WO2024109918A1 - Agent de dégradation de gspt1 et son utilisation en médecine - Google Patents

Agent de dégradation de gspt1 et son utilisation en médecine Download PDF

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Publication number
WO2024109918A1
WO2024109918A1 PCT/CN2023/133911 CN2023133911W WO2024109918A1 WO 2024109918 A1 WO2024109918 A1 WO 2024109918A1 CN 2023133911 W CN2023133911 W CN 2023133911W WO 2024109918 A1 WO2024109918 A1 WO 2024109918A1
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Prior art keywords
alkyl
alkylene
optionally substituted
membered
carbocyclyl
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PCT/CN2023/133911
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English (en)
Chinese (zh)
Inventor
张晨
赵晨飞
马俊杰
李凯
袁帅
柴金龙
于小娟
唐平明
余彦
李瑶
严庞科
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西藏海思科制药有限公司
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Publication of WO2024109918A1 publication Critical patent/WO2024109918A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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 invention relates to a compound described by general formula (I) or its stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and intermediates and preparation methods thereof, as well as use of the compound in preparing drugs for treating diseases related to GSPT1 or MYC.
  • MYC (including C-MYC, N-MYC and L-MYC) is a group of common oncogenes in human cancer.
  • the MYC gene is dysregulated in about 70% of human cancers. Therefore, MYC is considered a key target for the treatment of various cancers (Cancer Treatment Reviews 94 (2021) 102154).
  • the occurrence of MYC-related cancers depends on abnormally active protein translation, which supports the unlimited proliferation of cancer cells and tumor growth.
  • GSPT1 is a translation termination factor required for protein synthesis. Therefore, targeted degradation of GSPT1 is expected to become a method for treating MYC-related cancers (Cancer Res (2022) 82 (12_Supplement): 3929). At present, no targeted drugs for GSPT1 have been approved for marketing.
  • molecular glue is a type of small molecule that promotes contact between target proteins and E3 ubiquitin ligases, induces interaction between the two, and thus leads to degradation of target proteins. From a functional perspective, molecular glue mainly promotes strong interaction between target proteins and E3 ubiquitin ligases by filling the gap between them and enhancing the binding interface between them (Nat. Commun., 2022, 13, 815). Compared with traditional small molecule inhibitors, molecular glue has the advantages of catalytic form to drive target protein degradation and does not require binding pockets on the target protein, and has the potential to act on undruggable targets.
  • the purpose of the present invention is to provide a compound capable of degrading a target protein or its stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, as well as its intermediates and preparation methods, and its use in the preparation of drugs for treating diseases related to GSPT1 or MYC regulators.
  • the present invention provides a compound of general formula (I) or its stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein
  • R 1 is selected from H
  • each Ra is independently selected from deuterium, halogen, OH, NH2 , CN, NO2 , COOH, CONH2 , C1-6 alkyl, C1-6 alkoxy, C3-8 cycloalkyl or 3-8 membered heterocyclyl, wherein the alkyl, alkoxy, cycloalkyl or heterocyclyl is optionally substituted with 1 to 4 Rk ;
  • each Ra is independently selected from deuterium, halogen, OH, NH2 , CN, NO2 , COOH, CONH2 , C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl or 3-8 membered heterocyclyl, wherein the alkyl, alkoxy, cycloalkyl or heterocyclyl is optionally substituted with 1 to 4 Rk ;
  • each Ra is independently selected from deuterium, F, Cl, Br, I, OH, NH2 , CN, NO2 , COOH, CONH2 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl is optionally substituted with 1 to 4 Rk ;
  • a 1 is selected from CR a , CH, N;
  • a 1 is selected from CR a , CH;
  • n is selected from 0, 1, 2, 3;
  • p is independently selected from 0, 1, 2, 3, 4, 5 or 6;
  • p is independently selected from 0, 1, 2, 3;
  • Selected from p is independently selected from 0, 1, and 2;
  • Ring B is selected from one of the following optionally substituted structures: When substituted, it is substituted by 1 to 4 R b , and its left side is directly connected to L 1 ; in a certain embodiment, D 1 , D 2 , and D 3 are each independently selected from C, O, S, N, NH, CH, CR b or NR b , and at least one of D 1 , D 2 , and D 3 is selected from O, S, N, NH or NR b ;
  • Ring B is selected from: Its left side is directly connected to L 1 ;
  • Selected from one of the following optionally substituted structures When substituted, it is substituted by 1 to 4 R b , the left side of which is directly connected to L 1 ; in a certain embodiment, D 1 and D 3 are each independently selected from C, O, S, N;
  • F 2 , F 3 , F 4 , and F 5 are each independently selected from C, CR b , CH, or N;
  • each F 1 is independently selected from NR b , NH;
  • F 6 is selected from CR b , CH;
  • E 2 , E 3 , E 4 , and E 5 are each independently selected from C, CR b , CH, or N;
  • Optionally substituted one of the following structures When substituted, it is replaced by 1 to 4 R b , the left side of which is directly connected to L 1 ;
  • Ring B is selected from one of the following optionally substituted structures: When substituted, it is substituted by 1 to 3 R b , and its left end is connected to L 1 ;
  • Ring B is selected from one of the following optionally substituted structures: When substituted, it is substituted by 1 to 3 R b , and its left end is connected to L 1 ;
  • Ring B is selected from one of the following optionally substituted structures: When substituted, it is substituted by 1 to 3 R b , and its left end is connected to L 1 ;
  • Ring B is selected from one of the following optionally substituted structures: When substituted, it is replaced by 1 or 2 R b , and its left end is connected to L 1 ;
  • Ring B is selected from one of the following optionally substituted structures: When substituted, it is replaced by 1 or 2 R b , and its left end is connected to L 1 ;
  • each R b is independently selected from deuterium, halogen, OH, cyano, NH 2 , NO 2 , N(C 1-4 alkyl) 2 , NH(C 1-4 alkyl), C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, -C( ⁇ O)R 1a , -S( ⁇ O) 2 R 1a , -P( ⁇ O)R 1a R 1b , C 3-10 carbocyclyl, 4 to 10 membered heterocyclyl, C 6-10 aryl or 5 to 10 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted with 1 to 4 groups selected from R k ;
  • L is selected from Its right side is directly connected to ring B;
  • L1 is selected from one of the following groups optionally substituted with 1, 2, or 3 RL : Its right side is directly connected to ring B;
  • L1 is selected from one of the following groups optionally substituted with 1, 2, or 3 RL : Its right side is directly connected to ring B;
  • L1 is selected from the following groups optionally substituted with 1, 2, or 3 RL : Its right side is directly connected to ring B;
  • L is selected from Selected from Its right side is directly connected to ring B;
  • the general formula (I) is selected from the structure shown in the general formula (II) or (III):
  • the general formula (I) is selected from the structure shown in the general formula (IV):
  • n is independently selected from 0, 1, 2, 3, 4; n2 is independently selected from 0, 1, 2, 3;
  • n1 and m2 are each independently selected from 1 and 2;
  • Ring B is selected from: Its left side is directly connected to X 2 ;
  • E 2 , E 3 , E 4 , and E 5 are each independently selected from CR b , CH or N;
  • D 1 and D 3 are each independently selected from CH, O, S, N, NH, and at least one of D 1 and D 3 is selected from O, S, N, NH; In certain embodiments, at least one of D 1 and D 3 is selected from O, S;
  • X 1 and X 2 are each independently selected from CR L or N, preferably CF, CH, CD or N;
  • the compound represented by formula (I), (II), (III) or (IV) contains at least one deuterium;
  • At least one RL contains at least one deuterium
  • At least one Ra contains at least one deuterium
  • At least one R b contains at least one deuterium
  • At least one R c contains at least one deuterium
  • q is independently selected from 0, 1, 2, 3, 4;
  • q is independently selected from 0, 1, 2, 3;
  • R 2 and R 3 are each independently selected from H, deuterium, C 1-6 alkyl, C 0-4 alkylene-C 6-10 aryl, C 0-4 alkylene-5 to 10 membered heteroaryl, C 0-4 alkylene-C 3-12 carbocyclyl, C 0-4 alkylene-4 to 12 membered heterocyclyl, wherein the alkyl, alkylene, aryl, heteroaryl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R c ;
  • R 2 is selected from H, deuterium, C 1-4 alkyl, said alkyl being optionally substituted with 1 to 4 R k ;
  • R 2 is selected from H, deuterium, methyl, ethyl, propyl, isopropyl, wherein the methyl, ethyl, propyl, isopropyl is optionally substituted with 1 to 3 R k ;
  • R 2 , R 3 and the nitrogen atom to which they are attached together form a 3- to 12-membered heterocyclic group, wherein the heterocyclic group is optionally substituted by 1 to 4 R c ;
  • R c is independently selected from R c1 ;
  • L 2 is selected from a bond or C 1-4 alkylene, said alkylene being optionally substituted with 1 to 4 R L ;
  • L2 is selected from a bond, a methylene group, an ethylene group, and the methylene group and the ethylene group are optionally substituted with 1 to 3 R L ;
  • L2 is selected from a bond, CH2 , CH2CH2 , said CH2 , CH2CH2 is optionally substituted with 1 to 3 RL , and its left end is connected to ring C2;
  • ring C1 is selected from 5- to 12-membered nitrogen-containing heteroaryl, 4- to 12-membered nitrogen-containing heterocyclic group, and the ring C1 is optionally substituted by 1 to 4 R c ;
  • L is selected from hour, Selected from R c1 -5-6 membered heteroaryl-NH-, wherein the heteroaryl is optionally substituted by 1, 2 or 3 R c ;
  • n1 and n3 are each independently selected from 1, 2 or 3; in certain embodiments, n2 is selected from 0, 1, 2 or 3;
  • ring C2 is selected from C 6-10 aryl, 5 to 10 membered heteroaryl, C 3-12 carbocyclyl, 4 to 12 membered heterocyclyl, and said ring C2 is optionally substituted by 1 to 4 R c ;
  • ring C2 is selected from 4-7 membered heteromonocyclic ring, 5-12 membered heterocyclic ring, 5-12 membered heterospirocyclic ring, 7-10 membered heterobridged ring, C 3-8 monocarbocyclyl, C 6-12 cycloalkyl, C 6-12 membered spirocycloalkyl, C 5-12 membered bridged cycloalkyl, benzo C 3-6 carbocyclyl, benzo 3 to 6 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, and the ring C2 is optionally substituted by 1 to 4 R c ;
  • ring C2 is selected from one of the following optionally substituted structures: cyclopropane, cyclobutane, cyclopentane, cyclohexane, azetidine, pyrrolidine, cyclohexene, azacyclohexine, piperidine, morpholine, piperazine, 1,4-diazepane, benzene, naphthalene, oxetane, tetrahydrofuran, tetrahydropyran, furan, pyrrole, pyrazole, imidazole, thiophene, thiazole, oxazole, isoxazole, triazole, pyridine, pyrimidine, pyrazine, pyridazine, 2-pyridone, benzopyrrole, benzopyrrolidine, benzothiophene, benzofuran, benzothiazole, benzopyrazole, benzimidazole
  • R 1a and R 1b are each independently selected from H, OH, NH 2 , C 1-4 alkyl, C 1-4 alkoxy, NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 3-6 carbocyclyl, 4 to 8 membered heterocyclyl, C 6-10 aryl or 5 to 10 membered heteroaryl, wherein the alkyl, alkoxy, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted by 1 to 4 R k ;
  • R 1a , R 1b are each independently selected from H, OH, NH 2 , NHCH 3 , N(CH 3 ) 2 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, imidazole, pyrazole, pyrrole or thiophene, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperid
  • two R b , two R a and the atoms to which they are attached together form a C 3-8 carbocyclyl or a 3 to 8 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R k ;
  • two R b , two R a and the atoms to which they are attached together form a C 3-6 carbocyclyl or a 3 to 6 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R k ;
  • two R b , two R a and the atoms to which they are attached together form a C 3-6 cycloalkyl or a 3 to 6 membered heterocycloalkyl group, wherein the cycloalkyl or heterocycloalkyl group is optionally substituted with 1 to 4 R k
  • two R b , two Ra and the atoms to which they are attached together form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, oxolanyl, pyrrolidinyl, piperidinyl, 1,3-dioxolanyl group, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, oxolanyl, pyrrolidinyl, piperidinyl, 1,3-dioxolanyl group is optionally substituted with 1 to 4 R k ;
  • the compound cannot be selected from
  • R 1 is selected from H, C 1-6 alkyl, -C( ⁇ O)R 1a , -S( ⁇ O) 2 R 1a , -P( ⁇ O)R 1a R 1b , C 3-8 carbocyclyl or 3 to 10 membered heterocyclyl, wherein the alkyl, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R k ;
  • a 1 is selected from CR a , CH, N;
  • R a is independently selected from deuterium, halogen, OH, NH 2 , CN, NO 2 , COOH, CONH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or 3-8 membered heterocyclyl, wherein the alkyl, alkoxy, cycloalkyl or heterocyclyl is optionally substituted by 1 to 4 R k ;
  • n 0, 1, 2, 3;
  • p is each independently selected from 0, 1, 2, 3, 4, 5 or 6;
  • q is each independently selected from 0, 1, 2, 3, 4;
  • Ring B is selected from one of the following optionally substituted structures: When substituted, it is replaced by 1 to 4 R b , the left side of which is directly connected to L 1 ;
  • D 1 , D 2 , and D 3 are each independently selected from C, O, S, N, NH, CH, CR b or NR b , and at least one of D 1 , D 2 , and D 3 is selected from O, S, N, NH or NR b ;
  • E 2 , E 3 , E 4 and E 5 are each independently selected from C, CR b , CH or N;
  • F 2 , F 3 , F 4 and F 5 are each independently selected from C, CR b , CH or N;
  • F 1 is independently selected from NR b , NH;
  • F6 is selected from CR b , CH;
  • R 2 and R 3 are each independently selected from H, deuterium, C 1-6 alkyl, C 0-4 alkylene-C 6-10 aryl, C 0-4 alkylene-5 to 10 membered heteroaryl, C 0-4 alkylene-C 3-12 carbocyclyl, C 0-4 alkylene-4 to 12 membered heterocyclyl, wherein the alkyl, alkylene, aryl, heteroaryl, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R c ;
  • R 1a , R 1b are each independently selected from H, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 3-8 carbocyclyl, 4 to 10 membered heterocyclyl, C 6-10 aryl or 5 to 10 membered heteroaryl, wherein the alkyl, alkoxy, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted by 1 to 4 R k ;
  • two R b , two Ra and the atoms to which they are attached together form a C 3-8 carbocyclic group or a 3 to 8 membered heterocyclic group, wherein The carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k ;
  • R 2 , R 3 and the nitrogen atom to which they are attached together form a 3- to 12-membered heterocyclic group, and the heterocyclic group is optionally substituted by 1 to 4 R c .
  • L2 is selected from a bond or C1-4 alkylene, said alkylene being optionally substituted with 1 to 4 R L ;
  • Ring C1 is selected from 5- to 12-membered nitrogen-containing heteroaryl and 4- to 12-membered nitrogen-containing heterocyclic group, and the ring C1 is optionally substituted by 1 to 4 R c ;
  • Ring C2 is selected from C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-12 carbocyclyl, 4- to 12-membered heterocyclyl, and the ring C2 is optionally substituted by 1 to 4 R c ;
  • a 1 is selected from CR a , CH;
  • R 1 is selected from H, C 1-4 alkyl, -C( ⁇ O)R 1a , -S( ⁇ O) 2 R 1a , -P( ⁇ O)R 1a R 1b , C 3-8 carbocyclyl or 3 to 10 membered heterocyclyl, wherein the alkyl, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R k ;
  • R a is independently selected from deuterium, halogen, OH, NH 2 , CN, NO 2 , COOH, CONH 2 , C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl or 3-8 membered heterocyclyl, wherein the alkyl, alkoxy, cycloalkyl or heterocyclyl is optionally substituted by 1 to 4 R k ;
  • R 2 is selected from H, deuterium, C 1-4 alkyl, C 0-4 alkylene-C 6-10 aryl, C 0-4 alkylene-5 to 10 membered heteroaryl, C 0-4 alkylene-C 3-10 carbocyclyl, C 0-4 alkylene-4 to 10 membered heterocyclyl, wherein the alkyl, alkylene, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R k ;
  • R 1a , R 1b are each independently selected from H, OH, NH 2 , C 1-4 alkyl, C 1-4 alkoxy, NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 3-6 carbocyclyl, 4 to 8 membered heterocyclyl, C 6-10 aryl or 5 to 10 membered heteroaryl, wherein the alkyl, alkoxy, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted by 1 to 4 R k ;
  • Ring C1 is selected from a 4-7 membered nitrogen-containing heteromonocyclic ring, a 5-12 membered nitrogen-containing heterocyclic ring, a 5-12 membered nitrogen-containing heterospirocyclic ring, a 7-10 membered nitrogen-containing heterobridged ring, a benzo 3- to 6-membered nitrogen-containing heterocyclic group, and a 5-10 membered nitrogen-containing heteroaryl group, and the ring C1 is optionally substituted by 1 to 4 R c ;
  • Ring C2 is selected from 4-7 membered heteromonocyclic ring, 5-12 membered heterocyclic ring, 5-12 membered heterospirocyclic ring, 7-10 membered heterobridged ring, C3-8 monocarbocyclyl, C6-12 cycloalkyl, C6-12 membered spirocycloalkyl, C5-12 membered bridged cycloalkyl, benzoC3-6 carbocyclyl, benzo3 to 6 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and the ring C2 is optionally substituted by 1 to 4 R c ;
  • L2 is selected from a bond, a methylene group, an ethylene group, and the methylene group and the ethylene group are optionally substituted by 1 to 3 R L ;
  • R 2 is selected from H, deuterium, C 1-4 alkyl, wherein the alkyl is optionally substituted with 1 to 4 R k ;
  • R 1a , R 1b are each independently selected from H, OH, NH 2 , NHCH 3 , N(CH 3 ) 2 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, imidazole, pyrazole, pyrrole or thiophene, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl,
  • Ra is independently selected from deuterium, F, Cl, Br, I, OH, NH2 , CN, NO2 , COOH, CONH2 , methyl, ethyl R k is substituted with 1 to 4 R k ;
  • R b is each independently selected from deuterium, F, Cl, Br, I, OH, cyano, NH 2 , NO 2 , NHCH 3 , N(CH 3 ) 2 , COOH, CONH 2 , -C( ⁇ O)-methyl, -C( ⁇ O)-ethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, imidazole, pyrazole, pyrrole or thiophene, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl
  • p is independently selected from 0, 1, 2, 3;
  • R1 is selected from H
  • Ring B is selected from one of the following optionally substituted structures:
  • Or ring B is selected from one of the following optionally substituted structures: When substituted, it is substituted by 1 to 3 R b , and its left end is connected to L 1 ;
  • Or ring B is selected from one of the following optionally substituted structures: When substituted, it is substituted by 1 to 3 R b , and its left end is connected to L 1 ;
  • Ring C2 is selected from one of the following structures which are optionally substituted: cyclopropane, cyclobutane, cyclopentane, cyclohexane, azetidine, pyrrolidine, cyclohexene, azacyclohexine, piperidine, morpholine, piperazine, 1,4-diazepane, benzene, naphthalene, oxetane, tetrahydrofuran, tetrahydropyran, furan, pyrrole, pyrazole, imidazole, thiophene, thiazole, oxazole, isoxazole, triazole, pyridine, pyrimidine, pyrazine, pyridazine, 2-pyridone, benzopyrrole, benzopyrrolidine, benzothiophene, benzofuran, benzothiazole, benzopyrazole, benzimidazole, benzo
  • R 2 is selected from H, deuterium, methyl, ethyl, propyl, isopropyl, wherein the methyl, ethyl, propyl, isopropyl is optionally substituted by 1 to 3 R k ;
  • two R b , two Ra and the atoms to which they are attached together form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, oxolanyl, pyrrolidinyl, piperidinyl, 1,3-dioxolanyl group, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, oxolanyl, pyrrolidinyl, piperidinyl, 1,3-dioxolanyl group
  • the oxopentyl group is optionally substituted with 1 to 4 R k ;
  • L2 is selected from a bond, CH2 , CH2CH2 , said CH2 , CH2CH2 is optionally substituted by 1 to 3 RLs , and its left end is connected to ring C2;
  • E 2 , E 3 , and E 5 are each independently selected from CR b , CH or N;
  • X 1 and X 2 are each independently selected from CR L or N;
  • n is selected from 0, 1, 2, 3, 4;
  • D 1 and D 3 are each independently selected from C, O, S, and N;
  • X 1 and X 2 are each independently selected from CR L or N;
  • n is selected from 0, 1, 2, 3, 4;
  • Ring B is selected from: Its left side is directly connected to X 2 ;
  • E 2 , E 3 , E 4 and E 5 are each independently selected from CR b , CH or N;
  • D 1 and D 3 are each independently selected from CH, O, S, N, and NH, and at least one of D 1 and D 3 is selected from O, S, N, and NH;
  • X 1 and X 2 are each independently selected from CR L or N, preferably CF, CH, CD or N;
  • n2 is each independently selected from 0, 1, 2, 3;
  • n1 and m2 are each independently selected from 1 and 2;
  • the present invention relates to the following compound or its stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from one of the structures in Table A below:
  • the present invention relates to a pharmaceutical composition, comprising the compound of the present invention or its stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition contains 1-1500 mg of the compound of the present invention or its stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the above-mentioned compound of the present invention or its stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and a pharmaceutically acceptable carrier
  • the present invention relates to use of the compound of the present invention or its stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in preparing a drug for treating diseases related to GSPT1 or MYC, preferably in preparing a tumor drug.
  • the pharmaceutical composition of the present invention may be in the form of a unit preparation (the amount of the main drug in the unit preparation is also referred to as "preparation strength").
  • an "effective amount” or “therapeutically effective amount” described in this application refers to the administration of a sufficient amount of the compound disclosed in this application, which will alleviate one or more symptoms of the disease or condition being treated (e.g., treatment of diseases related to GSPT1 or MYC such as tumors) to some extent.
  • the result is a reduction and/or alleviation of the signs, symptoms or causes of the disease, or any other desired changes in the biological system.
  • an "effective amount” for therapeutic use is the amount of the compound disclosed in this application required to provide a clinically significant reduction in disease symptoms.
  • therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 2-600 mg, 3-600 mg, 4-600 mg, 5-600 mg, 6-600 mg, 10-600 mg, 20-600 mg, 25-600 mg, 30-600 mg, 40-600 mg, 50-600 mg, 60-600 mg, 70-600 mg, 75-600 mg, 80-600 mg, 90-600 mg, 100-600 mg, 200-600 mg, 1-500 mg, 2-500mg, 3-500mg, 4-500mg, 5-500mg, 6-500mg, 10-500mg, 20-500mg, 25-500mg, 30-500mg, 40-500mg, 50-500mg, 60-500mg, 70-500mg, 75-500mg, 80-500mg, 90-500mg, 100-500mg, 125-500mg, 150-500mg, 200-500mg, 250-500mg, 300-500m
  • the pharmaceutical composition includes but is not limited to 1-1000 mg, 20-800 mg, 40-800 mg, 40-400 mg, 25-200 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 300 mg, 320 mg, 400 mg, 480 mg, 500 mg, 600 mg, 640 mg, 840 mg of a compound of the present invention or a stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.
  • a method for treating a disease in a mammal comprising administering to a subject a therapeutically effective amount of a compound of the present invention or a stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, the therapeutically effective amount preferably being 1-1500 mg, and the disease preferably being a GSPT1 or MYC regulator-related disease (such as a tumor).
  • a method for treating a disease in a mammal comprising administering a drug compound of the present invention or a stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof to a subject at a daily dose of 1-1000 mg/day
  • the daily dose may be a single dose or divided doses, in some embodiments, the daily dose includes but is not limited to 10-1500 mg/day, 10-1000 mg/day, 10-800 mg/day, 25-800 mg/day, 50-800 mg/day, 100-800 mg/day, 200-800 mg/day / day, 25-400 mg/day, 50-400 mg/day, 100-400 mg/day, 200-400 mg/day, in some embodiments, daily doses include but are not limited to 10 mg/day, 20 mg/day, 25 mg/day, 50 mg/day, 80 mg/day, 100 mg/day, 125 mg/day, 150 mg/day, 160 mg/day, 200 mg/day, 300 mg
  • the present invention relates to a kit, which may include a composition in a single-dose or multi-dose form, and the kit contains a compound of the present invention or a stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and the amount of the compound of the present invention or its stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal is the same as its amount in the above-mentioned pharmaceutical composition.
  • the present invention relates to the use of the above-mentioned compound of the present invention or its stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal or the above-mentioned pharmaceutical composition in the preparation of drugs for treating diseases related to GSPT1 or MYC regulators.
  • the present invention relates to the above-mentioned compound of the present invention or its stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, or the use of the above-mentioned pharmaceutical composition, and the disease is selected from tumors.
  • the amount of the compound according to the invention or its stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal is in each case calculated as the free base.
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds described in the present invention all include their isotopes, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds described in the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein carbon isotopes include 12 C, 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super tritium), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Cl, and bromine isotopes include 79 Br and 81 Br.
  • carbon isotopes include 12 C, 13 C and 14 C
  • hydrogen isotopes include pro
  • CN refers to cyano
  • Halogen refers to F, Cl, Br or I.
  • Halogen substituted refers to substitution with F, Cl, Br or I, including but not limited to substitution with 1 to 10 substituents selected from F, Cl, Br or I, substitution with 1 to 6 substituents selected from F, Cl, Br or I, and substitution with 1 to 4 substituents selected from F, Cl, Br or I.
  • Halogen substituted is abbreviated as "halo”.
  • Alkyl refers to a substituted or unsubstituted straight or branched chain saturated aliphatic hydrocarbon group, including but not limited to 1 to 20 carbon atoms.
  • alkyl refers to an alkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 6 carbon atoms, an alkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 6 carbon atoms, or an alkyl group having 1 to 4 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched chain isomers thereof; the alkyl group may be monovalent, divalent, trivalent, or tetravalent.
  • Heteroalkyl refers to a substituted or unsubstituted alkyl in which one or more (including but not limited to 2, 3, 4, 5 or 6) carbon atoms are replaced by heteroatoms (including but not limited to N, O or S).
  • Non-limiting examples include -X-( CH2 )vX-( CH2 )vX-( CH2 )vH (v is an integer from 1 to 5, each X is independently selected from a bond or a heteroatom, the heteroatom includes but is not limited to N, O or S, and at least one X is selected from a heteroatom, and the N or S in the heteroatom can be oxidized to various oxidation states).
  • the heteroalkyl group can be monovalent, divalent, trivalent or tetravalent.
  • Alkylene refers to a substituted or unsubstituted straight-chain or branched divalent saturated hydrocarbon group, including -(CH 2 ) v -(v is an integer from 1 to 10). Examples of alkylene include, but are not limited to, methylene, ethylene, propylene, and butylene.
  • Heteroalkylene refers to a substituted or unsubstituted alkylene in which one or more (including but not limited to 2, 3, 4, 5 or 6) carbon atoms are replaced by heteroatoms (including but not limited to N, O or S).
  • Non-limiting examples include -X-(CH 2 )vX-(CH 2 )vX-(CH 2 )v-(CH 2 )v-, v is an integer from 1 to 5, each X is independently selected from a bond, N, O or S, and at least one X is selected from N, O or S.
  • Cycloalkyl refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon radical, typically having 3 to 12 carbon atoms, and the cycloalkyl can be a monocyclic, cyclic, bridged, and spirocyclic ring. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutyl-cyclobutyl, cyclobutyl-spirocyclobutyl, adamantane, etc.
  • the cycloalkyl can be monovalent, divalent, trivalent, or tetravalent.
  • Heterocycloalkyl refers to a substituted or unsubstituted saturated cyclic hydrocarbon containing heteroatoms, including but not limited to 3 to 12 atoms, 3 to 8 atoms, including 1 to 3 heteroatoms selected from N, O, S or Se, and the C, N, S on the ring of the heterocycloalkyl can be oxidized to various oxidation states. Heterocycloalkyl can be a monocyclic, cyclic, bridged and spirocyclic.
  • Heterocycloalkyl can be connected to a heteroatom or a carbon atom, and non-limiting examples include oxirane, aziridine, oxadiazine, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolane, dioxane, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazininyl, morpholinyl, hexahydropyrimidinyl, piperazinyl,
  • the heterocycloalkyl group may be monovalent, divalent, trivalent or tetravalent.
  • alkenyl refers to a substituted or unsubstituted straight chain or branched unsaturated hydrocarbon group having at least one, typically one, two or three carbon-carbon double bonds, with a backbone of 2 to 10, 2 to 6 or 2 to 4 carbon atoms.
  • alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-2 ...
  • alkenyl group can be monovalent, divalent, trivalent or tetravalent.
  • Alkynyl refers to substituted or unsubstituted straight and branched unsaturated hydrocarbon groups having at least one, typically one, two or three carbon-carbon triple bonds, with a backbone comprising 2 to 10 carbon atoms, including but not limited to 2 to 6 carbon atoms in the backbone, 2 to 4 carbon atoms in the backbone, examples of alkynyl groups include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl, 2- Methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexyny
  • Alkoxy refers to substituted or unsubstituted -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropyloxy, and cyclobutyloxy.
  • Carbocyclyl or “carbocycle” refers to a substituted or unsubstituted aromatic or non-aromatic ring, which can be a 3-8-membered monocyclic ring, a 4-12-membered bicyclic ring, a 10-15-membered tricyclic ring, or a 12-18-membered quaternary system.
  • the carbocyclyl can be attached to an aromatic ring or a non-aromatic ring, and the ring can be optionally a monocyclic ring, a cyclic ring, a bridged ring, or a spirocyclic ring.
  • Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, benzene ring, naphthalene ring, "Carbocyclyl” or “carbocycle” can be monovalent, divalent, trivalent or tetravalent.
  • Heterocyclyl or “heterocycle” refers to a substituted or unsubstituted aromatic or non-aromatic ring, which can be a 3-8 membered monocyclic ring, a 4-12 membered bicyclic ring, a 10-15 membered tricyclic ring, or a 12-18 membered quaternary system, and contains 1 or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O, S or Se.
  • the C, N, S or Se selectively substituted in the heterocyclyl ring can be oxidized to various oxidation states.
  • the heterocyclic group can be connected to a heteroatom or a carbon atom, and can be connected to an aromatic ring or a non-aromatic ring.
  • the heterocyclic group is optionally a monocyclic, bridged, fused or spirocyclic ring.
  • Non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxhexacyclyl, azepanyl, pyridyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, dihydrofuranyl, dihydropyranyl, dithiolanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridin
  • Spiro or “spirocyclic group” refers to a polycyclic group in which substituted or unsubstituted monocyclic rings share one atom (called a spiro atom).
  • the number of ring atoms in the spirocyclic system includes but is not limited to 5 to 20, 6 to 14, 6 to 12, 6 to 10, wherein one
  • Spirocycle or “spirocyclyl” may be monovalent, divalent, trivalent or tetravalent.
  • the number of ring atoms in the cyclic system includes but is not limited to 5 to 20, 5 to 14, 5 to 12, 5 to 10. Non-limiting examples include:
  • Bicyclic or "bicyclic group” can be monovalent, divalent, trivalent or tetravalent.
  • Carbospirocycle refers to a “spirocycle” wherein the ring system consists of only carbon atoms.
  • Carbocyclic refers to a “cyclic” ring system consisting of only carbon atoms.
  • Carbobridged ring refers to a “bridged ring” wherein the ring system consists of only carbon atoms.
  • Heteromonocycle refers to a monocyclic ring system of "heterocyclyl” or “heterocycle”,
  • Heterocyclic ring refers to a “cyclic ring” containing a heteroatom.
  • Heterospirocycle refers to a “spirocycle” containing a heteroatom.
  • Heterobridged ring refers to a “bridged ring” containing a heteroatom.
  • Aryl or “aromatic ring” refers to a substituted or unsubstituted aromatic hydrocarbon group having a single ring or fused rings, wherein the ring atoms The number includes, but is not limited to, 6 to 18, 6 to 12, or 6 to 10 carbon atoms.
  • the aryl ring may be fused to a saturated or unsaturated carbocyclic ring, wherein the ring connected to the parent structure is an aryl ring, non-limiting examples of which include a benzene ring, a naphthalene ring, "Aryl” or “aromatic ring” can be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the point of attachment is on the aryl ring.
  • heteroaryl examples include but are not limited to pyridyl, furanyl, thienyl, selenophenyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazolyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, pyridonyl, and the like.
  • the heteroaryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, wherein the ring connected to the parent structure is an aryl ring, non-limiting examples include
  • the heteroaryl groups appearing in this article have the same definition as this definition.
  • the heteroaryl group can be monovalent, divalent, trivalent or tetravalent. When it is divalent, trivalent or tetravalent, the attachment site is located on the aromatic ring.
  • X-Y membered rings (X, Y are integers, and 3 ⁇ X ⁇ Y, X ⁇ Y ⁇ 20 are selected from any integer between 4 and 20) include X, X+1, X+2, X+3, X+4....Y membered rings.
  • Rings include heterocyclic rings, carbocyclic rings, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocyclic rings, heterocyclic rings, heterospirocyclic rings or heterobridged rings.
  • 4--7 membered heteromonocyclic rings refer to 4-, 5-, 6- or 7-membered heteromonocyclic rings
  • 5--10 membered heterocyclic rings refer to 5-, 6-, 7-, 8-, 9- or 10-membered heterocyclic rings
  • Cxy carbocycle (including aryl, cycloalkyl, monocyclic carbocycle, spirocyclic carbocycle, cyclic carbocycle or bridged carbocycle) includes Cx , Cx +1 , Cx +2 , Cx +3 , Cx +4 ... Cy- membered ring (x is an integer, and 3 ⁇ x ⁇ y, y is selected from any integer between 4 and 20), for example.
  • C3-6 cycloalkyl refers to C3 , C4 , C5 or C6 cycloalkyl;
  • any one or more of the sites of the group can be bonded by chemical bonding. Connect with other groups.
  • the chemical bond connection mode is non-positional and there are hydrogen atoms at the connectable site, when the chemical bond is connected, the number of H atoms at the site will decrease accordingly with the number of chemical bonds connected to become a group with the corresponding valence.
  • any connectable site on the piperidine group can be connected to other groups through one chemical bond, including at least These four connection methods, even if the H atom is drawn on -N-, Also included For example Indicates that the R group on the piperidinyl group can be located on C, can be located on N, and at least includes
  • connection directions include connection from left to right and from right to left in reading order, for example, A-L-B, when L is selected from -M-W-, includes A-M-W-B and A-W-M-B.
  • alkyl optionally substituted with F means that alkyl may but need not be substituted with F, and the description includes situations where alkyl is substituted with F and situations where alkyl is not substituted with F.
  • “Pharmaceutically acceptable salt” or “pharmaceutically acceptable salt thereof” refers to a salt of the compound of the present invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, and the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.
  • “Pharmaceutical composition” refers to a mixture of one or more compounds of the present invention, or stereoisomers, racemates, tautomers, deuterated forms, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals thereof and other chemical components, wherein “other chemical components” refers to pharmaceutically acceptable carriers, excipients and/or one or more other therapeutic agents.
  • Preparation specifications refers to the weight of the main drug contained in each vial, tablet or other unit preparation.
  • Carrier refers to a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
  • Prodrug refers to a compound of the present invention that can be converted into a biologically active compound through in vivo metabolism.
  • the prodrug of the present invention is prepared by modifying the amino or carboxyl group in the compound of the present invention, and the modification can be removed by conventional operations or in vivo to obtain the parent compound.
  • the prodrug of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free amino or carboxyl group.
  • Co-crystal refers to a crystal formed by the active pharmaceutical ingredient (API) and the co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, in which the pure state of API and CCF are solid at room temperature and there is a fixed stoichiometric ratio between the components.
  • Co-crystal is a multi-component crystal, including both binary eutectics formed between two neutral solids and multi-component eutectics formed between neutral solids and salts or solvates.
  • Animal is meant to include mammals, such as humans, companion animals, zoo animals, and livestock, preferably humans, horses, or dogs.
  • Stepoisomers refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers and conformational isomers.
  • Tautomers refer to functional group isomers produced by the rapid movement of an atom in a molecule between two positions, such as keto-enol isomerism and amide-imino alcohol isomerism.
  • IC50 is the concentration of a drug or inhibitor required to inhibit a specified biological process (or a component of such a process, such as an enzyme, receptor, cell, etc.) by half.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • HPLC determination was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100 ⁇ 4.6mm, 3.5 ⁇ M);
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the silica gel plate used in thin layer chromatography (TLC) uses a specification of 0.15mm-0.20mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm;
  • the known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from companies such as Titan Technology, Anage Chemical, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology.
  • DMA N,N-dimethylacetamide
  • DMF N,N-dimethylformamide
  • DCM dichloromethane
  • DMSO dimethyl sulfoxide
  • MeOH methanol
  • TFA trifluoroacetic acid
  • NBS N-bromosuccinimide
  • DIPEA N,N-diisopropylethylamine
  • HATU 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • DMAP 4-dimethylaminopyridine
  • Zinc powder (0.67 g, 10.24 mmol) was added to DMA (15 mL), and 1.2-dibromoethane (0.19 g, 1.01 mmol) and trimethylsilyl chloride (0.11 g, 1.01 mmol) were slowly added under nitrogen atmosphere, and stirred at room temperature for 0.5 h, and then 2A (2.89 g, 10.21 mmol) was added and stirred for 2 h.
  • Zinc powder (1.56 g, 23.85 mmol) was added to DMA (15 mL), and 1.2-dibromoethane (0.39 g, 2.08 mmol) and trimethylsilyl chloride (0.17 g, 1.56 mmol) were slowly added under nitrogen atmosphere, and stirred at room temperature for 0.5 h, and then 3A (2.02 g, 6.80 mmol) was added and stirred for 2 h.
  • 1A (1.1 g, 3.40 mmol), cuprous iodide (0.13 g, 0.68 mmol), 1,1-bis(dibromo)-1-yl)-1-nitrogen-1-yl was added under nitrogen atmosphere.
  • Zinc powder (1.01 g, 15.44 mmol) was added to DMA (10 mL), and 1.2-dibromoethane (87 mg, 0.46 mmol) and trimethylsilyl chloride (51 mg, 0.47 mmol) were slowly added under nitrogen atmosphere, and stirred at room temperature for 0.5 h, and then 5A (1.45 g, 4.66 mmol) was added and stirred for 2 h.
  • the concentrate was purified by preparative liquid phase (instrument: waters 2767 preparative chromatographic column: SunFire@Prep C18 (19 mm ⁇ 150 mm); mobile phase composition: acetonitrile/water (containing 0.1% trifluoroacetic acid)) to obtain compound 5 (16 mg, yield: 21%).
  • Zinc powder (606 mg, 9.27 mmol) was added to DMA (15 mL), and 1,2-dibromoethane (0.17 g, 0.90 mmol) and trimethylsilyl chloride (0.1 g, 0.92 mmol) were slowly added under nitrogen atmosphere. The mixture was stirred at room temperature for 0.5 h, and then 2A (2.62 g, 9.25 mmol) was added. The mixture was stirred for 2 h.
  • Zinc powder (175 mg, 2.68 mmol) was added to DMA (10 mL), and 1,2-dibromoethane (50 mg, 0.27 mmol) and trimethylsilyl chloride (29 mg, 0.27 mmol) were slowly added under nitrogen atmosphere, and stirred at room temperature for 0.5 h, then 2A (756 mg, 2.67 mmol) was added and stirred at 30 ° C for 2 h.
  • Zinc powder (394 mg, 6.03 mmol) was added to DMA (20 mL), and 1,2-dibromoethane (113 mg, 0.60 mmol) and trimethylsilyl chloride (66 mg, 0.61 mmol) were slowly added under nitrogen atmosphere, and stirred at room temperature for 0.5 h, and then 12E (1701 mg, 6.03 mmol) was added and stirred for 2 h.
  • the product was concentrated under reduced pressure, and the residue was purified by reverse phase preparation (instrument: Waters2767; chromatographic column: SunFire@Prep C18 19*250; mobile phase: A-acetonitrile, B-water (containing 0.1% trifluoroacetic acid); gradient elution: A phase from 5% to 40% (0-20min); flow rate: 17mL/min) and the obtained preparation solution was lyophilized to obtain compound 12, and compound 12 was separated by reverse phase preparation (instrument: Waters2767; chromatographic column: XSelect@Prep C18 19*250; mobile phase: A-acetonitrile, B-water (containing 5nM ammonium acetate); gradient elution: A phase from 10% to 40% (0-20min); flow rate: 15mL/min) and the obtained preparation solution was lyophilized to obtain compound 12-1 (retention time 17min, 21mg) and compound 12-2 (retention time 18min, 11mg).
  • reverse phase preparation instrument: Waters2767; chromatographic column:
  • H3 and H4 of compound 12-2 both have NOE signals with H1 and H2, and its configuration is as shown in the figure below.
  • 24D (1.30 g, 3.22 mmol) was added to dichloromethane (5 mL), and trifluoroacetic acid (5 mL) was added, stirred at room temperature for 0.5 h, and concentrated under reduced pressure.
  • the concentrate was added to DMF (10 mL), and DIPEA (2.08 g, 16.09 mmol) and HATU (1.84 g, 4.84 mmol) were added in sequence, and reacted at room temperature for 4 h.
  • compound 27 was purified by reverse phase preparation (instrument: Waters 2767; chromatographic column: Waters SunFire C18 19*250 5um; mobile phase: A-acetonitrile, B-water (containing 0.1% trifluoroacetic acid); gradient elution: phase A from 20% to 65% (0-18min), 65% to 68% (18-18.8min); flow rate: 15mL/min) and the obtained preparation solution was lyophilized to obtain compound 27-1 (retention time 16.68min, 5mg) and compound 27-2 (retention time 18.16min, 10mg).
  • H3 and H4 of compound 27-1 both have NOE signals with H1 and H2, and its configuration is as shown in the figure below.
  • Example 12 the final product was purified by reverse phase preparation ( Instrumnent : SHIMADZU LC-20AP; Column: C18; Mobile phase: A is 10mmol/L NH4HCO3 in H2O , B is acetonitrile; Gradient: Phase B from 30 to 60 in 15min; Flow rate: 75mL/min) and the obtained preparation solution was lyophilized to obtain compound 29-1 (retention time 3.828min, 20mg) and compound 29-2 (retention time 3.921min, 29mg).
  • H3 and H4 of compound 29-1 both have NOE signals with H1 and H2, and its configuration is as shown in the figure below.
  • reaction solution was purified by preparative liquid chromatography (instrument: waters 2767 preparative chromatography column: SunFire@Prep C18 (19mm ⁇ 150mm); mobile phase composition: acetonitrile/water (containing 5mmol/L ammonium acetate)) to obtain compound 34 (20mg).
  • 35B (4.0 g, 21.95 mmol) and NBS (7.81 g, 43.88 mmol) were added to DMF (25 mL) and reacted at 60°C for 5 h under nitrogen atmosphere.
  • Water 50 mL was added and extracted with ethyl acetate (40 mL ⁇ 2).
  • the reaction solution was purified by preparative liquid chromatography (instrument: waters 2767 preparative chromatography column: SunFire@Prep C18 (19mm ⁇ 150mm); mobile phase composition: acetonitrile/water (containing 0.1% trifluoroacetic acid)) to obtain compound 36 (32 mg).
  • NCI-H1155 cells (ATCC, Cat#30-2001) were cultured with RPMI 1640 medium (with 5% FBS and 1% double antibody), and the cells were collected and plated when the degree of fusion reached 80%-90%. The cells were transferred to a sterile centrifuge tube and centrifuged at 1000rpm for 3 minutes. After centrifugation, the cells were removed and the supernatant was discarded. The culture medium was added to the centrifuge tube to resuspend the cells and count them. According to the counting results, the cell suspension was adjusted to an appropriate concentration and added to a 96-well cell culture plate (Corning, Cat#3903). The compound was dissolved in DMSO to 10mM and stored for later use.
  • the compound mother solution was diluted in sequence.
  • the compound was added 24 hours after plating, and the culture was continued for 72 hours at 37°C and 5% CO2 .
  • CELL VIABILITY reagent Promega, Cat#G7573
  • the cells were gently shaken 5 times, and then the chemiluminescence readings were detected using a BMG microplate reader (PHERAstar FSX).
  • the cell proliferation inhibition rate was calculated according to the formula [(1-(RLU compound -RLU blank )/(RLU control -RLU blank )) ⁇ 100%].
  • the IC50 value was obtained by four-parameter nonlinear fitting using GraphPad Prism software.
  • the compounds of the present invention have good NCI-H1155 cell proliferation inhibitory activity, wherein compound 35 has an inhibitory activity IC 50 of 16.26 nM on NCI-H1155 cell proliferation.
  • NCI-H526 cells (ATCC, CRL-5811) were cultured with RPMI 1640 medium (with 10% FBS and 1% double antibody), and the cells were collected and plated when the cells reached the appropriate density. The cells were transferred to a sterile centrifuge tube and centrifuged at 1000rpm for 3 minutes. After centrifugation, the cells were removed and the supernatant was discarded. An appropriate amount of trypsin was added to the centrifuge tube to digest the cells to single cells, and the culture medium was added and centrifuged. After centrifugation, the cells were removed and the supernatant was discarded. The cells were resuspended in the culture medium and counted.
  • the cell suspension was adjusted to an appropriate concentration and added to a 96-well cell culture plate (Corning, Cat#3903).
  • the compound was dissolved in DMSO to 10mM and stored for later use.
  • the compound mother solution was diluted in sequence.
  • the compound was added 24 hours after plating, and the culture was continued for 72 hours at 37°C and 5% CO2 .
  • CELL VIABILITY reagent Promega, Cat#G7573
  • the cell proliferation inhibition rate was calculated according to the formula [(1-(RLU compound -RLU blank )/(RLU control -RLU blank )) ⁇ 100%].
  • the IC50 value was obtained by four-parameter nonlinear fitting using GraphPad Prism software.
  • the compounds of the present invention such as the compounds in the examples, have good NCI-H526 cell proliferation inhibitory activity.
  • Test Example 3 Study on GSPT1 protein degradation activity in NCI-H1155 cells
  • NCI-H1155 cells (ATCC, CRL-5818) were cultured with RPMI 1640 medium (with 10% FBS and 1% double antibody), and the cells were collected and plated when they reached the appropriate density. The cells were transferred to a sterile centrifuge tube and centrifuged at 1000rpm for 3 minutes. After centrifugation, the cells were taken out, the supernatant was discarded, the cells were resuspended in culture medium, and counted. According to the counting results, the cell suspension was adjusted to an appropriate concentration and added to a 6-well cell culture plate, and the cell information and plating date were marked. The compound was dissolved in DMSO to 10mM and stored for later use. During the experiment, the compound mother solution was diluted in sequence.
  • the compounds of the present invention have good degradation activity on GSPT1 protein in NCI-H1155 cells.
  • reference compound 1 is as follows, and its synthesis refers to patent WO2021087093A1.
  • mice Male ICR mice, 25-30 g, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
  • mice On the day of the experiment, ICR mice were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours one day before administration and fed 4 hours after administration.
  • Intravenous administration solvent 5% DMA + 5% Solutol + 90% Saline
  • Oral administration solvent 0.5% MC
  • the compounds of the present invention such as the compounds in the examples, have good oral absorption.
  • mice Male SD rats, 200-250 g, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
  • Intravenous administration solvent 5% DMA + 5% Solutol + 90% Saline
  • Oral administration solvent 0.5% MC
  • the compounds of the present invention such as the compounds in the examples, have good pharmacokinetic properties.
  • Test Example 6 hERG potassium channel action test
  • Cell line Chinese hamster ovary (CHO) cell line stably expressing hERG potassium channel
  • CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channels were used to record hERG potassium channel currents using the whole-cell patch clamp technique at room temperature.
  • the glass microelectrode was pulled from a glass electrode blank (BF150-86-10, Sutter) by a puller.
  • the tip resistance after perfusion of the electrode liquid was about 2-5M ⁇ .
  • the glass microelectrode was inserted into the amplifier probe to connect to the patch clamp amplifier.
  • the clamping voltage and data recording were controlled and recorded by pClamp 10 software through a computer, with a sampling frequency of 10kHz and a filter frequency of 2kHz.
  • the cell was clamped at -80mV, and the step voltage to induce the hERG potassium current (I hERG ) was given a 2s depolarization voltage from -80mV to +20mV, then repolarized to -50mV, and returned to -80mV after 1s.
  • This voltage stimulation was given every 10s, and the drug administration process was started after the hERG potassium current was determined to be stable (at least 1 minute).
  • Compounds were administered for at least 1 min at each tested concentration, and at least 2 cells (n ⁇ 2) were tested at each concentration.
  • Inhibition% represents the inhibition percentage of the compound on hERG potassium current
  • I and Io represent the amplitude of hERG potassium current after and before drug addition, respectively.
  • X is the Log value of the test sample concentration
  • Y is the inhibition percentage at the corresponding concentration
  • Bottom and Top are Minimum and maximum inhibition percentages.
  • the compounds of the present invention have weak inhibition on hERG, among which compound 29-1 has an inhibitory activity on hERG with an IC 50 value > 40 ⁇ M.
  • Test Example 7 CYP450 enzyme inhibition test
  • the purpose of this study was to evaluate the effects of the test substances on the activities of five isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) of human liver microsomal cytochrome P450 (CYP) using an in vitro test system.
  • CYP human liver microsomal cytochrome P450
  • Specific probe substrates of CYP450 isoenzymes were incubated with human liver microsomes and different concentrations of the test substances, and the reaction was initiated by adding reduced nicotinamide adenine dinucleotide phosphate (NADPH).
  • the metabolites produced by the specific substrates were quantitatively detected by treating the samples and using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to determine the changes in CYP enzyme activity, calculate IC 50 values, and evaluate the inhibitory potential of the test substances on each CYP enzyme subtype.
  • LC-MS/MS liquid chromatography-tandem mass spectrometry
  • the compounds of the present invention such as the compounds in the examples, have weak inhibition on CYP enzymes.

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Abstract

L'invention concerne un composé tel que représenté par la formule générale (I) ou un stéréoisomère, un racémate, une substance deutérée, un solvate, un promédicament, un métabolite, un sel ou co-cristal pharmaceutiquement acceptable de celui-ci, un intermédiaire de celui-ci, et son procédé de préparation ; et l'utilisation du composé dans la préparation d'un médicament pour le traitement de maladies associées à GSPT1 ou associées à MYC.
PCT/CN2023/133911 2022-11-24 2023-11-24 Agent de dégradation de gspt1 et son utilisation en médecine WO2024109918A1 (fr)

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CN202211471660 2022-11-24
CN202211471660.9 2022-11-24
CN202310060279.1 2023-01-14
CN202310060279 2023-01-14
CN202310427746.X 2023-04-20
CN202310427746 2023-04-20
CN202310642374.2 2023-06-01
CN202310642374 2023-06-01
CN202310830211 2023-07-07
CN202310830211.7 2023-07-07
CN202311105423 2023-08-30
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180264000A1 (en) * 2017-03-14 2018-09-20 Biotheryx, Inc. Compounds targeting proteins, compositions, methods, and uses thereof
CN111285850A (zh) * 2018-12-06 2020-06-16 中国科学院上海药物研究所 一类异吲哚啉类化合物、其制备方法、药物组合物及其应用
CN112745298A (zh) * 2019-10-30 2021-05-04 中国科学院上海药物研究所 多取代异吲哚啉类化合物、其制备方法、药物组合物及用途
WO2022066835A1 (fr) * 2020-09-23 2022-03-31 St. Jude Children's Research Hospital, Inc. Analogues de n-(2-(2,6-dioxopipéridine-3-yl)-1,3-dioxoisoindoline-5-yl)arylsulfonamide substitués en tant que modulateurs de la protéine cereblon
CN114650868A (zh) * 2019-10-30 2022-06-21 达纳-法伯癌症研究公司 Helios的小分子降解剂及其使用方法
CN115304606A (zh) * 2021-06-21 2022-11-08 清华大学 一种同时靶向btk和gspt1蛋白的降解剂

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180264000A1 (en) * 2017-03-14 2018-09-20 Biotheryx, Inc. Compounds targeting proteins, compositions, methods, and uses thereof
CN111285850A (zh) * 2018-12-06 2020-06-16 中国科学院上海药物研究所 一类异吲哚啉类化合物、其制备方法、药物组合物及其应用
CN112745298A (zh) * 2019-10-30 2021-05-04 中国科学院上海药物研究所 多取代异吲哚啉类化合物、其制备方法、药物组合物及用途
CN114650868A (zh) * 2019-10-30 2022-06-21 达纳-法伯癌症研究公司 Helios的小分子降解剂及其使用方法
WO2022066835A1 (fr) * 2020-09-23 2022-03-31 St. Jude Children's Research Hospital, Inc. Analogues de n-(2-(2,6-dioxopipéridine-3-yl)-1,3-dioxoisoindoline-5-yl)arylsulfonamide substitués en tant que modulateurs de la protéine cereblon
CN115304606A (zh) * 2021-06-21 2022-11-08 清华大学 一种同时靶向btk和gspt1蛋白的降解剂

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