CN109422754A

CN109422754A - Pyrazolo [3,4-d] pyrimidine -3- ketone derivatives, its pharmaceutical composition and application

Info

Publication number: CN109422754A
Application number: CN201810945415.4A
Authority: CN
Inventors: 高大新; 赵志明; 陈寿军; 武志恒
Original assignee: Shanghai de Novo Pharmatech Co Ltd
Current assignee: Shanghai de Novo Pharmatech Co Ltd
Priority date: 2017-08-24
Filing date: 2018-08-20
Publication date: 2019-03-05
Also published as: WO2019037678A1

Abstract

The present invention relates to one kind pyrazoles [3 as shown in formula (I) or (I '), 4-d] pyrimidine -3- ketone derivatives and/or its pharmaceutically acceptable salt, and contain purposes in the sensitizer of the composition and/or its pharmaceutically acceptable salt of the compound as shown in formula (I) or (I '), preparation method and its purposes as Wee1 inhibitor and its chemotherapy as cancer or radiation therapy；Pyrazoles [3,4-d] pyrimidine -3- ketone derivatives of the invention can effectively inhibit Wee-1 and associated signal paths, have the function of good treatment and/or alleviation cancer.

Description

Pyrazolo [3,4-d] pyrimidine -3- ketone derivatives, its pharmaceutical composition and application

Technical field

The present invention relates to pyrazolo [3,4-d] pyrimidine -3- ketone derivatives that one kind can inhibit Wee1 and its signal path And its pharmaceutically acceptable salt, the pharmaceutical composition comprising the derivative and its pharmaceutically-acceptable salts and described spread out The medicine of the disease of biology and its pharmaceutically-acceptable salts in treatment by the Wee1 disease mediated and preparation for treating Wee1 mediation The application in object space face.

Background technique

Wee1 (Wee1G2 test point kinases；Gene is numbered: 7465) being one in serine/threonine protein kitase family Member, can Direct Phosphorylation cell cycle protein dependent kinase 1 (CDK1), phosphorylation site be CDK1 15 residue of tyrosine, The site is an inhibition phosphorylation site, plays passive adjustment effect to CDK1 activity.The activation of G2 test point is mainly logical Inhibition mitosis is crossed, cell periodic protein B-CDK1 compound is promoted.Normal cell G1 arrest in the phase to the DNA of damage into Row is repaired, however cancer cell G1-S test point usually lacks, and needs to carry out DNA reparation by the function of G2-M test point.Example Such as, P53 defect tumour cell lacks the function of G1 test point, thus relies on G2 test point as cell cycle arrest and damage to DNA Wound carries out responsing reaction.After DNA is impaired, G2 test point prevents damaged cell from entering mitosis, and then has protecteded from silk Divide disaster and Apoptosis.Wee1 is essential factor in G2 test point Function.It is given up by Wee1 inhibitor Keep P53 defective cancer cell sensitive to DNA damage except the possible selectivity of G2 test point, avoids generating shadow to normal surrounding tissue It rings.Wee1 also adjusts the CDK activity of S phase, prevents the induction of DNA damage in normal S phase process.In addition, Wee1 is homologous heavy Group (HR) plays positive conciliation in repairing, and homologous recombination repair is the important path of DNA double chain fracture restoration.

The up-regulation of visible Wee1 in a variety of different types of cancers, including hepatocellular carcinoma (Masaki, et al, 2003), Breast cancer, cervical carcinoma, lung cancer (Iom, et al, 2009), squamous cell carcinoma (Magnussen, et al, 2013), neuroglia Tumor DIPG (Mueller, et al, 2014), glioblastoma) Mir, et al, 2010；Music, et al, 2016), at nerve Solencyte tumor (Harris, et al, 2014), and leukaemia (Tibas, et al, 2012；Porter, et al, 2012), melanin Tumor (Magnussen, et al, 2012) and oophoroma (Slipicevic, et al, 2014).In addition, the height of Wee1 is expressed It is related with the poor prognosis of multiple types cancer.Inhibit Wee1 that can cause the apoptosis of some P53 inactivation tumour cells.Inhibit Wee1 It can make to generate the sensitivity that the cancer cell resisted becomes to chemotherapy and radiotherapy.Newest research (Pfister, et al, 2015) illustrates Interaction between synthetic lethal and H3K36me3 missing, the change of part cancer cell epigenetics and Wee1 inhibition, thus Wee1 is inhibited and more accurate target gene changes the relationship between specific cancer patient and provides strong evidence.

Thus, Wee1 becomes the noticeable therapy target of field of cancer treatment height at present.In addition to existing to Wee1 Research outside, still go to extend its application there are also many opportunities and therefrom benefit.It there is no at present using Wee1 as therapy target Drug listing.Compound described in the invention, its composition and methods for using them will be helpful to the development of Wee1 inhibitor, full The clinical unsatisfied medication demand of foot.

Summary of the invention

Technical problem to be solved by the present invention lies in providing a kind of novel pyrazole, simultaneously [3,4-d] pyrimidine -3- ketone is derivative Object, preparation method, pharmaceutical composition and application.Pyrazolo [3,4-d] pyrimidine -3- ketone derivatives of the invention are to Wee1 and phase OFF signal access has good inhibiting effect, can effectively treat and/or alleviate cancer.

The present invention provides one kind compound as shown in formula (I), its isomers, prodrug, stable isotope derivatives or Pharmaceutically acceptable salt；

Wherein, W is N or CR₇；

X is CR₈Or N；Y is NR₉、CHR₈、-C(R₈)=C (R₁₁)-, O or S；Alternatively, Y is-N=C (R₁₁)-；

U and V is respectively selected from N or CH, and U and V are not N simultaneously；Alternatively, U and V are respectively selected from N or CR₈, and U and V It is not simultaneously N；

R₁For hydrogen, halogen, C_2-6Alkynyl, C_2-6Alkenyl, aryl, naphthenic base, Heterocyclylalkyl, heteroaryl or substituted alkyl； When the alkyl is substituted, optionally replaced at an arbitrary position by following one or more groups: halogen, haloalkoxy Base, aminocycloalkyl ,-SR_a、-OR_a、-OC(O)R_a、-OC(O)NR_aR_b、-C(O)OR_a、-C(O)R_a、-C(O)NR_aR_b、-NR_aR_b、- NR_aC(O)R_b、-NR_aS(O)₂R_b、-S(O)_1-2R_b、-S(O)₂NR_aR_bWith-NR_aS(O)₂NR_aR_b；

R₂For alkyl, halogenated alkyl, cycloalkyl-alkyl, hetercycloalkylalkyl, aryl alkyl, heteroaryl alkyl, alkenyl or Alkynyl；

R₃For hydrogen, halogen ,-CN ,-NO₂、-SR_c、-OR_c、-OC(O)R_c、-OC(O)OR_c、-OC(O)NR_cR_d、-C(O)OR_c、- C(O)R_c、-C(O)NR_cR_d、-NR_cR_d、-NR_cC(O)R_d、-N(R_c)C(O)OR_d、-N(R_c)C(O)NR_cR_d、-NR_cS(O)₂R_d、- NR_cC (=NH) R_d、-NR_cC (=NH) NR_cR_d、-S(O)_1-2R_c、-S(O)₂NR_cR_d、-NR_cS(O)₂NR_cR_d, it is substituted or unsubstituted Alkyl, substituted or unsubstituted naphthenic base, substituted or unsubstituted Heterocyclylalkyl, substituted or unsubstituted aryl, substitution or not It is substituted heteroaryl, substituted or unsubstituted cycloalkyl-alkyl, substituted or unsubstituted hetercycloalkylalkyl, substituted or unsubstituted Aryl alkyl, substituted or unsubstituted heteroaryl alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl；Institute State alkyl, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyl-alkyl, hetercycloalkylalkyl, aryl alkyl, heteroaryl alkane Base, alkenyl or alkynyl be substituted when, optionally by it is following one or more groups replace at an arbitrary position: halogen, alkyl, Halogenated alkyl, halogenated alkoxy, hydroxy alkyl, aminoalkyl, aminocycloalkyl, alkenyl, alkynyl ,-CN ,-NO₂、-SR_a、- OR_a、-OC(O)R_a、-OC(O)OR_a、-OC(O)NR_aR_b、-C(O)OR_a、-C(O)R_a、-C(O)NR_aR_b、-NR_aR_b、-NR_aC(O) R_b、-N(R_a)C(O)OR_b、-N(R_a)C(O)NR_aR_b、-NR_aS(O)₂R_b、-NR_aC (=NH) R_b、-NR_aC (=NH) NR_aR_b、-S (O)_1-2R_b、-S(O)₂NR_aR_bWith-NR_aS(O)₂NR_aR_b；

R₄、R₅、R₆And R₇Separately for hydrogen, halogen, hydroxyl, cyano, nitro, sulfydryl, amino, alkyl, alkoxy, Alkylthio group, halogenated alkyl, halogenated alkoxy, C_2-6Alkynyl, C_2-6Alkenyl, aryl, naphthenic base, Heterocyclylalkyl, heteroaryl ,-OC (O) R_c、-OC(O)OR_c、-OC(O)N(R_c)₂、-C(O)OR_c、-C(O)R_c、-C(O)N(R_c)₂、-N(R_c)₂、-NHC(O)R_c、-NHC(O) OR_c、-NHC(O)N(R_c)₂、-NHS(O)₂R_c、-S(O)_0-2R_cOr-S (O)₂N(R_c)₂；

R₃And R₄For independent substituent group, alternatively, R₃And R₄The annular atom being connect with it is formed together A ring, and the A ring is Substituted or unsubstituted naphthenic base, substituted or unsubstituted Heterocyclylalkyl, substituted or unsubstituted phenyl or substituted or unsubstituted 5-6 unit's heteroaryl；When the A ring is substituted, optionally replaced at an arbitrary position by following one or more groups: oxygen Dai Ji, thio group, halogen ,-CN ,-NO₂、-SR_c、-OR_c、-OC(O)R_c、-OC(O)OR_c、-OC(O)NR_cR_d、-C(O)OR_c、-C (O)R_c、-C(O)NR_cR_d、-NR_cR_d、-NR_cC(O)R_d、-N(R_c)C(O)OR_d、-N(R_c)C(O)NR_cR_d、-NR_cS(O)₂R_d、-NR_cC (=NH) R_d、-NR_cC (=NH) NR_cR_d、-S(O)_1-2R_c、-S(O)₂NR_cR_d、-NR_cS(O)₂NR_cR_d, substituted or unsubstituted alkane Base, substituted or unsubstituted naphthenic base, substituted or unsubstituted Heterocyclylalkyl, substituted or unsubstituted aryl, substitution do not take It is the heteroaryl in generation, substituted or unsubstituted cycloalkyl-alkyl, substituted or unsubstituted hetercycloalkylalkyl, substituted or unsubstituted Aryl alkyl, substituted or unsubstituted heteroaryl alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl；It is described Alkyl, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyl-alkyl, hetercycloalkylalkyl, aryl alkyl, heteroaryl alkyl, When alkenyl or alkynyl is substituted, optionally replaced at an arbitrary position by following one or more groups: halogen, alkyl, halogen Substituted alkyl, halogenated alkoxy, hydroxy alkyl, aminoalkyl, alkenyl, alkynyl ,-CN ,-NO₂、-SR_c、-OR_c、-OC(O)R_c、-OC (O)OR_c、-OC(O)N(R_c)₂、-C(O)OR_c、-C(O)R_c、-C(O)N(R_c)₂、-N(R_c)₂、-NHC(O)R_c、-NHC(O)OR_c、- NHC(O)N(R_c)₂、-NHS(O)₂R_c,-NHC (=NH) R_c,-NHC (=NH) N (R_c)₂、-S(O)_1-2R_c、-S(O)₂N(R_c)₂With- NHS(O)₂N(R_c)₂；

R₈、R₉Or R₁₁It is separately hydrogen ,-C (O) OR_c、-C(O)R_c、-C(O)NR_cR_d、-S(O)_1-2R_c、-S(O)₂NR_cR_d, substituted or unsubstituted alkyl, substituted or unsubstituted naphthenic base, substituted or unsubstituted Heterocyclylalkyl, substitution or not Substituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl-alkyl, substituted or unsubstituted heterocycle alkane Base alkyl, substituted or unsubstituted heteroaryl alkyl, substituted or unsubstituted alkenyl, takes substituted or unsubstituted aryl alkyl Generation or unsubstituted alkynyl；The alkyl, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyl-alkyl, Heterocyclylalkyl alkane When base, aryl alkyl, heteroaryl alkyl, alkenyl or alkynyl are substituted, optionally by following one or more R₁₀It is substituted in Any position；Alternatively, R₈Or R₁₁Separately it is selected from-NR_cR_d、-NR_cS(O)_1-2R_d、-NR_cC(O)R_dOr-NR_cS(O)₂NR_cR_d；

R₁And R₉For independent substituent group, alternatively, R₁And R₉It is interconnected to form 4-8 membered heterocycloalkyl, the Heterocyclylalkyl is also It can be further by 1~3 C_1-6Alkyl or C_3-6Naphthenic base arbitrarily replaces；

Each R₁₀Separately for hydrogen, halogen, alkyl, halogenated alkyl, halogenated alkoxy, hydroxy alkyl, aminoalkyl, Aminocycloalkyl, alkenyl, alkynyl ,-CN ,-NO₂、-SR_a、-OR_a、-OC(O)R_a、-OC(O)OR_a、-OC(O)NR_aR_b、-C(O) OR_a、-C(O)R_a、-C(O)NR_aR_b、-NR_aR_b、-NR_aC(O)R_b、-N(R_a)C(O)OR_b、-N(R_a)C(O)NR_aR_b、-NR_aS(O)₂R_b、-NR_aC (=NH) R_b、-NR_aC (=NH) NR_aR_b、-S(O)_1-2R_b、-S(O)₂NR_aR_bWith-NR_aS(O)₂NR_aR_b；Or each R₁₀ It is separately naphthenic base or Heterocyclylalkyl；Or each R₁₀It is separately R_a；

Each R_aWith each R_bSeparately it is selected from hydrogen, C_1-6Alkyl, C_1-6Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, C_3-8Ring Alkyl, 3-8 membered heterocycloalkyl, C_6-10Aryl, 5-6 unit's heteroaryl, C_3-8Naphthenic base C_1-6Alkyl, 3-8 membered heterocycloalkyl C_1-6Alkane Base, phenyl C_1-6Alkyl or 5-6 unit's heteroaryl C_1-6Alkyl；The C_1-6Alkyl, C_1-6Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, C_3-8 Naphthenic base, 3-8 membered heterocycloalkyl, C_6-10Aryl or 5-6 unit's heteroaryl are unsubstituted or are selectively selected from halogen by 1~3 Element, hydroxyl, amino, carboxyl, C_1-6Alkyl, halogenated C_1-6Alkyl, C_1-6Alkoxy, C_1-6Alkylamino and halogenated C_1-6In alkoxy One or more substituent groups replace at an arbitrary position；

R_aAnd R_bFor independent substitution, alternatively, the R_aAnd R_bThe N atom connected together is formed together 3-12 circle heterocyclic ring Alkyl, the Heterocyclylalkyl further can also be selected from N, O, S (O) containing 1~3_0-2, C (O) hetero atom or group；It is described Heterocyclylalkyl is selected from halogen, hydroxyl, amino, carboxyl, C by 1~3 for unsubstituted or selectivity_1-6Alkyl, halogenated C_1-6Alkane Base, C_1-6Alkoxy, C_1-6Alkylamino and halogenated C_1-6One of alkoxy or a variety of substituent groups replace at an arbitrary position；

Each R_cWith each R_dSeparately it is selected from hydrogen, C_1-6Alkyl, C_1-6Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, C_3-8Ring Alkyl, 3-8 membered heterocycloalkyl, C_6-10Aryl, 5-6 unit's heteroaryl, C_3-8Naphthenic base C_1-6Alkyl, 3-8 membered heterocycloalkyl C_1-6Alkane Base, phenyl C_1-6Alkyl or 5-6 unit's heteroaryl C_1-6Alkyl；The C_1-6Alkyl, C_1-6Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, C_3-8 Naphthenic base, 3-8 membered heterocycloalkyl, C_6-10Aryl or 5-6 unit's heteroaryl are unsubstituted or are selectively selected from halogen by 1~3 Element, hydroxyl, amino, carboxyl, C_1-6Alkyl, halogenated C_1-6Alkyl, C_1-6Alkoxy, C_1-6Alkylamino and halogenated C_1-6In alkoxy One or more substituent groups replace at an arbitrary position.

The present invention provides one kind compound as shown in formula (I '), its isomers, prodrug, stable isotope derivatives or Pharmaceutically acceptable salt；

Wherein, W is N or CR₇；

X is CR₈Or N；Y is NR₉、CHR₈、-C(R₈)=C (R₁₁)-,-N=C (R₁₁)-, O or S；

U and V is respectively selected from N or CR₈, and U and V are not N simultaneously；

R₈、R₉Or R₁₁It is separately hydrogen ,-C (O) OR_c、-C(O)R_c、-C(O)NR_cR_d、-S(O)_1-2R_c、-S(O)₂NR_cR_d, substituted or unsubstituted alkyl, substituted or unsubstituted naphthenic base, substituted or unsubstituted Heterocyclylalkyl, substitution or not Substituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl-alkyl, substituted or unsubstituted heterocycle alkane Base alkyl, substituted or unsubstituted heteroaryl alkyl, substituted or unsubstituted alkenyl, takes substituted or unsubstituted aryl alkyl Generation or unsubstituted alkynyl；The alkyl, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyl-alkyl, Heterocyclylalkyl alkane When base, aryl alkyl, heteroaryl alkyl, alkenyl or alkynyl are substituted, optionally by following one or more R₁₀It is substituted in Any position；Alternatively, R₈Or R₁₁Separately it is selected from-NR_cR_d、-NR_cS(O)_1-2R_d、-NR_cC(O)R_dOr-NR_cS(O)₂NR_cR_d；Each R₁₀It is separately hydrogen, halogen, alkyl, halogenated alkyl, halogenated alkoxy, hydroxy alkyl, aminoalkyl, ammonia Basic ring alkyl, alkenyl, alkynyl, naphthenic base, Heterocyclylalkyl ,-CN ,-NO₂、-SR_a、-OR_a、-OC(O)R_a、-OC(O)OR_a、-OC(O) NR_aR_b、-C(O)OR_a、-C(O)R_a、-C(O)NR_aR_b、-NR_aR_b、-NR_aC(O)R_b、-N(R_a)C(O)OR_b、-N(R_a)C(O) NR_aR_b、-NR_aS(O)₂R_b、-NR_aC (=NH) R_b、-NR_aC (=NH) NR_aR_b、-S(O)_1-2R_b、-S(O)₂NR_aR_bWith-NR_aS(O)₂NR_aR_b；Or each R₁₀It is separately R_a；

In the present invention, the W is preferably N.

In the present invention, the U is preferably CH.

In the present invention, the V is preferably CR₈；Wherein, R₈It is defined as described above.

In the present invention, the X and Y are preferably following any combination:

1) X is N, Y NR₉；Wherein, R₉It is defined as described above.

2) X is CH, Y NR₉；Wherein, R₉It is defined as described above.

3) X is CR₈, Y O；Wherein, R₈It is defined as described above.

4) X is CR₈, Y O；Wherein, R₈It is defined as described above.

5) X is CR₈, Y be-C (R₈)=C (R₁₁)-.Wherein, R₈And R₁₁It is defined as described above.

In the present invention, it is CH, Y NR that the X and Y, which are more preferably X,₉；Wherein, R₉It is defined as described above.

In the present invention, groupIt is preferred that being connected by (1) position with parent nucleus；

In the present invention, groupIt is preferred that being connected by (2) position with parent nucleus.

In the present invention, groupPreferably with flowering structure:

In the present invention, the R₁Preferably H or substituted C_1-6Alkyl；The R₁More preferably H.

In the present invention, the R₂It is preferred that are as follows:

In the present invention, the R₂More preferably:

In the present invention, the R₃In, the alkyl, naphthenic base, Heterocyclylalkyl, cycloalkyl-alkyl or Heterocyclylalkyl are substituted When, preferably replaced at an arbitrary position by 1~3 substituent group.The substituent group is as defined above.

In the present invention, the R₃Preferably substituted or unsubstituted C_1-6Alkyl, when the alkyl is substituted, preferably by 1 A hydroxyl replaces at an arbitrary position.

In the present invention, the R₄Preferably H.

In the present invention, the R₃And R₄The annular atom being connect with it is formed together A ring, and the A ring preferably replaces or not Substituted monocyclic cycloalkyl, substituted or unsubstituted monocyclic heterocycloalkyl, substituted or unsubstituted phenyl or substituted or unsubstituted 5-6 unit's heteroaryl；

In the present invention, the A ring is preferably unsubstituted.

In the present invention, when the A ring is substituted, preferably replaced at an arbitrary position by 1~3 substituent group.The substituent group It is as defined above.

In the present invention, the R₅Preferably H.

In the present invention, the R₆Preferably H.

In the present invention, the R₈Preferably H；

In the present invention, the R₈Preferably-NR_cR_d、-NR_cS(O)_1-2R_d、-NR_cC(O)R_d、-NR_cS(O)₂NR_cR_d、-C(O) OR_c、-C(O)R_c、-C(O)NR_cR_d、-S(O)_1-2R_c、-S(O)₂NR_cR_d, substituted or unsubstituted alkyl, substituted or unsubstituted ring Alkyl, substituted or unsubstituted Heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substitution or not Substituted cycloalkyl-alkyl, substituted or unsubstituted hetercycloalkylalkyl, substituted or unsubstituted aryl alkyl, substitution do not take The heteroaryl alkyl in generation, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl；The alkyl, naphthenic base, heterocycle alkane Base, aryl, heteroaryl, cycloalkyl-alkyl, hetercycloalkylalkyl, aryl alkyl, heteroaryl alkyl, alkenyl or alkynyl are substituted When, optionally by following one or more R₁₀Replace at an arbitrary position；It is preferred that by 1~3 R₁₀Replace at an arbitrary position.

In the present invention, the R₈In, the substituted or unsubstituted alkyl is preferably substituted or unsubstituted C_1-6Alkyl； More preferably substituted or unsubstituted C_1-4Alkyl；

The R₈In, the substituted or unsubstituted naphthenic base is preferably substituted or unsubstituted C_3-8Naphthenic base；

The R₈In, the substituted or unsubstituted Heterocyclylalkyl is preferably substituted or unsubstituted 3-8 membered heterocycloalkyl；

The R₈In, the substituted or unsubstituted Heterocyclylalkyl is preferably substituted or unsubstituted following any group: Azelidinyl, pyrrolidinyl, piperidyl, piperazinyl, high piperazine base, morpholinyl, (1S, 4S) -2,5- diazabicyclo [2.2.1] heptyl, (1R, 4R) -2,5- diazabicyclo [2.2.1] heptyl, (1R, 4R) -2- oxygen -5- azabicyclo [2.2.1] Heptyl, (1S, 4S) -2- oxygen -5- azabicyclo [2.2.1] heptyl or 4,7- diaza spiro [2.5] octyl；

The R₈In, the substituted or unsubstituted cycloalkyl-alkyl is preferably substituted or unsubstituted C_3-8Naphthenic base C_1-3 Alkyl；

The R₈In, the substituted or unsubstituted hetercycloalkylalkyl is preferably substituted or unsubstituted 3-8 circle heterocyclic ring Alkyl C_1-3Alkyl；

The R₈In, the substituted or unsubstituted aryl is preferably substituted or unsubstituted phenyl.

The R₈In, the substituted or unsubstituted heteroaryl is preferably substituted or unsubstituted 5-6 unit's heteroaryl.

In the present invention, the R₉In, the substituted or unsubstituted alkyl is preferably substituted or unsubstituted C_1-6Alkyl； More preferably substituted or unsubstituted C_1-4Alkyl；

The R₉In, the substituted or unsubstituted naphthenic base is preferably substituted or unsubstituted C_3-8Naphthenic base；

The R₉In, the substituted or unsubstituted Heterocyclylalkyl is preferably substituted or unsubstituted 3-8 membered heterocycloalkyl；

The R₉In, the substituted or unsubstituted Heterocyclylalkyl is preferably substituted or unsubstituted following any group: Pyrrolidinyl, piperidyl, azacycloheptyl, azelidinyl, oxetanylmethoxy, 4- azaspiro [2.5] octyl or 5- azaspiro [2.5] octyl；

The R₉In, the substituted or unsubstituted cycloalkyl-alkyl is preferably substituted or unsubstituted C_3-8Naphthenic base C_1-3 Alkyl；

The R₉In, the substituted or unsubstituted hetercycloalkylalkyl is preferably substituted or unsubstituted 3-8 circle heterocyclic ring Alkyl C_1-3Alkyl；

The R₉In, the substituted or unsubstituted aryl is preferably substituted or unsubstituted phenyl.

The R₉In, the substituted or unsubstituted heteroaryl is preferably substituted or unsubstituted 5-6 unit's heteroaryl.

In the present invention, each R₁₀It is independently preferably H, F, Cl, C_1-6Alkyl, halogenated C_1-6Alkyl, halogenated C_1-6Alkoxy, Hydroxyl C_1-6Alkyl, amino C_1-6Alkyl, amino C_3-8Naphthenic base, C_2-6Alkenyl, C_2-6Alkynyl ,-CN ,-NO₂、-SR_a、-OR_a、-OC (O)R_a、-OC(O)OR_a、-OC(O)NR_aR_b、-C(O)OR_a、-C(O)R_a、-C(O)NR_aR_b、-NR_aR_b、-NR_aC(O)R_b、-N(R_a)C (O)OR_b、-N(R_a)C(O)NR_aR_b、-NR_aS(O)₂R_b、-NR_aC (=NH) R_b、-NR_aC (=NH) NR_aR_b、-S(O)_1-2R_b、-S(O)₂NR_aR_bOr-NR_aS(O)₂NR_aR_b；Alternatively, each R₁₀It is independently preferably C_3-8Naphthenic base or 3-8 membered heterocycloalkyl；R_aAnd R_b Separately it is selected from H or C_1-6Alkyl.R_aAnd R_bFor independent substitution, alternatively, the R_aAnd R_bThe N atom connected together It is formed together 3-8 membered heterocycloalkyl, the Heterocyclylalkyl further can also be selected from N, O, S (O) containing 1~3_0-2, C (O) Hetero atom or group；The Heterocyclylalkyl is selected from C by 1 for unsubstituted or selectivity_1-6The substituent group of alkyl is substituted in arbitrarily Position；

In the present invention, each R₁₀Independently be more preferably H, D, F, Cl, amino, hydroxyl, methyl, ethyl, propyl, butyl, Isopropyl, isobutyl group, tert-butyl, cyclopropane, cyclobutane, pentamethylene, azelidinyl, oxetanylmethoxy, trifluoromethyl, 1,1- Bis-fluoro ethyls, 1,1,1- trifluoroethyl, methoxyl group, ethyoxyl, trifluoromethoxy, 1,1- difluoroethoxy, amino-ethyl, hydroxyl Ethyl ,-C (O) CH₃、-C(O)OCH₃、-NHCH₃Or-N (CH₃)₂。

In some embodiments, the compound as shown in formula (I) and/or pharmaceutically acceptable salt are as shown in formula (II) Compound and/or its pharmaceutically acceptable salt:

Wherein, R₁、R₂、R₃、R₄、R₅、R₉, V, X and W it is defined as described above.

In some embodiments, the compound as shown in formula (I) and/or pharmaceutically acceptable salt are such as formula (III) institute Show compound and/or its pharmaceutically acceptable salt:

Wherein, 0,1,2 or 3 n；

R₁、R₃、R₄、R₅、X、R_a、R_bIt is defined as described above with W.

Following preferred embodiment is included in the definition of formula (III):

In some preferred embodiments, 1 n.

In some embodiments, the compound as shown in formula (I) and/or pharmaceutically acceptable salt are as shown in formula (IV) Compound and/or its pharmaceutically acceptable salt:

Wherein, Z is N or CH；L is CH₂、CH(CH₃)、C(CH₃)₂OrU is 0,1 or 2；V is 0,1 or 2；

R₁、R₃、R₄、R₅、R₁₀, X and W it is defined as described above.

Following preferred embodiment is included in the definition of formula (IV):

In some preferred embodiments, L is

In some preferred embodiments, 1 u, v 1；

In some preferred embodiments, 1 u, v 2；

In some preferred embodiments, 0 u, v 1；

In some preferred embodiments, 0 u, v 2；

In some preferred embodiments, 1 u, v 0；

In some preferred embodiments, 2 u, v 0；

In some preferred embodiments, Z N；And R₁₀For hydrogen, C_1-6Alkyl, halogenated C_1-6Alkyl, hydroxyl C_1-6Alkyl, ammonia Base C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl ,-OR_a、-C(O)OR_a、-C(O)R_a、-C(O)NR_aR_b、-S(O)_1-2R_bOr-S (O)₂NR_aR_b；R_aAnd R_bIt is separately hydrogen or C_1-6Alkyl.

In some embodiments, the compound as shown in formula (I) and/or pharmaceutically acceptable salt are as shown in formula (V) Compound and/or its pharmaceutically acceptable salt:

Wherein, R₁、R₂、R₃、R₄、R₅、R₈、R₉, U and W it is defined as described above.

Following preferred embodiment is included in the definition of formula (V):

In some preferred embodiments, U CH；

In some preferred embodiments, R₁For H or methyl；

In some preferred embodiments, R₈For-NR_cR_d；

In some preferred embodiments, R₈For substituted or unsubstituted 3-8 membered heterocycloalkyl；When the 3-8 circle heterocyclic ring When alkyl is substituted, selectivity is by 1~3 C_1-4Alkyl or C_3-6Naphthenic base replaces at an arbitrary position；

In some preferred embodiments, R₉For C_1-4Alkyl, hydroxyl C_1-4Alkyl, C_3-8Naphthenic base or 3-8 circle heterocyclic ring alkane Base；

In some preferred embodiments, R₂For

In some embodiments, the compound as shown in formula (I ') and/or pharmaceutically acceptable salt are such as formula (VI) institute Show compound and/or its pharmaceutically acceptable salt:

Following preferred embodiment is included in the definition of formula (VI):

In some preferred embodiments, U CH；

In some preferred embodiments, R₈For-NR_cR_d；；

In some preferred embodiments, R₉For C_1-4Alkyl, hydroxyl C_1-4Alkyl, C_3-8Naphthenic base or 3-8 circle heterocyclic ring alkane Base.

In some embodiments, if formula (I) compound represented and/or pharmaceutically acceptable salt are optionally followingization Close object:

The present invention also provides the compound as shown in formula (I), its isomers, prodrugs, stable isotope derivatives Or the preparation method of pharmaceutically acceptable salt, it is following either method:

Method 1:

In method 1, the R₁、R₂、R₃、R₄、R₅、R₆, U, V, Y and W definition as described above；Method 1 includes following step Rapid: 1a and 1b are obtained compound 1c by buchwald coupling reaction by step 1)；Step 2) is by the methyl mercapto in compound 1c Sulfoxide, which is oxidized to, with metachloroperbenzoic acid (m-CPBA) obtains compound 1d；Step 3) is by compound 1d and 1e or 1e ' in alkali Property under the conditions of reaction obtain compound shown in general formula I or I '.

In method 1, the condition and step can be the condition and step of the reaction of this field routine, and the present invention is especially excellent Select following reaction condition: under step 1) nitrogen protection, in Isosorbide-5-Nitrae-dioxane solvent, in alkali (1,2-N, N- dimethyl second two Amine, potassium carbonate) and stannous chloride under the action of react and obtain, described dose of dosage preferably 1~50mL/mmol compound 1a, institute It is 0-24 hours preferred to state the reaction time, the preferred room temperature of temperature to solvent refluxing, more preferably 80~100 DEG C, compound 1a and 1b The preferred 1:0.9~1:1.5 of molar ratio.In step 2) dichloromethane solvent, obtained with metachloroperbenzoic acid oxidized compound 1c To compound 1d；Described dose of dosage preferably 1~50mL/mmol compound 1c, the reaction time is 0-24 hours preferred, temperature It is preferred that 0 DEG C~room temperature, the preferred 1:1~1:3 of molar ratio of compound 1c and m-CPBA；In step 3) toluene, under alkaline condition (N, N- diisopropylethylamine or triethylamine), 1d and 1e or Ie ' reaction obtain compound shown in general formula I or I ', and described dose of dosage is excellent 1~50mL/mmol compound 1d is selected, the reaction time is 0-24 hours preferred, the preferred room temperature of temperature to solvent refluxing, compound Preferred 1:0.9:1~the 1:2.5:2.5 of the molar ratio of 1d, 1e and alkali；Compound 1d, 1e ' and alkali the preferred 1:0.9:1 of molar ratio~ 1:2.5:2.5。

The acidity such as p-methyl benzenesulfonic acid, hydrochloric acid, hydrogen chloride or trifluoroacetic acid are used in the last synthesis step of the above method System, or in purification process, such as: it is there are when above-mentioned acid system in the mobile phase of prep-HPLC, then described such as Formulas I Or I ' compound represented will be corresponding tosilate, hydrochloride or trifluoroacetate etc..The above method is last In the purification process of synthesis step, such as: it the use of the elution requirement of silica gel column chromatography or prep-TLC is petroleum ether, acetic acid second One of ester, methylene chloride, methanol, n-hexane or a variety of or prep-HPLC mobile phase use the alkaline body such as ammonium hydrogen carbonate It is when being, then described as Formulas I or I ' compound represented will be free alkali form.

In the above-mentioned methods, in 1a, 1b, 1e or 1e ' it is middle in the presence of the amino group, hydroxyl group or carboxyl that are not involved in reaction When group, the amino group, hydroxyl group or carboxylic group are preferably protected by protecting group, avoid any side reaction. It then needs to obtain after subsequent deprotection steps such as Formulas I if there is above-mentioned amido protecting group or hydroxy-protective group And compound shown in I '.Any suitable amido protecting group, such as: tertbutyloxycarbonyl (Boc) group may be incorporated for protecting Amino group.If using Boc as protecting group, subsequent deprotection reaction can be in standard conditions, for example, to toluene sulphur Acid/methanol system, methylene chloride/trifluoroacetic acid system, the ether solution of hydrogen chloride of saturation or trifluoromethanesulfonic acid trimethyl silicane It is carried out in ester/2,6- lutidines/dichloromethane system；Any suitable hydroxy-protective group, such as: benzyl, it can be with For protecting amino group, subsequent deprotection reaction can be in standard conditions, for example, palladium carbon/hydrogen；Any suitable carboxyl Blocking group, such as: it is formed carboxylate group (for example, carboxylate methyl ester, carboxylic acid, ethyl ester), may be incorporated for protection carboxylic group, Subsequent deprotection reaction can be in standard conditions, for example, sodium hydroxide, potassium hydroxide, lithium hydroxide are in tetrahydrofuran, water And/or it is deprotected in methanol solvate.Above-mentioned deprotection reaction is preferably carried out in final step.

The compound as shown in formula (I) or (I '), pharmaceutically acceptable salt can be closed by general chemical method At.

Under normal circumstances, the preparation of salt can by free alkali or acid and equal chemical equivalents or excess acid (inorganic acid or Organic acid) or alkali (inorganic base or organic base) reacted in suitable solvent or solvent compositions be made.

The present invention also provides a kind of pharmaceutical compositions comprising the active component of therapeutically effective amount and can pharmaceutically connect The auxiliary material received；The active component includes the compound as shown in formula (I) or (I '), its isomers, prodrug, stable isotope derivative method One of biology and pharmaceutically acceptable salt are a variety of.

In described pharmaceutical composition, the active component may also include its of cancer, virus infection or autoimmune disease Its therapeutic agent.

In described pharmaceutical composition, the pharmaceutically acceptable auxiliary material may include pharmaceutically acceptable carrier, dilution Agent and/or excipient.

According to therapeutic purposes, pharmaceutical composition can be made to various types of administration unit dosage forms, such as tablet, pill, powder Agent, liquid, suspension, lotion, granule, capsule, suppository and injection (solution and suspension) etc., preferred liquid, suspension, cream Liquid, suppository and injection (solution and suspension) etc..

In order to shape the pharmaceutical composition of tablet form, it can be used this field any known and widely used figuration Agent.For example, carrier, such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, avicel cellulose and silicon Acid etc.；Adhesive, such as water, ethyl alcohol, propyl alcohol, common syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose Element, lac, methylcellulose and potassium phosphate, polyvinylpyrrolidone etc.；Disintegrating agent, such as dried starch, mosanom, agar powder and sea Band powder, sodium bicarbonate, calcium carbonate, the aliphatic ester of polyethylene sorbitan, lauryl sodium sulfate, stearic acid monoglycerides, Starch and lactose etc.；Disintegration inhibitor, such as white sugar, glycerol tristearate, coconut oil and hydrogenated oil and fat；Adsorption enhancer, such as season Amine base and lauryl sodium sulfate etc.；Wetting agent, such as glycerol, starch；Adsorbent, such as starch, lactose, kaolin, bentonite With colloid silicic acid etc.；And lubricant, such as pure talcum, stearate, boric acid powder and polyethylene glycol etc..It can also be according to need Select common coated material be made sugar coated tablet, apply gelatin film tablet, enteric coated tablets, film coated tablets, duplicature tablet and Multilayer tablet.

In order to shape the pharmaceutical composition of pill, it can be used this field any of and widely used figuration Agent, for example, carrier, such as lactose, starch, coconut oil, hardened vegetable oils, kaolin and talcum powder etc.；Adhesive, such as Arabic tree Rubber powder, tragacanth gum powder, gelatin and ethyl alcohol etc.；Disintegrating agent, such as agar and Kelp Powder.

In order to shape the pharmaceutical composition of suppository form, it can be used this field any known and widely used inborn nature Agent, for example, polyethylene glycol, coconut oil, higher alcohol, the ester of higher alcohol, gelatin and semi-synthetic glyceride etc..

In order to prepare the pharmaceutical composition of injection form, (suitable chlorine can will be preferably added after solution or suspension liquid disinfectant Change sodium, glucose or glycerol etc.), it is made and the isotonic injection of blood.When preparing injection, it is possible to use in the art any Common carrier.For example, water, ethyl alcohol, propylene glycol, the isooctadecanol of ethoxylation, the isooctadecanol and polyethylene of polyoxy The aliphatic ester etc. of anhydro sorbitol.In addition, common lytic agent, buffer and analgesic etc. can also be added.

In the present invention, content of the composition in pharmaceutical composition, can be in a wide range without specifically limited It is selected, generally can be the 5~95% of mass percent, preferably mass percent 30~80%.

In the present invention, the medication of described pharmaceutical composition is not particularly limited.Can according to patient age, gender and its Its condition and symptom select the preparation of various dosage forms to be administered.For example, tablet, pill, solution, suspension, lotion, granule or Capsule oral administration；Injection can be administered alone, or mixed with injection conveying liquid (such as glucose solution and amino acid solution) Conjunction is injected intravenously；Suppository is to be administered into rectum.

The present invention also provides the compound as shown in formula (I) or (I '), its isomers, prodrug, stable isotope are derivative Object or pharmaceutically acceptable salt or described pharmaceutical composition are preparing the application in Wee1 inhibitor.

The present invention also provides the compound as shown in formula (I) or (I '), its isomers, prodrug, stable isotope are derivative Object or pharmaceutically acceptable salt or described pharmaceutical composition are in the chemotherapy of preparation cancer or the sensitizer of radiation therapy In application.Wherein, the sensitizer of the chemotherapy or radiotherapy refers in field of cancer treatment, by with put Radiotherapy and/or be applied in combination using the chemotherapy of anticancer agent, additively or synergistically improve these radiotherapies and/ Or the drug of chemotherapeutic therapeutic effect.

The present invention also provides the compound as shown in formula (I) or (I '), its isomers, prodrug, stable isotope are derivative Object or pharmaceutically acceptable salt or described pharmaceutical composition in preparation treatment and/or alleviate the related disease mediated by Wee1 Drug in application；Present invention preferably provides the compound as shown in formula (I), its isomers, prodrug, stable isotope derivative methods The related disease that biology or pharmaceutically acceptable salt or described pharmaceutical composition are mediated in preparation treatment and/or prevention by Wee1 Application in the drug of disease；The disease includes tumour and non-neoplastic disease.The disease is preferably cancer.

The present invention preferably uses the compound as shown in formula (I) or (I '), its isomers, prodrug, the stable isotope derivative method The application of biology or pharmaceutically acceptable salt or described pharmaceutical composition in preparation treatment and/or alleviation cancer drug.

The present invention is still further provided with the compound as shown in formula (I) or (I '), its isomers, the prodrug, stabilization Isotope derivatives or pharmaceutically acceptable salt or described pharmaceutical composition treating cancer method, comprising: give lactation Dosage needed for treatment of animals as formula (I) or (I ') described compound, its isomers, prodrug, stable isotope derivatives or Pharmaceutically acceptable salt or pharmaceutical composition.

The mammal, preferably people.

The present invention still further provides the compound as shown in formula (I) or (I '), its isomers, prodrug, stable Isotope derivatives or pharmaceutically acceptable salt or described pharmaceutical composition can also be with the treatments of one or more other types Agent and/or treatment method are combined for treating and/or alleviating the related disease mediated by Wee1, and the disease is preferably cancer Disease.

The present invention furthermore provides a kind of combination formulations, including the compound as shown in formula (I) or (I '), its isomers, Prodrug, stable isotope derivatives or pharmaceutically acceptable salt or described pharmaceutical composition and other types for controlling The therapeutic agent and/or treatment method for treating cancer share.

In the present invention, and the therapeutic agents of other types (such as: the therapeutic agent of other types for treating cancer) it can To be made into the therapeutic dosage forms of single administration with the compound as shown in formula (I) or (I '), or it is taken up in order of priority controlling for administration Treat dosage form.

In the present invention, the therapeutic agent and/or treatment method for treating cancer of other types may include but unlimited In use for cancer treatment: Antitubulin, topological enzyme I/II inhibitor, platinum-like compounds, antibiotic, resists alkylating agent It is metabolized class drug, hormone and hormone analogs, targeted therapy (such as: special kinase inhibitor), immunotherapeutic agent, interference One of plain, other anticancer agents use for cancer treatment and radiotherapy are a variety of.

In the present invention, the Antitubulin be may be selected from but not limited to: and vincaleukoblastinum series (such as: vincaleukoblastinum, Changchun New alkali, vinorelbine, eldisine), one of taxanes (docetaxel, taxol) and methanesulfonic acid eribulin or more Kind.

In the present invention, the alkylating agent be may be selected from but not limited to: mustargen, ethylenimine derivatives, Loprazolam esters, Asia One of nitre ureas and Triazenes are a variety of.

In the present invention, the topological enzyme I/II inhibitor be may be selected from but not limited to: camptothecine, 10-hydroxycamptothecine, Yi Li For health, Irinotecan metabolite SN-38, topotecan, hinotec, Exactecan, Karenitecin, 9- nitro camplotheca acuminata One of alkali, adriamycin and dexrazoxane are a variety of.

In the present invention, the platinum-like compounds be may be selected from but not limited to: cis-platinum, carboplatin, Nedaplatin, oxaliplatin, horse difficult to understand Platinum, four platinum, iproplatin, Spiroplatin, two water platinum (II) of cis- diamino-ion or dichloro (ethylenediamine)-platinum (II).

In the present invention, the antimetabolitas be may be selected from but not limited to: antifol, pyrimidine analogue, purines Like object, adenosine deaminase inhibitors, such as: methotrexate (MTX), 5 FU 5 fluorouracil, fluridine, cytarabine, Ismipur, 6- One of thioguanine, fludarabine phosphate, Pentostatin and gemcitabine are a variety of.

In the present invention, the immunotherapeutic agent be may be selected from but not limited to: and anti-tumor vaccine (such as: synthetic peptide, DNA vaccination And recombinant virus), oncolytic virus, monoclonal antibody (such as: PD-1 monoclonal antibody, PD-L1 monoclonal antibody, CTLA-4 monoclonal antibody etc.), novel assistant Agent, cytokine therapy (such as: IL2 and GM-CSF), Chimeric antigen receptor T cell cure (CAR-T), small molecule immune tune Save one of agent, tumor microenvironment regulator and anti-angiogenesis or a variety of.

In the present invention, the antibiotic use for cancer treatment be may be selected from but not limited to: actinomycin D, Doxorubicin, soft Erythromycin, bleomycin, Peplomycin, mitomycin C, Aclarubicin, pirarubicin, epirubicin, Zinostatin stimalamer, she Up to than one of star, sirolimus and valrubicin or a variety of.

In the present invention, the interferon use for cancer treatment be may be selected from but not limited to: interferon-' alpha ', is done Intederon Alpha-2a Disturb plain α -2b, interferon beta, interferon gamma -1a or interferon gamma-n1 etc..

In the present invention, the cancer includes metastatic and non-metastatic cancer, also includes the sum of Familial Occurrence Sporadic cancer, may also include solid tumor and non-solid tumors.

In the present invention, the specific example of the solid tumor be may include but be not limited to: eye, bone, lung, stomach, pancreas, mammary gland, (matrix generated including those from epithelial cell is thin for prostate, brain (including glioblastoma and medulloblastoma), ovary Born of the same parents, reproduction cell and interstitial cell), bladder, testis, spinal cord, kidney (including gland cancer, the nephroblastoma), mouth, lip, throat, mouth Chamber (including squamous cell carcinoma), nasal cavity, small intestine, colon, rectum, parathyroid gland, gall-bladder, bile duct, uterine neck, the heart, hypopharyngeal gland, branch gas Pipe, liver, ureter, vagina, anus, larynx gland, thyroid gland (including thyroid cancer and cephaloma), esophagus, nasopharynx adenohypophysis, saliva Gland, adrenal gland, incidence intraepithelial neoplasia (including Bowen disease and paget's disease), sarcoma (including leiomyosarcoma, cross Line muscle tumor, embryonal-cell lipoma, fibrosarcoma, osteosarcoma), skin (including melanoma, Kaposi's sarcoma, basocellular Cancer and squamous cell carcinoma) etc. relevant tumour.

In the present invention, the solid tumor is preferably cancer eye, osteocarcinoma, lung cancer, gastric cancer, cancer of pancreas, the breast cancer, forefront of people Gland cancer, the cancer of the brain (including but not limited to glioblastoma, medulloblastoma), oophoroma, bladder cancer, cervix cancer, testis Cancer, kidney (including but not limited to gland cancer, kidney mother cell cancer), carcinoma of mouth (including squamous cell carcinoma), tongue cancer, laryngocarcinoma, nasopharyngeal carcinoma, Head and neck cancer, colon cancer, carcinoma of small intestine, the carcinoma of the rectum, parathyroid carcinoma, thyroid cancer, the cancer of the esophagus, gallbladder cancer, cholangiocarcinoma, cervical carcinoma, Liver cancer, lung cancer (including but not limited to Small Cell Lung Cancer, non-small cell lung cancer), chorioepithelium cancer, osteosarcoma, tumor Ewing, soft group Knit one of sarcoma and cutaneum carcinoma or a variety of.

In the present invention, the specific example of the non-solid tumors (including haematological tumours) be may include but be not limited to: lymph Property leukaemia (including acute lymphoblastic leukemia, lymthoma, myeloma, chronic lymphocytic leukemia, Huo Qijin lymph Tumor, non-Hodgkin lymphoma, T cell chronic lymphatic leukemia, B cell chronic lymphatic leukemia), the relevant white blood of marrow Sick one of (including acute myeloid leukaemia, chronic myelogenous leukemia) and the relevant leukaemia of AIDs or a variety of.

In the present invention, unless otherwise indicated, term " selectively being replaced at an arbitrary position by one or more groups " is Refer to any one or multiple hydrogen atoms specified group substitution, condition of one or more atoms specified on group It is no more than the normal chemical valence of specified atom, the substitution is the common reasonable substitution in this field at an arbitrary position.

In the present invention, when with substituent group be bonded display in connection ring two atoms be bonded intersect when, then in this way The bonding any bonding annular atom on ring of substituent group.

Unless otherwise indicated, the following term occurred in description of the invention and claims has the meaning that

Term " alkyl " refers to saturated straight chain or branched hydrocarbyl comprising 1-20 carbon atom, preferably 1-10 carbon atom, More preferable 1-8,1-6,1-4 or 1-3 carbon atom, the representative example of alkyl includes but is not limited to: methyl, ethyl, positive third Base, isopropyl, normal-butyl, sec-butyl, tert-butyl, isobutyl group, amyl, hexyl, heptyl, octyl, nonyl, decyl, 4,4- diformazan Base amyl, 2,2,4- tri-methyl-amyls, undecyl, dodecyl and their various isomers etc..

Term " naphthenic base " refers to the saturation comprising 3-20 carbon atom or part unsaturated (comprising 1 or 2 double bond) One or more cyclic groups." monocyclic cycloalkyl " preferably 3-10 unit monocycle alkyl, more preferable 3-8 unit monocycle alkyl, such as: cyclopropyl Base, cyclobutyl, cyclopenta, cyclohexyl, suberyl, cyclooctyl, cyclodecyl, cyclo-dodecyl, cyclohexenyl group." polycyclic naphthene base " Including " bridged ring base ", " fused cycloalkyl " and " spiro cycloalkyl group ", the representative example of " bridged ring base " includes but is not limited to: borneol It is base, bicyclic [2.2.1] heptenyl, bicyclic [3.1.1] heptane base, bicyclic [2.2.1] heptane base, bicyclic [2.2.2] octyl, double Ring [3.2.2] nonyl, bicyclic [3.3.1] nonyl, bicyclic [4.2.1] nonyl and adamantyl etc.." fused cycloalkyl " Comprising the cycloalkyl ring being fused on phenyl, naphthenic base or heteroaryl, fused cycloalkyl includes but is not limited to: benzocyclobutene, 2,3- dihydro -1-H- indenes, 2,3- cyclopenta pyridine, 5,6- dihydro -4H- cyclopenta [B] thiophene, decahydronaphthalene etc.." spirocyclane Base " refers to that two monocyclic cycloalkyls share the bicyclic radicals that a carbon atom is formed, and spiro cycloalkyl group includes but is not limited to: spiral shell [2, 5] octyl, spiral shell [2,4] heptyl, spiral shell [4,5] decyl etc..The polycyclic naphthene base preferably comprises 7~12 carbon atoms.Monocycle cycloalkanes Base or polycyclic naphthene base can be connected on parent molecule by arbitrary 1 on ring or 2 carbon atom chains.

Term " Heterocyclylalkyl " refers to by carbon atom and the saturation or part insatiable hunger that form selected from hetero atoms such as nitrogen, oxygen or sulphur The non-aromatic cyclic radical of (including 1 or 2 double bond), this cyclic group can be one or more cyclic groups, in the present invention, miscellaneous Hetero atom number preferably 1,2,3 or 4 in naphthenic base, nitrogen, carbon or sulphur atom in Heterocyclylalkyl are optionally oxidized.Nitrogen-atoms It can optionally further be replaced by other groups and form tertiary amine or quaternary ammonium salt." monocyclic heterocycloalkyl " preferably 3-10 unit monocycle heterocycle Alkyl, more preferable 3-8 unit monocycle Heterocyclylalkyl.Such as: '-aziridinoAzelidinylAzacyclo- HeptylOxetanylmethoxyPyrrolidinylTetrahydrofuran baseMorpholinylThio-morpholinylThio-morpholinyl-S- oxidePiperidylPiperazinylHigh piperazine baseDeng." polycyclic Heterocyclylalkyl " includes " annelated heterocycles alkyl ", " spiro heterocyclic radical " and " bridge Heterocyclylalkyl "." annelated heterocycles alkyl " includes the monocyclic heterocycloalkyl for being fused to phenyl, naphthenic base, Heterocyclylalkyl or heteroaryl Ring, annelated heterocycles alkyl includes but is not limited to: 2,3- dihydro benzo furyls, 1,3- dihydroisobenzofuran base, indoline Base, 2,3- dihydrobenzo [b] thienyl, dihydrobenzo piperazine are muttered base, 1,2,3,4- tetrahydric quinoline group etc.." spiro heterocyclic radical " refers to two A Heterocyclylalkyl or a naphthenic base and a Heterocyclylalkyl share the bicyclic radicals that a carbon atom is formed, and spiro heterocyclic radical includes But it is not limited to: 5- azepine [2.5] octyl4- azepine [2.5] octyl4- azepine [2.4] heptyl4,7- diaza spiro [2.5] octylDeng." bridge Heterocyclylalkyl " refers to that monocyclic heterocycloalkyl is any Two annular atoms not being linked are connect that (described is straight by the straight chain group bridging that 1 to 3 additional carbon atoms or hetero atom are formed Chain group is selected from but not limited to :-CH₂-、-CH₂CH₂-、-CH₂O-、-CH₂NH-、-CH₂CH₂CH₂), bridge Heterocyclylalkyl includes but not It is limited to: (1R, 4R) -2,5- diazabicyclo [2.2.1] heptyl(1S, 4S) -2,5- diazabicyclo [2.2.1] Heptyl(1S, 4S) -2- oxygen -5- azabicyclo [2.2.1] heptyl(1R, 4R) -2- oxygen -5- azepine is double Ring [2.2.1] heptyl(1S, 4R) -2- azabicyclo [2.2.1] heptyl(1R, 4S) -2- azabicyclo [2.2.1] heptylDeng.Monocyclic heterocycloalkyl and polycyclic Heterocyclylalkyl can pass through arbitrary 1 on ring or 2 ring originals Subchain is connected on parent molecule.Above-mentioned annular atom refers in particular to the carbon atom and/or nitrogen-atoms of composition ring skeleton.

Term " cycloalkyl-alkyl ", which refers to, to be connected between naphthenic base and mother nucleus structure by alkyl." naphthenic base alkane as a result, Base " includes the definition of abovementioned alkyl and naphthenic base.

Term " hetercycloalkylalkyl ", which refers to, to be connected between Heterocyclylalkyl and mother nucleus structure by alkyl." heterocycle alkane as a result, Base alkyl " includes the definition of abovementioned alkyl and Heterocyclylalkyl.

Term " alkoxy " refers to has the carbon atom number purpose cyclic annular or acyclic alkyl groups by what oxygen bridge connected, packet Containing alkyl oxy, cycloalkyl oxy and Heterocyclylalkyl oxygroup." alkoxy " includes abovementioned alkyl, Heterocyclylalkyl and cycloalkanes as a result, The definition of base.

Term " hydroxy alkyl " refers to that any one or more hydrogen atoms are replaced hydroxyl on alkyl, including but unlimited In :-CH₂OH、-CH₂CH₂OH、-CH₂CH₂C(CH₃)₂OH、-CH(CH₃)₂OH。

Term " alkylthio group " refers to has the carbon atom number purpose cyclic annular or acyclic alkyl groups by what sulphur bridge connected, institute Stating alkylthio group includes alkyl sulfenyl, cycloalkylsulfanyl and Heterocyclylalkyl sulfenyl." alkylthio group " includes abovementioned alkyl, heterocycle as a result, The definition of alkyl and naphthenic base.

Term " alkenyl " refers to the straight chain containing at least one carbon-carbon double bond, branch or cyclic annular non-aromatic alkyl.It wherein can be with There are 1-3 carbon-carbon double bonds, preferably there is 1 carbon-carbon double bond.Term " C_2-4Alkenyl " refers to the alkenyl with 2-4 carbon atom, Term " C_2-6Alkenyl " refers to the alkenyl with 2-6 carbon atom, including vinyl, acrylic, cyclobutenyl, 2- methyl butene base And cyclohexenyl group.The alkenyl can be substituted.

Term " alkynyl " refers to the straight chain containing at least one triple carbon-carbon bonds, branch or cyclic hydrocarbon group.Wherein may exist Preferably there are 1 triple carbon-carbon bonds in 1-3 triple carbon-carbon bonds.Term " C_2-6Alkynyl " refers to the alkynyl with 2-6 carbon atom, including Acetenyl, propinyl, butynyl and 3- methylbutynyl.

Term " aryl " refers to any stable 6-20 unit monocycle or Ppolynuclear aromatic group, such as: phenyl, naphthalene, four Hydrogen naphthalene, indanyl or xenyl etc..

Term " heteroaryl " refers to that the carbon atom at least one ring is formed by the hetero atom displacement selected from nitrogen, oxygen or sulphur Aromatic group, can be 5-7 unit monocycle structure or 7-20 condensed ring structure, preferably 5-6 unit's heteroaryl.In the present invention, Hetero atom number preferably 1,2 or 3, including but not limited to: pyridyl group, pyrimidine radicals, piperazinyl, (2H) -one of pyridazine -3 base, furans Base, thienyl, thiazolyl, pyrrole radicals, imidazole radicals, pyrazolyl, oxazolyl, isoxazolyl, 1,2,5- oxadiazoles base, 1,2,4- are disliked Di azoly, 1,3,4- oxadiazoles base, 1,3,4- thiadiazoles, 1,2,4- triazol radical, 1,2,3- triazol radical, tetrazole base, Yin Oxazolyl, iso indazolyl, indyl, isoindolyl, benzofuranyl, benzothienyl, benzo [d] [1,3] dioxolanyl, benzene Benzothiazolyl, benzoxazolyl, benzimidazolyl, 1H- benzo [d] [1,2,3] triazol radical, quinolyl, isoquinolyl, isoquinoline Quinoline ketone group, quinazolyl, 1H- pyrrolo- [2,3-b] pyridyl group, 4- hydroxy thiophene simultaneously [3,2-c] pyridyl group, 4,5- dihydro -4- Oxo furans [3,2] pyridyl group, 4- hydroxyl -5- azaindolyl, furans [2,3-c] and (6H) -one of pyridine -7 base, thiophene [2, 3-c] and pyridine -7 (6H) -one base etc..

Term " aryl alkyl ", which refers to, to be connected between aryl and mother nucleus structure by alkyl." aryl alkyl " includes as a result, The definition of abovementioned alkyl and aryl.

Term " heteroaryl alkyl ", which refers to, to be connected between Heterocyclylalkyl and mother nucleus structure by alkyl." heteroaryl alkane as a result, Base " includes the definition of abovementioned alkyl and heteroaryl.

Term " halogen " indicates fluorine, chlorine, bromine or iodine.

Term " halogenated alkyl " refers to the alkyl arbitrarily replaced by halogen.As a result, " halogenated alkyl " include the above halogen and The definition of alkyl.

Term " halogenated alkoxy " refers to the alkoxy arbitrarily replaced by halogen.More than " halogenated alkoxy " include as a result, The definition of halogen and alkoxy.

Term " amino " refers to-NH₂, term " alkylamino " refers to that at least one hydrogen atom is replaced alkyl on amino, Including but not limited to :-NHCH₃、-N(CH₃)₂、-NHCH₂CH₃、-N(CH₂CH₃)₂.Term " aminoalkyl " refers to any on alkyl One hydrogen atom is replaced amino, including but not limited to :-CH₂NH₂、-CH₂CH₂NH₂." aminoalkyl " and " alkane ammonia as a result, Base " includes the definition of abovementioned alkyl and amino.Term " aminocycloalkyl " refers to that any one hydrogen atom is by amino in naphthenic base It is replaced, including but not limited to:" ammonia as a result, Basic ring alkyl " includes the definition of above-mentioned naphthenic base and amino.

Term " nitro " refers to-NO₂。

Term " cyano " refers to-CN.

Term " sulfydryl " refers to-SH.

" room temperature " of the present invention refers to 15-30 DEG C.

The isotope substitutive derivative include: in Formulas I arbitrary hydrogen atom replaced by 1-5 D-atom it is same The isotope substitutive derivative or formula that arbitrary carbon atom is replaced by 1-3 14 atom of carbon in the plain substitutive derivative in position, Formulas I The isotope substitutive derivative that arbitrary oxygen atom is replaced by 1-3 18 atom of oxygen in I.

" prodrug ", which refers to, is converted into original activity compound after compound is metabolized in vivo.Typically say, it is preceding Medicine is that perhaps specific activity parent compound activity is small but can provide convenient operation, is administered or improve generation for inert matter Thank to characteristic.

" pharmaceutically acceptable salt " of the present invention is in Berge, et al., " Pharmaceutically Acceptable salts ", J.Pharm.Sci., 66,1-19 are discussed in (1977), and for Pharmaceutical Chemist be it is aobvious and Be clear to, the salt is substantially avirulent, and pharmacokinetic property needed for capable of providing, palatability, absorption, distribution, Metabolism or excretion etc..Compound of the present invention can have acidic-group, basic group or amphiprotic group, typically pharmaceutically Acceptable salt includes the salt that compound and acid reaction are prepared through the invention, such as: hydrochloride, hydrobromate, sulfuric acid Salt, pyrosulfate, disulfate, sulphite, bisulfites, phosphate, dibasic alkaliine, dihydric phosphate, metaphosphoric acid Salt, pyrophosphate, nitrate, acetate, propionate, caprate, caprylate, formates, acrylates, isobutyrate, caproic acid Salt, enanthate, oxalates, malonate, succinate, suberate, benzoate, methyl benzoic acid salt, phthalic acid Salt, maleate, mesylate, tosilate, (D, L)-tartaric acid, citric acid, maleic acid, (D, L)-malic acid are rich Horse acid, succinic acid, succinate, lactate, fluoroform sulphonate, naphthalene -1- sulfonate, mandelate, acetonate, stearic acid Salt, ascorbate, salicylate.When the compounds of this invention contains acidic-group, pharmaceutically acceptable salt can be with It include: alkali metal salt, such as sodium or sylvite；Alkali salt, such as calcium or magnesium salts；Organic alkali salt, for example, with ammonia, alkyl ammonia The salt of the formation such as class, hydroxy alkyl Ammonia, amino acid (lysine, arginine), N-METHYL-ALPHA-L-GLUCOSAMINE.

" isomers " of the present invention refer to formula of the invention (I) compound can have asymmetric center and racemic modification, Racemic mixture and single diastereoisomer, all these isomers, including stereoisomer, geometric isomer include In the present invention.In the present invention, compound of formula I or its salt in the form of stereomeric (for example, its contain it is one or more not Symmetric carbon atom) in the presence of, individual stereoisomer (enantiomter and diastereoisomer) and their mixture It is included within the scope of the invention.The independent isomers of the compound or salt that are indicated the invention also includes Formulas I, and with wherein one The mixture of the isomers of a or multiple chiral centers reversion.Scope of the invention include that the mixture of stereoisomer, and The enantiomter or enantiomter of purifying/diastereoisomer enrichment mixture.The present invention includes all enantiomerisms The mixture of the stereoisomer of body and all possible various combination of non-corresponding isomers.The present invention includes institute defined above There are the whole combinations and subset of the stereoisomer of specific group.The invention also includes compound of formula I or the geometrical isomerisms of its salt Body, the geometric isomer include cis-trans-isomer.

Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can any combination to get the present invention it is each preferably Example.

The reagents and materials used in the present invention are commercially available.

Detailed description of the invention

Attached drawing 1 is compound 7-2-1 (15mg/kg, 30mg/kg, qd) and AZD1775 (60mg/kg, bid) in human lung cancer Tumor volume change curve in H1299 xenograft tumor models.

Specific embodiment

The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to the reality It applies among a range.In the following examples, the experimental methods for specific conditions are not specified, according to conventional methods and conditions, or according to quotient The selection of product specification.

The structure of all compounds of the present invention can by nuclear magnetic resonance (¹H NMR) and/or Mass Spectrometer Method (MS) identification.

¹H nmr chemical is displaced (δ) with PPM record (10^-6).NMR is carried out by Bruker AVANCE-400 spectrometer.It closes Suitable solvent is deuterated chloroform (CDCl₃), deuterated methanol (CD₃OD), deuterated dimethyl sulfoxide (DMSO-d₆), tetramethylsilane conduct Internal standard (TMS).

Low resolution mass spectrometry (MS) is measured by Agilent 1200HPLC/6120 mass spectrograph, using XBridge C18,4.6 × 50mm, 3.5 μm, condition of gradient elution 1:80-5% solvent A₁With 20-95% solvent B₁(1.8 minutes), then 95% solvent B₁ With 5% solvent A₁(3 minutes or more), percentage are the percentage by volume that a certain solvent accounts for total solvent volume.Solvent A₁: 0.01% The aqueous solution of trifluoroacetic acid (TFA)；Solvent B₁: the acetonitrile solution of 0.01% trifluoroacetic acid；Percentage is the body that solute accounts for solution Product percentage.Condition of gradient elution 2:80-5% solvent A₂With 20-95% solvent B₂(1.5 minutes), then 95% solvent B₂With 5% solvent A₂(2 minutes or more), percentage are the percentage by volume that a certain solvent accounts for total solvent volume.Solvent A₂: the carbon of 10mM The aqueous solution of sour hydrogen ammonium；Solvent B₂: acetonitrile.

All compounds of the present invention can pass through high performance liquid chromatograph, silica gel column chromatography, thin-layer chromatography chromatography or fast Fast column chromatography chromatogram is separated.

High performance liquid chromatograph (prep-HPLC) uses Shimadzu LC-20 preparative liquid chromatography, chromatographic column are as follows: waters XbridgePre C18,10um, 19mmx250mm.Separation condition 1: mobile phase A: 0.05% trifluoroacetic acid aqueous solution, mobile phase B: acetonitrile；Mobile phase B is 40%, elution time: 20 minutes.Separation condition 2: mobile phase A: 10mmol/L ammonium hydrogen carbonate is water-soluble Liquid, Mobile phase B: acetonitrile；Gradient elution Mobile phase B is from 25% to 80%, and elution time 30 minutes.Separation condition 3: mobile phase A: 0.05% aqueous hydrochloric acid solution, Mobile phase B: acetonitrile；Gradient elution Mobile phase B is from 75% to 25%, elution time: 30 minutes.Inspection Survey wavelength: 214nm&254nm；Flow velocity: 15.0mL/ minutes.

Each compound of the specific embodiment of the invention 37~75 can purify to obtain by prep-HPLC, use separation condition 1 Obtained compound is trifluoroacetate, and the compound that use condition 2 obtains is free alkali, the compound that use condition 3 obtains For hydrochloride.

Rapid column chromatography (Flash column chromatography) (flash system/Cheetah^TM) use Agela Technologies MP200, matching used splitter are Flash columm Silica-CS (80g), Cat No.CS140080-0。

Thin-layer chromatography chromatography (prep-TLC) is the new promise chemical industry in Yantai, 0.2 ± 0.03mm of coating layer thickness, specification 20 × 20cm.Silica gel column chromatography generally uses Yantai Huanghai Sea 200-300 mesh silica gel as carrier.

The eluant, eluent or solvent that silica gel column chromatography, thin-layer chromatography chromatography or rapid column chromatography chromatography use are selected from One of ethyl acetate, methanol, methylene chloride, petroleum ether and n-hexane are a variety of.

Nitrogen atmosphere described in the embodiment of the present invention is provided with hydrogen balloon.

Embodiment 1: the synthesis of compound 1.3

Step 1: by 5- nitroindoline (1g, 6.2mmol), dimethylamino-chloroethane hydrochloride (1.3g, 9.3mmol) and nothing N,N-Dimethylformamide (DMF) (15mL) mixture of aqueous carbonate potassium (3.4g, 25mmol) stirs 3 hours at 70 DEG C.? To mixture be cooled to room temperature, be subsequently poured into ice water (50mL) stirring, mixture is extracted with ethyl acetate (20mL × 3), closes And organic phase, water, saturated common salt water washing are successively used, organic phase is dry with anhydrous sodium sulfate, filtering, is concentrated, residue silicon Plastic column chromatography (methylene chloride/methanol=20/1) purify compound 1.2 (700mg, yield: 32%) be colourless oil liquid.

Step 2: the methanol (20mL) that compound 1.2 (700mg, 3.0mmol) is added to palladium carbon (100mg, 10%) is mixed It closes in object, is replaced reaction system 3 times with hydrogen, obtained mixture is stirred overnight at room temperature under a hydrogen atmosphere, reaction solution silicon Diatomaceous earth Filtration of catalyst, filtrate be concentrated to get 1- (2- (dimethylamino) ethyl) -1H- indoles -5- amine (compound 1.3, 600mg, yield: 98%) being brown oil.m/z:[M+H]⁺204.0。

Embodiment 2: the synthesis of compound 1.7

Step 1: under condition of ice bath, being added portionwise into DMF (100mL) solution of 5- nitroindoline (4g, 24.7mmol) Sodium hydrogen (3.95g, 60%, 98.8mmol), obtained mixture are slowly increased to room temperature and stir 2 hours.Then by reaction solution ice Bath cooling, is added ethylene bromohyrin (12.3g, 98.4mmol).Mixture continues to be stirred at room temperature 24 hours.Then by reactant System is diluted with ethyl acetate, successively uses water, saturated common salt water washing, and organic phase is dry with anhydrous sodium sulfate, filtering, is concentrated, residual Stay object with silica gel column chromatography (methylene chloride/methanol=20/1) purify compound 1.4 (2.1g, yield: 41%) be colorless oil Shape object.

Step 2: under condition of ice bath, adding in batches into methylene chloride (20mL) solution of compound 1.4 (1g, 4.85mmol) Enter Dai Si-Martin reagent (6.2g, 14.7mmol).Obtained mixture is warmed to room temperature stirring 3 hours.Then reaction solution is used Saturated salt solution (20mL × 2) washing, anhydrous sodium sulfate dry, filter, are concentrated to give compound 1.5 (810mg, yield: 82%) For yellow solid.

Step 3: to the methanol of compound 1.5 (400mg, 1.96mmol) and azetidine (168mg, 2.94mmol) In (10mL) solution plus after a drop acetic acid, reaction system is stirred at room temperature 30 minutes.Cyano is added portionwise into reaction solution Sodium borohydride (369mg, 5.88mmol).Obtained mixture is continued to stirring 1 hour at room temperature.Then reaction solution is direct Concentration, residue purify to obtain compound 1.6 (270mg, yield: 57%) with silica gel column chromatography (methylene chloride/methanol=10/1) For yellow solid.

Step 4: being mixed to the ethyl acetate (5mL) and tetrahydrofuran (5mL) of compound 1.6 (270mg, 1.10mmol) molten Palladium charcoal (50mg, 10%) is added in liquid, obtained mixture is replaced 3 times with hydrogen, and then mixture under a hydrogen atmosphere stir by room temperature It mixes 3 hours.Reaction system is filtered with diatomite, and filtrate decompression is concentrated to get 1- (2- (azetidine -1- base) ethyl) -1H- (compound 1.7,270mg, yield: 100%) being yellow solid to indoles -5- amine.

Embodiment 3: the synthesis of compound 1.8~1.9

Using the synthetic method of compound 1.7, the azetidine in step 3 is replaced with into pyrrolidines and obtains 1- (2- (pyrrole Cough up alkane -1- base) ethyl) -1H- indoles -5- amine (compound 1.8), m/z:[M+H]⁺230.0。

Using the synthetic method of compound 1.7, the azetidine in step 3 is replaced with into piperidines and obtains 1- (2- (piperazine Pyridine -1- base) ethyl) -1H- indoles -5- amine (compound 1.9), m/z:[M+H]⁺244.0。

Embodiment 4: the synthesis of compound 2.5

Step 1: being slowly added to sodium hydrogen into DMF (10.0mL) solution of 5- nitroindoline (1.01g, 6.2mmol) (0.5g, 60%, 12.4mmol).Reaction system is stirred at room temperature 30 minutes, then 1-Boc-4- mesyloxy piperidines (1.72g, 6.2mmol) is added in above-mentioned reaction system, and reaction system is stirred 12 hours at 100 DEG C.Then, it adds water and quenches It goes out reaction, is extracted with ethyl acetate.Merge organic phase and use saturated common salt water washing, separation organic phase simultaneously with anhydrous sodium sulfate do Dry, filtering, concentration, residue silica gel column chromatography (35% ethyl acetate petroleum ether solution) purifying obtain compound 2.2 (0.85g, yield: 75%) being yellow oily.m/z:[M+H]⁺346.0。

Step 2: the trifluoroacetic acid (2.0mL) of compound 2.2 (0.85g, 2.4mmol) and methylene chloride (4.0mL) is mixed It closes solution to be stirred at room temperature 1 hour, it is yellow that reaction system, which is then concentrated under reduced pressure to give compound 2.3 (0.55g, crude product), Grease.m/z:[M+H]⁺246.0。

Step 3: by compound 2.3 (0.50g, 2.0mmol), 37% formaldehyde (0.33g, 4.0mmol), triethylamine 1,2- dichloroethanes (10mL) solution of (0.1mL), acetic acid (2 drop) is stirred at room temperature 1 hour.Then sodium cyanoborohydride (0.39g, 6.0mmol) is added in above-mentioned reaction system, and obtained mixture is stirred at room temperature 2 hours again.Use hydroxide Sodium water solution (1.0M) quenching reaction, obtained mixture are extracted with ethyl acetate after being diluted with water.Merge organic phase and with satisfy And brine It, separation organic phase are simultaneously dried, filtered with anhydrous sodium sulfate, are concentrated, residue silica gel column chromatography (5% Methanol dichloromethane solution) purifying obtain compound 2.4 (0.35g, yield: 66%) be yellow solid.m/z:[M+H]⁺ 260.0。

Step 4: into methanol (10.0mL) solution of compound 2.4 (0.35g, 1.3mmol) be added palladium carbon (0.05g, 10%), reaction system is replaced 3 times with hydrogen, and then reaction system is stirred at room temperature 12 hours under a hydrogen atmosphere.Filter, depressurize it is dense It is faint yellow solid that contracting, which obtains 1- (1- methyl piperidine -4- base) -1H- indoles -5- amine (compound 2.5,0.10g, crude product),.m/z: [M+H]⁺230.2。

Embodiment 5: the synthesis of compound 2.6~2.9

Using the synthetic method of compound 2.5, the 1-Boc-4- mesyloxy piperidines in step 1 is replaced with into 1- respectively Boc-3- mesyloxy pyrrolidines, 1-Boc-3- bromine cyclobutane, 1-Boc-3- mesyloxy piperidines obtain compound 2.6, 2.7,2.9:

Using the synthetic method of compound 2.5, the formaldehyde in step 3 is replaced with into acetone and obtains compound 2.8:

Number	Title	MS
			2.6	1- (1- methylpyrrolidin- 3- yl) -1H- indoles -5- amine	m/z:[M+H]⁺216.0
2.7	1- (1- methyl azetidine -3- base) -1H- indoles -5- amine	m/z:[M+H]⁺202.2
			2.8	1- (1- isopropyl piperidin-4-yl) -1H- indoles -5- amine	m/z:[M+H]⁺258.2
2.9	1- (1- methyl piperidine -3- base) -1H- indoles -5- amine	m/z:[M+H]⁺230.2

Embodiment 6: the synthesis of compound 2.10~2.11

Using the synthetic method of compound 2.5, the 5- nitroindoline in step 1 is replaced with into 5- nitro -1H- pyrrolo- 37% formaldehyde in [2,3-] pyridine, step 3 replace with acetone obtain 1- (1- isopropyl piperidin-4-yl) -1H- pyrrolo- [2, 3-b] pyridin-5-amine (compound 2.10).

Using the synthetic method of compound 2.5, the 5- nitroindoline in step 1 is replaced with into 5- nitro -1H- pyrrolo- [2,3-b] pyridine obtains 1- (1- methyl piperidine -4- base) -1H- pyrrolo- [2,3-b] pyridin-5-amine (compound 2.11).

Embodiment 7: the synthesis of compound 2.15

Step 1: by 5- nitroindoline (1.62g, 10.0mmol) and 4- THP trtrahydropyranyl methanesulfonates (3.6g, It 20.0mmol) is dissolved in DMF (20mL), cesium carbonate (6.5g, 20.0mmol) then is added, obtained mixture is at 100 DEG C Under be stirred overnight, after then cooling to room temperature use water (100mL) quenching reaction, be extracted with ethyl acetate, organic phase separation after use Anhydrous sodium sulfate is dry, is concentrated under reduced pressure, and residue silica gel column chromatography (petrol ether/ethyl acetate=2/1) purifying obtains chemical combination (950mg, yield: 39%) being faint yellow solid to object 2.14.m/z:[M+H]⁺247.3。

Step 2: into methanol (30mL) solution of compound 2.14 (950mg, 3.8mmol) be added palladium carbon (50mg, 10%), reaction system is replaced 3 times with hydrogen, is then stirred 30 minutes under a hydrogen atmosphere.Mixture is filtered through diatomite, is filtered Liquid be concentrated under reduced pressure after obtain 1- (tetrahydro -2H- pyrans -4- base) -1H- indoles -5- amine (compound 2.15,710mg, yield: It 85%) is brown oil.m/z:[M+H]⁺217.2。

Embodiment 8: the synthesis of compound 3.1

Using the synthetic method of compound 2.5, it is with 5- nitro -1H- benzimidazole and 1-Boc-3- bromine azetidine Starting material reacts to obtain 1- (1- methyl azetidine -3- base) -1H- benzo [d] imidazoles -5- amine (compound 3.1).m/z: [M+H]⁺203.2。

Embodiment 9: the synthesis of compound 4.2

Step 1: under condition of ice bath, by acetic anhydride (49.9mg, 0.49mmol) be added to compound 2.3 (0.1g, 0.41mmol) and in methylene chloride (5mL) solution of triethylamine (82.4mg, 0.82mmol), reaction system is stirred at room temperature 2 Hour.Then it is diluted with methylene chloride, mixture water and saturated common salt water washing, separate organic phase and is done with anhydrous sodium sulfate It is dry, it filters, being concentrated to get compound 4.1, (0.1g, yield: 85%) being yellow solid.

Step 2: using the synthetic method of 2.5 step 4 of compound, being reacted with compound 4.1 (100mg, 0.35mmol) To 1- (4- (5- amino -1H- indoles -1- base) piperidin-1-yl) ethyl ketone, (compound 4.2,80mg, yield: 89%) being faint yellow Solid.

Embodiment 10: the synthesis of compound 5.2

Step 1: 2,2,2- trifluoroethyl trifluoromethayl sulfonic acid esters (284mg, 1.22mmol) are added to compound 2.3 In tetrahydrofuran (10mL) solution of (0.1g, 0.41mmol) and triethylamine (124mg, 1.22mmol), reaction system is at 70 DEG C Under be stirred overnight.Then reaction solution is cooled to room temperature, is directly concentrated under reduced pressure, residue silica gel column chromatography (10% methanol Dichloromethane solution) purifying obtain compound 5.1 (95mg, yield: 71%) be colourless liquid.m/z:[M+H]⁺288.2。

Step 2: using the synthetic method of 2.5 step 4 of compound, being obtained with compound 5.1 (95mg, 0.29mmol) reaction (compound 5.2,85mg, yield: 100%) being yellowish to 1- (1- (2,2,2- trifluoroethyl) piperidin-4-yl) -1H- indoles -5- amine Color solid.

Embodiment 11: the synthesis of compound 6.6

Step 1: under condition of ice bath, the DMF (50mL) to 5- nitroindoline -2- Ethyl formate (2.34g, 10.0mmol) is molten Sodium hydrogen (600mg, 60%, 15.0mmol) is added in liquid, obtained mixture is stirred at room temperature 0.5 hour, and N- is then added Boc- bromine ethamine (2.92g, 13.0mmol), reaction system are stirred overnight at 70 DEG C.Then dilute with ethyl acetate (100mL) It releases, organic phase saturated common salt water washing.Separation organic phase is simultaneously dried, filtered with anhydrous sodium sulfate, is concentrated under reduced pressure.Residue is used Silica gel column chromatography (petrol ether/ethyl acetate=4/1) purifying obtains compound 6.1, and (3.05g, yield: 81%) being pale yellow colored solid Body.m/z:[M-Boc]⁺278.1。

Step 2: the trifluoroacetic acid (4mL) of compound 6.1 (3.05g, 8.1mmol) and methylene chloride (20mL) being mixed molten Liquid is stirred at room temperature 2 hours, then with the sodium bicarbonate aqueous solution quenching reaction of saturation, is diluted with water, obtained mixture It is extracted with dichloromethane.Merge organic phase and use saturated common salt water washing, separation organic phase simultaneously with anhydrous sodium sulfate dry, mistake Filter is concentrated under reduced pressure, and residue silica gel column chromatography (methylene chloride/methanol=10/1) purifying obtains compound 6.2, and (1.1g is produced Rate: 49%) being faint yellow solid.m/z:[M+H]⁺278.2。

Step 3: the ethanol solution (20mL) of compound 6.2 (1.1g, 4.0mmol) and sodium methoxide (643mg, 11.9mmol) It is stirred 2 hours at 55 DEG C.Then saturated salt solution is added into reaction system, is extracted with dichloromethane.Merge organic phase, and Dried, filtered with anhydrous sodium sulfate, be concentrated under reduced pressure compound 6.3 (361mg, yield: 39%) be yellow solid.m/z:[M+ H]⁺232.4。

Step 4: under condition of ice bath, into DMF (20mL) solution of compound 6.3 (310mg, 1.3mmol), sodium hydrogen is added (81mg, 2.0mmol, 60%), obtained mixture are stirred at room temperature 15 minutes, be then added iodomethane (285mg, 2.0mmol), reaction system continues stirring 30 minutes at room temperature.Then it is diluted with ethyl acetate (100mL), organic phase is used full And brine It.Separation organic phase and dried, filtered with anhydrous sodium sulfate, be concentrated under reduced pressure compound 6.4 (358mg, slightly Product) it is yellow solid.m/z:[M+H]⁺246.4。

Step 5: palladium carbon (180mg, 10%) is added into methanol (15mL) solution of compound 6.4 (358mg), reactant After system is replaced 3 times with hydrogen, stir 0.5 hour under a hydrogen atmosphere.Reaction solution is filtered with diatomite, and filtrate decompression concentration obtains Compound 6.5 (277mg, crude product) is red solid.m/z:[M+H]⁺216.2。

Step 6: under condition of ice bath, into methyl tertiary butyl ether(MTBE) (30mL) solution of compound 6.5 (275mg, 1.3mmol) The tetrahydrofuran solution (1.95mL, 4.9mmol, 2.5M) of Lithium Aluminium Hydride is added dropwise, reaction system stirs 5 hours at 60 DEG C.Then With the aqueous sodium potassium tartrate quenching reaction of saturation, ethyl acetate (100mL) dilution, organic phase saturated common salt water washing. Separation organic phase is simultaneously dried, filtered with anhydrous sodium sulfate, 2- methyl-1 is concentrated under reduced pressure to obtain, and 2,3,4- tetrahydropyridines are simultaneously [1,2-a] (6.6,248mg, 3 step yield of compound: 96%) being red solid to indoles -8- amine.m/z:[M+H]⁺202.2。

Embodiment 12: the synthesis of compound 7.6

Step 1: at -10 DEG C, isobutyl chlorocarbonate (10.2mL, 78mmol) being added drop-wise to 1,1- cyclopropyl diformate mono In tetrahydrofuran (200mL) solution of methyl esters (10g, 69.4mmol) and triethylamine (10.8mL, 78mmol), and at -10 DEG C Stirring 1 hour, rises to 0 DEG C for reaction solution, filters out solid in reaction solution, filtrate is stand-by.Under condition of ice bath, by sodium borohydride (7.87g, 208mmol) is added in the mixed solution of tetrahydrofuran (100mL) and water (25mL), is then added drop-wise to above-mentioned filtrate In, time for adding 1 hour.Obtained mixture continuation is stirred 1 hour under condition of ice bath.Reaction solution is poured into 20% lemon It in lemon acid ice water solution, stirs 5 minutes, organic solution is removed in concentration, and water phase is extracted with ethyl acetate, and merges organic phase, successively Washed with water and saturated common salt, anhydrous sodium sulfate is dry, filtering, be concentrated under reduced pressure to give compound 7.1 (6.9g, yield: It 77%) is oily liquids.

Step 2: under condition of ice bath, by methylsufonyl chloride (7.4g, 64.5mmol) be added drop-wise to compound 7.1 (5.6g, 43mmol) and in methylene chloride (100mL) solution of triethylamine (8.7mL, 86mmol), obtained mixture is stirred at room temperature 3 hours.Reaction solution is quenched with methylene chloride, successively with hydrochloric acid (1.0M), water and saturated common salt water washing, the anhydrous sulphur of organic phase Sour sodium is dry, filter, being concentrated under reduced pressure to give compound 7.2, (8.9g, yield: 100%) being white solid.

Step 3: compound 7.2 (10.7g, 51.5mmol) is added to 5- nitroindoline (5.56g, 34.3mmol) and carbon In DMF (60mL) solution of sour caesium (33.5g, 103mmol), obtained mixture is stirred overnight at 100 DEG C, and reaction solution is cooling It to room temperature and is poured into water, water phase is extracted with ethyl acetate (20mL × 3), merges organic phase, successively uses water, saturated salt solution Washing, organic phase be concentrated under reduced pressure, residue silica gel column chromatography purify (petrol ether/ethyl acetate=5/1) obtain compound 7.3 (8g, yield: 72%) being yellow solid.m/z:[M+H]⁺275.2。

Step 4: the aqueous solution (10mL) of a hydronium(ion) lithia (475mg, 11.3mmol) is added drop-wise to compound 7.3 In tetrahydrofuran (30mL) solution of (1.24g, 4.5mmol), reaction system is stirred at room temperature overnight, and is concentrated under reduced pressure and is removed four Hydrogen furans, water phase are first washed with petrol ether/ethyl acetate mixed solution (1/1), then with the aqueous citric acid solution tune pH of saturation =3, water phase is extracted with ethyl acetate (10mL × 3), merge organic phase and use water and saturated common salt water washing, anhydrous sodium sulfate do It is dry, filter, be concentrated under reduced pressure to give compound 7.4 (920mg, yield: 79%) be yellow solid.

Step 5: under condition of ice bath, diphenyl phosphate azide (605mg, 2.2mmol) being added drop-wise to compound 7.4 In toluene (15mL) solution of (520mg, 2.0mmol) and triethylamine (607mg, 6.0mmol), reaction system stirs 2 at 0 DEG C Hour, then reaction system is warmed to room temperature and continues stirring 4 hours, the tert-butyl alcohol (10mL) is added in reaction system and is warming up to It flows back and is stirred overnight.Then reaction solution is cooled to room temperature, is concentrated, dissolves the residue in methylene chloride (20mL), successively use Saturated sodium bicarbonate aqueous solution, water, saturated common salt water washing, are concentrated organic phase, and residue silica gel column chromatography purifies (petroleum Ether/ethyl acetate=5/1) obtaining compound 7.5, (460mg, yield: 69%) being yellow solid.m/z:[M-55]⁺276.2。

Step 6: compound 7.5 (460mg, 1.39mmol) and palladium carbon (100mg, 10%) are mixed in methanol (30mL) solution In.Reaction system is replaced 3 times with hydrogen, is then stirred 2 hours under a hydrogen atmosphere.It is filtered with diatomite, gained filtrate decompression is dense Contracting obtain (1- ((5- amino -1H- indoles -1- base) methyl) cyclopropyl) aminomethyl tert-butyl ester (compound 7.6,308mg, yield: It 74%) is brown solid.m/z:[M+H]⁺302.2。

Embodiment 13: the synthesis of compound 7.8

Step 1: under condition of ice bath, by sodium hydrogen (121mg, 3.0mmol, 60%) be added to compound 7.5 (500mg, In DMF (10mL) solution 1.5mmol), after reaction system stirs 0.5 hour, iodomethane (639mg, 4.5mmol) is added to In above-mentioned reaction system, reaction solution is poured into ice water after being stirred at room temperature 2 hours, water phase be extracted with ethyl acetate (20mL × 3), merge organic phase, successively use water, saturated common salt water washing, organic phase, residue silica gel column chromatography (petroleum ether/second is concentrated Acetoacetic ester=5/1) purifying obtain compound 7.7 (362mg, yield: 70%) be oily liquids.m/z:[M+H]⁺290.2。

Step 2: by methanol (15mL) mixture of compound 7.7 (362mg, 1.0mmol) and palladium carbon (100mg, 10%) It is replaced 3 times, is then stirred at room temperature under a hydrogen atmosphere 2 hours with hydrogen.Reaction solution is filtered with diatomite, filtrate decompression is concentrated to give (1- ((5- amino -1H- indoles -1- base) methyl) cyclopropyl) (methyl) aminomethyl tert-butyl ester (compound 7.8,315mg, yield: It 100%) is brown solid.m/z:[M+H]⁺316.2。

Embodiment 14: the synthesis of compound 8.3

Step 1: methanol (50mL), tetrahydrofuran (20mL) to 5- nitroindoline -2- carboxylic acid, ethyl ester (5g, 21.3mmol) Sodium hydroxide (2.5g, 64.0mmol) is added in the mixture solution of water (10mL), it is small that reaction system is stirred at room temperature 16 When.Water (100mL) is added to dilute, then water phase is adjusted pH=6 with hydrochloric acid (2.0M) with petroleum ether extraction (50mL × 2) by water phase, It is extracted with ethyl acetate (50mL × 3), is dried, filtered, depressurized with saturated common salt water washing, anhydrous sodium sulfate after merging organic phase Being concentrated to get compound 8.1, (4g, yield: 91%) being faint yellow solid.m/z:[M+H]⁺207.0。

Step 2: by compound 8.1 (4g, 19.4mmol), dimethylamine hydrochloride (2.4g, 29.1mmol), HATU DMF (50mL) solution of (11.0g, 29.1mmol) and n,N-diisopropylethylamine (9.6mL, 58.2mmol) is stirred at room temperature 3 hours, water (150mL) quenching reaction is added, obtained mixture is extracted with ethyl acetate (100mL × 3), after merging organic phase It successively dried, filtered, be concentrated under reduced pressure with water, saturated common salt water washing, anhydrous sodium sulfate, residue with Ethyl acetate petroleum ether is molten Liquid (10%) mashing, compound 8.2 is obtained after filtering, filter cake vacuum drying, and (1.5g, yield: 33%) being faint yellow solid.m/ z:[M+H]⁺234.2。

Step 3: at room temperature, being added dropwise into anhydrous tetrahydro furan (5mL) solution of compound 8.2 (310mg, 1.3mmol) Then reaction system is stirred 2 hours at 70 DEG C, is cooled to room temperature by the tetrahydrofuran solution (4.0mL, 1.0M) of lithium aluminium hydride reduction, And with sodium hydrate aqueous solution (2.0M, 10mL) quenching reaction, then it is extracted with ethyl acetate (50mL × 3), merges organic phase Dried, filtered, be concentrated under reduced pressure with saturated common salt water washing, anhydrous sodium sulfate afterwards, residue with Flash column chromatograph (methylene chloride/ Methanol=10/1) purifying obtain 2- ((dimethylamino) methyl) -1H- indoles -5- amine (compound 8.3,34mg, yield 14%) For crocus grease.m/z:[M+H]⁺190.2；¹H NMR(400MHz,DMSO-d₆): δ 10.46 (s, 1H), 6.99 (d, J= 8.4Hz, 1H), 6.60 (s, 1H), 6.41 (d, J=8.4Hz, 1H), 5.96 (s, 1H), 4.38 (br.s, 2H), 3.44 (s, 2H), 2.16(s,6H)。

Embodiment 15: the synthesis of compound 9.1

By the bromo- 2- amino naphthalenes (500mg, 2.25mmol) of 6-, 1- methyl piperazine (270mg, 2.7mmol), cesium hydroxide water Dimethyl sulfoxide (5.0mL) solution for closing object (760mg, 4.5mmol) stirs 20 hours at 120 DEG C, then by reaction system It is cooled to room temperature, ice water (10mL) dilution is added, water phase is extracted with methylene chloride (20mL × 2), organic phase washed with water, saturation Brine It, anhydrous sodium sulfate are dried, filtered, are concentrated, and residue chromatographs (petrol ether/ethyl acetate=1/3) with Flash column Purifying obtains 6- (4- methylpiperazine-1-yl) naphthalene -2- amine, and (compound 9.1,70mg, yield: 13%) being brown solid.m/z:[M +H]⁺242.2。

Embodiment 16: the synthesis of compound 10.4

Step 1: by the fluoro- 4- p-nitrile (2g, 12.0mmol) of 2-, ethyl thioglycolate (1.37g, 11.4mmol) and three Ethamine (5mL, 36mmol) is added in acetonitrile (30mL), and reaction system is stirred at room temperature 16 hours.Reaction solution is depressurized dense After contracting, the mixed solution of residue petroleum ether and ethyl acetate (4/1) is washed, and filtering, filter cake are dried in vacuo to obtain compound 10.1 (1.5g, yield: 48%) be brown solid.

Step 2: by compound 10.1 (600mg, 2.25mmol), nitrite tert-butyl (349mg, 3.38mmol) and bromination Acetonitrile (20mL) mixture of copper (1g, 4.51mmol) stirs 16 hours at 65 DEG C.Reaction solution reduced pressure is fallen back In, filtering, filter cake be dried in vacuo compound 10.2 (600mg, yield: 81%) be off-white powder.m/z:[M+H]⁺ 329.8。

Step 3: by compound 10.2 (600mg, 1.82mmol), 1- methyl piperazine (219mg, 2.18mmol), three (two Asias Benzylacetone) two palladiums (83mg, 0.091mmol), the bis- diphenyl phosphines of 1,1'- dinaphthalene -2,2'- (113mg, 0.182mmol) and carbonic acid Caesium (1.18g, 3.64mmol) is added in toluene (15mL), and reaction system is heated to reflux 16 hours under nitrogen protection.It will be anti- Liquid is answered to filter, filtrate concentration, residue purifies to obtain compound 10.3 with silica gel column chromatography (petrol ether/ethyl acetate=1/1) (150mg, yield: 24%) being yellow solid.m/z:[M+H]⁺349.8。

Step 4: compound 10.3 (100mg, 0.28mmol) and palladium carbon (50mg, 10%) are added to ethyl acetate In (15mL), reaction system is replaced 3 times with hydrogen, is then stirred 0.5 hour under a hydrogen atmosphere, with diatomite filtering reacting liquid, Filter cake is washed with ethyl acetate, and filtrate decompression is concentrated to get 6- amino -3- (4- methyl piperidine -1- base) benzo [b] thiophene -2- carboxylic Acetoacetic ester (compound 10.4,90mg, crude product) is brown oil.m/z:[M+H]⁺319.8。

Embodiment 17: the synthesis of compound 10.7

Step 1: compound 10.1 (500mg, 1.88mmol) and lithium chloride (995mg, 23.5mmol) are added to diformazan In base sulfoxide (10mL), reaction system stirs 5 hours at 160 DEG C.After reaction solution cooling, it is poured into water, uses ethyl acetate Extraction is concentrated under reduced pressure, residue silica gel column chromatography (petrol ether/ethyl acetate=1/ after organic phase anhydrous sodium sulfate drying 1) purify compound 10.5 (200mg, yield: 55%) be class brown solid.m/z:[M+H]⁺194.8。

Step 2: by compound 10.5 (200mg, 1.03mmol), nitrogen mustard hydrochloride (297mg, 1.54mmol) and potassium carbonate (569mg, 4.12mmol) is added in the tert-butyl alcohol (15mL), and reaction system microwave heating is stirred 3 hours to 140 DEG C.It will be anti- Liquid is answered to filter, (40mg is produced with prep-TLC (petrol ether/ethyl acetate=1/1) isolated compound 10.6 after reduced pressure Rate: 14%) being brown liquid.m/z:[M+H]⁺277.8。

Step 3: by compound 10.6 (40mg, 0.144mmol), iron powder (40mg, 0.72mmol), ammonium chloride (39mg, It 0.72mmol) is added in ethyl alcohol (15mL) with water (1mL), reaction system is heated to reflux 2 hours.Then reaction solution is cooled to The mixed solvent of room temperature, filtering, filtrate concentration, residue methylene chloride and methanol (10/1) washs, and cleaning solution is concentrated to get (compound 10.7,34mg, yield: 95%) being dark brown liquid to 3- (4- methylpiperazine-1-yl) benzo [b] thiophene -6- amine.m/ z:[M+H]⁺247.8。

Embodiment 18: the synthesis of compound 11.2

Step 1: by compound 2.3 (110mg, 0.45mmol), bromoethanol (168mg, 1.35mmol) and potassium carbonate DMF (5mL) solution of (186mg, 1.35mmol) is stirred overnight at 100 DEG C.Reaction solution is cooled to room temperature, and water quenching is added to go out instead It answers, water phase is extracted with ethyl acetate (15mL × 3), merges organic phase, successively uses water, saturated common salt water washing, organic phase nothing Aqueous sodium persulfate is dry, filtering, is concentrated under reduced pressure, residue with prep-TLC purify (methylene chloride/methanol=10/1) obtain chemical combination (82mg, yield: 60%) being brown oil to object 11.1.m/z:[M+H]⁺290.2。

Step 2: by methanol (10.0mL) solution of compound 11.1 (82mg, 0.28mmol) and palladium carbon (40mg, 10%) It is replaced 3 times, is then stirred at room temperature under a hydrogen atmosphere 2 hours with hydrogen.Reaction solution is filtered with diatomite, and filtrate decompression is concentrated to get 2- (4- (5- amino -1H- indoles -1- base) piperidin-1-yl) ethyl alcohol (compound 11.2,74mg, yield: 100%) solid for brown Body.

Embodiment 19: the synthesis of compound 12.2

Step 1: to the first of 6- nitroindoline (1.62g, 10.0mmol) and 1- methyl -4- piperidones (2.26g, 20mmol) Potassium hydroxide (1.12g, 20mmol) is added in alcohol (20mL) solution.Reaction system is heated to 90 DEG C and is stirred overnight.It then will be anti- Liquid is answered to be cooled to room temperature Hou Jiashui (100mL) quenching reaction, water phase is extracted with ethyl acetate, and separates organic phase, uses anhydrous slufuric acid Sodium is dry, filtering, is concentrated under reduced pressure, and residue silica gel column chromatography (methylene chloride/methanol=10/1) purifying obtains compound 12.1 (760mg, yield: 30%) be faint yellow solid.m/z:[M+H]⁺258.4。

Step 2: into methanol (30mL) solution of compound 12.1 (760mg, 2.9mmol) be added palladium carbon (50mg, 10%), reaction system is replaced 3 times with hydrogen, is then stirred 30 minutes under a hydrogen atmosphere.Mixture is filtered through diatomite, is filtered Liquid obtains 3- (1- methyl piperidine -4- base) -1H- indoles -6- amine (compound 12.2,510mg, yield: 77%) after being concentrated under reduced pressure For brown oil.m/z:[M+H]⁺230.2。

Embodiment 20: the synthesis of compound 12.3

Using the synthetic method of compound 12.2, the 6- nitroindoline in step 1 is replaced with into 1- methyl -6- nitro -1H- Indoles obtains 1- methyl -3- (1- methyl piperidine -4- base) -1H- indoles -6- amine (compound 12.3).

Embodiment 21: the synthesis of compound 13.4

Step 1: to 2- Amino-4-nitrobenzoic Acid (1.82g, 10.0mmol) and potassium carbonate (2.76g, 20.0mmol) Monoxone (945mg, 10.0mmol) is added in water (30mL) solution.Obtained mixture is stirred overnight at 90 DEG C, is cooled to Hydrochloric acid (1M, 100mL) quenching reaction is used after room temperature and adjusts pH=4, yellow mercury oxide is filtered, and is obtained after filter cake vacuum drying (1.76g, yield: 73%) being faint yellow solid to compound 13.1.

Step 2: at room temperature, vinegar is added into acetic anhydride (20mL) suspension of compound 13.1 (1.76g, 7.33mmol) Sour sodium (2.39g, 29.2mmol), reaction system are stirred 4 hours at 130 DEG C, are then cooled to room temperature, and are quenched with water (100mL) Go out uses methylene chloride (20mL × 2) to extract after reacting, and separates organic phase, with anhydrous sodium sulfate drying, filters, reduced pressure.It is residual Yellow solid is precipitated after staying object cooling, filters, filter cake petroleum ether rinse, obtained after vacuum drying compound 13.2 (1.05g, Yield: 55%) being yellow-brown solid.m/z:[M+H]⁺263.4。

Step 3: compound 13.2 (200mg, 0.76mmol), 1- methyl piperazine (305mg, 3.05mmol) are dissolved in acetic acid In (5mL), reaction system microwave reaction 0.5 hour at 150 DEG C.Through silica gel column chromatography (dichloromethane after reaction solution reduced pressure Alkane/methanol=10/1) purifying obtain compound 13.3 (76.0mg, yield: 33%) be brown solid.m/z:[M+H]⁺303.4。

Step 4: Raney's nickel (5mg) is added into methanol (5.0mL) solution of compound 13.3 (20mg, 0.07mmol), System is replaced 3 times with hydrogen, is then stirred at room temperature under a hydrogen atmosphere 1 hour.Filtering, filtrate decompression are concentrated to get 3- (4- methyl Piperazine -1- base) (compound 13.4,16mg, yield: 89%) being brown solid to -1H- indoles -6- amine.m/z:[M+H]⁺231.2。

Embodiment 22: the synthesis of compound 13.7

Step 1: triethylamine is added into methanol (10.0mL) solution of compound 13.3 (110mg, 0.36mmol) (120mg, 1.10mmol), reaction system stir 3 hours at 80 DEG C.Reaction system is concentrated under reduced pressure to give compound 13.5 (94mg, yield: 100%) being yellow solid.m/z:[M+H]⁺261.4。

Step 2: under condition of ice bath, dividing into tetrahydrofuran (5.0mL) solution of compound 13.5 (94mg, 0.36mmol) It criticizes and sodium hydrogen (60%, 20mg, 0.47mmol) is added, stirred 0.5 hour at 0 DEG C of reaction system, addition iodomethane (80mg, 0.54mmol), it then proceedes to stir 1 hour at 0 DEG C.Reaction system is directly concentrated under reduced pressure, residue prep-TLC (two Chloromethanes/methanol=10/1) purifying obtain compound 13.6 (45mg, yield: 46%) be yellow solid.m/z:[M+H]⁺ 275.4。

Step 3: Raney's nickel (20mg) is added into methanol (5.0mL) solution of compound 13.6 (45mg, 0.16mmol), Reaction system is replaced 3 times with hydrogen, is then stirred 1 hour under a hydrogen atmosphere.Filtering, filtrate decompression are concentrated to get 1- methyl -3- (compound 13.7,40mg, yield: 100%) being brown solid to (4- methylpiperazine-1-yl) -1H- indoles -6- amine.m/z:[M+ H]⁺245.2。

Embodiment 23: the synthesis of compound 14.2

Step 1: under nitrogen protection, successively into toluene (10.0mL) solution of 6- nitroindoline (500mg, 3.1mmol) 2- bromopyridine (410mg, 2.6mmol), cuprous iodide (25mg, 0.13mmol), potassium phosphate (1.32g, 6.2mmol), N is added, N '-dimethyl ethylenediamine (55mg, 0.63mmol) then stirs reaction system 16 hours at 110 DEG C.Reaction system decompression Concentration, residue obtain compound 14.1 (430mg, yield are through Flash column chromatography (methylene chloride/methanol=50/1) purifying It 58%) is yellow solid.m/z:[M+H]⁺240.2。

Step 2: Raney's nickel is added into methanol (10.0mL) solution of compound 14.1 (130mg, 0.54mmol) (20mg), reaction system are replaced 3 times with hydrogen, are then stirred 1 hour in nitrogen atmosphere.Filtering, filtrate decompression are concentrated to get 1- (compound 14.2,113mg, yield: 99%) being brown solid to (pyridine -2- base) -1H- indoles -5- amine.m/z:[M+H]⁺ 210.3。

Embodiment 24: the synthesis of compound 14.3~14.4

Using the synthetic method of compound 14.2, the 2- bromopyridine in step 1 is replaced with into 3- bromopyridine and obtains 1- (pyrrole Pyridine -3- base) -1H- indoles -5- amine (compound 14.3), m/z:[M+H]⁺210.2。

Using the synthetic method of compound 14.2, the 2- bromopyridine in step 1 is replaced with into 4- bromopyridine and obtains 1- (pyrrole Pyridine -4- base) -1H- indoles -5- amine (compound 14.4), m/z:[M+H]⁺210.2。

Embodiment 25: the synthesis of compound 14.7~14.8

It is starting with 5- nitro -1H- pyrrolo- [2,3-] pyridine and 3- bromopyridine using the synthetic method of compound 14.2 Raw material obtains 1- (pyridin-3-yl) -1H- pyrroles [2,3-b] pyridin-5-amine (compound 14.7), m/z:[M+H]⁺211.4。

It is starting with 5- nitro -1H- pyrrolo- [2,3-] pyridine and 2- bromopyridine using the synthetic method of compound 14.2 Raw material obtains 1- (pyridine -2- base) -1H- pyrroles [2,3-b] pyridin-5-amine (compound 14.8), m/z:[M+H]⁺211.4。

Embodiment 26: the synthesis of compound 15.3

Step 1: under condition of ice bath, sodium hydrogen (229mg, 5.73mmol, 60%) being added to the bromo- 6- nitro -1H- indoles of 4- In anhydrous DMF (15mL) solution of (690mg, 2.86mmol), obtained mixture is stirred at room temperature 0.5 hour, then will Iodomethane (1.22g, 8.59mmol) is added in said mixture, and reaction system is continued stirring 2 hours.Then by reaction solution It is poured slowly into the ice water of stirring, water phase is extracted with ethyl acetate (10mL × 2), merges organic phase, successively uses water, saturated common salt Water washing, is concentrated organic phase, and residue silica gel column chromatography (petrol ether/ethyl acetate=5/1) purifying obtains compound 15.1 (529mg, yield: 73%) being yellow solid.

Step 2: by three (dibenzalacetone) palladiums (7.2mg, 7.8 μm of ol) be added to compound 15.1 (200mg, 0.784mmol), 1- methyl piperazine (78.4mg, 0.784mmol), cesium carbonate (767.1mg, 2.35mmol) and (±) -2,2'- It, will with nitrogen in Isosorbide-5-Nitrae-dioxane (15mL) solution of double-(diphenyl phosphine) -1,1'- dinaphthalene (14.7mg, 0.024mmol) Reaction system is replaced 3 times, and reaction system is stirred overnight at 110 DEG C under nitrogen protection, uses diatomite after being then cooled to room temperature Filtering, filter cake are washed with ethyl acetate, filtrate decompression concentration, and residue is pure with prep-TLC (methylene chloride/methanol=10/1) Change obtains compound 15.2, and (210mg, yield: 98%) being yellow solid.

Step 3: by methanol (15mL) mixture of compound 15.2 (210mg, 0.77mmol) and palladium carbon (60mg, 5%) It is replaced 3 times with hydrogen.Then reaction system is stirred at room temperature under a hydrogen atmosphere 1 hour.Solution filtering, filtrate decompression are concentrated to get 1- methyl -4- (4- methylpiperazine-1-yl) -1H- indoles -6- amine (compound 15.3,205mg, yield: 100%) solid for brown Body.

Embodiment 27: the synthesis of compound 15.4~15.10

Using the synthetic method of compound 15.3, the 1- methyl piperazine in step 2 is replaced with into pyrrolidines and obtains 1- methyl- 4- (pyrrolidin-1-yl) -1H- indoles -6- amine (compound 15.4).

Using the synthetic method of compound 15.3, the 1- methyl piperazine in step 2 is replaced with into dimethylamine hydrochloride and is obtained N⁴,N⁴, 1- trimethyl -1H- indoles -4,6- diamines (compound 15.5).

Using the synthetic method of compound 15.3, the 1- methyl piperazine in step 2 is replaced with into morpholine and obtains 1- methyl -4- Morpholinyl -1H- indoles -6- amine (compound 15.6).

Using the synthetic method of compound 15.3, the 1- methyl piperazine in step 2 is replaced with into 1-Boc- piperazine and obtains 1- Methyl -4- (1-N-Boc- piperazine -4- base) -1H- indoles -6- amine (compound 15.7).m/z:[M+H]⁺331.0。

Using the synthetic method of compound 15.3, the 1- methyl piperazine in step 2 is replaced with into (S) -1-Boc-2- methyl Piperazine obtains (S) -1- methyl -4- (1-N-Boc-2- methyl piperazine -4- base) -1H- indoles -6- amine (compound 15.8).m/z: [M+H]⁺345.2。

Using the synthetic method of compound 15.3, the 1- methyl piperazine piperazine in step 2 is replaced with into 1- isopropyl-piperazine and is obtained To 4- (4- isopropyl piperazine -1- base) -1- Methyl-1H-indole -6- amine (compound 15.9).m/z:[M+H]⁺273.0。

Using the synthetic method of compound 15.3, the 1- methyl piperazine in step 2 is replaced with into methyl -2 (1S, 4S) -2-, 5- diazabicyclo [2.2.1] heptane obtains 1- methyl -4- ((1S, 4S) -5- methyl -2,5- diazabicyclo [2.2.1] hept- 2- yl) -1H- indoles -6- amine (compound 15.10).m/z:[M+H]⁺257.2。

Embodiment 28: the synthesis of compound 16.3

Step 1: at room temperature, by N- bromo-succinimide (2.12g, 12mmol) be added to 7- nitroquinoline (1.74g, In acetic acid (20mL) solution 10mmol).Then reaction system stirs 2 hours at 80 DEG C.Reaction solution is cooled to room temperature simultaneously There is white precipitate after static 2 hours, filter, filter cake petroleum ether, vacuum drying obtains compound 16.1, and (2.10g is produced Rate: 84%) being white solid.

Step 2: compound 16.1 (2.1g, 8.33mmol) being dissolved in dimethyl sulfoxide (20mL), 1- first is sequentially added Base piperazine (0.9g, 9mmol), potassium carbonate (2.2g, 16mmol) and cuprous iodide (152mg, 0.8mmol).Reaction system nitrogen After gas is replaced 3 times, stirs 3 hours at 120 DEG C, then reaction solution is poured into ice water, water phase acetic acid under nitrogen protection Ethyl ester extracts (20mL × 3), merges organic phase, successively uses water, saturated common salt water washing, is concentrated under reduced pressure, residue is through silicagel column Chromatography (methylene chloride/methanol=10/1) purify compound 16.2 (540mg, yield: 24%) be brown solid.

Step 3: compound 16.2 (540mg, 1.99mmol) and Raney's nickel (60mg) are incorporated in methanol (15mL).Instead System hydrogen is answered to replace 3 times.Then reaction system is stirred at room temperature under a hydrogen atmosphere 1 hour.Filtering, filtrate are concentrated to get 3- (compound 16.3,480mg, yield: 100%) being brown solid to (4- methylpiperazine-1-yl) quinoline -7- amine.

Embodiment 29: the synthesis of compound 16.5

Step 1: the chloro- 6- nitroquinoline (300mg, 1.44mmol) of 2- is added to the ethyl alcohol of 1- methyl piperazine (5mL) In (20mL) solution, reaction system is heated to reflux stirring 16 hours.Reaction solution is cooled to room temperature, reduced pressure is fallen back In, cross filter solid, solid be dried in vacuo compound 16.4 (300mg, yield: 77%) be yellow solid.

Step 2: by compound 16.4 (100mg, 0.367mmol), palladium carbon (30mg, 10%) is added to methanol (15mL) In, reaction system is replaced 3 times with hydrogen, is then stirred at room temperature under a hydrogen atmosphere 2 hours.Reaction solution is filtered, filtrate decompression is dense Contracting obtains 2- (4- methylpiperazine-1-yl) quinoline -6- amine, and (compound 16.5,80mg, yield: 91%) being brown liquid.

Embodiment 30: the synthesis of compound 17.2

Step 1: sequentially adding cesium carbonate into DMF (10.0mL) solution of 6- nitroindoline (150mg, 0.93mmol) (910mg, 2.79mmol) and 3- iodine oxetanes (205mg, 1.11mmol), reaction system stir 3 hours at 70 DEG C.So After be cooled to room temperature and diluted with ethyl acetate (50mL), obtained mixture successively uses water (20mL), saturated salt solution (20mL) washing, organic phase are dried, filtered with anhydrous sodium sulfate, are concentrated under reduced pressure, residue prep-TLC (petroleum ether/acetic acid Ethyl ester=2/1) purifying obtain compound 17.1 (73mg, yield: 36%) be yellow solid.m/z:[M+H]⁺219.2。

Step 2: Raney's nickel (20mg) is added into methanol (5mL) solution of compound 17.1 (73mg, 0.33mmol), instead It answers system hydrogen to replace 3 times, is then stirred 1 hour in nitrogen atmosphere.Filtering, filtrate decompression are concentrated to get 1- (oxa- ring fourth Alkane -3- base) (compound 17.2,60mg, yield: 95%) being yellow solid to -1H- indoles -6- amine.m/z:[M+H]⁺189.2。

Embodiment 31: the synthesis of compound 17.3

Using the synthetic method of compound 17.2, the 3- iodine oxetanes in step 1 is replaced with into iodomethane and obtains 1- Methyl-1H-indole -6- amine (compound 17.3).m/z:[M+H]⁺147.2。

Embodiment 32: the synthesis of compound 18.3

Step 1: by the bromo- 6- nitro -1H- indoles (200mg, 0.83mmol) of 4-, cyclopropylboronic acid (143mg, 1.66mmol), sodium carbonate (176mg, 1.66mmol), copper acetate (151mg, 0.83mmol) and 2,2- bipyridyl (130mg, Methylene chloride (5mL) solution 0.83mmol) is warming up to 100 DEG C and is stirred overnight in tube sealing.Then reaction system is cooled to Room temperature, and diluted with methylene chloride, organic phase is washed with water.Separate organic phase, concentration, residue silica gel column chromatography (petroleum Ether/ethyl acetate=5/1) purifying obtain compound 18.1 (215mg, yield: 92%) be yellow solid.

Step 2&3: using the synthetic method of compound 15.3 step 2 and step 3,1- ring is obtained with the reaction of compound 18.1 Propyl -4- (4- methylpiperazine-1-yl) -1H- indoles -6- amine (compound 18.3) is brown solid.

Embodiment 33: the synthesis of compound 19.3

Step 1: by the bromo- 6- nitro -1H- indoles (300mg, 1.24mmol) of 4-, bromoethanol (467mg, 3.73mmol) and DMF (10mL) suspension of potassium carbonate (176mg, 1.66mmol) is stirred overnight at 100 DEG C.Then reaction system is cooled to Room temperature is poured into ice water, and water phase is extracted with ethyl acetate, organic phase washed with water and saturated common salt water washing.Organic phase is separated, Concentration, residue silica gel column chromatography (petrol ether/ethyl acetate=1/1) purifying obtain compound 19.1 (320mg, yield: It 90%) is yellow solid.

Step 2&3: using the synthetic method of compound 15.3 step 2 and step 3,2- is obtained with the reaction of compound 19.1 (6- amino -4- (4- methylpiperazine-1-yl) -1H- indoles -1- base) ethyl alcohol (compound 19.3) is brown solid.

Embodiment 34: the synthesis of compound 20.3

Step 1: to the bromo- 6- nitro -1H- indoles (200mg, 0.83mmol) of 4- and dicarbapentaborane di tert butyl carbonate (271mg, 4-dimethylaminopyridine (10mg, 0.083mmol) is added in methylene chloride (10mL) solution 1.24mmol), reaction system exists It stirs 1 hour at room temperature.Then reaction solution is directly concentrated, residue silica gel column chromatography (petrol ether/ethyl acetate=10/ 1) purifying obtain compound 20.1 (283mg, yield: 100%) be yellow solid.

Step 2: by compound 20.1 (140mg, 0.41mmol), palladium acetate (4.6mg, 0.02mmol), 1- methyl piperazine (41mg, 0.41mmol), cesium carbonate (200mg, 0.62mmol) and 2- dicyclohexyl phosphorus -2', 6'- diisopropoxy -1,1'- connection Isosorbide-5-Nitrae-dioxane (10mL) mixture of benzene (19.3mg, 0.04mmol) is replaced 3 times with nitrogen, and then reaction system heats up It stirs 2 hours, is filtered after reaction system is cooled to room temperature with diatomite, filter cake is eluted with ethyl acetate, and filtrate is dense to 110 DEG C Contracting, residue silica gel column chromatography (ethyl acetate) purifying obtains compound 20.2, and (110mg, yield: 74%) being brown solid. m/z:[M+H]⁺361.2。

Step 3: using the synthetic method of 15.3 step 3 of compound, obtaining 6- amino -4- (4- with the reaction of compound 20.2 Methylpiperazine-1-yl) -1H- indoles -1- carboxylic acid tert-butyl ester (compound 20.3) be brown solid.

Embodiment 35: the synthesis of compound 21.5

Step 1: iron powder (2.2g, 39.2mmol) is added to compound 15.1 (2g, 7.84mmol) and ammonium chloride In acetic acid (20mL) solution of (629mg, 11.8mmol), obtained mixture return stirring 1 hour.By reaction solution heat filtering, Filter cake is washed with acetic acid, and gained filtrate concentration, residue silica gel column chromatography (petrol ether/ethyl acetate=5/1) purifying obtains (1.1g, yield: 62%) being brown solid to compound 21.1.m/z:[M+H]⁺225.0。

Step 2: compound 21.1 (1.05g, 4.67mmol) being added in di-tert-butyl dicarbonate (10mL), is obtained Mixture is warming up to 100 DEG C and stirs 1 hour, is concentrated under reduced pressure and removes solvent, residue silica gel column chromatography (petroleum ether/acetic acid second Ester=10/1) purifying obtain compound 21.2 (1.3g, yield: 86%) be white solid.m/z:[M+H]⁺325.2。

At 3:-78 DEG C of step, by tetrahydrofuran solution (2.5M, 2.5mL, 6.28mmol) being added dropwise to of n-BuLi In anhydrous tetrahydro furan (20mL) solution for closing object 21.2 (680mg, 2.09mmol), condition of the obtained mixture at -78 DEG C Lower stirring 1 hour, then anhydrous tetrahydro furan (1mL) solution of 1- methyl -4- piperidones (284mg, 2.50mmol) is added dropwise Enter into above-mentioned reaction solution, continue to stir 2 hours in this temperature, with the aqueous solution quenching reaction of saturated ammonium chloride, what is obtained is mixed It closes object to be extracted with ethyl acetate, organic phase concentration, residue is obtained with silicon column glue chromatographic purifying (methylene chloride/methanol=10/1) (268mg, yield: 36%) being brown liquid to compound 21.3.m/z:[M+H]⁺360.0。

Step 4: compound 21.3 (268mg, 0.75mmol) being added in hydrochloric acid (6M, 10mL), obtained mixture It is stirred 3 hours at 100 DEG C, reduced pressure removing solvent obtains compound 21.4, and (207mg, yield: 100%) being brown solid. m/z:[M+H]⁺242.0。

Step 5: the methanol (15mL) of compound 21.4 (207mg, 0.75mmol) and 10% palladium/carbon (100mg) is mixed Object is closed to be replaced 3 times with hydrogen.Then it is stirred at room temperature under a hydrogen atmosphere 1 hour.Solution filtering, filtrate decompression concentration, residue are molten In the sodium bicarbonate aqueous solution of saturation, water phase is extracted with dichloromethane, and merges organic phase and, decompression dry with anhydrous sodium sulfate Concentration, residue purify gained 1- methyl -4- (1- methyl piperidine -4- base)-with prep-TLC (methylene chloride/methanol=10/1) (compound 21.5,35mg, yield: 19%) being brown solid to 1H- indoles -6- amine.m/z:[M+H]⁺244.2。

Embodiment 36: the synthesis of compound 1-4

Step 1: successively that compound 1-1 (222mg, 1.0mmol), compound 1-2 (215mg, 1.0mmol), iodate is sub- Copper (191mg, 1.0mmol), Anhydrous potassium carbonate (276mg, 2.0mmol) and N, N- dimethyl-ethylenediamine (88mg, 1mmol) are added To in Isosorbide-5-Nitrae-dioxane (20mL), reaction system is warming up to 100 DEG C and is stirred overnight.Then reaction system is cooled to room Temperature filters reaction solution, filtrate decompression concentration, residue silica gel column chromatography purify (petrol ether/ethyl acetate=1/1) must change Closing object 1-3, (120mg, yield: 34%) being brown solid.m/z:[M+H]⁺358.2。

Step 2: metachloroperbenzoic acid (68mg, 0.34mmol) is added to compound 1-3 (120mg, 0.34mmol) Methylene chloride (10mL) solution in, reaction system is stirred at room temperature 1 hour, be concentrated under reduced pressure remove methylene chloride obtain 2- alkene Propyl -1- (6- (2- hydroxyl propyl- 2- yl) pyridine -2- base) -6- (methylsulfinyl) -1H- pyrazolo [3,4-d] pyrimidine -3 (compound 1-4,125mg, yield: 100%) being white solid to (2H) -one.m/z:[M+H]⁺374.2。

Embodiment 37: the synthesis of compound 1-1-1

By compound 1-4 (125mg, 0.34mmol), n,N-diisopropylethylamine (87mg, 0.68mmol) and compound 1.3 (68mg, 0.34mmol) are added in toluene (10mL), and reaction system is warming up to 70 DEG C and is stirred overnight, and are then concentrated under reduced pressure Solvent is removed, residue is purified with prep-HPLC (condition 1) and obtains 2- allyl -6- ((1- (2- (dimethylamino) ethyl) - 1H- indoles -5- base) amino) -1- (6- (2- hydroxyl propyl- 2- yl) pyridine -2- base) -1H- pyrazolo [3,4-d] pyrimidine -3 (2H) - (compound 1-1-1,97.6mg, yield: 46%) being white solid to ketone trifluoroacetate.m/z:[M+H]⁺513.4；¹H NMR (400MHz,CD₃OD): δ 8.81 (s, 1H), 7.99 (br.s, 1H), 7.96 (t, J=8.0Hz, 2H), 7.85 (d, J=8.0Hz, 1H), 7.64 (dd, J=0.8,8.0Hz, 1H), 7.40 (d, J=8.8Hz, 1H), 7.23 (dd, J=2.4,8.8Hz, 1H), 7.29 (d, J=3.2Hz, 1H), 6.44 (d, J=2.8Hz, 1H), 5.69-5.76 (m, 1H), 5.05 (dd, J=1.2, 10.4Hz, 1H), 4.93 (dd, J=1.2,17.2Hz, 1H), 4.85 (d, J=6.0Hz, 2H), 4.33 (t, J=7.2Hz, 2H), 2.78 (t, J=7.2Hz, 2H), 2.33 (s, 6H), 1.58 (s, 6H).

Embodiment 38: the synthesis of compound 1-1-2

Using the synthetic method of compound 1-1-1, compound 1.3 is replaced with 7.6 and obtains compound 2-1.

Trifluoroacetic acid (2mL) is added drop-wise in the methylene chloride (10mL) of compound 2-1 (130mg, 0.21mmol), is reacted System is stirred at room temperature 2 hours, and reaction solution concentration, residue is purified with prep-HPLC (condition 1) and obtains 2- allyl -6- ((1- ((1- amino cyclopropyl) methyl) -1H- indoles -5- base) amino) -1- (6- (2- hydroxyl propyl- 2- yl) pyridine -2- base) - 1H- pyrazolo [3,4-d] (2H) -one of pyrimidine -3 trifluoroacetate (compound 1-1-2,46.7mg, yield: 36%) solid for yellow Body.m/z:[M+H]⁺510.8；¹H NMR(400MHz,CD₃OD): δ 8.71 (s, 1H), 7.95 (br.s, 1H), 7.85 (t, J= 8.0Hz, 1H), 7.72 (d, J=7.6Hz, 1H), 7.54 (dd, J=0.8,7.6Hz, 1H), 7.35 (d, J=8.8Hz, 1H), 7.28 (dd, J=6.8,8.8Hz, 1H), 7.22 (d, J=3.2Hz, 1H), 6.47 (d, J=3.2Hz, 1H), 5.65-5.57 (m, 1H), 4.95 (dd, J=1.2,10.6Hz, 1H), 4.79 (dd, J=1.2,17.2Hz, 1H), 4.84-4.72 (m, 2H), 4.38 (s,2H),1.48(s,6H),1.07-0.95(m,4H)。

Embodiment 39: the synthesis of compound 1-1-3

Using the synthetic method of compound 1-1-1, compound 1.3 is replaced with 7.8 and obtains compound 2-2.

Using the synthetic method of compound 1-1-2, reacted to obtain 2- allyl -1- (6- (2- hydroxyl propyl- with compound 2-2 2- yl) pyridine -2- base) -6- ((1- ((1- (methylamino) cyclopropyl) methyl) -1H- indoles -5- base) amino) -1H- pyrazolo [3,4-d] pyrimidine -3 (2H) -one trifluoroacetate (compound 1-1-3).m/z:[M+H]⁺525.4；¹H NMR(400MHz, DMSO-d₆): δ 10.31 (s, 1H), 8.86 (s, 1H), 8.44 (br.s, 2H), 8.14 (s, 1H), 8.01 (t, J=8.0Hz, 1H), 7.83 (d, J=7.2Hz, 1H), 7.62 (d, J=7.2Hz, 1H), 7.56 (d, J=8.8Hz, 1H), 7.46 (d, J= 2.8Hz, 1H), 7.42 (d, J=9.6Hz, 1H), 6.54 (d, J=3.2Hz, 1H), 5.72-5.62 (m, 1H), 5.34-5.31 (m, 1H), 5.00 (dd, J=1.2,10.8Hz, 1H), 4.83 (dd, J=1.2,17.2Hz, 1H), 4.70 (d, J=5.2Hz, 2H),2.53(s,3H),1.46(s,3H),1.10-0.95(m,4H)。

Embodiment 40: the synthesis of compound 1-2-1~1-2-3

Using the synthetic method of compound 1-1-1, compound 1.3 is replaced with 1.7,1.8 or 1.9 and obtains 2- allyl- 6- ((1- (2- (azetidine -1- base) ethyl) -1H- indoles -5- base) amino) -1- (6- (2- hydroxyl propyl- 2- yl) pyridine - 2- yl) -1H- pyrazolo [3,4-d] pyrimidine -3 (2H) -one (1-2-1), 2- allyl -1- (6- (2- hydroxyl propyl- 2- yl) pyridine - 2- yl) -6- ((1- (2- (pyrrolidin-1-yl) ethyl) -1H- indoles -5- base) amino) -1H- pyrazolo [3,4-d] pyrimidine -3 (2H) -one (1-2-2) and 2- allyl -1- (6- (2- hydroxyl propyl- 2- yl) pyridine -2- base) -6- ((1- (2- (piperidin-1-yl) Ethyl) -1H- indoles -5- base) amino) -1H- pyrazolo [3,4-d] pyrimidine -3 (2H) -one (1-2-3):

Embodiment 41: the synthesis of compound 1-3-1~1-3-4

Using the synthetic method of compound 1-1-1, compound 1.3 is replaced with 2.5,2.6,2.7 or 2.9 and obtains 2- allyl Base -1- (6- (2- hydroxyl propyl- 2- yl) pyridine -2- base) -6- ((1- (1- methyl piperidine -4- base) -1H- indoles -5- base) -1H- pyrrole Azoles simultaneously [3,4-d] pyrimidine -3 (2H) -one (1-3-1), 2- allyl -1- (6- (2- hydroxyl propyl- 2- yl) pyridine -2- base) -6- ((1- (1- methylpyrrole alkyl -3- base) -1H- indoles -5- base) amino) -1H- pyrazolo [3,4-d] (2H) -one of pyrimidine -3 (1- 3-2), 2- allyl -1- (6- (2- hydroxyl propyl- 2- yl) pyridine -2- base) -6- ((1- (1- methyl azetidine -3- base) - 1H- indoles -5- base) amino) -1H- pyrazolo [3,4-d] pyrimidine -3 (2H) -one (1-3-3) and 2- allyl -1- (6- (2- hydroxyl Base propyl- 2- yl) pyridine -2- base) -6- ((1- (1- methyl piperidine -3- base) -1H- indoles -5- base) amino) -1H- pyrazolo [3, 4-d] pyrimidine -3 (2H) -one (1-3-4):

Embodiment 42: the synthesis of compound 1-4-1~1-4-4

Using the synthetic method of compound 1-1-1, compound 1.3 is replaced with 2.8,4.2,5.2 or 11.2 and obtains 2- alkene Propyl -1- (6- (2- hydroxyl propyl- 2- yl) pyridine -2- base) -6- ((1- (1- isopropyl piperidin-4-yl) -1H- indoles -5- base) ammonia Base) -1H- pyrazolo [3,4-d] pyrimidine -3 (2H) -one (1-4-1), 6- ((1- (1- Acetylpiperidin -4- base) -1H- indoles -5- Base) amino) -2- allyl -1- (6- (2- hydroxyl propyl- 2- yl) pyridine -2- base) -1H- pyrazolo [3,4-d] pyrimidine -3 (2H) - Ketone trifluoroacetate (1-4-2), 2- allyl -1- (6- (2- hydroxyl propyl- 2- yl) pyridine -2- base) -6- ((1- (1- (2,2,2- Trifluoroethyl) piperidin-4-yl) -1H- indoles -5- base) amino) -1H- pyrazolo [3,4-d] pyrimidine -3 (2H) -one (1-4-3) and 2- allyl -6- ((1- (1- (2- hydroxyethyl) piperidin-4-yl) -1H- indoles -5- base) amino) -1- (6- (2- hydroxyl propyl- 2- Base) pyridine -2- base) -1H- pyrazolo [3,4-d] (2H) -one trifluoroacetate of pyrimidine -3 (1-4-4):

Embodiment 43: the synthesis of compound 1-5-1

Using the synthetic method of compound 1-1-1, compound 1.3 is replaced with 2.15 and obtains 2- allyl -1- (6- (2- Hydroxyl propyl- 2- yl) pyridine -2- base) -6- ((1- (tetrahydro -2H- pyrans -4- base) -1H- indoles -5- base) amino) -1H- pyrazolo [3,4-d] pyrimidine -3 (2H) -one trifluoroacetate (compound 1-5-1):

m/z:[M+H]⁺526.4；¹H NMR(400MHz,DMSO-d₆):δ10.22(s,1H),8.84(s,1H),8.07(s, 1H), 8.02 (t, J=8.0Hz, 1H), 7.83 (d, J=8.0Hz, 1H), 7.62 (d, J=7.6Hz, 1H), 7.53 (d, J= 8.8Hz, 1H), 7.52 (d, J=2.8Hz, 1H), 7.38 (d, J=8.0Hz, 1H), 6.45 (d, J=3.2Hz, 1H), 5.72- 5.62 (m, 1H), 5.00 (dd, J=1.2,10.0Hz, 1H), 4.83 (dd, J=1.2,17.2Hz, 1H), 4.70 (d, J= 5.2Hz, 2H), 4.65-4.58 (m, 1H), 4.01 (dd, J=4.0,11.2Hz, 2H), 3.58 (dd, J=9.6,12.0Hz, 2H),2.06-1.96(m,4H),1.49(s,6H)。

Embodiment 44: the synthesis of compound 1-6-1

Using the synthetic method of compound 1-1-1, compound 1.3 is replaced with 8.3 and obtains 2- allyl -6- ((2- ((two Methylamino) methyl) -1H- indoles -5- base) amino) -1- (6- (2- hydroxyl propyl- 2- yl) pyridine -2- base) -1H- pyrazolo [3, 4-d] pyrimidine -3 (2H) -one trifluoroacetate (compound 1-6-1):

m/z:[M+H]⁺499.4；¹H NMR(400MHz,DMSO-d₆):δ11.23(s,1H),10.26(s,1H),9.72 (s, 1H), 8.81 (s, 1H), 8.10 (br.s, 1H), 7.97 (t, J=7.6Hz, 1H), 7.83 (d, J=8.0Hz, 1H), 7.66 (d, J=7.6Hz, 1H), 7.41 (s, 2H), 6.65 (d, J=2.0Hz, 1H), 5.72-5.62 (m, 1H), 5.01 (dd, J= 1.2,10.0Hz, 1H), 4.83 (dd, J=1.2,17.2Hz, 1H), 4.70 (d, J=5.2Hz, 2H), 4.42 (d, J=4.0Hz, 2H), 2.80 (d, J=4.4Hz, 6H), 1.51 (s, 6H).

Embodiment 45: the synthesis of compound 1-7-1~1-7-3

Using the synthetic method of compound 1-1-1, compound 1.3 is replaced with 14.2,14.3 or 14.4 and obtains 2- allyl Base -1- (6- (2- hydroxyl propyl- 2- yl) pyridine -2- base) -6- ((1- (pyridine -2- base) -1H- indoles -5- base) amino) -1H- pyrrole Azoles simultaneously [3,4-d] pyrimidine -3 (2H) -one (1-7-1), 2- allyl -1- (6- (2- hydroxyl propyl- 2- yl) pyridine -2- base) -6- ((1- (pyridin-3-yl) -1H- indoles -5- base) amino) -1H- pyrazolo [3,4-d] pyrimidine -3 (2H) -one (1-7-2) and 2- alkene Propyl -1- (6- (2- hydroxyl propyl- 2- yl) pyridine -2- base) -6- ((1- (pyridin-4-yl) -1H- indoles -5- base) amino) -1H- Pyrazolo [3,4-d] pyrimidine -3 (2H) -one (1-7-3):

Embodiment 46: the synthesis of compound 2-1-1

Step 1: under room temperature, to compound 1-1-1 (210mg, 0.41mmol) and formic acid ammonia (52mg, 0.82mmol) Isosorbide-5-Nitrae-dioxane (10mL) solution in be added ferrocene palladium chloride (34mg, 0.041mmol), by reaction system nitrogen Displacement 3 times, is then slowly increased to 100 DEG C for reaction system and is stirred overnight.Reaction solution is cooled to room temperature, filtering, filter cake methanol Washing, gained filtrate concentration, residue silica gel column chromatography purify (methylene chloride/methanol=10/1) obtain compound 2-1 (110mg, yield: 57%) being brown solid.

Step 2: under condition of ice bath, sodium hydrogen being added into DMF (5mL) solution of compound 2-1 (110mg, 0.233mmol) Then reaction system is slowly increased to room temperature and stirred 0.5 hour, Cyclopropylmetyl bromide is added by (19mg, 0.47mmol, 60%) (94mg, 0.7mmol), mixture continue to be stirred overnight under room temperature.Then reaction solution is cooled to 0 DEG C again, ice water is added dropwise and quenches It goes out reaction, solution is extracted with dichloromethane (5mL × 3), merges organic phase, and successively use water, saturated common salt water washing, organic phase Concentration, residue purify to obtain 2- (Cvclopropvlmethvl) -6- ((1- (2- (dimethylamino) ethyl)-with prep-HPLC (condition 1) 1H- indoles -5- base) amino) -1- (6- (2- hydroxyl propyl- 2- yl) pyridine -2- base) -1H- pyrazolo [3,4-d] pyrimidine -3 (2H) - (compound 2-1-1,24.3mg, yield: 20%) being white solid to ketone trifluoroacetate.m/z:[M+H]⁺526.9；¹H NMR (400MHz,CD₃OD):δ8.10-9.00(b,2H),7.59-7.66(m,2H),7.20-7.44(m,3H),6.66(s,1H), 5.10-5.15 (m, 2H), 4.65-4.69 (m, 2H), 4.03-4.08 (m, 2H), 3.69-3.72 (t, J=6.8Hz, 2H), 3.01 (s,6H),1.50-1.60(b,6H),0.50-0.54(m,2H),0.25-0.27(m,2H)。

Embodiment 47: the synthesis of compound 3-1-1

Using the synthetic method of compound 1-1-1, compound 1.3 is replaced with 3.1 and obtains 2- allyl -1- (6- (2- hydroxyl Base propyl- 2- yl) pyridine -2- base) -6- ((1- (1- methyl azetidine -3- base) -1H- benzo [d] imidazoles -5- base) amino) - 1H- pyrazolo [3,4-d] pyrimidine -3 (2H) -one (compound 3-1-1):

m/z:[M+H]⁺512.0；¹H NMR(400MHz,CD₃OD):δ9.89(s,1H),8.94(s,1H),8.52(s, 1H), 8.08-8.12 (m, 1H), 7.91 (s, 1H), 7.80-7.82 (d, J=8.0Hz, 1H), 7.69-7.71 (d, J=7.6Hz, 1H),5.80-6.10(m,1H),5.71-5.78(m,1H),5.00-5.08(m,4H),4.78-4.84(m,4H),3.32(s, 3H),1.60(s,6H)。

Embodiment 48: the synthesis of compound 4-1-1

Using the synthetic method of compound 1-1-1, compound 1.3 is replaced with 6.6 and obtains 2- allyl -1- (6- (2- hydroxyl Base propyl- 2- yl) pyridine -2- base) -6- ((2- methyl-1,2,3,4- tetrahydro pyrazine simultaneously [1,2-a] indoles -8- base) amino) -1H- Pyrazolo [3,4-d] pyrimidine -3 (2H) -one (compound 4-1-1):

m/z:[M+H]⁺511.1；¹H NMR(400MHz,CDCl₃):δ8.84(s,1H),7.97-7.80(m,3H),7.60 (br.s,1H),7.36-7.30(m,1H),7.25-7.17(m,2H),6.18(s,1H),5.76-5.65(m,1H),5.07- 5.02 (m, 1H), 4.98-4.91 (m, 1H), 4.76 (d, J=6.4Hz, 2H), 4.12 (t, J=5.6Hz, 2H), 3.97 (br.s, 1H), 3.80 (s, 2H), 2.95 (t, J=5.6Hz, 2H), 2.53 (s, 3H), 1.58 (s, 6H).

Embodiment 49: the synthesis of compound 5-1-1

Using the synthetic method of compound 1-1-1, compound 1.3 is replaced with 9.1 and obtains 2- allyl -1- (6- (2- hydroxyl Base propyl- 2- yl) pyridine -2- base) -6- ((6- (4- methylpiperazine-1-yl) naphthalene -2- base) amino) -1H- pyrazolo [3,4-d] is phonetic Pyridine -3 (2H) -one trifluoroacetate (compound 5-1-1):

m/z:[M+H]⁺551.4；¹H NMR(400MHz,CDCl₃): δ 8.86 (s, 1H), 8.29 (s, 1H), 8.03 (t, J= 8.0Hz, 1H), 7.86 (d, J=8.0Hz, 1H), 7.69 (dd, J=4.4,8.4Hz, 2H), 7.68 (d, J=8.4Hz, 1H), 7.59 (d, J=8.8Hz, 1H), 7.36 (dd, J=2.4,9.2Hz, 1H), 7.25 (d, J=2.0Hz, 1H), 5.76-5.69 (m, 1H), 5.03 (d, J=10.4Hz, 1H), 4.92 (dd, J=1.2,17.2Hz, 1H), 4.89-4.85 (m, 2H), 3.97 (d, J= 12.8Hz, 2H), 3.67 (d, J=11.2Hz, 2H), 3.38-3.29 (m, 2H), 3.15-3.09 (m, 2H), 3.01 (s, 3H), 1.58(s,3H)。

Embodiment 50: the synthesis of compound 6-1-1

Using the synthetic method of compound 1-1-1, compound 1.3 is replaced with 10.4 and obtains 6- ((2- allyl -1- (6- (2- hydroxyl propyl- 2- yl) pyridine -2- base) -3- oxygen -2,3- dihydro-1 h-pyrazole simultaneously [3,4-d] pyrimidine -6- base) amino) -3- (4- Methylpiperazine-1-yl) benzo [b] thiophene-2-carboxylic acid ethyl ester trifluoroacetate (compound 6-1-1):

m/z:[M+H]⁺628.9；¹H NMR(400MHz,CD₃OD): δ 8.89 (s, 1H), 8.53 (s, 1H), 8.08 (t, J= 8.0Hz, 1H), 7.84 (d, J=1.6Hz, 1H), 7.82 (d, J=3.2Hz, 1H), 7.22 (d, J=7.6Hz, 1H), 7.45 (dd, J=3.2,9.2Hz, 1H), 5.77-5.70 (m, 1H), 5.04 (dd, J=1.2,10.0Hz, 1H), 4.92 (dd, J= 1.2,17.2Hz, 1H), 4.88-4.83 (m, 2H), 4.35 (q, J=7.2Hz, 2H), 3.48-3.45 (m, 4H), 2.70 (br.s, 4H), 2.41 (s, 3H), 1.58 (s, 6H), 1.40 (t, J=7.2Hz, 3H).

Embodiment 51: the synthesis of compound 6-1-2

Using the synthetic method of compound 1-1-1, compound 1.3 is replaced with 10.7 and obtains 2- allyl -1- (6- (2- Hydroxyl propyl- 2- yl) pyridine -2- base) -6- ((3- (4- methylpiperazine-1-yl) benzo [b] thiophene -5- base) amino) -1H- pyrazoles And [3,4-d] pyrimidine -3 (2H) -one (compound 6-1-2):

m/z:[M+H]⁺557.2；¹H NMR(400MHz,CD₃OD): δ 8.87 (s, 1H), 8.54 (s, 1H), 8.06 (t, J= 8.0Hz, 1H), 7.83 (d, J=8.0Hz, 1H), 7.68 (d, J=5.2Hz, 1H), 7.67 (d, J=6.4Hz, 1H), 7.44 (d, J=8.0Hz, 1H), 6.75 (s, 1H), 5.74-5.69 (m, 1H), 5.04 (dd, J=1.6,10.0Hz, 1H), 4.91 (dd, J= 1.6,17.6Hz,1H),4.58(s,2H),3.18(s,4H),2.73(s,4H),2.40(s,3H),1.58(s,6H)。

Embodiment 52: the synthesis of compound 7-1-1

Using the synthetic method of compound 1-1-1, compound 1.3 is replaced with 12.2 and obtains 2- allyl -1- (6- (2- Hydroxyl propyl- 2- yl) pyridine -2- base) -6- ((3- (1- methyl piperidine -4- base) -1H- indoles -6- base) amino) -1H- pyrazolo [3,4-d] pyrimidine -3 (2H) -one trifluoroacetate (compound 7-1-1):

m/z:[M+H]⁺538.9；¹H NMR(400MHz,DMSO-d₆):δ10.85(s,1H),10.18(s,1H),8.87 (s, 1H), 8.06-8.01 (m, 1H), 7.91-7.82 (m, 3H), 7.60 (d, J=7.6Hz, 1H), 7.54 (d, J=8.8Hz, 1H), 7.27 (d, J=8.0Hz, 1H), 7.11 (d, J=2.0Hz, 1H), 5.73-5.63 (m, 1H), 5.01 (d, J=10.4Hz, 1H), 4.84 (d, J=17.2Hz, 1H), 4.70 (d, J=6.0Hz, 2H), 3.21-3.12 (m, 2H), 3.09-2.98 (m, 1H), 2.84 (d, J=4.8Hz, 3H), 2.21-2.12 (m, 2H), 1.93-1.81 (m, 1H), 1.48 (s, 6H).

Embodiment 53: the synthesis of compound 7-1-2

Using the synthetic method of compound 1-1-1, compound 1.3 is replaced with 13.4 and obtains 2- allyl -1- (6- (2- Hydroxyl propyl- 2- yl) pyridine -2- base) -6- ((3- (4- methylpiperazine-1-yl) -1H- indoles -6- base) amino) -1H- pyrazolo [3,4-d] pyrimidine -3 (2H) -one (compound 7-1-2):

m/z:[M+H]⁺540.2。

Embodiment 54: the synthesis of compound 7-1-3

Using the synthetic method of compound 1-1-1, compound 1.3 is replaced with 13.7 and obtains 2- allyl -1- (6- (2- Hydroxyl propyl- 2- yl) pyridine -2- base) -6- ((1- methyl -3- (4- methylpiperazine-1-yl) -1H- indoles -6- base) amino) -1H- Pyrazolo [3,4-d] pyrimidine -3 (2H) -one (compound 7-1-3):

m/z:[M+H]⁺554.4；¹H NMR(400MHz,CD₃OD): δ 8.84 (s, 1H), 7.94 (t, J=8.0Hz, 1H), 7.82 (s, 1H), 7.81 (s, 1H), 7.67 (d, J=8.0Hz, 1H), 7.51 (d, J=8.4Hz, 1H), 7.17 (d, J= 1.6Hz, 1H), 6.79 (s, 1H), 5.77-5.68 (m, 1H), 5.04 (d, J=10.0Hz, 1H), 4.84 (d, J=16.0Hz, 1H), 4.80 (d, J=6.0Hz, 2H), 3.66 (s, 3H), 3.12 (s, 4H), 2.71 (s, 4H), 2.39 (s, 3H), 1.58 (s, 6H)。

Embodiment 55: the synthesis of compound 7-1-4

Using the synthetic method of compound 1-1-1, compound 1.3 is replaced with 12.3 and obtains 2- allyl -1- (6- (2- Hydroxyl propyl- 2- yl) pyridine -2- base) -6- ((1- methyl -3- (1- methyl piperidine -4- base) -1H- indoles -6- base) amino) -1H- Pyrazolo [3,4-d] pyrimidine -3 (2H) -one trifluoroacetate (compound 7-1-4):

m/z:[M+H]⁺553.4；¹H NMR(400MHz,DMSO-d₆):δ10.30(br.s,1H),9.33(br.s,1H), 8.88 (s, 1H), 8.05-7.74 (m, 4H), 7.69-7.50 (m, 2H), 7.23 (d, J=9.2Hz, 1H), 7.09 (s, 1H), 5.73-5.60 (m, 2H), 4.66 (d, J=6.0Hz, 2H), 3.68 (s, 3H), 3.20-2.94 (m, 5H), 2.84 (d, J= 4.8Hz,3H),2.22-1.76(m,4H),1.46(s,6H)。

Embodiment 56: the synthesis of compound 7-1-5

Using the synthetic method of compound 1-1-1, compound 1.3 is replaced with 17.2 and obtains 2- allyl -1- (6- (2- Hydroxyl propyl- 2- yl) pyridine -2- base) -6- ((1- (oxetanes -3- base) -1H- indoles -6- base) amino) -1H- pyrazolo [3,4-d] pyrimidine -3 (2H) -one (compound 7-1-5):

m/z:[M+H]⁺498.2；¹H NMR(400MHz,CDCl₃):δ8.89(s,1H),7.91-7.85(m,2H),7.77- 7.75 (m, 2H), 7.59 (d, J=8.4Hz, 1H), 7.45 (d, J=3.2Hz, 1H), 7.39 (d, J=7.6Hz, 1H), 6.60 (d, J=3.2Hz, 1H), 5.73-5.68 (m, 1H), 5.51-5.46 (m, 1H), 5.13-5.08 (m, 2H), 5.05-5.02 (m, 2H), 4.93 (dd, J=17.2,1.2Hz, 2H), 4.74 (d, J=6.0Hz, 2H), 1.59 (s, 6H).

Embodiment 57: the synthesis of compound 7-1-6

Using the synthetic method of compound 1-1-1, compound 1.3 is replaced with 17.3 and obtains 2- allyl -1- (6- (2- Hydroxyl propyl- 2- yl) pyridine -2- base) -6- ((1- Methyl-1H-indole -6- base) amino) -1H- pyrazolo [3,4-d] pyrimidine -3 (2H) -one (compound 7-1-6):

m/z:[M+H]⁺456.2；¹H NMR(400MHz,CDCl₃): δ 8.88 (s, 1H), 7.82 (d, J=3.6Hz, 2H), 7.73 (s, 1H), 7.57 (d, J=8.4Hz, 1H), 7.35-7.32 (m, 1H), 7.14 (d, J=7.6Hz, 1H), 7.05 (d, J= 3.2Hz, 1H), 6.48 (d, J=2.8Hz, 1H), 5.70 (m, 1H), 5.04 (dd, J=10.4,0.8Hz, 1H), 4.93 (dd, J =16.8,1.2Hz, 1H), 4.75 (d, J=6.0Hz, 2H), 3.76 (s, 3H), 1.58 (s, 6H).

Embodiment 58: the synthesis of compound 7-2-1

Using the synthetic method of compound 1-1-1, compound 1.3 is replaced with 15.3 and obtains 2- allyl -1- (6- (2- Hydroxyl propyl- 2- yl) pyridine -2- base) -6- ((1- methyl -4- (4- methylpiperazine-1-yl) -1H- indoles -6- base) amino) -1H- Pyrazolo [3,4-d] pyrimidine -3 (2H) -one trifluoroacetate (compound 7-2-1):

m/z:[M+H]⁺554.4；¹H NMR(400MHz,CDCl₃): δ 8.80 (s, 1H), 8.25 (d, J=2.0Hz, 1H), 8.22 (s, 1H), 7.75 (t, J=7.6Hz, 1H), 7.68 (d, J=8.0Hz, 1H), 7.30 (d, J=3.6Hz, 1H), 7.27 (d, J=7.6Hz, 1H), 6.39 (d, J=3.6Hz, 1H), 5.67-5.60 (m, 1H), 4.97 (d, J=10.4Hz, 1H), 4.87 (d, J=18.0Hz, 1H), 4.75-4.71 (m, 1H), 4.69 (d, J=6.4Hz, 1H), 3.84 (s, 1H), 2.96 (d, J= 11.6Hz,2H),2.31(s,3H),2.23-2.16(m,2H),2.04-2.01(m,4H),1.51(s,6H)。

Compound 7-2-1prep-HPLC purification process use purification condition 2 or 3, obtain the corresponding free alkali of 7-2-1 and Hydrochloride.

Embodiment 59: the synthesis of compound 7-2-2

Using the synthetic method of compound 1-1-1, compound 1.3 is replaced with 15.4 and obtains 2- allyl -1- (6- (2- Hydroxyl propyl- 2- yl) pyridine -2- base) -6- ((1- methyl -4- (pyrrolidin-1-yl) -1H- indoles -6- base) amino) -1H- pyrazoles And [3,4-d] pyrimidine -3 (2H) -one trifluoroacetate (compound 7-2-2):

m/z:[M+H]⁺525.2；¹H NMR(400MHz,DMSO-d₆):δ10.07(br.s,1H),8.85(s,1H), 8.00-7.92 (m, 1H), 7.86-7.77 (m, 1H), 7.63 (d, J=7.6Hz, 1H), 7.33 (s, 1H), 7.05 (d, J= 3.2Hz, 1H), 6.53 (d, J=2.8Hz, 1H), 6.28 (s, 1H), 5.72-5.59 (m, 1H), 5.36 (s, 1H), 5.02-4.96 (m, 1H), 4.84-4.75 (m, 1H), 4.64 (d, J=7.2Hz, 1H), 3.64 (s, 3H), 3.50-3.41 (m, 4H), 2.02- 1.89(m,4H),1.45(s,6H)。

Embodiment 60: the synthesis of compound 7-2-3

Using the synthetic method of compound 1-1-1, compound 1.3 is replaced with 15.5 and obtains 2- allyl -6- ((4- (two Methylamino) -1- Methyl-1H-indole -6- base) amino) -1- (6- (2- hydroxyl propyl- 2- yl) pyridine -2- base) -1H- pyrazolo [3,4-d] pyrimidine -3 (2H) -one trifluoroacetate (compound 7-2-3):

m/z:[M+H]⁺499.2；¹H NMR(400MHz,DMSO-d₆):δ10.29(br.s,1H),9.52(s,1H), 7.99-7.95 (m, 1H), 7.82-7.75 (m, 2H), 7.63 (d, J=7.8Hz, 1H), 7.30 (br.s, 1H), 6.97-6.96 (m,1H),6.57(s,1H),5.69-5.61(m,1H),5.05-4.98(m,1H),4.83-4.78(m,1H),4.66-4.62 (m,2H),3.72(s,3H),3.04(s,6H),1.45(s,6H)。

Embodiment 61: the synthesis of compound 7-2-4

Using the synthetic method of compound 1-1-1, compound 1.3 is replaced with 18.3 and obtains 2- allyl -6- ((1- ring Propyl -4- (4- methylpiperazine-1-yl) -1H- indoles -6- base) amino) -1- (6- (2- hydroxyl propyl- 2- yl) pyridine -2- base) - 1H- pyrazolo [3,4-d] pyrimidine -3 (2H) -one (compound 7-2-4):

m/z:[M+H]⁺580.3；¹H NMR(400MHz,CDCl₃):δ8.89(s,1H),7.75-7.79(m,2H),7.48- 7.54 (m, 2H), 7.35 (d, J=8.0Hz, 1H), 7.05-7.06 (m, 1H), 6.68 (s, 1H), 6.40-6.41 (m, 1H), 5.69-5.75 (m, 1H), 5.07 (d, J=10.0Hz, 1H), 4.95 (d, J=16.8Hz, 1H), 4.74 (d, J=6.0Hz, 1H),4.00(br.s,1H),3.22-3.30(m,4H),2.66(m,4H),2.41(s,3H),1.59(s,6H),0.98(s, 4H)。

Embodiment 62: the synthesis of compound 7-2-5

Using the synthetic method of compound 1-1-1, compound 1.3 is replaced with 19.3 and obtains 2- allyl -6- ((1- (2- Hydroxyethyl) -4- (4- methylpiperazine-1-yl) -1H- indoles -6- base) amino) -1- (6- (2- hydroxyl propyl- 2- yl) pyridine -2- Base) -1H- pyrazolo [3,4-d] pyrimidine -3 (2H) -one (compound 7-2-5):

m/z:[M+H]⁺584.3；¹H NMR(400MHz,CDCl₃):δ8.92(s,1H),8.40(br.s,1H),7.86(t, J=8.0Hz, 1H), 7.74 (d, J=8.4Hz, 1H), 7.39 (d, J=6.8Hz, 1H), 7.10 (s, 1H), 6.59 (s, 1H), 6.48 (s, 1H), 5.66-5.74 (m, 1H), 5.05 (d, J=10.0Hz, 1H), 4.93 (d, J=16.8Hz, 1H), 4.73 (d, J =6.0Hz, 1H), 4.21-4.24 (m, 3H), 3.95 (t, J=4.8Hz, 2H), 3.17 (s, 4H), 2.61-2.65 (m, 4H), 2.40(s,3H),1.62(s,6H)。

Embodiment 63: the synthesis of compound 7-2-6

Using the synthetic method of compound 1-1-1, compound 1.3 is replaced with 15.6 and obtains 2- allyl -1- (6- (2- Hydroxyl propyl- 2- yl) pyridine -2- base) -6- ((1- methyl -4- morpholinyl -1H- indoles -6- base) amino) -1H- pyrazolo [3,4- D] pyrimidine -3 (2H) -one (compound 7-2-6):

m/z:[M+H]⁺541.2；¹H NMR(400MHz,CD₃OD): δ 8.78 (s, 1H), 7.89 (t, J=8.0Hz, 1H), 7.73 (d, J=7.6Hz, 1H), 7.63 (d, J=7.7Hz, 1H), 7.52 (s, 1H), 7.02 (d, J=3.2Hz, 1H), 6.63 (s, 1H), 6.36 (d, J=3.2Hz, 1H), 5.72-5.63 (m, 1H), 5.00 (d, J=10.0Hz, 1H), 4.84 (s, 1H), 4.74 (d, J=6.0Hz, 2H), 3.85-3.83 (m, 4H), 3.65 (s, 3H), 3.13-3.05 (m, 4H), 1.55 (s, 6H).

Embodiment 64: the synthesis of compound 7-2-7 and 7-2-8

Using the synthetic method of compound 1-1-1, compound 1.3 is replaced with 15.7 and obtains 4- (6- ((2- allyl -1- (6- (2- hydroxyl propyl- 2- yl) pyridine -2- base) -3- oxo -2,3- dihydro-1 h-pyrazole simultaneously [3,4-d] pyrimidine -6- base) amino) - 1- Methyl-1H-indole -4- base) piperazine -1- carboxylic acid tert-butyl ester (compound 7-2-7).

Compound 7-2-7 (125mg, 0.19mmol) is dissolved in methylene chloride and trifluoroacetic acid (4mL, 1:1), is reacted After system is stirred at room temperature 1 hour, directly concentration removes solvent, and residue is purified with prep-HPLC (method 1) and obtains 2- alkene Propyl -1- (6- (2- hydroxyl propyl- 2- yl) pyridine -2- base) -6- ((1- methyl -4- (piperazine -1- base) -1H- indoles -6- base) ammonia Base) (compound 7-2-8,30mg, yield: 36%) being yellow to -1H- pyrazolo [3,4-d] (2H) -one of pyrimidine -3 trifluoroacetate Solid.m/z:[M+H]⁺540.2；¹H NMR(400MHz,DMSO-d₆):δ10.20(s,1H),8.88(s,1H),8.79(s, 1H), 8.04-7.94 (m, 1H), 7.85-7.60 (m, 1H), 7.24 (d, J=3.2Hz, 1H), 6.71 (s, 1H), 6.42 (d, J= 2.8Hz,1H),5.72-5.60(m,1H),5.02-4.96(m,1H),4.85-4.77(m,1H),4.68-4.62(m,2H), 3.70(s,3H),3.37-3.24(m,8H),1.45(s,6H)。

Embodiment 65: the synthesis of compound 7-2-9 and 7-2-10

Using the synthetic method of compound 1-1-1, compound 1.3 is replaced with 20.3 and obtains 6- ((2- allyl -1- (6- (2- hydroxyl propyl- 2- yl) pyridine -2- base) -3- oxo -2,3- dihydro-1 h-pyrazole simultaneously [3,4-d] pyrimidine -6- base) amino) -4- (4- methylpiperazine-1-yl) -1H- indoles -1- carboxylic acid tert-butyl ester (compound 7-2-9).m/z:[M+H]⁺640.4；¹H NMR (400MHz,CDCl₃):δ9.04(s,1H),8.28(br.s,1H),7.80-7.89(m,3H),7.51-7.52(m,1H),7.34 (d, J=7.6Hz, 1H), 6.79 (s, 1H), 6.56 (s, 1H), 5.68-5.78 (m, 1H), 5.07 (d, J=10.8Hz, 1H), 4.96 (d, J=16.8Hz, 1H), 4.75-4.80 (m, 2H), 4.10-4.16 (b, 1H), 3.15 (s, 4H), 2.66 (s, 4H), 2.43(s,3H),1.61(s,9H),1.57(s,6H)。

Using the synthetic method of compound 7-2-8, compound 7-2-7 is replaced with into 7-2-9 and obtains 2- allyl -1- (6- (2- hydroxyl propyl- 2- yl) pyridine -2- base) -6- ((4- (4- methylpiperazine-1-yl) -1H- indoles -6- base) amino) -1H- pyrazoles And [3,4-d] pyrimidine -3 (2H) -one trifluoroacetate (compound 7-2-10).m/z:[M+H]⁺540.2；¹H NMR(400MHz, CDCl₃): δ 8.83 (s, 1H), 7.99 (t, J=8.0Hz, 1H), 7.79-7.82 (m, 1H), 7.64-7.74 (m, 2H), 7.23- 7.27 (m, 1H), 6.68 (br.s, 1H), 6.48 (s, 1H), 5.68-5.76 (m, 1H), 5.05 (d, J=10.4Hz, 1H), 4.91-4.94 (m, 1H), 4.82-4.86 (m, 2H), 3.83-3.86 (m, 2H), 3.65 (d, J=12.0Hz, 2H), 3.42- 3.47(m,2H),3.03-3.15(m,5H),1.58(s,6H)。

Embodiment 66: the synthesis of compound 7-2-11 and 7-2-12

Using the synthetic method of compound 1-1-1, compound 1.3 is replaced with 15.8 and obtains (S) -4- (6- ((2- allyl Base -1- (6- (2- hydroxyl propyl- 2- yl) pyridine -2- base) -3- oxo -2,3- dihydro-1 h-pyrazole simultaneously [3,4-d] pyrimidine -6- base) Amino) -1- Methyl-1H-indole -4- base) -2- methyl piperazine -1- carboxylic acid tert-butyl ester (compound 7-2-11).m/z:[M+H]⁺ 654.4。

Using the synthetic method of compound 7-2-8, compound 7-2-7 is replaced with into 7-2-11 and obtains (S) -2- allyl - 1- (6- (2- hydroxyl propyl- 2- yl) pyridine -2- base) -6- ((1- methyl -4- (3- methylpiperazine-1-yl) -1H- indoles -6- base) ammonia Base) -1H- pyrazolo [3,4-d] pyrimidine -3 (2H) -one (compound 7-2-12).m/z:[M+H]⁺554.2；¹H NMR(400MHz, CDCl₃): δ 8.86 (s, 1H), 7.79 (d, J=2.2Hz, 2H), 7.44 (s, 1H), 7.34 (t, J=4.0Hz, 1H), 6.98 (d, J=3.0Hz, 1H), 6.48 (s, 1H), 6.45 (d, J=2.8Hz, 1H), 5.73-5.64 (m, 1H), 5.03 (d, J=10.0Hz, 1H), 4.92 (d, J=17.2Hz, 1H), 4.74 (d, J=6.0Hz, 2H), 3.72 (s, 3H), 3.55 (d, J=11.2Hz, 2H), 3.20-3.09 (m, 3H), 2.76-2.70 (m, 1H), 2.42 (t, J=10.8Hz, 1H), 1.57 (s, 6H), 1.12 (d, J= 6.4Hz,3H)。

Embodiment 67: the synthesis of compound 7-2-13

Using the synthetic method of compound 1-1-1, compound 1.3 is replaced with 15.9 and obtains 2- allyl -1- (6- (2- Hydroxyl propyl- 2- yl) pyridine -2- base) -6- ((4- (4- isopropyl piperazine -1- base) -1- Methyl-1H-indole -6- base) amino) - 1H- pyrazolo [3,4-d] pyrimidine -3 (2H) -one (compound 7-2-13):

m/z:[M+H]⁺582.0；¹H NMR(400MHz,CD₃OD):δ8.90-8.73(m,1H),8.02-7.81(m,1H), 7.80-7.69(m,1H),7.68-7.45(m,2H),7.08-6.96(m,1H),6.67-6.54(m,1H),6.43-6.30(m, 1H),5.80-5.57(m,1H),5.11-4.99(m,1H),4.79-4.69(m,2H),3.74-3.56(m,3H),3.16(s, 4H),2.88-2.60(m,5H),1.56(s,6H),1.20-1.03(m,6H)。

Embodiment 68: the synthesis of compound 7-2-14

Using the synthetic method of compound 1-1-1, compound 1.3 is replaced with 15.10 and obtains 2- allyl -1- (6- (2- Hydroxyl propyl- 2- yl) pyridine -2- base) -6- ((1- methyl -4- ((1S, 4S) -5- methyl -2,5- diazabicyclo [2.2.1] hept- 2- yl) -1H- indoles -6- base) amino) -1H- pyrazolo [3,4-d] pyrimidine -3 (2H) -one (compound 7-2-14):

m/z:[M+H]⁺566.3；¹H NMR(400MHz,CDCl₃): δ 8.86 (s, 1H), 7.81 (d, J=3.6Hz, 2H), 7.35 (t, J=4.0Hz, 1H), 7.20 (s, 1H), 6.90 (d, J=3.2Hz, 1H), 6.51 (d, J=2.8Hz, 1H), 6.08 (s, 1H), 5.73-5.65 (m, 1H), 5.03 (d, J=10.0Hz, 1H), 4.93 (d, J=16.8Hz, 1H), 4.78-4.68 (m, 2H), 4.33 (s, 1H), 3.77-3.72 (m, 2H), 3.69 (s, 3H), 3.59 (s, 1H), 3.03 (d, J=8.4Hz, 1H), 2.86 (d, J=9.6Hz, 1H), 2.41 (s, 3H), 2.06-1.98 (m, 2H), 1.57 (s, 6H).

Embodiment 69: the synthesis of compound 7-3-1

Using the synthetic method of compound 1-1-1, compound 1.3 is replaced with 21.5 and obtains 2- allyl -1- (6- (2- Hydroxyl propyl- 2- yl) pyridine -2- base) -6- ((1- methyl -4- (1- methyl piperidine -4- base) -1H- indoles -6- base) amino) -1H- Pyrazolo [3,4-d] pyrimidine -3 (2H) -one trifluoroacetate (compound 7-3-1):

m/z:[M+H]⁺553.0。

Embodiment 70: the synthesis of compound 8-1-1

Using the synthetic method of compound 1-1-1, compound 1.3 is replaced with 2.10 and obtains 2- allyl -1- (6- (2- Hydroxyl propyl- 2- yl) pyridine -2- base) -6- ((1- (1- isopropyl piperidin-4-yl) -1H- pyrrolo- [2,3-b] pyridine -5- base) ammonia Base) -1H- pyrazolo [3,4-d] pyrimidine -3 (2H) -one (compound 8-1-1):

m/z:[M+H]⁺568.4；¹H NMR(400MHz,CDCl₃): δ 8.86 (s, 1H), 8.31 (d, J=2.0Hz, 1H), 8.29 (s, 1H), 7.83 (t, J=8.0Hz, 1H), 7.55 (d, J=8.0Hz, 1H), 7.41 (d, J=3.6Hz, 1H), 7.34 (d, J=7.6Hz, 1H), 6.46 (d, J=3.2Hz, 1H), 5.74-5.67 (m, 1H), 5.04 (d, J=10.4Hz, 1H), 4.94 (d, J=17.2Hz, 1H), 4.81-4.77 (m, 1H), 4.76 (d, J=6.4Hz, 2H), 3.91 (s, 1H), 3.09 (d, J= 10.4Hz, 2H), 2.87 (s, 1H), 2.49 (s, 2H), 2.12 (s, 4H), 1.59 (d, J=10.4Hz, 6H), 1.13 (d, J= 6.4Hz,6H)。

Embodiment 71: the synthesis of compound 8-1-2

Using the synthetic method of compound 1-1-1, compound 1.3 is replaced with 2.11 and obtains 2- allyl -1- (6- (2- Hydroxyl propyl- 2- yl) pyridine -2- base) -6- ((1- (1- methyl piperidine -4- base) -1H- pyrrolo- [2,3-b] pyridine -5- base) ammonia Base) -1H- pyrazolo [3,4-d] pyrimidine -3 (2H) -one (compound 8-1-2):

m/z:[M+H]⁺540.3；¹H NMR(400MHz,CDCl₃): δ 8.80 (s, 1H), 8.25 (d, J=2.0Hz, 1H), 8.22 (s, 1H), 7.75 (t, J=7.6Hz, 1H), 7.68 (d, J=8.0Hz, 1H), 7.30 (d, J=3.6Hz, 1H), 7.27 (d, J=7.6Hz, 1H), 6.39 (d, J=3.6Hz, 1H), 5.67-5.60 (m, 1H), 4.97 (d, J=10.4Hz, 1H), 4.87 (dd, J=0.8,17.2Hz, 1H), 4.75-4.70 (m, 1H), 4.69 (d, J=6.4Hz, 2H), 3.84 (s, 1H), 2.96 (d, J =10.6Hz, 2H), 2.31 (s, 3H), 2.23-2.16 (m, 2H), 2.04-2.01 (m, 4H), 1.53 (s, 6H).

Embodiment 72: the synthesis of compound 8-2-1

Using the synthetic method of compound 1-1-1, compound 1.3 is replaced with 14.7 and obtains 2- allyl -1- (6- (2- Hydroxyl propyl- 2- yl) pyridine -2- base) -6- ((1- (pyridin-3-yl) -1H- pyrrolo- [2,3-b] pyridine -5- base) amino) -1H- Pyrazolo [3,4-d] pyrimidine -3 (2H) -one (compound 8-2-1):

m/z:[M+H]⁺520.2；¹H NMR(400MHz,CD₃OD): δ 9.04 (d, J=2.4Hz, 1H), 8.89 (s, 1H), 8.60 (dd, J=1.6,4.8Hz, 1H), 8.41 (s, 2H), 8.29 (dd, J=1.2,8.4Hz, 1H), 7.87 (t, J=7.6Hz, 1H), 7.75 (dd, J=4.0,8.4Hz, 1H), 7.59 (d, J=4.0Hz, 1H), 7.51 (dd, J=4.8,8.8Hz, 1H), 7.37 (dd, J=4.0,7.6Hz, 1H), 6.68 (d, J=3.6Hz, 1H), 5.76-5.66 (m, 1H), 5.05 (dd, J=1.2, 10.0Hz, 1H), 4.95 (dd, J=1.6,17.2Hz, 1H), 4.76 (d, J=6.0Hz, 2H), 1.58 (d, J=8.8Hz, 6H).

Embodiment 73: the synthesis of compound 8-2-2

Using the synthetic method of compound 1-1-1, compound 1.3 is replaced with 14.8 and obtains 2- allyl -1- (6- (2- Hydroxyl propyl- 2- yl) pyridine -2- base) -6- ((1- (pyridine -2- base) -1H- pyrrolo- [2,3-b] pyridine -5- base) amino) -1H- Pyrazolo [3,4-d] pyrimidine -3 (2H) -one (compound 8-2-2):

m/z:[M+H]⁺520.2；¹H NMR(400MHz,CD₃OD): δ 8.87 (s, 1H), 8.81 (d, J=8.4Hz, 1H), 8.53-8.46 (m, 3H), 8.34 (d, J=4.0Hz, 1H), 8.04-7.94 (m, 2H), 7.78 (d, J=7.6Hz, 1H), 7.66 (d, J=8.0Hz, 1H), 7.30-7.26 (m, 1H), 6.69 (d, J=4.0Hz, 1H), 5.79-5.66 (m, 1H), 5.07-5.02 (m,2H),4.87-4.77(m,2H),1.57(s,6H)。

Embodiment 74: the synthesis of compound 9-1-1

Using the synthetic method of compound 1-1-1, compound 1.3 is replaced with 16.3 and obtains 2- allyl -1- (6- (2- Hydroxyl propyl- 2- yl) pyridine -2- base) -6- ((3- (4- methylpiperazine-1-yl) quinoline -7- base) amino) -1H- pyrazolo [3,4- D] pyrimidine -3 (2H) -one trifluoroacetate (compound 9-1-1):

m/z:[M+H]⁺552.3；¹H NMR(400MHz,DMSO-d₆):δ10.52(br.s,1H),8.95(s,1H),8.86 (s, 1H), 8.48 (s, 1H), 8.09-8.03 (m, 1H), 7.89 (d, J=8.4Hz, 1H), 7.82-7.70 (m, 2H), 7.64 (d, J=7.6Hz, 1H), 7.50 (s, 1H), 5.77-5.62 (m, 1H), 5.35 (s, 1H), 5.04-4.80 (m, 2H), 4.73 (d, J= 5.2Hz,2H),3.30-3.25(m,4H),2.58-2.51(m,4H),2.26(s,3H),1.47(s,6H)。

Embodiment 75: the synthesis of compound 9-2-1

Using the synthetic method of compound 1-1-1, compound 1.3 is replaced with 16.5 and obtains 2- allyl -1- (6- (2- Hydroxyl propyl- 2- yl) pyridine -2- base) -6- ((2- (4- methylpiperazine-1-yl) quinoline -6- base) amino) -1H- pyrazolo [3,4- D] pyrimidine -3 (2H) -one trifluoroacetate (compound 9-2-1):

m/z:[M+H]⁺552.4；¹H NMR(400MHz,CD₃OD):δ10.50(br.s,1H),9.85(br.s,1H), 8.93 (s, 1H), 8.30 (br.s, 1H), 8.00-8.10 (m, 2H), 7.82-7.89 (m, 2H), 7.63 (t, J=7.2Hz, 2H), 7.36 (d, J=9.2Hz, 1H), 5.62-5.74 (m, 1H), 5.00 (dd, J=10.4,1.6Hz, 1H), 4.83 (dd, J= 17.2,1.2Hz,1H),4.55-4.75(m,4H),3.55(s,3H),3.20-3.32(m,2H),3.07-3.19(m,2H), 2.87(s,3H),1.46(s,6H)。

Biological test embodiment

The Enzyme assay of embodiment 1:Wee1

In the present invention, shines with ATP-Glo Max and detect kinase reagent box (Promega) progress Wee1 enzymatic examination It tests.Kinase activity is evaluated by the ATP quantity retained in solution after quantitative detection kinase reaction.In test luminous signal with ATP quantity is proportional, is in inverse ratio with kinase activity.Compound concentration range is 0.5nM~30 μM in test.Compound is used 10%DMSO dissolution, takes the solution of 5 μ L to be added in the reaction of 50 μ L, and the concentration of DMSO is 1% in end reaction.It is anti-at 30 DEG C It answers 50 minutes.It include 40mM trishydroxymethylaminomethane, pH7.4,10mM MgCl in 50 μ L reaction mixtures₂, 0.1mg/ml BSA, 2mM DTT, 0.1mg/ml Poly (Lys, Tyr) substrate, 10 μM of ATP and Wee1.After enzymatic reaction, 50 μ L are added ATP-Glo Max, which shines, detects kinase assay solution (Promega), and hatches 15 minutes at room temperature.It is measured using microplate reader Luminous signal.In part test, known Wee1 inhibitor is added as positive control.It analyzes and sends out with Graphpad software Light data.Luminous intensity difference in the case of luminous intensity and Wee1 presence under Wee1 deletion condition is defined as 100% activity (Lut–Luc).Luminous intensity signal (Lu) in the case of existing using compound, % activity calculate in accordance with the following methods:

% activity={ (Lut-Lu)/(Lut-Luc) } × 100%, the wherein luminous intensity of Lu=compound:

% activity value and corresponding series compound concentration amount effect curve, equation Y are drawn with nonlinear regression analysis =B+ (T-B)/1+10 ((LogEC₅₀- X) × Hill Slope), Y=percent activity, B=minimum percent activity, T=is most Logarithm=the slope factor or Hill coefficient of big percent activity, X=compound and the Hill gradient.IC₅₀Value is by causing half most Big percent activity concentration determines.

Embodiment 2: by p-CDK1Y15ELISA test based on Wee1 cytoactive detection

In the present invention, the bioactivity of compound is evaluated with test cell line.Human colon is used in this test Gland cell system WiDr carries out.The activity of specific Wee1 inhibitor is assessed with p-CDK1Y15ELISA test method(s).Test in detail Method is described as follows:

WiDr cell is placed in Dulbecco ' s Modified Eagle ' the s medium containing 10%FBS and is cultivated, is cultivated 37 DEG C of environment and 5%CO₂.Compound concentration range 0.5nM~30 μM.It will be added after diluted chemical compound into 24 orifice plates, and it is thin Born of the same parents hatch 24 hours together.Using DMSO as negative control.Known Wee1 inhibitor is added in part test as sun Property control.According to the instruction of production firm, in p-CDK1Y15 test, cell is dissolved and passes through the survey of colorimetric ELISA kit Examination judges the quantity of p-CDK1Y15.Spectrophotometer measures optical density.OD data are analyzed with Graphpad software, are obtained To IC₅₀The matched curve of value and compound.

Compound number	IC₅₀(nM)
		1-1-1	99.7
1-3-1	55.5
		1-3-2	65.3
1-4-1	59.4
		7-1-1	41.1
7-2-1	65.7
		AZD1775	254

Embodiment 3: cell proliferation test

In the present invention, the bioactivity of compound is evaluated with cell assay.MG63 (ATCC CRL-1427), people Class osteosarcoma cell line cultivates cell kind in 96 orifice plate of Dulbecco ' s Modified Eagle ' s medium, supply 10% Fetal calf serum and 1% (V/V) l-glutamine, culture environment are 37 DEG C and 5%CO₂.Compound concentration range is 4.5nM~30 μM.Wee1 inhibitor stock solution is dissolved in into DMSO and is added into the medium of instruction concentration, is hatched 72 hours.Negative control cell Only handled with vehicle.In part test, known Wee1 inhibitor is added as positive control.In the description of product Cell counting Kit -8 (CCK-8, Sigma-Aldrich) is used to evaluate cell activity under the instruction of book.With Graphpad software analyzes data, and obtains IC₅₀Value and compound matched curve.

Embodiment 4: effect experiment in human lung cancer H1299 xenograft tumor models body

Cell culture: human lung cancer H1299 cell (being purchased from ATCC) recovery after, routine culture in containing 10% heat inactivate tire ox Serum, 100U/mL penicillin, 100 μ g/mL streptomysins and L-Glutamine (2mM) EMEM culture medium in, be placed in 5%CO₂'s Constant incubator, 37 DEG C of cultures.With secondary culture 2 times weekly after trypsase-EDTA digestion.Collect the cell of exponential phase of growth And count, for inoculation.

Experimental animal: BALB/c nude mouse, 7-8 weeks, 16-21g, is purchased from Beijing dimension tonneau China experimental animal skill by 24 Art Co., Ltd.

4 experimental groups are set, and dosage regimen is as shown in table 1:

Table 1

Group	Mouse quantity	Test-compound	Dosage	Administration mode	Drug dosage schedule
						1	6	Vehicle	--	p.o.	Bid × 16 day
2	6	AZD1775	60mg/kg	p.o.	Bid × 16 day
						3	6	Compound 7-2-1	30mg/kg	p.o.	Qd × 16 day
4	6	Compound 7-2-1	15mg/kg	p.o.	Qd × 16 day

Note: p.o.: it is oral, bid:2 times/day, qd:1 times/day

Experimental method: by H1299 cell strain (5 × 10⁶A/only) and it is inoculated in dorsal sc on the right side of experiment mice, it is every small Mouse inoculum concentration is the PBS:Matrigel (volume ratio 1:1) of 0.1mL, the growing state of routine observation tumour, extremely to tumour growth 100mm³It is grouped, is administered according to dosage regimen (table 1), whole experiment process at random according to tumor size and mouse weight when left and right In, 2~3 mouse weights and tumor size are measured weekly.

Tumor size calculation formula: gross tumor volume (mm³)=0.5 × (tumour major diameter × tumour minor axis²)。

Four experimental group tumor volume change curves are shown in attached drawing 1, the results showed that compared to positive control AZD1775, this hair Bright compound 7-2-1 is in the case where lower dosage and longer dosing interval, in human lung cancer H1299 xenograft tumor models On can also show better tumor killing effect.

Positive control in the present invention in biological Examples 1,2,3 and 4 is AZD1775, chemical name: 2- allyl -1- (6- (2- hydroxyl propyl- 2- yl) pyridine -2- base) -6- ((4- (4- methylpiperazine-1-yl) phenyl) amino) -1H- pyrazolo [3,4- D] pyrimidine -3 (2H) -one (2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -6- ((4- (4- Methylpiperazin-1-yl) phenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-3 (2H)-one), close It can refer to WO2007126122A1 embodiment 9 at method.

Claims

1. a kind of compound as shown in Formulas I or I ', its isomers, prodrug, stable isotope derivatives or pharmaceutically acceptable Salt；

Wherein, W is N or CR₇；

U and V is respectively selected from N or CR₈；And U and V are not N simultaneously；

R₁For hydrogen, halogen, C_2-6Alkynyl, C_2-6Alkenyl, aryl, naphthenic base, Heterocyclylalkyl, heteroaryl or substituted alkyl；The alkane When base is substituted, optionally replaced at an arbitrary position by following one or more groups: halogen, halogenated alkoxy, amino Naphthenic base ,-SR_a、-OR_a、-OC(O)R_a、-OC(O)NR_aR_b、-C(O)OR_a、-C(O)R_a、-C(O)NR_aR_b、-NR_aR_b、-NR_aC(O) R_b、-NR_aS(O)₂R_b、-S(O)_1-2R_b、-S(O)₂NR_aR_bWith-NR_aS(O)₂NR_aR_b；

R₃For hydrogen, halogen ,-CN ,-NO₂、-SR_c、-OR_c、-OC(O)R_c、-OC(O)OR_c、-OC(O)NR_cR_d、-C(O)OR_c、-C(O) R_c、-C(O)NR_cR_d、-NR_cR_d、-NR_cC(O)R_d、-N(R_c)C(O)OR_d、-N(R_c)C(O)NR_cR_d、-NR_cS(O)₂R_d、-NR_cC (= NH)R_d、-NR_cC (=NH) NR_cR_d、-S(O)_1-2R_c、-S(O)₂NR_cR_d、-NR_cS(O)₂NR_cR_d, substituted or unsubstituted alkyl, take It is generation or unsubstituted naphthenic base, substituted or unsubstituted Heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted miscellaneous Aryl, substituted or unsubstituted cycloalkyl-alkyl, substituted or unsubstituted hetercycloalkylalkyl, substituted or unsubstituted aryl alkane Base, substituted or unsubstituted heteroaryl alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl；The alkyl, ring Alkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyl-alkyl, hetercycloalkylalkyl, aryl alkyl, heteroaryl alkyl, alkenyl or When alkynyl is substituted, optionally replaced at an arbitrary position by following one or more groups: halogen, alkyl, halogenated alkyl, Halogenated alkoxy, hydroxy alkyl, aminoalkyl, aminocycloalkyl, alkenyl, alkynyl ,-CN ,-NO₂、-SR_a、-OR_a、-OC(O) R_a、-OC(O)OR_a、-OC(O)NR_aR_b、-C(O)OR_a、-C(O)R_a、-C(O)NR_aR_b、-NR_aR_b、-NR_aC(O)R_b、-N(R_a)C(O) OR_b、-N(R_a)C(O)NR_aR_b、-NR_aS(O)₂R_b、-NR_aC (=NH) R_b、-NR_aC (=NH) NR_aR_b、-S(O)_1-2R_b、-S(O)₂NR_aR_bWith-NR_aS(O)₂NR_aR_b；

R₄、R₅、R₆And R₇It is separately hydrogen, halogen, hydroxyl, cyano, nitro, sulfydryl, amino, alkyl, alkoxy, alkane sulphur Base, halogenated alkyl, halogenated alkoxy, C_2-6Alkynyl, C_2-6Alkenyl, aryl, naphthenic base, Heterocyclylalkyl, heteroaryl ,-OC (O) R_c、- OC(O)OR_c、-OC(O)N(R_c)₂、-C(O)OR_c、-C(O)R_c、-C(O)N(R_c)₂、-N(R_c)₂、-NHC(O)R_c、-NHC(O)OR_c、- NHC(O)N(R_c)₂、-NHS(O)₂R_c、-S(O)_0-2R_cOr-S (O)₂N(R_c)₂；

R₃And R₄For independent substituent group, alternatively, R₃And R₄The annular atom being connect with it is formed together A ring, the A ring be replace or Unsubstituted naphthenic base, substituted or unsubstituted Heterocyclylalkyl, substituted or unsubstituted phenyl or substituted or unsubstituted 5-6 Unit's heteroaryl；When the A ring is substituted, optionally replaced at an arbitrary position by following one or more groups: oxo base, Thio group, halogen ,-CN ,-NO₂、-SR_c、-OR_c、-OC(O)R_c、-OC(O)OR_c、-OC(O)NR_cR_d、-C(O)OR_c、-C(O)R_c、- C(O)NR_cR_d、-NR_cR_d、-NR_cC(O)R_d、-N(R_c)C(O)OR_d、-N(R_c)C(O)NR_cR_d、-NR_cS(O)₂R_d、-NR_cC (=NH) R_d、-NR_cC (=NH) NR_cR_d、-S(O)_1-2R_c、-S(O)₂NR_cR_d、-NR_cS(O)₂NR_cR_d, substituted or unsubstituted alkyl, substitution Or unsubstituted naphthenic base, substituted or unsubstituted Heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl Base, substituted or unsubstituted cycloalkyl-alkyl, substituted or unsubstituted hetercycloalkylalkyl, substituted or unsubstituted aryl alkane Base, substituted or unsubstituted heteroaryl alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl；The alkyl, ring Alkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyl-alkyl, hetercycloalkylalkyl, aryl alkyl, heteroaryl alkyl, alkenyl or When alkynyl is substituted, optionally replaced at an arbitrary position by following one or more groups: halogen, alkyl, halogenated alkyl, Halogenated alkoxy, hydroxy alkyl, aminoalkyl, alkenyl, alkynyl ,-CN ,-NO₂、-SR_c、-OR_c、-OC(O)R_c、-OC(O)OR_c、- OC(O)N(R_c)₂、-C(O)OR_c、-C(O)R_c、-C(O)N(R_c)₂、-N(R_c)₂、-NHC(O)R_c、-NHC(O)OR_c、-NHC(O)N (R_c)₂、-NHS(O)₂R_c,-NHC (=NH) R_c,-NHC (=NH) N (R_c)₂、-S(O)_1-2R_c、-S(O)₂N(R_c)₂With-NHS (O)₂N (R_c)₂；

R₈And R₁₁It is separately hydrogen ,-C (O) OR_c、-C(O)R_c、-C(O)NR_cR_d、-S(O)_1-2R_c、-S(O)₂NR_cR_d、- NR_cR_d、-NR_cS(O)_1-2R_d、-NR_cC(O)R_d、-NR_cS(O)₂NR_cR_d, substituted or unsubstituted alkyl, substituted or unsubstituted ring Alkyl, substituted or unsubstituted Heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substitution or not Substituted cycloalkyl-alkyl, substituted or unsubstituted hetercycloalkylalkyl, substituted or unsubstituted aryl alkyl, substitution do not take The heteroaryl alkyl in generation, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl；The alkyl, naphthenic base, heterocycle alkane Base, aryl, heteroaryl, cycloalkyl-alkyl, hetercycloalkylalkyl, aryl alkyl, heteroaryl alkyl, alkenyl or alkynyl are substituted When, optionally by following one or more R₁₀Replace at an arbitrary position；

R₉For hydrogen ,-C (O) OR_c、-C(O)R_c、-C(O)NR_cR_d、-S(O)_1-2R_c、-S(O)₂NR_cR_d, substituted or unsubstituted alkyl, It is substituted or unsubstituted naphthenic base, substituted or unsubstituted Heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted Heteroaryl, substituted or unsubstituted cycloalkyl-alkyl, substituted or unsubstituted hetercycloalkylalkyl, substituted or unsubstituted aryl Alkyl, substituted or unsubstituted heteroaryl alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl；The alkyl, Naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyl-alkyl, hetercycloalkylalkyl, aryl alkyl, heteroaryl alkyl, alkenyl Or alkynyl be substituted when, optionally by following one or more R₁₀Replace at an arbitrary position；

R₁And R₉For independent substituent group, alternatively, R₁And R₉It is interconnected to form 4-8 membered heterocycloalkyl, the Heterocyclylalkyl can also be into One step is by 1~3 C_1-6Alkyl or C_3-6Naphthenic base arbitrarily replaces；

Each R₁₀It is separately hydrogen, halogen, alkyl, halogenated alkyl, halogenated alkoxy, hydroxy alkyl, aminoalkyl, amino Naphthenic base, alkenyl, alkynyl, naphthenic base, Heterocyclylalkyl, R_a、-CN、-NO₂、-SR_a、-OR_a、-OC(O)R_a、-OC(O)OR_a、-OC (O)NR_aR_b、-C(O)OR_a、-C(O)R_a、-C(O)NR_aR_b、-NR_aR_b、-NR_aC(O)R_b、-N(R_a)C(O)OR_b、-N(R_a)C(O) NR_aR_b、-NR_aS(O)₂R_b、-NR_aC (=NH) R_b、-NR_aC (=NH) NR_aR_b、-S(O)_1-2R_b、-S(O)₂NR_aR_bOr-NR_aS(O)₂NR_aR_b；

R_aAnd R_bSeparately it is selected from hydrogen, C_1-6Alkyl, C_1-6Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, C_3-8Naphthenic base, 3-8 member are miscellaneous Naphthenic base, C_6-10Aryl, 5-6 unit's heteroaryl, C_3-8Naphthenic base C_1-6Alkyl, 3-8 membered heterocycloalkyl C_1-6Alkyl, phenyl C_1-6Alkane Base or 5-6 unit's heteroaryl C_1-6Alkyl；The C_1-6Alkyl, C_1-6Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, C_3-8Naphthenic base, 3-8 member Heterocyclylalkyl, C_6-10Aryl or 5-6 unit's heteroaryl are unsubstituted or are selectively selected from halogen, hydroxyl, ammonia by 1~3 Base, carboxyl, C_1-6Alkyl, halogenated C_1-6Alkyl, C_1-6Alkoxy, C_1-6Alkylamino and halogenated C_1-6One of alkoxy is a variety of Substituent group replaces at an arbitrary position；Alternatively, the R_aAnd R_bThe N atom connected together is formed together 3-12 membered heterocycloalkyl, The Heterocyclylalkyl further can also be selected from N, O, S (O) containing 1~3_0-2, C (O) hetero atom or group；The heterocycle Alkyl is selected from halogen, hydroxyl, amino, carboxyl, C by 1~3 for unsubstituted or selectivity_1-6Alkyl, halogenated C_1-6Alkyl, C_1-6 Alkoxy, C_1-6Alkylamino and halogenated C_1-6One of alkoxy or a variety of substituent groups replace at an arbitrary position；

R_cAnd R_dSeparately it is selected from hydrogen, C_1-6Alkyl, C_1-6Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, C_3-8Naphthenic base, 3-8 member are miscellaneous Naphthenic base, C_6-10Aryl, 5-6 unit's heteroaryl, C_3-8Naphthenic base C_1-6Alkyl, 3-8 membered heterocycloalkyl C_1-6Alkyl, phenyl C_1-6Alkane Base or 5-6 unit's heteroaryl C_1-6Alkyl；The C_1-6Alkyl, C_1-6Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, C_3-8Naphthenic base, 3-8 member Heterocyclylalkyl, C_6-10Aryl or 5-6 unit's heteroaryl are unsubstituted or are selectively selected from halogen, hydroxyl, ammonia by 1~3 Base, carboxyl, C_1-6Alkyl, halogenated C_1-6Alkyl, C_1-6Alkoxy, C_1-6Alkylamino and halogenated C_1-6One of alkoxy is a variety of Substituent group replaces at an arbitrary position.

2. as described in claim 1 such as Formulas I or I ' compound represented, its isomers, prodrug, stable isotope derivatives Or pharmaceutically acceptable salt, it is characterised in that: R₂For

3. as described in claim 1 such as Formulas I or I ' compound represented, its isomers, prodrug, stable isotope derivatives Or pharmaceutically acceptable salt, it is characterised in that: groupFor following any structure:

GroupFor following any structure:

R₁、R₈、R₉、R₁₁Definition it is as described in claim 1.

4. compound shown in formula I as described in claim 1, its isomers, prodrug, stable isotope derivatives or medicine Acceptable salt on, it is characterised in that: the compound shown in formula I be III, IV or V,

In III, n 0,1,2 or 3；R₁、R₃、R₄、R₅、X、R_a、R_bIt is as described in claim 1 with the definition of W；

In IV, Z is N or CH；L is CH₂、CH(CH₃)、C(CH₃)₂OrU is 0,1 or 2；V is 0,1 or 2；R₁、R₃、R₄、 R₅、R₁₀, the definition of X and W it is as described in claim 1；

In V, R₁、R₂、R₃、R₄、R₅、R₈、R₉, the definition of U and W it is as described in claim 1.

5. compound shown in formula I as claimed in claim 4, its isomers, prodrug, stable isotope derivatives or medicine Acceptable salt on, it is characterised in that: W N；

And/or R₃For substituted or unsubstituted C_1-6Alkyl can be substituted in any position by 1 hydroxyl when the alkyl is substituted It sets；

And/or R₄For H；

And/or R₅For H.

6. compound shown in formula I as claimed in claim 4, its isomers, prodrug, stable isotope derivatives or medicine Acceptable salt on, it is characterised in that: the compound shown in formula I is V,

Wherein, U CH；

And/or R₁For H or methyl；

And/or R₂For

And/or R₈For-NR_cR_dOr substituted or unsubstituted 3-8 membered heterocycloalkyl；When the 3-8 membered heterocycloalkyl is substituted When, selectivity is by 1~3 C_1-4Alkyl or C_3-6Naphthenic base replaces at an arbitrary position；

And/or R₉For C_1-4Alkyl, hydroxyl C_1-4Alkyl, C_3-8Naphthenic base or 3-8 membered heterocycloalkyl.

7. as described in claim 1 such as Formulas I or I ' compound represented, its isomers, prodrug, stable isotope derivatives Or pharmaceutically acceptable salt, it is characterised in that: described such as Formulas I or I ' compound represented are as follows:

8. a kind of pharmaceutical composition comprising the active component of therapeutically effective amount and pharmaceutically acceptable auxiliary material；The work Property component include as described in any one of claims 1 to 7 such as Formulas I or I ' compound represented, its isomers, prodrug, stabilization Isotope derivatives or pharmaceutically acceptable salt；The pharmaceutically acceptable auxiliary material is pharmaceutically acceptable load Body, diluent and/or excipient.

9. it is as described in any one of claims 1 to 7 such as Formulas I or I ' compound represented, it is its isomers, prodrug, stable same The plain derivative in position or pharmaceutically acceptable salt, or pharmaceutical composition as claimed in claim 8 is in preparing Wee1 inhibitor Using.

10. it is as described in any one of claims 1 to 7 such as Formulas I or I ' compound represented, it is its isomers, prodrug, stable same The plain derivative in position or pharmaceutically acceptable salt, or chemotherapy of the pharmaceutical composition in preparation cancer as claimed in claim 8 Or the application in the sensitizer of radiation therapy.

11. it is as described in any one of claims 1 to 7 such as Formulas I or I ' compound represented, it is its isomers, prodrug, stable same The plain derivative in position or pharmaceutically acceptable salt, or as claimed in claim 8 pharmaceutical composition preparation treatment and/or alleviate by Application in the drug for the related disease that Wee1 is mediated.

12. application as claimed in claim 11, it is characterised in that: the related disease that the Wee1 is mediated is cancer.

13. a kind of combination formulations, including the compound as shown in Formulas I or I ', its isomers, prodrug, stable isotope derivatives Or therapeutic agent for treating cancer and/or the treatment of pharmaceutically acceptable salt or described pharmaceutical composition and other types Method shares；The therapeutic agent and/or treatment method for treating cancer of other types may include use for cancer treatment: Antitubulin, alkylating agent, topological enzyme I/II inhibitor, platinum-like compounds, antibiotic, antimetabolitas, hormone and Hormone analogs, immunotherapeutic agent, interferon, other are used for treatment of cancer at targeted therapy (such as: special kinase inhibitor) Anticancer agent and one of radiotherapy or a variety of.