WO2022095909A1 - Composé utilisé comme inhibiteur de ntrk et son application - Google Patents

Composé utilisé comme inhibiteur de ntrk et son application Download PDF

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WO2022095909A1
WO2022095909A1 PCT/CN2021/128500 CN2021128500W WO2022095909A1 WO 2022095909 A1 WO2022095909 A1 WO 2022095909A1 CN 2021128500 W CN2021128500 W CN 2021128500W WO 2022095909 A1 WO2022095909 A1 WO 2022095909A1
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substituted
group
alkyl
compound
cancer
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沈毅
朱必成
万义良
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上海瑶琪生物科技有限公司
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    • 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
    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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 invention relates to the technical field of medicine, in particular to a compound used as an NTRK kinase inhibitor, a preparation method thereof, and an application in the preparation of a medicament for treating NTRK and other kinase-mediated diseases.
  • the tropomyosin receptor kinase (TRK) family belongs to the transmembrane receptor tyrosine kinases (RTKs), which are involved in the regulation of synaptic growth and functional maintenance of the mammalian nervous system, the occurrence and development of memory, and the protection of neurons from damage, etc. .
  • TRK kinase is a class of nerve growth factor receptors, and its family consists of highly homologous tropomyosin-related kinase A (TRKA), tropomyosin-related kinase B (Tropomyosin-related kinase B, TRKB) and Tropomyosin-related kinase C (TRKC), which are encoded by NTRK1, NTRK2 and NTRK3 genes respectively.
  • TRKA tropomyosin-related kinase A
  • TRKB Tropomyosin-related kinase B
  • TRKC Tropomyosin-related kinase C
  • the complete TRK kinase includes three parts: the extracellular domain, the transmembrane domain and the intracellular domain.
  • the extracellular domain of the TRK kinase binds to the corresponding ligand to form a dimer, which can cause TRK kinase activation.
  • the intracellular region undergoes autophosphorylation to activate its own kinase activity and further activate downstream signal transduction pathways.
  • TRK kinase affects cell proliferation, differentiation, metabolism and apoptosis through downstream pathways such as Ras/MAPK, PI3K/AKT and PLc ⁇ .
  • the NTRKs gene When the NTRKs gene is fused or mutated, it will change or eliminate the extracellular domain receptor (Greco, A. et. al, Mol. Cell. Biol.
  • TRK protein itself is in a highly activated kinase activity state without ligand binding, so that it can continuously activate the downstream signal transduction pathway, which can lead to abnormal regulation of the downstream signaling pathway of TRK kinase, induce cell proliferation, and promote The occurrence and development of tumors.
  • NTRKs gene fusions occur in a variety of adult and pediatric solid tumors, including breast cancer, colorectal cancer, non-small cell lung cancer, papillary thyroid cancer, Spitz-like melanoma, glioma, and various sarcomas.
  • common cancers such as non-small cell lung cancer, colorectal cancer, etc.
  • the incidence of NTRK gene fusion is low, roughly 1%-3%, but in some rare cancers, such as infantile fibrosarcoma, breast secretion Type cancer, etc., the incidence of NTRK gene fusion can reach more than 90%.
  • the earliest TPM3-TRKA fusion proteins were found in colon cancer cells. Later, more types of NTRK fusion proteins, such as CD74-NTRKA, MPRIP- NTEKA, QKI-NTRKB, ETV6-NTRKC, BTB1-NTRKC, etc.
  • NTRK fusion protein has become an effective anticancer target and a hot spot in the development of anticancer drugs.
  • WO2010048314, WO2010033941, WO2012116217, WO2011146336, etc. all disclose a series of TRK kinase inhibitors with different structures.
  • TRK fusion protein types and mutation types have been discovered (Russo, M. et. al Cancer Discovery, 2016, 6, 36; Drilon, A. et al. al, Annals of Oncology, 2016, 27, 920), so there is an urgent need to develop new NTRK inhibitors with better activity and wider effect in clinical practice, so as to solve the problem of the treatment of tumors caused by these NTRK protein fusions or mutations.
  • the main purpose of the present invention is to provide a selective NTRK kinase inhibitor.
  • the first aspect of the present invention provides a compound represented by formula I, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug,
  • R1 is selected from :
  • R 2 is selected from the group consisting of substituted or unsubstituted groups: C6-C14 aryl, 5-14-membered heteroaryl; wherein, the substitution refers to being substituted by one or more R r ;
  • R m , R n , R 3 and R 4 are each independently selected from the group consisting of substituted or unsubstituted groups: H, halogen, NR p R p' , -CN, -OH, C1-C6 alkyl group, C1-C6 alkoxy group, C3-C12 cycloalkyl group, 3-12-membered heterocyclic group, C6-C14 aryl group, 5-14-membered heteroaryl group; wherein, the substitution refers to being replaced by One or more R r substitutions;
  • R p and R p' are each independently selected from the group consisting of substituted or unsubstituted groups: H, C1-C6 alkyl, C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12 membered heterocyclyl , C6-C14 aryl, 5-14-membered heteroaryl; wherein, the substitution refers to being substituted by one or more R r ;
  • R 3 and R p together with the atoms to which they are attached form a substituted or unsubstituted group of the following groups: C3-C12 cycloalkyl, 3-12 membered heterocyclyl; wherein, the substitution refers to substitution by one or more R r substituted;
  • R 3 and R p' together with the atoms to which they are attached form a substituted or unsubstituted group of the following group: C3-C12 cycloalkyl, 3-12 membered heterocyclyl; wherein, the substitution refers to being replaced by one or more R r substitutions;
  • R 3 and R m together with the atoms to which they are attached form a substituted or unsubstituted group of the following group: C3-C12 cycloalkyl, 3-12 membered heterocyclyl; wherein, the substitution refers to being replaced by one or more R r substituted;
  • R 8 is each independently selected from the group consisting of substituted or unsubstituted: halogen, NR p R p' , -CN, -OH, C1-C6 alkyl, C1-C6 alkoxy; wherein, the substitution refers to being substituted by one or more R r ;
  • n 0, 1, 2 or 3;
  • n 0, 1, 2, 3, 4, 5 or 6;
  • s is 1, 2 or 3;
  • R r is selected from: deuterium, halogen, NR p R p' , -CN, -OH, C1-C6 alkyl, C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12-membered heterocyclyl, C6-C14 aryl, 5-14-membered heteroaryl;
  • R', R" are each independently selected from: H, C1-C6 alkyl, halogenated C1-C6 alkyl; or R', R" together with the N atom to which they are attached form a substituted or unsubstituted 3-8 membered heterocyclic Cyclic group, wherein the substitution refers to being substituted by one or more groups selected from the group consisting of deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy;
  • R is selected from: H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, ( CH 2 ) s C6-C10 aryl.
  • the compound of formula I its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, wherein, R 2 Selected from the group consisting of substituted or unsubstituted groups: phenyl, naphthyl, pyridinyl, pyridyl, pyrimidinyl, benzofuranyl, benzotetrahydrofuranyl, chromanyl, benzodioxy Hexacyclyl, chroman, benzopyrazine; wherein, the substitution refers to being substituted by one or more groups selected from the group consisting of deuterium, halogen, NR p R p' , -CN, -OH, C1-C6 alkyl, C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12-membered heterocyclyl, C6-C14 aryl, 5-14-membered heteroaryl;
  • R p , R p' , R, R' and R" are defined as above.
  • the compound of formula I its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug has formula II Structure shown:
  • R 1 , R 2 , R 8 and m are as described above.
  • the compound of formula I its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug has formula III Structure shown:
  • R 9 is selected from: H, halogen, CN, OH, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylamino, C1-C6 haloalkylamino;
  • X is selected from: N, CR 10 , wherein, R 10 is selected from: H, halogen, CN, OH, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C1-C6 halogenated alkoxy base, C1-C6 alkylamino, C1-C6 haloalkylamino,
  • R 1 , R 8 , R', R" and m are as defined above.
  • the compound of formula I its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug has formula IV Structure shown:
  • R 9 is selected from: H, halogen, CN, OH, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylamino, C1-C6 haloalkylamino;
  • X is selected from: N, CR 10 , wherein, R 10 is selected from: H, halogen, CN, OH, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C1-C6 halogenated alkoxy base, C1-C6 alkylamino, C1-C6 haloalkylamino,
  • R1 is selected from :
  • R, R', R", Rm , Rn , Rp , R3 and R4 are as defined above.
  • the compound of formula I has the formula V and the structure shown in formula VI:
  • X is selected from: N, CR 10 ;
  • R 10 and R 9 are each independently selected from: H, halogen, CN, OH, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 Alkylamino, C1-C6 halogenated alkylamino;
  • R 3 and R 4 are each independently selected from the group consisting of substituted or unsubstituted groups: H, halogen, NR p R p' , -CN, -OH, C1-C6 alkyl, C1-C6 alkoxy, C3 -C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl; wherein, the substitution refers to being substituted by one or more R r ;
  • R r is selected from: deuterium, halogen, NR p R p' , -CN, -OH, C1-C6 alkyl, C1-C6 alkoxy;
  • R p , R p' , R, R' and R" are defined as above.
  • R 1 , R 2 , R 8 , m and n are specific groups corresponding to the specific compounds in the embodiments.
  • the compound of formula I its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, wherein the The compound is selected from the following compounds:
  • the compound represented by formula I is selected from the compounds shown in the examples.
  • the second aspect of the present invention provides a pharmaceutical composition, which contains i) a therapeutically effective amount of the compound represented by formula I, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable and ii) one or more pharmaceutically acceptable carriers.
  • the pharmaceutical composition further comprises a drug selected from the group consisting of PD-1 inhibitors (such as nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT1306, AK105, LZM 009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as durvalumab, Atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F 520, GR1405, MSB2311 or biosimilars of the above etc.), CD20 antibodies (such as rituximab, obinutuzumab, ofatumumab, veltuzumab,
  • the third aspect of the present invention provides a preparation method of a pharmaceutical composition, comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound described in the first aspect of the present invention or its stereoisomer or optical isomer, The pharmaceutically acceptable salts, prodrugs or solvates are mixed to form a pharmaceutical composition.
  • the compounds of the present invention can be prepared into powders, tablets, granules, capsules, solutions, emulsions, suspensions and the like.
  • the fourth aspect of the present invention provides a compound of formula I according to the first aspect, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof for the preparation of a medicament for the prevention and/or treatment of diseases characterized by NTRK-mediated pathology.
  • the diseases characterized by NTRK-mediated pathology include cancer, sarcoma and pain.
  • the cancer is selected from: breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer , ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, peritoneal tumor, melanoma, glioma, glioblastoma, head and neck cancer, mastoid nephroma, leukemia, lymphoma, myeloma, thyroid tumor.
  • substituents When substituents are described by conventional chemical formulae written from left to right, the substituents also include the chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH2O- is equivalent to -OCH2- .
  • the term “about” means that the value may vary by no more than 1% from the recited value.
  • 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)” can be open, semi-closed, and closed. In other words, the term also includes “consisting essentially of,” or “consisting of.”
  • alkyl includes straight or branched chain alkyl groups.
  • C 1 -C 6 alkyl means straight or branched chain alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl Wait.
  • Haloalkyl refers to an alkyl group, as defined herein, wherein one or more hydrogens are replaced by the same or different halogen.
  • haloalkyl groups include -CH2Cl , -CH2CF3 , -CH2CCl3 , perfluoroalkyl (eg, -CF3 ) , and the like.
  • alkenyl includes straight or branched chain alkenyl groups.
  • C 2 -C 6 alkenyl refers to straight or branched alkenyl having 2-6 carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2 -butenyl, or similar groups.
  • alkynyl includes straight or branched chain alkynyl groups.
  • C2 - C6alkynyl refers to a straight or branched chain alkynyl group having 2 to 6 carbon atoms, such as ethynyl, propynyl, butynyl, or the like.
  • cycloalkyl refers to a cyclic alkyl group containing the specified number of C atoms, eg "C3-C10 cycloalkyl” refers to a cyclic alkyl group having 3-10 (preferably 3, 4, 5, 6, 7 or 8) carbon atoms cycloalkyl. It may be a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or the like. Bicyclic forms, such as bridged or spiro forms, are also possible. In the present invention, cycloalkyl is intended to include substituted cycloalkyl.
  • C1-C6alkoxy refers to a straight or branched chain alkoxy group having 1-6 carbon atoms; it has the formula C1-C6alkyl-O- or -C1-C5alkane Alkyl-O-C1-C5 alkyl (eg, -CH2 -O- CH2CH3 , -CH2 - O- ( CH2 ) 2CH3 , -CH2CH2 - O - CH2CH3 ) Structure, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, and the like.
  • Alkylamino refers to a group of formula -NRaRb wherein Ra is H or alkyl as defined herein, Rb is alkyl as defined herein, or Ra and Rb taken together with the N atom to which they are attached form a substituted or unsubstituted Substituted 3-8 membered heterocyclyl.
  • heterocyclyl refers to a saturated or partially saturated cyclic group having heteroatoms selected from N, S, and O
  • heterocyclyl refers to 3-10 atoms A saturated or partially saturated cyclic group of which 1-3 atoms are heteroatoms selected from the following groups N, S and O. It may be monocyclic or bicyclic, eg bridged or spirocyclic.
  • the 3-10-membered heterocyclic group is preferably a 3-8-membered heterocyclic group, more preferably a 6-8-membered heterocyclic group.
  • aryl refers to an aromatic ring group containing no heteroatoms in the ring
  • C6-C12 aryl refers to an aromatic ring group having 6 to 12 carbon atoms that contains no heteroatoms in the ring
  • the aryl group can be fused to a heteroaryl group, a heterocyclic group or a cycloalkyl ring, wherein the ring connected with the parent structure is an aryl ring.
  • the C6-C12 aryl group is preferably a C6-C10 aryl group.
  • Aryl groups can be optionally substituted or unsubstituted.
  • heteroaryl refers to a cyclic aromatic group having 1-3 atoms that are heteroatoms selected from the following groups of N, S, and O
  • heteroaryl refers to a group having 5-12 atoms A cyclic aromatic group of atoms wherein 1-3 atoms are heteroatoms selected from the following groups N, S and O. It may be a single ring or a fused ring form.
  • heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring.
  • Heteroaryl groups can be optionally substituted or unsubstituted.
  • the substituents are preferably one or more of the following groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio , alkylamino, halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylthio, oxo, amido, sulfonamido, Formyl, formamide, carboxyl and carboxylate, etc.
  • 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.
  • substituted refers to the replacement of one or more hydrogen atoms on a specified group with a specified substituent.
  • substituents are those described correspondingly in the preceding paragraphs, or the substituents appearing in the various examples.
  • a substituted group may have at any substitutable position of the group a substituent selected from a particular group, which may be the same or different at each position. It will be understood by those skilled in the art that combinations of substituents contemplated by the present invention are those that are stable or chemically achievable.
  • the group described in the present invention is "substituted or unsubstituted", the group of the present invention can be substituted by a substituent selected from the following group: deuterium, halogen, cyano, nitro, hydroxyl , amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl base, C6-C12 aryl.
  • a substituent selected from the following group: deuterium, halogen, cyano, nitro, hydroxyl , amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl base, C6-C
  • the structural formulas described herein are intended to include all isomeric forms (such as enantiomers, diastereomers and geometric isomers (or conformational isomers)): for example, those containing asymmetric R, S configuration of the center, (Z), (E) isomer of double bond, etc. Accordingly, individual stereochemical isomers or mixtures of enantiomers, diastereomers or geometric isomers (or conformational isomers) of the compounds of the present invention are within the scope of the present invention.
  • tautomer means that structural isomers having different energies can exceed a low energy barrier, thereby interconverting.
  • proton tautomers ie, protonation
  • Valence tautomers include interconversion by some bonding electron recombination.
  • solvate refers to a complex in which a compound of the present invention coordinates with solvent molecules to form a complex in specified proportions.
  • compound of the present invention or “active ingredient of the present invention” are used interchangeably to refer to a compound of formula I, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts , hydrate, solvate or prodrug.
  • a compound of formula I has the following structure,
  • R 1 , R 2 , R 8 , m and n are as defined above.
  • the compound of formula I has the structure shown in formula II:
  • R 1 , R 2 , R 8 and m are as described above.
  • R 2 is selected from the group consisting of substituted or unsubstituted groups: phenyl, naphthyl, pyridone, pyridyl, pyrimidinyl, benzofuranyl, benzotetrahydrofuranyl, benzoyl Tetrahydropyranyl, chromanyl, chroman, benzopyrazine;
  • substitution refers to being substituted by one or more groups selected from the group consisting of deuterium, halogen, NR p R p' , -CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12-membered heterocyclyl, C6-C14 aryl, 5-14-membered heteroaryl;
  • R p , R p' , R, R' and R" are defined as above.
  • the compound described in formula I has the structure shown in formula III:
  • the compound described in formula I has the structure shown in formula IV:
  • the compound of formula I has the structure shown in formula V or formula VI:
  • X is selected from: N, CR 10 ;
  • R 10 and R 9 are each independently selected from: H, halogen, CN, OH, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy;
  • R 1 is selected from: H, C1-C6 alkyl
  • R 3 and R 4 are each independently selected from the group consisting of substituted or unsubstituted groups: H, halogen, NR p R p' , -CN, -OH, C1-C6 alkyl, C1-C6 alkoxy, C3 -C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl; wherein, the substitution refers to being substituted by one or more R r ;
  • R r is selected from: deuterium, halogen, NR p R p' , -CN, -OH, C1-C6 alkyl, C1-C6 alkoxy;
  • R p , R p' , R, R' and R" are defined as above.
  • salts that the compounds of the present invention may form are also within the scope of the present invention. Unless otherwise specified, compounds in the present invention are understood to include their salts.
  • the term “salt” refers to salts formed with inorganic or organic acids and bases in the acid or basic form.
  • a compound of the present invention contains a basic moiety, which includes, but is not limited to, pyridine or imidazole, and when it contains an acidic moiety, including, but is not limited to, a carboxylic acid, the zwitterion (“inner salt”) that may be formed is contained in within the scope of the term "salt”.
  • compositions of the present invention may form salts, for example, by reacting Compound I with an amount, eg, an equivalent, of an acid or base, salting out in a medium, or lyophilizing in an aqueous solution.
  • salts refer to salts of compounds of the present invention with acids or bases that are suitable for use as pharmaceuticals.
  • Pharmaceutically acceptable salts include inorganic and organic salts.
  • a preferred class of salts are the salts of the compounds of the present invention with acids.
  • Acids suitable for forming salts include, but are not limited to, inorganic acids such as hydrochloric, hydrobromic, hydrofluoric, sulfuric, nitric, phosphoric, formic, acetic, propionic, oxalic, malonic, succinic, fumaric, Maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenemethanesulfonic acid, benzenesulfonic acid and other organic acids; and acidic amino acids such as aspartic acid and glutamic acid.
  • inorganic acids such as hydrochloric, hydrobromic, hydrofluoric, sulfuric, nitric, phosphoric, formic, acetic, propionic, oxalic, malonic, succinic, fumaric, Maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzene
  • Prodrugs and solvates of the compounds of the present invention are also contemplated.
  • the term "prodrug” as used herein refers to a compound that undergoes chemical transformation through a metabolic or chemical process to yield the compound, salt, or solvate of the present invention in the treatment of a related disease.
  • the compounds of the present invention include solvates, such as hydrates.
  • the compounds, salts or solvates of the present invention may exist in tautomeric forms (eg amides and imine ethers). All of these tautomers are part of the present invention.
  • Stereoisomers of all compounds are contemplated by the present invention.
  • Individual stereoisomers of the compounds of the present invention may not exist concurrently with other isomers (eg, as a pure or substantially pure optical isomer with specific activity), or may be mixtures such as Racemates, or mixtures with all other stereoisomers or a part thereof.
  • the chiral center of the present invention has two configurations, S or R, as defined by the 1974 recommendation of the International Union of Theoretical and Applied Chemistry (IUPAC).
  • the racemic form can be resolved by physical methods, such as fractional crystallization, or by derivatization to diastereomer separation crystallization, or by chiral column chromatography.
  • the individual optical isomers can be obtained from the racemates by suitable methods, including but not limited to conventional methods, such as salt formation with an optically active acid followed by crystallization.
  • the compound in the present invention the compound obtained by successively preparing, isolating and purifying the compound whose weight content is equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure” compound), is described in the text List. Herein such "very pure" compounds of the invention are also intended to be part of the invention.
  • Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention covers all compounds including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, Spin mixtures and other mixtures. Additionally asymmetric carbon atoms may represent substituents such as alkyl groups. All isomers, as well as mixtures thereof, are encompassed by the present invention.
  • a mixture of isomers may contain isomers in various ratios.
  • isomers in various ratios.
  • Similar ratios readily understood by those of ordinary skill in the art, as well as ratios that are mixtures of more complex isomers, are also within the scope of the invention.
  • the present invention also includes isotopically labeled compounds, equivalent to the original compounds disclosed herein. In practice, however, it usually occurs that one or more atoms are replaced by atoms with different atomic weights or mass numbers.
  • isotopes that may be listed as compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, respectively , 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
  • Isotopically-labeled compounds can be prepared by conventional methods by substituting readily available isotopically-labeled reagents for non-isotopically-labeled reagents using the protocols disclosed in the Examples.
  • a synthesis of a particular enantiomer of a compound of the present invention can be prepared by asymmetric synthesis, or by derivatization with a chiral auxiliary, separation of the resulting diastereomeric mixture, and removal of the chiral auxiliary to obtain pure enantiomer.
  • a suitable optically active acid or base can be used to form diastereomeric salts with it, and then the diastereomeric salts can be formed by separation crystallization or chromatography, etc. Separation by conventional means then yields the pure enantiomer.
  • the compounds of the present invention may be taken with any number of substituents or functional groups to extend their encompassing scope.
  • the general formula for including substituents in the formulations of the present invention refers to the replacement of a hydrogen radical with a specified structural substituent.
  • the substituents may be the same or different at each position.
  • substituted as used herein includes all permissible substitutions of organic compounds.
  • permissible substituents include acyclic, cyclic, branched unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds.
  • heteroatom nitrogen may have hydrogen substituents or any permissible organic compound as described above to supplement its valence.
  • the present invention is not intended to limit in any way the permissible substituted organic compounds.
  • the present invention contemplates that the combination of substituents and variable groups is well suited for the treatment of diseases in the form of stable compounds.
  • the term "stable" refers to compounds that are stable enough to be detected for a sufficient period of time to maintain the structural integrity of the compound, preferably for a sufficient period of time, as used herein for the above-mentioned purposes.
  • the compounds of the present invention can optionally be conveniently prepared by combining various synthetic methods described in this specification or known in the art, and such combinations can be readily performed by those skilled in the art to which the present invention pertains.
  • each reaction is usually carried out in an inert solvent at -60°C to 100°C, preferably -60°C to 80°C.
  • the reaction time is usually 0.1 to 60 hours, preferably 0.5 to 48 hours.
  • the preferred synthetic route is as follows:
  • X is selected from: Cl, Br, I;
  • R t is C1-C6 alkyl
  • R 1 , R 2 , R 8 , R m , R n , R p , R 3 , R 4 , m and n are as defined above.
  • the starting materials of the present invention are all known and commercially available, or can be synthesized according to literature data reported in the art.
  • compositions and methods of administration are provided.
  • the pharmaceutical composition of the present invention is used for preventing and/or treating the following diseases: inflammation, cancer, cardiovascular disease, infection, immune disease, metabolic disease.
  • the compounds of the present invention may be used in combination with other drugs known to treat or ameliorate similar conditions.
  • the mode of administration and dosage of the original drug may remain unchanged, while the compound of the present invention is administered concurrently or subsequently.
  • a pharmaceutical composition containing one or more known drugs and the compound of the present invention at the same time can be preferably used.
  • Drug combinations also include administration of a compound of the present invention with one or more other known drugs at overlapping time periods.
  • the dose of the compound of the present invention or known drugs may be lower than the doses of the compounds of the present invention administered alone.
  • the dosage form of the pharmaceutical composition of the present invention includes (but is not limited to): injection, tablet, capsule, aerosol, suppository, film, drop pill, external liniment, controlled-release or sustained-release or nanometer preparation.
  • the pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier within a safe and effective amount.
  • 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 of the present invention/dose, more preferably, 10-1000 mg of the compound of the present invention/dose.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to one or more compatible solid or liquid filler or gelling substances which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity. "Compatibility” as used herein means that the components of the composition can be admixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds.
  • Examples of pharmaceutically acceptable carrier moieties include 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 oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavors, 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, etc.
  • the mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration .
  • 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 (a) fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators such as quaternary amine compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostearate; (
  • Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions may be in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric substances and waxes. If desired, the active compound may also be in microencapsulated 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.
  • liquid dosage forms may contain inert diluents conventionally employed 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, and the like.
  • inert diluents conventionally employed 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, dimethylform
  • compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
  • suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
  • the therapeutic methods of the present invention may be administered alone or in combination with other therapeutic means or therapeutic agents.
  • a safe and effective amount of the compound of the present invention is suitable for mammals (such as people) in need of treatment, and the dose is a pharmaceutically considered effective dose when administered, and for a person with a body weight of 60kg, the daily dose is
  • the administered dose is usually 1-2000 mg, preferably 10-1000 mg.
  • the specific dosage should also take into account the route of administration, the patient's health and other factors, which are all within the skill of the skilled physician.
  • the present invention also provides a preparation method of a pharmaceutical composition, comprising the steps of: carrying out a pharmaceutically acceptable carrier with the compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof. mixed to form a pharmaceutical composition.
  • the present invention also provides a method of treatment comprising the steps of: administering to a subject in need of treatment a compound described in the present invention, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, or administering the present invention
  • a pharmaceutical composition of the invention is used to selectively inhibit the fusion mutation of NTRK and its drug resistance mutation.
  • the compounds of the present invention have good selective inhibitory ability to NTRK kinase
  • the compound of the present invention has better inhibitory ability on the activity of NTRK drug resistance mutation
  • the compound of the present invention has better pharmacodynamics, pharmacokinetic properties and lower toxic and side effects;
  • the compounds of the present invention have great potential to be developed into drugs targeting NTRK that are urgently needed in clinical practice.
  • Step 1 (the first step)
  • Step 2 (the second step)
  • 1,2-Propanediamine (0.12g, 0.016mol, 2eq) was dissolved in dry toluene (2ml), the reaction system was lowered to 0°C under argon protection, and then trimethylaluminum (0.9 ml, 2M, dissolved in toluene), after the dropwise addition, the temperature was raised to room temperature and continued to react for 2h, then lowered to 0°C, and the toluene solution (3ml) of compound 2 (0.3g, 0.0080mol, 1eq) was slowly added dropwise. After the addition was completed, the reaction was continued for 30 min, and then the temperature was raised to 80 °C for 16 h.
  • reaction system was lowered to 0 °C, and then methanol was added to quench, filter, spin dry the filtrate, and purify the filtrate twice to obtain compound C. -5 (80 mg, tan solid, purity 98.6%, yield 26%).
  • Step 1 (the first step)
  • 1,2-Diamino-2-methylpropane (0.14g, 0.016mol, 2eq) was dissolved in dry toluene (2ml), and the reaction system was lowered to 0°C under argon protection, followed by the slow dropwise addition of three Methylaluminum (1.1ml, 2M, dissolved in toluene) was added dropwise and the temperature was raised to room temperature to continue the reaction for 2h, then lowered to 0°C, and the toluene solution of compound 2 (0.3g, 0.0080mol, 1eq) was slowly added dropwise (3ml), after the dropwise addition was completed, the reaction was continued for 30min, then the temperature was raised to 80°C for 16h.
  • Methylaluminum 1.1ml, 2M, dissolved in toluene
  • reaction system was lowered to 0°C, and then methanol was added to quench, filter, spin dry the filtrate, and then purify through a column Twice, compound C-6 was obtained (60 mg, off-white solid, purity 98.4%, yield 18.7%).
  • Step 1 (the first step)
  • reaction system was lowered to 0°C, then quenched by adding methanol, filtered, and the filtrate was spin-dried and purified by column to obtain compound 5 (0.52 g, yellow foam, purity 94.6%, yield 54%).
  • Step 2 (the second step)
  • Step 3 (third step)
  • Step 4 (the fourth step)
  • compound 7 (0.14g, 0.00039mol, 1eq) and 2,2-dimethoxypropane (0.081g, 0.00078mol, 2eq) were dissolved in acetic acid and then heated to 40°C for 20h reaction. After the completion of the reaction, spin off most of the acetic acid, then in the reaction system, the aqueous solution of saturated sodium bicarbonate is extracted three times with ethyl acetate, and the organic phase is washed with brine, dried over anhydrous sodium sulfate, and spin-dried to obtain compound C-7 ( 40 mg, off-white solid, purity 94%, yield 25.6%).
  • Step1 (the first step)
  • Step2 (the second step)
  • Step3 (third step)
  • the synthetic route is as follows:
  • Examples 13-35 were further specifically synthesized, as shown in Table 1.
  • Test Example 1 Inhibitory activity of the compounds of the present invention on NTRK and its drug-resistant kinase NTRK1-G667C
  • the activity inhibition experiments of compounds on protein kinases were carried out on the HotSpot kinase experimental platform radiolabeled by Reaction Biology Corporation.
  • Prepare a fresh reaction solution containing the corresponding substrate (20 mM HEPES pH 7.5, 10 mM MgCl 2 , 1 mM EGTA, 0.02% Brij35, 0.02 mg/mL BSA, 0.1 mM Na 3 VO 4 , 2 mM DTT, 1% DMSO), add the required auxiliary
  • the factor and the kinase to be tested were added to the above solution and mixed gently.
  • the DMSO solution of the test compound was added to each well (the blank control group was added with the corresponding volume of DMSO), and 33P-ATP (final specific activity 0.01 ⁇ Ci/ ⁇ L) to start the reaction, and the reaction solution was incubated at room temperature for 120 minutes.
  • the incubated reaction solution was transferred to P81 ion exchange chromatography paper (Whatman #3698-915), eluted with 0.75% phosphoric acid solution, and the amount of the remaining radioactive phosphorylated substrate on the chromatography paper was detected.
  • Table 2 shows the IC50 values of the inhibitory activities of some compounds of the present invention on NTRK1, NTRK2 and NTRK3 and the drug resistance mutation NTRK1-G667C, where A ⁇ 1.0nM, 1.0nM ⁇ B ⁇ 20nM, 20nM ⁇ C ⁇ 100nM, D ⁇ 100 nM.
  • Table 3 shows the specific IC50 values of the inhibitory activities of some compounds of the present invention on NTRK1, NTRK2 and NTRK3 and the drug resistance mutation NTRK1-G667C.
  • the series of compounds of the present invention have good inhibitory activity on various fused NTRKs, and also have good inhibitory activity on various NTRK mutations. At the same time, it has good selectivity for other kinases such as ALK and/or ROS1. It has great potential for the treatment of diseases mediated by NTRK.

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Abstract

La présente invention concerne un composé utilisé comme inhibiteur de NTRK et son application. Plus particulièrement, la présente invention concerne un composé tel que présenté dans la formule I ou un stéréoisomère ou un isomère optique, un sel pharmaceutiquement acceptable, un promédicament ou un solvate associé, et concerne également une composition pharmaceutique du composé et l'utilisation du composé comme inhibiteur de NTRK, et une utilisation du composé dans la préparation d'un médicament pour prévenir et/ou traiter une maladie liée à NTRK.
PCT/CN2021/128500 2020-11-03 2021-11-03 Composé utilisé comme inhibiteur de ntrk et son application WO2022095909A1 (fr)

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CN112979654B (zh) * 2019-12-16 2024-03-19 赛诺哈勃药业（成都）有限公司 杂芳基稠环化合物、其制备方法及应用

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