WO2020078362A1 - Composé à cycle aromatique imidazole, son procédé de préparation et son application - Google Patents

Composé à cycle aromatique imidazole, son procédé de préparation et son application Download PDF

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WO2020078362A1
WO2020078362A1 PCT/CN2019/111336 CN2019111336W WO2020078362A1 WO 2020078362 A1 WO2020078362 A1 WO 2020078362A1 CN 2019111336 W CN2019111336 W CN 2019111336W WO 2020078362 A1 WO2020078362 A1 WO 2020078362A1
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group
substituted
unsubstituted
compound
alkyl
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PCT/CN2019/111336
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Chinese (zh)
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江磊
冯志勇
乔智
尚珂
寿建勇
吴淡宜
徐圆
许灵灵
张宇星
张淑芸
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上海轶诺药业有限公司
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Priority to CN201980067894.7A priority Critical patent/CN113242857A/zh
Publication of WO2020078362A1 publication Critical patent/WO2020078362A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/499—Spiro-condensed pyrazines or piperazines
    • 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
    • A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • 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
    • C07D471/02—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 two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • C07D471/22—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 systems contains four or more hetero rings
    • 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
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
    • 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

Definitions

  • the present invention relates to the field of small molecule drugs, in particular, the present invention relates to a TRK kinase inhibitor and its preparation and use.
  • Tropomyosin receptor kinase is a class of nerve growth factor receptors, belonging to the receptor tyrosine kinase family, mainly including three highly homologous members TRKA, TRKB and TRKC, respectively It is encoded by the three genes NTRK1, NTRK2 and NTRK3. These receptor tyrosine kinases are mainly expressed in nerve tissue, and play an important role in the development and physiological functions of the nervous system through the activation of neurotrophins (neurotrophins). TRK acts as a tyrosine kinase receptor, and each TRK has its corresponding ligand to bind and activate its downstream signaling pathway.
  • NGF nerve growth factor
  • TRKB ligands include BDGF (brain-derived growth factor) and NT-4 / 5 (neurotrophin-4 / 5); NT-3 specifically binds and activates TRKC . All three TRK receptors contain an extracellular domain for ligand binding, a transmembrane domain, and an intracellular domain with kinase activity.
  • a specific ligand When a specific ligand binds to the extracellular domain of the corresponding receptor, it will trigger oligomerization of the receptor and phosphorylation of specific tyrosine residues in the intracytoplasmic kinase domain, resulting in downstream signaling pathways such as Ras /
  • downstream signaling pathways such as Ras /
  • the activation of MAPK, PLC ⁇ / PKC and PI3K / AKT signaling pathways regulates a series of physiological processes such as neural cell proliferation, differentiation and survival (Bergman, et al. 1999).
  • the TRK signaling pathway is usually precisely regulated, and its abnormal activation is closely related to tumorigenesis (Amatu, et al. 2016).
  • the object of the present invention is to provide a novel TRK kinase inhibitor.
  • X 1 is CR or N
  • R is selected from the group consisting of H, fluorine, chlorine and cyano
  • R 1 is selected from the group consisting of H, -NH 2 , halogen, methyl, -CH 2 NH 2 , methoxy;
  • R A is selected from the group consisting of H, substituted or unsubstituted C 6 -C 10 aryl groups, substituted or unsubstituted 5-10 membered heteroaryl groups having 1-3 heteroatoms selected from N, S and O ;
  • R B is selected from the group consisting of H, NH 2 , OH, -COOH, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 1 -C 8 alkoxy, substituted or unsubstituted C 6 -C 10 aryl, substituted or unsubstituted 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O, Or a substituted or unsubstituted 5-12 membered heterocyclic group having 1-3 heteroatoms selected from N, S and O (including monocyclic, paracyclic, spiro or bridged rings);
  • the additional condition is that the compound of formula I has a chemically stable structure.
  • R A and R B are connected to form a group selected from the group consisting of substituted or unsubstituted C1-C8 alkylene, substituted or unsubstituted C1-C8 alkylene-O-, substituted Or unsubstituted C1-C8 alkylene- (5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O), substituted or unsubstituted C1-C8 alkylene-O -(5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S, and O), substituted or unsubstituted C1-C8 alkylene- (having 1-3 selected from N, S 5-10 membered heterocyclic group with hetero atom of O), substituted or unsubstituted C1-C8 alkylene-O- (5-10 membered with 1-3 heteroatoms selected from N, S and O Heterocyclyl).
  • said L 1 is selected from the following group:
  • n is selected from the group: 0, 1, 2 or 3;
  • R 2 , R 2a and R 2b are each independently selected from the group consisting of H, OH, halogen, substituted or unsubstituted C 1 -C 8 alkyl;
  • R A is Among them, the Refers to the connection site of R A and L 1 ;
  • R B is Among them, the It is the connection site of R B and L 2 .
  • R 3 is selected from the group consisting of H, halogen, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy;
  • R 4 and R 5 are each independently selected from the group consisting of H, OH, halogen, C 1 -C 6 alkyl OH, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, C 1- C 6 alkylamide,-(C 1 -C 6 alkyl) -NH- (C 1 -C 6 alkyl), -C 1 -C 6 alkylamide-(C 1 -C 6 alkyl) ;
  • R 6a , R 6b , R 7a , R 7b are each independently selected from the group consisting of H, OH, halogen; or R 6a , R 6b , R 7a , R 7b and the carbon atom to which they are connected together constitute 1-3 5-12 membered heterocyclyl from heteroatoms of N, S and O.
  • the compound has the structure represented by the following formula II:
  • Rb and Rc are independently selected from the group consisting of H, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl; or said Rb Together with Rc and the adjacent N atom, a substituted or unsubstituted 5-12 membered heterocyclic group (including monocyclic, paracyclic, spiro or bridged rings) is formed.
  • the compound has a structure selected from the group consisting of:
  • a pharmaceutical composition comprising (1) the compound according to the first aspect of the present invention or its stereoisomer or tautomer, or a pharmaceutically acceptable salt thereof , Hydrate or solvate; (2) a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is an injection, sachet, tablet, pill, powder, or granule.
  • the disease is selected from the group consisting of cancer, proliferative disease, pain, skin disease or disorder, metabolic disease, muscle disease, neurological disease, autoimmune disease, pruritus caused by dermatitis, inflammation-related Diseases, bone-related diseases.
  • the cancer is selected from cancers (including but not limited to) related to TRK dysfunction (TRK gene amplification, or overexpression, or mutation, or dysfunctional activation caused by gene fusion): Cell tumor, prostate cancer, thyroid cancer, lung cancer, ovarian cancer, pancreatic cancer, colorectal cancer, non-small cell lung cancer, fibrosarcoma, etc.
  • cancers including but not limited to) related to TRK dysfunction (TRK gene amplification, or overexpression, or mutation, or dysfunctional activation caused by gene fusion): Cell tumor, prostate cancer, thyroid cancer, lung cancer, ovarian cancer, pancreatic cancer, colorectal cancer, non-small cell lung cancer, fibrosarcoma, etc.
  • a compound as described in the first aspect of the present invention or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or
  • the use of the pharmaceutical composition according to the second aspect of the present invention characterized in that it is used to prepare and prevent or treat TRK dysfunction (TRK gene amplification, or overexpression, or mutation, or gene fusion-induced function Abnormal activation) pharmaceutical composition of related diseases.
  • TRK dysfunction TRK gene amplification, or overexpression, or mutation, or gene fusion-induced function Abnormal activation
  • the combination drug combination includes, but is not limited to, other first-line kinase inhibitors, immunomodulators (tumor immune checkpoint inhibitors), cell division blockers, and other conventional first-line chemotherapy drugs.
  • the disease is selected from the group consisting of cancer, proliferative disease, pain, skin disease or disorder, metabolic disease, muscle disease, neurological disease, autoimmunity Disease, itching caused by dermatitis.
  • the cancer is selected from cancers (including but not limited to) related to TRK dysfunction (TRK gene amplification, or overexpression, or mutation, or dysfunctional activation caused by gene fusion): Cell tumor, prostate cancer, thyroid cancer, lung cancer, ovarian cancer, pancreatic cancer, colorectal cancer, non-small cell lung cancer, fibrosarcoma, etc.
  • cancers including but not limited to) related to TRK dysfunction (TRK gene amplification, or overexpression, or mutation, or dysfunctional activation caused by gene fusion): Cell tumor, prostate cancer, thyroid cancer, lung cancer, ovarian cancer, pancreatic cancer, colorectal cancer, non-small cell lung cancer, fibrosarcoma, etc.
  • a TRK inhibitor characterized in that the inhibitor comprises the compound according to the first aspect of the present invention, or a stereoisomer or tautomer thereof, or a pharmaceutical thereof Acceptable salts, hydrates or solvates.
  • the term “about” means that the value may vary from the recited value by no more than 1%.
  • the expression “about 100” includes all values between 99 and 101 and (eg, 99.1, 99.2, 99.3, 99.4, etc.).
  • the terms "containing” or “including (including)” may be open, semi-closed, and closed. In other words, the term also includes “consisting essentially of” or “consisting of”.
  • alkyl includes linear or branched alkyl groups.
  • C 1 -C 8 alkyl represents a linear or branched alkyl group having 1-8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl Wait.
  • alkenyl includes straight-chain or branched alkenyl.
  • C 2 -C 6 alkenyl refers to a straight-chain or branched alkenyl group having 2-6 carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2 -Butenyl, or similar groups.
  • alkynyl includes linear or branched alkynyl groups.
  • C 2 -C 6 alkynyl refers to a linear or branched alkynyl group having 2 to 6 carbon atoms, such as ethynyl, propynyl, butynyl, or the like.
  • C 3 -C 8 cycloalkyl means a cycloalkyl group having 3-8 carbon atoms. It may be a single ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or similar groups. It may also be in the form of a double ring, such as a bridge ring or a spiro ring.
  • C 1 -C 8 alkoxy refers to a linear or branched alkoxy group having 1-8 carbon atoms; for example, methoxy, ethoxy, propoxy, iso Propoxy, butoxy, isobutoxy, tert-butoxy, etc.
  • the term "3-10 membered heterocycloalkyl having 1-3 heteroatoms selected from the group consisting of N, S, and O" refers to having 3-10 atoms and of which 1-3 atoms are A saturated or partially saturated cyclic group of heteroatoms selected from the group consisting of N, S, and O. It may be a single ring or a double ring, such as a bridge ring or a spiro ring. Specific examples may be oxetane, azetidine, tetrahydro-2H-pyranyl, piperidinyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl and the like.
  • C 6 -C 10 aryl refers to an aryl group having 6 to 10 carbon atoms, for example, phenyl or naphthyl and the like.
  • the term "5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S, and O” refers to having 5-10 atoms and wherein 1-3 atoms are selected from Cyclic aromatic groups of heteroatoms of N, S and O in the lower group. It can be monocyclic or fused ring.
  • Specific examples may be pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3) -triazolyl and (1,2, 4) -Triazolyl, tetrazolyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl and the like.
  • the groups of the present invention may be substituted by substituents selected from the group consisting of halogen, nitrile, nitro, hydroxy, amino, C 1 -C 6 alkyl-amine, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl, halogenated C 2 -C 6 alkenyl, halogen Substituted C 2 -C 6 alkynyl, halogenated C 1 -C 6 alkoxy, allyl, benzyl, C 6 -C 12 aryl, C 1 -C 6 alkoxy-C 1 -C 6 alkane Group, C 1 -C 6 alkoxy-carbonyl, phenoxycarbonyl, C 2 -C 6 alkynyl-carbonyl, C 2 -C 6 alkenyl-carbonyl, C 3
  • halogen or halogen atom refers to F, Cl, Br, and I. More preferably, the halogen or halogen atom is selected from F, Cl and Br. "Halogenated” means substituted with an atom selected from F, Cl, Br, and I.
  • the structural formulas described in the present invention are intended to include all isomeric forms (such as enantiomers, diastereomers and geometric isomers (or conformers)): for example containing asymmetric The R and S configurations of the center, the (Z) and (E) isomers of the double bond, etc. Therefore, single stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers or geometric isomers (or conformers) are within the scope of the present invention.
  • tautomer means that structural isomers with different energies can exceed the low energy barrier and thus convert to each other.
  • proton tautomers ie, proton shift
  • Valence tautomers include interconversion through some bond-forming electron recombination.
  • solvate refers to a compound of the present invention that coordinates with a solvent molecule to form a complex in a specific ratio.
  • the present invention provides a compound represented by the following formula I:
  • X 1 is CR or N
  • R is selected from the group consisting of H, substituted or unsubstituted C 1 -C 8 alkyl, halogen;
  • R 1 is selected from the group consisting of H, -NH 2 , -OH, halogen, C 1 -C 6 amino group, substituted or unsubstituted C 1 -C 8 alkyl group, substituted or unsubstituted C 1 -C 8 alkyl group Oxy;
  • R A is selected from the group consisting of H, substituted or unsubstituted C 6 -C 10 aryl groups, substituted or unsubstituted 5-10 membered heteroaryl groups having 1-3 heteroatoms selected from N, S and O ;
  • R B is selected from the group consisting of H, NH 2 , OH, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 1 -C 8 alkoxy, substituted or unsubstituted C 6 -C 10 aryl, substituted or unsubstituted 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O, or substituted or unsubstituted having 1-3 selected from N, S and 5-12 membered heterocyclic group of hetero atom of O (including monocyclic, paracyclic, spiro or bridged ring);
  • the additional condition is that the compound of formula I has a chemically stable structure.
  • X 1 , L 1 , L 2 , R 1 , R A and R B are each independently a corresponding group of the compounds in the embodiments.
  • the compound of formula I of the present invention is the compound prepared in the examples.
  • the compound of formula I of the present invention can be prepared by the following method:
  • the compound of the present invention has excellent TRK kinase inhibitory activity
  • the pharmaceutical composition of can be used to prevent and / or treat diseases related to TRK kinase activity or expression level (for example, cancer).
  • the pharmaceutical composition of the present invention contains a safe and effective amount of the compound of the present invention and a pharmaceutically acceptable excipient or carrier.
  • the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound / dose of the present invention, more preferably 10-200 mg of the compound / dose of the present invention.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility” here means that the components of the composition can be blended with the compound of the present invention and between them without significantly reducing the efficacy of the compound.
  • Examples of pharmaceutically acceptable carrier parts are cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid) , Magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier (such as Tween ), Wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate
  • the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, parenteral (intravenous, intramuscular, or subcutaneous).
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) retarding solvents, such as paraffin; (f) Absorption accelerators, for example, quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and
  • Solid dosage forms such as tablets, sugar pills, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain an opaque agent, and the release of the active compound or compound in this composition may be released in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be used are polymeric substances and waxy substances. If necessary, the active compound can also be formed into a microcapsule form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures.
  • the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide, and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.
  • inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide
  • composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents and flavoring agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents and flavoring agents.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances, and the like.
  • composition for parenteral injection may contain a physiologically acceptable sterile aqueous or non-aqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • the compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.
  • the pharmaceutical composition When administered in combination, the pharmaceutical composition also includes one or more other pharmaceutically acceptable compounds.
  • One or more of the other pharmaceutically acceptable compounds can be administered simultaneously, separately, or sequentially with the compounds of the present invention.
  • a safe and effective amount of the compound of the present invention is suitable for mammals (such as humans) in need of treatment, wherein the dose when administered is a pharmaceutically effective dose, for 60kg body weight
  • the dose to be administered is usually 1 to 2000 mg, preferably 20 to 500 mg.
  • the specific dosage should also consider factors such as the route of administration, the patient's health status, etc., which are within the skills of skilled physicians.
  • a solution of 2- (2-bromoethyl) -1,3-dioxane (14.3g, 73.47mmol) in tetrahydrofuran (40mL) was slowly added dropwise to the system and the temperature was controlled at 40-50 ° C. After completion, keep at 40 °C and stir for 1h.
  • the target compound was prepared under conditions similar to the preparation of compound (2R, 4S) -2- (2,5-difluorophenyl) -4-fluoropyrrolidine.
  • the target compound was prepared under conditions similar to (2R, 4S) -2- (2,5-difluorophenyl) -4-fluoropyrrolidine.
  • the target compound was prepared from compound C4 and intermediate D under conditions similar to Example 1.
  • the target compound was prepared from compound C4 and intermediate E under conditions similar to Example 1.
  • the target compound was prepared from the compound under conditions similar to Example 1.
  • the target compound was prepared from compound B4 and cyclopropylamine under conditions similar to Example 1.
  • the target compound was prepared from compound B4 and aminoethanol under conditions similar to Example 1.
  • the target compound was prepared from intermediate B and methanesulfonamide under conditions similar to Example 1.
  • the target compound was prepared from 6-((2R, 4S) -2- (2,5-difluorophenyl) -4-fluoropyrrolidin-1-yl) imidazo [1, 2-a] Pyrazine-3-carboxylic acid and methylamine hydrochloride.
  • the target compound was prepared from (R) -2- (2,5-difluorophenyl) -4,4-difluoropyrrolidine under conditions similar to Example 5.
  • the target compound was prepared from (R) -2- (pyrrolidin-2-yl) pyridine under conditions similar to Example 5.
  • the target compound was prepared from compound B4 and 1-amino-2-methylpropan-2-ol under conditions similar to Example 1.
  • the target compound was prepared from 3-phenylmorpholine under conditions similar to Example 5.
  • the target compound was prepared from compound B4 and 2-methoxyethane-1-amine under conditions similar to Example 1.
  • the target compound was prepared from 6- (3-phenylmorpholino) imidazo [1,2-a] pyrazine-3-carboxylic acid and aminoethanol under conditions similar to Example 5.
  • the target compound was prepared from 2-phenylazobutadiidine and aminoethanol under conditions similar to Example 5.
  • the target compound was prepared from 2-phenylazobutadiidine and ammonium chloride under conditions similar to Example 5.
  • the target compound was prepared from pyridin-4-ylboronic acid under conditions similar to Example 20.
  • the target compound was prepared from phenylboronic acid under conditions similar to Example 20.
  • TRKA, TRKB, and TRKC proteins were purchased from Carna Biosciences.
  • HTRFkinEASETK is purchased from CisbioBioassays. Use BioTek Microplate Reader Synergy Neo 2 to read the plate.
  • test compound was subjected to a three-fold concentration gradient dilution with a final concentration of 1 ⁇ M to 0.05 nM and 10 concentrations, each with two replicate wells; the content of DMSO in the detection reaction was 1%.
  • TRKA protein kinase 1 ⁇ M TK Substrate-biotin peptide substrate, 14.68 ⁇ M ATP, 1 ⁇ enzymatic buffer, 5mM MgCl 2 , 1mM DTT.
  • the detection plate was White Proxiplate 384-Plus plate (PerkinElmer), which was reacted at room temperature for 40 minutes, and the reaction system was 10 ⁇ l.
  • TRKB protein kinase 1 ⁇ M TK Substrate-biotin peptide substrate, 4.77 ⁇ M ATP, 1 ⁇ enzymatic buffer, 5mM MgCl 2 , 1mM MnCl 2 , 1mM DTT.
  • the detection plate was a White Proxiplate 384-Plus plate (PerkinElmer), which was reacted at room temperature for 50 minutes, and the reaction system was 10 ⁇ l.
  • TRKC protein kinase 0.037ng / ⁇ l TRKC protein kinase, 1 ⁇ M TK Substrate-biotin peptide substrate, 25.64 ⁇ M ATP, 1 ⁇ enzymatic buffer, 5mM MgCl 2 , 1mM DTT.
  • the detection plate was White Proxiplate 384-Plus plate (PerkinElmer), which was reacted at room temperature for 40 minutes, and the reaction system was 10 ⁇ l.
  • Ratio max is a positive control without test compound
  • Ratio test is the test value of each concentration of different compounds. 4 Parameter curve fitting measured IC50 (nM) data, see Table 1 for details.
  • Example 19 ⁇ 500 ⁇ 100 ⁇ 500
  • Example 20 ⁇ 10 ⁇ 10 ⁇ 10
  • Example 21 ⁇ 10 ⁇ 10 ⁇ 10
  • Example 22 ⁇ 100 ⁇ 10 ⁇ 100
  • the NIH-3T3 cell line stably expressing normal TRKA or TRKB or TRKC was constructed by plasmid transfection.
  • Human colon cancer cell line KM12-LUC (LUC, stably expressing Luciferace) containing the TPM3-NTRK1 fusion gene was used as a model for evaluating the pharmacological efficacy of the test compounds at the cytological level.
  • the TRK fusion gene in KM12-LUC cells makes it independent of the stimulation of extracellular growth factors, and can continue to spontaneously activate and activate its downstream signaling pathways MAPK-ERK, PI3K-AKT and other signaling pathways closely related to cell proliferation. Therefore, inhibition of TRK activity in KM12-LUC cells can significantly inhibit cell proliferation.
  • the method is as follows: On the first day, cells are seeded in a 384-well plate at 2000 cells / well; on the second day, different concentrations of the test compound are added; on the fifth day, CellTiter-Glo (Promega) is added to detect cell viability and the cells are counted for 72 hours Proliferation inhibition rate. The prism5 was used for statistical analysis and the IC 50 value of the test compound was obtained.
  • Example 1 Chemical compound KM12-LUC IC 50 (nm) Example 1 ⁇ 100 Example 5 ⁇ 10 Example 11 ⁇ 10 Example 12 ⁇ 100 Example 13 > 500 Example 20 ⁇ 100 Example 21 ⁇ 10
  • KM12-LUC cells (5 ⁇ 10 5 ) were injected subcutaneously into the dorsal area of mice.
  • the tumor volume was monitored by measuring the diameter with a caliper, and calculated by the following formula: length ⁇ (width 2) / 2.
  • mice are randomly selected to receive the diluent, 60 mg / kg / dose or 200 mg / kg / dose of the test compound.
  • the test compound is administered once a day by oral administration for 14 days. After the last administration, the mice were weighed, and tissues and blood were collected 3 hours, 6 hours, and 24 hours after the administration. Calculate the tumor inhibition rate, detect the concentration of the compound to be tested in the tumor and blood samples, detect the phosphorylation level of TRKA and the phosphorylation level of downstream signaling molecules such as ERK or AKT in the tumor sample.
  • TRKA G595R
  • TRKA G667C
  • TRKC G623R
  • HTRFkinEASETK is purchased from CisbioBioassays. Use BioTek Microplate Reader Synergy Neo 2 to read the plate.
  • test compound was subjected to 4-fold concentration gradient dilution, with a final concentration of 1 ⁇ M to 0.004 nM and 10 concentrations, each with two replicate wells; the content of DMSO in the detection reaction was 1%.
  • TRKA TRKA (G595R) protein kinase
  • 1 ⁇ M TK Substrate-biotin peptide substrate
  • 4.5 ⁇ M ATP 1 ⁇ enzymatic buffer
  • 5 mM MgCl 2 1 mM DTT.
  • the detection plate was a White Proxiplate 384-Plus plate (PerkinElmer), which was reacted at room temperature for 30 minutes, and the reaction system was 10 ⁇ l.
  • TRKA TRKA (G667C) protein kinase
  • 1 ⁇ M TK Substrate-biotin peptide substrate, 5.5 ⁇ M ATP, 1 ⁇ enzymatic buffer, 5 mM MgCl 2 , 1 mM DTT.
  • the detection plate was White Proxiplate 384-Plus plate (PerkinElmer), which was reacted at room temperature for 30 minutes, and the reaction system was 10 ⁇ l.
  • Ratio max is a positive control without test compound
  • Ratio test is the test value of each concentration of different compounds. 4 IC50 (nM) data measured by parameter curve fitting, see Table 3 for details.
  • Test compounds were given to ICR mice in single intravenous (IV) and oral (PO) injections. Blood samples were collected at different time points. LC-MS / MS was used to determine the concentration of the test substance in mouse plasma and related parameters were calculated. The details are as follows: take the required amount for the test product, dissolve it in 5% DMSO + 10% Solutol + 85% water for injection, and prepare a solution of the required concentration for intravenous or oral administration. The animals were about 6-8 weeks old at the start of the dosing experiment. Venous blood collection time: 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 8h and 24h after administration.
  • Oral blood collection time 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h and 24h after administration.
  • test compounds were given to SD rats in a single intravenous (IV) and oral (PO) injection, blood samples were collected at different time points, and the concentration of the test substance in the rat plasma was determined by LC-MS / MS and related parameters were calculated. The details are as follows: take the required amount for the test product, dissolve it in 5% DMSO + 10% Solutol + 85% water for injection, and prepare a solution of the required concentration for intravenous or oral administration. The animals were about 6-8 weeks old at the start of the dosing experiment. Venous blood collection time: 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 8h and 24h after administration.
  • Oral blood collection time 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h and 24h after administration.

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Abstract

L'invention concerne un composé hétérocyclique à 5 éléments, son procédé de préparation, sa composition pharmaceutique et son application. Le composé présente une activité inhibitrice de la kinase TRK et peut servir comme composition pharmaceutique pour traiter des maladies liées à un dysfonctionnement de TRK.
PCT/CN2019/111336 2018-10-15 2019-10-15 Composé à cycle aromatique imidazole, son procédé de préparation et son application WO2020078362A1 (fr)

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CN111620881A (zh) * 2020-07-08 2020-09-04 浙江合聚生物医药有限公司 拉罗替尼衍生物及其制备方法和应用
CN112645955A (zh) * 2020-12-24 2021-04-13 四川国康药业有限公司 一种[1,2,4]三唑并[4,3-b]哒嗪类化合物及其制备方法和用途
WO2023011616A1 (fr) * 2021-08-06 2023-02-09 正大天晴药业集团股份有限公司 Utilisation d'un composé d'aminolopyrimidine dans le traitement d'une tumeur induite par une kinase trk
US11739078B2 (en) 2019-02-22 2023-08-29 Insilico Medicine Ip Limited Methods of inhibiting kinases

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WO2021228248A1 (fr) * 2020-05-15 2021-11-18 石药集团中奇制药技术（石家庄）有限公司 Composé amide aza-hétérocyclique condensé et son utilisation
CN112979646B (zh) * 2021-03-08 2022-01-14 北京富龙康泰生物技术有限公司 一种咪唑并吡啶类衍生物
WO2023083356A1 (fr) * 2021-11-15 2023-05-19 石药集团中奇制药技术（石家庄）有限公司 Composé amide hétérocyclique condensé à l'azote sous forme solide et son utilisation
WO2023083362A1 (fr) * 2021-11-15 2023-05-19 石药集团中奇制药技术（石家庄）有限公司 Médicament pour le traitement de tumeurs
CN116120322A (zh) * 2021-11-15 2023-05-16 石药集团中奇制药技术（石家庄）有限公司 氮杂稠环酰胺类化合物的盐、其结晶形式及其用途

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CN112645955A (zh) * 2020-12-24 2021-04-13 四川国康药业有限公司 一种[1,2,4]三唑并[4,3-b]哒嗪类化合物及其制备方法和用途
CN112645955B (zh) * 2020-12-24 2022-11-04 四川国康药业有限公司 一种[1,2,4]三唑并[4,3-b]哒嗪类化合物及其制备方法和用途
WO2023011616A1 (fr) * 2021-08-06 2023-02-09 正大天晴药业集团股份有限公司 Utilisation d'un composé d'aminolopyrimidine dans le traitement d'une tumeur induite par une kinase trk

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