WO2022148358A1 - Dérivé de cyclohexadiimide substitué par un hétérocyclyle fusionné, procédé de préparation associé et application pharmaceutique correspondante - Google Patents

Dérivé de cyclohexadiimide substitué par un hétérocyclyle fusionné, procédé de préparation associé et application pharmaceutique correspondante Download PDF

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WO2022148358A1
WO2022148358A1 PCT/CN2022/070210 CN2022070210W WO2022148358A1 WO 2022148358 A1 WO2022148358 A1 WO 2022148358A1 CN 2022070210 W CN2022070210 W CN 2022070210W WO 2022148358 A1 WO2022148358 A1 WO 2022148358A1
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general formula
pharmaceutically acceptable
acceptable salt
compound represented
alkyl
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PCT/CN2022/070210
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English (en)
Chinese (zh)
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贾敏强
汤焕宇
杨方龙
贺峰
陶维康
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江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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Priority to CN202280008923.4A priority Critical patent/CN116669736A/zh
Publication of WO2022148358A1 publication Critical patent/WO2022148358A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the present disclosure belongs to the field of medicine, and relates to a fused heterocyclic group-substituted cyclohexanediimide derivative, a preparation method thereof and its application in medicine.
  • the present disclosure relates to a fused heterocyclyl-substituted cyclohexanediimide derivative represented by general formula (I), a method for its preparation and a pharmaceutical composition containing the derivative, and its use as a Cereblon modulator in the treatment of Use in the field of multiple myeloma.
  • MM Multiple myeloma
  • MM is a malignant tumor whose main symptoms include hypercalcemia, kidney damage, anemia and bone disease.
  • MM is the second most common hematological malignancy after non-Hodgkin lymphoma, with 4 to 6 people per 100,000 people in the world 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 widely used in clinical practice namely, immunomodulators, proteasome inhibitors, hormones and monoclonal antibodies. Wait. The mechanisms of action of these drugs are different, and combined use can often achieve better efficacy.
  • IiDs immunomodulators
  • CRBN Cereblon
  • IKZF1 transcription factors Ikaros
  • IKZF3 Aiolos
  • 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.
  • 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 IMiDs 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 IMiDs drugs include thalidomide, lenalidomide and pomalidomide, all from Celgene (now merged by BMS).
  • the binding force of these three compounds to CRBN increased in turn, so the clinical dosage decreased in turn.
  • the main indication of these three compounds is MM, and thalidomide and lenalidomide can also treat other indications, especially lenalidomide, which can be used to treat myelodysplastic syndrome (MDS).
  • MDS myelodysplastic syndrome
  • 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.
  • IMiDs The adipimide portion of all IMiDs binds 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 modification of the molecular surface of CRBN, and the preference for substrate recognition is also different. Therefore, modification of IMiDs may lead to the degradation of other transcription factors, causing unnecessary toxic side effects.
  • This mode of action of IMiDs also known as molecular glue, visualizes the binding effect of this small molecule on two protein substrates.
  • Ring A is aryl or heteroaryl
  • R 1 is selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino and hydroxy;
  • R 2 is the same or different at each occurrence and is each independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, Cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, One or more substituents of alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl replaced;
  • R 3 and R 4 are the same or different, and are each independently selected from hydrogen atoms, halogens, and alkyl groups;
  • R 6 is the same or different at each occurrence and is each independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, Cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, One or more substituents of alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl replaced;
  • n 1, 2 or 3;
  • n 0, 1, 2 or 3;
  • Rings A, X, Y, Z, G 1 , G 2 , G 3 , R 1 to R 7 , m, n, p and q are as defined in general formula (I).
  • the compound represented by the general formula (I), the general formula (I-1) or a pharmaceutically acceptable salt thereof is the compound represented by the general formula (I-1-1) or Its pharmaceutically acceptable salts:
  • the compound represented by the general formula (I), the general formula (I-1) or a pharmaceutically acceptable salt thereof is the compound represented by the general formula (I-1-2) or Its pharmaceutically acceptable salts:
  • Rings A, X, Y, Z, G 1 , G 2 , G 3 , R 1 to R 7 , m, n, p and q are as defined in general formula (I).
  • the compound represented by general formula (I), general formula (I-1), general formula (II) or a pharmaceutically acceptable salt thereof is general formula (II-1)
  • Rings A, X, Z, G 1 , G 2 , G 3 , R 1 , R 2 , R 5 to R 7 , m, n, p and q are as defined in general formula (I).
  • the general formula (I), general formula (I-1), general formula (I-1-1), general formula (II), general formula (II-1) The compound shown or a pharmaceutically acceptable salt thereof is the compound represented by the general formula (II-1-1) or a pharmaceutically acceptable salt thereof:
  • Rings A, X, Z, G 1 , G 2 , G 3 , R 1 , R 2 , R 5 to R 7 , m, n, p and q are as defined in general formula (I).
  • the general formula (I), general formula (I-1), general formula (I-1-2), general formula (II), general formula (II-1) are The compound shown or a pharmaceutically acceptable salt thereof is the compound represented by the general formula (II-1-2) or a pharmaceutically acceptable salt thereof:
  • Rings A, X, Z, G 1 , G 2 , G 3 , R 1 , R 2 , R 5 to R 7 , m, n, p and q are as defined in general formula (I).
  • the general formula (I), general formula (I-1), general formula (I-1-1), general formula (I-1-2), general formula (II) a compound represented by general formula (II-1), general formula (II-1-1), general formula (II-1-2) or a pharmaceutically acceptable salt thereof, wherein X is CH 2 .
  • the general formula (I), general formula (I-1), general formula (I-1-1), general formula (I-1-2), general formula (II) the compound represented by general formula (II-1), general formula (II-1-1), general formula (II-1-2) or a pharmaceutically acceptable salt thereof, wherein Z is CR a R b ; R a The same as R b , and each independently a hydrogen atom or a halogen; preferably, R a and R b are the same, and each independently a hydrogen atom or a fluorine atom.
  • the compound represented by general formula (I), general formula (II) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof :
  • the pharmaceutically acceptable salt is the compound represented by the general formula (III-1) or a pharmaceutically acceptable salt thereof:
  • Rings A, G 1 , G 2 , G 3 , R 1 , R 2 , R 5 to R 7 , m, n, p and q are as defined in general formula (I).
  • the compound represented by formula (II-1-1), general formula (III), general formula (III-1) or a pharmaceutically acceptable salt thereof is the compound represented by general formula (III-1-1) or its pharmaceutically acceptable salt.
  • Rings A, G 1 , G 2 , G 3 , R 1 , R 2 , R 5 to R 7 , m, n, p and q are as defined in general formula (I).
  • Rings A, G 1 , G 2 , G 3 , R 1 , R 2 , R 5 to R 7 , m, n, p and q are as defined in general formula (I).
  • the general formula (I), general formula (I-1), general formula (I-1-1), general formula (I-1-2), general formula (II) , general formula (II-1), general formula (II-1-1), general formula (II-1-2), general formula (III), general formula (III-1), general formula (III-1- 1) The compound represented by the general formula (III-1-2) or a pharmaceutically acceptable salt thereof, wherein G 1 , G 2 and G 3 are all CR 8 ; R 8 is a hydrogen atom.
  • the general formula (I), general formula (I-1), general formula (I-1-1), general formula (I-1-2), general formula (II) ), general formula (II-1), general formula (II-1-1), general formula (II-1-2), general formula (III), general formula (III-1), general formula (III-1 -1) The compound represented by the general formula (III-1-2) or a pharmaceutically acceptable salt thereof, wherein q is 0, 1 or 2; preferably, q is 1.
  • the general formula (I), general formula (I-1), general formula (I-1-1), general formula (I-1-2), general formula (II) , general formula (II-1), general formula (II-1-1), general formula (II-1-2), general formula (III), general formula (III-1), general formula (III-1- 1) The compound represented by the general formula (III-1-2) or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2.
  • the compound represented by general formula (I), general formula (I-1), general formula (II), general formula (II-1) or a pharmaceutically acceptable salt thereof in for example, the compound represented by general formula (I), general formula (I-1), general formula (II), general formula (II-1) or a pharmaceutically acceptable salt thereof, in for example, the compound represented by general formula (I), general formula (I-1), general formula (II), general formula (II-1) or a pharmaceutically acceptable salt thereof, in for
  • the compound represented by general formula (I), general formula (I-1), general formula (I-1-1), general formula (I-1-2) or A pharmaceutically acceptable salt thereof wherein G 1 , G 2 and G 3 are all CR 8 ; R 8 is a hydrogen atom; Z is CR a R b ; R a and R b are the same, and are each independently a hydrogen atom or a halogen ; X is CH 2 ; Y is an oxygen atom; Ring A is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group; R 1 is a hydrogen atom; R 2 is a hydrogen atom; R 3 and R 4 are both hydrogen atoms ; R 5 is the same or different at each occurrence, and each is independently a hydrogen atom or a C 1-6 alkyl; R 6 is the same or different at each occurrence, and each is independently selected from a hydrogen atom, halogen, C 1-6 alkyl, C
  • the compound represented by general formula (I), general formula (I-1) or a pharmaceutically acceptable salt thereof wherein G 1 , G 2 and G 3 are all CR 8 R 8 is a hydrogen atom; Z is CR a R b ; R a and R b are the same, and are each independently a hydrogen atom or a halogen; X is CH 2 ; Y is an oxygen atom; Ring A is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group; R 1 is a hydrogen atom; R 2 is a hydrogen atom; R 3 and R 4 are both hydrogen atoms; R 5 is the same or different at each occurrence, and is each independently a hydrogen atom or C 1-6 alkyl; R 6 is the same or different at each occurrence, and each is independently selected from hydrogen atom, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 halo
  • the compound represented by general formula (II), general formula (II-1), general formula (II-1-1), general formula (II-1-2) or A pharmaceutically acceptable salt thereof wherein G 1 , G 2 and G 3 are all CR 8 ; R 8 is a hydrogen atom; Z is CR a R b ; R a and R b are the same, and are each independently a hydrogen atom or fluorine Atom; X is CH 2 ; Ring A is phenyl; R 1 is a hydrogen atom; R 2 is a hydrogen atom; R 5 is the same or different at each occurrence and is each independently a hydrogen atom or a C 1-6 alkyl group ; R 6 is the same or different at each occurrence and is each independently selected from a hydrogen atom, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 haloalkane oxy; R 7 is cyano; p is 0, 1 or
  • the compound represented by general formula (II), general formula (II-1) or a pharmaceutically acceptable salt thereof wherein G 1 , G 2 and G 3 are all CR 8 ; R 8 is a hydrogen atom; Z is CR a R b ; R a and R b are the same, and are each independently a hydrogen atom or a fluorine atom; X is CH 2 ; Ring A is a phenyl group; R 1 is a hydrogen atom; R 2 is a hydrogen atom; R 5 is the same or different at each occurrence, and each is independently a hydrogen atom or a C 1-6 alkyl; R 6 is the same or different at each occurrence, and each is independently selected from a hydrogen atom , halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy; R 7 is cyano; p is 0, 1 or 2; q is 0 , 1,
  • the compound represented by general formula (III), general formula (III-1), general formula (III-1-1), general formula (III-1-2) or A pharmaceutically acceptable salt thereof wherein G 1 , G 2 and G 3 are all CR 8 ; R 8 is a hydrogen atom; Ring A is a phenyl group; R 1 is a hydrogen atom; R 2 is a hydrogen atom ; appearing the same or different, and each independently is a hydrogen atom or a C 1-6 alkyl; R 6 is the same or different at each occurrence, and each is independently selected from a hydrogen atom, a halogen, a C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy; R 7 is cyano; p is 0, 1 or 2; q is 0, 1 or 2; n is 1 or 2 ; m is 0.
  • the compound represented by general formula (III), general formula (III-1) or a pharmaceutically acceptable salt thereof wherein G 1 , G 2 and G 3 are all CR 8 R 8 is a hydrogen atom; Ring A is a phenyl group; R 1 is a hydrogen atom; R 2 is a hydrogen atom; R 5 is the same or different at each occurrence and is each independently a hydrogen atom or a C 1-6 alkyl group ; R 6 is the same or different at each occurrence and is each independently selected from a hydrogen atom, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 haloalkane oxy; R 7 is cyano; p is 0, 1 or 2; q is 0, 1 or 2; n is 2;
  • the compound represented by general formula (III), general formula (III-1), general formula (III-1-1), general formula (III-1-2) or A pharmaceutically acceptable salt thereof wherein G 1 , G 2 and G 3 are all CR 8 ; R 8 is a hydrogen atom; Ring A is a phenyl group; R 1 is a hydrogen atom; R 5 is the same or different at each occurrence, and each independently a hydrogen atom or a C 1-6 alkyl group; R 6 is the same or different at each occurrence, and each is independently selected from a hydrogen atom, a halogen, a C 1-6 alkyl group, a C 1-6 alkoxy group R 7 is cyano; p is 0, 1 or 2; q is 0, 1 or 2; n is 1 or 2; m is 0.
  • the compound represented by general formula (III), general formula (III-1), general formula (III-1-1), general formula (III-1-2) or Its pharmaceutically acceptable salt wherein G 1 , G 2 and G 3 are all CR 8 ; R 8 is a hydrogen atom; for R 1 is a hydrogen atom; R 6 is a halogen; R 7 is a cyano group; p is 0; q is 1; n is 1 or 2;
  • Typical compounds of the present disclosure include, but are not limited to:
  • Another aspect of the present disclosure relates to a compound of formula (IA) or a salt thereof,
  • R m is C 1-6 alkyl; preferably, R m is tert-butyl;
  • Rings A, X, Y, Z, G 1 , G 2 , G 3 , R 1 to R 7 , m, n, p and q are as defined for compounds of general formula (I).
  • Another aspect of the present disclosure relates to a compound represented by general formula (IA-1) or a salt thereof,
  • R m is C 1-6 alkyl; preferably, R m is tert-butyl;
  • Rings A, X, Y, Z, G 1 , G 2 , G 3 , R 1 to R 7 , m, n, p and q are as defined for compounds of general formula (I-1).
  • Another aspect of the present disclosure relates to a compound represented by the general formula (IA-1-1) or a salt thereof,
  • R m is C 1-6 alkyl; preferably, R m is tert-butyl;
  • Rings A, X, Y, Z, G 1 , G 2 , G 3 , R 1 to R 7 , m, n, p and q are as defined for the compound of general formula (I-1-1).
  • Another aspect of the present disclosure relates to a compound represented by the general formula (IA-1-2) or a salt thereof,
  • R m is C 1-6 alkyl; preferably, R m is tert-butyl;
  • Rings A, X, Y, Z, G 1 , G 2 , G 3 , R 1 to R 7 , m, n, p and q are as defined for compounds of general formula (I-1-2).
  • Another aspect of the present disclosure relates to a compound of general formula (IIA) or a salt thereof:
  • R m is C 1-6 alkyl; preferably, R m is tert-butyl;
  • Rings A, X, Z, G 1 , G 2 , G 3 , R 1 , R 2 , R 5 to R 7 , m, n, p and q are as defined for compounds of general formula (II).
  • Another aspect of the present disclosure relates to a compound of general formula (IIA-1) or a salt thereof:
  • R m is C 1-6 alkyl; preferably, R m is tert-butyl;
  • Rings A, X, Z, G 1 , G 2 , G 3 , R 1 , R 2 , R 5 to R 7 , m, n, p and q are as defined for compounds of general formula (II-1).
  • Another aspect of the present disclosure relates to a compound represented by the general formula (IIA-1-1) or a salt thereof:
  • R m is C 1-6 alkyl; preferably, R m is tert-butyl;
  • Rings A, X, Z, G 1 , G 2 , G 3 , R 1 , R 2 , R 5 to R 7 , m, n, p and q are as defined in the compound of general formula (II-1-1).
  • Another aspect of the present disclosure relates to a compound of general formula (IIA-1-2) or a salt thereof:
  • R m is C 1-6 alkyl; preferably, R m is tert-butyl;
  • Rings A, X, Z, G 1 , G 2 , G 3 , R 1 , R 2 , R 5 to R 7 , m, n, p and q are as defined for the compound of general formula (II-1-2).
  • Another aspect of the present disclosure relates to a compound of general formula (IIIA) or a salt thereof:
  • R m is C 1-6 alkyl; preferably, R m is tert-butyl;
  • Rings A, G 1 , G 2 , G 3 , R 1 , R 2 , R 5 to R 7 , m, n, p and q are as defined for compounds of general formula (III).
  • Another aspect of the present disclosure relates to a compound represented by the general formula (IIIA-1) or a salt thereof:
  • R m is C 1-6 alkyl; preferably, R m is tert-butyl;
  • Ring A, G 1 , G 2 , G 3 , R 1 , R 2 , R 5 to R 7 , m, n, p and q are as defined for compounds of general formula (III-1).
  • Another aspect of the present disclosure relates to a compound represented by the general formula (IIIA-1-1) or a salt thereof:
  • R m is C 1-6 alkyl; preferably, R m is tert-butyl;
  • Ring A, G 1 , G 2 , G 3 , R 1 , R 2 , R 5 to R 7 , m, n, p and q are as defined for the compound of general formula (III-1-1).
  • Another aspect of the present disclosure relates to a compound of general formula (IIIA-1-2) or a salt thereof:
  • R m is C 1-6 alkyl; preferably, R m is tert-butyl;
  • Ring A, G 1 , G 2 , G 3 , R 1 , R 2 , R 5 to R 7 , m, n, p and q are as defined for the compound of general formula (III-1-2).
  • Typical intermediate compounds of the present disclosure include, but are not limited to:
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound represented by the general formula (IA) or a salt thereof undergoes an intramolecular ring closure reaction to obtain the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof,
  • R m is C 1-6 alkyl; preferably, R m is tert-butyl;
  • Rings A, X, Y, Z, G 1 , G 2 , G 3 , R 1 to R 7 , m, n, p and q are as defined in general formula (I).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I-1) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound represented by the general formula (IA-1) or a salt thereof undergoes an intramolecular ring closure reaction to obtain the compound represented by the general formula (I-1) or a pharmaceutically acceptable salt thereof,
  • R m is C 1-6 alkyl; preferably, R m is tert-butyl;
  • Rings A, X, Y, Z, G 1 , G 2 , G 3 , R 1 to R 7 , m, n, p and q are as defined in general formula (I-1).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I-1-1) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound represented by the general formula (IA-1-1) or a salt thereof undergoes an intramolecular ring-closing reaction to obtain the compound represented by the general formula (I-1-1) or a pharmaceutically acceptable salt thereof,
  • the compound represented by the general formula (IA-1-2) or a salt thereof undergoes an intramolecular ring-closing reaction to obtain the compound represented by the general formula (I-1-2) or a pharmaceutically acceptable salt thereof,
  • R m is C 1-6 alkyl; preferably, R m is tert-butyl;
  • Rings A, X, Y, Z, G 1 , G 2 , G 3 , R 1 to R 7 , m, n, p and q are as defined in the general formula (I-1-2).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II), or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound represented by the general formula (IIA) or a salt thereof undergoes an intramolecular ring closure reaction to obtain the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof,
  • R m is C 1-6 alkyl; preferably, R m is tert-butyl;
  • Rings A, X, Z, G 1 , G 2 , G 3 , R 1 , R 2 , R 5 to R 7 , m, n, p and q are as defined for compounds of general formula (II).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II-1) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound represented by the general formula (IIA-1) or a salt thereof undergoes an intramolecular ring closure reaction to obtain the compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof,
  • R m is C 1-6 alkyl; preferably, R m is tert-butyl;
  • Rings A, X, Z, G 1 , G 2 , G 3 , R 1 , R 2 , R 5 to R 7 , m, n, p and q are as defined for compounds of general formula (II-1).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II-1-1) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound represented by the general formula (IIA-1-1) or a salt thereof undergoes an intramolecular ring closure reaction to obtain the compound represented by the general formula (II-1-1) or a pharmaceutically acceptable salt thereof,
  • R m is C 1-6 alkyl; preferably, R m is tert-butyl;
  • Rings A, X, Z, G 1 , G 2 , G 3 , R 1 , R 2 , R 5 to R 7 , m, n, p and q are as defined in the compound of general formula (II-1-1).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II-1-2) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound represented by the general formula (IIA-1-2) or a salt thereof undergoes an intramolecular ring closure reaction to obtain the compound represented by the general formula (II-1-2) or a pharmaceutically acceptable salt thereof,
  • R m is C 1-6 alkyl; preferably, R m is tert-butyl;
  • Rings A, X, Z, G 1 , G 2 , G 3 , R 1 , R 2 , R 5 to R 7 , m, n, p and q are as defined for the compound of general formula (II-1-2).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound represented by the general formula (IIIA) or a salt thereof undergoes an intramolecular ring-closing reaction to obtain the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof,
  • R m is C 1-6 alkyl; preferably, R m is tert-butyl;
  • Rings A, G 1 , G 2 , G 3 , R 1 , R 2 , R 5 to R 7 , m, n, p and q are as defined for compounds of general formula (III).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III-1) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound represented by the general formula (IIIA-1) or a salt thereof undergoes an intramolecular ring-closing reaction to obtain the compound represented by the general formula (III-1) or a pharmaceutically acceptable salt thereof,
  • R m is C 1-6 alkyl; preferably, R m is tert-butyl;
  • Ring A, G 1 , G 2 , G 3 , R 1 , R 2 , R 5 to R 7 , m, n, p and q are as defined for compounds of general formula (III-1).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III-1-1) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound represented by the general formula (IIIA-1-1) or a salt thereof undergoes an intramolecular ring-closing reaction to obtain the compound represented by the general formula (III-1-1) or a pharmaceutically acceptable salt thereof,
  • R m is C 1-6 alkyl; preferably, R m is tert-butyl;
  • Ring A, G 1 , G 2 , G 3 , R 1 , R 2 , R 5 to R 7 , m, n, p and q are as defined for the compound of general formula (III-1-1).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III-1-2) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound represented by the general formula (IIIA-1-2) or a salt thereof undergoes an intramolecular ring-closing reaction to obtain the compound represented by the general formula (III-1-2) or a pharmaceutically acceptable salt thereof,
  • R m is C 1-6 alkyl; preferably, R m is tert-butyl;
  • Ring A, G 1 , G 2 , G 3 , R 1 , R 2 , R 5 to R 7 , m, n, p and q are as defined for the compound of general formula (III-1-2).
  • Another aspect of the present disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the general formula (I), the general formula (I-1), the general formula (I-1-1), the general formula (I- 1-2), general formula (II), general formula (II-1), general formula (II-1-1), general formula (II-1-2), general formula (III), general formula (III- 1), the compound shown in general formula (III-1-1), general formula (III-1-2) and the compound shown in Table A or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carrier, diluent or excipient.
  • the present disclosure further relates to general formula (I), general formula (I-1), general formula (I-1-1), general formula (I-1-2), general formula (II), general formula (II-1) ), general formula (II-1-1), general formula (II-1-2), general formula (III), general formula (III-1), general formula (III-1), general formula (III) -
  • general formula (I), general formula (I-1), general formula (I-1-1), general formula (I-1-2), general formula (III), general formula (III-1), general formula (III-1-1), general formula (III) Use of the compounds shown in 1-2) and the compounds shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of 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-1-1), general formula (I-1-2), general formula (II), general formula (II-1) ), general formula (II-1-1), general formula (II-1-2), general formula (III), general formula (III-1), general formula (III-1), general formula (III)
  • the compound shown in -1-2) and the compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same are prepared for the treatment and/or prevention of cancer, angiogenesis-related disorders, pain, Macular degeneration or related syndrome, skin disease, lung disease, asbestos-related disease, parasitic disease, immunodeficiency disease, central nervous system (CNS) disease, CNS injury, atherosclerosis or related disorder, sleep disturbance or related disorder , use in a medicament for an infectious disease, 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.
  • the present disclosure also relates to a method for treating and/or preventing a disease 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-1- 1), general formula (I-1-2), general formula (II), general formula (II-1), general formula (II-1-1), general formula (II-1-2), general formula ( III), the compound represented by the general formula (III-1), the general formula (III-1-1), the general formula (III-1-2) and the compound shown in Table A or a pharmaceutically acceptable salt thereof, or containing its pharmaceutical composition.
  • 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 TNF ⁇ related disorders, preferably a method 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-1-1), general formula (I-1-2), general formula (II), general formula (I-1-2), general formula (II), general formula formula (II), general formula formula (II-1), general formula (II-1-1), general formula (II-1-2), general formula (III), general formula (III-1), general formula (III-1), general formula (III-1-1) , the compound represented by the general formula (III-1-2) and the compound represented by Table A or a pharmaceutical
  • the present disclosure further relates to a general formula (I), general formula (I-1), general formula (I-1-1), general formula (I-1-2), general formula (II), general formula (II) -1), general formula (II-1-1), general formula (II-1-2), general formula (III), general formula (III-1), general formula (III-1-1), general formula (III-1), general formula (III-1), general formula (III-1), general formula
  • the present disclosure further relates to general formula (I), general formula (I-1), general formula (I-1-1), general formula (I-1-2), general formula (II), general formula (II-1) ), general formula (II-1-1), general formula (II-1-2), general formula (III), general formula (III-1), general formula (III-1), general formula (III)
  • the compounds shown in -1-2) and the compounds shown in Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, are used 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-1-1), general formula (I-1-2), general formula (II), general formula (II-1) ), general formula (II-1-1), general formula (II-1-2), general formula (III), general formula (III-1), general formula (III-1), general formula (III)
  • the compound shown in -1-2) and the compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the 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 conditions, sleep disorders or related conditions, infectious diseases, Hemoglobinopathies or related disorders or TNF ⁇ related disorders; preferably for the treatment and/or prevention of cancer or CNS damage.
  • 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 cancer described in this disclosure is selected from the group consisting of leukemia, myeloma, lymphoma, melanoma, skin cancer, liver cancer (eg, hepatocellular carcinoma), kidney cancer, lung cancer (eg, non-small cell lung cancer and small cell lung cancer), nasopharyngeal carcinoma cancer, gastric cancer, esophageal cancer (also known as esophageal cancer), colorectal cancer (such as colon and rectal cancer), gallbladder cancer, bile duct cancer, chorioepithelial cancer, pancreatic cancer, polycythemia vera, pediatric oncology, cervical cancer, Ovarian cancer, breast cancer, bladder cancer, urothelial cancer, ureteral tumor, prostate cancer, seminoma, testicular tumor, head and neck cancer, head and neck squamous cell carcinoma, endometrial cancer, thyroid cancer, sarcoma (such as osteosarcoma and soft tissue sarcomas), osteomas, neuro
  • Said myeloma is preferably multiple myeloma (MM) and myelodysplastic syndrome (MDS); more preferably, said multiple myeloma is relapsed, refractory or resistant; most preferably Preferably, the multiple myeloma is lenalidomide or pomalidomide refractory or resistant.
  • 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.
  • 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.
  • CNS disorders include, but are not limited to, disorders described in US Publication No. 2005/0143344, 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 in a short period of time, and 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 disorders described in US Publication No. 2006/0122228, 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 spinal cord injury (SCI), incomplete SCI, acute SCI, subcutaneous Acute SCI, chronic SCI, central spinal cord syndrome, hemisection cord syndrome, anterior cord syndrome, conus medullaris syndrome, cauda equina syndrome, neurogenic shock, spinal shock, altered level of consciousness, headache, nausea, vomiting, memory Depression, dizziness, diplopia, blurred vision, mood swing
  • 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 sustained release 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 straight or branched chain aliphatic hydrocarbon group having 1 to 20 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (ie C 1-20 alkyl).
  • the alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (ie, a C 1-12 alkyl group), and more preferably an alkyl group having 1 to 6 carbon atoms (ie, a C 1-6 alkyl group).
  • Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2 -methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl
  • lower alkyl groups having 1 to 6 carbon atoms include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl , n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3 -Methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl , 2,3-dimethylbutyl, etc.
  • Alkyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from the group consisting of D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkane One or more of oxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • alkylene refers to a divalent alkyl group, wherein the alkyl group is as defined above, having from 1 to 20 (eg, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (ie C 1-20 alkylene).
  • the alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (ie, a C 1-12 alkylene group), and more preferably an alkylene group having 1 to 6 carbon atoms (ie, a C 1-6 alkylene group).
  • Non-limiting examples of alkylene groups include, but are not limited to: methylene ( -CH2- ), 1,1-ethylene (-CH( CH3 )-), 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 base (-CH 2 CH 2 CH 2 -), 1,4-butylene (-CH 2 CH 2 CH 2 CH 2 -) and the like.
  • Alkylene may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy group, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, ring One or more of alkoxy, 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 and has 2 to 12 (eg 2, 3, 4, 5, 6, 7, 8 , 9, 10, 11 or 12) carbon atoms (ie C 2-12 alkenyl).
  • the alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (ie, a C 2-6 alkenyl group).
  • Non-limiting examples include: vinyl, propenyl, butenyl, pentenyl, hexenyl, and the like.
  • Alkenyl can be substituted or unsubstituted, when substituted, the substituent is preferably selected from alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy , one or more of hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • alkynyl refers to an alkyl compound containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above and has 2 to 12 (eg 2, 3, 4, 5, 6, 7, 8 , 9, 10, 11 or 12) carbon atoms (ie C 2-12 alkynyl).
  • the alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (ie, a C 2-6 alkynyl group).
  • Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably selected from alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy , one or more of hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • alkoxy refers to -O-(alkyl), wherein alkyl is as defined above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy.
  • Alkoxy can be optionally substituted or unsubstituted, when substituted, the substituent is preferably selected from D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, hetero One or more of cyclooxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent having 3 to 20 cycloalkyl rings (eg 3, 4, 5, 6, 7, 8, 9, 10 , 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (ie 3 to 20 membered cycloalkyl), preferably 3 to 12 carbon atoms (ie 3 to 12 membered ring alkyl), more preferably 3 to 8 carbon atoms (ie 3 to 8 membered cycloalkyl), most preferably 3 to 6 carbon atoms (ie 3 to 6 membered cycloalkyl).
  • 3 to 20 cycloalkyl rings eg 3, 4, 5, 6, 7, 8, 9, 10 , 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20
  • carbon atoms ie 3 to 20 membered cycloalkyl
  • preferably 3 to 12 carbon atoms ie 3 to 12 membered ring alkyl
  • Non-limiting examples of monocyclic cycloalkyl groups include: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptyl Alkenyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocycloalkyl groups, fused cycloalkyl groups, and bridged cycloalkyl groups.
  • spirocycloalkyl refers to a polycyclic group of 5 to 20 membered monocyclic rings sharing one carbon atom (called a spiro atom), which may contain one or more double bonds. Preferably 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 divided into mono-spirocycloalkyl groups or multi-spirocycloalkyl groups (such as bis-spirocycloalkyl groups), preferably mono-spirocycloalkyl groups or double-spirocycloalkyl groups .
  • spirocycloalkyl More preferably 3 yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 6 yuan/4 yuan, 6-membered/5-membered or 6-membered/6-membered monospirocycloalkyl.
  • spirocycloalkyl include:
  • fused cycloalkyl refers to an all-carbon polycyclic group in which an adjacent pair of carbon atoms is shared between 5- to 20-membered rings, one or more of which may contain one or more double bonds.
  • 6 to 14 yuan more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan).
  • bicyclic, tricyclic, tetracyclic and other polycyclic fused cycloalkyl groups preferably bicyclic or tricyclic fused cycloalkyl groups, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered RMB, RMB 4/RMB 4, RMB 4/RMB 5, RMB 4/RMB 6, RMB 5/RMB 4, RMB 5/RMB 5, RMB 5/RMB 6, RMB 6/RMB 3, RMB 6/RMB 4, 6-membered/5-membered and 6-membered/6-membered bicyclic fused cycloalkyl.
  • fused cycloalkyl groups include:
  • bridged cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members in which any two rings share two non-directly attached carbon atoms, which may contain one or more double bonds.
  • 6 to 14 yuan more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan).
  • it can be divided into bicyclic, tricyclic, tetracyclic and other polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic bridged cycloalkyl groups, more preferably bicyclic or tricyclic bridged cycloalkyl groups.
  • Non-limiting examples of 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, when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy , one or more of 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 having 3 to 20 (eg 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen, and sulfur, optionally oxo ( i.e. forming a sulfoxide or sulfone), but excluding ring moieties of -O-O-, -O-S- or -S-S-, the remaining ring atoms are carbon.
  • Non-limiting examples of monocyclic heterocyclyl groups include: pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpho olinyl, homopiperazinyl, etc.
  • Polycyclic heterocyclyls include spiro heterocyclyls, fused heterocyclyls and bridged heterocyclyls.
  • spiroheterocyclyl refers to a 5- to 20-membered monocyclic polycyclic heterocyclic group sharing one atom (called a spiro atom), 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.
  • 6 to 14 yuan more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan).
  • spiroheterocyclyl groups are classified into mono-spiroheterocyclyl groups or poly-spiroheterocyclyl groups (such as bis-spiroheterocyclyl groups), preferably mono-spiroheterocyclyl groups and bis-spiro-heterocyclyl groups . More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, 5-membered/6-membered or 6-membered/6-membered monospiroheterocyclyl.
  • Non-limiting examples of spiroheterocyclyl include:
  • fused heterocyclic group refers to a polycyclic heterocyclic group in which a 5- to 20-membered ring shares an adjacent pair of atoms, one or more of which may contain one or more double bonds, wherein one or more of the rings may contain one or more double bonds.
  • the 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.
  • 6 to 14 yuan more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan).
  • the number of constituent rings it can be divided into bicyclic, tricyclic, tetracyclic polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic fused heterocyclic groups, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/ 6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/3 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 5 yuan/7 yuan , 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/6-membered bicyclic fused heterocyclic
  • bridged heterocyclyl refers to a polycyclic heterocyclic group of 5 to 14 members 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
  • the sulfur may optionally be oxo (ie to form a sulfoxide or sulfone), the remaining ring atoms being carbon.
  • 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, the substituents are preferably selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy , one or more of cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • 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, the substituents are preferably selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, One or more of cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • heteroaryl refers to a heteroaromatic system comprising 1 to 4 heteroatoms (eg 1, 2, 3 and 4), 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • Heteroaryl is preferably 5-10-membered (eg 5, 6, 7, 8, 9 or 10-membered), more preferably 5- or 6-membered, eg furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrole base, 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 may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy , one or more of cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • cycloalkyl, heterocyclyl, aryl and heteroaryl groups include residues derived by removing one hydrogen atom from the parent ring atom, or removing two hydrogen atoms from the same ring atom or two different ring atoms of the parent Residues derived from atoms are "cycloalkylene", “heterocyclylene”, “arylene”, “heteroarylene”.
  • amino protecting group refers to a group introduced on an amino group that is easily removed in order to keep the amino group unchanged when other parts of the molecule are reacted.
  • Non-limiting examples include: (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butoxycarbonyl (Boc), acetyl, p-toluenesulfonyl (Ts), benzyl, allyl and p-Methoxybenzyl, etc. These groups may be optionally substituted with 1-3 substituents selected from halogen, alkoxy or nitro.
  • hydroxyl protecting group refers to an easily removed group introduced on a hydroxy group, which is usually used to block or protect the hydroxy group while reacting on other functional groups of the compound.
  • Non-limiting examples include: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl, tert-butyl, C 1-6 alkoxy C 1-6 alkyl substituted with phenyl or C 1-6 alkyl substituted by phenyl (such as methoxymethyl (MOM) and ethoxyethyl, etc.), (C 1-10 alkyl or aryl) Acyl (such as: formyl, acetyl, benzoyl, p-nitrobenzoyl, etc.), (C 1-6 alkyl or 6- to 10-membered aryl) sulfonyl, (C 1-6 alkoxy or 6- to 10-membered
  • 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.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • hydroxy refers to -OH.
  • thiol refers to -SH.
  • amino refers to -NH2 .
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • carboxylate refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O )O-, wherein alkyl, cycloalkyl are as defined above.
  • stereoisomer refers to isomers that are structurally identical but differ in the arrangement of the atoms in space. It includes cis and trans (or Z and E) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)- and (L)-isomers, tautomers, atropisomers, conformers and mixtures thereof (e.g. racemates, mixtures of diastereomers) . Substituents in the compounds of the present disclosure may have additional asymmetric atoms.
  • Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers, and (D)- and (D)- and (+)-isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques (L)-isomer.
  • An isomer of a certain compound of the present disclosure can be prepared by asymmetric synthesis or chiral auxiliaries, or, when the molecule contains basic functional groups (such as amino groups) or acidic functional groups (such as carboxyl groups), with appropriate optical Active acids or bases form diastereomeric salts, which are then resolved by conventional methods known in the art to yield the pure isomers. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by chromatography.
  • the bond Indicates an unspecified configuration, i.e. if a chiral isomer exists in the chemical structure, the bond can be or or both and Two configurations.
  • tautomer or tautomeric form refers to a structural isomer that exists in equilibrium and is readily converted from one isomeric form to another. It includes all possible tautomers, ie as a single isomer or as a mixture of said tautomers in any ratio. Non-limiting examples include: keto-enols, imine-enamines, lactam-lactams, and the like. An example of a lactam-lactam equilibrium is shown below:
  • the compounds of the present disclosure include all suitable isotopic derivatives of the compounds thereof.
  • isotopic derivative refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass.
  • isotopes that can be incorporated into the compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, such as 2 H (deuterium, D), respectively, 3 H (tritium, T), 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 32 p, 33 p, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 125 I, 129 I and 131 I, etc., preferably deuterium.
  • deuterated drugs Compared with non-deuterated drugs, deuterated drugs have the advantages of reducing toxic and side effects, increasing drug stability, enhancing curative effect, and prolonging the biological half-life of drugs. All transformations of the isotopic composition of the compounds of the present disclosure, whether radioactive or not, are included within the scope of the present disclosure.
  • Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom, wherein the replacement of deuterium can be partial or complete, and a partial replacement of deuterium means that at least one hydrogen is replaced by at least one deuterium.
  • a position when a position is specifically designated as “deuterium” or “D”, that position is understood to be at least 1000 times more abundant (i.e., deuterium) than the natural abundance of deuterium, which is 0.015%. at least 15% deuterium incorporation).
  • the abundance of deuterium per designated deuterium atom is at least 1000 times greater than the natural abundance of deuterium (ie, at least 15% deuterium incorporation).
  • the abundance of deuterium per designated deuterium atom is at least 2000 times greater than the natural abundance of deuterium (ie, at least 30% deuterium incorporation).
  • the abundance of deuterium per designated deuterium atom is at least 3000 times greater than the natural abundance of deuterium (ie, at least 45% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 3340 times greater than the natural abundance of deuterium (ie, at least 50.1% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 3500 times greater than the natural abundance of deuterium (ie, at least 52.5% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 4000 times greater than the natural abundance of deuterium (ie, at least 60% deuterium incorporation).
  • the abundance of deuterium per designated deuterium atom is at least 4500 times greater than the natural abundance of deuterium (ie, at least 67.5% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 5000 times greater than the natural abundance of deuterium (ie, at least 75% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 5500 times greater than the natural abundance of deuterium (ie, at least 82.5% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6000 times greater than the natural abundance of deuterium (ie, at least 90% deuterium incorporation).
  • the abundance of deuterium per designated deuterium atom is at least 6333.3 times greater than the natural abundance of deuterium (i.e., at least 95% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6466.7 times greater than the natural abundance of deuterium (ie, at least 97% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6600 times greater than the natural abundance of deuterium (ie, at least 99% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (ie, at least 99.5% deuterium incorporation).
  • C 1-6 alkyl optionally (optionally) substituted by halogen or cyano means that halogen or cyano may, but need not, be present, and the description includes the case where the alkyl is substituted by halogen or cyano and the alkane The case where the group is not substituted by halogen and cyano.
  • Substituted or “substituted” means that one or more hydrogen atoms in a group, preferably 1 to 6, 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 pharmaceutically acceptable salt thereof, in admixture with other chemical components, as well as other components such as pharmaceutically acceptable carriers 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 salt” refers to a salt of a compound of the present disclosure, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals, and have due 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.
  • the term "therapeutically effective amount” refers to an amount of the drug or agent sufficient to achieve, or at least partially achieve, the desired effect.
  • the determination of the therapeutically effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the specific active substance, and the appropriate therapeutically effective amount in each case 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.
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound represented by the general formula (IA) or a salt thereof undergoes an intramolecular ring-closure reaction under acidic conditions to obtain the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof,
  • R m is C 1-6 alkyl; preferably, R m is tert-butyl;
  • Rings A, X, Y, Z, G 1 , G 2 , G 3 , R 1 to R 7 , m, n, p and q are as defined in general formula (I).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I-1) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound represented by the general formula (IA-1) or a salt thereof undergoes an intramolecular ring-closure reaction under acidic conditions to obtain the compound represented by the general formula (I-1) or a pharmaceutically acceptable salt thereof,
  • R m is C 1-6 alkyl; preferably, R m is tert-butyl;
  • Rings A, X, Y, Z, G 1 , G 2 , G 3 , R 1 to R 7 , m, n, p and q are as defined in general formula (I-1).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound represented by the general formula (IIA) or a salt thereof undergoes an intramolecular ring-closing reaction under acidic conditions to obtain the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof,
  • R m is C 1-6 alkyl; preferably, R m is tert-butyl;
  • Rings A, X, Z, G 1 , G 2 , G 3 , R 1 , R 2 , R 5 to R 7 , m, n, p and q are as defined for compounds of general formula (II).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II-1) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound represented by the general formula (IIA-1) or a salt thereof undergoes an intramolecular ring-closing reaction under acidic conditions to obtain the compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof,
  • R m is C 1-6 alkyl; preferably, R m is tert-butyl;
  • Rings A, X, Z, G 1 , G 2 , G 3 , R 1 , R 2 , R 5 to R 7 , m, n, p and q are as defined for compounds of general formula (II-1).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III), or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound represented by the general formula (IIIA) or a salt thereof undergoes an intramolecular ring-closure reaction under acidic conditions to obtain the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof,
  • R m is C 1-6 alkyl; preferably, R m is tert-butyl;
  • Rings A, G 1 , G 2 , G 3 , R 1 , R 2 , R 5 to R 7 , m, n, p and q are as defined for compounds of general formula (III).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III-1) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound represented by the general formula (IIIA-1) or a salt thereof undergoes an intramolecular ring-closure reaction under acidic conditions to obtain the compound represented by the general formula (III-1) or a pharmaceutically acceptable salt thereof,
  • R m is C 1-6 alkyl; preferably, R m is tert-butyl;
  • Ring A, G 1 , G 2 , G 3 , R 1 , R 2 , R 5 to R 7 , m, n, p and q are as defined for compounds of general formula (III-1).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I-1-1) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound represented by the general formula (IA-1-1) or a salt thereof undergoes an intramolecular ring-closure reaction under acidic conditions to obtain the compound represented by the general formula (I-1-1) or a pharmaceutically acceptable salt thereof,
  • R m is C 1-6 alkyl; preferably, R m is tert-butyl;
  • Rings A, X, Y, Z, G 1 , G 2 , G 3 , R 1 to R 7 , m, n, p and q are as defined in the general formula (I-1-1).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I-1-2) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound represented by the general formula (IA-1-2) or a salt thereof undergoes an intramolecular ring-closure reaction under acidic conditions to obtain the compound represented by the general formula (I-1-2) or a pharmaceutically acceptable salt thereof,
  • R m is C 1-6 alkyl; preferably, R m is tert-butyl;
  • Rings A, X, Y, Z, G 1 , G 2 , G 3 , R 1 to R 7 , m, n, p and q are as defined in the general formula (I-1-2).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II-1-1) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound represented by the general formula (IIA-1-1) or a salt thereof undergoes an intramolecular ring-closure reaction under acidic conditions to obtain the compound represented by the general formula (II-1-1) or a pharmaceutically acceptable salt thereof ,
  • R m is C 1-6 alkyl; preferably, R m is tert-butyl;
  • Rings A, X, Z, G 1 , G 2 , G 3 , R 1 , R 2 , R 5 to R 7 , m, n, p and q are as defined in the compound of general formula (II-1-1).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II-1-2) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound represented by the general formula (IIA-1-2) or a salt thereof undergoes an intramolecular ring-closure reaction under acidic conditions to obtain the compound represented by the general formula (II-1-2) or a pharmaceutically acceptable salt thereof ,
  • R m is C 1-6 alkyl; preferably, R m is tert-butyl;
  • Rings A, X, Z, G 1 , G 2 , G 3 , R 1 , R 2 , R 5 to R 7 , m, n, p and q are as defined for the compound of general formula (II-1-2).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III-1-1) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound represented by the general formula (IIIA-1-1) or a salt thereof undergoes an intramolecular ring-closure reaction under acidic conditions to obtain the compound represented by the general formula (III-1-1) or a pharmaceutically acceptable salt thereof ,
  • R m is C 1-6 alkyl; preferably, R m is tert-butyl;
  • Ring A, G 1 , G 2 , G 3 , R 1 , R 2 , R 5 to R 7 , m, n, p and q are as defined for the compound of general formula (III-1-1).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III-1-2) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound represented by the general formula (IIIA-1-2) or a salt thereof undergoes an intramolecular ring-closure reaction under acidic conditions to obtain the compound represented by the general formula (III-1-2) or a pharmaceutically acceptable salt thereof ,
  • R m is C 1-6 alkyl; preferably, R m is tert-butyl;
  • Ring A, G 1 , G 2 , G 3 , R 1 , R 2 , R 5 to R 7 , m, n, p and q are as defined for the compound of general formula (III-1-2).
  • 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; Preferred is 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 shows the efficacy data of the compound of Example 2-1 and CC-92480 on NCI-H929 xenografts in CB-17SCID mice.
  • Figure 2 shows the effect of the compound of Example 2-1 and CC-92480 on the body weight of CB-17SCID mice.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • Agilent 1200/1290DAD-6110/6120 Quadrupole MS LC/MS was used for MS determination (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).
  • Silica gel column chromatography generally uses Yantai Huanghai silica gel 200 to 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, J&K, Shaoyuan Chemical Technology (Accela ChemBio Inc. ), Shanghai Bide Pharmaceuticals, Darui Chemicals and other companies.
  • reaction can be carried out in an argon atmosphere or a nitrogen atmosphere.
  • 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, ranging from 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 (20 mL), and extracted with ethyl acetate (20 mL ⁇ 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography with eluent system A to give the title compound li (85 mg, yield: 95%).
  • NCI-H929 cells (ATCC, CRL-9068) were treated with complete medium (i.e. RPMI1640 medium containing 10% fetal bovine serum (Corning, 35-076-CV) and 0.05 mM 2-mercaptoethanol (Sigma, M3148) ( Hyclone, SH30809.01)) were cultured.
  • complete medium i.e. RPMI1640 medium containing 10% fetal bovine serum (Corning, 35-076-CV) and 0.05 mM 2-mercaptoethanol (Sigma, M3148) ( Hyclone, SH30809.01)
  • H929 cells were seeded in a 96-well plate at a density of 6,000 cells/well using complete medium, with 100 ⁇ L of cell suspension per well, and 10 ⁇ L of the compound to be tested in gradient dilution prepared in complete medium was added to each well.
  • the compound was 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.
  • Example 4-2 0.31
  • the compounds of the present disclosure have a good activity of inhibiting the proliferation of NCI-H929 cells.
  • Example 2-1 The compound of Example 2-1 and CC-92480 were evaluated to inhibit the growth of human multiple myeloma cell NCI-H929 (lenalidomide-resistant strain) xenograft tumor in CB-17SCID mice.
  • CC-92480 (Synthesized with reference to the method of Example 2 of WO2019014100A1);
  • mice CB-17SCID female mice, purchased from Beijing Weitong Lihua Laboratory Animal Co., Ltd. (certificate number: 20170011006049, SCXK (Shanghai) 2017-0011), with a weight of about 19 g at the time of purchase.
  • Breeding conditions 5 animals/cage, 12/12 hours light/dark cycle adjustment, constant temperature of 23 ⁇ 1°C, humidity of 50 to 60%, free food and water.
  • mice were grouped as follows:
  • the NCI-H929 cells in logarithmic growth phase were inoculated subcutaneously in the right flank of female CB-17SCID mice at 5 ⁇ 10 6 cells/mouse/100 ⁇ L (containing 50 ⁇ L of Matrigel). After 11 days, the tumor volume of the tumor-bearing mice was When it reached about 130mm 3 , the mice were randomly divided into 6 groups according to tumor volume and body weight: vehicle control group, CC-92480-0.1mpk, CC-92480-1mpk, Example 2-1-0.1mpk, Example 2- 1-0.3mpk and Example 2-1-1mpk, 8 per group.
  • the day of grouping was set as D0, and the oral administration was started once a day for a total of 14 days, and the 14th day after administration was set as D14 (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 control group at the end of the experiment; T 0 and C 0 are the experimental Tumor volume at the start.
  • TGI (%) 1-T/C (%), when TGI (%) exceeds 100%, no specific value will be displayed, only >100%.
  • Tumor regression (%) [(T 0 -T)/T 0 ] ⁇ 100(%).
  • qd means administration once a day; d means day; i.g means intragastric administration; SEM means standard error.
  • the compound of Example 2-1 was administered 11 days after tumor cell transplantation, once a day. After 14 days of administration, the tumor inhibition rate of the low-dose 0.1mpk group was 74%, and the tumor-inhibitory rate of the middle-dose 0.3mpk group was 91%. The tumor volume in the 1mpk group regressed with a regression rate of 5%, and the administration had no effect on the body weight of the mice. Under the same conditions, the tumor inhibition rate of CC-92480 was 37% in the low-dose 0.1mpk group and 91% in the high-dose 1mpk group, and the tumor did not regress.
  • the LC/MS/MS method was used to determine the drug concentrations in plasma at different times after the beagle dogs were given the compound of Example 2-1 and CC-92480 by gavage. To study the pharmacokinetic behavior of the disclosed compounds in beagle dogs, and to evaluate their pharmacokinetic characteristics.
  • Example 2-1 Compound and CC-92480.
  • Example 2-1 used 4 beagle dogs, half male and half, and were divided into 2 groups on average, and 3 beagle dogs were used for CC-92480, male, all provided by Shanghai Medicilon Biomedical Co., Ltd.
  • Example 2-1 The compound of Example 2-1 was weighed and dissolved by adding 5% DMSO, 30% PG and 30% PEG400, and then adding 35% physiological saline to prepare.
  • mice were administered by gavage.
  • the doses of the compound of Example 2-1 and CC-92480 were both 2 mg/kg, and the administration volumes were both 5 mL/kg.
  • Example 2-1 and CC-92480 were administered by gavage, and 1 mL of blood was collected before administration and 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 12h, and 24h after administration, and EDTA-K2 antibody was placed.
  • a coagulation test tube centrifuge at 10,000 rpm for 5 minutes (4°C), separate the plasma within 1 hour, and store at -80°C. Food was taken 3 hours after administration. The blood was collected until the centrifugation process was operated under ice bath conditions.
  • Determination of the content of the test compound in the beagle dog plasma after drug administration of different concentrations take 20 ⁇ L of beagle dog plasma at each time after administration, add the internal standard solution (the internal standard solution of the compound of Example 2-1 is toluenesulfonic acid) Butylurea 100ng/mL, the internal standard solution of CC-92480 is camptothecin 100ng/mL) and methanol 400 ⁇ L, vortex mixed for 1min, and centrifuged for 10min (18000g). Transfer 200 ⁇ L of supernatant to a 96-well plate. 1 ⁇ L of the supernatant of the plasma samples was taken for LC/MS/MS analysis.
  • Example 2-1 of the present disclosure has better pharmacokinetic absorption than CC-92480, and has a pharmacokinetic advantage.

Abstract

La présente invention concerne un dérivé de cyclohexadiimide substitué par un hétérocyclyle fusionné, et un procédé de préparation associé ainsi qu'une application pharmaceutique correspondante. De façon spécifique, la présente invention concerne un dérivé de cyclohexadiimide substitué par un hétérocyclyle fusionné et représenté par la formule générale (I), un procédé de préparation de celui-ci, et une composition pharmaceutique comprenant le dérivé et une utilisation associée en tant qu'agent de traitement, et en particulier une utilisation en tant qu'agent d'ajustement du céréblon dans le domaine du traitement du myélome multiple.
PCT/CN2022/070210 2021-01-05 2022-01-05 Dérivé de cyclohexadiimide substitué par un hétérocyclyle fusionné, procédé de préparation associé et application pharmaceutique correspondante WO2022148358A1 (fr)

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