WO2022017365A1 - 含硫异吲哚啉类衍生物、其制备方法及其在医药上的应用 - Google Patents

含硫异吲哚啉类衍生物、其制备方法及其在医药上的应用 Download PDF

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WO2022017365A1
WO2022017365A1 PCT/CN2021/107297 CN2021107297W WO2022017365A1 WO 2022017365 A1 WO2022017365 A1 WO 2022017365A1 CN 2021107297 W CN2021107297 W CN 2021107297W WO 2022017365 A1 WO2022017365 A1 WO 2022017365A1
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general formula
tautomer
racemate
meso
compound
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French (fr)
Chinese (zh)
Inventor
杨方龙
贾敏强
陈刚
郭沛骅
张利敏
贺峰
陶维康
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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Priority to US18/017,388 priority Critical patent/US20230257366A1/en
Priority to EP21847148.0A priority patent/EP4183781A4/en
Priority to AU2021314401A priority patent/AU2021314401A1/en
Priority to CN202510102009.1A priority patent/CN120004860A/zh
Priority to CN202510100913.9A priority patent/CN120004859A/zh
Priority to CN202180041057.4A priority patent/CN115916768B/zh
Priority to CA3184711A priority patent/CA3184711A1/en
Priority to MX2023000868A priority patent/MX2023000868A/es
Priority to KR1020237005618A priority patent/KR20230042057A/ko
Priority to JP2023503463A priority patent/JP2023534528A/ja
Priority to BR112023000817A priority patent/BR112023000817A2/pt
Publication of WO2022017365A1 publication Critical patent/WO2022017365A1/zh
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Definitions

  • the present disclosure belongs to the field of medicine, and relates to a sulfur-containing isoindoline derivative, a preparation method thereof and its application in medicine.
  • the present disclosure relates to a sulfur-containing isoindoline derivative represented by the general formula (I), a preparation method thereof, and a pharmaceutical composition containing the derivative, as well as its use as a Cereblon modulator in the field of treatment of multiple myeloma the use of.
  • MM Multiple myeloma
  • MM is a malignant tumor with major symptoms including hypercalcemia, kidney damage, anemia and bone disease.
  • MM is the second most common hematological malignancy after non-Hodgkin's lymphoma, with 4 to 6 people per 100,000 people worldwide and about 1.6 people per 100,000 people in China each year.
  • the current treatment methods are mainly drug therapy and autologous stem cell transplantation.
  • Drugs in clinical research stage include double antibody, ADC, CAR-T, etc.
  • the mechanisms of action of these drugs are different, and combined use can often achieve better efficacy.
  • double, triple, or even quadruple drugs are generally used, usually immunomodulators, proteasome inhibitors and hormones. Add antibody.
  • lenalidomide is the most commonly used immunomodulator, first-line therapy, maintenance therapy after stem cell transplantation, and second- and third-line therapy after relapse.
  • the drug's sales in 2018/2019 reached $9.7 billion.
  • the entire MM market is also considerable and growing rapidly.
  • the mechanism of action of immunomodulators (IMiD) in the treatment of MM is mainly that after the IMiD drug binds to Cereblon (CRBN) protein, it will activate the E3 ligase activity of CRBN, and then selectively interact with the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3). binds; resulting in rapid ubiquitination and degradation of Ikaros and Aiolos. Down-regulation of Ikaros/Aiolos results in down-regulation of c-Myc, followed by down-regulation of IRF4, and finally leads to myeloma cell growth inhibition and apoptosis.
  • IKZF1 transcription factors
  • IKZF3 Aiolos
  • IKZF3 can also inhibit the transcription of IL2 and TNF cytokines in T/NK cells. After the degradation of IKZF3, this inhibition can be relieved to promote the release of these cytokines and play a role in immune regulation.
  • Clinical trials have also shown that the clinical benefit of IMiD drugs is also related to the level of CRBN expression. After knockdown of CRBN in lenalidomide-sensitive cell lines (OPM2 and KMS18), it was found that the activity of lenalidomide to inhibit cell growth disappeared, resulting in drug resistance.
  • the level of CRBN knockdown was related to the degree of drug resistance; in cell proliferation
  • reducing the expression level of CRBN in cells U266-CRBN60 and U266-CRBN75
  • the activities of lenalidomide and pomalidomide in inhibiting cell growth were reduced.
  • the currently approved IMiD drugs are thalidomide, lenalidomide and pomalidomide, all from Celgene (currently merged by BMS).
  • the binding force of the three compounds to CRBN increased in turn, so the clinical dosage decreased in turn.
  • the main indication for the three compounds is MM, and there are other indications for thalidomide and lenalidomide, especially lenalidomide, which can be used to treat myelodysplastic syndromes (MDS).
  • MDS myelodysplastic syndromes
  • lenalidomide and pomalidomide have similar performance and have obvious myelosuppressive effects, which are target-related toxicity; thalidomide has some other side effects, such as sedation, constipation, and neurological side effects. Wait.
  • IMiD adipimide moiety of all IMiDs bind to a hydrophobic pocket defined by three tryptophan residues in CRBN (called the "thalidomide binding pocket").
  • the phthalimide/isoindolinone ring is exposed to the solvent and alters the molecular surface of CRBN, thereby regulating substrate recognition.
  • Different IMiDs lead to obvious surface modification of CRBN molecules and different preferences for substrate recognition. Therefore, modification of IMiDs may lead to the degradation of other transcription factors, causing unnecessary toxic side effects.
  • This mode of action of IMiD also known as molecular glue, visualizes the binding effect of this small molecule on two protein substrates.
  • the purpose of the present disclosure is to provide a compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or its In the form of a mixture, or a pharmaceutically acceptable salt thereof:
  • Ring A is aryl or heteroaryl
  • Ring B is cycloalkyl or heterocyclyl
  • Y is CH 2 or C (O);
  • R 1 are the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro and hydroxy ;
  • R 2 is selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxyl, cycloalkyl, heterocyclyl , aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkane one of radical, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl or more substituents;
  • R 3 are the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro and hydroxy ;
  • R 4 is selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl , aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkane one of radical, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl or more substituents;
  • R 5 and R 6 are the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro radicals, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • n 0, 1, 2 or 3;
  • p 0, 1, 2, 3, or 4;
  • q 0, 1 or 2;
  • t 0, 1, 2 or 3.
  • the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Construct, or a mixture thereof, or a pharmaceutically acceptable salt thereof which is the compound represented by the general formula (I-1) or its tautomer, meso, racemate, enantiomer A isomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:
  • Ring A, Ring B, Y, R 1 to R 6 , n, p, q and t are as defined in general formula (I).
  • the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Construct, or a mixture thereof, or a pharmaceutically acceptable salt thereof which is the compound represented by the general formula (I-2) or its tautomer, meso, racemate, enantiomer A isomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:
  • Ring A, Ring B, Y, R 1 to R 6 , n, p, q and t are as defined in general formula (I).
  • the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Construct, or its mixture form, or its pharmaceutically acceptable salt which is the compound represented by general formula (II) or its tautomer, meso, racemate, enantiomer , a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:
  • Ring A, Ring B, Y, R 1 to R 4 , n, p and t are as defined in general formula (I).
  • the compound represented by the general formula (I) or the general formula (II) or its tautomer, meso, racemate, enantiomer isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof which are compounds represented by general formula (II-1) or general formula (II-2) or tautomers thereof , meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:
  • Ring A, Ring B, Y, R 1 to R 4 , n, p and t are as defined in general formula (II).
  • ring B is a 3- to 8-membered heterocyclyl; preferably, ring B is selected from piperidinyl, pyrrolidinyl and N-heterocyclobutyl; more preferably ring B is a 6-membered heterocyclyl; most preferably Ring B is piperidinyl.
  • the compound represented by the general formula (I) or the general formula (II) or its tautomer, meso, racemate, enantiomer isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof which are compounds represented by the general formula (IIG) or tautomers, mesomers, and racemates thereof , enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:
  • G 1 , G 2 and G 3 are the same or different, and are each independently a carbon atom or a nitrogen atom;
  • R 4a and R 4b are the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, Hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocycle substituted with one or more substituents in aryl, aryl and heteroaryl;
  • r 0, 1 or 2;
  • J is 0 or 1
  • k 0 or 1
  • Y, R 1 to R 3 , n and p are as defined in general formula (I).
  • the compound represented by the general formula (I), the general formula (I-1), the general formula (II), the general formula (II-1) or the general formula (IIG) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof which is of the general formula (IIG
  • the compound represented by -1) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof which is of the general formula (IIG
  • the compound represented by -1) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof is of the general formula (IIG
  • the compound represented by -1) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof
  • G 1 , G 2 and G 3 are the same or different, and are each independently a carbon atom or a nitrogen atom;
  • R 4a and R 4b are the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, Hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocycle substituted with one or more substituents in aryl, aryl and heteroaryl;
  • r 0, 1 or 2;
  • J is 0 or 1
  • k 0 or 1
  • Y, R 1 to R 3 , n and p are as defined in general formula (I).
  • G 1 , G 2 and G 3 are the same or different, and are each independently a carbon atom or a nitrogen atom;
  • R 4a and R 4b are the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, Hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocycle substituted with one or more substituents in aryl, aryl and heteroaryl;
  • r 0, 1 or 2;
  • J is 0 or 1
  • k 0 or 1
  • Y, R 1 to R 3 , n and p are as defined in general formula (I).
  • the compound represented by the general formula (I), the general formula (II) or the general formula (IIG) or its tautomer, meso, racem isomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof which are compounds represented by the general formula (III) or tautomers, mesoisomers isomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:
  • R 4a and R 4b are the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, Hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocycle substituted with one or more substituents in aryl, aryl and heteroaryl;
  • r 0, 1 or 2;
  • Y, R 1 to R 3 , n and p are as defined in general formula (I).
  • the general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (IIG), general formula (IIG-1) or the compound represented by the general formula (III) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof which is the compound represented by the general formula (III-1) or its tautomer, meso, racemate, enantiomer, and diastereomer body, or a mixture thereof, or a pharmaceutically acceptable salt thereof:
  • Y, R 1 to R 3 , R 4a , R 4b , r, n and p are as defined in general formula (III).
  • Y, R 1 to R 3 , R 4a , R 4b , r, n and p are as defined in general formula (III).
  • the general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1), general formula formula (II-2), general formula (IIG), general formula (IIG-1), general formula (IIG-2), general formula (III), general formula (III-1) or general formula (III-2) The compound shown, or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof or a pharmaceutically acceptable salt thereof, wherein Y is CH 2 .
  • the salts used, wherein R 4 are the same or different, and each is independently selected from hydrogen atom, halogen, C 1-6 alkyl, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl and 5 to 10 membered heteroaryl groups, wherein said 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl groups are each independently optionally Selected from halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl
  • the salt used, wherein R 4a is selected from 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl, wherein said 3 to 8 membered cycloalkane group, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl are each independently optionally selected from halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2 -6 alkynyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C
  • the general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1), general formula formula (II-2), general formula (IIG), general formula (IIG-1), general formula (IIG-2), general formula (III), general formula (III-1) or general formula (III-2) The compound shown, or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof or a pharmaceutically acceptable salt thereof, wherein R 1 is the same or different, and each is independently selected from a hydrogen atom, a halogen and a C 1-6 alkyl group; preferably, R 1 is a hydrogen atom.
  • the general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1), general formula (II-2), general formula (IIG), general formula (IIG-1), general formula (IIG-2), general formula (III), general formula (III-1) or general formula (III-2) The compound shown or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from a hydrogen atom, a C 1-6 alkyl group and a 3- to 8-membered cycloalkyl group; preferably, R 2 is a hydrogen atom.
  • the general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1), general formula (II-2), general formula (IIG), general formula (IIG-1), general formula (IIG-2), general formula (III), general formula (III-1) or general formula (III-2) The compound shown or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 3 The same or different, and each is independently selected from a hydrogen atom, a halogen and a C 1-6 alkyl group.
  • the general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1), general formula (II-2), general formula (IIG), general formula (IIG-1), general formula (IIG-2), general formula (III), general formula (III-1) or general formula (III-2) The compound shown or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 3 The same or different, and each independently a hydrogen atom or a halogen; preferably a hydrogen atom.
  • the general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1), general formula (II-2), general formula (IIG), general formula (IIG-1), general formula (IIG-2), general formula (III), general formula (III-1) or general formula (III-2) The compound shown or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1.
  • the general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1), general formula (II-2), general formula (IIG), general formula (IIG-1), general formula (IIG-2), general formula (III), general formula (III-1) or general formula (III-2) The compound shown or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein p is 0, 1 or 2.
  • Typical compounds of the present disclosure include, but are not limited to:
  • Another aspect of the present disclosure pertains to compounds of formula (IA) or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof form, or a salt thereof,
  • Ring A is selected from phenyl, pyridyl and pyrimidinyl; preferably phenyl;
  • Ring B is heterocyclyl; preferably 3- to 8-membered heterocyclyl; more preferably piperidinyl, pyrrolidinyl or N-heterocyclobutyl;
  • R 2 to R 6 , p, q and t are as defined in general formula (I).
  • Another aspect of the present disclosure pertains to compounds of general formula (IIA) or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof form, or a salt thereof,
  • Ring A is selected from phenyl, pyridyl and pyrimidinyl; preferably phenyl;
  • Ring B is heterocyclyl; preferably 3- to 8-membered heterocyclyl; more preferably piperidinyl, pyrrolidinyl or N-heterocyclobutyl;
  • R 2 to R 4 , p and t are as defined in general formula (II).
  • Another aspect of the present disclosure pertains to compounds of general formula (IIGA) or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof form, or a salt thereof,
  • G 1 , G 2 , G 3 , R 2 , R 3 , R 4a , R 4b , J, k, p and r are as defined in general formula (IIG).
  • Another aspect of the present disclosure pertains to compounds of formula (IIIA) or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof form, or a salt thereof,
  • R 2 , R 3 , R 4a , R 4b , p and r are as defined in general formula (III).
  • Typical intermediate compounds of the present disclosure include, but are not limited to:
  • Another aspect of the present disclosure pertains to compounds of general formula (IC) or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof form, or a salt thereof,
  • R m is C 1-6 alkyl; preferably tert-butyl
  • Ring A, Ring B, Y, R 1 to R 6 , n, p, q and t are as defined in general formula (I).
  • Another aspect of the present disclosure relates to a compound represented by general formula (I-1C) or a tautomer, meso, racemate, enantiomer, diastereomer, or in the form of a mixture thereof, or a salt thereof,
  • R m is C 1-6 alkyl; preferably tert-butyl
  • Ring A, ring B, Y, R 1 to R 6 , n, p, q and t are as defined in general formula (I-1).
  • Another aspect of the present disclosure pertains to compounds of general formula (IIC) or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof form, or a salt thereof,
  • R m is C 1-6 alkyl; preferably tert-butyl
  • Ring A, Ring B, Y, R 1 to R 4 , n, p and t are as defined in general formula (II).
  • Another aspect of the present disclosure relates to the compound represented by general formula (II-1C) or its tautomer, meso, racemate, enantiomer, diastereomer, or in the form of a mixture thereof, or a salt thereof,
  • R m is C 1-6 alkyl; preferably tert-butyl
  • Ring A, ring B, Y, R 1 to R 4 , n, p and t are as defined in the general formula (II-1).
  • Another aspect of the present disclosure pertains to compounds of general formula (IIGC) or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof form, or a salt thereof,
  • R m is C 1-6 alkyl; preferably tert-butyl
  • G 1 , G 2 , G 3 , Y, R 1 to R 3 , R 4a , R 4b , J, k, r, n and p are as defined in general formula (IIG).
  • Another aspect of the present disclosure relates to a compound represented by general formula (IIGC-1) or a tautomer, meso, racemate, enantiomer, diastereomer, or in the form of a mixture thereof, or a salt thereof,
  • R m is C 1-6 alkyl; preferably tert-butyl
  • G 1 , G 2 , G 3 , Y, R 1 to R 3 , R 4a , R 4b , J, k, r, n and p are as defined in general formula (IIG-1).
  • Another aspect of the present disclosure pertains to a compound of formula (IIIC) or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof form, or a salt thereof,
  • R m is C 1-6 alkyl; preferably tert-butyl
  • Y, R 1 to R 3 , R 4a , R 4b , r, n and p are as defined in general formula (III).
  • Another aspect of the present disclosure relates to a compound represented by general formula (III-1C) or a tautomer, meso, racemate, enantiomer, diastereomer, or in the form of a mixture thereof, or a salt thereof,
  • R m is C 1-6 alkyl; preferably tert-butyl
  • Y, R 1 to R 3 , R 4a , R 4b , r, n and p are as defined in the general formula (III-1).
  • Typical intermediate compounds of the present disclosure include, but are not limited to:
  • Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or a method of a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:
  • Ring A, Ring B, Y, R 1 to R 6 , n, p, q and t are as defined in general formula (I).
  • Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or a method of a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:
  • the compound of general formula (IC) undergoes an intramolecular ring-closing reaction to obtain the compound of general formula (I),
  • R m is C 1-6 alkyl; preferably tert-butyl
  • Ring A, Ring B, Y, R 1 to R 6 , n, p, q and t are as defined in general formula (I).
  • Another aspect of the present disclosure relates to the preparation of the compound represented by the general formula (I-1) or its tautomer, meso, racemate, enantiomer, and diastereomer body, or a mixture thereof, or a method of a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound of general formula (I-1C) undergoes an intramolecular ring-closing reaction to obtain the compound of general formula (I-1),
  • R m is C 1-6 alkyl; preferably tert-butyl
  • Ring A, ring B, Y, R 1 to R 6 , n, p, q and t are as defined in general formula (I-1).
  • Another aspect of the present disclosure relates to the preparation of a compound represented by the general formula (I-2) or its tautomer, meso, racemate, enantiomer, diastereomer
  • R m is C 1-6 alkyl; preferably tert-butyl
  • Ring A, Ring B, Y, R 1 to R 6 , n, p, q and t are as defined in general formula (I).
  • Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer, or a method of a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:
  • Ring A, Ring B, Y, R 1 to R 4 , n, p and t are as defined in general formula (II).
  • Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer, or a method of a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:
  • the compound of general formula (IIC) undergoes an intramolecular ring-closing reaction to obtain the compound of general formula (II),
  • R m is C 1-6 alkyl; preferably tert-butyl
  • Ring A, Ring B, Y, R 1 to R 4 , n, p and t are as defined in general formula (II).
  • Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (II-1) or its tautomer, meso, racemate, enantiomer, and diastereomer body, or a mixture thereof, or a method of a pharmaceutically acceptable salt thereof, the method comprising:
  • R m is C 1-6 alkyl; preferably tert-butyl
  • Ring A, Ring B, Y, R 1 to R 4 , n, p and t are as defined in general formula (II).
  • Another aspect of the present disclosure relates to the preparation of the compound represented by the general formula (II-2) or its tautomer, meso, racemate, enantiomer, diastereomer body, or a mixture thereof, or a method of a pharmaceutically acceptable salt thereof, the method comprising:
  • R m is C 1-6 alkyl; preferably tert-butyl
  • Ring A, Ring B, Y, R 1 to R 4 , n, p and t are as defined in general formula (II).
  • Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (IIG) or its tautomer, meso, racemate, enantiomer, diastereomer, or a method of a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:
  • G 1 , G 2 , G 3 , Y, R 1 to R 3 , R 4a , R 4b , J, k, n, p and r are as defined in general formula (IIG).
  • Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (IIG) or its tautomer, meso, racemate, enantiomer, diastereomer, or a method of a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:
  • the compound of general formula (IIGC) undergoes an intramolecular ring-closing reaction to obtain the compound of general formula (IIG),
  • R m is C 1-6 alkyl; preferably tert-butyl
  • G 1 , G 2 , G 3 , Y, R 1 to R 3 , R 4a , R 4b , J, k, n, p and r are as defined in general formula (IIG).
  • Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (IIG-1) or its tautomer, meso, racemate, enantiomer, and diastereomer body, or a mixture thereof, or a method of a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound of general formula (IIGC-1) undergoes an intramolecular ring-closing reaction to obtain the compound of general formula (IIG-1),
  • R m is C 1-6 alkyl; preferably tert-butyl
  • G 1 , G 2 , G 3 , Y, R 1 to R 3 , R 4a , R 4b , J, k, n, p and r are as defined in general formula (IIG-1).
  • Another aspect of the present disclosure relates to a preparation of the compound represented by the general formula (IIG-2) or its tautomer, meso, racemate, enantiomer, diastereomer body, or a mixture thereof, or a method of a pharmaceutically acceptable salt thereof, the method comprising:
  • R m is C 1-6 alkyl; preferably tert-butyl
  • G 1 , G 2 , G 3 , Y, R 1 to R 3 , R 4a , R 4b , J, k, n, p and r are as defined in general formula (IIG).
  • Another aspect of the present disclosure relates to the preparation of the compound represented by the general formula (III) or its tautomer, meso, racemate, enantiomer, diastereomer, or a method of a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:
  • Y, R 1 to R 3 , R 4a , R 4b , n, p and r are as defined in general formula (III).
  • Another aspect of the present disclosure relates to the preparation of the compound represented by the general formula (III) or its tautomer, meso, racemate, enantiomer, diastereomer, or a method of a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:
  • R m is C 1-6 alkyl; preferably tert-butyl
  • Y, R 1 to R 3 , R 4a , R 4b , n, p and r are as defined in general formula (III).
  • Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (III-1) or its tautomer, meso, racemate, enantiomer, and diastereomer body, or a mixture thereof, or a method of a pharmaceutically acceptable salt thereof, the method comprising:
  • R m is C 1-6 alkyl; preferably tert-butyl
  • Y, R 1 to R 3 , R 4a , R 4b , n, p and r are as defined in the general formula (III-1).
  • Another aspect of the present disclosure relates to the preparation of the compound represented by the general formula (III-2) or its tautomer, meso, racemate, enantiomer, and diastereomer body, or a mixture thereof, or a method of a pharmaceutically acceptable salt thereof, the method comprising:
  • R m is C 1-6 alkyl; preferably tert-butyl
  • Y, R 1 to R 3 , R 4a , R 4b , n, p and r are as defined in general formula (III).
  • Another aspect of the present disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II), general formula formula (II-1), general formula (II-2), general formula (IIG), general formula (IIG-1), general formula (IIG-2), general formula (III), general formula (III-1) , the compound shown in general formula (III-2) or Table A or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • the present disclosure further relates to general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1), general formula (II-2), general formula (IIG), general formula (IIG-1), general formula (IIG-2), general formula (III), general formula (III-1), general formula (III-2) or the compound shown in Table A or its Tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same Use in a medicament for the treatment and/or prevention of CRBN protein-related diseases.
  • the present disclosure further relates to general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1), general formula (II-2), general formula (IIG), general formula (IIG-1), general formula (IIG-2), general formula (III), general formula (III-1), general formula (III-2) or the compound shown in Table A or its Tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same
  • angiogenesis-related disorders pain, macular degeneration or related syndromes, skin diseases, lung diseases, asbestos-related diseases, parasitic diseases, immunodeficiency diseases, CNS diseases, CNS damage, Use in atherosclerosis or related disorders, sleep disorders or related disorders, infectious diseases, hemoglobinopathies or related disorders, or TNF ⁇ related disorders; preferably, in the manufacture of a medicament for the treatment and/or prevention of cancer or CNS damage use in medicines.
  • the present disclosure also relates to a method for treating and/or preventing diseases associated with CRBN protein, comprising administering to a patient in need thereof a therapeutically effective amount of general formula (I), general formula (I-1), general formula (I-2) , general formula (II), general formula (II-1), general formula (II-2), general formula (IIG), general formula (IIG-1), general formula (IIG-2), general formula (III) , compounds of general formula (III-1), general formula (III-2) or shown in Table A or their tautomers, mesomers, racemates, enantiomers, diastereomers Isomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same.
  • the present disclosure also relates to a treatment and/or prevention of cancer, angiogenesis-related disorders, pain, macular degeneration or related syndromes, skin diseases, lung diseases, asbestos-related diseases, parasitic diseases, immunodeficiency diseases, CNS diseases , CNS damage, atherosclerosis or related disorders, sleep disorders or related disorders, infectious diseases, hemoglobinopathies or related disorders, or methods for TNF ⁇ related disorders, preferably for the treatment and/or prevention of cancer or CNS damage, which Including the administration of a therapeutically effective amount of general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1), general formula (II- 2), general formula (IIG), general formula (IIG-1), general formula (IIG-2), general formula (III), general formula (III-1), general formula (III-2) or as shown in Table A
  • the present disclosure further relates to a general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1), general formula (II-2), Compounds of general formula (IIG), general formula (IIG-1), general formula (IIG-2), general formula (III), general formula (III-1), general formula (III-2) or Table A or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same , which is used as a medicine.
  • the present disclosure further relates to general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1), general formula (II-2), general formula (IIG), general formula (IIG-1), general formula (IIG-2), general formula (III), general formula (III-1), general formula (III-2) or the compound shown in Table A or its Tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same, which For the treatment and/or prevention of CRBN protein-related diseases.
  • the CRBN protein-related diseases described in the present disclosure are selected from cancer, angiogenesis-related disorders, pain, macular degeneration or related syndromes, skin diseases, lung diseases, asbestos-related diseases, parasitic diseases, immunodeficiency diseases , CNS disease, CNS injury, atherosclerosis or related disorders, sleep disorders or related disorders, infectious diseases, hemoglobinopathies or related disorders, or TNF[alpha] related disorders; preferably cancer or CNS injury.
  • the present disclosure further relates to general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1), general formula (II-2), general formula (IIG), general formula (IIG-1), general formula (IIG-2), general formula (III), general formula (III-1), general formula (III-2) or the compound shown in Table A or its Tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same, which
  • angiogenesis-related disorders pain, macular degeneration or related syndromes, skin diseases, lung diseases, asbestos-related diseases, parasitic diseases, immunodeficiency diseases, CNS diseases, CNS damage, Atherosclerosis or related disorders, sleep disorders or related disorders, infectious diseases, hemoglobinopathies or related disorders, or TNF[alpha] related disorders; preferably cancer or CNS damage.
  • the cancer described in this disclosure is selected from the group consisting of leukemia, myeloma, lymphoma, melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, gastric cancer, esophageal cancer, colorectal cancer, gallbladder cancer, bile duct cancer, choriocarcinoma, pancreatic cancer, polycythemia vera, pediatric cancer, cervical cancer, ovarian cancer, breast cancer, bladder cancer, urothelial cancer, ureteral cancer, prostate cancer, seminoma, testicular tumor, head and neck tumor, Head and neck squamous cell carcinoma, endometrial carcinoma, thyroid carcinoma, sarcoma, osteoma, neuroblastoma, neuroendocrine carcinoma, brain tumor, CNS carcinoma, astrocytoma and glioma; preferably, the liver cancer is hepatocellular carcinoma; the colorectal cancer is colon cancer or rectal cancer; the sarcom
  • the leukemia is preferably chronic lymphocytic leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML) and hairy cell leukemia
  • the lymphoma is preferably Small lymphocytic lymphoma, marginal zone lymphoma, follicular lymphoma, mantle cell lymphoma, non-Hodgkin lymphoma (NHL), lymphoplasmacytic lymphoma, extranodal marginal zone lymphoma, T-cell lymphoma , B-cell lymphoma and diffuse large B-cell lymphoma
  • the myeloma is preferably multiple myeloma (MM) and myelodysplastic syndrome (MDS).
  • Cancers described in the present disclosure include primary or metastatic cancers. Cancers described in the present disclosure also include refractory or resistant to chemotherapy or radiation therapy. More preferably, the multiple myeloma is relapsed, refractory or resistant. Most preferably, the multiple myeloma is lenalidomide or pomalidomide refractory or resistant.
  • CNS disorders include, but are not limited to, disorders described in US Publication No. US2005/0143344A1, published June 30, 2005, the contents of which are incorporated herein by reference. Specific examples include, but are not limited to, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis and other neuroimmune diseases such as Tourette syndrome, delusions, Or disturbance of consciousness that occurs within a short period of time, or amnesia, or diffuse memory impairment that occurs when other central nervous system impairments are not present.
  • CNS injuries and related syndromes include, but are not limited to, the diseases described in US Publication No. US2006/0122228A1, published June 8, 2006, the contents of which are incorporated herein by reference.
  • Specific examples include, but are not limited to, CNS injury/impairment and related syndromes including but not limited to primary brain injury, secondary brain injury, traumatic brain injury, focal brain injury, diffuse axonal injury, craniocerebral injury Injury, concussion, post-concussion syndrome, cerebral contusion, subdural hematoma, epidermal hematoma, post-traumatic epilepsy, chronic autonomic state, complete SCI, incomplete SCI, acute SCI, subacute SCI, chronic SCI, central cord syndrome, hemisection syndrome, anterior cord syndrome, conus medullaris syndrome, cauda equina syndrome, neurogenic shock, spinal shock, altered level of consciousness, headache, nausea, vomiting, memory loss, dizziness, Double vision, blurred vision, mood swings, sleep disturbances,
  • Diseases associated with angiogenesis include, but are not limited to, inflammatory diseases, autoimmune diseases, viral diseases, genetic diseases, allergic diseases, bacterial diseases, ocular neovascular diseases, choroidal neovascular diseases, retinal neovascularization Sexual disease, and iris erythema (angle neovascularization).
  • Preferred include but are not limited to arthritis, endometriosis, Crohn's disease, heart failure, severe heart failure, renal impairment, endotoxemia, toxic shock syndrome, osteoarthritis, retroviral replication , wasting disease, meningitis, silica-induced fibrosis, asbestos-induced fibrosis, veterinary disease, malignancy-related hypercalcemia, stroke, circulatory shock, periodontitis, gingivitis, macrocytic anemia , refractory anemia, and 5q deletion syndrome.
  • the active compounds can be formulated in a form suitable for administration by any suitable route, and the compositions of the present disclosure can be formulated by conventional methods using one or more pharmaceutically acceptable carriers. Accordingly, the active compounds of the present disclosure can be formulated in various dosage forms for oral administration, injection (eg, intravenous, intramuscular, or subcutaneous) administration, inhalation or insufflation.
  • the compounds of the present disclosure may also be formulated in dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injectable solutions, dispersible powders or granules, suppositories, lozenges or syrups.
  • the active compound is preferably presented in a unit dose or in a form that the patient can self-administer in a single dose.
  • a unit dose of a compound or composition of the present disclosure may be expressed as a tablet, capsule, cachet, vial, powder, granule, lozenge, suppository, reconstituted powder, or liquid.
  • a suitable unit dose may be 0.1 to 1000 mg.
  • the pharmaceutical composition of the present disclosure may contain one or more excipients selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients Wait.
  • the composition may contain from 0.1 to 99% by weight of active compound.
  • Tablets contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients suitable for the manufacture of tablets.
  • excipients may be inert excipients, granulating agents, disintegrating agents, binders and lubricants. These tablets may be uncoated or they may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained release over an extended period of time.
  • Oral formulations can also be presented in soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or in which the active ingredient is mixed with a water-soluble or oily vehicle.
  • Aqueous suspensions contain the active substances in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents.
  • the aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.
  • Oily suspensions can be formulated by suspending the active ingredient in vegetable or mineral oils.
  • the oily suspensions may contain thickening agents.
  • the aforementioned sweetening and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.
  • compositions of the present disclosure may also be in the form of oil-in-water emulsions.
  • the oily phase can be vegetable oil, or mineral oil or a mixture thereof.
  • Suitable emulsifying agents may be naturally occurring phospholipids, and the emulsions may also contain sweetening, flavoring, preservative and antioxidant agents.
  • Such formulations may also contain a demulcent, a preservative, a coloring agent and an antioxidant.
  • compositions of the present disclosure may be in the form of sterile injectable aqueous solutions.
  • acceptable vehicles or solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • a sterile injectable preparation can be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oily phase.
  • the injectable solution or microemulsion can be injected into the bloodstream of a patient by local bulk injection.
  • solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of the compounds of the present disclosure.
  • a continuous intravenous drug delivery device can be used.
  • An example of such a device is the Deltec CADD-PLUS.TM.5400 IV pump.
  • compositions of the present disclosure may be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent.
  • sterile fixed oils are conveniently employed as a solvent or suspending medium. For this purpose, any blending and fixing oil can be used.
  • fatty acids are also available in the preparation of injectables.
  • the compounds of the present disclosure can be administered in the form of suppositories for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and therefore will melt in the rectum to release the drug.
  • the compounds of the present disclosure can be administered by the addition of water to prepare dispersible powders and granules for aqueous suspension.
  • These pharmaceutical compositions can be prepared by admixing the active ingredient with a dispersing or wetting agent, suspending agent or one or more preservatives.
  • the dosage of a drug to be administered depends on a variety of factors including, but not limited to, the following factors: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient , patient's diet, time of administration, mode of administration, rate of excretion, combination of drugs, severity of disease, etc.; in addition, optimal treatment mode such as mode of treatment, daily dose of compound or pharmaceutically acceptable salt Species can be verified against conventional treatment protocols.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably 1 to 12 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) alkyl groups of carbon atoms, more preferably alkyl groups containing 1 to 6 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhe
  • lower alkyl groups containing 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-Methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylpropyl butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl base, 2,3-dimethylbutyl, etc.
  • the alkyl group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably the substituents are independently optionally selected from the group consisting of D atom, halogen, alkoxy, haloalkyl, One or more of haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl Substituents.
  • alkylene refers to a saturated straight-chain or branched aliphatic hydrocarbon group, which is a residue derived from the parent alkane by removal of two hydrogen atoms on the same carbon atom or two different carbon atoms, which is a residue containing 1 to A straight or branched chain group of 20 carbon atoms, preferably containing from 1 to 12 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, more Preference is given to alkylene groups containing 1 to 6 carbon atoms.
  • Non-limiting examples of alkylene include, but are not limited to, methylene (-CH 2 -), 1,1- ethylene (-CH (CH 3) -) , 1,2- ethylene (-CH 2 CH 2 )-, 1,1-propylene (-CH(CH 2 CH 3 )-), 1,2-propylene (-CH 2 CH(CH 3 )-), 1,3-propylene (-CH 2 CH 2 CH 2 -), 1,4-butylene (-CH 2 CH 2 CH 2 CH 2 -), and the like.
  • the alkylene group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably the substituents are independently optionally selected from alkenyl, alkynyl, alkoxy, haloalkane Oxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, One or more substituents of cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo.
  • alkenyl refers to an alkyl compound having at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above.
  • Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy group, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • alkynyl refers to an alkyl compound having at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above.
  • Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cyclic Alkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably containing from 3 to 12 carbon atoms (which can be a specific point, It can also be an interval consisting of optional two points, such as 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 ring atoms, 4 to 11 ring atoms, 6 to 12 ring atoms, etc.) , preferably contains 3 to 8 carbon atoms (eg 3, 4, 5, 6, 7 and 8), more preferably contains 3 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.
  • spirocycloalkyl refers to a 5- to 20-membered polycyclic group having one carbon atom (called a spiro atom) shared between the monocyclic rings, which may contain one or more double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of spiro atoms shared between the rings, spirocycloalkyl groups are classified into mono-spirocycloalkyl groups, double-spirocycloalkyl groups or poly-spirocycloalkyl groups, preferably mono-spirocycloalkyl groups and double-spirocycloalkyl groups.
  • spirocycloalkyl More preferably, it is 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospirocycloalkyl.
  • spirocycloalkyl include:
  • fused cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more rings. Multiple double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan).
  • bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered , 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan Member/5-membered and 6-membered/6-membered bicycloalkyl.
  • fused cycloalkyl groups include:
  • bridged cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two non-directly attached carbon atoms, which may contain one or more double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • bridged cycloalkyl include:
  • the cycloalkyl ring includes a cycloalkyl (including monocyclic, spiro, fused and bridged) as described above fused to an aryl, heteroaryl or heterocycloalkyl ring where it is attached to the parent structure Rings together are cycloalkyl, non-limiting examples include etc.; preferred
  • Cycloalkyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably independently optionally selected from hydrogen atoms, halogens, alkyl, alkoxy , haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl one or more substituents.
  • alkoxy refers to -O-(alkyl), wherein alkyl is as defined above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, and butoxy.
  • the alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of D atom, halogen, alkoxy, haloalkyl, haloalkoxy alkyl, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent containing from 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen and sulfur,
  • the sulfur may optionally be oxo (ie, to form a sulfoxide or sulfone), but does not include ring moieties of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • Preferably it contains 3 to 12 ring atoms, of which 1 to 4 (eg 1, 2, 3 and 4) are heteroatoms; more preferably 3 to 8 ring atoms (eg 3, 4, 5, 6, 7 and 8), of which 1-3 are heteroatoms (eg 1, 2 and 3); more preferably contain 3 to 6 ring atoms, of which 1-3 are heteroatoms; most preferably contain 5 or 6 ring atoms , of which 1-3 are heteroatoms.
  • 1 to 4 eg 1, 2, 3 and 4
  • 3 to 8 ring atoms eg 3, 4, 5, 6, 7 and 8
  • 1-3 heteroatoms
  • Non-limiting examples of monocyclic heterocyclyl groups include oxetanyl, pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholine base, thiomorpholinyl, homopiperazinyl, etc.
  • Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.
  • spiroheterocyclyl refers to a 5- to 20-membered polycyclic heterocyclic group with one atom (called a spiro atom) shared between the monocyclic rings, wherein one or more ring atoms are heterocyclic groups selected from nitrogen, oxygen and sulfur.
  • the sulfur may optionally be oxo (ie to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan (e.g. 7, 8, 9 or 10 yuan).
  • spiroheterocyclyls are classified into mono-spiroheterocyclyl, bis-spiroheterocyclyl or poly-spiroheterocyclyl, preferably mono-spiroheterocyclyl and bis-spiroheterocyclyl. More preferably 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiroheterocyclyl.
  • Non-limiting examples of spiroheterocyclyl include:
  • fused heterocyclyl refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more of the rings may contain one or more Double bonds in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, which may be optionally oxo (ie, to form a sulfoxide or sulfone), and the remaining ring atoms are carbon.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan).
  • bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered , 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan Member/5-membered and 6-membered/6-membered bicyclic fused heterocyclic group.
  • fused heterocyclyl groups include:
  • bridged heterocyclyl refers to a 5- to 14-membered, polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds in which one or more ring atoms is a heteroatom selected from nitrogen, oxygen, and sulfur, which may optionally be oxo (ie, to form a sulfoxide or sulfone), and the remaining ring atoms are carbon.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan).
  • bridged heterocyclyl groups include:
  • the heterocyclyl ring includes a heterocyclyl group (including monocyclic, spiroheterocycle, fused heterocycle and bridged heterocycle) as described above fused to an aryl, heteroaryl or cycloalkyl ring, wherein the
  • the rings to which the structure is attached are heterocyclyl, non-limiting examples of which include:
  • Heterocyclyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably the substituents are independently optionally selected from halogen, alkyl, alkoxy, haloalkyl , one or more of haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl a substituent.
  • aryl refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic are rings that share adjacent pairs of carbon atoms) groups having a conjugated pi-electron system, preferably 6 to 10 membered , such as phenyl and naphthyl.
  • the aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring linked to the parent structure is an aryl ring, non-limiting examples of which include :
  • Aryl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably the substituents are independently optionally selected from halogen, alkyl, alkoxy, haloalkyl, One or more of haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl Substituents.
  • heteroaryl refers to a heteroaromatic system comprising 1 to 4 (eg 1, 2, 3 and 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • Heteroaryl is preferably 5 to 10 membered (eg 5, 6, 7, 8, 9 or 10 membered), more preferably 5 or 6 membered, eg furyl, thienyl, pyridyl, pyrrolyl, N-alkane pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl and the like.
  • the heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclyl or cycloalkyl ring as described above, wherein the ring linked to the parent structure is a heteroaryl ring, non-limiting examples of which include :
  • Heteroaryl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, preferably the substituents are independently optionally selected from halogen, alkyl, alkoxy, haloalkyl , one or more of haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl a substituent.
  • cycloalkyl, heterocyclyl, aryl and heteroaryl groups include residues derived by removing one hydrogen atom from the parent carbon atom, or removing two hydrogen atoms from the same carbon atom or two different carbon atoms from the parent Residues derived from atoms, namely "divalent cycloalkyl", “divalent heterocyclyl", “arylene” and "heteroarylene".
  • the bond Indicates an unspecified configuration, i.e. if a chiral isomer exists in the chemical structure, the bond can be or both Two configurations.
  • tautomer or tautomeric form
  • proton tautomers include interconversions via migration of protons, such as keto-enol and imine-enamine isomerizations.
  • An example of a lactam-lactam equilibrium is between A and B as shown below.
  • the compounds of the present disclosure may exist in specific geometric or stereoisomeric forms.
  • This disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to within the scope of this disclosure.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of this disclosure.
  • Optically active (R)- and (S)-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereomeric salt is formed with an appropriate optically active acid or base, followed by conventional methods known in the art
  • the diastereoisomers were resolved and the pure enantiomers recovered.
  • separation of enantiomers and diastereomers is usually accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (eg, from amines to amino groups) formate).
  • amino protecting group is used to protect the amino group with a group that is easy to remove in order to keep the amino group unchanged when the other part of the molecule is reacted.
  • Non-limiting examples include (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, t-butoxycarbonyl, acetyl, benzyl, allyl, p-methoxybenzyl, and the like. These groups may be optionally substituted with 1-3 substituents selected from halogen, alkoxy or nitro.
  • the amino protecting groups are preferably (trimethylsilyl)ethoxymethyl and tert-butoxycarbonyl.
  • hydroxyl protecting group is a suitable group for hydroxyl protection known in the art, see the literature ("Protective Groups in Organic Synthesis", 5 Th Ed. TW Greene & P. GMWuts) for hydroxyl protecting groups.
  • the hydroxyl protecting group can be a (C 1-10 alkyl or aryl) 3 silyl group, such as: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl Silyl, tert-butyldiphenylsilyl, etc.; can be C 1-10 alkyl or substituted alkyl, preferably alkoxy or aryl substituted alkyl, more preferably C 1-6 alkoxy substituted C 1-6 alkyl or phenyl substituted C 1-6 alkyl, most preferably C 1-4 alkoxy substituted C 1-4 alkyl, for example: methyl, tert-butyl, allyl, benzyl
  • heterocyclylalkyl refers to an alkyl group substituted with one or more heterocyclyl groups, wherein heterocyclyl and alkyl are as defined above.
  • heteroarylalkyl refers to an alkyl group substituted with one or more heteroaryl groups, wherein heteroaryl and alkyl are as defined above.
  • cycloalkyloxy refers to cycloalkyl-O-, wherein cycloalkyl is as defined above.
  • heterocyclyloxy refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.
  • aryloxy refers to aryl-O-, wherein aryl is as defined above.
  • heteroaryloxy refers to heteroaryl-O-, wherein heteroaryl is as defined above.
  • alkylthio refers to alkyl-S-, wherein alkyl is as defined above.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.
  • deuterated alkyl refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.
  • hydroxyalkyl refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • hydroxy refers to -OH.
  • thiol refers to -SH.
  • amino means -NH 2.
  • cyano refers to -CN.
  • nitro refers to -NO 2.
  • carboxylate refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O )O-, wherein alkyl and cycloalkyl are as defined above.
  • the compounds of the present disclosure include other isotopic derivatives.
  • isotopic derivatives refers to compounds that differ in structure only by the presence of one or more isotopically enriched atoms.
  • a structure of the present disclosure with “deuterium” or “tritium” in place of a hydrogen, fluorine or instead of fluorine-labeled with 18 F- (18 F isotope), or with 11 C-, 13 C- or 14 C- enriched
  • Compounds in which carbon ( 11 C-, 13 C- or 14 C-carbon labels; 11 C-, 13 C- or 14 C-isotopes) instead of carbon atoms are within the scope of this disclosure.
  • Such compounds can be used, for example, as analytical tools or probes in biological assays, or as tracers for in vivo diagnostic imaging of disease, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies.
  • each available hydrogen atom attached to a carbon atom may be independently replaced by a deuterium atom.
  • Those skilled in the art can refer to the relevant literature to synthesize deuterated forms of the compounds.
  • deuterated starting materials can be used in preparing deuterated forms of the compounds, or they can be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated borane, trideuterated borane in tetrahydrofuran , Deuterated lithium aluminum hydride, deuterated iodoethane and deuterated iodomethane, etc.
  • Deuterated compounds generally retain comparable activity to undeuterated compounds, and when deuterated at certain specific sites can achieve better metabolic stability, resulting in certain therapeutic advantages.
  • Optional or “optionally” means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs or instances where it does not.
  • a heterocyclic group optionally substituted with an alkyl group means that an alkyl group may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group .
  • Substituted means that one or more hydrogen atoms in a group, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms, independently of one another, are substituted by the corresponding number of substituents.
  • a person skilled in the art can determine possible or impossible substitutions (either experimentally or theoretically) without undue effort.
  • amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as a physiological/pharmaceutically acceptable carrier and excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
  • “Pharmaceutically acceptable salts” refers to salts of the compounds of the present disclosure that are safe and effective when used in mammals, and that possess the desired biological activity.
  • the salts can be prepared separately during the final isolation and purification of the compounds, or by reacting a suitable group with a suitable base or acid.
  • Bases commonly used to form pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonia.
  • Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.
  • prevention refers to the treatment or administration of compounds provided herein with or without other active compounds prior to the onset of symptoms, particularly to those at risk of cancer and/or other Patients with the disorders described herein.
  • prevention includes the inhibition or alleviation of symptoms of a particular disease.
  • patients with a family history of the disease are particularly candidates for preventive regimens.
  • patients with a history of symptom recurrence are also potential candidates for prevention.
  • prophylaxis is used interchangeably with the term “prophylactic treatment”.
  • the term "therapeutically effective amount” refers to a non-toxic but sufficient amount of the drug or agent to achieve the desired effect.
  • the determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance, and the appropriate effective amount in individual cases can be determined by those skilled in the art based on routine experiments.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with patient tissue without undue toxicity, irritation, allergic response or Other problems or complications with a reasonable benefit/risk ratio and are effective for the intended use.
  • the compound represented by the general formula (I) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its
  • the preparation method of pharmaceutically acceptable salt comprises the following steps:
  • Ring A, Ring B, Y, R 1 to R 6 , n, p, q and t are as defined in general formula (I).
  • the compound represented by the general formula (I) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its
  • the preparation method of pharmaceutically acceptable salt comprises the following steps:
  • the compound of general formula (IC) undergoes an intramolecular ring-closing reaction under acidic conditions to obtain the compound of general formula (I),
  • R m is C 1-6 alkyl; preferably tert-butyl
  • Ring A, Ring B, Y, R 1 to R 6 , n, p, q and t are as defined in general formula (I).
  • the preparation method of its pharmaceutically acceptable salt comprises the following steps:
  • the compound of general formula (I-1C) undergoes an intramolecular ring closure reaction under acidic conditions to obtain the compound of general formula (I-1),
  • R m is C 1-6 alkyl; preferably tert-butyl
  • Ring A, ring B, Y, R 1 to R 6 , n, p, q and t are as defined in general formula (I-1).
  • the preparation method of its pharmaceutically acceptable salt comprises the following steps:
  • R m is C 1-6 alkyl; preferably tert-butyl
  • Ring A, Ring B, Y, R 1 to R 6 , n, p, q and t are as defined in general formula (I).
  • the preparation method of medicinal salt comprises the following steps:
  • Ring A, Ring B, Y, R 1 to R 4 , n, p and t are as defined in general formula (II).
  • the preparation method of medicinal salt comprises the following steps:
  • the compound of general formula (IIC) undergoes an intramolecular ring-closing reaction under acidic conditions to obtain the compound of general formula (II),
  • R m is C 1-6 alkyl; preferably tert-butyl
  • Ring A, Ring B, Y, R 1 to R 4 , n, p and t are as defined in general formula (II).
  • the preparation method of its pharmaceutically acceptable salt comprises the following steps:
  • the compound of general formula (II-1C) undergoes an intramolecular ring-closing reaction under acidic conditions to obtain the compound of general formula (II-1),
  • R m is C 1-6 alkyl; preferably tert-butyl
  • Ring A, ring B, Y, R 1 to R 4 , n, p and t are as defined in the general formula (II-1).
  • the preparation method of its pharmaceutically acceptable salt comprises the following steps:
  • R m is C 1-6 alkyl; preferably tert-butyl
  • Ring A, Ring B, Y, R 1 to R 4 , n, p and t are as defined in general formula (II).
  • the preparation method of medicinal salt comprises the following steps:
  • G 1 , G 2 , G 3 , Y, R 1 to R 3 , R 4a , R 4b , J, k, n, p and r are as defined in general formula (IIG).
  • the preparation method of medicinal salt comprises the following steps:
  • the compound of general formula (IIGC) undergoes an intramolecular ring-closing reaction under acidic conditions to obtain the compound of general formula (IIG),
  • R m is C 1-6 alkyl; preferably tert-butyl
  • G 1 , G 2 , G 3 , Y, R 1 to R 3 , R 4a , R 4b , J, k, n, p and r are as defined in general formula (IIG).
  • the compound of general formula (IIGC-1) undergoes an intramolecular ring closure reaction under acidic conditions to obtain the compound of general formula (IIG-1),
  • R m is C 1-6 alkyl; preferably tert-butyl
  • G 1 , G 2 , G 3 , Y, R 1 to R 3 , R 4a , R 4b , J, k, n, p and r are as defined in general formula (IIG-1).
  • the preparation method of its pharmaceutically acceptable salt comprises the following steps:
  • R m is C 1-6 alkyl; preferably tert-butyl
  • G 1 , G 2 , G 3 , Y, R 1 to R 3 , R 4a , R 4b , J, k, n, p and r are as defined in general formula (IIG).
  • the compound represented by the general formula (III) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form or its pharmaceutically acceptable comprises the following steps:
  • Y, R 1 to R 3 , R 4a , R 4b , n, p and r are as defined in general formula (III).
  • the preparation method of medicinal salt comprises the following steps:
  • R m is C 1-6 alkyl; preferably tert-butyl
  • Y, R 1 to R 3 , R 4a , R 4b , n, p and r are as defined in general formula (III).
  • the preparation method of its pharmaceutically acceptable salt comprises the following steps:
  • R m is C 1-6 alkyl; preferably tert-butyl
  • Y, R 1 to R 3 , R 4a , R 4b , n, p and r are as defined in the general formula (III-1).
  • the preparation method of its pharmaceutically acceptable salt comprises the following steps:
  • R m is C 1-6 alkyl; preferably tert-butyl
  • Y, R 1 to R 3 , R 4a , R 4b , n, p and r are as defined in general formula (III).
  • the reagents that provide alkaline conditions in the above synthesis scheme include organic bases and inorganic bases, and the organic bases include but are not limited to: triethylamine, N,N-diisopropylethylamine, n-butyllithium, diisopropylethylamine Lithium isopropylamide, sodium acetate, potassium acetate, sodium tert-butoxide or potassium tert-butoxide, the inorganic bases include but are not limited to: sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, hydroxide Sodium, lithium hydroxide monohydrate, lithium hydroxide and potassium hydroxide; potassium carbonate is preferred.
  • the organic bases include but are not limited to: triethylamine, N,N-diisopropylethylamine, n-butyllithium, diisopropylethylamine Lithium isopropylamide, sodium acetate, potassium acetate
  • Reagents providing acidic conditions in the above synthetic scheme include but are not limited to p-toluenesulfonic acid, p-toluenesulfonic acid monohydrate, benzenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, sulfuric acid, hydrochloric acid, nitric acid and trifluoroacetic acid; It is preferably selected from the group consisting of p-toluenesulfonic acid, p-toluenesulfonic acid monohydrate and benzenesulfonic acid.
  • the above reaction is preferably carried out in a solvent, and the solvent used includes but is not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane Alkane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide and mixtures thereof.
  • the solvent used includes but is not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane Alkane, dimethyl sulfoxide, 1,4-
  • Figure 1 The efficacy data of the compound of Example 6 and the control example CC-92480 on NCI-H929 xenografted tumor in CB-17SCID mice.
  • Figure 2 Effects of compound of Example 6 and control CC-92480 on body weight of CB-17SCID mice.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • MS The determination of MS was performed with Agilent 1200/1290 DAD-6110/6120 Quadrupole MS LC/MS (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS), waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS Model: waters ACQuity Qda Detector/waters SQ Detector), THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).
  • HPLC High performance liquid chromatography
  • Chiral HPLC analysis was determined using an Agilent 1260 DAD high performance liquid chromatograph.
  • HPLC preparations used Waters 2545-2767, Waters 2767-SQ Detector2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.
  • the CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm, and the size of the TLC separation and purification products is 0.4mm ⁇ 0.5mm.
  • Silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
  • the average inhibition rate and IC 50 value of kinases were measured with NovoStar microplate reader (BMG, Germany).
  • the known starting materials of the present disclosure can be synthesized using or according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Shanghai Bi De Pharmaceutical, Darui Chemicals and other companies.
  • Argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.
  • Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1 L.
  • the pressure hydrogenation reaction uses Parr 3916EKX hydrogenation apparatus and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenation apparatus.
  • the hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.
  • the microwave reaction used a CEM Discover-S 908860 microwave reactor.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20°C to 30°C.
  • the monitoring of the reaction progress in the embodiment adopts thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of the column chromatography used for purifying the compound and the developing solvent system of the thin layer chromatography method include: A: Dichloromethane/methanol system; B: n-hexane/ethyl acetate system.
  • the volume ratio of the solvent is adjusted according to the polarity of the compound, and can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.
  • reaction solution was diluted with water (200 mL), then extracted with ethyl acetate (100 mL ⁇ 3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was It was concentrated under reduced pressure, and the residue was purified by column chromatography with eluent system B to give the title compound 1b (2.66 g, yield: 88%).
  • reaction solution was filtered and prepared by high performance liquid phase (Waters 2767-SQ Detector2, elution system: 10 mmol/L ammonium bicarbonate aqueous solution and acetonitrile, gradient of acetonitrile: 55%-70%, flow rate: 30 mL/min) to obtain the title compound 1 (16 mg, 28% yield).
  • reaction solution was poured into ice water (20 mL), then extracted with ethyl acetate (30 mL ⁇ 3), the organic phases were combined, washed with saturated sodium chloride solution (20 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was It was concentrated under reduced pressure, and the residue was purified by column chromatography with eluent system B to give the title compound 3b (500 mg, yield: 88%).
  • reaction solution was diluted with water (30 mL), then extracted with ethyl acetate (40 mL ⁇ 3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue Purification by column chromatography with eluent system B afforded the title compound 6b (1.0 g, yield: 96%).
  • the obtained crude 6'a was subjected to chiral preparation (separation conditions: chiral preparative column CHIRALPAK IE 20*250mm (Daicel); mobile phase: n-hexane and ethanol, gradient of ethanol: 80%; flow rate: 20 mL/min) to obtain The prepared solution was concentrated under reduced pressure in a water bath of less than 20°C to obtain the title compound 6' (25 mg), yield: 5.0%.
  • the title compound 10 (63 mg) was prepared using the synthetic route of compound 4 in Example 4, in which the starting compound 3,4-difluorobenzaldehyde was replaced by the starting compound 2,3,4-trifluorobenzaldehyde.
  • the title compound 12 (20 mg) was prepared using the synthetic route of compound 4 in Example 4, in which the starting compound 3,4-difluorobenzaldehyde was replaced by the starting compound 3,4,5-trifluorobenzaldehyde.
  • reaction solution was diluted with water (200 mL), then extracted with ethyl acetate (100 mL ⁇ 3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue Purification by column chromatography with eluent system B afforded the title compound 17b (1.0 g, 42% yield).
  • the following method was used to determine the inhibitory activity of the disclosed compounds on the proliferation of NCI-H929 cells.
  • the experimental method is briefly described as follows.
  • NCI-H929 cells (ATCC, CRL-9068) were cultured in complete medium ie RPMI1640 medium (Hyclone) containing 10% fetal bovine serum (Corning, 35-076-CV) and 0.05 mM 2-mercaptoethanol (Sigma, M3148). , SH30809.01) were cultured.
  • NCI-H929 cells were seeded in a 96-well plate at a density of 6000 cells/well in complete medium, 100 ⁇ L of cell suspension was added to each well, and 10 ⁇ L of gradient dilution prepared in complete medium was added to each well.
  • the compounds were first dissolved in DMSO with an initial concentration of 10 mM, and serially diluted by 5-fold concentration gradient, with a total of 9 concentration points, and the blank control was 100% DMSO. Then 5 ⁇ L of the compound dissolved in DMSO was added to 95 ⁇ L of complete medium, that is, the compound was diluted 20 times with complete medium. Finally, 10 ⁇ L of each well of the compound diluted in complete medium was added to the cell suspension, that is, the final concentration of the compound was 9 concentration points for 5-fold serial dilution starting from 50 ⁇ M, and a blank control containing 0.5% DMSO was set. Place in a 37 °C, 5% CO 2 cell incubator for 5 days.
  • the compounds of the present disclosure have a good activity of inhibiting the proliferation of NCI-H929 cells.
  • Example 6 The compound of Example 6 and the control CC-92480 were evaluated for their effect on inhibiting the growth of human multiple myeloma cell NCI-H929 xenografts in CB-17 SCID mice.
  • Example 6 The compound of Example 6 and the control CC-92480 were formulated with 5% DMSO + 20% PEG400 + 70% (10% TPGS) + 5% (1% HPMC K100LV).
  • SCID female mice were purchased from Beijing Weitong Lihua Laboratory Animal Co., Ltd. (certificate number: 20170011006049, SCXK (Shanghai) 2017-0011), weighing about 19g at the time of purchase, 5 mice/cage were raised, 12/12 hours light/dark cycle adjustment, temperature 23 ⁇ 1°C constant temperature, humidity 50-60%, free food and water.
  • mice were grouped as follows:
  • mice 5 ⁇ 10 6 cells/mouse/100 ⁇ L (containing 50 ⁇ L Matrigel) of NCI-H929 cells in logarithmic growth phase were subcutaneously inoculated into the right flank of 30 female CB-17 SCID mice.
  • vehicle control group CC-92480-1mpk
  • compound of Example 6-1mpk 7 mice in each group.
  • the day of the grouping was set as Day0 (D0), and the oral administration was started once a day for a total of 11 days (Table 2).
  • Tumor volume in tumor-bearing mice was measured with a caliper and body weight with a balance twice a week and the data were recorded. Tumor-bearing animals were euthanized as experimental endpoints when tumor volume reached 2000 mm 3 or when most tumors ruptured or lost 20% of body weight.
  • V tumor volume
  • T/C(%) (TT 0 )/(CC 0 ) ⁇ 100(%), where: T and C are the tumor volumes of the treatment group and the control group at the end of the experiment; T 0 and C 0 are the Tumor volume at the start of the experiment.
  • TGI (%) 1-T/C (%), when TGI (%) exceeds 100%, no specific value will be displayed, only >100%.
  • Tumor regression (%) [(T 0 -T)/T 0 ] ⁇ 100(%).
  • the compound of Example 6 was administered 10 days after tumor cell transplantation, once a day, and the tumor volume regressed significantly after 11 days of administration.
  • the calculated tumor inhibition rate was >100%, and the tumor regression rate was 88%.
  • the tumor regression rate of the control CC-92480 was 34%.
  • mice Using mice as the test animals, the LC/MS/MS method was used to determine the drug concentrations in the plasma at different times after the mice were given the compound of Example 6 and the control example CC-92480 by gavage. The pharmacokinetic behavior of the disclosed compounds in mice was studied, and their pharmacokinetic characteristics were evaluated.
  • mice Female, were purchased from Weitong Lihua Laboratory Animal Co., Ltd., animal production license number: SCXK (Shanghai) 2017-0005.
  • Example 6 Weigh the compound of Example 6, add 5% volume of DMSO and 5% Tween 80 (Shanghai Titan Technology Co., Ltd.) to dissolve it, and then add 90% normal saline to prepare a 0.1 mg/mL clear solution.
  • mice Nine mice were given the compound of Example 6 by gavage at a dose of 2 mg/kg, and the administration volume was 0.2 mL/10 g.
  • mice Nine mice were given the compound control example CC-92480 by gavage at a dose of 2 mg/kg, and the administration volume was 0.2 mL/10 g.
  • mice were given the compound of Example 6 and the control example CC-92480 by gavage, and 0.2 mL of blood was collected before and after administration at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours (each time 3 animals), placed in an EDTA-K2 anticoagulation test tube, centrifuged at 10,000 rpm for 1 minute (4°C), separated plasma within 1 hour, and stored at -20°C for testing. The blood was collected until the centrifugation process was operated under ice bath conditions.
  • Determination of the content of the test compound in mouse plasma after drug administration of different concentrations take 25 ⁇ L of mouse plasma at each time after administration, add 50 ⁇ L (100 ng/mL) of internal standard solution camptothecin (China Institute for Biological Products) and 175 ⁇ L of acetonitrile, mixed by vortex for 5 minutes, centrifuged for 10 minutes (3700 rpm), and 1 ⁇ L of the supernatant from the plasma sample was subjected to LC/MS/MS (API4000 triple quadrupole tandem mass spectrometer, Applied Biosystems, USA; Shimadzu LC -30AD ultra-high performance liquid chromatography system, Japan Shimadzu company) analysis.
  • LC/MS/MS API4000 triple quadrupole tandem mass spectrometer, Applied Biosystems, USA; Shimadzu LC -30AD ultra-high performance liquid chromatography system, Japan Shimadzu company
  • CONCLUSION The disclosed compounds have good pharmacokinetic absorption and have pharmacokinetic advantages.
  • Example 6 The compound of Example 6 and the control example CC-92480 were quantitatively determined by LC-MS/MS in monkey cryopreserved plasma after incubation at 37°C for 0, 15, 30, 60, 120, 180, and 240 minutes, respectively.
  • Monkey plasma was purchased from Shanghai Medicilon Biopharmaceutical Co., Ltd.

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