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WO2025201449A1 - Dérivés hétérocycliques et leur utilisation en médecine - Google Patents

Dérivés hétérocycliques et leur utilisation en médecine

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Publication number
WO2025201449A1
WO2025201449A1 PCT/CN2025/085314 CN2025085314W WO2025201449A1 WO 2025201449 A1 WO2025201449 A1 WO 2025201449A1 CN 2025085314 W CN2025085314 W CN 2025085314W WO 2025201449 A1 WO2025201449 A1 WO 2025201449A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
cyclopropyl
cycloalkyl
optionally substituted
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2025/085314
Other languages
English (en)
Chinese (zh)
Inventor
张晨
何平
雷鸣
孟庆元
黄江坤
黄清平
廖鹏飞
袁万强
李瑶
严庞科
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Haisco Pharmaceutical Group Co Ltd
Original Assignee
Haisco Pharmaceutical Group Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Haisco Pharmaceutical Group Co Ltd filed Critical Haisco Pharmaceutical Group Co Ltd
Publication of WO2025201449A1 publication Critical patent/WO2025201449A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/18—Bridged systems

Definitions

  • the present invention relates to a compound of general formula (I) or its racemate, stereoisomer, tautomer, pharmaceutically acceptable salt, and intermediates and preparation methods, as well as use of the compound in preparing drugs for treating autoimmune diseases or inflammatory diseases.
  • Tumor necrosis factor a member of the tumor necrosis factor superfamily, is a cytokine involved in systemic inflammation. It plays a crucial role in immune responses by regulating multiple signaling pathways, including direct inflammatory responses in immune cells and subsequent proliferation and programmed cell necrosis or apoptosis. It is a type II transmembrane protein. Its precursor consists of 233 amino acids, including a 76-amino acid signal peptide, and is bound to the cell membrane as a trimer (tmTNF ⁇ ).
  • TNF ⁇ -converting enzyme TNF ⁇ -converting enzyme
  • sTNF ⁇ soluble mature TNF ⁇
  • TNFR tumor necrosis factor receptor
  • TNF ⁇ is primarily produced by activated monocytes and macrophages, but is also produced by other immune cells such as T cells, B cells, NK cells, and neutrophils. Its biological functions are diverse. In general, TNF- ⁇ interacts with transmembrane TNFRs to control cell survival or induce apoptosis through unique and complex signaling pathways, thereby conferring resistance to certain types of infections.
  • the purpose of the present invention is to provide a class of compounds with inhibitory activity against TNF ⁇ .
  • This class of compounds has good inhibitory activity against TNF- ⁇ /TNFR1 binding and good oral bioavailability. It has weak inhibitory effects on various CYP enzyme subtypes CYP1A2, CYP2C9, CYP2D6, CYP2C19, and CYP3A4-M, especially on CYP1A2. It has better human liver microsome stability, lower clearance rate and longer half-life.
  • the present invention provides a compound represented by general formula (IA) or a stereoisomer, a pharmaceutically acceptable salt or a cocrystal thereof.
  • the compound represented by general formula (IA) is selected from the group consisting of general formula (I)
  • ring M is selected from 5-membered heteroaryl or 5-membered unsaturated heterocyclyl, said heteroaryl or heterocyclyl being optionally substituted with 1 to 4 R m ;
  • the compound represented by general formula (I) is selected from the compounds represented by general formula (Ia) and (Ib). In some embodiments, the compound represented by general formula (IA) is selected from the compounds represented by (Ic), (Id), and (Ie).
  • each R m is independently selected from deuterium, halogen, CN, ⁇ O, ⁇ S, OH, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 4 to 7 membered heterocycloalkyl, and said alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted with 1 to 4 R k ;
  • R m is independently selected from deuterium, F, Cl, Br, CN, OH, methyl, ethyl, methoxy, ethoxy, cyclopropyl, wherein the methyl, ethyl, methoxy, ethoxy, cyclopropyl is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, CF 3 , CHF 2 , CH 2 F, CD 3 , CHD 2 , CH 2 D, C 1-4 alkyl, C 1-4 alkoxy;
  • each R m is independently selected from deuterium, F, Cl, Br, CN, methyl, ethyl, cyclopropyl, CF 3 , CHF 2 , CH 2 F, CD 3 , CHD 2 , CH 2 D, CH 2 CD 3 , CH 2 CF 3 ;
  • X is selected from N, O, S, C(R x ), C(R x ) 2 or N(R x );
  • R q1 is selected from H, deuterium, C 1-6 alkyl, said alkyl optionally substituted with 1 to 4 R k ;
  • R q1 is selected from H, deuterium, C 1-4 alkyl, said alkyl optionally substituted with 1 to 4 R k ;
  • R q2 and R q3 are each independently selected from H, CN, OH, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, and the alkyl, alkoxy or cycloalkyl is optionally substituted with 1 to 4 R k ;
  • R q2 and R q3 are each independently selected from H, CN, OH, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, and the alkyl, alkoxy or cycloalkyl is optionally substituted with 1 to 4 R k ;
  • R q1 is selected from H, deuterium, F, Cl, Br, CN, OH, NH 2 , methyl, ethyl, or cyclopropyl, wherein the methyl, ethyl, or cyclopropyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, NH 2 , CF 3 , CHF 2 , CH 2 F, CD 3 , CHD 2 , CH 2 D, C 1-4 alkyl, or C 1-4 alkoxy;
  • R q2 is selected from H, OH, CN, NH 2 , methyl, ethyl, methoxy, ethoxy, wherein the methyl, ethyl, methoxy, ethoxy is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, NH 2 , CF 3 , CHF 2 , CH 2 F, CD 3 , CHD 2 , CH 2 D, C 1-4 alkyl, C 1-4 alkoxy;
  • R q1 is selected from H, deuterium, F, Cl, Br, CN, OH, NH 2 , methyl, ethyl, or cyclopropyl, wherein the methyl, ethyl, or cyclopropyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, NH 2 , CF 3 , CHF 2 , CH 2 F, CD 3 , CHD 2 , CH 2 D, methyl, or ethyl;
  • W is selected from -CR w1 R w2 -, -(CR w1 R w2 ) 2 -;
  • R w1 and R w2 are each independently selected from H, deuterium, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, and the alkyl or cycloalkyl is optionally substituted with 1 to 4 R k ;
  • R w1 and R w2 are directly linked to form a C 3-6 cycloalkyl group, which is optionally substituted with 1 to 4 R k groups;
  • R w1 and R w2 are each independently selected from H, deuterium, halogen, C 1-4 alkyl, C 3-6 cycloalkyl, and the alkyl or cycloalkyl is optionally substituted with 1 to 4 R k ;
  • R w1 and R w2 are directly linked to form a C 3-6 cycloalkyl group, which is optionally substituted with 1 to 4 R k groups;
  • W is selected from -CH2- , -CH( CH3 )-, -CH( CF3 )-, -CH( CD3 )-, -CFH-, -CF2- , -CH2CH2- , or
  • Ring A is selected from 5-membered heteroaryl, In some embodiments, Ring A is selected from thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, pyrazolyl, In some embodiments, Z 1 is selected from N or C(R z1 );
  • Z 2 is selected from N or C(R z2 );
  • Z3 is selected from N or C( Rz3 );
  • Z 4 is selected from N or C
  • Z 5 is selected from N or C
  • Z 3 is selected from N;
  • R 1 is selected from C 5-10 bicyclic cycloalkyl, C 7-12 tricyclic cycloalkyl, -6 to 12 membered bicyclic heterocycloalkyl-R 1b , said R 1 being optionally substituted with 1 to 4 R 1a ;
  • R 1 is selected from C 5-10 bridged cycloalkyl, C 6-10 cycloalkyl, C 5-10 spirocycloalkyl, -6 to 10 membered bridged heterocycloalkyl-R 1b , -6 to 12 membered cycloheterocycloalkyl-R 1b , -6 to 12 membered spiro heterocycloalkyl-R 1b , said R 1 is optionally substituted with 1 to 4 R 1a ;
  • R 1 is selected from The R 1 is optionally substituted by 1 to 4 R 1a , s1, s3, and s5 are each independently selected from 0, 1, or 2, and s2 and s4 are each independently selected from 0 or 1; in some embodiments, s3 and s4 are not 0 at the same time, and s1 and s2 are not 0 at the same time;
  • R 1 is selected from Said R 1 is optionally substituted by 1 to 4 R 1a ;
  • R 1 is selected from one of the following groups wherein the ring is optionally substituted: When substituted, it is optionally substituted with 1 to 3 substituents selected from deuterium, F, Cl , Br, CN, OH, NH2, NH( CH3 ), NH( CH2CH3 ) , N( CH3 ) 2 , N( CH2CH3 ) 2 , CF3, CHF2 , CH2F , CD3 , CHD2 , CH2D , -CH2OH , methyl, ethyl , methoxy, ethoxy ;
  • each R 1a is independently selected from deuterium, halogen, CN, OH, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, -C 0-4 alkylene-C 3-6 cycloalkyl, -C 0-4 alkylene-4 to 7 membered heterocycloalkyl, -C( ⁇ O)C 1-6 alkyl, -C( ⁇ O)C 3-7 carbocyclyl, -C( ⁇ O)-4 to 7 membered heterocyclyl, -NHC( ⁇ O)C 1-6 alkyl, -NHC( ⁇ O)C 3-6 cycloalkyl, -S( ⁇ O)C 1-6 alkyl, -S( ⁇ O)C 3-7 carbocyclyl, -NHS( ⁇ O)C 1-6 alkyl, -S( ⁇ O)C
  • each R 1a is independently selected from deuterium, F, Cl, Br, CN, OH, NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , N(CH 2 CH 3 ) 2 , methyl, ethyl, methoxy, ethoxy, cyclopropyl, -CH 2 -cyclopropyl, -S( ⁇ O)CH 3 , -S( ⁇ O)cyclopropyl, -NHS( ⁇ O)-CH 3 , -S( ⁇ O) 2 -CH 3 , -S( ⁇ O) 2 cyclopropyl, -NHS( ⁇ O) 2 CH 3 , -S( ⁇ O) 2 NHCH 3 , -P( ⁇ O)(CH 3 ) 2 , wherein the CH 2 , methyl, ethyl, methoxy, ethoxy, and cyclopropyl are optionally substituted with 1 to
  • R 1b is selected from H, C 1-6 alkyl, C 2-6 alkynyl, C 3-7 carbocyclyl, 4 to 7 membered heterocyclyl, -C 1-2 alkylene-C 3-7 carbocyclyl, -C 1-2 alkylene-4 to 7 membered heterocyclyl, -C( ⁇ O)C 1-2 alkylene-C 3-7 carbocyclyl, -C( ⁇ O)C 1-6 alkyl, -C( ⁇ O)C 3-7 carbocyclyl, -C( ⁇ O)C 1-2 alkylene-4 to 7 membered heterocyclyl, -C( ⁇ O)-4 to 7 membered heterocyclyl, said alkylene, alkyl, alkynyl, carbocyclyl or heterocyclyl being optionally substituted with 1 to 4 R k ;
  • R 1b is selected from H, C 1-4 alkyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 4 to 7 membered heterocycloalkyl, -C 1-2 alkylene-C 3-6 cycloalkyl, -C 1-2 alkylene-4 to 7 membered heterocycloalkyl, -C( ⁇ O)C 1-2 alkylene-C 3-6 cycloalkyl, -C( ⁇ O)C 1-4 alkyl, -C( ⁇ O)C 3-6 cycloalkyl, -C( ⁇ O)-C 1-2 alkylene-4 to 7 membered heterocycloalkyl, -C( ⁇ O)-4 to 7 membered heterocycloalkyl, said alkylene, alkyl, alkynyl, cycloalkyl or heterocycloalkyl being optionally substituted with 1 to 4 R k ;
  • R 1b is selected from H or one of the following groups optionally substituted with 1 to 4 R k : methyl, ethynyl, -CH 2 -ethynyl, propynyl, butynyl, butyn-2-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, -CH 2 -oxetanyl, -CH 2 -tetrahydrofuranyl, -CH 2 -oxetanyl, -CH 2 --CH 2
  • R 3 is selected from H, deuterium, halogen, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl is optionally substituted with 1 to 4 R k ;
  • R 3 is selected from H, deuterium, halogen, CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl is optionally substituted with 1 to 4 R k ;
  • R 3 is selected from H, deuterium, F, Cl, methyl, deuterated methyl, or fluoromethyl;
  • ring S is selected from C 6-10 aryl or 5 to 10 membered heteroaryl
  • ring S is selected from phenyl, benzoC 4-6 carbocyclyl, benzo 4 to 6 membered heterocyclyl, 5 to 6 membered heteroaryl, or 8 to 10 membered heteroaryl;
  • ring S is selected from phenyl, thienyl, thiazolyl, furanyl, oxazolyl, pyrazolyl, pyrrolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl;
  • ring S is selected from The left side is directly connected to R 1 ;
  • Selected from The left side is directly connected to R 1 ;
  • ring T is selected from phenyl, 5- to 6-membered heteroaryl, benzoC 4-6 carbocyclyl, benzo 4- to 6-membered heterocyclyl, or 8- to 10-membered heteroaryl;
  • ring T is selected from phenyl, thienyl, furanyl, pyridinyl, pyrimidinyl, pyridonyl, benzocyclopentyl, imidazopyridinyl, pyrazolopyridinyl, pyrrolopyridinyl;
  • ring T is selected from phenyl, thienyl, or pyridinyl;
  • Selected from In some embodiments, Selected from
  • R t2 is selected from methyl, ethyl, wherein the methyl, ethyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, NH 2 , CF 3 , CHF 2 , CH 2 F, CD 3 , CHD 2 , CH 2 D, methyl or ethyl;
  • R 2 , R z1 , R z2 , and R z3 are each independently selected from H, deuterium, halogen, CN, OH, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OC 1-6 alkyl, -SC 1-6 alkyl, -OC 3-7 carbocyclyl, -C 0-4 alkylene-C 3-7 carbocyclyl, -C 0-4 alkylene-4 to 7 membered heterocyclyl, -S( ⁇ O)C 1-6 alkyl, -S( ⁇ O)C 3-7 carbocyclyl, -NHS( ⁇ O)C 1-6 alkyl, -S( ⁇ O) 2 C 1-6 alkyl, -S( ⁇ O) 2 C 3-7 carbocyclyl, -NHS( ⁇ O) 2 C 1-6 alkyl, -
  • R 2 and R z3 are directly linked to form a C 4-6 carbocyclyl or a 4- to 6-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R k ;
  • R 2 and R z1 are directly linked to form a C 4-6 carbocyclyl or a 4- to 6-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R k ;
  • R 2 and R z3 are directly linked to form a C 4-6 carbocyclyl or a 4- to 6-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R k ;
  • R 2 and R z1 are directly linked to form a C 4-6 carbocyclyl or a 4- to 6-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R k ;
  • R 2 , R z1 , R z2 , and R z3 are each independently selected from H, deuterium, halogen, CN, OH, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, -SC 1-4 alkyl, -OC 3-6 cycloalkyl, C 3-6 cycloalkyl, 4 to 7 membered heterocycloalkyl, -C 1-2 alkylene-C 3-7 carbocyclyl, -C 1-2 alkylene-4 to 7 membered heterocyclyl, wherein the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, carbocyclyl, or heterocyclyl is optionally substituted with 1 to 4 R k ;
  • R 2 , R z1 , and R z2 are each independently selected from H, deuterium, F, Cl, Br, CN, OH, NH 2 , methyl, ethyl, methoxy, ethoxy, and cyclopropyl, wherein the methyl, ethyl, methoxy, ethoxy, and cyclopropyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, NH 2 , CF 3 , CHF 2 , CH 2 F, CD 3 , CHD 2 , CH 2 D, methyl, or ethyl;
  • ring S is selected from phenyl or 5- to 6-membered heteroaryl
  • ring S is selected from The left side is directly connected to R 1 ;
  • Y is selected from N or CH;
  • the compound represented by the above general formula (I-A) or its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt is represented by the above general formula (I-A) or its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt,
  • R w1 and R w2 are each independently selected from H, deuterium, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, and the alkyl or cycloalkyl group is optionally substituted with 1 to 4 R k ;
  • Z2 is selected from N or C( Rz2 );
  • Z3 is selected from N or C( Rz3 );
  • Z 4 is selected from N or C
  • Z5 is selected from N or C
  • Z6 is selected from N or C
  • R 1 is selected from C 5-10 bicyclic cycloalkyl, C 7-12 tricyclic cycloalkyl, -6 to 12 membered bicyclic heterocycloalkyl-R 1b , said R 1 being optionally substituted with 1 to 4 R 1a ;
  • R 1a is each independently selected from deuterium, halogen, CN, OH, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, -C 0-4 alkylene-C 3-6 cycloalkyl, -C 0-4 alkylene-4 to 7 membered heterocycloalkyl, -C( ⁇ O)C 1-6 alkyl, -C( ⁇ O)C 3-7 carbocyclyl, -C( ⁇ O)-4 to 7 membered heterocyclyl, -NHC( ⁇ O)C 1-6 alkyl, -NHC( ⁇ O)C 3-6 cycloalkyl, -S( ⁇ O)C 1-6 alkyl, -S( ⁇ O)C 3-7 carbocyclyl, -NHS( ⁇ O)C 1-6 alkyl, -S( ⁇ O) 2
  • R 1b is selected from H, C 1-6 alkyl, C 2-6 alkynyl, C 3-7 carbocyclyl, 4- to 7-membered heterocyclyl, -C 1-2 alkylene-C 3-7 carbocyclyl, -C 1-2 alkylene-4- to 7-membered heterocyclyl, -C( ⁇ O)C 1-2 alkylene-C 3-7 carbocyclyl, -C( ⁇ O)C 1-6 alkyl, -C( ⁇ O)C 3-7 carbocyclyl, -C( ⁇ O)C 1-2 alkylene-4- to 7-membered heterocyclyl, -C( ⁇ O)-4- to 7-membered heterocyclyl, wherein the alkylene, alkyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R k ;
  • R 3 is selected from H, deuterium, halogen, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, wherein the alkyl, alkenyl, alkynyl, and cycloalkyl are optionally substituted with 1 to 4 R k ;
  • Ring S is selected from C 6-10 aryl or 5- to 10-membered heteroaryl
  • Ring T is selected from phenyl, 5- to 6-membered heteroaryl, benzoC4-6 carbocyclyl, benzo4- to 6-membered heterocyclyl or 8- to 10-membered heteroaryl;
  • R 2 and R z3 are directly linked to form a C 4-6 carbocyclic group or a 4- to 6-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k ;
  • R s and R t are each independently selected from deuterium, halogen, CN, OH, NH 2 , SF 5 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OC 1-6 alkyl, -SC 1-6 alkyl, -OC 3-7 carbocyclyl, -OC 1-4 alkylene-C 3-7 carbocyclyl, -SC 3-7 carbocyclyl, -SC 1-4 alkylene-C 3-7 carbocyclyl, -C 0-4 alkylene-C 3-7 carbocyclyl, -C 0-4 alkylene-4 to 7 membered heterocyclyl, -S( ⁇ O)C 1-6 alkyl, -S( ⁇ O)C 3-7 carbocyclyl, -NHS( ⁇ O)C 1-6 alkyl, -S( ⁇ O) 2 C 1-6 alkyl
  • n1 and n2 are each independently selected from 0, 1, 2, 3 or 4.
  • R m is independently selected from deuterium, halogen, CN, ⁇ O, ⁇ S, OH, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 4 to 7 membered heterocycloalkyl, wherein said alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted with 1 to 4 R k ;
  • R q1 is selected from H, deuterium, C 1-4 alkyl, said alkyl being optionally substituted with 1 to 4 R k ;
  • R q2 and R q3 are each independently selected from H, CN, OH, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, wherein the alkyl, alkoxy or cycloalkyl is optionally substituted with 1 to 4 R k ;
  • R 1 is selected from C 5-10 bridged cycloalkyl, C 6-10 cycloheteroalkyl, C 5-10 spirocycloalkyl, -6 to 10-membered bridged heterocycloalkyl-R 1b , -6 to 12-membered cycloheterocycloalkyl-R 1b , and -6 to 12-membered spiro heterocycloalkyl-R 1b , wherein R 1 is optionally substituted with 1 to 4 R 1a ;
  • R 1b is selected from H, C 1-4 alkyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 4- to 7-membered heterocycloalkyl, -C 1-2 alkylene-C 3-6 cycloalkyl, -C 1-2 alkylene-4- to 7-membered heterocycloalkyl, -C( ⁇ O)C 1-2 alkylene-C 3-6 cycloalkyl, -C( ⁇ O)C 1-4 alkyl, -C( ⁇ O)C 3-6 cycloalkyl, -C( ⁇ O)-C 1-2 alkylene-4- to 7-membered heterocycloalkyl, -C( ⁇ O)-4- to 7-membered heterocycloalkyl, wherein the alkylene, alkyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally substituted with 1 to 4 R k ;
  • R w1 and R w2 are each independently selected from H, deuterium, halogen, C 1-4 alkyl, C 3-6 cycloalkyl, and the alkyl or cycloalkyl group is optionally substituted with 1 to 4 R k ;
  • R w1 and R w2 are directly linked to form a C 3-6 cycloalkyl group, which is optionally substituted with 1 to 4 R k groups;
  • R 3 is selected from H, deuterium, halogen, CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, wherein the alkyl, alkenyl, alkynyl, and cycloalkyl are optionally substituted with 1 to 4 R k ;
  • Ring S is selected from phenyl, benzoC 4-6 carbocyclyl, benzo 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, or 8- to 10-membered heteroaryl;
  • R 2 and R z1 are directly linked to form a C 4-6 carbocyclic group or a 4- to 6-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k ;
  • R m is selected from one of the following groups optionally substituted by 1 to 3 R m :
  • Ring S is selected from phenyl or 5- to 6-membered heteroaryl
  • R q1 is selected from H, deuterium, F, Cl, Br, CN, OH, NH 2 , methyl, ethyl or cyclopropyl, wherein the methyl, ethyl or cyclopropyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, NH 2 , CF 3 , CHF 2 , CH 2 F, CD 3 , CHD 2 , CH 2 D, C 1-4 alkyl or C 1-4 alkoxy;
  • R 1 is selected from Said R 1 is optionally substituted by 1 to 4 R 1a ;
  • R 1a is each independently selected from deuterium, F, Cl, Br, CN, OH, NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , N(CH 2 CH 3 ) 2 , methyl, ethyl, methoxy, ethoxy, cyclopropyl, -CH 2 -cyclopropyl, -S( ⁇ O)CH 3 , -S( ⁇ O)cyclopropyl, -NHS( ⁇ O)-CH 3 , -S( ⁇ O) 2 -CH 3 , -S( ⁇ O) 2 cyclopropyl, -NHS( ⁇ O) 2 CH 3 , -S( ⁇ O) 2 NHCH 3 , -P( ⁇ O)(CH 3 ) 2 , wherein the CH 2 , methyl, ethyl, methoxy, ethoxy, and cyclopropyl are optionally substituted by 1 to 4 R k
  • R 1b is selected from H or one of the following groups optionally substituted with 1 to 4 R k : methyl, ethynyl, -CH 2 -ethynyl, propynyl, butynyl, butyn-2-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, -CH 2 -oxetanyl, -CH 2 -tetrahydrofuranyl, -CH 2 -oxetanyl, -CH 2 -azeti
  • Rt1 is selected from H, deuterium, F, Cl, Br, CN, OH, NH2 , SF5 , NH( CH3 ), NH( CH2CH3 ), N( CH3 ) 2 , N ( CH2CH3 ) 2 , methyl, ethyl, vinyl , ethynyl, methoxy, ethoxy, -S-methyl, -S-ethyl, cyclopropyl, cyclobutyl, -CH2 -cyclopropyl, -CH2 -cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, -O- CH2 -cyclopropyl, -O- CH2 -cyclobutyl, -S-cyclopropyl, -S-cyclobutyl, -S-cyclopropyl, -S-cyclobutyl, -S- CH2 -cyclopropyl,
  • each R k is independently selected from deuterium, F, Cl, Br, I, CN, OH, -CH 2 OH, CF 3 , CHF 2 , CH 2 F, CD 3 , CHD 2 , CH 2 D, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;
  • R m is each independently selected from deuterium, F, Cl, Br, CN, methyl, ethyl, cyclopropyl, CF 3 , CHF 2 , CH 2 F, CD 3 , CHD 2 , CH 2 D, CH 2 CD 3 , CH 2 CF 3 ;
  • R 1 is selected from one of the following groups wherein the ring is optionally substituted: When substituted, it is optionally substituted with 1 to 3 substituents selected from deuterium, F, Cl , Br, CN, OH, NH2, NH( CH3 ), NH( CH2CH3 ) , N( CH3 ) 2 , N( CH2CH3 ) 2 , CF3, CHF2 , CH2F , CD3 , CHD2 , CH2D , -CH2OH , methyl, ethyl , methoxy, ethoxy ;
  • R t1 is selected from SF 5 , methyl, ethyl, methoxy, ethoxy, -S-methyl, -S-ethyl, -O-cyclopropyl, -O-cyclobutyl, -OCH 2 -cyclopropyl, -OCH 2 -cyclobutyl, -S-cyclopropyl, -S-cyclobutyl, -SCH 2 -cyclopropyl, -SCH 2 -cyclobutyl, wherein the methyl, ethyl, methoxy, ethoxy, cyclopropyl or cyclobutyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, NH 2 , CF 3 , CHF 2 , CH 2 F, CD 3 , CHD 2 , CH 2 D, methyl or ethyl;
  • R q1 is selected from H, deuterium, F, Cl, Br, CN, OH, NH 2 , methyl, ethyl or cyclopropyl, wherein the methyl, ethyl or cyclopropyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, NH 2 , CF 3 , CHF 2 , CH 2 F, CD 3 , CHD 2 , CH 2 D, methyl or ethyl;
  • R q2 is selected from H, OH, CN, NH 2 , methyl, ethyl, methoxy, ethoxy, wherein the methyl, ethyl, methoxy, ethoxy is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, NH 2 , CF 3 , CHF 2 , CH 2 F, CD 3 , CHD 2 , CH 2 D, methyl or ethyl;
  • R 2 , R z1 , and R z2 are each independently selected from H, deuterium, F, Cl, Br, CN, OH, NH 2 , methyl, ethyl, methoxy, ethoxy, and cyclopropyl, wherein the methyl, ethyl, methoxy, ethoxy, and cyclopropyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, NH 2 , CF 3 , CHF 2 , CH 2 F, CD 3 , CHD 2 , CH 2 D, methyl, ethyl, methoxy, or ethoxy;
  • the present invention relates to the compound shown below or its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt, wherein the compound is selected from one of the structures shown below in Table E.
  • the compounds of the present invention include racemates, stereoisomers, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof.
  • Alkyl refers to a substituted or unsubstituted straight or branched chain saturated aliphatic hydrocarbon group, including but not limited to alkyl groups of 1 to 20 carbon atoms, alkyl groups of 1 to 8 carbon atoms, alkyl groups of 1 to 6 carbon atoms, and alkyl groups of 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; alkyl groups 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.
  • Cycloalkyl refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon radical, typically having 3 to 12 carbon atoms. Cycloalkyl groups can be monocyclic, fused, bridged, or spirocyclic. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutyl-cyclobutyl, cyclobutyl-spirocyclobutyl, and adamantane. Cycloalkyl groups can be monovalent, divalent, trivalent, or tetravalent.
  • Heterocycloalkyl refers to a saturated cyclic hydrocarbon radical containing heteroatoms that is substituted or unsubstituted, including but not limited to 3 to 12 atoms, 3 to 8 atoms, comprising 1 to 3 heteroatoms selected from N, O, S or Se, and the C, N, S on the ring of heterocycloalkyl can be oxidized to various oxidation states.
  • Heterocycloalkyl can be a monocycle, a ring, a bridged ring and a spirocycle.
  • Heterocycloalkyl can be connected to a heteroatom or a carbon atom, and non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolane, dioxane, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazolidinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl,
  • the heterocycloalkyl group can 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-3-butenyl, and the like; an 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 and 2 to 4 carbon atoms in the backbone.
  • 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, and the like; alkynyl groups can be monovalent, divalent, trivalent, or tetravalent.
  • Alkoxy refers to a substituted or unsubstituted -O-alkyl group. 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 monocycle, a 4-12 membered bicycle, a 10-15 membered tricycle, or a 12-18 membered quaternary system.
  • the carbocyclyl can be attached to the aromatic or non-aromatic ring, and the ring can be optionally a monocycle, a cyclic ring, a bridged ring, or a spirocycle.
  • 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, a benzene ring, a 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 ring, and contains one 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 optionally substituted in the heterocyclyl ring can be oxidized to various oxidation states.
  • the heterocyclic group can be attached to a heteroatom or a carbon atom, and can be attached 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-dioxolane, 1,4-dioxolane, 1,3-dioxane, azepanyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithiazyl, dihydrofuranyl, dihydropyranyl, dithiolanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridinyl, pyrrolopyr
  • Spirocycle or “spirocyclyl” 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 parallel ring system includes but is not limited to 5 to 20, 5 to 14, 5 to 12, and 5 to 10.
  • Non-limiting examples include: "Bicyclic" or "bicyclic group” can be monovalent, divalent, trivalent or tetravalent.
  • Carbobridged ring refers to a “bridged ring” in which the ring system consists of only carbon atoms.
  • Heteromonocycle refers to a monocyclic ring system of "heterocyclyl” or “heterocycle”,
  • Heterocyclo refers to a "cyclo" containing a heteroatom.
  • Heterospirocycle refers to a “spirocycle” containing a heteroatom.
  • Aryl or “aromatic ring” refers to a substituted or unsubstituted aromatic hydrocarbon group having a single ring or a fused ring, wherein the number of ring atoms in the aromatic ring 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 carbon ring, wherein the ring connected to the parent structure is the aryl ring, non-limiting examples of which include benzene ring, 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.
  • the number of ring atoms in the heteroaromatic ring is, but not limited to, 5 to 15, 5 to 10 or 5 to 6.
  • heteroaryl include but are not limited to pyridyl, furyl, thienyl, selenophenyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazolyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, pyridonyl and the like.
  • 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 of which include When heteroaryl appears in this document, its definition is consistent with this definition.
  • Heteroaryl can be monovalent, divalent, trivalent or tetravalent. When it is divalent, trivalent or tetravalent, the attachment point is located on the ring with aromaticity.
  • 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 rings (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 sites of the group can be connected to other groups through chemical bonds.
  • the chemical bond connection mode is non-positional and there are hydrogen atoms at the bondable sites
  • the number of H atoms at the site will decrease accordingly with the number of chemical bonds connected, and the group will become a group with the corresponding valence.
  • connection directions include connection from left to right and from right to left in the reading order, for example, A-L-B, when L is selected from -M-W-, includes A-M-W-B and A-W-M-B.
  • Preparation specifications refers to the weight of the main drug contained in each vial, tablet or other unit preparation.
  • Stepoisomers refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, optical isomers, enantiomers, diastereomers and conformational isomers.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • HPLC determination was performed using an Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100 ⁇ 4.6 mm, 3.5 ⁇ M);
  • Thin layer chromatography silica gel plates used were Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates.
  • the specifications of the silica gel plates used for thin layer chromatography (TLC) were 0.15 mm to 0.20 mm, and the specifications used for thin layer chromatography separation and purification products were 0.4 mm to 0.5 mm.
  • the compounds used in the reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and/or compounds described in the chemical literature.
  • “Commercially available chemicals” are obtained from standard commercial sources, including Shanghai Aladdin Biochemical Technology Co., Ltd., Shanghai McLean Biochemical Technology Co., Ltd., Sigma-Aldrich, Alfa Aesar (China) Chemical Co., Ltd., TCI (Shanghai) Chemical Industry Development Co., Ltd., Anage Chemical, Shanghai Titan Technology Co., Ltd., Kelon Chemical, Bailingwei Technology Co., Ltd., etc.
  • Retention time Unless otherwise specified in the examples, it represents the retention time corresponding to the analytical method.
  • Pre-HPLC conditions Instrument: Waters 2767 Preparative HPLC; Column: XSelect CSH C18 (19 mm ⁇ 250 mm). Samples were dissolved in DMF and filtered through a 0.45 ⁇ M filter to prepare the sample solution.
  • Preparative chromatography conditions a. Mobile phase A: acetonitrile; b. Water (50 mM ammonium bicarbonate); Gradient elution from 15% to 60% mobile phase A; c. Flow rate: 12 mL/min; d. Elution time: 15 minutes.
  • Compound 4f was prepared by referring to the synthetic route of WO2018206820.
  • Mobile phase A, B composition Mobile phase A: acetonitrile, mobile phase B: water (containing 50 mM ammonium bicarbonate); b. Gradient elution, mobile phase A content ranging from 25% to 70%; c. Flow rate: 12 ml/min; d. Elution time: 15 min) to obtain compound 7 (4.3 mg, yield: 45.97%).
  • 8c (0.35 g, 0.87 mmol) was dissolved in 1 mL of 1,4-dioxane, and diboronic acid pinacol ester (0.44 g, 1.74 mmol), potassium acetate (0.26 g, 2.61 mmol), tricyclohexylphosphine tetrafluoroborate (32 mg, 0.087 mmol), and Pd 2 (dba) 3 (80 mg, 0.087 mmol) were added in sequence.
  • the reaction mixture was microwaved at 140°C for 3 h under a nitrogen atmosphere.
  • the reaction mixture was cooled to room temperature and concentrated under reduced pressure.
  • the residue was purified by silica gel chromatography to give 8d (0.32 g, 74% yield).
  • 9a (60 g, 151.9 mmol) was dissolved in 300 mL of dichloromethane. A 20% aqueous solution of potassium hydroxide (255.2 g, 911.4 mmol) was added dropwise on an ice bath. A 200 mL solution of TMSCF 2 Br (61.6 g, 303.8 mmol) in dichloromethane was then added dropwise. The reaction was continued for 0.5 hour. The reaction solution was concentrated, and ethyl acetate and water were added. The resulting organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to afford 9b (28.5 g, 42%).
  • the crude product 9s from the previous step was dissolved in 2 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added. The reaction mixture was allowed to react at room temperature for 1 hour. After concentration, an appropriate amount of ethyl acetate and saturated sodium bicarbonate solution were added and stirred for 2 minutes. The organic phase was concentrated to obtain a crude product that was purified by preparative HPLC (Preparative conditions: Instrument: Waters Automated Purification System; Column: SunFire (19 mm ⁇ 250 mm); 2. The sample was dissolved in DMF and filtered through a 0.45 ⁇ m filter to prepare a sample solution; 3. Preparative chromatography conditions: a.
  • 17a (7 g, 31.96 mmol) was dissolved in 70 mL of acetonitrile.
  • Aqueous potassium hydroxide (8.97 g, 159.8 mmol) was added dropwise at -20°C.
  • TMSCF2Br (12.9 g, 63.92 mmol) was then added dropwise. The reaction was continued for 0.5 hour after the addition was complete. Ethyl acetate and water were added, and the resulting organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to afford 17b (28.5 g, 42%).
  • 17b (6.3 g, 25.1 mmol), (S)-tert-butylsulfenamide (3.35 g, 27.61 mmol), and cesium carbonate (12.27 g, 37.65 mmol) were added to 100 mL of dichloromethane and reacted at room temperature for 4 hours. Appropriate amounts of water and dichloromethane were added, and the obtained organic phase was dried, concentrated, and purified by silica gel column chromatography to obtain 17c (7.3 g, 78%).
  • Zinc powder (12.89 g, 197.1 mmol) and cuprous chloride (5.85 g, 59.13 mmol) were added to 150 mL of tetrahydrofuran and reacted at 70°C for 2 hours.
  • Ethyl bromoacetate (9.87 g, 59.13 mmol) was slowly added at room temperature and reacted at 50°C for 1 hour.
  • the reaction solution was cooled to room temperature and a solution of 17c (7.3 g, 19.71 mmol) in tetrahydrofuran (30 mL) was added dropwise. After reacting at room temperature for 1 hour, saturated ammonium chloride solution was added to quench the reaction. An appropriate amount of ethyl acetate was added to the mixture.
  • the mixture was filtered and washed to obtain an organic phase which was dried, concentrated, and purified by silica gel column chromatography to afford 17d (7.3 g, 80%).
  • Substrate 26b (5.45 g, 20 mmol) and hydrochloric acid (6N, 16.7 mL, 100 mmol) were added to a reaction flask. 10 mL of sodium nitrite (2.76 g, 40 mmol) was added dropwise in an ice-salt bath. The reaction was continued for one hour. Hypophosphorous acid (50 wt.%, 5.12 g, 40 mmol) was then added dropwise and the reaction continued for another two hours. The reaction mixture was extracted twice with ethyl acetate. The resulting organic phase was dried, concentrated, and purified by silica gel column chromatography to yield compound 26c (3.45 g, 67%).
  • Substrate 26c (3.45 g, 13.4 mmol) was dissolved in 40 mL of tetrahydrofuran.
  • LDA (2 M, 7.4 mL, 14.7 mmol) was added dropwise in a dry ice-ethanol bath and the reaction was continued for 2 hours.
  • An appropriate amount of dry ice thoroughly rinsed with tetrahydrofuran was added to the reaction solution.
  • the reaction solution was concentrated and dilute hydrochloric acid was slowly added to adjust the pH to about 3.
  • the reaction solution was extracted twice with ethyl acetate to obtain an organic phase, which was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product of the target compound 26d.
  • the compounds were tested for their inhibition of TNF- ⁇ /TNFR1 binding using the TR-FRET method.
  • Protein TNF- ⁇ (ACRO, Cat#TNA-H82E3) and TNFR1 (ACRO, Cat#TN1-H5251) solutions were prepared in reaction buffer PPI (Revvity, Cat#61DB10RDF).
  • the final concentration of TNF- ⁇ /TNFR1 in the reaction mixture was 0.15 nM.
  • the starting concentration of the test compound was 1 ⁇ M, diluted 3 times, and 10 doses.
  • 0.1 ⁇ L of the diluted test compound in the reaction buffer was transferred to a 384-well plate (Grenier, Cat#784075) using acoustic liquid delivery technology (Echo655) and centrifuged at 1000 rpm for 1 minute; 2.5 ⁇ L of TNF- ⁇ solution was transferred to the 384 reaction plate and centrifuged at 1000 rpm for 1 minute, incubated at 25°C for 15 minutes; 2.5 ⁇ L of TNFR1 solution was transferred to the 384 reaction plate and centrifuged at 1000 rpm for 1 minute; 5 ⁇ L of Streptavidin-Tb was transferred to the 384 reaction plate and centrifuged at 1000 rpm for 1 minute.
  • the cryptate and PAb Anti-Human IgG-XL665 assay mixture was added to a 384-well plate and centrifuged at 1000 rpm for 1 minute. The mixture was then incubated at 25°C for 60 minutes.
  • HTRF signals (Ratio 665/620 nm) were read using a BMG High-Throughput Drug Screening Multi-Purpose Microplate Reader. IC50 values and nonlinear regression curve fitting were obtained using GraphPad Prism software.
  • the compounds of the present invention such as the compounds in the examples, have good inhibitory activity against TNF- ⁇ /TNFR1 binding.
  • H_TNF ⁇ CHO-K1 Cell Line plate In a sterile 96-well V-bottom plate, perform a gradient dilution of the Anti-TNF ⁇ drug with Assay Buffer. Remove the overnight Membrane Bound H_TNF ⁇ CHO-K1 Cell Line plate, discard the supernatant, add serially diluted drug at 50 ⁇ L/well, and incubate for 1 hour. After 1 hour, add effector cells (H_TNFR1/H_TNFR2 reporter cell line) at 50 ⁇ L/well, cover the plate, and incubate for another 6 hours. Collect samples for luciferase analysis.
  • the compounds of the present invention have good inhibitory activity on mTNF ⁇ /TNFR1 binding. Specifically, the inhibitory activity of compound 1 on mTNF ⁇ /TNFR1 binding is 6.81 nM.
  • HT-29 (ATCC) cells were seeded at 12,000 cells/100 ⁇ L/well in a 96-well plate (corning, 3599) and allowed to adhere overnight.
  • TNF- ⁇ R&D, 210-TA-020
  • Compounds were added at varying concentrations (starting at 10 ⁇ M, with 3-fold serial dilutions across nine concentration points) and pre-incubated at 37°C for 1 hour.
  • the compounds of the present invention have good inhibitory activity against HT-29 cells.
  • mice Male C57 mice, 20-25 g, 6 mice per compound, purchased from Beijing Huafukang Biotechnology Co., Ltd.
  • mice On the day of the experiment, six C57 mice were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours before administration and fed 4 hours after administration.
  • Intravenous administration solvent 10% DMA + 10% Solutol + 80% Saline; Oral administration solvent: 0.5% MC
  • DMA dimethylacetamide
  • Solutol polyethylene glycol-15-hydroxystearate
  • Saline normal saline
  • 0.5% MC 0.5% methylcellulose aqueous solution
  • the compounds of the present invention such as the compounds in the examples, have good pharmacokinetic properties.
  • 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 effect in rats.
  • mice Male beagle dogs, weighing approximately 8-11 kg, 3 per compound, purchased from Beijing Masi Biotechnology Co., Ltd.
  • test method On the day of the test, beagle dogs (3 per compound) were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours before administration and fed 4 hours after administration.
  • the compounds of the present invention such as the compounds in the examples, have good oral absorption effects in beagle dogs.
  • mice Male cynomolgus monkeys, 3-5 kg, 3-6 years old, 6 per compound, purchased from Suzhou Xishan Biotechnology Co., Ltd.
  • Intravenous administration solvent 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 0.5% MC.
  • 1.0 mL of blood was collected from a limb vein and placed in an EDTAK2 centrifuge tube. The samples were centrifuged at 5000 rpm at 4°C for 10 minutes, and plasma was collected. Blood was collected from both the intravenous and oral administration groups at the following time points: 0, 5 minutes, 15 minutes, 30 minutes, and 1, 2, 4, 6, 8, 10, 12, and 24 hours. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS/MS.
  • the compounds of the present invention such as the compounds in the examples, have good oral absorption effect in monkeys.
  • cytochrome P450 cytochrome P450
  • CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4-M cytochrome P450
  • Specific probe substrates for each CYP450 isoform were incubated with human liver microsomes and varying concentrations of the test compounds.
  • the reaction was initiated by the addition of reduced nicotinamide adenine dinucleotide phosphate (NADPH). Following the reaction, samples were processed and metabolites generated from the specific substrates were quantitatively detected by liquid chromatography-tandem mass spectrometry (LC-MS/MS).
  • NADPH reduced nicotinamide adenine dinucleotide phosphate
  • IC50 values were calculated to evaluate the inhibitory potential of the test compounds against each CYP isoform, CYP1A2, CYP2C9, CYP2D6, CYP2C19, and CYP3A4-M, using midazolam as a substrate.
  • Dilute BD PhosflowTM Lysis/Fixation Buffer (5 ⁇ ) 1:5 with distilled water (perform at room temperature) and preheat the solution to 37°C.
  • the working solution should be freshly prepared for each experiment.
  • Use a 1200 ⁇ L pipette to add 1 mL of 1 ⁇ BD PhosflowTM Lysis/Fixation Buffer to each well of the deep-well plate. Transfer the blood to the preheated solution, mix well, and incubate in a 37°C water bath for 15 minutes. Centrifuge at 1200 g/min for 5 minutes and discard the supernatant. Add 1 mL of PBS to each well and centrifuge at 1200 g/min for 5 minutes and discard the supernatant. Resuspend the cells in 100 ⁇ L of Cell Staining Buffer and store the plate at 4°C overnight. Acquire data on the flow cytometer CytoFLEX S.
  • the compounds of the present invention have good inhibitory activity on the expression of CD11b on granulocytes activated by zymosan in human whole blood.
  • the experiment used a monolayer of Caco-2 cells and was incubated in triplicate in a 96-well Transwell plate.
  • Transport buffer solution (HBSS, 10mM HEPES, pH 7.4 ⁇ 0.05) containing the compound of the present invention (2 ⁇ M) or the control compounds digoxin (10 ⁇ M), nadolol (2 ⁇ M) and metoprolol (2 ⁇ M) was added to the dosing port well on the apical or basolateral side.
  • Transport buffer solution containing DMSO was added to the corresponding receiving port well. After incubation at 37 ⁇ 1°C for 2 hours, the cell plate was removed and appropriate amounts of samples were taken from the top and bottom ends to a new 96-well plate.
  • acetonitrile containing an internal standard was added to precipitate the protein.
  • the samples were analyzed using LC MS/MS and the concentrations of the compound of the present invention and the control compound were determined. The concentration data were used to calculate the apparent permeability coefficient for transport from the apical side to the basolateral side and from the basolateral side to the apical side of the monolayer cells, thereby calculating the efflux rate.
  • the integrity of the monolayer cells after 2 hours of incubation was evaluated by leakage of fluorescent yellow.
  • the compounds of the present invention such as the compounds in the examples, have good permeability.

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Abstract

La présente invention concerne des dérivés hétérocycliques et leur utilisation en médecine, en particulier des composés représentés par la formule générale (I) ou des stéréoisomères, des sels pharmaceutiquement acceptables ou des cocristaux et des intermédiaires de ceux-ci, leur procédé de préparation et leur utilisation dans la préparation de médicaments pour le traitement de maladies auto-immunes ou de maladies inflammatoires.
PCT/CN2025/085314 2024-03-27 2025-03-27 Dérivés hétérocycliques et leur utilisation en médecine Pending WO2025201449A1 (fr)

Applications Claiming Priority (10)

Application Number Priority Date Filing Date Title
CN202410355926.6 2024-03-27
CN202410355926 2024-03-27
CN202410898079.8 2024-07-05
CN202410898079 2024-07-05
CN202411158514.X 2024-08-22
CN202411158514 2024-08-22
CN202411599283.6 2024-11-11
CN202411599283 2024-11-11
CN202510049429.8 2025-01-13
CN202510049429 2025-01-13

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107108672A (zh) * 2014-10-03 2017-08-29 Ucb生物制药私人有限公司 稠合的五环咪唑衍生物
CN109219609A (zh) * 2016-04-01 2019-01-15 Ucb生物制药私人有限公司 作为tnf活性调节剂的稠合六环咪唑衍生物
CN110582495A (zh) * 2017-04-25 2019-12-17 Ucb生物制药私人有限公司 作为tnf活性的调节剂的稠合五环咪唑衍生物

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107108672A (zh) * 2014-10-03 2017-08-29 Ucb生物制药私人有限公司 稠合的五环咪唑衍生物
CN109219609A (zh) * 2016-04-01 2019-01-15 Ucb生物制药私人有限公司 作为tnf活性调节剂的稠合六环咪唑衍生物
CN110582495A (zh) * 2017-04-25 2019-12-17 Ucb生物制药私人有限公司 作为tnf活性的调节剂的稠合五环咪唑衍生物

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