CN105294683B - Compound of CDK type small molecular inhibitors and application thereof - Google Patents

Compound of CDK type small molecular inhibitors and application thereof Download PDF

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CN105294683B
CN105294683B CN201510444529.7A CN201510444529A CN105294683B CN 105294683 B CN105294683 B CN 105294683B CN 201510444529 A CN201510444529 A CN 201510444529A CN 105294683 B CN105294683 B CN 105294683B
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compound
present
hydrogen
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disease
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CN105294683A (en
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刘兵
张英俊
聂凛凛
柏舜
管鸣宇
李旭珂
郑常春
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Guangdong HEC Pharmaceutical
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Abstract

The present invention relates to compound of CDK type small molecular inhibitors and application thereof, specifically, the present invention provides the new compound (as shown in formula (I)) and its pharmaceutical composition as CDK type small molecular inhibitors, further relate to the purposes of these compounds and composition in the disease for the treatment of hyperproliferative disorders, wherein, B rings, R1、R2、R3And L1It is defined as in the description.Novel compound of present invention is strong cell cycle protein dependent kinase 4 (cdk4) or cell cycle protein dependent kinase 6 (cdk6) inhibitor.

Description

Compound of CDK type small molecular inhibitors and application thereof
Invention field
The present invention relates to new compound and its pharmaceutical composition as CDK type small molecular inhibitors, these are further related to The purposes of compound and composition in the disease for the treatment of hyperproliferative disorders.
Background of invention
In recent years, tumour has surmounted angiocardiopathy, turns into global first big dead disease, and antineoplastic research has Important science and realistic meaning.Research finds, almost all of tumour all with cell cycle disorder caused by Unregulated cell growth, differentiation is obstructed and abnormal apoptosis is relevant.
The beginning of mammalian cell cycle, carry out and terminate by the very crucial cyclin of various cell growths Dependant kinase (CDK) compound regulates and controls.These compounds comprise at least catalysis (CDK is in itself) and regulation and control (cyclin) Subunit.For cell cycle regulating some prior compounds include cyclin A (CDK1- is also referred to as CDC2, And CDK2), cell periodic protein B 1-B3 (CDK1) and cyclin D1-D3 (CDK2, CDK4, CDK5, CDK6), cell Cyclin E protein (CDK2).These compounds each participate in the moment of cell cycle.CDK activity by with other albumen Of short duration association and be adjusted upon translation by the change of its intracellular targeting.Tumour occurs and CDK and its modulator Gene alteration and it is out of control be closely related, this shows that CDK inhibitor can be used for anticancer therapy.
CDK and its GAP-associated protein GAP are planned as a whole with playing some biochemical routes during driving the cell cycle in proliferative cell Key effect.Targeted therapies are used in general CDK or specific C DK, available for proliferative disorder for example：Cancer is controlled Treat.It is envisioned that CDK inhibitor can be used for treating other illnesss, such as viral infection, autoimmune disease and god Through degenerative disease etc..CDK targeted therapies are combined treatment with existing medicine, can obtain more preferable clinical effectiveness.Compared to many Existing antineoplastic, the treatment of CDK target anticancers has more potentiality advantages, because they are not direct mutual with DNA Effect, so the risk of secondary tumor development be able to should be reduced.
Although there is many CDK inhibitor class compounds to be disclosed, due to the pathology mediated by CDK, There is still a need for it is largely used to treat the high amount of drug of the obstacle relevant with CDK, particularly CDK4/6 inhibitor class medicine.
Summary of the invention
The obstacle relevant with protein kinase is largely used to, can be especially useful for treating or preventing or improving cancer, itself exempts from The compound of one or more symptoms of epidemic disease disease and infection class disease is still within needs.Compound provided by the invention Available for the activity of regulatory protein kinases such as CDK series, mainly adjust or suppress CDK1, CDK2, CDK4, CDK6 or CDK9 Activity, CDK4 or CDK6 activity is particularly adjusted or suppressed, there is preferable potential applicability in clinical practice.With existing similar chemical combination Thing is compared, and compound of the invention has inside more preferable drug effect, medicine for property and/or toxicological characteristics.The compounds of this invention Precursor structure compared with prior art, has entirely different structure, while prior art is not given to the technical inspiration of correlation, The compounds of this invention has to CDK4/6 preferably inhibitory action, has prominent substantive distinguishing features.
On the one hand, the present invention provides a kind of compound, and it is the compound as shown in formula (I), or the chemical combination shown in formula (I) The stereoisomer of thing, geometric isomer, dynamic isomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically Acceptable salt or prodrug,
Wherein：
B rings are
Wherein, Y, Y1And Y2It is each independently-C (R4)2- ,-N (R5)-,-O- ,-S (=O)t- or-C (=O)-；
Y3, Y4, Y5, Y6, Y8And Y7It is each independently CR4Or N；
R1And R2It is each independently hydrogen, fluorine, chlorine, bromine, hydroxyl, C1-4Alkyl, C1-4Haloalkyl or C1-4Alkoxy；
L1For key ,-(C (R4c)2)n1- ,-(C (R4c)2)n1- C (=O)-N (R5c)-(C(R4c)2)n1- ,-(C (R4c)2)n1-N (R5c)-(C(R4c)2)n1- ,-(C (R4c)2)n1-O-(C(R4c)2)n1- ,-(C (R4c)2)n1- S (=O)t-(C(R4c)2)n1- or-(C (R4c)2)n1- C (=O)-(C (R4c)2)n1-；
R3For hydrogen, C5-12The miscellaneous bicyclic group of spiral shell, C5-12The miscellaneous bicyclic group of bridge, C5-12Condense miscellaneous bicyclic group, C3-9Cycloalkyl, C3-9It is miscellaneous Ring group or C1-9Heteroaryl；
Each R4cAnd R4It independently is hydrogen, C1-6Alkyl, hydroxyl, fluorine, chlorine, bromine, carboxyl, amino, C1-6Alkoxy, H2N- (CH2)n-, N (R6R7)-C (=O)-, aldehyde radical, H- (CH2)n- O-C (=O)-(CH2)n-, H- (CH2)n-O-(CH2)n-, CN- (CH2)n- C (=O)-, C3-9Heterocyclic radical, C1-9Heteroaryl, C1-6Haloalkyl or C1-6Alkylamino；
Each R5cAnd R5It independently is hydrogen, C1-6Alkyl, C1-6Haloalkyl, H- (C (R4)2)n- O-C (=O)-(C (R4)2)n-, (R6R7)N-(C(R4)2)n-, HO- (C (R4)2)n- C (=O)-, N (R6R7)-C (=O)-, HO- (C (R4)2)n-, H- (C (R4)2)n- O-(C(R4)2)n-, H- (C (R4)2)n-SO2-(C(R4)2)n-, H- (C (R4)2)n- C (=O)-(C (R4)2)n-, CN- (C (R4)2)n- C (=O)-, H- (C (R4)2)n- O-C (=O)-C (=O)-(C (R4)2)n-, C3-9Heterocyclic radical or C1-9Heteroaryl；
Each n and n1 independently are 0,1,2,3 or 4；
Each t independently is 0,1, or 2；
Each R6And R7It independently is hydrogen, C1-6Alkyl, hydroxyl, carboxyl, amino, C1-6Alkoxy, H2N-(CH2)n-, NH2-C (=O)-, aldehyde radical, H- (CH2)n- O-C (=O)-(CH2)n-, C3-9Heterocyclic radical, C1-9Heteroaryl, C1-6Haloalkyl or C1-6Alkane ammonia Base；
The subformula that described B is represented is optionally independently by hydrogen, C1-6Alkyl, fluorine, chlorine, bromine, amino, hydroxyl, carboxyl, C1-6Alkoxy, C1-6Haloalkyl, (R6R7)N-(C(R4)2)n-, N (R6R7)-C (=O)-, H- (C (R4)2)n- O-C (=O)-(C (R4)2)n-, HO- (C (R4)2)n- C (=O)-, HO- (C (R4)2)n-, H- (C (R4)2)n-O-(C(R4)2)n-, H- (C (R4)2)n- SO2-(C(R4)2)n-, H- (C (R4)2)n- C (=O)-(C (R4)2)n-, CN- (C (R4)2)n- C (=O)-, H- (C (R4)2)n-O-C (=O)-C (=O)-(C (R4)2)n-, cyano group or monosubstituted or identical or different polysubstituted of nitro；
Described R1, R2, R5c, R3And R5Described in alkyl, alkoxy, haloalkyl, alkylamino, the miscellaneous bicyclic group of spiral shell, bridge Miscellaneous bicyclic group, condense miscellaneous bicyclic group, heterocyclic radical, heteroaryl, aryl, cycloalkyl, H- (C (R4)2)n- O-C (=O)-(C (R4)2 )n-, (R6R7)N-(C(R4)2)n-, HO- (C (R4)2)n- C (=O)-, N (R6R7)-C (=O)-, HO- (C (R4)2)n-, H- (C (R4)2)n-O-(C(R4)2)n-, H- (C (R4)2)n-SO2-(C(R4)2)n-, H- (C (R4)2)n- C (=O)-(C (R4)2)n-, CN- (C (R4)2)n- C (=O)-and H- (C (R4)2)n- O-C (=O)-C (=O)-(C (R4)2)n-, optionally independently by R8Monosubstituted or phase Same or different is polysubstituted；
Each R8It independently is hydrogen, oxo (=O), C1-6Alkyl, fluorine, chlorine, bromine, amino, hydroxyl, carboxyl, C1-6Alkoxy, C1-6Alkylamino, C1-6Haloalkyl, cyano group, C3-9Heterocyclic radical, C1-9Heteroaryl, H- (CH2)n- O-C (=O)-(CH2)n-, H2N- (CH2)n-, H- (CH2)n-SO2-(CH2)n-, HO- (CH2)n-, HO- (CH2)n- C (=O)-, NH2- C (=O)-, CN- (CH2)n-C (=O)-, C3-9Cycloalkyl or nitro；Each R8Described in alkyl, alkoxy, alkylamino, haloalkyl, H- (CH2)n- O-C (= O)-(CH2)n-, H2N-(CH2)n-, H- (CH2)n-SO2-(CH2)n-, HO- (CH2)n- C (=O)-, HO- (CH2)n-, NH2- C (= O)-, heterocyclic radical, cycloalkyl and heteroaryl are optionally independently by R9Monosubstituted or identical or different is polysubstituted；
Each R9It independently is hydrogen, oxo (=O), C1-6Alkyl, fluorine, chlorine, bromine, amino, hydroxyl, carboxyl, C1-6Alkoxy, C1-6Alkylamino, C1-6Haloalkyl, aldehyde radical, cyano group, HO- (C (R4)2)n-, H- (C (R4)2)n- O-C (=O)-(C (R4)2)n-, CN-C(R4)2- C (=O)-, H2N-(C(R4)2)n-, H- (C (R4)2)n-SO2-(C(R4)2)n-, HO- (C (R4)2)n- C (=O)-, N (R6R7)-C (=O)-, C3-9Heterocyclic radical, C1-9Heteroaryl, C3-9Cycloalkyl or nitro.
In some embodiments, compound of the present invention, it is the compound as shown in formula (II) or formula (III), or The stereoisomer of compound shown in formula (II) or formula (III), geometric isomer, dynamic isomer, nitrogen oxides, hydration Thing, solvate, metabolite, pharmaceutically acceptable salt or prodrug,
Wherein, whenForWhen, T1For Y6；
WhenForWhen, T1For Y1；
Wherein, R1, R2, R3, L1, Y, Y1, Y2, Y3, Y4, Y5And Y6With implication as described in the present invention.
In some embodiments,
Each R5cAnd R5It independently is hydrogen, C1-4Alkyl, C1-4Haloalkyl, H- (C (R4)2)n- O-C (=O)-(C (R4)2)n-, (R6R7)N-(C(R4)2)n-, HO- (C (R4)2)n- C (=O)-, N (R6R7)-C (=O)-, HO- (C (R4)2)n-, H- (C (R4)2)n- O-(C(R4)2)n-, H- (C (R4)2)n-SO2-(C(R4)2)n-, H- (C (R4)2)n- C (=O)-(C (R4)2)n-, CN- (C (R4)2)n- C (=O)-, H- (C (R4)2)n- O-C (=O)-C (=O)-(C (R4)2)n-, C3-6Heterocyclic radical or C1-9Heteroaryl；
Each R4cAnd R4It independently is hydrogen, H2N-(CH2)n-, N (R6R7)-C (=O)-, H- (CH2)n- O-C (=O)- (CH2)n-, CN- (CH2)n- C (=O)-, H- (CH2)n-O-(CH2)n-, C1-4Alkyl, hydroxyl, fluorine, chlorine, bromine, carboxyl, amino, C1-4 Alkoxy, C3-6Heterocyclic radical, C1-9Heteroaryl, C1-4Haloalkyl or C1-4Alkylamino；
Each R6And R7It independently is hydrogen, C1-4Alkyl, hydroxyl, carboxyl, amino, C1-4Alkoxy, H2N-(CH2)n-, NH2-C (=O)-, H- (CH2)n- O-C (=O)-(CH2)n-, C3-9Heterocyclic radical, C1-9Heteroaryl, C1-4Haloalkyl or C1-4Alkylamino；
Wherein, each n has implication as described in the present invention.
In some embodiments,
Each R5cAnd R5It independently is H- (C (R4)2)n- O-C (=O)-(C (R4)2)n-, (R6R7)N-(C(R4)2)n-, HO- (C (R4)2)n- C (=O)-, N (R6R7)-C (=O)-, HO- (C (R4)2)n-, H- (C (R4)2)n-O-(C(R4)2)n-, H- (C (R4)2)n- SO2-(C(R4)2)n-, H- (C (R4)2)n- C (=O)-(C (R4)2)n-, CN- (C (R4)2)n- C (=O)-, H- (C (R4)2)n-O-C (=O)-C (=O)-(C (R4)2)n-, hydrogen, trifluoromethyl, 2- fluoro ethyls, 3,3,3- trifluoro propyls, methyl, ethyl, n-propyl, Isopropyl, the tert-butyl group, 2- methyl-propyls, or normal-butyl；
Each R4cAnd R4It independently is hydrogen, methyl, ethyl, n-propyl, isopropyl, the tert-butyl group, normal-butyl, 2- methyl-propyls, Hydroxyl, carboxyl, amino, methoxyl group, H2N-(CH2)n-, N (R6R7)-C (=O)-, H- (CH2)n- O-C (=O)-(CH2)n-, CN- (CH2)n- C (=O)-, H- (CH2)n-O-(CH2)n-, trifluoromethyl or methylamino；
Each R6And R7It independently is hydrogen, methyl, ethyl, n-propyl, isopropyl, the tert-butyl group, normal-butyl, 2- methyl-propyls, hydroxyl Base, carboxyl, amino, methoxyl group, H2N-(CH2)n-, NH2- C (=O)-, H- (CH2)n- O-C (=O)-(CH2)n-, trifluoromethyl or Methylamino；
Wherein, each n has implication as described in the present invention.
In some embodiments,
Each R8It independently is hydrogen, oxo (=O), C1-4Alkyl, fluorine, chlorine, bromine, amino, hydroxyl, carboxyl, C1-4Alkoxy, C1-4Alkylamino, C1-4Haloalkyl, H- (CH2)n- O-C (=O)-(CH2)n-, H2N-(CH2)n-, H- (CH2)n-SO2-(CH2)n-, HO-(CH2)n-, HO- (CH2)n- C (=O)-, NH2- C (=O)-, cyano group, CN- (CH2)n- C (=O)-, C1-9Heteroaryl,Or nitro；
Each R9It independently is hydrogen, oxo (=O), C1-4Alkyl, fluorine, chlorine, bromine, amino, hydroxyl, carboxyl, C1-4Alkoxy, C1-4Alkylamino, C1-4Haloalkyl, cyano group, HO- (C (R4)2)n-, H- (C (R4)2)n- O-C (=O)-(C (R4)2)n-, CN-C (R4)2- C (=O)-, H2N-(C(R4)2)n-, H- (C (R4)2)n-SO2-(C(R4)2)n-, HO- (C (R4)2)n- C (=O)-, N (R6R7)-C (=O)-,C1-9Heteroaryl or nitro；
X and X1It is each independently-C (R4a)2- ,-N (R5a)-,-O- ,-S (=O)t- or-C (=O)-；
Each R5aIt independently is hydrogen, C1-4Alkyl, C1-4Haloalkyl, H- (C (R4)2)n- O-C (=O)-(C (R4)2)n-, (R6R7)N-(C(R4)2)n-, HO- (C (R4)2)n- C (=O)-, N (R6R7)-C (=O)-, HO- (C (R4)2)n-, H- (C (R4)2)n- O-(C(R4)2)n-, H- (C (R4)2)n-SO2-(C(R4)2)n-, H- (C (R4)2)n- C (=O)-(C (R4)2)n-, CN- (C (R4)2)n- C (=O)-, H- (C (R4)2)n- O-C (=O)-C (=O)-(C (R4)2)n-, C3-6Heterocyclic radical or C1-9Heteroaryl；
Each R4aIt independently is hydrogen, H2N-(CH2)n-, N (R6R7)-C (=O)-, H- (CH2)n- O-C (=O)-(CH2)n-, CN- (CH2)n- C (=O)-, H- (CH2)n-O-(CH2)n-, C1-4Alkyl, hydroxyl, fluorine, chlorine, bromine, carboxyl, amino, C1-4Alkoxy, C3-6 Heterocyclic radical, C1-9Heteroaryl, C1-4Haloalkyl or C1-4Alkylamino；
Each e and f independently are 0,1,2 or 3；
Wherein, t, each n, R4, R6And R7With implication as described in the present invention.
In some embodiments,
Each R8It independently is hydrogen, oxo (=O), methyl, ethyl, n-propyl, isopropyl, the tert-butyl group, normal-butyl, 2- methyl Propyl group, fluorine, chlorine, bromine, amino, hydroxyl, carboxyl, methoxyl group, ethyoxyl, 1- chloroethyls, dimethylamino, diethylamino, first Base amino, trifluoromethyl, cyano group, H-(CH2)n- O-C (=O)-(CH2)n-, H2N-(CH2)n-, H- (CH2)n-SO2-(CH2)n-, HO- (CH2)n-, HO- (CH2)n- C (=O)-, NH2- C (=O)-, CN- (CH2)n- C (=O)-, or nitro；
Each R9It independently is hydrogen, oxo (=O), methyl, ethyl, n-propyl, isopropyl, the tert-butyl group, normal-butyl, 2- methyl Propyl group, fluorine, chlorine, bromine, amino, hydroxyl, carboxyl, C1-4Alkoxy, C1-4Alkylamino, C1-4Haloalkyl, HO- (C (R4)2)n-, H- (C(R4)2)n- O-C (=O)-(C (R4)2)n-, CN-C (R4)2- C (=O)-, H2N-(C(R4)2)n-, H- (C (R4)2)n-SO2-(C (R4)2)n-, cyano group, HO- (C (R4)2)n- C (=O)-, N (R6R7)-C (=O)-, C1-9Heteroaryl or nitro；
Wherein, each n, R4, R6And R7With implication as described in the present invention.
In some embodiments,
R3For hydrogen,
Wherein, X2, X6And X7It is each independently-C (R4b)2- ,-N (R5b)-,-O- ,-S (=O)t- or-C (=O)-；
X3, X4And X5It is each independently CR4bOr N；
Each R5bIt independently is hydrogen, C1-4Alkyl, C1-4Haloalkyl, H- (C (R4)2)n- O-C (=O)-(C (R4)2)n-, (R6R7)N-(C(R4)2)n-, HO- (C (R4)2)n- C (=O)-, N (R6R7)-C (=O)-, HO- (C (R4)2)n-, H- (C (R4)2)n- O-(C(R4)2)n-, H- (C (R4)2)n-SO2-(C(R4)2)n-, H- (C (R4)2)n- C (=O)-(C (R4)2)n-, CN- (C (R4)2)n- C (=O)-, H- (C (R4)2)n- O-C (=O)-C (=O)-(C (R4)2)n-, C3-6Heterocyclic radical or C1-9Heteroaryl；
Each R4bIt independently is hydrogen, H2N-(CH2)n-, N (R6R7)-C (=O)-, H- (CH2)n- O-C (=O)-(CH2)n-, CN- (CH2)n- C (=O)-, H- (CH2)n-O-(CH2)n-, C1-4Alkyl, hydroxyl, fluorine, chlorine, bromine, carboxyl, amino, C1-4Alkoxy, C3-6 Heterocyclic radical, C1-9Heteroaryl, C1-4Haloalkyl or C1-4Alkylamino；
Each e, g and f independently are 0,1,2 or 3；
R3Optionally independently by R8Monosubstituted or identical or different is polysubstituted；
Each R8Optionally independently by R9Monosubstituted or identical or different is polysubstituted；
Wherein, t, R4, R6, R7, each R8With each R9With implication as described in the present invention.
In other embodiment,
R3For hydrogen,
N is 0,1,2 or 3；
Described R3Representative subformula is optionally independently by R8Monosubstituted or identical or different is polysubstituted；
Each R8With implication as described in the present invention.
In some embodiments
B rings are
The subformula that described B is represented is optionally independently by hydrogen, C1-4Alkyl, fluorine, chlorine, bromine, amino, hydroxyl, carboxyl, C1-4Alkoxy, C1-6Haloalkyl, (R6R7)N-(C(R4)2)n-, N (R6R7)-C (=O)-, H- (C (R4)2)n- O-C (=O)-(C (R4)2)n-, HO- (C (R4)2)n- C (=O)-, HO- (C (R4)2)n-, H- (C (R4)2)n-O-(C(R4)2)n-, H- (C (R4)2)n- SO2-(C(R4)2)n-, H- (C (R4)2)n- C (=O)-(C (R4)2)n-, CN- (C (R4)2)n- C (=O)-, H- (C (R4)2)n-O-C (=O)-C (=O)-(C (R4)2)n-, cyano group or monosubstituted or identical or different polysubstituted of nitro；
Wherein, R5, R4, R7, R6There is implication as described in the present invention with n.
On the one hand, the present invention provides a kind of pharmaceutical composition, includes a kind of compound as described in the present invention.
In some embodiments, pharmaceutical composition of the present invention, further comprising pharmaceutically acceptable carrier, figuration At least one of agent, diluent, assistant agent, medium.
In some embodiments, pharmaceutical composition of the present invention, further comprising additional therapeutic agent, these add and controlled Treatment agent is chemotherapeutic agent, antiproliferative, immunodepressant, immunostimulant, and anti-inflammatory reagent is athero- for treating artery The medicine of hardening, for treating the medicine or combinations thereof of pulmonary fibrosis.
In some embodiments, pharmaceutical composition of the present invention, wherein described additional therapeutic agent is Chlorambucil, Melphalan, endoxan, ifosfamide, busulfan, BCNU, lomustine, Streptozotocin, cis-platinum, carboplatin are difficult to understand husky Sharp platinum, Dacarbazine, Temozolomide, procarbazine, methotrexate (MTX), fluorouracil, cytarabine, gemcitabine, purinethol, Fludarabine, vincaleukoblastinum, vincristine, vinorelbine, taxol, Docetaxel, TPT, Irinotecan, rely on pool Glycosides, ET-743, dactinomycin D, Doxorubicin, epirubicin, daunomycin, mitoxantrone, bleomycin, mitomycin C, Ipsapirone, TAM, Flutamide, Gonadorelin analog, megestrol acetate, prednisone, dexamethasone, methylprednisolone are husky Sharp degree amine, interferon-' alpha ', Calciumlevofolinate, sirolimus, temsirolimus, everolimus, Afatinib, alisertib, Amuvatinib, Ah pa replace Buddhist nun, Axitinib, bortezomib, SKI-606, brivanib, cabozantinib, Xi Dini Cloth, crenolanib, gram Zhuo replace Buddhist nun, dabrafenib, dacomitinib, danusertib, Dasatinib, dovitinib, Tarceva, foretinib, ganetespib, Gefitinib, ibrutinib, Conmana, Imatinib, iniparib, Lapatinib, lenvatinib, linifanib, linsitinib, Masitinib, momelotinib, not for husky Buddhist nun, come that and replace Buddhist nun, nilotinib, niraparib, oprozomib, olaparib, pazopanib, pictilisib, ponatinib, Quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, saracatinib, saridegib, Sorafenib, Sutent, tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, Trametinib, ZD6474, veliparib, Wei Luofeini, vismodegib, volasertib, alemtuzumab, shellfish cut down list It is anti-, brentuximab vedotin, catumaxomab, Cetuximab, ground promise monoclonal antibody, lucky trastuzumab, her monoclonal antibody, Buddhist nun Trastuzumab, difficult to understand, Victibix, Rituximab, tositumomab, Herceptin, card is rich to replace Buddhist nun, and Pu Na is replaced Buddhist nun, Midostaurin, Pacritinib, quizartinib, gilteritinib, AKN-028, AT-9283, Crenolanib, ENMD-2076, Famitinib, Dovitinib, PLX-3397, palbociclib, abemaciclib, Ribociclib, rigosertib sodium, Selinexor, Roniciclib, AT-7519, Seliciclib, Alvocidib or combinations thereof.
On the other hand, compound of the present invention or pharmaceutical composition of the present invention are being prepared for preventing, and are located Reason, treatment or mitigates patient by abnormal cell proliferation, autoimmunity, in obstacle caused by inflammatory or infection or the medicine of illness Purposes.
In some embodiments, purposes of the present invention, wherein described abnormal cell proliferation disease refers to oophoroma, son Cervical carcinoma, carcinoma of testis, cancer of the esophagus, stomach cancer, cutaneum carcinoma, lung cancer, osteocarcinoma, acute myeloid leukaemia, chronic myelogenous leukemia, stomach and intestine Stromal tumors, acute myelocytic leukemia (AML), the chronic myelogenous leukemia (CML) of mutation, ALL (ALL), colorectal cancer, stomach cancer, breast cancer, lung cancer, liver cancer, prostate cancer, cancer of pancreas, thyroid cancer, kidney, brain tumor, neck cancer, The cancer of central nervous system, glioblastoma, myeloproliferative disease, atherosclerosis, pulmonary fibrosis, leukaemia, lymph cancer, Rheumatic disease, cryoglobulinemia, non-lymphoreticular system tumour, papular mucinosis, familial splenic anemia, Huppert's disease, amyloidosis, solitary plasmacytoma, heavy chain disease, light chain disease, malignant lymphoma, chronic lymphocytic are white Blood disease, primary macroglobulinaemia, half molecule disease, monocytic leukemia, primary macroglobulinaemia purpura, Secondary cases Benign monoclonal gammopathy, osteolytic lesion, lymphoblastoma, part NHL, Sezary synthesis Sign, infectious mononucleosis, acute histocytic increase disease, Hodgkin lymphoma, hairy cell leukemia, colon cancer, The carcinoma of the rectum, polyposis intestinalis, ED-SCLC, neuroblastoma, neuroendocrine cell tumour, islet-cell tumour, thyroid gland Cephaloma, melanoma, retinoblastoma, uterine cancer, oophoroma, G. cephalantha, malignant tumor of digestive tract are non-small thin Born of the same parents' lung cancer, cervical carcinoma, orchioncus, glioblastoma, lymphoma mantle cell, chronic myelocytic leukemia, acute myelogenous Leukaemia, carcinoma of urinary bladder or myeloma.
In some embodiments, purposes of the present invention, wherein, the autoimmune disease is rheumatic arthritis, wolf Sore, multiple sclerosis, thyroiditis, type i diabetes, sarcoidosis, inflammatory bowel disease, Crohn's disease or systemic lupus.
In some embodiments, purposes of the present invention, wherein, wherein described inflammatory disease refers to diverticulitis, colon Inflammation, pancreatitis, hepatitis, chronic hepatitis, hepatic sclerosis, cholecystitis or chronic inflammation.
In some embodiments, purposes of the present invention, wherein described infectious disease refers to virus infection and fungi sense Dye.
In some embodiments, purposes of the present invention, wherein the obstacle or illness are cyclin dependants Disease caused by kinases change.
In other embodiment, purposes of the present invention, wherein described cell cycle protein dependent kinase is Refer to CDK1, CDK2, CDK4, CDK6 or CDK9.
In some embodiments, purposes of the present invention, wherein the obstacle or illness are CDK4 or CDK6 protein kinases Disease caused by change.
On the one hand, the present invention provides a kind of medication combined, and it includes compound of the present invention or of the present invention Pharmaceutical composition and one or more other active drugs for being used to treat proliferative diseases, autoimmune disease or inflammatory disease Agent.
It is of the present invention medication combined in some embodiments, wherein other described active agents refer to chemotherapy Medicine, antiproliferative, immunodepressant, immunostimulant, anti-inflammatory reagent, CDK4/6 kinase inhibitors, ABL inhibitor, ABL/Scr inhibitor, aurora kinase inhibitors, Bcr-ABL non-ATP competitive inhibitors, c-KIT inhibition from mutation agent, RET Inhibitor, PDGFR inhibitor, VEGFR inhibitor, CSF1R inhibitor, FLT3 inhibitor, FLT3-ITD inhibitor or they Combination.
On the one hand, the present invention provides a kind of protection, processing, treatment or mitigates patient's abnormal cell proliferation, and autoimmunity is scorching Property or infection caused by the method for obstacle or illness, its method, which includes, gives the patient of the infection or disease as described herein Compound or pharmaceutical composition of the present invention effective therapeutic dose.
On the other hand, compound of the present invention or described pharmaceutical composition are used to protect, handle, treat or mitigate Obstacle or illness caused by patient's abnormal cell proliferation, autoimmunity, inflammatory or infection.
The compound of the present invention suitably particularly can be effective as the activating agent in pharmaceutical composition, described pharmaceutical composition The treatment illness relevant with protein kinase, such as cancer, graft rejection and autoimmune disease.In various embodiments Pharmaceutical composition has activating agent of the invention and other pharmaceutically acceptable excipient, carrier, the filling of pharmacy effective dose Agent, diluent etc..Wording " pharmacy effective dose " used herein is expressed as realizing treatment results, especially regulates and controls, adjusts or presses down Protein kinase activity processed, for example, suppress protein kinase activity or treating cancer, graft rejection or autoimmune disease and must Host must be applied to or be applied to the amount of the cell of host, tissue or organ.
In addition, the invention provides a kind of method for suppressing protein kinase activity.This method includes making cell and any one The compound contact of the kind present invention.In a related embodiment, this method is further provided with effectively selectivity Suppress the compound existing for the amount of protein kinase activity.
Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects.Other aspects Content will make more specific complete description below.
Detailed description of the invention book
Definition and general terms
It will now be described in more detail certain embodiments of the present invention, the example is by the structural formula and chemical formula explanation enclosed.This Invention is intended to cover all replacement, modification and equivalent technical solutions, and they are included in the present invention defined such as claim In the range of.Those skilled in the art will appreciate that many can be used in reality with similar or equivalent method described herein and material Trample the present invention.The present invention is not limited to method described herein and material.The one of document, patent and the similar material combined Or more it is different from the application or in the case of contradicting it is (including but not limited to defined term, term application, described Technology, etc.), be defined by the application.
It will further be appreciated that some features of the present invention, are clearly visible, are carried out in multiple independent embodiments Description, but can also be provided in combination in single embodiment.Conversely, the various features of the present invention, for brevity, It is described, but can also be provided individually or with arbitrarily suitable sub-portfolio in single embodiment.
Unless otherwise indicated, all scientific and technical terminologies used in the present invention have with those skilled in the art of the invention's It is generally understood that identical implication.All patents of the present invention and public publication are integrally incorporated this hair by reference It is bright.
Unless otherwise indicated, following definition used herein should be applied.For purposes of the present invention, chemical element with Periodic table of elements CAS versions, and《Handbook of Chemistry and Physics》, the 75th edition, 1994 is consistent.In addition, organic chemistry General Principle can join Examine " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito:1999, With " March's Advanced Organic Chemistry " by Michael B.Smith and Jerry March, John Wiley&Sons,New York:Description in 2007, entire contents are incorporated herein by reference.
There is obvious conflict unless otherwise indicated or in context, article " one " used herein, " one (kind) " " described " is intended to include " at least one " or " one or more ".Therefore, these articles used herein refer to one or The article of more than one (i.e. at least one) object.For example, " component " refers to one or more components, it is possible to has more than one Component be taken into account in the embodiment of the embodiment and use or use.
Term " study subject " used in the present invention refers to animal.Typically described animal is mammal.It is tested right As, such as also refer to primate (such as mankind, sex), ox, sheep, goat, horse, dog, cat, rabbit, rat, small Mouse, fish, bird etc..In certain embodiments, the study subject is primate.In other embodiments, it is described by It is people to try object.
Term " patient " used in the present invention refers to people (including adult and children) or other animals.In some implementations In scheme, " patient " refers to people.
Term "comprising" is open language, that is, includes the content specified by the present invention, but be not precluded from otherwise Content.
" stereoisomer " refers to there is identical chemical constitution, but the spatially different change of arrangement mode of atom or group Compound.Stereoisomer includes enantiomter, diastereoisomer, rotamer (rotational isomer), geometric isomer (cis/trans) isomers, atropisomer, etc..
" chirality " be with its mirror image can not overlapping property molecule；And " achirality " refer to can be with overlapping with its mirror image Molecule.
" enantiomter " refers to that two of a compound can not isomers that is overlapping but being mutually mirror.
" diastereoisomer " refers to have two or more chiral centres and its molecule not alloisomerism of mirror image each other Body.Diastereoisomer has different physical properties, such as fusing point, boiling point, spectral quality and reactivity.Diastereoisomer mixes Compound can be operated such as electrophoresis and chromatogram, such as HPLC by high resolution analysis to separate.
Stereochemical definitions used in the present invention and rule typically follow S.P.Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York；and Eliel, E.and Wilen, S., " Stereochemistry of Organic Compounds ", John Wiley＆Sons, Inc., New York, 1994.
Many organic compounds exist with optical active forms, i.e., they, which have, rotates the plane of linearly polarized light Ability.When describing optically active compound, represent molecule on one or more hand using prefix D and L or R and S The absolute configuration at property center.Prefix d and l or (+) and (-) are the symbols rotated for linearly polarized light caused by appointed compound, Wherein (-) or l represent that compound is left-handed.Prefix is (+) or d compound is dextrorotation.A kind of specific alloisomerism Body is enantiomter, and the mixture of this isomers is referred to as enantiomeric mixture.The 50 of enantiomter:50 mixtures Referred to as racemic mixture or racemic modification, when chemical reaction or during there is no stereoselectivity or stereospecificity when, It may occur in which such case.
Any asymmetric atom (for example, carbon etc.) that the present invention discloses compound can be enriched with racemic or enantiomer Form exist, such as (R)-, (S)-or (R, S)-configuration be present.In certain embodiments, each asymmetric atom exists (R)-or (S)-configuration in terms of there is at least 50% enantiomeric excess, at least at least 60% enantiomeric excess, 70% enantiomer mistake Amount, at least at least 80% enantiomeric excess, at least 90% enantiomeric excess, 95% enantiomeric excess, or at least 99% enantiomer It is excessive.
According to the selection of starting material and method, the compounds of this invention can with one in possible isomers or they Mixture, such as the form of racemic modification and non-enantiomer mixture (this depends on the quantity of asymmetric carbon atom) deposits .Chiral synthon or chiral reagent can be used to prepare for optically active (R)-or (S)-isomers, or be torn open using routine techniques Point.If compound contains a double bond, substituent may be E or Z configurations；If contain dibasic cycloalkanes in compound Base, the substituent of cycloalkyl may have cis or trans configuration.
The mixture of any stereoisomer of gained can be separated into according to the difference in component physicochemical properties Pure or substantially pure geometric isomer, enantiomter, diastereoisomer, for example, passing through chromatography and/or fractional crystallization Method.
The racemic modification of any gained end-product or intermediate can be passed through into those skilled in the art with known method Known method splits into optical antipode, e.g., is separated by its diastereoisomeric salt to acquisition.Racemic production Thing can also be separated by chiral chromatogram, e.g., use the high performance liquid chromatography (HPLC) of chiral sorbent.Especially, mapping Isomers can be prepared by asymmetric syntheses, for example, Jacques is referred to, et al., Enantiomers, Racemates and Resolutions(Wiley Interscience,New York,1981)；Principles of Asymmetric Synthesis(2ndEd.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel, E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany, 2007)。
What term " dynamic isomer " or " tautomeric form " referred to have different-energy can build (low by low energy Energy barrier) mutually inversion of phases constitutional isomer.If tautomerism is possible (as in the solution), can reach The chemical balance of dynamic isomer.For example, (also referred to as proton translocation mutually makes a variation proton tautomer (protontautomer) Structure body (prototropic tautomer)) include by proton migration the mutual inversion of phases that carries out, such as keto-enol isomerization and Imine-enamine isomerizations.Valence tautomerism body (valence tautomer) include by the restructuring of some bonding electrons come The mutual inversion of phases carried out.The instantiation of ketoenol tautomerization is that pentane -2,4- diketone and the amyl- 3- alkene -2- ketone of 4- hydroxyls are mutual The change of tautomeric.Another tautomeric example is phenol-keto tautomerism.One of phenol-keto tautomerism is specific real Example is the change of pyridine -4- alcohol and pyridine -4 (1H) -one dynamic isomer.Unless otherwise noted, the compounds of this invention is all Tautomeric forms are within the scope of the present invention.
As described in the invention, compound of the invention optionally can be substituted by one or more substituents, such as General formula compound above, or as example special inside embodiment, subclass, and a kind of compound that the present invention is included. It should be appreciated that this term can exchange use to " optionally substituting " this term with " substituted or non-substituted ".In general, art Language is " substituted " to represent that institute is substituted to one or more of structure hydrogen atom by specific substituent.Unless other aspect tables Bright, an optional substituted radical can be substituted in each commutable position of group.When in given structural formula not Only a position can be substituted by one or more substituents selected from specific group, then substituent can with identical or different Substitute in each position.
In each several part of this specification, the substituent that the present invention discloses compound discloses according to radical species or scope.It is special Do not point out, the present invention includes each independent sub-combinations thereof of each member of these radical species and scope.For example, term “C1-C6Alkyl " refers in particular to individually disclosed methyl, ethyl, C3Alkyl, C4Alkyl, C5Alkyl and C6Alkyl.
In each several part of the present invention, connect substituent is described.When the structure clearly needs linking group, for this Markush variable cited by group is interpreted as linking group.If for example, the structure needs linking group and for being somebody's turn to do The Markush group definition of variable lists " alkyl " or " aryl ", then is represented respectively it should be understood that being somebody's turn to do " alkyl " or " aryl " The alkylidene group or arylene group of connection.
As described in the invention, compound of the invention optionally can be substituted by one or more substituents, such as General formula compound above, or as example special inside embodiment, subclass, and a kind of compound that the present invention is included. It should be appreciated that this term can exchange use to " optionally substituting " this term with " substituted or non-substituted ".In general, art Language " optionally " is whether located at before term " substituted ", and expression gives one or more of structure hydrogen atom can be by Specific substituent is substituted.Unless otherwise indicated, an optional substituted radical can have a substituent in group Each commutable position is substituted.When more than one position can be by one selected from specific group in given structural formula Or multiple substituents are substituted, then substituent with identical or different can substitute in each position.Wherein described substituent It can be, but be not limited to：Hydrogen, oxo (=O), alkyl, fluorine, chlorine, bromine, amino, hydroxyl, carboxyl, alkoxy, alkylamino, halogen Substituted alkyl, aldehyde radical, cyano group, heterocyclic radical, H- (C (R4)2)n- O-C (=O)-(C (R4)2)n-, H2N-(C(R4)2)n-, H- (C (R4)2)n-SOt-(C(R4)2)n-, HO- (C (R4)2)n-, HO- (C (R4)2)n- C (=O)-, N (R6R7)-C (=O)-, CN- (C (R4)2)n- C (=O)-, heteroaryl, cycloalkyl or nitro etc., wherein, R4, R6, R7, n and t have implication as described in the present invention.
Terminology used in the present invention " alkyl " includes the univalence hydrocarbyl of 1-20 carbon atom saturated straight chain or side chain, wherein alkane Base with individually optional can be substituted by one or more substituents described in the invention.Some of embodiments are alkyl Group contains 1-10 carbon atom, and other embodiment is that alkyl group contains 1-8 carbon atom, other embodiment It is that alkyl group contains 1-6 carbon atom, other embodiment is that alkyl group contains 1-4 carbon atom, other Embodiment is that alkyl group contains 1-3 carbon atom, and other embodiment is that alkyl group contains 2-6 carbon atom.Alkane The further example of base group includes, but is not limited to, methyl (Me ,-CH3), ethyl (Et ,-CH2CH3), n-propyl (n- Pr ,-CH2CH2CH3), isopropyl (i-Pr ,-CH (CH3)2), normal-butyl (n-Bu ,-CH2CH2CH2CH3), 2- methyl-propyls or different Butyl (i-Bu ,-CH2CH(CH3)2), 1- methyl-propyls or sec-butyl (s-Bu ,-CH (CH3)CH2CH3), the tert-butyl group (t-Bu ,-C (CH3)3), n-pentyl (- CH2CH2CH2CH2CH3), 2- amyl groups (- CH (CH3)CH2CH2CH3), 3- amyl groups (- CH (CH2CH3)2), 2- Methyl -2- butyl (- C (CH3)2CH2CH3), 3- methyl -2- butyl (- CH (CH3)CH(CH3)2), 3- methyl isophthalic acids-butyl (- CH2CH2CH(CH3)2), 2-methyl-1-butene base (- CH2CH(CH3)CH2CH3), n-hexyl (- CH2CH2CH2CH2CH2CH3), 2- oneself Base (- CH (CH3)CH2CH2CH2CH3), 3- hexyls (- CH (CH2CH3)(CH2CH2CH3)), 2- methyl -2- amyl groups (- C (CH3)2CH2CH2CH3), 3- methyl -2- amyl groups (- CH (CH3)CH(CH3)CH2CH3), 4- methyl -2- amyl groups (- CH (CH3)CH2CH (CH3)2), 3- methyl -3- amyl groups (- C (CH3)(CH2CH3)2), 2- methyl -3- amyl groups (- CH (CH2CH3)CH(CH3)2), 2,3- Dimethyl -2- butyl (- C (CH3)2CH(CH3)2), 3,3- dimethyl -2- butyl (- CH (CH3)C(CH3)3),N-heptyl, it is just pungent Base, etc..Term " alkyl " and its prefix " alkane " use here, the saturated carbon chains all comprising straight chain and side chain.
Term " haloalkyl " represents the situation that alkyl can be substituted by one or more identical or different halogen atoms. Wherein alkyl group has implication as described in the present invention, and such example includes, but is not limited to trifluoromethyl, 1- chloroethenes Base, difluoromethyl, 2- fluoro ethyls, 3,3,3- trifluoro propyls, etc..
Term " amino " refers to-NH2。
Term " ring " includes carbocyclic ring, heterocycle, aromatic ring, hetero-aromatic ring, loop coil, condensed ring, etc., wherein the carbocyclic ring, heterocycle, virtue Ring, hetero-aromatic ring, loop coil, condensed ring group have implication as described in the present invention.
Term " alkylamino " or " alkyl amino " include " N- alkyl aminos " and " N, N- dialkyl amido ", wherein amino Group is separately substituted by one or two alkyl group, and wherein alkyl group has implication as described in the present invention. Some of embodiments are that alkyl amino is one or two C1-6Alkyl is connected to the alkyl amino of the lower level on nitrogen-atoms Group.Other embodiment is that alkyl amino is C1-3Lower level alkylamino group.Suitable alkylamino group Can be alkyl monosubstituted amino or dialkyl amido, such example includes, but is not limited to, methylamino, ethylamino, diformazan ammonia Base, lignocaine etc..
Term " aminoalkyl " refers to the alkyl group of amino group substitution, and wherein alkyl group has as described herein Implication.Some of embodiments are that aminoalkyl is amino C1-6Alkyl group.Other embodiment is amino C1-3Alkane Base group.Suitable aminoalkyl groups can be, but be not limited to, amino methyl, amino-ethyl, aminopropyl etc..
Term " alkoxy " used in the present invention, is related to alkyl, as defined in the present invention, is connected by oxygen atom It is connected in main carbochain.Such embodiment includes, but is not limited to, methoxyl group, ethyoxyl, propoxyl group etc..
Term " cycloalkyl " refers to monovalence or multivalence, non-aromatic, saturation or part unsaturation ring, and does not include miscellaneous original Son, including monocyclic or 7-12 carbon atom two rings or three rings of 3-12 carbon atom.Double carbon with 7-12 atom Ring can be two rings [4,5], [5,5], [5,6] or [6,6] system, while it can be two to have the bicyclic carbocyclic rings of 9 or 10 atoms Ring [5,6] or [6,6] system.Suitable group of naphthene base includes, but is not limited to, cycloalkyl, cycloalkenyl group and cycloalkynyl radical.Cycloalkanes The example of base group further comprises, but is not limited to, cyclopropyl, cyclobutyl, cyclopenta, 1- cyclopenta -1- alkenyls, 1- rings penta Base -2- alkenyls, 1- cyclopenta -3- alkenyls, cyclohexyl, 1- cyclohexyl -1- alkenyls, 1- cyclohexyl -2- alkenyls, 1- cyclohexyl -3- Alkenyl, cyclohexadienyl, suberyl, cyclooctyl, cyclononyl, cyclodecyl, ring undecyl, cyclo-dodecyl, adamantyl etc. Deng.Depending on structure, cycloalkyl can be monoradical or divalent group, i.e. cycloalkylidene.
Term " aryl " can be it is monocyclic, it is bicyclic, and the carbocyclic ring system of three rings, wherein, at least one member ring systems are fragrance Race, each of which member ring systems include 3-7 atom.Term " aryl " can be exchanged with term " aromatic rings " and used, such as virtue Fragrant ring can include phenyl, naphthyl and anthracene.Depending on structure, aryl can be monoradical or divalent group, i.e. arlydene.
Term " heteroaryl ", " hetero-aromatic ring " are used interchangeably here, all referring to monocyclic, bicyclic, three rings or four ring bodies System, wherein, Bicyclic heteroaromatic rings, three ring hetero-aromatic rings or Fourth Ring heteroaromatic ring systems are cyclic in the form of condensing.Wherein, heteroaryl ring body System is armaticity, on ring one or more atoms substituted individually optionally by hetero atom (hetero atom is selected from N, O, P, S, This N, S or P optionally substitute to obtain as NO, SO, SO by one or more oxygen atoms2, PO, PO2Group).Heteroaryl system can To be connected on any hetero atom or carbon atom in main structure so as to form stable compound.Heteroaryl system group can be with It is 3-7 former molecular monocyclic, or 7-10 original is molecular bicyclic, or 10-15 former molecular three ring.With 7-10 The bicyclic of individual atom can be two rings [4,5], [5,5], [5,6] or [6,6] system, and three rings with 10-15 atom can be with It is three rings [5,5,6], [5,7,6] or [6,5,6] system.Depending on structure, heteroaryl can be monoradical or divalent group, i.e., Inferior heteroaryl.
Other embodiment is that heteroaryl system (including heteroaryl, hetero-aromatic ring) includes example below, but is not limited to this A little examples：2- furyls, 3- furyls, TMSIM N imidazole base, 2- imidazole radicals, 4- imidazole radicals, 5- imidazole radicals, 3- isoxazolyls, 4- are different Oxazolyl, 5- isoxazolyls, 2- oxazolyls, 4- oxazolyls, 5- oxazolyls, 4- methyl-isoxazole -5- bases, N- pyrrole radicals, 2- pyrroles Cough up base, 3- pyrrole radicals, 2- pyridine radicals, 3- pyridine radicals, 4- pyridine radicals, 2- pyrimidine radicals, 4- pyrimidine radicals, pyrimidine -5- bases, pyridazinyl (such as 3- pyridazinyls) base, 2- thiazolyls, 4- thiazolyls, 5- thiazolyls, tetrazole radical (such as 5- tetrazole radicals), triazolyl (such as 2- triazoles Base and 5- triazolyls), 2- thienyls, 3- thienyls, pyrazolyl (such as 2- pyrazolyls), isothiazolyl, 1,2,3- oxadiazolyl, 1, 2,5- oxadiazolyls, 1,2,4- oxadiazolyl, 1,2,3-triazoles base, 1,2,3- thio biphosphole base, 1,3,4- thio biphosphole base, 1, 2,5- thio biphosphole bases, 1,3,4- thiadiazoles -2- bases, pyrazinyl, pyrazine -2- bases, 1,3,5-triazines base, benzo [d] thiazole -2- Base, imidazo [1,5-a] pyridine -6- bases, benzimidazolyl, benzoxazolyl, quinoxalinyl, 1,8- phthalazinyl, benzo Furyl, benzothienyl, benzothiazolyl, indoles (such as 2- indyls) base, purine radicals, quinolyl (such as 2- quinolyls, 3- quinolines Quinoline base, 4- quinoline), isoquinolyl (such as 1- isoquinolyls, 3- isoquinolyls or 4- isoquinolyls), tetralyl, benzopyrazoles Base, acridinyl, benzimidazolyl, benzindole base, Ben Bing Yi oxazinyls, benzo [4,6] imidazo [1,2-a] pyridine radicals, benzene And [d] imidazoles [2,1-b] thiazolyl, benzofuranyl, benzo aphthofurans base, diazosulfide base, benzothiazolyl, benzo Thio-phenyl, BTA base, benzo thiopyranyl, benzoxazinyl, benzoxazolyl, benzothiazolyl, B-carboline base, Carbazyl, cinnoline base, dibenzofuran group, imidazopyridyl, Imidazothiazole base, indazolyl, indolizine base, Yin Diindyl base, different benzo thienyl, iso-dihydro-indole-group, isoquinolyl, isothiazole alkyl, isothiazolyl, naphthyridines base, ten hydrogen indoles Base, decahydro isoindolyl , oxazolidinedione Ji , oxazolidines Ji , oxazoles and pyridine radicals , oxazolyls, Oxyranyle, the embedding phenodiazine of tea Phenyl, phenanthridinyl, phenanthroline base, phenarsazine base, phenazinyl, phenothiazinyl , phenoxazine groups, phthalazinyl, pteridyl, pyrido pyrrole Piperidinyl, quinazolyl , quinoxalinyls, thio-phenyl, triazine radical, 2H- pyrrolo-es [3,4-c] pyridine radicals, pyrazolo [2 ', 1 ':2, 3] oxazole simultaneously [4,5-c] pyridine radicals, imidazo [2 ', 1 ':2,3] thiazole simultaneously [4,5-c] pyridine radicals, imidazo [2 ', 1 ':2,3] Thiazole simultaneously [4,5-b] pyridine radicals, imidazo [2 ', 1 ':2,3] thiazole simultaneously [5,4-b] pyridine radicals, pyrazolo [2 ', 1 ':2,3] thiophene Azoles simultaneously [4,5-b] pyrazinyl, 1H- benzos [4,5] thieno [2,3-d] imidazole radicals, 1- methyl isophthalic acid H- benzos [4,5] thieno [2,3-d] imidazole radicals, imidazo [2', 1':2,3] thiazole simultaneously [4,5-b] pyrazinyl, imidazo [2', 1':2,3] thiazole simultaneously [5, 4-b] pyridine radicals, imidazo [2', 1':2,3] thiazole simultaneously [4,5-c] pyridine radicals, 1H- benzos [f] imidazo [4,5-b] [Isosorbide-5-Nitrae] Sulphur azatropylidene base etc..
Term " heterocyclic radical ", " heterocycle ", " miscellaneous alicyclic " or " heterocycle " are used interchangeably here, all referring to monocyclic, Bicyclic, three rings or tetracyclic ring system, one or more atoms are substituted by hetero atom individually optionally in its middle ring, and ring can be It is fully saturated or comprising one or more degrees of unsaturation, but the definitely not fragrant same clan.Heterocyclic system can be in any hetero atom Or it is connected on carbon atom in main structure so as to form stable compound.One or more ring hydrogen atoms are individually optional Ground is substituted by one or more substituents described in the invention.Some of embodiments are " heterocyclic radicals ", and " heterocycle " is " miscellaneous It is alicyclic " or " heterocycle " group be 3-7 yuan of rings it is monocyclic (1-6 carbon atom and selected from N, O, P, S 1-3 hetero atom, This N, S or P optionally substitute to obtain as NO, NO by one or more oxygen atoms2, SO, SO2, PO, PO2Group, meanwhile ,- CH2- group can be optionally by-C (=O)-replacement；When described ring is three-membered ring, only one of which hetero atom), or 7-10 it is former it is molecular it is bicyclic (4-9 carbon atom and selected from N, O, P, S 1-3 hetero atom, this N, S or P optionally by One or more oxygen atoms substitute to obtain as NO, NO2, SO, SO2, PO, PO2Group, meanwhile ,-CH2- group can be optional Ground is by-C (=O)-replacement；).Depending on structure, heterocyclic radical can be monoradical or divalent group, i.e., sub- heterocyclic radical.Some realities Apply in example, the N atoms in nitrogenous heterocycle are oxidized, and form nitrogen oxides.
" heterocyclic radical " can be carbon-based or hetero atom base." heterocyclic radical " equally also includes heterocyclic group and saturation or part not Saturated rings or heterocycle simultaneously close formed group.The example of heterocycle includes, but is not limited to, 1,2,3,6- tetrahydro pyridyl, piperazine Piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, THP trtrahydropyranyl, dihydro pyranyl, Tetrahydro thiapyran base, azelidinyl, oxetanylmethoxy, thietanyl, homopiperidinyl, glycidyl, azacycloheptyl, oxa- Suberyl, thia suberyl, N- morpholinyls, 2- morpholinyls, morpholinyl, thio-morpholinyl, homopiperazine base, piperidyl, oxygen nitrogen Miscellaneous Zhuo Ji, diazepine base, sulphur azatropylidene base, pyrrolin -1- bases, 2- pyrrolinyls, 3- pyrrolinyls, indolinyl, 2- Indoline base, 2H- pyranoses, 4H- pyranoses, dioxane hexyl, 1,3- dioxies amyl group, dithiane base, dithiode alkyl, two Hydrogen thienyl, 1,2,3,4- tetrahydro isoquinolyls, 1,2,6- thiadiazine alkane 1,1- dioxy -2- bases, hexahydro -2H- [1,4] dioxin [2,3-c] pyrrole radicals, 1,1- titanium dioxide thio-morpholinyls, 2,3,3a, 7a- tetrahydrochysene -1H- isoindolyls, isoindoline base, 1,2, 3,4- tetrahydric quinoline groups, N- pyridine radicals urea, dioxolanyl, dihydro pyrazine base, dihydropyridine base, pyrazoline base, dihydro Pyrimidine radicals, pyrrolin base, 1,4- dithiane base, morpholinyl, decahydro indyl, decahydro isoindolyl, piperazinyl, piperidyl, Pteridyl and purine radicals.
Term " loop coil base ", " loop coil ", " spiral shell bicyclic group ", " spiral shell is bicyclic " represent a ring originating from special on another ring Ring-type carbon.For example, as disclosed below, the bridged-ring system (ring D and B') of a saturation is referred to as " condensed-bicyclic ", on the contrary Ring A and ring D shares a carbon atom in the member ring systems of two saturations, then is referred to as " loop coil ".Each ring inside loop coil It is or that carbocyclic ring is miscellaneous alicyclic.Such example includes, but is not limited to, 4- azaspiros [2.4] heptane -5- bases, 4- Oxaspiro [2.4] heptane -5- bases, 5- azaspiros [2.4] heptane -5- bases, spiral shell [2.4] heptane base, spiral shell [4.4] nonyl, 7- hydroxyls Base -5- azaspiros [2.4] heptane -5- bases etc..
Term " the miscellaneous bicyclic group of spiral shell " represents a ring originating from particularly ring-shaped carbon on another ring.For example, as institute above Description, the bridged-ring system (ring D and B') of a saturation is referred to as " condensed-bicyclic ", otherwise ring A and ring D is in the ring of two saturations A carbon atom is shared in system, then is referred to as " loop coil ".And at least one member ring systems include one or more hetero atoms, wherein Each member ring systems includes 3-7 atom, i.e., comprising 1-6 carbon atom and selected from N, O, P, S 1-3 hetero atom, in this N, S Or P optionally substitutes to obtain as NO, NO by one or more oxygen atoms2, SO, SO2, PO, PO2Group ,-CH2- group can With optionally by-C (=O)-replacement；Such example includes, but is not limited to 4- azaspiros [2.4] heptane base, 4- oxaspiros [2.4] heptane base, 5- azaspiros [2.4] heptane base, 7- hydroxyl -5- azaspiros [2.4] heptane base, 2- azaspiros [4.5] decane Base, 2- azepine spiroheptane bases, 2- azaspiros [4.4] nonyl, 2- methyl -2,6- diaza spiro [4.5] decyl, 3- Azaspiro [5.4] decyl, 2- methyl -2- azepine spiroheptane bases, 2- oxygen -6- azepine spiroheptane bases, 2,6- bis- Azepine spiroheptane base, 2- sulphur -6- azepine spiroheptane base 2- monoxide, 2- sulphur -6- azepine spiroheptane bases 2,2- dioxide etc..Depending on structure, the miscellaneous bicyclic group of spiral shell can be monoradical or divalent group, i.e., the sub- miscellaneous bicyclic group of spiral shell.
Term " condensed-bicyclic ", " condensed ring ", " condensed-bicyclic base " or " condensed ring radical " represent saturation or undersaturated condensed ring body System, is related to the bicyclic system of non-aromatic, at least one ring is nonaromatic.Such system can include independent Or the undersaturated condition of conjugation, but its core texture does not include aromatic rings or heteroaromatic (but aromatic series can be as thereon Substituent).Each ring in condensed-bicyclic is either carbocyclic ring or is miscellaneous alicyclic, and such example includes, but and unlimited In, hexahydro-furans [3,2-b] furyl, 2,3,3a, 4,7,7a- hexahydro -1H- indenyls, 7- azabicyclos [2.2.1] heptane base, Condensed-bicyclic [3.3.0] octyl, condensed-bicyclic [3.1.0] hexyl, 1,2,3,4,4a, 5,8,8a- octahydro naphthyls, these are all Within the system of condensed-bicyclic.
Term " condensing miscellaneous bicyclic group " represents saturation or undersaturated fused ring system, is related to the bicyclic body of non-aromatic System, at least one ring is nonaromatic.Such system can include independent or conjugation undersaturated condition, but its core Core structure does not include aromatic rings or heteroaromatic (but aromatic series can be as substituent thereon).And at least one member ring systems bag Containing one or more hetero atoms, each of which member ring systems include 3-7 former molecular ring, i.e., comprising 1-6 carbon atom with Selected from N, O, P, S 1-3 hetero atom, optionally substituted to obtain picture NO by one or more oxygen atoms in this N, S or P, NO2, SO, SO2, PO, PO2Group ,-CH2- group optionally can be included by-C (=O)-replacement, such example, but simultaneously It is not limited to, hexahydro -2H- [Isosorbide-5-Nitrae] dioxin [2,3-c] pyrrole radicals, 3- azabicyclos [3.3.0] octyl, 8- azabicyclos [4.3.0] nonyl, 8- azabicyclos [4.3.0] nonane 3- bases, 3- azabicyclos [4.3.0] nonane -3- bases, 1,5- dioxy - 8- azabicyclos [4.3.0] nonyl, (1R, 6S) -2,5- dioxy -8- azabicyclos [4.3.0] nonyl, (1R, 6R) -2,5- Dioxy -8- azabicyclos [4.3.0] nonyl, isoindoline base, 1,2,3,4- tetrahydric quinoline group, 3- nitrogen -7- oxabicyclos [3.3.0] octyl, 3,7- diazabicyclos [3.3.0] octyl, 2,6- diazabicyclos [3.3.0] octyl, 2,7- bis- Azabicyclo [3.3.0] octyl, 2,8- diazabicyclos [4.3.0] nonyl, 3- oxygen -8- azabicyclos [4.3.0] nonane Base, 2- oxygen -8- azabicyclos [4.3.0] nonyl, 2,8- phenodiazine -5- oxabicyclos [4.3.0] nonyls, 4,9- diazas are double Ring [4.3.0] nonyl, 2,9- diazabicyclos [4.3.0] nonyl, 3- oxos -2,4, the azabicyclos of 8- tri- [4.3.0] nonyl Alkyl, 3- oxos -4- oxygen -2,8- diazabicyclo [4.3.0] nonyl, 3- oxos -2,8- diazabicyclo [4.3.0] nonane Base, 3,8- diazabicyclos [4.3.0] nonyl, 3,7- diazabicyclos [4.3.0] nonyl, 3,9- diazabicyclos [4.3.0] nonyl, 3- oxygen -8- azabicyclos [4.3.0] nonyl, 3- sulphur -8- azabicyclos [4.3.0] nonyl, 5,6- Dihydro -4H- pyrrolo-es [3,4-c] isoxazolyl, [1,2,4] triazole [4,3-a] and piperidyl, isoxazole simultaneously [4,3-c] piperazine Piperidinyl, 4,5,6,7- tetrahydrochysene isoxazoles simultaneously [3,4-c] pyridine radicals, [1,2,4] triazole simultaneously [4,3-a] piperazinyl, 2- oxygen -7- nitrogen Miscellaneous bicyclic [4.4.0] decyl, 1,5- dioxy -9- azabicyclos [4.4.0] decyl, 3- azabicyclos [4.4.0] decyl, 2,7- diaza decahydro naphthyls or 2- oxygen -8- azabicyclos [4.4.0] decyl etc..
Term " bridge bicyclic group " represents saturation or undersaturated bridged-ring system, is related to the bicyclic system of non-aromatic.This The system of sample can include independent or conjugation undersaturated condition, but its core texture does not include aromatic rings or aromatic ring (still Aromatic series can be as substituent thereon).Each of which member ring systems include 3-7 atom, and such example includes, but simultaneously It is not limited to, bicyclic [2.2.1] heptane base, 2- methyl-miscellaneous two ring [2.2.1] heptane base, etc..
Term " the miscellaneous bicyclic group of bridge " represents saturation or undersaturated bridged-ring system, is related to the bicyclic system of non-aromatic. Such system can include independent or conjugation undersaturated condition, but its core texture does not include aromatic rings or heteroaromatic (but aromatic series can be as substituent thereon).And at least one member ring systems include one or more hetero atoms, wherein often One member ring systems includes 3-7 atom, i.e., comprising 1-6 carbon atom and selected from N, O, P, S 1-3 hetero atom, in this N, S or P optionally substitutes to obtain as NO, NO by one or more oxygen atoms2, SO, SO2, PO, PO2Group ,-CH2- group can be with Optionally by-C (=O)-replacement, such example includes, but is not limited to 2- oxygen -5- azabicyclos [2.2.1] heptane base, 2- Thio -5- azabicyclos [2.2.1] heptane base, 2- oxo -5- azabicyclos [2.2.1] heptane base, 2,5- diazabicylos [2.2.1] heptane base, (1S, 4S) -2,5- diazabicyclos [2.2.1] heptane base, 3,8- diazabicyclos [3.2.1] octane Base, (1S, 5S) -3,8- diazabicyclos [3.2.1] octyl, Isosorbide-5-Nitrae-diazabicyclo [3.2.2] nonane -3- ketone-base, 8- Oxygen -3- nitrogen-miscellaneous bicyclic [3.2.1] octyl, etc..
" antiproliferative " refers to antimetabolite (for example, 5- fluoro-uracil, methotrexate, fludarabine), anti-micro- Pipe agent (for example, Vinca alkaloids such as vincristine, vinblastine, taxane such as taxol, polyenoid taxol), alkylation examination Agent (such as endoxan, melphalan, carmustine, nitroso ureas such as double chlorethylnitrosoureas and hydroxycarbamide), platinum reagent (such as Cis-platinum, Kapo Platinum, Oxalipratin, JM-216, Cl-973), anthracyclines (such as doxrubicin, daunomycins), Antitumor antibiotics (such as mitomycin, jaundice element, adriamycin, daunomycins), topoisomerase inhibitors (such as sufficient leaf second Glucoside, camptothecine), anti-angiogenic agent (such as and Bevacizumab) or any cytotoxic agent (estramustine phosphate, sprinkle Buddhist nun Mustargen), hormone or hormone activator, antagonist, partial agonist agent or topical antagonist, kinase inhibitor and radiation control Treat.
As described in the present invention, substituent R ' member ring systems that are formed by a key connection to the ring at center represent substituent R ' any on ring can may replace or any rational position is substituted.For example, formula a represent it is any on A ' rings or B ' rings can Can substituted position can be substituted by R ', such as formula b, formula c, formula d, formula e, formula f, formula g, and shown in formula h.
As described in the present invention, attachment point can be connected any attachable position on ring with molecule remainder.Example Such as, formula i represent any position that may be connected on A ' rings or B ' rings can be as the point of connection.
As described in the invention, there are two tie points to be connected with molecule remainder on ring C, for example, such as formula j institutes Show, expression can be E ends or be that E ' ends are connected with the remainder of molecule, i.e., the connected mode at both ends can exchange. As described in the invention, for example, "-(C (R4)2)n1- C (=O)-N (R5)-(C(R4)2)n1- ", or "-(C (R4)2)m1-O-(C (R4)2)n1- " connected mode at both ends can exchange.
As described in the present invention, attachment point can be connected any attachable position on ring with molecule remainder, together When the both ends that connect can exchange.For example, formula x represent any position that may be connected on ring can be as the point of connection, together When tie point both ends can exchange.
In addition, it is necessary to explanation, unless otherwise explicitly pointing out, the describing mode used in the whole text herein " each ... and ... independently be ", " ... and ... be each independently " and " ... and ... separately for " can exchange, and should do extensively Reason and good sense solution, it can both refer in different groups, not influenceed mutually between expressed specific option between same-sign, It can represent in identical group, not influenceed mutually between expressed specific option between same-sign.For example, "-(C (R4)2)n1- C (=O)-N (R5)-(C(R4)2)n1- " in each R4Specific option can be with identical, can also be different, and mutually it Between expressed specific item it is also different；Each n1 specific option can be with identical, can also be different, and expressed between each other Specific item it is also different；In another example in formula y, each R4Specific option can be with identical, can also be different, and between each other Expressed specific item is also different.
SymbolRepresent as described in the present invention singly-bound "" or double bond "”。
It is that term " pharmaceutically acceptable " refers to when giving people to apply pharmaceutical formulation and general do not produce allergy Or similar unsuitable reaction, such as the molecular entity and composition of digestive discomfort, dizziness etc..Preferably, art used herein Language " pharmaceutically acceptable " refers to federal regulator or national government approval or American Pharmacopeia or other typically approve Pharmacopeia lift in animal, be more in particular in what is used in human body.
Term " carrier " refers to the diluent together applied with the compound, assistant agent, excipient or matrix.These medicines carry Body can be sterile liquid, such as water and oils, including oil, animal, plant or synthesis source, such as peanut oil, soybean Oil, mineral oil, sesame oil etc..Water and aqueous solution saline solution and aqueous glucose are preferably used as carrier, spy with glycerite It is not Injectable solution.Suitable pharmaceutical carrier is described in E.W.Martin " Remington ' s Pharmaceutical In Sciences ".
The definition of neutral body chemistry of the present invention and the use of convention are typically referenced to documents below：S.P.Parker,Ed., McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York；and Eliel,E.and Wilen,S.,"Stereochemistry of Organic Compounds",John Wiley＆Sons, Inc., New York, the compound of 1994. present invention can include asymmetric center or chiral centre, therefore Different stereoisomers be present.All stereoisomeric forms in any ratio of compound of the invention, including but not limited to, diastereomeric Body, enantiomter, atropisomer, and their mixture, such as racemic mixture, constitute a part of the invention. Many organic compounds all exist with optical active forms, i.e. the plane of their capable Plane of rotation polarised lights.In description light When learning reactive compound, prefix D, L or R, S are used for representing the absolute configuration at molecular chiral center.Prefix d, l or (+), (-) use To name the symbol that compound linearly polarized light rotates, (-) or l refer to that compound is left-handed, and prefix (+) or d refer to chemical combination Thing is dextrorotation.The chemical constitution of these stereoisomers is identical, but their stereochemical structure is different.It is specific vertical Body isomers can be enantiomer, and the mixture of isomers is commonly referred to as enantiomeric mixture.50:50 enantiomer mixing Thing is referred to as racemic mixture or racemic modification, and this may cause do not have stereoselectivity or three-dimensional fixed in chemical reaction process Tropism.Term " racemic mixture " and " racemic modification " refer to the mixture of equimolar two enantiomters, lack light Learn activity.
" isomers " is the different compounds with identical molecular formula." stereoisomer " is the space arrangement of only atom The different isomers of mode.Term " isomers " as used herein includes any and all geometric isomer and alloisomerism Body.For example, " isomers " includes cis and trans isomers, E- and Z- isomers, R- and S- enantiomters, diastereo-isomerism Body, (d) isomers, (l)-isomers, its racemic mixture and its other mixture for falling into this specification scope.
" hydrate " of the present invention refers to compound or its salt provided by the present invention, and it also includes chemical quantity or non-chemical The water that equivalent is combined by non-covalent intermolecular forces, can also say it is that solvent molecule is the associated matter that water is formed.
" solvate " of the present invention refers to the association that the compound of one or more solvent molecules and the present invention are formed Thing.The solvent for forming solvate includes, but is not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, second Acid, ethylaminoethanol.
It is hydrolyzable in vivo that " ester " of the present invention refers to that the formula (I) containing hydroxyl-compound shown in formula (III) can be formed Ester.Such ester is the pharmaceutically acceptable ester that hydrolysis produces parent alcohol for example in human or animal's body.Formula containing hydroxyl (I) group of hydrolyzable ester includes, but not limited to phosphate in compound body shown in-formula (III), acetoxymethoxy, 2,2- dimethylpropionyloxymethoxies, alkanoyl, benzoyl, the acyl group of benzene first and second, alkoxy carbonyl, dialkylcarbamoyl Base and N- (di-alkyaminoethyl group)-N- alkyl-carbamoyls etc..
" nitrogen oxides " of the present invention refers to that when compound contains several amine functional groups nitrogen that can be by 1 or more than 1 is former Son oxidation forms N- oxides.The particular example of N- oxides is the N- oxidations of the N- oxides or nitrogen heterocyclic ring nitrogen-atoms of tertiary amine Thing.The corresponding amine formation N- oxides of available oxidant such as hydrogen peroxide or peracid (such as peroxycarboxylic acid) processing (referring to Advanced Organic Chemistry, Wiley Interscience, the 4th edition, Jerry March, pages).Especially It is that N- oxides can be prepared (Syn.Comm.1977,7,509-514) with L.W.Deady method, wherein for example molten in inertia In agent such as dichloromethane, amines is set to be reacted with m- chloroperoxybenzoic acid (MCPBA).
A variety of different geometric isomers and dynamic isomer, the formula (I)-formula (III) compound bag may be present in compound Include all such forms.To avoid feeling uncertain, when compound with one of several geometric isomers or dynamic isomer exist and only When specifically describing or showing a kind of, it is clear that all other form is included in formula (I)-formula (III).
Term " prodrug " used in the present invention, represent a compound and be converted into vivo shown in formula (I)-formula (III) Compound.Such conversion is hydrolyzed or is precursor structure through enzymatic conversion in blood or tissue in blood by pro-drug Influence.Pro-drug compounds of the present invention can be ester, and ester can have phenyl ester as pro-drug in existing invention Class, aliphatic (C1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.Such as the present invention In a compound include hydroxyl, you can be acylated to obtain the compound of prodrug form.Other pro-drugs Form includes phosphate, if these phosphate compounds are being obtained through the di on parent.On pro-drug Complete discuss may be referred to documents below：T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,Vol.14 of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al,Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008,51,2328-2345.
Unless otherwise indicated, all tautomeric forms of the compound of the present invention are included in the scope of the present invention Within.
In addition, unless otherwise indicated, the structural formula of compound described in the invention includes one or more differences Atom enriched isotope.The present invention includes the compound of isotope marks, and they are equal to described in formula (I)-formula (III) Compound, but wherein one or more atoms are different from the common atomic mass or quality of nature by atomic mass or mass number Several atoms are replaced.The example for the isotope that can be introduced into the compounds of this invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and The isotope of chlorine, respectively for example2H、3H、13C、11C、14C、15N、18O、17O、31P、32P、35S、18F and36Cl.Contain above-mentioned isotope And/or the compounds of this invention, its pro-drug and the compound of other isotopes of other atoms or the pro-drug Pharmaceutically acceptable salt belong to the scope of the present invention.The compounds of this invention of some isotope marks, for example, introduce and put Injectivity isotope (such as3H and14C) those can be used for medicine and/or substrate tissue measure of spread.This hair of isotope marks Compound and its pro-drug can typically be prepared shown in bright formula (I)-formula (III), carry out following flows and/or implementation When example is with technique disclosed in preparation example, the reagent of nonisotopic labels is replaced with the reagent for the isotope marks being readily obtained.
" metabolite " refers to specific compound or its salt in vivo by the product obtained by metabolism.One change The metabolite of compound can be identified that its activity can be retouched by such as the present invention by technology known to art Adopt as stating and experimentally characterized.Such product can be by, by aoxidizing, being reduced, water to drug compound The methods of solution, amidated, desamido- effect, esterification, degreasing, enzymatic lysis etc., obtains.Correspondingly, the present invention includes compound Metabolite, including by the present invention compound metabolite caused by a period of time is fully contacted with mammal.
The various pharmaceutically acceptable salt forms of the compounds of this invention are all useful.Term is " pharmaceutically acceptable Salt " refers to that those salt forms are it will be apparent that i.e. they are substantially nontoxic and needed for providing for pharmaceutical chemistry man Pharmacokinetic property, palatability, absorption, distribution, metabolism or excretion.Other factors, it is more practical in nature, for choosing Select also critically important, these are：The costs of raw material, the easy of crystallization, yield, stability, the stream of hygroscopicity and result bulk drug Dynamic property.Simply, pharmaceutical composition can be prepared by active ingredient and pharmaceutically acceptable carrier.
" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of the compound of the present invention.Medicine Acceptable salt is known to us in art on, such as document：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,66: It is 1-19,1977. described.The salt that pharmaceutically acceptable nontoxic acid is formed includes, but is not limited to, anti-with amino group The inorganic acid salt that should be formed has hydrochloride, hydrobromate, phosphate, sulfate, perchlorate, nitrate etc., and acylate Such as acetate, propionate, glycollate, oxalates, maleate, malonate, succinate, fumarate, tartrate, Citrate, benzoate, mandelate, mesylate, esilate, toluene fulfonate, sulfosalicylate etc., or pass through Described other method such as ion-exchange obtains these salt on books document.
Other pharmaceutically acceptable salts include adipate, malate, 2 hydroxy propanoic acid, alginates, ascorbic acid Salt, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, camphor hydrochlorate, camsilate, ring Amyl group propionate, digluconate, lauryl sulfate, esilate, formates, fumarate, glucoheptonic acid Salt, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2- hydroxy-ethanesulfonate salts, lactose Aldehydic acid salt, lactate, laruate, lauryl sulfate, malate, malonate, mesylate, 2- naphthalene sulfonates, cigarette Hydrochlorate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3- phenylpropionic acids salt, picrate, spy Valerate, propionate, stearate, rhodanate, tosilate, undecylate, valerate, etc..By appropriate The salt that alkali obtains includes alkali metal, alkaline-earth metal, ammonium and N+(C1-4Alkyl)4Salt.
The present invention is also intended to contemplate the quaternary ammonium salt that the compound of any included N group is formed.Water-soluble or oil is molten Property or dispersion product can be obtained by quaternization.Alkali metal or alkali salt include sodium salt, lithium salts, sylvite, calcium salt, Magnesium salts, molysite, zinc salt, mantoquita, manganese salt, aluminium salt etc..Pharmaceutically acceptable salt further comprises appropriate, nontoxic ammonium, The amine cation that quaternary ammonium salt and gegenions are formed, such as halide, hydroxide, carboxylate, hydrosulphate, phosphoric acid compound, Nitric acid compound, C1-8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.Amine salt, such as, but not limited to N, N '-dibenzyl-ethylenediamin, the general Shandong of chlorine Cacaine, choline, ammonia, diethanol amine and other hydroxyalkyl amines, ethylenediamine, N- methyl glucamines, procaine, N- benzyl benzene Ethamine, the p- chlorobenzyl -2- pyrrolidines -1 ' of 1--ylmethyl-benzimidazole, diethylamine and other alkylamines, piperazine and three (hydroxyl first Base) aminomethane；Alkali salt, such as, but not limited to barium, calcium and magnesium；Transition metal salt, such as, but not limited to zinc.
When term " blocking group " or " Pg " refer to a substituent with other reacted with functional groups, commonly used to hinder It is disconnected or protect special feature.For example, " blocking group of amino " refers to that a substituent is connected with amino group to block Or the feature of amino in compound is protected, suitable amido protecting group includes acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl (BOC), benzyloxycarbonyl group (CBZ) and 9- fluorenes methylene oxygen carbonyls (Fmoc).Similarly, " hydroxy-protective group " refers to the substitution of hydroxyl Base is used for blocking or protecting the feature of hydroxyl, and suitable blocking group includes acetyl group and silicyl." carboxyl-protecting group Group " refers to that the substituent of carboxyl is used for blocking or protect the feature of carboxyl, in general carboxyl-protecting group includes- CH2CH2SO2Ph, cyano ethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxyl methyl, 2- is (to toluene Sulfonyl) ethyl, 2- (p-nitrophenyl sulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitro-ethyl, etc..For protection The description of group in general refers to document：T W.Greene,Protective Groups in Organic Synthesis, John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme, Stuttgart,2005.
In this manual, if any difference between chemical name and chemical constitution be present, structure is dominant.
The abbreviation of any blocking group used in the present invention, amino acid and other compounds, unless otherwise indicated, all with Their usually used, generally acknowledged abbreviations are defined, or with reference to IUPAC-IUB Commission on Biochemical Nomenclature (referring to Biochem.1972,11：942-944).
The description of the compounds of this invention
The obstacle relevant with protein kinase is largely used to, also can be used for treating or preventing or improving cancer, autoimmunity Property disease and the compound of one or more symptoms of infection class disease be still within needs.Compound provided by the invention can For the activity of regulatory protein kinases such as CDK series, particularly regulation or suppression CDK4 or CDK6 activity.
On the one hand, the present invention provides a kind of compound, and it is the compound as shown in formula (I), or the chemical combination shown in formula (I) The stereoisomer of thing, geometric isomer, dynamic isomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically Acceptable salt or prodrug,
Wherein：R1, R2, R3, L1There is implication as described in the present invention with B rings.
In some embodiments, B rings are
Wherein, Y, Y1And Y2It is each independently-C (R4)2- ,-N (R5)-,-O- ,-S (=O)t- or-C (=O)-；
Y3, Y4, Y5, Y6, Y8And Y7It is each independently CR4Or N；
The subformula that described B is represented is optionally independently by hydrogen, C1-6Alkyl, fluorine, chlorine, bromine, amino, hydroxyl, carboxyl, C1-6Alkoxy, C1-6Haloalkyl, (R6R7)N-(C(R4)2)n-, N (R6R7)-C (=O)-, H- (C (R4)2)n- O-C (=O)-(C (R4)2)n-, HO- (C (R4)2)n- C (=O)-, HO- (C (R4)2)n-, H- (C (R4)2)n-O-(C(R4)2)n-, H- (C (R4)2)n- SO2-(C(R4)2)n-, H- (C (R4)2)n- C (=O)-(C (R4)2)n-, CN- (C (R4)2)n- C (=O)-, H- (C (R4)2)n-O-C (=O)-C (=O)-(C (R4)2)n-, cyano group or monosubstituted or identical or different polysubstituted of nitro；
R4, t, R6, R7, R5, and n has implication as described in the present invention.
In some embodiments, R1For hydrogen, fluorine, chlorine, bromine, hydroxyl, C1-4Alkyl, C1-4Haloalkyl or C1-4Alkoxy, R1Appoint Choosing is independently by R8Monosubstituted or identical or different is polysubstituted；
R8With implication as described in the present invention.
In some embodiments, R2For hydrogen, fluorine, chlorine, bromine, hydroxyl, C1-4Alkyl, C1-4Haloalkyl or C1-4Alkoxy, R2Appoint Choosing is independently by R8Monosubstituted or identical or different is polysubstituted；
R8With implication as described in the present invention.
In some embodiments, L1For key ,-(C (R4c)2)n1- ,-(C (R4c)2)n1- C (=O)-N (R5c)-(C(R4c)2)n1- ,- (C(R4c)2)n1-N(R5c)-(C(R4c)2)n1- ,-(C (R4c)2)n1-O-(C(R4c)2)n1- ,-(C (R4c)2)n1- S (=O)t-(C (R4c)2)n1- or-(C (R4c)2)n1- C (=O)-(C (R4c)2)n1-；
R4c, R5cThere is implication as described in the present invention with n1.
In some embodiments, R3For hydrogen, C5-12The miscellaneous bicyclic group of spiral shell, C5-12The miscellaneous bicyclic group of bridge, C5-12Condense miscellaneous bicyclic group, C3-9 Cycloalkyl, C3-9Heterocyclic radical or C1-9Heteroaryl, R3Optionally independently by R8Monosubstituted or identical or different is polysubstituted；
R8With implication as described in the present invention.
In some embodiments, each R4It independently is hydrogen, C1-6Alkyl, hydroxyl, fluorine, chlorine, bromine, carboxyl, amino, C1-6Alcoxyl Base, H2N-(CH2)n-, N (R6R7)-C (=O)-, aldehyde radical, H- (CH2)n- O-C (=O)-(CH2)n-, H- (CH2)n-O-(CH2)n-, CN-(CH2)n- C (=O)-, C3-9Heterocyclic radical, C1-9Heteroaryl, C1-6Haloalkyl or C1-6Alkylamino；
R6, R7There is implication as described in the present invention with n.
In some embodiments, each R5It independently is hydrogen, C1-6Alkyl, C1-6Haloalkyl, H- (C (R4)2)n- O-C (=O)- (C(R4)2)n-, (R6R7)N-(C(R4)2)n-, HO- (C (R4)2)n- C (=O)-, N (R6R7)-C (=O)-, HO- (C (R4)2)n-, H-(C(R4)2)n-O-(C(R4)2)n-, H- (C (R4)2)n-SO2-(C(R4)2)n-, H- (C (R4)2)n- C (=O)-(C (R4)2)n-, CN-(C(R4)2)n- C (=O)-, H- (C (R4)2)n- O-C (=O)-C (=O)-(C (R4)2)n-, C3-9Heterocyclic radical or C1-9Heteroaryl Base, optionally independently by R8Monosubstituted or identical or different is polysubstituted；
R4, R6, R7, R8, and n has implication as described in the present invention.
In some embodiments, each R4cIt independently is hydrogen, C1-6Alkyl, hydroxyl, fluorine, chlorine, bromine, carboxyl, amino, C1-6Alcoxyl Base, H2N-(CH2)n-, N (R6R7)-C (=O)-, aldehyde radical, H- (CH2)n- O-C (=O)-(CH2)n-, H- (CH2)n-O-(CH2)n-, CN-(CH2)n- C (=O)-, C3-9Heterocyclic radical, C1-9Heteroaryl, C1-6Haloalkyl or C1-6Alkylamino；
R6, R7There is implication as described in the present invention with n.
In some embodiments, each R5cIt independently is hydrogen, C1-6Alkyl, C1-6Haloalkyl, H- (C (R4)2)n- O-C (=O)- (C(R4)2)n-, (R6R7)N-(C(R4)2)n-, HO- (C (R4)2)n- C (=O)-, N (R6R7)-C (=O)-, HO- (C (R4)2)n-, H-(C(R4)2)n-O-(C(R4)2)n-, H- (C (R4)2)n-SO2-(C(R4)2)n-, H- (C (R4)2)n- C (=O)-(C (R4)2)n-, CN-(C(R4)2)n- C (=O)-, H- (C (R4)2)n- O-C (=O)-C (=O)-(C (R4)2)n-, C3-9Heterocyclic radical or C1-9Heteroaryl Base, optionally independently by R8Monosubstituted or identical or different is polysubstituted；
R4, R6, R7, R8, and n has implication as described in the present invention.
In some embodiments, each n1 independently is 0,1,2,3 or 4.
In some embodiments, each n independently is 0,1,2,3 or 4.
In some embodiments, each t independently is 0,1, or 2.
In some embodiments, each R6It independently is hydrogen, C1-6Alkyl, hydroxyl, carboxyl, amino, C1-6Alkoxy, H2N- (CH2)n-, NH2- C (=O)-, aldehyde radical, H- (CH2)n- O-C (=O)-(CH2)n-, C3-9Heterocyclic radical, C1-9Heteroaryl, C1-6Halo Alkyl or C1-6Alkylamino；
N has implication as described in the present invention.
In some embodiments, each R7It independently is hydrogen, C1-6Alkyl, hydroxyl, carboxyl, amino, C1-6Alkoxy, H2N- (CH2)n-, NH2- C (=O)-, aldehyde radical, H- (CH2)n- O-C (=O)-(CH2)n-, C3-9Heterocyclic radical, C1-9Heteroaryl, C1-6Halo Alkyl or C1-6Alkylamino；
N has implication as described in the present invention.
In some embodiments, each R8It independently is hydrogen, oxo (=O), C1-6Alkyl, fluorine, chlorine, bromine, amino, hydroxyl, carboxylic Base, C1-6Alkoxy, C1-6Alkylamino, C1-6Haloalkyl, cyano group, C3-9Heterocyclic radical, C1-9Heteroaryl, H- (CH2)n- O-C (=O)- (CH2)n-, H2N-(CH2)n-, H- (CH2)n-SO2-(CH2)n-, HO- (CH2)n-, HO- (CH2)n- C (=O)-, NH2- C (=O)-, CN-(CH2)n- C (=O)-, C3-9Cycloalkyl or nitro；Each R8Described in alkyl, alkoxy, alkylamino, haloalkyl, H- (CH2)n- O-C (=O)-(CH2)n-, H2N-(CH2)n-, H- (CH2)n-SO2-(CH2)n-, HO- (CH2)n- C (=O)-, HO- (CH2)n-, NH2- C (=O)-, heterocyclic radical, cycloalkyl and heteroaryl are optionally independently by R9Monosubstituted or identical or different is more Substitution；
Each R9It independently is hydrogen, oxo (=O), C1-6Alkyl, fluorine, chlorine, bromine, amino, hydroxyl, carboxyl, C1-6Alkoxy, C1-6Alkylamino, C1-6Haloalkyl, aldehyde radical, cyano group, HO- (C (R4)2)n-, H- (C (R4)2)n- O-C (=O)-(C (R4)2)n-, CN-C(R4)2- C (=O)-, H2N-(C(R4)2)n-, H- (C (R4)2)n-SO2-(C(R4)2)n-, HO- (C (R4)2)n- C (=O)-, N (R6R7)-C (=O)-, C3-9Heterocyclic radical, C1-9Heteroaryl, C3-9Cycloalkyl or nitro；
R4, R6, R7There is implication as described in the present invention with n.
In some embodiments, compound of the present invention, it is the compound as shown in formula (II), or shown in formula (II) Compound stereoisomer, geometric isomer, dynamic isomer, nitrogen oxides, hydrate, solvate, metabolite, Pharmaceutically acceptable salt or prodrug,
Wherein, whenForWhen, T1For Y6；
WhenForWhen, T1For Y1；
Wherein, Y and Y1It is each independently-C (R4)2- ,-N (R5)-,-O- ,-S (=O)t- or-C (=O)-；
Y3, Y4, Y5And Y6It is each independently CR4Or N；
Wherein, R1, R2, R3, L1, t, each R4With each R5With implication as described in the present invention.
In some embodiments, compound of the present invention, it is compound as shown in formula (III), or formula (III) institute The stereoisomer for the compound shown, geometric isomer, dynamic isomer, nitrogen oxides, hydrate, solvate, metabolism production Thing, pharmaceutically acceptable salt or prodrug,
Wherein, Y, Y2And Y1It is each independently-C (R4)2- ,-N (R5)-,-O- ,-S (=O)t- or-C (=O)-；
Y3, Y4, Y5And Y6It is each independently CR4Or N；
Wherein, R1, R2, R3, L1, t, each R4With each R5With implication as described in the present invention.
In some embodiments,
Each R5It independently is hydrogen, C1-4Alkyl, C1-4Haloalkyl, H- (C (R4)2)n- O-C (=O)-(C (R4)2)n-, (R6R7)N-(C(R4)2)n-, HO- (C (R4)2)n- C (=O)-, N (R6R7)-C (=O)-, HO- (C (R4)2)n-, H- (C (R4)2)n- O-(C(R4)2)n-, H- (C (R4)2)n-SO2-(C(R4)2)n-, H- (C (R4)2)n- C (=O)-(C (R4)2)n-, CN- (C (R4)2)n- C (=O)-, H- (C (R4)2)n- O-C (=O)-C (=O)-(C (R4)2)n-, C3-6Heterocyclic radical or C1-9Heteroaryl；
Wherein, R4, R7, R6, n has implication as described in the present invention.
In some embodiments,
Each R4It independently is hydrogen, H2N-(CH2)n-, N (R6R7)-C (=O)-, H- (CH2)n- O-C (=O)-(CH2)n-, CN- (CH2)n- C (=O)-, H- (CH2)n-O-(CH2)n-, C1-4Alkyl, hydroxyl, fluorine, chlorine, bromine, carboxyl, amino, C1-4Alkoxy, C3-6 Heterocyclic radical, C1-9Heteroaryl, C1-4Haloalkyl or C1-4Alkylamino；
Wherein, each R7, each R6, each n has implication as described in the present invention.
In some embodiments,
Each R5cIt independently is hydrogen, C1-4Alkyl, C1-4Haloalkyl, H- (C (R4)2)n- O-C (=O)-(C (R4)2)n-, (R6R7)N-(C(R4)2)n-, HO- (C (R4)2)n- C (=O)-, N (R6R7)-C (=O)-, HO- (C (R4)2)n-, H- (C (R4)2)n- O-(C(R4)2)n-, H- (C (R4)2)n-SO2-(C(R4)2)n-, H- (C (R4)2)n- C (=O)-(C (R4)2)n-, CN- (C (R4)2)n- C (=O)-, H- (C (R4)2)n- O-C (=O)-C (=O)-(C (R4)2)n-, C3-6Heterocyclic radical or C1-9Heteroaryl；
Wherein, R4, R7, R6, n has implication as described in the present invention.
In some embodiments,
Each R4cIt independently is hydrogen, H2N-(CH2)n-, N (R6R7)-C (=O)-, H- (CH2)n- O-C (=O)-(CH2)n-, CN- (CH2)n- C (=O)-, H- (CH2)n-O-(CH2)n-, C1-4Alkyl, hydroxyl, fluorine, chlorine, bromine, carboxyl, amino, C1-4Alkoxy, C3-6 Heterocyclic radical, C1-9Heteroaryl, C1-4Haloalkyl or C1-4Alkylamino；
Wherein, each R7, each R6, each n has implication as described in the present invention.
In some embodiments,
Each R6It independently is hydrogen, C1-4Alkyl, hydroxyl, carboxyl, amino, C1-4Alkoxy, H2N-(CH2)n-, NH2- C (= O)-, H- (CH2)n- O-C (=O)-(CH2)n-, C3-9Heterocyclic radical, C1-9Heteroaryl, C1-4Haloalkyl or C1-4Alkylamino；
Wherein, each n has implication as described in the present invention.
In some embodiments,
Each R7It independently is hydrogen, C1-4Alkyl, hydroxyl, carboxyl, amino, C1-4Alkoxy, H2N-(CH2)n-, NH2- C (= O)-, H- (CH2)n- O-C (=O)-(CH2)n-, C3-9Heterocyclic radical, C1-9Heteroaryl, C1-4Haloalkyl or C1-4Alkylamino；
Wherein, each n has implication as described in the present invention.
In some embodiments,
Each R5It independently is H- (C (R4)2)n- O-C (=O)-(C (R4)2)n-, (R6R7)N-(C(R4)2)n-, HO- (C (R4)2)n- C (=O)-, N (R6R7)-C (=O)-, HO- (C (R4)2)n-, H- (C (R4)2)n-O-(C(R4)2)n-, H- (C (R4)2)n- SO2-(C(R4)2)n-, H- (C (R4)2)n- C (=O)-(C (R4)2)n-, CN- (C (R4)2)n- C (=O)-, H- (C (R4)2)n-O-C (=O)-C (=O)-(C (R4)2)n-, hydrogen, trifluoromethyl, 2- fluoro ethyls, 3,3,3- trifluoro propyls, methyl, ethyl, n-propyl, Isopropyl, the tert-butyl group, 2- methyl-propyls, or normal-butyl；
Wherein, each R4, each R7, each R6, each n has implication as described in the present invention.
In some embodiments,
Each R4It independently is hydrogen, methyl, ethyl, n-propyl, isopropyl, the tert-butyl group, normal-butyl, 2- methyl-propyls, hydroxyl, Carboxyl, amino, methoxyl group, H2N-(CH2)n-, N (R6R7)-C (=O)-, H- (CH2)n- O-C (=O)-(CH2)n-, CN- (CH2)n- C (=O)-, H- (CH2)n-O-(CH2)n-, trifluoromethyl or methylamino；
Wherein, each R7, each R6, each n has implication as described in the present invention.
In some embodiments,
Each R5cIt independently is H- (C (R4)2)n- O-C (=O)-(C (R4)2)n-, (R6R7)N-(C(R4)2)n-, HO- (C (R4)2)n- C (=O)-, N (R6R7)-C (=O)-, HO- (C (R4)2)n-, H- (C (R4)2)n-O-(C(R4)2)n-, H- (C (R4)2)n- SO2-(C(R4)2)n-, H- (C (R4)2)n- C (=O)-(C (R4)2)n-, CN- (C (R4)2)n- C (=O)-, H- (C (R4)2)n-O-C (=O)-C (=O)-(C (R4)2)n-, hydrogen, trifluoromethyl, 2- fluoro ethyls, 3,3,3- trifluoro propyls, methyl, ethyl, n-propyl, Isopropyl, the tert-butyl group, 2- methyl-propyls, or normal-butyl；
Wherein, each R4, each R7, each R6, each n has implication as described in the present invention.
In some embodiments,
Each R4cIt independently is hydrogen, methyl, ethyl, n-propyl, isopropyl, the tert-butyl group, normal-butyl, 2- methyl-propyls, hydroxyl, Carboxyl, amino, methoxyl group, H2N-(CH2)n-, N (R6R7)-C (=O)-, H- (CH2)n- O-C (=O)-(CH2)n-, CN- (CH2)n- C (=O)-, H- (CH2)n-O-(CH2)n-, trifluoromethyl or methylamino；
Wherein, each R7, each R6, each n has implication as described in the present invention.
In some embodiments,
Each R6It independently is hydrogen, methyl, ethyl, n-propyl, isopropyl, the tert-butyl group, normal-butyl, 2- methyl-propyls, hydroxyl, Carboxyl, amino, methoxyl group, H2N-(CH2)n-, NH2- C (=O)-, H- (CH2)n- O-C (=O)-(CH2)n-, trifluoromethyl or first Amino；
Wherein, each n has implication as described in the present invention.
In some embodiments,
Each R7It independently is hydrogen, methyl, ethyl, n-propyl, isopropyl, the tert-butyl group, normal-butyl, 2- methyl-propyls, hydroxyl, Carboxyl, amino, methoxyl group, H2N-(CH2)n-, NH2- C (=O)-, H- (CH2)n- O-C (=O)-(CH2)n-, trifluoromethyl or first Amino；
Wherein, each n has implication as described in the present invention.
In some embodiments,
Each R8It independently is hydrogen, oxo (=O), C1-4Alkyl, fluorine, chlorine, bromine, amino, hydroxyl, carboxyl, C1-4Alkoxy, C1-4Alkylamino, C1-4Haloalkyl, H- (CH2)n- O-C (=O)-(CH2)n-, H2N-(CH2)n-, H- (CH2)n-SO2-(CH2)n-, HO-(CH2)n-, HO- (CH2)n- C (=O)-, NH2- C (=O)-, cyano group, CN- (CH2)n- C (=O)-, C1-9Heteroaryl,Or nitro；
Wherein, X1, X, e, f, each n has implication as described in the present invention.
In some embodiments,
Each R9It independently is hydrogen, oxo (=O), C1-4Alkyl, fluorine, chlorine, bromine, amino, hydroxyl, carboxyl, C1-4Alkoxy, C1-4Alkylamino, C1-4Haloalkyl, cyano group, HO- (C (R4)2)n-, H- (C (R4)2)n- O-C (=O)-(C (R4)2)n-, CN-C (R4)2- C (=O)-, H2N-(C(R4)2)n-, H- (C (R4)2)n-SO2-(C(R4)2)n-, HO- (C (R4)2)n- C (=O)-, N (R6R7)-C (=O)-,C1-9Heteroaryl or nitro；
Wherein, each R4, R7, R6, X1, X, e, f, each n has implication as described in the present invention.
In some embodiments,
X and X1It is each independently-C (R4a)2- ,-N (R5a)-,-O- ,-S (=O)t- or-C (=O)-；
Wherein, each R4a, each R5a, t has implication as described in the present invention.
In some embodiments,
Each R5aIt independently is hydrogen, C1-6Alkyl, C1-6Haloalkyl, H- (C (R4)2)n- O-C (=O)-(C (R4)2)n-, (R6R7)N-(C(R4)2)n-, HO- (C (R4)2)n- C (=O)-, N (R6R7)-C (=O)-, HO- (C (R4)2)n-, H- (C (R4)2)n- O-(C(R4)2)n-, H- (C (R4)2)n-SO2-(C(R4)2)n-, H- (C (R4)2)n- C (=O)-(C (R4)2)n-, CN- (C (R4)2)n- C (=O)-, H- (C (R4)2)n- O-C (=O)-C (=O)-(C (R4)2)n-, C3-9Heterocyclic radical or C1-9Heteroaryl；
Wherein, each R4, each R7, each R6, each n has implication as described in the present invention.
In some embodiments,
Each R4aIt independently is hydrogen, C1-6Alkyl, hydroxyl, fluorine, chlorine, bromine, carboxyl, amino, C1-6Alkoxy, H2N-(CH2)n-, N (R6R7)-C (=O)-, aldehyde radical, H- (CH2)n- O-C (=O)-(CH2)n-, H- (CH2)n-O-(CH2)n-, CN- (CH2)n- C (= O)-, C3-9Heterocyclic radical, C1-9Heteroaryl, C1-6Haloalkyl or C1-6Alkylamino；
Wherein, each R7, each R6, each n has implication as described in the present invention.
In some embodiments,
Each e independently is 0,1,2 or 3.
In some embodiments,
Each f independently is 0,1,2 or 3.
In some embodiments,
Each R8It independently is hydrogen, oxo (=O), methyl, ethyl, n-propyl, isopropyl, the tert-butyl group, normal-butyl, 2- methyl Propyl group, fluorine, chlorine, bromine, amino, hydroxyl, carboxyl, methoxyl group, ethyoxyl, 1- chloroethyls, dimethylamino, diethylamino, first Base amino, trifluoromethyl, cyano group, H-(CH2)n- O-C (=O)-(CH2)n-, H2N-(CH2)n-, H- (CH2)n-SO2-(CH2)n-, HO- (CH2)n-, HO- (CH2)n- C (=O)-, NH2- C (=O)-, CN- (CH2)n- C (=O)-, or nitro；
N has implication as described in the present invention.
In some embodiments,
Each R9It independently is hydrogen, oxo (=O), methyl, ethyl, n-propyl, isopropyl, the tert-butyl group, normal-butyl, 2- methyl Propyl group, fluorine, chlorine, bromine, amino, hydroxyl, carboxyl, C1-4Alkoxy, C1-4Alkylamino, C1-4Haloalkyl, HO- (C (R4)2)n-, H- (C(R4)2)n- O-C (=O)-(C (R4)2)n-, CN-C (R4)2- C (=O)-, H2N-(C(R4)2)n-, H- (C (R4)2)n-SO2-(C (R4)2)n-, cyano group, HO- (C (R4)2)n- C (=O)-, N (R6R7)-C (=O)-, C1-9Heteroaryl or nitro；
Each R4, R6, R7, n has implication as described in the present invention.
In some embodiments,
R3For hydrogen,
Wherein, X2, X6And X7It is each independently-C (R4b)2- ,-N (R5b)-,-O- ,-S (=O)t- or-C (=O)-；
X3, X4And X5It is each independently CR4bOr N；
Each e, g and f independently are 0,1,2 or 3；
R3Optionally independently by R8Monosubstituted or identical or different is polysubstituted；
Each R8Optionally independently by R9Monosubstituted or identical or different is polysubstituted；
Wherein, each R4b, each R5b, each t, each R8With each R9With implication as described in the present invention.
In some embodiments,
Each R5bIt independently is hydrogen, C1-6Alkyl, C1-6Haloalkyl, H- (C (R4)2)n- O-C (=O)-(C (R4)2)n-, (R6R7)N-(C(R4)2)n-, HO- (C (R4)2)n- C (=O)-, N (R6R7)-C (=O)-, HO- (C (R4)2)n-, H- (C (R4)2)n- O-(C(R4)2)n-, H- (C (R4)2)n-SO2-(C(R4)2)n-, H- (C (R4)2)n- C (=O)-(C (R4)2)n-, CN- (C (R4)2)n- C (=O)-, H- (C (R4)2)n- O-C (=O)-C (=O)-(C (R4)2)n-, C3-9Heterocyclic radical or C1-9Heteroaryl；
Wherein, each R4, each R7, each R6, each n has implication as described in the present invention.
In some embodiments,
Each R4bIt independently is hydrogen, C1-6Alkyl, hydroxyl, fluorine, chlorine, bromine, carboxyl, amino, C1-6Alkoxy, H2N-(CH2)n-, N (R6R7)-C (=O)-, aldehyde radical, H- (CH2)n- O-C (=O)-(CH2)n-, H- (CH2)n-O-(CH2)n-, CN- (CH2)n- C (= O)-, C3-9Heterocyclic radical, C1-9Heteroaryl, C1-6Haloalkyl or C1-6Alkylamino；
Wherein, each R7, each R6, each n has implication as described in the present invention.
In some embodiments,
Each R5bIt independently is H- (C (R4)2)n- O-C (=O)-(C (R4)2)n-, (R6R7)N-(C(R4)2)n-, HO- (C (R4)2)n- C (=O)-, N (R6R7)-C (=O)-, HO- (C (R4)2)n-, H- (C (R4)2)n-O-(C(R4)2)n-, H- (C (R4)2)n- SO2-(C(R4)2)n-, H- (C (R4)2)n- C (=O)-(C (R4)2)n-, CN- (C (R4)2)n- C (=O)-, H- (C (R4)2)n- O-C (= O)-C (=O)-(C (R4)2)n-, hydrogen, trifluoromethyl, 2- fluoro ethyls, 3,3,3- trifluoro propyls, methyl, ethyl, n-propyl, isopropyl Base, the tert-butyl group, 2- methyl-propyls, Or Normal-butyl；
Wherein, each R4, each R7, each R6, each n has implication as described in the present invention.
In some embodiments,
Each R4bIt independently is hydrogen, methyl, ethyl, n-propyl, isopropyl, the tert-butyl group, normal-butyl, 2- methyl-propyls, hydroxyl, Carboxyl, amino, methoxyl group, H2N-(CH2)n-, N (R6R7)-C (=O)-, H- (CH2)n- O-C (=O)-(CH2)n-, CN- (CH2)n- C (=O)-, H- (CH2)n-O-(CH2)n-, Trifluoromethyl or methylamino；
Wherein, each R7, each R6, each n has implication as described in the present invention.
In some embodiments,
R3For hydrogen,
N is 0,1,2 or 3；
Described R3Representative subformula is optionally independently by R8Monosubstituted or identical or different is polysubstituted；
Each R8With implication as described in the present invention.
In some embodiments
B rings are
R4And R5With implication as described in the present invention.
In some embodiments,For following subformula：
Wherein, Y, Y1And Y2It is each independently-C (R4)2- ,-N (R5)-,-O- ,-S (=O)t- or-C (=O)-；
Y3, Y4, Y5And Y6It is each independently CR4Or N；
T, R4And R5With implication as described in the present invention.
In some embodiments,For following subformula：
R4And R5With implication as described in the present invention.
In some embodiments, compound of the present invention, it is the compound with one of following structure, or under having The stereoisomer of one of the row compound of structure, geometric isomer, dynamic isomer, nitrogen oxides, hydrate, solvation Thing, metabolite, pharmaceutically acceptable salt or prodrug,
On the one hand, the present invention provides a kind of pharmaceutical composition, includes a kind of compound as described herein.
In some embodiments, pharmaceutical composition of the present invention, further comprising pharmaceutically acceptable carrier, figuration At least one of agent, diluent, assistant agent, medium.
In some embodiments, pharmaceutical composition of the present invention, further comprising additional therapeutic agent, these add and controlled Treatment agent is chemotherapeutic agent, antiproliferative, immunodepressant, immunostimulant, and anti-inflammatory reagent is athero- for treating artery The medicine of hardening, for treating the medicine or combinations thereof of pulmonary fibrosis.
In some embodiments, pharmaceutical composition of the present invention, wherein described additional therapeutic agent is Chlorambucil, Melphalan, endoxan, ifosfamide, busulfan, BCNU, lomustine, Streptozotocin, cis-platinum, carboplatin are difficult to understand husky Sharp platinum, Dacarbazine, Temozolomide, procarbazine, methotrexate (MTX), fluorouracil, cytarabine, gemcitabine, purinethol, Fludarabine, vincaleukoblastinum, vincristine, vinorelbine, taxol, Docetaxel, TPT, Irinotecan, rely on pool Glycosides, ET-743, dactinomycin D, Doxorubicin, epirubicin, daunomycin, mitoxantrone, bleomycin, mitomycin C, Ipsapirone, TAM, Flutamide, Gonadorelin analog, megestrol acetate, prednisone, dexamethasone, methylprednisolone are husky Sharp degree amine, interferon-' alpha ', Calciumlevofolinate, sirolimus, temsirolimus, everolimus, Afatinib, alisertib, Amuvatinib, Ah pa replace Buddhist nun, Axitinib, bortezomib, SKI-606, brivanib, cabozantinib, Xi Dini Cloth, crenolanib, gram Zhuo replace Buddhist nun, dabrafenib, dacomitinib, danusertib, Dasatinib, dovitinib, Tarceva, foretinib, ganetespib, Gefitinib, ibrutinib, Conmana, Imatinib, iniparib, Lapatinib, lenvatinib, linifanib, linsitinib, Masitinib, momelotinib, not for husky Buddhist nun, come that and replace Buddhist nun, nilotinib, niraparib, oprozomib, olaparib, pazopanib, pictilisib, ponatinib, Quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, saracatinib, saridegib, Sorafenib, Sutent, tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, Trametinib, ZD6474, veliparib, Wei Luofeini, vismodegib, volasertib, alemtuzumab, shellfish cut down list It is anti-, brentuximab vedotin, catumaxomab, Cetuximab, ground promise monoclonal antibody, lucky trastuzumab, her monoclonal antibody, Buddhist nun Trastuzumab, difficult to understand, Victibix, Rituximab, tositumomab, Herceptin, card is rich to replace Buddhist nun, and Pu Na is replaced Buddhist nun, Midostaurin, Pacritinib, quizartinib, gilteritinib, AKN-028, AT-9283, Crenolanib, ENMD-2076, Famitinib, Dovitinib, PLX-3397, palbociclib, abemaciclib, Ribociclib, rigosertib sodium, Selinexor, Roniciclib, AT-7519, Seliciclib, Alvocidib or combinations thereof.
On the other hand, compound of the present invention or pharmaceutical composition of the present invention are being prepared for preventing, and are located Reason, treatment or mitigates patient by abnormal cell proliferation, autoimmunity, in obstacle caused by inflammatory or infection or the medicine of illness Purposes.
In some embodiments, purposes of the present invention, wherein described abnormal cell proliferation disease refers to oophoroma, son Cervical carcinoma, carcinoma of testis, cancer of the esophagus, stomach cancer, cutaneum carcinoma, lung cancer, osteocarcinoma, acute myeloid leukaemia, chronic myelogenous leukemia, stomach and intestine Stromal tumors, acute myelocytic leukemia (AML), the chronic myelogenous leukemia (CML) of mutation, ALL (ALL), colorectal cancer, stomach cancer, breast cancer, lung cancer, liver cancer, prostate cancer, cancer of pancreas, thyroid cancer, kidney, brain tumor, neck cancer, The cancer of central nervous system, glioblastoma, myeloproliferative disease, atherosclerosis, pulmonary fibrosis, leukaemia, lymph cancer, Rheumatic disease, cryoglobulinemia, non-lymphoreticular system tumour, papular mucinosis, familial splenic anemia, Huppert's disease, amyloidosis, solitary plasmacytoma, heavy chain disease, light chain disease, malignant lymphoma, chronic lymphocytic are white Blood disease, primary macroglobulinaemia, half molecule disease, monocytic leukemia, primary macroglobulinaemia purpura, Secondary cases Benign monoclonal gammopathy, osteolytic lesion, lymphoblastoma, part NHL, Sezary synthesis Sign, infectious mononucleosis, acute histocytic increase disease, Hodgkin lymphoma, hairy cell leukemia, colon cancer, The carcinoma of the rectum, polyposis intestinalis, ED-SCLC, neuroblastoma, neuroendocrine cell tumour, islet-cell tumour, thyroid gland Cephaloma, melanoma, retinoblastoma, uterine cancer, oophoroma, G. cephalantha, malignant tumor of digestive tract are non-small thin Born of the same parents' lung cancer, cervical carcinoma, orchioncus, glioblastoma, lymphoma mantle cell, chronic myelocytic leukemia, acute myelogenous Leukaemia, carcinoma of urinary bladder or myeloma.
In some embodiments, purposes of the present invention, wherein, the autoimmune disease is rheumatic arthritis, wolf Sore, multiple sclerosis, thyroiditis, type i diabetes, sarcoidosis, inflammatory bowel disease, Crohn's disease or systemic lupus.
In some embodiments, purposes of the present invention, wherein, wherein described inflammatory disease refers to diverticulitis, colon Inflammation, pancreatitis, hepatitis, chronic hepatitis, hepatic sclerosis, cholecystitis or chronic inflammation.
In some embodiments, purposes of the present invention, wherein described infectious disease refers to virus infection and fungi sense Dye.
In some embodiments, purposes of the present invention, change wherein the disease is cell cycle protein dependent kinase Disease caused by change.
In other embodiment, purposes of the present invention, wherein described cell cycle protein dependent kinase is Refer to CDK1, CDK2, CDK4, CDK6 or CDK9.
In some embodiments, purposes of the present invention, draw wherein the disease is the change of CDK4 or CDK6 protein kinases The disease risen.
On the one hand, the present invention provides a kind of medication combined, and it includes compound of the present invention or of the present invention Pharmaceutical composition and one or more other active drugs for being used to treat proliferative diseases, autoimmune disease or inflammatory disease Agent.
It is of the present invention medication combined in some embodiments, wherein other described active agents refer to chemotherapy Medicine, antiproliferative, immunodepressant, immunostimulant, anti-inflammatory reagent, CDK4/6 kinase inhibitors, ABL inhibitor, ABL/Scr inhibitor, aurora kinase inhibitors, Bcr-ABL non-ATP competitive inhibitors, c-KIT inhibition from mutation agent, RET Inhibitor, PDGFR inhibitor, VEGFR inhibitor, CSF1R inhibitor, FLT3 inhibitor, FLT3-ITD inhibitor or they Combination.
On the one hand, the present invention provides a kind of protection, processing, treatment or mitigates patient's abnormal cell proliferation, and autoimmunity is scorching Property or infection caused by the method for obstacle or illness, its method, which includes, gives the patient of the infection or disease as described herein Compound or pharmaceutical composition of the present invention effective therapeutic dose.
On the other hand, compound of the present invention or described pharmaceutical composition are used to protect, handle, treat or mitigate Obstacle or illness caused by patient's abnormal cell proliferation, autoimmunity, inflammatory or infection.
Unless otherwise indicated, the stereoisomer that the compound of the present invention is all, geometric isomer, tautomerism Body, nitrogen oxides, hydrate, solvate, metabolite, salt and pharmaceutically acceptable prodrug belong to the model of the present invention Enclose.Specifically, salt is pharmaceutically acceptable salt." pharmaceutically acceptable " material or composition of including of term must be suitable Combination or toxicology, with forming the other components of preparation and relevant for the mammal for the treatment of.The compound of the present invention Salt also includes being used to preparing or purifying formula (I)-intermediate of compound shown in formula (III) or formula (I)-chemical combination shown in formula (III) The salt of the enantiomter of thing separation, but it is not necessarily pharmaceutically acceptable salt.
If the compound of the present invention is alkaline, conceivable salt can be any suitable by what is provided on document Method is prepared, for example, using inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid etc..Or using organic Acid, such as acetic acid, maleic acid, butanedioic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, malic acid, Lactic acid citric acid, Oxalic acid, glycolic and salicylic acid；Pyrans saccharic acid, such as glucuronic acid and galacturonic acid；Alpha-hydroxy acid, such as citric acid and winestone Acid；Amino acid, such as asparatate and glutamic acid；Aromatic acid, such as benzoic acid and cinnamic acid；Sulfonic acid, such as p-methyl benzenesulfonic acid, benzene Sulfonic acid, methanesulfonic acid, ethyl sulfonic acid, trifluoromethanesulfonic acid etc. or combinations thereof.
If the compound of the present invention is acid, conceivable salt can be prepared by suitable method, e.g., Using inorganic base or organic base, such as ammonia (primaquine, parahelium, tertiary ammonia), alkali metal hydroxide, ammonium, N+(R14)4Salt and alkaline earth gold Belong to hydroxide, etc..Suitable salt includes, but is not limited to, the organic salt obtained from amino acid, such as glycine and smart ammonia Acid, ammonia, such as primaquine, parahelium and tertiary ammonia, N+(R14)4Salt, such as R14It is H, C1-4Alkyl, C6-10Aryl, C6-10Aryl C1-4Alkyl Deng, and ring-type ammonia, such as piperidines, morpholine and piperazine etc., and obtain inorganic salts from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminium and lithium. Also appropriate, nontoxic ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halide, hydroxide, carboxylation are included Thing, hydrosulphate, phosphoric acid compound, nitric acid compound, C1-8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.
The compounds of this invention is CDK4 and CDK6 special inhibitor, and therefore can be used for treatment to increase with abnormal cell Grow the disease being characterized or obstacle.Specifically, the compounds of this invention can be used for treating cancer.
The effect that CDK4 and CDK6 passes through their cell cycles of pRb phosphorylated regulation.It is expected the compounds of this invention (its Effective inhibitor of CDK4/6 activity so as to suppressing pRb phosphorylations) suppress in any cancer types cell propagation (and because This suppresses tumour growth), cell is bred and comprising functional complete Rb1 gene (its in described cancer types Encode pRb).Therefore, the compounds of this invention can be used for treatment mammal in pRb+ cancers, such as colorectal cancer, breast cancer, Lung cancer, prostate cancer, chronic myelocytic leukemia, acute myeloblastic leukemia (Fry, D.W. et al. .Mol.Cancer Ther. (2004), 3 (11), 1427), lymphoma mantle cell (Marzec, M. et al., Blood (2006), 108 (5), 1744), oophoroma (Kim, T.M. et al., Cancer Research (1994), 54,605), cancer of pancreas (Schutte, M. et al., Cancer Research (1997), 57,3126), chromoma and metastatic malignant melanoma (Maelandsmo, G.M. et al., British Journal of Cancer (1996), 73,909).It is also expected to the compounds of this invention can be used for treating mammal In rhabdomyosarcoma (Saab, R. et al., Mol.Cancer Ther. (2006), 5 (5), 1299) and Huppert's disease (Baughn, L.B. et al., Cancer Res. (2006), 66 (15), 7661).Some embodiments, the mammal treated are People.
The compounds of this invention can be used for treating the method for cancer in mammal, particularly above-mentioned cancer, this method bag Include to need the treatment mammal apply effective dose the compounds of this invention.
In certain embodiments, the compounds of this invention can be used for the method for the treatment of cancer, and described cancer is selected from colon The carcinoma of the rectum, lymphoma mantle cell, breast cancer, glioblastoma, acute myeloblastic leukemia and lung cancer, particularly non-small cell Lung cancer.
In further embodiments, the compounds of this invention can be used for the method for the treatment of cancer, and described cancer is selected from knot The intestines carcinoma of the rectum, glioblastoma, acute myeloblastic leukemia and lung cancer.
In further embodiments, the compounds of this invention can be used for treating glioblastoma or star in mammal The method of cytoma, described method include applying therapeutically effective the compounds of this invention and to the mammal needed for not azoles The combination of amine.
In further embodiments, the compounds of this invention can be used for treating non-small cell lung cancer, pancreas in mammal The method of cancer, oophoroma or metastatic breast cancer, this method include applying the therapeutically effective present invention to the mammal needed The combination of compound and gemcitabine hydrochloride.
In addition, the compounds of this invention can be used for preparing the medicine for treating cancer, particularly above-mentioned cancer.
In certain embodiments, the compounds of this invention can be used for preparing the medicine for treating cancer, described cancer Selected from colorectal cancer, lymphoma mantle cell, breast cancer, glioblastoma, acute myeloblastic leukemia and lung cancer, it is particularly Non-small cell lung cancer.
In further embodiments, the compounds of this invention, which can be used for preparing, is used for treating cancer medicine, described cancer Selected from colorectal cancer, glioblastoma, acute myeloblastic leukemia and lung cancer.
In further embodiments, the invention provides the compounds of this invention prepare be used for treat glioblastoma or Purposes in the medicine of astrocytoma, wherein medicine also include Temozolomide either with Temozolomide simultaneously, separate or according to Secondary administration.
In further embodiments, the invention provides the compounds of this invention prepare be used for treat non-small cell lung cancer, Purposes in the medicine of cancer of pancreas, oophoroma or metastatic breast cancer, wherein medicine also include gemcitabine hydrochloride either with What gemcitabine hydrochloride was simultaneously, separately or sequentially applied.The pharmaceutical preparation for the treatment of cancer, particularly above-mentioned cancer is additionally provided, Described pharmaceutical preparation includes the compounds of this invention or its officinal salt and pharmaceutical acceptable carrier.
In certain embodiments, the pharmaceutical preparation for the treatment of cancer is additionally provided, described cancer is selected from colorectal cancer, set Cell lymphoma, breast cancer, glioblastoma, acute myeloblastic leukemia and lung cancer, particularly non-small cell lung cancer, it is described Pharmaceutical preparation include the compounds of this invention or its officinal salt and pharmaceutical acceptable carrier.
In certain embodiments, the pharmaceutical preparation for the treatment of cancer is additionally provided, described cancer is selected from colorectal cancer, glue Matter blastoma, acute myeloblastic leukemia and lung cancer, described pharmaceutical preparation include the compounds of this invention or its officinal salt And pharmaceutical acceptable carrier.
In further embodiments, the invention provides treatment glioblastoma or astrocytoma pharmaceutical preparation, Described pharmaceutical preparation includes the compounds of this invention and Temozolomide and pharmaceutical acceptable carrier.
In further embodiments, the invention provides treatment non-small cell lung cancer, cancer of pancreas, oophoroma or metastatic breast The pharmaceutical preparation of gland cancer, described pharmaceutical preparation include the compounds of this invention and gemcitabine hydrochloride and pharmaceutical acceptable carrier.
Present invention also offers pharmaceutical preparation, and it includes the compounds of this invention or its officinal salt and Temozolomide, and Pharmaceutical acceptable carrier, diluent or excipient.
Present invention also offers pharmaceutical preparation, and it includes the compounds of this invention or its officinal salt and gemcitabine hydrochloride, And pharmaceutical acceptable carrier, diluent or excipient.
Invention further provides pharmaceutical preparation, and it includes the compounds of this invention or its officinal salt and pharmaceutically acceptable load Body and optional other therapeutic components.
Purposes in cancer, graft rejection and autoimmune disease
The compound of the present invention has valuable pharmacological property, available for treating disease.In certain embodiments, originally The compound of invention can be used for treatment proliferative diseases or cancer.
Proliferative diseases are mainly tumor disease (or cancer) (and/or any transfer stove).The compound of the present invention is special It is that can be used for treating following tumour：Breast cancer, apparatus urogenitalis cancer, lung cancer, human primary gastrointestinal cancers, epidermoid carcinoma, melanoma, oophoroma, Cancer of pancreas, neuroblastoma, head and/or neck cancer or carcinoma of urinary bladder, or from the perspective of from more broadly, available for treatment kidney, the cancer of the brain Or stomach cancer；Particularly (i) mammary tumor；Epiderm-like tumour, such as epiderm-like head and/or neck tumour or mouth neoplasm；Lung neoplasm, example Such as cellule or non-fire power；Stomach and intestine tumor, for example, colorectal tumours；Or urogenital neoplasm, for example, Tumor of prostate (especially hormone tumor of prostate difficult to treat)；Or (ii) with other chemotherapeutics proliferative difficult to treat Disease；Or (iii) due to multi-drug resistant and with other chemotherapeutics tumour difficult to treat.
The present invention it is more broadly on, proliferative diseases can also be excess proliferative (hyperproliferative) feelings Condition, such as leukaemia, hyperplasia, fibrosis (especially pulmonary fibrosis, such as also other types of fibrosis, kidney fibrosis), blood vessel Generation, psoriasis, atherosclerosis and vascular smooth muscle hyperplasia, such as the narrow and ISR of postangioplasty.
Regardless of the position of tumour and/or transfer stove, in the case where referring to tumour, tumor disease, cancer or cancer, make For alternative or additionally, also include the transfer stove in initial organ or tissue and/or any other position.
Compared with normal cell, compound of the invention has selection toxicity or bigger toxicity to the cell bred rapidly, There is significant antiproliferative to make for the cell the bred rapidly particularly human cancer cell, such as cancerous tumour, the compound With and promote to break up, such as cell cycle arrest and Apoptosis.
In other some embodiments, compound of the invention can be used for treating graft rejection.The present invention can be used The example of graft rejection of compounds for treating include but is not limited to graft versus host disease(GVH disease), the row relevant with heterograft Reprimand, the repulsion relevant with organ transplant, the repulsion relevant with acute graft, xenograft or homograft rejection and device The ischemic or reperfusion injury that official occurs during transplanting.
In again other some embodiments, compound of the invention can be used for treating autoimmune disease.It can use The present invention compounds for treating autoimmune disease example include but is not limited to autoimmune hemolytic anemia, itself Immunity neonate decrease of platelet, ITP, LADA haemocyte are reduced, hemolytic is poor Blood, antiphospholipid syndrome, dermatitis, allergic encephalitis, myocarditis, relapsing polychondritis, rheumatic heart disease, glomerulus Ephritis, multiple sclerosis, neuritis, uveitis ophthalmia, polyendocrinopathy, purpura, Reiter, stiff man syndrome, from Body immunity pneumonia, autism, Ji-bar syndrome, insulin-dependent diabetes mellitus, autoimmune inflammatory illness in eye, itself exempt from Epidemic disease thyroiditis, hypothyroidism, systemic loupus erythematosus, goodman's syndrome, pemphigus, acceptor autoimmunity Property, autoimmune hemolytic anemia, autoimmune thrombocytopenic purpura, rheumatoid arthritis, Combination connective Organize disease, polymyositis/dermatomyositis, pernicious anaemia, idiopathic Addison disease, infertile, glomerulonephritis, bullous pemphigoid, It is Sjogren syndrome, diabetes, adrenergic agent drug resistance, CAH, PBC, white After spot, vasculitis, MI, cardiotomy syndrome, nettle rash, atopic dermatitis, asthma, inflammatory myopathy, CAH, PBC and the cell-mediated hypersensitivity disease of T-
If not stated otherwise, when suitable and favourable, term " purposes " includes in the following example of the present invention respectively It is any one or more of：Purposes in the illness relevant with protein kinase is treated；It is used to treat these diseases preparing Purposes in pharmaceutical composition, for example, the purposes in medicine is prepared；The chemical combination of the present invention is used in the treatment of these diseases The method of thing；For the pharmaceutical preparation for the compound containing the present invention for treating these diseases；With for treating these diseases The compound of the present invention.The disease and the preferable purposes of compound therefore of the invention treated are especially selected from cancer, moved Plant repels or autoimmune disease and those diseases dependent on protein kinase activity.Term " purposes " further comprises Be enough to act as the embodiment of this paper combined with protein kinase of tracer or label composition so that when and fluorescence (fluor) or label coupling or be prepared as radioactivity when, can be used as investigational agent or as diagnosticum or developer.
The composition of the compound of the present invention
The present invention provides pharmaceutical composition, the formula (I) comprising therapeutically effective amount-compound or its pharmacy shown in formula (III) Upper acceptable salt and pharmaceutically acceptable carrier, diluent or excipient.When the compound of the present invention is in the form of medicine When being applied to mammal such as people, its can by compound in itself in the form of be given or can with containing such as 0.1 to The form of the pharmaceutical composition of 99.5% (more preferably 0.5 to 90%) active component and pharmaceutically acceptable carrier is given.
" effective dose " is to treat or prevent the illness relevant with protein kinase for example to prevent the illness relevant with protein kinase Various forms and somatization and/or disease as described herein or needed for situation or enough amounts.In an example, The effective dose of the compound of the present invention is the amount for being enough to treat the illness relevant with protein kinase of individual.Effective dose can basis The size and body weight of individual, the factor such as particular compound of the type of illness or the present invention and change.For example, the present invention The selection of compound can influence the composition of " effective dose ".Those of ordinary skill in the art be able to will study the factor that is contained herein and The effective dose of the compound of the present invention is determined in the case of without excessively experiment.
Application program can influence the composition of effective dose.The compound of the present invention can break out in the illness relevant with protein kinase Before or after be applied to individual.Furthermore, it is possible to daily or the multiple divided doses of sequential application and the dosage to stagger, Huo Zheke It is administered with continuous infusion, or can be with inject administration.In addition, the dosage of the compound of the present invention can be according to treatment or prevention The urgency of situation takes the circumstances into consideration to increase or decrease in proportion.
" joint " represents the medicine box of the fixed Combination in single dose unit form or the part for combined administration, its The middle present invention discloses compound and combined partner can be in same time individual application or can be at a certain time interval Apply respectively, joint is closed companion and show cooperation, for example act synergistically.Term " co-administered " as used herein Or " administering drug combinations " etc. are intended to include to be applied to selected COMBINATION OF THE INVENTION needs its single individual (such as patient), and anticipate It is intended to include wherein material without going through identical route of administration or the therapeutic scheme being administered simultaneously.Term " medicine as used herein Combination product " represents more than one active components to be mixed or combined resulting product, and both consolidating including active component Fixed combination also includes non-fixed combinations.Term " fixing joint " represents that active component discloses compound and COMBINATION OF THE INVENTION such as the present invention It is administered simultaneously in the form of single entities or dosage in patient.Term " on-fixed joint " represents that active component discloses such as the present invention Compound Compound and COMBINATION OF THE INVENTION are successively applied to trouble with limiting simultaneously, jointly or without special time as corpus separatum Person, wherein this be applied in the treatment level of significance that patient's body provides two kinds of compounds.The latter applies also for HAART, Such as using 3 kinds or more kind active components.
The compound of the present invention can be used for treating state, illness or disease as described herein, or treat these for preparing The pharmaceutical composition of disease.Application method of the compound in these disease treatments of the present invention or for treating these diseases The pharmaceutical preparation of compound containing the present invention.
Wording " pharmaceutical composition " includes being suitable to the preparation for being applied to mammal such as people.When the present invention compound with When the form of medicine is applied to mammal such as people, its can by compound in itself in the form of be given or can with containing Such as 0.1 to 99.5% (more preferably 0.5 to 90%) active component and pharmaceutically acceptable carrier pharmaceutical composition shape Formula is given.
Wording " pharmaceutically acceptable carrier " is generally acknowledged in the art, including suitable for the compound of the present invention is applied In pharmaceutically acceptable material, composition or the carrier of mammal.The carrier include participate in carry theme material or by its The liquid or solid filler, dilute of another part of another organ or body is transferred to from a part for an organ or body Release agent, excipient, solvent or encapsulating material.Each carrier is in the sense that compatible with other compositions in preparation and harmless to patient Must be " acceptable ".Can be used as some examples of the material of pharmaceutically acceptable carrier includes：Carbohydrate, such as lactose, grape Sugar and sucrose；Starch, such as cornstarch and farina；Cellulose and its derivates, such as sodium carboxymethylcellulose, ethyl Cellulose and cellulose acetate；Powdered gum tragacanth；Malt；Gelatin；Talcum powder；Excipient, such as cocoa butter and suppository wax class；Oil Class, such as peanut oil, cotton seed oil, safflower oil, sesame oil, olive oil, corn oil and soya-bean oil；Glycols, such as propane diols；Polyalcohol Class, such as glycerine, sorbierite, mannitol and polyethylene glycol；Esters, such as ethyl oleate and ethyl laurate；Agar；Buffer, such as Magnesium hydroxide and aluminium hydroxide；Alginic acid；Pyrogen-free water；Isotonic salt solution；Ringer's solution；Ethanol；Phosphate buffer；With Other nontoxic compatible materials used in pharmaceutical preparation.
In the composition there may also be wetting agent, emulsifying agent and lubricant such as lauryl sodium sulfate and magnesium stearate, And colouring agent, releasing agent, coating agent, sweetener, flavouring and aromatic, preservative and antioxidant.
The example of pharmaceutically acceptable antioxidant includes：Water soluble antioxidant, such as ascorbic acid, CYSTEAMINE HCL Acid, niter cake, sodium pyrosulfite, sodium sulfite etc.；Oil-soluble inhibitor, such as ascorbyl palmitate, butylation hydroxyl Base methyl phenyl ethers anisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol etc.；And metal-chelator, such as lemon Lemon acid, ethylenediamine tetra-acetic acid (EDTA), sorbierite, tartaric acid, phosphoric acid etc..
The preparation of the present invention includes being suitable to oral, nose, part, mouth containing, sublingual, rectum, vagina and/or parenteral administration Those.Preparation easily can exist and can be made by any method known to pharmaceutical field with unit dosage forms It is standby.It can be combined with carrier mass to prepare the compound that the amount of the active component of single dose form is usually generation therapeutic action Amount.In general, in units of 1 percent, the amount is about 1% to about 99% active component, preferably from about 5% to about 70%, Most preferably from about 10 to about 30%.
Prepare the method for these preparations or composition include making the compound of the present invention and carrier, optionally with it is a kind of or more The step of kind auxiliary element combines.In general, preparation is by by compound and the liquid-carrier of the present invention or very thin consolidating Body carrier or both uniformly and be bound tightly together and then if desired, the product is molded to prepare.
Preparation of the invention suitable for orally administering can be that capsule, cachet, pill, tablet, lozenge (use flavoring Matrix, usually sucrose and Arabic gum or tragacanth), powder, granule or in water-based or non-aqueous liquid Solution or supensoid agent or oil-in-water or water-in-oil liquid emulsion or elixir or syrup or pastille (use Inert base, such as gelatin and glycerine or sucrose and Arabic gum) and/or collutory form, it is each containing given amount The compound of the present invention is as active component.The compound of the present invention can also be applied in the form of bolus, electuary or paste With.
In solid dosage forms (capsule, tablet, pill, dragee, powder, the granule of the invention for orally administering Deng) in, by active component and one or more pharmaceutically acceptable carriers such as sodium citrate or Dicalcium Phosphate and/or any following Material mixing：Filler or extender, such as starch, lactose, sucrose, glucose, mannitol and/or silicic acid；Adhesive, example Such as, carboxymethyl cellulose, alginic acid salt, gelatin, polyvinylpyrrolidone, sucrose and/or Arabic gum；NMF, such as glycerine； Disintegrant, such as agar, calcium carbonate, farina or tapioca, alginic acid, some silicic acid and sodium carbonate；Solution retarding agents (solution retarding agent), such as paraffin；Sorbefacient, such as quaternary ammonium compound；Wetting agent, for example, cetanol And glyceryl monostearate；Adsorbent, such as kaolin and bentonite；Lubricant, such as talcum powder, calcium stearate, magnesium stearate, solid Polyethylene glycol, lauryl sodium sulfate, and its mixture；And colouring agent.In the case of capsule, tablet and pill, medicine Compositions can also include buffer.The solid composite of similar type can also use excipient such as lactose or toffee and height It is used as filler in the soft hard-filled gelatin capsule of molecular weight polyethylene glycol etc..
Tablet can be prepared by suppressing or moulding, optionally using one or more auxiliary elements.Compressed tablets can With with adhesive (for example, gelatin or hydroxypropyl methyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, Sodium starch glycolate or Ac-Di-Sol), it is prepared by surfactant or dispersant.Molded tablet can be by that will use The mixture of the powder compound of inert liquid diluent wetting is moulded in suitable machine to prepare.
For example dragee, capsule, pill and granule can for other solid dosage forms of the pharmaceutical composition of tablet and the present invention Optionally it is scored or is coated with coating and shell are other as known to enteric coating and pharmaceutical field to prepare.They can also be used Such as the hydroxypropyl methyl cellulose of various ratios of releasing properties needed for providing, other polymer substrates, liposome and/or micro- Ball is prepared to provide the slow release of active component therein or control release.Can be thin for example by using retention by them The filter of bacterium is filtered or by being dissolvable in water using preceding incorporation at once in sterilized water or some other injectable sterile vehicles The bactericidal agent of aseptic solid composite form is sterilized.These compositions also optionally contain opacifier and can be Only or preferentially discharge active component in some part in intestines and stomach, optionally with the combination of delayed mode discharge active component Thing.The example of workable embedding composition includes polymer material and wax class.Active component can also be the form of microencapsulation, If appropriate, using one or more above-mentioned excipient.
The liquid dosage form of compound of the invention for orally administering include pharmaceutically acceptable emulsion, micro emulsion, solution, Suspension, syrup and elixir.In addition to the active ingredient (s, liquid dosage form also contains inert diluent example commonly used in the art As water or other solvents, solubilizer and emulsifying agent for example ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzylalcohol, Ergol, Propane diols, 1,3 butylene glycol, oils (particularly cotton seed oil, peanut oil, corn oil, embryo oil, olive oil, castor oil and sesame Oil), glycerine, tetrahydrofurfuryl alcohol alcohol, polyethylene glycol and the fatty acid ester of anhydrous sorbitol and its mixture.
Besides inert diluents, Orally administered composition can also include assistant agent (adjuvant) such as wetting agent, emulsifying agent and help Suspension, sweetener, flavouring, colouring agent, aromatic and preservative.
In addition to reactive compound, supensoid agent can also include mixture-aid agent, such as ethoxylated isostearyl alcohols, polyoxyethylene mountain Pears alcohol and sorbitan ester, microcrystalline cellulose, inclined aluminium hydroxide (aluminummetahydroxide), bentonite, agar and west Bassora gum and its mixture.
Can exist for rectum or the preparation of the pharmaceutical composition of the invention of vaginal application in the form of suppository, it can With by by the compounds of one or more present invention and one or more suitable non-stimulated excipient or carrier (including example Such as cocoa butter, polyethylene glycol, suppository wax or salicylate) mix to prepare, and it is solid at room temperature, but in body temperature Under be liquid, therefore will be melted in rectum or vaginal canal and discharge reactive compound.
Preparation of the invention suitable for vaginal application also includes the vaginal plug containing carrier suitable as is generally known in the art, defended Raw bolt, cream, gel, paste, foaming agent or spray agent.
The formulation for being used for part or transdermal administration of the compound of the present invention include powder, spray, ointment, paste, Cream, lotion, gel, solution, patch and inhalant.Can by active component aseptically with it is pharmaceutically acceptable Carrier and may need any preservative, buffer or propellant mixing.
In addition to the reactive compound of the present invention, ointment, paste, cream and gel can also include excipient, such as Animal and plant fat, oils, wax class, paraffin class, starch, tragacanth, cellulose derivative, polyethylene glycols, siloxanes Class, bentonite class, silicic acid, talcum powder and zinc oxide or its mixture.
In addition to the compound of the present invention, powder and spray can also include excipient such as lactose, talcum powder, silicic acid, hydrogen The mixture of aluminum oxide, calcium silicates and polyamide powder or these materials.Spray can also include conventional propellant such as CFC Class and volatile unsubstituted hydro carbons, such as butane and propane.
Transdermal patch has the additional advantage that the control for the compound for providing the present invention for body is transmitted.Such formulation can With by the way that compound is dissolved or dispersed in suitable solvent to prepare.Skin can also be passed through using sorbefacient to increase The compound flux of skin.By providing rate-controlling membrane or reactive compound can be scattered in polymer substrate or gel to control The speed of such flowing.
Also include eye-drops preparations, ophthalmic ointment, powder, solution etc. within the scope of the invention.
Pharmaceutical composition of the invention suitable for parenteral administration includes the compound and one of one or more present invention Kind or a variety of pharmaceutically acceptable sterile isotonic water-based or non-aqueous solution, dispersion, supensoid agent or emulsions or can be Using the preceding aseptic powdery being recombined at once in sterile Injectable solution or dispersion, it can include antioxidant, buffering Agent, bacteriostatic agent, cause the blood of preparation and recipient isotonic solute or suspending agent or thickener.
Available for the suitable water-based and example of non-aqueous carrier in the pharmaceutical composition of the present invention include water, ethanol, Polyalcohol (such as glycerine, propane diols, polyethylene glycol etc.) and its suitable mixture, plant oil are such as olive oil and injectable Organosilane ester such as ethyl oleate.Can for example by using coating material such as lecithin, pass through maintenance in the case of dispersion Required granularity and suitable mobility is maintained by using surfactant.
These compositions can also include assistant agent such as preservative, wetting agent, emulsifying agent and dispersant.Can be by comprising various Antibacterial agent and antifungal agent ensure the work of pre- preventing microorganism such as nipagin esters, anesin, phenol, sorbic acid With.It it may also be desirable to include isotonic agent such as carbohydrate, sodium chloride etc. in the composition.Furthermore, it is possible to by including delay absorption Material such as aluminum monostearate and gelatin come cause the extension of injectable drug form absorb.
In some cases, the drug absorption subcutaneously or intramuscularly injected is derived from, it is necessary to slow down to extend the effect of medicine. This can be realized by using the crystallinity of poorly water-soluble or the liquid suspension of amorphous substance.So, the absorption of medicine Speed will depend on its dissolution rate, and dissolution rate is likely to be dependent on crystal size and crystalline form again.Or by the way that medicine is dissolved Or it is suspended in oleaginous base to realize that the extension of the medicament forms of parenteral administration absorbs.
The depot forms of injectable are by forming master in biodegradable polymer such as polylactide-polyglycolide The microencapsule matrices of compound are inscribed to prepare.According to the property of the ratio and particular compound used of medicine and polymer, Can be with Drug controlled release speed.The example of other biodegradable polymers includes poly- (ortho esters) and poly- (acid anhydrides).Can The depot formulations of injection can also be prepared by by medicine bag in the liposome or micro emulsion with tissue-compatible.
The preparation of the present invention can be by oral, parenteral, part or rectal administration.They are certainly to be suitable for each administration The form of approach is given.For example, they are administered in the form of tablet or capsule, by injection, inhalant, ophthalmically acceptable wash Agent, ointment, suppository etc. are administered, and are administered by injecting, being transfused or suck；It is applied topically by lotion or ointment； By suppository by rectal administration.Preferably oral and/or intravenous administration.
Wording " parenteral administration " used herein means the method for application in addition to enteral and local application, typically logical Cross injection to apply, without limitation including intravenous, intramuscular, intra-arterial, in intrathecal, intracapsular, socket of the eye, intracardiac, intradermal, peritonaeum Under interior, transtracheal, subcutaneous, epidermis, under intra-articular, capsule, under arachnoid, in backbone and breastbone inner injection and infusion.
Wording " systemic administration " used herein and " periphery administration " mean that removing for compound, medicine or other materials is direct The administration being applied to beyond central nervous system, so that it enters in the system of patient and therefore carries out metabolism and other phases Like process, such as subcutaneous administration.
These compounds can be applied to people and other animals to be treated by any suitable route of administration, including Orally, nose (such as with spray form), rectum, intravaginal, in parenteral, brain pond and local (with powder, ointment or drops Form) to apply, the local application includes mouth containing and sublingual administration.
, can be with suitable with conventional method well known by persons skilled in the art regardless of selected route of administration The compound of the invention and/or the pharmaceutical composition of the present invention that hydrated form uses are configured to pharmaceutically acceptable formulation.
The actual dose level of active component in the pharmaceutical composition of the present invention can be changed to obtain to particular patient, group Treatment response, the amount of the active component nontoxic to patient needed for can effectively being realized for compound and method of application.
Selected dosage level will depend on many factors, including specific compound of the invention used or its Ester, the activity of salt or acid amides, route of administration, time of application, particular compound used discharge rate, treatment it is lasting when Between, with the particular compound other medicines, compound and/or the material that are applied in combination used, the age of the patient treated, property Not, known similar factor in body weight, situation, general health and the past medical history and medical domain.
Doctor or animal doctor with this area common skill can be readily determined and issue out required pharmaceutical composition Effective dose.For example, doctor or animal doctor can be with the horizontal beginning medicine groups less than the dosage required for therapeutic action needed for acquisition The dosage of compound of the invention used in compound simultaneously gradually increases its dosage until realizing required effect.
In general, the suitable daily dose of the compound of the present invention will be effective lowest dose level for producing therapeutic action Chemical combination object amount.Such effective dose will typically depend on above-mentioned factor.In general, when for shown analgesic activity, this The intravenous and subcutaneous dosage that the compound of invention is used for patient is about 0.0001 to about 100mg/kg body weight/days, more preferably from about 0.01 to about 50mg/kg/ days, still more preferably about 1.0 to about 100mg/kg/ days.Effective dose is that treatment is relevant with protein kinase Illness amount.
If desired, the daily dose of reactive compound can in one day with the two of separate administration, three, four, 5th, six or more sub-doses are applied with suitable time interval, and optionally, the sub-doses are unit dosage forms.
For about 50-70kg individual, pharmaceutical composition of the invention or combination can be about 1-1000mg active components Unit dose, either about 1-500mg or about 1-250mg or about 1-150mg or about 0.5-100mg or about 1-50mg Active component.The treatment effective dose of compound, its pharmaceutical composition or combination depends on the species, body weight, age of individual With individual condition, the obstacle for the treatment of or disease or its order of severity.Doctor, clinician or animal doctor with ordinary skill can It is readily determined prevention, treatment or the effective dose for suppressing every kind of active component needed for the process of obstacle or disease.
Above-mentioned dosage property applies favourable mammal, such as mouse, rat, dog, monkey in testing in vitro and in vivo Or its related organ, tissue or prepared product can illustrate.The compounds of this invention can be in vitro with the solution such as aqueous solution The form application of agent, and can be in vivo with enteral, non-bowel, advantageously to be intravenously for example used as supensoid agent or the aqueous solution Agent application.External dosage range can be about 10-3Mole to 10-9Between molar concentration.Interior therapeutic effective dose scope can take It is between about 0.1-500mg/kg or about 1-100mg/kg certainly in route of administration.
Term " individual " used herein means animal.Generally, animal is mammal.Individual still means that such as primate (such as people, sex), ox, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird etc..In some embodiments In, individual is primate.In other embodiments, individual is people.
Although the compound of the present invention can be administered alone, it is preferred that applying the chemical combination in the form of pharmaceutical composition Thing.
It is medication combined
Using one or more compounds provided by the present invention or composition, or its pharmaceutically acceptable derivates with Other active agent of medicament, which are combined, carrys out combined therapy, for treating disease and illness as described herein.
Oral, systemic transmission, which will be formulated for, includes parenterally or intravenous transmission or for part or surface applied The composition of the compound of effective dose or compound comprising treatment valid density, which is given, to be shown disease or condition symptoms and needs The individual to be treated.The amount effectively treats, controls or alleviated one or more symptoms of the disease or illness.
The skilled artisan will appreciate that compound provided by the present invention, isomers, pro-drug and pharmacy Upper acceptable derivates, including pharmaceutical composition and the preparation comprising these compounds, can be widely applied to therapeutic alliance with Treat and of the present invention do not accommodate disease.Therefore, the present invention is expected by compound provided by the present invention, isomers, precursor Medicine and pharmaceutically acceptable derivates are used in combination with other active medicines, for treat disease of the present invention/ It is uncomfortable.
Compound provided by the present invention or composition or its pharmaceutically acceptable derivates can be in one or more While other active agent deliveries, before or after be administered.Other active medicines particularly have for treating puzzlement subject Proliferative disorders or cancer therapeutic agent.
In some embodiments, one or more other active medicines are selected from anticancer (such as cellular signal transduction suppression Agent, mitotic inhibitor, alkylating agent, antimetabolite, chimeric (intercalating) anticancer, topoisomerase enzyme inhibitor, Immunotherapeutic agent, or antihormone agent), steroid medicine, methotrexate (MTX), leflunomide, anti-tnf-alpha agent, calcineurin (calcineurin) inhibitor, antihistamine drug, chemotherapeutic agent, antiproliferative, immunodepressant, immunostimulant, resist Inflammatory agent, CDK4/6 kinase inhibitors, ABL inhibitor, ABL/Scr inhibitor, aurora kinase inhibitors, Bcr-ABL's is non- ATP competitive inhibitors, c-KIT inhibition from mutation agent, RET inhibitor, PDGFR inhibitor, VEGFR inhibitor, CSF1R suppress Agent, FLT3 inhibitor, FLT3-ITD inhibitor or combinations thereof.
In some embodiments, anticancer is selected from alkylating agent and (such as endoxan, an endoxan, melphalan, disappeared in vain Peace, Nimustine, Ranimustine, Dacarbazine, Temozolomide, mustine hydrochlcride, dibromannitol etc.), platinum complexing agent it is (such as suitable Platinum, carboplatin, oxaliplatin etc.), metabolic antagonist (such as methotrexate (MTX), 5 FU 5 fluorouracil, Tegafur, gemcitabine, card times he Shore, fulvestrant, pemetrexed etc.), plant alkaloid it is (such as vincristine, vincaleukoblastinum, eldisine, Etoposide, more western His match, taxol, Irinotecan, vinorelbine, mitoxantrone, vinflunine, TPT etc.), antibody drug it is (such as bent appropriate Monoclonal antibody, handkerchief trastuzumab, Rituximab, Cetuximab, Victibix, bevacizumab etc.), hormone anticancer it is (such as bright Third Rayleigh, Goserelin, dutasteride, dexamethasone, tamoxifen etc.), proteasome inhibitor (such as bortezomib, come That degree amine etc.), aromatization do not have inhibitor (such as Exemestane, Letrozole, Anastrozole etc.), VEGFR inhibitor (such as Buddhist nun of relaxing For Buddhist nun, Sorafenib, Imatinib, Gefitinib, Erlotinib, ZD6474, pa azoles for Buddhist nun, Lapatinib etc.), mTOR suppressions Preparation (such as everolimus, sirolimus, Zuo Tamosi etc.).
In some embodiments, other active medicines can be：Streptozotocin, oxaliplatin, Temozolomide, first ammonia Pterin, fluorouracil, gemcitabine, purinethol, vinorelbine, Docetaxel, TPT, Irinotecan, bent shellfish are replaced It is fixed, dactinomycin D, mitomycin C, Ipsapirone, Gonadorelin analog, megestrol acetate, prednisone, methylprednisolone, Sha Lidu Amine, interferon-' alpha ', Calciumlevofolinate, sirolimus, temsirolimus, everolimus, Afatinib, alisertib, Amuvatinib, Ah pa replace Buddhist nun, Axitinib, bortezomib, SKI-606, brivanib, cabozantinib, Xi Dini Cloth, crenolanib, gram Zhuo replace Buddhist nun, dabrafenib, dacomitinib, danusertib, Dasatinib, dovitinib, Tarceva, foretinib, ganetespib, Gefitinib, ibrutinib, Conmana, Imatinib, iniparib, Lapatinib, lenvatinib, linifanib, linsitinib, Masitinib, momelotinib, not for husky Buddhist nun, come that and replace Buddhist nun, nilotinib, niraparib, oprozomib, olaparib, pazopanib, pictilisib, ponatinib, Quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, saracatinib, saridegib, Sorafenib, Sutent, tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, Trametinib, ZD6474, veliparib, Wei Luofeini, vismodegib, volasertib, alemtuzumab, shellfish cut down list It is anti-, brentuximab vedotin, catumaxomab, Cetuximab, ground promise monoclonal antibody, lucky trastuzumab, her monoclonal antibody, Buddhist nun Trastuzumab, difficult to understand, Victibix, Rituximab, tositumomab, Herceptin, busulfan, di-n-propylamine sulphur Ester, piposulfan, benzcarbimine, carboquone, tetramethyl urethane imines, urethimine, hexamethyl melamine, tretamine, triethylene phosphinylidyne Amine (triethylenephosphoramide), triethylene thiophosphoramide (triethylenethiophosphoramide), trimethylolmelamine, Chlorambucil, Chlornaphazine, endoxan are female not take charge of Spit of fland, ifosfamide, mustargen, hydrochloric acid nitromin, melphalan, novoembichin, phenesterin, prednimustine, three mustard ring phosphinylidynes Amine, uracil mastard, BCNU, chlorozotocin, Fotemustine (fotemustine), lomustine (lomustine), Buddhist nun Mo Siting (nimustine), Ranimustine (ranimustine), Dacarbazine, mannomustine, dibromannitol, dibromo winged euonymus Alcohol, pipobroman, aclacinomycin, D actinomycin D F (1), anthramycin, azaserine, bleomycin, act-C, card It is soft soft redder than star (carubicin), cardinophyllin (carzinophilin), chromomycin (chromomycin), actinomycin D Mycin (daunorubicin), daunomycin (daunomycin), 6- diazo -5- oxo -1- nor-leucines, Doxorubicin, Epirubicin, mitomycin C, Mycophenolic Acid, nogalamycin (nogalamycin), olivomycin (olivomycin), training Lip river are mould Plain (peplomycin), plicamycin (plicamycin), porfiromycin (porfiromycin), puromycin (puromycin), broneomycin (streptonigrin), streptozotocin (streptozocin), tubercidin (tubercidin), ubenimex (ubenimex), Zinostatin (zinostatin), zorubicin, denopterin (denopterin), methopterin, pteropterin (pteropterin), Trimetrexate (trimetrexate), fludarabine, sulphur Miaow purine (thiamiprine), thioguanine (thioguanine), ancitabine (ancitabine), azacitidine (azacitidine), 6- azauridines (6-azauridine), Carmofur (carmofur), cytarabine (cytarabine), two BrdU (dideoxyuridine), doxifluridine (doxifluridine), enocitabine (enocitabine), fluorine urine Glycosides (floxuridine), fluorouracil (fluorouracil), Tegafur, L-Asnase, Ah method's DNA Enzyme, aceglatone, aldophosphamide glycosides (aldophosphamide glycoside), amino-laevulic acid, amsacrine, Bestrabucil, bisantrene, carboplatin, cis-platinum, Defosfamide (defofamide), demecolcine, diaziquone, Elfornithine, Elliptinium Acetate, ethoglucid, Etoposide, Flutamide, gallium nitrate, hydroxycarbamide, interferon-' alpha ', interference Plain β, interferon gamma, interleukin 2, lentinan, Lonidamine, metacortandracin, dexamethasone, formyl tetrahydrofolic acid, third meter Hydrazone, mitoxantrone, cover an amine alcohol (mopidamol), C-283, Pentostatin, Phenamet, THP (pirarubicin), podophyllic acid, 2- ethylhydrazides, procarbazine, razoxane, sizofiran (sizofiran), Spirogermanium (spirogermanium), taxol, TAM, Teniposide, tenuazonic acid, triethyleneiminobenzoquinone, 2,2 ', 2 "-three Chlorine triethylamine, urethane, vincaleukoblastinum, vincristine, eldisine, ground draw Ross, and card, which is won, replaces Buddhist nun, Ponatinib, Midostaurin, Pacritinib, quizartinib, gilteritinib, AKN-028, AT-9283, Crenolanib, ENMD-2076, Famitinib, Dovitinib, PLX-3397, palbociclib, abemaciclib, ribociclib, Rigosertib sodium, Selinexor, Roniciclib, AT-7519, Seliciclib, Alvocidib or their group Close.
In some embodiments, pharmaceutical composition is additionally provided, it includes compound provided by the present invention or its medicine Acceptable derivates on, and one or more other active medicines, can be used as single dosage form or with compound and The separated part as multiple dose form of composition.Other active medicines can be given simultaneously with compound disclosed by the invention Or asynchronously give.In the latter case, administration can stagger, such as：6 hours, 12 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month or 2 months..
In some embodiments, conjoint therapy is also provided, its treat or prevent symptom or with cancer and relevant disease and The generation of the related complication of illness, the therapy include giving a kind of chemical combination disclosed in this invention to the individual for having such a needs Thing or composition or its pharmaceutically acceptable derivates, and one or more other active medicines.
In some embodiments, during administered in combination, there is two ways：1) by compound of the present invention or medicine Compositions with can associated with other active medicines be respectively prepared single preparation, two kinds of formulations can be used with identical or different When can successively use, can also use simultaneously；Successively in use, it is that the first medicine does not lose it also to give second of medicine Useful effect in vivo；2) by the compounds of this invention or pharmaceutical composition and can associated with other active medicines unitary system is made Agent, it is administered simultaneously.
In some embodiments, FLT3 inhibitor or FLT3-ITD inhibitor and CDK4/6 kinase inhibitors are especially provided It is medication combined.Compound or composition or its pharmaceutically acceptable derivates of the present invention as CDK4/6 kinase inhibitors Can while one or more other active therapeutic agents administration, before or after be administered.Other active medicines are particularly FLT3 inhibitor or FLT3-ITD inhibitor.
In some embodiments, to be that card is rich replace Buddhist nun for FLT3 inhibitor or FLT3-ITD inhibitor, Ponatinib, Midostaurin, Pacritinib, quizartinib, gilteritinib, AKN-028, AT-9283, Crenolanib, ENMD-2076, Famitinib, Dovitinib, PLX-3397, etc..
General synthetic method
Usually, compound of the invention can be prepared by method described in the invention, unless there are further Explanation, the wherein definition of substituent compound as shown in formula (I)-(III).Following reaction scheme and embodiment is used for into one Step illustrates present disclosure.
Those skilled in the art will realize that：Chemical reaction described in the invention can be used for suitably preparing perhaps Other compounds of more present invention, and other methods of the compound for preparing the present invention are considered as the model in the present invention Within enclosing.For example, can be successfully by those skilled in the art according to the synthesis of the compound of those non-illustrations of the invention Completed by method of modifying, such as appropriate protection interference group, by using other known reagent except described in the invention , or reaction condition is made into some conventional modifications.In addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is applied to the preparation of other compounds of the invention.
The embodiments described below, unless other aspects show that all temperature are set to degree Celsius.Reagent is bought in business Product supplier such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, all without by not being further purified during use, unless other aspects show.In general reagent is from the western Gansu Province chemical industry in Shantou Imperial chemistry examination is risen in factory, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Companies, Qingdao Agent Co., Ltd, and Haiyang Chemical Plant, Qingdao are commercially available.
Anhydrous tetrahydro furan, dioxane, toluene, ether are dried to obtain by metallic sodium backflow.Anhydrous methylene chloride With chloroform it is dried to obtain by calcium hydride backflow.Ethyl acetate, petroleum ether, n-hexane, DMA and N, N- Dimethylformamide is to dry to use in advance through anhydrous sodium sulfate.
Reaction is usually that a drying tube is covered under nitrogen or argon gas positive pressure or on anhydrous solvent (unless other aspects below Show), reaction bulb all by syringe squeezed into beyond the Great Wall by suitable rubber stopper, substrate.Glassware is all dried.
Chromatographic column is to use silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.Spectroscopic data of the nuclear magnetic resonance Surveyed by the nuclear magnetic resonance spectrometers of Bruker Avance 400 or the nuclear magnetic resonance spectrometers of Bruker Avance III HD 600 It is fixed, with CDC13,d6-DMSO,CD3OD or d6- acetone is solvent (reporting in units of ppm), with TMS (0ppm) or chloroform (7.25ppm) is used as reference standard.When there is multiplet, following abbreviation will be used：S (singlet, unimodal), d (doublet, bimodal), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of doublets, quartet), dt (doublet of triplets, double triplets), ddd (doublet of Doublet of doublets, in pairs doublet), and ddt (doublet of doublet of triplets, it is triple in pairs Peak), dddd (doublet of doublet of doublet of doublets, in pairs double doublet).Coupling constant, use Hertz (Hz) represents.
The condition of Algorithm (MS) data determination is：Quadrupole HPLC-MS (the pillars of Agilent 6120 Model：Zorbax SB-C18,2.1x 30mm, 3.5 μm, 6min, flow velocity 0.6mL/min, mobile phase：5%-95% (contains The CH3CN of 0.1% formic acid) ratio in the H2O of 0.1% formic acid (contain))), detected in 210/254nm with UV, use electron spray Ionization pattern (ESI).
The characteristic manner of compound purity is：The preparative high performance liquid chromatographies of Agilent 1260 (Pre-HPLC) or The preparative high performance liquid chromatographies of Calesep Pump 250 (Pre-HPLC) (pillar model：NOVASEP, 50/80mm, DAC), 210nm/254nm is detected with UV.
The use of brief word below is through the present invention：
BOC, Boc tert-butoxycarbonyl
CHCl3Chloroform
CDC13Deuterochloroform
DMF N,N-dimethylformamides
DMSO-d6Deuterated dimethyl sulfoxide
HATU 2- (7- azos BTA)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid esters
EDC, EDCI 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides
MeOH,CH3OH methanol
CH2Cl2, DCM dichloromethane
ML, ml milliliter
N2Nitrogen
Pd/C palladiums/carbon
RT rt room temperatures
Rt retention times
Synthetic schemes
Synthetic intermediate scheme 1
The compounds of this invention intermediate can be obtained by the synthetic method of synthetic intermediate scheme 1：Compound (1a) with In the basic conditions, heating response generates compound (3a) to compound (2a)；Compound (3a) obtains centre by catalytic hydrogenation Body compound (1).Wherein B, R3And L1With implication as described in the present invention.
Synthetic intermediate scheme 2
The compounds of this invention intermediate can be obtained by the synthetic method of synthetic intermediate scheme 2：Compound (1ad) exists The lower still that occurs of tin reagent effect reacts to obtain compound (1ae), and then in alkali, (alkali can be compound (1ae), but unlimited In R3-L1-NH2) heating cyclization obtains compound (1af) down for effect, compound (1af) reducing amide obtains compound (1ag), Compound (1ag) is under HBr and AcOH effects, and demethylation obtains compound (1ah), and compound (1ah) is in POCl3Under effect To compound (1ai), further compound (4d) is obtained under ammoniacal liquor effect.Wherein L1And R3With containing as described in the present invention Justice.
Synthetic schemes 1
The compounds of this invention can be obtained by the synthetic method of synthetic schemes 1：Compound (1) is with compound (5) in palladium Under catalyst action, Buchwald cross-coupling reactions occur and obtain target compound (2).Wherein, B, L1, R1, R2And R3Have Implication as described in the present invention.
Synthetic schemes 2
The compounds of this invention can be obtained by the synthetic method of synthetic schemes 2：Compound (13) is with compound (5) in palladium Under catalyst action, Buchwald cross-coupling reactions occur and obtain target compound (14).Wherein, L1, R1, R2And R3Have Implication as described in the present invention.
Synthetic schemes 3
The compounds of this invention can be obtained by the synthetic method of synthetic schemes 3：Compound (4d) is with compound (5) in palladium Under catalyst action, Buchwald cross-coupling reactions occur and obtain target compound (14a).Wherein, L1, R1, R2And R3Have Implication as described in the present invention.The following examples can be so that the present invention will be further described, however, these embodiments should not As limiting the scope of the present invention.
Embodiment
Embodiment 1
N- (the fluoro- 4- of 5- (fluoro- 1- isopropyls -2- methyl isophthalic acids H- benzos [d] imidazoles -6- bases of 4-)-pyrimidine -2-base) -3- (1- Methyl isophthalic acid, 2,3,6- tetrahydropyridine -4- bases) -1H- indoles -5- amine
Under nitrogen protection, fluoro- 1- isopropyls -2- methyl isophthalic acids H- benzos [d] miaows of 6- (the chloro- 5-FU -4- bases of 2-) -4- Azoles (100mg, 0.31mmol) (synthesized reference document WO2010075074 preparation examples 43), 3- (1- methyl isophthalic acids, 2,3,6- tetrahydrochysene pyrroles Pyridine -4- bases) -1H- indoles -5- amine (72mg, 0.31mmol), cesium carbonate (0.20g, 0.62mmol), 4,5- double phenyl phosphorus -9,9- Dimethyl xanthene (18mg, 0.025mmol), three (dibenzalacetone) two palladium (14mg, 0.016mmol) are dissolved in Isosorbide-5-Nitrae-dioxy Six rings (15mL) are heated with stirring to 110 DEG C, react 3h.It is cooled to room temperature, adds dichloromethane (40mL) dilution, diatomite filters, It is concentrated under reduced pressure, concentrate carries out column chromatography for separation (CH2Cl2/CH3OH (V/V)=10/1) obtain yellow solid (15mg, 9.15%).
MS-ESI:(ESI,pos.ion)m/z:514.5[M+1]+；
1H NMR(400MHz,CDCl3) δ 8.87 (d, J=9.0Hz, 1H), 8.61 (d, J=3.4Hz, 1H), 8.38 (d, J =3.8Hz, 1H), 8.26 (s, 1H), 8.22 (d, J=1.8Hz, 1H), 8.16 (s, 1H), 7.85 (dd, J=25.7,11.7Hz, 2H), 7.60 (d, J=7.3Hz, 1H), 6.32 (s, 1H), 4.77-4.65 (m, 1H), 3.11 (s, 2H), 2.74 (s, 2H), 2.73 (s, 2H), 2.69 (s, 3H), 2.43 (s, 3H), 1.75 (d, J=6.9Hz, 6H)
Embodiment 2
N- (the fluoro- 4- of 5- (fluoro- 1- isopropyls -2- methyl isophthalic acids H- benzos [d] imidazoles -6- bases of 4-) pyrimidine -2-base) -5,6,7, 8- tetrahydrochysene -1,6- naphthyridines -2- amine
Step 1) 2- ((the fluoro- 4- of 5- (fluoro- 1- isopropyls -2- methyl isophthalic acids H- benzos [d] imidazoles -6- bases of 4-) pyrimidine -2-base) Amido) -6 (5H)-carboxylic acid tert-butyl ester of -7,8- dihydro -1,6- naphthyridines
Under nitrogen protection, by the fluoro- 1- isopropyls -2- methyl isophthalic acids H- benzos [d] of 6- (the chloro- 5-FU -4- bases of 2-) -4- Imidazoles (synthesized reference document WO2010075074 preparation examples 43) (322mg, 1.0mmol), 2- amino -7,8- dihydro -1,6- naphthalenes Pyridine -6 (5H)-carboxylic acid tert-butyl ester (250mg, 1.0mmol) (WO2009056556 intermediates 34), cesium carbonate (652mg, 2.0mmol), double phenyl phosphorus -9, the 9- dimethyl xanthenes (58mg, 0.1mmol) of 4,5- and three (dibenzalacetone) two palladium (92mg, 0.1mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (25mL) and is heated with stirring to 110 DEG C, reacts 3h.It is cooled to room temperature, adds dichloro Methane (30mL) dilutes, diatomite filtering, and filtrate decompression, which concentrates, is evaporated off solvent, residue progress column chromatography for separation (dichloromethane/ Methanol (V/V)=10/1) obtain faint yellow solid (246mg, 46.0%).
MS-ESI:(ESI,pos.ion)m/z:536.4[M+1]+.
Step 2) N- (the fluoro- 4- of 5- (fluoro- 1- isopropyls -2- methyl isophthalic acids H- benzos [d] imidazoles -6- bases of 4-) pyrimidine -2-base) - 5,6,7,8- tetrahydrochysene -1,6- naphthyridines -2- amine
By 2- ((the fluoro- 4- of 5- (fluoro- 1- isopropyls -2- methyl isophthalic acids H- benzos [d] imidazoles -6- bases of 4-) pyrimidine -2-base) amine Base) -7,8- dihydros -1,6- naphthyridines -6 (5H)-carboxylic acid tert-butyl ester (200mg, 0.37mmol) be dissolved in dichloromethane (30mL), Trifluoroacetic acid (0.42g, 3.7mmol) is added, 3h is stirred at room temperature, is concentrated, saturated sodium carbonate adjusts PH to 7-8, dichloromethane extraction (100mL) three times, organic phase are dried, and concentration, obtain yellow oily (115mg, 71.3%).
MS-ESI:(ESI,pos.ion)m/z:436.5[M+1]+；
1H NMR(400MHz,DMSO-d6) δ 9.95 (s, 1H), 8.67 (s, 1H), 8.30 (s, 1H), 8.08 (d, J= 8.4Hz, 1H), 7.69 (d, J=12.1Hz, 1H), 7.49 (d, J=8.4Hz, 1H), 4.91-4.78 (m, 1H), 3.97 (s, 2H), 3.18 (d, J=5.9Hz, 2H), 3.17 (s, 1H), 2.82 (s, 2H), 2.64 (s, 3H), 1.63 (d, J=6.5Hz, 6H)
Embodiment 3
Similar synthetic method using corresponding initiation material by embodiment 2, the compound of embodiment 3 is prepared：
Embodiment 4
1- (7- ((the fluoro- 4- of 5- (fluoro- 1- isopropyls -2- methyl isophthalic acids H- benzos [d] imidazoles -6- bases of 4-) pyrimidine -2-base) amine Base) -3,4-2H-2,6- naphthyridines -2 (1H)-yl) -2- hydroxyethanones
In N- (the fluoro- 4- of 5- (fluoro- 1- isopropyls -2- methyl isophthalic acids H- benzos [d] imidazoles -6- bases of 4-) pyrimidine -2-base) -5,6, In dichloromethane (10mL) solution of 7,8- tetrahydrochysene -1,6- naphthyridines -2- amine (101mg, 0.232mmol) add HATU (93.3mg, 0.24mmol) and DIPEA (0.10mL, 0.59mmol), after stirring 10min, add glycolic (30.8mg, 0.41mmol), reaction 3h is stirred at room temperature.Stop reaction, removal of solvent under reduced pressure, add silica gel mixed sample, column chromatography for separation (dichloromethane Alkane/methanol (V/V)=10/1), obtain yellow solid (34mg, 30%).MS-ESI:(ESI,pos.ion)m/z:494.6[M+ 1]+；
1H NMR(600MHz,DMSO-d6) δ 10.05 (s, 1H), 8.68 (d, J=3.2Hz, 1H), 8.31 (s, 1H), 8.14 (d, J=7.8Hz, 1H), 7.70 (d, J=11.9Hz, 1H), 7.60 (dd, J=34.4,8.2Hz, 1H), 4.90-4.80 (m, 1H), 4.63 (s, 1H), 4.56 (s, 1H), 4.21 (d, J=17.6Hz, 2H), 3.90 (s, 1H), 3.82 (s, 1H), 3.70 (s, 1H), 2.90 (s, 1H), 2.82 (s, 1H), 2.65 (s, 3H), 1.64 (d, J=6.8Hz, 6H)
Embodiment 5
N- (the fluoro- 4- of 5- (fluoro- 1- isopropyls -2- methyl isophthalic acids H- benzos [d] imidazoles -6- bases of 4-) pyrimidine -2-base) -6- (3, 3,3- trifluoro propyls) -5,6,7,8-4H-1,6- naphthyridines -2- amine
By N- (the fluoro- 4- of 5- (fluoro- 1- isopropyls -2- methyl isophthalic acids H- benzos [d] imidazoles -6- bases of 4-) pyrimidine -2-base) -5,6, 7,8- tetrahydrochysene -1,6- naphthyridines -2- amine (72mg, 0.17mmol) and 3,3,3- trifluoros propionic aldehyde (41.5mg, 0.370mmol) are dissolved in DMF (10mL), after stirring 10min, add sodium cyanoborohydride (35mg, 0.55mmol).Stirring reaction at room temperature.LC-MS Display reaction is complete, stops reaction, removal of solvent under reduced pressure, adds silica gel mixed sample, column chromatography for separation (methylene chloride/methanol (V/V) =10/1) yellow solid (11mg, 13%) is obtained.
MS-ESI:(ESI,pos.ion)m/z:532.4[M+1]+；
1H NMR(600MHz,CDCl3)δ:8.43 (d, J=3.6Hz, 1H), 8.25 (d, J=8.4Hz, 1H), 8.21 (s, 1H), 8.00 (s, 1H), 7.80 (d, J=11.6Hz, 1H), 7.39 (d, J=8.4Hz, 1H), 4.75 (td, J=13.8, 6.8Hz, 1H), 3.67 (s, 2H), 3.00 (t, J=5.6Hz, 2H), 2.90 (t, J=5.8Hz, 2H), 2.84 (dd, J=16.3, 8.2Hz, 2H), 2.72 (s, 3H), 2.46 (td, J=20.7,10.5Hz, 2H), 1.73 (d, J=6.9Hz, 6H)
The 2- of embodiment 6 (2- ((the fluoro- 4- of 5- (fluoro- 1- isopropyls -2- methyl isophthalic acids H- benzos [d] imidazoles -6- bases of 4-) pyrimidine - 2- yls) amino) -6 (5H)-yl of -7,8- dihydro -1,6-- naphthyridines)-ethanol
In 100mL single-necked flasks, ethylene bromohyrin (55mg, 0.44mmol) is dissolved in DMF (24mL), in condition of ice bath Lower addition N- (the fluoro- 4- of 5- (fluoro- 1- isopropyls -2- methyl isophthalic acids H- benzos [d] imidazoles -6- bases of 4-) pyrimidine -2-base) -5,6,7,8- Tetrahydrochysene -1,6- naphthyridines -2- amine (148mg, 0.34mmol) and potassium carbonate (155mg, 1.12mmol) stirring 30min, then slowly It is warmed to room temperature stirring 6h.Remove organic solvent under reduced pressure, dichloromethane (100mL) and water (100mL) are added into residue, it is organic Layer saturated sodium bicarbonate solution (80mL × 3), saturated common salt water washing (80mL × 1), organic layer anhydrous sodium sulfate drying And concentrate.Residual thing carry out column chromatography for separation (methylene chloride/methanol (V/V)=10/1) obtain faint yellow solid (51mg, 31.3%).
MS-ESI:(ESI,pos.ion)m/z:480.5[M+1]+；
1H NMR(400MHz,DMSO-d6) δ 9.90 (s, 1H), 8.67 (d, J=3.8Hz, 1H), 8.31 (s, 1H), 8.05 (d, J=8.4Hz, 1H), 7.69 (d, J=11.9Hz, 1H), 7.45 (d, J=8.5Hz, 1H), 4.85 (dt, J=14.0, 7.0Hz, 1H), 4.48 (s, 1H), 3.59 (s, 2H), 2.90-2.75 (m, 4H), 2.65 (s, 3H), 2.59 (t, J=6.1Hz, 2H), 1.64 (d, J=6.9Hz, 6H), 1.23 (s, 2H)
The N- of embodiment 7 (the fluoro- 4- of 5- (fluoro- 1- isopropyls -2- methyl isophthalic acids H- benzos [d] imidazoles -6- bases of 4-) pyrimidine -2- Base) -6- (2- methoxy ethyls) -5,6,7,8- tetrahydrochysene -1,6- naphthyridines -2- amine
In 100mL single-necked flasks, ethylene bromohyrin methyl ether (89mg, 0.64mmol) is dissolved in DMF (24mL), in ice bath Under the conditions of add N- [the fluoro- 4- of 5- (the fluoro- 3- isopropyls -2- methyl of 7--benzo [d] imidazoles -5- bases) pyrimidine -2-base] -5,6,7, 8- tetra- -1,6- diaza naphthyridines -2- amine (235mg, 0.54mmol) and potassium carbonate (149mg, 1.08mmol) stirring 30min, so After be slowly increased to that 6h is stirred at room temperature.Remove organic solvent under reduced pressure, dichloromethane (100mL) and water are added into residue (100mL), organic layer saturated sodium bicarbonate solution (80mL × 3), saturated common salt water washing (80mL × 1), organic layer nothing Aqueous sodium persulfate is dried and concentrated.Residual thing carries out column chromatography for separation (methylene chloride/methanol (V/V)=10/1) and obtains faint yellow solid (21mg, 12.5%)
MS-ESI:(ESI,pos.ion)m/z:494.5[M+1]+；
1H NMR(600MHz,DMSO-d6) δ 9.99 (s, 1H), 8.67 (d, J=3.7Hz, 1H), 8.29 (s, 1H), 8.11 (d, J=8.5Hz, 1H), 7.69 (d, J=12.0Hz, 1H), 7.59 (d, J=8.5Hz, 1H), 4.88-4.81 (m, 1H), 4.55 (s, 2H), 3.71 (t, J=5.9Hz, 2H), 3.65 (s, 3H), 3.52 (s, 2H), 2.89 (s, 1H), 2.83 (t, J=5.8Hz, 2H), 2.73 (s, 1H), 2.64 (s, 3H), 1.63 (d, J=6.9Hz, 6H)
The 3- of embodiment 8 (2- ((the fluoro- 4- of 5- (fluoro- 1- isopropyls -2- methyl isophthalic acids H- benzos [d] imidazoles -6- bases of 4-) pyrimidine - 2- yls) amino) -6 (5H)-yl of -7,8- dihydro -1,6- naphthyridines) propyl- 1- alcohol
Step 1) 6- (3- ((tert-butyl group (dimethyl) silylation) epoxide) propyl group)-N- (the fluoro- 4- of 5- (fluoro- 1- isopropyls of 4- Base -2- methyl isophthalic acid H- benzos [d] imidazoles -6- bases) pyrimidine -2-base) -5,6,7,8- tetrahydrochysene -1,6- naphthyridines -2- amine
(3- bromines propoxyl group) t-butyldimethyl silane (0.15mL) is sequentially added in the single-necked flask that 100mL is dried, N- (the fluoro- 4- of 5- (fluoro- 1- isopropyls -2- methyl isophthalic acids H- benzos [d] imidazoles -6- bases of 4-) pyrimidine -2-base) -5,6,7,8- tetrahydrochysenes - 1,6- naphthyridines -2- amine (148mg, 0.34mmol) and potassium carbonate (200mg, 1.03mmol) and DMF (24mL), reaction solution is in room Stirred under the conditions of temperature.The display reaction of TLC and LC-MS testing results has been basically completed, and decompression steams solvent, and residue is poured into In 100mL water, and extracted (2x100mL) with dichloromethane, saturated common salt washing (1x100mL), merge organic layer and depressurize rotation It is dry, yellow solid (151mg, 73.10%) is obtained after purification through column chromatography (methylene chloride/methanol (V/V)=10/1).
MS-ESI:(ESI,pos.ion)m/z:608.2[M+1]+；
Step 2) 3- (2- ((the fluoro- 4- of 5- (fluoro- 1- isopropyls -2- methyl isophthalic acids H- benzos [d] imidazoles -6- bases of 4-) pyrimidine -2- Base) amino) -6 (5H)-yl of -7,8- dihydro -1,6- naphthyridines) propyl- 1- alcohol
Under nitrogen protection, by 6- (3- ((tert-butyl group (dimethyl) silylation) epoxide) propyl group)-N- (fluoro- 4- (4- of 5- Fluoro- 1- isopropyls -2- methyl isophthalic acid H- benzos [d] imidazoles -6- bases) pyrimidine -2-base) -5,6,7,8- tetrahydrochysene -1,6- naphthyridines -2- amine (139.7mg, 0.23mmol) is dissolved in tetrahydrofuran (19mL, 234mmol), add tetrabutyl ammonium fluoride (1.6mL, 1.6mmol, 1.0mol/L), it is stirred at room temperature.TLC monitoring reactions.Tetrahydrofuran is sloughed in decompression after reaction solution cooling, adds saturation Sodium bicarbonate aqueous solution (100mL), ethyl acetate extraction (150mL × 3), organic phase are washed with saturated aqueous common salt (50mL), nothing Aqueous sodium persulfate is dried, and filtering, obtains white solid (88mg, 78.19%).
MS-ESI:(ESI,pos.ion)m/z:494.5[M+1]+；
1H NMR(600MHz,DMSO-d6)δ:9.97 (s, 1H), 8.67 (d, J=3.0Hz, 1H), 8.30 (s, 1H), 8.08 (d, J=8.2Hz, 1H), 7.69 (d, J=11.9Hz, 1H), 7.50 (d, J=8.1Hz, 1H), 4.89-4.80 (m, 1H), 4.16 (m, 2H), 3.72 (s, 2H), 2.90 (s, 2H), 2.64 (s, 3H), 1.75-1.68 (m, 4H), 1.62 (t, J=6.9Hz, 6H), 1.24 (t, J=7.8Hz, 2H)
Embodiment 9-11
Similar synthetic method using corresponding initiation material by embodiment 4 or 5, is prepared embodiment 9-11 change Compound：
Embodiment 12-35
Similar synthetic method using corresponding initiation material by embodiment 1, embodiment 12-35 chemical combination is prepared Thing：
Embodiment 36
The fluoro- 4- of 6- ethyls-N-5- (fluoro- 1- isopropyls -2- methyl isophthalic acids H- benzos [d] imidazoles -6- bases of 4-) pyrimidine -2-base) - 5,6,7,8- tetrahydrochysene -1,6- naphthyridines -2- amine
By iodoethane (41.8mg, 0.27mmol) and N- (the fluoro- 4- of 5- (the fluoro- 1- isopropyls -2- methyl isophthalic acids H- benzos [d] of 4- Imidazoles -6- bases) pyrimidine -2-base) -5,6,7,8- tetrahydrochysene -1,6- naphthyridines -2- amine (embodiment 2) (113mg, 0.26mmol) is dissolved in DMF (15mL), add potassium carbonate (70mg, 0.50mmol).Stirring reaction at room temperature.LC-MS display reactions are complete, stop anti- Should, removal of solvent under reduced pressure, dichloromethane (100mL) and water extraction, organic phase are dried, and concentration, add silica gel mixed sample, column chromatography point Yellow solid (59mg, 49.4%) is obtained from (methylene chloride/methanol (V/V)=10/1).
MS-ESI:(ESI,pos.ion)m/z:564.4[M+1]+；
1H NMR(600MHz,DMSO-d6) δ 10.18 (s, 1H), 8.70 (d, J=3.5Hz, 1H), 8.30 (s, 1H), 8.18 (d, J=8.4Hz, 1H), 7.70 (d, J=12.0Hz, 1H), 7.62 (d, J=8.4Hz, 1H), 4.85 (dd, J=13.7, 6.8Hz, 1H), 4.28 (s, 2H), 3.67 (s, 2H), 3.19 (s, 2H), 3.08 (s, 2H), 2.65 (s, 3H), 1.64 (d, J= 6.8Hz, 6H), 1.30 (d, J=6.4Hz, 3H)
The 7- of embodiment 37 ((the fluoro- 4- of 5- (fluoro- 1- isopropyls -2- methyl isophthalic acids H- benzos [d] imidazoles -6- bases of 4-) pyrimidine -2- Base) amido) -2 (1H)-methyl formate of -3,4- dihydro -2,6- naphthyridines
In 100mL single-necked flasks, by N- (the fluoro- 4- of 5- (fluoro- 1- isopropyls -2- methyl isophthalic acids H- benzos [d] imidazoles -6- of 4- Base) pyrimidine -2-base) -5,6,7,8- tetrahydrochysene -1,6- naphthyridines -2- amine (embodiment 2) (158mg, 0.36mmol) is dissolved in dichloromethane In (40mL), under condition of ice bath add methylchloroformate (0.4mL, 5.0mmol) and diisopropylethylamine (0.5mL, 30min is stirred after 3.2mmol), is then slowly increased to that 6h is stirred at room temperature.Remove organic solvent under reduced pressure, two are added into residue Chloromethanes (100mL) and water (100mL), organic layer saturated sodium bicarbonate solution (80mLx3), saturated common salt water washing (80mLx1), organic layer anhydrous sodium sulfate drying simultaneously concentrate.Residual thing carry out column chromatography for separation (methylene chloride/methanol (V/V)= 10/1) faint yellow solid (51mg, 28.48%) is obtained.
MS-ESI:(ESI,pos.ion)m/z:494.5[M+1]+；
1H NMR(600MHz,DMSO-d6) δ 9.99 (s, 1H), 8.67 (d, J=3.7Hz, 1H), 8.29 (s, 1H), 8.11 (d, J=8.5Hz, 1H), 7.69 (d, J=12.0Hz, 1H), 7.59 (d, J=8.5Hz, 1H), 4.84 (dt, J=13.9, 6.9Hz, 1H), 4.55 (s, 2H), 3.71 (t, J=5.9Hz, 2H), 3.65 (s, 3H), 2.83 (t, J=5.8Hz, 2H), 2.63 (d, J=10.0Hz, 3H), 1.63 (d, J=6.9Hz, 6H)
(((the fluoro- 4- of 5- (fluoro- 1- isopropyls -2- methyl isophthalic acids H- benzos [d] imidazoles -6- bases of 4-) are phonetic by 7- by the 3- of embodiment 38 Pyridine -2- bases) amido) -2 (1H)-yl of -3,4- dihydro -2,6- naphthyridines) -3- oxo propionitriles
In 100mL single-necked flasks, by N- (the fluoro- 4- of 5- (fluoro- 1- isopropyls -2- methyl isophthalic acids H- benzos [d] imidazoles -6- of 4- Base) pyrimidine -2-base) -5,6,7,8- tetrahydrochysene -1,6- naphthyridines -2- amine (embodiment 2) (151mg, 0.35mmol) is dissolved in dichloromethane In (40mL), 2- cyanoacetic acids (50mg, 0.59mmol), diisopropylethylamine (0.5mL, 3mmol) are added under condition of ice bath 30min is stirred afterwards with HATU (170mg, 0.43mmol), is then slowly increased to that 6h is stirred at room temperature.Remove organic solvent under reduced pressure, to Dichloromethane (100mL) and water (100mL), organic layer saturated sodium bicarbonate solution (80mLx3), saturation are added in residue Brine It (80mLx1), organic layer anhydrous sodium sulfate drying simultaneously concentrate.Residual thing carry out column chromatography for separation (dichloromethane/ Methanol (V/V)=10/1) obtain faint yellow solid (51mg, 29.27%).
MS-ESI:(ESI,pos.ion)m/z:503.5[M+1]+；
1H NMR(600MHz,DMSO-d6) δ 10.03 (d, J=13.8Hz, 1H), 8.65 (d, J=3.7Hz, 1H), 8.29 (s, 1H), 8.12 (dd, J=11.8,8.6Hz, 1H), 7.67 (d, J=12.0Hz, 1H), 7.62-7.50 (m, 1H), 4.84 (dt, J=13.5,6.7Hz, 1H), 4.60 (d, J=27.0Hz, 2H), 4.17 (d, J=20.6Hz, 2H), 3.83-3.68 (m, 2H), 2.92 (dd, J=14.4,8.7Hz, 1H), 2.82 (t, J=5.7Hz, 1H), 2.64 (s, 3H), 1.63 (d, J=6.9Hz, 6H).
The N- of embodiment 39 [the fluoro- 4- of 5- (fluoro- 1- isopropyls -2- methyl isophthalic acids H- benzos [d] imidazoles -6- bases of 4-) pyrimidine -2- Base] -6- (oxetanes -3- bases) -5,6.7,8- tetrahydrochysene -2,6- naphthyridines -3- amine
By N- (the fluoro- 4- of 5- (fluoro- 1- isopropyls -2- methyl isophthalic acids H- benzos [d] imidazoles -6- bases of 4-) pyrimidine -2-base) -5,6, 7,8- tetrahydrochysene -1,6- naphthyridines -2- amine (148mg, 0.34mmol) are dissolved in dichloromethane (19mL), and 3- is added dropwise under condition of ice bath Oxetanone (41mg, 0.57mmol), after being stirred at room temperature 30 minutes, add sodium cyanoborohydride (0.1g, 2mmol), reaction Liquid is stirred at room temperature.Reaction is complete, solvent is removed under reduced pressure, after column chromatography purifies (methylene chloride/methanol (V/V)=10/1) Obtain faint yellow solid compound (38mg, 22.75%).
MS-ESI:(ESI,pos.ion)m/z:492.4[M+1]+；
1H NMR(600MHz,DMSO-d6) δ 10.10 (s, 1H), 8.76 (d, J=3.3Hz, 1H), 8.49 (s, 1H), 8.05 (d, J=8.4Hz, 1H), 7.96 (d, J=12.6Hz, 1H), 7.48 (d, J=8.5Hz, 1H), 5.10-5.08 (m, 1H), 4.64 (t, J=6.5Hz, 2H), 4.55 (t, J=6.1Hz, 2H), 3.64 (dd, J=12.6,6.3Hz, 1H), 3.46 (s, 2H), 2.89 (s, 3H), 2.86 (t, J=5.7Hz, 2H), 2.64 (t, J=5.8Hz, 2H), 1.71 (d, J=6.9Hz, 6H)
The N- of embodiment 40 (the fluoro- 4- of 5- (fluoro- 1- isopropyls -2- methyl isophthalic acids H- benzos [d] imidazoles -6- bases of 4-) pyrimidine -2- Base) -6- (piperidin-4-yl) -5,6,7,8- tetrahydrochysene -2,6- naphthyridines -3- amine
Step 1) 4- [7- [[the fluoro- 4- of 5- (fluoro- 1- isopropyls -2- methyl isophthalic acids H- benzos [d] imidazoles -6- bases of 4-) pyrimidine -2- Base] amido] -2 (1H)-yl of -3,4- dihydro -2,6- naphthyridines] piperidines -1- t-butyl formates
By N- (the fluoro- 4- of 5- (fluoro- 1- isopropyls -2- methyl isophthalic acids H- benzos [d] imidazoles -6- bases of 4-) pyrimidine -2-base) -5,6, 7,8- tetrahydrochysene -1,6- naphthyridines -2- amine (298mg, 0.68mmol), are dissolved in dichloromethane (19mL), are added dropwise under condition of ice bath N- tertbutyloxycarbonyl -4- piperidones (181mg, 0.91mmol), after being stirred at room temperature 30 minutes, add sodium cyanoborohydride (0.11g, 1.7mmol), reaction solution is stirred at room temperature.Reaction is complete, removes solvent under reduced pressure, (dichloromethane is purified through column chromatography Alkane/methanol (V/V)=10/1) after faint yellow solid compound (38mg, 8.98%).
MS-ESI:(ESI,pos.ion)m/z:619.5[M+1]+；
Step 2) N- (the fluoro- 4- of 5- (fluoro- 1- isopropyls -2- methyl isophthalic acids H- benzos [d] imidazoles -6- bases of 4-) pyrimidine -2-base) - 6- (piperidin-4-yl) -5,6,7,8- tetrahydrochysene -2,6- naphthyridines -3- amine
4- [7- [[the fluoro- 4- of 5- (the fluoro- 1- isopropyls -2- methyl isophthalic acids H- benzos of 4- are added in the single port bottle that 100mL is dried [d] imidazoles -6- bases) pyrimidine -2-base] amido] -2 (1H)-yl of -3,4- dihydro -2,6- naphthyridines] piperidines -1- t-butyl formates (105mg, 0.17mmol), dissolved with dichloromethane (19mL), continuously add trifluoroacetic acid (7mL).Reaction solution stirs at room temperature Mix reaction overnight.Stop stirring, filtering, filtrate concentrates, and residue purifies (methylene chloride/methanol (V/V)=10/ through column chromatography 1) faint yellow solid (67mg, 76.13%), is obtained.
MS-ESI:(ESI,pos.ion)m/z:519.5[M+1]+；
1H NMR(600MHz,DMSO-d6)δ10.08(s,1H),9.97(s,1H),8.68(s,1H),8.31(s,1H), 8.08 (d, J=8.3Hz, 1H), 7.70 (d, J=11.9Hz, 1H), 7.47 (d, J=8.3Hz, 1H), 4.89-4.81 (m, 1H), 4.64 (t, J=6.1Hz, 2H), 4.58-4.47 (m, 2H), 3.68-3.60 (m, 1H), 3.51 (s, 1H), 3.46 (s, 2H), 3.18 (d, J=4.8Hz, 1H), 2.86 (s, 2H), 2.65 (s, 3H), 1.66 (d, J=21.3Hz, 6H), 1.26-1.22 (m, 4H).
The N- of embodiment 41 (the fluoro- 4- of 5- (fluoro- 1- isopropyls -2- methyl isophthalic acids H- benzos [d] imidazoles -6- bases of 4-) pyrimidine -2- Base) -6- (1- methyl piperazine -4- bases) -5,6,7,8- tetrahydrochysene -2,6- naphthyridines -3- amine
By N- (the fluoro- 4- of 5- (fluoro- 1- isopropyls -2- methyl isophthalic acids H- benzos [d] imidazoles -6- bases of 4-) pyrimidine -2-base) -6- (piperidin-4-yl) -5,6,7,8- tetrahydrochysene -2,6- naphthyridines -3- amine (104mg, 0.20mmol) and formalin (25mg, DMF (20mL) 0.31mmol) is dissolved in, after stirring 10min, adds sodium triacetoxy borohydride (53mg, 0.24mmol), room The lower stirring reaction of temperature.Reaction is complete, stops reacting, addition silica gel mixed sample, removal of solvent under reduced pressure, column chromatography for separation (dichloromethane/ Methanol (v/v)=10/1), obtain yellow solid (56mg, 52%).
LC-MS:(pos.ion)m/z：533.5[M+1]+；
1H NMR(600MHz,DMSO-d6) δ 10.12 (s, 1H), 8.72 (s, 1H), 8.31 (s, 1H), 8.05 (d, J= 8.3Hz, 1H), 7.72 (d, J=11.9Hz, 1H), 7.45 (d, J=8.3Hz, 1H), 4.89-4.81 (m, 1H), 4.64 (t, J= 6.1Hz, 2H), 4.58-4.47 (m, 2H), 3.65-3.63 (m, 1H), 3.56 (s, 1H), 3.45 (s, 2H), 3.15 (d, J= 4.8Hz, 1H), 2.86 (s, 2H), 2.65 (s, 3H), 2.34 (s, 3H), 1.66 (d, J=21.3Hz, 6H), 1.26-1.22 (m, 4H).
The determination of activity of the compounds of this invention
The external zymetology inhibitory activity of the compounds of this invention of example 1
Experimental method：
Representative implication of being abridged in following experiments is as follows：
HEPES：Hydroxyethyl piperazine second thiosulfonic acid；Brij-35：Brij-35；DTT：Dithiothreitol (DTT)； EDTA：Ethylenediamine tetra-acetic acid；CDK4/CycD3：Cyclin dependent kinase 4；CDK6/CycD3：Cyclin-Dependent Property protein kinase 6；Peptide FAM-P22：FAM-labeled peptide 22；ATP：Triphosphoric acid adenosine monophosphate；DMSO：Dimethyl sulfoxide (DMSO)； Staurosporine：Staurosporine；Coating Reagent#3：#3 fruit glaze agents
1. 1 × kinase buffer liquid and termination test buffer are prepared：
(1) 1 × be free of MnCl2Kinase buffer liquid (50mM HEPES, pH 7.5,0.0015%Brij-35,10mM MgCl2,2mM DTT)；(2) test buffer (100mM HEPES, pH 7.5,0.015%Brij-35,0.2% is terminated Coating Reagent#3,50mM EDTA)。
2. the compound serial dilution of test kinase prepares：
(1) using 100%DMSO by 50 times of diluted chemical compound to highest final concentration.By the compound of the 100 μ L concentration Solution is transferred to a hole of 96 orifice plates.(2) ratio diluted in 20 μ L original solutions with 60 μ L DMSO diluted compounds 10 successively Concentration.(3) 100 μ L 100%DMSO solution are added in two emptying apertures, compareed as without compound control and without enzyme.(4) Prepare an intermediate plate, each concentration compounds of 10 μ L are transferred to intermediate plate from raw sheet respectively, and add 90 μ 1 × kinases of L Buffer solution, vibration mix 10 minutes.(5) preparing experiment plate：The corresponding aperture transferase 45 μ L compound solutions from the intermediate plate of 96 orifice plates Into corresponding 384 orifice plate.
3. kinase reaction
(1) 2.5 × enzyme solutions are prepared：Enzyme is added in 1 × kinase buffer liquid.(2) 2.5 × peptide solution is prepared：By fluorescence Element mark peptide and ATP are added in 1 × kinase buffer liquid.(3) 10 μ 2.5 × enzyme solutions of L are added to containing 5 μ L DMSO contents In the 384 hole brassboards for 10% compound solution, it is incubated at room temperature 10 minutes.(4) 10 2.5 × peptide solutions of μ L are added 384 In the brassboard of hole.(5) kinase reaction and termination：28 DEG C are incubated the corresponding time, add 25 μ L stop buffer terminating reactions.
4. DATA REASONING：Read data and collect.
5. curve matching
(1) data of measurement are collected and are converted to inhibiting rate, inhibiting rate=(maximum-sample value)/(maximum-minimum Value) * 100；" maximum " is without compound control value；" minimum value " is without enzyme control value.(2) it is soft to enter data into corresponding analysis Part Xlfit draws IC50Value.
6. experimental result is as follows：
The external zymetology inhibitory activity of the compounds of this invention of table 2
Experiment conclusion：
As seen from Table 2, the compounds of this invention has stronger inhibitory action to CDK4, CDK6 kinases, and external zymetology suppresses Activity is respectively less than 0.1 μm, and external activity is preferable.
The pharmacodynamic activity of the compounds of this invention of example 2
Experimental method：
Experiment reagent and test sample used are as follows：
Propranolol：Propranolol (internal standard)；MTBE：Methyl tertiary butyl ether(MTBE)；Cremophor EL：Polyoxyethylene castor Sesame oil；KolliphorHS 15：The hydroxy stearic acid ester of polyethylene glycol 12；DMSO：Dimethyl sulfoxide；PEG400：Polyethylene glycol 400； SD rats：Male, 18.
1. the preparation of testing compound solution：
By 5%DMSO+10%KolliphorHS 15+35%Saline or 5%DMSO+60%PEG400+35% Saline configures solution, is adjusted with specific reference to the dissolving situation of each compound, compound is completely dissolved.
2. zoopery
190-250g male SD rats are taken, are randomly divided into two groups, one group of intravenous injection testing compound, dosage 1.0mg/ Kg, another group is orally given testing compound, dosage 5mg/kg；Be injected intravenously after administration temporally point 0.0833,0.25, 0.5th, 1,2,5,7 and 24 hour tail vein blood；Oral administration gavage temporally puts 0.25,0.5,1,2,5,7 and 24 hour tail vein Blood sampling.The standard curve of OK range is established according to sample concentration, test compounds in plasma sample are determined using LC-MS/MS methods The concentration of thing.According to pharmaceutical concentration-time curve, pharmacokinetics ginseng is calculated using the non-compartment model method of the softwares of WinNonLin 6.3 Number.
3. experimental result is as follows：
Table 3：The pharmacodynamic activity of the compounds of this invention
"/" represents not detect.
Experiment conclusion：It is metabolized inside the compounds of this invention preferably, there is preferably absorption and exposed amount, bioavilability It is higher, and bioavilability is substantially better than Abemaciclib.
Pharmacodynamic activity of the compounds of this invention of example 3 in Mice Body
Experimental method：
By 18 body weight in the ICR mouse of 18~25g scopes are randomly divided into 3 groups, every group 6, every group 3 mouse veins Injection and 3 mouse stomaches give testing compound, by the time point collection blood of design, each time point collection one after administration Animal blood is organized, blood plasma is taken after centrifugal blood, blood concentration is tested with LC-MS/MS after processing, with Winnonlin with non-chamber Model calculates medicine for parameter.
Table 4：The mouse PK pharmacodynamic activities of the compounds of this invention
Experiment conclusion：Metabolism of the compounds of this invention in Mice Body is preferable, there is preferably absorption and exposed amount, biology Availability is higher, and exposed amount is substantially better than Abemaciclib.

Claims (12)

1. a kind of compound, it is the compound as shown in formula (I), or the pharmaceutically acceptable salt of compound shown in formula (I),
Wherein：
B rings are
R1And R2It is each independently hydrogen, fluorine, chlorine or bromine；
L1For key；
R3For hydrogen；
R5For hydrogen, C1-6Alkyl, C1-6Haloalkyl, HO- (C (R4)2)n- C (=O)-；
R4For hydrogen；
N independently is 1,2,3 or 4.
2. compound according to claim 1, wherein,
R5It independently is hydrogen, C1-4Alkyl, C1-4Haloalkyl, HO- (C (R4)2)n- C (=O)-；
R4For hydrogen.
3. compound according to claim 1, wherein,
R5For HO- (C (R4)2)n- C (=O)-, hydrogen, trifluoromethyl, 2- fluoro ethyls, 3,3,3- trifluoro propyls, methyl, ethyl, positive third Base, isopropyl, the tert-butyl group, 2- methyl-propyls or normal-butyl；
R4For hydrogen.
4. compound according to claim 1, it is the compound with one of following structure or one of following structuring The pharmaceutically acceptable salt of compound：
5. a kind of pharmaceutical composition, include the compound as described in claim any one of 1-4.
6. pharmaceutical composition according to claim 5, further comprising pharmaceutically acceptable assistant agent.
7. pharmaceutical composition according to claim 6, the assistant agent includes being selected from carrier, excipient, diluent and medium At least one of thing.
8. pharmaceutical composition according to claim 6, further comprising additional therapeutic agent, the additional therapeutic agent is change Learn medicine, antiproliferative, immunodepressant, immunostimulant, anti-inflammatory reagent, for treating the medicine of atherosclerosis Thing, for treating the medicine or combinations thereof of pulmonary fibrosis.
9. pharmaceutical composition according to claim 8, wherein described additional therapeutic agent is Chlorambucil, melphalan, Endoxan, ifosfamide, busulfan, BCNU, lomustine, Streptozotocin, cis-platinum, carboplatin, oxaliplatin, reach Carbazine, Temozolomide, procarbazine, methotrexate (MTX), fluorouracil, cytarabine, gemcitabine, purinethol, fluorine, which reaches, to be drawn Shore, vincaleukoblastinum, vincristine, vinorelbine, taxol, Docetaxel, TPT, Irinotecan, Etoposide, bent shellfish For fixed, dactinomycin D, Doxorubicin, epirubicin, daunomycin, mitoxantrone, bleomycin, mitomycin C, Yi Sha It is grand, TAM, Flutamide, Gonadorelin analog, megestrol acetate, prednisone, dexamethasone, methylprednisolone, Thalidomide, Interferon-' alpha ', Calciumlevofolinate, sirolimus, temsirolimus, everolimus, Afatinib, alisertib, Amuvatinib, Ah pa replace Buddhist nun, Axitinib, bortezomib, SKI-606, brivanib, cabozantinib, Xi Dini Cloth, crenolanib, gram Zhuo replace Buddhist nun, dabrafenib, dacomitinib, danusertib, Dasatinib, dovitinib, Tarceva, foretinib, ganetespib, Gefitinib, ibrutinib, Conmana, Imatinib, iniparib, Lapatinib, lenvatinib, linifanib, linsitinib, Masitinib, momelotinib, not for husky Buddhist nun, come that and replace Buddhist nun, nilotinib, niraparib, oprozomib, olaparib, pazopanib, pictilisib, ponatinib, Quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, saracatinib, saridegib, Sorafenib, Sutent, tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, Trametinib, ZD6474, veliparib, Wei Luofeini, vismodegib, volasertib, alemtuzumab, shellfish cut down list It is anti-, brentuximab vedotin, catumaxomab, Cetuximab, ground promise monoclonal antibody, lucky trastuzumab, her monoclonal antibody, Buddhist nun Trastuzumab, difficult to understand, Victibix, Rituximab, tositumomab, Herceptin, card is rich to replace Buddhist nun, and Pu Na is replaced Buddhist nun, Midostaurin, Pacritinib, quizartinib, gilteritinib, AKN-028, AT-9283, Crenolanib, ENMD-2076, Famitinib, Dovitinib, PLX-3397, palbociclib, abemaciclib, Ribociclib, rigosertib sodium, Selinexor, Roniciclib, AT-7519, Seliciclib, Alvocidib or combinations thereof.
10. prepared by the pharmaceutical composition described in compound or claim any one of 5-9 described in claim any one of 1-4 For preventing, processing, treatment or mitigation patient are by abnormal cell proliferation, autoimmunity, obstacle or disease caused by inflammatory or infection Purposes in the medicine of disease.
11. purposes according to claim 10, change wherein the obstacle or illness are cell cycle protein dependent kinases Disease caused by change；
Wherein described cell cycle protein dependent kinase refers to CDK1, CDK2, CDK4, CDK6 or CDK9.
12. a kind of drug combination composition, it includes the compound or claim 5-9 described in claim any one of 1-4 Pharmaceutical composition described in one and it is one or more be used to treating proliferative diseases, autoimmune disease or inflammatory disease its His active agents；
Other wherein described active agents refer to chemotherapeutic agent, antiproliferative, immunodepressant, immunostimulant, resist Inflammatory agent, CDK4/6 kinase inhibitors, ABL inhibitor, ABL/Scr inhibitor, aurora kinase inhibitors, Bcr-ABL's is non- ATP competitive inhibitors, c-KIT inhibition from mutation agent, RET inhibitor, PDGFR inhibitor, VEGFR inhibitor, CSF1R suppress Agent, FLT3 inhibitor, FLT3-ITD inhibitor or combinations thereof.
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