CN103748095B - Bicyclic heteroaromatic compounds - Google Patents
Bicyclic heteroaromatic compounds Download PDFInfo
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- CN103748095B CN103748095B CN201280040780.1A CN201280040780A CN103748095B CN 103748095 B CN103748095 B CN 103748095B CN 201280040780 A CN201280040780 A CN 201280040780A CN 103748095 B CN103748095 B CN 103748095B
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Abstract
Compound of formula I (wherein X1、X2、X3、X4、X5、R1、R2、R3、R4、R5And R6There is the implication pointed out in claim 1) it is inhibitors of kinases, and in addition to other purposes, may be used for treating tumor.
Description
Background of invention
It is an object of the invention to find the noval chemical compound with valuable character, particularly can be used for preparing medicine that
A bit.
The present invention relates to the suppression of the signal transduction to kinases (particularly tyrosine kinase), regulate and/or regulate and control to act as
Compound, further to comprising the pharmaceutical composition of these compounds, and it is sharp for treating to relate to described compound
The purposes of the disease of enzyme induction.
In particular it relates to suppress, regulate and/or regulate and control the compound of the signal transduction of tyrosine kinase, relate to
Comprise the compositions of these compounds, and the disease of the tyrosine-kinase enzyme induction being directed to use with in its treatment mammal and disease
Disease (such as cancer, tumor growth, arteriosclerosis, the degeneration of macula caused due to the age, diabetic retinopathy, inflammatory disease
Sick etc.) method.
Tyrosine kinase is that the terminal phosphate of the adenosine triphosphate in a class catalytic proteins substrate turns to tyrosine residue
The enzyme moved.It is believed that, in many cell functions, tyrosine kinase plays important by substrate phosphorylation in signal transduction
Effect.Although the precise mechanism of signal transduction is the most unclear, it has been demonstrated that tyrosine kinase is at cell proliferation, carcinogenic work
With with cell break up in key factor.
Tyrosine kinase can be categorized as receptor type tyrosine kinase or intracellular tyrosine kinase.Receptor type tyrosine
Kinases has extracellular part, transmembrane segment and intracellular portion, and intracellular tyrosine kinase is the most intracellular.
Intracellular tyrosine kinase is made up of multiple subtribes, including Src, Frk, Btk, Csk, Abl, Zap70, Fes/Fps,
Fak, Jak, Ack and LIMK.Each in these subtribes is further subdivided into not isoacceptor.Swash about intracellular tyrosine
Being discussed more fully of enzyme, sees the paper of BolenOncogene, 8:2025-2031 (1993), it is incorporated by reference into this
Literary composition.
Receptor type tyrosine kinase and intracellular tyrosine kinase both of which involve in and cause many pathogenic disorders (to include cancer
Disease, psoriasis and hyperimmune response) cell signaling pathway.
The present invention relates to the compound as FAK (focal adhesion kinase) inhibitor.
FAK (by PTK2 gene code) is nonreceptor tyrosine kinase, its integrate from integrin and somatomedin-
The signal of receptor.(the McLean etc. it has been reported that FAK plays a role in regulating cell survival, growing, spread, migrate and attack
People 2005, Nat Rev Cancer 5:505-515).Additionally, by the phosphorylated regulation on multiple tyrosine residues with sharp
Live FAK.Have recorded FAK mRNA and/or the protein process LAN in many people's tumors, including breast carcinoma, colon cancer,
Thyroid carcinoma and carcinoma of prostate (Owens et al.. 1995, Cancer Research 55:2752-2755;Agochiya etc.
People. 1999, Oncogene 18:5646-5653;Gabarro-Niecko et al.. 2003, Cancer Metastasis
Rev. 22:359-374).The more important thing is, evidence suggests, compared with normal structure, the FAK of phosphorylation is in malignant tissue
Increase (Grisaru-Granovsky et al.. 2005, Int. J. Cancer 113:372-378).
It turned out, RNAi can be at people's mammary gland-and melanoma cell series to the suppression of FAK or the expression of dominant-negative FAK
Middle induced adherence power disappearance and cell death, and in ovarian cancer cell, increase the apoptosis of docetaxel mediation
(Beviglia et al. 2003, Biochem J. 373:201-210, Smith et al. 2005, Melanoma Res. 15:
357-362, Haider et al. 2005, Clin. Cancer Res. 11:8829-8836).It was verified however that normal person becomes
In fibrocyte or immortalized mammalian cell (MCFlOA), the suppression of FAK is not to adhere to disappearance or apoptotic cause
(Xu et al.. 1996 Cell Growth and Diff 7:413-418).It has also been confirmed that, by dominant negative expression inhibiting
FAK can reduce tumor growth, and eliminates Lung metastases (the van Nimwegen etc. of mammal adenocarcinoma cell in homology rat model
People 2005, Cancer Res. 65:4698-4706).Equally, Lung metastases can be suppressed by shRNA suppression FAK, and make homology
Fatality rate in mouse model reduces by 40% (Mitra et al. 2006, Oncogene 25:4429-4440).In this study,
The transient state of wild type is expressed (but being not without the FAK of kinase activity) again and is caused the sudden change again of shRNA phenotype.At mice-4TI-
In cancerous cell by dominant negative expression inhibiting FAK can reduce the tumor growth in mice and angiogenesis (Mitra et al.,
2006, Oncogene 25:5969-5984).
Additionally, the disappearance of FAK catalysis activity (FAK-/-cell and the reconstruct of FAK without kinase activity) can reduce in mice
The growth of v-Src tumor and reduce angiogenesis.
Therefore, having sufficient evidence to show, the suppression of FAK activity can inducing cell apoptosis, the disappearance of adhesion, cell growth
With the suppression of transfer, and such suppression can reduce angiogenesis.Therefore, the compound of suppression FAK activity can be used for treating
Cancer.
Compound according to the present invention also shows in the suppression of serine/threonine-kinases PDK1, IKK ε and TBK1
Certain effect.
PDK1 makes the subgroup of AGC protein kinase family, including PKB, SGK, S6K and PKC isotype phosphorylation and activation.This
A little kinases participate in PI3K signal transduction pathways, and control basic cell function and such as survive, grow and break up.Therefore, PDK1
It it is the important regulator of various metabolism, propagation and life maintenance effect.
IKK ε and TBK1 is very high homology and the serine/threonine kinase with other IkB kinases very high homology each other.
These 2 kinds of kinases play integration in innate immune system.Double-stranded RNA-virus is solved by Toll-sample receptor 3 and 4 and RNA-
Rotation enzyme RIG-I and MDA-5 identifies, and causes the activation of TRIF-TBK1/IKK ε-IRF3 signal cascade, and this causes I type interferon
Response.
In 2007, IKK ε was described as new breast carcinoma oncogene [J.S. Boehm et al., Cell by Boehm and colleague
129, 1065-1079, 2007].Have studied 354 kinds of kinases and recur Ras-conversion together with the activation form of mapk kinase Mek
The ability of phenotype.Here IKK ε is differentiated as cooperation oncogene.It addition, this author is able to verify that, IKBKE is at numerous mammary gland
Cancerous cell line and tumor sample exist amplification and process LAN.The gene table in breast cancer cell is reduced by means of RNA interference
Reaching can inducing cell apoptosis and its propagation of minimizing.Eddy has obtained similar discovery with colleague in 2005, and this discovery highlights
IKK ε importance [S.F.Eddy et al., Cancer Res. 2005 in breast cancer disease; 65 (24), 11375-
11383]。
The rush tumor generating effect of TBK1 reported first in 2006.In the gene library comprising 251,000 kinds of cDNA
Screening in, Korherr et al. identifies 3 kinds of genes TRIF, TBK1 and IRF3 equally, they usually used as Angiogensis because of
Son involves in innate immune defense [C.Korherr et al., PNAS, 103,4240-4245,2006].
In 2006, Chien and colleague [Y.Chien et al., Cell 127,157-170,2006] were disclosed that, make
Only can convert TBK1-/-cell conditionally with carcinogenic Ras, this makes people expect TBK1 involving in the conversion that Ras mediates.
Additionally, they are able to verify that, the TBK1 of RNAi mediation knocks down the apoptosis that can trigger MCF-7 and Panc-1 cell.
Barbie and colleague are disclosed that recently, and TBK1 is most important in the cancerous cell line of numerous K-Ras with sudden change, and this makes people think
Arrive, TBK1 intervene can have in corresponding tumor treatment importance [D.A.Barbie et al., Nature Letters 1-5,
2009]。
Therefore, the qualification of the little compound specifically suppressing, regulate and/or regulating and controlling FAK signal transduction is desired,
And it is the target of the present invention.
Have been found that compound of formula I and salt thereof have the most valuable pharmacological property, there is good tolerance simultaneously
Property.
Additionally, one or more compounds that the present invention relates to the present invention in treatment and/or prevent disease, retouch the most herein
Purposes in the disease stated, described disease is caused by FAK, mediates and/or propagates.
Generally disease discussed herein is divided into two groups: hyperproliferative and non-hyperproliferative disease.In this respect, will
Psoriasis, arthritis, inflammation, endometriosis, cicatrization, benign prostatic hyperplasia, immunological diseases, autoimmune disease
Sick and immune deficiency disorder is considered as non-hyperproliferative disease.In this respect, can be by the brain cancer, pulmonary carcinoma, squamous cell cancer, wing
Guang cancer, gastric cancer, cancer of pancreas, hepatocarcinoma, renal carcinoma, colorectal cancer, breast carcinoma, head cancer, neck cancer, esophageal carcinoma, gynecological cancer, thyroid
Cancer, lymphoma, chronic leukemia and acute leukemia regard as Cancerous disease, and they are the most generally considered hyperproliferative disease.
Specifically, cancerous cell growth is the disease of targeting of the present invention.Therefore subject of the present invention be described disease treatment and/or
In prevention, the compound as medicine and/or the compound of the present invention of active constituents of medicine and the present invention is used for preparing treatment
And/or prevent the purposes of the medicine of described disease, and the method treating described disease, described method include to needs this to
The patient of medicine uses one or more compounds of the present invention.
May certify that, according to the compound of the present invention, in vivo there is anti-proliferative effect.Suffered from hyperproliferative disease
Sick patient uses the compound according to the present invention, such as, be used for suppressing tumor growth, is used for alleviating with lymphoproliferative disease
Sick occur inflammation, for suppressing transplant rejection or the nerve injury etc. caused by tissue repair.This compound is suitable for pre-
Prevent or therapeutic purposes.Term used herein " is treated " and is prevented disease and the existing disease for the treatment of for expression.By aobvious in generation
Property disease before use the compound according to the present invention, it is achieved prevent hypertrophy, such as, be used for preventing tumor growth, stop transitivity
The restenosis etc. that growth, minimizing occur with cardiovascular surgical procedure.Or use described compound for by stablizing or changing
The clinical symptoms of kind patient treats persistence disease.
Host or patient may belong to any mammalian species, such as primate, the particularly mankind;Grinding tooth moves
Thing, including mice, rat and hamster;Rabbit;Horse, cattle, Canis familiaris L., cat etc..Animal model is meaningful to experimentation, and wherein they are
The treatment of human diseases provides model.
Pass through testing in vitro, it may be determined that specific cells is to the susceptibility by the compound treatment according to the present invention.Generally
Cell culture is combined a period long enough from the compound according to the present invention under different concentration, usually about 1
Hour between 1 week, so that activating agent energy inducing cell death or suppression cell migration.Can use from biopsy samples
Cultivate the cell obtained in vitro tests.Then the cell of residual after counting processes.
Dosage changes according to particular compound used, disease specific, patient's states etc..Therapeutic dose is typically enough to show
Write ground and reduce undesirable cell colony in target tissue, and maintain the viability of patient simultaneously.Generally continue to treatment until cell
Load has produced significantly reduction, such as, reduce at least about 50%, and can be with continual cure until the most not
Undesirable cell detected again.
In order to differentiate inhibitors of kinases, available various mensuration systems.At Scintillation Proximity Assay (Sorg et al., J.
Of Biomolecular Screening, 2002,7,11-19) and dodge in plate algoscopy, use γ ATP to determine conduct
The protein of substrate or the radioactive phosphorylation of peptide.In the presence of inhibition compound, undetectable to radiated signal or
Can detect that radiated signal reduces.Additionally, available homogeneous time-resolved FRET (fluorescence resonance energy transfer) (HTR-FRET) and glimmering
Light polarization (FP) technology as assay method (Sills et al., J. of Biomolecular Screening, 2002,
191-214)。
Other on-radiation ELISA assay method uses specificity phosphoric acid-antibody (phosphoric acid-AB).Phosphoric acid-AB is only in conjunction with phosphorus
The substrate of acidifying.The second peroxidase-conjugated anti-sheep antibody can be used to detect this combination by chemiluminescence
(Ross et al., 2002, Biochem. J., 366:977-981).
There is a lot of disease occurred with cell proliferation and the imbalance of cell death (apoptosis).Disease interested
Disease includes but not limited to following those.Compound according to the present invention can be used for treating a series of different disease, Qi Zhongping
Sliding myocyte and/or proliferation of inflammatory cells and/or migrate in tunica intima layer, the blood flow causing this blood vessel is limited, such as
In the case of new intima occlusive disease.Occlusive graft angiopathy interested includes atherosclerosis, shifting
Plant that rear coronary vessels diseases, vein transplantation be narrow, prosthese restenosis (peri-anastomotische around anastomotic stoma
Prosthesenrestenose), angioplasty or stent restenosis etc..
Background technology
And WO 2006/114180 describes other bicyclic heterocycles in WO 2003/035065.
In WO 2009/105498 and WO 2008/115369, pyridine derivate is described as Fak inhibitor.
Other pyrimidine derivatives for anti-curing cancers is described in WO 2004/056807 and WO 2010/055117.
Summary of the invention
The present invention relates to compound of formula I and officinal salt, tautomer and stereoisomer, owning including them
The mixture of ratio
Wherein
X1Represent C or N,
X2Represent C or N,
X3Represent C or N,
X4Represent C or N,
X5Represent C or N,
R1At X1Do not exist during=N
Or
Represent NH (CH2)nHet or NH (CH2)nAr,
R2At X2Do not exist during=N
Or
Represent H or Het1,
R3At X3Do not exist during=N,
Or
Represent H, N, A, Hal, Cyc, OH or OA,
R4At X4Do not exist during=N
Or
Represent H, NH (CH2)nHet1、Het1、O(CH2)nHet1、NH(CH2)nAr1、-≡-Ar1、(CH2)nAr1Or NH-Cyc,
R5At X5Do not exist during=N
Or
Represent H or Hal,
R6Represent H, Ar2、A、Het2、COHet3、CONH2、CONHA、CONA2Or Cyc,
R7Represent H or there is the alkyl of 1,2,3 or 4 C atoms,
Het represents unsubstituted or single-, two-by A and/or=O or three-following radicals of replacing: furyl, thiophene
Base, pyrrole radicals, imidazole radicals, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridine radicals, pyrimidine radicals, triazolyl,
Tetrazole radical, di azoly, thiadiazolyl group, pyridazinyl, pyrazinyl, benzimidazolyl, benzotriazole base, quinolyl, quinoxalinyl,
Quinazolyl, pyrrolopyridinyl, purine radicals, indyl, indolinyl, indazolyl, tetrahydric quinoline group, dihydrobenzo azoles
Base, dihydropyridine base, dihydrogen dazin base, dihydrobenzo imidazole radicals, dihydro-benzothiazole base, piperidyl, pyrrolidinyl, morpholine
Base, piperazinyl, imidazolidinyl, oxazolidinyl or THP trtrahydropyranyl,
Ar represent unsubstituted or single-, two-by following substituent group, three-, four-or the five-phenyl that replaces: Hal, A,
(CH2)nOH、(CH2)nOA、(CH2)nCN、NO2、SO2A、COOH、COOA、NH2、NHA、NA2、CHO、COA、(CH2)nCONH2、
(CH2)nCONHA、(CH2)nCONA2、Het3、NHCOHet3、SO2NH2、SO2NHA and/or NHCOA,
Het1Represent unsubstituted or by A, OH, NR7SO2A and/or=O is single-, two-or three-substituted following radicals:
Furyl, thienyl, pyrrole radicals, imidazole radicals, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridine radicals, phonetic
Piperidinyl, triazolyl, tetrazole radical, di azoly, thiadiazolyl group, pyridazinyl, pyrazinyl, benzimidazolyl, benzotriazole base, quinoline
Base, quinoxalinyl, quinazolyl, pyrrolopyridinyl, purine radicals, indyl, indolinyl, indazolyl, tetrahydric quinoline group,
Dihydrobenzo oxazolyl, dihydropyridine base, dihydrogen dazin base, dihydrobenzo imidazole radicals, dihydro-benzothiazole base, piperidyl, pyrrole
Cough up alkyl, morpholinyl, piperazinyl, imidazolidinyl, oxazolidinyl or THP trtrahydropyranyl,
Ar1Represent unsubstituted or single-, two-by following substituent group, three-, four-or the five-phenyl that replaces: Hal, A,
(CH2)nOH、(CH2)nOA、(CH2)nCN、NO2、SO2A、COOH、COOA、NH2、NHA、NA2、CHO、COA、(CH2)nCONR7、
Het3、NHCOHet3、NR7SO2A and/or NHCOA,
Het2Represent unsubstituted or by A, NR7SO2A、Het3And/or=O is single-, two-or three-substituted following base
Group: furyl, thienyl, pyrrole radicals, imidazole radicals, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridine radicals,
Pyrimidine radicals, triazolyl, tetrazole radical, di azoly, thiadiazolyl group, pyridazinyl, pyrazinyl, benzimidazolyl, benzotriazole base, quinoline
Quinoline base, quinoxalinyl, quinazolyl, pyrrolopyridinyl, purine radicals, indyl, indoline base, indolinyl, indazolyl,
Tetrahydric quinoline group, dihydrobenzo oxazolyl, dihydropyridine base, dihydrogen dazin base, dihydrobenzo imidazole radicals, dihydro-benzothiazole
Base, piperidyl, pyrrolidinyl, morpholinyl, piperazinyl, imidazolidinyl, 6,7-dihydro-5H-cyclopenta [b] pyridine radicals,
Oxazolidinyl or THP trtrahydropyranyl,
Ar2Represent unsubstituted or single-, two-by following substituent group, three-, four-or the five-phenyl that replaces: Hal, A,
(CH2)nOH、(CH2)nOA、(CH2)nCN、NO2、SO2A、COOH、COOA、NH2、NHA、NA2、CHO、COA、(CH2)nCONH2、
(CH2)nCONHA、(CH2)nCONA2、CONHHet3、COHet3、Het3、NHCOHet3、NR7SO2A and/or NHCOA,
Or indanyl, it can replace by=O,
Het3Represent unsubstituted or by A, (CH2)nN(R7)2And/or=O mono--or the following radicals of di-substituted: piperazine
Piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, imidazolidinyl, oxazolidinyl, THP trtrahydropyranyl, indanyl, dihydrogen dazin base, rattle away
Piperazine base, pyridine radicals, pyrimidine radicals, triazolyl, tetrazole radical, 6,7-dihydro-5H-cyclopenta [b] pyridine radicals, indolinyl
(indoyl), dihydropyridine base, indyl, indazolyl, oxazolyl, isoxazolyl, furyl, thienyl, pyrrole radicals, imidazoles
Base, pyrazolyl, quinolyl, quinoxalinyl, quinazolyl or tetrahydric quinoline group,
A represents the straight or branched alkyl with 1-10 C atom, and wherein 1-7 H atom can be substituted by F, and/or
Wherein 1 or 2 non-conterminous CH-and/or CH2-group can be substituted by O, NH and/or NA',
A' represents the straight or branched alkyl with 1-6 C atom,
Cyc represents the cyclic alkyl with 3,4,5,6 or 7 C atoms, and it is unsubstituted or by CON (R7)2Or
NR7SO2A is monosubstituted,
Hal represents F, Cl, Br or I,
N represents 0,1 or 2,
Precondition is,
a) X1、X2、X3And X4In at least 1 expression N, and most 2 represent N simultaneously,
If b) X1=N, then X4≠ N and R4≠ H,
If c) X4=N, then X1≠N。
Subject of the present invention is compound of formula I and salt thereof, and for formula I and officinal salt, change
Isomer and the method for stereoisomer, in described compound of formula I
X1Represent N,
X2Represent C,
X3Represent C,
X4Represent C,
X5Represent C,
R4Represent NH (CH2)nHet1Or NH (CH2)nAr1,
Described method is characterised by,
Make Formula II compound
Wherein
X1Represent N,
X2、X3、X4、X5Represent C,
Hal represents Cl, Br or I,
L represents silyl-protecting groups,
And
R1、R2、R3、R5There is the implication pointed out in claim 1,
React with the compound of formula III a or IIIb
H2N(CH2)nHet1 IIIa H2N(CH2)nAr1IIIb,
Wherein Het1、Ar1There is the implication pointed out in claim 1 with n,
And/or
By one of the alkali of Formulas I or acid salt changing into it.
Also compound of formula I is interpreted as hydrate and the solvate of these compounds.
The invention still further relates to the optically active form (stereoisomer) of these compounds, enantiomer, racemate, non-right
Reflect body and hydrate and solvate.It is interpreted as being formed due to their mutual attractive force by the solvate of this compound
Atent solvent adduction on this compound.Solvate is such as single-or dihydrate or alcohol adduct.
Pharmaceutical usable derivatives means the salt of such as compound according to the present invention and so-called prodrug compound.
It is interpreted as utilizing that such as alkyl or acyl group, sugar or oligopeptide are modified and the quickest by prodrug derivant
It is cracked into the compound of formula I of the active compound according to the present invention.
They also include the Biodegradable polymeric derivant of the compound according to the present invention, such as at Int. J.
Pharm. 115, described in 61-67 (1995).
Subject of the present invention is naturally also the solvate of the salt of compound of formula I.
Subject of the present invention is also the mixture of the compound of formula I according to the present invention, mixing of such as 2 kinds of diastereomers
Compound, such as with ratio 1:1,1:2,1:3,1:4,1:5,1:10,1:100 or 1:1000.
These are particularly preferably the mixture of stereoisomeric compounds.
Statement " effective dose " represent cause in tissue, system, animals or humans such as research worker or doctor pursuit or
The biology wanted or the medicine of medical treatment response or the amount of active constituents of medicine.
Additionally, statement " therapeutically effective amount " represents have following result compared with the individuality not accepting this amount accordingly
Amount: the treatment of improvement, healing, prevent or eliminate a disease, symptom, disease event, discomfort, disorder or side effect or palliate a disease,
Uncomfortable or disorderly development.
Statement " therapeutically effective amount " also includes the amount being effectively increased normal physiological function.
For occurring more than all residues of 1 time, such as, A, their implication is independent of one another.
SEM-Cl=2-(trimethyl silyl) ethoxyl methyl chlorine
S-Phos=2-dicyclohexyl phosphino--2', 6'-dimethoxy-biphenyl
Double (the diphenylphosphino)-9,9-dimethyl ton of Xanthphos=4,5-
DABCO=1,4-diazabicyclo [2.2.2] octane
TFA=trifluoroacetic acid
A represents alkyl, is non-branched (straight chain) or side chain, and has 1,2,3,4,5,6,7,8,9 or 10 C atoms.A
Preferably represent methyl, also ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl or the tert-butyl group, in addition with amyl group,
1-, 2-or 3-methyl butyl, 1,1-, 1,2-or 2,2-dimethyl propyl, 1-ethyl propyl, hexyl, 1-, 2-, 3-or 4-methyl
Amyl group, 1,1-, 1,2-, 1,3-, 2,2-, 2,3-or 3,3-dimethylbutyl, 1-or 2-ethyl-butyl, 1-ethyl-1-methyl-prop
Base, 1-Ethyl-2-Methyl propyl group, 1,1,2-or 1,2,2-thmethylpropyl, the most such as trifluoromethyl.
A very particularly preferably represents the alkyl with 1,2,3,4,5 or 6 C atoms, preferably methyl, ethyl, propyl group,
Isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group, amyl group, hexyl, trifluoromethyl, pentafluoroethyl group or 1,1,1-trifluoroethyl.
In described alkyl 1 or 2 non-conterminous CH and/or CH2Group can also be substituted by O, NH and/or NA'.
Alkyl can also represent CH2O-CH2-CH2-OH or CH2-CH2N(CH3)2。
A' preferably represents the alkyl with 1,2,3,4,5 or 6 C atoms, preferably methyl, ethyl, propyl group, isopropyl,
Butyl, isobutyl group, sec-butyl, the tert-butyl group, amyl group, hexyl or benzyl.
Cyclic alkyl preferably represents cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl.
OA represents alkoxyl, and is preferably the most such as, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, trifluoro
Methoxyl group or cyclopentyloxy.
-COA (acyl group) preferably represents acetyl group, propiono, also illustrate that in addition bytyry, valeryl, caproyl or
Such as benzoyl.
Hal preferably represents F, Cl or Br, but also illustrates that I.
X1Preferably represent N.
X2Preferably represent C.
X3Preferably represent C.
X4Preferably represent C.
X5Preferably represent C.
R7Preferably represent H or methyl.
Ar represents, such as, unsubstituted phenyl, further preferably represent such as single-, two-by following substituent group or three-
Substituted phenyl: A, fluorine, chlorine, bromine, iodine, hydroxyl, methoxyl group, ethyoxyl, propoxyl group, butoxy, amoxy, hexyloxy, nitro,
Cyano group, formoxyl, acetyl group, propiono, trifluoromethyl, amino, methylamino, ethylamino, dimethylamino, diethyl amino
Base, sulfonamido, sulfonyloxy methyl amino, ethyl sulfonamido, propylsulfonamido, butyl sulfonamido, dimethyl sulphonyl ammonia
Base, phenylsulfonyl-amido, carboxyl, methoxycarbonyl, ethoxy carbonyl, amino carbonyl, Het3And/or NHCOHet3。
Ar particularly preferably represents by (CH2)nOA and/or Het3Single-or the phenyl of di-substituted.
Ar1Represent, such as, unsubstituted phenyl, further preferably represent such as single-, two-by following substituent group or
Three-substituted phenyl: A, fluorine, chlorine, bromine, iodine, hydroxyl, methoxyl group, ethyoxyl, propoxyl group, butoxy, amoxy, hexyloxy, nitre
Base, cyano group, formoxyl, acetyl group, propiono, trifluoromethyl, amino, methylamino, ethylamino, dimethylamino, diethyl
Base amino, sulfonamido, sulfonyloxy methyl amino, ethyl sulfonamido, propylsulfonamido, butyl sulfonamido, dimethyl methyl
Acylamino-, phenylsulfonyl-amido, carboxyl, methoxycarbonyl, ethoxy carbonyl, amino carbonyl, Het3And/or NHCOHet3。
Ar1Particularly preferably represent by Hal, (CH2)nCN、NH2、NHA、NA2、(CH2)nCONR7And/or NR7SO2A is mono--or
The phenyl of di-substituted.
Ar2Represent, such as, unsubstituted phenyl, further preferably represent such as single-, two-by following substituent group or
Three-substituted phenyl: A, fluorine, chlorine, bromine, iodine, hydroxyl, methoxyl group, ethyoxyl, propoxyl group, butoxy, amoxy, hexyloxy, nitre
Base, cyano group, formoxyl, acetyl group, propiono, trifluoromethyl, amino, methylamino, ethylamino, dimethylamino, diethyl
Base amino, sulfonamido, sulfonyloxy methyl amino, ethyl sulfonamido, propylsulfonamido, butyl sulfonamido, dimethyl methyl
Acylamino-, phenylsulfonyl-amido, carboxyl, methoxycarbonyl, ethoxy carbonyl, amino carbonyl, Het3And/or NHCOHet3。
Ar2Particularly preferably represent, three-four-or the five-phenyl that replace: Hal, A single-, two-by following substituent group,
(CH2)nOH、(CH2)nOA、COOA、NH2、NHA、NA2、(CH2)nCONH2、(CH2)nCONHA、(CH2)nCONA2、CONHHet3、
COHet3、Het3And/or NHCOHet3,
Or indanyl, it can be replaced by=O.
Het preferably represents unsubstituted or single-, two-by A and/or=O or three-following radicals of replacing: furan
Base, thienyl, pyrrole radicals, imidazole radicals, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridine radicals, pyrimidine radicals,
Triazolyl, tetrazole radical, di azoly, thiadiazolyl group, pyridazinyl, pyrazinyl, benzimidazolyl, benzotriazole base, quinolyl, quinoline
Quinoline base, quinazolyl, pyrrolopyridinyl, purine radicals, indyl, indolinyl, indazolyl, tetrahydric quinoline group, dihydro
Benzoxazolyl group, dihydropyridine base, dihydrogen dazin base, dihydrobenzo imidazole radicals, dihydro-benzothiazole base, piperidyl, pyrrolidine
Base, morpholinyl, piperazinyl, imidazolidinyl, oxazolidinyl or THP trtrahydropyranyl.
Het particularly preferably represents by A or the mono-substituted pyrazolyl of=O or indolinyl.
Het1Preferably represent unsubstituted or by A, NR7SO2A and/or=O is single-, two-or three-substituted following base
Group: furyl, thienyl, pyrrole radicals, imidazole radicals, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridine radicals,
Pyrimidine radicals, triazolyl, tetrazole radical, di azoly, thiadiazolyl group, pyridazinyl, pyrazinyl, benzimidazolyl, benzotriazole base, quinoline
Quinoline base, quinoxalinyl, quinazolyl, pyrrolopyridinyl, purine radicals, indyl, indolinyl, indazolyl, tetrahydroquinoline
Base, dihydrobenzo oxazolyl, dihydropyridine base, dihydrogen dazin base, dihydrobenzo imidazole radicals, dihydro-benzothiazole base, piperidyl,
Pyrrolidinyl, morpholinyl, piperazinyl, imidazolidinyl, oxazolidinyl or THP trtrahydropyranyl.
Het1Particularly preferably represent by A, NR7SO2A and/or=O is single-, two-or three-substituted pyridine radicals, pyrazolyl or
Indolinyl.
Het2Preferably represent unsubstituted or by A, NR7SO2A and/or=O is single-, two-or three-substituted following base
Group: furyl, thienyl, pyrrole radicals, imidazole radicals, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridine radicals,
Pyrimidine radicals, triazolyl, tetrazole radical, di azoly, thiadiazolyl group, pyridazinyl, pyrazinyl, benzimidazolyl, benzotriazole base, quinoline
Quinoline base, quinoxalinyl, quinazolyl, pyrrolopyridinyl, purine radicals, indyl, indoline base, indolinyl, indazolyl,
Tetrahydric quinoline group, dihydrobenzo oxazolyl, dihydropyridine base, dihydrogen dazin base, dihydrobenzo imidazole radicals, dihydro-benzothiazole
Base, piperidyl, pyrrolidinyl, morpholinyl, piperazinyl, imidazolidinyl, 6,7-dihydro-5H-cyclopenta [b] pyridine radicals,
Oxazolidinyl or THP trtrahydropyranyl.
Het2Particularly preferably represent by A, NR7SO2A、Het3And/or=O mono--or the pyridine radicals of di-substituted, diazole
Base, dihydropyridine base, pyridazinyl, pyrimidine radicals, oxazolyl, isoxazolyl, 6,7-dihydro-5H-cyclopenta [b] pyridine radicals,
Indoline base or pyrazolyl.
Het3Preferably represent unsubstituted or by A, (CH2)nN(R7)2And/or=O mono--or the following base of di-substituted
Group: piperidyl, pyrrolidinyl, morpholinyl, piperazinyl, imidazolidinyl, oxazolidinyl, THP trtrahydropyranyl, indanyl, dihydrogen dazin
Base, pyridazinyl, pyridine radicals, pyrimidine radicals, triazolyl, tetrazole radical, 6,7-dihydro-5H-cyclopenta [b] pyridine radicals, dihydro Yin
Diindyl base (indoyl), dihydropyridine base, indyl, indazolyl, oxazolyl, isoxazolyl, furyl, thienyl, pyrrole radicals, miaow
Oxazolyl, pyrazolyl, quinolyl, quinoxalinyl, quinazolyl or tetrahydric quinoline group.
Het3Particularly preferably represent unsubstituted or by A, (CH2)nN(R7)2And/or=O mono--or the piperazine of di-substituted
Piperidinyl, pyrrolidinyl, morpholinyl or piperazinyl.
Therefore, the most such compound of formula I of subject of the present invention, at least one of wherein said residue has
One of preferred meaning that face is pointed out.Some preferred group of compound can be represented by following minor Ia to Ig, described minor Ia
Meet Formulas I to Ig, and there is without the group pointed out in more detail the implication pointed out in Formulas I, but wherein
In Ia, Ar represents by (CH2)nOA and/or Het3Single-or the phenyl of di-substituted;
In Ib, Het represents pyrazolyl or indolinyl, and each of which is monosubstituted by A or=O;
In Ic, Het1Representing pyridine radicals, pyrazolyl or indolinyl, each of which is by A, OH, NR7SO2A
And/or=O is single-, two-or three-replacement;
In Id, Ar1Represent by Hal, (CH2)nCN、NH2、NHA、NA2、(CH2)nCONR7And/or NR7SO2A is mono--or two-
Substituted phenyl;
In Ie, Het2Represent pyridine radicals, di azoly, dihydropyridine base, pyridazinyl, pyrimidine radicals, oxazolyl, isoxazole
Base, 6,7-dihydro-5H-cyclopenta [b] pyridine radicals, indoline base or pyrazolyl, each of which is by A, NR7SO2A、
Het3And/or=O mono--or di-substituted;
In If, Ar2Represent single-, two-by following substituent group, three-, four-or the five-phenyl that replaces: Hal, A, (CH2)nOH、(CH2)nOA、COOA、NH2、NHA、NA2、(CH2)nCONH2、(CH2)nCONHA、(CH2)nCONA2、CONHHet3、COHet3、
Het3And/or NHCOHet3,
Or indanyl, it can be replaced by=O;
In Ig, Het3Representing piperidyl, pyrrolidinyl, morpholinyl or piperazinyl, each of which is not taken
Generation, or by A, (CH2)nN(R7)2And/or=O mono--or di-substituted,
In Ih, X1Represent C or N,
X2Represent C or N,
X3Represent C or N,
X4Represent C or N,
X5Represent C or N,
R1At X1Do not exist during=N
Or
Represent NH (CH2)nHet or NH (CH2)nAr,
R2At X2Do not exist during=N
Or
Represent H or Het1,
R3At X3Do not exist during=N,
Or
Represent H, CN, A, Hal, Cyc, OH or OA,
R4At X4Do not exist during=N
Or
Represent H, NH (CH2)nHet1、O(CH2)nHet1、NH(CH2)nAr1、-≡-Ar1、(CH2)nAr1Or NH-Cyc,
R5At X5Do not exist during=N
Or
Represent H or Hal,
R6Represent H, Ar2、A、Het2、COHet3、CONH2、CONHA、CONA2Or Cyc,
R7Represent H or there is the alkyl of 1,2,3 or 4 C atoms,
Het represents pyrazolyl or indolinyl, and each of which is monosubstituted by A or=O,
Ar represents by (CH2)nOA and/or Het3Single-or the phenyl of di-substituted,
Het1Representing pyridine radicals, pyrazolyl or indolinyl, each of which is by A, OH, NR7SO2A and/or=O
It is single-, two-or three-to replace,
Ar1Represent by Hal, (CH2)nCN、NH2、NHA、NA2、(CH2)nCONR7And/or NR7SO2A is mono--or di-substituted
Phenyl,
Het2Represent pyridine radicals, di azoly, dihydropyridine base, pyridazinyl, pyrimidine radicals, oxazolyl, isoxazolyl, 6,7-
Dihydro-5H-cyclopenta [b] pyridine radicals, indoline base or pyrazolyl, each of which is by A, NR7SO2A、Het3With/
Or=O mono--or di-substituted,
Ar2Represent single-, two-by following substituent group, three-, four-or the five-phenyl that replaces: Hal, A, (CH2)nOH、(CH2)nOA、COOA、NH2、NHA、NA2、(CH2)nCONH2、(CH2)nCONHA、(CH2)nCONA2、CONHHet3、COHet3、Het3And/or
NHCOHet3,
Or indanyl, it can replace by=O,
Het3Representing piperidyl, pyrrolidinyl, morpholinyl or piperazinyl, each of which is unsubstituted, or
Person is by A, (CH2)nN(R7)2And/or=O mono--or di-substituted,
A represents the straight or branched alkyl with 1-10 C atom, and wherein 1-7 H atom can be substituted by F, and/or
Wherein 1 or 2 non-conterminous CH and/or CH2Group can be substituted by O, NH and/or NA',
A' represents the straight or branched alkyl with 1-6 C atom,
Cyc represents the cyclic alkyl with 3,4,5,6 or 7 C atoms, and it is unsubstituted or by CON (R7)2Or
NR7SO2A is monosubstituted,
Hal represents F, Cl, Br or I,
N represents 0,1 or 2,
Precondition is,
a) X1、X2、X3And X4In at least 1 expression N, and most 2 represent N simultaneously,
If b) X1=N, then X4≠ N and R4≠ H,
If c) X4=N, then X1≠N;
In Ii, X1Represent N,
X2Represent C,
X3Represent C,
X4Represent C,
X5Represent C,
R1Do not exist
R2Represent H or Het1,
R3Represent H, CN, A, Hal, Cyc, OH or OA,
R4Represent H, NH (CH2)nHet1、O(CH2)nHet1、NH(CH2)nAr1、-≡-Ar1、(CH2)nAr1Or NH-Cyc,
R5Represent H or Hal,
R6Represent H, Ar2、A、Het2、COHet3、CONH2、CONHA、CONA2Or Cyc,
R7Represent H or there is the alkyl of 1,2,3 or 4 C atoms,
Het represents pyrazolyl or indolinyl, and each of which is monosubstituted by A or=O,
Ar represents by (CH2)nOA and/or Het3Single-or the phenyl of di-substituted,
Het1Representing pyridine radicals, pyrazolyl or indolinyl, each of which is by A, OH, NR7SO2A and/or=O
It is single-, two-or three-to replace,
Ar1Represent by Hal, (CH2)nCN、NH2、NHA、NA2、(CH2)nCONR7And/or NR7SO2A is mono--or di-substituted
Phenyl,
Het2Represent pyridine radicals, di azoly, dihydropyridine base, pyridazinyl, pyrimidine radicals, oxazolyl, isoxazolyl, 6,7-
Dihydro-5H-cyclopenta [b] pyridine radicals, indoline base or pyrazolyl, each of which is by A, NR7SO2A、Het3With/
Or=O mono--or di-substituted,
Ar2Represent single-, two-by following substituent group, three-, four-or the five-phenyl that replaces: Hal, A, (CH2)nOH、(CH2)nOA、COOA、NH2、NHA、NA2、(CH2)nCONH2、(CH2)nCONHA、(CH2)nCONA2、CONHHet3、COHet3、Het3And/or
NHCOHet3,
Or indanyl, it can replace by=O,
Het3Representing piperidyl, pyrrolidinyl, morpholinyl or piperazinyl, each of which is unsubstituted, or
Person is by A, (CH2)nN(R7)2And/or=O mono--or di-substituted,
A represents the straight or branched alkyl with 1-10 C atom, and wherein 1-7 H atom can be substituted by F, and/or
Wherein 1 or 2 non-conterminous CH and/or CH2Group can be substituted by O, NH and/or NA',
A' represents the straight or branched alkyl with 1-6 C atom,
Cyc represents the cyclic alkyl with 3,4,5,6 or 7 C atoms, and it is unsubstituted or by CON (R7)2Or
NR7SO2A is monosubstituted,
Hal represents F, Cl, Br or I,
N represents 0,1 or 2;
And officinal salt, tautomer and stereoisomer, including the mixture of their all proportions.
Additionally, by method known per se, or rather under the reaction condition of known and applicable described reaction, system
The compound of standby Formulas I and the raw material of preparation thereof, (such as in classic, such as Houben--in described method such as document
Weyl, Methoden der organischen Chemie, Georg-Thieme-Verlag, Stuttgart) described.
The scheme known per se the most more specifically mentioned can also be used at this.
If necessary, it is also possible to be formed in situ initiation material, from reactant mixture, do not separate them, but
Immediately they are further converted into compound of formula I.
The compound of Formula II and formula III is generally known.But, if they are novel, then can by itself
Prepared by the method known.
Preferably by making Formula II compound react with formula III compound, compound of formula I can be obtained.
This reaction is carried out by method known to those skilled in the art.
This reaction is carried out in atent solvent.
Suitably atent solvent is such as, hydrocarbon, such as hexane, petroleum ether, benzene, toluene or dimethylbenzene;Chlorohydrocarbon, such as three
Vinyl chloride, 1,2-dichloroethanes, carbon tetrachloride, chloroform or dichloromethane;Alcohol, such as methanol, ethanol, isopropanol, normal propyl alcohol, just
Butanol or the tert-butyl alcohol;Ether, such as ether, Di Iso Propyl Ether, oxolane (THF) or dioxane;Glycol ether, such as ethylene glycol list
Methyl ether or ethylene glycol monomethyl ether (glycol monomethyl ether or ethylene glycol monoethyl ether), ethylene glycol dimethyl ether (diethylene glycol dimethyl
Ether);Ketone, such as acetone or butanone;Amide, such as acetamide, dimethyl acetylamide or dimethylformamide (DMF);Nitrile, such as
Acetonitrile;Sulfoxide, such as dimethyl sulfoxide (DMSO);Carbon bisulfide;Carboxylic acid, such as formic acid or acetic acid;Nitro compound, such as nitro
Methane or Nitrobenzol;Ester, such as ethyl acetate or the mixture of described solvent.
Particularly preferably dioxane.
According to condition used, the response time between several minutes to 14 day, reaction temperature between about-30 ° to 160 °,
Generally between 20 ° to 150 °, particularly between about 40 ° to about 140 °.
Described reaction is preferably carried out under the conditions of Buchwald, and described condition is well known by persons skilled in the art.
Further preferably, by making formula IV compound react with Formula V compound, compound of formula I can be obtained.
This reaction is carried out in atent solvent.
Suitably atent solvent is such as, hydrocarbon, such as hexane, petroleum ether, benzene, toluene or dimethylbenzene;Chlorohydrocarbon, such as three
Vinyl chloride, 1,2-dichloroethanes, carbon tetrachloride, chloroform or dichloromethane;Alcohol, such as methanol, ethanol, isopropanol, normal propyl alcohol, just
Butanol or the tert-butyl alcohol;Ether, such as ether, Di Iso Propyl Ether, oxolane (THF) or dioxane;Glycol ether, such as ethylene glycol list
Methyl ether or ethylene glycol monomethyl ether (glycol monomethyl ether or ethylene glycol monoethyl ether), ethylene glycol dimethyl ether (diethylene glycol dimethyl
Ether);Ketone, such as acetone or butanone;Amide, such as acetamide, dimethyl acetylamide or dimethylformamide (DMF);Nitrile, such as
Acetonitrile;Sulfoxide, such as dimethyl sulfoxide (DMSO);Carbon bisulfide;Carboxylic acid, such as formic acid or acetic acid;Nitro compound, such as nitro
Methane or Nitrobenzol;Ester, such as ethyl acetate or the mixture of described solvent.
Particularly preferably n-butyl alcohol.
According to condition used, the response time between several minutes to 14 day, reaction temperature between about-30 ° to 140 °,
Generally between-10 ° to 90 °, particularly between about 0 ° to about 70 °.
Pharmaceutical salts and other form
The described compound according to the present invention can use with their final salt-independent shape.On the other hand, the present invention is also
Including with can be derived from their pharmaceutically useful salt shape of various organic and inorganic bronsted lowry acids and bases bronsted lowry according to approach as known in the art
Formula uses these compounds.The pharmaceutically useful salt form of the compound according to the present invention is mainly prepared by a conventional method.If
Compound according to the present invention contains hydroxy-acid group, then can produce corresponding alkali by making this compound with suitable alkali reaction
Addition salts forms one of its suitable salt.Such alkali is such as alkali metal hydroxide, including potassium hydroxide, sodium hydroxide
And Lithium hydrate;Alkaline earth metal hydroxide, such as barium hydroxide and calcium hydroxide;Alkali metal alcoholates, such as potassium ethoxide and propanol
Sodium;With various organic bases, such as piperidines, diethanolamine and N-methylglucamine.Include the aluminium salt of compound of formula I equally.At certain
In the case of a little compound of formula I, can by with pharmaceutically acceptable organic and mineral acid, such as hydrogen halides, as hydrogen chloride, hydrogen bromide or
Hydrogen iodide, other mineral acid and corresponding salt thereof, sulfate, nitrate or phosphate etc. and alkyl-and single arylsulphonate, as
Esilate, toluene fulfonate and benzene sulfonate, and other organic acid and corresponding salt thereof, such as acetate, trifluoroacetate, wine
Stone hydrochlorate, maleate, succinate, citrate, benzoate, salicylate, Ascorbate etc. process these chemical combination
Thing forms acid-addition salts.Correspondingly, the pharmaceutically acceptable acid addition salts of the compound of Formulas I includes following: acetate, adipate,
Alginate, arginine salt, aspartate, benzoate, benzene sulfonate (benzene sulfonate), disulfate, bisulfites, bromine
Compound, butyrate, Camphora hydrochlorate, camsilate, caprylate, chloride, chloro benzoate, citrate, Pentamethylene. propanoic acid
Salt, digluconate, dihydric phosphate, dinitro-benzoate, lauryl sulfate, esilate, fumarate, viscous
Hydrochlorate (being formed by glactaric acid), galacturonic acid hydrochlorate, gluceptate, gluconate, glutamate, Glu, glycerophosphate, half succinum
Hydrochlorate, Hemisulphate, enanthate, caproate, hippurate, hydrochlorate, hydrobromide, hydriodide, 2-ethylenehydrinsulfonic acid
Salt, iodide, isethionate, isobutyrate, lactate, lactobionate, malate, maleate, malonate,
Mandelate, metaphosphate, mesylate, ar-Toluic acid salt, dibasic alkaliine, 2-naphthalene sulfonate, nicotinate, nitrate,
Oxalates, oleate, embonate (Palmoat), pectinic acid salt, persulfate, phenyl acetate salt, 3-phenylpropionic acid
Salt, phosphate, phosphonate, phthalate, but this and unrestricted.
Additionally, according to the alkali salt of the compound of the present invention include aluminum-, ammonium-, calcium-, copper-, ferrum (III)-, ferrum (II)-,
Lithium-, magnesium-, manganese (III)-, manganese (II)-, potassium-, sodium and zinc salt, but this does not represent and is limited to this.In above-mentioned salt, preferably ammonium;Sodium and
The alkali metal salt of potassium, and calcium and the alkali salt of magnesium.The compounds of this invention derived from pharmaceutically useful organic nontoxic alkali
Salt includes primary amine, secondary amine and tertiary amine, replacement amine, also includes naturally occurring replacement amine, cyclammonium and deacidite, example
Such as arginine, glycine betaine, caffeine, chloroprocaine, choline, N, N'-dibenzyl-ethylenediamin (benzathine benzylpenicillin
(Benzathin)), dicyclohexylamine, diethanolamine, diethylamine, 2-DEAE diethylaminoethanol, 2-dimethylamino
Ethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glycosamine, histidine, Kazakhstan amine
(Hydrabamin), 2-aminopropane., lignocaine, lysine, meglumine, N-methyl-D-glucosamine, morpholine, piperazine, piperidines, poly-
Polyimide resin, procaine, purine, theobromine, triethanolamine, triethylamine, trimethylamine, tripropyl amine (TPA) and three (hydroxyl first
Base) salt of methyl amine (trometamol), but this does not represent and is limited to this.
Can be with following reagent by quaternized for the compound of the present invention containing Basic nitrogen-containing groups: (C1-C4) alkyl
Halogenide, the such as chloride of methyl, ethyl, isopropyl and the tert-butyl group, bromide and iodide;Sulphuric acid two (C1-C4) alkyl
Ester, such as dimethyl sulfate, dithyl sulfate and diamyl sulfates;(C10-C18) alkyl halide, such as decyl, dodecane
The chloride of base, lauryl, myristyl and stearyl, bromide and iodide;And aryl (C1-C4) alkyl halide, example
Such as benzyl chloride and phenethyl bromide.Water solublity and the compound of the oil-soluble present invention can be prepared with such salt.
Preferred above-mentioned pharmaceutical salts includes acetate, trifluoroacetate, benzene sulfonate, citrate, fumarate, glucose
Hydrochlorate, hemisuccinic acid salt, hippurate, hydrochlorate, hydrobromate, isethionate, mandelate, meglumine, nitrate,
Oleate, phosphonate, pivalate, sodium phosphate, stearate, sulfate, sulfosalicylate, tartrate, sulfur are for Fructus Mali pumilae
Hydrochlorate, toluene fulfonate and tromethane, but this is not intended to represent restriction.
By making free alkali form contact with enough required acid, form salt the most in a usual manner and prepare according to this
The acid-addition salts of bright alkali compounds.Can contact with alkali by making salt form and separate free alkali in a usual manner and regenerate
Free alkali.Free alkali form in some aspects, in some physical property, is different from it in terms of the dissolubility in polar solvent
Corresponding salt form;But within the scope of the present invention, this salt in other side corresponding to its respective free alkali form.
As it has been described above, form the compound according to the present invention with metal or amine such as alkali and alkaline earth metal ions or organic amine
Pharmaceutically acceptable base addition salts.Preferably metal is sodium, potassium, magnesium and calcium.Preferably organic amine is N, and N '-dibenzyl-ethylenediamin, chlorine are general
Shandong caine, choline, diethanolamine, ethylenediamine, N-methyl-D-glucosamine and procaine.
By making free acid form contact with enough required alkali, form salt the most in a usual manner and prepare according to this
The base addition salts of bright acid compound.Can contact with acid by making salt form and separate free acid in a usual manner and regenerate
Free acid.Free acid form in some aspects, in some physical property, is different from it in terms of the dissolubility in polar solvent
Corresponding salt form;But within the scope of the present invention, this salt in other side corresponding to its respective free acid form.
If the compound according to the present invention contains the more than one group that can form such officinal salt, the then present invention
Also include complex salt.Typical complex salt form includes such as, biatrate, diacetate, difumarate, two Portugal's first
Amine, diphosphate, disodium and tri hydrochloride, but this is not intended to represent restriction.
According to above it can be seen that term " pharmaceutically useful salt " is here and hereinafter meant that the root comprising the form with one of its salt
According to the active component of the compounds of this invention, particularly, with the free form of active component or this active component of using before
Other salt form any is compared, if this salt form imparts the pharmacokinetic property that this active component improves.This activity
That the pharmaceutically useful salt form of composition also can not have before giving this active component first and even at its therapeutic efficacy in vivo
Aspect has the required pharmacokinetic property of actively impact to the pharmacodynamics of this active component.
Compound according to the present invention can be chirality due to their molecular structure and can correspondingly produce various
Enantiomeric form.Therefore they can exist with raceme and optically active form.
Owing to the racemate of the compound according to the present invention or the pharmaceutically active of stereoisomer may be different, Ke Nengxi
Hope and use enantiomer.In these cases, end product or even intermediate can pass through chemistry well known by persons skilled in the art
Or physical measure is separated into enantiomeric compounds or is even used as such for synthesis.
In the case of racemic amines, this mixture form diastereomer by reacting with optically active resolving agent.Make
For resolving agent suitably the most e.g. optically active acid, such as R-and the S-form of following substances: tartaric acid, acetyl tartaric acid,
Dibenzoyl tartaric acid, mandelic acid, malic acid, lactic acid, suitably protection N aminoacid (such as N-benzoyl proline or
N-benzenesulfonyl proline) or the camphorsulfonic acid of various optically active.Also advantageously by optically active resolving agent (such as
Other derivant of dinitrobenzoyl phenylglycine, cellulose triacetate or carbohydrate or be fixed on silica gel
The methacrylate polymers of chiral derivatization) chromatograph Chiral Separation.Suitable eluant for this purposes be water or
The solvent mixture of alcohol, such as ratio are the hexane/isopropyl alcohol/acetonitrile of 82:15:3.
Isotope
In addition intending, compound of formula I includes its isotope-labeled form.Except for the facts that in addition, compound of formula I
Isotope-labeled form is equal to described compound: one or more atoms of described compound are by atomic mass or matter
Measure the atomic mass of the number described atom common from nature or the atom replacement that mass number is different.It is prone to commercially available and can
Such as to include the same of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine according to the isotope in well-known method introduction-type I
Position element, such as2H、3H、13C、14C、15N、18O、17O、31P、32P、35S、18F and36Cl.Containing one or more above-mentioned isotopes and/or
Other isotopic compound of formula I, its prodrug or the officinal salt of other atom are defined as the ingredient of the present invention.Coordination
Element labelling compound of formula I can by multiple favourable in the way of use.Such as, isotope-labeled compound of formula I is (the most such as
Have been incorporated into radiosiotope such as3H or14C) measure of spread of medicine and/or substrate tissue it is suitable for.Owing to they are prone to
Preparation and outstanding detectability, particularly preferably these radiosiotope, i.e. tritium (3H) and carbon-14 (14C).At Formulas I chemical combination
Thing introduces heavier isotope, such as deuterium (2H), thank to stability due to the higher generation of this isotope-labeled compound and have
There is treatment advantage.Higher generation is thanked to stability and is directly meaned the dosage of the Half-life in vivo or lower increased, and this is in most of feelings
The preferred embodiments of the invention are represented under condition.Generally, by carry out synthetic schemes and about describe in, in an embodiment and
Operation disclosed in the preparation part of this specification can prepare isotope-labeled compound of formula I, wherein same be easy to get
The reactant of position element labelling replaces nonisotopically labelled reactant.
For the oxidative metabolism by compound described in primary kinetic isotope effect control, it is also possible to by deuterium (2H) draw
Enter in compound of formula I.Described primary kinetic isotope effect is the chemical reaction rate caused by the exchange of Isotopes
Change, described change is again by caused by the change of the Ground State Energy formed after this isotopic Exchange needed for covalent bond.Heavier same
The exchange of position element typically results in the Ground State Energy of chemical bond and reduces, and therefore makes the rate reduction of speed limit bond fission.If bond fission
Occur along the saddle point district of coordinate of many products reaction or its near, then can substantially change products distribution ratio.Such as, if
Deuterium bond is combined on the carbon atom in the most replaceable site, kM/kDSpeed difference be typically 2-7.If by this speed difference success
Ground for being prone to the compound of formula I of oxidation, then can the internal character of compound described in appreciable impact, and cause the medicine generation improved dynamic
Mechanical property.
When finding and develop therapeutic agent, those skilled in the art attempt to optimize pharmacokinetic parameter, and keep simultaneously
Desired body outer property.Having reason to speculate, the compound much with poor pharmacokinetic property is prone to oxidative metabolism.By mesh
Front available Vitro hepatic microsome measures the valuable information obtaining the process about this kind of oxidative metabolism, due to described letter
Breath can have the compound of formula I of the deuterate of the stability of raising by resisting this oxidative metabolism by reasonable design again.By
This can significantly improve the pharmacokinetic property of compound of formula I, and can be expressed as the Half-life in vivo increased quantitatively
(t1/2), maximum hospital benefit time concentration (Cmax), area (AUC) under dose response curve and F;And the removing reduced
Rate, dosage and material cost.
Herein below is intended to explain foregoing: will have the potential attack site of multiple oxidative metabolism (on such as benzyl
Hydrogen atom and with the hydrogen atom of nitrogen atom bonding) compound of formula I be prepared as a series of analog, wherein hydrogen atom is not
With combination substituted by D-atom so that in these hydrogen atoms some, largely or entirely substituted by D-atom.By measuring
Half-life is determined to advantageously and is accurately determined the improvement degree of the oxidative metabolism resistance having been carried out.The most permissible
Determining, due to this deuterium-hydrogen exchange, the half-life of initial compounds can extend most 100%.
Deuterium in compound of formula I-hydrogen exchange metabolite spectrum that can also be used for beneficially modifying initial compounds, to reduce
Or eliminate undesirable toxic metabolite.Such as, if owing to the fracture of oxidisability carbon-hydrogen (C-H) key and produce toxicity generation
Thank to product, then it can be reasonably assumed that, deuterated analogue can substantially reduce or eliminate undesirable metabolite, though each oxygen
Changing is not rate-limiting step.About the out of Memory of the prior art of deuterium-hydrogen exchange, it is given at such as, Hanzlik et al., J.
Org. Chem. 55,3992-3997,1990, Reider et al., J. Org. Chem. 52,3326-3334,
1987, Foster, Adv. Drug Res. 14,1-40,1985, Gillette et al., Bio chemistry 33
(10), 2927-2937,1994, and Jarman et al., Carcinogenesis 16 (4), 683-688,1993.
Additionally, subject of the present invention is that described compound and/or its physiologically acceptable salt are for preparing medicine (medicine
Compositions) purposes, especially with non-chemical method.Here, can be by them and at least one solid, liquid and/or half liquid
Body excipient or adjuvant are together and optionally and the combined suitable agent changed into herein of one or more other reactive compounds
Type.
Additionally, the present invention relates to comprise at least one according to the compound of the present invention and/or its pharmaceutically useful derivant, molten
Agent compound and stereoisomer, the mixture including its all proportions and optional excipient and/or the medicine of adjuvant.
Pharmaceutical preparation can be administered with the dosage unit form of the active component that every dosage unit comprises scheduled volume.According to controlling
Treat the age of disease event, route of administration and patient, body weight and situation, such unit can comprise such as 0.1 mg to 3 g,
Preferably 1 mg to 700 mg, the compound according to the present invention of particularly preferred 5 mg to 100 mg, or pharmaceutical preparation can be with often
The dosage unit form that dosage unit comprises the active component of scheduled volume is administered.Preferably dosage unit preparations is to comprise as above to refer to
Those of the active component of the daily dose shown or divided dose or its appropriate section.In addition it is possible to use it is known in pharmaceutical field
Method prepares such pharmaceutical preparation.
Pharmaceutical preparation is applicable to use via any appropriate approach, such as oral (including buccal or Sublingual), rectum,
Nose, locally (include buccal, Sublingual or transdermal), vagina or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) method.
By all methods known in pharmaceutical field, such as, by being mixed with excipient or adjuvant by active component, can be prepared such
Preparation.
The pharmaceutical preparation being suitable for oral administration can be as individual, such as capsule or tablet;Powder or granule;At water
Solution in property or non-aqueous liquid or suspension;Edible foam or foam food prods;Or oil-in-water liquid emulsion or Water-In-Oil
Liquid emulsion is administered.
It is therefoie, for example, in the case of the oral administration of tablet or capsule form, can be by active component with oral, nontoxic
Merge with pharmaceutically useful inert excipient, such as ethanol, glycerol, water etc..By this compound is ground to suitable fine granularity
And by itself and the drug excipient ground in a similar manner, the most edible carbohydrate, such as starch or mannitol are mixed
Close, prepare powder.There is likely to be correctives, preservative, dispersant and dyestuff.
Fill shaping gelatin shell by mixture of powders prepared as described above and with it, manufacture capsule.Padding it
Before can by the high dispersive silicon dioxide of fluidizer and lubricant, such as solid form, Talcum, magnesium stearate, calcium stearate or
Polyethylene Glycol adds in this mixture of powders.Disintegrating agent or solubilizing agent, such as agar, calcium carbonate or carbonic acid can also be added
Sodium, takes the availability of medicine after capsule to improve.
If additionally, need or necessary, it is also possible to suitable binding agent, lubricant and disintegrating agent and dyestuff being mixed should
In mixture.Suitably binding agent includes starch, gelatin, natural sugar, such as glucose or beta lactose, the sweet taste being made up of Semen Maydis
Agent, natural and synthetic rubber, such as Radix Acaciae senegalis, Tragacanth or sodium alginate, carboxymethyl cellulose, Polyethylene Glycol, wax etc..This
In a little dosage forms, lubricant used includes enuatrol, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride etc..Collapse
Solve agent and include, but not limited to starch, methylcellulose, agar, bentonite, xanthan gum etc..Mix by such as preparing powder
This mixture of thing, granulation or dry-pressing, adds lubricant and disintegrating agent and by they whole tablets that are pressed into prepare tablet.Pass through
By the compound pulverized in a suitable manner and diluent as above or base material and optional and binding agent, such as carboxymethyl cellulose
Element, alginate, gelatin or polyvinyl pyrrolidone, dissolution blocker, such as paraffin, absorption enhancer, such as quaternary ammonium salt,
And/or the mixing of absorbent, such as bentonite, Kaolin or dicalcium phosphate, prepare mixture of powders.Can by with binding agent,
The solution-wet of such as syrup, gelatinized corn starch, mucialga of arabic gummy (Aacadia-Schleim) or cellulose-or polymeric material is also
Pressed through sieve to be granulated this mixture of powders.Replace granulation, can make mixture of powders through tablet machine, to produce shape
Uneven agglomerate, is smashed formation granule.Granule can be made by adding stearic acid, stearate, Talcum or mineral oil
Grease is to prevent from being adhered on slab mould.Then the mixture through fat liquoring is pressed into tablet.Chemical combination according to the present invention
Thing can also merge with free-pouring inert excipient, is then directly pressed in the case of not carrying out pelletize or dry compressing step
Tablet.The transparent or opaque protective layer being made up of Lac sealant, sugar or polymer material layer and waxed gloss layer can be there is.
Can add dye in these coatings so that different dosage units can be distinguished.
Oral liquid, such as solution, syrup and elixir can be prepared so that the amount given comprises predetermined with dosage unit form
The compound of amount.By this compound dissolution being prepared in the aqueous solution containing suitable correctives syrup, and nothing can be used
Poison alcohols vehicle prepares elixir.Suspension can be prepared by being dispersed in nontoxic vehicle by this compound.Can also
Adding solubilizing agent and emulsifying agent, such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ether, preservative, taste masking add
Agent, such as Oleum menthae, or natural sweetener or saccharin, or other artificial sweetening agent etc..
Dosage unit preparations for oral administration can optionally be encapsulated in microcapsule.To extend or release can also be postponed
Mode prepares said preparation, such as by by microparticle material coating or be embedded in polymer, wax etc..
Compound and the derivant of salt, solvate and physiological function thereof according to the present invention can also be with liposome delivery
The form of the least unilamellar vesicle of system, big unilamellar vesicle and multilamellar vesicle is used.Can be by various phospholipid such as cholesterol, stearylamine
Or phosphatidylcholine forms liposome.
Compound and salt thereof according to the present invention can also use monoclonal antibody to be coupled to it as this compound molecule
On separate carrier defeated pass.This compound also can be with the soluble polymer coupling as target medicine carrier.Such polymer
Polyvinylpyrrolidone, pyran co-polymer, poly-hydroxypropyl methyl acrylamido phenol, poly-hydroxyethyl N base can be included
Phenol or polyethylene-oxide polylysine, it is replaced by palmitoyl residues.Additionally, this compound can be coupled to be adapted for carrying out medicine
The one biodegradable polymer of class, such as polylactic acid, poly-epsilon-caprolactone, poly butyric, poe, bunching of thing controlled release
Aldehyde, poly-dihydroxy pyran, polybutylcyanoacrylate and crosslinking or on the block copolymer hydrogel of amphiphilic.
The pharmaceutical preparation being suitable to applied dermally can be as the independent plaster contacted with the epidermis long-term close of receiver
Use.It is therefoie, for example, active component can be made to deliver from plaster, such as Pharmaceutical by ionotherapy
Research, 3 (6), described in the generic term in 318 (1986).
Be suitable for topical medical compounds can be formulated as ointment, ointment, suspension, lotion, powder, solution,
Paste, gel, spray, aerosol or oil.
In order to treat eyes or other outside organization, such as oral cavity and skin, said preparation is preferably with topical ointments or breast
The form of unguentum is used.In the case of being configured to ointment, active component can be together with paraffinic or water miscibility cream base
Use.Or, active component can be configured to unguentum together with oil-in-water type emulsifiable paste matrix or water-in-oil base.
The pharmaceutical preparation being suitable for being locally applied to eyes includes eye drop, is wherein dissolved or suspended in properly by active component
Carrier, particularly in aqueous solvent.
The pharmaceutical preparation being suitable for being locally applied to oral cavity includes lozenge, pastille and collutory.
The pharmaceutical preparation being suitable for rectally can be administered with the form of suppository or enema.
Wherein carrier mass is that the pharmaceutical preparation of applicable nose administration of solid includes that granularity is such as 20-500 micron
Coarse powder, it is administered in the way of snuffing, is i.e. quickly sucked near the container containing powder of nose by via intranasal application passage.
The activity one-tenth being included in water or oil as the preparation being suitable as nasal spray or nasal drop administration of carrier mass using liquid
Divide solution.
Fitting through that the pharmaceutical preparation of inhalation comprises can be by various types of pressurization allotters containing aerosol, spray
Fine-grained powder that day with fog or insufflator generate or mist.
The pharmaceutical preparation being suitable for vagina administration can be as pessulum, cotton sliver, ointment, gel, paste, foam or spraying system
Agent is administered.
The pharmaceutical preparation being suitable for Parenteral administration includes comprising antioxidant, buffer agent, antibacterial and so that this system
The aqueous of the solute that agent is isotonic with the blood of treated receptor and non-aqueous sterile injection liquid;Suspension media and thickening can be comprised
The aqueous of agent and non-aqueous sterile suspensions.Said preparation can be at single dose or multi-dose container, the ampoule such as sealed and little
It is administered in Ping and stores with lyophilization (lyophilizing) state, in order to only need to add sterile carrier liquid such as injection before use
Water.The injection solution prepared according to prescription and suspension can be prepared by sterilized powder, granule and tablet.
Self-evidently, in addition to the composition that it should be particularly mentioned above, said preparation also can comprise in this area according to preparation
Other reagent that particular type is common;It is therefoie, for example, be suitable for oral preparation can comprise correctives.
The therapeutically effective amount of the compound according to the present invention depends on many factors, including such as human or animal age and
Weight, the precise condition needing treatment and the order of severity, the character of preparation and application process, and final by the doctor in charge or beast
Doctor determines.But, the effective dose for the compound according to the present invention for the treatment of typically (is fed at 0.1-100 mg/kg receptor
Breast animal) scope of body weight/day, and especially generally in the scope of 1-10 mg/kg body weight/day.Therefore, it is 70kg for body weight
Adult Mammals for, the actual amount of every day is generally between 70-700mg, and wherein this amount can be as the single of every day
Dosage is used, or generally uses in a series of broken doses (such as, 2,3,4,5 or 6 parts) of every day so that total daily dose
Identical.The effective dose of its salt or solvate can be determined by the ratio of the effective dose of the compound according to the present invention itself.
Similar dosage is deemed applicable to treat Other diseases situation mentioned above.
Additionally, the present invention relates to comprise at least one according to the compound of the present invention and/or its officinal salt, tautomerism
Body and stereoisomer, including their mixture of all proportions and the medicine of at least one other medicines active component.
Other medicines active component is preferably chemotherapeutant, and especially suppression angiogenesis also thus suppresses tumor thin
Those of the growth of born of the same parents and diffusion;It is preferred here that vegf receptor inhibitor, including the ribozyme for vegf receptor
And antisense thing and angiostatin and endostatin (robozyme).
The example of the antitumor agent can being used in combination with the compounds of this invention generally includes: alkylating agent, antimetabolite;Replace
Buddhist nun moors glycosides;Antitumor enzyme;Topoisomerase enzyme inhibitor;Procarbazine;Mitoxantrone or platinum coordination complex.
Antitumor agent is preferably chosen from following kind:
In anthracycline, winca drugs, mitomycin, bleomycin, cytotoxic nucleoside, Epothilones, dish suberite
Esters (Discodermolide), pteridine class, Enediyne and podophillotoxines.
At described kind of apoplexy due to endogenous wind it is particularly preferred that such as, carminomycin, daunorubicin, aminopterin, methotrexate, first
Aminopterin, dichioromethotrexate, ametycin, porphyromycin, 5-fluorouracil, Ismipur, gemcitabine, arabinose born of the same parents
Pyrimidine (Cytosinarabinosid), podophyllotoxin or podophyllotoxin derivative (such as, etoposide, etoposide phosphate or
Teniposide), melphalan, vincaleucoblastine, vincristine, leurosidine, vindesine, leurosine and paclitaxel.Other
Preferably antitumor agent selected from estramustine, carboplatin, cyclophosphamide, bleomycin, gemcitabine, ifosfamide, melphalan,
Altretamine, phosphinothioylidynetrisaziridine, cytosine arabinoside, edatrexate (Idatrexate), trimetrexate, dacarbazine, ASP,
Camptothecine, CPT-11, hycamtin, cytosine arabinoside, bicalutamide, flutamide, leuprorelin, pyrido benzindole are derivative
Thing, interferon and interleukin.
The invention still further relates to by the following box set (test kit) formed of individually wrapping:
The compound according to the present invention of (a) effective dose and/or its officinal salt, tautomer and stereoisomer,
Including the mixture of their all proportions,
With
The other medicines active component of (b) effective dose.
This box set comprises suitable container, such as box or carton box, single bottle, bag or ampoule.This box set can comprise such as
Separate ampoule, each ampoule each comprises the compound according to the present invention and/or its officinal salt, the tautomerism of effective dose
Body and stereoisomer, include the mixture of their all proportions,
Dissolving with effective dose or the other medicines active component of freeze-dried.
Purposes
The compound of the present invention is suitable in the treatment of disease caused in tyrosine kinase as mammal, especially people
The pharmaceutically active substance of class.These diseases include: the propagation of tumor cell, promote the pathologic neovascularization shape of implanted solid tumor growth
Becoming (or angiogenesis), intraocular neovascularization forms (degeneration of macula etc. that diabetic retinopathy, age cause) and inflammation
(psoriasis, rheumatoid arthritis etc.).
The present invention include compound of formula I and/or its physiologically acceptable salt, tautomer and stereoisomer for
Preparing the purposes of medicine, described medicine is for treatment or prophylaxis of cancer.For treatment, preferably cancer derives from: the brain cancer, urinary system
Reproductive tract cancer, lymphsystem cancer, gastric cancer, laryngeal carcinoma and pulmonary carcinoma.Another organizes preferred cancer forms: monocytic leukemia, lung
Adenocarcinoma, small cell lung cancer, cancer of pancreas, glioblastoma multiforme and breast carcinoma.
Also compound and/or its physiologically acceptable salt, the tautomer of the present invention according to claim 1 are included
With stereoisomer for preparing the purposes of medicine, described medicine relates to the disease of angiogenesis for treatment or prevention.
Such disease relating to angiogenesis is oculopathy, such as Retinal neovascularization, diabetic retinopathy, age
The degeneration of macula etc. caused.
Compound of formula I and/or its physiologically acceptable salt, tautomer and stereoisomer be used for preparing treatment or
The purposes of the medicine of prevention inflammatory diseases also falls in the scope of the invention.The example of such inflammatory diseases includes that rheumatoid closes
Joint inflammation, psoriasis, contact dermatitis, delayed hypersensitivity etc..
Also include that compound of formula I and/or its physiologically acceptable salt, tautomer and stereoisomer are for preparing
The purposes of medicine, disease or tyrosine kinase that described medicine causes for treating or prevent the tyrosine kinase of mammal are made
The disease become, the most in the method, is administered to need this treatment by the compound according to the present invention of therapeutically effective amount
Afflicted mammal.Described therapeutic dose changes with disease specific, and can be by those skilled in the art without excessive effort
Determine.
The present invention also includes that compound of formula I and/or its physiologically acceptable salt and solvate are for preparing medicine
Purposes, described medicine is used for treating or preventing Retinal neovascularization.
For treating or preventing the method for oculopathy (degeneration of macula that such as diabetic retinopathy and age cause) together
Sample is the part of the present invention.For treating or preventing inflammatory diseases (such as rheumatoid arthritis, psoriasis, contact skin
Inflammation and delayed hypersensitivity) and it is selected from osteosarcoma, osteoarthritis and the purposes of rachitic osteopathia for treatment or prevention,
Also fall within the scope of the invention.
Statement " disease that tyrosine kinase causes or disease " represents the activity depending on one or more tyrosine kinase
Pathological conditions.Tyrosine kinase either directly or indirectly participate in various kinds of cell activity (include propagation, adhere to and migrate and
Differentiation) signal transduction pathway.The disease relevant with tyrosine kinase activity includes: the propagation of tumor cell, promotes solid tumor
The Angiogenesis of growth, ocular neovascular forms the (degeneration of macula that diabetic retinopathy, age cause
Deng) and inflammation (psoriasis, rheumatoid arthritis etc.).
Compound of formula I can be administered to patient to treat the tumor of cancer, especially fast-growth.
Therefore, subject of the present invention is compound of formula I and pharmaceutically useful salt, tautomer and stereoisomer, bag
Including their mixture of all proportions for preparing the purposes of medicine, described medicine is for treating pressing down of signal transduction of kinases
Make, regulate and/or regulate and control the disease worked wherein.
Preferably, compound of formula I and pharmaceutically useful salt, tautomer and stereoisomer, include their institute
Proportional mixture is for preparing the purposes of medicine, and described medicine is passed through by compound according to claim 1 for treatment
Suppression tyrosine kinase and affected disease.
It is particularly preferred that for the purposes treating disease, wherein said disease is solid tumor.
Described solid tumor is preferably selected from: lung, squamous epithelial cancer, bladder, stomach, kidney, head and neck, esophagus, cervix uteri, thyroid,
The tumor of intestinal, liver, brain, prostate, urogenital tract, lymphsystem, stomach and/or larynx.
Additionally, described solid tumor be preferably selected from adenocarcinoma of lung, small cell lung cancer, cancer of pancreas, glioblastoma multiforme, colon cancer and
Breast carcinoma.
It is then preferred that for the purposes treating blood-and immune tumor, be preferred for treatment selected from acute myelogenous
The purposes of the tumor of leukemia, chronic myelogenous leukemia, acute lymphatic leukemia and/or chronic lymphatic leukemia.
Can by disclosed compound of formula I and other known treatment agent, include that anticarcinogen is combined.Term used herein
" anticarcinogen " refers to be applied to cancer patient, is intended to treat any reagent of cancer.
Here the anticancer therapy defined can be applied as monotherapy, or outside digging up the roots according to the compound of the present invention, also may be used
To include conventional operation or radiotherapy or chemotherapy.This based chemotherapy can include one or more in following classification antineoplastic agent:
I () such as antiproliferative/the antitumor in Medical oncology/DNA-damage agent and combinations thereof, such as alkylating agent (example
Such as cisplatin, carboplatin, cyclophosphamide, chlormethine, melphalan, chlorambucil, busulfan and nitroso ureas);Antimetabolite is (the most anti-
Folic acid agent, such as fluoropyrimidine class such as 5-fluorouracil and ftorafur, Raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea and Ji Xi
His shore);Antitumor antibiotics (such as anthracycline antibiotics, as mould in adriamycin, bleomycin, doxorubicin, road promise
Element, epirubicin, idarubicin, Mitomycin-C, actinomycin D and mithramycin);Antimitotic agent (such as Herba Catharanthi Rosei
Alkaloid, such as vincristine, vincaleucoblastine, vindesine and vinorelbine and taxanes such as paclitaxel and docetaxel
(Taxoter));Topoisomerase enzyme inhibitor (replace by such as epipodophyllotoxin such as etoposide and teniposide, amsacrine, topology
Health, irinotecan and camptothecine) and cell differential agent (such as all-trans retinoic acid, 13CRA and fenretinide);
(ii) cytostatics, such as antiestrogen (such as tamoxifen, toremifene, raloxifene, droloxifene
With idoxifene (Iodoxyfen), estrogen receptor down-regulation agent (such as fulvestrant), antiandrogen (such as than card
Shandong amine, flutamide, nilutamide and cyproterone acetate), lhrh antagonist or LHRH agonist (such as goserelin, bright third
Rayleigh and buserelin), progestational hormone (such as megestrol acetate), aromatase inhibitor (such as Anastrozole, letrozole, volt
Chlorazol (Vorazol) and exemestane) and 5α-reductase inhibitor such as finasteride;
(iii) anticancer invade medicine (such as inhibitors of metalloproteinase such as Marimastat and urokinase-
Plasminogen activator receptor depressant of functions);
(iv) somatomedin depressant of functions, the most this kind of inhibitor includes that growth factor antibodies, growth factor receptors are anti-
Body (the most anti-erbb2-antibody trastuzumab [HerceptinTM] and anti-erbb1-antibody cetuximab [C225]), method Buddhist nun
Transferase inhibitors, tyrosine kinase inhibitor and serine/threonine kinase inhibitor, such as epidermal growth factor Zijia
Group inhibitor (such as EGFR family tyrosine kinase inhibitor, asN-(3-chloro-4-fluorophenyl)-7-methoxyl group-6-(3-morpholine
For propoxyl group) quinazoline-4-amine (gefitinib, AZD1839),NDouble (the 2-methoxyl group ethoxy of-(3-ethynyl phenyl)-6,7-
Base) quinazoline-4-amine (Erlotinib, OS1-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholino
Propoxyl group) quinazoline-4-amine (Cl 1033));Such as platelet derived growth factor man group inhibitor and such as hepatic cell growth
Factor family inhibitor;
V () anti-angiogenic agent, as the effect of suppression VEGF, (such as anti-Vascular Endothelial is thin
Antibody bevacizumab [the Avastin of the intracellular growth factorTM], as being disclosed in international patent application WO 97/22596, the WO of announcement
97/30035, those compounds in WO 97/32856 and WO 98/13354) and the compound that worked by other mechanism
(such as linomide, integrin-α v β 3 depressant of functions and angiostatin (Angiostatin));
(vi) blood vessel injury agent, such as Combretastatin (Combretastatin) A4 and be disclosed in international patent application WO
99/02166, the chemical combination in WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213
Thing;
(vii) antisense therapy, such as those of the above-mentioned target enumerated, such as anti-Ras antisense thing ISIS 2503;
(viii) gene therapy approach, including such as replacing the gene of change, the p53 such as changed or the BRCA1 of change
Or the scheme of BRCA2;GDEPT (gene targeting enzyme prodrug therapy) scheme, it uses cytosine deaminase, thymidine kinase or thin
Those of bacterium nitroreductase;With increase patient to chemotherapy or the scheme of radiotherapy toleration, such as multidrug resistance gene therapy;With
(ix) immunotherapy scheme, including such as increase patient tumors cell immunogenicity ex vivo-
With internal scheme, as use cytokine such as interleukin II, interleukin-4 or granular leukocyte macrophage colony stimulation because of
The transfection of son;For reducing the scheme of T-cell anergy;Use the immunocyte of transfection as used the tree of cytokine transfection
The scheme of prominent cell;Use the scheme of the tumor cell line of cytokine transfection;With the scheme using anti-idiotype antibody.
Medicine from table 1 below preferably but is non-exclusively combined with compound of formula I.
Each component that such therapeutic alliance can by means of simultaneously, continuously or individually distribute in treatment realizes.This kind
The combination product of type uses the compound according to the present invention.
Subject of the present invention be for treat the compound of formula I of following disease and pharmaceutically useful salt thereof, tautomer and
Stereoisomer, including the mixture of their all proportions: tumor, cancer, tumor generate ,-growth and-diffusion, tremulous pulse hard
Change, ophthalmic (degeneration of macula, choroidal neovascularization and diabetic retinopathy that the such as age causes), inflammatory disease
Disease, arthritis, thrombosis, fibrosis, glomerulonephritis, neural degeneration, psoriasis, restenosis, wound healing, transplanting row
Scold, metabolic disease and disease of immune system, autoimmune disease, liver cirrhosis, diabetes and angiopathy.
Measure
By the compound measuring the present invention that inspection describes in an embodiment described below, and find that it has kinases
Inhibitory activity.From document, know that other measures, and can easily be carried out by those skilled in the art (see, e.g.,
Dhanabal et al.,Cancer Res. 59:189-197;Xin et al.,J. Biol. Chem. 274:9116-
9121;Sheu et al.,Anticancer Res. 18:4435-4441;Ausprunk et al.,Dev. Biol. 38:
237-248;Gimbrone et al.,J. Natl. Cancer Inst. 52:413-427;Nicosia et al.,In Vitro 18:538- 549)。
FAK kinase assays (autophosphorylation)
Dodge plate mensuration (such as measuring for Topcount) form with 384-hole or measure (use with 384-hole pattern picture sudden strain of a muscle plate
Measure in LEADseeker) form, carry out focal adhesion kinase (FAK) and measure.50 μ l cumulative volumes (60 mM Hepes, 10
mM MgCl2, 1.2 mM dithiothreitol, DTTs, the Brij35 of 0.02%, the BSA of 0.1%, pH 7.5) in, at 30 DEG C, by 2 nM
FAK, the 400 biotinylated substrates of nM (His-TEV-hsFAK (31 686) (K454R) x biotin) and 1 μM of ATP is (
Through mixed with the 33P-ATP/ hole of 0.25 Ci) with and without test compound incubation 2 hours.Use 25 μ l 200 mM EDTA
Stop this reaction.After 30 DEG C of 30 min, liquid is removed, and uses 100 l 0.9% sodium chloride solutions to be washed in each hole
Wash three times.In the presence of 1 M EMD 1076893/0 (PF--562271), determine nonspecific reaction.Use Topcount
(in the case of using sudden strain of a muscle plate) or use LEADseeker (in the case of using image to dodge plate) measure radioactivity.Make
With such as Symyx Assay Explorer result of calculation (such as IC50 value).
Method for the test cell line of FAK inhibitors of kinases
In order to analyze the cytoactive of FAK, determine that FAK is at cheese ammonia by means of mensuration based on Luminex with 96-well format
Autophosphorylation degree at acid 397.With 30,000 cells/well, HT29 cell is seeded in 100 μ l culture medium (90%
The FCS of DMEM/10%) in, and second day under without serum condition together with the serial dilution (7 kinds of concentration) of substances
Incubation 30 minutes.Use subsequently every hole 90 μ l lysis buffer (20mM tris/HCl pH 8.0,150mM NaCl, 1%
NP40, the glycerol of 10%, inhibitors of phosphatases II, 20mM β-glycerophosphate of 1%, the protease inhibitor cocktail of 0.1%
III, the nuclease of 0.01%) cell lysis, and be centrifuged by means of through 96-hole filter plate (0.65 m), make lysate with insoluble
Cellular component separate.Lysate is had with coupling together with the Luminex pearl of anti-total FAK antibody, shake incubation mistake at 4 DEG C
Night.At second day, by adding P-Y397-FAK antibody and the second antibody of material specific PE-labelling, detect.Logical
Cross measuring in Luminex100 instrument and detect P-by mensuration 100 events in each chamber within the measurement time of 60 seconds
Y397-FAK.Deduct from other batches all as pharmacology blank from the FAK of 30 μMs with reference to inhibitor process thin
The signal that born of the same parents obtain.Use the signal of the cell only processed with solvent (DMSO of 0.3%) as the FAK maximum phosphoric acid at Y397
The control value changed.The value of the batch that use substances processes is calculated as the percentage ratio of comparison from it, and by means of Assay
Explorer determines IC50 value.
The test of PDK1 suppression
With 384 holes/titer plate, in dodging plate system, carry out experimentai batches.
In each case, by PDK1 sample His6-PDK1 (Δ 1-50) (3.4 nM), PDK1 substrate biotin-bA-
BA-KTFCGTPEYLAPEVRREPRILSEEEQEMFRDFDYIADWC (400 nM), 4 M ATP are (containing 0.2 Ci's33P-
ATP/ hole) and tested substance in 50 μ l normal experiment solution/hole 30 DEG C of incubations 60 minutes.With respective concentration (optionally with dilute
Release series) application tested substance.In the presence of there is no tested substance, compare.Use conventional method to terminate reaction, and wash
Wash.Kinase whose activity is measured with the radioactivity that TOP-Count mixes.In order to determine nonspecific kinase reaction (blank value),
Experimentai batches is carried out in the presence of 100 nM D-82041 DEISENHOFENs.
Evaluate
Putting of blank value (in the presence of D-82041 DEISENHOFEN, do not use tested substance) is deducted from other radioactive values all
Penetrating property (decompose/minute).Comparison (being not added with the kinase activity of tested substance) is set as 100%, other radioactive values all
(after deducting blank value) represents (percentage ratio for example, compareed) associatedly:
Calculate:
IC is measured by statistical procedure such as RS150Value (50% suppression).The IC of the compound according to the present invention50Data are shown in
In table 2.
APCI-MS (Atmosphere Pressure Chemical Ionization (APCI)-mass spectrography) (M+H)+。
The IC of the compound according to the present invention displayed in Table 150Data.
IKK ε-kinase assay (IKK ε)
Kinase assays is dodged plate mensuration as 384-hole and is carried out.
50 μ l cumulative volumes (10 mM MOPS, 10 mM magnesium acetates, 0.1 mM EGTA, 1 mM dithiothreitol, DTT, 0.02%
Brij35, the BSA of 0.1%, the BioStab of 0.1%, pH 7.5) in, at 30 DEG C, by 1 nM IKK ε, 800 nM biotinylations
I κ B α (19-42)-peptide (biotin-C6-C6-GLKKERLLDDRHDSGLDSMKDEE) and 10 M ATP (containing 0.3 Ci
's33P-ATP/ hole) with and without test compound incubation 120 min.Use 25 l 200 mM EDTA solution stopped reaction,
After room temperature 30 min, sucking filtration goes out, and is washed 3 times in hole by the NaCl solution of 100 l 0.9%.Use 3 M EMD
1126352 (BX-795), determine non-specific ratios's (blank) of kinase reaction.Radioactivity is measured in Topcount.Use
RS1 calculates IC50Value.
TBK1-kinase assay
The form dodging plate mensuration with 384-hole carries out kinase assays.
50 μ l cumulative volumes (10 mM MOPS, 10 mM magnesium acetates, 0.1 mM EGTA, 1 mM DTT, 0.02%
Brij35, the BSA of 0.1%, pH 7.5) in, at 30 DEG C, 0.6 nM TANK is combined kinases (TBK1), 800 nM biotinylations
Peptide (biotin-Ah-Ah-AKPKGNKDYHLQTCCGSLAYRRR) derivative for MELK-and 10 M ATP (containing 0.25 Ci
's33P-ATP/ hole) with and without test compound incubation 120 min.Use 25 l 200 mM EDTA solution stopped reaction,
After room temperature 30 min, sucking filtration goes out, and is washed 3 times in hole by the NaCl solution of 100 l 0.9%.Use 100 nM star spores
Rhzomorph, determines non-specific ratios's (blank) of kinase reaction.Radioactivity is measured in Topcount.RS1 is used to calculate IC50
Value.
Within a context, all temperature are all DEG C to represent.In the examples below, " conventional post processing " refers to: if necessary
If, add water;If it is necessary to according to the composition of end-product, pH value is adjusted to 2 to 10, with ethyl acetate or dichloromethane
Alkane extracts, and separates, and organic facies is dried over sodium sulfate, and evaporation is purified by silica gel chromatography and/or by crystallization.Silicon
Rf value on glue;Eluant: ethyl acetate/methanol 9:1.
Mass spectrography (MS): EI (electron impact ionization) M+
FAB (fast atom bombardment) (M+H)+
ESI (electrospray ionization) (M+H)+(unless otherwise noted).
Embodiment 1
Route map 1 shows the summary that how can prepare the 7-azaindole according to the present invention, but pyrrolopyrimidine
Such as " A14 " also can be obtained by this approach.
Route map 1
5-trifluoromethyl-PA 1 that iodate is obtained commercially at the standard conditions, obtains 2.Make its with 1-acetylene-
4-fluorobenzene changes into 3 in Sonogashira-reacts.Form pyrrolopyridine 4 in the basic conditions, and be oxidized to peracid
5.Under reproducibility chlorization condition, 6 are produced by means of phosphoryl chloride phosphorus oxychloride.After turning halogenation, obtain 7, protect NH functional group, obtain 8.?
After, under the conditions of Buchwald, obtain " A32 ".
Described order can also be walked around intermediate 8 and carry out, but yield will be deteriorated.
Embodiment 2
Following embodiment describes and substitutes CF with CN3Order, and ignore intermediate 7 and 8 because 6 direct
Buchwald-coupling is also possible to obtain end-product.
HPLC method: 1_100_2 (instrument: LaChrom)
Post: Chromolith Performance RP18e 100-3mm
Flow velocity: 2 ml/min (pump: L-7100)
Solvent orange 2 A: the HCOOH of water+0.05%
The HCOOH of solvent B: acetonitrile+0.04%
Wavelength: 220 nm (detector: L-7455)
Gradient: the A of 0-0.2 min:99%, the A of 0.2-3.8 min:99%--> B of 100%, 3.8-4.4
The B of min:100%, the B of 4.4-4.5 min:100%--> A, the A of 4.5-5.1 min:99% of 99%
LC-MS method: polar.M (instrument: Agilent 1100/1200 series)
Post: Chromolith Speed Rod RP18e-50-4.6
Flow velocity: 2.4ml/min
Solvent orange 2 A: the HCOOH of water+0.05%
The HCOOH of solvent B: acetonitrile+0.04%
WL:220 nm
The B of the B of the B of gradient: 0-2.8min:4% to 100%, 2.8-3.3min:100%.
N-(3-{ [5-cyano group-2-(4-fluorophenyl)-1H-pyrrolo-[2,3-b] pyridin-4-yl amino] methyl } pyridine-2-
Base) preparation of-N-methylmethanesulfonamide (" A9 ")
A) synthesis of 6-amino-5-iodine nicotinic acid nitrile
In flask merge 6-amino-3-pyridine carbonitrile (10.0 g, 0.081 mol), silver trifluoroacetate (25.5 g,
0.115 mol) and 160 ml 1,2-dichloroethanes, and heat 5 h under reflux.Add iodine (29.5 g, 0.116 mol),
And mixture is heated other 18 h.After cooling, mixture is filtered, and distribute between water and dichloroethanes.Use kieselguhr
(Celite) organic facies and aqueous phase are filtered.Aqueous phase is extracted completely, and the organic facies merged is merged, is dried and evaporation.By residual
Excess is dissolved in ethyl acetate, and washs with hypo solution.After removing solvent, obtain the 6.6 slightly yellow crystal of g and produce
Thing.It is reacted the most further;HPLC:2.57 min;LCMS:246 [M+H]+。
B) synthesis of 6-amino-5-(4-fluorophenylethynyl) nicotinic acid nitrile
Iodine compound (300 mg), Hydro-Giene (Water Science). (I) (20 mg) and carbonic acid prepared above is merged in three-neck flask
Caesium (1.7 g), and it is dried in a vacuum 1 h at 100 DEG C.Add THF (50 ml), 1-acetylene-4-fluorobenzene the most under a nitrogen
(250 mg) and Pd (dppf)2Cl2 x CH2Cl2 (78 mg)。
By this batch of material 100 DEG C of stirrings, in the meantime, black suspension is produced.For carrying out post processing, by the reaction of cooling
Mixture is added to the water, and is extracted with ethyl acetate subsequently.Organic facies is dried and evaporates.By chromatography purification residue,
To 220 mg title compounds.HPLC [retention time] 3.31 min; [M+H]+238。
C) synthesis of 2-(4-fluorophenyl)-1H-pyrrolo-[2,3-b] pyridine-5-carbonitriles
Under a nitrogen by previously-introduced for NaH (150 mg) in 5 ml NMP.Under agitation add alkynes prepared above
(220 mg;It is dissolved in 5 ml NMP), and stir 12 h at 60 DEG C.Produce into dark brown solution.Under agitation by this batch of material
It is added to the water.Form the thinnest crystalline precipitate thing, dissolved by adding ethyl acetate.After Xiang Fenliing, by organic
Wash, through Na by saturated NaCl solution mutually2SO4Being dried, sucking filtration goes out, and is evaporated in vacuo, and obtains residue.In this way
To title compound react the most further;
LC-MS: 238 [M+H]+; HPLC: 3.26 (Rt/min)。
D) synthesis of 2-(4-fluorophenyl)-7-Oxy-1 H-pyrrolo-[2,3-b] pyridine-5-carbonitriles
Bicyclic compound (260 mg) prepared above is dissolved in 20 ml ethylene glycol dimethyl ether by ultra sonic bath.
Add 270 mg metachloroperbenzoic acids, and mixture is stirred at room temperature 4 h.In order to make reaction complete, add other 135 mg
Acid, and mixture is stirred at room temperature other 12 h.Reactant mixture is evaporated in vacuo to give residue, adds water (slightly
Micro-muddiness), then use saturated K2CO3Solution is by mixture regulation to pH12 (visible precipitate thing).This batch of material is stirred at room temperature
Other 2 h, then sucking filtration goes out.It is dried in a vacuum precipitate;
Yield: 250 mg;LC-MS:254 [M+H]+;HPLC:2.77 (Rt/min).
E) synthesis of the chloro-2-of 4-(4-fluorophenyl)-1H-pyrrolo-[2,3-b] pyridine-5-carbonitriles
N-oxide prepared above for 250 mg is joined in 5 ml phosphoryl chloride phosphorus oxychlorides, and stirs 2 h at 80 DEG C.By cooling
Batch of material is carefully added in water, and at POCl3Completely after reaction, with NaOH regulation to pH 13.Then this it is extracted with ethyl acetate
Phase.Organic facies is through Na2SO4Being dried, sucking filtration goes out, and is evaporated in vacuo to give residue.Obtain 210 mg crude products, led to
Cross chromatography to be purified.Obtain 39 mg;HPLC:3.57 (Rt/min);LC-MS:272 [M+H]+。
F) synthesis of " A9 "
By chloro-for 4-2-(4-fluorophenyl)-1H-pyrrolo-[2,3-b] pyridine-5-carbonitriles (30 mg, 0.11 mmol), N-
(3-aminomethyl pyridine-2-base)-N-methylmethanesulfonamide (159 mg, 0.552 mmol) and N-ethyl diisopropylamine
(0.282 ml, 1.656 mmol) are suspended in 0.4 ml 1-Methyl-2-Pyrrolidone, and 170 DEG C of heating in microwave
40 min.After other 40 min, this reaction remains on the most completely, so adding N-(the 3-amino methyl of another equivalent
Pyridine-2-base)-N-methylmethanesulfonamide (31.8 mg, 0.110 mmol), and this batch of material is heated other 60 at 170 DEG C
min.For carrying out post processing, this batch of material is distributed between water and ethyl acetate, organic facies is dried (Na2SO4) and evaporate,
To brown oil, it is purified by chromatography;Yield: 17 mg (34%);LC-MS:451 [M+H]+;HPLC:3.07
(retention time/min).
Embodiment 3
Replacement is shown below synthesize:
Route map 2
The synthesis of 2 in route map 2
Under agitation last 10 minutes at 0 DEG C and 144 g m-CPBA (metachloroperbenzoic acid) portionings are added 50 g 7-
In azaindole solution in 1.5 L ethyl acetate.Add after terminating, mixture is stirred at room temperature other 1 h.Reaction knot
Shu Hou, leaches solid, and is dissolved in chloroform/methanol=9:1, and neutralizes with saturated sodium carbonate solution.After Xiang Fenliing, will
Organic facies is dried over sodium sulfate, and evaporated.The N-oxide as colorless solid is obtained using 60% yield (34 g);
。
The synthesis of 3
At 52 DEG C, 32 ml mesyl chlorides are added dropwise in the 18.5 g intermediate 2 solution in 1 L DMF.Add
After end, this batch of material is stirred other 2 h at 72 DEG C.For carrying out post processing, this batch of material is poured on trash ice, and uses 5N NaOH
Neutralize.Precipitate is leached and is dried.The 4-Cl-7-azaindole as colorless solid is obtained using 75% yield (16 g);
LCMS:(method A) 153.0 (M+H), retention time 2.10 min, 93.4% (maximum), 93.6% (254
nm).(TFA of method A-0.1% is at H2In O, the TFA of B-0.1% is in ACN: flow velocity-2.0 ml/min.Post: X Bridge
C8 (50 x 4.6mm, 3.5 μm+ve patterns);
。
The synthesis of 4
At 0 DEG C, 5 g NaH (60% on mineral oil) portioning is joined 16 g intermediate 3 in 500 ml THF
In solution.Add after terminating, mixture is stirred at a given temperature other 20 min, and is added dropwise over 22.3 in this temperature
G triisopropylsilyl chlorine.After reaction terminates, use saturated ammonium chloride solution post processing, dilute with water, and extract with petroleum ether
Take.The crude product obtained is used petroleum ether chromatographic isolation on silica gel.The product as colourless liquid is obtained using 92% (30g) yield
Thing 4;
LCMS:(method A) 309.2 (M+H), retention time 7.56 min, 93.4% (maximum);
。
The synthesis of 5
Last 30 min at-78 DEG C and 53 ml sec-BuLi are added dropwise to 11 g intermediate 4 in 250 ml THF
In solution.After 1 h, last 30 min and be added dropwise over 18 g iodine.While this batch of material is warmed to 0 DEG C, form suspension.
Use saturated ammonium chloride solution post processing, and be extracted with ethyl acetate.By the organic phase washed with water merged and the washing of saturated NaCL solution
And be dried with sodium sulfate.Obtain 5.25 g (53%) the chloro-5-of the product 4-iodo-1-triisopropyl monosilane as colorless solid
Base-1H-pyrrolo-[2,3-b] pyridine;LCMS:(method A) 435.0 (M+H), retention time 7.98 min, 96.9% (
Greatly).
The synthesis of 6
At 0 DEG C by 27 ml TBAF (tetra-n-butyl ammonium fluorides;1M solution in THF) join 11 g intermediate 5 and exist
In solution in 250 ml THF, and stir the mixture for other 30 min.Remove solvent the most in a vacuum, residue is molten
Solution, in ethyl acetate, is washed by water and saturated NaCl solution, and is dried by organic phase with sodium sulfate.With 99% yield after evaporation
(7 g) obtains the product 6 as light yellow solid;
LCMS:(method A) 279.0 (M+H), retention time 3.97 min, 63.5% (maximum).
Embodiment 4
From route map 2 it can be seen that from 8 to 9 functionalization not success.Therefore, described below how to use and replace
End-product is obtained for protection group strategy.
Route map 3 summarizes how to obtain target molecule.
In the course of reaction of intermediate 2, introduce the substituent group of 5, be shown as CF the most clearly3。
In the course of reaction of intermediate 4, introduce the substituent R of 2, and introduce 4 in the course of reaction of intermediate 6
R '.
Route map 3
Embodiment 5
N-methyl-2-[2-(6-morpholine-4-yl pyridines-3-base)-5-Trifluoromethyl-1 H-pyrrolo-[2,3-b] pyridine-4-
Base amino] preparation of Benzoylamide (" A33 ")
The TFA of LCMS method: A-0.1% is at H2In O, the TFA of B-0.1% is in ACN: flow velocity-2.0 ml/min.
Post: X Bridge C8 (50 x 4.6 mm, 3.5 μm)+ve pattern.
The TFA of HPLC method: A-0.1% is in H2O, and the TFA of B-0.1% is in ACN: flow velocity-2.0 ml/min.
Post: Xbridge C8 (50 x 4.6 mm, 3.5 μm).
A) conjunction of the iodo-1-of the chloro-5-of 4-(2-trimethylsilylethoxymethyl)-1H-pyrrolo-[2,3-b] pyridine
Become
The azaindole 6 deriving from route map 2 prepared above for 7 g is dissolved in 75 ml THF, and is cooled to 0 DEG C.?
This temperature portioning adds 1.2 g NaH (60% on mineral oil), and after 30 min, lasts 15 min and be added dropwise over chemistry
The SEMCl of metered amount.After reaction terminates, use aqueous ammonium chloride solution post processing, and be extracted with ethyl acetate.With water and saturated NaCl
Solution washs, and obtains the product as yellow oil using 88% (9g) yield;
LCMS:(method A) 409.0 (M+H), retention time 6.51 min, 57.4% (maximum).
B) 4-chloro-5-Trifluoromethyl-1-(2-trimethylsilylethoxymethyl)-1H-pyrrolo-[2,3-b] pyrrole
The synthesis of pyridine
By initiation material prepared above for 9 g and 4.2 g Hydro-Giene (Water Science) .s and 8.5 ml 2-fluorosulfonyl methyl difluoroacetates
It is suspended in together in 45 ml DMF, and warms 2h at 100 DEG C.After reaction terminates, mantoquita is leached, and by residue acetic acid
Ethyl ester extracts.Organic extract water and saturated NaCl solution are washed, and is dried with sodium sulfate.Evaporate with silica gel chromatography
The residue later obtained.Obtain 4.6 g (59%) colorless solid;LCMS:(method A) 351.0 (M+H), retention time
6.75 min, 43.3% (maximum);
。
C) the chloro-2-of 4-iodo-5-Trifluoromethyl-1-(2-trimethylsilyl-ethoxy methyl)-1H-pyrrolo-[2,
3-b] synthesis of pyridine
Construction unit prepared above for 4.6 g is dissolved in 50 ml THF, and is added dropwise over stoichiometry at-45 DEG C
The nBuLi of amount.After 30 min, it is added dropwise over 8.32 g iodine solution in 25 ml THF at a given temperature.Slowly temperature
Hot to room temperature, use saturated ammonium chloride solution post processing, and product separated as described above, obtain 4 g (64%) filbert solid
Body;LCMS:(method A) 477.0 (M+H), retention time 7.1 min, 74.6% (maximum);
。
D) the chloro-2-of 4-(6-morpholine-4-yl pyridines-3-base)-5-Trifluoromethyl-1-(2-trimethylsilylethoxy)
Methyl) synthesis of-1H-pyrrolo-[2,3-b] pyridine
By 290 mg 6-(morpholine-4-base) pyridine-3-pinacol borate, 19 mg acid chlorides, 34 mg S-Phos and
800 mg cesium carbonates add in intermediate prepared above for the 400 mg solution in 2.7 ml dioxanes and 0.3 ml water.Will be mixed
Compound warms 12 h at 60 DEG C, then with water and ethyl acetate at room temperature post processing.Obtain 250 mg (58%) as light brown
The title compound of color oil.
E) N-methyl-2-[2-(6-morpholine-4-yl pyridines-3-base)-5-Trifluoromethyl-1-(2-trimethyl silyl
Ethoxyl methyl)-1H-pyrrolo-[2,3-b] pyridin-4-yl amino] synthesis of Benzoylamide
By intermediate prepared above for 80 mg, 23 mg N-methylanthranilic Methanamide (anthranilamide),
148 mg cesium carbonates and the double diphenylphosphine-9,9-dimethyl xanthene (Xanthphos) of 18 mg 4,5-are suspended in 2 ml degassings
Dioxane in, and add 7 mg acid chlorides.Mixture is warmed 12 h at 100 DEG C, then carries out conventional post processing in room temperature
And purification.The title compound as yellow oil is obtained using 46% yield (45 mg).
LCMS:(method A) 626.8 (M+H), retention time 5.24 min, 74.7%.
F) synthesis of title compound " A33 "
30 mg initiation materials are dissolved in 5 ml THF, and add 0.25 ml 4N HCl solution.Mixture is being returned
Flow down and boil 5 h, and evaporate after the completion of reaction.Residue with ethyl acetate is dissolved, and neutralizes with sodium carbonate liquor.Conventional
12 mg (65%) white solid is obtained after operation.
(analysis sees embodiment form).
Embodiment 6
5-azaindole can be prepared according to following route map, such as, derive from embodiment form " A1-" A3 ":
Route map 4
A) under argon gas initiation material 2 (1.8 g) is dissolved in the acetonitrile of 150 ml degassings, and adds 7.8 ml
TBAF (1M solution in THF) keeps 10 min.It is subsequently added initiation material 1 (1.5 g), 1.2 ml DABCO, 34 mg
Hydro-Giene (Water Science). (I) and 340 mg tetrakis triphenylphosphine palladiums (0).This mixture is stirred 2 h at 90 DEG C.After cooling, in a vacuum
Remove solvent, residue is distributed between ethyl acetate and water, and the organic coarse finally obtained at chromatographed on silica gel is produced
Thing-fraction.Obtain the 970 slightly yellow viscous solids of mg 3;LCMS:337.0 (M+H), retention time 1.797 min.
B) solid 3 prepared above for 920 mg is dissolved in the sodium terachloraurate dihydrate (54 in 20 ml THF
Mg), and at 75 DEG C stir 48h.The reaction solution that will be cooled to room temperature is evaporated in vacuo, and with methylene chloride/methanol=
95.5 separate in silica gel spectrum.Obtain the 930 slightly yellow oil of mg;LCMS:337.0 (M+H), retention time 1.699 min.
C) intermediate 4 (125 mg) and 4-amino hydroxyindole (60 mg) are dissolved in 5 ml ethanol, and are adding
After several 4N HCl solution in dioxane, in microwave, heat 1h at 120 DEG C.70 mg title compound are obtained after filtration
Thing " A1 " (embodiment form is shown in analysis).
Embodiment 7
Purine derivative (imidazopyrimidine), such as " A4 "-" A6 ", but also include imidazopyridine derivatives, such as
Derive from " A17 " of embodiment form, can obtain via the order shown in route map 5.
Route map 5
A) 2-chlorine apellagrin methyl ester 2 (8.8 g) and methyl sulphonyl methylamine 1 (6.3 g) are dissolved in 180 ml and are dried
Dioxane in, and use argon-degassed.By double to 2.4 g cesium carbonates, 1.1 g acid chlorides and 4.3 g 4,5-diphenylphosphino-9,
9-dimethyl-9H-ton adds in this solution.After 100 DEG C of 2 h, reaction terminates.After conventional post processing, use acetic acid second
Ester/heptane=2:1 composes separating mixture at silica gel, obtains 9.7 g yellow oils, and it solidifies after storage;LCMS: 245.0
(M+H), retention time 1.315 min.
B) this intermediate of 7.9 g is dissolved in 70 ml THF and 70 ml water, and adds 2.7 g Lithium hydrates.In room
After temperature stirring 2 h, reaction completely, and with 2N HCl solution post processing.Mixture is extracted with ethyl acetate, and uses sodium sulfate
After drying, obtaining yellow solid, it reacts the most further;LCMS:231.0 (M+H), retention time 1.027 min.
C) 2-(N-methyl methyl sulfonamide) nicotinic acid obtained in this way by 1.6 g is suspended in 10 ml dichloromethane
In, and it is added dropwise over 0.6 ml thionyl chloride.This suspension is stirred 3h at 40 DEG C, and after adding several DMF, makes 3 to stand
The most further with 1 g 6-chloropyrimide-4,5-diamidogen at room temperature reaction 16 h.Remove solvent and obtain 2.3 g position isomers 4
1:3 mixture, reacts it to 48 h at 50 DEG C in 30 ml POCl3 the most further, obtains 5.Methylene chloride/methanol=
After the chromatography of 100:0-> 90:10, obtain 810 mg colorless solids;LCMS:339.0 (M+H), retention time 1.341
min。
D) 100 mg intermediate 5 are dissolved in 5 ml ethanol together with 70 mg 2-methoxyl group-4-morpholine-4-base aniline
In, and after adding several 4N HCl, in microwave, heat 2h at 120 DEG C.After preparation HPLC purification, with 32% yield
(49 mg) obtains product " A17 " (analysis sees embodiment form).
Embodiment 8
4-(4-fluorophenyl)-2-(piperidin-4-yl)-5-(trifluoromethyl)-1H-pyrrolo-[2,3-b] pyridine (" A91 ")
Synthesis
A) in flask merge the chloro-2-of 4-iodo-5-Trifluoromethyl-1-(2-trimethylsilylethoxymethyl)-
1H-pyrrolo-[2,3-b] pyridine (476 mg), 4-(4,4,5,5-tetramethyl-1,3-dioxaborolan alkane-2-base)-5,
6-dihydropyridine-1 (2H)-t-butyl formate (311 mg), double (di-t-butyl-(4-dimethylaminophenyl) phosphine) palladium chloride
(II) (14 mg) and cesium carbonate (954 mg), and be suspended in 4.5 ml dioxanes and 0.5 ml water.By this mixture 60
DEG C warm 12 h.After being cooled to room temperature, mixture is diluted with 10 ml water, and extracts completely by ethyl acetate.Mixture is entered
The conventional post processing of row, obtains 325 mg (61%) 4-(4-chloro-5-(trifluoromethyl)-the 1-((2-(three as slightly yellow foam
Methyl silicane base) ethyoxyl) methyl)-1H-pyrrolo-[2,3-b] pyridine-2-base)-5,6-dihydropyridine-1 (2H)-formic acid
The tert-butyl ester;
。
B) by intermediate (265 mg) prepared above, (4-fluorophenyl) boric acid (84 mg), double (di-t-butyl (4-bis-
Methylamino phenyl) phosphine) palladium chloride (II) (7 mg) and cesium carbonate (477 mg) be suspended in dioxane (2.7 ml)/water
In (0.3 ml), and stir 12 h at 60 DEG C.Mixture is carried out conventional post processing, obtains 165 mg (56%) as micro-Huang
4-(4-(4-fluorophenyl)-5-(trifluoromethyl)-1-((2-(trimethyl silyl) ethyoxyl) the methyl)-1H-pyrrole of color foam
Cough up also [2,3-b] pyridine-2-base)-5,6-dihydropyridine-1 (2H)-t-butyl formate.
LCMS:(method A) 594.2 (M+H), retention time 7.722 min, 65.9% (maximum), 72.6% (254
nm)。
C) intermediate (160 mg) prepared above is dissolved in dry methanol (10 ml), and adds 10% activity
Palladium on carbon (40 mg).Close flask with hydrogen balloon, and stir 1 h.It is subsequently filtered out insoluble component, and after evaporation, incites somebody to action thick
4-(4-(4-fluorophenyl)-5-(trifluoromethyl)-1-((2-(trimethyl silyl) ethyoxyl) the methyl)-1H-pyrrolo-of system
[2,3-b] pyridine-2-base) piperidines-1-t-butyl formate reacts the most further.For this purpose it is proposed, 80 mg are dissolved in 2 ml
In 4N HCl solution in dioxane, and warm 5 h at 60 DEG C.Obtain as colourless solid after conventional post processing and Careful purification
The title compound " A91 " of body.
Embodiment 9
2-(3-methoxyphenyl)-4-(1-methyl isophthalic acid H-pyrazoles-4-base)-5-(trifluoromethyl)-1H-pyrrolo-[2,3-
B] synthesis of pyridine (" A88 ")
A) in embodiment 8a) under as described in, use the chloro-2-of 4-iodo-5-Trifluoromethyl-1-(2-trimethyl silyl second
Epoxide methyl)-1H-pyrrolo-[2,3-b] pyridine (476 mg), 3-methoxyphenyl-boronic acid (152 mg), double (di-t-butyl
(4-dimethylaminophenyl) phosphine) palladium chloride (II) (14 mg) and cesium carbonate (954 mg).Obtain 275 mg (60%) to make
The chloro-2-of 4-(3-methoxyphenyl)-5-(trifluoromethyl)-1-((2-(trimethyl silyl) ethyoxyl) for colorless solid
Methyl)-1H-pyrrolo-[2,3-b] pyridine;
LCMS:(method A) 457.0 (M+H), retention time 7.94 min, 94.8% (maximum), 96.2% (254
nm)。
B) in embodiment 8b) under as described in, use the chloro-2-of 4-(3-methoxyphenyl)-5-(trifluoromethyl)-1-((2-
(trimethyl silyl) ethyoxyl) methyl)-1H-pyrrolo-[2,3-b] pyridine (228 mg), 1-methylpyrazole-4-boric acid
(75 mg), double (di-t-butyl-(4-dimethylaminophenyl) phosphine) palladium chloride (II) (7 mg) and cesium carbonate (477 mg).
Using 9% yield (48 mg) obtain 2-(3-the methoxyphenyl)-4-(1-methyl isophthalic acid H-pyrazoles-4-base) as light yellow solid-
5-(trifluoromethyl)-1-((2-(trimethyl silyl) ethyoxyl) methyl)-1H-pyrrolo-[2,3-b] pyridine;
LCMS:(method A) 503.0 (M+H), retention time 6.733 min, 86.5% (maximum), 90.4% (254
nm)。
C) as in embodiment 8c) Part II described in, be used herein 90 mg in embodiment 9b) under preparation in
Mesosome.The title compound " A88 " as colorless solid is obtained using 9.8% (6.4 mg) yield.
Embodiment 10
2-((2-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrrolo-[2,3-b] pyridin-4-yl) epoxide) benzonitrile
The synthesis of (" A93 ")
A) by 2-hydroxy benzonitrile (179 mg) and potassium carbonate (415 mg) solution in 5 ml DMSO 100 DEG C of heating
15 min, are subsequently adding the chloro-2-of 4-(4-fluorophenyl)-5-(trifluoromethyl)-1-((2-(trimethyl silyl) ethyoxyl) first
Base)-1H-pyrrolo-[2,3-b] pyridine (444 mg).Mixture is stirred other 12 h in given temperature, and adds 20 ml
Water carries out post processing.Mixture is extracted with ethyl acetate, and uses saturated NaCl solution and sodium sulfate to be dried.On silica gel
57 mg (11%) 2-((2-(4-fluorophenyl)-5-(trifluoromethyl)-the 1-((2-as hazel-color solid is obtained after chromatography
(trimethyl silyl) ethyoxyl) methyl)-1H-pyrrolo-[2,3-b] pyridin-4-yl) epoxide) benzonitrile;
LCMS:(method A) 528.3 (M+H), retention time 7.124 min, 93.2% (maximum), 76.6% (254
nm)。
B) as in embodiment 8c) Part II described in, be used herein 52 mg in embodiment 10a) under preparation
Intermediate.Obtain the title compound " A93 " as colorless solid.
Embodiment 11
N-(2-((2-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrrolo-[2,3-b] pyridin-4-yl) acetenyl) benzene
Base) synthesis of-N-methylmethanesulfonamide (" A27 ")
By CuI (19 mg), Pd (OAc)2(22 mg) and Cs2CO3(1.27g) 4-chloro-2-(4-fluorobenzene is joined
Base)-5-(trifluoromethyl)-1H-pyrrolo-[2,3-b] pyridine (628 mg), N-(2-ethynyl phenyl)-N-methylmethanesulfonamide
In (450 mg) de gassed solution in Isosorbide-5-Nitrae-dioxane (10 ml), and mixture is stirred 5 h at 100 DEG C.Conventional post processing
Title compound is obtained after purification with 70% yield (663 mg).
Embodiment 12
N-(2-(2-(2-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrrolo-[2,3-b] pyridin-4-yl) ethyl) benzene
Base) synthesis of-N-methylmethanesulfonamide (" A28 ")
The methanol being dried with 20 ml, under the pressure of 40 kg, make according to embodiment 11 preparation compound (50 mg) with
The palladium cylinder that the flow velocity of 20 ml/h is passed through in H-Cube.Title compound is obtained after purification with 65% yield (37 mg).
It is similarly obtained following compound with the embodiment of explanation.
$)
HPLC
Post: Xbridge C8 (50x4.6) mm, 3.5 m
Flowing phase:
The TFA of A:0.1% is at H2In O
The TFA of B:0.1% is in ACN
Flow velocity: 2.0 ml/min
Gradient:
The % of time B
0 5
8.0 100
8.1 100
8.5 5
10.0 5
2) LC-MS
Post: Xbridge C8,3.5 m, 4.6 x 50 mm;+ ve pattern
Solvent orange 2 A: the TFA of water+0.1%;
The TFA of solvent B:ACN+0.1%;
Flow velocity: 2 ml/min;
Gradient:
The % of Min B
0 05
8.0 100
8.1 100
8.5 05
10.0 05
%
Only 2 min run the time
%6
Only 6 min run the time
&
Post: Waters Xbridge (C18,50x2.1mm, 3.5 micron)
Flow velocity: 0.8 ml/min column temperature: 25 DEG C
Eluant A: acetonitrile 95%+10mM ammonium hydrogen carbonate 5%
Eluant B:10 mM ammonium bicarbonate aqueous solution
The A of A, the t=6 min 98% of linear gradient: the A of t=0 min 2%, t=3.5 min 98%
Detection: DAD (220-320 nm)
Detection: MSD (ESI pos/neg) mass range: 100 800.
Pharmacological test results
Table 1 suppresses according to the FAK of some compound of formula I of the present invention
IC50:<0.3-3 μM=B of 0.3 μM=A>3-50 μM=C.
Table 2 according to the IKK ε of some compound of formula I of the present invention-, PDK1-and TBK1-suppression
IC50:< 0.3 μM = A 0.3 - 3 μM = B > 3-50 μM = C。
Following embodiment relates to pharmaceutical preparation:
Embodiment A: injection vials
Use 2 N hydrochloric acid by the active component of 100 grams of Formulas I and 5 grams of disodium hydrogen phosphates the solution in 3 liters of double distilled waters adjust
Joint, to pH 6.5, aseptic filtration, pours in injection vials, aseptically lyophilizing aseptically sealing.Each note
Penetrate bottle and contain 5 milligrams of active component.
Embodiment B: suppository
By active component and the mixture fusing of 100 grams of soybean lecithins and 1400 grams of cupu oils of 20 grams of Formulas I, pour mould into
In tool and be allowed to cool.Each suppository contains 20 milligrams of active component.
Embodiment C: solution
By the active component of 1 gram of Formulas I, 9.38 grams of NaH in 940 milliliters of double distilled waters2PO4 ∙ 2 H2O, 28.48 grams
Na2HPO4 ∙ 12 H2O and 0.1 gram of benzalkonium chloride prepare solution.By pH regulator to 6.8, this solution is assigned to 1 liter and passes through spoke
Penetrate sterilization.This solution can use with eye drop form.
Embodiment D: ointment
Active component and 99.5 grams of vaseline of 500 milligrams of Formulas I are aseptically mixed.
Embodiment E: tablet
By the active component of 1 kilogram of Formulas I, 4 kg lactose, 1.2 kilograms of potato starch, 0.2 kilogram of Talcum and 0.1 kilogram
The mixture of magnesium stearate is the most so pressed into tablet, so that each tablet contains 10 milligrams of active component.
Embodiment F: dragee
With embodiment E compressed tablets similarly the most in a usual manner with sucrose, potato starch, Talcum, Tragacanth
Coating material coating with dyestuff.
Embodiment G: capsule
The active component of 2 kilograms of Formulas I is introduced in a usual manner in hard gelatin capsule so that each capsule contains 20 milligrams
This active component.
Embodiment H: ampulla
The active component of 1 kilogram of Formulas I solution sterile in 60 liters of double distilled waters is filtered, pours in ampoule, aseptic
Under the conditions of lyophilizing aseptically sealing.Each ampoule contains 10 milligrams of active component.
Sequence table
<110> Merck Patent GmbH
<120>bicyclic heteroaromatic compounds
<130> P 11/138-ve/ms
<150> DE102011111400.2
<151> 2011-08-23
<160> 3
<170> PatentIn version 3.5
<210> 1
<211> 39
<212> PRT
<213>artificial sequence
<220>
<223> PDK1
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223>biotin-bA-bA
<400> 1
Lys Thr Phe Cys Gly Thr Pro Glu Tyr Leu Ala Pro Glu Val Arg Arg
1 5 10 15
Glu Pro Arg Ile Leu Ser Glu Glu Glu Gln Glu Met Phe Arg Asp Phe
20 25 30
Asp Tyr Ile Ala Asp Trp Cys
35
<210> 2
<211> 23
<212> PRT
<213>artificial sequence
<220>
<223> IKKε
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223>biotin-C6-C6
<400> 2
Gly Leu Lys Lys Glu Arg Leu Leu Asp Asp Arg His Asp Ser Gly Leu
1 5 10 15
Asp Ser Met Lys Asp Glu Glu
20
<210> 3
<211> 23
<212> PRT
<213>artificial sequence
<220>
<223> TBK1
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223>biotin-Ah-Ah
<400> 3
Ala Lys Pro Lys Gly Asn Lys Asp Tyr His Leu Gln Thr Cys Cys Gly
1 5 10 15
Ser Leu Ala Tyr Arg Arg Arg
20
Claims (7)
1. selected from following compound and officinal salt, tautomer and stereoisomer, including their all proportions
Mixture:
2. medicine, its compound comprising at least one claim 1 and/or its pharmaceutically useful salt, tautomer and solid
Isomer, include the mixture of their all proportions, and comprise optional excipient and/or adjuvant.
3. the compound of claim 1 and pharmaceutically useful salt, tautomer and stereoisomer, include their all ratios
The mixture of example, in preparation purposes in the medicine treating following disease: the formation of tumor, cancer, tumor ,-growth and-expansion
Dissipate, arteriosclerosis, ophthalmic, inflammatory diseases, neural degeneration, psoriasis, restenosis, wound healing, transplant rejection, metabolic disease and
Disease of immune system, liver cirrhosis, diabetes and angiopathy.
4. the purposes of claim 3, wherein said ophthalmic be cause at the age degeneration of macula, choroidal neovascularization and
Diabetic retinopathy.
5. the purposes of claim 3, wherein said inflammatory diseases is arthritis and glomerulonephritis.
6. the purposes of claim 3, wherein said disease of immune system is autoimmune disease.
7. the purposes of claim 3, wherein said angiopathy is thrombosis and fibrosis.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE102011111400A DE102011111400A1 (en) | 2011-08-23 | 2011-08-23 | Bicyclic heteroaromatic compounds |
DE102011111400.2 | 2011-08-23 | ||
PCT/EP2012/003171 WO2013026516A1 (en) | 2011-08-23 | 2012-07-26 | Bicyclic heteroaromatic compounds |
Publications (2)
Publication Number | Publication Date |
---|---|
CN103748095A CN103748095A (en) | 2014-04-23 |
CN103748095B true CN103748095B (en) | 2016-11-30 |
Family
ID=
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