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WO2017071636A1 - Phthalazine ketone derivative, and preparation method and use thereof - Google Patents

Phthalazine ketone derivative, and preparation method and use thereof Download PDF

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Publication number
WO2017071636A1
WO2017071636A1 PCT/CN2016/103735 CN2016103735W WO2017071636A1 WO 2017071636 A1 WO2017071636 A1 WO 2017071636A1 CN 2016103735 W CN2016103735 W CN 2016103735W WO 2017071636 A1 WO2017071636 A1 WO 2017071636A1
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Prior art keywords
dihydro
pyrimidin
carbonyl
pyrrolo
group
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PCT/CN2016/103735
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French (fr)
Chinese (zh)
Inventor
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
谢一
葛勇
王利春
王晶翼
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Sichuan Kelun Biotech Biopharmaceutical Co Ltd
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Sichuan Kelun Biotech Biopharmaceutical Co Ltd
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Priority to CN201680007634.7A priority Critical patent/CN107428762B/en
Publication of WO2017071636A1 publication Critical patent/WO2017071636A1/en
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present application relates to the field of medicine, and in particular to a pyridazinone derivative, a preparation method thereof and use thereof.
  • PARP Poly ADP-Ribose Polymerase
  • ADP is used as a substrate to synthesize poly(ARP) ribose (PAR) on receptor proteins (including itself) (Sakamoto- Hojo E T, Balajee A S. Targeting Poly (ADP) ribose Polymerase I (PARP-I) and PARP-Iinteracting Proteins for cancer treatment.
  • ARP poly(ARP) ribose
  • PARP-I ribose Polymerase I
  • PARP-1 is involved in DNA damage repair and transcriptional regulation and is considered to be an important regulator of cell survival and death. It is also involved in the regulation of some transcription factors in tumorigenesis and inflammation (Peralta-Leal A, 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). Up to now, PARP-1 has been found to be highly expressed in various human malignant tumors, such as malignant lymphoma, breast cancer, Ewing's sarcoma, and hepatocellular carcinoma.
  • PARP-1 activity inhibitor can promote cancer cell death.
  • a large number of studies have confirmed that drug inhibition or gene knockout PARP-1 can not only avoid tissue damage caused by oxidative stress-related diseases, but also improve the prognosis of cancer patients.
  • the use of PARP-1 inhibitor alone also has a killing effect on tumors (mainly breast cancer) with defects in DNA damage repair.
  • the literature also reports the relationship between PARP-1 inhibitors and angiogenesis.
  • VEGF vascular endothelial growth factor
  • the inventors of the present application have systematically studied the structure-activity relationship of pyridazinone compounds and found a class of compounds having excellent PARP inhibitory activity, and the present application has been completed based on the above findings.
  • a first aspect of the present application provides a compound of Formula I, a prodrug, metabolite form, pharmaceutically acceptable salt or ester thereof, or an isomer, hydrate, solvate or crystalline form thereof,
  • a and B together with the attached atoms form an alicyclic, heteroalicyclic, aromatic or heteroaryl ring, optionally wherein the alicyclic, heteroalicyclic, aromatic or heteroaryl ring is independently one or more (for example, 1, 2, 3 or 4) selected from the group consisting of halogen, hydroxy, amino, cyano, carboxy, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aromatic Base, heteroaryl, RO-, ROC(O)-, RC(O)O-, RC(O)-, RR'N-, RC(O)NH-, RR'NC(O)-, RS( O) a -, RR'NSO 2 - and RSO 2 N(R')- substituent substitution, wherein a is 0, 1 or 2;
  • R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, cyano, carboxy, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, Aryl, heteroaryl, RO-, ROC(O)-, RC(O)O-, RC(O)-, RR'N-, RC(O)NH-, and RR'NC(O)-,
  • the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl are each independently one or more (eg 1, 2, 3 or 4) a) selected from the group consisting of halogen, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, 3-8 membered cycloalkyl, 5-8 membered heterocycloalkyl, 6-10 membered aryl or 5-10 Substit
  • D and E are each independently selected from C and N, and together with the attached atoms form a 5-10 membered (e.g., 5, 6, 7, 8, 9, 10) ring X wherein the ring X is selected from the group consisting of an alicyclic ring. , an aromatic ring and a heteroaryl ring, preferably a heteroaromatic ring, such as a pyridine ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring or a triazine ring;
  • R 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of hydrogen, hydroxy, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyl-alkane , heterocycloalkyl-alkyl, RO-, RC(O)-, RC(O)O-, RR'N-, RC(O)NH-, and RR'NC(O)-, optionally, Wherein the alkyl group, cycloalkyl group, heterocycloalkyl group, heteroaryl group, cycloalkyl-alkyl group or heterocycloalkyl-alkyl group are each independently further one or more (for example, one, two, 3 or 4) selected from the group consisting of halogen, hydroxy, cyano, amino, carboxy, nitro, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl
  • R 5 and R 6 together with the Y atom form an alicyclic, aromatic ring, alicyclic or heteroaryl ring, optionally wherein the alicyclic, aromatic ring, alicyclic or heteroaryl ring is each independently further Or a plurality (for example, 1, 2, 3 or 4) of substituents selected from the group consisting of halogen, hydroxy, cyano, RS(O) a -, alkyl, RR'N-, and RO-, wherein a is 0, 1 or 2;
  • R and R' are each independently selected from the group consisting of hydrogen, hydroxy, C 1-10 alkyl, 3-20 membered cycloalkyl, 5-20 membered heterocycloalkyl, 6-20 membered aryl, 5-20 membered heteroaryl.
  • the C 1-10 alkyl group, the 3-20 membered cycloalkyl group, the 5-20 membered heterocycloalkyl group, the 6-20 membered aryl group, the 5-20 membered heteroaryl group are each independently One or more (eg, 1, 2, 3 or 4) are selected from the group consisting of halogen, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, 3-8 membered cycloalkyl, 5-8 Substituent substitution of a heterocycloalkyl group, a 6-10 membered aryl group, and a 5-10 membered heteroaryl group.
  • the limiting condition of the compound of Formula I is
  • R 1 , R 2 , and R 3 are all hydrogen, R 4 is fluorine, and m and n are both 1,
  • a ring 6 is not a 5-membered ring, a heterocyclic six-membered heterocyclic heterocyclic ring, and a six-membered aliphatic heterocyclic ring having a hetero atom of N and O;
  • the compound has the structure shown in Formula Ia,
  • a and B together with the attached atoms form an alicyclic, heteroalicyclic, aromatic or heteroaryl ring, optionally wherein the alicyclic, heteroalicyclic, aromatic or heteroaryl ring is independently one or more (for example, 1, 2, 3 or 4) selected from the group consisting of halogen, hydroxy, amino, cyano, carboxy, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aromatic Base, heteroaryl, RO-, ROC(O)-, RC(O)O-, RC(O)-, RR'N-, RC(O)NH-, RR'NC(O)-, RS( O) a -, RR'NSO 2 - and RSO 2 N(R')- substituent substitution, wherein a is 0, 1 or 2;
  • R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, cyano, carboxy, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, Aryl, heteroaryl, RO-, ROC(O)-, RC(O)O-, RC(O)-, RR'N-, RC(O)NH-, and RR'NC(O)-,
  • the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl are each independently one or more (eg 1, 2, 3 or 4) a) selected from the group consisting of halogen, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, 3-8 membered cycloalkyl, 5-8 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 Substi
  • D, E, G, J, K and L are each independently selected from C and N, and form a six-membered aromatic ring system
  • R 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of hydrogen, hydroxy, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyl-alkane , heterocycloalkyl-alkyl, RO-, RC(O)-, RC(O)O-, RR'N-, RC(O)NH-, and RR'NC(O)-, optionally, Wherein the alkyl group, cycloalkyl group, heterocycloalkyl group, heteroaryl group, cycloalkyl-alkyl group or heterocycloalkyl-alkyl group are each independently further one or more (for example, one, two, 3 or 4) selected from the group consisting of halogen, hydroxy, cyano, amino, carboxy, nitro, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl
  • R 5 and R 6 together with the Y atom form an alicyclic, aromatic ring, alicyclic or heteroaryl ring, optionally wherein the alicyclic, aromatic ring, alicyclic or heteroaryl ring is each independently further Or a plurality (for example, 1, 2, 3 or 4) of substituents selected from the group consisting of halogen, hydroxy, alkyl, cyano, RS(O) a -, RR'N-, and RO-, wherein a is 0, 1 or 2;
  • R and R' are each independently selected from the group consisting of hydrogen, hydroxy, C 1-10 alkyl, 3-20 membered cycloalkyl, 5-20 membered heterocycloalkyl, 6-20 membered aryl, 5-20 membered heteroaryl.
  • the C 1-10 alkyl group, the 3-20 membered cycloalkyl group, the 5-20 membered heterocycloalkyl group, the 6-20 membered aryl group, the 5-20 membered heteroaryl group are each independently One or more (eg, 1, 2, 3 or 4) are selected from the group consisting of halogen, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, 3-8 membered cycloalkyl, 5-8 Substituent substitution of a heterocyclic group, a 6-10 membered aryl group and a 5-10 membered heteroaryl group.
  • the limiting conditions for the compound of Formula Ia are:
  • R 1 , R 2 , and R 3 are all hydrogen, and R 4 is fluorine, Not the following groups:
  • the compound is as shown in Formula Iaa,
  • a and B together with the attached atoms form an alicyclic, heteroalicyclic, aromatic or heteroaryl ring, optionally wherein the alicyclic, heteroalicyclic, aromatic or heteroaryl ring is independently one or more (for example, 1, 2, 3 or 4) selected from the group consisting of halogen, hydroxy, amino, cyano, carboxy, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aromatic Base, heteroaryl, RO-, ROC(O)-, RC(O)O-, RC(O)-, RR'N-, RC(O)NH-, RR'NC(O)-, RS( O) a -, RR'NSO 2 - and RSO 2 N(R')- substituent substitution, wherein a is 0, 1 or 2;
  • R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, cyano, carboxy, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, Aryl, heteroaryl, RO-, ROC(O)-, RC(O)O-, RC(O)-, RR'N-, RC(O)NH-, and RR'NC(O)-,
  • the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl are each independently one or more (eg 1, 2, 3 or 4) a) selected from the group consisting of halogen, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, 3-8 membered cycloalkyl, 5-8 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 Substi
  • D, E, G, J, K and L are each independently selected from C and N, and form a six-membered aromatic ring system
  • R 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of hydrogen, hydroxy, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyl-alkane , heterocycloalkyl-alkyl, RO-, RC(O)-, RC(O)O-, RR'N-, RC(O)NH-, and RR'NC(O)-, optionally, Wherein the alkyl group, cycloalkyl group, heterocycloalkyl group, heteroarylcycloalkyl-alkyl group or heterocycloalkyl-alkyl group are each independently further one or more (for example, 1, 2, 3) Or 4) selected from the group consisting of halogen, hydroxy, cyano, amino, carboxy, nitro, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo
  • R 5 and R 6 together with the Y atom form an alicyclic, aromatic ring, alicyclic or heteroaryl ring, optionally wherein the alicyclic, aromatic ring, alicyclic or heteroaryl ring is each independently further Or a plurality (for example, 1, 2, 3 or 4) of substituents selected from the group consisting of halogen, hydroxy, alkyl, cyano, RS(O) a -, RR'N-, and RO-, wherein a is 0, 1 or 2;
  • R and R' are each independently selected from the group consisting of hydrogen, hydroxy, C 1-10 alkyl, 3-20 membered cycloalkyl, 5-20 membered heterocycloalkyl, 6-20 membered aryl, 5-20 membered heteroaryl.
  • the C 1-10 alkyl group, the 3-20 membered cycloalkyl group, the 5-20 membered heterocycloalkyl group, the 6-20 membered aryl group, the 5-20 membered heteroaryl group are each independently One or more (eg, 1, 2, 3 or 4) are selected from the group consisting of halogen, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, 3-8 membered cycloalkyl, 5-8 Substituent substitution of a heterocycloalkyl group, a 6-10 membered aryl group, and a 5-10 membered heteroaryl group.
  • the limiting condition of the compound of Formula Iaa is that when A and B together with the attached atoms form a phenyl ring, R 1 , R 2 , R 3 are both hydrogen, and R 4 When it is fluorine, the Not the following groups:
  • the compound is as shown in Formula Iaa-1,
  • a and B together with the attached atoms form an alicyclic, heteroalicyclic, aromatic or heteroaryl ring, optionally wherein the alicyclic, heteroalicyclic, aromatic or heteroaryl ring is independently one or more (for example, 1, 2, 3 or 4) selected from the group consisting of halogen, hydroxy, amino, cyano, carboxy, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aromatic Base, heteroaryl, RO-, ROC(O)-, RC(O)O-, RC(O)-, RR'N-, RC(O)NH-, RR'NC(O)-, RS( O) a -, RR'NSO 2 - and RNSO 2 N(R')- substituent substitution, wherein a is 0, 1 or 2;
  • R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, cyano, carboxy, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, Aryl, heteroaryl, RO-, ROC(O)-, RC(O)O-, RC(O)-, RR'N-, RC(O)NH-, and RR'NC(O)-,
  • the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl are each independently one or more (eg 1, 2, 3 or 4) a) selected from the group consisting of halogen, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, 3-8 membered cycloalkyl, 5-8 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 Substi
  • D, E, G, J, K and L are each independently selected from C and N, and form a six-membered aromatic ring system
  • R 5 , R 6 and R 8 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, RC (O)-, RC(O)O-, RR'N-, RC(O)NH-, and RR'NC(O)-, optionally wherein the alkyl group, cycloalkyl group, heterocycloalkyl group , aryl, heteroaryl, cycloalkyl-alkyl or heterocycloalkyl-alkyl, each independently further one or more (eg, 1, 2, 3 or 4) selected from halogen, Hydroxy, cyano, amino, carboxyl, nitro, C 1-4 alkyl, halo C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, 3-8 membered cycloalky
  • R and R' are each independently selected from the group consisting of hydrogen, hydroxy, C 1-10 alkyl, 3-20 membered cycloalkyl, 5-20 membered heterocycloalkyl, 6-20 membered aryl, 5-20 membered heteroaryl.
  • the C 1-10 alkyl group, the 3-20 membered cycloalkyl group, the 5-20 membered heterocycloalkyl group, the 6-20 membered aryl group, the 5-20 membered heteroaryl group are each independently One or more (eg, 1, 2, 3 or 4) are selected from the group consisting of halogen, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, 3-8 membered cycloalkyl, 5-8 Substituent substitution of a heterocycloalkyl group, a 6-10 membered aryl group, and a 5-10 membered heteroaryl group.
  • the compound is as shown in Formula Iaa-2,
  • a and B together with the attached atoms form an alicyclic, heteroalicyclic, aromatic or heteroaryl ring, optionally wherein the alicyclic, heteroalicyclic, aromatic or heteroaryl ring is independently one or more (for example, 1, 2, 3 or 4) selected from the group consisting of halogen, hydroxy, amino, cyano, carboxy, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aromatic Base, heteroaryl, RO-, ROC(O)-, RC(O)O-, RC(O)-, RR'N-, RC(O)NH-, RR'NC(O)-, RS( O) a -, RR'NSO 2 - and RSO 2 N(R')- substituent substitution, wherein a is 0, 1 or 2;
  • R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, cyano, carboxy, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, Aryl, heteroaryl, RO-, ROC(O)-, RC(O)O-, RC(O)-, RR'N-, RC(O)NH-, and RR'NC(O)-,
  • the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl are each independently one or more (eg 1, 2, 3 or 4) a) selected from the group consisting of halogen, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, 3-8 membered cycloalkyl, 5-8 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 Substi
  • D, E, G, J, K and L are each independently selected from C and N, and form a six-membered aromatic ring system
  • R 5 and R 8 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cyano, nitro, heterocycloalkyl, aryl, heteroaryl, cycloalkyl-alkyl, heterocycloalkyl-alkane a group, RO-, RC(O)-, RC(O)O-, RR'N-, RC(O)NH-, and RR'NC(O)-, optionally, wherein the alkyl group, naphthenic group
  • the group, heterocycloalkyl, aryl, heteroaryl, cycloalkyl-alkyl or heterocycloalkyl-alkyl are each independently further one or more (eg 1, 2, 3 or 4) ) selected from the group consisting of halogen, hydroxy, amino, cyano, carboxy, nitro, C 1-4 alkyl, halo C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2 -4
  • R and R' are each independently selected from the group consisting of hydrogen, hydroxy, C 1-10 alkyl, 3-20 membered cycloalkyl, 5-20 membered heterocycloalkyl, 6-20 membered aryl, 5-20 membered heteroaryl.
  • the C 1-10 alkyl group, the 3-20 membered cycloalkyl group, the 5-20 membered heterocycloalkyl group, the 6-20 membered aryl group, the 5-20 membered heteroaryl group are each independently One or more (eg, 1, 2, 3 or 4) are selected from the group consisting of halogen, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, 3-8 membered cycloalkyl, 5-8 Substituent substitution of a heterocycloalkyl group, a 6-10 membered aryl group, and a 5-10 membered heteroaryl group.
  • the limiting conditions for the compound of Formula Iaa-2 are:
  • R 1 , R 2 , and R 3 are all hydrogen, and R 4 is fluorine, Not the following groups:
  • the compound is as shown in Formula Iaa-3,
  • a and B together with the attached atoms form an alicyclic, heteroalicyclic, aromatic or heteroaryl ring, optionally wherein the alicyclic, heteroalicyclic, aromatic or heteroaryl ring is independently one or more (for example, 1, 2, 3 or 4) selected from the group consisting of halogen, hydroxy, amino, cyano, carboxy, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aromatic Base, heteroaryl, RO-, ROC(O)-, RC(O)O-, RC(O)-, RR'N-, RC(O)NH-, RR'NC(O)-, RS( O) a -, RR'NSO 2 - and RSO 2 N(R')- substituent substitution, wherein a is 0, 1 or 2;
  • R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, cyano, carboxy, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, Aryl, heteroaryl, RO-, ROC(O)-, RC(O)O-, RC(O)-, RR'N-, RC(O)NH-, and RR'NC(O)-,
  • the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl are each independently one or more (eg 1, 2, 3 or 4) a) selected from the group consisting of halogen, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, 3-8 membered cycloalkyl, 5-8 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 Substi
  • D, E, G, J, K and L are each independently selected from C and N, and form a six-membered aromatic ring system
  • R 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of hydrogen, hydroxy, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyl-alkane , heterocycloalkyl-alkyl, RO-, RC(O)-, RC(O)O-, RR'N-, RC(O)NH-, and RR'NC(O)-, optionally, Wherein the alkyl group, cycloalkyl group, heterocycloalkyl group, heteroarylcycloalkyl-alkyl group or heterocycloalkyl-alkyl group are each independently further one or more (for example, 1, 2, 3) Or 4) selected from the group consisting of halogen, hydroxy, cyano, carboxy, nitro, amino, C 1-4 alkyl, halo C 1-4 alkyl, C 1-4 alkoxy, C 2-4 olefin
  • R 5 and R 6 together with the attached C atom form an alicyclic, aromatic ring, alicyclic or heteroaryl ring, optionally wherein the alicyclic, aromatic ring, alicyclic or heteroaryl ring is independently further independently
  • One or more are selected from the group consisting of halogen, hydroxy, cyano, RS(O) a -, C 1-4 alkyl, C 1-4 alkoxy and Substituted by a substituent of RR'N-, wherein a is 0, 1 or 2;
  • R and R' are each independently selected from the group consisting of hydrogen, hydroxy, C 1-10 alkyl, 3-20 membered cycloalkyl, 5-20 membered heterocycloalkyl, 6-20 membered aryl, 5-20 membered heteroaryl.
  • the C 1-10 alkyl group, the 3-20 membered cycloalkyl group, the 5-20 membered heterocycloalkyl group, the 6-20 membered aryl group, the 5-20 membered heteroaryl group are each independently One or more (eg, 1, 2, 3 or 4) are selected from the group consisting of halogen, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, 3-8 membered cycloalkyl, 5-8 Substituent substitution of a heterocycloalkyl group, a 6-10 membered aryl group, and a 5-10 membered heteroaryl group.
  • the limiting conditions for the compound of Formula Iaa-3 are:
  • R 1 , R 2 , and R 3 are all hydrogen, and R 4 is fluorine, Not the following groups:
  • the compound of formula I is Selected from the following structure:
  • the compound of Formula I is as shown in Formula Iaaa,
  • a and B together with the attached atoms form a 3-8 membered alicyclic ring, a 5-8 membered alicyclic ring, a 6-10 membered aromatic ring or a 5-10 membered heteroaryl ring, optionally wherein said 3-8 member
  • the alicyclic ring, the 5-8 membered alicyclic ring, the 6-10 membered aromatic ring or the 5-10 membered heteroaryl ring are each independently selected from one or more (for example, 1, 2, 3 or 4) halogen.
  • R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, cyano, carboxy, nitro, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 Alkynyl, 3-10 membered cycloalkyl, 5-10 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, RO-, ROC(O)-, RC(O)O- , RC(O)-, RR'N-, RC(O)NH-, and RR'NC(O)-, optionally, wherein said C 1-10 alkyl group, C 2-10 alkenyl group, C 2 -10 alkynyl, 3-10 membered cycloalkyl, 5-10 membered heterocycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl are each independently one or more (eg, 1, 2 , 3 or 4) selected from
  • L and J are each independently selected from C and N;
  • R 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of hydrogen, hydroxy, cyano, nitro, C 1-10 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-8 membered cycloalkyl-C 1-4 alkyl, 3-8 membered heterocycloalkyl-C 1-4 alkyl, RO-, RC (O)-, RC(O)O-, RR'N-, RC(O)NH-, and RR'NC(O)-, optionally, wherein the C 1-10 alkyl group, 3-8 members Cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-8 membered cycloalkyl-C 1-4 alkyl or 3-8 membered heterocycloalkane
  • R 5 and R 6 together with the Y atom form a 3-8 membered alicyclic ring, a 6-10 membered aromatic ring, a 5-8 membered heterocyclic ring or a 5-10 membered heteroaryl ring, optionally wherein said 3-8
  • the alicyclic ring, the 6-10 membered aromatic ring, the 5-8 membered alicyclic ring or the 5-10 membered heteroaryl ring are each independently further selected by one or more (for example, 1, 2, 3 or 4) Substituted from a substituent of halogen, hydroxy, cyano, RS(O) a -, C 1-4 alkyl, C 1-4 alkoxy and RR 'N-, wherein a is 0, 1 or 2;
  • R and R' are each independently selected from the group consisting of hydrogen, hydroxy, C 1-10 alkyl, 3-20 membered cycloalkyl, 5-20 membered heterocycloalkyl, 6-20 membered aryl, 5-20 membered heteroaryl.
  • the C 1-10 alkyl group, the 3-20 membered cycloalkyl group, the 5-20 membered heterocycloalkyl group, the 6-20 membered aryl group, the 5-20 membered heteroaryl group are each independently One or more (eg, 1, 2, 3 or 4) are selected from the group consisting of halogen, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, 3-8 membered cycloalkyl, 5-8 Substituent substitution of a heterocycloalkyl group, a 6-10 membered aryl group, and a 5-10 membered heteroaryl group.
  • the limiting conditions for the compound of Formula Iaaa are:
  • R 1 , R 2 , and R 3 are all hydrogen, and R 4 is fluorine, Not the following groups:
  • Y in Formula I, Ia, Iaa or Iaaa is N.
  • said R 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of hydrogen, hydroxy, cyano, nitro, C 1-6 alkyl, C 1-6 Alkoxy, C 1-6 alkyl acyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl (eg phenyl, naphthyl), 5-10 membered heteroaryl a 3-8 membered cycloalkyl-C 1-4 alkyl group, a 3-8 membered heterocycloalkyl-C 1-4 alkyl group, optionally wherein the C 1-6 alkyl group, C 1- 6 alkoxy, C 1-6 alkyl acyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-8 membered ring
  • R 5 and R 6 together with the attached Y atom form a 3-8 membered alicyclic ring, a 3-8 membered alicyclic ring, a 6-10 membered aromatic ring or a 5-10 membered heteroaryl ring, optionally wherein said 3
  • the -8 membered alicyclic ring, the 3-8 membered alicyclic ring, the 6-10 membered aromatic ring or the 5-10 membered heteroaryl ring are each independently further one or more (for example, 1, 2, 3 or 4) a substituent substitution selected from the group consisting of halogen, hydroxy, cyano, RS(O) a -, C 1-4 alkyl and C 1-4 alkoxy, wherein a is 0, 1 or 2;
  • R and R' are each independently selected from the group consisting of hydrogen and C 1-4 alkyl.
  • said R 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of hydrogen, methyl, ethyl, cyclopropylmethyl, oxocyclobutylmethyl, tetrahydrofuran.
  • R 5 and R 6 together with the attached Y atom form a tetrahydrofuran ring, a piperidine ring or a piperazine ring.
  • a and B together with the attached atoms form an aromatic ring.
  • a and B together with the attached atoms form a 6-14 membered aromatic ring wherein the 6-14 membered aromatic ring is unsubstituted or one or two selected from halogen,
  • the substituents of the hydroxy group, the amino group, the cyano group, the carboxyl group, the nitro group and the C 1-10 alkyl group are substituted.
  • a and B together with the attached atoms form an unsubstituted benzene ring.
  • a and B together with the attached atoms form a phenyl ring wherein the phenyl ring is substituted with one or two substituents selected from halogen.
  • a and B together with the attached atoms form a phenyl ring wherein the phenyl ring is substituted with one fluoro.
  • R 1 , R 2 and R 3 are hydrogen.
  • R 4 is halogen
  • R 4 is fluoro
  • R 5 is selected from the group consisting of hydroxyl, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyl-alkyl, hetero a cycloalkyl-alkyl group, RO-, RC(O)-, RC(O)O-, RR'N-, RC(O)NH-, and RR'NC(O)-, optionally wherein said Alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, cycloalkyl-alkyl or heterocycloalkyl-alkyl are each independently further one or more (eg, 1, 2, 3 or 4) selected from the group consisting of halogen, hydroxy, cyano, amino, carboxyl, nitro, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, ary
  • R and R' are each independently selected from the group consisting of hydrogen, hydroxy, C 1-10 alkyl, 3-20 membered cycloalkyl, 5-20 membered heterocycloalkyl, 6-20 membered aryl, 5-20 membered heteroaryl.
  • the C 1-10 alkyl group, the 3-20 membered cycloalkyl group, the 5-20 membered heterocycloalkyl group, the 6-20 membered aryl group, the 5-20 membered heteroaryl group are each independently One or more (eg, 1, 2, 3 or 4) are selected from the group consisting of halogen, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, 3-8 membered cycloalkyl, 5-8 Substituent substitution of a heterocycloalkyl group, a 6-10 membered aryl group, and a 5-10 membered heteroaryl group.
  • R 5 is selected from the group consisting of hydroxy, cyano, nitro, C 1-10 alkyl, 3-20 membered cycloalkyl, 3-20 membered heterocycloalkyl, 6-20 Aroaryl, 5-20 membered heteroaryl, 3-20 membered cycloalkyl-C 1-10 alkyl, 3-20 membered heterocycloalkyl-C 1-10 alkyl, RO-, RC(O) -, RC(O)O-, RR'N-, RC(O)NH- and RR'NC(O)-; optionally wherein the C 1-10 alkyl group, 3-20 membered cycloalkyl group 3-20 membered heterocycloalkyl, 6-20 membered aryl, 5-20 membered heteroaryl, 3-20 membered cycloalkyl-C 1-10 alkyl group and 3-20 membered heterocycloalkyl-C
  • the 1-10 alkyl groups are each independently
  • R and R' are each independently selected from hydrogen and C 1-10 alkyl; optionally wherein the C 1-10 alkyl is one or more (eg, 1, 2, 3 or 4) Substituent substitutions selected from the group consisting of halogen, hydroxy, C 1-4 alkyl and C 1-4 alkoxy.
  • R 5 is selected from the group consisting of hydroxy, cyano, nitro, C 1-6 alkyl, 3-12 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-14 a aryl group, a 5-10 membered heteroaryl group, a 3-12 membered cycloalkyl-C 1-6 alkyl group and a 3-8 membered heterocycloalkyl-C 1-6 alkyl group; optionally wherein said C 1-6 alkyl, 3-12 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-14 membered heteroaryl, 5-10 membered heteroaryl, 3-12 membered cycloalkyl-C 1
  • the -6 alkyl group and the 3-8 membered heterocycloalkyl-C 1-6 alkyl group are each independently selected from one or more (for example, 1, 2, 3 or 4) selected from the group consisting of halogen, hydroxy, and
  • R and R' are each independently selected from the group consisting of hydrogen, C 1-6 alkyl and halo C 1-6 alkyl.
  • R 5 is selected from the group consisting of hydroxyl, C 1-4 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 5-6 membered heteroaryl, 3 -8 membered cycloalkyl-C 1-4 alkyl and 3-8 membered heterocycloalkyl-C 1-4 alkyl; optionally wherein said C 1-4 alkyl, 3-8 membered cycloalkane a 3-8 membered heterocycloalkyl group, a 5-6 membered heteroaryl group, a 3-8 membered cycloalkyl-C 1-4 alkyl group and a 3-8 membered heterocycloalkyl-C 1-4 alkyl group Independently one or more (e.g., 1, 2, 3 or 4) selected from the group consisting of halogen, hydroxy, cyano, amino, carboxy, nitro, C 1-4 alkyl, halo C 1-4 Substit
  • R and R' are each independently selected from the group consisting of hydrogen, C 1-4 alkyl and halo C 1-4 alkyl.
  • R 5 is selected from the group consisting of hydroxyl, methyl, ethyl, cyclopropylmethyl, oxocyclobutylmethyl, tetrahydrofuranylmethyl, methoxymethyl, methoxyB.
  • R 5 is selected from the group consisting of C 1-4 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 5-6 membered heteroaryl, 3-8 a monocycloalkyl-C 1-4 alkyl group, optionally, the C 1-4 alkyl group, a 3-8 membered cycloalkyl group and a 5-6 membered heteroaryl group are selected from the group consisting of a hydroxyl group, an RO- and an RR' Substituent substitution of N-;
  • R and R' are each independently selected from C 1-4 alkyl.
  • R 5 is selected from the group consisting of ethyl, 2-hydroxyethyl, dimethylaminoethyl, methoxyethyl, cyclopropyl, 1-methylcyclopropyl, 4- Hydroxycyclohexyl, cyclopropylmethyl, oxocyclobutyl, tetrahydrofuranyl, tetrahydropyranyl and N-methylpyrazolyl.
  • R 6 is selected from the group consisting of hydrogen and C 1-10 alkyl.
  • R 6 is hydrogen
  • R 6 is selected from C 1-6 alkyl.
  • R 6 is selected from C 1-4 alkyl.
  • R 6 is methyl
  • R 5 and R 6 together with the Y atom form a 3-20 membered heteroalicyclic ring
  • the 3-20 membered heterocyclic ring is one or more (eg, 1 , 2, 3 or 4) substituents selected from the group consisting of halogen, hydroxy, cyano, C 1-10 alkyl, RR'N- and RO-;
  • R and R' are each independently selected from the group consisting of hydrogen and C 1-10 alkyl
  • Y is C or N.
  • R 5 and R 6 together with the Y atom form a 5-8 membered heterocyclic ring
  • the 5-8 membered heterocyclic ring is one or more (eg, 1 , 2, 3 or 4) substituents selected from the group consisting of halogen, hydroxy, cyano, C 1-6 alkyl, RR'N- and RO-;
  • R and R' are each independently selected from hydrogen and C 1-6 alkyl
  • Y is C or N.
  • R 5 and R 6 together with the Y atom form a 6-membered heteroalicyclic ring
  • the 6-membered heterocyclic heterocyclic ring is one or more (eg, 1 or 2 , 3 or 4) substituents selected from the group consisting of halogen, hydroxy, cyano, C 1-4 alkyl, RR'N- and RO-;
  • R and R' are each independently selected from hydrogen and C 1-4 alkyl
  • Y is N.
  • R 5 and R 6 together with the Y atom form a piperidine ring or a piperazine ring, optionally, the piperidine ring or piperazine ring is selected from one or two selected from C. a substituent of 1-4 alkyl and RR'N-;
  • R and R' are each independently selected from hydrogen and C 1-4 alkyl
  • Y is N.
  • R 5 and R 6 together with the Y atom form a piperidine ring and a piperazine ring, optionally, the piperidine ring or piperazine ring is a methyl or dimethylamine.
  • Y is N.
  • R 5 and R 6 together with the Y atom form a 5-6 membered heterocyclic ring
  • the 5-6 membered heterocyclic ring is one or more (eg, 1 , 2, 3 or 4) substituents selected from the group consisting of halogen, hydroxy, cyano, C 1-4 alkyl, RR'N- and RO-;
  • R and R' are each independently selected from hydrogen and C 1-4 alkyl
  • Y is C.
  • R 5 and R 6 together with the Y atom form a tetrahydrofuran ring or a piperidine ring, and optionally, the tetrahydrofuran ring or piperidine ring is selected from one or two selected from C 1- Substituted with a 4- alkyl substituent;
  • Y is C.
  • R 5 and R 6 together with the Y atom form a tetrahydrofuran ring or a piperidine ring, optionally, the piperidine ring is substituted with a methyl group;
  • Y is C.
  • R 7 is hydrogen
  • R 8 is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, C 1-10 alkyl, optionally wherein said C 1-10 alkyl is taken by one or A plurality (for example, 1, 2, 3 or 4) of substituents selected from the group consisting of halogen, hydroxy, cyano, amino, carboxyl and nitro are substituted.
  • R 8 is selected from the group consisting of hydrogen, hydroxy, C 1-6 alkyl, and halo C 1-6 alkyl.
  • R 8 is selected from the group consisting of hydrogen, hydroxy, C 1-4 alkyl, and halo C 1-4 alkyl.
  • R 8 is selected from the group consisting of hydrogen, hydroxy, methyl, and trifluoromethyl.
  • a and B together with the attached atoms form a benzene ring
  • R 1 , R 2 and R 3 are hydrogen
  • R 4 is fluorine
  • R 1 , R 2 and R 3 are hydrogen
  • R 4 is fluorine
  • a and B together with the attached atoms form a benzene ring
  • R 1 , R 2 and R 3 are hydrogen
  • R 4 is fluorine
  • Y is a nitrogen atom.
  • the compound has the structure of Formula Iaa-1, wherein
  • a and B together with the attached atoms form a benzene ring
  • R 1 , R 2 and R 3 are all hydrogen
  • R 4 is fluorine
  • R 5 is selected from C 1-4 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 5-6 membered heteroaryl, 3-8 membered cycloalkyl-C 1-4 alkyl
  • the C 1-4 alkyl group, the 3-8 membered cycloalkyl group and the 5-6 membered heteroaryl group are substituted with a substituent selected from the group consisting of a hydroxyl group, RO- and RR'N-; wherein R and R' is each independently selected from C 1-4 alkyl;
  • R 6 is hydrogen
  • R 8 is selected from the group consisting of hydrogen and C 1-4 alkyl.
  • the compound has the structure of Formula Iaa-1, wherein
  • a and B together with the attached atoms form a benzene ring
  • R 1 , R 2 and R 3 are all hydrogen
  • R 4 is fluorine
  • R 5 is selected from the group consisting of ethyl, 2-hydroxyethyl, dimethylaminoethyl, methoxyethyl, cyclopropyl, 1-methylcyclopropyl, 4-hydroxycyclohexyl, cyclopropylmethyl, oxygen Cyclobutyl, tetrahydrofuranyl, tetrahydropyranyl and N-methylpyrazolyl;
  • R 6 is hydrogen
  • R 8 is selected from the group consisting of hydrogen and methyl.
  • the hydrogen described herein is hydrazine (H) or hydrazine (D).
  • the application provides a process for the preparation of the compound selected from the following synthetic routes:
  • reaction of Lg represents a nucleophilic substitution leaving group such as halogen, -OCOR, -OTs, -SO 2 R and the like, for example, methanesulfonyl group, each atom and the remaining definitions of the substituent groups described hereinabove.
  • the condensation reaction operates as follows: 0.8-1.2 equivalents of Compound A and 1.0 equivalent of Compound B or Compound B' (free amine or hydrochloride) are dissolved in a solvent (eg, DMF or THF), adding 0.8-1.2 equivalents of a condensing agent (such as HATU, EDCI, T3P, etc.) and 2.0-5.0 equivalents of a base (for example, DIPEA, Et 3 N, pyridine, etc.) at room temperature, and adding to the reaction liquid after the reaction is completed.
  • a solvent eg, DMF or THF
  • a condensing agent such as HATU, EDCI, T3P, etc.
  • a base for example, DIPEA, Et 3 N, pyridine, etc.
  • the nucleophilic substitution reaction operates as follows: Compound C' (1.0 eq.) is dissolved in an organic solvent (eg, acetonitrile, etc.) in a base (eg, potassium carbonate, sodium carbonate) The nucleophile (1.0-1.5 eq.) is added in the presence of triethylamine, DIPEA, etc., 1.0-3.0 eq.), and reacted at room temperature or under heating (40-120 ° C) to give the compound of formula I.
  • an organic solvent eg, acetonitrile, etc.
  • a base eg, potassium carbonate, sodium carbonate
  • the method comprises the steps of:
  • the method comprises the steps of:
  • the method comprises the steps of:
  • Compound B or B' is commercially available or can be prepared by routine experimentation in the art.
  • the synthesis of Compound B or B' includes, but is not limited to, the following methods:
  • the 3-pyrrolidone and the DMF-DMA whose amino group is protected by a P group are reacted under heating (for example, 60 to 120 ° C), and then concentrated under reduced pressure to remove DMF-DMA, and the obtained solid is solvent (for example, methyl tert-butyl ether) Washing with tetrahydrofuran, diethyl ether or acetonitrile can obtain the reaction product of the first step; the product can be reacted with methylthio sulfonate in a solvent (for example, ethanol, methanol or isopropanol) to obtain a ring-closing product; Oxidation of the ring-closing product in a solvent such as methylene chloride, acetonitrile or DMF to give a sulfone intermediate; the sulfone intermediate with an amine at 20-100
  • the reaction of °C can obtain a derivative of 2-aminopyrimidine (the reaction can be carried out without
  • the P group is an amino protecting group.
  • the 3-pyrrolidone and the DMF-DMA whose amino group is protected by a P group are reacted under heating (for example, 60 to 120 ° C), and then concentrated under reduced pressure to remove DMF-DMA, and the obtained solid is solvent (for example, methyl tert-butyl ether) Washing with tetrahydrofuran, diethyl ether or acetonitrile to obtain the reaction product of the first step; reacting the product with urea under basic conditions or heating to obtain a 2-hydroxypyrimidine derivative intermediate, the intermediate and phosphorus oxychloride The reaction can obtain a 2-chloropyrimidine derivative; then the obtained product and the amine are obtained at room temperature or elevated temperature to obtain a 2-aminopyrimidine derivative, and the reaction can be carried out using a palladium-containing catalyst (for example, Pd(dppf)Cl 2 dichloromethane.
  • a palladium-containing catalyst for example, Pd(dppf)Cl 2 dichlor
  • a compound or Pd(OAc) 2 a compound or Pd(OAc) 2 ), a ligand (such as BINAP, Xantphos or Brett Phosphate) and a base (such as DIPEA, Cs 2 CO 3 or NaOt-Bu) to promote the reaction (the reaction may be carried out without a solvent, or using, for example, toluene, Solvents such as dioxane, DMF or DMSO).
  • the 2-pyrimidine derivative is obtained by finally removing the protecting group on N (such as trifluoroacetic acid or hydrochloric acid).
  • the 3-pyrrolidone and the DMF-DMA whose amino group is protected by a P group are reacted under heating (for example, 60 to 120 ° C), and then concentrated under reduced pressure to remove DMF-DMA, and the obtained solid is solvent (for example, methyl tert-butyl ether) Washing with tetrahydrofuran, diethyl ether or acetonitrile to obtain the reaction product of the first step; reacting the product with urea under basic conditions to obtain a 2-hydroxypyrimidine derivative intermediate; reacting the intermediate with trifluoromethanesulfonic anhydride A triflate intermediate is obtained which is reacted with an amine to give a 2-aminopyrimidine derivative which may be a palladium-containing catalyst (for example Pd(dppf)Cl2 dichloromethane complex or Pd(OAc) 2 ), a ligand (such as Xantphos or Brett Phosphate) and a base (such as Cs 2 CO
  • the 3-pyrrolidone and the DMF-DMA whose amino group is protected by the P group are reacted under heating (for example, 60-120 ° C), and then concentrated under reduced pressure to remove DMF-DMA; the obtained solid is solvent (for example, methyl tert-butyl ether)
  • the reaction product of the first step can be obtained by washing with tetrahydrofuran, diethyl ether or acetonitrile; the 2-pyrimidine derivative can also be obtained by reacting the intermediate with the substituted hydrazine under basic conditions.
  • the application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound described herein, a prodrug thereof, a metabolite form, a pharmaceutically acceptable salt or ester, or the aforementioned isomer, hydrate,
  • the solvate or crystalline form optionally, further comprises a pharmaceutically acceptable carrier or excipient.
  • the compound, prodrug, metabolite form, pharmaceutically acceptable salt or ester thereof, or the aforementioned isomer, hydrate, solvate or crystal form Can be combined with one or more drugs.
  • the pharmaceutical composition further comprises one or more drugs.
  • the drug is an anti-tumor drug.
  • the anti-tumor drug is selected from the group consisting of temozolomide, doxorubicin, paclitaxel, cisplatin, carboplatin, dacarbazine, topotecan, irinotecan, gemcitabine, bevacizumab , anti-CTLA-4 monoclonal antibody Ipilimumab, anti-PD-1 Monoclonal pembrolizumab and Nivolumab as well as anti-PD-L1 monoclonal antibody atezolizumab.
  • the carrier includes, but is not limited to, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, phosphate, glycerin, sorbic acid, potassium sorbate, saturated Partial glyceride mixture of plant fatty acids, water, protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic material, poly Ethylene glycol, sodium carboxymethyl cellulose, polyacrylate, beeswax, lanolin.
  • the excipient refers to an addenda other than the main drug in the pharmaceutical preparation.
  • the pharmaceutical composition can be administered by parenteral, topical, intravenous, oral, subcutaneous, intraarterial, intradermal, transdermal, rectal, intracranial, intraperitoneal, intranasal, intramuscular route or as inhalation. Agent.
  • the pharmaceutical composition can be formulated into various suitable dosage forms depending on the route of administration.
  • the compounds of the present application can be formulated into any orally acceptable formulation including, but not limited to, tablets, capsules, aqueous solutions or aqueous suspensions.
  • the carrier used for the tablet generally includes lactose and corn starch, and a lubricant such as magnesium stearate may also be added.
  • the diluent used in the capsule formulation generally comprises lactose and dried cornstarch.
  • Aqueous suspension formulations are usually prepared by admixing the active ingredient with a suitable emulsifier and suspension.
  • some sweeteners, fragrances or colorants may also be added to the above oral formulation forms.
  • the compounds of the present application can be formulated into a suitable ointment, lotion or cream, in which the active ingredient is suspended or dissolved in one or more carriers.
  • Carriers which may be used in ointment preparations include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; and detergents or creams which may be used include, but are not limited to, minerals Oil, sorbitan monostearate, Tween 60, cetyl esters wax, hexadecene aryl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the compounds of the present application can also be administered in the form of a sterile injectable preparation, including sterile injectable aqueous or oily suspensions or sterile injection solutions, or in lyophilized form.
  • a sterile injectable preparation including sterile injectable aqueous or oily suspensions or sterile injection solutions, or in lyophilized form.
  • the carrier and solvent package that can be used Water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils may also be employed as a solvent or suspension medium such as a monoglyceride or a diglyceride.
  • the pharmaceutical preparation of the present application includes any preparation pharmaceutically acceptable, such as an oral preparation, a parenteral preparation, and the like.
  • compositions and pharmaceutical preparations of the present application may contain from 0.01 to 2000 mg of the compound of the present application, preferably from 0.1 to 1000 mg of the compound of the present application, preferably from 1 to 800 mg of the compound of the present application, more preferably from 10 to 600 mg of the compound of the present application, particularly preferably 50-500 mg of the compound of the present application.
  • suitable in vitro or in vivo assays are performed to determine the efficacy of the compositions of the present application and whether the administration is suitable for treating a disease or medical condition in a subject. Examples of such assays are described below in connection with specific diseases or medical treatments in non-limiting embodiments.
  • an effective amount of a composition of the present application sufficient to achieve a prophylactic or therapeutic effect is from about 0.001 mg/kg body weight/day to about 10,000 mg/kg body weight/day.
  • the dosage is from about 0.01 mg/kg body weight/day to about 1000 mg/kg body weight/day.
  • the dosage may range from about 0.01 to 1000 mg/kg of host body weight per day, every two days or every three days, more typically from 0.1 to 500 mg/kg of host body weight.
  • An exemplary treatment regimen is once every two days or once a week or once a month.
  • the agent is usually administered multiple times, and the interval between single doses can be daily, weekly, monthly or yearly.
  • the agent can be administered in the form of a sustained release formulation, in which case less dosing frequency is required.
  • the dose and frequency will vary depending on the half-life of the agent in the subject. It can also be different depending on whether it is a preventive treatment or a therapeutic treatment.
  • relatively low doses are administered chronically at relatively low frequency intervals.
  • the application provides the compound, prodrug, metabolite form, pharmaceutically acceptable salt or ester thereof, or the aforementioned isomer, hydrate, solvate or crystalline form, or the present application Use of the pharmaceutical composition in the preparation of a PARP-inhibiting agent.
  • the agent is an agent that inhibits PARP-1.
  • the present application also provides a method of inhibiting PARP activity, the method comprising administering to a cell in need thereof an effective amount of a compound described herein, a prodrug thereof, a metabolite form, pharmaceutically acceptable Salt or ester, or the aforementioned isomer, hydrate, solvate or crystalline form, or a pharmaceutical composition as described herein.
  • the method is for inhibiting PARP-1 activity.
  • the method is for inhibiting PARP-1 in a cell active.
  • the cell is a cell line or a cell from a subject.
  • the application provides the compound, prodrug, metabolite form, pharmaceutically acceptable salt or ester thereof, or the aforementioned isomer, hydrate, solvate or crystalline form, or the present application
  • the application provides the compound, prodrug, metabolite form, pharmaceutically acceptable salt or ester thereof, or the aforementioned isomer, hydrate, solvate or crystalline form, or the present application
  • the pharmaceutical composition for use in adjuvant treatment of a tumor or for enhancing radiation or chemotherapeutic effects.
  • the application provides a method of adjuvant treatment of a tumor or enhancing the effect of radiation or chemotherapy, the method comprising administering to a subject in need thereof an effective amount of a compound described herein, a prodrug thereof, A metabolite form, a pharmaceutically acceptable salt or ester, or an isomer, hydrate, solvate or crystalline form as described above, or a pharmaceutical composition as described herein.
  • the application provides the compound, prodrug, metabolite form, pharmaceutically acceptable salt or ester thereof, or the aforementioned isomer, hydrate, solvate or crystalline form, or the present application Use of the pharmaceutical composition for the preparation of a medicament for treating a tumor.
  • the application provides the compound, prodrug, metabolite form, pharmaceutically acceptable salt or ester thereof, or the aforementioned isomer, hydrate, solvate or crystalline form, or the present application
  • the pharmaceutical composition for treating a tumor is provided.
  • the application provides a method of treating a tumor, the method comprising providing an effective amount of a compound described herein, a prodrug thereof, a metabolite form, pharmaceutically acceptable to a subject in need thereof Salt or ester, or the aforementioned isomer, hydrate, solvate or crystalline form, or a pharmaceutical composition as described herein.
  • the application provides the compound, prodrug, metabolite form, pharmaceutically acceptable salt or ester thereof, or the aforementioned isomer, hydrate, solvate or crystalline form, or the present application Said pharmaceutical composition for the treatment of vascular disease, neurodegenerative disease or nervous system Use in inflammatory drugs.
  • the application provides the compound, prodrug, metabolite form, pharmaceutically acceptable salt or ester thereof, or the aforementioned isomer, hydrate, solvate or crystalline form, or the present application
  • the application provides a method of treating a vascular disease, a neurodegenerative disease, or a nervous system inflammation, the method comprising administering to a subject in need thereof an effective amount of a compound described herein, a precursor thereof A pharmaceutical, metabolite form, pharmaceutically acceptable salt or ester, or an isomer, hydrate, solvate or crystalline form as described above, or a pharmaceutical composition as described herein.
  • the application provides the compound, prodrug, metabolite form, pharmaceutically acceptable salt or ester thereof, or the aforementioned isomer, hydrate, solvate or crystalline form, or the present application
  • the pharmaceutical composition for inhibiting PARP activity in a cell is provided.
  • the cell is a cell line or a cell from a subject.
  • the present application also provides a method of inhibiting PARP activity in a cell, the method comprising administering to the cell an effective amount of a compound described herein, a prodrug thereof, a metabolite form, a pharmaceutically acceptable salt Or an ester, or an isomer, hydrate, solvate or crystalline form as described above, or a pharmaceutical composition as described herein.
  • the method is for inhibiting PARP-1 activity.
  • the cell is a cell line or a cell from a subject.
  • the method is performed in vivo.
  • the method is performed in vitro.
  • the application further provides the compound, a prodrug thereof, a metabolite form, a pharmaceutically acceptable salt or ester, or an isomer, hydrate, solvate or crystalline form, or Use of a pharmaceutical composition as claimed in the preparation of a reagent as a compound, a prodrug thereof, a metabolite form, a pharmaceutically acceptable salt or ester, or the aforementioned isomer, hydrate, solvent
  • the agent or the crystal form assists the inhibition of tumor cell proliferation or the effect of enhancing radiation or chemical inhibition of tumor cell proliferation.
  • the tumor cell is a tumor cell line or a tumor cell from a subject.
  • the agent is for use in an in vivo method.
  • the agent is for use in an in vitro method.
  • the application further provides the compound, a prodrug thereof, a metabolite form, a pharmaceutically acceptable salt or ester, or an isomer, hydrate, solvate or crystalline form, or
  • the pharmaceutical composition of the invention is used for assisting in inhibiting tumor cell proliferation or for enhancing the effect of radiation or chemical inhibition of tumor cell proliferation.
  • the tumor cell is a tumor cell line or a tumor cell from a subject.
  • the compound, ester, prodrug, isomer, hydrate, solvate, crystalline form, pharmaceutically acceptable salt thereof, metabolite form thereof, or Any combination or mixture of the above, or a medicament described herein, is used in an in vitro method.
  • the present application also provides a method of inhibiting tumor cell proliferation or enhancing the effect of radiation or chemical inhibition of tumor cell proliferation, the method comprising administering to a tumor cell an effective amount of a compound described herein, preceded by a drug, a metabolite form, a pharmaceutically acceptable salt or ester, or an isomer, hydrate, solvate or crystalline form as described above, or a pharmaceutical composition as described herein.
  • the tumor cell is a tumor cell line or a tumor cell from a subject.
  • the method is performed in vitro.
  • the method is performed in vivo.
  • the application further provides the compound, a prodrug thereof, a metabolite form, a pharmaceutically acceptable salt or ester, or an isomer, hydrate, solvate or crystalline form, or Use of the pharmaceutical composition of the invention for the preparation of a reagent for inhibiting tumor cell proliferation.
  • the agent is for use in an in vivo method.
  • the agent is for use in an in vitro method.
  • the application further provides the compound, a prodrug thereof, a metabolite form, a pharmaceutically acceptable salt or ester, or an isomer, hydrate, solvate or crystalline form, or
  • the pharmaceutical composition of the invention is for use in inhibiting tumor cell proliferation.
  • the tumor cell is a tumor cell line or a tumor cell from a subject.
  • the present application also provides a method of inhibiting proliferation of a tumor cell, the method comprising administering to the cell an effective amount of a compound described herein, a prodrug thereof, a metabolite form, a pharmaceutically acceptable salt or An ester, or an isomer, hydrate, solvate or crystalline form as described above, or a pharmaceutical composition as described herein.
  • the tumor is selected from the group consisting of breast cancer, ovarian cancer, colorectal cancer, melanoma, lung cancer, gastrointestinal stromal tumor, brain cancer, cervical cancer, pancreatic cancer, prostate cancer, Gastric cancer, chronic myeloid leukemia, liver cancer, lymphoma, peritoneal cancer, soft tissue sarcoma, neuroendocrine tumors, and glioblastoma.
  • the tumor cell is selected from the group consisting of a breast cancer cell, an ovarian cancer cell, a colorectal cancer cell, a melanoma cell, a lung cancer cell, a gastrointestinal stromal tumor cell, a brain cancer cell, a cervix Cancer cells, pancreatic cancer cells, prostate cancer cells, gastric cancer cells, chronic myeloid leukocytes, liver cancer cells, lymphoma cells, peritoneal cancer cells, soft tissue sarcoma cells, neuroendocrine tumor cells, and glioblastoma cells.
  • the tumor cell is a tumor cell line or is derived from Tumor cells of the subject.
  • Tumors described herein include malignant and benign tumors, and correspondingly, the tumor cells include malignant and benign tumor cells.
  • the subject described herein is a mammal, such as a bovine, equine, ovine, porcine, canine, feline, rodent, primate; wherein, particularly preferred The subject is a human.
  • hydrogen as used herein and hydrogen in each of the groups includes hydrazine (H), hydrazine (D), hydrazine (T). In certain preferred embodiments of the present application, the hydrogen is hydrazine (H).
  • alkyl refers to a straight or branched saturated hydrocarbon group, such as C 1-10 alkyl, C 1-6 alkyl or C 1-4 alkyl, and non-limiting examples of alkyl include methyl , ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like.
  • the alkyl group is unsubstituted or may be further substituted with a substituent to form a substituted alkyl group, which may be selected from halogen, cycloalkyl, heterocycloalkyl, RO- or RR'N-, wherein R and R 'Definition as described herein.
  • the substituted alkyl group is a haloalkyl group as described herein, including a halogenated C 1-6 alkyl group (e.g., fluoro C 1-6 alkyl group) and a halogenated group.
  • C 1-4 alkyl e.g., fluoro C 1-4 alkyl
  • the substituted alkyl group is a cycloalkyl-alkyl group as described herein, including a 3-20 membered cycloalkyl-C 1-10 alkyl group, a 3-12 membered ring.
  • the substituted alkyl group is a heterocycloalkyl-alkyl group as described herein, including a 3-20 membered heterocycloalkyl-C 1-10 alkyl group, 3- 8-membered heterocycloalkyl-C 1-6 alkyl, 3-8 membered heterocycloalkyl-C 1-4 alkyl, 3-membered heterocycloalkyl-methyl, 4-membered heterocycloalkyl-methyl, 5-membered heterocycloalkyl-methyl, 6-membered heterocycloalkyl-methyl, 7-membered heterocycloalkyl-methyl and 8-membered heterocycloalkyl-methyl and the like.
  • the substituted alkyl group is an RO-alkyl group, and includes, for example, RO-C 1-10 alkyl group, RO-C 1-6 alkyl group, RO-C 1-4 alkyl group, RO-methyl and RO-ethyl and the like, wherein the R group is as described herein.
  • R is hydrogen or C 1-10 alkyl, and thus, the RO-alkyl group can be a hydroxy-substituted alkyl group or a C 1-10 alkoxyalkyl group.
  • the hydroxy-substituted alkyl group includes a hydroxy C 1-10 alkyl group, a hydroxy C 1-6 alkyl group, a hydroxy C 1-4 alkyl group and the like.
  • the C 1-10 alkoxyalkyl group includes a C 1-6 alkoxy-C 1-6 alkyl group and a C 1-4 alkoxy-C 1-4 alkyl group and the like.
  • the substituted alkyl group is RR'N-alkyl, and includes, for example, RR'NC 1-10 alkyl, RR'NC 1-6 alkyl, RR'NC 1- 4- alkyl, RR'N-methyl and RR'N-ethyl, and the like, wherein the R and R' groups are as described herein.
  • R and R' are hydrogen or C 1-10 alkyl, and thus, the RR 'N-alkyl group may be an amino substituted alkyl group or a C 1-10 alkylamino alkyl group. Or a di-C 1-10 alkylaminoalkyl group.
  • the RR'N-alkyl group is, for example, an amino-substituted C 1-10 alkyl group, an amino-substituted C 1-6 alkyl group, an amino-substituted C 1-4 alkyl group, or a C 1-6 alkylamino group-C 1- 6 alkyl, C 1-4 alkylamino-C 1-4 alkyl, di C 1-6 alkylamino-C 1-6 alkyl and di C 1-4 alkylamino-C 1-4 alkyl, and the like.
  • alkenyl refers to a straight or branched chain hydrocarbon radical containing at least one carbon to carbon double bond, such as a C 2-10 alkenyl group, a C 2-6 alkenyl group or a C 2-4 alkenyl group, an alkenyl group.
  • Restrictive examples include ethenyl, propenyl, butenyl, 2-methylpropenyl, pentenyl, 2-methylbutenyl, 3-methylbutenyl, hexenyl, 2-methyl Pentenyl, 3-methylpentenyl, 4-methylpentenyl, 2-ethylbutenyl and the like.
  • alkynyl denotes a straight or branched chain hydrocarbon radical containing at least one carbon-carbon triple bond, such as a C 2-10 alkynyl group, a C 2-6 alkynyl group or a C 2-4 alkynyl group, a nonyl alkynyl group.
  • Limitative examples include ethynyl, propynyl, butynyl, pentynyl, 3-methylbutynyl, hexynyl, 3-methylpentynyl and the like.
  • alkoxy refers to a group having the structure "alkyl-O-", such as C 1-10 alkoxy, C 1-6 alkoxy or C 1-4 alkoxy, alkoxy
  • alkoxy Non-limiting examples of the group include methoxy, ethoxy, propoxy, isopropoxy and t-butoxy groups and the like.
  • ROC(O)- refers to a substituted oxycarbonyl group such as an alkoxycarbonyl group.
  • R-OC(O)- include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, t-butoxycarbonyl, benzomethoxycarbonyl, and the like.
  • R(O)O- refers to a substituted acyloxy group, such as an alkyl acyloxy group.
  • R-C(O)O- include formyloxy, acetoxy, propanoyloxy, benzoyloxy and the like.
  • R(O)- refers to a substituted acyl group such as an alkanoyl group.
  • R-C(O)- include acetyl, propionyl, butyryl, benzoyl and the like.
  • RR'NH- means a substituted amino group such as an alkylamino group, a dialkylamino group or the like.
  • Non-limiting examples of RR'NH- include methylamino, ethylamino, propylamino, N,N-dimethylamino, N,N-diethylamino and the like.
  • R(O)NH- refers to substituted amide groups such as alkanoylamino and aroylamino groups and the like.
  • R-C(O)NH- include formylamino, acetamido, benzoylamino, and the like.
  • RR'NHC(O)- means a substituted aminoacyl group such as an alkanoyl group and a dialkylamino group.
  • Non-limiting examples of RR'NHC(O)- include carbamoyl, ethoxylyl, N,N-dimethylamino, N,N-diethylamino and the like.
  • RS(O) a - refers to a substituted fluorenyl, sulfonyl or sulfinyl group
  • a non-limiting example of RS(O) a - includes a fluorenyl group, a Sulfonyl, ethylsulfonyl, phenylsulfonyl, p-methylbenzenesulfonyl and the like.
  • RR'NSO 2 - refers to a substituted aminosulfonyl group, and non-limiting examples of RR'NSO 2 - include dimethylaminosulfonyl and the like.
  • RSO 2 N(R')- means a substituted sulfonamide group such as an alkylsulfonylamino group and an arylsulfonylamino group.
  • RSO 2 N(R')- include methanesulfonamide, ethanesulfonylamino, benzenesulfonylamino and p-toluenesulfonylamino groups, and the like.
  • R and R' are each independently selected from the group consisting of hydrogen, hydroxy, C 1-10 alkyl, 3-20 membered cycloalkyl, 5-20 membered heterocycloalkyl, 6-20 membered aryl, and 5-20 yuan heteroaryl. In certain preferred embodiments of the present application, R and R' are hydrogen or C 1-10 alkyl. When a substituent as referred to herein contains R or R', it includes all chemically bonded valence rules. R or R' as defined above.
  • cycloalkyl refers to a monocyclic or polycyclic cyclic alkyl group, for example a cycloalkyl group containing from 3 to 20 carbon atoms, for example a cycloalkyl group containing from 3 to 12 carbon atoms, for example including 3- A cycloalkyl group of 10 carbon atoms, for example, a cycloalkyl group having 3 to 8 carbon atoms, for example, a cycloalkyl group having 5 to 8 carbon atoms.
  • Non-limiting examples of monocycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptylcyclooctyl and the like.
  • Polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups.
  • heterocycloalkyl refers to a cycloalkyl group as defined above containing at least one heteroatom selected from N, O and S, for example a heterocycloalkyl group containing one or two N atoms, containing one a heterocycloalkyl group of an O atom, a heterocycloalkyl group having one S atom, for example, a 3-20 membered heterocycloalkyl group, for example, a 5-20 membered heterocycloalkyl group, for example, a 3-8 membered heterocycloalkyl group For example, it contains a 5-8 membered heterocycloalkyl group.
  • heterocycloalkyl groups include propylene oxide, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl. Wait.
  • aryl refers to a 6-20 membered monocyclic or fused polycyclic (eg bicyclic or tricyclic) aromatic group, preferably a 6-14 membered aryl group, more preferably a 6-10 membered aryl group.
  • aryl groups include, but are not limited to, phenyl and naphthyl and the like.
  • heteroaryl refers to a 5-14 membered aromatic heterocyclic group substituted with at least one hetero atom selected from N, O or S, preferably 5-10 members.
  • a heteroaryl group containing one or two N atoms a heteroaryl group containing one O atom or a heteroaryl group containing one S atom.
  • heteroaryl groups include furyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, Pyrimidinyl and pyrazinyl and the like.
  • alicyclic refers to a saturated or partially saturated carbocyclic ring having no aromatic character. For example, it includes a 3-20-membered alicyclic ring, a 3-12-membered alicyclic ring, a 3-8-membered alicyclic ring, a 4-membered alicyclic ring, a 5-membered alicyclic ring, a 6-membered alicyclic ring, and a 7-membered alicyclic ring.
  • aliphatic heterocycle means that at least one ring member is a heterologous selected from the group consisting of N, O and S.
  • a fatty aliphatic group For example, an aliphatic heterocyclic ring containing one or two N atoms, for example, an aliphatic heterocyclic ring containing only one O atom, for example, an aliphatic heterocyclic ring containing only one S atom, or the like.
  • it includes a 3-20-membered alicyclic ring, a 3-12-membered alicyclic ring, a 3-8-membered alicyclic ring, a 4-membered alicyclic ring, a 5-membered alicyclic ring, a 6-membered alicyclic ring, a 7-membered alicyclic ring, and the like. .
  • aromatic ring refers to an aromatic ring in which all ring members are carbon atoms. For example, it includes a 6-20 membered aromatic ring, a 6-14 membered aromatic ring, and a 6-10 membered aromatic ring.
  • heteromatic ring refers to an aromatic cyclic group in which at least one ring member is a hetero atom selected from N, O and S.
  • a heteroaromatic ring containing one or two N atoms for example, a heteroaromatic ring containing only one O atom, for example, a heteroaryl ring containing only one S atom, or the like.
  • it includes a 5-20 membered heteroaryl ring, a 5-14 membered heteroaryl ring, a 5-10 membered heteroaryl ring, a 5-6 membered heteroaryl ring, and the like.
  • halogen as used herein includes fluoro, chloro, bromo and iodo.
  • the fused ring may be substituted with an R 5 R 6 N- group, the substitution position being selected in accordance with the valence bond theory.
  • isomers as used herein includes all possible isomers of the compounds of formula I herein. Forms such as enantiomers, diastereomers, epimers, cis and trans isomers, conformational isomers and the like. For example, enantiomers of the R and S configurations as well as cis and trans isomers of the Z and E configurations are within the scope of the present application.
  • the compound of the formula I or a pharmaceutically acceptable salt thereof may also form a solvate such as a hydrate, an alcoholate or the like.
  • the compounds of formula I herein may also be in the form of a prodrug or which release the active ingredient after metabolic changes in the body. Selection and preparation of suitable prodrugs are well known to those skilled in the art.
  • the compound of the formula I or a pharmaceutically acceptable salt thereof may also exist in the form of a crystal, wherein the crystal refers to an arrangement in which molecules, atoms or ions constituting the compound are repeated in a regular cycle in a space, and the arrangement thereof has a periodicity of a three-dimensional space. Repeatedly at a certain distance.
  • the compounds may exist in two or more crystalline states, and the molecules having the same structure are crystallized into different solid forms, which are called "polymorphs", that is, polymorphs or polymorphs.
  • crystal form When referring to a particular crystalline form or polymorph, collectively referred to as "crystal form", the term "crystalline form" as used herein, the application encompasses any crystalline form of the compound of Formula I or a pharmaceutically acceptable salt thereof.
  • an effective amount refers to an amount sufficient to achieve the desired prophylactic and/or therapeutic effect, for example, to achieve an amount that prevents or reduces the symptoms associated with the condition to be treated.
  • treating refers to both therapeutic treatment and prophylactic measures, the purpose of which is to prevent or delay (reduce) the disease state or condition to which it is directed. If the subject receives a therapeutic amount of a compound, or an isomer, solvate, pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, as described herein, the subject has one or more indications and symptoms Subjects exhibit an observable and/or detectable reduction or improvement and the subject is successfully "treated”. It will also be understood that the prevention or treatment of the disease state or condition includes not only complete prevention or treatment, but also failure to achieve complete prevention or treatment, but achieving some biological or medical related results.
  • vascular disease mainly refers to myocardial ischemia/reperfusion injury, various forms of heart failure after injury, cardiomyopathy, circulatory shock, cardiovascular aging, cardiovascular complications of diabetes, cardiac hypertrophy, atherosclerosis Hardening, vascular remodeling, angiogenesis.
  • neurodegenerative disease and inflammation of the nervous system mainly refers to stroke, brain trauma, neurodegenerative diseases (Parkinson's disease, Alzheimer's disease and the like) caused by the harmful effects of oxidation and nitrosation stress.
  • Alzheimer's disease and the like mainly refers to stroke, brain trauma, neurodegenerative diseases (Parkinson's disease, Alzheimer's disease and the like) caused by the harmful effects of oxidation and nitrosation stress.
  • Amyotrophic lateral sclerosis and inflammation of the nervous system such as multiple sclerosis.
  • the present application provides a class of pyridazinone compounds by intensive investigation of pyridazinone PARP inhibitors, which can achieve at least one of the following technical effects:
  • the compound of the present application has excellent long-acting property, whereby the number of administrations can be reduced, and patient compliance can be improved.
  • Figure 1 shows the inhibitory effect of the compounds of the present application on the proliferation of breast cancer MDA-MB-453.
  • Figures 2-1 and 2-2 show the inhibitory effect of the compounds of the present application on the proliferation of breast cancer MDA-MB-468.
  • Figure 3 shows the inhibitory effect of the compounds of the present application on proliferation of pancreatic cancer Capan-1.
  • Figure 4 shows the inhibitory effect of the compounds of the present application on the proliferation of rectal cancer HCT116.
  • the structure of the compound is determined by nuclear magnetic resonance ( 1 H NMR) or mass spectrometry (MS).
  • the MS was measured using an Agilent (ESI) mass spectrometer, manufacturer: Agilent, model: Agilent 6120B.
  • a high performance liquid phase was prepared using Shimadzu LC-8A preparative liquid chromatograph (YMC, ODS, 250 x 20 mml column).
  • the thin layer chromatography silica gel plate was prepared by using an aluminum plate (20 ⁇ 20 cm) manufactured by Merck, and was purified by thin layer chromatography using a GF254 (0.4-0.5 nm) manufactured by Yantai.
  • reaction was monitored by thin layer chromatography (TLC) or LCMS using the developing solvent system: dichloromethane and methanol system, n-hexane and ethyl acetate system, petroleum ether and ethyl acetate system, solvent volume ratio according to compound
  • TLC thin layer chromatography
  • LCMS LCMS using the developing solvent system: dichloromethane and methanol system, n-hexane and ethyl acetate system, petroleum ether and ethyl acetate system, solvent volume ratio according to compound
  • the polarity is adjusted differently or adjusted by adding triethylamine or the like.
  • the microwave reaction was carried out using a Biotage Initiator + (400 W, RT - 300 ° C) microwave reactor.
  • Column chromatography generally uses Qingdao Ocean 200-300 mesh silica gel as a carrier.
  • the system of the eluent includes: dichloromethane and methanol systems, n-hexane and ethyl acetate systems, and the volume ratio of the solvent is adjusted depending on the polarity of the compound, and may also be adjusted by adding a small amount of triethylamine.
  • reaction temperature is room temperature (20 ° C to 30 ° C).
  • the reagents used in the present application were purchased from companies such as Acros Organics, Aldrich Chemical Company, and Tebe Chemical.
  • DIPEA N,N-diisopropylethylamine
  • DMF-DMA N,N-dimethylformamide dimethyl acetal
  • HATU 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate
  • NMP N-methylpyrrolidone
  • the TLC monitored the disappearance of the starting materials, and after quenching the reaction system with water, the ethanol was concentrated to remove.
  • the aqueous phase was extracted with ethyl acetate (50 mL ⁇ 4).
  • the organic phase was dried and washed with methyl tert-butyl ether to give the title compound (3.3 g, pale yellow solid, yield: 59%).
  • the third step of 2-methylsulfonyl-5,7-dihydro-pyrrole[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester (300 mg, 1.00 mmol) was dissolved in 5 mL of acetonitrile, potassium carbonate (207 mg, 1.50 mmol) and ethylamine (132.6 mg, 2 mmol) were added, and the mixture was reacted at 70 ° C for 6 hours, quenched with water and extracted with dichloromethane . The methylene chloride layer was dried over anhydrous sodium sulfate (MgSO4).
  • MgSO4 anhydrous sodium sulfate
  • Step 6 4-[3-(2-Ethylamino-5,7-dihydro-pyrrole[3,4-d]pyrimidin-6-carbonyl)-4-fluorobenzyl]-2H-pyridazine- 1-ketone
  • Step 4 2-Cyclopropylamino-5,7-dihydro-pyrrole[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester
  • the third step of 2-methylsulfonyl-5,7-dihydro-pyrrole[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester (300 mg, 1.00 mmol) was dissolved in 5 mL of acetonitrile and potassium carbonate was added. (207 mg, 1.50 mmol) and cyclopropane The amine (2 mmol) was reacted at 75 ° C for 8 hours, quenched with water and extracted with dichloromethane. The methylene chloride layer was dried over anhydrous sodium sulfate (MgSO4).
  • Step 5 N-cyclopropyl-6,7-dihydro-5H-pyrrole[3,4-d]pyrimidin-2-amine hydrochloride
  • 2-cyclopropylamino-5,7- Dihydro-pyrrole[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester 400 mg, 18 mmol
  • ethyl acetate 3 mL
  • EtOAc ethyl acetate
  • Step 6 4-[3-(2-Cyclopropylamino-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl)-4-fluorobenzyl)-2H-indole Pyrazin-1-one
  • Step 5 4-[3-(2-Cyclopropylmethylamino-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl)-4-fluorobenzyl]-2H -pyridazine-1-one
  • Step 5 4- ⁇ 4-Fluoro-3-[2-(2-hydroxyethylamino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl ⁇ -2H-phthalazin-1-one
  • the title compound was synthesized by the method of the fourth step of Example 1, and the ethylamine used in the fourth step of Example 1 was replaced with N,N-dimethylethylenediamine.
  • the title compound was synthesized by the method of the fifth step of Example 1, and replaced with 2-(2-dimethylaminoethylamino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-tert-butyl ester.
  • the third step 4- ⁇ 3-[2-(2-dimethylaminoethylamino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]-4-fluorobenzyl -2 ⁇ -2H-phthalazin-1-one
  • the title compound was synthesized by the method of the fourth step of Example 1, and the ethylamine used in the fourth step of Example 1 was replaced with 4-amino-tetrahydro-pyran.
  • the second step N-(tetrahydro-pyran-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine hydrochloride.
  • the title compound was synthesized by the method of the fifth step of Example 1, using 2-(tetrahydro-pyran-4-amino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonate Butyl ester replaces 2-ethylamino-5,7-dihydro-pyrrole [3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester.
  • the title compound was synthesized by the method of the fourth step of Example 1, and the ethylamine used in the fourth step of Example 1 was replaced with a dimethylamine methanol solution.
  • the second step N, N-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine hydrochloride.
  • the title compound was synthesized by the method of the fifth step of Example 1, substituting 2-ethylamino-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonate tert-butyl ester to 2-ethylamino- tert-Butyl 5,7-dihydro-pyrrole[3,4-d]pyrimidine-6-carboxylate.
  • Step 6 4- ⁇ 4-Fluoro-3-[2-(2-methoxyethylamine)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]- Benzyl ⁇ -2H-phthalazin-1-one
  • the title compound was synthesized by the method of the fourth step of Example 1, and the ethylamine used in the fourth step of Example 1 was replaced with 1-amino-2-methylpropyl-2-ol.
  • the second step 1-(6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amino)-2-methylpropyl-2-ol hydrochloride.
  • the title compound was synthesized by the method of the fifth step of Example 1, using 2-(2-hydroxy-2-methylpropylamino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6- Tert-butyl carbonate was substituted for tert-butyl 2-ethylamino-5,7-dihydro-pyrrole [3,4-d]pyrimidine-6-carboxylate.
  • the third step 4- ⁇ 4-fluoro-3-[2-(2-hydroxy-2-methylpropylamino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6- Carbonyl]-benzyl ⁇ -2H-phthalazin-1-one
  • the title compound was synthesized by the method of the fourth step of Example 1, and the ethylamine used in the fourth step of Example 1 was replaced with N-methylcyclopropylamine.
  • the second step N-cyclopropyl-N-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine hydrochloride.
  • the title compound was synthesized by the method of the fifth step of Example 1, using 2-(cyclopropylmethylamino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonate tert-butyl ester. Substituting tert-butyl 2-ethylamino-5,7-dihydro-pyrrole[3,4-d]pyrimidine-6-carboxylate.
  • the title compound was synthesized by the method of the fourth step of Example 1, and the ethylamine used in the fourth step of Example 1 was replaced with 1-methylcyclopropylamine.
  • the second step N-(1-methylcyclopropyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine hydrochloride.
  • the title compound was synthesized by the method of the fifth step of Example 1, using 2-(1-methylcyclopropylamino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonate tert-butyl.
  • the ester is substituted with tert-butyl 2-ethylamino-5,7-dihydro-pyrrole [3,4-d]pyrimidine-6-carboxylate.
  • the third step 4- ⁇ 4-fluoro-3-[2-(1-methylcyclopropylamino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]- Benzyl ⁇ -2H-phthalazin-1-one
  • Step 6 4-(4-Fluoro-3-(2-(oxetan-3-ylamino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-6- Carbonyl)benzyl)pyridazine-1(2H)-one
  • the title compound was synthesized by the method of the fifth step of Example 1, substituting 2-ethylamino group with 2-methylsulfonyl-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonate tert-butyl ester. -5,7-Dihydro-pyrrole [3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester.
  • Second step 4-[4-Fluoro-3-(2-methylsulfonyl-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl)benzyl]-2H-indole Pyrazin-1-one.
  • Example 2 The synthesis was carried out by the method of the sixth step of Example 1, and the N-ethyl group used in Example 1 was replaced with 2-methylsulfonyl-5,7-dihydro-pyrrolo[3,4-d]pyrimidine hydrochloride. 5,7-Dihydro-pyrrole [3,4-d]pyrimidin-2-amine hydrochloride.
  • the title compound was synthesized by the method of the fourth step of Example 1, substituting 4-aminocyclohexanol for the ethylamine used in the fourth step of Example 1, using 4-[4-fluoro-3-(2-methylsulfonyl-) Substituting 5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl)benzyl]-2H-phthalazin-1-one for the 2-methylsulfonyl-5 used in the fourth step of Example 1. , 7-Dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonate tert-butyl ester.
  • Second step 4-(4-fluoro-3-(2-(methylsulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-6-carbonyl)benzyl) Pyridazine-1(2H)-one.
  • Step 3 4-(4-Fluoro-3-(2-((tetrahydrofuran-3-yl)amino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-6-carbonyl Benzyl)pyridazine-1(2H)-one
  • the title compound was synthesized by the method of the third step of Example 14 and the 4-aminocyclohexanol used in the third step of Example 13 was replaced with tetrahydrofuran-3-amine.
  • Second step 4-(4-fluoro-3-(2-(methylsulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-6-carbonyl)benzyl) Pyridazine-1(2H)-one.
  • the third step 4-(3-(2-(4-(dimethylamino)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-6- Carbonyl)-4-fluorobenzyl)pyridazine-1(2H)-one
  • the title compound was synthesized by the method of the third step of Example 13, and the 4-aminocyclohexanol used in the third step of Example 14 was replaced with 4-dimethylaminopiperidine.
  • Second step 4-(4-fluoro-3-(2-(methylsulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-6-carbonyl)benzyl) Pyridazine-1(2H)-one.
  • the third step 4-(4-fluoro-3-(2-(4-methylpiperazin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-6 -carbonyl)benzyl)pyridazine-1(2H)-one
  • the title compound was synthesized by the method of the third step of Example 13, and the 4-aminocyclohexanol used in the third step of Example 13 was replaced with 1-methylpiperazine.
  • Second step 4-(4-fluoro-3-(2-(methylsulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-6-carbonyl)benzyl) Pyridazine-1(2H)-one.
  • the third step 4-(4-fluoro-3-(2-((1-methylpiperidin-4-yl)amino)-6,7-dihydro-5H-pyrrolo[3,4-d] Pyrimidine-6-carbonyl)benzyl)pyridazine-1(2H)-one
  • the title compound was synthesized by the method of the third step of Example 13, and the 4-aminocyclohexanol used in the third step of Example 13 was replaced with 1-methylpiperidin-4-amine.
  • Second step 4-(4-fluoro-3-(2-(methylsulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-6-carbonyl)benzyl) Pyridazine-1(2H)-one.
  • the title compound was synthesized by the method of the third step of Example 13, and the 4-aminocyclohexanol used in the third step of Example 13 was replaced with 4,4-difluorocyclohexylamine.
  • Second step 4-(4-fluoro-3-(2-(methylsulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-6-carbonyl)benzyl) Pyridazine-1(2H)-one.
  • the third step 4-(4-fluoro-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-6,7-dihydro-5H-pyrrolo[3,4 -d]pyrimidine-6-carbonyl)benzyl)pyridazine-1(2H)-one
  • the title compound was synthesized by the method of the third step of Example 13, and the 4-aminocyclohexanol used in the third step of Example 13 was replaced with 1-methyl-1H-pyrazol-4-amine.
  • Second step 4-(4-fluoro-3-(2-(methylsulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-6-carbonyl)benzyl) Pyridazine-1(2H)-one.
  • the third step 4-(4-fluoro-3-(2-((1-methyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-pyrazolo[3, 4-d]pyrimidin-6-carbonyl)benzyl)pyridazine-1(2H)-one
  • the title compound was synthesized by the method of the third step of Example 13, and the 4-aminocyclohexanol used in the third step of Example 13 was replaced with 1-methyl-1H-pyrazol-3-amine.
  • Step 2 4-(4-Fluoro-3-(2-(methylsulfonyl)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl)benzyl)pyridazine -1(2H)-ketone.
  • the title compound was synthesized in a similar manner to that in the third step of Example 13, except that the 4-aminocyclohexanol used in the third step of Example 13 was replaced with (S)-1-methoxy-2-propylamine.
  • Second step 4-(4-fluoro-3-(2-(methylsulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-6-carbonyl)benzyl) Pyridazine-1(2H)-one.
  • Example 1 The N-ethyl group used in Example 1 was replaced with 2-methylsulfonyl-5,7-dihydro-pyrrolo[3,4-d]pyrimidine hydrochloride using a similar procedure as in the sixth step of Example 1. 5,7-Dihydro-pyrrole[3,4-d]pyrimidin-2-amine hydrochloride gave the title compound.
  • the title compound was synthesized in a similar manner to that in the third step of Example 13 except that the 4-aminocyclohexanol used in the third step of Example 13 was replaced with (R)-1-methoxy-2-propylamine.
  • Enzyme activity screening of PARP-1 inhibitors was performed using the PARP1 chemiluminescence kit from BPS Bioscience.
  • Test compound a compound of the examples of the present application.
  • Kit PARP1 Chemiluminescent Assay Kit, manufacturer: BPS Bioscience.
  • Kit pretreatment Add the microplate to 50 ⁇ L/well of 1 ⁇ PARP buffer diluted 1 ⁇ histone and incubate overnight at 4°C; discard the liquid in the microplate the next day and use 200 ⁇ l/well PBST (1 ⁇ Wash the plate with PBS and 1% Triton X-100), remove all the washing solution; then add 200 ⁇ l of stop buffer per well, incubate for 90 min at room temperature, discard the liquid; wash the plate with 200 ⁇ l/well PBST, and finally remove all the washing solution.
  • Detection After completion of the reaction, the well plate was rinsed with PBST (200 ⁇ l/well), and finally the washed solution was completely removed; 50 ⁇ l of diluted Strep-HRP was added to each well, and cultured at room temperature for 30 min; using PBST (200 ⁇ L/well) After rinsing the plate, remove all the cleaning solution; mix HRP substrates A and B on an ice bath, then add 100 ⁇ l per well (50 ⁇ l of colorimetric substrate A and 50 ⁇ l of colorimetric substrate B per well); finally chemiluminescence (Luminometric Measurement) High sensitivity mode was used to detect the inhibitory activity of the test compound against PARP1 kinase, and the results are shown in Table 3.
  • the compounds of the present application have a significant inhibitory effect on PARP1 kinase activity.
  • the effect of the compound on cell proliferation was determined by the CCK-8 method.
  • Test compound a compound of the examples of the present application.
  • Kit CCK-8 kit (Cell Counting Kit-8), manufacturer: Beyotime.
  • Cell culture The cells were cultured according to the following conditions, and the cells were counted by a cell counter after digestion, and the cells were adjusted to the desired concentration according to the following requirements, and then 100 ⁇ l of the cells were seeded per well, and administered 24 hours after the inoculation.
  • test compound preparation After one day of culture, the test compound and olrapani were dissolved in DMSO to prepare a mother liquid, and an appropriate amount of the mother liquid was taken up to the culture solution to be mixed, and the drug solution was set to the corresponding incubation concentration.
  • Incubation time Incubation was continued for 7 days in the incubator after administration.
  • Table 5-1 and Figure 1 suggest that the compounds of the present application have significant proliferation inhibitory effects on breast cancer MDA-MB-453 cells.
  • Compound 1, 2, 3, 4, 6, 8, and Compounds 64, 65, and 68 significantly inhibited the proliferation of breast cancer cell MDA-MB-453 over olaparib.
  • Table 5-2 and Figures 2-1 and 2-2 suggest that the compound of the present application has a significant proliferation inhibitory effect on breast cancer cell MDA-MB-468.
  • Compounds 1, 2, 3, 4, 6, 8, 12, 13, 19, 20, and Compounds 64, 65, and 68 significantly inhibited the proliferation of breast cancer cell MDA-MB-468 over Orapa Ni.
  • cancer cells such as breast cancer cells, colorectal cancer cells, and pancreatic cancer cells.
  • the compounds of the present application have proliferation inhibitory activity against cancer cells such as breast cancer cells, colorectal cancer cells, and pancreatic cancer cells.
  • IV and PO intravenous and intragastric administration of the compound of the present application and olaparib, respectively, to examine the pharmacokinetic characteristics.
  • IV and PO oral
  • blood was collected at different time points, blood was anticoagulated with sodium heparin, and plasma samples were centrifuged, and the plasma samples were subjected to LC-MS/MS analysis after being subjected to precipitated protein treatment.
  • LC-MS/MS the column was a Waters X-Bridge C18 column (21 mm*50 mm, 3.5 ⁇ m); the mobile phase A phase was water + 2 mM ammonium acetate, the phase B was methanol + 2 mM ammonium acetate, and the flow rate was 0.4 mL/min.
  • the column temperature is 40 °C.
  • the ion source is used as the ESI source positive ion mode, and the scanning mode is multiple reaction monitoring (MRM).
  • IV and PO administration were 1 and 5 mg/kg, respectively, and the vehicle system was 10% DMSO: 10% solutol: 80% normal saline.
  • IV and PO administration Blood was collected at different time points, blood was anticoagulated with heparin sodium, and plasma samples obtained after centrifugation were stored at -80 °C. Plasma samples were subjected to LC-MS/MS analysis after treatment with precipitated proteins.
  • the PK properties of the compounds of the present application in dogs are superior to olaparib in the same administration route and dose administered as 3.1 rat PK.
  • the potassium channel encoded by the human Ether-a-go-go Related Gene mediates a delayed rectifier potassium current (IKr). IKr inhibition is the most important mechanism for drug-induced QT interval prolongation. In the hERG test, if the criteria for the test compound IC 50> 30 ⁇ M, it is determined that no inhibitory effect on hERG test compound.
  • the present application detecting compounds on hERG potassium ion channel, a concentration of the test 3,10,30 ⁇ M.
  • the test results showed that the 50% inhibitory concentration (IC 50 value) of Compound 1, Compound 2, Compound 3, and Compound 6 for hERG was more than 30 ⁇ M. It is suggested that the compound of the present application has no inhibitory effect on hERG, indicating that the compound of the present application has no safety risk of prolonging the QT interval of the heart.
  • KM mice were administered by gavage, and the toxicity of a single administration of the test compound was examined to determine the maximum tolerated dose (MTD).
  • MTD maximum tolerated dose
  • the dose was set to: Compound 1: 300 mg/kg; Compounds 2, 3, 6: 200, 300 mg/kg, administered by single gavage, the vehicle was 10% DMSO and 50% PEG, and the balance of physiological saline, after administration. Observe for 7 days.
  • Compound 1 Maximum Tolerance (MTD) is greater than 300 mg/kg;
  • Compound 2 is less than 200 mg/kg;
  • Compound 3 is greater than 300 mg/kg
  • the compounds of the present application are well tolerated under single dose high dose conditions.
  • This example was used to evaluate the effectiveness of the compounds of the present application against tumor growth inhibition by different routes of administration.
  • pancreatic cancer Capan-1 tumor-bearing mice were evaluated by measuring the tumor volume changes of human pancreatic cancer cell line Capan-1 subcutaneous xenograft mice after administration of the compound of the present application via the PO administration route.
  • TGI (%) [1- (VT end - VT start ) / (VC end - VC start )] * 100%
  • VT is the end of the tumor volume at the end of the treatment group
  • VT start tumor volume mean at the beginning of treatment in the treatment group
  • End of VC mean volume of tumor at the end of the vehicle control experiment
  • VC start mean volume of tumor at the beginning of drug control group administration
  • the tumor inhibition rates of each group of compounds against pancreatic cancer are shown in Table 7 below.
  • Table 7 Tumor inhibition rate in Panan-1 model of pancreatic cancer cell line
  • Tumor inhibition rate (%) 1 Solvent control P.o. / 2 Olapani (100mg/kg) P.o. 9.2 3 Compound 2 (3mg/kg) P.o. 109.7 4 Compound 2 (0.3 mg/kg) P.o. 44.3 5 Compound 3 (10 mg/kg) P.o. 48.6 6 Compound 3 (3mg/kg) P.o. 36.0 7 Compound 6 (10 mg/kg) P.o. 56.8 8 Compound 6 (3mg/kg) P.o. 20.2
  • the effects of each compound on breast cancer MX-1 tumor-bearing mice were evaluated by measuring the tumor volume changes of human breast cancer cell line MX-1 subcutaneously transplanted mice after administration of the compound of the present application via the PO administration route.
  • the antitumor effect of the test compound was relative tumor proliferation rate T/C (%).
  • T/C (%) (start of V T / start of V T ) / ( start of V C / start of V C ) * 100%
  • VT is the end of the tumor volume at the end of the treatment group
  • VT start tumor volume mean at the beginning of treatment in the treatment group
  • End of VC mean volume of tumor at the end of the vehicle control experiment
  • VC start mean volume of tumor at the beginning of drug control group administration
  • the evaluation criteria were: T/C (%) > 40% was ineffective; T / C (%) ⁇ 40%, and statistically treated P ⁇ 0.05 was effective.
  • the experimental results show that the compound in the present invention has a relative tumor growth rate of less than 55% in the human breast cancer cell line MX-1 tumor-bearing mouse model at a dose of 5 mg/kg and 10 mg/kg of PO, and has excellent inhibition. Tumor effect.
  • composition of the immediate release tablets is shown in Table 8:
  • Standard immediate release tablets are made using direct compression.
  • Compound 1 and lactose, microcrystalline cellulose, croscarmellose sodium, and sodium lauryl sulfate were weighed into glass vials, and the above mixture occupied approximately 75% of the volume of the vial, which was then mixed together for 30 minutes in a tumble mixer. , to get blended materials.
  • the blended material was sieved through a 40 mesh (425 ⁇ m) sieve and then drum mixed for another 15 minutes. Magnesium stearate was then added and the blend was shaken for approximately 20 seconds.
  • the resulting mixture was then dispensed into 400 mg aliquots and compressed into tablet cores using a hand press equipped with a 10 mm die with 0.5 ton of target compression.
  • composition of the capsule preparation is shown in Table 9:
  • the lauroyl group was melted at about 50-70 ° C and then weighed into a stainless steel container. Compound 2 was added and the contents were mixed to be uniformly suspended. The mixing was continued while the mixture was dispensed into a capsule using a thermostatically controlled automatic capsule filling machine to prepare a 500 mg/granule capsule preparation.

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Abstract

Provided are a phthalazine ketone derivative, and a preparation method and a use thereof. Specifically, a compound as shown in formula I, a prodrug, a metabolite form, a pharmaceutically acceptable salt or ester, an isomer, a hydrate, a solvate or a crystal form thereof, and a preparation method and a use thereof are provided. The compound of the invention can significantly suppress proliferation of tumor cells, increase in vivo molecular stability, and reduce the likelihood of generating toxic metabolites. Alternatively, structural modification can be performed on a phthalazine ketone compound, thereby reducing the oxidative metabolism ability of the compound under the action of an in vivo cytochrome P450 enzyme system, and increasing bioavailability.

Description

酞嗪酮衍生物、其制备方法及用途Pyridazinone derivative, preparation method and use thereof 技术领域Technical field

本申请涉及医药领域，具体涉及酞嗪酮衍生物、其制备方法及用途。The present application relates to the field of medicine, and in particular to a pyridazinone derivative, a preparation method thereof and use thereof.

背景技术Background technique

聚腺苷二磷酸核糖聚合酶(Poly ADP-Ribose Polymerase，PARP)是一种113kDa的多结构域蛋白质，其通过识别和快速结合断裂的DNA单链或双链参与DNA损伤的信号传导(D’Amours D.et al.，Poly(ADP-ribosyl)ation reactions in the regulation of nuclear functions.Biochem.J.342:249-268(1999))。PARP家族现在包括约18种蛋白质，其中PARP-1(最早发现的成员)和PARP-2是目前发现的仅有的通过发生DNA断裂而激活其催化活性的酶，这使得它们在该家族中非常独特。而PARP-1是PARP家族中结构最典型，也是研究最多的，其分子量为114KDa，以ADP为底物在受体蛋白(包括自身)上合成聚腺苷酸二磷酸核糖(PAR)(Sakamoto-Hojo E T，Balajee A S.Targeting Poly(ADP)ribose PolymeraseⅠ(PARP-Ⅰ)and PARP-Ⅰinteracting Proteins for cancer treatment.Anticancer Agents Med Chem,2008,8(4):402-416)。Poly ADP-Ribose Polymerase (PARP) is a 113 kDa multidomain protein that participates in DNA damage signaling by recognizing and rapidly binding to broken DNA single or double strands (D' Amours D. et al., Poly (ADP-ribosyl)ation reactions in the regulation of nuclear functions. Biochem. J. 342: 249-268 (1999)). The PARP family now includes approximately 18 proteins, of which PARP-1 (the earliest discovered member) and PARP-2 are the only enzymes found to activate their catalytic activity by DNA fragmentation, making them very unique. PARP-1 is the most typical and most studied structure in the PARP family. Its molecular weight is 114KDa. ADP is used as a substrate to synthesize poly(ARP) ribose (PAR) on receptor proteins (including itself) (Sakamoto- Hojo E T, Balajee A S. Targeting Poly (ADP) ribose Polymerase I (PARP-I) and PARP-Iinteracting Proteins for cancer treatment. Anticancer Agents Med Chem, 2008, 8(4): 402-416).

PARP-1参与DNA损伤修复及转录调节，并被认为是细胞存活和死亡的重要调节因子，还参与肿瘤发生及炎症反应中一些转录因子的调控(Peralta-Leal A,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)。目前为止人们已发现PARP-1在多种人类的恶性肿瘤中高表达，如恶性淋巴瘤，乳腺癌，尤文氏肉瘤，肝细胞癌等。PARP-1 is involved in DNA damage repair and transcriptional regulation and is considered to be an important regulator of cell survival and death. It is also involved in the regulation of some transcription factors in tumorigenesis and inflammation (Peralta-Leal A, 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). Up to now, PARP-1 has been found to be highly expressed in various human malignant tumors, such as malignant lymphoma, breast cancer, Ewing's sarcoma, and hepatocellular carcinoma.

由于PARP-1参与DNA损伤修复，单独应用PARP-1活性抑制剂或与DNA损伤药物联用可以促进癌细胞的死亡。大量的研究已经证实药物抑制或基因敲除PARP-1不仅能避免氧化应激相关疾病引起的组织损伤，还能改善肿瘤病人的预后。单独应用PARP-1抑制剂对存在DNA损伤修复缺陷的肿瘤(主要是乳腺癌)也有杀伤作用。另外文献还报道了PARP-1抑制剂与血管生成的关系，目前至少有五种PARP抑制剂在体外能抑制血管内皮细胞生长因子(VEGF)诱导的人脐静脉内皮细胞的增殖和迁移以及血管形成。因为大脑很容易受到氧化应激的影响(Sriram C S,et al.Multiple facets of poly(ADP-ribose)polymerase-1in neurological diseases.Neural Regen Res.2015；10(1):49-51)，PARP-1的神经病理学研究也逐渐受到重视。 Since PARP-1 is involved in DNA damage repair, the use of PARP-1 activity inhibitor alone or in combination with DNA damage drugs can promote cancer cell death. A large number of studies have confirmed that drug inhibition or gene knockout PARP-1 can not only avoid tissue damage caused by oxidative stress-related diseases, but also improve the prognosis of cancer patients. The use of PARP-1 inhibitor alone also has a killing effect on tumors (mainly breast cancer) with defects in DNA damage repair. In addition, the literature also reports the relationship between PARP-1 inhibitors and angiogenesis. Currently, at least five PARP inhibitors inhibit vascular endothelial growth factor (VEGF)-induced proliferation and migration of human umbilical vein endothelial cells and angiogenesis in vitro. . Because the brain is susceptible to oxidative stress (Sriram C S, et al. Multiple facets of poly (ADP-ribose) polymerase-1 in neurological diseases. Neural Regen Res. 2015; 10(1): 49-51), PARP The neuropathological study of -1 has also received increasing attention.

因此，开发新型PARP抑制剂具有较高临床应用价值。Therefore, the development of new PARP inhibitors has high clinical value.

发明内容Summary of the invention

本申请的发明人通过对酞嗪酮类化合物的构效关系进行系统的研究，发现了一类具有优异PARP抑制活性的化合物，本申请即是基于以上发现而完成。The inventors of the present application have systematically studied the structure-activity relationship of pyridazinone compounds and found a class of compounds having excellent PARP inhibitory activity, and the present application has been completed based on the above findings.

因此，本申请的第一方面提供式I化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型，Accordingly, a first aspect of the present application provides a compound of Formula I, a prodrug, metabolite form, pharmaceutically acceptable salt or ester thereof, or an isomer, hydrate, solvate or crystalline form thereof,

Figure PCTCN2016103735-appb-000001
Figure PCTCN2016103735-appb-000001

其中，among them,

A和B与相连的原子一起形成脂环、脂杂环、芳环或杂芳环，任选地，其中所述脂环、脂杂环、芳环或杂芳环各自独立地被一个或多个(例如1个、2个、3个或4个)选自卤素、羟基、氨基、氰基、羧基、硝基、烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、RO-、ROC(O)-、RC(O)O-、RC(O)-、RR’N-、RC(O)NH-、RR’NC(O)-、RS(O)a-、RR’NSO2-和RSO2N(R’)-的取代基取代，其中a为0、1或2；A and B together with the attached atoms form an alicyclic, heteroalicyclic, aromatic or heteroaryl ring, optionally wherein the alicyclic, heteroalicyclic, aromatic or heteroaryl ring is independently one or more (for example, 1, 2, 3 or 4) selected from the group consisting of halogen, hydroxy, amino, cyano, carboxy, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aromatic Base, heteroaryl, RO-, ROC(O)-, RC(O)O-, RC(O)-, RR'N-, RC(O)NH-, RR'NC(O)-, RS( O) a -, RR'NSO 2 - and RSO 2 N(R')- substituent substitution, wherein a is 0, 1 or 2;

R1、R2、R3和R4各自独立地选自氢、卤素、羟基、氨基、氰基、羧基、硝基、烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、RO-、ROC(O)-、RC(O)O-、RC(O)-、RR’N-、RC(O)NH-和RR’NC(O)-，任选地，其中所述烷基、烯基、炔基、环烷基、杂环烷基、芳基或杂芳基各自独立地被一个或多个(例如1个、2个、3个或4个)选自卤素、羟基、C1-4烷基、C1-4烷氧基、3-8元环烷基、5-8元杂环烷基、6-10元芳基或5-10元杂芳基的取代基取代；R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, cyano, carboxy, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, 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, cycloalkyl, heterocycloalkyl, aryl or heteroaryl are each independently one or more (eg 1, 2, 3 or 4) a) selected from the group consisting of halogen, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, 3-8 membered cycloalkyl, 5-8 membered heterocycloalkyl, 6-10 membered aryl or 5-10 Substituent substitution of a heteroaryl group;

D和E各自独立地选自C和N，且与相连的原子一起形成5-10元(例如5、6、7、8、9、10)环X，其中所述环X选自脂杂环、芳环和杂芳环，优选为杂芳环，例如吡啶环、哒嗪环、嘧啶环、吡嗪环或三嗪环；D and E are each independently selected from C and N, and together with the attached atoms form a 5-10 membered (e.g., 5, 6, 7, 8, 9, 10) ring X wherein the ring X is selected from the group consisting of an alicyclic ring. , an aromatic ring and a heteroaryl ring, preferably a heteroaromatic ring, such as a pyridine ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring or a triazine ring;

m和n各自独立地选自0、1和2，且m+n＝2；m and n are each independently selected from 0, 1, and 2, and m+n=2;

Y独立地选自C、O、S和N，条件是，当Y＝O或S时，R6和R7不存在，当Y＝N时，R7不存在；Y is independently selected from C, O, S and N, provided that when Y = O or S, R 6 and R 7 are absent, and when Y = N, R 7 is absent;

R5，R6，R7和R8各自独立地选自氢、羟基、氰基、硝基、烷基、环 烷基、杂环烷基、芳基、杂芳基、环烷基-烷基、杂环烷基-烷基、RO-、RC(O)-、RC(O)O-、RR’N-、RC(O)NH-和RR’NC(O)-，任选地，其中所述烷基、环烷基、杂环烷基、杂芳基、环烷基-烷基或杂环烷基-烷基各自独立地进一步被一个或多个(例如1个、2个、3个或4个)选自卤素、羟基、氰基、氨基、羧基、硝基、烷基、卤代烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、RO-、RR’N-、RO-C1-10烷基、RR’N-C1-10烷基、RS(O)a-、RR’NSO2-和RSO2N(R’)-的取代基取代，其中a为0、1或2；或者R 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of hydrogen, hydroxy, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyl-alkane , heterocycloalkyl-alkyl, RO-, RC(O)-, RC(O)O-, RR'N-, RC(O)NH-, and RR'NC(O)-, optionally, Wherein the alkyl group, cycloalkyl group, heterocycloalkyl group, heteroaryl group, cycloalkyl-alkyl group or heterocycloalkyl-alkyl group are each independently further one or more (for example, one, two, 3 or 4) selected from the group consisting of halogen, hydroxy, cyano, amino, carboxy, nitro, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Substituents for RO-, RR'N-, RO-C 1-10 alkyl, RR'NC 1-10 alkyl, RS(O) a -, RR'NSO 2 - and RSO 2 N(R')- Substituted, where a is 0, 1, or 2; or

R5和R6与Y原子一起形成脂环、芳环、脂杂环或杂芳环，任选地，其中所述脂环、芳环、脂杂环或杂芳环各自独立地进一步被一个或多个(例如1个、2个、3个或4个)选自卤素、羟基、氰基、RS(O)a-、烷基、RR’N-、和RO-的取代基取代，其中a为0、1或2；R 5 and R 6 together with the Y atom form an alicyclic, aromatic ring, alicyclic or heteroaryl ring, optionally wherein the alicyclic, aromatic ring, alicyclic or heteroaryl ring is each independently further Or a plurality (for example, 1, 2, 3 or 4) of substituents selected from the group consisting of halogen, hydroxy, cyano, RS(O) a -, alkyl, RR'N-, and RO-, wherein a is 0, 1 or 2;

R和R’各自独立地选自氢、羟基、C1-10烷基、3-20元环烷基、5-20元杂环烷基、6-20元芳基、5-20元杂芳基，任选地，所述C1-10烷基、3-20元环烷基、5-20元杂环烷基、6-20元芳基、5-20元杂芳基各自独立地被一个或多个(例如1个、2个、3个或4个)选自卤素、羟基、C1-4烷基、C1-4烷氧基、3-8元环烷基、5-8元杂环烷基、6-10元芳基和5-10元杂芳基的取代基取代。R and R' are each independently selected from the group consisting of hydrogen, hydroxy, C 1-10 alkyl, 3-20 membered cycloalkyl, 5-20 membered heterocycloalkyl, 6-20 membered aryl, 5-20 membered heteroaryl. And optionally, the C 1-10 alkyl group, the 3-20 membered cycloalkyl group, the 5-20 membered heterocycloalkyl group, the 6-20 membered aryl group, the 5-20 membered heteroaryl group are each independently One or more (eg, 1, 2, 3 or 4) are selected from the group consisting of halogen, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, 3-8 membered cycloalkyl, 5-8 Substituent substitution of a heterocycloalkyl group, a 6-10 membered aryl group, and a 5-10 membered heteroaryl group.

在本申请的某些优选实施方案中，所述式I化合物的限制性条件为，In certain preferred embodiments of the present application, the limiting condition of the compound of Formula I is

当A和B与相连的原子一起形成苯环，R1、R2、R3均为氢，R4为氟，并且m和n均为1时，When A and B together with the attached atoms form a benzene ring, R 1 , R 2 , and R 3 are all hydrogen, R 4 is fluorine, and m and n are both 1,

1)环X不为5元环、杂原子为N的六元脂杂环以及杂原子为N和O的六元脂杂环；且，1) a ring 6 is not a 5-membered ring, a heterocyclic six-membered heterocyclic heterocyclic ring, and a six-membered aliphatic heterocyclic ring having a hetero atom of N and O;

2)所述

Figure PCTCN2016103735-appb-000002
不为如下基团：2) stated
Figure PCTCN2016103735-appb-000002
Not the following groups:

Figure PCTCN2016103735-appb-000003
Figure PCTCN2016103735-appb-000003

在本申请的某些优选实施方案中，所述化合物具有式Ia所示的结构，In certain preferred embodiments of the present application, the compound has the structure shown in Formula Ia,

Figure PCTCN2016103735-appb-000004
Figure PCTCN2016103735-appb-000004

其中，among them,

A和B与相连的原子一起形成脂环、脂杂环、芳环或杂芳环，任选地，其中所述脂环、脂杂环、芳环或杂芳环各自独立地被一个或多个(例如1个、2个、3个或4个)选自卤素、羟基、氨基、氰基、羧基、硝基、烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、RO-、ROC(O)-、RC(O)O-、RC(O)-、RR’N-、RC(O)NH-、RR’NC(O)-、RS(O)a-、RR’NSO2-和RSO2N(R’)-的取代基取代，其中a为0、1或2；A and B together with the attached atoms form an alicyclic, heteroalicyclic, aromatic or heteroaryl ring, optionally wherein the alicyclic, heteroalicyclic, aromatic or heteroaryl ring is independently one or more (for example, 1, 2, 3 or 4) selected from the group consisting of halogen, hydroxy, amino, cyano, carboxy, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aromatic Base, heteroaryl, RO-, ROC(O)-, RC(O)O-, RC(O)-, RR'N-, RC(O)NH-, RR'NC(O)-, RS( O) a -, RR'NSO 2 - and RSO 2 N(R')- substituent substitution, wherein a is 0, 1 or 2;

R1、R2、R3和R4各自独立地选自氢、卤素、羟基、氨基、氰基、羧基、硝基、烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、RO-、ROC(O)-、RC(O)O-、RC(O)-、RR’N-、RC(O)NH-和RR’NC(O)-，任选地，其中所述烷基、烯基、炔基、环烷基、杂环烷基、芳基或杂芳基各自独立地被一个或多个(例如1个、2个、3个或4个)选自卤素、羟基、C1-4烷基、C1-4烷氧基、3-8元环烷基、5-8元杂环烷基、6-10元芳基和5-10元杂芳基的取代基取代；R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, cyano, carboxy, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, 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, cycloalkyl, heterocycloalkyl, aryl or heteroaryl are each independently one or more (eg 1, 2, 3 or 4) a) selected from the group consisting of halogen, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, 3-8 membered cycloalkyl, 5-8 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 Substituent substitution of a heteroaryl group;

D、E、G、J、K和L各自独立地选自C和N，并形成六元芳香环系；D, E, G, J, K and L are each independently selected from C and N, and form a six-membered aromatic ring system;

m和n各自独立地选自0、1和2，且m+n＝2；m and n are each independently selected from 0, 1, and 2, and m+n=2;

Y选自C、O、S和N，条件是，当Y＝O或S时，R6和R7不存在，当Y＝N时，R7不存在；Y is selected from C, O, S and N, provided that when Y = O or S, R 6 and R 7 are absent, and when Y = N, R 7 is absent;

R5，R6，R7和R8各自独立地选自氢、羟基、氰基、硝基、烷基、环烷基、杂环烷基、芳基、杂芳基、环烷基-烷基、杂环烷基-烷基、RO-、RC(O)-、RC(O)O-、RR’N-、RC(O)NH-和RR’NC(O)-，任选地，其中所述烷基、环烷基、杂环烷基、杂芳基、环烷基-烷基或杂环烷基-烷基各自独立地进一步被一个或多个(例如1个、2个、3个或4个)选自卤素、羟基、氰基、氨基、羧基、硝基、烷基、卤代烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、RO-、RR’N-、RO-C1-10烷基、RR’N-C1-10烷基、RS(O)a-、RR’NSO2-和RSO2NR’-的取代基取代，其中a为0、1或2；或者R 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of hydrogen, hydroxy, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyl-alkane , heterocycloalkyl-alkyl, RO-, RC(O)-, RC(O)O-, RR'N-, RC(O)NH-, and RR'NC(O)-, optionally, Wherein the alkyl group, cycloalkyl group, heterocycloalkyl group, heteroaryl group, cycloalkyl-alkyl group or heterocycloalkyl-alkyl group are each independently further one or more (for example, one, two, 3 or 4) selected from the group consisting of halogen, hydroxy, cyano, amino, carboxy, nitro, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Substituent substitution of RO-, RR'N-, RO-C 1-10 alkyl, RR'NC 1-10 alkyl, RS(O) a -, RR'NSO 2 - and RSO 2 NR'-, wherein a is 0, 1 or 2; or

R5和R6与Y原子一起形成脂环、芳环、脂杂环或杂芳环，任选地，其中所述脂环、芳环、脂杂环或杂芳环各自独立地进一步被一个或多个(例如1个、2个、3个或4个)选自卤素、羟基、烷基、氰基、RS(O)a-、RR’N-、和RO-的取代基取代，其中a为0、1或2；R 5 and R 6 together with the Y atom form an alicyclic, aromatic ring, alicyclic or heteroaryl ring, optionally wherein the alicyclic, aromatic ring, alicyclic or heteroaryl ring is each independently further Or a plurality (for example, 1, 2, 3 or 4) of substituents selected from the group consisting of halogen, hydroxy, alkyl, cyano, RS(O) a -, RR'N-, and RO-, wherein a is 0, 1 or 2;

R和R’各自独立地选自氢、羟基、C1-10烷基、3-20元环烷基、5-20元杂环烷基、6-20元芳基、5-20元杂芳基，任选地，所述C1-10烷基、3-20元环烷基、5-20元杂环烷基、6-20元芳基、5-20元杂芳基各自独立地被一个或多个(例如1个、2个、3个或4个)选自卤素、羟基、C1-4烷基、C1-4 烷氧基、3-8元环烷基、5-8元杂环基、6-10元芳基和5-10元杂芳基的取代基取代。R and R' are each independently selected from the group consisting of hydrogen, hydroxy, C 1-10 alkyl, 3-20 membered cycloalkyl, 5-20 membered heterocycloalkyl, 6-20 membered aryl, 5-20 membered heteroaryl. And optionally, the C 1-10 alkyl group, the 3-20 membered cycloalkyl group, the 5-20 membered heterocycloalkyl group, the 6-20 membered aryl group, the 5-20 membered heteroaryl group are each independently One or more (eg, 1, 2, 3 or 4) are selected from the group consisting of halogen, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, 3-8 membered cycloalkyl, 5-8 Substituent substitution of a heterocyclic group, a 6-10 membered aryl group and a 5-10 membered heteroaryl group.

在本申请的某些优选实施方案中，所述式Ia化合物的限制性条件为：In certain preferred embodiments of the present application, the limiting conditions for the compound of Formula Ia are:

当A和B与相连的原子一起形成苯环，R1、R2、R3均为氢，并且R4为氟时，所述

Figure PCTCN2016103735-appb-000005
不为如下基团：When A and B together with the attached atoms form a benzene ring, R 1 , R 2 , and R 3 are all hydrogen, and R 4 is fluorine,
Figure PCTCN2016103735-appb-000005
Not the following groups:

Figure PCTCN2016103735-appb-000006
Figure PCTCN2016103735-appb-000006

在本申请的某些优选实施方案中，所述化合物如式Iaa所示，In certain preferred embodiments of the present application, the compound is as shown in Formula Iaa,

Figure PCTCN2016103735-appb-000007
Figure PCTCN2016103735-appb-000007

其中，among them,

A和B与相连的原子一起形成脂环、脂杂环、芳环或杂芳环，任选地，其中所述脂环、脂杂环、芳环或杂芳环各自独立地被一个或多个(例如1个、2个、3个或4个)选自卤素、羟基、氨基、氰基、羧基、硝基、烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、RO-、ROC(O)-、RC(O)O-、RC(O)-、RR’N-、RC(O)NH-、RR’NC(O)-、RS(O)a-、RR’NSO2-和RSO2N(R’)-的取代基取代，其中a为0、1或2；A and B together with the attached atoms form an alicyclic, heteroalicyclic, aromatic or heteroaryl ring, optionally wherein the alicyclic, heteroalicyclic, aromatic or heteroaryl ring is independently one or more (for example, 1, 2, 3 or 4) selected from the group consisting of halogen, hydroxy, amino, cyano, carboxy, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aromatic Base, heteroaryl, RO-, ROC(O)-, RC(O)O-, RC(O)-, RR'N-, RC(O)NH-, RR'NC(O)-, RS( O) a -, RR'NSO 2 - and RSO 2 N(R')- substituent substitution, wherein a is 0, 1 or 2;

R1、R2、R3和R4各自独立地选自氢、卤素、羟基、氨基、氰基、羧基、硝基、烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、RO-、ROC(O)-、RC(O)O-、RC(O)-、RR’N-、RC(O)NH-和RR’NC(O)-，任选地，其中所述烷基、烯基、炔基、环烷基、杂环烷基、芳基或杂芳基各自独立地被一个或多个(例如1个、2个、3个或4个)选自卤素、羟基、C1-4烷基、C1-4烷氧基、3-8元环烷基、5-8元杂环烷基、6-10元芳基和5-10元杂芳基的取代基取代；R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, cyano, carboxy, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, 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, cycloalkyl, heterocycloalkyl, aryl or heteroaryl are each independently one or more (eg 1, 2, 3 or 4) a) selected from the group consisting of halogen, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, 3-8 membered cycloalkyl, 5-8 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 Substituent substitution of a heteroaryl group;

D、E、G、J、K和L各自独立地选自C和N，并形成六元芳香环系；D, E, G, J, K and L are each independently selected from C and N, and form a six-membered aromatic ring system;

Y选自C、O、S和N，条件是，当Y＝O或S时，R6和R7不存在，当Y＝N时，R7不存在；Y is selected from C, O, S and N, provided that when Y = O or S, R 6 and R 7 are absent, and when Y = N, R 7 is absent;

R5，R6，R7和R8各自独立地选自氢、羟基、氰基、硝基、烷基、环 烷基、杂环烷基、芳基、杂芳基、环烷基-烷基、杂环烷基-烷基、RO-、RC(O)-、RC(O)O-、RR’N-、RC(O)NH-和RR’NC(O)-，任选地，其中所述烷基、环烷基、杂环烷基、杂芳基环烷基-烷基或杂环烷基-烷基各自独立地进一步被一个或多个(例如1个、2个、3个或4个)选自卤素、羟基、氰基、氨基、羧基、硝基、烷基、卤代烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、RO-、RR’N-、RO-C1-10烷基、RR’N-C1-10烷基、RS(O)a-、RR’NSO2-和RSO2NR’-、的取代基取代，其中a为0、1或2；或者R 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of hydrogen, hydroxy, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyl-alkane , heterocycloalkyl-alkyl, RO-, RC(O)-, RC(O)O-, RR'N-, RC(O)NH-, and RR'NC(O)-, optionally, Wherein the alkyl group, cycloalkyl group, heterocycloalkyl group, heteroarylcycloalkyl-alkyl group or heterocycloalkyl-alkyl group are each independently further one or more (for example, 1, 2, 3) Or 4) selected from the group consisting of halogen, hydroxy, cyano, amino, carboxy, nitro, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, RO a substituent substitution of RR'N-, RO-C 1-10 alkyl, RR'NC 1-10 alkyl, RS(O) a -, RR'NSO 2 - and RSO 2 NR'-, wherein a is 0, 1 or 2; or

R5和R6与Y原子一起形成脂环、芳环、脂杂环或杂芳环，任选地，其中所述脂环、芳环、脂杂环或杂芳环各自独立地进一步被一个或多个(例如1个、2个、3个或4个)选自卤素、羟基、烷基、氰基、RS(O)a-、RR’N-、和RO-的取代基取代，其中a为0、1或2；R 5 and R 6 together with the Y atom form an alicyclic, aromatic ring, alicyclic or heteroaryl ring, optionally wherein the alicyclic, aromatic ring, alicyclic or heteroaryl ring is each independently further Or a plurality (for example, 1, 2, 3 or 4) of substituents selected from the group consisting of halogen, hydroxy, alkyl, cyano, RS(O) a -, RR'N-, and RO-, wherein a is 0, 1 or 2;

R和R’各自独立地选自氢、羟基、C1-10烷基、3-20元环烷基、5-20元杂环烷基、6-20元芳基、5-20元杂芳基，任选地，所述C1-10烷基、3-20元环烷基、5-20元杂环烷基、6-20元芳基、5-20元杂芳基各自独立地被一个或多个(例如1个、2个、3个或4个)选自卤素、羟基、C1-4烷基、C1-4烷氧基、3-8元环烷基、5-8元杂环烷基、6-10元芳基和5-10元杂芳基的取代基取代。R and R' are each independently selected from the group consisting of hydrogen, hydroxy, C 1-10 alkyl, 3-20 membered cycloalkyl, 5-20 membered heterocycloalkyl, 6-20 membered aryl, 5-20 membered heteroaryl. And optionally, the C 1-10 alkyl group, the 3-20 membered cycloalkyl group, the 5-20 membered heterocycloalkyl group, the 6-20 membered aryl group, the 5-20 membered heteroaryl group are each independently One or more (eg, 1, 2, 3 or 4) are selected from the group consisting of halogen, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, 3-8 membered cycloalkyl, 5-8 Substituent substitution of a heterocycloalkyl group, a 6-10 membered aryl group, and a 5-10 membered heteroaryl group.

在本申请的某些优选实施方案中，所述式Iaa化合物的限制性条件为：当A和B与相连的原子一起形成苯环，R1、R2、R3均为氢，并且R4为氟时，所述

Figure PCTCN2016103735-appb-000008
不为如下基团：In certain preferred embodiments of the present application, the limiting condition of the compound of Formula Iaa is that when A and B together with the attached atoms form a phenyl ring, R 1 , R 2 , R 3 are both hydrogen, and R 4 When it is fluorine, the
Figure PCTCN2016103735-appb-000008
Not the following groups:

Figure PCTCN2016103735-appb-000009
Figure PCTCN2016103735-appb-000009

在本申请的某些优选实施方案中，所述化合物如式Iaa-1所示，In certain preferred embodiments of the present application, the compound is as shown in Formula Iaa-1,

Figure PCTCN2016103735-appb-000010
Figure PCTCN2016103735-appb-000010

其中，among them,

A和B与相连的原子一起形成脂环、脂杂环、芳环或杂芳环，任选地， 其中所述脂环、脂杂环、芳环或杂芳环各自独立地被一个或多个(例如1个、2个、3个或4个)选自卤素、羟基、氨基、氰基、羧基、硝基、烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、RO-、ROC(O)-、RC(O)O-、RC(O)-、RR’N-、RC(O)NH-、RR’NC(O)-、RS(O)a-、RR’NSO2-和RNSO2N(R’)-的取代基取代，其中a为0、1或2；A and B together with the attached atoms form an alicyclic, heteroalicyclic, aromatic or heteroaryl ring, optionally wherein the alicyclic, heteroalicyclic, aromatic or heteroaryl ring is independently one or more (for example, 1, 2, 3 or 4) selected from the group consisting of halogen, hydroxy, amino, cyano, carboxy, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aromatic Base, heteroaryl, RO-, ROC(O)-, RC(O)O-, RC(O)-, RR'N-, RC(O)NH-, RR'NC(O)-, RS( O) a -, RR'NSO 2 - and RNSO 2 N(R')- substituent substitution, wherein a is 0, 1 or 2;

R1、R2、R3和R4各自独立地选自氢、卤素、羟基、氨基、氰基、羧基、硝基、烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、RO-、ROC(O)-、RC(O)O-、RC(O)-、RR’N-、RC(O)NH-和RR’NC(O)-，任选地，其中所述烷基、烯基、炔基、环烷基、杂环烷基、芳基或杂芳基各自独立地被一个或多个(例如1个、2个、3个或4个)选自卤素、羟基、C1-4烷基、C1-4烷氧基、3-8元环烷基、5-8元杂环烷基、6-10元芳基和5-10元杂芳基的取代基取代；R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, cyano, carboxy, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, 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, cycloalkyl, heterocycloalkyl, aryl or heteroaryl are each independently one or more (eg 1, 2, 3 or 4) a) selected from the group consisting of halogen, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, 3-8 membered cycloalkyl, 5-8 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 Substituent substitution of a heteroaryl group;

D、E、G、J、K和L各自独立地选自C和N，并形成六元芳香环系；D, E, G, J, K and L are each independently selected from C and N, and form a six-membered aromatic ring system;

R5、R6和R8各自独立地选自氢、烷基、环烷基、杂环烷基、芳基、杂芳基、环烷基-烷基、杂环烷基-烷基、RC(O)-、RC(O)O-、RR’N-、RC(O)NH-和RR’NC(O)-，任选地，其中所述烷基、环烷基、杂环烷基、芳基、杂芳基、环烷基-烷基或杂环烷基-烷基、各自独立地进一步被一个或多个(例如1个、2个、3个或4个)选自卤素、羟基、氰基、氨基、羧基、硝基、C1-4烷基、卤代C1-4烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、3-8元环烷基、5-8元杂环烷基、6-10元芳基、5-10元杂芳基、RR’N-、RO-C1-10烷基、RR’N-C1-10烷基、RS(O)a-、RR’NSO2-和RSO2N(R’)-的取代基取代，其中a为0、1或2；或者R 5 , R 6 and R 8 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, RC (O)-, RC(O)O-, RR'N-, RC(O)NH-, and RR'NC(O)-, optionally wherein the alkyl group, cycloalkyl group, heterocycloalkyl group , aryl, heteroaryl, cycloalkyl-alkyl or heterocycloalkyl-alkyl, each independently further one or more (eg, 1, 2, 3 or 4) selected from halogen, Hydroxy, cyano, amino, carboxyl, nitro, C 1-4 alkyl, halo C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, 3-8 membered cycloalkyl, 5-8 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, RR'N-, RO-C 1-10 alkyl, RR'NC 1 a substituent of -10 alkyl, RS(O) a -, RR'NSO 2 - and RSO 2 N(R')-, wherein a is 0, 1 or 2;

R5和R6与相连的N原子一起形成脂杂环或杂芳环，任选地，其中所述脂杂环或杂芳环各自独立地进一步被一个或多个(例如1个、2个、3个或4个)选自卤素、羟基、氰基、RS(O)a-、C1-4烷基、C1-4烷氧基和RR’N-的取代基取代，其中a为0、1或2；R 5 and R 6 together with the attached N atom form an alicyclic or heteroaryl ring, optionally wherein the alicyclic or heteroaryl ring is each independently further one or more (for example, one or two) , 3 or 4) substituent substitutions selected from the group consisting of halogen, hydroxy, cyano, RS(O) a -, C 1-4 alkyl, C 1-4 alkoxy and RR'N-, wherein a is 0, 1 or 2;

R和R’各自独立地选自氢、羟基、C1-10烷基、3-20元环烷基、5-20元杂环烷基、6-20元芳基、5-20元杂芳基，任选地，所述C1-10烷基、3-20元环烷基、5-20元杂环烷基、6-20元芳基、5-20元杂芳基各自独立地被一个或多个(例如1个、2个、3个或4个)选自卤素、羟基、C1-4烷基、C1-4烷氧基、3-8元环烷基、5-8元杂环烷基、6-10元芳基和5-10元杂芳基的取代基取代。R and R' are each independently selected from the group consisting of hydrogen, hydroxy, C 1-10 alkyl, 3-20 membered cycloalkyl, 5-20 membered heterocycloalkyl, 6-20 membered aryl, 5-20 membered heteroaryl. And optionally, the C 1-10 alkyl group, the 3-20 membered cycloalkyl group, the 5-20 membered heterocycloalkyl group, the 6-20 membered aryl group, the 5-20 membered heteroaryl group are each independently One or more (eg, 1, 2, 3 or 4) are selected from the group consisting of halogen, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, 3-8 membered cycloalkyl, 5-8 Substituent substitution of a heterocycloalkyl group, a 6-10 membered aryl group, and a 5-10 membered heteroaryl group.

在本申请的某些优选具体实施方案中，所述化合物如式Iaa-2所示， In certain preferred embodiments of the present application, the compound is as shown in Formula Iaa-2,

Figure PCTCN2016103735-appb-000011
Figure PCTCN2016103735-appb-000011

其中，among them,

A和B与相连的原子一起形成脂环、脂杂环、芳环或杂芳环，任选地，其中所述脂环、脂杂环、芳环或杂芳环各自独立地被一个或多个(例如1个、2个、3个或4个)选自卤素、羟基、氨基、氰基、羧基、硝基、烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、RO-、ROC(O)-、RC(O)O-、RC(O)-、RR’N-、RC(O)NH-、RR’NC(O)-、RS(O)a-、RR’NSO2-和RSO2N(R’)-的取代基取代，其中a为0、1或2；A and B together with the attached atoms form an alicyclic, heteroalicyclic, aromatic or heteroaryl ring, optionally wherein the alicyclic, heteroalicyclic, aromatic or heteroaryl ring is independently one or more (for example, 1, 2, 3 or 4) selected from the group consisting of halogen, hydroxy, amino, cyano, carboxy, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aromatic Base, heteroaryl, RO-, ROC(O)-, RC(O)O-, RC(O)-, RR'N-, RC(O)NH-, RR'NC(O)-, RS( O) a -, RR'NSO 2 - and RSO 2 N(R')- substituent substitution, wherein a is 0, 1 or 2;

R1、R2、R3和R4各自独立地选自氢、卤素、羟基、氨基、氰基、羧基、硝基、烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、RO-、ROC(O)-、RC(O)O-、RC(O)-、RR’N-、RC(O)NH-和RR’NC(O)-，任选地，其中所述烷基、烯基、炔基、环烷基、杂环烷基、芳基或杂芳基各自独立地被一个或多个(例如1个、2个、3个或4个)选自卤素、羟基、C1-4烷基、C1-4烷氧基、3-8元环烷基、5-8元杂环烷基、6-10元芳基和5-10元杂芳基的取代基取代；R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, cyano, carboxy, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, 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, cycloalkyl, heterocycloalkyl, aryl or heteroaryl are each independently one or more (eg 1, 2, 3 or 4) a) selected from the group consisting of halogen, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, 3-8 membered cycloalkyl, 5-8 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 Substituent substitution of a heteroaryl group;

D、E、G、J、K和L各自独立地选自C和N，并形成六元芳香环系；D, E, G, J, K and L are each independently selected from C and N, and form a six-membered aromatic ring system;

R5和R8各自独立地选自氢、烷基、环烷基、氰基、硝基、杂环烷基、芳基、杂芳基、环烷基-烷基、杂环烷基-烷基、RO-、RC(O)-、RC(O)O-、RR’N-、RC(O)NH-和RR’NC(O)-，任选地，其中所述烷基、环烷基、杂环烷基、芳基、杂芳基、环烷基-烷基或杂环烷基-烷基各自独立地进一步被一个或多个(例如1个、2个、3个或4个)选自卤素、羟基、氨基、氰基、羧基、硝基、C1-4烷基、卤代C1-4烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、3-8元环烷基、5-8元杂环烷基、6-10元芳基、5-10元杂芳基、RR’N-、RO-C1-10烷基、RR’N-C1-10烷基、RS(O)a-、RR’NSO2-和RSO2N(R’)-的取代基取代，其中，a为0、1或2；R 5 and R 8 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cyano, nitro, heterocycloalkyl, aryl, heteroaryl, cycloalkyl-alkyl, heterocycloalkyl-alkane a group, RO-, RC(O)-, RC(O)O-, RR'N-, RC(O)NH-, and RR'NC(O)-, optionally, wherein the alkyl group, naphthenic group The group, heterocycloalkyl, aryl, heteroaryl, cycloalkyl-alkyl or heterocycloalkyl-alkyl are each independently further one or more (eg 1, 2, 3 or 4) ) selected from the group consisting of halogen, hydroxy, amino, cyano, carboxy, nitro, C 1-4 alkyl, halo C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2 -4 alkynyl, 3-8 membered cycloalkyl, 5-8 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, RR'N-, RO-C 1-10 alkyl a substituent substituted with RR'NC 1-10 alkyl, RS(O) a -, RR'NSO 2 - and RSO 2 N(R')-, wherein a is 0, 1 or 2;

R和R’各自独立地选自氢、羟基、C1-10烷基、3-20元环烷基、5-20元杂环烷基、6-20元芳基、5-20元杂芳基，任选地，所述C1-10烷基、3-20元环烷基、5-20元杂环烷基、6-20元芳基、5-20元杂芳基各自独立地被一个或多个(例如1个、2个、3个或4个)选自卤素、羟基、C1-4烷基、C1-4烷氧基、3-8元环烷基、5-8元杂环烷基、6-10元芳基和5-10元杂芳基的取 代基取代。R and R' are each independently selected from the group consisting of hydrogen, hydroxy, C 1-10 alkyl, 3-20 membered cycloalkyl, 5-20 membered heterocycloalkyl, 6-20 membered aryl, 5-20 membered heteroaryl. And optionally, the C 1-10 alkyl group, the 3-20 membered cycloalkyl group, the 5-20 membered heterocycloalkyl group, the 6-20 membered aryl group, the 5-20 membered heteroaryl group are each independently One or more (eg, 1, 2, 3 or 4) are selected from the group consisting of halogen, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, 3-8 membered cycloalkyl, 5-8 Substituent substitution of a heterocycloalkyl group, a 6-10 membered aryl group, and a 5-10 membered heteroaryl group.

在本申请的某些优选实施方案中，所述式Iaa-2化合物的限制性条件为：In certain preferred embodiments of the present application, the limiting conditions for the compound of Formula Iaa-2 are:

当A和B与相连的原子一起形成苯环，R1、R2、R3均为氢，并且R4为氟时，所述

Figure PCTCN2016103735-appb-000012
不为如下基团：When A and B together with the attached atoms form a benzene ring, R 1 , R 2 , and R 3 are all hydrogen, and R 4 is fluorine,
Figure PCTCN2016103735-appb-000012
Not the following groups:

Figure PCTCN2016103735-appb-000013
Figure PCTCN2016103735-appb-000013

在本申请的某些优选实施方案中，所述化合物如式Iaa-3所示，In certain preferred embodiments of the present application, the compound is as shown in Formula Iaa-3,

Figure PCTCN2016103735-appb-000014
Figure PCTCN2016103735-appb-000014

其中，among them,

A和B与相连的原子一起形成脂环、脂杂环、芳环或杂芳环，任选地，其中所述脂环、脂杂环、芳环或杂芳环各自独立地被一个或多个(例如1个、2个、3个或4个)选自卤素、羟基、氨基、氰基、羧基、硝基、烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、RO-、ROC(O)-、RC(O)O-、RC(O)-、RR’N-、RC(O)NH-、RR’NC(O)-、RS(O)a-、RR’NSO2-和RSO2N(R’)-的取代基取代，其中，a为0、1或2；A and B together with the attached atoms form an alicyclic, heteroalicyclic, aromatic or heteroaryl ring, optionally wherein the alicyclic, heteroalicyclic, aromatic or heteroaryl ring is independently one or more (for example, 1, 2, 3 or 4) selected from the group consisting of halogen, hydroxy, amino, cyano, carboxy, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aromatic Base, heteroaryl, RO-, ROC(O)-, RC(O)O-, RC(O)-, RR'N-, RC(O)NH-, RR'NC(O)-, RS( O) a -, RR'NSO 2 - and RSO 2 N(R')- substituent substitution, wherein a is 0, 1 or 2;

R1、R2、R3和R4各自独立地选自氢、卤素、羟基、氨基、氰基、羧基、硝基、烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、RO-、ROC(O)-、RC(O)O-、RC(O)-、RR’N-、RC(O)NH-和RR’NC(O)-，任选地，其中所述烷基、烯基、炔基、环烷基、杂环烷基、芳基或杂芳基各自独立地被一个或多个(例如1个、2个、3个或4个)选自卤素、羟基、C1-4烷基、C1-4烷氧基、3-8元环烷基、5-8元杂环烷基、6-10元芳基和5-10元杂芳基的取代基取代；R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, cyano, carboxy, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, 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, cycloalkyl, heterocycloalkyl, aryl or heteroaryl are each independently one or more (eg 1, 2, 3 or 4) a) selected from the group consisting of halogen, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, 3-8 membered cycloalkyl, 5-8 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 Substituent substitution of a heteroaryl group;

D、E、G、J、K和L各自独立地选自C和N，并形成六元芳香环系；D, E, G, J, K and L are each independently selected from C and N, and form a six-membered aromatic ring system;

R5、R6、R7和R8各自独立地选自氢、羟基、氰基、硝基、烷基、环烷基、杂环烷基、芳基、杂芳基、环烷基-烷基、杂环烷基-烷基、RO-、RC(O)-、RC(O)O-、RR’N-、RC(O)NH-和RR’NC(O)-，任选地，其中所 述烷基、环烷基、杂环烷基、杂芳基环烷基-烷基或杂环烷基-烷基各自独立地进一步被一个或多个(例如1个、2个、3个或4个)选自卤素、羟基、氰基、羧基、硝基、氨基、C1-4烷基、卤代C1-4烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、3-8元环烷基、5-8元杂环烷基、6-10元芳基、5-10元杂芳基、RR’N-、RO-C1-10烷基、RR’N-C1-10烷基、RS(O)a-、RR’NSO2-和RSO2N(R’)-的取代基取代，其中，a为0、1或2；或者R 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of hydrogen, hydroxy, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyl-alkane , heterocycloalkyl-alkyl, RO-, RC(O)-, RC(O)O-, RR'N-, RC(O)NH-, and RR'NC(O)-, optionally, Wherein the alkyl group, cycloalkyl group, heterocycloalkyl group, heteroarylcycloalkyl-alkyl group or heterocycloalkyl-alkyl group are each independently further one or more (for example, 1, 2, 3) Or 4) selected from the group consisting of halogen, hydroxy, cyano, carboxy, nitro, amino, C 1-4 alkyl, halo C 1-4 alkyl, C 1-4 alkoxy, C 2-4 olefin , C 2-4 alkynyl, 3-8 membered cycloalkyl, 5-8 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, RR'N-, RO-C 1 Substituted with a substituent of -10 alkyl, RR'NC 1-10 alkyl, RS(O) a -, RR'NSO 2 - and RSO 2 N(R')-, wherein a is 0, 1 or 2; or

R5和R6与相连的C原子一起形成脂环、芳环、脂杂环或杂芳环，任选地，其中所述脂环、芳环、脂杂环或杂芳环各自独立地进一步被一个或多个(例如1个、2个、3个或4个)选自卤素、羟基、氰基、RS(O)a-、C1-4烷基、C1-4烷氧基和RR’N-的取代基取代，其中a为0、1或2；R 5 and R 6 together with the attached C atom form an alicyclic, aromatic ring, alicyclic or heteroaryl ring, optionally wherein the alicyclic, aromatic ring, alicyclic or heteroaryl ring is independently further independently One or more (for example, 1, 2, 3 or 4) are selected from the group consisting of halogen, hydroxy, cyano, RS(O) a -, C 1-4 alkyl, C 1-4 alkoxy and Substituted by a substituent of RR'N-, wherein a is 0, 1 or 2;

R和R’各自独立地选自氢、羟基、C1-10烷基、3-20元环烷基、5-20元杂环烷基、6-20元芳基、5-20元杂芳基，任选地，所述C1-10烷基、3-20元环烷基、5-20元杂环烷基、6-20元芳基、5-20元杂芳基各自独立地被一个或多个(例如1个、2个、3个或4个)选自卤素、羟基、C1-4烷基、C1-4烷氧基、3-8元环烷基、5-8元杂环烷基、6-10元芳基和5-10元杂芳基的取代基取代。R and R' are each independently selected from the group consisting of hydrogen, hydroxy, C 1-10 alkyl, 3-20 membered cycloalkyl, 5-20 membered heterocycloalkyl, 6-20 membered aryl, 5-20 membered heteroaryl. And optionally, the C 1-10 alkyl group, the 3-20 membered cycloalkyl group, the 5-20 membered heterocycloalkyl group, the 6-20 membered aryl group, the 5-20 membered heteroaryl group are each independently One or more (eg, 1, 2, 3 or 4) are selected from the group consisting of halogen, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, 3-8 membered cycloalkyl, 5-8 Substituent substitution of a heterocycloalkyl group, a 6-10 membered aryl group, and a 5-10 membered heteroaryl group.

在本申请的某些优选实施方案中，所述式Iaa-3化合物的限制性条件为：In certain preferred embodiments of the present application, the limiting conditions for the compound of Formula Iaa-3 are:

当A和B与相连的原子一起形成苯环，R1、R2、R3均为氢，并且R4为氟时，所述

Figure PCTCN2016103735-appb-000015
不为如下基团：When A and B together with the attached atoms form a benzene ring, R 1 , R 2 , and R 3 are all hydrogen, and R 4 is fluorine,
Figure PCTCN2016103735-appb-000015
Not the following groups:

Figure PCTCN2016103735-appb-000016
Figure PCTCN2016103735-appb-000016

在本申请的某些优选实施方案中，所述式I化合物中

Figure PCTCN2016103735-appb-000017
选自以下结构：In certain preferred embodiments of the present application, the compound of formula I is
Figure PCTCN2016103735-appb-000017
Selected from the following structure:

Figure PCTCN2016103735-appb-000018
Figure PCTCN2016103735-appb-000018

在本申请的某些优选实施方案中，所述式I化合物如式Iaaa所示， In certain preferred embodiments of the present application, the compound of Formula I is as shown in Formula Iaaa,

Figure PCTCN2016103735-appb-000019
Figure PCTCN2016103735-appb-000019

其中，among them,

A和B与相连的原子一起形成3-8元脂环、5-8元脂杂环、6-10元芳环或5-10元杂芳环，任选地，其中所述3-8元脂环、5-8元脂杂环、6-10元芳环或5-10元杂芳环各自独立地被一个或多个(例如1个、2个、3个或4个)选自卤素、羟基、氨基、氰基、羧基、硝基、C1-4烷基、C2-4烯基、C2-4炔基、3-8元环烷基、5-8元杂环烷基、6-10元芳基、5-10元杂芳基、RO-、ROC(O)-、RC(O)O-、RC(O)-、RR’N-、RC(O)NH-、RR’NC(O)-、RS(O)a-、RR’NSO2-和RSO2N(R’)-的取代基取代，其中，a为0、1或2；A and B together with the attached atoms form a 3-8 membered alicyclic ring, a 5-8 membered alicyclic ring, a 6-10 membered aromatic ring or a 5-10 membered heteroaryl ring, optionally wherein said 3-8 member The alicyclic ring, the 5-8 membered alicyclic ring, the 6-10 membered aromatic ring or the 5-10 membered heteroaryl ring are each independently selected from one or more (for example, 1, 2, 3 or 4) halogen. , hydroxy, amino, cyano, carboxy, nitro, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-8 membered cycloalkyl, 5-8 membered heterocycloalkyl , 6-10 membered aryl, 5-10 membered heteroaryl, RO-, ROC(O)-, RC(O)O-, RC(O)-, RR'N-, RC(O)NH-, a substituent substituted with RR'NC(O)-, RS(O) a -, RR'NSO 2 - and RSO 2 N(R')-, wherein a is 0, 1 or 2;

R1、R2、R3和R4各自独立地选自氢、卤素、羟基、氨基、氰基、羧基、硝基、C1-10烷基、C2-10烯基、C2-10炔基、3-10元环烷基、5-10元杂环烷基、6-10元芳基、5-10元杂芳基、RO-、ROC(O)-、RC(O)O-、RC(O)-、RR’N-、RC(O)NH-和RR’NC(O)-，任选地，其中所述C1-10烷基、C2-10烯基、C2-10炔基、3-10元环烷基、5-10元杂环烷基、6-10元芳基或5-10元杂芳基各自独立地被一个或多个(例如1个、2个、3个或4个)选自卤素、羟基、C1-4烷基、C1-4烷氧基、3-8元环烷基、5-8元杂环烷基、6-10元芳基和5-10元杂芳基的取代基取代；R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, cyano, carboxy, nitro, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 Alkynyl, 3-10 membered cycloalkyl, 5-10 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, RO-, ROC(O)-, RC(O)O- , RC(O)-, RR'N-, RC(O)NH-, and RR'NC(O)-, optionally, wherein said C 1-10 alkyl group, C 2-10 alkenyl group, C 2 -10 alkynyl, 3-10 membered cycloalkyl, 5-10 membered heterocycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl are each independently one or more (eg, 1, 2 , 3 or 4) selected from the group consisting of halogen, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, 3-8 membered cycloalkyl, 5-8 membered heterocycloalkyl, 6-10 Substituent substitution of an aryl group and a 5-10 membered heteroaryl group;

L和J各自独立地选自C和N；L and J are each independently selected from C and N;

Y选自C、O、S和N，条件是，当Y＝O或S时，R6和R7不存在，当Y＝N时，R7不存在；Y is selected from C, O, S and N, provided that when Y = O or S, R 6 and R 7 are absent, and when Y = N, R 7 is absent;

R5，R6，R7和R8各自独立地选自氢、羟基、氰基、硝基、C1-10烷基、3-8元环烷基、3-8元杂环烷基、6-10元芳基、5-10元杂芳基、3-8元环烷基-C1-4烷基、3-8元杂环烷基-C1-4烷基、RO-、RC(O)-、RC(O)O-、RR’N-、RC(O)NH-和RR’NC(O)-，任选地，其中所述C1-10烷基、3-8元环烷基、3-8元杂环烷基、6-10元芳基、5-10元杂芳基、3-8元环烷基-C1-4烷基或3-8元杂环烷基-C1-4烷基各自独立地进一步被一个或多个(例如1个、2个、3个或4个)选自卤素、羟基、氰基、氨基、羧基、硝基、C1-4烷基、卤代C1-4烷基、C2-4烯基、C2-4炔基、3-8元环烷基、5-8元杂环烷基、6-10元芳基、5-10元杂芳基、RO-、RR’N-、RO-C1-4烷基、RR’N-C1-4烷基、RS(O)a-、RR’NSO2-和RSO2NR’-的取代基取代，其中，a为0、1或2；或者； R 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of hydrogen, hydroxy, cyano, nitro, C 1-10 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-8 membered cycloalkyl-C 1-4 alkyl, 3-8 membered heterocycloalkyl-C 1-4 alkyl, RO-, RC (O)-, RC(O)O-, RR'N-, RC(O)NH-, and RR'NC(O)-, optionally, wherein the C 1-10 alkyl group, 3-8 members Cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-8 membered cycloalkyl-C 1-4 alkyl or 3-8 membered heterocycloalkane The base-C 1-4 alkyl groups are each independently further one or more (for example, 1, 2, 3 or 4) selected from the group consisting of halogen, hydroxy, cyano, amino, carboxy, nitro, C 1- 4- alkyl, halo C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-8 membered cycloalkyl, 5-8 membered heterocycloalkyl, 6-10 membered aryl 5-10 membered heteroaryl, RO-, RR'N-, RO-C 1-4 alkyl, RR'NC 1-4 alkyl, RS(O) a -, RR'NSO 2 - and RSO 2 Substituted by a substituent of NR'-, wherein a is 0, 1, or 2; or;

R5和R6与Y原子一起形成3-8元脂环、6-10元芳环、5-8元脂杂环或5-10元杂芳环，任选地，其中所述3-8元脂环、6-10元芳环、5-8元脂杂环或5-10元杂芳环各自独立地进一步被一个或多个(例如1个、2个、3个或4个)选自卤素、羟基、氰基、RS(O)a-、C1-4烷基、C1-4烷氧基和RR’N-的取代基取代，其中a为0、1或2；R 5 and R 6 together with the Y atom form a 3-8 membered alicyclic ring, a 6-10 membered aromatic ring, a 5-8 membered heterocyclic ring or a 5-10 membered heteroaryl ring, optionally wherein said 3-8 The alicyclic ring, the 6-10 membered aromatic ring, the 5-8 membered alicyclic ring or the 5-10 membered heteroaryl ring are each independently further selected by one or more (for example, 1, 2, 3 or 4) Substituted from a substituent of halogen, hydroxy, cyano, RS(O) a -, C 1-4 alkyl, C 1-4 alkoxy and RR 'N-, wherein a is 0, 1 or 2;

R和R’各自独立地选自氢、羟基、C1-10烷基、3-20元环烷基、5-20元杂环烷基、6-20元芳基、5-20元杂芳基，任选地，所述C1-10烷基、3-20元环烷基、5-20元杂环烷基、6-20元芳基、5-20元杂芳基各自独立地被一个或多个(例如1个、2个、3个或4个)选自卤素、羟基、C1-4烷基、C1-4烷氧基、3-8元环烷基、5-8元杂环烷基、6-10元芳基和5-10元杂芳基的取代基取代。R and R' are each independently selected from the group consisting of hydrogen, hydroxy, C 1-10 alkyl, 3-20 membered cycloalkyl, 5-20 membered heterocycloalkyl, 6-20 membered aryl, 5-20 membered heteroaryl. And optionally, the C 1-10 alkyl group, the 3-20 membered cycloalkyl group, the 5-20 membered heterocycloalkyl group, the 6-20 membered aryl group, the 5-20 membered heteroaryl group are each independently One or more (eg, 1, 2, 3 or 4) are selected from the group consisting of halogen, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, 3-8 membered cycloalkyl, 5-8 Substituent substitution of a heterocycloalkyl group, a 6-10 membered aryl group, and a 5-10 membered heteroaryl group.

在本申请的某些优选实施方案中，所述式Iaaa化合物的限制性条件为：In certain preferred embodiments of the present application, the limiting conditions for the compound of Formula Iaaa are:

当A和B与相连的原子一起形成苯环，R1、R2、R3均为氢，并且R4为氟时，所述

Figure PCTCN2016103735-appb-000020
不为如下基团：When A and B together with the attached atoms form a benzene ring, R 1 , R 2 , and R 3 are all hydrogen, and R 4 is fluorine,
Figure PCTCN2016103735-appb-000020
Not the following groups:

Figure PCTCN2016103735-appb-000021
Figure PCTCN2016103735-appb-000021

在本申请的某些优选实施方案中，所述式I、Ia、Iaa或Iaaa中的Y为N。In certain preferred embodiments of the present application, Y in Formula I, Ia, Iaa or Iaaa is N.

在本申请的某些优选实施方案中，所述R5、R6、R7和R8各自独立地选自氢、羟基、氰基、硝基、C1-6烷基、C1-6烷氧基、C1-6烷基酰基、3-8元环烷基、3-8元杂环烷基、6-10元芳基(例如苯基、萘基)、5-10元杂芳基、3-8元环烷基-C1-4烷基、3-8元杂环烷基-C1-4烷基，任选地，其中所述C1-6烷基、C1-6烷氧基、C1-6烷基酰基、3-8元环烷基、3-8元杂环烷基、6-10元芳基、5-10元杂芳基、3-8元环烷基-C1-4烷基或3-8元杂环烷基-C1-4烷基各自独立地进一步被一个或多个(例如1个、2个、3个或4个)选自卤素(例如氟)、羟基、C1-4烷基、卤代C1-4烷基、C1-4烷氧基、3-8元环烷基、3-8元杂环烷基、6-10元芳基、5-10元杂芳基、RR’N-、RO-C1-4烷基、RR’N-C1-4烷基、RR’NSO2-和RSO2-的取代基取代；或者In certain preferred embodiments of the present application, said R 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of hydrogen, hydroxy, cyano, nitro, C 1-6 alkyl, C 1-6 Alkoxy, C 1-6 alkyl acyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl (eg phenyl, naphthyl), 5-10 membered heteroaryl a 3-8 membered cycloalkyl-C 1-4 alkyl group, a 3-8 membered heterocycloalkyl-C 1-4 alkyl group, optionally wherein the C 1-6 alkyl group, C 1- 6 alkoxy, C 1-6 alkyl acyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-8 membered ring The alkyl-C 1-4 alkyl group or the 3-8 membered heterocycloalkyl-C 1-4 alkyl group is each independently further selected from one or more (for example, 1, 2, 3 or 4) Halogen (for example, fluorine), hydroxyl group, C 1-4 alkyl group, halogenated C 1-4 alkyl group, C 1-4 alkoxy group, 3-8 membered cycloalkyl group, 3-8 membered heterocycloalkyl group, 6 -10-membered aryl, 5-10 membered heteroaryl, RR'N-, RO-C 1-4 alkyl, RR'NC 1-4 alkyl, RR'NSO 2 - and RSO 2 - substituent substitution ;or

R5和R6与相连的Y原子一起形成3-8元脂环、3-8元脂杂环、6-10元芳环或5-10元杂芳环，任选地，其中所述3-8元脂环、3-8元脂杂环、6-10元芳环或5-10元杂芳环各自独立地进一步被一个或多个(例如1个、2个、3个或4个)选自卤素、羟基、氰基、RS(O)a-、C1-4烷基和C1-4烷氧基的 取代基取代，其中a为0、1或2；R 5 and R 6 together with the attached Y atom form a 3-8 membered alicyclic ring, a 3-8 membered alicyclic ring, a 6-10 membered aromatic ring or a 5-10 membered heteroaryl ring, optionally wherein said 3 The -8 membered alicyclic ring, the 3-8 membered alicyclic ring, the 6-10 membered aromatic ring or the 5-10 membered heteroaryl ring are each independently further one or more (for example, 1, 2, 3 or 4) a substituent substitution selected from the group consisting of halogen, hydroxy, cyano, RS(O) a -, C 1-4 alkyl and C 1-4 alkoxy, wherein a is 0, 1 or 2;

其中R和R’各自独立地选自氢和C1-4烷基。Wherein R and R' are each independently selected from the group consisting of hydrogen and C 1-4 alkyl.

在本申请的某些优选实施方案中，所述R5、R6、R7和R8各自独立地选自氢、甲基、乙基、环丙基甲基、氧代环丁基甲基、四氢呋喃基甲基、甲氧基乙基、2-乙氧基乙基、2-羟基乙基、三氟乙基、二氟乙基、氟乙基、N,N-二甲氨基乙基、(R)-1-甲氧基-2-丙基、(S)-1-甲氧基-2-丙基、(R)-2-甲氧基丙基、(S)-2-甲氧基丙基、甲磺酰基乙基、二甲氨基磺酰基乙基、2-羟基-异丁基、环丙基、1-甲基环丙基、1-甲氧甲基环丙基、2,2-二甲基环丙基、1-三氟甲基环丙基、(R)-2-氟环丙基、(S)-2-氟环丙基、2,2-二氟环丙基、氧代环丁基、4-羟基环己基、4,4-二氟环己基、四氢吡喃基、2,2-二甲基四氢吡喃基、4-甲基-四氢吡喃基、N-甲基哌啶基、N,N-二甲氨基哌啶基、N-甲基哌嗪基、哌啶基、N-甲基吡唑基和3-氧代-双环[3.1.0]己基；或者，In certain preferred embodiments of the present application, said R 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of hydrogen, methyl, ethyl, cyclopropylmethyl, oxocyclobutylmethyl, tetrahydrofuran. Methyl, methoxyethyl, 2-ethoxyethyl, 2-hydroxyethyl, trifluoroethyl, difluoroethyl, fluoroethyl, N,N-dimethylaminoethyl, (R )-1-methoxy-2-propyl, (S)-1-methoxy-2-propyl, (R)-2-methoxypropyl, (S)-2-methoxypropane , methanesulfonylethyl, dimethylaminosulfonylethyl, 2-hydroxy-isobutyl, cyclopropyl, 1-methylcyclopropyl, 1-methoxymethylcyclopropyl, 2,2- Dimethylcyclopropyl, 1-trifluoromethylcyclopropyl, (R)-2-fluorocyclopropyl, (S)-2-fluorocyclopropyl, 2,2-difluorocyclopropyl, oxygen Cyclobutyl, 4-hydroxycyclohexyl, 4,4-difluorocyclohexyl, tetrahydropyranyl, 2,2-dimethyltetrahydropyranyl, 4-methyl-tetrahydropyranyl, N-methylpiperidinyl, N,N-dimethylaminopiperidinyl, N-methylpiperazinyl, piperidinyl, N-methylpyrazolyl and 3-oxo-bicyclo[3.1.0]己基; or,

R5和R6与相连的Y原子一起形成四氢呋喃环、哌啶环或哌嗪环。R 5 and R 6 together with the attached Y atom form a tetrahydrofuran ring, a piperidine ring or a piperazine ring.

在本申请的某些优选实施方案中，A和B与相连的原子一起形成芳环。In certain preferred embodiments of the present application, A and B together with the attached atoms form an aromatic ring.

在本申请的某些优选实施方案中，A和B与相连的原子一起形成6-14元芳环，其中，所述6-14元芳环未被取代或被一个或两个选自卤素、羟基、氨基、氰基、羧基、硝基和C1-10烷基的取代基取代。In certain preferred embodiments of the present application, A and B together with the attached atoms form a 6-14 membered aromatic ring wherein the 6-14 membered aromatic ring is unsubstituted or one or two selected from halogen, The substituents of the hydroxy group, the amino group, the cyano group, the carboxyl group, the nitro group and the C 1-10 alkyl group are substituted.

在本申请的某些优选实施方案中，A和B与相连的原子一起形成未取代的苯环。In certain preferred embodiments of the present application, A and B together with the attached atoms form an unsubstituted benzene ring.

在本申请的某些优选实施方案中，A和B与相连的原子一起形成苯环，其中，所述苯环被一个或两个选自卤素的取代基取代。In certain preferred embodiments of the present application, A and B together with the attached atoms form a phenyl ring wherein the phenyl ring is substituted with one or two substituents selected from halogen.

在本申请的某些优选实施方案中，A和B与相连的原子一起形成苯环，其中，所述苯环被一个氟取代。In certain preferred embodiments of the present application, A and B together with the attached atoms form a phenyl ring wherein the phenyl ring is substituted with one fluoro.

在本申请的某些优选实施方案中，R1、R2和R3为氢。In certain preferred embodiments of the present application, R 1 , R 2 and R 3 are hydrogen.

在本申请的某些优选实施方案中，R4为卤素。In certain preferred embodiments of the present application, R 4 is halogen.

在本申请的某些优选实施方案中，R4为氟。In certain preferred embodiments of the present application, R 4 is fluoro.

在本申请的某些优选实施方案中，R5选自羟基、氰基、硝基、烷基、环烷基、杂环烷基、芳基、杂芳基、环烷基-烷基、杂环烷基-烷基、RO-、RC(O)-、RC(O)O-、RR’N-、RC(O)NH-和RR’NC(O)-，任选地，其中所述烷基、环烷基、杂环烷基、杂芳基、环烷基-烷基或杂环烷基-烷基各自独立地进一步被一个或多个(例如1个、2个、3个或4个)选自卤素、羟基、氰基、氨基、羧基、硝基、烷基、卤代烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、RO-、RR’N-、RO-C1-10烷基、RR’N-C1-10烷基、RS(O)a-、RR’NSO2-和RSO2N(R’)-的取代基取代，其中a为0、1或2；In certain preferred embodiments of the present application, R 5 is selected from the group consisting of hydroxyl, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyl-alkyl, hetero a cycloalkyl-alkyl group, RO-, RC(O)-, RC(O)O-, RR'N-, RC(O)NH-, and RR'NC(O)-, optionally wherein said Alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, cycloalkyl-alkyl or heterocycloalkyl-alkyl are each independently further one or more (eg, 1, 2, 3 or 4) selected from the group consisting of halogen, hydroxy, cyano, amino, carboxyl, nitro, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, RO-, Substituent substitution of RR'N-, RO-C 1-10 alkyl, RR'NC 1-10 alkyl, RS(O) a -, RR'NSO 2 - and RSO 2 N(R')-, wherein a is 0, 1 or 2;

R和R’各自独立地选自氢、羟基、C1-10烷基、3-20元环烷基、5-20元杂 环烷基、6-20元芳基、5-20元杂芳基，任选地，所述C1-10烷基、3-20元环烷基、5-20元杂环烷基、6-20元芳基、5-20元杂芳基各自独立地被一个或多个(例如1个、2个、3个或4个)选自卤素、羟基、C1-4烷基、C1-4烷氧基、3-8元环烷基、5-8元杂环烷基、6-10元芳基和5-10元杂芳基的取代基取代。R and R' are each independently selected from the group consisting of hydrogen, hydroxy, C 1-10 alkyl, 3-20 membered cycloalkyl, 5-20 membered heterocycloalkyl, 6-20 membered aryl, 5-20 membered heteroaryl. And optionally, the C 1-10 alkyl group, the 3-20 membered cycloalkyl group, the 5-20 membered heterocycloalkyl group, the 6-20 membered aryl group, the 5-20 membered heteroaryl group are each independently One or more (eg, 1, 2, 3 or 4) are selected from the group consisting of halogen, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, 3-8 membered cycloalkyl, 5-8 Substituent substitution of a heterocycloalkyl group, a 6-10 membered aryl group, and a 5-10 membered heteroaryl group.

在本申请的某些优选实施方案中，R5选自羟基、氰基、硝基、C1-10烷基、3-20元环烷基、3-20元杂环烷基、6-20元芳基、5-20元杂芳基、3-20元环烷基-C1-10烷基、3-20元杂环烷基-C1-10烷基、RO-、RC(O)-、RC(O)O-、RR’N-、RC(O)NH-和RR’NC(O)-；任选地，其中所述C1-10烷基、3-20元环烷基、3-20元杂环烷基、6-20元芳基、5-20元杂芳基、3-20元环烷基-C1-10烷基和3-20元杂环烷基-C1-10烷基各自独立地被一个或多个(例如1个、2个、3个或4个)选自卤素、羟基、氰基、氨基、羧基、硝基、C1-10烷基、卤代C1-10烷基、C2-10烯基、C2-10炔基、3-20元环烷基、3-20元杂环烷基、6-20元芳基、5-20元杂芳基、RO-、RR’N-、RO-C1-10烷基、RR’N-C1-10烷基、RSO2-和RR’NSO2-的取代基取代；In certain preferred embodiments of the present application, R 5 is selected from the group consisting of hydroxy, cyano, nitro, C 1-10 alkyl, 3-20 membered cycloalkyl, 3-20 membered heterocycloalkyl, 6-20 Aroaryl, 5-20 membered heteroaryl, 3-20 membered cycloalkyl-C 1-10 alkyl, 3-20 membered heterocycloalkyl-C 1-10 alkyl, RO-, RC(O) -, RC(O)O-, RR'N-, RC(O)NH- and RR'NC(O)-; optionally wherein the C 1-10 alkyl group, 3-20 membered cycloalkyl group 3-20 membered heterocycloalkyl, 6-20 membered aryl, 5-20 membered heteroaryl, 3-20 membered cycloalkyl-C 1-10 alkyl group and 3-20 membered heterocycloalkyl-C The 1-10 alkyl groups are each independently selected from one or more (for example, 1, 2, 3 or 4) selected from the group consisting of halogen, hydroxy, cyano, amino, carboxy, nitro, C 1-10 alkyl, Halogen C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, 3-20 membered cycloalkyl, 3-20 membered heterocycloalkyl, 6-20 membered aryl, 5-20 Substituent substitution of a heteroaryl group, RO-, RR'N-, RO-C 1-10 alkyl, RR'NC 1-10 alkyl, RSO 2 - and RR'NSO 2 -;

R和R’各自独立地选自氢和C1-10烷基；任选地，其中所述C1-10烷基被一个或多个(例如1个、2个、3个或4个)选自卤素、羟基、C1-4烷基和C1-4烷氧基的取代基取代。R and R' are each independently selected from hydrogen and C 1-10 alkyl; optionally wherein the C 1-10 alkyl is one or more (eg, 1, 2, 3 or 4) Substituent substitutions selected from the group consisting of halogen, hydroxy, C 1-4 alkyl and C 1-4 alkoxy.

在本申请的某些优选实施方案中，R5选自羟基、氰基、硝基、C1-6烷基、3-12元环烷基、3-8元杂环烷基、6-14元芳基、5-10元杂芳基、3-12元环烷基-C1-6烷基和3-8元杂环烷基-C1-6烷基；任选地，其中所述C1-6烷基、3-12元环烷基、3-8元杂环烷基、6-14元杂芳基、5-10元杂芳基、3-12元环烷基-C1-6烷基和3-8元杂环烷基-C1-6烷基各自独立地被一个或多个(例如1个、2个、3个或4个)选自卤素、羟基、氰基、氨基、羧基、硝基、C1-6烷基、卤代C1-6烷基、RO-、RR’N-、RO-C1-6烷基、RR’N-C1-6烷基、RSO2-和RR’NSO2-的取代基取代；In certain preferred embodiments of the present application, R 5 is selected from the group consisting of hydroxy, cyano, nitro, C 1-6 alkyl, 3-12 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-14 a aryl group, a 5-10 membered heteroaryl group, a 3-12 membered cycloalkyl-C 1-6 alkyl group and a 3-8 membered heterocycloalkyl-C 1-6 alkyl group; optionally wherein said C 1-6 alkyl, 3-12 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-14 membered heteroaryl, 5-10 membered heteroaryl, 3-12 membered cycloalkyl-C 1 The -6 alkyl group and the 3-8 membered heterocycloalkyl-C 1-6 alkyl group are each independently selected from one or more (for example, 1, 2, 3 or 4) selected from the group consisting of halogen, hydroxy, and cyano. , amino, carboxyl, nitro, C 1-6 alkyl, halo C 1-6 alkyl, RO-, RR'N-, RO-C 1-6 alkyl, RR'NC 1-6 alkyl, Substituted by RSO 2 - and RR'NSO 2 -;

R和R’各自独立地选自氢、C1-6烷基和卤代C1-6烷基。R and R' are each independently selected from the group consisting of hydrogen, C 1-6 alkyl and halo C 1-6 alkyl.

在本申请的某些优选实施方案中，R5选自羟基、C1-4烷基、3-8元环烷基、3-8元杂环烷基、5-6元杂芳基、3-8元环烷基-C1-4烷基和3-8元杂环烷基-C1-4烷基；任选地，其中所述C1-4烷基、3-8元环烷基、3-8元杂环烷基、5-6元杂芳基、3-8元环烷基-C1-4烷基和3-8元杂环烷基-C1-4烷基各自独立地被一个或多个(例如1个、2个、3个或4个)选自卤素、羟基、氰基、氨基、羧基、硝基、C1-4烷基、卤代C1-4烷基、RO-、RR’N-、RO-C1-4烷基、RR’N-C1-4烷基、RSO2-和RR’NSO2-的取代基取代；In certain preferred embodiments of the present application, R 5 is selected from the group consisting of hydroxyl, C 1-4 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 5-6 membered heteroaryl, 3 -8 membered cycloalkyl-C 1-4 alkyl and 3-8 membered heterocycloalkyl-C 1-4 alkyl; optionally wherein said C 1-4 alkyl, 3-8 membered cycloalkane a 3-8 membered heterocycloalkyl group, a 5-6 membered heteroaryl group, a 3-8 membered cycloalkyl-C 1-4 alkyl group and a 3-8 membered heterocycloalkyl-C 1-4 alkyl group Independently one or more (e.g., 1, 2, 3 or 4) selected from the group consisting of halogen, hydroxy, cyano, amino, carboxy, nitro, C 1-4 alkyl, halo C 1-4 Substituent substitution of alkyl, RO-, RR'N-, RO-C 1-4 alkyl, RR'NC 1-4 alkyl, RSO 2 - and RR'NSO 2 -;

R和R’各自独立地选自氢、C1-4烷基和卤代C1-4烷基。R and R' are each independently selected from the group consisting of hydrogen, C 1-4 alkyl and halo C 1-4 alkyl.

在本申请的某些优选实施方案中，R5选自羟基、甲基、乙基、环丙基 甲基、氧代环丁基甲基、四氢呋喃基甲基、甲氧基甲基、甲氧基乙基、2-乙氧基乙基、2-羟基乙基、三氟乙基、二氟乙基、氟乙基、三氟甲氧基乙基、N,N-二甲氨基乙基、(R)-1-甲氧基-2-丙基、(S)-1-甲氧基-2-丙基、(R)-2-甲氧基丙基、(S)-2-甲氧基丙基、甲磺酰基乙基、二甲氨基磺酰基乙基、2-羟基-异丁基、环丙基、1-甲基环丙基、(R)-2-甲基环丙基、(S)-2-甲基环丙基、1-甲氧甲基环丙基、2,2-二甲基环丙基、1-三氟甲基环丙基、(R)-2-氟环丙基、(S)-2-氟环丙基、2,2-二氟环丙基、环丁基、氧代环丁基、四氢呋喃基、4-羟基环己基、4,4-二氟环己基、4-甲氧基环己基、四氢吡喃基、2,2-二甲基四氢吡喃基、4-甲基-四氢吡喃基、N-甲基哌啶基、N,N-二甲氨基哌啶基、N-甲基哌嗪基、哌啶基、N-甲基吡唑基、2-二甲氨基甲基-1,3-二氧六环基、5-二甲氨基甲基-1,3-二氧六环基和3-氧代-双环[3.1.0]己基。In certain preferred embodiments of the present application, R 5 is selected from the group consisting of hydroxyl, methyl, ethyl, cyclopropylmethyl, oxocyclobutylmethyl, tetrahydrofuranylmethyl, methoxymethyl, methoxyB. , 2-ethoxyethyl, 2-hydroxyethyl, trifluoroethyl, difluoroethyl, fluoroethyl, trifluoromethoxyethyl, N,N-dimethylaminoethyl, (R )-1-methoxy-2-propyl, (S)-1-methoxy-2-propyl, (R)-2-methoxypropyl, (S)-2-methoxypropane , methanesulfonylethyl, dimethylaminosulfonylethyl, 2-hydroxy-isobutyl, cyclopropyl, 1-methylcyclopropyl, (R)-2-methylcyclopropyl, (S -2-methylcyclopropyl, 1-methoxymethylcyclopropyl, 2,2-dimethylcyclopropyl, 1-trifluoromethylcyclopropyl, (R)-2-fluorocyclopropyl , (S)-2-fluorocyclopropyl, 2,2-difluorocyclopropyl, cyclobutyl, oxocyclobutyl, tetrahydrofuranyl, 4-hydroxycyclohexyl, 4,4-difluorocyclohexyl , 4-methoxycyclohexyl, tetrahydropyranyl, 2,2-dimethyltetrahydropyranyl, 4-methyl-tetrahydropyranyl, N-methylpiperidinyl, N,N -dimethylaminopiperidinyl, N-methylpiperazinyl, piperidinyl, N-methylpyrazolyl, 2- Methylamino-1,3-dioxane-yl, 5-dimethylamino-1,3-dioxane and 3-oxo - bicyclo [3.1.0] hexyl.

在本申请的某些优选实施方案中，R5选自C1-4烷基、3-8元环烷基、3-8元杂环烷基、5-6元杂芳基、3-8元环烷基-C1-4烷基、任选地，所述C1-4烷基、3-8元环烷基和5-6元杂芳基被选自羟基、RO-和RR’N-的取代基取代；In certain preferred embodiments of the present application, R 5 is selected from the group consisting of C 1-4 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 5-6 membered heteroaryl, 3-8 a monocycloalkyl-C 1-4 alkyl group, optionally, the C 1-4 alkyl group, a 3-8 membered cycloalkyl group and a 5-6 membered heteroaryl group are selected from the group consisting of a hydroxyl group, an RO- and an RR' Substituent substitution of N-;

R和R’各自独立地选自C1-4烷基。R and R' are each independently selected from C 1-4 alkyl.

在本申请的某些优选实施方案中，R5选自乙基、2-羟基乙基、二甲氨基乙基、甲氧基乙基、环丙基、1-甲基环丙基、4-羟基环己基、环丙基甲基、氧代环丁基、四氢呋喃基、四氢吡喃基和N-甲基吡唑基。In certain preferred embodiments of the present application, R 5 is selected from the group consisting of ethyl, 2-hydroxyethyl, dimethylaminoethyl, methoxyethyl, cyclopropyl, 1-methylcyclopropyl, 4- Hydroxycyclohexyl, cyclopropylmethyl, oxocyclobutyl, tetrahydrofuranyl, tetrahydropyranyl and N-methylpyrazolyl.

在本申请的某些优选实施方案中，R6选自氢和C1-10烷基。In certain preferred embodiments of the present application, R 6 is selected from the group consisting of hydrogen and C 1-10 alkyl.

在本申请的某些优选实施方案中，R6为氢。In certain preferred embodiments of the present disclosure, R 6 is hydrogen.

在本申请的某些优选实施方案中，R6选自C1-6烷基。In certain preferred embodiments of the present application, R 6 is selected from C 1-6 alkyl.

在本申请的某些优选实施方案中，R6选自C1-4烷基。In certain preferred embodiments of the present application, R 6 is selected from C 1-4 alkyl.

在本申请的某些优选实施方案中，R6为甲基。In certain preferred embodiments of the present application, R 6 is methyl.

在本申请的某些优选实施方案中，R5和R6与Y原子一起形成3-20元脂杂环，任选地，所述3-20元脂杂环被一个或多个(例如1个、2个、3个或4个)选自卤素、羟基、氰基、C1-10烷基、RR’N-和RO-的取代基取代；In certain preferred embodiments of the present application, R 5 and R 6 together with the Y atom form a 3-20 membered heteroalicyclic ring, optionally, the 3-20 membered heterocyclic ring is one or more (eg, 1 , 2, 3 or 4) substituents selected from the group consisting of halogen, hydroxy, cyano, C 1-10 alkyl, RR'N- and RO-;

R和R’各自独立地选自氢和C1-10烷基；R and R' are each independently selected from the group consisting of hydrogen and C 1-10 alkyl;

Y为C或N。Y is C or N.

在本申请的某些优选实施方案中，R5和R6与Y原子一起形成5-8元脂杂环，任选地，所述5-8元脂杂环被一个或多个(例如1个、2个、3个或4个)选自卤素、羟基、氰基、C1-6烷基、RR’N-和RO-的取代基取代；In certain preferred embodiments of the present application, R 5 and R 6 together with the Y atom form a 5-8 membered heterocyclic ring, optionally, the 5-8 membered heterocyclic ring is one or more (eg, 1 , 2, 3 or 4) substituents selected from the group consisting of halogen, hydroxy, cyano, C 1-6 alkyl, RR'N- and RO-;

R和R’各自独立地选自氢和C1-6烷基；R and R' are each independently selected from hydrogen and C 1-6 alkyl;

Y为C或N。 Y is C or N.

在本申请的某些优选实施方案中，R5和R6与Y原子一起形成6元脂杂环，任选地，所述6元脂杂环被一个或多个(例如1个、2个、3个或4个)选自卤素、羟基、氰基、C1-4烷基、RR’N-和RO-的取代基取代；In certain preferred embodiments of the present application, R 5 and R 6 together with the Y atom form a 6-membered heteroalicyclic ring, optionally, the 6-membered heterocyclic heterocyclic ring is one or more (eg, 1 or 2 , 3 or 4) substituents selected from the group consisting of halogen, hydroxy, cyano, C 1-4 alkyl, RR'N- and RO-;

R和R’各自独立地选自氢和C1-4烷基；R and R' are each independently selected from hydrogen and C 1-4 alkyl;

Y为N。Y is N.

在本申请的某些优选实施方案中，R5和R6与Y原子一起形成哌啶环或哌嗪环，任选地，所述哌啶环或哌嗪环被一个或两个选自C1-4烷基和RR’N-的取代基取代；In certain preferred embodiments of the present application, R 5 and R 6 together with the Y atom form a piperidine ring or a piperazine ring, optionally, the piperidine ring or piperazine ring is selected from one or two selected from C. a substituent of 1-4 alkyl and RR'N-;

R和R’各自独立地选自氢和C1-4烷基；R and R' are each independently selected from hydrogen and C 1-4 alkyl;

Y为N。Y is N.

在本申请的某些优选实施方案中，R5和R6与Y原子一起形成哌啶环和哌嗪环，任选地，所述哌啶环或哌嗪环被一个甲基或二甲胺基取代；In certain preferred embodiments of the present application, R 5 and R 6 together with the Y atom form a piperidine ring and a piperazine ring, optionally, the piperidine ring or piperazine ring is a methyl or dimethylamine. Base substitution

Y为N。Y is N.

在本申请的某些优选实施方案中，R5和R6与Y原子一起形成5-6元脂杂环，任选地，所述5-6元脂杂环被一个或多个(例如1个、2个、3个或4个)选自卤素、羟基、氰基、C1-4烷基、RR’N-和RO-的取代基取代；In certain preferred embodiments of the present application, R 5 and R 6 together with the Y atom form a 5-6 membered heterocyclic ring, optionally, the 5-6 membered heterocyclic ring is one or more (eg, 1 , 2, 3 or 4) substituents selected from the group consisting of halogen, hydroxy, cyano, C 1-4 alkyl, RR'N- and RO-;

R和R’各自独立地选自氢和C1-4烷基；R and R' are each independently selected from hydrogen and C 1-4 alkyl;

Y为C。Y is C.

在本申请的某些优选实施方案中，R5和R6与Y原子一起形成四氢呋喃环或哌啶环，任选地，所述四氢呋喃环或哌啶环被一个或两个选自C1-4烷基的取代基取代；In certain preferred embodiments of the present application, R 5 and R 6 together with the Y atom form a tetrahydrofuran ring or a piperidine ring, and optionally, the tetrahydrofuran ring or piperidine ring is selected from one or two selected from C 1- Substituted with a 4- alkyl substituent;

Y为C。Y is C.

在本申请的某些优选实施方案中，R5和R6与Y原子一起形成四氢呋喃环或哌啶环，任选地，所述哌啶环被一个甲基取代；In certain preferred embodiments of the present application, R 5 and R 6 together with the Y atom form a tetrahydrofuran ring or a piperidine ring, optionally, the piperidine ring is substituted with a methyl group;

Y为C。Y is C.

在本申请的某些优选实施方案中，R7为氢。In certain preferred embodiments of the present application, R 7 is hydrogen.

在本申请的某些优选实施方案中，R8选自氢、卤素、羟基、氰基、硝基、C1-10烷基，任选地，其中所述C1-10烷基被一个或多个(例如1个、2个、3个或4个)选自卤素、羟基、氰基、氨基、羧基和硝基的取代基取代。In certain preferred embodiments of the present application, R 8 is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, C 1-10 alkyl, optionally wherein said C 1-10 alkyl is taken by one or A plurality (for example, 1, 2, 3 or 4) of substituents selected from the group consisting of halogen, hydroxy, cyano, amino, carboxyl and nitro are substituted.

在本申请的某些优选实施方案中，R8选自氢、羟基、C1-6烷基和卤代C1-6烷基。In certain preferred embodiments of the present application, R 8 is selected from the group consisting of hydrogen, hydroxy, C 1-6 alkyl, and halo C 1-6 alkyl.

在本申请的某些优选实施方案中，R8选自氢、羟基、C1-4烷基和卤代C1-4烷基。In certain preferred embodiments of the present application, R 8 is selected from the group consisting of hydrogen, hydroxy, C 1-4 alkyl, and halo C 1-4 alkyl.

在本申请的某些优选实施方案中，R8选自氢、羟基、甲基和三氟甲基。 In certain preferred embodiments of the present application, R 8 is selected from the group consisting of hydrogen, hydroxy, methyl, and trifluoromethyl.

在本申请的某些优选实施方案中，In certain preferred embodiments of the present application,

A和B与相连的原子一起形成苯环；A and B together with the attached atoms form a benzene ring;

R1、R2和R3为氢；且，R 1 , R 2 and R 3 are hydrogen;

R4为为氟。R 4 is fluorine.

在本申请的某些优选实施方案中，In certain preferred embodiments of the present application,

A和B与相连的原子一起形成苯环，其中，所述苯环被一个氟取代；A and B together with the attached atoms form a benzene ring, wherein the benzene ring is substituted by a fluorine;

R1、R2和R3为氢；且，R 1 , R 2 and R 3 are hydrogen;

R4为氟。R 4 is fluorine.

在本申请的某些优选实施方案中，In certain preferred embodiments of the present application,

A和B与相连的原子一起形成苯环；A and B together with the attached atoms form a benzene ring;

R1、R2和R3为氢；且，R 1 , R 2 and R 3 are hydrogen;

R4为为氟；R 4 is fluorine;

Y为氮原子。Y is a nitrogen atom.

在本申请的某些优选实施方案中，所述化合物具有式Iaa-1所示结构，其中，In certain preferred embodiments of the present application, the compound has the structure of Formula Iaa-1, wherein

A和B与相连的原子一起形成苯环；A and B together with the attached atoms form a benzene ring;

R1、R2和R3均为氢；R 1 , R 2 and R 3 are all hydrogen;

R4为氟；R 4 is fluorine;

D、E、G和K均为C；D, E, G and K are all C;

L和J为N；L and J are N;

R5选自C1-4烷基、3-8元环烷基、3-8元杂环烷基、5-6元杂芳基、3-8元环烷基-C1-4烷基、任选地，所述C1-4烷基、3-8元环烷基和5-6元杂芳基被选自羟基、RO-和RR’N-的取代基取代；其中，R和R’各自独立地选自C1-4烷基；R 5 is selected from C 1-4 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 5-6 membered heteroaryl, 3-8 membered cycloalkyl-C 1-4 alkyl Optionally, the C 1-4 alkyl group, the 3-8 membered cycloalkyl group and the 5-6 membered heteroaryl group are substituted with a substituent selected from the group consisting of a hydroxyl group, RO- and RR'N-; wherein R and R' is each independently selected from C 1-4 alkyl;

R6为氢；R 6 is hydrogen;

R8选自氢和C1-4烷基。R 8 is selected from the group consisting of hydrogen and C 1-4 alkyl.

在本申请的某些优选实施方案中，所述化合物具有式Iaa-1所示结构，其中，In certain preferred embodiments of the present application, the compound has the structure of Formula Iaa-1, wherein

A和B与相连的原子一起形成苯环；A and B together with the attached atoms form a benzene ring;

R1、R2和R3均为氢；R 1 , R 2 and R 3 are all hydrogen;

R4为氟；R 4 is fluorine;

D、E、G和K均为C；D, E, G and K are all C;

L和J为N；L and J are N;

R5选自乙基、2-羟基乙基、二甲氨基乙基、甲氧基乙基、环丙基、1-甲基环丙基、4-羟基环己基、环丙基甲基、氧代环丁基、四氢呋喃基、四 氢吡喃基和N-甲基吡唑基；R 5 is selected from the group consisting of ethyl, 2-hydroxyethyl, dimethylaminoethyl, methoxyethyl, cyclopropyl, 1-methylcyclopropyl, 4-hydroxycyclohexyl, cyclopropylmethyl, oxygen Cyclobutyl, tetrahydrofuranyl, tetrahydropyranyl and N-methylpyrazolyl;

R6为氢；R 6 is hydrogen;

R8选自氢和甲基。R 8 is selected from the group consisting of hydrogen and methyl.

在本申请的某些优选实施方案中，本申请所述的氢为氕(H)或氘(D)。In certain preferred embodiments of the present application, the hydrogen described herein is hydrazine (H) or hydrazine (D).

根据本申请第一方面所述的化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型，其中所述化合物选自：A compound, a prodrug, a metabolite form, a pharmaceutically acceptable salt or ester thereof, or an isomer, hydrate, solvate or crystalline form thereof, according to the first aspect of the present application, wherein the compound From:

4-[3-(2-乙胺基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基)-4-氟苄基]-2H-酞嗪-1-酮；4-[3-(2-Ethylamino-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one ;

4-[3-(2-环丙基氨基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基)-4-氟苄基]-2H-酞嗪-1-酮；4-[3-(2-cyclopropylamino-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl)-4-fluorobenzyl]-2H-pyridazine-1- ketone;

4-[3-(2-环丙基甲基氨基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基)-4-氟苄基]-2H-酞嗪-1-酮；4-[3-(2-Cyclopropylmethylamino-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl)-4-fluorobenzyl]-2H-pyridazine- 1-ketone;

4-{4-氟-3-[2-(2-羟乙基氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-(2-hydroxyethylamino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl}-2H-indole Pyrazin-1-one;

4-{3-[2-(2-二甲基氨基乙氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]-4-氟苄基}-2H-酞嗪-1-酮；4-{3-[2-(2-Dimethylaminoethylamino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]-4-fluorobenzyl}-2H -pyridazine-1-one;

4-{4-氟-3-[2-(四氢-吡喃-4-氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]-苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-(tetrahydro-pyran-4-amino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]-benzyl} -2H-phthalazin-1-one;

4-[3-(2-二甲氨基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基)-4-氟苄基]-2H-酞嗪-1-酮；4-[3-(2-Dimethylamino-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one ;

4-{4-氟-3-[2-(2-甲氧基乙基胺)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]-苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-(2-methoxyethylamine)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]-benzyl}- 2H-phthalazin-1-one;

4-{4-氟-3-[2-(2-羟基-2-甲基丙基氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]-苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-(2-hydroxy-2-methylpropylamino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]-benzyl }}-2H-phthalazin-1-one;

4-{3-[2-(环丙基甲基氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]-4-氟-苄基}-2H-酞嗪-1-酮；4-{3-[2-(Cyclopropylmethylamino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]-4-fluoro-benzyl}-2H- Pyridazin-1-one;

4-{4-氟-3-[2-(1-甲基环丙基氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]-苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-(1-methylcyclopropylamino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]-benzyl}- 2H-phthalazin-1-one;

4-{4-氟-3-[2-(3-氧杂环丁基氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-(3-oxetanylamino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl}-2H -pyridazine-1-one;

4-{4-氟-3-[2-(4-羟基环己基氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-(4-hydroxycyclohexylamino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl}-2H-indole Pyrazin-1-one;

4-{4-氟-3-[2-(四氢呋喃-3-氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮； 4-{4-Fluoro-3-[2-(tetrahydrofuran-3-amino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl}-2H-pyridazine -1-one;

4-{3-[2-(4-二甲氨基哌啶-1-基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]-4-氟苄基}-2H-酞嗪-1-酮；4-{3-[2-(4-Dimethylaminopiperidin-1-yl)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]-4-fluorobenzyl }-2H-pyridazin-1-one;

4-{4-氟-3-[2-(4-甲基哌嗪-1-基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-(4-methylpiperazin-1-yl)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl} -2H-phthalazin-1-one;

4-{4-氟-3-[2-(1-甲基哌啶-4-氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-(1-methylpiperidin-4-amino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl} -2H-phthalazin-1-one;

4-{3-[2-(4,4-二氟环己基氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]-4-氟苄基}-2H-酞嗪-1-酮；4-{3-[2-(4,4-Difluorocyclohexylamino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]-4-fluorobenzyl}- 2H-phthalazin-1-one;

4-{4-氟-3-[2-(1-甲基-1H-吡唑-4-氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-(1-methyl-1H-pyrazole-4-amino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl] Benzyl}-2H-phthalazin-1-one;

4-{4-氟-3-[2-(1-甲基-1H-吡唑-3-氨基)-5,7-二氢-吡唑并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-(1-methyl-1H-pyrazol-3-amino)-5,7-dihydro-pyrazolo[3,4-d]pyrimidin-6-carbonyl Benzyl}-2H-phthalazin-1-one;

4-{4-氟-3-[2-(甲基甲氧乙基氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-(methylmethoxyethylamino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl}-2H- Pyridazin-1-one;

4-[3-(2-乙氧乙氨基-5,7-二氢-吡咯[3,4-d]嘧啶-6-羰基)-4-氟苄基]-2H-酞嗪-1-酮；4-[3-(2-ethoxyethylamino-5,7-dihydro-pyrrole[3,4-d]pyrimidin-6-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one ;

(S)-4-{4-氟-3-[2-(甲氧丙基-2-氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；(S)-4-{4-Fluoro-3-[2-(methoxypropyl-2-amino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl }}-2H-phthalazin-1-one;

(R)-4-{4-氟-3-[2-(甲氧丙基-2-氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；(R)-4-{4-fluoro-3-[2-(methoxypropyl-2-amino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl }}-2H-phthalazin-1-one;

(S)-4-{4-氟-3-[2-(2-甲氧基丙氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；(S)-4-{4-Fluoro-3-[2-(2-methoxypropylamino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl }-2H-pyridazin-1-one;

(R)-4-{4-氟-3-[2-(2-甲氧基丙氨基)-5,7-二氢-吡咯[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；(R)-4-{4-fluoro-3-[2-(2-methoxypropylamino)-5,7-dihydro-pyrrole[3,4-d]pyrimidin-6-carbonyl]benzyl} -2H-phthalazin-1-one;

4-{4-氟-3-[2-(四氢呋喃-3-基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-(tetrahydrofuran-3-yl)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl}-2H-pyridazine -1-one;

4-{4-氟-3-[2-(四氢呋喃-2-基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-(tetrahydrofuran-2-yl)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl}-2H-pyridazine -1-one;

4-{4-氟-3-[2-(1-甲基哌啶-4-基)-5,7-二氢-吡咯[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-(1-methylpiperidin-4-yl)-5,7-dihydro-pyrrole[3,4-d]pyrimidin-6-carbonyl]benzyl}- 2H-phthalazin-1-one;

4-{4-氟-3-[2-(哌啶-4-基)-5,7-二氢-吡咯[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-(piperidin-4-yl)-5,7-dihydro-pyrrole[3,4-d]pyrimidin-6-carbonyl]benzyl}-2H-pyridazine -1-one;

4-[3-(2-环丙基甲基-5,7-二氢-吡咯[3,4-d]嘧啶-6-羰基)-4-氟苄基]-2H-酞嗪-1-酮；4-[3-(2-cyclopropylmethyl-5,7-dihydro-pyrrole[3,4-d]pyrimidin-6-carbonyl)-4-fluorobenzyl]-2H-pyridazine-1- ketone;

4-{4-氟-3-[2-((1R,2R)-2-甲基环丙基氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6- 羰基]苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-((1R,2R)-2-methylcyclopropylamino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6- Carbonyl]benzyl}-2H-phthalazin-1-one;

4-{3-[2-环丁基氨基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]-4-氟苄基}-2H-酞嗪-1-酮；4-{3-[2-Cyclobutylamino-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]-4-fluorobenzyl}-2H-pyridazine-1- ketone;

4-{3-[2-环丙基甲氧基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]-4-氟苄基}-2H-酞嗪-1-酮；4-{3-[2-cyclopropylmethoxy-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]-4-fluorobenzyl}-2H-pyridazine- 1-ketone;

4-{4-氟-3-[2-(2-羟基丙-2-基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-(2-hydroxypropan-2-yl)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl}-2H -pyridazine-1-one;

4-{4-氟-3-[2-(1-甲氧基甲基环丙基氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-(1-methoxymethylcyclopropylamino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl }-2H-pyridazin-1-one;

4-{4-氟-3-[2-((1R,2S)-2-甲基环丙基氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-((1R,2S)-2-methylcyclopropylamino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl Benzyl}-2H-phthalazin-1-one;

4-{3-[2-环丙基氨基-4-甲基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]-4-氟苄基}-2H-酞嗪-1-酮；4-{3-[2-Cyclopropylamino-4-methyl-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]-4-fluorobenzyl}-2H- Pyridazin-1-one;

4-{4-氟-3-[2-(1-三氟甲基环丙基)氨基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-(1-trifluoromethylcyclopropyl)amino-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl} -2H-phthalazin-1-one;

4-{3-[2-(2,2-二氟环丙基)氨基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]-4-氟苄基}-2H-酞嗪-1-酮；4-{3-[2-(2,2-difluorocyclopropyl)amino-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]-4-fluorobenzyl} -2H-phthalazin-1-one;

4-{3-[2-(2,2-二甲基环丙基)氨基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]-4-氟苄基}-2H-酞嗪-1-酮；4-{3-[2-(2,2-dimethylcyclopropyl)amino-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]-4-fluorobenzyl }-2H-pyridazin-1-one;

4-{4-氟-3-[2-((1R,2S)-2-氟环丙基)氨基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-((1R,2S)-2-fluorocyclopropyl)amino-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl] Benzyl}-2H-phthalazin-1-one;

4-{4-氟-3-[2-((1R,2R)-2-氟环丙基)氨基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-((1R,2R)-2-fluorocyclopropyl)amino-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl] Benzyl}-2H-phthalazin-1-one;

4-{4-氟-3-[2-(2-甲基磺酰基乙基)氨基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-(2-methylsulfonylethyl)amino-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl}- 2H-phthalazin-1-one;

N,N-二甲基-2-{6-[2-氟-5-(4-氧代-3,4-二氢酞嗪-1-甲基)苯甲酰基]-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-氨基}-乙磺酰胺；N,N-Dimethyl-2-{6-[2-fluoro-5-(4-oxo-3,4-dihydropyridazin-1-methyl)benzoyl]-6,7-di Hydrogen-5H-pyrrolo[3,4-d]pyrimidin-2-amino}-ethanesulfonamide;

4-[3-(2-环丙基氨基-5,7-二氢-吡咯并[3,4-b]吡啶-6-羰基)-4-氟苄基]-2H-酞嗪-1-酮；4-[3-(2-cyclopropylamino-5,7-dihydro-pyrrolo[3,4-b]pyridine-6-carbonyl)-4-fluorobenzyl]-2H-pyridazine-1- ketone;

4-[3-(6-环丙基氨基-1,3-二氢-吡咯并[3,4-c]吡啶-2-羰基)-4-氟苄基]-2H-酞嗪-1-酮；4-[3-(6-cyclopropylamino-1,3-dihydro-pyrrolo[3,4-c]pyridine-2-carbonyl)-4-fluorobenzyl]-2H-pyridazine-1- ketone;

4-[3-(2-环丙基氨基-5,7-二氢-吡咯并[3,4-b]吡嗪-6-羰基)-4-氟苄基]-2H-酞嗪-1-酮；4-[3-(2-cyclopropylamino-5,7-dihydro-pyrrolo[3,4-b]pyrazine-6-carbonyl)-4-fluorobenzyl]-2H-pyridazine-1 -ketone;

4-{3-[2-(2,2-二甲基-四氢吡喃-4-氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]-4-氟苄基}-2H-酞嗪-1-酮； 4-{3-[2-(2,2-Dimethyl-tetrahydropyran-4-amino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]- 4-fluorobenzyl}-2H-phthalazin-1-one;

4-{4-氟-3-[2-(4-甲基-四氢-吡喃-4-氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-(4-methyl-tetrahydro-pyran-4-amino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl Benzyl}-2H-phthalazin-1-one;

4-{3-[2-(3-氮杂双环[3.1.0]己基-6-氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]-4-氟苄基}-2H-酞嗪-1-酮；4-{3-[2-(3-Azabicyclo[3.1.0]hexyl-6-amino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]-4 -fluorobenzyl}-2H-phthalazin-1-one;

4-{4-氟-3-[2-(2,2,2-三氟乙基)氨基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-(2,2,2-trifluoroethyl)amino-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl }-2H-pyridazin-1-one;

4-{3-[2-(2,2-二氟乙基)氨基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]-4-氟苄基}-2H-酞嗪-1-酮；4-{3-[2-(2,2-difluoroethyl)amino-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]-4-fluorobenzyl}- 2H-phthalazin-1-one;

4-{4-氟-3-[2-(2-氟乙基)氨基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-(2-fluoroethyl)amino-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl}-2H-indole Pyrazin-1-one;

4-{4-氟-3-[2-(氧杂环丁基-2-甲基)氨基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-(oxetanyl-2-methyl)amino-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl }-2H-pyridazin-1-one;

4-{4-氟-3-[2-(氧杂环丁基-3-甲基)氨基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-(oxetanyl-3-methyl)amino-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl }-2H-pyridazin-1-one;

4-{4-氟-3-[2-(四氢呋喃-2-甲基)氨基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-(tetrahydrofuran-2-methyl)amino-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl}-2H- Pyridazin-1-one;

4-{3-[2-(环丙基氨基)-4-三氟甲基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]-4-氟苄基}-2H-酞嗪-1-酮；4-{3-[2-(cyclopropylamino)-4-trifluoromethyl-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]-4-fluorobenzyl }-2H-pyridazin-1-one;

4-{4-氟-3-[2-(2-三氟甲氧基乙基)氨基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-(2-trifluoromethoxyethyl)amino-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl} -2H-phthalazin-1-one;

4-{3-[2-环丙基氨基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]-4-氟苄基}-7-氟-2H-酞嗪-1-酮；4-{3-[2-cyclopropylamino-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]-4-fluorobenzyl}-7-fluoro-2H-indole Pyrazin-1-one;

7-氟-4-{4-氟-3-[2-(2-甲氧基乙基)氨基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；7-fluoro-4-{4-fluoro-3-[2-(2-methoxyethyl)amino-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl }}-2H-phthalazin-1-one;

7-氟-4-{4-氟-3-[2-(四氢吡喃-4-氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；7-Fluoro-4-{4-fluoro-3-[2-(tetrahydropyran-4-amino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl }}-2H-phthalazin-1-one;

4-{4-氟-3-[2-(4-甲氧基环己基)氨基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-(4-methoxycyclohexyl)amino-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl}-2H -pyridazine-1-one;

(R)-4-{3-[2-(3-四氢呋喃基)氨基-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-6-羰基]-4-氟苄基}-2H酞嗪-1-酮；(R)-4-{3-[2-(3-tetrahydrofuryl)amino-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-6-carbonyl]-4-fluorobenzyl }-2H pyridazin-1-one;

(S)-4-{3-[2-(3-四氢呋喃基)氨基-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-6-羰基]-4-氟苄基}-2H酞嗪-1-酮；(S)-4-{3-[2-(3-tetrahydrofuryl)amino-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-6-carbonyl]-4-fluorobenzyl }-2H pyridazin-1-one;

4-{3-[2-(((2R,5R)-5-二甲基氨基-1,3-二噁烷-2-基)甲基)氨基-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-6-羰基]-4-氟苄基}-2H酞嗪-1-酮；4-{3-[2-((2R,5R)-5-dimethylamino-1,3-dioxan-2-yl)methyl)amino-6,7-dihydro-5H-pyrrole And [3,4-d]pyrimidin-6-carbonyl]-4-fluorobenzyl}-2H-pyridazin-1-one;

4-{3-[2-((2R,5R)-2-(二甲基氨基)甲基-1,3-二噁烷-5-基)氨基-6,7-二氢-5H- 吡咯并[3,4-d]嘧啶-6-羰基]-4-氟苄基}-2H酞嗪-1-酮；和，4-{3-[2-((2R,5R)-2-(dimethylamino)methyl-1,3-dioxan-5-yl)amino-6,7-dihydro-5H- Pyrrolo[3,4-d]pyrimidin-6-carbonyl]-4-fluorobenzyl}-2H-pyridazin-1-one;

4-{3-[4-甲基-2-(4-四氢呋喃基)氨基-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-6-羰基]-4-氟苄基}-2H酞嗪-1-酮。4-{3-[4-Methyl-2-(4-tetrahydrofuryl)amino-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-6-carbonyl]-4-fluorobenzyl Base}-2H oxazin-1-one.

在另一个方面，本申请提供所述化合物的制备方法，其选自以下合成路线：In another aspect, the application provides a process for the preparation of the compound selected from the following synthetic routes:

路线一：Route 1:

Figure PCTCN2016103735-appb-000022
Figure PCTCN2016103735-appb-000022

将化合物A与化合物B进行缩合反应得到式I化合物；或者Condensation of Compound A with Compound B to give a compound of Formula I; or

路线二：Route 2:

Figure PCTCN2016103735-appb-000023
Figure PCTCN2016103735-appb-000023

将化合物A与化合物B’进行缩合反应得到化合物C’；将化合物C’与化合物

Figure PCTCN2016103735-appb-000024
进行亲核取代反应制得式I化合物；Condensation of compound A with compound B' to give compound C'; compound C' with compound
Figure PCTCN2016103735-appb-000024
Preparing a compound of formula I by nucleophilic substitution reaction;

其中，Lg代表亲核取代反应的离去基团，例如为卤素、-OCOR、-OTs、-SO2R等，例如为甲磺酰基，其余各原子和取代基的定义如上文中所述。Wherein, the reaction of Lg represents a nucleophilic substitution leaving group such as halogen, -OCOR, -OTs, -SO 2 R and the like, for example, methanesulfonyl group, each atom and the remaining definitions of the substituent groups described hereinabove.

在本申请的某些优选实施方案中，所述缩合反应的操作如下：将0.8-1.2当量的化合物A和1.0当量的化合物B或化合物B’(游离胺或者盐酸盐)溶于溶剂(例如DMF或THF)，室温下加入0.8-1.2当量的缩合剂(例如HATU，EDCI，T3P等)和2.0-5.0当量的碱(例如DIPEA，Et3N，吡啶等)，反应结束后向反应液加入水和有机溶剂(例如乙酸乙酯或甲基叔丁基醚)，分液，萃取，干燥和旋干，粗品经制备薄层色谱纯化或柱层析纯化得到目标产物式I化合物或化合物C’。 In certain preferred embodiments of the present application, the condensation reaction operates as follows: 0.8-1.2 equivalents of Compound A and 1.0 equivalent of Compound B or Compound B' (free amine or hydrochloride) are dissolved in a solvent (eg, DMF or THF), adding 0.8-1.2 equivalents of a condensing agent (such as HATU, EDCI, T3P, etc.) and 2.0-5.0 equivalents of a base (for example, DIPEA, Et 3 N, pyridine, etc.) at room temperature, and adding to the reaction liquid after the reaction is completed. Water and an organic solvent (such as ethyl acetate or methyl tert-butyl ether), liquid separation, extraction, drying and spin-drying, the crude product is purified by preparative thin layer chromatography or column chromatography to obtain the target product of formula I or compound C' .

在本申请的某些优选实施方案中，所述亲核取代反应的操作如下：将化合物C’(1.0eq.)溶于有机溶剂中(例如乙腈等)，在碱(例如碳酸钾、碳酸钠、三乙胺、DIPEA等，1.0-3.0eq.)的存在下加入亲核试剂(1.0-1.5eq.)，室温或加热(40-120℃)反应，得产物式I化合物。In certain preferred embodiments of the present application, the nucleophilic substitution reaction operates as follows: Compound C' (1.0 eq.) is dissolved in an organic solvent (eg, acetonitrile, etc.) in a base (eg, potassium carbonate, sodium carbonate) The nucleophile (1.0-1.5 eq.) is added in the presence of triethylamine, DIPEA, etc., 1.0-3.0 eq.), and reacted at room temperature or under heating (40-120 ° C) to give the compound of formula I.

在本申请的某些优选实施方案中，所述方法包括以下步骤：In certain preferred embodiments of the present application, the method comprises the steps of:

Figure PCTCN2016103735-appb-000025
Figure PCTCN2016103735-appb-000025

将化合物A与化合物2B进行缩合反应得到式Ia化合物，其中各原子和取代基的定义如上文中所述。Condensation of Compound A with Compound 2B provides a compound of Formula Ia wherein each atom and substituent are as defined above.

在本申请的某些优选实施方案中，所述方法包括以下步骤：In certain preferred embodiments of the present application, the method comprises the steps of:

Figure PCTCN2016103735-appb-000026
Figure PCTCN2016103735-appb-000026

将化合物A与化合物3B进行缩合反应得到式Iaa化合物，其中各原子和取代基的定义如上文中所述。Condensation of compound A with compound 3B provides a compound of formula Iaa wherein each atom and substituent are as defined above.

在本申请的某些优选实施方案中，所述方法包括以下步骤：In certain preferred embodiments of the present application, the method comprises the steps of:

Figure PCTCN2016103735-appb-000027
Figure PCTCN2016103735-appb-000027

将化合物A与化合物4B进行缩合反应得到式Iaaa化合物，其中各原子和取代基的定义如上文中所述。Condensation of Compound A with Compound 4B provides a compound of Formula Iaaa wherein each atom and substituent are as defined above.

化合物B或B’为市售可得或通过本领域常规实验方法制备得到。在本申请的某些优选实施方案中，以2-嘧啶衍生物的合成为例，化合物B或B’的合成方法包括但是不限于下列方法：Compound B or B' is commercially available or can be prepared by routine experimentation in the art. In certain preferred embodiments of the present application, taking the synthesis of a 2-pyrimidine derivative as an example, the synthesis of Compound B or B' includes, but is not limited to, the following methods:

方法一： method one:

Figure PCTCN2016103735-appb-000028
Figure PCTCN2016103735-appb-000028

将氨基被P基团保护的3-吡咯烷酮和DMF-DMA在加热的条件下(例如60-120℃)反应，然后减压浓缩除去DMF-DMA，所得固体用溶剂(例如甲基叔丁基醚、四氢呋喃、乙醚或乙腈)洗涤即可得到第一步的反应产物；该产物与硫酸甲硫基脒在溶剂中(例如乙醇、甲醇或异丙醇)反应可以得到关环产物；用氧化剂(例如m-CPBA、过氧化水或过氧乙酸)在溶剂中(例如二氯甲烷、乙腈或DMF)氧化所述关环产物即可得到砜类中间体；该砜类中间体与胺在20-100℃的条件下反应可得到2-氨基嘧啶的衍生物(该反应可不用溶剂，也可采用例如DMF或者DMSO等溶剂)；最后脱除N上的保护基(例如采用三氟醋酸或者盐酸)即得所述2-嘧啶衍生物；The 3-pyrrolidone and the DMF-DMA whose amino group is protected by a P group are reacted under heating (for example, 60 to 120 ° C), and then concentrated under reduced pressure to remove DMF-DMA, and the obtained solid is solvent (for example, methyl tert-butyl ether) Washing with tetrahydrofuran, diethyl ether or acetonitrile can obtain the reaction product of the first step; the product can be reacted with methylthio sulfonate in a solvent (for example, ethanol, methanol or isopropanol) to obtain a ring-closing product; Oxidation of the ring-closing product in a solvent such as methylene chloride, acetonitrile or DMF to give a sulfone intermediate; the sulfone intermediate with an amine at 20-100 The reaction of °C can obtain a derivative of 2-aminopyrimidine (the reaction can be carried out without a solvent, and a solvent such as DMF or DMSO can also be used); finally, the protecting group on N (for example, trifluoroacetic acid or hydrochloric acid) is removed. The 2-pyrimidine derivative is obtained;

在本申请的某些优选实施方案中，所述P基团为氨基保护基。In certain preferred embodiments of the present application, the P group is an amino protecting group.

方法二：Method Two:

Figure PCTCN2016103735-appb-000029
Figure PCTCN2016103735-appb-000029

将氨基被P基团保护的3-吡咯烷酮和DMF-DMA在加热的条件下(例如60-120℃)反应，然后减压浓缩除去DMF-DMA，所得固体用溶剂(例如甲基叔丁基醚、四氢呋喃、乙醚或乙腈)洗涤即可得到第一步的反应产物；将该产物与脲在碱性条件室温或加热反应得到2-羟基嘧啶衍生物中间体，将此中间体与三氯氧磷反应可以得到2-氯嘧啶衍生物；然后所得产物和胺在室温或升温的条件下得到2-氨基嘧啶衍生物，该反应可以采用含钯的催化剂(例如Pd(dppf)Cl2二氯甲烷络合物或Pd(OAc)2)、配体(例如BINAP、Xantphos或BrettPhosphate)和碱(例如DIPEA、Cs2CO3或NaOt-Bu)来促进反应(该反应可不用溶剂，或采用例如甲苯、二氧六环、DMF或者DMSO等溶剂)。最后脱除N上的保护基(譬如三氟醋酸或者盐酸)即得所述2-嘧啶衍生物。The 3-pyrrolidone and the DMF-DMA whose amino group is protected by a P group are reacted under heating (for example, 60 to 120 ° C), and then concentrated under reduced pressure to remove DMF-DMA, and the obtained solid is solvent (for example, methyl tert-butyl ether) Washing with tetrahydrofuran, diethyl ether or acetonitrile to obtain the reaction product of the first step; reacting the product with urea under basic conditions or heating to obtain a 2-hydroxypyrimidine derivative intermediate, the intermediate and phosphorus oxychloride The reaction can obtain a 2-chloropyrimidine derivative; then the obtained product and the amine are obtained at room temperature or elevated temperature to obtain a 2-aminopyrimidine derivative, and the reaction can be carried out using a palladium-containing catalyst (for example, Pd(dppf)Cl 2 dichloromethane. a compound or Pd(OAc) 2 ), a ligand (such as BINAP, Xantphos or Brett Phosphate) and a base (such as DIPEA, Cs 2 CO 3 or NaOt-Bu) to promote the reaction (the reaction may be carried out without a solvent, or using, for example, toluene, Solvents such as dioxane, DMF or DMSO). The 2-pyrimidine derivative is obtained by finally removing the protecting group on N (such as trifluoroacetic acid or hydrochloric acid).

方法三： Method three:

Figure PCTCN2016103735-appb-000030
Figure PCTCN2016103735-appb-000030

将氨基被P基团保护的3-吡咯烷酮和DMF-DMA在加热的条件下(例如60-120℃)反应，然后减压浓缩除去DMF-DMA，所得固体用溶剂(例如甲基叔丁基醚、四氢呋喃、乙醚或乙腈)洗涤即可得到第一步的反应产物；将该产物与脲在碱性条件下反应得到2-羟基嘧啶衍生物中间体；将此中间体与三氟甲磺酸酐反应得到三氟甲磺酸酯中间体，此中间体与胺反应得到2-氨基嘧啶衍生物，该反应可以采用含钯的催化剂(例如Pd(dppf)Cl2二氯甲烷络合物或Pd(OAc)2)、配体(例如Xantphos或BrettPhosphate)和碱(例如Cs2CO3或NaOt-Bu)来促进反应(该反应可不用溶剂，或采用例如甲苯、二氧六环、DMF或者DMSO等溶剂)，然后脱除N上保护基可得所述2-嘧啶衍生物。The 3-pyrrolidone and the DMF-DMA whose amino group is protected by a P group are reacted under heating (for example, 60 to 120 ° C), and then concentrated under reduced pressure to remove DMF-DMA, and the obtained solid is solvent (for example, methyl tert-butyl ether) Washing with tetrahydrofuran, diethyl ether or acetonitrile to obtain the reaction product of the first step; reacting the product with urea under basic conditions to obtain a 2-hydroxypyrimidine derivative intermediate; reacting the intermediate with trifluoromethanesulfonic anhydride A triflate intermediate is obtained which is reacted with an amine to give a 2-aminopyrimidine derivative which may be a palladium-containing catalyst (for example Pd(dppf)Cl2 dichloromethane complex or Pd(OAc) 2 ), a ligand (such as Xantphos or Brett Phosphate) and a base (such as Cs 2 CO 3 or NaOt-Bu) to promote the reaction (the reaction can be carried out without a solvent, or using a solvent such as toluene, dioxane, DMF or DMSO) The 2-pyrimidine derivative can then be obtained by removing the protecting group on N.

或者，方法四：Or, method four:

Figure PCTCN2016103735-appb-000031
Figure PCTCN2016103735-appb-000031

将氨基被P基团保护的3-吡咯烷酮和DMF-DMA在加热的条件下(例如60-120℃)反应，然后减压浓缩除去DMF-DMA；所得固体用溶剂(例如甲基叔丁基醚、四氢呋喃、乙醚或乙腈)洗涤即可得到第一步的反应产物；将此中间体与被取代的胍在碱性条件反应也可得到所述2-嘧啶衍生物。The 3-pyrrolidone and the DMF-DMA whose amino group is protected by the P group are reacted under heating (for example, 60-120 ° C), and then concentrated under reduced pressure to remove DMF-DMA; the obtained solid is solvent (for example, methyl tert-butyl ether) The reaction product of the first step can be obtained by washing with tetrahydrofuran, diethyl ether or acetonitrile; the 2-pyrimidine derivative can also be obtained by reacting the intermediate with the substituted hydrazine under basic conditions.

在另一个方面，本申请提供一种药物组合物，其包含本申请所述化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型，任选地，其还包含药学可接受的载体或赋形剂。In another aspect, the application provides a pharmaceutical composition comprising a compound described herein, a prodrug thereof, a metabolite form, a pharmaceutically acceptable salt or ester, or the aforementioned isomer, hydrate, The solvate or crystalline form, optionally, further comprises a pharmaceutically acceptable carrier or excipient.

在本申请的某些优选实施方案中，所述化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型还可与一种或多种药物联用。因此，在本申请的某些优选实施方案中，所述药物组合物还包含一种或多种药物。在本申请的某些优选实施方案中，所述药物为抗肿瘤药物。在本申请的某些优选实施方案中，所述抗肿瘤药物选自替莫唑胺、阿霉素、紫杉醇、顺铂、卡铂、达卡巴嗪、拓扑替康、伊立替康、吉西他滨、贝伐单抗、anti-CTLA-4单抗Ipilimumab、anti-PD-1 单抗pembrolizumab和Nivolumab以及anti-PD-L1单抗atezolizumab。In certain preferred embodiments of the present application, the compound, prodrug, metabolite form, pharmaceutically acceptable salt or ester thereof, or the aforementioned isomer, hydrate, solvate or crystal form Can be combined with one or more drugs. Accordingly, in certain preferred embodiments of the present application, the pharmaceutical composition further comprises one or more drugs. In certain preferred embodiments of the present application, the drug is an anti-tumor drug. In certain preferred embodiments of the present application, the anti-tumor drug is selected from the group consisting of temozolomide, doxorubicin, paclitaxel, cisplatin, carboplatin, dacarbazine, topotecan, irinotecan, gemcitabine, bevacizumab , anti-CTLA-4 monoclonal antibody Ipilimumab, anti-PD-1 Monoclonal pembrolizumab and Nivolumab as well as anti-PD-L1 monoclonal antibody atezolizumab.

在本申请的某些优选实施方案中，所述载体包括但不限于：氧化铝，硬脂酸铝，卵磷脂，血清蛋白如人血清蛋白，磷酸盐，甘油，山梨酸，山梨酸钾，饱和植物脂肪酸的部分甘油酯混合物，水，硫酸鱼精蛋白，磷酸氢二钠，磷酸氢钾，氯化钠，锌盐，胶态氧化硅，三硅酸镁，聚乙烯吡咯烷酮，纤维素物质，聚乙二醇，羧甲基纤维素钠，聚丙烯酸酯，蜂蜡，羊毛脂。所述赋形剂是指在药物制剂中除主药以外的附加物。其性质稳定，与主药无配伍禁忌，不产生副作用，不影响疗效，在常温下不易变形、干裂、霉变、虫蛀、对人体无害、无生理作用，不与主药产生化学或物理作用，不影响主药的含量测定等。如片剂中的黏合剂、填充剂、崩解剂、润滑剂；中药丸剂中的酒、醋、药汁等；半固体制剂软膏剂、霜剂中的基质部分；液体制剂中的防腐剂、抗氧剂、矫味剂、芳香剂、助溶剂、乳化剂、增溶剂、渗透压调节剂、着色剂等均可称为赋形剂。In certain preferred embodiments of the present application, the carrier includes, but is not limited to, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, phosphate, glycerin, sorbic acid, potassium sorbate, saturated Partial glyceride mixture of plant fatty acids, water, protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic material, poly Ethylene glycol, sodium carboxymethyl cellulose, polyacrylate, beeswax, lanolin. The excipient refers to an addenda other than the main drug in the pharmaceutical preparation. Its nature is stable, no compatibility with the main drug, no side effects, no effect on the effect, not easy to deform, chapped, mildew, insects, harmless to the human body, no physiological effects at room temperature, does not produce chemical or physical with the main drug The effect does not affect the determination of the content of the main drug. Such as adhesives, fillers, disintegrants, lubricants in tablets; wine, vinegar, medicinal juices in traditional Chinese medicine pills; semi-solid preparation ointments, matrix parts in creams; preservatives in liquid preparations, Antioxidants, flavoring agents, fragrances, solubilizers, emulsifiers, solubilizers, osmotic pressure regulators, colorants, and the like can be referred to as excipients.

本申请的化合物、其酯、前体药物、异构体、水合物、溶剂合物、晶型、药学上可接受的盐、它们的代谢物形式、或上述各项的任意组合或混合物、或其药物组合物可以通过以下途径给药：胃肠外、局部、静脉内、口服、皮下、动脉内、真皮内、经皮、直肠、颅内、腹膜内、鼻内、肌内途径或作为吸入剂。a compound, an ester, a prodrug, an isomer, a hydrate, a solvate, a crystalline form, a pharmaceutically acceptable salt thereof, a metabolite form thereof, or any combination or mixture of the foregoing, or The pharmaceutical composition can be administered by parenteral, topical, intravenous, oral, subcutaneous, intraarterial, intradermal, transdermal, rectal, intracranial, intraperitoneal, intranasal, intramuscular route or as inhalation. Agent.

本申请的化合物、其酯、前体药物、异构体、水合物、溶剂合物、晶型、药学上可接受的盐、它们的代谢物形式、或上述各项的任意组合或混合物、或其药物组合物可根据给药途径配成各种适宜的剂型。a compound, an ester, a prodrug, an isomer, a hydrate, a solvate, a crystalline form, a pharmaceutically acceptable salt thereof, a metabolite form thereof, or any combination or mixture of the foregoing, or The pharmaceutical composition can be formulated into various suitable dosage forms depending on the route of administration.

当口服用药时，本申请化合物可制成任意口服可接受的制剂形式，包括但不限于片剂、胶囊、水溶液或水悬浮液。其中，片剂使用的载体一般包括乳糖和玉米淀粉，另外也可加入润滑剂如硬脂酸镁。胶囊制剂使用的稀释剂一般包括乳糖和干燥玉米淀粉。水悬浮液制剂则通常是将活性成分与适宜的乳化剂和悬浮剂混合使用。任选地，以上口服制剂形式中还可加入一些甜味剂、芳香剂或着色剂。When administered orally, the compounds of the present application can be formulated into any orally acceptable formulation including, but not limited to, tablets, capsules, aqueous solutions or aqueous suspensions. Among them, the carrier used for the tablet generally includes lactose and corn starch, and a lubricant such as magnesium stearate may also be added. The diluent used in the capsule formulation generally comprises lactose and dried cornstarch. Aqueous suspension formulations are usually prepared by admixing the active ingredient with a suitable emulsifier and suspension. Optionally, some sweeteners, fragrances or colorants may also be added to the above oral formulation forms.

当皮肤局部施用时，本申请化合物可制成适当的软膏、洗剂或霜剂等制剂形式，其中将活性成分悬浮或溶解于一种或多种载体中。软膏制剂可使用的载体包括但不限于：矿物油、液体凡士林、白凡士林、丙二醇、聚氧化乙烯、聚氧化丙烯、乳化蜡和水；洗剂或霜剂可使用的载体包括但不限于：矿物油、脱水山梨糖醇单硬脂酸酯、吐温60、十六烷酯蜡、十六碳烯芳醇、2-辛基十二烷醇、苄醇和水。When the skin is applied topically, the compounds of the present application can be formulated into a suitable ointment, lotion or cream, in which the active ingredient is suspended or dissolved in one or more carriers. Carriers which may be used in ointment preparations include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; and detergents or creams which may be used include, but are not limited to, minerals Oil, sorbitan monostearate, Tween 60, cetyl esters wax, hexadecene aryl alcohol, 2-octyldodecanol, benzyl alcohol and water.

本申请化合物还可以无菌注射制剂形式用药，包括无菌注射水或油悬浮液或无菌注射溶液，也可以是冻干形式。其中，可使用的载体和溶剂包 括水、林格氏溶液和等渗氯化钠溶液。另外，灭菌的非挥发油也可用作溶剂或悬浮介质，如单甘油酯或二甘油酯。The compounds of the present application can also be administered in the form of a sterile injectable preparation, including sterile injectable aqueous or oily suspensions or sterile injection solutions, or in lyophilized form. Among them, the carrier and solvent package that can be used Water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils may also be employed as a solvent or suspension medium such as a monoglyceride or a diglyceride.

本申请的药物制剂包括药学上可实施的任何制剂，例如口服制剂、肠胃外给药制剂等。The pharmaceutical preparation of the present application includes any preparation pharmaceutically acceptable, such as an oral preparation, a parenteral preparation, and the like.

本申请的药物组合物和药物制剂可以含有0.01-2000mg的本申请化合物，优选含有0.1-1000mg本申请化合物，优选含有1-800mg本申请化合物，更优选含有10-600mg本申请化合物，特别优选含有50-500mg本申请化合物。The pharmaceutical compositions and pharmaceutical preparations of the present application may contain from 0.01 to 2000 mg of the compound of the present application, preferably from 0.1 to 1000 mg of the compound of the present application, preferably from 1 to 800 mg of the compound of the present application, more preferably from 10 to 600 mg of the compound of the present application, particularly preferably 50-500 mg of the compound of the present application.

在本申请的实施方案中，进行合适的体外或体内测定来确定本申请组合物的效果以及给药是否适用于治疗个体所患疾病或医学疾病状态。这些测定的实例在下文非限制性实施例结合具体疾病或医学治疗进行了描述。通常，足以实现预防或治疗效果的本申请组合物的有效量为约0.001mg/千克体重/天至约10,000mg/千克体重/天。合适的情况下，剂量为约0.01mg/千克体重/天至约1000mg/千克体重/天。剂量范围可以为每天、每两天或每三天约0.01至1000mg/kg宿主体重，更通常为0.1至500mg/kg宿主体重。示例性的治疗方案为每两天一次或每周一次或每月一次给药。通常多次给予所述试剂，单次剂量之间的间隔可以是每天、每周、每月或每年。或者，可以以缓释制剂的形式给予所述试剂，在这种情况下，需要较少的给药频率。剂量和频率根据试剂在受试者中的半衰期而不同。也可以根据是预防性处理还是治疗性处理而不同。在预防性应用中，以相对低频率的间隔长期给予相对低的剂量。在治疗性应用中，有时需要以相对短的间隔给予相对高的剂量，直至疾病的进展被延缓或停止，并优选地直至个体表现出疾病症状的部分或完全改善，在此之后，可以给予患者预防方案。In embodiments of the present application, suitable in vitro or in vivo assays are performed to determine the efficacy of the compositions of the present application and whether the administration is suitable for treating a disease or medical condition in a subject. Examples of such assays are described below in connection with specific diseases or medical treatments in non-limiting embodiments. Generally, an effective amount of a composition of the present application sufficient to achieve a prophylactic or therapeutic effect is from about 0.001 mg/kg body weight/day to about 10,000 mg/kg body weight/day. Suitably, the dosage is from about 0.01 mg/kg body weight/day to about 1000 mg/kg body weight/day. The dosage may range from about 0.01 to 1000 mg/kg of host body weight per day, every two days or every three days, more typically from 0.1 to 500 mg/kg of host body weight. An exemplary treatment regimen is once every two days or once a week or once a month. The agent is usually administered multiple times, and the interval between single doses can be daily, weekly, monthly or yearly. Alternatively, the agent can be administered in the form of a sustained release formulation, in which case less dosing frequency is required. The dose and frequency will vary depending on the half-life of the agent in the subject. It can also be different depending on whether it is a preventive treatment or a therapeutic treatment. In prophylactic applications, relatively low doses are administered chronically at relatively low frequency intervals. In therapeutic applications, it is sometimes desirable to administer relatively high doses at relatively short intervals until the progression of the disease is delayed or stopped, and preferably until the individual exhibits partial or complete improvement in the symptoms of the disease, after which the patient can be administered Prevention program.

在另一个方面，本申请提供所述化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型、或本申请所述的药物组合物在制备抑制PARP的试剂中的用途。In another aspect, the application provides the compound, prodrug, metabolite form, pharmaceutically acceptable salt or ester thereof, or the aforementioned isomer, hydrate, solvate or crystalline form, or the present application Use of the pharmaceutical composition in the preparation of a PARP-inhibiting agent.

在本申请的某些优选实施方案中，所述试剂为抑制PARP-1的试剂。In certain preferred embodiments of the present application, the agent is an agent that inhibits PARP-1.

在另一个方面，本申请还提供一种抑制PARP活性的方法，所述方法包括向有需要的细胞施用有效量的本申请所述的化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型、或本申请所述的药物组合物。In another aspect, the present application also provides a method of inhibiting PARP activity, the method comprising administering to a cell in need thereof an effective amount of a compound described herein, a prodrug thereof, a metabolite form, pharmaceutically acceptable Salt or ester, or the aforementioned isomer, hydrate, solvate or crystalline form, or a pharmaceutical composition as described herein.

在本申请的某些优选实施方案中，所述方法用于抑制PARP-1活性。In certain preferred embodiments of the present application, the method is for inhibiting PARP-1 activity.

在本申请的某些优选实施方案中，所述方法用于抑制细胞中PARP-1 活性。In certain preferred embodiments of the present application, the method is for inhibiting PARP-1 in a cell active.

在本申请的某些优选实施方案中，所述细胞为细胞系或来自受试者的细胞。In certain preferred embodiments of the present application, the cell is a cell line or a cell from a subject.

在另一个方面，本申请提供所述化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型、或本申请所述的药物组合物在制备辅助治疗肿瘤的试剂或是用于增强放射或化学治疗效果的药物中的用途。In another aspect, the application provides the compound, prodrug, metabolite form, pharmaceutically acceptable salt or ester thereof, or the aforementioned isomer, hydrate, solvate or crystalline form, or the present application Use of the pharmaceutical composition in the preparation of a medicament for adjuvant treatment of a tumor or a medicament for enhancing the effect of radiation or chemotherapy.

在另一个方面，本申请提供所述化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型、或本申请所述的药物组合物，其用于辅助治疗肿瘤或是用于增强放射或化学治疗效果。In another aspect, the application provides the compound, prodrug, metabolite form, pharmaceutically acceptable salt or ester thereof, or the aforementioned isomer, hydrate, solvate or crystalline form, or the present application The pharmaceutical composition for use in adjuvant treatment of a tumor or for enhancing radiation or chemotherapeutic effects.

在另一个方面，本申请提供一种辅助治疗肿瘤或增强放射或化学治疗效果的方法，所述方法包括向有需要的受试者施用有效量的本申请所述的化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型、或本申请所述的药物组合物。In another aspect, the application provides a method of adjuvant treatment of a tumor or enhancing the effect of radiation or chemotherapy, the method comprising administering to a subject in need thereof an effective amount of a compound described herein, a prodrug thereof, A metabolite form, a pharmaceutically acceptable salt or ester, or an isomer, hydrate, solvate or crystalline form as described above, or a pharmaceutical composition as described herein.

在另一个方面，本申请提供所述化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型、或本申请所述的药物组合物在制备治疗肿瘤的药物中的用途。In another aspect, the application provides the compound, prodrug, metabolite form, pharmaceutically acceptable salt or ester thereof, or the aforementioned isomer, hydrate, solvate or crystalline form, or the present application Use of the pharmaceutical composition for the preparation of a medicament for treating a tumor.

在另一个方面，本申请提供所述化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型、或本申请所述的药物组合物，其用于治疗肿瘤。In another aspect, the application provides the compound, prodrug, metabolite form, pharmaceutically acceptable salt or ester thereof, or the aforementioned isomer, hydrate, solvate or crystalline form, or the present application The pharmaceutical composition for treating a tumor.

在另一个方面，本申请提供一种治疗肿瘤的方法，所述方法包括向有需要的受试者提供有效量的本申请所述的化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型、或本申请所述的药物组合物。In another aspect, the application provides a method of treating a tumor, the method comprising providing an effective amount of a compound described herein, a prodrug thereof, a metabolite form, pharmaceutically acceptable to a subject in need thereof Salt or ester, or the aforementioned isomer, hydrate, solvate or crystalline form, or a pharmaceutical composition as described herein.

在另一个方面，本申请提供所述化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型、或本申请所述的药物组合物在制备治疗血管疾病、神经退变性疾病或神经系 统炎症的药物中的用途。In another aspect, the application provides the compound, prodrug, metabolite form, pharmaceutically acceptable salt or ester thereof, or the aforementioned isomer, hydrate, solvate or crystalline form, or the present application Said pharmaceutical composition for the treatment of vascular disease, neurodegenerative disease or nervous system Use in inflammatory drugs.

在另一个方面，本申请提供所述化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型、或本申请所述的药物组合物，其用于治疗血管疾病、神经退变性疾病或神经系统炎症。In another aspect, the application provides the compound, prodrug, metabolite form, pharmaceutically acceptable salt or ester thereof, or the aforementioned isomer, hydrate, solvate or crystalline form, or the present application The pharmaceutical composition for treating a vascular disease, a neurodegenerative disease or a nervous system inflammation.

在另一个方面，本申请提供一种治疗血管疾病、神经退变性疾病或神经系统炎症的方法，所述方法包括向有需要的受试者施用有效量的本申请所述的化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型、或本申请所述的药物组合物。In another aspect, the application provides a method of treating a vascular disease, a neurodegenerative disease, or a nervous system inflammation, the method comprising administering to a subject in need thereof an effective amount of a compound described herein, a precursor thereof A pharmaceutical, metabolite form, pharmaceutically acceptable salt or ester, or an isomer, hydrate, solvate or crystalline form as described above, or a pharmaceutical composition as described herein.

在另一个方面，本申请提供所述化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型、或本申请所述的药物组合物，其用于抑制细胞中PARP活性。In another aspect, the application provides the compound, prodrug, metabolite form, pharmaceutically acceptable salt or ester thereof, or the aforementioned isomer, hydrate, solvate or crystalline form, or the present application The pharmaceutical composition for inhibiting PARP activity in a cell.

在本申请的某些优选实施方案中，所述化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型、或本申请所述的药物组合物用于抑制细胞中PARP-1活性。In certain preferred embodiments of the present application, the compound, a prodrug thereof, a metabolite form, a pharmaceutically acceptable salt or ester, or an isomer, hydrate, solvate or crystalline form, Or the pharmaceutical composition described herein is used to inhibit PARP-1 activity in a cell.

在本申请的某些优选实施方案中，所述细胞为细胞系或来自受试者的细胞。In certain preferred embodiments of the present application, the cell is a cell line or a cell from a subject.

在本申请的某些优选实施方案中，所述化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型、或本申请所述的药物组合物用于体内方法中。In certain preferred embodiments of the present application, the compound, a prodrug thereof, a metabolite form, a pharmaceutically acceptable salt or ester, or an isomer, hydrate, solvate or crystalline form, Or the pharmaceutical compositions described herein are used in an in vivo method.

在本申请的某些优选实施方案中，所述化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型、或本申请所述的药物组合物用于体外方法中。In certain preferred embodiments of the present application, the compound, a prodrug thereof, a metabolite form, a pharmaceutically acceptable salt or ester, or an isomer, hydrate, solvate or crystalline form, Or the pharmaceutical compositions described herein are used in an in vitro method.

在另一个方面，本申请还提供一种抑制细胞中PARP活性的方法，所述方法包括给予细胞有效量的本申请所述的化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型、或本申请所述的药物组合物。In another aspect, the present application also provides a method of inhibiting PARP activity in a cell, the method comprising administering to the cell an effective amount of a compound described herein, a prodrug thereof, a metabolite form, a pharmaceutically acceptable salt Or an ester, or an isomer, hydrate, solvate or crystalline form as described above, or a pharmaceutical composition as described herein.

在本申请的某些优选实施方案中，所述方法用于抑制PARP-1活性。In certain preferred embodiments of the present application, the method is for inhibiting PARP-1 activity.

在本申请的某些优选实施方案中，所述细胞为细胞系或来自受试者的细胞。In certain preferred embodiments of the present application, the cell is a cell line or a cell from a subject.

在本申请的某些优选实施方案中，所述方法在体内进行。 In certain preferred embodiments of the present application, the method is performed in vivo.

在本申请的某些优选实施方案中，所述方法在体外进行。In certain preferred embodiments of the present application, the method is performed in vitro.

在另一个方面，本申请还提供所述化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型、或本申请所述的药物组合物在制备试剂中的用途，所述试剂作为化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型辅助抑制肿瘤细胞增殖的试剂或是用于增强放射或化学方法抑制肿瘤细胞增殖的效果。In another aspect, the application further provides the compound, a prodrug thereof, a metabolite form, a pharmaceutically acceptable salt or ester, or an isomer, hydrate, solvate or crystalline form, or Use of a pharmaceutical composition as claimed in the preparation of a reagent as a compound, a prodrug thereof, a metabolite form, a pharmaceutically acceptable salt or ester, or the aforementioned isomer, hydrate, solvent The agent or the crystal form assists the inhibition of tumor cell proliferation or the effect of enhancing radiation or chemical inhibition of tumor cell proliferation.

在本申请的某些优选实施方案中，所述肿瘤细胞为肿瘤细胞系或来自受试者的肿瘤细胞。In certain preferred embodiments of the present application, the tumor cell is a tumor cell line or a tumor cell from a subject.

在本申请的某些优选实施方案中，所述试剂用于体内方法中。In certain preferred embodiments of the present application, the agent is for use in an in vivo method.

在本申请的某些优选实施方案中，所述试剂用于体外方法中。In certain preferred embodiments of the present application, the agent is for use in an in vitro method.

在另一个方面，本申请还提供所述化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型、或本申请所述的药物组合物，其用于辅助抑制肿瘤细胞增殖或用于增强放射或化学方法抑制肿瘤细胞增殖的效果。In another aspect, the application further provides the compound, a prodrug thereof, a metabolite form, a pharmaceutically acceptable salt or ester, or an isomer, hydrate, solvate or crystalline form, or The pharmaceutical composition of the invention is used for assisting in inhibiting tumor cell proliferation or for enhancing the effect of radiation or chemical inhibition of tumor cell proliferation.

在本申请的某些优选实施方案中，所述肿瘤细胞为肿瘤细胞系或来自受试者的肿瘤细胞。In certain preferred embodiments of the present application, the tumor cell is a tumor cell line or a tumor cell from a subject.

在本申请的某些优选实施方案中，所述化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型、或本申请药物组合物用于体内方法中。In certain preferred embodiments of the present application, the compound, a prodrug thereof, a metabolite form, a pharmaceutically acceptable salt or ester, or an isomer, hydrate, solvate or crystalline form, Or the pharmaceutical composition of the present application is used in an in vivo method.

在本申请的某些优选实施方案中，所述化合物、其酯、前体药物、异构体、水合物、溶剂合物、晶型、药学上可接受的盐、它们的代谢物形式、或上述各项的任意组合或混合物、或本申请所述的药物用于体外方法中。In certain preferred embodiments of the present application, the compound, ester, prodrug, isomer, hydrate, solvate, crystalline form, pharmaceutically acceptable salt thereof, metabolite form thereof, or Any combination or mixture of the above, or a medicament described herein, is used in an in vitro method.

在另一个方面，本申请还提供一种辅助抑制肿瘤细胞增殖或增强放射或化学方法抑制肿瘤细胞增殖的效果的方法，所述方法包括给予肿瘤细胞有效量的本申请所述的化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型、或本申请所述的药物组合物。In another aspect, the present application also provides a method of inhibiting tumor cell proliferation or enhancing the effect of radiation or chemical inhibition of tumor cell proliferation, the method comprising administering to a tumor cell an effective amount of a compound described herein, preceded by a drug, a metabolite form, a pharmaceutically acceptable salt or ester, or an isomer, hydrate, solvate or crystalline form as described above, or a pharmaceutical composition as described herein.

在本申请的某些优选实施方案中，所述肿瘤细胞为肿瘤细胞系或来自受试者的肿瘤细胞。In certain preferred embodiments of the present application, the tumor cell is a tumor cell line or a tumor cell from a subject.

在本申请的某些优选实施方案中，所述方法在体外进行。In certain preferred embodiments of the present application, the method is performed in vitro.

在本申请的某些优选实施方案中，所述方法在体内进行。 In certain preferred embodiments of the present application, the method is performed in vivo.

在另一个方面，本申请还提供所述化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型、或本申请所述的药物组合物在制备试剂中的用途，所述试剂用于抑制肿瘤细胞增殖。In another aspect, the application further provides the compound, a prodrug thereof, a metabolite form, a pharmaceutically acceptable salt or ester, or an isomer, hydrate, solvate or crystalline form, or Use of the pharmaceutical composition of the invention for the preparation of a reagent for inhibiting tumor cell proliferation.

在本申请的某些优选实施方案中，所述试剂用于体内方法中。In certain preferred embodiments of the present application, the agent is for use in an in vivo method.

在本申请的某些优选实施方案中，所述试剂用于体外方法中。In certain preferred embodiments of the present application, the agent is for use in an in vitro method.

在另一个方面，本申请还提供所述化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型、或本申请所述的药物组合物，其用于抑制肿瘤细胞增殖。In another aspect, the application further provides the compound, a prodrug thereof, a metabolite form, a pharmaceutically acceptable salt or ester, or an isomer, hydrate, solvate or crystalline form, or The pharmaceutical composition of the invention is for use in inhibiting tumor cell proliferation.

在本申请的某些优选实施方案中，所述肿瘤细胞为肿瘤细胞系或来自受试者的肿瘤细胞。In certain preferred embodiments of the present application, the tumor cell is a tumor cell line or a tumor cell from a subject.

在本申请的某些优选实施方案中，所述化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型、或本申请所述的药物组合物用于体内方法中。In certain preferred embodiments of the present application, the compound, a prodrug thereof, a metabolite form, a pharmaceutically acceptable salt or ester, or an isomer, hydrate, solvate or crystalline form, Or the pharmaceutical compositions described herein are used in an in vivo method.

在本申请的某些优选实施方案中，所述化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型、或本申请所述的药物组合物用于体外方法中。In certain preferred embodiments of the present application, the compound, a prodrug thereof, a metabolite form, a pharmaceutically acceptable salt or ester, or an isomer, hydrate, solvate or crystalline form, Or the pharmaceutical compositions described herein are used in an in vitro method.

在另一个方面，本申请还提供一种抑制肿瘤细胞增殖的方法，所述方法包括给予细胞有效量的本申请所述的化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型、或本申请所述的药物组合物。In another aspect, the present application also provides a method of inhibiting proliferation of a tumor cell, the method comprising administering to the cell an effective amount of a compound described herein, a prodrug thereof, a metabolite form, a pharmaceutically acceptable salt or An ester, or an isomer, hydrate, solvate or crystalline form as described above, or a pharmaceutical composition as described herein.

在本申请的某些优选实施方案中，所述肿瘤选自乳腺癌、卵巢癌、结直肠癌、黑色素瘤、肺癌、胃肠道间质瘤、脑癌、宫颈癌、胰腺癌、前列腺癌、胃癌、慢性髓样白细胞过多症、肝癌、淋巴瘤、腹膜癌、软组织肉瘤、神经内分泌肿瘤和胶质母细胞瘤。In certain preferred embodiments of the present application, the tumor is selected from the group consisting of breast cancer, ovarian cancer, colorectal cancer, melanoma, lung cancer, gastrointestinal stromal tumor, brain cancer, cervical cancer, pancreatic cancer, prostate cancer, Gastric cancer, chronic myeloid leukemia, liver cancer, lymphoma, peritoneal cancer, soft tissue sarcoma, neuroendocrine tumors, and glioblastoma.

在本申请的某些优选实施方案中，所述肿瘤细胞选自乳腺癌细胞、卵巢癌细胞、结直肠癌细胞、黑色素瘤细胞、肺癌细胞、胃肠道间质瘤细胞、脑癌细胞、宫颈癌细胞、胰腺癌细胞、前列腺癌细胞、胃癌细胞、慢性髓样白细胞、肝癌细胞、淋巴瘤细胞、腹膜癌细胞、软组织肉瘤细胞、神经内分泌肿瘤细胞和胶质母细胞瘤细胞。In certain preferred embodiments of the present application, the tumor cell is selected from the group consisting of a breast cancer cell, an ovarian cancer cell, a colorectal cancer cell, a melanoma cell, a lung cancer cell, a gastrointestinal stromal tumor cell, a brain cancer cell, a cervix Cancer cells, pancreatic cancer cells, prostate cancer cells, gastric cancer cells, chronic myeloid leukocytes, liver cancer cells, lymphoma cells, peritoneal cancer cells, soft tissue sarcoma cells, neuroendocrine tumor cells, and glioblastoma cells.

在本申请的某些优选实施方案中，所述肿瘤细胞为肿瘤细胞系或来自 受试者的肿瘤细胞。In certain preferred embodiments of the present application, the tumor cell is a tumor cell line or is derived from Tumor cells of the subject.

本申请所述的肿瘤包括恶性和良性肿瘤，相应地，所述肿瘤细胞包括恶性和良性肿瘤细胞。Tumors described herein include malignant and benign tumors, and correspondingly, the tumor cells include malignant and benign tumor cells.

本申请所述受试者为哺乳动物，例如牛科动物、马科动物、羊科动物、猪科动物、犬科动物、猫科动物、啮齿类动物、灵长类动物；其中，特别优选的受试者为人。The subject described herein is a mammal, such as a bovine, equine, ovine, porcine, canine, feline, rodent, primate; wherein, particularly preferred The subject is a human.

以下对本申请的术语进行解释，对于特定的术语，如果本申请中的含义与本领域技术人员通常理解的含义不一致，则以本申请中的含义为准；如果在本申请中没有定义，则其具有本领域技术人员通常理解的含义。除非有相反陈述，本申请中使用的术语具有下述含义。The terminology of the present application is explained below. For a specific term, if the meaning in the present application is inconsistent with the meaning commonly understood by those skilled in the art, the meaning in the present application shall prevail; if not defined in the present application, There is a meaning that is generally understood by those skilled in the art. Unless otherwise stated, the terms used in this application have the following meanings.

本文所用术语“氢”及所述各基团中的氢，其包括氕(H)，氘(D)，氚(T)。在本申请的某些优选实施方案中，所述氢为氕(H)。The term "hydrogen" as used herein and hydrogen in each of the groups includes hydrazine (H), hydrazine (D), hydrazine (T). In certain preferred embodiments of the present application, the hydrogen is hydrazine (H).

本文所用术语“烷基”是指直链或支链饱和烃基，例如C1-10烷基、C1-6烷基或C1-4烷基，烷基的非限制性实施例包括甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、己基等。The term "alkyl" as used herein, refers to a straight or branched saturated hydrocarbon group, such as C 1-10 alkyl, C 1-6 alkyl or C 1-4 alkyl, and non-limiting examples of alkyl include methyl , ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like.

所述烷基未被取代，或可以被取代基进一步取代形成取代烷基，所述取代基可选自卤素、环烷基、杂环烷基、RO-或RR’N-，其中R和R’定义如本申请所述。The alkyl group is unsubstituted or may be further substituted with a substituent to form a substituted alkyl group, which may be selected from halogen, cycloalkyl, heterocycloalkyl, RO- or RR'N-, wherein R and R 'Definition as described herein.

当取代基为卤素(例如氟)时，该取代后的烷基即为本申请所述的卤代烷基，包括卤代C1-6烷基(例如氟代C1-6烷基)和卤代C1-4烷基(例如氟代C1-4烷基)等。When the substituent is a halogen (e.g., fluoro), the substituted alkyl group is a haloalkyl group as described herein, including a halogenated C 1-6 alkyl group (e.g., fluoro C 1-6 alkyl group) and a halogenated group. C 1-4 alkyl (e.g., fluoro C 1-4 alkyl) and the like.

当取代基为环烷基时，该取代后的烷基即为本申请所述的环烷基-烷基，包括3-20元环烷基-C1-10烷基、3-12元环烷基-C1-6烷基、3-8元环烷基-C1-4烷基、3元环烷基-甲基、4元环烷基-甲基、5元环烷基-甲基、6元环烷基-甲基、7元环烷基-甲基和8元环烷基-甲基等。When the substituent is a cycloalkyl group, the substituted alkyl group is a cycloalkyl-alkyl group as described herein, including a 3-20 membered cycloalkyl-C 1-10 alkyl group, a 3-12 membered ring. Alkyl-C 1-6 alkyl, 3-8 membered cycloalkyl-C 1-4 alkyl, 3-membered cycloalkyl-methyl, 4-membered cycloalkyl-methyl, 5-membered cycloalkyl-methyl A 6-membered cycloalkyl-methyl group, a 7-membered cycloalkyl-methyl group, and an 8-membered cycloalkyl-methyl group.

当取代基为杂环烷基时，该取代后的烷基即为本申请所述的杂环烷基-烷基，包括3-20元杂环烷基-C1-10烷基、3-8元杂环烷基-C1-6烷基、3-8元杂环烷基-C1-4烷基、3元杂环烷基-甲基、4元杂环烷基-甲基、5元杂环烷基-甲基、6元杂环烷基-甲基、7元杂环烷基-甲基和8元杂环烷基-甲基等。When the substituent is a heterocycloalkyl group, the substituted alkyl group is a heterocycloalkyl-alkyl group as described herein, including a 3-20 membered heterocycloalkyl-C 1-10 alkyl group, 3- 8-membered heterocycloalkyl-C 1-6 alkyl, 3-8 membered heterocycloalkyl-C 1-4 alkyl, 3-membered heterocycloalkyl-methyl, 4-membered heterocycloalkyl-methyl, 5-membered heterocycloalkyl-methyl, 6-membered heterocycloalkyl-methyl, 7-membered heterocycloalkyl-methyl and 8-membered heterocycloalkyl-methyl and the like.

当取代基为RO-时，该取代后的烷基即为RO-烷基，例如包括RO-C1-10烷基、RO-C1-6烷基、RO-C1-4烷基、RO-甲基和RO-乙基等，其中所述R基团如本申请所述。在本申请的某些优选实施方案中，R为氢或C1-10烷基，因此，该RO-烷基可为羟基取代的烷基或C1-10烷氧基烷基。该羟基取代的烷基包括羟基C1-10烷基、羟基C1-6烷基和羟基C1-4烷基等。该C1-10烷氧 基烷基包括C1-6烷氧基-C1-6烷基和C1-4烷氧基-C1-4烷基等。When the substituent is RO-, the substituted alkyl group is an RO-alkyl group, and includes, for example, RO-C 1-10 alkyl group, RO-C 1-6 alkyl group, RO-C 1-4 alkyl group, RO-methyl and RO-ethyl and the like, wherein the R group is as described herein. In certain preferred embodiments of the present application, R is hydrogen or C 1-10 alkyl, and thus, the RO-alkyl group can be a hydroxy-substituted alkyl group or a C 1-10 alkoxyalkyl group. The hydroxy-substituted alkyl group includes a hydroxy C 1-10 alkyl group, a hydroxy C 1-6 alkyl group, a hydroxy C 1-4 alkyl group and the like. The C 1-10 alkoxyalkyl group includes a C 1-6 alkoxy-C 1-6 alkyl group and a C 1-4 alkoxy-C 1-4 alkyl group and the like.

当取代基为RR’N-时，该取代后的烷基即为RR’N-烷基，例如包括RR’N-C1-10烷基、RR’N-C1-6烷基、RR’N-C1-4烷基、RR’N-甲基和RR’N-乙基等，其中所述R和R’基团如本申请所述。在本申请的某些优选实施方案中，R和R’为氢或C1-10烷基，因此，该RR’N-烷基可为氨基取代的烷基或C1-10烷氨基烷基或二C1-10烷氨基烷基。所述RR’N-烷基例如为氨基取代的C1-10烷基、氨基取代的C1-6烷基、氨基取代的C1-4烷基、C1-6烷氨基-C1-6烷基、C1-4烷氨基-C1-4烷基、二C1-6烷氨基-C1-6烷基和二C1-4烷氨基-C1-4烷基等。本文所用术语“烯基”是指含有至少一个碳碳双键的直链或支链烃基，例如C2-10烯基、C2-6烯基或C2-4烯基，烯基的非限制性实施例包括乙烯基、丙烯基、丁烯基、2-甲基丙烯基、戊烯基、2-甲基丁烯基、3-甲基丁烯基、己烯基、2-甲基戊烯基、3-甲基戊烯基、4-甲基戊烯基、2-乙基丁烯基等。本文所用术语“炔基”是指含有至少一个碳碳叁键的直链或支链烃基，例如C2-10炔基、C2-6炔基或C2-4炔基，炔基的非限制性实施例包括乙炔基、丙炔基、丁炔基、戊炔基、3-甲基丁炔基、己炔基、3-甲基戊炔基等。本文所用术语“烷氧基”是指具有“烷基-O-”结构的基团，例如C1-10烷氧基、C1-6烷氧基或C1-4烷氧基，烷氧基的非限制性实施例包括甲氧基、乙氧基、丙氧基、异丙氧基和叔丁氧基等。When the substituent is RR'N-, the substituted alkyl group is RR'N-alkyl, and includes, for example, RR'NC 1-10 alkyl, RR'NC 1-6 alkyl, RR'NC 1- 4- alkyl, RR'N-methyl and RR'N-ethyl, and the like, wherein the R and R' groups are as described herein. In certain preferred embodiments of the present application, R and R' are hydrogen or C 1-10 alkyl, and thus, the RR 'N-alkyl group may be an amino substituted alkyl group or a C 1-10 alkylamino alkyl group. Or a di-C 1-10 alkylaminoalkyl group. The RR'N-alkyl group is, for example, an amino-substituted C 1-10 alkyl group, an amino-substituted C 1-6 alkyl group, an amino-substituted C 1-4 alkyl group, or a C 1-6 alkylamino group-C 1- 6 alkyl, C 1-4 alkylamino-C 1-4 alkyl, di C 1-6 alkylamino-C 1-6 alkyl and di C 1-4 alkylamino-C 1-4 alkyl, and the like. The term "alkenyl" as used herein, refers to a straight or branched chain hydrocarbon radical containing at least one carbon to carbon double bond, such as a C 2-10 alkenyl group, a C 2-6 alkenyl group or a C 2-4 alkenyl group, an alkenyl group. Restrictive examples include ethenyl, propenyl, butenyl, 2-methylpropenyl, pentenyl, 2-methylbutenyl, 3-methylbutenyl, hexenyl, 2-methyl Pentenyl, 3-methylpentenyl, 4-methylpentenyl, 2-ethylbutenyl and the like. The term "alkynyl" as used herein, denotes a straight or branched chain hydrocarbon radical containing at least one carbon-carbon triple bond, such as a C 2-10 alkynyl group, a C 2-6 alkynyl group or a C 2-4 alkynyl group, a nonyl alkynyl group. Limitative examples include ethynyl, propynyl, butynyl, pentynyl, 3-methylbutynyl, hexynyl, 3-methylpentynyl and the like. The term "alkoxy" as used herein, refers to a group having the structure "alkyl-O-", such as C 1-10 alkoxy, C 1-6 alkoxy or C 1-4 alkoxy, alkoxy Non-limiting examples of the group include methoxy, ethoxy, propoxy, isopropoxy and t-butoxy groups and the like.

本文所用化学式“ROC(O)-”是指取代的氧羰基，例如烷氧羰基。R-OC(O)-的非限制性实施例包括甲氧羰基、乙氧羰基、丙氧羰基、叔丁氧羰基、苯甲氧甲酰基等。The chemical formula "ROC(O)-" as used herein refers to a substituted oxycarbonyl group such as an alkoxycarbonyl group. Non-limiting examples of R-OC(O)- include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, t-butoxycarbonyl, benzomethoxycarbonyl, and the like.

本文所用化学式“RC(O)O-”是指取代的酰氧基，例如烷基酰氧基。R-C(O)O-的非限制性实施例包括甲酰氧基、乙酰氧基、丙酰氧基和苯甲酰氧基等。The chemical formula "RC(O)O-" as used herein refers to a substituted acyloxy group, such as an alkyl acyloxy group. Non-limiting examples of R-C(O)O- include formyloxy, acetoxy, propanoyloxy, benzoyloxy and the like.

本文所用化学式“RC(O)-”是指取代的酰基，例如烷酰基。R-C(O)-的非限制性实施例包括乙酰基、丙酰基、丁酰基和苯甲酰基等。The chemical formula "RC(O)-" as used herein refers to a substituted acyl group such as an alkanoyl group. Non-limiting examples of R-C(O)- include acetyl, propionyl, butyryl, benzoyl and the like.

本文所用化学式“RR’NH-”是指取代的氨基，例如烷氨基，二烷氨基等。RR’NH-的非限制性实施例包括甲氨基、乙氨基、丙氨基、N,N-二甲氨基、N,N-二乙氨基等。The chemical formula "RR'NH-" as used herein means a substituted amino group such as an alkylamino group, a dialkylamino group or the like. Non-limiting examples of RR'NH- include methylamino, ethylamino, propylamino, N,N-dimethylamino, N,N-diethylamino and the like.

本文所用化学式“RC(O)NH-”是指取代的酰胺基，例如烷酰氨基和芳酰氨基等。R-C(O)NH-的非限制性实施例包括甲酰氨基、乙酰氨基和苯甲酰氨基等。The chemical formula "RC(O)NH-" as used herein refers to substituted amide groups such as alkanoylamino and aroylamino groups and the like. Non-limiting examples of R-C(O)NH- include formylamino, acetamido, benzoylamino, and the like.

本文所用化学式“RR’NHC(O)-”是指取代的氨酰基，例如烷氨酰基和二烷氨酰基等。RR’NHC(O)-的非限制性实施例包括甲氨酰基、乙氨酰基、N,N-二甲氨酰基、N,N-二乙氨酰基等。 The chemical formula "RR'NHC(O)-" as used herein means a substituted aminoacyl group such as an alkanoyl group and a dialkylamino group. Non-limiting examples of RR'NHC(O)- include carbamoyl, ethoxylyl, N,N-dimethylamino, N,N-diethylamino and the like.

本文所用化学式“RS(O)a-”，其中a＝0、1或2，是指取代的巯基、磺酰基或亚磺酰基，RS(O)a-的非限制性实施例包括巯基、甲磺酰基、乙磺酰基、苯磺酰基、对甲基苯磺酰基等。As used herein, the formula "RS(O) a -", wherein a = 0, 1 or 2, refers to a substituted fluorenyl, sulfonyl or sulfinyl group, and a non-limiting example of RS(O) a - includes a fluorenyl group, a Sulfonyl, ethylsulfonyl, phenylsulfonyl, p-methylbenzenesulfonyl and the like.

本文所用化学式“RR’NSO2-”是指取代的氨基磺酰基，RR’NSO2-的非限制性实施例包括二甲氨基磺酰基等。The chemical formula "RR'NSO 2 -" as used herein refers to a substituted aminosulfonyl group, and non-limiting examples of RR'NSO 2 - include dimethylaminosulfonyl and the like.

本文所用化学式“RSO2N(R’)-”是指取代的磺酰胺基，例如烷基磺酰胺基和芳基磺酰胺基等。RSO2N(R’)-的非限制性实施例包括甲磺酰胺基、乙磺酰氨基、苯磺酰胺基和对甲苯磺酰胺基等。The chemical formula "RSO 2 N(R')-" as used herein means a substituted sulfonamide group such as an alkylsulfonylamino group and an arylsulfonylamino group. Non-limiting examples of RSO 2 N(R')- include methanesulfonamide, ethanesulfonylamino, benzenesulfonylamino and p-toluenesulfonylamino groups, and the like.

本文所用“R”和“R’”各自独立地选自氢、羟基、C1-10烷基、3-20元环烷基、5-20元杂环烷基、6-20元芳基和5-20元杂芳基。在本申请的某些优选实施方案中，所述R和R’为氢或C1-10烷基当本文所指代的取代基含有R或R’时，其包括所有符合化学价键规则的上述定义的R或R’。As used herein, "R" and "R'" are each independently selected from the group consisting of hydrogen, hydroxy, C 1-10 alkyl, 3-20 membered cycloalkyl, 5-20 membered heterocycloalkyl, 6-20 membered aryl, and 5-20 yuan heteroaryl. In certain preferred embodiments of the present application, R and R' are hydrogen or C 1-10 alkyl. When a substituent as referred to herein contains R or R', it includes all chemically bonded valence rules. R or R' as defined above.

本文所用术语“环烷基”是指单环或多环环状烷基，例如包含3-20个碳原子的环烷基，例如包含3-12个碳原子的环烷基，例如包含3-10个碳原子的环烷基，例如包含3-8个碳原子的环烷基，例如包含5-8个碳原子的环烷基。单环烷基的非限制性实施例包括环丙基、环丁基、环戊基、环己基、环庚基环辛基等。多环环烷基包括螺环、稠环和桥环的环烷基。本文所用术语“杂环烷基”是指包含至少一个选自N、O和S的杂原子的如前文所述的环烷基，例如含有一个或两个N原子的杂环烷基、含有一个O原子的杂环烷基、含有一个S原子的杂环烷基、例如包含3-20元杂环烷基，例如包含5-20元杂环烷基，例如包含3-8元杂环烷基，例如包含5-8元杂环烷基。杂环烷基的非限制性实施例包括环氧丙烷基、四氢呋喃基、吡咯烷基、四氢吡喃基、哌啶基、哌嗪基、吗啉基、硫吗啉基、高哌嗪基等。本文所用术语“芳基”是指6-20元单环或稠合多环(例如双环或三环)具有芳香性的基团，优选6-14元芳基，更优选6-10元芳基，芳基的非限制性实施例包括但不限于苯基和萘基等。本文所用术语“杂芳基”是指被至少一个选自N、O或S的杂原子取代的5-14元芳香杂环基团，优选为5-10元。例如含有一个或两个N原子的杂芳基、含有一个O原子的杂芳基或含有一个S原子的杂芳基。杂芳基的非限制性实施例包括呋喃基、噻吩基、吡咯基、咪唑基、恶唑基、噻唑基、吡唑基、三氮唑基、四氮唑基、吡啶基、哒嗪基、嘧啶基和吡嗪基等。The term "cycloalkyl" as used herein, refers to a monocyclic or polycyclic cyclic alkyl group, for example a cycloalkyl group containing from 3 to 20 carbon atoms, for example a cycloalkyl group containing from 3 to 12 carbon atoms, for example including 3- A cycloalkyl group of 10 carbon atoms, for example, a cycloalkyl group having 3 to 8 carbon atoms, for example, a cycloalkyl group having 5 to 8 carbon atoms. Non-limiting examples of monocycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptylcyclooctyl and the like. Polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups. The term "heterocycloalkyl" as used herein, refers to a cycloalkyl group as defined above containing at least one heteroatom selected from N, O and S, for example a heterocycloalkyl group containing one or two N atoms, containing one a heterocycloalkyl group of an O atom, a heterocycloalkyl group having one S atom, for example, a 3-20 membered heterocycloalkyl group, for example, a 5-20 membered heterocycloalkyl group, for example, a 3-8 membered heterocycloalkyl group For example, it contains a 5-8 membered heterocycloalkyl group. Non-limiting examples of heterocycloalkyl groups include propylene oxide, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl. Wait. The term "aryl" as used herein refers to a 6-20 membered monocyclic or fused polycyclic (eg bicyclic or tricyclic) aromatic group, preferably a 6-14 membered aryl group, more preferably a 6-10 membered aryl group. Non-limiting examples of aryl groups include, but are not limited to, phenyl and naphthyl and the like. The term "heteroaryl" as used herein, refers to a 5-14 membered aromatic heterocyclic group substituted with at least one hetero atom selected from N, O or S, preferably 5-10 members. For example, a heteroaryl group containing one or two N atoms, a heteroaryl group containing one O atom or a heteroaryl group containing one S atom. Non-limiting examples of heteroaryl groups include furyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, Pyrimidinyl and pyrazinyl and the like.

本文所用术语“脂环”是指饱和或部分饱和的不具有芳香特性的碳环。例如包括3-20元脂环、3-12元脂环、3-8元脂环、4元脂环、5元脂环、6元脂环、7元脂环等。The term "alicyclic" as used herein refers to a saturated or partially saturated carbocyclic ring having no aromatic character. For example, it includes a 3-20-membered alicyclic ring, a 3-12-membered alicyclic ring, a 3-8-membered alicyclic ring, a 4-membered alicyclic ring, a 5-membered alicyclic ring, a 6-membered alicyclic ring, and a 7-membered alicyclic ring.

本文所用术语“脂杂环”是指至少一个环成员为选自N、O和S的杂原 子的脂肪族环状基团。例如含有1个或2个N原子的脂杂环、例如只含一个O原子的脂杂环、例如只含一个S原子的脂杂环等。例如包括3-20元脂杂环、3-12元脂杂环、3-8元脂杂环、4元脂杂环、5元脂杂环、6元脂杂环、7元脂杂环等。The term "aliphatic heterocycle" as used herein means that at least one ring member is a heterologous selected from the group consisting of N, O and S. A fatty aliphatic group. For example, an aliphatic heterocyclic ring containing one or two N atoms, for example, an aliphatic heterocyclic ring containing only one O atom, for example, an aliphatic heterocyclic ring containing only one S atom, or the like. For example, it includes a 3-20-membered alicyclic ring, a 3-12-membered alicyclic ring, a 3-8-membered alicyclic ring, a 4-membered alicyclic ring, a 5-membered alicyclic ring, a 6-membered alicyclic ring, a 7-membered alicyclic ring, and the like. .

本文所用术语“芳环”是指所有环成员均为碳原子的芳香环。例如包括6-20元芳环、6-14元芳环、6-10元芳环等。The term "aromatic ring" as used herein refers to an aromatic ring in which all ring members are carbon atoms. For example, it includes a 6-20 membered aromatic ring, a 6-14 membered aromatic ring, and a 6-10 membered aromatic ring.

本文所用术语“杂芳环”是指至少一个环成员为选自N、O和S的杂原子的具有芳香性的环状基团。例如含有1个或2个N原子的杂芳环、例如只含一个O原子的杂芳环、例如只含一个S原子的杂芳环等。例如包括5-20元杂芳环、5-14元杂芳环、5-10元杂芳环、5-6元杂芳环等。The term "heteroaromatic ring" as used herein refers to an aromatic cyclic group in which at least one ring member is a hetero atom selected from N, O and S. For example, a heteroaromatic ring containing one or two N atoms, for example, a heteroaromatic ring containing only one O atom, for example, a heteroaryl ring containing only one S atom, or the like. For example, it includes a 5-20 membered heteroaryl ring, a 5-14 membered heteroaryl ring, a 5-10 membered heteroaryl ring, a 5-6 membered heteroaryl ring, and the like.

本文所用术语“卤素”包括氟、氯、溴和碘。The term "halogen" as used herein includes fluoro, chloro, bromo and iodo.

在本文所述式I化合物中，其中

Figure PCTCN2016103735-appb-000032
的非限制性实施例包括：In the compounds of formula I described herein, wherein
Figure PCTCN2016103735-appb-000032
Non-limiting examples include:

Figure PCTCN2016103735-appb-000033
Figure PCTCN2016103735-appb-000033

Figure PCTCN2016103735-appb-000034
Figure PCTCN2016103735-appb-000034

所述稠环可被R5R6N-基团取代，所述取代位置的选择符合价键理论。The fused ring may be substituted with an R 5 R 6 N- group, the substitution position being selected in accordance with the valence bond theory.

本领域技术人员应当理解，当本申请所述化合物的分子结构中存在共轭体系时，符合价键理论的共振结构也在本申请的保护范围之内，例如，

Figure PCTCN2016103735-appb-000035
式a、式b和式c均在本申请的保护范围内。It will be understood by those skilled in the art that when a conjugated system exists in the molecular structure of the compound described herein, a resonance structure conforming to the valence bond theory is also within the scope of the present application, for example,
Figure PCTCN2016103735-appb-000035
Formula a, formula b and formula c are all within the scope of protection of the present application.

本文所用术语“异构体”包括本申请通式I化合物的所有可能的异构体 形式，例如对映异构体、非对映异构体、差向异构体、顺反异构体、构象异构体等。例如，R和S构型的对映异构体以及Z和E构型的顺反异构体等均在本申请的保护范围内。The term "isomer" as used herein includes all possible isomers of the compounds of formula I herein. Forms such as enantiomers, diastereomers, epimers, cis and trans isomers, conformational isomers and the like. For example, enantiomers of the R and S configurations as well as cis and trans isomers of the Z and E configurations are within the scope of the present application.

本申请式Ⅰ化合物或其药学可接受的盐还可以形成溶剂合物，例如水合物、醇合物等。The compound of the formula I or a pharmaceutically acceptable salt thereof may also form a solvate such as a hydrate, an alcoholate or the like.

本申请式I化合物还可以是前药或可在体内代谢变化后释放出活性成分的形式。选择和制备适当的前药是本领域技术人员公知技术。The compounds of formula I herein may also be in the form of a prodrug or which release the active ingredient after metabolic changes in the body. Selection and preparation of suitable prodrugs are well known to those skilled in the art.

本申请式Ⅰ化合物或其药学可接受的盐还可以以晶体存在，所述晶体是指构成化合物的分子、原子或离子在空间按一定规律周期重复的排列，其排列具有三维空间的周期性，隔一定的距离重复出现。化合物均可以两种或多种结晶状态存在，结构相同的分子结晶成不同的固体形式，称为“polymorph”，即为多晶型物或多晶形等。当涉及具体结晶形式或多晶型时，统称“crystal form”，即为本申请中使用的术语“晶型”，本申请包含所述式I化合物或其药学可接受的盐的任意晶型。The compound of the formula I or a pharmaceutically acceptable salt thereof may also exist in the form of a crystal, wherein the crystal refers to an arrangement in which molecules, atoms or ions constituting the compound are repeated in a regular cycle in a space, and the arrangement thereof has a periodicity of a three-dimensional space. Repeatedly at a certain distance. The compounds may exist in two or more crystalline states, and the molecules having the same structure are crystallized into different solid forms, which are called "polymorphs", that is, polymorphs or polymorphs. When referring to a particular crystalline form or polymorph, collectively referred to as "crystal form", the term "crystalline form" as used herein, the application encompasses any crystalline form of the compound of Formula I or a pharmaceutically acceptable salt thereof.

本文所用术语“有效量”是指足以实现所需预防和/或治疗效果的量，例如，实现预防或减轻与待治疗疾病相关的症状的量。The term "effective amount" as used herein refers to an amount sufficient to achieve the desired prophylactic and/or therapeutic effect, for example, to achieve an amount that prevents or reduces the symptoms associated with the condition to be treated.

本文所用的术语“治疗”是指治疗性处理和预防性措施，其目的是预防或延缓(减轻)所针对的疾病状态或病症。如果受试者按照本文所述方法接受了治疗量的化合物、或其异构体、溶剂合物、药学可接受的盐或其药物组合物，该受试者一种或多种指征和症状表现出可观察到的和/或可检测出的降低或改善，则受试者被成功地“治疗”了。还应当理解，所述的疾病状态或病症的预防或治疗的不仅包括完全地预防或治疗，还包括未达到完全地预防或治疗，但实现了一些生物学或医学相关的结果。The term "treating" as used herein refers to both therapeutic treatment and prophylactic measures, the purpose of which is to prevent or delay (reduce) the disease state or condition to which it is directed. If the subject receives a therapeutic amount of a compound, or an isomer, solvate, pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, as described herein, the subject has one or more indications and symptoms Subjects exhibit an observable and/or detectable reduction or improvement and the subject is successfully "treated". It will also be understood that the prevention or treatment of the disease state or condition includes not only complete prevention or treatment, but also failure to achieve complete prevention or treatment, but achieving some biological or medical related results.

本文所用术语“血管疾病”主要是指心肌缺血/再灌注损伤，损伤后各种形式的心脏衰竭，心肌病，循环性休克，心血管衰老，糖尿病的心血管并发症，心肌肥大，动脉粥样硬化，血管重塑，血管生成。The term "vascular disease" as used herein mainly refers to myocardial ischemia/reperfusion injury, various forms of heart failure after injury, cardiomyopathy, circulatory shock, cardiovascular aging, cardiovascular complications of diabetes, cardiac hypertrophy, atherosclerosis Hardening, vascular remodeling, angiogenesis.

本文所用术语“神经退变性疾和神经系统炎症”主要是指由于氧化，亚硝化应激的有害影响而导致的中风，脑外伤，神经变性疾病(帕金森氏病，阿尔茨海默氏病和肌萎缩性侧索硬化)和神经系统发炎如多发性硬化等。The term "neurodegenerative disease and inflammation of the nervous system" as used herein mainly refers to stroke, brain trauma, neurodegenerative diseases (Parkinson's disease, Alzheimer's disease and the like) caused by the harmful effects of oxidation and nitrosation stress. Amyotrophic lateral sclerosis) and inflammation of the nervous system such as multiple sclerosis.

发明的有益效果Advantageous effects of the invention

本申请通过对酞嗪酮类PARP抑制剂进行深入研究，提供了一类酞嗪酮类化合物，所述化合物能实现下述的至少一种技术效果：The present application provides a class of pyridazinone compounds by intensive investigation of pyridazinone PARP inhibitors, which can achieve at least one of the following technical effects:

(1)能够明显提高对肿瘤细胞或/和癌细胞的增殖抑制作用；(1) The proliferation inhibition effect on tumor cells or/and cancer cells can be significantly improved;

(2)能够增加分子体内稳定性，降低产生毒性代谢物的可能性； (2) It can increase the stability of the molecule in vivo and reduce the possibility of producing toxic metabolites;

(3)能降低药物分子的毒性，使其在疾病治疗方面的安全性得到进一步的提高，扩展了此类药物的适用病群范围；(3) It can reduce the toxicity of drug molecules, and further improve the safety of disease treatment, and expand the range of applicable diseases of such drugs;

(4)通过对酞嗪酮类化合物的结构修饰，减低了化合物在体内P450细胞色素酶系作用下的氧化代谢能力，提高了生物利用率；另外，(4) By modifying the structure of the pyridazinone compound, the oxidative metabolism ability of the compound under the action of P450 cytochrome system in vivo is reduced, and the bioavailability is improved;

(6)本申请的化合物具有优良的长效性，由此可以减少给药次数，提高患者的依从性。(6) The compound of the present application has excellent long-acting property, whereby the number of administrations can be reduced, and patient compliance can be improved.

本申请的化合物良好的理化性质使得其在开发具有优异生物利用度、抑制有效性和安全性的PARP抑制剂方面有很大的潜力。The good physicochemical properties of the compounds of the present application make them a great potential in the development of PARP inhibitors with excellent bioavailability, inhibition effectiveness and safety.

附图说明DRAWINGS

图1显示了，本申请化合物对乳腺癌MDA-MB-453的增殖抑制作用。Figure 1 shows the inhibitory effect of the compounds of the present application on the proliferation of breast cancer MDA-MB-453.

图2-1、图2-2显示了,本申请化合物对乳腺癌MDA-MB-468的增殖抑制作用。Figures 2-1 and 2-2 show the inhibitory effect of the compounds of the present application on the proliferation of breast cancer MDA-MB-468.

图3显示了，本申请化合物对胰腺癌Capan-1的增殖抑制作用。Figure 3 shows the inhibitory effect of the compounds of the present application on proliferation of pancreatic cancer Capan-1.

图4显示了，本申请化合物对直肠癌HCT116的增殖抑制作用。Figure 4 shows the inhibitory effect of the compounds of the present application on the proliferation of rectal cancer HCT116.

具体实施方式Detailed ways

下面将结合实施例对本发明的实施方案进行详细描述，但是本领域技术人员将会理解，下列实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。The embodiments of the present invention will be described in detail below with reference to the accompanying drawings, however, the following examples are intended to illustrate the invention and are not intended to limit the scope of the invention. Those who do not specify the specific conditions in the examples are carried out according to the conventional conditions or the conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are conventional products that can be obtained commercially.

化合物的结构是通过核磁共振(1HNMR)或质谱(MS)来确定的。The structure of the compound is determined by nuclear magnetic resonance ( 1 H NMR) or mass spectrometry (MS).

实施例中使用的核磁共振(NMR)图谱中的缩写示于以下：The abbreviations in the nuclear magnetic resonance (NMR) spectra used in the examples are shown below:

s：单峰(singlet)、d：二重峰(doublet)、t：三重峰(triplet)、q：四重峰(quartet)、AB：双二重峰(double doublet)、m：多重峰(multiplet)、br：宽峰(broad)。s: singlet, d: doublet, t: triplet, q: quartet, AB: double doublet, m: multiplet ( Multiplet), br: broad (broad).

1HNMR的测定是用JEOL Eclipse 400核磁仪，测定溶剂为氘代甲醇(CD3OD)、氘代氯仿(CDCl3)，六氘代二甲基亚砜(DMSO-d6)，内标为四甲基硅烷(TMS)，化学位移是以10-6(ppm)作为单位给出。 1 H NMR was measured by JEOL Eclipse 400 NMR, and the solvent was deuterated methanol (CD 3 OD), deuterated chloroform (CDCl 3 ), hexamethylene dimethyl sulfoxide (DMSO-d6), internal standard was four. Methylsilane (TMS), chemical shifts are given in units of 10 -6 (ppm).

MS的测定用Agilent(ESI)质谱仪，生产商:Agilent，型号:Agilent6120B。The MS was measured using an Agilent (ESI) mass spectrometer, manufacturer: Agilent, model: Agilent 6120B.

制备高效液相使用岛津LC-8A制备液相色谱仪(YMC，ODS,250×20mml色谱柱)。A high performance liquid phase was prepared using Shimadzu LC-8A preparative liquid chromatograph (YMC, ODS, 250 x 20 mml column).

薄层色谱硅胶板(TLC)使用Merck产的铝板(20×20cm)，薄层层析分离纯化采用的规格是烟台产GF254(0.4-0.5nm)。 The thin layer chromatography silica gel plate (TLC) was prepared by using an aluminum plate (20×20 cm) manufactured by Merck, and was purified by thin layer chromatography using a GF254 (0.4-0.5 nm) manufactured by Yantai.

反应的监测采用薄层色谱法(TLC)或LCMS，使用的展开剂体系有：二氯甲烷和甲醇体系，正己烷和乙酸乙酯体系，石油醚和乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节或者加入三乙胺等进行调节。The reaction was monitored by thin layer chromatography (TLC) or LCMS using the developing solvent system: dichloromethane and methanol system, n-hexane and ethyl acetate system, petroleum ether and ethyl acetate system, solvent volume ratio according to compound The polarity is adjusted differently or adjusted by adding triethylamine or the like.

微波反应使用Biotage Initiator+(400W,RT-300℃)微波反应器。The microwave reaction was carried out using a Biotage Initiator + (400 W, RT - 300 ° C) microwave reactor.

柱层析一般使用青岛海洋200-300目硅胶为载体。洗脱剂的体系包括:二氯甲烷和甲醇体系，正己烷和乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺进行调节。Column chromatography generally uses Qingdao Ocean 200-300 mesh silica gel as a carrier. The system of the eluent includes: dichloromethane and methanol systems, n-hexane and ethyl acetate systems, and the volume ratio of the solvent is adjusted depending on the polarity of the compound, and may also be adjusted by adding a small amount of triethylamine.

实施例中无特殊说明，反应的温度为室温(20℃-30℃)。There is no particular description in the examples, and the reaction temperature is room temperature (20 ° C to 30 ° C).

本申请所使用的试剂购自Acros Organics，Aldrich Chemical Company，特伯化学等公司。The reagents used in the present application were purchased from companies such as Acros Organics, Aldrich Chemical Company, and Tebe Chemical.

在常规的合成法以及实施例、和中间体合成例中，各缩写的意思如以下所示：In the conventional synthesis methods and examples, and intermediate synthesis examples, the meanings of the abbreviations are as follows:

DCM：二氯甲烷；DCM: dichloromethane;

DIPEA：N,N-二异丙基乙胺；DIPEA: N,N-diisopropylethylamine;

DMAP：4-二甲氨基吡啶；DMAP: 4-dimethylaminopyridine;

MeOH：甲醇；MeOH: methanol;

THF：四氢呋喃；THF: tetrahydrofuran;

EtOH：乙醇；EtOH: ethanol;

DMF：N,N-二甲基甲酰胺；DMF: N,N-dimethylformamide;

DMF-DMA:N,N-二甲基甲酰胺二甲基缩醛；DMF-DMA: N,N-dimethylformamide dimethyl acetal;

HATU：2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯；HATU: 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate;

NMP：N-甲基吡咯烷酮；NMP: N-methylpyrrolidone;

LCMS：液相质谱联用仪；LCMS: liquid chromatography mass spectrometer;

TLC：薄层色谱。TLC: thin layer chromatography.

实施例1：Example 1:

4-[3-(2-乙胺基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基)-4-氟苄基]-2H-酞嗪-1-酮(化合物1)4-[3-(2-Ethylamino-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one (Compound 1)

Figure PCTCN2016103735-appb-000036
Figure PCTCN2016103735-appb-000036

反应路线： Reaction route:

Figure PCTCN2016103735-appb-000037
Figure PCTCN2016103735-appb-000037

第一步：1-叔丁氧基羰基-3-二甲氨基甲烯基-4-吡咯烷酮First step: 1-tert-butoxycarbonyl-3-dimethylaminomethenyl-4-pyrrolidone

向N-Boc-3-吡咯烷酮(56.2g)中加入300mLDMF-DMA，65℃下搅拌过夜。TLC显示原料反应完全。浓缩除去DMF-DMA后，用甲基叔丁基醚洗涤所得固体，过滤，将固体浓缩至干，得到目标产物(47.2g，黄色固体，收率：64％)。To N-Boc-3-pyrrolidone (56.2 g), 300 mL of DMF-DMA was added, and the mixture was stirred at 65 ° C overnight. TLC showed the starting material to react completely. After concentrating to remove DMF-DMA, the obtained solid was washed with EtOAc (EtOAc).

MS m/z(ESI):241.1[M+H]+。MS m / z (ESI): 241.1 [M + H] +.

第二步：2-甲硫基-5,7-二氢-吡咯[3,4-d]嘧啶-6-羧酸叔丁酯The second step: 2-methylthio-5,7-dihydro-pyrrole [3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester

室温下，向250mL乙醇钠(6.6g，93mmol)的乙醇溶液中加入硫酸甲硫基脒(7.8g，41.6mmol)，搅拌约30分钟后，加入第一步的1-叔丁氧基羰基-3-二甲氨基甲烯基-4-吡咯烷酮(5g，20.8mmol)并回流搅拌6小时。TLC监测原料未反应完全，补加硫酸甲硫基脒(7.8g，41.6mmol)和乙醇钠(6.6g，93mmol)，回流过夜。TLC监测原料消失，加水淬灭反应体系后，浓缩除去乙醇。水相用乙酸乙酯(50mL×4)萃取,合并有机相,无水硫酸钠干燥。将有机相旋干后再用甲基叔丁基醚洗涤后得到目标分子(3.3g，淡黄色固体，收率：59％)。To a solution of 250 mL of sodium ethoxide (6.6 g, 93 mmol) in ethanol was added methyl mercaptosulfate (7.8 g, 41.6 mmol) at room temperature, and after stirring for about 30 minutes, the 1-tert-butoxycarbonyl group of the first step was added. 3-Dimethylaminoalkenyl-4-pyrrolidone (5 g, 20.8 mmol) was stirred at reflux for 6 h. The TLC monitored the starting material to be completely unreacted, and added methylthiosulfonium sulfate (7.8 g, 41.6 mmol) and sodium ethoxide (6.6 g, 93 mmol), and refluxed overnight. The TLC monitored the disappearance of the starting materials, and after quenching the reaction system with water, the ethanol was concentrated to remove. The aqueous phase was extracted with ethyl acetate (50 mL×4). The organic phase was dried and washed with methyl tert-butyl ether to give the title compound (3.3 g, pale yellow solid, yield: 59%).

MS m/z(ESI):268.1[M+H]+.MS m/z (ESI): 268.1 [M+H] + .

第三步：2-甲砜基-5,7-二氢-吡咯[3,4-d]嘧啶-6-羧酸叔丁酯The third step: 2-methylsulfonyl-5,7-dihydro-pyrrole [3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester

0℃下，向50mL2-甲硫基-5,7-二氢-吡咯[3,4-d]嘧啶-6-羧酸叔丁酯(3.3g，12.3mmol)的二氯甲烷溶液中加入间氯过氧苯甲酸(6.3g，37.1mmol)，自然升至室温，TLC跟踪监测。5小时后原料反应完全。向反应液中加入10％亚硫酸钠溶液，搅拌30分钟后再加入10％碳酸钠溶液，搅拌片刻后，用二氯甲烷(50mL×4)萃取，合并有机相，无水硫酸钠干燥，旋干，所得残余物再用甲基叔丁基醚洗涤后得到目标分子，收率：86.7％。To a solution of 50 mL of 2-methylthio-5,7-dihydro-pyrrole [3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester (3.3 g, 12.3 mmol) in dichloromethane at 0 ° C Chloroperoxybenzoic acid (6.3 g, 37.1 mmol) was naturally warmed to room temperature and was monitored by TLC. The raw material reaction was complete after 5 hours. Add 10% sodium sulfite solution to the reaction solution, stir for 30 minutes, then add 10% sodium carbonate solution, stir for a while, then extract with dichloromethane (50 mL × 4), and combine the organic phases, dried over anhydrous sodium sulfate, and dried. The obtained residue was washed with methyl t-butyl ether to give the title compound, yield: 86.7%.

MS m/z(ESI):300.3[M+H]+.MS m/z (ESI): 300.3 [M+H] + .

第四步：2-乙氨基-5,7-二氢-吡咯[3,4-d]嘧啶-6-羧酸叔丁酯Step 4: 2-Ethylamino-5,7-dihydro-pyrrole[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester

将第三步的2-甲砜基-5,7-二氢-吡咯[3,4-d]嘧啶-6-羧酸叔丁酯 (300mg,1.00mmol)溶于5mL乙腈中,加入碳酸钾(207mg,1.50mmol)和乙胺(132.6mg,2mmol)，所得混合物在70℃下反应6小时，用水淬灭反应，二氯甲烷萃取。二氯甲烷层经无水硫酸钠干燥，浓缩得到残余物经制备薄层色谱纯化后得到目标产物(110mg，收率：38％)。The third step of 2-methylsulfonyl-5,7-dihydro-pyrrole[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester (300 mg, 1.00 mmol) was dissolved in 5 mL of acetonitrile, potassium carbonate (207 mg, 1.50 mmol) and ethylamine (132.6 mg, 2 mmol) were added, and the mixture was reacted at 70 ° C for 6 hours, quenched with water and extracted with dichloromethane . The methylene chloride layer was dried over anhydrous sodium sulfate (MgSO4).

MS m/z(ESI):265[M+H]+.MS m/z (ESI): 265 [M+H] + .

第五步：N-乙基-6,7-二氢-5H-吡咯[3,4-d]嘧啶-2-胺盐酸盐Step 5: N-Ethyl-6,7-dihydro-5H-pyrrole[3,4-d]pyrimidin-2-amine hydrochloride

将第四步的2-乙氨基-5,7-二氢-吡咯[3,4-d]嘧啶-6-羧酸叔丁酯(10mg,0.45mmol)溶于氯化氢的乙酸乙酯溶液(3mL),室温下搅拌过夜。反应液浓缩后得到的残余物直接用于下一步反应。The fourth step of 2-ethylamino-5,7-dihydro-pyrrole[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester (10 mg, 0.45 mmol) was dissolved in ethyl acetate in ethyl acetate (3 mL) ), stir at room temperature overnight. The residue obtained after concentration of the reaction mixture was used directly for the next reaction.

MS m/z(ESI):165[M+H]+.MS m/z (ESI): 165 [M+H] + .

第六步：4-[3-(2-乙胺基-5,7-二氢-吡咯[3,4-d]嘧啶-6-羰基)-4-氟苄基]-2H-酞嗪-1-酮Step 6: 4-[3-(2-Ethylamino-5,7-dihydro-pyrrole[3,4-d]pyrimidin-6-carbonyl)-4-fluorobenzyl]-2H-pyridazine- 1-ketone

将5-(3,4-二氢-4-氧代-1-酞嗪基)甲基-2-氟苯甲酸(134.2mg,0.45mmol),第五步的N-乙基-6,7-二氢-5H-吡咯[3,4-d]嘧啶-2-胺盐酸盐(74.5mg,0.45mmol),HATU(188.2mg,0.50mmol)和DIPEA(348.3mg,2.7mmol)溶于DMF，室温搅拌过夜。反应完全后，向反应液中加入水和乙酸乙酯，分液，乙酸乙酯层经无水硫酸钠干燥后浓缩。残余物经制备薄层色谱纯化后得到目标产物(15mg，收率：7.5％)。5-(3,4-Dihydro-4-oxo-1-pyridazinyl)methyl-2-fluorobenzoic acid (134.2 mg, 0.45 mmol), N-ethyl-6,7 -Dihydro-5H-pyrrole[3,4-d]pyrimidin-2-amine hydrochloride (74.5 mg, 0.45 mmol), HATU (188.2 mg, 0.50 mmol) and DIPEA (348.3 mg, 2.7 mmol) dissolved in DMF Stir at room temperature overnight. After the reaction was completed, water and ethyl acetate were added to the mixture and the mixture was evaporated. The residue was purified by preparative thin-layer chromatography toield (yield:

MS m/z(ESI):445[M+H]+.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). 1 H NMR (400 MHz, 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 = 8 Hz) .

实施例2：Example 2:

4-[3-(2-环丙基氨基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基)-4-氟苄基]-2H-酞嗪-1-酮(化合物2)4-[3-(2-cyclopropylamino-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl)-4-fluorobenzyl]-2H-pyridazine-1- Ketone (compound 2)

Figure PCTCN2016103735-appb-000038
Figure PCTCN2016103735-appb-000038

反应路线： Reaction route:

Figure PCTCN2016103735-appb-000039
Figure PCTCN2016103735-appb-000039

第一步：1-叔丁氧基羰基-3-二甲氨基甲烯基-4-吡咯烷酮First step: 1-tert-butoxycarbonyl-3-dimethylaminomethenyl-4-pyrrolidone

向N-Boc-3-吡咯烷酮(56.2g)中加入300mLDMF-DMA，120℃下搅拌过夜。TLC显示原料反应完全。浓缩除去DMF-DMA后，用甲基叔丁基醚洗涤所得固体，过滤，将固体浓缩至干，得到目标产物(43g，黄色固体，收率：58％)。To N-Boc-3-pyrrolidone (56.2 g), 300 mL of DMF-DMA was added, and the mixture was stirred at 120 ° C overnight. TLC showed the starting material to react completely. The residue was washed with EtOAc (EtOAc)EtOAc.

MS m/z(ESI):241.1[M+H]+。MS m / z (ESI): 241.1 [M + H] +.

第二步：2-甲硫基-5,7-二氢-吡咯[3,4-d]嘧啶-6-羧酸叔丁酯The second step: 2-methylthio-5,7-dihydro-pyrrole [3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester

室温下，向250mL乙醇钠(6.6g，93mmol)的乙醇溶液中加入硫酸甲硫基脒(15.6g，83.2mmol)，搅拌约40分钟后，加入第一步的1-叔丁氧基羰基-3-二甲氨基甲烯基-4-吡咯烷酮(5g，20.8mmol)并回流搅拌过夜。TLC监测原料消失，加水淬灭后，浓缩除去乙醇。水相用乙酸乙酯(50mL×4)萃取,合并有机相,无水硫酸钠干燥，减压浓缩后再用甲基叔丁基醚洗涤后得到目标分子(10g，淡黄色固体，收率：89％)。To a solution of 250 mL of sodium ethoxide (6.6 g, 93 mmol) in ethanol was added methyl mercaptosulfate (15.6 g, 83.2 mmol) at room temperature, and after stirring for about 40 minutes, the 1-tert-butoxycarbonyl group of the first step was added. 3-Dimethylaminoalkenyl-4-pyrrolidone (5 g, 20.8 mmol) was stirred at reflux overnight. The TLC monitored the disappearance of the starting materials, and after quenching with water, the ethanol was concentrated to remove. The aqueous phase was extracted with ethyl acetate (50 mL×4). EtOAcjjjjjjjj 89%).

MS m/z(ESI):268.1[M+H]+.MS m/z (ESI): 268.1 [M+H] + .

第三步：2-(甲砜基)-5,7-二氢-吡咯[3,4-d]嘧啶-6-羧酸叔丁酯The third step: 2-(methylsulfonyl)-5,7-dihydro-pyrrole [3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester

0℃下，向50mL2-甲硫基-5,7-二氢-吡咯[3,4-d]嘧啶-6-羧酸叔丁酯(3.3g，12.3mmol)的二氯甲烷溶液中加入间氯过氧苯甲酸(6.3g，37.1mmol)，自然升至室温，反应完全后。向反应液中加入10％亚硫酸钠溶液，搅拌30分钟后再加入10％碳酸钠溶液，搅拌片刻后，用二氯甲烷(50mL×4)萃取，合并有机相，无水硫酸钠干燥，减压浓缩，再用甲基叔丁基醚洗涤后得到目标分子，收率：86.7％)。To a solution of 50 mL of 2-methylthio-5,7-dihydro-pyrrole [3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester (3.3 g, 12.3 mmol) in dichloromethane at 0 ° C Chloroperoxybenzoic acid (6.3 g, 37.1 mmol) was naturally warmed to room temperature and the reaction was completed. A 10% sodium sulfite solution was added to the reaction mixture, and the mixture was stirred for 30 minutes, and then a 10% sodium carbonate solution was added thereto. After stirring for a while, it was extracted with dichloromethane (50 mL×4). The target molecule was obtained by washing with methyl tert-butyl ether in a yield of 86.7%.

MS m/z(ESI):300.3[M+H]+.MS m/z (ESI): 300.3 [M+H] + .

第四步：2-环丙氨基-5,7-二氢-吡咯[3,4-d]嘧啶-6-羧酸叔丁酯Step 4: 2-Cyclopropylamino-5,7-dihydro-pyrrole[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester

将第三步的2-甲砜基-5,7-二氢-吡咯[3,4-d]嘧啶-6-羧酸叔丁酯(300mg,1.00mmol)溶于5mL乙腈中,加入碳酸钾(207mg,1.50mmol)和环丙 基胺(2mmol)，所得混合物在75℃下反应8小时,用水淬灭反应，二氯甲烷萃取。二氯甲烷层经无水硫酸钠干燥，浓缩得到残余物经制备薄层色谱纯化后得到目标产物(400mg,收率：69％)。The third step of 2-methylsulfonyl-5,7-dihydro-pyrrole[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester (300 mg, 1.00 mmol) was dissolved in 5 mL of acetonitrile and potassium carbonate was added. (207 mg, 1.50 mmol) and cyclopropane The amine (2 mmol) was reacted at 75 ° C for 8 hours, quenched with water and extracted with dichloromethane. The methylene chloride layer was dried over anhydrous sodium sulfate (MgSO4).

MS m/z(ESI):265[M+H]+.MS m/z (ESI): 265 [M+H] + .

第五步：N-环丙基-6,7-二氢-5H-吡咯[3,4-d]嘧啶-2-胺盐酸盐将第四步的2-环丙氨基-5,7-二氢-吡咯[3,4-d]嘧啶-6-羧酸叔丁酯(400mg,18mmol)溶于氯化氢的乙酸乙酯溶液(3mL),室温下搅拌过夜。反应液浓缩后得到的残余物直接用于下一步反应。Step 5: N-cyclopropyl-6,7-dihydro-5H-pyrrole[3,4-d]pyrimidin-2-amine hydrochloride The fourth step of 2-cyclopropylamino-5,7- Dihydro-pyrrole[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester (400 mg, 18 mmol) was dissolved in ethyl acetate (3 mL) EtOAc. The residue obtained after concentration of the reaction mixture was used directly for the next reaction.

MS m/z(ESI):165[M+H]+.MS m/z (ESI): 165 [M+H] + .

第六步：4-[3-(2-环丙基氨基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基)-4-氟苄基)-2H-酞嗪-1-酮Step 6: 4-[3-(2-Cyclopropylamino-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl)-4-fluorobenzyl)-2H-indole Pyrazin-1-one

将5-(3,4-二氢-4-氧代-1-酞嗪基)甲基-2-氟苯甲酸(134.2mg,0.45mmol),第五步的N-环丙胺基-6,7-二氢-5H吡咯[3,4,-d]嘧啶-2-胺盐酸盐(95mg,0.45mmol),HATU(188.2mg,0.50mmol)和DIPEA(348.3mg,2.7mmol)溶于DMF，室温搅拌过夜。反应完全后，向反应液中加入水和乙酸乙酯，分液，乙酸乙酯层经无水硫酸钠干燥后浓缩。残余物经制备薄层色谱纯化后得到目标产物(76mg,收率：37％)。5-(3,4-Dihydro-4-oxo-1-pyridazinyl)methyl-2-fluorobenzoic acid (134.2 mg, 0.45 mmol), N-cyclopropylamino-6 of the fifth step, 7-Dihydro-5Hpyrrole[3,4,-d]pyrimidin-2-amine hydrochloride (95 mg, 0.45 mmol), HATU (188.2 mg, 0.50 mmol) and DIPEA (348.3 mg, 2.7 mmol) dissolved in DMF Stir at room temperature overnight. After the reaction was completed, water and ethyl acetate were added to the mixture and the mixture was evaporated. The residue was purified by preparative thin-layer chromatography to afford the desired product (76 mg, yield: 37%).

MS m/z(ESI):457[M+H]+.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). 1 H NMR (400 MHz, 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).

实施例3：Example 3:

4-[3-(2-环丙基甲基氨基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基)-4-氟苄基]-2H-酞嗪-1-酮(化合物3)4-[3-(2-Cyclopropylmethylamino-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl)-4-fluorobenzyl]-2H-pyridazine- 1-ketone (compound 3)

Figure PCTCN2016103735-appb-000040
Figure PCTCN2016103735-appb-000040

反应路线：Reaction route:

Figure PCTCN2016103735-appb-000041
Figure PCTCN2016103735-appb-000041

Figure PCTCN2016103735-appb-000042
Figure PCTCN2016103735-appb-000042

第一步：1-叔丁氧基羰基-3-二甲氨基甲烯基-4-吡咯烷酮First step: 1-tert-butoxycarbonyl-3-dimethylaminomethenyl-4-pyrrolidone

向N-Boc-3-吡咯烷酮(18.5g)中加入300mL DMF-DMA,60℃下搅拌过夜。TLC显示原料反应完全。浓缩除去DMF-DMA后，用甲基叔丁基醚洗涤所得固体，过滤，将固体浓缩至干，得到目标产物(20g，黄色固体，收率：83％)。To N-Boc-3-pyrrolidone (18.5 g) was added 300 mL of DMF-DMA, and the mixture was stirred at 60 ° C overnight. TLC showed the starting material to react completely. After the DMF-DMA was removed, the obtained solid was washed with EtOAc (EtOAc).

MS m/z(ESI):241.1[M+H]+。MS m / z (ESI): 241.1 [M + H] +.

第二步：2-羟基-5,7-二氢-吡咯[3,4-d]嘧啶-6-羧酸叔丁酯Second step: 2-hydroxy-5,7-dihydro-pyrrole [3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester

室温下，向250mL乙醇钠(13.2g，186mmol)的乙醇溶液中加入脲(10g，166.4mmol)，搅拌约40分钟后，加入第一步的1-叔丁氧基羰基-3-二甲氨基甲烯基-4-吡咯烷酮(10g，41.6mmol)并回流搅拌过夜。TLC监测原料消失，加水淬灭后，浓缩除去乙醇。水相用乙酸乙酯(50mL×4)萃取,合并有机相,无水硫酸钠干燥。旋干后再用甲基叔丁基醚洗涤后得到目标分子(6.2g，淡黄色固体，收率：63％)。Urea (10 g, 166.4 mmol) was added to a solution of 250 mL of sodium ethoxide (13.2 g, 186 mmol) in ethanol at room temperature. After stirring for about 40 minutes, the first step of 1-tert-butoxycarbonyl-3-dimethylamino was added. Methylenyl-4-pyrrolidone (10 g, 41.6 mmol) was stirred at reflux overnight. The TLC monitored the disappearance of the starting materials, and after quenching with water, the ethanol was concentrated to remove. The aqueous phase was extracted with ethyl acetate (50 mL×4). After spin-drying and washing with methyl tert-butyl ether, the title compound (6.2 g, pale yellow solid, yield: 63%) was obtained.

MS m/z(ESI):268.1[M+H]+.MS m/z (ESI): 268.1 [M+H] + .

第三步：2-氯-6,7-二氢-5H-吡咯并[3,4-d]嘧啶盐酸盐The third step: 2-chloro-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine hydrochloride

0℃下，将2-羟基-5,7-二氢-吡咯[3,4-d]嘧啶-6-羧酸叔丁酯(6.2g，26.2mmol)溶于三氯氧磷(10mL)得到的溶液自然升温至室温反应至原料消失，蒸除三氯氧磷后得到的残余物直接用于下一步反应。2-Hydroxy-5,7-dihydro-pyrrole[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester (6.2 g, 26.2 mmol) was dissolved in phosphorus oxychloride (10 mL) at 0 ° C. The solution was naturally warmed to room temperature until the starting material disappeared, and the residue obtained after evaporation of phosphorus oxychloride was directly used for the next reaction.

MS m/z(ESI):156[M+H]+.MS m/z (ESI): 156 [M+H] + .

第四步：N-(环丙基甲基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-胺Step 4: N-(cyclopropylmethyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine

将2-氯-6,7-二氢-5H-吡咯并[3,4-d]嘧啶盐酸盐(385mg,2mmol)加热下加入到环丙甲基胺(10mL)中，TLC监测反应完全后，制备TLC纯化得到目标产物40mg,收率10.5％。2-Chloro-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine hydrochloride (385 mg, 2 mmol) was added to cyclopropylmethylamine (10 mL) under heating, and the reaction was completely monitored by TLC. After purification by preparative TLC, 40 mg of the aimed product was obtained, yield: 10.5%.

第五步：4-[3-(2-环丙基甲基氨基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基)-4-氟苄基]-2H-酞嗪-1-酮Step 5: 4-[3-(2-Cyclopropylmethylamino-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl)-4-fluorobenzyl]-2H -pyridazine-1-one

将5-(3,4-二氢-4-氧代-1-酞嗪基)甲基-2-氟苯甲酸(63mg,0.21mmol),第四步的N-(环丙基甲基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-胺(40mg,0.21mmol),HATU(95mg,0.25mmol)和DIPEA(38.7mg,0.3mmol)溶于DMF， 室温搅拌过夜。反应完全后，向反应液中加入水和乙酸乙酯，分液，乙酸乙酯层经无水硫酸钠干燥后浓缩。残余物经制备薄层色谱纯化后得到目标产物(32.6mg,收率：33％)。5-(3,4-Dihydro-4-oxo-1-pyridazinyl)methyl-2-fluorobenzoic acid (63 mg, 0.21 mmol), N-(cyclopropylmethyl) in the fourth step -6,7-Dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine (40 mg, 0.21 mmol), HATU (95 mg, 0.25 mmol) and DIPEA (38.7 mg, 0.3 mmol) dissolved in DMF , Stir at room temperature overnight. After the reaction was completed, water and ethyl acetate were added to the mixture and the mixture was evaporated. The residue was purified by preparative thin-layer chromatography toield (32.6mg, yield: 33%).

MS m/z(ESI):471[M+H]+ 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). 1 H NMR (400 MHz, 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).

实施例4：Example 4:

4-{4-氟-3-[2-(2-羟乙基氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮(化合物4)4-{4-Fluoro-3-[2-(2-hydroxyethylamino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl}-2H-indole Pyrazin-1-one (compound 4)

Figure PCTCN2016103735-appb-000043
Figure PCTCN2016103735-appb-000043

反应路线：Reaction route:

Figure PCTCN2016103735-appb-000044
Figure PCTCN2016103735-appb-000044

第一步：1-叔丁氧基羰基-3-二甲氨基甲烯基-4-吡咯烷酮First step: 1-tert-butoxycarbonyl-3-dimethylaminomethenyl-4-pyrrolidone

向N-Boc-3-吡咯烷酮(37g)中加入300mL DMF-DMA,60℃下搅拌过夜。TLC显示原料反应完全。浓缩除去DMF-DMA后，用四氢呋喃洗涤所得固体，过滤，将固体浓缩至干，得到目标产物(35g，黄色固体，收率：72.6％)。To N-Boc-3-pyrrolidone (37 g) was added 300 mL of DMF-DMA, and the mixture was stirred at 60 ° C overnight. TLC showed the starting material to react completely. After concentrating to remove DMF-DMA, the obtained solid was washed with EtOAc (EtOAc).

MS m/z(ESI):241.1[M+H]+。MS m / z (ESI): 241.1 [M + H] +.

第二步：2-羟基-5,7-二氢-吡咯[3,4-d]嘧啶-6-羧酸叔丁酯Second step: 2-hydroxy-5,7-dihydro-pyrrole [3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester

室温下，向250mL乙醇钠(26.4g，372mmol)的乙醇溶液中加入脲(20 g，332.8mmol)，搅拌约40分钟后，加入第一步的1-叔丁氧基羰基-3-二甲氨基甲烯基-4-吡咯烷酮(20g，83.2mmol)并回流搅拌过夜。TLC监测原料消失，加水淬灭后，浓缩除去乙醇。水相用乙酸乙酯(50mL×5)萃取,合并有机相,无水硫酸钠干燥。旋干后再用甲基叔丁基醚洗涤后得到目标分子(11g，淡黄色固体，收率：55.9％)。Urea (20) was added to a solution of 250 mL of sodium ethoxide (26.4 g, 372 mmol) in ethanol at room temperature. g, 332.8 mmol), after stirring for ca. 40 min, then 1-t-butoxycarbonyl-3-dimethylamino- </RTI> <RTIgt; </RTI> <RTIgt; The TLC monitored the disappearance of the starting materials, and after quenching with water, the ethanol was concentrated to remove. The aqueous phase was extracted with ethyl acetate (50 mL×5). After spin-drying and washing with methyl tert-butyl ether, the title compound was obtained (11 g, pale yellow solid, yield: 55.9%).

MS m/z(ESI):268.1[M+H]+.MS m/z (ESI): 268.1 [M+H] + .

第三步：2-氯-6,7-二氢-5H-吡咯并[3,4-d]嘧啶盐酸盐The third step: 2-chloro-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine hydrochloride

0℃下，将2-羟基-5,7-二氢-吡咯[3,4-d]嘧啶-6-羧酸叔丁酯(10g，42mmol)溶于三氯氧磷(40mL)得到的溶液自然升温至室温反应至原料消失，蒸除三氯氧磷后得到的残余物直接用于下一步反应。a solution of 2-hydroxy-5,7-dihydro-pyrrole[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester (10 g, 42 mmol) dissolved in phosphorus oxychloride (40 mL) at 0 ° C The mixture was naturally warmed to room temperature until the starting material disappeared, and the residue obtained after evaporation of phosphorus oxychloride was directly used for the next reaction.

MS m/z(ESI):156[M+H]+.MS m/z (ESI): 156 [M+H] + .

第四步：2-((6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-基)氨基)乙醇Step 4: 2-((6,7-Dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)ethanol

将2-氯-6,7-二氢-5H-吡咯并[3,4-d]嘧啶盐酸盐(385mg,2mmol)加热下加入到乙醇胺(50mL)中，TLC监测反应完全后，制备TLC纯化得到目标产物29.6mg,收率7.8％。2-Chloro-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine hydrochloride (385 mg, 2 mmol) was added to ethanolamine (50 mL) under heating, and the reaction was completed by TLC to prepare TLC. Purification gave the desired product 29.6 mg,yield 7.8%.

第五步：4-{4-氟-3-[2-(2-羟乙基氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮Step 5: 4-{4-Fluoro-3-[2-(2-hydroxyethylamino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl} -2H-phthalazin-1-one

将5-(3,4-二氢-4-氧代-1-酞嗪基)甲基-2-氟苯甲酸(63mg,0.21mmol),第四步的2-((6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-基)氨基)乙醇(29.6mg,0.16mmol),HATU(95mg,0.25mmol)和DIPEA(38.7mg,0.3mmol)溶于DMF，室温搅拌过夜。反应完全后，向反应液中加入水和乙酸乙酯，分液，甲基叔丁基醚层经无水硫酸钠干燥后浓缩。残余物经制备薄层色谱纯化后得到目标产物(20.6mg,收率：28％)。5-(3,4-Dihydro-4-oxo-1-pyridazinyl)methyl-2-fluorobenzoic acid (63 mg, 0.21 mmol), 2-((6,7-II) Hydrogen-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)ethanol (29.6 mg, 0.16 mmol), HATU (95 mg, 0.25 mmol) and DIPEA (38.7 mg, 0.3 mmol) were dissolved in DMF. Stir at room temperature overnight. After the reaction was completed, water and ethyl acetate were added to the mixture, and the mixture was evaporated. The residue was purified by preparative thin-layer chromatography to afford the desired product (20.6mg, yield: 28%).

MS m/z(ESI):461[M+H]+.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). 1 H NMR (400 MHz, 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).

实施例5：Example 5:

4-{3-[2-(2-二甲基氨基乙氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]-4-氟苄基}-2H-酞嗪-1-酮(化合物5)4-{3-[2-(2-Dimethylaminoethylamino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]-4-fluorobenzyl}-2H -pyridazine-1-one (Compound 5)

Figure PCTCN2016103735-appb-000045
Figure PCTCN2016103735-appb-000045

Figure PCTCN2016103735-appb-000046
Figure PCTCN2016103735-appb-000046

反应路线：Reaction route:

Figure PCTCN2016103735-appb-000047
Figure PCTCN2016103735-appb-000047

第一步：2-(2-二甲氨基乙氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6碳酸叔丁酯First step: 2-(2-dimethylaminoethylamino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-tert-butyl ester

标题化合物采用实施例1第四步的方法合成,用N,N-二甲基乙二胺取代实施例1第四步所用的乙胺。The title compound was synthesized by the method of the fourth step of Example 1, and the ethylamine used in the fourth step of Example 1 was replaced with N,N-dimethylethylenediamine.

第二步：N1-(6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-基)-N,N-二甲基乙基-1,2-二胺盐酸盐.Second step: N 1 -(6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-N,N-dimethylethyl-1,2-diamine salt Acid salt.

标题化合物采用实施例1第五步的方法合成，用2-(2-二甲氨基乙氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6碳酸叔丁酯取代2-乙氨基-5,7-二氢-吡咯[3,4-d]嘧啶-6-羧酸叔丁酯。The title compound was synthesized by the method of the fifth step of Example 1, and replaced with 2-(2-dimethylaminoethylamino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-tert-butyl ester. 2-Ethylamino-5,7-dihydro-pyrrole[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester.

第三步：4-{3-[2-(2-二甲基氨基乙氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]-4-氟苄基}-2H-酞嗪-1-酮The third step: 4-{3-[2-(2-dimethylaminoethylamino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]-4-fluorobenzyl -2}-2H-phthalazin-1-one

采用类似于实施例1第六步的实验步骤合成,用N1-(6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-基)-N,N-二甲基乙基-1,2-二胺盐酸盐取代实施例1中所用的N-乙基-6,7-二氢-5H-吡咯[3,4-d]嘧啶-2-胺盐酸盐。Synthesis using an experimental procedure similar to the sixth step of Example 1, using N 1 -(6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-N,N-dimethyl The ethylethyl-1,2-diamine hydrochloride replaces the N-ethyl-6,7-dihydro-5H-pyrrole[3,4-d]pyrimidin-2-amine hydrochloride used in Example 1. .

MS m/z(ESI):488[M+H]+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). 1 H NMR (400MHz, DMSO- d 6) 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).

实施例6Example 6

4-{4-氟-3-[2-(四氢-吡喃-4-氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]-苄基}-2H-酞嗪-1-酮(化合物6) 4-{4-Fluoro-3-[2-(tetrahydro-pyran-4-amino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]-benzyl} -2H-phthalazin-1-one (compound 6)

Figure PCTCN2016103735-appb-000048
Figure PCTCN2016103735-appb-000048

反应路线：Reaction route:

Figure PCTCN2016103735-appb-000049
Figure PCTCN2016103735-appb-000049

第一步：2-(四氢-吡喃-4-氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-碳酸叔丁酯First step: 2-(tetrahydro-pyran-4-amino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonate tert-butyl ester

标题化合物采用实施例1第四步的方法合成,用4-氨基-四氢-吡喃取代实施例1第四步所用的乙胺。The title compound was synthesized by the method of the fourth step of Example 1, and the ethylamine used in the fourth step of Example 1 was replaced with 4-amino-tetrahydro-pyran.

第二步：N-(四氢-吡喃-4-基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-胺盐酸盐.The second step: N-(tetrahydro-pyran-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine hydrochloride.

标题化合物采用实施例1第五步的方法合成，用2-(四氢-吡喃-4-氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-碳酸叔丁酯取代2-乙氨基-5,7-二氢-吡咯[3,4-d]嘧啶-6-羧酸叔丁酯。The title compound was synthesized by the method of the fifth step of Example 1, using 2-(tetrahydro-pyran-4-amino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonate Butyl ester replaces 2-ethylamino-5,7-dihydro-pyrrole [3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester.

第三步：4-{4-氟-3-[2-(四氢-吡喃-4-氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]-苄基}-2H-酞嗪-1-酮Third step: 4-{4-fluoro-3-[2-(tetrahydro-pyran-4-amino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl] -benzyl}-2H-phthalazin-1-one

采用类似于实施例1第六步的实验步骤合成,用N-(四氢-吡喃-4-基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-胺盐酸盐取代实施例1中所用的N-乙基-6,7-二氢-5H-吡咯[3,4-d]嘧啶-2-胺盐酸盐。Synthesis using an experimental procedure similar to the sixth step of Example 1, using N-(tetrahydro-pyran-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-2 The amine hydrochloride salt replaces the N-ethyl-6,7-dihydro-5H-pyrrole[3,4-d]pyrimidin-2-amine hydrochloride used in Example 1.

MS m/z(ESI):501[M+H]+ 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). 1 H NMR (400 MHz, 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).

实施例7Example 7

4-[3-(2-二甲氨基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基)-4-氟苄基]-2H-酞嗪-1-酮(化合物7)4-[3-(2-Dimethylamino-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one (Compound 7)

Figure PCTCN2016103735-appb-000050
Figure PCTCN2016103735-appb-000050

反应路线Reaction route

Figure PCTCN2016103735-appb-000051
Figure PCTCN2016103735-appb-000051

第一步：2-二甲氨基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-碳酸叔丁酯First step: 2-dimethylamino-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonate tert-butyl ester

标题化合物采用实施例1第四步的方法合成,用二甲胺甲醇溶液取代实施例1第四步所用的乙胺。The title compound was synthesized by the method of the fourth step of Example 1, and the ethylamine used in the fourth step of Example 1 was replaced with a dimethylamine methanol solution.

第二步：N,N-二甲基-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-胺盐酸盐.The second step: N, N-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine hydrochloride.

标题化合物采用实施例1第五步的方法合成，用2-二甲氨基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-碳酸叔丁酯取代2-乙氨基-5,7-二氢-吡咯[3,4-d]嘧啶-6-羧酸叔丁酯。The title compound was synthesized by the method of the fifth step of Example 1, substituting 2-ethylamino-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonate tert-butyl ester to 2-ethylamino- tert-Butyl 5,7-dihydro-pyrrole[3,4-d]pyrimidine-6-carboxylate.

第三步：third step:

4-[3-(2-二甲氨基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基)-4-氟苄基]-2H-酞嗪-1-酮采用类似于实施例1第六步的实验步骤合成,用N,N-二甲基-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-胺盐酸盐取代实施例1中所用的N-乙基-6,7-二氢-5H-吡咯[3,4-d]嘧啶-2-胺盐酸盐。4-[3-(2-Dimethylamino-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one Synthesis using an experimental procedure similar to the sixth step of Example 1, substituting N,N-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine hydrochloride N-ethyl-6,7-dihydro-5H-pyrrole[3,4-d]pyrimidin-2-amine hydrochloride used in Example 1.

MS m/z(ESI):445[M+H]+ 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). 1 H 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).

实施例8Example 8

4-{4-氟-3-[2-(2-甲氧基乙基胺)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]-苄 基}-2H-酞嗪-1-酮(化合物8)4-{4-Fluoro-3-[2-(2-methoxyethylamine)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]-benzyl }}-2H-phthalazin-1-one (compound 8)

Figure PCTCN2016103735-appb-000052
Figure PCTCN2016103735-appb-000052

反应路线：Reaction route:

Figure PCTCN2016103735-appb-000053
Figure PCTCN2016103735-appb-000053

第一步：1-叔丁氧基羰基-3-二甲氨基甲烯基-4-吡咯烷酮First step: 1-tert-butoxycarbonyl-3-dimethylaminomethenyl-4-pyrrolidone

向N-Boc-3-吡咯烷酮(37g)中加入300mL DMF-DMA,80℃下搅拌过夜。TLC显示原料反应完全。浓缩除去DMF-DMA后，用乙醚洗涤所得固体，过滤，将固体浓缩至干，得到目标产物(35g，黄色固体，收率：72.6％)。To N-Boc-3-pyrrolidone (37 g) was added 300 mL of DMF-DMA, and the mixture was stirred at 80 ° C overnight. TLC showed the starting material to react completely. After the removal of DMF- DMA, EtOAc (EtOAc:EtOAc)

MS m/z(ESI):241.1[M+H]+。MS m / z (ESI): 241.1 [M + H] +.

第二步：2-羟基-5,7-二氢-吡咯[3,4-d]嘧啶-6-羧酸叔丁酯Second step: 2-hydroxy-5,7-dihydro-pyrrole [3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester

室温下，向250mL乙醇钠(26.4g，372mmol)的乙醇溶液中加入脲(20g，332.8mmol)，搅拌约40分钟后，加入第一步的1-叔丁氧基羰基-3-二甲氨基甲烯基-4-吡咯烷酮(20g，83.2mmol)并回流搅拌过夜。TLC监测原料消失，加水淬灭后，浓缩除去乙醇。水相用乙酸乙酯(50mL×5)萃取,合并有机相,无水硫酸钠干燥。减压浓缩后再用甲基叔丁基醚洗涤后得到目标分子(11g，淡黄色固体，收率：55.9％)。To a solution of 250 mL of sodium ethoxide (26.4 g, 372 mmol) in ethanol was added urea (20 g, 332.8 mmol) at room temperature, and after stirring for about 40 minutes, the first step of 1-tert-butoxycarbonyl-3-dimethylamino was added. Methylenyl-4-pyrrolidone (20 g, 83.2 mmol) was stirred at reflux overnight. The TLC monitored the disappearance of the starting materials, and after quenching with water, the ethanol was concentrated to remove. The aqueous phase was extracted with ethyl acetate (50 mL×5). After concentration under reduced pressure, the title compound (11 g, pale yellow solid, yield: 55.9%).

MS m/z(ESI):268.1[M+H]+.MS m/z (ESI): 268.1 [M+H] + .

第三步：2-(((三氟甲基)磺酰基)氧基)-5H-吡咯并[3,4-d]嘧啶-6(7H)-碳酸叔丁酯Third step: 2-(((trifluoromethyl)sulfonyl)oxy)-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-tert-butyl carbonate

将2-羟基-5,7-二氢-吡咯[3,4-d]嘧啶-6-羧酸叔丁酯(237mg,1mmol)和N-甲基吗啉(253mg,2.5mmol)溶于THF(10mL)，冰浴下滴加三氟甲磺酸酐(338.4mg,1.2mmol)的THF溶液(5mL)。TLC监测反应结束 后蒸干THF，加入水和乙酸乙酯，乙酸乙酯层用无水硫酸钠干燥，旋干后得到目标产物的粗品直接用于下一步反应。2-Hydroxy-5,7-dihydro-pyrrole[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester (237 mg, 1 mmol) and N-methylmorpholine (253 mg, 2.5 mmol) were dissolved in THF (10 mL), a solution of trifluoromethanesulfonic anhydride (338.4 mg, 1.2 mmol) in THF (5 mL). TLC monitors the end of the reaction After the THF was evaporated to dryness, water and ethyl acetate were added, and ethyl acetate layer was dried over anhydrous sodium sulfate.

第四步：2-((2-甲氧基乙基)氨基)-5H-吡咯并[3,4-d]嘧啶-6(7H)-碳酸叔丁酯Step 4: 2-((2-Methoxyethyl)amino)-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-tert-butyl carbonate

将2-(((三氟甲基)磺酰基)氧基)-5H-吡咯并[3,4-d]嘧啶-6(7H)-碳酸叔丁酯(370mg,1mmol)和2-甲氧基乙胺(75mg,1mmol)溶于THF，然后加入Pd(dppf)Cl2二氯甲烷络合物(30mg),DIPEA(142mg,1.1mmol)和BrettPhos(60mg)。所得混合物在回流下反应完全后，蒸干THF加入水和乙酸乙酯萃取(10mLx8)。蒸干乙酸乙酯，残余物制备TLC纯化得到目标产物110mg,收率37％。2-((((Trifluoromethyl)sulfonyl)oxy)-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-tert-butyl carbonate (370 mg, 1 mmol) and 2-methoxy Ethylethylamine (75 mg, 1 mmol) was dissolved in THF, then Pd(dppf)Cl2 dichloromethane (30 mg), DIPEA (142 mg, 1.1 mmol) and BrettPhos (60 mg). After the reaction mixture was completed under reflux, THF was evaporated and evaporated and ethylamine Ethyl acetate was evaporated to dryness.

第五步：N-(2-甲氧基乙基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-胺盐酸盐Step 5: N-(2-methoxyethyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine hydrochloride

将第四步的2-((2-甲氧基乙基)氨基)-5H-吡咯并[3,4-d]嘧啶-6(7H)-碳酸叔丁酯(110mg,0.37mmol)溶于氯化氢的乙酸乙酯溶液(3mL),室温下搅拌过夜。反应液浓缩后得到的残余物直接用于下一步反应。Dissolving the second step of 2-((2-methoxyethyl)amino)-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-tert-butyl carbonate (110 mg, 0.37 mmol) A solution of hydrogen chloride in ethyl acetate (3 mL) was stirred at room temperature overnight. The residue obtained after concentration of the reaction mixture was used directly for the next reaction.

MS m/z(ESI):194[M+H]+.MS m/z (ESI): 194 [M+H] + .

第六步：4-{4-氟-3-[2-(2-甲氧基乙基胺)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]-苄基}-2H-酞嗪-1-酮Step 6: 4-{4-Fluoro-3-[2-(2-methoxyethylamine)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]- Benzyl}-2H-phthalazin-1-one

将5-(3,4-二氢-4-氧代-1-酞嗪基)甲基-2-氟苯甲酸(89.4mg,0.3mmol),第五步的N-(2-甲氧基乙基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-胺盐酸盐(65mg,0.28mmol),HATU(114mg,0.30mmol)和DIPEA(77.4mg,0.6mmol)溶于DMF，室温搅拌过夜。反应完全后，向反应液中加入水和乙酸乙酯，分液，乙酸乙酯层经无水硫酸钠干燥后浓缩。残余物经制备薄层色谱纯化后得到目标产物(32mg,收率：22.5％)。5-(3,4-Dihydro-4-oxo-1-pyridazinyl)methyl-2-fluorobenzoic acid (89.4 mg, 0.3 mmol), N-(2-methoxy) in the fifth step Ethyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine hydrochloride (65 mg, 0.28 mmol), HATU (114 mg, 0.30 mmol) and DIPEA (77.4 mg, 0.6 mmol) was dissolved in DMF and stirred at room temperature overnight. After the reaction was completed, water and ethyl acetate were added to the mixture and the mixture was evaporated. The residue was purified by preparative thin-layer chromatography toield (yield: 22%).

MS m/z(ESI):475[M+H]+ 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). 1 H 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), 3.25 and 3.23 (s, 3H).

实施例9Example 9

4-{4-氟-3-[2-(2-羟基-2-甲基丙基氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]-苄基}-2H-酞嗪-1-酮(化合物9) 4-{4-Fluoro-3-[2-(2-hydroxy-2-methylpropylamino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]-benzyl }}-2H-phthalazin-1-one (compound 9)

Figure PCTCN2016103735-appb-000054
Figure PCTCN2016103735-appb-000054

反应路线：Reaction route:

Figure PCTCN2016103735-appb-000055
Figure PCTCN2016103735-appb-000055

第一步：2-(2-羟基-2-甲基丙基氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-碳酸叔丁酯First step: 2-(2-hydroxy-2-methylpropylamino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonate tert-butyl ester

标题化合物采用实施例1第四步的方法合成,用1-氨基-2-甲基丙基-2-醇取代实施例1第四步所用的乙胺。The title compound was synthesized by the method of the fourth step of Example 1, and the ethylamine used in the fourth step of Example 1 was replaced with 1-amino-2-methylpropyl-2-ol.

第二步：1-(6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-氨基)-2-甲基丙基-2-醇盐酸盐.The second step: 1-(6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amino)-2-methylpropyl-2-ol hydrochloride.

标题化合物采用实施例1第五步的方法合成，用2-(2-羟基-2-甲基丙基氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-碳酸叔丁酯取代2-乙氨基-5,7-二氢-吡咯[3,4-d]嘧啶-6-羧酸叔丁酯。The title compound was synthesized by the method of the fifth step of Example 1, using 2-(2-hydroxy-2-methylpropylamino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6- Tert-butyl carbonate was substituted for tert-butyl 2-ethylamino-5,7-dihydro-pyrrole [3,4-d]pyrimidine-6-carboxylate.

第三步：4-{4-氟-3-[2-(2-羟基-2-甲基丙基氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]-苄基}-2H-酞嗪-1-酮The third step: 4-{4-fluoro-3-[2-(2-hydroxy-2-methylpropylamino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6- Carbonyl]-benzyl}-2H-phthalazin-1-one

采用类似于实施例1第六步的实验步骤合成,用1-(6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-氨基)-2-甲基丙基-2-醇盐酸盐取代实施例1中所用的N-乙基-6,7-二氢-5H-吡咯[3,4-d]嘧啶-2-胺盐酸盐。Synthesis using an experimental procedure similar to the sixth step of Example 1, using 1-(6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amino)-2-methylpropyl- The 2-alcohol hydrochloride salt replaces the N-ethyl-6,7-dihydro-5H-pyrrole[3,4-d]pyrimidin-2-amine hydrochloride used in Example 1.

MS m/z(ESI):489[M+H]+ 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). 1 H 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), 1.09 and 1.07 (s, 6H).

实施例10Example 10

4-{3-[2-(环丙基甲基氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]-4-氟-苄基}-2H-酞嗪-1-酮(化合物10) 4-{3-[2-(Cyclopropylmethylamino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]-4-fluoro-benzyl}-2H- Pyridazin-1-one (compound 10)

Figure PCTCN2016103735-appb-000056
Figure PCTCN2016103735-appb-000056

反应路线Reaction route

Figure PCTCN2016103735-appb-000057
Figure PCTCN2016103735-appb-000057

第一步：2-(环丙基甲基胺基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-碳酸叔丁酯First step: 2-(cyclopropylmethylamino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonate tert-butyl ester

标题化合物采用实施例1第四步的方法合成,用N-甲基环丙胺取代实施例1第四步所用的乙胺。The title compound was synthesized by the method of the fourth step of Example 1, and the ethylamine used in the fourth step of Example 1 was replaced with N-methylcyclopropylamine.

第二步：N-环丙基-N-甲基-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-胺盐酸盐.The second step: N-cyclopropyl-N-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine hydrochloride.

标题化合物采用实施例1第五步的方法合成，用2-(环丙基甲基胺基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-碳酸叔丁酯取代2-乙氨基-5,7-二氢-吡咯[3,4-d]嘧啶-6-羧酸叔丁酯。The title compound was synthesized by the method of the fifth step of Example 1, using 2-(cyclopropylmethylamino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonate tert-butyl ester. Substituting tert-butyl 2-ethylamino-5,7-dihydro-pyrrole[3,4-d]pyrimidine-6-carboxylate.

第三步：4-{3-[2-(环丙基甲基氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]-4-氟-苄基}-2H-酞嗪-1-酮Third step: 4-{3-[2-(cyclopropylmethylamino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]-4-fluoro-benzyl }-2H-pyridazin-1-one

采用类似于实施例1第六步的实验步骤合成,用N-环丙基-N-甲基-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-胺盐酸盐取代实施例1中所用的N-乙基-6,7-二氢-5H-吡咯[3,4-d]嘧啶-2-胺盐酸盐。Synthesis using an experimental procedure similar to the sixth step of Example 1, using N-cyclopropyl-N-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine The acid salt was substituted for N-ethyl-6,7-dihydro-5H-pyrrole[3,4-d]pyrimidin-2-amine hydrochloride used in Example 1.

MS m/z(ESI):471[M+H]+ 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). 1 H NMR (400 MHz, DMSO-d 6 ) 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 = 3.6 Hz), 4.42-4.32 (m, 4H), 3.06 (d, 3H, J = 8 Hz), 2.80-2.69 ( m, 1H), 0.87-0.74 (m, 2H), 0.66-0.55 (m, 2H).

实施例11Example 11

4-{4-氟-3-[2-(1-甲基环丙基氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]-苄 基}-2H-酞嗪-1-酮(化合物11)4-{4-Fluoro-3-[2-(1-methylcyclopropylamino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]-benzyl }}-2H-phthalazin-1-one (compound 11)

Figure PCTCN2016103735-appb-000058
Figure PCTCN2016103735-appb-000058

反应路线Reaction route

Figure PCTCN2016103735-appb-000059
Figure PCTCN2016103735-appb-000059

第一步：2-(1-甲基环丙基氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-碳酸叔丁酯First step: 2-(1-methylcyclopropylamino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonate tert-butyl ester

标题化合物采用实施例1第四步的方法合成，用1-甲基环丙胺取代实施例1第四步所用的乙胺。The title compound was synthesized by the method of the fourth step of Example 1, and the ethylamine used in the fourth step of Example 1 was replaced with 1-methylcyclopropylamine.

第二步：N-(1-甲基环丙基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-胺盐酸盐.The second step: N-(1-methylcyclopropyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine hydrochloride.

标题化合物采用实施例1第五步的方法合成，用2-(1-甲基环丙基氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-碳酸叔丁酯取代2-乙氨基-5,7-二氢-吡咯[3,4-d]嘧啶-6-羧酸叔丁酯。The title compound was synthesized by the method of the fifth step of Example 1, using 2-(1-methylcyclopropylamino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonate tert-butyl. The ester is substituted with tert-butyl 2-ethylamino-5,7-dihydro-pyrrole [3,4-d]pyrimidine-6-carboxylate.

第三步：4-{4-氟-3-[2-(1-甲基环丙基氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]-苄基}-2H-酞嗪-1-酮The third step: 4-{4-fluoro-3-[2-(1-methylcyclopropylamino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]- Benzyl}-2H-phthalazin-1-one

采用类似于实施例1第六步的实验步骤合成，用N-(1-甲基环丙基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-胺盐酸盐取代实施例1中所用的N-乙基-6,7-二氢-5H-吡咯[3,4-d]嘧啶-2-胺盐酸盐。Synthesis using an experimental procedure similar to the sixth step of Example 1, using N-(1-methylcyclopropyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine The hydrochloride salt was substituted for the N-ethyl-6,7-dihydro-5H-pyrrole[3,4-d]pyrimidin-2-amine hydrochloride used in Example 1.

MS m/z(ESI):471[M+H]+ 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). 1 H NMR (400 MHz, DMSO-d 6 ) 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=4.4 Hz, 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).

实施例12Example 12

4-{4-氟-3-[2-(3-氧杂环丁基氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮(化合物12)4-{4-Fluoro-3-[2-(3-oxetanylamino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl}-2H -pyridazine-1-one (Compound 12)

Figure PCTCN2016103735-appb-000060
Figure PCTCN2016103735-appb-000060

反应路线Reaction route

Figure PCTCN2016103735-appb-000061
Figure PCTCN2016103735-appb-000061

第一步：1-叔丁氧基羰基-3-二甲氨基甲烯基-4-吡咯烷酮First step: 1-tert-butoxycarbonyl-3-dimethylaminomethenyl-4-pyrrolidone

向N-Boc-3-吡咯烷酮(37g)中加入300mL DMF-DMA,100℃下搅拌过夜。TLC显示原料反应完全。浓缩除去DMF-DMA后，用甲基叔丁基醚洗涤所得固体，过滤，将固体浓缩至干，得到目标产物(35g，黄色固体，收率：72.6％)。To N-Boc-3-pyrrolidone (37 g) was added 300 mL of DMF-DMA, and the mixture was stirred at 100 ° C overnight. TLC showed the starting material to react completely. After concentrating to remove DMF-DMA, the obtained solid was washed with EtOAc (EtOAc).

MS m/z(ESI):241.1[M+H]+。MS m / z (ESI): 241.1 [M + H] +.

第二步：2-羟基-5,7-二氢-吡咯[3,4-d]嘧啶-6-羧酸叔丁酯Second step: 2-hydroxy-5,7-dihydro-pyrrole [3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester

室温下，向250mL乙醇钠(26.4g，372mmol)的乙醇溶液中加入脲(20g，332.8mmol)，搅拌约50分钟后，加入第一步的1-叔丁氧基羰基-3-二甲氨基甲烯基-4-吡咯烷酮(20g，83.2mmol)并回流搅拌过夜。TLC监测原料消失，加水淬灭后，浓缩除去乙醇。水相用乙酸乙酯(50mL×5)萃取,合并有机相,无水硫酸钠干燥。减压浓缩后再用甲基叔丁基醚洗涤后得到目标分子(11g，淡黄色固体，收率：55.9％)。Urea (20 g, 332.8 mmol) was added to a solution of 250 mL of sodium ethoxide (26.4 g, 372 mmol) in ethanol at room temperature. After stirring for about 50 minutes, the first step of 1-tert-butoxycarbonyl-3-dimethylamino was added. Methylenyl-4-pyrrolidone (20 g, 83.2 mmol) was stirred at reflux overnight. The TLC monitored the disappearance of the starting materials, and after quenching with water, the ethanol was concentrated to remove. The aqueous phase was extracted with ethyl acetate (50 mL×5). After concentration under reduced pressure, the title compound (11 g, pale yellow solid, yield: 55.9%).

MS m/z(ESI):268.1[M+H]+. MS m/z (ESI): 268.1 [M+H] + .

第三步：2-(((三氟甲基)磺酰基)氧基)-5H-吡咯并[3,4-d]嘧啶-6(7H)-碳酸叔丁酯Third step: 2-(((trifluoromethyl)sulfonyl)oxy)-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-tert-butyl carbonate

将2-羟基-5,7-二氢-吡咯[3,4-d]嘧啶-6-羧酸叔丁酯(237mg,1mmol)和N-甲基吗啉(253mg,2.5mmol)溶于THF(10mL)，冰浴下滴加三氟甲磺酸酐(338.4mg,1.2mmol)的THF溶液(5mL)。TLC监测反应结束后蒸干THF，加入水和乙酸乙酯，乙酸乙酯层用无水硫酸钠干燥，旋干后得到目标产物的粗品直接用于下一步反应。2-Hydroxy-5,7-dihydro-pyrrole[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester (237 mg, 1 mmol) and N-methylmorpholine (253 mg, 2.5 mmol) were dissolved in THF (10 mL), a solution of trifluoromethanesulfonic anhydride (338.4 mg, 1.2 mmol) in THF (5 mL). After the completion of the TLC, the THF was evaporated to dryness, and water and ethyl acetate were evaporated. The ethyl acetate layer was dried over anhydrous sodium sulfate.

第四步：2-(氧杂环丁基-3-基氨基)-5H-吡咯并[3,4-d]嘧啶-6(7H)-碳酸叔丁酯Fourth step: 2-(oxetanyl-3-ylamino)-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-tert-butyl carbonate

将2-(((三氟甲基)磺酰基)氧基)-5H-吡咯并[3,4-d]嘧啶-6(7H)-碳酸叔丁酯(370mg,1mmol)和氧杂环丁-3胺(73mg,1mmol)溶于THF，然后加入[1,1'-双(二苯基磷)二茂铁]二氯化钯/二氯甲烷络合物(30mg),DIPEA(142mg,1.1mmol)和二环己基[3,6-二甲氧基-2',4',6'-三异丙基[1,1'-联苯]-2-基]膦(60mg)。所得混合物在回流下反应完全后，浓缩除去THF，将所得残余物中加入水和乙酸乙酯萃取(10mLx8)。浓缩除去乙酸乙酯，残余物制备TLC纯化得到目标产物53mg,收率18％。2-((((Trifluoromethyl)sulfonyl)oxy)-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-tert-butyl carbonate (370 mg, 1 mmol) and oxetane -3 amine (73 mg, 1 mmol) was dissolved in THF, then [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride/dichloromethane complex (30 mg), DIPEA (142 mg, 1.1 mmol) and dicyclohexyl [3,6-dimethoxy-2',4',6'-triisopropyl[1,1'-biphenyl]-2-yl]phosphine (60 mg). After the reaction mixture was completed under reflux, THF was evaporated to dryness, and ethyl acetate (ethyl acetate) The ethyl acetate was concentrated to remove the residue.

第五步：N-(氧杂环丁基-3-基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-胺盐酸盐Step 5: N-(oxetanyl-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine hydrochloride

将第四步的2-(氧杂环丁基-3-基氨基)-5H-吡咯并[3,4-d]嘧啶-6(7H)-碳酸叔丁酯(53mg,0.18mmol)溶于氯化氢的乙酸乙酯溶液(3mL),室温下搅拌过夜。反应液浓缩后得到的残余物直接用于下一步反应。The fourth step of 2-(oxetanyl-3-ylamino)-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-tert-butyl carbonate (53 mg, 0.18 mmol) was dissolved. A solution of hydrogen chloride in ethyl acetate (3 mL) was stirred at room temperature overnight. The residue obtained after concentration of the reaction mixture was used directly for the next reaction.

MS m/z(ESI):193[M+H]+.MS m/z (ESI): 193 [M+H] + .

第六步：4-(4-氟-3-(2-(氧杂环丁-3-基氨基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-6-羰基)苄基)酞嗪-1(2H)-酮Step 6: 4-(4-Fluoro-3-(2-(oxetan-3-ylamino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-6- Carbonyl)benzyl)pyridazine-1(2H)-one

将5-(3,4-二氢-4-氧代-1-酞嗪基)甲基-2-氟苯甲酸(89.4mg,0.3mmol),第五步的N-(氧杂环丁基-3-基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-胺盐酸盐(34mg,0.15mmol),HATU(114mg,0.30mmol)和DIPEA(77.4mg,0.6mmol)溶于DMF，室温搅拌过夜。反应完全后，向反应液中加入水和乙酸乙酯，分液，乙酸乙酯层经无水硫酸钠干燥后浓缩。残余物经制备薄层色谱纯化后得到目标产物(12mg,收率：2.5％)。5-(3,4-Dihydro-4-oxo-1-pyridazinyl)methyl-2-fluorobenzoic acid (89.4 mg, 0.3 mmol), N-(oxetanyl) in the fifth step 3-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine hydrochloride (34 mg, 0.15 mmol), HATU (114 mg, 0.30 mmol) and DIPEA (77.4 Mg, 0.6 mmol) was dissolved in DMF and stirred at room temperature overnight. After the reaction was completed, water and ethyl acetate were added to the mixture and the mixture was evaporated. The residue was purified by preparative thin-layer chromatography toield (yield:

MS m/z(ESI):473[M+H]+ 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). 1 H NMR (400 MHz, DMSO-d 6 ) 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).

实施例13Example 13

4-{4-氟-3-[2-(4-羟基环己基氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮(化合物13)4-{4-Fluoro-3-[2-(4-hydroxycyclohexylamino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl}-2H-indole Pyrazin-1-one (compound 13)

反应路线Reaction route

Figure PCTCN2016103735-appb-000062
Figure PCTCN2016103735-appb-000062

第一步：2-甲基磺酰基-5,7-二氢-吡咯并[3,4-d]嘧啶盐酸盐First step: 2-methylsulfonyl-5,7-dihydro-pyrrolo[3,4-d]pyrimidine hydrochloride

标题化合物采用实施例1第五步的方法合成，用2-甲基磺酰基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-碳酸叔丁酯取代2-乙氨基-5,7-二氢-吡咯[3,4-d]嘧啶-6-羧酸叔丁酯。The title compound was synthesized by the method of the fifth step of Example 1, substituting 2-ethylamino group with 2-methylsulfonyl-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonate tert-butyl ester. -5,7-Dihydro-pyrrole [3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester.

第二步：4-[4-氟-3-(2-甲基磺酰基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基)苄基]-2H-酞嗪-1-酮.Second step: 4-[4-Fluoro-3-(2-methylsulfonyl-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl)benzyl]-2H-indole Pyrazin-1-one.

采用实施例1第六步方法合成,用2-甲基磺酰基-5,7-二氢-吡咯并[3,4-d]嘧啶盐酸盐取代实施例1中所用的N-乙基-5,7-二氢-吡咯[3,4-d]嘧啶-2-胺盐酸盐。The synthesis was carried out by the method of the sixth step of Example 1, and the N-ethyl group used in Example 1 was replaced with 2-methylsulfonyl-5,7-dihydro-pyrrolo[3,4-d]pyrimidine hydrochloride. 5,7-Dihydro-pyrrole [3,4-d]pyrimidin-2-amine hydrochloride.

第三步：4-{4-氟-3-[2-(4-羟基环己基氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮Third step: 4-{4-fluoro-3-[2-(4-hydroxycyclohexylamino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl} -2H-phthalazin-1-one

标题化合物采用实施例1第四步的方法合成,用4-氨基环己醇取代实施例1第四步所用的乙胺，用4-[4-氟-3-(2-甲基磺酰基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基)苄基]-2H-酞嗪-1-酮取代实施例1第四步所用2-甲基磺酰基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-碳酸叔丁酯。The title compound was synthesized by the method of the fourth step of Example 1, substituting 4-aminocyclohexanol for the ethylamine used in the fourth step of Example 1, using 4-[4-fluoro-3-(2-methylsulfonyl-) Substituting 5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl)benzyl]-2H-phthalazin-1-one for the 2-methylsulfonyl-5 used in the fourth step of Example 1. , 7-Dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonate tert-butyl ester.

MS m/z(ESI):515[M+H]+ 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). 1 H NMR (400 MHz, DMSO-d 6 ) 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).

实施例14Example 14

4-{4-氟-3-[2-(四氢呋喃-3-氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮(化合物14) 4-{4-Fluoro-3-[2-(tetrahydrofuran-3-amino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl}-2H-pyridazine -1-ketone (compound 14)

Figure PCTCN2016103735-appb-000063
Figure PCTCN2016103735-appb-000063

反应路线Reaction route

Figure PCTCN2016103735-appb-000064
Figure PCTCN2016103735-appb-000064

第一步：2-(甲基磺酰基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶盐酸盐First step: 2-(methylsulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine hydrochloride

参见实施例13第一步。See the first step of Example 13.

第二步：4-(4-氟-3-(2-(甲基磺酰基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-6-羰基)苄基)酞嗪-1(2H)-酮.Second step: 4-(4-fluoro-3-(2-(methylsulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-6-carbonyl)benzyl) Pyridazine-1(2H)-one.

参见实施例13第二步。See the second step of Example 13.

第三步：4-(4-氟-3-(2-((四氢呋喃-3-基)氨基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-6-羰基)苄基)酞嗪-1(2H)-酮Step 3: 4-(4-Fluoro-3-(2-((tetrahydrofuran-3-yl)amino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-6-carbonyl Benzyl)pyridazine-1(2H)-one

标题化合物采用实施例14第三步的方法合成,用四氢呋喃-3-胺取代实施例13第三步所用的4-氨基环己醇。The title compound was synthesized by the method of the third step of Example 14 and the 4-aminocyclohexanol used in the third step of Example 13 was replaced with tetrahydrofuran-3-amine.

MS m/z(ESI):487[M+H]+ 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). 1 H NMR (400 MHz, DMSO-d 6 ) 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).

实施例15Example 15

4-{3-[2-(4-二甲氨基哌啶-1-基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]-4-氟苄基}-2H-酞嗪-1-酮(化合物15) 4-{3-[2-(4-Dimethylaminopiperidin-1-yl)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]-4-fluorobenzyl }-2H-phthalazin-1-one (compound 15)

Figure PCTCN2016103735-appb-000065
Figure PCTCN2016103735-appb-000065

反应路线Reaction route

Figure PCTCN2016103735-appb-000066
Figure PCTCN2016103735-appb-000066

第一步：2-(甲基磺酰基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶盐酸盐First step: 2-(methylsulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine hydrochloride

参见实施例13第一步。See the first step of Example 13.

第二步：4-(4-氟-3-(2-(甲基磺酰基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-6-羰基)苄基)酞嗪-1(2H)-酮.Second step: 4-(4-fluoro-3-(2-(methylsulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-6-carbonyl)benzyl) Pyridazine-1(2H)-one.

参见实施例13第二步。See the second step of Example 13.

第三步：4-(3-(2-(4-(二甲氨基)哌啶-1-基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-6-羰基)-4-氟苄基)酞嗪-1(2H)-酮The third step: 4-(3-(2-(4-(dimethylamino)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-6- Carbonyl)-4-fluorobenzyl)pyridazine-1(2H)-one

标题化合物采用实施例13第三步的方法合成，用4-二甲氨基哌啶取代实施例14第三步所用的4-氨基环己醇。The title compound was synthesized by the method of the third step of Example 13, and the 4-aminocyclohexanol used in the third step of Example 14 was replaced with 4-dimethylaminopiperidine.

MS m/z(ESI):528[M+H]+ 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) 1 H NMR (400 MHz, DMSO-d 6 ) 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)

实施例16Example 16

4-{4-氟-3-[2-(4-甲基哌嗪-1-基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮(化合物16)4-{4-Fluoro-3-[2-(4-methylpiperazin-1-yl)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl} -2H-phthalazin-1-one (Compound 16)

Figure PCTCN2016103735-appb-000067
Figure PCTCN2016103735-appb-000067

Figure PCTCN2016103735-appb-000068
Figure PCTCN2016103735-appb-000068

反应路线Reaction route

Figure PCTCN2016103735-appb-000069
Figure PCTCN2016103735-appb-000069

第一步：2-(甲基磺酰基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶盐酸盐First step: 2-(methylsulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine hydrochloride

参见实施例13第一步。See the first step of Example 13.

第二步：4-(4-氟-3-(2-(甲基磺酰基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-6-羰基)苄基)酞嗪-1(2H)-酮.Second step: 4-(4-fluoro-3-(2-(methylsulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-6-carbonyl)benzyl) Pyridazine-1(2H)-one.

参见实施例13第二步。See the second step of Example 13.

第三步：4-(4-氟-3-(2-(4-甲基哌嗪-1-基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-6-羰基)苄基)酞嗪-1(2H)-酮The third step: 4-(4-fluoro-3-(2-(4-methylpiperazin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-6 -carbonyl)benzyl)pyridazine-1(2H)-one

标题化合物采用实施例13第三步的方法合成,用1-甲基哌嗪取代实施例13第三步所用的4-氨基环己醇。The title compound was synthesized by the method of the third step of Example 13, and the 4-aminocyclohexanol used in the third step of Example 13 was replaced with 1-methylpiperazine.

MS m/z(ESI):514[M+H]+ 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). 1 H NMR (400 MHz, DMSO-d 6 ) 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 = 3.2 Hz, 2H), 4.41-4.32 (m, 4H), 3.76-3.65 (m, 4H), 2.38-2.29 (m, 4H), 2.20 (d, J = 4.0 Hz, 3H).

实施例17Example 17

4-{4-氟-3-[2-(1-甲基哌啶-4-氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮(化合物17)4-{4-Fluoro-3-[2-(1-methylpiperidin-4-amino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl} -2H-phthalazin-1-one (Compound 17)

Figure PCTCN2016103735-appb-000070
Figure PCTCN2016103735-appb-000070

反应路线 Reaction route

Figure PCTCN2016103735-appb-000071
Figure PCTCN2016103735-appb-000071

第一步：2-(甲基磺酰基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶盐酸盐First step: 2-(methylsulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine hydrochloride

参见实施例13第一步。See the first step of Example 13.

第二步：4-(4-氟-3-(2-(甲基磺酰基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-6-羰基)苄基)酞嗪-1(2H)-酮.Second step: 4-(4-fluoro-3-(2-(methylsulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-6-carbonyl)benzyl) Pyridazine-1(2H)-one.

参见实施例13第二步。See the second step of Example 13.

第三步：4-(4-氟-3-(2-((1-甲基哌啶-4-基)氨基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-6-羰基)苄基)酞嗪-1(2H)-酮The third step: 4-(4-fluoro-3-(2-((1-methylpiperidin-4-yl)amino)-6,7-dihydro-5H-pyrrolo[3,4-d] Pyrimidine-6-carbonyl)benzyl)pyridazine-1(2H)-one

标题化合物采用实施例13第三步的方法合成,用1-甲基哌啶-4-胺取代实施例13第三步所用的4-氨基环己醇。The title compound was synthesized by the method of the third step of Example 13, and the 4-aminocyclohexanol used in the third step of Example 13 was replaced with 1-methylpiperidin-4-amine.

MS m/z(ESI):514[M+H]+ 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). 1 H NMR (400 MHz, DMSO-d 6 ) 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 = 3.6 Hz, 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).

实施例18Example 18

4-{3-[2-(4,4-二氟环己基氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]-4-氟苄基}-2H-酞嗪-1-酮(化合物18)4-{3-[2-(4,4-Difluorocyclohexylamino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]-4-fluorobenzyl}- 2H-phthalazin-1-one (compound 18)

Figure PCTCN2016103735-appb-000072
Figure PCTCN2016103735-appb-000072

反应路线 Reaction route

Figure PCTCN2016103735-appb-000073
Figure PCTCN2016103735-appb-000073

第一步：2-(甲基磺酰基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶盐酸盐First step: 2-(methylsulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine hydrochloride

参见实施例13第一步。See the first step of Example 13.

第二步：4-(4-氟-3-(2-(甲基磺酰基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-6-羰基)苄基)酞嗪-1(2H)-酮.Second step: 4-(4-fluoro-3-(2-(methylsulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-6-carbonyl)benzyl) Pyridazine-1(2H)-one.

参见实施例13第二步。See the second step of Example 13.

第三步：4-(3-(2-((4,4-二氟环己基)氨基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-6-羰基)-4-氟苄基)酞嗪-1(2H)-酮Third step: 4-(3-(2-((4,4-difluorocyclohexyl)amino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-6-carbonyl) -4-fluorobenzyl)pyridazine-1(2H)-one

标题化合物采用实施例13第三步的方法合成,用4,4-二氟环己胺取代实施例13第三步所用的4-氨基环己醇。The title compound was synthesized by the method of the third step of Example 13, and the 4-aminocyclohexanol used in the third step of Example 13 was replaced with 4,4-difluorocyclohexylamine.

MS m/z(ESI):535[M+H]+ 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). 1 H NMR (400 MHz, DMSO-d 6 ) 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 = 4.0 Hz, 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).

实施例19Example 19

4-{4-氟-3-[2-(1-甲基-1H-吡唑-4-氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮(化合物19)4-{4-Fluoro-3-[2-(1-methyl-1H-pyrazole-4-amino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl] Benzyl}-2H-phthalazin-1-one (Compound 19)

Figure PCTCN2016103735-appb-000074
Figure PCTCN2016103735-appb-000074

反应路线 Reaction route

Figure PCTCN2016103735-appb-000075
Figure PCTCN2016103735-appb-000075

第一步：2-(甲基磺酰基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶盐酸盐First step: 2-(methylsulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine hydrochloride

参见实施例13第一步。See the first step of Example 13.

第二步：4-(4-氟-3-(2-(甲基磺酰基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-6-羰基)苄基)酞嗪-1(2H)-酮.Second step: 4-(4-fluoro-3-(2-(methylsulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-6-carbonyl)benzyl) Pyridazine-1(2H)-one.

参见实施例13第二步。See the second step of Example 13.

第三步：4-(4-氟-3-(2-((1-甲基-1H-吡唑-4-基)氨基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-6-羰基)苄基)酞嗪-1(2H)-酮The third step: 4-(4-fluoro-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-6,7-dihydro-5H-pyrrolo[3,4 -d]pyrimidine-6-carbonyl)benzyl)pyridazine-1(2H)-one

标题化合物采用实施例13第三步的方法合成,用1-甲基-1H-吡唑-4-胺取代实施例13第三步所用的4-氨基环己醇。The title compound was synthesized by the method of the third step of Example 13, and the 4-aminocyclohexanol used in the third step of Example 13 was replaced with 1-methyl-1H-pyrazol-4-amine.

MS m/z(ESI):497[M+H]+ 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). 1 H NMR (400 MHz, DMSO-d 6 ) 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 = 2.4 Hz, 2H), 4.48-4.33 (m, 4H), 3.79 (d, J = 8.0 Hz, 1H).

实施例20Example 20

4-{4-氟-3-[2-(1-甲基-1H-吡唑-3-氨基)-5,7-二氢-吡唑并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮(化合物20)4-{4-Fluoro-3-[2-(1-methyl-1H-pyrazol-3-amino)-5,7-dihydro-pyrazolo[3,4-d]pyrimidin-6-carbonyl ]benzyl}-2H-pyridazin-1-one (compound 20)

Figure PCTCN2016103735-appb-000076
Figure PCTCN2016103735-appb-000076

反应路线 Reaction route

Figure PCTCN2016103735-appb-000077
Figure PCTCN2016103735-appb-000077

第一步：2-(甲基磺酰基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶盐酸盐First step: 2-(methylsulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine hydrochloride

参见实施例13第一步。See the first step of Example 13.

第二步：4-(4-氟-3-(2-(甲基磺酰基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-6-羰基)苄基)酞嗪-1(2H)-酮.Second step: 4-(4-fluoro-3-(2-(methylsulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-6-carbonyl)benzyl) Pyridazine-1(2H)-one.

参见实施例13第二步。See the second step of Example 13.

第三步：4-(4-氟-3-(2-((1-甲基-1H-吡唑-3-基)氨基)-6,7-二氢-5H-吡唑并[3,4-d]嘧啶-6-羰基)苄基)酞嗪-1(2H)-酮The third step: 4-(4-fluoro-3-(2-((1-methyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-pyrazolo[3, 4-d]pyrimidin-6-carbonyl)benzyl)pyridazine-1(2H)-one

标题化合物采用实施例13第三步的方法合成,用1-甲基-1H-吡唑-3-胺取代实施例13第三步所用的4-氨基环己醇。The title compound was synthesized by the method of the third step of Example 13, and the 4-aminocyclohexanol used in the third step of Example 13 was replaced with 1-methyl-1H-pyrazol-3-amine.

MS m/z(ESI):497[M+H]+ 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). 1 H NMR (400 MHz, DMSO-d 6 ) 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) .

实施例21Example 21

(S)-4-{4-氟-3-[2-(甲氧丙基-2-氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮(化合物23)(S)-4-{4-Fluoro-3-[2-(methoxypropyl-2-amino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl }}-2H-phthalazin-1-one (compound 23)

Figure PCTCN2016103735-appb-000078
Figure PCTCN2016103735-appb-000078

反应路线 Reaction route

Figure PCTCN2016103735-appb-000079
Figure PCTCN2016103735-appb-000079

第一步：2-(甲基磺酰基)-5,7-二氢-吡咯并[3,4-d]嘧啶盐酸盐First step: 2-(methylsulfonyl)-5,7-dihydro-pyrrolo[3,4-d]pyrimidine hydrochloride

采用实施例1第五步类似的操作，用2-甲基磺酰基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-碳酸叔丁酯代替2-乙氨基-5,7-二氢-吡咯[3,4-d]嘧啶-6-羧酸叔丁酯，得到标题化合物。Substituting the similar procedure of the fifth step of Example 1, replacing 2-ethylamino-5 with 2-methylsulfonyl-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonate tert-butyl ester , tert-Butyl 7-dihydro-pyrrole[3,4-d]pyrimidine-6-carboxylate gave the title compound.

第二步：4-(4-氟-3-(2-(甲基磺酰基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基)苄基)酞嗪-1(2H)-酮.Step 2: 4-(4-Fluoro-3-(2-(methylsulfonyl)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl)benzyl)pyridazine -1(2H)-ketone.

采用实施例1第六步类似的操作，用2-甲基磺酰基-5,7-二氢-吡咯并[3,4-d]嘧啶盐酸盐取代实施例1中所用的N-乙基-5,7-二氢-吡咯[3,4-d]嘧啶-2-胺盐酸盐，得到标题化合物。Substituting the N-ethyl group used in Example 1 with 2-methylsulfonyl-5,7-dihydro-pyrrolo[3,4-d]pyrimidine hydrochloride using a procedure similar to the sixth step of Example 1. -5,7-Dihydro-pyrrole[3,4-d]pyrimidin-2-amine hydrochloride gave the title compound.

第三步：(S)-4-{4-氟-3-[2-(甲氧丙基-2-氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮The third step: (S)-4-{4-fluoro-3-[2-(methoxypropyl-2-amino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6 -carbonyl]benzyl}-2H-phthalazin-1-one

标题化合物采用实施例13中第三步的类似方法合成，其中只是用(S)-1-甲氧基-2-丙胺取代实施例13第三步所用的4-氨基环己醇。The title compound was synthesized in a similar manner to that in the third step of Example 13, except that the 4-aminocyclohexanol used in the third step of Example 13 was replaced with (S)-1-methoxy-2-propylamine.

MS m/z(ESI):489[M+H]+ 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). 1 H NMR (400 MHz, CDCl 3 ) 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. 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 = 4 Hz, 3H).

实施例22Example 22

(R)-4-{4-氟-3-[2-(甲氧丙基-2-氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮(化合物24)(R)-4-{4-fluoro-3-[2-(methoxypropyl-2-amino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl }}-2H-phthalazin-1-one (compound 24)

Figure PCTCN2016103735-appb-000080
Figure PCTCN2016103735-appb-000080

反应路线 Reaction route

Figure PCTCN2016103735-appb-000081
Figure PCTCN2016103735-appb-000081

第一步：2-(甲基磺酰基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶盐酸盐First step: 2-(methylsulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine hydrochloride

采用实施例1第五步类似操作，用2-甲基磺酰基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-碳酸叔丁酯代替2-乙氨基-5,7-二氢-吡咯[3,4-d]嘧啶-6-羧酸叔丁酯，得到标题化合物。Using a similar procedure as in the fifth step of Example 1, substituting 2-methylsulfonyl-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonate tert-butyl ester for 2-ethylamino-5, tert-Butyl 7-dihydro-pyrrole[3,4-d]pyrimidine-6-carboxylate gave the title compound.

第二步：4-(4-氟-3-(2-(甲基磺酰基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-6-羰基)苄基)酞嗪-1(2H)-酮.Second step: 4-(4-fluoro-3-(2-(methylsulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-6-carbonyl)benzyl) Pyridazine-1(2H)-one.

采用实施例1第六步类似操作，用2-甲基磺酰基-5,7-二氢-吡咯并[3,4-d]嘧啶盐酸盐取代实施例1中所用的N-乙基-5,7-二氢-吡咯[3,4-d]嘧啶-2-胺盐酸盐，得到标题化合物。The N-ethyl group used in Example 1 was replaced with 2-methylsulfonyl-5,7-dihydro-pyrrolo[3,4-d]pyrimidine hydrochloride using a similar procedure as in the sixth step of Example 1. 5,7-Dihydro-pyrrole[3,4-d]pyrimidin-2-amine hydrochloride gave the title compound.

第三步：(R)-4-{4-氟-3-[2-(甲氧丙基-2-氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮The third step: (R)-4-{4-fluoro-3-[2-(methoxypropyl-2-amino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6 -carbonyl]benzyl}-2H-phthalazin-1-one

标题化合物采用实施例13中第三步的类似方法合成，其中只是用(R)-1-甲氧基-2-丙胺取代实施例13第三步所用的4-氨基环己醇。The title compound was synthesized in a similar manner to that in the third step of Example 13 except that the 4-aminocyclohexanol used in the third step of Example 13 was replaced with (R)-1-methoxy-2-propylamine.

MS m/z(ESI):489[M+H]+ 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). 1 H NMR (400 MHz, CDCl 3 ) 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. 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 = 4 Hz, 3H).

参照本申请实施例所述方法，本申请还合成了以下化合物：Referring to the method described in the examples of the present application, the present application also synthesizes the following compounds:

表1Table 1

Figure PCTCN2016103735-appb-000082
Figure PCTCN2016103735-appb-000082

Figure PCTCN2016103735-appb-000083
Figure PCTCN2016103735-appb-000083

Figure PCTCN2016103735-appb-000084
Figure PCTCN2016103735-appb-000084

Figure PCTCN2016103735-appb-000085
Figure PCTCN2016103735-appb-000085

Figure PCTCN2016103735-appb-000086
Figure PCTCN2016103735-appb-000086

Figure PCTCN2016103735-appb-000087
Figure PCTCN2016103735-appb-000087

Figure PCTCN2016103735-appb-000088
Figure PCTCN2016103735-appb-000088

生物学活性Biological activity

实验例1.PARP1激酶活性筛选 Experimental Example 1. PARP1 kinase activity screening

PARP-1抑制剂的酶活筛选采用BPS Bioscience的PARP1化学发光试剂盒进行。Enzyme activity screening of PARP-1 inhibitors was performed using the PARP1 chemiluminescence kit from BPS Bioscience.

待测化合物：本申请实施例化合物； Test compound: a compound of the examples of the present application;

试剂盒：PARP1Chemiluminescent Assay Kit，厂家：BPS Bioscience。Kit: PARP1 Chemiluminescent Assay Kit, manufacturer: BPS Bioscience.

实验方法experimental method

试剂盒预处理：将微孔板加入50μL/孔的1×PARP缓冲稀释的1×组蛋白，4℃孵育过夜；次日弃去微孔板中的液体，并采用200μl/孔PBST(1×PBS及1％Triton X-100)洗板，除去全部清洗液；然后每孔加入200μl的终止缓冲液，室温孵育90min后弃去液体；并采用200μl/孔PBST洗板，最后除去全部清洗液。Kit pretreatment: Add the microplate to 50 μL/well of 1×PARP buffer diluted 1× histone and incubate overnight at 4°C; discard the liquid in the microplate the next day and use 200 μl/well PBST (1× Wash the plate with PBS and 1% Triton X-100), remove all the washing solution; then add 200 μl of stop buffer per well, incubate for 90 min at room temperature, discard the liquid; wash the plate with 200 μl/well PBST, and finally remove all the washing solution.

反应：按以下所列步骤与用量依次加入底物和酶及测试化合物等，室温孵育1h。Reaction: Substrate and enzyme and test compound were added sequentially according to the procedures and dosages listed below, and incubated for 1 h at room temperature.

表2反应体系Table 2 reaction system

Figure PCTCN2016103735-appb-000089
Figure PCTCN2016103735-appb-000089

检测：反应结束后，用PBST(200μl/孔)润洗孔板，最后将清洗的溶液全部除去；向每孔中加入50μl稀释后的Strep-HRP，室温培养30min；用PBST(200μL/孔)润洗孔板后，将清洗溶液全部除去；冰浴上混合HRP底物A和B，然后每孔加入100μl(每孔50μl比色底物A和50μl比色底物B)；最后化学发光法(Luminometric Measurement)高敏模式检测待测化合物对PARP1激酶抑制活性，结果如表3所示。Detection: After completion of the reaction, the well plate was rinsed with PBST (200 μl/well), and finally the washed solution was completely removed; 50 μl of diluted Strep-HRP was added to each well, and cultured at room temperature for 30 min; using PBST (200 μL/well) After rinsing the plate, remove all the cleaning solution; mix HRP substrates A and B on an ice bath, then add 100 μl per well (50 μl of colorimetric substrate A and 50 μl of colorimetric substrate B per well); finally chemiluminescence (Luminometric Measurement) High sensitivity mode was used to detect the inhibitory activity of the test compound against PARP1 kinase, and the results are shown in Table 3.

结果：result:

表3已测试化合物单点浓度抑制率Table 3 Single compound concentration inhibition rate of tested compounds

化合物IDCompound ID 单点浓度抑制率％Single point concentration inhibition rate% 11 99.3％(5nM)99.3% (5nM) 22 73.0％(5nM)73.0% (5nM) 33 84.8％(5nM)84.8% (5nM) 44 97.8％(5nM)97.8% (5nM) 55 98.9％(5nM)98.9% (5nM) 66 97.7％(5nM)97.7% (5nM) 88 84.7％(5nM)84.7% (5nM) 1111 80.1％(5nM)80.1% (5nM)

由表3可以看出，本申请的化合物对PARP1激酶活性具有明显的抑制作用。As can be seen from Table 3, the compounds of the present application have a significant inhibitory effect on PARP1 kinase activity.

本申请其它化合物对PARP1激酶活性具有相类似的抑制作用，抑制率在70-99％范围内。Other compounds of the present application have similar inhibitory effects on PARP1 kinase activity with inhibition rates ranging from 70 to 99%.

实验例2.细胞增殖抑制实验 Experimental Example 2. Cell proliferation inhibition experiment

采用CCK-8法测定化合物对细胞增殖的影响。The effect of the compound on cell proliferation was determined by the CCK-8 method.

待测化合物：本申请实施例化合物；Test compound: a compound of the examples of the present application;

阳性对照化合物：奥拉帕尼，实验室自合成；Positive control compound: Olapani, laboratory self-synthesis;

试剂盒：CCK-8试剂盒(Cell Counting Kit-8)，厂家：Beyotime。Kit: CCK-8 kit (Cell Counting Kit-8), manufacturer: Beyotime.

实验方法experimental method

细胞培养：根据以下条件培养细胞，细胞消化后采用细胞计数器计数，并根据以下要求调整细胞至所需浓度，然后每孔接种细胞100μl，接种后24小时给药。Cell culture: The cells were cultured according to the following conditions, and the cells were counted by a cell counter after digestion, and the cells were adjusted to the desired concentration according to the following requirements, and then 100 μl of the cells were seeded per well, and administered 24 hours after the inoculation.

表4细胞培养条件Table 4 cell culture conditions

细胞名称Cell name 培养液Culture medium 培养箱条件Incubator condition 乳腺癌MDA-MB-453Breast cancer MDA-MB-453 DMEM/F12+10％FBSDMEM/F12+10%FBS 5％CO2，37℃5% CO 2 , 37 ° C 乳腺癌MDA-MB-468Breast cancer MDA-MB-468 DMEM/F12+10％FBSDMEM/F12+10%FBS 5％CO2，37℃5% CO 2 , 37 ° C 结直肠癌HCT116Colorectal cancer HCT116 1640+10％FBS1640+10% FBS 5％CO2，37℃5% CO 2 , 37 ° C 胰腺癌Capan-1Pancreatic cancer Capan-1 IMEM+20％FBSIMEM+20%FBS 5％CO2，37℃5% CO 2 , 37 ° C

化合物配制：培养一天后，用DMSO溶解待测化合物和奥拉帕尼制成母液，吸取适量母液至培养液中混匀，药品溶液配置为相应的孵育浓度。Compound preparation: After one day of culture, the test compound and olrapani were dissolved in DMSO to prepare a mother liquid, and an appropriate amount of the mother liquid was taken up to the culture solution to be mixed, and the drug solution was set to the corresponding incubation concentration.

孵育时间：给药后于培养箱中继续孵育7天。Incubation time: Incubation was continued for 7 days in the incubator after administration.

检测：孵育结束后换新鲜培养液200μl/孔置于培养基中稳定2h后加20μl/孔的CCK8孵育3h以上，在450nm波长，参考波长650nm进行双波长测定吸光度。IC50值用GraphPad计算得到，结果详见表5-1～5-4和图1～图4：Detection: After the incubation, the fresh medium was replaced with 200 μl/well in the medium for 2 h, then 20 μl/well of CCK8 was incubated for more than 3 h, and the absorbance was measured at a wavelength of 450 nm and a reference wavelength of 650 nm. IC 50 values were calculated using GraphPad. The results are shown in Tables 5-1 to 5-4 and Figures 1 to 4:

表5-1本申请化合物抑制乳腺癌MDA-MB-453的作用Table 5-1 Effect of the compound of the present application on inhibiting breast cancer MDA-MB-453

Figure PCTCN2016103735-appb-000090
Figure PCTCN2016103735-appb-000090

Figure PCTCN2016103735-appb-000091
Figure PCTCN2016103735-appb-000091

表5-1和图1提示本申请化合物对乳腺癌MDA-MB-453细胞具有明显的增殖抑制作用。尤其地，化合物1、2、3、4、6、8、以及化合物64、65和68对乳腺癌细胞MDA-MB-453的增殖抑制作用显著优于奥拉帕尼。Table 5-1 and Figure 1 suggest that the compounds of the present application have significant proliferation inhibitory effects on breast cancer MDA-MB-453 cells. In particular, Compound 1, 2, 3, 4, 6, 8, and Compounds 64, 65, and 68 significantly inhibited the proliferation of breast cancer cell MDA-MB-453 over olaparib.

表5-2本申请化合物抑制乳腺癌MDA-MB-468的作用Table 5-2 Effect of the compound of the present application on inhibiting breast cancer MDA-MB-468

Figure PCTCN2016103735-appb-000092
Figure PCTCN2016103735-appb-000092

表5-2和图2-1、图2-2提示本申请化合物对乳腺癌细胞MDA-MB-468具有明显的增殖抑制作用。尤其地，化合物1、2、3、4、6、8、12、13、19、20、以及化合物64、65和68对乳腺癌细胞MDA-MB-468的增殖抑制作用显著优于奥拉帕尼。Table 5-2 and Figures 2-1 and 2-2 suggest that the compound of the present application has a significant proliferation inhibitory effect on breast cancer cell MDA-MB-468. In particular, Compounds 1, 2, 3, 4, 6, 8, 12, 13, 19, 20, and Compounds 64, 65, and 68 significantly inhibited the proliferation of breast cancer cell MDA-MB-468 over Orapa Ni.

表5-3本申请化合物抑制胰腺癌Capan-1的作用Table 5-3 Effect of the Compound of the Present Application on Capan-1 in Pancreatic Cancer

Figure PCTCN2016103735-appb-000093
Figure PCTCN2016103735-appb-000093

Figure PCTCN2016103735-appb-000094
Figure PCTCN2016103735-appb-000094

由表5-3和图3提示本申请化合物对胰腺癌细胞Capan-1具有明显的增殖抑制作用。尤其地，化合物1、2、3、4、5、6、8、以及化合物64、65和68对胰腺癌细胞Capan-1的增殖抑制作用显著优于奥拉帕尼。It is suggested from Tables 5-3 and 3 that the compound of the present application has a significant proliferation inhibitory effect on pancreatic cancer cell line Capan-1. In particular, compounds 1, 2, 3, 4, 5, 6, 8, and compounds 64, 65 and 68 significantly inhibited the proliferation of pancreatic cancer cell line Capan-1 over olaparib.

表5-4本申请化合物抑制结直肠癌HCT116的作用Table 5-4 Effect of the compound of the present application on inhibiting colorectal cancer HCT116

Figure PCTCN2016103735-appb-000095
Figure PCTCN2016103735-appb-000095

由表5-4和图4提示本申请化合物对直肠癌细胞HCT116具有明显的增殖抑制作用。尤其地，化合物1、2、3、4、6、13、19和20对直肠癌细胞HCT116的增殖抑制作用显著优于奥拉帕尼。It is suggested from Tables 5-4 and 4 that the compound of the present application has a significant proliferation inhibitory effect on rectal cancer cell HCT116. In particular, Compound 1, 2, 3, 4, 6, 13, 19, and 20 significantly inhibited the proliferation of rectal cancer cell HCT116 over olaparib.

本申请其它化合物对于乳腺癌细胞、结直肠癌细胞和胰腺癌细胞等癌细胞均具有相类似的增殖抑制活性。Other compounds of the present application have similar proliferation inhibitory activities against cancer cells such as breast cancer cells, colorectal cancer cells, and pancreatic cancer cells.

综上，本申请的化合物对于乳腺癌细胞、结直肠癌细胞和胰腺癌细胞等癌细胞均具有增殖抑制活性。In conclusion, the compounds of the present application have proliferation inhibitory activity against cancer cells such as breast cancer cells, colorectal cancer cells, and pancreatic cancer cells.

实验例3.化合物的药代动力学(PK)研究 Experimental Example 3. Pharmacokinetics (PK) Study of Compounds

3.1大鼠PK研究3.1 Rat PK study

分别通过静脉和灌胃给予雄性SD大鼠本申请化合物和奥拉帕尼，考察药代动力学特点。静脉内(IV)和口服(PO)的给药剂量分别是1和5mg/kg。IV和PO给药后在不同时间点收集血液，血液采用肝素钠抗凝，离心得血浆样品，将所述血浆样品经已经沉淀蛋白处理后进行LC-MS/MS分析。Male SD rats were administered intravenous and intragastric administration of the compound of the present application and olaparib, respectively, to examine the pharmacokinetic characteristics. Intravenous (IV) and oral (PO) doses were 1 and 5 mg/kg, respectively. After IV and PO administration, blood was collected at different time points, blood was anticoagulated with sodium heparin, and plasma samples were centrifuged, and the plasma samples were subjected to LC-MS/MS analysis after being subjected to precipitated protein treatment.

LC-MS/MS，色谱柱为Waters X-Bridge C18柱(21mm*50mm,3.5μm)；流动相A相为水+2mM乙酸铵，B相为甲醇+2mM乙酸铵，流速为0.4mL/min，柱温为40℃。采用离子源为ESI源正离子模式，扫描方式为多重反应监测(MRM)。LC-MS/MS, the column was a Waters X-Bridge C18 column (21 mm*50 mm, 3.5 μm); the mobile phase A phase was water + 2 mM ammonium acetate, the phase B was methanol + 2 mM ammonium acetate, and the flow rate was 0.4 mL/min. The column temperature is 40 °C. The ion source is used as the ESI source positive ion mode, and the scanning mode is multiple reaction monitoring (MRM).

应用WinNonlin 6.3软件，采用非房室模型计算药代动力学参数，结果见表6。The pharmacokinetic parameters were calculated using WinNonlin 6.3 software using a non-compartmental model. The results are shown in Table 6.

表6大鼠体内的IV药代动力学参数Table 6 IV pharmacokinetic parameters in rats

Figure PCTCN2016103735-appb-000096
Figure PCTCN2016103735-appb-000096

静脉内给药方式的结果提示本申请化合物具有良好的药代动力学特性。尤其地，化合物1、2、3、6和8在大鼠体内的药代动力学参数优于奥拉帕尼。The results of the intravenous administration mode suggest that the compounds of the present application have good pharmacokinetic properties. In particular, the pharmacokinetic parameters of Compounds 1, 2, 3, 6 and 8 in rats were superior to Olapani.

PO结果也表明，在相同口服给药剂量下，化合物1、化合物2、化合物3、化合物6的血浆暴露量均高于奥拉帕尼，其AUC值在约305-1200h*ng/ml范围内。The PO results also showed that Compound 1, Compound 2, Compound 3, and Compound 6 had higher plasma exposures than olaparib at the same oral dose, and the AUC value was in the range of about 305-1200 h*ng/ml. .

另外，在本药代动力学试验中意外发现，奥拉帕尼的半衰期是1.31小时，本申请化合物2的半衰期为2.3小时，由此表明本申请化合物2的药效作用时间更长久。In addition, it was unexpectedly found in the present pharmacokinetic test that the half-life of olrapani was 1.31 hours, and the half-life of the compound 2 of the present application was 2.3 hours, thereby indicating that the pharmacodynamic action of the compound 2 of the present application was longer.

3.2犬PK研究3.2 Canine PK Study

分别通过静脉和灌胃给予雄性Beagle犬待测化合物，考察药代动力学特点。静脉内(IV)给药和口服(PO)给药的给药剂量分别是1和5mg/kg，溶媒系统均为10％DMSO:10％solutol:80％生理盐水。IV和PO给药后 不同时间点收集血液，血液采用肝素钠抗凝，将离心后得到的血浆样品保存于-80℃。血浆样品经已经沉淀蛋白处理后进行LC-MS/MS分析。Male Beagle dogs were administered intravenously and intragastrically to test the pharmacokinetic characteristics. The doses for intravenous (IV) administration and oral (PO) administration were 1 and 5 mg/kg, respectively, and the vehicle system was 10% DMSO: 10% solutol: 80% normal saline. After IV and PO administration Blood was collected at different time points, blood was anticoagulated with heparin sodium, and plasma samples obtained after centrifugation were stored at -80 °C. Plasma samples were subjected to LC-MS/MS analysis after treatment with precipitated proteins.

在与3.1大鼠PK相同给药途径和给药剂量下，本申请化合物在犬体内的PK性质优于奥拉帕尼。The PK properties of the compounds of the present application in dogs are superior to olaparib in the same administration route and dose administered as 3.1 rat PK.

本申请的其他化合物在大鼠和犬体内具有类似的药代动力学性质。Other compounds of the present application have similar pharmacokinetic properties in rats and dogs.

实验例4.安全性试验 Experimental Example 4. Safety Test

4.1、hERG测试4.1, hERG test

在心肌细胞中，human Ether-a-go-go Related Gene(hERG)编码的钾通道介导一种延迟整流钾电流(IKr)。IKr抑制是药物导致QT间期延长最重要的机制。在hERG测试中，判定标准为若待测化合物IC50>30μM，则判定待测化合物对hERG无抑制作用。In cardiomyocytes, the potassium channel encoded by the human Ether-a-go-go Related Gene (hERG) mediates a delayed rectifier potassium current (IKr). IKr inhibition is the most important mechanism for drug-induced QT interval prolongation. In the hERG test, if the criteria for the test compound IC 50> 30μM, it is determined that no inhibitory effect on hERG test compound.

采用PredictorTM hERG Fluorescence Polarization Assay，检测本申请化合物对hERG钾离子通道的作用，测试浓度为3，10，30μM。试验结果显示，化合物1、化合物2、化合物3、化合物6对于hERG的50％抑制浓度(IC50值)均大于30μM。提示本申请化合物对hERG无抑制作用，表明本申请化合物无心脏QT间期延长的安全性隐患。Using Predictor TM hERG Fluorescence Polarization Assay, the present application detecting compounds on hERG potassium ion channel, a concentration of the test 3,10,30μM. The test results showed that the 50% inhibitory concentration (IC 50 value) of Compound 1, Compound 2, Compound 3, and Compound 6 for hERG was more than 30 μM. It is suggested that the compound of the present application has no inhibitory effect on hERG, indicating that the compound of the present application has no safety risk of prolonging the QT interval of the heart.

4.2小鼠急毒试验4.2 mouse acute toxicity test

通过灌胃给予KM小鼠，考察待测化合物单次给药毒性反应，初步判断最大耐受量(MTD)。KM mice were administered by gavage, and the toxicity of a single administration of the test compound was examined to determine the maximum tolerated dose (MTD).

剂量设置为，化合物1：300mg/kg；化合物2、3、6：200、300mg/kg，单次灌胃给药，溶媒为10％DMSO和50％PEG以及余量的生理盐水，给药后观察7天。The dose was set to: Compound 1: 300 mg/kg; Compounds 2, 3, 6: 200, 300 mg/kg, administered by single gavage, the vehicle was 10% DMSO and 50% PEG, and the balance of physiological saline, after administration. Observe for 7 days.

在本实验中，试验结果如下：In this experiment, the test results are as follows:

化合物1：最大耐受量(MTD)大于300mg/kg；Compound 1: Maximum Tolerance (MTD) is greater than 300 mg/kg;

化合物2：MTD小于200mg/kg；Compound 2: MTD is less than 200 mg/kg;

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

化合物6：MTD为200mg/kg；Compound 6: MTD was 200 mg/kg;

综上，本申请化合物在单次给药高剂量条件下有良好的耐受性。In summary, the compounds of the present application are well tolerated under single dose high dose conditions.

本申请的其它化合物具有类似的安全性和高剂量耐受性。Other compounds of the present application have similar safety and high dose tolerance.

实施例5.体内抑瘤实验 Example 5 : In vivo anti-tumor experiment

本实施例用于评价本申请化合物经不同给药途径对肿瘤增殖抑制的有效性。This example was used to evaluate the effectiveness of the compounds of the present application against tumor growth inhibition by different routes of administration.

5.1人胰腺癌细胞株Capan-1荷瘤鼠模型体内抑瘤实验 Inhibition of tumor in 5.1 human pancreatic cancer cell line Capan-1 tumor-bearing mouse model

本实施例通过测量经PO给药途径施用本申请化合物后人胰腺癌细胞株Capan-1皮下移植瘤小鼠肿瘤体积变化，评价各化合物对胰腺癌Capan-1荷瘤鼠的药效。In the present example, the effects of each compound on pancreatic cancer Capan-1 tumor-bearing mice were evaluated by measuring the tumor volume changes of human pancreatic cancer cell line Capan-1 subcutaneous xenograft mice after administration of the compound of the present application via the PO administration route.

选择肿瘤体积100-200mm3的荷瘤鼠随机分组，给药体积为10ml/kg，每天1次给药，共约两周。给药后一周2次测量肿瘤体积。肿瘤体积的计算公式为：V＝0.5a×b2，a和b分别表示肿瘤的长径和短径。待测化合物的抑瘤疗效用肿瘤生长抑制率TGI(％)评价。Tumor-bearing mice with a tumor volume of 100-200 mm 3 were randomly assigned to a dose of 10 ml/kg administered once a day for about two weeks. Tumor volume was measured twice a week after administration. The calculation formula of tumor volume is: V = 0.5a × b 2 , and a and b represent the long diameter and short diameter of the tumor, respectively. The antitumor effect of the test compound was evaluated by the tumor growth inhibition rate TGI (%).

TGI(％)＝[1-(VT末-VT始)/(VC末-VC始)]*100％TGI (%) = [1- (VT end - VT start ) / (VC end - VC start )] * 100%

其中VT末：处理组实验结束时肿瘤体积均值Where VT is the end of the tumor volume at the end of the treatment group

VT始：处理组给药开始时肿瘤体积均值VT start : tumor volume mean at the beginning of treatment in the treatment group

VC末：溶媒对照组实验结束时肿瘤体积均值 End of VC: mean volume of tumor at the end of the vehicle control experiment

VC始：溶媒对照组给药开始时肿瘤体积均值VC start : mean volume of tumor at the beginning of drug control group administration

各组化合物对胰腺癌的抑瘤率如下表7所示。The tumor inhibition rates of each group of compounds against pancreatic cancer are shown in Table 7 below.

表7：胰腺癌细胞株Capan-1模型中抑瘤率Table 7: Tumor inhibition rate in Panan-1 model of pancreatic cancer cell line

组别Group 化合物Compound 给药途径Route of administration 抑瘤率(％)Tumor inhibition rate (%) 11 溶媒对照Solvent control p.o.P.o. // 22 奥拉帕尼(100mg/kg)Olapani (100mg/kg) p.o.P.o. 9.29.2 33 化合物2(3mg/kg)Compound 2 (3mg/kg) p.o.P.o. 109.7109.7 44 化合物2(0.3mg/kg)Compound 2 (0.3 mg/kg) p.o.P.o. 44.344.3 55 化合物3(10mg/kg)Compound 3 (10 mg/kg) p.o.P.o. 48.648.6 66 化合物3(3mg/kg)Compound 3 (3mg/kg) p.o.P.o. 36.036.0 77 化合物6(10mg/kg)Compound 6 (10 mg/kg) p.o.P.o. 56.856.8 88 化合物6(3mg/kg)Compound 6 (3mg/kg) p.o.P.o. 20.220.2

本试验条件下，化合物2具有惊人的药效，在3mg/kg下该化合物抑瘤率达到109.7％，肿瘤部分消退，在低剂量下(0.3mg/kg)也有44.3％的抑瘤率。化合物3、化合物6的药效也均优于阳性对照组。Under the conditions of this experiment, Compound 2 had surprising efficacy. The inhibition rate of the compound reached 109.7% at 3 mg/kg, and the tumor partially subsided. At low dose (0.3 mg/kg), the tumor inhibition rate was also 44.3%. The pharmacodynamics of Compound 3 and Compound 6 were also superior to those of the positive control group.

5.2人乳腺癌细胞株MX-1荷瘤鼠模型体内抑瘤实验In vivo anti-tumor experiment of 5.2 human breast cancer cell line MX-1 tumor-bearing mouse model

本实施例通过测量经PO给药途径施用本申请化合物后人乳腺癌细胞株MX-1皮下移植瘤小鼠肿瘤体积变化，评价各化合物对乳腺癌MX-1荷瘤鼠的药效。In this example, the effects of each compound on breast cancer MX-1 tumor-bearing mice were evaluated by measuring the tumor volume changes of human breast cancer cell line MX-1 subcutaneously transplanted mice after administration of the compound of the present application via the PO administration route.

选择肿瘤体积100-200mm3的荷瘤鼠随机分组，给药体积为10ml/kg，每天1次给药，共约30天。给药后一周2次测量肿瘤体积。肿瘤体积的计算公式为：V＝0.5×a×b2，a和b分别表示肿瘤的长径和短径。待测化合物的抑瘤疗效用相对肿瘤增殖率T/C(％)。 Tumor-bearing mice with a tumor volume of 100-200 mm 3 were randomly assigned to a dose of 10 ml/kg administered once a day for about 30 days. Tumor volume was measured twice a week after administration. The calculation formula of tumor volume is: V = 0.5 × a × b 2 , and a and b represent the long diameter and short diameter of the tumor, respectively. The antitumor effect of the test compound was relative tumor proliferation rate T/C (%).

T/C(％)＝(VT末/VT始)/(VC末/VC始)*100％T/C (%) = (start of V T / start of V T ) / ( start of V C / start of V C ) * 100%

其中VT末：处理组实验结束时肿瘤体积均值Where VT is the end of the tumor volume at the end of the treatment group

VT始：处理组给药开始时肿瘤体积均值VT start : tumor volume mean at the beginning of treatment in the treatment group

VC末：溶媒对照组实验结束时肿瘤体积均值 End of VC: mean volume of tumor at the end of the vehicle control experiment

VC始：溶媒对照组给药开始时肿瘤体积均值VC start : mean volume of tumor at the beginning of drug control group administration

评价标准为：T/C(％)>40％为无效；T/C(％)≤40％，并经统计学处理P<0.05为有效。The evaluation criteria were: T/C (%) > 40% was ineffective; T / C (%) ≤ 40%, and statistically treated P < 0.05 was effective.

实验结果表明，在PO给药5mg/kg和10mg/kg的剂量下，本申请化合物在人乳腺癌细胞株MX-1荷瘤鼠模型中的体内相对肿瘤增殖率小于55％，具有优异的抑瘤作用。The experimental results show that the compound in the present invention has a relative tumor growth rate of less than 55% in the human breast cancer cell line MX-1 tumor-bearing mouse model at a dose of 5 mg/kg and 10 mg/kg of PO, and has excellent inhibition. Tumor effect.

本申请的其它化合物具有相类似的抑瘤作用。Other compounds of the present application have similar antitumor effects.

制剂例1片剂 Formulation Example 1 tablet

速释片剂的组成由表8所示：The composition of the immediate release tablets is shown in Table 8:

表8速释片剂的组成Table 8 Composition of immediate release tablets

成分ingredient mg/片剂Mg/tablet 占片剂芯重量的百分比(％)Percentage of tablet core weight (%) 化合物1Compound 1 100.00100.00 25.0025.00 乳糖lactose 238.00238.00 50.0050.00 微晶纤维素Microcrystalline cellulose 40.0040.00 10.0010.00 交联羧甲基纤维素钠Croscone sodium 16.0016.00 4.004.00 月桂基硫酸钠Sodium lauryl sulfate 2.002.00 0.500.50 硬脂酸镁Magnesium stearate 4.004.00 1.001.00 片剂芯重量Tablet core weight 400.00400.00 //

制备方法Preparation

使用直接压制法制造标准速释片剂。将化合物1和乳糖、微晶纤维素、交联羧甲基纤维素钠和月桂基硫酸钠称入玻璃小管，上述混合物大约占据该小管体积75％，随后在转鼓混合机中一起混合30分钟，得掺和材料。该掺合材料经40目(425μm)筛子筛分，随后再转鼓混合15分钟。随后加入硬脂酸镁并摇振该掺合物大约20秒。随后将所得混合物分配成400毫克的小份，并使用配有10毫米模具的手压机用0.5吨目标压缩力压制成片剂芯。Standard immediate release tablets are made using direct compression. Compound 1 and lactose, microcrystalline cellulose, croscarmellose sodium, and sodium lauryl sulfate were weighed into glass vials, and the above mixture occupied approximately 75% of the volume of the vial, which was then mixed together for 30 minutes in a tumble mixer. , to get blended materials. The blended material was sieved through a 40 mesh (425 μm) sieve and then drum mixed for another 15 minutes. Magnesium stearate was then added and the blend was shaken for approximately 20 seconds. The resulting mixture was then dispensed into 400 mg aliquots and compressed into tablet cores using a hand press equipped with a 10 mm die with 0.5 ton of target compression.

制剂例2胶囊制剂 Formulation Example 2 Capsule preparation

胶囊制剂的组成由表9所示： The composition of the capsule preparation is shown in Table 9:

表9胶囊制剂的组成Table 9 Composition of capsule preparation

Figure PCTCN2016103735-appb-000097
Figure PCTCN2016103735-appb-000097

制备方法Preparation

将月桂酰在大约50-70℃下熔融，随后称入不锈钢容器中。加入化合物2并混合内容物以均匀悬浮。继续混合，同时使用恒温控制的自动胶囊填充机将该混合物分配到胶囊中，制成500毫克/粒的胶囊制剂。The lauroyl group was melted at about 50-70 ° C and then weighed into a stainless steel container. Compound 2 was added and the contents were mixed to be uniformly suspended. The mixing was continued while the mixture was dispensed into a capsule using a thermostatically controlled automatic capsule filling machine to prepare a 500 mg/granule capsule preparation.

尽管本发明的具体实施方式已经得到详细的描述，本领域技术人员将会理解：根据已经公开的所有教导，可以对细节进行各种修改和替换，这些改变均在本发明的保护范围之内。本发明的全部范围由所附权利要求及其任何等同物给出。 While the invention has been described with respect to the embodiments of the present invention, various modifications and changes may be made in the details of the present invention. The full scope of the invention is given by the appended claims and any equivalents thereof.

Claims (31)

式I化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型；a compound of formula I, a prodrug thereof, a metabolite form, a pharmaceutically acceptable salt or ester, or an isomer, hydrate, solvate or crystalline form as described above;
Figure PCTCN2016103735-appb-100001
Figure PCTCN2016103735-appb-100001
 其中，among them, A和B与相连的原子一起形成脂环、脂杂环、芳环或杂芳环，任选地，其中所述脂环、脂杂环、芳环或杂芳环各自独立地被一个或多个选自卤素、羟基、氨基、氰基、羧基、硝基、烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、RO-、ROC(O)-、RC(O)O-、RC(O)-、RR’N-、RC(O)NH-、RR’NC(O)-、RS(O)a-、RR’NSO2-和RSO2N(R’)-的取代基取代，其中a为0、1或2；A and B together with the attached atoms form an alicyclic, heteroalicyclic, aromatic or heteroaryl ring, optionally wherein the alicyclic, heteroalicyclic, aromatic or heteroaryl ring is independently one or more Selected from halogen, hydroxy, amino, cyano, carboxy, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, RO-, ROC(O)- , RC(O)O-, RC(O)-, RR'N-, RC(O)NH-, RR'NC(O)-, RS(O) a -, RR'NSO 2 - and RSO 2 N Substituted by (R')-, wherein a is 0, 1 or 2; R1、R2、R3和R4各自独立地选自氢、氘、卤素、羟基、氨基、氰基、羧基、硝基、烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、RO-、ROC(O)-、RC(O)O-、RC(O)-、RR’N-、RC(O)NH-和RR’NC(O)-，任选地，其中所述烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基各自独立地被一个或多个选自卤素、羟基、C1-4烷基、C1-4烷氧基、3-8元环烷基、5-8元杂环基、6-10元芳基或5-10元杂芳基的取代基取代；R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, amino, cyano, carboxy, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkane. Base, aryl, heteroaryl, RO-, ROC(O)-, RC(O)O-, RC(O)-, RR'N-, RC(O)NH- and RR'NC(O)- Optionally, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are each independently selected from one or more selected from the group consisting of halogen, hydroxy, C 1-4 Substituent substitution of an alkyl group, a C 1-4 alkoxy group, a 3-8 membered cycloalkyl group, a 5-8 membered heterocyclic group, a 6-10 membered aryl group or a 5-10 membered heteroaryl group; D和E各自独立地选自C和N，且与相连的原子一起形成5-10元(例如5、6、7、8、9、10元)环X，其中所述环X选自脂杂环、芳环或杂芳环；m和n各自独立地选自0、1和2，且m+n＝2；D and E are each independently selected from C and N, and together with the attached atoms form a 5-10 membered (e.g., 5, 6, 7, 8, 9, 10 membered) ring X, wherein said ring X is selected from the group consisting of a ring, an aromatic ring or a heteroaryl ring; m and n are each independently selected from 0, 1 and 2, and m + n = 2; Y选自C、O、S和N，条件是，当Y＝O或S时，R6和R7不存 在，当Y＝N时，R7不存在；Y is selected from C, O, S and N, provided that when Y = O or S, R 6 and R 7 are absent, and when Y = N, R 7 is absent; R5，R6，R7和R8各自独立地选自氢、羟基、氰基、硝基、烷基、环烷基、杂环烷基、芳基、杂芳基、环烷基-烷基、杂环烷基-烷基、RO-、RC(O)-、RC(O)O-、RR’N-、RC(O)NH-和RR’NC(O)-，任选地，其中所述烷基、环烷基、杂环基、杂芳基、环烷基-烷基或杂环烷基-烷基各自独立地进一步被一个或多个选自卤素、羟基、氰基、氨基、羧基、硝基、烷基、卤代烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、RO-、RR’N-、RO-C1-10烷基、RR’N-C1-10烷基、RS(O)a-、RR’NSO2-或RSO2N(R’)-的取代基取代，其中a为0、1或2；或者R 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of hydrogen, hydroxy, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyl-alkane , heterocycloalkyl-alkyl, RO-, RC(O)-, RC(O)O-, RR'N-, RC(O)NH-, and RR'NC(O)-, optionally, Wherein the alkyl group, cycloalkyl group, heterocyclic group, heteroaryl group, cycloalkyl-alkyl group or heterocycloalkyl-alkyl group are each independently further one or more selected from the group consisting of halogen, hydroxy, cyano, Amino, carboxyl, nitro, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, RO-, RR'N-, RO-C 1-10 alkane Substituted by a substituent of RR'NC 1-10 alkyl, RS(O) a -, RR'NSO 2 - or RSO 2 N(R')-, wherein a is 0, 1 or 2; R5和R6与Y原子一起形成脂杂环、芳环、脂杂环或杂芳环，任选地，其中所述脂杂环、芳环、脂杂环或杂芳环各自独立地进一步被一个或多个选自卤素、羟基、氰基、RS(O)a-、烷基、RR’N-、或RO-的取代基取代,其中a为0-2；R 5 and R 6 together with the Y atom form an aliphatic heterocyclic ring, an aromatic ring, an alicyclic ring or a heteroaryl ring, optionally wherein the alicyclic, aromatic ring, alicyclic or heteroaryl ring is independently further independently Substituted by one or more substituents selected from halogen, hydroxy, cyano, RS(O) a -, alkyl, RR'N-, or RO-, wherein a is 0-2; R和R’各自独立地选自氢、羟基、C1-10烷基、3-20元环烷基、5-20元杂环烷基、6-20元芳基、5-20元杂芳基，任选地，所述C1-10烷基、3-20元环烷基、5-20元杂环烷基、6-20元芳基、5-20元杂芳基各自独立地被一个或多个选自卤素、羟基、C1-4烷基、C1-4烷氧基、3-8元环烷基、5-8元杂环基、6-10元芳基或5-10元杂芳基的取代基取代；R and R' are each independently selected from the group consisting of hydrogen, hydroxy, C 1-10 alkyl, 3-20 membered cycloalkyl, 5-20 membered heterocycloalkyl, 6-20 membered aryl, 5-20 membered heteroaryl. And optionally, the C 1-10 alkyl group, the 3-20 membered cycloalkyl group, the 5-20 membered heterocycloalkyl group, the 6-20 membered aryl group, the 5-20 membered heteroaryl group are each independently One or more selected from the group consisting of halogen, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, 3-8 membered cycloalkyl, 5-8 membered heterocyclyl, 6-10 membered aryl or 5- a substituent of a 10-membered heteroaryl group; 其中，所述式I化合物的限制性条件为，Wherein the limiting condition of the compound of formula I is 当A和B与相连的原子一起形成苯环，R1、R2、R3均为氢，R4为氟，m和n均为1时，When A and B together with the attached atoms form a benzene ring, R 1 , R 2 , and R 3 are all hydrogen, and R 4 is fluorine. When m and n are both 1, 1)环X不为5元环、杂原子为N的六元脂杂环以及杂原子为N和O的六元脂杂环；且，1) a ring 6 is not a 5-membered ring, a heterocyclic six-membered heterocyclic heterocyclic ring, and a six-membered aliphatic heterocyclic ring having a hetero atom of N and O; 2)所述
Figure PCTCN2016103735-appb-100002
不为如下基团：2) stated
Figure PCTCN2016103735-appb-100002
Not the following groups:
Figure PCTCN2016103735-appb-100003
Figure PCTCN2016103735-appb-100003
 权利要求1的化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型，其具有式Ia所示的结构，A compound, a prodrug, a metabolite form, a pharmaceutically acceptable salt or ester thereof, or an isomer, hydrate, solvate or crystalline form thereof, having the structure of Formula Ia,
Figure PCTCN2016103735-appb-100004
Figure PCTCN2016103735-appb-100004
 其中，among them, G、J、K和L各自独立地选自C和N，并与D和E形成六元芳香环系；G, J, K and L are each independently selected from C and N, and form a six-membered aromatic ring system with D and E; 其余各原子或取代基定义如权利要求1所述；The remaining atoms or substituents are defined as set forth in claim 1; 所述式Ia化合物的限制性条件为：The limiting conditions for the compound of formula Ia are: 当A和B与相连的原子一起形成苯环，R1、R2、R3均为氢，并且R4为氟时，所述
Figure PCTCN2016103735-appb-100005
不为如下基团：When A and B together with the attached atoms form a benzene ring, R 1 , R 2 , and R 3 are all hydrogen, and R 4 is fluorine,
Figure PCTCN2016103735-appb-100005
Not the following groups:
Figure PCTCN2016103735-appb-100006
Figure PCTCN2016103735-appb-100006
 权利要求1或2的化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型，其中所述化合物如式Iaa所示，A compound according to claim 1 or 2, a prodrug, a metabolite form, a pharmaceutically acceptable salt or ester thereof, or an isomer, hydrate, solvate or crystalline form as described above, wherein the compound is of the formula Iaa As shown,
Figure PCTCN2016103735-appb-100007
Figure PCTCN2016103735-appb-100007
 其中，各原子和取代基定义如权利要求2所述；Wherein each atom and substituent are as defined in claim 2; 所述式Iaa化合物的限制性条件为：The limiting conditions for the compound of formula Iaa are: 当A和B与相连的原子一起形成苯环，R1、R2、R3均为氢，R4为氟时，所述
Figure PCTCN2016103735-appb-100008
不为如下基团：When A and B together with the attached atoms form a benzene ring, R 1 , R 2 , and R 3 are both hydrogen and R 4 is fluorine,
Figure PCTCN2016103735-appb-100008
Not the following groups:
Figure PCTCN2016103735-appb-100009
Figure PCTCN2016103735-appb-100009
 权利要求1-3任一项的化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型，其中所述化合物如式Iaa-1所示，A compound, a prodrug, a metabolite form, a pharmaceutically acceptable salt or ester thereof, or an isomer, hydrate, solvate or crystalline form thereof, according to any one of claims 1 to 3, wherein the compound As shown in the formula Iaa-1,
Figure PCTCN2016103735-appb-100010
Figure PCTCN2016103735-appb-100010
 其中，各原子和取代基定义如权利要求1所述。Wherein each atom and substituent are as defined in claim 1. 权利要求1-3任一项的化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型，其中所述化合物如式Iaa-2所示，A compound, a prodrug, a metabolite form, a pharmaceutically acceptable salt or ester thereof, or an isomer, hydrate, solvate or crystalline form thereof, according to any one of claims 1 to 3, wherein the compound As shown in the formula Iaa-2,
Figure PCTCN2016103735-appb-100011
Figure PCTCN2016103735-appb-100011
 其中，各原子和取代基定义如权利要求1所述；Wherein each atom and substituent are as defined in claim 1; 所述式Iaa-2化合物的限制性条件为： The limiting conditions for the compound of formula Iaa-2 are: 当A和B与相连的原子一起形成苯环，R1、R2、R3均为氢，R4为氟时，所述
Figure PCTCN2016103735-appb-100012
不为如下基团：When A and B together with the attached atoms form a benzene ring, R 1 , R 2 , and R 3 are both hydrogen and R 4 is fluorine,
Figure PCTCN2016103735-appb-100012
Not the following groups:
Figure PCTCN2016103735-appb-100013
Figure PCTCN2016103735-appb-100013
 权利要求1-3任一项的化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型，其中所述化合物如式Iaa-3所示，A compound, a prodrug, a metabolite form, a pharmaceutically acceptable salt or ester thereof, or an isomer, hydrate, solvate or crystalline form thereof, according to any one of claims 1 to 3, wherein the compound As shown in the formula Iaa-3,
Figure PCTCN2016103735-appb-100014
Figure PCTCN2016103735-appb-100014
 其中，各原子和取代基定义如权利要求1所述；Wherein each atom and substituent are as defined in claim 1; 所述式Iaa-3化合物的限制性条件为：The limiting conditions for the compound of formula Iaa-3 are: 当A和B与相连的原子一起形成苯环，R1、R2、R3均为氢，R4为氟时，所述
Figure PCTCN2016103735-appb-100015
不为如下基团：When A and B together with the attached atoms form a benzene ring, R 1 , R 2 , and R 3 are both hydrogen and R 4 is fluorine,
Figure PCTCN2016103735-appb-100015
Not the following groups:
Figure PCTCN2016103735-appb-100016
Figure PCTCN2016103735-appb-100016
 权利要求1-6任一项的化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型，其中所述化合物如式Iaaa所示， A compound according to any one of claims 1 to 6, a prodrug, metabolite form, pharmaceutically acceptable salt or ester thereof, or an isomer, hydrate, solvate or crystalline form thereof, wherein the compound As shown in the formula Iaaa,
Figure PCTCN2016103735-appb-100017
Figure PCTCN2016103735-appb-100017
 其中，各原子和取代基定义如权利要求1所述，Wherein each atom and substituent are as defined in claim 1. 所述式Iaaa化合物的限制性条件为：The limiting conditions for the compound of formula Iaaa are: 当A和B与相连的原子一起形成苯环，R1、R2、R3均为氢，R4为氟时，所述
Figure PCTCN2016103735-appb-100018
不为如下基团：When A and B together with the attached atoms form a benzene ring, R 1 , R 2 , and R 3 are both hydrogen and R 4 is fluorine,
Figure PCTCN2016103735-appb-100018
Not the following groups:
Figure PCTCN2016103735-appb-100019
Figure PCTCN2016103735-appb-100019
 权利要求1-7任一项的化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型，A compound according to any one of claims 1 to 7, a prodrug, a metabolite form, a pharmaceutically acceptable salt or ester thereof, or an isomer, hydrate, solvate or crystalline form as described above, 所述R5、R6、R7或R8各自独立地选自氢、羟基、氰基、硝基、C1-6烷基、C1-6烷氧基、C1-6烷基酰基、3-8元环烷基、3-8元杂环烷基、6-10元环芳基(例如苯基、萘基)、5-10元杂芳基、3-8元环烷基-C1-4烷基、3-8元杂环烷基-C1-4烷基，任选地，其中所述C1-6烷基、C1-6烷氧基、C1-6烷基酰基、3-8元环烷基、3-8元杂环烷基、6-10元环芳基或5-10元杂芳基、3-8元环烷基-C1-4烷基或3-8元杂环烷基-C1-4烷基各自独立地进一步被一个或多个选自卤素(例如氟)、羟基、C1-4烷基、卤代C1-4烷基、C1-4烷氧基、3-8元环烷基、3-8元杂环基、6-10元芳基或5-10元杂芳基、RR’N-、RO-C1-4烷基、RR’N-C1-4烷基、RR’NSO2-或RSO2-的取代基取代；或者The R 5 , R 6 , R 7 or R 8 are each independently selected from the group consisting of hydrogen, hydroxy, cyano, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl acyl 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered cycloaryl (eg phenyl, naphthyl), 5-10 membered heteroaryl, 3-8 membered cycloalkyl- C 1-4 alkyl, 3-8 membered heterocycloalkyl-C 1-4 alkyl, optionally wherein said C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkane Alkyl group, 3-8 membered cycloalkyl group, 3-8 membered heterocycloalkyl group, 6-10 membered cycloaryl group or 5-10 membered heteroaryl group, 3-8 membered cycloalkyl-C 1-4 alkyl group Or a 3-8 membered heterocycloalkyl-C 1-4 alkyl group, each independently further selected from one or more selected from the group consisting of halogen (e.g., fluoro), hydroxy, C 1-4 alkyl, halo C 1-4 alkyl , C 1-4 alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl, RR'N-, RO-C 1- Substituted by a substituent of 4 alkyl, RR'NC 1-4 alkyl, RR'NSO 2 - or RSO 2 -; or R5和R6与相连的Y原子一起形成3-8元脂环、3-8元脂杂环、6-10元芳环或5-10元杂芳环，任选地，其中所述3-8元脂环、3-8元脂杂环、6-10元芳环或5-10元杂芳环各自独立地进一步被一个或多个选自 卤素、羟基、氰基、RS(O)a-、C1-4烷基或C1-4烷氧基的取代基取代，其中a为0、1或2；R 5 and R 6 together with the attached Y atom form a 3-8 membered alicyclic ring, a 3-8 membered alicyclic ring, a 6-10 membered aromatic ring or a 5-10 membered heteroaryl ring, optionally wherein said 3 The -8 membered alicyclic ring, the 3-8 membered alicyclic ring, the 6-10 membered aromatic ring or the 5-10 membered heteroaryl ring are each independently further selected from one or more selected from the group consisting of halogen, hydroxy, cyano, and RS(O). Substituted by a substituent of a -, C 1-4 alkyl or C 1-4 alkoxy, wherein a is 0, 1 or 2; 其中R和R’各自独立地选自H和C1-4烷基。Wherein R and R' are each independently selected from the group consisting of H and C 1-4 alkyl. 权利要求1-8任一项的化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型，A compound according to any one of claims 1-8, a prodrug, a metabolite form, a pharmaceutically acceptable salt or ester thereof, or an isomer, hydrate, solvate or crystalline form as described above, 所述R5、R6、R7或R8各自独立地选自氢、甲基、乙基、环丙基甲基、氧代环丁基甲基、四氢呋喃基甲基、甲氧基乙基、2-乙氧基乙基、2-羟基乙基、三氟乙基、二氟乙基、氟乙基、N,N-二甲氨基乙基、(R)-2-甲氧基-1-甲基乙基、(S)-2-甲氧基-1-甲基乙基、(R)-2-甲氧基丙基、(S)-2-甲氧基丙基、甲磺酰基乙基、二甲氨基磺酰基乙基、2-羟基-异丁基、环丙基、1-甲基环丙基、1-甲氧甲基环丙基、2,2-二甲基环丙基、1-三氟甲基环丙基、(R)-2-氟环丙基、(S)-2-氟环丙基、2,2-二氟环丙基、氧代环丁基、4-羟基环己基、4,4-二氟环己基、四氢吡喃基、2,2-二甲基四氢吡喃基、4-甲基-四氢吡喃基、N-甲基哌啶基、N,N-二甲氨基哌啶基、N-甲基哌嗪基、哌啶基、N-甲基吡唑基或3-氧代-双环[3.1.0]己基；或者The R 5 , R 6 , R 7 or R 8 are each independently selected from the group consisting of hydrogen, methyl, ethyl, cyclopropylmethyl, oxocyclobutylmethyl, tetrahydrofuranylmethyl, methoxyethyl, 2 -ethoxyethyl, 2-hydroxyethyl, trifluoroethyl, difluoroethyl, fluoroethyl, N,N-dimethylaminoethyl, (R)-2-methoxy-1-methyl Ethyl ethyl, (S)-2-methoxy-1-methylethyl, (R)-2-methoxypropyl, (S)-2-methoxypropyl, methylsulfonylethyl , dimethylaminosulfonylethyl, 2-hydroxy-isobutyl, cyclopropyl, 1-methylcyclopropyl, 1-methoxymethylcyclopropyl, 2,2-dimethylcyclopropyl, 1-Trifluoromethylcyclopropyl, (R)-2-fluorocyclopropyl, (S)-2-fluorocyclopropyl, 2,2-difluorocyclopropyl, oxocyclobutyl, 4- Hydroxycyclohexyl, 4,4-difluorocyclohexyl, tetrahydropyranyl, 2,2-dimethyltetrahydropyranyl, 4-methyl-tetrahydropyranyl, N-methylpiperidinyl , N,N-dimethylaminopiperidinyl, N-methylpiperazinyl, piperidinyl, N-methylpyrazolyl or 3-oxo-bicyclo[3.1.0]hexyl; R5和R6与相连的Y原子一起形成四氢呋喃基、哌啶基或哌嗪基。R 5 and R 6 together with the attached Y atom form a tetrahydrofuranyl, piperidinyl or piperazinyl group. 权利要求1-9任一项的化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型，其中A和B与相连的原子一起形成芳环，优选为苯环。A compound according to any one of claims 1-9, a prodrug, a metabolite form, a pharmaceutically acceptable salt or ester thereof, or an isomer, hydrate, solvate or crystalline form as described above, wherein A and B Together with the attached atoms, an aromatic ring is formed, preferably a benzene ring. 权利要求1-10任一项的化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型，其中R4为卤素，优选为氟。A compound according to any one of claims 1 to 10, a prodrug, metabolite form, pharmaceutically acceptable salt or ester thereof, or an isomer, hydrate, solvate or crystalline form thereof, wherein R 4 is Halogen, preferably fluorine. 权利要求1-11任一项的化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型， 其中R1、R2和R3为氢。A compound according to any one of claims 1 to 11, a prodrug, a metabolite form, a pharmaceutically acceptable salt or ester thereof, or an isomer, hydrate, solvate or crystalline form thereof, wherein R 1 , R 2 and R 3 are hydrogen. 权利要求1-12任一项的化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型，其中Y为氮。A compound according to any one of claims 1 to 12, a prodrug, metabolite form, pharmaceutically acceptable salt or ester thereof, or an isomer, hydrate, solvate or crystalline form thereof, wherein Y is nitrogen . 权利要求1-13任一项的化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型，其选自以下化合物：A compound according to any one of claims 1 to 13, a prodrug, metabolite form, pharmaceutically acceptable salt or ester thereof, or an isomer, hydrate, solvate or crystalline form thereof, selected from the group consisting of Compound: 4-[3-(2-乙胺基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基)-4-氟苄基]-2H-酞嗪-1-酮；4-[3-(2-Ethylamino-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one ; 4-[3-(2-环丙基氨基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基)-4-氟苄基]-2H-酞嗪-1-酮；4-[3-(2-cyclopropylamino-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl)-4-fluorobenzyl]-2H-pyridazine-1- ketone; 4-[3-(2-环丙基甲基氨基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基)-4-氟苄基]-2H-酞嗪-1-酮；4-[3-(2-Cyclopropylmethylamino-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl)-4-fluorobenzyl]-2H-pyridazine- 1-ketone; 4-{4-氟-3-[2-(2-羟乙基氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-(2-hydroxyethylamino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl}-2H-indole Pyrazin-1-one; 4-{3-[2-(2-二甲基氨基乙氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]-4-氟苄基}-2H-酞嗪-1-酮；4-{3-[2-(2-Dimethylaminoethylamino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]-4-fluorobenzyl}-2H -pyridazine-1-one; 4-{4-氟-3-[2-(四氢-吡喃-4-氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]-苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-(tetrahydro-pyran-4-amino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]-benzyl} -2H-phthalazin-1-one; 4-[3-(2-二甲氨基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基)-4-氟苄基]-2H-酞嗪-1-酮；4-[3-(2-Dimethylamino-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one ; 4-{4-氟-3-[2-(2-甲氧基乙基胺)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]-苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-(2-methoxyethylamine)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]-benzyl}- 2H-phthalazin-1-one; 4-{4-氟-3-[2-(2-羟基-2-甲基丙基氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]-苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-(2-hydroxy-2-methylpropylamino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]-benzyl }}-2H-phthalazin-1-one; 4-{3-[2-(环丙基甲基氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]-4-氟-苄基}-2H-酞嗪-1-酮； 4-{3-[2-(Cyclopropylmethylamino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]-4-fluoro-benzyl}-2H- Pyridazin-1-one; 4-{4-氟-3-[2-(1-甲基环丙基氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]-苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-(1-methylcyclopropylamino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]-benzyl}- 2H-phthalazin-1-one; 4-{4-氟-3-[2-(3-氧杂环丁基氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-(3-oxetanylamino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl}-2H -pyridazine-1-one; 4-{4-氟-3-[2-(4-羟基环己基氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-(4-hydroxycyclohexylamino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl}-2H-indole Pyrazin-1-one; 4-{4-氟-3-[2-(四氢呋喃-3-氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-(tetrahydrofuran-3-amino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl}-2H-pyridazine -1-one; 4-{3-[2-(4-二甲氨基哌啶-1-基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]-4-氟苄基}-2H-酞嗪-1-酮；4-{3-[2-(4-Dimethylaminopiperidin-1-yl)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]-4-fluorobenzyl }-2H-pyridazin-1-one; 4-{4-氟-3-[2-(4-甲基哌嗪-1-基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-(4-methylpiperazin-1-yl)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl} -2H-phthalazin-1-one; 4-{4-氟-3-[2-(1-甲基哌啶-4-氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-(1-methylpiperidin-4-amino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl} -2H-phthalazin-1-one; 4-{3-[2-(4,4-二氟环己基氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]-4-氟苄基}-2H-酞嗪-1-酮；4-{3-[2-(4,4-Difluorocyclohexylamino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]-4-fluorobenzyl}- 2H-phthalazin-1-one; 4-{4-氟-3-[2-(1-甲基-1H-吡唑-4-氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-(1-methyl-1H-pyrazole-4-amino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl] Benzyl}-2H-phthalazin-1-one; 4-{4-氟-3-[2-(1-甲基-1H-吡唑-3-氨基)-5,7-二氢-吡唑并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-(1-methyl-1H-pyrazol-3-amino)-5,7-dihydro-pyrazolo[3,4-d]pyrimidin-6-carbonyl Benzyl}-2H-phthalazin-1-one; 4-{4-氟-3-[2-(甲基甲氧乙基氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-(methylmethoxyethylamino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl}-2H- Pyridazin-1-one; 4-[3-(2-乙氧乙氨基-5,7-二氢-吡咯[3,4-d]嘧啶-6-羰基)-4-氟苄基]-2H-酞嗪-1-酮；4-[3-(2-ethoxyethylamino-5,7-dihydro-pyrrole[3,4-d]pyrimidin-6-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one ; (S)-4-{4-氟-3-[2-(甲氧丙基-2-氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；(S)-4-{4-Fluoro-3-[2-(methoxypropyl-2-amino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl }}-2H-phthalazin-1-one; (R)-4-{4-氟-3-[2-(甲氧丙基-2-氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；(R)-4-{4-fluoro-3-[2-(methoxypropyl-2-amino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl }}-2H-phthalazin-1-one; (S)-4-{4-氟-3-[2-(2-甲氧基丙氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰 基]苄基}-2H-酞嗪-1-酮；(S)-4-{4-Fluoro-3-[2-(2-methoxypropylamino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl Benzyl]-2-H-pyridazin-1-one; (R)-4-{4-氟-3-[2-(2-甲氧基丙氨基)-5,7-二氢-吡咯[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；(R)-4-{4-fluoro-3-[2-(2-methoxypropylamino)-5,7-dihydro-pyrrole[3,4-d]pyrimidin-6-carbonyl]benzyl} -2H-phthalazin-1-one; 4-{4-氟-3-[2-(四氢呋喃-3-基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-(tetrahydrofuran-3-yl)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl}-2H-pyridazine -1-one; 4-{4-氟-3-[2-(四氢呋喃-2-基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-(tetrahydrofuran-2-yl)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl}-2H-pyridazine -1-one; 4-{4-氟-3-[2-(1-甲基哌啶-4-基)-5,7-二氢-吡咯[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-(1-methylpiperidin-4-yl)-5,7-dihydro-pyrrole[3,4-d]pyrimidin-6-carbonyl]benzyl}- 2H-phthalazin-1-one; 4-{4-氟-3-[2-(哌啶-4-基)-5,7-二氢-吡咯[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-(piperidin-4-yl)-5,7-dihydro-pyrrole[3,4-d]pyrimidin-6-carbonyl]benzyl}-2H-pyridazine -1-one; 4-[3-(2-环丙基甲基-5,7-二氢-吡咯[3,4-d]嘧啶-6-羰基)-4-氟苄基]-2H-酞嗪-1-酮；4-[3-(2-cyclopropylmethyl-5,7-dihydro-pyrrole[3,4-d]pyrimidin-6-carbonyl)-4-fluorobenzyl]-2H-pyridazine-1- ketone; 4-{4-氟-3-[2-((1R,2R)-2-甲基环丙基氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-((1R,2R)-2-methylcyclopropylamino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl Benzyl}-2H-phthalazin-1-one; 4-{3-[2-环丁基氨基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]-4-氟苄基}-2H-酞嗪-1-酮；4-{3-[2-Cyclobutylamino-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]-4-fluorobenzyl}-2H-pyridazine-1- ketone; 4-{3-[2-环丙基甲氧基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]-4-氟苄基}-2H-酞嗪-1-酮；4-{3-[2-cyclopropylmethoxy-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]-4-fluorobenzyl}-2H-pyridazine- 1-ketone; 4-{4-氟-3-[2-(2-羟基丙-2-基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-(2-hydroxypropan-2-yl)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl}-2H -pyridazine-1-one; 4-{4-氟-3-[2-(1-甲氧基甲基环丙基氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-(1-methoxymethylcyclopropylamino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl }-2H-pyridazin-1-one; 4-{4-氟-3-[2-((1R,2S)-2-甲基环丙基氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-((1R,2S)-2-methylcyclopropylamino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl Benzyl}-2H-phthalazin-1-one; 4-{3-[2-环丙基氨基-4-甲基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]-4-氟苄基}-2H-酞嗪-1-酮；4-{3-[2-Cyclopropylamino-4-methyl-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]-4-fluorobenzyl}-2H- Pyridazin-1-one; 4-{4-氟-3-[2-(1-三氟甲基环丙基)氨基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮； 4-{4-Fluoro-3-[2-(1-trifluoromethylcyclopropyl)amino-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl} -2H-phthalazin-1-one; 4-{3-[2-(2,2-二氟环丙基)氨基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]-4-氟苄基}-2H-酞嗪-1-酮；4-{3-[2-(2,2-difluorocyclopropyl)amino-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]-4-fluorobenzyl} -2H-phthalazin-1-one; 4-{3-[2-(2,2-二甲基环丙基)氨基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]-4-氟苄基}-2H-酞嗪-1-酮；4-{3-[2-(2,2-dimethylcyclopropyl)amino-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]-4-fluorobenzyl }-2H-pyridazin-1-one; 4-{4-氟-3-[2-((1R,2S)-2-氟环丙基)氨基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-((1R,2S)-2-fluorocyclopropyl)amino-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl] Benzyl}-2H-phthalazin-1-one; 4-{4-氟-3-[2-((1R,2R)-2-氟环丙基)氨基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-((1R,2R)-2-fluorocyclopropyl)amino-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl] Benzyl}-2H-phthalazin-1-one; 4-{4-氟-3-[2-(2-甲基磺酰基乙基)氨基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-(2-methylsulfonylethyl)amino-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl}- 2H-phthalazin-1-one; N,N-二甲基-2-{6-[2-氟-5-(4-氧代-3,4-二氢酞嗪-1-甲基)苯甲酰基]-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-氨基}-乙磺酰胺；N,N-Dimethyl-2-{6-[2-fluoro-5-(4-oxo-3,4-dihydropyridazin-1-methyl)benzoyl]-6,7-di Hydrogen-5H-pyrrolo[3,4-d]pyrimidin-2-amino}-ethanesulfonamide; 4-[3-(2-环丙基氨基-5,7-二氢-吡咯并[3,4-b]吡啶-6-羰基)-4-氟苄基]-2H-酞嗪-1-酮；4-[3-(2-cyclopropylamino-5,7-dihydro-pyrrolo[3,4-b]pyridine-6-carbonyl)-4-fluorobenzyl]-2H-pyridazine-1- ketone; 4-[3-(6-环丙基氨基-1,3-二氢-吡咯并[3,4-c]吡啶-2-羰基)-4-氟苄基]-2H-酞嗪-1-酮；4-[3-(6-cyclopropylamino-1,3-dihydro-pyrrolo[3,4-c]pyridine-2-carbonyl)-4-fluorobenzyl]-2H-pyridazine-1- ketone; 4-[3-(2-环丙基氨基-5,7-二氢-吡咯并[3,4-b]吡嗪-6-羰基)-4-氟苄基]-2H-酞嗪-1-酮；4-[3-(2-cyclopropylamino-5,7-dihydro-pyrrolo[3,4-b]pyrazine-6-carbonyl)-4-fluorobenzyl]-2H-pyridazine-1 -ketone; 4-{3-[2-(2,2-二甲基-四氢吡喃-4-氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]-4-氟苄基}-2H-酞嗪-1-酮；4-{3-[2-(2,2-Dimethyl-tetrahydropyran-4-amino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]- 4-fluorobenzyl}-2H-phthalazin-1-one; 4-{4-氟-3-[2-(4-甲基-四氢-吡喃-4-氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-(4-methyl-tetrahydro-pyran-4-amino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl Benzyl}-2H-phthalazin-1-one; 4-{3-[2-(3-氮杂双环[3.1.0]己基-6-氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]-4-氟苄基}-2H-酞嗪-1-酮；4-{3-[2-(3-Azabicyclo[3.1.0]hexyl-6-amino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]-4 -fluorobenzyl}-2H-phthalazin-1-one; 4-{4-氟-3-[2-(2,2,2-三氟乙基)氨基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-(2,2,2-trifluoroethyl)amino-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl }-2H-pyridazin-1-one; 4-{3-[2-(2,2-二氟乙基)氨基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]-4-氟苄基}-2H-酞嗪-1-酮；4-{3-[2-(2,2-difluoroethyl)amino-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]-4-fluorobenzyl}- 2H-phthalazin-1-one; 4-{4-氟-3-[2-(2-氟乙基)氨基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基] 苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-(2-fluoroethyl)amino-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl] Benzyl}-2H-phthalazin-1-one; 4-{4-氟-3-[2-(氧杂环丁基-2-甲基)氨基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-(oxetanyl-2-methyl)amino-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl }-2H-pyridazin-1-one; 4-{4-氟-3-[2-(氧杂环丁基-3-甲基)氨基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-(oxetanyl-3-methyl)amino-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl }-2H-pyridazin-1-one; 4-{4-氟-3-[2-(四氢呋喃-2-甲基)氨基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-(tetrahydrofuran-2-methyl)amino-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl}-2H- Pyridazin-1-one; 4-{3-[2-(环丙基氨基)-4-三氟甲基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]-4-氟苄基}-2H-酞嗪-1-酮；4-{3-[2-(cyclopropylamino)-4-trifluoromethyl-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]-4-fluorobenzyl }-2H-pyridazin-1-one; 4-{4-氟-3-[2-(2-三氟甲氧基乙基)氨基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-(2-trifluoromethoxyethyl)amino-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl} -2H-phthalazin-1-one; 4-{3-[2-环丙基氨基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]-4-氟苄基}-7-氟-2H-酞嗪-1-酮；4-{3-[2-cyclopropylamino-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]-4-fluorobenzyl}-7-fluoro-2H-indole Pyrazin-1-one; 7-氟-4-{4-氟-3-[2-(2-甲氧基乙基)氨基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；7-fluoro-4-{4-fluoro-3-[2-(2-methoxyethyl)amino-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl }}-2H-phthalazin-1-one; 7-氟-4-{4-氟-3-[2-(四氢吡喃-4-氨基)-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；7-Fluoro-4-{4-fluoro-3-[2-(tetrahydropyran-4-amino)-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl }}-2H-phthalazin-1-one; 4-{4-氟-3-[2-(4-甲氧基环己基)氨基-5,7-二氢-吡咯并[3,4-d]嘧啶-6-羰基]苄基}-2H-酞嗪-1-酮；4-{4-Fluoro-3-[2-(4-methoxycyclohexyl)amino-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-carbonyl]benzyl}-2H -pyridazine-1-one; (R)-4-{3-[2-(3-四氢呋喃基)氨基-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-6-羰基]-4-氟苄基}-2H酞嗪-1-酮；(R)-4-{3-[2-(3-tetrahydrofuryl)amino-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-6-carbonyl]-4-fluorobenzyl }-2H pyridazin-1-one; (S)-4-{3-[2-(3-四氢呋喃基)氨基-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-6-羰基]-4-氟苄基}-2H酞嗪-1-酮；(S)-4-{3-[2-(3-tetrahydrofuryl)amino-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-6-carbonyl]-4-fluorobenzyl }-2H pyridazin-1-one; 4-{3-[2-(((2R,5R)-5-二甲基氨基-1,3-二噁烷-2-基)甲基)氨基-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-6-羰基]-4-氟苄基}-2H酞嗪-1-酮；4-{3-[2-((2R,5R)-5-dimethylamino-1,3-dioxan-2-yl)methyl)amino-6,7-dihydro-5H-pyrrole And [3,4-d]pyrimidin-6-carbonyl]-4-fluorobenzyl}-2H-pyridazin-1-one; 4-{3-[2-((2R,5R)-2-(二甲基氨基)甲基-1,3-二噁烷-5-基)氨基-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-6-羰基]-4-氟苄基}-2H酞嗪-1-酮；和，4-{3-[2-((2R,5R)-2-(dimethylamino)methyl-1,3-dioxan-5-yl)amino-6,7-dihydro-5H-pyrrole And [3,4-d]pyrimidin-6-carbonyl]-4-fluorobenzyl}-2H-pyridazin-1-one; 4-{3-[4-甲基-2-(4-四氢呋喃基)氨基-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-6-羰基]-4-氟苄基}-2H酞嗪-1-酮。 4-{3-[4-Methyl-2-(4-tetrahydrofuryl)amino-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-6-carbonyl]-4-fluorobenzyl Base}-2H oxazin-1-one. 权利要求1-14任一项的化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型的制备方法，其选自以下合成路线：A method of preparing a compound according to any one of claims 1 to 14, a prodrug, a metabolite form, a pharmaceutically acceptable salt or ester thereof, or the aforementioned isomer, hydrate, solvate or crystalline form, Selected from the following synthetic routes: 路线1：Route 1:
Figure PCTCN2016103735-appb-100020
Figure PCTCN2016103735-appb-100020
 将化合物A与化合物B进行缩合反应得到式I化合物；或者Condensation of Compound A with Compound B to give a compound of Formula I; or 路线2：Route 2:
Figure PCTCN2016103735-appb-100021
Figure PCTCN2016103735-appb-100021
 将化合物A与化合物B’进行缩合反应得到化合物C’；将化合物C’与化合物
Figure PCTCN2016103735-appb-100022
进行亲核取代反应制得式I化合物；Condensation of compound A with compound B' to give compound C'; compound C' with compound
Figure PCTCN2016103735-appb-100022
Preparing a compound of formula I by nucleophilic substitution reaction; 其中，Lg代表亲核取代反应的离去基团，例如为卤素、-OCOR、-OTs、-SO2R等，例如为甲磺酰基，其余各原子和取代基的定义如权利要求1-14任一项所述。 Wherein Lg represents a leaving group of a nucleophilic substitution reaction, such as halogen, -OCOR, -OTs, -SO 2 R, etc., such as a methylsulfonyl group, and the remaining atoms and substituents are as defined in claims 1-14 Any of the above. 药物组合物，其包含权利要求1-14任一项所述的化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型，任选地，其还包含药学可接受的载体或赋形剂。A pharmaceutical composition comprising a compound according to any one of claims 1 to 14, a prodrug thereof, a metabolite form, a pharmaceutically acceptable salt or ester, or the aforementioned isomer, hydrate, solvate Or crystalline form, optionally, it further comprises a pharmaceutically acceptable carrier or excipient. 权利要求16所述的药物组合物，其中所述组合物含有权利要求1-14任一项所述化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型的含量为0.01-2000mg，优选为0.1-1000mg，更优选为1-800mg，更优选为10-600mg，特别优选为50-500mg。The pharmaceutical composition according to claim 16, wherein the composition contains the compound according to any one of claims 1 to 14, a prodrug thereof, a metabolite form, a pharmaceutically acceptable salt or ester, or the aforementioned The content of the construct, hydrate, solvate or crystal form is from 0.01 to 2000 mg, preferably from 0.1 to 1000 mg, more preferably from 1 to 800 mg, still more preferably from 10 to 600 mg, particularly preferably from 50 to 500 mg. 权利要求16或17的药物组合物，其还包含一种或多种抗肿瘤药物，优选地，所述抗肿瘤药物选自替莫唑胺、阿霉素、紫杉醇、顺铂、卡铂、达卡巴嗪、拓扑替康、伊立替康、吉西他滨和贝伐单抗、anti-CTLA-4单抗Ipilimumab、anti-PD-1单抗pembrolizumab和Nivolumab以及anti-PD-L1单抗atezolizumab。The pharmaceutical composition according to claim 16 or 17, which further comprises one or more antitumor drugs, preferably, the antitumor drug is selected from the group consisting of temozolomide, doxorubicin, paclitaxel, cisplatin, carboplatin, dacarbazine, Topotecan, irinotecan, gemcitabine and bevacizumab, anti-CTLA-4 mAb Ipilimumab, anti-PD-1 mAb pembrolizumab and Nivolumab, and anti-PD-L1 mAb atezolizumab. 权利要求1-14任一项所述的化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型、或权利要求16-18任一项所述的药物组合物在制备抑制PARP的试剂中的用途；优选地，所述试剂为抑制PARP-1抑制剂。A compound according to any one of claims 1 to 14, a prodrug, a metabolite form, a pharmaceutically acceptable salt or ester thereof, or an isomer, hydrate, solvate or crystal form, or a right thereof. The use of the pharmaceutical composition according to any one of 16 to 18 for the preparation of a PARP-inhibiting agent; preferably, the agent is a PARP-1 inhibitor. 权利要求1-14任一项所述的化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型、或权利要求16-18任一项所述的药物组合物，其用于抑制PARP活性；优选地，其用于抑制PARP-1活性。A compound according to any one of claims 1 to 14, a prodrug, a metabolite form, a pharmaceutically acceptable salt or ester thereof, or an isomer, hydrate, solvate or crystal form, or a right thereof. The pharmaceutical composition according to any one of 16 to 18, which is for inhibiting PARP activity; preferably, it is for inhibiting PARP-1 activity. 一种抑制PARP活性的方法，所述方法包括向有需要的受试者施用有效量的权利要求1-14任一项所述的化合物、其前体药物、代 谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型、或权利要求16-18任一项所述的药物组合物；优选地，所述方法用于抑制PARP-1活性；优选地，用于抑制细胞中PARP-1活性；优选地，所述细胞为细胞系或来自受试者的细胞。A method of inhibiting PARP activity, the method comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1-14, a prodrug thereof, a progeny thereof a pharmaceutical composition, a pharmaceutically acceptable salt or ester, or an isomer, hydrate, solvate or crystalline form, or a pharmaceutical composition according to any one of claims 16-18; preferably, The method is for inhibiting PARP-1 activity; preferably, for inhibiting PARP-1 activity in a cell; preferably, the cell is a cell line or a cell derived from a subject. 权利要求1-14任一项所述的化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型、或权利要求16-18任一项所述的药物组合物在制备辅助治疗肿瘤的试剂或是用于增强放射或化学治疗肿瘤效果的药物中的用途。A compound according to any one of claims 1 to 14, a prodrug, a metabolite form, a pharmaceutically acceptable salt or ester thereof, or an isomer, hydrate, solvate or crystal form, or a right thereof. The use of the pharmaceutical composition according to any one of 16 to 18 for the preparation of a medicament for adjuvant treatment of a tumor or for use in a medicament for enhancing the effect of radiation or chemotherapy on a tumor. 权利要求1-14任一项所述的化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型、或权利要求16-18任一项所述的药物组合物，其用于辅助治疗肿瘤或是用于增强放射或化学治疗效果。A compound according to any one of claims 1 to 14, a prodrug, a metabolite form, a pharmaceutically acceptable salt or ester thereof, or an isomer, hydrate, solvate or crystal form, or a right thereof. The pharmaceutical composition of any of 16-18 for use in the treatment of a tumor or for enhancing a radiological or chemotherapeutic effect. 一种辅助治疗肿瘤或增强放射或化学治疗效果的方法，所述方法包括向有需要的受试者施用有效量的权利要求1-14任一项所述的化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型、或权利要求16-18任一项所述的药物组合物。A method of adjuvant treatment of a tumor or enhancing the effect of radiation or chemotherapy, the method comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1-14, a prodrug thereof, a metabolite thereof Form, pharmaceutically acceptable salt or ester, or the aforementioned isomer, hydrate, solvate or crystalline form, or the pharmaceutical composition of any of claims 16-18. 权利要求1-14任一项所述的化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型、或权利要求16-18任一项所述的药物组合物在制备治疗肿瘤的药物中的用途。A compound according to any one of claims 1 to 14, a prodrug, a metabolite form, a pharmaceutically acceptable salt or ester thereof, or an isomer, hydrate, solvate or crystal form, or a right thereof. The use of the pharmaceutical composition according to any one of 16 to 18 for the preparation of a medicament for treating a tumor. 权利要求1-14任一项所述的化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型、或权利要求16-18任一项所述的药物组合物，其用于治疗肿瘤。 A compound according to any one of claims 1 to 14, a prodrug, a metabolite form, a pharmaceutically acceptable salt or ester thereof, or an isomer, hydrate, solvate or crystal form, or a right thereof. The pharmaceutical composition of any of 16-18 for use in the treatment of a tumor. 一种治疗肿瘤的方法，所述方法包括向有需要的受试者提供有效量的权利要求1-14任一项所述的化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型、或权利要求16-18任一项所述的药物组合物。A method of treating a tumor, the method comprising providing an effective amount of the compound of any one of claims 1-14, a prodrug thereof, a metabolite form, a pharmaceutically acceptable salt, to a subject in need thereof Or an ester, or an isomer, hydrate, solvate or crystalline form as described above, or a pharmaceutical composition according to any one of claims 16-18. 权利要求22-27任一项的用途、方法或化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型、或药物组合物，其中所述肿瘤选自乳腺癌、卵巢癌、结直肠癌、黑色素瘤、肺癌、胃肠道间质瘤、脑癌、宫颈癌、胰腺癌、前列腺癌、胃癌、慢性髓样白细胞过多症、肝癌、淋巴瘤、腹膜癌、软组织肉瘤、神经内分泌肿瘤和胶质母细胞瘤。Use, method or compound, prodrug, metabolite form, pharmaceutically acceptable salt or ester thereof, or an isomer, hydrate, solvate or crystalline form thereof, according to any one of claims 22-27, Or a pharmaceutical composition, wherein the tumor is selected from the group consisting of breast cancer, ovarian cancer, colorectal cancer, melanoma, lung cancer, gastrointestinal stromal tumor, brain cancer, cervical cancer, pancreatic cancer, prostate cancer, gastric cancer, chronic myeloid Leukocytosis, liver cancer, lymphoma, peritoneal cancer, soft tissue sarcoma, neuroendocrine tumors, and glioblastoma. 权利要求1-14任一项所述的化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型、或权利要求16-18任一项所述的药物组合物在制备治疗血管疾病、神经退变性疾病或神经系统炎症的药物中的用途。A compound according to any one of claims 1 to 14, a prodrug, a metabolite form, a pharmaceutically acceptable salt or ester thereof, or an isomer, hydrate, solvate or crystal form, or a right thereof. The use of the pharmaceutical composition according to any one of 16 to 18 for the preparation of a medicament for treating a vascular disease, a neurodegenerative disease or a nervous system inflammation. 权利要求1-14任一项所述的化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型、或权利要求16-18任一项所述的药物组合物，其用于治疗血管疾病、神经退变性疾病或神经系统炎症。A compound according to any one of claims 1 to 14, a prodrug, a metabolite form, a pharmaceutically acceptable salt or ester thereof, or an isomer, hydrate, solvate or crystal form, or a right thereof. The pharmaceutical composition according to any one of 16 to 18, which is for use in the treatment of a vascular disease, a neurodegenerative disease or a nervous system inflammation. 一种治疗血管疾病、神经退变性疾病或神经系统炎症的方法，所述方法包括向有需要的受试者施用有效量的权利要求1-14任一项所述的化合物、其前体药物、代谢物形式、药学上可接受的盐或酯、或前述的异构体、水合物、溶剂合物或晶型、或权利要求16-18任一项所述的药物组合物。 A method of treating a vascular disease, a neurodegenerative disease, or a nervous system inflammation, the method comprising administering to a subject in need thereof an effective amount of the compound of any one of claims 1-14, a prodrug thereof, A metabolite form, a pharmaceutically acceptable salt or ester, or an isomer, hydrate, solvate or crystalline form as described above, or a pharmaceutical composition according to any one of claims 16-18.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020068530A1 (en) 2018-09-26 2020-04-02 Eli Lilly And Company 6-fluoro-2-methylbenzo[d]thiazol-5-yl compounds

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110845425B (en) * 2019-11-07 2023-09-08 合肥工业大学 A kind of phthalazine derivative and its preparation method and application
US20230159469A1 (en) * 2020-05-08 2023-05-25 Txinno Bioscience Inc. Novel phthalazine derivative having ectonucloeotide pyrophosphatase/phosphodieste rase inhibitory activity, and use thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1788000A (en) * 2003-03-12 2006-06-14 库多斯药物有限公司 Phthalazinone derivatives
WO2012019426A1 (en) * 2010-08-09 2012-02-16 上海恒瑞医药有限公司 Phthalazinone derivative, and preparation method and pharmaceutical use thereof

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102898377B (en) * 2012-02-14 2016-01-20 南京圣和药业股份有限公司 One class phthalazinone derivatives and uses thereof
CN103570722A (en) * 2012-07-19 2014-02-12 中国科学院上海药物研究所 Fused ring pyridazinone compounds, preparation method and uses thereof
SG11201503670YA (en) * 2012-12-31 2015-07-30 Cadila Healthcare Ltd Substituted phthalazin-1 (2h)-one derivatives as selective inhibitors of poly (adp-ribose) polymerase-1

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1788000A (en) * 2003-03-12 2006-06-14 库多斯药物有限公司 Phthalazinone derivatives
WO2012019426A1 (en) * 2010-08-09 2012-02-16 上海恒瑞医药有限公司 Phthalazinone derivative, and preparation method and pharmaceutical use thereof

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020068530A1 (en) 2018-09-26 2020-04-02 Eli Lilly And Company 6-fluoro-2-methylbenzo[d]thiazol-5-yl compounds

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