CN117597128A - Use of amino-containing macrocyclic compounds for the treatment of TRK kinase mediated tumors - Google Patents

Use of amino-containing macrocyclic compounds for the treatment of TRK kinase mediated tumors Download PDF

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Publication number
CN117597128A
CN117597128A CN202280046303.XA CN202280046303A CN117597128A CN 117597128 A CN117597128 A CN 117597128A CN 202280046303 A CN202280046303 A CN 202280046303A CN 117597128 A CN117597128 A CN 117597128A
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China
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mutant
fusion gene
ntrk1
tumor
cancer
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CN202280046303.XA
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Chinese (zh)
Inventor
万晓婧
张喜全
王训强
田心
于鼎
陈琴
郭方方
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Capital Pharmaceutical Holdings Beijing Co ltd
Chia Tai Tianqing Pharmaceutical Group Co Ltd
Lianyungang Runzhong Pharmaceutical Co Ltd
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Capital Pharmaceutical Holdings Beijing Co ltd
Chia Tai Tianqing Pharmaceutical Group Co Ltd
Lianyungang Runzhong Pharmaceutical Co Ltd
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Publication of CN117597128A publication Critical patent/CN117597128A/en
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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

Abstract

Use of a macrocyclic compound containing an amino group in the treatment of a TRK kinase mediated tumour. In particular to the use of (13E, 14E,22R, 24S) -12-amino-24, 35-difluoro-4-oxa-7-aza-1 (5, 3) -pyrazolo [1,5-a ] pyrimidine-3 (3, 2) -pyridine-2 (1, 2) -pyrrolidine ring Xin Bo-8-ketone or pharmaceutically acceptable salt thereof in the treatment of TRK kinase mediated tumors.

Description

Use of amino-containing macrocyclic compounds for the treatment of TRK kinase mediated tumors
Citation of related application
The present application claims priority and equity to the 202110967771.8 chinese patent application filed at 2021, 23 and 08 to the national intellectual property agency of the people's republic, the entire contents of which are hereby incorporated by reference in their entirety.
Technical Field
The application belongs to the field of medicines, and relates to application of a macrocyclic compound containing amino in treating TRK kinase mediated tumors. Specifically, it relates to a compound (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]Use of pyrimidine-3 (3, 2) -pyridin-2 (1, 2) -pyrrolidin-ring Xin Bo-8-one or a pharmaceutically acceptable salt thereof in the treatment of a TRK kinase mediated tumor.
Background
TRK is a family of nerve growth factor activated tyrosine kinases including TRKA, TRKB and TRKC 3 subtypes, encoded by the NTRK1 (neurotrophic receptor tyrosine kinase) 1, NTRK2 and NTRK3 genes, respectively. The complete TRK kinase includes three parts, an extracellular region, a transmembrane region, and an intracellular region. After the extracellular receptor region of TRK kinase is combined with a corresponding ligand, the extracellular receptor region can cause the change of kinase configuration to form a dimer, and the intracellular kinase region is subjected to autophosphorylation so as to activate the kinase activity of the extracellular receptor region, so that downstream signal transduction pathways (such as MAPK, AKT, PKC and the like) are further activated to generate corresponding biological functions; wherein NGF (nerve growth factor) binds TRKA, BDNF (derived neurotrophic factor) binds TRKB, and NT3 (neurotrophic factor 3) binds TRKC.
TRK kinase plays important physiological functions in the development of nerves, including the growth and functional maintenance of neuronal axons, the development and progression of memory, protection of neurons from injury, and the like. Meanwhile, a great deal of research shows that the activation of TRK signal transduction pathway has strong correlation with the occurrence and development of tumors, and activated TRK signal proteins are found in neuroblastoma, prostatic cancer, breast cancer and the like. The discovery of various TRK fusion proteins has been shown in recent years to further demonstrate their biological function in promoting tumorigenesis. The earliest TPM3-TRKA fusion proteins were found in colon cancer cells with about 1.5% incidence in clinical patients examined. Later on, different types of TRK fusion proteins, such as CD74-NTRK1, MPRIP-NTRK1, QKI-NTRK2, ETV6-NTRK3, BTB1-NTRK3, etc., were found in different types of clinical tumor patient samples, such as lung cancer, head and neck cancer, breast cancer, thyroid cancer, glioma, etc. These different TRK fusion proteins are themselves in a highly activated kinase active state without ligand binding, and thus are capable of sustained phosphorylation of downstream signaling pathways, inducing cell proliferation, and promoting tumor development and progression. Thus, in recent years, TRK fusion proteins have become an effective anticancer 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) -pyridin-2 (1, 2) -pyrrolidin-2-one Xin Bo-8-one (a compound of formula I) which has TRK kinase inhibitory activity is useful in the treatment of TRK kinase mediated diseases.
Disclosure of Invention
In one aspect, the present application provides a method of treating a TRK kinase mediated tumor comprising administering to a subject an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof
In some embodiments, the present application provides a method of treating a TRK kinase mediated tumor comprising 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.
In another aspect, 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 manufacture of a medicament for the treatment of a TRK kinase mediated tumor. The present application also provides a compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the treatment of a TRK kinase mediated tumor. The present application also provides the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, of the present application for the treatment of a TRK kinase mediated tumor.
In some embodiments, 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 manufacture of a medicament for the treatment of a TRK kinase mediated tumor, wherein the medicament comprises from 0.5 to 100mg of the compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, based on the weight of the compound of formula I.
In some embodiments, the compounds of formula I, or pharmaceutically acceptable salts thereof, are used as a single active agent.
In some embodiments, the compounds of formula I, or pharmaceutically acceptable salts thereof, of the present application are used as a single active agent in a single dose or daily dose of 0.5-100mg (based on the weight of the compounds of formula I).
In some embodiments, the compounds of formula I, or pharmaceutically acceptable salts thereof, of the present application are used in a single or daily dose of 0.5-100mg (based on the weight of the compounds of formula I).
In some embodiments, the pharmaceutical compositions described herein comprise 0.5-100mg (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.
In some embodiments, the pharmaceutical composition comprises a compound of formula I or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable adjuvant.
In some embodiments, the present application provides a method of treating a TRK kinase mediated tumor comprising daily administration to a subject (e.g., primate, preferably human) of 0.5-100mg of a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof (based on the weight of the compound of formula I).
In some embodiments, the present application also provides a kit for treating a TRK kinase mediated tumor comprising: a pharmaceutical composition comprising as an active ingredient a compound of formula I or a pharmaceutically acceptable salt thereof; optionally, instructions for use of the pharmaceutical composition of the compound of formula I or a pharmaceutically acceptable salt thereof are also included. In some embodiments, the pharmaceutical composition is a single dose pharmaceutical composition comprising 0.5-100mg of a compound of formula I, or a pharmaceutically acceptable salt thereof (based on the weight of the compound of formula I) as an active ingredient.
In some embodiments, the methods of treating a tumor provided herein comprise:
1) Identifying a tumor in the subject as a tumor mediated by a TRK kinase; and;
2) Administering to the identified subject a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
In some embodiments, the subject is a primate, preferably a human.
In some embodiments, the tumor is mediated by TRKA, and/or TRKB, and/or TRKC.
In some embodiments, the tumor is mediated by wild-type (non-mutant) or mutant TRK. In some embodiments, the tumor is mediated by wild-type (non-mutant) or mutant TRKA, and/or TRKB, and/or TRKC.
In some embodiments, the tumor is mediated by a mutant TRK comprising G667C, G595R or G623R.
In some embodiments, the tumor is mediated by a mutant TRKA comprising G667C or G595R, and/or TRKB, and/or a mutant TRKC comprising G623R.
In some embodiments, the mutant is selected from TRKA G595R 、TRKA G667C Or TRKC G623R 。
In some embodiments, the tumor is selected from tumors that have a TRK fusion protein. In some embodiments, the TRK kinase mediated tumor is selected from tumors with non-mutated or mutated TRK fusion proteins. In some embodiments, the TRK fusion protein is selected from a non-mutant or mutant TRKA fusion protein, and/or a TRKB fusion protein, and/or a TRKC fusion protein. In some embodiments, the TRK fusion protein is selected from a non-mutant TRKA fusion protein, and/or a TRKB fusion protein, and/or a TRKC fusion protein. In some embodiments, the TRK fusion protein is selected from a mutant TRKA fusion protein, and/or a TRKB fusion protein, and/or a TRKC fusion protein.
In some embodiments, the tumor is selected from a tumor having a NTRK fusion gene. In some embodiments, the NTRK fusion gene is selected from a non-mutant or mutant NTRK fusion gene. In some embodiments, the NTRK fusion gene is selected from the group consisting of a NTRK1 fusion gene, a NTRK2 fusion gene, and a NTRK3 fusion gene. In some embodiments, the NTRK fusion gene is selected from a non-mutant or mutant NTRK1 fusion gene, and/or a NTRK2 fusion gene, and/or a NTRK3 fusion gene. In some embodiments, the NTRK fusion gene is selected from a non-mutated or mutated NTRK1 fusion gene. In some embodiments, the NTRK fusion gene is selected from a non-mutated or mutated NTRK2 fusion gene. In some embodiments, the NTRK fusion gene is selected from a non-mutated or mutated NTRK3 fusion gene. In some embodiments, the NTRK fusion gene is selected from a non-mutant NTRK1 fusion gene, and/or a NTRK2 fusion gene, and/or a NTRK3 fusion gene. In some embodiments, the NTRK fusion gene is selected from a mutant NTRK1 fusion gene, and/or a NTRK2 fusion gene, and/or a NTRK3 fusion gene. In some embodiments, the NTRK fusion gene may 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 may be an ETV6-NTRK3 fusion gene.
In some embodiments, the NTRK fusion gene may express a TRK fusion protein in the tumor.
In some embodiments, the NTRK fusion gene may express a wild-type (i.e., non-mutant) or mutant TRK fusion protein in the tumor.
In some embodiments, the NTRK1 fusion gene may express a wild-type (i.e., non-mutant) or mutant TRKA fusion protein in the tumor.
In some embodiments, the NTRK2 fusion gene may express a wild-type (i.e., non-mutant) or mutant TRKB fusion protein in the tumor.
In some embodiments, the NTRK3 fusion gene may express a wild-type (i.e., non-mutant) or mutant TRKC fusion protein in the tumor.
In some embodiments, in the tumor, the NTRK1 fusion gene can express a wild-type (i.e., non-mutant) or mutant TRKA fusion protein; and/or the NTRK2 fusion gene may express a wild-type (i.e., non-mutant) or mutant TRKB fusion protein; and/or the NTRK3 fusion gene may express a wild-type (i.e., non-mutant) or mutant TRKC fusion protein.
In some embodiments, the mutant NTRK fusion gene is selected from the group consisting of having NTRK1 G595R 、NTRK1 G667C And/or NTRK3 G623R Is a fusion gene of (a).
In some embodiments, the mutant NTRK fusion gene is selected from the group consisting of CD74-NTRK1 G667C Fusion gene and/or ETV6-NTRK3 G623R Fusion genes. In some embodiments, the mutant NTRK fusion gene is selected from ETV6-NTRK3 G623R Fusion genes.
In some embodiments, the NTRK1 fusion gene is selected from the group consisting of a non-mutant TPM3-NTRK1 fusion gene, a non-mutant CD74-NTRK1 fusion gene, or a mutant with NTRK1 G595R And/or NTRK1 G667C Mutant NTRK1 fusion genes (e.g., having NTRK 1) G595R And/or NTRK1 G667C TPM3-NTRK1 fusion gene or CD74-NTRK1 fusion gene). In some embodiments, the NTRK1 fusion gene is selected from the group consisting of a non-mutant TPM3-NTRK1 fusion gene, having NTRK1 G595R Mutant NTRK1 fusion gene, non-mutant CD74-NTRK1 fusion gene, or CD74-NTRK1 G667C Fusion genes.
In some embodiments, the NTRK3 fusion gene is selected from a non-mutant ETV6-NTRK3 fusion gene, or has NTRK3 G623R Mutant NTRK3 fusion genes (e.g., having NTRK3 G623R ETV6-NTRK3 fusion gene). In some embodiments, the NTRK3 fusion gene is selected from the group consisting of a non-mutant ETV6-NTRK3 fusion gene, or ETV6-NTRK3 G623R Fusion genes.
In some embodiments, the methods of treating a tumor provided herein comprise:
1) Assaying a tumor sample obtained from a subject to determine whether the subject has a NTRK fusion gene or/and a TRK fusion protein; and
2) Administering to a subject having a NTRK fusion gene or/and a TRK fusion protein a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
In some embodiments, the NTRK fusion gene is selected from a non-mutant or mutant NTRK fusion gene. In some embodiments, the NTRK fusion gene is selected from a NTRK1 fusion gene, a NTRK2 fusion gene, and/or a NTRK3 fusion gene. In some embodiments, the NTRK fusion gene is selected from the group consisting of NTRK1 fusion genes. In some embodiments, the NTRK fusion gene is selected from the group consisting of NTRK2 fusion genes. In some embodiments, the NTRK fusion gene is selected from the group consisting of NTRK3 fusion genes. In some embodiments, the NTRK fusion gene is selected from the group consisting of non-mutant NTRK fusion genes. In some embodiments, the NTRK fusion gene is selected from a mutant NTRK fusion gene. In some embodiments, the mutation of the NTRK fusion gene is selected from an acquired mutation or a non-acquired mutation. In some embodiments, the mutant NTRK fusion gene is selected from a drug resistant mutant NTRK fusion gene. In some embodiments, the NTRK fusion gene is selected from a NTRK1 fusion gene, a NTRK2 fusion gene, and/or a NTRK3 fusion gene. In some embodiments, the NTRK fusion gene is selected from a mutant NTRK1 fusion gene, a NTRK2 fusion gene, and/or a NTRK3 fusion gene.
In some embodiments, the NTRK fusion gene may be selected from a non-mutated or mutated TPM3-NTRK1 fusion gene, an ETV6-NTRK3 fusion gene, or a CD74-NTRK1 fusion gene.
In some embodiments, the NTRK fusion gene may be selected from a TPM3-NTRK1 fusion gene, an ETV6-NTRK3 fusion gene, or a CD74-NTRK1 fusion gene.
In some embodiments, the NTRK fusion gene may be ETV6-NTRK3.
In some embodiments, the mutant NTRK fusion gene is selected from the group consisting of having NTRK1 G595R 、NTRK1 G667C Or NTRK3 G623R Is a fusion gene of (a). In some embodiments, the mutant NTRK fusion gene is selected from the group consisting of having NTRK3 G623R Is a fusion gene of (a).
In some embodiments, the TRK fusion protein is selected from a wild-type (i.e., non-mutant) or mutant TRK fusion protein. In some embodiments, the TRK fusion protein is selected from a TRKA fusion protein, a TRKB fusion protein, and/or a TRKC fusion protein. In some embodiments, the TRK fusion protein is selected from a wild-type (i.e., non-mutant) or mutant TRKA fusion protein, a wild-type (i.e., non-mutant) or mutant TRKB fusion protein, and/or a wild-type (i.e., non-mutant) or mutant TRKC fusion protein.
In some embodiments, the mutant TRK fusion protein is selected from a mutant TRKA with G595R and/or G667C or a mutant TRKC with G623R. In some embodiments, the mutant TRK fusion protein is selected from a mutant TRKA with G595R, a mutant TRKA with G667C, or a mutant TRKC with G623R.
In some embodiments, the mutant TRK fusion protein is selected from TRKA G595R 、TRKA G667C Or TRKC G623R 。
In some embodiments, 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 the group consisting of acquired drug resistant mutant TRK fusion proteins.
In some embodiments, the fusion genes described herein may contain NTRK gene point mutations or not. In some embodiments, the fusion genes described herein may contain a NTRK gene point mutation. In some embodiments, the fusion genes described herein may not contain a NTRK gene point mutation.
In some embodiments, the tumors described herein may be from subjects and/or patients carrying a NTRK1, NTRK2, or NTRK3 gene fusion and not containing a point mutation of the NTRK gene. In some embodiments, the tumors described herein may be from subjects and/or patients harboring a NTRK1, NTRK2, or NTRK3 gene fusion and containing a point mutation of the NTRK gene.
In some embodiments, the methods provided herein comprise performing a morphological diagnosis, or a molecular test, or a combination of both, prior to administering a compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
In some embodiments, the methods provided herein include assaying a tumor sample obtained from a subject to determine that the subject has a deregulation of the NTRK fusion gene, the TRK protein, or expression or level thereof.
In some embodiments, the methods provided herein include assaying a tumor sample obtained from a subject to determine that the subject has a NTRK fusion gene or/and a TRK fusion protein.
In some embodiments, the method of assaying 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-stranded conformational polymorphism assays, molecular beacon assays, dynamic hybridization assays, PCR-based assays, or denaturing high performance liquid chromatography.
In some embodiments, the mutants described herein are selected from the group consisting of G595R, G667C or G623R type mutations. In some embodiments, the mutant is selected from the group consisting of a G595R-type mutation. In some embodiments, the mutant is selected from the group consisting of a G667C mutant. In some embodiments, the mutant is selected from the group consisting of G623R type mutations.
In some embodiments, the fusion genes described herein are selected from non-mutant or mutant NTRK1, NTRK2, or NTRK3 gene fusions. In some embodiments, the fusion genes described herein are selected from non-mutant or mutant NTRK1 gene fusions. In some embodiments, the fusion genes described herein are selected from non-mutant or mutant NTRK2 gene fusions. In some embodiments, the fusion genes described herein are selected from non-mutant or mutant NTRK3 gene fusions.
In some embodiments, the NTRK fusion gene described herein may be selected from non-mutated or mutated TPM3-NTRK1, ETV6-NTRK3, or CD74-NTRK1. In some embodiments, the NTRK fusion gene described herein may be selected from the group consisting of non-mutated or mutated TPM3-NTRK1. In some embodiments, the NTRK fusion genes described herein may be selected from non-mutant or mutant ETV6-NTRK3. In some embodiments, the NTRK fusion genes described herein may be selected from non-mutant or mutant CD74-NTRK1.
In some embodiments, the compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is administered at a weight of 0.0001mg/kg to 20mg/kg (calculated as 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 administered at 0.5-100mg, 0.5-25mg, or 2.5-25mg (by 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 administered at 0.5-20mg (by 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 administered at 0.5-15mg (by 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 administered at 2.5-10mg (by 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 administered at 5-10mg (by weight of the compound of formula I) per administration.
In some embodiments, 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 0.5-100mg, 0.5-25mg, or 2.5-25mg. In some of the embodiments of the present invention, the daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof (based on the weight of the compound of formula I) is selected from 0.5mg, or 1mg, or 1.5mg, or 2mg, 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 9.5mg, 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 15.5mg, or 16mg, or 16.5mg, or 17mg, 18mg, or 18.5mg, or 19mg, or 19.5mg, or 20.5mg, 21, 21.5mg, or 22.5mg, 24mg, 23, 25, or 23, or 25mg, or 13mg, or 13.5mg, or 14.5mg, or 16.5mg, or the compound of the pharmaceutically acceptable salt thereof or 25.5mg, or 26mg, or 26.5mg, or 27mg, or 27.5mg, or 28mg, or 28.5mg, or 29mg, or 29.5mg, or 30mg, or 30.5mg, or 31mg, or 31.5mg, or 32mg, or 32.5mg, or 33mg, or 33.5mg, or 34mg, or 34.5mg, or 35mg, or 35.5mg, or 36mg, or 36.5mg, or 37mg, or 37.5mg, or 38mg, or 38.5mg, or 39mg, or 39.5mg, or 40mg, or 42.5mg, or 45mg, or 47.5mg, or 50mg, or 52.5mg, or 55mg, or 57.5mg, or 60mg, or 62.5mg, or 65mg, or 67.5mg, or 70mg, or 72.5mg, or 75mg, or 77.5mg, or 80mg, or 82.5mg, or 92.5mg, or 85.5 mg, or 95, or 100.5 mg, or 90, or any of the ranges described above. In some embodiments, 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 0.5mg to 20mg. In some embodiments, 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 0.5mg to 15mg. In some embodiments, 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 2.5mg to 10mg. In some embodiments, 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 5mg to 10mg. In some embodiments, the frequency of administration of the compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, may be 3 times daily, 2 times daily, 1 time every two days, 1 time every three days, 1 time every four days, 1 time every five days, 1 time every six days, 3 times every week, 2 times every week, 1 time every two weeks, or 1 time every three weeks. In some embodiments, the frequency of administration of the compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, may be 1 time per day. In some embodiments, the frequency of administration of the compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, may be 2 times daily.
In some embodiments of the present application, the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is administered at a dose of 2-20mg gauge, e.g., 2.5mg, 5mg, or 10mg gauge (calculated as weight of the compound of formula I).
In some embodiments of the present application, the compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is administered at a rate of 0.0001 to 20mg/kg weight (calculated as the weight of the compound of formula I).
In some embodiments, the administration period for the administration of the compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is 1-6 cycles. In some embodiments, the period of administration of the compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is 1, 2, 3, 4, 5, 6 periods, or ranges from any of the above. In some embodiments, 1 dosing cycle is 8-32 days, e.g., 1 dosing cycle is 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. In some embodiments, the administration period is 1 at 28 days or 32 days. In some embodiments, the period of administration is 1 administration over 28-32 days.
In some embodiments, administering to the subject an effective amount of a compound of formula I of the present application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is a continuous administration.
In some embodiments, the compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is administered in single or multiple dose form.
In some embodiments, the subject is selected from a subject with a pathologically and/or cytologically definitively diagnosed advanced malignant solid tumor, and/or a subject who lacks conventional effective treatment methods or who fails or recurs after treatment by conventional methods.
In some embodiments, the tumor is selected from tumor patients with or without prior treatment history. In some embodiments, the tumor is selected from tumor patients having a prior history of treatment.
In some embodiments, the subject is selected from a subject who has been previously treated with a TRK inhibitor or has not been treated with a TRK inhibitor.
In some embodiments, the subject is selected from a subject who has been previously treated with one or more TRK inhibitors.
In some embodiments, the TRK inhibitor is selected from larotinib, TL118, and/or SIM1803.
In some embodiments, the subject is selected from a subject who has not previously been treated with a TRK inhibitor.
In some embodiments, the tumor is selected from solid tumors.
In some embodiments, the tumor is selected from advanced malignant solid tumors.
In some embodiments, the tumor is selected from advanced malignant solid tumors in adults.
In some embodiments, the 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, ductal breast cancer, head and neck cancer, cell cancer, pancreatic cancer, male and female reproductive system tumor, renal cancer, cholangiocarcinoma, gastric cancer, bronchial cancer, thoracic cancer, neuroendocrine tumor, lymphoma, or melanoma.
In some embodiments, the tumor is selected from soft tissue sarcoma, salivary gland tumor, thyroid cancer, lung cancer, melanoma, colorectal cancer, gastric cancer, stromal tumor, bile duct cancer, breast cancer, or pancreatic cancer.
In some embodiments, the tumor is selected from lung cancer, adenocarcinoma, or oral cancer. In some embodiments, the lung cancer is selected from lung adenocarcinoma; the adenocarcinoma is selected from parotid adenocarcinoma or lung adenocarcinoma; the oral cancer is selected from the group consisting of basal mouth cancer.
In some embodiments, the tumor is selected from lung adenocarcinoma, parotid adenocarcinoma, basal mouth carcinoma, acinar cell carcinoma, or intestinal cancer.
A compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof
The compounds of formula I of the present application may be administered in the form of their free base, as well as in the form of their pharmaceutically acceptable salts, hydrates and prodrugs which are convertible in vivo into the free base form of the compounds of formula I.
In some embodiments, 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.
In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is in the form of a pharmaceutical composition, wherein the pharmaceutical composition is a single dose of 0.5-100mg, preferably 0.5-25 mg, preferably from 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, 21.5mg, 22.23.24 mg, 24mg, or any combination thereof, by weight of the compound of formula I.
In some embodiments, the pharmaceutical compositions of the present application are administered orally.
In some embodiments, each pharmaceutical composition of the present application is a solid pharmaceutical composition.
In some embodiments, the solid pharmaceutical composition of the present application is formulated in the form of a tablet.
Definition and description
The following terms used in this application have the following meanings, unless otherwise indicated. A particular term, unless otherwise defined, shall not be construed as being ambiguous or otherwise unclear, but shall be construed in accordance with the ordinary meaning in the art.
For TRKA, TRKB and TRKC, they are encoded by the genes NTRK1, NTRK2 and NTRK3, respectively.
The term "administering" or "administration" means physically introducing a therapeutic agent or a composition comprising a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those of skill in the art. The terms "administration" or "administration" are used interchangeably herein.
The term "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. As used herein, "treatment" encompasses any treatment of a disease in a patient, including: (a) inhibiting the symptoms of the disease, i.e., arresting its development; or (b) alleviating a symptom of the disease, i.e., causing regression of the disease or symptom.
The term "effective amount" means an amount of a compound of the present application that (i) treats or prevents a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. 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 one of ordinary skill in the art based on his own knowledge and disclosure.
The terms "subject," "patient," or "subject" are used interchangeably herein to refer to animals, preferably mammals, preferably primates, including humans and non-human primates (e.g., apes, monkeys, chimpanzees, and chimpanzees, such as cynomolgus monkeys, spider monkeys, and macaques, such as rhesus monkeys), and most preferably humans, who have been the subject of treatment, observation, or experimentation. In some embodiments, the subject has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented. The term "individual" may be a mammal, preferably a primate, most preferably a human.
As used herein, the compound of formula I or a pharmaceutically acceptable salt thereof may be administered by any suitable route and method, such as by oral or parenteral (e.g., intravenous) administration.
The term "about" is to be understood to include within three standard deviations of the average value or within standard tolerances in the particular field. In certain embodiments, a variation of no more than about 0.5 is understood. "about" modifies all values recited thereafter. For example, "about 1, 2, 3" means "about 1", "about 2", "about 3".
The term "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 excipients. 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.
The term "pharmaceutically acceptable excipients" refers to those excipients which do not significantly stimulate the organism and which do not impair the biological activity and properties of the active compound. Suitable excipients are well known to the person 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 compositions of the present application may be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, for example, in solid formulations such as tablets, pills, capsules and the like.
The pharmaceutical compositions of the present application may be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, freeze-drying, and the like.
The term "pharmaceutically acceptable" is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
Solid oral pharmaceutical compositions may be prepared by conventional mixing, filling or tabletting methods. For example, it can be obtained by the following method: the active compound is mixed with solid auxiliary materials, the resulting mixture is optionally milled, if desired with other suitable auxiliary materials, and the mixture is then processed to granules, giving tablets or capsules or dragee cores. Suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
The term "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" refers to salts of the compounds of the present application that are within the definition of "pharmaceutically acceptable".
Unless specifically stated otherwise, singular terms encompass a plurality of terms and plural terms encompass singular terms. The terms "a" or "an" mean "at least one" or "at least one" unless specifically indicated otherwise. The use of "or" means "and/or" unless stated otherwise.
In this document, the terms "comprises, comprising, and/or equivalents are used in an open-ended fashion, meaning that additional elements, components, and steps are not recited in addition to the recited elements, components, and steps.
As used herein, unless otherwise indicated, "by weight" refers to the weight of the free form of the compound of formula I.
The term "single dose" refers to the smallest packaging unit containing a quantity of a drug, e.g., a box of seven capsules, each capsule being a single dose; or a single dose per bottle of injectate. The term "multi-dose" consists of a plurality of single doses.
All patents, patent applications, and other identified publications are expressly incorporated herein by reference for the purpose of description and disclosure. These publications are provided solely for their disclosure prior to the filing date of the present application. All statements as to the date or representation as to the contents of these documents are based on the information available to the applicant and do not constitute any admission as to the correctness of the dates or contents of these documents. Moreover, any reference to such publications in this document does not constitute an admission that the publications are part of the common general knowledge in the art, in any country.
In one embodiment, the pharmaceutical combinations of the present application may be formulated into pharmaceutical compositions suitable for single or multiple administration. In one embodiment, the pharmaceutical combination of the present application may be a single dose or a multi-dose pharmaceutical composition.
The term "Objective Remission Rate (ORR)": the proportion of subjects required to achieve a predetermined value for tumor volume reduction and to maintain the minimum time limit (at the time of the next image evaluation) included cases of Complete Remission (CR) and Partial Remission (PR).
The term "Disease Control Rate (DCR)": the proportion of patients who shrink or stabilize and remain for a certain period of time for tumors, including CR, PR and disease Stabilization (SD) cases.
The term "Progression Free Survival (PFS)": the time between the onset of first dose and disease Progression (PD) or pre-PD death; if no PD or pre-PD death occurs, the last imaging evaluation date is taken as the expiration date.
The term "duration of remission (DOR)": in CR or PR subjects, tumors are first assessed as time between CR or PR to PD or pre-PD death; if the subject of CR or PR does not have PD or die before PD, the last imaging evaluation date is taken as the expiration date.
The term "Adverse Event (AE)" refers to all Adverse medical events that occur after a subject has received a test drug, and may be manifested as symptoms, signs, disease, or laboratory abnormalities, but are not necessarily causally related to the test drug. The evaluation criteria for the nature and severity of adverse events were carried out in compliance with the common toxicity response criteria of the national cancer institute (NCI-CTC AE v 5.0). Items that cannot be evaluated according to this criteria can be rated according to the following criteria:
Light: has only slight influence on the daily life of the patient.
And (3) moderately: the daily life of the patient is obviously affected.
Severe: causing patient dysfunction or severely interfering with daily life.
The term "OS": refers to the total survival time of tumor patients.
The term "DFS": refers to the disease-free survival time of tumor patients.
The term "TTP": refers to the time of disease progression in tumor patients.
Technical effects
The treatment scheme has better curative effect on treating TRK-mediated tumors. The compounds of formula I described herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, are useful for at least the evaluation of survival efficacy (e.g., OS, median survival); has excellent effect in at least one aspect of tumor response efficacy evaluation (e.g. DFS, median DFS, PFS, TTP, ORR, DCR, DOR), such as ORR. In addition, the compound of the formula I or the pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof has low effective dose, good patient tolerance and small side effects (such as small influence on respiratory system, central nervous system and the like) and fewer adverse events; no obvious accumulation exists in the body; the exposure level was excellent. Which illustrates that the compounds of formula I or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, of the present application have good pharmaceutical value.
Detailed Description
For clarity, the present application is further illustrated with examples, but the examples do not limit the scope of the present application. All reagents used in this application are commercially available and can be used without further purification.
The compounds of formula I may be prepared by reference to the methods disclosed in WO2019037761A1, example 14.
Example 1 in vitro experiments
1.1 in vitro kinase Activity assay
Detection of TRKA, TRKB and TRKC kinase, TRKA, by Mobility shift assay method G595R 、TRKA G667C 、TRKC G623R Kinase (kinase derived from the sondi medical technology (Shanghai) limited liability company) level. In the kinase activity measurement, the inhibition ratio was calculated from the measured fluorescence value to obtain IC 50 Specific values are shown in Table 1.
TABLE 1 influence of Compounds of formula I on kinase Activity
1.2 in vitro cell Activity assay
KM12 tumor cells: inoculating 7200 KM12 tumor cells per well on a 96-well transparent culture plate, allowing a compound (0.7812-200 mu M, 2-fold dilution, three compound wells per concentration) of formula I to act on the cells for 72 hours, discarding the culture solution, adding a precooled 10% trichloroacetic acid (TCA) solution to each well to fix the cells, placing the cells in a refrigerator at 4 ℃ for fixing for 2 hours, washing each well of the culture plate with deionized water for 5 times to remove the trichloroacetic acid solution, drying, adding a SRB solution (4 mg/mL) prepared by 1% acetic acid to each well, placing the culture plate at room temperature for 20 minutes, discarding the liquid in each well, washing with 1% acetic acid for 5 times, washing unbound SRB dye, air-drying, adding a proper volume of 10mM Tris-base (Tris) solution per well for dissolving, and measuring the absorbance OD value at 515nm wavelength by an enzyme marker instrument after complete dissolving.
CD74-NTRK1 G595R 3T3 tumor cells: inoculation of 3600/well of CD74-NTRK1 G595R 3T3 tumor cells were plated on 96-well transparent plates, after 72h of cells were treated with the compound of formula I (0.3125-20. Mu.M, 2-fold dilution, three compound wells per concentration), the culture solution was discarded, cells were fixed by adding a pre-chilled 10% trichloroacetic acid (TCA) solution to each well, the plates were fixed in a refrigerator at 4℃for 2h, each well was washed with deionized water to remove trichloroacetic acid solution, dried, 1% acetic acid-formulated SRB solution (4 mg/mL) was added to each well, left at room temperature for 20 min, the liquid in each well was discarded, washed 5 times with 1% acetic acid, unbound SRB dye was washed, air-dried, and after complete dissolution, the absorbance OD value was measured at 515nm by an ELISA.
ETV6-NTRK3 G623R BaF3 tumor cells: inoculation of 3000/well ETV6-NTRK3 G623R BaF3 tumor cells in 96-well transparent culture plate, after the compound of formula I (0.03125-8 nM, 2-fold dilution, three compound wells per concentration) acts on the cells for 72h, the compound of formula I acts on the cells for 4h before 72h, the prepared MTT solution of 5mg/mL is added, after continuous co-incubation for 4h, centrifugation at 1500rpm for 5min, the supernatant is discarded, 200 μl DMSO is added to each well, and after shaking and dissolution in a shaker, absorbance OD value is measured at 570nm wavelength of the microplate reader.
(ETV6-NTRK3 G623R BaF3 cells are suspension cells, and IC is measured by MTT method 50 )
The specific results are shown in Table 2 below.
TABLE 2 proliferation inhibition of TRK highly expressed cell lines by Compounds of formula I
Example 2 Effect of Compounds of formula I on TRK kinase and Signal transduction pathway mediated thereby
The experiment uses Western Blot method and adopts artificially constructed TRK point mutated CD74-NRTK1 G595R 3T3 cells to investigate the effect of compounds of formula I on TRK kinase phosphorylation levels and downstream signal transduction pathways.
CD74-NTRK1 G595R 3T3 cells were plated in 6 well plates at 37℃in 5% CO 2 Culturing in an incubator. Cells were treated with compounds of formula I at concentrations of 1.25. Mu.M, 2.5. Mu.M, and 5. Mu.M for 24h, 48h, cells were collected by digestion, protein samples were prepared by lysis, and protein TRK, PLC. Gamma.1, AKT and Erk expression levels were detected by Western Blot. The results show that: the compound of the formula I can inhibit activation of TRK receptor and downstream PLC gamma 1, AKT and Erk signal channels thereof at 24 and 48 hours, and inhibit the level of phosphorylated protein, thereby playing a role in inhibiting proliferation of tumor cells.
Example 3: in vivo experiments
KM12 cells: will be 5X 10 6 The individual colon cancer cells KM12 were injected into the left armpit of SPF-class female nude mice (Jiangsu Ji Yikang Biotechnology Co., ltd.) until the tumor grew to an average volume of 100mm 3 After left and right animals were randomly grouped according to tumor volume and dosed. The tumor volume was weighed and measured 2 times per week 1 time per day by gavage administration of 3mg/kg, 10mg/kg, 30mg/kg of the compound of formula I, 11 days of the administration cycle, after weighing and measuring the tumor volume on day 12, the Relative Tumor Volume (RTV) and relative tumor proliferation rate (T/C) were calculated, the mice were sacrificed on day 12, tumors were dissected, tumor weights were weighed, and Inhibition Rate (IR) was calculated for statistical analysis.
CD74-NTRK1 G595R 3T3: will be 5X 10 6 Mouse embryonic fibroblast CD74-NTRK1 G595R 3T3 is injected into the left armpit of SPF-class female nude mice (Jiangsu Ji Yikang Biotechnology Co., ltd.) until the tumor grows to an average volume of 50-100mm 3 Animals were then randomly grouped according to tumor volume and dosed. The compound of the formula I is administrated by stomach irrigation at a dosage of 0.8mg/kg, 2.4mg/kg and 8mg/kg 2 times per day; 2mg/kg of a compound of formula I are administered intragastrically 1 time a day; tumor volume was weighed and measured 2 times per week for 8 or 20 days of the dosing cycle, and after weighing and measuring tumor volume on day 8 or 21, relative Tumor Volume (RTV) and relative tumor increase were calculatedThe rate of proliferation (T/C), mice were sacrificed on day 8 or 21, tumors were dissected, tumor weights were measured, IR calculated, and statistical analysis was performed.
ETV6-NTRK3 G623R BaF3: will be 5X 10 6 Individual mouse primordial B cells ETV6-NTRK3 G623R BaF3 is injected into the left armpit of nude mice (Jiangsu Ji Yikang Biotechnology Co., ltd.) until the tumor grows to an average volume of 100mm 3 After left and right animals were randomly grouped according to tumor volume and dosed. The compound of formula I was given by gavage at 0.2mg/kg, 0.6mg/kg, 2mg/kg 1 time per day, tumor volume was weighed and measured 2 times per week, dosing period was 20 days, relative Tumor Volume (RTV) and relative tumor proliferation rate (T/C) were calculated after weighing and measuring tumor volume on day 21, mice were sacrificed on day 21, tumors were dissected, tumor weights were measured, IR was calculated, and statistical analysis was performed.
The results show that: the compound of formula I can inhibit the growth of the cell transplantation tumor in a dose-dependent manner, and has no obvious influence on the body weight of a nude mouse.
TABLE 3 influence of Compounds of formula I on in vivo transplantations
T/C: relative tumor proliferation rate; IR: percent tumor inhibition.
Example 4 clinical trial
1. Test drug
A compound of formula I: specifications of 2.5mg, 5mg and 10mg, tablets.
2. Group-entered subjects
1) Patients with advanced malignancy who have failed standard therapy or lack effective treatment methods as judged by histological and/or cytological confirmation;
2) Age: 18-75 years of age (when informed consent was signed);
3) ECOG score: 0-1 min;
4) The expected lifetime exceeds 3 months;
5) The major organs function normally, i.e. meet the following criteria:
a) Blood routine examination (no transfusion and no correction with hematopoietic stimulatory factor type drugs within 7 days prior to screening): a) Hemoglobin (HGB) is more than or equal to 80g/L; neutrophil count (NEUT) 1.5X10. Gtoreq. 9 L; platelet count (PLT) 90×10 or more 9 /L；
b) Biochemical examination: glutamic-pyruvic transaminase (ALT) and glutamic-pyruvic transaminase (AST) are less than or equal to 2.5 XULN (primary liver and gall tumor or tumor liver metastasis: ALT and AST are less than or equal to 5 XULN); total Bilirubin (TBIL) is less than or equal to 1.5 XULN (Gilbert syndrome patient: TBIL is less than or equal to 3 XULN); creatinine (CRE) is less than or equal to 1.5 XULN or creatinine clearance is more than or equal to 60mL/min;
c) Coagulation function: activated Partial Thrombin Time (APTT), international Normalized Ratio (INR), prothrombin Time (PT) less than or equal to 1.5 XULN;
d) Thyroid Stimulating Hormone (TSH) is less than or equal to ULN; if the abnormality should examine the levels of T3 and T4, the levels of T3 and T4 are normal, and then the selection can be carried out;
e) Left Ventricular Ejection Fraction (LVEF) is greater than or equal to 50%;
6) Female patients of the gestational age must be negative for serum or urine HCG examination within 7 days prior to study entry into the group and must be non-lactating; the patient should agree that contraceptive measures must be taken during the study period and within 6 months after the end of the study period;
7) Patients voluntarily added the study, signed informed consent, and compliance was good.
3. Dosing regimen
The tablet, qd, of the compound of formula I is administered under fasting conditions (no food is taken within one hour after administration) and the time of each administration should be approximately similar.
4. Effectiveness index
The index includes ORR, DCR, PFS, DOR, SD, PR, CR and the like.
5. Test results
Safety of
AE is mostly grade 1, most of which is classified as improvement.
The total occurrence rate of adverse events is low, and the safety is good.
Effectiveness of the method
Of the 8 patients in the group, 7 patients with efficacy can be evaluated. The Objective Remission Rate (ORR) was 57% (4/7), the Partial Remission (PR) was 4, the Stable Disease (SD) was 2, and the Disease Control Rate (DCR) was 85.7% (6/7). As a result, the treatment regimens of the present disclosure were found to be clinically beneficial.
Representative disease example results are shown in table 4 below.
TABLE 4 Table 4
* Indicating the extent to which the sum of the target lesion diameters was reduced from the baseline level (sum of target lesion diameters at stage C0).
a The product is a molecule of the advanced malignant solid tumor which is proposed to be used for treating NTRK gene fusion by the Tao biotechnology in Suzhou.
b The product is a molecule intended to be used for the treatment of solid tumors by the pharmaceutical industry group of congenital pharmaceutical companies.
c Each administration period is indicated as 28-32 days, e.g. C6 indicates 6 administration periods of 28-32 days each.
d Indicating the best efficacy that has been monitored at present.

Claims (13)

  1. A method of treating a TRK kinase mediated tumor comprising daily administration to a subject of 0.5 to 100mg of a compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof
  2. Use of a compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of a TRK kinase mediated tumor, comprising administering to a subject 0.5-100mg of a compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, daily,
  3. a compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating a TRK kinase-mediated tumor, comprising administering to a subject 0.5-100mg of a compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, daily,
  4. the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the treatment of a TRK kinase mediated tumor, comprising administering to a subject 0.5-100mg of a compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, daily,
  5. a kit for treating a TRK kinase mediated tumor comprising: a pharmaceutical composition comprising as an active ingredient a compound of formula I or a pharmaceutically acceptable salt thereof, preferably a pharmaceutical composition comprising as an active ingredient 0.5-100mg of a compound of formula I or a pharmaceutically acceptable salt thereof; optionally, instructions for use of the pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof,
  6. A method of treating a tumor, the method comprising:
    1) Identifying a tumor in a subject or subject as a tumor mediated by a TRK kinase; and
    2) Administering to the identified subject or subject a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof,
  7. the method, use, compound or kit of any one of claims 1-6, wherein the tumor is mediated by TRKA, and/or TRKB, and/or TRKC;
    alternatively, the tumor is mediated by wild-type (i.e., non-mutant) or mutant TRKA, and/or TRKB, and/or TRKC;
    alternatively, the tumor is mediated by a mutant TRK comprising G667C, G595R or G623R;
    optionally, the mutant is selected from TRKA G595R 、TRKA G667C Or TRKC G623R ；
    Alternatively, the tumor is mediated by a mutant TRKA comprising G667C or G595R, and/or TRKB, and/or a mutant TRKC comprising G623R;
    optionally, the tumor is selected from a tumor having a NTRK fusion gene;
    optionally, the NTRK fusion gene is selected from a non-mutant or mutant NTRK fusion gene;
    optionally, the NTRK fusion gene is selected from a non-mutated or mutated NTRK1 fusion gene, a NTRK2 fusion gene and/or a NTRK3 fusion gene;
    optionally, the NTRK fusion gene is selected from a non-mutated or mutated TPM3-NTRK1 fusion gene, an ETV6-NTRK3 fusion gene and/or a CD74-NTRK1 fusion gene;
    Optionally, the mutant NTRK fusion gene is selected from the group consisting of having NTRK1 G595R 、NTRK1 G667C Or NTRK3 G623R Is a fusion gene of (2);
    optionally, the NTRK1 fusion gene is selected from a non-mutant TPM3-NTRK1 fusion gene, a non-mutant CD74-NTRK1 fusion gene, or a fusion gene having NTRK1 G595R And/or NTRK1 G667C Is a mutant NTRK1 fusion gene; optionally, the said compositions have NTRK1 G595R And/or NTRK1 G667C Is selected from the group consisting of mutant NTRK1 fusion genes having NTRK1 G595R And/or NTRK1 G667C TPM3-NTRK1 fusion gene or CD74-NTRK1 fusion gene;
    optionally, the NTRK1 fusion gene is selected from the group consisting of a non-mutant TPM3-NTRK1 fusion gene, having NTRK1 G595R Mutant NTRK1 fusion gene, non-mutant CD74-NTRK1 fusion gene, or CD74-NTRK1 G667C Fusion genes;
    optionally, the NTRK3 fusion gene is selected from a non-mutant ETV6-NTRK3 fusion gene, or has NTRK3 G623R Is a mutant NTRK3 fusion gene; optionally, the said compositions having NTRK3 G623R Is selected from the group consisting of a mutant NTRK3 fusion gene having NTRK3 G623R ETV6-NTRK3 fusion gene of (a);
    optionally, the NTRK3 fusion gene is selected from a non-mutant ETV6-NTRK3 fusion gene, or ETV6-NTRK3 G623R Fusion genes.
  8. A method of treating a tumor, the method comprising:
    1) Assaying a tumor sample obtained from a subject to determine whether the subject has a NTRK fusion gene or/and a TRK fusion protein; and
    2) Administering to a subject having a NTRK fusion gene or/and a TRK fusion protein a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof,
    optionally, the TRK fusion protein is selected from a wild-type (non-mutant) or mutant TRK fusion protein;
    alternatively, the TRK fusion protein is selected from a TRKA fusion protein, a TRKB fusion protein, and/or a TRKC fusion protein;
    alternatively, the TRK fusion protein is selected from a wild-type (non-mutant) or mutant TRKA fusion protein, a wild-type (non-mutant) or mutant TRKB fusion protein, and/or a wild-type (non-mutant) or mutant TRKC fusion protein;
    alternatively, the TRKA fusion protein is selected from a non-mutant TRKA fusion protein, or a mutant TRKA fusion protein having G595R and/or G667C;
    alternatively, the TRKC fusion protein is selected from a non-mutant TRKC fusion protein, or a mutant TRKC fusion protein having G623R;
    alternatively, the mutant TRK fusion protein is selected from TRKA G595R 、TRKA G667C Or TRKC G623R ；
    Optionally, the NTRK fusion gene is selected from a non-mutant or mutant NTRK fusion gene;
    optionally, the NTRK fusion gene is selected from the group consisting of non-mutant NTRK fusion genes;
    optionally, the NTRK fusion gene is selected from a mutant NTRK fusion gene;
    Alternatively, the NTRK fusion gene is selected from the group consisting of a NTRK1 fusion gene, a NTRK2 fusion gene, and a NTRK3 fusion gene;
    alternatively, the NTRK fusion gene may be a TPM3-NTRK1 fusion gene, an ETV6-NTRK3 fusion gene or a CD74-NTRK1 fusion gene;
    alternatively, the mutant NTRK fusion gene is selected from the group consisting of a gene having NTRK1 G595R 、NTRK1 G667C Or NTRK3 G623R Is a fusion gene of (2);
    optionally, the NTRK1 fusion gene is selected from a non-mutant TPM3-NTRK1 fusion gene, a non-mutant CD74-NTRK1 fusion gene, or a fusion gene having NTRK1 G595R And/or NTRK1 G667C Is a mutant NTRK1 fusion geneThe method comprises the steps of carrying out a first treatment on the surface of the Optionally, the said compositions have NTRK1 G595R And/or NTRK1 G667C Is selected from the group consisting of mutant NTRK1 fusion genes having NTRK1 G595R And/or NTRK1 G667C TPM3-NTRK1 fusion gene or CD74-NTRK1 fusion gene;
    optionally, the NTRK1 fusion gene is selected from the group consisting of a non-mutant TPM3-NTRK1 fusion gene, having NTRK1 G595R Mutant NTRK1 fusion gene, non-mutant CD74-NTRK1 fusion gene, or CD74-NTRK1 G667C Fusion genes;
    optionally, the NTRK3 fusion gene is selected from a non-mutant ETV6-NTRK3 fusion gene, or has NTRK3 G623R Is a mutant NTRK3 fusion gene; optionally, the said compositions having NTRK3 G623R Is selected from the group consisting of a mutant NTRK3 fusion gene having NTRK3 G623R ETV6-NTRK3 fusion gene of (a);
    Optionally, the NTRK3 fusion gene is selected from a non-mutant ETV6-NTRK3 fusion gene, or ETV6-NTRK3 G623R Fusion genes.
  9. The method, use, compound or kit of any one of claims 1-8, wherein the daily dose of the compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is selected from 0.5-100mg, or 0.5-25mg, or 2.5-25mg;
    or, the daily dosage is selected from 0.5mg, or 1mg, or 1.5mg, or 2mg, 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 9.5mg, 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 15.5mg, or 16mg, or 16.5mg, or 17mg, or 17.5mg, or 18mg, or 18.5mg, or 19mg, or 19.5mg, or 20mg, or 20.5mg, or 21mg, or 21.5mg, or 22mg, or 22.5mg, or 23mg, or 23.5mg, or 24mg, or 24.5mg, or 25mg, or 25.5mg, or 26mg, or 26.5mg, or 27mg, or or 27.5mg, or 28mg, or 28.5mg, or 29mg, or 29.5mg, or 30mg, or 30.5mg, or 31mg, or 31.5mg, or 32mg, or 32.5mg, or 33mg, or 33.5mg, or 34mg, or 34.5mg, or 35mg, or 35.5mg, or 36mg, or 36.5mg, or 37mg, or 37.5mg, or 38mg, or 38.5mg, or 39mg, or 39.5mg, or 40mg, or 42.5mg, or 45mg, or 47.5mg, or 50mg, or 52.5mg, or 55mg, or 57.5mg, or 60mg, or 62.5mg, or 65mg, or 67.5mg, or 70mg, or 72.5mg, or 75mg, or 77.5mg, or 80mg, or 82.5mg, or 85mg, or 87.5mg, or 90mg, or 92.5mg, or 97.5mg, or 100.5 mg, or any range thereof.
  10. The method, use, compound or kit of any one of claims 1-9, wherein the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is administered 3 times daily, 2 times daily, 1 time every two days, 1 time every three days, 1 time every four days, 1 time every five days, 1 time every six days, 3 times every week, 2 times every week, 1 time every two weeks, or 1 time every three weeks.
  11. The method, use, compound or kit of any one of claims 1-10, wherein the subject and/or subject is selected from a subject or subject with a pathologically and/or cytologically definitively diagnosed advanced malignant solid tumor, and/or a subject or subject who lacks conventional effective treatment methods or who fails or recurs after treatment by conventional methods; wherein the subject or subject is selected from primates, preferably humans;
    alternatively, the subject or subject is selected from a subject or subject who has been previously treated with a TRK inhibitor or who has not been previously treated with a TRK inhibitor.
  12. The method, use, compound or kit of any one of claims 1-11, wherein the tumor is selected from a solid tumor;
    alternatively, the tumor is selected from advanced malignant solid tumors;
    alternatively, the tumor is selected from adult advanced malignant solid tumors;
    Alternatively, the tumor is selected from glioma, tumor of the central nervous system, sarcoma, tumor of the peripheral primitive neuroectodermal, wilms' tumor, lung cancer, thyroid cancer, colorectal cancer, salivary gland cancer, biliary tract cancer, brain cancer, breast cancer, ductal breast cancer, head and neck cancer, cell cancer, pancreatic cancer, tumor of the male and female reproductive system, renal cancer, biliary duct cancer, gastric cancer, bronchi cancer, thoracic cancer, neuroendocrine tumor, lymphoma or melanoma;
    alternatively, the tumor is selected from soft tissue sarcoma, salivary gland tumor, thyroid cancer, lung cancer, melanoma, colorectal cancer, gastric cancer, interstitial tumor, bile duct cancer, breast cancer or pancreatic cancer;
    alternatively, the tumor is selected from lung cancer, adenocarcinoma, or oral cancer;
    alternatively, the lung cancer is selected from lung adenocarcinoma, the adenocarcinoma is selected from parotid adenocarcinoma or lung adenocarcinoma, and the oral cavity cancer is selected from basal mouth cancer;
    alternatively, the tumor is selected from lung adenocarcinoma, parotid adenocarcinoma, basal mouth carcinoma, acinar cell carcinoma or intestinal cancer.
  13. The method, use, compound or kit of any one of claims 1-11, wherein the tumor is selected from lung cancer, adenocarcinoma or oral cancer;
    alternatively, the lung cancer is selected from lung adenocarcinoma;
    alternatively, the adenocarcinoma is selected from parotid or lung adenocarcinoma;
    Alternatively, the oral cancer is selected from the group consisting of basal mouth cancer.
CN202280046303.XA 2021-08-23 2022-08-23 Use of amino-containing macrocyclic compounds for the treatment of TRK kinase mediated tumors Pending CN117597128A (en)

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RU2594742C2 (en) * 2010-05-20 2016-08-20 Эррэй Биофарма Инк. Macrocyclic compounds as trk kinase inhibitors
WO2017004342A1 (en) * 2015-07-02 2017-01-05 Tp Therapeutics, Inc. Chiral diaryl macrocycles as modulators of protein kinases
KR102619444B1 (en) * 2017-08-23 2023-12-29 치아타이 티안큉 파마수티컬 그룹 주식회사 Macrocycle containing aminopyrazole and pyrimidine and pharmaceutical compositions and uses thereof
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