WO2023025141A1 - 含有氨基的大环化合物在治疗trk激酶介导的肿瘤中的用途 - Google Patents

含有氨基的大环化合物在治疗trk激酶介导的肿瘤中的用途 Download PDF

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WO2023025141A1
WO2023025141A1 PCT/CN2022/114215 CN2022114215W WO2023025141A1 WO 2023025141 A1 WO2023025141 A1 WO 2023025141A1 CN 2022114215 W CN2022114215 W CN 2022114215W WO 2023025141 A1 WO2023025141 A1 WO 2023025141A1
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Prior art keywords
fusion gene
ntrk1
mutant
ntrk3
compound
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PCT/CN2022/114215
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English (en)
French (fr)
Inventor
万晓婧
张喜全
王训强
田心
于鼎
陈琴
郭方方
Original Assignee
正大天晴药业集团股份有限公司
首药控股(北京)股份有限公司
连云港润众制药有限公司
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Priority to CN202280046303.XA priority Critical patent/CN117597128A/zh
Publication of WO2023025141A1 publication Critical patent/WO2023025141A1/zh

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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
    • A61K31/505—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
    • A61P35/00—Antineoplastic agents
    • 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

Definitions

  • the application belongs to the field of medicine and relates to the use of amino-containing macrocyclic compounds in the treatment of tumors mediated by TRK kinase.
  • TRK is a family of tyrosine kinases activated by nerve growth factor, including three subtypes, TRKA, TRKB and TRKC, encoded by NTRK1 (neurotrophic receptor tyrosine kinase 1), NTRK2 and NTRK3 genes, respectively.
  • the complete TRK kinase includes three parts: extracellular region, transmembrane region and intracellular region. After the extracellular receptor region of TRK kinase binds to the corresponding ligand, it can cause a change in the kinase configuration and form a dimer.
  • the intracellular kinase region is autophosphorylated to activate its own kinase activity, and further activate the downstream signal transduction.
  • NGF nerve growth factor
  • BDNF derived neurotrophic factor
  • TRKB TRKB
  • NT3 neurotrophic factor 3
  • TRK kinases play important physiological functions in the development of nerves, including the growth and function maintenance of neuronal axons, the occurrence and development of memory, and the protection of neurons from injury and so on.
  • TRK signal transduction pathways Activated TRK signaling proteins have been found in neurocytoma, prostate cancer, and breast cancer.
  • TRK fusion proteins have shown its biological function of promoting tumorigenesis. The earliest TPM3-TRKA fusion protein was found in colon cancer cells, with an incidence of about 1.5% in clinical patients tested.
  • TRK fusion proteins were found in different types of clinical tumor patient samples such as lung cancer, head and neck cancer, breast cancer, thyroid cancer, glioma, etc., such as CD74-NTRK1, MPRIP-NTRK1, QKI-NTRK2, ETV6 -NTRK3, BTB1-NTRK3, etc.
  • These different TRK fusion proteins are in a state of highly activated kinase activity without the need for ligand binding, so they can continuously phosphorylate downstream signaling pathways, induce cell proliferation, and promote the occurrence and development of tumors. Therefore, in recent years, TRK fusion protein has become an effective anti-cancer target and research hotspot.
  • WO2019037761A1 discloses macrocyclic compounds containing aminopyrazolopyrimidines such as (1 3 E, 1 4 E, 2 2 R, 2 4 S)-1 2 -amino-2 4 ,3 5 -difluoro-4-oxa -7-Aza-1(5,3)-pyrazolo[1,5-a]pyrimidine-3(3,2)-pyridine-2(1,2)-pyrrolidinecyclooctane-8-one (compound of formula I), which has TRK kinase inhibitory activity, can be used for treating diseases mediated by TRK kinase.
  • aminopyrazolopyrimidines such as (1 3 E, 1 4 E, 2 2 R, 2 4 S)-1 2 -amino-2 4 ,3 5 -difluoro-4-oxa -7-Aza-1(5,3)-pyrazolo[1,5-a]pyrimidine-3(3,2)-pyridine-2(1,2)-pyrrolidinecyclooctane-8-one (
  • the application provides a method for treating TRK kinase-mediated tumors, which comprises administering to a subject an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof
  • the present application provides a method for treating TRK kinase-mediated tumors, which comprises administering to a subject a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the present application provides the use of the compound of formula I or its pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of a medicament for treating tumors mediated by TRK kinase.
  • the present application also provides a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for treating TRK kinase-mediated tumors.
  • the present application also provides the use of the compound of formula I of the present application or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for treating tumors mediated by TRK kinase.
  • the present application provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for treating TRK kinase-mediated tumors, wherein the medicament comprises, with Based on the weight of the compound of formula I, 0.5-100mg of the compound of formula I or its pharmaceutically acceptable salt or its pharmaceutical composition.
  • the compound of formula I of the present application is used as a single active agent.
  • the compound of formula I of the present application or a pharmaceutically acceptable salt thereof is used as a single active agent in a single dose or a daily dose of 0.5-100 mg (based on the weight of the compound of formula I).
  • the compound of formula I of the present application or a pharmaceutically acceptable salt thereof is used in a single dose or a daily dose of 0.5-100 mg (based on the weight of the compound of formula I).
  • the pharmaceutical composition described herein comprises 0.5-100 mg (based on the weight of the compound of formula I) of the compound of formula I or a pharmaceutically acceptable salt thereof as a single active agent.
  • the pharmaceutical composition comprises a compound of formula I or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients.
  • the application provides a method for treating TRK kinase-mediated tumors, which comprises daily administration of 0.5-100 mg of a compound of formula I or its pharmaceutically acceptable A salt, or a pharmaceutical composition thereof (based on the weight of the compound of formula I).
  • the present application also provides a kit for treating TRK kinase-mediated tumors, comprising: a pharmaceutical composition containing a compound of formula I or a pharmaceutically acceptable salt thereof as an active ingredient; optionally, Instructions for use of pharmaceutical compositions comprising a compound of formula I or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition is a single-dose pharmaceutical composition comprising 0.5-100 mg of the compound of formula I or a pharmaceutically acceptable salt thereof (based on the weight of the compound of formula I) as an active ingredient.
  • the method for treating tumor provided by the application comprises:
  • the subject is a primate, preferably a human.
  • the tumor is mediated by TRKA, and/or TRKB, and/or TRKC.
  • the tumor is mediated by wild-type (non-mutated) or mutated TRK. In some embodiments, the tumor is mediated by wild-type (non-mutated) or mutant TRKA, and/or TRKB, and/or TRKC.
  • the tumor is mediated by a mutant TRK comprising G667C, G595R, or G623R.
  • the tumor is mediated by mutant TRKA comprising G667C or G595R, and/or TRKB, and/or mutant TRKC comprising G623R.
  • the mutant is selected from TRKA G595R , TRKA G667C or TRKC G623R .
  • the tumor is selected from tumors with a TRK fusion protein.
  • the TRK kinase-mediated tumor is selected from tumors with non-mutated or mutated TRK fusion proteins.
  • the TRK fusion protein is selected from non-mutant or mutant TRKA fusion protein, and/or TRKB fusion protein, and/or TRKC fusion protein.
  • the TRK fusion protein is selected from non-mutated TRKA fusion protein, and/or TRKB fusion protein, and/or TRKC fusion protein.
  • the TRK fusion protein is selected from a mutant TRKA fusion protein, and/or TRKB fusion protein, and/or TRKC fusion protein.
  • the tumor is selected from tumors with an NTRK fusion gene.
  • the NTRK fusion gene is selected from non-mutated or mutant NTRK fusion genes.
  • the NTRK fusion gene is selected from an NTRK1 fusion gene, an NTRK2 fusion gene, and an NTRK3 fusion gene.
  • the NTRK fusion gene is selected from non-mutant or mutant NTRK1 fusion gene, and/or NTRK2 fusion gene, and/or NTRK3 fusion gene.
  • the NTRK fusion gene is selected from non-mutant or mutant NTRK1 fusion genes.
  • the NTRK fusion gene is selected from non-mutant or mutant NTRK2 fusion genes. In some embodiments, the NTRK fusion gene is selected from non-mutant or mutant NTRK3 fusion genes. In some embodiments, the NTRK fusion gene is selected from non-mutated NTRK1 fusion gene, and/or NTRK2 fusion gene, and/or NTRK3 fusion gene. In some embodiments, the NTRK fusion gene is selected from a mutant NTRK1 fusion gene, and/or NTRK2 fusion gene, and/or NTRK3 fusion gene.
  • the NTRK fusion gene can be a TPM3-NTRK1 fusion gene, an ETV6-NTRK3 fusion gene, and/or a CD74-NTRK1 fusion gene. In some embodiments, the NTRK fusion gene can be an ETV6-NTRK3 fusion gene.
  • the NTRK fusion gene expresses a TRK fusion protein in the tumor.
  • the NTRK fusion gene in the tumor, can express wild-type (ie, non-mutated) or mutant TRK fusion protein.
  • the NTRK1 fusion gene can express wild-type (ie, non-mutated) or mutant TRKA fusion protein in the tumor.
  • the NTRK2 fusion gene may express wild-type (ie, non-mutated) or mutant TRKB fusion protein in the tumor.
  • the NTRK3 fusion gene in the tumor, can express wild-type (ie, non-mutated) or mutant TRKC fusion protein.
  • the NTRK1 fusion gene in the tumor, can express wild-type (ie, non-mutated) or mutant TRKA fusion protein; and/or the NTRK2 fusion gene can express wild-type (ie, non-mutated) or mutant TRKB fusion protein; and/or NTRK3 fusion gene can express wild-type (ie, non-mutated) or mutant TRKC fusion protein.
  • the mutant NTRK fusion gene is selected from fusion genes with NTRK1 G595R , NTRK1 G667C and/or NTRK3 G623R .
  • the mutant NTRK fusion gene is selected from the CD74-NTRK1 G667C fusion gene and/or the ETV6-NTRK3 G623R fusion gene. In some embodiments, the mutant NTRK fusion gene is selected from the ETV6-NTRK3 G623R fusion gene.
  • the NTRK1 fusion gene is selected from a non-mutated TPM3-NTRK1 fusion gene, a non-mutated CD74-NTRK1 fusion gene, or a mutant NTRK1 fusion gene with NTRK1 G595R and/or NTRK1 G667C (e.g., with TPM3-NTRK1 fusion gene or CD74-NTRK1 fusion gene of NTRK1 G595R and/or NTRK1 G667C ).
  • the NTRK1 fusion gene is selected from a non-mutant TPM3-NTRK1 fusion gene, a mutant NTRK1 fusion gene with NTRK1 G595R , a non-mutant CD74-NTRK1 fusion gene, or a CD74-NTRK1 G667C fusion gene.
  • the NTRK3 fusion gene is selected from a non-mutant ETV6-NTRK3 fusion gene, or a mutant NTRK3 fusion gene with NTRK3 G623R (eg, an ETV6-NTRK3 fusion gene with NTRK3 G623R ). In some embodiments, the NTRK3 fusion gene is selected from a non-mutant ETV6-NTRK3 fusion gene, or an ETV6-NTRK3 G623R fusion gene.
  • the method for treating tumor provided by the application comprises:
  • the NTRK fusion gene is selected from non-mutated or mutant NTRK fusion genes. In some embodiments, the NTRK fusion gene is selected from an NTRK1 fusion gene, an NTRK2 fusion gene, and/or an NTRK3 fusion gene. In some embodiments, the NTRK fusion gene is selected from an NTRK1 fusion gene. In some embodiments, the NTRK fusion gene is selected from an NTRK2 fusion gene. In some embodiments, the NTRK fusion gene is selected from an NTRK3 fusion gene. In some embodiments, the NTRK fusion gene is selected from non-mutated NTRK fusion genes.
  • the NTRK fusion gene is selected from mutant NTRK fusion genes.
  • the mutation of the NTRK fusion gene is selected from an acquired mutation or a non-acquired mutation.
  • the mutant NTRK fusion gene is selected from a drug-resistant mutant NTRK fusion gene.
  • the NTRK fusion gene is selected from an NTRK1 fusion gene, an NTRK2 fusion gene, and/or an NTRK3 fusion gene.
  • the NTRK fusion gene is selected from a mutant NTRK1 fusion gene, NTRK2 fusion gene, and/or NTRK3 fusion gene.
  • the NTRK fusion gene can be selected from non-mutant or mutant TPM3-NTRK1 fusion gene, ETV6-NTRK3 fusion gene or CD74-NTRK1 fusion gene.
  • the NTRK fusion gene may be selected from a TPM3-NTRK1 fusion gene, an ETV6-NTRK3 fusion gene, or a CD74-NTRK1 fusion gene.
  • the NTRK fusion gene may be ETV6-NTRK3.
  • the mutant NTRK fusion gene is selected from fusion genes with NTRK1 G595R , NTRK1 G667C or NTRK3 G623R . In some embodiments, the mutant NTRK fusion gene is selected from fusion genes with NTRK3 G623R .
  • the TRK fusion protein is selected from wild-type (ie non-mutated) or mutant TRK fusion protein. In some embodiments, the TRK fusion protein is selected from TRKA fusion protein, TRKB fusion protein, and/or TRKC fusion protein. In some embodiments, the TRK fusion protein is selected from wild-type (ie non-mutant) or mutant TRKA fusion protein, wild-type (ie non-mutant) or mutant TRKB fusion protein, and/or wild-type (ie non-mutant) or mutant TRKC fusion protein.
  • the mutant TRK fusion protein is selected from mutant TRKA with G595R and/or G667C or mutant TRKC with G623R. In some embodiments, the mutant TRK fusion protein is selected from mutant TRKA with G595R, mutant TRKA with G667C, or mutant TRKC with G623R.
  • the mutant TRK fusion protein is selected from TRKA G595R , TRKA G667C or TRKC G623R .
  • the mutation of the mutant TRK fusion protein is selected from an acquired mutation or a non-acquired mutation. In some embodiments, the mutant TRK fusion protein is selected from a drug-resistant mutant TRK fusion protein. In some embodiments, the mutant TRK fusion protein is selected from acquired drug resistance mutant TRK fusion proteins.
  • the fusion gene described in the present application may contain a point mutation of NTRK gene or not contain a point mutation of NTRK gene. In some embodiments, the fusion gene described herein may contain a point mutation in the NTRK gene. In some embodiments, the fusion gene described in this application may not contain NTRK gene point mutation.
  • the tumors described herein may be from subjects and/or patients carrying NTRK1, NTRK2, or NTRK3 gene fusions without NTRK point mutations. In some embodiments, the tumors described herein may be from subjects and/or patients carrying NTRK1, NTRK2 or NTRK3 gene fusions and NTRK gene point mutations.
  • the methods provided herein include performing morphological diagnosis, or molecular testing, or a combination of both before administering the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the methods provided herein comprise assaying a tumor sample obtained from a subject to determine that the subject has a dysregulation of NTRK fusion gene, TRK protein, or expression or level thereof.
  • the methods provided herein include assaying a tumor sample obtained from a subject to determine that the subject has an NTRK fusion gene or/and a TRK fusion protein.
  • the assay method is selected from one or more of the following methods: denaturing gradient gel electrophoresis (DGGE), temperature gradient gel electrophoresis (TGGE), temperature gradient capillary electrophoresis, single-strand conformation multiple morphological assays, molecular beacon assays, kinetic hybridization assays, PCR-based assays, or denaturing high-performance liquid chromatography.
  • DGGE denaturing gradient gel electrophoresis
  • TGGE temperature gradient gel electrophoresis
  • TGGE temperature gradient capillary electrophoresis
  • single-strand conformation multiple morphological assays single-strand conformation multiple morphological assays
  • molecular beacon assays kinetic hybridization assays
  • PCR-based assays or denaturing high-performance liquid chromatography.
  • the mutants described herein are selected from G595R, G667C or G623R mutations. In some embodiments, the mutant is selected from a G595R-type mutation. In some embodiments, the mutant is selected from a G667C-type mutation. In some embodiments, the mutant is selected from a G623R-type mutation.
  • the fusion gene described herein is selected from non-mutant or mutant NTRK1, NTRK2 or NTRK3 gene fusions. In some embodiments, the fusion gene described herein is selected from a non-mutant or mutant NTRK1 gene fusion. In some embodiments, the fusion gene described herein is selected from a non-mutant or mutant NTRK2 gene fusion. In some embodiments, the fusion gene described herein is selected from a non-mutant or mutant NTRK3 gene fusion.
  • the NTRK fusion gene described herein can be selected from non-mutant or mutant TPM3-NTRK1, ETV6-NTRK3 or CD74-NTRK1. In some embodiments, the NTRK fusion gene described herein can be selected from non-mutant or mutant TPM3-NTRK1. In some embodiments, the NTRK fusion gene described herein can be selected from non-mutant or mutant ETV6-NTRK3. In some embodiments, the NTRK fusion gene described herein can be selected from non-mutated or mutant CD74-NTRK1.
  • the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered at a weight of 0.0001 mg/kg to 20 mg/kg (calculated by the weight of the compound of formula I) per administration.
  • the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is 0.5-100 mg, 0.5-25 mg or 2.5-25 mg (calculated by the weight of the compound of formula I) per administration. In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is 0.5-20 mg (calculated by the weight of the compound of formula I) for each administration. In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is 0.5-15 mg (calculated by the weight of the compound of formula I) for each administration.
  • the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is 2.5-10 mg (calculated by the weight of the compound of formula I) for each administration. In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is 5-10 mg (calculated by the weight of the compound of formula I) for each administration.
  • the daily dosage of the compound of formula I or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof (based on the weight of the compound of formula I) is selected from 0.5-100 mg, 0.5-25 mg or 2.5-25 mg.
  • the daily dose (by weight of the compound of formula I) of the compound of formula I or its pharmaceutically acceptable salt or pharmaceutical composition thereof is selected from 0.5 mg, or 1 mg, or 1.5 mg, or 2 mg, or 2.5mg, or 3mg, or 3.5mg, or 4mg, or 4.5mg, or 5mg, or 5.5mg, or 6mg, or 6.5mg, or 7mg, or 7.5mg, or 8mg, or 8.5mg, or 9mg, or 9.5 mg, or 10mg, or 10.5mg, or 11mg, or 11.5mg, or 12mg, or 12.5mg, or 13mg, or 13.5mg, or 14mg, or 14.5mg, or 15mg, or 15.5m
  • the daily dose (based on the weight of the compound of formula I) of the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is selected from 0.5 mg-20 mg. In some schemes, the daily dose (based on the weight of the compound of formula I) of the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is selected from 0.5 mg-15 mg. In some schemes, the daily dose (based on the weight of the compound of formula I) of the compound of formula I or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof is selected from 2.5 mg-10 mg.
  • the daily dose (based on the weight of the compound of formula I) of the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is selected from 5 mg-10 mg.
  • the administration frequency of the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof may be 3 times a day, 2 times a day, 1 time a day, 1 time every two days, Once every three days, once every four days, once every five days, once every six days, three times a week, twice a week, once a week, once every two weeks, or once every three weeks Second-rate.
  • the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof may be administered once a day.
  • the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof may be administered twice a day.
  • the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered with a specification dose of 2-20 mg each time, such as a specification dose of 2.5 mg, 5 mg or 10 mg (weight of the compound of formula I calculate).
  • the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered at a weight of 0.0001 to 20 mg/kg (calculated by the weight of the compound of formula I) each time.
  • the administration cycle of the compound of formula I or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof is 1-6 cycles. In some embodiments, the administration cycle of the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is 1, 2, 3, 4, 5, 6 cycles or the range formed by any value above.
  • 8-32 days is used as a dosing cycle, for example, 8-28 days, 8-21 days, 8-15 days, 15-28 days, 15-21 days, 21-28 days , 21-32 days, 28-32 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, or 32 days constitute one administration cycle.
  • 28 days or 32 days are used as one administration cycle.
  • 28-32 days is taken as one administration cycle.
  • administering an effective amount of the compound of formula I of the present application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a subject is continuous administration.
  • the compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered in single or multiple doses.
  • the subject is selected from subjects with advanced malignant solid tumors diagnosed pathologically and/or cytologically, and/or subjects who lack conventional effective treatment methods or fail or relapse after conventional treatment. tester.
  • the tumor is selected from tumor patients with or without prior treatment. In some embodiments, the tumor is selected from patients with previously treated tumors.
  • the subject is selected from subjects who have or have not previously received treatment with a TRK inhibitor.
  • the subject is selected from subjects who have previously been treated with one or more TRK inhibitors.
  • the TRK inhibitor is selected from larotrectinib, TL118 and/or SIM1803.
  • the subject is selected from subjects who have not previously received TRK inhibitor treatment.
  • the aforementioned tumor is selected from solid tumors.
  • the aforementioned tumor is selected from advanced malignant solid tumors.
  • the aforementioned tumor is selected from adult advanced malignant solid tumors.
  • the aforementioned tumor is selected from glioma, central nervous system tumor, sarcoma, peripheral primitive neuroectodermal tumor, Wilms tumor, lung cancer, thyroid cancer, colorectal cancer, salivary gland cancer, biliary tract cancer, brain cancer , breast cancer, breast ductal carcinoma, head and neck cancer, cell carcinoma, pancreatic cancer, male and female reproductive system tumors, kidney cancer, bile duct cancer, gastric cancer, bronchial cancer, chest cancer, neuroendocrine tumor, lymphoma or melanoma.
  • the aforementioned tumor is selected from soft tissue sarcoma, salivary adenoma, thyroid cancer, lung cancer, melanoma, colorectal cancer, gastric cancer, stromal tumor, cholangiocarcinoma, breast cancer, or pancreatic cancer.
  • the aforementioned tumor is selected from lung cancer, adenocarcinoma or oral cancer.
  • the aforementioned lung cancer is selected from lung adenocarcinoma; the adenocarcinoma is selected from parotid gland carcinoma or lung adenocarcinoma; and the oral cavity cancer is selected from mouth floor cancer.
  • the aforementioned tumor is selected from lung adenocarcinoma, parotid gland carcinoma, floor of the mouth carcinoma, acinar cell carcinoma, or intestinal carcinoma.
  • the compound of formula I in the present application can be administered in the form of its free base, and can also be administered in the form of its pharmaceutically acceptable salt, hydrate and prodrug, and the prodrug can be converted into the free base form of the compound of formula I in vivo.
  • the pharmaceutical composition of the compound of formula I or a pharmaceutically acceptable salt thereof is selected from solid pharmaceutical compositions, preferably tablets or capsules.
  • the compound of formula I or a pharmaceutically acceptable salt thereof is in the form of a pharmaceutical composition, wherein, based on the weight of the compound of formula I, the pharmaceutical composition is a single dose of 0.5-100 mg, preferably 0.5 mg- 25 mg of the pharmaceutical composition, preferably from a single dose of 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg , 8.5mg, 9mg, 9.5mg, 10mg, 10.5mg, 11mg, 11.5mg, 12mg, 12.5mg, 13mg, 13.5mg, 14mg, 14.5mg, 15mg, 15.5mg, 16mg, 16.5mg, 17mg, 17.5mg, 18mg , 18.5mg, 19mg, 19.5mg, 20mg, 20.5mg, 21mg, 21.5m
  • the pharmaceutical composition of the present application is administered orally.
  • each pharmaceutical composition of the present application is a solid pharmaceutical composition.
  • the preparation form of the solid pharmaceutical composition of the present application is a tablet.
  • TRKA TRKB and TRKC, it is encoded by the genes NTRK1, NTRK2 and NTRK3, respectively.
  • administration refers to the physical introduction of a therapeutic agent or a composition comprising a therapeutic agent to a subject using any of a variety of methods and delivery systems known to those skilled in the art.
  • administration or “administration” or “administration” are used interchangeably herein.
  • treatment generally refers to obtaining a desired pharmacological and/or physiological effect.
  • the effect may be therapeutic in terms of partial or complete stabilization or cure of the disease and/or side effects due to the disease.
  • treatment encompasses any treatment of a disease in a patient, including: (a) inhibiting the symptoms of the disease, ie arresting its development; or (b) relieving the symptoms of the disease, ie causing regression of the disease or symptoms.
  • the term "effective amount” means (i) treating or preventing a particular disease, condition or disorder, (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) preventing or delaying the The amount of a compound of the application for the onset of one or more symptoms of a particular disease, condition or disorder described in .
  • the amount of a compound of the present application that constitutes a “therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by a person skilled in the art according to its own knowledge and this disclosure.
  • subject refers to an animal, preferably a mammal, preferably a primate, including humans and non-humans, who has been the subject of treatment, observation or experimentation Primates (such as apes, monkeys, orangutans, and chimpanzees, such as cynomolgus monkeys, spider monkeys, and macaques, such as rhesus monkeys), most preferably humans.
  • the subject has experienced and/or exhibited at least one symptom of the disease or condition to be treated and/or prevented.
  • the term "individual” may be a mammal, preferably a primate, most preferably a human.
  • the compound of formula I or a pharmaceutically acceptable salt thereof may be administered by any suitable route and method, such as orally or parenterally (eg, intravenously).
  • pharmaceutical composition refers to a mixture of one or more compounds of the present application or a pharmaceutical combination or salt thereof and pharmaceutically acceptable auxiliary materials.
  • the purpose of the pharmaceutical composition is to facilitate administration of a compound of the present application, or a pharmaceutical combination thereof, to a subject.
  • pharmaceutically acceptable excipients refers to those excipients that have no obvious stimulating effect on the organism and will not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.
  • the pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, for example, it can be formulated into solid preparations such as tablets, pills, capsules and the like.
  • the pharmaceutical composition of the present application can be produced by methods well known in the art, such as conventional mixing methods, dissolving methods, granulating methods, dragee-making methods, pulverizing methods, emulsifying methods, freeze-drying methods and the like.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without excessive Toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • Solid oral pharmaceutical compositions can be prepared by conventional mixing, filling or tabletting methods. It can be obtained, for example, by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if desired, and processing the mixture into granules to obtain tablets or the core of a capsule or dragee.
  • suitable auxiliary materials include but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.
  • pharmaceutically acceptable salt or “pharmaceutically acceptable salt” refers to a salt of a compound of the present application that falls within the definition of "pharmaceutically acceptable”.
  • single dose refers to the smallest packaging unit containing a certain amount of medicine.
  • a box of medicine has seven capsules, and each capsule is a single dose; or each bottle of injection is a single dose.
  • multiple dose consists of a number of single doses.
  • the pharmaceutical combination of the present application can be formulated as a pharmaceutical composition suitable for single or multiple administrations. In one embodiment, the pharmaceutical combination of the present application can be a single-dose or multi-dose pharmaceutical composition.
  • ORR Objective Response Rate
  • DCR disease control rate
  • progression-free survival the time from the first medication to disease progression (PD) or death before PD; if there is no PD or death before PD, the date of the last imaging assessment is used as the cut-off date.
  • Term “Duration of Response (DOR)” In subjects with CR or PR, the time between when the tumor was first assessed as CR or PR and death before PD or PD; if the subjects with CR or PR did not develop PD or died before PD, the date of the last imaging assessment was used as the cut-off date.
  • AE Adverse Event
  • NCI-CTC AE v5.0 Common Toxic Reaction Criteria
  • Moderate Significantly affects the patient's daily life.
  • OS refers to the overall survival time of cancer patients.
  • DFS refers to the disease-free survival period of cancer patients.
  • TTP refers to the time to disease progression of a tumor patient.
  • the treatment plan of the present application has a good curative effect on the treatment of TRK-mediated tumors.
  • the compound of formula I described in the application or its pharmaceutically acceptable salt, or its pharmaceutical composition is at least in survival efficacy evaluation (such as OS, median survival period); in tumor response efficacy evaluation (such as DFS, median DFS, PFS, At least one of TTP, ORR, DCR, DOR) has an excellent effect, such as ORR.
  • the compound of formula I described in the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition has a low onset dose, good patient tolerance, and small side effects (for example, little impact on the respiratory system and central nervous system, etc.), Few adverse events; no obvious accumulation in the body; excellent exposure level. It shows that the compound of formula I of the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition has good pharmaceutical value.
  • the compound of formula I can be prepared by referring to the method disclosed in Example 14 of WO2019037761A1.
  • the Mobility shift assay method was used to detect the effect of the compound of formula I on the levels of TRKA, TRKB and TRKC kinases, as well as TRKA G595R , TRKA G667C and TRKC G623R kinases (the kinases were from Sandia Pharmaceutical Technology (Shanghai) Co., Ltd.).
  • the inhibition rate was calculated according to the measured fluorescence value and the IC 50 was obtained. The specific values are shown in Table 1.
  • KM12 tumor cells inoculate 7200 KM12 tumor cells per well in a 96-well transparent culture plate, compound of formula I (0.7812-200 ⁇ M, 2-fold dilution, three duplicate wells for each concentration) acts on the cells for 72 hours, discard the culture medium, Add pre-cooled 10% trichloroacetic acid (TCA) solution to each well to fix the cells, place in a refrigerator at 4°C for 2 hours, wash each well of the culture plate with deionized water 5 times to remove the TCA solution, and dry each well Add the SRB solution (4mg/mL) prepared by 1% acetic acid, let it stand at room temperature for 20 minutes, discard the liquid in each well and wash it with 1% acetic acid for 5 times, wash the unbound SRB dye and air-dry it, add appropriate amount to each well Volume of 10mM Tris-base (trishydroxymethylaminomethane) solution was dissolved, and after complete dissolution, the absorbance OD value was measured at a wavelength of 515nm with
  • CD74-NTRK1 G595R /3T3 tumor cells inoculate 3600/well CD74-NTRK1 G595R /3T3 tumor cells in a 96-well transparent culture plate, compound of formula I (0.3125-20 ⁇ M, 2-fold dilution, three replicate wells for each concentration) After acting on the cells for 72 h, the culture medium was discarded, and pre-cooled 10% trichloroacetic acid (TCA) solution was added to each well to fix the cells, and placed in a refrigerator at 4°C for 2 h, and each well of the culture plate was washed 5 times with deionized water, and Remove the trichloroacetic acid solution, add SRB solution (4mg/mL) prepared by 1% acetic acid to each well after drying, place at room temperature for 20 minutes, discard the liquid in each well and wash 5 times with 1% acetic acid to wash away unbound After the SRB dye was air-dried, an appropriate volume of 10 mM Tris-base (tris
  • ETV6-NTRK3 G623R /BaF3 tumor cells Inoculate 3000 ETV6-NTRK3 G623R /BaF3 tumor cells per well in a 96-well transparent culture plate, compound of formula I (0.03125-8nM, 2-fold dilution, three duplicate holes for each concentration) After acting on the cells for 72 hours, add the prepared 5 mg/mL MTT solution 4 hours before acting on the cells for 72 hours, continue to incubate for 4 hours, centrifuge at 1500 rpm for 5 minutes, discard the supernatant, add 200 ⁇ L DMSO to each well, and shake to dissolve Afterwards, the absorbance OD value was measured at a wavelength of 570 nm with a microplate reader.
  • ETV6-NTRK3 G623R /BaF3 cells are suspension cells, IC 50 is determined by MTT method
  • Table 2 formula I compound is to the proliferation inhibitory effect of TRK high expression cell line
  • CD74-NTRK1 G595R /3T3 cells were planted in 6-well culture plates and cultured in a 37°C, 5% CO 2 incubator.
  • the cells were treated with compounds of formula I at concentrations of 1.25 ⁇ M, 2.5 ⁇ M, and 5 ⁇ M for 24 hours and 48 hours, the cells were digested and collected, and protein samples were lysed to prepare protein samples.
  • the expression levels of proteins TRK, PLC ⁇ 1, AKT and Erk were detected by Western Blot. The results show that the compound of formula I can inhibit the activation of TRK receptor and its downstream PLC ⁇ 1, AKT and Erk signaling pathways at 24 and 48 hours, and inhibit the level of its phosphorylated protein, thereby exerting the effect of inhibiting tumor cell proliferation.
  • Embodiment 3 experiment in vivo
  • KM12 cells 5 ⁇ 10 6 human colon cancer cells KM12 were injected into the left armpit of SPF-grade female nude mice (Jiangsu Jicui Yaokang Biotechnology Co., Ltd.). After the tumor grew to an average volume of about 100 mm 3 , the animals were pressed The tumor volume was randomized and then administered. 3 mg/kg, 10 mg/kg, and 30 mg/kg of the compound of formula I were administered orally, once a day, and the tumor volume was weighed and measured twice a week. The administration cycle was 11 days, and the body weight and tumor volume were measured on the 12th day After the volume, the relative tumor volume (RTV) and relative tumor proliferation rate (T/C) were calculated. On the 12th day, the mice were sacrificed, the tumor was dissected, the tumor weight was weighed, and the inhibition rate (IR) was calculated for statistical analysis. .
  • RTV relative tumor volume
  • T/C relative tumor proliferation rate
  • CD74-NTRK1 G595R /3T3 Inject 5 ⁇ 106 mouse embryonic fibroblasts CD74-NTRK1 G595R /3T3 into the left armpit of SPF female nude mice (Jiangsu Jicui Yaokang Biotechnology Co., Ltd.), and treat the tumor After growing to an average volume of 50-100 mm 3 , animals were randomly divided into groups according to tumor volume and administered. Oral administration of 0.8mg/kg, 2.4mg/kg, 8mg/kg of the compound of formula I, 2 times a day; oral administration of 2mg/kg of the compound of formula I, once a day; weekly weighing and measurement of tumor volume 2 times , the administration cycle was 8 days or 20 days.
  • the relative tumor volume (RTV) and relative tumor proliferation rate (T/C) were calculated, and on the 8th or 21st day.
  • the mice were sacrificed, the tumors were dissected, the tumor weights were weighed, and the IR was calculated for statistical analysis.
  • ETV6-NTRK3 G623R /BaF3 Inject 5 ⁇ 106 mouse primary B cells ETV6-NTRK3 G623R /BaF3 into the left armpit of nude mice (Jiangsu Jicui Yaokang Biotechnology Co., Ltd.), and wait until the tumor grows to the average volume After about 100 mm 3 , the animals were randomly divided into groups according to the tumor volume and administered.
  • RTV relative tumor volume
  • T/C relative tumor proliferation rate
  • T/C relative tumor proliferation rate
  • IR tumor inhibition percentage
  • Embodiment 4 clinical trials
  • Compound of formula I strength 2.5mg, 5mg and 10mg, tablet.
  • the expected survival period is more than 3 months
  • a) Blood routine examination (no blood transfusion and no hematopoietic stimulating factor drugs corrected within 7 days before screening): a) hemoglobin (HGB) ⁇ 80g/L; neutrophil count (NEUT) ⁇ 1.5 ⁇ 10 9 /L; Platelet count (PLT) ⁇ 90 ⁇ 10 9 /L;
  • ALT alanine aminotransferase
  • AST aspartate aminotransferase
  • TBIL total bilirubin
  • CRE creatinine
  • Coagulation function activated partial thrombin time (APTT), international normalized ratio (INR), prothrombin time (PT) ⁇ 1.5 ⁇ ULN;
  • the compound tablet of formula I, qd is administered under fasting conditions (not taking food within one hour after administration), and the time of each administration should be roughly similar.
  • Indicators include ORR, DCR, PFS, DOR, SD, PR, CR, etc.
  • the objective response rate (ORR) was 57% (4/7), 4 patients had partial response (PR), 2 patients had stable disease (SD), and the disease control rate (DCR) was 85.7% (6/7 ).
  • the treatment regimens of the present disclosure were found to have clinical benefit.
  • This product is a molecule proposed by Suzhou Taolue Biotechnology for the treatment of advanced malignant solid tumors with NTRK gene fusion.
  • This product is a molecule proposed by Simcere Pharmaceutical Group Co., Ltd. for the treatment of solid tumors.
  • each medication cycle is 28-32 days, for example, C6 represents 6 cycles of medication, each cycle is 28-32 days.
  • d represents the best curative effect that has been monitored so far.

Abstract

含有氨基的大环化合物在治疗TRK激酶介导的肿瘤中的用途。具体而言，涉及(13E,14E,22R,24S)-12-氨基-24,35-二氟-4-氧杂-7-氮杂-1(5,3)-吡唑并[1,5-a]嘧啶-3(3,2)-吡啶-2(1,2)-吡咯烷环辛蕃-8-酮或其药学上可接受的盐在治疗TRK激酶介导的肿瘤中的用途。

Description

含有氨基的大环化合物在治疗TRK激酶介导的肿瘤中的用途
相关申请的引用
本申请要求于2021年08月23日向中华人民共和国国家知识产权局提交的第202110967771.8号中国专利申请的优先权和权益，在此将其全部内容以援引的方式整体并入文本中。
技术领域
本申请属于医药领域，涉及含有氨基的大环化合物在治疗TRK激酶介导的肿瘤中的用途。具体而言，涉及化合物(1 3E,1 4E,2 2R,2 4S)-1 2-氨基-2 4,3 5-二氟-4-氧杂-7-氮杂-1(5,3)-吡唑并[1,5-a]嘧啶-3(3,2)-吡啶-2(1,2)-吡咯烷环辛蕃-8-酮或其可药用盐在治疗TRK激酶介导的肿瘤中的用途。
背景技术
TRK是一类神经生长因子激活的酪氨酸激酶家族，包括TRKA、TRKB和TRKC 3个亚型，分别由NTRK1(neurotrophic receptor tyrosine kinase 1)、NTRK2和NTRK3基因编码。完整的TRK激酶包括胞外区、跨膜区和胞内区三个部分。TRK激酶的胞外受体区与相应的配体结合之后，能够引起激酶构型变化，形成二聚体，胞内激酶区发生自体磷酸化从而激活自身的激酶活性，进而进一步激活下游的信号转导通路(如MAPK，AKT，PKC等)，产生相应的生物学功能；其中，NGF(神经生长因子)结合TRKA，BDNF(衍生的神经营养因子)结合TRKB，NT3(神经营养因子3)结合TRKC。
TRK激酶在神经的发育过程中发挥重要的生理功能，包括神经元轴突的生长与功能维持、记忆的发生发展以及保护神经元免受伤害等等。同时，大量的研究表明TRK信号转导通路的活化与肿瘤的发生发展也有很强的相关性，在神经细胞瘤、***癌、乳腺癌等中都发现了活化的TRK信号蛋白。近几年来多种TRK融合蛋白的发现，更显示了其促进肿瘤发生的生物学功能。最早的TPM3-TRKA融合蛋白是在结肠癌细胞中发现的，在检测的临床病人中约有1.5％的发生率。后来在不同类型的临床肿瘤病人样本如肺癌、头颈癌、乳腺癌、甲状腺癌、神经胶质瘤等中发现了不同类型的TRK融合蛋白，如CD74-NTRK1、MPRIP-NTRK1、QKI-NTRK2、ETV6-NTRK3、BTB1-NTRK3等。这些不同的TRK融合蛋白在不需要配体结合的情况下，自身处于高度活化的激酶活性状态，因而能够持续性的磷酸化下游的信号途径，诱导细胞增殖，促进肿瘤的发生、发展。因此，近几年来，TRK融合蛋白已经成为一个有效的抗癌靶点和研究热点。
WO2019037761A1公开了含有氨基吡唑并嘧啶的大环化合物例如(1 3E,1 4E,2 2R,2 4S)-1 2-氨基-2 4,3 5-二氟-4-氧杂-7-氮杂-1(5,3)-吡唑并[1,5-a]嘧啶-3(3,2)-吡啶-2(1,2)-吡咯烷环辛蕃-8-酮(式I化合物)，其具有TRK激酶抑制活性，可用于治疗TRK激酶介导的疾病。
发明内容
一方面，本申请提供治疗TRK激酶介导的肿瘤的方法，其包括向受试者施用有效量的式I化合物或其可药用盐、或其药物组合物
Figure PCTCN2022114215-appb-000001
在一些实施方式中，本申请提供治疗TRK激酶介导的肿瘤的方法，其包括向受试者施用治疗有效量的式I化合物或其可药用盐、或其药物组合物。
另一方面，本申请提供了式I化合物或其可药用盐、或其药物组合物在制备用于治疗TRK激酶介导的肿瘤的药物中的用途。本申请还提供用于治疗TRK激酶介导的肿瘤的式I化合物或其可药用盐、或其药物组合物。本申请还提供本申请的式I化合物或其可药用盐、或其药物组合物用于治疗TRK激酶介导的肿瘤的用途。
在一些实施方案中，本申请提供了式I化合物或其可药用盐、或其药物组合物在制备用于治疗TRK激酶介导的肿瘤的药物中的用途，其中，所述药物包含，以式I化合物重量计，0.5-100mg的式I化合物或其可药用盐或其药物组合物。
在一些实施方案中，本申请式I化合物、或其可药用盐是作为单一活性剂使用。
在一些实施方案中，本申请的式I化合物或其可药用盐以单剂量或每日剂量0.5-100mg(以式I化合物重量计)作为单一活性剂使用。
在一些实施方案中，本申请的式I化合物或其可药用盐以单剂量或每日剂量0.5-100mg(以式I化合物重量计)使用。
在一些实施方案中，本申请所述药物组合物包含0.5-100mg(以式I化合物重量计)的式I化合物或其可药用盐作为单一活性剂。
在一些实施方案中，所述药物组合物包含式I化合物或其可药用盐，还含有药学上可接受的辅料。
在一些实施方案中，本申请提供了治疗TRK激酶介导的肿瘤的方法，其包括向受试者(例如灵长类动物、优选人)每日施用0.5-100mg的式I化合物或其可药用盐、或其药物组合物(以式I化合物重量计)。
在一些实施方案中，本申请还提供了用于治疗TRK激酶介导的肿瘤的试剂盒，其中包含：含有式I化合物或其可药用盐作为活性成分的药物组合物；任选地，还包括式I化合物或其可药用盐的药物组合物的使用说明。在一些实施方案中，所述药物组合物为包含0.5-100mg的式I化合物或其可药用盐(以式I化合物重量计)作为活性成分的单剂量药物组合物。
在一些实施方案中，本申请提供的***的方法包括：
1)将对象中的肿瘤鉴定为由TRK激酶介导的肿瘤；以及；
2)给予所鉴定的对象治疗有效量的式I化合物或其可药用盐、或其药物组合物。
在一些实施方案中，所述对象为灵长类动物、优选人。
在一些实施方案中，所述肿瘤由TRKA、和/或TRKB、和/或TRKC介导。
在一些实施方案中，所述肿瘤由野生型(非突变型)或者突变型的TRK介导。在一些实施方案中，所述肿瘤由野生型(非突变型)或者突变型TRKA、和/或TRKB、和/或TRKC介导。
在一些实施方案中，所述肿瘤由包含G667C、G595R或G623R的突变型TRK介导。
在一些实施方案中，所述肿瘤由包含G667C或G595R的突变型TRKA、和/或TRKB、和/或含G623R的突变型TRKC介导。
在一些实施方案中，所述突变型选自TRKA G595R、TRKA G667C或TRKC G623R。
在一些实施方案中，所述肿瘤选自具有TRK融合蛋白的肿瘤。在一些实施方案中，所述TRK激酶介导的肿瘤选自具有非突变型或突变型TRK融合蛋白的肿瘤。在一些实施方案中，所述TRK融合蛋白选自非突变型或突变型的TRKA融合蛋白、和/或TRKB融合蛋白、和/或TRKC融合蛋白。在一些实施方案中，所述TRK融合蛋白选自非突变型的TRKA融合蛋白、和/或TRKB融合蛋白、和/或TRKC融合蛋白。在一些实施方案中，所述TRK融合蛋白选自突变型的TRKA融合蛋白、和/或TRKB融合蛋白、和/或TRKC融合蛋白。
在一些实施方案中，所述肿瘤选自具有NTRK融合基因的肿瘤。在一些实施方式中，所述NTRK融合基因选自非突变型或突变型NTRK融合基因。在一些实施方案中，所述NTRK融合基因选自NTRK1融合基因、NTRK2融合基因和NTRK3融合基因。在一些实施方案中，所述NTRK融合基因选自非突变型或突变型的NTRK1融合基因、和/或NTRK2融合基因、和/或NTRK3融合基因。在一些实施方案中，所述NTRK融合基因选自非突变型或突变型的NTRK1融合基因。在一些实施方案中，所述NTRK融合基因选自非突变型或突变型的NTRK2融合基因。在一些实施方案中，所述NTRK融合基因选自非突变型或突变型的NTRK3融合基因。在一些实施方案中，所述NTRK融合基因选自非突变型的NTRK1融合基因、和/或NTRK2融合基因、和/或NTRK3融合基因。在一些实施方案中，所述NTRK融合基因选自突变型的NTRK1融合基因、和/或NTRK2融合基因、和/或NTRK3融合基因。在一些实施方案中，所述NTRK融 合基因可以是TPM3-NTRK1融合基因、ETV6-NTRK3融合基因和/或CD74-NTRK1融合基因。在一些实施方案中，所述NTRK融合基因可以是ETV6-NTRK3融合基因。
在一些实施方案中，所述肿瘤中，NTRK融合基因可表达TRK融合蛋白。
在一些实施方案中，所述肿瘤中，NTRK融合基因可表达野生型(即非突变型)或突变型TRK融合蛋白。
在一些实施方案中，所述肿瘤中，NTRK1融合基因可表达野生型(即非突变型)或突变型TRKA融合蛋白。
在一些实施方案中，所述肿瘤中，NTRK2融合基因可表达野生型(即非突变型)或突变型TRKB融合蛋白。
在一些实施方案中，所述肿瘤中，NTRK3融合基因可表达野生型(即非突变型)或突变型TRKC融合蛋白。
在一些实施方案中，所述肿瘤中，NTRK1融合基因可表达野生型(即非突变型)或突变型TRKA融合蛋白；和/或NTRK2融合基因可表达野生型(即非突变型)或突变型TRKB融合蛋白；和/或NTRK3融合基因可表达野生型(即非突变型)或突变型TRKC融合蛋白。
在一些实施方案中，所述突变型NTRK融合基因选自具有NTRK1 G595R、NTRK1 G667C和/或NTRK3 G623R的融合基因。
在一些实施方案中，所述突变型NTRK融合基因选自CD74-NTRK1 G667C融合基因和/或ETV6-NTRK3 G623R融合基因。在一些实施方案中，所述突变型NTRK融合基因选自ETV6-NTRK3 G623R融合基因。
在一些实施方案中，所述NTRK1融合基因选自非突变型TPM3-NTRK1融合基因、非突变型CD74-NTRK1融合基因、或具有NTRK1 G595R和/或NTRK1 G667C的突变型NTRK1融合基因(例如，具有NTRK1 G595R和/或NTRK1 G667C的TPM3-NTRK1融合基因或CD74-NTRK1融合基因)。在一些实施方案中，所述NTRK1融合基因选自非突变型TPM3-NTRK1融合基因、具有NTRK1 G595R的突变型NTRK1融合基因、非突变型CD74-NTRK1融合基因、或CD74-NTRK1 G667C融合基因。
在一些实施方案中，所述NTRK3融合基因选自非突变型ETV6-NTRK3融合基因、或具有NTRK3 G623R的突变型NTRK3融合基因(例如具有NTRK3 G623R的ETV6-NTRK3融合基因)。在一些实施方案中，所述NTRK3融合基因选自非突变型ETV6-NTRK3融合基因、或ETV6-NTRK3 G623R融合基因。
在一些实施方案中，本申请提供的***的方法包括：
1)对从受试者获得的肿瘤样品进行测定，以确定受试者是否具有NTRK融合基因或/和TRK融合蛋白；以及
2)向具有NTRK融合基因或/和TRK融合蛋白的受试者施用治疗有效量的式I化合物或其可药用盐、或其药物组合物。
在一些实施方式中，所述NTRK融合基因选自非突变型或突变型NTRK融合基因。在一些实施方式中，所述NTRK融合基因选自NTRK1融合基因、NTRK2融合基因、和/或NTRK3融合基因。在一些实施方式中，所述NTRK融合基因选自NTRK1融合基因。在一些实施方式中，所述NTRK融合基因选自NTRK2融合基因。在一些实施方式中，所述NTRK融合基因选自NTRK3融合基因。在一些实施方式中，所述NTRK融合基因选自非突变型NTRK融合基因。在一些实施方式中，所述NTRK融合基因选自突变型NTRK融合基因。在一些实施方案中，所述NTRK融合基因的突变选自获得性突变或非获得性突变。在一些实施方案中，所述突变型NTRK融合基因选自耐药突变型NTRK融合基因。在一些实施方式中，所述NTRK融合基因选自NTRK1融合基因、NTRK2融合基因、和/或NTRK3融合基因。在一些实施方式中，所述NTRK融合基因选自突变型NTRK1融合基因、NTRK2融合基因、和/或NTRK3融合基因。
在一些实施方案中，所述NTRK融合基因可选自非突变型或突变型TPM3-NTRK1融合基因、ETV6-NTRK3融合基因或CD74-NTRK1融合基因。
在一些实施方案中，所述NTRK融合基因可选自TPM3-NTRK1融合基因、ETV6-NTRK3融合基因或CD74-NTRK1融合基因。
在一些实施方案中，所述NTRK融合基因可以是ETV6-NTRK3。
在一些实施方案中，所述突变型NTRK融合基因选自具有NTRK1 G595R、NTRK1 G667C或NTRK3 G623R的融合基因。在一些实施方案中，所述突变型NTRK融合基因选自具有NTRK3 G623R的融合基因。
在一些实施方式中，所述TRK融合蛋白选自野生型(即非突变型)或突变型TRK融合蛋白。在一些实施方式中，所述TRK融合蛋白选自TRKA融合蛋白、TRKB融合蛋白、和/或TRKC融合蛋白。在一些实施方式中，所述TRK融合蛋白选自野生型(即非突变型)或突变型TRKA融合蛋白、野生型(即非突变型)或突变型TRKB融合蛋白、和/或野生型(即非突变型)或突变型TRKC融合蛋白。
在一些实施方案中，所述突变型TRK融合蛋白选自具有G595R和/或G667C的突变型TRKA或具有G623R的突变型TRKC。在一些实施方案中，所述突变型TRK融合蛋白选自具有G595R的突变型TRKA、具有G667C的突变型TRKA或具有G623R的突变型TRKC。
在一些实施方案中，所述突变型TRK融合蛋白选自TRKA G595R、TRKA G667C或TRKC G623R。
在一些实施方案中，所述突变型TRK融合蛋白的突变选自获得性突变或非获得性突变。在一些实施方案中，所述突变型TRK融合蛋白选自耐药突变型TRK融合蛋白。在一些实施方案中，所述突变型TRK融合蛋白选自获得性耐药突变型TRK融合蛋白。
在一些实施方案中，本申请所述的融合基因可含有NTRK基因点突变或不含有NTRK基因点突变。在一些实施方案中，本申请所述的融合基因可含有NTRK基因点突变。在一些实施方案中，本申请所述的融合基因可不含有NTRK基因点突变。
在一些实施方案中，本申请所述的肿瘤可来自携带NTRK1、NTRK2或NTRK3基因融合且不含NTRK基因点突变的受试者和/或患者。在一些实施方案中，本申请所述的肿瘤可来自携带NTRK1、NTRK2或NTRK3基因融合且含NTRK基因点突变的受试者和/或患者。
在一些实施方案中，本申请提供的方法包括在施用式I化合物或其可药用盐、或其药物组合物之前进行形态学诊断、或分子测试，或两者的组合。
在一些实施方案中，本申请提供的方法包括对从受试者获得的肿瘤样品进行测定，以确定受试者具有NTRK融合基因、TRK蛋白、或其表达或水平的失调。
在一些实施方案中，本申请提供的方法包括对从受试者获得的肿瘤样品进行测定，以确定受试者具有NTRK融合基因或/和TRK融合蛋白。
在一些实施方案中，所述测定的方法选自以下方法中的一种或多种：变性梯度凝胶电泳(DGGE)、温度梯度凝胶电泳(TGGE)、温度梯度毛细管电泳、单链构象多态性测定、分子信标测定、动态杂交测定、基于PCR的测定或变性高效液相色谱。
在一些实施方案中，本申请所述突变型选自G595R、G667C或G623R型突变。在一些实施方案中，所述突变型选自G595R型突变。在一些实施方案中，所述突变型选自G667C型突变。在一些实施方案中，所述突变型选自G623R型突变。
在一些实施方案中，本申请所述的融合基因选自非突变型或突变型NTRK1、NTRK2或NTRK3基因融合。在一些实施方案中，本申请所述的融合基因选自非突变型或突变型NTRK1基因融合。在一些实施方案中，本申请所述的融合基因选自非突变型或突变型NTRK2基因融合。在一些实施方案中，本申请所述的融合基因选自非突变型或突变型NTRK3基因融合。
在一些实施方案中，本申请所述的NTRK融合基因可选自非突变型或突变型TPM3-NTRK1、ETV6-NTRK3或CD74-NTRK1。在一些实施方案中，本申请所述的NTRK融合基因可选自非突变型或突变型TPM3-NTRK1。在一些实施方案中，本申请所述的NTRK融合基因可选自非突变型或突变型ETV6-NTRK3。在一些实施方案中，本申请所述的NTRK融合基因可选自非突变型或突变型CD74-NTRK1。
在一些实施方案中，所述式I化合物或其可药用盐、或其药物组合物每次施用0.0001mg/kg到20mg/kg重量(以式I化合物重量计算)。
在一些实施方案中，所述式I化合物或其可药用盐、或其药物组合物每次施用0.5-100mg、0.5-25mg或2.5-25mg(以式I化合物重量计算)。在一些实施方案中，所述式I化合物或其可药用盐、或其药物组合物每次施用0.5-20mg(以式I化合物重量计算)。在一些实施方案中，所述式I化合物或其可药用盐、或其药物组合物每次施用0.5-15mg(以式I化合物重量计算)。在一些实施方案中，所述式I化合物或其可药用盐、或其药物组合物每次施用2.5-10mg(以式I化合物重量计算)。在一些实施方案中，所述式I化合物或其可药用盐、或其药物组合物每次施用5-10mg(以式I化合物重量计算)。
在一些实施方案中，所述式I化合物或其可药用盐、或其药物组合物的每日剂量(以式I化合物重量计)选自0.5-100mg、0.5-25mg或2.5-25mg。在一些方案中，所述式I化合物或其可药用盐、或其药物组合物的每日剂量(以式I化合物重量计)选自0.5mg、或1mg、或1.5mg、或2mg、或2.5mg、或3mg、或3.5mg、或4mg、或4.5mg、或5mg、或5.5mg、或6mg、或6.5mg、或7mg、或7.5mg、或8mg、或8.5mg、或9mg、或9.5mg、或10mg、或10.5mg、或11mg、或11.5mg、或12mg、或12.5mg、或13mg、或13.5mg、或14mg、或14.5mg、或15mg、或15.5mg、或16mg、或16.5mg、或17mg、或17.5mg、或18mg、或18.5mg、或19mg、或19.5mg、或20mg、或20.5mg、或21mg、或21.5mg、或22mg、或22.5mg、或23mg、或23.5mg、或24mg、或24.5mg、或25mg、或25.5mg、或26mg、或26.5mg、或27mg、或27.5mg、或28mg、或28.5mg、或29mg、或29.5mg、或30mg、或30.5mg、或31mg、或31.5mg、或32mg、或32.5mg、或33mg、或33.5mg、或34mg、或34.5mg、或35mg、或35.5mg、或36mg、或36.5mg、或37mg、或37.5mg、或38mg、或38.5mg、或39mg、或39.5mg、或40mg、或42.5mg、或45mg、或47.5mg、或50mg、或52.5mg、或55mg、或57.5mg、或60mg、或62.5mg、或65mg、或67.5mg、或70mg、或72.5mg、或75mg、或77.5mg、或80mg、或82.5mg、或85mg、或87.5mg、或90mg、或92.5mg、或95mg、或97.5mg、或100mg或上述任意值形成的范围。在一些方案中，所述式I化合物或其可药用盐、或其药物组合物的每日剂量(以式I化合物重量计)选自0.5mg-20mg。在一些方案中，所述式I化合物或其可药用盐、或其药物组合物的每日剂量(以式I化合物重量计)选自0.5mg-15mg。在一些方案中，所述式I化合物或其可药用盐、或其药物组合物的每日剂量(以式I化合物重量计)选自2.5mg-10mg。在一些方案中，所述式I化合物或其可药用盐、或其药物组合物的每日剂量(以式I化合物重量计)选自5mg-10mg。在一些实施方案中，所述式I化合物或其可药用盐、或其药物组合物的给药频率可以是每日3次、每日2次、每日1次、每两日1次、每三日1次、每四日1次、每五天1次、每六天1次、每一周3次、每一周2次、每一周1次、每两周1次、或每三周1次。在一些实施方案中，所述式I化合物或其可药用盐、或其药物组合物的给药频率可以是每日1次。在一些实施方案中，所述式I化合物或其可药用盐、或其药物组合物的给药频率可以是每日2次。
在本申请的一些实施方案中，所述式I化合物或其可药用盐、或其药物组合物每次施用2-20mg规格剂量，例如2.5mg、5mg或10mg规格剂量(以式I化合物重量计算)。
在本申请的一些实施方案中，所述式I化合物或其可药用盐、或其药物组合物每次施用0.0001到20mg/kg重量(以式I化合物重量计算)。
在一些实施方案中，所述给予式I化合物或其可药用盐、或其药物组合物的给药周期是1-6个周期。在一些实施方案中，所述给予式I化合物或其可药用盐、或其药物组合物的给药周期是1、2、3、4、5、6个周期或上述任意值形成的范围。在一些实施方案中，以8-32天为1个给药周期，例如，以8-28天、8-21天、8-15天、15-28天、15-21天、21-28天、21-32天、28-32天、8天、9天、10天、11天、12天、13天、14天、15天、16天、17天、18天、19天、20天、21天、22天、23天、24天、25天、26天、27天、28天、29天、30天、31天、或32天为1个给药周期。在一些实施方案中，以28天或32天为1个给药周期。在一些实施方案中，以28-32天为1个给药周期。
在一些实施方案中，向受试者施用有效量的本申请的式I化合物或其可药用盐、或其药物组合物为连续施用。
在一些实施方案中，所述式I化合物或其可药用盐、或其药物组合物以单剂量或多剂量形式给药。
在一些实施方案中，所述受试者选自经病理和/或细胞学明确诊断的晚期恶性实体肿瘤受试者，和/或缺乏常规的有效治疗方法或常规方法治疗后失败或复发的受试者。
在一些实施方案中，所述肿瘤选自既往有或无治疗史的肿瘤患者。在一些实施方案中，所述肿瘤选自既往有治疗史的肿瘤患者。
在一些实施方案中，所述受试者选自既往接受过或未接受过TRK抑制剂治疗的受试者。
在一些实施方案中，所述受试者选自既往接受过一种或多种TRK抑制剂治疗的受试者。
在一些实施方案中，所述TRK抑制剂选自拉罗替尼、TL118和/或SIM1803。
在一些实施方案中，所述受试者选自既往未接受过TRK抑制剂治疗的受试者。
在一些实施方案中，上述肿瘤选自实体瘤。
在一些实施方案中，上述肿瘤选自晚期恶性实体瘤。
在一些实施方案中，上述肿瘤选自成人晚期恶性实体瘤。
在一些实施方案中，上述肿瘤选自胶质瘤、中枢神经***肿瘤、肉瘤、外周原始神经外胚层肿瘤、维尔姆斯肿瘤、肺癌、甲状腺癌、结直肠癌、唾液腺癌、胆道癌、脑癌、乳腺癌、乳腺导管癌、头颈癌、细胞癌、胰腺癌、男女生殖***肿瘤、肾癌、胆管癌、胃癌、支气管癌、胸腔癌、神经内分泌瘤、淋巴瘤或黑色素瘤。
在一些实施方案中，上述肿瘤选自软组织肉瘤、唾液腺瘤、甲状腺癌、肺癌、黑色素瘤、结直肠癌、胃癌、间质瘤、胆管癌、乳腺癌或胰腺癌。
在一些实施方案中，上述肿瘤选自肺癌、腺癌或口腔癌。在一些实施方案中，上述肺癌选自肺腺癌；所述腺癌选自腮腺癌或肺腺癌；所述口腔癌选自口底癌。
在一些实施方案中，上述肿瘤选自肺腺癌、腮腺癌、口底癌、腺泡细胞癌或肠癌。
式I化合物或其可药用盐、或其药物组合物
本申请式I化合物可以以其游离碱形式给药，也可以以其可药用盐、水合物和前药的形式给药，该前药可在体内转换成式I化合物的游离碱形式。
在一些实施方案中，所述式I化合物或其可药用盐的药物组合物选自固体药物组合物，优选片剂或胶囊。
在一些实施方案中，所述式I化合物或其可药用盐呈药物组合物形式，其中，以式I化合物的重量计，所述药物组合物为单剂量为0.5-100mg、优选0.5mg-25mg的药物组合物，优选自单剂量为0.5mg、1mg、1.5mg、2mg、2.5mg、3mg、3.5mg、4mg、4.5mg、5mg、5.5mg、6mg、6.5mg、7mg、7.5mg、8mg、8.5mg、9mg、9.5mg、10mg、10.5mg、11mg、11.5mg、12mg、12.5mg、13mg、13.5mg、14mg、14.5mg、15mg、15.5mg、16mg、16.5mg、17mg、17.5mg、18mg、18.5mg、19mg、19.5mg、20mg、20.5mg、21mg、21.5mg、22mg、22.5mg、23mg、23.5mg、24mg、24.5mg、25mg或上述任意值形成的范围的药物组合物。
在一些实施方案中，本申请的药物组合物通过口服给药。
在一些实施方案中，本申请的各药物组合物为固体药物组合物。
在一些实施方案中，本申请的固体药物组合物的制剂形式为片剂。
定义和说明
除非另有说明，本申请中所用的下列术语具有下列含义。一个特定的术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照本领域普通的含义去理解。
对于TRKA、TRKB和TRKC，其分别由基因NTRK1、NTRK2和NTRK3编码。
术语“施用”或“给予”或“给药”表示，使用本领域技术人员已知的多种方法和递送***中的任一种，向主体物理引入治疗剂或包含治疗剂的组合物。术语“施用”或“给予”或“给药”在本文中可互换使用。
术语“治疗”一般是指获得需要的药理和/或生理效应。该效应根据部分或完全稳定或治愈疾病和/或由于疾病产生的副作用，可以是治疗性的。本文使用的“治疗”涵盖了对患者疾病的任何治疗，包括：(a)抑制疾病的症状，即阻止其发展；或(b)缓解疾病的症状，即，导致疾病或症状退化。
术语“有效量”意指(i)治疗或预防特定疾病、病况或障碍，(ii)减轻、改善或消除特定疾病、病况或障碍的一种或多种症状，或(iii)预防或延迟本文中所述的特定疾病、病况或障碍的一种或多种症状发作的本申请化合物的用量。构成“治疗有效量”的本申请化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。
术语“受试者”、“患者”或“对象”在本文中科互换使用，是指已成为治疗、观察或实验对象的动物，优选哺乳动物，优选灵长类动物，包括人和非人灵长类动物(如猿、猴、猩猩和黑猩猩，如食蟹猴、蜘蛛猴和猕猴，如恒河猴)，最优选人。在一些实施方式中，受试者已经历和/或表现出待治疗和/或预防的疾病或病症的至少一种症状。术语“个体”可为哺乳动物，优选灵长类动物，最优选人。
如本申请所用，所述式I化合物或其可药用盐可以通过任何适用的途径和方法给药，例如通过口服或肠胃外(例如，静脉内)给药。
术语“约”应理解为包括在平均值的三个标准偏差内或特定领域中的标准公差范围内。在某些实施方式中，约应理解为不超过0.5的变异。“约”修饰其后所有列举的值。例如，“约1、2、3”表示“约1”、“约2”、“约3”。
术语“药物组合物”是指一种或多种本申请的化合物或其药物组合或其盐与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对受试者给予本申请的化合物或其药物组合。
术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。
本申请的药物组合物可通过将本申请的化合物与适宜的药学上可接受的辅料组合而制备，例如可配制成固态制剂，如片剂、丸剂、胶囊剂等。
本申请的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。
术语“药学上可接受的”是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
可以通过常规的混合、填充或压片方法来制备固体口服药物组合物。例如，可通过下述方法获得：将所述的活性化合物与固体辅料混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅料，然后将该混合物加工成颗粒，得到了片剂或胶囊或糖衣剂的核心。适合的辅料包括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。
术语“药学上可接受的盐”或“可药用盐”是指在“药学上可接受的”的定义范围内的本申请的化合物的盐。
除非另外特别说明，否则单数术语涵盖复数术语，并且复数术语涵盖单数术语。除非另外特别说明，否则词语“一个”或“一种”意指“至少一个”或“至少一种”。除非另外说明，否则“或”的使用意指“和/或”。
在本文中，除非另有说明，否则术语“包含、包括和含有”或等同物为开放式表述，意味着除所列出的要素、组分和步骤外，还可涵盖其它未指明的要素、组分和步骤。
如本申请所用，除非另有指明，“以重量计”指以式I化合物的游离形式的重量计。
术语“单剂量”是指含有一定量药品的最小包装单元，例如一盒药有七粒胶囊，则每个胶囊为单剂量；或者每瓶注射液为单剂量。术语“多剂量”由多个单剂量组成。
为了描述和公开的目的，以引用的方式将所有的专利、专利申请和其它已确定的出版物在此明确地并入本文。这些出版物仅因为它们的公开早于本申请的申请日而提供。所有关于这些文件的日期的声明或这些文件的内容的表述是基于申请者可得的信息，并且不构成任何关于这些文件的日期或这些文件的内容的正确性的承认。而且，在任何国家，在本中对这些出版物的任何引用并不构成关于该出版物成为本领域的公知常识的一部分的认可。
在一个实施方案中，本申请的药物组合可以配制成适合于单次或多次施用的药物组合物。在一个实施方案中，本申请的药物组合可为单剂量或多剂量的药物组合物。
术语“客观缓解率(ORR)”：为肿瘤体积缩小达到预先规定值并能维持最低时限(下次影像评估时)要求的受试者比例，包含完全缓解(CR)和部分缓解(PR)的病例。
术语“疾病控制率(DCR)”：为肿瘤缩小或稳定且保持一定时间的病人的比例，包含CR、PR和疾病稳定(SD)的病例。
术语“无进展生存期(PFS)”：从首次用药开始至疾病进展(PD)或PD前死亡之间的时间；若没有出现PD或PD前死亡，以最后一次影像学评估日期作为截止日期。
术语“缓解持续时间(DOR)”：在CR或PR受试者中，肿瘤第一次评估为CR或PR至PD或PD前死亡之间的时间；若CR或PR的受试者没有出现PD或PD前死亡，以最后一次影像学评估日期作为截止日期。
术语“不良事件(Adverse Event,AE)”指受试者接受试验用药品后出现的所有不良医学事件，可以表现为症状体征、疾病或实验室检查异常，但不一定与试验用药品有因果关系。不良事件性质和严重程度的评价标准遵照美国国立癌症研究所的常见毒性反应标准(NCI-CTC AE v5.0)进行。无法根据此标准进行评估的项目，可按照以下标准评定：
轻度：对病人日常生活只有轻微影响。
中度：明显影响病人日常生活。
重度：导致病人功能障碍或严重干扰日常生活。
术语“OS”：指肿瘤病人的总生存时间。
术语“DFS”：指肿瘤病人的无病生存期。
术语“TTP”：指肿瘤病人的疾病进展时间。
技术效果
本申请的治疗方案，在治疗TRK介导的肿瘤上具有较好的疗效。本申请所述的式I化合物或其可药用盐、或其药物组合物至少在生存疗效评价(例如OS、中位生存期)；在肿瘤反应疗效评价(例如DFS、中位DFS、PFS、TTP、ORR、DCR、DOR)中的至少一个方面具有优异的效果，例如ORR。并且，本申请所述的式I化合物或其可药用盐、或其药物组合物起效剂量低，患者耐受性好，副作用小(例如针对呼吸***和中枢神经***等的影响小)，不良事件少；体内不会有明显蓄积；暴露水平优异。其说明本申请的式I化合物或其可药用盐、或其药物组合物具有良好的药用价值。
具体实施方式
为清楚起见，进一步用实施例来阐述本申请，但是实施例并非限制本申请的范围。本申请所使用的所有试剂是市售的，无需进一步纯化即可使用。
式I化合物可以参考WO2019037761A1中实施例14公开的方法制备获得。
实施例1体外实验
1.1体外激酶活性试验
采用Mobility shift assay方法检测式I化合物对TRKA、TRKB和TRKC激酶、以及TRKA G595R、TRKA G667C、TRKC G623R激酶(激酶来源于桑迪亚医药技术(上海)有限责任公司)水平的影响。激酶活性测定中根据测得荧光值计算抑制率并求得IC 50，具体数值见表1。
表1.式I化合物对激酶活性的影响
Figure PCTCN2022114215-appb-000002
1.2体外细胞活性试验
KM12肿瘤细胞：接种7200个/孔的KM12肿瘤细胞于96孔透明培养板，式I化合物(0.7812-200μM，2倍稀释，每个浓度三个复孔)作用细胞72h后，弃去培养液，每孔加入预冷的10％三氯乙酸(TCA)溶液固定细胞，置于4℃冰箱进行固定2h，培养板各孔以去离子水洗涤5遍，以去除三氯乙酸溶液，干燥后每孔加入1％乙酸配制的SRB溶液(4mg/mL)，室温下放置20分钟，弃去各孔内液体后用1％乙酸洗涤5遍，洗净未结合的SRB染料后空气干燥，每孔加入适当体积的10mM Tris-base(三羟甲基胺基甲烷)溶液进行溶解，完全溶解后，酶标仪515nm波长下测定吸光度OD值。
CD74-NTRK1 G595R/3T3肿瘤细胞：接种3600个/孔的CD74-NTRK1 G595R/3T3肿瘤细胞于96孔透明培养板，式I化合物(0.3125-20μM，2倍稀释，每个浓度三个复孔)作用细胞72h后，弃去培养液，每孔加入预冷的10％三氯乙酸(TCA)溶液固定细胞，置于4℃冰箱进行固定2h，培养板各孔以去离子水洗涤5遍，以去除三氯乙酸溶液，干燥后每孔加入1％乙酸配制的SRB溶液(4mg/mL)，室温下放置20分钟，弃去各孔内液体后用1％乙酸洗涤5遍，洗净未结合的SRB染料后空气干燥，每孔加入适当体积的10mMTris-base(三羟甲基胺基甲烷)溶液进行溶解，完全溶解后，酶标仪515nm波长下测定吸光度OD值。
ETV6-NTRK3 G623R/BaF3肿瘤细胞：接种3000个/孔的ETV6-NTRK3 G623R/BaF3肿瘤细胞于96孔透明培养板，式I化合物(0.03125-8nM，2倍稀释，每个浓度三个复孔)作用细胞72h后，式I化合物作用细胞72h前4h，加入配制好的5mg/mL的MTT溶液，继续共孵育4h后，1500rpm离心5min，弃去上清，每孔加入200μL DMSO，摇床震荡溶解后，酶标仪570nm波长下测定吸光度OD值。
(ETV6-NTRK3 G623R/BaF3细胞为悬浮细胞，采用MTT法测定IC 50)
具体结果见下表2。
表2式I化合物对TRK高表达细胞株的增殖抑制作用
Figure PCTCN2022114215-appb-000003
实施例2式I化合物对TRK激酶及其介导的信号转导通路的影响
本实验应用Western Blot法，采用人工构建的TRK点突变的CD74-NRTK1 G595R/3T3细胞来研究式I化合物对TRK激酶磷酸化水平和下游信号转导通路的影响。
CD74-NTRK1 G595R/3T3细胞于6孔培养板种，置于37℃，5％CO 2培养箱中培养。给予浓度为1.25μM、2.5μM、和5μM的式I化合物处理细胞24h、48h，消化收集细胞，裂解制备蛋白样本，Western Blot法检测蛋白TRK、PLCγ1、AKT和Erk表达水平。结果显示：式I化合物在24、48h能够抑制TRK受体及其下游PLCγ1、AKT和Erk信号通路的活化，抑制其磷酸化蛋白水平，从而发挥抑制肿瘤细胞增殖的作用。
实施例3：体内实验
KM12细胞：将5×10 6个人结肠癌细胞KM12注射至SPF级雌性裸小鼠(江苏集萃药康生物科技有限公司)左侧腋下，待肿瘤生长至平均体积100mm 3左右后，将动物按瘤体积随机分组后给药。灌胃给予 3mg/kg、10mg/kg、30mg/kg的式I化合物，每天1次，每周称重和测量肿瘤体积2次，给药周期11天，于第12天称量体重和测量肿瘤体积后，计算相对肿瘤体积(RTV)和相对肿瘤增殖率(T/C)，于第12天，处死小鼠，剖取肿瘤，称量瘤重，计算抑制率(IR)，做统计学分析。
CD74-NTRK1 G595R/3T3：将5×10 6个小鼠胚胎成纤维细胞CD74-NTRK1 G595R/3T3注射至SPF级雌性裸小鼠(江苏集萃药康生物科技有限公司)左侧腋下，待肿瘤生长至平均体积50-100mm 3后，将动物按瘤体积随机分组后给药。灌胃给予0.8mg/kg、2.4mg/kg、8mg/kg的式I化合物，每天2次；灌胃给予2mg/kg的式I化合物，每天1次；每周称重和测量肿瘤体积2次，给药周期8天或20天，于第8天或21天称量体重和测量肿瘤体积后，计算相对肿瘤体积(RTV)和相对肿瘤增殖率(T/C)，于第8天或21天，处死小鼠，剖取肿瘤，称量瘤重，计算IR，做统计学分析。
ETV6-NTRK3 G623R/BaF3：将5×10 6个小鼠原B细胞ETV6-NTRK3 G623R/BaF3注射至裸小鼠(江苏集萃药康生物科技有限公司)左侧腋下，待肿瘤生长至平均体积100mm 3左右后，将动物按瘤体积随机分组后给药。灌胃给予0.2mg/kg、0.6mg/kg、2mg/kg的式I化合物，每天1次，每周称重和测量肿瘤体积2次，给药周期20天，于第21天称量体重和测量肿瘤体积后，计算相对肿瘤体积(RTV)和相对肿瘤增殖率(T/C)，于第21天，处死小鼠，剖取肿瘤，称量瘤重，计算IR，做统计学分析。
结果显示：式I化合物可剂量依赖性地抑制上述细胞移植瘤的生长，且对裸小鼠体重无明显影响。
表3.式I化合物对体内移植瘤的影响
Figure PCTCN2022114215-appb-000004
T/C：相对肿瘤增殖率；IR：肿瘤抑制百分率。
实施例4临床试验
1.试验药物
式I化合物：规格2.5mg、5mg和10mg，片剂。
2.入组受试者
1)经组织和/或细胞学确诊，标准治疗失败或无法接受标准治疗或缺乏有效治疗方法的晚期恶性肿瘤患者；
2)年龄：18-75周岁(签署知情同意书时)；
3)ECOG评分：0-1分；
4)预计生存期超过3个月；
5)主要器官功能正常，即符合下列标准：
a)血常规检查(筛选前7天内未输血且未使用造血刺激因子类药物纠正)：a)血红蛋白(HGB)≥80g/L；中性粒细胞计数(NEUT)≥1.5×10 9/L；血小板计数(PLT)≥90×10 9/L；
b)生化检查：谷丙转氨酶(ALT)及谷草转氨酶(AST)≤2.5×ULN(原发肝胆肿瘤或肿瘤肝脏转移者：ALT、AST≤5×ULN)；总胆红素(TBIL)≤1.5×ULN(Gilbert综合症患者：TBIL≤3×ULN)；肌酐(CRE)≤1.5×ULN或肌酐清除率≥60mL/min；
c)凝血功能：活化部分凝血酶时间(APTT)、国际标准化比值(INR)、凝血酶原时间(PT)≤1.5×ULN；
d)促甲状腺激素(TSH)≤ULN；如果异常应考察T3和T4水平，T3和T4水平正常则可以入选；
e)左心室射血分数(LVEF)≥50％；
6)育龄期女性患者在研究入组前的7天内血清或尿HCG检查必须为阴性，且必须为非哺乳期；患者应同意在研究期间和研究期结束后6个月内必须采用避孕措施；
7)患者自愿加入本研究，签署知情同意书，依从性好。
3.给药方案
式I化合物片，qd，空腹条件下给药(用药后一小时内不得进食)，每次服药时间应大致相近。
4.有效性指标
指标包括ORR、DCR、PFS、DOR、SD、PR、CR等。
5.试验结果
安全性
AE大多为1级，大部分转归为好转。
不良事件总体发生率低，安全性较好。
有效性
入组的8例患者中，可评估疗效7例。客观缓解率(ORR)为57％(4/7)，部分缓解(PR)的患者为4例，病情稳定(SD)的患者为2例，疾病控制率(DCR)为85.7％(6/7)。结果发现本公开的治疗方案具有临床收益。
代表性病例结果如下表4。
表4
Figure PCTCN2022114215-appb-000005
*表示靶病灶直径之和比基线水平(C0期靶病灶直径之和)减少程度。
a该产品是苏州韬略生物科技拟用于治疗NTRK基因融合的晚期恶性实体瘤的分子。
b该产品是先声药业集团有限公司拟用于治疗实体瘤的分子。
c表示的每一个用药周期为28-32天，例如C6表示用药6个周期，每个周期28-32天。
d表示目前已经监测到的最佳疗效。

Claims (13)

  1. 一种治疗TRK激酶介导的肿瘤的方法，其包括向受试者每日施用0.5-100mg的式I化合物或其可药用盐、或其药物组合物
    Figure PCTCN2022114215-appb-100001
  2. 式I化合物或其可药用盐、或其药物组合物在制备用于治疗TRK激酶介导的肿瘤的药物中的用途，其包括向受试者每日施用0.5-100mg的式I化合物或其可药用盐、或其药物组合物，
    Figure PCTCN2022114215-appb-100002
  3. 用于治疗TRK激酶介导的肿瘤的式I化合物或其可药用盐、或其药物组合物，其包括向受试者每日施用0.5-100mg的式I化合物或其可药用盐、或其药物组合物，
    Figure PCTCN2022114215-appb-100003
  4. 式I化合物或其可药用盐、或其药物组合物用于治疗TRK激酶介导的肿瘤的用途，其包括向受试者每日施用0.5-100mg的式I化合物或其可药用盐、或其药物组合物，
    Figure PCTCN2022114215-appb-100004
  5. 用于治疗TRK激酶介导的肿瘤的试剂盒，其中包含：含有式I化合物或其可药用盐作为活性成分的药物组合物，优选含有0.5-100mg式I化合物或其可药用盐作为活性成分的药物组合物；任选地，还包含式I化合物或其可药用盐的药物组合物的使用说明，
    Figure PCTCN2022114215-appb-100005
  6. 一种***的方法，所述包括:
    1)将对象或受试者中的肿瘤鉴定为由TRK激酶介导的肿瘤；以及
    2)给予所鉴定的对象或受试者治疗有效量的式I化合物或其可药用盐、或其药物组合物，
    Figure PCTCN2022114215-appb-100006
  7. 权利要求1-6任一项所述的方法、用途、化合物或试剂盒，其中，所述肿瘤由TRKA、和/或TRKB、和/或TRKC介导；
    或者，所述肿瘤由野生型(即非突变型)或者突变型的TRKA、和/或TRKB、和/或TRKC介导；
    或者，所述肿瘤由包含G667C、G595R或G623R的突变型TRK介导；
    任选地，所述突变型选自TRKA G595R、TRKA G667C或TRKC G623R；
    或者，所述肿瘤由包含G667C或G595R的突变型TRKA、和/或TRKB、和/或包含G623R的突变型TRKC介导；
    任选地，所述肿瘤选自具有NTRK融合基因的肿瘤；
    任选地，所述NTRK融合基因选自非突变型或突变型NTRK融合基因；
    任选地，所述NTRK融合基因选自非突变型或突变型的NTRK1融合基因、NTRK2融合基因和/或NTRK3融合基因；
    任选地，所述NTRK融合基因选自非突变型或突变型的TPM3-NTRK1融合基因、ETV6-NTRK3融合基因和/或CD74-NTRK1融合基因；
    任选地，所述突变型NTRK融合基因选自具有NTRK1 G595R、NTRK1 G667C或NTRK3 G623R的融合基因；
    任选地，所述NTRK1融合基因选自非突变型TPM3-NTRK1融合基因、非突变型CD74-NTRK1融合基因、或具有NTRK1 G595R和/或NTRK1 G667C的突变型NTRK1融合基因；任选地，所述具有NTRK1 G595R和/或NTRK1 G667C的突变型NTRK1融合基因选自具有NTRK1 G595R和/或NTRK1 G667C的TPM3-NTRK1融合基因或CD74-NTRK1融合基因；
    任选地，所述NTRK1融合基因选自非突变型TPM3-NTRK1融合基因、具有NTRK1 G595R的突变型NTRK1融合基因、非突变型CD74-NTRK1融合基因、或CD74-NTRK1 G667C融合基因；
    任选地，所述NTRK3融合基因选自非突变型ETV6-NTRK3融合基因、或具有NTRK3 G623R的突变型NTRK3融合基因；任选地，所述具有NTRK3 G623R的突变型NTRK3融合基因选自具有NTRK3 G623R的ETV6-NTRK3融合基因；
    任选地，所述NTRK3融合基因选自非突变型ETV6-NTRK3融合基因、或ETV6-NTRK3 G623R融合基因。
  8. 一种***的方法，所述方法包括:
    1)对从受试者获得的肿瘤样品进行测定，以确定受试者是否具有NTRK融合基因或/和TRK融合蛋白；以及
    2)向具有NTRK融合基因或/和TRK融合蛋白的受试者施用治疗有效量的式I化合物或其可药用盐、或其药物组合物，
    Figure PCTCN2022114215-appb-100007
    任选地，所述TRK融合蛋白选自野生型(非突变型)或突变型TRK融合蛋白；
    或者，所述TRK融合蛋白选自TRKA融合蛋白、TRKB融合蛋白、和/或TRKC融合蛋白；
    或者，所述TRK融合蛋白选自野生型(非突变型)或突变型TRKA融合蛋白、野生型(非突变型)或突变型TRKB融合蛋白、和/或野生型(非突变型)或突变型TRKC融合蛋白；
    或者，所述TRKA融合蛋白选自非突变型TRKA融合蛋白、或具有G595R和/或G667C的突变型TRKA融合蛋白；
    或者，所述TRKC融合蛋白选自非突变型TRKC融合蛋白、或具有G623R的突变型TRKC融合蛋白；
    或者，所述突变型TRK融合蛋白选自TRKA G595R、TRKA G667C或TRKC G623R；
    任选地，所述NTRK融合基因选自非突变型或突变型NTRK融合基因；
    任选地，所述NTRK融合基因选自非突变型NTRK融合基因；
    任选地，所述NTRK融合基因选自突变型NTRK融合基因；
    或者，所述NTRK融合基因选自NTRK1融合基因、NTRK2融合基因和NTRK3融合基因；
    或者，所述NTRK融合基因可以是TPM3-NTRK1融合基因、ETV6-NTRK3融合基因或CD74-NTRK1融合基因；
    或者，所述突变型NTRK融合基因选自具有NTRK1 G595R、NTRK1 G667C或NTRK3 G623R的融合基因；
    任选地，所述NTRK1融合基因选自非突变型TPM3-NTRK1融合基因、非突变型CD74-NTRK1融合基因、或具有NTRK1 G595R和/或NTRK1 G667C的突变型NTRK1融合基因；任选地，所述具有NTRK1 G595R和/或NTRK1 G667C的突变型NTRK1融合基因选自具有NTRK1 G595R和/或NTRK1 G667C的TPM3-NTRK1融合基因或CD74-NTRK1融合基因；
    任选地，所述NTRK1融合基因选自非突变型TPM3-NTRK1融合基因、具有NTRK1 G595R的突变型NTRK1融合基因、非突变型CD74-NTRK1融合基因、或CD74-NTRK1 G667C融合基因；
    任选地，所述NTRK3融合基因选自非突变型ETV6-NTRK3融合基因、或具有NTRK3 G623R的突变型NTRK3融合基因；任选地，所述具有NTRK3 G623R的突变型NTRK3融合基因选自具有NTRK3 G623R的ETV6-NTRK3融合基因；
    任选地，所述NTRK3融合基因选自非突变型ETV6-NTRK3融合基因、或ETV6-NTRK3 G623R融合基因。
  9. 权利要求1-8任一项所述的方法、用途、化合物或试剂盒，其中，所述式I化合物或其可药用盐、或其药物组合物的每日剂量选自0.5-100mg、或0.5-25mg、或2.5-25mg；
    或者，每日剂量选自0.5mg、或1mg、或1.5mg、或2mg、或2.5mg、或3mg、或3.5mg、或4mg、或4.5mg、或5mg、或5.5mg、或6mg、或6.5mg、或7mg、或7.5mg、或8mg、或8.5mg、或9mg、或9.5mg、或10mg、或10.5mg、或11mg、或11.5mg、或12mg、或12.5mg、或13mg、或13.5mg、或14mg、或14.5mg、或15mg、或15.5mg、或16mg、或16.5mg、或17mg、或17.5mg、或18mg、或18.5mg、或19mg、或19.5mg、或20mg、或20.5mg、或21mg、或21.5mg、或22mg、或22.5mg、或23mg、或23.5mg、或24mg、或24.5mg、或25mg、或25.5mg、或26mg、或26.5mg、或27mg、或27.5mg、或28mg、或28.5mg、或29mg、或29.5mg、或30mg、或30.5mg、或31mg、或31.5mg、或32mg、或32.5mg、或33mg、或33.5mg、或34mg、或34.5mg、或35mg、或35.5mg、或36mg、或36.5mg、或37mg、或37.5mg、或38mg、或38.5mg、或39mg、或39.5mg、或40mg、或42.5mg、或45mg、或47.5mg、或50mg、或52.5mg、或55mg、或57.5mg、或60mg、或62.5mg、或65mg、或67.5mg、或70mg、或72.5mg、或75mg、或77.5mg、或80mg、或82.5mg、或85mg、或87.5mg、或90mg、或92.5mg、或95mg、或97.5mg、或100mg或上述任意值形成的范围。
  10. 权利要求1-9任一项所述的方法、用途、化合物或试剂盒，其中，所述式I化合物或其可药用盐、或其药物组合物的给药频率为每日3次、每日2次、每日1次、每两日1次、每三日1次、每四日1次、每五天1次、每六天1次、每一周3次、每一周2次、每一周1次、每两周1次、或每三周1次。
  11. 权利要求1-10任一项所述的方法、用途、化合物或试剂盒，其中，所述对象和/或受试者选自经病理和/或细胞学明确诊断的晚期恶性实体肿瘤受试者或对象，和/或缺乏常规的有效治疗方法或常规方法治疗后失败或复发的受试者或对象；其中，所述受试者或对象选自灵长类动物，优选人；
    或者，所述受试者或对象选自既往接受过或未接受过TRK抑制剂治疗的受试者或对象。
  12. 权利要求1-11任一项所述的方法、用途、化合物或试剂盒，其中，所述肿瘤选自实体瘤；
    或者，上述肿瘤选自晚期恶性实体瘤；
    或者，上述肿瘤选自成人晚期恶性实体瘤；
    或者，上述肿瘤选自胶质瘤、中枢神经***肿瘤、肉瘤、外周原始神经外胚层肿瘤、维尔姆斯肿瘤、肺癌、甲状腺癌、结直肠癌、唾液腺癌、胆道癌、脑癌、乳腺癌、乳腺导管癌、头颈癌、细胞癌、胰腺癌、男女生殖***肿瘤、肾癌、胆管癌、胃癌、支气管癌、胸腔癌、神经内分泌瘤、淋巴瘤或黑色素瘤；
    或者，上述肿瘤选自软组织肉瘤、唾液腺瘤、甲状腺癌、肺癌、黑色素瘤、结直肠癌、胃癌、间质瘤、胆管癌、乳腺癌或胰腺癌；
    或者，所述肿瘤选自肺癌、腺癌或口腔癌；
    或者，所述肺癌选自肺腺癌，所述腺癌选自腮腺癌或肺腺癌，所述口腔癌选自口底癌；
    或者，所述肿瘤选自肺腺癌、腮腺癌、口底癌、腺泡细胞癌或肠癌。
  13. 权利要求1-11任一项所述的方法、用途、化合物或试剂盒，其中，所述肿瘤选自肺癌、腺癌或口 腔癌；
    或者，所述肺癌选自肺腺癌；
    或者，所述腺癌选自腮腺癌或肺腺癌；
    或者，所述口腔癌选自口底癌。
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