WO2017071636A1 - Dérivé de phthalazine cétone, son procédé de préparation et son utilisation - Google Patents

Dérivé de phthalazine cétone, son procédé de préparation et son utilisation Download PDF

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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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dihydro
pyrimidin
carbonyl
pyrrolo
group
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PCT/CN2016/103735
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English (en)
Chinese (zh)
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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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四川科伦博泰生物医药股份有限公司
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Priority to CN201680007634.7A priority Critical patent/CN107428762B/zh
Publication of WO2017071636A1 publication Critical patent/WO2017071636A1/fr

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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

L'invention concerne un dérivé de phthalazine cétone, ainsi que son procédé de préparation et une utilisation de ce dernier. Plus précisément, un composé de formule I, un promédicament, une forme métabolite, un sel ou un ester pharmaceutiquement acceptable, un isomère, un hydrate, un solvate ou une forme cristalline de ce dernier, et un procédé de préparation et une utilisation associée sont décrits. Le composé de l'invention permet de supprimer de façon significative la prolifération de cellules tumorales, d'accroître la stabilité moléculaire in vivo, et de réduire la probabilité de génération de métabolites toxiques. En variante, la modification structurelle peut être effectuée sur un composé phtalazine cétone, réduisant ainsi la capacité métabolique oxydative du composé sous l'action d'un système enzymatique de cytochrome P450 in vivo, et augmentant la biodisponibilité.
PCT/CN2016/103735 2015-10-30 2016-10-28 Dérivé de phthalazine cétone, son procédé de préparation et son utilisation WO2017071636A1 (fr)

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CN110845425B (zh) * 2019-11-07 2023-09-08 合肥工业大学 一种酞嗪衍生物及其制备方法和应用
WO2021225407A1 (fr) * 2020-05-08 2021-11-11 주식회사 티씨노바이오사이언스 Nouveau dérivé de phtalazine ayant une activité d'inhibition de l'ectonucléotide pyrophosphatase/phosphodiestérase, et son utilisation

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CN103570722A (zh) * 2012-07-19 2014-02-12 中国科学院上海药物研究所 稠环哒嗪酮类化合物及其制备方法和用途
MA38080A1 (fr) * 2012-12-31 2018-02-28 Cadila Healthcare Ltd Dérivés substitués de phtalazin-1(2h)-one comme inhibiteurs sélectifs de la poly(adp-ribose) polymérase-1

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WO2012019426A1 (fr) * 2010-08-09 2012-02-16 上海恒瑞医药有限公司 Dérivé de phtalazinone, son procédé de préparation et utilisation pharmaceutique

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