CN108727377A - 3- cyano pyrazoles simultaneously [1,5-a] pyrimidine derivatives and its preparation method and application - Google Patents

3- cyano pyrazoles simultaneously [1,5-a] pyrimidine derivatives and its preparation method and application Download PDF

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CN108727377A
CN108727377A CN201710244804.XA CN201710244804A CN108727377A CN 108727377 A CN108727377 A CN 108727377A CN 201710244804 A CN201710244804 A CN 201710244804A CN 108727377 A CN108727377 A CN 108727377A
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alkyl
reaction
halogen
alkoxy
aryl
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杨胜勇
李琳丽
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Sichuan University
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Sichuan University
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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
    • C07D471/12—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 three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Abstract

The invention belongs to chemical medicines, and in particular to 3- cyano pyrazoles simultaneously [1,5-a] pyrimidine derivatives and its preparation method and application.The present invention provides a kind of 3- cyano pyrazoles simultaneously [1,5-a] pyrimidine derivatives, and structure is as shown in formula I.The present invention also provides the preparation methods and purposes of above-mentioned 3- cyano pyrazoles simultaneously [1,5-a] pyrimidine derivatives.

Description

3- cyano pyrazoles simultaneously [1,5-a] pyrimidine derivatives and its preparation method and application
Technical field
The invention belongs to chemical medicines, and in particular to simultaneously [1,5-a] pyrimidine derivatives and its preparation of 3- cyano pyrazoles Method and purposes.
Background technology
Gene transcription process in organism is adjusted in epigenetic, thus develops related basic physiology mistake with life growth Journey (such as cell differentiation, division, adjusting of proliferation etc.) is closely related.The study found that epigenetic modification regulation and control are lacked of proper care and are permitted More single factor test diseases, complicated syndrome (such as cerebral disease, diabetes etc.) or even the occurrence and development of cancer have substantial connection.
Epigenetic modification mechanism is different by substrate specificity, can be divided into following number of mechanisms：DNA modification, histone modification, The modification of RNA, chromatin modification, non-coding RNA and X chromosome inactivation etc..Wherein, histone modification includes mainly：First Base modification, acetylation modification, phosphorylation modification, ubiquitination, ubiquitin-likeization modification etc..And histone methylated modification In, it is most studied with histone lysine methylation.Histone lysine methylation is happened at different sites, including group egg Lysine lysine residue 26 (H1K26), H3K4, H3K9, H3K27, H3K36, H3K79, H4K20 on white H1 etc..Histone The modification that methylates can lead to activation or the silence of genetic transcription, it is however generally that, the activation of H3K4 to methylate with open gene Correlation, in contrast, H3K9 and H3K27's methylates, and leads to the silence of transcription.Histone lysine methylation level can To be regulated and controled jointly by histone methylated transferase (HMTs) and histone demethylase (KDMs).Histone demethylation Enzyme is divided into two classes according to mechanism of action difference：One kind is flavine dependence lysine demethylase, including LSD1 (KDM1A) and LSD2 (KDM1B)；Another kind of is the istone lysine demethylase containing jumonji catalytic domains (JmjC), Catalytic process depends on Fe (II) and α-ketoglutaric acid.
Recent studies indicate that istone lysine demethylase (KDMs) and many morbid states are closely related.Example Such as, istone lysine demethylase KDM4D is related with the generation of kinds of tumors, development, at the same can also by mediate by Inflammatory reaction caused by cell factor (such as TNF-α) stimulation, to adjust the growth of tumor microenvironment and immunocyte.In addition, Recent study is also shown that KDM4D is the common regulatory factor of androgen receptor, and the formation with sperm has close association.Group egg White lysine demethylase KDM5A and the development of neuron, the maintenance of gene and strengthening, tumor suppressor gene and Carcinoma cell differentiation base The inhibition of cause, the activation etc. of the proliferation of cell, natural killer cells have substantial connection.Mistake regulation and control and a variety of diseases of KDM5A The sick especially generation, development of tumour and drug resistance is closely related, such as lung cancer, gastric cancer, breast cancer, prostate cancer, cancer of pancreas, acute Myelogenous leukemia etc..
Have some KDMs inhibitor at present to be found, they can be mainly divided by the difference of molecular structure following several Class：(1) α-ketoglutaric acid analog；(2) pyridine-4-formic acid and its derivative；(3) hydroxamic acid inhibitor；(4) pyrido Pyrimdinone inhibitor.Although this few class inhibitor has KDMs pretty good inhibitory activity, lock into its specificity it is not high, answer It is affected with foreground.Therefore, high activity is developed, the histone demethylase inhibitor of high specific not only contributes to disclose Mechanism of action of the histone demethylase in tumour generation, while also to kinds cancer, (such as lung cancer, prostate cancer, knot are straight Intestinal cancer etc.), the treatment important in inhibiting of genital system diseases.
Invention content
The present invention provides a kind of 3- cyano pyrazoles simultaneously [1,5-a] pyrimidine derivatives, and structure is as shown in formula I：
Wherein, A C5~C10Aromatic ring or 5~10 yuan of heteroaromatics；The hetero atom of the heteroaromatic is N, O, S, hetero atom Number is 1~3；
R1For-H ,-OH, halogen ,-CN, C1~C8Alkyl, C1~C8Alkoxy or substituted or unsubstituted C5~C10Aryl； The substitution C5~C10The substituent group of aryl is-H, halogen or C1~C8Alkyl；
R2For-H ,-OH, halogen, C1~C8Alkyl, C1~C8Alkoxy or substituted or unsubstituted C5~C10Aryl；It is described Replace C5~C10The substituent group of aryl is-H, halogen or C1~C8Alkyl；
R3For-H, halogen ,-CN ,-NO2、-CF3、-NH2、-SO2Me、C1~C8Alkyl, C1~C8Alkoxy or
R4For-H, C1~C8Alkyl, C3~C8Naphthenic base,
X is halogen；N=1~3.
As the preferred embodiment of the present invention, above-mentioned 3- cyano pyrazoles simultaneously [1,5-a] pyrimidine derivatives,
Wherein, A C5~C8Aromatic ring or 5~8 yuan of heteroaromatics；The hetero atom of the heteroaromatic is N, O, S, hetero atom number It is 1~3；
R1For-H ,-OH, halogen ,-CN, C1~C6Alkyl, C1~C6Alkoxy or substituted or unsubstituted C5~C8Aryl； The substituent group of substitution C5~C8 aryl is-H, halogen or C1~C6Alkyl；
R2For-H ,-OH, halogen, C1~C6Alkyl, C1~C6Alkoxy or substituted or unsubstituted C5~C8Aryl；It is described Replace C5~C8The substituent group of aryl is-H, halogen or C1~C6Alkyl；
R3For-H, halogen ,-CN ,-NO2、-CF3、-NH2、-SO2Me、C1~C6Alkyl, C1~C6Alkoxy or
R4For-H, C1~C6Alkyl or
X is halogen；N=1~3.
Preferably, above-mentioned 3- cyano pyrazoles simultaneously [1,5-a] pyrimidine derivatives,
Wherein, A C5~C6Aromatic ring or 5~6 yuan of heteroaromatics；The hetero atom of the heteroaromatic is N, O, S, hetero atom number It is 1~3；
R1For-H ,-OH, halogen ,-CN, C1~C6Alkyl, C1~C4Alkoxy or substituted or unsubstituted C5~C6Aryl； The substitution C5~C6The substituent group of aryl is-H, halogen or C1~C4Alkyl；
R2For-H ,-OH, halogen, C1~C4Alkyl, C1~C6Alkoxy or substituted or unsubstituted C5~C8Aryl；It is described Replace C5~C8The substituent group of aryl is-H, halogen or C1~C4Alkyl；
R3For-H, halogen ,-CN ,-NO2、-CF3、-NH2、-SO2Me、C1~C4Alkyl, C1~C4Alkoxy or
R4For-H, C1~C4Alkyl or
X is halogen；N=1~3.
Further, above-mentioned 3- cyano pyrazoles simultaneously [1,5-a] pyrimidine derivatives,
Wherein, A C5~C6Aromatic ring or 5~6 yuan of heteroaromatics；The hetero atom of the heteroaromatic is N, O, S, hetero atom number It is 1~2；
R1For-H ,-OH, halogen ,-CN, C1~C6Alkyl, C1~C4Alkoxy or substituted or unsubstituted phenyl；It is described to take Substituent group for phenyl is-H, halogen or C1~C4Alkyl；
R2For-H ,-OH, halogen, C1~C4Alkyl, C1~C6Alkoxy or substituted or unsubstituted phenyl；The substituted benzene The substituent group of base is-H, halogen or C1~C4Alkyl；
R3For-H, halogen ,-CN ,-NO2、-CF3、-NH2、-SO2Me、C1~C4Alkyl, C1~C4Alkoxy or
R4For-H, C1~C4Alkyl or
X is halogen；N=1~3.
Further, above-mentioned 3- cyano pyrazoles simultaneously [1,5-a] pyrimidine derivatives,
Wherein, A is phenyl ring or 6 yuan of heteroaromatics；The hetero atom of the heteroaromatic is N, and hetero atom number is 1~2；
R1For-H ,-OH ,-F ,-Cl ,-Br ,-CN, C1~C6Alkyl, C1~C4Alkoxy or substituted or unsubstituted phenyl； The substituent group of the substituted-phenyl is-H, halogen or C1~C4Alkyl；
R2For-H ,-OH ,-F ,-Cl ,-Br or C1~C4Alkyl；
R3For-H ,-F ,-Cl ,-Br ,-CN ,-NO2、-CF3、-NH2、-SO2Me、C1~C4Alkyl, C1~C4Alkoxy or
R4For-H, C1~C4Alkyl or
X is halogen；N=1~3.
Most preferably, above-mentioned 3- cyano pyrazoles simultaneously [1,5-a] pyrimidine derivatives,
Wherein, A is phenyl ring or 6 yuan of heteroaromatics；The hetero atom of the heteroaromatic is N, and hetero atom number is 1~2；
R1For-H ,-OH ,-F ,-Cl ,-Br ,-CN, methyl, ethyl, isopropyl, butyl, propyl or phenyl；
R2For-H ,-OH ,-F ,-Cl ,-Br, methyl, ethyl, propyl, isopropyl or butyl；
R3For-H ,-F ,-Cl ,-Br ,-CN ,-NO2、-CF3、-NH2、-SO2Me, methyl, ethyl, propyl, isopropyl, butyl Or
R4For-H, methyl, ethyl, propyl, butyl or
X is-F ,-Cl ,-Br；N=1.
Simultaneously [1,5-a] pyrimidine derivatives, structural formula are as follows for above-mentioned 3- cyano pyrazoles：
The present invention also provides the preparation methods of above-mentioned 3- cyano pyrazoles simultaneously [1,5-a] pyrimidine derivatives：
Work as R2For-OH or halogen when, synthetic route is：
Work as R2For-H, C1~C8Alkyl, C1~C8Alkoxy or substitution are substituted C5~C10When aryl, synthetic route For：
The preparation method of above-mentioned 3- cyano pyrazoles simultaneously [1,5-a] pyrimidine derivatives, includes the following steps：
A, raw material 1 carries out chlorination preparation under conditions of n,N-Dimethylformamide (DMF) is catalyzed with chlorinating agent Obtain intermediate 1；The chlorinating agent is in thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus pentachloride, trichloro-triazine etc. Any one；The molar ratio of the raw material 1 and chlorinating agent, DMF is 1 ﹕, 1.2 ﹕ 0.01；The solvent of the reaction is dichloromethane Any one in alkane (DCM), benzene, toluene etc.；The temperature of the reaction is 25~80 DEG C；The time of the reaction be 0.5~ 10h；
B, raw material 2 carries out nucleophilic substitution with hydrazine hydrate and intermediate 2 is prepared in addition reaction；The raw material 1 with The molar ratio of hydrazine hydrate is 1 ﹕ 3~5；The solvent of the reaction is any one in methanol, ethyl alcohol, isopropanol, n-butanol, water etc. Kind；The temperature of the reaction is 25~80 DEG C；The time of the reaction is 0.5~12h；
C, intermediate 3 is prepared in intermediate 1 and intermediate 2 in the presence of a base；The alkali is triethylamine (TEA), N, N Diisopropyl aniline (DIPEA), triethylene diamine (DABCO), 11 carbon -7- alkene (DBU) of 1,8- diazabicylos, potassium carbonate, Any one in sodium carbonate；The molar ratio of the intermediate 1 and intermediate 2, alkali is 1 ﹕, 0.9~1 ﹕ 2；The solvent of the reaction For any one in dichloromethane, tetrahydrofuran (THF), 1,4- dioxane, DMF etc.；The temperature of the reaction is 0~25 ℃；The time of the reaction is 0.5~3h；
D, compound 4 is prepared in itself ring closure reaction to intermediate 3 in the presence of a base；The alkali be TEA, DIPEA, Any one in DABCO, DBU, potassium carbonate, sodium carbonate etc.；The molar ratio of the intermediate 3 and alkali is 1 ﹕ 1.5；The reaction Solvent be 1,2- dichloroethanes (DCE), dimethyl sulfoxide (DMSO) (DMSO), tetrahydrofuran, acetonitrile, DMF, DMAC N,N' dimethyl acetamide Any one in；The temperature of the reaction is 80~140 DEG C；The time of the reaction is 4~12h；
E, the compound 4 containing nitro carries out reduction reaction and compound 5 is prepared in the presence of a reducing agent；It is described to go back Former agent is any one in iron powder, stannous chloride, zinc powder, sodium hydrosulfite, hydrogen, ammonium formate etc.；The solvent of the reaction is first Any one in alcohol, ethyl alcohol, water, acetic acid；The temperature of the reaction is 25~100 DEG C；The time of the reaction be 0.5~ 3h；
F, compound 6 is prepared in compound 5 with acyl chloride reaction in the presence of base；The acyl chlorides is formyl chloride, second Any one in acyl chlorides, propionyl chloride, butyl chloride, chloracetyl chloride, 2- chlorpromazine chlorides, acryloyl chloride, propine acyl chlorides etc.；The alkali For any one in TEA, DIPEA, DABCO, DBU, potassium carbonate, sodium carbonate etc.；Mole of the compound 5 and acyl chlorides and alkali Than for 1 ﹕, 1.1~1.5 ﹕ 2；The solvent is any one in dichloromethane, tetrahydrofuran, DMF etc.；The temperature of the reaction It is 0~25 DEG C；The time of the reaction is 0.5~3h.
G, compound 4 carries out halogenating reaction with halogenating agent and compound 7 is prepared under conditions of DMF is catalyzed；It is described Halogenating agent be any one in thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, phosphorus tribromide etc.；The compound 4 and halogen Molar ratio for reagent is 1 ﹕ 3~5；The solvent of the reaction is any one in dichloromethane, toluene, benzene etc.；It is described anti- The temperature answered is 25~80 DEG C；The time of the reaction is 2~12h.
H, raw material 3 and intermediate 2 ring closure reaction occur under metal catalytic compound 7 are prepared；The metal is Any one in stannous chloride, cuprous bromide, cuprous iodide, copper acetate etc.；The ligand of the reaction be L-PROLINE, N, Appointing in N'- dimethyl-ethylenediamines (DMEDA), 1,10- phenanthrolines, DBU, ethylenediamine (en), tetramethylethylenediamine (TMEDA) etc. Meaning is a kind of；The alkali of the reaction is sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, the tert-butyl alcohol Any one in potassium, TEA etc.；The raw material 3, intermediate 2, metal, ligand and alkali molar ratio be 1 ﹕, 1.2 ﹕, 0.2 ﹕, 0.2 ﹕ 2；The solvent of the reaction is any one in dichloromethane, DMF, DMSO, 1,4- dioxane etc.；The temperature of the reaction It is 70~110 DEG C；The time of the reaction is 3~16h.
The present invention also provides above-mentioned 3- cyano pyrazoles simultaneously [1,5-a] pyrimidine derivatives pharmaceutically acceptable salts.
Term used herein " pharmaceutically acceptable " refer in rational medical judgment scope, can be adapted to for It contacts with the tissue of the mankind and other mammals, without improper toxicity, stimulation, allergic reaction etc., is administered to receptor When the prodrug of the compound of the present invention or compound can be directly or indirectly provided.
The present invention also provides the above-mentioned 3- cyano pyrazoles simultaneously pharmaceutically acceptable hydrates of [1,5-a] pyrimidine derivatives. Term " hydrate " expression further passes through the change of Non-covalent molecular intermolecular forces combination stoichiometry or non-stoichiometric water Close object.
The present invention also provides the above-mentioned 3- cyano pyrazoles simultaneously pharmaceutically acceptable polymorphics of [1,5-a] pyrimidine derivatives Object.Term " polymorph " indicates compound or the solid crystallization way of its compound, can pass through physical method, such as X. Ray powder diffraction pattern or infrared spectrum are characterized.
The present invention also provides the above-mentioned 3- cyano pyrazoles simultaneously pharmaceutically acceptable pharmaceutical compositions of [1,5-a] pyrimidine derivatives Object, this pharmaceutical composition are simultaneously [1,5-a] pyrimidine derivatives and its addition of salt or hydrate of the 3- cyano pyrazoles shown in Formulas I Pharmaceutically the complementary ingredient of acceptable is prepared.
Aforementioned pharmaceutical compositions can be liquid form or solid form.Wherein, the liquid form can be water-soluble Liquid form.The solid form can be powder, particle, tablet or freeze-dried powder form.The pharmaceutical composition also contains injection With water, saline solution, glucose solution, injection/infusion brine, injection/infusion glucose, Ge Linshi solution or contain The Ge Linshi solution of lactate.
The present invention also provides above-mentioned 3- cyano pyrazoles simultaneously [1,5-a] pyrimidine derivatives, salt, hydrate or pharmaceutical compositions It is preparing using histone demethylase as the purposes in the drug of target spot.
The present invention provides a kind of novel 3- cyano pyrazoles simultaneously [1,5-a] pyrimidine derivatives, and provide 3- of the present invention Easy, efficient, the low-cost preparation method of cyano pyrazole simultaneously [1,5-a] pyrimidine derivatives.The 3- cyano pyrazoles of the present invention And [1,5-a] pyrimidine derivatives have good inhibitory activity to a variety of histone demethylases, are the group egg in this field The preparation of white demethylation enzyme inhibitor, the preparation of histone demethylase Small-molecule probe provide new effective selection, With good application prospect.
Specific implementation mode
Embodiment 1：The preparation of the chloro- 5- nitros nicotinoyl chlorines (intermediate 1a) of 2-
The chloro- 5- nitronicotinic acids (446mg, 2mmol) of 2-, 3~4 drop DMF and 10mL chlorinations are added in 100mL round-bottomed flasks Sulfoxide is placed on 80 DEG C of reaction 2h.After completion of the reaction, it is cooled to room temperature, vacuum distillation removes excessive thionyl chloride, obtains grey orange Color solid, solid are not further purified and are directly used in subsequent reactions.
According to the similar preparation conditions of intermediate 1a, using corresponding carboxylic acid as raw material, made with thionyl chloride or oxalyl chloride For chlorinating agent, using thionyl chloride or DCM as solvent, intermediate 1b- can be prepared in room temperature, low temperature or heating reaction 1t, intermediate structure are as follows：
The structure of 1 intermediate 1b-t of table
Embodiment 2：The preparation of 3- amino -4- cyano pyrazoles (intermediate 2a)
2- (methoxymethylene) malononitrile (1.08g, 10mmol) is added in 250mL round-bottomed flasks, with 100mL ethyl alcohol After being completely dissolved, hydrazine hydrate (485 μ L, 30mmol) is slowly added dropwise, 80 DEG C of stirring 3h are placed reaction liquid into after being added dropwise. After completion of the reaction, it is cooled to room temperature, vacuum distillation removes solvent, obtains solid crude product, and residue 50mL DCM are dissolved, mixed Sample is purified using column chromatography, and eluent selects petroleum ether (PE)：Ethyl acetate (EA)=3:1, obtain white solid 872mg, yield 80.7%.
1H NMR(400MHz,DMSO-d6)δ11.90(s,1H),7.82(s,1H),6.04(s,2H).ESI-ms(m/z): 108.1[M+H]+
Embodiment 3：The preparation of the chloro- N- of 2- (4- cyano -1H- pyrazole-3-yls) -5- nitro niacinamide (intermediate 3a)
By in chloro- 5- nitros nicotinoyl chlorine (221mg, 1mmol) the dissolving 25mL tetrahydrofurans of 2-, it is slowly dropped at 0 DEG C In the tetrahydrofuran solution of 3- amino -4- cyano pyrazoles (97mg, 0.9mmol) and TEA (280 μ L, 2mmol).Wait for that acyl chlorides is added dropwise After, it is warming up to 25 DEG C of reactions.Reaction finishes after 3 hours, and vacuum distillation removes solvent, and 50mL distilled water is added in residue, It is extracted twice with 100mL ethyl acetate, merges organic phase, dried with anhydrous magnesium sulfate, filtered, vacuum distillation removing solvent obtains yellow Color solid 214mg, yield 73%.
1H NMR(400MHz,DMSO-d6) δ 9.39 (d, J=2.7Hz, 1H), 9.19 (s, 1H), 9.15 (d, J=2.7Hz, 1H),6.52(s,2H).ESI-ms(m/z):293.0[M+H]+
According to the similar preparation methods of intermediate 3a, intermediate 3b-3i can be prepared.Characterize data is as follows：
The structure of 2 intermediate 3b-i of table,1H NMR and ESI-ms
Embodiment 4：5- hydroxyl -7- nitropyrazoles simultaneously [1,5-a] pyrido [3,2-e] pyrimidine -3- formonitrile HCNs (compound 4a) Preparation
By the chloro- N- of 2- (4- cyano -1H- pyrazole-3-yls) -5- nitros niacinamide (100mg, 0.34mmol), potassium carbonate (71mg, 0.51mmol) is added in 50mL two-mouth bottles, after 10mL anhydrous DMFs are added, vacuumizes, and three times with argon gas displacement, is placed in 90 DEG C are reacted, and are reacted and are finished after 12h.It is cooled to room temperature, filters, DMF washs filter cake, and solvent is distilled off in filtrate decompression, remains Object is dissolved with methanol, mixes sample, is purified using column chromatography, and eluent selects PE:EA=1:5, obtain yellow solid 31mg, yield 35%.
1H NMR(400MHz,DMSO-d6) δ 9.40 (d, J=3.0Hz, 1H), 9.07 (d, J=3.0Hz, 1H), 8.35 (s, 1H).ESI-ms(m/z):257.0[M+H]+
According to the similar preparation methods of compound 4a, compound 4b-4i can be prepared.Characterize data is as follows：
The structure of 3 intermediate 4b-i of table,1H NMR and ESI-ms
Embodiment 5：The preparation of 5- hydroxypyrazoles simultaneously [1,5-a] pyrido [3,2-e] pyrimidine -3- formonitrile HCNs (compound 4j)
2- chloronicotinoyl chlorides (176mg, 1mmol) are dissolved in 5mL anhydrous DMFs, are slowly added dropwise in 0 DEG C to 3- amino -4- cyano In the anhydrous DMF solution of pyrazoles (97mg, 0.9mmol) and TEA (280 μ L, 2mmol).After being added dropwise, it is warming up to 25 DEG C instead It answers, reaction process is detected using thin-layer chromatography (TLC).After after 3- amino -4- cyano pyrazoles, the reaction was complete, reaction system is taken out true Sky three times with argon gas displacement is continuously heating to 140 DEG C of reactions overnight, after completion of the reaction, is cooled to room temperature, filter, washed with DMF Filter cake is washed, solvent is distilled off in filtrate decompression, and residue is dissolved with methanol, mixes sample, is purified using column chromatography, and eluent is selected PE:EA=1:5, obtain faint yellow solid 113mg, yield 54%.
1H NMR(400MHz,DMSO-d6) δ 8.67 (dd, J=4.7,1.9Hz, 1H), 8.40 (dd, J=7.7,1.9Hz, 1H), 8.01 (s, 1H), 7.45 (dd, J=7.7,4.7Hz, 1H) .ESI-ms (m/z):212.1[M+H]+.
According to the similar preparation methods of compound 4j, compound 4k-s can be prepared.Characterize data is as follows：
The structure of 4 intermediate 4k-s of table,1H NMR and ESI-ms
Embodiment 6：The preparation of 9- amino -5- hydroxypyrazoles simultaneously [1,5-a] quinazoline -3- formonitrile HCNs (compound 5a)
Be added in 50mL bottle with two necks 5- hydroxyl -9- nitropyrazoles simultaneously [1,5-a] quinazoline -3- formonitrile HCNs (100mg, 0.4mmol), after being completely dissolved with 10mL methanol and 10mL water, be added 10%Pd/C (10mg, wet basis, 10%W W), will react System vacuumizes, and after hydrogen displacement three times, is heated to 60 DEG C and reacts 2h in a hydrogen atmosphere.After completion of the reaction, it is cooled to room Temperature is filtered with diatomite, and solvent is distilled off in filtrate decompression, and residue is added the washing of 5mL methanol, filters to obtain pale solid 63mg, yield 72%.
1H NMR(400MHz,DMSO-d6) δ 8.09 (s, 1H), 7.33 (dd, J=7.9,1.7Hz, 1H), 6.83-6.78 (m, 1H), 6.76 (dd, J=7.3,1.7Hz, 1H), 5.30 (s, 2H) .ESI-ms (m/z):226.1[M+H]+
Embodiment 7：The preparation of 8- amino -5- hydroxypyrazoles simultaneously [1,5-a] quinazoline -3- formonitrile HCNs (compound 5b)
Using preparation method identical with compound 5a, compound 5b can be prepared.
1H NMR(400MHz,DMSO-d6) δ 7.84 (s, 1H), 7.68 (d, J=8.5Hz, 1H), 6.97 (d, J=2.1Hz, 1H), 6.53 (dd, J=8.6,2.2Hz, 1H), 5.81 (s, 2H) .ESI-ms (m/z):226.1[M+H]+
Embodiment 8：The chloro- N- of 2- (3- cyano -5- hydroxypyrazoles simultaneously [1,5-a] quinazoline -8- bases) acetamide (compound 6) Preparation
Chloracetyl chloride (96 μ L, 1.2mmol) is dissolved in 5mL anhydrous DMFs, is slowly added dropwise in 0 DEG C to 8- amino -5- hydroxyl pyrroles Azoles simultaneously in the anhydrous DMF solution of [1,5-a] quinazoline -3- formonitrile HCNs (225mg, 1mmol) and TEA (278 μ L, 2mmol), drips Bi Hou is warming up to 25 DEG C of reactions.Reaction finishes after 3 hours, and vacuum distillation removes solvent, and residue is added methanol, mixes sample, uses Column chromatography purifies, and eluent selects dichloromethane：Methanol=10:1, obtain white solid 201mg, yield 67%.
1H NMR(400MHz,DMSO-d6) δ 13.19 (s, 1H), 11.14 (s, 1H), 8.59 (d, J=2.0Hz, 1H), 8.35 (s, 1H), 8.13 (d, J=8.7Hz, 1H), 7.66 (dd, J=8.7,2.1Hz, 1H), 4.39 (s, 2H) .ESI-ms (m/ z):302.0[M+H]+
Embodiment 9：The preparation of 3- amino -5- methyl-1 H- pyrazoles -4- formonitrile HCNs (intermediate 2b)
The first step：Prepare 2- (1- methoxyethlyens) malononitrile：
The addition malononitrile (3.3g, 0.05mol) in the round-bottomed flask of 100mL, trimethyl orthoacetate (27.6mL, 0.15mol), acetic anhydride 1.5mL.110 DEG C of reactions are warming up to, reacts and finishes after 12h, be cooled to room temperature.Reaction solution is poured into It in 250mL water, is extracted 3 times with EA, merges organic phase, anhydrous sodium sulfate drying, concentration is mixed sample, purified, washed using column chromatography De- liquid selects PE:EA=8:1, obtain brown oil 5.1g, yield 84%.ESI-ms(m/z):123.1[M+H]+
Second step：Prepare 3- amino -5- methyl-1 H- pyrazoles -4- formonitrile HCNs
Using the synthetic method described in embodiment 2, intermediate 2b can be prepared.
1H NMR(400MHz,DMSO-d6)δ11.81(s,1H),5.92(s,2H),2.10(s,3H).ESI-ms(m/z): 123.1[M+H]+
According to the similar preparation methods of intermediate 2b, 2- (1- methoxyl groups propylidene) malononitrile etc. is raw material, with hydrazine hydrate Intermediate 2c-2g can be prepared in reaction.Characterize data is as follows：
The structure of 5 intermediate 2c-g of table,1H NMR and ESI-ms
Embodiment 10：The preparation of intermediate 3t-ac
Using synthetic method described in embodiment 3, intermediate 3t-ac can be prepared.Characterize data is as follows：
The structure of 6 intermediate 3t-w of table,1H NMR and ESI-ms
Embodiment 11：5- hydroxy-2-methyls pyrazolo [1,5-a] pyrido [3,2-e] pyrimidine -3- formonitrile HCNs (compound 4) Preparation
Using the synthetic method described in embodiment 4, compound 4t-ac can be prepared.Characterize data is as follows：
The structure of 7 intermediate 4t-w of table,1H NMR and ESI-ms
Embodiment 12：The preparation of 5- chlorine pyrazolo [1,5-a] pyrido [3,2-e] pyrimidine -3- formonitrile HCNs (compound 7)
5- hydroxypyrazoles simultaneously [1,5-a] pyrido [3,2-e] pyrimidine -3- formonitrile HCNs are added in 50mL round-bottomed flasks (100mg, 0.45mmol), 3~4 drop DMF and 10mL phosphorus oxychloride are placed on 80 DEG C of reaction 12h.After completion of the reaction, it is cooled to room Temperature, vacuum distillation remove excessive phosphorus oxychloride.20mL ice water is added into residue, pH is adjusted with saturated sodium bicarbonate solution It to 8~9, is extracted with ethyl acetate three times, anhydrous sodium sulfate drying, vacuum distillation removes solvent, obtains yellow solid 51mg, yield 51%.
1H NMR(400MHz,DMSO-d6) δ 9.20 (dd, J=4.6,1.7Hz, 1H), 8.86 (s, 1H), 8.83 (dd, J= 8.2,1.7Hz, 1H), 7.95 (dd, J=8.2,4.6Hz, 1H) .ESI-ms (m/z):230.0[M+H]+
Embodiment 13：The preparation of pyrazolo [1,5-a] pyrido [3,2-e] pyrimidine -3- formonitrile HCNs (compound 8a)
By 2- chloro-3-pyridyls formaldehyde (100mg, 0.71mmol), 3- amino -4- cyano pyrazoles (92mg, 0.85mmol), iodine Change cuprous (27mg, 0.14mmol), ethylenediamine (10 μM, 0.14mmol) and potassium carbonate (195mg, 1.4mmol) and 50mL two is added It in mouth bottle, after 10mL anhydrous DMFs are added, vacuumizes, three times with argon gas displacement, is placed in 110 DEG C of reaction 12h.After completion of the reaction, cold But to room temperature, the dilution of 50mL ethyl acetate is added, insoluble matter is filtered to remove using diatomite, is washed with water, saturated nacl aqueous solution It washs, organic phase is dried with anhydrous sodium sulfate, and filtering is mixed sample, purified using column chromatography, and eluent selects PE:EA=2：1, it obtains Faint yellow solid 67mg, yield 49%.
1H NMR(400MHz,DMSO-d6) δ 9.47 (s, 1H), 9.15 (dd, J=4.6,1.8Hz, 1H), 8.87-8.82 (m, 2H), 7.91 (dd, J=7.9,4.6Hz, 1H) .ESI-ms (m/z):196.1[M+H]+
Using the synthetic method similar with compound 8a, compound 8b-f can be prepared.Characterize data is as follows：
The structure of 8 intermediate 8b-f of table,1H NMR and ESI-ms
Embodiment 14：External inhibitory activity of the compound to histone demethylase
The purpose of this experiment is detection the compounds of this invention in vitro to the inhibitory activity of histone demethylase, use The method of AlphaLisa Screen (also referred to as AlphaLISA protein-protein competition screen) Test its external inhibitory activity to histone demethylases such as KDM2B, KDM3B, KDM4D, KDM5A.Test-compound The inhibitory activity IC of histone demethylase50(half-inhibition concentration) or test-compound are under 10 μM of concentration to histone Demethylase active inhibiting rate indicates.IC50Value can by test-compound under a series of various concentrations to histone The active inhibiting rate of demethylase is calculated and is obtained.
Experiment material：α-ketoglutaric acid (2-OG), Fe (II), sodium ascorbate, daminozide (Daminozide), N- oxalyl The histone demethylations such as glycine (N-OG), 2,4- pyridinedicarboxylic acids (2,4-PDCA), KDM2B, KDM3B, KDM4D, KDM5A Enzyme, the above material are provided by Shanghai Ruizhi Chemical Study Co., Ltd..Test-compound is by biological therapy country of Sichuan University Key lab provides.
Experimental principle：It measures in histone demethylase active process, by the ends C- of histone H 3 or the ends N- with life Object element (Biotin) label, is connected with Streptavidin (Streptavidin) with donor bead, acceptor bead (Acceptor Beads) surface is wrapped up with albumin A, and albumin A (Protein A) is connected to the antibody that H3K methylates.If first occurs for histone Base will be combined with specific antibody albumin A, between acceptor bead and donor bead in Distance Shortened to 200nm.When by When the laser excitation of 680nm, the free oxygen of donor bead release is diffused into the concurrently biochemical cold light reaction of neighbouring acceptor bead, production The transmitting light of raw 615nm, methylation can be measured by measuring transmitting light yield, to indirect reaction demethylase Activity.
Experimental procedure：To include that the HEPES buffer solution of histone demethylase and test-compound is placed at room temperature It is incubated 15 minutes, substrate polypeptide, sodium ascorbate, 2-OG and Fe (II) is then added to start to react.After being incubated 1 hour, add Enter receptor solution and donor solution, is placed in and co-cultures 1 hour at room temperature.It is detected and is read using plate reader.
Inhibiting rate (%)=(control group-drug processing group)/(control group-blank control) * 100%
Finally half-inhibition concentration (IC is obtained with the fitting of Graphpad Prism softwares50)。
By the above experimental method, test compound in the present invention be directed to respectively KDM2B, KDM3B, KDM4D, The inhibitory activity of the histone demethylases such as KDM5A.
Table 9 gives part test-compound under 10 μM of concentration respectively to KDM2B, KDM3B, KDM4D, KDM5A etc. The active inhibiting rate of histone demethylase (%).
Table 10 gives IC of the test-compound to the inhibitory activity of KDM2B, KDM3B, KDM4D, KDM5A50Value.
9 test-compound of table is under 10 μM of concentration to the active inhibiting rate of a variety of histone demethylases
Inhibitory activity of 10 test-compound of table to a variety of histone demethylases
Table 9 the result shows that compound 4b, 4f, 4o, 4p, 4t, 4w, 5a and 8a to histone demethylase KDM4D, KDM5A has good inhibitory activity.
Table 10 the result shows that compound 4f, 4t, 4w and 8a show to histone demethylase KDM4D have it is good Selectivity, compound 4b, 4o, 4p and 5a, which are shown, has good selectivity histone demethylase KDM5A.

Claims (9)

1.3- cyano pyrazoles simultaneously [1,5-a] pyrimidine derivatives, structure is as shown in formula I：
Wherein, A C5~C10Aromatic ring or 5~10 yuan of heteroaromatics；The hetero atom of the heteroaromatic is N, O, S, and hetero atom number is 1 ~3；
R1For-H ,-OH, halogen ,-CN, C1~C8Alkyl, C1~C8Alkoxy or substituted or unsubstituted C5~C10Aryl；It is described Replace C5~C10The substituent group of aryl is-H, halogen or C1~C8Alkyl；
R2For-H ,-OH, halogen, C1~C8Alkyl, C1~C8Alkoxy or substituted or unsubstituted C5~C10Aryl；The substitution C5~C10The substituent group of aryl is-H, halogen or C1~C8Alkyl；
R3For-H, halogen ,-CN ,-NO2、-CF3、-NH2、-SO2Me、C1~C8Alkyl, C1~C8Alkoxy or
R4For-H, C1~C8Alkyl, C3~C8Naphthenic base,
X is halogen；N=1~3.
2. 3- cyano pyrazoles according to claim 1 simultaneously [1,5-a] pyrimidine derivatives, it is characterised in that：A is C5~C8Virtue Ring or 5~8 yuan of heteroaromatics；The hetero atom of the heteroaromatic is N, O, S, and hetero atom number is 1~3；
R1For-H ,-OH, halogen ,-CN, C1~C6Alkyl, C1~C6Alkoxy or substituted or unsubstituted C5~C8Aryl；It is described to take For C5~C8The substituent group of aryl is-H, halogen or C1~C6Alkyl；
R2For-H ,-OH, halogen, C1~C6Alkyl, C1~C6Alkoxy or substituted or unsubstituted C5~C8Aryl；The substitution C5 ~C8The substituent group of aryl is-H, halogen or C1~C6Alkyl；
R3For-H, halogen ,-CN ,-NO2、-CF3、-NH2、-SO2Me、C1~C6Alkyl, C1~C6Alkoxy or
R4For-H, C1~C6Alkyl or
X is halogen；N=1~3；
Preferably, A C5~C6Aromatic ring or 5~6 yuan of heteroaromatics；The hetero atom of the heteroaromatic is N, O, S, and hetero atom number is 1 ~3；
R1For-H ,-OH, halogen ,-CN, C1~C6Alkyl, C1~C4Alkoxy or substituted or unsubstituted C5~C6Aryl；It is described to take For C5~C6The substituent group of aryl is-H, halogen or C1~C4Alkyl；
R2For-H ,-OH, halogen, C1~C4Alkyl, C1~C6Alkoxy or substituted or unsubstituted C5~C8Aryl；The substitution C5 ~C8The substituent group of aryl is-H, halogen or C1~C4Alkyl；
R3For-H, halogen ,-CN ,-NO2、-CF3、-NH2、-SO2Me、C1~C4Alkyl, C1~C4Alkoxy or
R4For-H, C1~C4Alkyl or
X is halogen；N=1~3；
Further, A C5~C6Aromatic ring or 5~6 yuan of heteroaromatics；The hetero atom of the heteroaromatic is N, O, S, hetero atom number It is 1~2；
R1For-H ,-OH, halogen ,-CN, C1~C6Alkyl, C1~C4Alkoxy or substituted or unsubstituted phenyl；The substituted benzene The substituent group of base is-H, halogen or C1~C4Alkyl；
R2For-H ,-OH, halogen, C1~C4Alkyl, C1~C6Alkoxy or substituted or unsubstituted phenyl；The substituted-phenyl Substituent group is-H, halogen or C1~C4Alkyl；
R3For-H, halogen ,-CN ,-NO2、-CF3、-NH2、-SO2Me、C1~C4Alkyl, C1~C4Alkoxy or
R4For-H, C1~C4Alkyl or
X is halogen；N=1~3；
Further, A is phenyl ring or 6 yuan of heteroaromatics；The hetero atom of the heteroaromatic is N, and hetero atom number is 1~2；
R1For-H ,-OH ,-F ,-Cl ,-Br ,-CN, C1~C6Alkyl, C1~C4Alkoxy or substituted or unsubstituted phenyl；It is described The substituent group of substituted-phenyl is-H, halogen or C1~C4Alkyl；
R2For-H ,-OH ,-F ,-Cl ,-Br or C1~C4Alkyl；
R3For-H ,-F ,-Cl ,-Br ,-CN ,-NO2、-CF3、-NH2、-SO2Me、C1~C4Alkyl, C1~C4Alkoxy or
R4For-H, C1~C4Alkyl or
X is halogen；N=1~3；
Most preferably, A is phenyl ring or 6 yuan of heteroaromatics；The hetero atom of the heteroaromatic is N, and hetero atom number is 1~2；
R1For-H ,-OH ,-F ,-Cl ,-Br ,-CN, methyl, ethyl, isopropyl, butyl, propyl or phenyl；
R2For-H ,-OH ,-F ,-Cl ,-Br, methyl, ethyl, propyl, isopropyl or butyl；
R3For-H ,-F ,-Cl ,-Br ,-CN ,-NO2、-CF3、-NH2、-SO2Me, methyl, ethyl, propyl, isopropyl, butyl or
R4For-H, methyl, ethyl, propyl, butyl or
X is-F ,-Cl or-Br；N=1.
3. 3- cyano pyrazoles according to claim 1 or 2 simultaneously [1,5-a] pyrimidine derivatives, it is characterised in that：Structural formula is such as Under：
4. the preparation method of any one of claims 1 to 3 3- cyano pyrazoles simultaneously [1,5-a] pyrimidine derivatives, feature exist In：
Work as R2For-OH or halogen when, synthetic route is：
Work as R2For-H, C1~C8Alkyl, C1~C8Alkoxy or substitution are substituted C5~C10When aryl, synthetic route is：
A, raw material 1 carries out chlorination with chlorinating agent and centre is prepared under conditions of n,N-Dimethylformamide is catalyzed Body 1；The chlorinating agent is any one in thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus pentachloride, trichloro-triazine etc. Kind；The molar ratio of the raw material 1 and chlorinating agent, DMF is 1 ﹕, 1.2 ﹕ 0.01；The solvent of the reaction is dichloromethane, benzene, first Any one in benzene etc.；The temperature of the reaction is 25~80 DEG C；The time of the reaction is 0.5~10h；
B, raw material 2 carries out nucleophilic substitution with hydrazine hydrate and intermediate 2 is prepared in addition reaction；The raw material 1 and hydration The molar ratio of hydrazine is 1 ﹕ 3~5；The solvent of the reaction is any one in methanol, ethyl alcohol, isopropanol, n-butanol, water etc.； The temperature of the reaction is 25~80 DEG C；The time of the reaction is 0.5~12h；
C, intermediate 3 is prepared in intermediate 1 and intermediate 2 in the presence of a base；The alkali is triethylamine, N, N diisopropyls Any one in aniline, triethylene diamine, 11 carbon -7- alkene of 1,8- diazabicylos, potassium carbonate, sodium carbonate；The centre The molar ratio of body 1 and intermediate 2, alkali is 1 ﹕, 0.9~1 ﹕ 2；The solvent of the reaction is dichloromethane, tetrahydrofuran, 1,4- bis- Any one in six ring of oxygen, DMF etc.；The temperature of the reaction is 0~25 DEG C；The time of the reaction is 0.5~3h；
D, compound 4 is prepared in itself ring closure reaction to intermediate 3 in the presence of a base；The alkali be TEA, DIPEA, DABCO, Any one in DBU, potassium carbonate, sodium carbonate etc.；The molar ratio of the intermediate 3 and alkali is 1 ﹕ 1.5；The solvent of the reaction For any one in 1,2- dichloroethanes, dimethyl sulfoxide (DMSO), tetrahydrofuran, acetonitrile, DMF, DMAC N,N' dimethyl acetamide etc.；Institute The temperature for stating reaction is 80~140 DEG C；The time of the reaction is 4~12h；
E, the compound 4 containing nitro carries out reduction reaction and compound 5 is prepared in the presence of a reducing agent；The reducing agent For any one in iron powder, stannous chloride, zinc powder, sodium hydrosulfite, hydrogen, ammonium formate etc.；The solvent of the reaction is methanol, second Any one in alcohol, water, acetic acid；The temperature of the reaction is 25~100 DEG C；The time of the reaction is 0.5~3h；
F, compound 6 is prepared in compound 5 with acyl chloride reaction in the presence of base；The acyl chlorides be formyl chloride, chloroacetic chloride, Any one in propionyl chloride, butyl chloride, chloracetyl chloride, 2- chlorpromazine chlorides, acryloyl chloride, propine acyl chlorides etc.；The alkali is Any one in TEA, DIPEA, DABCO, DBU, potassium carbonate, sodium carbonate etc.；The molar ratio of the compound 5 and acyl chlorides and alkali For 1 ﹕, 1.1~1.5 ﹕ 2；The solvent is any one in dichloromethane, tetrahydrofuran, DMF etc.；The temperature of the reaction is 0~25 DEG C；The time of the reaction is 0.5~3h；
G, compound 4 carries out halogenating reaction with halogenating agent and compound 7 is prepared under conditions of DMF is catalyzed；The halogen It is any one in thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, phosphorus tribromide etc. for reagent；The compound 4 and halogenated examination The molar ratio of agent is 1 ﹕ 3~5；The solvent of the reaction is any one in dichloromethane, toluene, benzene etc.；The reaction Temperature is 25~80 DEG C；The time of the reaction is 2~12h；
H, raw material 3 and intermediate 2 ring closure reaction occur under metal catalytic compound 7 are prepared；The metal is chlorination Any one in cuprous, cuprous bromide, cuprous iodide, copper acetate etc.；The ligand of the reaction is L-PROLINE, N, N'- bis- Any one in methyl ethylenediamine, 1,10- phenanthrolines, DBU, ethylenediamine, tetramethylethylenediamine etc.；The alkali of the reaction is carbon Any one in sour sodium, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, TEA etc.；It is described Raw material 3, intermediate 2, metal, ligand and alkali molar ratio be 1 ﹕, 1.2 ﹕, 0.2 ﹕, 0.2 ﹕ 2；The solvent of the reaction is dichloromethane Any one in alkane, DMF, DMSO, 1,4- dioxane etc.；The temperature of the reaction is 70~110 DEG C；The reaction when Between be 3~16h；
Wherein, A C5~C10Aromatic ring or 5~10 yuan of heteroaromatics；The hetero atom of the heteroaromatic is N, O, S, and hetero atom number is 1 ~3；
R1For-H ,-OH, halogen ,-CN, C1~C8Alkyl, C1~C8Alkoxy or substituted or unsubstituted C5~C10Aryl；It is described It is-H, halogen or C to replace the substituent group of C5~C10 aryl1~C8Alkyl；
R3For-H, halogen ,-CN ,-NO2、-CF3、-NH2、-SO2Me、C1~C8Alkyl, C1~C8Alkoxy or
R4For-H, C1~C8Alkyl, C3~C8Naphthenic base,
X is halogen；N=1~3.
5. claims 1 to 3 any one of them 3- cyano pyrazoles simultaneously [1,5-a] pyrimidine derivatives pharmaceutically acceptable salt.
6. the simultaneously pharmaceutically acceptable hydration of [1,5-a] pyrimidine derivatives of claims 1 to 3 any one of them 3- cyano pyrazoles Object.
7. it is by any one of claims 1 to 3 3- cyano pyrazoles simultaneously [1,5-a] pyrimidine derivatives, right pharmaceutical composition It is required that pharmaceutically the complementary ingredient of acceptable is prepared for hydrate addition described in salt or claim 5 described in 4.
8. any one of claims 1 to 3 3- cyano pyrazoles simultaneously [1,5-a] pyrimidine derivatives, the salt described in claim 4, The pharmaceutical composition described in hydrate or claim 6 described in claim 5 is being prepared using histone demethylase as target Purposes in the drug of point.
9. any one of claims 1 to 3 3- cyano pyrazoles simultaneously [1,5-a] pyrimidine derivatives, the salt described in claim 4, The pharmaceutical composition described in hydrate or claim 6 described in claim 5 is in preparing oral or intravenous preparation Purposes.
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Application publication date: 20181102