CN114728932A - Polyarylates as EGFR kinase inhibitors - Google Patents

Polyarylates as EGFR kinase inhibitors Download PDF

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Publication number
CN114728932A
CN114728932A CN202080081283.0A CN202080081283A CN114728932A CN 114728932 A CN114728932 A CN 114728932A CN 202080081283 A CN202080081283 A CN 202080081283A CN 114728932 A CN114728932 A CN 114728932A
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compound
amino
formula
methoxy
methyl
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刘磊
刘扬
周峰
唐任宏
任晋生
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Jiangsu Simcere Pharmaceutical Co Ltd
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Jiangsu Simcere Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The invention relates to a fourth generation (T790M/C797S mutation) EGFR kinase inhibitor and a medical application thereof, and particularly discloses a compound shown as a formula (I) or a pharmaceutically acceptable salt thereof. The compound has better curative effect on diseases caused by EGFR Del19/T790M/C797S and L858R/T790M/C797S abnormal mutation.

Description

Polyarylates as EGFR kinase inhibitors Technical Field
The present application relates to polyarylates as EGFR kinase inhibitors, processes for their preparation, pharmaceutical compositions containing the compounds, and their use in the treatment of EFGR kinase-associated diseases.
Background
EGFR (epidermal Growth Factor receptor) is a receptor for cell proliferation and signaling by the Epidermal Growth Factor (EGF). EGFR belongs to the ErbB receptor family, which includes EGFR (ErbB-1), HER2/c-neu (ErbB-2), HER3(ErbB-3), and HER4 (ErbB-4). EGFR is also known as HER1, ErbB 1. The EGFR is widely distributed on the cell surfaces of epithelial cells, fibroblasts, glial cells, keratinocytes and the like of mammals, and an EGFR signal channel plays an important role in the physiological processes of growth, proliferation, differentiation and the like of cells. EGFR is divided into three regions: an extracellular ligand binding domain, a transmembrane domain, and an intracellular kinase domain. After being bound by corresponding ligands, EGFR can be induced to form homo-or heterodimers, so that an intracellular tyrosine kinase pathway is activated, and the EGFR can be self-phosphorylated, thereby guiding downstream phosphorylation including MAPK, Akt and JNK pathways and inducing cell proliferation.
An EGFR Tyrosine Kinase Inhibitor (TKI) inhibits receptor phosphorylation and activation of downstream signal transduction molecules by blocking binding of endogenous ATP to an intracellular Kinase domain, thereby blocking proliferation of tumor cells. Although EGFR targeted therapies have been successfully advanced into the clinical stage and drugs are already on the market, genetic mutations in EGFR have led to drug resistance. The mutation mainly occurs in exons 18-21, wherein deletion of exon 19 and point mutation of L858R of exon 21 are the most common mutant subtypes, accounting for 90% of all mutant types. With the development and use of drugs, most of the drug resistance occurs in the secondary mutation of the gatekeeper region T790M of the kinase. The third-generation irreversible inhibitor developed in recent years has good inhibitory activity on T790M mutation, but C797S mutation is also inevitable and is the main drug resistance mechanism (about 40%) of the star drug AZD 9291. AZD9291 has already entered first-line treatment in 2018, and development of novel, safer and more effective EGFR TKIs is urgently needed for C797S mutation.
Disclosure of Invention
The present application relates to compounds of formula (I) or pharmaceutically acceptable salts thereof,
Figure PCTCN2020132188-APPB-000001
wherein the content of the first and second substances,
R 1selected from phenyl and 5-6 membered heteroaryl, optionally substituted with R7Substitution;
or R1Is composed of
Figure PCTCN2020132188-APPB-000002
Wherein R is11、R 12Independently selected from C1-4Alkyl radical, said C1-4Alkyl optionally substituted by hydroxy or C1-4Alkoxy substitution;
R 2is a 4-14 membered heterocycloalkyl group, said 4-14 membered heterocycloalkyl group being optionally substituted with R8Substitution;
u, V, W is independently selected from CR6And N;
ring A is selected from phenyl and 5-6 membered heteroaryl;
R 3selected from H, halogen, cyano, C1-4Alkyl and C1-4An alkoxy group;
R 4、R 5independently selected from C1-4Alkyl and C1-4An alkoxy group;
R 6independently selected from H, C1-4Alkyl radical, C1-4Alkoxy and halogen;
R 7independently selected from halogen, hydroxy, amino, C1-4Alkyl and C1-4Alkoxy radical, said C1-4Alkyl and C1-4Alkoxy optionally substituted with hydroxy;
R 8independently selected from halogen, OH, C1-6Alkyl radical, C1-6Alkoxy, amino, C3-8Cycloalkyl and 3-8 membered heterocycloalkyl, said amino, C3-8Cycloalkyl and 3-8 membered heterocycloalkyl are optionally substituted with R9Substitution;
R 9independently selected from halogen, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Acyl and oxo.
In some embodiments, R1Selected from 5-6 membered heteroaryl, said 5-6 membered heteroaryl optionally substituted with R7And (4) substitution.
In some embodiments, R1Selected from 5-membered heteroaryl, said 5-membered heteroaryl being optionally substituted by R7And (4) substitution.
In some embodiments, R1Selected from phenyl, pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, tetrazolyl and triazolyl, said phenyl, pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, tetrazolyl and triazolyl being optionally substituted by R 7And (4) substitution.
In some embodiments, R1Selected from the group consisting of pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, tetrazolyl and triazolyl, optionally substituted with R7And (4) substitution.
In some embodiments, R1Selected from phenyl, pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl and triazolyl, said phenyl, pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl and triazolyl being optionally substituted by R7And (4) substitution.
In some embodiments, R1Selected from phenyl, pyridyl, pyrazolyl and imidazolyl optionally substituted with R7And (4) substitution.
In some embodiments, R1Selected from the group consisting of pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl and triazolyl, said pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl and triazolyl being optionally substituted with R7And (4) substitution.
In some embodiments, R7Independently selected from halogen, hydroxy and C1-4Alkyl radical, said C1-4Alkyl is optionally substituted with hydroxy.
In some embodiments, R7Independently selected from C1-4Alkyl radical, said C1-4Alkyl is optionally substituted with hydroxy.
In some embodiments, R7Independently selected from methyl and hydroxyethyl.
In some embodiments, R7Independently selected from methyl.
In some embodiments, R1Selected from phenyl,
Figure PCTCN2020132188-APPB-000003
Figure PCTCN2020132188-APPB-000004
In some embodiments, R1Selected from phenyl,
Figure PCTCN2020132188-APPB-000005
In some embodiments, R1Is selected from
Figure PCTCN2020132188-APPB-000006
Figure PCTCN2020132188-APPB-000007
In some embodiments, R1Is composed of
Figure PCTCN2020132188-APPB-000008
Wherein R is11Is selected from C1-4Alkyl radical, R12Selected from C optionally substituted by hydroxy1-4An alkyl group.
In some embodiments, R1Is composed of
Figure PCTCN2020132188-APPB-000009
Wherein R is11Is methyl, R12Is methyl or hydroxyethyl.
In some embodiments, R2Is a 5-12 membered heterocycloalkyl group, said 5-12 membered heterocycloalkyl group being optionally substituted with R8And (4) substitution.
In some embodiments, R2Is 6-11 membered heterocycloalkyl, said 6-11 membered heterocycloalkyl is optionally substituted with R8And (4) substitution.
In some embodiments, R2Selected from the group consisting of piperidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, 1, 4-thioxanyl, 1, 4-dioxanyl, thiomorpholinyl, 1, 3-dithianyl, 1, 4-dithianyl, azepanyl, oxepanyl, thiepanyl, 3, 9-diazaspiro [5.5]Undecyl, 2, 9-diazaspiro [5.5 ]]Undecyl group,
Figure PCTCN2020132188-APPB-000010
Figure PCTCN2020132188-APPB-000011
The piperidine group, tetrahydropyranyl group, morpholinyl group, piperazinyl group, 1, 4-thioxanyl group, 1, 4-dioxane group, thiomorpholinyl group, 1, 3-dithianyl group, 1, 4-dithianyl group, azepane group, oxepanyl group, thiepane group, 3, 9-diazaspiro [5.5]Undecyl, 2, 9-diazaspiro [5.5 ]]Undecyl group,
Figure PCTCN2020132188-APPB-000012
Optionally substituted with R8And (4) substitution.
In some embodiments, R2Selected from the group consisting of piperidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, 1, 4-thioxanyl, 1, 4-dioxanyl, thiomorpholinyl, 1, 3-dithianyl, 1, 4-dithianyl, azepanyl, oxepanyl, thiepanyl, 3, 9-diazaspiro [5.5]Undecyl, 2, 9-diazaspiro [5.5 ]]Undecyl group,
Figure PCTCN2020132188-APPB-000013
The piperidine group, tetrahydropyranyl group, morpholinyl group, piperazinyl group, 1, 4-thioxanyl group, 1, 4-dioxane group, thiomorpholinyl group, 1, 3-dithianyl group, 1, 4-dithianyl group, azepane group, oxepanyl group, thiepane group, 3, 9-diazaspiro [5.5]Undecyl, 2, 9-diazaspiro [5.5 ]]Undecyl group,
Figure PCTCN2020132188-APPB-000014
Optionally substituted with R8And (4) substitution.
In some embodiments, R2Selected from piperidinyl, piperazinyl, morpholinyl, 3, 9-diazaspiro [5.5]An undecyl group,
Figure PCTCN2020132188-APPB-000015
Figure PCTCN2020132188-APPB-000016
The piperidyl, the piperazinyl, the morpholinyl, the 3, 9-diazaspiro [5.5]Undecyl group,
Figure PCTCN2020132188-APPB-000017
Figure PCTCN2020132188-APPB-000018
Optionally substituted with R8And (4) substitution.
In some embodiments, R2Selected from piperidinyl, piperazinyl, morpholinyl, 3, 9-diazaspiro [5.5]Undecyl group,
Figure PCTCN2020132188-APPB-000019
Figure PCTCN2020132188-APPB-000020
The piperidyl, the piperazinyl, the morpholinyl, the 3, 9-diazaspiro [5.5]Undecyl group,
Figure PCTCN2020132188-APPB-000021
Figure PCTCN2020132188-APPB-000022
Optionally substituted with R8And (4) substitution.
In some embodiments, R2Selected from the group consisting of piperidinyl, piperazinyl, morpholinyl,
Figure PCTCN2020132188-APPB-000023
Piperidinyl, piperazinyl, morpholinyl,
Figure PCTCN2020132188-APPB-000024
Optionally substituted with R8And (4) substitution.
In some embodiments, R2Selected from the group consisting of piperidinyl, morpholinyl and 3, 9-diazaspiro [5.5]Undecyl, piperidinyl, morpholinyl and 3, 9-diazaspiro [5.5 ]]Undecyl being optionally substituted by R8And (4) substitution.
In some embodiments, R8Independently selected from halogen, C1-6Alkyl radical, C1-6Alkoxy, amino, C3-8Cycloalkyl and 3-8 membered heterocycloalkyl, said amino, C3-8Cycloalkyl and 3-8 membered heterocycloalkyl optionally substituted with R9And (4) substitution.
In some embodiments, R8Independently selected from halogen, OH, C1-4Alkyl, amino, C3-7Cycloalkyl and 3-7 membered heterocycloalkyl, said amino, C3-7Cycloalkyl and 3-7 membered heterocycloalkyl are optionally substituted with R9And (4) substitution.
In some embodiments, R8Independently selected from halogen, OH, amino and 3-7 membered heterocycloalkyl, said amino and 3-7 membered heterocycloalkyl optionally substituted with R9And (4) substitution.
In some embodiments, R8Independently selected from C1-4Alkyl, amino,C 3-7Cycloalkyl and 3-7 membered heterocycloalkyl, said amino, C3-7Cycloalkyl and 3-7 membered heterocycloalkyl optionally substituted with R9And (4) substitution.
In some embodiments, R8Independently selected from F, OH, methyl, amino, piperazinyl, 1, 3-oxazinyl, 1, 4-diazepanyl, 1, 3-oxazepanyl, 1, 4-oxazepanyl, oxetanyl, morpholinyl, pyrrolidinyl, tetrahydropyranyl, azetidinyl, said amino, piperazinyl, 1, 3-oxazinyl, 1, 4-diazepanyl, 1, 3-oxazepanyl, 1, 4-oxazepanyl, oxetanyl, morpholinyl, pyrrolidinyl, tetrahydropyranyl, azetidinyl optionally substituted with R9And (4) substitution.
In some embodiments, R8Independently selected from F, OH, methyl, amino, piperazinyl, 1, 3-oxazinyl, 1, 4-diazepanyl, 1, 3-oxazepanyl, 1, 4-oxazepanyl, oxetanyl, morpholinyl, pyrrolidinyl, tetrahydropyranyl, said amino, piperazinyl, 1, 3-oxazinyl, 1, 4-diazepanyl, 1, 3-oxazepanyl, 1, 4-oxazepanyl, oxetanyl, morpholinyl, pyrrolidinyl, tetrahydropyranyl being optionally substituted with R9And (4) substitution.
In some embodiments, R8Independently selected from F, OH, amino, piperazinyl, 1, 4-oxazepanyl, oxetanyl, morpholinyl, pyrrolidinyl, tetrahydropyranyl, said amino, piperazinyl, 1, 4-oxazepanyl, oxetanyl, morpholinyl, pyrrolidinyl, tetrahydropyranyl being optionally substituted with R9And (4) substitution.
In some embodiments, R8Independently selected from the group consisting of methyl, amino, piperazinyl, 1, 3-oxazinyl, 1, 4-diazepanyl, 1, 3-oxazepanyl, and 1, 4-oxazepanyl, said amino, piperazinyl, 1, 3-oxazinyl, 1, 4-diazepanyl, 1, 3-oxazepanyl, and 1,4-oxazepanyl optionally substituted by R9And (4) substitution.
In some embodiments, R9Independently selected from halogen, C1-4Alkyl radical, C1-4Acyl radical, C1-4Alkoxy and oxo.
In some embodiments, R9Independently selected from halogen, C1-4Alkyl and C1-4An acyl group.
In some embodiments, R9Independently selected from halogen, C1-4Alkyl radical, C1-4Alkoxy and oxo.
In some embodiments, R9Independently selected from F, methyl, acetyl and oxo.
In some embodiments, R9Independently selected from the group consisting of F, methyl and acetyl.
In some embodiments, R9Independently selected from methyl and oxo.
In some embodiments, R2Is selected from
Figure PCTCN2020132188-APPB-000025
Figure PCTCN2020132188-APPB-000026
In some embodiments, R2Is selected from
Figure PCTCN2020132188-APPB-000027
Figure PCTCN2020132188-APPB-000028
In some embodiments, R2Is selected from
Figure PCTCN2020132188-APPB-000029
Figure PCTCN2020132188-APPB-000030
In some embodiments, R2Is selected from
Figure PCTCN2020132188-APPB-000031
Figure PCTCN2020132188-APPB-000032
In some embodiments, U is CR6。
In some embodiments, R6Independently selected from C1-4An alkoxy group.
In some embodiments, R6Is methoxy.
In some embodiments, V is selected from CH and N.
In some embodiments, W is selected from CH and N.
In some embodiments, ring a is selected from phenyl, pyrazinyl, and pyridyl.
In some embodiments, ring a is selected from phenyl and pyrazinyl.
In some embodiments of the present invention, the substrate is,
Figure PCTCN2020132188-APPB-000033
is selected from
Figure PCTCN2020132188-APPB-000034
In some embodiments of the present invention, the substrate is,
Figure PCTCN2020132188-APPB-000035
is selected from
Figure PCTCN2020132188-APPB-000036
In some embodiments of the present invention, the substrate is,
Figure PCTCN2020132188-APPB-000037
is selected from
Figure PCTCN2020132188-APPB-000038
In some embodiments, R3Selected from halogen and C1-4An alkyl group.
In some embodiments, R3Selected from Cl and Br.
In some embodiments, R4、R 5Independently selected from C1-3An alkyl group.
In some embodiments, R4、R 5Is methyl.
In some embodiments, the compound of formula (I) herein is selected from compounds of formula (II),
Figure PCTCN2020132188-APPB-000039
wherein R is1、R 2、R 3、R 6And V is as defined above.
In some embodiments, the compound of formula (I) herein is selected from compounds of formula (III),
Figure PCTCN2020132188-APPB-000040
wherein R is1、R 2、R 3、R 6And V is as defined above.
In some embodiments, the compounds of formula (I) herein are selected from the following compounds:
Figure PCTCN2020132188-APPB-000041
Figure PCTCN2020132188-APPB-000042
Figure PCTCN2020132188-APPB-000043
Figure PCTCN2020132188-APPB-000044
Figure PCTCN2020132188-APPB-000045
Figure PCTCN2020132188-APPB-000046
in another aspect, the present application relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
In another aspect, the present application relates to a method of treating a disease mediated by EGFR in a mammal, comprising administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
In another aspect, the present application relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the prevention or treatment of EGFR mediated diseases.
In another aspect, the present application relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the prevention or treatment of EGFR mediated diseases.
In another aspect, the present application relates to a compound of formula (i) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the prevention or treatment of EGFR-mediated diseases.
Definition of
The following terms used in the present application have the following meanings, unless otherwise specified. A particular term should not be considered as ambiguous or unclear without special definition, but rather construed according to ordinary meaning in the art. When a trade name appears herein, it is intended to refer to its corresponding commercial product or its active ingredient.
The term "substituted" means that any one or more hydrogen atoms on a particular atom is replaced with a substituent, so long as the valence of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., ═ O), meaning that two hydrogen atoms are substituted, oxo does not occur on the aryl.
The terms "optionally" or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, ethyl is "optionally" substituted with halo, meaning that ethyl may be unsubstituted (CH)2CH 3) Monosubstituted (e.g. CH)2CH 2F) Polysubstituted (e.g. CHFCH)2F、CH 2CHF 2Etc.) or completely substituted (CF2CF 3). It will be appreciated by those skilled in the art that any group containing one or more substituents will not incorporate any substitution or substitution patterns which are sterically impossible and/or synthetically impossible.
Herein Cm-nIt means that the moiety has an integer number of carbon atoms in the given range. E.g. "C1-6By "is meant that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.
When any variable (e.g., R) occurs more than one time in the composition or structure of a compound, its definition in each case is independent. For example, if a group is substituted with 2R, then each R has independent options.
The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.
The term "hydroxy" refers to an-OH group.
The term "cyano" refers to the group — CN.
The term "amino" refers to the group-NH2A group.
The term "alkyl" refers to a group of formula CnH 2n+1A hydrocarbon group of (1). The alkyl group may be linear or branched. For example, the term "C1- 6Alkyl "means an alkyl group having 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, and the like). Similarly, the alkyl portion (i.e., alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl and alkylthio groups have the same definitions as above.
The term "alkoxy" refers to-O-alkyl. The term "C1-4The alkoxy group "may be methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy or the like.
The term "acyl" denotes a group of formula-C (═ O) R, where R is hydrogen or alkyl as defined herein; the term "C1-4Acyl "refers to-C (═ O) R containing 1 to 4 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl.
The term "cycloalkyl" refers to a carbon ring that is fully saturated and may exist as a single ring, a bridged ring, or a spiro ring. Unless otherwise indicated, the carbocycle is typically a 3 to 10 membered ring. Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo [2.2.1 ] n]Heptyl), bicyclo [2.2.2]Octyl, adamantyl, and the like. Preferably, "cycloalkyl" includes "C3-8Cycloalkyl radicals "and" C3-7Cycloalkyl groups ".
The term "C3-8Cycloalkyl "is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring which forms a 3-8 membered carbocyclic ring from 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. "C3-8Cycloalkyl "preferably contains" C3-7Cycloalkyl groups ". "C3-7Cycloalkyl "is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring which forms a 3-7 membered carbocyclic ring from 3-7 carbon atoms.
The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and may exist as a single ring, a bicyclic ring, a bridged ring, or a spiro ring. Unless otherwise indicated, the heterocyclic ring typically contains 1 to 5 heteroatoms (preferably 1 or 2 or 3 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen as ring atoms, and the total number of ring atoms is typically 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13 or 14.
The term "heterocycloalkyl" as used herein includes, but is not limited to, 3-membered heterocycloalkyl such as oxiranyl, thienylethyl, cycloazethynyl, 4-membered heterocycloalkyl such as azetidinyl, oxetanyl, thienylyl, 5-membered heterocycloalkyl such as tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, tetrahydropyrazolyl, 6-membered heterocycloalkyl such as piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1, 4-thioxanyl, 1, 4-dioxanyl, thiomorpholinyl, 1, 3-dithianyl, 1, 4-dithianyl, 7-membered heterocycloalkyl such as azepanyl, oxepanyl, thiepanyl.
The term "4-14 membered heterocycloalkyl" refers to a monocyclic, bicyclic, bridged or spiro ring which is fully saturated, contains 1 to 5, preferably 1 to 3 heteroatoms independently selected from N, O and/or S as ring atoms and has 4,5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms respectively.
The term "5-12 membered heterocycloalkyl" means fully saturated, containing 1-5, preferably 1-3 heteroatoms independently selected from N, O and/or S as ring atoms, and having 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms as monocyclic, bicyclic, bridged or spiro rings, respectively.
The terms "4-to 14-membered heterocycloalkyl" and "5-to 12-membered heterocycloalkyl" herein preferably encompass "6-to 11-membered heterocycloalkyl", "3-to 8-membered heterocycloalkyl" or "3-to 7-membered heterocycloalkyl" and the like.
The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O, S, the remaining ring atoms being C, and having at least one aromatic ring. Preferred heteroaryls have a single 4-to 8-membered ring, especially a single 5-to 8-membered ring, or multiple fused rings containing 6 to 14, especially 6 to 10 ring atoms. Non-limiting examples of heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, and the like. Preferably, "heteroaryl" encompasses "5-6 membered heteroaryl".
The term "5-6 membered heteroaryl" refers to an aromatic ring system having 5 or 6 ring atoms and which contains 1-3, preferably 1-2 heteroatoms independently selected from N, O and S. In particular, "5-6 membered heteroaryl" includes, but is not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl, and the like.
The term "treating" means administering a compound or formulation described herein to prevent, ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
(i) preventing the occurrence of a disease or condition in a mammal, particularly when such mammal is susceptible to the disease condition, but has not yet been diagnosed as having the disease condition;
(ii) inhibiting the disease or disease state, i.e., arresting its development;
(iii) alleviating the disease or condition, i.e., causing regression of the disease or condition.
The term "therapeutically effective amount" means an amount of a compound of the present application that (i) treats or prevents a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of a compound of the present application that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art with their own knowledge and this disclosure.
The term "pharmaceutically acceptable" is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As the pharmaceutically acceptable salt, for example, a metal salt, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, and the like can be mentioned.
The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or salts thereof and pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.
The term "pharmaceutically acceptable adjuvants" refers to those adjuvants which do not have a significant irritating effect on the organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, for example carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.
The words "comprise" or "comprise" and variations thereof such as "comprises" or "comprising," are to be understood in an open, non-exclusive sense, i.e., "including but not limited to.
The present application also includes isotopically-labeled compounds of the present application, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as respectively2H、 3H、 11C、 13C、 14C、 13N、 15N、 15O、 17O、 18O、 31P、 32P、 35S、 18F、 123I、 125I and36cl, and the like.
Certain isotopically-labelled compounds of the present application (e.g. with3H and14c-labeled ones) can be used in compound and/or substrate tissue distribution assays. Tritiated (i.e. by tritiation)3H) And carbon-14 (i.e.14C) Isotopes are particularly preferred for their ease of preparation and detectability. Positron emitting isotopes, such as15O、 13N、 11C and18f can be used in Positron Emission Tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the present application can generally be prepared by following procedures analogous to those disclosed in the schemes and/or in the examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
In addition, heavier isotopes are used (such as deuterium (i.e., deuterium)2H) Substitution may provide some of those resulting from greater metabolic stabilityTherapeutic advantages (e.g., increased in vivo half-life or reduced dosage requirements), and thus may be preferred in certain circumstances, where deuterium substitution may be partial or complete, partial deuterium substitution meaning that at least one hydrogen is replaced with deuterium.
The compounds of the present application may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms (optical centers) or asymmetric double bonds. Racemates, enantiomers, diastereomers, geometric isomers are included within the scope of the present invention.
The enantiomers or enantiomerically pure compounds herein are illustrated by Maehr, J.chem.Ed.1985, 62: 114-120. Using wedge and virtual wedge keys, unless otherwise indicated
Figure PCTCN2020132188-APPB-000047
Indicating the absolute configuration of a stereocenter. An additional asymmetric carbon atom, asymmetric sulfur atom, asymmetric nitrogen atom or asymmetric phosphorus atom may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are included within the scope of the present invention. The compounds of the present application containing asymmetric atoms or asymmetric double bonds can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from a racemic mixture or synthesized by using chiral starting materials or chiral reagents.
The compounds and intermediates of the present application may also exist in different tautomeric forms, and all such forms are included within the scope of the present application. The term "tautomer" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also referred to as proton transfer tautomers) include interconversion via proton migration, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is an imidazole moiety, wherein the proton can migrate between two ring nitrogens. Valence tautomers include interconversion by recombination of some of the bonding electrons.
The pharmaceutical compositions of the present application can be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, for example, can be formulated into solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres, aerosols, and the like.
Typical routes of administration of a compound of the present application or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.
The pharmaceutical compositions of the present application can be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, emulsifying, lyophilizing, and the like.
In some embodiments, the pharmaceutical composition is in an oral form. For oral administration, the pharmaceutical compositions may be formulated by mixing the active compounds with pharmaceutically acceptable excipients well known in the art. These adjuvants enable the compounds of the present application to be formulated as tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions and the like, for oral administration to a patient.
Solid oral compositions may be prepared by conventional mixing, filling or tableting methods. For example, it can be obtained by the following method: the active compounds are mixed with solid adjuvants, optionally the mixture obtained is milled, if desired with further suitable adjuvants, and the mixture is then processed to granules, to give tablets or dragee cores. Suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents and the like.
The pharmaceutical compositions may also be adapted for parenteral administration, as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.
In all methods of administration of the compounds of the general formula I described herein, the daily dose is from 0.01 to 200mg/kg body weight, preferably from 0.05 to 40mg/kg body weight, more preferably from 0.1 to 20mg/kg body weight, in single or divided doses.
The compounds of the present application may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combinations thereof with other chemical synthetic methods, and equivalents thereof known to those skilled in the art, with preferred embodiments including, but not limited to, the examples of the present application.
The chemical reactions of the embodiments herein are carried out in a suitable solvent that is compatible with the chemical changes of the present application and the reagents and materials required therefor. In order to obtain the compounds of the present application, it is sometimes necessary for a person skilled in the art to modify or select the synthesis steps or reaction schemes based on the existing embodiments.
In some embodiments, the compounds of general formula (I) herein may be prepared by one skilled in the art of organic synthesis via scheme 1:
Figure PCTCN2020132188-APPB-000048
reacting a compound shown in the formula (a) with a compound shown in the formula (b) in the presence of sodium carbonate and a [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex to generate a compound shown in the formula (c), catalytically hydrogenating the compound shown in the formula (c) to generate a compound shown in the formula (d), and reacting the compound shown in the formula (d) with a compound shown in the formula (e) to generate a compound shown in the formula (I).
For clarity, the present application is further illustrated by examples, which do not limit the scope of the present application. All reagents used herein were commercially available and used without further purification.
Detailed Description
The following examples illustrate the technical solutions of the present invention in detail, but the scope of the present invention includes but is not limited thereto.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) and/or Mass Spectrometry (MS). NMR shift in units of 10-6(ppm). The solvent for NMR determination is deuterated dimethyl sulfoxide or deuterated dimethyl sulfoxideChloroform, deuterated methanol and the like, and the internal standard is Tetramethylsilane (TMS); ' IC50"half inhibitory concentration" means the concentration at which half of the maximum inhibitory effect is achieved.
EXAMPLE 1 preparation of (3- ((5-bromo-2- ((4- (4- (dimethylamino) piperidin-1-yl) -2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) phenyl) amino) pyrimidin-4-yl) amino) quinolin-4-yl) dimethylphosphine oxide (Compound 1) trifluoroacetate
Figure PCTCN2020132188-APPB-000049
Compounds 1 to 2:
Figure PCTCN2020132188-APPB-000050
quinoline-3-amine (1-1) (1g, 6.9mmol) was dissolved in N, N-dimethylformamide (10mL) at room temperature, and a solution of iodosuccinimide (1.7g, 7.6mmol) in N, N-dimethylformamide (10mL) was added dropwise at 0 ℃ to stir the reaction at room temperature for 1 hour. After completion of the reaction, the reaction mixture was poured into water (100mL), the mixture was extracted with ethyl acetate (50mL X3), the organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent gradient: petroleum ether: ethyl acetate: 3:1, Rf: 0.5) to give the objective 4-iodoquinolin-3-amine (1-2) (670mg, yield: 36%).
LCMS:Rt:1.505min；MS m/z(ESI):271.0[M+H] +。
Compounds 1-3:
Figure PCTCN2020132188-APPB-000051
4-iodoquinolin-3-amine (1-2) (370mg, 1.37mmol), dimethylphosphine oxide (214mg, 2.74mmol), cesium carbonate (1.34g, 4.11mmol), tris (dibenzylideneacetone) dipalladium (247mg, 0.27mmol) and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (258mg, 0.54mmol) were added to N, N-dimethylformamide (6mL) at room temperature, and the system was heated to 100 ℃ under nitrogen and stirred for 12 hours. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent gradient: dichloromethane: methanol 20:1, Rf 0.5) to give the objective product (3-aminoquinolin-4-yl) dimethylphosphine oxide (1-3) (180mg, yield: 60%).
LCMS:Rt:1.235min；MS m/z(ESI):221.3[M+H] +。
Compounds 1-4:
Figure PCTCN2020132188-APPB-000052
(3-aminoquinolin-4-yl) dimethylphosphine oxide (1-3) (180mg, 0.82mmol), 5-bromo-2, 4-dichloropyrimidine (374mg, 1.64mmol) and diisopropylethylamine (1.06g, 8.2mmol) were dissolved in ethanol (5mL) at room temperature, and the system was heated to 100 ℃ under nitrogen and stirred for reaction 12 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent gradient: dichloromethane: methanol 20:1, Rf 0.5) to give the objective product (3- ((5-bromo-2-chloropyrimidin-4-yl) amino) quinolin-4-yl) dimethylphosphine oxide (1-4) (120mg, yield: 36%).
LCMS:Rt:1.620min；MS m/z(ESI):413.2[M+H] +。
Compounds 1-6:
Figure PCTCN2020132188-APPB-000053
n, N-dimethylpiperidin-4-amine (1-5) (500mg,2.71mmol) and 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene (604mg,2.44mmol) are dissolved in acetonitrile (15mL) at room temperature, followed by the addition of potassium carbonate (5.3g,8.13 mmol). The reaction solution is heated to 80 ℃ under the protection of argon gas, stirred and reacted for 4 hours until the reaction is complete. The reaction mixture was directly concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent gradient: methanol: dichloromethane: 1:30 to 1:10) to give the target product, 1- (2-bromo-5-methoxy-4-nitrophenyl) -N, N-dimethylpiperidin-4-amine (1-6) (560mg, yield: 57.9%).
LCMS：Rt:0.952min；MS m/z(ESI):358.1[M+H] +。
Compounds 1-7:
Figure PCTCN2020132188-APPB-000054
1- (2-bromo-5-methoxy-4-nitrophenyl) -N, N-dimethylpiperidin-4-amine (1-6) (300mg, 0.84mmol), 1-methyl-4-1H-pyrazole-boronic acid pinacol ester (524mg, 2.52mmol), sodium carbonate (268mg, 2.52mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (55.2mg, 0.16mmol) were dissolved in a mixture of dioxane (10mL) and water (1mL) at room temperature, and the reaction mixture was heated to 100 ℃ under nitrogen protection and stirred for 12 hours. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent gradient: dichloromethane: methanol 20:1, Rf 0.5) to give the objective product 1- (5-methoxy-2- (1-methyl-1H-pyrazol-4-yl) -4-nitrophenyl) -N, N-dimethylpiperidin-4-amine (1-7) (250mg, yield: 82.7%).
LCMS：Rt:0.980min；MS m/z(ESI):360.5[M+H] +。
Compounds 1-8:
Figure PCTCN2020132188-APPB-000055
1- (5-methoxy-2- (1-methyl-1H-pyrazol-4-yl) -4-nitrophenyl) -N, N-dimethylpiperidine-4-amine (1-7) (250mg,0.69mmol) is dissolved in ethanol (15mL) at room temperature, a palladium-carbon catalyst (25mg) is added, and the reaction solution is heated to 50 ℃ under a hydrogen atmosphere and stirred for reaction for 3 hours until the reaction is complete. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the crude desired product, 1- (4-amino-5-methoxy-2- (1-methyl-1H-pyrazol-4-yl) phenyl) -N, N-dimethylpiperidin-4-amine (1-8) (190mg, yield: 83.7%).
LCMS：Rt:0.382min；MS m/z(ESI):330.5[M+H] +。
Trifluoroacetic acid salt of compound 1:
Figure PCTCN2020132188-APPB-000056
1- (4-amino-5-methoxy-2- (1-methyl-1H-pyrazol-4-yl) phenyl) -N, N-dimethylpiperidin-4-amine (1-8) (100mg, 0.30mmol) and (3- ((5-bromo-2-chloropyrimidin-4-yl) amino) quinolin-4-yl) dimethylphosphine oxide (1-4) (80mg,0.20 mmol) were dissolved in isopropanol (3mL) at room temperature, and trifluoroacetic acid (228mg, 2.0mmol) was added; the reaction solution was heated to 100 ℃ and stirred to react for 24 hours. After completion of the reaction, the reaction solution was cooled to room temperature, then concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography with eluent gradients as shown in the following table:
Figure PCTCN2020132188-APPB-000057
the objective compound (3- ((5-bromo-2- ((4- (4- (dimethylamino) piperidin-1-yl) -2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) phenyl) amino) pyrimidin-4-yl) amino) quinolin-4-yl) dimethylphosphine oxide (compound 1) trifluoroacetate was obtained (29.8mg, yield: 14.1%).
1H NMR(400MHz,CD 3OD)δ：9.46(d,J＝4.8Hz,1H),8.23(s,1H),8.15-8.13(m,1H),7.82(brs,2H),7.68(d,J＝6.0Hz,3.2Hz,2H),7.56(s,1H),7.38(brs,1H),6.76(s,1H),3.88(s,3H),3.51(s,3H),3.20-3.14(m,3H),2.87(s,6H)2.70-2.63(m,2H),2.19(s,3H),2.16(s,3H),2.11-2.07(m,2H),1.81-1.75(m,2H).
19F NMR(376.5MHz,CD 3OD):δ-76.89.
31P NMR(162.0MHz,CD 3OD):δ47.59.
LCMS：Rt:1.021min；MS m/z(ESI):704.1,706.1[M+H] +。
Example 2 preparation of (3- ((5-chloro-2- ((2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -4-morpholinophenyl) amino) pyrimidin-4-yl) amino) quinolin-4-yl) dimethylphosphine oxide (Compound 2) trifluoroacetate
Figure PCTCN2020132188-APPB-000058
Compound 2-1:
Figure PCTCN2020132188-APPB-000059
(3-aminoquinolin-4-yl) dimethylphosphine oxide (1-3) (1.0g,4.52mmol) was dissolved in ethanol (10mL) at room temperature, 2,4, 5-trichloropyrimidine (1.65g,9.04mmol) and N, N-diisopropylethylamine (3.5g,27.1mmol) were added, and the reaction was heated to 120 ℃ under argon atmosphere and stirred for 72 hours until the reaction was complete. The reaction solution was directly concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent gradient: ethyl acetate: petroleum ether ═ 1:10 to 1:1) to give the target product (3- ((2, 5-dichloropyrimidin-4-yl) amino) quinolin-4-yl) dimethylphosphine oxide (2-1) (0.56g, yield: 30%).
LCMS：Rt:1.517min；MS m/z(ESI):367.2[M+H] +。
Compounds 2-3:
Figure PCTCN2020132188-APPB-000060
morpholine (2-2) (2.0g,22.98mmol) and 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene (5.17g,20.68mmol) were dissolved in acetonitrile (25mL) at room temperature, followed by the addition of potassium carbonate (9.5g,68.94 mmol). The reaction solution is heated to 80 ℃ under the protection of argon gas, stirred and reacted for 4 hours until the reaction is completed. The reaction mixture was directly concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent gradient: methanol: dichloromethane: 1:30 to 1:10) to give the target product, 4- (2-bromo-5-methoxy-4-nitrophenyl) morpholine (2-3) (3.4g, yield: 79.2%).
LCMS：Rt:1.715min；MS m/z(ESI):319.0[M+H] +。
Compounds 2-4:
Figure PCTCN2020132188-APPB-000061
4- (2-bromo-5-methoxy-4-nitrophenyl) morpholine (2-3) (2.0g, 6.33mmol), 1-methyl-4-1H-pyrazole-boronic acid pinacol ester (3.94mg, 18.9mmol), sodium carbonate (2.0g, 18.9mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (926mg, 1.26mmol) were dissolved in a mixture of dioxane (10mL) and water (1mL) at room temperature, and the reaction was stirred at 100 ℃ under nitrogen blanket for 12 hours. After completion of the reaction, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent gradient: dichloromethane: methanol 20:1, Rf: 0.5) to give 4- (5-methoxy-2- (1-methyl-1H-pyrazol-4-yl) -4-nitrophenyl) morpholine (2-4) (800mg, yield: 40%) as an objective product.
LCMS：Rt:1.410min；MS m/z(ESI):319.1[M+H] +。
Compounds 2-5:
Figure PCTCN2020132188-APPB-000062
4- (5-methoxy-2- (1-methyl-1H-pyrazol-4-yl) -4-nitrophenyl) morpholine (2-4) (500mg,1.57mmol) was dissolved in ethanol (15mL) at room temperature, a palladium-carbon catalyst (25mg) was added, and the reaction solution was heated to 50 ℃ under a hydrogen atmosphere and stirred for reaction for 3H until the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give crude 2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -4-morpholinylamine (2-5) (450mg, yield: 99%) as a target product.
LCMS：Rt:0.901min；MS m/z(ESI):289.4[M+H] +。
Trifluoroacetate salt of compound 2:
Figure PCTCN2020132188-APPB-000063
2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -4-morpholinanilide (2-5) (112mg, 0.309mmol) and (3- ((2, 5-dichloropyrimidin-4-yl) amino) quinolin-4-yl) dimethylphosphine oxide (2-1) (150mg, 0.309mmol) were dissolved in isopropanol (8mL) at room temperature, and trifluoroacetic acid (352.26mg, 3.09mmol) was added; the reaction solution was heated to 100 ℃ and stirred for reaction for 24 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, then concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (eluent gradient: same as in example 1) to give the objective compound (3- ((5-chloro-2- ((2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -4-morpholinophenyl) amino) pyrimidin-4-yl) amino) quinolin-4-yl) dimethylphosphine oxide (compound 2) trifluoroacetate (29.8mg, yield: 15.7%).
1H NMR(400MHz,CD 3OD)δ:9.46(brs,1H),8.21-8.17(m,2H),7.98-7.94(m,1H),7.82-7.65(m,4H),7.41(s,1H),6.81(s,1H),3.90(s,3H),3.83-3.60(m,7H),2.85(brs,4H),2.18(s,3H),2.14(s,3H).
19F NMR(376.5MHz,CD 3OD):δ-77.37.
31P NMR(162.0MHz,CD 3OD):δ47.45.
LCMS：Rt:1.320min；MS m/z(ESI):619.1[M+H] +。
EXAMPLE 3 preparation of the trifluoroacetate salt of (3- ((5-bromo-2- ((2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -4-morpholinophenyl) amino) pyrimidin-4-yl) amino) quinolin-4-yl) dimethylphosphine oxide (Compound 3)
Figure PCTCN2020132188-APPB-000064
Trifluoroacetate salt of compound 3:
Figure PCTCN2020132188-APPB-000065
(3- ((5-bromo-2-chloropyrimidin-4-yl) amino) quinolin-4-yl) dimethylphosphine oxide (1-4) (150mg, 0.363mmol), 2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -4-morpholinylaniline (2-5) (104.6mg, 0.363mmol) and trifluoroacetic acid (413.82mg, 3.63mmol) were dissolved in isopropanol (5mL) at room temperature and the reaction stirred at 100 ℃ for 24H. After completion of the reaction, the reaction mixture was cooled and concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (eluent gradient: same as in example 1) to give a pure product, namely, 3- ((5-bromo-2- ((2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -4-morpholinophenyl) amino) pyrimidin-4-yl) amino) quinolin-4-yl) dimethylphosphine oxide (compound 3) trifluoroacetate (30.1mg, yield: 7.1%).
1H NMR(400MHz,CD 3OD)δ:9.35(brs,1H),8.22-8.20(m,2H),7.96(s,1H),7.83-7.54(m,4H),7.42(s,1H),6.79(s,1H),3.90(brs,3H),3.76-3.73(m,7H),2.84(brs,4H),2.17(s,3H),2.14(s,3H).
19F NMR(376.5MHz,CD 3OD):δ-77.32.
31P NMR(162.0MHz,CD 3OD):δ46.95.
LCMS：Rt:1.388min；MS m/z(ESI):663.3,665.3[M+H] +。
EXAMPLE 4 preparation of (6- ((5-bromo-2- ((2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -6-morpholinopyridin-3-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (Compound 4) trifluoroacetate
Figure PCTCN2020132188-APPB-000066
Compound 4-2:
Figure PCTCN2020132188-APPB-000067
2,3, 6-trichloro-5-nitropyridine (4-1) (625mg, 2.75mmol) and methanol (89mg, 2.75mmol) were dissolved in tetrahydrofuran (20mL) at 0 deg.C, and sodium hydrogen (98.8mg, 4.13mmol) was added; after the reaction was continued stirring at 0 ℃ for 0.5 hour, the reaction was quenched with water (50mL), the mixture was extracted with ethyl acetate (30mL X3), the organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give a mixture of crude desired product 2, 3-dichloro-6-methoxy-5-nitropyridine (4-2) and 2, 5-dichloro-6-methoxy-3-nitropyridine (4-2A) (500mg, yield: 82%).
Compound 4-3:
Figure PCTCN2020132188-APPB-000068
2, 3-dichloro-6-methoxy-5-nitropyridine (4-2) and a mixture of 2, 5-dichloro-6-methoxy-3-nitropyridine (4-2A) (500mg,2.24mmol), morpholine (391mg,4.48mmol) were added to N, N-dimethylformamide (5mL) at room temperature. The reaction solution was stirred at room temperature for 5 hours. After completion of the reaction, the reaction mixture was poured into water (10mL), the mixture was extracted with ethyl acetate (30mL X3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution gradient: dichloromethane: methanol ═ 10:1) to give the desired product, 4- (3-chloro-6-methoxy-5-nitropyridin-2-yl) morpholine (4-3) (80mg, yield: 45.8%).
LCMS：Rt:1.683min；MS m/z(ESI):274.2[M+H] +。
Compounds 4-4:
Figure PCTCN2020132188-APPB-000069
4- (3-chloro-6-methoxy-5-nitropyridin-2-yl) morpholine (4-3) (170mg, 0.62mmol), 1-methyl-4-1H-pyrazole-boronic acid pinacol ester (259mg,1.24mmol) and sodium carbonate (606mg) were added to a mixed solvent of dioxane (3mL) and water (1mL) at room temperature, and the system was evacuated and charged with argon three times. Bis [ di-tert-butyl- (4-dimethylaminophenyl) phosphine ] palladium dichloride (88mg,0.124mmol) was then added and the mixture was evacuated and argon purged three times. The reaction solution was heated to 105 ℃ and stirred to react for 16 hours. After completion of the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by preparative thin layer chromatography (eluent gradient: dichloromethane: methanol 10:1) to give the objective 4- (6-methoxy-3- (1-methyl-1H-pyrazol-4-yl) -5-nitropyridin-2-yl) morpholine (4-4) (170.26mg, yield: 86%).
LCMS：Rt:1.457min；MS m/z(ESI):320.1[M+H] +。
Compounds 4-5:
Figure PCTCN2020132188-APPB-000070
4- (6-methoxy-3- (1-methyl-1H-pyrazol-4-yl) -5-nitropyridin-2-yl) morpholine (4-4) (170.26mg,0.53mmol) was added to ethanol (5mL) at room temperature, palladium on carbon catalyst (45mg) was added, the reaction system was evacuated and charged with hydrogen gas three times, and then the reaction solution was heated to 50 ℃ for reaction for 3 hours. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the desired product, 2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -6-morpholinopyridin-3-amine (4-5) (140mg, yield: 90.7%).
LCMS：Rt:1.058min；MS m/z(ESI):290.1[M+H] +。
Compounds 4 to 7:
Figure PCTCN2020132188-APPB-000071
quinoxaline-6-amine (4-6) (5.0g,34.48mmol) was dissolved in acetic acid (150mL) at room temperature, a solution of iodine chloride (6.1g,37.58mmol) in acetic acid (55mL) was slowly added dropwise to the reaction solution, and the reaction solution was stirred at 20 ℃ under argon atmosphere for 2 hours until the reaction was complete. The reaction solution was directly concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent gradient: ethyl acetate: petroleum ether: 1:20 to 1:3) to obtain the target product 5-iodoquinoxaline-6-amine (4-7) (6.0g, yield: 67%).
LCMS:Rt:1.325min；MS m/z(ESI):272.1[M+H] +。
Compounds 4-8:
Figure PCTCN2020132188-APPB-000072
5-Iodoquinoxalin-6-amine (4-7) (6.0g,22.1mmol), dimethylphosphinoxy (2.6g,33.2mmol) and potassium phosphate (7.0g,33.2mmol), 4, 5-bis diphenylphosphino-9, 9-dimethylxanthene (1.2g,2.2mmol), palladium acetate (494mg,2.2mmol) were dissolved in N, N-dimethylformamide (100mL) and water (20mL) at room temperature. The reaction solution was heated to 120 ℃ under argon atmosphere and stirred for 24 hours until the reaction was complete. The reaction solution was directly concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent gradient: ethyl acetate: petroleum ether: 1:10 to 1:1) to obtain the target product (6-aminoquinoxalin-5-yl) dimethylphosphine oxide (4-8) (4.0g, yield: 67%).
LCMS:Rt:0.902min；MS m/z(ESI):221.9[M+H] +。
Compounds 4-9:
Figure PCTCN2020132188-APPB-000073
(6-Aminoquinoxalin-5-yl) dimethylphosphine oxide (4-8) (1.0g,4.52mmol) was dissolved in ethanol (20mL) at room temperature, and 5-bromo-2, 4-dichloropyrimidine (2.0g,9.04mmol) and N, N-diisopropylethylamine (3.5g,27.1mmol) were added. The reaction solution is heated to 90 ℃ under the protection of argon gas, stirred and reacted for 72 hours until the reaction is completed. The reaction solution was directly concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent gradient: ethyl acetate: petroleum ether: 1:10 to 1:1) to obtain the target product (6- ((5-bromo-2-chloropyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (4-9) (0.5g, yield: 27%).
LCMS:Rt:1.453min；MS m/z(ESI):411.9[M+H] +。
Trifluoroacetate salt of compound 4:
Figure PCTCN2020132188-APPB-000074
2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -6-morpholinopyridin-3-amine (4-5) (140mg,0.48mmol), (6- ((5-bromo-2-chloropyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (4-9) (160mg,0.39mmol) was added to isopropanol (3mL) at room temperature, trifluoroacetic acid (547mg,4.8mmol) was further added, and the reaction mixture was heated to 100 ℃ and stirred for reaction for 16 hours. After completion of the reaction, the reaction solution was cooled to room temperature, then concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (eluent gradient: same as in example 1). To give a trifluoroacetate salt of a target compound (6- ((5-bromo-2- ((2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -6-morpholinopyridin-3-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (compound 4) (25mg, yield: 9.6%).
1H NMR(400MHz,CD 3OD)：δ8.87(d,J＝1.6Hz,1H),8.84(d,J＝1.6Hz,1H),8.70(brs,1H),8.29(s,1H),7.91(s,1H),7.84(s,1H),7.71(brs,1H),7.52(brs,1H),3.99(s,3H),3.80-3.78(m,7H),3.18-3.12(m,4H),2.17(s,3H),2.13(s,3H).
31P NMR(162.0MHz,CD 3OD)：δ53.12.
19F NMR(376.5MHz,CD 3OD)：δ-77.40.
LCMS:Rt:1.572min；MS m/z(ESI):665.1,667.1[M+H] +。
Example 5 preparation of (3- ((5-bromo-2- ((2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -4- (piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) amino) quinolin-4-yl) dimethylphosphine oxide (Compound 5) trifluoroacetate
Figure PCTCN2020132188-APPB-000075
Compound 5-2:
Figure PCTCN2020132188-APPB-000076
1-chloro-2-iodo-5-methoxy-4-nitrobenzene (5-1) (2.0g, 6.38mmol), 1-methyl-4-1H-pyrazole-boronic acid pinacol ester (1.32g, 6.38mmol) and sodium carbonate (2.0g, 19.14mmol) were added to dioxane (20mL) and water (6mL) at room temperature, after three times of argon displacement, [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (930mg, 1.27mmol) was added, and after three times of argon displacement, the reaction mixture was warmed to 90 ℃ and stirred for 4 hours. After completion of the reaction, the reaction mixture was directly concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent gradient: ethyl acetate/petroleum ether ═ 1/4) to give the objective compound 4- (2-chloro-4-methoxy-5-nitrophenyl) -1-methyl-1H-pyrazole (5-2) (1.5g, yield: 88%).
LCMS：Rt:0.76min；MS m/z(ESI):268.1[M+H] +。
Compound 5-3:
Figure PCTCN2020132188-APPB-000077
4- (2-chloro-4-methoxy-5-nitrophenyl) -1-methyl-1H-pyrazole (5-2) (1.3g, 4.86mmol), 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaboron-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (1.5g, 4.86mmol) and sodium carbonate (1.55g, 14.58mmol) were added to dioxane (20mL) and water (6mL) at room temperature, argon was substituted three times, dichloro-di-tert-butyl- (4-dimethylaminophenyl) phosphonium palladium (II) (344mg, 0.486mmol) was added, and after argon was substituted three times, the reaction mixture was heated to 105 ℃ and stirred for reaction for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent gradient: ethyl acetate/petroleum ether ═ 1/4) to give the target intermediate, tert-butyl 4- (5-methoxy-2- (1-methyl-1H-pyrazol-4-yl) -4-nitrophenyl) -3, 6-dihydropyridine-1 (2H) -carboxylate (5-3) (1.0g, yield: 50%).
LCMS：Rt:1.815min；MS m/z(ESI):415.1[M+H] +。
Compounds 5-4:
Figure PCTCN2020132188-APPB-000078
tert-butyl 4- (5-methoxy-2- (1-methyl-1H-pyrazol-4-yl) -4-nitrophenyl) -3, 6-dihydropyridine-1 (2H) -carboxylate (5-3) (900mg, 2.17mmol) was dissolved in methanol (2mL) at room temperature, followed by addition of a methanol solution (2N,11mL) hydrochloride, and the reaction was stirred at room temperature for 2H. After completion of the reaction, the reaction mixture was directly concentrated under reduced pressure to give a crude target product, 4- (5-methoxy-2- (1-methyl-1H-pyrazol-4-yl) -4-nitrophenyl) -1,2,3, 6-tetrahydropyridine (5-4) (700mg, yield: 100%).
LCMS：Rt:0.876min；MS m/z(ESI):315.3[M+H] +。
Compounds 5-5:
Figure PCTCN2020132188-APPB-000079
4- (5-methoxy-2- (1-methyl-1H-pyrazol-4-yl) -4-nitrophenyl) -1,2,3, 6-tetrahydropyridine (5-4) (700mg, 2.23mmol) and 4-dimethylaminopyridine (272mg, 2.23mmol) were dissolved in dichloromethane (20mL) at room temperature, trifluoroacetic anhydride (560mg, 2.67mmol) was added, and the reaction was stirred at room temperature for 6 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent gradient: ethyl acetate/petroleum ether ═ 1/3) to give the objective intermediate 2,2, 2-trifluoroacetyl-1- (4- (5-methoxy-2- (1-methyl-1H-pyrazol-4-yl) -4-nitrophenyl) -3, 6-dihydropyridine (5-5) (600mg, yield: 66%).
LCMS：Rt:1.561min；MS m/z(ESI):411.0[M+H] +。
Compounds 5-6:
Figure PCTCN2020132188-APPB-000080
adding 2,2, 2-trifluoroacetyl-1- (4- (5-methoxy-2- (1-methyl-1H-pyrazol-4-yl) -4-nitrophenyl) -3, 6-dihydropyridine (5-5) (600mg, 1.46mmol) and a palladium carbon catalyst (150mg) into methanol (30mL) at room temperature, replacing the reaction system with hydrogen for four times, heating to 70 ℃, stirring and reacting for 28 hours, filtering the reaction solution, and concentrating the filtrate under reduced pressure to obtain a crude target intermediate 2,2, 2-trifluoroacetyl-1-4- (4-amino-5-methoxy-2- (1-methyl-1H-pyrazol-4-yl) phenyl) piperidine (5-6) (450mg, yield 80%).
LCMS：Rt:1.275min；MS m/z(ESI):383.1[M+H] +。
Compounds 5 to 7:
Figure PCTCN2020132188-APPB-000081
1- (2,2, 2-trifluoroacetyl) -4- (4-amino-5-methoxy-2- (1-methyl-1H-pyrazol-4-yl) phenyl) piperidine (5-6) (100mg,0.26mmol), (3- ((5-bromo-2-chloropyrimidin-4-yl) amino) quinolin-4-yl) dimethylphosphine oxide (1-4) (86mg,0.21mmol) and trifluoroacetic acid (300mg,2.6mmol) were dissolved in isopropanol (20mL) at room temperature, and the reaction solution was heated to 105 ℃ under argon atmosphere and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was slurried with ethyl acetate (10mL), the suspension was filtered, and the solid was dried to give the intermediate 1-trifluoroacetyl-4- (4- ((5-bromo-4- ((4- (dimethylphosphoryl) quinolin-3-yl) amino) pyrimidin-2-yl) amino) -5-methoxy-2- (1-methyl-1H-pyrazol-4-yl) phenyl) piperidine (5-7) (80g, yield: 40%).
LCMS：Rt:1.33min；MS m/z(ESI):759.3[M+H] +。
Trifluoroacetate salt of compound 5:
Figure PCTCN2020132188-APPB-000082
1-trifluoroacetyl-4- (4- ((5-bromo-4- ((4- (dimethylphosphoryl) quinolin-3-yl) amino) pyrimidin-2-yl) amino) -5-methoxy-2- (1-methyl-1H-pyrazol-4-yl) phenyl) piperidine (5-7) (60mg,0.079mmol), potassium hydroxide (44mg,0.79mmol) was added to methanol (5mL) and water (2mL) at room temperature. The reaction solution was heated to 60 ℃ under argon atmosphere and stirred for reaction for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (eluent gradient: same as in example 1) to give the objective compound (3- ((5-bromo-2- ((2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -4- (piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) amino) quinolin-4-yl) dimethylphosphine oxide (compound 5) trifluoroacetate (46mg, yield: 88%).
1H NMR(400MHz,CD 3OD)：δ9.44(d,J＝4.0Hz,1H),8.28(s,1H),8.20(d,J＝8.4Hz,1H),7.99(d,J＝8.0Hz,1H),7.81-7.71(m,2H),7.59(d,J＝4.0Hz,1H),7.33(s,1H),7.23(s,1H),6.93(s,1H),3.94(s,3H),3.67(s,3H),3.46(d,J＝12.8Hz,2H),3.13-3.10(m,1H),3.06-2.98(m,2H),2.18(s,3H),2.14(s,3H),1.93-1.90(m,4H).
31P NMR(162.0MHz,CD 3OD)：δ47.33.
19F NMR(376.5MHz,CD 3OD)：δ-77.24.
LCMS:Rt:0.946min；MS m/z(ESI):661.1,663.1[M+H] +。
EXAMPLE 6 preparation of (6- ((5-bromo-2- ((2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -6- (piperidin-4-yl) pyridin-3-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (Compound 6) trifluoroacetate
Figure PCTCN2020132188-APPB-000083
Compound 6-2:
Figure PCTCN2020132188-APPB-000084
2, 3-dichloro-6-methoxy-5-nitropyridine (4-2) (5.0g,22.42mmol), tert-butyl 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaboro-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate (6.93g,22.42mmol), sodium carbonate (5.94g,56.05mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (1.6g,2.242mmol) were added to dioxane (50mL) and water (12mL) at room temperature. The reaction system was replaced with argon three times and reacted at 90 ℃ for 5 hours. After completion of the reaction, the reaction solution was cooled to room temperature and filtered, the filtrate was extracted with ethyl acetate (80mL X3), the combined organic phases were washed with saturated brine (60mL), and then dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent gradient: ethyl acetate: petroleum ether ═ 1:50) to give the desired product, 3-chloro-6-methoxy-5-nitro-3 ',6' -dihydro- [2,4' -bipyridine ] -1' (2' H) -carboxylic acid tert-butyl ester (6-2) (450mg, yield: 5.4%).
1H NMR(400MHz,CDCl 3)：δ8.35(s,1H),6.55(brs，1H)，4.16(br,1H),4.10(s,3H),3.66-3.64(m,2H),2.63(br,2H),1.50(s,9H).
Compound 6-3:
Figure PCTCN2020132188-APPB-000085
3-chloro-6-methoxy-5-nitro-3 ',6' -dihydro- [2,4' -bipyridine ] -1' (2' H) -carboxylic acid tert-butyl ester (6-2) (450mg,0.95mmol), 1-methyl-4-1H-pyrazole-boronic acid pinacol ester (197mg,0.95mmol), cesium carbonate (770mg,2.37mmol) and dichloro-di-tert-butyl- (4-dimethylaminophenyl) phosphonium palladium (II) (67mg,0.09mmol) were added to dioxane (5mL) and water (2mL) at room temperature. The system was replaced with argon three times and reacted at 105 ℃ for 5 hours until the reaction was complete. The reaction solution was cooled to room temperature and filtered, the filtrate was extracted with ethyl acetate (30mL X3), the combined organic phases were washed with saturated brine (20mL), then dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent gradient: ethyl acetate: petroleum ether ═ 1:20) to give the desired product, tert-butyl 6-methoxy-3- (1-methyl-1H-pyrazol-4-yl) -5-nitro-3 ',6' -dihydro- [2,4' -dihydro ] -1' (2' H) -carboxylate (6-3) (210mg, yield: 53.41%).
Compounds 6-4:
Figure PCTCN2020132188-APPB-000086
tert-butyl 6-methoxy-3- (1-methyl-1H-pyrazol-4-yl) -5-nitro-3 ',6' -dihydro- [2,4' -dihydro ] -1' (2' H) -carboxylate (6-3) (210mg,0.51mmol) was dissolved in dichloromethane (6mL) at room temperature, followed by trifluoroacetic acid (3 mL). The reaction system is reacted for 3 hours at room temperature until the reaction is complete. The reaction solution was concentrated under reduced pressure to obtain the target product 6-methoxy-3- (1-methyl-1H-pyrazol-4-yl) -5-nitro-1 ',2',3',6' -tetrahydro-2, 4' -bipyridine (6-4) (160mg, crude product). Directly used for the next reaction.
LCMS:Rt:0.907min；MS m/z(ESI):315.9[M+H] +。
Compounds 6-5:
Figure PCTCN2020132188-APPB-000087
6-methoxy-3- (1-methyl-1H-pyrazol-4-yl) -5-nitro-1 ',2',3',6' -tetrahydro-2, 4' -bipyridine (6-4) (160mg,0.507mmol), triethylamine (256mg,2.53mmol), and N, N-dimethyl-4-aminopyridine (6mg) were dissolved in dichloromethane (8mL) at room temperature, and trifluoroacetic anhydride (160mg,0.761mmol) was added. The reaction was carried out at room temperature for 12 hours until completion. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative thin layer chromatography (eluent gradient: ethyl acetate: petroleum ether ═ 1:1) to give the desired product 6-5(80mg, yield: 38.5%).
LCMS:Rt:1.797min；MS m/z(ESI):412.0[M+H] +。
Compounds 6-6:
Figure PCTCN2020132188-APPB-000088
intermediate compound 6-5(40mmol,0.097mmol)) was dissolved in ethanol (5mL) at room temperature and palladium on carbon catalyst (5mg, 10% wt) was added. The reaction system is replaced by hydrogen for 3 times and then heated to 50 ℃ for reaction for 5 hours until the reaction is complete. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give the target product trifluoroacetyl-1- (4- (5-amino-6-methoxy-3- (1-methyl-1H-pyrazol-4-yl) pyridin-2-yl) piperidine (6-6) (30mg, crude product) which was used directly in the next reaction.
LCMS:Rt:1.297min；MS m/z(ESI):384.0[M+H] +。
Compounds 6 to 7:
Figure PCTCN2020132188-APPB-000089
1-trifluoroacetyl-4- (5-amino-6-methoxy-3- (1-methyl-1H-pyrazol-4-yl) pyridin-2-yl) piperidine (6-6) (30mg,0.078mmol), (6- ((5-bromo-2-chloropyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (32mg,0.078mmol) was dissolved in isopropanol (5mL) at room temperature, trifluoroacetic acid (89mg,0.78mmol) was added, and the reaction was heated to 100 ℃ for 16 hours until the reaction was complete. The reaction solution was cooled and concentrated under reduced pressure, and the residue was purified by preparative thin layer chromatography (eluent gradient: dichloromethane: methanol ═ 10:1) to give the objective product 1-trifluoroacetyl- (4- (5- ((5-bromo-4- ((5- (methylphosphoryl) quinoxalin-6-yl) amino) pyrimidin-2-yl) amino) -6-methoxy-3- (1-methyl-1H-pyrazol-4-yl) pyridin-2-yl) piperidine (6-7) (27mg, 45.4%).
LCMS:Rt:1.567min；MS m/z(ESI):761.4[M+H] +。
Trifluoroacetate salt of compound 6:
Figure PCTCN2020132188-APPB-000090
1-trifluoroacetyl- (4- (5- ((5-bromo-4- ((5- (methylphosphoryl) quinoxalin-6-yl) amino) pyrimidin-2-yl) amino) -6-methoxy-3- (1-methyl-1H-pyrazol-4-yl) pyridin-2-yl) piperidine (6-7) (27mg,0.035mmol) was dissolved in methanol (3mL) and water (0.5mL) at room temperature, potassium carbonate (48mg,0.35mmol) was added, the reaction was heated to 70 ℃ for 16 hours until completion of the reaction, the reaction liquid was cooled and concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (eluent gradient: same as in example 1) to obtain the objective product (6- ((5-bromo-2- ((2-methoxy-5- (1-methyl-methoxy-5-pyridin-2-yl) yl-1H-pyrazol-4-yl) -6- (piperidin-4-yl) pyridin-3-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (compound 6) trifluoroacetate (17mg, yield: 72.07%).
1H NMR(400MHz,CD 3OD)：δ8.85-8.83(m,2H),8.74(d,J＝4.0Hz,1H),8.33(s,1H),8.28(s,1H),7.60(d,J＝12.0Hz,1H),7.59(s,1H),7.23(s,1H),4.07(s,3H),3.81(s,3H),3.49-3.46(m,2H),3.25-3.22(m,1H),3.11-3.05(m,2H),2.29-2.19(m,2H),2.16(s,3H),2.12(s,3H),1.95-1.92(m,2H).
31P NMR(162.0MHz,CD 3OD)：δ52.86.
19F NMR(376.5MHz,CD 3OD)：δ-77.12.
LCMS:Rt:1.000min；MS m/z(ESI):663.1,665.1[M+H] +。
Example 7 preparation of (3- ((5-bromo-2- ((5- (1- (2-hydroxyethyl) -1H-pyrazol-4-yl) -2-methoxy-4-morpholinophenyl) amino) pyrimidin-4-yl) amino) quinolin-4-yl) dimethylphosphine oxide (Compound 7) trifluoroacetate
Figure PCTCN2020132188-APPB-000091
Compound 7-2:
Figure PCTCN2020132188-APPB-000092
4-Pyrazoleboronic acid pinacol ester (7-1) (1.00g,5.154mmol), (2-bromoethoxy) -tert-butyldimethylsilane (1.85g,7.730mmol) and potassium carbonate (1.42g,10.308mmol) were added to acetonitrile (10mL) at room temperature. The reaction mixture was reacted at 90 ℃ for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent gradient: ethyl acetate: petroleum ether ═ 1:10) to give the desired product, 1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -1H-pyrazole-boronic acid pinacol ester (7-2) (570mg, yield: 31.4%).
LCMS:Rt:2.115min；MS m/z(ESI):353.5[M+H] +。
Compound 7-3:
Figure PCTCN2020132188-APPB-000093
1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -1H-pyrazole-boronic acid pinacol ester (7-2) (250.00mg,0.708mmol), 4- (2-bromo-5-methoxy-4-nitrophenyl) morpholine (224.60mg,0.708mmol), cesium carbonate (461.35mg,1.416mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (51.81mg,0.071mmol) were added to dioxane (7.5mL) and water (1.5mL) at room temperature. The reaction system was replaced with argon three times and reacted at 100 ℃ for 16 hours. After completion of the reaction, the reaction solution was cooled to room temperature, the compound was filtered, the filtrate was extracted with ethyl acetate (30mL X3), the combined organic phases were washed with saturated brine (20mL), and then dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent gradient: ethyl acetate) to give the objective product, 4- (2- (1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -1H-pyrazol-4-yl) -5-methoxy-4-nitrophenyl) morpholine (7-3) (175mg, yield: 53.5%).
LCMS:Rt:2.046min；MS m/z(ESI):463.0[M+H] +。
Compounds 7-4:
Figure PCTCN2020132188-APPB-000094
4- (2- (1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -1H-pyrazol-4-yl) -5-methoxy-4-nitrophenyl) morpholine (7-3) (175mg,0.379mmol), palladium on carbon catalyst (40mg) was added to ethanol (4mL) at room temperature. The reaction was heated to 50 ℃ under hydrogen atmosphere for 6 hours. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the desired product, 5- (1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -1H-pyrazol-4-yl) -2-methoxy-4-morpholinylamine (7-4) (100mg, yield: 61%).
LCMS:Rt:1.562min；MS m/z(ESI):433.2[M+H] +。
Trifluoroacetate salt of compound 7:
Figure PCTCN2020132188-APPB-000095
5- (1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -1H-pyrazol-4-yl) -2-methoxy-4-morpholinanilide (7-4) (100.00mg,0.231mmol), (3- ((5-bromo-2-chloropyrimidin-4-yl) amino) quinolin-4-yl) dimethylphosphine oxide (1-4) (76.06mg,0.185mmol) and trifluoroacetic acid (263.53mg,2.311mmol) were dissolved in isopropanol (6mL) at room temperature. The reaction was carried out at 100 ℃ for 16 hours to completion. The reaction solution was cooled, concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (eluent gradient: same as in example 1) to give the objective compound (3- ((5-bromo-2- ((5- (1- (2-hydroxyethyl) -1H-pyrazol-4-yl) -2-methoxy-4-morpholinophenyl) amino) pyrimidin-4-yl) amino) quinolin-4-yl) dimethylphosphine oxide (compound 7) trifluoroacetate (35mg, yield: 21.8%).
1H NMR(400MHz,CD 3OD)：δ9.36(s,1H),8.22(s,1H)，8.21(d,J＝8.0Hz,1H),7.98(d,J＝8.0Hz,1H),7.88(brs,1H),7.80-7.72(m,2H),7.61(brs,1H),7.45(s,1H),6.79(s,1H),4.07(brs,2H),3.89(s,3H),3.81-3.76(m,6H),2.84(brs,4H),2.17(s,3H),2.13(s,3H).
31P NMR(162.0MHz,CD 3OD)：δ46.97.
19F NMR(376.5MHz,CD 3OD)：δ-77.29.
LCMS:Rt:1.258min；MS m/z(ESI):693.4,695.4[M+H] +。
EXAMPLE 8 preparation of (6- ((5-bromo-2- ((6- (4- (dimethylamino) piperidin-1-yl) -2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (Compound 8) trifluoroacetate
Figure PCTCN2020132188-APPB-000096
Compound 8-2:
Figure PCTCN2020132188-APPB-000097
a mixture of 2, 3-dichloro-6-methoxy-5-nitropyridine (4-2) and 2, 5-dichloro-6-methoxy-3-nitropyridine (4-2A) (1.0g,4.48mmol), N, N-dimethylpiperidin-4-amine (1.14g,8.96mmol) was added to N, N-dimethylformamide (10mL) at room temperature. The reaction solution was stirred at room temperature for 5 hours. After completion of the reaction, water (80mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (90mL X3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent gradient: dichloromethane: methanol ═ 10:1) to give a mixture of the objective product 1- (3-chloro-6-methoxy-5-nitropyridin-2-yl) -N, N-dimethylpiperidin-4-amine (8-2) and 1- (5-chloro-6-methoxy-3-nitropyridin-2-yl) -N, N-dimethylpiperidin-4-amine (8-2) (590mg, yield: 41.84%).
LCMS:Rt:0.943min；MS m/z(ESI):315.2[M+H] +。
Compound 8-3:
Figure PCTCN2020132188-APPB-000098
a mixture of 1- (3-chloro-6-methoxy-5-nitropyridin-2-yl) -N, N-dimethylpiperidin-4-amine (8-2) and 1- (5-chloro-6-methoxy-3-nitropyridin-2-yl) -N, N-dimethylpiperidin-4-amine (8-2A) (490mg,1.56mmol), 1-methylpyrazole-4-boronic acid pinacol ester (649mg,3.12mmol) and cesium carbonate (1.53g,4.68mmol) was added to N, N-dimethylformamide at room temperature: in water (3:1,8mL), the reaction system was evacuated and filled with argon three times, dichlorobis [ di-tert-butyl- (4-dimethylaminophenyl) phosphine ] palladium (220mg,0.312mmol) was added, and the reaction system was evacuated and filled with argon three times. The reaction solution was heated to 120 ℃ and stirred to react for 16 hours. After completion of the reaction, the reaction solution was cooled to room temperature and diluted with water (80mL), and the mixture was extracted with ethyl acetate (100mL X3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid preparative chromatography (eluent gradient: the same as in example 1) to give the objective 1- (6-methoxy-3- (1-methyl-1H-pyrazol-4-yl) -5-nitropyridin-2-yl) -N, N-dimethylpiperidin-4-amine (8-3) (90mg, yield: 20%) and 1- (6-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -3-nitropyridin-2-yl) -N, N-dimethylpiperidin-4-amine (8-3A) (25mg, yield: 20%).
LCMS:Rt:0.920min；MS m/z(ESI):361.1[M+H]。
Compounds 8-4:
Figure PCTCN2020132188-APPB-000099
1- (6-methoxy-3- (1-methyl-1H-pyrazol-4-yl) -5-nitropyridin-2-yl) -N, N-dimethylpiperidin-4-amine (8-3) (90mg,0.25mmol) and palladium on carbon catalyst (13.5mg) were added to ethanol (5mL) at room temperature, and the system was evacuated and charged with hydrogen three times. The reaction solution was heated to 50 ℃ and stirred to react for 5 hours. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Crude desired product 6- (4- (dimethylamino) piperidin-1-yl) -2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-amine (8-4) was obtained (28mg, yield: 33.89%).
LCMS:Rt:0.560min；MS m/z(ESI):331.1[M+H]。
Trifluoroacetate salt of compound 8:
Figure PCTCN2020132188-APPB-000100
6- (4- (dimethylamino) piperidin-1-yl) -2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-amine (8-4) (28mg,0.085mmol) and (6- ((5-bromo-2-chloropyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (4-9) (34.96mg,0.085mmol) were dissolved in isopropanol (2mL) at room temperature, and trifluoroacetic acid (96.92mg,0.85mmol) was added. The reaction mixture was heated to 100 ℃ and reacted for 16 hours. After completion of the reaction, the reaction solution was cooled to room temperature, then concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (eluent gradient: same as in example 1) to give the objective compound (6- ((5-bromo-2- ((6- (4- (dimethylamino) piperidin-1-yl) -2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) amino) pyrimidin-4-yl) quinoxalin-5-yl) dimethylphosphine oxide (compound 8) trifluoroacetate (12mg, yield: 20%).
1H NMR(400MHz,CD 3OD)δ：8.85(s,1H)),8.85-8.79(m,2H),8.28(s,1H),8.09(s,1H),7.72(s,1H),7.61(br,1H),7.52(s,1H),4.00(s,3H),3.73(s,3H),3.67-3.64(m,2H),3.35-3.31(m,1H),2.93(s,6H),2.93-2.84(m,2H),2.17(s,3H),2.11(s,3H),2.17-2.09(m,2H),1.88-1.84(m,8.2Hz,2H).
19F NMR(376.5MHz,CD 3OD):δ-77.22.
31P NMR(162.0MHz,CD 3OD):δ52.93.
LCMS：Rt:1.107min；MS m/z(ESI):706.4,708.4[M+H] +。
Example 9 preparation of (E) - (3- ((5-bromo-2- ((4- (4- (dimethylamino) piperidin-1-yl) -2-methoxy-5- (1- (methoxyimino) ethyl) phenyl) amino) pyrimidin-4-yl) amino) quinolin-4-yl) dimethylphosphine oxide (Compound 9) trifluoroacetate
Figure PCTCN2020132188-APPB-000101
Compound 9-2:
Figure PCTCN2020132188-APPB-000102
1- (2-bromo-5-methoxy-4-nitrophenyl) -N, N-dimethylpiperidin-4-amine (1-6) (600.00mg,1.675mmol), tributyl (1-ethoxyvinyl) tin (907.34mg,2.519mmol) and tetrakis (triphenylphosphine) palladium (193.55mg,0.168mmol) were added to 1, 4-dioxane (12mL) at room temperature. The system was replaced with argon three times and heated to 110 ℃ for 16 hours. LCMS showed the reaction was complete and the reaction was cooled to room temperature and filtered. Adding dilute hydrochloric acid into the filtrate, stirring for 30 minutes at normal temperature until the reaction is completed, adding a potassium fluoride aqueous solution into the filtrate, and continuing stirring for 30 minutes. The reaction mixture was filtered, the filtrate was extracted with ethyl acetate (30mL X3), the organic phase was dried and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent gradient: methanol: dichloromethane ═ 1:20) to give the desired product, 1- (2- (4- (dimethylamino) piperidin-1-yl) -4-methoxy-5-nitrophenyl) ethyl-1-one (9-2) (520mg, yield: 96.6%).
LCMS：Rt:1.069min；MS m/z(ESI):350.4[M+H] +。
Compound 9-3:
Figure PCTCN2020132188-APPB-000103
1- (2- (4- (dimethylamino) piperidin-1-yl) -4-methoxy-5-nitrophenyl) ethyl-1-one (9-2) (520.00mg,1.618mmol) was dissolved in a mixture of ethanol (8mL) and water (8mL) at room temperature, and ammonium chloride (259.64mg,4.854mmol) and iron powder (271.10mg,4.854mmol) were added. The reaction mixture was reacted at 80 ℃ for 16 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, the mixture was filtered, the filtrate was extracted with ethyl acetate (30mL X3), the organic phases were combined and washed with saturated brine (20mL), then dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent gradient: methanol: dichloromethane ═ 1:20) to give the objective product 1- (5-amino-2- (4- (dimethylamino) piperidin-1-yl) -4-methoxyphenyl) ethyl-1-one (9-3) (300mg, yield: 63.5%).
LCMS：Rt:0.355min；MS m/z(ESI):292.5[M+H] +。
Compounds 9-4:
Figure PCTCN2020132188-APPB-000104
1- (5-amino-2- (4- (dimethylamino) piperidin-1-yl) -4-methoxyphenyl) ethyl-1-one (9-3) (300.00mg,1.030mmol) and (6- ((5-bromo-2-chloropyrimidin-4-yl) amino) quinolin-5-yl) dimethylphosphine oxide (1-4) (300.00mg,0.729mmol) were dissolved in isopropanol at room temperature and added to trifluoroacetic acid (1000.00mg,8.770 mmol). The reaction solution was reacted at 100 ℃ for 24 hours until the reaction was completed. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent gradient: methanol: dichloromethane ═ 1:10) to give the objective product 1- (5- ((5-bromo-4- ((4- (dimethylphosphoryl) quinolin-3-yl) amino) pyrimidin-2-yl) amino) -2- (4- (dimethylamino) piperidin-1-yl) -4-methoxyphenyl) ethyl-1-one (9-4) (300 mg).
LCMS：Rt:0.893min；MS m/z(ESI):666.1[M+H] +。
Trifluoroacetate salt of compound 9:
Figure PCTCN2020132188-APPB-000105
1- (5- ((5-bromo-4- ((4- (dimethylphosphoryl) quinolin-3-yl) amino) pyrimidin-2-yl) amino) -2- (4- (dimethylamino) piperidin-1-yl) -4-methoxyphenyl) ethyl-1-one (9-4) (125.00mg,0.188mmol), methoxylamine hydrochloride (46.99mg,0.563mmol) and glacial acetic acid (112.894mg,1.880mmol) were dissolved in 1, 2-dichloroethane (2mL) at room temperature. The reaction was carried out at 50 ℃ for 16 hours to completion. The reaction mixture was cooled, concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (eluent gradient: same as in example 1) to give a pure target product (E) - (3- ((5-bromo-2- ((4- (4- (dimethylamino) piperidin-1-yl) -2-methoxy-5- (1- (methoxyimino) ethyl) phenyl) amino) pyrimidin-4-yl) amino) quinolin-4-yl) dimethylphosphine oxide (compound 9) trifluoroacetate (65mg, yield: 49.7%).
1H NMR(400MHz,CD 3OD)δ：9.41(d,J＝4.4Hz,1H),8.26(d,J＝6.0Hz,1H),8.26(s,1H),8.09(d,J＝8.4Hz,1H),7.82-7.71(m,2H),7.53(s,1H),6.82(s,1H),3.92(s,3H),3.61(s,3H),3.38-3.26(m,4H),2.92(s,6H),2.86-2.79(m,1H),2.21-2.12(m,2H),2.18(s,3H),2.12(s,3H),2.02(s,3H),1.86-1.76(m,2H).
19F NMR(376.5MHz,CD 3OD):δ-77.18.
31P NMR(162.0MHz,CD 3OD):δ47.08.
LCMS：Rt:1.058min；MS m/z(ESI):695.5,697.5[M+H] +。
EXAMPLE 10 preparation of (E) - (3- ((5-bromo-2- ((4- (4- (dimethylamino) piperidin-1-yl) -5- (1- ((2-hydroxyethoxy) imino) ethyl) -2-methoxyphenyl) amino) pyrimidin-4-yl) amino) quinolin-4-yl) dimethylphosphine oxide (Compound 10) trifluoroacetate
Figure PCTCN2020132188-APPB-000106
Trifluoroacetate salt of compound 10:
Figure PCTCN2020132188-APPB-000107
1- (5- ((5-bromo-4- ((4- (dimethylphosphoryl) quinolin-3-yl) amino) pyrimidin-2-yl) amino) -2- (4- (dimethylamino) piperidin-1-yl) -4-methoxyphenyl) ethyl-1-one (9-4) (125.00mg,0.188mmol), 2-aminooxyethanol (43.40mg,0.563mmol) and glacial acetic acid (112.894mg,1.880mmol) were dissolved in 1, 2-dichloroethane (2mL) at room temperature. The reaction was carried out at 50 ℃ for 16 hours to completion. The reaction mixture was cooled and concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (eluent gradient: same as in example 1) to give the objective product (E) - (3- ((5-bromo-2- ((4- (4- (dimethylamino) piperidin-1-yl) -5- (1- ((2-hydroxyethoxy) imino) ethyl) -2-methoxyphenyl) amino) pyrimidin-4-yl) amino) quinolin-4-yl) dimethylphosphine oxide (compound 10) trifluoroacetate (35mg, yield: 25.7%).
1H NMR(400MHz,CD3OD)δ：9.42-9.40(m,1H),8.27(d,J＝8.4Hz,1H),8.25(s,1H),8.10(d,J＝8.3Hz,1H),7.80-7.72(m,2H),7.53(s,1H),6.81(d,J＝6.0Hz,1H),3.96-3.87(m,2H),3.88(s,3H),3.66-3.64(m,2H),3.37-3.34(m,3H),2.94(s,6H),2.90-2.75(m,2H),2.17-2.13(m,2H),2.17(s,3H),2.13(s,3H),2.03(s,3H),1.85(brs,2H).
19F NMR(376.5MHz,CD3OD):δ-77.22.
31P NMR(162.0MHz,CD3OD):δ47.08.
LCMS：Rt:1.016min；MS m/z(ESI):725.4,727.4[M+H] +。
EXAMPLE 11 preparation of (3- ((5-bromo-2- ((2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) quinolin-4-yl) dimethylphosphine oxide (Compound 82) trifluoroacetate
Figure PCTCN2020132188-APPB-000108
Compound 82-2:
Figure PCTCN2020132188-APPB-000109
1-bromo-2-fluoro-4-methoxy-5-nitrobenzene (4.2g,16.80mmol) and 1-methyl-4- (piperidin-4-yl) piperazine (82-1) (3.08g,16.80mmol) were dissolved in N, N-dimethylformamide (20mL) at room temperature, potassium carbonate (6.97g,50.4mmol) was added, and the reaction was heated to 60 ℃ under argon atmosphere and stirred for 4 hours until the reaction was complete. The reaction mixture was directly concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent gradient: methanol: dichloromethane ═ 1:30 to 1:10) to give the objective 1- (1- (2-bromo-5-methoxy-4-nitrophenyl) piperidin-4-yl) -4-methylpiperazine (82-2) (1.5g, yield: 22%).
Compound 82-3:
Figure PCTCN2020132188-APPB-000110
1- (1- (2-bromo-5-methoxy-4-nitrophenyl) piperidin-4-yl) -4-methylpiperazine (82-2) (500mg,1.21mmol), 1-methylpyrazole-4-boronic acid pinacol ester (504mg,2.42mmol), and sodium carbonate (385mg,3.63mmol) were added to a mixed solvent of 1, 4-dioxane and water (1, 4-dioxane: water ═ 3:1.8mL) at room temperature, the system was evacuated and charged with argon three times, and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (89mg,0.121mmol) was added and further evacuated and charged with argon three times. The reaction solution was heated to 105 ℃ and stirred to react for 16 hours. After completion of the reaction was checked by LCMS, the reaction was cooled to room temperature. The reaction mixture was added to water (60mL), the mixture was diluted with ethyl acetate (70mL), the mixture was filtered through celite, the filtrate was extracted with ethyl acetate (70mL X3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent gradient: dichloromethane: methanol ═ 15: 1) to give the desired product 1- (1- (5-methoxy-2- (1-methyl-1H-pyrazol-4-yl) -4-nitrophenyl) piperidin-4-yl) -4-methylpiperazine (82-3) (164mg, yield: 33.0%).
LCMS:Rt:0.880min；MS m/z(ESI):415.1[M+H] +。
Compound 82-4:
Figure PCTCN2020132188-APPB-000111
1- (1- (5-methoxy-2- (1-methyl-1H-pyrazol-4-yl) -4-nitrophenyl) piperidin-4-yl) -4-methylpiperazine (82-3) (164mg,0.4mmol) and a palladium on carbon catalyst (30mg) were added to ethanol (3mL) at room temperature, and the system was vacuum-evacuated and replaced with hydrogen gas three times. The reaction mixture was heated to 50 ℃ and reacted for 6 hours. The reaction was checked by LCMS, after completion of the reaction, the reaction was cooled to room temperature and filtered, and the filtrate was concentrated under reduced pressure to give the crude desired product 2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) aniline (82-4) (118mg, yield: 76.7%).
LCMS:Rt:0.300min；MS m/z(ESI):385.2[M+H] +。
Trifluoroacetate salt of compound 82:
Figure PCTCN2020132188-APPB-000112
2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) aniline (82-4) (118mg,0.31mmol), (3- ((5-bromo-2-chloropyrimidin-4-yl) amino) quinolin-4-yl) dimethylphosphine oxide (1-4) (115mg,0.28mmol) was dissolved in isopropanol (3mL) at room temperature, trifluoroacetic acid (353mg,3.1mmol) was added, and the reaction was heated to 100 ℃ and stirred for 13 hours until completion of the reaction by LCMS. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (eluent gradient: same as in example 1) to give the objective compound (3- ((5-bromo-2- ((2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) quinolin-4-yl) dimethylphosphine oxide (compound 82) trifluoroacetate (26mg, yield: 11%).
1H NMR(400MHz,CD 3OD):δ9.43(d,J＝4.4Hz,1H),8.22(s,1H),8.14-8.10(m,1H),7.82-7.78(m,2H),7.70-7.66(m,2H),7.48(d,J＝6.4Hz,2H),6.75(s,1H),3.87(s,3H),3.53(brs,3H),3.08(d,J＝11.6Hz,2H),2.80-2.40(m,9H),2.32-2.24(m,2H),2.31(s,3H),2.18(s,3H),2.15(s,3H),1.96-1.92(m,2H),1.60-1.55(m,2H).
19F NMR(377MHz,CD 3OD):δ-76.94.
31P NMR(162MHz,CD 3OD):δ47.58.
LCMS:Rt:0.788min；MS m/z(ESI):759.2,761.2[M+H] +。
EXAMPLE 12 preparation of (6- ((5-bromo-2- ((2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -4-morpholinophenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (Compound 12)
Figure PCTCN2020132188-APPB-000113
Referring to the synthesis method of example 2, (3- ((2, 5-dichloropyrimidin-4-yl) amino) quinolin-4-yl) dimethylphosphine oxide (2-1) was replaced with (6- ((5-bromo-2-chloropyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (4-9) to give the objective compound (6- ((5-bromo-2- ((2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -4-morpholinophenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (compound 12).
1H NMR(400MHz,CD 3OD)δ:8.81(s,2H),8.76(s,1H),8.24(s,1H),7.93(s,1H),7.86(s,1H),7.52-7.43(m,2H),6.82(s,1H),3.91(s,3H),3.80(br,4H),3.68(s,3H),2.88(br,4H),2.16(s,3H),2.12(s,3H).
31P NMR(162.0MHz,CD 3OD)δ：52.84.
LCMS：Rt:6.757min；MS m/z(ESI):664.1，666.1[M+H] +
EXAMPLE 13 preparation of (6- ((5-bromo-2- ((2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -6- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) pyridin-3-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (Compound 13) trifluoroacetate
Figure PCTCN2020132188-APPB-000114
Compound 13-2:
Figure PCTCN2020132188-APPB-000115
2, 3-dichloro-6-methoxy-5-nitropyridine (4-2) (4.0g,17.9mmol) and 1-methyl-4- (piperidin-4-yl) piperazine (3.62g,19.7mmol) were added to N, N-dimethylformamide (30ml) at room temperature, and reacted at room temperature for 12 hours. TLC showed complete reaction, and 100mL of water was added to the reaction mixture, extracted with ethyl acetate (40mL X4), and the organic phases were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Column chromatography (eluent: dichloromethane: methanol 50:1) gave the desired product 1- (1- (3-chloro-6-methoxy-5-nitropyridin-2-yl) piperidin-4-yl) -4-methylpiperazine (13-2) (3.7g, yield: 55.77%).
LCMS:Rt:0.940min；MS m/z(ESI):370.1[M+H] +。
Compound 13-3:
Figure PCTCN2020132188-APPB-000116
1- (1- (3-chloro-6-methoxy-5-nitropyridin-2-yl) piperidin-4-yl) -4-methylpiperazine (13-2) (1.0g,2.71mmol) was added to N, N-dimethylformamide (10mL) and water (2.5mL) at room temperature, and 1-methyl-4-pyrazoleboronic acid pinacol ester (733mg,3.52mmol), cesium carbonate (1.8g, 5.42mmol) and di-tert-butyl- (4-dimethylaminophenyl) phosphonium palladium (II) dichloride (191mg,0.27mmol) were added. The mixture was purged with nitrogen three times and reacted at 120 ℃ for 12 hours. TLC showed the reaction was complete, the reaction was cooled to room temperature, filtered, extracted with ethyl acetate (30mL X3), and the organic phases were combined, washed with saturated brine (20mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Column chromatography (eluent: dichloromethane: methanol 50:1) purified 1- (1- (6-methoxy-3- (1-methyl-1H-pyrazol-4-yl) -5-nitropyridin-2-yl) piperidin-4-yl) -4-methylpiperazine (13-3) (90mg, yield: 8%) as a target product.
LCMS:Rt:0.843min；MS m/z(ESI):416.2[M+H] +。
Compounds 13-4:
Figure PCTCN2020132188-APPB-000117
1- (1- (6-methoxy-3- (1-methyl-1H-pyrazol-4-yl) -5-nitropyridin-2-yl) piperidin-4-yl) -4-methylpiperazine (13-3) was dissolved in methanol/tetrahydrofuran (2mL/2mL) at room temperature, and palladium on carbon (10mg, 10% wt) was added. Replace 3 times with hydrogen, react at room temperature for 12 hours, and detect reaction completion by LCMS. The reaction mixture was cooled to room temperature, filtered, and the mother liquor was concentrated to give the objective 2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -6- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) pyridin-3-amine (13-4) (80mg, yield: 98.9%). The crude product was used directly in the next reaction.
LCMS:Rt＝0.443min；MS m/z(ESI):386.2[M+H] +。
Trifluoroacetate salt of compound 13:
Figure PCTCN2020132188-APPB-000118
2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -6- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) pyridin-3-amine (13-4) (80mg,0.207mmol) and (6- ((5-bromo-2-chloropyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (4-9) (85mg,0.207mmol) were dissolved in 3mL of isopropanol at room temperature, trifluoroacetic acid (0.5mL) was added, and the reaction was heated to 105 ℃ for 12 hours. The reaction solution was cooled and then concentrated, and the residue was purified by prep-HPLC (eluent gradient reference example 1) to give the trifluoroacetate salt of the objective compound 13 (30mg, 19.1%).
1H NMR(400MHz,CD 3OD)δ8.87-8.71(m,3H),8.30(s,1H),7.95(s,1H),7.80(s,1H),7.68(s,1H),7.48(s,1H),3.99(s,3H),3.79(s,3H),3.67(d,J＝12.1Hz,2H),3.52(br,8H),3.24(br,1H),2.97–2.82(m,5H),2.17-2.14(m,8H),1.88-1.86(m,2H).
19F NMR(162MHz,CD 3OD)δ-77.26.
31P NMR(162MHz,CD 3OD)δ53.07.
LCMS:Rt:1.020min；MS m/z(ESI):761.2,763.2[M+H] +。
EXAMPLE 14 preparation of (6- ((5-bromo-2- ((2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (Compound 14)
Figure PCTCN2020132188-APPB-000119
Compound 14:
Figure PCTCN2020132188-APPB-000120
2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) aniline (82-4) (156mg,0.41mmol), (6- ((5-bromo-2-chloropyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (4-9) (140mg,0.34mmol) was dissolved in isopropanol (3mL) at room temperature, followed by the addition of trifluoroacetic acid (389mg,3.41 mmol). The reaction mixture was heated to 100 ℃ and reacted for 16 hours. The reaction was checked by LCMS and after completion, the reaction was cooled to room temperature. Then, the reaction mixture was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (eluent gradient reference example 1) to give the objective compound (6- ((5-bromo-2- ((2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide trifluoroacetate (50mg), and the product was dissolved in 5mL of dichloromethane, washed with a saturated aqueous sodium carbonate solution (5mL of X3), washed with 10mL of water, dried, and spin-dried to give the objective compound (6- ((5-bromo-2- ((2-methoxy-5- (1-methyl-5-methoxy-5) phosphine oxide -1H-pyrazol-4-yl) -4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (compound 14) (25mg, yield: 9.68%).
1H NMR(400MHz,MeOD):δ8.81-8.77(m,3H),8.24(s,1H),7.91(s,1H),7.84(s,1H),7.45-7.36(m,2H),6.82(s,1H),3.90(s,3H),3.69(s,3H),3.15-3.12(m,2H),2.63–2.58(m,10H),2.31(br,4H),2.16(s,3H),2.11(s,3H),1.98-1.95(m,2H),1.64-1.59(m,2H).
31P NMR(162MHz,MeOD):δ52.85.
LCMS：Rt:1.014min；MS m/z(ESI):760.1,762.1[M+H] +。
EXAMPLE 15 preparation of ((6- ((5-bromo-2- ((4- (3-fluoro-4-morpholinopiperidin-1-yl) -2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (Compound 83) trifluoroacetate
Figure PCTCN2020132188-APPB-000121
Compound 83-2:
Figure PCTCN2020132188-APPB-000122
at room temperature, 3-fluoro-4-oxopiperidine-1-carboxylic acid tert-butyl ester (500.00mg,2.302mmol), morpholine (240.66mg,2.762mmol) and 1, 2-dichloroethane (10mL) were dissolved, glacial acetic acid (207.18mg,3.453mmol) were added, the mixture was reacted at 50 ℃ for 5 hours, then the temperature was lowered to room temperature, sodium triacetoxyborohydride (976.05mg,4.604mmol) was slowly added, the reaction was stirred at room temperature for 1 hour after the completion of the addition, TLC showed completion of the reaction, saturated aqueous sodium carbonate solution was added to adjust the pH to 9 to 10, extraction was performed with dichloromethane (30mL X3), and the mixture was washed with saturated aqueous sodium chloride solution (30mL), dried over anhydrous sodium sulfate, and concentrated to obtain the target product, 3-fluoro-4-morpholinopiperidine-1-carboxylic acid tert-butyl ester (83-2) (650.00mg, yield: 97.9%).
LCMS:Rt＝0.820min；MS m/z(ESI):289.1[M+H] +。
Compound 83-3:
Figure PCTCN2020132188-APPB-000123
tert-butyl 3-fluoro-4-morpholinopiperidine-1-carboxylate (83-2) (650mg,2.254mmol) was added to dioxane hydrochloride solution (4M,15mL) at room temperature and reacted for 2 hours at room temperature. The reaction was completed by LCMS and the reaction mixture was concentrated to give the objective 4- (3-fluoropiperidin-4-yl) morpholine hydrochloride (83-3) (420.00mg, yield: 62.7%).
LCMS:Rt＝0.445min；MS m/z(ESI):189.5[M+H] +。
Compound 83-4:
Figure PCTCN2020132188-APPB-000124
4- (3-Fluoropiperidin-4-yl) morpholine hydrochloride (83-3) (420.00mg,1.414mmol), 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene (353.50mg,1.414mmol) were dissolved in N, N-dimethylformamide (8mL) at room temperature, potassium carbonate (585.40mg,4.242mmol) was added, the reaction was stirred at 50 ℃ for 16 hours and checked for completion by LCMS. The reaction mixture was filtered, concentrated, and subjected to column chromatography to give the objective 4- (1- (2-bromo-5-methoxy-4-nitrophenyl) -3-fluoropiperidin-4-yl) morpholine (83-4) (200.00mg, yield: 33.8%).
LCMS:Rt＝1.010min；MS m/z(ESI):418.0[M+H] +。
Compound 83-5:
Figure PCTCN2020132188-APPB-000125
dissolving 4- (1- (2-bromo-5-methoxy-4-nitrophenyl) -3-fluoropiperidin-4-yl) morpholine (83-4) (200.00mg,0.478mmol), 1-methyl-4-pyrazoleboronic acid pinacol ester (99.42mg,0.478mmol and sodium carbonate (55.09mg,0.956mmol) in a mixed solution of 1, 4-dioxane (5mL) and water (1mL) at room temperature, adding [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (35.09mg,0.048mmol), displacing nitrogen three times, stirring at 100 ℃ for 16 hours, detecting completion of reaction by LCMS, filtering the reaction solution, and concentrating to obtain the target product 4- (3-fluoro-1- (5-methoxy-2- (1-methyl-1H-pyrazol-4-yl) -4-nitrophenyl) -4) Piperidin-4-yl) morpholine (83-5) (180.00mg, yield: 89.8%) was used directly in the next step.
LCMS:Rt＝1.030min；MS m/z(ESI):420.5[M+H] +。
Compound 83-6:
Figure PCTCN2020132188-APPB-000126
4- (3-fluoro-1- (5-methoxy-2- (1-methyl-1H-pyrazol-4-yl) -4-nitrophenyl) piperidin-4-yl) morpholine (83-5) (180.00mg,0.429mmol) was dissolved in anhydrous ethanol (30mL) at room temperature, and wet palladium on carbon (100mg (Pd) (100 mg)>＝10％,H 2Owt% ═ 50%)) was replaced with hydrogen three times at 60 deg.cThe reaction was carried out for 4 hours. The reaction mixture was filtered through celite to remove palladium on carbon, and concentrated to give the objective 4- (3-fluoro-4-morpholinopiperidin-1-yl) -2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) aniline (83-6) (150.00mg, yield: 89.8%).
LCMS:Rt＝0.430min；MS m/z(ESI):390.5[M+H] +。
Trifluoroacetic acid salt of compound 83:
Figure PCTCN2020132188-APPB-000127
4- (3-fluoro-4-morpholinopiperidin-1-yl) -2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) aniline (83-6) (150.00mg,0.385mmol) and (6- ((5-bromo-2-chloropyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (4-9) (158.91mg,0.385mmol) were dissolved in isopropanol (5mL) at room temperature, trifluoroacetic acid (0.8mL) was added, and the reaction was carried out at 105 ℃ for 16 hours. The reaction liquid was separated and purified by high performance liquid preparative chromatography (eluent gradient refer to example 1) to give the objective product ((6- ((5-bromo-2- ((4- (3-fluoro-4-morpholinopiperidin-1-yl) -2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (compound 83) trifluoroacetate (60.00mg, yield: 20.3%).
1H NMR(400MHz,CDCl 3)δ12.59(s,1H),8.96(d,J＝9.5,4.2Hz,1H),8.71(d,J＝10.4,1.8Hz,2H),8.29(d,J＝3.9Hz,2H),7.98(br,1H),7.55(br,1H),7.40-7.36(m,2H),6.67(s,1H),5.26(br,1H),3.95-3.90(m,7H),3.79(s,3H),3.54-3.49(m,1H),3.26-3.25(m,1H),2.97–2.57(m,7H),2.14–2.10(m,7H),1.91(br,1H).
19F NMR(377MHz,CDCl 3)δ-198.78.
31P NMR(162MHz,CDCl 3)δ49.33.
LCMS：Rt:1.010min；MS m/z(ESI):765.2，767.2[M+H] +。
EXAMPLE 16 preparation of (6- ((5-chloro-2- ((2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -4-morpholinophenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) -dimethylphosphine oxide (Compound 84)
Figure PCTCN2020132188-APPB-000128
Compound 84-2:
Figure PCTCN2020132188-APPB-000129
(6-Aminoquinoxalin-5-yl) dimethylphosphine oxide (4-8) (1.0g,4.52mmol) and 2,4, 5-trichloropyrimidine (2.81g, 15.32mmol) are dissolved in ethanol (30mL) at room temperature and stirred at room temperature, and diisopropylethylamine (4.0mL,22.87 mmol) is added. After the addition was complete, the mixture was stirred at room temperature for 10 minutes, and the reaction was placed in an oil bath at 100 ℃ and heated under reflux for 22 hours. The reaction was stopped and cooled to room temperature and spin dried. The resulting crude product was separated and purified by silica gel column chromatography (dichloromethane: methanol ═ 30:1) to give (6- ((2, 5-dichloropyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (84-2) (150mg, yield: 49.8%).
LCMS:Rt:1.500min；MS m/z(ESI):368.0[M+H] +。
Compound 84:
Figure PCTCN2020132188-APPB-000130
(6- ((2, 5-dichloropyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (84-2) (179mg, 0.485mmol) and 4- (5-methoxy-2- (1-methyl-1H-pyrazol-4-yl) -4-nitrophenyl) morpholine (2-4) (140mg, 0.485mmol) were dissolved in isopropanol (6mL) at room temperature and stirred at room temperature, and trifluoroacetic acid (0.4mL, 4.85mmol) was added. After the addition, the reaction was put in an oil bath at 100 ℃ and heated under reflux for 14 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and the resulting crude product was purified by high performance liquid preparative chromatography to give the objective product (6- ((5-chloro-2- ((2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -4-morpholinophenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) -dimethylphosphine oxide (compound 84) (110mg, yield: 36.6%).
1H NMR(400MHz,CDCl 3)δ:12.78(s,1H),9.16-9.13(m,1H),8.73(d,J＝1.9Hz,1H),8.70(d,J＝1.9Hz,1H),8.23(s,1H),8.18(s,1H),7.77(s,1H),7.64(s,1H),7.60-7.58(m,1H),7.34(s,1H),6.71(s,1H),3.93(s,3H),3.81-3.78(m,4H),3.78(s,3H),2.95–2.86(m,4H),2.14(s,3H),2.10(s,3H).
31P NMR(162.0MHz,CDCl 3)δ：49.739.
LCMS：Rt:6.667min；MS m/z(ESI):620.1[M+H] +。
EXAMPLE 17 preparation of (6- ((5-bromo-2- ((4- ((2S,6R) -2, 6-dimethylmorpholine) -2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (Compound 85)
Figure PCTCN2020132188-APPB-000131
Referring to the synthetic method of example 2, morpholine was replaced with cis-2, 6-dimethylmorpholine, and (3- ((2, 5-dichloropyrimidin-4-yl) amino) quinolin-4-yl) dimethylphosphine oxide (2-1) was replaced with (6- ((5-bromo-2-chloropyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (4-9) to give the objective product (6- ((5-bromo-2- ((4- ((2S,6R) -2, 6-dimethylmorpholine) -2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) phenyl) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (Compound 85) ).
1H NMR(400MHz,MeOD):δ8.89(s,3H),8.31(s,1H),8.02(s,1H),7.63–7.31(m,3H),6.88(s,1H),3.94–3.81(m,8H),3.05-3.03(m,2H),2.46-2.43(m,2H),2.18(s,3H),2.14(s,3H) 1.28-1.16(m,6H).
31P NMR(162.0MHz,MeOD)δ：53.32.
HPLC：96.01％@214nm，99.80％@254nm
LCMS：Rt:1.640min；MS m/z(ESI):692.1，694.1[M+H] +。
EXAMPLE 18 preparation of (6- ((5-chloro-2- ((2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (Compound 86)
Figure PCTCN2020132188-APPB-000132
Referring to the synthetic method of example 2, morpholine was replaced with 1-methyl-4- (piperidin-4-yl) piperazine and (3- ((2, 5-dichloropyrimidin-4-yl) amino) quinolin-4-yl) dimethylphosphine oxide (2-1) was replaced with (6- ((2, 5-dichloropyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (84-2) to give the objective product (6- ((5-chloro-2- ((2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-4-yl) amino) -5-yl) dimethylphosphine oxide (compound 86).
1H NMR(400MHz,MeOD):δ9.00–8.91(m,1H),8.80(d,J＝1.8Hz,1H),8.76(d,J＝1.8Hz,1H),8.12(s,1H),7.92(s,1H),7.87(s,1H),7.48–7.44(m,2H),6.79(s,1H),3.89(s,3H),3.71(s,3H),3.15(d,J＝11.5Hz,2H),2.94–2.38(m,10H),2.36–2.25(m,4H),2.14(s,3H),2.11(s,3H),1.96(d,J＝11.5Hz,2H),1.85-1.57(m,2H).
31PNMR(162MHz,MeOD):δ53.27
LCMS：Rt:0.960min；MS m/z(ESI):716.3[M+H] +。
EXAMPLE 19 preparation of (6- ((5-bromo-2- ((4- ((1R,5S) -3-hydroxy-8-azabicyclo [3.2.1] octan-8-yl) -2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (Compound 87)
Figure PCTCN2020132188-APPB-000133
With reference to the synthetic method of example 2, morpholine was replaced with nortropine, and (3- ((2, 5-dichloropyrimidin-4-yl) amino) quinolin-4-yl) dimethylphosphine oxide (2-1) was replaced with (6- ((5-bromo-2-chloropyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (4-9), to obtain an object product (6- ((5-bromo-2- ((4- ((1R,5S) -3-hydroxy-8-azabicyclo [3.2.1] octan-8-yl) -2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) Dimethyl phosphine oxide (compound 87).
1H NMR(400MHz,CDCl 3)δ12.72(s,1H),8.98-8.94(m,1H),8.75-8.69(m,2H),8.26-7.41(m, 6H),6.56(br,1H),4.18-3.62(m,7H),2.30-2.15(m,2H),2.13(s,3H),2.09(s,3H),2.00(s,3H),1.96-1.64(m,6H).
31P NMR(162MHz,CDCl 3)δ49.42(s).
HPLC：99.36％@214nm，99.54％@254nm
LCMS:Rt:1.593min；MS m/z(ESI):704.8,706.8[M+H] +。
EXAMPLE 20 preparation of (6- ((2- ((4- ((1R,5S) -3-oxa-8-azabicyclo [3.2.1] octan-8-yl) -2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) phenyl) amino) -5-bromopyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (Compound 88)
Figure PCTCN2020132188-APPB-000134
Referring to the synthesis method of example 2, morpholine was replaced with 3-oxa-8-aza-bicyclo [3.2.1] octane and (3- ((2, 5-dichloropyrimidin-4-yl) amino) quinolin-4-yl) dimethylphosphine oxide (2-1) was replaced with (6- ((5-bromo-2-chloropyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (4-9) to obtain the target product (6- ((2- ((4- ((1R,5S) -3-oxa-8-azabicyclo [3.2.1] octan-8-yl) -2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) phenyl) amino) -5-bromopyrimidin-4-yl) -yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (compound 88).
1H NMR(400MHz,MeOD):δ8.90(br,1H),8.82(d,J＝2Hz,1H),8.78(d,J＝1.6Hz,1H),8.23(s,1H),7.76-7.73(m,2H),7.57-7.48(m,2H),6.64(s,1H),3.89(s,3H),3.86(d,J＝10.8Hz,2H),3.72(s,3H),3.62(s,2H),3.60-3.53(m,2H),2.16(s,3H),2.12(s,3H),1.93(br,4H)
31P NMR(162MHz,MeOD):δ52.86
LCMS：Rt:6.187min；MS m/z(ESI):690.1,692.1[M+H] +。
EXAMPLE 21 preparation of (6- ((2- ((4- (8-oxa-3-azabicyclo [3.2.1] oct-3-yl) -2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) phenyl) amino) -5-bromopyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (Compound 89)
Figure PCTCN2020132188-APPB-000135
Referring to the synthesis method of example 2, morpholine was replaced with 8-oxa-3-azabicyclo [3.2.1] octane and (3- ((2, 5-dichloropyrimidin-4-yl) amino) quinolin-4-yl) dimethylphosphine oxide (2-1) was replaced with (6- ((5-bromo-2-chloropyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (4-9) to obtain the objective product (6- ((2- ((4- (8-oxa-3-azabicyclo [3.2.1] octan-3-yl) -2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) phenyl) amino) -5-bromopyrimidin-4-yl) amino) quinoxalin- 5-yl) dimethylphosphine oxide (Compound 89).
1H NMR(400MHz,MeOD):δ8.85–8.80(m,3H),8.24(s,1H),7.83(s,1H),7.62(s,1H),7.56(br,1H),7.39(s,1H),6.88(s,1H),4.28(br,2H),3.91(s,3H),3.74(s,3H),2.95-2.92(m,2H),2.75-2.72(m,2H),2.15(s,3H),2.11(s,3H),1.97-1.84(m,4H)
31PNMR(162MHz,MeOD):δ52.85
LCMS：Rt:6.357min；MS m/z(ESI):690.1,692.1[M+H] +。
EXAMPLE 22 preparation of 1- (4- (1- (4- ((5-bromo-4- ((5- (dimethylphosphoryl) quinoxalin-6-yl) amino) pyrimidin-2-yl) amino) -5-methoxy-2- (1-methyl-1H-pyrazol-4-yl) phenyl) piperidin-4-yl) piperazin-1-yl) ethan-1-one (Compound 90)
Figure PCTCN2020132188-APPB-000136
Compound 90-2:
Figure PCTCN2020132188-APPB-000137
tert-butyl piperazine-1-carboxylate (8.0g, 42.88mmol), benzyl 4-oxopiperidine-1-carboxylate (5.0g, 21.44mmol) and acetic acid (1.9g, 32.16mmol) were added to dichloroethane (100mL) at room temperature, and the reaction was stirred at 50 ℃ for 5 hours. The reaction was cooled to room temperature, and sodium borohydride acetate (9.0g, 42.88mmol) was added to the reaction mixture to react at room temperature for 1.5 hours. Aqueous sodium hydroxide solution was added to adjust the pH to 11, and the mixture was extracted with methylene chloride (100mL X3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to give crude tert-butyl 4- (1- ((benzyloxy) carbonyl) piperidin-4-yl) piperazine-1-carboxylate (90-2) (7.0g, yield: 81%) which was used in the next step.
LCMS:Rt:0.470min；MS m/z(ESI):404.2[M+H] +。
Compound 90-3:
Figure PCTCN2020132188-APPB-000138
tert-butyl 4- (1- ((benzyloxy) carbonyl) piperidin-4-yl) piperazine-1-carboxylate (90-2) (7.0g, 17.35mmol) was dissolved in dioxane (10mL) at room temperature, and dioxane hydrochloride (4M, 50mL) was added and the reaction was stirred at room temperature for 16 hours. Spin-dry to give benzyl 4- (piperazin-1-yl) piperidine-1-carboxylate (90-3) (10.0g) as intermediate, and the crude was used directly in the next step.
LCMS:Rt:0.450min；MS m/z(ESI):304.2[M+H] +。
Compound 90-4:
Figure PCTCN2020132188-APPB-000139
benzyl 4- (piperazin-1-yl) piperidine-1-carboxylate (90-3) (6.0g, 19.77mmol), triethylamine (6.0g, 59.33mmol) was added to dichloromethane (120mL) at room temperature and stirred for 5 min. Acetic anhydride (4.0g, 39.54mmol) was added and reacted at room temperature for 2 h. 100mL of water was added, and the mixture was extracted with methylene chloride (100mL of X2), washed with saturated brine, dried over anhydrous sodium sulfate, filtered and spun to give benzyl 4- (4-acetylpiperazin-1-yl) piperidine-1-carboxylate (90-4) (7.0g, yield: 100%) as an intermediate, which was used in the next step.
LCMS:Rt:0.440min；MS m/z(ESI):346.2[M+H]。
Compound 90-5:
Figure PCTCN2020132188-APPB-000140
benzyl 4- (4-acetylpiperazin-1-yl) piperidine-1-carboxylate (90-4) (7.0g, 20.26mmol), wet palladium on carbon (1.5g (Pd)>＝10％,H 2O wt% ═ 50%)). Added to methanol (100mL) and after the addition was complete, the reaction was placed under an atmosphere of hydrogen (-15 psi) and allowed to warm to 60 deg.C with stirring for 4 hours. Filtration and spin-drying gave intermediate 1- (4- (piperidin-4-yl) piperazin-1-yl) ethanone (90-5) (4.0g, yield: 93%).
LCMS:Rt:0.350min；MS m/z(ESI):212.2[M+H] +。
Compound 90-6:
Figure PCTCN2020132188-APPB-000141
1- (4- (piperidin-4-yl) piperazin-1-yl) ethanone (90-5) (2.0g, 9.46mmol), 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene (2.36g, 9.46mmol) were added to acetonitrile (40mL) respectively at room temperature, and the reaction was stirred at 50 ℃ for 16 hours. LCMS to check the reaction was complete, spin-dried and purified on silica gel column (eluent gradient: dichloromethane/methanol-20/1) to afford intermediate 1- (4- (1- (2-bromo-5-methoxy-4-nitrophenyl) piperidin-4-yl) piperazin-1-yl) ethanone (6) (2.0g, yield: 48%).
LCMS:Rt:0.833min；MS m/z(ESI):441.1[M+H] +。
Remaining procedures referring to example 2, (3- ((2, 5-dichloropyrimidin-4-yl) amino) quinolin-4-yl) dimethylphosphine oxide (2-1) was replaced with (6- ((5-bromo-2-chloropyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (4-9) to give the desired product 1- (4- (1- (4- ((5-bromo-4- ((5- (dimethylphosphoryl) quinoxalin-6-yl) amino) pyrimidin-2-yl) amino) -5-methoxy-2- (1-methyl-1H-pyrazol-4-yl) phenyl) piperidin-4-yl) piperazin-1-yl) ethan-1-one ((2-1-4- ((5-bromo-2-chloropyrimidin-4-yl) amino) Compound 90).
1H NMR(400MHz,CDCl 3)：δ12.58(s,1H),9.01-8.97(m,1H),8.73(d,J＝2.0Hz,1H),8.69(d,J＝2.0Hz,1H),8.29(s,1H),8.21(s,1H),7.69(s,1H),7.61-7.56(m,2H),7.31(s,1H),6.70(s,1H),3.90(s,3H),3.75(s,3H),3.67-3.64(m,2H),3.51-3.48(m,2H),3.21(d,J＝11.6Hz,2H)，2.61-2.56(m,6H)，2.34-2.27(m,1H)，2.14(s,3H),2.11(s,6H),1.89(d,J＝11.2Hz,2H)，1.65-1.56(m,2H).
31P NMR(162.0MHz,CDCl 3)：δ49.26.
LCMS:Rt:1.040min；MS m/z(ESI):788.1，790.1[M+H] +。
Example 23 preparation of (3- ((5-bromo-2- ((2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -4- (4-morpholin-piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) quinolin-4-yl) dimethylphosphine oxide (Compound 91)
Figure PCTCN2020132188-APPB-000142
With reference to the synthesis method of example 15, tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate was replaced with N-tert-butoxycarbonyl-4-piperidone, and (6- ((5-bromo-2-chloropyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (4-9) was replaced with (3- ((5-bromo-2-chloropyrimidin-4-yl) amino) quinolin-4-yl) dimethylphosphine oxide (1-4) to obtain the objective compound (3- ((5-bromo-2- ((2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -4- (4-morpholin-1-yl) phenyl) amino) pyrimidine- 4-yl) amino) quinolin-4-yl) dimethylphosphine oxide (Compound 91).
1H NMR(400MHz,CDCl 3)δ11.99(s,1H),9.91(d,J＝4.8Hz,1H),8.27-8.25(m,2H),8.03(d,J＝8.0Hz,1H),7.77(s,1H),7.67-7.56(m,4H),7.25(s,1H),6.66(s,1H),3.88(s,3H),3.76-3.72(m,7H),3.21-3.18(m,2H),2.58-2.53(m,5H),2.18(s,3H),2.15(s,3H),1.91(d,J＝11.6Hz,2H),1.67-1.47(m,4H).
31P NMR(162MHz,CDCl 3)δ43.52.
LCMS:Rt:1.615min；MS m/z(ESI):746.2,748.2[M+H] +。
EXAMPLE 24 Synthesis of (6- ((5-bromo-2- ((6- ((2S,6R) -2, 6-dimethylmorpholine) -2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (Compound 92)
Figure PCTCN2020132188-APPB-000143
Referring to the synthesis procedure of example 13, 1-methyl-4- (piperidin-4-yl) piperazine was replaced with cis-2, 6-dimethylmorpholine to give the objective compound (6- ((5-bromo-2- ((6- ((2S,6R) -2, 6-dimethylmorpholine) -2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (compound 92).
1H NMR(400MHz,MeOD)δ8.81-8.77(m,3H),8.26(s,1H),8.10(s,1H),7.74(s,1H),7.59(s,1H),7.44(s,1H),3.99(s,3H),3.84(br,2H),3.71(s,3H),3.24(br,2H),2.51(t,J＝11.2Hz,2H),2.16(s,3H),2.16(s,3H),1.15(s,3H),1.13(s,3H).
31P NMR(162MHz,MeOD)δ52.84.
LCMS:Rt:1.760min；MS m/z(ESI):693.1,695.1[M+H] +。
EXAMPLE 25 preparation of (6- ((2- ((6- ((1R,5S) -3-oxa-8-azabicyclo [3.2.1] octan-8-yl) -2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) amino) -5-bromopyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (Compound 93) trifluoroacetate
Figure PCTCN2020132188-APPB-000144
Referring to the synthesis procedure of example 13, 1-methyl-4- (piperidin-4-yl) piperazine was replaced with 3-oxa-8-aza-bicyclo [3.2.1] octane to give the objective compound (6- ((2- ((6- ((1R,5S) -3-oxa-8-azabicyclo [3.2.1] octan-8-yl) -2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) amino) -5-bromopyrimidin-4-yl) quinoxalin-5-yl) dimethylphosphine oxide (compound 93) trifluoroacetate.
1H NMR(400MHz,MeOD)δ8.87–8.71(m,3H),8.27(s,1H),7.78(br,3H),7.52(s,1H),4.03(s,2H),3.95(s,3H),3.88(d,J＝10.5Hz,2H),3.82(s,3H),3.54(d,J＝10.0Hz,2H),2.17(s,3H),2.13(s,3H),1.91(s,4H).
19F NMR(162MHz,MeOD)δ-77.42.
31P NMR(162MHz,MeOD)δ53.18.
LCMS:Rt:1.577min；MS m/z(ESI):691.1,693.1[M+H] +。
EXAMPLE 26 preparation of (6- ((5-bromo-2- ((2-methoxy-6-morpholin-5- (1H-pyrazol-4-yl) pyridin-3-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (Compound 94) trifluoroacetate
Figure PCTCN2020132188-APPB-000145
Referring to the synthesis procedure of example 13, 1-methyl-4- (piperidin-4-yl) piperazine was replaced with morpholine and 1-methyl-4-pyrazoleboronic acid pinacol ester was replaced with 4-pyrazoleboronic acid pinacol ester to give the objective compound (6- ((5-bromo-2- ((2-methoxy-6-morpholin-5- (1H-pyrazol-4-yl) pyridin-3-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (compound 94) trifluoroacetate.
1H NMR(400MHz,DMSO):δ12.82(s,1H),8.87-8.70(m,4H),8.30(s,1H),8.02-8.00(m,2H),7.86(s,1H),7.57(s,1H),3.88(s,3H),3.74-3.72(m,4H),3.09-3.07(m,4H),2.03(s,3H),2.00(s,3H).
19F NMR(376.5MHz,DMSO):δ-74.893
31P NMR(162.0MHz,DMSO):δ48.569
LCMS:Rt:1.491min；MS m/z(ESI):651.4,653.4[M+H] +。
EXAMPLE 27 preparation of (6- ((5-bromo-2- ((2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -6- (4-morpholinopiperidin-1-yl) pyridin-3-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (Compound 95)
Figure PCTCN2020132188-APPB-000146
Referring to the synthesis procedure of example 13, 1-methyl-4- (piperidin-4-yl) piperazine was replaced with 4- (4-piperidyl) morpholine to give the objective compound (6- ((5-bromo-2- ((2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -6- (4-morpholinopiperidin-1-yl) pyridin-3-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (compound 95).
1H NMR(400MHz,MeOD):δ8.82-8.75(m,3H),8.25(s,1H),8.08(s,1H),7.77(s,1H),7.59(br,1H),7.43(s,1H),3.98(s,3H),3.74-3.72(m,7H),3.52-3.49(m,2H),2.79-2.73(m,2H),2.62(br,4H),2.32-2.26(m,1H),2.16(s,3H),2.12(s,3H),1.96(d,J＝11.3Hz,2H),1.63-1.55(m,2H).
31P NMR(162MHz,MeOD):δ52.85(s).
LCMS:Rt:4.117min；MS m/z(ESI):748.1,750.1[M+H] +。
EXAMPLE 28 preparation of (6- ((5-bromo-2- ((6- (3-fluoro-4-morpholinopiperidin-1-yl) -2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (Compound 96) trifluoroacetate
Figure PCTCN2020132188-APPB-000147
Referring to the synthesis procedure of example 13, 1-methyl-4- (piperidin-4-yl) piperazine was replaced with 4- (3-fluoropiperidin-4-yl) morpholine hydrochloride (83-3) to obtain the objective compound (6- ((5-bromo-2- ((6- (3-fluoro-4-morpholinopiperidin-1-yl) -2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (compound 96) trifluoroacetate.
1H NMR(400MHz,CDCl 3)δ13.50(s,1H),8.79(s,1H),8.75(s,1H),8.64(d,J＝5.4Hz,1H),8.05(s,1H),7.87-7.85(m,2H),7.58(d,J＝9.4Hz,1H),7.52(s,1H),5.31–5.19(m,1H),4.06(s,3H),4.01–3.96(m,5H),3.93-3.85(m,5H),3.59–3.55(m,2H),3.50-3.47(m,2H),3.35–2.96(m,2H),2.35-2.33(m,1H),2.14(s,3H),2.11(s,3H),1.99-1.96(m,1H).
19F NMR(377MHz,CDCl 3)δ-75.83(s).-196.61(s),
31P NMR(162MHz,CDCl 3)δ51.16(s).
LCMS：Rt:1.003min；MS m/z(ESI):766.1，768.1[M+H] +。
EXAMPLE 29 preparation of (6- ((5-bromo-2- ((6- (3-fluoro-4- (1, 4-oxazepin-4-yl) piperidin-1-yl) -2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (Compound 97) trifluoroacetate
Figure PCTCN2020132188-APPB-000148
Referring to the synthesis procedure of example 15, morpholine was replaced with homomorpholine, 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene was replaced with 2, 3-dichloro-6-methoxy-5-nitropyridine (4-2), to give the objective compound (6- ((5-bromo-2- ((6- (3-fluoro-4- (1, 4-oxazepin-4-yl) piperidin-1-yl) -2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (compound 97) trifluoroacetate).
1H NMR(400MHz,MeOD)δ8.85–8.70(m,3H),8.26(d,J＝7.4Hz,1H),8.17(s,1H),7.74(s,1H),7.57(s,1H),7.43(s,1H),5.30(d,J＝50.5Hz,1H),4.00(s,3H),3.93(d,J＝3.7Hz,2H),3.85(dd,J＝13.1,7.3Hz,2H),3.78(s,1H),3.69(s,3H),3.59-3.51(s,6H),3.11(dd,J＝40.1,14.2Hz,1H),3.10-2.89(m,1H),2.29-2.26(m,1H),2.17-2.09(m,9H).
19F NMR(162MHz,MeOD)δ-76.92,-201.27.
31P NMR(162MHz,MeOD)δ52.85.
LCMS:Rt:1.027min；MS m/z(ESI):780.1,782.1[M+H] +。
EXAMPLE 30 preparation of (6- ((5-bromo-2- ((2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -6- (4- (oxetan-3-yl) piperazin-1-yl) pyridin-3-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (Compound 98)
Figure PCTCN2020132188-APPB-000149
Compound 98-2:
Figure PCTCN2020132188-APPB-000150
tert-butyl piperazine-1-carboxylate (2.0g, 10.73mmol), 2, 3-dichloro-6-methoxy-5-nitropyridine (4-2) (2.39g, 10.73mmol) were added to tetrahydrofuran (50mL) respectively at room temperature, and the reaction was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel column (petroleum ether/ethyl acetate: 5/1) to give tert-butyl 4- (3-chloro-6-methoxy-5-nitropyridin-2-yl) piperazine-1-carboxylate (98-2) (2.0g, yield: 50%).
LCMS:Rt:1.550min；MS m/z(ESI):373.0[M+H] +。
Compound 98-3:
Figure PCTCN2020132188-APPB-000151
tert-butyl 4- (3-chloro-6-methoxy-5-nitropyridin-2-yl) piperazine-1-carboxylate (98-2) (2.0g, 5.36mmol), 1-methyl-4-pyrazoloboroate pinacol (1.67g, 8.04mmol), potassium phosphate (3.41g, 16.08mmol) were added to dioxane (25mL) and water (2.5mL) respectively at room temperature, argon was substituted four times, bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) palladium (II) dichloride (380mg, 0.536mmol) was added, argon was substituted four times, and the reaction was stirred at 105 ℃ for 4 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column (eluent gradient: petroleum ether/ethyl acetate 20/1) to give intermediate tert-butyl 4- (6-methoxy-3- (1-methyl-1H-pyrazol-4-yl) -5-nitropyridin-2-yl) piperazine-1-carboxylate (98-3) (2.0g, yield: 89%).
LCMS:Rt:0.963min；MS m/z(ESI):419.1[M+H] +。
Compound 98-4:
Figure PCTCN2020132188-APPB-000152
tert-butyl 4- (6-methoxy-3- (1-methyl-1H-pyrazol-4-yl) -5-nitropyridin-2-yl) piperazine-1-carboxylate (98-3) (2.0g, 4.78mmol) was dissolved in dioxane (10mL) at room temperature, dioxane solution (4M, 20mL) was added, and the reaction was stirred at room temperature for 4 hours. The reaction solution was concentrated to dryness under reduced pressure to give intermediate 1- (6-methoxy-3- (1-methyl-1H-pyrazol-4-yl) -5-nitropyridin-2-yl) piperazine (98-4) (2.0 g).
LCMS:Rt:0.880min；MS m/z(ESI):319.1[M+H] +。
Compound 98-5:
Figure PCTCN2020132188-APPB-000153
1- (6-methoxy-3- (1-methyl-1H-pyrazol-4-yl) -5-nitropyridin-2-yl) piperazine (98-4) (2.0g, 6.28mmol) and 4-dimethylaminopyridine (766mg, 6.28mmol) were added to dichloromethane (20mL) at room temperature and stirred for 5 minutes, trifluoroacetic anhydride (2.64g, 12.56mmol) was added thereto and stirred at room temperature for reaction for 2 hours, and the reaction mixture was directly concentrated to dryness under reduced pressure and purified by a silica gel column to obtain intermediate 2,2, 2-trifluoro-1- (4- (6-methoxy-3- (1-methyl-1H-pyrazol-4-yl) -5-nitropyridin-2-yl) piperazin-1-yl) ethanone (98-5) (2.0g, yield 77%).
LCMS:Rt:1.253min；MS m/z(ESI):415.5[M+H] +。
Compound 98-6:
Figure PCTCN2020132188-APPB-000154
2,2, 2-trifluoro-1- (4- (6-methoxy-3- (1-methyl-1H-pyrazol-4-yl) -5-nitropyridin-2-yl) piperazin-1-yl) ethanone (98-5) (2.0g, 4.83mmol), wet palladium on carbon (500mg (Pd) at room temperature>＝10％,H 250% O by weight) were added to ethanol (30mL), and after completion of the addition, the reaction was placed under an atmosphere of hydrogen (15 psi), heated to 55 ℃ and stirred for 2 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to dryness to give intermediate 1- (4- (5-amino-6-methoxy-3- (1-methyl-1H-pyrazol-4-yl) pyridin-2-yl) piperazin-1-yl) -2,2, 2-trifluoroethane-1-one (98-6) (1.7g, yield: 92%).
LCMS:Rt:1.560min；MS m/z(ESI):385.1[M+H] +。
Compound 98-7:
Figure PCTCN2020132188-APPB-000155
1- (4- (5-amino-6-methoxy-3- (1-methyl-1H-pyrazol-4-yl) pyridin-2-yl) piperazin-1-yl) -2,2, 2-trifluoroethane-1-one (98-6) (1.0g, 2.6mmol), (6- ((5-bromo-2-chloropyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (4-9) (859mg, 2.08mmol), trifluoroacetic acid (2.96g, 26mmol) were added to isopropanol (30mL) respectively at room temperature, the temperature was raised to 95 ℃ under the protection of argon, the reaction was stirred for 16 hours, the reaction solution was concentrated, and a silica gel column (eluent gradient: dichloromethane/methanol ═ 20/1) was purified to obtain an intermediate, 1- (4- (5-) (20/1) (5-bromo-4- ((5- (dimethylphosphoryl) quinoxalin-6-yl) amino) pyrimidin-2-yl) amino) -6-methoxy-3- (1-methyl-1H-pyrazol-4-yl) pyridin-2-yl) piperazin-1-yl) -2,2, 2-trifluoroethan-1-one (98-7) (1.5g, yield: 76%).
LCMS:Rt:1.500min；MS m/z(ESI):762.1[M+H] +。
Compound 98-8:
Figure PCTCN2020132188-APPB-000156
1- (4- (5- ((5-bromo-4- ((5- (dimethylphosphoryl) quinoxalin-6-yl) amino) pyrimidin-2-yl) amino) -6-methoxy-3- (1-methyl-1H-pyrazol-4-yl) pyridin-2-yl) piperazin-1-yl) -2,2, 2-trifluoroethan-1-one (98-7) (500mg, 0.657mmol), potassium hydroxide (370mg, 6.57mmol) were added to methanol (20mL) and water (2mL), respectively, and the reaction was stirred at 60 ℃ for 5H at room temperature. Diluting with 50mL of dichloromethane and 30mL of water, extracting with dichloromethane (50mL X3), drying the organic phase with anhydrous sodium sulfate, and concentrating to dryness to obtain intermediate (6- ((5-bromo-2- ((2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -6- (piperazin-1-yl) pyridin-3-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (98-8) (300mg, yield: 69%).
LCMS:Rt:0.843min；MS m/z(ESI):666.1[M+H] +。
Compound 98:
Figure PCTCN2020132188-APPB-000157
(6- ((5-bromo-2- ((2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -6- (piperazin-1-yl) pyridin-3-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (98-8) (300mg,0.451mmol), 3-oxetanone (33mg,0.451mmol), acetic acid (41mg,0.677mmol) were added to 1, 2-dichloroethane (10mL) respectively at room temperature. The reaction solution was heated to 50 ℃ and stirred to react for 5 hours. Sodium triacetoxyborohydride (191mg,0.902mmol) was added thereto, and the reaction was carried out at room temperature for 1 hour. The reaction mixture was adjusted to pH 11 with aqueous sodium hydroxide solution, extracted with dichloromethane, concentrated to dryness, the residue was added to N, N-dimethylformamide (5mL), filtered and purified by high performance liquid preparative chromatography (eluent gradient reference example 1) to give (6- ((5-bromo-2- ((2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -6- (4- (oxetan-3-yl) piperazin-1-yl) pyridin-3-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide trifluoroacetate. The product was lyophilized and dissolved in 5mL of methylene chloride, washed with saturated sodium carbonate (10mL X2), washed with water (10mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to dryness to give the objective product (6- ((5-bromo-2- ((2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -6- (4- (oxetan-3-yl) piperazin-1-yl) pyridin-3-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (compound 98) (15mg, yield: 4.64%).
1H NMR(400MHz,MeOD)：δ8.82(d,J＝2.0Hz,1H)，8.78-8.75(m,2H)，8.25(s,1H),8.12(s,1H),7.73(s,1H),7.56(br,1H),7.43(s,1H),4.74-4.70(m,2H),4.66-4.62(m,2H),3.99(s,3H),3.70(s,3H),3.64-3.58(m,1H),3.17(br,4H),2.49(br,4H),2.16(s,3H),2.12(s,3H).
31P NMR(162.0MHz,MeOD)：δ52.83.
LCMS:Rt:1.008min；MS m/z(ESI):720.1,722.1[M+H] +。
EXAMPLE 31 preparation of (6- ((5-bromo-2- ((6- (3-fluoro-4- (4-methylpiperazin-1-yl) piperidin-1-yl) -2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (Compound 99) trifluoroacetate
Figure PCTCN2020132188-APPB-000158
Referring to the synthesis procedure of example 15, morpholine was replaced with N-methylpiperazine, 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene was replaced with 2, 3-dichloro-6-methoxy-5-nitropyridine (4-2) to give the objective compound (6- ((5-bromo-2- ((6- (3-fluoro-4- (4-methylpiperazin-1-yl) piperidin-1-yl) -2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (compound 99) trifluoroacetate.
1H NMR(400MHz,CDCl 3)δ13.26(s,1H),8.80(d,J＝1.8Hz,1H),8.76–8.65(m,2H),8.07(s,1H),7.81(d,J＝13.8Hz,2H),7.65(d,J＝8.9Hz,1H),7.47(s,1H),5.12-5.01(m,1H),3.97(s,3H),3.87(s,3H),3.69-3.65(m,1H),3.56(s,1H),3.34-3.22(m,6H),3.04-3.02(m,1H),2.92(d,J＝14.2Hz,1H),2.88–2.80(m,6H),2.79-2.74(m,1H),2.20-2.18(m,1H),2.14(s,3H),2.11(s,3H),1.87-1.85(m,1H).
19F NMR(377MHz,CDCl 3)δ-75.81,-198.61,
31P NMR(162MHz,CDCl 3)δ50.78.
LCMS：Rt:0.946min；MS m/z(ESI):779.2,781.2[M+H] +。
EXAMPLE 32 preparation of (6- ((5-bromo-2- ((2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -6- (4-morpholinopiperidin-1-yl) pyridin-3-yl) amino) pyrimidin-4-yl) amino) quinolin-5-yl) dimethylphosphine oxide (Compound 100) trifluoroacetate
Figure PCTCN2020132188-APPB-000159
Compound 100-2:
Figure PCTCN2020132188-APPB-000160
quinolin-6-amine (4.0g,27.78mmol) and tetrabutylammonium bromide (13.39g, 27.78mmol) were added to dichloromethane/methanol (75ml/25ml) at room temperature. The reaction was carried out at room temperature for 2 hours. After completion of the reaction, the reaction mixture was adjusted to pH 8 with a saturated sodium thiosulfate solution, and extracted with ethyl acetate (80 mL. times.4). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted through a silica gel column (petroleum ether: ethyl acetate: 8:1) to give 5-bromoquinolin-6-amine (100-2) (4.0g, yellow solid).
LCMS:Rt:0.860min；MS m/z(ESI):223.0[M+H] +。
Compound 100-3:
Figure PCTCN2020132188-APPB-000161
the compound 5-bromoquinolin-6-amine (100-2) (1.0g,4.48mmol), dimethylphosphine (480mg,6.73mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (260mg,0.45mmol), palladium acetate (100mg,0.45mmol) and potassium phosphate (1.43g,6.73mmol) were dissolved in N, N-dimethylformamide and water (40mL/8mL) at room temperature, and the reaction mixture was heated to 120 ℃ and stirred for reaction for 16 hours. The reaction solution was cooled to room temperature, then 150mL of water was added, extraction was performed with ethyl acetate (50mL X3), the organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate, and elution was performed with a silica gel column (petroleum ether: ethyl acetate ═ 1:1) to obtain compound (6-aminoquinolin-5-yl) dimethylphosphine oxide (100-3) (1.0g, yellow solid).
Compound 100-4:
Figure PCTCN2020132188-APPB-000162
(6-Aminoquinoxalin-5-yl) dimethylphosphine oxide (100-3) (40mg,0.18mmol) was dissolved in ethanol (5mL) at room temperature, and 5-bromo-2, 4-dichloropyrimidine (82mg,0.36mmol) and N, N-diisopropylethylamine (3.5g,27.1mmol) were added. The reaction solution is heated to 90 ℃ under the protection of argon gas, stirred and reacted for 16 hours until the reaction is complete. The reaction solution was directly concentrated under reduced pressure, and the residue was purified by silica gel plate chromatography (ethyl acetate: petroleum ether ═ 1:1) to give the objective product (6- ((5-bromo-2-chloropyrimidin-4-yl) amino) quinolin-5-yl) dimethylphosphine oxide (100-4) (40mg, yield: 54%).
LCMS:Rt:1.245min；MS m/z(ESI):413.0[M+H] +。
Remaining procedures referring to the synthesis method of example 13, (6- ((5-bromo-2-chloropyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (4-9) is replaced with 4- (4-piperidyl) morpholine and (6- ((5-bromo-2-chloropyrimidin-4-yl) amino) quinolin-5-yl) dimethylphosphine oxide (100-4) to obtain the objective compound (6- ((5-bromo-2- ((2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -6- (4-morpholinopiperidin-1-yl) pyridin-3-yl) ) Amino) pyrimidin-4-yl) amino) quinolin-5-yl) dimethylphosphine oxide (compound 100) trifluoroacetate salt.
1H NMR(400MHz,MeOD):δ8.84(d,J＝4.3Hz,1H),8.74(d,J＝8.8Hz,1H),8.48–8.32(m,1H),8.26(s,1H),7.95(s,1H),7.75(s,1H),7.65(dd,J＝8.8,4.3Hz,1H),7.56(s,1H),7.48(s,1H),4.14–4.11(m,2H),3.97(s,3H),3.80-3.74(m,2H),3.69(s,3H),3.66–3.49(m,4H),3.32(br,1H),3.13-3.09(m,2H),2.82(t,J＝12.0Hz,2H),2.19-2.13(m,8H),1.86-1.78(m,2H).
19F NMR(377MHz,MeOD):δ-77.11.
31P NMR(162MHz,MeOD):δ47.37.
LCMS：Rt:3.797min；MS m/z(ESI):747.1,749.1[M+H] +。
Example 33 preparation of (6- ((5-bromo-2- ((2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -4- (4-morpholinopiperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (Compound 101)
Figure PCTCN2020132188-APPB-000163
Compound 101-2:
Figure PCTCN2020132188-APPB-000164
4- (piperidin-4-yl) morpholine (540mg, 3.17mmol) and 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene (793mg, 3.17mmol) were each added to acetonitrile (20mL) at room temperature, and the reaction was stirred at 50 ℃ for 16 hours. The reaction mixture was concentrated to dryness under reduced pressure, and purified with silica gel column (eluent gradient: dichloromethane/methanol-20/1) to give 4- (1- (2-bromo-5-methoxy-4-nitrophenyl) piperidin-4-yl) morpholine (101-2) (900mg, yield: 71%).
LCMS:Rt:0.843min；MS m/z(ESI):400.4[M+H] +。
Compound 101-3:
Figure PCTCN2020132188-APPB-000165
4- (1- (2-bromo-5-methoxy-4-nitrophenyl) piperidin-4-yl) morpholine (101-2) (800mg, 1.99mmol), 1-methylpyrazole-4-boronic acid pinacol ester (499mg, 2.39mmol), cesium carbonate (1.96g, 5.99mmol) were added to dioxane (20mL) and water (5mL) respectively at room temperature, replaced four times with argon, and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (280mg, 0.39mmol) was added, replaced four times with argon, and the reaction was stirred at 105 ℃ for 16 hours. Reaction completion was checked by LCMS. The reaction mixture was concentrated under reduced pressure and purified with silica gel column (eluent gradient: dichloromethane/methanol ═ 20/1) to give intermediate 4- (1- (5-methoxy-2- (1-methyl-1H-pyrazol-4-yl) -4-nitrophenyl) piperidin-4-yl) morpholine (101-3) (450mg, yield: 56%).
LCMS:Rt:1.020min；MS m/z(ESI):402.1[M+H] +。
Compound 101-4:
Figure PCTCN2020132188-APPB-000166
4- (1- (5-methoxy-2- (1-methyl-1H-pyrazol-4-yl) -4-nitrophenyl) piperidin-4-yl) morpholine (101-3) (450mg, 1.12mmol), wet palladium on carbon (200mg (Pd) at room temperature>＝10％,H 250% O by weight) were added to ethanol (20mL), and after completion of the addition, the reaction was placed under an atmosphere of hydrogen (15 psi), and the temperature was raised to 50 ℃ and the reaction was stirred for 2 hours. The catalyst was removed by filtration through Celite, and the filtrate was concentrated under reduced pressure to dryness to give intermediate 2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -4- (4-morpholineproperidin-1-yl) aniline (101-4) (200mg, yield: 48%).
LCMS:Rt:0.445min；MS m/z(ESI):372.1[M+H] +。
Compound 101:
Figure PCTCN2020132188-APPB-000167
2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -4- (4-morpholin-piperidin-1-yl) aniline (101-4) (200mg,0.54mmol), (6- ((5-bromo-2-chloropyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (4-9) (185mg,0.45mmol), trifluoroacetic acid (614mg,5.38mmol) was added to isopropanol (20mL) at room temperature, respectively. The reaction solution was heated to 95 ℃ and stirred to react for 16 hours. The reaction mixture was concentrated under reduced pressure, the residue was taken up in N, N-dimethylformamide (5mL), filtered and purified by high performance liquid preparative chromatography (eluent gradient reference example 1) to give the compound (6- ((5-bromo-2- ((2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -4- (4-morpholinopiperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide trifluoroacetate which, after lyophilization, was dissolved in 5mL of dichloromethane and washed twice with saturated sodium carbonate (10mL X2) and then with water (10mL), dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure, to obtain the objective product (6- ((5-bromo-2- ((2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -4- (4-morpholinopiperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (compound 101) (141mg, yield: 19%).
1H NMR(400MHz,CDCl 3)：δ12.58(s,1H),8.99(dd,J＝4.4,9.6Hz,1H),8.84-8.70(m,2H),8.29(s,1H),8.22(s,1H),7.76(s,1H),7.58(br,1H),7.50(br,1H),7.32(s,1H),6.71(s,1H),3.90(s,3H),3.77(br,7H),3.21(d,J＝11.2Hz,2H),2.59(s,6H),2.37-2.18(m,1H),2.14(s,3H),2.11(s,3H),1.95(d,J＝10.8Hz,2H),1.63-1.57(m,2H).
31P NMR(162.0MHz,CDCl 3)：δ49.29.
LCMS:Rt:1.019min；MS m/z(ESI):747.1,749.1[M+H] +。
EXAMPLE 34 preparation of (6- ((2- ((4- (4- (1, 4-oxazepin-4-yl) piperidin-1-yl) -2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) phenyl) amino) -5-bromopyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (Compound 24)
Figure PCTCN2020132188-APPB-000168
Referring to the synthesis procedure of example 15, tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate was replaced with N-tert-butoxycarbonyl-4-piperidone and morpholine was replaced with homomorpholine to give the objective compound (6- ((2- ((4- (4- (1, 4-oxazepin-4-yl) piperidin-1-yl) -2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) phenyl) amino) -5-bromopyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (compound 24).
1H NMR(400MHz,CDCl 3):δ12.59(s,1H),8.98-8.95(m,1H),8.74-8.71(m,2H),8.29(s,1H),8.21(s,1H),7.62-7.52(m,3H),7.33(s,1H),6.65(s,1H),3.95-3.80(m,7H),3.75(s,3H),3.27-2.62(m,10H),2.30-2.27(m,2H),2.15(s,3H),2.13(s,3H),2.06-1.91(m,3H)
31P NMR(162.0MHz,CDCl 3)δ：49.38.
LCMS：Rt:0.920min；MS m/z(ESI):761.1,763.1[M+H] +
Example 35 preparation of (6- ((5-bromo-2- ((4- (4- (3, 3-difluoropyrrolidin-1-yl) piperidin-1-yl)) -2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (compound 102)
Figure PCTCN2020132188-APPB-000169
Referring to the synthesis procedure of example 15, tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate was replaced with N-tert-butoxycarbonyl-4-piperidone and morpholine was replaced with 3, 3-difluoropyrrolidine to give the objective compound (6- ((5-bromo-2- ((4- (4- (3, 3-difluoropyrrolidin-1-yl) piperidin-1-yl)) -2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (compound 102).
1H NMR(400MHz,MeOD):δ8.83(s,1H),8.77(d,J＝1.9Hz,1H),8.26(s,1H),7.93(s,1H),7.80(s,1H),7.49-7.46(m,2H),7.36-7.34(m,1H),6.83(s,1H),3.91(s,3H),3.69(s,3H),3.24-3.21(m,3H),2.71-2.70(m,2H),2.55-2.53(m,4H),2.17-2.13(m,10H),1.86(s,2H).
31P NMR(162.0MHz,MeOD)δ：52.89.
LCMS：Rt:1.120min；MS m/z(ESI):767.1,769.1[M+H] +.
EXAMPLE 36 preparation of (6- ((5-bromo-2- ((4- (3-fluoro-4- (4-methylpiperazin-1-yl) piperidin-1-yl) -2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (Compound 103) trifluoroacetate
Figure PCTCN2020132188-APPB-000170
Referring to the synthesis procedure of example 15, morpholine was replaced with N-methylpiperazine to give the title compound (6- ((5-bromo-2- ((4- (3-fluoro-4- (4-methylpiperazin-1-yl) piperidin-1-yl) -2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (compound 103) trifluoroacetate.
1H NMR(400MHz,CDCl 3)δ13.34(s,1H),10.66(s,1H),8.83(s,1H),8.76(d,J＝1.6Hz,1H),8.73-8.68(m,1H),8.06(s,1H),7.93(s,1H),7.63(s,1H),7.52-7.47(m,2H),6.69(s,1H),5.40-5.22(m,1H),3.90(s,3H),3.89(s,3H),3.63-3.32(m,10H),3.24-3.15(m,1H),2.95-2.77(m,5H),2.31-2.23(m,1H),2.17(s,3H),2.13(s,3H),2.05–2.04(m,1H).
19F NMR(377MHz,CDCl 3)δ-75.88,-197.22.
31P NMR(162MHz,CDCl3)δ52.33.
LCMS：Rt:1.100min；MS m/z(ESI):778.1,780.1[M+H] +。
EXAMPLE 37 preparation of (6- ((5-bromo-2- ((4- (3, 3-difluoro-4- (pyrrolidin-1-yl) piperidin-1-yl) -2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (Compound 104)
Figure PCTCN2020132188-APPB-000171
Referring to the synthesis procedure of example 15, tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate was replaced with tert-butyl 3, 3-difluoro-4-oxopiperidine-1-carboxylate and morpholine was replaced with pyrrolidine to give the objective compound (6- ((5-bromo-2- ((4- (3, 3-difluoro-4- (pyrrolidin-1-yl) piperidin-1-yl) -2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (compound 104).
1H NMR(400MHz,MeOD)δ:8.83-8.77(m,3H),8.27(s,1H),8.02(s,1H),7.90(s,1H),7.52-7.48(m,1H),7.30(s,1H),6.85(s,1H),3.93(s,3H),3.70(s,3H),3.13-2.97(m,2H),2.85-2.69(m,7H),2.17(s,3H),2.13(s,3H),2.10-1.93(m,2H),1.84-1.76(m,4H).
19F NMR(376.5MHz,MeOD)δ：-101.05,-101.69.
31P NMR(162.0MHz,MeOD)δ：52.89.
LCMS：Rt:4.102min；MS m/z(ESI):767.2,769.2[M+H] +.
EXAMPLE 38 preparation of (6- ((5-bromo-2- ((2-methoxy-5- (1-methyl-1H-pyrrol-3-yl) -4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (Compound 36)
Figure PCTCN2020132188-APPB-000172
Referring to the synthesis method of example 11, substitution of 1-methylpyrazole-4-boronic acid pinacol ester with 1-methylpyrrole-3-boronic acid pinacol ester and substitution of (3- ((5-bromo-2-chloropyrimidin-4-yl) amino) quinolin-4-yl) dimethylphosphine oxide (1-4) with (6- ((5-bromo-2-chloropyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (4-9) gave the objective product (6- ((5-bromo-2- ((2-methoxy-5- (1-methyl-1H-pyrrol-3-yl) -4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) Phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (compound 36).
1H NMR(400MHz,CDCl 3):δ12.53(s,1H),9.00(dd,J＝9.5,4.2Hz,1H),8.71(d,J＝1.8Hz,1H),8.67(d,J＝1.8Hz,1H),8.27(s,1H),8.14(s,1H),7.54(br,1H),7.23(s,1H),7.01(s,1H),6.66(s,1H),6.31(s,1H),6.24(s,1H),3.87(s,3H),3.48(s,3H),3.30(d,J＝11.0Hz,2H),2.66-2.52(m,10H),2.32-225(m,4H),2.13(s,3H),2.09(s,3H),1.95-1.92(m,2H),1.65-1.62(m,2H).
31PNMR(162MHz,CDCl 3):δ49.08
LCMS：Rt:0.960min；MS m/z(ESI):759.5,761.5[M+H] +。
Example 39 preparation of 6- ((5-bromo-2- ((2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) -5- (thien-3-yl) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (Compound 45)
Figure PCTCN2020132188-APPB-000173
Referring to the synthesis method of example 11, substitution of 1-methylpyrazole-4-boronic acid pinacol ester with 3-thiopheneboronic acid and substitution of (3- ((5-bromo-2-chloropyrimidin-4-yl) amino) quinolin-4-yl) dimethylphosphine oxide (1-4) with (6- ((5-bromo-2-chloropyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (4-9) gave the objective product 6- ((5-bromo-2- ((2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) -5- (thiophen-3-yl) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-9 -yl) dimethylphosphine oxide (compound 45).
1H NMR(400MHz,CDCl 3)δ12.48(s,1H),8.88-8.85(m,1H),8.72-8.68(m,2H),8.27(s,1H),8.20(s,1H),7.60-7.58(m,1H),7.39(d,J＝4.8Hz,1H),7.30(s,1H),7.26(m,1H),7.03(s,1H),6.64(s,1H),3.90(s,3H),3.16-3.13(m,2H),2.71-2.51(m,10H),2.34(s,3H),2.22(s,1H),2.13(s,3H),2.09(s,3H),1.88-1.85(m,2H),1.58-1.50(m,2H).
31P NMR(162MHz,CDCl 3)δ59.38.
LCMS:Rt:2.036min；MS m/z(ESI):762.2,764.2[M+H] +。
EXAMPLE 40 preparation of (6- ((5-bromo-2- ((5- (furan-3-yl) -2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (Compound 54)
Figure PCTCN2020132188-APPB-000174
Referring to the synthesis method of example 11, 1-methylpyrazole-4-boronic acid pinacol ester was replaced with 3-furanboronic acid, and (3- ((5-bromo-2-chloropyrimidin-4-yl) amino) quinolin-4-yl) dimethylphosphine oxide (1-4) was replaced with (6- ((5-bromo-2-chloropyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (4-9) to obtain the objective product (6- ((5-bromo-2- ((5- (furan-3-yl) -2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-9) -yl) dimethylphosphine oxide (compound 54).
1H NMR(400MHz,CDCl 3)：δ12.50(s,1H),8.90-887(m,1H),8.74(d,J＝1.6Hz,1H),8.70(d,J＝2.0Hz,1H),8.28(s,1H),8.19(s,1H),7.69(s,2H),7.33(s,1H),7.03(s,1H),6.69(s,1H),6.55(s,1H),3.90(s,3H),3.20(d,J＝12Hz,2H),2.71-2.56(m,10H),2.33(s,3H),2.32-2.45(m,1H),2.14(s,3H),2.11(s,3H),1.93(d,J＝11.2Hz,2H),1.67-1.59(m,2H).
31P NMR(162.0MHz,CDCl 3)：δ49.15.
LCMS:Rt:1.090min；MS m/z(ESI):746.1,748.1[M+H] +。
EXAMPLE 41 preparation of (6- ((5-bromo-2- ((4-methoxy-6- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) - [1,1' -biphenyl ] -3-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) -dimethylphosphine oxide (Compound 105)
Figure PCTCN2020132188-APPB-000175
With reference to the synthesis method of example 11, 1-methylpyrazole-4-boronic acid pinacol ester was replaced with phenylboronic acid, and (3- ((5-bromo-2-chloropyrimidin-4-yl) amino) quinolin-4-yl) dimethylphosphine oxide (1-4) was replaced with (6- ((5-bromo-2-chloropyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (4-9), to obtain the objective product (6- ((5-bromo-2- ((4-methoxy-6- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) - [1,1' -biphenyl ] -3-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5- Yl) -dimethylphosphine oxide (compound 105).
1H NMR(400MHz,CDCl 3)δ:12.45(s,1H),8.83(d,J＝5.5Hz,1H),8.70(d,J＝16.8Hz,2H),8.26(s,1H),8.11(s,1H),7.56(s,1H),7.46(d,J＝7.2Hz,2H),7.32(s,1H),7.07–7.00(m,3H),6.64(s,1H),3.92(s,3H),3.13-3.10(m,2H),2.76–2.37(m,10H),2.30(s,3H),2.21-2.14(m,1H),2.12(s,3H),2.08(s,3H),1.77-1.74(m,2H),1.48–1.34(m,2H).
31P NMR(162.0MHz,CDCl 3)δ：49.12.
LCMS：Rt:4.157min；MS m/z(ESI):756.2,758.2[M+H] +。
EXAMPLE 42 preparation of (6- ((5-bromo-2- ((2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) -5- (pyridin-4-yl) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (Compound 106) trifluoroacetate
Figure PCTCN2020132188-APPB-000176
Referring to the synthesis method of example 11, substitution of 1-methylpyrazole-4-boronic acid pinacol ester with 4-pyridineboronic acid and substitution of (3- ((5-bromo-2-chloropyrimidin-4-yl) amino) quinolin-4-yl) dimethylphosphine oxide (1-4) with (6- ((5-bromo-2-chloropyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (4-9) gave the objective product (6- ((5-bromo-2- ((2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) -5- (pyridin-4-yl) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-9) -yl) dimethylphosphine oxide (compound 106) trifluoroacetate.
1H NMR(400MHz,MeOD)δ8.82(d,J＝2.0Hz,1H),8.76(d,J＝2.0Hz,1H),8.68(br,1H),8.25(s,1H),8.20(d,J＝4.4Hz,2H),8.06(s,1H),7.70(d,J＝5.2Hz,2H),7.53(br,1H),6.85(s,1H),3.96(s,3H),3.15-2.98(m,9H),2.76(s,3H),2.72-2.66(m,4H),2.15(s,3H),2.11(s,3H),1.89(d,J＝10.8Hz,2H),1.55-1.52(m,2H).
19F NMR(376.5MHz,MeOD):δ-76.88
31P NMR(162MHz,MeOD):δ52.74
LCMS：Rt:3.347min；MS m/z(ESI):757.1,759.1[M+H] +。
EXAMPLE 43 preparation of (6- ((5-bromo-2- ((2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -6- (4- (tetrahydro-2H-pyran-4-yl) piperazin-1-yl) pyridin-3-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (Compound 108)
Figure PCTCN2020132188-APPB-000177
Compound 108:
Figure PCTCN2020132188-APPB-000178
(6- ((5-bromo-2- ((2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -6- (piperazin-1-yl) pyridin-3-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (98-8) (100mg,0.15mmol), tetrahydropyranone (30mg,0.30mmol), glacial acetic acid (14mg,0.225mmol) were added to 1, 2-dichloroethane (8mL) respectively at room temperature. The reaction solution was heated to 50 ℃ under argon atmosphere and stirred for reaction for 3 hours, cooled to room temperature, and then added with sodium triacetoxyborohydride (64mg,0.30mmol) to react at room temperature for 1 hour. The reaction mixture was adjusted to pH ≈ 7 with aqueous sodium hydroxide solution and extracted with dichloromethane (5ml X3). The organic phase was concentrated to dryness under reduced pressure, the residue was taken up in DMF (5mL), filtered and purified by high performance liquid preparative chromatography (eluent gradient:
Figure PCTCN2020132188-APPB-000179
) Purification gave the target compound (6- ((5-bromo-2- ((2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -6- (4- (tetrahydro-2H-pyran-4-yl) piperazin-1-yl) pyridin-3-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (compound 108) (15mg, yield: 14%).
1H NMR(400MHz,MeOD)：δ8.82(d,J＝2.0Hz,1H)，8.77(d,J＝2.0Hz,2H)，8.25(s,1H),8.12(s,1H),7.73(s,1H),7.56(br,1H),7.46(s,1H),4.03-4.02(m,2H),3.99(s,3H),3.70(s,3H),3.48-3.40(m,2H),3.17-3.15(m,4H),2.73(br,4H),2.53-2.47(m,1H),2.16(s,3H),2.13(s,3H),1.91(d,J＝10.8Hz,2H),1.61-1.50(m,2H).
31P NMR(162.0MHz,MeOD)：δ52.88.
LCMS:Rt:1.076min；MS m/z(ESI):748.0，750.0[M+H] +。
EXAMPLE 44 preparation of (6- ((5-chloro-2- ((2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -6- (4- (oxetan-3-yl) piperazin-1-yl) pyridin-3-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (Compound 109) trifluoroacetate
Figure PCTCN2020132188-APPB-000180
Compound 109-2:
Figure PCTCN2020132188-APPB-000181
1- (4- (5-amino-6-methoxy-3- (1-methyl-1H-pyrazol-4-yl) pyridin-2-yl) piperazin-1-yl) -2,2, 2-trifluoroethan-1-one (98-6) (200mg, 0.52mmol), (6- ((2, 5-dichloropyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (84-2) (155mg, 0.42mmol) and trifluoroacetic acid (593mg, 5.2mmol) were added to isopropanol (10mL) respectively at room temperature, and the reaction was stirred with warming to 95 ℃ under argon protection for 16 hours. The reaction solution was directly spin-dried, and prepared by thin layer preparative chromatography (dichloromethane: methanol ═ 20:1) to give intermediate 1- (4- (5- ((5-chloro-4- ((5- (dimethylphosphide) quinoxalin-6-yl) amino) pyrimidin-2-yl) amino) -6-methoxy-3- (1-methyl-1H-pyrazol-4-yl) pyridin-2-yl) piperazin-1-yl) -2,2, 2-trifluoroethan-1-one (109-2) (350mg, yield: 94%).
LCMS:Rt:1.388min；MS m/z(ESI):716.5[M+H] +。
Compound 109-3:
Figure PCTCN2020132188-APPB-000182
1- (4- (5- ((5-chloro-4- ((5- (dimethylphosphoryl) quinoxalin-6-yl) amino) pyrimidin-2-yl) amino) -6-methoxy-3- (1-methyl-1H-pyrazol-4-yl) pyridin-2-yl) piperazin-1-yl) -2,2, 2-trifluoroethan-1-one (109-2) (350mg, 0.488mmol), potassium hydroxide (273mg, 4.88mmol) were added to methanol (25mL) and water (2mL), respectively, and the reaction was stirred at 60 ℃ for 5H at room temperature. The reaction solution was directly spin-dried, and intermediate (6- ((5-chloro-2- ((2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -6- (piperazin-1-yl) pyridin-3-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (109-3) (150mg, yield: 50%) was prepared by thin layer preparative chromatography (dichloromethane: methanol ═ 20: 1).
LCMS:Rt:0.903min；MS m/z(ESI):620.6[M+H] +。
The trifluoroacetate salt of compound 109:
Figure PCTCN2020132188-APPB-000183
(6- ((5-chloro-2- ((2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -6- (piperazin-1-yl) pyridin-3-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (109-3) (150mg,0.242mmol), 3-oxetanone (35mg,0.484mmol), acetic acid (30mg,0.484mmol) were added to 1, 2-dichloromethane (15mL) respectively at room temperature. The reaction solution was heated to 50 ℃ under argon atmosphere and stirred for reaction for 5 hours. The temperature was reduced to room temperature, sodium triacetoxyborohydride (103mg,0.484mmol) was added, and the reaction was carried out at room temperature for 1 hour. The reaction mixture was adjusted to pH ≈ 7 with an aqueous sodium hydroxide solution, extracted with dichloromethane, the organic phase was spin-dried, the residue was taken into DMF (5mL), and after filtration, purification was performed by high performance liquid preparative chromatography (eluent gradient: reference example 1) to obtain the objective title compound (6- ((5-chloro-2- ((2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -6- (4- (oxetan-3-yl) piperazin-1-yl) pyridin-3-yl) amino) pyrimidin-4-yl) quinoxalin-5-yl) dimethylphosphine oxide (compound 109) trifluoroacetate (10mg, yield: 6.1%).
1H NMR(400MHz,MeOD)：δ8.89-8.88(m,1H)，8.86(d,J＝2.0Hz,1H)，8.81(d,J＝2.0Hz,1H),8.21(s,1H),8.18(s,1H),7.84(s,1H),7.62-7.60(m,1H),7.54(s,1H),4.95-4.82(m,4H),4.56-4.49(m,1H),4.02(s,3H),3.77(s,3H),3.48-3.13(m,8H),2.17(s,3H),2.13(s,3H).
19F NMR(376.5MHz,CD 3OD):δ-77.23.
31P NMR(162.0MHz,MeOD)：δ53.45.
LCMS:Rt:1.007min；MS m/z(ESI):676.0[M+H] +。
EXAMPLE 45 preparation of (6- ((5-bromo-2- ((2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -6- (4- (1-methylazetidin-3-yl) piperazin-1-yl) pyridin-3-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (Compound 110)
Figure PCTCN2020132188-APPB-000184
Compound 110-2:
Figure PCTCN2020132188-APPB-000185
(6- ((5-bromo-2- ((2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -6- (piperazin-1-yl) pyridin-3-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (98-8) (100mg,0.15mmol), tert-butyl 3-oxoazetidine-1-carboxylate (51mg, 0.30mmol), glacial acetic acid (14mg,0.225mmol) were added to 1, 2-dichloroethane (10mL) respectively at room temperature, and the reaction was stirred at 50 ℃ for 2 hours. The temperature is reduced to room temperature, sodium triacetoxyborohydride (64mg,0.30mmol) is added, and the reaction is stirred at room temperature for 14 h. The pH was adjusted to approximately 7 with saturated sodium carbonate solution, extraction was performed with dichloromethane (20mL X3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and prepared by thin layer preparative chromatography (dichloromethane: methanol ═ 20:1) to give intermediate t-butyl 3- (4- (5- ((5-bromo-4- ((5- (dimethylphosphoryl) quinoxalin-6-yl) amino) pyrimidin-2-yl) amino) -6-methoxy-3- (1-methyl-1H-pyrazol-4-yl) pyridin-2-yl) piperazin-1-yl) azetidine-1-carboxylate (110-2) (100mg, yield: 81%).
LCMS:Rt:1.222min；MS m/z(ESI):819.7,821.7[M+H] +。
Compound 110-3:
Figure PCTCN2020132188-APPB-000186
tert-butyl 3- (4- (5- ((5-bromo-4- ((5- (dimethylphosphoryl) quinoxalin-6-yl) amino) pyrimidin-2-yl) amino) -6-methoxy-3- (1-methyl-1H-pyrazol-4-yl) pyridin-2-yl) piperazin-1-yl) azetidine-1-carboxylate (110-2) (100mg, 0.121mmol) was added to a solution of dioxane (1M,1.2mL, 1.22mmol) hydrochloride at room temperature and the reaction was stirred at room temperature for 1H. The reaction solution was vacuum-dried, DCM (10mL) was added and vacuum-dried again to obtain a crude product of intermediate (6- ((2- ((6- (4- (azetidin-3-yl) piperazin-1-yl) -2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) amino) -5-bromopyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (110-3) (100mg, yield: 100%) which was used directly in the next reaction.
LCMS:Rt:1.050min；MS m/z(ESI):719.1,721.1[M+H] +。
Compound 110:
Figure PCTCN2020132188-APPB-000187
(6- ((2- ((6- (4- (azetidin-3-yl) piperazin-1-yl) -2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) amino) -5-bromopyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (110-3) (80mg,0.111mmol), aqueous formaldehyde (1M,1.2mL,1.11mmol), triethylamine (111mg,0.111mmol) were added to methanol (3mL) respectively at room temperature. After stirring at room temperature for 5 hours, sodium triacetoxyborohydride (118mg,0.555mmol) was added and reacted at room temperature for 11 hours. The reaction mixture was adjusted to pH ≈ 7 with aqueous sodium hydroxide, extracted with dichloromethane (20mL X3), the organic phase was spin-dried, the residue was added to DMF (5mL), after filtration, the filtrate was purified by high performance liquid preparative chromatography (eluent gradient: reference example 43) to give the objective compound (6- ((5-bromo-2- ((2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -6- (4- (1-methylazetidin-3-yl) piperazin-1-yl) pyridin-3-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (compound 110) (4mg, yield: 4.9%).
1H NMR(400MHz,MeOD)：δ8.82(d,J＝1.6Hz,1H)，8.77(d,J＝2.0Hz,2H)，8.26(s,1H),8.12(s,1H),7.75(s,1H),7.56(br,1H),7.42(s,1H),3.99(s,3H),3.71(s,3H),3.60(t,J＝5.4Hz,2H),3.14(br,4H),3.11-3.01(m,3H),3.46(br,4H),2.39(s,3H),2.16(s,3H),2.13(s,3H).
31P NMR(162.0MHz,MeOD)：δ52.880.
LCMS:Rt:1.115min；MS m/z(ESI):733.4,735.4[M+H] +。
EXAMPLE 46 preparation of (6- ((5-bromo-2- ((6- (2- (dimethylamino) -7-azaspiro [3.5] nonan-7-yl) -2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (Compound 111) trifluoroacetate
Figure PCTCN2020132188-APPB-000188
Compound 111-2:
Figure PCTCN2020132188-APPB-000189
tert-butyl 2-oxo-7-azaspiro [3.5] nonane-7-carboxylate (200mg,0.837mmol), dimethylamine (0.5mL,1.0mmol, 2M in THF) were dissolved in methanol (5mL) at room temperature, glacial acetic acid (75mg,1.255mmol) was added and the reaction was allowed to react at room temperature for 2 hours, sodium triacetoxyborohydride (354mg,1.67mmol,2.0eq) was slowly added and after the addition the reaction was stirred at room temperature for 16 hours. TLC (ethyl acetate/petroleum ether ═ 1/2) showed the reaction was complete, the reaction was poured into saturated aqueous sodium bicarbonate (50mL), extracted with dichloromethane (100mL X3), washed with saturated aqueous sodium chloride (50mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated after filtration to give the desired product tert-butyl 2- (dimethylamino) -7-azaspiro [3.5] nonane-7-carboxylate (111-2) (200mg, crude) which was used directly in the next step.
LCMS:Rt＝0.920min；MS m/z(ESI):269.2[M+H] +。
Compound 111-3:
Figure PCTCN2020132188-APPB-000190
tert-butyl 2- (dimethylamino) -7-azaspiro [3.5] nonane-7-carboxylate (111-2) (200mg,0.746mmol) was dissolved in anhydrous dichloromethane (4mL) at room temperature, trifluoroacetic acid (0.5mL, 4.386mmol) was added, and the reaction was carried out at room temperature for 2 hours. The reaction was completed by LCMS detection, and the reaction mixture was concentrated to give the desired product N, N-dimethyl-7-azaspiro [3.5] nonan-2-amine (111-3) (0.60g crude) which was used directly in the next step.
LCMS:Rt＝0.310min；MS m/z(ESI):169.2[M+H] +。
Compound 111-4:
Figure PCTCN2020132188-APPB-000191
crude N, N-dimethyl-7-azaspiro [3.5] nonan-2-amine (111-3) (0.60g,3.55mmol), 2, 3-dichloro-6-methoxy-5-nitropyridine (165mg,0.744mmol) was dissolved in N, N-dimethylformamide (6mL) at room temperature, and potassium carbonate (308mg, 2.232mmol), diisopropylethylamine (192mg, 1.488mmol) were added. The reaction was stirred at 50 ℃ for 16 h and LCMS checked for completion. The reaction solution was filtered and concentrated, and the obtained residue was purified by silica gel plate chromatography (eluent gradient: dichloromethane: methanol 10:1) to give the objective product 7- (3-chloro-6-methoxy-5-nitropyridin-2-yl) -N, N-dimethyl-7-azaspiro [3.5] nonan-2-amine (111-4) (220mg, yield: 83.7%).
LCMS:Rt＝1.107min；MS m/z(ESI):355.1[M+H] +。
Remaining procedures referring to the synthesis method of example 13, 1- (1- (3-chloro-6-methoxy-5-nitropyridin-2-yl) piperidin-4-yl) -4-methylpiperazine (13-2) was replaced with 7- (3-chloro-6-methoxy-5-nitropyridin-2-yl) -N, N-dimethyl-7-azaspiro [3.5] nonan-2-amine (111-4) to give the objective product (6- ((5-bromo-2- ((6- (2- (dimethylamino) -7-azaspiro [3.5] nonan-7-yl) -2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) pyridin-2-yl) -3-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (compound 111) trifluoroacetate.
1H NMR(400MHz,MeOD)δ8.84(d,J＝1.9Hz,1H),8.80(d,J＝1.9Hz,1H),8.74(brs,1H),8.27(s,1H),7.99(s,1H),7.76(s,1H),7.63(brs,1H),7.50(s,1H),3.98(s,3H),3.74-3.67(m,4H),3.13-3.08(m,2H),3.07-3.01(m,2H),2.81(s,6H),2.44-2.38(m,2H),2.16(s,3H),2.13(s,3H),1.98-1.96(m,2H),1.80-1.67(m,4H).
31P NMR(376.5MHz,MeOD)δ53.02.
19F NMR(162MHz,MeOD)δ-77.10.
LCMS：Rt:4.377min；MS m/z(ESI):746.1,748.1[M+H] +。
With reference to the synthetic methods of the above examples, the present invention also synthesizes the following compounds, whose characterization data are:
Figure PCTCN2020132188-APPB-000192
Figure PCTCN2020132188-APPB-000193
Figure PCTCN2020132188-APPB-000194
Figure PCTCN2020132188-APPB-000195
Figure PCTCN2020132188-APPB-000196
Figure PCTCN2020132188-APPB-000197
Figure PCTCN2020132188-APPB-000198
Figure PCTCN2020132188-APPB-000199
examples of biological Activity and related Properties
The compounds of the following test examples, which were prepared according to the methods of the examples described above in this application, were either the free base or the trifluoroacetate salt form, and were determined according to the specific form of the product prepared in the examples above.
In the following test examples, "NA" means no test.
Test example 1: enzymology EGFR inhibition experiment
Experimental materials:
HTRF KinEASE-TKkit was purchased from CisBio (France).
The 384-well assay plate was purchased from greiner bio-one (Germany).
384-well source plate was purchased from LABCYTE (USA).
MgCl 2，MnCl 2DTT, TritonX-100, HEPES, BSA were purchased from Sigma (USA).
EGFR WT-WT, EGFR WT-del19/T790M/C797S, EGFR WT-L858R/T790M/C797S, EGFR WT-del19/T790M, EGFR WT-L858R/T790M refer to Nature.2016; 534(7605) 129-132 and purifying.
An experimental instrument:
automatic micropore pipettor: precision PRC384U (BioTek, USA)
Nano-liter acoustic wave shift system:
Figure PCTCN2020132188-APPB-000200
HANDLE RS(LABCYTE，USA)
multi-label detection analyzer: envision Multilabel Reader (PerkinElmer, USA)
The experimental method comprises the following steps:
1. a kinase buffer solution (1 Xenzyme buffer,1mM MnCl2,1mM MgCl2, 1mM DTT, 0.01% BSA) was prepared.
2. Preparation of the compound. The final concentration of the compound tested was 10. mu.M, and was formulated in 100-fold concentration, 1mM, using DMSO. Test compounds were diluted in 4-fold gradients using an automated micropore pipette (Precision PRC384U) to obtain 10 dose concentrations from 1mM to 3.8nM, and test compounds were transferred to 384-well plates at 100nL of compound per well.
3. And (3) kinase reaction. 2 Xenzyme reaction solution (WT-WT: 3nM, WT-d 19/TM/CS: 1nM, WT-LR/TM/CS: 0.1nM, WT-LR/TM: 0.5nM, WT-d 19/TM: 1nM) was prepared using kinase buffer and 5. mu.l of the enzyme reaction solution was transferred to 384-well reaction wells, and 5. mu.l of kinase buffer was added to the negative control wells. The mixture was shaken at 450rpm and incubated at room temperature for 10 minutes. A2 Xsubstrate/ATP solution (ATP concentration: WT-WT: 4.8. mu.M, WT-d 19/TM/CS: 4. mu.M, WT-LR/TM/CS: 0.24. mu.M, WT-LR/TM: 0.86. mu.M, WT-d 19/TM: 3.8. mu.M) was prepared using a kinase buffer, 5. mu.l of the substrate/ATP solution was transferred to a 384-well reaction well to initiate the reaction, the reaction was shaken at 450rpm and mixed, and incubated at room temperature for 60 minutes.
4. The reaction was terminated. Mu.l of a reaction stop solution (Streptavidin-XL665, TK Antibody-Cryptate) was added to the 384-well reaction plate, centrifuged at 1000rpm for 1 minute, and left at room temperature for 60 minutes, and the plate was read by Envision.
5. And (6) fitting a curve. Data from the Envision program were reproduced for luminescence readings and the ratio of 665nM/615nM was converted to percent inhibition by the formula: (max-signal ratio)/(max-min) × 100. "min" is the ratio of fluorescence readings of a control sample reacted without enzyme; "max" is the ratio of fluorescence readings for samples with DMSO added as a control. Data were imported into MS Excel and curve-fitted using XLFit Excel add-in version 5.4.0.8: y ═ Bottom + (Top-Bottom)/(1+ (IC50/X) ^ HillSlope).
Inhibition of enzymatic Activity of Compounds of the invention IC50As shown below (del19 is abbreviated as d19, T790M is abbreviated as TM, L858R is abbreviated as LR, and C797S is abbreviated as CS).
Figure PCTCN2020132188-APPB-000201
Test example 2: anti-proliferation assay for BaF3 cells
Experimental materials:
RPMI1640 was purchased from Gibco (USA).
FBS is available from excell (China).
IL-3Recombinant Mouse Protein was purchased from Gibco (USA).
Cell
Figure PCTCN2020132188-APPB-000202
The Luminescent Cell Viability kit was purchased from Promega (USA).
BaF3 cells were purchased from Riken (Japan).
BaF3/EGFR-WT, BaF3/EGFR-Del19/T790M/C797S cells were constructed by the Mediterranean crown Biotechnology (Taicang) Inc.
BaF3 medium: RPMI1640+ 10% FBS +8ng/ml IL-3Recombinant Mouse Protein.
BaF3/EGFR-WT, BaF3/EGFR-Del19/T790M/C797S culture medium: RPMI1640+ 10% FBS.
Plate reading instrument: EnVision (Perkinelmer, USA).
The experimental method comprises the following steps:
adjusting the cell concentration, preparing 2000 BaF3, BaF3/EGFR-WT or BaF3/EGFR-Del19/T790M/C797S cells in 90 μ l volume in each well of a 96-well plate, preparing 1000X test compound mother liquor by DMSO, diluting the test compound by 3-fold gradient (total 9 concentrations) by DMSO, diluting by 100-fold with corresponding cell culture medium, adding 10 μ l (10X concentration) of test compound (three duplicate wells per compound concentration), 5% CO in each well2And cultured at 37 ℃ for 72 hours. After 72 hours, 50. mu.l Cell Titer-Glo was added to each well, mixed well on a plate shaker for 2min, and after incubation for 10min, read with EnVision.
And (3) data analysis:
cell viability was plotted using GraphPad Prism version 5, and the IC50 data was calculated by fitting a curve to a nonlinear regression model with a labeled dose response. The test results are shown in the following table.
Figure PCTCN2020132188-APPB-000203
Figure PCTCN2020132188-APPB-000204
Test example 3: PC9EGFR-Del19/T790M/C797S and HEK293T cell proliferation experiments
Experimental materials:
RPMI1640 was purchased from Gibco (USA).
DMEM is purchased from Gibco (USA).
FBS is available from Gibco (USA).
Puromycin is purchased from invitrogen (usa).
Pancreatin was purchased from Invitrogen (USA).
DMSO was purchased from Sigma (USA).
Cell Counting Kit-8(CCK-8) Cell proliferation toxicity test Kit was purchased from Dong ren chemical technology (Shanghai) Co., Ltd.
PC9EGFR-Del19/T790M/C797S cells were constructed by Mediterranean Biotechnology (Taicang) Inc.
HEK293T cells were purchased from atcc (usa).
PC9EGFR-Del19/T790M/C797S medium: RPMI1640+ 10% FBS +0.5ug/mL puromycin.
HEK293T medium: DMEM + 10% FBS.
Plate reading instrument: EnVision (Perkinelmer, USA).
The experimental method comprises the following steps:
the cells are cultured for 2-3 days until the confluency reaches 80-90%. Cells were digested with pancreatin, resuspended by centrifugation, counted, and cell concentrations adjusted to 1000 per well (HEK293T) and 3000 per well (PC9EGFR-Del19/T790M/C797S), 90. mu.l volume, 5% CO2Incubated at 37 ℃ overnight. Preparing 200 Xtest compound mother liquor by DMSO, diluting test compound by 3 times gradient (total 8 concentrations) by DMSO, diluting by 20 times by serum-free medium, adding 10 μ l (10 Xconcentration) test compound (each compound has two wells per concentration), and adding 5% CO2And cultured at 37 ℃ for 72 hours. After 72 hours, 10. mu.l of CCK-8 was added to each well, centrifuged, mixed, incubated at 37 ℃ for 1-4 hours, mixed on a plate shaker for 2min, incubated for 10min, and read the OD450 with EnVision.
And (3) data analysis:
the inhibition rate was calculated according to the following formula:
Inhibition％＝(OD cell control–OD sample)/(OD cell control–OD media control)*100
IC50 data were calculated using IDBS Xlfit Model 205 with a 4-parameter fit
The test results are shown in the following table:
Figure PCTCN2020132188-APPB-000205
Figure PCTCN2020132188-APPB-000206
Figure PCTCN2020132188-APPB-000207
test example 4: mouse pharmacokinetic experiment
Experimental materials:
CD-1 mice were purchased from Schbefu (Beijing) Biotechnology, Inc.
DMSO, MC (methyl cellulose), Tween80 were purchased from Sigma (USA).
Acetonitrile was purchased from Merck (USA).
HP-beta-CD was purchased from Nippon food and chemical Co.
The experimental method comprises the following steps:
female CD-1 mice were 6 (20-30g, 4-6 weeks, three per group) and randomized into 2 groups of 3 mice each. Group 1 was given compound 82 by tail vein injection at a dose of 1mg/kg, vehicle 5% DMSO in 10% HP- β -CD in water, group 2 was given compound 82 orally at a dose of 5mg/kg, vehicle 0.5% MC/0.25% Tween80in water. Feeding water before animal experiment. Mice in each group were bled intravenously before and 0.083 (i.v. only), 0.25, 0.5, 1,2, 4, 6, 8 and 24h post-dose. The collected whole blood sample is placed in a K2EDTA anticoagulation tube, and after centrifugation for 5min (4000rpm, 4 ℃), plasma is taken for testing.
Taking 30 mu L of mouse plasma sample, supplementing 3 mu L of blank solvent, adding 200 mu L of acetonitrile solvent (containing an internal standard compound) to precipitate protein, vortexing for 0.5min, centrifuging (4700rpm, 4 ℃) for 15min, diluting the supernatant by 3 times with water, and injecting 10 mu L of the diluted supernatant into an LC-MS/MS system (AB Sciex Triple Quad 5500) for quantitative detection. The CD-1 mouse plasma standard curve (linear range: 0.5-1000ng/mL) and quality control samples were followed in determining the sample concentration. For 10 Xdilution samples, take 3 uL sample and add 27 uL blank plasma; samples were diluted 3X, 10. mu.L of sample was added to 20. mu.L of blank plasma, and the remaining processing steps varied to dilute the samples.
The PK test results are shown below:
Figure PCTCN2020132188-APPB-000208
Figure PCTCN2020132188-APPB-000209

Claims (36)

  1. a compound of formula (I) or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2020132188-APPB-100001
    wherein the content of the first and second substances,
    R 1selected from phenyl and 5-6 membered heteroaryl, optionally substituted with R7Substitution;
    or R1Is composed of
    Figure PCTCN2020132188-APPB-100002
    Wherein R is11、R 12Independently selected from C1-4Alkyl radical, said C1-4Alkyl optionally substituted by hydroxy or C1-4Alkoxy substitution;
    R 2is selected from C1-6Alkyl radical, C4-14Cycloalkyl, 4-14 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl, said C1-6Alkyl radical, C4-14Cycloalkyl, 4-14 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl optionally substituted with R8Substitution;
    u, V, W is independently selected from CR6And N;
    ring A is selected from phenyl and 5-6 membered heteroaryl;
    R 3selected from H, halogen, cyano, C1-4Alkyl and C1-4An alkoxy group;
    R 4、R 5independently selected from C1-4Alkyl and C1-4An alkoxy group;
    R 6independently selected from H, C1-4Alkyl radical, C1-4Alkoxy and halogen;
    R 7independently selected from halogen, hydroxy, amino, C1-4Alkyl and C1-4Alkoxy radical, said C1-4Alkyl and C1-4Alkoxy optionally substituted with hydroxy;
    R 8independently selected from halogen, OH, C1-6Alkyl radical, C1-6Alkoxy, oxo, amino, C3-8Cycloalkyl and 3-8 membered heterocycloalkyl, said amino, C3-8Cycloalkyl and 3-8 membered heterocycloalkyl optionally substituted with R9Substitution;
    R 9independently selected from halogen, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Acyl and oxo.
  2. A compound of formula (I) as claimed in claim 1 wherein R1Selected from 5-6 membered heteroaryl, said 5-6 membered heteroaryl optionally substituted with R7And (4) substitution.
  3. A compound of formula (I) as claimed in claim 2 wherein R1Selected from 5-membered heteroaryl, said 5-membered heteroaryl being optionally substituted by R7And (4) substitution.
  4. A compound of formula (I) according to claim 3, wherein R1Selected from phenyl, pyridyl, pyrrolyl, furyl, thiophenylPhenyl, pyridyl, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, tetrazolyl and triazolyl optionally substituted with R7And (4) substitution.
  5. A compound of formula (I) as claimed in claim 4 wherein R1Selected from phenyl, pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl and triazolyl, said phenyl, pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl and triazolyl being optionally substituted by R7And (4) substitution.
  6. A compound of formula (I) as claimed in any one of claims 1 to 5 wherein R7Independently selected from halogen, hydroxy and C1-4Alkyl radical, said C1-4Alkyl is optionally substituted with hydroxy.
  7. A compound of formula (I) according to claim 6, wherein R7Independently selected from C1-4Alkyl radical, said C1-4Alkyl is optionally substituted with hydroxy.
  8. A compound of formula (I) according to claim 7, wherein R7Independently selected from methyl and hydroxyethyl.
  9. A compound of formula (I) as claimed in claim 1 wherein R1Selected from phenyl,
    Figure PCTCN2020132188-APPB-100003
    Figure PCTCN2020132188-APPB-100004
  10. A compound of formula (I) as claimed in claim 1Wherein R is1Is composed of
    Figure PCTCN2020132188-APPB-100005
    Wherein R is11Is selected from C1-4Alkyl, R12Selected from C optionally substituted by hydroxy1-4An alkyl group.
  11. A compound of formula (I) according to claim 10, wherein R11Is methyl, R12Is methyl or hydroxyethyl.
  12. A compound of formula (I) as claimed in any one of claims 1 to 11 wherein R2Is selected from C5-12Cycloalkyl and 5-12 membered heterocycloalkyl, said C5-12Cycloalkyl and 5-12 membered heterocycloalkyl optionally substituted with R8And (4) substitution.
  13. A compound of formula (I) according to claim 12, wherein R2Is a 5-12 membered heterocycloalkyl group, said 5-12 membered heterocycloalkyl group being optionally substituted with R8And (4) substitution.
  14. A compound of formula (I) according to claim 13, wherein R2Selected from the group consisting of piperidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, 1, 4-thioxanyl, 1, 4-dioxanyl, thiomorpholinyl, 1, 3-dithianyl, 1, 4-dithianyl, azepanyl, oxepanyl, thiepanyl, 3, 9-diazaspiro [5.5]Undecyl, 2, 9-diazaspiro [5.5 ]]An undecyl group,
    Figure PCTCN2020132188-APPB-100006
    The piperidyl, tetrahydropyranyl, morpholinyl, piperazinyl, 1, 4-thioxanyl, 1, 4-dioxanyl, thiomorpholinyl, 1, 3-dithianyl, 1, 4-dithianyl, azepanyl, oxepanyl, thiepanyl, 3, 9-dithranyl-diazaspiro [5.5]Undecyl, 2, 9-diazaspiro [5.5 ]]Undecyl group,
    Figure PCTCN2020132188-APPB-100007
    Figure PCTCN2020132188-APPB-100008
    Optionally substituted with R8And (4) substitution.
  15. A compound of formula (I) according to claim 14, wherein R2Selected from piperidinyl, piperazinyl, morpholinyl, 3, 9-diazaspiro [5.5]Undecyl group,
    Figure PCTCN2020132188-APPB-100009
    The piperidyl, the piperazinyl, the morpholinyl, the 3, 9-diazaspiro [5.5]Undecyl group,
    Figure PCTCN2020132188-APPB-100010
    Optionally substituted with R8And (4) substitution.
  16. A compound of formula (I) as claimed in any one of claims 1 to 15 wherein R8Independently selected from halogen, OH, C1-4Alkyl, amino, C3-7Cycloalkyl and 3-7 membered heterocycloalkyl, said amino, C3-7Cycloalkyl and 3-7 membered heterocycloalkyl optionally substituted with R9And (4) substitution.
  17. A compound of formula (I) according to claim 16, wherein R8Independently selected from F, OH, methyl, amino, piperazinyl, 1, 3-oxazinyl, 1, 4-diazepanyl, 1, 3-oxazepanyl, 1, 4-oxazepanyl, oxetanyl, morpholinyl, pyrrolidinyl, tetrahydropyranyl, azetidinyl, said amino, piperazinyl, 1, 3-oxazinyl, and said amino-oxazinalkyl, 1, 4-diazepanyl, 1, 3-oxazepanyl, 1, 4-oxazepanyl, oxetanyl, morpholinyl, pyrrolidinyl, tetrahydropyranyl, azetidinyl optionally substituted with R9And (4) substitution.
  18. A compound of formula (I) as claimed in any one of claims 1 to 17 wherein R9Independently selected from halogen, C1-4Alkyl radical, C1-4Acyl radical, C1-4Alkoxy and oxo.
  19. A compound of formula (I) according to claim 18, wherein R9Independently selected from F, methyl, acetyl and oxo.
  20. A compound of formula (I) as claimed in any one of claims 1 to 19 wherein R2Is selected from
    Figure PCTCN2020132188-APPB-100011
    Figure PCTCN2020132188-APPB-100012
  21. A compound of formula (I) as claimed in any one of claims 1 to 20 wherein U is CR6。
  22. A compound of formula (I) according to claim 21, wherein R6Independently selected from C1-4An alkoxy group.
  23. A compound of formula (I) according to claim 22, wherein R6Is methoxy.
  24. A compound of formula (I) as claimed in any one of claims 1 to 23 wherein V is selected from CH and N.
  25. A compound of formula (I) as claimed in any one of claims 1 to 24 wherein W is selected from CH and N.
  26. A compound of formula (I) as claimed in any one of claims 1-25 wherein ring a is selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrazinyl and pyridazinyl.
  27. A compound of formula (I) as claimed in claim 26 wherein ring a is selected from phenyl and pyrazinyl.
  28. The compound of formula (I) according to any one of claims 1 to 27, wherein,
    Figure PCTCN2020132188-APPB-100013
    is selected from
    Figure PCTCN2020132188-APPB-100014
  29. The compound of formula (I) according to claim 28, wherein,
    Figure PCTCN2020132188-APPB-100015
    is selected from
    Figure PCTCN2020132188-APPB-100016
  30. A compound of formula (I) as claimed in any one of claims 1 to 29 wherein R3Selected from halogen and C1-4An alkyl group.
  31. A compound of formula (I) according to claim 30, wherein R3Selected from Cl and Br.
  32. A compound of formula (I) as claimed in any one of claims 1 to 31 wherein R4、R 5Independently selected from C1-3An alkyl group.
  33. A compound of formula (I) according to claim 32, wherein R4、R 5Is methyl.
  34. A compound of formula (I) according to claim 1, selected from the following compounds:
    Figure PCTCN2020132188-APPB-100017
    Figure PCTCN2020132188-APPB-100018
    Figure PCTCN2020132188-APPB-100019
    Figure PCTCN2020132188-APPB-100020
    Figure PCTCN2020132188-APPB-100021
    Figure PCTCN2020132188-APPB-100022
  35. a pharmaceutical composition comprising a compound of formula (I) as described in any one of claims 1-34 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant.
  36. Use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-34, or a pharmaceutical composition as claimed in claim 35, in the manufacture of a medicament for the prevention or treatment of an EGFR-mediated disease.
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