WO2020078402A1 - 作为TGF-βR1抑制剂的化合物及其应用 - Google Patents

作为TGF-βR1抑制剂的化合物及其应用 Download PDF

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WO2020078402A1
WO2020078402A1 PCT/CN2019/111568 CN2019111568W WO2020078402A1 WO 2020078402 A1 WO2020078402 A1 WO 2020078402A1 CN 2019111568 W CN2019111568 W CN 2019111568W WO 2020078402 A1 WO2020078402 A1 WO 2020078402A1
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alkyl
alkoxy
amino
alkylamino
hydroxy
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PCT/CN2019/111568
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English (en)
French (fr)
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王勇
赵立文
王亚洲
张雁
王小伟
王海
郭壮
吕坤志
常玉杰
陈宏雁
徐国峰
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南京圣和药业股份有限公司
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Priority to AU2019362242A priority Critical patent/AU2019362242A1/en
Priority to CN201980067259.9A priority patent/CN112839941B/zh
Priority to US17/285,180 priority patent/US20210395235A1/en
Priority to CA3116425A priority patent/CA3116425A1/en
Priority to JP2021520911A priority patent/JP2022504982A/ja
Priority to KR1020217014232A priority patent/KR20210076069A/ko
Priority to EP19874641.4A priority patent/EP3868755A4/en
Publication of WO2020078402A1 publication Critical patent/WO2020078402A1/zh

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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
    • A61K31/47—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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—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 sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • 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
    • 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 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 ⁇ . It is the most abundantly expressed subtype in the liver and the strongest known liver fibrosis inducing factor. It develops from chronic liver disease to end-stage liver disease. Plays an important role (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, thereby regulating the entire signaling pathway, and regulating a series of related to fibrosis and tumorigenesis Target gene expression.
  • TGF- ⁇ has a promotion effect on liver cancer mainly in promoting tumor cell metastasis, strengthening 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.
  • the reason is Due to the low target selectivity and specificity of these 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 ⁇ ), which in turn produces many Expected off-target side effects. Therefore, there is still a need to develop more selective inhibitors of TGF ⁇ R1 in order to specifically regulate the TGF- ⁇ signaling pathway 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 present invention is to provide a method for preparing the compound of the general formula I of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal, electron isostere or prodrug.
  • 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 Compounds, and compositions comprising compounds of the general formula I or isomers, pharmaceutically acceptable salts, solvates, crystals, electron isosteres or prodrugs of the invention and another drug or 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.,
  • X 1 is selected from N and CH;
  • R 1 is selected from the group consisting of hydroxy, cyano, carboxy, nitro, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, cycloalkylalkoxy, heterocycle Alkoxy, cycloalkylalkyl, heterocyclylalkyl, monoalkylamino, dialkylamino, cycloalkylamino, heterocyclylamino, arylamino, heteroarylamino, cycloalkyl, Heterocyclyl, aryl, heteroaryl, arylheterocyclyl, and heteroarylheterocyclyl, which are optionally substituted by one or more halogen, hydroxy, amino, carboxy, cyano, nitro, oxo Group, alkylsulfonyl, aminosulfonyl, alkylsulfonylalkyl, alkyl, cycloalkyl
  • R 2 and R 3 are independently selected from hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, mono Alkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, dialkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein Halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylacylamino, alkylacyl , Aminoacyl, alkylaminoacyl, dialkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclyl,
  • R 4 is selected from hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, alkylamino, alkylacyl Amino, alkylacyl, aminoacyl, alkylaminoacyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylamino, heterocycloalkylaryl, arylamino and heteroarylamino , Wherein the halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, alkylamino, alkylacylamino, Alkyl acyl, aminoacyl, alkylaminoacyl, cycloalkyl, heterocycloalkyl, aryl, heteroary
  • R 5 and R 6 are independently selected from hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, mono Alkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, dialkylamino and cycloalkyl;
  • n and n are independently selected from 1, 2, and 3, respectively.
  • 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 X 1 is N .
  • 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 X 1 is CH.
  • 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 Hydroxy, cyano, carboxy, nitro, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyloxy Group, C 3-6 heterocycloalkyloxy, C 3-6 cycloalkyl C 1-3 alkoxy, C 3-6 heterocyclyl C 1-3 alkoxy, C 3-6 cycloalkyl C 1-3 alkyl, C 3-6 heterocyclyl C 1-3 alkyl, mono C 1-6 alkylamino, bis C 1-6 alkylamino, C 3-6 cycloalkylamino, C 3 -6 heterocyclylamino, C 6-12 arylamino, C 5-8 heteroarylamino, C 3-6 cycloalkyl
  • R 1 is selected from hydroxyl, cyano, carboxy, nitro, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyloxy, C 3-6 heterocycloalkyloxy, C 3-6 cycloalkyl C 1-3 alkoxy, C 3-6 heterocyclyl C 1-3 alkoxy, C 3-6 cycloalkyl C 1-3 alkyl, C 3-6 heterocyclyl C 1-3 alkyl, mono C 1-6 alkylamino, di C 1-6 alkylamino, C 3-6 Cycloalkylamino, C 6-12 arylamino, C 5-8 heteroarylamino, C 3-6 heterocyclylamino, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 6- 12 aryl, C 5-12 heteroaryl, C 6-12 aryl C 3-10 heterocyclyl and C 5-12 heteroaryl C 3-6 heterocyclyl,
  • R 1 is selected from hydroxyl, cyano, carboxyl, nitro, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, hydroxymethyl, hydroxyethyl, hydroxy Propyl, 2-hydroxypropyl, methoxy, ethoxy, propoxy, isopropoxy, nitro, carboxy, cyano, amino, methylamino, ethylamino, propylamino, isopropyl Amino, dimethylamino, diethylamino, methylethylamino, dipropylamino, methylpropylamino, ethylpropylamino, methylacylamino, ethylacylamino, vinylacylamino, methylacyl , Ethylacyl, vinylacyl, aminoacyl, methylaminoacyl, ethylaminoacyl, vinyl, propenyl,
  • 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 and R 3 are independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy 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, C 1-6 alkylacylamino , C 1-6 alkylacyl, aminoacyl, C 1-6 alkylaminoacyl, bis C 1-6 alkylamino, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkane Group, 3-10 membered heterocycloalkyl group, C 6-18 aryl group and 5-18 membered heteroaryl group, wherein the fluorine, chlorine, bromine, iodine, hydroxyl, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C
  • 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 , R 5 and R 6 are independently selected from hydrogen, halogen, hydroxy, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy 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, C 1-6 alkylacylamino, C 1 -6 alkylacyl, aminoacyl, C 1-6 alkylaminoacyl, bis C 1-6 alkylamino, C 3-10 cycloalkyl.
  • R 4 is 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, C 1-6 alkylamino, C 1-6 alkylacylamino, C 1-6 alkylacyl, amino Acyl, C 1-6 alkylamino acyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 6-12 aryl, C 5-12 heteroaryl, C 3-8 cycloalkyl Amino, C 3-8 heterocycloalkylaryl, C 6-12 arylamino and C 5-8 heteroarylamino, wherein the halogen, hydroxy, C 1-6 alkyl, halo C 1-6 Alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 al
  • the compound of general formula I of the present invention is the following 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 , R 6 , m, n are as defined in claims 1 to 5;
  • X 2 and X 2 ′ are independently selected from N and C (R 7 ), wherein R 7 is selected from hydrogen, halogen, hydroxyl, oxo group, alkylsulfonyl, alkylsulfonylalkyl, alkyl, Haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylamino Acyl, dialkylamino and cycloalkyl;
  • R 8 is selected from hydrogen, halogen, hydroxyl, oxo group, alkylsulfonyl, alkylsulfonylalkyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, Nitro, carboxy, cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, dialkylamino, and cycloalkyl; and
  • p is selected from 1, 2, and 3.
  • the compound of general formula Ia or its isomer, pharmaceutically acceptable salt, solvate, crystal, electron isostere or prodrug according to the present invention wherein X 2 and X 2 ' Independently selected from N and C (R 7 ), preferably, X 2 is N and X 2 ′ is C (R 7 ) or X 2 is C (R 7 ) and X 2 ′ is N, wherein R 7 is selected From hydrogen, halogen, hydroxyl, oxo group, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonyl C 1-6 alkyl, C 1-6 alkyl, halogenated C 1-6 alkyl Group, hydroxy 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, C 1-6 alkylacylamino, C
  • 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 , R 6 , X 1 , m, n are as defined in the general formula I;
  • X 3 and X 4 are independently selected from N, C, CH, CH 2 , O and S;
  • Y 1 is selected from NH, C (O) NH or absent;
  • R 9 is selected from hydrogen, halogen, hydroxy, oxo group, alkylsulfonyl, alkylsulfonylalkyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, Nitro, carboxy, cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, dialkylamino, cycloalkyl; preferably, R 9 is selected from hydrogen, Fluorine, chlorine, bromine, iodine, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, 2-hydroxypropyl , Methoxy, ethoxy, propoxy, isopropoxy, nitro, carboxy, cyano, amino, methylamino
  • q is selected from 1, 2, 3, 4, and 5.
  • the compound of general formula I of the present invention is a 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 , R 6 , X 1 , m, n are as defined in the general formula I;
  • Y 2 is selected from NH, C (O) NH or absent;
  • R 10 is selected from hydrogen, halogen, hydroxy, oxo group, alkylsulfonyl, alkylsulfonylalkyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, Nitro, carboxy, cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, dialkylamino, cycloalkyl; preferably, R 10 is selected from hydrogen, Fluorine, chlorine, bromine, iodine, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, 2-hydroxypropyl , Methoxy, ethoxy, propoxy, isopropoxy, nitro, carboxy, cyano, amino, methylamino
  • t is selected from 1, 2, and 3.
  • the compounds of the present invention are compounds of general formula I, Ia, Ib or Ic or isomers, pharmaceutically acceptable salts, solvates, crystals, electron isosteres or prodrugs, among them:
  • R 1 is selected from cyclopentyl, cyclohexyl, 4-6 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 6-12 arylamino, C 5-8 heteroaryl Amino, C 6-10 aryl and 5-10 membered heterocyclic group and 5-10 membered heteroaryl and 5-6 membered heterocyclic group, which are optionally substituted by one or more C 1-3 alkyl, halogenated C 1-3 alkyl, hydroxy, hydroxy C 1-3 alkyl, halogen, oxo group, C 1-3 alkoxy, carboxy, cyano, amino, mono C 1-3 alkylamino or double C 1-3 alkylamino group;
  • R 2 and R 3 are independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tert-butyl, methylamino, ethylamino, Propylamino, isopropylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, thienyl, furyl, pyridyl, pyridine Azinyl, pyrimidinyl, azetidinyl, oxetanyl, tetrahydropyrrolyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, and morpholinyl, which are optionally substituted by one or more hydroxyl groups, Methyl
  • R 4 is selected from hydrogen, hydrogen, fluorine, chlorine, bromine, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl , 2-hydroxypropyl, methoxy, ethoxy, propoxy, isopropoxy, nitro, carboxy, cyano, amino, methylamino, ethylamino, propylamino, isopropylamino, Dimethylamino, diethylamino, methylethylamino, dipropylamino, methylpropylamino, ethylpropylamino, methylacylamino, ethylacylamino, vinylacylamino, methylacyl, ethyl Acyl, vinyl acyl, aminoacyl, methylaminoacyl, ethylaminoacyl, cyclopropyl
  • R 5 and R 6 are independently selected from hydrogen, fluorine, chlorine, bromine, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, hydroxymethyl, hydroxyethyl , Hydroxypropyl, 2-hydroxypropyl, methoxy, ethoxy, propoxy, isopropoxy, nitro, carboxy, cyano, amino, methylamino, ethylamino, propylamino, iso Propylamino, dimethylamino, diethylamino, methylethylamino, dipropylamino, methylpropylamino, ethylpropylamino, methylacylamino, ethylacylamino, vinylacylamino, methyl Acyl, ethylacyl, vinylacyl, aminoacyl, methylaminoacyl, ethylaminoacyl, cyclopropy
  • R 8 , R 9 and R 10 are independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl and hydroxymethyl Group, hydroxyethyl, hydroxypropyl, 2-hydroxypropyl, methoxy, ethoxy, propoxy, isopropoxy, nitro, carboxyl, cyano, amino, methylamino, ethylamino, Propylamino, isopropylamino, dimethylamino, diethylamino, methylethylamino, dipropylamino, methylpropylamino, ethylpropylamino, methylacylamino, ethylacylamino, ethylene Acylamino, methylacyl, ethylacyl, vinylacyl, aminoacyl, methylaminoacyl, eth
  • X 1 is N
  • X 2 is N and X 2 ′ is C (R 7 ), or X 2 is C (R 7 ) and X 2 ′ is N, where R 7 is selected from hydrogen, halogen, hydroxyl, oxo group, alkylsulfonate Acyl, alkylsulfonylalkyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkylacyl Amino, alkylacyl, aminoacyl, alkylaminoacyl, dialkylamino and cycloalkyl;
  • X 3 and X 4 are independently selected from N, C, CH, CH 2 , O and S;
  • Y 1 and Y 2 are independently selected from NH and non-existence
  • n, p, and q are independently selected from 1 and 2, respectively.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and n are as defined in the general formula I.
  • the compounds of the present invention are compounds of general formula I or Id or isomers, pharmaceutically acceptable salts, solvates, crystals, electron isosteres or prodrugs, wherein R 1 is selected From C 1-6 alkoxy, morpholinyl, piperidinyl, pyrazolyl, phenyl, pyridyl, pyridylamino, pyrrolopyrazolyl, triazolopyrazinyl, thiomorpholinyl, which Optionally substituted by one or more halogen, hydroxy, amino, carboxy, cyano, nitro, oxo, C 1-6 alkylsulfonyl, aminosulfonyl, C 1-6 alkylsulfonyl C 1- 6 alkyl, C 1-6 alkyl, C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-6 alkyl C 3-10 heterocyclyl, C 1-6 alkoxy, halo Substitute
  • R 2 and R 3 are independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tert-butyl, methylamino, Ethylamino, propylamino, isopropylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, thienyl, furyl, Pyridyl, pyrazinyl, pyrimidinyl, azetidinyl, oxetanyl, tetrahydropyrrolyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, and morpholinyl, which are optionally Multiple hydroxyl, methyl,
  • R 4 is selected from the group consisting of hydrogen, aminoacyl and pyrazolylamino, the aminoacyl and pyrazolylamino optionally being substituted by one or more C 1-6 alkyl, C 1-6 alkoxy, C 6-12 aryloxy , C 1-6 alkylamino, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, C 6-12 aryl, C 5-8 heteroaryl, C 6-12 arylamino, halogen, Hydroxy, amino, nitro, carboxy, cyano, alkyl acyl, amino acyl, alkylamino acyl, sulfonyl or mercapto substitution.
  • the compounds of the present invention are compounds of general formula I or Id or isomers, pharmaceutically acceptable salts, solvates, crystals, electron isosteres or prodrugs thereof, wherein X 1 is N, R 1 is selected from the following groups: R 2 is tetrahydropyranyl; R 3 is selected from C 1-6 alkyl and C 3-6 cycloalkyl; R 4 is selected from H,
  • 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 , R 8 , R 9 , R 10 , X 1 , X 2 , X 2 ' , X 3 , X 4 , Y 1 , Y 2 , m, n, p, q and t have the meaning in the general formula I;
  • A is 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.
  • Methods of administration 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 (e.g., oral mucosa or rectum, etc.). Administration can be systemic or local.
  • formulations 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, electrons, etc. or prodrugs represented by the general formula I, Ia, Ib, Ic or Id of the present invention Or use of a pharmaceutical composition containing the same in the preparation of a medicament for the treatment and / or prevention of cancer, tissue hyperplasia, fibrosis or inflammatory diseases, wherein the cancer, tissue hyperplasia, fibrosis or inflammatory diseases
  • the pathology includes but is not limited to: melanoma, papillary thyroid tumor, cholangiocarcinoma, colon cancer, ovarian cancer, lung cancer, malignant lymphoma, cancer and sarcoma of liver, kidney, bladder, prostate, breast and pancreas, as well as skin, colon , Primary and recurrent solid tumors or leukemia of thyroid, lung and ovary, glioblastoma (glioma), myelodysplastic syndrome (MDS), myeloprolif
  • 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, 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.
  • heterocyclic group refers to a 3- to 12-membered non-aromatic ring system having 1 to 4 ring heteroatoms (where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon) Group ("3-12 membered heterocyclic group").
  • a heterocyclyl group containing one or more nitrogen atoms the point of attachment can be a carbon or nitrogen atom, as long as valency permits.
  • Heterocyclyl groups can either be monocyclic (“monocyclic heterocyclyl") or fused, bridged or spiro ring systems (eg bicyclic systems ("bicyclic heterocyclyl”)) And may be saturated or may be partially unsaturated.
  • Suitable saturated and partially saturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, isoxazolinyl and the like.
  • Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or two rings.
  • Heterocyclyl also includes ring systems where the heterocycle, as defined above, is fused with one or more carbocyclyl groups (where the point of attachment is on the carbocyclyl group or on the heterocycle), or the ring system
  • the heterocycle in, as defined above, is fused with one or more aryl or heteroaryl groups (where the point of attachment is on the heterocycle), and in such cases, the number of ring members continues to be referred to as heterocycle The number of ring members in the ring system.
  • each instance of heterocyclyl is independently optionally substituted, ie, unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted hetero Cyclic group "), such as substituted or unsubstituted piperidinyl, substituted or unsubstituted bridged ring morpholinyl and the like.
  • the heterocyclyl group is a substituted 4-10 membered heterocyclyl.
  • Exemplary 5-membered heterocyclic groups fused to the C 6 aryl ring include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophene, benzo Oxazolone group and so on.
  • Exemplary 6-membered heterocyclic groups fused to the C 6 aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
  • Exemplary 5- and 6-membered heterocycloalkyl groups fused to 5-membered heteroaromatic rings include, but are not limited to Wait.
  • aryl group refers to an aromatic system that may contain a single ring or a fused polycyclic ring, preferably an aromatic system containing a single ring or a fused bicyclic ring, 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 "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 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 often referred to as a hydrate, for example, hemihydrate, monohydrate, dihydrate, trihydrate, or their replacement 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 spatial and / or electronic characteristics
  • electrospray or "electronic isostere” for short
  • Crystall in the present invention refers to a solid whose internal structure is formed by repeatedly forming atoms (or groups thereof) in three dimensions, which is different from an amorphous solid that does not have such a regular internal structure.
  • Prodrug refers to a compound that is converted into Formula I, Ia, Ib, Ic, or Id by reaction with an enzyme, 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 a 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.
  • the DMSO referred to in " 1 H NMR (400 MHz, DMSO)" of the present invention refers to hexadeuterated dimethyl sulfoxide, namely DMSO-d 6 .
  • Step 1 Synthesis of 2-((7-bromoquinolin-4-yl) oxy) -1- (tetrahydro-2H-pyran-4-yl) ethan-1-one
  • Step 2 (E) -2-((7-Bromoquinolin-4-yl) oxy) -3- (dimethylamino) -1- (tetrahydro-2H-pyran-4-yl) propane Synthesis of -2-en-1-one
  • Step 3 Synthesis of 7-bromo-4-((3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) quinoline
  • Step 4 Synthesis of 7-bromo-4-((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) quinoline
  • the reaction system was stirred at 75 ° C for 2 hours under an oxygen atmosphere, and cooled to room temperature.
  • the reaction solution was diluted with ethyl acetate (20 mL), filtered through a short column of silica gel, and rinsed with ethyl acetate (50 mL).
  • the filtrate was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 88 mg of the title compound.
  • Step 5 2- (4-((4-((1-Cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) quinoline Synthesis of -7-yl) amino) pyridin-2-yl) propan-2-ol
  • the preparation method is the same as that in Example 1, except that morpholine is used instead of 2- (4-amino-2-pyridyl) propane-2-ol hydrochloride to prepare the title compound.
  • the preparation method is the same as that in Example 1, except that thiomorpholine-1,1-dioxide is used instead of 2- (4-amino-2-pyridyl) propane-2-ol hydrochloride to obtain the title compound .
  • the preparation method is the same as that in Example 1, except that 4-methyl-4-hydroxypiperidine is used instead of 2- (4-amino-2-pyridyl) propane-2-ol hydrochloride to prepare the title compound.
  • the preparation method is the same as Example 3, except that 2- (2,2,2-trifluoroethyl) -2,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole hydrochloride is used The salt replaced 3- (trifluoromethyl) -5,6,7,8-tetrahydro- [1,2,4] triazolo [4,3-a] pyrazine hydrochloride to prepare the title compound.
  • the preparation method is the same as that in Example 7, except that 4- (4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl) -1H-pyrazole is used instead of 1- Methyl-1H-pyrazole-4-boronic acid pinacol to prepare the title compound.
  • Example 11 1- (4- (4-((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) quinoline- 7-yl) -1H-pyrazol-1-yl) -2-methylpropan-2-ol
  • the preparation method is the same as that of Example 7, except that the commercially available raw material 1-isopropyl-1H-pyrazole-4-boronic acid pinacol ester is used instead of 1-methyl-1H-pyrazole-4-boronic acid pin That alcohol ester, the title compound.
  • Step 1 2 – ((7-Bromoquinolin-4-yl) oxy) -1-phenylethyl-1-one
  • Step 2 Preparation of 2-((7-bromoquinolin-4-yl) oxy) -3- (dimethylamino) -1-phenylprop-2-en-1-one
  • Step 2 Preparation of 7-bromo-4-((3-phenyl-1H-pyrazol-4-yl) oxy) quinoline
  • Step 3 Preparation of 7-bromo-4-((1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl) oxy) quinoline
  • the reaction mixture was stirred and reacted under an oxygen atmosphere at 75 ° C for 2h, and cooled to room temperature. Dilute with ethyl acetate (100 mL), filter through a short column of silica gel, and rinse with ethyl acetate. The filtrate was washed with water and a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, the filtrate was concentrated, and silica gel column chromatography was performed to obtain the title compound. LC-MS m / z: 405.9, 407.9 [M + H] + .
  • Step 4 4-((1-Cyclopropyl-3-phenyl-1H-pyrazol-4-yl) oxy) -7- (1-methyl-1H-pyrazol-4-yl) quinoline Preparation
  • Step 1 4-((1-Cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) -7- (4,4,5 Of 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) quinoline
  • Step 2 2- (4- (4-((1-Cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) quinoline- Synthesis of 7-yl) pyridin-2-yl) propan-2-ol
  • Step 3 Preparation of 1- (dimethylamino) -3-oxo-3- (tetrahydro-2H-pyran-4-yl) prop-1-en-2-ylbenzoate
  • Step 4 Preparation of methyl 3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-ylbenzoate
  • Step 7 4-((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) -7-methoxyquinoline- Preparation of 6-formamide
  • Step 2 4-((1-Cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) -7-methoxy-N- (1-methyl-1H-pyrazol-4-yl) quinoline-6-amine
  • Step 3 4-((1-Cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxa) -7-methoxy-N- ( Synthesis of 1- (oxetane-3-yl) -1H-pyrazol-4-yl) quinoline-6-amine
  • the preparation method is the same as Example 7, except that (1- (methylsulfonyl) -1,2,3,6-tetrahydropyridin-4-yl) boronic acid is used instead of 1-methyl-1H-pyrazole- 4-Poronic acid borate to prepare the title compound.
  • the preparation method is the same as Example 1, except that 2- (trifluoromethyl) -5,6,7,8-tetrahydro- [1,2,4] triazolo [1,5-a] pyridine is used Substitute azine for 2- (4-amino-2-pyridyl) propane-2-ol hydrochloride to prepare the title compound.
  • the compound of the present invention prepared in the above examples after each compound was formulated into 10 mM with DMSO, was sequentially diluted to 3.333 ⁇ M, 1.111 ⁇ M, 370 nM, 123 nM, 41 nM, 14 nM, 4.6 nM, 1.5 nM, 0.5 nM.
  • ALK5 purchased from Carna, Cat. No. 09-141; p38 ⁇ was purchased from Carna, Cat. No. 04-152; TGF ⁇ R1 peptide was purchased from SignalChem, Cat. No. T36-58; Sulfoxide (DMSO), purchased from Sigma, USA; EDTA, purchased from Sigma, USA; ADP-Glo Kinase Assay, purchased from Promega, Cat. No. v9102 / 3, 1 ⁇ kinase buffer (40mM Tris, pH 7.5, 0.10% BSA, 20 mM MgCl 2 , 1 mM DTT), prepared immediately before use.
  • the final concentration of the compound is 10 ⁇ M, which is configured to be 50-fold concentration, ie 500 ⁇ M: add 95 ⁇ l of 100% DMSO to the second well of the 96-well plate, and then add 5 ⁇ l of 10 mM compound solution. Formulated into a 1000 ⁇ M compound solution. Add 60 ⁇ l of 100% DMSO to the other wells. Take 30 ⁇ l of compound from the second well and add it to the third well, and make a 3-fold dilution in turn, diluting a total of 10 concentrations.
  • Dilution instrument automatic micropore pipette (Precision PRC384U).
  • FAM-labeled polypeptide and ATP were added to 1-fold kinase buffer to form a 2-fold substrate solution.
  • the 384-well plate was incubated at 28 degrees for 120 minutes.
  • Percent inhibition (max-sample RLU) / (max-min) * 100. "Min” is the fluorescence reading of the control sample without enzyme; “max” is the fluorescence reading of the sample added DMSO as a control.
  • the compounds of the present invention have a good inhibitory activity against ALK5 kinase, while having a low inhibitory effect on p38 ⁇ and high selectivity. It shows that the compound of the present invention has higher side effects and lower side effects.
  • Test compound The compound of the present invention prepared in the above examples, each compound was formulated into 4mM with DMSO, and then sequentially diluted 4 times to 20000.00nM, 5000.00nM, 1250.00nM, 312.5nM, 78.125nM, 19.53nM, 4.88nM, 1.22nM.
  • Luc-Smad2 / 3-NIH3T3 mouse fibroblasts (over-expressed SMAD2 after engineering, 3-responsive promoter) were donated by the Laboratory of China Pharmaceutical University.
  • DMEM purchased from Invitrogen, USA
  • FBS purchased from Invitrogen, USA
  • DMSO purchased from Sigma, USA
  • GloLysis Buffer, purchased from Progema, USA
  • Bright-Glo Luciferaseassay system purchased from American Promega
  • TGF ⁇ purchased from American PeproTech.
  • Cell resuscitation Dissolve the cells in a 37-degree water bath, then transfer to 15mL of pre-warmed medium, centrifuge at 1000rpm for 5 minutes, discard the medium, resuspend the cells with 15mL of fresh medium, and transfer to a 10cm Petri dish And placed in a 37 ° C, 5% CO 2 incubator, and the cells were replaced with fresh medium after 24 hours.
  • Cell passaging Transfer the recovered cells to a 50 mL sterile centrifuge tube, centrifuge at 1000 rpm for 5 minutes, discard the culture medium, take a uniformly dispersed cell count, adjust the appropriate cell concentration to 15 mL of fresh culture medium, and add it to a 10 cm Petri dish Incubate in a 37 ° C, 5% CO 2 incubator.
  • Luc-Smad2 / 3-NIH3T3 cells were normally cultured in a 10cm Petri dish until the confluence reached 80% -90%. After digestion, they were collected in 15mL centrifuge tubes. After centrifugation at 1000xg for 5 minutes, the supernatant was removed and resuspended in 1mL medium Afterwards, dilute the count by 10 times, dilute the cells according to the result of the count, and transfer the cell number of 4 ⁇ 10 3 / well into a 96-well plate (add 100 ⁇ l of resuspended cells per well).
  • the drug is weighed 1-2 mg (pre-weighed) and formulated into 4 mM stock solution using DMSO. After 24 hours, the medium was removed. Dilute the drug with 2% FBS medium and add 100 ⁇ l 1x drug solution to make the final drug concentration 20002000nM, 5000.00nM, 1250.00nM, 312.5nM, 78.125nM, 19.53nM, 4.88nM, 1.22nM, TGF ⁇ 1 final concentration 4 ng / mL, diluted with 2% FBS medium together with the compound.
  • the compounds of the present invention show good inhibitory activity on the TGF ⁇ -ALK5-SMAD2 / 3 signaling pathway in NIH3T3 cells, and are very promising as therapeutic agents for various cancer-related diseases.

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Abstract

涉及一类作为TGF-βR1抑制剂的化合物及其应用，具体地，提供式I所示的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药，它们的制备方法以及含有这些化合物的药物组合物和这些化合物或组合物用于治疗和/或预防TGF-βR1相关疾病，例如癌症、组织增生类疾病、纤维化和炎性疾病等类疾病的用途。该类化合物对TGF-βR1激酶表现出了显著的抑制活性，有希望成为TGF-βR1相关疾病的治疗剂。

Description

作为TGF-βR1抑制剂的化合物及其应用 技术领域
本发明属于医药化学领域，具体涉及一类TGF-βR1抑制剂的化合物或其药学上可接受的盐、异构体、溶剂化物、结晶或前药，它们的制备方法以及含有这些化合物的药物组合物和这些化合物或组合物用于治疗和/或预防TGF-βR1表达相关疾病，例如治疗癌症、骨髓发育不良综合征等疾病的用途。
背景技术
TGF-β(转换生长因子β)是一类重要的细胞因子，迄今为止已发现6种不同的亚型(TGF-β1～6)，彼此间的同源性各不相同，而在哺乳动物中只表达3种亚型，即TGF-β1、TGF-β2和TGF-β3。它是一个多功能生长因子超家族，具有广泛的生物学活性，参与早期胚胎发育，软骨和骨的形成，包外基质的合成，炎症，间质纤维化，免疫和内分泌功能的调节，肿瘤的形成和发展。同时，这3种异构体结构相似，它们的氨基酸序列具有高度同源性，但在各自基因敲除小鼠模型中，却表现为完全不同的表型，提示每一种异构体在体内均有特异的且互不交叉的功能。TGF-β家族的配体都可以与膜表面的受体结合，启动细胞内下游信号的传递。
TGF-β1是TGFβ最常见也是最重要的一种亚型，是肝脏中表达最丰富的一种亚型，也是已知最强的肝纤维化诱导因子，在慢性肝病向终末肝病发展的过程中发挥着举足轻重的作用(Yamazaki,et al.Digestive Disease,2011,29:284-288)。多项研究显示，TGF-β1和TGFβ受体在肝脏病变器官、血管和细胞外间质通常高表达。在经典的TGFβ-TGFβR-Smads通路中，TGF-β1激活信号通路中的TGFβR1(转换生长因子β受体1,ALK5)，进而调控整个信号通路，实现调控一系列与纤维化和肿瘤发生发展相关的靶基因的表达。目前普遍认为，TGF-β具对肝癌的促进作用主要表现在促进肿瘤细胞转移、加强肿瘤细胞免疫逃逸和诱导血管生成等方面(Ling,et al.Current Pharmaceutical Biotechnology,2011,12:2190-2202)。
关于靶向TGF-β通路的药物研究已进行了多年，但是TGFβR1抑制剂如Galunisertib等在动物模型上表现出一定的心脏毒性(如出血、功能退化、炎性损伤等)，究其原因，是由于该类药物的靶点选择性和特异性较低，药物在抑制TGFβR1激酶活化位点的同时，对其他具有相同激酶区域的蛋白也产生较强的抑制作用(如p38α)，进而产生众多非预期的脱靶毒副作用。因此，仍然需要开发选择性更高的TGFβR1抑制剂，以便特异性地调节TGF-β信号通路，从而用于TGF-β相关疾病的治疗。
发明内容
本发明的一个目的是提供以下通式I所示的一类具有TGF-βR1抑制活性的化合物或其药学上可接受的盐、异构体、溶剂化物、结晶或前药，
Figure PCTCN2019111568-appb-000001
本发明的另一个目的是提供制备本发明的通式I的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药的方法。
本发明的再一个目的是提供包含本发明的通式I的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药和药学可接受的载体的组合物，以及包含本发明的通式I的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药和另一种或多种药物的组合物。
本发明的还一个目的是提供本发明的通式I的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药治疗和/或预防TGF-βR1相关的疾病的方法，以及本发明的通式I的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药在制备用于治疗和/或预防TGF-βR1相关的疾病的药物中的应用。
针对上述目的，本发明提供以下技术方案：
第一方面，本发明提供通式I所示的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药，
X 1选自N和CH；
R 1选自羟基、氰基、羧基、硝基、烷基、卤代烷基、羟基烷基、烷氧基、环烷基氧基、杂环烷基氧基、环烷基烷氧基、杂环基烷氧基、环烷基烷基、杂环基烷基、单烷基氨基、双烷基氨基、环烷基氨基、杂环基氨基、芳基氨基、杂芳基氨基、环烷基、杂环基、芳基、杂芳基、芳基并杂环基和杂芳基并杂环基，其任选被一个或多个卤素、羟基、氨基、羧基、氰基、硝基、氧代基团、烷基磺酰基、氨基磺酰基、烷基磺酰基烷基、烷基、环烷基、杂环基、烷基杂环基、烷氧基、卤代烷基、羟基烷基、氨基烷基、羧基烷基、氰基烷基、硝基烷基、环烷基烷基、杂环烷基烷基、烷氧基烷基、单烷基氨基、双烷基氨基、烷基酰基、烷氧基酰基、烷基酰基氧基、氨基酰基、烯基酰基、单烷基氨基烯基酰基、双烷基氨基烯基酰基、单烷基氨基酰基、双烷基氨基酰基、烷基酰基氨基或烷基酰基氨基烷基取代；
R 2、R 3分别独立地选自氢、卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、双烷基氨基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述卤素、羟基、烷基、卤代烷基、羟基烷基、 烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、双烷基氨基、烯基、炔基、环烷基、杂环基、芳基或杂芳基任选被一个或者多个烷基、卤代烷基、羟基、羟基烷基、卤素、氧代基团、烷氧基、羧基、氰基、氨基、单烷基氨基或双烷基氨基取代；
R 4选自氢、卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、环烷基、杂环烷基、芳基、杂芳基、环烷基氨基、杂环烷基芳基、芳基氨基和杂芳基氨基，其中所述卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、环烷基、杂环烷基、芳基、杂芳基、环烷基氨基、杂环烷基芳基、芳基氨基和杂芳基氨基任选被一个或多个烷基、烷氧基、芳氧基、烷氨基、环烷基、杂环烷基、芳基、杂芳基、芳基氨基、卤素、羟基、氨基、硝基、羧基、氰基、烷基酰基、氨基酰基、烷氨基酰基、磺酰基或巯基取代；
R 5、R 6分别独立地选自氢、卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、双烷基氨基和环烷基；
m、n分别独立地选自1、2和3。
在一些具体的实施方案中，本发明的化合物为通式I的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药，其中，X 1为N。
在另一些具体的实施方案中，本发明的化合物为通式I的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药，其中，X 1为CH。
在一些具体的实施方案中，本发明的化合物为通式I的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药，其中：R 1选自羟基、氰基、羧基、硝基、C 1-6烷基、卤代C 1-6烷基、羟基C 1-6烷基、C 1-6烷氧基、C 3-6环烷基氧基、C 3-6杂环烷基氧基、C 3-6环烷基C 1-3烷氧基、C 3-6杂环基C 1-3烷氧基、C 3-6环烷基C 1-3烷基、C 3-6杂环基C 1-3烷基、单C 1-6烷基氨基、双C 1-6烷基氨基、C 3-6环烷基氨基、C 3-6杂环基氨基、C 6-12芳基氨基、C 5-8杂芳基氨基、C 3-6环烷基、C 3-6杂环基、C 6-12芳基、C 5-12杂芳基、C 6-12芳基并C 3-10杂环基和C 5-12杂芳基并C 3-6杂环基，其任选被一个或多个卤素、羟基、氨基、羧基、氰基、硝基、氧代基团、C 1-6烷基磺酰基、氨基磺酰基、C 1-6烷基磺酰基C 1-6烷基、C 1-6烷基、C 3-10环烷基、C 3-10杂环基、C 1-6烷基C 3-10杂环基、C 1-6烷氧基、卤代C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基、羧基C 1-6烷基、氰基C 1-6烷基、硝基C 1-6烷基、C 3-6环烷基C 1-6烷基、C 3-6杂环烷基C 1-6烷基、C 1-6烷氧基C 1-6烷基、单C 1-6烷基氨基、双C 1-6烷基氨基、C 1-6烷基酰基、C 1-6烷氧基酰基、C 1-6烷基酰基氧基、氨基酰基、C 2-10烯基酰基、 单C 1-6烷基氨基C 2-10烯基酰基、双C 1-6烷基氨基C 2-10烯基酰基、单C 1-6烷基氨基酰基、双C 1-6烷基氨基酰基、C 1-6烷基酰基氨基或C 1-6烷基酰基氨基C 1-6烷基取代；
优选地，R 1选自羟基、氰基、羧基、硝基、C 1-6烷基、卤代C 1-6烷基、羟基C 1-6烷基、C 1-6烷氧基、C 3-6环烷基氧基、C 3-6杂环烷基氧基、C 3-6环烷基C 1-3烷氧基、C 3-6杂环基C 1-3烷氧基、C 3-6环烷基C 1-3烷基、C 3-6杂环基C 1-3烷基、单C 1-6烷基氨基、双C 1-6烷基氨基、C 3-6环烷基氨基、C 6-12芳基氨基、C 5-8杂芳基氨基、C 3-6杂环基氨基、C 3-6环烷基、C 3-6杂环基、C 6-12芳基、C 5-12杂芳基、C 6-12芳基并C 3-10杂环基和C 5-12杂芳基并C 3-6杂环基，其任选被一个或多个卤素、羟基、氨基、羧基、氰基、硝基、氧代基团、C 1-3烷基磺酰基、氨基磺酰基、C 1-3烷基磺酰基C 1-3烷基、C 1-3烷基、C 3-6环烷基、C 3-6杂环基、C 1-3烷基C 3-6杂环基、C 1-3烷氧基、卤代C 1-3烷基、羟基C 1-3烷基、氨基C 1-3烷基、羧基C 1-3烷基、氰基C 1-3烷基、硝基C 1-3烷基、C 3-6环烷基C 1-3烷基、C 3-6杂环烷基C 1-3烷基、C 1-3烷氧基C 1-3烷基、单C 1-3烷基氨基、双C 1-3烷基氨基、C 1-3烷基酰基、C 1-3烷氧基酰基、C 1-3烷基酰基氧基、氨基酰基、C 2-6烯基酰基、单C 1-3烷基氨基C 2-6烯基酰基、双C 1-3烷基氨基C 2-6烯基酰基、单C 1-3烷基氨基酰基、双C 1-3烷基氨基酰基、C 1-3烷基酰基氨基或C 1-3烷基酰基氨基C 1-3烷基取代；
进一步优选地，R 1选自羟基、氰基、羧基、硝基、甲基、乙基、丙基、异丙基、三氟甲基、三氟乙基、羟甲基、羟乙基、羟丙基、2-羟基丙基、甲氧基、乙氧基、丙氧基、异丙氧基、硝基、羧基、氰基、氨基、甲氨基、乙基氨基、丙基氨基、异丙基氨基、二甲氨基、二乙氨基、甲基乙基氨基、二丙氨基、甲基丙基氨基、乙基丙基氨基、甲基酰基氨基、乙基酰基氨基、乙烯基酰基氨基、甲基酰基、乙基酰基、乙烯基酰基、氨基酰基、甲基氨基酰基、乙基氨基酰基、乙烯基、丙烯基、丁烯基、3-甲基-2-丁烯基、乙炔基、丙炔基、丁炔基、戊炔基、环丙基、环丁基、环戊基、环己基、4-6元杂环烷基、C 6-10芳基、5-10元杂芳基、C 6-12芳基氨基、C 5-8杂芳基氨基、C 6-10芳基并5-10元杂环基和5-10元杂芳基并5-6元杂环基，其任选被一个或者多个C 1-3烷基、卤代C 1-3烷基、羟基、羟基C 1-3烷基、卤素、氧代基团、C 1-3烷氧基、羧基、氰基、硝基、氨基、C 1-3烷基磺酰基、氨基磺酰基、C 1-3烷基磺酰基C 1-3烷基、单C 1-3烷基氨基或双C 1-3烷基氨基取代。
在一些具体的实施方案中，本发明的化合物为通式I的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药，其中：
R 2、R 3分别独立地选自氢、氟、氯、溴、碘、羟基、C 1-6烷基、卤代C 1-6烷基、羟基C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、羟基C 1-6烷氧基、硝基、羧基、氰基、氨基、单C 1-6烷基氨基、C 1-6烷基酰基氨基、C 1-6烷基酰基、氨基酰基、C 1-6烷基氨基酰基、双C 1-6烷基氨基、C 2-10烯基、C 2-10炔基、C 3-10环烷基、3-10元杂环烷基、C 6-18芳基和5-18元杂芳基，其中所述所述氟、氯、溴、碘、羟基、C 1-6烷基、卤代C 1-6烷基、羟基C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、 羟基C 1-6烷氧基、硝基、羧基、氰基、氨基、单C 1-6烷基氨基、C 1-6烷基酰基氨基、C 1-6烷基酰基、氨基酰基、C 1-6烷基氨基酰基、双C 1-6烷基氨基、C 2-10烯基、C 2-10炔基、C 3-10环烷基、3-10元杂环烷基、C 6-18芳基和5-18元杂芳基任选被一个或者多个烷基、卤代烷基、羟基、羟基烷基、卤素、氧代基团、烷氧基、羧基、氰基、氨基、单烷基氨基或双烷基氨基取代；优选地，R 2、R 3分别独立地选自氢、氟、氯、溴、碘、羟基、甲基、乙基、丙基、丁基、异丙基、异丁基、叔丁基、甲基氨基、乙基氨基、丙基氨基、异丙基氨基、环丙基、环丁基、环戊基、环己基、苯基、吡咯基、咪唑基、吡唑基、噻唑基、噻吩基、呋喃基、吡啶基、吡嗪基、嘧啶基、氮杂环丁基、氧杂环丁基、四氢吡咯基、四氢呋喃基、哌啶基、四氢吡喃基和吗啉基，它们任选被一个或多个羟基、甲基、乙基、丙基、丁基、异丙基、异丁基、叔丁基、羧基、氟、氯、溴、三氟甲基、三氟乙基、氨基甲基、氨基乙基、氨基丙基、甲基氨基、乙基氨基、丙基氨基、异丙基氨基、甲氧基、乙氧基、丙氧基、异丙氧基、氧代基团、甲酰基、乙酰基、丙酰基、异丙酰基、乙烯基、丙烯基、乙炔基、并炔基、苯基、萘基、吡咯基、咪唑基、吡唑基、噻唑基、噻吩基、呋喃基、吡啶基、吡嗪基和嘧啶基取代。
在一些具体的实施方案中，本发明的化合物为通式I的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药，其中：
R 4、R 5、R 6分别独立地选自氢、卤素、羟基、C 1-6烷基、卤代C 1-6烷基、羟基C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、羟基C 1-6烷氧基、硝基、羧基、氰基、氨基、单C 1-6烷基氨基、C 1-6烷基酰基氨基、C 1-6烷基酰基、氨基酰基、C 1-6烷基氨基酰基、双C 1-6烷基氨基、C 3-10环烷基。
优选地，R 4选自氢、卤素、羟基、C 1-6烷基、卤代C 1-6烷基、羟基C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、羟基C 1-6烷氧基、硝基、羧基、氰基、氨基、C 1-6烷基氨基、C 1-6烷基酰基氨基、C 1-6烷基酰基、氨基酰基、C 1-6烷基氨基酰基、C 3-8环烷基、C 3-8杂环烷基、C 6-12芳基、C 5-12杂芳基、C 3-8环烷基氨基、C 3-8杂环烷基芳基、C 6-12芳基氨基和C 5-8杂芳基氨基，其中所述卤素、羟基、C 1-6烷基、卤代C 1-6烷基、羟基C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、羟基C 1-6烷氧基、硝基、羧基、氰基、氨基、C 1-6烷基氨基、C 1-6烷基酰基氨基、C 1-6烷基酰基、氨基酰基、C 1-6烷基氨基酰基、C 3-8环烷基、C 3-8杂环烷基、C 6-12芳基、C 5-12杂芳基、C 3-8环烷基氨基、C 3-8杂环烷基芳基、C 6-12芳基氨基和C 5-8杂芳基氨基任选被一个或多个C 1-6烷基、C 1-6烷氧基、C 6-12芳氧基、C 1-6烷氨基、C 3-6环烷基、C 3-6杂环烷基、C 6-12芳基、C 5-8杂芳基、C 6-12芳基氨基、卤素、羟基、氨基、硝基、羧基、氰基、烷基酰基、氨基酰基、烷氨基酰基、磺酰基或巯基取代；R 5、R 6分别独立地选自氢、氟、氯、溴、碘、羟基、甲基、乙基、丙基、异丙基、三氟甲基、三氟乙基、羟甲基、羟乙基、羟丙基、2-羟基丙基、甲氧基、乙氧基、丙氧基、异丙氧基、硝基、羧基、氰基、氨基、甲氨基、乙基氨基、丙基氨基、异丙基氨基、二甲氨基、二乙氨基、甲基乙基氨基、二丙氨基、甲基丙基氨基、 乙基丙基氨基、甲基酰基氨基、乙基酰基氨基、乙烯基酰基氨基、甲基酰基、乙基酰基、乙烯基酰基、氨基酰基、甲基氨基酰基、乙基氨基酰基、环丙基、环丁基、环戊基、环己基。
在一些优选的实施方案中，本发明的通式I的化合物为以下通式Ia的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药，
Figure PCTCN2019111568-appb-000002
其中，R 2、R 3、R 4、R 5、R 6、m、n如权利要求1～5中所定义；
X 2和X 2’分别独立地选自N和C(R 7)，其中R 7选自氢、卤素、羟基、氧代基团、烷基磺酰基、烷基磺酰基烷基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、双烷基氨基和环烷基；
R 8选自氢、卤素、羟基、氧代基团、烷基磺酰基、烷基磺酰基烷基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、双烷基氨基和环烷基；和
p选自1、2和3。
在一些具体的实施方案中，根据本发明的通式Ia的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药，其中X 2和X 2’分别独立地选自N和C(R 7)，优选地，X 2为N且X 2’为C(R 7)或X 2为C(R 7)且X 2’为N，其中R 7选自氢、卤素、羟基、氧代基团、C 1-6烷基磺酰基、C 1-6烷基磺酰基C 1-6烷基、C 1-6烷基、卤代C 1-6烷基、羟基C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、羟基C 1-6烷氧基、硝基、羧基、氰基、氨基、单C 1-6烷基氨基、C 1-6烷基酰基氨基、C 1-6烷基酰基、氨基酰基、C 1-6烷基氨基酰基、双C 1-6烷基氨基和C 3-6环烷基；R 8选自氢、卤素、羟基、氧代基团、C 1-6烷基磺酰基、C 1-6烷基磺酰基C 1-6烷基、C 1-6烷基、卤代C 1-6烷基、羟基C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、羟基C 1-6烷氧基、硝基、羧基、氰基、氨基、单C 1-6烷基氨基、C 1-6烷基酰基氨基、C 1-6烷基酰基、氨基酰基、C 1-6烷基氨基酰基、双C 1-6烷基氨基和C 3-6环烷基；和p选自1、2和3。
在一些优选的实施方案中，本发明的通式I的化合物为以下通式Ib的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药，
Figure PCTCN2019111568-appb-000003
其中，R 2、R 3、R 4、R 5、R 6、X 1、m、n如通式I中所定义；
X 3、X 4分别独立地选自N、C、CH、CH 2、O和S；
Y 1选自NH、C(O)NH或不存在；
Figure PCTCN2019111568-appb-000004
为单键或双键；
R 9选自氢、卤素、羟基、氧代基团、烷基磺酰基、烷基磺酰基烷基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、双烷基氨基、环烷基；优选地，R 9选自氢、氟、氯、溴、碘、羟基、甲基、乙基、丙基、异丙基、三氟甲基、三氟乙基、羟甲基、羟乙基、羟丙基、2-羟基丙基、甲氧基、乙氧基、丙氧基、异丙氧基、硝基、羧基、氰基、氨基、甲氨基、乙基氨基、丙基氨基、异丙基氨基、二甲氨基、二乙氨基、甲基乙基氨基、二丙氨基、甲基丙基氨基、乙基丙基氨基、甲基酰基氨基、乙基酰基氨基、乙烯基酰基氨基、甲基酰基、乙基酰基、乙烯基酰基、氨基酰基、甲基氨基酰基、乙基氨基酰基、环丙基、环丁基、环戊基、环己基；和
q选自1、2、3、4和5。
在一些优选的实施方案中，本发明的通式I的化合物为以下通式Ic的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药，
Figure PCTCN2019111568-appb-000005
其中，R 2、R 3、R 4、R 5、R 6、X 1、m、n如通式I中所定义；
Y 2选自NH、C(O)NH或不存在；
R 10选自氢、卤素、羟基、氧代基团、烷基磺酰基、烷基磺酰基烷基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、双烷基氨基、环烷基；优选地，R 10选自氢、氟、氯、溴、碘、羟基、甲基、乙基、丙基、异丙基、三氟甲基、三氟乙基、羟甲基、羟乙基、羟丙基、2-羟基丙基、甲氧基、乙氧基、丙氧基、异丙氧基、硝基、羧基、氰基、氨基、甲氨基、乙基氨基、丙基氨基、异丙基氨基、二甲氨基、二乙氨基、甲基乙基氨基、二丙氨基、甲基丙基氨基、乙基丙基氨基、甲基酰基氨基、乙基酰基氨基、乙烯基酰基氨基、 甲基酰基、乙基酰基、乙烯基酰基、氨基酰基、甲基氨基酰基、乙基氨基酰基、环丙基、环丁基、环戊基、环己基；和
t选自1、2和3。
在一些优选的实施方案中，本发明的化合物为通式I、Ia、Ib或Ic的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药，其中：
R 1选自环戊基、环己基、4-6元杂环烷基、C 6-10芳基、5-10元杂芳基、C 6-12芳基氨基、C 5-8杂芳基氨基、C 6-10芳基并5-10元杂环基和5-10元杂芳基并5-6元杂环基，其任选被一个或者多个C 1-3烷基、卤代C 1-3烷基、羟基、羟基C 1-3烷基、卤素、氧代基团、C 1-3烷氧基、羧基、氰基、氨基、单C 1-3烷基氨基或双C 1-3烷基氨基取；
R 2、R 3分别独立地选自氢、氟、氯、溴、甲基、乙基、丙基、丁基、异丙基、异丁基、叔丁基、甲基氨基、乙基氨基、丙基氨基、异丙基氨基、环丙基、环丁基、环戊基、环己基、苯基、吡咯基、咪唑基、吡唑基、噻唑基、噻吩基、呋喃基、吡啶基、吡嗪基、嘧啶基、氮杂环丁基、氧杂环丁基、四氢吡咯基、四氢呋喃基、哌啶基、四氢吡喃基和吗啉基，它们任选被一个或多个羟基、甲基、乙基、丙基、丁基、异丙基、异丁基、叔丁基、羧基、氟、氯、溴、三氟甲基、三氟乙基、氨基甲基、氨基乙基、氨基丙基、甲基氨基、乙基氨基、丙基氨基、异丙基氨基、甲氧基、乙氧基、丙氧基、异丙氧基、氧代基团、甲酰基、乙酰基、丙酰基、异丙酰基、乙烯基、丙烯基、乙炔基、并炔基取代；
R 4选自氢、氢、氟、氯、溴、羟基、甲基、乙基、丙基、异丙基、三氟甲基、三氟乙基、羟甲基、羟乙基、羟丙基、2-羟基丙基、甲氧基、乙氧基、丙氧基、异丙氧基、硝基、羧基、氰基、氨基、甲氨基、乙基氨基、丙基氨基、异丙基氨基、二甲氨基、二乙氨基、甲基乙基氨基、二丙氨基、甲基丙基氨基、乙基丙基氨基、甲基酰基氨基、乙基酰基氨基、乙烯基酰基氨基、甲基酰基、乙基酰基、乙烯基酰基、氨基酰基、甲基氨基酰基、乙基氨基酰基、环丙基、环丁基、环戊基、环己基、4-6元杂环烷基、C 6-10芳基、5-10元杂芳基、C 6-12芳基氨基、C 5-8杂芳基氨基、C 6-10芳基、C 3-8环烷基氨基、C 3-8杂环烷基芳基、C 6-12芳基氨基、C 5-8杂芳基氨基、氨基甲酰基、氨基乙酰基，其任选被一个或者多个C 1-6烷基、C 1-6烷氧基、C 6-12芳氧基、C 1-6烷氨基、C 3-6环烷基、C 3-6杂环烷基、C 6-12芳基、C 5-8杂芳基、C 6-12芳基氨基、卤素、羟基、氨基、硝基、羧基、氰基、烷基酰基、氨基酰基、烷氨基酰基、磺酰基或巯基取代；
R 5、R 6分别独立地选自氢、氟、氯、溴、羟基、甲基、乙基、丙基、异丙基、三氟甲基、三氟乙基、羟甲基、羟乙基、羟丙基、2-羟基丙基、甲氧基、乙氧基、丙氧基、异丙氧基、硝基、羧基、氰基、氨基、甲氨基、乙基氨基、丙基氨基、异丙基氨基、二甲氨基、二乙氨基、甲基乙基氨基、二丙氨基、甲基丙基氨基、乙基丙基氨基、甲基酰基氨基、乙基酰基氨基、乙烯基酰基氨基、甲基酰基、乙基酰基、乙烯基酰基、氨基酰基、甲基氨基酰基、乙基氨基酰基、环丙基、 环丁基、环戊基、环己基；
R 8、R 9、R 10分别独立地选自氢、氟、氯、溴、碘、羟基、甲基、乙基、丙基、异丙基、三氟甲基、三氟乙基、羟甲基、羟乙基、羟丙基、2-羟基丙基、甲氧基、乙氧基、丙氧基、异丙氧基、硝基、羧基、氰基、氨基、甲氨基、乙基氨基、丙基氨基、异丙基氨基、二甲氨基、二乙氨基、甲基乙基氨基、二丙氨基、甲基丙基氨基、乙基丙基氨基、甲基酰基氨基、乙基酰基氨基、乙烯基酰基氨基、甲基酰基、乙基酰基、乙烯基酰基、氨基酰基、甲基氨基酰基、乙基氨基酰基、环丙基、环丁基、环戊基、环己基；
X 1为N；
X 2为N且X 2’为C(R 7)，或X 2为C(R 7)且X 2’为N，其中R 7选自氢、卤素、羟基、氧代基团、烷基磺酰基、烷基磺酰基烷基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、双烷基氨基和环烷基；
X 3、X 4分别独立地选自N、C、CH、CH 2、O和S；
Y 1、Y 2分别独立地选自NH和不存在；和
m、n、p、q分别独立地选自1和2。
在一些实施方案中，根本发明的化合物或其药学上可接受的盐、异构体、溶剂化物、结晶或前药，其中通式I具有以下通式Id的结构，
Figure PCTCN2019111568-appb-000006
其中，R 1、R 2、R 3、R 4、R 5、R 6、n如通式I中所定义。
在一些具体的实施方案中，本发明的化合物为通式I或Id的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药，其中R 1选自C 1-6烷氧基、吗啉基、哌啶基、吡唑基、苯基、吡啶基、吡啶氨基、吡咯并吡唑基、三唑并吡嗪基、硫代吗啉基，其任选被一个或多个卤素、羟基、氨基、羧基、氰基、硝基、氧代基团、C 1-6烷基磺酰基、氨基磺酰基、C 1-6烷基磺酰基C 1-6烷基、C 1-6烷基、C 3-10环烷基、C 3-10杂环基、C 1-6烷基C 3-10杂环基、C 1-6烷氧基、卤代C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基、羧基C 1-6烷基、氰基C 1-6烷基、硝基C 1-6烷基、C 3-6环烷基C 1-6烷基、C 3-6杂环烷基C 1-6烷基、C 1-6烷氧基C 1-6烷基、单C 1-6烷基氨基、双C 1-6烷基氨基、C 1-6烷基酰基、C 1-6烷氧基酰基、C 1-6烷基酰基氧基、氨基酰基、C 2-10烯基酰基、单C 1-6烷基氨基C 2-10烯基酰基、双C 1-6烷基氨基C 2-10烯基酰基、单C 1-6烷基氨基酰基、双C 1-6烷基氨基酰基、C 1-6烷基酰基氨基或C 1-6烷基酰基氨基C 1-6烷基取代；
R 2、R 3分别独立地选自氢、氟、氯、溴、碘、羟基、甲基、乙基、丙基、 丁基、异丙基、异丁基、叔丁基、甲基氨基、乙基氨基、丙基氨基、异丙基氨基、环丙基、环丁基、环戊基、环己基、苯基、吡咯基、咪唑基、吡唑基、噻唑基、噻吩基、呋喃基、吡啶基、吡嗪基、嘧啶基、氮杂环丁基、氧杂环丁基、四氢吡咯基、四氢呋喃基、哌啶基、四氢吡喃基和吗啉基，它们任选被一个或多个羟基、甲基、乙基、丙基、丁基、异丙基、异丁基、叔丁基、羧基、氟、氯、溴、三氟甲基、三氟乙基、氨基甲基、氨基乙基、氨基丙基、甲基氨基、乙基氨基、丙基氨基、异丙基氨基、甲氧基、乙氧基、丙氧基、异丙氧基、氧代基团、甲酰基、乙酰基、丙酰基、异丙酰基、乙烯基、丙烯基、乙炔基、并炔基、苯基、萘基、吡咯基、咪唑基、吡唑基、噻唑基、噻吩基、呋喃基、吡啶基、吡嗪基和嘧啶基取代；和
R 4选自氢、氨酰基和吡唑氨基，所述氨酰基和吡唑氨基任选被一个或多个C 1-6烷基、C 1-6烷氧基、C 6-12芳氧基、C 1-6烷氨基、C 3-6环烷基、C 3-6杂环烷基、C 6-12芳基、C 5-8杂芳基、C 6-12芳基氨基、卤素、羟基、氨基、硝基、羧基、氰基、烷基酰基、氨基酰基、烷氨基酰基、磺酰基或巯基取代。
在一个实施方案中，根据本发明的通式I或Id的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药，其中R 4被氧杂环丁基取代。
在一些实施方案中，本发明的化合物为通式I或Id的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药，其中X 1为N，R 1选自以下基团：
Figure PCTCN2019111568-appb-000007
Figure PCTCN2019111568-appb-000008
Figure PCTCN2019111568-appb-000009
R 2为四氢吡喃基；R 3选自C 1-6烷基和C 3-6环烷基；R 4选自H、
Figure PCTCN2019111568-appb-000010
本发明提供了以下具体化合物或其药学上可接受的盐、异构体、溶剂化物、结晶或前药：
Figure PCTCN2019111568-appb-000011
Figure PCTCN2019111568-appb-000012
另一方面，本发明提供本发明的通式化合物或其药学上可接受的盐、异构体、溶剂化物、结晶或前药的制备方法，包括：
Figure PCTCN2019111568-appb-000013
Figure PCTCN2019111568-appb-000014
或者
Figure PCTCN2019111568-appb-000015
或者
Figure PCTCN2019111568-appb-000016
1)式1的化合物与式2的化合物反应制得式3的化合物；
2)式3的化合物经反应制得式4的化合物；
3)式4的化合物经反应制得式5的化合物；
4)式5的化合物与式6的化合物反应制得式Ia的化合物；或者
5)式5的化合物与式7的化合物反应制得式8的化合物；
6)式8的化合物与式9或10的化合物反应制得式Ib的化合物；或者
7)式5的化合物与式11或12的化合物反应制得式Ic的化合物。
其中，R 1、R 2、R 3、R 4、R 5、R 6、R 8、R 9、R 10、X 1、X 2、X 2’、X 3、X 4、Y 1、Y 2、
Figure PCTCN2019111568-appb-000017
m、n、p、q和t具有通式I中的含义；A为卤素，优选为溴。
第三方面，本发明提供的药物组合物，其包含本发明的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药。
在一些实施方案中，本发明提供的药物组合物，其包含本发明的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药，还包含选自下列组成的组中的一种或多种药剂：TGF-βR1抑制剂、酪氨酸蛋白酶抑制剂、EGFR抑制剂、VEGFR抑制剂、Bcr-Abl抑制剂、c-kit抑制剂、c-Met抑制剂、Raf抑制剂、MEK抑制剂、组蛋白去乙酰酶抑制剂、IDH抑制剂、VEGF抗体、EGF抗体、HIV蛋白激酶抑制剂、HMG-CoA还原酶抑制剂等。
在一些实施方案中，本发明提供本发明的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药及包含本发明的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药的药物组合物，所述化合物或药物组合物用于治疗和/或预防TGF-βR1相关的疾病的药物中的应用。
可以将本发明的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药与药学上可接受的载体、稀释剂或赋形剂混合制备成药物制剂，以适合于经口或胃肠外给药。给药方法包括，但不限于皮内、肌内、腹膜内、静脉内、皮下、鼻内和经口途径。所述制剂可以通过任何途径施用，例如通过输注 或推注，通过经上皮或皮肤粘膜(例如口腔粘膜或直肠等)吸收的途径施用。给药可以是全身的或局部的。经口施用制剂的实例包括固体或液体剂型，具体而言，包括片剂、丸剂、粒剂、粉剂、胶囊剂、糖浆、乳剂、混悬剂等。所述制剂可通过本领域已知的方法制备，且包含药物制剂领域常规使用的载体、稀释剂或赋形剂。
第四方面，本发明提供本发明通式I、Ia、Ib、Ic或Id所示的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药，或包含其的药物组合物在制备治疗和/或预防癌症、组织增生类疾病、纤维化或炎性疾病的药物中的应用，其中所述的癌症、组织增生类疾病、纤维化或炎性疾病的病状包括但不限于：黑色素瘤、乳头状甲状腺肿瘤、胆管癌、结肠癌、卵巢癌、肺癌、恶性淋巴肿瘤，肝、肾、膀胱、前列腺、乳腺和胰腺的癌和肉瘤，以及皮肤、结肠、甲状腺、肺和卵巢的原发和复发性实体瘤或者白血病、成胶质细胞瘤(神经胶质瘤)、骨髓增生异常综合征(MDS)、骨髓组织增殖性赘生物(MPN)、急性骨髓性白血病(AML)、肉瘤、非小细胞肺癌、软骨肉瘤、胆管癌或血管免疫母细胞性淋巴、肝纤维化和慢性肾脏疾病。
术语说明
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。
本发明化合物中的“氢”、“碳”、“氧”包括其所有同位素。同位素应理解为包括具有相同原子数但具有不同质量数的那些原子。举例来说，氢的同位素包括氚和氘，碳的同位素包括 13C和 14C，氧的同位素包括 16O和 18O等。
本发明的“卤素”是指氟、氯、溴、碘。本发明的“卤代”是指被氟、氯、溴或碘取代。
本发明的“烷基”指直链或支链的饱和脂肪烃基团，优选含1至6个碳原子的直链或支链基团，更优选含1至3个碳原子的直链或支链基团，非限制性实例包括甲基、乙基、正丙基和异丙基等。烷基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上。
本发明的“卤代烷基”是指至少被一个卤素取代的烷基。
本发明的“羟基烷基”是指至少被一个羟基取代的烷基。
本发明的“烷氧基”是指-O-烷基。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、正丙氧基和异丙氧基等。烷氧基可以是任选取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上。
本发明的“环烷基”是指环状的饱和烃基，例如环丙基和环丁基等。
本发明的“杂环基”是指具有1至4个环杂原子(其中每个杂原子独立地选自氮、氧、硫、硼、磷以及硅)的3至12元非芳香族环系统的基团(“3-12元杂环基”)。在包含一个或多个氮原子的杂环基基团中，连接点可以是碳或氮原子，只要化合价许可。杂环基基团或者可以是单环的(“单环的杂环基”)或者是融合 的、桥联的或螺的环系统(例如二环系统(“二环的杂环基”))并且可以是饱和的或可以是部分不饱和的。合适的饱和和部分饱和的杂环基包括但不限于四氢呋喃基、四氢噻吩基、吡咯烷基、哌啶基、哌嗪基、吗啉基、异噁唑啉基等。杂环基二环的环系统可以在一个或两个环中包括一个或多个杂原子。“杂环基”也包括环系统，其中杂环，如以上定义的，是与一个或多个碳环基基团融合的(其中连接点在碳环基或在杂环上)，或环系统中的杂环，如以上定义的，是与一个或多个芳基或杂芳基融合的(其中连接点在杂环上)，并且在此类情况下，环成员的数目继续称作在杂环系统中的环成员的数目。除非另有规定，杂环基的每个实例是独立地任选取代地，即，未取代的(“未取代的杂环基”)或用一个或多个取代基取代的(“取代的杂环基”)，如取代或未取代的哌啶基、取代或未取代的桥环吗啉基等。在某些实例中，该杂环基基团是取代的4-10元杂环基。融合至C 6芳基环的示例性5-元杂环基基团包括但不限于，吲哚啉基、异吲哚啉基、二氢苯并呋喃基、二氢苯并噻吩基、苯并噁唑啉酮基等等。融合至C 6芳基环的示例性6-元杂环基基团包括但不限于，四氢喹啉基、四氢异喹啉基等。融合至5-元杂芳环的5-和6-元杂环烷基基团示例性包括但不限于
Figure PCTCN2019111568-appb-000018
Figure PCTCN2019111568-appb-000019
等。
本发明的“芳基”是指可以包含单环或稠合多环的芳香体系，优选包含单环或稠合双环的芳香体系，其含有6个至18个碳原子，优选含有约6至约12个碳原子。合适的芳基包括但不限于苯基、萘基、蒽基、四氢萘基、芴基、茚满基。芳基可以是任选取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上。
本发明的“杂芳基”(其本身或在任何组合基团中，例如“杂芳基氨基”)是指至少有一个碳原子被杂原子替代的芳基，由5-20个原子构成(5-20元杂芳基)，进一步优选由5-12个原子组成(5-12元杂芳基)，所述的杂原子可以为O、S、N，包括但不限于咪唑基、苯并咪唑基、咪唑并吡啶基、喹唑啉酮基、吡咯基、咪唑酮基、呋喃基、噻吩基、吡唑基、噁唑基、噻唑基、异噁唑基、异噻唑基、噁二唑基、三唑基、嘧啶基、吡啶基、吡嗪基、哒嗪基、嘧啶并吡唑基、嘧啶并咪唑基等。杂芳基可以是任选取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上。
本发明的“异构体”是具有相同分子式的但在性质上或在其原子的键序列上或在其原子的空间排列上不同的化合物。立体异构体是其原子在空间排列上不同的异构体。彼此不成镜像的立体异构体是非对映体并且互相是非重叠的镜像的立体异构体是对映体。当化合物具有不对称中心时，例如，它被键合到四个不同的基团，一对对映体是可能的。对映体以其不对称中心的绝对构型为特征并且通过 Cahn和Prelog的R-和S-测序规则，或通过分子旋转偏振光的平面的方法被描述并指定作为右旋的或左旋的(即分别作为(+)或(-)-异构体)。手性化合物可以作为单一的对映体或其混合物存在。包含对映体的相等比例的混合物称作“外消旋混合物”。
本发明的“药学上可接受的盐”是指本发明化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。
本发明的“溶剂化物”在常规意义上是指溶质(如活性化合物、活性化合物的盐)和溶剂(如水)组合形成的复合物。溶剂是指本领域的技术人员所知的或容易确定的溶剂。如果是水，则溶剂化物通常被称作水合物，例如半水合物、一水合物、二水合物、三水合物或其替代量等。
本发明生物电子等排体(或简称“电子等排体”子是用于定义其中一个或多个原子(或原子团)已被具有与它们所置换的那些原子具有相似空间和/或电子特征的置换原子(或原子团)所取代的药物类似物的本领域中一般公认的术语。
本发明的“结晶”是指其内部结构是在三维上规律地重复构成原子(或其集团)而形成的固体，有别于不具有这种规律的内部结构的无定形固体。
“前药”是指在生物体中的生理条件下，由于与酶、胃酸等反应而转化成式I、Ia、Ib、Ic或Id的化合物。
本发明的“药物组合物”是指包含任何一种本文所述的化合物，包括对应的异构体、前药、溶剂化物、药学上可接受的盐或其化学的保护形式，和一种或多种药学上可接受载体的混合物。
本发明的“赋形剂”指加入到药用组合物中以进一步促进给予化合物的惰性物质。赋形剂可以包括碳酸钙、磷酸钙、多种糖类和多种类型的淀粉、纤维素衍生物、明胶、植物油、聚乙二醇。
本发明的“药学上可接受的载体”是指对有机体不引起明显刺激性和不干扰所给予化合物的生物活性和性质的载体，包含所有的溶剂、稀释剂或其它赋形剂、分散剂、表面活性剂等渗剂、增稠剂或乳化剂、防腐剂、固体粘合剂、润滑剂等。除非任何常规载体介质与本发明化合物不相容。可以作为药学上可接受的载体的一些实例包括，但不限于糖类，如乳糖；淀粉，如玉米淀粉；纤维素及其衍生物，如羧甲基纤维素钠；麦芽、明胶等。
本发明的“ 1H NMR(400MHz,DMSO)”中涉及的DMSO均指六氘代二甲亚砜，即DMSO-d 6。
具体实施方式
下面代表性的实施例是为了更好地说明本发明，而非用于限制本发明的保护范围。以下实施例中使用的材料如无特殊说明均为商购获得。
实施例1 2-(4-((4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)喹啉-7-基)氨基)吡啶-2-基)丙-2-醇
Figure PCTCN2019111568-appb-000020
步骤1：2-((7-溴喹啉-4-基)氧基)-1-(四氢-2H-吡喃-4-基)乙-1-酮的合成
Figure PCTCN2019111568-appb-000021
取7-溴-4-羟基喹啉(2g,8.9mmol)和丙酮(20mL)置于反应瓶，将2-溴-1-(四氢-2H-吡喃-4-基)乙酮(2.3g,11.1mmol)和碳酸钾(1.53g,11.1mmol)加入上述反应瓶，反应体系于40℃下搅拌反应5h。反应完成，过滤，减压浓缩滤液，柱层析纯化得标题化合物665mg。LC-MS m/z:350.1,352.1[M+H] +。
步骤2：(E)-2-((7-溴喹啉-4-基)氧基)-3-(二甲基氨基)-1-(四氢-2H-吡喃-4-基)丙-2-烯-1-酮的合成
Figure PCTCN2019111568-appb-000022
取2-((7-溴喹啉-4-基)氧基)-1-(四氢-2H-吡喃-4-基)乙-1-酮(665mg,1.9mmol)和N,N-二甲基甲酰胺二甲基缩醛(2mL)置于反应瓶，体系于100℃搅拌反应2h。反应完成，冷却至室温，减压浓缩，将残余物溶于乙酸乙酯(40mL)中。用水(50mL)和饱和氯化钠水溶液(50mL)洗涤。无水硫酸钠干燥有机相，减压浓缩得到标题化合物，直接投入下一步。
步骤3：7-溴-4-((3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)喹啉的合成
Figure PCTCN2019111568-appb-000023
取(E)-2-((7-溴喹啉-4-基)氧基)-3-(二甲基氨基)-1-(四氢-2H-吡喃-4-基)丙-2-烯-1-酮(665mg,1.64mmol)和乙酸(10mL)置于反应瓶，冷却到0℃，加入肼-水合物(0.5mL)，恢复至室温，氮气氛围下搅拌反应过夜。将混合物倒入冰水混合物(25mL)中，用乙酸乙酯萃取，合并有机相。有机相依次用水(20mL)、饱和碳酸氢钠和饱和食盐水(100mL)洗涤，无水硫酸钠干燥，减压浓缩，柱层析纯化得350mg。LC-MS m/z:374.0,376.0[M+H] +。
步骤4：7-溴-4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)喹啉的合成
Figure PCTCN2019111568-appb-000024
取2,2-联吡啶(46mg,0.3mmol)和乙酸铜(54mg,0.3mmol)置于反应瓶，加入1,2-二氯乙烷(2mL)，于75℃回流25分钟，然后冷却至室温。加入7-溴-4-((3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)喹啉(100mg,0.26mmol)的1.2-二氯乙烷(1mL)溶液，最后加入环丙基硼酸(46mg,0.52mmol)和碳酸钠(57mg,0.52mmol)。将反应体系在氧气氛围下于75℃搅拌反应2h，冷却到室温。乙酸乙酯(20mL)稀释反应液，经硅胶短柱过滤，用乙酸乙酯(50mL)冲洗。将滤液用水和饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩得标题化合物88mg。LC-MS m/z:414.1,416.1[M+H] +。
步骤5：2-(4-((4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)喹啉-7-基)氨基)吡啶-2-基)丙-2-醇的合成
Figure PCTCN2019111568-appb-000025
将7-溴-4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)喹啉(88mg,0.21mmol)、2-(4-氨基-2-吡啶基)丙烷-2-醇盐酸盐(48mg,0.25mmol)、叔丁醇钠(60mg,0.63mmol)、2-二环己基磷-2’,4’,6’-三异丙基联苯(8mg,0.017mmol)和三(二亚苄基丙酮)二钯(0)(4mg,0.004mmol)置于反应瓶，加入2mL叔丁醇溶解，在氩气氛围下于100℃搅拌反应过夜。冷却至室温，加入50mL乙酸乙酯和10mL水萃取，有机相用无水硫酸钠干燥、减压浓缩，柱析纯化得到标题化合物12mg。LC-MS m/z:486.2[M+H] +. 1H NMR(400MHz,DMSO)δ10.06(s,1H),8.66(d,J＝5.1Hz,1H),8.29(d,J＝8.9Hz,1H),8.24(d,J＝6.1Hz,1H),7.96(s,1H),7.82(s,1H),7.57(d,J＝8.8Hz,1H),7.44(s,1H),7.11(s,1H),6.68(d,J＝5.0Hz,1H),5.59(s,1H),3.79(d,J＝11.1Hz,2H),3.76-3.60(m,1H),3.29-3.17(m,2H),2.76(dt,J＝15.5,7.9Hz,1H),1.81-1.56(m,4H),1.48(s,6H),1.06(d,J＝3.1Hz,2H),0.96(d,J＝5.3Hz,2H).
实施例2 4-(4–((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)喹啉-7-基)吗啉
Figure PCTCN2019111568-appb-000026
制备方法同实施例1，不同之处为用吗啉代替2-(4-氨基-2-吡啶基)丙烷-2-醇盐酸盐，制得标题化合物。LC-MS m/z:420.9[M+H] +. 1H NMR(400MHz,CDCl 3)δ8.55(d,J＝5.2Hz,1H),8.16(d,J＝9.2Hz,1H),7.35(s,2H),7.30(dd,J＝9.2,2.1Hz,1H),6.47(d,J＝5.3Hz,1H),3.97-3.83(m,5H),3.56(td,J＝10.9,7.2,3.7Hz,1H),3.35-3.31(m,5H),2.91-2.61(m,3H),1.86(td,J＝16.0,12.5,4.3Hz,2H),1.73(d,J＝11.7Hz,2H),1.14–1.06(m,2H),1.04-0.96(m,2H).
实施例3 4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-7-(3-(三氟甲基)-5,6-二氢-[1,2,4]三唑并[4,3-a]吡嗪-7(8H)-基)喹啉
Figure PCTCN2019111568-appb-000027
将7-溴-4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)喹啉(50mg,0.12mmol)、3-(三氟甲基)-5,6,7,8-四氢-[1,2,4]三唑并[4,3-a]吡嗪盐酸盐(35mg,0.14mmol)、碳酸铯(118mg,0.36mmol)、2-二环己基磷-2,4,6-三异丙基联苯(14mg,0.024mmol)和醋酸钯(3mg,0.012mmol)置于反应瓶，加入5mL的二氧六环，氮气保护，于100℃条件下搅拌反应3h。反应完成，恢复至室温，加入水稀释，然后乙酸乙酯萃取，有机相用水和饱和氯化钠水溶液洗涤，无水硫酸钠干燥，减压浓缩，柱层析纯化得标题化合物。LC-MS m/z:526.3[M+H] +. 1H NMR(400MHz,CDCl 3)δ:8.63(d,J＝5.2Hz,1H),8.29(d,J＝7.1Hz,1H),7.52(s,1H),7.45–7.30(m,2H),6.57(d,J＝5.3Hz,1H),4.85(s,2H),4.37(t,J＝5.2Hz,2H),3.99-3.94(m,2H),3.91(s,2H),3.59(m,1H),3.36(m,2H),2.88-2.75(m,1H),1.75(d,J＝13.6Hz,4H),1.17-1.10(m,2H),1.05(m,2H). 1H NMR(400MHz,DMSO)δ8.59(d,J＝5.2Hz,1H),8.17(d,J＝11.2Hz,1H),7.94(s,1H),7.64(dd,J＝11.2,2.4Hz,1H),7.45(d,J＝2.4Hz,1H),6.56(d,J＝5.2Hz,1H),4.91(s,2H),4.34(t,J＝5.1Hz,2H),4.02(t,J＝5.2Hz,2H),3.88–3.71(m,2H),3.73–3.63(m,1H),3.30–3.19(m,2H),2.82–2.65(m,1H),1.78–1.59(m,4H),1.12–1.01(m,2H),1.01–0.88(m,2H).
实施例4 4-(4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)喹啉-7-基)硫代吗啉-1,1-二氧化物
Figure PCTCN2019111568-appb-000028
制备方法同实施例1，不同之处为用硫代吗啉-1,1-二氧化物代替2-(4-氨基-2- 吡啶基)丙烷-2-醇盐酸盐，制得标题化合物。LC-MS m/z:469.2[M+H] +. 1H NMR(400MHz,DMSO)δ8.57(d,J＝5.2Hz,1H),8.14(d,J＝9.2Hz,1H),7.93(s,1H),7.54(dd,1H),7.39(d,J＝2.3Hz,1H),6.54(d,J＝5.2Hz,1H),3.99(s,4H),3.77(dd,J＝8.1,3.0Hz,2H),3.69(m,1H),3.29-3.24(m,2H),3.20(s,4H),2.79-2.68(m,1H),1.72-1.59(m,4H),1.09-1.02(m,2H),0.95(dt,J＝12.6,6.1Hz,2H).
实施例5 1-(4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)喹啉-7-基)-4-甲基哌啶-4-醇
Figure PCTCN2019111568-appb-000029
制备方法同实施例1，不同之处为用4-甲基-4-羟基哌啶代替2-(4-氨基-2-吡啶基)丙烷-2-醇盐酸盐，制得标题化合物。LC-MS m/z:449.2[M+H] +. 1H NMR(400MHz,DMSO)δ8.51(d,J＝5.3Hz,1H),8.06(d,J＝9.3Hz,1H),7.92(s,1H),7.47(dd,J＝9.4,2.4Hz,1H),7.20(d,J＝2.3Hz,1H),6.47(d,J＝5.3Hz,1H),4.38(s,1H),3.84-3.73(m,2H),3.68(m,1H),3.63-3.50(m,2H),3.25(m,4H),2.73(m,1H),1.63(m,8H),1.17(s,3H),1.09-1.01(m,2H),0.94(td,J＝7.4,5.5Hz,2H).
实施例6 4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-7-(2-(2,2,2-三氟乙基)-2,6二氢吡咯并[3,4-c]吡唑-5(4H)-基)喹啉
Figure PCTCN2019111568-appb-000030
制备方法同实施例3，不同之处为用2-(2,2,2-三氟乙基)-2,4,5,6-四氢吡咯并[3,4-c]吡唑盐酸盐代替3-(三氟甲基)-5,6,7,8-四氢-[1,2,4]三唑并[4,3-a]吡嗪盐酸盐，制得标题化合物。LC-MS m/z:525.2[M+H] +. 1H NMR(400MHz,CDCl 3)δ8.57–8.53(m,1H),8.22(d,J＝9.0Hz,1H),7.47(s,1H),7.40–7.34(m,1H),7.13–7.03(m,2H),6.42(t,J＝5.0Hz,1H),4.78-4.70(m,2H),4.65(d,J＝15.7Hz,2H),4.61(s,2H),3.97–3.87(m,2H),3.65–3.53(m,1H),3.41-3.32(m,2H),2.89–2.76(m,1H),1.97-1.82(m,2H),1.80-1.71(m,2H),1.17-1.10(m,2H),1.07–1.00(m,2H).
实施例7 4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-7-(1-甲基-1H-吡唑-4-基)喹啉
Figure PCTCN2019111568-appb-000031
将7-溴-4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)喹啉(650mg,1.57mmol)、1-甲基-1H-吡唑-4-硼酸频那酯(650mg,3.15mmol)、碳酸钾(430mg,3.15mmol)和1,1'-双二苯基膦二茂铁二氯化钯(55mg,0.08mmol)置于反应瓶，加入二氧六环(20mL)和水(2mL)，氮气保护，升温至100℃搅拌反应1.5h。反应完成，加入水和乙酸乙酯萃取，有机相用水和饱和氯化钠水溶液洗涤，无水硫酸钠干燥，减压浓缩，柱层析纯化得标题化合物。LC-MS m/z:416.2[M+H] +. 1HNMR(400MHz,CDCl 3)δ8.67(d,J＝4.9Hz,1H),8.30(d,J＝8.5Hz,1H),8.16(s,1H),7.94(s,1H),7.80(s,1H),7.72(d,J＝8.5Hz,1H),7.39(s,1H),6.61(d,J＝5.0Hz,1H),4.00(s,3H),3.93(d,J＝10.3Hz,2H),3.59(d,J＝3.5Hz,1H),3.36(t,J＝11.4Hz,2H),2.82(t,J＝11.6Hz,1H),1.94-1.83(m,2H),1.77(d,J＝12.6Hz,2H),1.12(m,2H),1.04(m,2H).
实施例8 4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-7-(1H-吡唑-4-基)喹啉
Figure PCTCN2019111568-appb-000032
制备方法同实施例7，不同之处为用4-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)-1H-吡唑代替1-甲基-1H-吡唑-4-硼酸频那酯，制得标题化合物。LC-MS m/z:402.2[M+H] +. 1H NMR(400MHz,DMSO)δ13.11(s,1H),8.68(d,J＝5.2Hz,1H),8.44(s,1H),8.26(d,J＝8.8Hz,2H),7.98(s,1H),7.96(dd,J＝8.6,1.7Hz,1H),6.70(d,J＝5.2Hz,1H),5.76(s,1H),3.78(dt,J＝11.2,3.1Hz,2H),3.70(m,1H),3.27(m,2H),2.81-2.71(m,1H),1.68(dt,J＝13.6,6.8Hz,4H),1.11-1.03(m,2H),0.96(td,J＝7.5,5.5Hz,2H).
实施例9 4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-7-(1-(甲基磺酰基)-1H-吡唑-4-基)喹啉
Figure PCTCN2019111568-appb-000033
将4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-7-(1H-吡唑-4-基)喹啉(50mg,0.12mmol)溶于二氯甲烷，加入三乙胺(18mg,0.18mmol)，冰浴下加入甲基磺酰氯(17mg,0.14mmol)，然后室温搅拌2h。反应完成，加入甲醇淬灭反应，加入水和乙酸乙酯萃取，用水和饱和食盐水洗涤有机相，无水硫酸钠干燥，减压浓缩，薄层纯化得标题化合物。LC-MS m/z:480.2[M+H] +. 1H NMR(400MHz,CDCl 3)δ8.72(d,J＝5.1Hz,1H),8.43(s,1H),8.37(d,J＝8.6Hz,1H),8.26(d,J＝10.4Hz,2H),7.73(dd,J＝8.6,1.5Hz,1H),7.41(s,1H),6.68(d,J＝5.2Hz,1H),3.98–3.88(m,2H),3.60(m,1H),3.43(s,3H),3.37(td,J＝11.7,1.9Hz,2H),2.83(m,1H),1.95–1.83(m,2H),1.82-1.73(m,2H),1.17–1.13(m,2H),1.05(m,2H).
实施例10 4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-7-(1-(2-(甲基磺酰基)乙基)-1H-吡唑-4-基)喹啉
Figure PCTCN2019111568-appb-000034
将4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-7-(1H-吡唑-4-基)喹啉(81mg,0.2mmol)、甲基乙烯基砜(22μL)和碳酸钾(56mg,0.4mmol)加至反应瓶中，加入N,N-二甲基甲酰胺(1mL)溶解，在80℃下搅拌反应2h。反应结束后，加入水和乙酸乙酯，萃取，有机相经无水硫酸钠干燥后，减压浓缩，柱层析纯化得标题化合物。LC-MS m/z:508.3[M+H] +. 1H NMR(400MHz,CDCl 3)δ8.71(d,J＝5.2Hz,1H),8.35(d,J＝8.6Hz,1H),8.21(s,1H),8.06(s,1H),7.99(s,1H),7.73(dd,J＝8.6,1.7Hz,1H),7.43(s,1H),6.66(d,J＝5.2Hz,1H),4.73(t,2H),4.00–3.89(m,2H),3.74(t,J＝6.0Hz,2H),3.67–3.58(m,1H),3.45–3.33(m,2H),2.91–2.79(m,1H),2.60(s,3H),1.98–1.85(m,2H),1.82–1.74(m,2H),1.19–1.13(m,2H),1.10–1.03(m,2H).
实施例11 1-(4-(4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)喹啉-7-基)-1H-吡唑-1-基)-2-甲基丙-2-醇
Figure PCTCN2019111568-appb-000035
将4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-7-(1H-吡唑-4-基)喹啉(40mg，0.1mmol)、2,2-二甲基环氧乙烷(2mL)和碳酸铯(48mg,0.15mmol) 加至微波管，于120℃微波条件下搅拌反应30min。反应完成后，二氯甲烷稀释反应液，过滤，收集滤液，减压浓缩，薄层纯化得标题化合物。LC-MS m/z:474.2[M+H] +. 1H NMR(400MHz,DMSO)δ8.67(d,J＝5.2Hz,1H),8.33(s,1H),8.26(d,J＝8.7Hz,1H),8.19(d,J＝1.5Hz,1H),8.11(s,1H),7.97(s,1H),7.91(dd,J＝8.7,1.7Hz,1H),6.69(d,J＝5.2Hz,1H),4.80(s,1H),4.08(s,2H),3.81–3.74(m,2H),3.69(m,1H),3.24(dd,J＝9.3,4.9Hz,2H),2.80–2.69(m,1H),1.67(dt,J＝13.8,6.7Hz,4H),1.12(s,6H),1.09-1.04(m,2H),0.97-0.92(m,2H).
实施例12 4–((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-7-(1-异丙基-1H-吡唑-4-基)喹啉的制备
Figure PCTCN2019111568-appb-000036
制备方法同实施例7，不同之处为用商业可得的原料1-异丙基-1H-吡唑-4-硼酸频那醇酯代替1-甲基-1H-吡唑-4-硼酸频那醇酯，制得标题化合物。LC-MS m/z:444.2[M+H] +. 1H NMR(400MHz,DMSO)δ8.68(d,J＝5.2Hz,1H),8.50(s,1H),8.24(dd,J＝13.9,4.9Hz,2H),8.11(s,1H),7.97(s,1H),7.93(dd,J＝8.7,1.5Hz,1H),6.70(d,J＝5.2Hz,1H),4.54(dq,J＝13.5,6.8Hz,1H),3.78(dd,J＝8.1,3.0Hz,2H),3.70(dq,J＝11.1,3.8Hz,1H),3.30-3.21(m,2H),2.82-2.70(m,1H),1.66(dt,J＝19.1,6.8Hz,4H),1.49(d,J＝6.7Hz,6H),1.11-1.03(m,2H),0.96(m,2H).
实施例13 4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-7-(1-(2,2,2-三氟乙基)-1H-吡唑-4-基)喹啉的制备
Figure PCTCN2019111568-appb-000037
将4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-7-(1H-吡唑-4-基)喹啉(40mg,0.1mmol)溶于无水四氢呋喃，0℃搅拌，加入氢化钠(5mg,0.15mmol)，搅拌反应1h，加入2,2,2-三氟乙基三氟甲烷磺酸酯(46mg,0.2mmol)，然后室温搅拌反应5h。加入甲醇淬灭反应，水和乙酸乙酯萃取，用水和饱和食盐水洗涤有机相，无水硫酸钠干燥，减压浓缩，薄层纯化得标题化合物。LC-MS m/z:484.2[M+H] +. 1H NMR(400MHz,CDCl 3)δ8.70(d,J＝4.9Hz,1H),8.33(d,J＝8.6Hz,1H),8.21(s,1H),8.04(s,1H),7.93(s,1H),7.72(dd,J＝8.6,1.5Hz,1H),7.40(s,1H),6.65(d,J＝5.2Hz,1H),4.80(q,J＝8.3Hz,2H),3.93(dd,J＝11.5,2.0Hz,2H),3.60(m,1H),3.37(td,J＝11.6,1.8Hz,2H),2.83(tt,J＝11.6,3.8Hz,1H),1.90(m, 2H),1.76(d,J＝13.2Hz,2H),1.18-1.10(m,2H),1.05(m,2H).
实施例14 4–((1-环丙基-3-苯基-1H-吡唑-4-基)氧基)-7-(1-甲基-1H-吡唑-4-基)喹啉
Figure PCTCN2019111568-appb-000038
步骤1：2–((7-溴喹啉-4-基)氧基)-1-苯基乙基-1-酮的制备
Figure PCTCN2019111568-appb-000039
取7-溴-4-羟基喹啉(5g,22.3mmol)和甲苯(100mL)置于反应瓶，加入2-溴苯乙酮(8.8g,44.6mmol)和碳酸银(11g,44.6mmol)，该反应体系于100℃下搅拌反应5h。过滤除去固体，将滤液在减压下浓缩，柱层析纯化得标题化合物。LC-MS m/z:342.2,344.2[M+H] +。
步骤2：2-((7-溴喹啉-4-基)氧基)-3-(二甲基氨基)-1-苯基丙-2-烯-1-酮的制备
Figure PCTCN2019111568-appb-000040
将2-((7-溴喹啉-4-基)氧基)-1-苯基乙基-1-酮(1g,2.9mmol)和N,N-二甲基甲酰胺二甲基缩醛(10mL)置于反应瓶，于100℃搅拌反应1h。反应完成后，冷却至室温，减压下浓缩。将残余物溶于乙酸乙酯，用水和饱和氯化钠水溶液洗涤，有机相经无水硫酸钠干燥，减压浓缩得到标题产物。
步骤2：7-溴-4-((3-苯基-1H-吡唑-4-基)氧基)喹啉的制备
Figure PCTCN2019111568-appb-000041
取2-((7-溴喹啉-4-基)氧基)-3-(二甲基氨基)-1-苯基丙-2-烯-1-酮(1g,2.52mmol)置于反应瓶，加入乙酸(10mL)，冷却到0℃。加入肼-水合物(0.7g)，在氮气条件下室温搅拌过夜。将混合物导入冰水混合物(25mL)中，用乙酸乙酯萃取。合并有机层，依次用水(50mL)、0.5M氢氧化钠和饱和食盐水洗涤2次，无水硫酸钠干燥，浓缩有机相得标题化合物。LC-MS m/z:366.1,368.1[M+H] +。
步骤3：7-溴-4–((1-环丙基-3-苯基-1H-吡唑-4-基)氧基)喹啉的制备
Figure PCTCN2019111568-appb-000042
取2,2-联吡啶(0.42g，2.7mmol)、乙酸铜(0.5g，2.7mmol)和1,2-二氯乙烷(10mL)置于反应瓶，75℃回流25分钟，然后冷却至室温。加入7-溴-4-((3-苯基-1H-吡唑-4-基)氧基)喹啉(0.9g,2.46mmol)的1,2-二氯乙烷(10mL)溶液，然后加入环丙基硼酸(0.42g,4.9mmol)和碳酸钠(0.5g,4.9mmol)。将反应混合物于75℃氧气氛围下搅拌反应2h，冷却到室温。用乙酸乙酯(100mL)稀释，经硅胶短柱过滤，用乙酸乙酯冲洗。将滤液用水和饱和氯化钠水溶液洗涤，无水硫酸钠干燥，浓缩滤液，硅胶柱层析得标题化合物。LC-MS m/z:405.9,407.9[M+H] +。
步骤4：4–((1-环丙基-3-苯基-1H-吡唑-4-基)氧基)-7-(1-甲基-1H-吡唑-4-基)喹啉的制备
Figure PCTCN2019111568-appb-000043
将7-溴-4-((1-环丙基-3-苯基-1H-吡唑-4-基)氧基)喹啉(80mg,0.19mmol)、1-甲基-1H-吡唑-4-硼酸频哪醇酯(80mg,0.38mmol)、碳酸钾(54mg,0.38mmol)和1,1'-双二苯基膦二茂铁二氯化钯(7mg,0.009mmol)加至反应瓶，加入4mL二氧六环和0.5mL水，氮气氛围下，80℃搅拌反应1h。反应完成，向反应液中加入水然后乙酸乙酯萃取，用水和饱和食盐水洗涤有机相，无水硫酸钠干燥，减压浓缩，薄层分离得到标题化合物。LC-MS m/z:408.2[M+H] +. 1H NMR(400MHz,DMSO)δ8.62(d,J＝5.2Hz,1H),8.41(s,1H),8.36(d,J＝8.7Hz,1H),8.19(s,2H),8.11(s,1H),7.94(dd,J＝8.7,1.5Hz,1H),7.75-7.65(m,2H),7.29(t,J＝7.4Hz,2H),7.21(t,J＝7.3Hz,1H),6.72(d,J＝5.2Hz,1H),3.92(s,3H),3.89-3.78(m,1H),1.21-1.14(m,2H),1.08-0.99(m,2H).
实施例15 4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-7-(4-(甲基磺酰基)苯基)喹啉
Figure PCTCN2019111568-appb-000044
将7-溴-4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)喹啉(50mg, 0.121mmol)、4-甲磺酰基苯硼酸(36mg,0.18mmol)、碳酸钾(25mg,0.18mmol)和1,1'-双二苯基膦二茂铁二氯化钯(5mg,0.006mmol)置于反应瓶，加入二氧六环(2mL)和水(0.5mL)中，氮气保护，升温至80℃，搅拌反应2h。冷却至室温，加入水和乙酸乙酯萃取，有机相用水和饱和氯化钠水溶液洗涤，无水硫酸钠干燥，减压浓缩，柱层析纯化得标题化合物。LC-MS m/z:490.2[M+H] +. 1H NMR(400MHz,DMSO)δ8.79(d,J＝5.2Hz,1H),8.47-8.38(m,2H),8.17(d,J＝8.4Hz,2H),8.12-8.04(m,3H),8.01(s,1H),6.84(d,J＝5.2Hz,1H),3.79(dd,J＝8.3,2.9Hz,2H),3.72(m,1H),3.31(s,3H),3.27(dd,J＝7.1,4.2Hz,2H),2.84-2.72(m,1H),1.73-1.63(m,4H),1.11-1.05(m,2H),0.97(dt,J＝12.7,6.2Hz,2H).
实施例16 2-(4-(4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)喹啉-7-基)吡啶-2-基)丙-2-醇
Figure PCTCN2019111568-appb-000045
步骤1：4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-7-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)喹啉的制备
Figure PCTCN2019111568-appb-000046
将7-溴-4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)喹啉(110mg,0.27mmol)、联硼酸频那醇酯(75mg,0.29mmol)、1,1'-双二苯基膦二茂铁二氯化钯(20mg,0.03mmol)和醋酸钾(121mg,0.81mmol)置于反应瓶，加入5mL二氧六环，升温至100℃，搅拌反应3h。加入水和乙酸乙酯萃取，有机相用水和饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩标题化合物，直接进行下一步。
步骤2：2-(4-(4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)喹啉-7-基)吡啶-2-基)丙-2-醇的合成
Figure PCTCN2019111568-appb-000047
将4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-7-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)喹啉(120mg,0.26mmol)、2-(4-溴吡啶-2-基)-2-丙 醇(50mg,0.23mmol)和1,1'-双二苯基膦二茂铁二氯化钯(15mg,0.026mmol)置于反应瓶，加入5mL甲苯，置换成氩气，室温搅拌溶解，加入碳酸钠溶液(0.5mL，2M)，升温至80℃搅拌反应3h。冷却至室温，加入乙酸乙酯和水萃取，有机相用无水硫酸钠干燥，减压浓缩，经薄层层析纯化得到标题化合物。LC-MS m/z:470.9[M+H] +. 1H NMR(400MHz,DMSO)δ8.79(d,J＝5.1Hz,1H),8.63(d,J＝4.9Hz,1H),8.51-8.38(m,2H),8.13(s,1H),8.08(d,J＝8.7Hz,1H),8.01(s,1H),7.75(d,J＝4.0Hz,1H),6.83(d,J＝5.1Hz,1H),5.40(s,1H),3.78(d,J＝11.5Hz,2H),3.74-3.67(m,1H),3.30-3.19(m,2H),2.79-2.73(m,1H),1.78-1.57(m,4H),1.52(s,6H),1.08-1.03(m,2H),0.98-0.94(m,2H).
实施例17 4-((1-环丙基-3-(四氢-2H-吡喃-4基)-1H-吡唑-4-基)氧基)-7-甲氧基喹啉-6-甲酰胺的合成
Figure PCTCN2019111568-appb-000048
步骤1:2-溴-1-(四氢-2H-吡喃-4-基)乙酮的制备
Figure PCTCN2019111568-appb-000049
先将1-(四氢-2H-吡喃-4-基)乙酮(10g,78.02mmol)加入到50mL的甲醇中，冷却至-10℃，氩气氛围下把液溴(4.0mL,78.02mmol)加入到反应中。然后在0℃下反应45min，随后在10℃下反应45min。把硫酸(27.5mL,11M)加入到上述体系中，恢复至室温后搅拌过夜。反应完成后，加入饱和食盐水和乙酸乙酯萃取，合并有机相，依次经饱和碳酸氢钠溶液和水洗涤，无水硫酸钠干燥，减压浓缩得标题产物。
步骤2:2-氧代-2-(四氢-2H-吡喃-4-基)乙基苯甲酸酯的制备
Figure PCTCN2019111568-appb-000050
取苯甲酸(0.440g,3.6mmol)、碳酸钾(0.829g,6.0mmol)和无水N,N-二甲基甲酰胺(15mL)置于反应瓶，在氩气氛围下把2-溴-1-(四氢-2H-吡喃-4-基)乙酮(0.621g,3.0mmol)的无水N,N-二甲基甲酰胺溶液加至上述反应体系中。室温反应过夜。反应完成，加入饱和食盐水和乙酸乙酯萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩得标题化合物。LC-MS m/z:249.2[M+H] +。
步骤3:1-(二甲基氨基)-3-氧代-3-(四氢-2H-吡喃-4-基)丙-1-烯-2-基苯甲酸酯的制备
Figure PCTCN2019111568-appb-000051
把2-氧代-2-(四氢-2H-吡喃-4-基)乙基苯甲酸酯(0.745g,3.0mmol)和1,1-二甲氧基-N,N-二甲基甲胺(1.54mL,12.75mmol)置于反应瓶，90℃搅拌反应2h。反应结束后，恢复至室温，向反应液中加入乙酸乙酯，饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩得标题化合物。LC-MS m/z:304.3[M+H] +。
步骤4:3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基苯甲酸甲酯的制备
Figure PCTCN2019111568-appb-000052
氩气氛围下，于0℃下把水合肼(1mL)加入到1-(二甲基氨基)-3-氧代-3-(四氢-2H-吡喃-4-基)丙-1-烯-2-基苯甲酸酯(0.90g,2.97mmol)的醋酸(10mL)溶液中。升温至室温，搅拌反应过夜。反应结束后加入乙酸乙酯和饱和碳酸氢钠溶液洗涤，无水硫酸钠干燥有机相，减压浓缩得标题产物。LC-MS m/z:273.2。
步骤5:1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基苯甲酸酯的制备
Figure PCTCN2019111568-appb-000053
将2,2'-联吡啶(0.515g,3.3mmol)、乙酸铜(0.599g,3.3mmol)和1,2-二氯乙烷(10mL)置于反应瓶，在75℃搅拌反应25分钟后冷却至室温。取环丙基硼酸(0.515g,6.0mmol)、碳酸钠(0.636g,6.0mmol)和3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基苯甲酸甲酯(0.670g,2.46mmol)的1,2-二氯乙烷(15mL)溶液加至上述反应体系中，在氧气氛围下于75℃搅拌反应2h。反应完成，冷却至室温，加入饱和食盐水，二氯甲烷萃取，无水硫酸钠干燥有机相，减压浓缩，柱层析纯化得标题化合物。LC-MS m/z:＝313.0[M+H] +。
步骤6:1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-醇的制备
Figure PCTCN2019111568-appb-000054
取1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基苯甲酸酯(0.50g,1.60mmol)和5.0mL的乙醇置于反应瓶，然后把氢氧化钠溶液(1M,5.0mL,5.0mmol)加至上述反应体系中，室温下反应3h。反应完成，向反应液中加入稀盐酸，中和体系至中性。经二氯甲烷萃取，无水硫酸钠干燥，减压浓缩得标题化合物。 LC-MS m/z:209.1[M+H] +。
步骤7:4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-7-甲氧基喹啉-6-甲酰胺的制备
Figure PCTCN2019111568-appb-000055
称取原料1-环丙基-3(-四氢-2H-吡喃-4-基)-1H-吡唑-4-醇(208mg,1mmol)、4-氯-7-甲氧基喹啉-6-甲酰胺(238mg,1mmol)和碳酸钾(280mg,2mmol)于100mL单口瓶中，加入20mL N,N-二甲基甲酰胺，氩气保护下，130℃反应1h，萃取，柱层析得标题产物。LC-MS m/z:408.9[M+H] +. 1H NMR(400MHz,DMSO)δ8.69(d,J＝5.2Hz,1H),8.66(s,1H),7.96(s,1H),7.88(s,1H),7.78(s,1H),7.52(s,1H),6.65(d,J＝5.2Hz,1H),3.78(d,J＝11.2Hz,2H),3.71(m,1H),3.36(s,1H),3.27(td,J＝11.3,5.5Hz,2H),2.83-2.69(m,1H),2.51(s,2H),1.73-1.58(m,4H),1.12-1.03(m,2H),0.96(dt,J＝12.8,6.2Hz,2H).
实施例18 4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-7-甲氧基-N-(1-甲基-1H-吡唑-4-基)喹啉-6-胺的制备
Figure PCTCN2019111568-appb-000056
步骤1：6-溴-4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-7-甲氧基喹啉的制备
Figure PCTCN2019111568-appb-000057
称取6-溴-4-氯-7-甲氧基喹啉(27mg,0.1mmol)、1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-醇(21mg,0.1mmol)和碳酸钾(28mg,0.2mmol)于50mL单口瓶中，加入10mL无水N,N-二甲基甲酰胺，氩气保护下，140℃搅拌反应2h。反应完全后，加入20mL水，乙酸乙酯萃取，合并有机相，饱和氯化钠溶液洗，无水硫酸钠干燥，减压浓缩得标题化合物，直接用于下步反应。LC-MS m/z:444.3，446.3[M+H] +。
步骤2：4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-7-甲氧基-N-(1-甲基-1H-吡唑-4-基)喹啉-6-胺
Figure PCTCN2019111568-appb-000058
将6-溴-4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-7-甲氧基喹啉(90mg,0.203mmol)、1-甲基-1H-吡唑-4-胺(19.7mg,0.203mmol)、三(二亚苄基丙酮)二钯(9.2mg,0.0102mmol)、4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(11.75mg,0.0203mmol)和碳酸铯(99mg,0.305mmol)加入到15mL的1,4-二氧六环中，氩气保护下于100℃搅拌反应12h。反应完成后，过滤，滤液经减压浓缩、柱层析纯化得标题产物。LC-MS m/z:461.3[M+H] +. 1H NMR(400MHz,DMSO)δ8.34(d,J＝5.2Hz,1H),7.90(s,1H),7.70(s,1H),7.49(s,1H),7.43(s,1H),7.33(s,1H),7.28(s,1H),6.57(d,J＝5.2Hz,1H),4.03(s,3H),3.83(s,3H),3.78(dt,J＝4.2,3.1Hz,2H),3.67(m,1H),3.25(dd,J＝16.5,9.1Hz,2H),2.70(dt,J＝15.5,7.9Hz,1H),1.69–1.58(m,4H),1.09-1.01(m,2H),0.94(dt,J＝10.9,5.3Hz,2H).
实施例19 4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧杂)-7-甲氧基-N-(1-(氧杂环丁烷-3-基)-1H-吡唑-4-基)喹啉-6-胺的合成
Figure PCTCN2019111568-appb-000059
步骤1:4-硝基-1-(氧杂环丁烷-3-基)-1H-吡唑的制备
Figure PCTCN2019111568-appb-000060
取4-硝基-1-(氧杂环丁烷-3-基)-1H-吡唑(1.13g,10mmol)、3-碘代氧杂环丁烷(2.76g,15mmol)，碳酸铯(6.52g,20mmol)和无水N,N-二甲基甲酰胺(40mL)置于反应瓶中，氩气氛围下加热至100℃，搅拌反应1h。反应完成后，过滤，加入乙酸乙酯和水，分液取有机相，减压浓缩，柱层析得标题化合物。LC-MS m/z:170.1[M+H] +。
步骤2 1-(氧杂环丁烷-3-基)-1H-吡唑-4-胺的制备
Figure PCTCN2019111568-appb-000061
称取2-甲基-2-(4-硝基-1H-吡唑-1-基)丙酰胺(980mg,5.80mmol)溶解于30mL甲醇，加入10％钯碳160mg，氢气氛围下搅拌反应5h。过滤，滤液经减压浓缩得标题产物。LC-MS m/z:140.1[M+H] +。
步骤3 4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧杂)-7-甲氧基-N-(1-(氧杂环丁烷-3-基)-1H-吡唑-4-基)喹啉-6-胺的合成
Figure PCTCN2019111568-appb-000062
称取6-溴-4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧杂)-7-甲氧基喹啉(50mg,0.11mmol)、1-(氧杂四元环-3-基)-1H-吡唑-4-胺(10mg,0.248mmol)、三(二亚苄基丙酮)二钯(10mg,0.011mmol)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(19mg,0.033mmol)和碳酸铯(40mg,0.23mmol)置于反应瓶，加入10mL二氧六环，氩气保护下，100℃反应过夜。过滤得滤液，加入水和乙酸乙酯萃取，浓缩有机相，粗品经柱层析纯化得标题化合物。LC-MS m/z:503.4[M+H] +. 1H NMR(400MHz,DMSO)δ8.35(d,J＝5.2Hz,1H),7.90(s,2H),7.68(s,1H),7.53(s,1H),7.33(d,J＝11.2Hz,2H),6.58(d,J＝5.2Hz,1H),5.59(dd,J＝14.0,6.7Hz,1H),4.97-4.85(m,4H),4.04(s,3H),3.77(dt,J＝11.1,3.0Hz,2H),3.67(m,1H),3.27-3.20(m,2H),2.70(dt,J＝7.4,6.0Hz,1H),1.67-1.59(m,4H),1.07–1.02(m,2H),0.97–0.90(m,2H).
实施例20 4-(4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)喹啉-7-基)苯磺酰胺
Figure PCTCN2019111568-appb-000063
制备方法同实施例7，不同之处为用4-(氨基磺酰基)苯硼酸代替1-甲基-1H-吡唑-4-硼酸频那酯，制得标题化合物。LC-MS m/z:491.1[M+H] +. 1H NMR(400MHz,CDCl 3)δ8.76(d,J＝5.2Hz,1H),8.43(d,J＝8.7Hz,1H),8.26(d,J＝1.4Hz,1H),8.05(d,J＝8.5Hz,2H),7.88–7.77(m,3H),7.43(s,1H),6.73(d,J＝5.2Hz,1H),5.36(s,2H),4.07–3.81(m,2H),3.65–3.56(m,1H),3.43–3.32(m,2H),2.91–2.75(m,1H),1.95–1.84(m,2H),1.79(d,J＝1.9Hz,2H),1.19–1.12(m,2H),1.11–1.02(m,2H).
实施例21 4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-7-(6-(甲基磺酰基)吡啶-3-基)喹啉
Figure PCTCN2019111568-appb-000064
制备方法同实施例7，不同之处为用2-甲磺酰基吡啶-5-硼酸代替1-甲基-1H- 吡唑-4-硼酸频那酯，制得标题化合物。LC-MS m/z:491.1[M+H] +. 1H NMR(400MHz,CDCl 3)δ9.12(d,J＝1.7Hz,1H),8.79(d,J＝5.2Hz,1H),8.50(d,J＝8.6Hz,1H),8.37(d,J＝1.5Hz,1H),8.34–8.28(m,1H),8.27–8.22(m,1H),7.84(dd,J＝8.6,1.7Hz,1H),7.44(s,1H),6.76(d,J＝5.2Hz,1H),3.94(dd,J＝11.6,2.1Hz,2H),3.66–3.58(m,1H),3.41–3.34(m,2H),3.32(s,3H),2.90–2.80(m,1H),1.95–1.86(m,2H),1.80–1.75(m,2H),1.19–1.13(m,2H),1.10–1.03(m,2H).
实施例22 4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-7-(1-(甲基磺酰基)-1,2,3,6-四氢吡啶-4-基)喹啉
Figure PCTCN2019111568-appb-000065
制备方法同实施例7，不同之处为用(1-(甲基磺酰基)-1,2,3,6-四氢吡啶-4-基)硼酸代替1-甲基-1H-吡唑-4-硼酸频那酯，制得标题化合物。LC-MS m/z:495.2[M+H] +. 1H NMR(400MHz,CDCl 3)δ8.68(d,J＝5.2Hz,1H),8.28(d,J＝8.8Hz,1H),8.03(d,J＝1.3Hz,1H),7.67(dd,J＝8.8,1.6Hz,1H),7.39(s,1H),6.65(d,J＝5.2Hz,1H),6.34(s,1H),4.06(d,J＝2.9Hz,2H),3.92(dd,J＝11.6,2.2Hz,2H),3.63–3.56(m,3H),3.40–3.32(m,2H),2.89(s,3H),2.86–2.78(m,3H),1.94–1.84(m,2H),1.77–1.74(m,2H),1.17–1.11(m,2H),1.08–1.01(m,2H).
实施例23 4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-7-(2-(三氟甲基)-5,6-二氢-[1,2,4]三唑并[1,5-a]吡嗪-7(8H)-基)喹啉
Figure PCTCN2019111568-appb-000066
制备方法同实施例1，不同之处为用2-(三氟甲基)-5,6,7,8-四氢-[1,2,4]三唑并[1,5-a]吡嗪代替2-(4-氨基-2-吡啶基)丙烷-2-醇盐酸盐，制得标题化合物。LC-MS m/z:526.2[M+H] +. 1H NMR(400MHz,CDCl 3)δ8.63(d,J＝5.2Hz,1H),8.29(d,J＝9.2Hz,1H),7.48(d,J＝2.3Hz,1H),7.39(s,1H),7.36(dd,J＝9.2,2.4Hz,1H),6.56(d,J＝5.2Hz,1H),4.75(s,2H),4.48(t,J＝5.3Hz,2H),4.02(t,J＝5.4Hz,2H),3.93(dd,J＝11.6,2.1Hz,2H),3.65–3.53(m,1H),3.42–3.30(m,2H),2.88–2.75(m,1H),1.90–1.86(m,2H),1.79–1.71(m,2H),1.18–1.10(m,2H),1.10–1.00(m,2H).
实验例1 化合物体外ALK5激酶活性评价
1.实验材料
1.1化合物
以上实施例制备的本发明的化合物，每个化合物用DMSO配制成10mM后，依次稀释至3.333μM、1.111μM、370nM、123nM、41nM、14nM、4.6nM、1.5nM、0.5nM。
1.2试剂和仪器
试剂：ALK5，购自于Carna公司，Cat.No.09-141；p38α购自于Carna公司，Cat.No.04-152；TGFβR1peptide购自于SignalChem公司，Cat.No.T36-58；二甲基亚砜(DMSO)，购自于美国Sigma公司；EDTA，购自于美国Sigma公司；ADP-Glo Kinase Assay，购自于Promega公司，Cat.No.v9102/3，1×激酶缓冲液(40mM Tris，pH 7.5，0.10％BSA，20mM MgCl 2，1mM DTT)，临用前配制。
仪器：2104Multilabel Reader，购自于美国Perkin Elmer公司。
2.实验方法
2.1配制1x的激酶缓冲液
1x assay buffer
40mM Tris,pH 7.5
20mM MgCl 2
0.10％BSA
1mM DTT
2.2化合物配制
2.2.1化合物稀释
2.2.1.1配制50倍的化合物：化合物的检测终浓度为10μM，配置成50倍浓度，即500μM：在96孔板上第二个孔中加入95μl的100％DMSO，再加入5μl 10mM化合物溶液，配制成1000μM化合物溶液。其他孔加入60μl的100％DMSO。从第二孔中取30μl化合物加入第三孔中，依次往下做3倍稀释，共稀释10个浓度。
稀释仪器：自动微孔移液器(Precision PRC384U)。
2.2.1.2用echo转移100nl化合物到反应板中。
2.3激酶反应
2.3.1配制2倍激酶溶液
将激酶加入1倍激酶缓冲液，形成2倍酶溶液。384孔反应板中已有100nl的100％DMSO溶解的化合物。向384孔反应板中加入2.5μl的2倍酶溶液。室温下孵育10分钟。
2.3.2配制2倍底物溶液
将FAM标记的多肽和ATP加入1倍激酶缓冲液，形成2倍底物溶液。向384孔反应板中加入2.5μl的2倍底物溶液。
2.4激酶反应
将384孔板于28度孵育120分钟。
2.5反应结果的检测
2.5.1将ADP-Glo试剂平衡到室温。
2.5.2转移5μl反应液到一块新的384孔板反应孔中。
2.5.3转移5μl ADP-Glo试剂到384孔板反应孔中终止反应。
2.5.4在28度孵育120分钟。
2.5.5转移10μl激酶检测试剂到每个反应孔中，振荡1分钟，室温静置30分钟。
2.6数据读取
在Envision上读取样品发光数值。
2.7曲线拟合
2.7.1从Envision程序上复制发光读数的数据
2.7.2将发光读数的值通过公式转换为抑制百分率。
Percent inhibition＝(max-sample RLU)/(max-min)*100.“min”为不加酶进行反应的对照样荧光读数；“max”为加入DMSO作为对照的样品荧光读数。
2.7.3将数据导入MS Excel并使用XLFit excel add-in version 5.4.0.8进行曲线拟合，拟合公式:Y＝Bottom+(Top-Bottom)/(1+(IC 50/X)^HillSlope)，结果见表1。
表1
Figure PCTCN2019111568-appb-000067
“-”表示未测。
从以上实验结果可以看出，本发明的化合物对ALK5激酶具有很好的抑制活性，同时对p38α具有低的抑制作用，选择性高。表明本发明的化合物在产生更高疗效的同时，副作用更低。
实验例2 化合物体外细胞荧光素酶实验评价
1.实验材料
受试化合物：以上实施例制备的本发明的化合物，每个化合物用DMSO配制成4mM，然后依次4倍稀释为20000.00nM、5000.00nM、1250.00nM、312.5nM、78.125nM、19.53nM、4.88nM、1.22nM。
Luc-Smad2/3-NIH3T3小鼠成纤维细胞(经工程化后过表达SMAD2，3-响应性启动子)由中国药科大学实验室馈赠。
试剂：DMEM，购自于美国Invitrogen公司；FBS，购自于美国Invitrogen公司；DMSO，购自于美国Sigma公司；Glo Lysis Buffer，购自于美国Progema公司；Bright-Glo Luciferase assay system，购自于美国Promega公司；TGFβ，购自于美国PeproTech公司。
仪器：MD SpectraMax M3多功能酶标仪，购自于美国Molecular Devices公司。
2.实验方法
2.1细胞培养：
细胞复苏：将细胞置于37度水浴中溶解，然后转移到15mL已预热的培养基中，1000rpm离心5分钟，弃去培养基，用15mL新鲜培养基重悬细胞，转移至10cm培养皿中，置于37℃、5％CO 2的培养箱中培养，24小时后细胞更换新鲜培养基。
细胞传代：将上述复苏的细胞转移到50mL无菌离心管中，1000rpm离心5分钟，弃去培养基，取分散均匀的细胞计数，调整合适的细胞浓度到15mL新鲜培养基，加入到10cm培养皿中，置于37℃、5％CO 2的培养箱中培养。
2.2实验步骤：
Day1：铺细胞(透底96孔板)
Luc-Smad2/3-NIH3T3细胞于10cm培养皿中正常培养至汇合度达80％-90％，消化后收集至15mL离心管中，1000xg离心5分钟后，去除上清，用1mL培养基重悬后，稀释10倍计数，根据计数后的结果稀释细胞，将4x10 3/孔细胞数传入96孔板中(每孔加入100μl重悬细胞)。
Day2：细胞给药
药物称量1-2mg(提前称好)，使用DMSO配制成4mM母液。24小时后，移去培养基。用2％FBS培养基稀释药物，加入100μl 1x药物溶液，使药物终浓度分别为20000.00nM、5000.00nM、1250.00nM、312.5nM、78.125nM、19.53nM、4.88nM、1.22nM，每孔TGFβ1终浓度为4ng/mL，与化合物一起用2％FBS培养基进行稀释。
Day3：荧光检测实验
将Glo Lysis Buffer和Bright-glo luciferase assay system以及细胞平衡至室温，移去细胞上清，每孔加入100μlglo Lysis Buffer，缓慢摇晃使其均匀溶解细胞，室温裂解5mins。之后每孔加入100μl Bright-glo luciferase assay system，室温孵育5 分钟，震荡2分钟，将180μl上清液转入白底96孔板，检测化学发光信号，检测条件为1s。
2.3数据处理：使用Graphpad Prism 5软件进行非线性曲线拟合和数据分析，拟合得IC 50，实验结果见表2。
表2
Figure PCTCN2019111568-appb-000068
“-”表示未测。
从以上实验可以看出，本发明的化合物对NIH3T3细胞中TGFβ-ALK5-SMAD2/3信号通路均表现出了良好的抑制活性，非常有希望成为多种癌症相关疾病的治疗剂。

Claims (10)

  1. 一种通式I的化合物或其药学上可接受的盐、异构体、溶剂化物、结晶或前药，
    Figure PCTCN2019111568-appb-100001
    其中，
    X 1选自N和CH；
    R 1选自羟基、氰基、羧基、硝基、烷基、卤代烷基、羟基烷基、烷氧基、环烷基氧基、杂环烷基氧基、环烷基烷氧基、杂环基烷氧基、环烷基烷基、杂环基烷基、单烷基氨基、双烷基氨基、环烷基氨基、杂环基氨基、芳基氨基、杂芳基氨基、环烷基、杂环基、芳基、杂芳基、芳基并杂环基和杂芳基并杂环基，其任选被一个或多个卤素、羟基、氨基、羧基、氰基、硝基、氧代基团、烷基磺酰基、氨基磺酰基、烷基磺酰基烷基、烷基、环烷基、杂环基、烷基杂环基、烷氧基、卤代烷基、羟基烷基、氨基烷基、羧基烷基、氰基烷基、硝基烷基、环烷基烷基、杂环烷基烷基、烷氧基烷基、单烷基氨基、双烷基氨基、烷基酰基、烷氧基酰基、烷基酰基氧基、氨基酰基、烯基酰基、单烷基氨基烯基酰基、双烷基氨基烯基酰基、单烷基氨基酰基、双烷基氨基酰基、烷基酰基氨基或烷基酰基氨基烷基取代；
    R 2、R 3分别独立地选自氢、卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、双烷基氨基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、双烷基氨基、烯基、炔基、环烷基、杂环基、芳基或杂芳基任选被一个或者多个烷基、卤代烷基、羟基、羟基烷基、卤素、氧代基团、烷氧基、羧基、氰基、氨基、单烷基氨基或双烷基氨基取代；
    R 4选自氢、卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、环烷基、杂环烷基、芳基、杂芳基、环烷基氨基、杂环烷基芳基、芳基氨基和杂芳基氨基，其中所述卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、环烷基、杂环烷基、芳基、杂芳基、环烷基氨基、杂环烷基芳基、芳基氨基和杂芳基氨基任选被一个或多个烷基、烷氧基、芳氧基、烷氨基、环烷基、杂环烷基、芳基、杂芳基、芳基氨基、卤素、羟基、氨基、硝基、羧基、氰基、烷基酰基、氨基酰基、烷氨基 酰基、磺酰基或巯基取代；
    R 5、R 6分别独立地选自氢、卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、双烷基氨基、环烷基；和
    m、n分别独立地选自1、2和3。
  2. 根据权利要求1所述的化合物或其异构体、药学上可接受的盐、结晶、溶剂化物或前药，其中R 1选自羟基、氰基、羧基、硝基、C 1-6烷基、卤代C 1-6烷基、羟基C 1-6烷基、C 1-6烷氧基、C 3-6环烷基氧基、C 3-6杂环烷基氧基、C 3-6环烷基C 1-3烷氧基、C 3-6杂环基C 1-3烷氧基、C 3-6环烷基C 1-3烷基、C 3-6杂环基C 1-3烷基、单C 1-6烷基氨基、双C 1-6烷基氨基、C 3-6环烷基氨基、C 3-6杂环基氨基、C 6-12芳基氨基、C 5-8杂芳基氨基、C 3-6环烷基、C 3-6杂环基、C 6-12芳基、C 5-12杂芳基、C 6-12芳基并C 3-10杂环基和C 5-12杂芳基并C 3-6杂环基，其任选被一个或多个卤素、羟基、氨基、羧基、氰基、硝基、氧代基团、C 1-6烷基磺酰基、氨基磺酰基、C 1-6烷基磺酰基C 1-6烷基、C 1-6烷基、C 3-10环烷基、C 3-10杂环基、C 1-6烷基C 3-10杂环基、C 1-6烷氧基、卤代C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基、羧基C 1-6烷基、氰基C 1-6烷基、硝基C 1-6烷基、C 3-6环烷基C 1-6烷基、C 3-6杂环烷基C 1-6烷基、C 1-6烷氧基C 1-6烷基、单C 1-6烷基氨基、双C 1-6烷基氨基、C 1-6烷基酰基、C 1-6烷氧基酰基、C 1-6烷基酰基氧基、氨基酰基、C 2-10烯基酰基、单C 1-6烷基氨基C 2-10烯基酰基、双C 1-6烷基氨基C 2-10烯基酰基、单C 1-6烷基氨基酰基、双C 1-6烷基氨基酰基、C 1-6烷基酰基氨基或C 1-6烷基酰基氨基C 1-6烷基取代。
  3. 根据权利要求1或2所述的化合物或其异构体、药学上可接受的盐、结晶、溶剂化物或前药，其中，R 2、R 3分别独立地选自氢、氟、氯、溴、碘、羟基、C 1-6烷基、卤代C 1-6烷基、羟基C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、羟基C 1-6烷氧基、硝基、羧基、氰基、氨基、单C 1-6烷基氨基、C 1-6烷基酰基氨基、C 1-6烷基酰基、氨基酰基、C 1-6烷基氨基酰基、双C 1-6烷基氨基、C 2-10烯基、C 2-10炔基、C 3-10环烷基、3-10元杂环烷基、C 6-18芳基和5-18元杂芳基，其中所述所述氟、氯、溴、碘、羟基、C 1-6烷基、卤代C 1-6烷基、羟基C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、羟基C 1-6烷氧基、硝基、羧基、氰基、氨基、单C 1-6烷基氨基、C 1-6烷基酰基氨基、C 1-6烷基酰基、氨基酰基、C 1-6烷基氨基酰基、双C 1-6烷基氨基、C 2-10烯基、C 2-10炔基、C 3-10环烷基、3-10元杂环烷基、C 6-18芳基和5-18元杂芳基任选被一个或者多个烷基、卤代烷基、羟基、羟基烷基、卤素、氧代基团、烷氧基、羧基、氰基、氨基、单烷基氨基或双烷基氨基取代。
  4. 根据权利要求1～3之任一项所述的化合物或其异构体、药学上可接受的盐、结晶、溶剂化物或前药，R 4选自氢、卤素、羟基、C 1-6烷基、卤代C 1-6烷基、羟基C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、羟基C 1-6烷氧基、硝基、羧基、 氰基、氨基、C 1-6烷基氨基、C 1-6烷基酰基氨基、C 1-6烷基酰基、氨基酰基、C 1-6烷基氨基酰基、C 3-8环烷基、C 3-8杂环烷基、C 6-12芳基、C 5-12杂芳基、C 3-8环烷基氨基、C 3-8杂环烷基芳基、C 6-12芳基氨基和C 5-8杂芳基氨基，其中所述卤素、羟基、C 1-6烷基、卤代C 1-6烷基、羟基C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、羟基C 1-6烷氧基、硝基、羧基、氰基、氨基、C 1-6烷基氨基、C 1-6烷基酰基氨基、C 1-6烷基酰基、氨基酰基、C 1-6烷基氨基酰基、C 3-8环烷基、C 3-8杂环烷基、C 6-12芳基、C 5-12杂芳基、C 3-8环烷基氨基、C 3-8杂环烷基芳基、C 6-12芳基氨基和C 5-8杂芳基氨基任选被一个或多个C 1-6烷基、C 1-6烷氧基、C 6-12芳氧基、C 1-6烷氨基、C 3-6环烷基、C 3-6杂环烷基、C 6-12芳基、C 5-8杂芳基、C 6-12芳基氨基、卤素、羟基、氨基、硝基、羧基、氰基、烷基酰基、氨基酰基、烷氨基酰基、磺酰基或巯基取代；R 5、R 6分别独立地选自氢、卤素、羟基、C 1-6烷基、卤代C 1-6烷基、羟基C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、羟基C 1-6烷氧基、硝基、羧基、氰基、氨基、单C 1-6烷基氨基、C 1-6烷基酰基氨基、C 1-6烷基酰基、氨基酰基、C 1-6烷基氨基酰基、双C 1-6烷基氨基和C 3-10环烷基。
  5. 根据权利要求1～4之任一项所述的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药，其中R 1选自C 1-6烷氧基、吗啉基、哌啶基、吡唑基、苯基、吡啶基、吡啶氨基、吡咯并吡唑基、三唑并吡嗪基、硫代吗啉基，其任选被一个或多个卤素、羟基、氨基、羧基、氰基、硝基、氧代基团、C 1-6烷基磺酰基、氨基磺酰基、C 1-6烷基磺酰基C 1-6烷基、C 1-6烷基、C 3-10环烷基、C 3-10杂环基、C 1-6烷基C 3-10杂环基、C 1-6烷氧基、卤代C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基、羧基C 1-6烷基、氰基C 1-6烷基、硝基C 1-6烷基、C 3-6环烷基C 1-6烷基、C 3-6杂环烷基C 1-6烷基、C 1-6烷氧基C 1-6烷基、单C 1-6烷基氨基、双C 1-6烷基氨基、C 1-6烷基酰基、C 1-6烷氧基酰基、C 1-6烷基酰基氧基、氨基酰基、C 2-10烯基酰基、单C 1-6烷基氨基C 2-10烯基酰基、双C 1-6烷基氨基C 2-10烯基酰基、单C 1-6烷基氨基酰基、双C 1-6烷基氨基酰基、C 1-6烷基酰基氨基或C 1-6烷基酰基氨基C 1-6烷基取代；R 2、R 3分别独立地选自氢、氟、氯、溴、碘、羟基、甲基、乙基、丙基、丁基、异丙基、异丁基、叔丁基、甲基氨基、乙基氨基、丙基氨基、异丙基氨基、环丙基、环丁基、环戊基、环己基、苯基、吡咯基、咪唑基、吡唑基、噻唑基、噻吩基、呋喃基、吡啶基、吡嗪基、嘧啶基、氮杂环丁基、氧杂环丁基、四氢吡咯基、四氢呋喃基、哌啶基、四氢吡喃基和吗啉基，它们任选被一个或多个羟基、甲基、乙基、丙基、丁基、异丙基、异丁基、叔丁基、羧基、氟、氯、溴、三氟甲基、三氟乙基、氨基甲基、氨基乙基、氨基丙基、甲基氨基、乙基氨基、丙基氨基、异丙基氨基、甲氧基、乙氧基、丙氧基、异丙氧基、氧代基团、甲酰基、乙酰基、丙酰基、异丙酰基、乙烯基、丙烯基、乙炔基、并炔基、苯基、萘基、吡咯基、咪唑基、吡唑基、噻唑基、噻吩基、呋喃基、吡啶基、吡嗪基和嘧啶基取代；和R 4选自氢、氨酰基和吡唑氨基，所述氨酰基和吡唑氨基任选被一个或多个C 1-6烷基、C 1-6烷氧基、C 6-12芳氧基、C 1-6烷氨基、C 3-6环烷 基、C 3-6杂环烷基、C 6-12芳基、C 5-8杂芳基、C 6-12芳基氨基、卤素、羟基、氨基、硝基、羧基、氰基、烷基酰基、氨基酰基、烷氨基酰基、磺酰基或巯基取代。
  6. 根据权利要求1～5之任一项所述的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药，其中通式I具有以下通式Ia的结构，
    Figure PCTCN2019111568-appb-100002
    其中，R 2、R 3、R 4、R 5、R 6、m、n如权利要求1～5中所定义；
    X 2和X 2’分别独立地选自N和C(R 7)，其中R 7选自氢、卤素、羟基、氧代基团、烷基磺酰基、烷基磺酰基烷基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、双烷基氨基和环烷基；
    R 8选自氢、卤素、羟基、氧代基团、烷基磺酰基、烷基磺酰基烷基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、双烷基氨基和环烷基；和
    p选自1、2和3。
  7. 根据权利要求1～5之任一项所述的的化合物或其药学上可接受的盐、异构体、溶剂化物、结晶或前药，其中通式I具有以下通式Id的结构，
    Figure PCTCN2019111568-appb-100003
    其中，R 1、R 2、R 3、R 4、R 5、R 6、n如权利要求1～5中所定义。
  8. 根据权利要求1所述的化合物或其异构体、药学上可接受的盐、结晶、溶剂化物或前药，其中所述化合物为选自以下的化合物：
    Figure PCTCN2019111568-appb-100004
    Figure PCTCN2019111568-appb-100005
  9. 一种药物组合物，其包含权利要求1～8之任一项所述的化合物或其药学上可接受的盐、异构体、溶剂化物、前药和药学上可接受的载体。
  10. 权利要求1～8之任一项所述的化合物或其药学上可接受的盐、异构体、溶剂化物或前药或权利要求9所述的药物组合物在制备用于治疗和/或预防TGF-βR1相关疾病的药物中的应用，优选地，所述疾病为癌症、组织增生类疾病、纤维化或炎性疾病的药物中的应用。
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