CN103833759A - Pteridinone derivatives as BLK and FLT3 inhibitors and applications thereof - Google Patents
Pteridinone derivatives as BLK and FLT3 inhibitors and applications thereof Download PDFInfo
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- CN103833759A CN103833759A CN201210484897.0A CN201210484897A CN103833759A CN 103833759 A CN103833759 A CN 103833759A CN 201210484897 A CN201210484897 A CN 201210484897A CN 103833759 A CN103833759 A CN 103833759A
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- 0 CC(C)(C)C(NC)NCC(N(C)CC(*)=C)=C(C)* Chemical compound CC(C)(C)C(NC)NCC(N(C)CC(*)=C)=C(C)* 0.000 description 7
- GAOHIOMKEDMGBG-SXHNFITHSA-N C/C(/CN)=C(/C=N\C(Cl)=C)\[N+]([O-])=O Chemical compound C/C(/CN)=C(/C=N\C(Cl)=C)\[N+]([O-])=O GAOHIOMKEDMGBG-SXHNFITHSA-N 0.000 description 1
- GFUIDOHQHWYMIX-ACAGNQJTSA-N CC(/N=C\C(C1)=C(N)N(C)C=C1I)=C Chemical compound CC(/N=C\C(C1)=C(N)N(C)C=C1I)=C GFUIDOHQHWYMIX-ACAGNQJTSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D475/00—Heterocyclic compounds containing pteridine ring systems
Abstract
The invention relates to pteridinone derivatives as BLK and FLT3 inhibitors and applications thereof. Particularly, the invention relates to a compound shown in the following formula I, a pharmaceutical composition containing the compound shown in the following formula I, and use of the compound in preparation of a drug for treating BLK and FLT3-mediated diseases or inhibiting BLK and FLT3.
Description
Technical field
The present invention relates to the synthetic of pteridinone compounds and the application in pharmaceutical chemistry and pharmacotherapeutics field thereof, specifically, the application of the pteridinone compounds that relates to different substituents in the medicine of preparation tumour, immunological disease.
Background technology
Protein tyrosine kinase (protein tyrosine kinase) is that the upper γ-phosphoric acid of a class catalysis ATP is transferred to the albumen in albumen particular amino acid residue, in intracellular signal transduction path, occupy very important status, and regulating a series of physiological processs such as Growth of Cells, differentiation, death.Existing data shows, exceedes 50% proto-oncogene and product thereof and all has protein tyrosine kinase activity, and their unconventionality expression will cause the disorder of cell life cycle, and then leads oncogenic generation.In addition, the unconventionality expression of Tyrosylprotein kinase is also closely related with transfer, the chemotherapy resistance etc. of tumour.
Bone-marrow-derived lymphocyte Tyrosylprotein kinase (B lymphocyte tyrosine kinase, BLK) belongs to non-receptor type Tyrosylprotein kinase, is equal to and is included into Src family with c-Src, Fyn, Lck, c-Yes, Fgr, Hck, Lyn.BLK is mainly expressed in bone-marrow-derived lymphocyte system, grows at the bone-marrow-derived lymphocyte except the plasmocyte phase expression that has BLK in whole process.BLK and relevant (the Molecular BiologyReports in b lymphocyte receptor (BCR) signal transduction downstream, 2011,38,4445-4453), and on the correlation function of pre-B lymphocyte acceptor there are impact (Journalof Experimental Medicine, 2003,198,1863-1873), therefore, BLK affects differentiation and the increment of bone-marrow-derived lymphocyte.The BLK that expresses constitutively activate in mouse B clone, T clone will cause respectively the generation (Proceedings of the National Academy of Sciences, 1998,95,7351-7356) of B cell lymphoma, t cell lymphoma.The more important thing is, in human skin t cell lymphoma (Cutaneous T-celllymphomas, CTCL), have the ectopic expression (Blood, 2009,113,5896-5904) of BLK, indicating that BLK can be used as potential antitumor drug target.In addition, BLK gene pleiomorphism and systemic lupus erythematous (systemic lupus erythematosus, SLE), morbidity closely related (The New England Journal of Medicine, 2008 of the autoimmune disorder such as rheumatoid arthritis (rheumatoid arthritis, RA), 358,900-909), the apoptosis of induction B cell can effectively be treated above-mentioned disease (Nat Reviews Immunology, 2006,6,394-403).
FMS sample Tyrosylprotein kinase 3(FMS-like tyrosine kinase 3, FLT3) belong to III receptor family tyrosine kinase, FLT3 play an important role (Oncogene, 1993,8,815-822) in the propagation of hematopoietic cell, differentiation and apoptosis process.After FLT3 is combined with FLT3L, activate multiple downstream signal paths, comprise STAT5, Ras/MAPK and PI3K/AKT path.Acute myelocytic leukemia (acutemyeloid leukemia about 1/3rd, AML) in patient, there is FLT3 sudden change (Blood, 2002,100,1532-1542), comprise amino acid whose disappearance or insertion (FLT3-TKD) sudden change in the activation ring of internal series-connection tumor-necrosis factor glycoproteins (FLT3-ITD) sudden change, tyrosine kinase domain of nearly membrane structure territory 14 and (or) 15 exons.In addition, have FLT3 high expression level phenomenon (Blood, 2004,103,1901) in acute leukemia patients, crossing of FLT3 expressed, FLT3-ITD suddenlys change and FLT3-TKD sudden change all can cause AML patient's prognosis mala.Therefore, FLT3 becomes the important target of AML treatment.Up to the present, there is no FLT3 inhibitor and be approved for clinical use, numerous clinical effectiveness in the FLT3 of clinical experimental stage inhibitor are still not ideal enough.
Therefore, improving small molecules kinase inhibitor clinical effective rate is just becoming the focus of current antineoplastic target medicament research and development, and the most promising strategy is, and exploitation is multiple kinase whose many target spots inhibitor relevant to disease (tumour) generation of target simultaneously.
Summary of the invention
Pteridinone compounds provided by the invention, has very high inhibition bone-marrow-derived lymphocyte kinases, FMS sample Tyrosylprotein kinase 3 activity, can be used for treating the exploitation of tumour, immunological disease medicine.
Pteridinone compounds of the present invention has structure shown in general formula I:
In formula,
A and B are for being with various substituent phenyl ring or five yuan or hexa-member heterocycle;
C is selected from arbitrary group as follows:
Wherein, X is selected from O, S and Se; R
1such as, for hydrogen, halogen atom, C1-C6 alkoxyl group (methoxyl group, oxyethyl group etc.), the optional C replacing
1-C
6alkyl (alkyl that for example halogen replaces), the optional aryl replacing (aryl that for example halogen replaces) or the optional aralkyl (for example arylmethyl) replacing;
R
2independently be selected from separately hydrogen, halogen, C1-C6 alkoxyl group, hydroxyl, the optional acyloxy replacing, amino, the optional amido replacing, the optional C replacing
1-C
6alkyl, CN, sulfonic group, amino-sulfonyl, formamyl, carboxyl, the optional alkoxyl formyl replacing, the optional phenyl replacing, the optional N-alkylpiperazinyl replacing, the optional morpholinyl replacing, the optional piperidyl replacing, the optional pyrryl replacing, optional the pyrrolidyl ,-NR replacing
ar
b, the optional pyridyl replacing; Wherein, R
aand R
bcan be selected from alkyl and alkenyl;
R
3independently be selected from separately hydrogen, halogen, C1-C6 alkoxyl group, hydroxyl, the optional acyloxy replacing, amino, the optional amido replacing, the optional C replacing
1-C
6alkyl, CN, sulfonic group, amino-sulfonyl, formamyl, carboxyl, the optional alkoxyl formyl replacing, the optional phenyl replacing, the optional N-alkylpiperazinyl replacing, the optional morpholinyl replacing, the optional piperidyl replacing, the optional pyrryl replacing, optional the pyrrolidyl ,-NR replacing
ar
b, the optional pyridyl replacing;
R
aand R
bindependently be selected from separately alkyl and alkenyl; With
M and n respectively do for oneself 0,1,2,3 or 4.
In one embodiment, C is following formula group:
In one embodiment, R
1be selected from H and alkyl.
In one embodiment, A and B are the optional phenyl replacing.
In one embodiment, R
2independently be selected from H, alkoxyl group, morpholinyl, halogen, N-alkyl-piperazinyl, piperidyl, pyrryl, pyrrolidyl, pyridyl ,-NR
ar
b, amido and formamyl (NH
2c (O)-), wherein, R
aand R
bcan be selected from alkyl and alkenyl.
In one embodiment, R
2independently be selected from 4-N-methylpiperazine base, N-morpholinyl, N-piperidyl, N-pyrryl, N-pyrrolidyl, N, N-ethylamino, N, N-methyl methylamino and 4-pyridyl.
In one embodiment, R
3independently be selected from hydrogen, amino, hydroxyl, amido, acyloxy and alkoxyl group, halogen, hydroxyl, alkyl, CN, sulfonic group, amino-sulfonyl, formamyl, carboxyl, morpholinyl, N-alkyl-piperazinyl, piperidyl, pyrryl, pyrrolidyl, pyridyl ,-NR
ar
b, amido and formamyl, wherein, R
aand R
bcan be selected from alkyl and alkenyl.
In one embodiment, R
3independently be selected from following group:
Wherein X is halogen.
In one embodiment, m is 1 or 2.
In one embodiment, n is 1,2,3 or 4.
In one embodiment, in the group shown in C, containing R
1the waviness of part be connected with C, and another part is connected with NH.
A preferred version of the present invention is that described compound has structure shown in general formula I I:
In formula,
Y is selected from N, CH;
Z is selected from N, CR
6;
R
1for hydrogen, halogen, C1-C6 alkoxyl group, the optional C replacing
1-C
6alkyl, the optional aryl replacing, the optional aralkyl replacing;
R
3independently be selected from hydrogen, amino, hydroxyl, amido, acyloxy and alkoxyl group, halogen, hydroxyl, alkyl, CN, sulfonic group, amino-sulfonyl, formamyl, carboxyl, morpholinyl, N-alkyl-piperazinyl, piperidyl, pyrryl, pyrrolidyl, pyridyl ,-NR
ar
b, amido and formamyl, wherein, R
aand R
bcan be selected from alkyl and alkenyl;
R
4, R
5, R
6and R
7independently be selected from separately hydrogen, halogen, C
1-C
6alkoxyl group,, hydroxyl, the optional acyloxy replacing, amino, the optional amido replacing, the optional C replacing
1-C
6alkyl, CN, sulfonic group, amino-sulfonyl, formamyl, carboxyl, the optional alkoxyl formyl replacing, the optional phenyl replacing, the optional N-alkylpiperazinyl replacing, the optional morpholinyl replacing, the optional piperidyl replacing, the optional pyrryl replacing, optional the pyrrolidyl ,-NR replacing
ar
b, the optional pyridyl replacing; Wherein, R
aand R
bcan be selected from alkyl and alkenyl; With
M is the integer of 0-3.
Of the present invention one more preferably scheme be that described compound has structure shown in general formula III:
In formula,
R
1for hydrogen, halogen, C1-C6 alkoxyl group, the optional C replacing
1-C
6alkyl, the optional aryl replacing, the optional aralkyl replacing;
R
3independently be selected from hydrogen, amino, hydroxyl, amido, acyloxy and alkoxyl group, halogen, hydroxyl, alkyl, CN, sulfonic group, amino-sulfonyl, formamyl, carboxyl, morpholinyl, N-alkyl-piperazinyl, piperidyl, pyrryl, pyrrolidyl, pyridyl ,-NR
ar
b, amido and formamyl, wherein, R
aand R
bcan be selected from alkyl and alkenyl;
R
5, R
6and R
7independently be selected from separately hydrogen, halogen, C
1-C
6alkoxyl group,, hydroxyl, the optional acyloxy replacing, amino, the optional amido replacing, the optional C replacing
1-C
6alkyl, CN, sulfonic group, amino-sulfonyl, formamyl, carboxyl, the optional alkoxyl formyl replacing, the optional phenyl replacing, the optional N-alkylpiperazinyl replacing, the optional morpholinyl replacing, the optional piperidyl replacing, the optional pyrryl replacing, optional the pyrrolidyl ,-NR replacing
ar
b, the optional pyridyl replacing; Wherein, R
aand R
bcan be selected from alkyl and alkenyl; With
M is 0,1,2 or 3.
In a preferred embodiment of formula III, R
1be selected from H and alkyl.
In a preferred embodiment of formula III, R
5and R
6independently be selected from H, alkoxyl group, morpholinyl, halogen, N-alkyl-piperazinyl, piperidyl, pyrrolidyl ,-NR
ar
b, amido and formamyl (NH
2c (O)-), wherein, R
aand R
bcan be selected from alkyl and alkenyl.
In a preferred embodiment of formula III, R
5be selected from H, alkoxyl group, morpholinyl, halogen, N-alkyl-piperazinyl, piperidyl, pyrryl, pyrrolidyl, pyridyl ,-NR
ar
b, amido and formamyl (NH
2c (O)-), wherein, R
aand R
bcan be selected from alkyl and alkenyl.
In a preferred embodiment of formula III, R
5be selected from H, alkoxyl group, morpholinyl, halogen, N-alkyl-piperazinyl, piperidyl, pyrryl, pyrrolidyl, pyridyl ,-NR
ar
b, amido and formamyl (NH
2c (O)-), wherein, R
aand R
bcan be selected from alkyl and alkenyl; R
6for H.
In a preferred embodiment of formula III, R
5be selected from halogen, 4-N-methylpiperazine base, N-morpholinyl, N-piperidyl, N-pyrryl, N-pyrrolidyl, N, N-diethylamino, N, N-dimethyl methyl amido and 4-pyridyl.
In a preferred embodiment of formula III, R
5and R
6for H, R
7for amido.
In a preferred embodiment of formula III, R
3independently be selected from amido, acyloxy and alkoxyl group.
In a preferred embodiment of formula III, R
3independently be selected from following group:
Wherein X is halogen.
In a preferred embodiment of formula III, m is 1.
In a preferred embodiment of formula III, m is 1, R
3at 4 of phenyl.
The preferred compound of the present invention is as shown in compound 001-032.
The present invention also comprise the compounds of this invention in preparation treatment by bone-marrow-derived lymphocyte kinases (BLK) or FMS sample Tyrosylprotein kinase 3(FLT3) purposes in the medicine of the disease of mediation.
In one embodiment, described disease is cancer.
In one embodiment, described cancer is selected from diffusivity B cell lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, follicular lymphoma, B cell prolymphocyte type leukemia, lymph-plasma cell lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmoma, extranodal marginal zone B cell lymphoma, lymphoma nodal marginal zone B cell, mantle cell lymphoma, thymus gland large B cell lymphoid tumor, intravascular large B cell lymphoma, lymphoma primary effusion, Burkitt lymphoma, lymphomatoid granulomatosis pain, lymphoblastic lymphoma, T cell lymphoblast leukemia, the granular Lymphocytic leukemia of T cell, aggressiveness NK-chronic myeloid leukemia, cutaneous T cell lymphoma, shaping large celllymphoma, periphery t cell lymphoma, adult T cell lymphoma, acute myelocytic leukemia, acute lymphoblastic leukemia, acute promyelocyte leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, CNL, acute nondifferentiated leukemia, retrogressive development large celllymphoma, prolymphocytic leukemia, teenager's myelomonocytic leukemia, adult T cell ALL, AML merges three pedigree myelodysplasias, mixed lineage leukemia, myelodysplastic syndrome, myelodysplastic syndrome, myeloproliferative disorder, multiple myeloma.
In one embodiment, described disease is immunological disease.
In one embodiment, described immunological disease is selected from sacroiliitis, lupus, inflammatory bowel, rheumatoid arthritis, psoriasis arthropathica, osteoarthritis, Still disease, adolescent arthritis, diabetes, myasthenia gravis, Hashimoto thyroiditis, Order thyroiditis, Graves disease, rheumatoid arthritis syndrome, multiple sclerosis, Guillain-Barre syndrome, acute transmitted encephalomyelitis, bronzed disease, aplastic anemia, autoimmune hepatitis, optic neuritis, argyraemia, graft versus host disease (GVH disease), transplant, blood transfusion anaphylaxis, transformation reactions, the allergy of I type, anaphylaxis conjunctivitis, allergic rhinitis, atopic dermatitis.
The present invention also comprises that the compounds of this invention suppresses bone-marrow-derived lymphocyte kinases (BLK) or FMS sample Tyrosylprotein kinase 3(FLT3 in preparation) medicine in purposes.
The present invention is the such use of formula III compound particularly preferably.
The present invention also comprises the pharmaceutical composition that contains the compounds of this invention, and this pharmaceutical composition also optionally contains pharmaceutically acceptable carrier, vehicle, thinner etc.
Embodiment
Further do following explanation for some terms that relate to herein:
Herein, " alkyl " refers to that carbon chain lengths is the saturated branched-chain or straight-chain alkyl of 1-10 carbon atom, and preferred alkyl comprises that a long 2-8 carbon atom, 1-6 are individual, a 1-4 carbon atom, a 3-8 carbon atom, 1-3 carbon atom alkyl not etc.The example of alkyl includes but not limited to methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, heptyl etc.
Alkyl can be replaced by one or more substituting groups, for example, replaced by halogen or haloalkyl.For example, the alkyl that alkyl can be replaced by 1-4 fluorine atom, or the alkyl alkyl that can be replaced by fluoro-alkyl.
Herein, " alkoxyl group " refers to the oxygen base being replaced by alkyl.Preferred alkoxyl group is the alkoxyl group of a long 1-6 carbon atom, the more preferably alkoxyl group of a long 1-4 carbon atom.The example of alkoxyl group includes but not limited to methoxyl group, oxyethyl group, propoxy-etc.
Herein, " alkenyl " ordinary representation has the univalence hydrocarbyl of at least one two key, conventionally contains 2-8 carbon atom, preferably contains 2-6 carbon atom, can be straight or branched.The example of alkenyl includes but not limited to vinyl, propenyl, pseudoallyl, butenyl, isobutenyl, hexenyl etc.
Herein, " alkynyl " ordinary representation has the univalence hydrocarbyl of at least one triple bond, conventionally contains 2-8 carbon atom, preferably contains 2-6 carbon atom, more generally contains 2-4 carbon atom, can be straight or branched.The example of alkenyl comprises ethynyl, proyl, isopropyl alkynyl, butynyl, isobutyl alkynyl, hexin base etc.
Herein, " halogen atom " or " halogen " refers to fluorine, chlorine, bromine and iodine.
" aryl " refers to the monocycle, dicyclo or the three ring aromatic groups that contain 6 to 14 carbon atoms, comprises phenyl, naphthyl, phenanthryl, anthryl, indenyl, Fluorene base, tetrahydro naphthyl, indanyl etc.Aryl optionally for example, is selected from following substituting group by 1-5 (, 1,2,3,4 or 5) and replaces: the alkyl (for example trifluoromethyl) that halogen, C1-4 aldehyde radical, C1-6 alkyl, cyano group, nitro, amino, hydroxyl, methylol, halogen replace, alkoxyl group (for example trifluoromethoxy), carboxyl, C1-4 alkoxyl group, ethoxycarbonyl, the N (CH that halogen replaces
3) and C1-4 acyl group etc., heterocyclic radical or heteroaryl etc.
Herein, " aralkyl " refers to the alkyl being replaced by aryl, the C1-C6 alkyl being for example substituted by phenyl.The example of aralkyl includes but not limited to arylmethyl, aryl ethyl etc., such as benzyl, styroyl etc.
For example, aryl can be selected from following group by 1-3 and replace: halogen ,-OH, C1-4 alkoxyl group, C1-4 alkyl ,-NO
2,-NH
2,-N (CH
3)
2, carboxyl, and ethoxycarbonyl etc.
" 5 yuan or 6 yuan of heterocycles " used herein include but not limited to contain 1-3 heteroatomic heterocyclic group that is selected from O, S and N, include but not limited to furyl, thienyl, pyrryl, pyrrolidyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, pyranyl, pyridyl, pyrimidyl, pyrazinyl, piperidyl, morpholinyl etc.
" heteroaryl " used herein refer to and contain 5-14 annular atoms, and have 6, and 10 or 14 electronics share in member ring systems.And contained annular atoms be carbon atom and from oxygen, nitrogen, sulphur optional 1-3 heteroatoms.Useful heteroaryl comprises piperazinyl, morpholinyl, piperidyl, pyrrolidyl, thienyl, furyl, pyranyl, pyrryl, imidazolyl, pyrazolyl, pyridyl, includes, but are not limited to 2-pyridyl, 3-pyridyl and 4-pyridyl, pyrazinyl, pyrimidyl etc.
Heteroaryl or 5 yuan or 6 yuan of heterocycles optionally for example, are selected from following substituting group by 1-5 (, 1,2,3,4 or 5) and replace: the alkyl (for example trifluoromethyl) that halogen, C1-4 aldehyde radical, C1-6 straight or branched alkyl, cyano group, nitro, amino, hydroxyl, methylol, halogen replace, alkoxyl group (for example trifluoromethoxy), carboxyl, C1-4 alkoxyl group, ethoxycarbonyl, the N (CH that halogen replaces
3) and C1-4 acyl group.
Herein, " acyloxy " refers to that structural formula is the group of " O-C (O)-R ", and wherein, R can be selected from alkyl, alkenyl and alkynyl.Described R is optionally substituted.
Herein, " amido " refers to that structural formula is the group of " R '-NH-C (O)-R ", and wherein, R ' can be selected from key or alkyl, and R can be selected from alkyl, alkenyl, alkynyl, by NR
ar
breplace alkyl, by NR
ar
bthe alkenyl and the NR that replace
ar
bthe alkynyl, the alkyl being replaced by halogen, the alkenyl being replaced by cyano group that replace,
wherein, R
aand R
bcan be selected from alkyl and alkenyl.
Herein; " optional replacement " refers to that its substituting group of modifying optionally for example, is selected from following substituting group by 1-5 (, 1,2,3,4 or 5) and replaces: the alkyl (for example trifluoromethyl) that halogen, C1-4 aldehyde radical, C1-6 straight or branched alkyl, cyano group, nitro, amino, hydroxyl, methylol, halogen replace, alkoxyl group (for example trifluoromethoxy), carboxyl, C1-4 alkoxyl group, ethoxycarbonyl, the N (CH that halogen replaces
3) and C1-4 acyl group.
The present invention includes a kind of pharmaceutical composition, said composition contains treats formula I of the present invention, the II of significant quantity or the compound of III or its pharmacy acceptable salt, and pharmaceutically acceptable carrier or vehicle.
The example of the pharmacy acceptable salt of the compounds of this invention includes but not limited to inorganic and organic acid salt, for example hydrochloride, hydrobromate, vitriol, Citrate trianion, lactic acid salt, tartrate, maleate, fumarate, mandelate and oxalate; And the inorganic and organic alkali salt forming with for example sodium hydroxyl, three (hydroxymethyl) amido methane (TRIS, amine trihydroxybutane) of alkali and N-METHYL-ALPHA-L-GLUCOSAMINE.
Although everyone demand is different, those skilled in the art can determine the optimal dose of every kind of activeconstituents in pharmaceutical composition of the present invention.Generally, compound of the present invention or its pharmacy acceptable salt, to Mammals oral administration every day, dose is according to approximately 0.0025 to 50 mgs/kg of body weight.But preferably approximately 0.01 to 10 milligrams of per kilogram oral administrations.For example, unit oral dosage can comprise approximately 0.01 to 50 milligrams, preferably the compounds of this invention of approximately 0.1 to 10 milligrams.Unitary dose can give one or many, and be one or more pieces every day, and every containing having an appointment 0.1 to 50 milligram, the eligibly the compounds of this invention of approximately 0.25 to 10 milligrams or its solvate.
Pharmaceutical composition of the present invention can be formulated into the dosage form that is applicable to various route of administration, includes but not limited to be formulated for outside intestines, subcutaneous, vein, muscle, intraperitoneal, transdermal, oral cavity, in sheath, encephalic, the form of nasal cavity or external application administration, is used for the treatment of tumour and other diseases.Dosage is effectively to improve or eliminate the dose of one or more illnesss.For the treatment of specified disease, significant quantity is the dose that is enough to improve or alleviate in some mode the symptom relevant with disease.Such dose can be used as single dose and uses, or can be according to effective treatment plan administration.Dosage is also permitted cure diseases, but administration is normally in order to improve the symptom of disease.Generally needing repetitively administered to realize required symptom improves.The dosage of medicine is according to patient's age, health and body weight, and the kind of concurrent treatment, the frequency for the treatment of, and required treatment benefit decides.
Pharmaceutical preparation of the present invention can give any Mammals, as long as they can obtain the result for the treatment of of the compounds of this invention.The most importantly mankind in these Mammalss.
It is various by bone-marrow-derived lymphocyte kinases (BLK) or FMS sample Tyrosylprotein kinase 3(FLT3 that compound of the present invention or its pharmaceutical composition can be used for treating) disease of mediation.Herein, be various cancers, immunological disease by the disease of BLK, FLT3 mediation.Described cancer includes but not limited to diffusivity B cell lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, follicular lymphoma, B cell prolymphocyte type leukemia, lymph-plasma cell lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmoma, extranodal marginal zone B cell lymphoma, lymphoma nodal marginal zone B cell, mantle cell lymphoma, thymus gland large B cell lymphoid tumor, intravascular large B cell lymphoma, lymphoma primary effusion, Burkitt lymphoma, lymphomatoid granulomatosis pain, lymphoblastic lymphoma, T cell lymphoblast leukemia, the granular Lymphocytic leukemia of T cell, aggressiveness NK-chronic myeloid leukemia, cutaneous T cell lymphoma, shaping large celllymphoma, periphery t cell lymphoma, adult T cell lymphoma, acute myelocytic leukemia, acute lymphoblastic leukemia, acute promyelocyte leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, CNL, acute nondifferentiated leukemia, retrogressive development large celllymphoma, prolymphocytic leukemia, teenager's myelomonocytic leukemia, adult T cell ALL, AML merges three pedigree myelodysplasias, mixed lineage leukemia, myelodysplastic syndrome, myelodysplastic syndrome, myeloproliferative disorder, multiple myeloma.Described immunological disease includes but not limited to sacroiliitis, lupus, inflammatory bowel, rheumatoid arthritis, psoriasis arthropathica, osteoarthritis, Still disease, adolescent arthritis, diabetes, myasthenia gravis, Hashimoto thyroiditis, Order thyroiditis, Graves disease, rheumatoid arthritis syndrome, multiple sclerosis, Guillain-Barre syndrome, acute transmitted encephalomyelitis, bronzed disease, aplastic anemia, autoimmune hepatitis, optic neuritis, argyraemia, graft versus host disease (GVH disease), transplant, blood transfusion anaphylaxis, transformation reactions, the allergy of I type, anaphylaxis conjunctivitis, allergic rhinitis, atopic dermatitis.
Pharmaceutical preparation of the present invention can be manufactured in a known manner.For example, by traditional mixing, granulate, ingot processed, dissolves, or freezing dry process manufacture.While manufacturing oral preparations, can be in conjunction with solid adjuvant material and active compound, selectivity grinding mixture.If need or add if desired after appropriate amount of addition agent, processing granular mixture, obtains tablet or lozenge core.
Particularly filler of suitable auxiliary material, for example carbohydrate is as lactose or sucrose, N.F,USP MANNITOL or sorbyl alcohol; Cellulose preparation or calcium phosphate, for example tricalcium phosphate or secondary calcium phosphate; And binding agent, for example starch paste, comprises W-Gum, wheat starch, Starch rice, yam starch, gelatin, tragacanth, methylcellulose gum, Vltra tears, Xylo-Mucine, or polyvinylpyrrolidone.If need, can increase disintegrating agent, such as starch above-mentioned, and carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, or alginic acid or its salt, as sodium alginate. auxiliary is flowing regulator and lubricant particularly, for example, silica, talcum, stearates, as magnesium calcium stearate, stearic acid or polyoxyethylene glycol.If needed, Ke Yi Give lozenge core core provides the suitable dressing that can resist gastric juice.For this reason, can apply concentrated saccharide solution.This solution can contain Sudan Gum-arabic, talcum, polyvinylpyrrolidone, polyoxyethylene glycol and/or titanium dioxide, paint solution and suitable organic solvent or solvent mixture.In order to prepare the dressing of resistant to gastric juice, can use suitable cellulose solution, for example cellulose acetate phthalic acid or Vltra tears phthalic acid.Can add dyestuff or pigment to the dressing of tablet or lozenge core core.For example,, for identifying or in order to characterize the combination of activeconstituents dosage.
Therefore, the present invention also provides the method for the disease of a kind of BLK for the treatment of or FLT3 mediation, and the method comprises that the object needing is with compound of the present invention or pharmaceutical composition.
Medication includes but not limited to the various medications that this area is known, can be determined according to patient's practical situation.These methods include but not limited to outside intestines, subcutaneous, vein, and muscle, intraperitoneal, transdermal, oral cavity, in sheath, encephalic, nasal cavity or external application administration.
The present invention also comprises the purposes in the medicine that the compounds of this invention uses in the disease of preparation treatment BLK or FLT3 mediation.
Inhibitor composite part
In following embodiment, will further illustrate the present invention.These embodiment are only for the present invention is described, but do not limit the present invention in any way.
Reagent and condition: (a) ArNH
2, DIPEA, Isosorbide-5-Nitrae-dioxane, room temperature; (b) ArNH
2, DIPEA, Isosorbide-5-Nitrae-dioxane, room temperature; (c) Pd/C, H
2, EtOH; (d) R
2cOCOOEt, HOAc, EtOH, refluxes; (e) trifluoroacetic acid, CH
2cl
2, 0 ° of C is to room temperature; (f) chloride of acid, Et
3n, CH
2cl
2, 0 ° of C is to room temperature, or chloride of acid, 1-Methyl-2-Pyrrolidone, CH
3cN, 0 ° of C is to room temperature.
In above-mentioned preparation flow, R
1-R
4definition as described above.Those skilled in the art can be according to the actual needs of preparing, and adopting the conventional various initial compounds that obtain in this area is raw material, prepares compound of the present invention.
Embodiment 1
The concrete synthetic method of above-mentioned steps a-f is as follows:
Synthetic (the step a) of (4-(the chloro-5-nitro-pyrimidine-4-of 2-amino) phenyl) t-butyl carbamate
Take the chloro-5-nitro-pyrimidine of 2,4-(95mg, 0.49mmol) and be placed in 10mL round-bottomed flask, add 3mL Isosorbide-5-Nitrae-dioxane, under room temperature, stir, separately get (4-aminophenyl) t-butyl carbamate (100mg, 0.48mmol), N, N-sec.-propyl ethamine (69mg, 0.53mmol) be dissolved in 2mL 1,4-dioxane, and be added drop-wise in above-mentioned reaction solution, after being added dropwise to complete, continue at room temperature to stir 0.5 hour, TLC tracks to raw material and transforms completely.Rotary evaporation is except desolventizing, and crude product separates through silica gel column chromatography (petrol ether/ethyl acetate=10:1, v/v), obtains (4-(the chloro-5-nitro-pyrimidine-4-of 2-amino) phenyl) t-butyl carbamate orange solids 144mg, productive rate 82%.
1H?NMR(400MHz，DMSO-d
6):δ10.38(s，1H)，9.46(s，1H)，9.12(s，1H)，7.49(d，J=8.6Hz，2H)，7.39(d，J=8.6Hz，2H)，1.49(s，9H)。
Synthetic (the step b) of (4-(2-(4-p-methoxy-phenyl amino)-5-nitro-pyrimidine-4-amino) phenyl) t-butyl carbamate
Take (4-(the chloro-5-nitro-pyrimidine-4-of 2-amino) phenyl) t-butyl carbamate (50mg, 0.14mmol), P-nethoxyaniline (17mg, 0.14mmol), N, N-diisopropylethylamine (18mg, 0.18mmol) be placed in 10mL round-bottomed flask, add 5mL Isosorbide-5-Nitrae-dioxane, under room temperature, stir 4 hours, TLC tracks to raw material and transforms completely.Rotary evaporation is except desolventizing, crude product is through silica gel column chromatography (petrol ether/ethyl acetate=4:1, v/v) purifying, obtain (4-(2-(4-p-methoxy-phenyl amino)-5-nitro-pyrimidine-4-amino) phenyl) t-butyl carbamate yellow solid 51mg, productive rate 82%.
1H?NMR(400MHz，DMSO-d
6):δ10.30(s，1H)，10.26(s，1H)，9.45(s，1H)，9.04(s，1H)，7.49(d，J=8.8Hz，2H)，7.45(d，J=8.8Hz，2H)，7.40(d，J=8.6Hz，2H)，6.75(d，J=8.6Hz，2H)，3.73(s，3H)，1.50(s，9H)。
Synthetic (the step c) of (4-(5-amino-2-(4-p-methoxy-phenyl amino) pyrimidine-4-amino) phenyl) t-butyl carbamate
Take (4-(2-(4-p-methoxy-phenyl amino)-5-nitro-pyrimidine-4-amino) phenyl) t-butyl carbamate (45mg, 0.10mmol) be placed in 50mL round-bottomed flask, add 20mL ethanol, 5mg palladium carbon (10%Pd), pass into hydrogen, under room temperature, stir and spend the night.After reaction finishes, suction filtration, filtrate is spin-dried for, crude product is through silica gel column chromatography (methylene chloride/methanol=5:1, v/v) purifying, obtain (4-(5-amino-2-(4-p-methoxy-phenyl amino) pyrimidine-4-amino) phenyl) t-butyl carbamate pale pink solid 30mg, productive rate 83%.
1H?NMR(400MHz，DMSO-d
6):δ9.23(s，1H)，8.42(s，1H)，8.10(s，1H)，7.62(d，J=9.2Hz，2H)，7.56(s，1H)，7.53(d，J=9.2Hz，2H)，7.40(d，J=8.8Hz，2H)，6.77(d，J=8.8Hz，2H)，3.70(s，3H)，1.48(s，9H)。
Synthetic (the step d) of (4-(2-(4-p-methoxy-phenyl amino)-7-oxo-8 (7H)-pteridyl) phenyl) t-butyl carbamate
Take (4-(5-amino-2-(4-p-methoxy-phenyl amino) pyrimidine-4-amino) phenyl) t-butyl carbamate (30mg, 0.07mmol) be placed in 10mL round-bottomed flask, add 0.29mL Glacial acetic acid, 5mL dehydrated alcohol, then add glyoxylic acid ethyl ester (50% toluene solution) (16mg, 0.08mmol), being heated to return stirring spends the night.After reaction finishes, there is solid to separate out, suction filtration, ethanol, ammoniacal liquor, deionized water wash for filter cake, dry.Obtain (4-(2-(4-p-methoxy-phenyl amino)-7-oxo-8 (7H)-pteridyl) phenyl) t-butyl carbamate yellow solid 18mg, productive rate 76%.
1H?NMR(400MHz，DMSO-d
6):δ10.08(s，1H)，9.64(s，1H)，8.84(s，1H)，8.03(s，1H)，7.65(d，J=8.4Hz，2H)，7.30-7.28(m，4H)，6.61(br，2H)，3.67(s，3H)，1.52(s，9H)。
Synthetic (the step e) of 8-(4-aminophenyl)-2-(4-p-methoxy-phenyl)-7 (8H)-pteridinones (compound 001)
Take (4-(2-(4-p-methoxy-phenyl amino)-7-oxo-8 (7H)-pteridyl) phenyl) t-butyl carbamate (18mg, 0.04mmol) be placed in 5mL round-bottomed flask, add 2mL methylene dichloride, under 0 ° of C, stir, add 0.5mL trifluoroacetic acid.Then continue to stir 1 hour under 0 ° of C, under room temperature, stir 1 hour.After reaction finishes, add saturated sodium bicarbonate solution to be neutralized to solution meta-alkalescence, with dichloromethane extraction (3 × 50mL), deionized water, saturated nacl aqueous solution washing for organic phase, anhydrous sodium sulfate drying, is spin-dried for solvent.Obtain 8-(4-aminophenyl)-2-(4-p-methoxy-phenyl)-7 (8H)-pteridinone yellow solid 14mg, productive rate 99%.
1h NMR (400MHz, DMSO-d
6): δ 10.04 (br, 1H), 8.81 (s, 1H), 8.00 (s, 1H), 7.40 (d, J=7.6Hz, 2H), 6.98 (d, J=8.4Hz, 2H), 6.73 (d, J=8.4Hz, 2H), 6.67 (b r, 2H), 5.44 (s, 2H), 3.70 (s, 3H).
13c NMR (100MHz, DMSO-d
6): δ 159.19,158.53,157.17,154.95,151.76,149.66,146.68,133.17,129.22,122.66,121.04,120.70,114.37,113.87,55.55.HRMS (ESI) calculated value C
19h
17n
6o
2[M+H]
+361.1413, experimental value 361.1414.
Synthetic (the step f) of N-(4-(2-(4-p-methoxy-phenyl amino)-7-oxo-8 (7H)-pteridyl) phenyl) acrylamide (compound 002)
Take 8-(4-aminophenyl)-2-(4-p-methoxy-phenyl)-7 (8H)-pteridinone (100mg, 0.28mmol) be placed in 100mL round-bottomed flask, add 50mL methylene dichloride, triethylamine (28mg, 0.28mmol), under 0 ° of C, stir, separately get acrylate chloride (29mg, 0.31mmol) and be dissolved in 5mL methylene dichloride, and be added drop-wise in above-mentioned reaction solution, be added dropwise to complete under rear room temperature and stir and spend the night.Rotary evaporation is except desolventizing, crude product is through silica gel column chromatography (dichloromethane/ethyl acetate=5:1, v/v) purifying, obtain N-(4-(2-(4-p-methoxy-phenyl amino)-7-oxo-8 (7H)-pteridyl) phenyl) acrylamide yellow solid 34mg, productive rate 30%.
1h NMR (400MHz, DMSO-d
6): δ 10.42 (s, 1H), 10.07 (br, 1H), 8.84 (s, 1H), 8.04 (s, 1H), 7.87 (d, J=8.8Hz, 2H), 7.38 (d, J=8.8Hz, 2H), 7.30 (br, 2H), 6.59 (br, 2H), 6.52 (dd, J=17.0,10.0Hz, 1H), 6.33 (dd, J=17.0,1.8Hz, 1H), 5.82 (dd, J=10.0,1.8Hz, 1H), 3.62 (s, 3H).
13c NMR (100MHz, DMSO-d
6): δ 163.90,159.28,158.51,156.68,155.02,151.44,146.65,139.72,133.00,130.18,129.50,127.72,121.02,120.61,113.77,55.40.HRMS (ESI) calculated value C
22h
19n
6o
3[M+H]
+415.1519, experimental value 415.1515.
Following compound all obtains according to the method for above-mentioned steps a-f is synthetic:
N-(4-(2-(4-morpholinyl phenyl amino)-7-oxo-8 (7H)-pteridyl) phenyl) acrylamide (compound 003)
1h NMR (400MHz, DMSO-d
6): δ 10.44 (s, 1H), 10.00 (s, 1H), 8.82 (s, 1H), 8.02 (s, 1H), 7.88 (d, J=8.0Hz, 1H), 7.36 (d, J=8.4Hz, 1H), 7.22 (br, 2H), 6.59 (br, 2H), 6.52 (dd, J=17.2,10.2Hz, 1H), 6.33 (d, J=17.2Hz, 1H), 5.85 (d, J=10.2Hz, 1H), 3.67 (b r, 4H), 2.92 (br, 4H) .HRMS (ESI) calculated value C
25h
24n
7o
3[M+H]
+470.1941, experimental value 470.1932.
N-(4-(2-(4-p-methoxy-phenyl amino)-6-methyl-7-oxo-8 (7H)-pteridyl) phenyl) acrylamide (compound 004)
1h NMR (400MHz, DMSO-d
6): δ 10.44 (s, 1H), 9.90 (br, 1H), 8.77 (s, 1H), 7.87 (d, J=8.8Hz, 2H), 7.50 (d, J=8.8Hz, 2H), 7.29 (br, 2H), 6.59 (br, 2H), 6.52 (dd, J=17.0,10.0Hz, 1H), 6.33 (dd, J=17.0,1.9Hz, 1H), 5.82 (dd, J=10.0,1.9Hz, 1H), 3.61 (s, 3H), 2.42 (s, 3H) .HRMS (ESI) calculated value C
23h
21n
6o
3[M+H]
+429.1675, experimental value 429.1671.
8-(3-aminophenyl)-2-(4-p-methoxy-phenyl)-7 (8H)-pteridinones (compound 005)
1h NMR (400MHz, DMSO-d
6): δ 10.06 (br, 1H), 8.83 (s, 1H), 8.01 (s, 1H), 7.41 (d, J=8.0Hz, 2H), 7.22 (t, J=8.0Hz, 1H), 6.75 (d, J=7.6Hz, 1H), 6.67 (br, 2H), 6.53 (s, 1H), 6.48 (d, J=7.6Hz, 1H), 5.35 (s, 2H), 3.69 (s, 3H) .HRMS (ESI) calculated value C
19h
17n
6o
2[M+H]
+361.1413, experimental value 361.1413.
N-(3-(2-(4-p-methoxy-phenyl amino)-7-oxo-8 (7H)-pteridyl) phenyl) acrylamide (compound 006)
1h NMR (400MHz, DMSO-d
6): δ 10.42 (s, 1H), 10.10 (br, 1H), 8.85 (s, 1H), 8.05 (s, 1H), 7.84 (d, J=8.0Hz, 1H), 7.78 (s, 1H), 7.56 (t, J=8.0Hz, 1H), 7.31 (br, 2H), 7.13 (d, J=8.0Hz, 1H), 6.58 (br, 2H), 6.45 (dd, J=16.8,10.4Hz, 1H), 6.26 (dd, J=16.8,1.6Hz, 1H), 5.77 (dd, J=10.4,1.6Hz, 1H), 3.65 (s, 3H) .HRMS (ESI) calculated value C
22h
19n
6o
3[M+H]
+415.1519, experimental value 415.1516.
N-(3-(2-(4-p-methoxy-phenyl amino)-7-oxo-8 (7H)-pteridyl) phenyl) propionic acid amide (compound 007)
1h NMR (400MHz, DMSO-d
6): δ 10.13 (s, 1H), 10.09 (s, 1H), 8.85 (s, 1H), 8.04 (s, 1H), 7.74 (d, J=8.0Hz, 1H), 7.71 (s, 1H), 7.53 (t, J=8.0Hz, 1H), 7.31 (br, 2H), 7.07 (d, J=8.0Hz, 1H), 6.59 (br, 2H), 3.67 (s, 3H), 2.33 (q, J=7.6Hz, 2H), 1.07 (t, J=7.6Hz, 3H) .HRMS (ESI) calculated value C
22h
21n
6o
3[M+H]
+417.1675, experimental value 417.1678.
N-(4-(2-(4-p-methoxy-phenyl amino)-7-oxo-8 (7H)-pteridyl) phenyl) propionic acid amide (compound 008)
1h NMR (400MHz, DMSO-d
6): δ 10.15 (s, 1H), 10.08 (br, 1H), 8.85 (s, 1H), 8.04 (s, 1H), 7.80 (d, J=8.4Hz, 2H), 7.35-7.33 (m, 4H), 6.61 (br, 2H), 3.67 (s, 3H), 2.41 (q, J=7.6Hz, 2H), 1.14 (t, J=7.6Hz, 3H) .HRMS (ESI) calculated value C
22h
21n
6o
3[M+H]
+417.1675, experimental value 417.1674.
4-(dimethylamino)-N-(4-(2-(4-p-methoxy-phenyl amino)-7-oxo-8 (7H)-pteridyl) phenyl)-2-butylene acid amides (compound 009)
1h NMR (400MHz, DMSO-d
6): δ 10.45 (s, 1H), 10.10 (br, 1H), 8.85 (s, 1H), 8.05 (s, 1H), 7.87 (d, J=8.8Hz, 2H), 7.37 (d, J=8.8Hz, 2H), 7.30 (br, 2H), 6.82 (td, J=15.4,6.0Hz, 1H), 6.60 (br, 2H), 6.40 (d, J=15.4Hz, 1H), 3.63 (s, 3H), 3.27 (d, J=5.2Hz, 2H), 2.33 (s, 6H) .HRMS (ESI) calculated value C
25h
26n
7o
3[M+H]
+472.2097, experimental value 472.2095.
4-(dimethylamino)-N-(3-(2-(4-p-methoxy-phenyl amino)-7-oxo-8 (7H)-pteridyl) phenyl)-2-butylene acid amides (compound 010)
1h NMR (400MHz, DMSO-d
6): δ 10.33 (s, 1H), 10.08 (br, 1H), 8.86 (s, 1H), 8.05 (s, 1H), 7.83 (d, J=8.0Hz, 1H), 7.78 (s, 1H), 7.55 (t, J=8.0Hz, 1H), 7.32 (br, 2H), 7.11 (d, J=8.0Hz, 1H), 6.74 (td, J=15.2,5.6Hz, 1H), 6.59 (br, 2H) 6.30 (d, J=15.2Hz, 1H), 3.66 (s, 3H), 3.06 (d, J=5.6Hz, 2H), 2.17 (s, 6H) .HRMS (ESI) calculated value C
25h
24n
7o
3[M+H]
+472.2097, experimental value 472.2094.
Vinylformic acid 4-(2-(4-p-methoxy-phenyl amino)-7-oxo-8 (7H)-pteridyl) phenyl ester (compound 011)
1h NMR (400MHz, DMSO-d
6): δ 10.15 (s, 1H), 8.87 (s, 1H), 8.06 (s, 1H), 7.51 (d, J=8.8Hz, 2H), 7.45 (d, J=8.8Hz, 2H), 7.31 (br, 2H), 6.69 (br, 2H), 6.60 (dd, J=17.2,1.6Hz, 1H), 6.51 (dd, J=17.2,9.9Hz, 1H), 6.22 (dd, J=9.9,1.6Hz, 1H), 3.67 (s, 3H) .HRMS (ESI) calculated value C
22h
18n
5o
4[M+H]
+416.1359, experimental value 416.1359.
4-(dimethylamino)-N-(4-(7-oxo-2-(phenyl amino)-8 (7H)-pteridyl) phenyl)-2-butylene acid amides (compound 012)
1h NMR (400MHz, DMSO-d
6): δ 10.37 (s, 1H), 10.19 (br, 1H), 8.90 (s, 1H), 8.08 (s, 1H), 7.87 (d, J=8.4Hz, 2H), 7.42 (d, J=7.6Hz, 2H), 7.38 (d, J=8.4Hz, 2H), 7.03 (br, 1H), 6.88 (t, J=7.6Hz, 1H), 6.82 (td, J=15.4,5.6Hz, 1H), 6.37 (d, J=15.4Hz, 1H), 3.14 (d, J=5.6Hz, 2H), 2.24 (s, 6H) .HRMS (ESI) calculated value C
24h
24n
7o
2[M+H]
+442.1991, experimental value 442.1989.
4-(dimethylamino)-N-(3-(7-oxo-2-(phenyl amino)-8 (7H)-pteridyl) phenyl)-2-butylene acid amides (compound 013)
1h NMR (400MHz, DMSO-d
6): δ 10.32 (s, 1H), 10.17 (s, 1H), 8.90 (s, 1H), 8.08 (s, 1H), 7.81-7.79 (m, 2H), 7.55 (t, J=8.0Hz, 1H), 7.41 (d, J=7.2Hz, 2H), 7.12 (d, J=8.0Hz, 1H), 7.01 (br, 2H), 6.87 (t, J=7.2Hz, 1H), 6.73 (td, J=15.2,5.6Hz, 1H), 6.28 (d, J=15.2Hz, 1H), 3.05 (d, J=5.6Hz, 2H), 2.16 (s, 6H) .HRMS (ESI) calculated value C
24h
24n
7o
2[M+H]
+442.1991, experimental value 442.1996.
N-(4-(7-oxo-2-(phenyl amino)-8 (7H)-pteridyl) phenyl) acrylamide (compound 014)
1h NMR (400MHz, DMSO-d
6): δ 10.44 (s, 1H), 10.19 (br, 1H), 8.90 (s, 1H), 8.09 (s, 1H), 7.88 (d, J=8.4Hz, 2H), 7.41-7.38 (m, 4H), 7.03 (br, 2H), 6.88 (t, J=7.2Hz, 1H), 6.53 (dd, J=16.8,10.4Hz, 1H), 6.35 (dd, J=16.8,1.6Hz, 1H), 5.84 (dd, J=10.4,1.6Hz, 1H) .HRMS (ESI) calculated value C
21h
17n
6o
2[M+H]
+385.1413, experimental value 385.1405.
N-(3-(7-oxo-2-(phenyl amino)-8 (7H)-pteridyl) phenyl) acrylamide (compound 015)
1h NMR (400MHz, DMSO-d
6): δ 10.42 (s, 1H), 10.19 (s, 1H), 8.91 (s, 1H), 8.09 (s, 1H), 7.84-7.81 (m, 2H), 7.57 (t, J=8.0Hz, 1H), 7.41 (br, 2H), 7.15 (d, J=7.6Hz, 1H), 7.02 (br, 2H), (6.87 t, J=7.6Hz, 1H), 6.45 (dd, J=16.8,10.4Hz, 1H), 6.26 (dd, J=16.8,1.6Hz, 1H), 5.77 (dd, J=10.4,1.6Hz, 1H) .HRMS (ESI) calculated value C
21h
17n
6o
2[M+H]
+385.1413, experimental value 385.1413.
N-(4-(2-(4-chloro-phenyl-amino)-7-oxo-8 (7H)-pteridyl) phenyl) acrylamide (compound 016)
1h NMR (400MHz, DMSO-d
6): δ 10.46 (s, 1H), 10.34 (s, 1H), 8.92 (s, 1H), 8.11 (s, 1H), 7.88 (d, J=8.8Hz, 2H), 7.41-7.36 (m, 4H), 7.06 (br, 2H), 6.53 (dd, J=16.8,10.4Hz, 1H), 6.36 (dd, J=16.8,1.6Hz, 1H), 5.84 (dd, J=10.4,1.6Hz, 1H) .HRMS (ESI) calculated value C
21h
16n
6o
2cl[M+H]
+419.1023, experimental value 419.1031.
N-(3-(2-(4-chloro-phenyl-amino)-7-oxo-8 (7H)-pteridyl) phenyl) acrylamide (compound 017)
1h NMR (400MHz, DMSO-d
6): δ 10.44 (s, 1H), 10.34 (br, 1H), 8.93 (s, 1H), 8.11 (s, 1H), 7.84 (s, 1H), 7.81 (d, J=8.4Hz, 1H), 7.59 (t, J=8.0Hz, 1H), 7.43 (d, J=7.2Hz, 2H), 7.15 (d, J=7.6Hz, 1H), 6.46 (dd, J=16.8,10.4Hz, 1H), 6.26 (dd, J=16.8,1.8Hz, 1H), 5.77 (dd, J=10.12,1.8Hz, 1H) .HRMS (ESI) calculated value C
21h
16n
6o
2cl[M+H]
+419.1023, experimental value 419.1027.
N-(3-(2-(4-morpholinyl phenyl amino)-7-oxo-8 (7H)-pteridyl) phenyl) acrylamide (compound 018)
1h NMR (400MHz, DMSO-d
6): δ 10.43 (s, 1H), 10.06 (s, 1H), 8.84 (s, 1H), 8.03 (s, 1H), 7.92 (br, 1H), 7.72 (s, 1H), 7.56 (t, J=7.6Hz, 1H), 7.27 (br, 2H), 7.12 (d, J=7.2Hz, 1H), 6.58 (br, 2H), 6.45 (dd, J=16.8,10.4Hz, 1H), 6.26 (d, J=16.8Hz, 1H), 5.78 (d, J=10.4Hz, 1H), 3.71 (br, 4H), 2.94 (br, 4H) .HRMS (ESI) calculated value C
25h
24n
7o
3[M+H]
+470.1941, experimental value 470.1939.
N-(4-(2-(4-(4-methyl isophthalic acid-piperazinyl) phenyl amino)-7-oxo-8 (7H)-pteridyl) phenyl) acrylamide (compound 019)
1h NMR (400MHz, DMSO-d
6): δ 10.51 (s, 1H), 10.06 (s, 1H), 8.83 (s, 1H), 8.03 (s, 1H), 7.89 (d, J=8.4Hz, 2H), 7.37 (d, J=8.4Hz, 2H), 7.17 (d, J=6.4Hz, 1H), 6.56-6.49 (m, 3H), 6.34 (d, J=16.8Hz, 1H), 5.85 (d, J=10.8Hz, 1H), 2.94 (br, 4H), 2.37 (br, 4H), 2.20 (s, 3H) .HRMS (ESI) calculated value C
26h
27n
8o
2[M+H]
+483.2257, experimental value 483.2259.
N-(3-(2-(4-(4-methyl isophthalic acid-piperazinyl) phenyl amino)-7-oxo-8 (7H)-pteridyl) phenyl) acrylamide (compound 020)
1h NMR (400MHz, DMSO-d
6): δ 10.45 (s, 1H), 10.06 (s, 1H), 8.84 (s, 1H), 8.04 (s, 1H), 7.93 (br, 1H), 7.73 (s, 1H), 7.56 (t, J=8.0Hz, 1H), 7.25 (br, 2H), 7.12 (d, J=8.0Hz, 1H), 6.57 (br, 2H), 6.46 (dd, J=16.8, 10.4Hz, 1H), 6.27 (dd, J=16.8, 1.8Hz, 1H), 5.78 (dd, J=10.4, 1.8Hz, 1H), 2.98 (br, 4H), 2.42 (br, 4H), 2.22 (s, 3H) .HRMS (ESI) calculated value C
26h
27n
8o
2[M+H]
+483.2257, experimental value 483.2259.
N-(3-(7-oxo-2-(4-(piperidino) phenyl amino)-8 (7H)-pteridyls) phenyl) acrylamide (compound 021)
1h NMR (400MHz, DMSO-d
6): δ 10.44 (s, 1H), 10.03 (s, 1H), 8.83 (s, 1H), 8.02 (s, 1H), 7.94 (br, 1H), 7.73 (s, 1H), 7.55 (t, J=8.0Hz, 1H), 7.24 (br, 2H), 7.11 (d, J=8.0Hz, 1H), 6.57 (br, 2H), 6.46 (dd, J=17.0, 10.2Hz, 1H), 6.26 (dd, J=17.0, 1.8Hz, 1H), 5.77 (dd, J=10.2, 1.8Hz, 1H), 2.95 (br, 4H), 1.57 (br, 4H), 1.49 (br, 2H) .HRMS (ESI) calculated value C
26h
26n
7o
2[M+H]
+468.2148, experimental value 468.2146.
N-(3-(7-oxo-2-(4-(1-pyrrolidyl) phenyl amino)-8 (7H)-pteridyls) phenyl) acrylamide (compound 022)
1h NMR (400MHz, DMSO-d
6): δ 10.40 (s, 1H), 9.92 (s, 1H), 8.79 (s, 1H), 7.99 (s, 1H), 7.90 (br, 1H), 7.74 (br, 1H), 7.54 (t, J=8.0Hz, 1H), 7.20 (br, 2H), 7.10 (d, J=8.0Hz, 1H), 6.46 (dd, J=17.0, 10.2Hz, 1H), 6.26 (dd, J=17.0, 1.8Hz, 1H), 6.20 (br, 2H), 5.77 (dd, J=10.2, 1.8Hz, 1H), 3.10 (br, 4H), 1.91 (br, 4H) .HRMS (ESI) calculated value C
25h
24n
7o
2[M+H]
+454.1991, experimental value 454.1995.
N-(3-(2-(4-(diethylamino) phenyl amino)-7-oxo-8 (7H)-pteridyl) phenyl) acrylamide (compound 023)
1h NMR (400MHz, DMSO-d
6): δ 10.42 (s, 1H), 9.92 (s, 1H), 8.80 (s, 1H), 8.00 (s, 1H), 7.92 (br, 1H), 7.73 (s, 1H), 7.53 (t, J=8.0Hz, 1H), 7.19 (br, 2H), 7.09 (d, J=8.0Hz, 1H), 6.46 (dd, J=17.0, 10.2Hz, 1H), 6.32 (br, 2H), 6.27 (dd, J=17.0, 1.8Hz, 1H), 5.76 (dd, J=10.2, 1.8Hz, 1H), 3.20 (br, 4H), 1.00 (t, J=6.8Hz, 6H) .HRMS (ESI) calculated value C
25h
26n
7o
2[M+H]
+456.2148, experimental value 456.2143.
N-(3-(2-(4-(kharophen) phenyl amino)-7-oxo-8 (7H)-pteridyl) phenyl) acrylamide (compound 024)
1h NMR (400MHz, DMSO-d
6): δ 10.43 (s, 1H), 10.16 (br, 1H), 9.78 (s, 1H), 8.87 (s, 1H), 8.06 (s, 1H), 7.82 (d, J=8.0Hz, 1H), 7.79 (s, 1H), 7.56 (t, J=8.0Hz, 1H), 7.32 (br, 2H), 7.23 (br, 2H), 7.15 (d, J=8.0Hz, 1H), 6.46 (dd, J=17.0, 10.2Hz, 1H), 6.25 (dd, J=17.0, 1.8Hz, 1H), 5.76 (dd, J=10.2, 1.8Hz, 1H), 1.98 (s, 3H) .HRMS (ESI) calculated value C
23h
20n
7o
3[M+H]
+442.1628, experimental value 442.1624.
4-(8-(3-acrylamide phenyl)-7-oxo-7,8-dihydropteridine-2-amino) benzamide (compound 025)
1h NMR (400MHz, DMSO-d
6): δ 10.43 (s, 1H), 10.40 (s, 1H), 8.95 (s, 1H), 8.13 (s, 1H), 7.86 (s, 1H), 7.79 (d, J=8.0Hz, 1H), 7.71 (br, 1H), 7.61 (t, J=8.0Hz, 1H), 7.55 (d, J=7.6Hz, 2H), 7.47 (br, 2H), 7.18 (d, J=7.6Hz, 2H), 6.44 (dd, J=17.0, 10.2Hz, 1H), 6.25 (dd, J=17.0, 1.8Hz, 1H), 5.76 (dd, J=10.2, 1.8Hz, 1H) .HRMS (ESI) calculated value C
22h
18n
7o
3[M+H]
+428.1471, experimental value 428.1476.
N-(3-(2-(4-p-methoxy-phenyl amino)-6-methyl-7-oxo-8 (7H)-pteridyl) phenyl) acrylamide (compound 026)
1h NMR (400MHz, DMSO-d
6): δ 10.42 (s, 1H), 9.93 (br, 1H), 8.78 (s, 1H), 7.83 (d, J=8.0Hz, 1H), 7.77 (s, 1H), 7.56 (t, J=8.0Hz, 1H), 7.31 (br, 2H), 7.11 (d, J=8.0Hz, 1H), 6.58 (br, 2H), 6.45 (dd, J=17.0,10.2Hz, 1H), 6.26 (d, J=17.0Hz, 1H), 5.77 (d, J=10.2Hz, 1H), 3.65 (s, 3H), 2.42 (s, 3H) .HRMS (ESI) calculated value C
23h
21n
6o
3[M+H]
+429.1675, experimental value 429.1675.
N-(3-(8-(4-p-methoxy-phenyl)-7-oxo-7,8-dihydropteridine-2-amino) phenyl) acrylamide (compound 027)
1h NMR (400MHz, DMSO-d
6): δ 10.17 (s, 1H), 10.01 (s, 1H), 8.89 (s, 1H), 8.07 (s, 1H), 7.63 (br, 1H), 7.33 (d, J=8.8Hz, 2H), 7.27 (d, J=8.0Hz, 1H), 7.23 (d, J=8.0Hz, 1H), 7.11 (d, J=8.8Hz, 2H), 6.89 (br, 1H), 6.46 (dd, J=17.0, 10.2Hz, 1H), 6.25 (dd, J=17.0, 1.8Hz, 1H), 5.74 (dd, J=10.2, 1.8Hz, 1H), 3.85 (s, 3H) .HRMS (ESI) calculated value C
22h
19n
6o
3[M+H]
+415.1519, experimental value 415.1519.
2-(3-aminophenyl amino)-8-(4-p-methoxy-phenyl)-7 (8H)-pteridinones (compound 028)
1h NMR (400MHz, DMSO-d
6): δ 9.91 (s, 1H), 8.85 (s, 1H), 8.04 (s, 1H), 7.35 (d, J=8.8Hz, 2H), 7.16 (d, J=8.8Hz, 2H), 6.68-6.65 (m, 3H), 6.16 (d, J=7.2Hz, 1H), 4.63 (s, 2H), 3.86 (s, 3H) .HRMS (ESI) calculated value C
19h
17n
6o
2[M+H]
+361.1413, experimental value 361.1411.
N-(4-(8-(4-p-methoxy-phenyl)-7-oxo-7,8-dihydropteridine-2-amino) phenyl) acrylamide (compound 029)
1h NMR (400MHz, DMSO-d
6): δ 10.19 (br, 1H), 10.03 (s, 1H), 8.87 (s, 1H), 8.05 (s, 1H), 7.36-7.34 (m, 6H), 7.16 (d, J=8.4Hz, 2H), 6.41 (dd, J=17.0,10.2Hz, 1H), 6.23 (dd, J=17.0,1.6Hz, 1H), 5.72 (dd, J=10.2,1.6Hz, 1H), 3.92 (s, 1H) .HRMS (ESI) calculated value C
22h
19n
6o
3[M+H]
+415.1519, experimental value 415.1524.
2-(4-aminophenyl amino)-8-(4-p-methoxy-phenyl)-7 (8H)-pteridinones (compound 030)
1h NMR (400MHz, DMSO-d
6): δ 9.87 (s, 1H), 8.77 (s, 1H), 7.97 (s, 1H), 7.32 (d, J=8.8Hz, 2H), 7.13 (d, J=8.8Hz, 2H), 7.08 (br, 2H), 6.24 (br, 2H), 4.84 (s, 2H), 3.88 (s, 3H) .HRMS (ESI) calculated value C
19h
17n
6o
2[M+H]
+361.1413, experimental value 361.1417.
N-(4-(2-(2-methoxyl group)-4-(4-methoxyl group-1-piperazinyl) phenyl amino)-7-oxo-8 (7H)-pteridyl) phenyl) acrylamide (compound 031)
1h NMR (400MHz, DMSO-d
6): δ 10.43 (s, 1H), 8.80 (s, 1H), 8.42 (s, 1H), 8.03 (s, 1H), 7.85 (d, J=8.6Hz, 2H), 7.34 (d, J=8.6Hz, 2H), 7.25 (d, J=8.8Hz, 1H), 6.54-6.48 (m, 2H), 6.33 (dd, J=17.0,1.6Hz, 1H), 6.02 (br, 1H), 5.84 (dd, J=10.2,1.6Hz, 1H), 3.76 (s, 3H), 3.02 (br, 4H), 2.43 (br, 4H), 2.23 (s, 3H) .HRMS (ESI) calculated value C
27h
29n
8o
3[M+H]
+513.2363, experimental value 513.2362.
N-(3-(2-(2-methoxyl group-4-(4-methyl isophthalic acid-piperazinyl) phenyl amino)-7-oxo-8 (7H)-pteridyl) phenyl) acrylamide (compound 032)
1h NMR (400MHz, DMSO-d
6): δ 10.41 (s, 1H), 8.80 (s, 1H), 8.44 (br, 1H), 8.02 (s, 1H), 7.86 (br, 1H), 7.71 (s, 1H), 7.52 (t, J=8.0Hz, 1H), 7.30 (d, J=7.6Hz, 1H), 7.09 (d, J=8.0Hz, 1H), 6.53 (s, 1H), 6.46 (dd, J=17.0, 10.2Hz, 1H), 6.26 (dd, J=17.0, 1.8Hz, 1H), 6.02 (br, 1H), 5.78 (dd, J=10.2, 1.8Hz, 1H), 3.76 (s, 3H), 3.04 (br, 4H), 2.44 (b r, 4H), 2.23 (s, 3H) .HRMS (ESI) calculated value C
27h
29n
8o
3[M+H]
+513.2363, experimental value 513.2361.
Embodiment 2
Biological activity test part
Compound provided by the invention carries out as follows to the extracorporeal extracorporeal suppression experiment of BLK, FLT3 kinase activity, and wherein BLK, FLT3 are purchased from BPS, with staurosporine (staurosporine) compound in contrast.
Preparation 1x kinases matrix damping fluid and stop buffer.1x kinases matrix damping fluid: 50mMHEPES, pH 7.5,0.0015%Brij-35,10mM magnesium chloride, 2mM DTT; Stop buffer: 100mM HEPES, pH 7.5,0.0015%Brij-35,0.2%Coating Reagent#3,50mMEDTA.Preparation compound solution.Compound is dissolved in to 100%DMSO, is mixed with 50 times of final solution of high inhibition concentration, and shifts the above-mentioned solution of 100 μ L in 96 orifice plates; Dilute successively above-claimed cpd solution to final desired concn; In two blank well of same 96 orifice plates, add 100 μ L 100%DMSO as contrasting without compound with without kinases, this orifice plate is as original orifice plate; Orifice plate in the middle of preparing, from original orifice plate transfer move 10 μ L compound solutions to another 96 orifice plate as middle orifice plate, toward the 1x kinase buffer liquid that adds 90 μ L in each hole of middle orifice plate, by middle orifice plate jolting 10 minutes.Prepare to analyze orifice plate, from the each hole of middle orifice plate, take out 5 μ L solution in 384 orifice plates, and repeat contrast.Kinase reaction.Preparation 2.5x kinase solution, 2.5x peptide solution, transferase 12 .5x kinase solution is to analyzing in orifice plate, analyze the 10%DMSO solution of orifice plate 5 μ L compounds, analyze the 2.5x kinase solution that adds 10 μ L in each hole of orifice plates toward 384 holes, at room temperature hatch 10 minutes, transferase 12 .5x peptide solution is in each hole, hatch after the corresponding time at 28 ° of C, add the stop buffer of 25 μ L to finish reaction.Gather experimental data in Caliper.Fitting of a curve copies experimental data from Caliper program, converts experimental data to inhibiting rate, and inhibition percentage=(Max-Conversion)/(Max-Min) * 100, " Max " represents DMSO contrast, and " Min " represents low contrast.
Test result is as following table 1.
Table 1 compound is to BLK, FLT3 kinase inhibiting activity
Claims (10)
1. there is the compound of structure shown in general formula I:
In formula,
A and B are for being with various substituent phenyl ring or five yuan or hexa-member heterocycle;
C is selected from arbitrary group as follows:
Wherein, X is selected from O, S and Se; R
1for hydrogen, halogen atom, C1-C6 alkoxyl group, the optional C replacing
1-C
6alkyl, the optional aryl replacing or the optional aralkyl replacing;
R
2independently be selected from separately hydrogen, halogen, C1-C6 alkoxyl group, hydroxyl, the optional acyloxy replacing, amino, the optional amido replacing, the optional C replacing
1-C
6alkyl, CN, sulfonic group, amino-sulfonyl, formamyl, carboxyl, the optional alkoxyl formyl replacing, the optional phenyl replacing, the optional N-alkylpiperazinyl replacing, the optional morpholinyl replacing, the optional piperidyl replacing, the optional pyrryl replacing, optional the pyrrolidyl ,-NR replacing
ar
b, the optional pyridyl replacing;
R
3independently be selected from separately hydrogen, halogen, C1-C6 alkoxyl group, hydroxyl, the optional acyloxy replacing, amino, the optional amido replacing, the optional C replacing
1-C
6alkyl, CN, sulfonic group, amino-sulfonyl, formamyl, carboxyl, the optional alkoxyl formyl replacing, the optional phenyl replacing, the optional N-alkylpiperazinyl replacing, the optional morpholinyl replacing, the optional piperidyl replacing, the optional pyrryl replacing, optional the pyrrolidyl ,-NR replacing
ar
b, the optional pyridyl replacing;
R
aand R
bindependently be selected from separately alkyl and alkenyl; With
M and n respectively do for oneself 0,1,2,3 or 4.
2. compound as claimed in claim 1, is characterized in that, described compound has structure shown in general formula I I:
In formula,
Y is selected from N, CH;
Z is selected from N, CR
6;
R
1for hydrogen, halogen, C1-C6 alkoxyl group, the optional C replacing
1-C
6alkyl, the optional aryl replacing, the optional aralkyl replacing;
R
3independently be selected from separately hydrogen, halogen, C1-C6 alkoxyl group, hydroxyl, the optional acyloxy replacing, amino, the optional amido replacing, the optional C replacing
1-C
6alkyl, CN, sulfonic group, amino-sulfonyl, formamyl, carboxyl, the optional alkoxyl formyl replacing, the optional phenyl replacing, the optional N-alkylpiperazinyl replacing, the optional morpholinyl replacing, the optional piperidyl replacing, the optional pyrryl replacing, optional the pyrrolidyl ,-NR replacing
ar
b, the optional pyridyl replacing;
R
4, R
5, R
6and R
7independently be selected from separately hydrogen, halogen, C
1-C
6alkoxyl group,, hydroxyl, the optional acyloxy replacing, amino, the optional amido replacing, the optional C replacing
1-C
6alkyl, CN, sulfonic group, amino-sulfonyl, formamyl, carboxyl, the optional alkoxyl formyl replacing, the optional phenyl replacing, the optional N-alkylpiperazinyl replacing, the optional morpholinyl replacing, the optional piperidyl replacing, the optional pyrryl replacing, optional the pyrrolidyl ,-NR replacing
ar
b, the optional pyridyl replacing;
R
aand R
bindependently be selected from separately alkyl and alkenyl; With
M and n respectively do for oneself 0,1,2,3 or 4.
3. compound as claimed in claim 1, is characterized in that, described compound has structure shown in general formula III:
In formula,
R
1for hydrogen, halogen, C1-C6 alkoxyl group, the optional C replacing
1-C
6alkyl, the optional aryl replacing, the optional aralkyl replacing;
R
3independently be selected from separately hydrogen, halogen, C1-C6 alkoxyl group, hydroxyl, the optional acyloxy replacing, amino, the optional amido replacing, the optional C replacing
1-C
6alkyl, CN, sulfonic group, amino-sulfonyl, formamyl, carboxyl, the optional alkoxyl formyl replacing, the optional phenyl replacing, the optional N-alkylpiperazinyl replacing, the optional morpholinyl replacing, the optional piperidyl replacing, the optional pyrryl replacing, optional the pyrrolidyl ,-NR replacing
ar
b, the optional pyridyl replacing;
R
5, R
6and R
7independently be selected from separately hydrogen, halogen, C
1-C
6alkoxyl group,, hydroxyl, the optional acyloxy replacing, amino, the optional amido replacing, the optional C replacing
1-C
6alkyl, CN, sulfonic group, amino-sulfonyl, formamyl, carboxyl, the optional alkoxyl formyl replacing, the optional phenyl replacing, the optional N-alkylpiperazinyl replacing, the optional morpholinyl replacing, the optional piperidyl replacing, the optional pyrryl replacing, optional the pyrrolidyl ,-NR replacing
ar
b, the optional pyridyl replacing;
R
aand R
bindependently be selected from separately alkyl and alkenyl; With
M and n respectively do for oneself 0,1,2,3 or 4.
4. compound as claimed in claim 3, is characterized in that,
R
1be selected from H and C1-C6 alkyl;
R
3be selected from hydrogen, amino, hydroxyl, amido, acyloxy and alkoxyl group, halogen, hydroxyl, alkyl, CN, sulfonic group, amino-sulfonyl, formamyl, carboxyl, morpholinyl, N-alkyl-piperazinyl, piperidyl, pyrryl, pyrrolidyl, pyridyl ,-NR
ar
b, amido and formamyl, wherein, R
aand R
bcan be selected from alkyl and alkenyl;
R
5be selected from H, alkoxyl group, morpholinyl, halogen, N-alkyl-piperazinyl, piperidyl, pyrryl, pyrrolidyl, pyridyl ,-NR
ar
b, amido and formamyl, wherein, R
aand R
bcan be selected from alkyl and alkenyl;
R
6be selected from H; With
R
7be selected from H or amido.
5. compound as claimed in claim 4, is characterized in that,
R
5be selected from halogen, 4-N-methylpiperazine base, N-morpholinyl, N-piperidyl, N-pyrryl, N-pyrrolidyl, N, N-ethylamino, N, N-dimethyl methyl amido and 4-pyridyl;
R
3be selected from any in following group:
Wherein X is halogen;
R
7for H.
6. be selected from following compound:
7. a pharmaceutical composition, is characterized in that, described pharmaceutical composition contains the compound described in any one or its pharmacy acceptable salt in claim 1-6, and pharmaceutically acceptable carrier or vehicle.
8. the disease that in claim 1-6, the compound described in any one is mediated by bone-marrow-derived lymphocyte Tyrosylprotein kinase, FMS sample Tyrosylprotein kinase 3 in preparation treatment or prevention, or suppress the purposes in the medicine of bone-marrow-derived lymphocyte Tyrosylprotein kinase, FMS sample Tyrosylprotein kinase 3.
9. purposes as claimed in claim 8, is characterized in that, described disease is cancer or immunological disease.
10. purposes as claimed in claim 9, it is characterized in that, described cancer is selected from diffusivity B cell lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, follicular lymphoma, B cell prolymphocyte type leukemia, lymph-plasma cell lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmoma, extranodal marginal zone B cell lymphoma, lymphoma nodal marginal zone B cell, mantle cell lymphoma, thymus gland large B cell lymphoid tumor, intravascular large B cell lymphoma, lymphoma primary effusion, Burkitt lymphoma, lymphomatoid granulomatosis pain, lymphoblastic lymphoma, T cell lymphoblast leukemia, the granular Lymphocytic leukemia of T cell, aggressiveness NK-chronic myeloid leukemia, cutaneous T cell lymphoma, shaping large celllymphoma, periphery t cell lymphoma, adult T cell lymphoma, acute myelocytic leukemia, acute lymphoblastic leukemia, acute promyelocyte leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, CNL, acute nondifferentiated leukemia, retrogressive development large celllymphoma, prolymphocytic leukemia, teenager's myelomonocytic leukemia, adult T cell ALL, AML merges three pedigree myelodysplasias, mixed lineage leukemia, myelodysplastic syndrome, myelodysplastic syndrome, myeloproliferative disorder, multiple myeloma,
Described immunological disease is selected from sacroiliitis, lupus, inflammatory bowel, rheumatoid arthritis, psoriasis arthropathica, osteoarthritis, Still disease, adolescent arthritis, diabetes, myasthenia gravis, Hashimoto thyroiditis, Order thyroiditis, Graves disease, rheumatoid arthritis syndrome, multiple sclerosis, Guillain-Barre syndrome, acute transmitted encephalomyelitis, bronzed disease, aplastic anemia, autoimmune hepatitis, optic neuritis, argyraemia, graft versus host disease (GVH disease), transplant, blood transfusion anaphylaxis, transformation reactions, the allergy of I type, anaphylaxis conjunctivitis, allergic rhinitis, atopic dermatitis.
Priority Applications (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210484897.0A CN103833759A (en) | 2012-11-23 | 2012-11-23 | Pteridinone derivatives as BLK and FLT3 inhibitors and applications thereof |
| CN201610325343.4A CN106008511B (en) | 2012-05-14 | 2013-04-02 | Pteridine ketone derivatives and its application as EGFR, BLK, FLT3 inhibitor |
| PCT/CN2013/073612 WO2013170671A1 (en) | 2012-05-14 | 2013-04-02 | Pteridine ketone derivative and applications thereof as egfr, blk, and flt3 inhibitor |
| JP2015511908A JP6114820B2 (en) | 2012-05-14 | 2013-04-02 | Pteridinone derivatives and applications as inhibitors of EGFR, BLK, FLT3 |
| DE112013002484.5T DE112013002484B4 (en) | 2012-05-14 | 2013-04-02 | Pteridine ketone derivative and applications of the same as EGFR, BLK and FLT3 inhibitor |
| US14/400,508 US9670213B2 (en) | 2012-05-14 | 2013-04-02 | Pteridine ketone derivative and applications thereof as EGFR, BLK, and FLT3 inhibitor |
| CN201380003282.4A CN103930425B (en) | 2012-05-14 | 2013-04-02 | Pteridinone derivative and the application as EGFR, BLK, FLT3 inhibitor thereof |
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