CN107428762A

CN107428762A - Phthalazinone derivatives, preparation method and the usage

Info

Publication number: CN107428762A
Application number: CN201680007634.7A
Authority: CN
Inventors: 刘钢; 于华; 任云; 杜静; 杨定菊; 李晓勇; 王坤建; 刘伟; 唐建川; 吴勇勇; 曾宏; 卿燕; 宋宏梅; 李少华; 谢; 谢一; 葛勇; 王利春; 王晶翼
Original assignee: Sichuan Kelun Biotech Biopharmaceutical Co Ltd
Current assignee: Sichuan Kelun Biotech Biopharmaceutical Co Ltd
Priority date: 2015-10-30
Filing date: 2016-10-28
Publication date: 2017-12-01
Anticipated expiration: 2036-10-28
Also published as: CN107428762B; WO2017071636A1

Abstract

This application provides a kind of phthalazinone derivatives, preparation method and the usage, specifically, a kind of compound, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester or foregoing isomers, hydrate, solvate or crystal formation, preparation method and the usage shown in formula I is provided, the compound of the application can significantly improve the inhibited proliferation to tumour cell；Stability in molecule body can be increased, reduce the possibility for producing toxic metabolites；Or it can reduce oxidative metabolism ability of the compound in vivo under the effect of P450 cytochromes enzyme system by the structural modification to phthalazines ketone compounds, and improve bioavailability.

Description

Phthalazinone derivatives, preparation method and the usage

Technical field

This application involves field of medicaments, and in particular to phthalazinone derivatives, preparation method and the usage.

Background technique

Poly adenosine diphosphate-ribose polymerase-1 (Poly ADP-Ribose Polymerase, PARP) be a kind of 113kDa multi-domain proteins, it combines the single-stranded or double-stranded signal transduction (D ' Amours D.et al., Poly (ADP-ribosyl) ation reactions in the regulation of nuclear functions.Biochem.J.342:249-268 (1999)) for participating in DNA damage of the DNA of fracture by identification and quickly.PARP family includes about 18 kinds of protein now, and wherein PARP-1 (member found earliest) and PARP-2 is the presently found enzyme that its catalytic activity is activated solely by generation DNA break, this makes them very unique in the family.And PARP-1 is structure most typically in PARP family, it is also most study, its molecular weight is 114KDa, polyadenylic acid diphosphonic acid ribose (PAR) (Sakamoto-Hojo E T is synthesized in receptor protein (including itself) as substrate using ADP, I (PARP- I) and PARP- of Balajee A S.Targeting Poly (ADP) ribose Polymerase, I interacting Proteins for cancer treatment.Anticancer Agents Med Chem, 2008,8 (4): 402-416).

PARP-1 participates in DNA damage reparation and transcriptional regulatory, it and is considered as cell survival and dead important regulatory factor, also participate in regulation (the Peralta-Leal A of some transcription factors in tumour generation and inflammatory reaction, Rodriguez-Vargas J M, Aguilar-Quesada R, et al.PARP inhibitors:New partners in the therapy of cancer and inflammatory diseases.Free Radical Biol Med, 2009,47 (l): 13-26).So far it has been discovered that PARP-1 high expression, such as malignant lymphoma, breast cancer, ewing's sarcoma, hepatocellular carcinoma etc. in the malignant tumour of a variety of mankind.

Since PARP-1 participates in DNA damage reparation, PARP-1 activity inhibitor is used alone or the death of cancer cell can be promoted with DNA damage drug combination.A large amount of research is it has been confirmed that Drug inhibition or gene knockout PARP-1 are not only avoided that tissue damage caused by oxidative stress related disease, moreover it is possible to improve the prognosis of tumour patient.PARP-1 inhibitor, which is used alone, also has lethal effect to the tumour (mainly breast cancer) for repairing defect there are DNA damage.In addition document also reported the relationship of PARP-1 inhibitor and angiogenesis, the proliferation and migration and vascularization of the Human umbilical vein endothelial cells that at least vascular endothelial growth factor (VEGF) can be inhibited to induce in vitro there are five types of PARP inhibitor at present.Because brain is highly susceptible to influence (Sriram C S, et al.Multiple facets of poly (ADP-ribose) the polymerase-1in neurological diseases.Neural Regen Res.2015 of oxidative stress；10 (1): 49-51), the Neuropathological Study of PARP-1 is also gradually taken seriously.

Therefore, novel PARP inhibitor is developed with higher clinical value.

Summary of the invention

Present inventor carries out systematic research by the structure-activity relationship to phthalazines ketone compounds, it was found that one kind has the compound of excellent PARP inhibitory activity, and the application is to be completed based on the above discovery.

Therefore, the first aspect of the application provides compound of formula I, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester or isomers above-mentioned, hydrate, solvate or crystal form,

Wherein,

A and B is formed together alicyclic ring, alicyclic heterocyclic, aromatic ring or hetero-aromatic ring with the atom being connected, optionally, wherein the alicyclic ring, alicyclic heterocyclic, aromatic ring or hetero-aromatic ring are selected from halogen, hydroxyl, amino, cyano, carboxyl, nitro, alkyl, alkenyl, alkynyl, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, RO-, ROC (O)-, RC (O) O-, RC (O)-, RR ' N-, RC (O) NH-, RR ' NC (O)-, RS (O) by one or more (such as 1,2,3 or 4) each independently_a-、RR’NSO₂And RSO₂The substituent group of N (R ')-replaces, and wherein a is 0,1 or 2；

R₁、R₂、R₃And R₄It is each independently selected from hydrogen, halogen, hydroxyl, amino, cyano, carboxyl, nitro, alkyl, alkenyl, alkynyl, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, RO-, ROC (O)-, RC (O) O-, RC (O)-, RR ' N-, RC (O) NH- and RR ' NC (O)-, optionally, wherein the alkyl, alkenyl, alkynyl, naphthenic base, Heterocyclylalkyl, aryl or heteroaryl are selected from halogen, hydroxyl, C by one or more (such as 1,2,3 or 4) each independently_1-4Alkyl, C_1-4Alkoxy, 3-8 member naphthenic base, 5-8 membered heterocycloalkyl, 6-10 member aryl or 5-10 unit's heteroaryl substituent group replace；

D and E are each independently selected from C and N, and 5-10 member (such as 5,6,7,8,9,10) ring X is formed together with the atom being connected, wherein the ring X is selected from alicyclic heterocyclic, aromatic ring and hetero-aromatic ring, preferably hetero-aromatic ring, such as pyridine ring, pyridazine ring, pyrimidine ring, pyridine ring or triazine ring；

M and n is each independently selected from 0,1 and 2, and m+n=2；

Y is independently selected from C, O, S and N, condition, as Y=O or S, R₆And R₇It is not present, as Y=N, R₇It is not present；

R₅, R₆, R₇And R₈It is each independently selected from hydrogen, hydroxyl, cyano, nitro, alkyl, ring Alkyl, Heterocyclylalkyl, aryl, heteroaryl, naphthenic base-alkyl, heterocycloalkyl-alkyl, RO-, RC (O)-, RC (O) O-, RR ' N-, RC (O) NH- and RR ' NC (O)-, optionally, the wherein alkyl, naphthenic base, Heterocyclylalkyl, heteroaryl, naphthenic base-alkyl or heterocycloalkyl-alkyl are each independently further by one or more (such as 1, 2, 3 or 4) it is selected from halogen, hydroxyl, cyano, amino, carboxyl, nitro, alkyl, halogenated alkyl, alkenyl, alkynyl, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, RO-, RR ' N-, RO-C_1-10Alkyl, RR ' N-C_1-10Alkyl, RS (O)_a-、RR’NSO₂And RSO₂The substituent group of N (R ')-replaces, and wherein a is 0,1 or 2；Or

R₅And R₆Alicyclic ring, aromatic ring, alicyclic heterocyclic or hetero-aromatic ring are formed together with Y atom, optionally, wherein the alicyclic ring, aromatic ring, alicyclic heterocyclic or hetero-aromatic ring are further selected from halogen, hydroxyl, cyano, RS (O) by one or more (such as 1,2,3 or 4) each independently_a, alkyl, RR ' N- and RO- substituent group replace, wherein a be 0,1 or 2；

R and R ' is each independently selected from hydrogen, hydroxyl, C_1-10Alkyl, 3-20 member naphthenic base, 5-20 membered heterocycloalkyl, 6-20 member aryl, 5-20 unit's heteroaryl, optionally, the C_1-10Alkyl, 3-20 member naphthenic base, 5-20 membered heterocycloalkyl, 6-20 member aryl, 5-20 unit's heteroaryl are selected from halogen, hydroxyl, C by one or more (such as 1,2,3 or 4) each independently_1-4Alkyl, C_1-4The substituent group substitution of alkoxy, 3-8 member naphthenic base, 5-8 membered heterocycloalkyl, 6-10 member aryl and 5-10 unit's heteroaryl.

In the certain preferred embodiments of the application, the restrictive condition of the compound of formula I is,

When A and B is formed together phenyl ring, R with the atom being connected₁、R₂、R₃It is hydrogen, R₄For fluorine, and when m and n are 1,

1) ring X is not hexa-atomic alicyclic heterocyclic that 5 member rings, hetero atom are N and hetero atom is N and the hexa-atomic alicyclic heterocyclic of O；And

2) describedIt is not following group:

In the certain preferred embodiments of the application, the compound has structure shown in Formulas I a,

Wherein,

R₁、R₂、R₃And R₄It is each independently selected from hydrogen, halogen, hydroxyl, amino, cyano, carboxyl, nitro, alkyl, alkenyl, alkynyl, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, RO-, ROC (O)-, RC (O) O-, RC (O)-, RR ' N-, RC (O) NH- and RR ' NC (O)-, optionally, wherein the alkyl, alkenyl, alkynyl, naphthenic base, Heterocyclylalkyl, aryl or heteroaryl are selected from halogen, hydroxyl, C by one or more (such as 1,2,3 or 4) each independently_1-4Alkyl, C_1-4The substituent group substitution of alkoxy, 3-8 member naphthenic base, 5-8 membered heterocycloalkyl, 6-10 member aryl and 5-10 unit's heteroaryl；

D, E, G, J, K and L are each independently selected from C and N, and form hexa-atomic aromatic ring；

M and n is each independently selected from 0,1 and 2, and m+n=2；

Y is selected from C, O, S and N, and condition is, as Y=O or S, R₆And R₇It is not present, as Y=N, R₇It is not present；

R₅, R₆, R₇And R₈It is each independently selected from hydrogen, hydroxyl, cyano, nitro, alkyl, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, naphthenic base-alkyl, heterocycloalkyl-alkyl, RO-, RC (O)-, RC (O) O-, RR ' N-, RC (O) NH- and RR ' NC (O)-, optionally, the wherein alkyl, naphthenic base, Heterocyclylalkyl, heteroaryl, naphthenic base-alkyl or heterocycloalkyl-alkyl are each independently further by one or more (such as 1, 2, 3 or 4) it is selected from halogen, hydroxyl, cyano, amino, carboxyl, nitro, alkyl, halogenated alkyl, alkenyl, alkynyl, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, RO-, RR ' N-, RO-C_1-10Alkyl, RR ' N-C_1-10Alkyl, RS (O)_a-、RR’NSO₂And RSO₂The substituent group of NR '-replaces, and wherein a is 0,1 or 2；Or

R₅And R₆Alicyclic ring, aromatic ring, alicyclic heterocyclic or hetero-aromatic ring are formed together with Y atom, optionally, wherein the alicyclic ring, aromatic ring, alicyclic heterocyclic or hetero-aromatic ring are further selected from halogen, hydroxyl, alkyl, cyano, RS (O) by one or more (such as 1,2,3 or 4) each independently_a, RR ' N- and RO- substituent group replace, wherein a be 0,1 or 2；

R and R ' is each independently selected from hydrogen, hydroxyl, C_1-10Alkyl, 3-20 member naphthenic base, 5-20 membered heterocycloalkyl, 6-20 member aryl, 5-20 unit's heteroaryl, optionally, the C_1-10Alkyl, 3-20 member naphthenic base, 5-20 membered heterocycloalkyl, 6-20 member aryl, 5-20 unit's heteroaryl are selected from halogen, hydroxyl, C by one or more (such as 1,2,3 or 4) each independently_1-4Alkyl, C_1-4 The substituent group substitution of alkoxy, 3-8 member naphthenic base, 5-8 circle heterocyclic ring base, 6-10 member aryl and 5-10 unit's heteroaryl.

In the certain preferred embodiments of the application, the restrictive condition of the Formulas I a compound are as follows:

When A and B is formed together phenyl ring, R with the atom being connected₁、R₂、R₃It is hydrogen, and R₄It is described when for fluorineIt is not following group:

In the certain preferred embodiments of the application, the compound as shown in Formulas I aa,

Wherein,

R₅, R₆, R₇And R₈It is each independently selected from hydrogen, hydroxyl, cyano, nitro, alkyl, ring Alkyl, Heterocyclylalkyl, aryl, heteroaryl, naphthenic base-alkyl, heterocycloalkyl-alkyl, RO-, RC (O)-, RC (O) O-, RR ' N-, RC (O) NH- and RR ' NC (O)-, optionally, the wherein alkyl, naphthenic base, Heterocyclylalkyl, Heteroarylcycloalkyl-alkyl or heterocycloalkyl-alkyl are each independently further by one or more (such as 1, 2, 3 or 4) it is selected from halogen, hydroxyl, cyano, amino, carboxyl, nitro, alkyl, halogenated alkyl, alkenyl, alkynyl, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, RO-, RR ' N-, RO-C_1-10Alkyl, RR ' N-C_1-10Alkyl, RS (O)_a-、RR’NSO₂And RSO₂NR '-, substituent group replace, and wherein a is 0,1 or 2；Or

In the certain preferred embodiments of the application, the restrictive condition of the Formulas I aa compound are as follows: when A and B is formed together phenyl ring, R with the atom being connected₁、R₂、R₃It is hydrogen, and R₄It is described when for fluorineIt is not following group:

In the certain preferred embodiments of the application, the compound as shown in Formulas I aa-1,

Wherein,

A and B is formed together alicyclic ring, alicyclic heterocyclic, aromatic ring or hetero-aromatic ring with the atom being connected, optionally, Wherein the alicyclic ring, alicyclic heterocyclic, aromatic ring or hetero-aromatic ring are selected from halogen, hydroxyl, amino, cyano, carboxyl, nitro, alkyl, alkenyl, alkynyl, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, RO-, ROC (O)-, RC (O) O-, RC (O)-, RR ' N-, RC (O) NH-, RR ' NC (O)-, RS (O) by one or more (such as 1,2,3 or 4) each independently_a-、RR’NSO₂And RNSO₂The substituent group of N (R ')-replaces, and wherein a is 0,1 or 2；

R₅、R₆And R₈It is each independently selected from hydrogen, alkyl, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, naphthenic base-alkyl, heterocycloalkyl-alkyl, RC (O)-, RC (O) O-, RR ' N-, RC (O) NH- and RR ' NC (O)-, optionally, wherein the alkyl, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, naphthenic base-alkyl or heterocycloalkyl-alkyl, being further selected from halogen, hydroxyl, cyano, amino, carboxyl, nitro, C by one or more (such as 1,2,3 or 4) each independently_1-4Alkyl, halogenated C_1-4Alkyl, C_1-4Alkoxy, C_2-4Alkenyl, C_2-4Alkynyl, 3-8 member naphthenic base, 5-8 membered heterocycloalkyl, 6-10 member aryl, 5-10 unit's heteroaryl, RR ' N-, RO-C_1-10Alkyl, RR ' N-C_1-10Alkyl, RS (O)_a-、RR’NSO₂And RSO₂The substituent group of N (R ')-replaces, and wherein a is 0,1 or 2；Or

R₅And R₆Alicyclic heterocyclic or hetero-aromatic ring are formed together with the N atom being connected, optionally, wherein the alicyclic heterocyclic or hetero-aromatic ring are further selected from halogen, hydroxyl, cyano, RS (O) by one or more (such as 1,2,3 or 4) each independently_a-、C_1-4Alkyl, C_1-4The substituent group of alkoxy and RR ' N- replace, and wherein a is 0,1 or 2；

In certain preferred embodiments of the application, the compound as shown in Formulas I aa-2,

Wherein,

R₅And R₈It is each independently selected from hydrogen, alkyl, naphthenic base, cyano, nitro, Heterocyclylalkyl, aryl, heteroaryl, naphthenic base-alkyl, heterocycloalkyl-alkyl, RO-, RC (O)-, RC (O) O-, RR ' N-, RC (O) NH- and RR ' NC (O)-, optionally, wherein the alkyl, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, naphthenic base-alkyl or heterocycloalkyl-alkyl are further selected from halogen, hydroxyl, amino, cyano, carboxyl, nitro, C by one or more (such as 1,2,3 or 4) each independently_1-4Alkyl, halogenated C_1-4Alkyl, C_1-4Alkoxy, C_2-4Alkenyl, C_2-4Alkynyl, 3-8 member naphthenic base, 5-8 membered heterocycloalkyl, 6-10 member aryl, 5-10 unit's heteroaryl, RR ' N-, RO-C_1-10Alkyl, RR ' N-C_1-10Alkyl, RS (O)_a-、RR’NSO₂And RSO₂The substituent group of N (R ')-replaces, wherein a 0,1 or 2；

R and R ' is each independently selected from hydrogen, hydroxyl, C_1-10Alkyl, 3-20 member naphthenic base, 5-20 membered heterocycloalkyl, 6-20 member aryl, 5-20 unit's heteroaryl, optionally, the C_1-10Alkyl, 3-20 member naphthenic base, 5-20 membered heterocycloalkyl, 6-20 member aryl, 5-20 unit's heteroaryl are selected from halogen, hydroxyl, C by one or more (such as 1,2,3 or 4) each independently_1-4Alkyl, C_1-4Alkoxy, 3-8 member naphthenic base, 5-8 membered heterocycloalkyl, 6-10 member aryl and 5-10 unit's heteroaryl take Replace for base.

In the certain preferred embodiments of the application, the restrictive condition of the Formulas I aa-2 compound are as follows:

In the certain preferred embodiments of the application, the compound as shown in Formulas I aa-3,

Wherein,

A and B is formed together alicyclic ring, alicyclic heterocyclic, aromatic ring or hetero-aromatic ring with the atom being connected, optionally, wherein the alicyclic ring, alicyclic heterocyclic, aromatic ring or hetero-aromatic ring are selected from halogen, hydroxyl, amino, cyano, carboxyl, nitro, alkyl, alkenyl, alkynyl, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, RO-, ROC (O)-, RC (O) O-, RC (O)-, RR ' N-, RC (O) NH-, RR ' NC (O)-, RS (O) by one or more (such as 1,2,3 or 4) each independently_a-、RR’NSO₂And RSO₂The substituent group of N (R ')-replaces, wherein a 0,1 or 2；

R₅、R₆、R₇And R₈It is each independently selected from hydrogen, hydroxyl, cyano, nitro, alkyl, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, naphthenic base-alkyl, heterocycloalkyl-alkyl, RO-, RC (O)-, RC (O) O-, RR ' N-, RC (O) NH- and RR ' NC (O)-, optionally, wherein institute It states alkyl, naphthenic base, Heterocyclylalkyl, Heteroarylcycloalkyl-alkyl or heterocycloalkyl-alkyl and halogen, hydroxyl, cyano, carboxyl, nitro, amino, C is further selected from by one or more (such as 1,2,3 or 4) each independently_1-4Alkyl, halogenated C_1-4Alkyl, C_1-4Alkoxy, C_2-4Alkenyl, C_2-4Alkynyl, 3-8 member naphthenic base, 5-8 membered heterocycloalkyl, 6-10 member aryl, 5-10 unit's heteroaryl, RR ' N-, RO-C_1-10Alkyl, RR ' N-C_1-10Alkyl, RS (O)_a-、RR’NSO₂And RSO₂The substituent group of N (R ')-replaces, wherein a 0,1 or 2；Or

R₅And R₆Alicyclic ring, aromatic ring, alicyclic heterocyclic or hetero-aromatic ring are formed together with the C atom being connected, optionally, wherein the alicyclic ring, aromatic ring, alicyclic heterocyclic or hetero-aromatic ring are further selected from halogen, hydroxyl, cyano, RS (O) by one or more (such as 1,2,3 or 4) each independently_a-、C_1-4Alkyl, C_1-4The substituent group of alkoxy and RR ' N- replace, and wherein a is 0,1 or 2；

In the certain preferred embodiments of the application, the restrictive condition of the Formulas I aa-3 compound are as follows:

In the certain preferred embodiments of the application, in the compound of formula ISelected from flowering structure:

In the certain preferred embodiments of the application, the compound of formula I as shown in Formulas I aaa,

Wherein,

A and B is formed together 3-8 member alicyclic ring, 5-8 member alicyclic heterocyclic, 6-10 member aromatic ring or 5-10 member hetero-aromatic ring with the atom being connected, optionally, wherein the 3-8 member alicyclic ring, 5-8 member alicyclic heterocyclic, 6-10 member aromatic ring or 5-10 member hetero-aromatic ring are selected from halogen, hydroxyl, amino, cyano, carboxyl, nitro, C by one or more (such as 1,2,3 or 4) each independently_1-4Alkyl, C_2-4Alkenyl, C_2-4Alkynyl, 3-8 member naphthenic base, 5-8 membered heterocycloalkyl, 6-10 member aryl, 5-10 unit's heteroaryl, RO-, ROC (O)-, RC (O) O-, RC (O)-, RR ' N-, RC (O) NH-, RR ' NC (O)-, RS (O)_a-、RR’NSO₂And RSO₂The substituent group of N (R ')-replaces, wherein a 0,1 or 2；

R₁、R₂、R₃And R₄It is each independently selected from hydrogen, halogen, hydroxyl, amino, cyano, carboxyl, nitro, C_1-10Alkyl, C_2-10Alkenyl, C_2-10Alkynyl, 3-10 member naphthenic base, 5-10 membered heterocycloalkyl, 6-10 member aryl, 5-10 unit's heteroaryl, RO-, ROC (O)-, RC (O) O-, RC (O)-, RR ' N-, RC (O) NH- and RR ' NC (O)-, optionally, wherein the C_1-10Alkyl, C_2-10Alkenyl, C_2-10Alkynyl, 3-10 member naphthenic base, 5-10 membered heterocycloalkyl, 6-10 member aryl or 5-10 unit's heteroaryl are selected from halogen, hydroxyl, C by one or more (such as 1,2,3 or 4) each independently_1-4Alkyl, C_1-4The substituent group substitution of alkoxy, 3-8 member naphthenic base, 5-8 membered heterocycloalkyl, 6-10 member aryl and 5-10 unit's heteroaryl；

L and J are each independently selected from C and N；

R₅, R₆, R₇And R₈It is each independently selected from hydrogen, hydroxyl, cyano, nitro, C_1-10Alkyl, 3-8 member naphthenic base, 3-8 membered heterocycloalkyl, 6-10 member aryl, 5-10 unit's heteroaryl, 3-8 member naphthenic base-C_1-4Alkyl, 3-8 membered heterocycloalkyl-C_1-4Alkyl, RO-, RC (O)-, RC (O) O-, RR ' N-, RC (O) NH- and RR ' NC (O)-, optionally, wherein the C_1-10Alkyl, 3-8 member naphthenic base, 3-8 membered heterocycloalkyl, 6-10 member aryl, 5-10 unit's heteroaryl, 3-8 member naphthenic base-C_1-4Alkyl or 3-8 membered heterocycloalkyl-C_1-4Alkyl is further selected from halogen, hydroxyl, cyano, amino, carboxyl, nitro, C by one or more (such as 1,2,3 or 4) each independently_1-4Alkyl, halogenated C_1-4Alkyl, C_2-4Alkenyl, C_2-4Alkynyl, 3-8 member naphthenic base, 5-8 membered heterocycloalkyl, 6-10 member aryl, 5-10 unit's heteroaryl, RO-, RR ' N-, RO-C_1-4Alkyl, RR ' N-C_1-4Alkyl, RS (O)_a-、RR’NSO₂And RSO₂The substituent group of NR '-replaces, wherein a 0,1 or 2；Or；

R₅And R₆3-8 member alicyclic ring, 6-10 member aromatic ring, 5-8 member alicyclic heterocyclic or 5-10 member hetero-aromatic ring are formed together with Y atom, optionally, wherein the 3-8 member alicyclic ring, 6-10 member aromatic ring, 5-8 member alicyclic heterocyclic or 5-10 member hetero-aromatic ring are further selected from halogen, hydroxyl, cyano, RS (O) by one or more (such as 1,2,3 or 4) each independently_a-、C_1-4Alkyl, C_1-4The substituent group of alkoxy and RR ' N- replace, and wherein a is 0,1 or 2；

In the certain preferred embodiments of the application, the restrictive condition of the Formulas I aaa compound are as follows:

In the certain preferred embodiments of the application, the Y in the Formulas I, Ia, Iaa or Iaaa is N.

In the certain preferred embodiments of the application, the R₅、R₆、R₇And R₈It is each independently selected from hydrogen, hydroxyl, cyano, nitro, C_1-6Alkyl, C_1-6Alkoxy, C_1-6Alkyl acyl, 3-8 member naphthenic base, 3-8 membered heterocycloalkyl, 6-10 member aryl (such as phenyl, naphthalene), 5-10 unit's heteroaryl, 3-8 member naphthenic base-C_1-4Alkyl, 3-8 membered heterocycloalkyl-C_1-4Alkyl, optionally, wherein the C_1-6Alkyl, C_1-6Alkoxy, C_1-6Alkyl acyl, 3-8 member naphthenic base, 3-8 membered heterocycloalkyl, 6-10 member aryl, 5-10 unit's heteroaryl, 3-8 member naphthenic base-C_1-4Alkyl or 3-8 membered heterocycloalkyl-C_1-4Alkyl is further selected from halogen (such as fluorine), hydroxyl, C by one or more (such as 1,2,3 or 4) each independently_1-4Alkyl, halogenated C_1-4Alkyl, C_1-4Alkoxy, 3-8 member naphthenic base, 3-8 membered heterocycloalkyl, 6-10 member aryl, 5-10 unit's heteroaryl, RR ' N-, RO-C_1-4Alkyl, RR ' N-C_1-4Alkyl, RR ' NSO₂And RSO₂Substituent group replace；Or

R₅And R₆3-8 member alicyclic ring, 3-8 member alicyclic heterocyclic, 6-10 member aromatic ring or 5-10 member hetero-aromatic ring are formed together with the Y atom being connected, optionally, wherein the 3-8 member alicyclic ring, 3-8 member alicyclic heterocyclic, 6-10 member aromatic ring or 5-10 member hetero-aromatic ring are further selected from halogen, hydroxyl, cyano, RS (O) by one or more (such as 1,2,3 or 4) each independently_a-、C_1-4Alkyl and C_1-4Alkoxy Substituent group replaces, and wherein a is 0,1 or 2；

Wherein R and R ' are each independently selected from hydrogen and C_1-4Alkyl.

In the certain preferred embodiments of the application, the R₅、R₆、R₇And R₈It is each independently selected from hydrogen, methyl, ethyl, Cvclopropvlmethvl, oxocyclobutylmethyl, tetrahydrofuran ylmethyl, methoxy ethyl, 2- ethoxyethyl group, 2- hydroxyethyl, trifluoroethyl, bis-fluoro ethyls, fluoro ethyl, N, N- dimethylaminoethyl, (R) -1- methoxyl group -2- propyl, (S) -1- methoxyl group -2- propyl, (R) -2- methoxy-propyl, (S) -2- methoxy-propyl, methylsulfonylethyl, dimethylaminosulfonyl ethyl, 2- hydroxyl-isobutyl group, cyclopropyl, 1- methylcyclopropyl groups, 1- methoxyl methyl cyclopropyl, 2, 2- Dimethvlcvclopropvl, 1- trifluoromethyl cyclopropyl, (R) -2- fluorine cyclopropyl, (S) -2- fluorine cyclopropyl, 2, 2- difluorocyclopropyl, oxocyclobutyl, 4- hydroxy-cyclohexyl, 4, 4- Difiuorocyclohexyl, THP trtrahydropyranyl, 2,2- dimethyl tetrahydro pyranose, 4- methyl-tetrahydro pyranose, N- methyl piperidine base, N, N- dimethylamino piperidine base, N methyl piperazine base, piperidyl, N- methylpyrazole base and bicyclic [3.1.0] hexyl of 3- oxo-；Alternatively,

R₅And R₆Tetrahydrofuran ring, piperidine ring or piperazine ring are formed together with the Y atom being connected.

In the certain preferred embodiments of the application, A and B are formed together aromatic ring with the atom being connected.

In the certain preferred embodiments of the application, A and B are formed together 6-14 member aromatic ring with the atom being connected, wherein the 6-14 member aromatic ring is unsubstituted or is selected from halogen, hydroxyl, amino, cyano, carboxyl, nitro and C by one or two_1-10The substituent group of alkyl replaces.

In the certain preferred embodiments of the application, A and B are formed together unsubstituted phenyl ring with the atom being connected.

In the certain preferred embodiments of the application, A and B are formed together phenyl ring with the atom being connected, wherein the phenyl ring is replaced by one or two substituent group for being selected from halogen.

In the certain preferred embodiments of the application, A and B are formed together phenyl ring with the atom being connected, wherein the phenyl ring is replaced by a fluorine.

In the certain preferred embodiments of the application, R₁、R₂And R₃For hydrogen.

In the certain preferred embodiments of the application, R₄For halogen.

In the certain preferred embodiments of the application, R₄For fluorine.

In the certain preferred embodiments of the application, R₅Selected from hydroxyl, cyano, nitro, alkyl, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, naphthenic base-alkyl, heterocycloalkyl-alkyl, RO-, RC (O)-, RC (O) O-, RR ' N-, RC (O) NH- and RR ' NC (O)-, optionally, the wherein alkyl, naphthenic base, Heterocyclylalkyl, heteroaryl, naphthenic base-alkyl or heterocycloalkyl-alkyl are each independently further by one or more (such as 1, 2, 3 or 4) it is selected from halogen, hydroxyl, cyano, amino, carboxyl, nitro, alkyl, halogenated alkyl, alkenyl, alkynyl, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, RO-, RR ' N-, RO-C_1-10Alkyl, RR ' N-C_1-10Alkyl, RS (O)_a-、RR’NSO₂And RSO₂The substituent group of N (R ')-replaces, and wherein a is 0,1 or 2；

R and R ' is each independently selected from hydrogen, hydroxyl, C_1-10Alkyl, 3-20 member naphthenic base, 5-20 member are miscellaneous Naphthenic base, 6-20 member aryl, 5-20 unit's heteroaryl, optionally, the C_1-10Alkyl, 3-20 member naphthenic base, 5-20 membered heterocycloalkyl, 6-20 member aryl, 5-20 unit's heteroaryl are selected from halogen, hydroxyl, C by one or more (such as 1,2,3 or 4) each independently_1-4Alkyl, C_1-4The substituent group substitution of alkoxy, 3-8 member naphthenic base, 5-8 membered heterocycloalkyl, 6-10 member aryl and 5-10 unit's heteroaryl.

In the certain preferred embodiments of the application, R₅Selected from hydroxyl, cyano, nitro, C_1-10Alkyl, 3-20 member naphthenic base, 3-20 membered heterocycloalkyl, 6-20 member aryl, 5-20 unit's heteroaryl, 3-20 member naphthenic base-C_1-10Alkyl, 3-20 membered heterocycloalkyl-C_1-10Alkyl, RO-, RC (O)-, RC (O) O-, RR ' N-, RC (O) NH- and RR ' NC (O)-；Optionally, wherein the C_1-10Alkyl, 3-20 member naphthenic base, 3-20 membered heterocycloalkyl, 6-20 member aryl, 5-20 unit's heteroaryl, 3-20 member naphthenic base-C_1-10Alkyl and 3-20 membered heterocycloalkyl-C_1-10Alkyl is selected from halogen, hydroxyl, cyano, amino, carboxyl, nitro, C by one or more (such as 1,2,3 or 4) each independently_1-10Alkyl, halogenated C_1-10Alkyl, C_2-10Alkenyl, C_2-10Alkynyl, 3-20 member naphthenic base, 3-20 membered heterocycloalkyl, 6-20 member aryl, 5-20 unit's heteroaryl, RO-, RR ' N-, RO-C_1-10Alkyl, RR ' N-C_1-10Alkyl, RSO₂And RR ' NSO₂Substituent group replace；

R and R ' are each independently selected from hydrogen and C_1-10Alkyl；Optionally, wherein the C_1-10Alkyl is selected from halogen, hydroxyl, C by one or more (such as 1,2,3 or 4)_1-4Alkyl and C_1-4The substituent group of alkoxy replaces.

In the certain preferred embodiments of the application, R₅Selected from hydroxyl, cyano, nitro, C_1-6Alkyl, 3-12 member naphthenic base, 3-8 membered heterocycloalkyl, 6-14 member aryl, 5-10 unit's heteroaryl, 3-12 member naphthenic base-C_1-6Alkyl and 3-8 membered heterocycloalkyl-C_1-6Alkyl；Optionally, wherein the C_1-6Alkyl, 3-12 member naphthenic base, 3-8 membered heterocycloalkyl, 6-14 unit's heteroaryl, 5-10 unit's heteroaryl, 3-12 member naphthenic base-C_1-6Alkyl and 3-8 membered heterocycloalkyl-C_1-6Alkyl is selected from halogen, hydroxyl, cyano, amino, carboxyl, nitro, C by one or more (such as 1,2,3 or 4) each independently_1-6Alkyl, halogenated C_1-6Alkyl, RO-, RR ' N-, RO-C_1-6Alkyl, RR ' N-C_1-6Alkyl, RSO₂And RR ' NSO₂Substituent group replace；

R and R ' is each independently selected from hydrogen, C_1-6Alkyl and halogenated C_1-6Alkyl.

In the certain preferred embodiments of the application, R₅Selected from hydroxyl, C_1-4Alkyl, 3-8 member naphthenic base, 3-8 membered heterocycloalkyl, 5-6 unit's heteroaryl, 3-8 member naphthenic base-C_1-4Alkyl and 3-8 membered heterocycloalkyl-C_1-4Alkyl；Optionally, wherein the C_1-4Alkyl, 3-8 member naphthenic base, 3-8 membered heterocycloalkyl, 5-6 unit's heteroaryl, 3-8 member naphthenic base-C_1-4Alkyl and 3-8 membered heterocycloalkyl-C_1-4Alkyl is selected from halogen, hydroxyl, cyano, amino, carboxyl, nitro, C by one or more (such as 1,2,3 or 4) each independently_1-4Alkyl, halogenated C_1-4Alkyl, RO-, RR ' N-, RO-C_1-4Alkyl, RR ' N-C_1-4Alkyl, RSO₂And RR ' NSO₂Substituent group replace；

R and R ' is each independently selected from hydrogen, C_1-4Alkyl and halogenated C_1-4Alkyl.

In the certain preferred embodiments of the application, R₅Selected from hydroxyl, methyl, ethyl, cyclopropyl Methyl, oxocyclobutylmethyl, tetrahydrofuran ylmethyl, methoxy, methoxy ethyl, 2- ethoxyethyl group, 2- hydroxyethyl, trifluoroethyl, bis-fluoro ethyls, fluoro ethyl, trifluoromethoxy ethyl, N, N- dimethylaminoethyl, (R) -1- methoxyl group -2- propyl, (S) -1- methoxyl group -2- propyl, (R) -2- methoxy-propyl, (S) -2- methoxy-propyl, methylsulfonylethyl, dimethylaminosulfonyl ethyl, 2- hydroxyl-isobutyl group, cyclopropyl, 1- methylcyclopropyl groups, (R) -2- methylcyclopropyl groups, (S) -2- methylcyclopropyl groups, 1- methoxyl methyl cyclopropyl, 2, 2- Dimethvlcvclopropvl, 1- trifluoromethyl cyclopropyl, (R) -2- fluorine cyclopropyl, (S) -2- fluorine cyclopropyl, 2, 2- difluoro cyclopropyl Base, cyclobutyl, oxocyclobutyl, tetrahydrofuran base, 4- hydroxy-cyclohexyl, 4,4- difiuorocyclohexyl, 4- methoxycyclohexyl, THP trtrahydropyranyl, 2,2- dimethyl tetrahydro pyranose, 4- methyl-tetrahydro pyranose, N- methyl piperidine base, N, N- dimethylamino piperidine base, N methyl piperazine base, piperidyl, N- methylpyrazole base, 2- dimethylamino methyl -1,3- dioxane, 5- dimethylamino methyl -1,3- dioxane and bicyclic [3.1.0] hexyl of 3- oxo -.

In the certain preferred embodiments of the application, R₅Selected from C_1-4Alkyl, 3-8 member naphthenic base, 3-8 membered heterocycloalkyl, 5-6 unit's heteroaryl, 3-8 member naphthenic base-C_1-4Alkyl, optionally, the C_1-4Alkyl, 3-8 member naphthenic base and 5-6 unit's heteroaryl are replaced by the substituent group selected from hydroxyl, RO- and RR ' N-；

R and R ' are each independently selected from C_1-4Alkyl.

In the certain preferred embodiments of the application, R₅Selected from ethyl, 2- hydroxyethyl, dimethylaminoethyl, methoxy ethyl, cyclopropyl, 1- methylcyclopropyl groups, 4- hydroxy-cyclohexyl, Cvclopropvlmethvl, oxocyclobutyl, tetrahydrofuran base, THP trtrahydropyranyl and N- methylpyrazole base.

In the certain preferred embodiments of the application, R₆Selected from hydrogen and C_1-10Alkyl.

In the certain preferred embodiments of the application, R₆For hydrogen.

In the certain preferred embodiments of the application, R₆Selected from C_1-6Alkyl.

In the certain preferred embodiments of the application, R₆Selected from C_1-4Alkyl.

In the certain preferred embodiments of the application, R₆For methyl.

In the certain preferred embodiments of the application, R₅And R₆It is formed together 3-20 member alicyclic heterocyclic with Y atom, optionally, the 3-20 member alicyclic heterocyclic is selected from halogen, hydroxyl, cyano, C by one or more (such as 1,2,3 or 4)_1-10The substituent group substitution of alkyl, RR ' N- and RO-；

R and R ' are each independently selected from hydrogen and C_1-10Alkyl；

Y is C or N.

In the certain preferred embodiments of the application, R₅And R₆It is formed together 5-8 member alicyclic heterocyclic with Y atom, optionally, the 5-8 member alicyclic heterocyclic is selected from halogen, hydroxyl, cyano, C by one or more (such as 1,2,3 or 4)_1-6The substituent group substitution of alkyl, RR ' N- and RO-；

R and R ' are each independently selected from hydrogen and C_1-6Alkyl；

Y is C or N.

In the certain preferred embodiments of the application, R₅And R₆6 yuan of alicyclic heterocyclics are formed together with Y atom, optionally, 6 yuan of alicyclic heterocyclics are selected from halogen, hydroxyl, cyano, C by one or more (such as 1,2,3 or 4)_1-4The substituent group substitution of alkyl, RR ' N- and RO-；

R and R ' are each independently selected from hydrogen and C_1-4Alkyl；

Y is N.

In the certain preferred embodiments of the application, R₅And R₆It is formed together piperidine ring or piperazine ring with Y atom, optionally, the piperidine ring or piperazine ring are selected from C by one or two_1-4The substituent group of alkyl and RR ' N- replace；

R and R ' are each independently selected from hydrogen and C_1-4Alkyl；

Y is N.

In the certain preferred embodiments of the application, R₅And R₆It is formed together piperidine ring and piperazine ring with Y atom, optionally, the piperidine ring or piperazine ring are replaced by a methyl or dimethylamino；

Y is N.

In the certain preferred embodiments of the application, R₅And R₆It is formed together 5-6 member alicyclic heterocyclic with Y atom, optionally, the 5-6 member alicyclic heterocyclic is selected from halogen, hydroxyl, cyano, C by one or more (such as 1,2,3 or 4)_1-4The substituent group substitution of alkyl, RR ' N- and RO-；

R and R ' are each independently selected from hydrogen and C_1-4Alkyl；

Y is C.

In the certain preferred embodiments of the application, R₅And R₆It is formed together tetrahydrofuran ring or piperidine ring with Y atom, optionally, the tetrahydrofuran ring or piperidine ring are selected from C by one or two_1-4The substituent group of alkyl replaces；

Y is C.

In the certain preferred embodiments of the application, R₅And R₆It is formed together tetrahydrofuran ring or piperidine ring with Y atom, optionally, the piperidine ring is replaced by a methyl；

Y is C.

In the certain preferred embodiments of the application, R₇For hydrogen.

In the certain preferred embodiments of the application, R₈Selected from hydrogen, halogen, hydroxyl, cyano, nitro, C_1-10Alkyl, optionally, wherein the C_1-10Alkyl is replaced by the substituent group that one or more (such as 1,2,3 or 4) is selected from halogen, hydroxyl, cyano, amino, carboxyl and nitro.

In the certain preferred embodiments of the application, R₈Selected from hydrogen, hydroxyl, C_1-6Alkyl and halogenated C_1-6Alkyl.

In the certain preferred embodiments of the application, R₈Selected from hydrogen, hydroxyl, C_1-4Alkyl and halogenated C_1-4Alkyl.

In the certain preferred embodiments of the application, R₈Selected from hydrogen, hydroxyl, methyl and trifluoromethyl.

In the certain preferred embodiments of the application,

A and B is formed together phenyl ring with the atom being connected；

R₁、R₂And R₃For hydrogen；And

R₄For for fluorine.

In the certain preferred embodiments of the application,

A and B is formed together phenyl ring with the atom being connected, wherein the phenyl ring is replaced by a fluorine；

R₁、R₂And R₃For hydrogen；And

R₄For fluorine.

In the certain preferred embodiments of the application,

A and B is formed together phenyl ring with the atom being connected；

R₁、R₂And R₃For hydrogen；And

R₄For for fluorine；

Y is nitrogen-atoms.

In the certain preferred embodiments of the application, the compound has structure shown in Formulas I aa-1, wherein

A and B is formed together phenyl ring with the atom being connected；

R₁、R₂And R₃It is hydrogen；

R₄For fluorine；

D, E, G and K are C；

L and J is N；

R₅Selected from C_1-4Alkyl, 3-8 member naphthenic base, 3-8 membered heterocycloalkyl, 5-6 unit's heteroaryl, 3-8 member naphthenic base-C_1-4Alkyl, optionally, the C_1-4Alkyl, 3-8 member naphthenic base and 5-6 unit's heteroaryl are replaced by the substituent group selected from hydroxyl, RO- and RR ' N-；Wherein, R and R ' are each independently selected from C_1-4Alkyl；

R₆For hydrogen；

R₈Selected from hydrogen and C_1-4Alkyl.

A and B is formed together phenyl ring with the atom being connected；

R₁、R₂And R₃It is hydrogen；

R₄For fluorine；

D, E, G and K are C；

L and J is N；

R₅Selected from ethyl, 2- hydroxyethyl, dimethylaminoethyl, methoxy ethyl, cyclopropyl, 1- methylcyclopropyl groups, 4- hydroxy-cyclohexyl, Cvclopropvlmethvl, oxocyclobutyl, tetrahydrofuran base, four Hydrogen pyranose and N- methylpyrazole base；

R₆For hydrogen；

R₈Selected from hydrogen and methyl.

In the certain preferred embodiments of the application, hydrogen described herein is protium (H) or deuterium (D).

According to compound described in the application first aspect, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester or isomers above-mentioned, hydrate, solvate or crystal form, wherein the compound is selected from:

4- [3- (2- ethylamino- -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl) -4- luorobenzyl] -2H- phthalazines -1- ketone；

4- [3- (2- cyclopropylamino -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl) -4- luorobenzyl] -2H- phthalazines -1- ketone；

4- [3- (2- Cyclopropyl-methyl-amino -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl) -4- luorobenzyl] -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (2- hydroxyethylamino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- { 3- [2- (2- dimethylaminoethylamino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] -4- luorobenzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (ttetrahydro-pyran -4- amino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl]-benzyl } -2H- phthalazines -1- ketone；

4- [3- (2- dimethylamino -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl) -4- luorobenzyl] -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (2- methoxy ethyl amine) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl]-benzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (2- hydroxy-2-methyl propylcarbamic) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl]-benzyl } -2H- phthalazines -1- ketone；

4- { 3- [2- (Cyclopropyl-methyl-amino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] the fluoro- benzyl of -4- } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (1- methylcyclopropyl groups amino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl]-benzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (3- oxetanylmethoxy amino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (4- hydroxy-cyclohexyl amino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (tetrahydrofuran -3- amino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- { 3- [2- (4- dimethylamino piperidine -1- base) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] -4- luorobenzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (4- methylpiperazine-1-yl) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (1- methyl piperidine -4- amino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- { 3- [2- (4,4- difiuorocyclohexyl amino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] -4- luorobenzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (1- methyl-1 H- pyrazoles -4- amino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (1- methyl-1 H- pyrazoles -3- amino) -5,7- dihydro-pyrazol simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (methyl methoxy ethylamino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- [3- (2- ethoxy ethylamino -5,7- dihydro-pyrrole [3,4-d] pyrimidine -6- carbonyl) -4- luorobenzyl] -2H- phthalazines -1- ketone；

(S) -4- { the fluoro- 3- of 4- [2- (methoxycarbonyl propyl -2- amino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

(R) -4- { the fluoro- 3- of 4- [2- (methoxycarbonyl propyl -2- amino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

(S) -4- { the fluoro- 3- of 4- [2- (2- methoxy propyl amino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

(R) -4- { the fluoro- 3- of 4- [2- (2- methoxy propyl amino) -5,7- dihydro-pyrrole [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (tetrahydrofuran -3- base) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (tetrahydrofuran -2- base) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (1- methyl piperidine -4- base) -5,7- dihydro-pyrrole [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (piperidin-4-yl) -5,7- dihydro-pyrrole [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- [3- (2- Cvclopropvlmethvl -5,7- dihydro-pyrrole [3,4-d] pyrimidine -6- carbonyl) -4- luorobenzyl] -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- ((1R, 2R) -2- methylcyclopropyl groups amino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- Carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- { 3- [2- Cyclobutylamino -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] -4- luorobenzyl } -2H- phthalazines -1- ketone；

4- { 3- [2- cyclo propyl methoxy -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] -4- luorobenzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (2- hydroxyl propyl- 2- yl) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (1- methoxy cyclopropylamino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- ((1R, 2S) -2- methylcyclopropyl groups amino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- { 3- [2- cyclopropylamino -4- methyl -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] -4- luorobenzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (1- trifluoromethyl cyclopropyl) amino -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- { 3- [2- (2,2- difluorocyclopropyl) amino -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] -4- luorobenzyl } -2H- phthalazines -1- ketone；

4- { 3- [2- (2,2- Dimethvlcvclopropvl) amino -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] -4- luorobenzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- ((1R, 2S) -2- fluorine cyclopropyl) amino -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- ((1R, 2R) -2- fluorine cyclopropyl) amino -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (2- methysulfonylethyl) amino -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

N, N- dimethyl -2- { 6- [the fluoro- 5- of 2- (4- oxo -3,4- dihydro phthalazines -1- methyl) benzoyl] -6,7- dihydro -5H- pyrrolo- [3,4-d] pyrimidine -2- amino }-ethyl sulfonamide；

4- [3- (2- cyclopropylamino -5,7- dihydro-pyrrole simultaneously [3,4-b] pyridine -6- carbonyl) -4- luorobenzyl] -2H- phthalazines -1- ketone；

4- [3- (6- cyclopropylamino -1,3- dihydro-pyrrole simultaneously [3,4-c] pyridine -2- carbonyl) -4- luorobenzyl] -2H- phthalazines -1- ketone；

4- [3- (2- cyclopropylamino -5,7- dihydro-pyrrole simultaneously [3,4-b] pyrazine -6- carbonyl) -4- luorobenzyl] -2H- phthalazines -1- ketone；

4- { 3- [2- (2,2- dimethyl-tetrahydro pyrans -4- amino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] -4- luorobenzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (4- methyl-tetrahydro-pyran -4- amino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- { 3- [2- (3- azabicyclo [3.1.0] hexyl -6- amino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] -4- luorobenzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (2,2,2- trifluoroethyl) amino -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- { 3- [2- (2,2- bis-fluoro ethyls) amino -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] -4- luorobenzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (2- fluoro ethyl) amino -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (oxetanylmethoxy -2- methyl) amino -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (oxetanylmethoxy -3- methyl) amino -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (tetrahydrofuran -2- methyl) amino -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- { 3- [2- (cyclopropylamino) -4- trifluoromethyl -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] -4- luorobenzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (2- trifluoromethoxy ethyl) amino -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- { 3- [2- cyclopropylamino -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] -4- luorobenzyl } fluoro- 2H- phthalazines -1- ketone of -7-；

The fluoro- 4- of 7- { the fluoro- 3- of 4- [2- (2- methoxy ethyl) amino -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

The fluoro- 4- of 7- { the fluoro- 3- of 4- [2- (oxinane -4- amino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (4- methoxycyclohexyl) amino -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

(R) -4- { 3- [2- (3- tetrahydrofuran base) amino -6,7- dihydro -5H- pyrrolo- [3,4-d] pyrimidine -6- carbonyl] -4- luorobenzyl } -2H phthalazines -1- ketone；

(S) -4- { 3- [2- (3- tetrahydrofuran base) amino -6,7- dihydro -5H- pyrrolo- [3,4-d] pyrimidine -6- carbonyl] -4- luorobenzyl } -2H phthalazines -1- ketone；

4- { 3- [2- (((2R, 5R) -5- dimethylamino -1,3- dioxanes -2- base) methyl) amino -6,7- dihydro -5H- pyrrolo- [3,4-d] pyrimidine -6- carbonyl] -4- luorobenzyl } -2H phthalazines -1- ketone；

4- { 3- [2- ((2R, 5R) -2- (dimethylamino) methyl-1,3- dioxanes -5- base) amino -6,7- dihydro -5H- Pyrrolo- [3,4-d] pyrimidine -6- carbonyl] -4- luorobenzyl } -2H phthalazines -1- ketone；With,

4- { 3- [4- methyl -2- (4- tetrahydrofuran base) amino -6,7- dihydro -5H- pyrrolo- [3,4-d] pyrimidine -6- carbonyl] -4- luorobenzyl } -2H phthalazines -1- ketone.

On the other hand, the application provides the preparation method of the compound, is selected from following synthetic route:

Route one:

Compound A and compound B is subjected to condensation reaction and obtains compound of formula I；Or

Route two:

Compound A and compound B ' is subjected to condensation reaction and obtains compound C '；By compound C ' and compoundIt carries out nucleophilic substitution and compound of formula I is made；

Wherein, Lg represents the leaving group of nucleophilic substitution, for example, halogen ,-OCOR ,-OTs ,-SO₂R etc., for example, mesyl, remaining each atom and substituent group are as defined above described in text.

In the certain preferred embodiments of the application, the operation of the condensation reaction is as follows: the compound B or compound B ' (unhindered amina or hydrochloride) of the compound A of 0.8-1.2 equivalent and 1.0 equivalents are dissolved in solvent (such as DMF or THF), condensing agent (such as the HATU of 0.8-1.2 equivalent is added at room temperature, EDCI, T3P etc.) and 2.0-5.0 equivalent alkali (such as DIPEA, Et₃N, pyridine etc.), water and organic solvent (such as ethyl acetate or methyl tertiary butyl ether(MTBE)) is added to reaction solution after reaction, liquid separation, extraction is dried and is spin-dried for, and crude product is prepared thin layer chromatography or column chromatographic purifying obtains target product compound of formula I or compound C '.

In the certain preferred embodiments of the application, the operation of the nucleophilic substitution is as follows: compound C ' (1.0eq.) is dissolved in organic solvent (such as acetonitrile etc.), in alkali (such as potassium carbonate, sodium carbonate, triethylamine, DIPEA etc., nucleopilic reagent (1.0-1.5eq.) is added in the presence of 1.0-3.0eq.), (40-120 DEG C) reaction of room temperature or heating, obtains product compound of formula I.

In the certain preferred embodiments of the application, it the described method comprises the following steps:

Compound A and compound 2B are subjected to condensation reaction and obtain Formulas I a compound, wherein each atom and substituent group be as defined above it is described in text.

Compound A and compound 3B are subjected to condensation reaction and obtain Formulas I aa compound, wherein each atom and substituent group be as defined above it is described in text.

Compound A and compound 4B are subjected to condensation reaction and obtain Formulas I aaa compound, wherein each atom and substituent group be as defined above it is described in text.

Compound B or B ' are commercially available or are prepared by this field routine experiment method.In the certain preferred embodiments of the application, by taking the synthesis of 2- pyrimidine derivatives as an example, the synthetic method of compound B or B ' include but is not limited to following method:

Method one:

Amino is reacted under heating conditions (such as 60-120 DEG C) by the 3- pyrrolidones and DMF-DMA of P radical protection; then it is concentrated under reduced pressure and removes DMF-DMA, obtained solid washs the reaction product that the first step can be obtained with solvent (such as methyl tertiary butyl ether(MTBE), tetrahydrofuran, ether or acetonitrile)；The product reacts available cyclization product in a solvent (such as ethyl alcohol, methanol or isopropanol) with sulfuric acid methyl mercapto amidine；With oxidant (such as m-CPBA, peroxidating water or Peracetic acid), sulfone class intermediate is can be obtained in (such as methylene chloride, acetonitrile or DMF) oxidation cyclization product in a solvent；The sulfone class intermediate reacts the derivative that 2- aminopyrimidine can be obtained with amine under conditions of 20-100 DEG C (reaction can not have to solvent, and such as DMF DMSO equal solvent can also be used)；Remove the protecting group (for example, by using trifluoracetic acid or hydrochloric acid) on N finally up to the 2- pyrimidine derivatives；

In the certain preferred embodiments of the application, the P group is amino protecting group.

Method two:

Amino is reacted under heating conditions (such as 60-120 DEG C) by the 3- pyrrolidones and DMF-DMA of P radical protection; then it is concentrated under reduced pressure and removes DMF-DMA, obtained solid washs the reaction product that the first step can be obtained with solvent (such as methyl tertiary butyl ether(MTBE), tetrahydrofuran, ether or acetonitrile)；The product is reacted to obtain 2- hydroxy pyrimidine derivatives intermediates with urea in alkaline condition room temperature or heating, by this intermediate and the available 2- chloro-pyrimidine derivatives of phosphorus oxychloride reaction；Then products therefrom and amine obtain 2- aminopyridine derivative under conditions of room temperature or heating, which can be using catalyst (such as Pd (dppf) Cl containing palladium₂Dichloromethane complex or Pd (OAc)₂), ligand (such as BINAP, Xantphos or BrettPhosphate) and alkali (such as DIPEA, Cs₂CO₃Or NaOt-Bu) come promote reaction (reaction can not have to solvent, or use such as toluene, dioxane, DMF DMSO equal solvent).Remove the protecting group (for example trifluoracetic acid or hydrochloric acid) on N finally up to the 2- pyrimidine derivatives.

Method three:

Amino is reacted under heating conditions (such as 60-120 DEG C) by the 3- pyrrolidones and DMF-DMA of P radical protection; then it is concentrated under reduced pressure and removes DMF-DMA, obtained solid washs the reaction product that the first step can be obtained with solvent (such as methyl tertiary butyl ether(MTBE), tetrahydrofuran, ether or acetonitrile)；The product is reacted under alkaline condition to obtain 2- hydroxy pyrimidine derivatives intermediates with urea；This intermediate and trifluoromethanesulfonic acid anhydride reactant are obtained into triflate intermediate, this intermediate reacts to obtain 2- aminopyridine derivative with amine, which can be using catalyst (such as Pd (dppf) Cl2 dichloromethane complex or Pd (OAc) containing palladium₂), ligand (such as Xantphos or BrettPhosphate) and alkali (such as Cs₂CO₃Or NaOt-Bu) come promote reaction (reaction can not have to solvent, or use such as toluene, dioxane, DMF DMSO equal solvent), then remove N on protecting group can obtain the 2- pyrimidine derivatives.

Alternatively, method four:

Amino is reacted under heating conditions (such as 60-120 DEG C) by the 3- pyrrolidones and DMF-DMA of P radical protection, is then concentrated under reduced pressure and removes DMF-DMA；Obtained solid washs the reaction product that the first step can be obtained with solvent (such as methyl tertiary butyl ether(MTBE), tetrahydrofuran, ether or acetonitrile)；This intermediate, which is reacted with substituted guanidine in alkaline condition, also can be obtained the 2- pyrimidine derivatives.

On the other hand, the application provides a kind of pharmaceutical composition, it includes herein described compound, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester or isomers above-mentioned, hydrate, solvate or crystal forms, it optionally, also include pharmaceutically acceptable carrier or excipient.

In the certain preferred embodiments of the application, the compound, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester or isomers above-mentioned, hydrate, solvate or crystal form can also be with one or more drug combinations.Therefore, in the certain preferred embodiments of the application, described pharmaceutical composition also includes one or more drugs.In the certain preferred embodiments of the application, the drug is anti-tumor drug.In the certain preferred embodiments of the application, the anti-tumor drug is selected from Temozolomide, adriamycin, taxol, cis-platinum, carboplatin, Dacarbazine, topotecan, Irinotecan, gemcitabine, bevacizumab, anti-CTLA-4 monoclonal antibody Ipilimumab, anti-PD-1 Monoclonal antibody pembrolizumab and Nivolumab and anti-PD-L1 monoclonal antibody atezolizumab.

In the certain preferred embodiments of the application, the carrier includes but is not limited to: aluminium oxide, aluminum stearate, lecithin, haemocyanin such as human albumin, phosphate, glycerol, sorbic acid, potassium sorbate, the partial glyceride mixtures of saturated vegetable fatty acid, water, protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, cabosil, magnesium trisilicate, polyvinylpyrrolidone, cellulosic material, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, beeswax, lanolin.The excipient refers to the additives in pharmaceutical preparation in addition to main ingredient.Its property is stablized, and with main ingredient without incompatibility, does not generate side effect, it does not affect the treatment, it is unlikely to deform at normal temperature, is dry and cracked, going mouldy, damaging by worms, is harmless, without physiological action, not acted on chemically or physically with main ingredient generation, do not influence the assay etc. of main ingredient.Such as binder, filler, disintegrating agent, the lubricant in tablet；Wine, vinegar, decoction in medicine pill etc.；Base portion in semi-solid preparation ointment, creme；Preservative, antioxidant, corrigent, aromatic, cosolvent, emulsifier, solubilizer, osmotic pressure regulator, colorant in liquid preparation etc. can be described as excipient.

The compound of the application, its ester, pro-drug, isomers, hydrate, solvate, crystal form, pharmaceutically acceptable salt, any combination or mixture of their metabolite form or above-mentioned items or its pharmaceutical composition can be administered by following approach: parenteral, local, intravenous, oral, subcutaneous, intra-arterial, intradermal, in percutaneous, rectum, encephalic, peritonaeum, intranasal, intramuscular route or as inhalant.

The compound of the application, its ester, pro-drug, isomers, hydrate, solvate, crystal form, pharmaceutically acceptable salt, any combination or mixture of their metabolite form or above-mentioned items or its pharmaceutical composition can be made into various suitable dosage forms according to administration route.

When oral medication, the application compound can be made into and arbitrarily take orally acceptable dosage form, including but not limited to tablet, capsule, aqueous solution or water slurry.Wherein, the carrier that tablet uses generally comprises lactose and cornstarch, and lubricant such as magnesium stearate in addition can also be added.The diluent that capsule preparations use generally comprises lactose and dried corn starch.Aqueous suspension preparation is then usually to be used in mixed way active constituent and suitable emulsifier and suspending agent.Optionally, some sweeteners, aromatic or colorant can also be added in the above oral dosage form.

When topical application, the application compound can be made into the dosage forms such as ointment, lotion or creme appropriate, wherein active constituent is suspended or dissolved in one or more carriers.Carrier workable for ointment formulation includes but is not limited to: mineral oil, Albolene, albolene, propylene glycol, polyethylene glycol oxide, polypropylene oxide, emulsifying wax and water；Carrier workable for lotion or creme includes but is not limited to: mineral oil, sorbitan monostearate, polysorbate60, cetyl ester wax, hexadecene be fragrant and mellow, 2- octyldodecanol, benzyl alcohol and water.

The application compound can the medication in the form of aseptic injection preparation, including aseptic injection water or oil suspension or aseptic injectable solution are also possible to lyophilized form.Wherein, workable carrier and solvent packet Include water, Ringer's solution and isotonic sodium chlorrde solution.In addition, the fixed oil of sterilizing also is used as solvent or suspension media, such as monoglyceride or two glyceride.

The pharmaceutical preparation of the application includes pharmaceutically enforceable any preparation, such as oral preparation, parenteral formulations etc..

The pharmaceutical composition and pharmaceutical preparation of the application can the application compound containing 0.01-2000mg, preferably comprise 0.1-1000mg the application compound, preferably comprise 1-800mg the application compound, further preferably 10-600mg the application compound particularly preferably contains 50-500mg the application compound.

In the embodiment of the application, carries out the suitable effect for measuring to determine the application composition in vitro or in vivo and whether administration is suitable for treating individual illnesses or medical condition.Non-limiting embodiment combination disease specific or therapeutic treatment are described the example of these measurements below.Usually, it is sufficient to realize the effective quantity of the application composition of prevention or therapeutic effect is about 0.001mg/ kg body weight/day to about 10,000mg/ kg body weight/day.In suitable situation, dosage is about 0.01mg/ kg body weight/day to about 1000mg/ kg body weight/day.Dosage range can for daily, every two days or every three days about 0.01 to 1000mg/kg host's weight, more typically 0.1 to 500mg/kg host's weight.Illustrative therapeutic scheme is once every two days or once-weekly or once-monthly administration.The reagent is repeatedly usually given, the interval between single dose can be daily, weekly, monthly or every year.Alternatively, the reagent can be given in the form of sustained release preparation, in this case it is necessary to less administration frequency.Dosage and frequency according to half-life period of the reagent in subject and it is different.It can also be according to being preventative process or therapeutic treatment and difference.In prophylactic use, relatively low dosage is given for a long time with the interval of rather low-frequency rate.In therapeutic application, it is sometimes desirable to give relatively high dosage with relatively short interval, until the progress of disease is delayed or stops, and be preferably up to individual and show the partially or completely improvement of disease symptoms that patient's prevention scheme can be given after this.

On the other hand, the application provides the purposes of the compound, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester or isomers above-mentioned, hydrate, solvate or crystal form or pharmaceutical composition described herein in the reagent that preparation inhibits PARP.

In the certain preferred embodiments of the application, the reagent is the reagent for inhibiting PARP-1.

On the other hand, the application also provides a kind of active method of inhibition PARP, and the method includes applying a effective amount of compound, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester described herein or isomers above-mentioned, hydrate, solvate or crystal form or pharmaceutical composition described herein to cell in need.

In the certain preferred embodiments of the application, the method is for inhibiting PARP-1 active.

In the certain preferred embodiments of the application, the method is for inhibiting PARP-1 in cell Activity.

In the certain preferred embodiments of the application, the cell is cell line or the cell from subject.

On the other hand, the application provide the compound, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester or isomers above-mentioned, hydrate, solvate or crystal form or pharmaceutical composition described herein the reagent for preparing adjuvant therapy of tumors or for enhance radiation or chemical therapeutic effect drug in purposes.

On the other hand, the application provides the compound, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester or isomers above-mentioned, hydrate, solvate or crystal form or pharmaceutical composition described herein, is used for adjuvant therapy of tumors or for enhancing radiation or chemical therapeutic effect.

On the other hand, the application provides a kind of method of adjuvant therapy of tumors or enhancing radiation or chemical therapeutic effect, and the method includes applying a effective amount of compound, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester described herein or isomers above-mentioned, hydrate, solvate or crystal form or pharmaceutical composition described herein to subject in need.

On the other hand, the application provides the purposes of the compound, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester or isomers above-mentioned, hydrate, solvate or crystal form or pharmaceutical composition described herein in the drug of preparation treatment tumour.

On the other hand, the application provides the compound, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester or isomers above-mentioned, hydrate, solvate or crystal form or pharmaceutical composition described herein, is used to treat tumour.

On the other hand, the application provides a kind of method for treating tumour, and the method includes providing a effective amount of compound, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester described herein or isomers above-mentioned, hydrate, solvate or crystal form or pharmaceutical composition described herein to subject in need.

On the other hand, the application provides the compound, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester or isomers above-mentioned, hydrate, solvate or crystal form or pharmaceutical composition described herein in preparation treatment vascular diseases, neurodegenerative diseases or nerveous system Purposes in the drug for inflammation of uniting.

On the other hand, the application provides the compound, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester or isomers above-mentioned, hydrate, solvate or crystal form or pharmaceutical composition described herein, is used to treat vascular diseases, neurodegenerative diseases or nervous system inflammation.

On the other hand, the application provides a kind of method for treating vascular diseases, neurodegenerative diseases or nervous system inflammation, and the method includes applying a effective amount of compound, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester described herein or isomers above-mentioned, hydrate, solvate or crystal form or pharmaceutical composition described herein to subject in need.

On the other hand, the application provides the compound, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester or isomers above-mentioned, hydrate, solvate or crystal form or pharmaceutical composition described herein, is used to inhibit PARP activity in cell.

In the certain preferred embodiments of the application, the compound, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester or isomers above-mentioned, hydrate, solvate or crystal form or pharmaceutical composition described herein are for inhibiting PARP-1 activity in cell.

In the certain preferred embodiments of the application, the compound, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester or isomers above-mentioned, hydrate, solvate or crystal form or pharmaceutical composition described herein are in vivo approaches.

In the certain preferred embodiments of the application, the compound, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester or isomers above-mentioned, hydrate, solvate or crystal form or pharmaceutical composition described herein are in in-vitro method.

On the other hand, the application also provides a kind of active method of PARP in inhibition cell, and the method includes giving cell a effective amount of compound, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester described herein or isomers above-mentioned, hydrate, solvate or crystal form or pharmaceutical composition described herein.

In the certain preferred embodiments of the application, the method carries out in vivo.

In the certain preferred embodiments of the application, the method carries out in vitro.

On the other hand, the application also provides the purposes of the compound, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester or isomers above-mentioned, hydrate, solvate or crystal form or pharmaceutical composition described herein in reagent preparation, and the reagent inhibits the reagent of tumor cell proliferation as compound, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester or isomers above-mentioned, hydrate, solvate or crystal form auxiliary or inhibits the effect of tumor cell proliferation for enhancing radiation or chemical method.

In the certain preferred embodiments of the application, the tumour cell is tumor cell line or the tumour cell from subject.

In the certain preferred embodiments of the application, the reagent is in vivo approaches.

In the certain preferred embodiments of the application, the reagent is in in-vitro method.

On the other hand, the application also provides the compound, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester or isomers above-mentioned, hydrate, solvate or crystal form or pharmaceutical composition described herein, is used to assist inhibiting tumor cell proliferation or inhibits the effect of tumor cell proliferation for enhancing radiation or chemical method.

In the certain preferred embodiments of the application, the compound, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester or isomers above-mentioned, hydrate, solvate or crystal form or the application pharmaceutical composition are in vivo approaches.

In the certain preferred embodiments of the application, the compound, its ester, pro-drug, isomers, hydrate, solvate, crystal form, pharmaceutically acceptable salt, any combination or mixture of their metabolite form or above-mentioned items or drug described herein are in in-vitro method.

On the other hand, the application also provides a kind of method of effect that auxiliary inhibits tumor cell proliferation or enhancing radiation or chemical method to inhibit tumor cell proliferation, and the method includes giving tumour cell a effective amount of compound, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester described herein or isomers above-mentioned, hydrate, solvate or crystal form or pharmaceutical composition described herein.

On the other hand, the application also provides the purposes of the compound, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester or isomers above-mentioned, hydrate, solvate or crystal form or pharmaceutical composition described herein in reagent preparation, and the reagent is for inhibiting tumor cell proliferation.

On the other hand, the application also provides the compound, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester or isomers above-mentioned, hydrate, solvate or crystal form or pharmaceutical composition described herein, is used to inhibit tumor cell proliferation.

On the other hand, the application also provides a kind of method for inhibiting tumor cell proliferation, and the method includes giving cell a effective amount of compound, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester described herein or isomers above-mentioned, hydrate, solvate or crystal form or pharmaceutical composition described herein.

In the certain preferred embodiments of the application, the tumour is selected from breast cancer, oophoroma, colorectal cancer, melanoma, lung cancer, gastrointestinal stromal tumor, the cancer of the brain, cervical carcinoma, cancer of pancreas, prostate cancer, gastric cancer, chronic marrow sample hypercytosis, liver cancer, lymthoma, peritoneal cancer, soft tissue sarcoma, neuroendocrine tumor and glioblastoma.

In the certain preferred embodiments of the application, the tumour cell is selected from breast cancer cell, ovarian cancer cell, colorectal cancer cell, melanoma cells, lung carcinoma cell, Gastrointestinal Stromal oncocyte, brain cancer cell, cervical cancer cell, pancreatic cancer cell, prostate gland cancer cell, stomach cancer cell, chronic marrow sample leucocyte, liver cancer cells, lymphoma cell, peritonaeum cancer cell, soft tissue sarcoma cell, neuroendocrine tumor cell and glioblastoma cells.

In the certain preferred embodiments of the application, the tumour cell is tumor cell line or comes from The tumour cell of subject.

Tumour described herein includes pernicious and benign tumour, and correspondingly, the tumour cell includes pernicious and benign tumor cells.

Herein described subject is mammal, such as bovid, equid, caprid, porcine animals, canid, felid, rodent, primate；It is wherein, particularly preferred that subject is a human.

The term of the application is explained below, for specific term, if the meaning and the normally understood meaning of those skilled in the art in the application are inconsistent, the meaning being subject in the application；If do not defined in this application, with the normally understood meaning of those skilled in the art.Unless stated to the contrary, term used herein has following meanings.

Hydrogen in terms used herein " hydrogen " and each group comprising protium (H), deuterium (D), tritium (T).In the certain preferred embodiments of the application, the hydrogen is protium (H).

Terms used herein " alkyl " refers to linear chain or branched chain saturated hydrocarbyl, such as C_1-10Alkyl, C_1-6Alkyl or C_1-4Alkyl, the non-limiting embodiment of alkyl include methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, sec-butyl, tert-butyl, amyl, hexyl etc..

The alkyl is unsubstituted, or can be substituted base and be further substituted with to form substitution alkyl, and the substituent group can be selected from halogen, naphthenic base, Heterocyclylalkyl, RO- or RR ' N-, and wherein R and R ' definition is as described in the present application.

When substituent group is halogen (such as fluorine), the alkyl after the substitution is halogenated alkyl described herein, including halogenated C_1-6Alkyl (such as fluoro C_1-6Alkyl) and halogenated C_1-4Alkyl (such as fluoro C_1-4Alkyl) etc..

When substituent group is naphthenic base, the alkyl after the substitution is naphthenic base-alkyl described herein, including 3-20 member naphthenic base-C_1-10Alkyl, 3-12 member naphthenic base-C_1-6Alkyl, 3-8 member naphthenic base-C_1-4Alkyl, 3 yuan of cycloalkylmethyls, 4 yuan of cycloalkylmethyls, 5 yuan of cycloalkylmethyls, 6 yuan of cycloalkylmethyls, 7 yuan of cycloalkylmethyls and 8 yuan of cycloalkylmethyls etc..

When substituent group is Heterocyclylalkyl, the alkyl after the substitution is heterocycloalkyl-alkyl described herein, including 3-20 membered heterocycloalkyl-C_1-10Alkyl, 3-8 membered heterocycloalkyl-C_1-6Alkyl, 3-8 membered heterocycloalkyl-C_1-4Alkyl, 3 membered heterocycloalkyls-methyl, 4 membered heterocycloalkyls-methyl, 5 membered heterocycloalkyls-methyl, 6 membered heterocycloalkyls-methyl, 7 membered heterocycloalkyls-methyl and 8 membered heterocycloalkyls-methyl etc..

When substituent group is RO-, the alkyl after the substitution is RO- alkyl, for example including RO-C_1-10Alkyl, RO-C_1-6Alkyl, RO-C_1-4Alkyl, RO- methyl and RO- ethyl etc., wherein the R group is as described in the present application.In the certain preferred embodiments of the application, R is hydrogen or C_1-10Alkyl, therefore, the alkyl or C which can replace for hydroxyl_1-10Alkoxyalkyl.The alkyl that the hydroxyl replaces includes hydroxyl C_1-10Alkyl, hydroxyl C_1-6Alkyl and hydroxyl C_1-4Alkyl etc..The C_1-10Alcoxyl Base alkyl includes C_1-6Alkoxy -C_1-6Alkyl and C_1-4Alkoxy -C_1-4Alkyl etc..

When substituent group is RR ' N-, the alkyl after the substitution is RR ' N- alkyl, for example including RR ' N-C_1-10Alkyl, RR ' N-C_1-6Alkyl, RR ' N-C_1-4Alkyl, RR ' N- methyl and RR ' N- ethyl etc., wherein the R and R ' group are as described in the present application.In the certain preferred embodiments of the application, R and R ' are hydrogen or C_1-10Alkyl, therefore, the alkyl or C which can replace for amino_1-10Alkyl amino alkyl or two C_1-10Alkyl amino alkyl.RR ' the N- alkyl is, for example, the C that amino replaces_1-10The C that alkyl, amino replace_1-6The C that alkyl, amino replace_1-4Alkyl, C_1-6Alkylamino-C_1-6Alkyl, C_1-4Alkylamino-C_1-4Alkyl, two C_1-6Alkylamino-C_1-6Alkyl and two C_1-4Alkylamino-C_1-4Alkyl etc..Terms used herein " alkenyl " refers to the linear chain or branched chain alkyl containing at least one carbon-carbon double bond, such as C_2-10Alkenyl, C_2-6Alkenyl or C_2-4Alkenyl, the non-limiting embodiment of alkenyl include vinyl, acrylic, cyclobutenyl, 2- methylpropenyl, pentenyl, 2- methyl butene base, 3- methyl butene base, hexenyl, 2- methylpent alkenyl, 3- methylpent alkenyl, 4- methylpent alkenyl, 2- ethyl cyclobutenyl etc..Terms used herein " alkynyl " refers to the linear chain or branched chain alkyl containing at least one carbon-carbon triple bond, such as C_2-10Alkynyl, C_2-6Alkynyl or C_2-4Alkynyl, the non-limiting embodiment of alkynyl include acetenyl, propinyl, butynyl, pentynyl, 3- methylbutynyl, hexin base, 3- methyl-pentinyl etc..Terms used herein " alkoxy " refers to the group with " alkyl-O- " structure, such as C_1-10Alkoxy, C_1-6Alkoxy or C_1-4Alkoxy, the non-limiting embodiment of alkoxy include methoxyl group, ethyoxyl, propoxyl group, isopropoxy and tert-butoxy etc..

Chemical formula " ROC (O)-" used herein refers to substituted oxygen carbonyl, such as alkoxy carbonyl group.The non-limiting embodiment of R-OC (O)-includes methoxycarbonyl group, carbethoxyl group, propylene carbonyl oxygen, tertbutyloxycarbonyl, carbobenzyloxy etc..

Chemical formula " RC (O) O- " used herein refers to substituted acyloxy, such as alkyl acyloxy.The non-limiting embodiment of R-C (O) O- includes formyloxy, acetoxyl group, propionyloxy and benzoyloxy etc..

Chemical formula " RC (O)-" used herein refers to substituted acyl group, such as alkanoyl.The non-limiting embodiment of R-C (O)-includes acetyl group, propiono, bytyry and benzoyl etc..

Chemical formula " RR ' NH- " used herein refers to substituted amino, such as alkylamino, dialkylamino etc..The non-limiting embodiment of RR ' NH- includes methylamino, ethylamino, the third amino, N, N- dimethylamino, N, N- lignocaine etc..

Chemical formula " RC (O) NH- " used herein refers to substituted amide groups, such as alkyl amido and aromatic acylamino etc..The non-limiting embodiment of R-C (O) NH- includes formamido group, acetylamino and benzamido etc..

Chemical formula " RR ' NHC (O)-" used herein refers to substituted aminoacyl, such as alkane aminoacyl and dioxane aminoacyl etc..The non-limiting embodiment of RR ' NHC (O)-includes carbamoyl group, second aminoacyl, N, bis- carbamoyl group of N-, N, N- diethyl aminoacyl etc..

Chemical formula " RS (O) used herein_a", wherein a=0,1 or 2, refer to substituted sulfydryl, sulfonyl or sulfinyl, RS (O)_aNon-limiting embodiment include sulfydryl, mesyl, ethylsulfonyl, benzenesulfonyl, to Methyl benzenesulfonyl base etc..

Chemical formula " RR ' NSO used herein₂" refer to substituted amino-sulfonyl, RR ' NSO₂Non-limiting embodiment include dimethylaminosulfonyl etc..

Chemical formula " RSO used herein₂N (R ')-" refers to substituted sulfoamido, such as alkylsulfonamido and aryl-sulfonyl amino etc..RSO₂The non-limiting embodiment of N (R ')-includes methylsulfonyl amido, second sulfonamido, benzene sulfonamido and tolysulfonyl amido etc..

" R " and " R ' " used herein are each independently selected from hydrogen, hydroxyl, C_1-10Alkyl, 3-20 member naphthenic base, 5-20 membered heterocycloalkyl, 6-20 member aryl and 5-20 unit's heteroaryl.In the certain preferred embodiments of the application, the R and R ' are hydrogen or C_1-10Alkyl is when the substituent group in generation referred to herein contains R or R ' comprising all to meet the R or R ' defined above of chemical valence key gauge then.

Terms used herein " naphthenic base " refers to monocycle or polycyclic cyclic alkyl, such as the naphthenic base comprising 3-20 carbon atom, such as the naphthenic base comprising 3-12 carbon atom, such as the naphthenic base comprising 3-10 carbon atom, such as the naphthenic base comprising 3-8 carbon atom, such as the naphthenic base comprising 5-8 carbon atom.The non-limiting embodiment of monocycle alkyl includes cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl cyclooctyl etc..Polycyclic naphthene base includes the naphthenic base of loop coil, condensed ring and bridged ring.Terms used herein " Heterocyclylalkyl " refers to the heteroatomic naphthenic base as previously described that N, O and S are selected from comprising at least one, such as the Heterocyclylalkyl containing one or two N atom, the Heterocyclylalkyl containing an O atom, the Heterocyclylalkyl containing a S atom, for example comprising 3-20 membered heterocycloalkyl, such as include 5-20 membered heterocycloalkyl, such as comprising 3-8 membered heterocycloalkyl, such as include 5-8 membered heterocycloalkyl.The non-limiting embodiment of Heterocyclylalkyl includes propylene oxide base, tetrahydrofuran base, pyrrolidinyl, THP trtrahydropyranyl, piperidyl, piperazinyl, morpholinyl, thiomorpholine base, high piperazine base etc..Terms used herein " aryl " refers to that 6-20 unit monocycle or fused polycycle (such as bicyclic or tricyclic) have the group of armaticity, it is preferred that 6-14 member aryl, more preferable 6-10 member aryl, the non-limiting embodiment of aryl includes but is not limited to phenyl and naphthalene etc..Terms used herein " heteroaryl " refers to the 5-14 membered aromatic heterocycle group that the hetero atom for being selected from N, O or S by least one replaces, preferably 5-10 member.Such as heteroaryl containing one or two N atom, the heteroaryl containing O atom or the heteroaryl containing a S atom.The non-limiting embodiment of heteroaryl includes furyl, thienyl, pyrrole radicals, imidazole radicals, oxazolyl, thiazolyl, pyrazolyl, triazol radical, tetrazole base, pyridyl group, pyridazinyl, pyrimidine radicals and pyrazinyl etc..

Terms used herein " alicyclic ring " refers to the carbocyclic ring without aromatic character of saturation or fractional saturation.For example including 3-20 member alicyclic ring, 3-12 member alicyclic ring, 3-8 member alicyclic ring, 4 yuan of alicyclic rings, 5 yuan of alicyclic rings, 6 yuan of alicyclic rings, 7 yuan of alicyclic rings etc..

Terms used herein " alicyclic heterocyclic " refers to that at least one ring members is the miscellaneous original selected from N, O and S The aliphatic cyclic group of son.Such as alicyclic heterocyclic containing 1 or 2 N atom, such as containing only the alicyclic heterocyclic of an O atom, for example containing only the alicyclic heterocyclic of a S atom.For example including 3-20 member alicyclic heterocyclic, 3-12 member alicyclic heterocyclic, 3-8 member alicyclic heterocyclic, 4 yuan of alicyclic heterocyclics, 5 yuan of alicyclic heterocyclics, 6 yuan of alicyclic heterocyclics, 7 yuan of alicyclic heterocyclics etc..

Terms used herein " aromatic ring " refers to that all ring members are the aromatic rings of carbon atom.For example including 6-20 member aromatic ring, 6-14 member aromatic ring, 6-10 member aromatic ring etc..

Terms used herein " hetero-aromatic ring " refers to that at least one ring members is the heteroatomic cyclic group with armaticity selected from N, O and S.Such as hetero-aromatic ring containing 1 or 2 N atom, such as containing only the hetero-aromatic ring of an O atom, for example containing only the hetero-aromatic ring of a S atom.For example including 5-20 member hetero-aromatic ring, 5-14 member hetero-aromatic ring, 5-10 member hetero-aromatic ring, 5-6 member hetero-aromatic ring etc..

Terms used herein " halogen " includes fluorine, chlorine, bromine and iodine.

In compound of formula I described herein, whereinNon-limiting embodiment include:

The condensed ring can be by R₅R₆N- group replaces, and the selection of described the position of substitution meets valence bond theory.

It will be appreciated by those skilled in the art that when in the molecular structure of herein described compound there are when conjugated system, meeting the resonant structure of valence bond theory also within the scope of protection of this application, for example,Formula a, formula b and formula c are within the scope of protection of this application.

Terms used herein " isomers " includes all possible isomers of the application compound of Formula I Form, such as enantiomter, diastereoisomer, epimer, cis-trans-isomer, conformer etc..For example, R and S configuration enantiomter and Z and E configuration cis-trans-isomer etc. within the scope of protection of this application.

The application type I compound or its pharmaceutically acceptable salt can also form solvate, such as hydrate, alcohol adduct etc..

The application compound of formula I can also be prodrug or can release the form of active constituent after metabolic alterations in vivo.Selecting and prepare prodrug appropriate is technology well known to those skilled in the art.

The application type I compound or its pharmaceutically acceptable salt can also exist with crystal, the crystal refers to the molecule, atom or the ion that constitute compound in space period duplicate arrangement according to certain rules, it arranges the periodicity with three-dimensional space, repeats every a certain distance.Compound can exist with two or more crystalline states, and the identical molecular crystalline of structure is at different solid forms, referred to as " polymorph ", as polymorph or polymorph etc..When being related to specific crystal form or polymorphic, it is referred to as " crystal form ", term as used herein " crystal form ", the application includes the compound of formula I or any crystal form of its pharmaceutically acceptable salt.

Terms used herein " effective quantity " refers to the amount for being enough to realize required prevention and/or therapeutic effect, for example, realizing prevention or mitigating the amount of symptom relevant to disease to be treated.

The term as used herein " treatment " refers to therapeutic treatment and preventive measure, and the purpose is to the morbid state for preventing or delaying (mitigation) targeted or illnesss.If subject receives the compound or its isomers, solvate, pharmaceutically acceptable salt or its pharmaceutical composition of therapeutic dose according to methods described herein, the one or more indications of the subject and Symptoms go out observable and/or detectable reduction or improvement, then subject successfully " is treated ".It is also understood that the prevention or treatment of morbid state or the illness not only include fully prevent or treat, it further include not up to fully preventing or treating, but realize some biology or the relevant result of medicine.

Terms used herein " vascular diseases " is primarily referred to as myocardial ischemia/reperfusion injury, various forms of heart failures, cardiomyopathy, cyclical shock after damage, cardiovascular aging, the cardiovascular complication of diabetes, myocardial hypertrophy, atherosclerosis, vascular remodeling, angiogenesis.

Terms used herein " neurodegenerative disease and nervous system inflammation " is primarily referred to as due to oxidation, apoplexy caused by the adverse effect of nitrosative stress, brain trauma, neurodegenerative disease (Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis) and nervous system inflammation such as multiple sclerosis etc..

Advantageous effect of the invention

The application provides a kind of phthalazines ketone compounds, the compound is able to achieve following at least one technical effects by furtheing investigate to phthalazines ketone PARP inhibitor:

(1) inhibited proliferation to tumour cell or/and cancer cell can be significantly improved；

(2) stability in molecule body can be increased, reduce a possibility that generating toxic metabolites；

(3) toxicity that can reduce drug molecule makes its safety in terms of disease treatment be further improved, and extends applicable sick group's range of such drug；

(4) by the structural modification to phthalazines ketone compounds, oxidative metabolism ability of the compound in vivo under the effect of P450 cytochromes enzyme system is reduced, bioavailability is improved；In addition,

(6) there is the compound of the application excellent long-term effect to improve the compliance of patient it is possible thereby to reduce administration number of times.

The good physicochemical property of the compound of the application makes it have very big potentiality in terms of developing the PARP inhibitor with excellent bioavailability, inhibition validity and safety.

Detailed description of the invention

Fig. 1 shows, inhibited proliferation of the application compound to breast cancer MDA-MB-453.

Fig. 2-1, Fig. 2-2 show, inhibited proliferation of the application compound to breast cancer MDA-MB-468.

Fig. 3 shows, the inhibited proliferation of the application compounds on pancreatic cancer Capan-1.

Fig. 4 shows, inhibited proliferation of the application compound to carcinoma of the rectum HCT116.

Specific embodiment

Embodiment of the present invention is described in detail below in conjunction with embodiment, it will be appreciated by those skilled in the art that the following example is merely to illustrate the present invention, and should not be taken as limiting the scope of the invention.The person that is not specified actual conditions in embodiment, carries out according to conventional conditions or manufacturer's recommended conditions.Reagents or instruments used without specified manufacturer, being can be with conventional products that are commercially available.

The structure of compound be by nuclear magnetic resonance (¹HNMR) or mass spectrum (MS) is come what is determined.

Abbreviation in nuclear magnetic resonance used in embodiment (NMR) map is shown in following:

S: unimodal (singlet), d: doublet (doublet), t: triplet (triplet), q: quartet (quartet), AB: double doublet (double doublet), m: multiplet (multiplet), br: broad peak (broad).

¹The measurement of HNMR is to use 400 nuclear magnetic resonance spectrometer of JEOL Eclipse, and measurement solvent is deuterated methanol (CD₃OD), deuterated chloroform (CDCl₃), hexadeuterated dimethyl sulfoxide (DMSO-d6) is inside designated as tetramethylsilane (TMS), and chemical shift is with 10^-6(ppm) it is provided as unit.

The measurement of MS Agilent (ESI) mass spectrograph, manufacturer: Agilent, model: Agilent6120B.

It prepares efficient liquid phase and uses Shimadzu LC-8A preparative liquid chromatograph (YMC, ODS, 250 × 20mml chromatographic column).

The aluminium sheet (20 × 20cm) that thin-layer chromatography silica gel plate (TLC) uses Merck to produce, the specification that thin-layer chromatography isolates and purifies use is that Yantai produces GF254 (0.4-0.5nm).

The monitoring of reaction uses thin-layered chromatography (TLC) or LCMS, the solvent system used has: methylene chloride and methanol system, n-hexane and ethyl acetate system, petroleum ether and ethyl acetate system, the volume ratio of solvent is different according to the polarity of compound and is adjusted or is added triethylamine etc. and be adjusted.

Microwave reaction uses Biotage Initiator+ (400W, RT-300 DEG C) microwave reactor.

Column chromatography is generally carrier using Qingdao Haiyang 200-300 mesh silica gel.The system of eluant, eluent includes: methylene chloride and methanol system, and n-hexane and ethyl acetate system, the volume ratio of solvent are adjusted according to the polarity difference of compound, a small amount of triethylamine can also be added and be adjusted.

Without specified otherwise in embodiment, the temperature of reaction is room temperature (20 DEG C -30 DEG C).

Reagent used in this application is purchased from Acros Organics, Aldrich Chemical Company, the companies such as special primary chemistry.

In conventional synthetic method and embodiment and intermediate synthesis example, the meaning respectively abridged is as shown below:

DCM: methylene chloride；

DIPEA:N, N- diisopropylethylamine；

DMAP:4- dimethylamino naphthyridine；

MeOH: methanol；

THF: tetrahydrofuran；

EtOH: ethyl alcohol；

DMF:N, dinethylformamide；

DMF-DMA:N, dinethylformamide dimethylacetal；

HATU:2- (7- azo benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester；

NMP:N- methyl pyrrolidone；

LCMS: liquid chromatography mass spectrometric combined instrument；

TLC: thin-layer chromatography.

Embodiment 1:

4- [3- (2- ethylamino- -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl) -4- luorobenzyl] -2H- phthalazines -1- ketone (compound 1)

Reaction route:

Step 1: 1- tert-butoxycarbonyl -3- dimethylamino methene -4- pyrrolidones

To 300mLDMF-DMA is added in N-Boc-3- pyrrolidones (56.2g), it is stirred overnight at 65 DEG C.TLC shows raw material fully reacting.After concentration removes DMF-DMA, obtained solid is washed with methyl tertiary butyl ether(MTBE), is filtered, by solids-enriched to doing, obtains target product (47.2g, yellow solid, yield: 64%).

MS m/z(ESI):241.1[M+H]⁺。

Step 2: 2- methyl mercapto -5,7- dihydro-pyrrole [3,4-d] pyrimidine -6- carboxylic acid tert-butyl ester

At room temperature, to 250mL sodium ethoxide (6.6g, sulfuric acid methyl mercapto amidine (7.8g is added in ethanol solution 93mmol), 41.6mmol), after stir about 30 minutes, 1- tert-butoxycarbonyl -3- dimethylamino methene -4- the pyrrolidones (5g, 20.8mmol) of the first step and return stirring 6 hours are added.TLC monitoring raw material unreacted is complete, adds sulfuric acid methyl mercapto amidine (7.8g, 41.6mmol) and sodium ethoxide (6.6g, 93mmol), is refluxed overnight.TLC monitors raw material and disappears, and water quenching is added to go out after reaction system, and concentration removes ethyl alcohol.Water phase is extracted with ethyl acetate (50mL × 4), merges organic phase, and anhydrous sodium sulfate is dry.Target molecule (3.3g, faint yellow solid, yield: 59%) are obtained after being washed again with methyl tertiary butyl ether(MTBE) after organic phase is spin-dried for.

MS m/z(ESI):268.1[M+H]⁺.

Step 3: 2- methylsulfonyl -5,7- dihydro-pyrrole [3,4-d] pyrimidine -6- carboxylic acid tert-butyl ester

At 0 DEG C, to 50mL2- methyl mercapto -5,7- dihydro-pyrrole [3,4-d] pyrimidine -6- carboxylic acid tert-butyl ester (3.3g, 12.3mmol) dichloromethane solution in be added metachloroperbenzoic acid (6.3g, 37.1mmol), naturally it is warmed to room temperature, TLC tracking and monitoring.Raw material fully reacting after 5 hours.10% sodium sulfite solution is added into reaction solution, stirring added 10% sodium carbonate liquor after 30 minutes, stirring is in a moment, it is extracted with methylene chloride (50mL × 4), merge organic phase, anhydrous sodium sulfate is dry, is spin-dried for, gained residue obtains target molecule after being washed again with methyl tertiary butyl ether(MTBE), yield: 86.7%.

MS m/z(ESI):300.3[M+H]⁺.

Step 4: 2- ethylamino -5,7- dihydro-pyrrole [3,4-d] pyrimidine -6- carboxylic acid tert-butyl ester

By 2- methylsulfonyl -5,7- dihydro-pyrrole [3,4-d] pyrimidine -6- carboxylic acid tert-butyl ester of third step (300mg, 1.00mmol) is dissolved in 5mL acetonitrile, and potassium carbonate (207mg, 1.50mmol) is added and ethamine (132.6mg, 2mmol), gained mixture react 6 hours at 70 DEG C, and reaction, methylene chloride extraction is quenched with water.Dichloromethane layer is dried over anhydrous sodium sulfate, and is concentrated to get residue and is obtained target product (110mg, yield: 38%) after preparing thin layer chromatography.

MS m/z(ESI):265[M+H]⁺.

Step 5: N- ethyl -6,7- dihydro -5H- pyrroles [3,4-d] pyrimidine -2- amine hydrochlorate

2- ethylamino -5,7- dihydro-pyrrole [3,4-d] pyrimidine -6- carboxylic acid tert-butyl ester (10mg, 0.45mmol) of 4th step is dissolved in the ethyl acetate solution (3mL) of hydrogen chloride, is stirred overnight at room temperature.The residue obtained after reaction solution concentration is directly used in react in next step.

MS m/z(ESI):165[M+H]⁺.

Step 6: 4- [3- (2- ethylamino- -5,7- dihydro-pyrrole [3,4-d] pyrimidine -6- carbonyl) -4- luorobenzyl] -2H- phthalazines -1- ketone

By 5- (3,4- dihydro -4- oxo -1- phthalazinyl) methyl -2- fluobenzoic acid (134.2mg, 0.45mmol), N- ethyl -6,7- dihydro -5H- pyrroles [3 of the 5th step, 4-d] pyrimidine -2- amine hydrochlorate (74.5mg, 0.45mmol), HATU (188.2mg, 0.50mmol) and DIPEA (348.3mg, it 2.7mmol) is dissolved in DMF, is stirred overnight at room temperature.After fully reacting, water is added into reaction solution and ethyl acetate, liquid separation, ethyl acetate layer are concentrated after being dried over anhydrous sodium sulfate.Residue obtains target product (15mg, yield: 7.5%) after preparing thin layer chromatography.

MS m/z(ESI):445[M+H]⁺.

¹HNMR (400MHz, DMSO-d6) δ: 12.61 (brs, 1H), 8.33-8.17 (m, 1H), 8.02-7.95 (m, 1H), 7.93-7.80 (m, 2H), 7.53-7.42 (m, 2H), 7.32-7.18 (m, 2H), 4.69-4.53 (m, 2H), 4.40-4.30 (m, 4H), 3.57-3.21 (m, 2H), 1.09 (q, 3H, J=8Hz)

Embodiment 2:

4- [3- (2- cyclopropylamino -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl) -4- luorobenzyl] -2H- phthalazines -1- ketone (compound 2)

Reaction route:

Step 1: 1- tert-butoxycarbonyl -3- dimethylamino methene -4- pyrrolidones

To 300mLDMF-DMA is added in N-Boc-3- pyrrolidones (56.2g), it is stirred overnight at 120 DEG C.TLC shows raw material fully reacting.After concentration removes DMF-DMA, obtained solid is washed with methyl tertiary butyl ether(MTBE), is filtered, by solids-enriched to doing, obtains target product (43g, yellow solid, yield: 58%).

MS m/z(ESI):241.1[M+H]⁺。

At room temperature, to 250mL sodium ethoxide (6.6g, sulfuric acid methyl mercapto amidine (15.6g is added in ethanol solution 93mmol), 83.2mmol), stir about is after forty minutes, 1- tert-butoxycarbonyl -3- dimethylamino methene -4- the pyrrolidones (5g, 20.8mmol) of the first step is added and return stirring is stayed overnight.TLC monitors raw material and disappears, and after adding water quenching to go out, concentration removes ethyl alcohol.Water phase is extracted with ethyl acetate (50mL × 4), merges organic phase, and anhydrous sodium sulfate is dry, and target molecule (10g, faint yellow solid, yield: 89%) are obtained after being washed again with methyl tertiary butyl ether(MTBE) after reduced pressure.

MS m/z(ESI):268.1[M+H]⁺.

Step 3: 2- (methylsulfonyl) -5,7- dihydro-pyrrole [3,4-d] pyrimidine -6- carboxylic acid tert-butyl ester

At 0 DEG C, to 50mL2- methyl mercapto -5,7- dihydro-pyrrole [3,4-d] pyrimidine -6- carboxylic acid tert-butyl ester (3.3g, 12.3mmol) dichloromethane solution in be added metachloroperbenzoic acid (6.3g, 37.1mmol), naturally it is warmed to room temperature, after fully reacting.10% sodium sulfite solution is added into reaction solution, stirring added 10% sodium carbonate liquor after 30 minutes, stirring is in a moment, it is extracted with methylene chloride (50mL × 4), merge organic phase, anhydrous sodium sulfate is dry, is concentrated under reduced pressure, target molecule, yield: 86.7%) are obtained after being washed again with methyl tertiary butyl ether(MTBE).

MS m/z(ESI):300.3[M+H]⁺.

Step 4: 2- cyclopropylamino -5,7- dihydro-pyrrole [3,4-d] pyrimidine -6- carboxylic acid tert-butyl ester

2- methylsulfonyl -5,7- dihydro-pyrrole [3,4-d] pyrimidine -6- carboxylic acid tert-butyl ester (300mg, 1.00mmol) of third step is dissolved in 5mL acetonitrile, potassium carbonate (207mg, 1.50mmol) and cyclopropyl is added Base amine (2mmol), gained mixture react 8 hours at 75 DEG C, and reaction, methylene chloride extraction is quenched with water.Dichloromethane layer is dried over anhydrous sodium sulfate, and is concentrated to get residue and is obtained target product (400mg, yield: 69%) after preparing thin layer chromatography.

MS m/z(ESI):265[M+H]⁺.

Step 5: N- cyclopropyl -6,7- dihydro -5H- pyrroles [3,4-d] pyrimidine -2- amine hydrochlorate is by the 2- cyclopropylamino -5 of the 4th step, 7- dihydro-pyrrole [3,4-d] pyrimidine -6- carboxylic acid tert-butyl ester (400mg, it 18mmol) is dissolved in the ethyl acetate solution (3mL) of hydrogen chloride, is stirred overnight at room temperature.The residue obtained after reaction solution concentration is directly used in react in next step.

MS m/z(ESI):165[M+H]⁺.

Step 6: 4- [3- (2- cyclopropylamino -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl) -4- luorobenzyl) -2H- phthalazines -1- ketone

By 5- (3,4- dihydro -4- oxo -1- phthalazinyl) methyl -2- fluobenzoic acid (134.2mg, 0.45mmol), the N- cyclopropyl amino -6 of the 5th step, 7- dihydro -5H pyrroles [3,4,-d] pyrimidine -2- amine hydrochlorate (95mg, 0.45mmol), HATU (188.2mg, 0.50mmol) and DIPEA (348.3mg, 2.7mmol) is dissolved in DMF, is stirred overnight at room temperature.After fully reacting, water is added into reaction solution and ethyl acetate, liquid separation, ethyl acetate layer are concentrated after being dried over anhydrous sodium sulfate.Residue obtains target product (76mg, yield: 37%) after preparing thin layer chromatography.

MS m/z(ESI):457[M+H]⁺.

¹HNMR(400MHz,DMSO-d6)δ:12.59(br s,1H),8.30-8.20(m,1H),8.00-7.95(m,1H),7.96-7.84(m,2H),7.56-7.45(m,2H),7.28-7.18(m,2H),4.69-4.53(m,2H),4.39(s,2H),3.80-3.74(m,1H),3.53-3.25(m,2H),1.23-1.12(m,4H).

Embodiment 3:

4- [3- (2- Cyclopropyl-methyl-amino -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl) -4- luorobenzyl] -2H- phthalazines -1- ketone (compound 3)

Reaction route:

Step 1: 1- tert-butoxycarbonyl -3- dimethylamino methene -4- pyrrolidones

To 300mL DMF-DMA is added in N-Boc-3- pyrrolidones (18.5g), it is stirred overnight at 60 DEG C.TLC shows raw material fully reacting.After concentration removes DMF-DMA, obtained solid is washed with methyl tertiary butyl ether(MTBE), is filtered, by solids-enriched to doing, obtains target product (20g, yellow solid, yield: 83%).

MS m/z(ESI):241.1[M+H]⁺。

Step 2: 2- hydroxyl -5,7- dihydro-pyrrole [3,4-d] pyrimidine -6- carboxylic acid tert-butyl ester

At room temperature, to 250mL sodium ethoxide (13.2g, urea (10g is added in ethanol solution 186mmol), 166.4mmol), stir about is after forty minutes, 1- tert-butoxycarbonyl -3- dimethylamino methene -4- the pyrrolidones (10g, 41.6mmol) of the first step is added and return stirring is stayed overnight.TLC monitors raw material and disappears, and after adding water quenching to go out, concentration removes ethyl alcohol.Water phase is extracted with ethyl acetate (50mL × 4), merges organic phase, and anhydrous sodium sulfate is dry.Target molecule (6.2g, faint yellow solid, yield: 63%) are obtained after being washed again with methyl tertiary butyl ether(MTBE) after being spin-dried for.

MS m/z(ESI):268.1[M+H]⁺.

Step 3: chloro- 6,7- dihydro -5H- pyrrolo- [3,4-d] pyrimidine hydrochloride of 2-

At 0 DEG C, by 2- hydroxyl -5,7- dihydro-pyrrole [3,4-d] pyrimidine -6- carboxylic acid tert-butyl ester (6.2g, it 26.2mmol) is dissolved in the solution that phosphorus oxychloride (10mL) obtains and warms naturally to room temperature reaction to raw material disappearance, the residue obtained after phosphorus oxychloride is evaporated off and is directly used in and reacts in next step.

MS m/z(ESI):156[M+H]⁺.

Step 4: N- (Cvclopropvlmethvl) -6,7- dihydro -5H- pyrrolo- [3,4-d] pyrimidine -2- amine

By chloro- 6,7- dihydro -5H- pyrrolo- [3, the 4-d] pyrimidine hydrochloride (385mg of 2-, it is added in cyclopropyl methyl amine (10mL) under 2mmol) heating, after TLC monitors fully reacting, preparation TLC purifies to obtain target product 40mg, yield 10.5%.

[3- (2- Cyclopropyl-methyl-amino -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl) -4- the luorobenzyl] -2H- phthalazines -1- ketone step 5: 4-

By 5- (3,4- dihydro -4- oxo -1- phthalazinyl) methyl -2- fluobenzoic acid (63mg, 0.21mmol), the N- (Cvclopropvlmethvl) -6 of the 4th step, 7- dihydro -5H- pyrrolo- [3,4-d] pyrimidine -2- amine (40mg, 0.21mmol), HATU (95mg, 0.25mmol) and DIPEA (38.7mg, 0.3mmol) it is dissolved in DMF It is stirred overnight at room temperature.After fully reacting, water is added into reaction solution and ethyl acetate, liquid separation, ethyl acetate layer are concentrated after being dried over anhydrous sodium sulfate.Residue obtains target product (32.6mg, yield: 33%) after preparing thin layer chromatography.

MS m/z(ESI):471[M+H]⁺

¹HNMR(400MHz,DMSO-d6)δ:12.61(br s,1H),8.31-8.13(m,2H),8.01-7.94(m,1H),7.94-7.80(m,2H),7.51-7.42(m,2H),7.38-7.22(m,2H),4.69-4.54(m,2H),4.40-4.30(m,4H),3.18-3.07(m,2H),1.09-1.00(m,1H),0.45-0.34(m,2H),0.24-0.15(m,2H).

Embodiment 4:

4- { the fluoro- 3- of 4- [2- (2- hydroxyethylamino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone (compound 4)

Reaction route:

Step 1: 1- tert-butoxycarbonyl -3- dimethylamino methene -4- pyrrolidones

To 300mL DMF-DMA is added in N-Boc-3- pyrrolidones (37g), it is stirred overnight at 60 DEG C.TLC shows raw material fully reacting.After concentration removes DMF-DMA, obtained solid is washed with tetrahydrofuran, is filtered, by solids-enriched to doing, obtains target product (35g, yellow solid, yield: 72.6%).

MS m/z(ESI):241.1[M+H]⁺。

At room temperature, urea (20 is added into the ethanol solution of 250mL sodium ethoxide (26.4g, 372mmol) G, 332.8mmol), stir about after forty minutes, is added the 1- tert-butoxycarbonyl -3- dimethylamino methene -4- pyrrolidones (20g, 83.2mmol) of the first step and return stirring is stayed overnight.TLC monitors raw material and disappears, and after adding water quenching to go out, concentration removes ethyl alcohol.Water phase is extracted with ethyl acetate (50mL × 5), merges organic phase, and anhydrous sodium sulfate is dry.Target molecule (11g, faint yellow solid, yield: 55.9%) are obtained after being washed again with methyl tertiary butyl ether(MTBE) after being spin-dried for.

MS m/z(ESI):268.1[M+H]⁺.

At 0 DEG C, by 2- hydroxyl -5,7- dihydro-pyrrole [3,4-d] pyrimidine -6- carboxylic acid tert-butyl ester (10g, it 42mmol) is dissolved in the solution that phosphorus oxychloride (40mL) obtains and warms naturally to room temperature reaction to raw material disappearance, the residue obtained after phosphorus oxychloride is evaporated off and is directly used in and reacts in next step.

MS m/z(ESI):156[M+H]⁺.

Step 4: 2- ((6,7- dihydro -5H- pyrrolo- [3,4-d] pyrimidine -2-base) amino) ethyl alcohol

By chloro- 6,7- dihydro -5H- pyrrolo- [3, the 4-d] pyrimidine hydrochloride (385mg of 2-, it is added in ethanol amine (50mL) under 2mmol) heating, after TLC monitors fully reacting, preparation TLC purifies to obtain target product 29.6mg, yield 7.8%.

{ the fluoro- 3- of 4- [2- (2- hydroxyethylamino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] the benzyl } -2H- phthalazines -1- ketone step 5: 4-

By 5- (3,4- dihydro -4- oxo -1- phthalazinyl) methyl -2- fluobenzoic acid (63mg, 0.21mmol), 2- ((6, the 7- dihydro -5H- pyrrolo-es [3 of the 4th step, 4-d] pyrimidine -2-base) amino) ethyl alcohol (29.6mg, 0.16mmol), HATU (95mg, 0.25mmol) and DIPEA (38.7mg, it 0.3mmol) is dissolved in DMF, is stirred overnight at room temperature.After fully reacting, water is added into reaction solution and ethyl acetate, liquid separation, methyl tert-butyl ether layers are concentrated after being dried over anhydrous sodium sulfate.Residue obtains target product (20.6mg, yield: 28%) after preparing thin layer chromatography.

MS m/z(ESI):461[M+H]⁺.

¹HNMR(400MHz,DMSO-d6)δ:12.61(br s,1H),8.33-8.13(m,2H),8.01-7.80(m,3H),7.51-7.43(m,2H),7.33-7.22(m,2H),7.18-7.06(m,1H),4.73-4.54(m,2H),4.42-4.30(m,3H),3.66-3.23(m,5H).

Embodiment 5:

4- { 3- [2- (2- dimethylaminoethylamino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] -4- luorobenzyl } -2H- phthalazines -1- ketone (compound 5)

Reaction route:

Step 1: 2- (2- dimethylaminoethylamino) -5,7- dihydro-pyrrole simultaneously -6 t-butyl carbonate of [3,4-d] pyrimidine

Title compound is synthesized using the method for the 4th step of embodiment 1, and with N, N- dimethyl-ethylenediamine replaces ethamine used in the 4th step of embodiment 1.

Step 2: N¹(6,7- dihydro -5H- pyrrolo- [3,4-d] pyrimidine -2-base)-N, N- dimethyl ethyl -1,2- diamine hydrochloride

Title compound is synthesized using the method for the 5th step of embodiment 1, with 2- (2- dimethylaminoethylamino) -5,7- dihydro-pyrrole, simultaneously -6 t-butyl carbonate of [3,4-d] pyrimidine replaces 2- ethylamino -5,7- dihydro-pyrrole [3,4-d] pyrimidine -6- carboxylic acid tert-butyl ester.

{ 3- [2- (2- dimethylaminoethylamino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] -4- the luorobenzyl } -2H- phthalazines -1- ketone step 3: 4-

It is synthesized using the experimental procedure for being similar to the 6th step of embodiment 1, uses N¹(6,7- dihydro -5H- pyrrolo- [3,4-d] pyrimidine -2-base)-N, N- dimethyl ethyl -1,2- diamine hydrochloride replace N- ethyl -6,7- dihydro -5H- pyrroles [3,4-d] pyrimidine -2- amine hydrochlorate used in embodiment 1.

MS m/z(ESI):488[M+H]+

¹H NMR(400MHz,DMSO-d₆)δ:12.61(br s,1H),8.32-8.24(m,2H),8.02-7.96(m,1H),7.94–7.79(m,2H),7.52-7.44(m,2H),7.32–7.23(m,1H),7.11–7.04(m,1H),4.67(s,1H),4.58(s,1H),4.40-4.31(m,4H),3.40–3.29(m,2H),2.48–2.40(m,2H),2.24–2.16(m,3H).

Embodiment 6

4- { the fluoro- 3- of 4- [2- (ttetrahydro-pyran -4- amino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl]-benzyl } -2H- phthalazines -1- ketone (compound 6)

Reaction route:

Step 1: 2- (ttetrahydro-pyran -4- amino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- t-butyl carbonate

Title compound is synthesized using the method for the 4th step of embodiment 1, replaces ethamine used in the 4th step of embodiment 1 with 4- amino-ttetrahydro-pyran.

Step 2: N- (ttetrahydro-pyran -4- base) -6,7- dihydro -5H- pyrrolo- [3,4-d] pyrimidine -2- amine hydrochlorate

Title compound is synthesized using the method for the 5th step of embodiment 1, with 2- (ttetrahydro-pyran -4- amino) -5,7- dihydro-pyrrole, simultaneously [3,4-d] pyrimidine -6- t-butyl carbonate replaces 2- ethylamino -5,7- dihydro-pyrrole [3,4-d] pyrimidine -6- carboxylic acid tert-butyl ester.

{ the fluoro- 3- of 4- [2- (ttetrahydro-pyran -4- amino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl]-the benzyl } -2H- phthalazines -1- ketone step 3: 4-

It is synthesized using the experimental procedure for being similar to the 6th step of embodiment 1, with N- (ttetrahydro-pyran -4- base) -6,7- dihydro -5H- pyrrolo- [3,4-d] pyrimidine -2- amine hydrochlorate replace embodiment 1 used in N- ethyl -6,7- dihydro -5H- pyrroles [3,4-d] pyrimidine -2- amine hydrochlorate.

MS m/z(ESI):501[M+H]⁺

¹HNMR(400MHz,DMSO-d6)δ:12.61(br s,1H),8.32-8.15(m,2H),8.02-7.96(m,1H),7.94-7.81(m,2H),7.52-7.42(m,2H),7.32–7.24(m,2H),4.67(s,1H),4.58(s,1H),4.39-4.31(m,4H),3.96–3.82(m,3H),3.43–3.35(m,1H),1.84–1.75(m,2H),1.55–1.43(m,2H),1.26–1.21(m,1H).

Embodiment 7

4- [3- (2- dimethylamino -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl) -4- luorobenzyl] -2H- phthalazines -1- ketone (compound 7)

Reaction route

Step 1: 2- dimethylamino -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- t-butyl carbonate

Title compound is synthesized using the method for the 4th step of embodiment 1, replaces ethamine used in the 4th step of embodiment 1 with dimethylamine methanol solution.

Step 2: N, N- dimethyl -6,7- dihydro -5H- pyrrolo- [3,4-d] pyrimidine -2- amine hydrochlorate

Title compound is synthesized using the method for the 5th step of embodiment 1, and with 2- dimethylamino -5,7- dihydro-pyrrole, simultaneously [3,4-d] pyrimidine -6- t-butyl carbonate replaces 2- ethylamino -5,7- dihydro-pyrrole [3,4-d] pyrimidine -6- carboxylic acid tert-butyl ester.

Step 3:

4- [3- (2- dimethylamino -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl) -4- luorobenzyl] and -2H- phthalazines -1- ketone use similar to the 6th step of embodiment 1 experimental procedure synthesize, with N, N- dimethyl -6,7- dihydro -5H- pyrrolo- [3,4-d] pyrimidine -2- amine hydrochlorate replaces N- ethyl -6 used in embodiment 1,7- dihydro -5H- pyrroles [3,4-d] pyrimidine -2- amine hydrochlorate.

MS m/z(ESI):445[M+H]⁺

¹H NMR(400MHz,DMSO-d6)δ:12.61(br s,1H),8.42-8.20(m,2H),8.03-7.80(m,3H),7.52-7.20(m,3H),4.70–4.55(m,2H),4.43-4.30(m,4H),3.15–3.06(m,6H).

Embodiment 8

4- { the fluoro- 3- of 4- [2- (2- methoxy ethyl amine) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl]-benzyl Base } -2H- phthalazines -1- ketone (compound 8)

Reaction route:

Step 1: 1- tert-butoxycarbonyl -3- dimethylamino methene -4- pyrrolidones

To 300mL DMF-DMA is added in N-Boc-3- pyrrolidones (37g), it is stirred overnight at 80 DEG C.TLC shows raw material fully reacting.After concentration removes DMF-DMA, obtained solid is washed with ether, is filtered, by solids-enriched to doing, obtains target product (35g, yellow solid, yield: 72.6%).

MS m/z(ESI):241.1[M+H]⁺。

At room temperature, to 250mL sodium ethoxide (26.4g, urea (20g is added in ethanol solution 372mmol), 332.8mmol), stir about is after forty minutes, 1- tert-butoxycarbonyl -3- dimethylamino methene -4- the pyrrolidones (20g, 83.2mmol) of the first step is added and return stirring is stayed overnight.TLC monitors raw material and disappears, and after adding water quenching to go out, concentration removes ethyl alcohol.Water phase is extracted with ethyl acetate (50mL × 5), merges organic phase, and anhydrous sodium sulfate is dry.Target molecule (11g, faint yellow solid, yield: 55.9%) are obtained after being washed again with methyl tertiary butyl ether(MTBE) after reduced pressure.

MS m/z(ESI):268.1[M+H]⁺.

Step 3: 2- (((trifluoromethyl) sulfonyl) oxygroup) -5H- pyrrolo- [3,4-d] pyrimidine -6 (7H)-t-butyl carbonate

By 2- hydroxyl -5,7- dihydro-pyrrole [3,4-d] pyrimidine -6- carboxylic acid tert-butyl ester (237mg, 1mmol) and N-methylmorpholine (253mg, 2.5mmol) it is dissolved in THF (10mL), the THF solution (5mL) of trifluoromethanesulfanhydride anhydride (338.4mg, 1.2mmol) is added dropwise under ice bath.TLC monitoring reaction terminates After be evaporated THF, water and ethyl acetate is added, ethyl acetate layer is dry with anhydrous sodium sulfate, and the crude product that target product is obtained after being spin-dried for is directly used in react in next step.

Step 4: 2- ((2- methoxy ethyl) amino) -5H- pyrrolo- [3,4-d] pyrimidine -6 (7H)-t-butyl carbonate

By 2- (((trifluoromethyl) sulfonyl) oxygroup) -5H- pyrrolo- [3; 4-d] pyrimidine -6 (7H)-t-butyl carbonate (370mg; 1mmol) and 2- methoxyethyl amine (75mg; 1mmol) it is dissolved in THF; then Pd (dppf) Cl2 dichloromethane complex (30mg) is added; DIPEA (142mg, 1.1mmol) and BrettPhos (60mg).Gained mixture after fully reacting, is evaporated THF and water and ethyl acetate extraction (10mLx8) is added under reflux.It is evaporated ethyl acetate, residue preparation TLC purifies to obtain target product 110mg, yield 37%.

Step 5: N- (2- methoxy ethyl) -6,7- dihydro -5H- pyrrolo- [3,4-d] pyrimidine -2- amine hydrochlorate

By 2- ((2- methoxy ethyl) amino) -5H- pyrrolo- [3 of the 4th step, 4-d] pyrimidine -6 (7H)-t-butyl carbonate (110mg, it 0.37mmol) is dissolved in the ethyl acetate solution (3mL) of hydrogen chloride, is stirred overnight at room temperature.The residue obtained after reaction solution concentration is directly used in react in next step.

MS m/z(ESI):194[M+H]⁺.

{ the fluoro- 3- of 4- [2- (2- methoxy ethyl amine) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl]-the benzyl } -2H- phthalazines -1- ketone step 6: 4-

By 5- (3,4- dihydro -4- oxo -1- phthalazinyl) methyl -2- fluobenzoic acid (89.4mg, 0.3mmol), N- (2- methoxy ethyl) -6,7- dihydro -5H- pyrrolo- [3 of the 5th step, 4-d] pyrimidine -2- amine hydrochlorate (65mg, 0.28mmol), HATU (114mg, 0.30mmol) and DIPEA (77.4mg, it 0.6mmol) is dissolved in DMF, is stirred overnight at room temperature.After fully reacting, water is added into reaction solution and ethyl acetate, liquid separation, ethyl acetate layer are concentrated after being dried over anhydrous sodium sulfate.Residue obtains target product (32mg, yield: 22.5%) after preparing thin layer chromatography.

MS m/z(ESI):475[M+H]⁺

¹H NMR(400MHz,DMSO-d6)δ:12.61(brs,1H),8.32-8.15(m,2H),8.01-7.96(m,1H),7.94-7.80(m,2H),7.50-7.43(m,2H),7.31-7.20(m,2H),4.67(s,1H),4.58(s,1H),4.40-4.31(m,4H),3.45–3.38(m,4H),3.25and3.23(s,3H).

Embodiment 9

4- { the fluoro- 3- of 4- [2- (2- hydroxy-2-methyl propylcarbamic) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl]-benzyl } -2H- phthalazines -1- ketone (compound 9)

Reaction route:

Step 1: 2- (2- hydroxy-2-methyl propylcarbamic) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- t-butyl carbonate

Title compound is synthesized using the method for the 4th step of embodiment 1, replaces ethamine used in the 4th step of embodiment 1 with 1- amino-2-methyl propyl -2- alcohol.

Step 2: 1- (6,7- dihydro -5H- pyrrolo- [3,4-d] pyrimidine -2- amino) -2- methyl-propyl -2- alcohol hydrochloride

Title compound is synthesized using the method for the 5th step of embodiment 1, with 2- (2- hydroxy-2-methyl propylcarbamic) -5,7- dihydro-pyrrole, simultaneously [3,4-d] pyrimidine -6- t-butyl carbonate replaces 2- ethylamino -5,7- dihydro-pyrrole [3,4-d] pyrimidine -6- carboxylic acid tert-butyl ester.

{ the fluoro- 3- of 4- [2- (2- hydroxy-2-methyl propylcarbamic) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl]-the benzyl } -2H- phthalazines -1- ketone step 3: 4-

It is synthesized using the experimental procedure for being similar to the 6th step of embodiment 1, with 1- (6,7- dihydro -5H- pyrrolo- [3,4-d] pyrimidine -2- amino) -2- methyl-propyl -2- alcohol hydrochloride replace embodiment 1 used in N- ethyl -6,7- dihydro -5H- pyrroles [3,4-d] pyrimidine -2- amine hydrochlorate.

MS m/z(ESI):489[M+H]⁺

¹H NMR(400MHz,DMSO-d6)δ:12.60(brs,1H),8.30-8.14(m,2H),8.01-7.70(m,3H),7.50-7.42(m,2H),7.31-7.23(m,1H),4.68-4.50(m,3H),4.40–4.31(m,4H),3.32–3.20(m,2H),1.09and 1.07(s,6H).

Embodiment 10

4- { 3- [2- (Cyclopropyl-methyl-amino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] the fluoro- benzyl of -4- } -2H- phthalazines -1- ketone (compound 10)

Reaction route

Step 1: 2- (Cvclopropvlmethvl amido) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- t-butyl carbonate

Title compound is synthesized using the method for the 4th step of embodiment 1, replaces ethamine used in the 4th step of embodiment 1 with N- methyl cyclopropylamine.

Step 2: N- cyclopropyl-N- methyl -6,7- dihydro -5H- pyrrolo- [3,4-d] pyrimidine -2- amine hydrochlorate

Title compound is synthesized using the method for the 5th step of embodiment 1, with 2- (Cvclopropvlmethvl amido) -5,7- dihydro-pyrrole, simultaneously [3,4-d] pyrimidine -6- t-butyl carbonate replaces 2- ethylamino -5,7- dihydro-pyrrole [3,4-d] pyrimidine -6- carboxylic acid tert-butyl ester.

{ 3- [2- (Cyclopropyl-methyl-amino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] the fluoro- benzyl of-the 4- } -2H- phthalazines -1- ketone step 3: 4-

It is synthesized using the experimental procedure for being similar to the 6th step of embodiment 1, replace N- ethyl -6 used in embodiment 1 with N- cyclopropyl-N- methyl -6,7- dihydro -5H- pyrrolo- [3,4-d] pyrimidine -2- amine hydrochlorate, 7- dihydro -5H- pyrroles [3,4-d] pyrimidine -2- amine hydrochlorate.

MS m/z(ESI):471[M+H]⁺

¹HNMR(400MHz,DMSO-d₆) δ: 12.61 (brs, 1H), 8.42-8.24 (m, 2H), 8.01-7.97 (m, 1H), 7.94-7.80 (m, 2H), 7.52-7.43 (m, 2H), 7.31-7.23 (m, 1H), (4.66 d, 2H, J=3.6Hz), 4.42-4.32 (m, 4H), 3.06 (d, 3H,), J=8Hz 2.80-2.69 (m, 1H), 0.87-0.74 (m, 2H), 0.66-0.55 (m, 2H)

Embodiment 11

4- { the fluoro- 3- of 4- [2- (1- methylcyclopropyl groups amino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl]-benzyl Base } -2H- phthalazines -1- ketone (compound 11)

Reaction route

Step 1: 2- (1- methylcyclopropyl groups amino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- t-butyl carbonate

Title compound is synthesized using the method for the 4th step of embodiment 1, replaces ethamine used in the 4th step of embodiment 1 with 1- methyl cyclopropylamine.

Step 2: N- (1- methylcyclopropyl groups) -6,7- dihydro -5H- pyrrolo- [3,4-d] pyrimidine -2- amine hydrochlorate

Title compound is synthesized using the method for the 5th step of embodiment 1, with 2- (1- methylcyclopropyl groups amino) -5,7- dihydro-pyrrole, simultaneously [3,4-d] pyrimidine -6- t-butyl carbonate replaces 2- ethylamino -5,7- dihydro-pyrrole [3,4-d] pyrimidine -6- carboxylic acid tert-butyl ester.

{ the fluoro- 3- of 4- [2- (1- methylcyclopropyl groups amino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl]-the benzyl } -2H- phthalazines -1- ketone step 3: 4-

It is synthesized using the experimental procedure for being similar to the 6th step of embodiment 1, replace N- ethyl -6 used in embodiment 1 with N- (1- methylcyclopropyl groups) -6,7- dihydro -5H- pyrrolo- [3,4-d] pyrimidine -2- amine hydrochlorate, 7- dihydro -5H- pyrroles [3,4-d] pyrimidine -2- amine hydrochlorate.

MS m/z(ESI):471[M+H]⁺

¹HNMR(400MHz,DMSO-d₆) δ: 12.61 (brs, 1H), 8.44-8.16 (m, 2H), 8.05-7.81 (m, 3H), 7.64-7.40 (m, 3H), (7.38-7.15 m, 1H), 4.62 (d, J=4.4Hz, 2H), 4.46-4.29 (m, 4H), 2.60-2.40 (s, 3H), 1.41-1.25 (m, 2H), 0.73-0.51 (m, 2H)

Embodiment 12

4- { the fluoro- 3- of 4- [2- (3- oxetanylmethoxy amino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone (compound 12)

Reaction route

Step 1: 1- tert-butoxycarbonyl -3- dimethylamino methene -4- pyrrolidones

To 300mL DMF-DMA is added in N-Boc-3- pyrrolidones (37g), it is stirred overnight at 100 DEG C.TLC shows raw material fully reacting.After concentration removes DMF-DMA, obtained solid is washed with methyl tertiary butyl ether(MTBE), is filtered, by solids-enriched to doing, obtains target product (35g, yellow solid, yield: 72.6%).

MS m/z(ESI):241.1[M+H]⁺。

At room temperature, to 250mL sodium ethoxide (26.4g, urea (20g is added in ethanol solution 372mmol), 332.8mmol), after stir about 50 minutes, 1- tert-butoxycarbonyl -3- dimethylamino methene -4- the pyrrolidones (20g, 83.2mmol) of the first step is added and return stirring is stayed overnight.TLC monitors raw material and disappears, and after adding water quenching to go out, concentration removes ethyl alcohol.Water phase is extracted with ethyl acetate (50mL × 5), merges organic phase, and anhydrous sodium sulfate is dry.Target molecule (11g, faint yellow solid, yield: 55.9%) are obtained after being washed again with methyl tertiary butyl ether(MTBE) after reduced pressure.

MS m/z(ESI):268.1[M+H]⁺.

By 2- hydroxyl -5,7- dihydro-pyrrole [3,4-d] pyrimidine -6- carboxylic acid tert-butyl ester (237mg, 1mmol) and N-methylmorpholine (253mg, 2.5mmol) it is dissolved in THF (10mL), the THF solution (5mL) of trifluoromethanesulfanhydride anhydride (338.4mg, 1.2mmol) is added dropwise under ice bath.TLC monitoring is evaporated THF after reaction, and water and ethyl acetate is added, and ethyl acetate layer is dry with anhydrous sodium sulfate, and the crude product that target product is obtained after being spin-dried for is directly used in react in next step.

Step 4: 2- (oxetanylmethoxy -3- base amino) -5H- pyrrolo- [3,4-d] pyrimidine -6 (7H)-t-butyl carbonate

By 2- (((trifluoromethyl) sulfonyl) oxygroup) -5H- pyrrolo- [3; 4-d] pyrimidine -6 (7H)-t-butyl carbonate (370mg; 1mmol) and 3 amine (73mg of oxa- ring butyl-; 1mmol) it is dissolved in THF; then it is added [1; bis- (diphenylphosphine) ferrocene of 1'-] palladium chloride/dichloromethane complex (30mg); DIPEA (142mg; 1.1mmol) and dicyclohexyl [3; 6- dimethoxy -2'; 4', 6'- triisopropyl [1,1'- biphenyl] -2- base] phosphine (60mg).For gained mixture under reflux after fully reacting, concentration removes THF, and water and ethyl acetate extraction (10mLx8) will be added in gained residue.Concentration removes ethyl acetate, and residue preparation TLC purifies to obtain target product 53mg, yield 18%.

Step 5: N- (oxetanylmethoxy -3- base) -6,7- dihydro -5H- pyrrolo- [3,4-d] pyrimidine -2- amine hydrochlorate

By 2- (oxetanylmethoxy -3- base amino) -5H- pyrrolo- [3 of the 4th step, 4-d] pyrimidine -6 (7H)-t-butyl carbonate (53mg, it 0.18mmol) is dissolved in the ethyl acetate solution (3mL) of hydrogen chloride, is stirred overnight at room temperature.The residue obtained after reaction solution concentration is directly used in react in next step.

MS m/z(ESI):193[M+H]⁺.

Step 6: 4- (the fluoro- 3- of 4- (2- (oxa- ring butyl- 3- base amino) -6,7- dihydro -5H- pyrrolo- [3,4-d] pyrimidine -6- carbonyl) benzyl) phthalazines -1 (2H) -one

By 5- (3,4- dihydro -4- oxo -1- phthalazinyl) methyl -2- fluobenzoic acid (89.4mg, 0.3mmol), N- (oxetanylmethoxy -3- base) -6, the 7- dihydro -5H- pyrrolo- [3 of the 5th step, 4-d] pyrimidine -2- amine hydrochlorate (34mg, 0.15mmol), HATU (114mg, 0.30mmol) and DIPEA (77.4mg, it 0.6mmol) is dissolved in DMF, is stirred overnight at room temperature.After fully reacting, water is added into reaction solution and ethyl acetate, liquid separation, ethyl acetate layer are concentrated after being dried over anhydrous sodium sulfate.Residue obtains target product (12mg, yield: 2.5%) after preparing thin layer chromatography.

MS m/z(ESI):473[M+H]⁺

¹HNMR(400MHz,DMSO-d₆)δ:12.60(brs,1H),8.33-8.18(m,2H),8.07-7.95(m,2H),7.93-7.81(m,2H),7.51-7.42(m,2H),7.30-7.24(m,1H),4.98-4.80(m,1H),4.78-4.70(m,2H),4.67-4.59(m,2H),4.52-4.45(m,2H),4.40-4.32(m,4H).

Embodiment 13

4- { the fluoro- 3- of 4- [2- (4- hydroxy-cyclohexyl amino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone (compound 13)

Reaction route

Step 1: 2- methyl sulphonyl -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine hydrochloride

Title compound is synthesized using the method for the 5th step of embodiment 1, and with 2- methyl sulphonyl -5,7- dihydro-pyrrole, simultaneously [3,4-d] pyrimidine -6- t-butyl carbonate replaces 2- ethylamino -5,7- dihydro-pyrrole [3,4-d] pyrimidine -6- carboxylic acid tert-butyl ester.

[the fluoro- 3- of 4- (2- methyl sulphonyl -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl) the benzyl] -2H- phthalazines -1- ketone step 2: 4-

It is synthesized using the 6th one step process of embodiment 1, with 2- methyl sulphonyl -5,7- dihydro-pyrrole, simultaneously [3,4-d] pyrimidine hydrochloride replaces N- ethyl -5,7- dihydro-pyrrole [3,4-d] pyrimidine -2- amine hydrochlorate used in embodiment 1.

{ the fluoro- 3- of 4- [2- (4- hydroxy-cyclohexyl amino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] the benzyl } -2H- phthalazines -1- ketone step 3: 4-

Title compound is synthesized using the method for the 4th step of embodiment 1; replace ethamine used in the 4th step of embodiment 1 with 4- aminocyclohexanol; with 4- [4- fluoro- 3- (2- methyl sulphonyl -5; 7- dihydro-pyrrole simultaneously [3; 4-d] pyrimidine -6- carbonyl) benzyl] and -2H- phthalazines -1- ketone replace the 4th step of embodiment 1 used in 2- methyl sulphonyl -5; 7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- t-butyl carbonate.

MS m/z(ESI):515[M+H]⁺

¹HNMR(400MHz,DMSO-d₆)δ:12.61(brs,1H),8.31-8.11(m,2H),8.00-7.95(m,1H),7.93-7.81(m,2H),7.51-7.42(m,2H),7.31-7.22(m,1H),7.15-7.04(m,1H),4.68-4.52(m,3H),4.39-4.29(m,4H),3.69-3.52(m,1H),3.43-3.35(m,1H),1.93-1.78(m,4H),1.31-1.12(m,4H).

Embodiment 14

4- { the fluoro- 3- of 4- [2- (tetrahydrofuran -3- amino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone (compound 14)

Reaction route

Step 1: 2- (methyl sulphonyl) -6,7- dihydro -5H- pyrrolo- [3,4-d] pyrimidine hydrochloride

Referring to 13 first step of embodiment.

Step 2: 4- (the fluoro- 3- of 4- (2- (methyl sulphonyl) -6,7- dihydro -5H- pyrrolo- [3,4-d] pyrimidine -6- carbonyl) benzyl) (2H) -one of phthalazines -1,

Referring to 13 second step of embodiment.

Step 3: 4- (the fluoro- 3- of 4- (2- ((tetrahydrofuran -3- base) amino) -6,7- dihydro -5H- pyrrolo- [3,4-d] pyrimidine -6- carbonyl) benzyl) phthalazines -1 (2H) -one

Title compound is synthesized using the method for 14 third step of embodiment, replaces 4- aminocyclohexanol used in 13 third step of embodiment with tetrahydrofuran -3- amine.

MS m/z(ESI):487[M+H]⁺

¹HNMR(400MHz,DMSO-d₆)δ:12.61(brs,1H),8.32-8.20(m,2H),8.05-7.94(m,2H),7.92-7.80(m,2H),7.53-7.43(m,2H),7.33-7.24(m,1H),4.98-4.80(m,1H),4.78-4.70(m,2H),4.67-4.59(m,2H),4.52-4.45(m,2H),4.40-4.32(m,4H),2.33-2.22(m,1H),1.92-1.83(m,1H).

Embodiment 15

4- { 3- [2- (4- dimethylamino piperidine -1- base) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] -4- luorobenzyl } -2H- phthalazines -1- ketone (compound 15)

Reaction route

Referring to 13 first step of embodiment.

Referring to 13 second step of embodiment.

Step 3: 4- (3- (2- (4- (dimethylamino) piperidin-1-yl) -6,7- dihydro -5H- pyrrolo- [3,4-d] pyrimidine -6- carbonyl) -4- luorobenzyl) phthalazines -1 (2H) -one

Title compound is synthesized using the method for 13 third step of embodiment, replaces 4- aminocyclohexanol used in 14 third step of embodiment with 4- dimethylamino piperidine.

MS m/z(ESI):528[M+H]⁺

¹HNMR(400MHz,DMSO-d₆)δ:12.61(brs,1H),8.43-8.20(m,2H),8.02-7.77(m,3H),7.52-7.40(m,2H),7.32-7.20(m,1H),4.72-4.55(m,3H),4.42-4.29(m,4H),2.95-2.82(m,2H),2.45-2.30(m,1H),2.19(s,6H),1.86-1.71(m,2H),1.31-1.18(m,3H)

Embodiment 16

4- { the fluoro- 3- of 4- [2- (4- methylpiperazine-1-yl) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone (compound 16)

Reaction route

Referring to 13 first step of embodiment.

Referring to 13 second step of embodiment.

Step 3: 4- (the fluoro- 3- of 4- (2- (4- methylpiperazine-1-yl) -6,7- dihydro -5H- pyrrolo- [3,4-d] pyrimidine -6- carbonyl) benzyl) phthalazines -1 (2H) -one

Title compound is synthesized using the method for 13 third step of embodiment, replaces 4- aminocyclohexanol used in 13 third step of embodiment with 1- methyl piperazine.

MS m/z(ESI):514[M+H]⁺

¹HNMR(400MHz,DMSO-d₆) δ: 12.61 (brs, 1H), 8.41-8.21 (m, 2H), 8.00-7.95 (m, 1H), 7.94-7.78 (m, 2H), 7.51-7.43 (m, 2H), 7.32-7.23 (m, 1H), 4.64 (d, J=3.2Hz, 2H), 4.41-4.32 (m, 4H), 3.76-3.65 (m, 4H), 2.38-2.29 (m, 4H), 2.20 (d, J=4.0Hz, 3H)

Embodiment 17

4- { the fluoro- 3- of 4- [2- (1- methyl piperidine -4- amino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone (compound 17)

Reaction route

Referring to 13 first step of embodiment.

Referring to 13 second step of embodiment.

Step 3: 4- (the fluoro- 3- of 4- (2- ((1- methyl piperidine -4- base) amino) -6,7- dihydro -5H- pyrrolo- [3,4-d] pyrimidine -6- carbonyl) benzyl) phthalazines -1 (2H) -one

Title compound is synthesized using the method for 13 third step of embodiment, replaces 4- aminocyclohexanol used in 13 third step of embodiment with 1- methyl piperidine -4- amine.

MS m/z(ESI):514[M+H]⁺

¹HNMR(400MHz,DMSO-d₆) δ: 12.61 (brs, 1H), 8.31-8.13 (m, 2H), 8.02-7.95 (m, 1H), 7.93-7.80 (m, 2H), 7.51-7.42 (m, 2H), 7.32-7.12 (m, 2H), (4.61 d, J=3.6Hz, 2H), 4.39-4.30 (m, 4H), 3.76-3.57 (m, 1H), 2.85-2.73 (m, 2H), 2.24-2.17 (m, 3H), 2.11-1.94 (m, 2H), 1.86-1.75 (m, 2H), (1.60-1.43 m, 2H)

Embodiment 18

4- { 3- [2- (4,4- difiuorocyclohexyl amino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] -4- luorobenzyl } -2H- phthalazines -1- ketone (compound 18)

Reaction route

Referring to 13 first step of embodiment.

Referring to 13 second step of embodiment.

Step 3: 4- (3- (2- ((4,4- difiuorocyclohexyl) amino) -6,7- dihydro -5H- pyrrolo- [3,4-d] pyrimidine -6- carbonyl) -4- luorobenzyl) phthalazines -1 (2H) -one

Title compound is synthesized using the method for 13 third step of embodiment, replaces 4- aminocyclohexanol used in 13 third step of embodiment with 4,4- difluorocyclohex amine.

MS m/z(ESI):535[M+H]⁺

¹HNMR(400MHz,DMSO-d₆) δ: 12.61 (brs, 1H), 8.35-8.14 (m, 2H), 8.02-7.79 (m, 3H), 7.51-7.42 (m, 2H), (7.37-7.22 m, 2H), 4.63 (d, J=4.0Hz, 2H), 4.40-4.32 (m, 4H), 3.96-3.81 (m, 1H), 2.11-1.83 (m, 6H), 1.64-1.50 (m, 2H)

Embodiment 19

4- { the fluoro- 3- of 4- [2- (1- methyl-1 H- pyrazoles -4- amino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone (compound 19)

Reaction route

Referring to 13 first step of embodiment.

Referring to 13 second step of embodiment.

Step 3: 4- (the fluoro- 3- of 4- (2- ((1- methyl-1 H- pyrazoles -4- base) amino) -6,7- dihydro -5H- pyrrolo- [3,4-d] pyrimidine -6- carbonyl) benzyl) phthalazines -1 (2H) -one

Title compound is synthesized using the method for 13 third step of embodiment, replaces 4- aminocyclohexanol used in 13 third step of embodiment with 1- methyl-1 H- pyrazoles -4- amine.

MS m/z(ESI):497[M+H]⁺

¹HNMR(400MHz,DMSO-d₆) δ: 12.61 (brs, 1H), 9.58-9.51 (m, 1H), 8.46-8.23 (m, 2H), 8.04-7.80 (m, 4H), 7.54-7.40 (m, 3H), 7.32-7.25 (m, 1H), 4.70 (d, J=2.4Hz, 2H), 4.48-4.33 (m, 4H), 3.79 (d, J=8.0Hz, 1H)

Embodiment 20

4- { the fluoro- 3- of 4- [2- (1- methyl-1 H- pyrazoles -3- amino) -5,7- dihydro-pyrazol simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone (compound 20)

Reaction route

Referring to 13 first step of embodiment.

Referring to 13 second step of embodiment.

Step 3: 4- (the fluoro- 3- of 4- (2- ((1- methyl-1 H- pyrazole-3-yl) amino) -6,7- dihydro -5H- pyrazolo [3,4-d] pyrimidine -6- carbonyl) benzyl) phthalazines -1 (2H) -one

Title compound is synthesized using the method for 13 third step of embodiment, replaces 4- aminocyclohexanol used in 13 third step of embodiment with 1- methyl-1 H- pyrazoles -3- amine.

MS m/z(ESI):497[M+H]⁺

¹HNMR(400MHz,DMSO-d₆) δ: 12.61 (brs, 1H), 9.83-9.79 (m, 1H), 8.47-8.24 (m, 2H), 8.02-7.80 (m, 3H), 7.55-7.45 (m, 3H), 7.32-7.23 (m, 1H), 6.56-6.49 (m, 1H), 4.70 (d, J=2.8Hz, 2H), 4.46-4.32 (m, 4H), 3.73 (s, 3H)

Embodiment 21

(S) -4- { the fluoro- 3- of 4- [2- (methoxycarbonyl propyl -2- amino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone (compound 23)

Reaction route

Step 1: 2- (methyl sulphonyl) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine hydrochloride

Using the similar operation of the 5th step of embodiment 1, with 2- methyl sulphonyl -5,7- dihydro-pyrrole, simultaneously [3,4-d] pyrimidine -6- t-butyl carbonate replaces 2- ethylamino -5,7- dihydro-pyrrole [3,4-d] pyrimidine -6- carboxylic acid tert-butyl ester, obtains title compound.

(the fluoro- 3- of 4- (2- (methyl sulphonyl) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl) benzyl step 2: 4-) (2H) -one of phthalazines -1,

Using the similar operation of the 6th step of embodiment 1, with 2- methyl sulphonyl -5,7- dihydro-pyrrole, simultaneously [3,4-d] pyrimidine hydrochloride replaces N- ethyl -5,7- dihydro-pyrrole [3,4-d] pyrimidine -2- amine hydrochlorate used in embodiment 1, obtains title compound.

{ the fluoro- 3- of 4- [2- (methoxycarbonyl propyl -2- amino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] the benzyl } -2H- phthalazines -1- ketone step 3: (S) -4-

Title compound is synthesized using the similar approach of third step in embodiment 13, wherein only replacing 4- aminocyclohexanol used in 13 third step of embodiment with (S) -1- methoxyl group -2- propylamine.

MS m/z(ESI):489[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ: 8.45-8.42 (m, 1H), 7.81-7.77 (m, 3H), 7.76-7.67 (m, 2H), 7.66-7.61 (m, 1H), 7.31-7.27 (m, 1H), 5.15-5.04 (m, 1H), 4.90-4.83 (m, 1H), 4.40 (AB, 1H), 4.38-4.28 (m, 1H), 3.96 (AB, 1H), 3.93-3.80 (m, 1H), 3.58-3.52 (m, 1H), 3.41-3.35 (m, 4H), 1.96 (s, 1H), 1.14 (d, J=4Hz, 3H)

Embodiment 22

(R) -4- { the fluoro- 3- of 4- [2- (methoxycarbonyl propyl -2- amino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone (compound 24)

Reaction route

Using the 5th step similar operations of embodiment 1, with 2- methyl sulphonyl -5,7- dihydro-pyrrole, simultaneously [3,4-d] pyrimidine -6- t-butyl carbonate replaces 2- ethylamino -5,7- dihydro-pyrrole [3,4-d] pyrimidine -6- carboxylic acid tert-butyl ester, obtains title compound.

Using the 6th step similar operations of embodiment 1, with 2- methyl sulphonyl -5,7- dihydro-pyrrole, simultaneously [3,4-d] pyrimidine hydrochloride replaces N- ethyl -5,7- dihydro-pyrrole [3,4-d] pyrimidine -2- amine hydrochlorate used in embodiment 1, obtains title compound.

{ the fluoro- 3- of 4- [2- (methoxycarbonyl propyl -2- amino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] the benzyl } -2H- phthalazines -1- ketone step 3: (R) -4-

Title compound is synthesized using the similar approach of third step in embodiment 13, wherein only replacing 4- aminocyclohexanol used in 13 third step of embodiment with (R) -1- methoxyl group -2- propylamine.

MS m/z(ESI):489[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ: 8.45-8.42 (m, 1H), 7.81-7.77 (m, 1H), 7.76-7.67 (m, 2H), 7.66-7.61 (m, 1H), 7.31-7.27 (m, 1H), 5.15-5.04 (m, 1H), 4.90-4.83 (m, 1H), 4.40 (AB, 1H), 4.38-4.28 (m, 1H), 3.96 (AB, 1H), 3.93-3.80 (m, 1H), 3.58-3.52 (m, 1H), 3.41-3.35 (m, 4H), 1.96 (s, 1H), 1.14 (d, J=4Hz, 3H)

Referring to the embodiment of the present application the method, the application has also synthesized following compound:

Table 1

Biological activity

Experimental example 1.PARP1 kinase activity screens

The enzyme activity screening of PARP-1 inhibitor is carried out using the PARP1 chemical luminescence reagent kit of BPS Bioscience.

Untested compound: the embodiment of the present application compound；

Kit: PARP1Chemiluminescent Assay Kit, producer: BPS Bioscience.

Experimental method

Kit pretreatment: 1 × PARP that 50 holes μ L/ are added in microwell plate is buffered into diluted 1 × histone, 4 DEG C of overnight incubations；Next day discards the liquid in microwell plate, and uses 200 μ l/ hole PBST (1 × PBS and 1%Triton X-100) board-washing, removes whole cleaning solutions；Then the stop buffer of 200 μ l is added in every hole, discards liquid after being incubated at room temperature 90min；And 200 hole μ l/ PBST board-washings are used, finally remove whole cleaning solutions.

Reaction: substrate and enzyme and test compound etc. are sequentially added by step set forth below and dosage, is incubated at room temperature 1h.

2 reaction system of table

Detection: after reaction, with PBST (200 hole μ l/) rinse orifice plate, finally the solution of cleaning is all removed；Strep-HRP, incubated at room temperature 30min after 50 μ l dilution is added into every hole；After PBST (200 hole μ L/) rinse orifice plate, cleaning solution is all removed；HRP substrate A and B are mixed on ice bath, then 100 μ l (every 50 μ l colorimetric substrates A of hole and 50 μ l colorimetric substrates B) is added in every hole；The last high quick mode detection untested compound of chemoluminescence method (Luminometric Measurement) is to PARP1 kinase inhibiting activity, and the results are shown in Table 3.

As a result:

Table 3 has tested compound single-point concentration inhibiting rate

Compound ID	Single-point concentration inhibiting rate %
1	99.3% (5nM)
2	73.0% (5nM)
3	84.8% (5nM)
4	97.8% (5nM)
5	98.9% (5nM)
6	97.7% (5nM)
8	84.7% (5nM)
11	80.1% (5nM)

As can be seen from Table 3, the compound of the application significantly inhibits PARP1 kinase activity.

The other compounds of the application have similar inhibiting effect to PARP1 kinase activity, and inhibiting rate is within the scope of 70-99%.

Experimental example 2Cell growth inhibition assay

Using the influence of CCK-8 method measurement compound on intracellular proliferation.

Untested compound: the embodiment of the present application compound；

Positive reference compound: olaparib, laboratory synthesize certainly；

Kit: CCK-8 kit (Cell Counting Kit-8), producer: Beyotime.

Experimental method

Cell culture: according to the following conditions culture cell, being counted after cell dissociation using cell counter, and according to adjustment cell claimed below to required concentration, then every 100 μ l of hole inoculating cell, is administered for 24 hours after inoculation.

4 cell culture condition of table

Cell Name	Culture solution	Incubator condition
Breast cancer MDA-MB-453	DMEM/F12+10%FBS	5%CO₂, 37 DEG C
Breast cancer MDA-MB-468	DMEM/F12+10%FBS	5%CO₂, 37 DEG C
Colorectal cancer HCT116	1640+10%FBS	5%CO₂, 37 DEG C
Cancer of pancreas Capan-1	IMEM+20%FBS	5%CO₂, 37 DEG C

Compound is prepared: after culture one day, dissolving untested compound with DMSO and mother liquor is made in olaparib, draw appropriate mother liquor and mix into culture solution, drug solution is configured to be incubated for concentration accordingly.

Incubation time: continue to be incubated for 7 days in incubator after administration.

Detection: the CCK8 incubation 3h or more that 200 hole μ l/ of fresh medium is placed in culture medium after stable 2h plus 20 holes μ l/ is changed after incubation, in 450nm wavelength, reference wavelength 650nm carries out dual wavelength and measures absorbance.IC₅₀Value is calculated with GraphPad, as a result see Table 5 for details -1~5-4 and FIG. 1 to FIG. 4:

The effect of table 5-1 the application compound inhibition breast cancer MDA-MB-453

Table 5-1 and Fig. 1 prompt the application compound to have apparent inhibited proliferation to breast cancer MDA-MB-453 cell.In particular, the inhibited proliferation of 64,65 and 68 couples of breast cancer cell MDA-MB-453 of compound 1,2,3,4,6,8 and compound is significantly better than olaparib.

The effect of table 5-2 the application compound inhibition breast cancer MDA-MB-468

Table 5-2 and Fig. 2-1, Fig. 2-2 prompt the application compound to have apparent inhibited proliferation to breast cancer cell MDA-MB-468.In particular, the inhibited proliferation of 64,65 and 68 couples of breast cancer cell MDA-MB-468 of compound 1,2,3,4,6,8,12,13,19,20 and compound is significantly better than olaparib.

The effect of table 5-3 the application compound inhibition cancer of pancreas Capan-1

Prompt the application compounds on pancreatic cancer cell Capan-1 that there is apparent inhibited proliferation by table 5-3 and Fig. 3.In particular, the inhibited proliferation of 64,65 and 68 couples of pancreatic cancer cell Capan-1 of compound 1,2,3,4,5,6,8 and compound is significantly better than olaparib.

The effect of table 5-4 the application compound inhibition colorectal cancer HCT116

Prompt the application compound that there is apparent inhibited proliferation to rectum cancer cell HCT116 by table 5-4 and Fig. 4.In particular, the inhibited proliferation of 1,2,3,4,6,13,19 and 20 couple of rectum cancer cell HCT116 of compound is significantly better than olaparib.

The other compounds of the application all have the cancer cells such as breast cancer cell, colorectal cancer cell and pancreatic cancer cell similar proliferation inhibition activity.

To sum up, the compound of the application all has proliferation inhibition activity for cancer cells such as breast cancer cell, colorectal cancer cell and pancreatic cancer cells.

Experimental example 3Pharmacokinetics (PK) research of compound

3.1 P of Rats K research

Male SD rat the application compound and olaparib are given by vein and stomach-filling respectively, investigates pharmacokinetic characteristics.Intravenously the dosage of (IV) and oral (PO) are 1 and 5mg/kg respectively.Blood is collected after IV and PO administration in different time points, blood is anticoagulant using heparin sodium, is centrifuged to obtain plasma sample, and the plasma sample is carried out LC-MS/MS analysis after the processing of protein precipitation.

LC-MS/MS, chromatographic column are Waters X-Bridge C18 column (21mm*50mm, 3.5 μm)；Mobile phase A Xiang Weishui+2mM ammonium acetate, B phase are methanol+2mM ammonium acetate, and flow velocity 0.4mL/min, column temperature is 40 DEG C.Use ion source for the source ESI positive ion mode, scanning mode is that multiple reaction monitors (MRM).

Using 6.3 software of WinNonlin, pharmacokinetic parameter is calculated using non-compartment model, the results are shown in Table 6.

The intracorporal IV pharmacokinetic parameter of 6 rat of table

The result of intravenous administration mode prompts the application compound to have good pharmacokinetic properties.In particular, compound 1,2,3,6 and 8 is better than olaparib in the intracorporal pharmacokinetic parameter of rat.

PO result also indicates that, under identical qf oral administration dosage, compound 1, compound 2, compound 3, compound 6 plasma exposure amount be above olaparib, AUC value is within the scope of about 305-1200h*ng/ml.

In addition, having been surprisingly found that in this pharmacokinetic trial, the half-life period of olaparib is 1.31 hours, and the half-life period of the application compound 2 is 2.3 hours, and the drug action time for being indicated above the application compound 2 is more permanent.

3.2 dog PK research

Male Beagle dog untested compound is given by vein and stomach-filling respectively, investigates pharmacokinetic characteristics.Intravenously the dosage of (IV) administration and oral (PO) administration is 1 and 5mg/kg respectively, and vehicle system is 10%DMSO:10%solutol:80% physiological saline.After IV and PO administration Different time points collect blood, and blood is anticoagulant using heparin sodium, and the plasma sample obtained after centrifugation is stored in -80 DEG C.Plasma sample carries out LC-MS/MS analysis after the processing of protein precipitation.

Under administration route identical as 3.1 P of Rats K and dosage, the application compound is better than olaparib in the intracorporal PK property of dog.

Other compounds of the application have similar pharmacokinetic property in rat with dog body.

Experimental example 4Safety testing

4.1, hERG is tested

In cardiac muscle cell, the potassium channel of human Ether-a-go-go Related Gene (hERG) coding mediates a kind of Delayed Rectifier Potassium Current (IKr).IKr inhibition is that drug leads to the most important mechanism of QT interval prolongation.In hERG test, if criterion is untested compound IC₅₀> 30 μM, then determine that untested compound acts on hERG unrestraint.

Using Predictor^TMHERG Fluorescence Polarization Assay, effect of the detection the application compound to hERG potassium-channel, 3,10,30 μM of test concentrations.Test result shows, compound 1, compound 2, compound 3, compound 6 for hERG 50% inhibition concentration (IC₅₀Value) it is all larger than 30 μM.It prompts the application compound to act on hERG unrestraint, shows the safety risks of the application compound acardia QT interval prolongation.

The anxious poison test of 4.2 mouse

KM mouse is given by stomach-filling, untested compound single-dose toxic reaction is investigated, tentatively judges maximal tolerance dose (MTD).

Dosage is set as, compound 1:300mg/kg；Compound 2,3,6:200,300mg/kg, single oral gavage administration, solvent is the physiological saline of 10%DMSO and 50%PEG and surplus, is observed 7 days after administration.

In this experiment, test result is as follows:

Compound 1: maximal tolerance dose (MTD) is greater than 300mg/kg；

Compound 2:MTD is less than 200mg/kg；

Compound 3:MTD is greater than 300mg/kg；

Compound 6:MTD is 200mg/kg；

To sum up, the application compound has good tolerance under the conditions of single-dose high dose.

Other compounds of the application have similar safety and high dose tolerance.

Embodiment 5Tumor inhibition

The present embodiment is for evaluating the validity that the application compound inhibits tumor proliferation through different way of administration.

5.1 human pancreas cancer cell strain Capan-1 mice with tumor model tumor inhibitions

The present embodiment evaluates the drug effect of each compounds on pancreatic cancer Capan-1 mice with tumor by measuring the human pancreas cancer cell strain Capan-1 subcutaneous transplantation tumor mouse tumor volume change after PO administration route applies the application compound.

Select gross tumor volume 100-200mm³Mice with tumor be grouped at random, administered volume 10ml/kg is administered 1 time a day, altogether about two weeks.Latter all 2 measurements gross tumor volumes are administered.The calculation formula of gross tumor volume are as follows: V=0.5a × b², a and b respectively indicate the major diameter and minor axis of tumour.The tumor suppression curative effect of untested compound is evaluated with inhibition rate of tumor growth TGI (%).

TGI (%)=[1- (VT_End-VT_Begin)/(VC_End-VC_Begin)] * 100%

Wherein VT_End: gross tumor volume mean value at the end of processing group is tested

VT_Begin: gross tumor volume mean value when the administration of processing group starts

VC_End: gross tumor volume mean value at the end of vehicle control group is tested

VC_Begin: gross tumor volume mean value when vehicle control group administration starts

The tumour inhibiting rate of each group compounds on pancreatic cancer is as shown in table 7 below.

Table 7: tumour inhibiting rate in pancreas cancer cell strain Capan-1 model

Group	Compound	Administration route	Tumour inhibiting rate (%)
1	Vehicle controls	p.o.	/
2	Olaparib (100mg/kg)	p.o.	9.2
3	Compound 2 (3mg/kg)	p.o.	109.7
4	Compound 2 (0.3mg/kg)	p.o.	44.3
5	Compound 3 (10mg/kg)	p.o.	48.6
6	Compound 3 (3mg/kg)	p.o.	36.0
7	Compound 6 (10mg/kg)	p.o.	56.8
8	Compound 6 (3mg/kg)	p.o.	20.2

Under this experimental condition, compound 2 has surprising drug effect, and the compound inhibitory rate is to 109.7% at 3mg/kg, and tumor partial regression, (0.3mg/kg) also has 44.3% tumour inhibiting rate under low dosage.Compound 3, compound 6 drug effect be also superior to positive controls.

5.2 Breast cancer lines MX-1 mice with tumor model tumor inhibitions

The present embodiment evaluates each compound to the drug effect of breast cancer MX-1 mice with tumor by measuring the Breast cancer lines MX-1 subcutaneous transplantation tumor mouse tumor volume change after PO administration route applies the application compound.

Select gross tumor volume 100-200mm³Mice with tumor be grouped at random, administered volume 10ml/kg is administered 1 time a day, altogether about 30 days.Latter all 2 measurements gross tumor volumes are administered.The calculation formula of gross tumor volume are as follows: V=0.5 × a × b², a and b respectively indicate the major diameter and minor axis of tumour.The tumor suppression curative effect of untested compound Relative tumor proliferation rate T/C (%).

T/C (%)=(V_{The end T}/V_{T begins})/(V_{The end C}/V_{C begins}) * 100%

Evaluation criterion are as follows: T/C (%) > 40% is invalid；T/C (%)≤40%, and it is effective for being statistically analyzed P < 0.05.

The experimental results showed that internal Relative tumor proliferation rate of the application compound in Breast cancer lines MX-1 lotus knurl mouse model has excellent tumor-inhibiting action less than 55% under the dosage of PO administration 5mg/kg and 10mg/kg.

Other compounds of the application have similar tumor-inhibiting action.

Preparation example 1Tablet

The composition of quick-release tablet is as shown in Table 8:

The composition of 8 quick-release tablet of table

Ingredient	Mg/ tablet	Account for the percentage (%) of tablet cores weight
Compound 1	100.00	25.00
Lactose	238.00	50.00
Microcrystalline cellulose	40.00	10.00
Croscarmellose sodium	16.00	4.00
NaLS	2.00	0.50
Magnesium stearate	4.00	1.00
Tablet cores weight	400.00	/

Preparation method

Use straight pressing manufacturer's standard quick-release tablet.Compound 1 and lactose, microcrystalline cellulose, croscarmellose sodium and NaLS are weighed into glass tubule, said mixture occupies about the small pipe volume 75%, is then mixed together in rotary drum mixer 30 minutes, obtains blended materials.The admixture is sieved through 40 mesh (425 μm) sieve, and then rotary drum mixes 15 minutes again.Magnesium stearate and shake the admixture about 20 seconds are then added.Gained mixture is then distributed into 400 milligrams of aliquot, and uses the 0.5 ton of tabletted core of target compression force of hand operated press for being furnished with 10 millimeters of molds.

Preparation example 2Capsule preparations

The composition of capsule preparations is as shown in Table 9:

The composition of 9 capsule preparations of table

Preparation method

Lauroyl is melted at about 50-70 DEG C, is then weighed into rustless steel container.Compound 2 is added and mixes content with even suspension.It continuess to mix, while the mixture being assigned in capsule using thermostatically controlled automatic capsule filling machine, the capsule preparations of 500 milligrams/are made.

Although a specific embodiment of the invention has obtained detailed description, it will be understood to those of skill in the art that: according to all introductions having disclosed, details can be carry out various modifications and be replaced, these changes are within the scope of the present invention.Full scope of the invention is given by the appended claims and any equivalents thereof.

Claims

Compound of formula I, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester or isomers above-mentioned, hydrate, solvate or crystal form；

Wherein,

A and B is formed together alicyclic ring, alicyclic heterocyclic, aromatic ring or hetero-aromatic ring with the atom being connected, optionally, wherein the alicyclic ring, alicyclic heterocyclic, aromatic ring or hetero-aromatic ring are selected from halogen, hydroxyl, amino, cyano, carboxyl, nitro, alkyl, alkenyl, alkynyl, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, RO-, ROC (O)-, RC (O) O-, RC (O)-, RR ' N-, RC (O) NH-, RR ' NC (O)-, RS (O) by one or more each independently_a-、RR’NSO₂And RSO₂The substituent group of N (R ')-replaces, and wherein a is 0,1 or 2；

R₁、R₂、R₃And R₄It is each independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, carboxyl, nitro, alkyl, alkenyl, alkynyl, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, RO-, ROC (O)-, RC (O) O-, RC (O)-, RR ' N-, RC (O) NH- and RR ' NC (O)-, optionally, wherein the alkyl, alkenyl, alkynyl, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl are selected from halogen, hydroxyl, C by one or more each independently_1-4Alkyl, C_1-4Alkoxy, 3-8 member naphthenic base, 5-8 circle heterocyclic ring base, 6-10 member aryl or 5-10 unit's heteroaryl substituent group replace；

D and E is each independently selected from C and N, and 5-10 member (such as 5,6,7,8,9,10 yuan) ring X is formed together with the atom being connected, wherein the ring X is selected from alicyclic heterocyclic, aromatic ring or hetero-aromatic ring；M and n is each independently selected from 0,1 and 2, and m+n=2；

Y is selected from C, O, S and N, and condition is, as Y=O or S, R₆And R₇It does not deposit , as Y=N, R₇It is not present；

R₅, R₆, R₇And R₈It is each independently selected from hydrogen, hydroxyl, cyano, nitro, alkyl, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, naphthenic base-alkyl, heterocycloalkyl-alkyl, RO-, RC (O)-, RC (O) O-, RR ' N-, RC (O) NH- and RR ' NC (O)-, optionally, the wherein alkyl, naphthenic base, heterocycle, heteroaryl, naphthenic base-alkyl or heterocycloalkyl-alkyl are further selected from halogen by one or more each independently, hydroxyl, cyano, amino, carboxyl, nitro, alkyl, halogenated alkyl, alkenyl, alkynyl, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, RO-, RR ' N-, RO-C_1-10Alkyl, RR ' N-C_1-10Alkyl, RS (O)_a-、RR’NSO₂Or RSO₂The substituent group of N (R ')-replaces, and wherein a is 0,1 or 2；Or

R₅And R₆It is formed together alicyclic heterocyclic, aromatic ring, alicyclic heterocyclic or hetero-aromatic ring with Y atom, optionally, wherein the alicyclic heterocyclic, aromatic ring, alicyclic heterocyclic or hetero-aromatic ring are further selected from halogen, hydroxyl, cyano, RS (O) by one or more each independently_a, alkyl, RR ' N- or RO- substituent group replace, wherein a be 0-2；

R and R ' is each independently selected from hydrogen, hydroxyl, C_1-10Alkyl, 3-20 member naphthenic base, 5-20 membered heterocycloalkyl, 6-20 member aryl, 5-20 unit's heteroaryl, optionally, the C_1-10Alkyl, 3-20 member naphthenic base, 5-20 membered heterocycloalkyl, 6-20 member aryl, 5-20 unit's heteroaryl are selected from halogen, hydroxyl, C by one or more each independently_1-4Alkyl, C_1-4Alkoxy, 3-8 member naphthenic base, 5-8 circle heterocyclic ring base, 6-10 member aryl or 5-10 unit's heteroaryl substituent group replace；

Wherein, the restrictive condition of the compound of formula I is,

When A and B is formed together phenyl ring, R with the atom being connected₁、R₂、R₃It is hydrogen, R₄For fluorine, when m and n are 1,

1) ring X is not hexa-atomic alicyclic heterocyclic that 5 member rings, hetero atom are N and hetero atom is N and the hexa-atomic alicyclic heterocyclic of O；And

2) describedIt is not following group:
The compound of claim 1, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester or isomers above-mentioned, hydrate, solvate or crystal form, with structure shown in Formulas I a,

Wherein,

G, J, K and L are each independently selected from C and N, and form hexa-atomic aromatic ring with D and E；

Remaining each atom or substituent group definition are as described in claim 1；

The restrictive condition of the Formulas I a compound are as follows:

When A and B is formed together phenyl ring, R with the atom being connected₁、R₂、R₃It is hydrogen, and R₄It is described when for fluorineIt is not following group:
The compound of claims 1 or 2, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester or isomers above-mentioned, hydrate, solvate or crystal form, wherein the compound is as shown in Formulas I aa,

Wherein, each atom and substituent group definition are as claimed in claim 2；

The restrictive condition of the Formulas I aa compound are as follows:

When A and B is formed together phenyl ring, R with the atom being connected₁、R₂、R₃It is hydrogen, R₄It is described when for fluorineIt is not following group:
The compound of any one of claim 1-3, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester or isomers above-mentioned, hydrate, solvate or crystal form, wherein the compound is as shown in Formulas I aa-1,

Wherein, each atom and substituent group definition are as described in claim 1.
The compound of any one of claim 1-3, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester or isomers above-mentioned, hydrate, solvate or crystal form, wherein the compound is as shown in Formulas I aa-2,

Wherein, each atom and substituent group definition are as described in claim 1；

The restrictive condition of the Formulas I aa-2 compound are as follows:

When A and B is formed together phenyl ring, R with the atom being connected₁、R₂、R₃It is hydrogen, R₄It is described when for fluorineIt is not following group:
The compound of any one of claim 1-3, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester or isomers above-mentioned, hydrate, solvate or crystal form, wherein the compound is as shown in Formulas I aa-3,

Wherein, each atom and substituent group definition are as described in claim 1；

The restrictive condition of the Formulas I aa-3 compound are as follows:

When A and B is formed together phenyl ring, R with the atom being connected₁、R₂、R₃It is hydrogen, R₄It is described when for fluorineIt is not following group:
The compound of any one of claim 1-6, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester or isomers above-mentioned, hydrate, solvate or crystal form, wherein the compound is as shown in Formulas I aaa,

Wherein, each atom and substituent group definition are as described in claim 1,

The restrictive condition of the Formulas I aaa compound are as follows:

When A and B is formed together phenyl ring, R with the atom being connected₁、R₂、R₃It is hydrogen, R₄It is described when for fluorineIt is not following group:
The compound of any one of claim 1-7, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester or isomers above-mentioned, hydrate, solvate or crystal form,

The R₅、R₆、R₇Or R₈It is each independently selected from hydrogen, hydroxyl, cyano, nitro, C_1-6Alkyl, C_1-6Alkoxy, C_1-6Alkyl acyl, 3-8 member naphthenic base, 3-8 membered heterocycloalkyl, 6-10 member ring aryl (such as phenyl, naphthalene), 5-10 unit's heteroaryl, 3-8 member naphthenic base-C_1-4Alkyl, 3-8 membered heterocycloalkyl-C_1-4Alkyl, optionally, wherein the C_1-6Alkyl, C_1-6Alkoxy, C_1-6Alkyl acyl, 3-8 member naphthenic base, 3-8 membered heterocycloalkyl, 6-10 member ring aryl or 5-10 unit's heteroaryl, 3-8 member naphthenic base-C_1-4Alkyl or 3-8 membered heterocycloalkyl-C_1-4Alkyl is further selected from halogen (such as fluorine), hydroxyl, C by one or more each independently_1-4Alkyl, halogenated C_1-4Alkyl, C_1-4Alkoxy, 3-8 member naphthenic base, 3-8 circle heterocyclic ring base, 6-10 member aryl or 5-10 unit's heteroaryl, RR ' N-, RO-C_1-4Alkyl, RR ' N-C_1-4Alkyl, RR ' NSO₂Or RSO₂Substituent group replace；Or

R₅And R₆3-8 member alicyclic ring, 3-8 member alicyclic heterocyclic, 6-10 member aromatic ring or 5-10 member hetero-aromatic ring are formed together with the Y atom being connected, optionally, wherein the 3-8 member alicyclic ring, 3-8 member alicyclic heterocyclic, 6-10 member aromatic ring or 5-10 member hetero-aromatic ring are further selected from by one or more each independently Halogen, hydroxyl, cyano, RS (O)_a-、C_1-4Alkyl or C_1-4The substituent group of alkoxy replaces, and wherein a is 0,1 or 2；

Wherein R and R ' are each independently selected from H and C_1-4Alkyl.
The compound of any one of claim 1-8, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester or isomers above-mentioned, hydrate, solvate or crystal form,

The R₅、R₆、R₇Or R₈It is each independently selected from hydrogen, methyl, ethyl, Cvclopropvlmethvl, oxocyclobutylmethyl, tetrahydrofuran ylmethyl, methoxy ethyl, 2- ethoxyethyl group, 2- hydroxyethyl, trifluoroethyl, bis-fluoro ethyls, fluoro ethyl, N, N- dimethylaminoethyl, (R) -2- methoxyl group -1- Methylethyl, (S) -2- methoxyl group -1- Methylethyl, (R) -2- methoxy-propyl, (S) -2- methoxy-propyl, methylsulfonylethyl, dimethylaminosulfonyl ethyl, 2- hydroxyl-isobutyl group, cyclopropyl, 1- methylcyclopropyl groups, 1- methoxyl methyl cyclopropyl, 2, 2- Dimethvlcvclopropvl, 1- trifluoromethyl cyclopropyl, (R) -2- fluorine cyclopropyl, (S) -2- fluorine cyclopropyl, 2, 2- difluorocyclopropyl, oxocyclobutyl, 4- hydroxy-cyclohexyl, 4,4- difiuorocyclohexyl, THP trtrahydropyranyl, 2,2- dimethyl tetrahydro pyranose, 4- methyl-tetrahydro pyranose, N- methyl piperidine base, N, N- dimethylamino piperidine base, N methyl piperazine base, piperidyl, N- methylpyrazole base or bicyclic [3.1.0] hexyl of 3- oxo-；Or

R₅And R₆Tetrahydrofuran base, piperidyl or piperazinyl are formed together with the Y atom being connected.
The compound of any one of claim 1-9, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester or isomers above-mentioned, hydrate, solvate or crystal form, wherein A and B is formed together aromatic ring, preferably phenyl ring with the atom being connected.
The compound of any one of claim 1-10, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester or isomers above-mentioned, hydrate, solvate or crystal form, wherein R₄For halogen, preferably fluorine.
The compound of any one of claim 1-11, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester or isomers above-mentioned, hydrate, solvate or crystal form, Wherein R₁、R₂And R₃For hydrogen.
The compound of any one of claim 1-12, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester or isomers above-mentioned, hydrate, solvate or crystal form, wherein Y is nitrogen.
The compound of any one of claim 1-13, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester or isomers above-mentioned, hydrate, solvate or crystal form are selected from following compound:

4- [3- (2- ethylamino- -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl) -4- luorobenzyl] -2H- phthalazines -1- ketone；

4- [3- (2- cyclopropylamino -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl) -4- luorobenzyl] -2H- phthalazines -1- ketone；

4- [3- (2- Cyclopropyl-methyl-amino -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl) -4- luorobenzyl] -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (2- hydroxyethylamino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- { 3- [2- (2- dimethylaminoethylamino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] -4- luorobenzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (ttetrahydro-pyran -4- amino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl]-benzyl } -2H- phthalazines -1- ketone；

4- [3- (2- dimethylamino -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl) -4- luorobenzyl] -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (2- methoxy ethyl amine) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl]-benzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (2- hydroxy-2-methyl propylcarbamic) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl]-benzyl } -2H- phthalazines -1- ketone；

4- { 3- [2- (Cyclopropyl-methyl-amino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] the fluoro- benzyl of -4- } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (1- methylcyclopropyl groups amino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl]-benzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (3- oxetanylmethoxy amino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (4- hydroxy-cyclohexyl amino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (tetrahydrofuran -3- amino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- { 3- [2- (4- dimethylamino piperidine -1- base) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] -4- luorobenzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (4- methylpiperazine-1-yl) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (1- methyl piperidine -4- amino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- { 3- [2- (4,4- difiuorocyclohexyl amino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] -4- luorobenzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (1- methyl-1 H- pyrazoles -4- amino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (1- methyl-1 H- pyrazoles -3- amino) -5,7- dihydro-pyrazol simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (methyl methoxy ethylamino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- [3- (2- ethoxy ethylamino -5,7- dihydro-pyrrole [3,4-d] pyrimidine -6- carbonyl) -4- luorobenzyl] -2H- phthalazines -1- ketone；

(S) -4- { the fluoro- 3- of 4- [2- (methoxycarbonyl propyl -2- amino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

(R) -4- { the fluoro- 3- of 4- [2- (methoxycarbonyl propyl -2- amino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

(S) -4- { the fluoro- 3- of 4- [2- (2- methoxy propyl amino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl Base] benzyl } -2H- phthalazines -1- ketone；

(R) -4- { the fluoro- 3- of 4- [2- (2- methoxy propyl amino) -5,7- dihydro-pyrrole [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (tetrahydrofuran -3- base) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (tetrahydrofuran -2- base) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (1- methyl piperidine -4- base) -5,7- dihydro-pyrrole [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (piperidin-4-yl) -5,7- dihydro-pyrrole [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- [3- (2- Cvclopropvlmethvl -5,7- dihydro-pyrrole [3,4-d] pyrimidine -6- carbonyl) -4- luorobenzyl] -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- ((1R, 2R) -2- methylcyclopropyl groups amino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- { 3- [2- Cyclobutylamino -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] -4- luorobenzyl } -2H- phthalazines -1- ketone；

4- { 3- [2- cyclo propyl methoxy -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] -4- luorobenzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (2- hydroxyl propyl- 2- yl) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (1- methoxy cyclopropylamino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- ((1R, 2S) -2- methylcyclopropyl groups amino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- { 3- [2- cyclopropylamino -4- methyl -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] -4- luorobenzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (1- trifluoromethyl cyclopropyl) amino -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- { 3- [2- (2,2- difluorocyclopropyl) amino -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] -4- luorobenzyl } -2H- phthalazines -1- ketone；

4- { 3- [2- (2,2- Dimethvlcvclopropvl) amino -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] -4- luorobenzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- ((1R, 2S) -2- fluorine cyclopropyl) amino -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- ((1R, 2R) -2- fluorine cyclopropyl) amino -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (2- methysulfonylethyl) amino -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

N, N- dimethyl -2- { 6- [the fluoro- 5- of 2- (4- oxo -3,4- dihydro phthalazines -1- methyl) benzoyl] -6,7- dihydro -5H- pyrrolo- [3,4-d] pyrimidine -2- amino }-ethyl sulfonamide；

4- [3- (2- cyclopropylamino -5,7- dihydro-pyrrole simultaneously [3,4-b] pyridine -6- carbonyl) -4- luorobenzyl] -2H- phthalazines -1- ketone；

4- [3- (6- cyclopropylamino -1,3- dihydro-pyrrole simultaneously [3,4-c] pyridine -2- carbonyl) -4- luorobenzyl] -2H- phthalazines -1- ketone；

4- [3- (2- cyclopropylamino -5,7- dihydro-pyrrole simultaneously [3,4-b] pyrazine -6- carbonyl) -4- luorobenzyl] -2H- phthalazines -1- ketone；

4- { 3- [2- (2,2- dimethyl-tetrahydro pyrans -4- amino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] -4- luorobenzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (4- methyl-tetrahydro-pyran -4- amino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- { 3- [2- (3- azabicyclo [3.1.0] hexyl -6- amino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] -4- luorobenzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (2,2,2- trifluoroethyl) amino -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- { 3- [2- (2,2- bis-fluoro ethyls) amino -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] -4- luorobenzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (2- fluoro ethyl) amino -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] Benzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (oxetanylmethoxy -2- methyl) amino -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (oxetanylmethoxy -3- methyl) amino -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (tetrahydrofuran -2- methyl) amino -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- { 3- [2- (cyclopropylamino) -4- trifluoromethyl -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] -4- luorobenzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (2- trifluoromethoxy ethyl) amino -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- { 3- [2- cyclopropylamino -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] -4- luorobenzyl } fluoro- 2H- phthalazines -1- ketone of -7-；

The fluoro- 4- of 7- { the fluoro- 3- of 4- [2- (2- methoxy ethyl) amino -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

The fluoro- 4- of 7- { the fluoro- 3- of 4- [2- (oxinane -4- amino) -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

4- { the fluoro- 3- of 4- [2- (4- methoxycyclohexyl) amino -5,7- dihydro-pyrrole simultaneously [3,4-d] pyrimidine -6- carbonyl] benzyl } -2H- phthalazines -1- ketone；

(R) -4- { 3- [2- (3- tetrahydrofuran base) amino -6,7- dihydro -5H- pyrrolo- [3,4-d] pyrimidine -6- carbonyl] -4- luorobenzyl } -2H phthalazines -1- ketone；

(S) -4- { 3- [2- (3- tetrahydrofuran base) amino -6,7- dihydro -5H- pyrrolo- [3,4-d] pyrimidine -6- carbonyl] -4- luorobenzyl } -2H phthalazines -1- ketone；

4- { 3- [2- (((2R, 5R) -5- dimethylamino -1,3- dioxanes -2- base) methyl) amino -6,7- dihydro -5H- pyrrolo- [3,4-d] pyrimidine -6- carbonyl] -4- luorobenzyl } -2H phthalazines -1- ketone；

4- { 3- [2- ((2R, 5R) -2- (dimethylamino) methyl-1,3- dioxanes -5- base) amino -6,7- dihydro -5H- pyrrolo- [3,4-d] pyrimidine -6- carbonyl] -4- luorobenzyl } -2H phthalazines -1- ketone；With,

4- { 3- [4- methyl -2- (4- tetrahydrofuran base) amino -6,7- dihydro -5H- pyrrolo- [3,4-d] pyrimidine -6- carbonyl] -4- luorobenzyl } -2H phthalazines -1- ketone.
The preparation method of the compound of any one of claim 1-14, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester or isomers above-mentioned, hydrate, solvate or crystal form is selected from following synthetic route:

Route 1:

Compound A and compound B is subjected to condensation reaction and obtains compound of formula I；Or

Route 2:

Compound A and compound B ' is subjected to condensation reaction and obtains compound C '；By compound C ' and compoundIt carries out nucleophilic substitution and compound of formula I is made；

Wherein, Lg represents the leaving group of nucleophilic substitution, for example, halogen ,-OCOR ,-OTs ,-SO₂R etc., for example, mesyl, the definition of remaining each atom and substituent group is as described in claim any one of 1-14.
Pharmaceutical composition, it includes the described in any item compounds of claim 1-14, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester or isomers above-mentioned, hydrate, solvate or crystal forms, it optionally, also include pharmaceutically acceptable carrier or excipient.
Pharmaceutical composition described in claim 16, the content that wherein composition contains any one of claim 1-14 compound, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester or isomers above-mentioned, hydrate, solvate or crystal form is 0.01-2000mg, preferably 0.1-1000mg, more preferably 1-800mg, more preferably 10-600mg, particularly preferably 50-500mg.
The pharmaceutical composition of claim 16 or 17, it also includes one or more anti-tumor drugs, preferably, the anti-tumor drug is selected from Temozolomide, adriamycin, taxol, cis-platinum, carboplatin, Dacarbazine, topotecan, Irinotecan, gemcitabine and bevacizumab, anti-CTLA-4 monoclonal antibody Ipilimumab, anti-PD-1 monoclonal antibody pembrolizumab and Nivolumab and anti-PD-L1 monoclonal antibody atezolizumab.
The purposes of the described in any item compounds of claim 1-14, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester or isomers above-mentioned, hydrate, solvate or crystal form or the described in any item pharmaceutical compositions of claim 16-18 in the reagent that preparation inhibits PARP；Preferably, the reagent is to inhibit PARP-1 inhibitor.
The described in any item compounds of claim 1-14, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester or isomers above-mentioned, hydrate, solvate or crystal form or the described in any item pharmaceutical compositions of claim 16-18 are used to inhibit PARP active；Preferably, it is used to inhibit PARP-1 active.
A kind of active method of inhibition PARP, the method includes applying the described in any item compounds of a effective amount of claim 1-14, its pro-drug, generation to subject in need Thank object form, pharmaceutically acceptable salt or ester or isomers above-mentioned, hydrate, solvate or crystal form or the described in any item pharmaceutical compositions of claim 16-18；Preferably, the method is for inhibiting PARP-1 active；Preferably, for inhibiting PARP-1 activity in cell；Preferably, the cell is cell line or the cell from subject.
The purposes of the described in any item compounds of claim 1-14, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester or isomers above-mentioned, hydrate, solvate or crystal form or the described in any item pharmaceutical compositions of claim 16-18 in the reagent for preparing adjuvant therapy of tumors or drug for enhancing radiation or chemotherapy of tumours effect.
The described in any item compounds of claim 1-14, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester or isomers above-mentioned, hydrate, solvate or crystal form or the described in any item pharmaceutical compositions of claim 16-18 are used for adjuvant therapy of tumors or for enhancing radiation or chemical therapeutic effect.
A kind of method of adjuvant therapy of tumors or enhancing radiation or chemical therapeutic effect, the method includes applying the described in any item compounds of a effective amount of claim 1-14, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester or isomers above-mentioned, hydrate, solvate or crystal form or the described in any item pharmaceutical compositions of claim 16-18 to subject in need.
The purposes of the described in any item compounds of claim 1-14, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester or isomers above-mentioned, hydrate, solvate or crystal form or the described in any item pharmaceutical compositions of claim 16-18 in the drug of preparation treatment tumour.
The described in any item compounds of claim 1-14, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester or isomers above-mentioned, hydrate, solvate or crystal form or the described in any item pharmaceutical compositions of claim 16-18, are used to treat tumour.
A method of tumour being treated, the method includes providing the described in any item compounds of a effective amount of claim 1-14, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester or isomers above-mentioned, hydrate, solvate or crystal form or the described in any item pharmaceutical compositions of claim 16-18 to subject in need.
Purposes, method or the compound of any one of claim 22-27, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester or isomers above-mentioned, hydrate, solvate or crystal form or pharmaceutical composition, wherein the tumour is selected from breast cancer, oophoroma, colorectal cancer, melanoma, lung cancer, gastrointestinal stromal tumor, the cancer of the brain, cervical carcinoma, cancer of pancreas, prostate cancer, gastric cancer, chronic marrow sample hypercytosis, liver cancer, lymthoma, peritoneal cancer, soft tissue sarcoma, neuroendocrine tumor and glioblastoma.
The purposes of the described in any item compounds of claim 1-14, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester or isomers above-mentioned, hydrate, solvate or crystal form or the described in any item pharmaceutical compositions of claim 16-18 in the drug of preparation treatment vascular diseases, neurodegenerative diseases or nervous system inflammation.
The described in any item compounds of claim 1-14, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester or isomers above-mentioned, hydrate, solvate or crystal form or the described in any item pharmaceutical compositions of claim 16-18, are used to treat vascular diseases, neurodegenerative diseases or nervous system inflammation.
A method of vascular diseases, neurodegenerative diseases or nervous system inflammation being treated, the method includes applying the described in any item compounds of a effective amount of claim 1-14, its pro-drug, metabolite form, pharmaceutically acceptable salt or ester or isomers above-mentioned, hydrate, solvate or crystal form or the described in any item pharmaceutical compositions of claim 16-18 to subject in need.