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WO2021249319A1 - Composé tricyclique, composition pharmaceutique et utilisation de celui-ci - Google Patents

Composé tricyclique, composition pharmaceutique et utilisation de celui-ci Download PDF

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Publication number
WO2021249319A1
WO2021249319A1 PCT/CN2021/098519 CN2021098519W WO2021249319A1 WO 2021249319 A1 WO2021249319 A1 WO 2021249319A1 CN 2021098519 W CN2021098519 W CN 2021098519W WO 2021249319 A1 WO2021249319 A1 WO 2021249319A1
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Prior art keywords
cancer
cycloalkyl
pyrrole
heterocycloalkyl
heteroaryl
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English (en)
Chinese (zh)
Inventor
黄立晔
李华
刘华斌
王志远
李涛
欧阳飞燕
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Shenzhen Bo Li Jian Medicine Co Ltd
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Shenzhen Bo Li Jian Medicine Co Ltd
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Priority to CN202180004265.7A priority Critical patent/CN114072412B/zh
Publication of WO2021249319A1 publication Critical patent/WO2021249319A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This application belongs to the technical field of medicinal chemistry, and specifically relates to a class of tricyclic compounds, pharmaceutical compositions containing such compounds, and applications of such compounds or pharmaceutical compositions in the preparation of medicines.
  • RET is a receptor tyrosine kinase.
  • RET plays a key role in fetal kidney development and neurogenesis.
  • the variation of RET promotes ligand-independent and sustained activation of RET kinase, thereby driving tumorigenesis (Reference 1).
  • RET kinase can be activated oncogenically through gene rearrangement or point mutations.
  • the RET gene rearrangement produces a continuously activated fusion protein dimer.
  • the most common RET fusion proteins are KIF5B-RET, CCDC6-RET, NCOA4-RET and TRIM33-RET (Reference 2).
  • RET fusion is present in 10-20% of papillary thyroid carcinoma (PTC), 1-2% of non-small cell lung cancer (NSCLC) (document 3-4) and other cancers (document 5).
  • RET mutations can occur in extracellular cysteine residues (such as C620R, C634R, or C634W), causing abnormal receptor dimerization, or in intracellular kinase regions (such as V804L, V804M, or M918T), promoting independent Ligand kinase activation.
  • RET mutations mainly exist in medullary thyroid carcinoma (MTC).
  • RET inhibitors have been clinically proven to be effective in the treatment of lung cancers with RET mutations in MTC and RET fusion-positive lung cancers (References 6-10).
  • vandetanib and cabozantinib have been approved for the treatment of metastatic or locally advanced MTC.
  • these drugs have limited disease control.
  • the reason is that these multi-kinase inhibitors were originally designed to inhibit other kinases.
  • the activity of inhibiting RET kinase is lower than that of other kinases. This results in off-target side effects and limits the ability of patients. Tolerable dose.
  • This application provides a tricyclic compound, a pharmaceutical composition and applications thereof.
  • this application provides a tricyclic compound having a structure as shown in Formula I:
  • R 1 is selected from H, halogen, C1-C10 linear or branched alkyl, C3-C10 cycloalkyl, C2-C10 heterocycloalkyl, C6-C20 aryl or C3-C20 heteroaryl;
  • R 2 and R 3 are each independently selected from H, C1-C10 straight or branched chain alkyl, C3-C10 cycloalkyl; said R 2 and R 3 are not connected or connected to form a ring through a chemical bond;
  • R 4 is selected from H, C1 ⁇ C10 straight or branched chain alkyl, C3 ⁇ C10 cycloalkyl, C2 ⁇ C10 heterocycloalkyl, C6 ⁇ C20 aryl, C3 ⁇ C20 heteroaryl, COR a , CONR b R c , CO 2 R d , SO 2 R a or SO 2 NR b R c ; the linear or branched alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are unsubstituted or substituted by 1 ⁇ 3 (for example, 1, 2, or 3) R 4a substitutions;
  • R 4a is selected from D, halogen, cyano, OR a1 , SR a1 , NR b1 R c1 , COR a1 , CONR b1 R c1 , CO 2 R d1 , SO 2 R a1 , SO 2 NR b1 R c1 , C1 ⁇ C10 Straight or branched chain alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C2-C10 heterocycloalkyl, C6-C20 aryl or C3-C20 heteroaryl; Straight-chain or branched alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are unsubstituted or substituted with 1 to 3 (for example, 1, 2, or 3) R 4b ;
  • R a , R b , R c , Rd , R a1 , R b1 , R c1 , R d1 are each independently selected from H, C1 ⁇ C10 linear or branched alkyl, C2 ⁇ C10 alkenyl, C2 ⁇ C10 Alkynyl, C3-C10 cycloalkyl, C2-C10 heterocycloalkyl, C6-C20 aryl or C3-C20 heteroaryl; the straight or branched chain alkyl, alkenyl, alkynyl, cycloalkyl , Heterocycloalkyl, aryl, and heteroaryl are unsubstituted or substituted with 1 to 4 (for example, 1, 2, 3, or 4) R 5 ;
  • R 4b and R 5 are each independently selected from D, halogen, cyano, hydroxyl, unsubstituted or halogenated C1 ⁇ C10 linear or branched alkyl, C2 ⁇ C10 alkenyl, C2 ⁇ C10 alkynyl, C3 ⁇ C10 Cycloalkyl, C2 ⁇ C10 heterocycloalkyl, C6 ⁇ C20 aryl, C3 ⁇ C20 heteroaryl, OR a2 , SR a2 , NR b2 R c2 , COR a2 , CONR b2 R c2 , CO 2 R d2 , SO 2 R a2 , SO 2 NR b2 R c2 , NR b2 COR d2 , NR a2 CONR b2 R c2 , NR b2 SO 2 R d2 , NR b2 SO 2 NR b2 R c2 or SOR a2 ; and
  • R a2 , R b2 , R c2 , and R d2 are each independently selected from H, C1-C10 linear or branched alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C2- C10 heterocycloalkyl, C6-C20 aryl or C3-C20 heteroaryl.
  • the two substituents R b and R c , R b1 and R c1 , R b2 and R c2 connected to the same N are not connected to each other, or are connected through a chemical bond to form a heterocycloalkyl group; heterocycloalkyl unsubstituted or 1 to 3 (e.g. 1, 2 or 3) substituents, the same substituents as the choice of the R 5.
  • C1 to C10 may be C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10.
  • the C3 to C10 can all be C3, C4, C5, C6, C7, C8, C9 or C10.
  • the C2 to C10 can all be C2, C3, C4, C5, C6, C7, C8, C9 or C10.
  • the C6 to C20 can all be C6, C10, C12, C13, C14, C16, C18, C19, C20, etc.
  • the C3 to C20 can all be C3, C4, C5, C6, C10, C12, C13, C14, C16, C18, C19, C20, etc.
  • the azatricyclic compound has a structure as shown in formula IA:
  • R 1 and R 4 each independently have the same defined range as in formula I.
  • R 1 is selected from H, halogen, C1-C10 linear or branched alkyl, C3-C10 cycloalkyl, C2-C10 heterocycloalkyl, C6-C20 aryl or C3-C20 Heteroaryl
  • R 4 is selected from H, C1 ⁇ C10 straight or branched chain alkyl, C3 ⁇ C10 cycloalkyl, C2 ⁇ C10 heterocycloalkyl, C6 ⁇ C20 aryl, C3 ⁇ C20 heteroaryl, COR a , CONR b R c , CO 2 R d , SO 2 R a or SO 2 NR b R c ; the linear or branched alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are unsubstituted or substituted by 1 ⁇ 3 R 4a substitutions;
  • R 4a is selected from D, halogen, cyano, OR a1 , SR a1 , NR b1 R c1 , COR a1 , CONR b1 R c1 , CO 2 R d1 , SO 2 R a1 , SO 2 NR b1 R c1 , C1 ⁇ C10 Straight or branched chain alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C2-C10 heterocycloalkyl, C6-C20 aryl or C3-C20 heteroaryl; Straight or branched chain alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are unsubstituted or substituted with 1 to 3 R 4b ;
  • R a , R b , R c , Rd , R a1 , R b1 , R c1 , R d1 are each independently selected from H, C1 ⁇ C10 linear or branched alkyl, C2 ⁇ C10 alkenyl, C2 ⁇ C10 Alkynyl, C3-C10 cycloalkyl, C2-C10 heterocycloalkyl, C6-C20 aryl or C3-C20 heteroaryl; the straight or branched chain alkyl, alkenyl, alkynyl, cycloalkyl , Heterocycloalkyl, aryl, and heteroaryl are unsubstituted or substituted with 1 to 4 R 5 ;
  • R 4b and R 5 are each independently selected from D, halogen, cyano, hydroxyl, unsubstituted or halogenated C1-C10 linear or branched alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 Cycloalkyl, C2 ⁇ C10 heterocycloalkyl, C6 ⁇ C20 aryl, C3 ⁇ C20 heteroaryl, OR a2 , SR a2 , NR b2 R c2 , COR a2 , CONR b2 R c2 , CO 2 R d2 , SO 2 R a2 , SO 2 NR b2 R c2 , NR b2 COR d2 , NR a2 CONR b2 R c2 , NR b2 SO 2 R d2 , NR b2 SO 2 NR b2 R c2 or SOR a2 ; and
  • R a2 , R b2 , R c2 , and R d2 are each independently selected from H, C1-C10 linear or branched alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C2- C10 heterocycloalkyl, C6-C20 aryl or C3-C20 heteroaryl.
  • the R 1 is selected from H or halogen.
  • the azatricyclic compound has a structure as shown in formula IB:
  • R 1 and R 4 each independently have the same defined range as in formula I.
  • R 1 is selected from H, halogen, C1-C10 linear or branched alkyl, C3-C10 cycloalkyl, C2-C10 heterocycloalkyl, C6-C20 aryl or C3-C20 Heteroaryl
  • R 4 is selected from H, C1 ⁇ C10 straight or branched chain alkyl, C3 ⁇ C10 cycloalkyl, C2 ⁇ C10 heterocycloalkyl, C6 ⁇ C20 aryl, C3 ⁇ C20 heteroaryl, COR a , CONR b R c , CO 2 R d , SO 2 R a or SO 2 NR b R c ; the linear or branched alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are unsubstituted or substituted by 1 ⁇ 3 R 4a substitutions;
  • R 4a is selected from D, halogen, cyano, OR a1 , SR a1 , NR b1 R c1 , COR a1 , CONR b1 R c1 , CO 2 R d1 , SO 2 R a1 , SO 2 NR b1 R c1 , C1 ⁇ C10 Straight or branched chain alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C2-C10 heterocycloalkyl, C6-C20 aryl or C3-C20 heteroaryl; Straight or branched chain alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are unsubstituted or substituted with 1 to 3 R 4b ;
  • R a , R b , R c , Rd , R a1 , R b1 , R c1 , R d1 are each independently selected from H, C1 ⁇ C10 linear or branched alkyl, C2 ⁇ C10 alkenyl, C2 ⁇ C10 Alkynyl, C3-C10 cycloalkyl, C2-C10 heterocycloalkyl, C6-C20 aryl or C3-C20 heteroaryl; the straight or branched chain alkyl, alkenyl, alkynyl, cycloalkyl , Heterocycloalkyl, aryl, and heteroaryl are unsubstituted or substituted with 1 to 4 R 5 ;
  • R 4b and R 5 are each independently selected from D, halogen, cyano, hydroxyl, unsubstituted or halogenated C1 ⁇ C10 linear or branched alkyl, C2 ⁇ C10 alkenyl, C2 ⁇ C10 alkynyl, C3 ⁇ C10 Cycloalkyl, C2 ⁇ C10 heterocycloalkyl, C6 ⁇ C20 aryl, C3 ⁇ C20 heteroaryl, OR a2 , SR a2 , NR b2 R c2 , COR a2 , CONR b2 R c2 , CO 2 R d2 , SO 2 R a2 , SO 2 NR b2 R c2 , NR b2 COR d2 , NR a2 CONR b2 R c2 , NR b2 SO 2 R d2 , NR b2 SO 2 NR b2 R c2 or SOR a2 ; and
  • R a2 , R b2 , R c2 , and R d2 are each independently selected from H, C1-C10 linear or branched alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C2- C10 heterocycloalkyl, C6-C20 aryl or C3-C20 heteroaryl.
  • the R 1 is selected from H or halogen.
  • the R 4 is selected from C1 to C10 (e.g., C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10) linear or branched alkyl, C3 to C10 (e.g. C3, C4 , C5, C6, C7, C8, C9 or C10) cycloalkyl, C2-C10 (e.g. C2, C3, C4, C5, C6, C7, C8, C9 or C10) heterocycloalkyl, COR a or CONR b R c ;
  • the linear or branched alkyl, cycloalkyl, and heterocycloalkyl are unsubstituted or substituted with 1 to 3 (for example, 1, 2, or 3) R 4a .
  • the R 4a is selected from D, halogen, cyano, OR a1 , C1 ⁇ C10 (for example, C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10) linear or branched alkanes Group, C3-C10 (e.g. C3, C4, C5, C6, C7, C8, C9 or C10) cycloalkyl, C2-C10 (e.g. C2, C3, C4, C5, C6, C7, C8, C9 or C10) Heterocycloalkyl, C6-C20 (e.g.
  • aryl or C3-C20 e.g. C3, C4, C5, C6, C10, C12, C13) , C14, C16, C18, C19 or C20, etc.
  • heteroaryl the straight or branched chain alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl is unsubstituted or is 1 to 3 ( For example, 1, 2 or 3) R 4b substitution.
  • the R a , R b , R c , Rd , R a1 , R b1 , R c1 , and R d1 are each independently selected from H, C1 to C10 (e.g., C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10) straight or branched chain alkyl, C3-C10 (e.g. C3, C4, C5, C6, C7, C8, C9 or C10) cycloalkyl, C2-C10 (e.g. C2, C3, C4, C5, C6, C7, C8, C9 or C10) heterocycloalkyl, C6 ⁇ C20 (e.g.
  • aryl or C3 ⁇ C20 such as C3, C4, C5, C6, C10, C12, C13, C14, C16, C18, C19 or C20, etc.
  • heteroaryl such as C3, C4, C5, C6, C10, C12, C13, C14, C16, C18, C19 or C20, etc.
  • the straight or branched chain alkyl, cycloalkyl, heterocycloalkyl , Aryl, and heteroaryl are unsubstituted or substituted with 1 to 4 (for example, 1, 2, 3, or 4) R 5 .
  • the R 4b and R 5 are each independently selected from D, halogen, cyano, hydroxyl, unsubstituted or halogenated C1 ⁇ C10 (e.g. C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10) straight or branched chain alkyl, C3-C10 (e.g. C3, C4, C5, C6, C7, C8, C9 or C10) cycloalkyl or C2-C10 (e.g. C2, C3, C4, C5, C6, C7, C8, C9 or C10) heterocycloalkyl.
  • C1 ⁇ C10 e.g. C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 straight or branched chain alkyl
  • C3-C10 e.g. C3, C4, C5, C6, C7, C8, C9 or C10
  • C2-C10 e.g. C2, C3, C4, C5, C6, C7, C8, C9 or C10)
  • the tricyclic compound includes any one of the following compounds:
  • the present application provides a stereoisomer, geometric isomer, tautomer of the above-mentioned tricyclic compound, or a pharmaceutically acceptable salt thereof.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising an active ingredient and at least one pharmaceutically acceptable carrier or excipient, the active ingredient comprising the tricyclic compound as described above, and/or, The above-mentioned stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts thereof.
  • the present application provides a tricyclic compound as described above, stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts thereof as described above, and drugs as described above Application of the composition in preparing a medicine for inhibiting RET kinase.
  • the RET kinase includes RET mutant kinase and RET fusion protein kinase.
  • the present application provides a tricyclic compound as described above, stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts thereof as described above, and drugs as described above Application of the composition in the preparation of a medicine for treating diseases mediated by RET kinase.
  • the disease is cancer.
  • the cancer includes breast cancer, small cell lung cancer, non-small cell lung cancer, bronchoalveolar cancer, prostate cancer, bile duct cancer, bone cancer, bladder cancer, head and neck cancer, kidney cancer, liver cancer, gastrointestinal tissue cancer, esophagus Cancer, ovarian cancer, pancreatic cancer, skin cancer, testicular cancer, thyroid cancer, uterine cancer, cervical cancer, vaginal cancer, leukemia, multiple myeloma or lymphoma.
  • the present application provides a novel tricyclic compound of chemical structure, which has the effect of kinase activity of RET significant inhibition, half RET kinase inhibition IC 50 concentrations as low as 0.53 ⁇ 2.1nM, and can effectively inhibit the proliferation of cancer cells, can be As RET kinase inhibitors and preparation of drugs for the treatment of RET kinase-mediated diseases, it has a good therapeutic effect in RET kinase-mediated cancers and other diseases, and has broad application prospects.
  • halo or halogen in this application includes fluorine, chlorine, bromine, and iodine.
  • straight or branched chain alkyl refers to a straight or branched saturated hydrocarbon group.
  • alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl, isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), pentyl ( Such as n-pentyl, isopentyl, neopentyl), hexyl (e.g.
  • heptyl e.g. n-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 2-methylhexyl, 3-methylhexyl, 2, 2-dimethylpentyl, 3,3-dimethylpentyl, 3-ethylpentyl-1, etc.
  • octyl e.g.
  • haloalkyl refers to an alkyl group having one or more halogen substituents.
  • the alkyl group and halo or halogen are as defined above.
  • Examples of haloalkyl groups include CH 2 F, CHF 2 , CF 3 , C 2 F 5 , CCl 3 , and the like.
  • alkenyl groups include vinyl, propenyl, allyl, 1-butenyl, 2-butenyl, 1,3-butadienyl, 1-pentenyl, 2-pentenyl, 1, 3-pentadienyl, 1-hexenyl, 2-hexenyl, etc., and similar groups.
  • alkynyl refers to a hydrocarbyl group having one or more C ⁇ C triple bonds.
  • alkynyl groups include ethynyl, propynyl, propargyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 1-hexynyl, 2-hexynyl Groups, etc., and similar groups.
  • cycloalkyl refers to a non-aromatic carbocyclic ring, including cyclized alkyl, cyclized alkenyl, and cyclized alkynyl.
  • Cycloalkyl groups may be monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) ring systems, including spirocyclic rings.
  • cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, 10 carbon atoms.
  • cycloalkyl also included in the definition of cycloalkyl are those moieties that have one or more aromatic rings fused to the cycloalkyl ring (for example, having a shared bond), such as pentane, pentene, hexane, and hexane. Benzo derivatives of alkenes, etc., and similar compounds.
  • the cycloalkyl group having one or more fused aromatic rings may be connected through an aromatic part or a non-aromatic part.
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadiene Group, adamantyl group, indenyl group, tetrahydronaphthyl group and similar groups.
  • heterocycloalkyl refers to a non-aromatic heterocyclic ring in which one or more of the atoms forming the ring is a heteroatom such as O, N, P, or S.
  • Heterocyclyl groups can include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) ring systems as well as spirocyclic rings.
  • heterocycloalkyl examples include but are not limited to: aziridinyl, azetidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, pyrrolidinyl, oxazolidinyl , Thiazolidinyl, imidazolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl, and similar groups.
  • heterocycloalkyl those moieties that have one or more aromatic rings fused to a non-aromatic heterocycloalkyl ring (for example, with a shared bond), such as 2,3-dihydrobenzene Furanyl, 1,3-benzodioxole, benzo-1,4-dioxanyl, phthalimide, naphthalimide, and similar Group.
  • Heterocycloalkyl groups having one or more fused aromatic rings may be connected through aromatic or non-aromatic moieties.
  • aryl refers to monocyclic or polycyclic (for example, having 2, 3, or 4 condensed rings) aromatic hydrocarbons, such as phenyl, naphthyl, anthryl, phenanthryl, indenyl, and the like.
  • heteroaryl refers to an aromatic heterocyclic ring having at least one heteroatom ring member such as O, N, or S.
  • Heteroaryl groups include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) ring systems. Any N atom that forms a ring in the heterocyclic group can also be oxidized to form an N-oxide.
  • heteroaryl groups include, but are not limited to: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, thienyl, imidazolyl, triazolyl, tetrazolyl, thiazole Group, isothiazolyl, 1,2,4-thiadiazolyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, benzofuranyl, benzothienyl, benzo Thiazolyl, indolyl, indazolyl, quinolinyl, isoquinolinyl, purinyl, carbazolyl, benzimidazolyl, pyrrolopyridyl, pyrrolopyrimidinyl, pyrazolopyridyl, pyrazole Pyrimidine group, and similar groups.
  • tricyclic compound as used herein, is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes.
  • the tricyclic compound of the present application may be asymmetric, for example having one or more stereo centers. Unless otherwise defined, all stereoisomers can be enantiomers and diastereomers.
  • the compounds of the application containing asymmetrically substituted carbon atoms can be separated into optically pure or racemic forms. Optically pure forms can be prepared by resolution of racemates, or by using chiral synthons or chiral reagents.
  • the tricyclic compounds of the present application may also include tautomeric forms.
  • the new form of tautomers is produced by the exchange of single bonds and adjacent double bonds together with the migration of protons.
  • the tricyclic compound of the present application may also include all isotopic forms of atoms present in the intermediate or final compound.
  • Isotopes include those atoms that have the same atomic number but different mass numbers.
  • isotopes of hydrogen include deuterium and tritium.
  • the application also includes pharmaceutically acceptable salts of the tricyclic compounds.
  • “Pharmaceutically acceptable salt” refers to a derivative of a compound in which the parent compound is converted into its salt form by the presence of a base part, or the parent compound is converted to it by the presence of an acid part Derivatives of modified compounds in the salt form.
  • Examples of pharmaceutically acceptable salts include, but are not limited to, salts of inorganic or organic acids with basic groups (such as ammonia), or salts with inorganic or organic bases of acidic groups (such as carboxylic acids).
  • the pharmaceutically acceptable salts of the present application can be synthesized from the parent compounds of Formula I, Formula IA, and Formula IB by reacting the free base forms of these compounds with 1 to 4 equivalents of an appropriate acid in a solvent system. Suitable salts are listed in Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, 1418 and Journal of Pharmaceutical Science, 66, 2, 1977.
  • the tricyclic compounds of the present application and their pharmaceutically acceptable salts also include solvate forms or hydrate forms.
  • the solvate form or the hydrate form and the unsolvated form or the non-hydrate form are equivalent, and both are included in the scope of the present application.
  • Some compounds of the present application may exist in multiple crystalline forms or amorphous forms. In general, all physical forms of the compound are included in the scope of this application.
  • the application also includes prodrugs of the tricyclic compounds.
  • a prodrug is a pharmacological substance (i.e., drug) derived from the parent drug. Once administered, the prodrug is metabolized in the body to become the parent drug.
  • Prodrugs can be prepared by substituting one or more functional groups present in the compound. The preparation and use of prodrugs can be found in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems", Vol. 14 of the AACS Symposium Series and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Found in Pharmaceutical Association and Pergamon Press, 1987.
  • the tricyclic compound includes the following compounds:
  • This application provides a pharmaceutical composition, which is composed of the tricyclic compound or its N-oxide derivative, individual isomers, or a mixture of isomers thereof, and a pharmaceutically acceptable salt and a pharmaceutically acceptable salt.
  • Accepted carrier or excipient composition The pharmaceutical composition of the present application can be administered by oral administration, parenteral administration (injection administration), spray inhalation, topical administration, rectal administration, nasal cavity administration, vaginal administration, intraperitoneal administration or via The implanted reservoir is administered.
  • the tricyclic compound and pharmaceutically acceptable salt may be used in combination with one or more other drugs.
  • the tricyclic compound of the present application and the combined medication may play a superimposed or synergistic effect.
  • the drugs used in combination can be small molecule drugs, monomer clone drugs, fusion protein drugs and anti-insensitive DNA drugs.
  • the tricyclic compound can be obtained by the following preparation route:
  • R 1 , R 2 , R 3 , R 4 each independently have the same selection range as in Formula I; Cbz and SEM both represent an amino protecting group; X represents a coupling reaction with -NH- Active groups, such as hydroxyl, halogen, etc.; Y represents an active group capable of substitution reaction, exemplary R 1 Y includes NCS or NBS, etc.; DIEA is N,N-diisopropylethylamine.
  • 2-amino-2-methylpropionitrile hydrochloride (25.0 g, 208.3 mmol) was dissolved in tetrahydrofuran (THF, 350 mL) and placed in an ice water bath to cool.
  • K 2 CO 3 (57.5 g, 416.6 mmol) was added to the above system and H 2 O was slowly added until K 2 CO 3 was completely dissolved, then Boc anhydride (45.8 g, 210.0 mmol) was added, and the reaction was heated to 50° C. for 16 h. After the reaction was completed, the layers were separated, and the aqueous phase was extracted with ethyl acetate (EtOAc).
  • tert-butyl (2-cyanopropan-2-yl) carbamate (30.0 g, 163.0 mmol) was dissolved in THF (500 mL) and placed in an ice-water bath to cool.
  • LiAlH 4 (6.2 g, 163.0 mmol) was slowly added to the above system, and the reaction was allowed to rise at room temperature for 16 hours.
  • LCMS (ESI): m/z 189 (M+H) + .
  • tert-butyl (1-amino-2-methylpropan-2-yl) carbamate (25.0g, 133.0mmol) was dissolved in CH 2 Cl 2 (400 mL), and three Ethylamine (Et 3 N, 40.3 g, 399.0 mmol) and N-benzyloxycarbonyloxysuccinimide (49.7 g, 199.5 mmol) were reacted at room temperature for 1 h. After the reaction is completed, water is added, the organic phase is washed with water, dried with anhydrous Na 2 SO 4 , filtered and concentrated to obtain a solid 38 g, which is directly used in the next reaction.
  • LCMS (ESI): m/z 323 (M+H) + .
  • benzyl (2-((6-chloropyrimidin-4-yl)amino)-2-methylpropanyl) carbamate (12.5g, 37.4mmol) was dissolved in glacial acetic acid ( 100mL), placed in an ice water bath to cool. Add N-iodosuccinimide (NIS, 25.2g, 112.2mmol) to the above system, and react at room temperature for 16h. After the reaction was completed, the reaction solution was poured into ice water, and extracted with EtOAc.
  • N-iodosuccinimide N-iodosuccinimide
  • Step 14 Synthesis of 9,9-dimethyl-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole[2,3-b]pyridine-2- Yl)-8,9-dihydropyrazine[1',2':1,5]pyrrole[2,3-d]pyrimidin-4-amine
  • Step 15 Synthesis of 9,9-dimethyl-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole[2,3-b]pyridine-2- Yl)-6,7,8,9-tetrahydropyrazine[1',2':1,5]pyrrole[2,3-d]pyrimidin-4-amine
  • Step 16 Synthesis of (4-amino-9,9-dimethyl-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole [2,3-b ]Pyridin-2-yl)-8,9-dihydropyrazine[1',2':1,5]pyrrole[2,3-d]pyrimidine-7(6H)-yl)(tetrahydro-2H- Pyran-4-yl)methanone
  • the ester phase was washed with saturated NaCl solution, dried with anhydrous Na 2 SO 4 , filtered and concentrated.
  • the obtained residue was purified by silica gel column chromatography (PE:EtOAc volume ratio 40:1) to obtain 5.6 g of product with a yield of 51%.
  • Step 1 Synthesis of 7-(2-methoxyethyl)-9,9-dimethyl-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H- Pyrrole[2,3-b]pyridin-2-yl)-6,7,8,9-tetrahydropyrazine[1',2':1,5]pyrrole[2,3-d]pyrimidine-4- amine
  • Examples 8 to 52 shown in Table 1 below were prepared according to the methods in Examples 1 to 7.
  • the method for testing the inhibitory activity of tricyclic compounds on RET kinase is as follows:
  • the mobility change assay was used to detect the inhibitory activity of the tricyclic compound on kinase RET under Km ATP (IC 50 ).
  • RET kinase was purchased from Carna Company (Cat. No.: 08-159, batch number: 13CBS-0134F), and Kinase Substrate 2 was purchased from GL Biochem (Cat. No.: 112394, batch number: P191104-TL112394).
  • Human thyroid cancer cell TT (RET C634W mutant) was used to detect the inhibition of cell proliferation by the tricyclic compound described in this application.
  • Example IC 50 (nM) Example IC 50 (nM) Example IC 50 (nM) Example IC 50 (nM) 1 3.5 19 11 37 5.7 2 4.4 20 8.5 38 1.5 3 16 twenty one 19 39 4.8 4 11 twenty two 12 40 12 5 twenty two twenty three 9.8 41 19 6 twenty three twenty four 7.9 42 12 7 3.5 25 13 43 11 8 9.3 26 6.4 44 2.5 9 10 27 7.5 45 11 10 8.5 28 11 46 5.5 11 12 29 70 47 2.0 12 8.5 30 12 48 8.5 13 9.2 31 15 49 9.5 14 16 32 18 50 7.0 15 15 33 twenty two 51 11 16 5.5 34 15 52 4.0 17 12 35 0.5 cabozantinib 256 18 10 36 1.5 To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To
  • the tricyclic compound provided in this application can effectively inhibit the activity of RET kinase, and the IC 50 of the half inhibitory concentration of RET kinase is as low as 0.53 to 2.1 nM, and it can also effectively inhibit the growth of cancer cells. Proliferation, the IC 50 value for TT of human thyroid cancer cells is as low as 0.5 ⁇ 23 nM, and its activity is significantly improved compared to the existing drug cabozantinib.

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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Medicinal Chemistry (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

La présente invention concerne un composé tricyclique, un isomère, un sel pharmaceutiquement acceptable, et une composition pharmaceutique de celui-ci et son utilisation, ledit composé tricyclique ayant une structure telle que représentée par la formule I. Le composé tricyclique a un effet inhibiteur significatif sur l'activité de la kinase RET et peut inhiber efficacement la prolifération de cellules cancéreuses. Le composé tricyclique peut être utilisé en tant qu'inhibiteur de la kinase RET et peut être utilisé dans la préparation d'un médicament pour le traitement de maladies médiées par la kinase RET, a un bon effet thérapeutique sur les maladies médiées par la kinase RET telles que le cancer et offre de larges perspectives d'application.
PCT/CN2021/098519 2020-06-10 2021-06-07 Composé tricyclique, composition pharmaceutique et utilisation de celui-ci Ceased WO2021249319A1 (fr)

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CN117964643B (zh) * 2024-04-01 2024-07-02 苏州朗睿生物医药有限公司 一种吡咯[2,3-b]并吡啶衍生物及其制备方法和用途

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