WO2024067694A1 - Composé hétérocyclique contenant de l'azote et son utilisation pharmaceutique - Google Patents

Composé hétérocyclique contenant de l'azote et son utilisation pharmaceutique Download PDF

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WO2024067694A1
WO2024067694A1 PCT/CN2023/122005 CN2023122005W WO2024067694A1 WO 2024067694 A1 WO2024067694 A1 WO 2024067694A1 CN 2023122005 W CN2023122005 W CN 2023122005W WO 2024067694 A1 WO2024067694 A1 WO 2024067694A1
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alkyl
heteroaryl
racemate
aryl
cycloalkyl
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PCT/CN2023/122005
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English (en)
Chinese (zh)
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刘国标
王国政
闫旭
李斌
任越
李建浩
辛丕明
赵礼坤
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中国医药研究开发中心有限公司
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Priority to CN202380014000.4A priority Critical patent/CN118139862A/zh
Publication of WO2024067694A1 publication Critical patent/WO2024067694A1/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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero 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 invention relates to nitrogen-containing heterocyclic compounds and their medical uses. Specifically, the present invention relates to nitrogen-containing heterocyclic compounds represented by general formula (I), preparation methods thereof, pharmaceutical compositions containing the same, and uses thereof as poly (ADP-ribose) polymerase 1 inhibitors for treating diseases associated with PARP1 activity.
  • PARPs Poly (ADP ribose) polymerases
  • the family includes 18 members with ADP-ribosyltransferase activity, catalyzing the addition of ADP-ribose units to DNA or different receptor proteins, affecting a variety of cellular processes.
  • PARP1 and PARP2 are the most widely studied PARPs because of their role in DNA damage repair.
  • PARP1 is the most important member of the PARP family. It is a nuclear protein composed of three domains: a DNA binding domain containing two zinc fingers at the N-terminus, a self-modification domain, and a C-terminal catalytic domain.
  • PARP2 has similar functions to PARP1, but the two differ in substrate selection.
  • PARP1 and PARP2 can repair DNA single-strand breaks (SSBs), and PARP1 can also repair DNA double-strand breaks (DSBs) and replication fork damage.
  • SSBs DNA single-strand breaks
  • DSBs DNA double-strand breaks
  • PARP1 is activated after DNA damage. It recognizes and binds to the DNA break site through the zinc finger domain, reduces recombination and protects damaged DNA from the action of exonucleases.
  • nicotinamide adenine dinucleotide NAD+
  • ADP ribose ADP ribose as a substrate to "PARize" the receptor protein and PARP1 itself, forming a PARP-ADP-ribose branch chain, which can prevent nearby DNA molecules from recombination with damaged DNA on the one hand, and attract DNA repair proteins to bind and reduce the affinity of PARP1 with DNA on the other hand, so that PARP1 dissociates from the DNA break, and then DNA repair proteins bind to the DNA gap to repair the damaged site.
  • NAD+ nicotinamide adenine dinucleotide
  • PARP1 The "PARization" of PARP1 will be cleared by other enzymes, allowing PARP1 to regain activity and look for the next DNA break.
  • PARP1 poly(ADP-ribose)glycohydrolase (PARG) and type 3 ADP ribose hydrolase (ARH3).
  • PARG poly(ADP-ribose)glycohydrolase
  • ARH3 type 3 ADP ribose hydrolase
  • PARP1, PARP2, PARP5A and PARP5B can catalyze the synthesis of PAR chains.
  • Most other enzymes in the superfamily can only catalyze the synthesis of a single ADP ribose unit, so they are also called mono(ADP-ribosyl)ases (MARs).
  • MARs mono(ADP-ribosyl)ases
  • PARP binding to DNA damage sites, catalytic activity, and release from DNA are all important steps in the tumor cell response to DNA damage caused by chemotherapeutic drugs and radiation.
  • Inhibition of PARP family enzymes has been used as a strategy to selectively kill tumor cells by inhibiting DNA repair pathways.
  • Small molecule inhibition of PARP1 has been shown to sensitize tumor cells to cytotoxic therapies (e.g., temozolomide, platinum, topoisomerase inhibitors, and radiation).
  • cytotoxic therapies e.g., temozolomide, platinum, topoisomerase inhibitors, and radiation.
  • tumors produced by mutation carriers usually lose the wild-type allele, which leads to tumor-specific homologous recombination repair (HRR) dysfunction when double-strand breaks occur, and thus rely on the function of PARP for survival.
  • HRR tumor-specific homologous recombination repair
  • PARP inhibitor treatment is mainly aimed at cancer patients with BRCA mutations, but for cancers with homologous recombination repair defects, each related gene may become a potential target for synthetic lethality of PARP inhibitors, and PARP inhibitors have great therapeutic value.
  • ATM deletion was found in patients with T-lymphocytic leukemia, B-cell chronic lymphocytic leukemia, and breast cancer
  • CHK2 germline mutations were found in sarcomas, breast cancer, ovarian cancer, and brain tumors
  • FANCC and FANCG mutations were confirmed in pancreatic cancer
  • FANCF promoter methylation also occurred in ovarian cancer, breast cancer, cervical cancer, and lung cancer.
  • homologous recombination repair-related genes have also been shown to constitute synthetic lethality with PARP.
  • Homologous recombination repair is a multifactorial process that ensures the repair of DNA double bond breaks at damaged replication forks.
  • PARP1 recruits MRE11 to the replication fork to promote base excision, and PARP1/2 binds to 5'-deoxyribonucleic acid. After PARP activation, it uses DNA polymerase ⁇ (Pol ⁇ ) and ligase III to recruit the BER scaffold protein XRCC1. Cells with defects in XRCC1 and Pol ⁇ are highly sensitive to PARPis.
  • PARP-DNA complex is a barrier to replication.
  • Ataxia telangiectasia and rad3-related protein kinase (ATR) and cycle checkpoint kinase 1 (CHK1) activate the S phase checkpoint, slow down replication forks and block replication initiation, maintain genome stability, inhibit ATR or CHK1 leading to loss of S phase checkpoint, replication initiation, and double bond breaks.
  • ATR rad3-related protein kinase
  • CHK1 cycle checkpoint kinase 1
  • FANCI-FANCD2 can stabilize the RAD51-DNA complex, PALB2 binds to BRCA2, promotes BRCA2 nuclear stability and accumulation, and BRCA1 interacts with many HRR-related factors (BARD1, CtIP, RAD51, BRCA2, PALB2, Abraxas, and RAP80) and accelerates HRR at multiple steps.
  • the BRD family and BET proteins recognize and recruit multiple proteins to chromatin and transcription sites, as well as bind to acetylated histones.
  • BET/BRD4 inhibitors inhibit HRR by blocking the transcription of DNA repair genes (such as CtIP, BRCA1, WEE1, TOPBP1, and RAD51), and show synergy with PARPis in cells with normal BRCA.
  • PARP1/2 inhibitors currently on the market or in clinical trials have severe hematological toxicity as monotherapy drugs, which limits chronic treatment plans or combination therapies. Therefore, there is a need to develop compounds that are highly selective for PARP1 and less toxic to meet clinical needs.
  • PARP1 poly (ADP-ribose) polymerase 1
  • the object of the present invention is to provide a compound represented by general formula (I) or its mesomorph, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.
  • X 1 , X 2 , X 3 , and X 4 are each independently selected from N or C(R 3 );
  • Ring A is selected from bicyclic aryl, bicyclic heteroaryl, bicyclic heterocyclic group, and the bicyclic aryl, bicyclic heteroaryl, bicyclic heterocyclic group is optionally further substituted by one or more R2 ;
  • R1 is selected from alkyl or haloalkyl
  • each R2 is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, thiol, oxo, thio, alkyl, alkoxy, -C(O) Rc , -S(O) Rc , -S (O) 2Rc , -C(O) NRaRb , -S ( O )NRaRb , -S(O) 2NRaRb , -OC(O) Rc , -N( Ra )C(O) Rc , -N ( Ra )S(O) Rc , -N( Ra )S(O ) 2Rc , cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, hetero
  • cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally further substituted by one or more groups selected from deuterium, halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;
  • Each R 3 is independently selected from hydrogen, alkyl, haloalkyl, halogen;
  • Ra and Rb are each independently selected from hydrogen, halogen, hydroxyl, thiol, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; or,
  • Ra and Rb together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group, which is optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl;
  • R c is selected from hydrogen, halogen, hydroxyl, thiol, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.
  • the compound represented by the general formula (I) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof is the compound represented by the general formula (II) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,
  • m is an integer from 0 to 2;
  • Ring A, R 1 and R 3 are as defined in the general formula (I).
  • the compound represented by the general formula (I) or the general formula (II) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof wherein:
  • Ring A is selected from C 8 -C 10 bicyclic aryl, 8 to 10 membered bicyclic heteroaryl or 8 to 10 membered bicyclic heterocyclyl; preferably 8 to 10 membered bicyclic heteroaryl; the C 8 -C 10 bicyclic aryl, 8 to 10 membered bicyclic heteroaryl and 8 to 10 membered bicyclic heterocyclyl are optionally further substituted by one or more R 2 ;
  • R2 is as defined in the general formula (I).
  • the compound represented by the general formula (I) or the general formula (II) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt is the compound represented by the general formula (III) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt,
  • Y is selected from N or C
  • Ring A1 is selected from a 5- to 6-membered heterocyclyl or a 5- to 6-membered heteroaryl
  • each R2a is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, thiol, oxo, thio, alkyl, alkoxy, -C(O) Rc , -S(O) Rc , -S (O) 2Rc , -C(O) NRaRb , -S ( O )NRaRb , -S(O) 2NRaRb , -OC(O) Rc , -N( Ra )C(O) Rc , -N ( Ra )S(O) Rc , -N( Ra )S(O ) 2Rc , cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl,
  • cycloalkyl, heterocyclyl, aryl, heteroaryl groups are optionally further substituted by one or more groups selected from deuterium, halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;
  • Each R2b is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, thiol, oxo, thio, alkyl, alkoxy, -C(O) Rc , -S(O) Rc , -S (O) 2Rc , -C(O) NRaRb , -S ( O )NRaRb , -S(O) 2NRaRb , -OC(O) Rc , -N( Ra )C(O) Rc , -N ( Ra )S(O) Rc , -N( Ra )S(O ) 2Rc , cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl,
  • Ra and Rb are each independently selected from hydrogen, halogen, hydroxyl, thiol, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; or,
  • Ra and Rb together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group, which is optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl;
  • R c is selected from hydrogen, halogen, hydroxyl, thiol, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl
  • n is an integer from 0 to 2;
  • p is an integer from 0 to 4.
  • q is an integer from 0 to 2;
  • R 1 and R 3 are as defined in the general formula (I).
  • the compound represented by the general formula (III) or its racemate, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (III) or its racemate, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each R 2a is independently selected from halogen, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl; p is an integer from 0 to 4.
  • the compound represented by the general formula (III) or its mesoform, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (III) or its mesoform, racemate, enantiomer, diastereoisomer, or mixture thereof
  • the invention relates to an isomer, a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each R 2b is independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl; and q is an integer from 0 to 2.
  • the compound represented by the general formula (I) or the general formula (II) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof wherein:
  • Ring A is selected from Preferably More preferred Further optimization
  • Ring A is optionally further substituted by one or more R 2 ;
  • R 2 is as defined in the general formula (I);
  • R 2 is selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, phenyl, -C(O)NR a R b ; wherein Ra and R b are each independently selected from hydrogen and C 1 -C 6 alkyl.
  • the compound represented by the general formula (I) or the general formula (II) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof wherein:
  • Ring A is selected from Further optimization
  • R 21 , R 22 , and R 23 are each independently selected from hydrogen and halogen;
  • R 24 and R 25 are each independently selected from hydrogen and C 1 -C 6 alkyl
  • R 26 , R 27 , and R 28 are each independently selected from hydrogen, halogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl;
  • R 29 is selected from hydrogen, C 1-6 alkyl, -C(O)NR a R b ; wherein Ra and R b are each independently selected from hydrogen and C 1 -C 6 alkyl;
  • R 210 is selected from hydrogen and C 1 -C 6 alkyl, preferably hydrogen;
  • R 211 is selected from hydrogen and C 1 -C 6 alkyl, preferably C 1 -C 6 alkyl;
  • R 212 is selected from hydrogen and C 1 -C 6 alkyl, preferably C 1 -C 6 alkyl.
  • the compound represented by the general formula (I) or the general formula (II) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof wherein:
  • Ring A is selected from
  • R 21 , R 22 , and R 23 are each independently selected from hydrogen and halogen;
  • R 24 and R 25 are each independently selected from hydrogen and C 1 -C 6 alkyl.
  • the compound represented by the general formula (I) or the general formula (II) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof wherein:
  • Ring A is selected from
  • R 26 , R 27 , and R 28 are each independently selected from hydrogen, halogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl;
  • R 29 is selected from hydrogen, C 1-6 alkyl, -C(O)NR a R b ; wherein Ra and R b are each independently selected from hydrogen and C 1 -C 6 alkyl;
  • R 210 is selected from hydrogen and C 1 -C 6 alkyl, preferably hydrogen.
  • the compound represented by the general formula (I) or the general formula (II) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof wherein:
  • Ring A is selected from
  • the compound represented by the general formula (I) or the general formula (II) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof wherein:
  • Ring A is selected from
  • the compound represented by the general formula (I) or the general formula (II) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof wherein:
  • Ring A is selected from
  • R 211 is selected from hydrogen and C 1 -C 6 alkyl, preferably C 1 -C 6 alkyl.
  • the compound represented by the general formula (I) or the general formula (II) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof wherein:
  • Ring A is selected from Wherein, R 212 is selected from hydrogen and C 1 -C 6 alkyl, preferably C 1 -C 6 alkyl.
  • the compound represented by the general formula (I), general formula (II) or general formula (III) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof is Formula, or a pharmaceutically acceptable salt thereof,
  • R 1 is selected from C 1-6 alkyl or C 1-6 haloalkyl.
  • Typical compounds of the present invention include, but are not limited to:
  • the present invention further provides a method for preparing the compound represented by general formula (II) according to the present invention or its mesomorph, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which comprises the following steps:
  • a compound of the general formula IId undergoes a substitution reaction with a compound of the general formula IIe to obtain a compound represented by the general formula (II) or its mesomorph, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof;
  • the present invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound according to the present invention or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
  • the present invention further relates to the use of the compound according to the present invention or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt or a pharmaceutical composition containing the same in the preparation of poly ADP-ribose polymerase 1 (PARP1) inhibitors.
  • PARP1 poly ADP-ribose polymerase 1
  • the present invention further relates to the use of the compound according to the present invention or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt or a pharmaceutical composition containing the same in the preparation of a drug for preventing and/or treating a disease associated with poly (ADP-ribose) polymerase 1 activity, wherein the disease is preferably a tumor disease, such as ovarian cancer, breast cancer, prostate cancer, etc.
  • a tumor disease such as ovarian cancer, breast cancer, prostate cancer, etc.
  • the present invention further relates to a compound according to the present invention or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a poly (ADP-ribose) polymerase 1 (PARP1) inhibitor.
  • PARP1 poly (ADP-ribose) polymerase 1
  • the present invention further relates to a compound according to the present invention or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used for preventing and/or treating diseases associated with poly (ADP-ribose) polymerase 1 activity, preferably tumor diseases, such as ovarian cancer, breast cancer, prostate cancer, etc.
  • diseases associated with poly (ADP-ribose) polymerase 1 activity preferably tumor diseases, such as ovarian cancer, breast cancer, prostate cancer, etc.
  • the present invention further relates to a compound according to the present invention or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a medicament for preventing and/or treating diseases associated with poly (ADP-ribose) polymerase 1 activity, such as ovarian cancer, breast cancer, prostate cancer, etc.
  • diseases associated with poly (ADP-ribose) polymerase 1 activity such as ovarian cancer, breast cancer, prostate cancer, etc.
  • the present invention further relates to a method for inhibiting poly (ADP-ribose) polymerase 1 (PARP1), which comprises administering to a patient in need thereof an effective amount of a compound according to the present invention or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • PARP1 poly (ADP-ribose) polymerase 1
  • the present invention further relates to a method for preventing and/or treating a disease associated with poly (ADP-ribose) polymerase 1 activity, comprising administering to a patient in need thereof a preventive or therapeutically effective amount of a compound according to the present invention or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; wherein the disease is preferably a tumor disease, such as ovarian cancer, breast cancer, prostate cancer, etc.
  • a tumor disease such as ovarian cancer, breast cancer, prostate cancer, etc.
  • the pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the following: sweeteners, flavoring agents, colorants and preservatives to provide pleasing and palatable pharmaceutical preparations. Tablets contain the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for preparing tablets for mixing.
  • excipients may be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrants such as microcrystalline cellulose, crosslinked sodium carboxymethyl cellulose, corn starch or alginic acid; binders such as starch, gelatin, polyvinyl pyrrolidone or gum arabic; and lubricants such as magnesium stearate, stearic acid or talc.
  • These tablets may be uncoated or may be coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release effect over a longer period of time.
  • water soluble taste masking materials such as hydroxypropyl methylcellulose or hydroxypropyl cellulose, or time extending materials such as ethyl cellulose, cellulose acetate butyrate may be used.
  • Oral preparations may also be provided in hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or in soft gelatin capsules wherein the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oily vehicle such as peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin
  • a water-soluble carrier such as polyethylene glycol or an oily vehicle such as peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions contain the active substance and excipients suitable for the preparation of aqueous suspensions for mixing.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone and gum arabic; dispersing agents or wetting agents, which may be naturally occurring phosphatides such as lecithin, or condensation products of alkylene oxides with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain fatty alcohols, for example heptadecaethyleneoxy cetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, for example polyethylene oxide sorbitan monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene oxide dehydrated sorbitan monooleate.
  • suspending agents for example sodium carboxymethylcellulose, methyl
  • the aqueous suspension may also contain one or more preservatives, for example ethylparaben or n-propylparaben, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, for example sucrose, saccharin or aspartame.
  • preservatives for example ethylparaben or n-propylparaben
  • coloring agents for example ethylparaben or n-propylparaben
  • flavoring agents for example sucrose, saccharin or aspartame.
  • sweetening agents for example sucrose, saccharin or aspartame.
  • Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin.
  • the oil suspension may contain a thickener such as beeswax, hard paraffin or cetyl alcohol.
  • the above-mentioned sweeteners and flavoring agents may be added to provide a palatable preparation.
  • These compositions may be preserved by adding an antioxidant such as butylated hydroxyanisole or alpha-tocopherol.
  • the pharmaceutical composition of the present invention can also be in the form of an oil-in-water emulsion.
  • the oil phase can be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or a mixture thereof.
  • Suitable emulsifiers can be naturally occurring phospholipids, such as soybean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of the partial esters and ethylene oxide, such as polyethylene oxide sorbitol monooleate.
  • Emulsions can also contain sweeteners, flavoring agents, preservatives and antioxidants.
  • Syrups and elixirs prepared with sweeteners such as glycerol, propylene glycol, sorbitol or sucrose can be used.
  • Such preparations can also contain a demulcent, a preservative, a coloring agent and an antioxidant.
  • the pharmaceutical composition of the present invention may be in the form of a sterile injectable aqueous solution.
  • Acceptable vehicles and solvents that may be used are water, Ringer's solution and isotonic sodium chloride solution.
  • the sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase.
  • the active ingredient is dissolved in a mixture of soybean oil and lecithin.
  • the oil solution is then added to a mixture of water and glycerol and processed to form a microemulsion.
  • the injection or microemulsion may be injected into the patient's bloodstream by local mass injection.
  • the solution and microemulsion may be preferably administered in a manner that maintains a constant circulating concentration of the compound of the present invention. To maintain such a constant concentration, a continuous intravenous drug delivery device may be used.
  • the pharmaceutical composition of the present invention can be in the form of a sterile injection water or oil suspension for intramuscular and subcutaneous administration.
  • the suspension can be prepared according to known techniques with the above-mentioned suitable dispersants or wetting agents and suspending agents.
  • the sterile injection preparation can also be a sterile injection solution or suspension prepared in a non-toxic parenterally acceptable diluent or solvent, such as a solution prepared in 1,3-butanediol.
  • sterile fixed oils can be conveniently used as solvents or suspension media. For this purpose, any blended fixed oils including synthetic mono- or diglycerides can be used.
  • fatty acids such as oleic acid can also be used to prepare injections.
  • the compounds of the invention may be administered in the form of suppositories for rectal administration.
  • These pharmaceutical compositions may be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and which will dissolve in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights and mixtures of fatty acid esters of polyethylene glycol.
  • the dosage of a drug depends on a variety of factors, including but not limited to the following factors: the activity of the specific compound used, the patient's age, the patient's weight, the patient's health condition, the patient's behavior, the patient's diet, the administration time, the administration method, the excretion rate, the combination of drugs, etc.
  • the best treatment method such as the mode of treatment, the daily dosage of the general compound or the type of pharmaceutically acceptable salt can be verified according to traditional treatment plans.
  • the present invention may contain a compound and a pharmaceutically acceptable salt, hydrate or solvate thereof as an active ingredient, mixed with a pharmaceutically acceptable carrier or excipient to prepare a composition, and prepared into a clinically acceptable dosage form.
  • the derivatives of the present invention may be used in combination with other active ingredients, as long as they do not produce other adverse effects, such as allergic reactions, etc.
  • the compounds of the present invention may be used as the sole active ingredient, or in combination with other drugs for treating diseases associated with tyrosine kinase activity. Combination therapy is achieved by administering the individual therapeutic components simultaneously, separately or sequentially.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, and more preferably an alkyl group containing 1 to 6 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl,
  • lower alkyl groups containing 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc.
  • Alkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment.
  • the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.
  • alkenyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc.
  • the alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio.
  • alkynyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, propynyl, butynyl, etc.
  • Alkynyl may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyls include spirocyclic, fused and bridged cycloalkyls.
  • spirocycloalkyl refers to a polycyclic group that shares a carbon atom (called a spiral atom) between 5 to 20 monocyclic rings, which may contain one or more double bonds, but no ring has a completely conjugated ⁇ electron system. Preferably, it is 6 to 14, more preferably 7 to 10. According to the number of spiral atoms shared between the rings, the spirocycloalkyl is divided into a single spiral cycloalkyl, a double spiral cycloalkyl or a multi-spirocycloalkyl, preferably a single spiral cycloalkyl and a double spiral cycloalkyl.
  • spirocycloalkyl includes:
  • condensed cycloalkyl refers to a 5 to 20-membered, all-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated ⁇ electron system.
  • it is 6 to 14 members, more preferably 7 to 10 members.
  • it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic alkyl.
  • condensed cycloalkyls include:
  • bridged cycloalkyl refers to a 5 to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated ⁇ electron system. Preferably, it is 6 to 14 members, and more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably a bicyclic, tricyclic or tetracyclic, and more preferably a bicyclic or tricyclic.
  • bridged cycloalkyl include:
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc.
  • the cycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2), but excluding the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon.
  • it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; most preferably, it contains 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; most preferably, it contains 5 to 7 ring atoms, of which 1 to 2 or 1 to 3 are heteroatoms.
  • Non-limiting examples of monocyclic heterocyclyls include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably 1, 2, 5-oxadiazolyl, pyranyl or morpholinyl.
  • the polycyclic heterocyclic group includes spiro, fused and bridged heterocyclic groups.
  • spiro heterocyclic group refers to a polycyclic heterocyclic group in which one atom (called a spiral atom) is shared between 5 to 20 monocyclic rings, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2), and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated ⁇ electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the spiral heterocyclic group is divided into a single spiral heterocyclic group, a double spiral heterocyclic group or a multi-spiro heterocyclic group, preferably a single spiral heterocyclic group and a double spiral heterocyclic group. More preferably, it is a 4-yuan/4-yuan, 4-yuan/5-yuan, 4-yuan/6-yuan, 5-yuan/5-yuan or 5-yuan/6-yuan single spiral heterocyclic group.
  • spiral heterocyclic groups include:
  • fused heterocyclic group refers to a polycyclic heterocyclic group of 5 to 20 members, each ring in the system shares a pair of atoms adjacent to other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated ⁇ electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2), and the remaining ring atoms are carbon.
  • it is 6 to 14 members, more preferably 8 to 10 members.
  • fused heterocyclic groups include:
  • bridged heterocyclic group refers to a polycyclic heterocyclic group of 5 to 14 members, wherein any two rings share two atoms that are not directly connected, which may contain one or more double bonds, but none of the rings has a completely conjugated ⁇ electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2), and the remaining ring atoms are carbon.
  • it is 6 to 14 members, more preferably 8 to 10 members.
  • bridged heterocyclic groups include:
  • the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include:
  • the heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.
  • aryl refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group having a conjugated ⁇ electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. More preferably phenyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, i.e., a fused ring aryl, wherein the ring connected to the parent structure is an aryl ring, non-limiting examples of which include:
  • the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
  • heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • the heteroaryl group is preferably 5 to 10 members, containing 1 to 3 heteroatoms; more preferably 5 or 6 members, containing 1 to 2 heteroatoms; preferably, for example, imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, thiazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably pyrazolyl or thiazolyl.
  • the heteroaryl ring can be fused to an aryl, heterocyclic or cycloalkyl ring, i.e., a fused ring heteroaryl, in which the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples thereof include:
  • the heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
  • alkoxy refers to-O-(alkyl) and-O-(non-substituted cycloalkyl), wherein the definitions of alkyl and cycloalkyl are as described above.
  • the non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy.
  • Alkoxy can be optionally substituted or non-substituted, and when substituted, substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
  • substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, hetero
  • the bond Indicates that the configuration is not specified, that is, if there are chiral isomers in the chemical structure, the bond Can be or or include both and Two configurations.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.
  • deuterated alkyl refers to an alkyl group substituted with one or more deuterium, wherein alkyl is as defined above.
  • deuterated alkoxy refers to an alkoxy group substituted with one or more deuterium, wherein alkoxy is as defined above.
  • hydroxyalkyl refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.
  • hydroxy refers to an -OH group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • amino refers to -NH2 .
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • thiol refers to -SH.
  • ester group refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
  • alkylacyl refers to a -C(O)R group, wherein R is alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl as defined above.
  • alkylsulfonyl refers to a -S(O) 2R group, wherein R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl as defined above.
  • aminoacyl refers to a -C(O)NHR group, where R is alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl as defined above.
  • the compounds of the present invention can be in deuterated form.
  • Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom.
  • Those skilled in the art can synthesize deuterated compounds with reference to the relevant literature.
  • Commercially available deuterated starting materials can be used when preparing deuterated compounds, or they can be synthesized using conventional techniques using deuterated reagents.
  • Optional or “optionally” means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur.
  • a heterocyclic group optionally substituted with an alkyl group means that an alkyl group may but need not be present, and the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.
  • Substituted means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the skilled person can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxy groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (e.g. olefinic) bonds.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.
  • “Pharmaceutically acceptable salts” refer to salts of the compounds of the present invention, which are safe and effective when used in mammals and have the desired biological activity.
  • the compound represented by the general formula (II) of the present invention can be prepared by the following scheme.
  • Step 1) In the presence of a catalyst, a compound of formula IIa and a compound IIb undergo a coupling reaction to obtain a A compound of formula IIc;
  • Step 2 Under acidic conditions, the compound of formula IIc undergoes a deprotection reaction to obtain a compound of formula IId;
  • Step 3 In the presence of a base, the compound of the general formula IId undergoes a substitution reaction with the compound of the general formula IIe to obtain a compound represented by the general formula (II) or its mesomorph, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof;
  • Reagents that provide acidic conditions include, but are not limited to, a 1,4-dioxane solution of hydrogen chloride, trifluoroacetic acid, formic acid, etc.
  • Reagents that provide alkaline conditions include, but are not limited to, sodium hydroxide and lithium hydroxide.
  • the catalysts include, but are not limited to, Pd2 (dba) 3 , RuPhosPdG3, Pd(t- Bu3P ) 2 , and Pd(OAc) 2 .
  • the above reaction can be carried out in a solvent, and the solvent used includes but is not limited to: methanol, toluene, acetonitrile, tetrahydrofuran, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, or N,N-dimethylformamide and a mixture thereof.
  • the solvent used includes but is not limited to: methanol, toluene, acetonitrile, tetrahydrofuran, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, or N,N-dimethylformamide and a mixture thereof.
  • the compounds of the present invention are prepared using convenient starting materials and common preparation steps.
  • the present invention provides typical or preferred reaction conditions, such as reaction temperature, time, solvent, pressure, and molar ratio of reactants. However, unless otherwise specified, other reaction conditions can also be adopted.
  • the optimized conditions may change with the use of specific reactants or solvents, but in general, the reaction optimized steps and conditions can be determined.
  • protecting groups may be used in the present invention to protect certain functional groups from unwanted reactions.
  • protecting groups suitable for various functional groups and their protection or deprotection conditions are widely known to those skilled in the art. For example, T. W. Greene and G. M. Wuts's “Protective Groups in Organic Preparations” (3rd edition, Wiley, New York, 1999 and references therein) describes in detail the protection or deprotection of a large number of protecting groups.
  • the separation and purification of compounds and intermediates can be carried out by appropriate methods and steps according to specific needs, such as filtration, extraction, distillation, crystallization, column chromatography, preparative thin layer plate chromatography, preparative high performance liquid chromatography or a combination of the above methods.
  • the specific use method can refer to the examples described in the present invention. Of course, other similar separation and purification means can also be adopted. Conventional methods (including physical constants and spectral data) can be used to characterize them.
  • the structures of the compounds were determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). NMR shifts were given in units of 10 -6 (ppm). NMR measurements were made using a Bruker 300 NMR spectrometer to measure the solvent. The reagents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was tetramethylsilane (TMS).
  • DMSO-d 6 deuterated dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS tetramethylsilane
  • MS was determined using LC (Agilent 1260 Infinity)/MS (G6125B) mass spectrometer (manufacturer: Agilent).
  • the preparative liquid chromatography method used an LC6000 high performance liquid chromatograph (manufacturer: Chuangxin Tongheng).
  • the chromatographic column was Daisogel C18 10 ⁇ m 100A (30 mm ⁇ 250 mm), and the mobile phase was acetonitrile/water.
  • Thin layer chromatography used Qingdao Ocean Chemical GF254 silica gel plate.
  • the silica gel plate used in reaction monitoring thin layer chromatography adopted a specification of 0.20 mm to 0.25 mm, and the silica gel plate used in separation and purification thin layer chromatography adopted a specification of 0.5 mm.
  • Silica gel column chromatography uses Qingdao marine silica gel 100-200 mesh, 200-300 mesh and 300-400 mesh silica gel as the carrier.
  • the known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from online shopping malls, Beijing Coupling, Sigma, Bailingwei, Yishiming, Shanghai Shuya, Shanghai Inokai, Anaiji Chemical, Shanghai Bid, Nanjing Yaoshi and other companies.
  • Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1L.
  • Reaction solvent organic solvent or inert solvent are each expressed as the solvent used that does not participate in the reaction under the described reaction conditions, including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, dichloromethane, ether, methanol, nitrogen-methylpyrrolidone (NMP), pyridine, etc.
  • the solution refers to an aqueous solution.
  • the chemical reactions described in the present invention are generally carried out under normal pressure.
  • the reaction time and conditions are, for example, between -78°C and 200°C at one atmosphere, and completed within about 1 to 24 hours. If the reaction is overnight, the reaction time is generally 16 hours. Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.
  • reaction progress in the examples was monitored by thin layer chromatography (TLC), and the developing solvent systems used in the reaction were: A: dichloromethane and methanol system, B: petroleum ether and ethyl acetate system, C: acetone, and the volume ratio of the solvents was adjusted according to the polarity of the compounds.
  • TLC thin layer chromatography
  • the eluent system of column chromatography and the developing solvent system of thin layer chromatography used for purifying compounds include: A: dichloromethane and methanol system, B: petroleum ether and ethyl acetate system.
  • A dichloromethane and methanol system
  • B petroleum ether and ethyl acetate system.
  • the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and trifluoroacetic acid can also be added for adjustment.
  • Step 2 Preparation of 6-[(E)-2-ethoxycarbonylbut-1-enyl]-5-nitro-pyridine-3-carboxylic acid ethyl ester (1b)
  • Step 4 Preparation of ethyl 7-ethyl-6-oxo-5,6,7,8-tetrahydro-1,5-naphthyridine-3-carboxylate (1d)
  • Step 5 Preparation of ethyl 7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridine-3-carboxylate (1e)
  • Step 7 Preparation of 7-(chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (1 g)
  • Step 8 Preparation of tert-butyl 5-bromo-1-oxoisoindoline-2-carboxylate (1h)
  • Step 9 Preparation of tert-butyl 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-1-oxoisoindoline-2-carboxylate (1i)
  • tert-butyl 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-1-oxoisoindoline-2-carboxylate 450 mg, 1.08 mmol
  • dichloromethane 10 mL
  • a dioxane hydrochloride solution 3.3 mL, 4 mol/L
  • the mixture was concentrated under reduced pressure to obtain 380 mg (crude) of the title compound as a light yellow solid.
  • Step 11 Preparation of 3-ethyl-7-(((4-(1-oxoisoindolin)-5-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one (1)
  • the title compound 2 was prepared in the same manner as in Example 1, except that 5-bromo-2-methylisoindolin-1-one was used instead of tert-butyl 5-bromo-1-oxoisoindolin-2-carboxylate (1h) in step 9.
  • the title compound 4 was prepared in the same manner as in Example 1, except that 5-bromo-1H-indazole was used instead of tert-butyl 5-bromo-1-oxoisoindoline-2-carboxylate (1h) in step 9.
  • the title compound 5 was prepared in the same manner as in Example 1, except that 6-bromo-imidazo[1,2-a]pyridine was used instead of tert-butyl 5-bromo-1-oxoisoindoline-2-carboxylate (1h) in step 9.
  • the title compound 6 was prepared in the same manner as in Example 1, except that 6-bromo-triazolo[1,2-a]pyridine was used instead of tert-butyl 5-bromo-1-oxoisoindoline-2-carboxylate (1h) in step 9.
  • Step 4 Preparation of tert-butyl 3-bromo-8-oxo-1,7-naphthyridine-7(8H)-carboxylate (8d)
  • the title compound 10 was prepared in the same manner as in Example 1, except that 6-bromo-8-methylimidazo[1,2-a]pyridine was used instead of tert-butyl 5-bromo-1-oxoisoindoline-2-carboxylate (1h) in step 9.
  • the title compound 12 was prepared in the same manner as in Example 1, except that 6-bromo-2-methylimidazo[1,2-a]pyridine was used instead of tert-butyl 5-bromo-1-oxoisoindoline-2-carboxylate (1h) in step 9.
  • the title compound 13 was prepared in the same manner as in Example 1, except that 5-bromo-2-methylbenzo[d]oxazole was used instead of tert-butyl 5-bromo-1-oxoisoindoline-2-carboxylate (1h) in step 9.
  • the title compound 15 was prepared in the same manner as in Example 1, except that 5-bromo-1-methyl-1H-indazole was used instead of tert-butyl 5-bromo-1-oxoisoindoline-2-carboxylate (1h) in step 9.
  • the title compound 16 was prepared in the same manner as in Example 1, except that 7-bromoquinazoline was used instead of tert-butyl 5-bromo-1-oxoisoindoline-2-carboxylate (1h) in step 9.
  • the title compound 17 was prepared in the same manner as in Example 1, except that 5-bromo-7-methyl-1H-indazole was used instead of tert-butyl 5-bromo-1-oxoisoindoline-2-carboxylate (1h) in step 9.
  • the title compound 18 was prepared in the same manner as in Example 1, except that 5-bromo-6-fluoro-1H-indazole was used instead of tert-butyl 5-bromo-1-oxoisoindoline-2-carboxylate (1h) in step 9.
  • the title compound 19 was prepared in the same manner as in Example 1, except that 5-bromo-4-fluoro-1H-indazole was used instead of tert-butyl 5-bromo-1-oxoisoindoline-2-carboxylate (1h) in step 9.
  • the title compound 23 was prepared in the same manner as in Example 1, except that 5-bromo-1-methyl-1H-benzo[d]imidazole was used instead of tert-butyl 5-bromo-1-oxoisoindoline-2-carboxylate (1h) in step 8.
  • the title compound 24 was prepared in the same manner as in Example 1, except that 6-bromo-1-methyl-1H-benzo[d]imidazole was used instead of tert-butyl 5-bromo-1-oxoisoindoline-2-carboxylate (1h) in step 9.
  • the title compound 26 was prepared in the same manner as in Example 1, except that 5-bromo-1H-benzo[d]imidazole was used instead of tert-butyl 5-bromo-1-oxoisoindoline-2-carboxylate (1h) in step 9.
  • Step 4 Preparation of tert-butyl 4-(7-fluoroimidazo[1,2-a]pyridin-6-yl)piperazine-1-carboxylate (27d)
  • Step 4 Preparation of tert-butyl 4-(7-methylimidazo[1,2-a]pyridin-6-yl)piperazine-1-carboxylate (28d)
  • the title compound 29 was prepared in the same manner as in Example 1, except that 6-bromo-3-methyl-[1,2,4]triazolo[4,3-a]pyridine was used instead of tert-butyl 5-bromo-1-oxoisoindoline-2-carboxylate (1h) in step 9.
  • Step 1 Preparation of ethyl 6-bromo-7-methylimidazo[1,2-a]pyridine-2-carboxylate (31a)
  • Step 2 Preparation of ethyl 6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-7-methylimidazo[1,2-a]pyridine-2-carboxylate (31b)
  • Ethyl 6-bromo-7-methylimidazo[1,2-a]pyridine-2-carboxylate (31a) 400 mg, 1.42 mmol was dissolved in 1,4-dioxane (10 mL), and tert-butyl piperazine-1-carboxylate (396 mg, 2.13 mmol), cesium carbonate (691 mg, 2.13 mmol), BINAP (176 mg, 0.284 mmol) and Pd 2 (dba) 3 (130 mg, 0.142 mmol) were added, and stirred at 110°C for 16 hours under nitrogen atmosphere.
  • Step 3 Preparation of tert-butyl 4-(7-methyl-2-(methylcarbamoyl)imidazo[1,2-a]pyridin-6-yl)piperazine-1-carboxylate (31c)
  • Step 1 Preparation of ethyl 6-bromo-5-methylimidazo[1,2-a]pyridine-2-carboxylate (32a)
  • Step 2 Preparation of ethyl 6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-methylimidazo[1,2-a]pyridine-2-carboxylate (32b)
  • Ethyl 6-bromo-5-methylimidazo[1,2-a]pyridine-2-carboxylate (32a) (450 mg, 1.59 mmol) was dissolved in 1,4-dioxane (10 mL), and tert-butyl piperazine-1-carboxylate (445 mg, 2.39 mmol), cesium carbonate (778 mg, 2.39 mmol) and Ruphos-Pd-G 3 (107 mg, 0.128 mmol) were added, and stirred at 110°C for 16 hours under nitrogen atmosphere.
  • Step 3 Preparation of tert-butyl 4-(5-methyl-2-(methylcarbamoyl)imidazo[1,2-a]pyridin-6-yl)piperazine-1-carboxylate (32c)
  • the title compound 38 was prepared by the same preparation method as in Example 1, except that 6-bromo-2-phenylimidazo[1,2-a]pyridine was used instead of tert-butyl 5-bromo-1-oxoisoindoline-2-carboxylate (1h) in step 9.
  • the title compound 39 was prepared in the same manner as in Example 1, except that 6-bromo-imidazo[1,5-a]pyridine was used instead of tert-butyl 5-bromo-1-oxoisoindoline-2-carboxylate (1h) in step 9.
  • the title compound 40 was prepared in the same manner as in Example 1, except that 5-bromo-2-methyl-2H-indazole was used instead of tert-butyl 5-bromo-1-oxoisoindoline-2-carboxylate (1h) in step 9.
  • the title compound 41 was prepared in the same manner as in Example 1, except that 5-bromo-2,4-dimethyl-2H-indazole was used instead of tert-butyl 5-bromo-1-oxoisoindoline-2-carboxylate (1h) in step 9.
  • the title compound 42 was prepared in the same manner as in Example 1, except that 5-bromo-1-methyl-1H-pyrazolo[3,4-b]pyridine was used instead of tert-butyl 5-bromo-1-oxoisoindoline-2-carboxylate (1h) in step 9.
  • the title compound 43 was prepared in the same manner as in Example 1, except that 5-bromo-1,3-dimethyl-3a,7a-dihydro-1H-indazole was used instead of tert-butyl 5-bromo-1-oxoisoindoline-2-carboxylate (1h) in step 9.
  • the title compound 44 was prepared in the same manner as in Example 1, except that 5-bromo-1-isopropyl-1H-indazole was used instead of tert-butyl 5-bromo-1-oxoisoindoline-2-carboxylate (1h) in step 9.
  • the title compound 45 was prepared in the same manner as in Example 1, except that 5-bromo-1,6-dimethyl-1H-indazole was used instead of tert-butyl 5-bromo-1-oxoisoindoline-2-carboxylate (1h) in step 9.
  • Step 1 Preparation of 4-bromo-2-(cyclopropanecarboxamido)phenylcyclopropanecarboxylate (47a)
  • N-(5-bromo-2-hydroxyphenyl)cyclopropanecarboxamide (350 mg, 1.36 mmol) was dissolved in 1,4-dioxane (5 mL), p-toluenesulfonic acid (470 mg, 2.72 mmol) was added, and the mixture was stirred at 110°C for 16 hours under a nitrogen atmosphere.
  • the title compound 48 was prepared in the same manner as in Example 1, except that 6-bromo-2-methylbenzo[d]oxazole was used instead of tert-butyl 5-bromo-1-oxoisoindoline-2-carboxylate (1h) in step 9.
  • the title compound 50 was prepared in the same manner as in Example 1, except that 7-bromoisoquinoline was used instead of tert-butyl 5-bromo-1-oxoisoindoline-2-carboxylate (1h) in step 9.
  • the title compound 51 was prepared in the same manner as in Example 1, except that 6-bromoquinoline was used instead of tert-butyl 5-bromo-1-oxoisoindoline-2-carboxylate (1h) in step 9.
  • the title compound 52 was prepared in the same manner as in Example 1, except that 5-bromo-2,2-difluorobenzo[d][1,3]dioxolane was used instead of tert-butyl 5-bromo-1-oxoisoindoline-2-carboxylate (1h) in step 9.
  • the title compound 53 was prepared in the same manner as in Example 1, except that 6-bromo-2,3-dihydrobenzo[b][1,4]dioxane was used instead of tert-butyl 5-bromo-1-oxoisoindoline-2-carboxylate (1h) in step 9.
  • Example 54 Preparation of 7-((4-(Benzo[d][1,3]dioxolan-5-yl)piperazin-1-yl)methyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (54)
  • the title compound 54 was prepared in the same manner as in Example 1, except that 5-bromobenzo[d][1,3]dioxolane was used instead of tert-butyl 5-bromo-1-oxoisoindoline-2-carboxylate (1h) in step 9.
  • the title compound 56 was prepared in the same manner as in Example 1, except that 5-bromo-1,3-dihydro-2H-benzo[d]imidazol-2-one was used instead of tert-butyl 5-bromo-1-oxoisoindoline-2-carboxylate (1h) in step 9.
  • the title compound 57 was prepared in the same manner as in Example 1, except that 5-bromo-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one was used instead of tert-butyl 5-bromo-1-oxoisoindoline-2-carboxylate (1h) in step 9.
  • the title compound 58 was prepared in the same manner as in Example 1, except that 5-bromo-4-methoxy-2-methyl-2H-indazole was used instead of tert-butyl 5-bromo-1-oxoisoindoline-2-carboxylate (1h) in step 9.
  • test compounds PARP1 (BPS, 80501), NAD (Sigma, 10127965001), DSB DNA probe-1 (Kanglong Chemical), Mab anti GST-Tb cryptate (cisbio, 61GSTTLA)
  • the buffer solution was prepared by the above method, the compound was dissolved in DMSO and diluted in a gradient manner, the compound was diluted to the test concentration using the experimental buffer, and the mixture was shaken on an oscillator for 15 min.
  • PARP1 enzyme was diluted 4X using assay buffer and GST-Tb was added simultaneously.
  • test compound was added to the experimental plate, 4 ⁇ L per well, and incubated in a room temperature incubator for 1 hour.
  • the % inhibition rate was calculated as follows:
  • SignalAve_PC The average value of the maximum fluorescence signal of the system
  • SignalAve_VC Average value of negative control fluorescence signal value
  • IC50 was calculated by fitting the percent inhibition values and logarithms of compound concentration to a nonlinear regression (dose response - variable slope) using Graphpad 5.0.
  • Table 1 provides the in vitro activities (IC 50 ) of the compounds of the present invention on PARP1 capture.
  • the PARP1 capture in vitro activity values of the compounds are: A refers to IC 50 ⁇ 10 nM; B refers to 10 nM ⁇ IC 50 ⁇ 100 nM; C refers to 100 nM ⁇ IC 50 ⁇ 1000 nM; D refers to IC 50 >1000 nM.
  • the compounds of the present invention have good capture activity on PARP1-DNA complex.
  • test compounds PARP2 (BPS, 80502), NAD (Sigma, 10127965001), DSB DNA probe-2 (Kanglong Chemical), Mab anti GST-Tb cryptate (cisbio, 61GSTTLA)
  • the reagents were prepared by the above method.
  • the compounds were dissolved in DMSO and serially diluted, and the compounds were diluted to the test concentration using the assay buffer and shaken on a shaker for 15 min.
  • PARP2 enzyme was diluted 4X using assay buffer and GST-Tb was added simultaneously.
  • test compound was added to the experimental plate, 4 ⁇ L per well, and incubated in a room temperature incubator for 1 hour.
  • SignalAve_PC The average value of the maximum fluorescence signal of the system
  • SignalAve_VC Average value of negative control fluorescence signal value
  • Table 2 provides the in vitro activities ( IC50 ) of the compounds of the invention on PARP2 capture.
  • the PARP2 capture in vitro activity values of the compounds are: A refers to IC 50 ⁇ 10 nM; B refers to 10 nM ⁇ IC 50 ⁇ 100 nM; C refers to 100 nM ⁇ IC 50 ⁇ 1000 nM; D refers to IC 50 >1000 nM.
  • the compounds of the present invention have low capture activity on PARP2-DNA complex.
  • test compounds test compounds, RPMI1640 medium (Corning, 10-040-CV), fetal bovine serum (Aus GeneX, FBS500-S), penicillin/streptomycin antibiotics (Gibco, 15140-122), CelltiterGlo analysis kit (CTG) (Promega, G7573), DLD-1WT (Punosai, CL-0074) and DLD-1BRCA2(-/-) (Horizon, HD 105-007) cell lines.
  • CCG CelltiterGlo analysis kit
  • the experimental method is as follows:
  • the cells were cultured in a 5% carbon dioxide incubator for 7 days.
  • Promega CellTiter-Glo assay was then performed.
  • the cell plate was removed and equilibrated at room temperature for 30 minutes.
  • 20 ⁇ L CTG was added to each well and the mixture was shaken to mix.
  • the cells were incubated at room temperature for 30 minutes and the luminescence was read using Envision (2105) multi-label analyzer.
  • SignalAve_PC The average value of the maximum chemiluminescence value of the system
  • SignalAve_VC Average value of negative control chemiluminescence value
  • Table 3 provides the inhibitory activity of the compounds of the present invention on the proliferation of DLD-1 WT and DLD-1 BRCA2(-/-) cells.
  • the inhibitory activity values of the compounds on the proliferation of DLD-1 WT and DLD-1 BRCA2(-/-) cells are as follows: A refers to IC 50 ⁇ 100 nM; B refers to 100 nM ⁇ IC 50 ⁇ 1000 nM; C refers to 1000 nM ⁇ IC 50 ⁇ 10000 nM; and D refers to IC 50 >10000 nM.
  • the compounds of the present invention have good antiproliferative activity against BRCA2 mutated DLD-1 cells, and almost no inhibitory activity against wild-type DLD-1 cells, indicating that the compounds of the present invention have good cell selectivity.
  • Test Example 4 Determination of the inhibitory effect of the compounds of the present invention on the proliferation activity of triple-negative breast cancer MDA-MB-436 cells
  • MDA-MB-436 cells (Wuhan Prosai Life Science Technology Co., Ltd., CL-0383A), Leibovitz's L-15 cell-specific culture medium (Wuhan Prosai Life Science Technology Co., Ltd., CM-0383A), PBS (Gibco, 8121763), CellTiter Glo assay kit (Promega, G7572), 384-well plate (Thermo, 164610), and microplate reader (Biotek, Cytation 3).
  • MDA-MB-436 cells were cultured in a dedicated Leibovitz's L-15 medium. After the cells were revived, they were passaged 1-3 times, and the cells were collected and centrifuged at 1000rpm for 5 minutes to prepare a cell suspension. The cells were counted and the cell density was adjusted to 1.33 ⁇ 10 4 /mL. The cell suspension was added to a 384-well plate, 45 ⁇ L per well, i.e. 600 viable cells/well. Compound solutions of different concentrations were prepared using DMSO and culture medium, and solvent control wells and blank control wells were set up at the same time.
  • Signalcmpd the chemiluminescence value of each concentration of the compound
  • SignalAve_VC the average chemiluminescence value of the solvent control
  • SignalAve_PC the average chemiluminescence value of the blank control.
  • Table 4 provides the inhibitory activity of the compounds of the present invention on the proliferation of MDA-MB-436 cells.
  • the inhibitory activity values of the compounds on MDA-MB-436 cell proliferation are as follows: A refers to IC 50 ⁇ 100 nM; B refers to 100 nM ⁇ IC 50 ⁇ 1000 nM; C refers to 1000 nM ⁇ IC 50 ⁇ 10000 nM; and D refers to IC 50 >10000 nM.
  • the compounds of the present invention have good antiproliferative activity against MDA-MB-436 cells.
  • Test Example 5 Pharmacokinetic evaluation of the compounds of the present invention in Wistar rats
  • the compound preparation solvent contained 5% DMSO and 20% hydroxypropyl- ⁇ -cyclodextrin, and the administration volume was 10 mL/kg.
  • Blood was collected from the canthal venous plexus before and after administration at 0.25, 0.50, 1.00, 2.00, 4.00, 6.00, 8.00 and 24.00 hours, respectively.
  • the blood was anticoagulated with sodium heparin, centrifuged at 4°C, 3500rpm for 10 minutes, and plasma was obtained and stored at -20°C until testing.
  • the compounds of the present invention have good pharmacokinetic properties in rats.

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Abstract

La présente invention concerne un composé hétérocyclique contenant de l'azote et son utilisation pharmaceutique. Spécifiquement, la présente invention concerne un composé hétérocyclique contenant de l'azote représenté par la formule générale (I), son procédé de préparation, une composition pharmaceutique le contenant, et son utilisation en tant qu'inhibiteur de poly(ADP-ribose) polymérase 1 (PARP1) pour le traitement d'une maladie liée à l'activité de PARP1. La définition de chaque groupe dans la formule générale (I) est la même que celle dans la description.
PCT/CN2023/122005 2022-09-30 2023-09-27 Composé hétérocyclique contenant de l'azote et son utilisation pharmaceutique WO2024067694A1 (fr)

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