WO2020187123A1 - 一类吡咯酰胺并吡啶酮类化合物、制备方法和用途 - Google Patents

一类吡咯酰胺并吡啶酮类化合物、制备方法和用途 Download PDF

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WO2020187123A1
WO2020187123A1 PCT/CN2020/078963 CN2020078963W WO2020187123A1 WO 2020187123 A1 WO2020187123 A1 WO 2020187123A1 CN 2020078963 W CN2020078963 W CN 2020078963W WO 2020187123 A1 WO2020187123 A1 WO 2020187123A1
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alkyl
group
membered
substituted
substituents
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PCT/CN2020/078963
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English (en)
French (fr)
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万惠新
潘建峰
马金贵
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上海凌达生物医药有限公司
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Priority to CA3133131A priority Critical patent/CA3133131A1/en
Priority to KR1020217033299A priority patent/KR20210139378A/ko
Priority to EP20773591.1A priority patent/EP3967690A4/en
Priority to JP2021556665A priority patent/JP2022529575A/ja
Priority to US17/440,040 priority patent/US20220185808A1/en
Priority to AU2020242411A priority patent/AU2020242411A1/en
Priority to BR112021018372A priority patent/BR112021018372A2/pt
Priority to SG11202110099YA priority patent/SG11202110099YA/en
Publication of WO2020187123A1 publication Critical patent/WO2020187123A1/zh
Priority to ZA2021/07832A priority patent/ZA202107832B/en

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Definitions

  • the invention belongs to the field of medicinal chemistry, and specifically relates to a class of pyrrolamide pyridone BET-BRD signal pathway inhibitor compounds, preparation methods and uses.
  • BRD4 is a member of the BET protein family. Due to its potential anti-tumor value, it has attracted great attention from major pharmaceutical companies and scientific research institutions.
  • BET protein also known as epigenetic recognition protein
  • BET protein can recognize changes in epigenetic information in cell histones and transmit signals that stimulate cell division.
  • the gene mutation of BET protein in blood cells can interfere with this signal transmission, causing diseased cells to divide uncontrollably, thereby damaging human tissues and organs.
  • BRD3/BRD4 bromodomain coding region and NUT (nucleoprotein in the testis) gene chromatin translocation to form BRD-NUT fusion proto-oncogene is the pathogenesis of midline cancer, and it is also the direct involvement of BRD4 protein in the pathogenesis of tumors. evidence.
  • MYC is directly silenced by interfering with the binding of BRD4 at the MYC site. Since various isomers of MYC are known to be important regulators of cell proliferation and survival, and MYC is a possible oncogene that is overexpressed in many cancers, bromodomain antagonism is also the first time for MYC-driven tumors. Generation provides an opportunity for action.
  • BRD4 also plays an important role in the transcriptional regulation of viral genes, and has a certain connection with the pathogenesis of viral tumors.
  • BRD4 is closely related to a variety of tumors, especially in some tumors that are difficult to cure or there is no effective treatment method.
  • Research on its relationship with tumors provides a new strategy for tumor treatment. By acting on the small molecule compounds of the bromodomain of BRD4 protein, it interferes with the specific binding of the bromodomain and acetylated lysine, and affects the transcriptional regulation and other cellular processes in tumor cells, which can achieve targeted tumor therapy.
  • BRD4 protein is a very promising new epigenetic target, and small molecule inhibitors acting on the bromodomain of BRD4 protein also have broad application prospects in tumor research, and it is possible to develop new anti-tumor agents from it. drug.
  • ABBV744's ABBV744 is a BRD4-BD2 selective inhibitor with high selectivity and high killing effect on some leukemia and prostate cancer cell lines.
  • ADME properties of ABBV744 need to be further optimized and improved. Therefore, it is a hot spot in epigenetic anti-tumor research to find highly effective and highly selective novel small molecule BRD protein specific BD domain inhibitors or BRD protein degradation agents.
  • One of the technical problems to be solved by the present invention is to provide a new type of BRD enzyme inhibitor or degrading agent for the preparation of therapeutic drugs for tumors or inflammatory diseases.
  • R1 is independently selected from hydrogen, C1-C8 alkyl, 3-8 membered cyclic hydrocarbon or heterocycloalkyl, alkoxyalkyl, alkylaminoalkyl, heterocyclylalkyl, arylcycloalkyl, etc.;
  • R2 Independently selected from hydrogen, C1-C6 alkyl;
  • X1 and X2 are each independently selected from CH or NH;
  • R3 and R5 are each independently selected from hydrogen, halogen, and C1-C6 alkyl
  • R4, R6, and R7 are independently selected from hydrogen, halogen, cyano, nitro, alkenyl, alkynyl, amido, ether or thioether, substituted or unsubstituted C1-C6 alkyl, 3-8 member Cycloalkyl or heterocycloalkyl, 5-10 membered aryl or heteroaryl, alkoxy, substituted or unsubstituted amino, alkylsulfone, alkylsulfoxide, alkylsulfonamide, alkyl Sulfonamide, urea, sulfonylurea, sulfonylurea, etc.;
  • a carbon atom or a heteroatom between R6 and R7 can form a 3-8 membered saturated, unsaturated or partially unsaturated ring system.
  • One or more hydrogen atoms on any of the above groups may be substituted by substituents selected from the following group: including but not limited to deuterium, halogen, hydroxyl, amino or cyclic amino, cyano, nitro, sulfone or sulfoxide Group, C1-C8 alkyl, 3-8 membered cycloalkyl or heterocycloalkyl, C1-C8 alkoxy or alkylthio, C1-C8 alkylamino, alkenyl, alkynyl, acyl or sulfonyl, urea Or sulfonylurea, 5- to 8-membered aryl or heteroaryl; wherein the heteroaryl group contains 1-3 heteroatoms selected from the group consisting of N, O, P or S, and the heterocyclic ring
  • the alkyl group contains 1 to 3 heteroatoms selected from the group consisting of N, O, P or S, and the ring system includes a saturated or partially unsatur
  • the compound having the general formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, Polymorphs or prodrugs preferably compounds represented by general formula (II):
  • R8 and R9 are independently selected from hydrogen, halogen, C1-C6 alkyl, 3-8 membered cycloalkyl or heterocycloalkyl, or R8 and R9 form a 3-8 member through carbon atom or heteroatom.
  • the saturated, unsaturated or partially unsaturated ring system; R10 is selected from hydrogen, C1-C10 alkyl, 3-10 membered cycloalkyl or heterocycloalkyl, 5-10 membered aryl or heteroaryl;
  • L is selected From O, S, NH, etc.; in addition, R1, R2, R3, R4, R5, R6 are as defined above.
  • the compound having the general formula (1), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, or solvate thereof Polymorphs or prodrugs, characterized by:
  • R1 is preferably selected from substituted or unsubstituted C2-C8 alkyl, substituted or unsubstituted 3-8 membered cycloalkyl or heterocycloalkyl;
  • R2 is preferably selected from hydrogen, C1-C6 alkyl; or R1 and R2 A 4- to 8-membered nitrogen-containing heterocycle is formed between them; further preferred are self-substituted or unsubstituted ethyl, ethoxyethyl, etc.;
  • R3, R5, and R6 are each independently preferably selected from hydrogen, fluorine, and C1-C6 alkyl;
  • R4 is preferably C1-C6 sulfone group, C1-C6 sulfonamide group, C1-C6 sulfoxide group, C1-C6 sulfinamide group, C1-C6 sulfonamide group, C1-C6 substitution alkyl;
  • R8 and R9 are each independently preferably selected from hydrogen, C1-C3 alkyl, or form a 3-6 membered ring system with each other;
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • X1 is CH; X2 is NH;
  • Ra and Rb are independently hydrogen or C1-C8 alkyl
  • L1 is a linkage, -(C1-C8 alkyl)-, -(C2-C6 alkynyl)-, or -(C1-C6 alkyl)-(CH 2 OCH 2 ) m1 -(C1-C6 alkyl) -;
  • n1 1, 2, 3 or 4;
  • L2 is the connection key, -O-,
  • R2 is hydrogen or C1-C6 alkyl
  • R3 and R5 are independently hydrogen, halogen or C1-C6 alkyl
  • R4, R6 and R7 are independently hydrogen or -L-R10;
  • L is independently a linkage, -O-, -(SO 2 )- or -(SO 2 )-NH- (including -NH-(SO 2 )-);
  • R10 is independently a C1-C6 alkyl group, a 6 to 10-membered aryl group, a C1-C6 alkyl group substituted by one or more substituents, or a 6 to 10-membered aryl group substituted by one or more substituents ;
  • the substituents in the C1-C6 alkyl group substituted by one or more substituents and the 6 to 10-membered aryl group substituted by one or more substituents are independently halogen, hydroxy, cyano or C1 -C6 alkyl; when there are multiple substituents, they are the same or different;
  • R6 and R7 are connected to form a 6-membered heterocycloalkyl group or a 6-membered heterocycloalkyl group substituted by one or more substituents together with the connected carbon atoms.
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • R1 is C1-C8 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 3-8 membered cycloalkyl substituted C1-C8 alkyl or For example, C1-C8 alkyl, 3-8 membered cycloalkyl or
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • R1 is C1-C8 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, or 3-8 membered cycloalkyl substituted C1-C8 alkyl; for example, C1-C8 alkyl or 3-8 Member cycloalkyl.
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • R2 is hydrogen
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • R1 and R2 are connected to form a 3-8 membered heterocycloalkyl group or a 3-8 membered heterocycloalkyl group substituted by one or more halogens together with the connected N.
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • R3 is hydrogen
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • R5 is hydrogen
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • R6 is hydrogen
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • L is independently a connecting bond, -O- or -(SO 2 )-, for example a connecting bond or -(SO 2 )-.
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • L is independently -O-.
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • R10 is independently a C1-C6 alkyl group or a C1-C6 alkyl group substituted with one or more substituents.
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • R10 is independently a 6 to 10 membered aryl group, or a 6 to 10 membered aryl group substituted with one or more substituents.
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • R4 is hydrogen or -L-R10, such as -L-R10, and for example, L is a linkage or -(SO 2 )-, and/or, R10 is a C1-C6 alkyl group, substituted by one or more substituents ⁇ C1-C6 alkyl.
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • R7 is hydrogen or -L-R10, such as -L-R10, another example is L is -O-, and/or, R10 is a 6 to 10 membered aryl group, or a 6 to 10 membered group substituted by one or more substituents Aryl.
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • R6 and R7 are connected to form a 6-membered heterocycloalkyl group or a 6-membered heterocycloalkyl group substituted by one or more substituents together with the connected carbon atoms.
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • R1 is C1-C8 alkyl and said C1-C8 alkyl is substituted by one or more substituents
  • said substituents are selected from halogen, cyano, C1-C6 alkyl, C1-C6 alkyl -O- and C1-C6 alkyl-(SO 2 )-.
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • R1 is a 3-8 membered cycloalkyl, a 3-8 membered cycloalkyl substituted C1-C8 alkyl, the 3-8 membered cycloalkyl and a 3-8 membered cycloalkyl substituted C1-C8 alkyl
  • the substituents are selected from halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkyl-O- and C1-C6 alkyl-(SO 2 )-; For example, halogen, C1-C6 alkyl or hydroxy, or halogen.
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • R1 is a C1-C8 alkyl substituted with a 3-8 membered cycloalkyl group
  • the C1-C8 alkyl group substituted with a 3-8 membered cycloalkyl group is substituted by one or more substituents
  • the substituents It is selected from halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 alkyl-O- and C1-C6 alkyl-(SO 2 )-; for example, halogen or hydroxy, for example halogen.
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • X1 is CH; X2 is NH;
  • R1 is C1-C8 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 3-8 membered cycloalkyl substituted C1-C8 alkyl, or
  • L1 is a linkage, -(C1-C8 alkyl)-, -(C2-C6 alkynyl)-, -(C1-C6 alkyl)-(CH 2 OCH 2 ) m1 -(C1-C6 alkyl)- ;
  • n1 1, 2, 3 or 4;
  • R2 is hydrogen
  • R3 and R5 are independently hydrogen, halogen or C1-C6 alkyl
  • R6 is hydrogen
  • R4 and R7 are independently hydrogen or -L-R10;
  • L is the connecting key, -O- or -(SO 2 )-;
  • R10 is independently a C1-C6 alkyl group, a 6 to 10-membered aryl group, a C1-C6 alkyl group substituted by one or more substituents, or a 6 to 10-membered aryl group substituted by one or more substituents ;
  • the substituents in the C1-C6 alkyl group substituted by one or more substituents and the 6 to 10-membered aryl group substituted by one or more substituents are independently halogen, hydroxy, cyano or C1 -C6 alkyl; when there are multiple substituents, they are the same or different;
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • X1 is CH; X2 is NH;
  • R1 is C1-C8 alkyl, 3-8 membered cycloalkyl; said C1-C8 alkyl, 3-8 membered cycloalkyl is optionally substituted by one or more substituents;
  • R2, R3, R5 and R6 are independently hydrogen
  • R4 and R7 are independently hydrogen or -L-R10;
  • R6 and R7 are connected to form a 6-membered heterocycloalkyl group or a 6-membered heterocycloalkyl group substituted with one or more substituents, and the substituents are C1-C6 alkane.
  • Base or O;
  • R4 is a C1-C6 alkyl group or a C1-C6 alkyl group substituted by one or more substituents;
  • R7 is -L-R10; L is -O-; R10 is a 6 to 10 membered aryl group, or a 6 to 10 membered aryl group substituted by one or more substituents.
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • X1 is CH; X2 is NH;
  • R1 is C1-C8 alkyl or
  • R2, R3, R5 and R6 are independently hydrogen
  • R4 and R7 are independently hydrogen or -L-R10;
  • R6 and R7 are connected to form a 6-membered heterocycloalkyl group or a 6-membered heterocycloalkyl group substituted with one or more substituents, and the substituents are C1-C6 alkane.
  • Base or O;
  • R1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R4 is -L-R10; L is a linkage or -(SO 2 )-; R10 is a C1-C6 alkyl group or a C1-C6 alkyl group substituted by one or more substituents;
  • R7 is -L-R10; L is -O-; R10 is a 6 to 10 membered aryl group or a 6 to 10 membered aryl group substituted by one or more substituents;
  • R6 and R7 are connected to form a 6-membered heterocycloalkyl group or a 6-membered heterocycloalkyl group substituted with one or more substituents, and the substituents are C1-C6 alkane.
  • Base or O;
  • L1 is the connection key
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • R1 is C1-C8 alkyl, C1-C8 alkyl substituted with 3-8 membered cycloalkyl, or C1-C8 alkyl substituted with 3-8 membered heterocycloalkyl, said C1-C8 alkyl,
  • the C1-C8 alkyl group in the 3-8 membered cycloalkyl substituted C1-C8 alkyl group and the 3-8 membered heterocycloalkyl group substituted C1-C8 alkyl group are independently C1-C4 alkyl groups, such as methyl, Ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; another example is methyl, ethyl or isopropyl.
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • R1 is a 3-8 membered cycloalkyl group or a 3-8 membered cycloalkyl substituted C1-C8 alkyl group
  • the 3-8 membered cycloalkyl group in the alkyl group is independently a 3-6 membered cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; another example is cyclopropyl, cyclobutyl or cyclopentyl base.
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • R1 is 3-8 membered heterocycloalkyl or 3-8 membered heterocycloalkyl substituted C1-C8 alkyl
  • said 3-8 membered heterocycloalkyl and 3-8 membered heterocycloalkyl are substituted
  • the 3-8 membered heterocycloalkyl group in the C1-C8 alkyl group is independently a 3-6 membered heterocycloalkyl group, wherein the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1 or 2; for example
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • R1 When the substituent in R1 is C1-C6 alkyl, C1-C6 alkyl-O- or C1-C6 alkyl-(SO 2 )-, said C1-C6 alkyl, C1-C6 alkyl
  • the C1-C6 alkyl group in the group -O- and C1-C6 alkyl-(SO 2 )- is independently a C 1 -C 4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n Butyl, isobutyl, sec-butyl or tert-butyl; another example is methyl or ethyl.
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • the C1-C8 alkyl is independently C1-C6 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl Group, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl; another example is methyl.
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • the C1-C8 alkyl is C1-C6 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl Group, sec-butyl, tert-butyl, n-pentyl or n-hexyl; another example is n-butyl, n-pentyl or n-hexyl.
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • L1 is -(C2-C6 alkynyl)-
  • the C2-C6 alkynyl is ethynyl or prop-1-ynyl But-1-ynyl Or pent-4-ynyl
  • a terminal means that it is connected to L2.
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • the C1-C6 alkyl is independently C 1 -C 4 alkyl, for example Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; another example is methyl, ethyl or n-propyl.
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • n1 2 or 3.
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • the C1-C6 alkyl group is a C1-C4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, S-butyl or tert-butyl; another example is methyl, ethyl or isopropyl.
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • R1 and R2 are connected to form a 3-8 membered heterocycloalkyl group or a 3-8 membered heterocycloalkyl group substituted by one or more halogens together with the connected N, the 3-8 membered
  • the 3-8 membered heterocycloalkyl group of the heterocycloalkyl group or the 3-8 membered heterocycloalkyl group substituted by one or more halogens is independently a 3-6 membered heterocycloalkyl group, wherein The hetero atom is the N; for example
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • R10 is independently a C1-C6 alkyl group or a C1-C6 alkyl group substituted by one or more substituents
  • the C1-C6 alkyl group is independently a C1-C4 alkyl group, such as methyl Group, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; another example is methyl or ethyl.
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • R10 is independently a 6 to 10 membered aryl group or a 6 to 10 membered aryl group substituted by one or more substituents
  • the 6 to 10 membered aryl group or substituted by one or more substituents is independently phenyl or naphthyl.
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • substituents in R10 are C1-C6 alkyl groups
  • the substituents are independently C1-C4 alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, Isobutyl, sec-butyl or tert-butyl; another example is methyl or ethyl.
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • the 6-membered heterocycloalkyl group When R6 and R7 are connected to form a 6-membered heterocycloalkyl group or a 6-membered heterocycloalkyl group substituted by one or more substituents, the 6-membered heterocycloalkyl group is In a 6-membered heterocycloalkyl group substituted with one or more substituents, the 6-membered heterocycloalkyl group is independently The b-terminus represents the connection with the benzene ring.
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • R6 and R7 When R6 and R7 are connected, together with the connected carbon atoms, they form: 6-membered heterocycloalkyl or 6-membered heterocycloalkyl substituted by one or more substituents, said substituents being C1-C6 alkyl
  • the C1-C6 alkyl group is a C1-C4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; For example, methyl or ethyl.
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • R1 is a C1-C8 alkyl group or a C1-C8 alkyl group substituted by one or more substituents, such as ethyl, isopropyl,
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • R1 is a 3-8 membered cycloalkyl group, or a 3-8 membered cycloalkyl group substituted by one or more substituents, such as cyclopropyl, cyclopentyl,
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • R1 is a 3-8 membered heterocycloalkyl group or a 3-8 membered heterocycloalkyl group substituted by one or more substituents, for example
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • R1 is a C1-C8 alkyl group substituted with a 3-8 membered cycloalkyl group, or a C1-C8 alkyl group substituted with a 3-8 membered cycloalkyl group substituted with one or more substituents, for example
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • R1 and R2 are connected to form a 3-8 membered heterocycloalkyl group or a 3-8 membered heterocycloalkyl group substituted by one or more halogens together with the connected N, for
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • R4 is -L-R10
  • L is independently a linkage
  • R10 is independently C1-C6 alkyl, C1-C6 alkyl substituted by one or more substituents, for example
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • R4 is -L-R10
  • L is independently -(SO 2 )-
  • R10 is independently a C1-C6 alkyl group or a C1-C6 alkyl group substituted by one or more substituents
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • R4 is -L-R10
  • L is independently -(SO 2 )-NH-
  • R10 is independently C1-C6 alkyl, or C1-C6 substituted by one or more substituents
  • alkyl group for example
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • R10 is independently a 6 to 10 membered aryl group substituted by one or more substituents, for example
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • R7 is -O-R10, for example
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof
  • Certain groups in, tautomers, solvates, polymorphs or prodrugs are defined as follows (undefined groups are the same as those described in any of the schemes of this application), and the pyrrole represented by formula I Amidopyridone compounds are shown in formula II-1 or II-2:
  • R1, R2, R3, R4, R5, R6, L and R10 are as defined above;
  • R8 and R9 are independently a C1-C6 alkyl group (defined as connected to R6 and R7 to form together with the connected carbon atom: 6-membered heterocycloalkyl or 6-membered heterocycloalkyl substituted by one or more substituents, the substituents are C1-C6 alkyl);
  • the pyrrolamide pyridone compound represented by formula I is represented by formula II-1' or II-2':
  • R1, R2, R4, R8, R9 are as defined above;
  • R10 is a C1-C6 alkyl group, or a C1-C6 alkyl group substituted by one or more substituents;
  • R10 is a 6 to 10 membered aryl group, or a 6 to 10 membered aryl group substituted with one or more substituents.
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • R6 and R7 are connected to form a 6-membered heterocycloalkyl group or a 6-membered heterocycloalkyl group substituted by one or more substituents together with the connected carbon atoms, for
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • the pyrrolamide pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.
  • the pyrrolamide pyridone compound represented by formula I is selected from any of the following structures:
  • a method for preparing a compound of formula I characterized in that the method comprises steps a-c:
  • the steps a), b), and c) are each performed in a solvent, and the solvent is selected from the group consisting of water, methanol, ethanol, isopropanol, butanol, ethylene glycol, and ethylene glycol.
  • Ether N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, toluene, methylene chloride, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethyl Acetamide, dioxane, or a combination thereof.
  • the transition metal catalyst is selected from the group consisting of tris(dibenzylideneacetone) dipalladium (Pd 2 (dba) 3 ), tetrakis(triphenylphosphine) palladium (Pd(PPh 3 ) 4 ), acetic acid Palladium, palladium chloride, palladium dichlorobis(triphenylphosphine), palladium trifluoroacetate, palladium triphenylphosphine acetate, [1,1'-bis(diphenylphosphino)ferrocene] dichloride Palladium, bis(tri-o-phenylmethylphosphine)palladium dichloride, 1,2-bis(diphenylphosphino)ethane palladium dichloride, or a combination thereof; the catalyst ligand is selected from the following group: Tri-tert-butyl phosphine, tri-tert-butyl phosphine tetrafluoroa
  • the inorganic base is selected from the following group: sodium hydride, potassium hydroxide, sodium acetate, potassium acetate, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, cesium fluoride, potassium phosphate, potassium carbonate, carbonic acid Potassium hydrogen, sodium carbonate, sodium hydrogen carbonate, or a combination thereof;
  • the organic base is selected from the group consisting of pyridine, triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] Undec-7-ene (DBU), lithium hexamethyldisilazide, sodium hexamethyldisilazide, lutidine, or a combination thereof.
  • the present invention also provides a preparation method of the pyrrolamidopyridone compound represented by formula I, which includes scheme 1 or scheme 2;
  • X1, X2, R1, R2, R3, R4, R5, R6 and R7 are as defined above.
  • said aspect 1 may further include the following steps: in a solvent, in the presence of a base and a transition metal catalyst, the compound represented by formula A and the compound represented by formula B
  • the metal-catalyzed coupling reaction shown below can be used to obtain the compound C shown in the formula;
  • X1, X2, R1, R2, R3, R4, R5, R6 and R7 are as defined above.
  • the operation and conditions of the condensation reaction can refer to the conventional operations and conditions in this type of reaction in the art.
  • said aspect 1 may also include the following steps: in a solvent, in the presence of a base, the compound represented by formula C is subjected to the hydrolysis reaction shown below to obtain the formula Just show D compound;
  • Ra is C1-C6 alkyl (preferably C1-C4 alkyl, such as methyl, ethyl, n-propyl, Isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; another example is methyl, ethyl or isopropyl).
  • the operation and conditions of the hydrolysis reaction can refer to the conventional operations and conditions in this type of reaction in the art.
  • said aspect 1 may further include the following steps: in a solvent, in the presence of a base and a transition metal catalyst, the compound represented by formula A and the compound represented by formula B
  • the metal-catalyzed coupling reaction shown below can be used to obtain the compound C shown in the formula;
  • X1, X2, R1, R2, R3, R4, R5, R6, R7 and Ra are as defined above.
  • the operations and conditions of the metal-catalyzed coupling reaction can refer to the conventional operations and conditions in this type of reaction in the art.
  • the following are preferred in the present invention:
  • the transition metal catalyst is selected from the group consisting of three (dibenzylideneacetone) two palladium (Pd 2 (dba) 3 ), tetrakis (triphenylphosphine) palladium (Pd( PPh 3 ) 4 ), palladium acetate, palladium chloride, palladium dichlorobis(triphenylphosphine), palladium trifluoroacetate, palladium triphenylphosphine acetate, [1,1'-bis(diphenylphosphine) Ferrocene]palladium dichloride, bis(tri-o-phenylmethylphosphine)palladium dichloride, 1,2-bis(diphenylphosphino)ethane palladium dichloride, or a combination thereof; the catalyst
  • the ligand is selected from the following group: tri-tert-butyl phosphine, tri-tert-butyl phosphine, tri-tert-
  • the condensation reaction, the hydrolysis reaction, and the metal-catalyzed coupling reaction are each carried out in a solvent, and the solvent is selected from the group consisting of water, methanol, ethanol, isopropanol, butanol, ethylene glycol, and ethylene glycol methyl ether. , N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, toluene, dichloromethane, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylethane Amide, dioxane, or a combination thereof.
  • the solvent is preferably an amide solvent (for example, N-dimethylformamide, N,N-dimethylacetamide, or a combination thereof).
  • the solvent is preferably a mixture of water and alcohol solvents (for example, one or more of methanol, ethanol, isopropanol, butanol, and ethylene glycol).
  • the solvent is preferably an alcohol solvent (such as one or more of methanol, ethanol, isopropanol, butanol, and ethylene glycol), an amide solvent (such as N- Dimethylformamide, N,N-dimethylacetamide, or combinations thereof)
  • an alcohol solvent such as one or more of methanol, ethanol, isopropanol, butanol, and ethylene glycol
  • an amide solvent such as N- Dimethylformamide, N,N-dimethylacetamide, or combinations thereof
  • the base may be an inorganic base and/or an organic base
  • the inorganic base is selected from the group consisting of sodium hydride, potassium hydroxide, sodium acetate, potassium acetate , Potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, cesium fluoride, potassium phosphate, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, or a combination thereof
  • the organic base is selected from the following group: Pyridine, triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), lithium hexamethyldisilazide, Sodium hexamethyldisilazide, lutidine, or a combination thereof.
  • the present invention provides a compound represented by formula D, formula C, formula A, and formula A',
  • X1, X2, R1, R2, R3, R4, R5, R6, R7 and Ra are as defined above.
  • the compound represented by formula D is selected from any of the following structures:
  • the compound represented by formula C is selected from any of the following structures:
  • Another object of the present invention is to provide a medicine and composition for treating or preventing tumors or inflammatory diseases.
  • the technical solutions to achieve the above objectives are as follows:
  • a pharmaceutical composition for the treatment of tumors or inflammatory diseases which is composed of a pyrrolamide and pyridone compound represented by the above general formula (I), or a pharmaceutically acceptable salt, or an enantiomer or non- Enantiomers, tautomers, solvates, polymorphs or prodrugs are composed of a pharmaceutically acceptable carrier.
  • Another object of the present invention is to provide a use of the above compound.
  • the technical solutions to achieve the above objectives are as follows:
  • the tumor is independently selected from non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, gastric cancer, bowel cancer, cholangiocarcinoma, brain cancer, leukemia, lymph Cancer, fibroma, sarcoma, basal cell carcinoma, glioma, kidney cancer, melanoma, bone cancer, thyroid cancer, nasopharyngeal cancer, pancreatic cancer, etc.
  • the immune diseases and inflammatory diseases are independently selected from the rejection of transplanted organs, gout, rhinitis, alopecia, Alzheimer's disease, appendicitis, atherosclerosis, asthma, arthritis, allergic dermatitis, shellfish Chett's disease, bullous skin disease, cholecystitis, chronic idiopathic thrombocytopenic purpura, chronic obstructive pulmonary disease, liver cirrhosis, degenerative joint disease, dermatitis, dermatomyositis, eczema, enteritis, encephalitis, Gastritis, nephritis, Hashimoto's thyroiditis, hepatitis, hypophysitis, inflammatory bowel disease, irritable bowel syndrome, Kawasaki disease, meningitis, multiple sclerosis, myocarditis, myasthenia gravis, mycosis fungoides, muscle Inflammation, nephritis, osteomyelitis, pan
  • the present invention relates to pyrrolamide and pyridone compounds with the structural characteristics of general formula (I), which can inhibit a variety of tumor cells, and especially can efficiently kill tumors related to abnormal signaling pathways such as BRD/c-Myc, such as leukemia, Prostate cancer, etc., are a class of therapeutic drugs with a new mechanism of action.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the pyrrolamide and pyridone compound represented by formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof Forms, tautomers, solvates, polymorphs or prodrugs, and pharmaceutically acceptable carriers.
  • the crystalline form or prodrug can be a therapeutically effective amount.
  • the present invention also provides a pyrrolamide and pyridone compound represented by formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, or tautomer thereof.
  • a pyrrolamide and pyridone compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, or tautomer thereof.
  • the present invention also provides a pyrrolamide and pyridone compound represented by formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, or tautomer thereof , Solvates, polymorphs or prodrugs, or the above-mentioned pharmaceutical compositions in the preparation of drugs for the treatment or prevention of diseases related to BRD and/or c-Myc protein activity or expression.
  • the drug or prodrug, or the above-mentioned pharmaceutical composition can inhibit a variety of tumor cells, especially can effectively kill tumors related to abnormal signaling pathways such as BRD/c-Myc, such as leukemia and prostate cancer.
  • the present invention also provides a pyrrolamide and pyridone compound represented by formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, or tautomer thereof , Solvates, polymorphs or prodrugs, or the application of the above-mentioned pharmaceutical composition in the preparation of medicines.
  • the drug can be a drug for treating or preventing tumors and/or inflammatory diseases.
  • the present invention also provides a method for treating tumors and/or inflammatory diseases, which comprises administering to a patient a therapeutically effective amount of the above-mentioned pyrrolamide and pyridone compound represented by formula I, or a pharmaceutically acceptable salt thereof, Or its enantiomers, diastereomers, tautomers, solvates, polymorphs or prodrugs, or the aforementioned pharmaceutical compositions.
  • the tumor is independently selected from: non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, gastric cancer, bowel cancer, cholangiocarcinoma, brain cancer, leukemia, Lymphoma, fibroma, sarcoma, basal cell carcinoma, glioma, kidney cancer, melanoma, bone cancer, thyroid cancer, nasopharyngeal cancer, pancreatic cancer, etc.
  • the immune diseases and inflammatory diseases are independently selected from the rejection of transplanted organs, gout, rhinitis, alopecia, Alzheimer's disease, appendicitis, atherosclerosis, asthma, arthritis, allergic dermatitis, shellfish Chett's disease, bullous skin disease, cholecystitis, chronic idiopathic thrombocytopenic purpura, chronic obstructive pulmonary disease, liver cirrhosis, degenerative joint disease, dermatitis, dermatomyositis, eczema, enteritis, encephalitis, Gastritis, nephritis, Hashimoto's thyroiditis, hepatitis, hypophysitis, inflammatory bowel disease, irritable bowel syndrome, Kawasaki disease, meningitis, multiple sclerosis, myocarditis, myasthenia gravis, mycosis fungoides, muscle Inflammation, nephritis, osteomyelitis, pan
  • the reagents and raw materials used in the present invention are all commercially available.
  • the pyrrolamide and pyridone compounds with the structural characteristics of formula I provided by the present invention can inhibit a variety of tumor cells, in particular, can effectively kill the abnormally related signal pathways such as BRD/c-Myc Tumors, such as leukemia, prostate cancer, etc., are a class of therapeutic drugs with a new mechanism of action.
  • the inventor prepared a class of compounds with a novel structure shown in Formula I, and found that it has better BRD enzyme inhibitory or degradation activity, and the compound is at a very low concentration (as low as ⁇ 10nmol/L), which specifically inhibits or degrades BRD enzyme, and has excellent inhibitory activity on BRD/c-MYc-related cell proliferation, so it can be used to treat BRD/c-MYc mutations or expression levels Related diseases caused by abnormalities such as tumors. Based on the above findings, the inventor completed the present invention.
  • the manufacturer's instructions for the use of the kit can be used, or the reaction and purification can be performed in a manner known in the art or the instructions of the present invention.
  • the above-mentioned techniques and methods can be implemented according to the descriptions in a number of summary and more specific documents cited and discussed in this specification according to conventional methods well known in the art.
  • groups and their substituents can be selected by those skilled in the art to provide stable structural parts and compounds.
  • substituent When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH 2 O- is equivalent to -OCH 2 -.
  • C1-6 alkyl refers to an alkyl group as defined below having a total of 1 to 6 carbon atoms.
  • the total number of carbon atoms in the simplified notation does not include carbons that may be present in the substituents of the group.
  • halogen refers to fluorine, chlorine, bromine or iodine
  • hydroxyl refers to the -OH group
  • hydroxyalkyl refers to an alkane as defined below substituted by a hydroxyl (-OH)
  • nitro refers to -NO 2
  • cyano refers to -CN
  • amino refers to -NH 2
  • substituted amino Refers to an amino group substituted with one or two alkyl groups, alkylcarbonyl groups, aralkyl groups, and heteroaralkyl groups as defined below, for example, monoalkylamino, dialkylamino, alkylamido, aralkyl Alkylamino, heteroaralkylamino; "carboxy” refers to -COOH.
  • alkyl means only composed of carbon atoms and hydrogen atoms without unsaturation A bond, a straight or branched hydrocarbon chain group having, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms and connected to the rest of the molecule by a single bond.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2 , 2-Dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl and decyl, etc.
  • alkenyl means consisting only of carbon atoms and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10 One, more preferably 2 to 6) carbon atoms and a straight or branched hydrocarbon chain group connected to the rest of the molecule through a single bond, such as but not limited to vinyl, propenyl, allyl, but- 1-alkenyl, but-2-enyl, pent-1-enyl, pent-1,4-dienyl, etc.
  • alkynyl means consisting only of carbon atoms and hydrogen atoms, containing at least one triple bond and optionally one or more double bonds, having for example A straight or branched hydrocarbon chain group having 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms and connected to the rest of the molecule by a single bond, such as but not limited to ethynyl , Prop-1-ynyl, but-1-ynyl, pent-1-en-4-ynyl, etc.
  • cycloalkyl means a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting of only carbon atoms and hydrogen atoms, which may include fused A ring system, a bridged ring system or a spiro ring system has 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms, and it is saturated or unsaturated and can pass any suitable The carbon atom of is connected to the rest of the molecule by a single bond. Unless specifically indicated otherwise in this specification, the carbon atoms in the cycloalkyl group may be optionally oxidized.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, 1H- Indenyl, 2,3-indanyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-dihydro-7H-benzene And cyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9,10-hexahydro-benzocyclooctenyl , Fluorenyl, bicyclo[2.2.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl
  • heterocyclic group means a group consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur Stable 3- to 20-membered non-aromatic cyclic group.
  • the heterocyclic group may be a monocyclic, bicyclic, tricyclic or more ring system, which may include a fused ring system, a bridged ring system or a spiro ring system; in the heterocyclic group
  • the nitrogen, carbon, or sulfur atoms of may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the heterocyclic group may be partially or fully saturated.
  • the heterocyclic group can be connected to the rest of the molecule via a carbon atom or a heteroatom and through a single bond.
  • one or more rings may be aryl or heteroaryl as defined below, provided that the point of attachment to the rest of the molecule is a non-aromatic ring atom.
  • the heterocyclic group is preferably a stable 4- to 11-membered non-aromatic monocyclic, bicyclic, bridged ring or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur
  • the group is more preferably a stable 4- to 8-membered non-aromatic monocyclic, bicyclic, bridged ring or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur.
  • heterocyclic groups include, but are not limited to: pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2,7-diaza-spiro[3.5]non Alkyl-7-yl, 2-oxa-6-aza-spiro[3.3]heptane-6-yl, 2,5-diaza-bicyclo[2.2.1]heptan-2-yl, aza Cyclobutanyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxopentyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, Imidazolidinyl, quinazinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, in
  • aryl means a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms (preferably having 6 to 10 carbon atoms).
  • the aryl group can be a monocyclic, bicyclic, tricyclic or more cyclic ring system, and can also be fused with a cycloalkyl or heterocyclic group as defined above, provided that the aryl group passes through The atoms on the aromatic ring are connected to the rest of the molecule through a single bond.
  • aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthryl, fluorenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1, 4-benzoxazine-3(4H)-one-7-yl and the like.
  • arylalkyl refers to the above-defined alkyl group substituted by the above-defined aryl group.
  • heteroaryl means having 1 to 15 carbon atoms (preferably having 1 to 10 carbon atoms) and 1 to 6 nitrogen atoms in the ring.
  • heteroaryl groups can be monocyclic, bicyclic, tricyclic or more cyclic ring systems, and can also be fused with cycloalkyl or heterocyclic groups as defined above, provided that the hetero The aryl group is connected to the rest of the molecule via a single bond through an atom on the aromatic ring.
  • the nitrogen, carbon or sulfur atoms in the heteroaryl group can be optionally oxidized; the nitrogen atom can be optionally quaternized.
  • the heteroaryl group is preferably a stable 5- to 12-membered aromatic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, and more preferably contains 1 to 4 selected heteroatoms.
  • heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, Benzimidazolyl, benzopyrazolyl, indolyl, furyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indazinyl, isoindolyl, indazolyl, isoindazolyl , Purinyl, Quinolinyl, Isoquinolinyl, Diazonaphthyl, Naphthyridinyl, Quinoxolinyl, Pteridinyl, Carbazolyl, Carboline, Phenanthridinyl, Phenanthrolinyl, Acridine Group, phen
  • heteroarylalkyl refers to the above-defined alkyl group substituted by the above-defined heteroaryl group.
  • optional or “optionally” means that the event or condition described later may or may not occur, and the description includes both occurrence and non-occurrence of the event or condition.
  • optionally substituted aryl group means that the aryl group is substituted or unsubstituted, and the description includes both substituted aryl groups and unsubstituted aryl groups.
  • part refers to specific fragments or functional groups in a molecule.
  • the chemical moiety is generally considered to be a chemical entity embedded or attached to a molecule.
  • Steps refer to compounds that consist of the same atoms and are bonded by the same bonds, but have different three-dimensional structures.
  • the present invention will cover various stereoisomers and mixtures thereof.
  • the compound of the present invention contains an olefinic double bond, unless otherwise specified, the compound of the present invention is intended to include E- and Z-geometric isomers.
  • Tautomer refers to an isomer formed by transferring a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the present invention will also be included in the scope of the present invention.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof may contain one or more chiral carbon atoms, and therefore may produce enantiomers, diastereomers and other stereoisomeric forms.
  • Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry.
  • the present invention is intended to include all possible isomers, as well as their racemates and optically pure forms.
  • racemates, diastereomers or enantiomers can be selected as raw materials or intermediates.
  • Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.
  • pharmaceutically acceptable salt includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to a salt formed with an inorganic acid or an organic acid that can retain the biological effectiveness of the free base without other side effects.
  • Inorganic acid salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc.
  • organic acid salts include, but are not limited to, formate, acetate, and 2,2-dichloroacetate , Trifluoroacetate, propionate, caproate, caprylate, caprate, undecylenate, glycolate, gluconate, lactate, sebacate, hexanoate Acid salt, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate , Cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate,
  • “Pharmaceutically acceptable base addition salt” refers to a salt formed with an inorganic base or an organic base that can maintain the biological effectiveness of the free acid without other side effects.
  • Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like.
  • Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts.
  • Salts derived from organic bases include but are not limited to the following salts: primary amines, secondary amines and tertiary amines, substituted amines, including natural substituted amines, cyclic amines and basic ion exchange resins , Such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, bicyclic Hexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperazine Pyridine, N-ethylpiperidine, polyamine resin, etc.
  • Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine
  • Polymorphs refer to different solid crystalline phases produced by the presence of two or more different molecular arrangements in certain compounds of the present invention in a solid state. Certain compounds of the present invention may exist in more than one crystal form, and the present invention is intended to include various crystal forms and mixtures thereof.
  • solvate refers to an aggregate comprising one or more molecules of the compound of the present invention and one or more solvent molecules.
  • the solvent may be water, and the solvate in this case is a hydrate.
  • the solvent may be an organic solvent. Therefore, the compounds of the present invention may exist as hydrates, including monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate, etc., and corresponding solvated forms.
  • the compound of the present invention can form a real solvate, but in some cases, it can also retain only the indeterminate water or a mixture of water and part of the indeterminate solvent.
  • the compound of the present invention can be reacted in a solvent or precipitated or crystallized from the solvent. Solvates of the compounds of the present invention are also included in the scope of the present invention.
  • the present invention also includes prodrugs of the aforementioned compounds.
  • the term “prodrug” means a compound that can be converted into the biologically active compound of the invention under physiological conditions or through solvolysis. Therefore, the term “prodrug” refers to a pharmaceutically acceptable metabolic precursor of the compound of the present invention.
  • the prodrug When administered to an individual in need, the prodrug may not be active, but is converted into the active compound of the invention in the body.
  • the prodrug is usually rapidly transformed in the body to produce the parent compound of the present invention, for example, by hydrolysis in the blood.
  • Prodrug compounds generally provide advantages in solubility, tissue compatibility, or sustained release in mammalian organisms.
  • Prodrugs include known amino protecting groups and carboxyl protecting groups.
  • pharmaceutical composition refers to a preparation of a compound of the present invention and a medium generally accepted in the art for delivering a biologically active compound to a mammal (such as a human).
  • the medium includes a pharmaceutically acceptable carrier.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, which is conducive to the absorption of the active ingredient and thus the biological activity.
  • pharmaceutically acceptable refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compound of the present invention, and is relatively non-toxic, that is, the substance can be administered to an individual without causing undesirable biological activity. Reacts or interacts in an undesirable manner with any components included in the composition.
  • pharmaceutically acceptable carriers include, but are not limited to, any adjuvants, carriers, excipients, glidants, and sweeteners that are approved by relevant government regulatory agencies as acceptable for use by humans or livestock , Diluents, preservatives, dyes/colorants, flavors, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers.
  • the "tumor” and “disorders related to abnormal cell proliferation” in the present invention include, but are not limited to, leukemia, gastrointestinal stromal tumors, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, lung squamous cell carcinoma, Lung adenocarcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, cervical cancer, ovarian cancer, bowel cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, kidney cancer, oral cancer, etc. disease.
  • preventive include reducing the likelihood of a disease or condition from occurring or worsening.
  • treatment and other similar synonyms include the following meanings:
  • an effective amount refers to at least one agent or compound that is sufficient to relieve one or more symptoms of the disease or condition being treated after administration The amount.
  • the result can be a reduction and/or alleviation of signs, symptoms or causes, or any other desired changes in the biological system.
  • the "effective amount” for treatment is the amount of the composition containing the compound disclosed herein that is required to provide significant disease relief clinically. Techniques such as dose escalation tests can be used to determine the effective amount suitable for any individual case.
  • administration refers to methods capable of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, transduodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration.
  • parenteral injections including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion
  • topical administration and rectal administration.
  • Those skilled in the art are familiar with the application techniques that can be used for the compounds and methods described herein, for example in Goodman and Gilman, The Pharmaceutical Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Science (current edition), Mack Publishing Co., Those discussed in Easton, Pa.
  • the compounds and compositions discussed herein are administered orally.
  • drug combination refers to drug treatments obtained by mixing or combining more than one active ingredient. It includes fixed and non-fixed combinations of active ingredients.
  • fixed combination refers to the simultaneous administration of at least one compound described herein and at least one co-agent to a patient in the form of a single entity or a single dosage form.
  • non-fixed combination refers to the simultaneous administration, combination or sequential administration of at least one compound described herein and at least one synergistic agent to a patient in the form of separate entities. These also apply to cocktail therapy, such as the administration of three or more active ingredients.
  • the functional group of the intermediate compound may need to be protected by an appropriate protecting group.
  • Such functional groups include hydroxyl, amino, mercapto and carboxylic acid.
  • Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl (e.g. tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) , Tetrahydropyranyl, benzyl, etc.
  • Suitable protecting groups for amino, amidino and guanidino include tert-butoxycarbonyl, benzyloxycarbonyl and the like.
  • Suitable protecting groups for mercapto include -C(O)-R" (wherein R" is an alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like.
  • Suitable carboxyl protecting groups include alkyl, aryl or aralkyl esters.
  • Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protective groups is detailed in Greene, T.W. and P.G.M. Wuts, Protective Groups in Organi Synthesis, (1999), 4th Ed., Wiley.
  • the protecting group can also be a polymer resin.
  • the first step Dissolve compound 1 (4g, 18.6mmol) and ethyl azide ethyl acetate (5.97g, 46.3mmol) in absolute ethanol (200mL), add sodium ethoxide (3.14g, 46.2mmol) to it, at room temperature React overnight.
  • the reaction solution was added with cold water, extracted with ethyl acetate, the organic phase was dried with anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography to obtain compound 2 (1.8 g, white solid).
  • the second step Dissolve compound 2 (1.8 g, 5.5 mmol) in toluene (100 mL), and heat to 135 degrees to react overnight. The reaction solution was concentrated and evaporated to dryness to obtain crude product 3 (1.5 g, yellow solid), which was directly used in the next reaction.
  • Step 3 Dissolve compound 3 (1.0g, crude product) in N,N-dimethylformamide DMF (15mL), add potassium carbonate (922mg, 6.68mmol) and 2-(trimethylsilyl)ethoxy in turn Methyl chloride SEMCl (665mg, 4.0mmol), react overnight at room temperature. Saturated ammonium chloride solution was added, extracted with ethyl acetate, the organic phase was concentrated, and the residue was purified by silica gel column chromatography to obtain compound 4 (0.6 g, colorless oil).
  • Step 5 Dissolve compound 5 (0.5 g, 1.2 mmol) in DMF (20 mL), add cesium carbonate (782 mg, 2.4 mmol) and methyl iodide (256 mg, 1.8 mmol) in sequence, and react overnight at room temperature. Saturated ammonium chloride solution was added, extracted with dichloromethane, the organic phase was concentrated, and the residue was purified by silica gel column chromatography to obtain compound 6 (320 mg, white solid).
  • Step 6 Dissolve compound 6 (320 mg, 0.75 mmol) in dichloromethane (10 mL), add trifluoroacetic acid (2 mL), and react at room temperature for 5 hours. The reaction solution was concentrated, saturated sodium bicarbonate solution was added, extracted with dichloromethane, and the organic phase was concentrated to obtain Intermediate A (200 mg, white solid).
  • LC-MS m/z 299.0/301.0 [M+H] + /[M+H+2] + .
  • Step 1 Dissolve compound 1 (3.8g, 16.8mmol) in N,N-dimethylformamide (DMF) (50mL), lower the temperature to 0°C, add sodium hydrogen (60% in mineral oil) in batches , 1.0g, 24mmol). After the addition, stirring was continued for 30 minutes, then p-toluenesulfonyl chloride (4.8 g, 25 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction was quenched by adding ice water (200 mL), the solid was precipitated out and filtered to obtain compound 2 (5.0 g, yellow solid).
  • DMF N,N-dimethylformamide
  • Step 2 Dissolve compound 2 (380 mg, 1.0 mmol) in tetrahydrofuran (10 mL), and cool to -70 degrees in a dry ice acetone bath. Lithium diisopropylamide LDA (2M, 1 mL, 2.0 mmol) was added dropwise, stirring was continued for 30 minutes, ethyl chloroformate (162 mg, 1.5 mmol) was added dropwise at -50 degrees, and the reaction was maintained at -50 degrees for 2 hours. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was concentrated to obtain a crude product. The crude product was slurried with methanol to obtain compound 3 (400 mg, yellow solid).
  • Step 3 Dissolve compound 3 (1.3g, 2.9mmol), sodium iodide (645mg, 4.3mmol) in acetonitrile (50mL), add trimethylchlorosilane (465mg, 4.3mmol) at room temperature, and stir for 1 hour. Add 0.2mL of water, heat up to 70 degrees and react for 2 hours. After cooling to room temperature, it was filtered, and the filtrate was concentrated to obtain compound 4 (1.3 g, crude product, yellow solid).
  • Step 4 Dissolve compound 4 (1.3g, crude product) in DMF (5mL), add cesium carbonate (1.3g, 3.9mmol) and methyl iodide (550mg, 3.9mmol). After stirring overnight at room temperature, water was added and extracted with ethyl acetate. The organic phase was dried and concentrated, and the residue was purified by silica gel column chromatography to obtain Intermediate B (1.2 g, white solid).
  • the first step Intermediate A (100 mg, 0.34 mmol) was dissolved in ethanol (10 mL), water (5 mL) and sodium hydroxide (53 mg, 1.32 mmol) were added, and the reaction was heated to 80 degrees for 4 hours. The reaction solution was concentrated to remove most of the ethanol, a small amount of water was added, and the pH value of dilute hydrochloric acid was adjusted to 3-4, and then freeze-dried to obtain 7-bromo-5-methyl-4-oxo-4,5-dihydro-1H-pyrrole [ 3,2-c]pyridine-2-carboxylic acid (90 mg, white solid).
  • 1 H NMR 400MHz, DMSO_d6): ⁇ 13.13 (brs, 1H), 12.39 (s, 1H), 7.87 (s, 1H), 7.20 (s, 1H), 3.46 (s, 3H).
  • Step 2 Dissolve 7-bromo-5-methyl-4-oxo-4,5-dihydro-1H-pyrrole[3,2-c]pyridine-2-carboxylic acid (90mg, 0.33mmol) DMF (5mL), add ethylamine hydrochloride (54mg, 0.67mmol) and N,N-isopropylethyldiamine DIEA (213mg, 1.65mmol), then add 2-(7-azabenzo Triazole)-N,N,N',N'-tetramethylurea hexafluorophosphate HATU (250mg, 0.66mmol), react overnight at room temperature.
  • the third step The 7-bromo-N-ethyl-5-methyl-4-oxo-4,5-dihydro-1H-pyrrole [3,2-c]pyridine-2-amide (40mg, 0.13 mmol) and (2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropyl-2-yl)phenyl)boronic acid (51mg, 0.16mmol) dissolved in DMF( 10mL), add cesium carbonate (131mg, 0.40mmol) and 1,1'-bisdiphenylphosphinoferrocene palladium dichloride Pd(dppf)Cl 2 (20mg, 0.027mmol) in sequence, and heat under nitrogen protection Reaction to 100 degrees overnight.
  • the first step Intermediate A (500mg, 1.68mmol) and 2-(4-(4-fluoro-2,6-dimethylphenoxy)-3-(4,4,5,5-tetramethyl -1,3,2-dioxoboran-2-yl)phenyl)propane-2-ol was dissolved in DMF (10mL), cesium carbonate Cs 2 CO 3 (1.6g, 4.91mmol) and Pd( dppf) Cl 2 (245mg, 0.33mmol), under the protection of nitrogen, the temperature was raised to 100°C to react overnight.
  • Step 2 Add sodium hydroxide NaOH (136mg, 1.68mmol) to 7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropyl-2- Yl)phenyl)-5-methyl-4-oxo-4,5-dihydro-1H-pyrrole[3,2-c]pyridine-2-carboxylic acid ethyl ester (420mg, 0.85mmol) in ethanol/ Water (10mL, volume ratio 1:1) solution. React overnight at room temperature.
  • the third step 7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropyl-2-yl)phenyl)-5-methyl-4 -Oxo-4,5-dihydro-1H-pyrrole[3,2-c]pyridine-2-carboxylic acid (28mg, 0.060mmol) and 3-(4-(5-aminopent-1-yne-1) -Yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride (18mg, 0.050mmol) was dissolved in DCM (2mL), and DIEA (36mg, 0.28mmol) ) And 1-n-propyl phosphoric anhydride T 3 P (88 mg, 0.28 mmol), stirred at room temperature for 2 hours.
  • Example 6 N-(3-(2-(2-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4- (Amino)propoxy)ethoxy)ethoxy)propyl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropyl) -2-yl)phenyl)-5-methyl-4-oxo-4,5-dihydro-1H-pyrrole[3,2-c]pyridine-2-amide
  • Example 7 N-(2-(2-(2-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4- (Yl)amino)-3-oxo-n-propoxy)ethoxy)ethyl)-5-methyl-4-oxo-7-(2,2,4-trimethyl-6-( Methylsulfone)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-4,5-dihydro-1H-pyrrole[3, 2-c]pyridine-2-amide
  • the first step under the protection of nitrogen, the 8-bromo-2,2,4-trimethyl-6-(methylsulfone)-2H-benzo[b][1,4]oxazine-3(4H )-Ketone (0.77g, 2.2mmol) dissolved in DMF (20mL), add double pinacol boron ester (1.1g, 4.4mmol), cesium carbonate (2.1g, 6.4mmol) and Pd(dppf)Cl 2 ( 160mg, 0.22mmol), heated to 110°C and stirred for 2 hours, then intermediate A (1.0g, 2.2mmol) was added, and stirring was continued overnight.
  • double pinacol boron ester 1.1g, 4.4mmol
  • cesium carbonate 2.1g, 6.4mmol
  • Pd(dppf)Cl 2 160mg, 0.22mmol
  • Step 2 Add sodium hydroxide (27 mg, 0.67 mmol) to the ethanol/water (10 mL, volume ratio 1:1) solution of the product (212 mg, 0.33 mmol) obtained in the first step. React overnight at room temperature. Spin off most of the ethanol, dilute with water, adjust the pH to acidity, extract with ethyl acetate, dry the organic phase, and concentrate to obtain 5-methyl-4-oxo-7-(2,2,4-trimethyl-6- (Methylsulfone)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-4,5-dihydro-1H-pyrrole[ 3,2-c]pyridine-2-carboxylic acid (130 mg, white solid).
  • LC-MS m/z 460.2 [M+H] + .
  • the third step The product obtained in the second step (46mg, 0.10mmol) and 3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)-N-(2-(2, 6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propionamide (48mg, 0.10mmol) was dissolved in DCM (2mL), and DIEA (26mg, 0.20mmol) ) And T 3 P (63 mg, 0.20 mmol), the reaction was stirred at room temperature for 2 hours.
  • Example 8 N-(6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)n-hexyl)-6-methyl -7-oxo-4-(2,2,4-trimethyl-6-(methylsulfone)-3-oxo-3,4-dihydro-2H-benzo[b][1,4] Oxazine-8-yl)-6,7-dihydro-1H-pyrrole[2,3-c]pyridine-2-amide
  • the first step Intermediate A (700mg, 2.35mmol), 2-(4-(4-fluoro-2,6-dimethylphenoxy)-3-(4,4,5,5-tetramethyl -1,3,2-dioxoboran-2-yl)phenyl)propane-2-ol (1.1g, 2.75mmol), cesium carbonate (2.3g, 7.06mmol), Pd(dppf)Cl 2 ( 400mg, 0.55mmol) was dissolved in DMF (15mL), replaced with nitrogen for 10 minutes, heated to 100°C under the protection of nitrogen, and reacted overnight.
  • the second step the 7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropyl-2-yl)phenyl)-5-methyl-4 -Oxo-4,5-dihydro-1H-pyrrole [3,2-c]pyridine-2-carboxylic acid ethyl ester (753mg, 1.53mmol) dissolved in ethanol (30mL), add NaOH (183mg, 4.59mmol) Aqueous solution (6 mL) at room temperature overnight.
  • the third step 7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropyl-2-yl)phenyl)-5-methyl-4 -Oxo-4,5-dihydro-1H-pyrrole[3,2-c]pyridine-2-carboxylic acid (80mg, 0.17mmol) dissolved in DMF (3mL), add HATU (99mg, 0.26mmol) and DIEA (66mg, 0.51mmol), stirred at room temperature for 5 minutes, added 2-methoxyethylamine (20mg, 0.26mmol), and reacted at room temperature for 2 hours.
  • Example 13 7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropyl-2-yl)phenyl)-N-isopropyl-5 -Methyl-4-oxo-4,5-dihydro-1H-pyrrole[3,2-c]pyridine-2-amide
  • Example 17 2-(Azetidine-1-carbonyl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropyl-2-yl) )Phenyl)-5-methyl-1,5-dihydro-4H-pyrrole[3,2-c]pyridin-4-one
  • comparative compound 1 was prepared by referring to the synthesis method of the embodiment in patent WO2017177955A1.
  • Test example 1 BRD4AlphaScreen determination
  • Examples 1 to 20 provided by the present invention have an inhibitory activity IC 50 value of less than 10 nM for BRD4-BD 2, and most of the examples have an inhibitory activity IC 50 value of less than 1 nM, showing that it is stronger than the comparative compound 1.
  • the inhibitory activity of some examples against BRD4-BD 1 also showed stronger activity than the comparative compound; at the same time, the example compounds of the present invention maintain the relative selectivity of BRD4-BD 2, with selectivity multiples ranging from 10 Times to more than 400 times.
  • Test Example 2 Test of the inhibitory activity of the compounds of the examples on the proliferation of MV4-11 cells
  • Inhibition rate % (DMSO-treated cell well-compound-treated cell well)/(DMSO-treated cell well-cell-free medium well) ⁇ 100.
  • the IC 50 value was obtained by the four-parameter regression using the software that came with the microplate reader. (See Table 2 for specific values)
  • Results part of the present invention provides value Example 1 20 pairs MV 4-11 cell inhibitory activity of Example embodiment, IC 50 values of less than 500nM, IC 50 values of inhibitory activity of the compound of Example portions even less than 10nM, more shows comparative The compound has stronger cell proliferation inhibitory activity.
  • Test Example 3 Test of the inhibitory activity of the compound of the example on different enzymes
  • BRD AlfaScreening method similar to Test Example 1 and the conventional kinase inhibitor test method some of the compounds of the present invention were tested against different BRDs such as BRD2BD1/2, BRD3BD1/2 and BRD-TBD1/2 enzymes, HDAC, EZH2, LSD1,
  • BRDs such as BRD2BD1/2, BRD3BD1/2 and BRD-TBD1/2 enzymes, HDAC, EZH2, LSD1
  • the inhibitory activity of G9a, etc. and different protein kinases such as EGFR, VEGFR, PDGFR, FGFR, RET, MET, Src, Lyn, Syk, MEK, CDK, RAF, etc. have also been tested.
  • Some of the example compounds are as in Examples 1, 11, 18 showed good BRD-BD2 selectivity and kinase target selectivity, with selectivity greater than 100 times.
  • Test Example 4 Test of the inhibitory activity of the compounds of the examples on the proliferation of different cell lines
  • Example 2 Using Test Example 2 and similar methods in the literature, some of the compounds of the examples were tested against different cell lines such as LNCAP (+R1881), SKM-1, 22RV1, DU145, MOLM13, MDA-PCA-2b, KASUMI 1, THP-1, KG -1, IEC6, H1299 and other proliferation inhibitory activities
  • the inhibitory activity IC 50 was less than 1000 nM, and some cell lines were even less than 100 nM.
  • Metabolic stability test 150 ⁇ L liver microsomes (final concentration 0.5mg/mL) were used for metabolic stability incubation.
  • the system contained NADPH (final concentration 1mM), 1 ⁇ M test compound and positive control midazole
  • the reaction was terminated with tinidazole-containing acetonitrile at 0 min, 5 min, 10 min and 30 min, respectively, for Lun or negative control atenolol, vortexed for 10 min, centrifuged at 15000 rpm for 10 min, and 50 ⁇ L of supernatant was injected into a 96-well plate.
  • the metabolic stability of the compound is calculated by measuring the relative reduction of the original drug. (The specific values are shown in Table 3)
  • Direct inhibition test Use 100 ⁇ L human liver microsomes (final concentration 0.2mg/mL) for direct inhibition incubation, the system contains NADPH (final concentration 1mM), 10 ⁇ M compound, positive inhibitor cocktail (Ketoconazole 10 ⁇ M, Quinidine 10 ⁇ M, Sulfapyrazole 100 ⁇ M, ⁇ -Naphthoflavone 10 ⁇ M, Trampanine 1000 ⁇ M), negative control (0.1% DMSO BPS) and mixed probe substrate (midazolam) 10 ⁇ M, testosterone 100 ⁇ M, dextromethorphan 10 ⁇ M, diclofenac 20 ⁇ M, phenacetin 100 ⁇ M, mephenytoin 100 ⁇ M), the reaction was terminated after incubation for 20 min. The relative enzyme activity is calculated by measuring the relative production of metabolites.
  • the body stability is greatly improved compared with the control compound 1; and the inhibitory IC 50 of Examples 1 and 18 on the main metabolic enzymes CYP1A2, 2C8, 2C19, 3A4, etc. are all greater than 15uM, showing high druggability.
  • Test Example 6 In vivo pharmacokinetic parameter test of the compounds of the examples in rats and mice
  • test compound was prepared into a suitable solution or suspension; one group was administered intravenously, and the other group was taken orally Administration.
  • Blood was collected by jugular vein puncture, and each sample was collected about 0.2mL/time point. Heparin sodium was anticoagulated.
  • the blood collection time points were as follows: before administration and 5, 15 and 30 minutes after administration, 1, 2, 4, 6, 8 and 24h; After collecting blood samples, place them on ice, centrifuge to separate plasma (centrifugation conditions: 8000 rpm, 6 minutes, 2-8°C), and store the collected plasma at -80°C before analysis.
  • the plasma samples were analyzed by LC-MS/MS.
  • the pharmacokinetic calculation software WinNonlin5.2 non-compartmental model to calculate the pharmacokinetic parameters AUC 0-t , AUC 0- ⁇ , MRT 0- ⁇ , C max , T max , T 1/2 and V d and other parameters and their average and standard deviation.
  • the bioavailability (F) will be calculated by the following formula.
  • samples taken before reaching C max should be calculated as zero, and samples at sampling points after reaching C max should be calculated as unquantifiable (BLQ).
  • mice fed by gavage at a dose of 5 mg/kg in Example 18 have excellent PK parameters, with Cmax greater than 1.5uM. T 1/2 is greater than 3 hours, and AUC (hr*nM) is greater than 5000.
  • the bioavailability of Example Compounds 1, 18 to mice is greater than 40%, which is better than that of Comparative Compound 1 (the bioavailability of Comparative Compound 1 in mice is 25%).
  • Example 1. The PK parameters of beagle dogs administered intragastrically at a dose of 10 mg/kg in Example 18 were excellent, with a Cmax of 2.0 uM, T 1/2 greater than 2 hours, and AUC (hr*nM) greater than 15000.
  • Test Example 7 Test of Example Compounds on Growth Inhibition of MV 4-11 Xenograft Tumor in Nude Mice
  • the tumor tissue in the vigorous growth period was cut into about 1.5 mm 3 and inoculated under aseptic conditions into the right axillary subcutaneously of nude mice.
  • the diameter of the transplanted tumor in nude mice was measured with a vernier caliper, and the animals were randomly divided into groups when the average tumor volume reached about 130 mm 3 .
  • Example compound or comparative compound 1 (prepared to the required concentration with 1% Tween80-containing water for injection) was orally administered at a given dose every day for three consecutive weeks.
  • the solvent control group was given the same amount of solvent.
  • the diameter of the transplanted tumor was measured twice a week, and the mice were weighed.
  • Example 18 at a lower dose such as 10mg/kg-30mg/kg, once a day, continuous intragastric administration 21 days, showed a good effect of inhibiting tumor growth, and its T/C ratio was less than 40%; at higher doses, such as 50mg/kg-100mg/kg, the tumor inhibiting effect was obvious, and experimental animals could Well tolerated.
  • the compound 1 and compound 18 of the examples have obvious inhibitory effects on the growth of xenograft tumors in nude mice, and the tumor-inhibiting effect is better than that of the comparative compound 1. (at a dose of 15 mpk, the tumor-inhibition rates of the examples 1 and 18 are 82%, and the comparative compound The tumor inhibition rate of 1 is about 60%).

Abstract

本发明公开了一种如通式I所示的吡咯酰胺并吡啶酮、或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药、其制备方法及在药学上的应用，其中各基团的定义如说明书中所述。

Description

一类吡咯酰胺并吡啶酮类化合物、制备方法和用途
本申请要求申请日为2019/3/17的中国专利申请201910200772.2的优先权以及申请日为2019/11/06的中国专利申请201911073573.6的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明属于药物化学领域，具体地，涉及一类吡咯酰胺并吡啶酮类BET-BRD信号通路抑制剂化合物、制备方法和用途。
背景技术
表观遗传调控的异常是导致肿瘤发生的重要因素之一。最新研究发现，BRD蛋白介导的表观遗传异常与癌基因的过表达密切相关，并与癌细胞的生长增殖关系密切。BRD4是BET蛋白家族的一员，由于在抗肿瘤方面的潜在价值，引起了各大制药公司和科研机构的极大关注。
BET蛋白也称为表观遗传识别蛋白，可以识别细胞组蛋白中的表观遗传学信息变化，并传递激发细胞***等的信号。以白血病为例，血细胞内BET蛋白的基因突变会干扰这种信号传输，导致病变细胞不受控制地***，从而损害人体的组织器官。BRD3/BRD4的溴结构域编码区与NUT(睾丸中的核蛋白)基因染色质易位形成BRD-NUT融合型原癌基因是中线癌的发病机理所在，也是目前BRD4蛋白参与肿瘤发病过程的直接证据。同时研究也发现，在造血***性癌症包括AML，Burkitt淋巴瘤，多发性骨髓瘤以及B细胞急性淋巴性白血病的模型中，通过干扰BRD4在MYC位点上的结合而直接将MYC沉默。由于已知各种MYC的异构体是细胞增殖和存活的重要调节因子，而且MYC是在许多癌症中过量表达的一个可能的癌基因，因此溴结构域拮抗性也首次为针对MYC驱动的肿瘤生成提供了一个作用机会。近期还发现BRD4在病毒基因的转录调控中也扮演了重要角色，并且与病毒瘤的发病机制存在一定联系。这些研究结果说明BRD4与多种肿瘤存在密切联系，尤其在一些至今难以治愈或者尚无有效治疗手段的肿瘤中具有重要作用，其与肿瘤关系的研究为肿瘤治疗提供了新的策略。通过作用于BRD4蛋白溴结构域的小分子化合物，干扰溴结构域与乙酰化赖氨酸的特异性结合，影响肿瘤细胞内的转录调节和其它细胞过程，可以实现对肿瘤的靶向治疗。
因此，BRD4蛋白是一个非常有前景的表观遗传新靶点，而作用于BRD4蛋白溴结构域的小分子抑制剂在肿瘤研究中也有着广阔的应用前景，而且有可能从中开发出新型抗肿瘤药物。已报道的BRD4蛋白的选择性抑制剂JQ1和IBET151等，其晶体复合物表明此类小分子抑制剂正是结合在溴结构域的乙酰化赖氨酸识别口袋中，从而阻断了溴结构域介导的乙酰化调控，这些抑制剂在几种癌症中的治疗作用已经得到了证实。目前，绝大部分已知的BRD4蛋白的小分子抑制剂结构类型少且对于BD1和BD2溴结构域的选择性还不够突出，限制了人们对含溴结构域蛋白的生物功能及其在抗肿瘤潜力方面开展深入地研究。此外，现有BRD蛋白抑制剂作用效果尚待提高、机制有待进一步阐明。艾伯伟公司的ABBV744是一个BRD4-BD2选择性抑制剂，选择性高，对于部分白血病和***癌细胞株 具有较高的杀伤作用，同时ABBV744的ADME性质有待进一步优化和提高。因此，寻找高效、高选择性的新型小分子BRD蛋白特定BD结构域的抑制剂或BRD蛋白降解剂是表观遗传抗肿瘤研究的一个热点。
发明内容
本发明需要解决的技术问题之一是提供一种新型的BRD酶抑制剂或降解剂，用于制备肿瘤或者炎性疾病的治疗药物。
解决上述技术问题的方案如下：
一种具有如通式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，
Figure PCTCN2020078963-appb-000001
式中：
R1独立地选自氢、C1-C8烷基、3-8元环烃基或杂环烷基、烷氧基烷基、烷氨基烷基、杂环基烷基、芳环基烷基等；R2独立地选自氢、C1-C6的烷基；
X1、X2分别独立地选自CH或NH；
R3、R5分别独立地选自氢、卤素、C1-C6的烷基；
R4、R6、R7分别独立地选自氢、卤素、氰基、硝基、烯基、炔基、酰胺基、醚或硫醚、取代或未取代的C1-C6的烷基、3-8元环烃基或杂环烷基、5-10元的芳基或杂芳基、烷氧基、取代或未取代的氨基、烷基砜基、烷基亚砜基、烷基磺酰胺基、烷基亚磺酰胺基、脲、磺酰脲、亚磺酰脲基等；
或者R6和R7之间可以通过碳原子或者杂原子形成3-8元的饱和、不饱和或者部分不饱和的环系。
上述任一基团上的一个或多个氢原子可以被选自下组的取代基取代：包括但不限于氘、卤素、羟基、氨基或环氨基、氰基、硝基、砜基或亚砜基、C1-C8烷基、3-8元环烷基或杂环烷基、C1-C8烷氧基或烷硫基、C1-C8烷氨基、烯基、炔基、酰基或磺酰基、脲或磺酰脲、5～8元芳基或杂芳基；其中，所述的杂芳基包含1-3个选自下组的杂原子：N、O、P或S，所述的杂环烷基包含1-3个选自下组的杂原子：N、O、P或S，所述的环系包含螺环、桥环、稠环、并环等饱和或部分不饱和的环系。
进一步的实施方式中，具有通式(I)所述的化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，优选为通式(II)所示的化合物：
Figure PCTCN2020078963-appb-000002
其中，R8、R9独立地选自氢、卤素、C1-C6烷基、3-8元环烷基或杂环烷基，或者R8和R9通过碳原子或者杂原子相互之间形成3-8元的饱和、不饱和或者部分不饱和的环系；R10选自氢、C1-C10烷基、3-10元环烷基或杂环烷基、5-10元芳基或杂芳基；L选自O、S、NH等；另外R1、R2、R3、R4、R5、R6如上文所定义。
更进一步的优选方式中，具有通式(1)所述的化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，其特征在于：
R1优选自取代或未取代的C2-C8的烷基、取代或未取代的3-8元的环烷基或杂环烷基；R2优选自氢、C1-C6的烷基；或者R1和R2之间形成4-8元的含氮杂环；进一步优选自取代或未取代的乙基、乙氧基乙基等；
R3、R5、R6分别独立地优选自氢、氟、C1-C6的烷基；
R4优选自C1-C6的砜基、C1-C6的磺酰胺基、C1-C6的亚砜基、C1-C6的亚磺酰胺基、C1-C6的磺酰亚胺基、C1-C6的取代烷基；
R8和R9分别独立地优选自氢、C1-C3的烷基或者相互之间形成3-6元的环系；
R10优选自氢、C1-C8的烷基、3-8元的环烷基和杂环烷基、5-8元的芳基和杂芳基；进一步优选为
Figure PCTCN2020078963-appb-000003
其中Rd选自氢、卤素、氰基、砜基、亚砜基、C1-C3的烷基或烷氧基，并且Rd跟苯环或环己烷环或另一个Rd取代基之间可以形成3-8元的饱和或部分不饱和的环系；n＝0～5，优选自2，3。
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团如下定义(未定义的基团同本申请任一方案所述)，
Figure PCTCN2020078963-appb-000004
其中，X1为CH；X2为NH；
R1为氢、C1-C8烷基、3-8元环烷基、3-8元杂环烷基、3-8元环烷基取代的C1-C8烷基、3-8元杂环烷基取代的C1-C8烷基或
Figure PCTCN2020078963-appb-000005
所述的3-8元杂环烷基和3-8元杂环烷基取代的C1-C8烷基中的3-8元杂环烷基中，杂原子选自N、O、S、-S(＝O)-和-S(＝O) 2-中的一种或多种，杂原子数为1、2或3个；所述的C1-C8烷基、3-8元环烷基、3-8元杂环烷基、3-8元环烷基取代的C1-C8烷基、3-8元杂环烷基取代的C1-C8烷基和
Figure PCTCN2020078963-appb-000006
任选被一个或多个取代基取代的，所述的取代基独立地选自：卤素、氰基、羟基、＝O、C1-C6烷基、C1-C6烷基-O-、C1-C6烷基-(SO 2)-和
Figure PCTCN2020078963-appb-000007
当取代基为多个时，相同或不同；
Ra和Rb独立地为氢或C1-C8烷基；
L1为连接键、-(C1-C8烷基)-、-(C2-C6炔基)-、或-(C1-C6烷基)-(CH 2OCH 2) m1-(C1-C6烷基)-；
m1为1、2、3或4；
L2为连接键、-O-、
Figure PCTCN2020078963-appb-000008
W为-CH 2-或-C(＝O)-；
R2为氢或C1-C6的烷基；
或者，R1和R2连接，与相连的N一起形成：3-8元的杂环烷基、或被一个或多个卤素取代的3-8元的杂环烷基；所述的3-8元的杂环烷基和被一个或多个卤素取代的3-8元的杂环烷基中的杂原子除所述的N，还包括0至2个选自N、O、S、-S(＝O)-和-S(＝O) 2-的杂原子；当取代基为多个时，相同或不同；
R3和R5独立地为氢、卤素或C1-C6的烷基；
R4、R6和R7独立地为氢或-L-R10；
L独立地为连接键、-O-、-(SO 2)-或-(SO 2)-NH-(包括-NH-(SO 2)-)；
R10独立地为C1-C6的烷基、6至10元芳基、被一个或多个取代基取代的C1-C6的烷基、或被一个或多个取代基取代的6至10元芳基；所述的被一个或多个取代基取代的C1-C6的烷基和被一个或多个取代基取代的6至10元芳基中的取代基独立地为卤素、羟基、氰基或C1-C6的烷基；当取代基为多个时，相同或不同；
或者，R6和R7连接，与相连的碳原子一起形成：6元杂环烷基、或被一个或多个取代基取代的6元杂环烷基，所述的6元的杂环烷基中的杂原子选自N、O、S、-S(＝O)-和-S(＝O) 2-中的一种或多种，杂原子数为1、2或3个；所述的取代基独立地为C1-C6的烷基或＝O；当取代基为多个时，相同或不同。在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可 接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团如下定义(未定义的基团同本申请任一方案所述)，
R1为C1-C8烷基、3-8元环烷基、3-8元杂环烷基、3-8元环烷基取代的C1-C8烷基或
Figure PCTCN2020078963-appb-000009
例如C1-C8烷基、3-8元环烷基或
Figure PCTCN2020078963-appb-000010
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团如下定义(未定义的基团同本申请任一方案所述)，
R1为C1-C8烷基、3-8元环烷基、3-8元杂环烷基或3-8元环烷基取代的C1-C8烷基；例如C1-C8烷基或3-8元环烷基。
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团如下定义(未定义的基团同本申请任一方案所述)，
R1为
Figure PCTCN2020078963-appb-000011
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团如下定义(未定义的基团同本申请任一方案所述)，
m1为3。
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团如下定义(未定义的基团同本申请任一方案所述)，
L2为连接键、
Figure PCTCN2020078963-appb-000012
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团如下定义(未定义的基团同本申请任一方案所述)，
R2为氢。
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团如下定义(未定义的基团同本申请任一方案所述)，
R1和R2连接，与相连的N一起形成：3-8元的杂环烷基、或被一个或多个卤素取代的3-8元的 杂环烷基。
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团如下定义(未定义的基团同本申请任一方案所述)，
R3为氢。
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团如下定义(未定义的基团同本申请任一方案所述)，
R5为氢。
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团如下定义(未定义的基团同本申请任一方案所述)，
R6为氢。
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团如下定义(未定义的基团同本申请任一方案所述)，
L独立地为连接键、-O-或-(SO 2)-，例如连接键或-(SO 2)-。
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团如下定义(未定义的基团同本申请任一方案所述)，
L独立地为-O-。
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团如下定义(未定义的基团同本申请任一方案所述)，
R10独立地为C1-C6的烷基、被一个或多个取代基取代的C1-C6的烷基。
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团如下定义(未定义的基团同本申请任一方案所述)，
R10独立地为6至10元芳基、或被一个或多个取代基取代的6至10元芳基。
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团如下定义(未定义的基团同本申请任一方案所述)，
R4为氢或-L-R10，例如-L-R10，又例如L为连接键或-(SO 2)-，和/或，R10为C1-C6的烷基、被一个或多个取代基取代的C1-C6的烷基。
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团如下定义(未定义的基团同本申请任一方案所述)，
R7为氢或-L-R10，例如-L-R10，又例如L为-O-，和/或，R10为6至10元芳基、或被一个或多个取代基取代的6至10元芳基。
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团如下定义(未定义的基团同本申请任一方案所述)，
R6和R7连接，与相连的碳原子一起形成：6元杂环烷基、或被一个或多个取代基取代的6元杂环烷基。
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团如下定义(未定义的基团同本申请任一方案所述)，
R1中，所述的取代基独立地选自：卤素、氰基、羟基、＝O、C1-C6烷基、C1-C6烷基-O-和C1-C6烷基-(SO 2)-；例如卤素、氰基、C1-C6烷基、C1-C6烷基-O-和C1-C6烷基-(SO 2)-。
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团如下定义(未定义的基团同本申请任一方案所述)，
当R1为C1-C8烷基、所述的C1-C8烷基被一个或多个取代基取代时，所述的取代基选自卤素、氰基、C1-C6烷基、C1-C6烷基-O-和C1-C6烷基-(SO 2)-。
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团如下定义(未定义的基团同本申请任一方案所述)，
当R1为3-8元环烷基、3-8元环烷基取代的C1-C8烷基，所述的3-8元环烷基和3-8元环烷基取代的C1-C8烷基独立地被一个或多个取代基取代时，所述的取代基选自卤素、羟基、氰基、C1-C6烷基、C1-C6烷基-O-和C1-C6烷基-(SO 2)-；例如卤素、C1-C6烷基或羟基，又例如卤素。
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团如下定义(未定义的基团同本申请任一方案所述)，
当R1为3-8元环烷基取代的C1-C8烷基、所述的3-8元环烷基取代的C1-C8烷基被一个或多个取代基取代时，所述的取代基选自卤素、羟基、氰基、C1-C6烷基、C1-C6烷基-O-和C1-C6烷基-(SO 2)-；例如卤素或羟基，又例如卤素。
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团 如下定义(未定义的基团同本申请任一方案所述)，
Figure PCTCN2020078963-appb-000013
其中，X1为CH；X2为NH；
R1为C1-C8烷基、3-8元环烷基、3-8元杂环烷基、3-8元环烷基取代的C1-C8烷基、或
Figure PCTCN2020078963-appb-000014
所述的3-8元杂环烷基中，杂原子选自N、O、S、-S(＝O)-和-S(＝O) 2-中的一种或多种，杂原子数为1、2或3个；所述的C1-C8烷基、3-8元环烷基、3-8元环烷基取代的C1-C8烷基和
Figure PCTCN2020078963-appb-000015
任选被一个或多个取代基取代，所述的取代基独立地选自：卤素、氰基、羟基、＝O、C1-C6烷基、C1-C6烷基-O-和C1-C6烷基-(SO 2)-；当取代基为多个时，相同或不同；
L1为连接键、-(C1-C8烷基)-、-(C2-C6炔基)-、-(C1-C6烷基)-(CH 2OCH 2) m1-(C1-C6烷基)-；
m1为1、2、3或4；
L2为连接键、
Figure PCTCN2020078963-appb-000016
W为-CH 2-或-C(＝O)-；
R2为氢；
或者，R1和R2连接，与相连的N一起形成：3-8元的杂环烷基、或被一个或多个卤素取代的3-8元的杂环烷基；所述的3-8元的杂环烷基和被一个或多个卤素取代的3-8元的杂环烷基中的杂原子除所述的N，还包括0至2个选自N、O、S、-S(＝O)-和-S(＝O) 2-的杂原子；当取代基为多个时，相同或不同；
R3和R5独立地为氢、卤素或C1-C6的烷基；
R6为氢；
R4和R7独立地为氢或-L-R10；
L为连接键、-O-或-(SO 2)-；
R10独立地为C1-C6的烷基、6至10元芳基、被一个或多个取代基取代的C1-C6的烷基、或被一个或多个取代基取代的6至10元芳基；所述的被一个或多个取代基取代的C1-C6的烷基和被一个 或多个取代基取代的6至10元芳基中的取代基独立地为卤素、羟基、氰基或C1-C6的烷基；当取代基为多个时，相同或不同；
或者，R6和R7连接，与相连的碳原子一起形成：6元杂环烷基、或被一个或多个取代基取代的6元杂环烷基，所述的取代基独立地为C1-C6的烷基或＝O。
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团如下定义(未定义的基团同本申请任一方案所述)，
X1为CH；X2为NH；
R1为C1-C8烷基、3-8元环烷基；所述的C1-C8烷基、3-8元环烷基任选被一个或多个取代基取代；
R2、R3、R5和R6独立地为氢；
R4和R7独立地为氢或-L-R10；
或者，R6和R7连接，与相连的碳原子一起形成：6元杂环烷基、或被一个或多个取代基取代的6元杂环烷基，所述的取代基为C1-C6的烷基或＝O；
较佳地，
R4为C1-C6的烷基、或被一个或多个取代基取代的C1-C6的烷基；
R7为-L-R10；L为-O-；R10为6至10元芳基、或被一个或多个取代基取代的6至10元芳基。
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团如下定义(未定义的基团同本申请任一方案所述)，
X1为CH；X2为NH；
R1为C1-C8烷基或
Figure PCTCN2020078963-appb-000017
R2、R3、R5和R6独立地为氢；
R4和R7独立地为氢或-L-R10；
或者，R6和R7连接，与相连的碳原子一起形成：6元杂环烷基、或被一个或多个取代基取代的6元杂环烷基，所述的取代基为C1-C6的烷基或＝O；
较佳地，R1为
Figure PCTCN2020078963-appb-000018
R4为-L-R10；L为连接键或-(SO 2)-；R10为C1-C6的烷基、或被一个或多个取代基取代的C1-C6的烷基；
R7为-L-R10；L为-O-；R10为6至10元芳基、或被一个或多个取代基取代的6至10元芳基；
或者，R6和R7连接，与相连的碳原子一起形成：6元杂环烷基、或被一个或多个取代基取代的6元杂环烷基，所述的取代基为C1-C6的烷基或＝O；
更佳地，L1为连接键；
L2为
Figure PCTCN2020078963-appb-000019
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团如下定义(未定义的基团同本申请任一方案所述)，
当R1为C1-C8烷基、3-8元环烷基取代的C1-C8烷基或3-8元杂环烷基取代的C1-C8烷基时，所述的C1-C8烷基、3-8元环烷基取代的C1-C8烷基和3-8元杂环烷基取代的C1-C8烷基中的C1-C8烷基独立地为C1-C4烷基，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；又例如甲基、乙基或异丙基。
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团如下定义(未定义的基团同本申请任一方案所述)，
当R1为3-8元环烷基或3-8元环烷基取代的C1-C8烷基时，所述的3-8元环烷基和3-8元环烷基取代的C1-C8烷基中的3-8元环烷基独立地为3-6元环烷基，例如环丙基、环丁基、环戊基及环己基；又例如环丙基、环丁基或环戊基。
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团如下定义(未定义的基团同本申请任一方案所述)，
当R1为3-8元杂环烷基或3-8元杂环烷基取代的C1-C8烷基时，所述的3-8元杂环烷基和3-8元杂环烷基取代的C1-C8烷基中的3-8元杂环烷基独立地为3-6元杂环烷基，其中杂原子选自N、O和S中的一种或多种，杂原子数为1或2个；例如
Figure PCTCN2020078963-appb-000020
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团如下定义(未定义的基团同本申请任一方案所述)，
当R1中所述的取代基为C1-C6烷基、C1-C6烷基-O-或C1-C6烷基-(SO 2)-时，所述的C1-C6烷基、C1-C6烷基-O-和C1-C6烷基-(SO 2)-中的C1-C6烷基独立地为C 1-C 4烷基，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；又例如甲基或乙基。
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团 如下定义(未定义的基团同本申请任一方案所述)，
当Ra和/或Rb独立地为C1-C8烷基时，所述的C1-C8烷基独立地为C1-C6烷基，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基或正己基；又例如甲基。
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团如下定义(未定义的基团同本申请任一方案所述)，
当L1为-(C1-C8烷基)-时，所述的C1-C8烷基为C1-C6烷基，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基或正己基；又例如正丁基、正戊基或正己基。
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团如下定义(未定义的基团同本申请任一方案所述)，
当L1为-(C2-C6炔基)-时，所述的C2-C6炔基为乙炔基、丙-1-炔基
Figure PCTCN2020078963-appb-000021
丁-1-炔基
Figure PCTCN2020078963-appb-000022
或戊-4-炔基
Figure PCTCN2020078963-appb-000023
又例如
Figure PCTCN2020078963-appb-000024
其中，a端表示与L2相连。
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团如下定义(未定义的基团同本申请任一方案所述)，
当L1为-(C1-C6烷基)-(CH 2OCH 2) m1-(C1-C6烷基)-时，所述的C1-C6烷基独立地为C 1-C 4烷基，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；又例如甲基、乙基或正丙基。
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团如下定义(未定义的基团同本申请任一方案所述)，
m1为2或3。
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团如下定义(未定义的基团同本申请任一方案所述)，
当R2为C1-C6的烷基时，所述的C1-C6的烷基为C1-C4烷基，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；又例如甲基、乙基或异丙基。
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团如下定义(未定义的基团同本申请任一方案所述)，
当R1和R2连接，与相连的N一起形成：3-8元的杂环烷基、或被一个或多个卤素取代的3-8元的杂环烷基时，所述的3-8元的杂环烷基、或被一个或多个卤素取代的3-8元的杂环烷基中的3-8元 的杂环烷基独立地为3-6元的杂环烷基，其中的杂原子为所述的N；例如
Figure PCTCN2020078963-appb-000025
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团如下定义(未定义的基团同本申请任一方案所述)，
当R10独立地为C1-C6的烷基、或被一个或多个取代基取代的C1-C6的烷基时，所述的C1-C6的烷基独立地为C1-C4烷基，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；又例如甲基或乙基。
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团如下定义(未定义的基团同本申请任一方案所述)，
当R10独立地为6至10元芳基、或被一个或多个取代基取代的6至10元芳基时，所述的6至10元芳基、或被一个或多个取代基取代的6至10元芳基中的6至10元芳基独立地为苯基或萘基。
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团如下定义(未定义的基团同本申请任一方案所述)，
当R10中所述的取代基为C1-C6的烷基时，所述的取代基独立地为C1-C4烷基，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；又例如甲基或乙基。
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团如下定义(未定义的基团同本申请任一方案所述)，
当R6和R7连接，与相连的碳原子一起形成：6元杂环烷基、或被一个或多个取代基取代的6元杂环烷基时，所述的6元杂环烷基、被一个或多个取代基取代的6元杂环烷基中6元杂环烷基独立地为
Figure PCTCN2020078963-appb-000026
b端表示与苯环并环连接。
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团如下定义(未定义的基团同本申请任一方案所述)，
当R6和R7连接，与相连的碳原子一起形成：6元杂环烷基、或被一个或多个取代基取代的6元杂环烷基，所述的取代基为C1-C6的烷基时，所述的C1-C6的烷基为C1-C4烷基，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；又例如甲基或乙基。
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团如下定义(未定义的基团同本申请任一方案所述)，
L1为
Figure PCTCN2020078963-appb-000027
Figure PCTCN2020078963-appb-000028
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团如下定义(未定义的基团同本申请任一方案所述)，
-L1-L2-为
Figure PCTCN2020078963-appb-000029
Figure PCTCN2020078963-appb-000030
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团如下定义(未定义的基团同本申请任一方案所述)，
Figure PCTCN2020078963-appb-000031
为
Figure PCTCN2020078963-appb-000032
例如
Figure PCTCN2020078963-appb-000033
Figure PCTCN2020078963-appb-000034
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团如下定义(未定义的基团同本申请任一方案所述)，
当R1为C1-C8烷基、或被一个或多个取代基取代的C1-C8烷基时，例如乙基、异丙基、
Figure PCTCN2020078963-appb-000035
Figure PCTCN2020078963-appb-000036
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团 如下定义(未定义的基团同本申请任一方案所述)，
当R1为3-8元环烷基、或被一个或多个取代基取代的3-8元环烷基时，例如环丙基、环戊基、
Figure PCTCN2020078963-appb-000037
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团如下定义(未定义的基团同本申请任一方案所述)，
当R1为3-8元杂环烷基、或被一个或多个取代基取代的3-8元杂环烷基时，例如
Figure PCTCN2020078963-appb-000038
Figure PCTCN2020078963-appb-000039
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团如下定义(未定义的基团同本申请任一方案所述)，
当R1为3-8元环烷基取代的C1-C8烷基、或被一个或多个取代基取代的3-8元环烷基取代的C1-C8烷基时，例如
Figure PCTCN2020078963-appb-000040
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团如下定义(未定义的基团同本申请任一方案所述)，
当R1为
Figure PCTCN2020078963-appb-000041
或被一个或多个取代基取代的
Figure PCTCN2020078963-appb-000042
时，例如
Figure PCTCN2020078963-appb-000043
Figure PCTCN2020078963-appb-000044
Figure PCTCN2020078963-appb-000045
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团如下定义(未定义的基团同本申请任一方案所述)，
当R1和R2连接，与相连的N一起形成：3-8元的杂环烷基、或被一个或多个卤素取代的3-8元的杂环烷基时，
Figure PCTCN2020078963-appb-000046
为
Figure PCTCN2020078963-appb-000047
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团如下定义(未定义的基团同本申请任一方案所述)，
当R4为-L-R10，L独立地为连接键，和/或，R10独立地为C1-C6的烷基、被一个或多个取代基取代的C1-C6的烷基时，例如
Figure PCTCN2020078963-appb-000048
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团如下定义(未定义的基团同本申请任一方案所述)，
当R4为-L-R10，L独立地为-(SO 2)-，和/或，R10独立地为C1-C6的烷基、或被一个或多个取代基取代的C1-C6的烷基时，例如
Figure PCTCN2020078963-appb-000049
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团如下定义(未定义的基团同本申请任一方案所述)，
当R4为-L-R10，L独立地为-(SO 2)-NH-，和/或，R10独立地为C1-C6的烷基、或被一个或多个取代基取代的C1-C6的烷基时，例如
Figure PCTCN2020078963-appb-000050
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团 如下定义(未定义的基团同本申请任一方案所述)，
当R10独立地为被一个或多个取代基取代的6至10元芳基时，例如
Figure PCTCN2020078963-appb-000051
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团如下定义(未定义的基团同本申请任一方案所述)，
当R7为-O-R10时，例如
Figure PCTCN2020078963-appb-000052
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团如下定义(未定义的基团同本申请任一方案所述)，所述的式I所示的吡咯酰胺并吡啶酮类化合物如式II-1或II-2所示：
Figure PCTCN2020078963-appb-000053
其中，R1、R2、R3、R4、R5、R6、L和R10如上文所定义；R8和R9独立地为C1-C6的烷基(定义同R6和R7连接，与相连的碳原子一起形成：6元杂环烷基、或被一个或多个取代基取代的6元杂环烷基中所述的取代基为C1-C6的烷基)；
较佳地，所述的式I所示的吡咯酰胺并吡啶酮类化合物如式II-1’或II-2’所示：
Figure PCTCN2020078963-appb-000054
其中，R1、R2、R4、R8、R9如上文所定义；
式II-1’中，R10为C1-C6的烷基，或被一个或多个取代基取代的C1-C6的烷基；
II-2’中，R10为6至10元芳基、或被一个或多个取代基取代的6至10元芳基。
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团 如下定义(未定义的基团同本申请任一方案所述)，
当R6和R7连接，与相连的碳原子一起形成：6元杂环烷基、或被一个或多个取代基取代的6元杂环烷基时，
Figure PCTCN2020078963-appb-000055
为
Figure PCTCN2020078963-appb-000056
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团如下定义(未定义的基团同本申请任一方案所述)，
当
Figure PCTCN2020078963-appb-000057
为
Figure PCTCN2020078963-appb-000058
时，例如
Figure PCTCN2020078963-appb-000059
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团如下定义(未定义的基团同本申请任一方案所述)，
当
Figure PCTCN2020078963-appb-000060
为
Figure PCTCN2020078963-appb-000061
时，例如
Figure PCTCN2020078963-appb-000062
Figure PCTCN2020078963-appb-000063
在本发明某些优选实施方案中，所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药中的某些基团如下定义(未定义的基团同本申请任一方案所述)，
所述的如式I所示的吡咯酰胺并吡啶酮类化合物选自如下任一结构：
Figure PCTCN2020078963-appb-000064
Figure PCTCN2020078963-appb-000065
Figure PCTCN2020078963-appb-000066
一种制备式I化合物的方法，其特征在于，所述方法包括步骤a-c：
a)将通式(A)化合物和通式(B)化合物通过金属催化偶联反应转化成通式(C)化合物；和
b)将通式(C)化合物在碱性条件下水解成中间体通式化合物(D)；和
c)将中间体通式化合物(D)在缩合试剂条件下与R1R2NH缩合，得到通式(I)化合物；
Figure PCTCN2020078963-appb-000067
所示各基团的定义如上所述；
优选地，所述步骤a)、b)、c)各自在溶剂中进行，且所述溶剂选自下组：水、甲醇、乙醇、异丙醇、丁醇、乙二醇、乙二醇甲醚、N-甲基吡咯烷酮、二甲基亚砜，四氢呋喃、甲苯、二氯甲烷、1，2-二氯乙烷、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二氧六环，或其组合物。
优选地，所述过渡金属催化剂选自下组：三(二亚苄基丙酮)二钯(Pd 2(dba) 3)、四(三苯基膦)钯(Pd(PPh 3) 4)、醋酸钯、氯化钯、二氯二(三苯基膦)钯、三氟醋酸钯、三苯基膦醋酸钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、双(三邻苯甲基膦)二氯化钯、1，2-二(二苯基膦基)乙烷二氯化钯，或其组合物；所述催化剂配体选自下组：三叔丁基膦、四氟硼酸三叔丁基膦、三正丁基膦、三苯基膦、三对苯甲基膦、三环己基膦、三邻苯甲基膦，或其组合物。
优选地，所述无机碱选自下组：氢化钠、氢氧化钾、醋酸钠、醋酸钾、叔丁醇钾、叔丁醇钠、氟化钾、氟化铯、磷酸钾、碳酸钾、碳酸氢钾、碳酸钠、碳酸氢钠，或其组合物；所述有机碱选自下组：吡啶，三乙胺，N，N-二异丙基乙胺、1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)、六甲基二硅基锂、六甲基二硅基钠、二甲基吡啶，或其组合物。
本发明还提供了所述的如式I所示的吡咯酰胺并吡啶酮类化合物的制备方法，其包括方案1或方案2；
方案1，其包括如下步骤：在溶剂中，在碱和缩合试剂存在下，将式所示D化合物与R1R2NH进行如下所示的缩合反应，得到所述的如式I所示的吡咯酰胺并吡啶酮类化合物即可；
Figure PCTCN2020078963-appb-000068
方案2，其包括如下步骤：在溶剂中，在碱和过渡金属催化剂存在下，将如式所示A’化合物和如式B所示的化合物进行如下所示的金属催化偶联反应，得到所述的如式I所示的吡咯酰胺并吡啶酮类化合物即可；
Figure PCTCN2020078963-appb-000069
其中，X1、X2、R1、R2、R3、R4、R5、R6和R7如上文所定义。
本发明的某一方案中，所述的方案1还可进一步包括如下步骤：在溶剂中，在碱和过渡金属催化剂存在下，将如式A所示的化合物和如式B所示的化合物进行如下所示的金属催化偶联反应，得到所述的式所示C化合物即可；
Figure PCTCN2020078963-appb-000070
其中，X1、X2、R1、R2、R3、R4、R5、R6和R7如上文所定义。
所述的制备方法中，所述的缩合反应的操作和条件可参考为本领域该类反应中常规的操作和条件。
本发明的某一方案中，所述的方案1还可包括如下步骤：在溶剂中，在碱存在下，将如式C所示的化合物进行如下所示的水解反应，得到所述的式所示D化合物即可；
Figure PCTCN2020078963-appb-000071
其中，X1、X2、R1、R2、R3、R4、R5、R6和R7如上文所定义；Ra为C1-C6烷基(优选C1-C4烷基，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；又例如甲基、乙基或异丙基)。
所述的水解反应的操作和条件可参考为本领域该类反应中常规的操作和条件。
本发明的某一方案中，所述的方案1还可进一步包括如下步骤：在溶剂中，在碱和过渡金属催化剂存在下，将如式A所示的化合物和如式B所示的化合物进行如下所示的金属催化偶联反应，得到所述的式所示C化合物即可；
Figure PCTCN2020078963-appb-000072
其中，X1、X2、R1、R2、R3、R4、R5、R6、R7和Ra如上文所定义。
所述的金属催化偶联反应的操作和条件可参考为本领域该类反应中常规的操作和条件。本发明中优选如下：
所述的金属催化偶联反应中，所述过渡金属催化剂选自下组：三(二亚苄基丙酮)二钯(Pd 2(dba) 3)、四(三苯基膦)钯(Pd(PPh 3) 4)、醋酸钯、氯化钯、二氯二(三苯基膦)钯、三氟醋酸钯、三苯基膦醋酸钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、双(三邻苯甲基膦)二氯化钯、1，2-二(二苯基膦基)乙烷二氯化钯，或其组合物；所述催化剂配体选自下组：三叔丁基膦、四氟硼酸三叔丁基膦、三正丁基膦、三苯基膦、三对苯甲基膦、三环己基膦、三邻苯甲基膦，或其组合物。
所述缩合反应、水解反应、金属催化偶联反应各自在溶剂中进行，且所述溶剂选自下组：水、甲醇、乙醇、异丙醇、丁醇、乙二醇、乙二醇甲醚、N-甲基吡咯烷酮、二甲基亚砜，四氢呋喃、甲苯、二氯甲烷、1，2-二氯乙烷、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二氧六环，或其组合物。
其中，所述的缩合反应中，所述的溶剂优选酰胺类溶剂(例如N-二甲基甲酰胺、N,N-二甲基乙酰胺，或其组合物)。
所述的水解反应中，所述的溶剂优选水和醇类溶剂(例如甲醇、乙醇、异丙醇、丁醇、乙二醇中的一种或多种)的混合物。
所述的金属催化偶联反应中，所述的溶剂优选醇类溶剂(例如甲醇、乙醇、异丙醇、丁醇、乙二醇中的一种或多种)、酰胺类溶剂(例如N-二甲基甲酰胺、N,N-二甲基乙酰胺，或其组合物)
所述缩合反应、水解反应、金属催化偶联反应中，所述的碱可为无机碱和/或有机碱，所述无机碱选自下组：氢化钠、氢氧化钾、醋酸钠、醋酸钾、叔丁醇钾、叔丁醇钠、氟化钾、氟化铯、磷酸钾、碳酸钾、碳酸氢钾、碳酸钠、碳酸氢钠，或其组合物；所述有机碱选自下组：吡啶，三乙胺，N，N-二异丙基乙胺、1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)、六甲基二硅基锂、六甲基二硅基钠、二甲基吡啶，或其组合物。
本发明提供了一种如式D、式C、式A、式A’所示的化合物，
Figure PCTCN2020078963-appb-000073
其中，X1、X2、R1、R2、R3、R4、R5、R6、R7和Ra如上文所定义。
在本发明的某一方案中，所述的如式D所示的化合物选自如下任一结构：
Figure PCTCN2020078963-appb-000074
在本发明的某一方案中，所述的如式C所示的化合物选自如下任一结构：
Figure PCTCN2020078963-appb-000075
在本发明的某一方案中，所述的如式A所示的化合物为
Figure PCTCN2020078963-appb-000076
在本发明的某一方案中，所述的如式A’所示的化合物选为
Figure PCTCN2020078963-appb-000077
本发明的另一目的是提供一种治疗或预防肿瘤或炎性疾病的药物及其组合物。实现上述目的的技术方案如下：
一种***或炎性疾病的药物组合物，其由上述通式(I)所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药与药学上可接受的载体组成。
本发明的另一目的是提供一种上述化合物的用途。实现上述目的的技术方案如下：
所述通式(I)所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非 对映异构体、互变异构体、溶剂化物、多晶型物或前药用于制备治疗与BRD、c-Myc等蛋白活性或表达量相关的疾病的药物，特别是肿瘤、免疫性疾病和炎症性疾病的治疗药物。所述的肿瘤独立地选自非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、乳腺癌、***癌、肝癌、皮肤癌、胃癌、肠癌、胆管癌、脑癌、白血病、淋巴癌、纤维瘤、肉瘤、基底细胞癌、胶质瘤、肾癌、黑色素瘤、骨癌、甲状腺癌、鼻咽癌、胰腺癌等。所述的免疫性疾病和炎症性疾病独立地选自移植器官的排斥反应、痛风、鼻炎、脱发、阿尔茨海默氏病、阑尾炎、动脉粥样硬化、哮喘、关节炎、过敏性皮炎、贝切特氏病、大疱性皮肤病、胆囊炎、慢性特发性血小板减少性紫癜、慢性阻塞性肺病、肝硬化、退行性关节病、皮肤炎、皮肌炎、湿疹、肠炎、脑炎、胃炎、肾炎、桥本氏甲状腺炎、肝炎、垂体炎、炎性肠病、肠易激综合征、川崎病、脑脊膜炎、多发性硬化、心肌炎、重症肌无力、蕈样真菌病、肌炎、肾炎、骨髓炎、胰腺炎、帕金森病、心包炎、恶性贫血、肺炎、原发性胆汁性硬化性胆管炎、结节性多动脉炎、银屑病、纤维化、红斑狼疮、组织移植排斥、甲状腺炎、I型糖尿病、尿道炎、葡萄膜炎、血管炎、白癜风、瓦尔登斯特伦氏巨球蛋白血症等。
本发明涉及具有通式(I)结构特征的吡咯酰胺并吡啶酮类化合物，可以抑制多种肿瘤细胞，尤其是能高效地杀死BRD/c-Myc等信号通路异常相关的肿瘤，比如白血病、***癌等，是一类全新作用机制的治疗药物。
本发明还提供了一种药物组合物，其包含上述如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，和药学上可接受的载体。所述的如式I所示吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药可为治疗有效量。
本发明还提供了一种上述如式I所示吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药、或者上述的药物组合物在制备BRD和/或c-Myc抑制剂中的应用。
本发明还提供了一种上述如式I所示吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药、或者上述的药物组合物在制备治疗或预防与BRD和/或c-Myc蛋白活性或表达量相关的疾病的药物中的应用。
上述如式I所示吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药、或者上述的药物组合物可以抑制多种肿瘤细胞，尤其是能高效地杀死BRD/c-Myc等信号通路异常相关的肿瘤，比如白血病、***癌等。
本发明还提供了一种上述如式I所示吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药、或者上述的药物组合物在制备药物中的应用。所述的药物可为治疗或预防肿瘤和/或炎性疾病的药物。
本发明还提供了一种***和/或炎性疾病的方法，其包括向患者施用治疗有效量的上述如式I所示吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药、或者上述的药物组合物。
所述的肿瘤独立地选自：非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、乳腺癌、***癌、肝癌、皮肤癌、胃癌、肠癌、胆管癌、脑癌、白血病、淋巴癌、纤维瘤、肉瘤、基底细胞癌、胶质瘤、肾癌、黑色素瘤、骨癌、甲状腺癌、鼻咽癌、胰腺癌等。所述的免疫性疾病和炎症性疾病独立地选自移植器官的排斥反应、痛风、鼻炎、脱发、阿尔茨海默氏病、阑尾炎、动脉粥样硬化、哮喘、关节炎、过敏性皮炎、贝切特氏病、大疱性皮肤病、胆囊炎、慢性特发性血小板减少性紫癜、慢性阻塞性肺病、肝硬化、退行性关节病、皮肤炎、皮肌炎、湿疹、肠炎、脑炎、胃炎、肾炎、桥本氏甲状腺炎、肝炎、垂体炎、炎性肠病、肠易激综合征、川崎病、脑脊膜炎、多发性硬化、心肌炎、重症肌无力、蕈样真菌病、肌炎、肾炎、骨髓炎、胰腺炎、帕金森病、心包炎、恶性贫血、肺炎、原发性胆汁性硬化性胆管炎、结节性多动脉炎、银屑病、纤维化、红斑狼疮、组织移植排斥、甲状腺炎、I型糖尿病、尿道炎、葡萄膜炎、血管炎、白癜风和瓦尔登斯特伦氏巨球蛋白血症等。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合、从而构成新的或优选的技术方案。限于篇幅在此不再一一累述。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：本发明提供的式I结构特征的吡咯酰胺并吡啶酮类化合物，可以抑制多种肿瘤细胞，尤其是能高效地杀死BRD/c-Myc等信号通路异常相关的肿瘤，比如白血病、***癌等，是一类全新作用机制的治疗药物。
具体实施方式
发明人经过长期而深入的研究，制备了一类具有式I所示结构新颖的化合物，并发现其具有较好的BRD酶抑制或降解活性,且所述的化合物在极低浓度(可低至≤10nmol/L)下，即对BRD酶产生特异性抑制或降解作用，并且对BRD/c-MYc相关的细胞增殖抑制活性相当优异，因而可以用于治疗与BRD/c-MYc突变或表达量异常引起的相关疾病如肿瘤。基于上述发现，发明人完成了本发明。
术语
除非另有定义，否则本文所有科技术语具有的涵义与权利要求主题所属领域技术人员通常理解的涵义相同。除非另有说明，本文全文引用的所有专利、专利申请、公开材料通过引用方式整体并入本文。
应理解，上述简述和下文的详述为示例性且仅用于解释，而不对本发明主题作任何限制。在本申请中，除非另有具体说明，否则使用单数时也包括复数。必须注意，除非文中另有清楚的说明，否则在本说明书和权利要求书中所用的单数形式包括所指事物的复数形式。还应注意，除非另有说明，否则所用“或”、“或者”表示“和/或”。此外，所用术语“包括”以及其它形式，例如“包含”、“含”和“含有”并非限制性。
可在参考文献(包括Carey and Sundberg"ADVANCED ORGANIC CHEMISTRY 4TH ED."Vols.A(2000)and B(2001),Plenum Press,New York)中找到对标准化学术语的定义。除非另有说明，否则采 用本领域技术范围内的常规方法，如质谱、NMR、IR和UV/VIS光谱法和药理学方法。除非提出具体定义，否则本文在分析化学、有机合成化学以及药物和药物化学的有关描述中采用的术语是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送，以及对患者的治疗中使用标准技术。例如，可利用厂商对试剂盒的使用说明，或者按照本领域公知的方式或本发明的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述，按照本领域熟知的常规方法实施上述技术和方法。在本说明书中，可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。
当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言，-CH 2O-等同于-OCH 2-。
本文所用的章节标题仅用于组织文章的目的，而不应被解释为对所述主题的限制。本申请中引用的所有文献或文献部分包括但不限于专利、专利申请、文章、书籍、操作手册和论文，均通过引用方式整体并入本文。
在本文中定义的某些化学基团前面通过简化符号来表示该基团中存在的碳原子总数。例如，C 1-6烷基是指具有总共1至6个碳原子的如下文所定义的烷基。简化符号中的碳原子总数不包括可能存在于所述基团的取代基中的碳。
除前述以外，当用于本申请的说明书及权利要求书中时，除非另外特别指明，否则以下术语具有如下所示的含义。
在本申请中，术语“卤素”是指氟、氯、溴或碘；“羟基”是指-OH基团；“羟基烷基”是指被羟基(-OH)取代的如下文所定义的烷基；“羰基”是指-C(＝O)-基团；“硝基”是指-NO 2；“氰基”是指-CN；“氨基”是指-NH 2；“取代的氨基”是指被一个或两个如下文所定义的烷基、烷基羰基、芳烷基、杂芳烷基取代的氨基，例如，单烷基氨基、二烷基氨基、烷基酰氨基、芳烷基氨基、杂芳烷基氨基；“羧基”是指-COOH。
在本申请中，作为基团或是其它基团的一部分(例如用在卤素取代的烷基等基团中)，术语“烷基”意指仅由碳原子和氢原子组成、不含不饱和键、具有例如1至12个(优选为1至8个，更优选为1至6个)碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团。烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、2-甲基丁基、2,2-二甲基丙基、正己基、庚基、2-甲基己基、3-甲基己基、辛基、壬基和癸基等。
在本申请中，作为基团或是其它基团的一部分，术语“烯基”意指仅由碳原子和氢原子组成、含有至少一个双键、具有例如2至14个(优选为2至10个，更优选为2至6个)碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团，例如但不限于乙烯基、丙烯基、烯丙基、丁-1-烯基、丁-2-烯基、戊-1-烯基、戊-1,4-二烯基等。
在本申请中，作为基团或是其它基团的一部分，术语“炔基”意指仅由碳原子和氢原子组成、含有至少一个三键和任选的一个或多个双键、具有例如2至14个(优选为2至10个，更优选为2至6个)碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团，例如但不限于乙炔基、丙-1-炔基、丁-1-炔基、戊-1-烯-4-炔基等。
在本申请中，作为基团或是其它基团的一部分，术语“环烷基”意指仅由碳原子和氢原子组成的稳定的非芳香族单环或多环烃基，其可包括稠合环体系、桥环体系或螺环体系，具有3至15个碳原子，优选具有3至10个碳原子，更优选具有3至8个碳原子，且其为饱和或不饱和并可经由任何适宜的碳原子通过单键与分子的其余部分连接。除非本说明书中另外特别指明，环烷基中的碳原子可以任选地被氧化。环烷基的实例包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环辛基、1H-茚基、2,3-二氢化茚基、1,2,3,4-四氢-萘基、5,6,7,8-四氢-萘基、8,9-二氢-7H-苯并环庚烯-6-基、6,7,8,9-四氢-5H-苯并环庚烯基、5,6,7,8,9,10-六氢-苯并环辛烯基、芴基、二环[2.2.1]庚基、7,7-二甲基-二环[2.2.1]庚基、二环[2.2.1]庚烯基、二环[2.2.2]辛基、二环[3.1.1]庚基、二环[3.2.1]辛基、二环[2.2.2]辛烯基、二环[3.2.1]辛烯基、金刚烷基、八氢-4,7-亚甲基-1H-茚基和八氢-2,5-亚甲基-并环戊二烯基等。
在本申请中，作为基团或是其它基团的一部分，术语“杂环基”意指由2至14个碳原子以及1至6个选自氮、磷、氧和硫的杂原子组成的稳定的3元至20元非芳香族环状基团。除非本说明书中另外特别指明，否则杂环基可以为单环、双环、三环或更多环的环体系，其可包括稠合环体系、桥环体系或螺环体系；其杂环基中的氮、碳或硫原子可任选地被氧化；氮原子可任选地被季铵化；且杂环基可为部分或完全饱和。杂环基可以经由碳原子或者杂原子并通过单键与分子其余部分连接。在包含稠环的杂环基中，一个或多个环可以是下文所定义的芳基或杂芳基，条件是与分子其余部分的连接点为非芳香族环原子。就本发明的目的而言，杂环基优选为包含1至3个选自氮、氧和硫的杂原子的稳定的4元至11元非芳香性单环、双环、桥环或螺环基团，更优选为包含1至3个选自氮、氧和硫的杂原子的稳定的4元至8元非芳香性单环、双环、桥环或螺环基团。杂环基的实例包括但不限于：吡咯烷基、吗啉基、哌嗪基、高哌嗪基、哌啶基、硫代吗啉基、2,7-二氮杂-螺[3.5]壬烷-7-基、2-氧杂-6-氮杂-螺[3.3]庚烷-6-基、2,5-二氮杂-双环[2.2.1]庚烷-2-基、氮杂环丁烷基、吡喃基、四氢吡喃基、噻喃基、四氢呋喃基、噁嗪基、二氧环戊基、四氢异喹啉基、十氢异喹啉基、咪唑啉基、咪唑烷基、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡咯烷基、吡唑烷基、邻苯二甲酰亚氨基等。
在本申请中，作为基团或是其它基团的一部分，术语“芳基”意指具有6至18个碳原子(优选具有6至10个碳原子)的共轭烃环体系基团。就本发明的目的而言，芳基可以为单环、双环、三环或更多环的环体系，还可以与上文所定义的环烷基或杂环基稠合，条件是芳基经由芳香环上的原子通过单键与分子的其余部分连接。芳基的实例包括但不限于苯基、萘基、蒽基、菲基、芴基、2,3-二氢-1H-异吲哚基、2-苯并噁唑啉酮、2H-1,4-苯并噁嗪-3(4H)-酮-7-基等。
在本申请中，术语“芳基烷基”是指被上文所定义的芳基所取代的上文所定义的烷基。
在本申请中，作为基团或是其它基团的一部分，术语“杂芳基”意指环内具有1至15个碳原子(优选具有1至10个碳原子)和1至6个选自氮、氧和硫的杂原子的5元至16元共轭环系基团。除非本说明书中另外特别指明，否则杂芳基可为单环、双环、三环或更多环的环体系，还可以与上文所定义的环烷基或杂环基稠合，条件是杂芳基经由芳香环上的原子通过单键与分子的其余部分连接。杂芳基 中的氮、碳或硫原子可任选地被氧化；氮原子可任选地被季铵化。就本发明的目的而言，杂芳基优选为包含1至5个选自氮、氧和硫的杂原子的稳定的5元至12元芳香性基团，更优选为包含1至4个选自氮、氧和硫的杂原子的稳定的5元至10元芳香性基团或者包含1至3个选自氮、氧和硫的杂原子的5元至6元芳香性基团。杂芳基的实例包括但不限于噻吩基、咪唑基、吡唑基、噻唑基、噁唑基、噁二唑基、异噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、苯并咪唑基、苯并吡唑基、吲哚基、呋喃基、吡咯基、***基、四唑基、三嗪基、吲嗪基、异吲哚基、吲唑基、异吲唑基、嘌呤基、喹啉基、异喹啉基、二氮萘基、萘啶基、喹噁啉基、蝶啶基、咔唑基、咔啉基、菲啶基、菲咯啉基、吖啶基、吩嗪基、异噻唑基、苯并噻唑基、苯并噻吩基、噁***基、噌啉基、喹唑啉基、苯硫基、中氮茚基、邻二氮杂菲基、异噁唑基、吩噁嗪基、吩噻嗪基、4,5,6,7-四氢苯并[b]噻吩基、萘并吡啶基、[1,2,4]***并[4,3-b]哒嗪、[1,2,4]***并[4,3-a]吡嗪、[1,2,4]***并[4,3-c]嘧啶、[1,2,4]***并[4,3-a]吡啶、咪唑并[1,2-a]吡啶、咪唑并[1,2-b]哒嗪、咪唑并[1,2-a]吡嗪等。
在本申请中，术语“杂芳基烷基”是指被上文所定义的杂芳基所取代的上文所定义的烷基。
在本申请中，“任选的”或“任选地”表示随后描述的事件或状况可能发生也可能不发生，且该描述同时包括该事件或状况发生和不发生的情况。例如，“任选地被取代的芳基”表示芳基被取代或未被取代，且该描述同时包括被取代的芳基与未被取代的芳基。
本文所用术语“部分”、“结构部分”、“化学部分”、“基团”、“化学基团”是指分子中的特定片段或官能团。化学部分通常被认为是嵌入或附加到分子上的化学实体。
“立体异构体”是指由相同原子组成，通过相同的键键合，但具有不同三维结构的化合物。本发明将涵盖各种立体异构体及其混合物。
当本发明的化合物中含有烯双键时，除非另有说明，否则本发明的化合物旨在包含E-和Z-几何异构体。
“互变异构体”是指质子从分子的一个原子转移至相同分子的另一个原子而形成的异构体。本发明的化合物的所有互变异构形式也将包含在本发明的范围内。
本发明的化合物或其药学上可接受的盐可能含有一个或多个手性碳原子，且因此可产生对映异构体、非对映异构体及其它立体异构形式。每个手性碳原子可以基于立体化学而被定义为(R)-或(S)-。本发明旨在包括所有可能的异构体，以及其外消旋体和光学纯形式。本发明的化合物的制备可以选择外消旋体、非对映异构体或对映异构体作为原料或中间体。光学活性的异构体可以使用手性合成子或手性试剂来制备，或者使用常规技术进行拆分，例如采用结晶以及手性色谱等方法。
制备/分离个别异构体的常规技术包括由合适的光学纯前体的手性合成，或者使用例如手性高效液相色谱法拆分外消旋体(或盐或衍生物的外消旋体)，例如可参见Gerald Gübitz and Martin G.Schmid(Eds.),Chiral Separations,Methods and Protocols,Methods in Molecular Biology,Vol.243,2004；A.M.Stalcup,Chiral Separations,Annu.Rev.Anal.Chem.3:341-63,2010；Fumiss et al.(eds.),VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED.,Longman Scientific and Technical Ltd.,Essex,1991,809-816；Heller,Acc.Chem.Res.1990,23,128。
在本申请中，术语“药学上可接受的盐”包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的，与无机酸或有机酸所形成的盐。无机酸盐包括但不限于盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐等；有机酸盐包括但不限于甲酸盐、乙酸盐、2,2-二氯乙酸盐、三氟乙酸盐、丙酸盐、己酸盐、辛酸盐、癸酸盐、十一碳烯酸盐、乙醇酸盐、葡糖酸盐、乳酸盐、癸二酸盐、己二酸盐、戊二酸盐、丙二酸盐、草酸盐、马来酸盐、琥珀酸盐、富马酸盐、酒石酸盐、柠檬酸盐、棕榈酸盐、硬脂酸盐、油酸盐、肉桂酸盐、月桂酸盐、苹果酸盐、谷氨酸盐、焦谷氨酸盐、天冬氨酸盐、苯甲酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、海藻酸盐、抗坏血酸盐、水杨酸盐、4-氨基水杨酸盐、萘二磺酸盐等。这些盐可通过本专业已知的方法制备。
“药学上可接受的碱加成盐”是指能够保持游离酸的生物有效性而无其它副作用的、与无机碱或有机碱所形成的盐。衍生自无机碱的盐包括但不限于钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等。优选的无机盐为铵盐、钠盐、钾盐、钙盐及镁盐。衍生自有机碱的盐包括但不限于以下的盐：伯胺类、仲胺类及叔胺类，被取代的胺类，包括天然的被取代胺类、环状胺类及碱性离子交换树脂，例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、三乙醇胺、二甲基乙醇胺、2-二甲氨基乙醇、2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、胆碱、甜菜碱、乙二胺、葡萄糖胺、甲基葡萄糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。优选的有机碱包括异丙胺、二乙胺、乙醇胺、三甲胺、二环己基胺、胆碱及咖啡因。这些盐可通过本专业已知的方法制备。
“多晶型物”是指本发明的某些化合物在固体状态下由于存在两种或两种以上不同分子排列而产生的不同固体结晶相。本发明的某些化合物可以存在多于一种晶型，本发明旨在包括各种晶型及其混合物。
通常，结晶化作用会产生本发明化合物的溶剂化物。本发明中使用的术语“溶剂化物”是指包含一个或多个本发明化合物分子与一个或多个溶剂分子的聚集体。溶剂可以是水，该情况下的溶剂化物为水合物。或者，溶剂可以是有机溶剂。因此，本发明的化合物可以以水合物存在，包括单水合物、二水合物、半水合物、倍半水合物、三水合物、四水合物等，以及相应的溶剂化形式。本发明化合物可形成真实的溶剂化物，但在某些情况下，也可以仅保留不定的水或者水加上部分不定溶剂的混合物。本发明的化合物可以在溶剂中反应或者从溶剂中沉淀析出或结晶出来。本发明化合物的溶剂化物也包含在本发明的范围之内。
本发明还包括上述化合物的前药。在本申请中，术语“前药”表示可在生理学条件下或通过溶剂分解而被转化成本发明的生物活性化合物的化合物。因此，术语“前药”是指本发明的化合物的药学上可接受的代谢前体。当被给予有需要的个体时，前药可以不具有活性，但在体内被转化成本发明的活性化合物。前药通常在体内迅速转化，而产生本发明的母体化合物，例如通过在血液中水解来实现。前药化合物通常在哺乳动物生物体内提供溶解度、组织相容性或缓释的优点。前药包括已知的氨基保护基和羧基保护基。具体的前药制备方法可参照Saulnier,M.G.,et al.,Bioorg.Med.Chem.Lett.1994,4, 1985-1990；Greenwald,R.B.,et al.,J.Med.Chem.2000,43,475。
在本申请中，“药物组合物”是指本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药，利于活性成分的吸收进而发挥生物活性。
本文所用术语“药学上可接受的”是指不影响本发明化合物的生物活性或性质的物质(如载体或稀释剂)，并且相对无毒，即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。
在本申请中，“药学上可接受的载体”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
本发明所述“肿瘤”，“细胞增殖异常相关疾病”等包括但不限于白血病、胃肠间质瘤、组织细胞性淋巴瘤、非小细胞肺癌、小细胞肺癌、胰腺癌、肺鳞癌、肺腺癌、乳腺癌、***癌、肝癌、皮肤癌、上皮细胞癌、***、卵巢癌、肠癌、鼻咽癌、脑癌、骨癌、食道癌、黑色素瘤、肾癌、口腔癌等疾病。
本文所用术语“预防的”、“预防”和“防止”包括使病患减少疾病或病症的发生或恶化的可能性。
本文所用的术语“治疗”和其它类似的同义词包括以下含义：
(i)预防疾病或病症在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病或病症，但尚未被诊断为已患有该疾病或病症时；
(ii)抑制疾病或病症，即遏制其发展；
(iii)缓解疾病或病症，即，使该疾病或病症的状态消退；或者
(iv)减轻该疾病或病症所造成的症状。
本文所使用术语“有效量”、“治疗有效量”或“药学有效量”是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种药剂或化合物的量。其结果可以为迹象、症状或病因的消减和/或缓解，或生物***的任何其它所需变化。例如，用于治疗的“有效量”是在临床上提供显著的病症缓解效果所需的包含本文公开化合物的组合物的量。可使用诸如剂量递增试验的技术测定适合于任意个体病例中的有效量。
本文所用术语“服用”、“施用”、“给药”等是指能够将化合物或组合物递送到进行生物作用的所需位点的方法。这些方法包括但不限于口服途径、经十二指肠途径、胃肠外注射(包括静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、局部给药和经直肠给药。本领域技术人员熟知可用于本文所述化合物和方法的施用技术，例如在Goodman and Gilman,The Pharmacological Basis of Therapeutics,current ed.；Pergamon；and Remington's,Pharmaceutical Sciences(current edition),Mack Publishing Co.,Easton,Pa中讨论的那些。在优选的实施方案中，本文讨论的化合物和组合物通过口服施用。
本文所使用术语“药物组合”、“药物联用”、“联合用药”、“施用其它治疗”、“施用其它治疗剂”等是指通过混合或组合不止一种活性成分而获得的药物治疗，其包括活性成分的固定和不固定组合。术语 “固定组合”是指以单个实体或单个剂型的形式向患者同时施用至少一种本文所述的化合物和至少一种协同药剂。术语“不固定组合”是指以单独实体的形式向患者同时施用、合用或以可变的间隔时间顺次施用至少一种本文所述的化合物和至少一种协同制剂。这些也应用到鸡尾酒疗法中，例如施用三种或更多种活性成分。
本领域技术人员还应当理解，在下文所述的方法中，中间体化合物官能团可能需要由适当的保护基保护。这样的官能团包括羟基、氨基、巯基及羧酸。合适的羟基保护基包括三烷基甲硅烷基或二芳基烷基甲硅烷基(例如叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基或三甲基甲硅烷基)、四氢吡喃基、苄基等。合适的氨基、脒基及胍基的保护基包括叔丁氧羰基、苄氧羰基等。合适的巯基保护基包括-C(O)-R”(其中R”为烷基、芳基或芳烷基)、对甲氧基苄基、三苯甲基等。合适的羧基保护基包括烷基、芳基或芳烷基酯类。
保护基可根据本领域技术人员已知的和如本文所述的标准技术来引入和除去。保护基的使用详述于Greene,T.W.与P.G.M.Wuts,Protective Groups in Organi Synthesis,(1999),4th Ed.,Wiley中。保护基还可为聚合物树脂。
本领域技术人员可以理解，根据本领域中使用的惯例，本申请描述基团的结构式中所使用的
Figure PCTCN2020078963-appb-000078
是指，相应的基团通过该位点与化合物中的其它片段、基团进行连接。
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
中间体A制备
Figure PCTCN2020078963-appb-000079
第一步：将化合物1(4g,18.6mmol)和叠氮乙酸乙酯(5.97g,46.3mmol)溶于无水乙醇(200mL)，向其加入乙醇钠(3.14g,46.2mmol)，室温下反应过夜。反应液加入冷水，乙酸乙酯萃取，无水硫酸钠干燥有机相，过滤，浓缩，残余物经硅胶柱层析纯化得到化合物2(1.8g,白色固体)。 1H NMR(400MHz,CDCl 3):δ8.60(d,J＝2.0Hz,1H),8.13(d,J＝2.4Hz,1H),7.10(s,1H),4.39(q,J＝7.2Hz,2H),3.97(s,3H),1.41(t,J＝7.2Hz,3H)。
第二步：将化合物2(1.8g,5.5mmol)溶于甲苯(100mL)，加热至135度下反应过夜。反应液浓缩蒸干，得到粗产品3(1.5g,黄色固体)，直接用于下一步反应。LC-MS:m/z 297.0[M-H] +。
第三步：将化合物3(1.0g,粗品)溶于N,N-二甲基甲酰胺DMF(15mL)中，依次加入碳酸钾(922mg,6.68mmol)和2-(三甲硅烷基)乙氧甲基氯SEMCl(665mg,4.0mmol)，室温下反应过夜。 加入饱和氯化铵溶液，乙酸乙酯萃取，浓缩有机相，残余物经硅胶柱层析纯化得到化合物4(0.6g,无色油状物)。 1H NMR(400MHz,CDCl 3):δ8.11(s,1H),7.51(s,1H),6.45(s,2H),4.45(q,J＝7.2Hz,2H),4.14(s,3H),3.60(t,J＝8.0Hz,2H),1.48(t,J＝7.2Hz,3H),0.95(t,J＝8.0Hz,2H),0.01(s,9H)。
第四步：将化合物4(0.6g,1.4mmol)溶于乙腈(30mL)，加入碘化钠(315mg,2.1mmol)和三甲基氯硅烷TMSCl(227mg,2.1mmol)，室温下反应1h后，加热至65度反应3h。反应液浓缩，加入硫代硫酸钠溶液，二氯甲烷萃取，有机相浓缩得到化合物5(0.5g,白色固体)。LC-MS:m/z 415.1[M+H] +。
第五步：将化合物5(0.5g,1.2mmol)溶于DMF(20mL)中，依次加入碳酸铯(782mg,2.4mmol)和碘甲烷(256mg,1.8mmol)，室温下反应过夜。加入饱和氯化铵溶液，二氯甲烷萃取，有机相浓缩，残余物经硅胶柱层析纯化得到化合物6(320mg,白色固体)。 1H NMR(400MHz,CDCl 3):δ7.70(s,1H),7.39(s,1H),6.37(s,2H),4.40(q,J＝7.2Hz,2H),3.64(s,3H),3.60(t,J＝8.0Hz,2H),1.44(t,J＝7.2Hz,3H),0.94(t,J＝8.0Hz,2H),0.01(s,9H)。
第六步：将化合物6(320mg,0.75mmol)溶于二氯甲烷(10mL)中，加入三氟乙酸(2mL)，室温下反应5h。反应液浓缩，加入饱和碳酸氢钠溶液，二氯甲烷萃取，有机相浓缩得到中间体A(200mg,白色固体)。LC-MS:m/z 299.0/301.0[M+H] +/[M+H+2] +。
中间体B制备
Figure PCTCN2020078963-appb-000080
第一步：将化合物1(3.8g,16.8mmol)溶于N,N-二甲基甲酰胺(DMF)(50mL)中，降温到0度，分批加入钠氢(60％在矿物油中，1.0g，24mmol)。加完后继续搅拌30分钟，然后加入对甲苯磺酰氯(4.8g，25mmol)，室温搅拌过夜。加入冰水(200mL)淬灭反应，析出固体过滤得到化合物2(5.0g，黄色固体)。 1H NMR(DMSO-d6,400MHz):δ8.18(d,J＝3.6Hz,1H),8.00(s,1H),7.86(d,J＝8.4Hz,2H),7.46(d,J＝8.4Hz,2H),6.81(d,J＝3.6Hz,1H).3.82(s,3H),2.39(s,3H)。LC-MS:m/z 380.9[M+H] +。
第二步：将化合物2(380mg，1.0mmol)溶于四氢呋喃(10mL)，干冰丙酮浴降温到-70度。滴加二异丙基胺基锂LDA(2M，1mL，2.0mmol)，继续搅拌30分钟，在-50度下滴加氯甲酸乙酯(162mg,1.5mmol)，保持-50度反应2小时。饱和氯化铵溶液淬灭反应，乙酸乙酯萃取，有机相浓缩得粗产品。粗产品用甲醇打浆得到化合物3(400mg，黄色固体)。 1H NMR(CDCl 3,400MHz):δ8.26(d,J＝8.4Hz,2H),7.99(s,1H),7.38(d,J＝8.4Hz,2H),7.08(s,1H),4.48(q,J＝6.8Hz,2H),3.91(s,3H),2.47(s,3H),1.45(t,J＝6.8Hz,3H)。LC-MS:m/z 453.0[M+H] +。
第三步：将化合物3(1.3g，2.9mmol)，碘化钠(645mg,4.3mmol)溶于乙腈(50mL)，室温下加入三甲基氯硅烷(465mg,4.3mmol)，搅拌1小时后加入0.2mL水，升温到70度反应2小时。降至室温后过滤，滤液浓缩得到化合物4(1.3g，粗品，黄色固体)。 1H NMR(CDCl 3,400MHz):δ8.32 (d,J＝8.4Hz,2H),7.42(s,1H),7.38(d,J＝8.0Hz,2H),6.99(s,1H),4.48(q,J＝7.2Hz,2H),2.45(s,3H),1.45(t,J＝7.2Hz,3H).LC-MS:m/z 438.9[M+H] +。
第四步：将化合物4(1.3g，粗品)溶于DMF(5mL)，加入碳酸铯(1.3g，3.9mmol)和碘甲烷(550mg，3.9mmol)。室温搅拌过夜后加入水，用乙酸乙酯萃取。有机相干燥，浓缩，残余物经硅胶柱层析纯化得到中间体B(1.2g，白色固体)。 1H NMR(CDCl 3,400MHz):δ8.48(d,J＝8.0Hz,2H),7.39(d,J＝8.4Hz,2H),7.26(s,1H),6.88(s,1H),4.46(q,J＝7.2Hz,2H),3.56(s,3H).2.45(s,3H),1.44(t,J＝7.2Hz,3H)。LC-MS:m/z 453.0[M+H] +。
实施例制备
实施例1：N-乙基-7-(2-(4-氟-2,6-二甲基苯氧基)-5-(2-羟基丙基-2-基)苯基)-5-甲基-4-氧-4,5-二氢-1H-吡咯[3,2-c]吡啶-2-酰胺
Figure PCTCN2020078963-appb-000081
第一步：将中间体A(100mg,0.34mmol)溶于乙醇(10mL)中，加入水(5mL)和氢氧化钠(53mg，1.32mmol)，加热至80度下反应4h。反应液浓缩除去大部分乙醇，加入少量水，稀盐酸调pH值至3～4，冷冻干燥得到7-溴-5-甲基-4-氧代-4,5-二氢-1H-吡咯[3,2-c]吡啶-2-羧酸(90mg，白色固体)。 1H NMR(400MHz,DMSO_d6):δ13.13(brs,1H),12.39(s,1H),7.87(s,1H),7.20(s,1H),3.46(s,3H)。
第二步：将7-溴-5-甲基-4-氧代-4,5-二氢-1H-吡咯[3,2-c]吡啶-2-羧酸(90mg,0.33mmol)溶于DMF(5mL)中，依次加入乙胺盐酸盐(54mg,0.67mmol)和N,N-异丙基乙基二胺DIEA(213mg,1.65mmol)，再加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯HATU(250mg,0.66mmol)，室温下反应过夜。加入饱和氯化铵溶液，二氯甲烷萃取，有机相浓缩，残余物柱层析纯化得到7-溴-N-乙基-5-甲基-4-氧代-4,5-二氢-1H-吡咯[3,2-c]吡啶-2-酰胺(50mg，白色固体)。LC-MS:m/z 298.0[M+H] +。
第三步：将7-溴-N-乙基-5-甲基-4-氧代-4,5-二氢-1H-吡咯[3,2-c]吡啶-2-酰胺(40mg,0.13mmol)和(2-(4-氟-2,6-二甲基苯氧基)-5-(2-羟基丙基-2-基)苯基)硼酸(51mg,0.16mmol)溶于DMF(10mL)中，依次加入碳酸铯(131mg,0.40mmol)和1,1'-双二苯基膦二茂铁二氯化钯Pd(dppf)Cl 2(20mg,0.027mmol)，氮气保护下，加热至100度反应过夜。降到室温后加入饱和氯化铵溶液，二氯甲烷萃取，有机相浓缩，残余物制备色谱纯化得到化合物N-乙基-7-(2-(4-氟-2,6-二甲基苯氧基)-5-(2-羟基丙基-2-基)苯基)-5-甲基-4-氧-4,5-二氢-1H-吡咯[3,2-c]吡啶-2-酰胺(15mg，白色固体)。LC-MS(M+H)492.2。 1H-NMR(DMSO-d6,400MHz)：δ10.85(s,1H),8.36(t,J＝5.6Hz,1H),7.50(d,J＝2.4Hz,1H),7.46(s,1H),7.37(dd,J＝2.4,8.8Hz,1H),7.27(s,1H),6.97(d,J＝9.2Hz,2H),6.32(d,J＝8.8Hz,1H),4.98(s,1H),3.54(s,3H),3.22-3.27(m,2H),2.03(s,6H),1.45(s,6H),1.10(t,J＝7.2Hz,3H)。
实施例2：N-乙基-5-甲基-4-氧-7-(2,2,4-三甲基-6-(甲基砜基)-3-氧-3,4-二氢-2H-苯并[b][1,4]噁嗪-8-基)-4,5-二氢-1H-吡咯[3,2-c]吡啶-2-酰胺
Figure PCTCN2020078963-appb-000082
在氮气保护下，将8-溴-2,2,4-三甲基-6-(甲基砜基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(35mg,0.1mmol)溶于DMF(3mL)，加入双联频哪醇硼酯(51mg，0.2mmol)，碳酸铯(98mg，0.3mmol)和Pd(dppf)Cl 2(7mg，0.01mmol)，升温至110度搅拌2小时，然后加入7-溴-N-乙基-5-甲基-4-氧代-4,5-二氢-1H-吡咯[3,2-c]吡啶-2-酰胺(30mg,0.1mmol)，继续搅拌过夜。降至室温，加水，二氯甲烷DCM萃取，有机相用无水硫酸钠干燥，浓缩，制备色谱纯化得到N-乙基-5-甲基-4-氧-7-(2,2,4-三甲基-6-(甲基砜基)-3-氧-3,4-二氢-2H-苯并[b][1,4]噁嗪-8-基)-4，5-二氢-1H-吡咯[2,3-c]吡啶-2-酰胺(3.6mg，白色固体)。LC-MS(M+H)487.1。 1H-NMR(CDCl 3,400MHz)：δ11.29(br,1H),7.74(d,J＝2.0Hz,1H),7.53(d,J＝2.0Hz,1H),7.09-7.12(m,2H),6.72(s,1H),3.75(s,3H),3.53(q,J＝7.2Hz,2H),3.48(s,3H),3.14(s,3H),1.47(s,6H),1.26(t,J＝7.2Hz,3H)。
实施例3：N-(5-(2-(2,6-二氧哌啶-3-基)-1-氧代异吲哚啉-4-基)戊-4-炔-1-基)-7-(2-(4-氟-2,6-二甲基苯氧基)-5-(2-羟基丙基-2-基)苯基)-5-甲基-4-氧代-4,5-二氢-1H-吡咯[3,2-c]吡啶-2-酰胺
Figure PCTCN2020078963-appb-000083
第一步：将中间体A(500mg，1.68mmol)和2-(4-(4-氟-2,6-二甲基苯氧基)-3-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)苯基)丙烷-2-醇溶于DMF(10mL)中，加入碳酸铯Cs 2CO 3(1.6g，4.91mmol)和Pd(dppf)Cl 2(245mg，0.33mmol)，氮气保护下，升温至100度反应过夜。直接浓缩，剩余物柱层析纯化得到7-(2-(4-氟-2,6-二甲基苯氧基)-5-(2-羟基丙基-2-基)苯基)-5-甲基-4-氧代-4,5-二氢-1H-吡咯[3,2-c]吡啶-2-羧酸乙酯(420mg，白色固体)。LC-MS:m/z 493.5[M+H] +。
第二步：将氢氧化钠NaOH(136mg，1.68mmol)加入到7-(2-(4-氟-2,6-二甲基苯氧基)-5-(2-羟基丙基-2-基)苯基)-5-甲基-4-氧代-4,5-二氢-1H-吡咯[3,2-c]吡啶-2-羧酸乙酯(420mg，0.85mmol)的乙醇/水(10mL，体积比1：1)溶液中。室温反应过夜。旋除大部分乙醇，加水稀释，调节pH至酸性，乙酸乙酯萃取，有机相干燥，浓缩得到7-(2-(4-氟-2,6-二甲基苯氧基)-5-(2-羟基丙基-2-基)苯基)-5-甲基-4-氧代-4,5-二氢-1H-吡咯[3,2-c]吡啶-2-羧酸(230mg，白色固体)。LC-MS:m/z 465.3[M+H] +。
第三步：将7-(2-(4-氟-2,6-二甲基苯氧基)-5-(2-羟基丙基-2-基)苯基)-5-甲基-4-氧代-4,5-二氢-1H-吡咯[3,2-c]吡啶-2-羧酸(28mg，0.060mmol)和3-(4-(5-氨基戊-1-炔-1-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮盐酸盐(18mg，0.050mmol)溶于DCM(2mL)中，加入DIEA(36mg，0.28mmol)和1-正丙基磷酸酐T 3P(88mg，0.28mmol)，室温搅拌反应2小时。直接浓缩，剩余物中性制备色谱纯化得到N-(5-(2-(2,6-二氧哌啶-3-基)-1-氧代异吲哚啉-4-基)戊-4-炔-1-基)-7-(2-(4-氟-2,6-二甲基苯氧基)-5-(2-羟基丙基-2-基)苯基)-5-甲基-4-氧代-4,5-二氢-1H-吡咯[3,2-c]吡啶-2-酰胺(3mg，白色固体)。LC- MS(M+H)772.6。 1H-NMR(CDCl 3,400MHz)：δ9.57(s,1H),8.63(s,1H),7.71(d,J＝6.4Hz,1H),7.63(s,1H),7.23-7.52(m,4H),6.76(d,J＝8.8Hz,2H),6.41(d,J＝8.8Hz,1H),5.17(br s,1H),4.25-4.60(m,2H),3.55-3.72(m,5H),2.79(br s,2H),2.57(br s,2H),1.96-2.17(m,10H),1.61(s,6H)。
实施例4：N-(5-(2-(2,6-二氧哌啶-3-基)-1-氧代异吲哚啉-4-基)戊基)-7-(2-(4-氟-2,6-二甲基苯氧基)-5-(2-羟基丙基-2-基)苯基)-5-甲基-4-氧代-4,5-二氢-1H-吡咯[3,2-c]吡啶-2-酰胺
Figure PCTCN2020078963-appb-000084
以3-(4-(5-氨基戊基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮为原料，操作同实施例3。LC-MS(M+H)776.6。 1H-NMR(CDCl 3,400MHz)：δ9.67(s,1H),9.49(s,1H),7.72(d,J＝7.2Hz,1H),7.58(d,J＝2.0Hz,1H),7.51(s,1H),7.26-7.45(m,4H),6.78(d,J＝8.8Hz,2H),6.57(t,J＝5.6Hz,1H),6.44(d,J＝8.4Hz,1H),5.27-5.35(m,1H),4.50(d,J＝15.6Hz,1H),4.28(d,J＝16.0Hz,1H),3.60-3.72(m,5H),3.10-3.15(m,1H),2.83-2.87(m,2H),2.71-2.76(m,1H),2.53-2.58(m,1H),2.04-2.35(m,11H),1.48-1.60(m,8H)。
实施例5：N-(4-(2-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚啉-4-基)氧代)乙酰胺基)丁基)-7-(2-(4-氟-2,6-二甲基苯氧基)-5-(2-羟基丙基-2-基)苯基)-5-甲基-4-氧代-4,5-二氢-1H-吡咯[3,2-c]吡啶-2-酰胺
Figure PCTCN2020078963-appb-000085
以N-(4-氨基丁基)-2-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚啉-4-基)氧代)乙酰胺为原料，操作同实施例3。LC-MS(M+H)849.5。 1H-NMR(CDCl 3,400MHz)：δ9.87(br s,1H),9.53(s,1H),7.53-7.75(m,4H),7.20-7.33(m,3H),6.85(br s,1H),6.77(d,J＝8.8Hz,2H),6.42(d,J＝8.4Hz,1H),4.93-4.98(m,1H),4.61-4.66(m,2H),3.68(s,3H),3.34-3.57(m,4H),2.68-2.86(m,3H),2.30-2.34(m,1H),1.90-2.15(m,8H),1.49-1.60(m,8H)。
实施例6：N-(3-(2-(2-(3-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚啉-4-基)氨基)丙氧基)乙氧基)乙氧基)丙基)-7-(2-(4-氟-2,6-二甲基苯氧基)-5-(2-羟基丙基-2-基)苯基)-5-甲基-4-氧代-4,5-二氢-1H-吡咯[3,2-c]吡啶-2-酰胺
Figure PCTCN2020078963-appb-000086
以4-((3-(2-(2-(3-氨基丙氧基)乙氧基)乙氧基)丙基)氨基)-2-(2,6-二氧哌啶-3-基)异吲哚啉-1,3-二酮盐酸盐为原料，操作同实施例3。LC-MS(M+H)923.7。 1H-NMR(CDCl 3,400MHz)：δ9.47(br s,1H), 8.72(s,1H),7.56(d,J＝2.0Hz,1H),7.43(t,J＝8.0Hz,1H),7.23-7.34(m,2H),7.04(d,J＝7.2Hz,1H),6.87(d,J＝8.4Hz,1H),6.77(d,J＝8.8Hz,2H),6.41-6.45(m,2H),4.87-4.91(m,1H),3.48-3.79(m,17H),3.34-3.36(m,2H),2.70-2.88(m,3H),2.26(br s,1H),2.10(s,6H),1.81-1.89(m,4H),1.59(s,6H)。
实施例7：N-(2-(2-(2-(3-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚啉-4-基)氨基)-3-氧正丙氧基)乙氧基)乙氧基)乙基)-5-甲基-4-氧-7-(2,2,4-三甲基-6-(甲基砜基)-3-氧-3,4-二氢-2H-苯并[b][1,4]噁嗪-8-基)-4，5-二氢-1H-吡咯[3，2-c]吡啶-2-酰胺
Figure PCTCN2020078963-appb-000087
第一步：氮气保护下，将8-溴-2,2,4-三甲基-6-(甲基砜基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(0.77g,2.2mmol)溶于DMF(20mL)，加入双联频哪醇硼酯(1.1g，4.4mmol)，碳酸铯(2.1g，6.4mmol)和Pd(dppf)Cl 2(160mg，0.22mmol)，升温至110度搅拌2小时，然后加入中间体A(1.0g,2.2mmol)，继续搅拌过夜。降至室温，加水，DCM萃取，有机相用无水硫酸钠干燥，浓缩，硅胶柱层析纯化得到5-甲基-4-氧代-7-(2,2,4-三甲基-6-(甲基砜基)-3-氧代-3,4-二氢-2H-苯并[b][1,4]噁嗪-8-基)-4,5-二氢-1H-吡咯[3,2-c]吡啶-2-羧酸乙酯(212mg，白色固体)。LC-MS:m/z 642.2[M-H] +。
第二步：将氢氧化钠(27mg，0.67mmol)加入到第一步所得产物(212mg，0.33mmol)的乙醇/水(10mL，体积比1：1)溶液中。室温反应过夜。旋除大部分乙醇，加水稀释，调节pH至酸性，乙酸乙酯萃取，有机相干燥，浓缩得到5-甲基-4-氧代-7-(2,2,4-三甲基-6-(甲基砜基)-3-氧代-3,4-二氢-2H-苯并[b][1,4]噁嗪-8-基)-4,5-二氢-1H-吡咯[3,2-c]吡啶-2-羧酸(130mg，白色固体)。LC-MS:m/z 460.2[M+H] +。
第三步：将第二步所得产物(46mg，0.10mmol)和3-(2-(2-(2-氨基乙氧基)乙氧基)乙氧基)-N-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚啉-4-基)丙酰胺(48mg，0.10mmol)溶于DCM(2mL)中，加入DIEA(26mg，0.20mmol)和T 3P(63mg，0.20mmol)，室温搅拌反应2小时。直接浓缩，剩余物中性制备色谱纯化得到N-(2-(2-(2-(3-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚啉-4-基)氨基)-3-氧正丙氧基)乙氧基)乙氧基)乙基)-5-甲基-4-氧-7-(2,2,4-三甲基-6-(甲基砜基)-3-氧-3,4-二氢-2H-苯并[b][1,4]噁嗪-8-基)-4，5-二氢-1H-吡咯[3，2-c]吡啶-2-酰胺(5mg，白色固体)。LC-MS(M+H)918.3。
实施例8：N-(6-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚啉-4-基)正己基)-6-甲基-7-氧-4-(2,2,4-三甲基-6-(甲基砜基)-3-氧-3,4-二氢-2H-苯并[b][1,4]噁嗪-8-基)-6,7-二氢-1H-吡咯[2,3-c]吡啶-2-酰胺
Figure PCTCN2020078963-appb-000088
以4-(6-氨基正己基)-2-(2,6-二氧哌啶-3-基)异吲哚啉-1,3-二酮为原料，操作同实施例7。LC-MS(M+H)799.3。
实施例9：7-(2-(4-氟-2,6-二甲基苯氧基)-5-(2-羟基丙基-2-基)苯基)-N-(2-甲氧乙基)-5-甲基-4-氧-4,5-二氢-1H-吡咯[3,2-c]吡啶-2-酰胺
Figure PCTCN2020078963-appb-000089
第一步：将中间体A(700mg,2.35mmol)，2-(4-(4-氟-2,6-二甲基苯氧基)-3-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)苯基)丙烷-2-醇(1.1g,2.75mmol)，碳酸铯(2.3g,7.06mmol)，Pd(dppf)Cl 2(400mg,0.55mmol)溶于DMF(15mL)，氮气置换10分钟，氮气保护下加热至100度反应过夜。冷却至室温，过滤，滤液浓缩，柱层析纯化得到7-(2-(4-氟-2,6-二甲基苯氧基)-5-(2-羟基丙基-2-基)苯基)-5-甲基-4-氧代-4,5-二氢-1H-吡咯[3,2-c]吡啶-2-羧酸乙酯(753mg，白色固体)。LC-MS:m/z 493.4[M-H] +。
第二步：将7-(2-(4-氟-2,6-二甲基苯氧基)-5-(2-羟基丙基-2-基)苯基)-5-甲基-4-氧代-4,5-二氢-1H-吡咯[3,2-c]吡啶-2-羧酸乙酯(753mg,1.53mmol)溶于乙醇(30mL)，加入NaOH(183mg,4.59mmol)的水溶液(6mL)，室温过夜。浓缩，加入二氯甲烷和水溶解，1M盐酸调节pH到7，振荡，分出有机相，浓缩得到7-(2-(4-氟-2,6-二甲基苯氧基)-5-(2-羟基丙基-2-基)苯基)-5-甲基-4-氧代-4,5-二氢-1H-吡咯[3,2-c]吡啶-2-羧酸(590mg，淡黄色固体)。LC-MS:m/z 465.4[M+H] +。
第三步：将7-(2-(4-氟-2,6-二甲基苯氧基)-5-(2-羟基丙基-2-基)苯基)-5-甲基-4-氧代-4,5-二氢-1H-吡咯[3,2-c]吡啶-2-羧酸(80mg,0.17mmol)溶于DMF(3mL)，加入HATU(99mg,0.26mmol)和DIEA(66mg,0.51mmol)，室温下搅拌5分钟，加入2-甲氧基乙胺(20mg,0.26mmol)，室温下反应2小时。过滤，滤液制备色谱纯化得到7-(2-(4-氟-2,6-二甲基苯氧基)-5-(2-羟基丙基-2-基)苯基)-N-(2-甲氧乙基)-5-甲基-4-氧-4,5-二氢-1H-吡咯[3,2-c]吡啶-2-酰胺(26.9mg，白色固体)。LC-MS(M+H)522.0。 1H-NMR(DMSO-d6,400MHz)：δ10.95(s,1H),8.47(t,J＝5.2Hz,1H),7.51(d,J＝2.4Hz,1H),7.46(s,1H),7.38(dd,J＝2.4,8.4Hz,1H),7.29(d,J＝2.0Hz,1H),6.97(d,J＝8.8Hz,2H),6.33(d,J＝8.8Hz,1H),4.98(s,1H),3.55(s,3H),3.38-3.44(m,4H),3.27(s,3H),2.04(s,6H),1.46(s,6H)。
实施例10：7-(2-(4-氟-2,6-二甲基苯氧基)-5-(2-羟基丙基-2-基)苯基)-5-甲基-N-(2-(甲砜基)乙基)-4-氧-4,5-二氢-1H-吡咯[3,2-c]吡啶-2-酰胺
Figure PCTCN2020078963-appb-000090
以2-甲砜基乙胺为原料，操作同实施例9。LC-MS(M+H)570.0。 1H-NMR(DMSO-d6,400MHz)：δ11.01(d,J＝1.6Hz,1H),8.66(t,J＝5.6Hz,1H),7.48(d,J＝2.4Hz,1H),7.46(s,1H),7.36(dd,J＝2.4,8.4Hz,1H),7.29(d,J＝2.0Hz,1H),6.97(d,J＝9.2Hz,2H),6.31(d,J＝8.4Hz,1H),4.97(s,1H),3.62-3.67(m,2H),3.54(s,3H), 3.33-3.37(m,2H),3.02(s,3H),2.04(s,6H),1.45(s,6H)。
实施例11：N-(2,2-二氟乙基)-7-(2-(4-氟-2,6-二甲基苯氧基)-5-(2-羟基丙基-2-基)苯基)-5-甲基-4-氧-4,5-二氢-1H-吡咯[3,2-c]吡啶-2-酰胺
Figure PCTCN2020078963-appb-000091
以2,2-二氟乙胺为原料，操作同实施例9。LC-MS(M+H)528.0。 1H-NMR(DMSO-d6,400MHz)：δ11.09(s,1H),8.73(t,J＝5.6Hz,1H),7.50(d,J＝2.0Hz,1H),7.47(s,1H),7.35-7.38(m,2H),6.96(d,J＝9.2Hz,2H),6.32(d,J＝8.4Hz,1H),5.95-6.23(m,1H),4.98(s,1H),3.61-3.71(m,2H),3.55(s,3H),2.03(s,6H),1.45(s,6H)。
实施例12：N-(环丙甲基)-7-(2-(4-氟-2,6-二甲基苯氧基)-5-(2-羟基丙基-2-基)苯基)-5-甲基-4-氧-4,5-二氢-1H-吡咯[3,2-c]吡啶-2-酰胺
Figure PCTCN2020078963-appb-000092
以环丙甲基胺为原料，操作同实施例9。LC-MS(M+H)518.0。 1H-NMR(DMSO-d6,400MHz)：δ10.93(s,1H),8.47(t,J＝5.6Hz,1H),7.50(d,J＝2.0Hz,1H),7.46(s,1H),7.37(dd,J＝2.4,8.8Hz,1H),7.29(d,J＝1.6Hz,1H),6.97(d,J＝9.2Hz,2H),6.33(d,J＝8.8Hz,1H),5.00(s,1H),3.55(s,3H),3.12(d,J＝6.0Hz,2H),2.04(s,6H),1.45(s,6H),0.81-0.86(m,1H),0.40-0.45(m,2H),0.18-0.22(m,2H)。
实施例13：7-(2-(4-氟-2,6-二甲基苯氧基)-5-(2-羟基丙基-2-基)苯基)-N-异丙基-5-甲基-4-氧-4,5-二氢-1H-吡咯[3,2-c]吡啶-2-酰胺
Figure PCTCN2020078963-appb-000093
以异丙基胺为原料，操作同实施例9。LC-MS(M+H)506.0。 1H-NMR(DMSO-d6,400MHz)：δ10.90(s,1H),8.17(d,J＝7.6Hz,1H),7.51(d,J＝2.0Hz,1H),7.47(s,1H),7.38(dd,J＝2.0,8.4Hz,1H),7.28(d,J＝2.0Hz,1H),6.98(d,J＝9.2Hz,2H),6.33(d,J＝8.8Hz,1H),5.02(s,1H),4.01-4.07(m,1H),3.51(s,3H),2.03(s,6H),1.45(s,6H),1.14(d,J＝6.8Hz,6H)。
实施例14：7-(2-(4-氟-2,6-二甲基苯氧基)-5-(2-羟基丙基-2-基)苯基)-5-甲基-4-氧-N-(2,2,2-三氟乙基)-4,5-二氢-1H-吡咯[3,2-c]吡啶-2-酰胺
Figure PCTCN2020078963-appb-000094
以2,2,2-三氟乙胺为原料，操作同实施例9。LC-MS(M+H)546.0。 1H-NMR(DMSO-d6/D 2O,400MHz)：δ7.50(d,J＝2.4Hz,2H),7.36-7.41(m,2H),6.97(d,J＝9.2Hz,2H),6.33(d,J＝8.4Hz,1H),4.07-4.11(m,2H),3.56(s,3H),2.02(s,6H),1.46(s,6H)。
实施例15：N-(氰基甲基)-7-(2-(4-氟-2,6-二甲基苯氧基)-5-(2-羟基丙基-2-基)苯基)-5-甲基-4-氧-4,5-二氢-1H-吡咯[3,2-c]吡啶-2-酰胺
Figure PCTCN2020078963-appb-000095
以2-氨基乙腈为原料，操作同实施例9。LC-MS(M+H)503.0。 1H-NMR(CD 3OD,400MHz)：δ7.60(d,J＝2.4Hz,1H),7.50(s,1H),7.40-7.42(m,2H),6.82(d,J＝8.8Hz,2H),6.43(d,J＝8.4Hz,1H),4.32(s,2H),3.70(s,3H),2.07(s,6H),1.56(s,6H)。
实施例16：N-环丙基-7-(2-(4-氟-2,6-二甲基苯氧基)-5-(2-羟基丙基-2-基)苯基)-5-甲基-4-氧-4,5-二氢-1H-吡咯[3,2-c]吡啶-2-酰胺
Figure PCTCN2020078963-appb-000096
以环丙基胺为原料，操作同实施例9。LC-MS(M+H)504.0。 1H-NMR(CD 3OD,400MHz)：δ7.60(d,J＝2.4Hz,1H),7.48(s,1H),7.41(dd,J＝2.4,8.8Hz,1H),7.35(s,1H),6.83(d,J＝8.8Hz,2H),6.44(d,J＝8.8Hz,1H),3.69(s,3H),2.79-2.82(m,1H),2.08(s,6H),1.56(s,6H),0.77-0.80(m,2H),0.60-0.64(m,2H)。
实施例17：2-(吖丁啶-1-羰基)-7-(2-(4-氟-2,6-二甲基苯氧基)-5-(2-羟基丙基-2-基)苯基)-5-甲基-1,5-二氢-4H-吡咯[3,2-c]吡啶-4-酮
Figure PCTCN2020078963-appb-000097
以吖丁啶为原料，操作同实施例9。LC-MS(M+H)504.0。 1H-NMR(CD 3OD,400MHz)：δ7.60(d,J＝2.4Hz,1H),7.51(s,1H),7.41(dd,J＝2.4,8.4Hz,1H),7.14(s,1H),6.83(d,J＝8.8Hz,2H),6.43(d,J＝8.8Hz,1H),4.61(t,J＝7.6Hz,2H),4.20(t,J＝7.6Hz,2H),3.70(s,3H),2.41-2.47(m,2H),2.08(s,6H),1.56(s,6H)。
实施例18：N-(3,3-二氟环丁基)-7-(2-(4-氟-2,6-二甲基苯氧基)-5-(2-羟基丙基-2-基)苯基)-5-甲基-4-氧-4,5-二氢-1H-吡咯[3,2-c]吡啶-2-酰胺
Figure PCTCN2020078963-appb-000098
以3,3-二氟环丁胺为原料，操作同实施例9。LC-MS(M+H)554.0。 1H-NMR(CD 3OD,400MHz)：δ7.60(d,J＝2.0Hz,1H),7.49(s,1H),7.39-7.43(m,2H),6.83(d,J＝9.2Hz,2H),6.44(d,J＝8.8Hz,1H),4.30-4.35(m,1H),3.70(s,3H),2.92-3.01(m,2H),2.66-2.74(m,2H),2.07(s,6H),1.56(s,6H)。
实施例19：2-(3,3-二氟吖丁啶-1-羰基)-7-(2-(4-氟-2,6-二甲基苯氧基)-5-(2-羟基丙基-2-基)苯基)-5-甲基-1,5-二氢-4H-吡咯[3,2-c]吡啶-4-酮
Figure PCTCN2020078963-appb-000099
以3,3-二氟吖丁啶为原料，操作同实施例9。LC-MS(M+H)540.0。 1H-NMR(CD 3OD,400MHz)：δ7.60(d,J＝2.0Hz,1H),7.52(s,1H),7.41(dd,J＝2.4,8.8Hz,1H),7.16(s,1H),6.83(d,J＝8.8Hz,2H),6.43(d,J＝8.8Hz,1H),4.40-5.00(m,4H),3.70(s,3H),2.08(s,6H),1.56(s,6H)。
实施例20：N-(1,3-二氟丙基-2-基)-7-(2-(4-氟-2,6-二甲基苯氧基)-5-(2-羟基丙基-2-基)苯基)-5-甲基-4-氧-4,5-二氢-1H-吡咯[3,2-c]吡啶-2-酰胺
Figure PCTCN2020078963-appb-000100
以1,3-二氟丙基-2-胺盐酸盐为原料，操作同实施例9。LC-MS(M+H)542.0。
对比化合物1：N-乙基-4-(2-(4-氟-2,6-二甲基苯氧基)-5-(2-羟基丙基-2-基)苯基)-6-甲基-7-氧代-6,7-二氢-1H-吡咯[2,3-c]吡啶-2-酰胺
Figure PCTCN2020078963-appb-000101
以中间体B为原料，参照专利WO2017177955A1中实施例的合成方法制备得到对比化合物1。LC-MS(M+H)492.1。 1H-NMR(CDCl 3,400MHz)：δ10.89(s,1H),7.59(s,1H),7.17(s,1H),6.76-6.78(m,4H),6.40(d,J＝8.8Hz,1H),5.46(bs,1H),3.73(s,3H),3.48-3.51(m,2H),2.07(s,6H),1.61(s,6H),1.25(t,J＝7.8Hz,3H)。
测试例1：BRD4AlphaScreen测定
(1)按照ReactionBiologyCorp.(RBC)公司的试剂盒要求配制1×Assay buffer。(2)化合物浓度梯度的配制：受试化合物测试终浓度均为10μM起始，3倍稀释10个浓度，每个浓度设置单孔测试。阳性对照化合物(+)-JQ-1测试终浓度为1μM起始，3倍稀释10个浓度，每个浓度设置复孔测试。在384孔Source板中梯度稀释成相应1000倍终浓度的溶液，然后用Echo550转移20nL到384孔反应板中待测。Max孔中转移20nL的100％DMSO，Min孔中转移20nL最高浓度的阳性化合物。(3)用1×反应溶液配制4×蛋白溶液。(4)在各孔中加5μL的4×蛋白溶液，1000rpm离心1min，室温孵育15分钟。(5)用1×反应溶液配制4×多肽溶液。(6)反应板各孔中加入5μL的4×多肽溶液，1000rpm离心1min。(7)加入10μL检测液，1000rpm离心60秒，轻轻振荡混匀后，室温孵育60分钟。(8)用EnVision读数。(9)采用分析软件GraphPad Prism 5拟合量效曲线，从而得出化合物对蛋白结合抑制的IC50值。(具体数值见表一)
表一、化合物对BRD4-BD1/BD2抑制的IC 50值
Figure PCTCN2020078963-appb-000102
结果:本发明提供的实施例1-实施例20，其对BRD4-BD 2的抑制活性IC 50值均小于10nM，大部分实施例的抑制活性IC 50小于1nM，显示了较对比化合物1更强的抑制活性；而部分实施例对BRD4-BD 1的抑制活性也显示了较对比化合物更强的活性；同时，本发明实施例化合物保持了BRD4- BD 2相对的选择性，选择性倍数从10倍至400倍以上。
测试例2：实施例化合物对MV4-11细胞增殖抑制活性的测试
具体实验步骤：1)Day 0:96接种细胞胰酶消化细胞并悬浮于细胞培养液中，利用细胞自动计数仪检测细胞密度并用培养液稀释细胞到合适的密度，96孔板中加入100μL细胞悬液，无细胞培养基作为对照孔，置于37℃，5％CO2的细胞培养箱孵育过夜；2)Day 1:加药处理细胞待测化合物共测试8个浓度，3倍稀释，10μM为待测化合物的起始检测浓度。具体步骤：配置200x化合物母液，利用培养基稀释化合物至3x终浓度即加入3μL 200x化合物到197μL培养液中，96孔板中的细胞每孔加入50μL稀释好的化合物，置于37℃，5％CO 2的细胞培养箱孵育72h；3)Day 4:细胞活力检测细胞96孔板先平衡到室温，每孔加入40μL的
Figure PCTCN2020078963-appb-000103
试剂，摇床上混合2分钟使细胞充***解，室温孵育10分钟稳定发光信号，Envision酶标仪读取发光值；4)数据处理使用GraphPad Prism 5.0软件分析数据，利用非线性S曲线回归来拟合数据得出剂量-效应曲线，并由此计算IC 50值。抑制率％＝(DMSO处理细胞孔-化合物处理细胞孔)/(DMSO处理细胞孔-无细胞培养基孔)x 100。IC 50值采用酶标仪随机附带软件以四参数法回归求得。(具体数值见表二)
表二、实施例化合物对MV 4-11细胞增殖抑制活性IC 50值
编号 MV4-11IC 50/nM 编号 MV4-11IC 50/nM 编号 MV4-11IC 50/nM
1 2.3 2 64.0 3 <1.5
4 <1.5 5 <1.5 6 10.2
7 <1.5 8 <1.5 9 19.8
10 19.8 11 20.4 12 12.7
13 6.6 14 31.3 15 33.3
16 7.95 17 248.5 18 10.6
19 146.7 20 4.8 对比化合物1 32.0
结果:本发明提供的部分实施例1-实施例20对MV 4-11细胞的增值抑制活性，IC 50值均小于500nM，部分实施例化合物的抑制活性IC 50值甚至小于10nM,显示了较对比化合物更强的细胞增殖抑制活性。
测试例3：实施例化合物对不同酶抑制活性的测试
采用测试例1类似的BRD AlfaScreening方法以及激酶抑制剂常规测试方法，将本发明部分实施例化合物对不同BRD如BRD2BD1/2，BRD3BD1/2和BRD-T BD1/2酶、HDAC、EZH2、LSD1、G9a等以及不同蛋白激酶如EGFR、VEGFR、PDGFR、FGFR、RET，MET，Src，Lyn、Syk、MEK、CDK、RAF等的抑制活性也进行了测试，部分实施例化合物如实施例1、11、18等显示了较好的BRD-BD2选择性和激酶靶点选择性，选择性大于100倍。
测试例4：实施例化合物对不同细胞株增殖抑制活性的测试
采用测试例2及文献类似的方法测试了部分实施例化合物对不同细胞株如LNCAP(+R1881)、SKM-1、22RV1、DU145、MOLM13、MDA-PCA-2b、KASUMI 1、THP-1、KG-1、IEC6、H1299等的 增殖抑制活性。部分实施例如实施例1、实施例11、实施例18等对大部分AML细胞株和***癌细胞株显示了较好的增殖抑制活性，抑制活性IC 50均小于1000nM，部分细胞株甚至小于100nM，如LNCAP、SKM-1、MOLM13、KASUMI 1、THP-1、KG-1等；而对IEC6和H1299细胞株的增殖抑制活性IC 50大于1000nM,显示了较高的细胞增殖抑制选择性。
测试例5：部分实施例化合物的ADME测试
(1)代谢稳定性试验：用体系为150μL的肝微粒体(终浓度0.5mg/mL)进行代谢稳定性温孵，体系含NADPH(终浓度1mM)、1μM受试化合物和阳性对照咪达***或阴性对照阿替洛尔，分别在0min、5min、10min和30min用含替硝唑的乙腈终止反应，涡旋10min，15000rmp离心10min，取50μL上清于96孔板中进样。通过测定原药的相对减少量计算化合物代谢稳定性。(具体数值如表三所示)
(2)直接抑制试验(DI试验)：用体系为100μL的人肝微粒体(终浓度0.2mg/mL)进行直接抑制温孵，体系含NADPH(终浓度1mM)、10μM化合物、阳性抑制剂cocktail(酮康唑10μM，奎尼丁10μM，磺胺苯吡唑100μM，α-萘黄酮10μM，反苯环丙胺1000μM)、阴性对照(0.1％DMSO的BPS)和混合探针底物(咪达***10μM、睾酮100μM、右美沙芬10μM、双氯芬酸20μM、非那西丁100μM，美芬妥英100μM)，温孵20min后终止反应。通过测定代谢物的相对生成量计算酶相对活性。
表三、实施例化合物对大鼠、小鼠、犬肝微粒体稳定性数值
编号 小鼠微粒体T 1/2(min) 大鼠微粒体T 1/2(min) 犬微粒体T 1/2(min)
实施例1 170 168 195
实施例11 39 77 403
实施例18 76 83 400
对比化合物1 19 62 68
实施例化合物1、11、18对大鼠、小鼠、犬的肝微粒体代谢稳定性与对照化合物1相比，各种属的微粒体稳定均有显著提升，特别是小鼠和犬的微粒体稳定性比对照化合物1大幅提高；并且实施例1、18对主要代谢酶CYP1A2、2C8、2C19、3A4等的抑制IC 50均大于15uM，显示了较高的成药性。
测试例6：实施例化合物在大鼠、小鼠的体内药代动力学参数测试
6只雄性SPF级SD大鼠或Balb c小鼠(上海西普尔-必凯实验动物)分别分成两组，受试化合物配置成合适溶液或混悬液；一组静脉注射给药，一组口服给药。经颈静脉穿刺采血，每个样品采集约0.2mL/时间点，肝素钠抗凝，采血时间点如下：给药前及给药后5、15和30min，1、2、4、6、8和24h；血液样本采集后置于冰上，离心分离血浆(离心条件：8000转/分钟，6分钟，2-8℃)，收集的血浆分析前存放于-80℃。血浆样品采用LC-MS/MS进行分析。
根据药物的血药浓度数据，使用药代动力学计算软件WinNonlin5.2非房室模型分别计算供试品的药代动力学参数AUC 0-t、AUC 0-∞、MRT 0-∞、C max、T max、T 1/2和V d等参数及其平均值和标准差。此外，生物利用度(F)将通过下面的公式进行计算。
Figure PCTCN2020078963-appb-000104
对于浓度低于定量下限的样品，在进行药代动力学参数计算时，在达到C max以前取样的样品应以零值计算，在达到C max以后取样点样品应以无法定量(BLQ)计算。
结果：本发明部分实施例化合物具有良好的动物体内药代动力学性质，如实施例1，实施例18在5mg/kg剂量下灌胃给药的小鼠PK参数优异，Cmax均大于1.5uM,T 1/2大于3小时，AUC(hr*nM)大于5000。实施例化合物1，18对小鼠的生物利用度均大于40％，优于对比化合物1(对比化合物1在小鼠体内的生物利用度为25％)。实施例1、实施例18在10mg/kg剂量下灌胃给药的比格犬的PK参数优异，Cmax均2.0uM,T 1/2大于2小时，AUC(hr*nM)大于15000。
测试例7：实施例化合物对裸小鼠MV 4-11移植瘤生长抑制的测试
取生长旺盛期的瘤组织剪切成1.5mm 3左右，在无菌条件下，接种于裸小鼠右侧腋窝皮下。裸小鼠皮下移植瘤用游标卡尺测量移植瘤直径，待肿瘤平均体积至130mm 3左右将动物随机分组。实施例化合物或对比化合物1(用含1％Tween80的注射用水配置到所需浓度后待用)以给定剂量每天口服给药，连续给药三周，溶剂对照组给等量溶剂。整个实验过程中，每周2次测量移植瘤直径，同时称量小鼠体重。肿瘤体积(tumor volume,TV)的计算公式为：TV＝1/2×a×b 2，其中a、b分别表示长、宽。根据测量的结果计算出相对肿瘤体积(relative tumor volume，RTV)，计算公式为：RTV＝Vt/V0。其中V0为分笼给药时(即d0)测量所得肿瘤体积，Vt为每一次测量时的肿瘤体积。抗肿瘤活性的评价指标为1)相对肿瘤增殖率T/C(％)，计算公式如下：T/C(％)＝(TRTV/CRTV)×100％，TRTV：治疗组RTV；CRTV：阴性对照组RTV；2)肿瘤体积增长抑制率GI％，计算公式如下：GI％＝[1-(TVt-TV0)/(CVt-CT0)]×100％，TVt为治疗组每次测量的瘤体积；TV0为治疗组分笼给药时所得瘤体积；CVt为对照组每次测量的瘤体积；CV0为对照组分笼给药时所得瘤体积；3)瘤重抑制率，计算公式如下：瘤重抑制率％＝(Wc-W T)/Wc×100％，Wc：对照组瘤重，W T：治疗组瘤重。
结果：本发明部分实施例化合物显示了优异的动物体内抑瘤效果，如实施例1，实施例18在较低剂量下如10mg/kg-30mg/kg剂量下，每天一次，连续灌胃给药21天，显示了较好的抑制肿瘤生长的效果,其T/C比小于40％；在较高剂量下，如50mg/kg-100mg/kg剂量下，抑瘤效果明显，且实验动物均能较好耐受。同等剂量下，实施例化合物1，18对裸小鼠移植瘤生长抑制作用明显，抑瘤效果优于对比化合物1(15mpk剂量下，实施例1和实施例18的抑瘤率82％，对比化合物1的抑瘤率约60％)。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (15)

  1. 一种如通式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，
    Figure PCTCN2020078963-appb-100001
    式中：
    R1独立地选自氢、C1-C8烷基、3-8元环烃基或杂环烷基、烷氧基烷基、烷氨基烷基、杂环基烷基、芳环基烷基等；R2独立地选自氢、C1-C6的烷基；
    X1、X2分别独立地选自CH或NH；
    R3、R5分别独立地选自氢、卤素、C1-C6的烷基；
    R4、R6、R7分别独立地选自氢、卤素、氰基、硝基、烯基、炔基、酰胺基、醚或硫醚、取代或未取代的C1-C6的烷基、3-8元环烃基或杂环烷基、5-10元的芳基或杂芳基、烷氧基、取代或未取代的氨基、烷基砜基、烷基亚砜基、烷基磺酰胺基、烷基亚磺酰胺基、脲、磺酰脲、亚磺酰脲基等；
    或者R6和R7之间可以通过碳原子或者杂原子形成3-8元的饱和、不饱和或者部分不饱和的环系；
    上述任一基团上的一个或多个氢原子可以被选自下组的取代基取代：包括但不限于氘、卤素、羟基、氨基或环氨基、氰基、硝基、砜基或亚砜基、C1-C8烷基、3-8元环烷基或杂环烷基、C1-C8烷氧基或烷硫基、C1-C8烷氨基、烯基、炔基、酰基或磺酰基、脲或磺酰脲、5～8元芳基或杂芳基；其中，所述的杂芳基包含1-3个选自下组的杂原子：N、O、P或S，所述的杂环烷基包含1-3个选自下组的杂原子：N、O、P或S，所述的环系包含螺环、桥环、稠环、并环等饱和或部分不饱和的环系。
  2. 如权利要求1所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，其特征在于：其为通式(II)所示的化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药：
    Figure PCTCN2020078963-appb-100002
    其中，R8、R9独立地选自氢、卤素、C1-C6烷基、3-8元环烷基或杂环烷基，或者R8和R9通过碳原子或者杂原子相互之间形成3-8元的饱和、不饱和或者部分不饱和的环系；R10选自氢、C1-C10烷基、3-10元环烷基或杂环烷基、5-10元芳基或杂芳基；L选自O、S、NH等；另外R1、R2、R3、R4、R5、R6如权利要求1中所定义。
  3. 如权利要求1、2所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，其特征在于：
    R1优选自取代或未取代的C2-C8的烷基、取代或未取代的3-8元的环烷基或杂环烷基；
    R2优选自氢、C1-C6的烷基；或者R1和R2之间形成4-8元的含氮杂环；进一步优选自取代或未取代的乙基、乙氧基乙基等；
    R3、R5、R6分别独立地优选自氢、氟、C1-C6的烷基；
    R4优选自C1-C6的砜基、C1-C6的磺酰胺基、C1-C6的亚砜基、C1-C6的亚磺酰胺基、C1-C6的磺酰亚胺基、C1-C6的取代烷基；
    R8和R9分别独立地优选自氢、C1-C3的烷基或者相互之间形成3-6元的环系；
    R10优选自氢、C1-C8的烷基、3-8元的环烷基和杂环烷基、5-8元的芳基和杂芳基；进一步优选为
    Figure PCTCN2020078963-appb-100003
    其中Rd选自氢、卤素、氰基、砜基、亚砜基、C1-C3的烷基或烷氧基，并且Rd跟苯环或环己烷环或另一个Rd取代基之间可以形成3-8元的饱和或部分不饱和的环系；n＝0～5，优选自2，3。
  4. 如权利要求1所述的式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，其特征在于：
    其中，X1为CH；X2为NH；
    R1为氢、C1-C8烷基、3-8元环烷基、3-8元杂环烷基、3-8元环烷基取代的C1-C8烷基、3-8元杂环烷基取代的C1-C8烷基或
    Figure PCTCN2020078963-appb-100004
    所述的3-8元杂环烷基和3-8元杂环烷基取代的C1-C8烷基中的3-8元杂环烷基中，杂原子选自N、O、S、-S(＝O)-和-S(＝O) 2-中的一种或多种，杂原子数为1、2或3个；所述的C1-C8烷基、3-8元环烷基、3-8元杂环烷基、3-8元环烷基取代的C1-C8烷基、3-8元杂环烷基取代的C1-C8烷基和
    Figure PCTCN2020078963-appb-100005
    任选被一个或多个取代基取代的，所述的取代基独立地选自：卤素、氰基、羟基、＝O、C1-C6烷基、C1-C6烷基-O-、C1-C6烷基-(SO 2)-和
    Figure PCTCN2020078963-appb-100006
    当取代基为多个时，相同或不同；
    Ra和Rb独立地为氢或C1-C8烷基；
    L1为连接键、-(C1-C8烷基)-、-(C2-C6炔基)-、或-(C1-C6烷基)-(CH 2OCH 2) m1-(C1-C6烷基)-；
    m1为1、2、3或4；
    L2为连接键、-O-、
    Figure PCTCN2020078963-appb-100007
    W为-CH 2-或-C(＝O)-；
    R2为氢或C1-C6的烷基；
    或者，R1和R2连接，与相连的N一起形成：3-8元的杂环烷基、或被一个或多个卤素取代的3-8元的杂环烷基；所述的3-8元的杂环烷基和被一个或多个卤素取代的3-8元的杂环烷基中的杂原子除所述的N，还包括0至2个选自N、O、S、-S(＝O)-和-S(＝O) 2-的杂原子；当取代基为多个时，相同或不同；
    R3和R5独立地为氢、卤素或C1-C6的烷基；
    R4、R6和R7独立地为氢或-L-R10；
    L独立地为连接键、-O-、-(SO 2)-或-(SO 2)-NH-；
    R10独立地为C1-C6的烷基、6至10元芳基、被一个或多个取代基取代的C1-C6的烷基、或被一个或多个取代基取代的6至10元芳基；所述的被一个或多个取代基取代的C1-C6的烷基和被一个或多个取代基取代的6至10元芳基中的取代基独立地为卤素、羟基、氰基或C1-C6的烷基；当取代基为多个时，相同或不同；
    或者，R6和R7连接，与相连的碳原子一起形成：6元杂环烷基、或被一个或多个取代基取代的6元杂环烷基，所述的6元的杂环烷基中的杂原子选自N、O、S、-S(＝O)-和-S(＝O) 2-中的一种或多种，杂原子数为1、2或3个；所述的取代基独立地为C1-C6的烷基或＝O；当取代基为多个时，相同或不同。
  5. 如权利要求4所述的式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，其特征在于：
    R1为C1-C8烷基、3-8元环烷基、3-8元杂环烷基、3-8元环烷基取代的C1-C8烷基或
    Figure PCTCN2020078963-appb-100008
    或者，R1和R2连接，与相连的N一起形成：3-8元的杂环烷基、或被一个或多个卤素取代的3-8元的杂环烷基；
    和/或，R1中，所述的取代基独立地选自：卤素、氰基、羟基、＝O、C1-C6烷基、C1-C6烷基-O-和C1-C6烷基-(SO 2)-；
    和/或，m1为3；
    和/或，L2为连接键、
    Figure PCTCN2020078963-appb-100009
    和/或，R3为氢；
    和/或，R5为氢；
    和/或，R6为氢；
    和/或，L独立地为连接键、-O-或-(SO 2)-；
    和/或，R4为-L-R10；
    和/或，R7为-L-R10；
    和/或，当R1为C1-C8烷基、所述的C1-C8烷基被一个或多个取代基取代时，所述的取代基选自卤素、氰基、C1-C6烷基、C1-C6烷基-O-和C1-C6烷基-(SO 2)-；
    和/或，当R1为3-8元环烷基、3-8元环烷基取代的C1-C8烷基，所述的3-8元环烷基和3-8元环烷基取代的C1-C8烷基独立地被一个或多个取代基取代时，所述的取代基选自卤素、羟基和C1-C6烷基；
    和/或，当R1为3-8元环烷基取代的C1-C8烷基、所述的3-8元环烷基取代的C1-C8烷基被一个或多个取代基取代时，所述的取代基选自卤素和羟基。
  6. 如权利要求5所述的式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，其特征在于：所述的式I所示的吡咯酰胺并吡啶酮类化合物为如下方案一、方案二或方案三；
    方案一：X1为CH；X2为NH；
    R1为C1-C8烷基、3-8元环烷基、3-8元杂环烷基、3-8元环烷基取代的C1-C8烷基、或
    Figure PCTCN2020078963-appb-100010
    所述的3-8元杂环烷基中，杂原子选自N、O、S、-S(＝O)-和-S(＝O) 2中的一种或多种，杂原子数为1、2或3个；所述的C1-C8烷基、3-8元环烷基、3-8元环烷基取代的C1-C8烷基和
    Figure PCTCN2020078963-appb-100011
    任选被一个或多个取代基取代，所述的取代基独立地选自：卤素、氰基、羟基、＝O、C1-C6烷基、C1-C6烷基-O-和C1-C6烷基-(SO 2)-；当取代基为多个时，相同或不同；
    L1为连接键、-(C1-C8烷基)-、-(C2-C6炔基)-、-(C1-C6烷基)-(CH 2OCH 2) m1-(C1-C6烷基)-；
    m1为1、2、3或4；
    L2为连接键、
    Figure PCTCN2020078963-appb-100012
    W为-CH 2-或-C(＝O)-；
    R2为氢；
    或者，R1和R2连接，与相连的N一起形成：3-8元的杂环烷基、或被一个或多个卤素取代的3-8元的杂环烷基；所述的3-8元的杂环烷基和被一个或多个卤素取代的3-8元的杂环烷基中的杂原子 除所述的N，还包括0至2个选自N、O、S、-S(＝O)-和-S(＝O) 2的杂原子；
    R3和R5独立地为氢、卤素或C1-C6的烷基；
    R6为氢；
    R4和R7独立地为氢或-L-R10；
    L独立地为连接键、-O-或-(SO 2)-；
    R10独立地为C1-C6的烷基、6至10元芳基、被一个或多个取代基取代的C1-C6的烷基、或被一个或多个取代基取代的6至10元芳基；所述的被一个或多个取代基取代的C1-C6的烷基和被一个或多个取代基取代的6至10元芳基中的取代基独立地为卤素、羟基、氰基或C1-C6的烷基；当取代基为多个时，相同或不同；
    或者，R6和R7连接，与相连的碳原子一起形成：6元杂环烷基、或被一个或多个取代基取代的6元杂环烷基，所述的取代基独立地为C1-C6的烷基或＝O；
    方案二：X1为CH；X2为NH；
    R1为C1-C8烷基、3-8元环烷基；所述的C1-C8烷基、3-8元环烷基任选被一个或多个取代基取代；
    R2、R3、R5和R6独立地为氢；
    R4和R7独立地为氢或-L-R10；
    或者，R6和R7连接，与相连的碳原子一起形成：6元杂环烷基、或被一个或多个取代基取代的6元杂环烷基，所述的取代基独立地为C1-C6的烷基或＝O；
    方案三：X1为CH；X2为NH；
    R1独立地为C1-C8烷基或
    Figure PCTCN2020078963-appb-100013
    R2、R3、R5和R6独立地为氢；
    R4和R7独立地为氢或-L-R10；
    或者，R6和R7连接，与相连的碳原子一起形成：6元杂环烷基、或被一个或多个取代基取代的6元杂环烷基，所述的取代基独立地为C1-C6的烷基或＝O。
  7. 如权利要求4-6中任一项所述的式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，其特征在于：
    当R1为C1-C8烷基、3-8元环烷基取代的C1-C8烷基或3-8元杂环烷基取代的C1-C8烷基时，所述的C1-C8烷基、3-8元环烷基取代的C1-C8烷基和3-8元杂环烷基取代的C1-C8烷基中的C1-C8烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；例如甲基、乙基或异丙基；
    和/或，当R1为3-8元环烷基或3-8元环烷基取代的C1-C8烷基时，所述的3-8元环烷基和3-8元环烷基取代的C1-C8烷基中的3-8元环烷基独立地为环丙基、环丁基、环戊基及环己基；例如环丙 基、环丁基或环戊基；
    和/或，当R1为3-8元杂环烷基或3-8元杂环烷基取代的C1-C8烷基时，所述的3-8元杂环烷基和3-8元杂环烷基取代的C1-C8烷基中的3-8元杂环烷基独立地为3-6元杂环烷基，其中杂原子选自N、O、S、-S(＝O)-和-S(＝O) 2-中的一种或多种，杂原子数为1或2个；例如
    Figure PCTCN2020078963-appb-100014
    和/或，当R1中所述的取代基为C1-C6烷基、C1-C6烷基-O-或C1-C6烷基-(SO 2)-时，所述的C1-C6烷基、C1-C6烷基-O-和C1-C6烷基-(SO 2)-中的C1-C6烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；例如甲基或乙基；
    和/或，当Ra和/或Rb独立地为C1-C8烷基时，所述的C1-C8烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基或正己基；例如甲基；
    和/或，当L1为-(C1-C8烷基)-时，所述的C1-C8烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基或正己基；又例如正丁基、正戊基或正己基；
    和/或，当L1为-(C2-C6炔基)-时，所述的C2-C6炔基为乙炔基、
    Figure PCTCN2020078963-appb-100015
    Figure PCTCN2020078963-appb-100016
    又例如
    Figure PCTCN2020078963-appb-100017
    和/或，当L1为-(C1-C6烷基)-(CH 2OCH 2) m1-(C1-C6烷基)-时，所述的C1-C6烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；例如甲基、乙基或正丙基；
    和/或，m1为2或3；
    和/或，当R2为C1-C6的烷基时，所述的C1-C6的烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；例如甲基、乙基或异丙基；
    和/或，当R1和R2连接，与相连的N一起形成：3-8元的杂环烷基、或被一个或多个卤素取代的3-8元的杂环烷基时，所述的3-8元的杂环烷基、或被一个或多个卤素取代的3-8元的杂环烷基中的3-8元的杂环烷基独立地为3-6元的杂环烷基，其中的杂原子为所述的N；例如
    Figure PCTCN2020078963-appb-100018
    和/或，当R10独立地为C1-C6的烷基、或被一个或多个取代基取代的C1-C6的烷基时，所述的C1-C6的烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；例如甲基或乙基；
    和/或，当R10独立地为6至10元芳基、或被一个或多个取代基取代的6至10元芳基时，所述的6至10元芳基、或被一个或多个取代基取代的6至10元芳基中的6至10元芳基独立地为苯基或萘基；
    和/或，当R10中所述的取代基为C1-C6的烷基时，所述的取代基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；例如甲基或乙基；
    和/或，当R6和R7连接，与相连的碳原子一起形成：6元杂环烷基、或被一个或多个取代基取代的6元杂环烷基时，所述的6元杂环烷基、被一个或多个取代基取代的6元杂环烷基中6元杂环烷 基独立地为
    Figure PCTCN2020078963-appb-100019
    和/或，当R6和R7连接，与相连的碳原子一起形成：6元杂环烷基、或被一个或多个取代基取代的6元杂环烷基，所述的取代基独立地为C1-C6的烷基时，所述的C1-C6的烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；例如甲基或乙基。
  8. 如权利要求7所述的式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，其特征在于：
    -L1-L2-为
    Figure PCTCN2020078963-appb-100020
    Figure PCTCN2020078963-appb-100021
    和/或，
    Figure PCTCN2020078963-appb-100022
    和/或，R4为
    Figure PCTCN2020078963-appb-100023
    和/或，R7为
    Figure PCTCN2020078963-appb-100024
    和/或，当R6和R7连接，与相连的碳原子一起形成：6元杂环烷基、或被一个或多个取代基取代的6元杂环烷基时，
    Figure PCTCN2020078963-appb-100025
    为
    Figure PCTCN2020078963-appb-100026
    和/或，所述的式I所示的吡咯酰胺并吡啶酮类化合物如式II-1或II-2所示：
    Figure PCTCN2020078963-appb-100027
    其中，R1、R2、R3、R4、R5、R6、L和R10如上文 所定义；R8和R9独立地为C1-C6的烷基。
  9. 如权利要求8所述的式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，其特征在于：
    R1为乙基、异丙基、
    Figure PCTCN2020078963-appb-100028
    环丙基、环戊基、
    Figure PCTCN2020078963-appb-100029
    Figure PCTCN2020078963-appb-100030
    和/或，当R1和R2连接，与相连的N一起形成：3-8元的杂环烷基、或被一个或多个卤素取代的3-8元的杂环烷基时，
    Figure PCTCN2020078963-appb-100031
    为
    Figure PCTCN2020078963-appb-100032
    和/或，当
    Figure PCTCN2020078963-appb-100033
    为
    Figure PCTCN2020078963-appb-100034
    时，为
    Figure PCTCN2020078963-appb-100035
    和/或，当
    Figure PCTCN2020078963-appb-100036
    为
    Figure PCTCN2020078963-appb-100037
    时，为
    Figure PCTCN2020078963-appb-100038
    Figure PCTCN2020078963-appb-100039
  10. 如权利要求1或4所述的式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，其特征在于：
    所述的如式I所示的吡咯酰胺并吡啶酮类化合物选自如下任一结构：
    Figure PCTCN2020078963-appb-100040
    Figure PCTCN2020078963-appb-100041
  11. 一种如权利要求1-10中任一项所述的如式I所示的吡咯酰胺并吡啶酮类化合物的制备方法，其特征在于，其包括方案1或方案2；
    方案1，其包括如下步骤：在溶剂中，在碱和缩合试剂存在下，将式所示D化合物与R1R2NH进行如下所示的缩合反应，得到所述的如式I所示的吡咯酰胺并吡啶酮类化合物即可；
    Figure PCTCN2020078963-appb-100042
    方案2，其包括如下步骤：在溶剂中，在碱和过渡金属催化剂存在下，将如式所示A’化合物和如式B所示的化合物进行如下所示的金属催化偶联反应，得到所述的如式I所示的吡咯酰胺并吡啶酮类化合物即可；
    Figure PCTCN2020078963-appb-100043
    其中，X1、X2、R1、R2、R3、R4、R5、R6和R7如权利要求1-10中任一项所定义。
  12. 一种药物组合物，其包含如权利要求1-10中任一项所述的如式I所示的吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，和药学上可接受的载体。
  13. 一种如权利要求1-10中任一项所述的如式I所示吡咯酰胺并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药、或者如权利要求12所述的药物组合物在制备BRD和/或c-Myc抑制剂、治疗或预防与BRD和/或c-Myc蛋白活性或表达量相关的疾病的药物、或治疗或预防肿瘤和/或炎性疾病的药物中的应用；
    所述的肿瘤选自非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、乳腺癌、***癌、肝癌、皮肤癌、胃癌、肠癌、胆管癌、脑癌、白血病、淋巴癌、纤维瘤、肉瘤、基底细胞癌、胶质瘤、肾癌、黑色素瘤、骨癌、甲状腺癌、鼻咽癌、胰腺癌等；所述的免疫性疾病和炎症性疾病独立地选自移植器官的排斥反应、痛风、鼻炎、脱发、阿尔茨海默氏病、阑尾炎、动脉粥样硬化、哮喘、关节炎、过敏性皮炎、贝切特氏病、大疱性皮肤病、胆囊炎、慢性特发性血小板减少性紫癜、慢性阻塞性肺病、肝硬化、退行性关节病、皮肤炎、皮肌炎、湿疹、肠炎、脑炎、胃炎、肾炎、桥本氏甲状腺炎、肝炎、垂体炎、炎性肠病、肠易激综合征、川崎病、脑脊膜炎、多发性硬化、心肌炎、重症肌无力、蕈样真菌病、肌炎、肾炎、骨髓炎、胰腺炎、帕金森病、心包炎、恶性贫血、肺炎、原发性胆汁性硬化性胆管炎、结节性多动脉炎、银屑病、纤维化、红斑狼疮、组织移植排斥、甲状腺炎、I型糖尿病、尿道炎、葡萄膜炎、血管炎、白癜风和瓦尔登斯特伦氏巨球蛋白血症。
  14. 一种如式D、式C、式A、式A’所示的化合物，
    Figure PCTCN2020078963-appb-100044
    其中，X1、X2、R1、R2、R3、R4、R5、R6和R7如权利要求1-10中任一项所定义；Ra为C1-C6烷基。
  15. 如权利要求14所述的如式D、式C、式A、式A’所示的化合物，其特征在于，
    所述的如式D所示的化合物选自如下任一结构：
    Figure PCTCN2020078963-appb-100045
    和/或，所述的如式C所示的化合物选自如下任一结构：
    Figure PCTCN2020078963-appb-100046
    和/或，所述的如式A所示的化合物为
    Figure PCTCN2020078963-appb-100047
    和/或，所述的如式A’所示的化合物选为
    Figure PCTCN2020078963-appb-100048
PCT/CN2020/078963 2019-03-17 2020-03-12 一类吡咯酰胺并吡啶酮类化合物、制备方法和用途 WO2020187123A1 (zh)

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