfluoroalkyl independently of one another; With
R 35Be independently hydrogen, halogen, nitro, cyano group, hydroxyl, replacement or unsubstituted alkyl, replacement or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted Heterocyclylalkyl ,-(CH 2) jCN ,-(CH 2) jOR 30,-(CH 2) jC (O) R 30,-(CH 2) jC (O) OR 30,-(CH 2) jNR 31R 32,-(CH 2) jC (O) NR 31R 32,-(CH 2) jOC (O) NR 31R 32,-(CH 2) jNR 33C (O) R 30,-(CH 2) jNR 33C (O) OR 30,-(CH 2) jN 33C (O) NR 31R 32,-(CH 2) jS (O) mR 34,-(CH 2) jS (O) 2NR 31R 32,-(CH 2) jNR 33S (O) 2R 34,
4. the compound of claim 3, wherein:
A is independently:
Figure A2007800385270009C2
Q be independently hydrogen, chloro, replacement or unsubstituted alkyl, perfluoroalkyl ,-NH 2,-NH (C 1-C 6) alkyl, or-N[(C 1-C 6) alkyl] 2,
Figure A2007800385270010C1
Wherein each alkyl is optional by 1-3 R 22Group replace independently and wherein w be the integer of 0-3 independently; Two R wherein 22Group and-O (CH 2CH 2) the optional ring texture that forms of O-;
R 1And R 2Be hydrogen independently of one another;
R 22Be independently-H ,-F, Cl, Br, I ,-(C 1-C 6) alkyl ,-(CH 2) jCN ,-(CH 2) jO (C 1-C 6) alkyl ,-(CH 2) jOH ,-(CH 2) jC (O) (C 1-C 6) alkyl ,-(CH 2) jNH 2,-(CH 2) jNH (C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) 2,-(CH 2) jC (O) NH 2,-(CH 2) jC (O) NH (C 1-C 6) alkyl ,-C (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jNHC (O) (C 1-C 6) alkyl ,-(CH 2) jNHSO 2(C 1-C 6) alkyl ,-(CH 2) jNHSO 2(C 1-C 6) alkyl ,-(CH 2) jSO 2CH 3,-(CH 2) jSO 2NH 2,-(CH 2) jSO 2NH (C 1-C 6)-alkyl ,-(CH 2) jSO 2N ((C 1-C 6) alkyl) 2,-(CH 2) jSO 2NH (C 1-C 6) alkyl (OH), phenyl,
Figure A2007800385270010C2
R 28' and R 28" be hydrogen, halogen, hydroxyl, (C independently of one another 1-C 6) alkyl or trifluoromethyl; With
R 35Be hydrogen, halogen, nitro, cyano group, hydroxyl, (C independently 1-C 6) alkyl, ring (C 3-C 10) alkyl, perfluor (C 1-C 6) alkyl ,-(CH 2) jCN ,-(CH 2) jO (C 1-C 6) alkyl ,-(CH 2) jC (O) (C 1-C 6) alkyl ,-(CH 2) jC (O) O (C 1-C 6) alkyl ,-(CH 2) jNH 2,-(CH 2) jNH (C 1-C 6) alkyl) ,-(CH 2) jN ((C 1-C 6) alkyl) 2,-(CH 2) jC (O) NH 2,-(CH 2) jC (O) NH (C 1-C 6) alkyl) ,-(CH 2) jC (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jOC (O) NH 2,-(CH 2) jOC (O) NH (C 1-C 6) alkyl) ,-(CH 2) jOC (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jNHC (O) (C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) C (O) (C 1-C 6) alkyl ,-(CH 2) jNHC (O) O (C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) C (O) O (C 1-C 6) alkyl ,-(CH 2) jNHC (O) NH 2,-(CH 2) jNHC (O) NH (C 1-C 6) alkyl) ,-(CH 2) jNHC (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jN ((C 1-C 6) alkyl) C (O) NH (C 1-C 6) alkyl) ,-(CH 2) jN ((C 1-C 6) alkyl) C (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jS (O) m(C 1-C 6) alkyl, (CH 2) jS (O) 2NH 2,-(CH 2) jS (O) 2NH (C 1-C 6) alkyl) ,-(CH 2) jS (O) 2N ((C 1-C 6) alkyl) 2,-(CH 2) jNHS (O) 2(C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) S (O) 2(C 1-C 6) alkyl,
Figure A2007800385270011C1
5. the compound of claim 4, wherein:
A is independently:
Figure A2007800385270011C2
Q is (C independently 1-C 6) alkyl, perfluoroalkyl ,-NH 2,-NH (C 1-C 6) alkyl ,-N[(C 1-C 6) alkyl] 2,
Figure A2007800385270011C3
R 28' and R 28" be hydrogen, halogen, (C independently of one another 1-C 6) alkyl or trifluoromethyl; With
R 35Be independently hydrogen, halogen, cyano group, hydroxyl ,-(C 1-C 6) alkyl ,-(CH 2) jCN ,-(CH 2) jO (C 1-C 6) alkyl ,-(CH 2) jOH ,-(CH 2) jC (O) (C 1-C 6) alkyl ,-(CH 2) jC (O) OH ,-(CH 2) jNH 2,-(CH 2) jNH (C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) 2,-(CH 2) jC (O) NH 2,-(CH 2) jC (O) NH (C 1-C 6) alkyl ,-C (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jNHC (O) (C 1-C 6) alkyl ,-(CH 2) jNHSO 2(C 1-C 6) alkyl ,-(CH 2) jNHSO 2(C 1-C 6) alkyl ,-(CH 2) jSO 2CH 3,-(CH 2) jSO 2NH 2,-(CH 2) jSO 2NH (C 1-C 6)-alkyl ,-(CH 2) jSO 2N ((C 1-C 6) alkyl) 2,-(CH 2) jSO 2NH ((C 1-C 6) alkyl (OH), phenyl,
Figure A2007800385270012C1
6. the compound of claim 1, described compound has formula II:
Figure A2007800385270012C2
Wherein:
A is independently for replacing or unsubstituted phenyl, replace or unsubstituted naphthyl, replace or unsubstituted biphenyl group, replace or unsubstituted pyrryl, replace or unsubstituted furyl, replace or unsubstituted thienyl, replace or do not replace the De oxazolyl, replace or unsubstituted thiazolyl, replace or unsubstituted imidazolyl, replace or unsubstituted pyrazolyl, replace or the unsubstituted pyridine base, replace or unsubstituted isoxazolyl, replace or unsubstituted isothiazolyl, replace or unsubstituted triazolyl, replace or unsubstituted pyrazinyl, replace or unsubstituted pyrimidyl, replace or unsubstituted benzothiazolyl, replace or unsubstituted purine radicals, replace or unsubstituted benzimidazolyl-, replace or unsubstituted indyl, replace or unsubstituted isoquinolyl, replace or unsubstituted quinoxalinyl, replace or the unsubstituted quinolines base, replace or unsubstituted benzoxazolyl, replacement or unsubstituted [1,5] phthalazinyl, replace or unsubstituted pyridine also [3,2-d] pyrimidyl, replacement or unsubstituted [1,7] phthalazinyl, replace or unsubstituted 1H-pyrrolo-[2,3-b] pyridyl, replace or unsubstituted pyrazolo [4,3-b] pyridyl, replace or unsubstituted pyrrolo-[2,3-b] pyridyl, replace or unsubstituted thieno-[2,3-b] pyridyl, replace or unsubstituted thiazole also [5,4-b] pyridyl, replace or unsubstituted pyridine base-2-ketone, replace or unsubstituted imidazo [1,2-b] pyridazinyl, replace or unsubstituted pyrazolo [1,5-a] pyrimidyl, replace or unsubstituted pyridazinyl-3-ketone, replace or unsubstituted imidazo [2,1-b] [1,3,4] thiadiazolyl group, replace or unsubstituted imidazo [2,1-b] thiazolyl, perhaps replace or unsubstituted imidazo [4,5-b] pyridyl;
Q is hydrogen independently, halogen, replace or unsubstituted alkyl, perfluoroalkyl, amino, replace or a unsubstituted amino alkyl, replace or unsubstituted amino dialkyl group, replace or unsubstituted phenyl, replace or unsubstituted phenoxy, replace or unsubstituted piperidyl, replace or unsubstituted piperazinyl, replace or unsubstituted pyrrolidyl, replace or unsubstituted morpholinyl, replace or unsubstituted pyrryl, replace or unsubstituted furyl, replace or unsubstituted thienyl, replace or do not replace the De oxazolyl, replace or unsubstituted thiazolyl, replace or unsubstituted imidazolyl, replace or unsubstituted pyrazolyl, replace or the unsubstituted pyridine base, replace or unsubstituted-O-pyridyl, replace or unsubstituted isoxazolyl, replace or unsubstituted isothiazolyl, perhaps replace or unsubstituted triazolyl;
R 22Be hydrogen independently, halogen, nitro, cyano group, hydroxyl, replace or unsubstituted alkyl, replace or unsubstituted cycloalkyl, perfluoroalkyl, replace or unsubstituted assorted alkyl, replace or unsubstituted Heterocyclylalkyl, replace or unsubstituted phenyl, replace or unsubstituted naphthyl, replace or unsubstituted biphenyl group, replace or unsubstituted pyrryl, replace or unsubstituted imidazolyl, replace or unsubstituted pyrazolyl, replace or unsubstituted furyl, replace or unsubstituted thienyl, replace or do not replace the De oxazolyl, replace or unsubstituted isoxazolyl, replace or unsubstituted thiazolyl, replace or the unsubstituted pyridine base, replace or unsubstituted pyrazinyl, replace or unsubstituted pyrimidyl, replace or unsubstituted benzothiazolyl, replace or unsubstituted purine radicals, replace or unsubstituted benzimidazolyl-, replace or unsubstituted indyl, replace or unsubstituted isoquinolyl, replace or unsubstituted quinoxalinyl, replace or the unsubstituted quinolines base, replace or unsubstituted benzoxazolyl, replacement or unsubstituted [1,5] phthalazinyl, replace or unsubstituted pyridine also [3,2-d] pyrimidyl, replacement or unsubstituted [1,7] phthalazinyl, replace or unsubstituted 1H-pyrrolo-[2,3-b] pyridyl, replace or unsubstituted pyrazolo [4,3-b] pyridyl, replace or unsubstituted pyrrolo-[2,3-b] pyridyl, replace or unsubstituted thieno-[2,3-b] pyridyl, replace or unsubstituted thiazole also [5,4-b] pyridyl, replace or unsubstituted pyridine base-2-ketone, replace or unsubstituted imidazo [1,2-b] pyridazinyl, replace or unsubstituted pyrazolo [1,5-a] pyrimidyl, replace or unsubstituted pyridazinyl-3-ketone, replace or unsubstituted imidazo [2,1-b] [1,3,4] thiadiazolyl group, replace or unsubstituted imidazo [2,1-b] thiazolyl, perhaps replace or unsubstituted imidazo [4,5-b] pyridyl,-(CH 2) jCN ,-(CH 2) jOR 23,-(CH 2) jC (O) R 23,-(CH 2) jC (O) OR 23,-(CH 2) jNR 24R 25,-(CH 2) jC (O) NR 24R 25,-(CH 2) jOC (O) NR 24R 25,-(CH 2) jNR 26C (O) R 23,-(CH 2) jNR 26C (O) OR 23,-(CH 2) jNR 26C (O) NR 24R 25,-(CH 2) jS (O) mR 27,-(CH 2) jS (O) 2NR 24R 25Or-(CH 2) jNR 26S (O) 2R 27
R 28' and R 28" be hydrogen, halogen, cyano group, hydroxyl, replacement or unsubstituted alkyl independently of one another, or perfluoroalkyl; With
R is hydrogen independently, halogen, nitro, cyano group, hydroxyl, replace or unsubstituted alkyl, replace or unsubstituted cycloalkyl, perfluoroalkyl, replace or unsubstituted assorted alkyl, replace or unsubstituted Heterocyclylalkyl, replace or unsubstituted azetidinyl, replace or unsubstituted phenyl, replace or unsubstituted naphthyl, replace or unsubstituted biphenyl group, replace or unsubstituted pyrryl, replace or unsubstituted imidazolyl, replace or unsubstituted pyrazolyl, replace or unsubstituted furyl, replace or unsubstituted thienyl, replace or do not replace the De oxazolyl, replace or unsubstituted isoxazolyl, replace or unsubstituted thiazolyl, replace or the unsubstituted pyridine base, replace or unsubstituted pyrazinyl, replace or unsubstituted pyrimidyl, replace or unsubstituted benzothiazolyl, replace or unsubstituted purine radicals, replace or unsubstituted benzimidazolyl-, replace or unsubstituted indyl, replace or unsubstituted isoquinolyl, replace or unsubstituted quinoxalinyl, replace or the unsubstituted quinolines base, replace or unsubstituted benzoxazolyl, replacement or unsubstituted [1,5] phthalazinyl, replace or unsubstituted pyridine also [3,2-d] pyrimidyl, replacement or unsubstituted [1,7] phthalazinyl, replace or unsubstituted 1H-pyrrolo-[2,3-b] pyridyl, replace or unsubstituted pyrazolo [4,3-b] pyridyl, replace or unsubstituted pyrrolo-[2,3-b] pyridyl, replace or unsubstituted thieno-[2,3-b] pyridyl, replace or unsubstituted thiazole also [5,4-b] pyridyl, replace or unsubstituted pyridine base-2-ketone, replace or unsubstituted imidazo [1,2-b] pyridazinyl, replace or unsubstituted pyrazolo [1,5-a] pyrimidyl, replace or unsubstituted pyridazinyl-3-ketone, replace or unsubstituted imidazo [2,1-b] [1,3,4] thiadiazolyl group, replace or unsubstituted imidazo [2,1-b] thiazolyl, perhaps replace or unsubstituted imidazo [4,5-b] pyridyl,-(CH 2) jCN ,-(CH 2) jOR 30,-(CH 2) jC (O) R 30,-(CH 2) jC (O) OR 30,-(CH 2) jNR 31R 32,-(CH 2) jC (O) NR 31R 32,-(CH 2) jOC (O) NR 31R 32,-(CH 2) jNR 33C (O) R 30,-(CH 2) jNR 33C (O) OR 30,-(CH 2) jNR 33C (O) NR 31R 32,-(CH 2) jS (O) mR 34,-(CH 2) jS (O) 2NR 31R 32Or-(CH 2) jNR 33S (O) 2R 34
7. the compound of claim 6, wherein:
A is independently for replacing or unsubstituted phenyl, replace or unsubstituted naphthyl, replace or unsubstituted biphenyl group, replace or unsubstituted pyrryl, replace or unsubstituted furyl, replace or unsubstituted thienyl, replace or do not replace the De oxazolyl, replace or unsubstituted thiazolyl, replace or unsubstituted imidazolyl, replace or unsubstituted pyrazolyl, replace or the unsubstituted pyridine base, replace or unsubstituted isoxazolyl, replace or unsubstituted isothiazolyl, replace or unsubstituted triazolyl, replace or unsubstituted pyrazinyl, replace or unsubstituted pyrimidyl, replace or unsubstituted benzothiazolyl, replace or unsubstituted purine radicals, replace or unsubstituted benzimidazolyl-, replace or unsubstituted indyl, replace or unsubstituted isoquinolyl, replace or unsubstituted quinoxalinyl, or replacement or unsubstituted quinolines base;
Q is hydrogen independently, halogen, replace or unsubstituted alkyl, perfluoroalkyl, amino, replace or a unsubstituted amino alkyl, replace or unsubstituted amino dialkyl group, replace or unsubstituted phenyl, replace or unsubstituted phenoxy, replace or unsubstituted piperidyl, replace or unsubstituted piperazinyl, replace or unsubstituted pyrrolidyl, replace or unsubstituted morpholinyl, replace or unsubstituted pyrryl, replace or unsubstituted furyl, replace or unsubstituted thienyl, replace or do not replace the De oxazolyl, replace or unsubstituted thiazolyl, replace or unsubstituted imidazolyl, replace or unsubstituted pyrazolyl, replace or the unsubstituted pyridine base, perhaps replace or unsubstituted-O-pyridyl;
R 22Be independently hydrogen, halogen, nitro, cyano group, hydroxyl, replacement or unsubstituted alkyl, replacement or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted Heterocyclylalkyl ,-(CH 2) jCN ,-(CH 2) jOR 23,-(CH 2) jC (O) R 23,-(CH 2) jC (O) OR 23,-(CH 2) jNR 24R 25,-(CH 2) jC (O) NR 24R 25,-(CH 2) jOC (O) NR 24R 25,-(CH 2) jNR 26C (O) R 23,-(CH 2) jNR 26C (O) OR 23,-(CH 2) jNR 26C (O) NR 24R 25,-(CH 2) jS (O) mNR 27,-(CH 2) jS (O) 2NR 24R 25Or-(CH 2) jNR 26S (O) 2R 27
R 28' and R 28" be hydrogen, halogen, hydroxyl, alkyl or perfluoroalkyl independently of one another; With
R 35Be independently hydrogen, halogen, nitro, cyano group, hydroxyl, replacement or unsubstituted alkyl, replacement or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted Heterocyclylalkyl ,-(CH 2) jCN ,-(CH 2) jOR 30,-(CH 2) jC (O) R 30,-(CH 2) jC (O) OR 30,-(CH 2) jNR 31R 32,-(CH 2) jC (O) NR 31R 32,-(CH 2) jOC (O) NR 31R 32,-(CH 2) jNR 33C (O) R 30,-(CH 2) jNR 33C (O) OR 30,-(CH 2) jN 33C (O) NR 31R 32,-(CH 2) jS (O) mR 34,-(CH 2) jS (O) 2NR 31R 32,-(CH 2) jNR 33S (O) 2R 34,
Figure A2007800385270016C1
8. the compound of claim 7, wherein:
A is independently:
Figure A2007800385270017C1
Q be independently hydrogen, chloro, replacement or unsubstituted alkyl, perfluoroalkyl ,-NH 2,-NH (C 1-C 6) alkyl, or-N[(C 1-C 6) alkyl] 2,
Figure A2007800385270017C2
Wherein each alkyl is optional by 1-3 R 22Group replace independently and wherein w be the integer of 0-3 independently; Two R wherein 22Group and-O (CH 2CH 2) the optional ring texture that forms of O-;
R 22Be independently-H ,-F, Cl, Br, I ,-(C 1-C 6) alkyl ,-(CH 2) jCN ,-(CH 2) jO (C 1-C 6) alkyl ,-(CH 2) jOH ,-(CH 2) jC (O) (C 1-C 6) alkyl ,-(CH 2) jNH 2,-(CH 2) jNH (C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) 2,-(CH 2) jC (O) NH 2,-(CH 2) jC (O) NH (C 1-C 6) alkyl ,-C (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jNHC (O) (C 1-C 6) alkyl ,-(CH 2) jNHSO 2(C 1-C 6) alkyl ,-(CH 2) jNHSO 2(C 1-C 6) alkyl ,-(CH 2) jSO 2CH 3,-(CH 2) jSO 2NH 2,-(CH 2) jSO 2NH (C 1-C 6)-alkyl ,-(CH 2) jSO 2N ((C 1-C 6) alkyl) 2,-(CH 2) jSO 2NH (C 1-C 6) alkyl (OH), phenyl,
R 28' and R 28" be hydrogen, halogen, hydroxyl, (C independently of one another 1-C 6) alkyl, or trifluoromethyl; With
R 35Be hydrogen, halogen, nitro, cyano group, hydroxyl, (C independently 1-C 6) alkyl, ring (C 3-C 10) alkyl, perfluor (C 1-C 6) alkyl ,-(CH 2) jCN ,-(CH 2) jO (C 1-C 6) alkyl ,-(CH 2) jC (O) (C 1-C 6) alkyl ,-(CH 2) jC (O) O (C 1-C 6) alkyl ,-(CH 2) jNH 2,-(CH 2) jNH (C 1-C 6) alkyl) ,-(CH 2) jN ((C 1-C 6) alkyl) 2,-(CH 2) jC (O) NH 2,-(CH 2) jC (O) NH (C 1-C 6) alkyl) ,-(CH 2) jC (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jOC (O) NH 2,-(CH 2) jOC (O) NH (C 1-C 6) alkyl) ,-(CH 2) jOC (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jNHC (O) (C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) C (O) (C 1-C 6) alkyl ,-(CH 2) jNHC (O) O (C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) C (O) O (C 1-C 6) alkyl ,-(CH 2) jNHC (O) NH 2,-(CH 2) jNHC (O) NH (C 1-C 6) alkyl) ,-(CH 2) jNHC (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jN ((C 1-C 6) alkyl) C (O) NH (C 1-C 6) alkyl) ,-(CH 2) jN ((C 1-C 6) alkyl) C (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jS (O) m(C 1-C 6) alkyl ,-(CH 2) jS (O) 2NH 2,-(CH 2) jS (O) 2NH (C 1-C 6) alkyl) ,-(CH 2) jS (O) 2N ((C 1-C 6) alkyl) 2,-(CH 2) jNHS (O) 2(C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) S (O) 2(C 1-C 6) alkyl,
Figure A2007800385270019C1
9. the compound of claim 8, wherein:
A is independently:
Figure A2007800385270019C2
Q is (C independently 1-C 6) alkyl, perfluoroalkyl ,-NH 2,-NH (C 1-C 6) alkyl ,-N[(C 1-C 6) alkyl] 2,
Figure A2007800385270019C3
R 28' and R 28" be hydrogen, halogen, (C independently of one another 1-C 6) alkyl or trifluoromethyl; With
R 35Be hydrogen, halogen, cyano group, hydroxyl, (C independently 1-C 6) alkyl ,-(CH 2) jCN ,-(CH 2) jO (C 1-C 6) alkyl ,-(CH 2) jOH ,-(CH 2) jC (O) (C 1-C 6) alkyl ,-(CH 2) jC (O) OH ,-(CH 2) jNH 2,-(CH 2) jNH (C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) 2,-(CH 2) jC (O) NH 2,-(CH 2) jC (O) NH (C 1-C 6) alkyl ,-C (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jNHC (O) (C 1-C 6) alkyl ,-(CH 2) jNHSO 2(C 1-C 6) alkyl ,-(CH 2) jNHSO 2(C 1-C 6) alkyl ,-(CH 2) jSO 2CH 3,-(CH 2) jSO 2NH 2,-(CH 2) jSO 2NH (C 1-C 6)-alkyl ,-(CH 2) jSO 2N ((C 1-C 6) alkyl) 2,-(CH 2) jSO 2NH (C 1-C 6) alkyl (OH), phenyl,
Figure A2007800385270020C1
10. the compound of claim 1, described compound has formula III:
Wherein:
Q is hydrogen independently, halogen, replace or unsubstituted alkyl, perfluoroalkyl, amino, replace or a unsubstituted amino alkyl, replace or unsubstituted amino dialkyl group, replace or unsubstituted phenyl, replace or unsubstituted phenoxy, replace or unsubstituted piperidyl, replace or unsubstituted piperazinyl, replace or unsubstituted pyrrolidyl, replace or unsubstituted morpholinyl, replace or unsubstituted pyrryl, replace or unsubstituted furyl, replace or unsubstituted thienyl, replace or do not replace the De oxazolyl, replace or unsubstituted thiazolyl, replace or unsubstituted imidazolyl, replace or unsubstituted pyrazolyl, replace or the unsubstituted pyridine base, replace or unsubstituted-O-pyridyl, replace or unsubstituted isoxazolyl, replace or unsubstituted isothiazolyl, perhaps replace or unsubstituted triazolyl;
R 22Be hydrogen independently, halogen, nitro, cyano group, hydroxyl, replace or unsubstituted alkyl, replace or unsubstituted cycloalkyl, perfluoroalkyl, replace or unsubstituted assorted alkyl, replace or unsubstituted Heterocyclylalkyl, replace or unsubstituted phenyl, replace or unsubstituted naphthyl, replace or unsubstituted biphenyl group, replace or unsubstituted pyrryl, replace or unsubstituted imidazolyl, replace or unsubstituted pyrazolyl, replace or unsubstituted furyl, replace or unsubstituted thienyl, replace or do not replace the De oxazolyl, replace or unsubstituted isoxazolyl, replace or unsubstituted thiazolyl, replace or the unsubstituted pyridine base, replace or unsubstituted pyrazinyl, replace or unsubstituted pyrimidyl, replace or unsubstituted benzothiazolyl, replace or unsubstituted purine radicals, replace or unsubstituted benzimidazolyl-, replace or unsubstituted indyl, replace or unsubstituted isoquinolyl, replace or unsubstituted quinoxalinyl, replace or the unsubstituted quinolines base, replace or unsubstituted benzoxazolyl, replacement or unsubstituted [1,5] phthalazinyl, replace or unsubstituted pyridine also [3,2-d] pyrimidyl, replacement or unsubstituted [1,7] phthalazinyl, replace or unsubstituted 1H-pyrrolo-[2,3-b] pyridyl, replace or unsubstituted pyrazolo [4,3-b] pyridyl, replace or unsubstituted pyrrolo-[2,3-b] pyridyl, replace or unsubstituted thieno-[2,3-b] pyridyl, replace or unsubstituted thiazole also [5,4-b] pyridyl, replace or unsubstituted pyridine base-2-ketone, replace or unsubstituted imidazo [1,2-b] pyridazinyl, replace or unsubstituted pyrazolo [1,5-a] pyrimidyl, replace or unsubstituted pyridazinyl-3-ketone, replace or unsubstituted imidazo [2,1-b] [1,3,4] thiadiazolyl group, replace or unsubstituted imidazo [2,1-b] thiazolyl, perhaps replace or unsubstituted imidazo [4,5-b] pyridyl,-(CH 2) jCN ,-(CH 2) jOR 23,-(CH 2) jC (O) R 23,-(CH 2) jC (O) OR 23,-(CH 2) jNR 24R 25,-(CH 2) jC (O) NR 24R 25,-(CH 2) jOC (O) NR 24R 25,-(CH 2) jNR 26C (O) R 23,-(CH 2) jNR 26C (O) OR 23,-(CH 2) jNR 26C (O) NR 24R 25,-(CH 2) jS (O) mR 27,-(CH 2) jS (O) 2NR 24R 25, or-(CH 2) jNR 26S (O) 2R 27
R 28' and R 28" be hydrogen, halogen, hydroxyl, alkyl or perfluoroalkyl independently of one another; With
R 35Be hydrogen independently, halogen, nitro, cyano group, hydroxyl, replace or unsubstituted alkyl, replace or unsubstituted cycloalkyl, perfluoroalkyl, replace or unsubstituted assorted alkyl, replace or unsubstituted Heterocyclylalkyl, replace or unsubstituted azetidinyl, replace or unsubstituted phenyl, replace or unsubstituted naphthyl, replace or unsubstituted biphenyl group, replace or unsubstituted pyrryl, replace or unsubstituted imidazolyl, replace or unsubstituted pyrazolyl, replace or unsubstituted furyl, replace or unsubstituted thienyl, replace or do not replace the De oxazolyl, replace or unsubstituted isoxazolyl, replace or unsubstituted thiazolyl, replace or the unsubstituted pyridine base, replace or unsubstituted pyrazinyl, replace or unsubstituted pyrimidyl, replace or unsubstituted benzothiazolyl, replace or unsubstituted purine radicals, replace or unsubstituted benzimidazolyl-, replace or unsubstituted indyl, replace or unsubstituted isoquinolyl, replace or unsubstituted quinoxalinyl, replace or the unsubstituted quinolines base, replace or unsubstituted benzoxazolyl, replacement or unsubstituted [1,5] phthalazinyl, replace or unsubstituted pyridine also [3,2-d] pyrimidyl, replacement or unsubstituted [1,7] phthalazinyl, replace or unsubstituted 1H-pyrrolo-[2,3-b] pyridyl, replace or unsubstituted pyrazolo [4,3-b] pyridyl, replace or unsubstituted pyrrolo-[2,3-b] pyridyl, replace or unsubstituted thieno-[2,3-b] pyridyl, replace or unsubstituted thiazole also [5,4-b] pyridyl, replace or unsubstituted pyridine base-2-ketone, replace or unsubstituted imidazo [1,2-b] pyridazinyl, replace or unsubstituted pyrazolo [1,5-a] pyrimidyl, replace or unsubstituted pyridazinyl-3-ketone, replace or unsubstituted imidazo [2,1-b] [1,3,4] thiadiazolyl group, replace or unsubstituted imidazo [2,1-b] thiazolyl, perhaps replace or unsubstituted imidazo [4,5-b] pyridyl,-(CH 2) jCN ,-(CH 2) jOR 30,-(CH 2) jC (O) R 30,-(CH 2) jC (O) OR 30,-(CH 2) jNR 31R 32,-(CH 2) jC (O) NR 31R 32,-(CH 2) jOC (O) NR 31R 32,-(CH 2) jNR 33C (O) R 30,-(CH 2) jNR 33C (O) OR 30,-(CH 2) jNR 33C (O) NR 31R 32,-(CH 2) jS (O) mR 34,-(CH 2) jS (O) 2NR 31R 32Or-(CH 2) jNR 33S (O) 2R 34
11. the compound of claim 10, wherein:
Q is hydrogen independently, halogen, replace or unsubstituted alkyl, perfluoroalkyl, amino, replace or a unsubstituted amino alkyl, replace or unsubstituted amino dialkyl group, replace or unsubstituted phenyl, replace or unsubstituted phenoxy, replace or unsubstituted piperidyl, replace or unsubstituted piperazinyl, replace or unsubstituted pyrrolidyl, replace or unsubstituted morpholinyl, replace or unsubstituted pyrryl, replace or unsubstituted furyl, replace or unsubstituted thienyl, replace or do not replace the De oxazolyl, replace or unsubstituted thiazolyl, replace or unsubstituted imidazolyl, replace or unsubstituted pyrazolyl, replace or the unsubstituted pyridine base, perhaps replace or unsubstituted-O-pyridyl;
R 22Be independently hydrogen, halogen, nitro, cyano group, hydroxyl, replacement or unsubstituted alkyl, replacement or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted Heterocyclylalkyl ,-(CH 2) jCN ,-(CH 2) jOR 23,-(CH 2) jC (O) R 23,-(CH 2) jC (O) OR 23,-(CH 2) jNR 24R 25,-(CH 2) jC (O) NR 24R 25,-(CH 2) jOC (O) NR 24R 25,-(CH 2) jNR 26C (O) R 23,-(CH 2) jNR 26C (O) OR 23,-(CH 2) jNR 26C (O) NR 24R 25,-(CH 2) jS (O) mR 27,-(CH 2) jS (O) 2NR 24R 25Or-(CH 2) jNR 26S (O) 2R 27
R 28' and R 28" be hydrogen, halogen, hydroxyl, alkyl or perfluoroalkyl independently of one another; With
R 35Be independently hydrogen, halogen, nitro, cyano group, hydroxyl, replacement or unsubstituted alkyl, replacement or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted Heterocyclylalkyl ,-(CH 2) jCN ,-(CH 2) jOR 30,-(CH 2) jC (O) R 30,-(CH 2) jC (O) OR 30,-(CH 2) jNR 31R 32,-(CH 2) jC (O) NR 31R 32,-(CH 2) jOC (O) NR 31R 32,-(CH 2) jNR 33C (O) R 30,-(CH 2) jNR 33C (O) OR 30,-(CH 2) jN 33C (O) NR 31R 32,-(CH 2) jS (O) mR 34,-(CH 2) jS (O) 2NR 31R 32,-(CH 2) jNR 33S (O) 2R 34,
Figure A2007800385270023C1
12. the compound of claim 11, wherein:
Q be independently hydrogen, chloro, replacement or unsubstituted alkyl, perfluoroalkyl ,-NH 2,-NH (C 1-C 6) alkyl, or-N[(C 1-C 6) alkyl] 2,
Figure A2007800385270023C2
Figure A2007800385270024C1
Wherein each alkyl is optional by 1-3 R 22Group replace independently and wherein w be the integer of 0-3 independently; Two R wherein 22Group and-O (CH 2CH 2) the optional ring texture that forms of O-;
R 22Be independently-H ,-F, Cl, Br, I ,-(C 1-C 6) alkyl ,-(CH 2) jCN ,-(CH 2) jO (C 1-C 6) alkyl ,-(CH 2) jOH ,-(CH 2) jC (O) (C 1-C 6) alkyl ,-(CH 2) jNH 2,-(CH 2) jNH (C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) 2,-(CH 2) jC (O) NH 2,-(CH 2) jC (O) NH (C 1-C 6) alkyl ,-C (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jNHC (O) (C 1-C 6) alkyl ,-(CH 2) jNHSO 2(C 1-C 6) alkyl ,-(CH 2) jNHSO 2(C 1-C 6) alkyl ,-(CH 2) jSO 2CH 3,-(CH 2) jSO 2NH 2,-(CH 2) jSO 2NH (C 1-C 6)-alkyl ,-(CH 2) jSO 2N ((C 1-C 6) alkyl) 2,-(CH 2) jSO 2NH (C 1-C 6) alkyl (OH), phenyl,
Figure A2007800385270024C2
R 28' and R 28" be hydrogen, halogen, hydroxyl, (C independently of one another 1-C 6) alkyl or trifluoromethyl; With
R 35Be hydrogen, halogen, nitro, cyano group, hydroxyl, (C independently 1-C 6) alkyl, ring (C 3-C 10) alkyl, perfluor (C 1-C 6) alkyl ,-(CH 2) jCN ,-(CH 2) jO (C 1-C 6) alkyl ,-(CH 2) jC (O) (C 1-C 6) alkyl ,-(CH 2) jC (O) O (C 1-C 6) alkyl ,-(CH 2) jNH 2,-(CH 2) jNH (C 1-C 6) alkyl) ,-(CH 2) jN ((C 1-C 6) alkyl) 2,-(CH 2) jC (O) NH 2,-(CH 2) jC (O) NH (C 1-C 6) alkyl) ,-(CH 2) jC (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jOC (O) NH 2,-(CH 2) jOC (O) NH (C 1-C 6) alkyl) ,-(CH 2) jOC (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jNHC (O) (C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) C (O) (C 1-C 6) alkyl ,-(CH 2) jNHC (O) O (C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) C (O) O (C 1-C 6) alkyl ,-(CH 2) jNHC (O) NH 2,-(CH 2) jNHC (O) NH (C 1-C 6) alkyl) ,-(CH 2) jNHC (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jN ((C 1-C 6) alkyl) C (O) NH (C 1-C 6) alkyl) ,-(CH 2) jN ((C 1-C 6) alkyl) C (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jS (O) m(C 1-C 6) alkyl ,-(CH 2) jS (O) 2NH 2,-(CH 2) jS (O) 2NH (C 1-C 6) alkyl) ,-(CH 2) jS (O) 2N ((C 1-C 6) alkyl) 2,-(CH 2) jNHS (O) 2(C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) S (O) 2(C 1-C 6) alkyl,
13. the compound of claim 12, wherein:
Wherein:
Q is (C independently 1-C 6) alkyl, perfluoroalkyl ,-NH 2,-NH (C 1-C 6) alkyl ,-N[(C 1-C 6) alkyl] 2,
Figure A2007800385270025C2
R 28' and R 28" be hydrogen, halogen, (C independently of one another 1-C 6) alkyl, or trifluoromethyl; With
R 35Be independently hydrogen, halogen, cyano group, hydroxyl ,-(C 1-C 6) alkyl ,-(CH 2) jCN ,-(CH 2) jO (C 1-C 6) alkyl ,-(CH 2) jOH ,-(CH 2) jC (O) (C 1-C 6) alkyl ,-(CH 2) jC (O) OH ,-(CH 2) jNH 2,-(CH 2) jNH (C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) 2,-(CH 2) jC (O) NH 2,-(CH 2) jC (O) NH (C 1-C 6) alkyl ,-C (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jNHC (O) (C 1-C 6) alkyl ,-(CH 2) jNHSO 2(C 1-C 6) alkyl ,-(CH 2) jNHSO 2(C 1-C 6) alkyl ,-(CH 2) jSO 2CH 3,-(CH 2) jSO 2NH 2,-(CH 2) jSO 2NH (C 1-C 6)-alkyl ,-(CH 2) jSO 2N ((C 1-C 6) alkyl) 2,-(CH 2) jSO 2NH (C 1-C 6) alkyl (OH), phenyl,
Figure A2007800385270026C1
14. the compound of claim 13, wherein:
Q is (C independently 1-C 6) alkyl;
T is CH 2
R 28And R 28' be hydrogen independently of one another; With
R 35For-(C 1-C 6) alkyl.
15. a compound, described compound is selected from:
Figure A2007800385270027C1
Figure A2007800385270028C1
Figure A2007800385270030C1
Figure A2007800385270031C1
16. a compound, described compound is selected from:
Figure A2007800385270031C2
Figure A2007800385270032C1
Figure A2007800385270034C1
17. a method of regulating protein kinase activity, this method comprise described protein kinase is contacted with the formula I compound of claim 1.
18. the method for claim 17, wherein said protein kinase are Ron receptor tyrosine kinase, Met receptor tyrosine kinase, ALK receptor tyrosine kinase, MER receptor tyrosine kinase, Tyro3/Sky receptor tyrosine kinase, axl receptor Tyrosylprotein kinase, TRKC receptor tyrosine kinase, ROS receptor tyrosine kinase, CSF1R/FMS receptor tyrosine kinase, BRAF kinases or Raf1 kinases.
19. the method for claim 18, wherein said protein kinase are the Met receptor tyrosine kinase.
20. treat method for cancer for one kind in the human patients of this kind of needs treatment, described method comprises the formula I compound of the claim 1 that gives described patient treatment significant quantity.
21. the method for claim 20, wherein said cancer are mammary cancer, lung cancer, melanoma, colorectal carcinoma, bladder cancer, ovarian cancer, prostate cancer, kidney, squamous cell carcinoma, glioblastoma, carcinoma of the pancreas, leiomyosarcoma, multiple myeloma, Papillary Renal Cell Carcinoma, cancer of the stomach, liver cancer, head and neck cancer, melanoma or leukemia (as myelomatosis, chronic lymphocytic leukemia, acute lymphocytoblast leukemia, chronic lymphocytoblast leukemia, Hokdkin disease and other leukemia and hematology cancer).
22. a medicinal compositions, it is included in the formula I compound of the claim 1 in the pharmaceutically acceptable vehicle.
23. a method for preparing the formula I compound of claim 1 said method comprising the steps of:
Figure A2007800385270034C2
A) under acidity or dehydration conditions, make the cyclodehydration of formula IV compound.
24. the method for claim 23, wherein said acidic conditions are acetate, POCl 3Or trifluoromethanesulfonic acid.
25. a method for preparing the formula I compound of claim 1 said method comprising the steps of:
A) make formula V compound and the coupling in solvent of formula VI compound, wherein LG is halogen or trifluoromethanesulfonic acid ester group.
26. the method for claim 25, wherein said solvent are alcohol.
27. a method for preparing the formula I compound of claim 1 said method comprising the steps of:
Figure A2007800385270035C2
A) make formula VII and formula VIII compound condensation, wherein R ' is C 1-C 6Alkyl.
28. formula IX compound:
Figure A2007800385270035C3
Or its enantiomorph, diastereomer, racemic modification or pharmacy acceptable salt or solvate, wherein:
A is independently for replacing or unsubstituted aryl or replacement or unsubstituted heteroaryl;
Q is hydrogen, amino, halogen, replacement or unsubstituted alkyl, replacement or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl, replacement or unsubstituted-O-aryl, replacement or unsubstituted arylalkyl, replacement or unsubstituted-O-heteroaryl independently, perhaps replace or unsubstituted heteroarylalkyl, wherein Q is optional by 1-3 R 22Replace independently;
T is CH (halogen), C (halogen) independently 2
X is N or CR 2
R 1And R 2Optional separately be independently hydrogen, halogen, nitro, cyano group, hydroxyl, replacement or unsubstituted alkyl, perfluoroalkyl ,-(CH 2) jCN ,-(CH 2) jOR 3,-(CH 2) jC (O) R 3,-(CH 2) jC (O) OR 3,-(CH 2) jNR 4R 5,-(CH 2) jC (O) NR 4R 5,-(CH 2) jOC (O) NR 4R 5,-(CH 2) jNR 6C (O) R 3,-(CH 2) jNR 6C (O) OR 3,-(CH 2) jNR 6C (O) NR 4R 5,-(CH 2) jS (O) mR 7,-(CH 2) jNR 6S (O) 2R 7,-(CH 2) jS (O) 2NR 4R 5, wherein each j is the integer of 0-6 independently; With m be the integer of 0-2 independently; Or
R 1And R 2Form replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl, perhaps replace or unsubstituted heteroaryl;
R 3, R 4, R 5, R 6And R 7Be hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl, replacement or unsubstituted-O-aryl, replacement or unsubstituted arylalkyl, replacement or unsubstituted heteroaryl, replacement or unsubstituted-O-heteroaryl independently of one another, perhaps replace or unsubstituted heteroarylalkyl, or
R 3, R 6And R 7As mentioned above, reach R 4And R 5N atom with they connect forms replacement or unsubstituted Heterocyclylalkyl, perhaps replaces or unsubstituted heteroaryl;
R 22Be independently hydrogen, halogen, nitro, cyano group, hydroxyl, replacement or unsubstituted alkyl, replacement or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl, replacement or unsubstituted-O-aryl, replacement or unsubstituted arylalkyl, replacement or unsubstituted heteroaryl, replacement or unsubstituted-O-heteroaryl, replacement or unsubstituted heteroarylalkyl ,-(CH 2) jCN ,-(CH 2) jOR 23,-(CH 2) jC (O) R 23,-(CH 2) jC (O) OR 23,-(CH 2) jNR 24R 25,-(CH 2) jC (O) NR 24R 25,-(CH 2) jOC (O) NR 24R 25,-(CH 2) jNR 26C (O) R 23,-(CH 2) jNR 26C (O) OR 23,-(CH 2) jNR 26C (O) NR 24R 25,-(CH 2) jS (O) mR 27,-(CH 2) jS (O) 2NR 24R 25, or-(CH 2) jNR 26S (O) 2R 27, wherein each j is the integer of 0-6 independently, and each m is the integer of 0-2 independently;
R 23, R 24, R 25, R 26And R 27Be hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl, replacement or unsubstituted-O-aryl, replacement or unsubstituted arylalkyl, replacement or unsubstituted heteroaryl, replacement or unsubstituted-O-heteroaryl independently of one another, perhaps replace or unsubstituted heteroarylalkyl, or
R 23, R 26And R 27As mentioned above, and R 24And R 25N atom with they connect forms replacement or unsubstituted Heterocyclylalkyl, perhaps replaces or unsubstituted heteroaryl;
R 28' and R 28" be hydrogen, halogen, nitro, cyano group, hydroxyl, replacement or unsubstituted alkyl, replacement or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted alkoxyl group, amino, an amino alkyl independently of one another, or amino dialkyl group;
R 35Be independently covalent linkage, hydrogen, halogen, nitro, cyano group, hydroxyl, replacement or unsubstituted alkyl, replacement or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl, replacement or unsubstituted arylalkyl, replacement or unsubstituted heteroaryl, replacement or unsubstituted heteroarylalkyl ,-(CH 2) jCN ,-(CH 2) jOR 30,-(CH 2) jC (O) R 30,-(CH 2) jC (O) OR 30,-(CH 2) jNR 31R 32,-(CH 2) jC (O) NR 31R 32,-(CH 2) jOC (O) NR 31R 32,-(CH 2) jNR 33C (O) R 30,-(CH 2) jNR 33C (O) OR 30,-(CH 2) jN 33C (O) NR 31R 32,-(CH 2) jS (O) mR 34,-(CH 2) jS (O) 2NR 31R 32Or-(CH 2) jNR 33S (O) 2R 34, wherein each j is that integer and the m of 0-6 is the integer of 0-2 independently independently;
Z is the integer of 0-3 independently;
R 30, R 31, R 32, R 33And R 34Be hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl, replacement or unsubstituted-O-aryl, replacement or unsubstituted arylalkyl, replacement or unsubstituted heteroaryl, replacement or unsubstituted-O-heteroaryl independently of one another, perhaps replace or unsubstituted heteroarylalkyl, or
R 30, R 33And R 34As mentioned above, and R 31And R 32N atom with they connect forms replacement or unsubstituted Heterocyclylalkyl, perhaps replaces or unsubstituted heteroaryl; With
R wherein 1, R 2, R 3, R 4, R 5, R 6, R 7, R 22, R 23, R 24, R 25, R 26, R 27, R 28', R 28", R 30, R 31, R 32, R 33, R 34And R 35Optionally separately replaced independently by 1-3 group, each group be independently selected from hydrogen, halogen, hydroxyl, amino, an amino alkyl, amino dialkyl group, cyano group, nitro, difluoromethyl, trifluoromethyl, oxo, alkyl ,-the O-alkyl and-the S-alkyl.
29. the compound of claim 28, wherein:
A is independently for replacing or unsubstituted phenyl, replace or unsubstituted naphthyl, replace or unsubstituted biphenyl group, replace or unsubstituted pyrryl, replace or unsubstituted furyl, replace or unsubstituted thienyl, replace or do not replace the De oxazolyl, replace or unsubstituted thiazolyl, replace or unsubstituted imidazolyl, replace or unsubstituted pyrazolyl, replace or the unsubstituted pyridine base, replace or unsubstituted isoxazolyl, replace or unsubstituted isothiazolyl, replace or unsubstituted triazolyl, replace or unsubstituted pyrazinyl, replace or unsubstituted pyrimidyl, replace or unsubstituted benzothiazolyl, replace or unsubstituted purine radicals, replace or unsubstituted benzimidazolyl-, replace or unsubstituted indyl, replace or unsubstituted isoquinolyl, replace or unsubstituted quinoxalinyl, replace or the unsubstituted quinolines base, replace or unsubstituted benzoxazolyl, replacement or unsubstituted [1,5] phthalazinyl, replace or unsubstituted pyridine also [3,2-d] pyrimidyl, replacement or unsubstituted [1,7] phthalazinyl, replace or unsubstituted 1H-pyrrolo-[2,3-b] pyridyl, replace or unsubstituted pyrazolo [4,3-b] pyridyl, replace or unsubstituted pyrrolo-[2,3-b] pyridyl, replace or unsubstituted thieno-[2,3-b] pyridyl, replace or unsubstituted thiazole also [5,4-b] pyridyl, replace or unsubstituted pyridine base-2-ketone, replace or unsubstituted imidazo [1,2-b] pyridazinyl, replace or unsubstituted pyrazolo [1,5-a] pyrimidyl, replace or unsubstituted pyridazinyl-3-ketone, replace or unsubstituted imidazo [2,1-b] [1,3,4] thiadiazolyl group, replace or unsubstituted imidazo [2,1-b] thiazolyl, perhaps replace or unsubstituted imidazo [4,5-b] pyridyl;
Q is hydrogen, halogen, replacement or unsubstituted alkyl, perfluoroalkyl, amino, replacement or a unsubstituted amino alkyl, replacement or unsubstituted amino dialkyl group, replacement or unsubstituted phenyl, replacement or unsubstituted phenoxy, replacement or unsubstituted piperidyl, replacement or unsubstituted piperazinyl, replacement or unsubstituted pyrrolidyl, replacement or unsubstituted morpholinyl, replacement or unsubstituted-O-pyridyl independently;
R 1And R 2Optional separately be independently hydrogen, halogen, nitro, cyano group, hydroxyl, replacement or unsubstituted alkyl, perfluoroalkyl ,-(CH 2) jCN ,-(CH 2) jOR 3,-(CH 2) jC (O) R 3,-(CH 2) jC (O) OR 3,-(CH 2) jNR 4R 5,-(CH 2) jC (O) NR 4R 5,-(CH 2) jOC (O) NR 4R 5,-(CH 2) jNR 6C (O) R 3,-(CH 2) jNR 6C (O) OR 3,-(CH 2) jNR 6C (O) NR 4R 5,-(CH 2) jS (O) mR 7,-(CH 2) jNR 6S (O) 2R 7,-(CH 2) jS (O) 2NR 4R 5
R 22Be hydrogen independently, halogen, nitro, cyano group, hydroxyl, replace or unsubstituted alkyl, replace or unsubstituted cycloalkyl, perfluoroalkyl, replace or unsubstituted assorted alkyl, replace or unsubstituted Heterocyclylalkyl, replace or unsubstituted phenyl, replace or unsubstituted naphthyl, replace or unsubstituted biphenyl group, replace or unsubstituted pyrryl, replace or unsubstituted imidazolyl, replace or unsubstituted pyrazolyl, replace or unsubstituted furyl, replace or unsubstituted thienyl, replace or do not replace the De oxazolyl, replace or unsubstituted isoxazolyl, replace or unsubstituted thiazolyl, replace or the unsubstituted pyridine base, replace or unsubstituted pyrazinyl, replace or unsubstituted pyrimidyl, replace or unsubstituted benzothiazolyl, replace or unsubstituted purine radicals, replace or unsubstituted benzimidazolyl-, replace or unsubstituted indyl, replace or unsubstituted isoquinolyl, replace or unsubstituted quinoxalinyl, replace or the unsubstituted quinolines base, replace or unsubstituted benzoxazolyl, replacement or unsubstituted [1,5] phthalazinyl, replace or unsubstituted pyridine also [3,2-d] pyrimidyl, replacement or unsubstituted [1,7] phthalazinyl, replace or unsubstituted 1H-pyrrolo-[2,3-b] pyridyl, replace or unsubstituted pyrazolo [4,3-b] pyridyl, replace or unsubstituted pyrrolo-[2,3-b] pyridyl, replace or unsubstituted thieno-[2,3-b] pyridyl, replace or unsubstituted thiazole also [5,4-b] pyridyl, replace or unsubstituted pyridine base-2-ketone, replace or unsubstituted imidazo [1,2-b] pyridazinyl, replace or unsubstituted pyrazolo [1,5-a] pyrimidyl, replace or unsubstituted pyridazinyl-3-ketone, replace or unsubstituted imidazo [2,1-b] [1,3,4] thiadiazolyl group, replace or unsubstituted imidazo [2,1-b] thiazolyl, perhaps replace or unsubstituted imidazo [4,5-b] pyridyl,-(CH 2) jCN ,-(CH 2) jOR 23,-(CH 2) jC (O) R 23,-(CH 2) jC (O) OR 23,-(CH 2) jNR 24R 25,-(CH 2) jC (O) NR 24R 25,-(CH 2) jOC (O) NR 24R 25,-(CH 2) jNR 26C (O) R 23,-(CH 2) jNR 26C (O) OR 23,-(CH 2) jNR 26C (O) NR 24R 25,-(CH 2) jS (O) mR 27,-(CH 2) jS (O) 2NR 24R 25, or-(CH 2) jNR 26S (O) 2R 27
R 28' and R 28" be hydrogen, halogen, cyano group, hydroxyl, replacement or unsubstituted alkyl independently of one another, or perfluoroalkyl; With
R 35Be hydrogen independently, halogen, nitro, cyano group, hydroxyl, replace or unsubstituted alkyl, replace or unsubstituted cycloalkyl, perfluoroalkyl, replace or unsubstituted assorted alkyl, replace or unsubstituted Heterocyclylalkyl, replace or unsubstituted azetidinyl, replace or unsubstituted phenyl, replace or unsubstituted naphthyl, replace or unsubstituted biphenyl group, replace or unsubstituted pyrryl, replace or unsubstituted imidazolyl, replace or unsubstituted pyrazolyl, replace or unsubstituted furyl, replace or unsubstituted thienyl, replace or do not replace the De oxazolyl, replace or unsubstituted isoxazolyl, replace or unsubstituted thiazolyl, replace or the unsubstituted pyridine base, replace or unsubstituted pyrazinyl, replace or unsubstituted pyrimidyl, replace or unsubstituted benzothiazolyl, replace or unsubstituted purine radicals, replace or unsubstituted benzimidazolyl-, replace or unsubstituted indyl, that replace or replace isoquinolyl, replace or unsubstituted quinoxalinyl, replace or the unsubstituted quinolines base, replace or unsubstituted benzoxazolyl, replacement or unsubstituted [1,5] phthalazinyl, replace or unsubstituted pyridine also [3,2-d] pyrimidyl, replacement or unsubstituted [1,7] phthalazinyl, replace or unsubstituted 1H-pyrrolo-[2,3-b] pyridyl, replace or unsubstituted pyrazolo [4,3-b] pyridyl, replace or unsubstituted pyrrolo-[2,3-b] pyridyl, replace or unsubstituted thieno-[2,3-b] pyridyl, replace or unsubstituted thiazole also [5,4-b] pyridyl, replace or unsubstituted pyridine base-2-ketone, replace or unsubstituted imidazo [1,2-b] pyridazinyl, replace or unsubstituted pyrazolo [1,5-a] pyrimidyl, replace or unsubstituted pyridazinyl-3-ketone, replace or unsubstituted imidazo [2,1-b] [1,3,4] thiadiazolyl group, replace or unsubstituted imidazo [2,1-b] thiazolyl, perhaps replace or unsubstituted imidazo [4,5-b] pyridyl,-(CH 2) jCN ,-(CH 2) jOR 30,-(CH 2) jC (O) R 30,-(CH 2) jC (O) OR 30,-(CH 2) jNR 31R 32,-(CH 2) jC (O) NR 31R 32,-(CH 2) jOC (O) NR 31R 32,-(CH 2) jNR 33C (O) R 30,-(CH 2) jNR 33C (O) OR 30,-(CH 2) jNR 33C (O) NR 31R 32,-(CH 2) jS (O) mR 34,-(CH 2) jS (O) 2NR 31R 32Or-(CH 2) jNR 33S (O) 2R 34
30. the compound of claim 29, wherein:
A is independently for replacing or unsubstituted phenyl, replace or unsubstituted naphthyl, replace or unsubstituted biphenyl group, replace or unsubstituted pyrryl, replace or unsubstituted furyl, replace or unsubstituted thienyl, replace or do not replace the De oxazolyl, replace or unsubstituted thiazolyl, replace or unsubstituted imidazolyl, replace or unsubstituted pyrazolyl, replace or the unsubstituted pyridine base, replace or unsubstituted isoxazolyl, replace or unsubstituted isothiazolyl, replace or unsubstituted triazolyl, replace or unsubstituted pyrazinyl, replace or unsubstituted pyrimidyl, replace or unsubstituted benzothiazolyl, replace or unsubstituted purine radicals, replace or unsubstituted benzimidazolyl-, replace or unsubstituted indyl, replace or unsubstituted isoquinolyl, replace or unsubstituted quinoxalinyl, or replacement or unsubstituted quinolines base;
Q is hydrogen, halogen, replacement or unsubstituted alkyl, perfluoroalkyl, amino, replacement or a unsubstituted amino alkyl, replacement or unsubstituted amino dialkyl group, replacement or unsubstituted phenyl, replacement or unsubstituted phenoxy, replacement or unsubstituted piperidyl, replacement or unsubstituted piperazinyl, replacement or unsubstituted pyrrolidyl, replacement or unsubstituted morpholinyl independently, perhaps replaces or unsubstituted-O-pyridyl;
R 1And R 2Be hydrogen, halogen, nitro, cyano group, hydroxyl, replacement or unsubstituted alkyl independently of one another, or perfluoroalkyl;
X is CR 2
R 22Be independently hydrogen, halogen, nitro, cyano group, hydroxyl, replacement or unsubstituted alkyl, replacement or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted Heterocyclylalkyl ,-(CH 2) jCN ,-(CH 2) jOR 23,-(CH 2) jC (O) R 23,-(CH 2) jC (O) OR 23,-(CH 2) jNR 24R 25,-(CH 2) jC (O) NR 24R 25,-(CH 2) jOC (O) NR 24R 25,-(CH 2) jNR 26C (O) R 23,-(CH 2) jNR 26C (O) OR 23,-(CH 2) jNR 26C (O) NR 24R 25,-(CH 2) jS (O) mR 27,-(CH 2) jS (O) 2NR 24R 25Or-(CH 2) jNR 26S (O) 2R 27
R 28' and R 28" be hydrogen, halogen, hydroxyl, alkyl or perfluoroalkyl independently of one another; With
R 35Be independently hydrogen, halogen, nitro, cyano group, hydroxyl, replacement or unsubstituted alkyl, replacement or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted Heterocyclylalkyl ,-(CH 2) jCN ,-(CH 2) jOR 30,-(CH 2) jC (O) R 30,-(CH 2) jC (O) OR 30,-(CH 2) jNR 31R 32,-(CH 2) jC (O) NR 31R 32,-(CH 2) jOC (O) NR 31R 32,-(CH 2) jNR 33C (O) R 30,-(CH 2) jNR 33C (O) OR 30,-(CH 2) jN 33C (O) NR 31R 32,-(CH 2) jS (O) mR 34,-(CH 2) jS (O) 2NR 31R 32,-(CH 2) jNR 33S (O) 2R 34,
Figure A2007800385270042C1
31. the compound of claim 30, wherein:
A is independently:
Figure A2007800385270042C2
Q be independently hydrogen, chloro, replacement or unsubstituted alkyl, perfluoroalkyl ,-NH 2,-NH (C 1-C 6) alkyl or-N[(C 1-C 6) alkyl] 2,
Figure A2007800385270043C1
Wherein each alkyl is optional by 1-3 R 22Group replace independently and wherein w be the integer of 0-3 independently; Two R wherein 22Group and-O (CH 2CH 2) the optional ring texture that forms of O-;
R 1And R 2Be hydrogen independently of one another;
R 22Be independently-H ,-F, Cl, Br, I ,-(C 1-C 6) alkyl ,-(CH 2) jCN ,-(CH 2) jO (C 1-C 6) alkyl ,-(CH 2) jOH ,-(CH 2) jC (O) (C 1-C 6) alkyl ,-(CH 2) jNH 2,-(CH 2) jNH (C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) 2,-(CH 2) jC (O) NH 2,-(CH 2) jC (O) NH (C 1-C 6) alkyl ,-C (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jNHC (O) (C 1-C 6) alkyl ,-(CH 2) jNHSO 2(C 1-C 6) alkyl ,-(CH 2) jNHSO 2(C 1-C 6) alkyl ,-(CH 2) jSO 2CH 3,-(CH 2) jSO 2NH 2,-(CH 2) jSO 2NH (C 1-C 6)-alkyl ,-(CH 2) jSO 2N ((C 1-C 6) alkyl) 2,-(CH 2) jSO 2NH (C 1-C 6) alkyl (OH), phenyl,
Figure A2007800385270044C1
R 28' and R 28" be hydrogen, halogen, hydroxyl, (C independently of one another 1-C 6) alkyl, or trifluoromethyl; With
R 35Be hydrogen, halogen, nitro, cyano group, hydroxyl, (C independently 1-C 6) alkyl, ring (C 3-C 10) alkyl, perfluor (C 1-C 6) alkyl ,-(CH 2) jCN ,-(CH 2) jO (C 1-C 6) alkyl ,-(CH 2) jC (O) (C 1-C 6) alkyl ,-(CH 2) jC (O) O (C 1-C 6) alkyl ,-(CH 2) jNH 2,-(CH 2) jNH (C 1-C 6) alkyl) ,-(CH 2) jN ((C 1-C 6) alkyl) 2,-(CH 2) jC (O) NH 2,-(CH 2) jC (O) NH (C 1-C 6) alkyl) ,-(CH 2) jC (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jOC (O) NH 2,-(CH 2) jOC (O) NH (C 1-C 6) alkyl) ,-(CH 2) jOC (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jNHC (O) (C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) C (O) (C 1-C 6) alkyl ,-(CH 2) jNHC (O) O (C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) C (O) O (C 1-C 6) alkyl ,-(CH 2) jNHC (O) NH 2,-(CH 2) jNHC (O) NH (C 1-C 6) alkyl) ,-(CH 2) jNHC (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jN ((C 1-C 6) alkyl) C (O) NH (C 1-C 6) alkyl) ,-(CH 2) jN ((C 1-C 6) alkyl) C (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jS (O) m(C 1-C 6) alkyl, (CH 2) jS (O) 2NH 2,-(CH 2) jS (O) 2NH (C 1-C 6) alkyl) ,-(CH 2) jS (O) 2N ((C 1-C 6) alkyl) 2,-(CH 2) jNHS (O) 2(C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) S (O) 2(C 1-C 6) alkyl,
Figure A2007800385270044C2
33. the compound of claim 31, wherein:
A is independently:
Figure A2007800385270045C1
Q is (C independently 1-C 6) alkyl, perfluoroalkyl ,-NH 2,-NH (C 1-C 6) alkyl ,-N[(C 1-C 6) alkyl] 2
R 28' and R 28" be hydrogen, halogen, (C independently of one another 1-C 6) alkyl or trifluoromethyl; With
R 35Be independently hydrogen, halogen, cyano group, hydroxyl ,-(C 1-C 6) alkyl ,-(CH 2) jCN ,-(CH 2) jO (C 1-C 6) alkyl ,-(CH 2) jOH ,-(CH 2) jC (O) (C 1-C 6) alkyl ,-(CH 2) jC (O) OH ,-(CH 2) jNH 2,-(CH 2) jNH (C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) 2,-(CH 2) jC (O) NH 2,-(CH 2) jC (O) NH (C 1-C 6) alkyl ,-C (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jNHC (O) (C 1-C 6) alkyl ,-(CH 2) jNHSO 2(C 1-C 6) alkyl ,-(CH 2) jNHSO 2(C 1-C 6) alkyl ,-(CH 2) jSO 2CH 3,-(CH 2) jSO 2NH 2,-(CH 2) jSO 2NH (C 1-C 6)-alkyl ,-(CH 2) jSO 2N ((C 1-C 6) alkyl) 2,-(CH 2) jSO 2NH (C 1-C 6) alkyl (OH), phenyl,
Figure A2007800385270045C2
33. formula X compound:
Figure A2007800385270045C3
Wherein:
T is CH (halogen), C (halogen) independently 2
A is independently for replacing or unsubstituted phenyl, replace or unsubstituted naphthyl, replace or unsubstituted biphenyl group, replace or unsubstituted pyrryl, replace or unsubstituted furyl, replace or unsubstituted thienyl, replace or do not replace the De oxazolyl, replace or unsubstituted thiazolyl, replace or unsubstituted imidazolyl, replace or unsubstituted pyrazolyl, replace or the unsubstituted pyridine base, replace or unsubstituted isoxazolyl, replace or unsubstituted isothiazolyl, replace or unsubstituted triazolyl, replace or unsubstituted pyrazinyl, replace or unsubstituted pyrimidyl, replace or unsubstituted benzothiazolyl, replace or unsubstituted purine radicals, replace or unsubstituted benzimidazolyl-, replace or unsubstituted indyl, replace or unsubstituted isoquinolyl, replace or unsubstituted quinoxalinyl, replace or the unsubstituted quinolines base, replace or unsubstituted benzoxazolyl, replacement or unsubstituted [1,5] phthalazinyl, replace or unsubstituted pyridine also [3,2-d] pyrimidyl, replacement or unsubstituted [1,7] phthalazinyl, replace or unsubstituted 1H-pyrrolo-[2,3-b] pyridyl, replace or unsubstituted pyrazolo [4,3-b] pyridyl, replace or unsubstituted pyrrolo-[2,3-b] pyridyl, replace or unsubstituted thieno-[2,3-b] pyridyl, replace or unsubstituted thiazole also [5,4-b] pyridyl, replace or unsubstituted pyridine base-2-ketone, replace or unsubstituted imidazo [1,2-b] pyridazinyl, replace or unsubstituted pyrazolo [1,5-a] pyrimidyl, replace or unsubstituted pyridazinyl-3-ketone, replace or unsubstituted imidazo [2,1-b] [1,3,4] thiadiazolyl group, replace or unsubstituted imidazo [2,1-b] thiazolyl, perhaps replace or unsubstituted imidazo [4,5-b] pyridyl;
Q is hydrogen, halogen, replacement or unsubstituted alkyl, perfluoroalkyl, amino, replacement or a unsubstituted amino alkyl, replacement or unsubstituted amino dialkyl group, replacement or unsubstituted phenyl, replacement or unsubstituted phenoxy, replacement or unsubstituted piperidyl, replacement or unsubstituted piperazinyl, replacement or unsubstituted pyrrolidyl, replacement or unsubstituted morpholinyl, replacement or unsubstituted-O-pyridyl independently;
R 22Be hydrogen independently, halogen, nitro, cyano group, hydroxyl, replace or unsubstituted alkyl, replace or unsubstituted cycloalkyl, perfluoroalkyl, replace or unsubstituted assorted alkyl, replace or unsubstituted Heterocyclylalkyl, replace or unsubstituted phenyl, replace or unsubstituted naphthyl, replace or unsubstituted biphenyl group, replace or unsubstituted pyrryl, replace or unsubstituted imidazolyl, replace or unsubstituted pyrazolyl, replace or unsubstituted furyl, replace or unsubstituted thienyl, replace or do not replace the De oxazolyl, replace or unsubstituted isoxazolyl, replace or unsubstituted thiazolyl, replace or the unsubstituted pyridine base, replace or unsubstituted pyrazinyl, replace or unsubstituted pyrimidyl, replace or unsubstituted benzothiazolyl, replace or unsubstituted purine radicals, replace or unsubstituted benzimidazolyl-, replace or unsubstituted indyl, replace or unsubstituted isoquinolyl, replace or unsubstituted quinoxalinyl, replace or the unsubstituted quinolines base, replace or unsubstituted benzoxazolyl, replacement or unsubstituted [1,5] phthalazinyl, replace or unsubstituted pyridine also [3,2-d] pyrimidyl, replacement or unsubstituted [1,7] phthalazinyl, replace or unsubstituted 1H-pyrrolo-[2,3-b] pyridyl, replace or unsubstituted pyrazolo [4,3-b] pyridyl, replace or unsubstituted pyrrolo-[2,3-b] pyridyl, replace or unsubstituted thieno-[2,3-b] pyridyl, replace or unsubstituted thiazole also [5,4-b] pyridyl, replace or unsubstituted pyridine base-2-ketone, replace or unsubstituted imidazo [1,2-b] pyridazinyl, replace or unsubstituted pyrazolo [1,5-a] pyrimidyl, replace or unsubstituted pyridazinyl-3-ketone, replace or unsubstituted imidazo [2,1-b] [1,3,4] thiadiazolyl group, replace or unsubstituted imidazo [2,1-b] thiazolyl, perhaps replace or unsubstituted imidazo [4,5-b] pyridyl,-(CH 2) jCN ,-(CH 2) jOR 23,-(CH 2) jC (O) R 23,-(CH 2) jC (O) OR 23,-(CH 2) jNR 24R 25,-(CH 2) jC (O) NR 24R 25,-(CH 2) jOC (O) NR 24R 25,-(CH 2) jNR 26C (O) R 23,-(CH 2) jNR 26C (O) OR 23,-(CH 2) jNR 26C (O) NR 24R 25,-(CH 2) jS (O) mR 27,-(CH 2) jS (O) 2NR 24R 25, or-(CH 2) jNR 26S (O) 2R 27
R 28' and R 28" be hydrogen, halogen, cyano group, hydroxyl, replacement or unsubstituted alkyl independently of one another, or perfluoroalkyl; With
R 35Be hydrogen independently, halogen, nitro, cyano group, hydroxyl, replace or unsubstituted alkyl, replace or unsubstituted cycloalkyl, perfluoroalkyl, replace or unsubstituted assorted alkyl, replace or unsubstituted Heterocyclylalkyl, replace or unsubstituted azetidinyl, replace or unsubstituted phenyl, replace or unsubstituted naphthyl, replace or unsubstituted biphenyl group, replace or unsubstituted pyrryl, replace or unsubstituted imidazolyl, replace or unsubstituted pyrazolyl, replace or unsubstituted furyl, replace or unsubstituted thienyl, replace or do not replace the De oxazolyl, replace or unsubstituted isoxazolyl, replace or unsubstituted thiazolyl, replace or the unsubstituted pyridine base, replace or unsubstituted pyrazinyl, replace or unsubstituted pyrimidyl, replace or unsubstituted benzothiazolyl, replace or unsubstituted purine radicals, replace or unsubstituted benzimidazolyl-, replace or unsubstituted indyl, replace or unsubstituted isoquinolyl, replace or unsubstituted quinoxalinyl, replace or the unsubstituted quinolines base, replace or unsubstituted benzoxazolyl, replacement or unsubstituted [1,5] phthalazinyl, replace or unsubstituted pyridine also [3,2-d] pyrimidyl, replacement or unsubstituted [1,7] phthalazinyl, replace or unsubstituted 1H-pyrrolo-[2,3-b] pyridyl, replace or unsubstituted pyrazolo [4,3-b] pyridyl, replace or unsubstituted pyrrolo-[2,3-b] pyridyl replacement or unsubstituted thieno-[2,3-b] pyridyl, replace or unsubstituted thiazole also [5,4-b] pyridyl, replace or unsubstituted pyridine base-2-ketone, replace or unsubstituted imidazo [1,2-b] pyridazinyl, replace or unsubstituted pyrazolo [1,5-a] pyrimidyl, replace or unsubstituted pyridazinyl-3-ketone, replace or unsubstituted imidazo [2,1 with] [1,3,4] thiadiazolyl group, replace or unsubstituted imidazo [2,1-b] thiazolyl, perhaps replace or unsubstituted imidazo [4,5-b] pyridyl,-(CH 2) jCN ,-(CH 2) jOR 30,-(CH 2) jC (O) R 30,-(CH 2) jC (O) OR 30,-(CH 2) jNR 31R 32,-(CH 2) jC (O) NR 31R 32,-(CH 2) jOC (O) NR 31R 32,-(CH 2) jNR 33C (O) R 30,-(CH 2) jNR 33C (O) OR 30,-(CH 2) jNR 33C (O) NR 31R 32,-(CH 2) jS (O) mR 34,-(CH 2) jS (O) 2NR 31R 32, or-(CH 2) jNR 33S (O) 2R 34
34. the compound of claim 33, wherein:
A is independently for replacing or unsubstituted phenyl, replace or unsubstituted naphthyl, replace or unsubstituted biphenyl group, replace or unsubstituted pyrryl, replace or unsubstituted furyl, replace or unsubstituted thienyl, replace or do not replace the De oxazolyl, replace or unsubstituted thiazolyl, replace or unsubstituted imidazolyl, replace or unsubstituted pyrazolyl, replace or the unsubstituted pyridine base, replace or unsubstituted isoxazolyl, replace or unsubstituted isothiazolyl, replace or unsubstituted triazolyl, replace or unsubstituted pyrazinyl, replace or unsubstituted pyrimidyl, replace or unsubstituted benzothiazolyl, replace or unsubstituted purine radicals, replace or unsubstituted benzimidazolyl-, replace or unsubstituted indyl, replace or unsubstituted isoquinolyl, replace or unsubstituted quinoxalinyl, perhaps replace or the unsubstituted quinolines base;
Q is hydrogen, halogen, replacement or unsubstituted alkyl, perfluoroalkyl, amino, replacement or a unsubstituted amino alkyl, replacement or unsubstituted amino dialkyl group, replacement or unsubstituted phenyl, replacement or unsubstituted phenoxy, replacement or unsubstituted piperidyl, replacement or unsubstituted piperazinyl, replacement or unsubstituted pyrrolidyl, replacement or unsubstituted morpholinyl independently, perhaps replaces or unsubstituted-O-pyridyl;
R 22Be independently hydrogen, halogen, nitro, cyano group, hydroxyl, replacement or unsubstituted alkyl, replacement or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted Heterocyclylalkyl ,-(CH 2) jCN ,-(CH 2) jOR 23,-(CH 2) jC (O) R 23,-(CH 2) jC (O) OR 23,-(CH 2) jNR 24R 25,-(CH 2) jC (O) NR 24R 25,-(CH 2) jOC (O) NR 24R 25,-(CH 2) jNR 26C (O) R 23,-(CH 2) jNR 26C (O) OR 23,-(CH 2) jNR 26C (O) NR 24R 25,-(CH 2) jS (O) mR 27,-(CH 2) jS (O) 2NR 24R 25, or-(CH 2) jNR 26S (O) 2R 27
R 28' and R 28" be hydrogen, halogen, hydroxyl, alkyl or perfluoroalkyl independently of one another; With
R 35Be independently hydrogen, halogen, nitro, cyano group, hydroxyl, replacement or unsubstituted alkyl, replacement or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted Heterocyclylalkyl ,-(CH 2) jCN ,-(CH 2) jOR 30,-(CH 2) jC (O) R 30,-(CH 2) jC (O) OR 30,-(CH 2) jNR 31R 32,-(CH 2) jC (O) NR 31R 32,-(CH 2) jOC (O) NR 31R 32,-(CH 2) jNR 33C (O) R 30,-(CH 2) jNR 33C (O) OR 30,-(CH 2) jN 33C (O) NR 31R 32,-(CH 2) jS (O) mR 34,-(CH 2) jS (O) 2NR 31R 32,-(CH 2) jNR 33S (O) 2R 34,
Figure A2007800385270049C1
35. the compound of claim 34, wherein:
A is independently:
Figure A2007800385270050C1
Q be independently hydrogen, chloro, replacement or unsubstituted alkyl, perfluoroalkyl ,-NH 2,-NH (C 1-C 6) alkyl, or-N[(C 1-C 6) alkyl] 2,
Figure A2007800385270050C2
Wherein each alkyl is optional by 1-3 R 22Group replace independently and wherein w be the integer of 0-3 independently; Two R wherein 22Group and-O (CH 2CH 2) the optional ring texture that forms of O-;
R 22Be independently-H ,-F, Cl, Br, I ,-(C 1-C 6) alkyl ,-(CH 2) jCN ,-(CH 2) jO (C 1-C 6) alkyl ,-(CH 2) jOH ,-(CH 2) jC (O) (C 1-C 6) alkyl ,-(CH 2) jNH 2,-(CH 2) jNH (C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) 2,-(CH 2) jC (O) NH 2,-(CH 2) jC (O) NH (C 1-C 6) alkyl ,-C (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jNHC (O) (C 1-C 6) alkyl ,-(CH 2) jNHSO 2(C 1-C 6) alkyl ,-(CH 2) jNHSO 2(C 1-C 6) alkyl ,-(CH 2) jSO 2CH 3,-(CH 2) jSO 2NH 2,-(CH 2) jSO 2NH (C 1-C 6)-alkyl ,-(CH 2) jSO 2N ((C 1-C 6) alkyl) 2,-(CH 2) jSO 2NH (C 1-C 6) alkyl (OH), phenyl,
Figure A2007800385270051C1
R 28' and R 28" be hydrogen, halogen, hydroxyl, (C independently of one another 1-C 6) alkyl, or trifluoromethyl; With
R 35Be hydrogen, halogen, nitro, cyano group, hydroxyl, (C independently 1-C 6) alkyl, ring (C 3-C 10) alkyl, perfluor (C 1-C 6) alkyl ,-(CH 2) jCN ,-(CH 2) jO (C 1-C 6) alkyl ,-(CH 2) jC (O) (C 1-C 6) alkyl ,-(CH 2) jC (O) O (C 1-C 6) alkyl ,-(CH 2) jNH 2,-(CH 2) jNH (C 1-C 6) alkyl) ,-(CH 2) jN ((C 1-C 6) alkyl) 2,-(CH 2) jC (O) NH 2,-(CH 2) jC (O) NH (C 1-C 6) alkyl) ,-(CH 2) jC (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jOC (O) NH 2,-(CH 2) jOC (O) NH (C 1-C 6) alkyl) ,-(CH 2) jOC (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jNHC (O) (C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) C (O) (C 1-C 6) alkyl ,-(CH 2) jNHC (O) O (C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) C (O) O (C 1-C 6) alkyl ,-(CH 2) jNHC (O) NH 2,-(CH 2) jNHC (O) NH (C 1-C 6) alkyl) ,-(CH 2) jNHC (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jN ((C 1-C 6) alkyl) C (O) NH (C 1-C 6) alkyl) ,-(CH 2) jN ((C 1-C 6) alkyl) C (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jS (O) m(C 1-C 6) alkyl ,-(CH 2) jS (O) 2NH 2,-(CH 2) jS (O) 2NH (C 1-C 6) alkyl) ,-(CH 2) jS (O) 2N ((C 1-C 6) alkyl) 2,-(CH 2) jNHS (O) 2(C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) S (O) 2(C 1-C 6) alkyl,
Figure A2007800385270052C1
36. the compound of claim 35, wherein:
A is independently:
Figure A2007800385270052C2
Q is (C independently 1-C 6) alkyl, perfluoroalkyl ,-NH 2,-NH (C 1-C 6) alkyl ,-N[(C 1-C 6) alkyl] 2
R 28' and R 28" be hydrogen, halogen, (C independently of one another 1-C 6) alkyl, or trifluoromethyl; With
R 35Be independently hydrogen, halogen, cyano group, hydroxyl ,-(C 1-C 6) alkyl ,-(CH 2) jCN ,-(CH 2) jO (C 1-C 6) alkyl ,-(CH 2) jOH ,-(CH 2) jC (O) (C 1-C 6) alkyl ,-(CH 2) jC (O) OH ,-(CH 2) jNH 2,-(CH 2) jNH (C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) 2,-(CH 2) jC (O) NH 2,-(CH 2) jC (O) NH (C 1-C 6) alkyl ,-C (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jNHC (O) (C 1-C 6) alkyl ,-(CH 2) jNHSO 2(C 1-C 6) alkyl ,-(CH 2) jNHSO 2(C 1-C 6) alkyl ,-(CH 2) jSO 2CH 3,-(CH 2) jSO 2NH 2,-(CH 2) jSO 2NH (C 1-C 6)-alkyl ,-(CH 2) jSO 2N ((C 1-C 6) alkyl) 2,-(CH 2) jSO 2NH (C 1-C 6)-alkyl (OH), phenyl,
Figure A2007800385270052C3
37. the compound of a formula XI:
Figure A2007800385270053C1
Wherein:
T is CH (halogen), C (halogen) independently 2
Q is hydrogen, halogen, replacement or unsubstituted alkyl, perfluoroalkyl, amino, replacement or a unsubstituted amino alkyl, replacement or unsubstituted amino dialkyl group, replacement or unsubstituted phenyl, replacement or unsubstituted phenoxy, replacement or unsubstituted piperidyl, replacement or unsubstituted piperazinyl, replacement or unsubstituted pyrrolidyl, replacement or unsubstituted morpholinyl, replacement or unsubstituted-O-pyridyl independently;
R 22Be hydrogen independently, halogen, nitro, cyano group, hydroxyl, replace or unsubstituted alkyl, replace or unsubstituted cycloalkyl, perfluoroalkyl, replace or unsubstituted assorted alkyl, replace or unsubstituted Heterocyclylalkyl, replace or unsubstituted phenyl, replace or unsubstituted naphthyl, replace or unsubstituted biphenyl group, replace or unsubstituted pyrryl, replace or unsubstituted imidazolyl, replace or unsubstituted pyrazolyl, replace or unsubstituted furyl, replace or unsubstituted thienyl, replace or do not replace the De oxazolyl, replace or unsubstituted isoxazolyl, replace or unsubstituted thiazolyl, replace or the unsubstituted pyridine base, replace or unsubstituted pyrazinyl, replace or unsubstituted pyrimidyl, replace or unsubstituted benzothiazolyl, replace or unsubstituted purine radicals, replace or unsubstituted benzimidazolyl-, replace or unsubstituted indyl, replace or unsubstituted isoquinolyl, replace or unsubstituted quinoxalinyl, replace or the unsubstituted quinolines base, replace or unsubstituted benzoxazolyl, replacement or unsubstituted [1,5] phthalazinyl, replace or unsubstituted pyridine also [3,2-d] pyrimidyl, replacement or unsubstituted [1,7] phthalazinyl, replace or unsubstituted 1H-pyrrolo-[2,3-b] pyridyl, replace or unsubstituted pyrazolo [4,3-b] pyridyl, replace or unsubstituted pyrrolo-[2,3-b] pyridyl, replace or unsubstituted thieno-[2,3-b] pyridyl, replace or unsubstituted thiazole also [5,4-b] pyridyl, replace or unsubstituted pyridine base-2-ketone, replace or unsubstituted imidazo [1,2-b] pyridazinyl, replace or unsubstituted pyrazolo [1,5-a] pyrimidyl, replace or unsubstituted pyridazinyl-3-ketone, replace or unsubstituted imidazo [2,1-b] [1,3,4] thiadiazolyl group, replace or unsubstituted imidazo [2,1-b] thiazolyl, perhaps replace or unsubstituted imidazo [4,5-b] pyridyl,-(CH 2) jCN ,-(CH 2) jOR 23,-(CH 2) jC (O) R 23,-(CH 2) jC (O) OR 23,-(CH 2) jNR 24R 25,-(CH 2) jC (O) NR 24R 25,-(CH 2) jOC (O) NR 24R 25,-(CH 2) jNR 26C (O) R 23,-(CH 2) jNR 26C (O) OR 23,-(CH 2) jNR 26C (O) NR 24R 25,-(CH 2) jS (O) mR 27,-(CH 2) jS (O) 2NR 24R 25Or-(CH 2) jNR 26S (O) 2R 27
R 28' and R 28" be hydrogen, halogen, hydroxyl, alkyl or perfluoroalkyl independently of one another; With
R 35Be hydrogen independently, halogen, nitro, cyano group, hydroxyl, replace or unsubstituted alkyl, replace or unsubstituted cycloalkyl, perfluoroalkyl, replace or unsubstituted assorted alkyl, replace or unsubstituted Heterocyclylalkyl, replace or unsubstituted azetidinyl, replace or unsubstituted phenyl, replace or unsubstituted naphthyl, replace or unsubstituted biphenyl group, replace or unsubstituted pyrryl, replace or unsubstituted imidazolyl, replace or unsubstituted pyrazolyl, replace or unsubstituted furyl, replace or unsubstituted thienyl, replace or do not replace the De oxazolyl, replace or unsubstituted isoxazolyl, replace or unsubstituted thiazolyl, replace or the unsubstituted pyridine base, replace or unsubstituted pyrazinyl, replace or unsubstituted pyrimidyl, replace or unsubstituted benzothiazolyl, replace or unsubstituted purine radicals, replace or unsubstituted benzimidazolyl-, replace or unsubstituted indyl, replace or unsubstituted isoquinolyl, replace or unsubstituted quinoxalinyl, replace or the unsubstituted quinolines base, replace or unsubstituted benzoxazolyl, replacement or unsubstituted [1,5] phthalazinyl, replace or unsubstituted pyridine also [3,2-d] pyrimidyl, replacement or unsubstituted [1,7] phthalazinyl, replace or unsubstituted 1H-pyrrolo-[2,3-b] pyridyl, replace or unsubstituted pyrazolo [4,3-b] pyridyl, replace or unsubstituted pyrrolo-[2,3-b] pyridyl, replace or unsubstituted thieno-[2,3-b] pyridyl, replace or unsubstituted thiazole also [5,4-b] pyridyl, replace or unsubstituted pyridine base-2-ketone, replace or unsubstituted imidazo [1,2-b] pyridazinyl, replace or unsubstituted pyrazolo [1,5-α] pyrimidyl, replace or unsubstituted pyridazinyl-3-ketone, replace or unsubstituted imidazo [2,1-b] [1,3,4] thiadiazolyl group, replace or unsubstituted imidazo [2,1-b] thiazolyl, perhaps replace or unsubstituted imidazo [4,5-b] pyridyl,-(CH 2) jCN ,-(CH 2) jOR 30,-(CH 2) jC (O) R 30,-(CH 2) jC (O) OR 30,-(CH 2) jNR 31R 32,-(CH 2) jC (O) NR 31R 32,-(CH 2) jOC (O) NR 31R 32,-(CH 2) jNR 33C (O) R 30,-(CH 2) jNR 33C (O) OR 30,-(CH 2) jNR 33C (O) NR 31R 32,-(CH 2) jS (O) mR 34,-(CH 2) jS (O) 2NR 31R 32Or-(CH 2) jNR 33S (O) 2R 34
38. the compound of claim 37, wherein:
Q is hydrogen, halogen, replacement or unsubstituted alkyl, perfluoroalkyl, amino, replacement or a unsubstituted amino alkyl, replacement or unsubstituted amino dialkyl group, replacement or unsubstituted phenyl, replacement or unsubstituted phenoxy, replacement or unsubstituted piperidyl, replacement or unsubstituted piperazinyl, replacement or unsubstituted pyrrolidyl, replacement or unsubstituted morpholinyl independently, perhaps replaces or unsubstituted-O-pyridyl;
R 22Be independently hydrogen, halogen, nitro, cyano group, hydroxyl, replacement or unsubstituted alkyl, replacement or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted Heterocyclylalkyl ,-(CH 2) jCN ,-(CH 2) jOR 23,-(CH 2) jC (O) R 23,-(CH 2) jC (O) OR 23,-(CH 2) jNR 24R 25,-(CH 2) jC (O) NR 24R 25,-(CH 2) jOC (O) NR 24R 25,-(CH 2) jNR 26C (O) R 23,-(CH 2) jNR 26C (O) OR 23,-(CH 2) jNR 26C (O) NR 24R 25,-(CH 2) jS (O) mR 27,-(CH 2) jS (O) 2NR 24R 25Or-(CH 2) jNR 26S (O) 2R 27
R 28' and R 28" be hydrogen, halogen, hydroxyl, alkyl or perfluoroalkyl independently of one another; With
R 35Be independently hydrogen, halogen, nitro, cyano group, hydroxyl, replacement or unsubstituted alkyl, replacement or unsubstituted cycloalkyl, perfluoroalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted Heterocyclylalkyl ,-(CH 2) jCN ,-(CH 2) jOR 30,-(CH 2) jC (O) R 30,-(CH 2) jC (O) OR 30,-(CH 2) jNR 31R 32,-(CH 2) jC (O) NR 31R 32,-(CH 2) jOC (O) NR 31R 32,-(CH 2) jNR 33C (O) R 30,-(CH 2) jNR 33C (O) OR 30,-(CH 2) jN 33C (O) NR 31R 32,-(CH 2) jS (O) mR 34,-(CH 2) jS (O) 2NR 31R 32,-(CH 2) jNR 33S (O) 2R 34,
Figure A2007800385270056C1
39. the compound of claim 38, wherein:
Q be independently hydrogen, chloro, replacement or unsubstituted alkyl, perfluoroalkyl ,-NH 2,-NH (C 1-C 6) alkyl or-N[(C 1-C 6) alkyl] 2,
Figure A2007800385270056C2
Wherein each alkyl is optional by 1-3 R 22Group replace independently and wherein w be the integer of 0-3 independently; Two R wherein 22Group and-O (CH 2CH 2) the optional ring texture that forms of O-;
R 22Be independently-H ,-F, C1, Br, I ,-(C 1-C 6) alkyl ,-(CH 2) jCN ,-(CH 2) jO (C 1-C 6) alkyl ,-(CH 2) jOH ,-(CH 2) jC (O) (C 1-C 6) alkyl ,-(CH 2) jNH 2,-(CH 2) jNH (C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) 2,-(CH 2) jC (O) NH 2,-(CH 2) jC (O) NH (C 1-C 6) alkyl ,-C (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jNHC (O) (C 1-C 6) alkyl ,-(CH 2) jNHSO 2(C 1-C 6) alkyl ,-(CH 2) jNHSO 2(C 1-C 6) alkyl ,-(CH 2) jSO 2CH 3,-(CH 2) jSO 2NH 2,-(CH 2) jSO 2NH (C 1-C 6)-alkyl ,-(CH 2) jSO 2N (C 1-C 6) alkyl) 2,-(CH 2) jSO 2NH (C 1-C 6) alkyl (OH), phenyl,
Figure A2007800385270057C1
R 28' and R 28" be hydrogen, halogen, hydroxyl, (C independently of one another 1-C 6) alkyl or trifluoromethyl; With
R 35Be hydrogen, halogen, nitro, cyano group, hydroxyl, (C independently 1-C 6) alkyl, ring (C 3-C 10) alkyl, perfluor (C 1-C 6) alkyl ,-(CH 2) jCN ,-(CH 2) jO (C 1-C 6) alkyl ,-(CH 2) jC (O) (C 1-C 6) alkyl ,-(CH 2) jC (O) O (C 1-C 6) alkyl ,-(CH 2) jNH 2,-(CH 2) jNH (C 1-C 6) alkyl) ,-(CH 2) jN ((C 1-C 6) alkyl) 2,-(CH 2) jC (O) NH 2,-(CH 2) jC (O) NH (C 1-C 6) alkyl) ,-(CH 2) jC (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jOC (O) NH 2,-(CH 2) jOC (O) NH (C 1-C 6) alkyl) ,-(CH 2) jOC (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jNHC (O) (C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) C (O) (C 1-C 6) alkyl ,-(CH 2) jNHC (O) O (C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) C (O) O (C 1-C 6) alkyl ,-(CH 2) jNHC (O) NH 2,-(CH 2) jNHC (O) NH (C 1-C 6) alkyl) ,-(CH 2) jNHC (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jN ((C 1-C 6) alkyl) C (O) NH (C 1-C6) alkyl) ,-(CH 2) jN ((C 1-C 6) alkyl) C (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jS (O) m(C 1-C 6) alkyl, (CH 2) jS (O) 2NH 2,-(CH 2) jS (O) 2NH (C 1-C 6) alkyl) ,-(CH 2) jS (O) 2N ((C 1-C 6) alkyl) 2,-(CH 2) jNHS (O) 2(C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) S (O) 2(C 1-C 6) alkyl,
Figure A2007800385270057C2
40. the compound of claim 39, wherein:
Q is (C independently 1-C 6) alkyl, perfluoroalkyl ,-NH 2,-NH (C 1-C 6) alkyl ,-N[(C 1-C 6) alkyl] 2
R 28' and R 28" be hydrogen, halogen, (C independently of one another 1-C 6) alkyl or trifluoromethyl; With
R 35Be independently hydrogen, halogen, cyano group, hydroxyl ,-(C 1-C 6) alkyl;-(CH 2) jCN ,-(CH 2) jO (C 1-C 6) alkyl ,-(CH 2) jOH ,-(CH 2) jC (O) (C 1-C 6) alkyl ,-(CH 2) jC (O) OH ,-(CH 2) jNH 2,-(CH 2) jNH (C 1-C 6) alkyl ,-(CH 2) jN ((C 1-C 6) alkyl) 2,-(CH 2) jC (O) NH 2,-(CH 2) jC (O) NH (C 1-C 6) alkyl ,-C (O) N ((C 1-C 6) alkyl) 2,-(CH 2) jNHC (O) (C 1-C 6) alkyl ,-(CH 2) jNHSO 2(C 1-C 6) alkyl ,-(CH 2) jNHSO 2(C 1-C 6) alkyl ,-(CH 2) jSO 2CH 3,-(CH 2) jSO 2NH 2,-(CH 2) jSO 2NH (C 1-C 6)-alkyl ,-(CH 2) jSO 2N ((C 1-C 6) alkyl) 2,-(CH 2) jSO 2NH (C 1-C 6) alkyl (OH), phenyl,
Figure A2007800385270058C1
41. formula XII compound:
Figure A2007800385270058C2
Wherein,
Q is (C independently 1-C 6) alkyl;
T is CHF or CF 2With
R 35For-(C 1-C 6) alkyl.
42. a compound, it is selected from following listed compound:
Figure A2007800385270059C1
Figure A2007800385270060C1
Figure A2007800385270061C1
Figure A2007800385270062C1
43. a compound, it is selected from following listed compound:
Figure A2007800385270064C1
44. a compound, it is selected from following listed compound:
Figure A2007800385270066C1
Figure A2007800385270067C1
Figure A2007800385270068C1
45. a compound, it is selected from following listed compound:
Figure A2007800385270070C1
Figure A2007800385270071C1
Figure A2007800385270072C1
Figure A2007800385270073C1
46. a method of regulating protein kinase activity, this method comprise described protein kinase is contacted with each compound among the claim 27-44.
47. the method for claim 46, wherein said protein kinase are Ron receptor tyrosine kinase, Met receptor tyrosine kinase, ALK receptor tyrosine kinase, MER receptor tyrosine kinase, Tyro3/Sky receptor tyrosine kinase, axl receptor Tyrosylprotein kinase, TRKC receptor tyrosine kinase, ROS receptor tyrosine kinase, CSFIR/FMS receptor tyrosine kinase, BRAF kinases or Raf1 kinases.
48. the method for claim 47, wherein said protein kinase are the Met receptor tyrosine kinase.
49. treat method for cancer for one kind in the patient of this kind of needs treatment, described method comprises among the claim 28-45 that gives described patient treatment significant quantity each compound.
50. a medicinal compositions, it is included among the claim 28-45 in the pharmaceutically acceptable vehicle each compound.
51. a method for preparing each compound among the claim 28-45 said method comprising the steps of:
Figure A2007800385270074C1
A) make compd A-48 cyclodehydration under acidity or dehydration conditions.
52. the method for claim 51, wherein said acidic conditions are acetate, POCl 3Or trifluoromethanesulfonic acid.
53. a method for preparing each compound among the claim 28-45 said method comprising the steps of:
Figure A2007800385270074C2
A) make formula A-50 compound and the coupling in solvent of formula B-50 compound, wherein LG is halogen or trifluoromethanesulfonic acid ester group.
54. the method for claim 53, wherein said solvent are alcohol.
55. a method for preparing each compound among the claim 28-45 said method comprising the steps of:
A) make formula A-52 compound and formula B-52 compound condensation, wherein R ' is C 1-C 6Alkyl.
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