WO2019149131A1 - Composé ayant une structure moléculaire macrocyclique et son utilisation - Google Patents

Composé ayant une structure moléculaire macrocyclique et son utilisation Download PDF

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Publication number
WO2019149131A1
WO2019149131A1 PCT/CN2019/072950 CN2019072950W WO2019149131A1 WO 2019149131 A1 WO2019149131 A1 WO 2019149131A1 CN 2019072950 W CN2019072950 W CN 2019072950W WO 2019149131 A1 WO2019149131 A1 WO 2019149131A1
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compound
formula
alkyl
present disclosure
solvate
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PCT/CN2019/072950
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English (en)
Chinese (zh)
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林菊芳
应永铖
廖敬礼
张秀
李宗然
袁纪军
贾伟
汪伟
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上海吉倍生物技术有限公司
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Priority to CN201980006719.7A priority Critical patent/CN111511749B/zh
Publication of WO2019149131A1 publication Critical patent/WO2019149131A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—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
    • C07D498/12—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 three hetero rings
    • C07D498/14—Ortho-condensed systems

Definitions

  • the present disclosure belongs to the field of medicinal chemistry, and in particular relates to a compound which is a small molecule kinase inhibitor having a macrocyclic molecular structure, a pharmaceutical composition comprising the compound, and a therapeutic use of the compound.
  • Recurrent gene fusion is a major factor driving the growth and survival of various malignancies.
  • Gene fusion mutations are distributed in almost all cancer types. With the development of NGS (next-generation sequencing) sequencing technology, the number of detectable fusion events has increased dramatically. Tumor fusion gene mutations not only play an important role in the diagnosis and prognosis, but also become an effective targeted drug. Research and development objects.
  • Tropomysin receptor kinase is a family of tyrosine kinases that regulate synaptic strength and plasticity in the mammalian nervous system, while NTRK (neurotrophic receptor tyrosine kinase) is a gene encoding TRK.
  • the NTRK gene includes NTRK1, NTRK2, and NTRK3, which are responsible for encoding the tropomyosin receptor kinase family proteins TRKA, TRKB, and TRKC, respectively.
  • Trk receptors can induce receptor dimerization, phosphorylation and activation of downstream PI3K, RAS/MAPK/ERK and PLC- ⁇ signaling cascades, and neural cell growth and development, pain perception, etc.
  • TRK is a potential target for the treatment of cancer. Although TRK fusion is very rare, it is widespread in a wide variety of rare tumors in adults and children. Due to the important role of TRK receptors in the nervous system and tumor cell growth and survival, TRK inhibitors are expected to be effective drugs for the treatment of pain and cancer.
  • NTRK inhibitors are Loxo Oncology's Larotrectinib (LOXO-101) and Ignyta's Entrectinib (RXDX-101), both of which show higher response rates in clinical trials, and Ignyta's Entrectinib has an activity that penetrates the blood-brain barrier and can have a positive effect on tumors that metastasize to the brain.
  • LOXO-101 Larotrectinib
  • RXDX-101 Ignyta's Entrectinib
  • Ignyta's Entrectinib has an activity that penetrates the blood-brain barrier and can have a positive effect on tumors that metastasize to the brain.
  • drug-resistant mutations against NTRK small molecule inhibitors have emerged in the clinic.
  • the second-generation drugs used to overcome the resistance of a generation of NTRK small molecule inhibitors have entered the clinic, including Loxo Oncology's LOXO- 195, and
  • ALK was first discovered in a subtype of anaplastic large cell lymphoma (ALCL), hence the name anaplasticlymphoma kinase (ALK). Subsequently, prior to the discovery of ALK gene rearrangement in non-small cell lung cancer, multiple types of ALK gene rearrangements were found in diffuse large B-cell lymphoma and inflammatory myofibroblastic tumor (IMT), respectively.
  • ALK is a potent carcinogenic driver gene.
  • ALK gene-associated translocations can be found in approximately 2-7% of non-small cell lung cancer (NSCLC), the most common being the EML4-ALK translocation. Rearrangement results in autophosphorylation and sustained activation of ALK, thereby activating the RAS and PI3K signaling cascades. RAS activation may result in more aggressive features of the tumor and a worse clinical outcome.
  • Pfizer's Crizotinib was the first FDA-approved ALK small molecule inhibitor. Later, Novartis's Ceritinib, Roche's Alectinib, and recently approved Ariad's Brigatinib were the second generation of Crizotinib, a second-line targeted drug that can effectively overcome Resistance to Crizotinib. The latest ALK inhibitor of the Pfizer ALK inhibitor, which has just acquired breakthrough therapy, has the highest ALK kinase activity and can more effectively overcome the resistance of first- and second-generation ALK inhibitors. Also clinically active is Beida's Ensartinib, and TP Therapeutics' TPX-0005.
  • the ROS1 gene encodes a receptor tyrosine kinase (RTK) that is involved in cell growth, proliferation, survival, and differentiation.
  • RTK receptor tyrosine kinase
  • the ROS1 gene can be fused to multiple genes. When ROS1 is fused with other genes, the kinase domain is generally retained and conserved at the breakpoint. Rearrangement of ROS1 leads to sustained activation of the kinase, up-regulation of SHP-1, SHP2, and PI3K, AKT, mTOR, MAPK, and ERK signaling pathways, resulting in sustained cell proliferation and tumorigenesis.
  • ROS1 gene The rearrangement of the ROS1 gene was first identified in human glioma cell lines, and subsequent rearrangements of ROS1 genes, such as cholangiocarcinoma, ovarian cancer, gastric cancer, and non-small cells, were also found in several other malignant tumors. Lung cancer, wherein the frequency of mutation in non-small cell lung cancer is 1% to 2%.
  • Crizotinib which has been approved by the FDA for accelerated clinical data, has better ROS1 inhibitory activity.
  • Ignyta's Entrectinib and Novartis's Ceritinib also have good ROS1 inhibitory activity, but they cannot effectively overcome the drug-resistant mutations produced by the first-line treatment of Crizotinib. Solvent front mutation etc. Therefore, they are also mainly conducting clinical trials of initial patients.
  • the present disclosure relates to a compound of the formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or a compound obtained by isotopic substitution of any atom in the compound of the formula (I),
  • R 1 , R 2 , R 3 , R 4 are each independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, C 1-6 alkyl, C 1-6 alkoxy, hydroxy, nitro, cyano or An amino group, wherein the C 1-6 alkyl group or C 1-6 alkoxy group may be optionally fluoro, chloro, bromo, iodo, C 1-4 alkyl, C 1-4 alkoxy, hydroxy, nitro Mono- or poly-substituted with a cyano group;
  • L is Or -(CH 2 ) n -NH-B-, where:
  • A is -(CH 2 ) m - or -CHR 5 -;
  • X is -CH 2 -, -NH- or -NR 6 -;
  • Z is -NH- or
  • R 5 and R 6 are each independently hydrazine, fluorine, chlorine, bromine, iodine, C 1-4 alkyl, C 1-4 alkoxy, hydroxy, nitro, cyano or amino, wherein said C 1-
  • the 4- alkyl or C 1-4 alkoxy group may be optionally monosubstituted by fluorine, chlorine, bromine, iodine, C 1-4 alkyl, C 1-4 alkoxy, hydroxy, nitro, cyano, amino Or multiple substitutions;
  • R 7 is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, C 1-4 alkyl, C 1-4 alkoxy, hydroxy, nitro, cyano or amino, wherein said C 1-4 alkyl or The C 1-4 alkoxy group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, C 1-4 alkyl, C 1-4 alkoxy, hydroxy, nitro, cyano, amino;
  • n are each independently 1, 2, 3, 4 or 5.
  • the present disclosure also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of the above formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer, a solvate or a compound of the formula (I) A compound obtained by replacement of any atom with its isotope, and a pharmaceutically acceptable carrier or excipient.
  • the present disclosure also relates to the preparation of a compound of the formula (I), a pharmaceutically acceptable salt, a stereoisomer, a solvate thereof or a compound obtained by isotopically replacing any of the compounds of the formula (I) Use in a medicament for treating or ameliorating the severity of the disease or condition, or in the preparation of one or more of tyrosine kinases including NTRK (eg NTRK1, NTRK2, NTRK3), ALK or ROS1 Use of a drug for an inhibitor.
  • NTRK eg NTRK1, NTRK2, NTRK3
  • ALK eg ROS1
  • the present disclosure also relates to a method of treating or lessening the severity of a disease or condition, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof , a stereoisomer, a solvate or a compound obtained by replacing any of the compounds of the formula (I) with an isotope thereof.
  • the present disclosure also relates to a method of inhibiting tyrosine kinases, including one or more of NTRK (eg, NTRK1, NTRK2, NTRK3), ALK, or ROS1, comprising causing at least one of the cells comprising the kinase and an effective amount a compound of the above formula (I), a pharmaceutically acceptable salt, a stereoisomer, a solvate thereof or a compound obtained by isotopically replacing any of the compounds of the formula (I), or at least one
  • the pharmaceutical compositions of the present disclosure are in contact, wherein the contacting is in vitro, ex vivo or in vivo.
  • the present disclosure also relates to a compound obtained by at least one compound of the above formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer, a solvate or a compound of the formula (I) which has been subjected to isotopic substitution thereof.
  • the severity of the disease or condition, or for inhibiting tyrosine kinases including one or more of NTRK (eg, NTRK1, NTRK2, NTRK3), ALK, or ROS1).
  • the disease or condition of the present disclosure is a plurality of childhood and/or adult solid tumors, such as breast cancer, colorectal cancer, that carry NTRK (eg, NTRK1, NTRK2, NTRK3), ALK, ROS1 gene fusion mutations, Lung cancer, pancreatic cancer, thyroid cancer, glioma, various sarcomas, and tumors of brain metastasis.
  • NTRK eg, NTRK1, NTRK2, NTRK3
  • ALK ROS1 gene fusion mutations
  • Lung cancer pancreatic cancer
  • thyroid cancer glioma
  • various sarcomas various sarcomas
  • tumors of brain metastasis a plurality of childhood and/or adult solid tumors, such as breast cancer, colorectal cancer, that carry NTRK (eg, NTRK1, NTRK2, NTRK3), ALK, ROS1 gene fusion mutations, Lung cancer, pancreatic cancer, thyroid cancer, gli
  • the present disclosure relates to a compound of the formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of the formula (I), which is obtained by isotopic substitution thereof Compound,
  • R 1 , R 2 , R 3 , R 4 are each independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, C 1-6 alkyl, C 1-6 alkoxy, hydroxy, nitro, cyano or An amino group, wherein the C 1-6 alkyl group or C 1-6 alkoxy group may be optionally fluoro, chloro, bromo, iodo, C 1-4 alkyl, C 1-4 alkoxy, hydroxy, nitro Mono- or poly-substituted with a cyano group;
  • L is Or -(CH 2 ) n -NH-B-, where:
  • A is -(CH 2 ) m - or -CHR 5 -;
  • X is -CH 2 -, -NH- or -NR 6 -;
  • Z is -NH- or
  • R 5 and R 6 are each independently hydrazine, fluorine, chlorine, bromine, iodine, C 1-4 alkyl, C 1-4 alkoxy, hydroxy, nitro, cyano or amino, wherein said C 1-
  • the 4- alkyl or C 1-4 alkoxy group may be optionally monosubstituted by fluorine, chlorine, bromine, iodine, C 1-4 alkyl, C 1-4 alkoxy, hydroxy, nitro, cyano, amino Or multiple substitutions;
  • R 7 is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, C 1-4 alkyl, C 1-4 alkoxy, hydroxy, nitro, cyano or amino, wherein said C 1-4 alkyl or The C 1-4 alkoxy group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, C 1-4 alkyl, C 1-4 alkoxy, hydroxy, nitro, cyano, amino;
  • n are each independently 1, 2, 3, 4 or 5.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I) after its isotopic substitution
  • the resulting compound, or any suitable embodiment of the present disclosure wherein:
  • R 1 , R 2 , R 3 , R 4 are each independently hydrogen, deuterium, fluorine, C 1-6 alkyl or C 1-6 alkoxy, wherein said C 1-6 alkyl or C 1-6 The alkoxy group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, C 1-4 alkyl, C 1-4 alkoxy, hydroxy, nitro, cyano, amino;
  • the C 1-6 alkyl or C 1-6 alkoxy group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, hydroxy, nitro, cyano, amino;
  • the C 1-6 alkyl or C 1-6 alkoxy group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, hydroxyl, nitro, amino.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein:
  • R 1 , R 2 , R 3 , R 4 are each independently hydrogen, fluoro, C 1-4 alkyl or C 1-4 alkoxy, wherein said C 1-4 alkyl or C 1-4 alkoxy The group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, C 1-4 alkyl, C 1-4 alkoxy, hydroxy, nitro, cyano, amino;
  • the C 1-4 alkyl or C 1-4 alkoxy group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino;
  • the C 1-4 alkyl or C 1-4 alkoxy group can be optionally mono- or polysubstituted by fluorine, chlorine, bromine, hydroxyl, nitro, amino.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein:
  • R 1 , R 2 , R 3 , R 4 are each independently hydrogen, fluoro or C 1-6 alkyl, wherein the C 1-6 alkyl group may be optionally fluoro, chloro, bromo, iodo, C 1 -4 alkyl, C 1-4 alkoxy, hydroxy, nitro, cyano, amino mono- or poly-substituted;
  • the C 1-4 alkyl group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino;
  • the C 1-4 alkyl group can be optionally mono- or polysubstituted by fluorine, chlorine, bromine, hydroxyl, nitro, amino.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein:
  • R 1 , R 2 , R 3 , R 4 are each independently hydrogen, fluoro or C 1-4 alkyl, wherein the C 1-4 alkyl group may be optionally fluoro, chloro, bromo, iodo, C 1 -4 alkyl, C 1-4 alkoxy, hydroxy, nitro, cyano, amino mono- or poly-substituted;
  • the C 1-4 alkyl group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino;
  • the C 1-4 alkyl group can be optionally mono- or polysubstituted by fluorine, chlorine, bromine, hydroxyl, nitro, amino.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 1 , R 2 , R 3 , R 4 are each independently hydrogen, fluoro or C 1-6 alkyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 1 , R 2 , R 3 , R 4 are each independently hydrogen, fluoro or C 1-4 alkyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope a compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 1 , R 2 , R 3 , R 4 are each independently hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl , isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy Or hexyloxy.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 1 , R 2 , R 3 , R 4 are each independently hydrogen, fluorine, chlorine, bromine, iodine.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope
  • R 1 , R 2 , R 3 , R 4 are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope a compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 1 , R 2 , R 3 , R 4 are each independently methoxy, ethoxy, propoxy, butoxy, pentyloxy Or hexyloxy.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope a compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 1 , R 2 , R 3 , R 4 are each independently hydrogen, fluoro, methyl, ethyl, n-propyl, isopropyl, or Butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy or butoxy.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope a compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 1 , R 2 , R 3 , R 4 are each independently hydrogen, fluoro, methyl, ethyl, n-propyl, isopropyl, or Butyl, isobutyl, tert-butyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 1 , R 2 , R 3 , R 4 are each independently hydrogen, fluoro, methyl, ethyl, n-propyl or isopropyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 1 , R 2 , R 3 , R 4 are each independently hydrogen, fluoro, methyl, ethyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 1 , R 2 , R 3 , R 4 are each independently hydrogen, fluoro or methyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I) after its isotopic substitution
  • R 1 is hydrogen, deuterium, C 1-6 alkyl or C 1-6 alkoxy, wherein said C 1-6 alkyl or C 1- 6 alkoxy can be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, C 1-4 alkyl, C 1-4 alkoxy, hydroxy, nitro, cyano, amino;
  • the C 1-6 alkyl or C 1-6 alkoxy group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, hydroxy, nitro, cyano, amino;
  • the C 1-6 alkyl or C 1-6 alkoxy group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, hydroxyl, nitro, amino.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope a compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 1 is hydrogen, C 1-4 alkyl or C 1-4 alkoxy, wherein said C 1-4 alkyl or C 1-4 The alkoxy group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, C 1-4 alkyl, C 1-4 alkoxy, hydroxy, nitro, cyano, amino;
  • the C 1-4 alkyl or C 1-4 alkoxy group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino;
  • the C 1-4 alkyl or C 1-4 alkoxy group can be optionally mono- or polysubstituted by fluorine, chlorine, bromine, hydroxyl, nitro, amino.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope a compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 1 is hydrogen or C 1-6 alkyl, wherein said C 1-6 alkyl group may be optionally fluoro, chloro, bromo, iodo, a mono- or poly-substituted C 1-4 alkyl group, a C 1-4 alkoxy group, a hydroxyl group, a nitro group, a cyano group, or an amino group;
  • the C 1-4 alkyl group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino;
  • the C 1-4 alkyl group can be optionally mono- or polysubstituted by fluorine, chlorine, bromine, hydroxyl, nitro, amino.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 1 is hydrogen or C 1-4 alkyl, wherein said C 1-4 alkyl group may be optionally fluoro, chloro, bromo, iodo, a mono- or poly-substituted C 1-4 alkyl group, a C 1-4 alkoxy group, a hydroxyl group, a nitro group, a cyano group, or an amino group;
  • the C 1-4 alkyl group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino;
  • the C 1-4 alkyl group can be optionally mono- or polysubstituted by fluorine, chlorine, bromine, hydroxyl, nitro, amino.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 1 is hydrogen or C 1-6 alkyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 1 is hydrogen or C 1-4 alkyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein: R 1 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl , isoamyl, neopentyl, hexyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy or hexyloxy.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope
  • R 1 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy , ethoxy, propoxy or butoxy.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope
  • R 1 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 1 is hydrogen, methyl, ethyl, n-propyl or isopropyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 1 is hydrogen, methyl, ethyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 1 is hydrogen or methyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 1 is hydrogen.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 1 is methyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 1 is ethyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 1 is n-propyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 1 is isopropyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 1 is n-butyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein: R 1 is isobutyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 1 is a tert-butyl group.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I) after its isotopic substitution
  • R 2 is hydrogen, deuterium, C 1-6 alkyl or C 1-6 alkoxy, wherein said C 1-6 alkyl or C 1- 6 alkoxy can be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, C 1-4 alkyl, C 1-4 alkoxy, hydroxy, nitro, cyano, amino;
  • the C 1-6 alkyl or C 1-6 alkoxy group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, hydroxy, nitro, cyano, amino;
  • the C 1-6 alkyl or C 1-6 alkoxy group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, hydroxyl, nitro, amino.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope a compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 2 is hydrogen, C 1-4 alkyl or C 1-4 alkoxy, wherein said C 1-4 alkyl or C 1-4 The alkoxy group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, C 1-4 alkyl, C 1-4 alkoxy, hydroxy, nitro, cyano, amino;
  • the C 1-4 alkyl or C 1-4 alkoxy group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino;
  • the C 1-4 alkyl or C 1-4 alkoxy group can be optionally mono- or polysubstituted by fluorine, chlorine, bromine, hydroxyl, nitro, amino.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 2 is hydrogen or C 1-6 alkyl, wherein said C 1-6 alkyl group may be optionally fluoro, chloro, bromo, iodo, a mono- or poly-substituted C 1-4 alkyl group, a C 1-4 alkoxy group, a hydroxyl group, a nitro group, a cyano group, or an amino group;
  • the C 1-4 alkyl group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino;
  • the C 1-4 alkyl group can be optionally mono- or polysubstituted by fluorine, chlorine, bromine, hydroxyl, nitro, amino.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope a compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 2 is hydrogen or C 1-4 alkyl, wherein said C 1-4 alkyl group may be optionally fluoro, chloro, bromo, iodo, a mono- or poly-substituted C 1-4 alkyl group, a C 1-4 alkoxy group, a hydroxyl group, a nitro group, a cyano group, or an amino group;
  • the C 1-4 alkyl group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino;
  • the C 1-4 alkyl group can be optionally mono- or polysubstituted by fluorine, chlorine, bromine, hydroxyl, nitro, amino.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 2 is hydrogen or C 1-6 alkyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 2 is hydrogen or C 1-4 alkyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein: R 2 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl , isoamyl, neopentyl, hexyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy or hexyloxy.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein: R 2 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy , ethoxy, propoxy or butoxy.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope
  • R 2 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope
  • R 2 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 2 is hydrogen, methyl, ethyl, n-propyl or isopropyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 2 is hydrogen, methyl, ethyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 2 is hydrogen or methyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 2 is H.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 2 is methyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 2 is ethyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 2 is n-propyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 2 is isopropyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 2 is n-butyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein: R 2 is isobutyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 2 is a tert-butyl group.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I) after its isotopic substitution
  • R 3 is hydrogen, deuterium, C 1-6 alkyl or C 1-6 alkoxy, wherein said C 1-6 alkyl or C 1- 6 alkoxy can be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, C 1-4 alkyl, C 1-4 alkoxy, hydroxy, nitro, cyano, amino;
  • the C 1-6 alkyl or C 1-6 alkoxy group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, hydroxy, nitro, cyano, amino;
  • the C 1-6 alkyl or C 1-6 alkoxy group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, hydroxyl, nitro, amino.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope a compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 3 is hydrogen, C 1-4 alkyl or C 1-4 alkoxy, wherein said C 1-4 alkyl or C 1-4 The alkoxy group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, C 1-4 alkyl, C 1-4 alkoxy, hydroxy, nitro, cyano, amino;
  • the C 1-4 alkyl or C 1-4 alkoxy group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino;
  • the C 1-4 alkyl or C 1-4 alkoxy group can be optionally mono- or polysubstituted by fluorine, chlorine, bromine, hydroxyl, nitro, amino.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 3 is hydrogen or C 1-6 alkyl, wherein said C 1-6 alkyl group may be optionally fluoro, chloro, bromo, iodo, a mono- or poly-substituted C 1-4 alkyl group, a C 1-4 alkoxy group, a hydroxyl group, a nitro group, a cyano group, or an amino group;
  • the C 1-4 alkyl group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino;
  • the C 1-4 alkyl group can be optionally mono- or polysubstituted by fluorine, chlorine, bromine, hydroxyl, nitro, amino.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope a compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 3 is hydrogen or C 1-4 alkyl, wherein said C 1-4 alkyl group may be optionally fluoro, chloro, bromo, iodo, a mono- or poly-substituted C 1-4 alkyl group, a C 1-4 alkoxy group, a hydroxyl group, a nitro group, a cyano group, or an amino group;
  • the C 1-4 alkyl group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino;
  • the C 1-4 alkyl group can be optionally mono- or polysubstituted by fluorine, chlorine, bromine, hydroxyl, nitro, amino.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 3 is hydrogen or C 1-6 alkyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 3 is hydrogen or C 1-4 alkyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope
  • R 3 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl , isoamyl, neopentyl, hexylmethoxy, ethoxy, propoxy, butoxy, pentyloxy or hexyloxy.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein: R 3 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy , ethoxy, propoxy or butoxy.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope
  • R 3 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope
  • R 3 is hydrogen, methyl, ethyl, n-propyl or isopropyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 3 is hydrogen, methyl or ethyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 3 is hydrogen or methyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 3 is H.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein: R 3 is methyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 3 is ethyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 3 is n-propyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 3 is isopropyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein: R 3 is n-butyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein: R 3 is isobutyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 3 is a tert-butyl group.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I) after its isotopic substitution
  • R 4 is hydrazine, fluorine, chlorine, bromine, iodine, C 1-6 alkyl or C 1-6 alkoxy, wherein said C 1-6
  • the alkyl or C 1-6 alkoxy group may be optionally monosubstituted by fluorine, chlorine, bromine, iodine, C 1-4 alkyl, C 1-4 alkoxy, hydroxy, nitro, cyano, amino or Multi-substitution
  • the C 1-6 alkyl or C 1-6 alkoxy group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, hydroxy, nitro, cyano, amino;
  • the C 1-6 alkyl or C 1-6 alkoxy group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, hydroxyl, nitro, amino.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope a compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 4 is fluoro, chloro, bromo, iodo, C 1-4 alkyl or C 1-4 alkoxy, wherein said C 1-4 alkane Or a C 1-4 alkoxy group may be optionally substituted by fluorine, chlorine, bromine, iodine, C 1-4 alkyl, C 1-4 alkoxy, hydroxy, nitro, cyano, amino or more Replace
  • the C 1-4 alkyl or C 1-4 alkoxy group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino;
  • the C 1-4 alkyl or C 1-4 alkoxy group can be optionally mono- or polysubstituted by fluorine, chlorine, bromine, hydroxyl, nitro, amino.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope
  • R 4 is fluoro, chloro, bromo, iodo, or C 1-6 alkyl, wherein said C 1-6 alkyl may be optionally fluorinated , chlorine, bromine, iodine, C 1-4 alkyl, C 1-4 alkoxy, hydroxy, nitro, cyano, amino mono- or poly-substituted;
  • the C 1-4 alkyl group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino;
  • the C 1-4 alkyl group can be optionally mono- or polysubstituted by fluorine, chlorine, bromine, hydroxyl, nitro, amino.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope a compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 4 is fluoro, chloro, bromo, iodo or C 1-4 alkyl, wherein said C 1-4 alkyl may be optionally fluoro, Chloro, bromo, iodo, C 1-4 alkyl, C 1-4 alkoxy, hydroxy, nitro, cyano, amino mono- or poly-substituted;
  • the C 1-4 alkyl group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino;
  • the C 1-4 alkyl group can be optionally mono- or polysubstituted by fluorine, chlorine, bromine, hydroxyl, nitro, amino.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 4 is fluorine, chlorine, bromine, iodine or a C 1-6 alkyl group.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope
  • R 4 is fluorine, chlorine, bromine, iodine or a C 1-4 alkyl group.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 4 is fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert Butyl, n-pentyl, isopentyl, neopentyl, hexyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy or hexyloxy.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 4 is fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert Butyl, methoxy, ethoxy, propoxy or butoxy.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 4 is fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert Butyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope
  • R 4 is fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl or isopropyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 4 is fluorine, chlorine, bromine, iodine, methyl or ethyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 4 is methyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 4 is ethyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein: R 4 is n-propyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 4 is isopropyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 4 is fluorine, chlorine, bromine or iodine.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 4 is fluoro.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 4 is chloro.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 4 is bromine.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 4 is iodine.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein:
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein:
  • L is Wherein: A, X, Y, Z are as defined in any suitable embodiment of the present disclosure.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope
  • L is -(CH 2 ) n -NH-B-, wherein: n, B are as defined in any suitable embodiment of the present disclosure.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope
  • A is -(CH 2 ) m -, wherein m is as defined in any of the applicable embodiments of the present disclosure.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope
  • A is -CHR 5 -, wherein R 5 is as defined in any of the applicable embodiments of the present disclosure.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope after the obtained compound, or any suitable embodiment disclosed in the present embodiment, wherein: X is -CH 2 -.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein: X is -NH-.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope
  • X is -NR 6 -, wherein R 6 is as defined in any of the applicable embodiments of the present disclosure.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein: Z is -NH-.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein: Z is
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope
  • B is -CHR 7 -, wherein R 7 is as defined in any of the applicable embodiments of the present disclosure.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 5 is hydrazine, fluorine, chlorine, bromine or iodine.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope a compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 5 is C 1-4 alkyl or C 1-4 alkoxy, wherein said C 1-4 alkyl or C 1-4 alkoxy The group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, C 1-4 alkyl, C 1-4 alkoxy, hydroxy, nitro, cyano, amino.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 5 is C 1-4 alkyl, wherein said C 1-4 alkyl group may be optionally fluoro, chloro, bromo, iodo, C 1 -4 alkyl, C 1-4 alkoxy, hydroxy, nitro, cyano, amino mono- or poly-substituted.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope a compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 5 is C 1-4 alkyl, wherein said C 1-4 alkyl group may be optionally monosubstituted by fluorine, chlorine, bromine, iodine or More substitution.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope a compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 5 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or t-butyl, wherein said R 5 It may optionally be mono- or polysubstituted by fluorine, chlorine, bromine or iodine.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 5 is methyl, ethyl, n-propyl, isopropyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 5 is n-propyl or isopropyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 5 is isopropyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 5 is hydroxy, nitro, cyano or amino.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 6 is hydrazine, fluorine, chlorine, bromine or iodine.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 6 is C 1-4 alkyl or C 1-4 alkoxy, wherein said C 1-4 alkyl or C 1-4 alkoxy The group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, C 1-4 alkyl, C 1-4 alkoxy, hydroxy, nitro, cyano, amino.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 6 is C 1-4 alkyl, wherein said C 1-4 alkyl group may be optionally fluoro, chloro, bromo, iodo, C 1 -4 alkyl, C 1-4 alkoxy, hydroxy, nitro, cyano, amino mono- or poly-substituted.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope a compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 6 is C 1-4 alkyl, wherein said C 1-4 alkyl group may be optionally monosubstituted by fluorine, chlorine, bromine or iodine or More substitution.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope a compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 6 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or t-butyl, wherein said R 6 It may optionally be mono- or polysubstituted by fluorine, chlorine, bromine or iodine.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 6 is methyl, ethyl, n-propyl, isopropyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 6 is methyl or ethyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 6 is methyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 6 is hydroxy, nitro, cyano or amino.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 7 is hydrazine, fluorine, chlorine, bromine or iodine.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope a compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 7 is C 1-4 alkyl or C 1-4 alkoxy, wherein said C 1-4 alkyl or C 1-4 alkoxy The group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, C 1-4 alkyl, C 1-4 alkoxy, hydroxy, nitro, cyano, amino.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 7 is C 1-4 alkyl, wherein said C 1-4 alkyl group may be optionally fluoro, chloro, bromo, iodo, C 1 -4 alkyl, C 1-4 alkoxy, hydroxy, nitro, cyano, amino mono- or poly-substituted.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope a compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 7 is C 1-4 alkyl, wherein said C 1-4 alkyl group may be optionally monosubstituted by fluorine, chlorine, bromine or iodine or More substitution.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope a compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 7 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or t-butyl, wherein said R 7 It may optionally be mono- or polysubstituted by fluorine, chlorine, bromine or iodine.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 7 is ethyl, n-propyl or isopropyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 7 is methyl, monofluoromethyl, difluoromethyl or trifluoromethyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 7 is methyl.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 7 is a trifluoromethyl group.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R 7 is hydroxy, nitro, cyano or amino.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: m is 1, 2 or 3.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein: m is 4 or 5.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein: m is 1 or 2.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope
  • m is 1.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein: m is 2.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein: n is 1, 2 or 3.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein: n is 4 or 5.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein: n is 1 or 2.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope
  • n is 1.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein: n is 2.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein:
  • A is -(CH 2 ) m - or -CHR 5 -;
  • X is -CH 2 -, -NH- or -NR 6 -;
  • Z is -NH- or
  • R 5 and R 6 are each independently hydrazine, fluorine, chlorine, bromine, iodine, C 1-4 alkyl, C 1-4 alkoxy, hydroxy, nitro, cyano or amino, wherein said C 1-
  • the 4- alkyl or C 1-4 alkoxy group may be optionally monosubstituted by fluorine, chlorine, bromine, iodine, C 1-4 alkyl, C 1-4 alkoxy, hydroxy, nitro, cyano, amino Or multiple substitutions;
  • n 1, 2, 3, 4 or 5.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein:
  • A is -(CH 2 ) m - or -CHR 5 -;
  • X is -CH 2 -, -NH- or -NR 6 -;
  • Z is -NH- or
  • R 5 and R 6 are each independently hydrazine, fluorine, chlorine, bromine, iodine, C 1-4 alkyl, C 1-4 alkoxy, hydroxy, nitro, cyano or amino, wherein said C 1-
  • the 4- alkyl or C 1-4 alkoxy group may be optionally monosubstituted by fluorine, chlorine, bromine, iodine, C 1-4 alkyl, C 1-4 alkoxy, hydroxy, nitro, cyano, amino Or multiple substitutions;
  • n 1 or 2.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein:
  • A is -(CH 2 ) m - or -CHR 5 -;
  • X is -CH 2 -, -NH- or -NR 6 -;
  • Z is -NH- or
  • R 5 and R 6 are each independently C 1-4 alkyl, wherein the C 1-4 alkyl group may be optionally fluoro, chloro, bromo, iodo, C 1-4 alkyl, C 1-4 alkane Oxyl, hydroxy, nitro, cyano, amino mono- or poly-substituted;
  • n 1 or 2.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein:
  • A is -(CH 2 ) m - or -CHR 5 -;
  • X is -CH 2 -, -NH- or -NR 6 -;
  • Z is -NH- or
  • R 5 and R 6 are each independently C 1-4 alkyl, wherein the C 1-4 alkyl group may be optionally monosubstituted by fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino or Multi-substitution
  • n 1 or 2.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein:
  • A is -(CH 2 ) m - or -CHR 5 -;
  • X is -CH 2 -, -NH- or -NR 6 -;
  • Z is -NH- or
  • R 5 and R 6 are each independently C 1-4 alkyl, wherein the C 1-4 alkyl group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine;
  • n 1 or 2.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein:
  • A is -(CH 2 ) m - or -CHR 5 -;
  • X is -CH 2 -, -NH- or -NR 6 -;
  • Z is -NH- or
  • R 5 and R 6 are each independently methyl, ethyl, n-propyl, isopropyl, methylpropyl, n-butyl, isobutyl or t-butyl;
  • n 1 or 2.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein:
  • A is -(CH 2 ) m - or -CHR 5 -;
  • X is -CH 2 -, -NH- or -NR 6 -;
  • Z is -NH-
  • R 5 and R 6 are each independently hydrazine, fluorine, chlorine, bromine, iodine, C 1-4 alkyl, C 1-4 alkoxy, hydroxy, nitro, cyano or amino, wherein said C 1-
  • the 4- alkyl or C 1-4 alkoxy group may be optionally monosubstituted by fluorine, chlorine, bromine, iodine, C 1-4 alkyl, C 1-4 alkoxy, hydroxy, nitro, cyano, amino Or multiple substitutions;
  • n 1 or 2.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein:
  • A is -(CH 2 ) m - or -CHR 5 -;
  • X is -NH- or -NR 6 -;
  • Z is -NH-
  • R 5 and R 6 are each independently C 1-4 alkyl, wherein the C 1-4 alkyl group may be optionally fluoro, chloro, bromo, iodo, C 1-4 alkyl, C 1-4 alkane Oxyl, hydroxy, nitro, cyano, amino mono- or poly-substituted;
  • n 1 or 2.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein:
  • A is -(CH 2 ) m - or -CHR 5 -;
  • X is -NH- or -NR 6 -;
  • Z is -NH-
  • R 5 and R 6 are each independently C 1-4 alkyl, wherein the C 1-4 alkyl group may be optionally monosubstituted by fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino or Multi-substitution
  • n 1 or 2.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein:
  • A is -(CH 2 ) m - or -CHR 5 -;
  • X is -NH- or -NR 6 -;
  • Z is -NH-
  • R 5 and R 6 are each independently C 1-4 alkyl, wherein the C 1-4 alkyl group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine;
  • n 1 or 2.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein:
  • A is -(CH 2 ) m - or -CHR 5 -;
  • X is -CH 2 -, -NH- or -NR 6 -;
  • Z is -NH-
  • R 5 and R 6 are each independently methyl, ethyl, n-propyl, isopropyl, methylpropyl, n-butyl, isobutyl or t-butyl;
  • n 1 or 2.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein:
  • A is -(CH 2 ) m - or -CHR 5 -;
  • X is -NH- or -NR 6 -;
  • Z is -NH-
  • R 5 and R 6 are each independently methyl, ethyl, n-propyl or isopropyl, wherein said R 5 and R 6 may be optionally mono- or polysubstituted by fluorine, chlorine, bromine or iodine;
  • n 1 or 2.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein:
  • A is -(CH 2 ) m - or -CHR 5 -;
  • X is -NH- or -NR 6 -;
  • Z is -NH-
  • R 5 is n-propyl or isopropyl
  • R 6 is methyl, trifluoromethyl, difluoromethyl or monofluoromethyl
  • n 1 or 2.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein:
  • A is -(CH 2 ) m - or -CHR 5 -;
  • X is -NH- or -NR 6 -;
  • Z is -NH-
  • R 5 is n-propyl or isopropyl
  • R 6 is a methyl group
  • n 1 or 2.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein:
  • A is -(CH 2 ) m - or -CHR 5 -;
  • X is -NH- or -NR 6 -;
  • Z is -NH-
  • R 5 is an isopropyl group
  • R 6 is a methyl group
  • n 1 or 2.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein:
  • A is -(CH 2 ) m - or -CHR 5 -;
  • X is -CH 2 -, -NH- or -NR 6 -;
  • Z is -NH-
  • R 5 and R 6 are each independently hydrazine, fluorine, chlorine, bromine, iodine, C 1-4 alkyl, C 1-4 alkoxy, hydroxy, nitro, cyano or amino, wherein said C 1-
  • the 4- alkyl or C 1-4 alkoxy group may be optionally monosubstituted by fluorine, chlorine, bromine, iodine, C 1-4 alkyl, C 1-4 alkoxy, hydroxy, nitro, cyano, amino Or multiple substitutions;
  • n 1 or 2.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein:
  • A is -(CH 2 ) m - or -CHR 5 -;
  • X is -NH- or -NR 6 -;
  • Z is -NH-
  • R 5 and R 6 are each independently C 1-4 alkyl, wherein the C 1-4 alkyl group may be optionally fluoro, chloro, bromo, iodo, C 1-4 alkyl, C 1-4 alkane Oxyl, hydroxy, nitro, cyano, amino mono- or poly-substituted;
  • n 1 or 2.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein:
  • A is -(CH 2 ) m - or -CHR 5 -;
  • X is -NH- or -NR 6 -;
  • Z is -NH-
  • R 5 and R 6 are each independently C 1-4 alkyl, wherein the C 1-4 alkyl group may be optionally monosubstituted by fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino or Multi-substitution
  • n 1 or 2.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein:
  • A is -(CH 2 ) m - or -CHR 5 -;
  • X is -NH- or -NR 6 -;
  • Z is -NH-
  • R 5 and R 6 are each independently C 1-4 alkyl, wherein the C 1-4 alkyl group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine;
  • n 1 or 2.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein:
  • A is -(CH 2 ) m - or -CHR 5 -;
  • X is -CH 2 -, -NH- or -NR 6 -;
  • Z is -NH-
  • R 5 and R 6 are each independently methyl, ethyl, n-propyl, isopropyl, methylpropyl, n-butyl, isobutyl or t-butyl;
  • n 1 or 2.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein:
  • A is -(CH 2 ) m - or -CHR 5 -;
  • X is -NH- or -NR 6 -;
  • Z is -NH-
  • R 5 and R 6 are each independently methyl, ethyl, n-propyl or isopropyl, wherein said R 5 and R 6 may be optionally mono- or polysubstituted by fluorine, chlorine, bromine or iodine;
  • n 1 or 2.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein:
  • A is -(CH 2 ) m - or -CHR 5 -;
  • X is -NH- or -NR 6 -;
  • Z is -NH-
  • R 5 is n-propyl or isopropyl
  • R 6 is methyl, trifluoromethyl, difluoromethyl or fluoromethyl
  • n 1 or 2.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein:
  • A is -(CH 2 ) m - or -CHR 5 -;
  • X is -NH- or -NR 6 -;
  • Z is -NH-
  • R 5 is n-propyl or isopropyl
  • R 6 is a methyl group
  • n 1 or 2.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein:
  • A is -(CH 2 ) m - or -CHR 5 -;
  • X is -NH- or -NR 6 -;
  • Z is -NH-
  • R 5 is an isopropyl group
  • R 6 is a methyl group
  • n 1 or 2.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein:
  • L is -(CH 2 ) n -NH-B-, where:
  • R 7 is C 1-4 alkyl, wherein the C 1-4 alkyl group may be optionally fluoro, chloro, bromo, iodo, C 1-4 alkyl, C 1-4 alkoxy, hydroxy, nitro Mono- or poly-substituted with a cyano group;
  • n 1, 2, 3, 4 or 5.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein:
  • L is -(CH 2 ) n -NH-B-, where:
  • R 7 is C 1-4 alkyl (for example methyl, ethyl, n-propyl, isopropyl, methylpropyl, n-butyl, isobutyl or tert-butyl), wherein said C 1-4 An alkyl group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, C 1-4 alkyl, C 1-4 alkoxy, hydroxy, nitro, cyano, amino;
  • n 1 or 2.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein:
  • L is -(CH 2 ) n -NH-B-, where:
  • R 7 is methyl, ethyl, n-propyl, isopropyl, trifluoromethyl
  • n 1 or 2.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein:
  • L is -(CH 2 ) n -NH-B-, where:
  • R 7 is methyl or trifluoromethyl
  • n 1 or 2.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein:
  • L is -(CH 2 ) n -NH-B-, where:
  • R 7 is a trifluoromethyl group
  • n 1 or 2.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein:
  • L is -(CH 2 ) n -NH-B-, where:
  • n 1 or 2.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein:
  • L is -(CH 2 ) n -NH-B-, where:
  • n 1.
  • the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein:
  • R 1 is hydrogen or methyl
  • R 2 is hydrogen or methyl
  • R 3 is hydrogen or methyl
  • R 4 is fluorine
  • L is Or -(CH 2 ) n -NH-B-, where:
  • A is -(CH 2 ) m - or -CHR 5 -;
  • X is -CH 2 -, -NH- or -NR 6 -;
  • Z is -NH- or
  • R 5 is an isopropyl group
  • R 6 is a methyl group
  • R 7 is a trifluoromethyl group
  • n 1 or 2;
  • n 1.
  • the present disclosure is directed to the compound of formula (I) selected from:
  • the present disclosure is also directed to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of the above formula (I), a pharmaceutically acceptable salt, stereoisomer, solvate thereof or formula (I) a compound obtained by replacing an arbitrary atom of a compound with its isotope, and a pharmaceutically acceptable carrier or excipient.
  • compositions described herein may contain one or more compounds of the present disclosure.
  • the pharmaceutical composition may contain more than one compound of the present disclosure.
  • the pharmaceutical composition can contain two or more compounds of the present disclosure.
  • the pharmaceutical composition may optionally further comprise one or more additional pharmaceutically active compounds.
  • the pharmaceutical composition comprises a compound of formula (I) of the present disclosure and a conventional pharmaceutical carrier or excipient.
  • the pharmaceutical composition can be administered by, for example, oral or parenteral routes.
  • the pharmaceutical compositions of the present disclosure can be prepared in a variety of dosage forms including, but not limited to, tablets, capsules, solutions, suspensions, granules or injections, etc., by conventional methods in the art, for example, by oral or parenteral routes.
  • the pharmaceutical compositions of the present disclosure may be presented in unit dosage forms containing a predetermined amount of active ingredient per unit dose.
  • Such units may contain from 0.001 to 1000 mg, for example, 0.05 mg, 0.1 mg, 0.5 mg, 1 mg, 10 mg, 20 mg, 50 mg, 80 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 500 mg, 750 mg or 1000 mg of the compound of the present disclosure, It depends on the disease being treated, the route of administration and the age, weight and condition of the subject, or the pharmaceutical composition may be present in unit dosage form containing a predetermined amount of active ingredient per unit dose.
  • the unit dose composition is those containing a daily or sub-dose as described herein, or an appropriate fraction thereof, of the active ingredient.
  • such pharmaceutical compositions can be prepared by any method known to those skilled in the art.
  • the compound of the general formula (I) of the present disclosure has an inhibitory activity against NTRK1, NTRK2, NTRK3, ALK and ROS1, and inhibits tumor growth and metastasis by inhibiting its related signaling pathway, and can be used for treating NTRK, ALK, and ROS1 genes.
  • NTRK1, NTRK2, NTRK3, ALK and ROS1 A variety of solid tumors in children and adults, including breast cancer, colorectal cancer, lung cancer, pancreatic cancer, thyroid cancer, glioma, and various sarcomas.
  • the compounds of the general formula (I) described in the present disclosure can also have a positive therapeutic effect on tumors of brain metastasis.
  • the present disclosure relates to a compound of the formula (I), a pharmaceutically acceptable salt, a stereoisomer, a solvate thereof or any of the compounds of the formula (I) which is obtained by isotopic substitution thereof
  • a compound in the manufacture of a medicament for treating or ameliorating the severity of the disease or condition, or in the preparation as a tyrosine kinase (including NTRK (eg, NTRK1, NTRK2, NTRK3), ALK or ROS1)
  • NTRK eg, NTRK1, NTRK2, NTRK3
  • ALK or ROS1 tyrosine kinase
  • the present disclosure is also directed to a method of treating or ameliorating the severity of a disease or condition, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula (I), which is pharmaceutically acceptable An acceptable salt, stereoisomer, solvate or a compound obtained by replacing any of the compounds of the formula (I) with an isotope thereof.
  • a compound of formula (I) which is pharmaceutically acceptable An acceptable salt, stereoisomer, solvate or a compound obtained by replacing any of the compounds of the formula (I) with an isotope thereof.
  • the present disclosure relates to methods of inhibiting tyrosine kinases, including one or more of NTRK (eg, NTRK1, NTRK2, NTRK3), ALK, or ROS1, comprising efficaciously containing cells in said kinase
  • NTRK eg, NTRK1, NTRK2, NTRK3
  • ALK e.g., NTRK1, NTRK2, NTRK3
  • ROS1 ROS1
  • the present disclosure also relates to a compound obtained by at least one compound of the above formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer, a solvate or a compound of the formula (I) which has been subjected to isotopic substitution thereof.
  • the severity of the disease or condition, or for inhibiting tyrosine kinases including one or more of NTRK (eg, NTRK1, NTRK2, NTRK3), ALK, or ROS1).
  • the disease or condition of the present disclosure is a plurality of childhood and/or adult solid tumors, such as breast cancer, colorectal cancer, that carry NTRK (eg, NTRK1, NTRK2, NTRK3), ALK, ROS1 gene fusion mutations, Lung cancer, pancreatic cancer, thyroid cancer, glioma, various sarcomas, and tumors of brain metastasis.
  • NTRK eg, NTRK1, NTRK2, NTRK3
  • ALK ROS1 gene fusion mutations
  • Lung cancer pancreatic cancer
  • thyroid cancer glioma
  • various sarcomas various sarcomas
  • tumors of brain metastasis a plurality of childhood and/or adult solid tumors, such as breast cancer, colorectal cancer, that carry NTRK (eg, NTRK1, NTRK2, NTRK3), ALK, ROS1 gene fusion mutations, Lung cancer, pancreatic cancer, thyroid cancer, gli
  • the method used in the preparation of the compounds of formula (I) herein depends on the desired compound.
  • the compounds of the present disclosure can be prepared by standard techniques known in the art and similar methods known in the art.
  • the various starting materials used in the reaction can be prepared by those skilled in the art based on prior knowledge, or can be obtained by methods well known in the literature, or can be passed. Commercially available.
  • the intermediates, starting materials, reagents, reaction conditions and the like used in the reaction scheme can be appropriately changed according to the knowledge of those skilled in the art.
  • the method of preparing the compound of formula (I) is as shown in the synthetic scheme below.
  • A is -(CH 2 ) m - or -CHR 5 -;
  • X is -NH- or -NR 6 -;
  • Z is -NH.
  • R 5 and R 6 are as defined in any suitable embodiment of the present disclosure.
  • alkyl refers to a monovalent saturated hydrocarbon chain having the specified number of carbon atoms.
  • a C 1-6 alkyl group means an alkyl group having 1 to 6 carbon atoms.
  • the C 1-4 alkyl group means an alkyl group having 1 to 4 carbon atoms.
  • the alkyl group can be straight or branched. In some embodiments, a branched alkyl group may have one, two or three branches.
  • Exemplary alkyl groups include, but are not limited to, methyl, methyl ethyl, ethyl, propyl (including n-propyl and isopropyl), methylpropyl, butyl (including n-butyl, isobutyl) And tert-butyl), pentyl (including n-pentyl, isopentyl and neopentyl) and hexyl.
  • alkoxy refers to the group -O-alkyl.
  • a C 1-6 alkoxy group contains from 1 to 6 carbon atoms.
  • the C 1-4 alkoxy group has 1 to 4 carbon atoms.
  • Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, and hexyloxy.
  • amino as used herein means -NH 2.
  • hydroxy as used herein means -OH.
  • cyano as used herein means -CN.
  • nitro as used herein means -NO 2 .
  • HATU 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • TEA Triethylamine, triethylamine
  • DCM Dichloromethane, dichloromethane
  • TFA Trifluoroacetic acid, trifluoroacetic acid
  • FDPP Pentafluorophenyl diphenylphosphinate, pentafluorophenyl diphenyl phosphate
  • DIPEA Diisopropylethylamine, N,N-diisopropylethylamine
  • DMF N, N-Dimethylformamide, N,N-dimethylformamide
  • DIAD Diisopropyl azodicarboxylate, diisopropyl azodicarboxylate;
  • TFAA Trifluoroacetic anhydride, trifluoroacetic anhydride
  • THF Tetrahydrofuran, tetrahydrofuran
  • DMSO dimethyl sulfoxide
  • ATP adenosine triphosphate, adenosine triphosphate
  • Tyr Tyrosine, tyrosine.
  • the unit “M” represents mol/L
  • ⁇ M represents ⁇ mol/L
  • nM represents nmol/L
  • subject refers to mammalian subjects (eg, dogs, cats, horses, cows, sheep, goats, monkeys, etc.) and human subjects, including male and female subjects, and includes newborns. , infants, adolescents, adolescents, adults and elderly subjects and also include a variety of races and ethnicities, including, but not limited to, whites, blacks, Asians, American Indians, and Hispanics.
  • pharmaceutically acceptable salt refers to a salt that retains the desired biological activity of the target compound and exhibits minimal undesirable toxicological effects.
  • pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compound or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid.
  • a "therapeutically effective amount" of a compound or other pharmaceutically active agent of the present disclosure is meant to be within a reasonable medical judgment sufficient to treat or prevent a disease in a patient but to be sufficiently low to avoid serious side effects (at a reasonable benefit/risk ratio) The amount.
  • the therapeutically effective amount of the compound will depend on the particular compound selected (eg, considering the potency, effectiveness, and half-life of the compound); the route of administration selected; the condition being treated; the severity of the condition being treated; the patient being treated Age, size, weight and physical condition; medical history of the patient being treated; duration of treatment; nature of concurrent therapy; desired therapeutic effect; and similar factors, but still routinely determined by one skilled in the art.
  • the dosage and method of use of the compounds of the present disclosure depend on a number of factors, including the age, weight, sex, natural health, nutritional status of the compound, the strength of the compound, the time of administration, the rate of metabolism, the severity of the condition, and the diagnosis and treatment. Subjective judgment of the physician.
  • a preferred dosage is from 0.001 to 1000 mg/kg body weight per day.
  • the amount administered is administered in a single daily dose or in several sub-doses per day, for example, 2, 3, 4, 5 or 6 doses per day. Alternatively, the administration can be carried out intermittently, for example once every other day, once a week or once a month.
  • a therapeutically effective amount of a salt or solvate or the like can be determined as a ratio of a therapeutically effective amount of the compound of the formula (I) itself.
  • the term "compound” refers to a compound of formula (I) as defined above, in any form, including various stereoisomers, any salt or non-salt form (eg, as a free acid or a free base).
  • Form, or as a salt, especially a pharmaceutically acceptable salt thereof, and any physical form thereof for example, including a non-solid form (eg, a liquid or semi-solid form) and a solid form (eg, an amorphous or crystalline form, specifically Polymorphic forms, solvate forms, including hydrated forms (e.g., mono-, di-, and hemi-hydrates), as well as mixtures of various forms.
  • Compound 14 was prepared by the preparation method described in Example 13.
  • This experiment uses The Kinase Assay Kit (purchased from Thermo Fisher Scientific, Cat. No. PV3190) measures the enzyme inhibitory activity of the test compound.
  • test compounds were the compounds 1-14 prepared in Examples 1 to 9 herein, and the positive control drugs RXDX-101, LOXO-101, TPX-0005 (where: RXDX101 was purchased from Selleck, Cat. No. S7998; LOXO-101 was purchased from Selleck , Item No.: S7960; TPX-0005 is prepared according to the method disclosed in WO2015112806A2).
  • test compound was dissolved in DMSO to prepare a mother liquor at a concentration of 20 mM.
  • the test compound was first diluted with DMSO to a different concentration gradient, and then 4 ⁇ l of the compound was added to 46 ⁇ l of H 2 O. , mix with the oscillator;
  • ATP configuration 5 ⁇ Kinase Buffer in the kit was made into 1.33 ⁇ Kinase Bufferr with deionized water, and 10 mM ATP was diluted with 1.33 ⁇ Kinase Buffer to prepare 4 times of the final concentration of different target experiments at different targets.
  • the final concentrations of ATP in the experiment were NTRK1: 400 uM; NTRK2: 25 uM; NTRK3: 50 uM.
  • the final concentration of NTRK1 was 1 ⁇ g/ml, and the final concentration of the substrate Tyr 01 was 2 ⁇ M.
  • the final concentration of NTRK2 was 0.3 ⁇ g/ml, and the final concentration of the substrate Tyr 01 was 2 ⁇ M.
  • the final concentration of NTRK3 was 1 ⁇ g/ml, and the final concentration of the substrate Tyr 01 was 2 ⁇ M.
  • a 384-well plate was taken, and the Kinase/Peptide mixed solution, ATP, and the test compound were separately added to a 384-well plate as shown in Table 1.
  • use development buffer to configure development reagent B add 5 ⁇ l per well, incubate for 1 hour at room temperature (20 ° C -25 ° C), and use Tecan microplate reader (purchase The values of IC 50 were calculated from the values of Tecan Corporation, model: Spark 10M (Ex. 400 nm, Em. 445 nm) and (Ex. 400 nm, Em. 520 nm). The results are shown in Table 2.

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Abstract

La présente invention concerne un composé représenté par la formule générale (1), le composé étant un petit inhibiteur de kinase moléculaire ayant une structure moléculaire macrocyclique. La présente invention concerne également une composition pharmaceutique comprenant le composé et son utilisation thérapeutique.
PCT/CN2019/072950 2018-01-30 2019-01-24 Composé ayant une structure moléculaire macrocyclique et son utilisation WO2019149131A1 (fr)

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CN114213329A (zh) * 2021-12-29 2022-03-22 中国农业科学院兰州畜牧与兽药研究所 一种芳基吡唑类化合物的制备方法
CN114929710A (zh) * 2019-12-03 2022-08-19 特普医药公司 用于治疗疾病的巨环
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US11878987B2 (en) 2018-06-25 2024-01-23 Beijing Innocare Pharma Tech Co., Ltd. Heterocyclic compound as TRK inhibitor
WO2021042890A1 (fr) * 2019-09-04 2021-03-11 罗欣药业(上海)有限公司 Composé hétérocyclique et son application en tant qu'inhibiteur de trk kinase
CN110804059A (zh) * 2019-09-30 2020-02-18 郑州泰基鸿诺医药股份有限公司 氨基甲酸酯类化合物、药物组合物及其应用
CN110804059B (zh) * 2019-09-30 2024-03-12 郑州泰基鸿诺医药股份有限公司 氨基甲酸酯类化合物、药物组合物及其应用
CN114929710A (zh) * 2019-12-03 2022-08-19 特普医药公司 用于治疗疾病的巨环
CN114929710B (zh) * 2019-12-03 2024-03-29 特普医药公司 用于治疗疾病的巨环
KR20230019833A (ko) * 2020-05-05 2023-02-09 뉴베일런트, 아이엔씨. 헤테로방향족 거대환식 에터 화학치료제
EP4146205A4 (fr) * 2020-05-05 2024-05-29 Nuvalent, Inc. Agents chimiothérapeutiques à base d'éther macrocyclique hétéroaromatique
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CN114213329B (zh) * 2021-12-29 2023-08-22 中国农业科学院兰州畜牧与兽药研究所 一种芳基吡唑类化合物的制备方法
CN114181152B (zh) * 2021-12-29 2023-08-22 中国农业科学院兰州畜牧与兽药研究所 一种芳基吡唑类药物中间体的制备方法
CN114213329A (zh) * 2021-12-29 2022-03-22 中国农业科学院兰州畜牧与兽药研究所 一种芳基吡唑类化合物的制备方法
CN114181152A (zh) * 2021-12-29 2022-03-15 中国农业科学院兰州畜牧与兽药研究所 一种芳基吡唑类药物中间体的制备方法
WO2024032390A1 (fr) * 2022-08-09 2024-02-15 苏州朗睿生物医药有限公司 Dérivé de triazole macrocyclique et son procédé de préparation et son utilisation

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