WO2021197467A1 - Composé antitumoral multicible, son procédé de préparation et son utilisation - Google Patents

Composé antitumoral multicible, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2021197467A1
WO2021197467A1 PCT/CN2021/085239 CN2021085239W WO2021197467A1 WO 2021197467 A1 WO2021197467 A1 WO 2021197467A1 CN 2021085239 W CN2021085239 W CN 2021085239W WO 2021197467 A1 WO2021197467 A1 WO 2021197467A1
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Prior art keywords
amino
pyran
tetrahydro
benzamide
indazol
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PCT/CN2021/085239
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English (en)
Chinese (zh)
Inventor
许忻
陈嘉
王贯
杨旭芹
***
张雨云
陈春桥
张小娟
瞿敏凯
周晓波
王艺瑾
王影
夏小二
Original Assignee
上海华汇拓医药科技有限公司
浙江华海药业股份有限公司
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Priority to CN202180022963.XA priority Critical patent/CN115916771A/zh
Publication of WO2021197467A1 publication Critical patent/WO2021197467A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention belongs to the field of medicinal chemistry, and specifically relates to a new type of small molecule compound with multiple kinase inhibitory activity and a preparation method thereof, as well as the use of this type of compound in preventing and treating tumors.
  • Gene fusion is a driving factor for many malignant tumors. Structurally, they fuse with upstream genes and maintain a complete tyrosine kinase domain, independent of ligand dimerization, leading to continuous activation of downstream signals to promote tumor cell growth and proliferation. With the continuous maturity and improvement of technologies such as second-generation sequencing and RT-PCR, many clinically relevant fusion genes have been detected. Including NTRK1, NTRK2, NTRK3 (encoding TRKA, TRKB and TRKC protein), ALK, ROS1, etc.
  • Tropomyosin receptor kinase Tropomyosin receptor kinase
  • TRK Tropomyosin receptor kinase
  • NTRK1, NTRK2 and NTRK3 genes which are found in neuronal tissues It is widely expressed and participates in the maintenance, signal transduction and survival of neuronal cells.
  • TRK is a transmembrane receptor composed of extracellular ligand binding domain, transmembrane and intracellular ATP binding domain.
  • TRKA, TRKB and TRKC show a high degree of structural similarity, including two immunoglobulin-like motifs (Ig1 and Ig2), which are considered to contain ligand binding sites, and three rich The 24-residue motif containing leucine (LRR1-3 motif), two cysteine clusters (C1 and C2) flanking the LRR1-3 motif are specific to TRK protein, Not found in other subfamily of amino acid kinases.
  • the TRKA is a high-affinity receptor for nerve growth factor (hereinafter referred to as NGF), and the TRKB is a high-affinity receptor for brain-derived neurotrophic factor (BDNF) and neurotrophic factor (hereinafter referred to as NT)-4/5. Affinity receptor, and the TRKC is a high affinity receptor for NT-3.
  • NGF nerve growth factor
  • BDNF brain-derived neurotrophic factor
  • NT neurotrophic factor-4/5.
  • Affinity receptor NT-4/5
  • the TRKC is a high affinity receptor for NT-3. It is known that the activation of TRKA in peripheral nerves by NGF causes hyperalgesia, including nociceptive pain, neuropathic pain, and osteoarthritis, chronic low back pain, rheumatoid arthritis, fractures, interstitial cystitis, and chronic pancreatitis. In cancer pain accompanied by two of the above-mentioned pain types.
  • the literature shows that the activation of the BDNF/TrkB pathway is also involved in various types of pain, including inflammatory pain, neuropathic pain and surgical pain, so TRKA kinase and other TRK kinase inhibitors can provide chronic pain states. Effective treatment.
  • changes in the TRK signaling pathway including gene fusion, protein overexpression, or single nucleotide changes, have been found to be associated with many cancers.
  • the cancer includes neuroblastoma, ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, multiple myeloma, astrocytoma and medulloblastoma, glioma, melanoma, thyroid cancer, lung gland Cancer, large cell neuroendocrine tumors, and colorectal cancer.
  • NTRK gene fusion is the most clear cause of cancer.
  • TRK fusion protein can drive the spread and growth of TRK fusion tumors by activating PI3K, RAS/MAPK/ERK and PLC- ⁇ pathways and triggering a permanent signal cascade reaction independently of ligand dimerization and phosphorylation.
  • the NTRK gene fusion can occur in any part of the body, so TRK fusion cancer may appear in a variety of adult and child solid tumors, including breast analog secreting carcinoma (MASC), colon cancer, lung cancer, pancreatic cancer, thyroid cancer, And various sarcomas.
  • MSC breast analog secreting carcinoma
  • NTRK gene fusions in lung cancer About 1 to 3% of NTRK gene fusions in lung cancer; 0.5% to 1% of NTRK gene fusions in colon cancer, breast cancer, thyroid cancer, and melanoma; salivary gland cancer, a juvenile breast-secreting cancer and infant fiber
  • the incidence of NTRK gene fusion in sarcoma exceeds 90%. Therefore, inhibitors of the TRK kinase family have utility in the treatment of cancer.
  • Anaplastic lymphoma kinase (hereinafter referred to as ALK) is a 200kd receptor tyrosine kinase encoded by the ALK gene on chromosome 2p23.
  • ALK belongs to the insulin receptor superfamily. ALK plays an important role in fetal development, but it is not expressed in adult tissues except brain tissue. ALK is considered to be an oncogene. Studies have found that it is abnormally expressed in B-cell lymphoma, inflammatory myofibroblastoma, some non-small cell lung cancer, kidney cancer, colorectal cancer, and neuroblastoma.
  • the ALK gene rearrangement allows it to get rid of the control of the silent promoter, accompanied by the transcription and translation activation protein of the fusion gene, and the ALK fusion protein is mainly expressed in the cytoplasm, which transduce mitosis, cell survival and anti-apoptotic signals to the nucleus through intracellular pathways. effect.
  • chromosomal translocation causes NPM-ALK gene fusion.
  • NPM small cell lung cancer
  • ALK abnormal expression tumors respond well to targeted small molecule inhibitors, such as crizotinib (crizotinib) has been approved for clinical treatment of advanced and metastatic ALK-positive non-small cell lung cancer, and in inflammatory myofibroblastoma and The effect is good in anaplastic large cell lymphoma. Therefore, small molecule inhibitors of ALK are beneficial for therapeutic intervention in ALCL, NSCLC, neuroblastoma, and other cancers that rely on ALK for growth and survival.
  • crizotinib crizotinib
  • ROS1 The c-ROS proto-oncogene 1 (hereinafter referred to as ROS1) was first discovered to be the transformation sequence of the proto-oncogene and the UR2 avian sarcoma virus.
  • the ROS1 gene is located on chromosome 6q22.1, with 46 exons and a total length of 127kb.
  • the protein encoded by this gene is a type I integral membrane protein with tyrosine kinase activity, belonging to the receptor tyrosine kinase family (RTK). ) Member, the protein contains 2347 amino acids and functions as a growth or differentiation factor receptor.
  • ROS1 protein is highest in the kidney, followed by the cerebellum, peripheral nerve tissue, stomach, small intestine and colon, and lower expression in other tissues.
  • ROS1 is a new tumor driver mutation gene, and its fusion is designated as a new molecular subtype in non-small cell lung cancer.
  • the ROS1 gene rearrangement was first identified in human glioma cell lines, and subsequent ROS1 gene rearrangements were also found in several other malignant tumors, such as cholangiocarcinoma, ovarian cancer, gastric cancer and non-small cells Lung cancer, where the mutation frequency in non-small cell lung cancer is 1%-2%.
  • ROS1 fuses with other genes, the extracellular region is lost, the transmembrane region and the intracellular tyrosine kinase region are retained, and the rearrangement sites mainly occur in exons 32 to 36 of the ROS1 gene.
  • the ROS1 gene rearrangement produces a fusion protein with a constitutively active kinase domain that activates downstream signaling pathways in cells that lead to oncogenic properties, including uncontrolled proliferation and prolonged tumor cell survival resistance Cell death. These pathways include the Ras-ERK pathway for cell proliferation, as well as the JAK-STAT pathway and PI3K/AKT pathway, which regulate cell survival (anti-apoptosis) and proliferation.
  • the ROS1 fusion protein can also activate the mTOR pathway, which is essential for regulating protein translation. Cancers that have these pathways activated tend to be more aggressive, and invasion and metastasis lead to poorer survival rates for patients.
  • the ROS1 gene can undergo fusion mutations with multiple genes, and the most important fusion partner is CD74. For example, in NSCLC, the ROS1 gene is mainly fused with SLC34A2 and CD74 and continuously activates the ROS1 tyrosine kinase domain and downstream signaling pathways, which in turn causes tumors.
  • Inhibitors of RTK have the potential to cause the death of cancer cells that depend on dysregulation of RTK activity without damaging normal tissues.
  • TRK family protein tyrosine kinase inhibitors can be used to treat pain, inflammation, cancer and certain infectious diseases. Therefore, small molecule inhibitors targeting TRK, ALK, and ROS1 have promising therapeutic prospects.
  • the present invention relates to a class of small molecule inhibitors targeting TRK, ALK, and ROS1, and specifically relates to a class of compounds represented by formula II or their tautomers, mesosomes, racemates, and enantiomers Isomers, diastereomers, and mixtures thereof, and pharmaceutically acceptable salts, polymorphs, solvates, prodrugs, metabolites, isotope derivatives, and compounds containing said compounds
  • the pharmaceutical composition can be used to prevent or treat various types of cancer,
  • Y 1 is carbon
  • Y 3 is nitrogen
  • Y 2 is carbon
  • Y 4 is carbon
  • Y 5 is carbon
  • Y 1 is nitrogen
  • Y 2 is nitrogen
  • Y 3 is carbon
  • Y 4 is carbon
  • Y 5 is carbon
  • X is carbon or nitrogen
  • R 1 is -CF 2 -R 6 ⁇
  • R 2 is -NR a R b , -SO 2 -NR a R b , -S(O)-NR a R b , -S(O)-(CH 2 ) 2 -NR a R b , 4-10 yuan Heterocyclic group, -C 4-10 cycloalkyl group, wherein said 4-10 membered heterocyclic group or said -C 4-10 cycloalkyl group includes monocyclic, bicyclic, tricyclic, bridged ring or spiro ring Structure of the compound group;
  • the 4-10 membered heterocyclic group or -C 4-10 cycloalkyl group may be mono- or multi-substituted by the following groups: -OH, -C 1-3 alkyl, -C 3-6 cycloalkyl, 4-6 membered heterocyclic group, 5-10 membered heteroaryl group, -OC 1-4 alkyl, -NR c R d , -NH 2 , halogen, -C 1-3 haloalkyl, phenyl or cyano;
  • R 2 is preferably
  • R a and R b are independently hydrogen, -C 1-3 alkyl, -C 3-6 cycloalkyl, -C 1-4 alkylene-OH, -C 1-3 alkylene-C 3 -9 heterocycloalkyl, -C 1-3 alkylene-C 5-6 oxoheterocycloalkyl , -C 1-3 alkylene-C 4-6 cycloalkyl, -C(O)- (CH 2 ) n -T, wherein the -C 3-9 heterocycloalkyl group includes a compound group with a monocyclic, bicyclic, tricyclic, bridged ring or spiro ring structure, wherein the -C 3-9
  • the heterocycloalkyl group may be mono- or poly-substituted by the following groups: -C 1-3 alkyl, halogen, -C 1-3 haloalkyl, -OH, oxo or cyano;
  • R a and R b or together with the nitrogen atom to which they are attached form a 4-9 membered heterocycloalkyl which is unsubstituted or substituted with a T group or -NR c R d , and T is -C 1-4 alkyl , -C 2-4 alkyl substituted by -C 1-3 alkyl, -C 3-6 cycloalkyl, 4-6 membered heterocyclic group, -C 1-3 haloalkyl, -(CH 2 ) n -NR c R d ;
  • R c and R d are independently hydrogen, -C 1-3 alkyl, -C 1-4 alkylene-OH, -C 2-4 alkylene -OCH 3 , -(CH 2 ) 2 -OC 1-3 alkyl;
  • R 3 is -NH-C 4-8 cycloalkyl, -NH-C 3-8 heterocycloalkyl, -NH-CH 2 -C 3-8 heterocycloalkyl or -OC 1-4 alkyl; R 3 is preferably -OC 1-4 alkyl, -NH-CH 2 -C 4-5 heterocycloalkyl; T is -C 1-4 alkyl; T 1 is -O, -S, -NH, -N-CH 3 ;
  • R 4 is phenyl, heteroaryl, -NH-phenyl, wherein the phenyl group may be substituted by R 2 and/or R k , and the heteroaryl group may be substituted by R 2 ;
  • R k is halogen or -OC 1-4 alkyl;
  • R 4 is preferably X 1 is carbon or nitrogen;
  • R 6 is a phenyl group or a 4-6 membered heterocycloalkyl group, wherein the phenyl group or a 4-6 membered heterocycloalkyl group is mono- or di-substituted by the following groups: halogen, -OH, -C 1-3 Alkyl, -C(CH 3 ) 2 -OH or cyano; R 6 is preferably
  • R 7 is hydrogen, -C 1-3 alkyl, -(CH 2 ) n -OH, C 1-3 haloalkyl, -(CH 2 ) n -OC 1-3 alkyl, -(CH 2 ) n- OC(O)-C 1-3 alkyl; R 7 is preferably hydrogen, -(CH 2 ) n -OH, -(CH 2 ) n -F, -(CH 2 ) n -OC 1-3 alkyl;
  • n 1 or 2.
  • the present invention provides a method for preparing a compound represented by general formula II, which is prepared by the following scheme:
  • the oxidizing agent is preferably Dess-Martin oxidizing agent, PCC, PDC and other oxidizing agents
  • the fluorinating agent is preferably BAST, DAST and other fluorinating agents.
  • the amide forming method is preferably carboxylic acid reacting with acid chloride to amine to make amide, or carboxylic acid After 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI)/1-hydroxybenzotriazole (HOBT), cyclohexylcarbodiimide (DCC), 2 -(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) and other condensing agents are activated to form amides with amines;
  • EDCI 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride
  • HOBT cyclohexy
  • the oxidizing agent is preferably Dess-Martin oxidant, PCC, PDC and other oxidants; the method of forming the three-membered ring is preferably diethyl zinc/diiodomethane, trimethyl sulfoxide iodide or trimethyl sulfoxide bromide Salt/sodium hydrogen; the boronating reagent is preferably borane, 9-BBN, etc.; the oxidizing reagent is preferably hydrogen peroxide; the fluorinating reagent is preferably fluorinating reagents such as BAST and DAST; To amide, or carboxylic acid through 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI)/1-hydroxybenzotriazole (HOBT), cyclohexyl carbodiimide Amine (DCC), 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea
  • halogenation is actually preferably bromine, iodine, N-bromosuccinimide, N-iodosuccinimide, etc., and the coupling reaction is preferably Stille reaction;
  • the nitrating reagent is preferably nitric acid, potassium nitrate, sodium nitrate, etc.
  • the reducing reagent is preferably iron powder, zinc powder, stannous chloride, hydrogen/palladium on carbon, hydrogen/nickel, etc.
  • the amide formation method is preferably carboxylic acid through acid chloride to amine Reaction to produce amide, or carboxylic acid through 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI)/1-hydroxybenzotriazole (HOBT), cyclohexyl carbon Diimine (DCC), 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) and other condensing agents are activated to form amides with amines;
  • EDCI 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydro
  • the pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.
  • Suitable acid addition salts are formed by acids that form non-toxic salts, examples include but are not limited to hydrochloride, sulfate/bisulfate, nitrate, phosphate/hydrogen phosphate/dihydrogen phosphate, hydrobromic acid Salt, hydroiodide, acetate, lactate, methanesulfonate, citrate, malate, maleate, fumarate, tartrate, salicylate, stearate , And its similar salt.
  • Suitable base addition salts are formed from bases that form non-toxic salts, for example as alkali metal salts, alkaline earth metal salts, or as ammonium salts. Examples include, but are not limited to, sodium, potassium, calcium, magnesium, or with ammonia Or organic amines such as ethylamine, ethanolamine, triethanolamine or salts of amino acids.
  • the present invention also includes internal salts or betaines (zwitterions) in addition to the salt forms mentioned.
  • the compound of formula (II) may exist in crystalline or amorphous form.
  • certain crystal forms of the compound of formula (II) may exist in polymorphic forms, which are included in the scope of the present invention.
  • Many conventional analysis techniques can be used including but not limited to single crystal X-ray powder diffraction (XRPD) patterns, infrared (IR) spectroscopy, Raman spectroscopy, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and solids Nuclear magnetic resonance (ssNMR) characterization to distinguish the polymorphic forms of the compound.
  • the compounds of the present invention also include tautomeric forms.
  • the tautomeric form is produced by the exchange of a single bond with an adjacent double bond and the accompanying migration of protons.
  • Tautomeric forms include proton transfer tautomers, which are isomeric protonated states with the same empirical formula and total charge. Examples of proton transfer tautomers include keto-enol pairings, amide-imine pairings, lactam-lactam pairings, enamine-imine pairings, and two in which protons can occupy the heterocyclic ring system.
  • Tautomeric forms can be in equilibrium or sterically fixed to one form by appropriate substitution.
  • the present invention further relates to the compound represented by the general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer, and mixtures thereof, and
  • the pharmaceutically acceptable salt or the pharmaceutical composition containing the same is further used in combination with another one or more agents for regulating the immune system of mammals, anticancer agents or anti-inflammatory agents.
  • the present invention further relates to the compound represented by the general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer, and mixtures thereof, and Its pharmaceutically acceptable salt or pharmaceutical composition containing it is used to treat or prevent the following cancers, including solid tumors (such as prostate cancer, kidney cancer, liver cancer, pancreatic cancer, stomach cancer, breast cancer, lung cancer, head and neck cancer, Thyroid cancer, glioblastoma, melanoma, etc.), blood cancer (such as lymphoma, leukemia, etc.), skin cancer (such as skin T-cell lymphoma, skin B-cell lymphoma), etc.
  • solid tumors such as prostate cancer, kidney cancer, liver cancer, pancreatic cancer, stomach cancer, breast cancer, lung cancer, head and neck cancer, Thyroid cancer, glioblastoma, melanoma, etc.
  • blood cancer such as lymphoma, leukemia, etc.
  • skin cancer such as skin T-cell lymph
  • the present invention also relates to a method for treating or preventing cancer, which comprises administering to a patient a therapeutically effective amount of a compound represented by general formula (II) or its tautomers, mesosomes, racemates, Enantiomers, diastereomers, and mixtures thereof, and pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them, wherein the cancer includes, for example, solid tumors (such as prostate cancer, renal cancer) , Liver cancer, pancreatic cancer, stomach cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, melanoma, etc.), blood cancer (such as lymphoma, leukemia, etc.), skin cancer (such as skin T- Cell lymphoma, skin B-cell lymphoma) and so on.
  • solid tumors such as prostate cancer, renal cancer
  • Liver cancer pancreatic cancer
  • stomach cancer breast cancer
  • lung cancer head and neck cancer
  • thyroid cancer glioblastoma, melanoma,
  • composition of the present invention can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. Therefore, the active compound of the present invention can be formulated into a dosage form for oral, buccal administration, intranasal, parenteral (for example, intravenous, intramuscular or subcutaneous) or rectal administration, or suitable for administration by inhalation or insufflation.
  • the dosage form of the medicine can also be formulated into sustained release dosage forms.
  • the pharmaceutical composition can be made into various types of administration unit dosage forms, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, and injections (solutions and suspensions). Or it is suitable for a dosage form for administration by inhalation or insufflation.
  • any excipient known and widely used in the art can be used.
  • carriers such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose and silicic acid, etc.
  • binders such as water, ethanol, propanol, ordinary syrup, glucose solution, starch Solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose and potassium phosphate, polyvinylpyrrolidone, etc.
  • disintegrating agent such as dry starch, sodium alginate, agar powder and kelp powder, sodium bicarbonate, carbonic acid Fatty acid esters of calcium, polyethylene sorbitan, sodium lauryl sulfate, monoglyceride stearate, starch and lactose, etc.
  • disintegration inhibitors such as white sugar, glyceryl tristearate, coconut oil and hydrogenated Oil
  • Adsorption promoters such as quaternary sulfate, sodium lauryl
  • any known and widely used excipients in the art can be used, for example, carriers such as lactose, starch, coconut oil, hardened vegetable oil, kaolin and talc, etc.; binders , Such as gum arabic powder, gum tragacanth powder, gelatin and ethanol; disintegrants such as agar and kelp powder.
  • carriers such as lactose, starch, coconut oil, hardened vegetable oil, kaolin and talc, etc.
  • binders Such as gum arabic powder, gum tragacanth powder, gelatin and ethanol
  • disintegrants such as agar and kelp powder.
  • any excipient known and widely used in the art can be used, for example, polyethylene glycol, coconut oil, higher alcohols, esters of higher alcohols, gelatin and semi-synthetic glycerides Wait.
  • the solution or suspension can be sterilized (preferably by adding an appropriate amount of sodium chloride, glucose or glycerol, etc.) to prepare an injection that is isotonic with blood.
  • any carriers commonly used in the art can also be used.
  • usual dissolving agents, buffering agents and analgesics can also be added.
  • the active compound of the present invention is suitably released in the form of a solution or suspension from a pump spray container received or squeezed or sucked, or in the form of a spray. Release from a pressurized container or aerosol, and use a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gases.
  • a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gases.
  • the dosage unit can be determined by a valve that provides a metered release.
  • the pressurized container or nebulizer may contain a solution or suspension of the active compound.
  • Capsules or cartridges (for example made of gelatin) used in inhalers or insufflators can be formulated as a powder mixture containing the compound of the invention and a suitable powder
  • stereoisomer means an isomer formed due to at least one asymmetric center. In compounds with one or more (for example, one, two, three or four) asymmetric centers, it can produce racemates, racemic mixtures, mesosomes, single enantiomers , Diastereomeric mixtures and individual diastereomers. Certain individual molecules can also exist as geometric isomers (cis/trans).
  • solvate refers to a form of a compound that is generally physically combined with a solvent through a solvolysis reaction. This physical bond includes hydrogen bonding.
  • solvents include water, ethanol, methanol, acetic acid and the like.
  • the compound of formula (II) can be prepared in crystalline form and can be in the form of a solvate (e.g., a hydrated form).
  • Suitable solvates include pharmaceutically acceptable solvates (such as hydrates), and further include stoichiometric solvates and non-stoichiometric solvates. In some cases, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be able to dissociate.
  • “Solvate” encompasses both solution-phase and dissociable solvates. Representative solvates include hydrates, ethanolates, methanolates, and the like.
  • prodrug refers to a derivative that is converted into a compound of the present invention by reaction with enzymes, gastric acid, etc. in the living body under physiological conditions, for example, through oxidation, reduction, hydrolysis, etc., respectively, catalyzed by enzymes.
  • metabolite refers to all molecules derived from any compound of the present invention in a cell or organism, preferably a human.
  • isotopic derivative refers to a compound that contains isotopes in unnatural proportions at one or more of the atoms constituting the compound.
  • deuterium 2 H or D
  • tritium 3 H or T
  • carbon-13 13 C
  • nitrogen-15 15 N
  • oxygen-18 18 O
  • pharmaceutical composition means a mixture containing one or more of the compounds of the present invention or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, such as physiologically/pharmaceutically acceptable Carriers and excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredient and thus the biological activity.
  • the carrier includes all pharmaceutical preparations in the pharmaceutical field that can be used for injection and non-injection administration routes, such as diluents, wetting agents, fillers, adhesives, slip agents, disintegrants, absorption enhancers, Surfactants, retarders, adsorbents, suspending agents, flocculants, deflocculants, emulsifiers, commonly used bases, solubilizers, co-solvents, latent solvents, preservatives, flavoring agents, coloring agents, antioxidants , Buffers, bacteriostatic agents, isotonic regulators, pH regulators, metal ion complexing agents, hardeners, thickeners, etc.
  • diluents wetting agents, fillers, adhesives, slip agents, disintegrants, absorption enhancers, Surfactants, retarders, adsorbents, suspending agents, flocculants, deflocculants, emulsifiers, commonly used bases, solubilizers, co-solvents, latent
  • the novel RTK inhibitor provided in the present application has the potential to cause the death of cancer cells that depend on the imbalance of RTK activity without damaging normal tissues at the same time.
  • the TRK family protein tyrosine kinase inhibitors provided in this application can be used to treat pain, inflammation, cancer and certain infectious diseases.
  • the inventors unexpectedly discovered that the RTK inhibitor provided in the present application can effectively inhibit the activities of tropomyosin receptor kinase A (TRKA), anaplastic lymphoma kinase (ALK), and proto-oncogene tyrosine kinase (ROS1).
  • TRKA tropomyosin receptor kinase A
  • ALK anaplastic lymphoma kinase
  • ROS1 proto-oncogene tyrosine kinase
  • Tumor cells, cancer cell proliferation and tumor growth have strong inhibitory effects, and the inhibitory activity is better than the prior art Entrectinib (Entrectinib).
  • the first step is the preparation of 4-fluoro-2-nitro-benzoic acid tert-butyl ester I-1b
  • the second step is the preparation of tert-butyl 4-(4-methylpiperazin-1-yl)-2-nitrobenzoate I-1c
  • the third step is the preparation of tert-butyl 4-(4-methylpiperazin-1-yl)-2-aminobenzoate I-1d
  • the fourth step is the preparation of tert-butyl 4-(4-methylpiperazin-1-yl)-2-(tetrahydropyran-4-yl)aminobenzoate I-1e
  • the sixth step 4-(4-methylpiperazin-1-yl)-2-(2,2,2-trifluoro-N-(tetrahydropyran-4-yl)acetamido)benzoic acid 1- 1 preparation
  • the first step is the preparation of (3-cyano-4-fluorophenyl)-(3,5-difluorophenyl)methanol I-2c
  • the second step is the preparation of (3-cyano-4-fluorophenyl)-(3,5-difluorophenyl)methane I-2d
  • the first step is the preparation of 5-chloro-3-nitropyrazolo[1,5-a]pyrimidine 1b
  • 5-Chloropyrazolo[1,5-a]pyrimidine 1a (2g, 13mmol) was dissolved in H 2 SO 4 (8mL), KNO 3 (2g, 19.6mmol) was added under ice bath, and the temperature was slowly heated to Room temperature. The mixture was slowly poured into ice water, a yellow solid precipitated out, filtered, the solid was collected and dried to obtain 5-chloro-3-nitropyrazolo[1,5-a]pyrimidine 1b (2g, 10.1mmol), the yield was 77 %.
  • the second step is the preparation of 5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3-nitropyrazolo[1,5-a]pyrimidine 1d
  • the third step is the preparation of 5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine 1e
  • the first step Preparation of tert-butyl-3-[bis(tert-butoxycarbonyl)amino]-5-bromo-1H-indazole-1-carboxylate 3b
  • the third step is the preparation of 5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-1H-indazol-3-amine 3d
  • the first step is the preparation of 5-bromo-1-triphenyl-1H-indazole 4b
  • the second step is the preparation of (3,5-difluorophenyl)(1-triphenyl-1H-indazol-5-yl)methanol 4c
  • reaction solution was quenched with saturated ammonium chloride solution and extracted with dichloromethane (100ml*2).
  • the organic phases were combined, dried with anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was purified by column chromatography to obtain the title compound 4c (6.5 g, 12.9 mmol) with a yield of 43%.
  • the third step is the preparation of (3,5-difluorophenyl)-(1H-indazol-5-yl)methanol 4d
  • Step 9 (5-(3,5-Difluorophenyl)-3-(2'-(4-methylpiperazin-1-yl)-[2,4'-bipyridyl]-6-yl) Preparation of -1H-indazol-1-yl)methanol 4j
  • the first step is the preparation of 1-(3-bromo-4-fluorophenyl)-1-(3,5-difluorophenyl)ethyl-1-ol 6c
  • the second step is the preparation of 2-bromo-4-(1-(3,5-difluorophenyl)vinyl)-1-fluorobenzene 6d
  • the third step is the preparation of 2-bromo-4-(1-(3,5-difluorophenyl)cyclopropyl)-1-fluorobenzene 6e
  • the fourth step is the preparation of 5-(1-(3,5-difluorophenyl)cyclopropyl)-2-fluorobenzonitrile 6f
  • the fifth step is the preparation of 5-(1-(3,5-difluorophenyl)cyclopropyl)-1H-indazole-3-amine 6g
  • the first step is the preparation of 5-(3,5-difluorobenzoyl)-2-fluorobenzonitrile 7a
  • the second step is the preparation of 5-((3,5-difluorophenyl)difluoromethyl)-2-fluorobenzonitrile 7b
  • the third step is the preparation of 5-((3,5-difluorophenyl)difluoromethyl)-1H-indazol-3-amine 7c
  • the first step is the preparation of ethyl 4-fluoro-2-nitrobenzoate 8b
  • the second step is the preparation of ethyl 4-((3-((2-ethylhexyl)oxo)-3-carbonylpropyl)thio)-2-nitrobenzoate 8d
  • the fourth step is the preparation of compound ethyl 4-(chlorosulfonyl)-2-nitrobenzoate 8f
  • the seventh step is the preparation of ethyl 4-((4-methylpiperazin-1-yl)sulfonyl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzoate 8i
  • the eighth step is the preparation of 4-((4-methylpiperazin-1-yl)sulfonyl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzoic acid 8j
  • Step 9 4-((4-Methylpiperazin-1-yl)sulfonyl)-2-(2,2,2-trifluoro-N-(tetrahydro-2H-pyran-4-yl)acetyl (Amino) benzoic acid 8k preparation
  • reaction solution was allowed to warm up naturally, and LCMS showed that the main peak was the product point.
  • the second step is the preparation of 5-(3,5-difluorobenzyl)pyrazolo[1,5-a]pyrimidine 9d
  • the third step is the preparation of 5-(3,5-difluorobenzyl)-3-iodopyrazolo[1,5-a]pyrimidine 9e
  • the first step is the preparation of (2-(3-bromo-4-fluorophenyl)-2-(3,5-difluorophenyl)ethyl)boronic acid 10a
  • reaction solution was stirred at room temperature for 2 hours, and then the reaction solution Ice water (150mL) was added, the reaction solution was stirred at room temperature for 3 hours, the reaction solution was concentrated and then extracted with ethyl acetate (200mL), the organic phase was washed with saturated sodium bicarbonate solution and brine, dried and spin-dried to obtain After purification by column chromatography, the crude product of compound 10a (10g) MS m/z(ESI): 383[M+23] + was obtained .
  • the second step is the preparation of (2-(3-bromo-4-fluorophenyl)-2-(3,5-difluorophenyl)ethyl-1-ol 10b
  • the third step is the preparation of 4-(2-(benzyloxy)-1-(3,5-difluorophenyl)ethyl)-2-bromo-1-fluorobenzene 10c
  • the fourth step is the preparation of 5-(2-(benzyloxy)-1-(3,5-difluorophenyl)ethyl)-2-fluorobenzonitrile 10d
  • Step 6 N-(5-(2-(Benzyloxy)-1-(3,5-difluorophenyl)ethyl)-1H-indazol-3-yl)-4-(4- Preparation of methylpiperazin-1-yl)-2-(2,2,2-trifluoro-N-(tetrahydro-2H-pyran-4-yl)acetamido)benzamide 10f
  • Step 8 N-(5-(1-(3,5-Difluorophenyl)-2-hydroxyethyl)-1H-indazol-3-yl)-4-(4-methylpiperazine-1 -Yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide 10
  • the first step is the preparation of N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-fluoro-2-nitrobenzamide 11b
  • the first step is the synthesis of 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine 17b
  • the third step is the synthesis of 5-(3,5-difluorobenzyl)-1H-pyrazolo[3,4-c]pyridine 17e
  • Dissolve compound 17d (400mg, 1.1mmol, 1.0eq) in 1,4-dioxane (30ml), add 4N HCl (20ml, 20.0mmol, 19.0eq), react at 70°C for 5h, and evaporate to dryness under reduced pressure. 17e, unpurified, used directly in the next step.
  • the first step is the preparation of 2-fluoro-5-hydroxybenzonitrile 19a
  • the second step is the preparation of 2-fluoro-5-bromomethylbenzonitrile 19b
  • Dissolve 19a (700mg, 4.6mmol) in dichloromethane (20mL), add phosphorus tribromide (800mg, 2.96mmol) under ice bath, stir for 2 hours at room temperature and then ice bath, add water (20mL), continue stirring for 30 After 5 minutes, let stand for layering, add anhydrous Na2SO4 to the organic phase, dry, filter, and concentrate to obtain the crude title compound 19b and use it directly in the next step.
  • the third step is the preparation of 2-fluoro-5-((4-(2-hydroxypropane-2-yl)piperidin-1-yl)methyl)benzonitrile 19d
  • the fourth step is the preparation of 2-(1-((3-amino-1-hydroindazol-5-yl)methyl)piperidin-4-yl)-2-propanol 19e
  • the first step is the preparation of 5-(1-(3,5-difluorophenyl)-2-hydroxyethyl)-2-fluorobenzeneacetonitrile 21a
  • the second step is the preparation of 5-(1-(3,5-difluorophenyl)-2-fluoroethyl)-2-fluorobenzeneacetonitrile 21b
  • the third step is the preparation of 5-(1-(3,5-difluorophenyl)-2-fluoroethyl)-1H-indazol-3-amine 21c
  • the first step is the preparation of 1-(3-methoxy-4-nitrophenyl)-4-methylpiperazine 22b
  • the fourth step is the preparation of tert-butyl 5-bromo-1H-indazole-3-carboxylate 22f
  • the seventh step is the preparation of tert-butyl 5-(3,5-difluorophenyl)-1-trityl-1H-indazole-3-carboxylate 22i
  • Step 8 Preparation of tert-butyl 5-(3,5-difluorophenyl)-1-trityl-1H-indazole-3-carboxylate 22j
  • Trifluoroacetic acid (2mL) was added to the dichloromethane (8mL) solution of compound 22i (200mg, 0.34mmol). The reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated and spin-dried to obtain compound 22j (60mg, 0.20mmol). The rate is 61%.
  • the first step is the preparation of 2-bromo-4-(1-(3,5-difluorophenyl)-2-methoxyethyl)-1-fluorobenzene 23a
  • the second step is the preparation of 5-(1-(3,5-difluorophenyl)-2-methoxyethyl)-2-fluorobenzonitrile 23b
  • the third step is the preparation of 5-(1-(3,5-difluorophenyl)-2-methoxyethyl)-1H-indazol-3-amine 23c
  • the first step 1- (6-bromo-1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroethane-1-one 24b
  • the third step is the preparation of 7-nitro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-6-carbonitrile 24d
  • the fifth step is the preparation of 2-methyl-7-nitro-1,2,3,4-tetrahydroisoquinoline-6-carbonitrile 24f
  • Step 8 7-Amino-N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-2-methyl-1,2,3,4-tetrahydroiso Preparation of quinoline-6-carboxamide 24i
  • the second step is the preparation of benzyl (1s, 3R, 5S, 7s)-4-(3-bromo-4-(ethoxycarbonyl)phenyl)-4-hydroxyadamantane-1-carboxylate 25d
  • the third step is the preparation of benzyl (1s, 3R, 5S, 7s)-4-(3-bromo-4-(ethoxycarbonyl)phenyl)adamantane-1-carboxylate 25e
  • Step 6 Ethyl 4-((1R,3S,5s,7s)-5-(((benzyloxy)carbonyl)amino)adamantan-2-yl)-2-((tert-butoxycarbonyl) Preparation of amino) benzoate 25h
  • the seventh step is the preparation of ethyl 2-amino-4-((1R,3S,5s,7s)-5-(((benzyloxy)carbonyl)amino)adamantan-2-yl)benzoate 25i
  • Step 8 Ethyl 4-((1R,3S,5s,7s)-5-(((benzyloxy)carbonyl)amino)adamantan-2-yl)-2-((tetrahydro-2H-pyran) Preparation of -4-yl)amino)benzoate 25j
  • Step 9 4-((1R,3S,5s,7s)-5-(((benzyloxy)carbonyl)amino)adamantan-2-yl)-2-((tetrahydro-2H-pyran-4 -(Yl)amino)benzoic acid 25k preparation
  • Step 10 4-((1R,3S,5s,7s)-5-(((benzyloxy)carbonyl)amino)adamantan-2-yl)-2-(2,2,2-trifluoro-N -(Tetrahydro-2H-pyran-4-yl)acetamido)benzoic acid 25l
  • Step 12 Benzyl ((1s,3R,5S,7s)-4-(4-((5-(3,5-difluorobenzyl)-1H-indazol-3-yl)carboxamide) Preparation of -3-((tetrahydro-2H-pyran-4-yl)amine)phenyl)adamantan-1-yl)carbamate 25n
  • the first step is the preparation of 4-((5-benzyloxycarbonylamino)adamantane)-2-yl)-2-((N-benzyloxycarbonylpiperidin-4-yl)amino)-benzoic acid ethyl ester 26a
  • 26a (900 mg, 1.35 mmol) was dissolved in 15 mL of ethanol, and 8 mL of 4M sodium hydroxide aqueous solution was added. The system was refluxed for 16 hours. LCMS monitors the reaction. After the reaction was completed, the solvent was rotated to remove most of the ethanol, and after adding 10 mL of water, the pH was adjusted to 4, and a solid was precipitated. The solid was filtered out and washed with water to obtain target compound 26b (780 mg) as a grayish solid with a yield of 91%. It was used directly in the next step without further purification.
  • Step 4 4-((5-Benzyloxycarbonylamino)adamantane)-2-yl)-2-(N-(1-benzyloxycarbonylpiperidin-4-yl)-2,2,2-trifluoro Preparation of acetamido)-benzoic acid 26c
  • 26b (780mg, 1.22mmol) was dissolved in 20mL of dichloromethane, and trifluoroacetic anhydride (1.2eq) and triethylamine (1.5eq) were added at 0°C. After the addition, stir at room temperature for three hours. Rotate the solvent to dryness, and the crude product obtained is 26c. It was not purified and used directly in the next step.
  • the first step 5-(2-(benzyloxy)-1-(3,5-difluorophenyl)ethyl)-3-(4-(4-methylpiperazin-1-yl)-2- ((Tetrahydro-2H-pyran-4)tert-butyl)amino)benzamido)-1H-indazole-1-carboxylic acid tert-butyl ester 29a
  • the third step 5-(2-acetoxy-1-(3,5-difluorophenyl)ethyl)-3-(4-(4-methylpiperazin-1-yl)-2-(( Tetrahydro-2H-pyran-4-yl)tert-butyl)amino)benzamido)-1H-indazole-1-carboxylate 29c
  • reaction solution was added with water and extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography to obtain the title compound 35c (3.4 g, 14.847 mmol).
  • the fifth step 5-(1-(2,5-difluorophenyl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c] Pyridine 35f
  • reaction solution was extracted with water and ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography to obtain the title compound 35f (1 g, 2.932 mmol).
  • the first step is the synthesis of tert-butyl 4-(ethyl(2-(pyrrolidin-1-yl)ethyl)amino)-2-nitrobenzoate 43a
  • the second step is the synthesis of tert-butyl 2-amino-4-(ethyl(2-(pyrrolidin-1-yl)ethyl)amino)benzoate 43b
  • Tetramethyltriacetoxyammonium borohydride (1130mg, 4.32mmol) was slowly added to a solution of compound 43b (360mg, 1.08mmol) in DCM (10mL) and trifluoroacetic acid (1mL), and the mixture was stirred at room temperature for 2 hours .
  • the reaction was quenched by adding saturated aqueous NaHCO 3 solution.
  • the fifth step 4-(ethyl(2-(pyrrolidin-1-yl)ethyl)amino)-2-(2,2,2-trifluoro-N-(tetrahydro-2H-pyran-4- (4) Acetylamino) benzoic acid 43e synthesis
  • Step 8 N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(ethyl(2-(pyrrolidin-1-yl)ethyl)amino )-2-((Tetrahydro-2H-pyran-4-yl)amino)benzamide 43
  • compound 50 can be obtained.
  • the first step Dimethyl 2-((tetrahydro-2H-pyran-4-yl)amino)terephthalate 60b
  • the second step Dimethyl 2-bromo-5-((tetrahydro-2H-pyran-4-yl)amino)terephthalate 60c
  • the third step Dimethyl 2-cyano-5-((tetrahydro-2H-pyran-4-yl)amino)terephthalate 60d
  • Step 7 2-(2-(Dimethylamino)ethyl)-1-carbonyl-6-((tetrahydro-2H-pyran-4-yl)amino)isoindoline-5-carboxylic acid 60h
  • Step 8 2-(2-(Dimethylamino)ethyl)-1-carbonyl-6-(2,2,2-trifluoro-N-(tetrahydro-2H-pyran-4-yl)acetamido )Isoindole-5-carboxylic acid 60i
  • Step 9 N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-2-(2-(dimethylamino)ethyl)-1-carbonyl-6- (2,2,2-Trifluoro-N-(tetrahydro-2H-pyran-4-yl)acetamido)isoindole-5-carboxamide 60j
  • Step 10 N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-2-(2-(dimethylamino)ethyl)-1-carbonyl-6- ((Tetrahydro-2H-pyran-4-yl)amino)isoindole-5-carboxamide 60

Abstract

L'invention concerne une nouvelle classe de composés à petites molécules ayant de multiples activités inhibitrices de kinase, lesdits composés ayant la structure telle que représentée dans la formule générale II ; et un composé tel que représenté dans la formule générale II a une bonne efficacité et une bonne innocuité dans la prévention ou le traitement de multiples indications de cancer telles que le cancer du poumon et le lymphome.
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