CN111196804B - TGF-beta R1 inhibitors and uses thereof - Google Patents

TGF-beta R1 inhibitors and uses thereof Download PDF

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CN111196804B
CN111196804B CN201911139134.0A CN201911139134A CN111196804B CN 111196804 B CN111196804 B CN 111196804B CN 201911139134 A CN201911139134 A CN 201911139134A CN 111196804 B CN111196804 B CN 111196804B
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CN111196804A (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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Abstract

The invention belongs to the field of medicinal chemistry, relates to a compound serving as a TGF-beta R1 inhibitor and application thereof, and in particular provides a compound shown in a formula I or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, a preparation method of the compound, a medicinal composition containing the compound and application of the compound or the composition in treating and/or preventing TGF-beta R1 related diseases such as cancers, tissue hyperplasia diseases, fibrosis and inflammatory diseases. The compounds of the present invention exhibit remarkable inhibitory activity against TGF-. Beta.R1 kinase and are highly promising as therapeutic agents for TGF-. Beta.R1-related diseases.

Description

TGF-beta R1 inhibitors and uses thereof
Technical Field
The invention belongs to the field of medicinal chemistry, and in particular relates to a compound of a TGF-beta R1 inhibitor or pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs 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 diseases related to TGF-beta R1 expression, such as cancer, myelodysplastic syndrome and the like.
Background
TGF-beta (transforming growth factor beta) is an important class of cytokines, and so far 6 different subtypes (TGF-beta 1-6) have been found, with homology to each other, and only 3 subtypes, TGF-beta 1, TGF-beta 2, and TGF-beta 3, are expressed in mammals. It is a multifunctional superfamily of growth factors with wide biological activity, involved in early embryo development, cartilage and bone formation, synthesis of the extracellular matrix, inflammation, interstitial fibrosis, modulation of immune and endocrine functions, formation and development of tumors. Meanwhile, the 3 isomers are similar in structure, and the amino acid sequences of the 3 isomers have high homology, but in the respective gene knockout mouse models, the 3 isomers are expressed as completely different phenotypes, so that each isomer has specific and mutually non-crossing functions in vivo. Ligands of the TGF-beta family can bind to receptors on membrane surfaces and initiate intracellular downstream signaling.
TGF- β1 is the most common and important subtype of TGF- β, the most abundantly expressed subtype in the liver, and is also known to be the strongest hepatic fibrosis inducer, playing a central role in the progression of chronic liver Disease to end liver Disease (Yamazaki, et al, diagnostic Disease,2011, 29:284-288). Several studies have shown that TGF- β1 and TGF- β receptors are often highly expressed in diseased organs of the liver, blood vessels, and extracellular matrix. In the classical tgfp-R-Smads pathway, tgfp- β1 activates tgfp-R1 (transforming growth factor βreceptor 1, alk 5) in the signaling pathway, thereby modulating the entire signaling pathway, achieving regulation of expression of a range of target genes associated with fibrosis and tumorigenesis development. It is currently widely believed that TGF-beta has promotion effects on liver cancer, and is mainly characterized in aspects of promoting tumor cell metastasis, enhancing tumor cell immune escape, inducing angiogenesis and the like (Ling, et al Current Pharmaceutical Biotechnology,2011, 12:2190-2202).
For many years, research on drugs targeting TGF- β pathway has been carried out, but TGF- βr1 inhibitors such as galunilerib and the like show certain cardiac toxicity (such as hemorrhage, functional degeneration, inflammatory injury and the like) on animal models, and the reason is that the drugs have lower target selectivity and specificity, and the drugs inhibit TGF-R1 kinase activation sites and simultaneously have stronger inhibition effect (such as p38 alpha) on other proteins with the same kinase region, thereby generating a plurality of unexpected off-target toxic side effects. Thus, there remains a need to develop more selective tgfβ -R1 inhibitors in order to specifically modulate TGF- β signaling pathways for the treatment of TGF- β related diseases.
Disclosure of Invention
It is an object of the present invention to provide a class of compounds having TGF-. Beta.R1 inhibitory activity as shown in the following formula I or pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs thereof,
it is another object of the invention to provide a process for preparing the compounds of formula I of the invention or isomers, pharmaceutically acceptable salts, solvates, crystals, isosteres or prodrugs thereof.
It is a further object of the present invention to provide compositions comprising a compound of formula I of the present invention, or an isomer, pharmaceutically acceptable salt, solvate, crystal, isostere or prodrug thereof, and a pharmaceutically acceptable carrier, as well as compositions comprising a compound of formula I of the present invention, or an isomer, pharmaceutically acceptable salt, solvate, crystal, isostere or prodrug thereof, and another drug or drugs.
It is a further object of the present invention to provide a method for the treatment and/or prophylaxis of a TGF- βR1 related disease using a compound of formula I or an isomer, pharmaceutically acceptable salt, solvate, crystal, isostere or prodrug thereof, and the use of a compound of formula I or an isomer, pharmaceutically acceptable salt, solvate, crystal, isostere or prodrug thereof in the manufacture of a medicament for the treatment and/or prophylaxis of a TGF- βR1 related disease.
In order to achieve the above object, the present invention provides the following technical solutions:
in a first aspect, the present invention provides a compound of formula I or an isomer, pharmaceutically acceptable salt, solvate, crystal, isostere or prodrug thereof,
R 1 selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylfused cycloalkyl, heteroarylfused cycloalkyl, heterocycloalkylfused aryl, arylfused heteroaryl, heteroarylfused heteroaryl, optionally substituted with one or more halo, hydroxy, amino, carboxyl, cyano, nitro, oxo, alkylsulfonyl, cycloalkylsulfonyl, alkylaminosulfonyl, aminosulfonyl, cycloalkylaminosulfonyl, alkylsulfonylalkyl, alkyl, cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted cycloalkylalkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, hydroxyalkylcarbonyl, hydroxycycloalkyl, hydroxyhaloalkyl, aminoalkyl, carboxyalkyl, cyanoalkyl, nitroalkylalkylhydroxyalkyl, alkoxyalkyl, monoalkylamino, dialkylamino, alkoxyacyl, alkylaminoalkenyloxy, alkenyl, alkynyl, aminoacyl, alkenylacyl, monoalkylaminoalkylalkenylacyl, dialkylaminoalkenylacyl, monoalkylaminoacyl, dialkylaminoacyl, hydroxyalkylaminoacyl, hydroxyalkylacylamino, alkylaminoalkyl, and heteroaryl;
R 2 Selected from the group consisting of 5-8 membered heterocycloalkyl, aryl, 5-8 membered heteroaryl, arylheteroaryl, heteroarylheteroaryl, 5-8 membered cycloalkyl, 6-10 membered spirocyclic, 6-10 membered bridged cyclic, 6-10 membered spirocyclic and 6-10 membered bridged heterocyclic, optionally substituted with one or more alkyl, haloalkyl, hydroxy, cycloalkyl, heterocycloalkyl, hydroxyalkyl, halogen, oxo, alkoxy, carboxy, cyano, amino, aminoalkyl, alkenyl, alkynyl, monoalkylamino and dialkylamino;
R 3 selected from cycloalkyl, heterocycloalkyl, cycloalkylacyl, halocycloalkyl, hydroxycycloalkyl, haloalkyloxycycloalkyl, alkoxycycloalkyl, aminocycloalkyl, monoaminoacylcycloalkyl, bisaminocycloalkylacyl, aminoacylcycloalkyl, alkenyl, alkynyl, optionally substituted with one or more alkyl groups, halo groupsAlkyl, hydroxy, hydroxyalkyl, halo, oxo, alkoxy, carboxy, cyano, amino, aminoalkyl, monoalkylamino, and dialkylamino substitutions;
R 4 、R 5 each independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkylamido, alkanoyl, aminoacyl, alkylaminoacyl, dialkylamino, cycloalkyl, alkenyl, alkynyl; m is selected from 1, 2 and 3;
When R is 2 R in the case of cycloalkyl, halocycloalkyl or heterocycloalkyl 1 Not aminoacylphenyl and unsubstituted cyanophenyl;
when R is 2 Is tetrahydro-2H-pyranyl and tetrahydrofuran-3-yl, R 3 In the case of cyclopropyl, R 1 Not optionally substituted pyridazinyl, 1-methyl-1H-pyrazolyl, optionally substituted pyridin-2 (1H) -one-4-yl;
when R is 1 Is pyridin-4-yl and 2-propanediol pyridin-4-yl, R 2 Is tetrahydro-2H-pyranyl and tetrahydrofuran-3-yl, R 3 In the case of cyclopropyl, R 1 Substituted with one or more carboxyl groups, optionally substituted cycloalkyl groups, optionally substituted heterocycloalkyl groups, alkylamido groups, carboxyalkyl groups, hydroxyalkylamino groups, hydroxyhaloalkyl groups, haloalkoxy groups, and cycloalkylhydroxyalkyl groups;
in some specific embodiments, the compounds of the present invention are compounds of formula I or isomers, pharmaceutically acceptable salts, solvates, crystals, isosteres, or prodrugs thereof, wherein: r is R 1 Selected from C 6-12 Aryl, C 5-12 Heteroaryl, C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, C 6-12 Aryl radical C 3-6 Cycloalkyl, C 5-12 heteroaryl-C 3-6 Cycloalkyl, C 3-6 Heterocyclylalkylo C 6-12 Aryl, C 6-12 Aryl radical C 5-12 Heteroaryl, C 5-12 heteroaryl-C 5-12 Heteroaryl, optionally substituted with one or more halogen, hydroxy, amino, carboxy, Cyano, nitro, oxo, C 1-6 Alkylsulfonyl, C 1-6 Alkylaminosulfonyl, aminosulfonyl, C 3-6 Cycloalkyl sulfamoyl, C 1-6 Alkylsulfonyl C 1-6 Alkyl, C 3-10 Cycloalkyl sulfonyl, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 3-10 Heterocyclyl, C 1-6 Alkyl C 3-10 Heterocyclyl, C 1-6 Alkoxy, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, cyano C 1-6 Alkyl, nitro C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, optionally substituted C 3-6 Heterocycloalkyl C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, mono C 1-6 Alkylamino, bis C 1-6 Alkylamino, C 1-6 Alkyl acyl, C 1-6 Alkoxyacyl, C 1-6 Alkylacyloxy, C 2-6 Alkenyl, C 2-6 Alkynyl, aminoacyl, C 2-10 Alkenyl acyl, mono C 1-6 Alkylamino C 2-10 Alkenyl acyl, bis C 1-6 Alkylamino C 2-10 Alkenyl acyl, mono C 1-6 Alkylaminoacyl, hydroxy C 1-6 Alkanoyl, bis C 1-6 Alkylaminoacyl, C 1-6 Alkylacylamino, C 1-6 Alkylacylamino C 1-6 Alkyl 5-6 membered heteroaryl substitutions.
Preferably, R 1 Selected from pyridyl, phenyl, isoquinolinyl, indazolyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl, isothiazolyl, imidazolyl, pyranyl, pyronyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, indole, benzopyranyl, benzopyronyl, purinyl, cyclohexenyl, morpholinyl, piperidinyl, pyrrolopyrazinyl, triazolopyrazinyl, optionally substituted with one or more halogen, hydroxy, amino, carboxy, cyano, nitro, oxo groups, C 1-6 Alkylsulfonyl, C 1-6 Alkylaminosulfonyl, aminosulfonyl, C 3-6 Cycloalkyl sulfamoyl, C 1-6 Alkylsulfonyl C 1-6 Alkyl, C 3-6 Cycloalkyl sulfonyl, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 3-10 Heterocyclyl, C 1-6 Alkyl C 3-10 Heterocyclyl, C 1-6 Alkoxy, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, cyano C 1-6 Alkyl, nitro C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl C 1-6 Alkyl, optionally substituted C 3-6 Heterocycloalkyl C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, mono C 1-6 Alkylamino, bis C 1-6 Alkylamino, C 1-6 Alkyl acyl, C 1-6 Alkoxyacyl, C 1-6 Alkylacyloxy, aminoacyl, C 2-10 Alkenyl acyl, mono C 1-6 Alkylamino C 2-10 Alkenyl acyl, bis C 1-6 Alkylamino C 2-10 Alkenyl acyl, hydroxy C 1-6 Alkanoyl, mono C 1-6 Alkylaminoacyl, bis C 1-6 Alkylaminoacyl, C 1-6 Alkylacylamino and C 1-6 Alkylacylamino C 1-6 Alkyl substitution;
in some specific embodiments, the compounds of the present invention are compounds of formula I or isomers, pharmaceutically acceptable salts, solvates, crystals, isosteres, or prodrugs thereof, wherein:
R 2 selected from 5-8 membered heterocycloalkyl, C 6-12 Aryl, 5-8 membered heteroaryl, C 6-12 Aryl radical C 6-12 Aryl, C 6-12 Aryl radical C 5-12 Heteroaryl, C 5-12 heteroaryl-C 6-12 Aryl, 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 C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, hydroxy C 1-6 Alkyl, halogen, oxo, C 1-6 Alkoxy, carboxyl, cyano, amino C 1-6 Alkyl, amino, C 2-6 Alkenyl, C 2-6 Alkynyl, mono C 1-6 Alkylamino and di-C 1-6 Alkylamino substitution;
preferably, R 2 Selected from the group consisting of tetrahydropyranyl, tetrahydrofuranyl, tetrahydropyrrolyl, cyclohexyl, morpholinyl, halocyclobutyl, halocyclohexyl, piperidinyl, phenyl, indenyl, naphthyl, pyranyl, pyronyl, pyridazinyl, pyrimidinyl, pyrazinyl, furanyl, thienyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, cyclopentyl, cyclohexyl, cycloheptyl, 6-10 membered spirocyclic, 6-10 membered bridged cyclic, 6-10 membered spirocyclic, and 6-10 membered bridged heterocyclic, optionally substituted with one or more hydroxy, cyano, methoxy, morpholinyl, oxetanyl, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, t-butyl, carboxy, fluoro, chloro, bromo, trifluoromethyl, trifluoroethyl, aminomethyl, aminoethyl, aminopropyl, methylamino, ethylamino, propylamino, isopropylamino, ethoxy, propoxy, isopropoxy, oxo, formyl, acetyl, propionyl, isopropynyl, vinyl, propenyl, and propynyl;
In some specific embodiments, the compounds of the present invention are compounds of formula I or isomers, pharmaceutically acceptable salts, solvates, crystals, isosteres, or prodrugs thereof, wherein:
R 3 selected from C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, C 3-6 Cycloalkyl acyl, halo C 3-6 Cycloalkyl, hydroxy C 3-6 Cycloalkyl, halo C 1-6 Alkoxy C 3-6 Cycloalkyl, C 1-6 Alkoxy C 3-6 Cycloalkyl, amino C 3-6 Cycloalkyl, mono C 1-6 Alkylaminoacyl C 3-6 Cycloalkyl, double C 1-6 Alkylamino C 3-6 Cycloalkyl acyl, aminoacyl C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, optionally substituted with one or more C 3-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, halogen, oxo, C 1-6 Alkoxy, carboxyl,cyano, amino C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, mono C 1-6 Alkylamino and di-C 1-6 Alkylamino substitution;
preferably, R 3 Selected from cyclopropyl, cyclopropylacyl, cyclobutyl, 2-fluoroethyl optionally substituted with one or more 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, isopropanyl, vinyl, propenyl, ethynyl and propynyl;
In some specific embodiments, the compounds of the present invention are compounds of formula I or isomers, pharmaceutically acceptable salts, solvates, crystals, isosteres, or prodrugs thereof, wherein:
R 4 、R 5 are independently selected from hydrogen, halogen, hydroxy, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, nitro, carboxyl, cyano, amino, mono C 1-6 Alkylamino, C 1-6 Alkylacylamino, C 1-6 Alkanoyl, aminoacyl, C 1-6 Alkylaminoacyl, bis C 1-6 Alkylamino and C 3-10 Cycloalkyl; preferably, R 4 、R 5 Are each independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, 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, methylamido, ethylamido, vinylacylamino,methylacyl, ethylacyl, vinylacyl, aminoacyl, methylaminoacyl, ethylaminoacyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
In some preferred embodiments, the compounds of formula I of the present invention are compounds of formula Ia or isomers, pharmaceutically acceptable salts, solvates, crystals, isosteres or prodrugs thereof,
wherein R is 2 、R 3 、R 4 、R 5 M is as defined in claims 1 to 5;
R 6 selected 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 the 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, carboxyl, hydroxyl, cyano, amino, alkyl, haloalkyl, alkoxy, hydroxyalkyl, oxo, aminoalkyl, alkylamino, alkylacyl, alkenyl, alkynyl;
and n is selected from 1, 2, 3, 4 and 5.
In some specific embodiments, a compound of formula Ia according to the invention, or an isomer, pharmaceutically acceptable salt, solvate, crystal, isostere or prodrug thereof, wherein R 6 Selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, cyano, azetidine, oxetane, piperazinyl, trifluoromethyl, difluoromethyl, propan-2-ol-2-yl,Wherein the fluorine, chlorine, bromine, iodine, cyano, azetidine, oxetane, piperazinyl, trifluoromethyl, difluoromethyl, propan-2-ol-2-yl,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; and n is selected from 1, 2 and 3.
In some preferred embodiments, the compounds of formula I of the present invention are compounds of formula Ib or an isomer, pharmaceutically acceptable salt, solvate, crystal, isostere or prodrug thereof,
Wherein R is 2 、R 3 、R 4 、R 5 M is defined as in formula I;
R 7 selected from the group consisting of hydrogen, carboxyl, heterocycloalkyl, hydroxy heterocycloalkyl, hydroxyalkyl, alkylaminoacyl, hydroxyalkylacyl, 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, wherein the carboxyl, heterocycloalkyl, hydroxy heterocycloalkyl, hydroxyalkyl, alkylaminoacyl, hydroxyalkylacyl, carboxyalkanoyl, carboxyalkyl, mono-Alkylamino, dialkylamino, aminoalkyl, alkylheterocycloalkyl, heterocycloalkylalkyl, alkylsulfonyl, cycloalkylsulfonyl, sulfamoyl, alkylaminosulfonyl, cycloalkylaminosulfonyl, cycloalkylalkyl, cycloalkyl, haloalkyl, oxo, alkoxy, haloalkoxy, alkylpyridyl, 1H-1,2, 4-triazolyl, cycloalkylacyl, and aminoalkylcycloalkyl optionally substituted with one or more fluoro, chloro, bromo, hydroxy, cyano, amino, carboxyl, 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 specific embodiments, a compound of formula Ib according to the invention, or an isomer, pharmaceutically acceptable salt, solvate, crystal, isostere or prodrug thereof, wherein R 7 Selected from hydrogen, carboxyl, C 3-6 Heterocycloalkyl, hydroxy C 3-6 Heterocycloalkyl, hydroxy C 1-6 Alkyl, C 1-6 Alkylaminoacyl, hydroxy C 1-6 Alkanoyl, carboxyl C 1-6 Alkanoyl, carboxyl C 1-6 Alkyl, mono C 1-6 Alkylamino, bis C 1-6 Alkylamino, amino C 1-6 Alkyl, C 1-6 Alkyl C 3-6 Heterocycloalkyl, C 3-6 Heterocycloalkyl C 1-6 Alkyl, C 1-6 Alkylsulfonyl, C 3-6 Cycloalkyl sulfonyl, aminosulfonyl, C 1-6 Alkylaminosulfonyl, C 3-6 Cycloalkyl sulfamoyl, C 3-6 Cycloalkylalkyl, C 3-6 Cycloalkyl, halo C 1-6 Alkyl, oxo, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 Alkylpyridyl, 1H-1,2, 4-triazolyl, C 3-6 Cycloalkyl acyl and aminoacyl C 3-6 Cycloalkyl, wherein the carboxy, heterocycloalkyl, hydroxy alkyl, alkylamino acyl, hydroxy alkanoyl, carboxy alkyl, monoalkylamino, dialkylamino, aminoalkyl, alkyl heterocycloalkyl, heterocycloalkyl alkyl, alkyl sulfoalkyl Acyl, cycloalkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, cycloalkylaminosulfonyl, cycloalkylalkyl, cycloalkyl, haloalkyl, oxo group, alkoxy, haloalkoxy, alkylpyridyl, 1H-1,2, 4-triazolyl, cycloalkylacyl, and aminoalkylcycloalkyl optionally substituted with one or more fluoro, chloro, bromo, hydroxy, cyano, amino, carboxyl, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyalkyl, oxo group, haloalkyl, aminoalkyl, aminoacyl, carboxyalkyl; and
p is selected from 1,2, 3 and 4.
In some preferred embodiments, the compounds of formula I of the present invention are compounds of formula Ic or an isomer, pharmaceutically acceptable salt, solvate, crystal, isostere or prodrug thereof,
wherein R is 2 、R 3 、R 4 、R 5 M is defined as in formula I;
R 8 selected from the group consisting of hydrogen, carboxyl, heterocycloalkyl, hydroxyheterocycloalkyl, hydroxyalkyl, alkylaminoacyl, hydroxyalkylacyl, carboxyalkanoyl, 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, wherein the carboxyl, heterocycloalkyl, hydroxyheterocycloalkyl, hydroxyalkyl, alkylaminoacyl, hydroxyalkylacyl, carboxyalkyl, monoalkylamino, dialkylamino, aminoalkyl, alkylheterocycloalkyl, heterocycloalkylsulfonyl, cycloalkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, cycloalkylaminosulfonyl, cycloalkylalkyl, cycloalkylacyl, and aminoacyl, 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, carboxyl, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyalkyl, oxo, haloalkyl, aminoalkyl, aminoacyl, carboxyalkyl; and
q is selected from 1,2 and 3.
In some specific embodiments, a compound of formula Ic according to the invention, or an isomer, pharmaceutically acceptable salt, solvate, crystal, isostere or prodrug thereof, wherein R 8 Selected from hydrogen, carboxyl, C 3-6 Heterocycloalkyl, hydroxy C 3-6 Heterocycloalkyl, hydroxy C 1-6 Alkyl, C 1-6 Alkylaminoacyl, hydroxy C 1-6 Alkanoyl, carboxyl C 1-6 Alkanoyl, carboxyl C 1-6 Alkyl, mono C 1-6 Alkylamino, bis C 1-6 Alkylamino, amino C 1-6 Alkyl, C 1-6 Alkyl C 3-6 Heterocycloalkyl, C 3-6 Heterocycloalkyl C 1-6 Alkyl, C 1-6 Alkylsulfonyl, C 3-6 Cycloalkyl sulfonyl, aminosulfonyl, C 1-6 Alkylaminosulfonyl, C 3-6 Cycloalkyl sulfamoyl, C 3-6 Cycloalkylalkyl, C 3-6 Cycloalkyl, halo C 1-6 Alkyl, oxo, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 Alkylpyridyl, 1H-1,2, 4-triazolyl, C 3-6 Cycloalkyl acyl and aminoacyl C 3-6 Cycloalkyl, wherein the carboxy, heterocycloalkyl, hydroxy heterocycloalkyl, hydroxyalkyl, alkylaminoacyl, hydroxyalkylacyl, carboxyalkanoyl, carboxyalkyl, monoalkylamino, dialkylamino, aminoalkyl, alkylheterocycloalkyl, heterocycloalkylalkyl, alkylsulfonyl, cycloalkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, cycloalkylaminosulfonyl, cycloalkylalkyl, cycloalkyl, haloalkyl, oxo, alkoxy, haloalkoxy, alkylpyridyl, 1H-1,2, 4-triazoleThe radicals cycloalkyl, cycloalkylacyl and aminoacylcycloalkyl are optionally substituted with one or more fluoro, chloro, bromo, hydroxy, cyano, amino, carboxyl, 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 invention are compounds of formula I or isomers, pharmaceutically acceptable salts, solvates, crystals, isosteres or prodrugs thereof, wherein:
R 1 Selected from phenyl, pyridyl, pyrazolyl and piperidinyl, optionally substituted with one or more of the following groups: carboxy, methyl, trifluoromethyl, propan-2-ol-2-yl, hydroxyethyl, cyclopropylsulfonyl, aminosulfonyl, methanesulfonyl, methylamino,
R 2 Selected from phenyl, halophenyl, cyanophenyl, methoxyphenyl, trifluoromethylphenyl, halocyclobutyl, and,
R 3 Selected from cyclopropyl, fluoroethyl, cyclopropylacyl; r is R 4 、R 5 Selected from hydrogen; m is selected from 1.
In other embodiments, the invention provides a compound of formula I, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein formula I has the structure of formula Id,
wherein,
the a and B rings are each independently selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylfused cycloalkyl, heteroarylfused cycloalkyl, heterocycloalkylfused aryl, arylfused heteroaryl, and heteroarylfused heteroaryl; or alternatively
When ring a is aryl-cycloalkyl, heteroaryl-cycloalkyl, heterocycloalkyl-aryl, aryl-heteroaryl, or heteroaryl-heteroaryl, ring B may be absent; and
R c and R is d Each independently selected from the group consisting of hydrogen, alkyl, halogen, hydroxy, amino, carboxyl, cyano, nitro, oxo, hydroxyalkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, alkanoyl, alkylsulfonyl, cycloalkylsulfonyl, alkylaminosulfonyl, aminosulfonyl, cycloalkylaminosulfonyl, alkylsulfonylalkyl, cycloalkyl, optionally substituted cycloalkylcarbonyl, heterocycloalkyl, heterocycloalkylalkyl, cycloalkylalkyl, hydroxyalkylcarbonyl, hydroxycycloalkyl, hydroxycaloalkyl, aminoalkyl, carboxyalkyl, cyanoalkyl, nitroalkyl, cycloalkylhydroxyalkyl, alkoxyalkyl, monoalkylamino, dialkylamino, alkoxyacyl, alkylaminoalkenyloxy, alkenyl, alkynyl, aminoacyl, alkenylacyl, monoalkylaminoalkylalkenylacyl, monoalkylaminoacyl, dialkylaminoacyl, hydroxyalkylaminoacyl, hydroxyalkylacyl, alkylaminoalkyl and heteroaryl, j and g are each independently 1, 2, 3 and 4;
R 2 、R 3 、R 4 、R 5 M is as defined in formula I above.
In some specific embodiments, a compound of formula Id according to the invention, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein the A ring and B ring are each independently selected from C 6-12 Aryl, C 5-12 Heteroaryl, C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, C 6-12 Aryl radical C 3-8 Cycloalkyl, C 5-12 heteroaryl-C 3-8 Cycloalkyl, C 3-8 Heterocyclylalkylo C 6-12 Aryl, C 6-12 Aryl radical C 5-12 Heteroaryl, C 5-12 heteroaryl-C 5-12 Heteroaryl; or when ring A is C 6-12 Aryl radical C 3-8 Cycloalkyl, C 5-12 heteroaryl-C 3-8 Cycloalkyl, C 3-8 Heterocyclylalkylo C 6-12 Aryl, C 6-12 Aryl radical C 5-12 Heteroaryl or C 5-12 heteroaryl-C 5-12 In the case of heteroaryl groups, the B ring may be absent; and R is c And R is d Each independently selected from hydrogen, C 1-6 Alkyl, halogen, hydroxy, amino, carboxy, cyano, nitro, oxo, hydroxy C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, C 1-6 Alkyl acyl, C 1-6 Alkylsulfonyl, C 3-8 Cycloalkyl sulfonyl, C 1-6 Alkylaminosulfonyl, aminosulfonyl, C 3-8 Cycloalkyl sulfamoyl, C 1-6 Alkylsulfonyl C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, C 3-8 Heterocycloalkyl C 1-6 Alkyl, C 3-8 Cycloalkyl C 1-6 Alkyl, hydroxy C 1-6 Alkylcarbonyl, hydroxy C 3-8 Cycloalkyl C 1-6 Alkyl, hydroxy halo C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, cyano C 1-6 Alkyl, nitro C 1-6 Alkyl, C 3-8 Cycloalkyl hydroxy C 1-6 Alkyl, alkoxy C 1-6 Alkyl, mono C 1-6 Alkylamino, bis C 1-6 Alkylamino, C 1-6 Alkoxyacyl, C 1-6 Alkylacyloxy, C 2-6 Alkenyl, C 2-6 Alkynyl, aminoacyl, C 2-6 Alkenyl acyl, mono C 1-6 Alkylamino C 2-6 Alkenyl acyl, bis C 1-6 Alkylamino C 2-6 Alkenyl acyl, mono C 1-6 Alkylaminoacyl, bis C 1-6 Alkylaminoacyl, hydroxy C 1-6 Alkyl acyl, C 1-6 Alkylacylamino, C 1-6 Alkylacylamino C 1-6 Alkyl and C 5-12 Heteroaryl, j and g are each independently 1, 2 and 3;R 2 、R 3 、R 4 、R 5 m is as defined in formula I above.
In some more specific embodiments, a compound of formula Id according to the invention, or an isomer, pharmaceutically acceptable salt, solvate, crystal or 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, benzopyronyl, purinyl, cyclohexenyl, morpholinyl, piperidinyl, pyrrolopyrazyl, triazolopyrazinyl; or when the a ring is benzopyrazolyl, benzopyridyl, quinolinyl, indole, benzopyranyl, benzopyronyl, purinyl, pyrrolopyrazinyl or triazolopyrazinyl, the B ring may be absent; and R is c And R is d Each independently selected from hydrogen, C 1-6 Alkyl, halogen, hydroxy, amino, carboxy, cyano, nitro, oxo, hydroxy C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, C 1-6 Alkyl acyl, C 1-6 Alkylsulfonyl, C 3-8 Cycloalkyl sulfonyl, C 1-6 Alkylaminosulfonyl, aminosulfonyl, C 3-8 Cycloalkyl sulfamoyl, C 1-6 Alkylsulfonyl C 1-6 Alkyl, C 3-8 Cycloalkyl, optionally substituted C 3-8 Cycloalkyl carbonyl, C 3-8 Heterocycloalkyl, C 3-8 Heterocycloalkyl C 1-6 Alkyl, C 3-8 Cycloalkyl C 1-6 Alkyl, hydroxy C 1-6 Alkylcarbonyl, hydroxy C 3-8 Cycloalkyl C 1-6 Alkyl, hydroxy halo C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, cyano C 1-6 Alkyl, nitro C 1-6 Alkyl, C 3-8 Cycloalkyl hydroxy C 1-6 Alkyl, alkoxy C 1-6 Alkyl, mono C 1-6 Alkylamino, bis C 1-6 Alkylamino, C 1-6 Alkoxy radicalAcyl radicals, C 1-6 Alkylacyloxy, C 2-6 Alkenyl, C 2-6 Alkynyl, aminoacyl, C 2-6 Alkenyl acyl, mono C 1-6 Alkylamino C 2-6 Alkenyl acyl, bis C 1-6 Alkylamino C 2-6 Alkenyl acyl, mono C 1-6 Alkylaminoacyl, bis C 1-6 Alkylaminoacyl, hydroxy C 1-6 Alkyl acyl, C 1-6 Alkylacylamino, C 1-6 Alkylacylamino C 1-6 Alkyl and C 5-12 Heteroaryl, j and g are each independently 1, 2 and 3; r is R 2 、R 3 、R 4 、R 5 M is as defined in formula I above.
In other embodiments, the invention provides a compound of formula I, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein formula I has the structure of formula Ie,
wherein R is a And R is b Each independently selected from the group consisting of hydrogen, alkyl, halogen, hydroxy, hydroxyalkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, dialkylamino, alkylamido, alkanoyl, aminoacyl, alkylaminoacyl, aminoalkyl, optionally substituted heterocycloalkyl, f is selected from 1, 2, 3 and 4; and
R 2 、R 3 、R 4 、R 5 m is as defined in formula I above.
In some specific embodiments, a compound of formula Ie according to the invention, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein R a And R is b Each independently selected from hydrogen, C 1-6 Alkyl, halogen, hydroxy C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, nitro, carboxylRadical, cyano, amino, mono C 1-6 Alkylamino, bis C 1-6 Alkylamino, C 1-6 Alkylacylamino, C 1-6 Alkanoyl, aminoacyl, C 1-6 Alkylaminoacyl, amino C 1-6 Alkyl, optionally substituted 3-6 membered heterocycloalkyl, f is selected from 1, 2 and 3; further, R a And R is b Each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, t-butyl, carboxyl, hydroxyl, cyano, fluoro, chloro, bromo, nitro, carboxyl, cyano, amino, trifluoromethyl, trifluoroethyl, aminomethyl, aminoethyl, aminopropyl, methylamino, ethylamino, propylamino, isopropylamino, methoxy, ethoxy, propoxy, isopropoxy, formyl, acetyl, propionyl, isoproyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, hydroxybutyl, hydroxymethyl, hydroxyethoxy, methoxyamino, ethoxyamino, propoxyamino, formylamino, acetamido, alkylhydroxyazetidinyl, f being selected from 1 and 2; r is R 2 Selected from tetrahydropyranyl, tetrahydrofuranyl, tetrahydropyrrolyl, cyclohexyl, morpholinyl, halocyclobutyl, halocyclohexyl, piperidinyl, phenyl, indenyl, naphthyl, pyranyl, pyronyl, pyridazinyl, pyrimidinyl, pyrazinyl, furanyl, thienyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, cyclopentyl, cyclohexyl, cycloheptyl, 6-10 membered spirocyclic group, 6-10 membered bridged cyclic group, 6-10 membered spiroheterocyclic group or 6-10 membered bridged heterocyclic group, 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 group, formyl, acetyl, propionyl, isoproyl, vinyl, propenyl, and propynyl; r is R 3 Selected from C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, C 3-6 Cycloalkyl acyl, halo C 3-6 Cycloalkyl group,Hydroxy C 3-6 Cycloalkyl, halo C 1-6 Alkoxy C 3-6 Cycloalkyl, C 1-6 Alkoxy C 3-6 Cycloalkyl, amino C 3-6 Cycloalkyl, mono C 1-6 Alkylaminoacyl C 3-6 Cycloalkyl, double C 1-6 Alkylamino C 3-6 Cycloalkyl acyl, aminoacyl C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, optionally substituted with one or more C 3-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, halogen, oxo, C 1-6 Alkoxy, carboxyl, cyano, amino C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, mono C 1-6 Alkylamino or di-C 1-6 Alkylamino substitution; and R is 4 、R 5 Are independently selected from hydrogen, halogen, hydroxy, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, nitro, carboxyl, cyano, amino, mono C 1-6 Alkylamino, C 1-6 Alkylacylamino, C 1-6 Alkanoyl, aminoacyl, C 1-6 Alkylaminoacyl, bis C 1-6 Alkylamino and C 3-10 Cycloalkyl, m is 1 or 2.
The present invention provides the following specific compounds, or pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs thereof:
in another aspect, the present invention provides a process for the preparation of a compound of the general formula or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof of the present invention comprising:
1) Reacting the compound of formula 1 with a compound of formula 2 to produce a compound of formula 3;
2) Reacting the compound of formula 3 with a compound of formula 4 to produce a compound of formula 5;
3) Reacting the compound of formula 5 to obtain a compound of formula 6;
4) Reacting the compound of formula 6 with a compound of formula 7 to produce a compound of formula 8;
5) Reacting the compound of formula 8 to obtain a compound of formula 9;
6) Reacting a compound of formula 9 with a compound of formula 10 to produce a compound of formula I; or alternatively
7) Reacting a compound of formula 11 with a compound of formula 9 to produce a compound of formula Ia;
8) Reacting a compound of formula 12 with a compound of formula 9 to produce a compound of formula Ib;
9) The compound of formula 11 is reacted with a compound of formula 9 to produce a compound of formula Ic.
Wherein R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R7、R 8 M, n, and p have the meanings given in formula I; a is halogen, preferably bromine; b is halogen (preferably chlorine) or amino; c is amino or halogen (preferably bromine).
In a third aspect, the invention provides a pharmaceutical composition comprising a compound of the invention or an isomer, pharmaceutically acceptable salt, solvate, crystal, isostere or prodrug thereof.
In some embodiments, the invention provides a pharmaceutical composition 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-beta 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 invention provides the use of a compound of the invention, or an isomer, pharmaceutically acceptable salt, solvate, crystal, isostere or prodrug thereof, or a pharmaceutical composition comprising a compound of the invention, or an isomer, pharmaceutically acceptable salt, solvate, crystal, isostere or prodrug thereof, for the treatment and/or prevention of a TGF- βr1 related disease.
The compounds of the present invention or isomers, pharmaceutically acceptable salts, solvates, crystals, isosteres or prodrugs thereof may be admixed with a pharmaceutically acceptable carrier, diluent or excipient to prepare a pharmaceutical formulation suitable for oral or parenteral administration. Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, and oral routes. The formulation may be administered by any route, for example by infusion or bolus injection, by absorption through the epithelial or skin mucosa (e.g. oral mucosa or rectum, etc.). Administration may be systemic or local. Examples of formulations for oral administration include solid or liquid dosage forms, specifically including tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions and the like. The formulations may be prepared by methods known in the art and comprise carriers, diluents or excipients conventionally used in the art of pharmaceutical formulations.
In a fourth aspect, the present invention provides the use of a compound of formula I, ia, ib or Ic of the invention or an isomer, pharmaceutically acceptable salt, solvate, crystal, isostere or prodrug thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment and/or prophylaxis of cancer, a tissue proliferative disease, fibrosis or an inflammatory disease, wherein the conditions of cancer, tissue proliferative disease, fibrosis or inflammatory disease include, but are not limited to: melanoma, papillary thyroid tumors, cholangiocarcinomas, 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 or leukemias of the skin, colon, thyroid, lung and ovary, glioblastomas (gliomas), myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPNs), acute Myelogenous Leukemia (AML), sarcomas, non-small cell lung cancer, chondrosarcoma, cholangiocarcinomas or angioimmunoblastic lymphomas, hepatic fibrosis and chronic kidney disease.
Description of the terms
Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
The terms "hydrogen", "carbon", "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, isotopes of carbon include 13 C and C 14 Isotopes of C, oxygen include 16 O and 18 o, etc.
The "halogen" in the present invention means fluorine, chlorine, bromine, iodine. "halo" in the present invention means substituted with fluorine, chlorine, bromine or iodine.
"alkyl" in the present invention refers to a straight or branched saturated aliphatic hydrocarbon group, preferably a straight or branched group containing 1 to 6 carbon atoms, more preferably a straight or branched group containing 1 to 3 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, and the like. Alkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be at any useful point of attachment.
"haloalkyl" in the present invention refers to an alkyl group substituted with at least one halogen.
"hydroxyalkyl" in the present invention refers to an alkyl group substituted with at least one hydroxy group.
"alkoxy" in the present invention refers to an-O-alkyl group. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, n-propoxy, isopropoxy, and the like. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents may be at any useful point of attachment.
"cycloalkyl" in the present invention refers to a cyclic saturated hydrocarbon group such as cyclopropyl, cyclobutyl, and the like.
"heterocycloalkyl" of the present invention refers to a group of a 3 to 12 membered non-aromatic ring system ("3-12 membered heterocycloalkyl") having 1 to 4 ring heteroatoms (wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon). In heterocycloalkyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as long as the valence permits. The heterocycloalkyl group may be monocyclic ("monocyclic heterocycloalkyl") or a fused, bridged or spiro ring system (e.g., bicyclic system ("bicyclic heterocycloalkyl")) and may be saturated or may be partially unsaturated. Suitable saturated and partially saturated heterocyclic groups include, but are not limited to, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, isoxazolinyl,Etc.
"aryl" in the present invention refers to aromatic systems which may comprise a single ring or a fused multiple ring, preferably a single ring or a fused double ring, containing 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 useful point of attachment.
"heteroaryl" (by itself or in any combination, e.g., "heteroarylamino") in the present invention refers to an aryl group having at least one carbon atom replaced with a heteroatom consisting of 5-20 atoms (5-20 membered heteroaryl), more preferably 5-12 atoms (5-12 membered heteroaryl), which may be O, S, N, including but not limited to imidazolyl, benzimidazolyl, imidazopyridinyl, quinazolinonyl, pyrrolyl, imidazolonyl, furanyl, thiophenyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, pyrimidinyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidopyrazyl, pyrimidoimidazolyl, and the like. Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents may be at any useful point of attachment.
Aryl-cycloalkyl of the present invention refers to one or more ring systems formed by fusing an aryl group to a group remaining from the cycloalkyl group by formally removing a hydrogen atom, including but not limited to Etc.
Heterocyclylalkylo-aryl of the invention means that the heterocycloalkyl is fused to one or more ring systems formed by the removal of one hydrogen atom from the aryl form, including but not limited to Etc.
Heteroaryl and aryl of the present invention refer to one or more ring systems in which the heteroaryl is fused to the aryl group from which one hydrogen atom remains removed, including but not limited to Etc.
Heteroaryl-heteroaryl of the present invention refers to one or more ring systems formed by fusing a heteroaryl group to a group remaining from the heteroaryl group by formally removing a hydrogen atom, including but not limited to purine, Etc.
"optionally substituted" in the context of the present invention means 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 alkyl, cycloalkylalkyl, hydroxyalkylcarbonyl, hydroxycycloalkyl, hydroxycaloalkyl, aminoalkyl, carboxyalkyl, cyanoalkyl, nitroalkyl, cycloalkylhydroxyalkyl, alkoxyalkyl, monoalkylamino, dialkylamino, alkoxyacyl, alkylacyloxy, alkenyl, alkynyl, aminoacyl, alkenylacyl, monoalkylaminoalkylalkenylacyl, dialkylaminoalkenylacyl, monoalkylaminoacyl, dialkylaminoacyl, hydroxyalkylaminoacyl, alkylaminoalkyl, and heteroaryl groups, e.g., C 1-6 Alkyl, halogen, hydroxy, amino, carboxy, cyano, nitro, oxo, acyloxy, hydroxy C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, C 1-6 Alkyl acyl, C 1-6 Alkylsulfonyl, C 3-8 Cycloalkyl sulfonyl, C 1-6 Alkylaminosulfonyl, aminosulfonyl, C 3-8 Cycloalkyl sulfamoyl, C 1-6 Alkylsulfonylalkyl, C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, C 3-8 Heterocycloalkyl alkyl, C 3-8 Cycloalkylalkyl, hydroxy C 1-6 Alkylcarbonyl, hydroxy C 3-8 Cycloalkyl C 1-6 Alkyl, hydroxy halo C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, cyano C 1-6 Alkyl, nitro C 1-6 Alkyl, C 3-8 Cycloalkyl hydroxy C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, mono C 1-6 Alkylamino, bis C 1-6 Alkylamino, C 1-6 Alkoxyacyl, C 1-6 Alkylacyloxy, C 2-6 Alkenyl, C 2-6 Alkynyl, aminoacyl, C 2-6 Alkenyl acyl, mono C 1-6 Alkylamino C 2-6 Alkenyl acyl, bis C 1-6 Alkylamino C 2-6 Alkenyl acyl, mono C 1-6 Alkylaminoacyl, bis C 1-6 Alkylaminoacyl, hydroxy C 1-6 Alkyl acyl, C 1-6 Alkylacylamino, C 1-6 Alkylacylamino C 1-6 Alkyl and heteroaryl.
"isomers" of the present invention are compounds of the same formula but differing in nature or in the bond sequence of their atoms or in the spatial arrangement of their atoms. Stereoisomers are isomers where the 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 a 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 either dextrorotatory or levorotatory (i.e., as (+) or (-) -isomers, respectively) by the R-and S-sequencing rules of Cahn and Prelog, or by the method of rotating the plane of polarized light of the molecule. The chiral compounds may exist as single enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is referred to as a "racemic mixture".
The term "pharmaceutically acceptable salts" as used herein refers to salts of the compounds of the present invention which are safe and effective when used in a mammal, and which possess the desired biological activity.
"solvate" according to the present invention is intended in the conventional sense to mean a complex formed by the combination of a solute (e.g. active compound, salt of active compound) and a solvent (e.g. water). The solvent refers to a solvent known to or easily determined by those skilled in the art. In the case of water, the solvate is generally referred to as a hydrate, such as a hemihydrate, a monohydrate, a dihydrate, a trihydrate, or an alternative amount thereof, and the like.
Bioisosteres (or simply "isosteres") of the present invention are generally recognized terms in the art used to define 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 to those atoms they replace.
The "crystal" of the present invention means a solid whose internal structure is formed by repeating constituent atoms (or groups thereof) regularly in three dimensions, unlike an amorphous solid which does not have such a regular internal structure.
"prodrug" refers to a compound that is converted to formula I, ia, ib, ic, id, ie under physiological conditions in an organism by reaction with enzymes, gastric acid, etc.
The term "pharmaceutical composition" of the present invention refers to a mixture comprising any of the compounds described herein, including the corresponding isomer, prodrug, solvate, pharmaceutically acceptable salt or chemically protected form thereof, and one or more pharmaceutically acceptable carriers.
The "excipient" 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.
The "pharmaceutically acceptable carrier" of the present invention refers to a carrier that does not cause significant irritation to the organism and does not interfere with the biological activity and properties of the compound being administered, and includes all solvents, diluents or other excipients, dispersants, surfactant isotonic agents, thickening or emulsifying agents, 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 invention and are not intended to limit the scope of the invention. The materials used in the examples below are commercially available unless otherwise specified.
Example 1 4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) picolinic acid
Step 1 2 Synthesis of bromo-1- (tetrahydro-2H-pyran-4-yl) ethan-1-one
1- (tetrahydro-2H-pyran-4-yl) ethanone (10.00 g,78.02 mmol) is dissolved in 50mL methanol and bromine (4.01 mL,78.02 mmol) is added dropwise at-10 ℃. After the completion of the dropping, 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,302.50 mmol) was added and stirred overnight at room temperature. The reaction was monitored by TLC, water and ethyl acetate were added to the reaction solution, extraction was performed, and the organic phase was washed with saturated aqueous sodium bicarbonate, water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound.
Step 2 2 Synthesis of- ((2-chloropyridin-4-yl) oxy) -1- (tetrahydro-2H-pyran-4-yl) ethan-1-one
2-bromo-1- (tetrahydro-2H-pyran-4-yl) ethan-1-one (10.00 g,48.29 mmol) and 2-chloro-4-hydroxypyridine (6.26 g,48.29 mmol) were dissolved in 20mL of N, N-dimethylformamide, and anhydrous potassium carbonate (6.91 g,50 mmol) was added and reacted overnight at 90 ℃. LC-MS detection reaction, adding ethyl acetate and water after the reaction is finished, extracting, washing an organic phase by water and 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 3 2 Synthesis of- ((2-chloropyridin-4-yl) oxy) -3- (dimethylamino) -1- (tetrahydro-2H-pyran-4-yl) prop-2-en-1-one
2- ((2-Chloropyridin-4-yl) oxy) -1- (tetrahydro-2H-pyran-4-yl) ethan-1-one (9.58 g,37.46 mmol) was dissolved in N, N-dimethylformamide dimethyl acetal (21.1 mL) and reacted at 100℃for 2H. After concentrating under reduced pressure, ethyl acetate was added, and the organic phase was washed with water and saturated sodium chloride solution in this order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound.
Step 4 2 Synthesis of chloro-4- ((3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine
2- ((2-Chloropyridin-4-yl) oxy) -3- (dimethylamino) -1- (tetrahydro-2H-pyran-4-yl) prop-2-en-1-one (9.58 g,30.9 mmol) was dissolved in 100mL of acetic acid, hydrazine hydrate (5.5 mL,113.2 mmol) was added dropwise under ice bath, and the mixture was transferred to room temperature for reaction overnight. LC-MS detection reaction, adding ice water and ethyl acetate after the reaction is finished, and extracting. The organic layers were combined, 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 5 2 Synthesis of chloro-4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine
2,2' -bipyridine (3.07 g,19.66 mmol) and copper acetate (3.92 g,19.66 mmol) were placed in a reaction flask, 1, 2-dichloroethane (50 mL) was added, and the reaction was refluxed for 1h. Cooled to room temperature, 2-chloro-4- ((3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine (5.00 g,17.87 mmol), sodium carbonate (3.79 g,35.74 mmol) and cyclopropylboronic acid (3.07 g,35.74 mmol) were added. The reaction was stirred at 80℃for 4h under oxygen atmosphere and detected by LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure, diluted with ethyl acetate, filtered through celite, and the organic layer was washed with water, saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by column chromatography to give the title compound. ESI-MSm/z 320.2[ M+H ]] + 。
Step 6 4 Synthesis of methyl- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) picolinate
2-chloro-4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine (200 mg, 625.41. Mu. Mol), methyl 4-aminopyridine-2-carboxylate (133.22 mg, 875.58. Mu. Mol), cesium carbonate (407.54 mg,1.25 mmol), palladium acetate (14.03 mg, 62.5. Mu. Mol) and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (72.3 mg, 125. Mu. Mol) were placed in a reaction flask, 10mL of dioxane was added, and the mixture was reacted overnight at 100 ℃. After the reaction was completed, the mixture was cooled to room temperature, and water and ethyl acetate were added thereto to conduct extraction. The organic phases were combined, 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 7 4 Synthesis of- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) picolinic acid
Methyl 4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) picolinate (200 mg,459.26 umol) was added to a mixed solvent of tetrahydrofuran (10 mL) and methanol (2 mL), and then 4mL of an aqueous solution containing lithium hydroxide (55 mg,2.30 mmol) was added thereto for reaction at room temperature for 2 hours. After the reaction was completed, the pH was adjusted to about 7 with a 3M hydrochloric acid solution, and tetrahydrofuran and methanol were removed by concentration under reduced pressure. Ethyl acetate was added, the extracts were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give the title compound. ESI-MS m/z 422.2[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 ):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 2 4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) -N- (2-morpholinopyridin-4-yl) pyridin-2-amine
Step 1 (Synthesis of 4- (4-nitropyridin-2-yl) morpholine
2-chloro-4-nitropyridine (5 g,0.032 mol) and morpholine (8.3 g,0.096 mol) were dissolved in 80mL of tetrahydrofuran and refluxed overnight. LC-MS detection reaction, decompression concentration after reaction, column chromatography purification to obtain the title compound. ESI-MS m/z 210.2[ M+H ] ] + 。
Step 2 2 Synthesis of morpholinopyridin-4-amine
(4- (4-nitropyridin-2-yl) morpholine (1.0 g,4.78 mmol) was dissolved in a methanol/dichloromethane (15 mL/5 mL) mixed solvent, palladium/carbon (10%, 100 mg) was added, hydrogen was displaced 5 times, and the reaction was performed overnight at room temperature, LC-MS was examined, after the completion of the reaction, celite was used for auxiliary filtration, the filter cake was washed with methanol, and the filtrate was concentrated under reduced pressure to give 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
2-chloro-4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine (200 mg,0.63 mmol), 2-morpholinopyridin-4-amine (93.5 mg,0.52 mmol), palladium acetate (11.7 mg,0.052 mmol), 4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthene (60 mg,0.104 mmol) and cesium carbonate (340 mg,1.04 mmol) were placed in a reaction flask, 10mL of anhydrous 1, 4-dioxane was added and reacted overnight at 100℃under the protection of argon. After the reaction, the reaction solution was concentrated and purified by column chromatography to give the title compound. ESI-MSm/z 463.2[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 ):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 3 2- (4- ((4- ((1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) propan-2-ol
Step 12 Synthesis of- ((2-chloropyridin-4-yl) oxy) -1-phenylethyl-1-one
2-bromo-1-phenylethan-1-one (5.00 g,25 mmol) and 2-chloro-4-hydroxypyridine (3.25 g,25 mmol) were dissolved in 4mL of N, N-dimethylformamide, anhydrous potassium carbonate (6.91 g,50 mmol) was added, and the mixture was reacted overnight at room temperature. After the reaction was completed, ethyl acetate was added, and the mixture was washed with water and a saturated sodium chloride solution in this order, 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 2 2 Synthesis of chloro-4- ((3-phenyl-1H-pyrazol-4-yl) oxy) pyridine
2- ((2-Chloropyridin-4-yl) oxy) -1-phenylethyl-1-one (1.0 g,4.03 mmol) was dissolved in N, N-dimethylformamide dimethyl acetal (4 mL,30.1 mmol) and reacted at 100℃under stirring for 2h. After completion of the reaction, the reaction mixture was returned to room temperature, ethyl acetate was added, 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 (0.6 mL,12.34 mmol) was added dropwise under ice-bath conditions, and the mixture was allowed to stand at room temperature overnight. After the reaction was completed, ice water and ethyl acetate were added, extraction was performed, and the organic phases were combined, washed with water, saturated sodium bicarbonate and sodium chloride solution in this 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 3 2 Synthesis of chloro-4- ((1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl) oxy) pyridine
2,2' -bipyridine (0.76 g,4.86 mmol) and copper acetate (0.97 g,4.86 mmol) were placed in a reaction flask, 1, 2-dichloroethane (20 mL) was added, and the mixture was heated to 80℃to react for 1h. Cooled to room temperature, and 2-chloro-4- ((3-phenyl-1H-pyrazol-4-yl) oxy) pyridine (1.21 g,4.42 mmol), carbonic acid were addedSodium (0.94 g,8.83 mmol) and cyclopropylboronic acid (1.18 g,8.83 mmol). The reaction was carried out at 80℃for 4h under oxygen. After the reaction was completed, the mixture was concentrated under reduced pressure. The concentrate was diluted with ethyl acetate, the filtrate was washed with water, saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give the title compound. ESI-MSm/z 312.8[ M+H ]] + 。
Step 42 Synthesis of- (4- ((4- ((1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) propan-2-ol
2-chloro-4- ((1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl) oxy) pyridine (200 mg,0.64 mmol), 2- (4-aminopyridin-2-yl) propan-2-ol (117 mg,0.78 mmol), palladium acetate (14 mg,0.06 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (70 mg,0.12 mmol) and cesium carbonate (390 mg,1.21 mmol) were taken in a reaction flask, 10mL of 1, 4-dioxane was added, and the reaction was carried out overnight at 100℃under the protection of argon. After the reaction, the reaction solution was concentrated and purified by column chromatography to give the title compound. ESI-MS m/z 428.2[ M+H ] ] + 。 1 H NMR(400MHz,DMSO-d 6 ):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 4 4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -N-methylpyridine amide
Step 1 4 Synthesis of amino-N-methylpyridine amide
Methyl 4-aminopyridine-2-carboxylate (500 mg,3.29 mmol) was dissolved in 10mL of 33% methyl amine in methanol and reacted overnight at 50 ℃. After the reaction was completed, the reaction solution was cooled to room temperature, methanol was removed by concentration under reduced pressure, ethyl acetate and water were added, extraction was performed, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by column chromatography to give the title compound. ESI-MS m/z 152.1[ M+H ]] + 。
Step 2 4 Synthesis of- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -N-methylpyridine amide
The procedure was followed except for using 4-amino-N-methylpyridine amide instead of 2-morpholinopyridin-4-amine to give the title compound as a compound in step 3 of example 2. ESI-MS m/z 435.2[ M+H ]] + 。 1 HNMR(400MHz,DMSO-d 6 ):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 5 4 Synthesis of- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) -2- ((2- (2-hydroxypropan-2-yl) pyridin-4-yl) amino) benzonitrile
The procedure was as for the preparation of the compounds of steps 1-6 of example 1, 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 to give the title compound. ESI-MS m/z 460.1[ M+H ] ] + 。 1 H NMR(400MHz,DMSO-d 6 ):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 6 2- (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
Step 1 6 Synthesis of bromo-3-methyl-1- (tetrahydro-2H-pyran-4-yl) -1H-indazole
6-bromo-3-methyl-1H-indazole (2.00 g,9.47 mmol), tetrahydro-2H-pyran-4-ol (3.87 g,37.9 mmol) and triphenylphosphine (4.97 g,18.94 mmol) were placed in a reaction flask, 20mL tetrahydrofuran was added and diisopropyl azodicarboxylate (3.83 g,18.94 mmol) was added dropwise. After the completion of the dropping, the mixture was reacted at room temperature overnight. After the reaction, ethyl acetate was added for dilution, followed by washing with water, saturated sodium chloride solution, drying the organic phase over anhydrous sodium sulfate, concentrating under reduced pressure, and purifying by column chromatography to give the title compound. ESI-MS m/z 295.5,297.2[ M+H ]] + 。
Step 2 3 Synthesis of methyl-1- (tetrahydro-2H-pyran-4-yl) -6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-indazole
6-bromo-3-methyl-1- (tetrahydro-2H-pyran-4-yl) -1H-indazole (410 mg,1.39 mmol), pinacol biborate (882 mg,3.47 mmol), potassium acetate (309 mg,4.17 mmol) and [1,1' -bis (diphenylphosphine) ferrocene]Palladium dichloride dichloromethane complex (102 mg,0.14 mmol) was placed in a reaction flask, 10mL dioxane was added and reacted overnight at 110 ℃. Concentrating under reduced pressure to remove solvent after reaction, adding ethyl acetate for dilution, and sequentially using water And saturated sodium chloride solution, drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure, and purifying by column chromatography to obtain the title compound. ESI-MS m/z 343.2[ M+H ]] + 。
Step 33 Synthesis of methyl-1- (tetrahydro-2H-pyran-4-yl) -1H-indazol-6-ol
3-methyl-1- (tetrahydro-2H-pyran-4-yl) -6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-indazole (200 mg,0.29 mmol) was dissolved in 2mL tetrahydrofuran, 0.5mL acetic acid and 1mL30% hydrogen peroxide were added and reacted overnight at room temperature. After the reaction, 20mL of saturated sodium thiosulfate solution was added, stirred for 30min, concentrated under reduced pressure, diluted with ethyl acetate and filtered with the aid of celite. The organic layer was washed with water and saturated sodium chloride in this order, dried over anhydrous sodium sulfate, and purified by column chromatography to give the title compound. ESI-MS m/z 233.1[ M+H ]] + 。
Step 4 6 Synthesis of- ((2-chloropyridin-4-yl) oxy) -3-methyl-1- (tetrahydro-2H-pyran-4-yl) -1H-indazole
3-methyl-1- (tetrahydro-2H-pyran-4-yl) -1H-indazol-6-ol (100 mg,0.43 mmol), 2-chloro-4-fluoropyridine (226 mg,1.72 mmol) and potassium carbonate (178 mg,1.29 mmol) were placed in a reaction flask, N-dimethylformamide was added and reacted overnight at 100 ℃. After the reaction, ethyl acetate was added for dilution, followed by washing with water and saturated sodium chloride solution, drying over anhydrous sodium sulfate, concentrating under reduced pressure, and purifying by column chromatography to obtain the title compound. ESI-MSm/z 344.1[ M+H ] ] + 。
Step 5 2 Synthesis of- (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
6- ((2-Chloropyridin-4-yl) oxy) -3-methyl-1- (tetrahydro-2H-pyran-4-yl) -1H-indazole (120 mg,0.35 mmol), 2- (4-aminopyridin-2-yl) propan-2-ol (72 mg,0.38 mmol), palladium acetate (8 mg,0.04 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (41 mg,0.07 mmol) and cesium carbonate (228 mg,0.72 mmol) were placed in a reaction flask, 5mL of 1, 4-dioxane was added and reacted overnight under argon atmosphere at 100 ℃. After the reaction, the reaction solution was concentrated and purified by column chromatography to give the title compound. ESI-MS m/z 460.2[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 ):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 7 1- (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
Step 12 Synthesis of methyl-1- (4-nitro-1H-pyrazol-1-yl) propan-2-ol
4-nitro-1H-pyrazole (1.70 g,15.03 mmol) and 1, 8-diazabicyclo [5.4.0]Undec-7-ene (4.57 g,30.06 mmol) was added to a double-necked flask, and after argon protection, 2-dimethyloxirane (3.47 g,48.10 mmol) was added to the double-necked flask using a syringe. Stirring for 20h at 60 ℃ under the oil bath condition. 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 2 1 Synthesis of- (4-amino-1H-pyrazol-1-yl) -2-methylpropan-2-ol
2-methyl-1- (4-nitro-1H-pyrazol-1-yl) propan-2-ol (1.35 g,7.30 mmol) was added to a single-necked flask, dissolved in 20mL of methanol, and then palladium on carbon (100%, 160 mg) was added, followed by three times of nitrogen substitution and three times of hydrogen substitution, and stirring was carried out at room temperature overnight. After the completion of the reaction, the reaction mixture was filtered with the aid of celite, and the filtrate was concentrated under reduced pressure to give the title compound.
Step 3 1 Synthesis of- (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
The procedure was followed except for using 1- (4-amino-1H-pyrazol-1-yl) -2-methylpropan-2-ol instead of 2-morpholinopyridin-4-amine in step 3 of example 2 to give the title compound. ESI-MS m/z 439.28[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 ):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 8 1- (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
The procedure was followed except for using 3, 5-dimethyl-4-nitro-1H-pyrazole instead of 4-nitro-1H-pyrazole to prepare the title compound as in example 7, steps 1-3. ESI-MS m/z 467.3[ M+H ] ] + 。 1 HNMR(400MHz,DMSO-d 6 ):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 9 2- (4- ((4- ((1-cyclopropyl-3- (3-methoxyphenyl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) propan-2-ol
The procedure was followed except for using 2-bromo-1- (3-methoxyphenyl) ethyl-1-one instead of 2-bromo-1-phenylethan-1-one to give the title compound. ESI-MS m/z 458.2[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 ):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 10 1- (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
Step 1 4 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
2-chloro-4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine (1 g,3.13 mmol), tert-butyl 4-aminopiperidine-1-carboxylate (939.44 mg,4.69 mmol), tris (dibenzylideneacetone) dipalladium (286.6 mg,313 umol), 4, 5-bis-phenylphosphine-9, 9-dimethylxanthene (361 mg,626 umol) and sodium t-butoxide (901.58 mg,9.38 mmol) were placed in a reaction flask, 10mL of dioxane was added, and the mixture was reacted overnight at 100℃under argon. After the reaction was completed, the reaction solution was cooled to room temperature, water and ethyl acetate were added, the extracts were combined, the organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give the title compound.
Step 2 4 Synthesis of- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) -N- (piperidin-4-yl) pyridin-2-amine hydrochloride
4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) piperidine-1-carboxylic acid tert-butyl ester (970 mg,2.01 mmol) was dissolved in 10mL of hydrochloric acid/dioxane solution and stirred overnight at room temperature. After completion of the reaction, the title compound was obtained by concentrating under reduced pressure.
Step 3 1 Synthesis of- (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
4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) -N- (piperidin-4-yl) pyridin-2-amine hydrochloride (100 mg,238 umol), 2-hydroxy-2-methylpropanoic acid (37.18 mg,357.1 umol), 2- (7-benzotriazol-oxide) -N, N, N ', N' -tetramethylurea hexafluorophosphate (108 mg,285.75 umol) and N, N-diisopropylethylamine (92.3 mg,714.3 umol) were placed in a reaction flask and reacted at room temperature under the protection of argon with 10mL of dichloromethane. After the reaction was completed, the reaction solution was cooled to room temperature, water and ethyl acetate were added, the extracts were combined, the organic phases were dried over anhydrous sodium sulfate, and after concentration under reduced pressure, the title compound was purified by column chromatography. ESI-MS m/z 470.3[ M+H ] ] + 。 1 H NMR(400MHz,DMSO-d 6 ):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 11 2- (4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) piperidin-1-yl) -2-methylpropanoic acid
Step 1 2 Synthesis of ethyl 4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) piperidin-1-yl) -2-methylpropionate
4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) -N- (piperidin-4-yl) pyridin-2-amine hydrochloride (700 mg,1.67 mmol), ethyl 2-bromo-2-methylpropionate (390.15 mg,2.00 mmol) and potassium carbonate (691.10 mg,5.0 mmol) were placed in a reaction flask, 10mL of acetonitrile was added, and the mixture was refluxed for 17H under argon atmosphere. After the reaction was completed, the reaction solution was cooled to room temperature, filtered to obtain a filtrate, which was concentrated under reduced pressure, and purified by column chromatography to obtain the title compound.
Step 2 2 Synthesis of- (4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) piperidin-1-yl) -2-methylpropanoic acid
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 (317 mg, 637.01. Mu. Mol) was dissolved in a mixed solvent of tetrahydrofuran/water (10 mL/2 mL), and aqueous sodium hydroxide solution (5 mL) 7.5M) was added dropwise to the above mixture, and the reaction was heated at 90℃for 24 hours. After the reaction was completed, the reaction solution was cooled to room temperature, 6M hydrochloric acid solution was added dropwise to adjust pH to 7, tetrahydrofuran was removed by concentration under reduced pressure, ethyl acetate was added, extraction was performed, the aqueous phase was taken, after concentration under reduced pressure, methanol was added for dissolution, the filtrate was obtained by filtration, concentration under reduced pressure, and the title compound was purified by column chromatography. ESI-MSm/z 470.3[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 ):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 12 2- (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
Step 1 1 Synthesis of cyclopropyl-4- (3-nitro-4- (trifluoromethyl) phenoxy) -3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazole
The procedure was as in example 1, steps 2-5, except that 3-nitro-4- (trifluoromethyl) phenol was used instead of 2-chloro-4-hydroxypyridine to give the title compound.
Step 2 5 Synthesis of- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) -2- (trifluoromethyl) aniline
1-cyclopropyl-4- (3-nitro-4- (trifluoromethyl) phenoxy) -3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazole (400 mg,1.01 mm)ol) a mixed solvent of methanol/tetrahydrofuran (6 mL/3 mL), ammonium chloride (324 mg,6.06 mmol), water (3 mL) and iron powder (226 mg,4.04 mmol) were added together to the reaction system, and the mixture was refluxed. LC-MS detection reaction, filtering the diatomite when the reaction is hot after the reaction is finished, and washing a filter cake with methanol. After concentrating under reduced pressure, ethyl acetate was added to dilute, and the mixture was 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 3 2 Synthesis of- (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
5- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) -2- (trifluoromethyl) aniline (200 mg,0.54 mmol), 2- (4-bromopyridin-2-yl) propan-2-ol (117 mg,0.54 mmol), palladium acetate (12 mg,0.054 mmol), 4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthene (63 mg,0.108 mmol) and cesium carbonate (35mg, 1.08 mmol) were placed in a reaction flask and reacted overnight under the protection of argon with 10mL of anhydrous 1, 4-dioxane. After the completion of the reaction, the reaction mixture was concentrated and purified by column chromatography to give the title compound. ESI-MS m/z 503.2[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 ):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 13 2- (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
The preparation method is the same as that of example 5, except that 6The title compound was prepared by substituting 2-bromo-4-hydroxybenzonitrile with-chloro-5-azaindole. ESI-MS m/z 459.2[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 ):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 14- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -2- (3-hydroxyazetidin-1-yl) benzonitrile
Step 14 Synthesis of bromo-2- (3-hydroxypyrrolidin-1-yl) benzonitrile
4-bromo-2-fluorobenzonitrile (1.35 g,6.74 mmol), azetidine-3-ol hydrochloride (886 mg,8.09 mmol) and potassium carbonate (2.33 g,16.85 mmol) were placed in a reaction flask and reacted with 20mL of dimethyl sulfoxide at 100℃for 3h. After the reaction, ethyl acetate was added for dilution, water and saturated sodium chloride solution were washed, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give 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-diphenyl imine
2-chloro-4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine (1.50 g,4.82 mmol) and benzophenone imine (0.960 g,5.31 mmol) were placed in a reaction flask, 15mL of toluene was added followed by palladium acetate (54.2 mg,0.241 mmol), 1 '-binaphthyl-2, 2' -bisdiphenylphosphine (300 mg, 0.480 mmol)l) and cesium carbonate (3.14 g,9.64 mmol), nitrogen displacement three times, and reaction overnight at 95 ℃. After the reaction was completed, suction filtration was performed, the solvent was distilled off from the filtrate under reduced pressure, and the title compound was obtained by separation through column chromatography. LC-MS m/z 465.2[ M+H ]] + 。
Step 3 4 Synthesis of- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-amine
N- (4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) -1, 1-diphenyl imine (1.98 g,4.34 mmol) was dissolved in hydrogen chloride/1, 4-dioxane solution (20 mL, 4.0M) and reacted overnight at room temperature. After completion of the reaction, a saturated aqueous solution (20 mL) of sodium carbonate was added thereto, and the mixture was stirred at room temperature for 30 minutes. Ethyl acetate was added to the reaction solution, the mixture was extracted, and 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 4 4 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
4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-amine (200 mg,0.667 mmol) and 4-bromo-2- (3-hydroxypyrrolidin-1-yl) benzonitrile (194 mg,0.733 mmol) were dissolved in 5mL of 1, 4-dioxane, tris (dibenzylideneacetone) dipalladium (61.1 mg,0.0667 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (116 mg,0.200 mmol) and cesium carbonate (435 mg,1.33 mmol) were added and reacted overnight at 100℃with nitrogen displacement three times. After the reaction was completed, suction filtration was performed, the solvent was distilled off from the filtrate under reduced pressure, and the title compound was obtained by separation through column chromatography. ESI-MS m/z 473.2[ M+H ] ] + 。 1 H NMR(400MHz,DMSO-d 6 ):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 15 2- (4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) -2-methylpropanoic acid
Step 12 Synthesis of methyl- (4-bromopyridin-2-yl) -2-methylpropionate
4-bromopyridine 1-oxide (1 g,5.75 mmol), 1-methoxy-1- (trimethylsiloxy) -2-methyl-1-propene (2 g,174.3 mmol), tripyrrolidinylphosphonium bromide hexafluorophosphate (3 g,6.43 mmol), and N, N-diisopropylethylamine (2.7 mL,16.33 mmol) were added to 50mL tetrahydrofuran. The reaction mixture was stirred at room temperature for 12h. 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 gave the title compound. ESI-MS m/z 258.2,260.2[ M+H ]] + 。
Step 22 Synthesis of methyl (4- ((tert-Butoxycarbonyl) amino) pyridin-2-yl) -2-methylpropionate
Methyl 2- (4-bromopyridin-2-yl) -2-methylpropionate (618 mg,2.39 mmol), t-butylcarbamate (336 mg,2.87 mmol), cesium carbonate (1.56 g,4.78 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (28 mg,0.05 mmol) and tris (dibenzylideneacetone) dipalladium (22 mg,0.07 mmol) were placed in a reaction flask, 20mL dioxane was added, and the mixture was reacted overnight at 100℃under argon. Reaction junction After the completion of the reaction, the reaction mixture was concentrated and purified by column chromatography to give the title compound. ESI-MS m/z 295.2[ M+H ]] + 。
Step 3 2 Synthesis of methyl- (4-aminopyridin-2-yl) -2-methylpropionate hydrochloride
Methyl 2- (4- ((tert-butoxycarbonyl) amino) pyridin-2-yl) -2-methylpropionate (600 mg,2.03 mmol) was dissolved in 10mL of hydrochloric acid/dioxane system and reacted overnight at room temperature. After the completion of the reaction, the reaction mixture was concentrated to give the title compound. ESI-MS m/z 195.5[ M-HCl+H ]] + 。
Step 5 2 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-methylpropanoic acid
The procedure was as in example 1, steps 6-7, except that methyl 2- (4-aminopyridin-2-yl) -2-methylpropionate hydrochloride was used instead of methyl 4-aminopyridin-2-carboxylate to give the title compound. ESI-MS m/z 464.3[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 ):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 16 2- (4- ((4- ((1-cyclopropyl-3- (3-fluorophenyl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) propan-2-ol
The preparation method is the same as in example 3, except that 2-bromo-1- (3-fluoro) is usedPhenyl) ethan-1-one instead of 2-bromo-1-phenylethan-1-one, the title compound was prepared. ESI-MS m/z 446.3[ M+H ] ] + 。 1 H NMR(400MHz,DMSO-d 6 ):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 17 2- (4- ((4- ((1-cyclopropyl-3- (2-fluorophenyl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) propan-2-ol
The procedure was followed except for using 2-bromo-1- (2-fluorophenyl) ethan-1-one instead of 2-bromo-1-phenylethan-1-one in the same manner as in example 3 to obtain the title compound. ESI-MS m/z 446.2[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 ):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 18 2- (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
Step 1 4 Synthesis of methyl-N' - (tetrahydro-4H-pyran-4-ylidene) benzenesulfonyl hydrazide
Tetrahydropyranone (5.0 g,26.87 mmol) and p-toluenesulfonyl hydrazide (2.7 g,26.87 mmol) were added to 50mL of methanol and stirred overnight at room temperature. After the reaction, the mixture was concentrated under reduced pressure to remove methanol 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
4-methyl-N' - (tetrahydro-4H-pyran-4-ylidene) benzenesulfonhydrazide (151 mg,0.746 mmol), 4-bromo-2-fluorobenzaldehyde (200 mg,0.746 mmol) and cesium carbonate (365 mg,1.12 mmol) were weighed into 20ml of 1, 4-dioxane. The reaction was heated to 110℃under argon and stirred overnight. After the reaction was completed, 1, 4-dioxane was removed, a saturated ammonium chloride solution and methylene chloride were added, the organic phase and the aqueous phase were separated, and the aqueous phase was extracted with methylene chloride. 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 3 5 Synthesis of bromo-3- (tetrahydro-2H-pyran-4-yl) -1H-indazole
(4-bromo-2-fluorophenyl) (tetrahydro-2H-pyran-4-yl) methanone (4.02 g,13.98 mmol) and hydrazine hydrate (2.53 g,50.60 mmol) were dissolved in 20mL dioxane and reacted overnight at 100 ℃. At the end of the reaction, the solvent was removed under reduced pressure, and 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 4 5 Synthesis of bromo-1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-indazole
2, 2-bipyridine (1.94 g,12.39 mmol) and copper acetate (2.25 g,12.39 mmol) were placed in a reaction flask, 20mL of 1, 2-dichloroethane was added, and the reaction was refluxed for 1h. Cooling to room temperature, adding 5-bromine-3- (tetrahydro-2H-pyran-4-yl) -1H-indazole (2.32 g,8.26 mmol), sodium carbonate (1.75 g,16.51 mmol) and cyclopropylboronic acid (1.42 g,16.51 mmol). The reaction was carried out at 80℃for 4h under oxygen. After the reaction, the mixture was concentrated under reduced pressure, diluted with ethyl acetate, and filtered with the aid of 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 ]] + 。
Step 8 2 Synthesis of- (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
The procedure was followed except for using 5-bromo-1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-indazole instead of 6-bromo-3-methyl-1- (tetrahydro-2H-pyran-4-yl) -1H-indazole to prepare the title compound according to the procedure for the preparation of the compound of step 2-5 of example 6. ESI-MS m/z 486.5[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 ):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 19 4- ((1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl) oxy) -N- (2-morpholinopyridin-4-yl) pyridin-2-amine
The procedure was followed except for using 2-morpholinopyridin-4-amine instead of 2- (4-aminopyridin-2-yl) propan-2-ol to give the title compound. 455.4[ M+H ] ESI-MS m/z] + 。 1 H NMR(400MHz,DMSO-d 6 ):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 20- ((1-cyclopropyl-3- (4, 4-difluorocyclohexyl) -1H-pyrazol-4-yl) oxy) -N- (2-morpholinopyridin-4-yl) pyridin-2-amine
Step 1 1 Synthesis of- (4, 4-difluorocyclohexyl) ethyl-1-one
4, 4-Difluorocyclohexane-1-carboxylic acid (2.0 g,12.18 mmol) was dissolved in 100ml of anhydrous tetrahydrofuran, and a solution of methyllithium (30.5 mL,1.6M,48.7 mmol) was added dropwise to the solution at 0℃using a constant pressure dropping funnel, the reaction was stirred for 2 hours, followed by dropwise addition of trimethylchlorosilane (24.74 mL,195 mmol) over a period of about 10 minutes. The reaction mixture was cooled to room temperature and reacted for 1 hour, 5mL of 1M hydrochloric acid was added thereto, the reaction mixture was stirred for 1 hour, and the mixture was concentrated under reduced pressure. Ethyl acetate was added to dilute the mixture, and the mixture was washed with water, saturated sodium hydrogencarbonate and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound.
Step 2 2 Synthesis of bromo-1- ((4, 4-difluorocyclohexyl) ethyl-1-one
1- (4, 4-Difluorocyclohexyl) ethyl-1-one (2.1 g,8.71 mmol) was dissolved in 15mL of methanol, precooled at-10℃and bromine (0.63 mL,12.3 mmol) was added dropwise using a constant pressure funnel to control the dropping rate. After the completion of the dropping, the mixture was stirred at 0℃for 1 hour, allowed to react at room temperature until the mixture became pale yellow, aqueous sulfuric acid (5 mL, 10M) was added, stirred overnight, water and ethyl acetate were added, and extraction was performed. 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 3 4 Synthesis of- ((1-cyclopropyl-3- (4, 4-difluorocyclohexyl) -1H-pyrazol-4-yl) oxy) -N- (2-morpholinopyridin-4-yl) pyridin-2-amine
The procedure was followed except for using 2-bromo-1- (4, 4-difluorocyclohexyl) ethyl-1-one instead of 2-bromo-1-phenylethan-1-one in example 19 to give the title compound. ESI-MS m/z 497.3[ M+H ]] + 。 1 H 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 21 3- (1-cyclopropyl-4- ((2- ((2- (2-hydroxypropan-2-yl) pyridin-4-yl) amino) pyridin-4-yl) oxy) -1H-pyrazol-3-yl) benzonitrile
The procedure was followed except for using 3- (2-bromoacetyl) benzonitrile instead of 2-bromo-1-phenylethan-1-one to give the title compound. ESI-MS m/z 453.2[ M+H ] ] + 。 1 H NMR(400MHz,DMSO-d 6 ):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 22- ((1-cyclopropyl-3- (3-fluorophenyl) -1H-pyrazol-4-yl) oxy) -N- (2-morpholinopyridin-4-yl) pyridin-2-amine
The procedure was followed except for using 2-bromo-1- (3-fluorophenyl) ethan-1-one instead of 2-bromo-1-phenylethan-1-one in example 19 to give the title compound. ESI-MS m/z 473.2[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 ):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 23- ((1-cyclopropyl-3- (2-fluorophenyl) -1H-pyrazol-4-yl) oxy) -N- (2-morpholinopyridin-4-yl) pyridin-2-amine
The procedure was followed except for using 2-bromo-1- (2-fluorophenyl) ethan-1-one instead of 2-bromo-1-phenylethan-1-one in example 19 to give the title compound. ESI-MS m/z 473.2[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 ):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 24- ((4- ((1-cyclopropyl-3- (4, 4-difluorocyclohexyl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -2- (3-hydroxy-3-methylazetidin-1-yl) benzonitrile
Step 1 2-chloro-4- ((1-cyclopropyl-3- (4, 4-difluorocyclohexyl) -1H-pyrazol-4-yl) oxy) pyridine
The title compound was obtained by the same procedures as those used in the preparation of the compounds in steps 1 to 3 of example 20. 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
The procedure was followed except for using 2-chloro-4- ((1-cyclopropyl-3 (4, 4-difluorocyclohexyl) -1H-pyrazol-4-yl) oxy) pyridine 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 in the same manner as in example 14 to prepare the title compound. The title compound was obtained. ESI-MS m/z 521.2[ M+H ] ] + 。 1 H NMR(400MHz,DMSO-d 6 ):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 25 1- (4- ((4- ((1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -1H-pyrazol-1-yl) -2-methylpropan-2-ol
The preparation was the same as in example 7 except that 2-chloro-4- ((1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl) oxy) pyridine was used instead 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 ]] + 。 1 H NMR(400MHz,DMSO-d 6 ):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 26- ((1-cyclopropyl-3- (2, 4-difluorophenyl) -1H-pyrazol-4-yl) oxy) -N- (2-morpholinopyridin-4-yl) pyridin-2-amine
The procedure was followed except for using 2-bromo-1- (2, 4-difluorobenzene) ethyl-1-one instead of 2-bromo-1-phenylethan-1-one in example 19 to give the title compound. ESI-MS m/z 491.2[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 ):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 27- ((1-cyclopropyl-3- (3- (trifluoromethyl) phenyl) -1H-pyrazol-4-yl) oxy) -N- (2-morpholinopyridin-4-yl) pyridin-2-amine
The procedure was followed except for using 2-bromo-1- (3- (trifluoromethyl) phenyl) ethan-1-one instead of 2-bromo-1-phenylethan-1-one in example 19 to give the title compound. ESI-MS m/z 523.2[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 ):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 28- ((1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl) oxy) -N- (2- ((2S, 6R) -2, 6-dimethylmorpholinyl) pyridin-4-yl) pyridin-2-amine
Step 1 Synthesis of (2S, 6R) -2, 6-dimethyl-4- (4-nitropyridin-2-yl) morpholine
2-chloro-4-nitropyridine (2 g,0.013 mol) and (2S, 6R) -2, 6-dimethylmorpholine (4.37 g,0.038 mol) were dissolved in 40mL tetrahydrofuran and heated to reflux overnight. After the reaction, the mixture was concentrated under reduced pressure and purified by column chromatography to give the title compound. ESI-MS m/z 238.2[ M+H ]] + 。
Step 2 2 Synthesis of- ((2S, 6R) -2, 6-dimethylmorpholine) pyridin-4-amine
(2S, 6R) -2, 6-dimethyl-4- (4-nitropyridin-2-yl) morpholine (1.18 g,4.78 mmol) was dissolved in a mixed solvent of methanol/dichloromethane (9 mL/3 mL), palladium on carbon (10%, 100 mg) was added, hydrogen was replaced 5 times, and the reaction was carried out at room temperature overnight. After the reaction was completed, celite was used for auxiliary filtration, 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 3 4 Synthesis of- ((1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl) oxy) -N- (2- ((2S, 6R) -2, 6-dimethylmorpholinyl) pyridin-4-yl) pyridin-2-amine
2-chloro-4- ((1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl) oxy) pyridine (120 mg,0.38 mmol), 2- ((2S, 6R) -2, 6-dimethylmorpholine) pyridin-4-amine (80 mg,0.38 mmol), tris (dibenzylideneacetone) dipalladium (35 mg,0.038 mmol), 4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthene (45 mg,0.076 mmol) and sodium phenolate (251 mg,0.76 mmol) were placed in a reaction flask, and 5mL of 1, 4-dioxane was added. The reaction was carried out overnight at 100℃under an argon atmosphere. After the completion of the reaction, the reaction mixture was concentrated and purified by column chromatography to give the title compound. ESI-MS m/z 483.2[ M+H ] ] + 。 1 H NMR(400MHz,DMSO-d 6 ):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 29- ((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
The procedure was followed except for using 2-chloro-4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine instead of 2-chloro-4- ((1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl) oxy) pyridine to prepare the title compound. ESI-MS [ M+H ]] + m/z:491.2。 1 H NMR(400MHz,DMSO-d 6 ):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 30- ((3- (3-chlorophenyl) -1-cyclopropyl-1H-pyrazol-4-yl) oxy) -N- (2-morpholinopyridin-4-yl) pyridin-2-amine
The procedure was followed except for using 2-bromo-1- (3-chlorophenyl) ethan-1-one instead of 2-bromo-1-phenylethan-1-one in example 19 to give the title compound. ESI-MS m/z 489.2[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 ):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 31 4- ((1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl) oxy) -N- (1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine
Step 1 4 Synthesis of nitro-1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazole
4-Nitro-1H-pyrazole (1.00 g,8.84 mmol), tetrahydro-2H-pyran-4-ol (803 mg,8.84 mmol) and triphenylphosphine (2.86 g,10.88 mmol) were placed in a reaction flask, 10mL tetrahydrofuran was added, argon was purged, and diisopropyl azodicarboxylate (2.33 g,11.5 mmol) was added dropwise at 0deg.C. After the completion of the dropping, the mixture was reacted at room temperature overnight. At the end of the reaction, ethyl acetate was added for dilution, water and saturated sodium chloride solution were washed, 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 2 1 Synthesis of- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-amine
4-nitro-1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazole (500 mg,2.54 mmol) and palladium on carbon (10%, 135 mg) were added to methanol and reacted overnight at room temperature under hydrogen atmosphere. After the reaction, suction filtration is carried out to obtain filtrate, and the filtrate is decompressed and concentrated to obtain the title compound. ESI-MS m/z 168.2[ M+H ]] + 。
Step 3 4 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
The procedure was followed except for using 1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-amine in place of 2- ((2S, 6R) -2, 6-dimethylmorpholine) pyridin-4-amine to prepare the title compound.ESI-MS[M+H] + m/z:443.2。 1 H NMR(400MHz,DMSO-d 6 ):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 32- ((1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl) oxy) -N- (1- ((3-methyloxetan-3-yl) methyl) -1H-pyrazol-4-yl) pyridin-2-amine
The procedure was followed except for using 1- ((3-methyloxetan-3-yl) methyl) -1H-pyrazol-4-amine in place of 2- (4-aminopyridin-2-yl) propan-2-ol to prepare the title compound. ESI-MSm/z 443.2[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 ):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 33 4- ((3- (2-chlorophenyl) -1-cyclopropyl-1H-pyrazol-4-yl) oxy) -N- (2-morpholinopyridin-4-yl) pyridin-2-amine
The procedure was followed except for using 2-bromo-1- (2-chlorophenyl) ethan-1-one instead of 2-bromo-1-phenylethan-1-one in example 19 to give the title compound. ESI-MS m/z 489.2[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 ):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 34 3- (1-cyclopropyl-4- ((2- ((2-morpholinopyridin-4-yl) amino) pyridin-4-yl) oxy) -1H-pyrazol-3-yl) benzonitrile
The procedure was followed except for using 3- (2-bromoacetyl) benzonitrile instead of 2-bromo-1-phenylethan-1-one in the same manner as in example 19 to give the title compound. ESI-MS m/z 480.2[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 ):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 35- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -N-methylbenzenesulfonamide
2-chloro-4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine (150 mg,0.47 mmol), 3-amino-N-methylbenzenesulfonamide (88 mg,0.47 mmol), tris (dibenzylideneacetone) dipalladium (43 mg,0.04 mmol), 4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthene (54 mg,0.09 mmol) and sodium phenolate (109 mg,0.94 mmol) were placed in a reaction flask and 8ml of 1, 4-dioxane was added thereto under the protection of argon gas and reacted overnight at 100 ℃. After the reaction, the reaction solution was concentrated, and the title compound was obtained by column chromatography separation and purification. ESI-MS m/z 470.2[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 )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 36 3- (1-cyclopropyl-4- ((2- ((1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) amino) pyridin-4-yl) oxy) -1H-pyrazol-3-yl) benzonitrile
Step 1 3 Synthesis of- (4- ((2-chloropyridin-4-yl) oxy) -1-cyclopropyl-1H-pyrazol-3-yl) benzonitrile
The procedure was as in example 3, steps 1-3, except that 3- (2-bromoacetyl) benzonitrile was used instead of 2-bromo-1-phenylethan-1-one to give the title compound. ESI-MS m/z 337.2[ M+H ]] + 。
Step 21 Synthesis of- (cyclopropylsulfonyl) -4-nitro-1H-pyrazole
4-nitro-1H-pyrazole (1.00 g,8.84 mmol) was dissolved in 50mL of acetonitrile, sodium hydride (0.39 g,16.21 mmol) was added at 0deg.C, and after stirring for 0.5H, cyclopropylsulfonyl chloride (1.24 g,8.84 mmol) was added. The reaction was carried out at room temperature for 16h and LC-MS detection was carried out. After the reaction was completed, cooling to room temperature, filtering, concentrating the filtrate, adding water and ethyl acetate, extracting, combining the organic phases, drying over 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 3 1 Synthesis of- (cyclopropylsulfonyl) -1H-pyrazol-4-amine
1- (cyclopropylsulfonyl) -4-nitro-1H-pyrazole (1.68 g,7.73 mmol) was dissolved in 50mL of methanol, and a palladium/carbon catalyst (10%, 168 mg) was added thereto, followed by hydrogen substitution multiple times at room temperatureThe reaction was carried out 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 Synthesis of- (4- ((2- ((1H-pyrazol-4-yl) amino) pyridin-4-yl) oxy) -1-cyclopropyl-1H-pyrazol-3-yl) benzonitrile
3- (4- ((2-Chloropyridin-4-yl) oxy) -1-cyclopropyl-1H-pyrazol-3-yl) benzonitrile (130 mg,0.39 mmol), 1- (cyclopropylsulfonyl) -1H-pyrazol-4-amine (80 mg,0.43 mmol), tris (dibenzylideneacetone) dipalladium (35 mg,0.04 mmo), 4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthene (45 mg,0.08 mmol) and sodium phenolate (90 mg,0.78 mmol) were placed in a reaction flask, and 5mL of 1, 4-dioxane was added thereto under argon atmosphere, and reacted overnight at 100 ℃. After the reaction, the reaction solution was concentrated, and the title compound was obtained by column chromatography separation and purification. ESI-MS m/z 384.2[ M+H ]] + 。
Step 5 3- (1-cyclopropyl-4- ((2- ((1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) amino) pyridin-4-yl) oxy) -1H-pyrazol-3-yl) benzonitrile
3- (4- ((2- ((1H-pyrazol-4-yl) amino) pyridin-4-yl) oxy) -1-cyclopropyl-1H-pyrazol-3-yl) benzonitrile (110 mg,0.29 mmol) was dissolved in 10mL of anhydrous tetrahydrofuran under argon, sodium hydride (46 mg,1.16 mmol) was added at 0℃and the reaction was stirred for 0.5H, then cyclopropylsulfonyl chloride (48 mg,0.34 mmol) was added and the mixture was allowed to react to room temperature. LC-MS detection reaction, ethyl acetate extraction, saturated saline water washing, anhydrous sodium sulfate drying, reduced pressure concentration, column chromatography separation to obtain the title compound. ESI-MS m/z 488.2[ M+H ] ] + 。 1 H NMR(400MHz,DMSO-d 6 )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 37- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -2-methylbenzenesulfonamide
2-chloro-4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine (800 mg,2.5 mmol), 3-amino-6-methylbenzenesulfonamide (512 mg,2.75 mmol), sodium phenolate (580 mg,5.00 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (90 mg,0.16 mmol) and tris (dibenzylideneacetone) dipalladium (72 mg,0.078 mmol) were placed in a reaction flask, 15mL of 1, 4-dioxane was added and reacted overnight at 100℃under argon. The reaction was monitored by LC-MS, and after completion of the reaction, the reaction mixture was concentrated and purified by column chromatography to give the title compound. ESI-MS m/z 470.2[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 )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 38- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -2-fluorobenzenesulfonamide
Step 12 Synthesis of fluoro-5-nitrobenzenesulfonamide
To the reaction flask was added p-fluoronitrobenzene (1.01 g,7.16 mmol), chlorosulfonic acid (4 mL) was added dropwise at 0deg.C, and the mixture was transferred to 110deg.C and reacted under stirring for 24h. Cooling to room temperature, adding ice-water mixture and ethyl acetate, extracting to obtain organic phase, drying with anhydrous sodium sulfate, concentrating under reduced pressure to obtain crude productThe product is obtained. The crude product was dissolved in 50mL of ethyl acetate, and ammonia water (25%, 50 mL) was added at 0℃and reacted for 4 hours. Standing for layering, extracting the 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
2-fluoro-5-nitrobenzenesulfonamide (230 mg,1.05 mmol), iron powder (293 mg,5.25 mmol) and ethanol (12 mL) were added to a reaction flask, and ammonium chloride (560 mg,10.5 mmol) was dissolved in 3mL water and added to the above system to reflux for 3h. Filtering while the mixture is hot, concentrating the mixture under reduced pressure to remove the solvent, adding ethyl acetate for dilution, washing the mixture with saturated saline solution, drying the mixture with anhydrous sodium sulfate, and concentrating the mixture under reduced pressure to obtain the title compound. ESI-MS m/z 191.0[ M+H ]] + 。
Step 3 5 Synthesis of- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -2-fluorobenzenesulfonamide
2-chloro-4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine (120 mg,0.38 mmol), 5-amino-2-fluorobenzenesulfonamide (71 mg,0.38 mmol), tris (dibenzylideneacetone) dipalladium (33 mg,0.038 mmol), 4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthene (42 mg,0.076 mmol) and sodium phenolate (85 mg,0.76 mmol) were placed in a reaction flask, 5mL of anhydrous 1, 4-dioxane was added, and reacted overnight at 100℃under argon. After the reaction, the reaction solution was concentrated, and the title compound was obtained by column chromatography separation and purification. ESI-MS m/z 474.2[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 )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 39 3- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) benzenesulfonamide
The procedure was followed except for using 3-aminobenzenesulfonamide instead of 3-amino-6-methylbenzenesulfonamide in the same manner as in example 37 to obtain the title compound. ESI-MS m/z 456.2[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 )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 40- ((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
The procedure was followed except for using 3-methylazetidin-3-ol in place of azetidin-3-ol hydrochloride in the same manner as in example 14 to give the title compound. ESI-MS m/z 487.0[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 )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 41- ((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
Step 14 Synthesis of bromo-2- (4- (methylsulfonyl) piperazin-1-yl) benzonitrile
The procedure was 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 2 4 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
The procedure was followed except for using 4-bromo-2- (4- (methylsulfonyl) piperazin-1-yl) benzonitrile instead of 5-amino-2-fluorobenzenesulfonamide in step 3 of example 38 to give the title compound. ESI-MS m/z 564.2[ M+H ] ] + 。 1 H NMR(400MHz,DMSO-d 6 )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 42 1- (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
Step 1 1 Synthesis of- (4-nitropyridin-2-yl) piperidin-4-ol
2-bromo-4-nitropyridine (200 mg,0.99 mmol), 4-hydroxypiperidine (149.48 mg,1.48 mmol) and cesium carbonate (642.02 mg,1.97 mmol) were placed in a reaction flask, 20mL of 1, 4-dioxane was added, and the mixture was reacted at 100℃overnight. After the reaction, 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 21 Synthesis of- (4-aminopyridin-2-yl) piperidin-4-ol
1- (4-nitropyridin-2-yl) piperidin-4-ol (210.0 mg,0.94 mmol) was dissolved in 20mL methanol, palladium on carbon catalyst (10% Pd/C,200.00 mg) was added, hydrogen was replaced multiple times, the reaction was allowed to proceed for 3h at room temperature, and TLC monitored. The reaction was complete, filtered and the filtrate concentrated to give the title compound. ESI-MS m/z 194.1[ M+H ]] + 。
Step 3 1 Synthesis of- (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
The procedure was followed except for using 1- (4-aminopyridin-2-yl) piperidin-4-ol instead of 2-morpholinopyridin-4-amine to give the title compound as a preparation for the compound in step 3 of example 2. ESI-MS m/z 477.3[ M+H ] ] + 。 1 H NMR(400MHz,DMSO-d 6 )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 43 3- (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
Step 1 3 Synthesis of- (4-bromopyridin-2-yl) oxetan-3-ol
2, 4-Dibromopyridine (3.00 g,12.66 mmol) was placed in a dry round bottom flask under nitrogen and dissolved in 20mL of anhydrous tetrahydrofuran solution. The temperature was lowered to-30℃and isopropyl magnesium chloride-lithium chloride (2.21 g,15.2 mmol) was slowly added dropwise, stirring was continued at low temperature for 1 hour, 3-oxetanone (1.1 g,15.2 mmol) was slowly added, the reaction was continued for 2 hours, and the LC-MS monitoring was completed. The reaction was quenched with saturated ammonium chloride solution, ethyl acetate was added, the organic phases were combined, concentrated and purified by column chromatography to give the title compound. ESI-MSm/z 229.9,231.9[ M+H ]] + 。
Step 23 Synthesis of- (4-aminopyridin-2-yl) oxetan-3-ol
3- (4-bromopyridin-2-yl) oxetan-3-ol (1.10 g,4.78 mmol) was dissolved in 20mL of aqueous ammonia, copper powder (206.6 mg,3.25 mmol) was added, and reacted in an open reaction flask at room temperature for 30min until it became dark blue. After sealing, heating to 120 ℃ for reaction overnight, detecting the end of the reaction by LC-MS, filtering, concentrating the filtrate, and directly putting the filtrate into the next step. ESI-MS m/z 167.1[ M+H ] ] + 。
Step 3 3 Synthesis of- (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
The procedure was followed except for using 3- (4-aminopyridin-2-yl) oxetan-3-ol instead of 2-morpholinopyridin-4-amine to give the title compound. ESI-MS m/z 450.2[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 )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 44- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -2- (2-hydroxyprop-2-yl) benzonitrile
Step 15 Synthesis of methyl amino-2-bromobenzoate
Methyl 2-bromo-5-nitrobenzoate (2.00 g,7.72 mmol) was dissolved in a mixed solvent of 20mL of ethanol and 5mL of water, and iron powder (1.73 g,30.9 mmol) and ammonium chloride (2.05 g,38.6 mmol) were added and reacted at 80℃for 3 hours. After completion of the TLC detection, the reaction was filtered, concentrated under reduced pressure to remove ethanol, water and ethyl acetate were added, extracted, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by filtration to give the title compound. LC-MS m/z 229.9,231.9[ M+H ]] + 。
Step 2 5 Synthesis of methyl amino-2-cyanobenzoate
5-amino-2-bromobenzoic acid methyl ester (1.57 g,6.86 mmol) was dissolved in 20mL N, N-To dimethylformamide was added cuprous cyanide (0.671 g,7.54 mmol), and the mixture was replaced with nitrogen three times and reacted at 150℃with stirring for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, water and ethyl acetate were added, the organic phases were combined, the organic phases were washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, followed by separation by column chromatography to give the title compound. LC-MS m/z 177.1[ M+H ] ] + 。
Step 3 5 Synthesis of methyl- ((tert-Butoxycarbonyl) amino) -2-cyanobenzoate
Methyl 5-amino-2-cyanobenzoate (173 mg,0.983 mmol) was dissolved in 5mL of methylene chloride, 4-dimethylaminopyridine (12.0 mg,0.0983 mmol) was added thereto, di-tert-butyl dicarbonate (428 mg,1.97 mmol) was added dropwise at 0℃and the mixture was allowed to react at room temperature for 5 hours. After completion of the TLC detection reaction, water and methylene chloride were added, extraction was performed, 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 separation. LC-MS m/z 277.1[ M+H ]] + 。
Step 4 Synthesis of tert-butyl (4-cyano-3- (2-hydroxy-prop-2-yl) phenyl) carbamate
3.0mol/L of a solution of methylmagnesium bromide in tetrahydrofuran (1.23 mL,3.69 mmol) was added to a nitrogen-substituted three-necked flask, and a solution of methyl 5- ((tert-butoxycarbonyl) amino) -2-cyanobenzoate (340 mg,1.23 mmol) in anhydrous tetrahydrofuran (5 mL) was slowly added dropwise at 0℃and the mixture was allowed to stand at room temperature for 6 hours. After completion of the reaction, it was quenched with 5mL of saturated ammonium chloride solution, ethyl acetate was added, the extracts were combined, the organic phases were dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the title compound was obtained by column chromatography separation. LC-MS m/z 277.2[ M+H ]] + 。
Step 5 4 Synthesis of amino-2- (2-hydroxypropan-2-yl) benzonitrile hydrochloride
Tert-butyl (4-cyano-3- (2-hydroxy-prop-2-yl) phenyl) carbamate (220 mg,0.797 mmol) was dissolved in 5mL of dichloromethane, and trifluoroacetic acid (0.178 mL, 2.3991 mmol) was added thereto and reacted at room temperature for 6h. The reaction was monitored by TLC and after completion of the reaction, the solvent was evaporated under reduced pressure to give the title compound. LC-MS m/z 177.1[ M-HCl+H ]] + 。
Step 6 4 Synthesis of- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -2- (2-hydroxypropyl-2-yl) benzonitrile
The procedure was followed except for using 4-amino-2- (2-hydroxypropan-2-yl) benzonitrile hydrochloride instead of 2-morpholinopyridin-4-amine to give the title compound. LC-MS m/z 460.2[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 )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 45 2- (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
Step 1 2 Synthesis of chloro-4- ((1- (2-fluoroethyl) -3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine
60% sodium hydride (108 mg,2.69 mmol) was added to 3mL of anhydrous N, N-dimethylformamide at 0deg.C, and after stirring for 5min, a solution of 2-chloro-4- ((3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine (500 mg,1.79 mmol) in anhydrous N, N-dimethylformamide (5 mL) was added, and after shifting to room temperature and stirring for 30min, 1-bromo-2-fluoroethane (0.146 mL,1.97 mmol) was added and reacted at room temperature for 3H. The reaction was monitored by TLC, after completion of the reaction, quenched by addition of 10mL of saturated ammonium chloride solution, added with ethyl acetate, extracted, combined with the organic phase, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, followed by column chromatography to give the title compound. LC-MS m/z 326.1[ M+H ] ] + 。
Step 2 2 Synthesis of- (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
2-chloro-4- ((1- (2-fluoroethyl) -3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine (360 mg,1.11 mmol) and 2- (4-aminopyridin-2-yl) propan-2-ol (140 mg,0.923 mmol) were placed in a reaction flask, 5mL of 1, 4-dioxane, tris (dibenzylideneacetone) dipalladium (42.3 mg,0.0462 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (53.4 mg,0.0923 mmol) and sodium phenolate (214 mg,1.85 mmol) were added, nitrogen was replaced three times, and the reaction was carried out at 100℃overnight. After completion of the reaction, the mixture was filtered off with suction, 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 ]] + 。 1 H NMR(400MHz,DMSO-d 6 )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-hydroxypropyl-2-yl) pyridin-4-yl) amino) pyridin-4-yl) oxy) -3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-1-yl) methanone
Step 12 Synthesis of chloro-4- ((3- (tetrahydro-2H-pyran-4-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-4-yl) oxy) pyridine
60% sodium hydride (284 mg,12.10 mmol) was added to a solution of 2-chloro-4- ((3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine (3.08 g,11.0 mmol) in tetrahydrofuran (100 mL) at 0deg.C, stirred for 15min, 2- (trimethylsilyl) ethoxy chloride (2.02 g,12.10 mmol) was added, stirred overnight at room temperature, filtered, concentrated, and isolated by column chromatography to give the title compound. LC-MS m/z 410.2[ M+H ] ] + 。
Step 2 2 Synthesis of- (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
The procedure was followed except for using 2-chloro-4- ((3- (tetrahydro-2H-pyran-4-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-4-yl) oxy) pyridine instead of 2-chloro-4- ((1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl) oxy) pyridine to prepare the title compound. LC-MS m/z 526.3[ M+H ]] + 。
Step 3 2 Synthesis of 4- ((4- ((3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) propan-2-ol
2- (4- ((4- (. About.)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 (450 mg,0.9 mmol), trifluoroacetic acid (6 ml) and triethylsilane (1 ml,6 mmol) were added to a three-port reaction flask and stirred at room temperature for 2H, and the reaction was completed. Concentrating under reduced pressure, adjusting pH to about 7 with saturated sodium bicarbonate solution, adding ethyl acetate, extracting, mixing 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-hydroxypropyl-2-yl) pyridin-4-yl) amino) pyridin-4-yl) oxy) -3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-1-yl) methanone
A solution 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 (115 mg,0.29 mmol) and N, N-diisopropylethylamine (56.38 mg,0.44 mmol) in methylene chloride (10 mL) was sequentially added to a 25mL three-necked flask, and a solution of cyclopropylchloride (30.4 mg,0.29 mmol) in methylene chloride (2 mL) was slowly added dropwise with stirring at room temperature, and after stirring for 10min, the reaction was completed. After quenching the reaction with water, dichloromethane was added, extraction was performed, washing was performed with saturated brine, drying was performed with anhydrous sodium sulfate, filtration was performed, concentration was performed under reduced pressure, and column chromatography was performed to obtain the title compound. LC-MS m/z 464.2[ M+H ]] + 。 1 H 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 47 2- (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
Step 1 3 Synthesis of- (4- ((2-chloropyridin-4-yl) oxy) -3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-1-yl) cyclobutan-1-one
2-chloro-4- ((3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine (1.00 g,3.57 mmol) was dissolved in 20mL of N, N-dimethylformamide, then 3-bromocyclobutanone (1.07 g,7.15 mmol) and potassium carbonate (988.15 mg,7.15 mmol) were added in sequence, the reaction was allowed to proceed overnight at room temperature, and the LC-MS detection reaction ended, diluted with ethyl acetate and filtered. The filtrate was concentrated and purified by column chromatography to give the title compound. ESI-MSm/z 348.1[ M+H ] ] + 。
Step 2 2 Synthesis of chloro-4- ((1- (3, 3-difluorocyclobutyl) -3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine
3- (4- ((2-Chloropyridin-4-yl) oxy) -3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-1-yl) cyclobutan-1-one (200.00 mg,0.58 mmol) was dissolved in 20mL of dichloromethane, protected by nitrogen, diethylaminosulfur trifluoride (1.5 mL,10.0 mmol) was added at-10℃and the reaction was continued for 4H after slowly warming to room temperature, monitored by LC-MS, and the reaction was complete. Adding saturated sodium bicarbonate solution into the reaction solution under 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 3 2 Synthesis of 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
The preparation method is the same as in example 45 step 2The title compound was prepared by substituting 2-chloro-4- ((1- (2-fluoroethyl) -3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine for 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 ] ] + 。 1 H NMR(400MHz,DMSO-d 6 )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 48 2- (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
Step 1 4 Synthesis of tert-butyl- (2- ((2-chloropyridin-4-yl) oxy) acetyl) piperidine-1-carboxylate
The procedure was as for the preparation of the compounds from steps 1 to 2 of example 1, except that tert-butyl 4-acetylpiperidine-1-carboxylate was used instead 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 salt
Tert-butyl 4- (2- ((2-chloropyridin-4-yl) oxy) acetyl) piperidine-1-carboxylate (2 g,5.6 mmol) and trifluoroacetic acid (20 mL) were added sequentially to a 50mL single-necked flask, stirred at room temperature for 2h, and monitored by LC-MS. Concentrating under reduced pressure after the reaction is completed, adding saturated sodium bicarbonate solution and ethyl acetate, extracting, and collecting organic matterThe phases were 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 3 2 Synthesis of- ((2-chloropyridin-4-yl) oxy) -1- (1- (oxetan-3-yl) piperidin-4-yl) ethan-1-one
2- ((2-Chloropyridin-4-yl) oxy) -1- (piperidin-4-yl) ethan-1-one (1.44 g,5.6 mmol), 3-oxetanone (1.22 g,16.9 mmol), sodium triacetoxyborohydride (3.60 g,16.9 mmol) and 25ml1, 2-dichloroethane were added sequentially to the reaction flask and reacted overnight at room temperature, monitored by LC-MS. And (5) finishing the reaction. Adding water to quench the reaction, adding dichloromethane, extracting, washing with saturated saline, 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 42 Synthesis of chloro-4- ((1-cyclopropyl-3- (1- (oxetan-3-yl) piperidin-4-yl) -1H-pyrazol-4-yl) oxy) pyridine
The procedure was followed except for using 2- ((2-chloropyridin-4-yl) oxy) -1- (1- (oxetan-3-yl) piperidin-4-yl) ethan-1-one instead of 2- ((2-chloropyridin-4-yl) oxy) -1- (tetrahydro-2H-pyran-4-yl) ethan-1-one to prepare the title compound as described in example 1, steps 3-5. ESI-MS m/z 375.2[ M+H ]] + 。
Step 5 2 Synthesis of- (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
Preparation method is the same as in example 45 step 2The title compound was prepared by substituting 2-chloro-4- ((1- (2-fluoroethyl) -3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine with 2-chloro-4- ((1-cyclopropyl-3- (1- (oxetan-3-yl) piperidin-4-yl) -1H-pyrazol-4-yl) oxy) pyridine. ESI-MS m/z 491.6[ M+H ]] + 。 1 H NMR(400MHz,CDCl 3 )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 49 2- (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
4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) -N- (piperidin-4-yl) pyridin-2-amine hydrochloride (158 mg,0.413 mmol), 2-bromoethanol (56.7 mg,0.454 mmol) were dissolved in 10mL acetonitrile, cesium carbonate (267 mg, 0.828 mmol) was added and reacted at 40℃for 3H. TLC detection is carried out, after the reaction is completed, a filtrate is obtained through suction filtration, a solvent is distilled off under reduced pressure, and the title compound is obtained through column chromatography separation. LC-MS m/z 428.3[ M+H ] ] + 。 1 H NMR(400MHz,DMSO-d 6 )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 50- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) -N- (2- (4, 4-difluoropiperidin-1-yl) pyridin-4-yl) pyridin-2-amine
Step 1 2 Synthesis of- (4, 4-difluoropiperidin-1-yl) -4-nitropyridine
2-bromo-4-nitropyridine (1.00 g,4.93 mmol), 4-difluoropiperidine hydrochloride (1.16 g,7.39 mmol) and cesium carbonate (4.82 g,14.78 mmol) were dissolved in 20mL of 1, 4-dioxane solution, heated to 100deg.C and reacted overnight for LC-MS detection. After the reaction, 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 2 2 Synthesis of- (4, 4-difluoropiperidin-1-yl) pyridin-4-amine
To a solution of 2- (4, 4-difluoropiperidin-1-yl) -4-nitropyridine (330.0 mg,1.36 mmol) in 25mL of ethanol/water (4:1) was added reduced iron powder (303.0 mg,5.43 mmol) and ammonium chloride (362.9 mg,6.78 mmol), the mixture was warmed to 80℃and reacted overnight, and LC-MS monitored that the reaction was complete. The method comprises the steps of performing auxiliary filtration by using diatomite, taking 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 3 4 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
The procedure was followed except for using 2- (4, 4-difluoropiperidin-1-yl) pyridin-4-amine instead of 2-morpholinopyridin-4-amine to prepare the title compound as step 3. ESI-MS m/z 497.3[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 )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 51 2- (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
Step 1 5 Synthesis of methyl amino-2-bromobenzoate
To a mixed solution of methyl 2-bromo-5-nitrobenzoate (5.0 g,19.31 mmol) in ethanol (40 mL) and water (10 mL), reduced iron powder (4.31 g,77.24 mmol) and ammonium chloride (5.12 g,96.55 mmol) were added, reacted at 80℃for 3h, and TLC detection. The reaction was completed, filtered off with suction, concentrated under reduced pressure to remove ethanol, added with water and ethyl acetate, extracted, combined with the organic phase, 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- ((t-butoxycarbonyl) amino) benzoate
Methyl 5-amino-2-bromobenzoate (4.46 g,19.31 mmol), di-tert-butyl dicarbonate (10.1 g,42.5 mmol), sodium carbonate (6 g,58 mmol) and methanol (30 mL) were added sequentially to the reaction flask and reacted at room temperature for 24h. Concentrating under reduced pressure 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-hydroxypropane-2-yl) phenyl) carbamate
Methyl magnesium bromide (3M, 12mL,36 mmol) was added to the flask under nitrogen protection, stirred at 0deg.C, a solution of methyl 2-bromo-5- ((tert-butoxycarbonyl) amino) benzoate (3.97 g,12 mmol) in anhydrous tetrahydrofuran (30 mL) was added dropwise, after the dropwise addition, the reaction was allowed to proceed to room temperature for 6h until TLC detection was complete, and quenched by addition of saturated ammonium chloride solution at 0deg.C. Ethyl acetate was added, the extracts were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to give 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
Tert-butyl (4-bromo-3- (2-hydroxypropan-2-yl) phenyl) carbamate (450 mg,1.36 mmol) was added to 20mL of N, N-dimethylformamide solution, nitrogen was purged three times, 1, 10-phenanthroline copper trifluoride (639 mg,2.04 mmol) was added, the mixture was sealed, reacted overnight at 50℃and detected by LC-MS. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with ethyl acetate, filtered with the aid of celite, and the filtrate was washed with 1M aqueous hydrochloric acid, and then with saturated sodium bicarbonate and saturated aqueous saline, 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
4mL of dioxane, 2mL of water and 2mL of hydrochloric acid were added to the reaction flask, and (3- (2-hydroxypropan-2-yl) -4- (trifluoromethyl) phenyl) amino group was addedTert-butyl formate (283 mg,0.9 mmol) was reacted overnight at room temperature to complete the reaction by TLC. Neutralizing the reaction solution with sodium hydroxide solution, adding ethyl acetate, extracting, collecting 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 6 2 Synthesis of- (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
The procedure was followed except for using 2- (5-amino-2- (trifluoromethyl) phenyl) propan-2-ol instead of 2-morpholinopyridin-4-amine to give the title compound. ESI-MS m/z 503.2[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 )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 52 1- (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
Step 1 1 Synthesis of- (4-nitropyridin-2-yl) azetidine-3-carbonitrile
2-bromo-4-nitropyridine (1.00 g,4.93 mmol), 3-acetonitrile cyclobutylamine hydrochloride (759.30 mg,6.40 mmol) and cesium carbonate (4.82 g,14.78 mmol) were placed in a reaction flask, 50mL of 1, 4-dioxane was added and reacted overnight at 100 ℃. LC-MS detection, reaction is finished, cooling to room temperature, 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 2 1 Synthesis of- (4-aminopyridin-2-yl) azetidine-3-carbonitrile
1- (4-nitropyridin-2-yl) azetidine-3-carbonitrile (510.00 mg,2.50 mmol) was dissolved in 20mL of methanol, palladium on carbon (200.0 mg, 10%) was added, and after hydrogen displacement the reaction was carried out at room temperature for 3h, monitored by TLC and the reaction was complete. Filtering to obtain filtrate, and concentrating under reduced pressure to obtain the title compound. ESI-MS m/z 175.1[ M+H ]] + 。
Step 3 1 Synthesis of- (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
The procedure was followed except for using 1- (4-aminopyridin-2-yl) azetidine-3-carbonitrile instead of 2-morpholinopyridin-4-amine to give the title compound. ESI-MSm/z 458.3[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 )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 53 2- (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
Step 1 2 Synthesis of- (6-bromoisoquinolin-3-yl) propan-2-ol
3.0mol/L of methyl magnesium bromide/tetrahydrofuran solution (3.57 mL,10.7 mmol) was added to a nitrogen-substituted three-necked flask, and 6-bromoisoquinoline-3-carboxylic acid ethyl ester (1.00 g,3.57 mmol) in anhydrous tetrahydrofuran (10 mL) was slowly added dropwise at 0℃and the mixture was allowed to react at room temperature for 6 hours. After the reaction was completed, the saturated ammonium chloride solution was quenched, ethyl acetate was added thereto, extraction was performed, the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the title compound was purified by column chromatography. LC-MS m/z 266.0,268.0[ M+H ] ] + 。
Step 2 2 Synthesis of- (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
4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-amine (200 mg,0.67 mmol) and 2- (6-bromoisoquinolin-3-yl) propan-2-ol (194 mg,0.73 mmol) were placed in a reaction flask, 5mL of 1, 4-dioxane was added, followed by addition of tris (dibenzylideneacetone) dipalladium (61.1 mg,0.0667 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (116 mg,0.20 mmol) and cesium carbonate (435 mg,1.33 mmol), nitrogen was replaced three times, and the reaction was continued overnight at 100 ℃. After the reaction was completed, the filtrate was obtained by suction filtration, the solvent was distilled off under reduced pressure, and the title compound was obtained by separation by column chromatography. LC-MS m/z 486.2[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 )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 54- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) -N- (2- (3-fluoroazetidin-3-yl) pyridin-4-yl) pyridin-2-amine
Step 13 Synthesis of tert-butyl- (4-bromopyridin-2-yl) -3-hydroxyazetidine-1-carboxylate
2, 4-dibromopyridine (3.00 g,12.7 mmol) was added to a three-necked flask, nitrogen was replaced three times, 30mL of anhydrous tetrahydrofuran was added thereto, and a 2.5M n-hexane solution (5.56 mL,13.9 mmol) of n-butyllithium was slowly added dropwise at-78℃and stirred for 1h after the completion of the dropwise addition. Then 15mL of an anhydrous tetrahydrofuran solution of 1-t-butoxycarbonyl-3-azetidinone (2.38 g,13.9 mmol) was slowly added dropwise to the reaction system, and the reaction was continued at-78deg.C for 1 hour after the completion of the dropwise addition. After completion of the reaction, 10mL of saturated ammonium chloride solution was added to quench, ethyl acetate was added, the extracts were combined, the organic phases were dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the title compound was obtained by column chromatography separation. LC-MS m/z 329.0,331.0[ M+H ] ] + 。
Preparation of step 2 3- (4-bromopyridin-2-yl) -3-fluoroazetidine-1-carboxylic acid tert-butyl ester
3- (4-bromopyridin-2-yl) -3-hydroxyazetidine-1-carboxylic acid tert-butyl ester (2.10 g,6.40 mmol) was dissolved in 20mL of methylene chloride, and diethylaminosulfur trifluoride (1.46 mL,12.8 mmol) was slowly added at 0℃and after the completion of the dropwise addition, the mixture was allowed to stand at room temperature for 0.5h. After completion of the reaction, 10mL of saturated sodium bicarbonate solution and ethyl acetate were added, 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 separation. 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
4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-amine (200 mg,0.667 mmol) and 3- (4-bromopyridin-2-yl) -3-fluoroazetidine-1-carboxylic acid tert-butyl ester (242 mg,0.733 mmol) were dissolved in 5mL of 1, 4-dioxane, tris (dibenzylideneacetone) dipalladium (61.1 mg,0.0667 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (116 mg,0.200 mmol) and cesium carbonate (435 mg,1.33 mmol) were added, and the reaction was carried out three times with nitrogen overnight at 100 ℃. After the reaction was completed, the filtrate was obtained by suction filtration, the solvent was distilled off under reduced pressure, and the title compound was obtained by separation by column chromatography. LC-MS m/z 551.3[ M+H ] ] + 。
Preparation of step 4 4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) -N- (2- (3-fluoroazetidin-3-yl) pyridin-4-yl) pyridin-2-amine
3- (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-carboxylic acid tert-butyl ester (210 mg,0.382 mmol) was dissolved in a solution of hydrogen chloride/1, 4-dioxane (10 mL,4.0 mol/L) and reacted overnight at room temperature. After the reaction was completed, the reaction solution was neutralized with sodium hydrogencarbonate solution, ethyl acetate was added thereto, extraction was performed, the solvent was distilled off under reduced pressure, and the title compound was obtained by separation through column chromatography. LC-MS m/z 451.2[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 )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 55 2- (-4- ((4- ((1-cyclopropyl-3- (piperidin-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) propan-2-ol hydrochloride
Synthesis of tert-butyl step 1 4- (4- ((2-chloropyridin-4-yl) oxy) -1-cyclopropyl-1H-pyrazol-3-yl) piperidine-1-carboxylate
The procedure was as in step 1-5 of example 1 except that tert-butyl 4-acetylpiperidine-1-carboxylate was used instead of 1- (tetrahydro-2H-pyran-4-yl) ethanone to give the title compound. ESI-MSm/z 363.88[ M-tBu+H ]] + 。
Step 2 4 Synthesis of tert-butyl 1- (1-cyclopropyl-4- ((2- ((2- (2-hydroxy-prop-2-yl) pyridin-4-yl) amino) pyridin-4-yl) oxy) -1H-pyrazol-3-yl) piperidine-1-carboxylate
The procedure was followed except for using tert-butyl 2- (4- ((2-chloropyridin-4-yl) oxy) -1-cyclopropyl-1H-pyrazol-3-yl) piperidine-1-carboxylate instead of 2-chloro-4- ((1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl) oxy) pyridine to prepare the title compound. ESI-MS m/z 535.66[ M+H ]] + 。
Step 3 2 Synthesis of- (-4- ((4- ((1-cyclopropyl-3- (piperidin-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) propan-2-ol hydrochloride
Tert-butyl 4- (1-cyclopropyl-4- ((2- ((2- (2-hydroxy-prop-2-yl) pyridin-4-yl) amino) pyridin-4-yl) oxy) -1H-pyrazol-3-yl) piperidine-1-carboxylate (309 mg, 7)64.97 umol) was dissolved in 6mL of hydrochloric acid/dioxane solution, and the reaction was stirred at 30 ℃. After completion of the TLC detection, the reaction solution was directly concentrated under reduced pressure to give the title compound. ESI-MS m/z 435.2[ M-HCl+H ]] + 。 1 H 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 56 1- (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
Step 1 4 Synthesis of methyl-1- (4-nitropyridin-2-yl) piperidin-4-ol
2-bromo-4-nitropyridine (1.00 g,4.93 mmol), 4-methylpiperidin-4-ol (709.23 mg,6.16 mmol) and cesium carbonate (2.41 g,7.39 mmol) were dissolved in 30mL of 1, 4-dioxane solution and reacted overnight at 100 ℃. LC-MS detection, reaction, cooling to room temperature, filtering, concentrating filtrate, and purifying by column chromatography to obtain the title compound. ESI-MS m/z 238.1[ M+H ] ] + 。
Step 2 1 Synthesis of- (4-aminopyridin-2-yl) -4-methylpiperidin-4-ol
4-methyl-1- (4-nitropyridin-2-yl) piperidin-4-ol (900.0 mg,3.79 mmol) was dissolved in 20mL methanol, palladium on carbon (10%, 300.0 mg) was added, the reaction was allowed to proceed for 3h at room temperature after hydrogen substitution many times, and TLC monitored the reaction was complete. Passing throughThe reaction solution was filtered, and the filtrate was concentrated to give the title compound. ESI-MS m/z 208.1[ M+H ]] + 。
Step 3 1 Synthesis of- (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
The procedure was followed except for using 1- (4-aminopyridin-2-yl) -4-methylpiperidin-4-ol instead of 3-amino-6-methylbenzenesulfonamide to give the title compound. ESI-MS m/z 491.3[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 )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 57 1-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
Step 1 1 Synthesis of- (4-bromopyridin-2-yl) ethan-1-one
2, 4-dibromopyridine (1.20 g,5.06 mmol) was added to a three-necked flask, replaced with nitrogen three times, and 10mL of toluene was added for dissolution. 2.5M n-hexane solution of n-butyllithium (2.23 mL,5.57 mmol) was slowly added dropwise at-78deg.C, and the mixture was stirred for 1h after the completion of the addition. N-methoxy-N-methylacetamide (1.56 g,15.2 mmol) was then slowly added dropwise, and the reaction was continued for 1h at-78deg.C after the addition. After the reaction was completed, 10mL of 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 the title compound was obtained by column chromatography separation. LC-MS m/z 199.9,201.9[ M+H ]] + 。
Step 2 1 Synthesis of- (4-bromopyridin-2-yl) -1-cyclopropylethyl-1-ol
1.0mol/L of a solution of cyclopropylmagnesium bromide in tetrahydrofuran (4.07 mL,4.07 mmol) was added to a three-necked flask replaced with nitrogen, and a solution of 1- (4-bromopyridin-2-yl) ethan-1-one (270 mg,1.36 mmol) in anhydrous tetrahydrofuran (10 mL) was slowly added dropwise at-78℃and the mixture was allowed to react at room temperature for 6 hours. After completion of the reaction, 10mL of saturated ammonium chloride solution was added to quench, ethyl acetate was added, the extracts were combined, the organic phases were dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the title compound was isolated by column chromatography. LC-MS m/z 242.0,244.0[ M+H ]] + 。
Step 3 1 Synthesis of 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
The procedure was followed except for using 1- (4-bromopyridin-2-yl) -1-cyclopropylethyl-1-ol instead of 2- (6-bromoisoquinolin-3-yl) propan-2-ol in preparation of the compound of step 4 of example 53, the title compound was obtained. LC-MS m/z 462.2[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 )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 58- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) -N- (3-morpholin-4- (trifluoromethyl) phenyl) pyridin-2-amine
Step 1 4 Synthesis of- (5-nitro-2- (trifluoromethyl) phenyl) morpholine
2-fluoro-4-nitro-1- (trifluoromethyl) benzene (700 mg,3.35 mmol) and morpholine (2.92 g,33.48 mmol) were placed in a reaction flask and 10mL of dimethyl sulfoxide was added and reacted overnight at 100deg.C, followed by TLC. After completion, the reaction solution was cooled to room temperature, water and ethyl acetate were added, the organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give the title compound. 277.6[ M+H ] ESI-MS m/z] + 。
Step 2 3 Synthesis of morpholine-4- (trifluoromethyl) aniline
4- (5-nitro-2- (trifluoromethyl) phenyl) morpholine (977 mg,3.54 mmol) was dissolved in 20mL of methanol, 10% palladium on carbon catalyst (80 mg) was added, and the mixture was reacted at room temperature under hydrogen protection for 3 hours. TLC detection, after the reaction was completed, celite was used for auxiliary filtration, and the filtrate was concentrated under reduced pressure to give the title compound. ESI-MS m/z 247.1[ M+H ]] + 。
Step 3 4 Synthesis of- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) -N- (3-morpholin-4- (trifluoromethyl) phenyl) pyridin-2-amine
The procedure was followed except for using 3-morpholin-4- (trifluoromethyl) aniline instead of 2-morpholinopyridin-4-amine to prepare the title compound. ESI-MS m/z:530.3[M+H] + 。 1 H NMR(400MHz,DMSO-d 6 )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 59 2- (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
Step 1 Synthesis of tert-butyl (3- (2-hydroxy-prop-2-yl) -4- (methylsulfonyl) phenyl) carbamate
Tert-butyl (4-bromo-3- (2-hydroxypropan-2-yl) phenyl) carbamate (200 mg,605.65 mol), methanesulfonic acid (74.19 mg,726.78 mol), L-proline (13.95 mg,121.13 mol), sodium hydroxide (4.84 mg,121.13 mol) and cuprous iodide (11.53 mg,60.57 mol) were placed in a reaction flask, and 5mL of dimethyl sulfoxide was added under argon, followed by stirring at 95℃for 48 hours. After the reaction was completed, the reaction solution was cooled to room temperature, water and ethyl acetate were added, 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 328.1[ M-H ]] - 。
Step 2 2 Synthesis of- (5-amino-2- (methylsulfonyl) phenyl) propan-2-ol hydrochloride
Tert-butyl (3- (2-hydroxy-prop-2-yl) -4- (methylsulfonyl) phenyl) carbamate (121 mg,367.32 umol) was dissolved in 10mL of hydrogen chloride/ethanol and reacted at 25 ℃. After the reaction is completed, the reaction solution is directly spin-dried to carry out the next reaction.
Step 32 Synthesis of- (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
The procedure was followed except for using 2- (5-amino-2- (methylsulfonyl) phenyl) propan-2-ol hydrochloride instead of 2-morpholinopyridin-4-amine to give the title compound. ESI-MSm/z 513.3[ M+H ]] + 。 1 H 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 60 1- (4- ((4- ((1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) azetidine-3-carbonitrile
The procedure was followed except for using 1- (4-aminopyridin-2-yl) azetidin-3-carbonitrile instead of 2- (4-aminopyridin-2-yl) propan-2-ol to give the title compound. ESI-MS m/z 450.3[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 )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 61 4- (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
Step 1 4 Synthesis of bromo-2- (1, 4-dioxaspiro [4.5] dec-7-en-8-yl) pyridine
2, 4-dibromopyridine (4.00 g,16.9 mmol) and 1, 4-dioxa-spiro [4, 5]]To a mixed solvent of 40mL of 1, 4-dioxane and 10mL of water was dissolved dec-7-ene-8-boronic acid pinacol ester (4.94 g,18.6 mmol), tetrakis (triphenylphosphine) palladium (0.975 g, 0.84mmol) and potassium carbonate (4.66 g,33.8 mmol) were added, the mixture was replaced with nitrogen gas three times, and the mixture was reacted at 90℃for 3 hours. After the reaction was completed, suction filtration was performed, the solvent was distilled off from the filtrate under reduced pressure, and the title compound was obtained by separation through column chromatography. LC-MS m/z 296.0,298.0[ M+H ] ] + 。
Step 2 4 Synthesis of- (4-bromopyridin-2-yl) cyclohex-3-en-1-one
4-bromo-2- (1, 4-dioxaspiro [4.5 ]]Dec-7-en-8-yl) pyridine (1.95 g,6.61 mmol) was dissolved in 5mL trifluoroacetic acid and reacted at room temperature for 2h. After completion of the reaction, the solvent was distilled off under reduced pressure to give the title compound. LC-MS m/z 251.9,253.9[ M+H ]] + 。
Step 3 4 Synthesis of- (4-bromopyridin-2-yl) cyclohex-3-en-1-ol
4- (4-bromopyridin-2-yl) cyclohex-3-en-1-one (1.66 g,6.61 mmol) was dissolved in 15mL of methanol, and sodium borohydride (0.502 g,13.2 mmol) was added at 0deg.C and the mixture was allowed to react at room temperature for 2h. After the reaction was completed, a saturated sodium hydrogencarbonate 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 the title compound was obtained by column chromatography separation. LC-MS m/z 254.0,256.0[ M+H ]] + 。
Step 4 4 Synthesis of- (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
The procedure was followed except for using 4- (4-bromopyridin-2-yl) cyclohex-3-en-1-ol instead of 2- (6-bromoisoquinolin-3-yl) propan-2-ol in the preparation of the compound of step 4 of example 53, to give the title compound. LC-MSm/z 474.2[ M+H ]] + 。
Step 54 Synthesis of- (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
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 (110 mg,0.232 mmol) was dissolved in 5mL of methanol, palladium on carbon catalyst (11.0 mg, 10%) was added, hydrogen was replaced three times, and the reaction was carried out at room temperature overnight. After the reaction was completed, suction filtration was performed, the solvent was distilled off from the filtrate under reduced pressure, and the title compound was obtained by separation through column chromatography. LC-MS m/z 476.3[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 )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 62 2- (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
Step 15 Synthesis of methyl bromo-1-methyl-1H-indazole-3-carboxylate
Methyl 5-bromo-1H-indazole-3-carboxylate (2.00 g,7.87 mmol) was dissolved in 20mL of acetonitrile, potassium carbonate (2.17 g,15.7 mmol) was added, methyl iodide (0.480 mL,7.87 mmol) was slowly added dropwise at 0deg.C, and after the addition, the reaction was allowed to proceed to room temperature for 2H. After completion of the reaction, the solvent was distilled off under reduced pressure and separated by column chromatography to give the title compound. LC-MS m/z 268.9,270.9[ M+H ]] + 。
Step 2 2 Synthesis of- (5-bromo-1-methyl-1H-indazol-3-yl) propan-2-ol
3.0mol/L of methyl magnesium bromide tetrahydrofuran (5.86 mL,17.6 mmol) was added to a nitrogen-substituted three-necked flask, and 5-bromo-1-methyl-1H-indazole-3-carboxylic acid methyl ester (1.57 g,5.86 mmol) in anhydrous tetrahydrofuran (15 mL) was slowly added dropwise at 0℃and the mixture was allowed to react at room temperature for 6 hours. After completion of the reaction, 10mL of saturated ammonium chloride solution was added to quench, extraction was performed 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 separation. LC-MS m/z 269.0,271.0[ M+H ] ] + 。
Step 3 2 Synthesis of- (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
Preparation method the same as in example 53 preparation method of the compound of step 4 except that 2- (6-bromoisoquinolin-3-yl) was replaced with 2- (5-bromo-1-methyl-1H-indazol-3-yl) propan-2-ol) Propan-2-ol to give the title compound. LC-MS m/z 489.3[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 )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 63 2- (4- ((4- ((1-cyclopropyl-3- (4-morpholinophenyl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) propan-2-ol
Step 1 2 Synthesis of bromo-1- (4-morpholinophenyl) ethan-1-one
1- (4-morpholinophenyl) ethyl-1-one (4.1 g,20 mmol) is taken and added into a round bottom flask, 20mL of a mixed solution of diethyl ether/1, 4-dioxane (1:1) is added, the temperature is reduced to minus 5 ℃, diethyl ether (10 mL) solution of liquid bromine (1.4 mL,27 mmol) is added, the mixture is dropwise added for 30min, the mixture is stirred and reacted for 3h, liquid bromine (0.4 mL,7.8 mmol) is added, and the mixture is reacted overnight at room temperature. The reaction solution was washed with sodium thiosulfate solution, ethyl acetate was added thereto, extraction was performed, the organic phases were combined, concentrated under reduced pressure, and separated by column chromatography to give the title compound. ESI-MS m/z 284.0,286.0[ M+H ]] + 。
Step 2 2 Synthesis of- (4- ((4- ((1-cyclopropyl-3- (4-morpholinophenyl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) propan-2-ol
The procedure was as in example 3, steps 1-4, except that 2-bromo-1- (4-morpholinophenyl) ethan-1-one was used instead of 2-bromo-1-phenylethan-1-one, to give the title compound. ESI-MS m/z 513.0[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 )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 64 2- (5- ((4- ((1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -2- (trifluoromethyl) phenyl) propan-2-ol
Step 1 2 Synthesis of- (5-amino-2- (trifluoromethyl) phenyl) propan-2-ol hydrochloride
Tert-butyl (3- (2-hydroxy-prop-2-yl) -4- (trifluoromethyl) phenyl) carbamate (365 mg,1.15 mmol) was dissolved in 20mL hydrogen chloride/dioxane and reacted at 25 ℃. After the reaction is completed, the reaction solution is directly spin-dried to carry out the next reaction.
Step 2 2 Synthesis of- (5- ((4- ((1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -2- (trifluoromethyl) phenyl) propan-2-ol
The procedure was followed except for using 2- (5-amino-2- (trifluoromethyl) phenyl) propan-2-ol hydrochloride instead of 2- (4-aminopyridin-2-yl) propan-2-ol to give the title compound as in example 3, step 4. ESI-MS m/z 495.2[ M+H ]] + 。 1 H 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 65 4- (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
Step 1 4 Synthesis of- (2-fluoro-5-nitrophenyl) thiomorpholine-1, 1-dioxide
2-bromo-1-fluoro-4-nitrobenzene (400 mg,1.82 mmol) and thiomorpholine-1, 1-dioxide (270 mg,2.20 mmol) were dissolved in 10mL 1, 4-dioxane, palladium acetate (22.3 mg,0.091 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (105 mg,0.182 mmol) and cesium carbonate (1.19 g,3.64 mmol) were added, nitrogen was replaced three times, and the reaction was continued overnight at 100 ℃. After the reaction was completed, the filtrate was obtained by suction filtration, the solvent was distilled off under reduced pressure, and the title compound was obtained by separation by column chromatography. ESI-MS m/z 275.0[ M+H ]] + 。
Step 24 Synthesis of- (5-amino-2-fluorophenyl) thiomorpholine-1, 1-dioxide
4- (2-fluoro-5-nitrophenyl) thiomorpholine 1, 1-dioxide (100 mg,0.365 mmol) was dissolved in a mixed solvent of 15mL ethanol/water (4:1), reduced iron powder (51.1 mg,0.912 mmol) and ammonium chloride (58.0 mg,1.09 mmol) were added and reacted at 80℃for 2h. After completion of the reaction, celite was added for filtration, the filtrate was taken, water and dichloromethane were added, extraction was performed, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give the title compound. ESI-MS m/z 245.1[ M+H ]] + 。
Step 3 4 Synthesis of 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
The procedure was followed except for using 4- (5-amino-2-fluorophenyl) thiomorpholine-1, 1-dioxide in place of 2-morpholinopyridin-4-amine to prepare the title compound. ESI-MSm/z 528.2[ M+H ]] + 。 1 H 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 66 Synthesis of 2- (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
The procedure was followed except for using 2- (5-amino-2- (methylsulfonyl) phenyl) propan-2-ol hydrochloride instead of 2- (4-aminopyridin-2-yl) propan-2-ol in example 48 to give the title compound. ESI-MS m/z 568.2[ M+H ]] + 。 1 H NMR(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 67 1- (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
Step 1 1 Synthesis of- (5-amino-2- (methylsulfonyl) phenyl) -3-methylazetidin-3-ol
3-fluoro-4- (methylsulfonyl) aniline (300 mg,1.59 mmol), 3-methylazetidin-3-ol hydrochloride (151.95 mg,1.74 mmol) and cesium carbonate (1.03 g,3.17 mmol) were placed in a reaction flask and reacted overnight at 140℃under the addition of 15mL of dimethyl sulfoxide and argon. The next day the reaction was cooled to room temperature, 15mL of water was added to quench the reaction solution, ethyl acetate was added, extraction was performed, and the organic phase was collected. 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. ESI-MS m/z 257.1[ M+H ] ] + 。
Step 2 1 Synthesis of- (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
The procedure was followed except for using 1- (5-amino-2- (methylsulfonyl) phenyl) -3-methylazetidin-3-ol instead of 2-morpholinopyridin-4-amine to give the title compound. ESI-MS m/z 540.3[ M+H ]] + 。 1 H 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 68 1- (5- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -2-fluorophenyl) azetidine-3-carbonitrile
Step 1 1 Synthesis of- (2-fluoro-5-nitrophenyl) azetidine-3-carbonitrile
2-bromo-1-fluoro-4-nitrobenzene (600 mg,2.73 mmol) and azetidine-3-carbonitrile (356 mg,3.00 mmol) were dissolved in 10mL 1, 4-dioxane, palladium acetate (33.4 mg,0.136 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (158 mg, 0.2793 mmol) and cesium carbonate (2.67 g,8.19 mmol) were added, nitrogen was replaced three times, and the reaction was continued overnight at 100 ℃. After the reaction was completed, the filtrate was obtained by suction filtration, the solvent was distilled off under reduced pressure, and the title compound was obtained by separation by column chromatography. 222.1[ M+H ] ESI-MS m/z] + 。
Step 2 1 Synthesis of- (5-amino-2-fluorophenyl) azetidine-3-carbonitrile
1- (2-fluoro-5-nitrophenyl) azetidine-3-carbonitrile (483 mg,2.19 mmol) was weighed out and dissolved in a mixed solvent of 15mL of ethanol/water (4:1), and reduced iron powder (306 mg,5.46 mmol) and ammonium chloride (348 mg,6.57 mmol) were added to react at 80℃for 2 hours. After completion of the reaction, celite was added for filtration, the filtrate was extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give the title compound. ESI-MS m/z 192.1[ M+H ]] + 。
Step 3 1 Synthesis of- (5- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -2-fluorophenyl) azetidine-3-carbonitrile
PreparationThe procedure was followed except for using 1- (5-amino-2-fluorophenyl) azetidine-3-carbonitrile instead of 2-morpholinopyridin-4-amine to prepare the title compound. ESI-MS m/z 475.2[ M+H ]] + 。 1 H NMR(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 69 3- (5- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -2-fluorophenyl) oxetan-3-ol
Step 11 Synthesis of- (3-bromo-4-fluorophenyl) -2, 5-dimethyl-1H-pyrrole
3-bromo-4-fluoroaniline (4.00 g,21.1 mmol) and 2, 5-hexanedione (2.64 g,23.2 mmol) were dissolved in 80mL of toluene, and p-toluenesulfonic acid (36.3 mg,0.211 mmol) was added thereto and reacted under reflux for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the title compound was obtained by separation by column chromatography. ESI-MS m/z 268.0,270.0[ M+H ] ] + 。
Step 2 3 Synthesis of- (5- (2, 5-dimethyl-1H-pyrrol-1-yl) -2-fluorophenyl) oxetan-3-ol
1- (3-bromo-4-fluorophenyl) -2, 5-dimethyl-1H-pyrrole (1.00 g,3.75 mmol) was added to a three-necked flask, replaced with nitrogen three times, and 10mL of anhydrous tetrahydrofuran was added for dissolution. Tetrahydrofuran solution of isopropyl magnesium chloride lithium chloride complex (3.46 mL,1.3M,4.50 mmol) was slowly added dropwise at-30deg.C) Stirring for 1h after the dripping is completed. Oxetan-3-one (0.297 g,4.12 mmol) was slowly added dropwise and the reaction was continued for 1h at-30 ℃. After completion of the reaction, 10mL of saturated ammonium chloride solution was added to quench, ethyl acetate was then added to extract, 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 separation. ESI-MSm/z 262.1[ M+H ]] + 。
Step 33 Synthesis of- (5-amino-2-fluorophenyl) oxetan-3-ol
3- (5- (2, 5-dimethyl-1H-pyrrol-1-yl) -2-fluorophenyl) oxetan-3-ol (400 mg,1.53 mmol) was dissolved in a mixed solvent of 16mL of ethanol/water (1:1), hydroxylamine hydrochloride (533 mg,7.66 mmol) and potassium hydroxide (257 mg,4.60 mmol) were added, and the mixture was reacted at room temperature for 3 hours. After completion of the reaction, dichloromethane was added, 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 separation. ESI-MS m/z 184.1[ M+H ] ] + 。
Step 4 3 Synthesis of- (5- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -2-fluorophenyl) oxetan-3-ol
The procedure was followed except for using 3- (5-amino-2-fluorophenyl) oxetan-3-ol instead of 2-morpholinopyridin-4-amine to prepare the title compound. ESI-MS m/z 467.2[ M+H ]] + 。 1 H NMR(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 70 4- (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
Step 1 4 Synthesis of- (5-nitro-2- (trifluoromethyl) phenyl) thiomorpholine-1, 1-dioxide
2-bromo-4-nitro-1- (trifluoromethyl) benzene (500 mg,1.86 mmol) and thiomorpholine-1, 1-dioxide (276 mg,2.04 mmol) were dissolved in 10mL 1, 4-dioxane, palladium acetate (20.9 mg,0.09 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (108 mg,0.186 mmol) and cesium carbonate (1.21 g,3.72 mmol) were added, nitrogen was replaced three times, and the reaction was continued overnight at 100 ℃. After the reaction was completed, the liquid was filtered by suction, the solvent was distilled off under reduced pressure, and the title compound was obtained by separation by column chromatography. ESI-MS m/z 325.0[ M+H ]] + 。
Synthesis of step 2 4- (5-amino-2- (trifluoromethyl) phenyl) thiomorpholine-1, 1-dioxide
4- (5-nitro-2- (trifluoromethyl) phenyl) thiomorpholine-1, 1-dioxide (426 mg,1.30 mmol) was dissolved in 10mL of methanol, palladium on carbon catalyst (42.1 mg, 10%) was added, hydrogen was replaced three times, and the reaction was carried out at room temperature overnight. After the reaction was completed, the filtrate was obtained by suction filtration, and the solvent was distilled off under reduced pressure to obtain the title compound. ESI-MS m/z 295.1[ M+H ]] + 。
Step 3 4 Synthesis of- (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
The procedure was followed except for using 4- (5-amino-2- (trifluoromethyl) phenyl) thiomorpholine-1, 1-dioxide instead of 2-morpholinopyridin-4-amine to prepare the title compound. 578.2[ M+H ] ESI-Ms m/z] + 。 1 H 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 71 2- (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
Step 1 2 Synthesis of- (4- (4-nitro-2- (trifluoromethyl) phenyl) piperazin-1-yl) ethan-1-ol
1-fluoro-4-nitro-2- (trifluoromethyl) benzene (1.00 g,4.78 mmol), 1- (2-hydroxyethyl) piperazine (1.87 g,14.35 mmol) and potassium carbonate (1.32 g,9.56 mmol) were dissolved in 50mL of dimethyl sulfoxide solution and reacted overnight at 90 ℃. After the reaction, cooling to room temperature, filtering, concentrating the filtrate, and purifying by column chromatography to obtain the title compound. ESI-MS m/z 320.2[ M+H ] ] + 。
Step 2 2 Synthesis of- (4- (4-amino-2- (trifluoromethyl) phenyl) piperazin-1-yl) ethan-1-ol
2- (4- (4-nitro-2- (trifluoromethyl) benzene)Base) piperazin-1-yl) ethan-1-ol (1.5 g,4.70 mmol) was dissolved in 20mL methanol, palladium on carbon catalyst (50 mg, 10%) was added, hydrogen was replaced multiple times, and reacted at room temperature for 3h. The reaction was complete, the filtrate was filtered and concentrated to give the title compound. ESI-MS m/z 290.2[ M+H ]] + 。
Step 3 2 Synthesis of- (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
The procedure was followed except for using 2- (4- (4-amino-2- (trifluoromethyl) phenyl) piperazin-1-yl) ethan-1-ol instead of 2-morpholinopyridin-4-amine to prepare the title compound. ESI-MS m/z 573.4[ M+H ]] + 。 1 H 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 72 1- (4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) -2, 2-trifluoroethyl-1-ol
Preparation of step 1 1- (4-bromopyridin-2-yl) -2, 2-trifluoroethyl-1-ol
4-bromopyridine-2-carbaldehyde (2.0 g,10.76 mmol) and trifluoromethyltrimethylsilane (1.84 g,12.90 mmol) were added to a 100mL three-necked flask, Under the protection of argon, 20mL of tetrahydrofuran is added for dissolution, cooled to 0 ℃, tetrabutylammonium fluoride (0.54 mL,0.54 mmol) is added dropwise, and the reaction is carried out for 2h at room temperature. After the reaction was completed, it was cooled to 0℃and hydrochloric acid solution (6 mL, 6M) was added thereto, stirring was continued for 30min, and pH was adjusted to 8 with sodium hydroxide solution. Ethyl acetate was added, extraction was performed, washing was performed with water, saturated sodium chloride solution, drying was performed with anhydrous sodium sulfate, and the title compound was obtained by concentration. LC-MS m/z 256.2,258.2[ M+H ]] + 。
Step 2 preparation of tert-butyl 2- (2, 2-trifluoro-1-hydroxyethyl) pyridin-4-yl) carbamate
1- (4-bromopyridin-2-yl) -2, 2-trifluoroethyl-1-ol (2.55 g,10 mmol), tert-butyl carbamate (1.4 g,12 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (227 mg,0.9 mmol), tris (dibenzylideneacetone) dipalladium (275 mg,0.3 mmol), cesium carbonate (6.52 g,20 mmol) and 35mL dioxane were added to a three-necked flask and reacted overnight at 90℃under argon. Detection shows that the reaction is complete, ethyl acetate is added, extraction is carried out, the organic phase is washed by water and saturated sodium chloride solution, dried by anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound. LC-MS m/z 293.1[ M+H ]] + 。
Preparation of step 3 1- (4-aminopyridin-2-yl) -2, 2-trifluoroethyl-1-ol
Tert-butyl (2- (2, 2-trifluoro-1-hydroxyethyl) pyridin-4-yl) carbamate (2.5 g,8.56 mmol) was weighed out and dissolved in 8mL methanol, and hydrochloric acid/dioxane solution (20 mL,4 m) was added dropwise, and after addition, stirring was carried out overnight at room temperature. After the reaction was completed, the mixture was concentrated, saturated sodium hydrogencarbonate solution and ethyl acetate were added, and the mixture was extracted, and the organic phase was washed with water, saturated sodium chloride solution and dried over anhydrous sodium sulfate, followed by concentration under reduced pressure to give the title compound. LC-MS m/z 193.4[ M+H ] ] + 。
Step 4 1 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-trifluoroethyl-1-ol
The procedure was followed except for using 1- (4-aminopyridin-2-yl) -2, -trifluoroethyl-1-ol instead of 2-morpholinopyridin-4-amine to give the title compound. LC-MSm/z 476.2[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 )δ9.95(s,1H),9.66(s,1H)，8.45(dd,J 1 ＝8.4Hz，J 2 ＝1.6Hz,1H),8.24-8.20(m,2H),7.90(s,1H),7.80(dd,J 1 ＝5.6Hz，J 2 ＝2.0Hz,1H),6.90(s,1H)，6.70(dd,J 1 ＝7.0Hz，J 2 ＝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 73 2- (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
Preparation of methyl step 1 5-bromo-2- (1H-1, 2, 4-triazol-1-yl) benzoate
Methyl 5-bromo-2-fluorobenzoate (2 g,4.3 mmol), 1H-1,2, 4-triazole (0.65 g,4.73 mmol), anhydrous potassium carbonate (1.4 g,5.16 mmol) and anhydrous N, N-dimethylformamide were added to a 100mL three-necked flask and reacted overnight at 80℃under argon. Cooling to room temperature, adding water and ethyl acetate, extracting, drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure, and performing column chromatography to obtain the title compound. LC-MS m/z 282.2,283.9[ M+H ]] + 。
Preparation of step 2 2- (5-bromo-2- (1H-1, 2, 4-triazol-1-yl) phenyl) propan-2-ol
Methyl 5-bromo-2- (1H-1, 2, 4-triazol-1-yl) benzoate (1.57 g,5.58 mmol) was dissolved in 20mL anhydrous tetrahydrofuran, cooled to 0deg.C, methyl magnesium bromide (5.4 mL,3M,16.2 mmol) was added dropwise, stirred for 30min, and then reacted overnight at room temperature. Saturated ammonium chloride solution and ethyl acetate are added under ice-water bath, extraction is carried out, and the organic layer is dried by anhydrous sodium sulfate, reduced pressure concentration and column chromatography purification are carried out 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
2- (5-bromo-2- (1H-1, 2, 4-triazol-1-yl) phenyl) propyl-2-ol (413 mg,1.46 mmol), tert-butyl carbamate (189 mg,1.61 mmol), tris (dibenzylideneacetone) dipalladium (134 mg,0.146 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (169 mg,0.292 mmol), potassium carbonate (951 mg,6.9 mmol) and 20mL dioxane were added to a 100mL three-necked flask. The reaction was carried out overnight at 100℃under argon. Filtering, concentrating the filtrate, and performing column chromatography to obtain the title product. LC-MS m/z 319.1[ M+H ]] + 。
Preparation of step 4 2- (5-amino-2- (1H-1, 2, 4-triazol-1-yl) phenyl) propan-2-ol
Tert-butyl (3- (2-hydroxypropyl-2-yl) -4- (1H-1, 2, 4-triazol-1-yl) phenyl) carbamate (356 mg,1.118 mmol) was dissolved in 10mL of methanol and stirred at room temperature, hydrochloric acid/dioxane solution (2.8 mL,4M,11.2 mmol) was added dropwise. After the completion of the dropping, the mixture was reacted at 30℃overnight. Reduction ofThe reaction system is concentrated under pressure, sodium bicarbonate and ethyl acetate are added, the liquid is separated, the organic phases are combined, and the next reaction is directly carried out after the concentration under reduced pressure. LC-MS m/z 219.2[ M+H ]] + 。
Step 5 2 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
The procedure was followed except for using 2- (5-amino-2- (1H-1, 2, 4-triazol-1-yl) phenyl) propyl-2-ol instead of 2-morpholinopyridin-4-amine to prepare the title compound. LC-MS m/z 502.2[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 )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 74 2- (4- ((4- ((1-cyclopropyl-3- (4, 4-difluorocyclohexyl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) propan-2-ol
The procedure was followed except for using 2- (4-aminopyridin-2-yl) propan-2-ol instead of 2-morpholinopyridin-4-amine to give the title compound. LC-MS m/z 470.2[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 )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 75 3- (4- (4- ((1-cyclopropyl-3- (4, 4-difluorocyclohexyl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) oxetan-3-ol
Step 1 preparation of tert-butyl (2-bromopyridin-4-yl) carbamate
2-bromo-4-aminopyridine (8.651 g,50.0 mmol), triethylamine (15.178 g,150 mmol) and dichloromethane (50 mL) were placed in a reaction flask, di-tert-butyl carbonate (16.369 g,75.0 mmol) was weighed and added to the flask at 0deg.C, and the mixture was stirred at 40deg.C for 4 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, saturated sodium hydrogencarbonate solution and methylene chloride were added to the reaction system, the mixture was extracted, and the organic phase was dried over anhydrous sodium sulfate. Concentrating under reduced pressure, and purifying by column chromatography to obtain the title compound. 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
Tert-butyl (2-bromopyridin-4-yl) carbamate (1.0 g,3.8 mmol) was weighed into a reaction flask with 40mL dry tetrahydrofuran, cooled to-78℃and n-butyllithium (30 mL,1.6M,5.7 mmol) was added dropwise. After the addition, 3-oxetanone (0.3 g,3.9 mmol) was added and slowly returned to room temperature and stirred overnight. After the reaction, saturated ammonium chloride solution and ethyl acetate are added into the reaction liquid, extraction is carried out, and the target product is obtained after decompression and concentration. LC-MSm/z 267.1[ M+H ]] + 。
Step 3 3- (4-aminopyridin-2-yl) oxetan-3-ol preparation
Tert-butyl (2- (3-hydroxyoxetan-3-yl) pyridin-4-yl) carbamate (0.330 g,1.24 mmol) was weighed out and dissolved in 10mL of dichloromethane, 1mL of concentrated hydrochloric acid was added at room temperature and the reaction was stirred for 2h. After the reaction is completed, anhydrous potassium carbonate is added for neutralization, filtration, liquid separation, drying of an organic phase and decompression concentration are carried out to obtain the target product. LC-MS m/z 167.1[ M+H ]] + 。
Step 4 3 preparation of- (4- ((4- ((1-cyclopropyl-3- (4, 4-difluorocyclohexyl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) oxetan-3-ol
2-chloro-4- ((1-cyclopropyl-3- (4, 4-difluorocyclohexyl) -1H-pyrazol-4-yl) oxy) pyridine (0.4573 g,1.283 mmol), 3- (4-aminopyridin-2-yl) oxetan-3-ol (0.20 g,1.2 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (0.058 g,0.10 mmol), potassium carbonate (0.460 g,4.0 mmol) and polydibenzylidene acetone dipalladium (0.046 g,0.05 mmol) were taken in a 100mL single-necked flask, and 20mL of 1, 4-dioxane was added. The reaction was carried out overnight at 100℃under an argon atmosphere. The reaction was completed, cooled to room temperature, and saturated brine and ethyl acetate were added to the reaction, extracted, concentrated under reduced pressure, and purified by column chromatography to give the title product. LC-MS m/z 484.3[ M+H ] ] + 。 1 H NMR(400MHz,DMSO-d 6 )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,J 1 ＝6.0Hz,J 2 ＝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 76 1- (4- ((4- ((1-cyclopropyl-3- (4, 4-difluorocyclohexyl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl-2, 2-trifluoroethyl-1-ol
The procedure was followed except for using 1- (4-aminopyridin-2-yl) -2, 2-trifluoroethyl-1-ol in place of 3- (4-aminopyridin-2-yl) oxetan-3-ol to prepare the title compound. 1 H NMR(400MHz,DMSO-d 6 )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 77 4- (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
The procedure was followed except for using tetrahydro-4H-pyran-4-one in place of 3-oxetanone to give the title compound as the compound in example 75. LC-MS m/z 512.2[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 )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 78 2- (5- ((4- ((1-cyclopropyl-3- (4, 4-difluorocyclohexyl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -2- (1H-1, 2, 4-triazol-1-yl) phenyl) propan-2-ol
The preparation was carried out in the same manner as in example 3 except that 2-bromo-1- (4, 4-difluorocyclohexyl) ethyl-1-one was used instead of 2-bromo-1-phenylethan-1-one and 2- (5-amino-2- (1)H-1,2, 4-triazol-1-yl) phenyl) propan-2-ol instead of 2- (4-aminopyridin-2-yl) propan-2-ol, the title compound was prepared. LC-MS m/z 536.2[ M+H ] ] + 。 1 H NMR(400MHz,DMSO-d 6 )δ9.36(s,1H),8.66(s,1H),8.14(s,1H),8.08(d,J＝6.0Hz,1H),8.05(dd,J 1 ＝8.8Hz,J 2 ＝2.8Hz,1H),7.87(s,1H),7.83(d,J＝2.4Hz,1H),7.07(d,J＝8.4Hz,1H),6.52(dd,J 1 ＝5.6Hz,J 2 ＝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 79 1- (4- (4- ((1-cyclopropyl-3- (3, 3-difluorocyclobutyl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) -2, 2-trifluoroethan-1-ol
Step 1 preparation of 3, 3-difluoro-N-methoxy-N-methylcyclobutane-1-carboxamide
3, 3-Difluorocyclobutane carboxylic acid (5.0 g,36.74 mmol) and 1-hydroxybenzotriazole (5.601 g,40.41 mmol) were added to a three-necked flask with 100mL of methylene chloride, cooled to 0deg.C, and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (7.747 g,40.41 mmol) was added. Then, the reaction was carried out at 0℃for 1 hour, followed by adding N, O-dimethylhydroxylamine hydrochloride (4.30 g,44.09 mmol) and triethylamine (11.153 g,110.22 mmol) to the reaction, and stirring was continued overnight at room temperature. Water and methylene chloride were added to the reaction, the extracts were combined, the organic phases were 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 ]] + 。
Preparation of step 2 1- (3, 3-difluorocyclobutyl) ethanone
3, 3-difluoro-N-methoxy-N-methylcyclobutane-1-carboxamide (6.5 g,36.3 mmol) was added to 100mL of anhydrous tetrahydrofuran and cooled to-1 ℃. Methyl magnesium bromide (18.1 mL,54.5 mmol) was added to the reaction under argon atmosphere, then reacted at-1℃for 1h, returned to room temperature with stirring for 2h, and the saturated ammonium chloride solution quenched. Saturated saline and ethyl acetate are added, extraction is carried out, the organic phases are combined, the saturated saline is washed, anhydrous sodium sulfate is dried, and the title product is obtained after decompression concentration and column chromatography purification. 1 H NMR(400MHz,CDCl 3 )δ3.08(pd,J＝8.7,2.7Hz,1H),2.84-2.67(m,4H),2.19(s,3H)。
Preparation of step 3 2-chloro-4- ((1-cyclopropyl-3- (3, 3-difluorocyclobutyl) -1H-pyrazol-4-yl) oxy) pyridine
Preparation method example 1 Compounds the title compound was prepared by the methods of preparation of compounds of steps 1-5 except that 1- (3, 3-difluorocyclobutyl) ethanone was used instead of 1- (tetrahydro-2H-pyran-4-yl) ethanone. LC-MS m/z 326.08[ M+H ]] + 。
Step 41 preparation of- (4- (4- ((1-cyclopropyl-3- (3, 3-difluorocyclobutyl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) -2, 2-trifluoroethan-1-ol
2-chloro-4- ((1-cyclopropyl-3- (3, 3-difluorocyclobutyl) -1H-pyrazol-4-yl) oxy) pyridine (0.29 g,0.90 mmol), 1- (4-aminopyridin-2-yl) -2, -trifluoroethyl-1-ol (0.28 g,1.46 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (0.05 g,0.090 mmol), cesium carbonate (0.41 g,3.60 mmol) and tris dibenzylideneacetone dipalladium (0.041 g,0.045 mmol) were weighed into a 100mL single-necked flask, 20mL of 1, 4-dioxane was added and heated to 100℃under argon atmosphere to react overnight. The reaction was cooled to room temperature, saturated brine and ethyl acetate were added thereto, and the mixture was extracted, concentrated and purified by column chromatography to give the title compound. LC-MS m/z 482.2[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 )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,J 1 ＝6.0Hz,J 2 ＝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 80 2- (4- ((4- (1-cyclopropyl-3- (4-fluorophenyl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) propan-2-ol
The procedure was followed, as in example 3, except for using 2-bromo-1- (4-fluorophenyl)) ethan-1-one instead of 2-bromo-1-phenylethan-1-one, to prepare the title compound. LC-MS m/z 446.2[ M+H ]] + 。 1 H 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 81 preparation of 3- (4- ((4- ((1-cyclopropyl-3- (3-fluorophenyl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) oxetan-3-ol
2-chloro-4- ((1-cyclopropyl-3- (3-fluorophenyl) -1H-pyrazol-4-yl) oxy) pyridine (200 mg,0.60 mmol), 3- (4-aminopyridin-2-yl) oxetan-3-ol (175.6 mg,0.78 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (0.056 g,0.0976 mmol), cesium carbonate (0.408 g,3.514 mmol), tris (dibenzylideneacetone) dipalladium (0.045 g,0.0488 mmol) and 1, 4-dioxane (12 mL) were placed in 100mIn an L reaction flask, the mixture was heated to 100℃under argon atmosphere and reacted overnight. The reaction was cooled to room temperature, saturated brine and methylene chloride 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 ]] + 。 1 H 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 82 4- (4- ((4- ((1-cyclopropyl-3- (3-fluorophenyl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) tetrahydro-2H-pyran-4-ol
The procedure was the same as in 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 to give the title compound. LC-MS m/z 488.2[ M+H ] ] + 。 1 H 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 83 3- (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
Preparation of step 1 1- (4- (3, 6-dihydro-2H-pyran-4-yl) -2-fluorophenyl) ethyl-1-one
1- (4-bromo-2-fluorophenyl) ethanone (1.6 g,5 mmol), 3, 6-dihydro-2H-pyran-4-boronic acid pinacol ester (1 g,4 mmol), tetrakis (triphenylphosphine) palladium (531 mg,0.46 mmol) and potassium carbonate (1.3 g,9.2 mmol) were placed in a 100mL round bottom flask, 50mL dioxane solution was added and reacted overnight at 90 ℃. After the reaction is completed, the mixture is filtered, concentrated under reduced pressure and purified by column chromatography to obtain the target 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
1- (4- (3, 6-dihydro-2H-pyran-4-yl) -2-fluorophenyl) ethyl-1-one (2.4 g,10.9 mmol) was weighed out in 25mL of methanol, 240mg of palladium on carbon/catalyst was added, and after hydrogen substitution, the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the filtrate was filtered, and concentrated under reduced pressure to give the title compound. LC-MS m/z 223.1[ M+H ]] + 。
Step 3: preparation of 2-bromo-1- (2-fluoro-4- (tetrahydro-2H-pyran-4-yl) phenyl) ethyl-1-one
1- (2-fluoro-4- (tetrahydro-2H-pyran-4-yl) phenyl) ethyl-1-one (1.5 g,6.8 mmol) was dissolved in 20mL glacial acetic acid and 350. Mu.L of liquid bromine was added dropwise under nitrogen atmosphere. Stirring at room temperature for 2h, and completing the reaction. After neutralization of saturated sodium bicarbonate solution, ethyl acetate was added, extraction was performed, and the organic phase was concentrated under reduced pressure to give the title compound. LC-MSm/z 301.0,303.2[ M+H ] ] + 。
Preparation of step 3 2-chloro-4- ((1-cyclopropyl-3- (2-fluoro-4- (tetrahydro-2H-pyran-4-yl) phenyl) -1H-pyrazol-4-yl) oxy) pyridine
The procedure was followed except for using 2-bromo-1- (2-fluoro-4- (tetrahydro-2H-pyran-4-yl) phenyl) ethyl-1-one instead of 2-bromo-1-phenylethan-1-one in the preparation of the compounds of steps 1 to 3 of example 3, to give the title compound. LC-MS m/z 414.1[ M+H ]] + 。
Step 4 3 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
2-chloro-4- ((1-cyclopropyl-3- (2-fluoro-4- (tetrahydro-2H-pyran-4-yl) phenyl) -1H-pyrazol-4-yl) oxy) pyridine (250 mg,0.6 mmol), 3- (4-aminopyridin-2-yl) oxetan-3-ol (120 mg,0.72 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (70 mg,0.12 mmol), cesium carbonate (140 mg,1.2 mmol), tris (dibenzylideneacetone) dipalladium (55 mg,0.06 mmol) and 1, 4-dioxane (5 mL) were placed in a 50mL single-neck flask and reacted overnight at 110℃under argon atmosphere. Cooling to room temperature, adding saturated saline and ethyl acetate, extracting, concentrating the organic phase under reduced pressure, and purifying by column chromatography to obtain the title compound. LC-MS m/z 544.2[ M+H ] ] + 。 1 H 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 84 1- (4- ((4- ((1-cyclopropyl-3- (3-fluorophenyl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) -2, 2-trifluoroethyl-1-ol
2-chloro-4- ((1-cyclopropyl-3- (3-fluorophenyl) -1H-pyrazol-4-yl) oxy) pyridine (200 mg,0.60 mmol), 1- (4-aminopyridin-2-yl) -2, 2-trifluoroethyl-1-ol (130 mg,0.6 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (70 mg,0.122 mmol), cesium carbonate (141 mg,1.22 mmol), tris (dibenzylideneacetone) dipalladium (56 mg,0.06 mmol) and 10mL of 1, 4-dioxane (placed in a 100mL reaction bottle for reaction at 100℃overnight under argon atmosphere) were taken, the reaction was cooled to room temperature, saturated brine and dichloromethane were added, extracted, concentrated under reduced pressure, and after column chromatography purification the title compound LC-MS m/z 486.2 M+H was obtained] + 。 1 HNMR(400MHz,DMSO-d 6 )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 85 2- (4- ((4- ((3- (3-oxabicyclo [3.1.0] hexan-6-yl) -1-cyclopropyl-1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) propan-2-ol
Step 13 preparation of oxabicyclo [3.1.0] hexane-6-carboxylic acid ethyl ester
Rhodium dimeric acetate (292 mg,1.43 mmol) and 200mL of anhydrous methylene chloride were added to a 1L three-necked flask, and 2, 5-dihydrofuran (21.5 mL, 284 mmol) was added thereto under an argon atmosphere. Ethyl diazoacetate (15 mL,143 mmol) was then dissolved in 430mL of anhydrous dichloromethane and added dropwise with a constant pressure dropping funnel for 48h. After the reaction is completed, the solution is concentrated under reduced pressure, and the target product is obtained after column chromatography purification. LC-MS m/z 157.1[ M+H ] ] + 。
Step 2 3 preparation of oxabicyclo [3.1.0] hexane-6-carboxylic acid
3-oxabicyclo [3.1.0]]Hexane-6-carboxylic acid ethyl ester (4.26 g,27.3 mmol) was dissolved in 100mL of tetrahydrofuran, and aqueous sodium hydroxide (50 mL,81.9 mmol) was added dropwise thereto under ice-water bath conditions, and reacted overnight at room temperature. The pH was adjusted to 3 with dilute hydrochloric acid, and the organic solvent was removed and lyophilized. The freeze-dried mixture was washed with methanol, suction filtered, and the filtrate was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to be directly used for 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
Weighing 3-oxabicyclo [3.1.0]]Hexane-6-carboxylic acid (5 g,31.25 mmol) was dissolved in 100mL of anhydrous methylene chloride, 1-hydroxybenzotriazole (5.81 g,34.3 mmol) was added, after nitrogen substitution, the mixture was reacted under ice-water bath conditions for 30 minutes, and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (8.21 g,34.4 mmol) was added to the system and the reaction was stirred for 1 hour. Methoxy methylamine hydrochloride (4.6 g,37.5 mmol) was then added and triethylamine (16.3 mL,94 mmol) was added dropwise and the reaction was continued overnight. After the reaction was completed, water and methylene chloride were added, followed by extraction and column chromatography purification to give the title product. LC-MS m/z 172.1[ M+H ]] + 。
Preparation of step 4 1- (3-oxabicyclo [3.1.0] hexan-6-yl) ethan-1-one
N-methoxy-N-methyl-3-oxabicyclo [3.1.0]Hexane-6-carboxamide (1.6 g,10.3 mmol) was dissolved in 20mL of anhydrous tetrahydrofuran, and methyl bromide was added dropwise to the system at 0℃under nitrogen atmosphereMagnesium oxide (6.9 mL,3M,20.6 mmol) was reacted overnight. After the reaction is completed, the filtrate is obtained through suction filtration, reduced pressure concentration and column chromatography purification are carried out to obtain the target product. LC-MS m/z 127.1[ M+H ]] + 。
Preparation of step 5 4- ((3- (3-oxabicyclo [3.1.0] hexan-6-yl) -1-cyclopropyl-1H-pyrazol-4-yl) oxy) -2-chloropyridine
The preparation method is the same as that of the compounds of steps 1 to 5 of 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) ethan-one gives the title compound. LC-MS m/z 318.1[ M+H ]] + 。
Step 6 2 preparation of- (4- ((4- ((3- (3-oxabicyclo [3.1.0] hexan-6-yl) -1-cyclopropyl-1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) propan-2-ol
The procedure is as for the preparation of the compound of step 2 of example 45, except that 4- ((3- (3-oxabicyclo [ 3.1.0) is used]Hexane-6-yl) -1-cyclopropyl-1H-pyrazol-4-yl) oxy) -2-chloropyridine replaces 2-chloro-4- ((1- (2-fluoroethyl) -3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridine to produce the title compound. LC-MS m/z 434.2[ M+H ] ] + 。 1 H NMR(400MHz,DMSO-d 6 )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 86 2- (5- ((4- ((3- (3-oxabicyclo [3.1.0] hexan-6-yl) -1-cyclopropyl-1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -2- (1H-1, 2, 4-triazol-1-yl) phenyl) propan-2-ol
The procedure was followed except for using 2- (5-amino-2- (1H-1, 2, 4-triazol-1-yl) phenyl) propan-2-ol instead of 2- (4-aminopyridin-2-yl) propan-2-ol to give the title compound. LC-MS m/z 500.1[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 )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 87 2- (6-cyclopropyl-2- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyrimidin-4-yl) propan-2-ol
Step 1 2 preparation of methyl-chloro-6-cyclopropylpyrimidine-4-carboxylate
Methyl 2, 6-dichloropyrimidine-4-carboxylate (1.5 g,7.24 mmol), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (0.53 g, 0.254 mmol), cyclopropylboronic acid (0.622 g,7.24 mmol) and potassium phosphate (3.84 g,18.1 mmol) were placed in a reaction flask, 25mL of tetrahydrofuran solution was added, nitrogen blanketed, and stirred overnight at 80 ℃. After the reaction, the filtrate was filtered and concentrated, and column chromatography was performed to obtain the title compound. LC-MS m/z 213.1[ M+H ]] + 。
Preparation of step 2 2- (2-chloro-6-cyclopropylpyrimidin-4-yl) propan-2-ol
Methyl 2-chloro-6-cyclopropylpyrimidine-4-carboxylate (600 mg,3.45 mmol) was weighed out and dissolved in 20mL of anhydrous tetrahydrofuran, and added dropwise to a solution of methylmagnesium bromide (1.5 mL, 3.0M) in anhydrous tetrahydrofuran (20 mL) at-78℃under argon atmosphere. The reaction was stirred at this temperature for 20min. Saturated ammonium chloride solution and ethyl acetate are added, an organic phase is obtained by extraction, anhydrous sodium sulfate is dried, reduced pressure concentration is carried out, and the title compound is obtained by column chromatography purification. LC-MSm/z 213.2[ M+H ] ] + 。
Step 3 2- (6-cyclopropyl-2- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyrimidin-4-yl) propan-2-ol
The procedure was followed except for using 2- (2-chloro-6-cyclopropylpyrimidin-4-yl) propan-2-ol instead of 2- (6-bromoisoquinolin-3-yl) propan-2-ol to afford the titled compound. LC-MS m/z 477.1[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 )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 88 2- (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
Step 1 2 Synthesis of Ethyl- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) oxazole-5-carboxylate
The procedure was followed except for using ethyl 2-aminooxazole-5-carboxylate instead of 2-morpholinopyridin-4-amine to give the title compound as a preparation for the compound of example 2 step 3. LC-MS m/z 440.2[ M+H ]] + 。
Step 2 2 Synthesis of- (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
Methyl magnesium bromide (3M, 0.75 mL) was taken in a 50mL three-necked flask under argon atmosphere, cooled to 0℃and 2- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) oxazole-5-carboxylic acid ethyl ester (245 mg,0.56 mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise, and after 0℃for 0.5H, the reaction was carried out at room temperature for 48H. After the reaction was completed, the mixture was quenched by adding a saturated ammonium chloride solution, saturated brine and ethyl acetate were added, the mixture was extracted, and the organic phase was concentrated under reduced pressure and purified by column chromatography to give the title product. LC-MS m/z 426.1[ M+H ] ] + 。 1 H NMR(400MHz,DMSO-d 6 )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 89 2- (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
Synthesis of methyl 1 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) picolinate
Methyl 4-bromopyridine carboxylate (1 g,9.3 mmol), pinacol diboronate (2.9 g,23.26 mmol) and [1,1' -bis (diphenylphosphino) ferrocene were taken]Palladium dichloride (0.34 g,0.93 mmol) and potassium acetate (1.14 g,23.26 mmol) were sequentially added to a reaction flask containing 1, 4-dioxane (30 mL), reacted overnight at 100℃and filtered, washed with saturated sodium chloride solution, extracted with ethyl acetate to give an organic phase, 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 Synthesis of methyl- (4-nitro-1H-pyrazol-1-yl) picolinate
2,2' -bipyridine (1.56 g,10 mmol), copper acetate (1.8 g,10 mmol), methyl 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) picolinate (2.4 g,9.13 mmol), sodium carbonate (1.94 g,18.26 mmol) and 4-nitropyrazole (1 g,9.13 mmol) were placed in a reaction flask, 30mL of 1, 2-dichloroethane was added and the mixture was stirred at 75℃under an oxygen atmosphere to react for 24h. Cooling to room temperature, adding saturated saline and dichloromethane, extracting, concentrating filtrate, and purifying by column chromatography to obtain the title compound. LC-MS m/z 249.1[ M+H ] ] + 。
Step 3 4 Synthesis of methyl- (4-amino-1H-pyrazol-1-yl) picolinate
Methyl 4- (4-nitro-1H-pyrazol-1-yl) picolinate (0.24 g,3.16 mmol) was dissolved in 50mL of methanol, 10% palladium on carbon (0.1 g), hydrogen was added for displacement, heated at 30℃under stirring for 2H, and the filtrate was filtered, concentrated under reduced pressure to give the title compound. LC-MS m/z 219.3[ M+H ]] + 。
Step 4 4 Synthesis of- (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
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 (200 mg,0.92 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (106 mg,0.184 mmol), cesium carbonate (599 mg,1.84 mmol), tris (dibenzylideneacetone) dipalladium (84 mg,0.092 mmol) and 1, 4-dioxane (25 mL) were taken in a 100mL reaction flask, and heated to 100℃under argon atmosphere, and reacted overnight. The reaction solution was cooled to room temperature, saturated brine and methylene chloride were added thereto, the mixture was extracted, and the organic phase was concentrated and purified by column chromatography to give the title compound. LC-MS m/z 486.2[ M-H ]] - 。
Step 5 4 Synthesis of Ethyl picolinate- (4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -1H-pyrazol-1-yl)
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 (200 mg,0.41 mmol) was dissolved in ethanol (20 mL), 13 drops of concentrated sulfuric acid were added, and the reaction was refluxed at 80℃overnight. The pH was adjusted to weakly alkaline with saturated potassium carbonate solution, methanol was removed by concentration, saturated sodium chloride solution and ethyl acetate were added, extraction was performed, the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound. LC-MS m/z 516.2[ M+H ]] + 。
Step 6 2 Synthesis of- (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
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 (200 mg,0.37 mmol) in anhydrous tetrahydrofuran (5 mL) was taken under an argon atmosphere and added dropwise to a solution of methylmagnesium bromide (1 mL,3.0 m) in anhydrous tetrahydrofuran (20 mL) at 0 ℃. After stirring and reacting for 1h at 0 ℃, reacting for 2h at room temperature. Saturated ammonium chloride solution and ethyl acetate were added, 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 502.1[ M+H ] ] + 。 1 H NMR(400MHz,DMSO-d 6 )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 90 3- (1-cyclopropyl-4- ((2- ((1- (2-hydroxy-2-methylpropyl) -1H-pyrazol-4-yl) amino) pyridin-4-yl) oxy) -1H-pyrazol-3-yl) benzonitrile
Preparation of step 1 3- (4- ((2-chloropyridin-4-yl) oxy) -1-cyclopropyl-1H-pyrazol-3-yl) benzonitrile
The procedure was as in example 3, steps 1-3, except that 3- (2-bromoacetyl) benzonitrile was used instead of 2-bromo-1-phenylethan-1-one to give the title compound. LC-MS m/z 337.3[ M+H ]] + 。
Preparation of step 2 3- (1-cyclopropyl-4- ((2- ((1- (2-hydroxy-2-methylpropyl) -1H-pyrazol-4-yl) amino) pyridin-4-yl) oxy) -1H-pyrazol-3-yl) benzonitrile
3- (4- ((2-Chloropyridin-4-yl) oxy) -1-cyclopropyl-1H-pyrazol-3-yl) benzonitrile (250 mg,0.564 mmol), 1- (4-amino-1H-pyrazol-1-yl) -2-methylpropan-2-ol (87 mg,0.564 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (65 mg,0.1129 mmol), cesium carbonate (268 mg,1.129 mmol), tris (dibenzylideneacetone) dipalladium (52 mg,0.0564 mmol) and 1, 4-dioxane (25 mL) were taken in a 100mL reaction flask, and heated to 100℃under 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 ] ] + 。 1 H 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 91 3- (1-cyclopropyl-4- ((2- ((2- (3-hydroxyoxetan-3-yl) pyridin-4-yl) amino) pyridin-4-yl) oxy) -1H-pyrazol-3-yl) benzonitrile
The procedure was followed except for using 3- (4-aminopyridin-2-yl) oxetan-3-ol instead of 1- (4-amino-1H-pyrazol-1-yl) -2-methylpropan-2-ol to prepare the title compound. LC-MS m/z 467.2[ M+H ]] + 。 1 H 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 92 2-chloro-5- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) benzenesulfonamide
Step 1 5 Synthesis of amino-2-chlorobenzenesulfonamide
2-chloro-5-nitrobenzenesulfonamide (0.71 g,3 mmol) was placed in a reaction flask, 30mL of ethyl acetate was added thereto, and 10% palladium on carbon (60 mg) was added thereto at room temperature, followed by reaction at room temperature for 4 hours. After completion of the reaction, the filtrate was concentrated under reduced pressure to give the title compound. LC-MS m/z 207.0[ M+H ]] + 。
Step 2 2 Synthesis of chloro-5- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) benzenesulfonamide
The procedure was followed except for using 2-chloro-5-aminobenzenesulfonamide in place of 2-morpholinopyridin-4-amine to give the title compound. LC-MS m/z 490.0[ M+H ] ] + 。 1 H 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 93 1- ((4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -2-methylpropan-2-ol
Preparation of step 1 2- ((2-hydroxy-2-methylpropyl) amino) -4-nitropyridin-1-oxide
2-chloro-4-nitropyridine-1-oxide (0.2 g,1.15 mmol) was dissolved in acetonitrile (20 mL) in a 50mL single vial, and 1-amino-2-methyl-2-propanol hydrochloride (0.12 g,1.26 mmol) and carbonic acid (1.12 g,3.44 mmol) were added. Reflux reaction is carried out for 4.5h at 90 ℃ under the protection of nitrogen. After the completion of the reaction, water and ethyl acetate were added, the organic phases were combined, the organic phases were 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 228.1[ M+H ]] + 。
Step 21 preparation of- ((4-aminopyridin-2-yl) amino) -2-methylpropan-2-ol
2- ((2-hydroxy-2-methylpropyl) amino) -4-nitropyridine-1-oxide (0.21 g,0.92 mmol) was dissolved in methanol (20 mL) and placed in a 50mL double-necked flask, 40mg palladium on carbon (10%) was added and the reaction stirred under hydrogen atmosphere for 2h. After the reaction, 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 ]] + 。
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
Preparation method the procedure was followed 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 to give the title compound。LC-MSm/z:465.3[M+H] + 。 1 H 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 94 1- (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
Preparation of step 1 2- (3-hydroxy-3-methylazetidin-1-yl) -4-nitropyridin-1-oxide
2-chloro-4-nitropyridine-N-oxide (0.2 g,1.14 mmol) was dissolved in 5mL of acetonitrile, then 3-methylazetidine-3-ol hydrochloride (0.35 g,2.8 mmol) and cesium carbonate (1.3 g,3.99 mmol) were added to the reaction system, followed by stirring under reflux for 1h. The reaction was completed and cooled to room temperature. Suction filtration, washing filter cake with acetonitrile, collecting filtrate, and concentrating under reduced pressure to obtain the title compound. LC-MS m/z 226.1[ M+H ]] + 。
Step 2 1 Synthesis of- (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
The preparation method is the same as that of the compound of step 2-3 of example 93 except that 2- (3-hydroxy-3-methylazetidin-1-yl) -4-nitropyridine is used The title compound was prepared from 1-oxide instead of 2- ((2-hydroxy-2-methylpropyl) amino) -4-nitropyridine-1-oxide. LC-MS m/z 463.2[ M+H ]] + 。 1 H NMR(400MHz,CDCl 3 )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 95 1- (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
The procedure was followed except that 3-trifluoromethyl-3-acridine hydrochloride was used instead of 3-methylazetidine-3-ol hydrochloride in the same manner as in step 1-2 of example 94 to obtain the title compound. LC-MSm/z 517.2[ M+H ]] + 。 1 H 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 96 4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) -N- (2- (3, 3-difluoroazetidin-1-yl) pyridin-4-yl) pyridin-2-amine
The procedure was followed except for using 3, 3-difluorotrimethoprim hydrochloride instead of 3-methylazetidine-3-ol hydrochloride in the preparation of the compound of step 1-2 of example 94 to obtain the title compound. LC-MSm/z 469.2[ M+H ]] + 。 1 H NMR(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 97- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) -N- (2- (3, 4-tetrafluoropyrrolidin-1-yl) pyridin-4-yl) pyridin-2-amino
The procedure was followed except for using 3, 4-tetrafluoropyrrolidine hydrochloride instead of 3-methylazetidine-3-ol hydrochloride in the preparation of the compounds of steps 1-2 of example 94 to obtain the title compound. LC-MSm/z 519.2[ M+H ] ] + 。 1 H NMR(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 98 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
Preparation of step 1 1- (4-bromopyridin-2-yl) cyclopropyl-1-carbonitrile
4-bromo-2-fluoropyridine (0.5 g,2.84 mmol) was dissolved in 20mL dry tetrahydrofuran and placed in a 100mL single-necked flask, lithium hexamethyldisilazide (6.77 mL,8.81 mmol) was added and stirred under nitrogen at-40℃for reactionShould be 1h. Cyclopropylnitrile (0.57 g,8.52 mmol) was added to the above system and the reaction was continued for 1.5h. After the reaction, the saturated ammonium chloride solution was quenched. Water and ethyl acetate were added, the extracts 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 223.0,225.0[ M+H ]] + 。
Step 21 preparation of- (4-aminopyridin-2-yl) cyclopropyl-1-carbonitrile hydrochloride
1- (4-bromopyridin-2-yl) cyclopropyl-1-carbonitrile (0.46 g,2.06 mmol), tert-butyl carbamate (0.293 g,2.50 mmol), palladium acetate (46.76 mg,0.21 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (0.24 g,0.42 mmol) and cesium carbonate (1.36 g,4.17 mmol) were placed in a 250mL double-necked flask, 120mL of 1, 4-dioxane was added, and the reaction was stirred under nitrogen at 100℃for 2 hours. After the reaction, water and ethyl acetate were added, extraction was performed, the organic phases were combined, the organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to give tert-butyl (2- (1-cyanocyclopropyl) pyridin-4-yl) carbamate. The intermediate compound was dissolved in hydrochloric acid/methanol solution (50 ml,3 m) and the reaction was continued for 2.5h, and the reaction was complete and concentrated under reduced pressure to give the title compound. LC-MS m/z 160.1[ M-HCl+H ] ] + 。
Step 3 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
The procedure was followed except for using 1- (4-aminopyridin-2-yl) cyclopropyl-1-carbonitrile hydrochloride instead of 2-morpholinopyridin-4-amine to give the title compound as in example 2, step 3. LC-MSm/z 443.2[ M+H ]] + 。 1 H 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 99 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
Preparation of step 1 2- (4-bromopyridin-2-yl) -2, 2-difluoroacetic acid ethyl ester
2, 4-dibromopyridine (1 g,4.22 mmol) and copper powder (1.07 g,16.88 mmol) were weighed into a reaction flask, 14mL of dimethyl sulfoxide was added, and ethyl 2-bromo-2, 2-difluoroacetate (1.71 g,8.44 mmol) was added to react overnight at room temperature. After the completion of the reaction, water and ethyl acetate were added, 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 ]] + 。
Preparation of step 2 1- (4-bromopyridin-2-yl) -1, 1-difluoro-2-methylpropan-2-ol
Ethyl 2- (4-bromopyridin-2-yl) -2, 2-difluoroacetate (1.36 g,4.86 mmol) was dissolved in 20mL of tetrahydrofuran, replaced with argon, and a methyl magnesium bromide/diethyl ether solution (3M, 4.2mL,12.15 mmol) was slowly added dropwise to the reaction system in an ice bath, and then the temperature of the reaction system was slowly raised to room temperature and the reaction was stirred for 1h. After the reaction, water and ethyl acetate were added to the reaction system, followed by extraction, drying of the organic phase over anhydrous sodium sulfate, concentration under reduced pressure, and purification by column chromatography. 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
1- (4-bromopyridin-2-yl) -1, 1-difluoro-2-methylpropan-2-ol (1 g,3.77 mmol), tert-butyl carbamate (531 mg,4.53 mmol), sodium tert-butoxide (508 mg,5.28 mmol), 2-dicyclohexylphosphorus-2 ',4',6' -triisopropylbiphenyl (144 mg,0.30 mmol) and tris (dibenzylideneacetone) dipalladium (0) (70 mg,0.076 mmol) were placed in a reaction flask, 5mL of tert-butanol was added, replaced with argon, and the mixture was refluxed at 100℃for 2 hours. After the reaction was completed, cooled to room temperature, water and ethyl acetate were added to the reaction system, 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 303.1[ M+H ]] + 。
Preparation of step 4 2- (1, 1-difluoro-2-hydroxy-2-methylpropyl) pyridin-4-amine-2, 2-trifluoroacetate salt
Tert-butyl (2- (1, 1-difluoro-2-hydroxy-2-methylpropyl) pyridin-4-yl) carbamate (706 mg,2.34 mmol) was dissolved in 10mL of a mixed solution of dichloromethane/trifluoroacetic acid (2:1), stirred at room temperature for 2h, the reaction was completed, and concentrated under reduced pressure to give the title compound.
Step 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
The preparation method is the same as that of the compound in the step 3 of the example 2, except that: 2- (1, 1-difluoro-2-hydroxy-2-methyl)The title compound was prepared by substituting 2-morpholinopyridin-4-amine with phenylpropyl) pyridin-4-amine-2, 2-trifluoroacetate. LC-MS m/z 486.2[ M+H ]] + 。 1 H NMR(400MHz,CDCl 3 )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 100 1- (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
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 (0.1 g, 0.447 mmol) of example 98 was dissolved in 2mL of methanol, followed by addition of indium chloride (0.06 g,0.268 mmol), displacement of argon, and stirred at 65 ℃ for 5H. After the reaction is completed, the reaction solution is concentrated, and the compound is obtained by column chromatography purification. LC-MS m/z 461.2[ M+H ]] + 。 1 HNMR(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 101 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-trifluoroethyl) azetidin-3-ol
Preparation of step 1 3- (4-bromopyridin-2-yl) -3-hydroxyazetidine-1-carboxylic acid tert-butyl ester
In a 100mL single-necked flask, 2, 4-dibromopyridine (0.5 g,2.11 mmol) was dissolved in 20mL of anhydrous tetrahydrofuran, and isopropyl magnesium bromide (1.95 mL,2.53 mmol) was added thereto, followed by stirring under nitrogen at-10℃for 1 hour. 3-Oxoazetidine-1-carboxylic acid tert-butyl ester (0.43 g,2.53 mmol) was dissolved in 10mL anhydrous tetrahydrofuran and the above system was added and the reaction was continued for 1.5h. After the reaction, the saturated ammonium chloride solution was quenched. Water and ethyl acetate were added, the extracts 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 329.0,331.0[ M+H ] ] + 。
Preparation of step 2 3- (4-bromopyridin-2-yl) -1- (2, 2-trifluoroethyl) azetidin-3-ol
3- (4-bromopyridin-2-yl) -3-hydroxyazetidine-1-carboxylic acid tert-butyl ester was dissolved in methanol hydrochloride (50 mL, 3M) and reacted for 2.5h with stirring. The reaction was complete and the solvent was removed by concentration to give a white solid. The above solid was dissolved in 25mL of anhydrous tetrahydrofuran, and triethylamine (0.65 mL,4.71 mmol) and trifluoroethyl triflate (0.44 g,1.57 mmol) were added thereto, and the reaction was stirred at room temperature for 2 hours. After the completion of the reaction, water and ethyl acetate were added, the organic phases were combined, the organic phases were 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 311.0,313.0[ M+H ]] + 。
Step 3 3 preparation of- (4-aminopyridin-2-yl) -1- (2, 2-trifluoroethyl) azetidin-3-yl hydrochloride
Will be 3- "4-bromopyridin-2-yl) -1- (2, 2-trifluoroethyl) azetidin-3-ol (0.32 g,2.06 mmol), tert-butyl carbamate (0.293 g,2.50 mmol), palladium acetate (46.76 mg,0.21 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (0.24 g,0.42 mmol) and cesium carbonate (1.36 g,4.17 mmol) were placed in a 250mL double-necked flask, 120mL of 1, 4-dioxane was added and reacted at 100℃under nitrogen atmosphere for 2h. After the completion of the reaction, water and ethyl acetate were added, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography. The purified product was dissolved in methanol hydrochloride (50 mL, 3M) and stirred for 2.5h to complete the reaction, which was concentrated under reduced pressure to give the title compound. LC-MS m/z 248.1[ M-HCl+H ] ] + 。
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-trifluoroethyl) azetidin-3-ol
The procedure was followed except for using 3- (4-aminopyridin-2-yl) -1- (2, 2-trifluoroethyl) azetidin-3-ol hydrochloride instead of 2-morpholinopyridin-4-amine to prepare the title compound. LC-MS m/z 531.2[ M+H ]] + 。 1 H NMR(400MHz,CDCl 3 )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 102 2- (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
Preparation of step 1 1- (4-bromopyridin-2-yl) cyclopropyl-1-carbonitrile
2-fluoro-4-bromopyridine (1 g,5.68 mmol) and cyclopropyl 1-carbonitrile (1.14 g,17.04 mmol) were dissolved in 20mL of anhydrous tetrahydrofuran solution, replaced with argon, lithium hexamethyldisilazide (17.6 mL,18.1 mmol) was added dropwise at-5℃and then stirred at room temperature for 3.5h. After the reaction, water quenching, ethyl acetate addition, extraction, anhydrous sodium sulfate drying of the organic phase, reduced pressure concentration, column chromatography purification to obtain the title compound. LC-MS m/z 223.1,225.1[ M+H ]] + 。
Step 2 1 preparation of- (4-bromopyridin-2-yl) cyclopropane-1-carboxylic acid
1- (4-bromopyridin-2-yl) cyclopropyl-1-carbonitrile (0.5 g,2.24 mmol) was dissolved in 5mL of ethanol, potassium hydroxide (0.5 g,8.9 mmol) was dissolved in 5mL of water and the reaction system was added thereto, and the reaction was stirred at 65℃overnight. Adjusting the pH to 2-3 with 6M hydrochloric acid aqueous solution, adding ethyl acetate, extracting, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain the title compound. LC-MS m/z 242.1,244.1[ M+H ]] + 。
Preparation of methyl step 3 1- (4-bromopyridin-2-yl) cyclopropane-1-carboxylate
Thionyl chloride (133 mg,1.12 mmol) was added dropwise to 5mL of methanol at-10℃followed by 1- (4-bromopyridin-2-yl) cyclopropane-1-carboxylic acid (270 mg,1.12 mmol), slowly brought to room temperature and stirred overnight. The reaction solution was neutralized with saturated aqueous sodium bicarbonate, ethyl acetate was added thereto, followed by extraction, drying over anhydrous sodium sulfate, and concentration under reduced pressure to give the title compound. LC-MS m/z 256.1,258.1[ M+H ]] + 。
Preparation of step 4 2- (1- (4-bromopyridin-2-yl) cyclopropyl) propan-2-ol
Methyl 1- (4-bromopyridin-2-yl) cyclopropane-1-carboxylate (0.15 g,0.6 mmol) was dissolved in 5mL of anhydrous tetrahydrofuran solution, replaced with argon, and methylmagnesium bromide (0.8 mL,2.4 mmol) was added dropwise to the reaction system at 0℃and the temperature was maintained for 1.5h. The reaction was quenched with aqueous ammonium chloride, added with ethyl acetate, 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
The procedure was followed except for using 2- (1- (4-bromopyridin-2-yl) cyclopropyl) propan-2-ol instead of 2- (6-bromoisoquinolin-3-yl) propan-2-ol in the procedure used in step 2 of example 53 to give the titled compound. LC-MS m/z 476.3[ M+H ]] + 。 1 H 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 103- ((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
Step 1 4 preparation of bromo-2- (3-fluorooxetan-3-yl) pyridine
3- (4-bromopyridin-2-yl) oxetan-3-ol (100 mg,0.435 mmol) was dissolved in 5mL of tetrahydrofuran, and reacted under stirring at-50℃under nitrogen, followed by dropwise addition of diethylaminosulfur trifluoride (85 mg,0.522 mmol) to the above-mentioned reaction system, followed by stirring under such conditions for 1h. Returning to room temperature, adding water and ethyl acetate into the reaction system, extracting, drying the 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 ]] + 。
Preparation of step 2 4- ((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
The procedure was followed except for using 4-bromo-2- (3-fluoro-oxetan-3-yl) pyridine instead of 2- (6-bromoisoquinolin-3-yl) propan-2-ol in the preparation of the compound in step 2 of example 53, to give the title compound. LC-MS m/z 452.2[ M+H ]] + 。 1 H NMR(400MHz,CDCl 3 ) Delta 8.27 (d, j=5.3 hz, 1H), 8.11 (d, j=5.8 hz, 1H), 7.66 (s, 1H), 7.33 (s, 1H), 7.29 (s, 1H), 7.08 (d, j=4.7 hz, 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, 2H), 1.77-1.74 (m, 2H), 1.16-1.07 (m, 2H), 1.06-1.2H). Example 104- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) -N- (2, 2-trifluoroethoxy) pyridin-4-yl) pyridin-2-amine
Step 1 4 preparation of bromo-2- (2, 2-trifluoroethoxy) pyridine
In a single vial 2, 4-dibromopyridine (1.0 g,4.22 mmol) was dissolved in 15mL of dimethyl sulfoxide and potassium hydroxide (1.18 g,21.11 mmol) and trifluoroethanol (2.11 g,21.11 mmol) were added. The reaction was stirred at 160℃for 8h. After the completion of the reaction, water and ethyl acetate were added, the organic phases were combined, the organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography to give the title compound. LC-MSm/z 256.0,258.0[ M+H ] ] + 。
Preparation of step 2 4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) -N- (2, 2-trifluoroethoxy) pyridin-4-yl) pyridin-2-amine
The procedure was followed except for using 4-bromo-2- (2, 2-trifluoroethoxy) pyridine instead of 2- (6-bromoisoquinolin-3-yl) propan-2-ol in the preparation of the compound of step 2 of example 53, to give the title compound. LC-MSm/z 476.0[ M+H ]] + 。 1 H NMR(400MHz,CDCl 3 )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 105 1- (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
The procedure was followed except for using 4, 4-difluorocyclohexanone instead of 3-oxetanone to give the title compound in example 43. LC-MS m/z 512.3[ M+H ]] + 。 1 H NMR(400MHz,CDCl 3 )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 106 2- (4- ((4- ((1-cyclopropyl-3- (3, 3-difluorocyclobutane) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) propan-2-ol
The procedure was followed except for using 2- (4-aminopyridin-2-yl) propan-2-ol instead of 1- (4-aminopyridin-2-yl) -2, -trifluoroethyl-1-ol to give the title compound. LC-MS m/z 442.2[ M+H ]] + 。 1 H NMR(400MHz,CDCl 3 )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 107 2- (4- ((4- ((1-cyclopropyl-3- (3, 3-difluorocyclobutyl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) -1, 1-trifluoropropan-2-ol
Preparation of step 1 1- (4-bromopyridin-2-yl) -2, 2-trifluoroethyl-1-one
Methyl 4-bromopyridine-2-carboxylate (0.5 g,2.31 mmol) was dissolved in 20mL of anhydrous tetrahydrofuran, and trifluoromethyltrimethylsilane (0.39 g,2.78 mmol) and cesium fluoride (0.42 g,2.78 mmol) were added and reacted at room temperature under nitrogen atmosphere for 2h. After the reaction, water and ethyl acetate were added, extraction was performed, 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 ]] + 。
Preparation of step 2 2- (4-bromopyridin-2-yl) -1, 1-trifluoropropan-2-ol
1- (4-bromopyridin-2-yl) -2, 2-trifluoroethyl-1-one (0.42 g,1.65 mmol) was dissolved in 20mL of anhydrous tetrahydrofuran, and methyl magnesium bromide (0.83 mL,3M,2.48 mmol) was added thereto, followed by stirring under nitrogen at-10℃for 2 hours. After the completion of the reaction, the saturated ammonium chloride solution was quenched, water and ethyl acetate were added, the mixture was extracted, 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-MSm/z 270.0,272.0[ M+H ]] + 。
Step 3 2 preparation of- (4-aminopyridin-2-yl) -1, 1-trifluoropropan-2-ol hydrochloride
2- (4-bromopyridin-2-yl) -1, 1-trifluoropropan-2-ol (0.28 g,1.05 mmol), tert-butyl carbamate (0.15 g,1.25 mmol), palladium acetate (23.38 mg,0.11 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (0.12 g,0.21 mmol) and cesium carbonate (0.68 g,2.09 mmol) were placed in a reaction flask, 60mL of 1, 4-dioxane was added, and the reaction was stirred under nitrogen at 100℃for 2 hours. After the completion of the reaction, water and ethyl acetate were added, extraction was performed, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography. Dissolving the purified product in Hydrochloric acid/methanol (50 mL, 3M) was stirred for 2.5h, the reaction was complete, and the solvent was concentrated to give the title compound. LC-MS m/z 207.0[ M-HCl+H ]] + 。
Step 4 2 preparation of- (4- ((4- ((1-cyclopropyl-3- (3, 3-difluorocyclobutyl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) -1, 1-trifluoropropan-2-ol
The procedure was followed except for using 2- (4-aminopyridin-2-yl) -1, 1-trifluoropropan-2-ol hydrochloride in place of 1- (4-aminopyridin-2-yl) -2, 2-trifluoroethyl-1-ol to give the title compound. LC-MS m/z 496.0[ M+H ]] + 。 1 H NMR(400MHz,CDCl 3 )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 108 3- (4- ((4- ((1-cyclopropyl-3- (3, 3-difluorocyclobutyl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) -1- (2, 2-trifluoroethyl) azetidin-3-ol
The procedure was followed except for using 3- (4-aminopyridin-2-yl) -1- (2, 2-trifluoroethyl) azetidin-3-ol instead of 1- (4-aminopyridin-2-yl) -2, 2-trifluoroethyl-1-ol to give the title compound. LC-MS m/z 537.1[ M+H ]] + 。 1 H NMR(400MHz,CDCl 3 )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 109- ((1-cyclopropyl-3- (3, 3-difluorocyclobutane) -1H-pyrazol-4-yl) oxy) -N- (2-morpholin-4-yl) pyridin-2-amine
The procedure was followed except for using 2-morpholinopyridin-4-amine instead of 3- (4-aminopyridin-2-yl) oxetan-3-ol hydrochloride in example 79 to give the title compound. LC-MS m/z 469.2[ M+H ] ] + 。 1 H NMR(400MHz,CDCl 3 )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 110 4- (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
Step 14 preparation of cyclohexanone-1-carboxylic acid
Ethyl 4-cyclohexanone formate (3.41 g,20 mmol) was dissolved in 30mL of methanol, aqueous sodium hydroxide (10 mL, 4M) was added to the system, the reaction was carried out at 40℃for 1 hour, 3M HCl solution was slowly added to the reaction system to give a reaction solution having a pH of 1-2, ethyl acetate was added, extraction was carried out, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound. LC-MS m/z 141.1[ M-H ]] - 。
Step 2 4 preparation of benzyl Cyclohexanoformate
4-Cyclohexanone-1-carboxylic acid (2.42 g,17.04 mmol) was dissolved in 30mL of N, N-dimethylformamide, potassium carbonate (1.51 g,10.91 mmol) was added, and bromobenzyl (2.4 mL,20.45 mmol) was then added dropwise to the reaction system and reacted at room temperature for 4 hours. After the reaction, water and ethyl acetate were added to the system, followed by extraction, concentration of the organic phase, and purification by column chromatography to give the title compound. 1 H NMR(400MHz,CDCl 3 )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 3 4 preparation of benzyl-4-methylcyclohexyl-1-carboxylate
Benzyl 4-cyclohexanone formate (3.0 g,12.91 mmol) was dissolved in 45mL of tetrahydrofuran solution and replaced with nitrogen, and a methyl magnesium bromide/tetrahydrofuran solution (5.2 mL, 3M) was slowly added dropwise to the reaction system at-20℃and the reaction was continued at that temperature for 2 hours. Adding water and ethyl acetate into the reaction system, extracting, combining organic phases, drying with anhydrous sodium sulfate, concentrating, and purifying by column chromatography to obtain the title compound.
Step 4 4 preparation of hydroxy-4-methylcyclohexyl-1-carboxylic acid
Benzyl 4-hydroxy-4-methylcyclohexyl-1-carboxylate (704 mg,2.83 mmol) was dissolved in 10mL of methanol, palladium hydroxide on carbon (20 mg,0.15 mmol) was added, hydrogen gas was introduced, and the reaction was carried out at room temperature for 3 hours. After the reaction was completed, celite was used for auxiliary filtration, and the filtrate was concentrated under reduced pressure to give the title compound. LC-MS m/z 157.1[ M-H ]] - 。
Step 5 4 preparation of- (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
The procedure was as in step 1-3 of example 20 except that 4-hydroxy-4-methylcyclohexyl-1-carboxylic acid was used instead of 4, 4-difluorocyclohexane-1-carboxylic acid and 2- (4-aminopyridin-2-yl) propan-2-ol was used instead of 2-morpholinopyridin-4-amine to give the title compound. LC-MS m/z 464.2[ M+H ]] + 。 1 H NMR(400MHz,CDCl 3 )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 111 4- (1-cyclopropyl-4- ((2- ((2- (2-hydroxypropan-2-yl) pyridin-4-yl) amino) pyridin-4-yl) oxy) -1H-pyrazol-3-yl) benzonitrile
The procedure was followed except for using 4- (2-bromoacetyl) benzonitrile instead of 2-bromo-1-phenylethan-1-one to give the title compound. LC-MS m/z 453.0[ M+H ]] + 。 1 H NMR(400MHz,CDCl 3 )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
1. Experimental materials
1.1 Compounds
The control compound was the compound disclosed in example 79 of patent application WO2016/057278 (LY-3200882), chemical name 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 by the methods described in patent WO2016/057278 and identified by hydrogen spectra and mass spectrometry.
The compounds of the present invention and control compounds prepared in the above examples were each diluted to 3.333. Mu.M, 1.111. Mu.M, 370nM, 123nM, 41nM, 14nM, 4.6nM, 1.5nM, 0.5nM after preparing 10mM of DMSO.
1.2 reagents and instruments
Reagent: ALK5, available from Cana, cat. No.09-141; p38 alpha is available from Carna corporation, cat.No.04-152; TGF-beta R1 peptide is available from SignalChem, cat.No. T36-58; ADP-Glo Kinase Assay, available from Promega, cat.No. v9102/3,1 Xkinase buffer (40mM Tris,pH 7.5,0.10%BSA,20mM MgCl 2 1mM DTT), formulated just prior to use.
Instrument: 2104 Multilabel Reader from Perkin Elmer, usa.
2. Experimental method
2.1 preparation of kinase buffer 1 x
1 x assay buffer
40mM Tris,pH 7.5
20mM MgCl 2
0.10％BSA
1mM DTT
2.2 Compound formulation
2.2.1 dilution of Compounds
2.2.1.1 formulation of 50-fold compound: the final concentration of the compound was 10. Mu.M, which was formulated at 50-fold concentration, i.e., 500. Mu.M: to a second well of a 96-well plate, 95. Mu.l of 100% DMSO was added, followed by 5. Mu.l of 10mM compound solution to prepare a 1000. Mu.M compound solution. Other wells were added 60 μl of 100% dmso. Mu.l of the compound was taken from the second well and added to the third well, followed by 3-fold dilution, 10 total concentrations.
2.2.1.2 transfer 100nl of compound to the reaction plate.
2.3 kinase reaction
2.3.1 preparation of a 2-fold kinase solution
Kinase was added to 1-fold kinase buffer to form a 2-fold enzyme solution. 100nl of 100% DMSO-dissolved compound was present in 384 well reaction plates. To 384-well reaction plates 2.5 μl of 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 384 well reaction plates 2.5 μl of 2-fold substrate solution was added.
2.4 kinase reaction
384 well plates were incubated at 28℃for 120 min,
2.5 detection of reaction results
2.5.1 the ADP-Glo reagent was equilibrated 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 ADP-Glo reagent to 384 well plate reaction wells to terminate the reaction.
2.5.4 incubation at 28℃for 120 min.
2.5.5 transfer 10. Mu.l of kinase assay reagent to each well, shake for 1 min, and leave it to stand at room temperature for 30 min.
2.6 data reading
The sample luminescence values 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 percent inhibition by the equation.
Percent inhibition = (max-sample RLU)/(max-min) ×100- "min" is the fluorescence reading of the control sample for the reaction without enzyme; "max" is the fluorescence reading of the sample with DMSO added as control.
2.7.3 data were imported into MS Excel and curve fitted using XLFIT Excel add-in version 5.4.0.8, fitting equation Y=bottom+ (Top-Bottom)/(1+ (IC) 50 X)/(HillSlope), the results are shown in Table 1.
TABLE 1
"-" indicates no measurement.
From the experimental results, the compound has good ALK5 kinase inhibition activity, low p38 alpha inhibition effect and high selectivity. It is suggested that the compounds of the present invention may have lower side effects while achieving higher therapeutic effects.
Experimental example 2 evaluation of in vitro cell luciferase assay
1. Experimental materials
Test compounds: the compounds of the invention prepared in the above examples were each formulated with DMSO at 4mM, followed by 4-fold dilutions of 20000.00nM, 5000.00nM, 1250.00nM, 312.5nM, 78.125nM, 19.53nM, 4.88nM, 1.22nM.
Luc-Smad2/3-NIH3T3 mouse fibroblasts (engineered to overexpress the SMAD2, 3-responsive promoter) were supplied by the university of Chinese medical science laboratory.
Reagent: DMEM, available from Invitrogen, usa; FBS, available from Invitrogen corporation, USA; DMSO, available from Sigma, usa; glo Lysis Buffer, available from Progema corporation, usa; bright-Glo Luciferase assay system, available from Promega corporation, USA; TGFbeta, available from PeproTech, USA.
Instrument: MD SpectraMax M3 multifunctional microplate reader, available from America Molecular Devices.
2. Experimental method
2.1 cell culture:
cell resuscitation: the cells were lysed in a 37℃water bath, then transferred to 15mL of pre-warmed medium, centrifuged at 1000rpm for 5 min, the medium was discarded, the cells were resuspended in 15mL of fresh medium, transferred to a 10cm dish, and placed at 37℃5％CO 2 Is cultured in an incubator of (2), and after 24 hours the cells are replaced with fresh medium.
Cell passage: transferring the resuscitated cells into a 50mL sterile centrifuge tube, centrifuging at 1000rpm for 5 min, discarding the culture medium, collecting uniformly dispersed cell count, adjusting appropriate cell concentration to 15mL fresh culture medium, adding into a 10cm culture dish, and placing at 37deg.C and 5% CO 2 Is cultured in an incubator of (a).
2.2 experimental procedure:
day1: spreading cell (transparent 96 hole plate)
Luc-Smad2/3-NIH3T3 cells were cultured normally in a 10cm dish until confluence reached 80% -90%, digested and collected in a 15mL centrifuge tube, centrifuged at 1000Xg for 5min, the supernatant removed, resuspended in 1mL medium, diluted 10-fold for counting, and the cells were diluted according to the counted results to give a concentration of 4X10 3 Cell number/well was transferred into 96-well plates (100. Mu.l of resuspended cells were added per well).
Day2: cell administration
1-2mg of the drug was weighed (weighed in advance) and prepared into a 4mM mother liquor using DMSO. After 24 hours, the medium was removed. The drug was diluted with 2% FBS medium and 100. Mu.l of 1 Xdrug 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 final TGF-beta 1 concentration per well of 4ng/mL, diluted with 2% FBS medium along with the compound.
Day3: fluorescence detection experiment
The Glo Lysis Buffer and Bright-Glo luciferase assay system and cells were equilibrated to room temperature, the cell supernatant was removed, 100 μ lglo Lysis Buffer was added to each well, and the wells were gently shaken to lyse the cells uniformly, and lysed for 5mins at room temperature. Then 100 μl Bright-glo luciferase assay system was added to each well, incubated at room temperature for 5min, shaken for 2 min, 180 μl supernatant was transferred to a white bottom 96 well plate, and chemiluminescent signal was detected under 1s.
2.3 data processing: nonlinear curve fitting and data analysis using Graphpad Prism 5 software, fitting to obtain IC 50 The experimental results are shown in Table 2.
TABLE 2
"-" indicates no measurement.
From the above experiments, it can be seen that the compounds of the present invention exhibit good inhibitory activity against TGF-ALK 5-SMAD2/3 signaling pathway in NIH3T3 cells.
Experimental example 3 curative effect experiment on CT26 engrafted tumor Balb/c mice
1. Cells and compounds
CT26 colon cancer cells were supplied by Jiangsu Kaiki Biotechnology Co., ltd.
The compound of the example of the present invention and the control compound LY-3200882 were formulated as 6mg/mL with a solution containing 50% PG, 5% ethanol, 10% solutol and 35% water at a concentration of 60mg/kg and a gavage administration volume of 10mL/kg.
2. Methods and materials
2.1. Experimental method
Balb/c mice, females, purchased from Shanghai BiKai laboratory animal Co., ltd, weighed 16-20g. Mice were acclimatized for 2-3 days and the experiment was started.
The right rib of Balb/c mouse was prepared one day in advance and inoculated subcutaneously with 1X 10 6 CT26 cells, fourth day after inoculation, were randomized and divided into solvent control, compound and control compound groups according to examples of the invention after tumor volume measurement. Each group of 6 mice was given 2 times daily by gavage for 21 consecutive days. The solvent control group was given a solution consisting of 50% pg, 5% ethanol, 10% solutol and 35% water. The compound group and the control compound group of the present invention were administered in an amount of 60mg/kg, respectively. Tumor volumes were measured 2 times per week.
2.2. Data statistics
Excel statistical software was used: the average value is calculated as avg; SD value is calculated as STDEV; SEM values were calculated as STDEV/SQRT;
v=0.5a×b2, a and b represent the long and short diameters of the tumor, respectively.
The tumor-inhibiting effect of the compound was evaluated by TGI (%). TGI (%) reflects the tumor growth inhibition rate. Calculation of TGI (%): TGI (%) = [ (1- (mean tumor volume at the end of the treatment group administration-mean tumor volume at the beginning of the treatment group administration))/(mean tumor volume at the end of the treatment with solvent control group-mean tumor volume at the beginning of the treatment with solvent control group) ]x100%.
3. Experimental results
Table 3 shows the tumor inhibition rates of CT26 transplanted tumors on day 21 after administration of a portion of the compounds of the present invention.
TABLE 3 Table 3
The compound of example 106 of the present invention had a tumor suppression rate of 66% for CT26 transplanted tumors on day 21 after administration, which was significantly superior to the control compound LY-3200882.
In addition, the inventors of the present invention also tested the inhibition of CT26 graft tumors by the compounds of example 19 and example 53 using the same method, with a 19 day experimental period. The results of the experiment showed that the compounds of example 19 and example 53 of the present invention showed inhibition of 67% and 52% of CT26 graft tumors, respectively, and 32% of the control compound LY-320088, at day 19 after administration. The compound of the invention is obviously better than LY-320088.
Experimental example 4 therapeutic Effect on H22-grafted tumor Balb/c mice
1. Cells and compounds
H22 hepatoma cells were supplied by Jiangsu Kaiki Biotechnology Co., ltd.
The compound of the present example was formulated with a solution containing 50% PG, 5% ethanol, 10% solutol and 35% water at a concentration of 60mg/kg and a gavage administration volume of 10mL/kg. The control compound LY-3200882 was formulated at two concentrations, 6mg/mL and 12mg/mL, at 60mg/kg and 120mg/kg, respectively, and at a gavage administration volume of 10mL/kg.
2. Methods and materials
2.1. Experimental method
Balb/c mice, females, purchased from Shanghai BiKai laboratory animal Co., ltd, weighed 16-20g. Mice were acclimatized for 2-3 days and the experiment was started.
Will contain 2X 10 6 200uL of cell PBS is inoculated into the abdominal cavity of a mouse, the cells are passaged once every week, the cells are passaged once, ascites are pumped out and counted before inoculation, and PBS is added to adjust the concentration to 8 multiplied by 10 6 Each cell/mL was inoculated with 100uL each, 8X 10 5 Individual cells. Cells were inoculated subcutaneously into the right back of each mouse and the following day of tumor inoculation started group administration. Each group of 6 mice was given 2 times daily by gavage for 19 consecutive days. The solvent control group was given a solution consisting of 50% pg, 5% ethanol, 10% solutol and 35% water. Tumor volumes were measured 2 times per week.
2.2. Data statistics
Excel statistical software was used: the average value is calculated as avg; SD value is calculated as STDEV; SEM values were calculated as STDEV/SQRT;
v=0.5a×b2, a and b represent the long and short diameters of the tumor, respectively.
The tumor-inhibiting effect of the compound was evaluated by TGI (%). TGI (%) reflects the tumor growth inhibition rate. Calculation of TGI (%): TGI (%) = [ (1- (mean tumor volume at the end of the treatment group administration-mean tumor volume at the beginning of the treatment group administration))/(mean tumor volume at the end of the treatment with solvent control group-mean tumor volume at the beginning of the treatment with solvent control group) ]x100%.
3. Experimental results
The therapeutic effects of the compound of the embodiment of the invention on H22 liver cancer cell transplantation tumor are shown in table 4:
TABLE 4 Table 4
Experimental results show that the inhibition rates of the compounds of the invention in the examples 38 and 71 on H22 transplanted tumors are 75% and 66% respectively after 19 days of administration, and the inhibition rate of the control compound LY3200882 at the same dosage is only 43%, and the inhibition rate of the compound LY3200882 at a dosage increased by 1 time is 66%. The compound has excellent tumor inhibiting effect.
Although the invention has been described in detail hereinabove, those skilled in the art will appreciate that various modifications and changes can be made thereto without departing from the spirit and scope of the invention. The scope of the invention is not limited by the detailed description set forth above, but rather is to be attributed to the claims.

Claims (4)

1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is a compound selected from the group consisting of:
2. a pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
3. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 2 in the manufacture of a medicament for the treatment and/or prophylaxis of a TGF- βr1 related disease.
4. The use according to claim 3, wherein the disease is cancer.
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