WO2019184918A1 - 3-aminopyrazole compound and application thereof - Google Patents

3-aminopyrazole compound and application thereof Download PDF

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Publication number
WO2019184918A1
WO2019184918A1 PCT/CN2019/079733 CN2019079733W WO2019184918A1 WO 2019184918 A1 WO2019184918 A1 WO 2019184918A1 CN 2019079733 W CN2019079733 W CN 2019079733W WO 2019184918 A1 WO2019184918 A1 WO 2019184918A1
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methyl
oxy
amino
pyrazole
substituted
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PCT/CN2019/079733
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French (fr)
Chinese (zh)
Inventor
丁克
耿美玉
陈成斌
丁健
谈理
艾菁
张章
彭霞
任小梅
季寅淳
段云鑫
戴阳
涂正超
陆小云
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暨南大学
中国科学院上海药物研究所
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Priority to CN201980022751.4A priority Critical patent/CN112313213B/en
Publication of WO2019184918A1 publication Critical patent/WO2019184918A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention relates to the technical field of chemical medicine, in particular to a 3-aminopyrazole compound and application thereof.
  • AXL is a class of receptor tyrosine kinases belonging to the TAM receptor tyrosine kinase family, which also includes two other members: Mer and Tyro3. TAM was first discovered in tumor cells, and its overexpression and ectopic expression are closely related to immune regulation, tumor proliferation, growth and migration. AXL was isolated from chronic myeloid leukemia patients and chronic myeloproliferative diseases in 1988. AXL is widely expressed in tissues such as the brain, immune cells, platelets, endothelial cells, skeletal muscle, heart, liver and kidney.
  • the vitamin K-dependent protein kinase Gas6 (growth arrest-specific 6) is the most widely studied AXL ligand, and other ligands of the TAM family include Protein S, Tubby, Tulp-1, and Galectin-3.
  • the TAMs family has a similar protein structure, consisting mainly of three parts: the extracellular domain, the transmembrane domain, and the intracellular domain.
  • the extracellular domain includes two N-terminal immunoglobulin-like regions Ig, and two fibronectin III repeats (FNIII). .
  • Gas6 binds to the extracellular domain of AXL to induce AXL dimerization, triggering trans-autophosphorylation in the intracellular domain, thereby activating intracellular signaling pathways and regulating a range of physiological activities.
  • AXL can also be activated in a ligand-independent manner. AXL is involved in the adhesion and immunoregulation of normal cells. It has been found that overexpression of AXL is present in a variety of tumor cells.
  • the signaling pathway regulated by Gas6/AXL is closely related to the occurrence and development of various tumors, such as chronic myeloid leukemia.
  • AXL is an effective target for targeted tumor therapy.
  • Bosutinib (SKI606, PF5208763, Bosulif; Pfizer, 2012), Cabozantinib (XL184, Cometriq; Exelixis, 2012), Sunitinib (SU11248, Sutent; Pfizer, 2006) and other marketed drugs, although having AXL activity, are multi-target drugs. Not specific. BGB324 (R428; Rigel Pharmaceuticals, BergenBio) is currently the most specific AXL small molecule inhibitor known in the clinical phase II study. In December 2014, the FDA granted BGB324 the orphan drug title for AML. Currently, no small molecule inhibitors against AXL kinase have been marketed.
  • the present invention provides a new class of 3-aminopyrazole compounds which have potent inhibitory activity against AXL kinase.
  • X is selected from: CH or N;
  • Z is selected from: O or NH
  • B is selected from the group consisting of C 5 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 6 cycloalkyl, C 7 -C 13 polycycloalkyl;
  • R 1 , R 2 and A ring constitute a substituted or unsubstituted heterocyclic ring m is 2 or 3, and Y is selected from C, N or O;
  • R 3 is selected from the group consisting of hydrogen, halogen, halogen-substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy or C 1 -C 6 alkyl;
  • R 4 is selected from the group consisting of hydrogen, C 1 -C 5 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy or R 21 is selected from the group consisting of hydrogen, halogen, C 1 -C 5 alkyl, C 3 -C 6 cycloalkyl or C 1 -C 5 alkoxy;
  • R 5 and R 6 are each independently selected from the group consisting of hydrogen, alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, aralkyl, substituted or unsubstituted Substituted heteroaryl, heteroarylalkyl, substituted or unsubstituted polycycloalkyl; or R 5 , R 6 together with the N atom to which they are attached constitute a monocyclic heterocyclic ring or a heterocyclic heterocyclic ring.
  • the 3-aminopyrazole compound has the structure of formula (II):
  • X is selected from: CH or N.
  • the substituted or unsubstituted heterocyclic ring Selected from the following structure:
  • R 12 and R 13 are each independently selected from: -O(CR 15 R 16 ) O R 14 ;
  • o is selected from an integer between 0 and 6;
  • R 19 and R 20 are each independently selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, or R 19 and R 20 are a saturated or unsaturated R 22 -substituted 5-8 membered heterocyclic group, wherein R 22 is selected from the group consisting of: -H, C 1 -C 5 alkyl;
  • R 12 and R 13 constitute a substituted or unsubstituted C 5 -C 18 aliphatic cycloalkyl group having 1 to 4 hetero atoms.
  • R 14 , R 15 , and R 16 are each independently selected from: R 14 , R 15 , and R 16 are each independently selected from: -H, C 1 -C 5 alkyl, -OR 19 or -NR 19 R 20 ;
  • R 19 and R 20 are each independently selected from the group consisting of: hydrogen, C 1 -C 6 alkyl, or R 19 , R 20 and N attached thereto to form a saturated or unsaturated R 22 -substituted 5-8 membered heterocyclic group. a group wherein R 22 is selected from the group consisting of: -H, C 1 -C 5 alkyl.
  • R 15 and R 16 are both hydrogen
  • R 14 is selected from the group consisting of: -H, -OR 19 or -NR 19 R 20 ;
  • R 19 and R 20 are each independently selected from a C 1 -C 3 alkyl group, or R 19 , R 20 and N attached thereto constitute a saturated R 22 -substituted 5-8 membered heterocyclic group, wherein R 22 It is selected from the group consisting of: -H, C 1 -C 3 alkyl.
  • R 12 and R 13 are each independently selected from: -O(CH 2 ) O R 14 ; o is selected from an integer between 0 and 4.
  • one of R 12 and R 13 is selected from the group consisting of C 1 -C 4 alkoxy groups, and the other is selected from: -O(CH 2 ) O R 14 ;
  • o is selected from an integer between 1 and 4;
  • R 14 is selected from the group consisting of: H, -OR 19 or -NR 19 R 20 ;
  • R 19 and R 20 are each independently selected from a C 1 -C 3 alkyl group, or R 19 , R 20 and N attached thereto constitute a R 22 -substituted 6-membered saturated heterocyclic group, wherein R 22 is selected from the group consisting of: - H, C 1 - C 3 alkyl.
  • R 12 and R 13 are each independently selected from the group consisting of: methoxy, ethoxy, propoxy, morpholinyl substituted propoxy, methoxy substituted ethoxy, methoxy A substituted propoxy group, a dimethylamino substituted propoxy group, a piperidine substituted propoxy group, and an N-methylpiperazine substituted propoxy group.
  • R 3 is selected from the group consisting of: H, halogen, trifluoromethyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxy.
  • R 3 is selected from the group consisting of: H, F, Cl, Br, methyl, ethyl, methoxy, ethoxy.
  • R 4 is selected from the group consisting of: C 1 -C 3 alkyl.
  • R 5 and R 6 are each independently selected from the group consisting of: hydrogen, C 1 -C 8 alkyl, R 8 -substituted C 3 -C 10 cycloalkyl, R 8 substituted 3-10 membered hetero Cycloalkyl, R 10 substituted C 5 -C 10 aryl, aralkyl, R 10 substituted 5-10 membered heteroaryl, heteroaralkyl, R 8 substituted C 7 -C 13 polycycloalkyl Or, R 5 , R 6 and the N atom to which it is bonded together constitute a 3-10 membered monocyclic heterocyclic ring or a bicyclic heterocyclic ring;
  • R 8 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, halogen
  • R 10 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, cyano, halogen-substituted C 1 -C 6 alkyl, halogen-substituted C 1 -C 6 alkoxy a cyano-substituted C 1 -C 6 alkyl group.
  • R 5 and R 6 are each independently selected from the group consisting of: hydrogen, C 1 -C 8 alkyl, R 8 -substituted C 3 -C 8 cycloalkyl, R 8 substituted 6-8 membered hetero a cycloalkyl group, a R 10 -substituted phenyl group, an adamantyl group, an R 10 -substituted 5-10 membered heteroaryl group; or, R 5 , R 6 and an N atom attached thereto constitute a 3-10 membered monocyclic hetero Ring or a heterocyclic ring.
  • R 6 is selected from the group consisting of: hydrogen, C 1 -C 5 alkyl;
  • R 5 is selected from: C 2 -C 8 alkyl, R 8 -substituted C 3 -C 8 cycloalkyl, R 8 Substituted 6-8 membered heterocycloalkyl, R 10 substituted phenyl, adamantyl; or, R 5 , R 6 and the N atom to which they are attached form a 3-10 membered monocyclic or heterocyclic ring ring.
  • R 6 is selected from the group consisting of: hydrogen, C 1 -C 5 alkyl;
  • R 5 is selected from: C 4 -C 8 alkyl, R 8 -substituted C 4 -C 8 cycloalkyl, R 10 Substituted phenyl, R 8 substituted 6-8 membered heterocycloalkyl, adamantyl; or R 5 , R 6 and the N atom to which they are attached form a 3-10 membered monocyclic or heterocyclic ring ring.
  • R 6 is selected from the group consisting of: hydrogen, C 1 -C 3 alkyl;
  • R 5 is selected from: R 8 -substituted C 5 -C 8 cycloalkyl, R 10 substituted phenyl, adamantyl .
  • R 8 is selected from the group consisting of: hydrogen, halogen; and R 10 is selected from the group consisting of hydrogen, halogen, C 1 -C 2 alkyl, methoxy.
  • the 3-aminopyrazole compound has the structure shown in formula (III):
  • R 3 is selected from the group consisting of: H, halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy;
  • R 6 is selected from the group consisting of hydrogen, C 1 -C 2 alkyl
  • R 5 is selected from the group consisting of: C 5 -C 8 cycloalkyl, R 10 -substituted phenyl, 6-8 membered heterocycloalkyl; or R 5 , R 6 and the N atom to which they are attached constitute a 3-10 member.
  • R 10 is selected from the group consisting of hydrogen, halogen, C 1 -C 2 alkyl, methoxy, halogen-substituted C 1 -C 2 alkoxy;
  • R 13 is selected from the group consisting of: -O(CH 2 ) O R 14 ; o is selected from an integer between 1 and 4;
  • R 14 is selected from the group consisting of: H, -OR 19 or -NR 19 R 20 ;
  • R 19 and R 20 are each independently selected from a C 1 -C 3 alkyl group, or R 19 , R 20 and N attached thereto constitute a R 22 -substituted 6-membered saturated heterocyclic group, wherein R 22 is selected from the group consisting of: - H, C 1 - C 3 alkyl.
  • the 3-aminopyrazole compound is selected from the group consisting of
  • the present invention also provides the use of the above 3-aminopyrazole compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.
  • the tumor is: hematological tumor, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer , prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, nasopharyngeal cancer.
  • the blood tumor such as leukemia or the like.
  • the invention also provides a pharmaceutical composition for preventing and treating tumors.
  • a pharmaceutical composition for preventing and treating tumors comprising the above 3-aminopyrazole compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof or a progeny thereof, and A pharmaceutically acceptable carrier.
  • the 3-aminopyrazole compound of the present invention or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof or a progeny thereof can effectively inhibit the action of a protein kinase such as AXL, thereby inhibiting various tumor cells
  • a protein kinase such as AXL
  • Proliferation, migration and invasion can be used to prepare anti-tumor drugs, and can be used in the preparation of drugs for preventing and/or treating hyperproliferative diseases such as tumors in humans and other mammals.
  • any variable e.g. R 1, R, etc.
  • R 1, R, etc. when any variable (e.g. R 1, R, etc.) appear in any component more than once defined, it is on each occurrence is independent of its definition at every other occurrence of. Also, combinations of substituents and variables are allowed as long as such combinations stabilize the compound.
  • a line drawn from a substituent into the ring system means that the bond referred to can be attached to any ring atom that can be substituted. If the ring system is polycyclic, it means that such a bond is only attached to any suitable carbon atom of the adjacent ring.
  • substituents and substituted forms of the compounds of the present invention can select substituents and substituted forms of the compounds of the present invention to provide compounds which are chemically stable and which are readily synthesized from readily available starting materials by techniques in the art and from the methods set forth below. If the substituent itself is substituted by more than one group, it is understood that these groups may be on the same carbon atom or on different carbon atoms as long as the structure is stabilized.
  • alkyl as used herein is meant to include branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • the definition of "C 1 -C 5 " in "C 1 -C 5 alkyl” includes a group having 1, 2, 3, 4 or 5 carbon atoms arranged in a straight chain or a branched chain.
  • “C 1 -C 5 alkyl” specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl.
  • cycloalkyl refers to a monocyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms.
  • cycloalkyl includes cyclopropyl, methyl-cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • heteroaryl denotes a stable monocyclic ring of up to 5 atoms in the ring or up to 5 atoms of a bicyclic carbocyclic ring in each ring, wherein at least one ring is an aromatic ring and contains from 1 to 4 selected from Heteroatoms of O, N and S.
  • Heteroaryl groups within the scope of this definition include, but are not limited to, imidazolyl, pyrazolyl, furyl, thienyl, oxazolyl, isoxazolyl, pyrazinyl, pyridyl, pyrimidinyl, pyrrolyl.
  • Heteroaryl is also understood to include any N-oxide derivative of a nitrogen-containing heteroaryl group for the definition of the following heteroaryl.
  • the heteroaryl substituent is bicyclic and contains a ring which is non-aromatic or contains no heteroatoms, it is understood that each is attached via an aromatic ring or via a heteroatom-containing ring.
  • heterocycle refers to a 5- to 6-membered aromatic or non-aromatic heterocyclic ring containing from 1 to 4 heteroatoms selected from O, N and S, and includes a bicyclic group. group.
  • heterocyclyl thus includes the heteroaryl groups mentioned above, as well as the dihydrogenated and tetrahydrogenated analogs thereof.
  • heterocyclyl examples include, but are not limited to, imidazolyl, thiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, oxetanyl, pyranyl, pyrazinyl , pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinoxalinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, oxazolyl.
  • the attachment of a heterocyclic substituent can be achieved by a carbon atom or by a hetero atom.
  • halo or halogen as used herein is meant to include chloro, fluoro, bromo and iodo.
  • alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl substituents may be unsubstituted or substituted.
  • (C 1 -C 6 )alkyl may be selected from one, two or three selected from OH, halogen, nitro, cyano, alkoxy, dialkylamino or heterocyclic groups such as morpholinyl, piperidine Substituents such as pyridine are substituted.
  • the invention includes the free forms of the compounds of Formulas I-III, as well as the pharmaceutically acceptable salts and stereoisomers thereof.
  • Some specific exemplary compounds herein are protonated salts of amine compounds.
  • the term "free form" refers to an amine compound in a non-salt form.
  • the pharmaceutically acceptable salts included include not only exemplary salts of the particular compounds described herein, but also all typical pharmaceutically acceptable salts of the free forms of the compounds of formula I.
  • the free form of the particular salt of the compound can be isolated using techniques known in the art.
  • the free form can be regenerated by treating the salt with a suitable dilute aqueous base such as a dilute aqueous solution of NaOH, a dilute aqueous solution of potassium carbonate, dilute aqueous ammonia, and a dilute aqueous solution of sodium bicarbonate.
  • a suitable dilute aqueous base such as a dilute aqueous solution of NaOH, a dilute aqueous solution of potassium carbonate, dilute aqueous ammonia, and a dilute aqueous solution of sodium bicarbonate.
  • the free form differs somewhat from its respective salt form in solubility in certain physical properties, such as in polar solvents, but for purposes of the invention such acid and base salts are otherwise pharmaceutically equivalent to their respective free forms.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of the present invention containing a basic moiety or an acidic moiety by conventional chemical methods.
  • the salt of the basic compound is prepared by ion exchange chromatography or by reaction of the free base with a stoichiometric or excess amount of the desired salt or mixture of the inorganic or organic acid in a suitable solvent or combination of solvents.
  • a salt of an acidic compound is formed by reaction with a suitable inorganic or organic base.
  • pharmaceutically acceptable salts of the compounds of the invention include the conventional non-toxic salts of the compounds of the invention which are formed by the reaction of a basic compound of the invention with an inorganic or organic acid.
  • conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, and also include organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, and hard.
  • Fatty acid lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetyl A salt prepared from oxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid or the like.
  • a suitable "pharmaceutically acceptable salt” refers to a salt prepared by pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases.
  • Salts derived from inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganese salts, manganese salts, potassium salts, sodium salts, zinc salts and the like. Ammonium salts, calcium salts, magnesium salts, potassium salts and sodium salts are particularly preferred.
  • a salt derived from a pharmaceutically acceptable organic non-toxic base comprising a salt of a primary, secondary and tertiary amine, the substituted amine comprising a naturally occurring substituted amine, a cyclic amine and a basic ion exchange resin such as a fine Amino acid, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, B Diamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydroxycobalamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine , piperidine, guanidine, polyamine resin, procaine, guanidine, theobromine, triethylamine, trimethylamine, tripropylamine, t
  • the acidic moiety such as a carboxyl group
  • a cationic moiety such as tetravalent
  • the compounds of the invention are potential internal salts or zwitterions.
  • the compounds of the invention can be prepared using the reactions as shown in the scheme below. Accordingly, the following illustrative schemes are for illustrative purposes and are not limited to the listed compounds or any particular substituents. The number of substituents shown in the scheme does not necessarily have to correspond to the number used in the claims, and for the sake of clarity, it is shown that the mono-substituent is attached to a compound which allows multiple substituents under the definition of formula (I) above.
  • the compound of formula (I) as shown in Scheme A can be synthesized from 6,7-dimethoxy-4-chloroquinoline as a starting material by a four-step reaction.
  • the compound of formula (I) as shown in Scheme B can be synthesized from 6-methoxy-7-benzyloxy-4-chloroquinoline starting from 6 steps.
  • the 3-aminopyrazole compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof provided by the present invention can be used for the treatment of hyperproliferative diseases or symptoms such as tumors in humans or other mammals.
  • hyperproliferative diseases or symptoms such as tumors in humans or other mammals.
  • histiocytic lymphoma non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer , drugs for hyperproliferative diseases such as epithelial cell carcinoma, prostate cancer, nasopharyngeal cancer, and leukemia.
  • the compounds designed by the present invention and pharmaceutically acceptable salts thereof or stereoisomers thereof can be adjusted with estrogen receptor modulators, androgen receptor modulators, retinoid receptors currently in use or in the development stage Agents, cytotoxins/cytostatics, antiproliferative agents, protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protein kinase inhibitors, reverse transcriptase inhibitors, angiogenesis inhibitors, cell proliferation and survival signal suppression Agents, drugs and apoptosis inducers that interfere with cell cycle checkpoints, cytotoxic drugs, tyrosine protein inhibitors, EGFR inhibitors, VEGFR inhibitors, serine/threonine protein inhibitors, Bcr-Abl inhibitors, c-Kit inhibitor, Met inhibitor, Raf inhibitor, MEK inhibitor, MMP inhibitor, topoisomerase inhibitor, histidine deacetylase inhibitor, proteasome inhibitor, CDK inhibitor, Bcl- 2 family protein inhibitors, MDM2 family protein inhibitors,
  • the compound having the structure of the formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a pharmaceutical composition thereof according to the present invention can be used for the preparation of a medicament for the prevention and treatment of the following diseases and other diseases not listed below. :
  • Respiratory cancers in humans or other mammals including but not limited to small cell & non-small cell lung cancer, as well as bronchial adenomas and pleural pulmonary blastomas.
  • Brain cancer in humans or other mammals including but not limited to brain stem and sub-glial glioma, cerebellum and cerebral astrocytoma, ependymoma, and neuroectoderm and pineal tumor.
  • tumors of male and female reproductive organs of humans or other mammals include, but are not limited to, prostate and testicular cancer; tumors of female reproductive organs include, but are not limited to, endometrial cancer, cervical cancer, ovarian cancer , vaginal cancer and vulvar cancer as well as intrauterine tumors.
  • Tumors of the digestive tract of human or other mammals including but not limited to anal cancer, colon cancer, colonic straight cancer, esophageal cancer, gastric cancer, pancreatic cancer, rectal cancer, small intestine cancer or salivary gland cancer.
  • Tumors of the urethra of a human or other mammal including but not limited to bladder cancer, penile cancer, renal cancer, renal pelvic cancer, ureteral cancer or urethral cancer.
  • Eye cancer in humans or other mammals including but not limited to intraocular melanoma and retinoblastoma.
  • Liver cancer of a human or other mammal including but not limited to hepatoma (stem cell carcinoma with or without fibril changes), cholangiocarcinoma (intrahepatic cholangiocarcinoma), and mixed hepatocellular cholangiocarcinoma.
  • Skin cancer of human or other mammals including, but not limited to, squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merck's cell skin cancer, and non-melanoma cell carcinoma.
  • Head and neck cancer in humans or other mammals including, but not limited to, larynx, hypopharynx, nasopharynx, oropharyngeal cancer, and lip and oral cancer.
  • Lymphoma of human or other mammals including but not limited to AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Hodgson's disease, and central nervous system lymphoma.
  • Sarcomas of human or other mammals including but not limited to soft tissue sarcoma, osteosarcoma, malignant fibrous histiocytoma, sarcoma and rhabdomyosarcoma.
  • Leukemia in humans or other mammals including but not limited to acute myeloid leukemia, acute forest cell leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.
  • the compounds of the invention may be administered to a mammal, preferably a human, alone or in a pharmaceutical composition, in combination with a pharmaceutically acceptable receptor, adjuvant or diluent, according to standard pharmaceutical techniques.
  • the compound can be administered orally or subcutaneously, intramuscularly, intraperitoneally, intravenously, rectally and topically, ocularly, pulmonaryly, nasally, or parenterally.
  • the use of a compound of formula (I) for the preparation of a medicament for treating or controlling a patient, such as cancer is administered at a dose ranging from 0.1 to 500 mg/day/kg body weight.
  • a suitable mode of administration is daily single dose administration or multiple administrations twice, three times, four times a day, or by sustained release techniques.
  • preferred dosages range from 0.1 to 1500 mg/day/kg body weight, preferably from 0.5 to 100 mg/day/kg body weight.
  • the daily dose is 1 to 500 mg.
  • the daily dose for adult patients can be as low as 0.1 mg/day.
  • Metabolites of the compounds and pharmaceutically acceptable salts thereof, and prodrugs which can be converted in vivo to the structures of the compounds and pharmaceutically acceptable salts thereof, are also included in the present application. In the claims.
  • the compounds of formula (I) may be combined with other agents known to treat or ameliorate similar conditions.
  • the mode of administration & dosage of the original drug remains unchanged, while the compound of formula (I) is administered simultaneously or subsequently.
  • the compound of the formula (I) is administered simultaneously with one or more other drugs, it is preferred to use a pharmaceutical composition containing both one or several known drugs and a compound of the formula (I).
  • Combination of drugs also includes the administration of a compound of formula (I) with one or more other known drugs over an overlapping period of time.
  • the dose of the compound of formula (I) or a known drug may be lower than when they are administered alone.
  • Drugs or active ingredients which may be combined with a compound of formula (I) include, but are not limited to:
  • the pharmaceutical or active ingredient that can be administered in combination with a compound of formula (I) includes, but is not limited to, leucine, alendronate, interferon, atraxine, allopurinol, Sodium decylate, palonosetron hydrochloride, hexamethylene melamine, aminoglutamine, amifostine, amrubicin, amsacrine, anastrozole, dolasetron, aranesp, arglabin, Arsenic trioxide, anoxin, 5-azacytidine, azathioprine, BCG or tici BCG, betahidine, betamethasone acetate, betamethasone sodium phosphate, bexarotene, bleomycin sulfate, bromine Gan, bortezomib, busulfan, calcitonin, alemzumab injection, capecitabine, carboplatin, constance, cefesone, simmein, daunorubicin, chlor
  • Step a1 Preparation of 4-(4-bromo-2-fluorophenoxy)-6,7-dimethoxyquinoline (Compound 2)
  • Step a2 3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl-1H-pyrazole-4 - Preparation of ethyl formate (compound 3)
  • Step a3 3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl-1H-pyrazole-4 - Preparation of formic acid (Compound 4)
  • Step a4 3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-N-(4-fluorophenyl)-1- Preparation of methyl-1H-pyrazole-4-carboxamide (CCB-049)
  • Example 28 3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-N-(4-(trifluoromethoxy) Preparation of phenyl)-1-methyl-1H-pyrazole-4-carboxamide (DL-037)
  • Step b1 Preparation of 7-(benzyloxy)-4-(4-bromo-2-fluorophenoxy)-6-methoxyquinoline (Compound 6)
  • Step b2 3-((4-((7-(Benzyloxy)-6-methoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl-1H -Preparation of pyrazole-4-carboxylic acid ethyl ester (Compound 7)
  • Step b3 3-((4-((7-(Benzyloxy)-6-methoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl-1H -Preparation of pyrazole-4-carboxylic acid (Compound 8)
  • Step b4 3-((4-((7-(Benzyloxy)-6-methoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-N-cyclohexyl-1 -Preparation of methyl-1H-pyrazole-4-carboxamide (Compound 9)
  • Step b5 N-cyclohexyl-3-((3-fluoro-4-((7-hydroxy-6-methoxyquinolin-4-yl)oxy)phenyl)amino)-1-methyl- Preparation of 1H-pyrazole-4-carboxamide (Compound 10)
  • Step b6 N-cyclohexyl-3-((3-fluoro-4-((6-methoxy-7-(3-morpholinepropoxy)quinolin-4-yl)oxy)phenyl)amino) Preparation of 1-methyl-1H-pyrazole-4-carboxamide (CCB-3233)
  • N-Cyclohexyl-3-((3-fluoro-4-((7-hydroxy-6-methoxyquinolin-4-yl)oxy)phenyl)amino)-1-methyl-1H- Pyrazole-4-carboxamide (Compound 10) (202 mg, 0.4 mmol), N-(3-chloropropyl)morpholine (131 mg, 0.8 mmol) and potassium carbonate (166 mg, 1.2 mmol) were dissolved in 2 mL DMF. The reaction was carried out at 80 ° C for 3 hours.
  • Example 48 3-aminopyrazole compounds on AXL kinase IC 50 test
  • kinases activity assay The inhibitory activity of compounds on kinases was tested by enzyme-linked immunosorbent assay (ELISA).
  • the enzyme reaction substrate Poly(Glu, Tyr) 4:1 was diluted with potassium-free PBS (10 mM sodium phosphate buffer, 150 mM NaCl, pH 7.2-7.4) to 20 ⁇ g/mL, 125 ⁇ L/well coated with the enzyme plate. The reaction was carried out at 37 ° C for 12-16 hours. After discarding the liquid in the well, the plate was washed, and the plate was washed three times with 200 ⁇ L/well of T-PBS (PBS containing 0.1% Tween-20) for 5 minutes each time. The plate was dried in an oven at 37 ° C for 1-2 hours.
  • reaction buffer 50 mM HEPES pH 7.4, 50 mM MgCl 2 , 0.5 mM MnCl 2 , 0.2 mM Na 3 VO 4 , 1 mM DTT
  • the compound was diluted to a suitable concentration in DMSO, 1 ⁇ L/well or containing the corresponding concentration of DMSO (negative control well), and the reaction was initiated by adding AXL kinase domain recombinant protein (eurofins, 14-512) diluted in 49 ⁇ L of reaction buffer.
  • AXL kinase domain recombinant protein (eurofins, 14-512) diluted in 49 ⁇ L of reaction buffer.
  • the experiment requires two wells without enzyme control wells.
  • the reaction was carried out for 1 hour at 37 ° C on a shaker (100 rpm).
  • the plate was washed three times with T-PBS.
  • One anti-PY99 dilution was added to 100 ⁇ L/well, and the reaction was shaken at 37 ° C for 0.5 hour.
  • the plate was washed three times with T-PBS.
  • a second anti-horseradish peroxidase-labeled goat anti-mouse IgG dilution was added at 100 ⁇ L/well, and shaken at 37 ° C for 0.5 hour.
  • the plate was washed three times with T-PBS.
  • the inhibition rate of the sample is obtained by the following formula:
  • IC 50 values were obtained by four-parameter regression using software attached to the microplate reader.
  • Compds AXL IC 50 (nM) Compds AXL IC 50 (nM) CCB-3152 >10000 CCB-3072 86.7 CCB-3151 237.8 DL-025 29.5 CCB-3088 585.6 DL-037 >500 CCB-3069 142.2 CCB-3049 39.7 CCB-3087 11.4 CCB-3236 9.4 CCB-3269 65 CCB-3243 21.6 CCB-3091 5.1 CCB-3235 8.6 CCB-3146 4.0 CCB-3237 7.8 CCB-3263 12.5 CCB-3244 5.6 CCB-3143 5.5 CCB-3265 2.9 CCB-3245 333 CCB-3256 3.2
  • Example 49 3-aminopyrazole compounds proliferation IC 50 of test cell-mediated AXL
  • Test method The proliferation inhibition effect of the compound on BaF3/TEL-AXL cells was detected by CCK-8 cell counting kit (Dojindo). The specific steps are as follows: BaF3/TEL-AXL cells in logarithmic growth phase were inoculated into 96-well culture plates at a suitable density, 90 ⁇ L per well, and cultured overnight, different concentrations of compounds were added for 72 hr, and the solvent control group was set ( Negative control). After the compound was treated for 72h, the effect of the compound on cell proliferation was detected by CCK-8 cell counting kit (Dojindo). Add 10 ⁇ L of CCK-8 reagent to each well and place in a 37 ° C incubator for 2-4 hours. The full-wavelength microplate reader SpectraMax 190 reads at a wavelength of 450 nm.
  • the inhibition rate (%) of the compound on tumor cell growth was calculated by the following formula:
  • Inhibition rate (%) (OD control well-OD administration well) / OD control well ⁇ 100%
  • IC 50 values were obtained by four-parameter regression using software attached to the microplate reader.
  • the 3-aminopyrazole compound of the present invention exhibited strong inhibitory activity against AXL-mediated cell proliferation.
  • Example 50 3-aminopyrazole compound MV4-11 proliferation and the IC 50 of the test cell
  • the 3-aminopyrazole compound of the present invention exhibited strong inhibitory activity against MV4-11 leukemia cell proliferation.

Abstract

The present invention relates to a 3-aminopyrazole compound represented by formula (I) or a pharmaceutically acceptable salt, stereoisomer, prodrug, or deuterated form thereof and an application of the same. The compound and a pharmaceutical composition thereof can be used as a protein kinase inhibitor, effectively inhibit AXL kinase activity, and inhibit proliferation, migration, and invasion of various tumor cells. (I)

Description

3-氨基吡唑类化合物及其应用3-aminopyrazole compounds and their applications 技术领域Technical field
本发明涉及化学医药技术领域，特别是涉及一种3-氨基吡唑类化合物及其应用。The invention relates to the technical field of chemical medicine, in particular to a 3-aminopyrazole compound and application thereof.
背景技术Background technique
AXL是一类受体酪氨酸激酶，属于TAM受体酪氨酸激酶家族，该家族还包括其他两个成员：Mer和Tyro3。TAM最早发现于肿瘤细胞，其过表达和异位表达与免疫调节，肿瘤增殖、生长和迁移等密切相关。AXL于1988年从慢性髓性白血病病人和慢性骨髓增殖性疾病中分离。AXL广泛表达于大脑、免疫细胞、血小板、内皮细胞、骨骼肌、心脏、肝和肾等组织。维生素K依赖蛋白激酶Gas6(growth arrest-specific 6)是目前发现的研究最为广泛的一个AXL配体，TAM家族的其他配体还包括Protein S，Tubby，Tulp-1，Galectin-3。TAMs家族具有相似的蛋白结构，主要由胞外域、跨膜区和胞内域三部分组成，胞外域包括两个N-端免疫球样区Ig，和二个纤连蛋白Ⅲ重复片段(FNⅢ)。Gas6与AXL胞外域结合以后诱导AXL二聚化，引发胞内域发生反式自磷酸化，从而激活胞内信号通路，调节一系列生理活动。如通过Src/MAPK/ERK通路，调节细胞的生长和增殖；通过PI3K/AKT通路刺激抗凋亡蛋白的表达；通过PI3K/p38/MAPK通路调节细胞迁移和增殖。AXL除了Gas6依赖的激活外，还可以通过配体非依赖的方式被激活。AXL参与正常细胞的粘附和免疫调节作用，研究发现AXL的过表达存在于多种肿瘤细胞中，Gas6/AXL调节的信号通路与多种肿瘤的发生和发展密切相关，如慢性髓细胞性白血病、乳腺癌、前列腺癌、非小细胞肺癌、胰腺癌、黑色素瘤、神经胶质瘤和肾细胞癌。已证实抑制AXL的表达可以降低胰腺癌细胞的增殖和生长，抑制乳腺癌细胞的侵袭和迁移。在非小细胞肺癌中，基因沉默AXL可以抑制肿瘤的生长。同时，AXL的高表达也与肿瘤的复发和其他抗癌药物的耐受相关，如伊马替尼(Gliver)、厄洛替尼(Tarceva)、拉帕替尼(Tyverb)。这些证据表明AXL是一个有效的肿瘤靶向治疗靶点。AXL is a class of receptor tyrosine kinases belonging to the TAM receptor tyrosine kinase family, which also includes two other members: Mer and Tyro3. TAM was first discovered in tumor cells, and its overexpression and ectopic expression are closely related to immune regulation, tumor proliferation, growth and migration. AXL was isolated from chronic myeloid leukemia patients and chronic myeloproliferative diseases in 1988. AXL is widely expressed in tissues such as the brain, immune cells, platelets, endothelial cells, skeletal muscle, heart, liver and kidney. The vitamin K-dependent protein kinase Gas6 (growth arrest-specific 6) is the most widely studied AXL ligand, and other ligands of the TAM family include Protein S, Tubby, Tulp-1, and Galectin-3. The TAMs family has a similar protein structure, consisting mainly of three parts: the extracellular domain, the transmembrane domain, and the intracellular domain. The extracellular domain includes two N-terminal immunoglobulin-like regions Ig, and two fibronectin III repeats (FNIII). . Gas6 binds to the extracellular domain of AXL to induce AXL dimerization, triggering trans-autophosphorylation in the intracellular domain, thereby activating intracellular signaling pathways and regulating a range of physiological activities. Cell growth and proliferation are regulated by the Src/MAPK/ERK pathway; anti-apoptotic protein expression is stimulated by the PI3K/AKT pathway; cell migration and proliferation are regulated by the PI3K/p38/MAPK pathway. In addition to Gas6-dependent activation, AXL can also be activated in a ligand-independent manner. AXL is involved in the adhesion and immunoregulation of normal cells. It has been found that overexpression of AXL is present in a variety of tumor cells. The signaling pathway regulated by Gas6/AXL is closely related to the occurrence and development of various tumors, such as chronic myeloid leukemia. , breast cancer, prostate cancer, non-small cell lung cancer, pancreatic cancer, melanoma, glioma and renal cell carcinoma. Inhibition of AXL expression has been shown to reduce proliferation and growth of pancreatic cancer cells and inhibit invasion and migration of breast cancer cells. In non-small cell lung cancer, gene silencing of AXL can inhibit tumor growth. At the same time, high expression of AXL is also associated with tumor recurrence and tolerance of other anticancer drugs, such as Ilvertinib, erlotinib (Tarceva), and lapatinib (Tyverb). These evidences suggest that AXL is an effective target for targeted tumor therapy.
Bosutinib(SKI606，PF5208763，Bosulif；Pfizer，2012)，Cabozantinib(XL184，Cometriq；Exelixis，2012)，Sunitinib(SU11248，Sutent；Pfizer，2006)等上市药物虽然具有AXL活性，但它们是多靶点药物，不具有特异性。BGB324(R428；Rigel Pharmaceuticals，BergenBio)是目前已知的特异性最高的AXL小分子抑制剂，正处于临床二期研究，2014年12月，FDA授予BGB324治疗AML的孤儿药称号。目前，还没有针对AXL激酶的小分子抑制剂上市。Bosutinib (SKI606, PF5208763, Bosulif; Pfizer, 2012), Cabozantinib (XL184, Cometriq; Exelixis, 2012), Sunitinib (SU11248, Sutent; Pfizer, 2006) and other marketed drugs, although having AXL activity, are multi-target drugs. Not specific. BGB324 (R428; Rigel Pharmaceuticals, BergenBio) is currently the most specific AXL small molecule inhibitor known in the clinical phase II study. In December 2014, the FDA granted BGB324 the orphan drug title for AML. Currently, no small molecule inhibitors against AXL kinase have been marketed.
发明内容Summary of the invention
基于此，本发明提供了一类新的3-氨基吡唑类化合物，该类化合物对AXL激酶具有强烈的抑制活性。Based on this, the present invention provides a new class of 3-aminopyrazole compounds which have potent inhibitory activity against AXL kinase.
具体技术方案如下：The specific technical solutions are as follows:
具有式(Ⅰ)所示结构的3-氨基吡唑类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子或者其氘代物：A 3-aminopyrazole compound having the structure represented by the formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof or a progeny thereof:
Figure PCTCN2019079733-appb-000001
Figure PCTCN2019079733-appb-000001
其中，X选自：CH或N；Wherein X is selected from: CH or N;
Z选自：O或NH；Z is selected from: O or NH;
B选自：C 5～C 10芳基、5～10元杂芳基、C 3～C 6环烷基、C 7～C 13多环烷基； B is selected from the group consisting of C 5 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 6 cycloalkyl, C 7 -C 13 polycycloalkyl;
R 1、R 2与A环组成取代或未取代的并杂环
Figure PCTCN2019079733-appb-000002
m为2或者3，Y选自C、N或O； R 1 , R 2 and A ring constitute a substituted or unsubstituted heterocyclic ring
Figure PCTCN2019079733-appb-000002
m is 2 or 3, and Y is selected from C, N or O;
R 3选自：氢、卤素、卤素取代的C 1～C 6烷基、C 1～C 6烷氧基或C 1～C 6烷基； R 3 is selected from the group consisting of hydrogen, halogen, halogen-substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy or C 1 -C 6 alkyl;
R 4选自：氢、C 1～C 5烷基、C 3～C 6环烷基、C 1～C 3烷氧基或
Figure PCTCN2019079733-appb-000003
R 21选自：氢、卤素、C 1～C 5烷基、C 3～C 6环烷基或C 1～C 5烷氧基； R 4 is selected from the group consisting of hydrogen, C 1 -C 5 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy or
Figure PCTCN2019079733-appb-000003
R 21 is selected from the group consisting of hydrogen, halogen, C 1 -C 5 alkyl, C 3 -C 6 cycloalkyl or C 1 -C 5 alkoxy;
R 5、R 6分别独立地选自：氢、烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、芳烷基、取代或未取代的杂芳基、杂芳烷基、取代或未取代的多环烷基；或者，R 5、R 6和与其相连的N原子一起组成单环杂环或并环杂环。 R 5 and R 6 are each independently selected from the group consisting of hydrogen, alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, aralkyl, substituted or unsubstituted Substituted heteroaryl, heteroarylalkyl, substituted or unsubstituted polycycloalkyl; or R 5 , R 6 together with the N atom to which they are attached constitute a monocyclic heterocyclic ring or a heterocyclic heterocyclic ring.
在其中一些实施例中，所述3-氨基吡唑类化合物具有式(Ⅱ)所示结构：In some of these embodiments, the 3-aminopyrazole compound has the structure of formula (II):
Figure PCTCN2019079733-appb-000004
Figure PCTCN2019079733-appb-000004
X选自：CH或N。X is selected from: CH or N.
在其中一些实施例中，所述取代或未取代的并杂环
Figure PCTCN2019079733-appb-000005
选自如下结构： In some of these embodiments, the substituted or unsubstituted heterocyclic ring
Figure PCTCN2019079733-appb-000005
Selected from the following structure:
Figure PCTCN2019079733-appb-000006
Figure PCTCN2019079733-appb-000006
其中，X为CH或N；Where X is CH or N;
R 12、R 13分别独立地选自：-O(CR 15R 16) OR 14； R 12 and R 13 are each independently selected from: -O(CR 15 R 16 ) O R 14 ;
其中，o选自0～6之间的整数；Wherein o is selected from an integer between 0 and 6;
R 14、R 15、R 16分别独立地选自：-H、C 1～C 5烷基、卤素、卤素取代的C 1～C 5烷基、卤素取代的C 1～C 5烷氧基、-OH、-COOH、-COOR 19、-(C＝O)-NR 19R 20、-SO m-NR 19R 20、-CHR 19R 20、-OR 19或-NR 19R 20；m＝1～2； R 14 , R 15 and R 16 are each independently selected from: -H, C 1 -C 5 alkyl, halogen, halogen-substituted C 1 -C 5 alkyl, halogen-substituted C 1 -C 5 alkoxy, -OH, -COOH, -COOR 19 , -(C=O)-NR 19 R 20 , -SO m -NR 19 R 20 , -CHR 19 R 20 , -OR 19 or -NR 19 R 20 ; m=1 ～2;
R 19、R 20分别独立地选自：氢、卤素、C 1～C 6烷基、或者R 19与R 20组成饱和或不饱和的R 22取代的5～8元杂环基团，其中R 22选自：-H、C 1～C 5烷基； R 19 and R 20 are each independently selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, or R 19 and R 20 are a saturated or unsaturated R 22 -substituted 5-8 membered heterocyclic group, wherein R 22 is selected from the group consisting of: -H, C 1 -C 5 alkyl;
或者，R 12、R 13组成含1～4个杂原子的取代或未取代的C 5～C 18脂肪环烷基。 Alternatively, R 12 and R 13 constitute a substituted or unsubstituted C 5 -C 18 aliphatic cycloalkyl group having 1 to 4 hetero atoms.
在其中一些实施例中，R 14、R 15、R 16分别独立地选自：R 14、R 15、R 16分别独立地选自：-H、C 1～C 5烷基、-OR 19或-NR 19R 20； In some of the embodiments, R 14 , R 15 , and R 16 are each independently selected from: R 14 , R 15 , and R 16 are each independently selected from: -H, C 1 -C 5 alkyl, -OR 19 or -NR 19 R 20 ;
R 19、R 20分别独立地选自：氢、C 1～C 6烷基、或者R 19、R 20和与其相连的N一起组成饱和或不饱和的R 22取代的5～8元杂环基团，其中R 22选自：-H、C 1～C 5烷基。 R 19 and R 20 are each independently selected from the group consisting of: hydrogen, C 1 -C 6 alkyl, or R 19 , R 20 and N attached thereto to form a saturated or unsaturated R 22 -substituted 5-8 membered heterocyclic group. a group wherein R 22 is selected from the group consisting of: -H, C 1 -C 5 alkyl.
在其中一些实施例中，R 15和R 16均为氢； In some of these embodiments, R 15 and R 16 are both hydrogen;
R 14选自：-H、-OR 19或-NR 19R 20； R 14 is selected from the group consisting of: -H, -OR 19 or -NR 19 R 20 ;
R 19、R 20分别独立地选自：C 1～C 3烷基、或者R 19、R 20和与其相连的N一起组成饱和的R 22取代的5～8元杂环基团，其中R 22选自：-H、C 1～C 3烷基。 R 19 and R 20 are each independently selected from a C 1 -C 3 alkyl group, or R 19 , R 20 and N attached thereto constitute a saturated R 22 -substituted 5-8 membered heterocyclic group, wherein R 22 It is selected from the group consisting of: -H, C 1 -C 3 alkyl.
在其中一些实施例中，R 12、R 13分别独立地选自：-O(CH 2) OR 14；o选自0～4之间的整数。 In some of these embodiments, R 12 and R 13 are each independently selected from: -O(CH 2 ) O R 14 ; o is selected from an integer between 0 and 4.
在其中一些实施例中，R 12和R 13中的一个选自C 1～C 4烷氧基，另一个选自：-O(CH 2) OR 14； In some of these embodiments, one of R 12 and R 13 is selected from the group consisting of C 1 -C 4 alkoxy groups, and the other is selected from: -O(CH 2 ) O R 14 ;
o选自1～4之间的整数；o is selected from an integer between 1 and 4;
R 14选自：H、-OR 19或-NR 19R 20； R 14 is selected from the group consisting of: H, -OR 19 or -NR 19 R 20 ;
R 19、R 20分别独立地选自：C 1～C 3烷基、或者R 19、R 20和与其相连的N一起组成R 22取代的6元饱和杂环基，其中R 22选自：-H、C 1～C 3烷基。 R 19 and R 20 are each independently selected from a C 1 -C 3 alkyl group, or R 19 , R 20 and N attached thereto constitute a R 22 -substituted 6-membered saturated heterocyclic group, wherein R 22 is selected from the group consisting of: - H, C 1 - C 3 alkyl.
在其中一些实施例中，R 12和R 13分别独立地选自：甲氧基、乙氧基、丙氧基、吗啉基取代的丙氧基、甲氧基取代的乙氧基、甲氧基取代的丙氧基、二甲胺基取代的丙氧基、哌啶取 代的丙氧基、N-甲基哌嗪取代的丙氧基。 In some of these embodiments, R 12 and R 13 are each independently selected from the group consisting of: methoxy, ethoxy, propoxy, morpholinyl substituted propoxy, methoxy substituted ethoxy, methoxy A substituted propoxy group, a dimethylamino substituted propoxy group, a piperidine substituted propoxy group, and an N-methylpiperazine substituted propoxy group.
在其中一些实施例中，R 3选自：H、卤素、三氟甲基、C 1～C 3烷基、C 1～C 3烷氧基。 In some of these embodiments, R 3 is selected from the group consisting of: H, halogen, trifluoromethyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxy.
在其中一些实施例中，R 3选自：H、F、Cl、Br、甲基、乙基、甲氧基、乙氧基。 In some of these embodiments, R 3 is selected from the group consisting of: H, F, Cl, Br, methyl, ethyl, methoxy, ethoxy.
在其中一些实施例中，R 4选自：C 1～C 3烷基。 In some of these embodiments, R 4 is selected from the group consisting of: C 1 -C 3 alkyl.
在其中一些实施例中，R 5、R 6分别独立地选自：氢、C 1～C 8烷基、R 8取代的C 3～C 10环烷基、R 8取代的3-10元杂环烷基、R 10取代的C 5-C 10芳基、芳烷基、R 10取代的5-10元杂芳基、杂芳烷基、R 8取代的C 7～C 13多环烷基；或者，R 5、R 6和与其相连的N原子一起组成3-10元的单环杂环或并环杂环； In some of these embodiments, R 5 and R 6 are each independently selected from the group consisting of: hydrogen, C 1 -C 8 alkyl, R 8 -substituted C 3 -C 10 cycloalkyl, R 8 substituted 3-10 membered hetero Cycloalkyl, R 10 substituted C 5 -C 10 aryl, aralkyl, R 10 substituted 5-10 membered heteroaryl, heteroaralkyl, R 8 substituted C 7 -C 13 polycycloalkyl Or, R 5 , R 6 and the N atom to which it is bonded together constitute a 3-10 membered monocyclic heterocyclic ring or a bicyclic heterocyclic ring;
R 8选自：氢、C 1～C 6烷基、卤素； R 8 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, halogen;
R 10选自：氢、卤素、C 1～C 6烷基、C 1～C 6烷氧基、氰基、卤素取代的C 1～C 6烷基、卤素取代的C 1～C 6烷氧基、氰基取代的C 1～C 6烷基。 R 10 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, cyano, halogen-substituted C 1 -C 6 alkyl, halogen-substituted C 1 -C 6 alkoxy a cyano-substituted C 1 -C 6 alkyl group.
在其中一些实施例中，R 5、R 6分别独立地选自：氢、C 1～C 8烷基、R 8取代的C 3～C 8环烷基、R 8取代的6-8元杂环烷基、R 10取代的苯基、金刚烷基、R 10取代的5-10元杂芳基；或者，R 5、R 6和与其相连的N原子一起组成3-10元的单环杂环或并环杂环。 In some of these embodiments, R 5 and R 6 are each independently selected from the group consisting of: hydrogen, C 1 -C 8 alkyl, R 8 -substituted C 3 -C 8 cycloalkyl, R 8 substituted 6-8 membered hetero a cycloalkyl group, a R 10 -substituted phenyl group, an adamantyl group, an R 10 -substituted 5-10 membered heteroaryl group; or, R 5 , R 6 and an N atom attached thereto constitute a 3-10 membered monocyclic hetero Ring or a heterocyclic ring.
在其中一些实施例中，R 6选自：氢、C 1～C 5烷基；R 5选自：C 2～C 8烷基、R 8取代的C 3～C 8环烷基、R 8取代的6-8元杂环烷基、R 10取代的苯基、金刚烷基；或者，R 5、R 6和与其相连的N原子一起组成3-10元的单环杂环或并环杂环。 In some of these embodiments, R 6 is selected from the group consisting of: hydrogen, C 1 -C 5 alkyl; R 5 is selected from: C 2 -C 8 alkyl, R 8 -substituted C 3 -C 8 cycloalkyl, R 8 Substituted 6-8 membered heterocycloalkyl, R 10 substituted phenyl, adamantyl; or, R 5 , R 6 and the N atom to which they are attached form a 3-10 membered monocyclic or heterocyclic ring ring.
在其中一些实施例中，R 6选自：氢、C 1～C 5烷基；R 5选自：C 4～C 8烷基、R 8取代的C 4～C 8环烷基、R 10取代的苯基、R 8取代的6-8元杂环烷基、金刚烷基；或者，R 5、R 6和与其相连的N原子一起组成3-10元的单环杂环或并环杂环。 In some of these embodiments, R 6 is selected from the group consisting of: hydrogen, C 1 -C 5 alkyl; R 5 is selected from: C 4 -C 8 alkyl, R 8 -substituted C 4 -C 8 cycloalkyl, R 10 Substituted phenyl, R 8 substituted 6-8 membered heterocycloalkyl, adamantyl; or R 5 , R 6 and the N atom to which they are attached form a 3-10 membered monocyclic or heterocyclic ring ring.
在其中一些实施例中，R 6选自：氢、C 1～C 3烷基；R 5选自：R 8取代的C 5～C 8环烷基、R 10取代的苯基、金刚烷基。 In some of these embodiments, R 6 is selected from the group consisting of: hydrogen, C 1 -C 3 alkyl; R 5 is selected from: R 8 -substituted C 5 -C 8 cycloalkyl, R 10 substituted phenyl, adamantyl .
在其中一些实施例中，R 8选自：氢、卤素；R 10选自：氢、卤素、C 1～C 2烷基、甲氧基。 In some of these embodiments, R 8 is selected from the group consisting of: hydrogen, halogen; and R 10 is selected from the group consisting of hydrogen, halogen, C 1 -C 2 alkyl, methoxy.
在其中一些实施例中，所述3-氨基吡唑类化合物具有式(Ⅲ)所示结构：In some of these embodiments, the 3-aminopyrazole compound has the structure shown in formula (III):
Figure PCTCN2019079733-appb-000007
Figure PCTCN2019079733-appb-000007
其中，R 3选自：H、卤素、C 1～C 3烷基、C 1～C 3烷氧基； Wherein R 3 is selected from the group consisting of: H, halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy;
R 6选自：氢、C 1～C 2烷基； R 6 is selected from the group consisting of hydrogen, C 1 -C 2 alkyl;
R 5选自：C 5～C 8环烷基、R 10取代的苯基、6-8元杂环烷基；或者，R 5、R 6和与其相连的N原子一起组成3-10元的单环杂环或并环杂环； R 5 is selected from the group consisting of: C 5 -C 8 cycloalkyl, R 10 -substituted phenyl, 6-8 membered heterocycloalkyl; or R 5 , R 6 and the N atom to which they are attached constitute a 3-10 member. Monocyclic or bicyclic heterocycle;
R 10选自：氢、卤素、C 1～C 2烷基、甲氧基、卤素取代的C 1～C 2烷氧基； R 10 is selected from the group consisting of hydrogen, halogen, C 1 -C 2 alkyl, methoxy, halogen-substituted C 1 -C 2 alkoxy;
R 13选自：-O(CH 2) OR 14；o选自1～4之间的整数； R 13 is selected from the group consisting of: -O(CH 2 ) O R 14 ; o is selected from an integer between 1 and 4;
R 14选自：H、-OR 19或-NR 19R 20； R 14 is selected from the group consisting of: H, -OR 19 or -NR 19 R 20 ;
R 19、R 20分别独立地选自：C 1～C 3烷基、或者R 19、R 20和与其相连的N一起组成R 22取代的6元饱和杂环基，其中R 22选自：-H、C 1～C 3烷基。 R 19 and R 20 are each independently selected from a C 1 -C 3 alkyl group, or R 19 , R 20 and N attached thereto constitute a R 22 -substituted 6-membered saturated heterocyclic group, wherein R 22 is selected from the group consisting of: - H, C 1 - C 3 alkyl.
在其中一些实施例中，所述3-氨基吡唑类化合物选自：In some of these embodiments, the 3-aminopyrazole compound is selected from the group consisting of
3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-N,1-二甲基-1H-吡唑-4-甲酰胺、3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-N,1-dimethyl-1H-pyrazole-4- Formamide,
3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-N-乙基-1-甲基-1H-吡唑-4-甲酰胺、3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-N-ethyl-1-methyl-1H-pyrazole- 4-formamide,
N-环丙基-3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺、N-cyclopropyl-3-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl-1H-pyrazole -4-carboxamide,
N-叔丁基-3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺、N-tert-butyl-3-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl-1H-pyrazole -4-carboxamide,
N-环戊基-3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺、N-cyclopentyl-3-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl-1H-pyrazole -4-carboxamide,
N-环己基-3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺、N-cyclohexyl-3-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl-1H-pyrazole- 4-formamide,
N-环庚基-3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺、N-cycloheptyl-3-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl-1H-pyrazole -4-carboxamide,
N-环辛基-3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺、N-cyclooctyl-3-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl-1H-pyrazole -4-carboxamide,
(3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-1H-吡唑-4-基)(哌啶-1-基)甲酮、(3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl-1H-pyrazol-4-yl) (piperidin-1-yl)methanone,
(3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-1H-吡唑-4-基)(八氢喹啉-1(2H)-基)甲酮、(3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl-1H-pyrazol-4-yl) (octahydroquinoline-1(2H)-yl)methanone,
N-(4,4-二氟环己基)-3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺、N-(4,4-Difluorocyclohexyl)-3-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1- Methyl-1H-pyrazole-4-carboxamide,
3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-N-(四氢-2H-吡喃)-1H-吡唑-4-甲酰胺、3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl-N-(tetrahydro-2H-pyran )-1H-pyrazole-4-carboxamide,
N-环己基-3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-N,1-二甲基-1H-吡唑-4-甲酰胺、N-cyclohexyl-3-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-N,1-dimethyl-1H- Pyrazole-4-carboxamide,
N-(金刚烷-1-基)-3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺、N-(adamantan-1-yl)-3-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl -1H-pyrazole-4-carboxamide,
3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-N-苯基-1H-吡唑-4-甲酰胺、3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl-N-phenyl-1H-pyrazole- 4-formamide,
3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-N-(邻甲苯基)-1H-吡唑-4-甲酰 胺、3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl-N-(o-tolyl)-1H- Pyrazole-4-carboxamide,
3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-N-(间甲苯基)-1H-吡唑-4-甲酰胺、3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl-N-(m-tolyl)-1H- Pyrazole-4-carboxamide,
3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-N-(3-乙苯基)-1H-吡唑-4-甲酰胺、3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl-N-(3-ethylphenyl)- 1H-pyrazole-4-carboxamide,
3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-N-(对甲苯基)-1H-吡唑-4-甲酰胺、3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl-N-(p-tolyl)-1H- Pyrazole-4-carboxamide,
3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-N-(2-甲氧苯基)-1-甲基-1H-吡唑-4-甲酰胺、3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-N-(2-methoxyphenyl)-1-methyl -1H-pyrazole-4-carboxamide,
3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-N-(3-甲氧苯基)-1-甲基-1H-吡唑-4-甲酰胺、3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-N-(3-methoxyphenyl)-1-methyl -1H-pyrazole-4-carboxamide,
3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-N-(4-甲氧苯基)-1-甲基-1H-吡唑-4-甲酰胺、3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-N-(4-methoxyphenyl)-1-methyl -1H-pyrazole-4-carboxamide,
N-(3-氯苯基)-3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺、N-(3-chlorophenyl)-3-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl- 1H-pyrazole-4-carboxamide,
N-(4-氯苯基)-3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺、N-(4-chlorophenyl)-3-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl- 1H-pyrazole-4-carboxamide,
3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-N-(3-氟苯基)-1-甲基-1H-吡唑-4-甲酰胺、3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-N-(3-fluorophenyl)-1-methyl- 1H-pyrazole-4-carboxamide,
3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-N-(4-氟苯基)-1-甲基-1H-吡唑-4-甲酰胺、3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-N-(4-fluorophenyl)-1-methyl- 1H-pyrazole-4-carboxamide,
3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-N-(4-异丙苯基)-1-甲基-1H-吡唑-4-甲酰胺、3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-N-(4-isopropylphenyl)-1-methyl -1H-pyrazole-4-carboxamide,
3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-N-(4-(三氟甲氧基)苯基)-1-甲基-1H-吡唑-4-甲酰胺、3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-N-(4-(trifluoromethoxy)phenyl) -1-methyl-1H-pyrazole-4-carboxamide,
N-(4-(二氟甲氧基)苯基)-3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺、N-(4-(Difluoromethoxy)phenyl)-3-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino) -1-methyl-1H-pyrazole-4-carboxamide,
N-(4-(氰甲基)苯基)-3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺、N-(4-(Cyanomethyl)phenyl)-3-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1 -methyl-1H-pyrazole-4-carboxamide,
N-环己基-3-((4-((6,7-二甲氧基喹啉-4-基)氧)苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺、N-cyclohexyl-3-((4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)amino)-1-methyl-1H-pyrazole-4-carboxamide ,
N-环己基-3-((4-((6,7-二甲氧基喹啉-4-基)氧)-2-氟苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺、N-cyclohexyl-3-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-2-fluorophenyl)amino)-1-methyl-1H-pyrazole- 4-formamide,
N-环己基-3-((4-((6,7-二甲氧基喹啉-4-基)氧)-2-甲苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺、N-cyclohexyl-3-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-2-methyl)amino)-1-methyl-1H-pyrazole-4 -formamide,
3-((3-氯-4-((6,7-二甲氧基喹啉-4-基)氧)苯基)氨基)-N-环己基-1-甲基-1H-吡唑-4-甲酰胺、3-((3-Chloro-4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)amino)-N-cyclohexyl-1-methyl-1H-pyrazole- 4-formamide,
N-环己基-3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-甲苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺、N-cyclohexyl-3-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-methyl)amino)-1-methyl-1H-pyrazole-4 -formamide,
N-环己基-3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-甲氧苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺、N-cyclohexyl-3-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-methoxyphenyl)amino)-1-methyl-1H-pyrazole -4-carboxamide,
N-环己基-3-((4-((7-乙氧基-6-甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺、N-cyclohexyl-3-((4-((7-ethoxy-6-methoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl-1H- Pyrazole-4-carboxamide,
N-环己基-3-((3-氟-4-((6-甲氧基-7-丙氧基喹啉-4-基)氧)苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺、N-cyclohexyl-3-((3-fluoro-4-((6-methoxy-7-propoxyquinolin-4-yl)oxy)phenyl)amino)-1-methyl-1H- Pyrazole-4-carboxamide,
N-环己基-3-((3-氟-4-((6-甲氧基-7-(2-甲氧乙氧基)喹啉-4-基)氧)苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺、N-cyclohexyl-3-((3-fluoro-4-((6-methoxy-7-(2-methoxyethoxy)quinolin-4-yl)oxy)phenyl)amino)-1 -methyl-1H-pyrazole-4-carboxamide,
N-环己基-3-((3-氟-4-((6-甲氧基-7-(3-甲氧丙氧基)喹啉-4-基)氧)苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺、N-cyclohexyl-3-((3-fluoro-4-((6-methoxy-7-(3-methoxypropoxy)quinolin-4-yl)oxy)phenyl)amino)-1 -methyl-1H-pyrazole-4-carboxamide,
N-环己基-3-((4-((7-(3-(二甲胺)丙氧基)-6-甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺、N-cyclohexyl-3-((4-((7-(3-(dimethylamino)propoxy)-6-methoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino )-1-methyl-1H-pyrazole-4-carboxamide,
N-环己基-3-((3-氟-4-((6-甲氧基-7-(3-(哌啶-1-基)丙氧基)喹啉-4-基)氧)苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺、N-cyclohexyl-3-((3-fluoro-4-((6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinolin-4-yl)oxy)benzene Amino)-1-methyl-1H-pyrazole-4-carboxamide,
N-环己基-3-((3-氟-4-((6-甲氧基-7-(3-(4-甲基哌嗪-1-基)丙氧基)喹啉-4-基)氧)苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺、N-cyclohexyl-3-((3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinolin-4-yl) Oxy)phenyl)amino)-1-methyl-1H-pyrazole-4-carboxamide,
N-环己基-3-((3-氟-4-((6-甲氧基-7-(3-吗啉丙氧基)喹啉-4-基)氧)苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺、N-cyclohexyl-3-((3-fluoro-4-((6-methoxy-7-(3-morpholinepropoxy)quinolin-4-yl)oxy)phenyl)amino)-1 -methyl-1H-pyrazole-4-carboxamide,
N-环庚基-3-((3-氟-4-((6-甲氧基-7-(3-吗啉丙氧基)喹啉-4-基)氧)苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺、N-cycloheptyl-3-((3-fluoro-4-((6-methoxy-7-(3-morpholinepropoxy)quinolin-4-yl)oxy)phenyl)amino)- 1-methyl-1H-pyrazole-4-carboxamide,
N-环戊基-3-((3-氟-4-((6-甲氧基-7-(3-吗啉丙氧基)喹啉-4-基)氧)苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺、N-cyclopentyl-3-((3-fluoro-4-((6-methoxy-7-(3-morpholinepropoxy)quinolin-4-yl)oxy)phenyl)amino)- 1-methyl-1H-pyrazole-4-carboxamide,
3-((3-氟-4-((6-甲氧基-7-(3-吗啉丙氧基)喹啉-4-基)氧)苯基)氨基)-N-(4-氟苯基)-1-甲基-1H-吡唑-4-甲酰胺。3-((3-fluoro-4-((6-methoxy-7-(3-morpholinepropoxy)quinolin-4-yl)oxy)phenyl)amino)-N-(4-fluoro Phenyl)-1-methyl-1H-pyrazole-4-carboxamide.
本发明还提供了上述3-氨基吡唑类化合物或者其药学上可接受的盐或者其立体异构体的应用。The present invention also provides the use of the above 3-aminopyrazole compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.
具体技术方案如下：The specific technical solutions are as follows:
上述的3-氨基吡唑类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子 在制备AXL激酶抑制剂中的应用。Use of the above 3-aminopyrazole compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof for the preparation of an AXL kinase inhibitor.
上述的3-氨基吡唑类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子或者其氘代物在制备防治肿瘤的药物中的应用。Use of the above 3-aminopyrazole compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof or a progeny thereof for the preparation of a medicament for controlling tumors.
在其中一些实施例中，所述肿瘤为：血液性肿瘤、胃肠间质瘤、组织细胞性淋巴癌、非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、鼻咽癌。所述血液性肿瘤比如白血病等。In some of the embodiments, the tumor is: hematological tumor, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer , prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, nasopharyngeal cancer. The blood tumor such as leukemia or the like.
本发明还提供了一种防治肿瘤的药物组合物。The invention also provides a pharmaceutical composition for preventing and treating tumors.
具体技术方案如下：The specific technical solutions are as follows:
一种防治肿瘤的药物组合物，所述药物组合物包括有上述的3-氨基吡唑类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子或者其氘代物，及药学上可接受的载体。A pharmaceutical composition for preventing and treating tumors, comprising the above 3-aminopyrazole compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof or a progeny thereof, and A pharmaceutically acceptable carrier.
本发明的3-氨基吡唑类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子或者其氘代物可以有效抑制AXL等蛋白激酶的作用，从而可抑制多种肿瘤细胞的增殖、迁移和侵袭，可用于制备抗肿瘤药物，可用于制备预防和/或治疗人类及其它哺乳动物的肿瘤等过度增殖性疾病的药物中。The 3-aminopyrazole compound of the present invention or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof or a progeny thereof can effectively inhibit the action of a protein kinase such as AXL, thereby inhibiting various tumor cells Proliferation, migration and invasion can be used to prepare anti-tumor drugs, and can be used in the preparation of drugs for preventing and/or treating hyperproliferative diseases such as tumors in humans and other mammals.
具体实施方式detailed description
下面结合实施例对本发明作进一步详细的描述，但本发明的实施方式不限于此。The present invention will be further described in detail below with reference to the embodiments, but the embodiments of the present invention are not limited thereto.
本发明所述化合物中，当任何变量(例如R 1、R等)在任何组分中出现超过一次，则其每次出现的定义独立于其它每次出现的定义。同样，允许取代基及变量的组合，只要这种组合使化合物稳定。自取代基划入环系统的线表示所指的键可连接到任何能取代的环原子上。如果环系统为多环，其意味着这种键仅连接到邻近环的任何适当的碳原子上。要理解本领域普通技术人员可选择本发明化合物的取代基及取代形式而提供化学上稳定的并可通过本领域技术和下列提出的方法自可容易获得的原料容易的合成的化合物。如果取代基自身被超过一个基团取代，应理解这些基团可在相同碳原子上或不同碳原子上，只要使结构稳定。 The compounds of the present invention, when any variable (e.g. R 1, R, etc.) appear in any component more than once defined, it is on each occurrence is independent of its definition at every other occurrence of. Also, combinations of substituents and variables are allowed as long as such combinations stabilize the compound. A line drawn from a substituent into the ring system means that the bond referred to can be attached to any ring atom that can be substituted. If the ring system is polycyclic, it means that such a bond is only attached to any suitable carbon atom of the adjacent ring. It will be understood that one of ordinary skill in the art can select substituents and substituted forms of the compounds of the present invention to provide compounds which are chemically stable and which are readily synthesized from readily available starting materials by techniques in the art and from the methods set forth below. If the substituent itself is substituted by more than one group, it is understood that these groups may be on the same carbon atom or on different carbon atoms as long as the structure is stabilized.
本文所用术语“烷基”意指包括具有特定碳原子数目的支链的和直链的饱和脂肪烃基。例如，“C 1-C 5烷基”中“C 1-C 5”的定义包括以直链或支链排列的具有1、2、3、4或5个碳原子的基团。例如，“C 1-C 5烷基”具体包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、戊基。术语“环烷基”指具有特定碳原子数目的单环饱和脂肪烃基。例如“环烷基”包括环丙基、甲基-环丙基、环丁基、环戊基、环己基等。 The term "alkyl" as used herein is meant to include branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, the definition of "C 1 -C 5 " in "C 1 -C 5 alkyl" includes a group having 1, 2, 3, 4 or 5 carbon atoms arranged in a straight chain or a branched chain. For example, "C 1 -C 5 alkyl" specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl. The term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms. For example, "cycloalkyl" includes cyclopropyl, methyl-cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
本文所用术语“杂芳基”代表环中多达5个原子的稳定的单环或每个环中多达5个原子双 环碳环，其中至少一个环为芳香环且含有1～4个选自O、N和S的杂原子。本定义范围内的杂芳基包括但不限于：咪唑基、吡唑基、呋喃基、噻吩基、噁唑基、异噁唑基、吡嗪基、吡啶基、嘧啶基、吡咯基。对于下列杂芳基的定义，“杂芳基”也理解为包括任何含有氮的杂芳基的N-氧化物衍生物。杂芳基取代基是双环的且含有一个环为非芳香性或不含有杂原子的例子中，应理解各自经芳香环或经含杂原子环连接。The term "heteroaryl" as used herein denotes a stable monocyclic ring of up to 5 atoms in the ring or up to 5 atoms of a bicyclic carbocyclic ring in each ring, wherein at least one ring is an aromatic ring and contains from 1 to 4 selected from Heteroatoms of O, N and S. Heteroaryl groups within the scope of this definition include, but are not limited to, imidazolyl, pyrazolyl, furyl, thienyl, oxazolyl, isoxazolyl, pyrazinyl, pyridyl, pyrimidinyl, pyrrolyl. "Heteroaryl" is also understood to include any N-oxide derivative of a nitrogen-containing heteroaryl group for the definition of the following heteroaryl. In the examples where the heteroaryl substituent is bicyclic and contains a ring which is non-aromatic or contains no heteroatoms, it is understood that each is attached via an aromatic ring or via a heteroatom-containing ring.
本文中所用术语“杂环”或“杂环基”是指含有1～4个选自O、N和S的杂原子的5元～6元芳香性或非芳香性杂环，且包括双环基团。“杂环基”因此包括上面提及的杂芳基，也包括其二氢化及四氢化类似物。“杂环基”进一步的实例包括但不限于：咪唑基、噻唑基、异噁唑基、噁二唑基、噁唑基、氧杂环丁烷基(oxetanyl)、吡喃基、吡嗪基、吡唑基、哒嗪基、吡啶基、嘧啶基、吡咯基、喹噁啉基、四唑基、噻二唑基、噻唑基、噻吩基、唑基。杂环取代基的连接可通过碳原子或通过杂原子实现。The term "heterocycle" or "heterocyclyl" as used herein, refers to a 5- to 6-membered aromatic or non-aromatic heterocyclic ring containing from 1 to 4 heteroatoms selected from O, N and S, and includes a bicyclic group. group. "Heterocyclyl" thus includes the heteroaryl groups mentioned above, as well as the dihydrogenated and tetrahydrogenated analogs thereof. Further examples of "heterocyclyl" include, but are not limited to, imidazolyl, thiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, oxetanyl, pyranyl, pyrazinyl , pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinoxalinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, oxazolyl. The attachment of a heterocyclic substituent can be achieved by a carbon atom or by a hetero atom.
正如本领域技术人员所理解的，本文中所用“卤素”(“halo”)或“卤素”意指包括氯、氟、溴和碘。As understood by those skilled in the art, "halo" or "halogen" as used herein is meant to include chloro, fluoro, bromo and iodo.
除非另有定义，烷基、环烷基、芳基、杂芳基和杂环基取代基可为未被取代的或取代的。例如，(C 1～C 6)烷基可被一个、两个或三个选自OH、卤素、硝基、氰基、烷氧基、二烷基氨基或杂环基例如吗啉基、哌啶基等的取代基取代。 Unless otherwise defined, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl substituents may be unsubstituted or substituted. For example, (C 1 -C 6 )alkyl may be selected from one, two or three selected from OH, halogen, nitro, cyano, alkoxy, dialkylamino or heterocyclic groups such as morpholinyl, piperidine Substituents such as pyridine are substituted.
本发明包括式Ⅰ～Ⅲ化合物的游离形式，也包括其药学上可接受的盐及立体异构体。本文中一些特定的示例性化合物为胺类化合物的质子化的盐。术语“游离形式”指以非盐形式的胺类化合物。包括在内的药学上可接受盐不仅包括本文所述特定化合物的示例性盐，也包括所有式Ⅰ化合物游离形式的典型的药学上可接受的盐。可使用本领域已知技术分离所述化合物特定盐的游离形式。例如，可通过用适当的碱稀水溶液例如NaOH稀水溶液、碳酸钾稀水溶液、稀氨水及碳酸氢钠稀水溶液处理该盐使游离形式再生。游离形式在某些物理性质例如在极性溶剂中溶解度上与其各自盐形式多少有些区别，但是为发明的目的这种酸盐及碱盐在其它药学方面与其各自游离形式相当。The invention includes the free forms of the compounds of Formulas I-III, as well as the pharmaceutically acceptable salts and stereoisomers thereof. Some specific exemplary compounds herein are protonated salts of amine compounds. The term "free form" refers to an amine compound in a non-salt form. The pharmaceutically acceptable salts included include not only exemplary salts of the particular compounds described herein, but also all typical pharmaceutically acceptable salts of the free forms of the compounds of formula I. The free form of the particular salt of the compound can be isolated using techniques known in the art. For example, the free form can be regenerated by treating the salt with a suitable dilute aqueous base such as a dilute aqueous solution of NaOH, a dilute aqueous solution of potassium carbonate, dilute aqueous ammonia, and a dilute aqueous solution of sodium bicarbonate. The free form differs somewhat from its respective salt form in solubility in certain physical properties, such as in polar solvents, but for purposes of the invention such acid and base salts are otherwise pharmaceutically equivalent to their respective free forms.
可通过常规化学方法自含有碱性部分或酸性部分的本发明化合物合成本发明的药学上可接受的盐。通常，通过离子交换色谱或通过游离碱和化学计算量或过量的所需盐形式的无机或有机酸在适当溶剂或多种溶剂的组合中反应制备碱性化合物的盐。类似的，通过和适当的无机或有机碱反应形成酸性化合物的盐。The pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of the present invention containing a basic moiety or an acidic moiety by conventional chemical methods. Typically, the salt of the basic compound is prepared by ion exchange chromatography or by reaction of the free base with a stoichiometric or excess amount of the desired salt or mixture of the inorganic or organic acid in a suitable solvent or combination of solvents. Similarly, a salt of an acidic compound is formed by reaction with a suitable inorganic or organic base.
因此，本发明化合物的药学上可接受的盐包括通过碱性本发明化合物和无机或有机酸反应形成的本发明化合物的常规无毒盐。例如，常规的无毒盐包括得自无机酸例如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸等的盐，也包括自有机酸例如乙酸、丙酸、琥珀酸、乙醇 酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、扑酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、对氨基苯磺酸、2-乙酰氧基一苯甲酸、富马酸、甲苯磺酸、甲磺酸、乙烷二磺酸、草酸、羟乙基磺酸、三氟乙酸等制备的盐。Thus, pharmaceutically acceptable salts of the compounds of the invention include the conventional non-toxic salts of the compounds of the invention which are formed by the reaction of a basic compound of the invention with an inorganic or organic acid. For example, conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, and also include organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, and hard. Fatty acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetyl A salt prepared from oxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid or the like.
如果本发明化合物为酸性的，则适当的“药学上可接受的盐”指通过药学上可接受的无毒碱包括无机碱及有机碱制备的盐。得自无机碱的盐包括铝盐、铵盐、钙盐、铜盐、铁盐、亚铁盐、锂盐、镁盐、锰盐、亚锰盐、钾盐、钠盐、锌盐等。特别优选铵盐、钙盐、镁盐、钾盐和钠盐。得自药学上可接受的有机无毒碱的盐，所述碱包括伯胺、仲胺和叔胺的盐，取代的胺包括天然存在的取代胺、环状胺及碱性离子交换树脂例如精氨酸、甜菜碱、咖啡因、胆碱、N,N'-二苄基乙二胺、二乙胺、2-二乙基氨基乙醇、2-二甲基氨基乙醇、氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡萄糖胺、氨基葡萄糖、组氨酸、羟钴胺、异丙基胺、赖氨酸、甲基葡萄糖胺、吗啉、哌嗪,哌啶、呱咤、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨基丁三醇等。If a compound of the invention is acidic, a suitable "pharmaceutically acceptable salt" refers to a salt prepared by pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganese salts, manganese salts, potassium salts, sodium salts, zinc salts and the like. Ammonium salts, calcium salts, magnesium salts, potassium salts and sodium salts are particularly preferred. A salt derived from a pharmaceutically acceptable organic non-toxic base, the base comprising a salt of a primary, secondary and tertiary amine, the substituted amine comprising a naturally occurring substituted amine, a cyclic amine and a basic ion exchange resin such as a fine Amino acid, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, B Diamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydroxycobalamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine , piperidine, guanidine, polyamine resin, procaine, guanidine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
Berg等，“Pharmaceutical Salts,”J.Pharm.Sci.1977:66:1-19.更详细描述了上文所述药学上可接受的盐及其它典型的药学上可接受的盐的制备。Berg et al, "Pharmaceutical Salts," J. Pharm. Sci. 1977: 66: 1-19. The preparation of the above-described pharmaceutically acceptable salts and other typical pharmaceutically acceptable salts is described in more detail.
由于在生理条件下化合物中脱质子化的酸性部分例如羧基可为阴离子的，而这种带有的电荷然后可被内部带有阳离子的质子化了的或烷基化的碱性部分例如四价氮原子平衡抵消，所以应注意本发明化合物是潜在的内盐或两性离子。Since the acidic moiety, such as a carboxyl group, which is deprotonated in a compound under physiological conditions, can be anionic, such charged charge can then be protonated or alkylated in the interior with a cationic moiety such as tetravalent The balance of nitrogen atoms is counteracted, so it should be noted that the compounds of the invention are potential internal salts or zwitterions.
除在文献中已知的或在实验程序中例证的标准方法外，可采用如下列方案中显示的反应制备本发明化合物。因此，下列说明性方案是为说明的目的而不是局限于所列化合物或任何特定的取代基。方案中显示的取代基数目并不必需符合权利要求中所用的数目，且为清楚起见，显示单取代基连接到在上文中式(I)的定义下允许有多取代基的化合物上。In addition to the standard methods known in the literature or exemplified in the experimental procedures, the compounds of the invention can be prepared using the reactions as shown in the scheme below. Accordingly, the following illustrative schemes are for illustrative purposes and are not limited to the listed compounds or any particular substituents. The number of substituents shown in the scheme does not necessarily have to correspond to the number used in the claims, and for the sake of clarity, it is shown that the mono-substituent is attached to a compound which allows multiple substituents under the definition of formula (I) above.
合成方案Synthetic scheme
如方案A中所示式(I)中化合物可以由6、7-二甲氧基-4-氯喹啉为起始原料通过4步反应合成。The compound of formula (I) as shown in Scheme A can be synthesized from 6,7-dimethoxy-4-chloroquinoline as a starting material by a four-step reaction.
方案A：Option A:
Figure PCTCN2019079733-appb-000008
Figure PCTCN2019079733-appb-000008
如方案B中所示式(I)中化合物可以由6-甲氧基-7-苄氧基-4-氯喹啉为起始原料通过6步反应合成。The compound of formula (I) as shown in Scheme B can be synthesized from 6-methoxy-7-benzyloxy-4-chloroquinoline starting from 6 steps.
方案B：Option B:
Figure PCTCN2019079733-appb-000009
Figure PCTCN2019079733-appb-000009
本发明提供的3-氨基吡唑类化合物或者其药学上可接受的盐或者其立体异构体可用于治疗人或其它哺乳动物肿瘤等过度增殖性疾病或症状。尤其是用于制备治疗或控制胃肠间质瘤、组织细胞性淋巴癌、非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、前列腺癌、鼻咽癌、白血病等过度增殖性疾病的药物中。The 3-aminopyrazole compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof provided by the present invention can be used for the treatment of hyperproliferative diseases or symptoms such as tumors in humans or other mammals. Especially for the preparation or treatment of gastrointestinal stromal tumors, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer , drugs for hyperproliferative diseases such as epithelial cell carcinoma, prostate cancer, nasopharyngeal cancer, and leukemia.
本发明所设计的化合物及其药学上可接受的盐或者其立体异构体可以与目前应用的或正处开发阶段的雌激素受体调节剂、雄激素受体调节剂、视网膜样受体调节剂、细胞毒素/细胞 抑制剂、抗增殖剂、蛋白转移酶抑制剂、HMG-CoA还原酶抑制剂、HIV蛋白激酶抑制剂、逆转录酶抑制剂、血管生成抑制剂、细胞增殖及生存信号抑制剂、干扰细胞周期关卡的药物和细胞凋亡诱导剂，细胞毒类药物、酪氨酸蛋白抑制剂、EGFR抑制剂、VEGFR抑制剂、丝氨酸/苏氨酸蛋白抑制剂、Bcr-Abl抑制剂，c-Kit抑制剂，Met抑制剂，Raf抑制剂,MEK抑制剂,MMP抑制剂,拓扑异构酶抑制剂、组氨酸去乙酰化酶抑制剂、蛋白酶体抑制剂、CDK抑制剂，Bcl-2家族蛋白抑制剂，MDM2家族蛋白抑制剂、IAP家族蛋白抑制剂、STAT家族蛋白抑制剂、PI3K抑制剂、AKT抑制剂、整联蛋白阻滞剂、干扰素-α、白介素-12、COX-2抑制剂、p53激活剂、VEGF抗体、EGF抗体等药物联合用药增加其临床效果。The compounds designed by the present invention and pharmaceutically acceptable salts thereof or stereoisomers thereof can be adjusted with estrogen receptor modulators, androgen receptor modulators, retinoid receptors currently in use or in the development stage Agents, cytotoxins/cytostatics, antiproliferative agents, protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protein kinase inhibitors, reverse transcriptase inhibitors, angiogenesis inhibitors, cell proliferation and survival signal suppression Agents, drugs and apoptosis inducers that interfere with cell cycle checkpoints, cytotoxic drugs, tyrosine protein inhibitors, EGFR inhibitors, VEGFR inhibitors, serine/threonine protein inhibitors, Bcr-Abl inhibitors, c-Kit inhibitor, Met inhibitor, Raf inhibitor, MEK inhibitor, MMP inhibitor, topoisomerase inhibitor, histidine deacetylase inhibitor, proteasome inhibitor, CDK inhibitor, Bcl- 2 family protein inhibitors, MDM2 family protein inhibitors, IAP family protein inhibitors, STAT family protein inhibitors, PI3K inhibitors, AKT inhibitors, integrin blockers, interferon-α, interleukin-12, C The combination of OX-2 inhibitor, p53 activator, VEGF antibody, EGF antibody and other drugs increases its clinical effect.
本发明所涉及的、具有式(I)结构的化合物及其药学上可接受的盐或者其立体异构体或其药用组合物可用于制备防治下列疾病以及下面没有列出的其它疾病的药物：The compound having the structure of the formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a pharmaceutical composition thereof according to the present invention can be used for the preparation of a medicament for the prevention and treatment of the following diseases and other diseases not listed below. :
(1)人或其它哺乳动物的乳腺癌，包括但不局限于侵袭性导管癌、侵袭性小叶癌、原位管癌和原位小叶癌。(1) Breast cancer in humans or other mammals, including but not limited to invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.
(2)人或其它哺乳动物的呼吸道癌，包括但不局限于小细胞&非小细胞肺癌以及支气管腺瘤和胸膜肺母细胞瘤。(2) Respiratory cancers in humans or other mammals, including but not limited to small cell & non-small cell lung cancer, as well as bronchial adenomas and pleural pulmonary blastomas.
(3)人或其它哺乳动物的脑癌，包括但不局限于脑干和眼下神经胶质瘤、小脑和大脑星形细胞瘤、室管膜细胞瘤以及神经外胚层和松果瘤体。(3) Brain cancer in humans or other mammals, including but not limited to brain stem and sub-glial glioma, cerebellum and cerebral astrocytoma, ependymoma, and neuroectoderm and pineal tumor.
(4)人或其它哺乳动物的雄、雌性生殖器官的肿瘤，雄性生殖器官的肿瘤包括但不限于前列腺和睾丸癌；雌性生殖器官的肿瘤包括但不限于子宫内膜癌、宫颈癌、卵巢癌、阴道癌和外阴癌以及子宫内瘤。(4) Tumors of male and female reproductive organs of humans or other mammals, tumors of male reproductive organs include, but are not limited to, prostate and testicular cancer; tumors of female reproductive organs include, but are not limited to, endometrial cancer, cervical cancer, ovarian cancer , vaginal cancer and vulvar cancer as well as intrauterine tumors.
(5)人或其它哺乳动物的消化道的肿瘤，包括但不限于肛门癌、结肠癌、结肠直道癌、食道癌、胃癌、胰腺癌直肠癌、小肠癌或唾腺癌。(5) Tumors of the digestive tract of human or other mammals, including but not limited to anal cancer, colon cancer, colonic straight cancer, esophageal cancer, gastric cancer, pancreatic cancer, rectal cancer, small intestine cancer or salivary gland cancer.
(6)人或其它哺乳动物的尿道的肿瘤，包括但不限于膀胱癌、阴茎癌、肾癌、肾盂癌、输尿管癌或尿道癌。(6) Tumors of the urethra of a human or other mammal, including but not limited to bladder cancer, penile cancer, renal cancer, renal pelvic cancer, ureteral cancer or urethral cancer.
(7)人或其它哺乳动物的眼癌，包括但不限于眼内黑素瘤和视网膜细胞瘤。(7) Eye cancer in humans or other mammals, including but not limited to intraocular melanoma and retinoblastoma.
(8)人或其它哺乳动物的肝癌，包括但不限于肝细胞瘤(具有或不具有纤维板变化的干细胞癌)、胆管癌(肝内胆管癌)以及混合的肝细胞性胆管癌。(8) Liver cancer of a human or other mammal, including but not limited to hepatoma (stem cell carcinoma with or without fibril changes), cholangiocarcinoma (intrahepatic cholangiocarcinoma), and mixed hepatocellular cholangiocarcinoma.
(9)人或其它哺乳动物的皮肤癌，包括但不限于扁平细胞癌、卡波济氏肉瘤、恶性黑素瘤、默克氏细胞皮肤癌以及非黑素瘤细胞癌。(9) Skin cancer of human or other mammals including, but not limited to, squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merck's cell skin cancer, and non-melanoma cell carcinoma.
(10)人或其它哺乳动物的头颈癌，包括但不限于喉、下咽、鼻咽、口咽癌以及唇和口腔癌。(10) Head and neck cancer in humans or other mammals including, but not limited to, larynx, hypopharynx, nasopharynx, oropharyngeal cancer, and lip and oral cancer.
(11)人或其它哺乳动物的淋巴瘤，包括但不限于AIDS相关淋巴瘤、非何杰金淋巴瘤、 皮肤T细胞淋巴瘤、何杰森病和中枢神经系统淋巴瘤。(11) Lymphoma of human or other mammals, including but not limited to AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Hodgson's disease, and central nervous system lymphoma.
(12)人或其它哺乳动物的肉瘤，包括但不限于软组织肉瘤、骨肉瘤、恶性纤维性组织细胞瘤、林把肉瘤和横纹肌肉瘤。(12) Sarcomas of human or other mammals, including but not limited to soft tissue sarcoma, osteosarcoma, malignant fibrous histiocytoma, sarcoma and rhabdomyosarcoma.
(13)人或其它哺乳动物的白血病，包括但不限于急性髓样白血病、急性林细胞白血病、慢性淋细胞白血病、慢性骨髓性白血病以及多毛细胞白血病。(13) Leukemia in humans or other mammals, including but not limited to acute myeloid leukemia, acute forest cell leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.
服用方式与剂量范围Mode of administration and dosage range
根据标准药学技术，本发明化合物可单独或在药用组合物中与药学上可接受的受体、辅料或稀释剂组合给予哺乳动物，优选人。可口服或皮下、肌注、腹膜内、静脉、直肠及局部、眼睛、肺部、鼻腔、胃肠外给予化合物。The compounds of the invention may be administered to a mammal, preferably a human, alone or in a pharmaceutical composition, in combination with a pharmaceutically acceptable receptor, adjuvant or diluent, according to standard pharmaceutical techniques. The compound can be administered orally or subcutaneously, intramuscularly, intraperitoneally, intravenously, rectally and topically, ocularly, pulmonaryly, nasally, or parenterally.
在一个实施方案中，利用式(I)化合物制备药物治疗或控制癌症等患者时，服用剂量范围为在口服0.1～500毫克/天/公斤体重。适当的给药方式为每日单剂量给药或每日二次、三次、四次等多次给药或利用缓释技术给药。对于多种大型哺乳动物，其优选的剂量范围为0.1～1500毫克/天/公斤体重，优选于0.5～100毫克/天/公斤体重。对于平均体重为70公斤的病人，其每日剂量为1～500毫克。对于一些特别高活性化合物，成年病人每日剂量可低达0.1毫克/天。In one embodiment, the use of a compound of formula (I) for the preparation of a medicament for treating or controlling a patient, such as cancer, is administered at a dose ranging from 0.1 to 500 mg/day/kg body weight. A suitable mode of administration is daily single dose administration or multiple administrations twice, three times, four times a day, or by sustained release techniques. For a variety of large mammals, preferred dosages range from 0.1 to 1500 mg/day/kg body weight, preferably from 0.5 to 100 mg/day/kg body weight. For patients with an average weight of 70 kg, the daily dose is 1 to 500 mg. For some particularly high active compounds, the daily dose for adult patients can be as low as 0.1 mg/day.
药物代谢物及前药Drug metabolites and prodrugs
本发明所涉及的化合物及其药学上可接受的盐的代谢产物，以及可以在体内转变为本申请所涉及的化合物及其药学上可接受的盐的结构的前药，也包含在本申请的权利要求中。Metabolites of the compounds and pharmaceutically acceptable salts thereof, and prodrugs which can be converted in vivo to the structures of the compounds and pharmaceutically acceptable salts thereof, are also included in the present application. In the claims.
联合用药Combined medication
式(I)化合物可以与已知的治疗或改进相似病状的其它药物联用。联合给药时，原来药物的给药方式&剂量保持不变，而同时或随后服用式(I)化合物。当式(I)化合物与其它一种或几种药物同时服用时，优选使用同时含有一种或几种已知药物和式(I)化合物的药用组合物。药物联用也包括在重叠的时间段服用式(I)化合物与其它一种或几种已知药物。当式(I)化合物与其它一种或几种药物进行药物联用时，式(I)化合物或已知药物的剂量可能比它们单独用药时的剂量较低。The compounds of formula (I) may be combined with other agents known to treat or ameliorate similar conditions. In the case of co-administration, the mode of administration & dosage of the original drug remains unchanged, while the compound of formula (I) is administered simultaneously or subsequently. When the compound of the formula (I) is administered simultaneously with one or more other drugs, it is preferred to use a pharmaceutical composition containing both one or several known drugs and a compound of the formula (I). Combination of drugs also includes the administration of a compound of formula (I) with one or more other known drugs over an overlapping period of time. When a compound of formula (I) is administered in combination with one or more other drugs, the dose of the compound of formula (I) or a known drug may be lower than when they are administered alone.
可以与式(I)化合物进行药物联用的药物或活性成分包括但不局限为：Drugs or active ingredients which may be combined with a compound of formula (I) include, but are not limited to:
雌激素受体调节剂、雄激素受体调节剂、视网膜样受体调节剂、细胞毒素/细胞抑制剂、抗增殖剂、蛋白转移酶抑制剂、HMG-CoA还原酶抑制剂、HIV蛋白激酶抑制剂、逆转录酶抑制剂、血管生成抑制剂、细胞增殖及生存信号抑制剂、干扰细胞周期关卡的药物和细胞凋亡诱导剂，细胞毒类药物、酪氨酸蛋白抑制剂、EGFR抑制剂、VEGFR抑制剂、丝氨酸/苏氨酸蛋白抑制剂、Bcr-Abl抑制剂、c-Kit抑制剂、Met抑制剂、Raf抑制剂、MEK抑制剂、MMP 抑制剂、拓扑异构酶抑制剂、组氨酸去乙酰化酶抑制剂、蛋白酶体抑制剂、CDK抑制剂、Bcl-2家族蛋白抑制剂、MDM2家族蛋白抑制剂、IAP家族蛋白抑制剂、STAT家族蛋白抑制剂、PI3K抑制剂、AKT抑制剂、整联蛋白阻滞剂、干扰素-α、白介素-12、COX-2抑制剂、p53、p53激活剂、VEGF抗体、EGF抗体等。Estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxin/cytostatics, antiproliferative agents, protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protein kinase inhibition Agents, reverse transcriptase inhibitors, angiogenesis inhibitors, cell proliferation and survival signal inhibitors, drugs that interfere with cell cycle checkpoints and inducers of apoptosis, cytotoxic drugs, tyrosine protein inhibitors, EGFR inhibitors, VEGFR inhibitor, serine/threonine protein inhibitor, Bcr-Abl inhibitor, c-Kit inhibitor, Met inhibitor, Raf inhibitor, MEK inhibitor, MMP inhibitor, topoisomerase inhibitor, histamine Acid deacetylase inhibitors, proteasome inhibitors, CDK inhibitors, Bcl-2 family protein inhibitors, MDM2 family protein inhibitors, IAP family protein inhibitors, STAT family protein inhibitors, PI3K inhibitors, AKT inhibitors , integrin blocker, interferon-α, interleukin-12, COX-2 inhibitor, p53, p53 activator, VEGF antibody, EGF antibody, and the like.
在一个实施方案中，可以与式(I)化合物进行药物联用的药物或活性成分包括但不局限为：阿地白介素、阿仑膦酸、干扰素、阿曲诺英、别嘌醇、别嘌醇钠、帕洛诺司琼盐酸盐、六甲蜜胺、氨基格鲁米特、氨磷汀、氨柔比星、安丫啶、阿纳托唑、多拉司琼、aranesp、arglabin、三氧化二砷、阿诺新、5-氮胞苷、硫唑嘌呤、卡介苗或tice卡介苗、贝他定、醋酸倍他米松、倍他米松磷酸钠制剂、贝沙罗汀、硫酸博来霉素、溴尿甘、bortezomib、白消安、降钙素、阿来佐单抗注射剂、卡培他滨、卡铂、康士得、cefesone、西莫白介素、柔红霉素、苯丁酸氮芥、顺铂、克拉屈滨、克拉屈滨、氯屈磷酸、环磷酰胺、阿糖胞昔、达卡巴嗪、放线菌素D、柔红霉素脂质体、地塞米松、磷酸地塞米松、戊酸雌二醇、地尼白介素2、狄波美、地洛瑞林、地拉佐生、己烯雌酚、大扶康、多西他奇、去氧氟尿苷、阿霉素、屈大麻酚、钦-166-壳聚糖复合物、eligard、拉布立酶、盐酸表柔比星、阿瑞吡坦、表阿霉素、阿法依伯汀、红细胞生成素、依铂、左旋咪唑片、雌二醇制剂、17-β-雌二醇、雌莫司汀磷酸钠、炔雌醇、氨磷汀、羟磷酸、凡毕复、依托泊甙、法倔唑、他莫昔芬制剂、非格司亭、非那司提、非雷司替、氟尿苷、氟康唑、氟达拉滨、5-氟脱氧尿嘧啶核苷一磷酸盐、5-氟尿嘧啶、氟甲睾酮、氟他胺、福麦斯坦、1-β-D-阿糖呋喃糖胞噻啶-5’-硬脂酰磷酸酯、福莫司汀、氟维司群、丙种球蛋白、吉西他滨、吉妥单抗、甲磺酸伊马替尼、卡氮芥糯米纸胶囊剂、戈舍瑞林、盐酸格拉尼西隆、组氨瑞林、和美新、氢化可的松、赤型-羟基壬基腺嘌呤、羟基脲、替坦异贝莫单抗、伊达比星、异环磷酰胺、干扰素α、干扰素-α2、干扰素α-2A、干扰素α-2B、干扰素α-nl、干扰素α-n3、干扰素β、干扰素γ-la、白细胞介素-2、内含子A、易瑞沙、依立替康、凯特瑞、硫酸香菇多糖、来曲唑、甲酰四氢叶酸、亮丙瑞林、亮丙瑞林醋酸盐、左旋四咪唑、左旋亚叶酸钙盐、左甲状腺素钠、左甲状腺素钠制剂、洛莫司汀、氯尼达明、屈大麻酚、氮芥、甲钴胺、甲羟孕酮醋酸酯、醋酸甲地孕酮、美法仑、酯化雌激素、6-琉基嘌呤、美司钠、氨甲蝶呤、氨基乙酰丙酸甲酯、米替福新、美满霉素、丝裂霉素C、米托坦、米托葱醌、曲洛司坦、柠檬酸阿霉素脂质体、奈达铂、聚乙二醇化非格司亭、奥普瑞白介素、neupogen、尼鲁米特、三苯氧胺、NSC-631570、重组人白细胞介素1-β、奥曲肽、盐酸奥丹西隆、去氢氢化可的松口服溶液剂、奥沙利铂、紫杉醇、泼尼松磷酸钠制剂、培门冬酶、派罗欣、喷司他丁、溶链菌制剂、盐酸匹鲁卡品、毗柔比星、普卡霉素、卟吩姆钠、泼尼莫司汀、司替泼尼松龙、泼尼松、倍美力、丙卡巴肼、重组人类红细胞生成素、雷替曲塞、利比、依替膦酸铼-186、美 罗华、力度伸-A、罗莫肽、盐酸毛果芸香碱片剂、奥曲肽、沙莫司亭、司莫司汀、西佐喃、索布佐生、唬钠甲强龙、帕福斯酸、干细胞治疗、链佐星、氯化锶-89、左旋甲状腺素钠、他莫昔芬、坦舒洛辛、他索那明、tastolactone、泰索帝、替西硫津、替莫唑胺、替尼泊苷、丙酸睾酮、甲睾酮、硫鸟嘌呤、噻替哌、促甲状腺激素、替鲁膦酸、拓扑替康、托瑞米芬、托西莫单抗、曲妥珠单抗、曲奥舒凡、维A酸、甲氨喋呤片剂、三甲基密胺、三甲曲沙、乙酸曲普瑞林、双羟萘酸曲普瑞林、优福定、尿苷、戊柔比星、维司力农、长春碱、长春新碱、长春酰胺、长春瑞滨、维鲁利秦、右旋丙亚胺、净司他丁斯酯、枢复宁、紫杉醇蛋白质稳定制剂、acolbifene、干扰素r-lb、affinitak、氨基喋呤、阿佐昔芬、asoprisnil、阿他美坦、阿曲生坦、BAY 43-9006、阿瓦斯丁、CCI-779、CDC-501、西乐葆、西妥昔单抗、克立那托、环丙孕酮醋酸酯、地西他滨、DN-101、阿霉素-MTC、dSLIM、度他雄胺、edotecarin、依氟鸟氨酸、依喜替康、芬维A胺、组胺二盐酸盐、组氨瑞林水凝胶植入物、钬-166 DOTMP、伊班膦酸、干扰素γ、内含子-PEG、ixabepilone、匙孔形血蓝蛋白、L-651582、兰乐肽、拉索昔芬、libra、lonafamib、米泼昔芬、米诺屈酸酯、MS-209、脂质体MTP-PE、MX-6、那法瑞林、奈莫柔比星、新伐司他、诺拉曲特、奥利默森、onco-TCS、osidem、紫杉醇聚谷氨酸酯、帛米酸钠、PN-401、QS-21、夸西洋、R-1549、雷洛昔芬、豹蛙酶、13-顺维A酸、沙铂、西奥骨化醇、T-138067、tarceva、二十二碳六烯酸紫杉醇、胸腺素αl、嘎唑呋林、tipifarnib、替拉扎明、TLK-286、托瑞米芬、反式MID-lo7R、伐司朴达、伐普肽、vatalanib、维替泊芬、长春氟宁、Z-100和唑来麟酸或它们的组合。In one embodiment, the pharmaceutical or active ingredient that can be administered in combination with a compound of formula (I) includes, but is not limited to, leucine, alendronate, interferon, atraxine, allopurinol, Sodium decylate, palonosetron hydrochloride, hexamethylene melamine, aminoglutamine, amifostine, amrubicin, amsacrine, anastrozole, dolasetron, aranesp, arglabin, Arsenic trioxide, anoxin, 5-azacytidine, azathioprine, BCG or tici BCG, betahidine, betamethasone acetate, betamethasone sodium phosphate, bexarotene, bleomycin sulfate, bromine Gan, bortezomib, busulfan, calcitonin, alemzumab injection, capecitabine, carboplatin, constance, cefesone, simmein, daunorubicin, chlorambucil, cisplatin, Cladribine, cladribine, clofibrate, cyclophosphamide, glucomannan, dacarbazine, actinomycin D, daunorubicin liposomes, dexamethasone, dexamethasone phosphate, valeric acid Estradiol, diltiazem 2, depomet, daruron, delasone, diethylstilbestrol, Dafukang, Sirtaqi, deoxyfluorouridine, doxorubicin, dronabinol, chin-166-chitosan complex, eligard, labyrin, epirubicin hydrochloride, aprepitant, epirubicin , Alfa Ibertin, erythropoietin, ibex, levamisole, estradiol preparation, 17-β-estradiol, estramustine sodium phosphate, ethinyl estradiol, amifostine, hydroxyphosphoric acid, Bifu, etoposide, fadrozole, tamoxifen preparation, filgrastim, phenacetin, non-Riesti, fluorouridine, fluconazole, fludarabine, 5-fluorodeoxyuridine Pyrimidine nucleoside monophosphate, 5-fluorouracil, fluorotestosterone, flutamide, formamide, 1-β-D-arabinofuranosyl-5'-stearoyl phosphate, formoterol , fulvestrant, gamma globulin, gemcitabine, gemtuzumab, imatinib mesylate, carmustine rice paper capsules, goserelin, graniseron hydrochloride, histrelin, and beauty New, hydrocortisone, erythro-hydroxydecyl adenine, hydroxyurea, tiltanopexumab, idarubicin, ifosfamide, interferon alpha, interferon-alpha 2, interferon alpha- 2A, interferon -2B, interferon alpha-nl, interferon alpha-n3, interferon beta, interferon gamma-la, interleukin-2, intron A, Iressa, irinotecan, ketyr, lentinan sulfate , letrozole, leucovorin, leuprolide, leuprolide acetate, levamisole, calcium levulinate, levothyroxine sodium, levothyroxine sodium preparation, lomustine, Chloridamine, dronabinol, nitrogen mustard, mecobalamin, medroxyprogesterone acetate, megestrol acetate, melphalan, esterified estrogen, 6-mercaptopurine, mesna, methotrex Chrysalis, methyl aminolevulinate, miltefosine, minocycline, mitomycin C, mitoxantrone, mitoxone, tromethamine, citrate citrate liposomes, neda Platinum, pegylated filgrastim, opal interleukin, neupogen, nilutamide, tamoxifen, NSC-631570, recombinant human interleukin 1-β, octreotide, ondansetron hydrochloride, dehydrohydrogenation Oral solution, oxaliplatin, paclitaxel, prednisone sodium phosphate, pemexene, pyromycin, pentastatin, lysogen preparation, hydrochloric acid Rukapin, pirarubicin, pucamycin, porphyrin sodium, prednisolstatin, stenipanibone, prednisone, premarin, procarbazine, recombinant human erythropoietin, Raltitrexed, Libby, etidronate-186, rituximab, vasodilating-A, romopeptide, pilocarpine hydrochloride tablets, octreotide, shamastigin, semustine, cilostaz, sobzo Health, strontium methylprednisolone, Paphos acid, stem cell therapy, streptozocin, strontium chloride-89, levothyroxine sodium, tamoxifen, tamsulosin, tazolamamine, tastolactone, peso Emperor, thizizine, temozolomide, teniposide, testosterone propionate, methyltestosterone, thioguanine, thiotepa, thyroid stimulating hormone, tiludronic acid, topotecan, toremifene, tosimo Monoclonal antibody, trastuzumab, tromethamine, retinoic acid, methotrexate tablets, trimethyl melamine, trimethoate, triptorelin acetate, triptorelin pamoate, Youfuding, uridine, valrubicin, visrinone, vinblastine, vincristine, vinblastine, vinorelbine, vilulic acid, dextrozine, net Statins, saponin, paclitaxel protein stable preparation, acolbifene, interferon r-lb, affinitak, aminoguanidine, arzoxifene, asoprisnil, atametem, atrasentan, BAY 43-9006, Vascin, CCI-779, CDC-501, Celebrex, Cetuximab, Clinato, Cyproterone acetate, Decitabine, DN-101, Doxorubicin-MTC, dSLIM, degrees Androstenamine, edotecarin, effluranine, exenotecan, fenretinide, histamine dihydrochloride, histrelin hydrogel implant, 钬-166 DOTMP, ibandronate, interference γ, intron-PEG, ixabepilone, keyhole limpet hemocyanin, L-651582, lanreotide, lasofoxifene, libra, lonafamib, mipoxifen, minoxidate, MS-209, Liposomes MTP-PE, MX-6, nafarelin, nemotropin, novvastatin, noratriprol, olimori, onco-TCS, osidem, paclitaxel polyglutamate, Sodium glutamate, PN-401, QS-21, Kwaxiyang, R-1549, raloxifene, leopard frog enzyme, 13-cis-retinoic acid, satraplatin, siocalcitol, T-138067, tarceva , docosahexaenoic acid paclitaxel, chest Adenin α1, oxazolidine, tipifarnib, tirapazamine, TLK-286, toremifene, trans MID-lo7R, valspardane, vapreotide, vatalanib, verteporfin, vinflunine , Z-100 and zolicin or a combination thereof.
下列实施例中所用试剂均可购买得到。The reagents used in the following examples are commercially available.
以下为具体的实施例：The following are specific examples:
实施例1：3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-N-(4-氟苯基)-1-甲基-1H-吡唑-4-甲酰胺(CCB-3049)的制备Example 1: 3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-N-(4-fluorophenyl)-1 -Preparation of methyl-1H-pyrazole-4-carboxamide (CCB-3049)
方案A.Option A.
Figure PCTCN2019079733-appb-000010
Figure PCTCN2019079733-appb-000010
步骤a1：4-(4-溴-2-氟苯氧基)-6,7-二甲氧基喹啉(化合物2)的制备Step a1: Preparation of 4-(4-bromo-2-fluorophenoxy)-6,7-dimethoxyquinoline (Compound 2)
将4-氯-6,7-二甲氧基喹啉(化合物1)(2.2g，10mmol)和4-溴-2-氟苯酚(2.2mL，20mmol)混合加热至140℃搅拌过夜。降至室温，加入饱和碳酸钠溶液，用二氯甲烷萃取，合并有机相，用饱和食盐水洗涤一遍，无水Na 2SO 4干燥，过滤旋干，经柱层析分离得固体3.2g(84.6％)。 1H NMR(300MHz,DMSO-d 6)δ8.82(d,J＝6.3Hz,1H),7.98(dd,J＝10.2,2.0Hz,1H),7.73(d,J＝7.7Hz,1H),7.70–7.57(m,1H),7.03(d,J＝6.3Hz,1H),4.03(d,J＝2.3Hz,3H).MS(ESI),m/z:378[M+H] +。 4-Chloro-6,7-dimethoxyquinoline (Compound 1) (2.2 g, 10 mmol) and 4-bromo-2-fluorophenol (2.2 mL, 20 mmol) were mixed and heated to 140 ° C and stirred overnight. Cooled to room temperature, saturated sodium carbonate solution and extracted with dichloromethane and the combined organic phases were washed once with saturated brine, dried over anhydrous Na 2 SO 4, filtered and rotary-dry, solid by column chromatography to give 3.2g (84.6 %). 1 H NMR (300MHz, DMSO- d 6) δ8.82 (d, J = 6.3Hz, 1H), 7.98 (dd, J = 10.2,2.0Hz, 1H), 7.73 (d, J = 7.7Hz, 1H) , 7.70 - 7.57 (m, 1H), 7.03 (d, J = 6.3 Hz, 1H), 4.03 (d, J = 2.3 Hz, 3H). MS (ESI), m/z: 378 [M+H] + .
步骤a2：3-((4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯基)氨基)-1-甲基-1H-吡唑-4-甲酸乙酯(化合物3)的制备Step a2: 3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl-1H-pyrazole-4 - Preparation of ethyl formate (compound 3)
将4-(4-溴-2-氟苯氧基)-6,7-二甲氧基喹啉(化合物2)(3.8g，10mmol)，3-氨基-1-甲基-1H-吡唑-4-甲酸乙酯(1.7g，10mmol)，Pd 2(dba) 3(275mg，0.3mmol)，Xantphos(579mg，1mmol)和碳酸铯(6.5g，20mmol)溶于50mL无水二氧六环，氩气保护，回流反应过夜。冷至室温，硅藻土抽滤，旋干，柱层析得固体3.5g(75.0％)。 1H NMR(300MHz,DMSO-d 6)δ8.51–8.39(m,1H),8.21(s,1H),7.90(d,J＝13.9Hz,1H),7.54(s,1H),7.49(d,J＝9.5Hz,1H),7.42–7.30(m,1H),6.43(d,J＝5.1Hz,1H),4.27(q,J＝7.0Hz,1H),3.95(s,3H),3.82(s,2H),1.30(t,J＝7.0Hz,1H).MS(ESI),m/z:467[M+H] +。 4-(4-Bromo-2-fluorophenoxy)-6,7-dimethoxyquinoline (Compound 2) (3.8 g, 10 mmol), 3-amino-1-methyl-1H-pyrazole Ethyl 4-carboxylate (1.7 g, 10 mmol), Pd 2 (dba) 3 (275 mg, 0.3 mmol), Xantphos (579 mg, 1 mmol) and cesium carbonate (6.5 g, 20 mmol) dissolved in 50 mL anhydrous dioxane Protected with argon and refluxed overnight. After cooling to room temperature, celite was suction filtered, dried, and then evaporated tolud. 1 H NMR (300MHz, DMSO- d 6) δ8.51-8.39 (m, 1H), 8.21 (s, 1H), 7.90 (d, J = 13.9Hz, 1H), 7.54 (s, 1H), 7.49 ( d, J = 9.5 Hz, 1H), 7.42 - 7.30 (m, 1H), 6.43 (d, J = 5.1 Hz, 1H), 4.27 (q, J = 7.0 Hz, 1H), 3.95 (s, 3H), 3.82 (s, 2H), 1.30 (t, J = 7.0 Hz, 1H). MS (ESI), m/z: 467[M+H] + .
步骤a3：3-((4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯基)氨基)-1-甲基-1H-吡唑-4-甲酸(化合物4)的制备Step a3: 3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl-1H-pyrazole-4 - Preparation of formic acid (Compound 4)
将3-((4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯基)氨基)-1-甲基-1H-吡唑-4-甲酸乙酯(化合物3)(2.3g，5mmol)和氢氧化钠(600mg，15mmol)溶于15mL乙醇和5mL水的溶合溶剂中，60℃下反应2小时。冷至室温，旋干乙醇，并用1N HCl溶液调至弱酸性，过滤，烘干，得固体2.0g(91.3％)。 1H NMR(300MHz,DMSO-d 6)δ8.76(s,1H),8.47(d,J＝5.2Hz,1H),8.08(s,1H),7.89(dd,J＝13.7,2.1Hz,1H),7.54(s,1H),7.48–7.28(m,2H),6.44(d,J＝5.1Hz,1H),3.95(s,3H),3.80(s,2H).MS(ESI),m/z:439[M+H] +。 3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl-1H-pyrazole-4-carboxylic acid Ethyl ester (Compound 3) (2.3 g, 5 mmol) and sodium hydroxide (600 mg, 15 mmol) were dissolved in a solvent mixture of 15 mL of ethanol and 5 mL of water, and reacted at 60 ° C for 2 hours. After cooling to room temperature, the ethanol was sparged and adjusted to a weak acid with a 1N HCl solution, filtered and dried to give a solid (2.0 g, 91.3%). 1 H NMR (300MHz, DMSO- d 6) δ8.76 (s, 1H), 8.47 (d, J = 5.2Hz, 1H), 8.08 (s, 1H), 7.89 (dd, J = 13.7,2.1Hz, 1H), 7.54 (s, 1H), 7.48 - 7.28 (m, 2H), 6.44 (d, J = 5.1 Hz, 1H), 3.95 (s, 3H), 3.80 (s, 2H). MS (ESI), m/z: 439 [M+H] + .
步骤a4：3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-N-(4-氟苯基)-1-甲基-1H-吡唑-4-甲酰胺(CCB-049)的制备Step a4: 3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-N-(4-fluorophenyl)-1- Preparation of methyl-1H-pyrazole-4-carboxamide (CCB-049)
将3-((4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯基)氨基)-1-甲基-1H-吡唑-4-甲酸(化合物4)(219mg，0.5mmol)，对氟苯胺(57μL，0.6mmol)和HATU(285mg，0.75mmol)溶于10mL DMF中，加入DIEA(259μL，1.5mmol)，室温搅拌过夜。加入饱和氯化钠溶液，用二氯甲烷萃取，合并有机相，用饱和食盐水洗涤三遍，无水Na 2SO 4干燥，过滤旋干，经柱层析分离得固体191mg(71.9％)。 1H NMR(300MHz,DMSO-d 6)δ9.93(s,1H),9.25(s, 1H),8.63(d,J＝5.7Hz,1H),8.39(s,1H),7.95(dd,J＝13.7,2.3Hz,1H),7.71(m,2H),7.64(s,1H),7.52–7.33(m,3H),7.20(t,J＝8.9Hz,2H),6.67(d,J＝5.7Hz,1H),3.99(s,6H),3.88(s,3H)。MS(ESI),m/z:532[M+H] +。 3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl-1H-pyrazole-4-carboxylic acid (Compound 4) (219 mg, 0.5 mmol), p-fluoroaniline (57 μL, 0.6 mmol) and HATU (285 mg, 0.75 mmol) were dissolved in 10 mL of DMF, and DIEA (259 μL, 1.5 mmol) was added and stirred at room temperature overnight. A saturated sodium chloride solution was added, and the mixture was combined with methylene chloride. The organic phase was combined and washed three times with saturated brine, dried over anhydrous Na 2 SO 4 and filtered and evaporated to give 191 mg (71.9%). 1 H NMR (300MHz, DMSO- d 6) δ9.93 (s, 1H), 9.25 (s, 1H), 8.63 (d, J = 5.7Hz, 1H), 8.39 (s, 1H), 7.95 (dd, J = 13.7, 2.3 Hz, 1H), 7.71 (m, 2H), 7.64 (s, 1H), 7.52 - 7.33 (m, 3H), 7.20 (t, J = 8.9 Hz, 2H), 6.67 (d, J = 5.7 Hz, 1H), 3.99 (s, 6H), 3.88 (s, 3H). MS (ESI), m/z: 532 [M+H] + .
实施例2：3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-N,1-二甲基-1H-吡唑-4-甲酰胺(CCB-3152)的制备Example 2: 3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-N,1-dimethyl-1H-pyridyl Preparation of azole-4-carboxamide (CCB-3152)
Figure PCTCN2019079733-appb-000011
Figure PCTCN2019079733-appb-000011
合成方法如实施例1。The synthesis method was as in Example 1.
1H NMR(400MHz,DMSO-d 6)δ9.39(s,1H),8.47(d,J＝5.2Hz,1H),8.21–8.00(m,2H),7.93–7.78(m,1H),7.55(s,1H),7.46–7.23(m,3H),6.44(dd,J＝5.3,1.1Hz,1H),3.96(d,J＝1.6Hz,6H),3.82(s,3H),2.76(d,J＝4.5Hz,3H).MS(ESI),m/z:452[M+H] +。 1 H NMR (400MHz, DMSO- d 6) δ9.39 (s, 1H), 8.47 (d, J = 5.2Hz, 1H), 8.21-8.00 (m, 2H), 7.93-7.78 (m, 1H), 7.55 (s, 1H), 7.46 - 7.23 (m, 3H), 6.44 (dd, J = 5.3, 1.1 Hz, 1H), 3.96 (d, J = 1.6 Hz, 6H), 3.82 (s, 3H), 2.76 (d, J = 4.5 Hz, 3H). MS (ESI), m/z: 452[M+H] + .
实施例3：3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-N-乙基-1-甲基-1H-吡唑-4-甲酰胺(CCB-3151)的制备Example 3: 3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-N-ethyl-1-methyl-1H -Preparation of pyrazole-4-carboxamide (CCB-3151)
Figure PCTCN2019079733-appb-000012
Figure PCTCN2019079733-appb-000012
合成方法如实施例1。The synthesis method was as in Example 1.
1H NMR(400MHz,DMSO-d 6)δ9.39(s,1H),8.46(d,J＝5.2Hz,1H),8.27(t,J＝5.5Hz,1H),8.20(s,1H),7.91–7.80(m,1H),7.54(s,1H),7.40(s,1H),7.37–7.28(m,2H),6.43(d,J＝5.2Hz,1H),3.95(m,6H),3.81(s,3H),3.25(m,2H),1.11(t,J＝7.2Hz,3H).MS(ESI),m/z:465[M+H] +。 1 H NMR (400MHz, DMSO- d 6) δ9.39 (s, 1H), 8.46 (d, J = 5.2Hz, 1H), 8.27 (t, J = 5.5Hz, 1H), 8.20 (s, 1H) , 7.91–7.80 (m, 1H), 7.54 (s, 1H), 7.40 (s, 1H), 7.37–7.28 (m, 2H), 6.43 (d, J = 5.2 Hz, 1H), 3.95 (m, 6H) ), 3.81 (s, 3H), 3.25 (m, 2H), 1.11 (t, J = 7.2 Hz, 3H). MS (ESI), m/z: 465[M+H] + .
实施例4：N-环丙基-3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺(CCB-3088)的制备Example 4: N-cyclopropyl-3-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl- Preparation of 1H-pyrazole-4-carboxamide (CCB-3088)
Figure PCTCN2019079733-appb-000013
Figure PCTCN2019079733-appb-000013
合成方法如实施例1。The synthesis method was as in Example 1.
1H NMR(400MHz,DMSO-d 6)δ9.38(s,1H),8.47(d,J＝5.2Hz,1H),8.16(d,J＝2.9Hz,1H),8.08(s,1H),7.86(d,J＝13.5Hz,1H),7.54(s,1H),7.40(s,1H),7.34(d,J＝5.7Hz,2H),6.43(d,J＝5.2Hz,1H),3.95(s,6H),3.80(s,3H),2.76(m,1H),0.69(m,2H),0.51(m,2H).MS(ESI),m/z:478[M+H] +。 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.38 (s, 1H), 8.47 (d, J = 5.2 Hz, 1H), 8.16 (d, J = 2.9 Hz, 1H), 8.08 (s, 1H) , 7.86 (d, J = 13.5 Hz, 1H), 7.54 (s, 1H), 7.40 (s, 1H), 7.34 (d, J = 5.7 Hz, 2H), 6.43 (d, J = 5.2 Hz, 1H) , 3.95 (s, 6H), 3.80 (s, 3H), 2.76 (m, 1H), 0.69 (m, 2H), 0.51 (m, 2H). MS (ESI), m/z: 478 [M+H ] + .
实施例5：N-叔丁基-3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺(CCB-3069)的制备Example 5: N-tert-Butyl-3-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl- Preparation of 1H-pyrazole-4-carboxamide (CCB-3069)
Figure PCTCN2019079733-appb-000014
Figure PCTCN2019079733-appb-000014
合成方法如实施例1。The synthesis method was as in Example 1.
1H NMR(300MHz,DMSO-d 6)δ9.35(s,1H),8.47(d,J＝5.2Hz,1H),8.28(s,1H),7.87(d,J＝13.5Hz,1H),7.54(s,1H),7.47–7.24(m,4H),6.43(d,J＝5.2Hz,1H),3.95(s,6H),3.80(s,3H),1.37(s,9H).MS(ESI),m/z:494[M+H] +。 1 H NMR (300MHz, DMSO- d 6) δ9.35 (s, 1H), 8.47 (d, J = 5.2Hz, 1H), 8.28 (s, 1H), 7.87 (d, J = 13.5Hz, 1H) , 7.54 (s, 1H), 7.47 - 7.24 (m, 4H), 6.43 (d, J = 5.2 Hz, 1H), 3.95 (s, 6H), 3.80 (s, 3H), 1.37 (s, 9H). MS (ESI), m/z: 495[M+H] + .
实施例6：N-环戊基-3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺(CCB-3091)的制备Example 6: N-cyclopentyl-3-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl- Preparation of 1H-pyrazole-4-carboxamide (CCB-3091)
Figure PCTCN2019079733-appb-000015
Figure PCTCN2019079733-appb-000015
合成方法如实施例1。The synthesis method was as in Example 1.
1H NMR(300MHz,DMSO-d 6)δ9.40(s,1H),8.47(d,J＝5.1Hz,1H),8.20(s,1H),7.97– 7.80(m,2H),7.54(s,1H),7.40(s,1H),7.33(m,2H),6.43(d,J＝5.1Hz,1H),4.20(m,1H),3.95(s,6H),3.81(s,3H),1.88(m,2H),1.78–1.62(m,2H),1.62–1.39(m,4H).MS(ESI),m/z:506[M+H] +。 1 H NMR (300MHz, DMSO- d 6) δ9.40 (s, 1H), 8.47 (d, J = 5.1Hz, 1H), 8.20 (s, 1H), 7.97- 7.80 (m, 2H), 7.54 ( s, 1H), 7.40 (s, 1H), 7.33 (m, 2H), 6.43 (d, J = 5.1 Hz, 1H), 4.20 (m, 1H), 3.95 (s, 6H), 3.81 (s, 3H) ), 1.88 (m, 2H), 1.78 - 1.62 (m, 2H), 1.62 - 1.39 (m, 4H). MS (ESI), m/z: 506 [M+H] + .
实施例7：N-环己基-3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺(CCB-3087)的制备Example 7: N-cyclohexyl-3-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl-1H -Preparation of pyrazole-4-carboxamide (CCB-3087)
Figure PCTCN2019079733-appb-000016
Figure PCTCN2019079733-appb-000016
合成方法如实施例1。The synthesis method was as in Example 1.
1H NMR(400MHz,DMSO-d 6)δ9.43(s,1H),8.47(d,J＝5.2Hz,1H),8.20(s,1H),7.93–7.81(m,2H),7.54(s,1H),7.40(s,1H),7.38–7.29(m,2H),6.43(d,J＝5.2Hz,1H),3.95(s,6H),3.81(s,3H),3.74(m,1H),1.83(m,2H),1.79–1.67(m,2H),1.61(m,1H),1.21(m,5H).MS(ESI),m/z:520[M+H] +。 1 H NMR (400MHz, DMSO- d 6) δ9.43 (s, 1H), 8.47 (d, J = 5.2Hz, 1H), 8.20 (s, 1H), 7.93-7.81 (m, 2H), 7.54 ( s, 1H), 7.40 (s, 1H), 7.38 - 7.29 (m, 2H), 6.43 (d, J = 5.2 Hz, 1H), 3.95 (s, 6H), 3.81 (s, 3H), 3.74 (m) , 1H), 1.83 (m, 2H), 1.79 - 1.67 (m, 2H), 1.61 (m, 1H), 1.21 (m, 5H). MS (ESI), m/z: 520 [M+H] + .
实施例8：N-环庚基-3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺(CCB-3146)的制备Example 8: N-cycloheptyl-3-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl- Preparation of 1H-pyrazole-4-carboxamide (CCB-3146)
Figure PCTCN2019079733-appb-000017
Figure PCTCN2019079733-appb-000017
合成方法如实施例1。The synthesis method was as in Example 1.
1H NMR(400MHz,DMSO-d 6)δ9.42(s,1H),8.47(d,J＝5.2Hz,1H),8.21(s,1H),7.91(d,J＝7.9Hz,1H),7.88–7.81(m,1H),7.54(s,1H),7.40(s,1H),7.33(m,2H),6.43(d,J＝5.2Hz,1H),3.94(m,7H),3.81(s,3H),1.92–1.79(m,2H),1.72–1.36(m,10H).MS(ESI),m/z:534[M+H] +。 1 H NMR (400MHz, DMSO- d 6) δ9.42 (s, 1H), 8.47 (d, J = 5.2Hz, 1H), 8.21 (s, 1H), 7.91 (d, J = 7.9Hz, 1H) , 7.88–7.81 (m, 1H), 7.54 (s, 1H), 7.40 (s, 1H), 7.33 (m, 2H), 6.43 (d, J = 5.2 Hz, 1H), 3.94 (m, 7H), 3.81 (s, 3H), 1.92 - 1.79 (m, 2H), 1.72 - 1.36 (m, 10H). MS (ESI), m/z: 534[M+H] + .
实施例9：N-环辛基-3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺(CCB-3263)的制备Example 9: N-cyclooctyl-3-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl- Preparation of 1H-pyrazole-4-carboxamide (CCB-3263)
Figure PCTCN2019079733-appb-000018
Figure PCTCN2019079733-appb-000018
合成方法如实施例1。The synthesis method was as in Example 1.
1H NMR(400MHz,DMSO-d 6)δ9.41(s,1H),8.47(d,J＝5.2Hz,1H),8.22(s,1H),7.86(m,2H),7.54(s,1H),7.40(s,1H),7.33(m,2H),6.48–6.39(d,J＝5.2Hz,1H),4.07–3.98(m,1H),3.95(s,6H),3.81(s,3H),1.82–1.42(m,14H).MS(ESI),m/z:548[M+H] +。 1 H NMR (400MHz, DMSO- d 6) δ9.41 (s, 1H), 8.47 (d, J = 5.2Hz, 1H), 8.22 (s, 1H), 7.86 (m, 2H), 7.54 (s, 1H), 7.40 (s, 1H), 7.33 (m, 2H), 6.48 - 6.39 (d, J = 5.2 Hz, 1H), 4.07 - 3.98 (m, 1H), 3.95 (s, 6H), 3.81 (s) , 3H), 1.82 - 1.42 (m, 14H). MS (ESI), m/z: 548[M+H] + .
实施例10：(3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-1H-吡唑-4-基)(哌啶-1-基)甲酮(CCB-3245)的制备Example 10: (3-((4-(6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl-1H-pyrazole- Preparation of 4-yl)(piperidin-1-yl)methanone (CCB-3245)
Figure PCTCN2019079733-appb-000019
Figure PCTCN2019079733-appb-000019
合成方法如实施例1。The synthesis method was as in Example 1.
1H NMR(400MHz,DMSO-d 6)δ9.02(s,1H),8.47(d,J＝5.2Hz,1H),8.05(s,1H),7.80(dd,J＝13.8,2.3Hz,1H),7.53(s,1H),7.40(s,1H),7.38–7.25(m,2H),6.42(d,J＝5.2Hz,1H),3.95(s,6H),3.82(s,3H),3.65–3.53(m,4H),1.64(m,2H),1.59–1.48(m,4H).MS(ESI),m/z:506[M+H] +。 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.02 (s, 1H), 8.47 (d, J = 5.2 Hz, 1H), 8.05 (s, 1H), 7.80 (dd, J = 13.8, 2.3 Hz, 1H), 7.53 (s, 1H), 7.40 (s, 1H), 7.38 - 7.25 (m, 2H), 6.42 (d, J = 5.2 Hz, 1H), 3.95 (s, 6H), 3.82 (s, 3H) ), 3.65 - 3.53 (m, 4H), 1.64 (m, 2H), 1.59 - 1.48 (m, 4H). MS (ESI), m/z: 506 [M+H] + .
实施例11：(3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-1H-吡唑-4-基)(八氢喹啉-1(2H)-基)甲酮(CCB-3252)的制备Example 11: (3-((4-(6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl-1H-pyrazole- Preparation of 4-yl)(octahydroquinoline-1(2H)-yl)methanone (CCB-3252)
Figure PCTCN2019079733-appb-000020
Figure PCTCN2019079733-appb-000020
合成方法如实施例1。The synthesis method was as in Example 1.
1H NMR(400MHz,DMSO-d 6)δ9.27(s,1H),8.47(d,J＝5.2Hz,1H),8.01(s,1H),7.81(dd,J＝13.8,2.3Hz,1H),7.54(s,1H),7.40(s,1H),7.38–7.25(m,2H),6.42(d,J＝5.2Hz,1H),3.95(s,6H),3.93–3.86(m,1H),3.82(s,3H),3.46–3.34(m,2H),2.08(m,1H),1.80–1.56(m,7H),1.44–1.20(m,3H),1.07(m,2H).MS(ESI),m/z:560[M+H] +。 1 H NMR (400MHz, DMSO- d 6) δ9.27 (s, 1H), 8.47 (d, J = 5.2Hz, 1H), 8.01 (s, 1H), 7.81 (dd, J = 13.8,2.3Hz, 1H), 7.54 (s, 1H), 7.40 (s, 1H), 7.38 - 7.25 (m, 2H), 6.42 (d, J = 5.2 Hz, 1H), 3.95 (s, 6H), 3.93 - 3.86 (m , 1H), 3.82 (s, 3H), 3.46–3.34 (m, 2H), 2.08 (m, 1H), 1.80–1.56 (m, 7H), 1.44–1.20 (m, 3H), 1.07 (m, 2H) MS (ESI), m/z: 560 [M+H] + .
实施例12：N-(4,4-二氟环己基)-3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺(CCB-3269)的制备Example 12: N-(4,4-Difluorocyclohexyl)-3-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino Preparation of 1-methyl-1H-pyrazole-4-carboxamide (CCB-3269)
Figure PCTCN2019079733-appb-000021
Figure PCTCN2019079733-appb-000021
合成方法如实施例1。The synthesis method was as in Example 1.
1H NMR(400MHz,DMSO-d 6)δ9.36(s,1H),8.47(d,J＝5.2Hz,1H),8.19(s,1H),7.97(d,J＝7.7Hz,1H),7.90–7.80(m,1H),7.54(s,1H),7.40(s,1H),7.38–7.27(m,2H),6.47–6.39(d,J＝5.2Hz,1H),3.95(m,7H),3.82(s,3H),1.98(m,6H),1.58(m,2H).MS(ESI),m/z:556[M+H] +。 1 H NMR (400MHz, DMSO- d 6) δ9.36 (s, 1H), 8.47 (d, J = 5.2Hz, 1H), 8.19 (s, 1H), 7.97 (d, J = 7.7Hz, 1H) , 7.90–7.80 (m, 1H), 7.54 (s, 1H), 7.40 (s, 1H), 7.38–7.27 (m, 2H), 6.47–6.39 (d, J=5.2 Hz, 1H), 3.95 (m) , 7H), 3.82 (s, 3H), 1.98 (m, 6H), 1.58 (m, 2H). MS (ESI), m/z: 556[M+H] + .
实施例13：3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-N-(四氢-2H-吡喃)-1H-吡唑-4-甲酰胺(CCB-3048)的制备Example 13: 3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl-N-(tetrahydro- Preparation of 2H-pyran)-1H-pyrazole-4-carboxamide (CCB-3048)
Figure PCTCN2019079733-appb-000022
Figure PCTCN2019079733-appb-000022
合成方法如实施例1。The synthesis method was as in Example 1.
1H NMR(300MHz,DMSO-d 6)δ9.37(s,1H),8.47(d,J＝5.2Hz,1H),8.19(s,1H),7.99(d,J＝7.6Hz,1H),7.85(d,J＝13.3Hz,1H),7.54(s,1H),7.40(s,1H),7.33(m,2H),6.43(d,J＝5.2Hz,1H),4.03–3.84(m,9H),3.82(s,3H),3.40(d,J＝10.8Hz,2H),1.77(d,J＝10.8Hz,2H),1.51(m,2H).MS(ESI),m/z:522[M+H] +。 1 H NMR (300MHz, DMSO- d 6) δ9.37 (s, 1H), 8.47 (d, J = 5.2Hz, 1H), 8.19 (s, 1H), 7.99 (d, J = 7.6Hz, 1H) , 7.85 (d, J = 13.3 Hz, 1H), 7.54 (s, 1H), 7.40 (s, 1H), 7.33 (m, 2H), 6.43 (d, J = 5.2 Hz, 1H), 4.03 - 3.84 ( m, 9H), 3.82 (s, 3H), 3.40 (d, J = 10.8 Hz, 2H), 1.77 (d, J = 10.8 Hz, 2H), 1.51 (m, 2H). MS (ESI), m/ z: 522 [M+H] + .
实施例14：N-环己基-3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-N,1-二甲基-1H- 吡唑-4-甲酰胺(CCB-3143)的制备Example 14: N-cyclohexyl-3-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-N, 1-dimethyl Preparation of keto-1H-pyrazole-4-carboxamide (CCB-3143)
Figure PCTCN2019079733-appb-000023
Figure PCTCN2019079733-appb-000023
合成方法如实施例1。The synthesis method was as in Example 1.
1H NMR(400MHz,DMSO-d 6)δ9.53(s,1H),8.47(d,J＝5.2Hz,1H),8.09(s,1H),7.83(dd,J＝13.8,1.8Hz,1H),7.54(s,1H),7.40(s,1H),7.38–7.26(m,2H),6.43(d,J＝5.2,1H),4.19(m,1H),3.97(s,6H),3.83(s,3H),2.99(s,3H),1.78(m,2H),1.70–1.44(m,5H),1.42–1.24(m,2H),1.13(m,1H).MS(ESI),m/z:534[M+H] +。 1 H NMR (400MHz, DMSO- d 6) δ9.53 (s, 1H), 8.47 (d, J = 5.2Hz, 1H), 8.09 (s, 1H), 7.83 (dd, J = 13.8,1.8Hz, 1H), 7.54 (s, 1H), 7.40 (s, 1H), 7.38 - 7.26 (m, 2H), 6.43 (d, J = 5.2, 1H), 4.19 (m, 1H), 3.97 (s, 6H) , 3.83 (s, 3H), 2.99 (s, 3H), 1.78 (m, 2H), 1.70 - 1.44 (m, 5H), 1.42 - 1.24 (m, 2H), 1.13 (m, 1H). ), m/z: 534 [M+H] + .
实施例15：N-(金刚烷-1-基)-3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺(CCB-3109)的制备Example 15: N-(adamantan-1-yl)-3-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)- Preparation of 1-methyl-1H-pyrazole-4-carboxamide (CCB-3109)
Figure PCTCN2019079733-appb-000024
Figure PCTCN2019079733-appb-000024
合成方法如实施例1。The synthesis method was as in Example 1.
1H NMR(400MHz,DMSO-d 6)δ9.34(s,1H),8.47(d,J＝5.2Hz,1H),8.29(s,1H),7.87(d,J＝13.6Hz,1H),7.54(s,1H),7.44–7.20(m,4H),6.43(d,J＝5.2Hz,1H),3.95(s,6H),3.79(s,3H),2.06(s,9H),1.66(s,6H).MS(ESI),m/z:572[M+H] +。 1 H NMR (400MHz, DMSO- d 6) δ9.34 (s, 1H), 8.47 (d, J = 5.2Hz, 1H), 8.29 (s, 1H), 7.87 (d, J = 13.6Hz, 1H) , 7.54 (s, 1H), 7.44 - 7.20 (m, 4H), 6.43 (d, J = 5.2 Hz, 1H), 3.95 (s, 6H), 3.79 (s, 3H), 2.06 (s, 9H), 1.66 (s, 6H) .MS ( ESI), m / z: 572 [m + H] +.
实施例16：3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-N-苯基-1H-吡唑-4-甲酰胺(CCB-3037)的制备Example 16: 3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl-N-phenyl-1H -Preparation of pyrazole-4-carboxamide (CCB-3037)
Figure PCTCN2019079733-appb-000025
Figure PCTCN2019079733-appb-000025
合成方法如实施例1。The synthesis method was as in Example 1.
1H NMR(300MHz,DMSO-d 6)δ9.87(s,1H),9.29(s,1H),8.66(d,J＝6.0Hz,1H),8.42(s,1H),7.96(dd,J＝13.7,2.4Hz,1H),7.75–7.62(m,3H),7.52–7.40(m,3H),7.40–7.30(m,2H),7.09(t,J＝7.4Hz,1H),6.72(d,J＝6.0Hz,1H),4.00(s,6H),3.88(s,3H).MS(ESI),m/z:514[M+H] +。 1 H NMR (300MHz, DMSO- d 6) δ9.87 (s, 1H), 9.29 (s, 1H), 8.66 (d, J = 6.0Hz, 1H), 8.42 (s, 1H), 7.96 (dd, J=13.7, 2.4 Hz, 1H), 7.75–7.62 (m, 3H), 7.52–7.40 (m, 3H), 7.40–7.30 (m, 2H), 7.09 (t, J=7.4 Hz, 1H), 6.72 (d, J = 6.0 Hz, 1H), 4.40 (s, 6H), 3.88 (s, 3H). MS (ESI), m/z: 514 [M+H] + .
实施例17：3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-N-(邻甲苯基)-1H-吡唑-4-甲酰胺(CCB-3099)的制备Example 17: 3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl-N-(o-tolyl) Preparation of -1H-pyrazole-4-carboxamide (CCB-3099)
Figure PCTCN2019079733-appb-000026
Figure PCTCN2019079733-appb-000026
合成方法如实施例1。The synthesis method was as in Example 1.
1H NMR(400MHz,DMSO-d 6)δ9.54(s,1H),9.26(s,1H),8.47(d,J＝5.2Hz,1H),8.35(s,1H),7.93–7.83(m,1H),7.54(s,1H),7.40(s,1H),7.37(m,2H),7.34–7.31(m,1H),7.28(d,J＝7.4Hz,1H),7.19(m,2H),6.44(d,J＝5.2Hz,1H),3.95(s,6H),3.88(s,3H),2.25(s,3H).MS(ESI),m/z:528[M+H] +。 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.54 (s, 1H), 9.26 (s, 1H), 8.47 (d, J = 5.2 Hz, 1H), 8.35 (s, 1H), 7.93 - 7.83 ( m,1H), 7.54 (s, 1H), 7.40 (s, 1H), 7.37 (m, 2H), 7.34 - 7.31 (m, 1H), 7.28 (d, J = 7.4 Hz, 1H), 7.19 (m) , 2H), 6.44 (d, J = 5.2 Hz, 1H), 3.95 (s, 6H), 3.88 (s, 3H), 2.25 (s, 3H). MS (ESI), m/z: 528 [M+ H] + .
实施例18：3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-N-(间甲苯基)-1H-吡唑-4-甲酰胺(CCB-3067)的制备Example 18: 3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl-N-(m-tolyl) Preparation of -1H-pyrazole-4-carboxamide (CCB-3067)
Figure PCTCN2019079733-appb-000027
Figure PCTCN2019079733-appb-000027
合成方法如实施例1。The synthesis method was as in Example 1.
1H NMR(400MHz,DMSO-d 6)δ9.78(s,1H),9.26(s,1H),8.54(d,J＝5.4Hz,1H),8.42(s,1H),7.94(dd,J＝13.6,2.2Hz,1H),7.58(m,2H),7.46(m,2H),7.42(s,1H),7.37(t,J＝9.0Hz,1H),7.23(t,J＝7.5Hz,1H),6.91(d,J＝7.5Hz,1H),6.55(d,J＝5.4Hz,1H),3.97(s,6H),3.88(s,3H),2.31(s,3H).MS(ESI),m/z:528[M+H] +。 1 H NMR (400MHz, DMSO- d 6) δ9.78 (s, 1H), 9.26 (s, 1H), 8.54 (d, J = 5.4Hz, 1H), 8.42 (s, 1H), 7.94 (dd, J = 13.6, 2.2 Hz, 1H), 7.58 (m, 2H), 7.46 (m, 2H), 7.42 (s, 1H), 7.37 (t, J = 9.0 Hz, 1H), 7.23 (t, J = 7.5) Hz, 1H), 6.91 (d, J = 7.5 Hz, 1H), 6.55 (d, J = 5.4 Hz, 1H), 3.97 (s, 6H), 3.88 (s, 3H), 2.31 (s, 3H). MS (ESI), m/z: 528 [M+H] + .
实施例19：3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-N-(3-乙苯基)-1H-吡唑-4-甲酰胺(CCB-3046)的制备Example 19: 3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl-N-(3-ethyl Preparation of Phenyl)-1H-pyrazole-4-carboxamide (CCB-3046)
Figure PCTCN2019079733-appb-000028
Figure PCTCN2019079733-appb-000028
合成方法如实施例1。The synthesis method was as in Example 1.
1H NMR(300MHz,DMSO-d 6)δ9.79(s,1H),9.25(s,1H),8.54(d,J＝5.5Hz,1H),8.42(s,1H),7.94(dd,J＝13.7,2.5Hz,1H),7.58(m,2H),7.55–7.41(m,3H),7.37(t,J＝8.9Hz,1H),7.25(t,J＝7.5Hz,1H),6.94(d,J＝7.5Hz,1H),6.55(d,J＝5.5Hz,1H),3.97(s,6H),3.88(s,3H),2.61(q,J＝7.8Hz,2H),1.20(t,J＝7.8Hz,3H).MS(ESI),m/z:542[M+H] +。 1 H NMR (300MHz, DMSO- d 6) δ9.79 (s, 1H), 9.25 (s, 1H), 8.54 (d, J = 5.5Hz, 1H), 8.42 (s, 1H), 7.94 (dd, J = 13.7, 2.5 Hz, 1H), 7.58 (m, 2H), 7.55 - 7.41 (m, 3H), 7.37 (t, J = 8.9 Hz, 1H), 7.25 (t, J = 7.5 Hz, 1H), 6.94 (d, J = 7.5 Hz, 1H), 6.55 (d, J = 5.5 Hz, 1H), 3.97 (s, 6H), 3.88 (s, 3H), 2.61 (q, J = 7.8 Hz, 2H), 1.20 (t, J = 7.8Hz, 3H) .MS (ESI), m / z: 542 [m + H] +.
实施例20：3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-N-(对甲苯基)-1H-吡唑-4-甲酰胺(CCB-3068)的制备Example 20: 3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl-N-(p-tolyl) Preparation of -1H-pyrazole-4-carboxamide (CCB-3068)
Figure PCTCN2019079733-appb-000029
Figure PCTCN2019079733-appb-000029
合成方法如实施例1。The synthesis method was as in Example 1.
1H NMR(400MHz,DMSO-d 6)δ9.80(s,1H),9.30(s,1H),8.65(d,J＝5.9Hz,1H),8.40(s,1H),7.95(dd,J＝13.6,2.0Hz,1H),7.66(s,1H),7.58(d,J＝8.2Hz,2H),7.51–7.36(m,3H),7.16(d,J＝8.2Hz,2H),6.71(d,J＝5.9Hz,1H),4.00(s,6H),3.87(s,3H),2.28(s,3H).MS(ESI),m/z:528[M+H] +。 1 H NMR (400MHz, DMSO- d 6) δ9.80 (s, 1H), 9.30 (s, 1H), 8.65 (d, J = 5.9Hz, 1H), 8.40 (s, 1H), 7.95 (dd, J = 13.6, 2.0 Hz, 1H), 7.66 (s, 1H), 7.58 (d, J = 8.2 Hz, 2H), 7.51 - 7.36 (m, 3H), 7.16 (d, J = 8.2 Hz, 2H), 6.71 (d, J = 5.9 Hz, 1H), 4.40 (s, 6H), 3.87 (s, 3H), 2.28 (s, 3H). MS (ESI), m/z: 528[M+H] + .
实施例21：3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-N-(2-甲氧苯基)-1-甲基-1H-吡唑-4-甲酰胺(CCB-3070)的制备Example 21: 3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-N-(2-methoxyphenyl)- Preparation of 1-methyl-1H-pyrazole-4-carboxamide (CCB-3070)
Figure PCTCN2019079733-appb-000030
Figure PCTCN2019079733-appb-000030
合成方法如实施例1。The synthesis method was as in Example 1.
1H NMR(400MHz,DMSO-d 6)δ9.20(s,2H),8.46(m,2H),7.79(m,2H),7.54(s,1H),7.40(s,1H),7.35(m,2H),7.21–7.05(m,2H),6.96(t,J＝7.6Hz,1H),6.43(d,J＝5.2Hz,1H),3.95(s,6H),3.86(s,3H),3.83(s,3H).MS(ESI),m/z:544[M+H] +。 1 H NMR (400MHz, DMSO- d 6) δ9.20 (s, 2H), 8.46 (m, 2H), 7.79 (m, 2H), 7.54 (s, 1H), 7.40 (s, 1H), 7.35 ( m, 2H), 7.21 - 7.05 (m, 2H), 6.96 (t, J = 7.6 Hz, 1H), 6.43 (d, J = 5.2 Hz, 1H), 3.95 (s, 6H), 3.86 (s, 3H) ), 3.83 (s, 3H). MS (ESI), m/z: 544 [M+H] + .
实施例22：3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-N-(3-甲氧苯基)-1-甲基-1H-吡唑-4-甲酰胺(CCB-3071)的制备Example 22: 3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-N-(3-methoxyphenyl)- Preparation of 1-methyl-1H-pyrazole-4-carboxamide (CCB-3071)
Figure PCTCN2019079733-appb-000031
Figure PCTCN2019079733-appb-000031
合成方法如实施例1。The synthesis method was as in Example 1.
1H NMR(300MHz,DMSO-d 6)δ9.83(s,1H),9.25(s,1H),8.65(d,J＝6.0Hz,1H),8.43(s,1H),7.96(dd,J＝13.7,2.3Hz,1H),7.66(s,1H),7.54–7.36(m,4H),7.26(m,2H),6.69(m,2H),4.00(s,6H),3.88(s,3H),3.76(s,3H).MS(ESI),m/z:544[M+H] +。 1 H NMR (300MHz, DMSO- d 6) δ9.83 (s, 1H), 9.25 (s, 1H), 8.65 (d, J = 6.0Hz, 1H), 8.43 (s, 1H), 7.96 (dd, J = 13.7, 2.3 Hz, 1H), 7.66 (s, 1H), 7.54 - 7.36 (m, 4H), 7.26 (m, 2H), 6.69 (m, 2H), 4.00 (s, 6H), 3.88 (s) , 3H), 3.76 (s, 3H). MS (ESI), m/z: 544 [M+H] + .
实施例23：3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-N-(4-甲氧苯基)-1-甲基-1H-吡唑-4-甲酰胺(CCB-3072)的制备Example 23: 3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-N-(4-methoxyphenyl)- Preparation of 1-methyl-1H-pyrazole-4-carboxamide (CCB-3072)
Figure PCTCN2019079733-appb-000032
Figure PCTCN2019079733-appb-000032
合成方法如实施例1。The synthesis method was as in Example 1.
1H NMR(300MHz,DMSO-d 6)δ9.77(s,1H),9.29(s,1H),8.56(d,J＝5.7Hz,1H),8.36(s, 1H),7.93(dd,J＝13.6,2.4Hz,1H),7.60(s,2H),7.57(s,1H),7.49–7.32(m,3H),6.95(s,1H),6.92(s,1H),6.58(d,J＝5.7Hz,1H),3.98(s,6H),3.87(s,3H),3.74(s,3H).MS(ESI),m/z:544[M+H] +。 1 H NMR (300MHz, DMSO- d 6) δ9.77 (s, 1H), 9.29 (s, 1H), 8.56 (d, J = 5.7Hz, 1H), 8.36 (s, 1H), 7.93 (dd, J = 13.6, 2.4 Hz, 1H), 7.60 (s, 2H), 7.57 (s, 1H), 7.49 - 7.32 (m, 3H), 6.95 (s, 1H), 6.92 (s, 1H), 6.58 (d , J = 5.7 Hz, 1H), 3.98 (s, 6H), 3.87 (s, 3H), 3.74 (s, 3H). MS (ESI), m/z: 544 [M+H] + .
实施例24：N-(3-氯苯基)-3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺(DL-026)的制备Example 24: N-(3-chlorophenyl)-3-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1 -Preparation of methyl-1H-pyrazole-4-carboxamide (DL-026)
Figure PCTCN2019079733-appb-000033
Figure PCTCN2019079733-appb-000033
合成方法如实施例1。The synthesis method was as in Example 1.
1H NMR(400MHz,DMSO-d 6)δ10.02(s,1H),9.16(s,1H),8.62–8.32(m,2H),8.10–7.85(m,2H),7.68–7.26(m,6H),7.15(dd,J＝7.8,2.1Hz,1H),6.45(d,J＝5.2Hz,1H),4.06–3.91(m,6H),3.89(s,3H).MS(ESI),m/z:548[M+H] +。 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.02 (s, 1H), 9.16 (s, 1H), 8.62 - 8.32 (m, 2H), 8.10 - 7.85 (m, 2H), 7.68 - 7.26 (m) , 6H), 7.15 (dd, J = 7.8, 2.1 Hz, 1H), 6.45 (d, J = 5.2 Hz, 1H), 4.06 - 3.91 (m, 6H), 3.89 (s, 3H). MS (ESI) , m/z: 548 [M+H] + .
实施例25：N-(4-氯苯基)-3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺(DL-025)的制备Example 25: N-(4-Chlorophenyl)-3-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1 -Preparation of methyl-1H-pyrazole-4-carboxamide (DL-025)
Figure PCTCN2019079733-appb-000034
Figure PCTCN2019079733-appb-000034
合成方法如实施例1。The synthesis method was as in Example 1.
1H NMR(400MHz,DMSO-d 6)δ9.99(s,1H),9.19(s,1H),8.57–8.30(m,2H),7.97–7.82(m,2H),7.55(d,J＝1.9Hz,1H),7.50–7.28(m,6H),6.45(dt,J＝4.5,2.2Hz,1H),3.96(d,J＝1.7Hz,6H),3.89(s,3H).MS(ESI),m/z:548[M+H] +。 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.99 (s, 1H), 9.19 (s, 1H), 8.57 - 8.30 (m, 2H), 7.97 - 7.82 (m, 2H), 7.55 (d, J) = 1.9 Hz, 1H), 7.50 - 7.28 (m, 6H), 6.45 (dt, J = 4.5, 2.2 Hz, 1H), 3.96 (d, J = 1.7 Hz, 6H), 3.89 (s, 3H). (ESI), m/z: 548[M+H] + .
实施例26：3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-N-(3-氟苯基)-1-甲基-1H-吡唑-4-甲酰胺(CCB-3098)的制备Example 26: 3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-N-(3-fluorophenyl)-1 -Preparation of methyl-1H-pyrazole-4-carboxamide (CCB-3098)
Figure PCTCN2019079733-appb-000035
Figure PCTCN2019079733-appb-000035
合成方法如实施例1。The synthesis method was as in Example 1.
1H NMR(400MHz,DMSO-d 6)δ10.04(s,1H),9.17(s,1H),8.48(d,J＝5.2Hz,1H),8.42(s,1H),7.93(dd,J＝13.6,2.6Hz,1H),7.73(dt,J＝11.9,2.2Hz,1H),7.55(s,1H),7.52–7.25(m,5H),6.99–6.86(m,1H),6.45(dd,J＝5.3,1.1Hz,1H),3.96(d,J＝1.8Hz,6H),3.89(s,3H).MS(ESI),m/z:532[M+H] +。 1 H NMR (400MHz, DMSO- d 6) δ10.04 (s, 1H), 9.17 (s, 1H), 8.48 (d, J = 5.2Hz, 1H), 8.42 (s, 1H), 7.93 (dd, J=13.6, 2.6 Hz, 1H), 7.73 (dt, J=11.9, 2.2 Hz, 1H), 7.55 (s, 1H), 7.52–7.25 (m, 5H), 6.99–6.86 (m, 1H), 6.45 (dd, J = 5.3, 1.1 Hz, 1H), 3.96 (d, J = 1.8 Hz, 6H), 3.89 (s, 3H). MS (ESI), m/z: 532[M+H] + .
实施例27：3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-N-(4-异丙苯基)-1-甲基-1H-吡唑-4-甲酰胺(DL-040)的制备Example 27: 3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-N-(4-isopropylphenyl)- Preparation of 1-methyl-1H-pyrazole-4-carboxamide (DL-040)
Figure PCTCN2019079733-appb-000036
Figure PCTCN2019079733-appb-000036
合成方法如实施例1。The synthesis method was as in Example 1.
1H NMR(400MHz,DMSO-d 6)δ9.82(s,1H),9.32(s,1H),8.67(d,J＝6.0Hz,1H),8.43(s,1H),7.96(dd,J＝13.6,2.5Hz,1H),7.73–7.56(m,3H),7.56–7.34(m,3H),7.29–7.16(m,2H),6.74(d,J＝5.9Hz,1H),4.01(s,6H),3.88(s,3H),2.87(hept,J＝6.9Hz,1H),1.21(d,J＝6.9Hz,6H).MS(ESI),m/z:556[M+H] +。 1H NMR (400MHz, DMSO-d 6 ) δ 9.82 (s, 1H), 9.32 (s, 1H), 8.67 (d, J = 6.0 Hz, 1H), 8.43 (s, 1H), 7.96 (dd, J =13.6, 2.5 Hz, 1H), 7.73–7.56 (m, 3H), 7.56–7.34 (m, 3H), 7.29–7.16 (m, 2H), 6.74 (d, J=5.9 Hz, 1H), 4.01 ( s, 6H), 3.88 (s, 3H), 2.87 (hept, J = 6.9 Hz, 1H), 1.21 (d, J = 6.9 Hz, 6H). MS (ESI), m/z: 556 [M+H ] + .
实施例28：3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-N-(4-(三氟甲氧基)苯基)-1-甲基-1H-吡唑-4-甲酰胺(DL-037)的制备Example 28: 3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-N-(4-(trifluoromethoxy) Preparation of phenyl)-1-methyl-1H-pyrazole-4-carboxamide (DL-037)
Figure PCTCN2019079733-appb-000037
Figure PCTCN2019079733-appb-000037
合成方法如实施例1。The synthesis method was as in Example 1.
1H NMR(400MHz,DMSO-d 6)δ10.05(s,1H),9.19(s,1H),8.48(dd,J＝5.2,1.7Hz,1H),8.42(s,1H),7.88–7.76(m,2H),7.60–7.23(m,7H),6.45(ddd,J＝5.0,3.8,1.1Hz,1H),3.96(d,J＝1.7Hz,6H),3.89(s,3H).MS(ESI),m/z:598[M+H] +。 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.05 (s, 1H), 9.19 (s, 1H), 8.48 (dd, J = 5.2, 1.7 Hz, 1H), 8.42 (s, 1H), 7.88– 7.76 (m, 2H), 7.60 - 7.23 (m, 7H), 6.45 (ddd, J = 5.0, 3.8, 1.1 Hz, 1H), 3.96 (d, J = 1.7 Hz, 6H), 3.89 (s, 3H) MS (ESI), m/z: 598 [M+H] + .
实施例29：N-(4-(二氟甲氧基)苯基)-3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺(DL-036)的制备Example 29: N-(4-(Difluoromethoxy)phenyl)-3-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorobenzene Preparation of phenyl)amino)-1-methyl-1H-pyrazole-4-carboxamide (DL-036)
Figure PCTCN2019079733-appb-000038
Figure PCTCN2019079733-appb-000038
合成方法如实施例1。The synthesis method was as in Example 1.
1H NMR(400MHz,DMSO-d 6)δ9.95(s,1H),9.22(s,1H),8.48(d,J＝5.3Hz,1H),8.41(s,1H),7.92(dd,J＝13.5,2.6Hz,1H),7.75(d,J＝9.0Hz,2H),7.55(s,1H),7.49–7.13(m,6H),6.46(d,J＝5.2Hz,1H),4.02–3.92(m,6H),3.89(s,3H).MS(ESI),m/z:580[M+H] +。 1 H NMR (400MHz, DMSO- d 6) δ9.95 (s, 1H), 9.22 (s, 1H), 8.48 (d, J = 5.3Hz, 1H), 8.41 (s, 1H), 7.92 (dd, J = 13.5, 2.6 Hz, 1H), 7.75 (d, J = 9.0 Hz, 2H), 7.55 (s, 1H), 7.49 - 7.13 (m, 6H), 6.46 (d, J = 5.2 Hz, 1H), 4.02 - 3.92 (m, 6H), 3.89 (s, 3H). MS (ESI), m/z: 580[M+H] + .
实施例30：N-(4-(氰甲基)苯基)-3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺(DL-032)的制备Example 30: N-(4-(Cyanomethyl)phenyl)-3-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl) Preparation of amino)-1-methyl-1H-pyrazole-4-carboxamide (DL-032)
Figure PCTCN2019079733-appb-000039
Figure PCTCN2019079733-appb-000039
合成方法如实施例1。The synthesis method was as in Example 1.
1H NMR(400MHz,DMSO-d 6)δ9.94(s,1H),9.22(s,1H),8.48(d,J＝5.2Hz,1H),8.43(s,1H),7.93(dd,J＝13.6,2.5Hz,1H),7.74(d,J＝8.4Hz,2H),7.55(s,1H),7.51–7.28(m,5H),6.52–6.41(m,1H),4.01(s,2H),3.96(d,J＝1.9Hz,6H),3.89(s,3H).MS(ESI),m/z:553[M+H] +。 1 H NMR (400MHz, DMSO- d 6) δ9.94 (s, 1H), 9.22 (s, 1H), 8.48 (d, J = 5.2Hz, 1H), 8.43 (s, 1H), 7.93 (dd, J=13.6, 2.5 Hz, 1H), 7.74 (d, J=8.4 Hz, 2H), 7.55 (s, 1H), 7.51–7.28 (m, 5H), 6.52–6.41 (m, 1H), 4.01 (s) , 2H), 3.96 (d, J = 1.9 Hz, 6H), 3.89 (s, 3H). MS (ESI), m/z: 553 [M+H] + .
实施例31：N-环己基-3-((4-((6,7-二甲氧基喹啉-4-基)氧)苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺(TL-140)的制备Example 31: N-cyclohexyl-3-((4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)amino)-1-methyl-1H-pyrazole- Preparation of 4-carboxamide (TL-140)
Figure PCTCN2019079733-appb-000040
Figure PCTCN2019079733-appb-000040
合成方法如实施例1。The synthesis method was as in Example 1.
1H NMR(400MHz,DMSO-d 6)δ9.28(s,1H),8.45(d,J＝5.2Hz,1H),8.17(s,1H),7.83(d,J＝7.9Hz,1H),7.69–7.59(m,2H),7.53(s,1H),7.38(s,1H),7.22–7.12(m,2H),6.41(d,J＝5.3Hz,1H),3.94(d,J＝1.1Hz,6H),3.79(s,3H),3.77–3.66(m,0H),1.82(d,J＝10.7Hz,2H),1.79–1.68(m,2H),1.61(d,J＝12.7Hz,1H),1.39–1.21(m,4H),1.21–1.06(m,1H).MS(ESI),m/z:502[M+H] +。 1 H NMR (400MHz, DMSO- d 6) δ9.28 (s, 1H), 8.45 (d, J = 5.2Hz, 1H), 8.17 (s, 1H), 7.83 (d, J = 7.9Hz, 1H) , 7.69–7.59 (m, 2H), 7.53 (s, 1H), 7.38 (s, 1H), 7.22–7.12 (m, 2H), 6.41 (d, J = 5.3 Hz, 1H), 3.94 (d, J) =1.1 Hz, 6H), 3.79 (s, 3H), 3.77 - 3.66 (m, 0H), 1.82 (d, J = 10.7 Hz, 2H), 1.79 - 1.68 (m, 2H), 1.61 (d, J = 12.7 Hz, 1H), 1.39 - 1.21 (m, 4H), 1.21 - 1.06 (m, 1H). MS (ESI), m/z: 502 [M+H] + .
实施例32：N-环己基-3-((4-((6,7-二甲氧基喹啉-4-基)氧)-2-氟苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺(TL-145)的制备Example 32: N-cyclohexyl-3-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-2-fluorophenyl)amino)-1-methyl-1H -Preparation of pyrazole-4-carboxamide (TL-145)
Figure PCTCN2019079733-appb-000041
Figure PCTCN2019079733-appb-000041
合成方法如实施例1。The synthesis method was as in Example 1.
1H NMR(400MHz,Chloroform-d)δ9.19(d,J＝3.2Hz,1H),8.48(d,J＝5.3Hz,1H),8.44–8.34(m,1H),7.56(s,1H),7.49(s,1H),7.41(s,1H),7.02–6.92(m,2H),6.48(d,J＝5.3Hz,1H),5.45(d,J＝8.2Hz,1H),4.06(s,3H),4.05(s,3H),4.02–3.90(m,1H),3.85(s,3H),2.09–1.96(m,3H),1.75(dt,J＝13.6,3.6Hz,2H),1.67(s,4H),1.50–1.33(m,2H),1.30–1.09(m,3H).MS(ESI),m/z:520[M+H] +。 1 H NMR (400 MHz, Chloroform-d) δ 9.19 (d, J = 3.2 Hz, 1H), 8.48 (d, J = 5.3 Hz, 1H), 8.44 - 8.34 (m, 1H), 7.56 (s, 1H) ), 7.49 (s, 1H), 7.41 (s, 1H), 7.02 - 6.92 (m, 2H), 6.48 (d, J = 5.3 Hz, 1H), 5.45 (d, J = 8.2 Hz, 1H), 4.06 (s, 3H), 4.05 (s, 3H), 4.02–3.90 (m, 1H), 3.85 (s, 3H), 2.09–1.96 (m, 3H), 1.75 (dt, J=13.6, 3.6 Hz, 2H) ), 1.67 (s, 4H), 1.50 - 1.33 (m, 2H), 1.30 - 1.09 (m, 3H). MS (ESI), m/z: 520 [M+H] + .
实施例33：N-环己基-3-((4-((6,7-二甲氧基喹啉-4-基)氧)-2-甲苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺(TL-151)的制备Example 33: N-cyclohexyl-3-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-2-methylphenyl)amino)-1-methyl-1H- Preparation of pyrazole-4-carboxamide (TL-151)
Figure PCTCN2019079733-appb-000042
Figure PCTCN2019079733-appb-000042
合成方法如实施例1。The synthesis method was as in Example 1.
1H NMR(400MHz,Chloroform-d)δ8.92(s,1H),8.45(d,J＝5.3Hz,1H),8.31(d,J＝8.8Hz,1H),7.61(s,1H),7.49(s,1H),7.41(s,1H),7.04(dd,J＝8.7,2.8Hz,1H),6.99(d,J＝2.8Hz,1H),6.46(d,J＝5.3Hz,1H),5.44(d,J＝8.3Hz,1H),4.05(d,J＝4.9Hz,6H),3.96(tdd,J＝8.1,5.4,3.5Hz,1H),3.85(s,3H),2.42(s,3H),2.09–1.94(m,3H),1.75(dt,J＝13.5,3.7Hz,2H),1.71–1.66(m,1H),1.51–1.35(m,2H),1.31–1.06(m,3H).MS(ESI),m/z:516[M+H] +。 1 H NMR (400MHz, Chloroform- d) δ8.92 (s, 1H), 8.45 (d, J = 5.3Hz, 1H), 8.31 (d, J = 8.8Hz, 1H), 7.61 (s, 1H), 7.49(s,1H), 7.41(s,1H), 7.04(dd,J=8.7,2.8Hz,1H),6.99(d,J=2.8Hz,1H),6.46(d,J=5.3Hz,1H ), 5.44 (d, J = 8.3 Hz, 1H), 4.05 (d, J = 4.9 Hz, 6H), 3.96 (tdd, J = 8.1, 5.4, 3.5 Hz, 1H), 3.85 (s, 3H), 2.42 (s, 3H), 2.09–1.94 (m, 3H), 1.75 (dt, J = 13.5, 3.7 Hz, 2H), 1.71–1.66 (m, 1H), 1.51–1.35 (m, 2H), 1.31–1.06 (m, 3H) .MS (ESI ), m / z: 516 [m + H] +.
实施例34：3-((3-氯-4-((6,7-二甲氧基喹啉-4-基)氧)苯基)氨基)-N-环己基-1-甲基-1H-吡唑-4-甲酰胺(TL-156)的制备Example 34: 3-((3-Chloro-4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)amino)-N-cyclohexyl-1-methyl-1H -Preparation of pyrazole-4-carboxamide (TL-156)
Figure PCTCN2019079733-appb-000043
Figure PCTCN2019079733-appb-000043
合成方法如实施例1。The synthesis method was as in Example 1.
1H NMR(400MHz,DMSO-d 6)δ9.42(s,1H),8.46(d,J＝5.2Hz,1H),8.20(s,1H),8.02(d,J＝2.7Hz,1H),7.88(d,J＝7.8Hz,1H),7.54(s,1H),7.50(dd,J＝8.9,2.7Hz,1H),7.40(s,1H),7.34(d,J＝8.9Hz,1H),6.33(d,J＝5.3Hz,1H),3.95(s,6H),3.81(s,3H),3.73(tdd,J＝10.2,7.0,3.6Hz,1H),1.83(d,J＝10.5Hz,2H),1.74(dd,J＝9.3,3.5Hz,2H),1.61(d,J＝12.4Hz,1H),1.39–1.08(m,6H).MS(ESI),m/z:536[M+H] +。 1 H NMR (400MHz, DMSO- d 6) δ9.42 (s, 1H), 8.46 (d, J = 5.2Hz, 1H), 8.20 (s, 1H), 8.02 (d, J = 2.7Hz, 1H) , 7.88 (d, J = 7.8 Hz, 1H), 7.54 (s, 1H), 7.50 (dd, J = 8.9, 2.7 Hz, 1H), 7.40 (s, 1H), 7.34 (d, J = 8.9 Hz, 1H), 6.33 (d, J = 5.3 Hz, 1H), 3.95 (s, 6H), 3.81 (s, 3H), 3.73 (tdd, J = 10.2, 7.0, 3.6 Hz, 1H), 1.83 (d, J) =10.5 Hz, 2H), 1.74 (dd, J=9.3, 3.5 Hz, 2H), 1.61 (d, J = 12.4 Hz, 1H), 1.39 - 1.08 (m, 6H). MS (ESI), m/z :536[M+H] + .
实施例35：N-环己基-3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-甲苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺(TL-154)的制备Example 35: N-cyclohexyl-3-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-methylphenyl)amino)-1-methyl-1H- Preparation of pyrazole-4-carboxamide (TL-154)
Figure PCTCN2019079733-appb-000044
Figure PCTCN2019079733-appb-000044
合成方法如实施例1。The synthesis method was as in Example 1.
1H NMR(400MHz,DMSO-d 6)δ9.24(s,1H),8.43(d,J＝5.2Hz,1H),8.17(s,1H),7.82(d,J＝7.8Hz,1H),7.60–7.53(m,2H),7.46(d,J＝2.8Hz,1H),7.39(s,1H),7.10(d,J＝8.7Hz,1H),6.28(d,J＝5.2Hz,1H),3.95(s,3H),3.94(s,3H),3.79(s,3H),3.72(ddd,J＝10.9,7.5,3.9Hz,1H),2.07(s,3H),1.90–1.67(m,4H),1.61(d,J＝12.7Hz,1H),1.40–1.06(m,5H).MS(ESI),m/z:516[M+H] +。 1 H NMR (400MHz, DMSO- d 6) δ9.24 (s, 1H), 8.43 (d, J = 5.2Hz, 1H), 8.17 (s, 1H), 7.82 (d, J = 7.8Hz, 1H) , 7.60–7.53 (m, 2H), 7.46 (d, J = 2.8 Hz, 1H), 7.39 (s, 1H), 7.10 (d, J = 8.7 Hz, 1H), 6.28 (d, J = 5.2 Hz, 1H), 3.95 (s, 3H), 3.94 (s, 3H), 3.79 (s, 3H), 3.72 (ddd, J = 10.9, 7.5, 3.9 Hz, 1H), 2.07 (s, 3H), 1.90 - 1.67 (m, 4H), 1.61 (d, J = 12.7 Hz, 1H), 1.40 - 1.06 (m, 5H). MS (ESI), m/z: 516 [M+H] + .
实施例36：N-环己基-3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-甲氧苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺(TL-170)的制备Example 36: N-cyclohexyl-3-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-methoxyphenyl)amino)-1-methyl- Preparation of 1H-pyrazole-4-carboxamide (TL-170)
Figure PCTCN2019079733-appb-000045
Figure PCTCN2019079733-appb-000045
合成方法如实施例1。The synthesis method was as in Example 1.
1H NMR(400MHz,DMSO-d 6)δ9.31(s,1H),8.41(d,J＝5.2Hz,1H),8.18(s,1H),7.84(d,J＝7.8Hz,1H),7.52(s,1H),7.36(d,J＝3.0Hz,2H),7.32(dd,J＝8.6,2.5Hz,1H),7.13(d,J＝8.6Hz,1H),6.29(d,J＝5.2Hz,1H),3.94(s,6H),3.79(s,3H),3.72(s,4H),1.92–1.67(m,4H),1.61(d,J＝12.6Hz,1H),1.40–1.06(m,5H).MS(ESI),m/z:532[M+H] +。 1 H NMR (400MHz, DMSO- d 6) δ9.31 (s, 1H), 8.41 (d, J = 5.2Hz, 1H), 8.18 (s, 1H), 7.84 (d, J = 7.8Hz, 1H) , 7.52 (s, 1H), 7.36 (d, J = 3.0 Hz, 2H), 7.32 (dd, J = 8.6, 2.5 Hz, 1H), 7.13 (d, J = 8.6 Hz, 1H), 6.29 (d, J=5.2 Hz, 1H), 3.94 (s, 6H), 3.79 (s, 3H), 3.72 (s, 4H), 1.92–1.67 (m, 4H), 1.61 (d, J = 12.6 Hz, 1H), 1.40-1.06 (m, 5H) .MS ( ESI), m / z: 532 [m + H] +.
实施例37：N-环己基-3-((3-氟-4-((6-甲氧基-7-(3-吗啉丙氧基)喹啉-4-基)氧)苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺(CCB-3233)的制备Example 37: N-cyclohexyl-3-((3-fluoro-4-((6-methoxy-7-(3-morpholinepropoxy)quinolin-4-yl)oxy)phenyl) Preparation of amino)-1-methyl-1H-pyrazole-4-carboxamide (CCB-3233)
方案B：.Option B:
Figure PCTCN2019079733-appb-000046
Figure PCTCN2019079733-appb-000046
步骤b1：7-(苄氧基)-4-(4-溴-2-氟苯氧基)-6-甲氧基喹啉(化合物6)的制备Step b1: Preparation of 7-(benzyloxy)-4-(4-bromo-2-fluorophenoxy)-6-methoxyquinoline (Compound 6)
将7-(苄氧基)-4-氯-6-甲氧基喹啉(化合物5)(3.0g，10mmol)和4-溴-2-氟苯酚(2.2mL，20mmol)加入12mL DIEA中，再加入6ml二甲苯，加热至140℃搅拌过夜。降至室温，有固体析出，过滤，用乙醇洗，抽干得白色固体3.7g(81.0％)。 1H NMR(400MHz,DMSO-d 6)δ8.48(d,J＝5.2Hz,1H),7.88(dd,J＝10.2,2.2Hz,1H),7.61–7.49(m,5H),7.49–7.40(m,3H),7.37(d,J＝7.2Hz,1H),6.53(d,J＝5.2Hz,1H),5.31(s,2H),3.95(s,3H).。MS(ESI),m/z:454[M+H] +。 Add 7-(benzyloxy)-4-chloro-6-methoxyquinoline (Compound 5) (3.0 g, 10 mmol) and 4-bromo-2-fluorophenol (2.2 mL, 20 mmol) to 12 mL DIEA. Further, 6 ml of xylene was added, and the mixture was heated to 140 ° C and stirred overnight. After cooling to room temperature, a solid precipitated, which was filtered, washed with ethanol and evaporated to give 3.7 g (81.0%) of white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.48 (d, J = 5.2 Hz, 1H), 7.78 (dd, J = 10.2, 2.2 Hz, 1H), 7.61 - 7.49 (m, 5H), 7.49 - 7.40 (m, 3H), 7.37 (d, J = 7.2 Hz, 1H), 6.53 (d, J = 5.2 Hz, 1H), 5.31 (s, 2H), 3.95 (s, 3H). MS (ESI), m/z: 454[M+H] + .
步骤b2：3-((4-((7-(苄氧基)-6-甲氧基喹啉-4-基)氧基)-3-氟苯基)氨基)-1-甲基-1H-吡唑-4-甲酸乙酯(化合物7)的制备Step b2: 3-((4-((7-(Benzyloxy)-6-methoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl-1H -Preparation of pyrazole-4-carboxylic acid ethyl ester (Compound 7)
将7-(苄氧基)-4-(4-溴-2-氟苯氧基)-6-甲氧基喹啉(化合物6)(4.5g，10mmol)，3-氨基-1-甲基-1H-吡唑-4-甲酸乙酯(1.7g，10mmol)，Pd 2(dba) 3(275mg，0.3mmol)，Xantphos(579mg，1mmol)和碳酸铯(6.5g，20mmol)溶于50mL无水二氧六环，氩气保护，回流反应过夜。冷至室温，硅藻土抽滤，旋干，柱层析得固体3.9g(72.0％)。 1H NMR(400MHz,DMSO-d 6)δ8.54–8.39(m,2H),8.21(s,1H),7.91(dd,J＝13.6,2.6Hz,1H),7.57(s,1H),7.54(d,J＝1.4Hz,1H),7.53–7.47(m,3H),7.46–7.40(m,2H),7.36(dd,J＝9.7,8.3Hz,2H),6.43(dd,J＝5.2,0.9Hz,1H),5.31(s,2H),4.27(q,J＝7.1Hz,2H),3.96(s,3H),3.82(s,3H),1.30(t,J＝7.1Hz,3H).。MS(ESI),m/z:543[M+H] +。 7-(Benzyloxy)-4-(4-bromo-2-fluorophenoxy)-6-methoxyquinoline (Compound 6) (4.5 g, 10 mmol), 3-amino-1-methyl -1H-pyrazole-4-carboxylic acid ethyl ester (1.7 g, 10 mmol), Pd 2 (dba) 3 (275 mg, 0.3 mmol), Xantphos (579 mg, 1 mmol) and cesium carbonate (6.5 g, 20 mmol) dissolved in 50 mL Water dioxane, protected by argon, refluxed overnight. After cooling to room temperature, celite was suction filtered, dried, and then purified to afford 3.9 g (72.0%). 1 H NMR (400MHz, DMSO- d 6) δ8.54-8.39 (m, 2H), 8.21 (s, 1H), 7.91 (dd, J = 13.6,2.6Hz, 1H), 7.57 (s, 1H), 7.54 (d, J = 1.4 Hz, 1H), 7.53 - 7.47 (m, 3H), 7.46 - 7.40 (m, 2H), 7.36 (dd, J = 9.7, 8.3 Hz, 2H), 6.43 (dd, J = 5.2, 0.9 Hz, 1H), 5.31 (s, 2H), 4.27 (q, J = 7.1 Hz, 2H), 3.96 (s, 3H), 3.82 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H). MS (ESI), m/z: 437 [M+H] + .
步骤b3：3-((4-((7-(苄氧基)-6-甲氧基喹啉-4-基)氧基)-3-氟苯基)氨基)-1-甲基-1H-吡唑-4-甲酸(化合物8)的制备Step b3: 3-((4-((7-(Benzyloxy)-6-methoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl-1H -Preparation of pyrazole-4-carboxylic acid (Compound 8)
将3-((4-((7-(苄氧基)-6-甲氧基喹啉-4-基)氧基)-3-氟苯基)氨基)-1-甲基-1H-吡唑-4-甲酸乙酯(化合物7)(2.7g，5mmol)和氢氧化钠(600mg，15mmol)溶于15mL乙醇和5mL水的溶合溶剂中，60℃下反应2小时。冷至室温，旋干乙醇，并用1N HCl溶液调至弱酸性，过滤，烘干，得固体2.4g(92.3％)。 1H NMR(400MHz,DMSO-d 6)δ12.57(br,1H),8.69(d,J＝6.0Hz,1H),8.59(s,1H),8.15(s,1H),7.95(dd,J＝13.6,2.5Hz,1H),7.72(d,J＝10.9Hz,2H),7.59–7.49(m,3H),7.48–7.36(m,4H),6.78(d,J＝6.0Hz,1H),5.36(s,2H),4.01(s,3H),3.82(s,3H).。MS(ESI),m/z:515[M+H] +。 3-((4-((7-(Benzyloxy)-6-methoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl-1H-pyridyl Ethyl azole-4-carboxylate (Compound 7) (2.7 g, 5 mmol) and sodium hydroxide (600 mg, 15 mmol) were dissolved in a solvent mixture of 15 mL of ethanol and 5 mL of water, and reacted at 60 ° C for 2 hours. After cooling to room temperature, the ethanol was sparged and adjusted to a weak acid with a 1N HCl solution, filtered and dried to give a solid, 2.4 g (92.3%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.57 (br, 1H), 8.69 (d, J = 6.0 Hz, 1H), 8.59 (s, 1H), 8.15 (s, 1H), 7.95 (dd, J=13.6, 2.5 Hz, 1H), 7.72 (d, J = 10.9 Hz, 2H), 7.59 - 7.49 (m, 3H), 7.48 - 7.36 (m, 4H), 6.78 (d, J = 6.0 Hz, 1H) ), 5.36 (s, 2H), 4.01 (s, 3H), 3.82 (s, 3H). MS (ESI), m/z: 515[M+H] + .
步骤b4：3-((4-((7-(苄氧基)-6-甲氧基喹啉-4-基)氧基)-3-氟苯基)氨基)-N-环己基-1-甲基-1H-吡唑-4-甲酰胺(化合物9)的制备Step b4: 3-((4-((7-(Benzyloxy)-6-methoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-N-cyclohexyl-1 -Preparation of methyl-1H-pyrazole-4-carboxamide (Compound 9)
将3-((4-((7-(苄氧基)-6-甲氧基喹啉-4-基)氧基)-3-氟苯基)氨基)-1-甲基-1H-吡唑-4-甲酸(化合物8)(2.6g，5mmol)，环己胺(687μL，6mmol)和HATU(2.9g，7.5mmol)溶于30mL DMF中，加入DIEA(2.6mL，15mmol)，室温搅拌过夜。加入饱和氯化钠溶液，用二氯甲烷萃取，合并有机相，用饱和食盐水洗涤三遍，无水Na 2SO 4干燥，过滤旋干，经柱层析分离得固体2.2g(75.0％)。 1H NMR(400MHz,DMSO-d 6)δ9.46(s,1H),8.57(d,J＝5.7Hz,1H),8.22(s,1H),7.96–7.83(m,2H),7.63(s,1H),7.55(dd,J＝9.9,8.5Hz,3H),7.48–7.41(m,2H),7.41–7.32(m,3H),6.61(d,J＝5.5Hz,1H),5.34(s,2H),3.99(s,3H),3.81(s,3H),3.78–3.65(m,1H),1.89–1.66(m,4H),1.61(d,J＝12.5Hz,1H),1.40–1.09(m,5H).。MS(ESI),m/z:596[M+H] +。 3-((4-((7-(Benzyloxy)-6-methoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl-1H-pyridyl Oxazole-4-carboxylic acid (Compound 8) (2.6 g, 5 mmol), cyclohexylamine (687 μL, 6 mmol) and HATU (2.9 g, 7.5 mmol) were dissolved in 30 mL DMF, and DIEA (2.6 mL, 15 mmol) overnight. Add a saturated sodium chloride solution, extract with methylene chloride, and combine the organic phase, washed three times with saturated brine, dried over anhydrous Na 2 SO 4 , filtered and evaporated to dryness. . 1 H NMR (400MHz, DMSO- d 6) δ9.46 (s, 1H), 8.57 (d, J = 5.7Hz, 1H), 8.22 (s, 1H), 7.96-7.83 (m, 2H), 7.63 ( s, 1H), 7.55 (dd, J = 9.9, 8.5 Hz, 3H), 7.48 - 7.41 (m, 2H), 7.41 - 7.32 (m, 3H), 6.61 (d, J = 5.5 Hz, 1H), 5.34 (s, 2H), 3.99 (s, 3H), 3.81 (s, 3H), 3.78 - 3.65 (m, 1H), 1.89 - 1.66 (m, 4H), 1.61 (d, J = 12.5 Hz, 1H), 1.40–1.09 (m, 5H). MS (ESI), m/z: 596 [M+H] + .
步骤b5：N-环己基-3-((3-氟-4-((7-羟基-6-甲氧基喹啉-4-基)氧基)苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺(化合物10)的制备Step b5: N-cyclohexyl-3-((3-fluoro-4-((7-hydroxy-6-methoxyquinolin-4-yl)oxy)phenyl)amino)-1-methyl- Preparation of 1H-pyrazole-4-carboxamide (Compound 10)
将3-((4-((7-(苄氧基)-6-甲氧基喹啉-4-基)氧基)-3-氟苯基)氨基)-N-环己基-1-甲基-1H-吡唑-4-甲酰胺(化合物9)(2.5g，5mmol)溶于20mL乙醇和10ml DMF的溶合溶剂中，加入Pd/C(250mg)，室温搅拌过夜。硅藻土抽滤，加入饱和氯化钠溶液，用二氯甲烷萃取，合并有机相，用饱和食盐水洗涤三遍，无水Na 2SO 4干燥，过滤旋干，经柱层析分离得固体2.2g(86.0％)。 1H NMR(400MHz,DMSO-d 6)δ10.12(s,1H),9.42(s,1H),8.40(d,J＝5.2Hz,1H),8.20(s,1H),7.95–7.79(m,2H),7.52(s,1H),7.32(dd,J＝4.2,1.6Hz,2H),7.28(d,J＝3.0Hz,1H),6.35(dd,J＝5.2,0.8Hz,1H),3.96(s,3H),3.82(d,J＝7.6Hz,3H),3.73(dd,J＝7.3,3.5Hz,1H),1.83(d,J＝9.7Hz,2H),1.74(dd,J＝9.4,2.9Hz,2H),1.61(d,J＝12.6Hz,1H),1.35–1.08(m,5H).。MS(ESI),m/z:506[M+H] +。 3-((4-((7-(Benzyloxy)-6-methoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-N-cyclohexyl-1-yl The hydrazine-1H-pyrazole-4-carboxamide (Compound 9) (2.5 g, 5 mmol) was dissolved in a solvent mixture of 20 mL of ethanol and 10 ml of DMF, and Pd/C (250 mg) was added and stirred at room temperature overnight. Celite filtration, a saturated sodium chloride solution, extracted with dichloromethane and the combined organic phases were washed three times with saturated brine, dried over anhydrous Na 2 SO 4, filtered rotary evaporation, a solid was isolated by column chromatography 2.2 g (86.0%). 1 H NMR (400MHz, DMSO- d 6) δ10.12 (s, 1H), 9.42 (s, 1H), 8.40 (d, J = 5.2Hz, 1H), 8.20 (s, 1H), 7.95-7.79 ( m, 2H), 7.52 (s, 1H), 7.32 (dd, J = 4.2, 1.6 Hz, 2H), 7.28 (d, J = 3.0 Hz, 1H), 6.35 (dd, J = 5.2, 0.8 Hz, 1H) ), 3.96 (s, 3H), 3.82 (d, J = 7.6 Hz, 3H), 3.73 (dd, J = 7.3, 3.5 Hz, 1H), 1.83 (d, J = 9.7 Hz, 2H), 1.74 (dd , J = 9.4, 2.9 Hz, 2H), 1.61 (d, J = 12.6 Hz, 1H), 1.35 - 1.08 (m, 5H). MS (ESI), m/z: 506[M+H] + .
步骤b6：N-环己基-3-((3-氟-4-((6-甲氧基-7-(3-吗啉丙氧基)喹啉-4-基)氧)苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺(CCB-3233)的制备Step b6: N-cyclohexyl-3-((3-fluoro-4-((6-methoxy-7-(3-morpholinepropoxy)quinolin-4-yl)oxy)phenyl)amino) Preparation of 1-methyl-1H-pyrazole-4-carboxamide (CCB-3233)
将N-环己基-3-((3-氟-4-((7-羟基-6-甲氧基喹啉-4-基)氧基)苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺(化合物10)(202mg，0.4mmol)，N-(3-氯丙基)吗啉(131mg，0.8mmol)和碳酸钾(166mg，1.2mmol)溶于2mL DMF中，80℃下反应3小时。冷至室温，加入饱和氯化钠溶液，用二氯甲烷萃取，合并有机相，用饱和食盐水洗涤三遍，无水Na 2SO 4干燥，过滤旋干，经柱层析分离得固体164mg(65.2％)。 1H NMR(400MHz,DMSO-d 6)δ9.42(s,1H),8.46(d,J＝5.2Hz,1H),8.20(s,1H),7.86(dd,J＝19.4,5.2Hz,2H),7.53(s,1H),7.39(s,1H),7.37–7.26(m,2H),6.42(dd,J＝5.2,0.9Hz,1H),4.20(t,J＝6.4Hz,2H),3.95(s,3H),3.82(d,J＝7.2Hz,3H),3.73(dd,J＝7.5,3.5Hz,1H),3.63–3.54(m,4H),2.47(t,J＝7.2Hz,2H),2.39(s,4H),2.03–1.93(m,2H),1.83(d,J＝9.8Hz,2H),1.74(dd,J＝9.4,2.9Hz,2H),1.61(d,J＝12.5Hz,1H),1.37–1.21(m,4H),1.17–1.10(m,1H).。MS(ESI),m/z:633[M+H] +。 N-Cyclohexyl-3-((3-fluoro-4-((7-hydroxy-6-methoxyquinolin-4-yl)oxy)phenyl)amino)-1-methyl-1H- Pyrazole-4-carboxamide (Compound 10) (202 mg, 0.4 mmol), N-(3-chloropropyl)morpholine (131 mg, 0.8 mmol) and potassium carbonate (166 mg, 1.2 mmol) were dissolved in 2 mL DMF. The reaction was carried out at 80 ° C for 3 hours. Cooled to room temperature, saturated sodium chloride solution, extracted with dichloromethane and the combined organic phases were washed three times with saturated brine, dried over anhydrous Na 2 SO 4, filtered and rotary-dry, solid by column chromatography to give 164mg ( 65.2%). 1 H NMR (400MHz, DMSO- d 6) δ9.42 (s, 1H), 8.46 (d, J = 5.2Hz, 1H), 8.20 (s, 1H), 7.86 (dd, J = 19.4,5.2Hz, 2H), 7.53 (s, 1H), 7.39 (s, 1H), 7.37 - 7.26 (m, 2H), 6.42 (dd, J = 5.2, 0.9 Hz, 1H), 4.20 (t, J = 6.4 Hz, 2H) ), 3.95 (s, 3H), 3.82 (d, J = 7.2 Hz, 3H), 3.73 (dd, J = 7.5, 3.5 Hz, 1H), 3.63 - 3.54 (m, 4H), 2.47 (t, J = 7.2 Hz, 2H), 2.39 (s, 4H), 2.03 - 1.93 (m, 2H), 1.83 (d, J = 9.8 Hz, 2H), 1.74 (dd, J = 9.4, 2.9 Hz, 2H), 1.61 ( d, J = 12.5 Hz, 1H), 1.37 - 1.21 (m, 4H), 1.17 - 1.10 (m, 1H). MS (ESI), m/z: 633[M+H] + .
实施例38：N-环己基-3-((4-((7-乙氧基-6-甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺(CCB-3236)的制备Example 38: N-cyclohexyl-3-((4-((7-ethoxy-6-methoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-yl) Preparation of keto-1H-pyrazole-4-carboxamide (CCB-3236)
Figure PCTCN2019079733-appb-000047
Figure PCTCN2019079733-appb-000047
合成方法如实施例37。The synthesis method was as in Example 37.
1H NMR(400MHz,DMSO-d 6)δ9.42(s,1H),8.46(d,J＝5.2Hz,1H),8.20(s,1H),7.86(m,2H),7.53(s,1H),7.38(s,1H),7.36–7.27(m,2H),6.42(d,J＝5.2Hz,1H),4.21(q,J＝7.0Hz,2H),3.95(s,3H),3.81(s,3H),3.73(m,1H),1.83(m,2H),1.78–1.67(m,2H),1.59(m,1H),1.43(t,J＝7.0Hz,3H),1.27(m,5H).MS(ESI),m/z:534[M+H] +。 1 H NMR (400MHz, DMSO- d 6) δ9.42 (s, 1H), 8.46 (d, J = 5.2Hz, 1H), 8.20 (s, 1H), 7.86 (m, 2H), 7.53 (s, 1H), 7.38 (s, 1H), 7.36 - 7.27 (m, 2H), 6.42 (d, J = 5.2 Hz, 1H), 4.21 (q, J = 7.0 Hz, 2H), 3.95 (s, 3H), 3.81 (s, 3H), 3.73 (m, 1H), 1.83 (m, 2H), 1.78 - 1.67 (m, 2H), 1.59 (m, 1H), 1.43 (t, J = 7.0 Hz, 3H), 1.27 (m, 5H) .MS (ESI ), m / z: 534 [m + H] +.
实施例39：N-环己基-3-((3-氟-4-((6-甲氧基-7-丙氧基喹啉-4-基)氧)苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺(CCB-3243)的制备Example 39: N-cyclohexyl-3-((3-fluoro-4-((6-methoxy-7-propoxyquinolin-4-yl)oxy)phenyl)amino)-1-yl Preparation of keto-1H-pyrazole-4-carboxamide (CCB-3243)
Figure PCTCN2019079733-appb-000048
Figure PCTCN2019079733-appb-000048
合成方法如实施例37。The synthesis method was as in Example 37.
1H NMR(400MHz,DMSO-d 6)δ9.42(s,1H),8.46(d,J＝5.2Hz,1H),8.20(s,1H),7.92–7.81(m,2H),7.54(s,1H),7.37(s,1H),7.36–7.29(m,2H),6.42(d,J＝5.2Hz,1H),4.11(t,J＝6.6Hz,2H),3.96(s,3H),3.82(s,3H),3.78–3.68(m,1H),1.84(m,4H),1.78–1.68(m,2H),1.61(m,1H),1.37–1.11(m,5H),1.04(t,J＝7.4Hz,3H).MS(ESI),m/z:548[M+H] +。 1 H NMR (400MHz, DMSO- d 6) δ9.42 (s, 1H), 8.46 (d, J = 5.2Hz, 1H), 8.20 (s, 1H), 7.92-7.81 (m, 2H), 7.54 ( s, 1H), 7.37 (s, 1H), 7.36 - 7.29 (m, 2H), 6.42 (d, J = 5.2 Hz, 1H), 4.11 (t, J = 6.6 Hz, 2H), 3.96 (s, 3H) ), 3.82 (s, 3H), 3.78 - 3.68 (m, 1H), 1.84 (m, 4H), 1.78 - 1.68 (m, 2H), 1.61 (m, 1H), 1.37 - 1.11 (m, 5H), 1.04 (t, J = 7.4Hz, 3H) .MS (ESI), m / z: 548 [m + H] +.
实施例40：N-环己基-3-((3-氟-4-((6-甲氧基-7-(2-甲氧乙氧基)喹啉-4-基)氧)苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺(CCB-3237)的制备Example 40: N-cyclohexyl-3-((3-fluoro-4-((6-methoxy-7-(2-methoxyethoxy)quinolin-4-yl)oxy)phenyl) Preparation of amino)-1-methyl-1H-pyrazole-4-carboxamide (CCB-3237)
Figure PCTCN2019079733-appb-000049
Figure PCTCN2019079733-appb-000049
合成方法如实施例37。The synthesis method was as in Example 37.
1H NMR(400MHz,DMSO-d 6)δ9.43(s,1H),8.46(d,J＝5.2Hz,1H),8.20(s,1H),7.86(m,2H),7.54(s,1H),7.41(s,1H),7.38–7.29(m,2H),6.43(d,J＝5.2Hz,1H),4.33–4.23(m,2H),3.96(s,3H),3.81(s,3H),3.79–3.66(m,3H),3.35(s,3H),1.83(m,2H),1.79–1.68(m,2H),1.61(m,1H),1.37–1.07(m,5H).MS(ESI),m/z:564[M+H] +。 1 H NMR (400MHz, DMSO- d 6) δ9.43 (s, 1H), 8.46 (d, J = 5.2Hz, 1H), 8.20 (s, 1H), 7.86 (m, 2H), 7.54 (s, 1H), 7.41 (s, 1H), 7.38 - 7.29 (m, 2H), 6.43 (d, J = 5.2 Hz, 1H), 4.33 - 4.23 (m, 2H), 3.96 (s, 3H), 3.81 (s , 3H), 3.79–3.66 (m, 3H), 3.35 (s, 3H), 1.83 (m, 2H), 1.79–1.68 (m, 2H), 1.61 (m, 1H), 1.37–1.07 (m, 5H) MS (ESI), m/z: 564[M+H] + .
实施例41：N-环己基-3-((3-氟-4-((6-甲氧基-7-(3-甲氧丙氧基)喹啉-4-基)氧)苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺(CCB-3235)的制备Example 41: N-cyclohexyl-3-((3-fluoro-4-((6-methoxy-7-(3-methoxypropoxy)quinolin-4-yl)oxy)phenyl) Preparation of amino)-1-methyl-1H-pyrazole-4-carboxamide (CCB-3235)
Figure PCTCN2019079733-appb-000050
Figure PCTCN2019079733-appb-000050
合成方法如实施例37。The synthesis method was as in Example 37.
1H NMR(400MHz,DMSO-d 6)δ9.42(s,1H),8.46(d,J＝5.2Hz,1H),8.19(s,1H),7.86(m,2H),7.54(s,1H),7.38(s,1H),7.36–7.28(m,2H),6.43(d,J＝5.2Hz,1H),4.20(t,J＝6.4Hz,2H),3.96(s,3H),3.81(s,3H),3.79–3.68(m,1H),3.53(t,J＝6.4Hz,2H),3.28(s,3H),2.05(m,2H),1.83(m,2H),1.74(m,2H),1.61(m,1H),1.36–1.15(m,5H).MS(ESI),m/z:578[M+H] +。 1 H NMR (400MHz, DMSO- d 6) δ9.42 (s, 1H), 8.46 (d, J = 5.2Hz, 1H), 8.19 (s, 1H), 7.86 (m, 2H), 7.54 (s, 1H), 7.38 (s, 1H), 7.36 - 7.28 (m, 2H), 6.43 (d, J = 5.2 Hz, 1H), 4.20 (t, J = 6.4 Hz, 2H), 3.96 (s, 3H), 3.81 (s, 3H), 3.79 - 3.68 (m, 1H), 3.53 (t, J = 6.4 Hz, 2H), 3.28 (s, 3H), 2.05 (m, 2H), 1.83 (m, 2H), 1.74 (m, 2H), 1.61 (m, 1H), 1.36 - 1.15 (m, 5H). MS (ESI), m/z: 578 [M+H] + .
实施例42：N-环己基-3-((4-((7-(3-(二甲胺)丙氧基)-6-甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺(CCB-3256)的制备Example 42: N-cyclohexyl-3-((4-((7-(3-(dimethylamino))propoxy)-6-methoxyquinolin-4-yl)oxy)-3-fluoro Preparation of Phenyl)amino)-1-methyl-1H-pyrazole-4-carboxamide (CCB-3256)
Figure PCTCN2019079733-appb-000051
Figure PCTCN2019079733-appb-000051
合成方法如实施例37。The synthesis method was as in Example 37.
1H NMR(400MHz,DMSO-d 6)δ9.42(s,1H),8.46(d,J＝4.8Hz,1H),8.20(s,1H),7.92–7.81(m,2H),7.53(s,1H),7.34(m,3H),6.42(d,J＝4.8Hz,1H),4.18(t,J＝6.5Hz,2H),3.95(s,3H),3.81(s,3H),3.78–3.68(m,1H),2.41(t,J＝7.1Hz,2H),2.19(s,6H),1.95(m,2H),1.83(m,2H),1.74(m,2H),1.61(m,1H),1.34–1.13(m,5H).MS(ESI),m/z:591[M+H] +。 1 H NMR (400MHz, DMSO- d 6) δ9.42 (s, 1H), 8.46 (d, J = 4.8Hz, 1H), 8.20 (s, 1H), 7.92-7.81 (m, 2H), 7.53 ( s, 1H), 7.34 (m, 3H), 6.42 (d, J = 4.8 Hz, 1H), 4.18 (t, J = 6.5 Hz, 2H), 3.95 (s, 3H), 3.81 (s, 3H), 3.78–3.68 (m,1H), 2.41 (t, J=7.1 Hz, 2H), 2.19 (s, 6H), 1.95 (m, 2H), 1.83 (m, 2H), 1.74 (m, 2H), 1.61 (m, 1H), 1.34 - 1.13 (m, 5H). MS (ESI), m/z: 591 [M+H] + .
实施例43：N-环己基-3-((3-氟-4-((6-甲氧基-7-(3-(哌啶-1-基)丙氧基)喹啉-4-基)氧)苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺(CCB-3244)的制备Example 43: N-Cyclohexyl-3-((3-fluoro-4-((6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinolin-4-yl) Preparation of Oxy)phenyl)amino)-1-methyl-1H-pyrazole-4-carboxamide (CCB-3244)
Figure PCTCN2019079733-appb-000052
Figure PCTCN2019079733-appb-000052
合成方法如实施例37。The synthesis method was as in Example 37.
1H NMR(400MHz,DMSO-d 6)δ9.42(s,1H),8.46(d,J＝5.2Hz,1H),8.19(s,1H),7.86(m,2H),7.53(s,1H),7.34(m,3H),6.42(d,J＝5.2Hz,1H),4.18(t,J＝6.4Hz,2H),3.95(s,3H),3.80(s,3H),3.77–3.67(m,1H),2.43(t,J＝7.1Hz,2H),2.35(br,4H),2.01–1.90(m,2H),1.83(m,2H),1.74(m,2H),1.61(m,1H),1.51(m,4H),1.39(m,2H),1.33–1.12(m,5H).MS(ESI),m/z: 631[M+H] +。 1 H NMR (400MHz, DMSO- d 6) δ9.42 (s, 1H), 8.46 (d, J = 5.2Hz, 1H), 8.19 (s, 1H), 7.86 (m, 2H), 7.53 (s, 1H), 7.34 (m, 3H), 6.42 (d, J = 5.2 Hz, 1H), 4.18 (t, J = 6.4 Hz, 2H), 3.95 (s, 3H), 3.80 (s, 3H), 3.77 - 3.67 (m, 1H), 2.43 (t, J = 7.1 Hz, 2H), 2.35 (br, 4H), 2.01 - 1.90 (m, 2H), 1.83 (m, 2H), 1.74 (m, 2H), 1.61 (m, 1H), 1.51 (m, 4H), 1.39 (m, 2H), 1.33 - 1.12 (m, 5H). MS (ESI), m/z: 631 [M+H] + .
实施例44：N-环己基-3-((3-氟-4-((6-甲氧基-7-(3-(4-甲基哌嗪-1-基)丙氧基)喹啉-4-基)氧)苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺(CCB-3265)的制备Example 44: N-cyclohexyl-3-((3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinoline) Preparation of -4-yl)oxy)phenyl)amino)-1-methyl-1H-pyrazole-4-carboxamide (CCB-3265)
Figure PCTCN2019079733-appb-000053
Figure PCTCN2019079733-appb-000053
合成方法如实施例37。The synthesis method was as in Example 37.
1H NMR(400MHz,DMSO-d 6)δ9.43(s,1H),8.46(d,J＝5.2Hz,1H),8.20(s,1H),7.87(m,2H),7.53(s,1H),7.46–7.26(m,3H),6.42(d,J＝5.2Hz,1H),4.17(t,J＝6.2Hz,2H),3.95(s,3H),3.81(s,3H),3.77–3.65(m,1H),2.42(m,7H),2.14(s,3H),2.03–1.89(m,2H),1.83(m,2H),1.78–1.68(m,2H),1.60(m,1H),1.35–1.08(m,6H),0.95(t,J＝7.1Hz,2H).MS(ESI),m/z:646[M+H] +。 1 H NMR (400MHz, DMSO- d 6) δ9.43 (s, 1H), 8.46 (d, J = 5.2Hz, 1H), 8.20 (s, 1H), 7.87 (m, 2H), 7.53 (s, 1H), 7.46–7.26 (m, 3H), 6.42 (d, J = 5.2 Hz, 1H), 4.17 (t, J = 6.2 Hz, 2H), 3.95 (s, 3H), 3.81 (s, 3H), 3.77–3.65 (m, 1H), 2.42 (m, 7H), 2.14 (s, 3H), 2.03–1.89 (m, 2H), 1.83 (m, 2H), 1.78–1.68 (m, 2H), 1.60 ( m, 1H), 1.35 - 1.08 (m, 6H), 0.95 (t,J = 7.1 Hz, 2H). MS (ESI), m/z: 646[M+H] + .
实施例45：N-环庚基-3-((3-氟-4-((6-甲氧基-7-(3-吗啉丙氧基)喹啉-4-基)氧)苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺(CCB-3266)的制备Example 45: N-cycloheptyl-3-((3-fluoro-4-((6-methoxy-7-(3-morpholinepropoxy)quinolin-4-yl)oxy)phenyl) Preparation of amino)-1-methyl-1H-pyrazole-4-carboxamide (CCB-3266)
Figure PCTCN2019079733-appb-000054
Figure PCTCN2019079733-appb-000054
合成方法如实施例37。The synthesis method was as in Example 37.
1H NMR(400MHz,DMSO-d 6)δ9.41(s,1H),8.46(d,J＝5.2Hz,1H),8.21(s,1H),7.94–7.81(m,2H),7.53(s,1H),7.39(s,1H),7.33(m,2H),6.42(d,J＝5.2Hz,1H),4.20(t,J＝6.4Hz,2H),3.94(m,4H),3.81(s,3H),3.65–3.50(m,4H),2.46(m,2H),2.39(m,4H),2.03–1.92(m,2H),1.85(m,2H),1.70–1.37(m,10H).MS(ESI),m/z:647[M+H] +。 1 H NMR (400MHz, DMSO- d 6) δ9.41 (s, 1H), 8.46 (d, J = 5.2Hz, 1H), 8.21 (s, 1H), 7.94-7.81 (m, 2H), 7.53 ( s, 1H), 7.39 (s, 1H), 7.33 (m, 2H), 6.42 (d, J = 5.2 Hz, 1H), 4.20 (t, J = 6.4 Hz, 2H), 3.94 (m, 4H), 3.81 (s, 3H), 3.65–3.50 (m, 4H), 2.46 (m, 2H), 2.39 (m, 4H), 2.03–1.92 (m, 2H), 1.85 (m, 2H), 1.70–1.37 ( m, 10H) .MS (ESI) , m / z: 647 [m + H] +.
实施例46：N-环戊基-3-((3-氟-4-((6-甲氧基-7-(3-吗啉丙氧基)喹啉-4-基)氧)苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺(CCB-3299)的制备Example 46: N-Cyclopentyl-3-((3-fluoro-4-((6-methoxy-7-(3-morpholinepropoxy)quinolin-4-yl)oxy)phenyl) Preparation of amino)-1-methyl-1H-pyrazole-4-carboxamide (CCB-3299)
Figure PCTCN2019079733-appb-000055
Figure PCTCN2019079733-appb-000055
合成方法如实施例37。The synthesis method was as in Example 37.
1H NMR(400MHz,DMSO-d 6)δ9.40(s,1H),8.46(d,J＝5.2Hz,1H),8.21(s,1H),7.93(d,J＝7.2Hz,1H),7.90–7.78(m,1H),7.54(s,1H),7.39(s,1H),7.33(d,J＝5.9Hz,2H),6.42(dd,J＝5.2,0.9Hz,1H),4.19(m,3H),3.95(s,3H),3.81(s,3H),3.64–3.52(m,4H),2.46(d,J＝7.1Hz,2H),2.39(s,4H),1.98(dd,J＝8.7,4.9Hz,2H),1.93–1.82(m,2H),1.74–1.60(m,2H),1.52(m,4H).MS(ESI),m/z:619[M+H] +。 1 H NMR (400MHz, DMSO- d 6) δ9.40 (s, 1H), 8.46 (d, J = 5.2Hz, 1H), 8.21 (s, 1H), 7.93 (d, J = 7.2Hz, 1H) , 7.90–7.78 (m, 1H), 7.54 (s, 1H), 7.39 (s, 1H), 7.33 (d, J = 5.9 Hz, 2H), 6.42 (dd, J = 5.2, 0.9 Hz, 1H), 4.19 (m, 3H), 3.95 (s, 3H), 3.81 (s, 3H), 3.64 - 3.52 (m, 4H), 2.46 (d, J = 7.1 Hz, 2H), 2.39 (s, 4H), 1.98 (dd, J=8.7, 4.9 Hz, 2H), 1.93–1.82 (m, 2H), 1.74–1.60 (m, 2H), 1.52 (m, 4H). MS (ESI), m/z: 619 [M +H] + .
实施例47：3-((3-氟-4-((6-甲氧基-7-(3-吗啉丙氧基)喹啉-4-基)氧)苯基)氨基)-N-(4-氟苯基)-1-甲基-1H-吡唑-4-甲酰胺(CCB-3330)的制备Example 47: 3-((3-Fluoro-4-((6-methoxy-7-(3-morpholinepropoxy)quinolin-4-yl)oxy)phenyl)amino)-N- Preparation of (4-fluorophenyl)-1-methyl-1H-pyrazole-4-carboxamide (CCB-3330)
Figure PCTCN2019079733-appb-000056
Figure PCTCN2019079733-appb-000056
合成方法如实施例37。The synthesis method was as in Example 37.
1H NMR(400MHz,DMSO-d 6)δ9.94(s,1H),9.22(s,1H),8.46(d,J＝5.3Hz,1H),8.39(s,1H),7.92(dd,J＝13.6,2.6Hz,1H),7.80–7.64(m,2H),7.54(s,1H),7.50–7.29(m,3H),7.27–7.13(m,2H),6.43(dd,J＝5.2,0.9Hz,1H),4.20(t,J＝6.4Hz,2H),3.95(s,3H),3.88(s,3H),3.59m,4H),2.48–2.30(m,6H),2.05–1.86(m,2H).MS(ESI),m/z:645[M+H] + 1 H NMR (400MHz, DMSO- d 6) δ9.94 (s, 1H), 9.22 (s, 1H), 8.46 (d, J = 5.3Hz, 1H), 8.39 (s, 1H), 7.92 (dd, J=13.6, 2.6 Hz, 1H), 7.80–7.64 (m, 2H), 7.54 (s, 1H), 7.50–7.29 (m, 3H), 7.27–7.13 (m, 2H), 6.43 (dd, J= 5.2, 0.9 Hz, 1H), 4.20 (t, J = 6.4 Hz, 2H), 3.95 (s, 3H), 3.88 (s, 3H), 3.59 m, 4H), 2.48 - 2.30 (m, 6H), 2.05 –1.86(m,2H).MS(ESI), m/z: 645[M+H] +
实施例48：3-氨基吡唑类化合物对AXL激酶的IC 50测试 Example 48: 3-aminopyrazole compounds on AXL kinase IC 50 test
激酶活性检测：应用酶联免疫吸附测定(ELISA)技术检测化合物对激酶的抑制活性。 将酶反应底物Poly(Glu,Tyr)4:1用无钾离子的PBS(10mM磷酸钠缓冲液，150mM NaCl,pH7.2-7.4)稀释成20μg/mL，125μL/孔包被酶标板，置37℃反应12-16小时。弃去孔中液体后洗板，用200μL/孔的T-PBS(含0.1％Tween-20的PBS)洗板三次，每次5分钟。于37℃烘箱中干燥酶标板1-2小时。每孔加入用反应缓冲液(50mM HEPES pH 7.4,50mM MgCl 2,0.5mM MnCl 2,0.2mM Na 3VO 4,1mM DTT)稀释的ATP溶液50μL，终浓度5μM。化合物用DMSO稀释成合适的浓度，1μL/孔或含相应浓度的DMSO(阴性对照孔)，再加入用49μL反应缓冲液稀释的AXL激酶域重组蛋白(eurofins，14-512)启动反应，每次实验需设无酶对照孔两孔。置37℃摇床(100rpm)反应1小时。T-PBS洗板三次。加入一抗PY99稀释液100μL/孔，37℃摇床反应0.5小时。T-PBS洗板三次。加入二抗辣根过氧化物酶标记羊抗鼠的IgG稀释液100μL/孔，37℃摇床反应0.5小时。T-PBS洗板三次。加入2mg/ml的OPD显色液100μL/孔(用含有0.03％H 2O 2的0.1M柠檬酸－柠檬酸钠缓冲液(pH＝5.4)稀释)，25℃避光反应1-10分钟。(OPD溶解时需用超声，显色液需现配现用)。加入2M H 2SO 4 50μL/孔中止反应，用可调波长式微孔板酶标仪SPECTRA MAX 190读数，波长为490nm。 Kinase activity assay: The inhibitory activity of compounds on kinases was tested by enzyme-linked immunosorbent assay (ELISA). The enzyme reaction substrate Poly(Glu, Tyr) 4:1 was diluted with potassium-free PBS (10 mM sodium phosphate buffer, 150 mM NaCl, pH 7.2-7.4) to 20 μg/mL, 125 μL/well coated with the enzyme plate. The reaction was carried out at 37 ° C for 12-16 hours. After discarding the liquid in the well, the plate was washed, and the plate was washed three times with 200 μL/well of T-PBS (PBS containing 0.1% Tween-20) for 5 minutes each time. The plate was dried in an oven at 37 ° C for 1-2 hours. 50 μL of ATP solution diluted with reaction buffer (50 mM HEPES pH 7.4, 50 mM MgCl 2 , 0.5 mM MnCl 2 , 0.2 mM Na 3 VO 4 , 1 mM DTT) was added to each well to a final concentration of 5 μM. The compound was diluted to a suitable concentration in DMSO, 1 μL/well or containing the corresponding concentration of DMSO (negative control well), and the reaction was initiated by adding AXL kinase domain recombinant protein (eurofins, 14-512) diluted in 49 μL of reaction buffer. The experiment requires two wells without enzyme control wells. The reaction was carried out for 1 hour at 37 ° C on a shaker (100 rpm). The plate was washed three times with T-PBS. One anti-PY99 dilution was added to 100 μL/well, and the reaction was shaken at 37 ° C for 0.5 hour. The plate was washed three times with T-PBS. A second anti-horseradish peroxidase-labeled goat anti-mouse IgG dilution was added at 100 μL/well, and shaken at 37 ° C for 0.5 hour. The plate was washed three times with T-PBS. 100 μL/well of 2 mg/ml OPD chromogenic solution (diluted with 0.1 M citric acid-sodium citrate buffer (pH=5.4) containing 0.03% H 2 O 2 ) was added, and the reaction was incubated at 25 ° C for 1-10 minutes in the dark. (Ultrasound is required for the dissolution of OPD, and the coloring solution needs to be used now). The reaction was quenched by the addition of 2 M H 2 SO 4 50 μL/well and read with a tunable wavelength microplate reader SPECTRA MAX 190 at a wavelength of 490 nm.
样品的抑制率通过下列公式求得：The inhibition rate of the sample is obtained by the following formula:
Figure PCTCN2019079733-appb-000057
Figure PCTCN2019079733-appb-000057
IC 50值采用酶标仪随机附带软件以四参数法回归求得。 IC 50 values were obtained by four-parameter regression using software attached to the microplate reader.
由表1结果可见：3-氨基吡唑类化合物与ATP的竞争实验中，本发明的化合物对AXL激酶表现出强烈的抑制活性。As can be seen from the results of Table 1, in the competition experiment of 3-aminopyrazoles with ATP, the compounds of the present invention exhibited strong inhibitory activity against AXL kinase.
表1化合物编号以及对应激酶活性结果。Table 1 Compound numbers and corresponding kinase activity results.
CompdsCompds AXL IC 50(nM) AXL IC 50 (nM) CompdsCompds AXL IC 50(nM) AXL IC 50 (nM)
CCB-3152CCB-3152 >10000>10000 CCB-3072CCB-3072 86.786.7
CCB-3151CCB-3151 237.8237.8 DL-025DL-025 29.529.5
CCB-3088CCB-3088 585.6585.6 DL-037DL-037 >500>500
CCB-3069CCB-3069 142.2142.2 CCB-3049CCB-3049 39.739.7
CCB-3087CCB-3087 11.411.4 CCB-3236CCB-3236 9.49.4
CCB-3269CCB-3269 6565 CCB-3243CCB-3243 21.621.6
CCB-3091CCB-3091 5.15.1 CCB-3235CCB-3235 8.68.6
CCB-3146CCB-3146 4.04.0 CCB-3237CCB-3237 7.87.8
CCB-3263CCB-3263 12.512.5 CCB-3244CCB-3244 5.65.6
CCB-3143CCB-3143 5.55.5 CCB-3265CCB-3265 2.92.9
CCB-3245CCB-3245 333333 CCB-3256CCB-3256 3.23.2
CCB-3252CCB-3252 46.046.0 CCB-3233CCB-3233 1.61.6
CCB-3109CCB-3109 13.213.2 CCB-3266CCB-3266 7.77.7
CCB-3037CCB-3037 25.425.4 DL-026DL-026 155155
CCB-3099CCB-3099 12.012.0 DL-036DL-036 64.064.0
CCB-3067CCB-3067 23.523.5 DL-040DL-040 >10000>10000
CCB-3068CCB-3068 23.123.1 DL-032DL-032 >1000>1000
CCB-3046CCB-3046 42.042.0 CCB-3048CCB-3048 119.7119.7
CCB-3070CCB-3070 80.080.0 CCB-3098CCB-3098 266266
TL140TL140 35.035.0 CCB-3299CCB-3299 3.83.8
CCB-3071CCB-3071 34.034.0 CCB-3330CCB-3330 4.14.1
TL-145TL-145 6.56.5 TL-156TL-156 16.616.6
TL-151TL-151 38.938.9 TL-170TL-170 136.6136.6
TL-154TL-154 40.440.4    
实施例49：3-氨基吡唑类化合物对AXL介导的细胞增殖IC 50测试 Example 49: 3-aminopyrazole compounds proliferation IC 50 of test cell-mediated AXL
试验方法：化合物对BaF3/TEL-AXL细胞的增殖抑制作用以CCK-8细胞计数试剂盒(Dojindo)检测。具体步骤如下：处于对数生长期的BaF3/TEL-AXL细胞按合适密度接种至96孔培养板中，每孔90μL，培养过夜后，加入不同浓度的化合物作用72hr，并设定溶剂对照组(阴性对照)。待化合物作用细胞72h后，化合物对细胞增殖的影响采用CCK-8细胞计数试剂盒(Dojindo)检测，每孔加入10μL CCK-8试剂，置于37℃培养箱中放置2-4小时后，用全波长式微孔板酶标仪SpectraMax 190读数，测定波长为450nm。Test method: The proliferation inhibition effect of the compound on BaF3/TEL-AXL cells was detected by CCK-8 cell counting kit (Dojindo). The specific steps are as follows: BaF3/TEL-AXL cells in logarithmic growth phase were inoculated into 96-well culture plates at a suitable density, 90 μL per well, and cultured overnight, different concentrations of compounds were added for 72 hr, and the solvent control group was set ( Negative control). After the compound was treated for 72h, the effect of the compound on cell proliferation was detected by CCK-8 cell counting kit (Dojindo). Add 10 μL of CCK-8 reagent to each well and place in a 37 ° C incubator for 2-4 hours. The full-wavelength microplate reader SpectraMax 190 reads at a wavelength of 450 nm.
采用以下列公式计算化合物对肿瘤细胞生长的抑制率(％)：The inhibition rate (%) of the compound on tumor cell growth was calculated by the following formula:
抑制率(％)＝(OD对照孔-OD给药孔)/OD对照孔×100％Inhibition rate (%) = (OD control well-OD administration well) / OD control well × 100%
IC 50值采用酶标仪随机附带软件以四参数法回归求得。 IC 50 values were obtained by four-parameter regression using software attached to the microplate reader.
实验结果如表2所示。The experimental results are shown in Table 2.
表2.化合物对BaF3/TEL-AXL细胞增殖抑制的IC 50值 Table 2. Compound of BaF3 / TEL-AXL cell proliferation inhibition IC 50 values
编号Numbering IC 50(nM) IC 50 (nM)
CCB-3233CCB-3233 4.74.7
CCB-3256CCB-3256 11.611.6
CCB-3265CCB-3265 9.09.0
CCB-3299CCB-3299 5.75.7
CCB-3330CCB-3330 6.76.7
R428R428 98.998.9
GilteritinibGilteritinib 16.816.8
由表2结果可见：本发明的3-氨基吡唑类化合物对AXL介导的细胞增殖表现出强烈的抑制活性。As can be seen from the results of Table 2, the 3-aminopyrazole compound of the present invention exhibited strong inhibitory activity against AXL-mediated cell proliferation.
实施例50：3-氨基吡唑类化合物对MV4-11细胞增殖IC 50测试 Example 50: 3-aminopyrazole compound MV4-11 proliferation and the IC 50 of the test cell
本实验使用的细胞MV4-11(急性髓性白血病细胞系)来自ATCC。3000-10000个上述细胞接种到96孔板中，然后加入不同浓度的化合物(0-3μM)连续处理72小时。加入CCK8试剂，继续孵育1-3小时，接着用超级酶标仪测定其在450nm及650nm的吸光值,计算各孔的实际吸光度值A＝OD450-OD650，根据A值计算各处理孔的细胞存活率；然后将细胞存活率数据及其化合物的浓度输入GraphPad Prism 5Demo软件，使用非线性回归模型计算化合物对细胞的IC 50值。 The cell MV4-11 (acute myeloid leukemia cell line) used in this experiment was from ATCC. 3000-10000 of the above cells were seeded into 96-well plates, and then treated with different concentrations of compounds (0-3 μM) for 72 hours. Add CCK8 reagent, continue to incubate for 1-3 hours, then measure the absorbance at 450nm and 650nm with a super-microplate reader, calculate the actual absorbance value of each well A=OD450-OD650, calculate the cell survival of each treatment well according to the A value. rate; the concentration of the compound and the cell viability and the data input software GraphPad Prism 5Demo, calculated on the cells compound IC 50 values using nonlinear regression models.
实验结果如表3所示。The experimental results are shown in Table 3.
表3.化合物对MV4-11白血病细胞增殖抑制的IC 50值 Table 3. Compound IC50 value for the MV4-11 leukemia cell proliferation IC
编号Numbering IC50(μM)IC50 (μM)
CCB-3087CCB-3087 0.2440.244
CCB-3091CCB-3091 0.3830.383
CCB-3233CCB-3233 0.0210.021
CCB-3266CCB-3266 0.0130.013
R428R428 0.3060.306
由表3结果可见：本发明的3-氨基吡唑类化合物对MV4-11白血病细胞增殖表现出强烈的抑制活性。As can be seen from the results of Table 3, the 3-aminopyrazole compound of the present invention exhibited strong inhibitory activity against MV4-11 leukemia cell proliferation.
以上所述实施例的各技术特征可以进行任意的组合，为使描述简洁，未对上述实施例中的各个技术特征所有可能的组合都进行描述，然而，只要这些技术特征的组合不存在矛盾，都应当认为是本说明书记载的范围。The technical features of the above-described embodiments may be arbitrarily combined. For the sake of brevity of description, all possible combinations of the technical features in the above embodiments are not described. However, as long as there is no contradiction between the combinations of these technical features, All should be considered as the scope of this manual.
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。The above-described embodiments are merely illustrative of several embodiments of the present invention, and the description thereof is more specific and detailed, but is not to be construed as limiting the scope of the invention. It should be noted that a number of variations and modifications may be made by those skilled in the art without departing from the spirit and scope of the invention. Therefore, the scope of the invention should be determined by the appended claims.

Claims (23)

  1. 具有式(Ⅰ)所示结构的3-氨基吡唑类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子或者其氘代物：A 3-aminopyrazole compound having the structure represented by the formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof or a progeny thereof:
    Figure PCTCN2019079733-appb-100001
    Figure PCTCN2019079733-appb-100001
    其中，X选自：CH或N；Wherein X is selected from: CH or N;
    Z选自：O或NH；Z is selected from: O or NH;
    B选自：C 5～C 10芳基、5～10元杂芳基、C 3～C 6环烷基、C 7～C 13多环烷基； B is selected from the group consisting of C 5 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 6 cycloalkyl, C 7 -C 13 polycycloalkyl;
    R 1、R 2与A环组成取代或未取代的并杂环
    Figure PCTCN2019079733-appb-100002
    m为2或者3，Y选自C、N或O；     R 1 , R 2 and A ring constitute a substituted or unsubstituted heterocyclic ring
    Figure PCTCN2019079733-appb-100002
    m is 2 or 3, and Y is selected from C, N or O;
    R 3选自：氢、卤素、卤素取代的C 1～C 6烷基、C 1～C 6烷氧基或C 1～C 6烷基； R 3 is selected from the group consisting of hydrogen, halogen, halogen-substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy or C 1 -C 6 alkyl;
    R 4选自：氢、C 1～C 5烷基、C 3～C 6环烷基、C 1～C 3烷氧基或
    Figure PCTCN2019079733-appb-100003
    R 21选自：氢、卤素、C 1～C 5烷基、C 3～C 6环烷基或C 1～C 5烷氧基；     R 4 is selected from the group consisting of hydrogen, C 1 -C 5 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy or
    Figure PCTCN2019079733-appb-100003
    R 21 is selected from the group consisting of hydrogen, halogen, C 1 -C 5 alkyl, C 3 -C 6 cycloalkyl or C 1 -C 5 alkoxy;
    R 5、R 6分别独立地选自：氢、烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、芳烷基、取代或未取代的杂芳基、杂芳烷基、取代或未取代的多环烷基；或者，R 5、R 6和与其相连的N原子一起组成单环杂环或并环杂环。 R 5 and R 6 are each independently selected from the group consisting of hydrogen, alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, aralkyl, substituted or unsubstituted Substituted heteroaryl, heteroarylalkyl, substituted or unsubstituted polycycloalkyl; or R 5 , R 6 together with the N atom to which they are attached constitute a monocyclic heterocyclic ring or a heterocyclic heterocyclic ring.
  2. 根据权利要求1所述的3-氨基吡唑类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子或者其氘代物，其特征在于，所述3-氨基吡唑类化合物具有式(Ⅱ)所示结构：The 3-aminopyrazole compound or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a prodrug molecule thereof or a progeny thereof, according to claim 1, wherein the 3-aminopyrazole The compound has the structure shown in formula (II):
    Figure PCTCN2019079733-appb-100004
    Figure PCTCN2019079733-appb-100004
    X选自：CH或N。X is selected from: CH or N.
  3. 根据权利要求1或2所述的3-氨基吡唑类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子或者其氘代物，其特征在于，所述取代或未取代的并杂环
    Figure PCTCN2019079733-appb-100005
    选自如下结构：     The 3-aminopyrazole compound or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a prodrug molecule thereof, or a progeny thereof, according to claim 1 or 2, wherein the substituted or unsubstituted Heterocyclic
    Figure PCTCN2019079733-appb-100005
    Selected from the following structure:
    Figure PCTCN2019079733-appb-100006
    Figure PCTCN2019079733-appb-100006
    其中，X为CH或N；Where X is CH or N;
    R 12、R 13分别独立地选自：-O(CR 15R 16) OR 14； R 12 and R 13 are each independently selected from: -O(CR 15 R 16 ) O R 14 ;
    其中，o选自0～6之间的整数；Wherein o is selected from an integer between 0 and 6;
    R 14、R 15、R 16分别独立地选自：-H、C 1～C 5烷基、卤素、卤素取代的C 1～C 5烷基、卤素取代的C 1～C 5烷氧基、-OH、-COOH、-COOR 19、-(C＝O)-NR 19R 20、-SO m-NR 19R 20、-CHR 19R 20、-OR 19或-NR 19R 20；m＝1～2； R 14 , R 15 and R 16 are each independently selected from: -H, C 1 -C 5 alkyl, halogen, halogen-substituted C 1 -C 5 alkyl, halogen-substituted C 1 -C 5 alkoxy, -OH, -COOH, -COOR 19 , -(C=O)-NR 19 R 20 , -SO m -NR 19 R 20 , -CHR 19 R 20 , -OR 19 or -NR 19 R 20 ; m=1 ～2;
    R 19、R 20分别独立地选自：氢、卤素、C 1～C 6烷基、或者R 19与R 20组成饱和或不饱和的R 22取代的5～8元杂环基团，其中R 22选自：-H、C 1～C 5烷基； R 19 and R 20 are each independently selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, or R 19 and R 20 are a saturated or unsaturated R 22 -substituted 5-8 membered heterocyclic group, wherein R 22 is selected from the group consisting of: -H, C 1 -C 5 alkyl;
    或者，R 12、R 13组成含1～4个杂原子的取代或未取代的C 5～C 18脂肪环烷基。 Alternatively, R 12 and R 13 constitute a substituted or unsubstituted C 5 -C 18 aliphatic cycloalkyl group having 1 to 4 hetero atoms.
  4. 根据权利要求3所述的3-氨基吡唑类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子或者其氘代物，其特征在于，R 14、R 15、R 16分别独立地选自：-H、C 1～C 5烷基、-OR 19或-NR 19R 20； The 3-aminopyrazole compound or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a prodrug molecule thereof or a progeny thereof, according to claim 3, wherein R 14 , R 15 , R 16 Individually selected from: -H, C 1 -C 5 alkyl, -OR 19 or -NR 19 R 20 ;
    R 19、R 20分别独立地选自：氢、C 1～C 6烷基、或者R 19、R 20和与其相连的N一起组成饱和或不饱和的R 22取代的5～8元杂环基团，其中R 22选自：-H、C 1～C 5烷基。 R 19 and R 20 are each independently selected from the group consisting of: hydrogen, C 1 -C 6 alkyl, or R 19 , R 20 and N attached thereto to form a saturated or unsaturated R 22 -substituted 5-8 membered heterocyclic group. a group wherein R 22 is selected from the group consisting of: -H, C 1 -C 5 alkyl.
  5. 根据权利要求4所述的3-氨基吡唑类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子或者其氘代物，其特征在于，R 15和R 16均为氢； The 3-aminopyrazole compound or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a prodrug molecule thereof or a deuterated product thereof, according to claim 4, wherein R 15 and R 16 are each hydrogen ;
    R 14选自：-H、-OR 19或-NR 19R 20； R 14 is selected from the group consisting of: -H, -OR 19 or -NR 19 R 20 ;
    R 19、R 20分别独立地选自：C 1～C 3烷基、或者R 19、R 20和与其相连的N一起组成饱和的R 22取代的5～8元杂环基团，其中R 22选自：-H、C 1～C 3烷基。 R 19 and R 20 are each independently selected from a C 1 -C 3 alkyl group, or R 19 , R 20 and N attached thereto constitute a saturated R 22 -substituted 5-8 membered heterocyclic group, wherein R 22 It is selected from the group consisting of: -H, C 1 -C 3 alkyl.
  6. 根据权利要求3所述的3-氨基吡唑类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子或者其氘代物，其特征在于，R 12、R 13分别独立地选自：-O(CH 2) OR 14；o选自0～4之间的整数。 The 3-aminopyrazole compound or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a prodrug molecule thereof, or a deuterated product thereof, according to claim 3, wherein R 12 and R 13 are each independently It is selected from: -O(CH 2 ) O R 14 ; o is selected from an integer between 0 and 4.
  7. 根据权利要求6所述的3-氨基吡唑类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子或者其氘代物，其特征在于，R 12和R 13中的一个选自C 1～C 4烷氧基，另一个选自：-O(CH 2) OR 14； The 3-aminopyrazole compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof or a deuterated product thereof according to claim 6, wherein one of R 12 and R 13 It is selected from the group consisting of C 1 -C 4 alkoxy groups, and the other is selected from: -O(CH 2 ) O R 14 ;
    o选自1～4之间的整数；o is selected from an integer between 1 and 4;
    R 14选自：H、-OR 19或-NR 19R 20； R 14 is selected from the group consisting of: H, -OR 19 or -NR 19 R 20 ;
    R 19、R 20分别独立地选自：C 1～C 3烷基、或者R 19、R 20和与其相连的N一起组成R 22取代的6元饱和杂环基，其中R 22选自：-H、C 1～C 3烷基。 R 19 and R 20 are each independently selected from a C 1 -C 3 alkyl group, or R 19 , R 20 and N attached thereto constitute a R 22 -substituted 6-membered saturated heterocyclic group, wherein R 22 is selected from the group consisting of: - H, C 1 - C 3 alkyl.
  8. 根据权利要求6所述的3-氨基吡唑类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子或者其氘代物，其特征在于，R 12和R 13分别独立地选自：甲氧基、乙氧基、丙氧基、吗啉基取代的丙氧基、甲氧基取代的乙氧基、甲氧基取代的丙氧基、二甲胺基取代的丙氧基、哌啶取代的丙氧基、N-甲基哌嗪取代的丙氧基。 The 3-aminopyrazole compound or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a prodrug molecule thereof or a progeny thereof, according to claim 6, wherein R 12 and R 13 are each independently Selected from: methoxy, ethoxy, propoxy, morpholinyl substituted propoxy, methoxy substituted ethoxy, methoxy substituted propoxy, dimethylamino substituted propoxy A piperidine-substituted propoxy group or a N-methylpiperazine-substituted propoxy group.
  9. 根据权利要求1或2所述的3-氨基吡唑类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子或者其氘代物，其特征在于，R 3选自：H、卤素、三氟甲基、C 1～C 3烷基、C 1～C 3烷氧基。 The 3-aminopyrazole compound or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a prodrug molecule thereof or a deuterated product thereof, according to claim 1 or 2, wherein R 3 is selected from the group consisting of: H And halogen, trifluoromethyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxy.
  10. 根据权利要求9所述的3-氨基吡唑类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子或者其氘代物，其特征在于，R 3选自：H、F、Cl、Br、甲基、乙基、甲氧基、乙氧基。 The 3-aminopyrazole compound according to claim 9, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a prodrug molecule thereof or a deuterated product thereof, wherein R 3 is selected from the group consisting of H, F , Cl, Br, methyl, ethyl, methoxy, ethoxy.
  11. 根据权利要求1或2所述的3-氨基吡唑类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子或者其氘代物，其特征在于，R 4选自：C 1～C 3烷基。 The 3-aminopyrazole compound or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a prodrug molecule thereof or a deuterated product thereof, according to claim 1 or 2, wherein R 4 is selected from the group consisting of C: 1 to C 3 alkyl.
  12. 根据权利要求1或2所述的3-氨基吡唑类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子或者其氘代物，其特征在于，R 5、R 6分别独立地选自：氢、C 1～C 8烷基、R 8取代的C 3～C 10环烷基、R 8取代的3-10元杂环烷基、R 10取代的C 5-C 10芳基、芳烷基、R 10取代的5-10元杂芳基、杂芳烷基、R 8取代的C 7～C 13多环烷基；或者，R 5、R 6和与其相连的N原子一起组成3-10元的单环杂环或并环杂环； The 3-aminopyrazole compound or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a prodrug molecule thereof or a progeny thereof, according to claim 1 or 2, wherein R 5 and R 6 are respectively Independently selected from: hydrogen, C 1 -C 8 alkyl, R 8 substituted C 3 -C 10 cycloalkyl, R 8 substituted 3-10 membered heterocycloalkyl, R 10 substituted C 5 -C 10 Aryl, aralkyl, R 10 substituted 5-10 membered heteroaryl, heteroaralkyl, R 8 substituted C 7 -C 13 polycycloalkyl; or, R 5 , R 6 and N attached thereto The atoms together form a 3-10 membered monocyclic or bicyclic heterocycle;
    R 8选自：氢、C 1～C 6烷基、卤素； R 8 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, halogen;
    R 10选自：氢、卤素、C 1～C 6烷基、C 1～C 6烷氧基、氰基、卤素取代的C 1～C 6烷基、卤素取代的C 1～C 6烷氧基、氰基取代的C 1～C 6烷基。 R 10 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, cyano, halogen-substituted C 1 -C 6 alkyl, halogen-substituted C 1 -C 6 alkoxy a cyano-substituted C 1 -C 6 alkyl group.
  13. 根据权利要求12所述的3-氨基吡唑类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子或者其氘代物，其特征在于，R 5、R 6分别独立地选自：氢、C 1～C 8烷基、R 8取代的C 3～C 8环烷基、R 8取代的6-8元杂环烷基、R 10取代的苯基、金刚烷基、R 10取代的5-10元杂芳基；或者，R 5、R 6和与其相连的N原子一起组成3-10元的单环杂环或并环杂环。 The 3-aminopyrazole compound or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a prodrug molecule thereof or a deuterated product thereof, according to claim 12, wherein R 5 and R 6 are each independently Selected from: hydrogen, C 1 -C 8 alkyl, R 8 substituted C 3 -C 8 cycloalkyl, R 8 substituted 6-8 membered heterocycloalkyl, R 10 substituted phenyl, adamantyl, R 10 substituted 5-10 membered heteroaryl; alternatively, R 5 , R 6 together with the N atom to which they are attached constitute a 3-10 membered monocyclic or paracyclic heterocyclic ring.
  14. 根据权利要求13所述的3-氨基吡唑类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子或者其氘代物，其特征在于，R 6选自：氢、C 1～C 5烷基；R 5选自：C 2～C 8烷基、R 8取代的C 3～C 8环烷基、R 8取代的6-8元杂环烷基、R 10取代的苯基、金刚烷基；或者，R 5、R 6和与其相连的N原子一起组成3-10元的单环杂环或并环杂环。 The 3-aminopyrazole compound or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a prodrug molecule thereof or a deuterated product thereof, according to claim 13, wherein R 6 is selected from the group consisting of hydrogen, C 1 to C 5 alkyl; R 5 is selected from C 2 to C 8 alkyl, R 8 substituted C 3 -C 8 cycloalkyl, R 8 substituted 6-8 membered heterocycloalkyl, R 10 substituted Phenyl, adamantyl; or R 5 , R 6 together with the N atom to which they are attached constitute a 3-10 membered monocyclic or paracyclic heterocyclic ring.
  15. 根据权利要求14所述的3-氨基吡唑类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子或者其氘代物，其特征在于，R 6选自：氢、C 1～C 5烷基；R 5选自：C 4～C 8烷基、R 8取代的C 4～C 8环烷基、R 10取代的苯基、R 8取代的6-8元杂环烷基、金刚烷基；或者，R 5、R 6和与其相连的N原子一起组成3-10元的单环杂环或并环杂环。 The 3-aminopyrazole compound or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a prodrug molecule thereof or a deuterated product thereof, according to claim 14, wherein R 6 is selected from the group consisting of hydrogen, C 1 C to C 5 alkyl; R 5 is selected from C 4 to C 8 alkyl, R 8 substituted C 4 to C 8 cycloalkyl, R 10 substituted phenyl, R 8 substituted 6-8 membered heterocyclic ring Alkyl, adamantyl; or R 5 , R 6 together with the N atom to which they are attached constitute a 3-10 membered monocyclic or paracyclic heterocyclic ring.
  16. 根据权利要求15所述的3-氨基吡唑类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子或者其氘代物，其特征在于，R 6选自：氢、C 1～C 3烷基；R 5选自：R 8取代的C 5～C 8环烷基、R 10取代的苯基、金刚烷基。 The 3-aminopyrazole compound or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a prodrug molecule thereof or a deuterated product thereof, according to claim 15, wherein R 6 is selected from the group consisting of hydrogen, C 1 to C 3 alkyl; R 5 is selected from the group consisting of R 8 -substituted C 5 -C 8 cycloalkyl, R 10 -substituted phenyl, adamantyl.
  17. 根据权利要求12所述的3-氨基吡唑类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子或者其氘代物，其特征在于，R 8选自：氢、卤素；R 10选自：氢、卤素、C 1～C 2烷基、甲氧基。 The 3-aminopyrazole compound or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a prodrug molecule thereof or a deuterated product thereof, according to claim 12, wherein R 8 is selected from the group consisting of hydrogen and halogen R 10 is selected from the group consisting of hydrogen, halogen, C 1 -C 2 alkyl, methoxy.
  18. 根据权利要求1或2所述的3-氨基吡唑类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子或者其氘代物，其特征在于，所述3-氨基吡唑类化合物具有式(Ⅲ)所示结构：The 3-aminopyrazole compound or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a prodrug molecule thereof or a progeny thereof, according to claim 1 or 2, wherein the 3-aminopyridinium The azole compound has the structure represented by the formula (III):
    Figure PCTCN2019079733-appb-100007
    Figure PCTCN2019079733-appb-100007
    其中，R 3选自：H、卤素、C 1～C 3烷基、C 1～C 3烷氧基； Wherein R 3 is selected from the group consisting of: H, halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy;
    R 6选自：氢、C 1～C 2烷基； R 6 is selected from the group consisting of hydrogen, C 1 -C 2 alkyl;
    R 5选自：C 5～C 8环烷基、R 10取代的苯基、6-8元杂环烷基；或者，R 5、R 6和与其相连的N原子一起组成3-10元的单环杂环或并环杂环； R 5 is selected from the group consisting of: C 5 -C 8 cycloalkyl, R 10 -substituted phenyl, 6-8 membered heterocycloalkyl; or R 5 , R 6 and the N atom to which they are attached constitute a 3-10 member. Monocyclic or bicyclic heterocycle;
    R 10选自：氢、卤素、C 1～C 2烷基、甲氧基、卤素取代的C 1～C 2烷氧基； R 10 is selected from the group consisting of hydrogen, halogen, C 1 -C 2 alkyl, methoxy, halogen-substituted C 1 -C 2 alkoxy;
    R 13选自：-O(CH 2) OR 14；o选自1～4之间的整数； R 13 is selected from the group consisting of: -O(CH 2 ) O R 14 ; o is selected from an integer between 1 and 4;
    R 14选自：H、-OR 19或-NR 19R 20； R 14 is selected from the group consisting of: H, -OR 19 or -NR 19 R 20 ;
    R 19、R 20分别独立地选自：C 1～C 3烷基、或者R 19、R 20和与其相连的N一起组成R 22取代 的6元饱和杂环基，其中R 22选自：-H、C 1～C 3烷基。 R 19 and R 20 are each independently selected from a C 1 -C 3 alkyl group, or R 19 , R 20 and N attached thereto constitute a R 22 -substituted 6-membered saturated heterocyclic group, wherein R 22 is selected from the group consisting of: - H, C 1 - C 3 alkyl.
  19. 根据权利要求1所述的3-氨基吡唑类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子或者其氘代物，其特征在于，所述3-氨基吡唑类化合物选自：The 3-aminopyrazole compound or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a prodrug molecule thereof or a progeny thereof, according to claim 1, wherein the 3-aminopyrazole The compound is selected from:
    3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-N,1-二甲基-1H-吡唑-4-甲酰胺、3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-N,1-dimethyl-1H-pyrazole-4- Formamide,
    3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-N-乙基-1-甲基-1H-吡唑-4-甲酰胺、3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-N-ethyl-1-methyl-1H-pyrazole- 4-formamide,
    N-环丙基-3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺、N-cyclopropyl-3-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl-1H-pyrazole -4-carboxamide,
    N-叔丁基-3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺、N-tert-butyl-3-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl-1H-pyrazole -4-carboxamide,
    N-环戊基-3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺、N-cyclopentyl-3-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl-1H-pyrazole -4-carboxamide,
    N-环己基-3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺、N-cyclohexyl-3-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl-1H-pyrazole- 4-formamide,
    N-环庚基-3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺、N-cycloheptyl-3-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl-1H-pyrazole -4-carboxamide,
    N-环辛基-3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺、N-cyclooctyl-3-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl-1H-pyrazole -4-carboxamide,
    (3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-1H-吡唑-4-基)(哌啶-1-基)甲酮、(3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl-1H-pyrazol-4-yl) (piperidin-1-yl)methanone,
    (3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-1H-吡唑-4-基)(八氢喹啉-1(2H)-基)甲酮、(3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl-1H-pyrazol-4-yl) (octahydroquinoline-1(2H)-yl)methanone,
    N-(4,4-二氟环己基)-3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺、N-(4,4-Difluorocyclohexyl)-3-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1- Methyl-1H-pyrazole-4-carboxamide,
    3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-N-(四氢-2H-吡喃)-1H-吡唑-4-甲酰胺、3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl-N-(tetrahydro-2H-pyran )-1H-pyrazole-4-carboxamide,
    N-环己基-3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-N,1-二甲基-1H-吡唑-4-甲酰胺、N-cyclohexyl-3-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-N,1-dimethyl-1H- Pyrazole-4-carboxamide,
    N-(金刚烷-1-基)-3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺、N-(adamantan-1-yl)-3-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl -1H-pyrazole-4-carboxamide,
    3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-N-苯基-1H-吡唑-4-甲酰胺、3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl-N-phenyl-1H-pyrazole- 4-formamide,
    3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-N-(邻甲苯基)-1H-吡唑-4-甲酰胺、3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl-N-(o-tolyl)-1H- Pyrazole-4-carboxamide,
    3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-N-(间甲苯基)-1H-吡唑-4-甲酰胺、3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl-N-(m-tolyl)-1H- Pyrazole-4-carboxamide,
    3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-N-(3-乙苯基)-1H-吡唑-4-甲酰胺、3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl-N-(3-ethylphenyl)- 1H-pyrazole-4-carboxamide,
    3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-N-(对甲苯基)-1H-吡唑-4-甲酰 胺、3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl-N-(p-tolyl)-1H- Pyrazole-4-carboxamide,
    3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-N-(2-甲氧苯基)-1-甲基-1H-吡唑-4-甲酰胺、3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-N-(2-methoxyphenyl)-1-methyl -1H-pyrazole-4-carboxamide,
    3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-N-(3-甲氧苯基)-1-甲基-1H-吡唑-4-甲酰胺、3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-N-(3-methoxyphenyl)-1-methyl -1H-pyrazole-4-carboxamide,
    3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-N-(4-甲氧苯基)-1-甲基-1H-吡唑-4-甲酰胺、3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-N-(4-methoxyphenyl)-1-methyl -1H-pyrazole-4-carboxamide,
    N-(3-氯苯基)-3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺、N-(3-chlorophenyl)-3-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl- 1H-pyrazole-4-carboxamide,
    N-(4-氯苯基)-3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺、N-(4-chlorophenyl)-3-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl- 1H-pyrazole-4-carboxamide,
    3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-N-(3-氟苯基)-1-甲基-1H-吡唑-4-甲酰胺、3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-N-(3-fluorophenyl)-1-methyl- 1H-pyrazole-4-carboxamide,
    3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-N-(4-氟苯基)-1-甲基-1H-吡唑-4-甲酰胺、3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-N-(4-fluorophenyl)-1-methyl- 1H-pyrazole-4-carboxamide,
    3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-N-(4-异丙苯基)-1-甲基-1H-吡唑-4-甲酰胺、3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-N-(4-isopropylphenyl)-1-methyl -1H-pyrazole-4-carboxamide,
    3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-N-(4-(三氟甲氧基)苯基)-1-甲基-1H-吡唑-4-甲酰胺、3-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-N-(4-(trifluoromethoxy)phenyl) -1-methyl-1H-pyrazole-4-carboxamide,
    N-(4-(二氟甲氧基)苯基)-3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺、N-(4-(Difluoromethoxy)phenyl)-3-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino) -1-methyl-1H-pyrazole-4-carboxamide,
    N-(4-(氰甲基)苯基)-3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺、N-(4-(Cyanomethyl)phenyl)-3-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1 -methyl-1H-pyrazole-4-carboxamide,
    N-环己基-3-((4-((6,7-二甲氧基喹啉-4-基)氧)苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺、N-cyclohexyl-3-((4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)amino)-1-methyl-1H-pyrazole-4-carboxamide ,
    N-环己基-3-((4-((6,7-二甲氧基喹啉-4-基)氧)-2-氟苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺、N-cyclohexyl-3-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-2-fluorophenyl)amino)-1-methyl-1H-pyrazole- 4-formamide,
    N-环己基-3-((4-((6,7-二甲氧基喹啉-4-基)氧)-2-甲苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺、N-cyclohexyl-3-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-2-methyl)amino)-1-methyl-1H-pyrazole-4 -formamide,
    3-((3-氯-4-((6,7-二甲氧基喹啉-4-基)氧)苯基)氨基)-N-环己基-1-甲基-1H-吡唑-4-甲酰胺、3-((3-Chloro-4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)amino)-N-cyclohexyl-1-methyl-1H-pyrazole- 4-formamide,
    N-环己基-3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-甲苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺、N-cyclohexyl-3-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-methyl)amino)-1-methyl-1H-pyrazole-4 -formamide,
    N-环己基-3-((4-((6,7-二甲氧基喹啉-4-基)氧)-3-甲氧苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺、N-cyclohexyl-3-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-methoxyphenyl)amino)-1-methyl-1H-pyrazole -4-carboxamide,
    N-环己基-3-((4-((7-乙氧基-6-甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-1H-吡唑-4-甲 酰胺、N-cyclohexyl-3-((4-((7-ethoxy-6-methoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-1-methyl-1H- Pyrazole-4-carboxamide,
    N-环己基-3-((3-氟-4-((6-甲氧基-7-丙氧基喹啉-4-基)氧)苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺、N-cyclohexyl-3-((3-fluoro-4-((6-methoxy-7-propoxyquinolin-4-yl)oxy)phenyl)amino)-1-methyl-1H- Pyrazole-4-carboxamide,
    N-环己基-3-((3-氟-4-((6-甲氧基-7-(2-甲氧乙氧基)喹啉-4-基)氧)苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺、N-cyclohexyl-3-((3-fluoro-4-((6-methoxy-7-(2-methoxyethoxy)quinolin-4-yl)oxy)phenyl)amino)-1 -methyl-1H-pyrazole-4-carboxamide,
    N-环己基-3-((3-氟-4-((6-甲氧基-7-(3-甲氧丙氧基)喹啉-4-基)氧)苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺、N-cyclohexyl-3-((3-fluoro-4-((6-methoxy-7-(3-methoxypropoxy)quinolin-4-yl)oxy)phenyl)amino)-1 -methyl-1H-pyrazole-4-carboxamide,
    N-环己基-3-((4-((7-(3-(二甲胺)丙氧基)-6-甲氧基喹啉-4-基)氧)-3-氟苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺、N-cyclohexyl-3-((4-((7-(3-(dimethylamino)propoxy)-6-methoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino )-1-methyl-1H-pyrazole-4-carboxamide,
    N-环己基-3-((3-氟-4-((6-甲氧基-7-(3-(哌啶-1-基)丙氧基)喹啉-4-基)氧)苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺、N-cyclohexyl-3-((3-fluoro-4-((6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinolin-4-yl)oxy)benzene Amino)-1-methyl-1H-pyrazole-4-carboxamide,
    N-环己基-3-((3-氟-4-((6-甲氧基-7-(3-(4-甲基哌嗪-1-基)丙氧基)喹啉-4-基)氧)苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺、N-cyclohexyl-3-((3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinolin-4-yl) Oxy)phenyl)amino)-1-methyl-1H-pyrazole-4-carboxamide,
    N-环己基-3-((3-氟-4-((6-甲氧基-7-(3-吗啉丙氧基)喹啉-4-基)氧)苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺、N-cyclohexyl-3-((3-fluoro-4-((6-methoxy-7-(3-morpholinepropoxy)quinolin-4-yl)oxy)phenyl)amino)-1 -methyl-1H-pyrazole-4-carboxamide,
    N-环庚基-3-((3-氟-4-((6-甲氧基-7-(3-吗啉丙氧基)喹啉-4-基)氧)苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺、N-cycloheptyl-3-((3-fluoro-4-((6-methoxy-7-(3-morpholinepropoxy)quinolin-4-yl)oxy)phenyl)amino)- 1-methyl-1H-pyrazole-4-carboxamide,
    N-环戊基-3-((3-氟-4-((6-甲氧基-7-(3-吗啉丙氧基)喹啉-4-基)氧)苯基)氨基)-1-甲基-1H-吡唑-4-甲酰胺、N-cyclopentyl-3-((3-fluoro-4-((6-methoxy-7-(3-morpholinepropoxy)quinolin-4-yl)oxy)phenyl)amino)- 1-methyl-1H-pyrazole-4-carboxamide,
    3-((3-氟-4-((6-甲氧基-7-(3-吗啉丙氧基)喹啉-4-基)氧)苯基)氨基)-N-(4-氟苯基)-1-甲基-1H-吡唑-4-甲酰胺。3-((3-fluoro-4-((6-methoxy-7-(3-morpholinepropoxy)quinolin-4-yl)oxy)phenyl)amino)-N-(4-fluoro Phenyl)-1-methyl-1H-pyrazole-4-carboxamide.
  20. 权利要求1-19任一项所述的3-氨基吡唑类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子或者其氘代物在制备AXL激酶抑制剂中的应用。Use of the 3-aminopyrazole compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a prodrug molecule thereof or a progeny thereof, for preparing an AXL kinase inhibitor .
  21. 权利要求1-19任一项所述的3-氨基吡唑类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子或者其氘代物在制备防治肿瘤的药物中的应用。Use of the 3-aminopyrazole compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof or a progeny thereof, for preparing a medicament for preventing and treating tumors .
  22. 根据权利要求21所述的应用，其特征在于，所述肿瘤为：血液性肿瘤、胃肠间质瘤、组织细胞性淋巴癌、非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌或鼻咽癌。The use according to claim 21, wherein the tumor is: hematological tumor, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma , pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma or nasopharyngeal cancer.
  23. 一种防治肿瘤的药物组合物，其特征在于，所述药物组合物包括有权利要求1-21任一项所述的3-氨基吡唑类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子或者其氘代物，及药学上可接受的载体。A pharmaceutical composition for controlling tumors, comprising the 3-aminopyrazole compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof or a stereoisomeric thereof A construct or a prodrug molecule thereof or a progeny thereof, and a pharmaceutically acceptable carrier.
PCT/CN2019/079733 2018-03-27 2019-03-26 3-aminopyrazole compound and application thereof WO2019184918A1 (en)

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