CN109503573A - 2- substituted anilinic pyrimidine derivatives and application thereof - Google Patents

2- substituted anilinic pyrimidine derivatives and application thereof Download PDF

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Publication number
CN109503573A
CN109503573A CN201710855984.5A CN201710855984A CN109503573A CN 109503573 A CN109503573 A CN 109503573A CN 201710855984 A CN201710855984 A CN 201710855984A CN 109503573 A CN109503573 A CN 109503573A
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base
methyl
dimethylamino
amino
compound
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周显波
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Kunming Shengjianan Biological Technology Co Ltd
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Kunming Shengjianan Biological Technology Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

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Abstract

The present invention relates to 2- substituted anilinic pyrimidine derivatives and its salt with formula (I), including the preparation method and purposes of officinal salt and its pharmaceutical composition.Such compound and its pharmaceutically acceptable salt, solvate, prodrug and pharmaceutical composition are suitable for treatment disease and symptom, especially with the related disease of activity and symptom of cell cycle protein dependent kinase CDK4/6, the diseases such as this and symptom are including (but not limited to) various cancers and inflammation.

Description

2- substituted anilinic pyrimidine derivatives and application thereof
Technical field
The present invention relates to new 2- substituted anilinic pyrimidines and its pharmaceutical composition in treatment disease and symptom, especially It is the related disease of activity and symptom with cell cycle protein dependent kinase 4/6 (CDK4/6), including but not limited to respectively Kind of cancer, angiocarpy and with the purposes in inflammation/immune-related disease and symptom.
Background technique
Cell Proliferation and division amplification were completed by the cell cycle.Cell cycle is divided into G0 (quiescent stage), G1 (DNA pre-synthesis phase), S (DNA synthesizes the phase), G2 (prophase) and M (m period).Cell cycle protein dependent kinase (CDKs) belong to serine/threonine kinase, in cell cycle regulating, genetic transcription, cell differentiation and process of cell death Play important regulative.What is be currently known has 13 CDK members (CDK1-13) and its corresponding 12 Cyclins (A-L). CDK needs its corresponding Cyclin to complete its function in turn in conjunction with to be activated.CDK4 and CDK6 regulating cell is by G1 to the S phase Conversion.
One typical characteristics of malignant tumour are cell cycle regulating disorders, lead to uncontrolled cellular proliferation, disdifferentiation And vicious transformation.About 50% tumour has the change of cell cycle pathways, such as Rb and p53 missing/mutation/mistake expression, Gene magnification or overexpression of Cyclin D1/CDK etc..Therefore, targeting cell-cycle regulates and controls GAP-associated protein GAP, controls imbalance Cell reenters the good approach that normal cell-cycle regulation is antineoplaston.CDK4/6 is including ER The downstream targets of a plurality of signal path.In ER positive breast cancer, estrogen receptor results in ER-Cyclin D1- The activity of CDK4/6 access increases, and CDK4/6 inhibitor is different from acting on the anti-tumor drug of signal transduction upstream target spot, can With the direct regulation and control cell cycle, tumour cell was blocked in the G1 phase.CDK4/6 inhibitor combined endocrine therapy can achieve double The effect inhibited again.Research finds that Small molecule CDK inhibitors can effectively inhibit the growth of kinds of tumor cells.It can also use The disease caused by treatment cardiovascular disorder and multi-infection agent, including fungi, protozoon parasite and DNA and RNA disease Poison.Meanwhile selective CDK micromolecular inhibitor can improve the consequence etc. of various autoimmune disorders.Therefore, CDK4/6 is targeted The research and development of protein kinase drug are a significant fields.
Has document report (Clinical Cancer about cell cycle protein dependent kinase micromolecular inhibitor Research, 2013,19,6173-6182).The present invention be it has been found that on the basis of, design the targeting CDK kinases of synthesis Micromolecular inhibitor, which has the potentiality for treating a variety of diseases.
Summary of the invention
The present disclosure generally relates to 2- substituted anilinic pyrimidines and its pharmaceutical compositions, are used as effective as selective CDK inhibitor, and be suitable for treat or prevent disease, especially via certain CDK (especially CDK4 and CDK6) mediate disease, Illness or medical condition, such as a plurality of types of cancers and the relevant symptom of inflammation.
One aspect of the present invention system is directed to formula (I) compound:
Or its pharmaceutically acceptable salt, solvate or prodrug, in which:
Ar is selected from 3H- imidazo [4, the 5-b] pyridine -5- base replaced, substituted 1H- imidazo [4,5-b] pyridine -6- Base, substituted 1H- indoles -6- base, substituted 1H- pyrrolo- [2,3-b] pyridine -6- base, substituted 1H- pyrrolo- [3,2-b] Pyridine -6- base, substituted 2H- indazole -5- base, substituted pyrazolo [1,5-a] pyridine -5- base；
R1Selected from hydrogen, fluorine, chlorine, methyl and cyano；
R2Selected from methoxyl group and methyl；
R3And R4The C selected from H and selectively replaced1-C6Alkyl, the two can also link together and NR3R4N in base A heterocycle, NR is collectively formed3R4Base includes but is not limited to: (3R) -3- (dimethylamino) pyrrolidin-1-yl, (3S) -3- (diformazan Base-amino) pyrrolidin-1-yl, 3- (dimethylamino) azetidine -1- base, [2- (dimethylamino) ethyl] (methyl) amino, [2- (methylamino) ethyl] (methyl) amino, 5- methyl -2,5- diazaspiracyclic [3.4] octyl- 2- base, (3aR, 6aR) -5- methyl Hexahydropyrrolo simultaneously [3,4-b] pyrroles -1 (2H)-base, 4- methylpiperazine-1-yl, 4- [2- (dimethylamino) -2- oxoethyl] piperazine Piperazine -1- base, methyl [2- (4- methylpiperazine-1-yl) ethyl] amino, methyl [2- (morpholine -4- base) ethyl] amino, 4- [(2S) -2- aminopropionyl] piperazine -1- base, morpholine -4- base；
Another aspect of the present invention system is directed to pharmaceutical composition, and it includes formula (I) compound or its is pharmaceutically acceptable Salt, solvate or prodrug and one or more pharmaceutically acceptable excipient, such as adjuvant, diluent and/or load Agent.
Another aspect of the present invention system is for treatment via at least one of cell cycle protein dependent kinase (CDK) The method of disease or symptom that (especially CDK4, CDK6 or combinations thereof) is mediated, comprising having to individuals in need application treatment Formula (I) compound or its pharmaceutically acceptable salt, solvate or prodrug of effect amount.
Another aspect of the present invention system is for treatment via at least one of cell cycle protein dependent kinase (CDK) The method of disease, illness or symptom that (especially CDK4, CDK6 or combinations thereof) is mediated, comprising being controlled to individuals in need application A effective amount of pharmaceutical composition is treated, which includes formula (I) compound or its pharmaceutically acceptable salt, solvate Or prodrug and one or more pharmaceutically acceptable excipient, such as adjuvant, diluent and/or carrier.
In one embodiment, with one or more cell cycle protein dependent kinases, especially CDK4, CDK6 or its group Close associated disease or illness, include cancer, may include (but being not limited to) lung cancer (especially non-small cell lung cancer, NSCLC), Breast cancer, prostate cancer, colorectal cancer, spongioblastoma, lymphoma mantle cell, chronic myelogenous leukemia and acute bone Myelogenous leukemia and its complication.
Another aspect of the present invention system is for the method for inhibiting cell Proliferation, and it includes with a effective amount of formula (I) compound Or its salt, solvate, prodrug or compositions-treated such cell.
Another aspect of the present invention system for inhibit cell cycle protein dependent kinase (CDK), especially CDK4, CDK6 or The method of a combination thereof, it includes with a effective amount of formula (I) compound or its salt, solvate, prodrug or compositions-treated such Kinases.
Another aspect of the present invention system is directed to the purposes of the compound of the present invention, is used in biology and pathological phenomena The research of CDK and the comparative evaluation for being used for new kinase inhibitor.
Another aspect of the present invention system is directed to according to formula (I) compound of any embodiment as described herein or its medicine Acceptable salt, solvate, prodrug or composition are in manufacture for treating and the active associated disease of CDK or illness on Purposes in terms of drug.The CDK activity is more preferably the activity or combinations thereof of CDK4, CDK6.
Another aspect of the present invention system for synthesis substantially as herein disclosed and the side of described formula (I) compound Method.
In view of following implementation and claim, and knowledge and technology conventional in the field are combined, the present invention Other aspect or advantage will be apparent to those skilled in the art are familiar with.
Specific embodiment
The present invention provides the new 2- substituted anilinic pyrimidine derivatives that can be used as CDK inhibitor.
In one aspect, the present invention provides formula (I) compound:
Wherein:
Ar is selected from 3H- imidazo [4, the 5-b] pyridine -5- base replaced, substituted 1H- imidazo [4,5-b] pyridine -6- Base, substituted 1H- indoles -6- base, substituted 1H- pyrrolo- [2,3-b] pyridine -6- base, substituted 1H- pyrrolo- [3,2-b] Pyridine -6- base, substituted 2H- indazole -5- base, substituted pyrazolo [1,5-a] pyridine -5- base；
R1Selected from hydrogen, fluorine, chlorine, methyl and cyano；
R2Selected from methoxyl group and methyl；
R3And R4The C selected from H and selectively replaced1-C6Alkyl, the two can also link together and NR3R4N in base A heterocycle, NR is collectively formed3R4Base includes but is not limited to: (3R) -3- (dimethylamino) pyrrolidin-1-yl, (3S) -3- (diformazan Base-amino) pyrrolidin-1-yl, 3- (dimethylamino) azetidine -1- base, [2- (dimethylamino) ethyl] (methyl) amino, [2- (methylamino) ethyl] (methyl) amino, 5- methyl -2,5- diazaspiracyclic [3.4] octyl- 2- base, (3aR, 6aR) -5- methyl Hexahydropyrrolo simultaneously [3,4-b] pyrroles -1 (2H)-base, 4- methylpiperazine-1-yl, 4- [2- (dimethylamino) -2- oxoethyl] piperazine Piperazine -1- base, methyl [2- (4- methylpiperazine-1-yl) ethyl] amino, methyl [2- (morpholine -4- base) ethyl] amino, 4- [(2S) -2- aminopropionyl] piperazine -1- base, morpholine -4- base；
In one embodiment, the compound or its pharmaceutically acceptable salt of the formula (I) as shown in above are provided, Wherein:
Ar is selected from 3H- imidazo [4, the 5-b] pyridine -5- base replaced, substituted 1H- imidazo [4,5-b] pyridine -6- Base, substituted 1H- indoles -6- base, substituted 1H- pyrrolo- [2,3-b] pyridine -6- base, substituted 1H- pyrrolo- [3,2-b] Pyridine -6- base, substituted 2H- indazole -5- base, substituted pyrazolo [1,5-a] pyridine -5- base；
R1It is selected from hydrogen, fluorine, chlorine, methyl and cyano；
R2It is methoxyl group；And
NR3R4Base is selected from (3R) -3- (dimethylamino) pyrrolidin-1-yl, (3S) -3- (dimethyl-amino) pyrrolidines - 1- base, 3- (dimethylamino) azetidine -1- base, [2- (dimethylamino) ethyl] (methyl) amino, [2- (methylamino) second Base] (methyl) amino, 5- methyl -2,5- diazaspiracyclic [3.4] octyl- 2- base, (3aR, 6aR) -5- methyl hexahydropyrrolo simultaneously [3, 4-b] pyrroles -1 (2H)-base, 4- methylpiperazine-1-yl, 4- [2- (dimethylamino) -2- oxoethyl] piperazine -1- base, methyl [2- (4- methylpiperazine-1-yl) ethyl] amino, methyl [2- (morpholine -4- base) ethyl] amino, 4- [(2S) -2- amino propionyl Base] piperazine -1- base.
In further embodiment, the compound (I) of formula as shown in above is provided or its is pharmaceutically acceptable Salt, in which:
Ar is selected from 3H- imidazo [4, the 5-b] pyridine -5- base replaced, substituted 1H- imidazo [4,5-b] pyridine -6- Base, substituted 1H- indoles -6- base, substituted 1H- pyrrolo- [2,3-b] pyridine -6- base, substituted 1H- pyrrolo- [3,2-b] Pyridine -6- base, substituted 2H- indazole -5- base, substituted pyrazolo [1,5-a] pyridine -5- base；
R1It is selected from hydrogen, fluorine, chlorine, methyl and cyano；
R2It is methoxyl group；And
NR3R4Base is selected from (3R) -3- (dimethylamino) pyrrolidin-1-yl, 3- (dimethylamino)-azetidine -1- Base, [2- (dimethylamino) ethyl] (methyl) amino, 4- methylpiperazine-1-yl.
In further embodiment, the compound of formula (I) as shown in above is provided or its is pharmaceutically acceptable Salt, in which:
Ar is selected from 2- methyl -3H- imidazo [4, the 5-b] pyridine -5- base replaced, substituted 2- methyl-1 H- imidazo [4,5-b] pyridine -6- base, substituted 2- Methyl-1H-indole -6- base, substituted 2- methyl-1 H- pyrrolo- [2,3-b] pyridine - 6- base, substituted 2- methyl-1 H- pyrrolo- [3,2-b] pyridine -6- base, substituted 2- methyl -2H- indazole -5- base are substituted 2- methyl pyrazole simultaneously [1,5-a] pyridine -5- base；
R1It is selected from hydrogen, fluorine, chlorine, methyl and cyano；
R2It is methoxyl group；And
NR3R4Base is selected from (3R) -3- (dimethylamino) pyrrolidin-1-yl, (3S) -3- (dimethyl-amino) pyrrolidines - 1- base, 3- (dimethylamino) azetidine -1- base, [2- (dimethylamino) ethyl] (methyl) amino, [2- (methylamino) second Base] (methyl) amino, 5- methyl -2,5- diazaspiracyclic [3.4] octyl- 2- base, (3aR, 6aR) -5- methyl hexahydropyrrolo simultaneously [3, 4-b] pyrroles -1 (2H)-base, 1- methyl-1,2,3,6- tetrahydropyridine -4- bases, 4- methylpiperazine-1-yl, 4- [2- (diformazan ammonia Base) -2- oxoethyl] piperazine -1- base, methyl [2- (4- methylpiperazine-1-yl) ethyl] amino, methyl [2- (morpholine -4- base) Ethyl] amino, 1- amino -1,2,3,6- tetrahydropyridine -4- bases, 4- [(2S) -2- aminopropionyl] piperazine -1- base；
In further embodiment, the compound of formula (I) as shown in above is provided or its is pharmaceutically acceptable Salt, in which:
Ar is selected from 2- methyl -3H- imidazo [4, the 5-b] pyridine -5- base replaced, substituted 2- methyl-1 H- imidazo [4,5-b] pyridine -6- base, substituted 2- Methyl-1H-indole -6- base, substituted 2- methyl-1 H- pyrrolo- [2,3-b] pyridine - 6- base, substituted 2- methyl-1 H- pyrrolo- [3,2-b] pyridine -6- base, substituted 2- methyl -2H- indazole -5- base are substituted 2- methyl pyrazole simultaneously [1,5-a] pyridine -5- base；
R1It is selected from hydrogen, chlorine, methyl and cyano；
R2It is methoxyl group；And
NR3R4Base is selected from (3R) -3- (dimethylamino) pyrrolidin-1-yl, 3- (dimethylamino)-azetidine -1- Base, [2- (dimethylamino) ethyl] (methyl) amino, 4- methylpiperazine-1-yl.
In certain preferred embodiments in this regard, the present invention provides compound listed in table 1 (seeing below), and its doctor Acceptable salt, solvate and prodrug on medicine.
On the other hand, the present invention provides a kind of pharmaceutical compositions, and it includes the changes according to any formula (I) as described herein Close object or its pharmaceutically acceptable salt, solvate or prodrug and one or more pharmaceutically acceptable adjuvants, Diluent and/or carrier.
On the other hand, the present invention provides treatments via at least one cell cycle protein dependent kinase (CDK) The method of disease, illness or symptom that activity mediates, it includes any formulas to individuals in need application therapeutically effective amount (I) compound or its pharmaceutically acceptable salt, solvate or prodrug.
In one embodiment in this regard, the present invention provides treatments via at least one cyclin dependant The method of disease, illness or symptom that the activity of kinases (CDK) mediates, it includes apply medicine group to individuals in need Close, the composition include therapeutically effective amount according to the compound of any formula (I) as described herein or its is pharmaceutically acceptable Salt, solvate or prodrug and one or more pharmaceutically acceptable adjuvants, diluent and/or carrier.
In a preferred embodiment in this regard, at least one CDK is CDK4, CDK6 or combinations thereof.
In another preferred embodiment in this regard, the disease or symptom are disease relevant to cancer or inflammation or disease Shape.
In another preferred embodiment in this regard, the cancer system is selected from (but being not limited to) colon and rectum carcinoma, cream It is cancer, lung cancer (especially non-small cell lung cancer, NSCLC), prostate cancer, spongioblastoma, lymphoma mantle cell (MCL), slow Property myelomatosis (CML), acute myelogenous leukemia (AML) and its complication.
On the other hand, the compound of the present invention can be used in combination and individuals in need with second therapeutic agent；This Two therapeutic agents are different CDK inhibitor, human epidermal growth factor acceptor (for example, HER2) inhibitor, silk amino acid/Soviet Union's amino acid Kinase inhibitor (such as mTOR mammal rapamycin target inhibitor) or EGF-R ELISA (EGFR) inhibitor.
On the other hand, the present invention provide inhibit cell Proliferation method, it includes with it is a effective amount of according to appoint One formula (I) compound or its salt, solvate, prodrug, or combinations thereof object handle the cells such as this.Inhibit the method for cell Proliferation In vivo (such as individual is in vivo) can occur, or in vitro (such as in the biological sample containing individual proliferative cell).
In a preferred embodiment in this regard, which is cancer cell, such as (but not limited to) colon cancer, The carcinoma of the rectum, breast cancer, lung cancer (especially non-small cell lung cancer, NSCLC), prostate cancer, spongioblastoma, lymphoma mantle cell (MCL), the cell of chronic myelogenous leukemia (CML), acute myelogenous leukemia (AML) or its complication.
On the other hand, the present invention provides the method for inhibiting cell cycle protein dependent kinase (CDK), and it includes with having Effect amount according to any formula (I) compound as described herein or its salt, solvate, prodrug, or combinations thereof object handle this and swash Enzyme.Inhibit the method for CDK that in vivo (such as individual is in vivo) can occur, or in vitro (such as contain individual proliferative cell In biological sample).
In a preferred embodiment in this regard, which is CDK4, CDK6 or its group It closes.
On the other hand, the present invention provide according to the compound of any formula (I) as described herein or its can pharmaceutically connect The purposes of the salt received, solvate, prodrug or combinations thereof object, be used to manufacture for treatment and the active associated disease of CDK or The drug of illness.The CDK activity is preferably the activity of CDK4, CDK6 or combinations thereof.
In one embodiment in this regard, the disease or illness system are selected from following disease: colon and rectum carcinoma, cream It is cancer, lung cancer (especially non-small cell lung cancer, NSCLC), prostate cancer, spongioblastoma, lymphoma mantle cell (MCL), slow Property myelomatosis (CML) and acute myelogenous leukemia (AML).
On the other hand, the present invention provides the preparation method of formula (I) compound, comprising intermediary F and acryloyl chloride is anti- The step of answering:
Wherein Ar, R1、R2、R3And R4System is defined according to any embodiment as described herein.
In one embodiment in this regard, this method further comprises intermediary D through amine (HNR3R4) substitution reaction conversion For intermediary E, and the step of converting intermediary F for the reduction of the nitro of intermediary E:
Wherein Ar, R1、R2、R3And R4System is defined according to any embodiment as described herein.
In one embodiment in this regard, this method further comprises converting initial substance A to by boronation reaction Intermediary B, then B and 2, the coupling of the chloro- 5- substituted pyrimidines of 4- bis- are converted into intermediary C, then C and 2,4,5- trisubstituted benzene amine couplings Conjunction is converted into the step of intermediary D:
Wherein Ar, R1、R2、R3And R4System is defined according to any embodiment as described herein；R5And R6It independently is alkyl, virtue Base, naphthenic base, or be combined and to form alkylidene, respectively optionally and independently selected from C1-C4Alkyl, halogen or substituted-phenyl.
Compound provided by the present invention is also applied for the research of kinases in biology and pathological phenomena, to equal sharp by this The research for the transduction path that enzyme mediates and comparative evaluation to new kinase inhibitor.
Unless otherwise stated, otherwise term " alkyl ", as used herein, including branched chain and linear saturation aliphatic hydrocarbyl, It contains 1 to 8 carbon, preferable 1 to 6, more preferably 1 to 4 carbon.The term covers (but being not limited to) methyl, ethyl, propyl, different Propyl, butyl, tert-butyl, isobutyl group, amyl, hexyl or its similar to group.
Unless otherwise stated, otherwise term " alkylidene " is meant from alkane by removing two hydrogen atoms as used herein And derivative divalent radical of saturated aliphatic group.Example includes but is not limited to methylene (- CH2), ethylidene (- CH2CH2), Asia third Base (- CH2CH2CH2) or its similar to group.
Unless otherwise stated, otherwise term " naphthenic base ", as used herein, individually or as one of another group Point, including the saturated rings alkane group with 3 to 8 carbon atoms.Example includes but is not limited to cyclopropyl, cyclobutyl, ring penta Base and cyclohexyl.
Unless otherwise stated, otherwise term " aryl ", as used herein, individually or as another group a part, Mean monocycle in loop section containing 6 to 10 carbon atoms or bicyclic aromatic base (such as phenyl and naphthalene, including 1- naphthalene and 2- naphthalene) and monocycle or bicyclic heterocycle aromatic group (such as pyridine, pyrimidine, indoles, pyrrolopyridine).
" halogen " or " halogen " means fluorine (F), chlorine (Cl), bromine (Br) and iodine (I) as used herein.
In addition, alkyl, alkylidene, naphthenic base and methyl cycloalkyl optionally can independently further through one or more, Preferable 1 to 3, substituent group replaces, such substituent group is independently selected from halogen and C1-C4Alkyl.
The compound of the present invention is acknowledged as organic base, can be reacted with sour (specific pharmaceutically acceptable acid) with Form pharmaceutically acceptable salt.
The term as used herein " pharmaceutically acceptable salt " means the suitable and people in the scope of rational medicine judgement Class and compared with lower animal tissue contact using and without improper toxicity, stimulation, allergic reaction and its similar situation, and with reasonable benefit The salt that place/Hazard ratio matches.Pharmaceutically acceptable salt has been known to such technical field.See, e.g. S.M.Berge et al., J.Pharm.Sci., 1977,66:1-19 are incorporated herein by reference.The compounds of this invention Pharmaceutically acceptable salt include derived from suitable inorganic and organic acid salt.Pharmaceutically acceptable non-toxic acid adds Example at salt be amido and inorganic acid (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and cross chloric acid) or organic acid (such as acetic acid, Ethanedioic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid) salt that is formed, or by using institute in such technology The salt that other methods (such as ion exchange) are formed.Other pharmaceutically acceptable salt include but is not limited to adipic acid Salt, alginate, ascorbate, aspartic acid salt, benzene sulfonate, benzoate, disulfate, borate, butyrate, camphor tree Olic acid salt, camsilate, citrate, cyclopentane propionate, digluconate, lauryl sulfate, ethane sulfonate, Formates, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydrogen Iodate, 2- hydroxy-ethanesulfonate, Lactobionate, lactate, laruate, lauryl sulfate, malate, suitable fourth Enedioic acid salt, malonate, methane sulfonates, 2- naphthalene sulfonate, nicotine hydrochlorate, nitrate, oleate, oxalate, palm Hydrochlorate, embonate, pectate, persulfate, 3- phenylpropionic acid salt, phosphate, pivalate, propionate, stearic acid Salt, succinate, sulfate, tartrate, rhodanate, tosilate, undecanoate, valerate and its similar Object.Preferred pharmaceutically acceptable salt includes hydrochloride.
Term " solvate " means the compounds of this invention and stoichiometry or non-stoichiometric molten as used herein The physical association object of agent molecule.For example, a molecule of the compound and one or more, preferable 1 to 3, solvent molecule In conjunction with.It could also be possible that multiple molecules (for example, 1.5 or 2) of compound share a solvent molecule.This physical combination can Including Hydrogenbond.In some cases, solvate will be used as Crystallization Separation.Solvent molecule in solvate can be with Ordered arrangement and/or disorderly arranged and exist.Exemplary solvates include but is not limited to hydrate, ethanolates, methanol Close object and isopropanol solvate.The method for forming solvate is commonly known in such technology.
Term " prodrug " means that compound in vivo can be inverted (such as logical to generate parent compound as used herein Cross in blood hydrolyze) derivative.The Common examples of prodrug in the present invention include but is not limited to active amine compound Amide or phosphamide, for example, formula (II) compound:
Wherein R7For acyl group (for example, acetyl group, propiono, formoxyl etc.) or phosphoryl [such as-P (=O) (OH)2]；Alternatively, As Ar, R in reactive compound3Or R4When group contains NH, corresponding amide or phosphamide compound may act as prodrug.It should Equal amides or phosphamide prodrug compound can the preparations of the method according to known to the technical field.
When for the therapeutically effective amount in therapy the compounds of this invention or its pharmaceutically acceptable salt or solvent close When object can be used as chemical raw material use and be possibly realized, active constituent can be made to manifest as medical composition.Therefore, the present invention is into one Step provides medical composition comprising any the compound of the present invention or its pharmaceutically acceptable salt or solvate, and It is one or more, preferable one to three kind, pharmaceutically acceptable carrier, diluent or other excipient.It is somebody's turn to do (s) carrier, dilute It releases agent or other excipient is necessary for acceptable, i.e., it is compatible with the other compositions of composite and harmless to individual treated.
Term " pharmaceutically acceptable " means as used herein and judges to be suitble in scope with patient's in rational medicine Tissue contact using and without overdosage toxicity, stimulation, allergic reaction or other problems or complication, and with reasonable benefit/relative risk Match, and the compound effective for its desired use, substance, composition and/or dosage form characteristic.
The unit dosage forms for the active constituent that medical formulation can contain predetermined amount with per unit dose manifest.In general, of the invention Medical composition every 1 to 5 day once or to about 1-5 times daily or as continuous infusion oral is administered.The administration It can be used as chronic or acute therapy.The amount of the active constituent of single formulation can be combined to produce with carrier material will be depending on being treated Symptom, the severity of symptom, administration time, administration route, the excretion rate of compound used therefor, duration for the treatment of and patient Age, gender, weight and symptom and change.Preferable single dose unit formulation is the daily dose as described above containing active constituent Or the formula of sub- dosage or its proper proportion.In general, treatment is with the low dose of starting of the optimal dose less than compound.This Afterwards, by increasing the best use of dosage when reaching this at leisure.In general, the compound is most preferably with substantially On obtain effective result without causing the concentration level of substantial adverse or toxic side effect to use.
When composition of the invention include the compound of the present invention with it is one or more, preferable one or two kind, additional treatment When agent or the combination of prophylactic, the compound and the additives are with the generally about dosage used in single medication course for the treatment of Between 10 to 150%, and more preferably about 10 to 80% dosage level.
Medical formulation may be adapted to be administered by any suitable pathways, for example, by oral (including in cheek or sublingual), rectum, Intranasal, part (including in cheek, sublingual or percutaneous), vagina or parenteral (including subcutaneous, intradermal, intramuscular, intra-articular, synovial membrane It is interior, breastbone is interior, intrathecal, intralesional, intravenous or intracutaneous injection or infusion) approach administration.The equal preparations can pass through pharmacy skill In art prepared by known any method (for example, by the way that active constituent and carrier or excipient associate).Oral administration is logical Injection is crossed to use preferably.
Formula suitable for orally using can be manifested in the form of discrete unit, such as capsule or tablet；Powder or particle；It is aqueous Or solution or suspension in non-aqueous liquid；Edible foaming body plays foam；Or oil-in-water liq lotion or Water-In-Oil Type lotion.
For example, for orally taking in the form of a tablet or capsule, can by active medicine component and it is oral, nontoxic, Pharmaceutically acceptable inert carrier (such as ethyl alcohol, glycerol, water, and the like) combination.By the way that compound powder is broken to Suitable fine size and with pharmaceutical carrier (such as the edible carbohydrate, such as starch or mannose equally through crushing Alcohol) it mixes to prepare powder.Also flavoring agent, preservative, dispersing agent and colorant may be present.
Capsule is manufactured by preparing mixture of powders as described above and filling molding gelatin shell.Padding it Before, it can be by the slip agents and lubricant of such as colloidal silicon dioxide, talcum, magnesium stearate, calcium stearate or solid polyethylene glycol It is added in mixture of powders.Also the dispersing agent or cosolvent of such as agar, calcium carbonate or sodium carbonate can be added to improve intake The availability of drug when capsule.
In addition, as desired or necessary, also suitable adhesive, lubricant, dispersing agent and colorant can be incorporated to mixing In object.Suitable adhesive includes starch, gelatin, natural sugar (such as glucose or beta lactose), corn sweetener, natural and conjunction Plastic (such as Arabic gum, bassora gum or sodium alginate), carboxymethyl cellulose, polyethylene glycol and the like.For these Lubricant in dosage form includes enuatrol, sodium chloride and the like.Dispersing agent includes but is not limited to starch, Methyl cellulose Element, agar, bentonite, Xanthan gum and the like.Such as by preparing mixture of powders, granulation or dry-pressing, addition lubricant And dispersing agent and tabletted deploy tablet.By by the compound suitably crushed and diluent as described above or matrix It mixes and optionally blocks with adhesive (such as carboxymethyl cellulose, alginate, gelatin or polyvinyl pyrrolidone), solution Agent (such as paraffin) reabsorbs accelerator (such as level Four salt) and/or absorbent (such as bentonite, kaolin or calcium monohydrogen phosphate) Mixing is to prepare mixture of powders.It can be by with adhesive (such as syrup, gelatinized corn starch, Acadia's rubber cement (acadiamucilage) or the solution of cellulose or polymeric material) wetting and be forced through sieve come granulated powder mixing Object.As granulated alternative, mixture of powders can be made to pass through ingot pressing machine and result not exclusively molding dry-pressing object fragmentation For particle.It can carry out lubricated granules by means of addition stearic acid, stearate, talcum or mineral oil to prevent from clinging tablet molding Mould.Then, the mixture through lubricating is compressed into tablet.It also can be by the compound of this disclosure and free mobility inert carrier It combines and is directly compressible into tablet and does not suffer from granulation or dry compressing step.It can provide the seal coating, sugar or polymer by shellac The coat composed transparent or opaque protective coating of the polishing of the coating and wax of matter.Dyestuff can be added to the area grade coatings Zhong Yi Divide different unit doses.
The oral solutions such as solution, syrup and elixir can be prepared with unit dosage forms, so that containing predetermined amount in specified rate Compound.Syrup can be by being dissolved in compound through preparing in suitably seasoned aqueous solution, and elixir is then via using It is prepared by nontoxic mediator.Also solubilizer and emulsifier (such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol can be added Ether), preservative, flavouring additive (such as peppermint oil or natural sweetener or saccharin or other artificial sweeteners) and its similar Object.
Where appropriate, the dosage unit formulations for orally taking can be made into micro-capsule.Also can be prepared into such as by coating or Embedding shot-like particle extends in polymer, wax or its analog or the formula of sustained release.
In addition to the above specifically mentioned ingredient, it is contemplated that the type of the formula, formula also may include in such technology Other known medicaments, the formula for being for example suitable for orally taking may include flavoring agent.
Term " individual " or " patient " include the mankind and other mammals, the preferably mankind.
Term " therapeutically effective amount " is meant when being administered for treatment disease to individual, it is sufficient to realize for controlling for the disease The amount of the compound or composition for the treatment of." therapeutically effective amount " can especially depending on compound, disease and its severity and be treated Individual age, weight or other factors and change.When the individual active constituents for being applied to individually take, which means it Separate constituent.When being applied to combination, which means and no matter consecutively or simultaneously applies in a joint manner, generates therapeutic effect The combined amount of active constituent.
In some embodiments, term " treatment (treating) " or " treatment (treatment) " are meant: (i) inhibits disease Disease, illness or symptom, that is, contain its development；(ii) alleviate disease, illness or symptom, that is, cause the disease, illness and/or The recession of symptom；Or (iii) is diagnosed as in possible susceptible disease, illness and/or symptom but not yet suffering from the individual pre- in vivo of its Prevent that the disease, illness or symptom occur.Therefore, in some embodiments, " treatment (treating) " or " treatment (treatment) " meaning improves disease or illness, may include improving one or more body parameters, although it is difficult to be controlled The appersonification for the treatment of.In some embodiments, " treatment (treating) " or " treatment (treatment) " includes (example on body Such as, the stabilization of symptom can be distinguished) or physiologically (for example, stabilization of body parameter) or both adjusts disease or illness.Again In some embodiments, " treatment (treating) " or " treatment (treatment) " includes the breaking-out for postponing disease or illness.
Method
Abbreviation
Following abbreviation can be used in this application:
B2pin2Two boron of=bis- (pinacol foundation)；
MeOH=methanol；
Pd(dppf)Cl2=[1,1 '-bis- (diphenylphosphino) ferrocene] dichloro palladium (II)；
Pd2(dba)3=ginseng (dibenzalacetone) two palladium (0)；
Pd(OAc)2=palladium acetate；
Bis- (diphenyl phosphine) -9,9- dimethyl dibenzo piperazines of Xantphos=4,5- are muttered；
nBu3P=tri--normal-butyl phosphine；
TCHP=tricyclohexyl phosphine；
K2CO3=potassium carbonate；
DMSO=dimethyl sulfoxide；
DCM=methylene chloride；
NH3=ammonia；
MeOH=methanol；
DIEA=diisopropylethylamine；
Hepes=4- hydroxyethyl piperazineethanesulfonic acid；
MgCl2=magnesium chloride；
Bis- (the 2- amino-ethyl ether) tetraacethyls of EGTA=ethylene glycol；
Brij 35=Brij-35；
Na3VO4=sodium vanadate；
DTT=dithiothreitol (DTT)；
33P-ATP=33P- adenosine triphyosphate；
CO2=carbon dioxide
H=hours；
Min=minutes；
ML=milliliters；
μ L=microlitre；
Mmol=mMs.
Chemical synthesis
The synthesis of formula (I) compound
The synthesis of formula (I) compound is illustrated in following general synthesis flow:
Synthesis flow
Initial substance A is converted into intermediary B by boronation reaction, then B and 2, the coupling conversion of the chloro- 5- substituted pyrimidines of 4- bis- For intermediary C, then C and 2, the coupling of 4,5- trisubstituted benzene amine are converted into intermediary D, during then D is converted into through amine substitution reaction Between object E, then E nitro, which is reduced, is converted into intermediary F, and last F reacts to form final product (I) with acryloyl chloride.
Example
Unrestricted example further illustrates certain aspects of the invention below.Such series of compounds is according to above-mentioned synthesis Process preparation.
The synthesis of example 1, compound 1
As illustrated example, during following prepare compound 1, some particular agents or reaction is provided separately Condition to be best understood from, but this etc. particular agents or condition do not represent any restrictions.Being familiar with such operator can be various Aspect realizes any specific of the preparation process using a variety of respective conditions (such as reagent, temperature, catalyst and/or solvent etc.) Step.
Isopropyl -2- methyl -6- (4,4,5,5- tetramethyls -1,3,2- dioxy boron pentane -2- base) -1H- pyrrolo- [2,3- B] pyridine (1B) preparation
In dry 100mL round-bottomed flask at room temperature successively by the bromo- 1- isopropyl -2- methyl-1 H- pyrrolo- of 6- [2, 3-b] pyridine (1A, 1.41mmol), potassium carbonate (0.141mmol), connection boric acid pinacol ester (B2pin2, 2.12mmol), three hexamethylenes Base phosphine (59mg, 0.212mmol), palladium acetate (0.141mmol) are added in dimethyl sulfoxide that be heated to 100 DEG C of reactions 2.5 small When.Saturated salt solution is added, ethyl acetate extracts (multiple).Merge organic layer, is dried, filtered with anhydrous sodium sulfate, filtrate subtracts Pressure concentration.N-hexane is added to be beaten to obtain 1- isopropyl -2- methyl -6- (4,4,5,5- tetramethyls -1,3,2- dioxy boron pentane - 2- yl) -1H- pyrrolo- [2,3-b] pyridine (1B, 380mg), m/z:ES+MH+: 301.2.
The preparation of 6- (the fluoro- 4- pyrimidine radicals of the chloro- 5- of 2-) -1- isopropyl -2- methyl-1 H- pyrrolo- [2,3-b] pyridine (1C)
In the 100mL round-bottomed flask for rinsing and keeping with inertia nitrogen atmosphere put 1- isopropyl -2- methyl -6- (4,4, 5,5- tetramethyls -1,3, penta ring -2- base of 2- dioxy boron) -1H- pyrrolo- [2,3-b] pyridine (1B, 7.5mmol), 2,4- bis- be chloro- 5-FU (9.9mmol), potassium carbonate (16.7mmol), Isosorbide-5-Nitrae-dioxanes (40mL) and water (10mL).Pd is added into solution (dppf)Cl2(0.83mmol).Acquired solution is stirred at 80 DEG C 2 hours and be then cooled to room temperature and be concentrated under vacuum. Residue is put on silicagel column and is eluted with ethyl acetate/petroleum ether (1: 2), the product component rotary evaporation being collected into is fallen Obtained after solvent product 6- (the fluoro- 4- pyrimidine radicals of the chloro- 5- of 2-) -1- isopropyl -2- methyl-1 H- pyrrolo- [2,3-b] pyridine (1C, 160mg), m/z:ES+MH+: 305.2.
The fluoro- N- of 5- (the fluoro- 2- methoxyl group -5- nitrobenzophenone of 4-) -4- (1- isopropyl -2- methyl-1 H- pyrrolo- [2,3-b] Pyridine -6- base) pyrimidine -2- amine (1D) preparation
6- (the fluoro- 4- pyrimidine radicals of the chloro- 5- of 2-) -1- isopropyl -2- methyl-1 H- pyrrolo- [2,3-b] pyridine (1C, 2.3mmol), the fluoro- 2- methoxyl group -5- nitroaniline (1.8mmol) of 4-, cesium carbonate (7.2mmol), Pd2(dba)3(0.18mmol) And mixture N of the Xantphos (0.18mmol) in 10mL Isosorbide-5-Nitrae-dioxanes2Degassing is then heated, while at 110 DEG C Lower stirring 4 hours.Mixture is cooled to room temperature, then via silica plug, and is sufficiently washed with DCM.Filtrate is concentrated simultaneously By silica gel column chromatography, DCM-2%NH is used3/ MeOH solvent gradient elution falls the product component rotary evaporation being collected into molten The fluoro- N- of 5- (the fluoro- 2- methoxyl group -5- nitrobenzophenone of 4-) -4- (1- isopropyl -2- methyl-1 H- pyrrolo- [2,3-b] is obtained after agent Pyridine -6- base) pyrimidine -2- amine (1D, 0.47g), m/z:ES+MH+: 455.2.
(2- (dimethylamino) ethyl)-(the fluoro- 4- of 5- (1- isopropyl -2- methyl-1 H- pyrrolo- [2,3-b] pyrrole Pyridine -6- base) pyrimidine -2-base) -5- methoxyl group -The preparation of methyl -2- nitrobenzene-Isosorbide-5-Nitrae-diamines (1E)
The fluoro- N- of 5- (the fluoro- 2- methoxyl group -5- nitrobenzophenone of 4-) -4- (1- isopropyl is sequentially added into the microwave tube of a 10mL Base -2- methyl-1 H- pyrrolo- [2,3-b] pyridine -6- base) pyrimidine -2- amine (1D, 0.79mmol), DIEA (1.97mmol), 2, 2,2- trifluoroethanols (5mL) and N1, N2, N3- Trimethylethane -1,2- diamines.By the reaction mixture in microwave reactor It is heated to 140 DEG C and continues 1 hour.It is extracted after reaction solution is cooling with methylene chloride and water.Organic layer is done with anhydrous sodium sulfate Concentration after dry, and concentrate is placed on silicagel column, with 0-4%7M NH3/ MeOH dichloromethane solution gradient elution, will collect To product component rotary evaporation fall solvent after obtain(2- (dimethylamino) ethyl)-(the fluoro- 4- of 5- (1- isopropyl -2- Methyl-1 H- pyrrolo- [2,3-b] pyridine -6- base) pyrimidine -2-base) -5- methoxyl group -Methyl -2- nitrobenzene-Isosorbide-5-Nitrae-diamines (1E, 260mg), m/z:ES+MH+: 537.3.
(2- (dimethylamino) ethyl)-(the fluoro- 4- of 5- (1- isopropyl -2- methyl-1 H- pyrrolo- [2,3-b] pyrrole Pyridine -6- base) pyrimidine -2-base) -5- methoxyl group -Methylbenzene -1,2, the preparation of 4- triamine (1F)
It is added into the round-bottomed flask of a 50mL(2- (dimethylamino) ethyl)-(the fluoro- 4- of 5- (1- isopropyl -2- Methyl-1 H- pyrrolo- [2,3-b] pyridine -6- base) pyrimidine -2-base) -5- methoxy-. N-methyl -2- nitrobenzene-Isosorbide-5-Nitrae-diamines (1E, 0.46mmol), iron powder (2.78mmol), ammonium chloride (0.32mmol), ethyl alcohol (12mL) and water (4mL) mix reaction Object is heated to reflux 2 hours, is extracted after rotary evaporation concentration with methylene chloride and water.It is dense after organic layer anhydrous sodium sulfate drying Contracting, concentrate is placed on silicagel column, with 0-5%7M NH3The elution of/MeOH-DCM solution gradient, the product group that will be collected into 1F (202mg), m/z:ES are obtained after dividing rotary evaporation to fall solvent+MH+: 507.3.
N- (2- ((2- (dimethylamino) ethyl) (methyl) amido) -5- (the fluoro- 4- of 5- (1- isopropyl -2- methyl-1 H- pyrrole Cough up simultaneously [2,3-b] pyridine -6- base) pyrimidine -2-base) amido) -4- methoxyphenyl) acrylamide (1) preparation
1F (0.38mmol) is added into Lee's type flask of a 25mL, methylene chloride (5mL) and DIEA (0.42mmol) are used Ice bath is cooling.Acryloyl chloride (0.38mL) is added dropwise at leisure under stiring.After dripping, continues stirring 90 minutes, use dichloromethane Alkane and water extract.Organic layer with anhydrous sodium sulfate it is dry after be concentrated, concentrate is placed on silicagel column, with 0-4%7M NH3/ The elution of MeOH-DCM solution gradient, obtains 1 (88mg), m/z:ES after the product component rotary evaporation being collected into is fallen solvent+MH+: 561.3。
The compound of the present invention 1 and other selected examples (compound 2-10) are listed in Table 1 below, and are or can be according to above-mentioned side Method preparation.
Table 1, selected examples of compounds
Biological analysis
Formula (I) compound is novel CDK4/6 inhibitor, can assess its enzymatic activity according to step as described below.
Enzymatic activity-biochemical analysis
96 hole Micro-CPE neutralization test disk of white polystyrene (96 hole flat chassises, catalog number (Cat.No.) 3917) It is middle by CDK4 or CDK6 be added containing cyclin D1 freshly prepd reaction buffer [20mM Hepes (pH 7.5), 10mMMgCl2, 1mM EGTA, 35 0.02%Brij, 0.02mg/mL BSA, 0.1mM Na3VO4, 2mM DTT, 1%DMSO] in And it is gently mixed.With 10 μM of 3 times originated dilutions with 8 dosage IC50Mode (each dosage is surveyed 3 times simultaneously) test compound is living Property.Diluted compound it will be added to kinase reaction mixture in DMSO by the liquid-transfering gun of nanoliter range and train at room temperature It educates 20 minutes.ATP (1 μM) is added in reaction mixture and starts enzyme reaction.Kinase reaction object is cultivated at room temperature and is suitable for Time.Then luminous detection reagent (the Promega kinases-of equivalent kinases is addedFluorescence kinase assay kit, catalog number (Cat.No.) V6711).After ten minutes, fluorescence is read with Tecan GENios microplate reader, to calculate remaining ATP amount for pushing away Calculate kinase activity.The IC50 valuation kinases of inhibitor is used in various dose inhibitor and activity without inhibitor Curve is fitted with nonlinear regression curve to calculate by four parameter logistic equations (GraphPad Prism).Under these conditions, Formula 1 is measured as 7.8nM and 6.7nM to the concentration (IC50 value) of CDK4 and CDK6 activity suppression 50% respectively.
Cell activation assay
It is micro thin that human breast cancer cell strain MCF7 with the total volume in 90 microlitres/hole is inoculated in transparent 96 hole of polystyrene Born of the same parents' culture plate (96 hole flat chassises, catalog number (Cat.No.) 3997) in.Containing moisture, 37 DEG C, 5%CO2And 95% is empty After being cultivated 24 hours in the cell culture case of gas, 1 compound of formula of 10 μ L 10 times of serial dilutions in growth medium is added To each hole (8 dose responses, each dosage are surveyed 3 times simultaneously).After cell culture case continues culture 72 hours, cell is trained Feeding disk moves to room temperature, balances 30 points of kinds then for 100 μ L CellTiter-Reagent (Promega catalog number (Cat.No.) G7571) addition It is mixed in each hole, shaking disk two minutes.Then stand balance 10 minutes.In Tecan GENios microplate reader Before upper reading fluorescent, by medium/CellTiter-Agent transfer to 96 hole Micro-CPE neutralization test disk of white polystyrene (96 hole flat chassises, catalog number (Cat.No.) 3917) in.The suppression of cell growth is calculated relative to untreated control wells Percentage processed.All tests carry out in triplicate under each concentration level.Using GraphPad Prism by using four Parameter logistic equation curve matching data come estimate test compound cell activity inhibit 50% cell of inhibition growth it is dense It spends (IC50 value).Under these conditions, formula 1 inhibits 50% concentration (IC50 value) to survey to MCF7 cell activity (survivaling cell amount) It is set to 10 μM.
Table 2 summarizes the biochemistry of the CDK4/6 inhibitor compound 1,2,4,6,8 and 9 of examples of compounds selected by table 1 And the result data based on MCF7 cell.The data such as this obtain under the analysis condition.
Table 2, the biochemistry of CDK4/6 inhibitor and test cell line data
It is familiar with such operator it is understood that in the case without departing from the gist of the present invention, it can be to the compound of the present invention, group It closes object and/or method carries out various modifications.Therefore, various embodiments of the present invention are only exemplary, not Represent the scope limiting the invention in any way.All references cited herein are in entirety by reference simultaneously Enter herein.

Claims (10)

1. a kind of compound of formula (I):
Or its pharmaceutically acceptable salt, solvate or prodrug, in which:
Ar is selected from 3H- imidazo [4, the 5-b] pyridine -5- base replaced, and substituted 1H- imidazo [4,5-b] pyridine -6- base takes 1H- indoles -6- the base in generation, substituted 1H- pyrrolo- [2,3-b] pyridine -6- base, substituted 1H- pyrrolo- [3,2-b] pyridine - 6- base, substituted 2H- indazole -5- base, substituted pyrazolo [1,5-a] pyridine -5- base, group including but not limited to below:
R1Selected from hydrogen, fluorine, chlorine, methyl and cyano；
R2Selected from methoxyl group and methyl；
R3And R4The C selected from H and selectively replaced1-C6Alkyl, the two can also link together and NR3R4N in base is common Form a heterocycle, NR3R4Base includes but is not limited to: (3R) -3- (dimethylamino) pyrrolidin-1-yl, (3S) -3- (dimethyl - Amino) pyrrolidin-1-yl, 3- (dimethylamino) azetidine -1- base, [2- (dimethylamino) ethyl] (methyl) amino, [2- (methylamino) ethyl] (methyl) amino, 5- methyl -2,5- diazaspiracyclic [3.4] octyl- 2- base, (3aR, 6aR) -5- methyl six Hydrogen pyrrolo- [3,4-b] pyrroles -1 (2H)-base, 4- methylpiperazine-1-yl, 4- [2- (dimethylamino) -2- oxoethyl] piperazine - 1- base, methyl [2- (4- methylpiperazine-1-yl) ethyl] amino, methyl [2- (morpholine -4- base) ethyl] amino, 4- [(2S) -2- Aminopropionyl] piperazine -1- base, morpholine -4- base.
2. compound as described in claim 1 or its pharmaceutically acceptable salt, solvate or prodrug, in which:
R2It is methoxyl group；And
NR3R4Base is selected from (3R) -3- (dimethylamino) pyrrolidin-1-yl, (3S) -3- (dimethyl-amino) pyrrolidin-1-yl, 3- (dimethylamino) azetidine -1- base, [2- (dimethylamino) ethyl] (methyl) amino, [2- (methylamino) ethyl] (methyl) Amino, 5- methyl -2,5- diazaspiracyclic [3.4] octyl- 2- base, (3aR, 6aR) -5- methyl hexahydropyrrolo simultaneously [3,4-b] pyrroles - 1 (2H)-base, 4- methylpiperazine-1-yl, 4- [2- (dimethylamino) -2- oxoethyl] piperazine -1- base, methyl [2- (4- methyl Piperazine -1- base) ethyl] amino, methyl [2- (morpholine -4- base) ethyl] amino, 4- [(2S) -2- aminopropionyl] piperazine -1- Base.
3. compound as claimed in claim 2 or its pharmaceutically acceptable salt, solvate or prodrug, in which:
NR3R4Base is selected from (3R) -3- (dimethylamino) pyrrolidin-1-yl, 3- (dimethylamino)-azetidine -1- base, [2- (dimethylamino) ethyl] (methyl) amino, 4- methylpiperazine-1-yl.
4. compound as claimed in claim 1 or its pharmaceutically acceptable salt, solvate or prodrug, listed by table 1 Compound.
5. a kind of medical composition, it includes compound according to any one of claims 1 to 4 or its pharmaceutically may be used Salt, solvate or the prodrug of receiving and one or more pharmaceutically acceptable adjuvants, diluent and/or carrier.
6. a kind of disease that treatment is mediated by the activity of at least one cell cycle protein dependent kinase (CDK) or symptom Method, the compound described in any one of Claims 1-4 including applying therapeutically effective amount to subject in need, or Its pharmaceutically acceptable salt, solvate or prodrug or pharmaceutical composition as claimed in claim 5.
7. method as claimed in claim 6, wherein at least one CDK is CDK4 and CDK6 or combinations thereof.
8. method as claimed in claim 6, wherein the disease or symptom are cancers.
9. method according to claim 8, wherein it (is especially non-small that the cancer, which is selected from colorectal cancer, breast cancer, lung cancer, Cell lung cancer, NSCLC), prostate cancer, spongioblastoma, lymphoma mantle cell (MCL), chronic Myelogenous from blood sick (CML), Acute myeloid leukaemia (AML) and its complication.
10. a kind of method for inhibiting cell Proliferation, including with a effective amount of according to any one of claim 1 to 4ization Close compositions-treated proliferative cell described in object or its solvate or prodrug or claim 5.
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CN115703760A (en) * 2021-08-11 2023-02-17 山东大学 2,4-disubstituted pyrimidines cyclin dependent kinase inhibitor and preparation method and application thereof
CN115703760B (en) * 2021-08-11 2024-05-31 山东大学 2, 4-Disubstituted pyrimidine cyclin dependent kinase enzyme inhibitor and preparation method and application thereof

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