CN111196804A - TGF- β R1 inhibitor and application thereof - Google Patents

TGF- β R1 inhibitor and application thereof Download PDF

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CN111196804A
CN111196804A CN201911139134.0A CN201911139134A CN111196804A CN 111196804 A CN111196804 A CN 111196804A CN 201911139134 A CN201911139134 A CN 201911139134A CN 111196804 A CN111196804 A CN 111196804A
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pyridin
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CN111196804B (en
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王勇
赵立文
王亚洲
全旭
刘海璇
王小伟
张雁
李雪
曹陈
郭壮
吕坤志
王海
郑国闯
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Nanjing Sanhome Pharmaceutical Co Ltd
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • 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
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    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Abstract

The invention belongs to the field of medical chemistry, and relates to a compound serving as a TGF- β R1 inhibitor and application thereof, in particular to a compound shown as a formula I or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, a preparation method of the compound, a pharmaceutical composition containing the compound, and application of the compound or the composition in treating and/or preventing TGF- β R1 related diseases, such as cancers, tissue proliferation diseases, fibrosis, inflammatory diseases and the like.

Description

TGF- β R1 inhibitor and application thereof
Technical Field
The invention belongs to the field of medicinal chemistry, and particularly relates to a TGF- β R1 inhibitor compound or pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, a preparation method thereof, a pharmaceutical composition containing the compound, and application of the compound or the composition in treating and/or preventing TGF- β R1 expression-related diseases, such as cancer, myelodysplastic syndrome and other diseases.
Background
TGF- β (transforming growth factor β) is an important class of cytokines, and 6 different subtypes (TGF- β 1-6) have been found to be different in homology to each other, and only 3 subtypes, i.e., TGF- β, TGF- β, and TGF- β 3, have been expressed in mammals, and are a multifunctional growth factor superfamily, with extensive biological activity, and are involved in early embryo development, cartilage and bone formation, extracellular matrix synthesis, inflammation, interstitial fibrosis, regulation of immune and endocrine functions, and tumor formation and development.
TGF- β is the most common and important subtype of TGF- β, the most abundant subtype expressed in liver, and the most powerful liver fibrosis induction factor known, and plays a very important role in the process of the development of chronic liver diseases to end liver diseases (Yamazaki, et al. diagnostic diseases, 2011,29: 284) 288. various studies show that TGF- β and TGF- β receptors are usually highly expressed in liver diseased organs, blood vessels and extracellular matrix. in the classical TGF β -TGF β -R-Smads pathway, TGF- β activates TGF β -R1 (transforming growth factor β receptor 1, ALK5) in the signaling pathway, and further regulates the whole signaling pathway, so as to regulate the expression of a series of target genes related to fibrosis and tumorigenesis.
The research on the medicine targeting the TGF- β pathway has been carried out for many years, but TGF- β R1 inhibitors such as Galunesertib and the like show certain cardiotoxicity (such as bleeding, function degradation, inflammatory injury and the like) on animal models, and the reason is that the medicine has low target selectivity and specificity, and can inhibit the TGF β -R1 kinase activation site, and simultaneously has strong inhibition effect on other proteins with the same kinase region (such as p38 α), so as to generate a plurality of unexpected off-target toxic and side effects.
Disclosure of Invention
The invention aims to provide a compound with TGF- β R1 inhibitory activity shown in the general formula I or pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof,
Figure BDA0002280414000000021
it is another object of the invention to provide a process for the preparation of a compound of formula I of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal, isostere or prodrug.
It is a further object of the present invention to provide compositions comprising a compound of formula I of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal, isostere or prodrug and a pharmaceutically acceptable carrier, and compositions comprising a compound of formula I of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal, isostere or prodrug and another drug or drugs.
Still another object of the present invention is to provide a method for treating and/or preventing TGF- β R1 related diseases by using the compound of formula I, or its isomer, pharmaceutically acceptable salt, solvate, crystal, isostere or prodrug, and the use of the compound of formula I, or its isomer, pharmaceutically acceptable salt, solvate, crystal, isostere or prodrug, in the preparation of drugs for treating and/or preventing TGF- β R1 related diseases.
Aiming at the above purpose, the invention provides the following technical scheme:
in a first aspect, the present invention provides a compound of formula I or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal, an isostere or a prodrug thereof,
R1selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylocycloalkyl, heteroarylocycloalkyl, heterocycloalkylaryl, aryloaryl, heteroaryloaryl, which are optionally substituted with one or more halogen, hydroxy, amino, carboxy, cyano, nitro, oxo, alkylsulfonyl, cycloalkylsulfonyl, alkylaminosulfonyl, aminosulfonyl, cycloalkylaminosulfonyl, alkylsulfonylalkyl, alkyl, cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted cycloalkylalkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, hydroxyalkylcarbonyl, hydroxycycloalkylalkyl, hydroxyhaloalkyl, aminoalkyl, carboxyalkyl, cyanoalkyl, nitroalkylcycloalkylhydroxyalkyl, alkoxyalkyl, monoalkylamino, dialkylamino, substituted heteroaryl, heteroarylalkyl, heteroaryloaryl, optionally substituted heterocycloalkylalkyl, cycloalkylalkyl, optionally substituted cycloalkylalkyl, alkoxy, haloalkoxy, hydroxyalkyl, hydroxyalkylcarbonyl, hydroxycycloalkylalkyl, hydroxyalkylalkyl, carboxyalkyl, cyanoalkyl, nitroalkyl, Alkoxyacyl, alkylacyloxy, alkenyl, alkynyl, aminoacyl, alkenylacyl, monoalkylaminoalkenylacyl, dialkylaminoalkenylacyl, monoalkylaminoacyl, dialkylaminoacyl, hydroxyalkylacyl, alkylacylamino, alkylacylaminoalkyl and heteroaryl substitution;
R2selected from the group consisting of 5-to 8-membered heterocycloalkyl, aryl, 5-to 8-membered heteroaryl, aryloaryl, heteroaryloaryl, 5-to 8-membered cycloalkyl, 6-to 10-membered spirocyclyl, 6-to 10-membered bridged cyclyl, 6-to 10-membered spiroheterocyclyl and 6-to 10-membered bridged heterocyclyl, optionally substituted with one or more alkyl, haloalkyl, hydroxy, cycloalkyl, heterocycloalkyl, hydroxyalkyl, halogen,Oxo, alkoxy, carboxy, cyano, amino, aminoalkyl, alkenyl, alkynyl, monoalkylamino, and dialkylamino;
R3selected from the group consisting of cycloalkyl, heterocycloalkyl, cycloalkylacyl, halocycloalkyl, hydroxycycloalkyl, haloalkoxycycloalkyl, alkoxycycloalkyl, aminocycloalkyl, monoaminoacylcycloalkyl, bisaminocycloalkylacyl, aminoacylcycloalkyl, alkenyl, alkynyl, optionally substituted with one or more alkyl, haloalkyl, hydroxy, hydroxyalkyl, halogen, oxo, alkoxy, carboxy, cyano, amino, aminoalkyl, monoalkylamino, and bisalkylamino;
R4、R5each independently selected from hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkylacylamino, alkanoyl, aminoacyl, alkylaminoacyl, dialkylamino, cycloalkyl, alkenyl, alkynyl; m is selected from 1,2 and 3;
when R is2When it is cycloalkyl, halocycloalkyl or heterocycloalkyl, R1Is not aminoacylphenyl and unsubstituted cyanophenyl;
when R is2Is tetrahydro-2H-pyranyl and tetrahydrofuran-3-yl, R3When it is cyclopropyl, R1Is not optionally substituted pyridazinyl, 1-methyl-1H-pyrazolyl, optionally substituted pyridin-2 (1H) -one-4-yl;
when R is1Is pyridin-4-yl and 2-propanediol pyridin-4-yl, R2Is tetrahydro-2H-pyranyl and tetrahydrofuran-3-yl, R3When it is cyclopropyl, R1Substituted with one or more of carboxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, alkylacylamino, carboxyalkyl, hydroxyalkylamino, hydroxyhaloalkyl, haloalkoxy and cycloalkylhydroxyalkyl;
in some embodiments, the compounds of the invention are of formula I or an isomer, pharmaceutically acceptable salt, solvate, crystal, isostere or prodrug thereof,wherein: r1Is selected from C6-12Aryl radical, C5-12Heteroaryl group, C3-6Cycloalkyl radical, C3-6Heterocycloalkyl radical, C6-12Aryl radical and C3-6Cycloalkyl radical, C5-12Heteroaryl and C3-6Cycloalkyl radical, C3-6Heterocycloalkyl radical C6-12Aryl radical, C6-12Aryl radical and C5-12Heteroaryl group, C5-12Heteroaryl and C5-12Heteroaryl, optionally substituted with one or more halogen, hydroxy, amino, carboxy, cyano, nitro, oxo, C1-6Alkylsulfonyl radical, C1-6Alkylaminosulfonyl, aminosulfonyl, C3-6Cycloalkylaminosulfonyl radical, C1-6Alkylsulfonyl radical C1-6Alkyl radical, C3-10Cycloalkylsulfonyl radical, C1-6Alkyl radical, C3-10Cycloalkyl radical, C3-10Heterocyclic group, C1-6Alkyl radical C3-10Heterocyclic group, C1-6Alkoxy, halo C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, carboxyl C1-6Alkyl, cyano C1-6Alkyl, nitro C1-6Alkyl radical, C3-6Cycloalkyl radical, C3-6Heterocycloalkyl, optionally substituted C3-6Heterocycloalkyl radical C1-6Alkyl, optionally substituted C3-6Cycloalkyl radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkyl, mono C1-6Alkylamino, di-C1-6Alkylamino radical, C1-6Alkyl acyl radical, C1-6Alkoxyacyl group, C1-6Alkyl acyloxy, C2-6Alkenyl radical, C2-6Alkynyl, aminoacyl, C2-10Alkenyl acyl, mono C1-6Alkylamino radical C2-10Alkenyl acyl, di-C1-6Alkylamino radical C2-10Alkenyl acyl, mono C1-6Alkylaminoacyl, hydroxy C1-6Alkyl acyl, di-C1-6Alkylaminoacyl radical, C1-6Alkylacylamino group, C1-6Alkylacylamino C1-6Alkyl 5-6 membered heteroaryl substituted.
Preferably, R1Selected from the group consisting of pyridyl, phenyl, isoquinolyl, indazolyl, oxazolyl, isoxazolyl, and,Pyrazolyl, thiazolyl, isothiazolyl, imidazolyl, pyranyl, pyronyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, indole, benzopyranyl, benzopyranonyl, purinyl, cyclohexane, morpholinyl, piperidinyl, pyrrolopyrazolyl, triazolopyrazinyl, optionally substituted with one or more halogen, hydroxy, amino, carboxy, cyano, nitro, oxo groups, C1-6Alkylsulfonyl radical, C1-6Alkylaminosulfonyl, aminosulfonyl, C3-6Cycloalkylaminosulfonyl radical, C1-6Alkylsulfonyl radical C1-6Alkyl radical, C3-6Cycloalkylsulfonyl radical, C1-6Alkyl radical, C3-10Cycloalkyl radical, C3-10Heterocyclic group, C1-6Alkyl radical C3-10Heterocyclic group, C1-6Alkoxy, halo C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, carboxyl C1-6Alkyl, cyano C1-6Alkyl, nitro C1-6Alkyl, optionally substituted C3-6Cycloalkyl radical C1-6Alkyl, optionally substituted C3-6Heterocycloalkyl radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkyl, mono C1-6Alkylamino, di-C1-6Alkylamino radical, C1-6Alkyl acyl radical, C1-6Alkoxyacyl group, C1-6Alkyl acyloxy, amino acyl, C2-10Alkenyl acyl, mono C1-6Alkylamino radical C2-10Alkenyl acyl, di-C1-6Alkylamino radical C2-10Alkenyl acyl, hydroxy C1-6Alkyl acyl, mono C1-6Alkylaminoacyl, di-C1-6Alkylaminoacyl radical, C1-6Alkylacylamino and C1-6Alkylacylamino C1-6Alkyl substitution;
in some particular embodiments, the compounds of the present invention are of formula I or an isomer, pharmaceutically acceptable salt, solvate, crystal, isostere or prodrug thereof, wherein:
R2selected from 5-to 8-membered heterocycloalkyl, C6-12Aryl, 5-to 8-membered heteroaryl, C6-12Aryl radical and C6-12Aryl radical, C6-12Aryl radical and C5-12Heteroaryl group, C5-12Heteroaryl and C6-12Aryl, 5-to 8-membered cycloalkyl, 6-to 10-membered spirocyclic, 6-to 10-membered bridged cyclic, 6-to 10-membered spiroheterocyclic and 6-to 10-membered bridged heterocyclic, optionally substituted with one or more C1-6Alkyl, halo C1-6Alkyl, hydroxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, hydroxy C1-6Alkyl, halogen, oxo, C1-6Alkoxy, carboxyl, cyano, amino C1-6Alkyl, amino, C2-6Alkenyl radical, C2-6Alkynyl, mono C1-6Alkylamino and di-C1-6Alkyl amino substitution;
preferably, R2Selected from tetrahydropyranyl, tetrahydrofuranyl, tetrahydropyrrolyl, cyclohexyl, morpholinyl, halocyclobutyl, halocyclohexyl, piperidinyl, phenyl, indenyl, naphthyl, pyranyl, pyronyl, pyridazinyl, pyrimidinyl, pyrazinyl, furyl, thienyl, pyrrolyl, quinolyl, isoquinolyl, indolyl, cyclopentyl, cyclohexyl, cycloheptyl, 6-10 membered spiro, 6-10 membered bridged, 6-10 membered spiro and 6-10 membered bridged, optionally substituted with one or more hydroxy, cyano, methoxy, morpholinyl, oxetanyl, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tert-butyl, carboxy, fluoro, chloro, bromo, trifluoromethyl, trifluoroethyl, aminomethyl, aminoethyl, aminopropyl, methylamino, ethylamino, propylamino, isopropylamino, Ethoxy, propoxy, isopropoxy, oxo, formyl, acetyl, propionyl, isopropionyl, ethenyl, propenyl, ethynyl and propynyl;
in some particular embodiments, the compounds of the present invention are of formula I or an isomer, pharmaceutically acceptable salt, solvate, crystal, isostere or prodrug thereof, wherein:
R3is selected from C3-6Cycloalkyl radical, C3-6Heterocycloalkyl radical, C3-6Cycloalkyl acyl, halo C3-6Cycloalkyl, hydroxy C3-6Cycloalkyl, halo C1-6Alkoxy radical C3-6Cycloalkyl radical, C1-6Alkoxy radical C3-6Cycloalkyl, amino C3-6Cycloalkyl, mono C1-6Alkylaminoacyl radical C3-6Cycloalkyl, di-C1-6Alkylamino radical C3-6Cycloalkyl acyl, amino acyl C3-6Cycloalkyl radical, C2-6Alkenyl radical, C2-6Alkynyl optionally substituted by one or more C3-6Alkyl, halo C1-6Alkyl, hydroxy C1-6Alkyl, halogen, oxo, C1-6Alkoxy, carboxyl, cyano, amino C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, mono C1-6Alkylamino and di-C1-6Alkyl amino substitution;
preferably, R3Selected from cyclopropyl, cyclopropylacyl, cyclobutyl, 2-fluoroethyl, optionally substituted with one or more of hydroxy, cyano, methoxy, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tert-butyl, carboxy, fluoro, chloro, bromo, trifluoromethyl, trifluoroethyl, aminomethyl, aminoethyl, aminopropyl, methylamino, ethylamino, propylamino, isopropylamino, ethoxy, propoxy, isopropoxy, oxo, formyl, acetyl, propionyl, isopropionyl, ethenyl, propenyl, ethynyl and propynyl;
in some particular embodiments, the compounds of the present invention are of formula I or an isomer, pharmaceutically acceptable salt, solvate, crystal, isostere or prodrug thereof, wherein:
R4、R5each independently selected from hydrogen, halogen, hydroxy, C1-6Alkyl, halo C1-6Alkyl, hydroxy C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy, hydroxy C1-6Alkoxy, nitro, carboxyl, cyano, amino, mono C1-6Alkylamino radical, C1-6Alkylacylamino group, C1-6Alkyl acyl, amino acyl, C1-6Alkylaminoacyl, di-C1-6Alkylamino and C3-10A cycloalkyl group; preferably, R4、R5Each independently selected from hydrogen, fluorine, chlorineBromine, iodine, hydroxyl, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, 2-hydroxypropyl, methoxy, ethoxy, propoxy, isopropoxy, nitro, carboxyl, cyano, amino, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, methylethylamino, dipropylamino, methylpropylamino, ethylpropylamino, methylacylamino, ethylacylamino, vinylacylamino, methylacyl, ethylacoyl, vinylacyl, aminoacyl, methylaminoacyl, ethylaminoacyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
In some preferred embodiments, the compound of formula I of the present invention is a compound of formula Ia below or an isomer, pharmaceutically acceptable salt, solvate, crystal, isostere or prodrug thereof,
Figure BDA0002280414000000061
wherein R is2、R3、R4、R5M is as defined in claims 1-5;
R6selected from the group consisting of hydrogen, halogen, cyano, amino, hydroxy, alkoxy, heterocyclyloxy, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, alkylsulfonyl, alkylaminosulfonyl, aminosulfonyl, cycloalkylaminosulfonyl, alkylsulfonylalkyl, cycloalkylsulfonyl, aryl, and heteroaryl, wherein said halogen, cyano, amino, hydroxy, alkoxy, heterocyclyloxy, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, alkylsulfonyl, alkylaminosulfonyl, aminosulfonyl, cycloalkylaminosulfonyl, alkylsulfonylalkyl, aryl, and heteroaryl are optionally substituted with one or more halogen, carboxy, hydroxy, cyano, amino, alkyl, haloalkyl, alkoxy, hydroxyalkyl, oxo, aminoalkyl, alkylamino, alkanoyl, alkenyl, alkynyl;
and n is selected from 1,2, 3,4 and 5.
In some particular embodiments, the compounds of general formula Ia according to the present invention, or isomers, pharmaceutically acceptable salts, solvates, crystals, isosteres or prodrugs thereof, wherein R6Selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, cyano, azetidinyl, oxetanyl, piperazinyl, trifluoromethyl, difluoromethyl, propan-2-ol-2-yl,
Figure BDA0002280414000000071
Wherein said fluorine, chlorine, bromine, iodine, cyano, azetidinyl, oxetanyl, piperazinyl, trifluoromethyl, difluoromethyl, propan-2-ol-2-yl, methyl, ethyl, trifluoromethyl,
Figure BDA0002280414000000072
Optionally substituted with one or more methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, carboxyl, hydroxyl, cyano, hydroxymethyl, hydroxyethyl, oxo, amino, aminomethyl, methylamino, ethylamino, isopropylamino, methoxy, ethoxy, isopropoxy, fluoro, chloro, bromo, trifluoromethyl, trifluoroethyl, formyl, acetyl, propenyl, ethenyl, propenyl, acryloyl, ethynyl, and propynyl groups; and n is selected from 1,2 and 3.
In some preferred embodiments, the compounds of formula I of the present invention are of formula Ib or an isomer, pharmaceutically acceptable salt, solvate, crystal, isostere or prodrug thereof,
Figure BDA0002280414000000073
wherein R is2、R3、R4、R5M is as defined in formula I;
R7selected from the group consisting of hydrogen, carboxyl, heterocycloalkyl, hydroxyheterocycloalkyl, hydroxyalkyl, alkylaminoacyl, hydroxyalkanoyl, carboxyalkylacyl, carboxyalkyl, monoalkylamino, dialkylamino, aminoalkyl, alkylheterocycloalkyl, heterocycloalkylalkyl, alkylsulfonylCycloalkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, cycloalkylaminosulfonyl, cycloalkylalkyl, cycloalkyl, haloalkyl, oxo, alkoxy, haloalkoxy, alkylpyridyl, 1H-1,2, 4-triazolyl, cycloalkylacyl, and aminoacylcycloalkyl, wherein the carboxy, heterocycloalkyl, hydroxyheterocycloalkyl, hydroxyalkyl, alkylaminoacyl, hydroxyalkanoyl, carboxyalkylacyl, carboxyalkyl, monoalkylamino, dialkylamino, aminoalkyl, alkylheterocycloalkyl, heterocycloalkylalkyl, alkylsulfonyl, cycloalkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, cycloalkylaminosulfonyl, cycloalkylalkyl, cycloalkyl, haloalkyl, oxo, alkoxy, haloalkoxy, alkylpyridyl, 1H-1,2, 4-triazolyl, cycloalkylacyl, and aminoacylcycloalkyl optionally substituted with one or more fluoro, chloro, bromo, hydroxy, cyano, amino, carboxy, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyalkyl, oxo, haloalkyl, aminoalkyl, aminoacyl, and carboxyalkyl groups; and
p is selected from 1,2, 3 and 4.
In some particular embodiments, the compounds according to the invention of general formula Ib, or isomers, pharmaceutically acceptable salts, solvates, crystals, isosteres or prodrugs thereof, wherein R7Selected from hydrogen, carboxyl, C3-6Heterocycloalkyl, hydroxy C3-6Heterocycloalkyl, hydroxy C1-6Alkyl radical, C1-6Alkylaminoacyl, hydroxy C1-6Alkyl acyl, carboxyl C1-6Alkyl acyl, carboxyl C1-6Alkyl, mono C1-6Alkylamino, di-C1-6Alkylamino radical, amino radical C1-6Alkyl radical, C1-6Alkyl radical C3-6Heterocycloalkyl radical, C3-6Heterocycloalkyl radical C1-6Alkyl radical, C1-6Alkylsulfonyl radical, C3-6Cycloalkylsulfonyl, aminosulfonyl, C1-6Alkylaminosulfonyl radical, C3-6Cycloalkylaminosulfonyl radical, C3-6Cycloalkylalkyl radical, C3-6Cycloalkyl, halo C1-6Alkyl, oxo, C1-6Alkoxy radicalRadical, halo C1-6Alkoxy radical, C1-6Alkyl pyridyl, 1H-1,2, 4-triazolyl, C3-6Cycloalkyl acyl and amino acyl C3-6Cycloalkyl, wherein the carboxy, heterocycloalkyl, hydroxyheterocycloalkyl, hydroxyalkyl, alkylaminoacyl, hydroxyalkylacyl, carboxyalkylacyl, carboxyalkyl, monoalkylamino, dialkylamino, aminoalkyl, alkylheterocycloalkyl, heterocycloalkylalkyl, alkylsulfonyl, cycloalkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, cycloalkylaminosulfonyl, cycloalkylalkyl, cycloalkyl, haloalkyl, oxo group, alkoxy, haloalkoxy, alkylpyridyl, 1H-1,2, 4-triazolyl, cycloalkylacyl, and aminoacylcycloalkyl optionally substituted with one or more fluoro, chloro, bromo, hydroxy, cyano, amino, carboxy, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyalkyl, oxo, haloalkyl, aminoalkyl, aminoacyl, carboxyalkyl; and
p is selected from 1,2, 3 and 4.
In some preferred embodiments, the compound of formula I of the present invention is a compound of formula Ic or an isomer, pharmaceutically acceptable salt, solvate, crystal, isostere or prodrug thereof,
Figure BDA0002280414000000091
wherein R is2、R3、R4、R5M is as defined in formula I;
R8selected from the group consisting of hydrogen, carboxyl, heterocycloalkyl, hydroxyheterocycloalkyl, hydroxyalkyl, alkylaminoacyl, hydroxyalkanoyl, carboxyalkylacyl, carboxyalkyl, monoalkylamino, dialkylamino, aminoalkyl, alkylheterocycloalkyl, heterocycloalkylalkyl, alkylsulfonyl, cycloalkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, cycloalkylaminosulfonyl, cycloalkylalkyl, cycloalkyl, haloalkyl, oxo, alkoxy, haloalkoxy, alkylpyridinyl, 1H-1,2, 4-triazolyl, cycloalkylacylAnd aminoacyl cycloalkyl, wherein the carboxy, heterocycloalkyl, hydroxyheterocycloalkyl, hydroxyalkyl, alkylaminoacyl, hydroxyalkylacyl, carboxyalkylacyl, carboxyalkyl, monoalkylamino, dialkylamino, aminoalkyl, alkylheterocycloalkyl, heterocycloalkylalkyl, alkylsulfonyl, cycloalkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, cycloalkylaminosulfonyl, cycloalkylaminoalkyl, cycloalkyl, haloalkyl, oxo, alkoxy, haloalkoxy, alkylpyridyl, 1H-1,2, 4-triazolyl, cycloalkylacyl, and aminoacyl cycloalkyl are optionally substituted with one or more of fluoro, chloro, bromo, hydroxy, cyano, amino, carboxy, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyalkyl, oxo, haloalkyl, aminoalkyl, aminoacyl, or a pharmaceutically acceptable salt thereof, Carboxyalkyl substitution; and
q is selected from 1,2 and 3.
In some particular embodiments, the compounds of general formula Ic according to the invention, or isomers, pharmaceutically acceptable salts, solvates, crystals, isosteres or prodrugs thereof, wherein R is8Selected from hydrogen, carboxyl, C3-6Heterocycloalkyl, hydroxy C3-6Heterocycloalkyl, hydroxy C1-6Alkyl radical, C1-6Alkylaminoacyl, hydroxy C1-6Alkyl acyl, carboxyl C1-6Alkyl acyl, carboxyl C1-6Alkyl, mono C1-6Alkylamino, di-C1-6Alkylamino radical, amino radical C1-6Alkyl radical, C1-6Alkyl radical C3-6Heterocycloalkyl radical, C3-6Heterocycloalkyl radical C1-6Alkyl radical, C1-6Alkylsulfonyl radical, C3-6Cycloalkylsulfonyl, aminosulfonyl, C1-6Alkylaminosulfonyl radical, C3-6Cycloalkylaminosulfonyl radical, C3-6Cycloalkylalkyl radical, C3-6Cycloalkyl, halo C1-6Alkyl, oxo, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkyl pyridyl, 1H-1,2, 4-triazolyl, C3-6Cycloalkyl acyl and amino acyl C3-6Cycloalkyl, wherein said carboxyl, heterocycloalkyl, hydroxyheterocycloalkyl, hydroxyalkyl, alkylAminoacyl, hydroxyalkylacyl, carboxyalkylacyl, carboxyalkyl, monoalkylamino, dialkylamino, aminoalkyl, alkylheterocycloalkyl, heterocycloalkylalkyl, alkylsulfonyl, cycloalkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, cycloalkylaminosulfonyl, cycloalkylalkyl, cycloalkyl, haloalkyl, oxo, alkoxy, haloalkoxy, alkylpyridyl, 1H-1,2, 4-triazolyl, cycloalkylacyl, and aminoacylcycloalkyl optionally substituted with one or more of fluoro, chloro, bromo, hydroxy, cyano, amino, carboxy, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyalkyl, oxo, haloalkyl, aminoalkyl, aminoacyl, carboxyalkyl; and
q is selected from 1 and 2.
In some preferred embodiments, the compounds of the present invention are of formula I or an isomer, pharmaceutically acceptable salt, solvate, crystal, isostere or prodrug thereof, wherein:
R1selected from phenyl, pyridyl, pyrazolyl and piperidinyl, optionally substituted with one or more of the following: carboxy, methyl, trifluoromethyl, propan-2-ol-2-yl, hydroxyethyl, cyclopropylsulfonyl, aminosulfonyl, methanesulfonyl, methylamino,
Figure BDA0002280414000000101
Figure BDA0002280414000000102
R2Selected from phenyl, halophenyl, cyanophenyl, methoxyphenyl, trifluoromethylphenyl, halocyclobutyl, and mixtures thereof,
Figure BDA0002280414000000103
R3Selected from cyclopropyl, fluoroethyl, cyclopropylacyl; r4、R5Selected from hydrogen; m is selected from 1.
In other embodiments, the present invention provides a compound of formula I or an isomer, a pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein formula I has the structure of formula Id,
Figure BDA0002280414000000111
wherein the content of the first and second substances,
ring a and ring B are each independently selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylocycloalkyl, heteroarylocycloalkyl, heterocycloalkylaryl, aryloaryl, and heteroaryloaryl; or
When ring a is arylocycloalkyl, heteroarylocycloalkyl, heterocycloalkylaryl, aryloaryl, or heteroaryloaryl, ring B may be absent; and
Rcand RdEach independently selected from the group consisting of hydrogen, alkyl, halo, hydroxy, amino, carboxy, cyano, nitro, oxo, hydroxyalkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, alkanoyl, alkylsulfonyl, cycloalkylsulfonyl, alkylaminosulfonyl, aminosulfonyl, cycloalkylaminosulfonyl, alkylsulfonylalkyl, cycloalkyl, optionally substituted cycloalkylcarbonyl, heterocycloalkyl, heterocycloalkylalkyl, cycloalkylalkyl, hydroxyalkylcarbonyl, hydroxycycloalkylalkyl, hydroxyhaloalkyl, aminoalkyl, carboxyalkyl, cyanoalkyl, nitroalkyl, cycloalkylhydroxyalkyl, alkoxyalkyl, monoalkylamino, dialkylamino, alkoxyacyl, alkylacyloxy, alkenyl, alkynyl, aminoacyl, alkenylacyl, monoalkylaminoalkenoyl, dialkylaminoalkenylacyl, cyano, nitro, cycloalkylhydroxyalkyl, alkoxyalkyl, monoalkylamino, dialkylamino, alkoxyacyl, Monoalkylaminoacyl, dialkylaminoacyl, hydroxyalkylacyl, alkylacylamino, alkylacylaminoalkyl and heteroaryl, j and g are each independently 1,2, 3 and 4;
R2、R3、R4、R5m is as defined above for formula I.
In some particular embodiments, the compound of formula Id according to the invention or its isomers, pharmaceutically acceptable salts, solvatesA crystal or a prodrug thereof, wherein the A ring and the B ring are each independently selected from C6-12Aryl radical, C5-12Heteroaryl group, C3-8Cycloalkyl radical, C3-8Heterocycloalkyl radical, C6-12Aryl radical and C3-8Cycloalkyl radical, C5-12Heteroaryl and C3-8Cycloalkyl radical, C3-8Heterocycloalkyl radical C6-12Aryl radical, C6-12Aryl radical and C5-12Heteroaryl group, C5-12Heteroaryl and C5-12A heteroaryl group; or when ring A is C6-12Aryl radical and C3-8Cycloalkyl radical, C5-12Heteroaryl and C3-8Cycloalkyl radical, C3-8Heterocycloalkyl radical C6-12Aryl radical, C6-12Aryl radical and C5-12Heteroaryl or C5-12Heteroaryl and C5-12When heteroaryl, ring B may be absent; and RcAnd RdEach independently selected from hydrogen and C1-6Alkyl, halogen, hydroxy, amino, carboxy, cyano, nitro, oxo, hydroxy C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy, hydroxy C1-6Alkoxy radical, C1-6Alkyl acyl radical, C1-6Alkylsulfonyl radical, C3-8Cycloalkylsulfonyl radical, C1-6Alkylaminosulfonyl, aminosulfonyl, C3-8Cycloalkylaminosulfonyl radical, C1-6Alkylsulfonyl radical C1-6Alkyl radical, C3-8Cycloalkyl radical, C3-8Heterocycloalkyl radical, C3-8Heterocycloalkyl radical C1-6Alkyl radical, C3-8Cycloalkyl radical C1-6Alkyl, hydroxy C1-6Alkylcarbonyl, hydroxy C3-8Cycloalkyl radical C1-6Alkyl, hydroxy-halogeno-C1-6Alkyl, amino C1-6Alkyl, carboxyl C1-6Alkyl, cyano C1-6Alkyl, nitro C1-6Alkyl radical, C3-8Cycloalkyl hydroxy C1-6Alkyl, alkoxy C1-6Alkyl, mono C1-6Alkylamino, di-C1-6Alkylamino radical, C1-6Alkoxyacyl group, C1-6Alkyl acyloxy, C2-6Alkenyl radical, C2-6Alkynyl, aminoacyl, C2-6Alkenyl acyl, mono C1-6Alkyl radicalAmino group C2-6Alkenyl acyl, di-C1-6Alkylamino radical C2-6Alkenyl acyl, mono C1-6Alkylaminoacyl, di-C1-6Alkylaminoacyl, hydroxy C1-6Alkyl acyl radical, C1-6Alkylacylamino group, C1-6Alkylacylamino C1-6Alkyl and C5-12Heteroaryl, j and g are each independently 1,2 and 3; r2、R3、R4、R5M is as defined above for formula I.
In some more specific embodiments, the compound of formula Id according to the present invention, or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, wherein ring a and ring B are each independently selected from phenyl, pyridyl, pyrazolyl, benzopyrazolyl, benzopyridyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyranyl, pyronyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, indole, benzopyranyl, benzopyranonyl, purinyl, cyclohexyl, morpholinyl, piperidinyl, pyrrolopyrazolyl, triazolopyrazinyl; or when ring a is benzopyrazolyl, benzopyridyl, quinolyl, indole, benzopyranyl, benzopyranonyl, purinyl, pyrrolopyrazolyl or triazolopyrazinyl, ring B may be absent; and RcAnd RdEach independently selected from hydrogen and C1-6Alkyl, halogen, hydroxy, amino, carboxy, cyano, nitro, oxo, hydroxy C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy, hydroxy C1-6Alkoxy radical, C1-6Alkyl acyl radical, C1-6Alkylsulfonyl radical, C3-8Cycloalkylsulfonyl radical, C1-6Alkylaminosulfonyl, aminosulfonyl, C3-8Cycloalkylaminosulfonyl radical, C1-6Alkylsulfonyl radical C1-6Alkyl radical, C3-8Cycloalkyl, optionally substituted C3-8Cycloalkyl carbonyl group, C3-8Heterocycloalkyl radical, C3-8Heterocycloalkyl radical C1-6Alkyl radical, C3-8Cycloalkyl radical C1-6Alkyl, hydroxy C1-6Alkylcarbonyl, hydroxy C3-8Cycloalkyl radical C1-6Alkyl, hydroxy-halogeno-C1-6Alkyl, amino C1-6Alkyl, carboxyl C1-6Alkyl, cyano C1-6Alkyl, nitro C1-6Alkyl radical, C3-8Cycloalkyl hydroxy C1-6Alkyl, alkoxy C1-6Alkyl, mono C1-6Alkylamino, di-C1-6Alkylamino radical, C1-6Alkoxyacyl group, C1-6Alkyl acyloxy, C2-6Alkenyl radical, C2-6Alkynyl, aminoacyl, C2-6Alkenyl acyl, mono C1-6Alkylamino radical C2-6Alkenyl acyl, di-C1-6Alkylamino radical C2-6Alkenyl acyl, mono C1-6Alkylaminoacyl, di-C1-6Alkylaminoacyl, hydroxy C1-6Alkyl acyl radical, C1-6Alkylacylamino group, C1-6Alkylacylamino C1-6Alkyl and C5-12Heteroaryl, j and g are each independently 1,2 and 3; r2、R3、R4、R5M is as defined above for formula I.
In other embodiments, the present invention provides a compound of formula I or an isomer, a pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein formula I has the structure of formula Ie,
Figure BDA0002280414000000131
wherein R isaAnd RbEach independently selected from the group consisting of hydrogen, alkyl, halogen, hydroxy, hydroxyalkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, dialkylamino, alkylacylamino, alkanoyl, aminoacyl, alkylaminoacyl, aminoalkyl, optionally substituted heterocycloalkyl, f is selected from 1,2, 3, and 4; and
R2、R3、R4、R5m is as defined above for formula I.
In some particular embodiments, the compounds of formula Ie according to the inventionOr an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, wherein RaAnd RbEach independently selected from hydrogen and C1-6Alkyl, halogen, hydroxy C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy, hydroxy C1-6Alkoxy, nitro, carboxyl, cyano, amino, mono C1-6Alkylamino, di-C1-6Alkylamino radical, C1-6Alkylacylamino group, C1-6Alkyl acyl, amino acyl, C1-6Alkylaminoacyl, amino C1-6Alkyl, optionally substituted 3-6 membered heterocycloalkyl, f is selected from 1,2 and 3; further, RaAnd RbEach independently selected from hydrogen, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tert-butyl, carboxyl, hydroxyl, cyano, fluorine, chlorine, bromine, nitro, carboxyl, cyano, amino, trifluoromethyl, trifluoroethyl, aminomethyl, aminoethyl, aminopropyl, methylamino, ethylamino, propylamino, isopropylamino, methoxy, ethoxy, propoxy, isopropoxy, formyl, acetyl, propionyl, isopropionyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, hydroxybutyl, hydroxymethoxy, hydroxyethoxy, methoxyamino, ethoxyamino, propoxyamino, carboxamido, acetamido, alkylhydroxyazetidinyl, f is selected from 1 and 2; r2Selected from tetrahydropyranyl, tetrahydrofuranyl, tetrahydropyrrolyl, cyclohexyl, morpholinyl, halocyclobutyl, halocyclohexyl, piperidinyl, phenyl, indenyl, naphthyl, pyranyl, pyronyl, pyridazinyl, pyrimidinyl, pyrazinyl, furyl, thienyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, cyclopentyl, cyclohexyl, cycloheptyl, 6-10 membered spiro, 6-10 membered bridged, 6-10 membered spiro or 6-10 membered bridged, optionally substituted with one or more hydroxy, cyano, methoxy, morpholinyl, oxetanyl, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tert-butyl, carboxy, fluoro, chloro, bromo, trifluoromethyl, trifluoroethyl, aminomethyl, aminoethyl, aminopropyl, methylamino, ethylamino, ethylcyclohexyl, piperidinyl, isoquinolinyl, indolyl, cyclopentyl, cyclohexyl, cycloheptyl, 6-10 membered spiro, 6-10 membered bridged, 6-10 membered spiro or 6-10 membered bridged, optionally substituted with one or more hydroxy groupsAlkylamino, propylamino, isopropylamino, ethoxy, propoxy, isopropoxy, oxo, formyl, acetyl, propionyl, isopropionyl, ethenyl, propenyl, ethynyl, and propynyl; r3Is selected from C3-6Cycloalkyl radical, C3-6Heterocycloalkyl radical, C3-6Cycloalkyl acyl, halo C3-6Cycloalkyl, hydroxy C3-6Cycloalkyl, halo C1-6Alkoxy radical C3-6Cycloalkyl radical, C1-6Alkoxy radical C3-6Cycloalkyl, amino C3-6Cycloalkyl, mono C1-6Alkylaminoacyl radical C3-6Cycloalkyl, di-C1-6Alkylamino radical C3-6Cycloalkyl acyl, amino acyl C3-6Cycloalkyl radical, C2-6Alkenyl radical, C2-6Alkynyl optionally substituted by one or more C3-6Alkyl, halo C1-6Alkyl, hydroxy C1-6Alkyl, halogen, oxo, C1-6Alkoxy, carboxyl, cyano, amino C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, mono C1-6Alkylamino or di-C1-6Alkyl amino substitution; and R4、R5Each independently selected from hydrogen, halogen, hydroxy, C1-6Alkyl, halo C1-6Alkyl, hydroxy C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy, hydroxy C1-6Alkoxy, nitro, carboxyl, cyano, amino, mono C1-6Alkylamino radical, C1-6Alkylacylamino group, C1-6Alkyl acyl, amino acyl, C1-6Alkylaminoacyl, di-C1-6Alkylamino and C3-10Cycloalkyl, m is 1 or 2.
The present invention provides the following specific compounds or pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs thereof:
Figure BDA0002280414000000141
Figure BDA0002280414000000151
Figure BDA0002280414000000161
Figure BDA0002280414000000171
Figure BDA0002280414000000181
in another aspect, the present invention provides a process for preparing a compound of the general formula or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, comprising:
Figure BDA0002280414000000182
1) reacting the compound of formula 1 with the compound of formula 2 to obtain a compound of formula 3;
2) reacting the compound of formula 3 with the compound of formula 4 to obtain a compound of formula 5;
3) reacting the compound shown in the formula 5 to obtain a compound shown in a formula 6;
4) reacting the compound of formula 6 with the compound of formula 7 to obtain a compound of formula 8;
5) reacting the compound of the formula 8 to obtain a compound of a formula 9;
6) reacting a compound of formula 9 with a compound of formula 10 to produce a compound of formula I; or
7) Reacting the compound of formula 11 with a compound of formula 9 to produce a compound of formula Ia;
8) reacting the compound of formula 12 with a compound of formula 9 to obtain a compound of formula Ib;
9) reaction of a compound of formula 11 with a compound of formula 9 affords a compound of formula Ic.
Wherein R is1、R2、R3、R4、R5、R6、R7、R8M, n and p have the meanings given in formula I; a is halogen, preferably bromine(ii) a B is halogen (preferably chlorine) or amino; c is amino or halogen (preferably bromine).
In a third aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention or an isomer, a pharmaceutically acceptable salt, solvate, crystal, isostere or prodrug thereof.
In some embodiments, the invention provides pharmaceutical compositions comprising a compound of the invention, or an isomer, pharmaceutically acceptable salt, solvate, crystal, isostere or prodrug thereof, further comprising one or more agents selected from the group consisting of TGF- β R1 inhibitors, tyrosine protease inhibitors, EGFR inhibitors, VEGFR inhibitors, Bcr-Abl inhibitors, c-kit inhibitors, c-Met inhibitors, Raf inhibitors, MEK inhibitors, histone deacetylase inhibitors, IDH inhibitors, VEGF antibodies, EGF antibodies, HIV protein kinase inhibitors, HMG-CoA reductase inhibitors, and the like.
In some embodiments, the present invention provides a compound of the present invention or an isomer, a pharmaceutically acceptable salt, solvate, crystal, isostere or prodrug thereof, and a pharmaceutical composition comprising a compound of the present invention or an isomer, a pharmaceutically acceptable salt, solvate, crystal, isostere or prodrug thereof, for use in a medicament for treating and/or preventing TGF- β R1 associated diseases.
The compound of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal, isostere or prodrug may 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 formulations may be administered by any route, for example by infusion or bolus injection, by a route of absorption through epithelial or cutaneous mucosa (e.g. oral mucosa or rectum, etc.). Administration may be systemic or local. Examples of the formulation for oral administration include solid or liquid dosage forms, specifically, tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions and the like. The formulations may be prepared by methods known in the art and include carriers, diluents or excipients conventionally used in the art of pharmaceutical formulation.
In a fourth aspect, the present invention provides a use of a compound represented by formula I, Ia, Ib or Ic of the present invention, or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal, an isostere or a prodrug thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for treating and/or preventing cancer, a tissue proliferative disease, fibrosis or inflammatory disease, wherein the cancer, the tissue proliferative disease, the fibrosis or the inflammatory disease condition includes but is not limited to: melanoma, papillary thyroid tumors, cholangiocarcinoma, colon cancer, ovarian cancer, lung cancer, malignant lymphoma, carcinomas and sarcomas of the liver, kidney, bladder, prostate, breast and pancreas, as well as primary and recurrent solid tumors of the skin, colon, thyroid, lung and ovary or leukemia, glioblastoma (glioma), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), Acute Myelogenous Leukemia (AML), sarcoma, non-small cell lung cancer, chondrosarcoma, cholangiocarcinomas or immunoblastic lymphomas, liver fibrosis and chronic kidney disease.
Description of the terms
Unless stated to the contrary, terms used in the specification and claims have the following meanings.
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. For example, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include13C and14c, isotopes of oxygen including16O and18o, and the like.
The "halogen" in the present invention means fluorine, chlorine, bromine and iodine. "halo" in the context of the present invention means substituted by fluorine, chlorine, bromine or iodine.
"alkyl" in the present invention means a straight or branched chain saturated aliphatic hydrocarbon group, preferably a straight or branched chain group having 1 to 6 carbon atoms, more preferably a straight or branched chain group having 1 to 3 carbon atoms, and non-limiting examples 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" in the context of the present invention means an alkyl group substituted with at least one halogen.
"hydroxyalkyl" in the context of the present invention means an alkyl group substituted with at least one hydroxyl group.
"alkoxy" in the context of the present invention means-O-alkyl. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, n-propoxy, isopropoxy, and the like. An alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent may be at any available point of attachment.
The "cycloalkyl group" in the present invention means a cyclic saturated hydrocarbon group such as cyclopropyl, cyclobutyl and the like.
"heterocycloalkyl" in the context of the present invention refers to a group of 3 to 12 membered non-aromatic ring systems having 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3-12 membered heterocycloalkyl"). In heterocycloalkyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valency permits. The heterocycloalkyl group can be monocyclic ("monocyclic heterocycloalkyl") or a fused, bridged, or spiro ring system (e.g., a bicyclic ring system ("bicyclic heterocycloalkyl")) and can be saturated or can be partially unsaturated. Suitable saturated and partially saturated heterocyclic groups include, but are not limited to, azetidinyl, oxetanyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, isoxazolinyl, piperidinyl, piperazinyl, piperidinyl, and piperidinyl,
Figure BDA0002280414000000211
And the like.
"aryl" as used herein refers to an aromatic system which may comprise a single ring or fused polycyclic ring, preferably a single ring or fused bicyclic ring, having from 6 to 18 carbon atoms, preferably from about 6 to about 12 carbon atoms. Suitable aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, tetrahydronaphthyl, fluorenyl, indanyl. Aryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents may be at any available point of attachment.
"heteroaryl" (by itself or in any combination, e.g., "heteroarylamino") refers to an aryl group having at least one carbon atom replaced by a heteroatom, which can be O, S, N, including but not limited to imidazolyl, benzimidazolyl, imidazopyridinyl, quinazolinyl, pyrrolyl, imidazolonyl, furanyl, thienyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, pyrimidinyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidopyrazolyl, pyrimidoimidazolyl, and the like (5-to 12-membered heteroaryl), consisting of 5 to 20 atoms, and more preferably consisting of 5 to 12 atoms (5-to 12-membered heteroaryl). Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents may be at any available point of attachment.
Arylcycloalkyl groups in accordance with the present invention refers to one or more ring systems fused to a cycloalkyl group except where one hydrogen atom has been formally removed from the aryl group, including but not limited to
Figure BDA0002280414000000212
Figure BDA0002280414000000213
And the like.
Heterocycloalkyl-aryl in accordance with the present invention refers to one or more ring systems formed by fusing a heterocycloalkyl group to a group that is formally removed from the aryl group by a hydrogen atom, including but not limited to
Figure BDA0002280414000000214
Figure BDA0002280414000000221
And the like.
Heteroaryl-aryl in the context of the present invention is understood to mean the radicals of heteroaryl and aryl which are left by formal removal of one hydrogen atomFused ring system or systems, including but not limited to
Figure BDA0002280414000000222
Figure BDA0002280414000000223
And the like.
Heteroaryloaryls according to the invention mean one or more ring systems fused from heteroaryl and the group remaining from heteroaryl formally minus one hydrogen atom, including but not limited to purines, heteroaryls, and the like,
Figure BDA0002280414000000224
Figure BDA0002280414000000225
And the like.
By "optionally substituted" in the present invention is meant that the group may be substituted with one or more of the following groups: alkyl, halogen, hydroxy, amino, carboxy, cyano, nitro, oxo, acyloxy, hydroxyalkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, alkanoyl, alkylsulfonyl, cycloalkylsulfonyl, alkylaminosulfonyl, aminosulfonyl, cycloalkylaminosulfonyl, alkylsulfonylalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, cycloalkylalkyl, hydroxyalkylcarbonyl, hydroxycycloalkylalkyl, hydroxyhaloalkyl, aminoalkyl, carboxyalkyl, cyanoalkyl, nitroalkyl, cycloalkylhydroxyalkyl, alkoxyalkyl, monoalkylamino, dialkylamino, alkoxyacyl, alkylacyloxy, alkenyl, alkynyl, aminoacyl, alkenylacyl, monoalkylaminoalkenoyl, dialkylaminoalkenoyl, monoalkylaminoacylamino, dialkylaminoacyl, dialkylaminoacylamino, acyloxy, hydroxyalkyl, haloalkoxy, hydroxyalkyl, Hydroxyalkyl acyl, alkylacylamino, alkylacylaminoalkyl and heteroaryl radicals, e.g. C1-6Alkyl, halogen, hydroxy, amino, carboxyl, cyano, nitro, oxo, acyloxy, hydroxy C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radicalHydroxy group C1-6Alkoxy radical, C1-6Alkyl acyl radical, C1-6Alkylsulfonyl radical, C3-8Cycloalkylsulfonyl radical, C1-6Alkylaminosulfonyl, aminosulfonyl, C3-8Cycloalkylaminosulfonyl radical, C1-6Alkylsulfonylalkyl group, C3-8Cycloalkyl radical, C3-8Heterocycloalkyl radical, C3-8Heterocycloalkyl alkyl, C3-8Cycloalkyl alkyl, hydroxy C1-6Alkylcarbonyl, hydroxy C3-8Cycloalkyl radical C1-6Alkyl, hydroxy-halogeno-C1-6Alkyl, amino C1-6Alkyl, carboxyl C1-6Alkyl, cyano C1-6Alkyl, nitro C1-6Alkyl radical, C3-8Cycloalkyl hydroxy C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkyl, mono C1-6Alkylamino, di-C1-6Alkylamino radical, C1-6Alkoxyacyl group, C1-6Alkyl acyloxy, C2-6Alkenyl radical, C2-6Alkynyl, aminoacyl, C2-6Alkenyl acyl, mono C1-6Alkylamino radical C2-6Alkenyl acyl, di-C1-6Alkylamino radical C2-6Alkenyl acyl, mono C1-6Alkylaminoacyl, di-C1-6Alkylaminoacyl, hydroxy C1-6Alkyl acyl radical, C1-6Alkylacylamino group, C1-6Alkylacylamino C1-6Alkyl and heteroaryl.
"isomers" of the present invention are compounds having the same molecular formula but differing in nature or in the bond sequence of their atoms or in the spatial arrangement of their atoms. Stereoisomers are isomers whose atoms differ in their spatial arrangement. Stereoisomers that are not mirror images of each other are diastereomers and stereoisomers that are non-overlapping mirror images of each other are enantiomers. When the compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers are characterized by the absolute configuration of their asymmetric centers and are described and designated as dextrorotatory or levorotatory (i.e., as (+) or (-) -isomers, respectively) by the R-and S-sequencing rules of Cahn and Prelog, or by methods in which molecules rotate the plane of polarized light. The chiral compound may exist as a single enantiomer or a mixture thereof. Mixtures containing equal proportions of enantiomers are referred to as "racemic mixtures".
The term "pharmaceutically acceptable salt" as used herein refers to salts of the compounds of the present invention which are safe and effective for use in the body of a mammal and which possess the requisite biological activity.
"solvate" of the present invention refers in the conventional sense to a complex of a solute (e.g., active compound, salt of active compound) and a solvent (e.g., water) in combination. Solvent means a solvent known or readily determined by one skilled in the art. If water, the solvate is often referred to as a hydrate, e.g., a hemihydrate, monohydrate, dihydrate, trihydrate or a substitute amount thereof, and the like.
Bioisosteres (or simply "isosteres") of the invention are terms commonly accepted in the art for defining pharmaceutical analogs in which one or more atoms (or groups of atoms) have been replaced with replacement atoms (or groups of atoms) having similar steric and/or electronic characteristics as those atoms with which they are replaced.
The "crystal" in the present invention is a solid whose internal structure is formed by repeating constituent atoms (or groups thereof) regularly in three dimensions, and is different from an amorphous solid having no such regular internal structure.
"prodrug" refers to a compound that is converted to the compounds of formula I, Ia, Ib, Ic, Id, Ie by reaction with enzymes, gastric acid, etc., under physiological conditions in the organism.
The "pharmaceutical composition" of the present invention is meant to comprise a mixture of any of the compounds described herein, including the corresponding isomers, prodrugs, solvates, pharmaceutically acceptable salts, or chemically protected forms thereof, and one or more pharmaceutically acceptable carriers.
"excipient" in the context of the present invention 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 types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols.
By "pharmaceutically acceptable carrier" herein is meant 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, including all solvents, diluents or other excipients, dispersants, surfactant isotonicity agents, thickeners or emulsifiers, preservatives, solid binders, lubricants and the like. Unless any conventional carrier medium is incompatible with the compounds of the present invention. Some examples of carriers that may be pharmaceutically acceptable 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.
Detailed Description
The following representative examples are intended to better illustrate the present invention and are not intended to limit the scope of the present invention. The materials used in the following examples are all commercially available unless otherwise specified.
Example 14- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) picolinic acid
Figure BDA0002280414000000241
Step Synthesis of 12-bromo-1- (tetrahydro-2H-pyran-4-yl) ethan-1-one
Figure BDA0002280414000000242
1- (tetrahydro-2H-pyran-4-yl) -ethanone (10.00g,78.02mmol) was dissolved in 50mL of methanol and liquid bromine (4.01mL,78.02mmol) was added dropwise at-10 ℃. After the dropwise addition, the reaction mixture was stirred at 0 ℃ for 1 hour and then stirred at room temperature for 1 hour. Aqueous sulfuric acid (11M,27.5mL,302.50mmol) was added and stirred at room temperature overnight. The reaction was monitored by TLC, water and ethyl acetate were added at the end of the reaction, extracted, and the organic phase was washed successively with saturated aqueous sodium bicarbonate solution, water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound.
Step 22 Synthesis of- ((2-Chloropyridin-4-yl) oxy) -1- (tetrahydro-2H-pyran-4-yl) ethan-1-one
Figure BDA0002280414000000243
2-bromo-1- (tetrahydro-2H-pyran-4-yl) -ethan-1-one (10.00g,48.29mmol) and 2-chloro-4-hydroxypyridine (6.26g,48.29mmol) were dissolved in 20mL of N, N-dimethylformamide, anhydrous potassium carbonate (6.91g,50mmol) was added, and reaction was carried out overnight at 90 ℃. And detecting the reaction by LC-MS, adding ethyl acetate and water after the reaction is finished, extracting, washing an organic phase by water and a saturated sodium chloride solution, drying by anhydrous sodium sulfate, and concentrating under reduced pressure to obtain the title compound. ESI-MS M/z 256.3[ M + H ]]+。
Step Synthesis of 32- ((2-chloropyridin-4-yl) oxy) -3- (dimethylamino) -1- (tetrahydro-2H-pyran-4-yl) prop-2-en-1-one
Figure BDA0002280414000000251
2- ((2-Chloropyridin-4-yl) oxy) -1- (tetrahydro-2H-pyran-4-yl) ethan-1-one (9.58g,37.46mmol) was dissolved in N, N-dimethylformamide dimethyl acetal (21.1mL) and reacted at 100 ℃ for 2H. After concentration under reduced pressure, ethyl acetate was added, the organic phase was washed successively with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound.
Step Synthesis of 42-chloro-4- ((3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine
Figure BDA0002280414000000252
2- ((2-Chloropyridin-4-yl) oxy) -3- (dimethylamino) -1- (tetrahydro-2H-pyran-4-yl) prop-2-en-1-one (9.58g,30.9mmol) was dissolved in 100mL of acetic acid, hydrazine hydrate (5.5mL,113.2mmol) was added dropwise while cooling on ice, and the mixture was allowed to stand at room temperature overnight. And detecting the reaction by LC-MS, adding ice water and ethyl acetate after the reaction is finished, and extracting. The combined organic layers were washed with water, saturated sodium bicarbonate, sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound. ESI-MS m-z:280.1[M+H]+。
Step 52 Synthesis of chloro-4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine
Figure BDA0002280414000000253
2,2' -bipyridine (3.07g, 19.66mmol) and copper acetate (3.92g, 19.66mmol) were placed in a reaction flask, 1, 2-dichloroethane (50mL) was added, and the reaction was refluxed for 1 h. Cooled to room temperature and 2-chloro-4- ((3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine (5.00g,17.87mmol), sodium carbonate (3.79g,35.74mmol) and cyclopropylboronic acid (3.07g,35.74mmol) were added. Stirring and reacting for 4h at 80 ℃ under the oxygen atmosphere, and detecting the reaction by LC-MS. After the reaction is finished, the reaction solution is concentrated under reduced pressure, diluted by ethyl acetate, filtered by diatomite, an organic layer is washed by water and saturated sodium chloride, dried by anhydrous sodium sulfate and purified by column chromatography to obtain the title compound. ESI-MSm/z 320.2[ M + H ]]+。
Step 64 Synthesis of methyl- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) picolinate
Figure BDA0002280414000000261
2-chloro-4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine (200mg,625.41umol), methyl 4-aminopyridine-2-carboxylate (133.22mg,875.58umol), cesium carbonate (407.54mg,1.25mmol), palladium acetate (14.03mg,62.5umol), and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (72.3mg,125umol) were placed in a reaction flask, 10mL of dioxane was added, argon was used as a shield, and the reaction was carried out overnight at 100 ℃. After the reaction was completed, the mixture was cooled to room temperature, and water and ethyl acetate were added to conduct extraction. The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by column chromatography to give the title compound. ESI-MS M/z 436.2[ M + H ]]+。
Step 74 Synthesis of- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) picolinic acid
Figure BDA0002280414000000262
Methyl 4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) picolinate (200mg,459.26umol) was added to a mixed solvent of tetrahydrofuran (10mL) and methanol (2mL), and then 4mL of an aqueous solution containing lithium hydroxide (55mg,2.30mmol) was added thereto and reacted at room temperature for 2 hours. After the reaction is completed, the pH is adjusted to about 7 by using a 3M hydrochloric acid solution, and the tetrahydrofuran and the methanol are removed by concentration under reduced pressure. Adding ethyl acetate, extracting, combining organic phases, drying by anhydrous sodium sulfate, concentrating under reduced pressure, and purifying by column chromatography to obtain the title compound. ESI-MS M/z 422.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6):δ10.23(s,1H),8.33–8.29(m,2H),8.25–8.24(d,1H),8.01–7.99(m,1H),7.91(s,1H),6.75–6.73(m,1H),6.47–6.46(d,1H),3.85–3.81(m,2H),3.71–3.65(m,2H),2.75–2.68(m,2H),1.68–1.65(m,4H),1.05–1.04(m,2H),0.97–0.95(m,2H)。
Example 24- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) -N- (2-morpholinopyridin-4-yl) pyridin-2-amine
Figure BDA0002280414000000271
Step 1 Synthesis of (4- (4-nitropyridin-2-yl) morpholine
Figure BDA0002280414000000272
2-chloro-4-nitropyridine (5g,0.032mol) and morpholine (8.3g,0.096mol) were dissolved in 80mL of tetrahydrofuran and refluxed overnight. And (5) detecting the reaction by LC-MS, concentrating under reduced pressure after the reaction is finished, and purifying by column chromatography to obtain the title compound. ESI-MSm/z 210.2[ M + H ]]+。
Step 22 Synthesis of Morpholinopyridin-4-amine
Figure BDA0002280414000000273
Dissolving (4- (4-nitropyridin-2-yl) morpholine (1.0g,4.78mmol) in a mixed solvent of methanol/dichloromethane (15mL/5mL), adding palladium/carbon (10%, 100mg), replacing with hydrogen for 5 times, reacting overnight at room temperature, detecting by LC-MS, after the reaction is finished, filtering with diatomaceous earth, washing the filter cake with methanol, and concentrating the filtrate under reduced pressure to obtain the title compound, ESI-MS M/z:180.2[ M + H ]]+。
Step 34 Synthesis of- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) -N- (2-morpholinopyridin-4-yl) pyridin-2-amine
Figure BDA0002280414000000274
2-chloro-4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine (200mg,0.63mmol), 2-morpholinopyridin-4-amine (93.5mg,0.52mmol), palladium acetate (11.7mg,0.052mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (60mg,0.104mmol), and cesium carbonate (340mg,1.04mmol) were placed in a reaction flask, 10mL of anhydrous 1, 4-dioxane were added, and reacted under argon atmosphere at 100 ℃ overnight. After the reaction is finished, the reaction solution is concentrated and purified by column chromatography to obtain the title compound. ESI-MSm/z 463.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6):δ9.30(s,1H),8.11(d,1H),7.89-7.88(m,2H),7.22(s,1H),6.95-6.92(m,1H),6.57-6.55(m,1H),6.33–6.32(m,1H),3.84-3.80(m,2H),3.71-3.64(m,4H),3.33-3.28(m,7H),2.75–2.67(m,1H),1.67–1.62(m,4H),1.06–0.92(m,4H)。
Example 32- (4- ((4- ((1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) propan-2-ol
Figure BDA0002280414000000281
Step Synthesis of 12- ((2-chloropyridin-4-yl) oxy) -1-phenylethyl-1-one
Figure BDA0002280414000000282
2-bromo-1-phenyleth-1-one (5.00g,25mmol) and 2-chloro-4-hydroxypyridine (3.25g,25mmol) were dissolved in 4mL of N, N-dimethylformamide, and anhydrous potassium carbonate (6.91g,50mmol) was added to react at room temperature overnight. After the reaction was complete, ethyl acetate was added, and the mixture was washed successively with water and saturated sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound. ESI-MS M/z 248.6[ M + H ]]+。
Step Synthesis of 22-chloro-4- ((3-phenyl-1H-pyrazol-4-yl) oxy) pyridine
Figure BDA0002280414000000283
2- ((2-Chloropyridin-4-yl) oxy) -1-phenylethyl-1-one (1.0g,4.03mmol) was dissolved in N, N-dimethylformamide dimethyl acetal (4mL,30.1mmol) and the reaction was stirred at 100 ℃ for 2 h. After completion of the reaction, the reaction mixture was returned to room temperature, ethyl acetate was added, and the mixture was washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was dissolved in 5mL of acetic acid, and hydrazine hydrate (0.6mL,12.34mmol) was added dropwise under ice-bath conditions, and the mixture was allowed to react overnight at room temperature after completion. After the reaction, ice water and ethyl acetate were added, extraction was performed, organic phases were combined, washed with water, saturated sodium bicarbonate and sodium chloride solution in order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound. ESI-MS M/z 272.7[ M + H ]]+。
Step Synthesis of 32-chloro-4- ((1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl) oxy) pyridine
Figure BDA0002280414000000291
2,2' -bipyridine (0.76g,4.86mmol) and copper acetate (0.97g,4.86mmol) were placed in a reaction flask, 1, 2-dichloroethane (20mL) was added, and the mixture was heated to 80 ℃ for 1 h. Cooled to room temperature and 2-chloro-4- ((3-phenyl-1H-pyrazol-4-yl) oxy) pyridine (1.21g,4.42mmol), sodium carbonate (0.94g,8.83mmol) and cyclopropylboronic acid (1.18g,8.83mmol) were added. Reacting for 4 hours at 80 ℃ under the condition of oxygen. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. For concentratesDiluting with ethyl acetate, filtering with the aid of diatomite, washing the obtained filtrate with water and saturated sodium chloride respectively, drying the filtrate with anhydrous sodium sulfate, concentrating the dried filtrate under reduced pressure, and purifying the concentrated filtrate by column chromatography to obtain the title compound. ESI-MSm/z 312.8[ M + H ]]+。
Step Synthesis of 42- (4- ((4- ((1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) propan-2-ol
Figure BDA0002280414000000292
2-chloro-4- ((1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl) oxy) pyridine (200mg,0.64mmol), 2- (4-aminopyridin-2-yl) propan-2-ol (117mg,0.78mmol), palladium acetate (14mg,0.06mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (70mg,0.12mmol) and cesium carbonate (394mg,1.21mmol) were placed in a reaction flask, 10mL1, 4-dioxane was added, and the reaction was carried out overnight at 100 ℃ under argon protection. After the reaction is finished, the reaction solution is concentrated and purified by column chromatography to obtain the title compound. ESI-MS M/z 428.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6):δ9.45(s,1H),8.14-8.19(m,2H),8.10(s,1H),7.64-7.70(m,4H),7.34-7.37(m,2H),7.25-7.28(m,1H),6.67-6.65(m,1H),6.41-6.42(d,J＝2.0Hz,1H),5.11(s,1H),3.79-3.84(m,1H),1.39(s,6H),1.14-1.17(m,2H),1.00-1.05(m,2H)。
Example 44- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -N-methylpyridinamide
Figure BDA0002280414000000301
Step 14 Synthesis of amino-N-methylpyridinamides
Figure BDA0002280414000000302
Methyl 4-aminopyridine-2-carboxylate (500mg,3.29mmol) was dissolved in 10mL of 33% methylamine in methanol and reacted at 50 ℃ overnight. After the reaction is completed, cooling the reaction liquid to room temperature, and concentrating under reduced pressure to removeRemoving methanol, adding ethyl acetate and water, extracting, combining organic phases, drying by anhydrous sodium sulfate, concentrating under reduced pressure, and purifying by column chromatography to obtain the title compound. ESI-MS M/z 152.1[ M + H ]]+。
Step synthesis of 24- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -N-methylpyridinamide
Figure BDA0002280414000000303
The title compound was prepared by the same procedure as the compound of example 2, step 3, except that 2-morpholinopyridin-4-amine was replaced with 4-amino-N-methylpyridinamide. ESI-MS M/z 435.2[ M + H ]]+。1HNMR(400MHz,DMSO-d6):δ9.78(s,1H),8.67–8.66(d,1H),8.34–8.33(d,1H),8.21–8.17(m,2H),7.94–7.93(m,1H),7.90(s,1H),6.66–6.64(m,1H),6.39–6.38(d,1H),3.84–3.81(m,2H),3.69–3.67(m,1H),3.32–3.28(m,2H),2.81–2.80(d,3H),2.74–2.71(m,1H),1.68–1.66(m,4H),1.06–1.04(m,2H),097–0.95(m,2H)。
Example Synthesis of 54- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) -2- ((2- (2-hydroxypropan-2-yl) pyridin-4-yl) amino) benzonitrile
Figure BDA0002280414000000311
The title compound was prepared by the same procedures as in example 1, steps 1 to 6, except that 2-bromo-4-hydroxybenzonitrile was used instead of 2-chloro-4-hydroxypyridine and 2- (4-aminopyridin-2-yl) propan-2-ol was used instead of 4-aminopyridine-2-carboxylic acid methyl ester. ESI-MS M/z 460.1[ M + H ]]+。1H NMR(400MHz,DMSO-d6):δ9.13(s,1H),8.18(d,1H),7.86(s,1H),7.79-7.76(m,1H),7.25(d,1H),6.91(d,1H),6.83-6.80(m,1H),6.75-6.73(m,1H),5.11(s,1H),3.83-3.79(m,2H),3.66-3.60(m,1H),3.47-3.38(m,2H),2.75-2.67(m,1H),1.65-1.59(m,4H),1.39(s,6H),0.99-0.87(m,4H)。
Example 62- (4- ((4- ((3-methyl-1- (tetrahydro-2H-pyran-4-yl) -1H-indazol-6-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) propan-2-ol
Figure BDA0002280414000000312
Step 16-Synthesis of bromo-3-methyl-1- (tetrahydro-2H-pyran-4-yl) -1H-indazole
Figure BDA0002280414000000313
6-bromo-3-methyl-1H-indazole (2.00g,9.47mmol), tetrahydro-2H-pyran-4-ol (3.87g,37.9mmol) and triphenylphosphine (4.97g,18.94mmol) were placed in a reaction flask, 20mL tetrahydrofuran was added, and diisopropyl azodicarboxylate (3.83g,18.94mmol) was added dropwise. After dropping, the reaction was carried out at room temperature overnight. And after the reaction is finished, adding ethyl acetate for dilution, washing with water and a saturated sodium chloride solution in sequence, drying an organic phase by using anhydrous sodium sulfate, concentrating under reduced pressure, and purifying by using column chromatography to obtain the title compound. ESI-MS M/z 295.5,297.2[ M + H ]]+。
Step 23 Synthesis of methyl-1- (tetrahydro-2H-pyran-4-yl) -6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-indazole
Figure BDA0002280414000000321
6-bromo-3-methyl-1- (tetrahydro-2H-pyran-4-yl) -1H-indazole (410mg,1.39mmol), pinacol bisboronate (882mg,3.47mmol), potassium acetate (409mg,4.17mmol) and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride dichloromethane complex (102mg,0.14mmol) was placed in a reaction flask and 10mL dioxane was added and reacted at 110 ℃ overnight. After the reaction is finished, the solvent is removed by decompression concentration, ethyl acetate is added for dilution, water and saturated sodium chloride solution are sequentially used for washing, the organic phase is dried by anhydrous sodium sulfate, decompression concentration is carried out, and the title compound is obtained by column chromatography purification. ESI-MS M/z 343.2[ M + H ]]+。
Step 33 Synthesis of methyl-1- (tetrahydro-2H-pyran-4-yl) -1H-indazol-6-ol
Figure BDA0002280414000000322
3-methyl-1- (tetrahydro-2H-pyran-4-yl) -6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-indazole (200mg,0.29mmol) was dissolved in 2mL of tetrahydrofuran, and 0.5mL of acetic acid and 1mL of 30% hydrogen peroxide were added and reacted at room temperature overnight. After the reaction was completed, 20mL of a saturated sodium thiosulfate solution was added, stirred for 30min, concentrated under reduced pressure, diluted with ethyl acetate, and filtered with celite. The organic layer was washed with water and saturated sodium chloride in sequence, dried over anhydrous sodium sulfate, and purified by column chromatography to give the title compound. ESI-MS M/z 233.1[ M + H ]]+。
Step 46 Synthesis of- ((2-chloropyridin-4-yl) oxy) -3-methyl-1- (tetrahydro-2H-pyran-4-yl) -1H-indazole
Figure BDA0002280414000000323
3-methyl-1- (tetrahydro-2H-pyran-4-yl) -1H-indazol-6-ol (100mg,0.43mmol), 2-chloro-4-fluoropyridine (226mg,1.72mmol), and potassium carbonate (178mg,1.29mmol) were placed in a reaction flask, N-dimethylformamide was added, and reacted at 100 ℃ overnight. After the reaction, ethyl acetate was added for dilution, and the mixture was washed with water and a saturated sodium chloride solution in this order, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give the title compound. ESI-MSm/z 344.1[ M + H ]]+。
Step 52- (4- ((4- ((3-methyl-1- (tetrahydro-2H-pyran-4-yl) -1H-indazol-6-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) propan-2-ol synthesis
Figure BDA0002280414000000331
6- ((2-Chloropyridin-4-yl) oxy) -3-methyl-1- (tetrahydro-2H-pyran-4-yl) -1H-indazole (120mg,0.35mmol), 2- (4-aminopyridin-2-yl) propan-2-ol (72mg,0.38mmol), palladium acetate (8mg, 0.04mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (41mg, 0.07mmol) and cesium carbonate (228mg, 0.72mmol) were placed in a reaction flask, and 5mL of 1, 4-dioxy-gen was addedSix rings, under the protection of argon, at 100 ℃ reaction overnight. After the reaction is finished, the reaction solution is concentrated and purified by column chromatography to obtain the title compound. ESI-MS M/z 460.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6):δ9.39(s,1H),8.19-8.16(m,2H),7.82-7.80(d,1H),7.68(s,2H),7.60(s,1H),6.95-6.92(m,1H),6.61-6.59(m,1H),6.30(s,1H),5.08(s,1H),4.81-4.75(m,1H),3.99-3.95(m,2H),3.53-3.48(m,2H),2.51(s,3H),2.13-2.04(m,2H),1.84-1.82(d,2H),1.38(s,6H)。
Example 71- (4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -1H-pyrazol-1-yl) -2-methylpropan-2-ol
Figure BDA0002280414000000332
Step Synthesis of 12-methyl-1- (4-nitro-1H-pyrazol-1-yl) propan-2-ol
Figure BDA0002280414000000333
4-Nitro-1H-pyrazole (1.70g,15.03mmol) and 1, 8-diazabicyclo [5.4.0]Undec-7-ene (4.57g,30.06mmol) was added to a two-necked flask, and 2, 2-dimethyloxirane (3.47g,48.10mmol) was added to the flask via syringe under argon. Stirring for 20h at 60 ℃ under the condition of oil bath. After the reaction is finished, cooling to room temperature, and concentrating under reduced pressure. The residue was dissolved in 100mL of ethyl acetate and washed with 2M hydrochloric acid solution. Washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound. ESI-MS M/z 186.20[ M + H ]]+。
Step synthesis of 21- (4-amino-1H-pyrazol-1-yl) -2-methylpropan-2-ol
Figure BDA0002280414000000341
2-methyl-1- (4-nitro-1H-pyrazol-1-yl) propan-2-ol (1.35g,7.30mmol) was added to a single-neck bottle, dissolved in 20mL of methanol, added with palladium/carbon (100%, 160mg), and then replaced with nitrogen and hydrogen three times in this order, and stirred at room temperature overnight. After completion of the reaction, the reaction solution was subjected to filtration with celite, and the filtrate was concentrated under reduced pressure to give the title compound.
Step synthesis of 31- (4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -1H-pyrazol-1-yl) -2-methylpropan-2-ol
Figure BDA0002280414000000342
The title compound was prepared as in example 2, step 3, except that 1- (4-amino-1H-pyrazol-1-yl) -2-methylpropan-2-ol was used instead of 2-morpholinopyridin-4-amine. ESI-MS M/z 439.28[ M + H ]]+。1H NMR(400MHz,DMSO-d6):8.75(s,1H),7.97(d,1H),7.89(s,1H),7.82(s,1H),7.34(s,1H),6.32(dd,1H),6.05(d,1H),4.64(s,1H),3.93(s,2H),3.83(dd,2H),3.65(m,1H),3.29(m,2H),2.69(m,1H),1.64(m,4H),1.03(m,8H),0.94(m,2H)。
Example 81- (4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -3, 5-dimethyl-1H-pyrazol-1-yl) -2-methylpropan-2-ol
Figure BDA0002280414000000343
The title compound was prepared by the same method as that of the compound of example 7, steps 1 to 3, except that 3, 5-dimethyl-4-nitro-1H-pyrazole was used in place of 4-nitro-1H-pyrazole. ESI-MS M/z 467.3[ M + H ]]+。1HNMR(400MHz,DMSO-d6):δ7.85(d,1H),7.73(s,1H),7.71(s,1H),6.23(dd,1H),5.60(s,1H),4.66(s,1H),3.82(s,2H),3.79(m,2H),3.59(m,1H),3.26(m,2H),2.63(m,1H),2.01(s,3H),1.89(s,3H),1.58(m,4H),1.05(m,8H),0.95(m,2H)。
Example 92- (4- ((4- ((1-cyclopropyl-3- (3-methoxyphenyl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) propan-2-ol
Figure BDA0002280414000000351
The title compound was obtained by the same procedure as in example 3 except for using 2-bromo-1- (3-methoxyphenyl) ethyl-1-one instead of 2-bromo-1-phenyleth-1-one. ESI-MS M/z 458.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6):δ9.50(s,1H),8.23-8.24(d,1H),8.18-8.20(d,1H),8.15(s,1H),7.74-7.75(m,1H),7.69-7.71(m,1H),7.31-7.33(m,2H),7.26-7.27(m,1H),6.87-6.90(m,1H),6.69-6.71(m,1H),6.45-6.46(m,1H),5.14(s,1H),3.83-3.89(m,1H),3.74(s,3H),1.44(s,6H),1.19-1.21(m,2H),1.05-1.10(m,2H)。
Example 101- (4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) piperidin-1-yl) -2-hydroxy-2-methylpropan-1-one
Figure BDA0002280414000000352
Step 14 Synthesis of tert-butyl- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) piperidine-1-carboxylate
Figure BDA0002280414000000353
2-chloro-4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine (1g,3.13mmol), tert-butyl 4-aminopiperidine-1-carboxylate (939.44mg,4.69mmol), tris (dibenzylideneacetone) dipalladium (286.6mg,313umol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (361mg,626umol) and sodium tert-butoxide (901.58mg,9.38mmol) were placed in a reaction flask, 10mL of dioxane were added, argon was used for protection, and the reaction was carried out at 100 ℃ overnight. After completion of the reaction, the reaction solution was cooled to room temperature, water and ethyl acetate were added, extraction was performed, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain the title compound.
Step 24 Synthesis of- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) -N- (piperidin-4-yl) pyridin-2-amine hydrochloride
Figure BDA0002280414000000361
Tert-butyl 4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) piperidine-1-carboxylate (970mg,2.01mmol) was dissolved in 10mL of hydrochloric acid/dioxane solution and stirred at room temperature overnight. After completion of the reaction, concentration under reduced pressure gave the title compound.
Step synthesis of 31- (4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) piperidin-1-yl) -2-hydroxy-2-methylpropan-1-one
Figure BDA0002280414000000362
4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) -N- (piperidin-4-yl) pyridin-2-amine hydrochloride (100mg,238umol), 2-hydroxy-2-methylpropanoic acid (37.18mg,357.1umol), 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (108mg,285.75umol) and N, N-diisopropylethylamine (92.3mg,714.3umol) were placed in a reaction flask, 10mL of dichloromethane were added, and the reaction was carried out at normal temperature for 2 hours under the protection of argon. After the reaction is completed, cooling the reaction liquid to room temperature, adding water and ethyl acetate, extracting, combining organic phases, drying by anhydrous sodium sulfate, concentrating under reduced pressure, and purifying by column chromatography to obtain the title compound. ESI-MS M/z 470.3[ M + H ]]+。1H NMR(400MHz,DMSO-d6):δ8.14(s,1H),7.82–7.81(d,1H),7.77(s,1H),6.52–6.50(d,1H),6.15–6.13(m,1H),5.90–5.89(d,1H),3.83–3.80(m,2H),3.64–3.59(m,2H),3.34–3.30(m,4H),2.70–2.67(m,1H),1.87–1.85(m,2H),1.66–1.61(m,4H),1.30(s,6H),1.25–1.22(m,4H),1.01–1.00(m,2H),0.93–0.91(m,2H)。
Example 112- (4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) piperidin-1-yl) -2-methylpropionic acid
Figure BDA0002280414000000371
Synthesis of step 12- (4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) piperidin-1-yl) -2-methylpropionic acid ethyl ester
Figure BDA0002280414000000372
4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) -N- (piperidin-4-yl) pyridin-2-amine hydrochloride (700mg,1.67mmol), ethyl 2-bromo-2-methylpropionate (390.15mg,2.00mmol) and potassium carbonate (691.10mg,5.0mmol) were placed in a reaction flask, and 10mL of acetonitrile was added, and the reaction was refluxed for 17 hours under an argon atmosphere. After the reaction is completed, the reaction solution is cooled to room temperature, filtered to obtain a filtrate, and subjected to reduced pressure concentration and column chromatography purification to obtain the title compound.
Step synthesis of 22- (4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) piperidin-1-yl) -2-methylpropionic acid
Figure BDA0002280414000000373
Ethyl 2- (4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) piperidin-1-yl) -2-methylpropionate (317mg,637.01umol) was dissolved in a mixed solvent of tetrahydrofuran/water (10mL/2mL), and an aqueous sodium hydroxide solution (5mL,7.5M) was added dropwise to the above mixed solution, followed by heating at 90 ℃ for reaction for 24 hours. After the reaction is completed, cooling the reaction liquid to room temperature, dropwise adding 6M hydrochloric acid solution to adjust the pH value to 7, carrying out reduced pressure concentration to remove tetrahydrofuran, adding ethyl acetate, extracting, taking the aqueous phase, carrying out reduced pressure concentration, adding methanol to dissolve, filtering to obtain a filtrate, carrying out reduced pressure concentration, and purifying the title compound by column chromatography. ESI-MSm/z 470.3[ M + H ]]+。1H NMR(400MHz,DMSO-d6):δ7.81–7.79(d,1H),7.77(s,1H),6.52–6.50(d,1H),6.14–6.12(m,1H),5.90–5.89(d,1H),3.83–3.80(m,4H),3.65–3.62(m,2H),3.34–3.27(m,2H),2.98–2.95(m,2H),2.72–2.65(m,1H),1.91–1.89(m,2H),1.64–1.63(m,4H),1.54–1.51(m,2H),1.15(s,6H),1.01–1.00(m,2H),0.93–0.91(m,2H)。
Example 122- (4- ((5- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) -2- (trifluoromethyl) phenyl) amino) pyridin-2-yl) propan-2-ol
Figure BDA0002280414000000381
Step Synthesis of 11-cyclopropyl-4- (3-nitro-4- (trifluoromethyl) phenoxy) -3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazole
Figure BDA0002280414000000382
The procedure is as in example 1, step 2-5 except that 3-nitro-4- (trifluoromethyl) phenol is used in place of 2-chloro-4-hydroxypyridine to give the title compound.
Step 25 Synthesis of- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) -2- (trifluoromethyl) aniline
Figure BDA0002280414000000383
1-cyclopropyl-4- (3-nitro-4- (trifluoromethyl) phenoxy) -3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazole (400mg,1.01mmol) was dissolved in a mixed solvent of methanol/tetrahydrofuran (6mL/3mL), and ammonium chloride (324mg,6.06mmol), water (3mL) and iron powder (226mg,4.04mmol) were added to the reaction system together, followed by reflux reaction. And detecting the reaction by LC-MS, filtering the reaction product with diatomite while the reaction product is hot, and washing a filter cake by methanol. After concentration under reduced pressure, ethyl acetate was added for dilution, washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound. ESI-MS M/z 368.2[ M + H ]]+。
Step Synthesis of 32- (4- ((5- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) -2- (trifluoromethyl) phenyl) amino) pyridin-2-yl) propan-2-ol
Figure BDA0002280414000000391
5- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) -2- (trifluoromethyl) aniline (200mg,0.54mmol), 2- (4-bromopyridin-2-yl) propan-2-ol (117mg,0.54mmol), palladium acetate (12mg, 0.054mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (63mg,0.108mmol), and cesium carbonate (355mg,1.08mmol) were placed in a reaction flask, anhydrous 10mL of 1, 4-dioxane were added, and the reaction was allowed to proceed overnight at 100 ℃ under argon. After the reaction, the reaction mixture was concentrated and purified by column chromatography to obtain the title compound. ESI-MS M/z 503.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6):δ8.28(s,1H),8.08(d,J＝8.0Hz,1H),7.85(s,1H),7.75-7.72(m,1H),7.15-7.13(m,1H),6.95-6.93(m,2H),6.58-6.56(m,1H),5.07(s,1H),3.85-3.80(m,2H),3.65-3.60(m,1H),3.34-3.30(m,2H),2.76-2.68(m,1H),1.66-1.60(m,4H),1.37(s,6H),1.00-0.88(m,4H)。
Example 132- (4- ((1- (1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) -1H-pyrrolo [3,2-c ] pyridin-6-yl) amino) pyridin-2-yl) propan-2-ol
Figure BDA0002280414000000392
Preparation the title compound was prepared according to the procedure for example 5 except that 6-chloro-5-azaindole was used instead of 2-bromo-4-hydroxybenzonitrile. ESI-MS M/z 459.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6):δ9.26(s,1H),8.63(s,1H),8.19-8.14(m,2H),7.65-7.59(m,2H),7.36(d,J＝4Hz,1H),6.69(d,J＝4Hz,1H),6.64(s,1H),3.78-3.75(m,4H),3.25-3.18(m,1H),2.72-2.64(m,1H),1.59-1.51(m,4H),1.41(s,6H),1.10-0.98(m,4H)。
Example 144- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -2- (3-hydroxyazetidin-1-yl) benzonitrile
Figure BDA0002280414000000401
Step 14 Synthesis of bromo-2- (3-hydroxypyrrolidin-1-yl) benzonitrile
Figure BDA0002280414000000402
4-bromo-2-fluorobenzonitrile (1.35g,6.74mmol), azetidine-3-ol hydrochloride (886mg,8.09mmol) and potassium carbonate (2.33g,16.85mmol) were placed in a reaction flask, 20mL of dimethyl sulfoxide was added, and the reaction was carried out at 100 ℃ for 3 h. After the reaction, ethyl acetate is added for dilution, water and saturated sodium chloride solution are used for washing, anhydrous sodium sulfate is used for drying, reduced pressure concentration and column chromatography purification are carried out to obtain the title compound. ESI-MS M/z 253.2,255.2[ M + H ]]+。
Step 2 Synthesis of N- (4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) -1, 1-diphenylimine
Figure BDA0002280414000000403
2-chloro-4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine (1.50g,4.82mmol) and benzophenone imine (0.960g,5.31mmol) were placed in a reaction flask, 15mL of toluene was added, followed by palladium acetate (54.2mg,0.241mmol), 1 '-binaphthyl-2, 2' -bis-diphenylphosphine (300mg,0.482mmol), and cesium carbonate (3.14g,9.64mmol), nitrogen was replaced three times, and the reaction was allowed to react overnight at 95 ℃. After the reaction is completed, the reaction product is filtered, the filtrate is decompressed, the solvent is removed by evaporation, and the title compound is obtained by column chromatography separation. LC-MS M/z 465.2[ M + H ]]+。
Step 34 Synthesis of- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-amine
Figure BDA0002280414000000404
N- (4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) -1, 1-diphenylimine (1.98g,4.34mmol) was dissolved in a hydrogen chloride/1, 4-dioxane solution (20mL,4.0M) and reacted at room temperature overnight. After completion of the reaction, a saturated aqueous solution of sodium carbonate (20mL) was added and the mixture was stirred at room temperature for 30 min. Adding ethyl acetate, extracting,the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give the title compound. LC-MS M/z 301.2[ M + H ]]+。
Step 44 Synthesis of- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -2- (3-hydroxyazetidin-1-yl) benzonitrile
Figure BDA0002280414000000411
4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-amine (200mg,0.667mmol) and 4-bromo-2- (3-hydroxypyrrolidin-1-yl) benzonitrile (194mg,0.733mmol) were dissolved in 5mL1, 4-dioxane, tris (dibenzylideneacetone) dipalladium (61.1mg,0.0667mmol), 4, 5-bis diphenylphosphine-9, 9-dimethylxanthene (116mg,0.200mmol) and cesium carbonate (435mg,1.33mmol) were added, and the mixture was replaced with nitrogen three times and reacted at 100 ℃ overnight. After the reaction is completed, the reaction product is filtered, the filtrate is decompressed, the solvent is removed by evaporation, and the title compound is obtained by column chromatography separation. ESI-MS M/z 473.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6):δ9.37(s,1H),8.08-8.10(d,1H),7.87(s,1H),7.30-7.32(d,1H),7.09-7.11(m,1H),6.99(s,1H),6.55-6.57(m,1H),6.31-6.32(m,1H),5.69-5.71(m,1H),4.52-4.56(m,1H),4.27-4.31(m,2H),3.80-3.83(m,2H),3.72-3.75(m,2H),3.65-3.67(m,2H),3.27-3.32(m,1H),2.67-2.74(m,1H),1.65-1.66(m,4H),1.03-1.04(m,2H),0.94-0.95(m,2H)。
Example 152- (4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) -2-methylpropionic acid
Figure BDA0002280414000000412
Step Synthesis of methyl 12- (4-bromopyridin-2-yl) -2-methylpropionate
Figure BDA0002280414000000413
4-Bromopyridine 1-oxide (1g,5.75mmol)1-methoxy-1- (trimethylsilyloxy) -2-methyl-1-propene (2g,174.3mmol), trispyrrolidinylphosphonium bromide hexafluorophosphate (3g,6.43mmol) and N, N-diisopropylethylamine (2.7mL,16.33mmol) were added to 50mL of tetrahydrofuran. The reaction mixture was stirred at room temperature for 12 h. After the reaction, water and ethyl acetate were added, extraction was performed, and the organic phase was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. Column chromatography separation gave the title compound. ESI-MS M/z 258.2,260.2[ M + H ]]+。
Step Synthesis of methyl 22- (4- ((tert-butoxycarbonyl) amino) pyridin-2-yl) -2-methylpropionate
Figure BDA0002280414000000421
Methyl 2- (4-bromopyridin-2-yl) -2-methylpropionate (618mg,2.39mmol), tert-butylcarbamate (336mg,2.87mmol), cesium carbonate (1.56g,4.78mmol), 4, 5-bis-diphenylphosphino-9, 9-dimethylxanthene (28mg,0.05mmol), and tris (dibenzylideneacetone) dipalladium (22mg,0.07mmol) were placed in a reaction flask, 20mL dioxane was added, and under argon, reacted at 100 ℃ overnight. After the reaction, the reaction mixture was concentrated and purified by column chromatography to obtain the title compound. ESI-MS M/z 295.2[ M + H ]]+。
Step Synthesis of methyl 32- (4-aminopyridin-2-yl) -2-methylpropionate hydrochloride
Figure BDA0002280414000000422
Methyl 2- (4- ((tert-butoxycarbonyl) amino) pyridin-2-yl) -2-methylpropionate (600mg,2.03mmol) was dissolved in 10mL of hydrochloric acid/dioxane system and reacted at room temperature overnight. After completion of the reaction, the reaction solution was concentrated to obtain the title compound. ESI-MS M/z 195.5[ M-HCl + H ]]+。
Step 52 Synthesis of 4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) -2-methylpropionic acid
Figure BDA0002280414000000423
The title compound was prepared by the same method as the method for preparing the compound in steps 6 to 7 of example 1, except that methyl 2- (4-aminopyridin-2-yl) -2-methylpropionate hydrochloride was used in place of methyl 4-aminopyridine-2-carboxylate. ESI-MS M/z 464.3[ M + H ]]+。1H NMR(400MHz,DMSO-d6):δ9.52(s,1H),8.20-8.21(d,1H),8.12-8.14(d,1H),7.88(s,1H),7.68-7.70(m,1H),7.50-7.51(m,1H),6.58-6.60(m,1H),6.33-6.34(m,1H),3.80-3.84(m,2H),3.64-3.68(m,2H),3.30-3.31(m,1H),2.67-2.72(m,1H),1.63-1.66(m,4H),1.45(s,6H),1.03-1.04(m,2H),0.94-0.96(m,2H)。
Example 162- (4- ((4- ((1-cyclopropyl-3- (3-fluorophenyl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) propan-2-ol
Figure BDA0002280414000000431
The title compound was prepared by the same procedure as in example 3 except for using 2-bromo-1- (3-fluorophenyl) ethan-1-one in place of 2-bromo-1-phenyleth-1-one. ESI-MS M/z 446.3[ M + H ]]+。1H NMR(400MHz,DMSO-d6):δ9.46(s,1H),8.18-8.19(m,1H),8.15-8.16(m,2H),7.65-7.69(m,2H),7.52-7.54(m,1H),7.38-7.44(m,2H),7.09-7.15(m,1H),6.67-6.69(m,1H),6.41-6.42(m,1H),3.81-3.87(m,1H),1.39(s,6H),1.15-1.17(m,2H),1.02-1.05(m,2H)。
Example 172- (4- ((4- ((1-cyclopropyl-3- (2-fluorophenyl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) propan-2-ol
Figure BDA0002280414000000432
The title compound was prepared by the same procedure as in example 3, except that 2-bromo-1- (2-fluorophenyl) ethan-1-one was used instead of 2-bromo-1-phenyleth-1-one. ESI-MS M/z 446.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6):δ9.45(s,1H),8.19(d,J＝8Hz,1H),8.14(s,1H),8.09(d,J＝4.0Hz,1H),7.69-7.65(m,2H),7.56-7.52(m,1H),7.40-7.35(m,1H),7.24-7.19(m,2H),6.57-6.55(m,1H),6.42(d,J＝4.0Hz,1H),3.87-3.81(m,1H),1.40(s,6H),1.18-1.14(m,2H),1.05-1.02(m,2H)。
Example 182- (4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-indazol-5-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) propan-2-ol
Figure BDA0002280414000000441
Step 14-methyl-N' - (tetrahydro-4H-pyran-4-ylidene) benzenesulfonylhydrazide synthesis
Figure BDA0002280414000000442
Tetrahydropyranone (5.0g,26.87mmol) and p-toluenesulfonylhydrazide (2.7g,26.87mmol) were added to 50mL of methanol, and the mixture was stirred at room temperature overnight. After the reaction was complete, methanol was removed by concentration under reduced pressure to give the title compound. ESI-MS M/z 269.0[ M + H ]]+。
Step 2 Synthesis of (4-bromo-2-fluorophenyl) (tetrahydro-2H-pyran-4-yl) methanone
Figure BDA0002280414000000443
4-methyl-N' - (tetrahydro-4H-pyran-4-ylidene) benzenesulfonylhydrazide (151mg,0.746mmol), 4-bromo-2-fluorobenzaldehyde (200mg,0.746mmol), and cesium carbonate (365mg,1.12mmol) were weighed into 20mL1, 4-dioxane. The reaction was heated to 110 ℃ under argon and stirred overnight. After the reaction is finished, removing the 1, 4-dioxane, adding saturated ammonium chloride solution and dichloromethane, separating an organic phase and an aqueous phase, and extracting the aqueous phase with dichloromethane. The organic phases were combined, concentrated under reduced pressure and purified by column chromatography to give the title compound. ESI-MS M/z 287.0,289.0[ M + H ]]+。
Step synthesis of 35-bromo-3- (tetrahydro-2H-pyran-4-yl) -1H-indazole
Figure BDA0002280414000000444
(4-bromo-2-fluorophenyl) (tetrahydro-2H-pyran-4-yl) methanone (4.02g,13.98mmol) and hydrazine hydrate (2.53g,50.60mmol) were dissolved in 20mL dioxane and reacted at 100 ℃ overnight. After the reaction, the solvent was removed under reduced pressure, and the mixture was diluted with ethyl acetate. The title compound was obtained by washing with water and saturated sodium chloride solution in this order, drying over anhydrous sodium sulfate, concentrating under reduced pressure and purifying by column chromatography. ESI-MS M/z 281.3,283.3[ M + H ]]+。
Step 45-Synthesis of bromo-1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-indazole
Figure BDA0002280414000000451
2, 2-bipyridine (1.94g,12.39mmol) and copper acetate (2.25g,12.39mmol) were placed in a reaction flask, 20mL of 1, 2-dichloroethane were added and the reaction was refluxed for 1 h. Cooled to room temperature, 5-bromo-3- (tetrahydro-2H-pyran-4-yl) -1H-indazole (2.32g,8.26mmol), sodium carbonate (1.75g,16.51mmol), and cyclopropylboronic acid (1.42g,16.51mmol) were added. Reacting for 4 hours at 80 ℃ under the condition of oxygen. After the reaction, the mixture was concentrated under reduced pressure, diluted with ethyl acetate and filtered with celite. The organic phase was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate and purified by column chromatography to give the title compound. ESI-MS M/z 321.2,323.2[ M + H ]]+。
Synthesis of step 82- (4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-indazol-5-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) propan-2-ol
Figure BDA0002280414000000452
The procedure is as in example 6, step 2-5 except that 5-bromo-1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-indazole is used instead of 6-bromo-3-methyl-1- (tetrahydro-2H-pyran-4-yl) -1H-indazole, to give the title compound. ESI-MS M/z 486.5[ M + H ]]+。1H NMR(400MHz,DMSO-d6):δ9.38(s,1H),8.17-8.19(m,1H),8.14-8.15(m,1H),7.73-7.75(m,1H),7.66-7.70(m,3H),7.25-7.28(m,1H),6.56-6.58(m,1H),6.22-6.23(m,1H),5.10(s,1H),3.92-3.95(m,2H),3.66-3.71(m,1H),3.45-3.51(m,2H),3.24-3.30(m,1H),1.78-1.81(m,4H),1.38(s,6H),1.09-1.14(m,4H)。
Example 194- ((1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl) oxy) -N- (2-morpholinopyridin-4-yl) pyridin-2-amine
Figure BDA0002280414000000453
Preparation the title compound was prepared as in example 3, except that 2-morpholinopyridin-4-amine was used instead of 2- (4-aminopyridin-2-yl) propan-2-ol. ESI-MS M/z 455.4[ M + H ]]+。1H NMR(400MHz,DMSO-d6):δ10.22(s,1H),8.72-8.25(m,1H),8.13(s,1H),7.83-7.85(m,1H),7.79(s,1H),7.67-7.69(m,2H),7.33-7.37(m,2H),7.25-7.29(m,1H),6.97-6.98(m,1H),6.85-6.87(m,1H),6.50-6.51(m,1H),3.80-3.85(m,1H),3.74-3.76(m,4H),3.44-3.47(m,4H),1.14-1.18(m,2H),1.01-1.06(m,2H)。
Example 204- ((1-cyclopropyl-3- (4, 4-difluorocyclohexyl) -1H-pyrazol-4-yl) oxy) -N- (2-morpholinopyridin-4-yl) pyridin-2-amine
Figure BDA0002280414000000461
Step 11- (4, 4-Difluorocyclohexyl) Ethyl-1-one Synthesis
Figure BDA0002280414000000462
4, 4-Difluorocyclohexane-1-carboxylic acid (2.0g,12.18mmol) was dissolved in 100mL of anhydrous tetrahydrofuran, and methyllithium solution (30.5mL,1.6M,48.7mmol) was added dropwise from a constant pressure dropping funnel at 0 ℃ and the reaction stirred for 2h, followed by dropwise addition of trimethylchlorosilane (24.74mL, 195mmol) over about 10 min. The reaction mixture was allowed to cool to room temperature for 1 hour, 5mL of 1M hydrochloric acid was added, the reaction mixture was stirred for 1 hour, and the reaction mixture was concentrated under reduced pressure. After dilution with ethyl acetate, the mixture was washed with water, saturated sodium bicarbonate and brine, respectively, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound.
Step Synthesis of 22-bromo-1- ((4, 4-difluorocyclohexyl) ethyl-1-one
Figure BDA0002280414000000463
1- (4, 4-Difluorocyclohexyl) ethyl-1-one (2.1g,8.71mmol) was dissolved in 15mL of methanol, precooled at-10 ℃ and added dropwise to bromine (0.63mL, 12.3mmol) with a constant pressure funnel, the rate of addition being controlled. After dropping, the mixture was stirred at 0 ℃ for 1 hour, and then allowed to react at room temperature to become pale yellow, an aqueous solution of sulfuric acid (5mL,10M) was added thereto, and the mixture was stirred overnight, followed by addition of water and ethyl acetate and extraction. The organic phase was washed with saturated sodium bicarbonate and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to give the title compound.
Step 34 Synthesis of- ((1-cyclopropyl-3- (4, 4-difluorocyclohexyl) -1H-pyrazol-4-yl) oxy) -N- (2-morpholinopyridin-4-yl) pyridin-2-amine
Figure BDA0002280414000000471
The title compound was prepared as in example 19, except that 2-bromo-1- (4, 4-difluorocyclohexyl) ethyl-1-one was used in place of 2-bromo-1-phenyleth-1-one. ESI-MS M/z 497.3[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ:9.29(s,1H),8.12(d,J＝4.0Hz,1H),7.89-7.88(m,2H),7.22(s,1H),6.96-6.92(m,1H),6.57-6.55(m,1H),6.33-6.32(m,1H),3.70-3.64(m,5H),3.36-3.33(m,4H),2.70-2.64(m,1H),2.05-1.62(m,8H),1.06-1.01(m,2H),0.99-0.92(m,2H)。
Example 213- (1-cyclopropyl-4- ((2- ((2- (2-hydroxypropan-2-yl) pyridin-4-yl) amino) pyridin-4-yl) oxy) -1H-pyrazol-3-yl) benzonitrile
Figure BDA0002280414000000472
The title compound was prepared according to the procedure for the preparation of example 3, except that 3- (2-bromoacetyl) benzonitrile was used instead of 2-bromo-1-phenyleth-1-one. ESI-MS M/z 453.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6):δ9.48(s,1H),8.23-8.16(m,3H),8.02-7.97(m,2H),7.77-7.74(m,1H),7.69-7.65(m,2H),7.62-7.58(m,1H),6.70-6.68(m,1H),6.44(d,J＝4.0Hz,1H),3.88-3.83(m,1H),1.39(s,6H),1.23-1.17(m,2H),1.09-1.07(m,2H)。
Example 224- ((1-cyclopropyl-3- (3-fluorophenyl) -1H-pyrazol-4-yl) oxy) -N- (2-morpholinopyridin-4-yl) pyridin-2-amine
Figure BDA0002280414000000473
The title compound was prepared as in example 19, except that 2-bromo-1- (3-fluorophenyl) ethan-1-one was used instead of 2-bromo-1-phenylethane-1-one. ESI-MS M/z 473.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6):δ9.25(s,1H),8.13-8.14(m,2H),7.86-7.87(m,1H),7.51-7.53(m,1H),7.38-7.43(m,2H),7.18(s,1H),7.09-7.14(m,1H),6.87-6.89(m,1H),6.64-6.66(m,1H),6.36-6.37(m,1H),3.80-3.85(m,1H),3.67-3.69(m,4H),3.31-3.34(m,4H),1.15-1.18(m,2H),1.00-1.05(m,2H)。
Example 234- ((1-cyclopropyl-3- (2-fluorophenyl) -1H-pyrazol-4-yl) oxy) -N- (2-morpholinopyridin-4-yl) pyridin-2-amine
Figure BDA0002280414000000481
The title compound was prepared as in example 19, except that 2-bromo-1- (2-fluorophenyl) ethan-1-one was used instead of 2-bromo-1-phenylethane-1-one. ESI-MS M/z 473.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6):δ9.23(s,1H),8.13-8.15(m,1H),8.05-8.07(m,1H),7.86-7.87(m,1H),7.51-7.55(m,1H),7.34-7.40(m,1H),7.18-7.23(m,3H),6.87-6.89(m,1H),6.52-6.54(m,1H),6.37-6.38(m,1H),3.80-3.85(m,1H),3.67-3.69(m,4H),3.32-3.34(m,4H),1.13-1.17(m,2H),1.01-1.05(m,2H)。
Example 244- ((4- ((1-cyclopropyl-3- (4, 4-difluorocyclohexyl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -2- (3-hydroxy-3-methylazetidin-1-yl) benzonitrile
Figure BDA0002280414000000482
Step 12-chloro-4- ((1-cyclopropyl-3- (4, 4-difluorocyclohexyl) -1H-pyrazol-4-yl) oxy) pyridine
Figure BDA0002280414000000491
The title compound was prepared in the same manner as in the preparation of the compound in example 20, steps 1 to 3. ESI-MSm/z 354.2[ M + H ]]+。
Step 24 Synthesis of- ((4- ((1-cyclopropyl-3- (4, 4-difluorocyclohexyl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -2- (3-hydroxy-3-methylazetidin-1-yl) benzonitrile
Figure BDA0002280414000000492
The procedure is as for the preparation of example 14 except that 2-chloro-4- ((1-cyclopropyl-3 (4, 4-difluorocyclohexyl) -1H-pyrazol-4-yl) oxy) pyridine is used instead of 2-chloro-4- ((3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine and 3-methylazetidin-3-ol instead of azetidin-3-ol hydrochloride to give the title compound. The title compound was obtained. ESI-MS M/z 521.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6):δ9.37(s,1H),8.10(d,1H),7.88(s,1H),7.31(d,1H),7.10-7.03(m,2H),6.58-6.56(dd,1H),6.32(d,1H),5.61(s,1H),3.98(d,2H),3.85(d,2H),3.69-3.66(m,1H),2.70-2.65(m,1H),2.08-1.67(m,8H),1.45(s,3H),1.06-0.92(m,4H)。
Example 251- (4- ((4- ((1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -1H-pyrazol-1-yl) -2-methylpropan-2-ol
Figure BDA0002280414000000493
The procedure is as in example 7, except that 2-chloro-4- ((1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl) oxy) pyridine is usedInstead of 2-chloro-4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine. ESI-MS M/z 431.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6):δ8.72(s,1H),8.05(s,1H),7.98(d,1H),7.87(s,1H),7.69(m,2H),7.35(m,2H),7.32(s,1H),7.26(m,1H),6.39(dd,1H),6.10(d,1H),4.63(s,1H),3.92(s,2H),3.80(m,1H),1.14(m,2H),1.02(s,6H),1.01(m,2H)。
Example 264- ((1-cyclopropyl-3- (2, 4-difluorophenyl) -1H-pyrazol-4-yl) oxy) -N- (2-morpholinopyridin-4-yl) pyridin-2-amine
Figure BDA0002280414000000501
The title compound was prepared as in example 19, except that 2-bromo-1- (2, 4-difluorophenyl) ethyl-1-one was used in place of 2-bromo-1-phenyleth-1-one. ESI-MS M/z 491.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6):δ9.24(s,1H),8.14(m,1H),8.06-8.07(m,1H),7.87-7.88(m,1H),7.53-7.59(m,1H),7.24-7.30(m,1H),7.18-7.19(m,1H),7.10-7.15(m,1H),6.88-6.90(m,1H),6.52-6.54(m,1H),6.36-6.37(m,1H),3.80-3.85(m,1H),3.67-3.69(m,4H),3.32-3.34(m,4H),1.13-1.17(m,2H),1.00-1.04(m,2H)。
Example 274- ((1-cyclopropyl-3- (3- (trifluoromethyl) phenyl) -1H-pyrazol-4-yl) oxy) -N- (2-morpholinopyridin-4-yl) pyridin-2-amine
Figure BDA0002280414000000502
The title compound was prepared as in example 19, except that 2-bromo-1- (3- (trifluoromethyl) phenyl) ethan-1-one was used instead of 2-bromo-1-phenylethan-1-one. ESI-MS M/z 523.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6):δ9.25(s,1H),8.13-8.18(m,3H),7.95-7.97(m,2H),7.86-7.87(m,1H),7.59-7.66(m,2H),7.18-7.19(m,1H),6.64-6.67(m,1H),6.37-6.38(m,1H),3.82-3.88(m,1H),3.67-3.69(m,4H),3.32-3.34(m,4H),1.16-1.23(m,2H),1.02-1.09(m,2H)。
Example 284- ((1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl) oxy) -N- (2- ((2S,6R) -2, 6-dimethylmorpholinyl) pyridin-4-yl) pyridin-2-amine
Figure BDA0002280414000000511
Step 1 Synthesis of (2S,6R) -2, 6-dimethyl-4- (4-nitropyridin-2-yl) morpholine
Figure BDA0002280414000000512
2-chloro-4-nitropyridine (2g,0.013mol) and (2S,6R) -2, 6-dimethylmorpholine (4.37g,0.038mol) were dissolved in 40mL of tetrahydrofuran and heated under reflux overnight. After the reaction, the reaction mixture was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. ESI-MS M/z 238.2[ M + H ]]+。
Step 22 Synthesis of- ((2S,6R) -2, 6-Dimethylmorpholine) pyridin-4-amine
Figure BDA0002280414000000513
(2S,6R) -2, 6-dimethyl-4- (4-nitropyridin-2-yl) morpholine (1.18g,4.78mmol) was dissolved in a mixed solvent of methanol/methylene chloride (9mL/3mL), and palladium/carbon (10%, 100mg) was added thereto, followed by replacement with hydrogen gas for 5 times and reaction at room temperature overnight. After the reaction was complete, filtration was assisted with celite, the filter cake was washed with methanol, and the filtrate was concentrated to give the title compound. ESI-MS M/z 208.2[ M + H ]]+。
Step 34 Synthesis of- ((1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl) oxy) -N- (2- ((2S,6R) -2, 6-dimethylmorpholinyl) pyridin-4-yl) pyridin-2-amine
Figure BDA0002280414000000514
Taking 2-chloro-4- ((1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl) oxy) pyridine (120mg,0.38mmol), 2- ((2S,6R) -2, 6-dimethylmorpholine) pyridin-4-amine (80mg,0.38mmol), tris (dibenzylideneacetone) dipalladium (35mg,0.038mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (45mg,0.076mmol) and sodium phenolate (251 mg, 251mg,0.76mmol) was placed in a reaction flask and 5mL of 1, 4-dioxane was added. The reaction was carried out overnight at 100 ℃ under the protection of argon. After the reaction, the reaction mixture was concentrated and purified by column chromatography to obtain the title compound. ESI-MS M/z 483.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6):δ9.41(s,1H),8.16-8.10(m,2H),7.87-7.84(m,1H),7.70-7.67(m,2H),7.38-7.34(m,2H),7.29-7.25(m,1H),7.19(s,1H),6.98-6.95(m,1H),6.68-6.66(m,1H),6.41-6.38(m,1H),3.96-3.92(m,2H),3.84-3.79(m,1H),3.65-3.57(m,2H),2.42-2.36(m,2H),1.23-1.00(m,10H)。
Example 294- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) -N- (2- ((2S,6R) -2, 6-dimethylmorpholinyl) pyridin-4-yl) pyridin-2-amine
Figure BDA0002280414000000521
The title compound was prepared similar to the preparation of example 28 except that 2-chloro-4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine was used instead of 2-chloro-4- ((1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl) oxy) pyridine. ESI-MS [ M + H ]]+m/z:491.2。1H NMR(400MHz,DMSO-d6):δ9.26(s,1H),8.14-8.11(m,1H),7.88-7.87(m,2H),7.11-7.10(m,1H),7.01-6.97(m,1H),6.56-6.54(m,1H),6.32-6.31(m,1H),3.99-3.95(m,2H),3.84-3.80(m,2H),3.71-3.57(m,3H),3.38-3.26(m,2H),2.75-2.67(m,1H),2.36-2.31(m,2H),1.72-1.60(m,4H),1.16-1.15(d,J＝4.0Hz,6H),1.06-1.02(m,2H),0.99-0.92(m,2H)。
Example 304- ((3- (3-chlorophenyl) -1-cyclopropyl-1H-pyrazol-4-yl) oxy) -N- (2-morpholinopyridin-4-yl) pyridin-2-amine
Figure BDA0002280414000000522
The title compound was prepared as in example 19, except that 2-bromo-1- (3-chlorophenyl) ethan-1-one was used instead of 2-bromo-1-phenylethane-1-one. ESI-MS M/z 489.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6):δ9.26(s,1H),8.13-8.14(m,2H),7.86-7.88(d,1H),7.69(s,1H),7.62-7.64(m,1H),7.38-7.42(m,1H),7.33-7.35(m,1H),7.19(s,1H),6.88-6.89(m,1H),6.64-6.66(m,1H),6.36-6.37(m,1H),3.81-3.86(m,1H),3.67-3.69(m,4H),3.32-3.34(m,4H),1.15-1.19(m,2H),1.01-1.19(m,2H)。
Example 314- ((1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl) oxy) -N- (1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine
Figure BDA0002280414000000531
Step 14 Synthesis of Nitro-1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazole
Figure BDA0002280414000000532
4-Nitro-1H-pyrazole (1.00g,8.84mmol), tetrahydro-2H-pyran-4-ol (903mg,8.84mmol) and triphenylphosphine (2.86g,10.88mmol) were placed in a reaction flask, 10mL tetrahydrofuran was added under argon protection, and diisopropyl azodicarboxylate (2.33g,11.5mmol) was added dropwise at 0 ℃. After dropping, the reaction was carried out at room temperature overnight. After the reaction, the mixture was diluted with ethyl acetate, washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give the title compound. ESI-MS M/z 198.3[ M + H ]]+。
Step synthesis of 21- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-amine
Figure BDA0002280414000000533
4-Nitro-1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazole (500mg,2.54mmol) and palladium on carbon (10%, 135mg) were added to methanol, and reacted at room temperature under a hydrogen atmosphere overnight. After the reaction, the filtrate was filtered and concentrated under reduced pressure to give the title compound. ESI-MS M/z 168.2[ M + H ]]+。
Step 34 Synthesis of- ((1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl) oxy) -N- (1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine
Figure BDA0002280414000000534
The title compound was prepared according to the procedure for the preparation of example 28, except that 1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-amine was used instead of 2- ((2S,6R) -2, 6-dimethylmorpholine) pyridin-4-amine. ESI-MS [ M + H ]]+m/z:443.2。1H NMR(400MHz,DMSO-d6):δ8.72(s,1H),8.06(s,1H),7.97-7.98(d,1H),7.89(s,1H),7.67-7.69(m,2H),7.33-7.37(m,3H),7.24-7.27(m,1H),6.38-6.40(m,1H),6.09-6.10(m,1H),4.27-4.34(m,1H),3.92-3.95(m,2H),3.76-3.82(m,1H),3.43-3.46(m,2H),1.86-1.95(m,4H),1.12-1.16(m,2H),0.99-1.03(m,2H)。
Example 324- ((1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl) oxy) -N- (1- ((3-methyloxetan-3-yl) methyl) -1H-pyrazol-4-yl) pyridin-2-amine
Figure BDA0002280414000000541
Preparation the title compound was prepared as in example 3, except that 1- ((3-methyloxetan-3-yl) methyl) -1H-pyrazol-4-amine was used instead of 2- (4-aminopyridin-2-yl) propan-2-ol. ESI-MSm/z 443.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6):δ8.75(s,1H),8.05(s,1H),7.97-7.98(d,1H),7.89(s,1H),7.67-7.69(m,2H),7.32-7.36(m,3H),7.24-7.28(m,1H),6.38-6.40(m,1H),6.09-6.10(m,1H),4.55-4.56(m,2H),4.23(s,1H),4.18-4.19(m,2H),3.77-3.82(m,1H),1.11-1.12(m,2H),1.10(s,3H),0.99-1.04(m,2H)。
Example 334- ((3- (2-chlorophenyl) -1-cyclopropyl-1H-pyrazol-4-yl) oxy) -N- (2-morpholinopyridin-4-yl) pyridin-2-amine
Figure BDA0002280414000000542
The title compound was prepared as in example 19, except that 2-bromo-1- (2-chlorophenyl) ethan-1-one was used instead of 2-bromo-1-phenylethane-1-one. ESI-MS M/z 489.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6):δ9.25(s,1H),8.12(s,1H),8.04(d,J＝4.0Hz,1H),7.88(d,J＝4.0Hz,1H),7.49-7.45(m,1H),7.43-7.40(m,1H),7.37-7.34(m,2H),7.20-7.19(m,1H),6.91-6.89(m,1H),6.50-6.48(m,1H),6.41-6.40(m,1H),3.86-3.80(m,1H),3.70-3.68(m,4H),3.35-3.32(m,4H),1.17-1.13(m,2H),1.07-0.98(m,2H)。
Example 343- (1-cyclopropyl-4- ((2- ((2-morpholinopyridin-4-yl) amino) pyridin-4-yl) oxy) -1H-pyrazol-3-yl) benzonitrile
Figure BDA0002280414000000551
The title compound was prepared as in example 19, except that 3- (2-bromoacetyl) benzonitrile was used instead of 2-bromo-1-phenyleth-1-one. ESI-MS M/z 480.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6):δ9.27(s,1H),8.19-8.14(m,2H),8.01-7.97(m,2H),7.88(d,J＝4.0Hz,1H),7.76(d,J＝8.0Hz,1H),7.62-7.58(m,1H),7.19(s,1H),6.89-6.87(m,1H),6.68-6.66(m,1H),6.40-6.38(m,1H),3.88-3.83(m,1H),3.70-3.67(m,4H),3.35-3.33(m,4H),1.21-1.17(m,2H),1.07-1.02(m,2H)。
Example 353- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -N-methylbenzenesulfonamide
Figure BDA0002280414000000552
2-chloro-4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine (150mg,0.47mmol), 3-amino-N-methylbenzenesulfonamide (88mg,0.47mmol), tris (dibenzylideneacetone) dipalladium (43mg,0.04mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (54mg,0.09mmol) and sodium phenolate (109mg,0.94mmol) were placed in a reaction flask, 8mL1, 4-dioxane was added, and reacted at 100 ℃ overnight under argon protection. After the reaction is finished, the reaction solution is concentrated and purified by column chromatography to obtain the title compound. ESI-MS M/z 470.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ:9.41(s,1H),8.18-8.17(m,1H),8.10-8.07(m,1H),7.91-7.87(m,2H),7.47-7.36(m,2H),7.25-7.23(m,1H),6.54-6.52(m,1H),6.29-6.28(m,1H),3.85-3.80(m,2H),3.70-3.64(m,1H),3.34-3.28(m,2H),2.76-2.68(m,1H),2.43(m,3H),1.67-1.63(m,4H),1.06-0.94(m,4H)。
Example 363- (1-cyclopropyl-4- ((2- ((1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) amino) pyridin-4-yl) oxy) -1H-pyrazol-3-yl) benzonitrile
Figure BDA0002280414000000561
Step Synthesis of 13- (4- ((2-chloropyridin-4-yl) oxy) -1-cyclopropyl-1H-pyrazol-3-yl) benzonitrile
Figure BDA0002280414000000562
The title compound was prepared by the same method as that of the compound of example 3, steps 1 to 3, except that 3- (2-bromoacetyl) benzonitrile was used instead of 2-bromo-1-phenyleth-1-one. ESI-MS M/z 337.2[ M + H ]]+。
Step Synthesis of 21- (cyclopropylsulfonyl) -4-nitro-1H-pyrazole
Figure BDA0002280414000000563
4-Nitro-1H-pyrazole (1.00g,8.84mmol) was dissolved in 50mL of acetonitrile, sodium hydride (0.39g,16.21mmol) was added at 0 deg.C, and after stirring for 0.5H, cyclopropylsulfonyl chloride (1.24g,8.84mmol) was added. The reaction is carried out for 16h at room temperature, and detection is carried out by LC-MS. After the reaction is finished, cooling to room temperature, filtering, concentrating the filtrate, adding water and ethyl acetate, extracting, combining organic phases, drying by anhydrous sodium sulfate, concentrating under reduced pressure, and purifying by column chromatography to obtain the title compound. ESI-MS M/z 218.2[ M + H ]]+。
Step 31- (Cyclopropylsulfonyl) -1H-pyrazol-4-amine Synthesis
Figure BDA0002280414000000564
1- (Cyclopropylsulfonyl) -4-nitro-1H-pyrazole (1.68g,7.73mmol) was dissolved in 50mL of methanol solution, and palladium on carbon catalyst (10%, 168mg) was added, and the mixture was replaced with hydrogen gas several times, reacted at room temperature overnight, and monitored by TLC. The reaction was complete, filtered and the filtrate was concentrated to give the title compound. ESI-MS M/z 188.3[ M + H ]]+。
Step 43- (4- ((2- ((1H-pyrazol-4-yl) amino) pyridin-4-yl) oxy) -1-cyclopropyl-1H-pyrazol-3-yl) benzonitrile Synthesis
Figure BDA0002280414000000571
3- (4- ((2-chloropyridin-4-yl) oxy) -1-cyclopropyl-1H-pyrazol-3-yl) benzonitrile (130mg,0.39mmol), 1- (cyclopropylsulfonyl) -1H-pyrazol-4-amine (80mg,0.43mmol), tris (dibenzylideneacetone) dipalladium (35mg,0.04 mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (45mg,0.08mmol) and sodium phenolate (90mg,0.78mmol) were placed in a reaction flask, 5mL of 1, 4-dioxane were added, and reacted overnight at 100 ℃ under argon. After the reaction is finished, the reaction solution is concentrated and purified by column chromatography to obtain the title compound. ESI-MS M/z 384.2[ M + H ]]+。
Step 53- (1-cyclopropyl-4- ((2- ((1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) amino) pyridin-4-yl) oxy) -1H-pyrazol-3-yl) benzonitrile
Figure BDA0002280414000000572
3- (4- ((2- ((1H-pyrazol-4-yl) amino) pyridin-4-yl) oxy) -1-cyclopropyl-1H-pyrazol-3-yl) benzonitrile (110mg,0.29mmol) was dissolved in 10mL of anhydrous tetrahydrofuran under the protection of argon, sodium hydride (46mg,1.16mmol) was added at 0 ℃, the reaction was stirred for 0.5H, cyclopropylsulfonyl chloride (48mg,0.34mmol) was added, and the mixture was allowed to warm to room temperature for reaction. And detecting the reaction by LC-MS, extracting by ethyl acetate after the reaction is finished, washing by saturated saline solution, drying by anhydrous sodium sulfate, concentrating under reduced pressure, and separating by column chromatography to obtain the title compound. ESI-MS M/z 488.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ:9.32(s,1H),8.44(s,1H),8.18(s,1H),8.14-8.13(m,1H),8.01-7.97(m,2H),7.85(s,1H),7.77-7.75(m,1H),7.62-7.58(m,1H),6.59-6.57(m,1H),6.23-6.22(m,1H),3.88-3.82(m,1H),3.06-3.00(m,1H),1.30-1.02(m,8H)。
Example 375- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -2-methylbenzenesulfonamide
Figure BDA0002280414000000581
2-chloro-4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine (800mg,2.5mmol), 3-amino-6-methylbenzenesulfonamide (512mg,2.75mmol), sodium phenolate (580mg,5.00mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (90mg,0.16mmol) and tris (dibenzylideneacetone) dipalladium (72mg,0.078mmol) were placed in a reaction flask, 15mL of 1, 4-dioxane were added, and reacted overnight at 100 ℃ under argon protection. Monitoring the reaction by LC-MS, concentrating the reaction solution after the reaction is finished, and purifying by column chromatography to obtain the title compound. ESI-MS M/z 470.2[ M + H ]]+。1HNMR(400MHz,DMSO-d6)δ:9.25(s,1H),8.13(d,1H),8.03(d,1H),7.86-7.89(m,2H),7.29(s,2H),7.20-7.22(m,1H),6.47-6.49(m,1H),6.26-6.27(m,1H),3.82-3.85(m,2H),3.65-3.68(m,1H),3.19-3.32(m,2H),2.68-2.76(m,1H),2.43(s,3H),1.63-1.67(m,4H),0.93-1.06(m,4H)。
Example 385- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -2-fluorobenzenesulfonamide
Figure BDA0002280414000000582
Step Synthesis of 12-fluoro-5-nitrobenzenesulfonamide
Figure BDA0002280414000000583
P-fluoronitrobenzene (1.01g,7.16mmol) was added to the reaction flask, chlorosulfonic acid (4mL) was added dropwise at 0 ℃ and the reaction mixture was stirred for 24 hours after the addition of chlorosulfonic acid (4 mL). Cooling to room temperature, adding ice-water mixture and ethyl acetate,extracting to obtain an organic phase, drying by anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude product. The crude product was dissolved in 50mL of ethyl acetate, and ammonia (25%, 50mL) was added at 0 ℃ to react for 4 h. Standing for layering, extracting a water layer with ethyl acetate, taking an organic layer, washing with saturated saline solution, drying with anhydrous sodium sulfate, and purifying by column chromatography to obtain the title compound. ESI-MSm/z:219[ M-H ]]-。
Step 25 Synthesis of amino-2-fluorobenzenesulfonamide
Figure BDA0002280414000000591
2-fluoro-5-nitrobenzenesulfonamide (230mg,1.05mmol), iron powder (293mg,5.25mmol) and ethanol (12mL) were added to a reaction flask, ammonium chloride (560mg,10.5mmol) was dissolved in 3mL of water and added to the above system, and the reaction was refluxed for 3 h. The mixture was filtered while hot, concentrated under reduced pressure to remove the solvent, diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound. ESI-MS M/z 191.0[ M + H ]]+。
Step Synthesis of 35- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -2-fluorobenzenesulfonamide
Figure BDA0002280414000000592
2-chloro-4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine (120mg,0.38mmol), 5-amino-2-fluorobenzenesulfonamide (71mg,0.38mmol), tris (dibenzylideneacetone) dipalladium (33mg,0.038mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (42mg,0.076mmol), and sodium phenolate (85mg,0.76mmol) were placed in a reaction flask, 5mL of anhydrous 1, 4-dioxane were added, and reacted at 100 ℃ overnight under argon protection. After the reaction is finished, the reaction solution is concentrated and purified by column chromatography to obtain the title compound. ESI-MS M/z 474.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ:9.33(s,1H),8.15-8.12(m,1H),8.05-8.04(m,1H),7.94-7.91(m,1H),7.87(s,1H),7.59(s,2H),7.30-7.26(m,1H),6.52-6.50(m,1H),6.24-6.23(m,1H),3.84-3.81(m,2H),3.69-3.64(m,1H),3.33-3.28(m,2H),2.75-2.68(m,1H),1.67-1.63(m,4H),1.06-0.89(m,4H)。
Example 393- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) benzenesulfonamide
Figure BDA0002280414000000593
The title compound was obtained by the same procedure as in example 37, except that 3-aminobenzenesulfonamide was used instead of 3-amino-6-methylbenzenesulfonamide. ESI-MS M/z 456.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ:9.37(s,1H),8.21-8.20(m,1H),8.08(dd,1H),7.87-7.84(m,2H),7.44-7.40(m,1H),7.33-7.30(m,3H),6.53(dd,1H),6.30(d,1H),3.85–3.81(m,2H),3.68–3.66(m,1H),3.35-3.29(m,2H),2.76-2.69(m,1H),1.68-1.64(m,4H),1.06-1.03(m,2H),0.98-0.94(m,2H)。
Example 404- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -2- (3-hydroxy-3-methylazetidin-1-yl) benzonitrile
Figure BDA0002280414000000601
The procedure is as in example 14 except that 3-methylazetidin-3-ol is used instead of azetidin-3-ol hydrochloride to give the title compound. ESI-MS M/z 487.0[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ:9.38(s,1H),8.10-8.09(m,1H),7.87(s,1H),7.32-7.30(d,J＝8.0Hz,1H),7.10-7.07(m,1H),7.03-7.02(m,1H),6.57-6.55(m,1H),6.31-6.30(m,1H),5.62(brs,1H),3.98-3.96(m,2H),3.85-3.81(m,4H),3.69-3.64(m,1H),3.34-3.27(m,2H),2.75-2.67(m,1H),1.66-1.58(m,4H),1.45(s,3H),1.06-1.01(m,2H),0.98-0.92(m,2H)。
Example 414- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -2- (4- (methylsulfonyl) piperazin-1-yl) benzonitrile
Figure BDA0002280414000000602
Step 14 Synthesis of bromo-2- (4- (methylsulfonyl) piperazin-1-yl) benzonitrile
Figure BDA0002280414000000603
The procedure was the same as in example 14, step 1, except that 1- (methylsulfonyl) piperazine was used instead of azetidine-3-ol hydrochloride, to give the title compound. ESI-MS M/z 344.0,346.0[ M + H ]]+。
Step 24 synthesis of- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -2- (4- (methylsulfonyl) piperazin-1-yl) benzonitrile
Figure BDA0002280414000000611
The title compound was prepared according to the procedure for the preparation of example 38, step 3, except that 4-bromo-2- (4- (methylsulfonyl) piperazin-1-yl) benzonitrile was used instead of 5-amino-2-fluorobenzenesulfonamide. ESI-MS M/z 564.2[ M + H ]]+。1HNMR(400MHz,DMSO-d6)δ:9.60(s,1H),8.13-8.14(d,1H),7.89(s,1H),7.56(s,2H),7.50(s,1H),6.60-6.62(m,1H),6.34-6.35(m,1H),3.81-3.84(m,2H),3.65-3.69(m,1H),3.19-3.34(m,10H),2.89(s,3H),2.68-2.73(m,1H),1.63-1.67(m,4H),0.93-1.06(m,4H)。
Example 421- (4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) piperidin-4-ol
Figure BDA0002280414000000612
Step Synthesis of 11- (4-Nitropyridin-2-yl) piperidin-4-ol
Figure BDA0002280414000000613
2-bromo-4-nitropyridine (200mg,0.99mmol), 4-hydroxypiperidine (149.48mg,1.48mmol) and cesium carbonate (642.02mg,1.97mmol) were placed in a reaction flask, 20mL of 1, 4-dioxane were added, and the reaction was allowed to proceed overnight at 100 ℃. After the reaction is finished, cooling to room temperature, filtering, concentrating the filtrate, and purifying by column chromatography to obtain the title compound. ESI-MS M/z 224.1[ M + H ]]+。
Step Synthesis of 21- (4-Aminopyridin-2-yl) piperidin-4-ol
Figure BDA0002280414000000621
1- (4-Nitropyridin-2-yl) piperidin-4-ol (210.0mg,0.94mmol) was dissolved in 20mL of methanol solution, and a palladium/carbon catalyst (10% Pd/C,200.00mg) was added thereto, followed by repeated replacement with hydrogen, reaction at room temperature for 3 hours, and reaction was monitored by TLC. The reaction was complete, filtered and the filtrate was concentrated to give the title compound. ESI-MS M/z 194.1[ M + H ]]+。
Synthesis of step 31- (4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) piperidin-4-ol
Figure BDA0002280414000000622
Preparation the title compound was prepared as in example 2, step 3, except that 1- (4-aminopyridin-2-yl) piperidin-4-ol was used instead of 2-morpholinopyridin-4-amine. ESI-MS M/z 477.3[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ9.27(s,1H),8.11(d,J＝5.3Hz,1H),7.87(s,1H),7.84(d,J＝5.4Hz,1H),7.19(s,1H),6.88(d,J＝4.2Hz,1H),6.55(d,J＝3.7Hz,1H),6.32(s,1H),4.68(s,1H),3.91(d,J＝12.3Hz,2H),3.82(d,J＝10.6Hz,2H),3.66(s,2H),3.00(t,J＝10.2Hz,2H),2.71(s,1H),1.75(s,2H),1.65(s,4H),1.34(d,J＝8.9Hz,2H),1.08–0.88(m,4H)。
Example 433- (4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) oxetan-3-ol
Figure BDA0002280414000000623
Step Synthesis of 13- (4-bromopyridin-2-yl) oxetan-3-ol
Figure BDA0002280414000000624
2, 4-dibromopyridine (3.00g,12.66mmol) was placed in a dry round-bottom flask under nitrogen and dissolved by addition of 20mL of anhydrous tetrahydrofuran solution. Cooling to-30 deg.C, slowly adding dropwise isopropyl magnesium chloride-lithium chloride (2.21g,15.2mmol), stirring at low temperature for 1 hr, slowly adding 3-oxetanone (1.1g,15.2mmol), reacting for 2 hr, and LC-MS monitoring reaction. Quenching the reaction with saturated ammonium chloride solution, adding ethyl acetate, extracting, combining organic phases, concentrating, and purifying by column chromatography to obtain the title compound. ESI-MSm/z 229.9,231.9[ M + H ]]+。
Step Synthesis of 23- (4-Aminopyridin-2-yl) oxetan-3-ol
Figure BDA0002280414000000631
3- (4-Bromopyridin-2-yl) oxetan-3-ol (1.10g,4.78mmol) was dissolved in 20mL of ammonia water, copper powder (206.6mg,3.25mmol) was added and the reaction was allowed to proceed in an open reaction flask at room temperature for 30min until it turned dark blue. Sealing, heating to 120 deg.C, reacting overnight, detecting by LC-MS, filtering, concentrating the filtrate, and directly adding into the next step. ESI-MS M/z 167.1[ M + H ]]+。
Step Synthesis of 33- (4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) oxetan-3-ol
Figure BDA0002280414000000632
The procedure is as in step 3 of example 2, except that 3- (4-aminopyridin-2-yl) oxetan-3-ol is used instead of2-morpholinopyridin-4-amine to afford the title compound. ESI-MS M/z 450.2[ M + H ]]+。1HNMR(400MHz,DMSO-d6)δ9.70(s,1H),8.15(d,1H),8.07(d,1H),7.86(s,1H),7.82(s,1H),7.50(d,1H),7.10(dd,1H),6.46(dd,1H),4.77(d,2H),4.61(d,2H),3.81(m,2H),3.66(m,1H),3.32–3.24(m,2H),2.70(m,1H),1.69–1.62(m,4H),1.03(m,2H),0.97–0.91(m,2H)。
Example 444- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -2- (2-hydroxypropan-2-yl) benzonitrile
Figure BDA0002280414000000641
Step 15 Synthesis of methyl amino-2-bromobenzoate
Figure BDA0002280414000000642
Methyl 2-bromo-5-nitrobenzoate (2.00g,7.72mmol) was dissolved in a mixed solvent of 20mL ethanol and 5mL water, and iron powder (1.73g,30.9mmol) and ammonium chloride (2.05g,38.6mmol) were added and reacted at 80 ℃ for 3 hours. After completion of the TLC detection reaction, filtration was carried out, concentration was carried out under reduced pressure to remove ethanol, water and ethyl acetate were added, extraction was carried out, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by filtration to obtain the title compound. LC-MS M/z 229.9,231.9[ M + H ]]+。
Step 25 Synthesis of methyl amino-2-cyanobenzoate
Figure BDA0002280414000000643
Methyl 5-amino-2-bromobenzoate (1.57g,6.86mmol) was dissolved in 20mL of N, N-dimethylformamide, cuprous cyanide (0.671g,7.54mmol) was added, nitrogen was substituted three times, and the reaction was stirred at 150 ℃ for 2 h. After the reaction is completed, cooling the reaction solution to room temperature, adding water and ethyl acetate, extracting, combining organic phases, washing the organic phases with water, drying the organic phases with anhydrous sodium sulfate, evaporating the solvent under reduced pressure, and carrying out column chromatography separation to obtain the title compound. LC-MS M/z 177.1[ M + H ]]+。
Step 35 Synthesis of methyl- ((tert-butoxycarbonyl) amino) -2-cyanobenzoate
Figure BDA0002280414000000644
Methyl 5-amino-2-cyanobenzoate (173mg,0.983mmol) was dissolved in 5mL of dichloromethane, 4-dimethylaminopyridine (12.0mg,0.0983mmol) was added, di-tert-butyl dicarbonate (429mg,1.97mmol) was added dropwise at 0 ℃ and the mixture was allowed to react at room temperature for 5 hours. After TLC detection reaction is completed, water and dichloromethane are added, extraction is carried out, organic phases are combined, drying is carried out through anhydrous sodium sulfate, solvent is removed through reduced pressure evaporation, and column chromatography separation is carried out to obtain the title compound. LC-MS M/z 277.1[ M + H ]]+。
Step 4 Synthesis of tert-butyl (4-cyano-3- (2-hydroxypropan-2-yl) phenyl) carbamate
Figure BDA0002280414000000651
A3.0 mol/L methylmagnesium bromide/tetrahydrofuran solution (1.23mL,3.69mmol) was added to a nitrogen-substituted three-necked flask, and a solution of methyl 5- ((tert-butoxycarbonyl) amino) -2-cyanobenzoate (340mg,1.23mmol) in dry tetrahydrofuran (5mL) was slowly added dropwise at 0 ℃ and allowed to stand at room temperature for 6 hours after completion of the dropwise addition. After completion of the reaction, the reaction mixture was quenched with 5mL of a saturated ammonium chloride solution, ethyl acetate was added, extraction was performed, the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and column chromatography was performed to obtain the title compound. LC-MS M/z 277.2[ M + H ]]+。
Step 54 Synthesis of amino-2- (2-hydroxypropan-2-yl) benzonitrile hydrochloride
Figure BDA0002280414000000652
Tert-butyl (4-cyano-3- (2-hydroxyprop-2-yl) phenyl) carbamate (220mg,0.797mmol) was dissolved in 5mL of dichloromethane, and trifluoroacetic acid (0.178mL,2.391mmol) was added to react at room temperature for 6 h. TLC detection reaction, after the reaction is completed, decompression is carried outThe solvent was evaporated to give the title compound. LC-MS M/z 177.1[ M-HCl + H ]]+。
Step Synthesis of 64- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -2- (2-hydroxypropan-2-yl) benzonitrile
Figure BDA0002280414000000653
Preparation the title compound was prepared as in example 2, step 3, except that 4-amino-2- (2-hydroxypropan-2-yl) benzonitrile hydrochloride was used in place of 2-morpholinopyridin-4-amine. LC-MS M/z 460.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ10.92-10.62(m,1H),10.02(s,1H),8.19(d,1H),8.10(s,1H),8.04(d,1H),7.90(s,1H),7.75(dd,1H),6.67(dd,1H),6.47(d,1H),3.84-3.81(m,2H),3.71-3.65(m,1H),3.59-3.44(m,4H),3.32-3.25(m,2H),2.76-2.68(m,1H),1.69-1.65(m,6H),1.07-1.02(m,2H),1.00-0.93(m,2H)。
Example 452- (4- ((4- ((1- (2-fluoroethyl) -3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) propan-2-ol
Figure BDA0002280414000000661
Step Synthesis of 12-chloro-4- ((1- (2-fluoroethyl) -3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine
Figure BDA0002280414000000662
60% sodium hydride (108mg,2.69mmol) was added to 3mL of anhydrous N, N-dimethylformamide at 0 ℃ and stirred for 5min, then a solution (5mL) of 2-chloro-4- ((3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine (500mg,1.79mmol) in anhydrous N, N-dimethylformamide was added, the mixture was allowed to stand at room temperature and stirred for 30min, and then 1-bromo-2-fluoroethane (0.146mL,1.97mmol) was added and reacted at room temperature for 3H. TLC detecting reaction, after the reaction is completed, adding 10mL saturated ammonium chloride solution to quench, adding ethyl acetate, extracting,the organic phases were combined, washed with water, dried over anhydrous sodium sulfate, evaporated under reduced pressure to remove the solvent and separated by column chromatography to give the title compound. LC-MS M/z 326.1[ M + H ]]+。
Step synthesis of 22- (4- ((4- ((1- (2-fluoroethyl) -3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) propan-2-ol
Figure BDA0002280414000000663
2-chloro-4- ((1- (2-fluoroethyl) -3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine (360mg,1.11mmol) and 2- (4-aminopyridin-2-yl) propan-2-ol (140mg,0.923mmol) were placed in a reaction flask, and 5mL of 1, 4-dioxane, tris (dibenzylideneacetone) dipalladium (42.3mg,0.0462mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (53.4mg,0.0923mmol) and sodium phenolate (214mg,1.85mmol) were added, and the mixture was replaced with nitrogen three times and reacted at 100 ℃ overnight. After the reaction was completed, suction filtration was carried out, the solvent was distilled off from the filtrate under reduced pressure, and the title compound was obtained by column separation. LC-MS M/z 442.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ8.32-8.21(m,1H),8.20-8.12(m,1H),7.88(s,1H),7.84-7.66(m,2H),7.29-7.14(m,1H),6.75-6.54(m,2H),6.49-6.37(m,1H),5.38-5.30(m,1H),4.88-4.81(m,1H),4.77-4.69(m,1H),4.44-4.38(m,1H),4.38-4.31(m,1H),3.87-3.81(m,1H),2.81-2.70(m,1H),1.72-1.64(m,2H),1.48-1.38(m,4H),1.29-1.21(m,6H)。
Example 46 cyclopropyl (4- ((2- ((2- (2-hydroxyprop-2-yl) pyridin-4-yl) amino) pyridin-4-yl) oxy) -3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-1-yl) methanone
Figure BDA0002280414000000671
Step Synthesis of 12-chloro-4- ((3- (tetrahydro-2H-pyran-4-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-4-yl) oxy) pyridine
Figure BDA0002280414000000672
60% sodium hydride (484mg,12.10mmol) was added to a solution of 2-chloro-4- ((3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine (3.08g,11.0mmol) in tetrahydrofuran (100mL) at 0 deg.C, the reaction was stirred for 15min, 2- (trimethylsilyl) ethoxy chloride (2.02g,12.10mmol) was added, warmed to room temperature and stirred overnight, filtered, concentrated, and isolated by column chromatography to give the title compound. LC-MS M/z 410.2[ M + H ]]+。
Step Synthesis of 22- (4- ((4- ((3- (tetrahydro-2H-pyran-4-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) propan-2-ol
Figure BDA0002280414000000673
Preparation the title compound was prepared as in example 3, step 4, except that 2-chloro-4- ((3- (tetrahydro-2H-pyran-4-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-4-yl) oxy) pyridine was used instead of 2-chloro-4- ((1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl) oxy) pyridine. LC-MS M/z 526.3[ M + H ]]+。
Step Synthesis of 32- (4- ((4- ((3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) propan-2-ol
Figure BDA0002280414000000681
2- (4- ((4- ((3- (tetrahydro-2H-pyran-4-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) propan-2-ol (450mg,0.9mmol), trifluoroacetic acid (6ml) and triethylsilane (1ml,6mmol) were added to a three-necked reaction flask and stirred at room temperature for 2H, completing the reaction. Concentrating under reduced pressure, adjusting pH to about 7 with saturated sodium bicarbonate solution, adding ethyl acetate, extracting, combining organic phases, concentrating under reduced pressure, and separating by column chromatography to obtain the title compound. LC-MS M/z 396.2[ M + H ]]+。
Step 4 Synthesis of cyclopropyl (4- ((2- ((2- (2-hydroxyprop-2-yl) pyridin-4-yl) amino) pyridin-4-yl) oxy) -3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-1-yl) methanone
Figure BDA0002280414000000682
A25 mL three-necked flask was sequentially charged with a dichloromethane solution (10mL) of 2- (4- ((4- ((3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) propan-2-ol (115mg,0.29mmol) and N, N-diisopropylethylamine (56.38mg,0.44mmol), and a dichloromethane solution (2mL) of cyclopropylpropionyl chloride (30.4mg,0.29mmol) was slowly added dropwise with stirring at room temperature, and after completion of the addition, the reaction was completed after stirring for 10 min. After quenching the reaction with water, dichloromethane was added, extraction was performed, washing with saturated brine, drying over anhydrous sodium sulfate, filtration, concentration under reduced pressure, and column chromatography purification was performed to give the title compound. LC-MS M/z 464.2[ M + H ]]+。1H NMR(400MHz,DMSO)δ10.16(s,1H),8.55(s,1H),8.32–8.22(m,2H),6.82–6.74(m,1H),6.59(s,1H),5.55(s,1H),3.92–3.83(m,2H),3.43–3.36(m,4H),3.16–3.05(m,1H),2.97–2.84(m,1H),1.83–1.65(m,4H),1.52–1.40(m,6H),1.23(M,2H),1.17–1.09(m,2H)。
Example 472- (4- ((4- ((1- (3, 3-difluorocyclobutyl) -3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) propan-2-ol
Figure BDA0002280414000000691
Step Synthesis of 13- (4- ((2-chloropyridin-4-yl) oxy) -3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-1-yl) cyclobutane-1-one
Figure BDA0002280414000000692
2-chloro-4- ((3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine (1.00g,3.57mmol) is dissolved in 20mL of N, N-dimethylformamide, and then 3-bromocyclobutane ketone (1.07g,7.15mmol) and potassium carbonate (988.15mg,7.15mmol) are sequentially added to react at room temperature overnight, and LC-MS (liquid chromatography-mass spectrometry) detects that the reaction is finished, and ethyl acetate is added to dilute and filter the mixture. FiltrateAfter concentration, the title compound was purified by column chromatography. ESI-MSm/z 348.1[ M + H ]]+。
Step Synthesis of 22-chloro-4- ((1- (3, 3-difluorocyclobutyl) -3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine
Figure BDA0002280414000000693
3- (4- ((2-chloropyridin-4-yl) oxy) -3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-1-yl) cyclobutane-1-one (200.00mg,0.58mmol) was dissolved in 20mL of dichloromethane, nitrogen protected, diethylaminosulfur trifluoride (1.5mL,10.0mmol) was added at-10 ℃ and the reaction was allowed to slowly rise to room temperature for 4H and continued to complete by LC-MS monitoring. And adding a saturated sodium bicarbonate solution into the reaction solution under an ice bath condition to quench the reaction, adding dichloromethane, extracting, combining organic phases, drying, concentrating under reduced pressure, and purifying by column chromatography to obtain the title compound. ESI-MS M/z 370.1[ M + H ]]+。
Step Synthesis of 32- (4- ((4- ((1- (3, 3-difluorocyclobutyl) -3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) propan-2-ol
Figure BDA0002280414000000701
Preparation the title compound was prepared as in example 45, step 2, except that 2-chloro-4- ((1- (3, 3-difluorocyclobutyl) -3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine was used instead of 2-chloro-4- ((1- (2-fluoroethyl) -3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine. ESI-MS M/z 486.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ9.50(s,1H),8.19(d,1H),8.14(d,1H),7.99(s,1H),7.70(s,1H),7.69(s,1H),6.58(dd,1H),6.38(d,1H),4.83(m,1H),3.83(dd,2H),3.40(d,1H),3.24–3.04(m,5H),2.77(m,1H),1.68(d,4H),1.39(s,6H)。
Example 482- (4- ((4- ((1-cyclopropyl-3- (1- (oxetan-3-yl) piperidin-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) propan-2-ol
Figure BDA0002280414000000702
Step 14 Synthesis of tert-butyl- (2- ((2-chloropyridin-4-yl) oxy) acetyl) piperidine-1-carboxylate
Figure BDA0002280414000000703
The procedure is as in example 1, steps 1-2 except that tert-butyl 4-acetylpiperidine-1-carboxylate is used in place of 1- (tetrahydro-2H-pyran-4-yl) ethanone to give the title compound. ESI-MS M/z 355.1[ M + H ]]+。
Step 22 Synthesis of- ((2-Chloropyridin-4-yl) oxy) -1- (piperidin-4-yl) ethan-1-one trifluoroacetate
Figure BDA0002280414000000704
Tert-butyl 4- (2- ((2-chloropyridin-4-yl) oxy) acetyl) piperidine-1-carboxylate (2g,5.6mmol) and trifluoroacetic acid (20mL) were added sequentially to a 50mL single-neck flask, stirred at room temperature for 2h and monitored by LC-MS. After the reaction, the mixture was concentrated under reduced pressure, and a saturated sodium bicarbonate solution and ethyl acetate were added to the mixture to extract the mixture, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound. ESI-MS M/z 255.1[ M + H ]]+。
Step Synthesis of 32- ((2-chloropyridin-4-yl) oxy) -1- (1- (oxetan-3-yl) piperidin-4-yl) ethan-1-one
Figure BDA0002280414000000711
2- ((2-Chloropyridin-4-yl) oxy) -1- (piperidin-4-yl) ethan-1-one (1.44g,5.6mmol), 3-oxetanone (1.22g,16.9mmol), sodium triacetoxyborohydride (3.60g,16.9mmol) and 25mL1, 2-dichloroethane were added to the reaction flask in this order, reacted overnight at room temperature, and monitored by LC-MS. And (5) finishing the reaction. Adding water to quench the reaction, adding dichloromethaneExtracting, washing with saturated salt water, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and purifying by column chromatography to obtain the title compound. ESI-MS M/z 311.8[ M + H ]]+。
Step synthesis of 42-chloro-4- ((1-cyclopropyl-3- (1- (oxetan-3-yl) piperidin-4-yl) -1H-pyrazol-4-yl) oxy) pyridine
Figure BDA0002280414000000712
The procedure is as in example 1, step 3-5, except that 2- ((2-chloropyridin-4-yl) oxy) -1- (1- (oxetan-3-yl) piperidin-4-yl) ethan-1-one is used instead of 2- ((2-chloropyridin-4-yl) oxy) -1- (tetrahydro-2H-pyran-4-yl) ethan-1-one, to afford the title compound. ESI-MS M/z 375.2[ M + H ]]+。
Synthesis of step 52- (4- ((4- ((1-cyclopropyl-3- (1- (oxetan-3-yl) piperidin-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) propan-2-ol
Figure BDA0002280414000000713
Preparation the title compound was prepared as in example 45, step 2, except that 2-chloro-4- ((1-cyclopropyl-3- (1- (oxetan-3-yl) piperidin-4-yl) -1H-pyrazol-4-yl) oxy) pyridine was used in place of 2-chloro-4- ((1- (2-fluoroethyl) -3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine. ESI-MS M/z 491.6[ M + H ]]+。1H NMR(400MHz,CDCl3)δ8.24(d,J＝6.0Hz,1H),8.16(d,J＝5.8Hz,1H),7.67(s,1H),7.55(t,J＝7.6Hz,1H),7.32(s,1H),6.63(s,1H),6.56(dd,J＝5.8,2.1Hz,1H),4.62(d,J＝6.5Hz,4H),3.58–3.43(m,2H),2.86–2.71(m,2H),2.61(d,J＝7.6Hz,1H),1.96–1.78(m,6H),1.56(s,6H),1.15–1.08(m,2H),1.04–0.95(m,2H)。
Example 492- (4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) piperidin-1-yl) ethan-1-ol
Figure BDA0002280414000000721
4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) -N- (piperidin-4-yl) pyridin-2-amine hydrochloride (158mg,0.413mmol), 2-bromoethanol (56.7mg,0.454mmol) were dissolved in 10mL of acetonitrile, and cesium carbonate (269mg,0.826mmol) was added, followed by reaction at 40 ℃ for 3H. And (3) detecting by TLC, after complete reaction, performing suction filtration to obtain a filtrate, performing reduced pressure distillation to remove the solvent, and performing column chromatography separation to obtain the title compound. LC-MS M/z 428.3[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ9.99-9.20(m,1H),7.84(d,1H),7.79(s,1H),6.70-6.64(m,1H),6.19(dd,1H),5.91(s,1H),5.44-4.91(m,1H),4.02-3.87(m,1H),3.86-3.79(m,2H),3.72-3.67(m,1H),3.66-3.60(m,1H),3.45-3.39(m,1H),3.30-3.18(m,2H),3.14-2.81(m,4H),2.73-2.64(m,1H),2.08-1.94(m,2H),1.73-1.46(m,6H),1.29-1.19(m,1H),1.06-0.97(m,2H),0.97-0.88(m,2H)。
Example 504- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) -N- (2- (4, 4-difluoropiperidin-1-yl) pyridin-4-yl) pyridin-2-amine
Figure BDA0002280414000000722
Synthesis of step 12- (4, 4-difluoropiperidin-1-yl) -4-nitropyridine
Figure BDA0002280414000000731
2-bromo-4-nitropyridine (1.00g,4.93mmol), 4-difluoropiperidine hydrochloride (1.16g,7.39mmol) and cesium carbonate (4.82g,14.78mmol) were dissolved in 20mL of 1, 4-dioxane solution, heated to 100 ℃ for reaction overnight and detected by LC-MS. After the reaction is finished, cooling to room temperature, filtering, concentrating the filtrate, and purifying by column chromatography to obtain the title compound. ESI-MS M/z 244.1[ M + H ]]+。
Step 22- (4, 4-Difluoropiperidin-1-yl) pyridin-4-amine Synthesis
Figure BDA0002280414000000732
2- (4, 4-Difluoropiperidin-1-yl) -4-nitropyridine (330.0mg,1.36mmol) was dissolved in 25mL of a mixed solution of ethanol/water (4:1), reduced iron powder (303.0mg,5.43mmol) and ammonium chloride (362.9mg,6.78mmol) were added, the mixture was warmed to 80 ℃ for reaction overnight, and LC-MS monitored completion of the reaction. Filtering with the assistance of diatomite, taking a filtrate, adding dichloromethane, extracting, combining organic phases, drying, concentrating, and purifying by column chromatography to obtain the title compound. ESI-MS M/z 214.1[ M + H ]]+。
Step 34 Synthesis of- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) -N- (2- (4, 4-difluoropiperidin-1-yl) pyridin-4-yl) pyridin-2-amine
Figure BDA0002280414000000733
Preparation the title compound was prepared as in example 2, step 3, except that 2- (4, 4-difluoropiperidin-1-yl) pyridin-4-amine was used instead of 2-morpholinopyridin-4-amine. ESI-MS M/z 497.3[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ9.31(s,1H),8.11(d,1H),7.89(d,1H),7.87(s,1H),7.30(d,1H),6.94(dd,1H),6.56(dd,1H),6.32(d,1H),3.86–3.82(m,1H),3.80(t,1H),3.66(m,1H),3.62–3.58(m,3H),2.75–2.66(m,1H),2.03–1.92(m,4H),1.72–1.56(m,4H),1.23(s,3H),1.03(m,2H),0.99–0.88(m,2H)。
Example 512- (5- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -2- (trifluoromethyl) phenyl) propan-2-ol
Figure BDA0002280414000000741
Step 15 Synthesis of methyl amino-2-bromobenzoate
Figure BDA0002280414000000742
Methyl 2-bromo-5-nitrobenzoate (5.0g,19.31mmol) was dissolved inTo a mixed solution of ethanol (40mL) and water (10mL) were added reduced iron powder (4.31g,77.24mmol) and ammonium chloride (5.12g,96.55mmol), and the mixture was reacted at 80 ℃ for 3 hours and checked by TLC. The reaction was completed, suction filtered, concentrated under reduced pressure to remove ethanol, added with water and ethyl acetate, extracted, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound. ESI-MS M/z 229.1,231.1[ M + H ]]+。
Step 22 Synthesis of methyl bromo-5- ((tert-butoxycarbonyl) amino) benzoate
Figure BDA0002280414000000743
Methyl 5-amino-2-bromobenzoate (4.46g,19.31mmol), di-tert-butyl dicarbonate (10.1g,42.5mmol), sodium carbonate (6g,58mmol) and methanol (30mL) were added successively to a reaction flask and reacted at room temperature for 24 h. Vacuum concentrating to remove methanol, adding water and ethyl acetate, extracting, concentrating the organic phase, and separating by column chromatography to obtain the title compound. ESI-MS M/z 230.2,232.2[ M-Boc + H [ ]]+。
Step 3 Synthesis of tert-butyl (4-bromo-3- (2-hydroxypropan-2-yl) phenyl) carbamate
Figure BDA0002280414000000744
Under the protection of nitrogen, methyl magnesium bromide (3M,12mL,36mmol) is added into a reaction bottle, stirred at 0 ℃, a solution of methyl 2-bromo-5- ((tert-butoxycarbonyl) amino) benzoate (3.97g,12mmol) in anhydrous tetrahydrofuran (30mL) is added dropwise, and after the dropwise addition, the mixture is moved to room temperature for reaction for 6 hours until the TLC detection reaction is finished, and saturated ammonium chloride solution is added at 0 ℃ for quenching. Adding ethyl acetate, extracting, combining organic phases, drying by anhydrous sodium sulfate, concentrating, and separating by column chromatography to obtain the title compound. ESI-MS M/z 330.1,332.1[ M + H ]]+。
Step 4 Synthesis of tert-butyl (3- (2-hydroxypropan-2-yl) -4- (trifluoromethyl) phenyl) carbamate
Figure BDA0002280414000000751
Adding (4-bromo-3- (2-hydroxypropane-2-yl) phenyl) carbamic acid tert-butyl ester (450mg,1.36mmol) into 20mL of N, N-dimethylformamide solution, performing nitrogen gas extraction three times, adding 1, 10-phenanthroline copper trifluoride (639mg,2.04mmol), sealing, reacting overnight at 50 ℃, and detecting by LC-MS. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with ethyl acetate, subjected to celite-assisted filtration, and the filtrate was washed with 1M aqueous hydrochloric acid, then washed with saturated sodium bicarbonate and saturated aqueous sodium chloride, respectively, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give the title compound. ESI-MS M/z 318.2[ M-H ]]-。
Step 52 Synthesis of (5-amino-2- (trifluoromethyl) phenyl) propan-2-ol
Figure BDA0002280414000000752
4mL of dioxane, 2mL of water and 2mL of hydrochloric acid were added to a reaction flask, and tert-butyl (3- (2-hydroxypropan-2-yl) -4- (trifluoromethyl) phenyl) carbamate (283mg,0.9mmol) was added to the system and allowed to react overnight at room temperature with TLC detection of completion. Neutralizing the reaction solution with sodium hydroxide solution, adding ethyl acetate, extracting, taking an organic phase, drying with anhydrous sodium sulfate, and separating by column chromatography to obtain the title compound. ESI-MS M/z 220.0[ M + H ]]+。
Step synthesis of 62- (5- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -2- (trifluoromethyl) phenyl) propan-2-ol
Figure BDA0002280414000000753
Preparation the title compound was prepared as in example 2, step 3, except that 2- (5-amino-2- (trifluoromethyl) phenyl) propan-2-ol was used instead of 2-morpholinopyridin-4-amine. ESI-MS M/z 503.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ9.40(s,1H),8.10(d,1H),7.98(d,1H),7.87(s,1H),7.78(s,1H),7.59(d,1H),6.56-6.51(m,1H),6.33(d,1H),5.06(s,1H),3.83(d,2H),3.69-3.65(m,1H),2.74-2.69(m,1H),1.68-1.60(m,4H),1.52(s,6H),1.10-0.90(m,4H)。
Example 521- (4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) azetidine-3-carbonitrile
Figure BDA0002280414000000761
Step 11- (4-nitropyridin-2-yl) azetidine-3-carbonitrile Synthesis
Figure BDA0002280414000000762
2-bromo-4-nitropyridine (1.00g,4.93mmol), 3-acetonitrile cyclobutylamine hydrochloride (759.30mg,6.40mmol) and cesium carbonate (4.82g,14.78mmol) were placed in a reaction flask and 50mL of 1, 4-dioxane was added and reacted at 100 ℃ overnight. And (5) detecting by LC-MS, cooling to room temperature after the reaction is finished, filtering to obtain filtrate, concentrating under reduced pressure, and purifying by column chromatography to obtain the title compound. ESI-MS M/z 205.1[ M + H ]]+。
Step Synthesis of 21- (4-aminopyridin-2-yl) azetidine-3-carbonitrile
Figure BDA0002280414000000763
1- (4-Nitropyridin-2-yl) azetidine-3-carbonitrile (510.00mg,2.50mmol) was dissolved in 20mL methanol, palladium on carbon (200.0mg, 10%) was added, and after hydrogen substitution, the reaction was carried out at room temperature for 3h, monitored by TLC and was complete. The filtrate was filtered and concentrated under reduced pressure to give the title compound. ESI-MS M/z 175.1[ M + H ]]+。
Step synthesis of 31- (4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) azetidine-3-carbonitrile
Figure BDA0002280414000000771
The preparation method is the same as that of the compound in step 3 of example 2Except that 1- (4-aminopyridin-2-yl) azetidine-3-carbonitrile was used instead of 2-morpholinopyridin-4-amine, the title compound was prepared. ESI-MSm/z 458.3[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ9.34(s,1H),8.10(d,1H),7.86(s,1H),7.84(d,1H),6.96(dd,1H),6.81(s,1H),6.57(dd,1H),6.33(d,1H),4.16(t,2H),4.01(dd,2H),3.87–3.78(m,3H),3.66(m,1H),3.35–3.26(m,2H),2.71(m,1H),1.70–1.59(m,4H),1.03(m,2H),1.00–0.91(m,2H)。
Example 532- (6- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) isoquinolin-3-yl) propan-2-ol
Figure BDA0002280414000000772
Step Synthesis of 12- (6-Bromoisoquinolin-3-yl) propan-2-ol
Figure BDA0002280414000000773
3.0mol/L methyl magnesium bromide/tetrahydrofuran solution (3.57mL,10.7mmol) was added into a nitrogen-substituted three-necked flask, and a solution (10mL) of 6-bromoisoquinoline-3-carboxylic acid ethyl ester (1.00g,3.57mmol) in anhydrous tetrahydrofuran was slowly added dropwise at 0 ℃ and then the mixture was allowed to react at room temperature for 6 hours. After the reaction was completed, the reaction was quenched with a saturated ammonium chloride solution, ethyl acetate was added, extraction was performed, organic phases were combined, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and column chromatography purification was performed to obtain the title compound. LC-MS M/z 266.0,268.0[ M + H ]]+。
Step Synthesis of 22- (6- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) isoquinolin-3-yl) propan-2-ol
Figure BDA0002280414000000774
4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-amine (200mg,0.67mmol) and 2- (6-bromoisoquinolin-3-yl) propan-2-ol (194mg,0.73mmol) were placed in a bathA reaction flask was charged with 5mL of 1, 4-dioxane, followed by tris (dibenzylideneacetone) dipalladium (61.1mg,0.0667mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (116mg,0.20mmol) and cesium carbonate (435mg,1.33mmol), and the mixture was reacted overnight at 100 ℃ with nitrogen substitution three times. After the reaction is completed, filtering to obtain filtrate, evaporating under reduced pressure to remove the solvent, and separating by column chromatography to obtain the title compound. LC-MS M/z 486.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ9.52(s,1H),8.99(s,1H),8.50(s,1H),8.19(d,1H),7.92-7.90(m,2H),7.78(s,1H),7.61(dd,1H),6.60(dd,1H),6.42(d,1H),5.19(brs,1H),3.86-3.82(m,2H),3.69-3.66(m,1H),3.40-3.30(m,2H),2.79-2.71(m,1H),1.70-1.65(m,4H),1.50(s,6H),1.08-1.02(m,2H),1.01-0.93(m,2H)。
Example 544- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) -N- (2- (3-fluoroazetidin-3-yl) pyridin-4-yl) pyridin-2-amine
Figure BDA0002280414000000781
Step 13- (4-bromopyridin-2-yl) -3-hydroxyazetidine-1-carboxylic acid tert-butyl ester synthesis
Figure BDA0002280414000000782
2, 4-dibromopyridine (3.00g,12.7mmol) was charged into a three-necked flask, nitrogen gas was substituted three times, 30mL of anhydrous tetrahydrofuran was added, and a 2.5M n-butyllithium n-hexane solution (5.56mL,13.9mmol) was slowly added dropwise at-78 ℃ and stirred for 1 hour after completion of the addition. Then, 15mL of anhydrous tetrahydrofuran solution of 1-tert-butoxycarbonyl-3-azetidinone (2.38g,13.9mmol) was slowly added dropwise to the reaction system, and the reaction was continued at-78 ℃ for 1 hour after the addition. After the reaction was completed, 10mL of a saturated ammonium chloride solution was added to quench, ethyl acetate was added, extraction was performed, organic phases were combined, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and column chromatography was performed to obtain the title compound. LC-MS M/z 329.0,331.0[ M + H ]]+。
Step 23- (4-Bromopyridin-2-yl) -3-fluoroazetidine-1-carboxylic acid tert-butyl ester preparation
Figure BDA0002280414000000791
3- (4-Bromopyridin-2-yl) -3-hydroxyazetidine-1-carboxylic acid tert-butyl ester (2.10g,6.40mmol) was dissolved in 20mL of dichloromethane, diethylamido sulfur trifluoride (1.46mL,12.8mmol) was added slowly at 0 ℃ and after dropping, the mixture was allowed to warm to room temperature for 0.5 h. After completion of the reaction, 10mL of a saturated sodium bicarbonate solution and ethyl acetate were added, extraction was performed, the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and column chromatography was performed to obtain the title compound. LC-MS M/z 331.0,333.0[ M + H ]]+。
Step 33 preparation of tert-butyl 4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) -3-fluoroazetidine-1-carboxylate
Figure BDA0002280414000000792
4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-amine (200mg,0.667mmol) and 3- (4-bromopyridin-2-yl) -3-fluoroazetidin-1-carboxylic acid tert-butyl ester (242mg,0.733mmol) were dissolved in 5mL of 1, 4-dioxane, and tris (dibenzylideneacetone) dipalladium (61.1mg,0.0667mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (116mg,0.200mmol) and cesium carbonate (435mg,1.33mmol) were added, nitrogen replaced three times, and reacted at 100 ℃ overnight. After the reaction is completed, filtering to obtain filtrate, evaporating under reduced pressure to remove the solvent, and separating by column chromatography to obtain the title compound. LC-MS M/z 551.3[ M + H ]]+。
Step 44 preparation of- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) -N- (2- (3-fluoroazetidin-3-yl) pyridin-4-yl) pyridin-2-amine
Figure BDA0002280414000000793
3- (4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridineTert-butyl (210mg,0.382mmol) of (2-yl) -3-fluoroazetidine-1-carboxylate was dissolved in a solution of hydrogen chloride in 1, 4-dioxane (10mL,4.0mol/L) and reacted at room temperature overnight. After the reaction is completed, sodium bicarbonate solution is used for neutralizing the reaction solution, ethyl acetate is added for extraction, the solvent is removed by evaporation under reduced pressure, and the title compound is obtained by column chromatography separation. LC-MS M/z:451.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ9.77(s,1H),8.22(d,1H),8.10(d,1H),7.83(s,2H),7.44(d,1H),7.09(d,1H),6.49(dd,1H),3.97(dd,2H),3.84-3.81(m,2H),3.72-3.64(m,3H),3.55-3.40(m,1H),2.78-2.68(m,1H),2.33(s,1H),2.03-1.98(m,1H),1.72-1.64(m,4H),1.11-1.01(m,2H),0.99-0.92(m,2H)。
Example 552- (-4- ((4- ((1-cyclopropyl-3- (piperidin-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) propan-2-ol hydrochloride
Figure BDA0002280414000000801
Step Synthesis of tert-butyl 14- (4- ((2-chloropyridin-4-yl) oxy) -1-cyclopropyl-1H-pyrazol-3-yl) piperidine-1-carboxylate
Figure BDA0002280414000000802
The preparation method is the same as the preparation method of the compound in the step 1-5 of the example 1, except that 4-acetylpiperidine-1-carboxylic acid tert-butyl ester is used for replacing 1- (tetrahydro-2H-pyran-4-yl) ethanone, so as to prepare the title compound. ESI-MSm/z 363.88[ M-tBu + H]+。
Step Synthesis of tert-butyl 24- (1-cyclopropyl-4- ((2- ((2- (2-hydroxypropan-2-yl) pyridin-4-yl) amino) pyridin-4-yl) oxy) -1H-pyrazol-3-yl) piperidine-1-carboxylate
Figure BDA0002280414000000803
Preparation method the same as that of the compound of step 4 in example 3, except that tert-butyl 2- (4- ((2-chloropyridin-4-yl) oxy) -1-cyclopropyl-1H-pyrazol-3-yl) piperidine-1-carboxylate was used instead2-chloro-4- ((1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl) oxy) pyridine to give the title compound. ESI-MS M/z 535.66[ M + H ]]+。
Step Synthesis of 32- (-4- ((4- ((1-cyclopropyl-3- (piperidin-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) propan-2-ol hydrochloride
Figure BDA0002280414000000811
Tert-butyl 4- (1-cyclopropyl-4- ((2- ((2- (2-hydroxypropan-2-yl) pyridin-4-yl) amino) pyridin-4-yl) oxy) -1H-pyrazol-3-yl) piperidine-1-carboxylate (409mg,764.97umol) was dissolved in 6mL of hydrochloric acid/dioxane solution, and the reaction was stirred at 30 ℃. After completion of the TLC detection reaction, the reaction mixture was directly concentrated under reduced pressure to obtain the title compound. ESI-MS M/z 435.2[ M-HCl + H ]]+。1H NMR(400MHz,DMSO-d6)δ:9.11–9.09(d,1H),8.93–8.90(d,1H),8.35–8.32(m,1H),8.30–8.28(d,1H),7.92(s,1H),6.82–6.80(m,2H),6.69–6.65(m,4H),3.70–3.58(m,2H),3.46–3.41(m,1H),3.23–3.20(m,2H),2.93–2.88(m,2H),2.85–2.80(m,1H),1.89–1.86(m,2H),1.56(s,6H),1.07–1.05(m,2H),0.96–0.94(m,2H)。
Example 561- (4- (4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) -4-methylpiperidin-4-ol
Figure BDA0002280414000000812
Step 14 Synthesis of methyl-1- (4-nitropyridin-2-yl) piperidin-4-ol
Figure BDA0002280414000000813
2-bromo-4-nitropyridine (1.00g,4.93mmol), 4-methylpiperidin-4-ol (709.23mg,6.16mmol) and cesium carbonate (2.41g,7.39mmol) were dissolved in 30mL of 1, 4-dioxane solution and reacted at 100 ℃ overnight. Detecting by LC-MS, cooling to room temperature, filtering, concentrating the filtrate, and performing column chromatographyPurification afforded the title compound. ESI-MS M/z 238.1[ M + H ]]+。
Step Synthesis of 21- (4-aminopyridin-2-yl) -4-methylpiperidin-4-ol
Figure BDA0002280414000000821
4-methyl-1- (4-nitropyridin-2-yl) piperidin-4-ol (900.0mg,3.79mmol) was dissolved in 20mL of methanol, palladium/carbon (10%, 300.0mg) was added, and after hydrogen substitution was repeated, the reaction was carried out at room temperature for 3 hours, and the reaction was monitored by TLC to complete the reaction. The reaction was filtered and the filtrate was concentrated to give the title compound. ESI-MS M/z 208.1[ M + H ]]+。
Synthesis of step 31- (4- (4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) -4-methylpiperidin-4-ol
Figure BDA0002280414000000822
Preparation the title compound was prepared similar to the preparation of the compound of example 37, except that 1- (4-aminopyridin-2-yl) -4-methylpiperidin-4-ol was used instead of 3-amino-6-methylbenzenesulfonamide. ESI-MS M/z 491.3[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ9.22(s,1H),8.17(s,1H),8.10(d,1H),7.86(s,1H),7.84(d,1H),7.16(s,1H),6.88(dd,1H),6.54(dd,1H),6.32(d,1H),3.82(m,2H),3.66(m,3H),3.33-3.21(m,4H),2.70(m,1H),1.68-1.61(m,4H),1.46(m,4H),1.13(s,3H),1.03(m,2H),0.98-0.91(m,2H).
Example 571-cyclopropyl-1- (4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) ethan-1-ol
Figure BDA0002280414000000823
Step Synthesis of 11- (4-bromopyridin-2-yl) ethan-1-one
Figure BDA0002280414000000831
2, 4-dibromopyridine (1.20g,5.06mmol) was charged into a three-necked flask, and the flask was purged with nitrogen three times and dissolved in 10mL of toluene. A2.5M n-hexane solution of n-butyllithium (2.23mL,5.57mmol) was slowly added dropwise at-78 deg.C, and after the addition was complete, stirring was carried out for 1 h. N-methoxy-N-methylacetamide (1.56g,15.2mmol) was slowly added dropwise, and the reaction was continued at-78 ℃ for 1h after the addition. After the reaction was completed, 10mL of a saturated ammonium chloride solution was added to quench, ethyl acetate was added, extraction was performed, organic phases were combined, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and column chromatography was performed to obtain the title compound. LC-MS M/z 199.9,201.9[ M + H ]]+。
Step Synthesis of 21- (4-bromopyridin-2-yl) -1-cyclopropylethan-1-ol
Figure BDA0002280414000000832
1.0mol/L cyclopropyl magnesium bromide/tetrahydrofuran solution (4.07mL,4.07mmol) was added to a nitrogen-substituted three-necked flask, and a solution of 1- (4-bromopyridin-2-yl) ethan-1-one (270mg,1.36mmol) in anhydrous tetrahydrofuran (10mL) was slowly added dropwise at-78 deg.C, after dropping, the mixture was allowed to cool to room temperature for reaction for 6 hours. After the reaction is completed, adding 10mL of saturated ammonium chloride solution for quenching, adding ethyl acetate, extracting, combining organic phases, drying through anhydrous sodium sulfate, evaporating under reduced pressure to remove the solvent, and separating by column chromatography to obtain the title compound. LC-MS M/z 242.0,244.0[ M + H ]]+。
Step synthesis of 31-cyclopropyl-1- (4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) ethan-1-ol
Figure BDA0002280414000000833
The title compound was prepared similar to the preparation of the compound in step 4 of example 53, except that 1- (4-bromopyridin-2-yl) -1-cyclopropylethan-1-ol was used instead of 2- (6-bromoisoquinolin-3-yl) propan-2-ol. LC-MS M/z 462.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ9.49(s,1H),8.22(d,1H),8.14(d,1H),7.87(s,1H),7.73(dd,1H),7.64(d,1H),6.58(dd,1H),6.37(d,1H),4.84(s,1H),3.85-3.81(m,2H),3.69-3.66(m,1H),3.32-3.28(m,2H),2.76-2.68(m,1H),1.68-1.63(m,4H),1.46(s,3H),1.28-1.21(m,1H),1.07-1.02(m,2H),1.00-0.93(m,2H),0.46-0.40(m,1H),0.35-0.27(m,2H),0.13-0.07(m,1H)。
Example 584- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) -N- (3-morpholin-4- (trifluoromethyl) phenyl) pyridin-2-amine
Figure BDA0002280414000000841
Step 14 Synthesis of- (5-nitro-2- (trifluoromethyl) phenyl) morpholine
Figure BDA0002280414000000842
2-fluoro-4-nitro-1- (trifluoromethyl) benzene (700mg,3.35mmol) and morpholine (2.92g,33.48mmol) were placed in a reaction flask, 10mL of dimethyl sulfoxide was added, the reaction was allowed to proceed overnight at 100 ℃ and checked by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, water and ethyl acetate were added, extraction was performed, the organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give the title compound. ESI-MS M/z 277.6[ M + H ]]+。
Step 23 Synthesis of morpholine-4- (trifluoromethyl) aniline
Figure BDA0002280414000000843
4- (5-Nitro-2- (trifluoromethyl) phenyl) morpholine (977mg,3.54mmol) was dissolved in 20mL of methanol, and 10% palladium on carbon catalyst (80mg) was added thereto, followed by reaction under hydrogen protection at room temperature for 3 hours. TLC detection, after the reaction was complete, celite assisted filtration, and the filtrate was concentrated under reduced pressure to give the title compound. ESI-MS M/z 247.1[ M + H ]]+。
Step 34 Synthesis of- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) -N- (3-morpholin-4- (trifluoromethyl) phenyl) pyridin-2-amine
Figure BDA0002280414000000844
The title compound was prepared by the same procedure as the preparation of the compound in step 3 of example 2, except that 3-morpholin-4- (trifluoromethyl) aniline was used instead of 2-morpholinopyridin-4-amine. ESI-MS M/z 530.3[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ:9.29(s,1H),8.07-8.05(m,2H),7.89-7.88(d,1H),7.87(s,1H),7.50-7.48(d,1H),6.52-6.50(m,1H),6.25-6.24(m,1H),3.84-3.82(m,2H),3.69-3.65(m,5H),3.37-3.33(m,1H),3.31-3.27(m,1H),2.80-2.78(m,4H),2.74-2.68(m,1H),1.68-1.64(m,4H),1.05-1.03(m,2H),0.96-0.95(m,2H)。
Example 592- (5- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -2- (methylsulfonyl) phenyl) propan-2-ol
Figure BDA0002280414000000851
Step 1 Synthesis of tert-butyl (3- (2-hydroxyprop-2-yl) -4- (methylsulfonyl) phenyl) carbamate
Figure BDA0002280414000000852
Tert-butyl (4-bromo-3- (2-hydroxypropan-2-yl) phenyl) carbamate (200mg,605.65umol), methanesulfonic acid (74.19mg,726.78umol), L-proline (13.95mg,121.13umol), sodium hydroxide (4.84mg,121.13umol) and cuprous iodide (11.53mg,60.57umol) were placed in a reaction flask, 5mL of dimethyl sulfoxide was added, argon gas was added, and the reaction was stirred at 95 ℃ for 48 hours. After the reaction is completed, cooling the reaction liquid to room temperature, adding water and ethyl acetate, extracting, collecting an organic phase, drying by anhydrous sodium sulfate, concentrating under reduced pressure, and purifying by column chromatography to obtain the title compound. ESI-MS M/z 328.1[ M-H ]]-。
Step Synthesis of 22- (5-amino-2- (methylsulfonyl) phenyl) propan-2-ol hydrochloride
Figure BDA0002280414000000853
Tert-butyl (3- (2-hydroxyprop-2-yl) -4- (methylsulfonyl) phenyl) carbamate (121mg,367.32umol) was dissolved in 10mL of hydrogen chloride/ethanol and reacted at 25 ℃. After the reaction is completed, the reaction solution is directly dried by spinning for the next reaction.
Step Synthesis of 32- (5- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -2- (methylsulfonyl) phenyl) propan-2-ol
Figure BDA0002280414000000861
The title compound was prepared by the same procedure as the preparation of the compound of step 3 of example 2, except that 2- (5-amino-2- (methylsulfonyl) phenyl) propan-2-ol hydrochloride was used instead of 2-morpholinopyridin-4-amine. ESI-MSm/z 513.3[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ:9.56(s,1H),8.12(m,1H),7.95-7.89(m,2H),7.73(m,1H),6.59(m,1H),6.32(m,1H),5.39(m,1H),3.83-3.81(m,2H),3.67(m,1H),3.38-3.35(m,7H),2.71(m,1H),1.62(m,8H),1.03-0.85(m,4H)。
Example 601- (4- ((4- ((1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) azetidine-3-carbonitrile
Figure BDA0002280414000000862
Preparation the title compound was prepared as in example 3, step 4 compound, except that 1- (4-aminopyridin-2-yl) azetidine-3-carbonitrile was used instead of 2- (4-aminopyridin-2-yl) propan-2-ol. ESI-MS M/z 450.3[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ9.31(s,1H),8.12(d,1H),8.10(s,1H),7.83(d,1H),7.71-7.66(m,2H),7.36(m,2H),7.27(m,1H),6.91(dd,1H),6.78(d,1H),6.65(dd,1H),6.36(d,1H),4.14(t,2H),3.99(m,2H),3.82(m,2H),1.18-1.12(m,2H),1.06-1.00(m,2H)。
Example 614- (4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) cyclohex-1-ol
Figure BDA0002280414000000863
Step 14 Synthesis of bromo-2- (1, 4-dioxaspiro [4.5] dec-7-en-8-yl) pyridine
Figure BDA0002280414000000871
2, 4-dibromopyridine (4.00g,16.9mmol) and 1, 4-dioxa-spiro [4, 5]]Dec-7-ene-8-boronic acid pinacol ester (4.94g,18.6mmol) was dissolved in a mixed solvent of 40mL of 1, 4-dioxane and 10mL of water, and tetrakis (triphenylphosphine) palladium (0.975g,0.840mmol) and potassium carbonate (4.66g,33.8mmol) were added, and the mixture was replaced with nitrogen three times and reacted at 90 ℃ for 3 hours. After the reaction is completed, the reaction product is filtered, the filtrate is decompressed, the solvent is removed by evaporation, and the title compound is obtained by column chromatography separation. LC-MS M/z 296.0,298.0[ M + H ]]+。
Step Synthesis of 24- (4-bromopyridin-2-yl) cyclohex-3-en-1-one
Figure BDA0002280414000000872
Reacting 4-bromo-2- (1, 4-dioxaspiro [4.5]]Dec-7-en-8-yl) pyridine (1.95g,6.61mmol) was dissolved in 5mL trifluoroacetic acid and reacted at room temperature for 2 h. After completion of the reaction, the solvent was distilled off under reduced pressure to obtain the title compound. LC-MS M/z 251.9,253.9[ M + H ]]+。
Step Synthesis of 34- (4-bromopyridin-2-yl) cyclohex-3-en-1-ol
Figure BDA0002280414000000873
4- (4-Bromopyridin-2-yl) cyclohex-3-en-1-one (1.66g,6.61mmol) was dissolved in 15mL of methanol, sodium borohydride (0.502g,13.2mmol) was added at 0 deg.C, and the mixture was allowed to warm to room temperature for 2 h. After the reaction is completed, adding saturated sodium bicarbonate solution and ethyl acetate, extracting, combining organic phases,drying over anhydrous sodium sulfate, removing the solvent by evaporation under reduced pressure, and separating by column chromatography to give the title compound. LC-MS M/z 254.0,256.0[ M + H ]]+。
Step Synthesis of 44- (4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) cyclohex-2-en-1-ol
Figure BDA0002280414000000874
The title compound was prepared similar to the preparation of the compound of step 4 of example 53, except that 4- (4-bromopyridin-2-yl) cyclohex-3-en-1-ol was used instead of 2- (6-bromoisoquinolin-3-yl) propan-2-ol. LC-MSm/z 474.2[ M + H ]]+。
Step 54- (4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) cyclohexan-1-ol Synthesis
Figure BDA0002280414000000881
4- (4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) cyclohex-2-en-1-ol (110mg,0.232mmol) was dissolved in 5mL of methanol, and a palladium/carbon catalyst (11.0mg, 10%) was added, and hydrogen was substituted three times, and the reaction was allowed to proceed at room temperature overnight. After the reaction is completed, the reaction product is filtered, the filtrate is decompressed, the solvent is removed by evaporation, and the title compound is obtained by column chromatography separation. LC-MS M/z 476.3[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ9.57-9.56(m,1H),8.08(d,1H),8.04-8.02(m,1H),7.82(s,1H),7.49-7.46(m,2H),6.76-6.74(m,1H),6.46(dd,1H),4.54-4.25(m,1H),3.95-3.87(m,1H),3.86-3.75(m,2H),3.69-3.64(m,1H),3.47-3.41(m,1H),2.77-2.68(m,1H),2.46-2.36(m,1H),1.94-1.91(m,1H),1.83-1.72(m,4H),1.68-1.64(m,3H),1.58-1.49(m,3H),1.42-1.39(m,1H),1.33-1.24(m,1H),1.06-1.01(m,2H),0.97-0.92(m,2H)。
Example 622- (5- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -1-methyl-1H-indazol-3-yl) propan-2-ol
Figure BDA0002280414000000882
Step 15-bromo-1-methyl-1H-indazole-3-carboxylic acid methyl ester synthesis
Figure BDA0002280414000000883
Methyl 5-bromo-1H-indazole-3-carboxylate (2.00g,7.87mmol) was dissolved in 20mL of acetonitrile, potassium carbonate (2.17g,15.7mmol) was added, methyl iodide (0.490mL,7.87mmol) was slowly added dropwise at 0 ℃, and after completion of the dropwise addition, the mixture was allowed to stand at room temperature for 2 hours. After the reaction is completed, the reaction product is filtered by suction, the solvent is removed by evaporation under reduced pressure, and the title compound is obtained by column chromatography separation. LC-MS M/z 268.9,270.9[ M + H ]]+。
Step 22- (5-bromo-1-methyl-1H-indazol-3-yl) propan-2-ol Synthesis
Figure BDA0002280414000000891
A3.0 mol/L methylmagnesium bromide tetrahydrofuran solution (5.86mL,17.6mmol) was added to a nitrogen-substituted three-necked flask, and a solution of methyl 5-bromo-1-methyl-1H-indazole-3-carboxylate (1.57g,5.86mmol) in anhydrous tetrahydrofuran (15mL) was slowly added dropwise at 0 deg.C, after dropping, the mixture was allowed to cool to room temperature and reacted for 6 hours. After the reaction was completed, 10mL of a saturated ammonium chloride solution was added to quench, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the title compound was obtained by column chromatography. LC-MS M/z 269.0,271.0[ M + H ]]+。
Step synthesis of 32- (5- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -1-methyl-1H-indazol-3-yl) propan-2-ol
Figure BDA0002280414000000892
Preparation the same as that of the compound of step 4 in example 53, except that 2- (5-bromo-1-methyl-1H-indazol-3-yl) propan-2-ol was usedThe title compound was prepared instead of 2- (6-bromoisoquinolin-3-yl) propan-2-ol. LC-MS M/z 489.3[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ8.92(s,1H),8.11(s,1H),7.98(d,1H),7.85(s,1H),7.61(dd,1H),7.43(d,1H),6.37(dd,1H),6.21(d,1H),5.15(s,1H),3.93(s,3H),3.83(d,2H),3.66(ddd,1H),3.33-3.27(m,2H),2.76-2.68(m,1H),1.67-1.65(m,4H),1.57(s,6H),1.07-0.99(m,2H),0.97-0.90(m,2H)。
Example 632- (4- ((4- ((1-cyclopropyl-3- (4-morpholinophenyl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) propan-2-ol
Figure BDA0002280414000000901
Step Synthesis of 12-bromo-1- (4-morpholinophenyl) ethan-1-one
Figure BDA0002280414000000902
Adding 1- (4-morpholinylphenyl) ethyl-1-ketone (4.1g,20mmol) into a round-bottom flask, adding 20mL of a mixed solution of diethyl ether/1, 4-dioxane (1:1), cooling to-5 ℃, adding a diethyl ether (10mL) solution of liquid bromine (1.4mL,27mmol), dropwise adding for 30min, stirring for reaction for 3h, supplementing liquid bromine (0.4mL,7.8mmol), and reacting at room temperature overnight. The reaction solution is washed by sodium thiosulfate solution, added with ethyl acetate, extracted, combined with organic phases, concentrated under reduced pressure and separated by column chromatography to obtain the title compound. ESI-MS M/z 284.0,286.0[ M + H ]]+。
Step Synthesis of 22- (4- ((4- ((1-cyclopropyl-3- (4-morpholinophenyl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) propan-2-ol
Figure BDA0002280414000000903
The procedure is as in example 3, steps 1 to 4 except that 2-bromo-1- (4-morpholinophenyl) ethan-1-one is used instead of 2-bromo-1-phenylethane-1-one to give the title compound. ESI-MS M/z 513.0[ M + H ]]+。1HNMR(400MHz,DMSO-d6)δ9.46(s,1H),8.18(d,1H),8.13(d,1H),8.03(s,1H),7.68(d,1H),7.64(dd,1H),7.54(d,2H),6.91(d,2H),6.63(dd,1H),6.38(d,1H),5.11(s,1H),3.76(m,1H),3.73–3.65(m,4H),3.13–3.03(m,4H),1.38(s,6H),1.15–1.09(m,2H),1.05–0.97(m,2H).
Example 642- (5- ((4- ((1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -2- (trifluoromethyl) phenyl) propan-2-ol
Figure BDA0002280414000000911
Step Synthesis of 12- (5-amino-2- (trifluoromethyl) phenyl) propan-2-ol hydrochloride
Figure BDA0002280414000000912
Tert-butyl (3- (2-hydroxyprop-2-yl) -4- (trifluoromethyl) phenyl) carbamate (368mg,1.15mmol) was dissolved in 20mL of hydrogen chloride/dioxane and reacted at 25 ℃. After the reaction is completed, the reaction solution is directly dried by spinning for the next reaction.
Step Synthesis of 22- (5- ((4- ((1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -2- (trifluoromethyl) phenyl) propan-2-ol
Figure BDA0002280414000000913
The title compound was prepared by the same procedure as the preparation of the compound of example 3, step 4, except that 2- (5-amino-2- (trifluoromethyl) phenyl) propan-2-ol hydrochloride was used instead of 2- (4-aminopyridin-2-yl) propan-2-ol. ESI-MSm/z 495.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ:9.35(s,1H),8.09(m,2H),7.93–7.91(m,1H),7.74–7.68(m,3H),7.57–7.55(m,1H),7.36–7.27(m,3H),6.63–6.62(m,1H),6.36(m,1H),5.04(s,1H),3.81(m,1H),1.50(s,6H),1.16–1.14(m,2H),1.03–1.02(m,2H)。
Example 654- (5- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -2-fluorophenyl) thiomorpholine-1, 1-dioxide
Figure BDA0002280414000000914
Step 14 Synthesis of- (2-fluoro-5-nitrophenyl) thiomorpholine-1, 1-dioxide
Figure BDA0002280414000000921
2-bromo-1-fluoro-4-nitrobenzene (400mg,1.82mmol) and thiomorpholine-1, 1-dioxide (270mg,2.20mmol) were dissolved in 10mL of 1, 4-dioxane, palladium acetate (22.3mg,0.091mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (105mg,0.182mmol) and cesium carbonate (1.19g,3.64mmol) were added, nitrogen was substituted three times, and reaction was carried out at 100 ℃ overnight. After the reaction is completed, filtering to obtain filtrate, evaporating under reduced pressure to remove the solvent, and separating by column chromatography to obtain the title compound. ESI-MSm/z 275.0[ M + H ]]+。
Step Synthesis of 24- (5-amino-2-fluorophenyl) thiomorpholine-1, 1-dioxide
Figure BDA0002280414000000922
4- (2-fluoro-5-nitrophenyl) thiomorpholine 1, 1-dioxide (100mg,0.365mmol) was dissolved in 15mL of a mixed solvent of ethanol/water (4:1), and reduced iron powder (51.1mg,0.912mmol) and ammonium chloride (58.0mg,1.09mmol) were added and reacted at 80 ℃ for 2 hours. After completion of the reaction, celite-assisted filtration was carried out, and the filtrate was taken, water and dichloromethane were added, extracted, and the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound. ESI-MS M/z 245.1[ M + H ]]+。
Step synthesis of 34- (5- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -2-fluorophenyl) thiomorpholine-1, 1-dioxide
Figure BDA0002280414000000923
Preparation the title compound was prepared as in example 2, step 3, except that 4- (5-amino-2-fluorophenyl) thiomorpholine-1, 1-dioxide was used instead of 2-morpholinopyridin-4-amine. ESI-MSm/z 528.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ9.01(s,1H),8.04-8.02(m,1H),7.86(s,1H),7.44(dd,1H),7.35-7.32(m,1H),7.05(dd,1H),6.46(dd,1H),6.21-6.19(m,1H),3.89-3.81(m,2H),3.69-3.64(m,1H),3.49-3.46(m,4H),3.32-3.26(m,6H),2.75-2.67(m,1H),1.67-1.63(m,4H),1.09-1.01(m,2H),0.99-0.84(m,2H)。
Example Synthesis of 662- (5- ((4- ((1-cyclopropyl-3- (1- (oxetan-3-yl) piperidin-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -2- (methylsulfonyl) phenyl) propan-2-ol
Figure BDA0002280414000000931
The title compound was prepared as in example 48, except that 2- (5-amino-2- (methylsulfonyl) phenyl) propan-2-ol hydrochloride was used instead of 2- (4-aminopyridin-2-yl) propan-2-ol. ESI-MS M/z 568.2[ M + H ]]+。1HNMR(400MHz,DMSO-d6)δ:9.54(s,1H),8.12-8.11(d,1H),7.95-7.94(m,2H),7.87(s,1H),7.73(s,1H),6.59-6.57(m,1H),6.33-6.32(m,1H),5.37(s,1H),4.49-4.46(m,2H),4.39-4.36(m,2H),3.67-3.65(m,1H),3.30(s,3H),2.68-2.66(m,1H),2.53-2.51(m,2H),2.49-2.47(m,2H),2.45-2.42(m,1H),1.75-1.72(m,2H),1.68-1.65(m,2H),1.62(s,6H),1.03-1.02(m,2H),0.95-0.94(m,2H)。
Example 671- (5- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -2- (methylsulfonyl) phenyl) -3-methylazetidin-3-ol
Figure BDA0002280414000000932
Step 11- (5-amino-2- (methylsulfonyl) phenyl) -3-methylazetidin-3-ol Synthesis
Figure BDA0002280414000000933
3-fluoro-4- (methylsulfonyl) aniline (300mg,1.59mmol), 3-methylazetidin-3-ol hydrochloride (151.95mg,1.74mmol) and cesium carbonate (1.03g,3.17mmol) were placed in a reaction flask, 15mL of dimethyl sulfoxide was added, under argon, and reacted at 140 ℃ overnight. The next day the reaction was cooled to room temperature, 15mL of water was added to quench the reaction, ethyl acetate was added, extraction was performed, and the organic phase was collected. The organic phase was washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give the title compound. ESI-MS M/z 257.1[ M + H ]]+。
Step synthesis of 21- (5- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -2- (methylsulfonyl) phenyl) -3-methylazetidin-3-ol
Figure BDA0002280414000000941
Preparation the title compound was prepared as in example 2, step 3, except that 1- (5-amino-2- (methylsulfonyl) phenyl) -3-methylazetidin-3-ol was used instead of 2-morpholinopyridin-4-amine. ESI-MSm/z 540.3[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ:9.42(s,1H),8.11-8.10(d,1H),7.88(s,1H),7.61-7.59(d,1H),7.22-7.21(m,1H),7.19-7.18(m,1H),6.57-6.55(m,1H),6.32-6.31(d,1H),5.53(s,1H),3.93-3.91(m,2H),3.85-3.83(m,2H),3.82-3.80(m,2H),3.67-3.66(m,1H),3.39-3.38(m,2H),3.16(s,3H),2.73-2.67(m,1H),2.02-1.97(m,2H),1.65-1.64(m,2H),1.46(s,3H),1.03-1.02(m,2H),0.96-0.94(m,2H)。
Example 681- (5- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -2-fluorophenyl) azetidine-3-carbonitrile
Figure BDA0002280414000000942
Step 11- (2-fluoro-5-nitrophenyl) azetidine-3-carbonitrile Synthesis
Figure BDA0002280414000000943
2-bromo-1-fluoro-4-nitrobenzene (600mg,2.73mmol) and azetidine-3-carbonitrile (356mg,3.00mmol) were dissolved in 10mL of 1, 4-dioxane, palladium acetate (33.4mg,0.136mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (158mg,0.273mmol) and cesium carbonate (2.67g,8.19mmol) were added, nitrogen was substituted three times, and reaction was carried out overnight at 100 ℃. After the reaction is completed, filtering to obtain filtrate, evaporating under reduced pressure to remove the solvent, and separating by column chromatography to obtain the title compound. ESI-MS M/z 222.1[ M + H ]]+。
Step 21- (5-amino-2-fluorophenyl) azetidine-3-carbonitrile Synthesis
Figure BDA0002280414000000951
1- (2-fluoro-5-nitrophenyl) azetidine-3-carbonitrile (483mg,2.19mmol) was weighed out and dissolved in 15mL of a mixed solvent of ethanol/water (4:1), and reduced iron powder (306mg,5.46mmol) and ammonium chloride (348mg,6.57mmol) were added thereto and reacted at 80 ℃ for 2 hours. After completion of the reaction, filtration with celite, extraction of the filtrate with dichloromethane, combination of the organic phases, drying over anhydrous sodium sulfate and removal of the solvent by evaporation under reduced pressure gave the title compound. ESI-MS M/z 192.1[ M + H ]]+。
Step synthesis of 31- (5- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -2-fluorophenyl) azetidine-3-carbonitrile
Figure BDA0002280414000000952
Preparation the title compound was prepared as in example 2, step 3, except that 1- (5-amino-2-fluorophenyl) azetidine-3-carbonitrile was used instead of 2-morpholinopyridin-4-amine. ESI-MS M/z 475.2[ M + H ]]+。1HNMR(400MHz,DMSO-d6)δ8.90(s,1H),8.00(d,1H),7.85(s,1H),7.11-7.08(m,1H),6.97-6.92(m,1H),6.85-6.83(m,1H),6.44(d,1H),6.20(s,1H),4.17-4.12(dd,2H),4.12-3.99(m,2H),3.84-3.79(m,3H),3.69-3.64(m,1H),3.32-3.28(m,2H),2.73-2.67(m,1H),1.68-1.63(m,4H),1.06-1.01(m,2H),0.99-0.92(m,2H)。
Example 693- (5- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -2-fluorophenyl) oxetan-3-ol
Figure BDA0002280414000000953
Step Synthesis of 11- (3-bromo-4-fluorophenyl) -2, 5-dimethyl-1H-pyrrole
Figure BDA0002280414000000954
3-bromo-4-fluoroaniline (4.00g,21.1mmol) and 2, 5-hexanedione (2.64g,23.2mmol) were dissolved in 80mL of toluene, p-toluenesulfonic acid (36.3mg,0.211mmol) was added, and the reaction was refluxed for 2 h. After completion of the reaction, the solvent was distilled off under reduced pressure, and the title compound was isolated by column chromatography. ESI-MS M/z 268.0,270.0[ M + H ]]+。
Step Synthesis of 23- (5- (2, 5-dimethyl-1H-pyrrol-1-yl) -2-fluorophenyl) oxetan-3-ol
Figure BDA0002280414000000961
1- (3-bromo-4-fluorophenyl) -2, 5-dimethyl-1H-pyrrole (1.00g,3.75mmol) was placed in a three-necked flask, and the flask was replaced with nitrogen three times, and then 10mL of anhydrous tetrahydrofuran was added to dissolve the mixture. A solution of isopropyl magnesium chloride lithium chloride complex in tetrahydrofuran (3.46mL,1.3M,4.50mmol) was slowly added dropwise at-30 deg.C and stirred for 1h after the addition was complete. Oxetan-3-one (0.297g,4.12mmol) was slowly added dropwise thereto, and the reaction was continued at-30 ℃ for 1 hour after the dropwise addition. After the reaction was completed, 10mL of a saturated ammonium chloride solution was added to quench, ethyl acetate was added, extraction was performed, the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and column chromatography was performed to obtain the title compound. ESI-MSm/z 262.1[ M + H ]]+。
Step Synthesis of 33- (5-amino-2-fluorophenyl) oxetan-3-ol
Figure BDA0002280414000000962
3- (5- (2, 5-dimethyl-1H-pyrrol-1-yl) -2-fluorophenyl) oxetan-3-ol (400mg,1.53mmol) was dissolved in 16mL of a mixed solvent of ethanol/water (1:1), and hydroxylamine hydrochloride (533mg,7.66mmol) and potassium hydroxide (257mg,4.60mmol) were added to react at room temperature for 3 hours. After the reaction is completed, dichloromethane is added, extraction is carried out, organic phases are combined, anhydrous sodium sulfate is dried, the solvent is removed through reduced pressure evaporation, and column chromatography separation is carried out to obtain the title compound. ESI-MS M/z 184.1[ M + H ]]+。
Step Synthesis of 43- (5- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -2-fluorophenyl) oxetan-3-ol
Figure BDA0002280414000000963
Preparation the title compound was prepared as in example 2, step 3, except that 3- (5-amino-2-fluorophenyl) oxetan-3-ol was used instead of 2-morpholinopyridin-4-amine. ESI-MS M/z 467.2[ M + H ]]+。1HNMR(400MHz,DMSO-d6)δ9.07(s,1H),8.03(t,1H),7.86(s,1H),7.77-7.65(m,1H),7.56(dd,1H),7.09(dd,1H),6.45(dd,1H),6.36(s,1H),6.21(d,1H),4.93(d,2H),4.69(d,2H),3.93-3.75(m,2H),3.72-3.59(m,1H),3.32-3.25(m,1H),2.80-2.61(m,1H),2.48-2.36(m,1H),1.78-1.54(m,4H),1.12-1.00(m,2H),0.98-0.91(m,2H)。
Example 704- (5- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -2- (trifluoromethyl) phenyl) thiomorpholine-1, 1-dioxide
Figure BDA0002280414000000971
Step 14 Synthesis of 5-Nitro-2- (trifluoromethyl) phenyl) thiomorpholine-1, 1-dioxide
Figure BDA0002280414000000972
2-bromo-4-nitro-1- (trifluoromethyl) benzene (500mg,1.86mmol) and thiomorpholine-1, 1-dioxide (276mg,2.04mmol) were dissolved in 10mL of 1, 4-dioxane, palladium acetate (20.9mg,0.09mmol), 4, 5-bis-diphenylphosphino-9, 9-dimethylxanthene (108mg,0.186mmol) and cesium carbonate (1.21g,3.72mmol) were added, nitrogen was substituted three times, and the reaction was carried out at 100 ℃ overnight. After the reaction is completed, the filtrate is obtained by suction filtration, the solvent is removed by evaporation under reduced pressure, and the title compound is obtained by column chromatography separation. ESI-MS M/z 325.0[ M + H ]]+。
Step Synthesis of 24- (5-amino-2- (trifluoromethyl) phenyl) thiomorpholine-1, 1-dioxide
Figure BDA0002280414000000973
4- (5-Nitro-2- (trifluoromethyl) phenyl) thiomorpholine-1, 1-dioxide (421mg,1.30mmol) was dissolved in 10mL of methanol, and a palladium/carbon catalyst (42.1mg, 10%) was added thereto, and the mixture was replaced with hydrogen three times and reacted at room temperature overnight. After completion of the reaction, the reaction mixture was filtered under suction to obtain a filtrate, and the solvent was distilled off under reduced pressure to obtain the title compound. ESI-MS M/z 295.1[ M + H ]]+。
Step synthesis of 34- (5- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -2- (trifluoromethyl) phenyl) thiomorpholine-1, 1-dioxide
Figure BDA0002280414000000981
The title compound was prepared by the same procedure as the preparation of the compound in step 3 of example 2, except that 4- (5-amino-2- (trifluoromethyl) phenyl) thiomorpholine-1, 1-dioxide was used instead of 2-morpholinopyridin-4-amine. ESI-Ms M/z 578.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ9.49(s,1H),8.14(d,1H),7.88(s,1H),7.85(s,1H),7.70(d,1H),7.54(d,1H),6.58(dd,1H),6.32(d,1H),3.91-3.77(m,2H),3.73-3.61(m,1H),3.48-3.34(m,2H),3.31-3.25(m,4H),3.25-3.10(m,4H),2.78-2.64(m,1H),1.75-1.55(m,4H),1.13-1.00(m,2H),1.00-0.87(m,2H)。
Example 712- (4- (4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -2- (trifluoromethyl) phenyl) piperazin-1-yl) ethan-1-ol
Figure BDA0002280414000000982
Step 12- (4- (4-nitro-2- (trifluoromethyl) phenyl) piperazin-1-yl) ethan-1-ol Synthesis
Figure BDA0002280414000000983
1-fluoro-4-nitro-2- (trifluoromethyl) benzene (1.00g, 4.78mmol), 1- (2-hydroxyethyl) piperazine (1.87g,14.35mmol) and potassium carbonate (1.32g,9.56mmol) were dissolved in 50mL of dimethyl sulfoxide solution and reacted at 90 ℃ overnight. After the reaction, the reaction mixture was cooled to room temperature, filtered, concentrated, and purified by column chromatography to give the title compound. ESI-MS M/z 320.2[ M + H ]]+。
Step 22- (4- (4-amino-2- (trifluoromethyl) phenyl) piperazin-1-yl) ethan-1-ol Synthesis
Figure BDA0002280414000000984
2- (4- (4-Nitro-2- (trifluoromethyl) phenyl) piperazin-1-yl) ethan-1-ol (1.5g,4.70mmol) was dissolved in 20mL of methanol solution, and palladium/carbon catalyst (50mg, 10%) was added, and hydrogen substitution was repeated several times, and reaction was carried out at room temperature for 3 h. The reaction was complete, the filtrate was filtered and concentrated to give the title compound. ESI-MS M/z 290.2[ M + H ]]+。
Synthesis of step 32- (4- (4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -2- (trifluoromethyl) phenyl) piperazin-1-yl) ethan-1-ol
Figure BDA0002280414000000991
The title compound was prepared by the same procedure as the preparation of the compound in step 3 of example 2, except that 2- (4- (4-amino-2- (trifluoromethyl) phenyl) piperazin-1-yl) ethan-1-ol was used instead of 2-morpholinopyridin-4-amine. ESI-MS M/z 573.4[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ:9.28(s,1H),8.24(s,1H),8.05-8.04(d,1H),8.03-8.02(d,1H),7.87(s,1H),7.86-7.84(m,1H),7.47-7.45(d,1H),6.51-6.49(m,1H),6.22-6.21(d,1H),3.83-3.80(m,2H),3.67-3.66(m,1H),3.53-3.50(m,2H),3.35-3.33(m,4H),3.32-3.25(m,4H),2.79-2.75(m,2H),2.75-2.69(m,1H),2.43-2.41(m,2H),1.66-1.62(m,4H),1.03-1.00(m,2H),0.95-0.94(m,2H)。
Example 721- (4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) -2,2, 2-trifluoroethyl-1-ol
Figure BDA0002280414000000992
Step preparation of 11- (4-bromopyridin-2-yl) -2,2, 2-trifluoroethyl-1-ol
Figure BDA0002280414000000993
4-bromopyridine-2-carbaldehyde (2.0g,10.76mmol) and trifluoromethyltrimethylsilane (1.84g,12.90mmol) were charged into a 100mL three-necked flask, dissolved under argon, in 20mL tetrahydrofuran, cooled to 0 deg.C, and tetrabutylammonium fluoride (0.54mL,0.54mmol) was added dropwise and reacted at room temperature for 2 h. After the reaction was complete, it was cooled to 0 deg.C, hydrochloric acid solution (6mL,6M) was added, stirring was continued for 30min, and the pH was adjusted to 8 with sodium hydroxide solution. Ethyl acetate was added, extracted, washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give the title compound. LC-MS M/z 256.2,258.2[ M + H ]]+。
Step 2 preparation of tert-butyl (2- (2,2, 2-trifluoro-1-hydroxyethyl) pyridin-4-yl) carbamate
Figure BDA0002280414000001001
1- (4-bromopyridin-2-yl) -2,2, 2-trifluoroethyl-1-ol (2.55g,10mmol), tert-butyl carbamate (1.4g,12mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (527mg,0.9mmol), tris (dibenzylideneacetone) dipalladium (275mg,0.3mmol), cesium carbonate (6.52g,20mmol) and 35mL dioxane were added to a three-necked flask and reacted under argon at 90 ℃ overnight. Detection shows that the reaction is complete, ethyl acetate is added, extraction is carried out, an organic phase is washed by water and saturated sodium chloride solution, anhydrous sodium sulfate is dried, and reduced pressure concentration is carried out to obtain the title compound. LC-MS M/z 293.1[ M + H ]]+。
Step 31 preparation of- (4-Aminopyridin-2-yl) -2,2, 2-trifluoroethyl-1-ol
Figure BDA0002280414000001002
Tert-butyl (2- (2,2, 2-trifluoro-1-hydroxyethyl) pyridin-4-yl) carbamate (2.5g,8.56mmol) was dissolved in 8mL of methanol, and a hydrochloric acid/dioxane solution (20mL,4M) was added dropwise thereto, followed by stirring at room temperature overnight. After the reaction was completed, concentration was performed, a saturated sodium bicarbonate solution and ethyl acetate were added, extraction was performed, the organic phase was washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then, concentration was performed under reduced pressure to obtain the title compound. LC-MS M/z 193.4[ M + H ]]+。
Step 41 preparation of 4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) -2,2, 2-trifluoroethyl-1-ol
Figure BDA0002280414000001003
Preparation the title compound was prepared as in example 2, step 3, except that 1- (4-aminopyridin-2-yl) -2,2, 2-trifluoroethyl-1-ol was used instead of 2-morpholinopyridin-4-amine. LC-MSm/z 476.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ9.95(s,1H),9.66(s,1H)，8.45(dd,J1＝8.4Hz，J2＝1.6Hz,1H),8.24-8.20(m,2H),7.90(s,1H),7.80(dd,J1＝5.6Hz，J2＝2.0Hz,1H),6.90(s,1H)，6.70(dd,J1＝7.0Hz，J2＝2.4Hz,1H),6.39(d,J＝2.4Hz，1H),3.84-3.80(m,2H),3.69-3.66(m,1H),3.41-3.28(m,2H),2.76-2.67(m,1H),1.68-1.62(m,4H),1.05-0.95(m,4H)。
Example 732- (5- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -2- (1H-1,2, 4-triazol-1-yl) phenyl) propan-2-ol
Figure BDA0002280414000001011
Step 15 preparation of methyl bromo-2- (1H-1,2, 4-triazol-1-yl) benzoate
Figure BDA0002280414000001012
Methyl 5-bromo-2-fluorobenzoate (2g,4.3mmol), 1H-1,2, 4-triazole (0.65g,4.73mmol), anhydrous potassium carbonate (1.4g,5.16mmol) and anhydrous N, N-dimethylformamide were added to a 100mL three-necked flask and reacted at 80 ℃ overnight under argon. Cooling to room temperature, adding water and ethyl acetate, extracting, drying the organic phase by anhydrous sodium sulfate, decompressing, concentrating and carrying out column chromatography to obtain the title compound. LC-MS M/z 282.2,283.9[ M + H ]]+。
Step 22- (5-bromo-2- (1H-1,2, 4-triazol-1-yl) phenyl) propan-2-ol preparation
Figure BDA0002280414000001013
Methyl 5-bromo-2- (1H-1,2, 4-triazol-1-yl) benzoate (1.57g,5.58mmol) was dissolved in 20mL of anhydrous tetrahydrofuran, cooled to 0 deg.C, methyl magnesium bromide (5.4mL,3M,16.2mmol) was added dropwise, the reaction was stirred for 30min, and then allowed to react at room temperature overnight. Adding saturated ammonium chloride solution and ethyl acetate in ice water bath, extracting, drying the organic layer by anhydrous sodium sulfate, decompressing, concentrating, and purifying by column chromatography to obtain the title product. LC-MS M/z 282.1,284.3[ M + H ]]+。
Step 3 preparation of tert-butyl (3- (2-hydroxypropyl-2-yl) -4- (1H-1,2, 4-triazol-1-yl) phenyl) carbamate
Figure BDA0002280414000001014
2- (5-bromo-2- (1H-1,2, 4-triazol-1-yl) phenyl) propyl-2-ol (413mg,1.46mmol), tert-butyl carbamate (189mg,1.61mmol), tris (dibenzylideneacetone) dipalladium (134mg,0.146mmol), 4, 5-bis diphenylphosphine-9, 9-dimethylxanthene (169mg,0.292mmol), potassium carbonate (951mg,6.9mmol) and 20mL dioxane were added to a 100mL three-necked flask. The reaction was carried out overnight at 100 ℃ under the protection of argon. The filtrate was filtered, concentrated and column chromatographed to give the title product. LC-MSm/z 319.1[ M + H]+。
Step preparation of 42- (5-amino-2- (1H-1,2, 4-triazol-1-yl) phenyl) propan-2-ol
Figure BDA0002280414000001021
Tert-butyl (3- (2-hydroxypropyl-2-yl) -4- (1H-1,2, 4-triazol-1-yl) phenyl) carbamate (356mg,1.118mmol) was dissolved in 10mL of methanol, stirred at room temperature, and a hydrochloric acid/dioxane solution (2.8mL,4M,11.2mmol) was added dropwise. After dropping, the reaction was carried out at 30 ℃ overnight. And (3) concentrating the reaction system under reduced pressure, adding sodium bicarbonate and ethyl acetate, separating, combining organic phases, concentrating under reduced pressure, and directly carrying out the next reaction. LC-MS M/z 219.2[ M + H ]]+。
Step 52 preparation of 5- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -2- (1H-1,2, 4-triazol-1-yl) phenyl) propan-2-ol
Figure BDA0002280414000001022
The title compound was prepared by the same method as the compound of step 3 of example 2, except that 2- (5-amino-2- (1H-1,2, 4-triazol-1-yl) phenyl) propyl-2-ol was used instead of 2-morpholinopyridin-4-amine. LC-MS M/z 502.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ9.35(s,1H),8.65(s,1H),8.14(s,1H),8.07(d,J＝5.8Hz,1H),8.02(dd,J＝2.4,8.6Hz,1H),7.86(s,1H),7.84(d,J＝2.4Hz,1H),7.05(d,J＝8.6Hz,1H),6.50(dd,J＝2.4,5.8Hz,1H),6.34(d,J＝2.4Hz,1H),5.10(s,1H),3.81–3.83(m,2H),3.63–3.66(m,1H),2.64-2.70(m,2H),2.32-2.33(m,1H),1.06–1.07(m,4H),1.16(s,6H),1.01–1.05(m,2H),0.91–0.93(m,2H)。
Example 742- (4- ((4- ((1-cyclopropyl-3- (4, 4-difluorocyclohexyl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) propan-2-ol
Figure BDA0002280414000001031
The title compound was prepared by the same procedure as the preparation of the compound of example 20, except that 2- (4-aminopyridin-2-yl) propan-2-ol was used instead of 2-morpholinopyridin-4-amine. LC-MS M/z 470.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ9.48(s,1H),8.21-8.20(d,1H),8.15-8.13(d,1H),7.88(s,1H),7.71-7.70(d,2H),6.59-6.57(d,1H),6.37(d,1H),5.11(s,1H),3.71-3.65(m,1H),2.71-2.66(t,1H),2.03-2.00(m,2H),1.87-1.78(m,4H),1.73-1.67(m,2H),1.41(s,6H),1.03-0.93(m,4H)。
Example 753- (4- (4- ((1-cyclopropyl-3- (4, 4-difluorocyclohexyl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) oxetan-3-ol
Figure BDA0002280414000001032
Step 1 preparation of tert-butyl (2-bromopyridin-4-yl) carbamate
Figure BDA0002280414000001033
2-bromo-4-aminopyridine (8.651g,50.0mmol), triethylamine (15.179g,150mmol) and dichloromethane (50mL) were taken and placed in a reaction flask, di-tert-butyl carbonate (16.369g,75.0mmol) was weighed and added to the reaction flask at 0 deg.C, after addition, the reaction was stirred at 40 deg.C for 4 h. After the reaction is finished, cooling to room temperature, and adding saturated sodium bicarbonate solution and di (ethyl acetate) into the reaction systemChloromethane, extracting, taking an organic phase, and drying by anhydrous sodium sulfate. The title compound was obtained by vacuum concentration and column chromatography purification. LC-MS M/z 273.2,275.2[ M + H ]]+。
Step 2 preparation of tert-butyl (2- (3-hydroxyoxetan-3-yl) pyridin-4-yl) carbamate
Figure BDA0002280414000001034
Tert-butyl (2-bromopyridin-4-yl) carbamate (1.0g,3.8mmol) was weighed into a reaction flask with 40mL of anhydrous tetrahydrofuran, cooled to-78 deg.C and n-butyllithium (30mL,1.6M,5.7mmol) was added dropwise. After the addition, 3-oxetanone (0.3g,3.9mmol) was added thereto, and the mixture was slowly returned to room temperature and stirred overnight. After the reaction, a saturated ammonium chloride solution and ethyl acetate were added to the reaction solution, followed by extraction and concentration under reduced pressure to give the title product. LC-MSm/z 267.1[ M + H ]]+。
Step 33- (4-Aminopyridin-2-yl) oxetan-3-ol preparation
Figure BDA0002280414000001041
Tert-butyl (2- (3-hydroxyoxetan-3-yl) pyridin-4-yl) carbamate (0.330g,1.24mmol) was weighed out and dissolved in 10mL of dichloromethane, and 1mL of concentrated hydrochloric acid was added thereto at room temperature, followed by stirring for 2 hours. After the reaction was completed, anhydrous potassium carbonate was added for neutralization, filtration, liquid separation, organic phase drying, and concentration under reduced pressure to obtain the title product. LC-MS M/z 167.1[ M + H ]]+。
Step 43- (4- ((4- ((1-cyclopropyl-3- (4, 4-difluorocyclohexyl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) oxetan-3-ol preparation
Figure BDA0002280414000001042
Collecting 2-chloro-4- ((1-cyclopropyl-3- (4, 4-difluorocyclohexyl) -1H-pyrazol-4-yl) oxy) pyridine (0.453g,1.283mmol), 3- (4-aminopyridin-2-yl) oxetan-3-ol (0.20g,1.2mmol), 4,5Bis-diphenylphosphine-9, 9-dimethylxanthene (0.058g,0.10mmol), potassium carbonate (0.464g,4.0mmol) and tris-dibenzylideneacetone dipalladium (0.046g,0.05mmol) were placed in a 100mL single-neck flask and 20mL of 1, 4-dioxane was added. The reaction was carried out overnight at 100 ℃ under an argon atmosphere. And (3) completely reacting, cooling to room temperature, adding saturated saline and ethyl acetate into the reaction, extracting, concentrating under reduced pressure, and purifying by column chromatography to obtain a target product. LC-MS M/z 484.3[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ9.57(s,1H),8.34(d,J＝5.6Hz,1H),8.15(d,J＝5.6Hz,1H),7.89(s,1H),7.76-7.73(m,2H),6.61(dd,J1＝6.0Hz,J2＝2.0Hz,2H),6.43(s,1H),4.90(d,J＝6.0Hz,2H),4.63(d,J＝6.0Hz,2H),3.70-3.65(m,1H),2.70(d,J＝7.2Hz,1H),2.02-1.64(m,8H),1.06-0.91(m,4H).
Example 761- (4- ((4- ((1-cyclopropyl-3- (4, 4-difluorocyclohexyl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl-2, 2, 2-trifluoroethyl-1-ol
Figure BDA0002280414000001051
The title compound was prepared by the same procedure for the preparation of the compound of example 75 except that 1- (4-aminopyridin-2-yl) -2,2, 2-trifluoroethyl-1-ol was used instead of 3- (4-aminopyridin-2-yl) oxetan-3-ol.1HNMR(400MHz,DMSO-d6)δ9.65(s,1H),8.28-8.27(d,1H),8.17-8.15(d,1H),7.9(s,1H),7.82-7.79(m,2H),6.63-6.61(dd,1H),6.37(s,1H),5.03-4.98(m,1H),3.7(m,1H),2.71-2.65(m,1H),2.0-1.93(m,2H),1.86-1.78(m,3H),1.70-1.64(m,3H),1.25(s,1H),1.06-1.03(m,2H),0.98-0.95(m,2H)。LC-MS m/z:510.2[M+H]+。
Example 774- (4- ((4- ((1-cyclopropyl-3- (4, 4-difluorocyclohexyl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) tetrahydro-2H-pyran-4-ol
Figure BDA0002280414000001052
The procedure is as for the preparation of the compound of example 75, except that tetrahydro is used-4H-pyran-4-one instead of 3-oxetanone to give the title compound. LC-MS M/z 512.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ9.52(s,1H),8.25-8.23(d,1H),8.15-8.13(d,1H),7.77(s,1H),7.71-7.69(dd,1H),6.59-6.57(dd,1H),6.38(d,1H),5.17(s,1H),3.78-3.65(m,5H),2.7-2.65(t,1H),2.16-2.11(m,1H),2.20-2.08(m,2H),2.07-2.0(m,2H),1.92-1.80(m,4H),1.73-1.61(m,2H),1.42-1.38(d,2H),1.06-1.01(m,2H),0.97-0.91(m,2H)。
Example 782- (5- ((4- ((1-cyclopropyl-3- (4, 4-difluorocyclohexyl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -2- (1H-1,2, 4-triazol-1-yl) phenyl) propan-2-ol
Figure BDA0002280414000001053
The title compound was prepared as in example 3, except that 2-bromo-1- (4, 4-difluorocyclohexyl) ethyl-1-one was used instead of 2-bromo-1-phenyleth-1-one and 2- (5-amino-2- (1H-1,2, 4-triazol-1-yl) phenyl) propan-2-ol instead of 2- (4-aminopyridin-2-yl) propan-2-ol. LC-MS M/z 536.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ9.36(s,1H),8.66(s,1H),8.14(s,1H),8.08(d,J＝6.0Hz,1H),8.05(dd,J1＝8.8Hz,J2＝2.8Hz,1H),7.87(s,1H),7.83(d,J＝2.4Hz,1H),7.07(d,J＝8.4Hz,1H),6.52(dd,J1＝5.6Hz,J2＝2.0Hz,1H),6.35(d,J＝2.4Hz,1H),5.11(s,1H),3.70-3.65(m,1H),2.72-2.66(m,1H),2.08-2.01(m,2H),1.91-1.78(m,4H),1.77-1.65(m,2H),5.11(s,6H),1.06-1.04(m,2H),0.97-0.94(m,2H)。
Example 791- (4- (4- ((1-cyclopropyl-3- (3, 3-difluorocyclobutyl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) -2,2, 2-trifluoroethan-1-ol
Figure BDA0002280414000001061
Step 13, preparation of 3-difluoro-N-methoxy-N-methylcyclobutane-1-carboxamide
Figure BDA0002280414000001062
3, 3-Difluorocyclobutanecarboxylic acid (5.0g,36.74mmol) and 1-hydroxybenzotriazole (5.601g,40.41mmol) were added to a three-necked flask with 100mL of dichloromethane, cooled to 0 deg.C, and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (7.747g,40.41mmol) was added. Then reacted at 0 ℃ for 1h, followed by addition of N, O-dimethylhydroxylamine hydrochloride (4.30g,44.09mmol) and triethylamine (11.153g,110.22mmol) to the reaction, which was allowed to return to room temperature and stirred overnight. Water and dichloromethane were added to the reaction, extraction was performed, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give the title compound. LC-MS M/z 180.1[ M + H ]]+。
Step 21- (3, 3-difluorocyclobutyl) ethanone preparation
Figure BDA0002280414000001063
3, 3-difluoro-N-methoxy-N-methylcyclobutane-1-carboxamide (6.5g,36.3mmol) was added to 100mL of anhydrous tetrahydrofuran and cooled to-1 ℃. Methyl magnesium bromide (18.1mL,54.5mmol) was added to the reaction under argon, followed by reaction at-1 ℃ for 1h, returning to room temperature and stirring for 2h, and the reaction was quenched with saturated ammonium chloride solution. Adding saturated saline and ethyl acetate, extracting, combining organic phases, washing with saturated saline, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and purifying by column chromatography to obtain the title product.1H NMR(400MHz,CDCl3)δ3.08(pd,J＝8.7,2.7Hz,1H),2.84-2.67(m,4H),2.19(s,3H)。
Step preparation of 32-chloro-4- ((1-cyclopropyl-3- (3, 3-difluorocyclobutyl) -1H-pyrazol-4-yl) oxy) pyridine
Figure BDA0002280414000001071
Preparation method example 1 preparation method of compound of step 1 to 5 except that 1- (3, 3-difluorocyclobutyl) ethanone was used in place of 1- (tetrahydro-2H-pyran-4-yl) ethanoneThe title compound. LC-MS M/z 326.08[ M + H ]]+。
Step 41 preparation of 4- (4- (4- ((1-cyclopropyl-3- (3, 3-difluorocyclobutyl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) -2,2, 2-trifluoroethan-1-ol
Figure BDA0002280414000001072
In a 100mL single neck flask, 2-chloro-4- ((1-cyclopropyl-3- (3, 3-difluorocyclobutyl) -1H-pyrazol-4-yl) oxy) pyridine (0.29g,0.90mmol), 1- (4-aminopyridin-2-yl) -2,2,2, -trifluoroethyl-1-ol (0.28g,1.46mmol), 4, 5-bis-diphenylphosphino-9, 9-dimethylxanthene (0.05g,0.090mmol), cesium carbonate (0.41g,3.60mmol) and tris-dibenzylideneacetone dipalladium (0.041g,0.045mmol) were weighed, 20mL of 1, 4-dioxane was added, and the mixture was heated to 100 ℃ under argon atmosphere for overnight reaction. The reaction was cooled to room temperature, and saturated brine and ethyl acetate were added to extract, concentrate, and purify by column chromatography to obtain the title compound. LC-MS M/z 482.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ9.63(s,1H),8.28(d,J＝5.6Hz,1H),8.17(d,J＝6.0Hz,1H),7.95(s,1H),7.81-7.78(m,2H),6.87(d,J＝6.0Hz,1H),6.62(dd,J1＝6.0Hz,J2＝2.4Hz,1H),6.35(d,J＝2.0Hz,1H),5.04-3.68(m,1H),3.73-3.68(m,1H),3.17-3.13(m,1H),2.81-2.76(m,4H),1.09-0.97(m,4H)。
Example 802- (4- ((4- (1-cyclopropyl-3- (4-fluorophenyl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) propan-2-ol
Figure BDA0002280414000001081
The title compound was prepared as in example 3, except that 2-bromo-1- (4-fluorophenyl)) ethan-1-one was used instead of 2-bromo-1-phenylethane-1-one. LC-MS M/z 446.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ9.44(s,1H),8.19(d,J＝5.6Hz,1H),8.15(d,J＝5.8Hz,1H),8.10(s,1H),7.76–7.68(m,3H),7.65(dd,J＝5.6,2.1Hz,1H),7.21(t,J＝8.9Hz,2H),6.65(dd,J＝5.8,2.2Hz,1H),6.42(d,J＝2.1Hz,1H),5.09(s,1H),3.82(tt,J＝7.3,3.7Hz,1H),1.40(s,6H),1.16(dt,J＝7.4,4.8Hz,2H),1.06–1.00(m,2H)。
Example preparation of 813- (4- ((4- ((1-cyclopropyl-3- (3-fluorophenyl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) oxetan-3-ol
Figure BDA0002280414000001082
2-chloro-4- ((1-cyclopropyl-3- (3-fluorophenyl) -1H-pyrazol-4-yl) oxy) pyridine (200mg,0.60mmol), 3- (4-aminopyridin-2-yl) oxetan-3-ol (175.6mg,0.78mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (0.056g,0.0976mmol), cesium carbonate (0.408g,3.514mmol), tris (dibenzylideneacetone) dipalladium (0.045g,0.0488mmol) and 1, 4-dioxane (12mL) were placed in a 100mL reaction flask, heated to 100 ℃ under an argon atmosphere, and reacted overnight. The reaction was cooled to room temperature, and saturated brine and dichloromethane were added to the reaction, followed by extraction, concentration under reduced pressure, and purification by column chromatography to give the title compound. LC-MS M/z 460.3[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ9.55(s,1H),8.34(d,J＝5.6Hz,1H),8.18(d,J＝5.8Hz,2H),7.77(s,1H),7.71(d,J＝5.6Hz,1H),7.53(d,1H),7.43(d,J＝5.2Hz,2H),7.15(t,1H),6.70(dd,J＝5.8,2.2Hz,1H),6.44(d,J＝2.1Hz,2H),4.88(d,J＝5.6Hz,2H),4.62(d,J＝5.6Hz,2H),3.81-3.87(m,1H),1.18-1.21(m,2H),1.08-1.03(m,2H)。
Example 824- (4- ((4- ((1-cyclopropyl-3- (3-fluorophenyl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) tetrahydro-2H-pyran-4-ol
Figure BDA0002280414000001091
Preparation method the title compound was prepared as for the compound of step 81, except that 4- (4-aminopyridin-2-yl) tetrahydro-2H-pyran-4-ol was used instead of 3- (4-aminopyridin-2-yl) oxetan-3-ol. LC-MS M/z 488.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ9.51(s,1H),8.25(d,J＝5.6Hz,1H),8.17(d,J＝5.8Hz,1H),8.15(s,1H),7.77(d,J＝1.6Hz,1H),7.67(dd,J＝2.0Hz,2.0Hz,1H),7.53(d,J＝1.6Hz,1H),7.43(q,2H),7.10-7.15(m,1H),6.69(dd,J＝5.8,2.2Hz,1H),6.44(d,J＝2.1Hz,1H),5.17(s,1H),3.81-3.86(m,1H),3.69-3.76(m,4H),2.08-2.20(m,2H),1.42(s,1H),1.38(s,1H),1.16-1.20(m,2H),1.02-1.07(m,2H)。
Example 833- (4- ((4- ((1-cyclopropyl-3- (2-fluoro-4- (tetrahydro-2H-pyran-4-yl) phenyl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) oxetan-3-ol
Figure BDA0002280414000001092
Step preparation of 11- (4- (3, 6-dihydro-2H-pyran-4-yl) -2-fluorophenyl) ethyl-1-one
Figure BDA0002280414000001093
1- (4-bromo-2-fluorophenyl) ethanone (1.6g,5mmol), 3, 6-dihydro-2H-pyran-4-boronic acid pinacol ester (1g,4mmol), tetrakis (triphenylphosphine) palladium (531mg,0.46mmol) and potassium carbonate (1.3g,9.2mmol) were placed in a 100mL round bottom flask, 50mL of dioxane solution was added, and reaction was allowed to proceed overnight at 90 ℃. After the reaction is completed, the product is filtered, decompressed, concentrated and purified by column chromatography to obtain the title product. LC-MS M/z 221.1[ M + H ]]+。
Step 2: preparation of 1- (2-fluoro-4- (tetrahydro-2H-pyran-4-yl) phenyl) ethyl-1-one
Figure BDA0002280414000001094
1- (4- (3, 6-dihydro-2H-pyran-4-yl) -2-fluorophenyl) ethyl-1-one (2.4g,10.9mmol) was dissolved in 25mL of methanol, and 240mg of palladium on carbon/catalyst was added, and after replacement with hydrogen, the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the filtrate was filtered and concentrated under reduced pressure to give the title compound. LC-MS M/z 223.1[ M + H ]]+。
And step 3: preparation of 2-bromo-1- (2-fluoro-4- (tetrahydro-2H-pyran-4-yl) phenyl) ethyl-1-one
Figure BDA0002280414000001101
1- (2-fluoro-4- (tetrahydro-2H-pyran-4-yl) phenyl) ethyl-1-one (1.5g,6.8mmol) was dissolved in 20mL of glacial acetic acid, and 350. mu.L of liquid bromine was added dropwise under a nitrogen atmosphere. The mixture was stirred at room temperature for 2 hours, and the reaction was complete. After neutralization with saturated sodium bicarbonate solution, ethyl acetate was added, extracted and the organic phase was concentrated under reduced pressure to give the title compound. LC-MSm/z 301.0,303.2[ M + H ]]+。
Step preparation of 32-chloro-4- ((1-cyclopropyl-3- (2-fluoro-4- (tetrahydro-2H-pyran-4-yl) phenyl) -1H-pyrazol-4-yl) oxy) pyridine
Figure BDA0002280414000001102
The procedure is as in example 3, steps 1 to 3 except that 2-bromo-1- (2-fluoro-4- (tetrahydro-2H-pyran-4-yl) phenyl) ethyl-1-one is used instead of 2-bromo-1-phenyleth-1-one to afford the title compound. LC-MSm/z 414.1[ M + H ]]+。
Step 43 preparation of 4- ((4- ((1-cyclopropyl-3- (2-fluoro-4- (tetrahydro-2H-pyran-4-yl) phenyl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) oxetan-3-ol
Figure BDA0002280414000001103
2-chloro-4- ((1-cyclopropyl-3- (2-fluoro-4- (tetrahydro-2H-pyran-4-yl) phenyl) -1H-pyrazol-4-yl) oxy) pyridine (250mg,0.6mmol), 3- (4-aminopyridin-2-yl) oxetan-3-ol (120mg,0.72mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (70mg,0.12mmol), cesium carbonate (140mg,1.2mmol), tris (dibenzylideneacetone) dipalladium (55mg,0.06mmol), and 1, 4-dioxane (5mL) were placed in a 50mL single-necked flask and reacted at 110 ℃ under argon atmosphere overnight. Cooling to room temperature, adding saturated saline and ethyl acetate, extracting, decompressing and concentrating the organic phase, and purifying by column chromatography to obtain the title compound. LC-MS M/z 544.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ9.55(s,1H),8.33(d,J＝5.6Hz,1H),8.13(s,1H),8.11(d,J＝5.9Hz,1H),7.78–7.74(m,1H),7.71(dd,J＝5.6,2.0Hz,1H),7.46(t,J＝7.8Hz,1H),7.12(d,J＝9.8Hz,2H),6.59(dd,J＝5.9,2.2Hz,1H),6.48–6.40(m,2H),4.89(d,J＝5.9Hz,2H),4.62(d,J＝5.9Hz,2H),3.92(dd,J＝10.6,3.2Hz,2H),3.83(tt,J＝7.4,3.8Hz,1H),3.39(td,J＝11.4,2.8Hz,2H),2.78(ddd,J＝17.9,8.9,3.3Hz,1H),1.71–1.57(m,4H),1.18–1.12(m,2H),1.03(td,J＝7.5,5.5Hz,2H)。
Example 841- (4- ((4- ((1-cyclopropyl-3- (3-fluorophenyl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) -2,2, 2-trifluoroethyl-1-ol
Figure BDA0002280414000001111
Taking 2-chloro-4- ((1-cyclopropyl-3- (3-fluorophenyl) -1H-pyrazol-4-yl) oxy) pyridine (200mg,0.60mmol), 1- (4-aminopyridin-2-yl) -2,2, 2-trifluoroethyl-1-ol (130mg,0.6mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (70mg,0.122mmol), cesium carbonate (141mg,1.22mmol), tris (dibenzylideneacetone) dipalladium (56mg,0.06mmol) and 10mL of 1, 4-dioxane (placed in a 100mL reaction bottle, reacting overnight at 100 ℃ under an argon atmosphere), cooling the reaction to room temperature, adding saturated brine and dichloromethane, extracting, concentrating under reduced pressure, column chromatography purification to give the title compound LC-MS m/z:486.2[ M + H.]+。1HNMR(400MHz,DMSO-d6)δ9.63(s,1H),8.27(d,J＝6.7Hz,1H),8.19(d,J＝6.0Hz,1H),8.16(s,2H),7.80–7.74(m,3H),7.55–7.51(m,1H),7.46–7.38(m,1H),6.87(d,J＝6.2Hz,1H),6.72(dd,J＝6.1,2.4Hz,1H),6.42(d,J＝2.6Hz,1H),5.00(m,1H),3.84(tt,J＝7.7,4.0Hz,1H),1.18(d,J＝3.9Hz,2H),1.05(dt,J＝7.6,3.9Hz,2H)。
Example 852- (4- ((4- ((3- (3-oxabicyclo [3.1.0] hex-6-yl) -1-cyclopropyl-1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) propan-2-ol
Figure BDA0002280414000001121
Step preparation of 13-Oxabicyclo [3.1.0] hexane-6-carboxylic acid ethyl ester
Figure BDA0002280414000001122
Rhodium diacetate dimer (632mg,1.43mmol) and 200mL of anhydrous methylene chloride were charged in a 1L three-necked flask, and 2, 5-dihydrofuran (21.5mL,285mmol) was added thereto under an argon atmosphere. Ethyl diazoacetate (15mL,143mmol) was then dissolved in 430mL dry dichloromethane and added dropwise over 48h using a constant pressure addition funnel. After the reaction is completed, the product is decompressed, concentrated and purified by column chromatography to obtain the title product. LC-MS M/z 157.1[ M + H ]]+。
Step preparation of 23-oxabicyclo [3.1.0] hexane-6-carboxylic acid
Figure BDA0002280414000001123
Weighing 3-oxabicyclo [3.1.0]Hexane-6-carboxylic acid ethyl ester (4.26g,27.3mmol) was dissolved in 100mL of tetrahydrofuran, and an aqueous sodium hydroxide solution (50mL,81.9mmol) was added dropwise thereto under ice-water bath conditions, followed by reaction at room temperature overnight. Adjusting pH to 3 with dilute hydrochloric acid, removing organic solvent, and lyophilizing. The lyophilized mixture was washed with methanol, filtered with suction, and the filtrate was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to be used directly in the next reaction. LC-MS M/z 129.1[ M + H ]]+。
Step 3 preparation of N-methoxy-N-methyl-3-oxabicyclo [3.1.0] hexane-6-carboxamide
Figure BDA0002280414000001124
Weighing 3-oxabicyclo [3.1.0]]Hexane-6-carboxylic acid (5g,31.25mmol) was dissolved in 100mL of anhydrous dichloromethane, 1-hydroxybenzotriazole (5.81g,34.3mmol) was added, the mixture was replaced with nitrogen, the reaction was carried out in an ice-water bath for 30min, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (8.21g,34.4mmol) was added to the system, and the reaction was stirred for 1 h. Methoxymethylaminehydrochloride (4.6g,37.5mmol) was then added and triethylamine (16.3mL,94mmol) was added dropwise and the reaction was allowed to proceed overnight. After the reaction is completed, adding water and dichloromethane, extracting, and purifying by column chromatography to obtain the standardThe title product. LC-MS M/z 172.1[ M + H ]]+。
Step 41 preparation of- (3-oxabicyclo [3.1.0] hex-6-yl) ethan-1-one
Figure BDA0002280414000001131
Reacting N-methoxy-N-methyl-3-oxabicyclo [3.1.0]Hexane-6-carboxamide (1.6g,10.3mmol) was dissolved in 20mL of anhydrous tetrahydrofuran, and methyl magnesium bromide (6.9mL,3M,20.6mmol) was added dropwise to the system at 0 ℃ under a nitrogen atmosphere, and the reaction was carried out overnight. After the reaction is completed, filtering to obtain filtrate, concentrating under reduced pressure, and purifying by column chromatography to obtain the title product. LC-MS M/z 127.1[ M + H ]]+。
Step 54 preparation of- ((3- (3-oxabicyclo [3.1.0] hex-6-yl) -1-cyclopropyl-1H-pyrazol-4-yl) oxy) -2-chloropyridine
Figure BDA0002280414000001132
The preparation method is the same as the preparation method of the compound in the step 1 to 5 of the example 1, except that 1- (3-oxabicyclo [3.1.0] is used]Hexane-6-yl) ethan-1-one instead of 1- (tetrahydro-2H-pyran-4-yl) ethanone, the title compound was prepared. LC-MS M/z 318.1[ M + H ]]+。
Step preparation of 62- (4- ((4- ((3- (3-oxabicyclo [3.1.0] hex-6-yl) -1-cyclopropyl-1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) propan-2-ol
Figure BDA0002280414000001133
The procedure is as in example 45, step 2 except that 4- ((3- (3-oxabicyclo [3.1.0] is used]Hexane-6-yl) -1-cyclopropyl-1H-pyrazol-4-yl) oxy) -2-chloropyridine instead of 2-chloro-4- ((1- (2-fluoroethyl) -3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine the title compound was prepared. LC-MS M/z 434.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ9.50(s,1H),8.20(d,J＝5.6Hz,1H),8.13(d,J＝5.8Hz,1H),7.85(s,1H),7.72(d,J＝1.8Hz,1H),7.69(dd,J＝5.6,2.1Hz,1H),6.59(dd,J＝5.8,2.2Hz,1H),6.42(d,J＝2.2Hz,1H),5.13(s,1H),3.76(d,J＝8.2Hz,2H),3.66(tt,J＝7.4,3.9Hz,1H),3.60(d,J＝8.0Hz,2H),1.87(d,J＝7.3Hz,2H),1.62(t,J＝7.8Hz,1H),1.40(s,6H),1.03(d,J＝4.1Hz,2H),0.97–0.91(m,2H)。
Example 862- (5- ((4- ((3- (3-oxabicyclo [3.1.0] hex-6-yl) -1-cyclopropyl-1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -2- (1H-1,2, 4-triazol-1-yl) phenyl) propan-2-ol
Figure BDA0002280414000001141
The title compound was prepared by the same procedure for the preparation of the compound of example 85 except that 2- (5-amino-2- (1H-1,2, 4-triazol-1-yl) phenyl) propan-2-ol was used instead of 2- (4-aminopyridin-2-yl) propan-2-ol. LC-MS M/z 500.1[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ9.36(s,1H),8.66(s,1H),8.14(s,1H),8.07(d,J＝5.8Hz,1H),8.02(dd,J＝8.6,2.5Hz,1H),7.85(d,J＝2.7Hz,2H),7.06(d,J＝8.5Hz,1H),6.52(dd,J＝5.8,2.2Hz,1H),6.39(d,J＝2.1Hz,1H),5.11(s,1H),3.77(d,J＝8.2Hz,2H),3.67(dq,J＝7.4,3.7Hz,1H),3.61(d,J＝7.9Hz,2H),1.88(d,J＝8.0Hz,2H),1.64(t,J＝7.8Hz,1H),1.17(s,6H),1.03(m,2H),0.97–0.92(m,2H)。
Example 872- (6-cyclopropyl-2- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyrimidin-4-yl) propan-2-ol
Figure BDA0002280414000001142
Step preparation of methyl 12-chloro-6-cyclopropylpyrimidine-4-carboxylate
Figure BDA0002280414000001143
Methyl 2, 6-dichloropyrimidine-4-carboxylate (1.5g,7.24mmol) and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (0.53g,0.724mmol), cyclopropylboronic acid (0622g,7.24mmol) and potassium phosphate (3.84g,18.1mmol) were placed in a reaction flask, 25mL tetrahydrofuran solution was added, nitrogen blanketed, and stirred at 80 ℃ overnight. After the reaction is finished, filtering, concentrating the filtrate, and carrying out column chromatography to obtain the title compound. LC-MS M/z 213.1[ M + H ]]+。
Step 22- (2-chloro-6-cyclopropylpyrimidin-4-yl) propan-2-ol preparation
Figure BDA0002280414000001151
Methyl 2-chloro-6-cyclopropylpyrimidine-4-carboxylate (600mg,3.45mmol) was weighed out and dissolved in 20mL of anhydrous tetrahydrofuran and added dropwise to a solution of methylmagnesium bromide (1.5mL,3.0M) in anhydrous tetrahydrofuran (20mL) at-78 ℃ under an argon atmosphere. The reaction was stirred for 20min with the temperature maintained. Adding saturated ammonium chloride solution and ethyl acetate, extracting to obtain an organic phase, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and purifying by column chromatography to obtain the title compound. LC-MSm/z 213.2[ M + H ]]+。
Step 32- (6-cyclopropyl-2- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyrimidin-4-yl) propan-2-ol
Figure BDA0002280414000001152
The procedure is similar to the one used for the preparation of the compound of example 53, except that 2- (2-chloro-6-cyclopropylpyrimidin-4-yl) propan-2-ol is used instead of 2- (6-bromoisoquinolin-3-yl) propan-2-ol, and the title compound is obtained. LC-MS M/z 477.1[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ9.46(s,1H),8.16(d,J＝5.7Hz,1H),7.91(d,J＝2.3Hz,1H),7.86(s,1H),7.08(s,1H),6.66(dd,J＝5.7,2.3Hz,1H),5.23(s,1H),3.80-3.84(m,2H),3.57-3.68(m,1H),3.25-3.31(m,2H),2.67-2.75(m,1H),1.96-2.02(m,1H),1.62-1.68(m,4H),1.27(s,6H),1.02-1.06(m,2H),0.97-1.01(m,2H),0.91-0.95(m,2H),0.86-0.88(m,2H)。
Example 882- (2- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) oxazol-5-yl) propan-2-ol
Figure BDA0002280414000001153
Step Synthesis of Ethyl 12- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) oxazole-5-carboxylate
Figure BDA0002280414000001161
Preparation the title compound was obtained by the same method as the preparation of the compound of example 2, step 3, except that 2-aminooxazole-5-carboxylic acid ethyl ester was used instead of 2-morpholinopyridin-4-amine. LC-MS M/z 440.2[ M + H ]]+。
Step Synthesis of 22- (2- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) oxazol-5-yl) propan-2-ol
Figure BDA0002280414000001162
Methyl magnesium bromide (3M,0.75mL) was placed in a 50mL three-necked flask under argon atmosphere, the temperature was reduced to 0 ℃, a solution (10mL) of ethyl 2- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) oxazole-5-carboxylate (245mg,0.56mmol) in anhydrous tetrahydrofuran was added dropwise, and the mixture was reacted at 0 ℃ for 0.5H and then at room temperature for 48H. After the reaction is finished, adding saturated ammonium chloride solution for quenching, adding saturated saline solution and ethyl acetate, extracting, decompressing and concentrating an organic phase, and purifying by column chromatography to obtain a target product. LC-MS M/z 426.1[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ10.64(s,1H),8.09(m,1H),7.82(s,1H),7.64(s,1H),6.67(s,1H),6.50-6.52(m,1H),5.16(s,1H),3.80-3.82(m,2H),3.63-3.67(m,1H),3.26-3.30(m,2H),2.70-2.74(m,1H),1.63-1.66(m,4H),1.41(s,6H),1.00-1.03(m,2H),0.94-0.97(m,2H)。
Example 892- (4- (4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -1H-pyrazol-1-yl) pyridin-2-yl) propan-2-ol
Figure BDA0002280414000001163
Step 14 Synthesis of methyl- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) picolinate
Figure BDA0002280414000001164
Taking methyl 4-bromopicolinate (1g,9.3mmol), pinacol diboron (2.9g,23.26mmol) and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (0.34g,0.93mmol) and potassium acetate (1.14g,23.26mmol) were sequentially added to a reaction flask containing 1, 4-dioxane (30mL), reacted at 100 ℃ overnight, filtered, washed with saturated sodium chloride solution, ethyl acetate was added, the organic phase was extracted, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound. LC-MS M/z 264.3[ M + H ]]+。
Step 24- (4-nitro-1H-pyrazol-1-yl) methyl picolinate synthesis
Figure BDA0002280414000001171
2,2' -bipyridine (1.56g,10mmol), copper acetate (1.8g,10mmol), methyl 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) picolinate (2.4g,9.13mmol), sodium carbonate (1.94g,18.26mmol) and 4-nitropyrazole (1g,9.13mmol) were placed in a reaction flask, 30mL of 1, 2-dichloroethane were added, and the reaction was stirred at 75 ℃ for 24h under an oxygen atmosphere. Cooling to room temperature, adding saturated saline and dichloromethane, extracting, concentrating the filtrate, and purifying by column chromatography to obtain the title compound. LC-MS M/z 249.1[ M + H ]]+。
Step 34 Synthesis of methyl 4-amino-1H-pyrazol-1-yl) picolinate
Figure BDA0002280414000001172
Methyl 4- (4-nitro-1H-pyrazol-1-yl) picolinate (0.24g,3.16mmol) was dissolved in 50mL of methanol, and 10% palladium was addedCarbon (0.1g), hydrogen displaced, heated at 30 ℃ and stirred for 2h, filtered to give a filtrate, which was concentrated under reduced pressure to give the title compound. LC-MS M/z 219.3[ M + H ]]+。
Step Synthesis of 44- (4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -1H-pyrazol-1-yl) picolinic acid
Figure BDA0002280414000001173
2-chloro-4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine, methyl 4- (4-amino-1H-pyrazol-1-yl) picolinate (200mg,0.92mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (106mg,0.184mmol), cesium carbonate (599mg,1.84mmol), tris (dibenzylideneacetone) dipalladium (84mg,0.092mmol), and 1, 4-dioxane (25mL) were placed in a 100mL reaction flask, heated to 100 ℃ under an argon atmosphere, and reacted overnight. The reaction solution was cooled to room temperature, and saturated brine and dichloromethane were added to extract, concentrate the organic phase, and purify by column chromatography to give the title compound. LC-MS M/z 486.2[ M-H ]]-。
Synthesis of step 54- (4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -1H-pyrazol-1-yl) picolinic acid ethyl ester
Figure BDA0002280414000001181
4- (4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -1H-pyrazol-1-yl) picolinic acid (200mg,0.41mmol) was dissolved in ethanol (20mL), 13 drops of concentrated sulfuric acid were added, and the reaction was refluxed at 80 ℃ overnight. Adjusting pH to alkalescence with saturated potassium carbonate solution, concentrating to remove methanol, adding saturated sodium chloride solution and ethyl acetate, extracting, mixing organic layers, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain the title compound. LC-MSm/z 516.2[ M + H]+。
Synthesis of step 62- (4- (4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -1H-pyrazol-1-yl) pyridin-2-yl) propan-2-ol
Figure BDA0002280414000001182
Under argon atmosphere, a solution of ethyl 4- (4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -1H-pyrazol-1-yl) picolinate (200mg,0.37mmol) in anhydrous tetrahydrofuran (5mL) was added dropwise to a solution of methyl magnesium bromide (1mL,3.0M) in anhydrous tetrahydrofuran (20mL) at 0 ℃. After stirring and reacting at 0 ℃ for 1h, reacting at room temperature for 2 h. Adding saturated ammonium chloride solution and ethyl acetate, extracting, drying the organic phase by anhydrous sodium sulfate, decompressing, concentrating and purifying by column chromatography to obtain the title compound. LC-MS M/z 502.1[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ9.22(s,1H),8.73(s,1H),8.50(d,J＝5.5Hz,1H),8.11(d,J＝5.9Hz,1H),8.01(d,J＝2.0Hz,1H),7.87(s,1H),7.80(s,1H),7.61(dd,J＝5.5,2.2Hz,1H),6.44(dd,J＝5.9,2.2Hz,1H),6.19(d,J＝2.1Hz,1H),5.39(s,1H),3.85-3.81(m,2H),3.69-3.64(m,1H),3.33-3.25(m,2H),2.77-2.69(m,1H),1.69-1.64(m,4H),1.47(s,6H),1.07-1.01(m,2H),0.97-0.94(m,2H)。
Example 903- (1-cyclopropyl-4- ((2- ((1- (2-hydroxy-2-methylpropyl) -1H-pyrazol-4-yl) amino) pyridin-4-yl) oxy) -1H-pyrazol-3-yl) benzonitrile
Figure BDA0002280414000001191
Step 13 preparation of- (4- ((2-chloropyridin-4-yl) oxy) -1-cyclopropyl-1H-pyrazol-3-yl) benzonitrile
Figure BDA0002280414000001192
The title compound was prepared by the same method as that of the compound of example 3, steps 1 to 3, except that 3- (2-bromoacetyl) benzonitrile was used instead of 2-bromo-1-phenyleth-1-one. LC-MS M/z 337.3[ M + H ]]+。
Step 23- (1-cyclopropyl-4- ((2- ((1- (2-hydroxy-2-methylpropyl) -1H-pyrazol-4-yl) amino) pyridin-4-yl) oxy) -1H-pyrazol-3-yl) benzonitrile preparation
Figure BDA0002280414000001193
3- (4- ((2-chloropyridin-4-yl) oxy) -1-cyclopropyl-1H-pyrazol-3-yl) benzonitrile (250mg,0.564mmol), 1- (4-amino-1H-pyrazol-1-yl) -2-methylpropan-2-ol (87mg,0.564mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (65mg,0.1129mmol), cesium carbonate (368mg,1.129mmol), tris (dibenzylideneacetone) dipalladium (52mg,0.0564mmol), and 1, 4-dioxane (25mL) were placed in a 100mL reaction flask, heated to 100 ℃ under an argon atmosphere, and reacted overnight. Cooling to room temperature, adding saturated saline and dichloromethane, extracting, taking an organic phase, concentrating, and purifying by column chromatography to obtain the title compound. LC-MS M/z 456.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ8.76(s,1H),8.15(s,1H),8.04-7.98(m,2H),7.97(s,1H),7.89(s,1H),7.75(d,J＝7.7Hz,1H),7.60(t,J＝7.8Hz,1H),7.34(s,1H),6.42(dd,J＝5.8,2.1Hz,1H),6.13(d,J＝2.1Hz,1H),4.64(s,1H),3.94(s,2H),3.83-3.89(m,1H),1.23-1.14(m,2H),1.08-1.04(m,2H),1.04(s,6H)。
Example 913- (1-cyclopropyl-4- ((2- ((2- (3-hydroxyoxetan-3-yl) pyridin-4-yl) amino) pyridin-4-yl) oxy) -1H-pyrazol-3-yl) benzonitrile
Figure BDA0002280414000001194
The title compound was prepared by the same method as the preparation of the compound of example 90, except that 3- (4-aminopyridin-2-yl) oxetan-3-ol was used instead of 1- (4-amino-1H-pyrazol-1-yl) -2-methylpropan-2-ol. LC-MSm/z 467.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ9.55(s,1H),8.33(d,J＝5.6Hz,1H),8.18(d,J＝5.8Hz,2H),8.02(s,1H),7.98(d,J＝5.6Hz,1H),7.76(d,2H),7.70(d,J＝5.2Hz,1H),7.60(t,1H),6.70(dd,J＝5.8,2.2Hz,1H),6.44(d,J＝2.1Hz,2H),4.88(d,J＝5.6Hz,2H),4.61(d,J＝5.6Hz,2H),3.83-3.89(m,1H),1.18-1.21(m,2H),1.08-1.03(m,2H)。
Example 922-chloro-5- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) benzenesulfonamide
Figure BDA0002280414000001201
Step Synthesis of 15-amino-2-chlorobenzenesulfonamide
Figure BDA0002280414000001202
2-chloro-5-nitrobenzenesulfonamide (0.71g,3mmol) was placed in a reaction flask, 30mL of ethyl acetate was added thereto, and 10% palladium on carbon (60mg) was added thereto at room temperature to react for 4 hours at room temperature. After completion of the reaction, filtration was carried out, and the filtrate was concentrated under reduced pressure to give the title compound. LC-MS M/z 207.0[ M + H ]]+。
Step Synthesis of 22-chloro-5- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) benzenesulfonamide
Figure BDA0002280414000001203
The title compound was prepared by the same procedure as the compound of example 2, step 3, except that 2-chloro-5-aminobenzenesulfonamide was used instead of 2-morpholinopyridin-4-amine. LC-MS M/z 490.0[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ9.50(s,1H),8.31(d,J＝2.6Hz,1H),8.08(d,J＝5.8Hz,1H),8.02(dd,J＝8.8,2.6Hz,1H),7.88(s,1H),7.52(s,2H),7.47(d,J＝8.8Hz,1H),6.55(dd,J＝5.8,2.1Hz,1H),6.29(d,J＝2.0Hz,1H),3.85(dd,J＝8.3,2.8Hz,2H),3.69-3.65(m,1H),3.33-3.29(m,2H),2.76-2.68(m,1H),1.68-1.63(m,4H),1.07-1.01(m,2H),0.99-0.93(m,2H)。
Example 931- ((4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -2-methylpropan-2-ol
Figure BDA0002280414000001211
Step 12 preparation of- ((2-hydroxy-2-methylpropyl) amino) -4-nitropyridine-1-oxide
Figure BDA0002280414000001212
2-chloro-4-nitropyridine-1-oxide (0.2g,1.15mmol) was dissolved in acetonitrile (20mL) in a 50mL single-neck flask and 1-amino-2-methyl-2-propanol hydrochloride (0.12g,1.26mmol) and carbonic acid (1.12g,3.44mmol) were added. The reflux reaction is carried out for 4.5h at 90 ℃ under the protection of nitrogen. After the reaction is finished, adding water and ethyl acetate, extracting, combining organic phases, washing the organic phases with saturated saline solution, drying the organic phases with anhydrous sodium sulfate, concentrating under reduced pressure, and purifying by column chromatography to obtain the title compound. LC-MS M/z 228.1[ M + H ]]+。
Step 21 preparation of- ((4-aminopyridin-2-yl) amino) -2-methylpropan-2-ol
Figure BDA0002280414000001213
2- ((2-hydroxy-2-methylpropane) amino) -4-nitropyridine-1-oxide (0.21g,0.92mmol) was dissolved in methanol (20mL) and placed in a 50mL two-necked flask, and 40mg of palladium on carbon (10%) was added and the reaction stirred under hydrogen atmosphere for 2 h. After the reaction is finished, filtering to obtain filtrate, concentrating under reduced pressure, and purifying by column chromatography to obtain the title compound. LC-MS M/z 182.1[ M + H ]]+。
And step 3: preparation of 1- ((4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -2-methylpropan-2-ol
Figure BDA0002280414000001214
Preparation the title compound was prepared as in example 2, step 3, except that 1- ((4-aminopyridin-2-yl) amino) -2-methyl-2-propanol was used instead of 2-morpholinopyridin-4-amine. LC-MSm/z 465.3[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ9.30(s,1H),8.11(d,J＝5.9Hz,1H),7.88(s,1H),7.67(d,J＝6.0Hz,1H),7.19(d,J＝1.9Hz,1H),6.63(dd,J＝6.0,1.9Hz,1H),6.57(dd,J＝5.8,2.3Hz,1H),6.52(s,1H),6.36(d,J＝2.3Hz,1H),3.83(dt,J＝11.2,3.4Hz,2H),3.69-3.67(m,1H),3.32-3.31(m,2H),3.18(d,J＝5.8Hz,2H),2.75-2.72(m,1H),2.52(s,1H),1.65-1.63(m,4H),1.11(s,6H),1.08-1.00(m,2H),0.98-0.91(m,2H)。
Example 941- (4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) -3-methylazetidin-3-ol
Figure BDA0002280414000001221
Step preparation of 12- (3-hydroxy-3-methylazetidin-1-yl) -4-nitropyridine-1-oxide
Figure BDA0002280414000001222
2-chloro-4-nitropyridine-N-oxide (0.2g,1.14mmol) was dissolved in 5mL of acetonitrile solution, and then 3-methylazetidin-3-ol hydrochloride (0.35g,2.8mmol) and cesium carbonate (1.3g,3.99mmol) were added to the reaction system, followed by stirring under reflux for 1 h. After the reaction was complete, it was cooled to room temperature. Suction filtration, washing the filter cake with acetonitrile, collecting the filtrate, and concentrating under reduced pressure to obtain the title compound. LC-MS M/z 226.1[ M + H ]]+。
Step synthesis of 21- (4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) -3-methylazetidin-3-ol
Figure BDA0002280414000001223
The procedure is as in example 93, step 2-3 except that 2- (3-hydroxy-3-methylazetidin-1-yl) -4-nitropyridine-1-oxide is used instead of 2- ((2-hydroxy-2-methylpropyl) amino) -4-nitropyridine-1-oxide, to give the title compound. LC-MS M/z 463.2[ M + H ]]+。1H NMR(400MHz,CDCl3)δ8.08(d,J＝5.9Hz,1H),7.83(d,J＝6.0Hz,1H),7.32(s,1H),6.65-6.55(m,3H),6.50(dd,J＝5.8,2.1Hz,1H),4.02-3.93(m,6H),3.59-3.53(m,1H),3.45-3.38(m,2H),2.83-2.77(m,1H),1.90-1.84(m,2H),1.75-1.71(m,2H),1.29(s,3H),1.15-1.08(m,1H),1.03-1.01(m,1H),0.90-0.86(m,2H)。
Example 951- (4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) -3- (trifluoromethyl) azetidin-3-ol
Figure BDA0002280414000001231
The procedure is as in example 94, step 1-2 except that 3-trifluoromethyl-3-acridine alkoxide is used instead of 3-methylazetidine-3-alkoxide to give the title compound. LC-MSm/z 517.2[ M + H]+。1H NMR(400MHz,DMSO)δ9.37(s,1H),8.11(d,J＝5.8Hz,1H),7.94-7.80(m,2H),7.29(s,1H),6.98-6.84(m,2H),6.58(dd,J＝5.8,2.2Hz,1H),6.33(d,J＝2.1Hz,1H),4.14(d,J＝9.4Hz,2H),3.89(d,J＝9.3Hz,2H),3.82(dd,J＝8.1,3.0Hz,2H),3.62-3.66(m,1H),3.33-3.25(m,2H),2.70(dd,J＝15.9,6.8Hz,1H),1.73-1.57(m,4H),1.07-0.90(m,4H)。
Example 964- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) -N- (2- (3, 3-difluoroazetidinyl-1-yl) pyridin-4-yl) pyridin-2-amine
Figure BDA0002280414000001232
The procedure is as in example 94, step 1-2 except that 3, 3-difluorotrimethylene imine hydrochloride is used in place of 3-methylazetidine-3-ol hydrochloride, to give the title compound. LC-MSm/z 469.2[ M + H ]]+。1HNMR(400MHz,DMSO-d6)δ9.39(s,1H),8.11(d,J＝5.8Hz,1H),7.87(d,J＝6.4Hz,2H),7.01(d,J＝5.8Hz,1H),6.92(s,1H),6.57(d,J＝5.8Hz,1H),6.34(d,J＝1.9Hz,1H),4.30(t,J＝12.4Hz,4H),4.08-3.97(m,1H),3.84(t,J＝14.2Hz,2H),3.70-3.62(m,1H),3.30-3.25(m,1H),2.79-2.61(m,1H),1.69-1.60(m,4H),0.93-0.99(m,4H)。
Example 974- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) -N- (2- (3,3,4, 4-tetrafluoropyrrolidin-1-yl) pyridin-4-yl) pyridin-2-amino
Figure BDA0002280414000001241
The procedure is as in example 94, step 1-2 except that 3,3,4, 4-tetrafluoropyrrolidine hydrochloride is used instead of 3-methylazetidine-3-ol hydrochloride to give the title compound. LC-MSm/z 519.2[ M + H ]]+。1HNMR(400MHz,DMSO-d6)δ9.43(s,1H),8.14(d,J＝5.8Hz,1H),7.95-7.80(m,2H),7.16-6.92(m,2H),6.59(dd,J＝5.8,2.2Hz,1H),6.36(d,J＝2.3Hz,1H),4.02-4.07(m,4H),3.83(dt,J＝11.0,3.1Hz,2H),3.71-3.58(m,1H),3.31(dd,J＝11.4,8.2,5.6Hz,2H),2.88-2.61(m,1H),1.65-1.67(m,4H),1.13-0.99(m,2H),0.95(m,2H)。
Example 981- (4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) cyclopropyl-1-carbonitrile
Figure BDA0002280414000001242
Step 11- (4-Bromopyridin-2-yl) cyclopropyl-1-carbonitrile preparation
Figure BDA0002280414000001243
4-bromo-2-fluoropyridine (0.5g,2.84mmol) was dissolved in 20mL of anhydrous tetrahydrofuran and placed in a 100mL single-neck flask, lithium hexamethyldisilazide (6.77mL,8.81mmol) was added, and the reaction was stirred at-40 ℃ for 1h under nitrogen. Cyclopropanecarbonitrile (0.57g,8.52mmol) was further added to the above system, and the reaction was continued for 1.5 h. After the reaction was completed, the solution was quenched with saturated ammonium chloride solution. Adding water and ethyl acetate, extracting, combining organic phases, washing the organic phases with saturated saline solution, drying the organic phases with anhydrous sodium sulfate, concentrating under reduced pressure, and purifying by column chromatography to obtain the title compound.LC-MS m/z:223.0,225.0[M+H]+。
Step 21- (4-Aminopyridin-2-yl) cyclopropyl-1-carbonitrile hydrochloride preparation
Figure BDA0002280414000001251
1- (4-bromopyridin-2-yl) cyclopropyl-1-carbonitrile (0.46g,2.06mmol), tert-butyl carbamate (0.293g,2.50mmol), palladium acetate (46.76mg,0.21mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (0.24g,0.42mmol) and cesium carbonate (1.36g,4.17mmol) were placed in a 250mL two-necked flask, 120mL of 1, 4-dioxane were added, and the reaction was stirred at 100 ℃ under nitrogen for 2 h. After the reaction is finished, adding water and ethyl acetate, extracting, combining organic phases, washing the organic phases with saturated saline solution, drying the organic phases with anhydrous sodium sulfate, decompressing and concentrating, and carrying out column chromatography separation to obtain the (2- (1-cyanocyclopropyl) pyridin-4-yl) carbamic acid tert-butyl ester. The intermediate compound was dissolved in hydrochloric acid/methanol solution (50mL,3M), the reaction was continued for 2.5h, the reaction was complete, and concentrated under reduced pressure to give the title compound. LC-MS M/z 160.1[ M-HCl + H]+。
Step 31- (4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) cyclopropyl-1-carbonitrile
Figure BDA0002280414000001252
Preparation the title compound was prepared as in example 2, step 3, except that 1- (4-aminopyridin-2-yl) cyclopropyl-1-carbonitrile hydrochloride was used instead of 2-morpholinopyridin-4-amine. LC-MSm/z 443.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ9.78(s,1H),8.18(dd,J＝17.0,5.8Hz,2H),7.88(d,J＝5.6Hz,2H),7.75(d,J＝5.8Hz,1H),6.65(dd,J＝5.8,2.3Hz,1H),6.38(d,J＝2.3Hz,1H),3.83(dt,J＝11.4,3.5Hz,2H),3.68(dt,J＝7.5,3.6Hz,1H),3.32-3.25(m,2H),2.79-2.66(m,1H),1.76-1.60(m,8H),1.05(q,J＝4.4Hz,2H),0.96(td,J＝7.2,4.6Hz,2H)。
Example 991- (4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) -1, 1-difluoro-2-methylpropan-2-ol
Figure BDA0002280414000001261
Step preparation of Ethyl 12- (4-bromopyridin-2-yl) -2, 2-difluoroacetate
Figure BDA0002280414000001262
2, 4-dibromopyridine (1g,4.22mmol) and copper powder (1.07g,16.88mmol) were weighed into a reaction flask, 14mL of dimethyl sulfoxide was added, ethyl 2-bromo-2, 2-difluoroacetate (1.71g,8.44mmol) was added, and the reaction was allowed to proceed at room temperature overnight. After the reaction, water and ethyl acetate were added, extraction was performed, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give the title compound. LC-MS M/z 280.05,282.05[ M + H ]]+。
Step preparation of 21- (4-bromopyridin-2-yl) -1, 1-difluoro-2-methylpropan-2-ol
Figure BDA0002280414000001263
Ethyl 2- (4-bromopyridin-2-yl) -2, 2-difluoroacetate (1.36g,4.86mmol) was dissolved in 20mL of tetrahydrofuran, replaced with argon, and a methylmagnesium bromide/diethyl ether solution (3M,4.2mL,12.15mmol) was slowly added dropwise to the reaction in an ice bath, after which the temperature of the reaction was slowly raised to room temperature and the reaction was stirred for 1 h. And after the reaction is finished, adding water and ethyl acetate into the reaction system, extracting, drying an organic phase by using anhydrous sodium sulfate, concentrating under reduced pressure, and purifying by using column chromatography to obtain the title compound. LC-MS M/z 266.1,268.1[ M + H ]]+。
Step 3 preparation of tert-butyl (2- (1, 1-difluoro-2-hydroxy-2-methylpropyl) pyridin-4-yl) carbamate
Figure BDA0002280414000001264
1- (4-bromopyridin-2-yl) -1, 1-difluoro-2-methylpropan-2-ol (1g,3.77mmol), tert-butyl carbamate (531mg,4.53mmol), sodium tert-butoxide (508mg,5.28mmol), 2-dicyclohexylphosphonium-2 ',4',6' -triisopropylbiphenyl (144mg,0.30mmol) and tris (dibenzylideneacetone) dipalladium (0) (70mg,0.076mmol) were placed in a reaction flask, 5mL of tert-butanol was added, argon was replaced, and the reaction was refluxed at 100 ℃ for 2 hours. After the reaction, the reaction mixture was cooled to room temperature, water and ethyl acetate were added to the reaction system, followed by extraction, drying of the organic phase with anhydrous sodium sulfate, concentration under reduced pressure, and purification by column amine chromatography to give the title compound. LC-MS M/z 303.1[ M + H ]]+。
Step preparation of 42- (1, 1-difluoro-2-hydroxy-2-methylpropyl) pyridin-4-amine-2, 2, 2-trifluoroacetate salt
Figure BDA0002280414000001271
Tert-butyl (2- (1, 1-difluoro-2-hydroxy-2-methylpropyl) pyridin-4-yl) carbamate (706mg,2.34mmol) was dissolved in 10mL of a mixed solution of dichloromethane/trifluoroacetic acid (2:1), the reaction was stirred at room temperature for 2h, the reaction was complete, and concentrated under reduced pressure to give the title compound.
And 5: preparation of 1- (4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) -1, 1-difluoro-2-methylpropan-2-ol
Figure BDA0002280414000001272
The procedure was the same as that for the preparation of the compound of step 3 in example 2, except that: 2- (1, 1-difluoro-2-hydroxy-2-methylpropyl) pyridin-4-amine-2, 2, 2-trifluoroacetate salt instead of 2-morpholinopyridin-4-amine, the title compound was prepared. LC-MS M/z 486.2[ M + H ]]+。1H NMR(400MHz,CDCl3)δ8.36(d,J＝5.7Hz,1H),8.20(d,J＝5.8Hz,1H),7.71-7.59(m,2H),7.33(s,1H),6.59(dd,J＝5.8,2.0Hz,1H),6.42(d,J＝1.8Hz,1H),3.99-3.95(m,2H),3.57-3.52(m,1H),3.49-3.36(m,2H),2.84-2.77(m,1H),1.94-1.82(m,2H),1.78-1.70(m,2H),1.33(s,6H),1.13-1.06(m,2H),1.05-0.99(m,2H)。
Example 1001- (4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) cyclopropane-1-carboxamide
Figure BDA0002280414000001273
The title compound 1- (4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) cyclopropyl-1-carbonitrile (0.1g,0.448mmol) from example 98 was dissolved in 2mL methanol, followed by addition of indium chloride (0.06g,0.268mmol), replacement with argon and stirring at 65 ℃ for 5H. After the reaction is finished, concentrating the reaction solution, and purifying by column chromatography to obtain the compound. LC-MS M/z 461.2[ M + H ]]+。1HNMR(400MHz,DMSO-d6)δ9.74(s,1H),8.23(d,J＝5.8Hz,1H),8.16(d,J＝5.8Hz,1H),7.88(s,1H),7.71(s,1H),7.59(s,1H),7.29(s,1H),7.16(s,1H),6.62(dd,J＝5.7,1.8Hz,1H),6.41(s,1H),3.90-3.77(m,2H),3.69-3.67(m,1H),3.33-3.30(m,2H),2.76-2.65(m,1H),1.76-1.53(m,4H),1.13(d,J＝2.8Hz,2H),1.04(dt,J＝7.7,4.0Hz,2H),0.98-0.80(m,4H)。
Example 1013 preparation of- (4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) -1- (2,2, 2-trifluoroethyl) azetidin-3-ol
Figure BDA0002280414000001281
Step 13 preparation of tert-butyl 4-bromopyridin-2-yl-3-hydroxyazetidine-1-carboxylate
Figure BDA0002280414000001282
In a 100mL single neck flask 2, 4-dibromopyridine (0.5g,2.11mmol) was dissolved in 20mL anhydrous tetrahydrofuran, isopropyl magnesium bromide (1.95mL,2.53mmol) was added and the reaction stirred at-10 ℃ for 1h under nitrogen. Tert-butyl 3-oxoazetidine-1-carboxylate (0.43g,2.53mmol) was dissolved in 10mL of anhydrous tetrahydrofuran and added to the system and the reaction was continued for 1.5 h. Inverse directionAfter the reaction was completed, the saturated ammonium chloride solution was quenched. Adding water and ethyl acetate, extracting, combining organic phases, washing the organic phases with saturated saline solution, drying the organic phases with anhydrous sodium sulfate, concentrating under reduced pressure, and purifying by column chromatography to obtain the title compound. LC-MS M/z 329.0,331.0[ M + H ]]+。
Step 23 preparation of- (4-bromopyridin-2-yl) -1- (2,2, 2-trifluoroethyl) azetidin-3-ol
Figure BDA0002280414000001283
3- (4-Bromopyridin-2-yl) -3-hydroxyazetidine-1-carboxylic acid tert-butyl ester was dissolved in methanol hydrochloride solution (50mL,3M) and stirred for 2.5 h. After the reaction was complete, the solvent was removed by concentration to give a white solid. The above solid was dissolved in 25mL of anhydrous tetrahydrofuran, triethylamine (0.65mL,4.71mmol) and trifluoroethyl trifluoromethanesulfonate (0.44g,1.57mmol) were added, and the reaction was stirred at room temperature for 2 h. After the reaction is finished, adding water and ethyl acetate, extracting, combining organic phases, washing the organic phases with saturated saline solution, drying the organic phases with anhydrous sodium sulfate, concentrating under reduced pressure, and purifying by column chromatography to obtain the title compound. LC-MS M/z 311.0,313.0[ M + H ]]+。
Step 33 preparation of 4-aminopyridin-2-yl-1- (2,2, 2-trifluoroethyl) azetidin-3-ol hydrochloride
Figure BDA0002280414000001291
3- (4-Bromopyridin-2-yl) -1- (2,2, 2-trifluoroethyl) azetidin-3-ol (0.32g,2.06mmol), tert-butyl carbamate (0.293g,2.50mmol), palladium acetate (46.76mg,0.21mmol), 4, 5-bis diphenylphosphine-9, 9-dimethylxanthene (0.24g,0.42mmol) and cesium carbonate (1.36g,4.17mmol) were placed in a 250mL two-necked flask and 120mL of 1, 4-dioxane were added and reacted at 100 ℃ for 2h under nitrogen. After the reaction, water and ethyl acetate are added for extraction, organic phases are combined, washed by saturated saline solution, dried by anhydrous sodium sulfate, concentrated under reduced pressure and purified by column chromatography. Dissolving the purified product in hydrochloric acid methanol solution (50mL,3M), stirring for 2.5h, reacting completely, and concentrating under reduced pressure to obtainThe title compound. LC-MS M/z 248.1[ M-HCl + H]+。
And 4, step 4: preparation of 3- (4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) -1- (2,2, 2-trifluoroethyl) azetidin-3-ol
Figure BDA0002280414000001292
The title compound was prepared by the same procedure as the preparation of the compound in step 3 of example 2, except that 3- (4-aminopyridin-2-yl) -1- (2,2, 2-trifluoroethyl) azetidin-3-ol hydrochloride was used instead of 2-morpholinopyridin-4-amine. LC-MS M/z 531.2[ M + H ]]+。1H NMR(400MHz,CDCl3)δ8.13(s,1H),8.02(s,1H),7.73(s,1H),7.59(s,1H),7.41(d,J＝13.0Hz,2H),7.26(s,1H),6.59(s,1H),3.97(d,J＝10.8Hz,2H),3.78(s,2H),3.70(d,J＝6.1Hz,2H),3.58(s,1H),3.42(t,J＝11.6Hz,2H),3.17(dd,J＝17.6,8.6Hz,2H),2.96(d,J＝2.6Hz,1H),2.88(d,J＝2.4Hz,1H),1.88(dd,J＝24.0,11.9Hz,2H),1.75(d,J＝12.8Hz,2H),1.16(s,2H),1.02(d,J＝6.4Hz,2H)。
Example 1022- (1- (4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) cyclopropyl) propan-2-ol
Figure BDA0002280414000001293
Step 11- (4-Bromopyridin-2-yl) cyclopropyl-1-carbonitrile preparation
Figure BDA0002280414000001301
2-fluoro-4-bromopyridine (1g,5.68mmol) and cyclopropyl 1-carbonitrile (1.14g,17.04mmol) were dissolved in 20mL of anhydrous tetrahydrofuran solution, replaced with argon, lithium hexamethyldisilazide (17.6mL,18.1mmol) was added dropwise at-5 deg.C, followed by stirring at room temperature for 3.5 h. After the reaction is finished, adding water for quenching, adding ethyl acetate, extracting, drying the organic phase by anhydrous sodium sulfate, concentrating under reduced pressure,column chromatography purification afforded the title compound. LC-MS M/z 223.1,225.1[ M + H ]]+。
Step preparation of 21- (4-bromopyridin-2-yl) cyclopropane-1-carboxylic acid
Figure BDA0002280414000001302
1- (4-Bromopyridin-2-yl) cyclopropyl-1-carbonitrile (0.5g,2.24mmol) was dissolved in 5mL of ethanol solution, potassium hydroxide (0.5g,8.9mmol) was dissolved in 5mL of water and the above reaction system was added, and the reaction was stirred at 65 ℃ overnight. And adjusting the pH to 2-3 by using a 6M hydrochloric acid aqueous solution, adding ethyl acetate, extracting, drying by using anhydrous sodium sulfate, and concentrating under reduced pressure to obtain the title compound. LC-MS M/z 242.1,244.1[ M + H ]]+。
Step 31 preparation of methyl 4-bromopyridin-2-yl cyclopropane-1-carboxylate
Figure BDA0002280414000001303
Thionyl chloride (133mg,1.12mmol) was added dropwise to 5mL of methanol at-10 ℃ followed by 1- (4-bromopyridin-2-yl) cyclopropane-1-carboxylic acid (270mg,1.12mmol) and allowed to slowly warm to room temperature and stirred overnight. The reaction solution was neutralized with saturated aqueous sodium bicarbonate, ethyl acetate was added, extracted, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound. LC-MS M/z 256.1,258.1[ M + H ]]+。
Step 42- (1- (4-bromopyridin-2-yl) cyclopropyl) propan-2-ol preparation
Figure BDA0002280414000001304
Methyl 1- (4-bromopyridin-2-yl) cyclopropane-1-carboxylate (0.15g,0.6mmol) was dissolved in 5mL of anhydrous tetrahydrofuran solution, argon gas was replaced, methylmagnesium bromide (0.8mL,2.4mmol) was added dropwise to the reaction system at 0 ℃ and the temperature was maintained and stirred for 1.5 h. The reaction was quenched with aqueous ammonium chloride, ethyl acetate was added, extracted, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound. LC-MS M/z 256.2,258.2[ M + H ]]+。
Step 52 preparation of 1- (4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) cyclopropyl) propan-2-ol
Figure BDA0002280414000001311
The title compound was prepared similar to the preparation of the compound of step 2 of example 53, except that 2- (1- (4-bromopyridin-2-yl) cyclopropyl) propan-2-ol was used instead of 2- (6-bromoisoquinolin-3-yl) propan-2-ol. LC-MS M/z 476.3[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ9.58(s,1H),8.19(d,J＝5.8Hz,1H),8.14(d,J＝5.8Hz,1H),7.87(s,1H),7.69(s,1H),7.50(s,1H),6.65-6.55(m,1H),6.36(s,1H),5.76(s,1H),3.82(dd,J＝8.1,3.1Hz,2H),3.70-3.66(m,1H),3.28(dd,J＝12.9,5.8Hz,2H),2.75-2.66(m,1H),1.68-1.60(m,4H),1.07(s,6H),1.03(dd,J＝8.1,4.2Hz,4H),0.97-0.81(m,4H)。
Example 1034- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) -N- (2- (3-fluorooxetan-3-yl) pyridin-4-yl) pyridin-2-amine
Figure BDA0002280414000001312
Step 14 preparation of bromo-2- (3-fluorooxetan-3-yl) pyridine
Figure BDA0002280414000001313
3- (4-Bromopyridin-2-yl) oxetan-3-ol (100mg,0.435mmol) was dissolved in 5mL of tetrahydrofuran, and the reaction was stirred at-50 ℃ under nitrogen, and then diethylaminosulfur trifluoride (85mg,0.522mmol) was slowly dropped into the above reaction system, under which stirring was carried out for 1 hour. And returning to room temperature, adding water and ethyl acetate into the reaction system, extracting, drying an organic phase by using anhydrous sodium sulfate, concentrating, and purifying by column chromatography to obtain the title compound. LC-MS M/z 232.1,232.4[ M + H ]]+。
Step 24 preparation of- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) -N- (2- (3-fluorooxetan-3-yl) pyridin-4-yl) pyridin-2-amine
Figure BDA0002280414000001321
The title compound was prepared similar to the preparation of the compound of step 2 of example 53, except that 4-bromo-2- (3-fluoro-oxetan-3-yl) pyridine was used instead of 2- (6-bromoisoquinolin-3-yl) propan-2-ol. LC-MS M/z 452.2[ M + H ]]+。1H NMR(400MHz,CDCl3) δ 8.27(d, J ═ 5.3Hz,1H),8.11(d, J ═ 5.8Hz,1H),7.66(s,1H),7.33(s,1H),7.29(s,1H),7.08(d, J ═ 4.7Hz,1H),6.50(dd, J ═ 5.8,2.1Hz,1H),5.11(dd, J ═ 20.8,8.1Hz,2H),4.83(dd, J ═ 20.1,8.2Hz,2H),3.99-3.95(m,2H),3.64-3.52(m,1H),3.42(td, J ═ 11.7,1.9Hz,2H),2.87-2.79(m,1H),1.97-1.85(m, 1.7), 1.7 (m,2H),1.06 (m, 1.06), 1.06 (m, 1H). Example 1044- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) -N- (2- (2,2, 2-trifluoroethoxy) pyridin-4-yl) pyridin-2-amine
Figure BDA0002280414000001322
Step 14 preparation of bromo-2- (2,2, 2-trifluoroethoxy) pyridine
Figure BDA0002280414000001323
In a single-necked flask, 2, 4-dibromopyridine (1.0g,4.22mmol) was dissolved in dimethyl sulfoxide (15mL), and potassium hydroxide (1.18g,21.11mmol) and trifluoroethanol (2.11g,21.11mmol) were added. The reaction was stirred at 160 ℃ for 8 h. After the reaction is finished, adding water and ethyl acetate, extracting, combining organic phases, washing the organic phases with saturated saline solution, drying the organic phases with anhydrous sodium sulfate, filtering, concentrating the filtrate, and purifying by column chromatography to obtain the title compound. LC-MSm/z 256.0,258.0[ M + H ]]+。
Step 24 preparation of- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) -N- (2- (2,2, 2-trifluoroethoxy) pyridin-4-yl) pyridin-2-amine
Figure BDA0002280414000001324
The title compound was prepared similar to the preparation of the compound of step 2 of example 53, except that 4-bromo-2- (2,2, 2-trifluoroethoxy) pyridine was used instead of 2- (6-bromoisoquinolin-3-yl) propan-2-ol. LC-MSm/z 476.0[ M + H ]]+。1H NMR(400MHz,CDCl3)δ8.07(dd,J＝12.9,5.9Hz,2H),7.40-7.38(m,1H),7.32(s,1H),7.06(s,1H),6.55-6.46(m,2H),4.43(q,J＝8.0Hz,2H),4.02-3.90(m,2H),3.60-3.57(m,1H),3.42(td,J＝11.7,2.2Hz,2H),2.84-2.82(m,1H),1.86(dd,J＝12.1,4.2Hz,2H),1.75(d,J＝13.2Hz,2H),1.16-1.06(m,2H),1.04(dd,J＝7.4,5.3Hz,2H)。
Example 1051- (4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) -4, 4-difluorocyclohexyl-1-ol
Figure BDA0002280414000001331
Preparation the title compound was obtained by the same procedure as the preparation of the title compound in the step of example 43 except that 4, 4-difluorocyclohexanone was used instead of 3-oxetanone. LC-MS M/z 512.3[ M + H ]]+。1H NMR(400MHz,CDCl3)δ8.16(d,J＝5.3Hz,1H),8.08(d,J＝5.8Hz,1H),7.55(s,1H),7.40-7.30(m,2H),6.89(d,J＝5.4Hz,1H),6.49(dd,J＝5.9,2.1Hz,1H),3.96(dd,J＝11.5,2.4Hz,2H),3.61-3.56(m,1H),3.41(td,J＝11.7,2.0Hz,2H),2.85-2.82(m,1H),2.28(dd,J＝34.4,13.5Hz,2H),2.07(d,J＝16.5Hz,2H),1.97-1.63(m,8H),1.11(dd,J＝8.0,4.2Hz,2H),1.03(dd,J＝7.0,5.4Hz,2H)。
Example 1062- (4- ((4- ((1-cyclopropyl-3- (3, 3-difluorocyclobutane) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) propan-2-ol
Figure BDA0002280414000001332
The title compound was prepared by the same procedure for the preparation of the compound of example 79, except that 2- (4-aminopyridin-2-yl) propan-2-ol was used instead of 1- (4-aminopyridin-2-yl) -2,2, 2-trifluoroethyl-1-ol. LC-MS M/z 442.2[ M + H ]]+。1H NMR(400MHz,CDCl3)δ8.30(d,J＝5.4Hz,1H),8.16(d,J＝5.8Hz,1H),7.41-7.39(m,2H),7.36(s,1H),7.30(d,J＝4.9Hz,1H),6.50(dd,J＝5.8,2.1Hz,1H),6.45-6.44(m,1H),3.57-3.51(m,1H),3.18-3.13(m,1H),2.92-2.72(m,4H),1.52(s,6H),1.15-1.07(m,2H),1.07-0.98(m,2H)。
Example 1072- (4- ((4- ((1-cyclopropyl-3- (3, 3-difluorocyclobutyl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) -1,1, 1-trifluoropropan-2-ol
Figure BDA0002280414000001341
Step 11- (4-Bromopyridin-2-yl) -2,2, 2-trifluoroethyl-1-one preparation
Figure BDA0002280414000001342
Methyl 4-bromopyridine-2-carboxylate (0.5g,2.31mmol) was dissolved in 20mL of anhydrous tetrahydrofuran, and trifluoromethyl trimethylsilane (0.39g,2.78mmol) and cesium fluoride (0.42g,2.78mmol) were added and reacted at room temperature for 2h under nitrogen. After the reaction, water and ethyl acetate were added, extracted, and the organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give the title compound. LC-MS M/z 254.0,256.0[ M + H ]]+。
Step 22 preparation of- (4-bromopyridin-2-yl) -1,1, 1-trifluoropropan-2-ol
Figure BDA0002280414000001343
1- (4-Bromopyridin-2-yl) -2,2, 2-trifluoroethyl-1-one (0.42g,1.65mmol) was dissolved in 20mL of anhydrous tetrahydrofuran, and methyl magnesium bromide (0.83mL,3M,2.48mmol) was added and stirred at-10 ℃ under nitrogenAnd reacting for 2 h. After the reaction, quenching with saturated ammonium chloride solution, adding water and ethyl acetate, extracting, washing the organic phase with saturated saline solution, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and purifying by column chromatography to obtain the title compound. LC-MSm/z 270.0,272.0[ M + H ]]+。
Step preparation of 32- (4-Aminopyridin-2-yl) -1,1, 1-trifluoropropan-2-ol hydrochloride
Figure BDA0002280414000001344
2- (4-Bromopyridin-2-yl) -1,1, 1-trifluoropropan-2-ol (0.28g,1.05mmol), tert-butyl carbamate (0.15g,1.25mmol), palladium acetate (23.38mg,0.11mmol), 4, 5-bis diphenylphosphine-9, 9-dimethylxanthene (0.12g,0.21mmol) and cesium carbonate (0.68g,2.09mmol) were placed in a reaction flask, 60mL1, 4-dioxane was added and the reaction stirred at 100 ℃ for 2h under nitrogen. After the reaction, water and ethyl acetate were added, extraction was performed, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography. The purified product was dissolved in hydrochloric acid/methanol solution (50mL,3M), stirred for 2.5h to complete the reaction, and concentrated to remove the solvent to give the title compound. LC-MS M/z 207.0[ M-HCl + H]+。
Step preparation of 42- (4- ((4- ((1-cyclopropyl-3- (3, 3-difluorocyclobutyl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) -1,1, 1-trifluoropropan-2-ol
Figure BDA0002280414000001351
The title compound was obtained by following the procedure for the preparation of the compound of example 79 except that 2- (4-aminopyridin-2-yl) -1,1, 1-trifluoropropan-2-ol hydrochloride was used instead of 1- (4-aminopyridin-2-yl) -2,2, 2-trifluoroethyl-1-ol. LC-MS M/z 496.0[ M + H ]]+。1H NMR(400MHz,CDCl3)δ8.36(dd,J＝5.5,0.7Hz,1H),8.19(d,J＝5.8Hz,1H),7.55-7.48(m,2H),7.36(s,1H),6.76(s,1H),6.53(dd,J＝5.8,2.2Hz,1H),6.37(d,J＝2.2Hz,1H),3.56(tt,J＝7.3,3.8Hz,1H),3.16(m,1H),2.83(m,4H),1.69(d,J＝1.1Hz,3H),1.13(m,2H),1.09-1.01(m,2H)。
Example 1083- (4- ((4- ((1-cyclopropyl-3- (3, 3-difluorocyclobutyl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) -1- (2,2, 2-trifluoroethyl) azetidin-3-ol
Figure BDA0002280414000001352
The title compound was prepared by the same procedure for the preparation of the compound of example 79, except that 3- (4-aminopyridin-2-yl) -1- (2,2, 2-trifluoroethyl) azetidin-3-ol was used instead of 1- (4-aminopyridin-2-yl) -2,2, 2-trifluoroethyl-1-ol. LC-MS M/z 537.1[ M + H ]]+。1H NMR(400MHz,CDCl3)δ8.18(d,J＝5.3Hz,1H),8.06(d,J＝5.9Hz,1H),7.54(s,1H),7.49(d,J＝2.1Hz,1H),7.37(s,1H),7.20(d,J＝5.3Hz,1H),6.46(dd,J＝5.8,2.2Hz,1H),3.80(d,J＝8.1Hz,2H),3.64-3.52(m,3H),3.27-3.09(m,3H),2.83(m,5H),1.17-1.09(m,2H),1.04(q,J＝7.0Hz,2H)。
Example 1094- ((1-cyclopropyl-3- (3, 3-difluorocyclobutane) -1H-pyrazol-4-yl) oxy) -N- (2-morpholin-4-yl) pyridin-2-amine
Figure BDA0002280414000001361
The title compound was prepared by the same method as in example 79, except that 2-morpholinopyridin-4-amine was used in place of 3- (4-aminopyridin-2-yl) oxetan-3-ol hydrochloride. LC-MSm/z 469.2[ M + H ]]+。1H NMR(400MHz,CDCl3)δ8.15(d,J＝5.8Hz,1H),8.05(d,J＝5.7Hz,1H),7.37(s,1H),6.85(s,1H),6.78(s,1H),6.58(dd,J＝5.7,1.8Hz,1H),6.51-6.43(m,2H),3.93-3.77(m,4H),3.58(td,J＝11.1,7.3,3.8Hz,1H),3.54-3.44(m,4H),3.24-3.16(m,1H),2.94-2.77(m,4H),1.19-1.12(m,2H),1.11-1.03(m,2H)。
Example 1104- (1-cyclopropyl-4- ((2- ((2- (2-hydroxypropyl-2-yl) pyridin-4-yl) amino) pyridin-4-yl) oxy) -1H-pyrazol-3-yl) -1-methylcyclohex-1-ol
Figure BDA0002280414000001362
Step 14 preparation of Cyclohexanone-1-carboxylic acid
Figure BDA0002280414000001363
Dissolving 4-cyclohexanone ethyl formate (3.41g,20mmol) in 30mL of methanol solution, adding sodium hydroxide aqueous solution (10mL, 4M) into the system, reacting at 40 ℃ for 1h, slowly adding 3M HCl solution into the reaction system to ensure that the pH value of the reaction solution is 1-2, adding ethyl acetate, extracting, combining organic phases, drying by anhydrous sodium sulfate, and concentrating under reduced pressure to obtain the title compound. LC-MSm/z 141.1[ M-H ]]-。
Step 24 preparation of Cyclohexanone benzyl formate
Figure BDA0002280414000001364
4-Cyclohexanone-1-carboxylic acid (2.42g,17.04mmol) was dissolved in 30mL of N, N-dimethylformamide solution, potassium carbonate (1.51g,10.91mmol) was added, and benzyl bromide (2.4mL,20.45mmol) was added dropwise to the above reaction system, followed by reaction at room temperature for 4 hours. After the reaction, water and ethyl acetate were added to the system, extracted, the organic phase was concentrated, and purified by column chromatography to give the title compound.1H NMR(400MHz,CDCl3)δ7.46-7.29(m,5H),5.15(s,2H),2.86-2.75(m,1H),2.45(dt,J＝14.2,5.0Hz,2H),2.40-2.28(m,2H),2.27-2.23(m,2H),2.10-1.95(m,2H)。
Step 34 preparation of benzyl hydroxy-4-methylcyclohexyl-1-carboxylate
Figure BDA0002280414000001371
4-Cyclohexanone benzyl formate (3.0g,12.91mmol) was dissolved in 45mL of tetrahydrofuran solution and replaced with nitrogen, and methyl magnesium bromide/tetrahydrofuran solution (5.2mL,3M) was slowly added dropwise to the reaction system at-20 ℃ and the reaction was continued for 2 hours at this temperature after completion of the addition. And adding water and ethyl acetate into the reaction system, extracting, combining organic phases, drying by anhydrous sodium sulfate, concentrating, and purifying by column chromatography to obtain the title compound.
Step 44 preparation of hydroxy-4-methylcyclohexyl-1-carboxylic acid
Figure BDA0002280414000001372
Benzyl 4-hydroxy-4-methylcyclohexyl-1-carboxylate (704mg,2.83mmol) was dissolved in 10mL of methanol, palladium hydroxide/carbon (20mg,0.15mmol) was added, and the mixture was reacted at room temperature for 3 hours with hydrogen gas. After completion of the reaction, filtration was assisted with celite and the filtrate was concentrated under reduced pressure to give the title compound. LC-MS M/z 157.1[ M-H ]]-。
Step 54 preparation of- (1-cyclopropyl-4- ((2- ((2- (2-hydroxypropyl-2-yl) pyridin-4-yl) amino) pyridin-4-yl) oxy) -1H-pyrazol-3-yl) -1-methylcyclohexan-1-ol
Figure BDA0002280414000001373
The procedure is as in example 20, steps 1 to 3 except that 4-hydroxy-4-methylcyclohexyl-1-carboxylic acid is used instead of 4, 4-difluorocyclohexane-1-carboxylic acid and 2- (4-aminopyridin-2-yl) propan-2-ol instead of 2-morpholinopyridin-4-amine to give the title compound. LC-MS M/z 464.2[ M + H ]]+。1H NMR(400MHz,CDCl3)δ8.28(s,1H),8.14(d,J＝5.4Hz,1H),7.50(s,1H),7.40(s,1H),7.31(s,1H),6.56-6.54(m,2H),3.58-3.48(m,1H),2.56(t,J＝11.1Hz,1H),1.71-1.41(m,8H),1.53(s,6H),1.22(s,3H),1.10-1.04(m,2H),1.01-1.00(m,2H)。
Example 1114- (1-cyclopropyl-4- ((2- ((2- (2-hydroxypropan-2-yl) pyridin-4-yl) amino) pyridin-4-yl) oxy) -1H-pyrazol-3-yl) benzonitrile
Figure BDA0002280414000001381
The procedure is as for the preparation of the compound of example 3, except that 4- (2-bromoacetyl) benzonitrile is used instead of 2-bromo-1-phenyleth-1-one to give the title compound. LC-MS M/z 453.0[ M + H ]]+。1H NMR(400MHz,CDCl3)δ9.51(s,1H),8.43(d,J＝5.1Hz,1H),8.19-7.98(m,2H),7.92-7.73(m,2H),7.65(d,J＝1.0Hz,1H),7.30(s,1H),6.66(dd,J＝4.9,1.1Hz,1H),6.17(d,J＝0.9Hz,1H),6.07(dd,J＝5.1,1.0Hz,1H),3.00(s,1H),2.45-2.42(m,1H),1.47(s,6H),0.98-0.70(m,2H),0.59-0.45(m,2H)。
Experimental example 1 evaluation of ALK5 kinase Activity in vitro with Compound
1. Experimental Material
1.1 Compounds
The control compound was the compound disclosed in example 79 of patent application WO2016/057278 (LY-3200882), chemically named 2- {4- [ (4- { [ 1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl ] oxy } pyridin-2-yl) amino ] pyridin-2-yl } propan-2-ol 4-methylbenzenesulfonate, prepared according to the method described in patent WO2016/057278 and identified by hydrogen and mass spectrometry.
The compounds of the present invention and the control compounds prepared in the above examples were each prepared in DMSO at 10mM, and then diluted to 3.333. mu.M, 1.111. mu.M, 370nM, 123nM, 41nM, 14nM, 4.6nM, 1.5nM, and 0.5nM, respectively.
1.2 reagents and instruments
ALK5 available from Carna, Cat.No.09-141, p38 α available from Carna, Cat.No.04-152, TGF β R1 peptide available from SignalChem, Cat.No. T36-58, ADP-Glo KinaseAssay, from Promega, Cat.No. v9102/3, 1 Xkinase buffer (40mM Tris, pH 7.5, 0.10% BSA, 20mM MgCl21mM DTT), prepared immediately prior to use.
The instrument comprises the following steps: 2104 Multilabel Reader, available from Perkin Elmer, USA.
2. Experimental methods
2.1 preparation of 1 Xkinase buffer
1 x assay buffer
40mM Tris,pH 7.5
20mM MgCl2
0.10％BSA
1mM DTT
2.2 preparation of the Compound
2.2.1 dilution of the Compound
2.2.1.1 formulation of 50-fold compound: the final concentration of the compound tested was 10 μ M, formulated to a 50-fold concentration, i.e. 500 μ M: a1000. mu.M solution of the compound was prepared by adding 95. mu.l of 100% DMSO to the second well of a 96-well plate and then adding 5. mu.l of a 10mM compound solution. Additional wells were added with 60. mu.l of 100% DMSO. Mu.l of compound from the second well was added to the third well and diluted 3-fold in sequence for a total of 10 concentrations.
2.2.1.2 transfer 100nl of compound to the reaction plate.
2.3 kinase reaction
2.3.1 preparation of 2-fold kinase solution
The kinase was added to 1 fold kinase buffer to form a 2 fold enzyme solution. 100nl of 100% DMSO-solubilized compound was present in 384 well plates. To a 384-well reaction plate, 2.5. mu.l of a 2-fold enzyme solution was added. Incubate for 10 minutes at room temperature.
2.3.2 preparation of 2-fold substrate solution
FAM-labeled polypeptide and ATP were added to 1-fold kinase buffer to form a 2-fold substrate solution. To a 384 well reaction plate 2.5. mu.l of a 2-fold substrate solution was added.
2.4 kinase reaction
The 384 well plates were incubated at 28 ℃ for 120 min,
2.5 detection of reaction results
2.5.1 equilibrate ADP-Glo reagent to room temperature.
2.5.2 transfer 5. mu.l of reaction to a new 384-well plate reaction well.
2.5.3 transfer 5. mu.l of ADP-Glo reagent to 384 well plate reaction wells to stop the reaction.
2.5.4 incubate at 28 ℃ for 120 minutes.
2.5.5 mu.l of the kinase detection reagent was transferred to each reaction well, shaken for 1 minute, and allowed to stand at room temperature for 30 minutes.
2.6 data reading
The luminescence values of the samples were read on Envision.
2.7 Curve fitting
2.7.1 copying data of luminescence readings from Envision program
2.7.2 the value of the luminescence reading is converted to a percentage inhibition by a formula.
"min" is the fluorescence reading for the control where the reaction was run without enzyme addition; "max" is the sample fluorescence reading with DMSO added as a control.
2.7.3 data were imported into MS Excel and curve-fitted using XLFit Excel add-in version 5.4.0.8, the fit being Y ═ Bottom + (Top-Bottom)/(1+ (IC)50/X) ^ HillSlope) and the results are shown in Table 1.
TABLE 1
Figure BDA0002280414000001401
Figure BDA0002280414000001411
Figure BDA0002280414000001421
"-" indicates not measured.
The experimental results show that the compound has good inhibitory activity on ALK5 kinase, low inhibitory action on p38 α and high selectivity, and the compound is suggested to obtain higher curative effect and lower side effect.
Experimental example 2 in vitro evaluation of cellular luciferase
1. Experimental Material
Test compounds: the compounds of the present invention prepared in the above examples, each of which was formulated in DMSO at 4mM, were sequentially diluted 4-fold at 20000.00nM, 5000.00nM, 1250.00nM, 312.5nM, 78.125nM, 19.53nM, 4.88nM, 1.22 nM.
Luc-Smad2/3-NIH3T3 mouse fibroblasts (engineered to overexpress SMAD2, 3-responsive promoter) were supplied by the university of Chinese medicine laboratory.
DMEM, available from Invitrogen, USA, FBS, available from Invitrogen, USA, DMSO, Sigma, Glo lysine Buffer, available from Progema, USA, Bright-GloLuciferase assay system, available from Promega, USA, TGF β, available from PeproTech, USA.
The instrument comprises the following steps: MD SpectraMax M3 multifunctional microplate reader, available from Molecular Devices, USA.
2. Experimental methods
2.1 cell culture:
cell recovery: the cells were lysed in a 37 ℃ water bath, transferred to 15mL of pre-warmed medium, centrifuged at 1000rpm for 5 minutes, the medium was discarded, the cells were resuspended in 15mL of fresh medium, transferred to a 10cm petri dish, placed at 37 ℃ in 5% CO2The culture was performed in the incubator (1), and after 24 hours, the cells were replaced with fresh medium.
Cell passage: transferring the recovered cells into a 50mL sterile centrifuge tube, centrifuging at 1000rpm for 5min, discarding the culture medium, counting the uniformly dispersed cells, adjusting the appropriate cell concentration to 15mL fresh culture medium, adding into a 10cm culture dish, placing at 37 deg.C with 5% CO2Cultured in an incubator.
2.2 Experimental procedures:
day 1: cell spreading (bottom 96 pore plate)
Culturing Luc-Smad2/3-NIH3T3 cells in a 10cm culture dish normally until the confluency reaches 80% -90%, collecting the cells into a 15mL centrifuge tube after digestion, centrifuging for 5 minutes at 1000Xg, removing supernatant, suspending the cells in 1mL culture medium, diluting by 10 times for counting, diluting the cells according to the counting result, and adding 4X103The number of cells per well was transferred to a 96-well plate (100. mu.l of resuspended cells per well).
Day 2: cell administration
Drugs were weighed 1-2mg (weighed in advance), prepared as 4mM stock solution in DMSO 24 hours later, media was removed, the drug was diluted in 2% FBS media, 100 μ l of 1x drug solution was added to give final drug concentrations of 20000.00nM, 5000.00nM, 1250.00nM, 312.5nM, 78.125nM, 19.53nM, 4.88nM, 1.22nM, and TGF β 1 was 4ng/mL per well, diluted with 2% FBS media together with compound.
Day 3: fluorescence detection experiment
The Glo Lysis Buffer and Bright-glociferase assay system and cells were equilibrated to room temperature, the cell supernatant was removed, 100. mu.l Glo Lysis Buffer was added to each well, the cells were uniformly lysed by gentle shaking, and 5mins were lysed at room temperature. Then, 100. mu.l of Bright-fluorescence assay system was added to each well, incubated at room temperature for 5 minutes, shaken for 2 minutes, and 180. mu.l of the supernatant was transferred to a 96-well white-bottomed plate, and a chemiluminescent signal was detected under 1s conditions.
2.3 data processing: nonlinear curve fitting and data analysis are carried out by using Graphpad Prism 5 software, and IC is obtained by fitting50The results are shown in Table 2.
TABLE 2
Figure BDA0002280414000001431
Figure BDA0002280414000001441
"-" indicates not measured.
As can be seen from the above experiments, the compounds of the invention all show good inhibitory activity on TGF β -ALK5-SMAD2/3 signaling pathway in NIH3T3 cells.
Experimental example 3 curative effect experiment on CT26 transplanted tumor Balb/c mouse
1. Cells and compounds
CT26 colon cancer cells were provided by Jiangsu Kaiyi Biotechnology GmbH.
The compound of the examples of the present invention and the control compound LY-3200882 were formulated to 6mg/mL using a solution containing 50% PG, 5% ethanol, 10% solutol and 35% water at an administration concentration of 60mg/kg and a gavage administration volume of 10 mL/kg.
2. Method and material
2.1. Experimental methods
Balb/c mice, female, purchased from Shanghai Biky laboratory animals Co., Ltd., weighing 16-20 g. The experiment was started after 2-3 days of acclimation of the mice.
Balb/c mice were prepared one day in advance on the right flank, and 1X 10 cells were subcutaneously inoculated6The individual CT26 cells, fourth day after inoculation, were randomly grouped after tumor volume measurement and divided into solvent control group, compound group of the present example and control compound group. Each group of 6 mice was gavaged 2 times daily for 21 consecutive days. Solvent control group was given a solution consisting of 50% PG, 5% ethanol, 10% solutol and 35% water. The dose of the compound group of the examples of the present invention and the control compound group was 60mg/kg, respectively. Tumor volumes were determined 2 times per week.
2.2. Data statistics
Using Excel statistical software: the average is calculated as avg; the SD value is calculated as STDEV; SEM values were calculated as STDEV/SQRT;
v ═ 0.5a × b2, with a and b indicating the major and minor diameters of the tumor, respectively.
Tumor suppressive therapeutic effect of the compounds TGI (%) evaluation. TGI (%) reflects the tumor growth inhibition rate. Calculation of TGI (%): TGI (%) × (1- (average tumor volume at the end of administration of a certain treatment group-average tumor volume at the start of administration of the treatment group))/(average tumor volume at the end of treatment in the solvent control group-average tumor volume at the start of treatment in the solvent control group) ] × 100%.
3. Results of the experiment
Table 3 shows the tumor inhibition rate of CT26 transplantable tumors on day 21 after administration of a part of the compounds of the present invention.
TABLE 3
Figure BDA0002280414000001451
The compound of example 106 of the invention showed a 66% significant improvement in tumor suppression against CT26 transplantable tumors on day 21 post-dose over the control compound LY-3200882.
In addition, the present inventors also tested the inhibition of CT26 transplants by the compounds of example 19 and example 53 using the same method, with an experimental period of 19 days. The results of the experiment showed that on day 19 after administration, the compounds of example 19 and example 53 of the present invention exhibited 67% and 52% inhibition of CT26 transplantable tumors, respectively, and that the control compound LY-320088 exhibited 32% inhibition of tumors. The compound of the present invention is significantly superior to LY-320088.
Experimental example 4 curative effect experiment on H22 transplanted tumor Balb/c mouse
1. Cells and compounds
H22 hepatoma cells were provided by Jiangsu Kai Biotechnology GmbH.
The compound of the embodiment of the invention is prepared into 6mg/mL by using a solution containing 50% PG, 5% ethanol, 10% solutol and 35% water, the administration concentration is 60mg/kg, and the intragastric administration volume is 10 mL/kg. Control Compound LY-3200882 was formulated at two concentrations, 6mg/mL and 12mg/mL, at 60mg/kg and 120mg/kg, respectively, and at a volume of 10mL/kg for intragastric administration.
2. Method and material
2.1. Experimental methods
Balb/c mice, female, purchased from Shanghai Biky laboratory animals Co., Ltd., weighing 16-20 g. The experiment was started after 2-3 days of acclimation of the mice.
Will contain 2X 106Inoculating 200uL PBS of cells to abdominal cavity of mouse, passaging once per week, co-passaging once, extracting ascites before inoculation, counting, adding PBS, and adjusting concentration to 8 × 106cells/mL, 100uL each, 8X 105And (4) cells. Cells were inoculated subcutaneously into the right hind back of each mouse, and divided dosing was started the day after inoculation. Each group of 6 mice was gavaged 2 times daily for 19 consecutive days. Solvent control group was given a solution consisting of 50% PG, 5% ethanol, 10% solutol and 35% water. Tumor volumes were determined 2 times per week.
2.2. Data statistics
Using Excel statistical software: the average is calculated as avg; the SD value is calculated as STDEV; SEM values were calculated as STDEV/SQRT;
v ═ 0.5a × b2, with a and b indicating the major and minor diameters of the tumor, respectively.
Tumor suppressive therapeutic effect of the compounds TGI (%) evaluation. TGI (%) reflects the tumor growth inhibition rate. Calculation of TGI (%): TGI (%) × (1- (average tumor volume at the end of administration of a certain treatment group-average tumor volume at the start of administration of the treatment group))/(average tumor volume at the end of treatment in the solvent control group-average tumor volume at the start of treatment in the solvent control group) ] × 100%.
3. Results of the experiment
The curative effect of the compound of the embodiment on H22 hepatoma cell transplantation tumor is shown in Table 4:
TABLE 4
Figure BDA0002280414000001461
Figure BDA0002280414000001471
The results of the experiment show that the inhibition rates of the compound of example 38 and example 71 of the invention on H22 transplanted tumors are 75% and 66% respectively after 19 days of administration, while the inhibition rate of the control compound LY3200882 is only 43% at the same dose, and the inhibition rate of the compound increased by 1 time is 66%. It can be seen that the compounds of the present invention have very excellent antitumor effects.
Although the present invention has been described in detail above, those skilled in the art will appreciate that various modifications and changes can be made to the present invention without departing from the spirit and scope of the invention. The scope of the invention is not to be limited by the above detailed description but is only limited by the claims.

Claims (10)

1. A compound of formula I or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof,
Figure FDA0002280413990000011
wherein the content of the first and second substances,
R1selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylocycloalkyl, heteroarylocycloalkyl, heterocycloalkylaryl, aryloateroaryl, heteroaryloateroaryl, which are optionally substituted with one or more halogen, hydroxy, amino, carboxy, cyano, nitro, oxo, alkylsulfonyl, cycloalkylSulfonyl, alkylaminosulfonyl, aminosulfonyl, cycloalkylaminosulfonyl, alkylsulfonylalkyl, alkyl, cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted cycloalkylalkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, hydroxyalkylcarbonyl, hydroxycycloalkylalkyl, hydroxyhaloalkyl, aminoalkyl, carboxyalkyl, cyanoalkyl, nitroalkyl, cycloalkylhydroxyalkyl, alkoxyalkyl, monoalkylamino, dialkylamino, alkoxyacyl, alkylacyloxy, alkenyl, alkynyl, aminoacyl, alkenylacyl, monoalkylaminoalkenoyl, dialkylaminoalkenoyl, monoalkylaminoacyl, dialkylaminoacyl, hydroxyalkylacyl, alkylacylamino, alkylacylaminoalkyl and heteroaryl substitution;
R2selected from the group consisting of 5-to 8-membered heterocycloalkyl, aryl, 5-to 8-membered heteroaryl, aryloaryl, heteroaryloaryl, 5-to 8-membered cycloalkyl, 6-to 10-membered spirocyclyl, 6-to 10-membered bridged cyclyl, 6-to 10-membered spiroheterocyclyl and 6-to 10-membered bridged heterocyclyl, optionally substituted with one or more alkyl, haloalkyl, hydroxy, cycloalkyl, heterocycloalkyl, hydroxyalkyl, halogen, oxo, alkoxy, carboxy, cyano, amino, aminoalkyl, alkenyl, alkynyl, monoalkylamino and dialkylamino;
R3selected from the group consisting of cycloalkyl, heterocycloalkyl, cycloalkylacyl, halocycloalkyl, hydroxycycloalkyl, haloalkoxycycloalkyl, alkoxycycloalkyl, aminocycloalkyl, monoaminoacylcycloalkyl, bisaminocycloalkylacyl, aminoacylcycloalkyl, alkenyl, alkynyl, optionally substituted with one or more alkyl, haloalkyl, hydroxy, hydroxyalkyl, halogen, oxo, alkoxy, carboxy, cyano, amino, aminoalkyl, monoalkylamino, and bisalkylamino;
R4、R5each independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkylacylamino, alkylAcyl, aminoacyl, alkylaminoacyl, dialkylamino, cycloalkyl, alkenyl, alkynyl; m is selected from 1,2 and 3;
when R is2When it is cycloalkyl, halocycloalkyl or heterocycloalkyl, R1Is not aminoacylphenyl and unsubstituted cyanophenyl;
when R is2Is tetrahydro-2H-pyranyl and tetrahydrofuran-3-yl, R3When it is cyclopropyl, R1Is not optionally substituted pyridazinyl, 1-methyl-1H-pyrazolyl, optionally substituted pyridin-2 (1H) -one-4-yl;
when R is1Is pyridin-4-yl and 2-propanediol pyridin-4-yl, R2Is tetrahydro-2H-pyranyl and tetrahydrofuran-3-yl, R3When it is cyclopropyl, R1Substituted with one or more of carboxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, alkylacylamino, carboxyalkyl, hydroxyalkylamino, hydroxyhaloalkyl, haloalkoxy and cycloalkylhydroxyalkyl.
2. The compound of claim 1, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein R1Selected from pyridyl, phenyl, isoquinolyl, indazolyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl, isothiazolyl, imidazolyl, pyranyl, pyronyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, indole, benzopyranyl, benzopyranonyl, purinyl, cyclohexyl, morpholinyl, piperidinyl, pyrrolopyrazolyl, triazolopyrazinyl, optionally substituted with one or more halogens, hydroxy, amino, carboxy, cyano, nitro, oxo, C1-6Alkylsulfonyl radical, C1-6Alkylaminosulfonyl, aminosulfonyl, C3-6Cycloalkylaminosulfonyl radical, C1-6Alkylsulfonyl radical C1-6Alkyl radical, C3-6Cycloalkylsulfonyl radical, C1-6Alkyl radical, C3-10Cycloalkyl radical, C3-10Heterocyclic group, C1-6Alkyl radical C3-10Heterocyclic group, C1-6Alkoxy, halo C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, carboxyl C1-6Alkyl, cyano C1-6Alkyl, nitro C1-6Alkyl, optionally substituted C3-6Cycloalkyl radical C1-6Alkyl, optionally substituted C3-6Heterocycloalkyl radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkyl, mono C1-6Alkylamino, di-C1-6Alkylamino radical, C1-6Alkyl acyl radical, C1-6Alkoxyacyl group, C1-6Alkyl acyloxy, amino acyl, C2-10Alkenyl acyl, mono C1-6Alkylamino radical C2-10Alkenyl acyl, di-C1-6Alkylamino radical C2-10Alkenyl acyl, hydroxy C1-6Alkyl acyl, mono C1-6Alkylaminoacyl, di-C1-6Alkylaminoacyl radical, C1-6Alkylacylamino and C1-6Alkylacylamino C1-6Alkyl substitution; r2Selected from tetrahydropyranyl, tetrahydrofuranyl, tetrahydropyrrolyl, cyclohexyl, morpholinyl, halocyclobutyl, halocyclohexyl, piperidinyl, phenyl, indenyl, naphthyl, pyranyl, pyronyl, pyridazinyl, pyrimidinyl, pyrazinyl, furyl, thienyl, pyrrolyl, quinolyl, isoquinolyl, indolyl, cyclopentyl, cyclohexyl, cycloheptyl, 6-10 membered spiro, 6-10 membered bridged, 6-10 membered spiro and 6-10 membered bridged, optionally substituted with one or more hydroxy, cyano, methoxy, morpholinyl, oxetanyl, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tert-butyl, carboxy, fluoro, chloro, bromo, trifluoromethyl, trifluoroethyl, aminomethyl, aminoethyl, aminopropyl, methylamino, ethylamino, propylamino, isopropylamino, Ethoxy, propoxy, isopropoxy, oxo, formyl, acetyl, propionyl, isopropionyl, ethenyl, propenyl, ethynyl, propynyl; r3Selected from cyclopropyl, cyclopropylacyl, cyclobutyl, 2-fluoroethyl, optionally substituted by one or more of hydroxy, cyano, methoxy, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tert-butyl, carboxy, fluoro, chloro, bromo, trifluoromethyl, trifluoroethyl, aminomethyl, aminoethyl, ammoniaCyclopropyl, methylamino, ethylamino, propylamino, isopropylamino, ethoxy, propoxy, isopropoxy, oxo, formyl, acetyl, propionyl, isopropionyl, ethenyl, propenyl, ethynyl, and propynyl.
3. The compound according to claim 1 or 2, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein formula I has the structure of the following formula Ie,
Figure FDA0002280413990000031
wherein R isaAnd RbEach independently selected from the group consisting of hydrogen, alkyl, halogen, hydroxy, hydroxyalkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, dialkylamino, alkylacylamino, alkanoyl, aminoacyl, alkylaminoacyl, aminoalkyl, optionally substituted heterocycloalkyl, f is selected from 1,2, 3, and 4; and
R2、R3、R4、R5m is as defined in claim 1 or 2.
4. The compound according to claim 1 or 2, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein formula I has the structure of the following formula Id,
Figure FDA0002280413990000032
wherein the content of the first and second substances,
ring a and ring B are each independently selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylocycloalkyl, heteroarylocycloalkyl, heterocycloalkylaryl, aryloaryl, and heteroaryloaryl;
Rcand RdEach independently selected from hydrogen, alkyl, halogen, hydroxy, amino, carboxyA group, a cyano group, a nitro group, an oxo group, a hydroxyalkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkoxy group, an alkanoyl group, an alkylsulfonyl group, a cycloalkylsulfonyl group, an alkylaminosulfonyl group, an cycloalkylaminosulfonyl group, an alkylsulfonylalkyl group, a cycloalkyl group, an optionally substituted cycloalkylcarbonyl group, a heterocycloalkyl group, a heterocycloalkylalkyl group, a cycloalkylalkyl group, a hydroxyalkylcarbonyl group, a hydroxycycloalkylalkyl group, a hydroxyhaloalkyl group, an aminoalkyl group, a carboxyalkyl group, a cyanoalkyl group, a nitroalkyl group, a cycloalkylhydroxyalkyl group, an alkoxyalkyl group, a monoalkylamino group, a dialkylamino group, an alkoxyacyl group, an alkylacyloxy group, an alkenyl group, an alkynyl group, an aminoacyl group, an alkenylacyl group, a monoalkylaminoalkenoyl group, a dialkylaminoacyl group, a monoalkyl, Alkylacylamino, alkylacylaminoalkyl and heteroaryl, j and g each independently being 1,2, 3 and 4;
R2、R3、R4、R5m is as defined in claim 1 or 2.
5. The compound according to claim 1 or 2, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein formula I has the structure of the following formula Ia,
Figure FDA0002280413990000041
wherein R is2、R3、R4、R5M is as defined in claim 1 or 2;
R6selected from the group consisting of hydrogen, halogen, cyano, amino, hydroxy, alkoxy, heterocyclyloxy, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, alkylsulfonyl, alkylaminosulfonyl, aminosulfonyl, cycloalkylaminosulfonyl, alkylsulfonylalkyl, cycloalkylsulfonyl, aryl, and heteroaryl, wherein said halogen, cyano, amino, hydroxy, alkoxy, heterocyclyloxy, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxy, alkoxy, heterocyclyloxy, cycloalkyl, heterocycloalkyl, and heteroarylAlkyl, alkylsulfonyl, alkylaminosulfonyl, aminosulfonyl, cycloalkylaminosulfonyl, alkylsulfonylalkyl, aryl, and heteroaryl optionally substituted with one or more halogen, carboxyl, hydroxyl, cyano, amino, alkyl, haloalkyl, alkoxy, hydroxyalkyl, oxo, aminoalkyl, alkylamino, alkylacyl, alkenyl, alkynyl; preferably, R6Selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, cyano, azetidinyl, oxetanyl, piperazinyl, trifluoromethyl, difluoromethyl, propan-2-ol-2-yl,
Figure FDA0002280413990000051
Figure FDA0002280413990000052
Wherein said fluorine, chlorine, bromine, iodine, cyano, azetidinyl, oxetanyl, piperazinyl, trifluoromethyl, difluoromethyl, propan-2-ol-2-yl, methyl, ethyl, trifluoromethyl,
Figure FDA0002280413990000053
Figure FDA0002280413990000054
Optionally substituted with one or more methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, carboxyl, hydroxyl, cyano, hydroxymethyl, hydroxyethyl, oxo, amino, aminomethyl, methylamino, ethylamino, isopropylamino, methoxy, ethoxy, isopropoxy, fluoro, chloro, bromo, trifluoromethyl, trifluoroethyl, formyl, acetyl, propenyl, ethenyl, propenyl, acryloyl, ethynyl, and propynyl groups; and
n is selected from 1,2, 3,4 and 5.
6. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein formula I has the structure of the following formula Ib,
Figure FDA0002280413990000055
wherein R is2、R3、R4、R5M is as defined in claim 1 or 2;
R7selected from the group consisting of hydrogen, carboxyl, heterocycloalkyl, hydroxyheterocycloalkyl, hydroxyalkyl, alkylaminoacyl, hydroxyalkylacyl, carboxyalkylacyl, carboxyalkyl, monoalkylamino, dialkylamino, aminoalkyl, alkylheterocycloalkyl, heterocycloalkylalkyl, alkylsulfonyl, cycloalkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, cycloalkylaminosulfonyl, cycloalkylalkyl, cycloalkyl, haloalkyl, oxo, alkoxy, haloalkoxy, alkylpyridinyl, 1H-1,2, 4-triazolyl, cycloalkylacyl, and aminoacylcycloalkyl, wherein said carboxyl, heterocycloalkyl, hydroxyheterocycloalkyl, hydroxyalkyl, alkylaminoacyl, hydroxyalkanoyl, carboxyalkylacyl, carboxyalkyl, monoalkylamino, bisalkylamino, aminoalkyl, alkylheterocycloalkyl, alkylaminoacyl, carboxyalkylacyl, carboxyalkyl, carboxyalkylamino, carboxyalkylheterocycloalkyl, carboxyalkylamino, Heterocycloalkylalkyl, alkylsulfonyl, cycloalkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, cycloalkylaminosulfonyl, cycloalkylalkyl, cycloalkyl, haloalkyl, oxo, alkoxy, haloalkoxy, alkylpyridyl, 1H-1,2, 4-triazolyl, cycloalkylacyl, and aminoacylcycloalkyl optionally substituted with one or more of fluoro, chloro, bromo, hydroxy, cyano, amino, carboxy, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyalkyl, oxo, haloalkyl, aminoalkyl, aminoacyl, carboxyalkyl; and
p is selected from 1,2, 3 and 4.
7. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein formula I has the structure of the following formula Ic,
Figure FDA0002280413990000061
wherein R is2、R3、R4、R5M is as defined in claim 1 or 2;
R8selected from the group consisting of hydrogen, carboxyl, heterocycloalkyl, hydroxyheterocycloalkyl, hydroxyalkyl, alkylaminoacyl, hydroxyalkylacyl, carboxyalkylacyl, carboxyalkyl, monoalkylamino, dialkylamino, aminoalkyl, alkylheterocycloalkyl, heterocycloalkylalkyl, alkylsulfonyl, cycloalkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, cycloalkylaminosulfonyl, cycloalkylalkyl, cycloalkyl, haloalkyl, oxo, alkoxy, haloalkoxy, alkylpyridinyl, 1H-1,2, 4-triazolyl, cycloalkylacyl, and aminoacylcycloalkyl, wherein said carboxyl, heterocycloalkyl, hydroxyheterocycloalkyl, hydroxyalkyl, alkylaminoacyl, hydroxyalkanoyl, carboxyalkylacyl, carboxyalkyl, monoalkylamino, bisalkylamino, aminoalkyl, alkylheterocycloalkyl, alkylaminoacyl, carboxyalkylacyl, carboxyalkyl, carboxyalkylamino, carboxyalkylheterocycloalkyl, carboxyalkylamino, Heterocycloalkylalkyl, alkylsulfonyl, cycloalkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, cycloalkylaminosulfonyl, cycloalkylalkyl, cycloalkyl, haloalkyl, oxo, alkoxy, haloalkoxy, alkylpyridyl, 1H-1,2, 4-triazolyl, cycloalkylacyl, and aminoacylcycloalkyl optionally substituted with one or more of fluoro, chloro, bromo, hydroxy, cyano, amino, carboxy, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyalkyl, oxo, haloalkyl, aminoalkyl, aminoacyl, carboxyalkyl; and
q is selected from 1,2 and 3.
8. The compound of claim 1, or an isomer, pharmaceutically acceptable salt, crystal, solvate or prodrug thereof, wherein the compound is a compound selected from the group consisting of:
Figure FDA0002280413990000071
Figure FDA0002280413990000081
Figure FDA0002280413990000091
Figure FDA0002280413990000101
9. a pharmaceutical composition comprising a compound of any one of claims 1-8, or a pharmaceutically acceptable salt, isomer, solvate, prodrug thereof and a pharmaceutically acceptable carrier.
10. Use of a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof, or a pharmaceutical composition according to claim 9, for the manufacture of a medicament for the treatment and/or prevention of a TGF- β R1-related disease, preferably a cancer, tissue proliferative disease, fibrosis or inflammatory disease.
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