WO2020103817A1 - INHIBITEUR DE TGF-βR1 ET SON UTILISATION - Google Patents

INHIBITEUR DE TGF-βR1 ET SON UTILISATION

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Publication number
WO2020103817A1
WO2020103817A1 PCT/CN2019/119413 CN2019119413W WO2020103817A1 WO 2020103817 A1 WO2020103817 A1 WO 2020103817A1 CN 2019119413 W CN2019119413 W CN 2019119413W WO 2020103817 A1 WO2020103817 A1 WO 2020103817A1
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WIPO (PCT)
Prior art keywords
amino
alkyl
reaction
cycloalkyl
oxy
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PCT/CN2019/119413
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English (en)
Chinese (zh)
Inventor
王勇
赵立文
王亚洲
全旭
刘海璇
王小伟
张雁
李雪
曹陈
郭壮
吕坤志
王海
郑国闯
Original Assignee
南京圣和药业股份有限公司
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Publication of WO2020103817A1 publication Critical patent/WO2020103817A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero 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
    • A61K31/435—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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/695—Silicon compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • 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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention belongs to the field of medicinal chemistry, and specifically relates to a class of TGF- ⁇ R1 inhibitor compounds or pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs thereof, methods for their preparation and pharmaceutical combinations containing these compounds And the use of these compounds or compositions for the treatment and / or prevention of diseases related to TGF- ⁇ R1 expression, such as the treatment of diseases such as cancer and myelodysplastic syndrome.
  • TGF- ⁇ transforming growth factor ⁇
  • TGF- ⁇ 1 ⁇ 6 6 different subtypes (TGF- ⁇ 1 ⁇ 6) have been found, and their homology is different from each other. Only three subtypes are expressed, namely TGF- ⁇ 1, TGF- ⁇ 2 and TGF- ⁇ 3. It is a multi-functional growth factor superfamily with a wide range of biological activities involved in early embryonic development, cartilage and bone formation, synthesis of extracellular matrix, inflammation, interstitial fibrosis, regulation of immune and endocrine functions, tumor Formation and development.
  • TGF- ⁇ 1 is the most common and important subtype of TGF- ⁇ , the most abundantly expressed subtype in the liver, and the strongest known hepatic fibrosis inducing factor, which develops from chronic liver disease to end-stage liver disease Plays an important role in the process (Yamazaki, et al. Digestive Disease, 2011, 29: 284-288). Multiple studies have shown that TGF- ⁇ 1 and TGF- ⁇ receptors are usually highly expressed in liver disease organs, blood vessels and extracellular matrix.
  • TGF- ⁇ 1 activates TGF ⁇ -R1 (transforming growth factor ⁇ receptor 1, ALK5) in the signaling pathway, which in turn regulates the entire signaling pathway to achieve a series of regulation and fibrosis and The expression of target genes related to tumorigenesis.
  • TGF- ⁇ has a promoting effect on liver cancer mainly in promoting tumor cell metastasis, enhancing tumor cell immune escape and inducing angiogenesis (Ling, et al. Current Pharmaceutical Biotechnology, 2011, 12: 2190-2202) .
  • TGF- ⁇ R1 inhibitors such as Galunisertib and others have shown certain cardiotoxicity (such as bleeding, functional degradation, inflammatory injury, etc.) in animal models. Is due to the low target selectivity and specificity of this class of drugs. While inhibiting the TGF ⁇ -R1 kinase activation site, the drugs also have a strong inhibitory effect on other proteins with the same kinase region (such as p38 ⁇ ). In turn, there are many unintended off-target side effects. Therefore, there is still a need to develop more selective TGF ⁇ -R1 inhibitors in order to specifically regulate the TGF- ⁇ signaling pathway, and thus be used for the treatment of TGF- ⁇ -related diseases.
  • An object of the present invention is to provide a compound represented by the following general formula I having TGF- ⁇ R1 inhibitory activity or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof,
  • Another object of the invention is to provide a method for preparing a compound of the general formula I or its isomers, pharmaceutically acceptable salts, solvates, crystals, electron isosteres or prodrugs of the present invention.
  • Still another object of the present invention is to provide a combination of a compound of the general formula I of the present invention or its isomers, pharmaceutically acceptable salts, solvates, crystals, isosteres or prodrugs and a pharmaceutically acceptable carrier Substances, and compositions comprising compounds of the general formula I of the present invention or isomers thereof, pharmaceutically acceptable salts, solvates, crystals, electron isosteres or prodrugs and one or more drugs.
  • Another object of the present invention is to provide compounds of the general formula I of the present invention or isomers, pharmaceutically acceptable salts, solvates, crystals, isosteres or prodrugs thereof for the treatment and / or prevention of TGF- ⁇ R1 related
  • the method of the disease, and the compounds of the general formula I or isomers, pharmaceutically acceptable salts, solvates, crystals, electron isosteres or prodrugs of the present invention are prepared for the treatment and / or prevention of TGF- Application of drugs in diseases related to ⁇ R1.
  • the present invention provides compounds or prodrugs of the compound represented by general formula I or its isomers, pharmaceutically acceptable salts, solvates, crystals, electrons, etc.,
  • R 1 is selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aryl-cycloalkyl, heteroaryl-cycloalkyl, heterocycloalkyl-aryl, aryl-heteroaryl, Heteroaryl and heteroaryl, which is optionally substituted by one or more halogen, hydroxyl, amino, carboxyl, cyano, nitro, oxo, alkylsulfonyl, cycloalkylsulfonyl, alkylaminosulfonate Acyl, aminosulfonyl, cycloalkylaminosulfonyl, alkylsulfonylalkyl, alkyl, cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted Cycloalkylalkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyal
  • R 2 is selected from the group consisting of 5-8 membered heterocycloalkyl, aryl, 5-8 membered heteroaryl, arylpyraryl, arylheteroaryl, heteroarylpyraryl, 5-8 membered cycloalkane Group, 6-10 membered spiro ring group, 6-10 membered bridged ring group, 6-10 membered spiro heterocyclic group and 6-10 membered bridged heterocyclic group, which are optionally substituted by one or more alkyl groups, haloalkyl groups, Hydroxy, cycloalkyl, heterocycloalkyl, hydroxyalkyl, halogen, oxo, alkoxy, carboxy, cyano, amino, aminoalkyl, alkenyl, alkynyl, monoalkylamino, and dialkyl Amino substitution;
  • R 3 is selected from cycloalkyl, heterocycloalkyl, cycloalkylacyl, halocycloalkyl, hydroxycycloalkyl, haloalkoxycycloalkyl, alkoxycycloalkyl, aminocycloalkyl, monoamino Acylcycloalkyl, diaminocycloalkylacyl, aminoacylcycloalkyl, alkenyl, alkynyl, which are optionally substituted by one or more alkyl, haloalkyl, hydroxy, hydroxyalkyl, halogen, oxo groups , Alkoxy, carboxyl, cyano, amino, aminoalkyl, monoalkylamino and dialkylamino substitution;
  • R 4 and R 5 are independently selected from hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, mono Alkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, dialkylamino, cycloalkyl, alkenyl, alkynyl; m is selected from 1, 2, and 3;
  • R 1 is not aminoacylphenyl and unsubstituted cyanophenyl
  • R 1 is not optionally substituted pyridazinyl, 1-methyl-1H-pyrazolyl, Optionally substituted pyridine-2 (1H) -one-4-yl;
  • R 1 is pyridin-4-yl and 2-propanediolpyridin-4-yl
  • R 2 is tetrahydro-2H-pyranyl and tetrahydrofuran-3-yl
  • R 3 is cyclopropyl
  • R 1 is substituted by one or Multiple carboxyl groups, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, alkylacylamino, carboxyalkyl, hydroxyalkylamino, hydroxyhaloalkyl, haloalkoxy and cycloalkylhydroxyalkyl substitution ;
  • the compound of the present invention is a compound of general formula I or its isomer, pharmaceutically acceptable salt, solvate, crystal, electron isostere or prodrug, wherein: R 1 is selected from C 6-12 aryl, C 5-12 heteroaryl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, C 6-12 aryl and C 3-6 cycloalkyl, C 5- 12 Heteroaryl C 3-6 cycloalkyl, C 3-6 heterocycloalkyl C 6-12 aryl, C 6-12 aryl C 5-12 heteroaryl, C 5-12 heteroaryl C 5-12 heteroaryl, which is optionally substituted by one or more halogen, hydroxy, amino, carboxy, cyano, nitro, oxo, C 1-6 alkylsulfonyl, C 1-6 Alkylsulfamoyl, aminosulfonyl, C 3-6 cycloalkylaminosulfonyl, C 1-6
  • R 1 is selected from pyridyl, phenyl, isoquinolinyl, indazolyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl, isothiazolyl, imidazolyl, pyranyl, pyridine Furanyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, indole, benzopyranyl, benzopyrone, purinyl, cyclohexane, morpholinyl, piperidinyl , Pyrrolopyrazolyl, triazolopyrazinyl, which is optionally substituted by one or more halogen, hydroxyl, amino, carboxyl, cyano, nitro, oxo, C 1-6 alkylsulfonyl, C 1-6 alkylaminosulfonyl, aminosulfonyl, C 3-6 cycloalkyl
  • the compound of the present invention is a compound of general formula I or its isomer, pharmaceutically acceptable salt, solvate, crystal, electron isostere or prodrug, wherein:
  • R 2 is selected from 5-8 membered heterocycloalkyl, C 6-12 aryl, 5-8 membered heteroaryl, C 6-12 aryl C 6-12 aryl, C 6-12 aryl C 5-12 heteroaryl, C 5-12 heteroaryl and C 6-12 aryl, 5-8 member cycloalkyl, 6-10 member spiro ring, 6-10 member bridge ring, 6-10 member Spiroheterocyclyl and 6-10 membered bridge heterocyclyl, which are optionally substituted by one or more C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy, 3-6 membered cycloalkyl, 3- 6-membered heterocycloalkyl, hydroxy C 1-6 alkyl, halogen, oxo group, C 1-6 alkoxy, carboxy, cyano, amino C 1-6 alkyl, amino, C 2-6 alkene Group, C 2-6 alkynyl, mono C 1-6 alkylamino and bis C 1-6 al
  • R 2 is selected from tetrahydropyranyl, tetrahydrofuranyl, tetrahydropyrrolyl, cyclohexyl, morpholinyl, halocyclobutyl, halocyclohexyl, piperidinyl, phenyl, indenyl, naphthalene , Pyranyl, pyranyl, pyridazinyl, pyrimidinyl, pyrazinyl, furyl, thienyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, cyclopentyl, cyclohexyl , Cycloheptyl, 6-10 membered spirocyclic group, 6-10 membered bridged ring group, 6-10 membered spiroheterocyclic group and 6-10 membered bridged heterocyclic group, which are optionally Group, methoxy, morpholinyl
  • the compound of the present invention is a compound of general formula I or its isomer, pharmaceutically acceptable salt, solvate, crystal, electron isostere or prodrug, wherein:
  • R 3 is selected from C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, C 3-6 cycloalkyl acyl, halogenated C 3-6 cycloalkyl, hydroxy C 3-6 cycloalkyl, halogen Substituted C 1-6 alkoxy C 3-6 cycloalkyl, C 1-6 alkoxy C 3-6 cycloalkyl, amino C 3-6 cycloalkyl, mono C 1-6 alkylamino acyl 3-6 cycloalkyl, bis C 1-6 alkylamino C 3-6 cycloalkyl acyl, amino acyl C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, any Selected one or more C 3-6 alkyl, halogenated C 1-6 alkyl, hydroxy, hydroxy C 1-6 alkyl, halogen, oxo group, C 1-6 alkoxy, carboxyl, cyano Group, amino, amino
  • R 3 is selected from cyclopropyl, cyclopropylacyl, cyclobutyl, 2-fluoroethyl, which is optionally substituted by one or more hydroxyl, cyano, methoxy, methyl, ethyl, Propyl, butyl, isopropyl, isobutyl, tert-butyl, carboxyl, fluorine, chlorine, bromine, trifluoromethyl, trifluoroethyl, aminomethyl, aminoethyl, aminopropyl, methyl Amino, ethylamino, propylamino, isopropylamino, ethoxy, propoxy, isopropoxy, oxo, formyl, acetyl, propionyl, isopropyl, vinyl, propylene Substituent, ethynyl and propynyl substitution;
  • the compound of the present invention is a compound of general formula I or its isomer, pharmaceutically acceptable salt, solvate, crystal, electron isostere or prodrug, wherein:
  • R 4 and R 5 are independently selected from hydrogen, halogen, hydroxy, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, hydroxy C 1-6 alkoxy, nitro, carboxy, cyano, amino, mono C 1-6 alkylamino, C 1-6 alkylacylamino, C 1-6 alkyl Acyl, aminoacyl, C 1-6 alkylamino acyl, bis C 1-6 alkylamino and C 3-10 cycloalkyl; preferably, R 4 and R 5 are independently selected from hydrogen, fluorine, chlorine , Bromine, iodine, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, 2-hydroxypropyl, methoxy Group, ethoxy, propoxy, iso
  • the compound of general formula I of the present invention is a compound of general formula Ia or its isomer, pharmaceutically acceptable salt, solvate, crystal, electron isostere or prodrug,
  • R 2 , R 3 , R 4 , R 5 and m are as defined in claims 1 to 5;
  • R 6 is selected from hydrogen, halogen, cyano, amino, hydroxy, alkoxy, heterocyclic oxy, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, alkylsulfonyl, alkylaminosulfonyl , Aminosulfonyl, cycloalkylaminosulfonyl, alkylsulfonylalkyl, cycloalkylsulfonyl, aryl and heteroaryl, wherein the halogen, cyano, amino, hydroxyl, alkoxy, hetero Epoxy, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, alkylsulfonyl, alkylaminosulfonyl, aminosulfonyl, cycloalkylaminosulfonyl, alkylsulfonylalkyl, aromatic
  • the group and heteroaryl are
  • n are selected from 1, 2, 3, 4, and 5.
  • the compound of general formula Ia or its isomer, pharmaceutically acceptable salt, solvate, crystal, electron isostere or prodrug according to the present invention wherein R 6 is selected from hydrogen , Fluorine, chlorine, bromine, iodine, cyano, azetyl, oxetane, piperazinyl, trifluoromethyl, difluoromethyl, propan-2-ol-2-yl, Among them, the fluorine, chlorine, bromine, iodine, cyano, azetyl, oxetane, piperazinyl, trifluoromethyl, difluoromethyl, propan-2-ol-2-yl , Optionally one or more methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, carboxyl, hydroxyl, cyano, hydroxymethyl, hydroxyethyl, ox
  • the compound of general formula I of the present invention is the following compound of general formula Ib or its isomer, pharmaceutically acceptable salt, solvate, crystal, electron isostere or prodrug,
  • R 2 , R 3 , R 4 , R 5 and m are as defined in the general formula I;
  • R 7 is selected from hydrogen, carboxyl, heterocycloalkyl, hydroxyheterocycloalkyl, hydroxyalkyl, alkylaminoacyl, hydroxyalkylacyl, carboxyalkylacyl, carboxyalkyl, monoalkylamino, dialkyl Amino, aminoalkyl, alkylheterocycloalkyl, heterocycloalkylalkyl, alkylsulfonyl, cycloalkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, cycloalkylaminosulfonyl, cycloalkane Alkyl, cycloalkyl, haloalkyl, oxo, alkoxy, haloalkoxy, alkylpyridyl, 1H-1,2,4-triazolyl, cycloalkylacyl and aminoacylcycloalkane Group, wherein the carboxyl, heterocycloalky
  • p is selected from 1, 2, 3 and 4.
  • the compound of general formula Ib or its isomer, pharmaceutically acceptable salt, solvate, crystal, electron isostere or prodrug according to the present invention wherein R 7 is selected from hydrogen , Carboxyl, C 3-6 heterocycloalkyl, hydroxy C 3-6 heterocycloalkyl, hydroxy C 1-6 alkyl, C 1-6 alkylaminoacyl, hydroxy C 1-6 alkylacyl, carboxy C 1-6 alkyl acyl, carboxy C 1-6 alkyl, mono C 1-6 alkylamino, bis C 1-6 alkylamino, amino C 1-6 alkyl, C 1-6 alkyl C 3- 6 heterocycloalkyl, C 3-6 heterocycloalkyl C 1-6 alkyl, C 1-6 alkylsulfonyl, C 3-6 cycloalkylsulfonyl, aminosulfonyl, C 1-6 alkyl Aminosulfonyl, C 3-6 cycloalkyl
  • p is selected from 1, 2, 3 and 4.
  • the compound of general formula I of the present invention is the following compound of general formula Ic or its isomer, pharmaceutically acceptable salt, solvate, crystal, electron isostere or prodrug,
  • R 2 , R 3 , R 4 , R 5 and m are as defined in the general formula I;
  • R 8 is selected from hydrogen, carboxyl, heterocycloalkyl, hydroxyheterocycloalkyl, hydroxyalkyl, alkylaminoacyl, hydroxyalkylacyl, carboxyalkylacyl, carboxyalkyl, monoalkylamino, dialkyl Amino, aminoalkyl, alkylheterocycloalkyl, heterocycloalkylalkyl, alkylsulfonyl, cycloalkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, cycloalkylaminosulfonyl, cycloalkane Alkyl, cycloalkyl, haloalkyl, oxo, alkoxy, haloalkoxy, alkylpyridyl, 1H-1,2,4-triazolyl, cycloalkylacyl and aminoacylcycloalkane Group, wherein the carboxyl, heterocycloalky
  • q is selected from 1, 2, and 3.
  • the compound of general formula Ic according to the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal, electron isostere or prodrug, wherein R 8 is selected from hydrogen , Carboxyl, C 3-6 heterocycloalkyl, hydroxy C 3-6 heterocycloalkyl, hydroxy C 1-6 alkyl, C 1-6 alkylaminoacyl, hydroxy C 1-6 alkylacyl, carboxy C 1-6 alkyl acyl, carboxy C 1-6 alkyl, mono C 1-6 alkylamino, bis C 1-6 alkylamino, amino C 1-6 alkyl, C 1-6 alkyl C 3- 6 heterocycloalkyl, C 3-6 heterocycloalkyl C 1-6 alkyl, C 1-6 alkylsulfonyl, C 3-6 cycloalkylsulfonyl, aminosulfonyl, C 1-6 alkyl Aminosulfonyl, C 3-6 cycloalkyl
  • q is selected from 1 and 2.
  • the compound of the present invention is a compound of general formula I or its isomer, pharmaceutically acceptable salt, solvate, crystal, electron isostere or prodrug, wherein:
  • R 1 is selected from phenyl, pyridyl, pyrazolyl and piperidinyl, which is optionally substituted with one or more of the following groups: carboxyl, methyl, trifluoromethyl, propan-2-ol-2- Group, hydroxyethyl, cyclopropylsulfonyl, aminosulfonyl, methanesulfonyl, methylamino,
  • R 2 is selected from phenyl, halophenyl, cyanophenyl, methoxyphenyl, trifluoromethylphenyl, halocyclobutyl,
  • R 3 is selected from cyclopropyl, fluoroethyl, and cyclopropyl acyl; R 4 and R 5 are selected from hydrogen; m is selected from 1.
  • the present invention provides compounds of general formula I or isomers, pharmaceutically acceptable salts, solvates, crystals, or prodrugs thereof, wherein general formula I has the structure of general formula Id,
  • Ring A and ring B are each independently selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aryl-cycloalkyl, heteroaryl-cycloalkyl, heterocycloalkyl-aryl, aryl Arylheteroaryl and heteroarylheteroaryl; or
  • ring A is aryl-cycloalkyl, heteroaryl-cycloalkyl, heterocycloalkyl-aryl, aryl-heteroaryl or heteroaryl-heteroaryl, ring B may not be present;
  • R c and R d are each independently selected from hydrogen, alkyl, halogen, hydroxy, amino, carboxy, cyano, nitro, oxo, hydroxyalkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy Alkoxy, alkylacyl, alkylsulfonyl, cycloalkylsulfonyl, alkylaminosulfonyl, aminosulfonyl, cycloalkylaminosulfonyl, alkylsulfonylalkyl, cycloalkyl, optionally substituted Cycloalkylcarbonyl, heterocycloalkyl, heterocycloalkylalkyl, cycloalkylalkyl, hydroxyalkylcarbonyl, hydroxycycloalkylalkyl, hydroxyhaloalkyl, aminoalkyl, carboxyalkyl, cyano Alkyl, nitroalkyl, cycloalkylhydroxyal
  • R 2 , R 3 , R 4 , R 5 and m are as defined in the general formula I above.
  • the compound of general formula Id according to the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug wherein ring A and ring B are each independently selected from C 6-12 aryl, C 5-12 heteroaryl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 6-12 aryl and C 3-8 cycloalkyl, C 5-12 Heteroaryl C 3-8 cycloalkyl, C 3-8 heterocycloalkyl C 6-12 aryl, C 6-12 aryl C 5-12 heteroaryl, C 5-12 heteroaryl And C 5-12 heteroaryl; or when ring A is C 6-12 aryl and C 3-8 cycloalkyl, C 5-12 heteroaryl and C 3-8 cycloalkyl, C 3-8 hetero Cycloalkyl C 6-12 aryl, C 6-12 aryl C 5-12 heteroaryl or C 5-12 heteroaryl C 5-12 heteroaryl, ring B may not be present;
  • the compound of general formula Id or its isomer, pharmaceutically acceptable salt, solvate, crystal, or prodrug according to the present invention wherein ring A and ring B are each independently selected from Phenyl, pyridyl, pyrazolyl, benzopyrazolyl, benzopyridyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyranyl, pyranyl, pyridyl Azinyl, pyrimidinyl, pyrazinyl, quinolinyl, indole, benzopyranyl, benzopyrone, purinyl, cyclohexane, morpholinyl, piperidinyl, pyrrolopyrazole Group, triazolopyrazinyl; or when ring A is benzopyrazolyl, benzopyridyl, quinolinyl, indole, benzo
  • the present invention provides compounds of general formula I or isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs thereof, wherein general formula I has the structure of general formula Ie below,
  • R a and R b are each independently selected from hydrogen, alkyl, halogen, hydroxy, hydroxyalkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino , Monoalkylamino, dialkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, aminoalkyl, optionally substituted heterocycloalkyl, f is selected from 1, 2, 3 and 4; and
  • R 2 , R 3 , R 4 , R 5 and m are as defined in the general formula I above.
  • the compound of general formula Ie or isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs thereof according to the present invention wherein R a and R b are each independently selected from hydrogen , C 1-6 alkyl, halogen, hydroxy, hydroxy C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1 -6 alkoxy, nitro, carboxy, cyano, amino, mono C 1-6 alkylamino, bis C 1-6 alkylamino, C 1-6 alkyl acylamino, C 1-6 alkyl acyl , an amino group, a C 1-6 alkylamino group, an amino C 1-6 alkyl, optionally substituted 3-6 membered heterocycloalkyl, f is selected from 1, 2 and 3; further, R a and R b are each independently selected from hydrogen, methyl, ethyl, propyl,
  • the present invention provides the following specific compounds or pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs thereof:
  • the present invention provides a method for preparing a compound of the present invention or a pharmaceutically acceptable salt, isomer, solvate, crystal, or prodrug thereof, including:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R7, R 8 , m, n, and p have the meanings in the general formula I;
  • A is halogen, preferably bromine;
  • B is halogen (Preferably chlorine) or amino;
  • C is amino or halogen (preferably bromine).
  • the pharmaceutical composition provided by the present invention comprises the compound of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal, electron isostere or prodrug.
  • the pharmaceutical composition provided by the present invention comprises a compound of the present invention or an isomer thereof, a pharmaceutically acceptable salt, a solvate, a crystal, an isostere or prodrug of an electron, and further comprises One or more agents in the group consisting of: TGF- ⁇ R1 inhibitor, tyrosine protease inhibitor, EGFR inhibitor, VEGFR inhibitor, Bcr-Abl inhibitor, c-kit inhibitor, c-Met inhibitor Agent, Raf inhibitor, MEK inhibitor, histone deacetylase inhibitor, IDH inhibitor, VEGF antibody, EGF antibody, HIV protein kinase inhibitor, HMG-CoA reductase inhibitor, etc.
  • TGF- ⁇ R1 inhibitor tyrosine protease inhibitor
  • EGFR inhibitor tyrosine protease inhibitor
  • VEGFR inhibitor VEGFR inhibitor
  • Bcr-Abl inhibitor c-kit inhibitor
  • c-Met inhibitor Agent Raf inhibitor
  • MEK inhibitor histone deacetylase inhibitor
  • the present invention provides compounds of the present invention or isomers, pharmaceutically acceptable salts, solvates, crystals, isosteres or prodrugs thereof, and compounds containing the present invention or isomers thereof, Pharmaceutical compositions of pharmaceutically acceptable salts, solvates, crystals, isosteres, or prodrugs, and the use of the compounds or pharmaceutical compositions for the treatment and / or prevention of TGF- ⁇ R1-related diseases.
  • the compound of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal, electron isostere or prodrug can be mixed with a pharmaceutically acceptable carrier, diluent or excipient to prepare a pharmaceutical preparation , Suitable for oral or parenteral administration.
  • Administration methods include, but are not limited to intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, and oral routes.
  • the formulation can be administered by any route, for example, by infusion or bolus injection, by the route of absorption through the epithelium or skin mucosa (eg, oral mucosa or rectum, etc.). Administration can be systemic or local.
  • preparations for oral administration include solid or liquid dosage forms, and specifically include tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions, and the like.
  • the formulations can be prepared by methods known in the art, and include carriers, diluents or excipients conventionally used in the field of pharmaceutical formulations.
  • the present invention provides compounds or their isomers, pharmaceutically acceptable salts, solvates, crystals, electron isosteres or prodrugs represented by the general formula I, Ia, Ib or Ic of the present invention, or comprising
  • the "hydrogen”, "carbon” and “oxygen” in the compounds of the present invention include all isotopes thereof.
  • Isotopes are understood to include those atoms having the same atomic number but different mass numbers.
  • hydrogen isotopes include tritium and deuterium
  • carbon isotopes include 13 C and 14 C
  • oxygen isotopes include 16 O and 18 O.
  • halogen in the present invention refers to fluorine, chlorine, bromine, and iodine.
  • halogenated in the present invention means substituted with fluorine, chlorine, bromine or iodine.
  • alkyl in the present invention refers to a linear or branched saturated aliphatic hydrocarbon group, preferably a linear or branched group containing 1 to 6 carbon atoms, and more preferably a linear or branched group containing 1 to 3 carbon atoms
  • chain groups include methyl, ethyl, n-propyl, isopropyl and the like.
  • the alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be at any available point of attachment.
  • haloalkyl group refers to an alkyl group substituted with at least one halogen.
  • hydroxyalkyl group refers to an alkyl group substituted with at least one hydroxy group.
  • alkoxy in the present invention refers to -O-alkyl.
  • alkoxy groups include: methoxy, ethoxy, propoxy, n-propoxy, isopropoxy, and the like.
  • the alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent may be at any available point of attachment.
  • cycloalkyl in the present invention refers to a cyclic saturated hydrocarbon group such as cyclopropyl and cyclobutyl.
  • heterocycloalkyl group refers to a 3 to 12-membered non-aromatic ring having 1 to 4 ring heteroatoms (where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon)
  • the radical of the system (“3-12 membered heterocycloalkyl”).
  • the point of attachment can be a carbon or nitrogen atom, as long as valency permits.
  • Heterocycloalkyl groups can be monocyclic ("monocyclic heterocycloalkyl") or fused, bridged or spiro ring systems (eg bicyclic systems ("bicyclic heterocycloalkyl” )) And may be saturated or may be partially unsaturated.
  • Suitable saturated and partially saturated heterocyclic groups include, but are not limited to, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, piperazine Radical, morpholinyl, isoxazolinyl, Wait.
  • aryl group refers to an aromatic system which may contain a single ring or a fused polycyclic ring, preferably a single ring or a fused bicyclic aromatic system, which contains 6 to 18 carbon atoms, and preferably contains about 6 to about 12 carbon atoms.
  • Suitable aryl groups include but are not limited to phenyl, naphthyl, anthracenyl, tetrahydronaphthyl, fluorenyl, indanyl.
  • the aryl group can be optionally substituted or unsubstituted, and when substituted, the substituent can be at any available point of attachment.
  • heteroaryl in itself or in any combination of groups, such as “heteroarylamino" refers to an aryl group having at least one carbon atom replaced by a heteroatom, consisting of 5-20 atoms ( 5-20 membered heteroaryl), further preferably composed of 5-12 atoms (5-12 membered heteroaryl), the heteroatom may be O, S, N, including but not limited to imidazolyl, benzo Imidazolyl, imidazopyridyl, quinazolinone, pyrrolyl, imidazolone, furanyl, thienyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazole Group, triazolyl group, pyrimidinyl group, pyridyl group, pyrazinyl group, pyridazinyl group, pyrimidopyrazolyl group, pyrimi
  • the aryl-cycloalkyl group of the present invention refers to one or more ring systems formed by fusing an aryl group and a cycloalkyl group with a hydrogen atom removed, including but not limited to Wait.
  • the heterocycloalkyl aryl group of the present invention refers to one or more ring systems fused by a heterocyclic alkyl group and a group remaining after removing a hydrogen atom from the aryl form, including but not limited to Wait.
  • the heteroaryl-aryl group of the present invention refers to one or more ring systems formed by the fusion of a heteroaryl group and an aryl group with one hydrogen atom removed from the form, including but not limited to Wait.
  • the heteroaryl-heteroaryl group of the present invention refers to one or more ring systems formed by fusing a heteroaryl group and a heteroaryl group with one hydrogen atom removed from the form, including but not limited to purine, Wait.
  • Optionally substituted in the present invention means that the group can be substituted with one or more of the following groups: alkyl, halogen, hydroxyl, amino, carboxyl, cyano, nitro, oxo, Acyloxy, hydroxyalkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, alkylacyl, alkylsulfonyl, cycloalkylsulfonyl, alkylaminosulfonyl, aminosulfonyl, cyclic Alkylaminosulfonyl, alkylsulfonylalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, cycloalkylalkyl, hydroxyalkylcarbonyl, hydroxycycloalkylalkyl, hydroxyhaloalkyl , Aminoalkyl, carboxyalkyl, cyanoalkyl, nitroalky
  • the "isomers" of the present invention are compounds that have the same molecular formula but differ in nature or in the bond sequence of their atoms or in the spatial arrangement of their atoms.
  • Stereoisomers are isomers whose atoms are arranged differently in space.
  • Stereoisomers that are not mirror images of each other are diastereomers and stereoisomers that are non-overlapping mirror images of each other are enantiomers.
  • a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
  • the enantiomer is characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the method of rotating the plane of polarized light by the molecule and designated as right-handed or left-handed ( That is, as (+) or (-)-isomers, respectively).
  • Chiral compounds can exist as a single enantiomer or a mixture thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture".
  • the “pharmaceutically acceptable salts” of the present invention refer to the salts of the compounds of the present invention. Such salts are safe and effective when used in mammals, and have proper biological activity.
  • the "solvate” of the present invention refers to a complex formed by a combination of a solute (such as an active compound, a salt of an active compound) and a solvent (such as water) in a conventional sense.
  • a solute such as an active compound, a salt of an active compound
  • a solvent such as water
  • the solvent refers to a solvent known or easily determined by those skilled in the art. If it is water, the solvate is usually referred to as a hydrate, for example, hemihydrate, monohydrate, dihydrate, trihydrate, or their substitution amounts.
  • bioelectronic isostere (or "electronic isostere” for short) of the present invention is used to define where one or more atoms (or groups of atoms) have been replaced by those atoms which have similar space and / or electronic characteristics
  • electroactive isostere or "electronic isostere” for short
  • Crystal in the present invention refers to a solid whose internal structure is formed by repeatedly repeating atoms (or groups thereof) in three dimensions, and is different from an amorphous solid that does not have such a regular internal structure.
  • Prodrug refers to a compound that is converted into Formulas I, Ia, Ib, Ic, Id, and Ie by reacting with enzymes, stomach acid, etc. under physiological conditions in an organism.
  • composition refers to containing any one of the compounds described herein, including the corresponding isomers, prodrugs, solvates, pharmaceutically acceptable salts or chemically protected forms thereof, and one or A mixture of multiple pharmaceutically acceptable carriers.
  • excipient refers to an inert substance added to the pharmaceutical composition to further facilitate administration of the compound.
  • Excipients may include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oil, polyethylene glycol.
  • the "pharmaceutically acceptable carrier” of the present invention refers to a carrier that does not cause significant irritation to the organism and does not interfere with the biological activity and properties of the administered compound, and includes all solvents, diluents or other excipients, dispersants, Surfactant isotonicity agent, thickener or emulsifier, preservative, solid binder, lubricant, etc. Unless any conventional carrier medium is incompatible with the compounds of the present invention.
  • Some examples of pharmaceutically acceptable carriers include, but are not limited to sugars, such as lactose; starches, such as corn starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose; malt, gelatin, and the like.
  • 2,2'-Bipyridine (3.07g, 19.66mmol) and copper acetate (3.92g, 19.66mmol) were placed in a reaction flask, 1,2-dichloroethane (50mL) was added, and the reaction was refluxed for 1h. After cooling to room temperature, 2-chloro-4-((3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine (5.00 g, 17.87 mmol), Sodium carbonate (3.79g, 35.74mmol) and cyclopropylboronic acid (3.07g, 35.74mmol).
  • Step 7 4-((4-((1-Cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) Synthesis of amino) picolinic acid
  • Methyl picolinate (200mg, 459.26umol) was added to a mixed solvent of tetrahydrofuran (10mL) and methanol (2mL), and then 4mL of an aqueous solution containing lithium hydroxide (55mg, 2.30mmol) was added thereto, and the reaction was performed at room temperature for 2h.
  • 2,2'-Bipyridine (0.76g, 4.86mmol) and copper acetate (0.97g, 4.86mmol) were placed in a reaction flask, 1,2-dichloroethane (20mL) was added, and heated to 80 ° C for 1h. Cool to room temperature, add 2-chloro-4-((3-phenyl-1H-pyrazol-4-yl) oxy) pyridine (1.21g, 4.42mmol), sodium carbonate (0.94g, 8.83mmol) and cyclic Propylboronic acid (1.18 g, 8.83 mmol). Under oxygen conditions, the reaction was carried out at 80 ° C for 4h. After the reaction was completed, it was concentrated under reduced pressure.
  • Step 2 4-((4-((1-Cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) Synthesis of amino) -N-picoline
  • the preparation method is the same as the compound in Step 3 of Example 2, except that 4-amino-N-picoline amide is used instead of 2-morpholinopyridine-4-amine to prepare the title compound.
  • the preparation method is the same as the compound of steps 1 to 6 in Example 1, except that 2-bromo-4-hydroxybenzonitrile is used instead of 2-chloro-4-hydroxypyridine and 2- (4-aminopyridin-2-yl) propane- Instead of methyl 4-aminopyridine-2-carboxylate, 2-alcohol produced the title compound.
  • Step 5 2- (4-((4-((3-methyl-1- (tetrahydro-2H-pyran-4-yl) -1H-indazol-6-yl) oxy) pyridine-2- Yl) amino) pyridin-2-yl) propan-2-ol
  • Example 7 1- (4-((4-((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine- 2-yl) amino) -1H-pyrazol-1-yl) -2-methylpropan-2-ol
  • Step 3 1- (4-((4-((1-Cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine-2 -Yl) amino) -1H-pyrazol-1-yl) -2-methylpropan-2-ol
  • the preparation method is the same as Step 3 in Example 2, except that 1- (4-amino-1H-pyrazol-1-yl) -2-methylpropan-2-ol is used instead of 2-morpholinopyridine-4- Amine to prepare the title compound.
  • Example 8 1- (4-((4-((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine- 2-yl) amino) -3,5-dimethyl-1H-pyrazol-1-yl) -2-methylpropan-2-ol
  • the preparation method is the same as the preparation method of the compounds of steps 1 to 3 in Example 7, except that 3,5-dimethyl-4-nitro-1H-pyrazole is used instead of 4-nitro-1H-pyrazole to obtain the title Compound.
  • the preparation method is the same as the preparation method of Example 3, except that 2-bromo-1- (3-methoxyphenyl) ethyl-1-one is used instead of 2-bromo-1-phenylethyl-1-one, The title compound was prepared.
  • Example 10 1- (4-((4-((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine- 2-yl) amino) piperidin-1-yl) -2-hydroxy-2-methylpropan-1-one
  • Step 1 4-((4-((1-Cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) Synthesis of tert-butylamino) piperidine-1-carboxylate
  • reaction solution was cooled to room temperature, water and ethyl acetate were added, extracted, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain the title compound.
  • Step 3 1- (4-((4-((1-Cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine-2 -Yl) amino) piperidin-1-yl) -2-hydroxy-2-methylpropan-1-one
  • Step 1 2- (4-((4-((1-Cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine-2 -Yl) amino) piperidin-1-yl) -2-methylpropionic acid ethyl ester
  • Step 2 2- (4-((4-((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine-2 -Yl) amino) piperidin-1-yl) -2-methylpropionic acid
  • reaction solution is cooled to room temperature, 6M hydrochloric acid solution is added dropwise to adjust the pH to 7, concentrated under reduced pressure to remove tetrahydrofuran, ethyl acetate is added, extracted, the aqueous phase is taken, after concentrated under reduced pressure, methanol is added, and the filtrate is filtered , Concentrate under reduced pressure, and purify the title compound by column chromatography.
  • the preparation method is the same as the preparation method of the compounds 2 to 5 in Example 1, except that 3-nitro-4- (trifluoromethyl) phenol is used instead of 2-chloro-4-hydroxypyridine to prepare the title compound.
  • Step 3 2- (4-((5-((1-Cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) -2- Synthesis of (trifluoromethyl) phenyl) amino) pyridin-2-yl) propan-2-ol
  • Step 4 4-((4-((1-Cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) Synthesis of amino) -2- (3-hydroxyazetidin-1-yl) benzonitrile
  • Step 5 2- (4-((4-((1-Cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine-2 -Yl) amino) pyridin-2-yl) -2-methylpropionic acid
  • the preparation method is the same as the preparation method of the compounds of steps 6 to 7 in Example 1, except that 2- (4-aminopyridin-2-yl) -2-methylpropionic acid methyl ester hydrochloride is used instead of 4-aminopyridine- 2-Methyl formate to prepare the title compound.
  • the preparation method is the same as the preparation method of Example 3, except that 2-bromo-1- (3-fluorophenyl) ethan-1-one is used instead of 2-bromo-1-phenylethan-1-one.
  • the title compound ESI-MS m / z: 446.3 [M + H] + .
  • the preparation method is the same as the preparation method of Example 3, except that 2-bromo-1- (2-fluorophenyl) ethan-1-one is used instead of 2-bromo-1-phenylethan-1-one.
  • the title compound ESI-MS m / z: 446.2 [M + H] + .
  • Tetrahydropyrone (5.0 g, 26.87 mmol) and p-toluenesulfonyl hydrazide (2.7 g, 26.87 mmol) were added to 50 mL of methanol, and stirred at room temperature overnight. After the reaction was completed, the methanol was concentrated under reduced pressure to obtain the title compound.
  • 2,2'-Bipyridine (1.94g, 12.39mmol) and copper acetate (2.25g, 12.39mmol) were placed in the reaction flask, 20mL 1,2-dichloroethane was added, and the reaction was refluxed for 1h. Cool to room temperature, add 5-bromo-3- (tetrahydro-2H-pyran-4-yl) -1H-indazole (2.32g, 8.26mmol), sodium carbonate (1.75g, 16.51mmol) and cyclopropyl Boric acid (1.42g, 16.51mmol). Under oxygen conditions, the reaction was carried out at 80 ° C for 4h.
  • Step 8 2- (4-((4-((1-Cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-indazol-5-yl) oxy) pyridine-2 -Yl) amino) pyridin-2-yl) propan-2-ol
  • the preparation method is the same as the preparation method of compounds 2 to 5 in Step 6 of Example 6, except that 5-bromo-1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-indazole is used Instead of 6-bromo-3-methyl-1- (tetrahydro-2H-pyran-4-yl) -1H-indazole, the title compound was prepared.
  • Step 3 4-((1-Cyclopropyl-3- (4,4-difluorocyclohexyl) -1H-pyrazol-4-yl) oxy) -N- (2-morpholinopyridine-4- Of pyridin-2-amine
  • the preparation method is the same as the preparation method of the compounds of steps 1 to 3 in Example 20 to obtain the title compound.
  • Step 2 4-((4-((1-Cyclopropyl-3- (4,4-difluorocyclohexyl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino)- Synthesis of 2- (3-hydroxy-3-methylazetidin-1-yl) benzonitrile
  • the preparation method is the same as the preparation method of Example 14, except that 2-chloro-4-((1-cyclopropyl-3 (4,4-difluorocyclohexyl) -1H-pyrazol-4-yl) is used Oxy) pyridine instead of 2-chloro-4-((3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine and 3-methyl nitrogen heterocycle Butane-3-ol instead of azetidine-3-ol hydrochloride prepared the title compound. The title compound was prepared. ESI-MS m / z: 521.2 [M + H] + .
  • the preparation method is the same as that of Example 7, except that 2-chloro-4-((1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl) oxy) pyridine is used instead of 2- Chloro-4-((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine.
  • the preparation method is the same as that in Example 19, except that 2-bromo-1- (2,4-difluorobenzene) ethyl-1-one is used instead of 2-bromo-1-phenylethan-1-one.
  • the title compound ESI-MS m / z: 491.2 [M + H] + .
  • Example 28 4-((1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl) oxy) -N- (2-((2S, 6R) -2,6-dimethyl Morpholinyl) pyridin-4-yl) pyridin-2-amine
  • Step 3 4-((1-Cyclopropyl-3-phenyl-1H-pyrazol-4-yl) oxy) -N- (2-((2S, 6R) -2,6-dimethyl Synthesis of pyrolinyl) pyridin-4-yl) pyridin-2-amine
  • the preparation method is the same as the preparation method of Example 28, except that 2-chloro-4-((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazole- 4-yl) oxy) pyridine instead of 2-chloro-4-((1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl) oxy) pyridine to prepare the title compound.
  • the preparation method is the same as that in Example 19, except that 2-bromo-1- (3-chlorophenyl) ethan-1-one is used instead of 2-bromo-1-phenylethan-1-one to prepare the title compound.
  • Step 3 4-((1-Cyclopropyl-3-phenyl-1H-pyrazol-4-yl) oxy) -N- (1- (tetrahydro-2H-pyran-4-yl) -1H -Pyrazol-4-yl) pyridine-2-amine synthesis
  • the preparation method is the same as the preparation method of Example 3, except that 1-((3-methyloxetan-3-yl) methyl) -1H-pyrazole-4-amine is used instead of 2- (4 -Aminopyridin-2-yl) propan-2-ol to prepare the title compound.
  • the preparation method is the same as the preparation method of the compounds of steps 1 to 3 in Example 3, except that 3- (2-bromoacetyl) benzonitrile is used instead of 2-bromo-1-phenylethan-1-one to obtain the title compound .
  • Step 5 3- (1-cyclopropyl-4-((2-((1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) amino) pyridin-4-yl) oxy)- 1H-pyrazol-3-yl) benzonitrile
  • the preparation method was the same as the preparation method in Step 1 of Example 14, except that 1- (methylsulfonyl) piperazine was used instead of azetidine-3-ol hydrochloride to obtain the title compound.
  • Step 2 4-((4-((1-Cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) Synthesis of amino) -2- (4- (methylsulfonyl) piperazin-1-yl) benzonitrile
  • the preparation method is the same as the preparation method in step 3 of Example 38, except that 4-bromo-2- (4- (methylsulfonyl) piperazin-1-yl) benzonitrile is used instead of 5-amino-2-fluorobenzenesulfon Amide to prepare the title compound.
  • Step 3 1- (4-((4-((1-Cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine-2 -Yl) amino) pyridin-2-yl) piperidin-4-ol
  • the preparation method is the same as the preparation method of the compound in Step 3 of Example 2, except that 1- (4-aminopyridin-2-yl) piperidin-4-ol is used instead of 2-morpholinopyridine-4-amine.
  • the title compound ESI-MS m / z: 477.3 [M + H] + .
  • 2,4-Dibromopyridine (3.00 g, 12.66 mmol) was placed in a dry round bottom flask, protected by nitrogen, and dissolved by adding 20 mL of anhydrous tetrahydrofuran solution. Cool down to -30 °C, slowly add isopropylmagnesium chloride-lithium chloride (2.21g, 15.2mmol), continue stirring for 1h at low temperature, then slowly add 3-oxetanone (1.1g, 15.2mmol), continue the reaction 2h, the reaction was monitored by LC-MS. The reaction was quenched with saturated ammonium chloride solution, ethyl acetate was added, extracted, the organic phases were combined, concentrated and purified by column chromatography to obtain the title compound. ESI-MS m / z: 229.9, 231.9 [M + H] + .
  • Step 3 3- (4-((4-((1-Cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine-2 -Yl) amino) pyridin-2-yl) oxetane-3-ol synthesis
  • the preparation method is the same as the preparation method of the compound in Step 3 of Example 2, except that 3- (4-aminopyridin-2-yl) oxetane-3-ol is used instead of 2-morpholinopyridine-4-amine To prepare the title compound.
  • Step 6 4-((4-((1-Cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) Synthesis of amino) -2- (2-hydroxyprop-2-yl) benzonitrile
  • the preparation method is the same as the preparation method of the compound in Step 3 of Example 2, except that 4-amino-2- (2-hydroxyprop-2-yl) benzonitrile hydrochloride is used instead of 2-morpholinopyridine-4- Amine to prepare the title compound.
  • Step 2 2- (4-((4-((1- (2-fluoroethyl) -3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy ) Synthesis of pyridin-2-yl) amino) pyridin-2-yl) propan-2-ol
  • Step 2 2- (4-((4-((3- (tetrahydro-2H-pyran-4-yl) -1-((2- (trimethylsilyl) ethoxy) methyl)- Synthesis of 1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) propan-2-ol
  • the preparation method is the same as the preparation method of the compound in Step 4 of Example 3, except that 2-chloro-4-((3- (tetrahydro-2H-pyran-4-yl) -1-((2- (tri Methylsilyl) ethoxy) methyl) -1H-pyrazol-4-yl) oxy) pyridine instead of 2-chloro-4-((1-cyclopropyl-3-phenyl-1H-pyrazole -4-yl) oxy) pyridine to prepare the title compound.
  • Step 3 2- (4-((4-((1- (3,3-difluorocyclobutyl) -3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazole-4- Yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) propan-2-ol
  • the preparation method is the same as the preparation method of the compound in Step 2 of Example 45, except that 2-chloro-4-((1- (3,3-difluorocyclobutyl) -3- (tetrahydro-2H-pyran -4-yl) -1H-pyrazol-4-yl) oxy) pyridine instead of 2-chloro-4-((1- (2-fluoroethyl) -3- (tetrahydro-2H-pyran-4 -Yl) -1H-pyrazol-4-yl) oxy) pyridine to prepare the title compound.
  • the preparation method is the same as the preparation method of compounds 1 to 2 in Example 1, except that 4-acetylpiperidine-1-carboxylic acid tert-butyl ester is used instead of 1- (tetrahydro-2H-pyran-4-yl) Ethyl ketone to prepare the title compound.
  • the preparation method is the same as the preparation method of compounds 3 to 5 in Example 1, except that 2-((2-chloropyridin-4-yl) oxy) -1- (1- (oxetane-3- Yl) piperidin-4-yl) ethyl-1-one instead of 2-((2-chloropyridin-4-yl) oxy) -1- (tetrahydro-2H-pyran-4-yl) ethyl-1 -Ketone to prepare the title compound.
  • ESI-MS m / z 375.2 [M + H] + .
  • Step 5 2- (4-((4-((1-Cyclopropyl-3- (1- (oxetan-3-yl) piperidin-4-yl) -1H-pyrazole-4- Yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) propan-2-ol
  • the preparation method is the same as the preparation method of the compound in Step 2 of Example 45, except that 2-chloro-4-((1-cyclopropyl-3- (1- (oxetane-3-yl) piperidine -4-yl) -1H-pyrazol-4-yl) oxy) pyridine instead of 2-chloro-4-((1- (2-fluoroethyl) -3- (tetrahydro-2H-pyran-4- Group) -1H-pyrazol-4-yl) oxy) pyridine to prepare the title compound.
  • ESI-MS m / z 491.6 [M + H] + .
  • Example 50 4-((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) -N- (2- (4, 4-difluoropiperidin-1-yl) pyridin-4-yl) pyridin-2-amine
  • Step 3 4-((1-Cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) -N- (2- (4,4 -Difluoropiperidin-1-yl) pyridin-4-yl) pyridin-2-amine
  • the preparation method is the same as the preparation method of the compound in Step 3 of Example 2, except that 2- (4,4-difluoropiperidin-1-yl) pyridin-4-amine is used instead of 2-morpholinopyridine-4-amine To prepare the title compound.
  • methyl magnesium bromide (3M, 12mL, 36mmol) was added to the reaction flask, stirred at 0 ° C, and methyl 2-bromo-5-((tert-butoxycarbonyl) amino) benzoate ( 3.97g, 12mmol) of anhydrous tetrahydrofuran (30mL) solution was added dropwise, moved to room temperature for 6h, until the reaction was completed by TLC detection, quenched by adding saturated ammonium chloride solution at 0 ° C. Ethyl acetate was added, extracted, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain the title compound.
  • ESI-MS m / z 330.1, 332.1 [M + H] + .
  • Step 6 2- (5-((4-((1-Cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine-2 -Yl) amino) -2- (trifluoromethyl) phenyl) propan-2-ol
  • the preparation method is the same as the preparation method of the compound in Step 3 of Example 2, except that 2- (5-amino-2- (trifluoromethyl) phenyl) propan-2-ol is used instead of 2-morpholinopyridine-4 -Amine to prepare the title compound.
  • Example 52 1- (4-((4-((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine- 2-yl) amino) pyridin-2-yl) azetidine-3-carbonitrile
  • Step 3 1- (4-((4-((1-Cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine-2 -Yl) amino) pyridin-2-yl) azetidine-3-carbonitrile
  • the preparation method is the same as the preparation method of the compound in Step 3 of Example 2, except that 1- (4-aminopyridin-2-yl) azetidine-3-carbonitrile is used instead of 2-morpholinopyridine-4-amine To prepare the title compound.
  • Step 2 2- (6-((4-((1-Cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine-2 -Yl) amino) isoquinolin-3-yl) propan-2-ol
  • Example 54 4-((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) -N- (2- (3- Fluoroazetidin-3-yl) pyridin-4-yl) pyridin-2-amine
  • Step 3 3- (4-((4-((1-Cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine-2 -Yl) amino) pyridin-2-yl) -3-fluoroazetidine-1-carboxylic acid tert-butyl ester
  • Step 4 4-((1-Cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) -N- (2- (3-fluoro Preparation of azetidine-3-yl) pyridin-4-yl) pyridin-2-amine
  • the preparation method is the same as the preparation method of the compounds of steps 1 to 5 in Example 1, except that 4-acetylpiperidine-1-carboxylic acid tert-butyl ester is used instead of 1- (tetrahydro-2H-pyran-4-yl) ethyl Ketone to prepare the title compound.
  • Step 2 4- (1-cyclopropyl-4-((2-((2- (2- (2-hydroxyprop-2-yl) pyridin-4-yl) amino) pyridin-4-yl) oxy) -1H Of tert-butyl pyrazol-3-yl) piperidine-1-carboxylate
  • the preparation method is the same as the preparation method of the compound in Step 4 of Example 3, except that 2- (4-((2-chloropyridin-4-yl) oxy) -1-cyclopropyl-1H-pyrazole-3 is used -Yl) piperidine-1-carboxylic acid tert-butyl ester instead of 2-chloro-4-((1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl) oxy) pyridine to prepare the title compound .
  • Step 3 1- (4- (4-((1-Cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine-2- Of amino) amino) pyridin-2-yl) -4-methylpiperidin-4-ol
  • the preparation method is the same as the preparation method of the compound of Example 37, except that 1- (4-aminopyridin-2-yl) -4-methylpiperidin-4-ol is used instead of 3-amino-6-methylbenzenesulfon Amide to prepare the title compound.
  • 2,4-Dibromopyridine (1.20 g, 5.06 mmol) was added to a three-necked flask, nitrogen was replaced three times, and 10 mL of toluene was added to dissolve.
  • 2.5M n-butyl lithium solution in n-hexane (2.23mL, 5.57mmol) was slowly added dropwise and stirred for 1h after the addition was completed.
  • N-methoxy-N-methylacetamide (1.56g, 15.2mmol) was slowly added dropwise, and the reaction was continued at -78 ° C for 1h after the drop.
  • Step 3 1-cyclopropyl-1- (4-((4-((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) Synthesis of oxy) pyridin-2-yl) amino) pyridin-2-yl) eth-1-ol
  • the preparation method is the same as the preparation method of the compound in Step 4 of Example 53, except that 1- (4-bromopyridin-2-yl) -1-cyclopropylethan-1-ol is used instead of 2- (6-bromoisoquine Lin-3-yl) propan-2-ol to prepare the title compound.
  • Example 58 4-((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) -N- (3-morpholine- 4- (trifluoromethyl) phenyl) pyridin-2-amine
  • Step 3 4-((1-Cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) -N- (3-morpholine-4 -(Trifluoromethyl) phenyl) pyridine-2-amine synthesis
  • the preparation method is the same as the preparation method of the compound in Step 3 of Example 2, except that 3-morpholin-4- (trifluoromethyl) aniline is used instead of 2-morpholinopyridine-4-amine to prepare the title compound.
  • Step 3 2- (5-((4-((1-Cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine-2 -Yl) amino) -2- (methylsulfonyl) phenyl) propan-2-ol
  • the preparation method is the same as the preparation method of the compound in Step 3 of Example 2, except that 2- (5-amino-2- (methylsulfonyl) phenyl) propan-2-ol hydrochloride is used instead of 2-morpholino Pyridine-4-amine to prepare the title compound.
  • the preparation method is the same as the preparation method of the compound in Step 4 of Example 3, except that 1- (4-aminopyridin-2-yl) azetidine-3-carbonitrile is used instead of 2- (4-aminopyridine-2- Group) propan-2-ol to prepare the title compound.
  • Step 4 4- (4-((4-((1-Cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine-2 -Yl) amino) pyridin-2-yl) cyclohex-2-en-1-ol
  • the preparation method is the same as the preparation method of the compound in Step 4 of Example 53, except that 4- (4-bromopyridin-2-yl) cyclohex-3-en-1-ol is used instead of 2- (6-bromoisoquinoline- 3-yl) propan-2-ol to prepare the title compound.
  • Step 5 4- (4-((4-((1-Cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine-2 -Yl) amino) pyridin-2-yl) cyclohexan-1-ol
  • Step 3 2- (5-((4-((1-Cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine-2 -Yl) amino) -1-methyl-1H-indazol-3-yl) propan-2-ol
  • the preparation method is the same as the preparation method of the compound in Step 4 of Example 53, except that 2- (5-bromo-1-methyl-1H-indazol-3-yl) propan-2-ol is used instead of 2- (6- Bromoisoquinolin-3-yl) propan-2-ol to prepare the title compound.
  • Step 2 2- (4-((4-((1-Cyclopropyl-3- (4-morpholinophenyl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino ) Synthesis of pyridin-2-yl) propan-2-ol
  • the preparation method is the same as the preparation method of the compounds of steps 1 to 4 in Example 3, except that 2-bromo-1- (4-morpholinophenyl) ethyl-1-one is used instead of 2-bromo-1-phenylethyl -1-one to prepare the title compound.
  • Step 2 2- (5-((4-((1-Cyclopropyl-3-phenyl-1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -2- (trifluoro Synthesis of methyl) phenyl) propan-2-ol
  • the preparation method is the same as the preparation method of the compound in Step 4 of Example 3, except that 2- (5-amino-2- (trifluoromethyl) phenyl) propan-2-ol hydrochloride is used instead of 2- (4- Aminopyridin-2-yl) propan-2-ol to prepare the title compound.
  • ESI-MS m / z 495.2 [M + H] + .
  • Example 65 4- (5-((4-((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine- 2-yl) amino) -2-fluorophenyl) thiomorpholine-1,1-dioxide
  • Step 3 4- (5-((4-((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine-2 -Yl) amino) -2-fluorophenyl) thiomorpholine-1,1-dioxide
  • the preparation method is the same as the preparation method of the compound in Step 3 of Example 2, except that 4- (5-amino-2-fluorophenyl) thiomorpholine-1,1-dioxide is used instead of 2-morpholinopyridine -4-amine to prepare the title compound.
  • the preparation method is the same as that in Example 48, except that 2- (5-amino-2- (methylsulfonyl) phenyl) propan-2-ol hydrochloride is used instead of 2- (4-aminopyridin-2-yl ) Propan-2-ol to prepare the title compound.
  • Step 2 1- (5-((4-((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine-2 -Yl) amino) -2- (methylsulfonyl) phenyl) -3-methylazetidine-3-ol
  • the preparation method is the same as the preparation method of the compound in Step 3 of Example 2, except that 1- (5-amino-2- (methylsulfonyl) phenyl) -3-methylazetidin-3-ol is used Instead of 2-morpholinopyridine-4-amine, the title compound was prepared.
  • Step 3 1- (5-((4-((1-Cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine-2 -Yl) amino) -2-fluorophenyl) azetidine-3-carbonitrile
  • the preparation method is the same as the preparation method of the compound in Step 3 of Example 2, except that 1- (5-amino-2-fluorophenyl) azetidine-3-carbonitrile is used instead of 2-morpholinopyridine-4- Amine to prepare the title compound.
  • Step 4 3- (5-((4-((1-Cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine-2 -Yl) amino) -2-fluorophenyl) oxetane-3-ol
  • the preparation method is the same as the preparation method of the compound in Step 3 of Example 2, except that 3- (5-amino-2-fluorophenyl) oxetane-3-ol is used instead of 2-morpholinopyridine-4- Amine to prepare the title compound.
  • Example 70 4- (5-((4-((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine- 2-yl) amino) -2- (trifluoromethyl) phenyl) thiomorpholine-1,1-dioxide
  • Step 3 4- (5-((4-((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine-2 -Yl) amino) -2- (trifluoromethyl) phenyl) thiomorpholine-1,1-dioxide
  • the preparation method is the same as the preparation method of the compound in Step 3 of Example 2, except that 4- (5-amino-2- (trifluoromethyl) phenyl) thiomorpholine-1,1-dioxide is used instead of 2. -Morpholinopyridine-4-amine to prepare the title compound.
  • Step 3 2- (4- (4-((4-((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) Synthesis of pyridin-2-yl) amino) -2- (trifluoromethyl) phenyl) piperazin-1-yl) eth-1-ol
  • the preparation method is the same as the preparation method of the compound in Step 3 of Example 2, except that 2- (4- (4-amino-2- (trifluoromethyl) phenyl) piperazin-1-yl) ethyl-1- Alcohol replaces 2-morpholinopyridine-4-amine to prepare the title compound.
  • Example 72 1- (4-((4-((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine- 2-yl) amino) pyridin-2-yl) -2,2,2-trifluoroethyl-1-ol
  • Step 4 1- (4-((4-((1-Cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine-2- Yl) amino) pyridin-2-yl) -2,2,2-trifluoroethyl-1-ol
  • the preparation method is the same as the preparation method of the compound in Step 3 of Example 2, except that 1- (4-aminopyridin-2-yl) -2,2,2, -trifluoroethyl-1-ol is used instead of 2-? Pyridin-4-amine to prepare the title compound.
  • Step 5 2- (5-((4-((1-Cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine-2 -Yl) amino) -2- (1H-1,2,4-triazol-1-yl) phenyl) propan-2-ol
  • the preparation method is the same as the preparation method of the compound in Step 3 of Example 2, except that 2- (5-amino-2- (1H-1,2,4-triazol-1-yl) phenyl) propyl-2 is used -Alcohol instead of 2-morpholinopyridine-4-amine to prepare the title compound.
  • the preparation method was the same as the preparation method of the compound in Example 20, except that 2- (4-aminopyridin-2-yl) propan-2-ol was used instead of 2-morpholinopyridine-4-amine to prepare the title compound.
  • Step 4 3- (4-((4-((1-Cyclopropyl-3- (4,4-difluorocyclohexyl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) Preparation of amino) pyridin-2-yl) oxetane-3-ol
  • Example 76 1- (4-((4-((1-cyclopropyl-3- (4,4-difluorocyclohexyl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl ) Amino) pyridin-2-yl-2,2,2-trifluoroethyl-1-ol
  • the preparation method is the same as the preparation method of the compound of Example 75, except that 1- (4-aminopyridin-2-yl) -2,2,2, -trifluoroethyl-1-ol is used instead of 3- (4- Aminopyridin-2-yl) oxetane-3-ol to prepare the title compound.
  • Example 78 2- (5-((4-((1-cyclopropyl-3- (4,4-difluorocyclohexyl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl ) Amino) -2- (1H-1,2,4-triazol-1-yl) phenyl) propan-2-ol
  • the preparation method is the same as Example 3, except that 2-bromo-1- (4,4-difluorocyclohexyl) ethyl-1-one is used instead of 2-bromo-1-phenylethan-1-one and 2 -(5-Amino-2- (1H-1,2,4-triazol-1-yl) phenyl) propan-2-ol instead of 2- (4-aminopyridin-2-yl) propan-2-ol To prepare the title compound. LC-MS m / z: 536.2 [M + H] + .
  • Step 4 (4- (4-((1-Cyclopropyl-3- (3,3-difluorocyclobutyl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) Preparation of amino) pyridin-2-yl) -2,2,2-trifluoroethane-1-ol
  • the preparation method is the same as that in Example 3, except that 2-bromo-1- (4-fluorophenyl)) ethyl-1-one is used instead of 2-bromo-1-phenylethyl-1-one to obtain the title compound .
  • Example 82 4- (4-((4-((1-cyclopropyl-3- (3-fluorophenyl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) Pyridin-2-yl) tetrahydro-2H-pyran-4-ol
  • the preparation method is the same as the preparation method of the compound in Step 81, except that 4- (4-aminopyridin-2-yl) tetrahydro-2H-pyran-4-ol is used instead of 3- (4-aminopyridin-2-yl ) Oxetane-3-ol to prepare the title compound.
  • Step 2 Preparation of 1- (2-fluoro-4- (tetrahydro-2H-pyran-4-yl) phenyl) ethyl-1-one
  • Step 3 Preparation of 2-bromo-1- (2-fluoro-4- (tetrahydro-2H-pyran-4-yl) phenyl) ethyl-1-one
  • the preparation method is the same as the preparation method of compounds 1 to 3 in Example 3, except that 2-bromo-1- (2-fluoro-4- (tetrahydro-2H-pyran-4-yl) phenyl) ethyl 1-bromo-1-one instead of 2-bromo-1-phenylethan-1-one to prepare the title compound.
  • Step 4 3- (4-((4-((1-Cyclopropyl-3- (2-fluoro-4- (tetrahydro-2H-pyran-4-yl) phenyl) -1H-pyrazole- Preparation of 4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) oxetane-3-ol
  • Example 84 1- (4-((4-((1-cyclopropyl-3- (3-fluorophenyl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) Pyridin-2-yl) -2,2,2-trifluoroethyl-1-ol
  • Rhodium diacetate (632 mg, 1.43 mmol) and 200 mL of anhydrous dichloromethane were added to a 1 L three-necked flask, and 2,5-dihydrofuran (21.5 mL, 285 mmol) was added to the above under an argon atmosphere.
  • ethyl diazoacetate (15 mL, 143 mmol) was dissolved in 430 mL of anhydrous dichloromethane, and added dropwise with a constant pressure dropping funnel for 48 h. After the reaction was completed, it was concentrated under reduced pressure and purified by column chromatography to obtain the title product.
  • LC-MS m / z 157.1 [M + H] + .
  • the preparation method is the same as the preparation method of the compounds of steps 1 to 5 in Example 1, except that 1- (3-oxabicyclo [3.1.0] hexane-6-yl) ethan-1-one is used instead of 1- ( Tetrahydro-2H-pyran-4-yl) ethanone to prepare the title compound.
  • Step 6 2- (4-((4-((3- (3-oxabicyclo [3.1.0] hexane-6-yl) -1-cyclopropyl-1H-pyrazol-4-yl) Preparation of oxy) pyridin-2-yl) amino) pyridin-2-yl) propan-2-ol
  • the preparation method is the same as the preparation method of the compound in Step 2 of Example 45, except that 4-((3- (3-oxabicyclo [3.1.0] hexane-6-yl) -1-cyclopropyl- 1H-pyrazol-4-yl) oxy) -2-chloropyridine instead of 2-chloro-4-((1- (2-fluoroethyl) -3- (tetrahydro-2H-pyran-4-yl ) -1H-pyrazol-4-yl) oxy) pyridine to prepare the title compound.
  • Example 86 2- (5-((4-((3- (3-oxabicyclo [3.1.0] hexane-6-yl) -1-cyclopropyl-1H-pyrazol-4-yl ) Oxy) pyridin-2-yl) amino) -2- (1H-1,2,4-triazol-1-yl) phenyl) propan-2-ol
  • the preparation method is the same as the preparation method of the compound of Example 85, except that 2- (5-amino-2- (1H-1,2,4-triazol-1-yl) phenyl) propan-2-ol is used instead 2- (4-aminopyridin-2-yl) propan-2-ol to prepare the title compound.
  • Step 3 2- (6-cyclopropyl-2-((4-((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) Oxy) pyridin-2-yl) amino) pyrimidin-4-yl) propan-2-ol
  • the preparation method was the same as the preparation method of the compound of Example 53, except that 2- (2-chloro-6-cyclopropylpyrimidin-4-yl) propan-2-ol was used instead of 2- (6-bromoisoquinoline- 3-yl) propan-2-ol to prepare the title compound.

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  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Urology & Nephrology (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention se rapporte au domaine de la chimie médicale, et concerne une classe de composés utilisés en tant qu'inhibiteurs de TGF-βR1 et une utilisation associée. La présente invention concerne particulièrement, un composé tel que représenté par la formule I, ou un isomère, un sel pharmaceutiquement acceptable, un solvate, un cristal ou un promédicament de celui-ci. L'invention concerne également, un procédé de préparation associé et une compositions pharmaceutique contenant ces composés ainsi qu'une utilisation de ces composés ou compositions pour le traitement et/ou la prévention de maladies associées au TGF-βR1, telles que des cancers, des maladies prolifératives tissulaires, des maladies fibrotiques et inflammatoires. Les composés selon la présente invention ont une activité inhibitrice significative sur les kinases TGF-βR1, et ont un potentiel très fort pour être des agents thérapeutiques pour des maladies associées au TGF-βR1. (I)
PCT/CN2019/119413 2018-11-20 2019-11-19 INHIBITEUR DE TGF-βR1 ET SON UTILISATION WO2020103817A1 (fr)

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Cited By (2)

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Publication number Priority date Publication date Assignee Title
WO2024111626A1 (fr) * 2022-11-25 2024-05-30 カルナバイオサイエンス株式会社 Nouveau dérivé de thiazole
US12102626B2 (en) 2018-12-27 2024-10-01 Nexys Therapeutics, Inc. (Pyridin-2-yl)amine derivatives as TGF-BETA R1 (ALK5) inhibitors for the treatment of cancer

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113698395B (zh) * 2020-05-22 2023-12-08 赛诺哈勃药业（成都）有限公司 转化生长因子受体拮抗剂、其制备方法和应用
CN115969801B (zh) * 2023-03-21 2023-08-25 劲方医药科技(上海)有限公司 用于癌症的药物组合物及其制备方法

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WO2009022171A1 (fr) * 2007-08-13 2009-02-19 Astrazeneca Ab Composés chimiques 1 - 821
CN106795139A (zh) * 2014-10-07 2017-05-31 伊莱利利公司 氨基吡啶基氧基吡唑化合物

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Publication number Priority date Publication date Assignee Title
WO2009022171A1 (fr) * 2007-08-13 2009-02-19 Astrazeneca Ab Composés chimiques 1 - 821
CN106795139A (zh) * 2014-10-07 2017-05-31 伊莱利利公司 氨基吡啶基氧基吡唑化合物

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12102626B2 (en) 2018-12-27 2024-10-01 Nexys Therapeutics, Inc. (Pyridin-2-yl)amine derivatives as TGF-BETA R1 (ALK5) inhibitors for the treatment of cancer
WO2024111626A1 (fr) * 2022-11-25 2024-05-30 カルナバイオサイエンス株式会社 Nouveau dérivé de thiazole

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