CN108264511B - Heterocyclic derivative, preparation method thereof and application thereof in medicine - Google Patents

Heterocyclic derivative, preparation method thereof and application thereof in medicine Download PDF

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CN108264511B
CN108264511B CN201710003456.7A CN201710003456A CN108264511B CN 108264511 B CN108264511 B CN 108264511B CN 201710003456 A CN201710003456 A CN 201710003456A CN 108264511 B CN108264511 B CN 108264511B
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naphthyridin
dimethoxyphenyl
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CN108264511A (en
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陈磊
关东亮
白骅
凌龙
赵松锋
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Zhejiang Hisun Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention relates to a novel heterocyclic derivative, a preparation method thereof, a pharmaceutical composition containing the derivative and application of the derivative as a therapeutic agent, in particular as an FGFR4 inhibitor. The preferred compounds of the invention have a better inhibitory effect on FGFR 4.

Description

Heterocyclic derivative, preparation method thereof and application thereof in medicine
Technical Field
The invention relates to a novel heterocyclic derivative, a preparation method thereof, a pharmaceutical composition containing the derivative and application of the derivative as a therapeutic agent, in particular as an FGFR4 inhibitor.
Background
The Fibroblast Growth Factor Receptor (FGFR) family is composed of four members (FGFR1, FGFR2, FGFR3 and FGFR4), which belong to the kinase family of receptor tyrosine kinases, with FGF binding leading to FGFR dimerization followed by receptor autophosphorylation and activation of downstream signaling pathways. Receptor activation is sufficient to restore and activate specific downstream signaling partners involved in the regulation of diverse processes such as cell growth, cell metabolism, and cell survival. Thus, FGF/FGFR signaling pathways have a multi-effect role in many biological processes critical for tumor cell proliferation, migration, infiltration, angiogenesis, and cell. The four members of the FGFR family differ from each other in their ligand affinity and tissue distribution. The genomic structure of the FGFR-4 gene contains 18 exons.
The human FGF19 gene is positioned at 11q13.1, FGFR4 specifically binds to a ligand FGF19 thereof to inhibit apoptosis and NF-kB signals, and up-regulates the expression of genes related to cell proliferation; activation of FGFR4 can lead to a decrease in Ikk β activity in TNF- α treated cells, with a concomitant decrease in NF-kB distribution in the cells and attenuation of apoptotic effects. Four FGFR genes are expressed in human liver, but only FGFR4 is abundantly expressed by mature hepatic parenchymal cells (hepatpytes). The FGFR4 can also have a regulation effect on the metabolism of bile acid by combining with a ligand thereof, the balance of the conversion of cholesterol into bile acid in an organism has a close relationship with various normal physiological functions of the organism, and the disruption of the balance can cause various diseases of the organism such as cardiovascular and cerebrovascular diseases such as fatty liver and arteriosclerosis and the like, so that the interaction of the FGFR4 and the FGF19 becomes a new target of cholesterol-lowering drugs such as hyperlipidemia and the like.
In recent years, there is increasing evidence for gene amplification mutations in FGFR1, FGFR2, FGFR3 and FGFR4 in various types of cancer. There is a large body of evidence that: FGFR1 has gene mutations in breast cancer, non-small cell lung cancer and glioblastoma, fusion protein formation by gene transposition in acute myelogenous leukemia, and overexpression in pancreatic cancer, bladder cancer, prostate cancer, esophageal cancer; FGFR2 has gene mutation and amplification phenomena in gastric cancer, breast cancer and uterine cancer, and has overexpression in prostatic cancer, esophageal cancer, ovarian cancer, pancreatic cancer, brain tumor and carcinoma of large intestine; FGFR3 has gene mutations in multiple myeloma and bladder cancer, and is overexpressed in ovarian cancer, non-small cell lung cancer, and hepatocellular carcinoma; FGFR4 has mutations and overexpression in lung cancer, ovarian cancer, prostate cancer, liver cancer, bile duct cancer and the like, and also has overexpression in thyroid cancer, ovarian cancer and the like (French et al 2012PLos ONE 7 (5): e 367313; Sia et al 2013Gastroejterology 144: 829-.
A series of FGFR inhibitor patents have been published, but there are few patents on selective inhibition of FGFR4, and an FGFR4 selective inhibitor has the advantage of low toxicity compared to an FGFR inhibitor (Brown, AP et al (2005), toxolol, pathol, 449-455), but at present, research and development of a novel FGFR4 inhibitor are still necessary because the FGFR4 inhibitor is far from sufficient for anti-tumor studies such as liver cancer.
Disclosure of Invention
One of the purposes of the invention is to disclose a novel heterocyclic derivative and a pharmaceutically acceptable salt thereof.
The invention provides a compound shown as a general formula (I) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof:
Figure BDA0001201979480000021
wherein:
Figure BDA0001201979480000022
is a single bond or a double bond; preferably a single bond;
x is selected from N or CH; preferably CH;
ring a is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;
each R1Each independently selected from the group consisting of hydrogen, alkyl, halogen, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) R9、-C(O)OR9、-NR10R11、-C(O)NR10R11or-NR10C(O)R11Wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more groups selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) R9、-C(O)OR9、-NR10R11、-C(O)NR10R11or-NR10C(O)R11Substituted with the substituent(s);
R2in ortho position to the-NH-of ring A, selected from the following groups:
-NR6C(O)CR7＝CHR8or-NR6C(O)C≡CR7；
Each R3Each independently selected from the group consisting of hydrogen, halogen, alkoxy, hydroxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) R9、-C(O)OR9、-NR10R11、-C(O)NR10R11or-NR10C(O)R11Wherein said alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from hydroxy, halogen, nitroRadical, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, haloalkoxy, -C (O) R9、-C(O)OR9、-NR10R11、-C(O)NR10R11or-NR10C(O)R11Substituted with the substituent(s);
(i)R4selected from alkyl, wherein said alkyl is further-NRARBSubstituted;
RAand RBEach independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally further substituted with one or more groups selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) R12、-C(O)OR12、-NR13R14、-C(O)NR13R14or-NR13C(O)R14Substituted with the substituent(s); or
(ii)R4Is selected from-CRCRD-(CH2)s-ORE；
RCAnd RDTo the connection RCAnd RDThe C atoms are cyclized together to form 3-6 membered cycloalkyl;
REselected from alkyl groups;
each R5Each independently selected from the group consisting of hydrogen, halogen, alkoxy, oxo, hydroxy, cyano, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more groups selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) R9、-C(O)OR9、-NR10R11、-C(O)NR10R11or-NR10C(O)R11Substituted with the substituent(s); preferably an oxo group;
each R6Each independently selected from a hydrogen atom or an alkyl group, wherein said alkyl group is optionally further substituted with one or more groups selected from hydroxylAlkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, haloalkoxy, -C (O) R9、-C(O)OR9、-NR10R11、-C(O)NR10R11or-NR10C(O)R11Substituted with the substituent(s);
R7and R8Each independently selected from hydrogen, alkyl or halogen, wherein said alkyl is optionally further substituted with one or more groups selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, haloalkoxy, -C (O) R9、-C(O)OR9、-NR10R11、-C(O)NR10R11or-NR10C(O)R11Substituted with the substituent(s);
R9、R10and R11Each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally further substituted with one or more groups selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) R12、-C(O)OR12、-NR13R14、-C(O)NR13R14or-NR13C(O)R14Substituted with the substituent(s);
or, R10And R11Together with the N atom to which they are attached form a 4-to 8-membered heterocyclic group containing one or more N, O, S (O) atoms in the 4-to 8-membered heterocyclic groupqAnd 4-to 8-membered heterocycle is further substituted with one or more substituents selected from the group consisting of hydroxy, halo, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═ O, -C (O) R12、-C(O)OR12、-NR13R14、-C(O)NR13R14or-NR13C(O)R14Substituted with the substituent(s);
R12、R13and R14Each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the ringThe alkyl, heterocyclyl, aryl or heteroaryl group is optionally further substituted with one or more substituents selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid or carboxylic acid ester;
m is 1,2, 3 or 4;
n is 0, 1 or 2; preferably 1;
p is 0, 1,2, 3 or 4;
q is 0, 1 or 2; and is
s is selected from 1,2, 3 or 4.
In a preferred embodiment of the present invention, the compound of formula (I) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, which is a compound of formula (II) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof:
Figure BDA0001201979480000031
wherein: r1～R4M and p are as defined in formula (I).
In a preferred embodiment of the present invention, there is provided a compound of formula (I) or (II) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein each R is1Each independently selected from halogen or alkoxy, preferably chloro or methoxy.
In a preferred embodiment of the present invention, there is provided a compound of formula (I) or (II) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R is2Selected from-NHC (O) CH ═ CH2。
In a preferred embodiment of the present invention, there is provided a compound of formula (I) or (II) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein each R is3Each independently selected from hydrogen atoms.
In a preferred embodiment of the present invention, there is provided a compound of formula (I) or (II) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein each R is3Each independently selected from heterocyclic groups, preferablyA 3-to 8-membered heterocyclic group, more preferably a 5-to 6-membered heterocyclic group, wherein said heterocyclic group is optionally further substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl.
In a preferred embodiment of the present invention, there is provided a compound of formula (I) or (II) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:
each R3Each independently selected from alkyl, said alkyl being further substituted with a heterocyclyl group, preferably a 3-to 8-membered heterocyclyl group, more preferably a 5-to 6-membered heterocyclyl group, wherein said heterocyclyl group is optionally further substituted with one or more substituents selected from alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl.
In a preferred embodiment of the present invention, there is provided a compound of formula (I) or (II) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:
each R3Each independently selected from-C (O) R9，R9Is selected from heterocyclic group, preferably 3-8-membered heterocyclic group, more preferably 5-6-membered heterocyclic group, wherein the heterocyclic group is optionally further substituted by one or more substituents selected from alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl or heteroaryl.
In a preferred embodiment of the present invention, there is provided a compound of formula (I) or (II) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein each R is3Each independently selected from halogen, preferably F, Cl or Br, more preferably F or Cl.
In a preferred embodiment of the present invention, there is provided a compound represented by the general formula (I) or (II) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein ring a is selected from a 4-to 8-membered heterocyclic group, preferably tetrahydrofuranyl or tetrahydropyranyl.
In a preferred embodiment of the present invention, there is provided a compound of formula (I) or (II) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein ring a is selected from phenyl.
In a preferred embodiment of the present invention, there is provided a compound of formula (I) or (II) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein
R4Is selected from- (CH)2)rNRARB；
r is selected from 1,2, 3 or 4;
RAand RBEach independently selected from a hydrogen atom or an alkyl group, wherein said alkyl group is optionally further substituted with one or more hydroxyl groups,
Halogen substituent.
In a preferred embodiment of the present invention, there is provided a compound of formula (I) or (II) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein
R4Is selected from-CRCRD-(CH2)s-ORE；
s is selected from 1,2, 3 or 4;
RCand RDTo the connection RCAnd RDThe C atoms are cyclized together to form 3-6 membered cycloalkyl;
REselected from alkyl groups.
In a preferred embodiment of the present invention, there is provided a compound of formula (I) or (II) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:
R2selected from-NHC (O) CH ═ CH2；
Each R3Each independently selected from hydrogen atoms.
In a preferred embodiment of the present invention, there is provided a compound of formula (I) or (II) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:
R2selected from-NHC (O) CH ═ CH2；
Each R3Each independently selected from the group consisting of heterocyclyl, preferably 3-to 8-membered heterocyclyl, more preferably 5-to 6-membered heterocyclyl, wherein said heterocyclyl is optionally further substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl.
In a preferred embodiment of the present invention, there is provided a compound of formula (I) or (II) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:
R2selected from-NHC (O) CH ═ CH2；
Each R3Each independently selected from alkyl, said alkyl being further substituted with a heterocyclyl group, preferably a 3-to 8-membered heterocyclyl group, more preferably a 5-to 6-membered heterocyclyl group, wherein said heterocyclyl group is optionally further substituted with one or more substituents selected from alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl.
In a preferred embodiment of the present invention, there is provided a compound of formula (I) or (II) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:
R2selected from-NHC (O) CH ═ CH2；
Each R3Each independently selected from-C (O) R9，R9Is selected from heterocyclic group, preferably 3-8-membered heterocyclic group, more preferably 5-6-membered heterocyclic group, wherein the heterocyclic group is optionally further substituted by one or more substituents selected from alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl or heteroaryl.
In a preferred embodiment of the present invention, there is provided a compound of formula (I) or (II) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein
R2Selected from-NHC (O) CH ═ CH2；
R4Is selected from- (CH)2)rNRARB；
r is selected from 1,2, 3 or 4;
RAand RBEach independently selected from a hydrogen atom or an alkyl group, wherein said alkyl group is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halo.
In a preferred embodiment of the present invention, there is provided a compound of formula (I) or (II) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein
R2Selected from-NHC (O) CH ═ CH2；
R4Is selected from-CRCRD-(CH2)s-ORE；
s is selected from 1,2, 3 or 4;
RCand RDTo the connection RCAnd RDThe C atoms are cyclized together to form 3-6 membered cycloalkyl;
REselected from alkyl groups.
Typical compounds of the invention include, but are not limited to:
Figure BDA0001201979480000051
Figure BDA0001201979480000061
Figure BDA0001201979480000071
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.
Further, the present invention provides a compound of the general formula (IA) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof,
Figure BDA0001201979480000072
wherein:
Raselected from hydrogen atoms or amino protecting groups, preferably phenylsulfonyl, benzyloxycarbonyl, formyl, trifluoroacetyl and tert-butoxycarbonyl; more preferably benzenesulfonyl and tert-butoxycarbonyl;
Figure BDA0001201979480000081
R1、R3～R5x, m, n and p are as defined in formula (I).
Compounds of formula (IA) include, but are not limited to:
Figure BDA0001201979480000082
Figure BDA0001201979480000091
Figure BDA0001201979480000101
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.
Further, the present invention provides a process for the preparation of a compound of formula (I), which process comprises:
Figure BDA0001201979480000102
the compound of formula (IA) and an acid halide compound, preferably Y-C (O) CR7＝CHR8Or Y-C (O) C ≡ CR7Reaction to give a compound of general formula (IB):
Figure BDA0001201979480000103
wherein:
Raselected from hydrogen atoms or amino protecting groups, preferably phenylsulfonyl, benzyloxycarbonyl, formyl, trifluoroacetyl and tert-butoxycarbonyl; more preferably benzenesulfonyl and tert-butoxycarbonyl;
y is halogen;
when R isaWhen the hydrogen atom is used, the compound of the general formula (IB) is the compound of the general formula (I);
when R isaWhen it is an amino-protecting group, R is further removedaTo obtain the compound of the general formula (I),
Figure BDA0001201979480000111
wherein:
Figure BDA0001201979480000112
R1～R5x, m, n and p are as defined in formula (I).
Further, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (I) or (II) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or a combination thereof.
The present invention provides a method of inhibiting FGFR4 comprising contacting the receptor with a compound of formula (I) or (II) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or with a pharmaceutical composition thereof.
The invention provides application of a compound shown in a general formula (I) or (II) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in preparing a medicament for inhibiting FGFR 4.
The invention provides application of a compound shown in a general formula (I) or (II) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in preparing a medicament for treating FGFR4 overexpression diseases.
The invention provides an application of a compound shown in a general formula (I) or (II) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in preparing a medicament for treating FGF19 amplified diseases.
The invention provides a compound shown in a general formula (I) or (II) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or an application of a pharmaceutical composition thereof in preparing a medicament for treating cancers, wherein the cancers are selected from non-small cell lung cancer, gastric cancer, multiple myeloma, liver cancer and bile duct cancer, and are preferably liver cancer and bile duct cancer.
Detailed description of the invention
Unless stated to the contrary, some of the terms used in the specification and claims of the present invention are defined as follows:
"alkyl" when taken as a group or part of a group means including C1-C20Straight-chain or branched aliphatic hydrocarbon groups. Preferably C1-C10Alkyl, more preferably C1-C6An alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. Alkyl groups may be substituted or unsubstituted.
"cycloalkyl" refers to saturated or partially saturated monocyclic, fused, bridged, and spiro carbocyclic rings. Preferably C3-C12Cycloalkyl, more preferably C3-C8Cycloalkyl, most preferably C3-C6A cycloalkyl group. Examples of monocyclic cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like, with cyclopropyl, cyclohexenyl being preferred.
"spirocycloalkyl" refers to a 5 to 18 membered polycyclic group having two or more cyclic structures with single rings sharing a single carbon atom (called the spiro atom) with each other, containing 1 or more double bonds within the ring, but no ring has a completely conjugated pi-electron aromatic system. Preferably 6 to 14, more preferably 7 to 10. Spirocycloalkyl groups are classified according to the number of spiro atoms shared between rings into mono-spiro, di-spiro, or multi-spiro cycloalkyl groups, preferably mono-spiro and di-spiro cycloalkyl groups, preferably 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered. Non-limiting examples of "spirocycloalkyl" include, but are not limited to: spiro [4.5] decyl, spiro [4.4] nonyl, spiro [3.5] nonyl, spiro [2.4] heptyl.
"fused cycloalkyl" refers to a 5 to 18 membered all carbon polycyclic group containing two or more cyclic structures sharing a pair of carbon atoms with each other, one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron aromatic system, preferably 6 to 12, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyls according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicycloalkyl. Non-limiting examples of "fused ring alkyl" include, but are not limited to: bicyclo [3.1.0] hexyl, bicyclo [3.2.0] hept-1-enyl, bicyclo [3.2.0] heptyl, decalinyl or tetradecaphenanthryl.
"bridged cycloalkyl" means a 5 to 18 membered all carbon polycyclic group containing two or more cyclic structures sharing two non-directly attached carbon atoms with each other, one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron aromatic system, preferably 6 to 12, more preferably 7 to 10. Preferably 6 to 14, more preferably 7 to 10. They may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic, depending on the number of constituent rings. Non-limiting examples of "bridged cycloalkyl" groups include, but are not limited to: (1s, 4s) -bicyclo [2.2.1] heptyl, bicyclo [3.2.1] octyl, (1s, 5s) -bicyclo [3.3.1] nonyl, bicyclo [2.2.2] octyl, and (1r, 5r) -bicyclo [3.3.2] decyl.
The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocyclyl ring, wherein the ring to which the parent structure is attached is cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like. Cycloalkyl groups may be optionally substituted or unsubstituted.
"Heterocyclyl", "heterocycle" or "heterocyclic" are used interchangeably herein and all refer to non-aromatic heterocyclic groups in which one or more of the ring-forming atoms is a heteroatom, such as oxygen, nitrogen, sulfur, and the like, including monocyclic, fused, bridged, and spiro rings. Preferably having a 5 to 7 membered monocyclic ring or a 7 to 10 membered bi-or tricyclic ring, which may contain 1,2 or 3 atoms selected from nitrogen, oxygen and/or sulfur. Examples of "heterocyclyl" include, but are not limited to, morpholinyl, thiomorpholinyl, tetrahydropyranyl, 1, 1-dioxo-thiomorpholinyl, piperidinyl, 1,2, 3, 6-tetrahydropyridinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo [3.2.1] octyl, and piperazinyl. The heterocyclic group may be substituted or unsubstituted.
"spiroheterocyclyl" refers to a 5-to 18-membered polycyclic group having two or more cyclic structures wherein the individual rings share an atom with one another and which contains 1 or more double bonds within the ring, but none of the rings have a fully conjugated pi-electron aromatic system wherein one or more of the ring atoms is selected from nitrogen, oxygen or S (O)q(wherein q is from 0, 1 or 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. The spiro heterocyclic group is classified into a mono-spiro heterocyclic group, a di-spiro heterocyclic group or a multi-spiro heterocyclic group, preferably a mono-spiro heterocyclic group and a di-spiro heterocyclic group, according to the number of spiro atoms shared between rings. More preferred is a 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered mono spiroheterocyclic group. Wherein "a-membered/b-membered monocyclic spiroheterocyclyl" refers to a spiroheterocyclyl in which an a-membered monocyclic ring and a b-membered monocyclic ring share one atom with each other. Non-limiting examples of "spiroheterocyclyl" include, but are not limited to: 1, 7-dioxaspiro [4.5]]Decyl, 2-oxa-7-azaspiro [4.4]Nonyl, 7-oxaspiro [3.5]]Nonyl and 5-oxaspiro [2.4]]A heptyl group.
"fused heterocyclyl" refers to an all-carbon polycyclic group containing two or more cyclic structures sharing a pair of atoms with each other, one or more of which rings may contain one or more double bonds, but none of which rings has a fully conjugated pi-electron aromatic system, wherein one or more of the ring atoms is selected from nitrogen, oxygen, or S (O)q(wherein q is selected from 0, 1 or 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. According to the number of component ringsCan be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of "fused heterocyclic groups" include, but are not limited to: octahydropyrrolo [3, 4-c]Pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo [3.1.0]Hexyl, octahydrobenzo [ b ]][1，4]Dioxins (dioxines).
"bridged heterocyclyl" means a 5-to 14-membered, 5-to 18-membered polycyclic group containing two or more cyclic structures sharing two atoms not directly attached to each other, one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron aromatic system in which one or more ring atoms are selected from nitrogen, oxygen, or S (O)n(wherein n is selected from 0, 1 or 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "fused heterocyclic groups" include, but are not limited to: 2-azabicyclo [2.2.1]Heptyl, 2-azabicyclo [2.2.2]Octyl and 2-azabicyclo [3.3.2]A decyl group. The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is heterocyclyl. The heterocyclic group may be optionally substituted or unsubstituted.
"aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be joined together in a fused fashion. The term "aryl" includes aromatic groups such as phenyl, naphthyl, tetrahydronaphthyl. Preferably aryl is C6-C10Aryl, more preferably aryl is phenyl and naphthyl, most preferably phenyl. The aryl group may be substituted or unsubstituted. The "aryl" may be fused to a heteroaryl, heterocyclyl or cycloalkyl group, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples include, but are not limited to:
Figure BDA0001201979480000131
"heteroaryl" refers to an aromatic 5-to 6-membered monocyclic or 9-to 10-membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur. Examples of "heteroaryl" include, but are not limited to, furyl, pyridyl, 2-oxo-1, 2-dihydropyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2, 3-thiadiazolyl, benzodioxolyl, benzimidazolyl, indolyl, isoindolyl, 1, 3-dioxo-isoindolyl, quinolinyl, indazolyl, benzisothiazolyl, benzoxazolyl, and benzisoxazolyl. Heteroaryl groups may be substituted or unsubstituted. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring joined together with the parent structure is a heteroaryl ring, non-limiting examples include, but are not limited to:
Figure BDA0001201979480000132
"alkoxy" refers to a radical of (alkyl-O-). Wherein alkyl is as defined herein. C1-C6Alkoxy groups of (4) are preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and the like.
"hydroxy" refers to an-OH group.
"halogen" means fluorine, chlorine, bromine and iodine, preferably chlorine, bromine and iodine.
"amino" means-NH2。
"cyano" means-CN.
"nitro" means-NO2。
"benzyl" means-CH2-phenyl.
"carboxy" refers to-C (O) OH.
"carboxylate" refers to-C (O) O (alkyl) or (cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
"oxo" refers to ═ O.
"amino protecting group" means in organic synthesis in order to make-NH2or-NH-is protected from the reaction by a reagent which is removed after the reaction is completed. Amino protecting groups include, but are not limited to, tert-butoxycarbonyl, benzyloxycarbonyl, formyl, or trifluoroacetyl.
"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort.
As used herein, "substituted" or "substituted," unless otherwise specified, means that the group may be substituted with one or more groups selected from: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxy, carboxylate, ═ O, -c (O) R9、-C(O)OR9、-NR10R11、-C(O)NR10R11or-NR10C(O)R11，
Wherein R is9、R10And R11Each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally further substituted with one or more groups selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) R12、-C(O)OR12、-NR13R14、-C(O)NR13R14or-NR13C(O)R14Substituted with the substituent(s);
or, R10And R11Together with the N atom to which they are attached form a 4-to 8-membered heterocyclic group in which the 4-to 8-membered heterocyclic ringContaining one or more N, O, S (O)qAnd 4-to 8-membered heterocycle is further substituted with one or more substituents selected from the group consisting of hydroxy, halo, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═ O, -C (O) R12、-C(O)OR12、-NR13R14、-C(O)NR13R14or-NR13C(O)R14Substituted with the substituent(s);
R12、R13and R14Each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid or carboxylic acid ester.
"pharmaceutically acceptable salts" refers to certain salts of the above compounds which retain their biological activity and are suitable for pharmaceutical use. Pharmaceutically acceptable salts of the compounds represented by formula (I) may be metal salts, preferably alkali metal, alkaline earth metal salts, amine salts formed with suitable acids, including inorganic and organic acids, such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, malic acid, maleic acid, mandelic acid, methanesulfonic acid, nitric acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid and the like. Particularly preferred are hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid, with the hydrochloride salt being most preferred.
"pharmaceutical composition" means a mixture containing one or more compounds described herein, or a physiologically acceptable salt or prodrug thereof, in admixture with other chemical components, as well as other components such as physiologically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.
Synthesis of the Compounds of the invention
In order to achieve the purpose of the invention, the invention adopts the following technical scheme:
the preparation method of the compound or the salt thereof of the general formula (I) comprises the following steps:
Figure BDA0001201979480000151
reacting a compound of formula (Ia) with a compound of formula (Ib) in the presence of 4, 5-bis diphenylphosphine-9, 9-dimethylxanthene and a palladium catalyst, preferably tris (dibenzylideneacetone) dipalladium, in the presence of a carbonate to give a compound of formula (Ic); r in the compound of the general formula (Ic)b-NH-to obtain a compound of general formula (IA); the compound of formula (IA) and an acid halide compound, preferably Y-C (O) CR7＝CHR8Or Y-C (O) C ≡ CR7Reacting to obtain a compound shown in a general formula (I);
wherein:
Raselected from hydrogen atoms;
Rbselected from amino protecting groups, preferably phenylsulfonyl, benzyloxycarbonyl, formyl, trifluoroacetyl and tert-butoxycarbonyl
A group; more preferably benzenesulfonyl and tert-butoxycarbonyl;
Rcselected from halogens;
y is selected from halogen;
Figure BDA0001201979480000152
R1～R5x, m, n and p are as defined in formula (I).
In a preferred embodiment of the present invention, the process for preparing the compound of formula (I) or a salt thereof comprises the steps of:
Figure BDA0001201979480000153
a compound of the general formula (Ia) in the presence of 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene and a palladium catalystUnder conditions, preferably tris (dibenzylideneacetone) dipalladium, in the presence of a carbonate, with a compound of general formula (Id) to give a compound of general formula (Ie); protection of the amino group in the compound of formula (Ie), preferably reaction with di-tert-butyl dicarbonate, gives RaProtected compounds of formula (If); further reducing the nitro group of the compound of formula (If) to an amino group to give a compound of formula (IA); the compound of formula (IA) and an acid halide compound, preferably Y-C (O) CR7＝CHR8Or Y-C (O) C ≡ CR7Reacting to obtain a compound of a general formula (IB); further removal of the amino protecting group R from the compound of formula (IB)aTo obtain the compound of the general formula (I);
wherein:
Raselected from amino protecting groups, preferably phenylsulfonyl, benzyloxycarbonyl, formyl, trifluoroacetyl and tert-butoxycarbonyl; more preferably benzenesulfonyl and tert-butoxycarbonyl;
Rcselected from halogens;
y is selected from halogen;
Figure BDA0001201979480000161
R1～R5x, m, n and p are as defined in formula (I).
Drawings
FIG. 1 is a graph showing the mean tumor volume changes of the compound of example 3 in test example 3 inhibited in a human hepatoma Hep 3B nude mouse graft tumor model.
FIG. 2 is a graph showing the relative mean tumor volume changes of the compound of example 3 in test example 3 inhibited in a human hepatoma Hep 3B nude mouse graft tumor model.
Detailed Description
The present invention will be further described with reference to the following examples, which are not intended to limit the scope of the present invention.
Examples
The examples show the preparation of representative compounds represented by formula (I) and the associated structural identification data. It must be noted that the following examples are intended to illustrate the inventionAnd not as restrictive.1The H NMR spectrum was obtained using a Bruker instrument (400MHz) and the chemical shifts were expressed in ppm. Tetramethylsilane internal standard (0.00ppm) was used.1Method for H NMR expression: s is singlet, d is doublet, t is triplet, m is multiplet, br is broadened, dd is doublet of doublet, dt is doublet of triplet. If a coupling constant is provided, it is in Hz.
The mass spectrum is measured by an LC/MS instrument, and the ionization mode can be ESI or APCI.
The thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.
The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.
In the following examples, all temperatures are in degrees Celsius unless otherwise indicated, and unless otherwise indicated, the various starting materials and reagents are commercially available or synthesized according to known methods, and none of the commercially available materials and reagents are used without further purification, and unless otherwise indicated, commercially available manufacturers include, but are not limited to, Aldrich Chemical Company, ABCR GmbH & Co. KG, Acros Organics, Prov Chemical science Inc. and Sci Chemical science Inc., and the like.
CD3OD: deuterated methanol.
CDCl3: deuterated chloroform.
DMSO-d6: deuterated dimethyl sulfoxide.
The argon atmosphere means that the reaction flask is connected with an argon balloon having a volume of about 1L.
In the examples, the solution in the reaction is an aqueous solution unless otherwise specified.
Purifying the compound by silica gel column chromatography using an eluent system selected from the group consisting of: a: petroleum ether and ethyl acetate systems; b: dichloromethane and methanol systems; c: dichloromethane: ethyl acetate; wherein the volume ratio of the solvent is different according to the polarity of the compound, and a small amount of acidic or basic reagent such as acetic acid or triethylamine can be added for the reaction.
Example 1
N- (4- ((3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) amino) tetrahydrofuran-3-yl) acrylamide
Figure BDA0001201979480000171
First step of
6-chloro-4- ((3- (dimethylamino) propyl) amino) nicotinic acid ethyl ester
4, 6-Dichloronicotinic acid ethyl ester 1a (30.1g, 136.99mmol) and N1，N1Dimethylpropane-1, 3-diamine 1b (18.95mL, 150.46mmol) was dissolved in 300mL of tetrahydrofuran and reacted at 60 ℃ for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a) to obtain ethyl 6-chloro-4- ((3- (dimethylamino) propyl) amino) nicotinate 1c (22.84g, white solid), yield: 58.5 percent.
MS m/z(ESI)：286.0[M+1]
Second step of
(6-chloro-4- ((3- (dimethylamino) propyl) amino) pyridin-3-yl) methanol
Ethyl 6-chloro-4- ((3- (dimethylamino) propyl) amino) nicotinate 1c (16.5g, 57.74mmol) was dissolved in 300mL tetrahydrofuran, cooled to 0 deg.C, added lithium aluminum hydride (78.0mL, 77.39mmol), and then warmed to room temperature for 10 min. To the reaction solution were added 4mL of water, 4mL of sodium hydroxide solution (20%) and 12mL of water in this order, anhydrous sodium sulfate (20.0g) was added, stirring was carried out for 1 hour, filtration was carried out, and the filtrate was concentrated under reduced pressure to give (6-chloro-4- ((3- (dimethylamino) propyl) amino) pyridin-3-yl) methanol 1d (13.26g, pale yellow solid), yield: 94.2 percent.
1H NMR(400MHz，CDCl3)δ7.64(s，1H)，6.42(s，1H)，6.35(s，1H)，4.51(s，2H)，3.45(s，1H)，3.16(d，J＝4.7Hz，2H)，2.34(t，J＝6.7Hz，2H)，2.18(s，6H)，1.80-1.70(m，2H).
The third step
6-chloro-4- ((3- (dimethylamino) propyl) amino) nicotinaldehyde
(6-chloro-4- ((3- (dimethylamino) propyl) amino) pyridin-3-yl) methanol 1d (17.8g, 73.0mmol) was dissolved in 600mL of dichloromethane, activated manganese dioxide (75.0g, 876mmol) was added, and the reaction solution was allowed to react at room temperature for 18 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to give crude 6-chloro-4- ((3- (dimethylamino) propyl) amino) nicotinaldehyde 1e (14.52g, yellow liquid), yield: 82.4 percent.
MS m/z(ESI)：241.9[M+1]
The fourth step
7-chloro-3- (3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -1, 6-naphthyridin-2 (1H) -one
6-chloro-4- ((3- (dimethylamino) propyl) amino) nicotinaldehyde 1e (1.49g, 6.17mmol), methyl 2- (3, 5-dimethoxyphenyl) acetate 1f (1.43g, 6.68mmol) and cesium carbonate (2.41g, 7.40mmol) were dissolved in 25mL of N, N-dimethylformamide and reacted with microwaves at 125 ℃ for 2 hours. To the reaction solution were added 30mL of dichloromethane and 30mL of water, the aqueous phase was extracted with dichloromethane (30mL × 2), the organic phases were combined, washed with water (30mL × 3), concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developer: system B) to give 1g (1.95g, yellow solid) of 7-chloro-3- (3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -1, 6-naphthyridin-2 (1H) -one, yield: 78.8 percent.
MS m/z(ESI)：401.9[M+1]
The fifth step
7-chloro-3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -1, 6-naphthyridin-2 (1H) -one
7-chloro-3- (3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -1, 6-naphthyridin-2 (1H) -one 1g (2.91g, 7.77mmol) was dissolved in 200mL acetonitrile, cooled to-20 deg.C and sulfonyl chloride (1.4mL, 17.3mmol) was dissolved in 40mL acetonitrile and reacted at room temperature for 10 min. The reaction was concentrated, 200mL of dichloromethane was added, the pH was adjusted to 8-9 with saturated sodium bicarbonate solution, the layers were separated, the aqueous phase was extracted with dichloromethane (100mL), the organic phases were combined and concentrated under reduced pressure to give 7-chloro-3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -1, 6-naphthyridin-2 (1H) -one 1H (3.22g, a pale yellow solid), yield: 88.2 percent.
MS m/z(ESI)：471.8[M+1]
The sixth step
(4- ((3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) amino) tetrahydrofuran-3-yl) carbamic acid tert-butyl ester
7-chloro-3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -1, 6-naphthyridin-2 (1H) -one 1H (200mg, 0.425mmol), (4-aminotetrahydrofuran-3-yl) carbamic acid tert-butyl ester 1i (86mg, 0.425mmol), 4, 5-bis-diphenylphosphino-9, 9-dimethylxanthene (49mg, 0.093mmol), tris (dibenzylideneacetone) dipalladium (39mg, 0.0425mmol) and cesium carbonate (415mg, 1.270mmol) were dissolved in 15mL of toluene under argon protection and heated to 120 ℃ for 4 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system C) to obtain tert-butyl (4- ((3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) amino) tetrahydrofuran-3-yl) carbamate 1j (95mg, pale yellow solid), yield: 35.2 percent.
MS m/z(ESI)：635.8[M+1]
Seventh step
7- ((4-Aminotetrahydrofuran-3-yl) amino) -3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -1, 6-naphthyridin-2 (1H) -one
Tert-butyl (4- ((3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) amino) tetrahydrofuran-3-yl) carbamate 1j (85mg, 0.133mmol) was dissolved in 3mL of dichloromethane, and 1mL of trifluoroacetic acid was added to react at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure to give crude 7- ((4-aminotetrahydrofuran-3-yl) amino) -3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -1, 6-naphthyridin-2 (1H) -one 1k (60mg, pale yellow solid), which was directly subjected to the next reaction without purification.
MS m/z(ESI)：535.8[M+1]
Eighth step
N- (4- ((3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) amino) tetrahydrofuran-3-yl) acrylamide
7- ((4-Aminotetrahydrofuran-3-yl) amino) -3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -1, 6-naphthyridin-2 (1H) -one 1k (60mg, 0.112mmol) was dissolved in 3mL of dichloromethane, and acryloyl chloride (9.30. mu.L, 0.112mmol) was added and reacted at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel thin layer chromatography (developing solvent: system B) to give N- (4- ((3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) amino) tetrahydrofuran-3-yl) acrylamide 1(8mg, pale yellow solid), yield: 12.1 percent.
MS m/z(ESI)：589.9[M+1]
1H NMR(400MHz，DMSO)δ8.39(s，1H)，8.12(d，J＝7.9Hz，1H)，7.66(s，1H)，6.96(s，1H)，6.91(d，J＝7.2Hz，1H)，6.44(s，1H)，6.22(dd，J＝17.1，10.2Hz，1H)，6.00(dd，J＝17.1，1.9Hz，1H)，5.52(dd，J＝10.2，1.9Hz，1H)，4.65(s，2H)，4.15-4.06(m，3H)，4.02(dd，J＝8.7，6.3Hz，1H)，3.94(s，6H)，3.72-3.61(m，2H)，2.32(t，J＝6.7Hz，2H)，2.17(d，J＝8.7Hz，6H)，1.76(d，J＝7.2Hz，2H).
Example 2
N- (2- ((3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) amino-3-fluorophenyl) acrylamide
Figure BDA0001201979480000191
Figure BDA0001201979480000201
First step of
3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -7- ((2-fluoro-6-nitrophenyl) amino) -1, 6-naphthyridin-2 (1H) -one
7-chloro-3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -1, 6-naphthyridin-2 (1H) -one was dissolved in 10mL of toluene under an argon atmosphere for 1H (200mg, 0.425mmol), 2-fluoro-6-nitroaniline 2a (94mg, 0.467mmol), 4, 5-bis-diphenylphosphino-9, 9-dimethylxanthene (49mg, 0.085mmol), tris (dibenzylideneacetone) dipalladium (39mg, 0.0425mmol) and cesium carbonate (415mg, 1.270mmol), and heated to 120 ℃ for 4 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel thin layer chromatography (developing solvent: system C) to give 3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -7- ((2-fluoro-6-nitrophenyl) amino) -1, 6-naphthyridin-2 (1H) -one 2b (199mg, yellow solid), yield: 80.0 percent.
MS m/z(ESI)：589.8[M+1]
Second step of
7- (tert-Butoxycarbonyl- (2-fluoro-6-nitrophenyl) amino) -3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -1, 6-naphthyridin-2 (1H) -one
3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -7- ((2-fluoro-6-nitrophenyl) amino) -1, 6-naphthyridin-2 (1H) -one 2b (199mg, 0.337mmol) was dissolved in 6mL of tetrahydrofuran, di-tert-butyl dicarbonate (146.9mg, 0.674mmol) and 4-dimethylaminopyridine (82.2mg, 0.674mmol) were added, and the mixture was heated to 80 ℃ for reaction for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give 7- (tert-butoxycarbonyl- (2-fluoro-6-nitrophenyl) amino) -3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -1, 6-naphthyridin-2 (1H) -one 2c (230mg, pale yellow solid), yield: 98.7 percent.
MS m/z(ESI)：690.2[M+1]
The third step
7- ((2-amino-6-fluorophenyl) (tert-butyloxycarbonyl) amino) -3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -1, 6-naphthyridin-2 (1H) -one
7- (tert-Butoxycarbonyl- (2-fluoro-6-nitrophenyl) amino) -3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -1, 6-naphthyridin-2 (1H) -one 2c (230mg, 0.33mmol) was dissolved in 5mL of methanol, and Raney nickel (200mg) was added and reacted at room temperature for 1 hour under hydrogen protection. The reaction was filtered and the filtrate was concentrated under reduced pressure to give 7- ((2-amino-6-fluorophenyl) (tert-butoxycarbonyl) amino) -3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -1, 6-naphthyridin-2 (1H) -one 2d (150mg, off-white solid), yield: 68.2 percent.
MS m/z(ESI)：662.3[M+1]
The fourth step
N- (2- (tert-Butoxycarbonyl- (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) amino) -3-fluorophenyl) acrylamide
7- ((2-amino-6-fluorophenyl) (tert-butoxycarbonyl) amino) -3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -1, 6-naphthyridin-2 (1H) -one 2d (100mg, 0.151mmol) was dissolved in 10mL of dichloromethane, and N, N-diisopropylethylamine (78mg, 0.606mmol) and acryloyl chloride (25. mu.L, 0.303mmol) were added under ice-bath and reacted at room temperature for 12 hours. The pH was adjusted to 8 to 9 with a saturated sodium bicarbonate solution, extracted with dichloromethane (10mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent: system B) to give N- (2- (tert-butoxycarbonyl- (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) amino) -3-fluorophenyl) acrylamide 2e (55mg, off-white solid), yield: 51 percent.
MS m/z(ESI)：714.2[M+1]
The fifth step
N- (2- ((3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) amino-3-fluorophenyl) acrylamide
N- (2- (tert-Butoxycarbonyl- (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) amino) -3-fluorophenyl) acrylamide 2e (55mg, 0.077mmol) was dissolved in 3mL of dichloromethane, and 1mL of trifluoroacetic acid was added to react at room temperature for 12 hours. The pH was adjusted to 8 to 9 with a saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane (10mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel thin-plate chromatography (developing solvent: system B) to obtain N- (2- ((3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) amino-3-fluorophenyl) acrylamide 2(17mg, gray solid) with a yield of 32.6%.
MS m/z(ESI)：613.8[M+1]
1H NMR(400MHz，CDCl3)δ9.09(s，1H)，8.39(s，1H)，7.91(s，1H)，7.75(s，1H)，7.52(s，1H)，7.22(d，J＝8.0Hz，1H)，6.97(t，J＝8.9Hz，1H)，6.77(s，1H)，6.61(s，1H)，6.36(d，J＝5.4Hz，2H)，5.70-5.62(m，1H)，4.24(s，2H)，3.93(s，6H)，3.00(s，2H)，2.67(s，6H)，2.22(s，2H).
Example 3
N- (2- ((3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) amino-5-morpholinylphenyl) acrylamide
Figure BDA0001201979480000211
Figure BDA0001201979480000221
First step of
N- (4-bromo-2-nitrophenyl) acetamide
4-bromo-2-nitroaniline 3a (30.3g, 138mmol) was dissolved in 240mL of acetic acid, acetic anhydride (22.44g, 220.2mmol) was added, and the mixture was heated to 95 ℃ for reaction for 7.5 hours. The reaction solution was cooled to room temperature and poured into 600mL of ice water, after the ice was dissolved, the mixture was extracted with dichloromethane (90mL × 3), the solid was dissolved in 600mL of dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give N- (4-bromo-2-nitrophenyl) acetamide 3b (35.4g, orange solid), yield: 99.1 percent.
MS m/z(ESI)：258.8[M+1]
Second step of
N- (4-morpholinyl-2-nitrophenyl) acetamide
N- (4-bromo-2-nitrophenyl) acetamide 3b (30.0g, 115.8mmol), morpholine 3c (10.1g, 115.8mmol), 4, 5-bis-diphenylphosphino-9, 9-dimethylxanthene (6.7g, 11.58mmol), tris (dibenzylideneacetone) dipalladium (5.3g, 5.79mmol) and cesium carbonate (113g, 347.4mmol) were dissolved in 1000mL of toluene under an argon atmosphere and reacted at 120 ℃ for 4 hours. The reaction mixture was cooled to room temperature, 800mL of dichloromethane and 500mL of water were added, the layers were separated, the aqueous phase was extracted with dichloromethane (500mL × 3), the organic phases were combined, washed with saturated brine (1000mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a) to obtain N- (4-morpholinyl-2-nitrophenyl) acetamide 3d (22.0g, black solid) with a yield: 73.3 percent.
MS m/z(ESI)：265.9[M+1]
The third step
4-morpholinyl-2-nitroaniline
(N- (4-morpholinyl-2-nitrophenyl) acetamide 3d (6.00g, 25.4mmol) and sodium hydroxide (7.00g, 125mmol) were dissolved in a mixed solvent of 110mL of ethanol and water (V/V ═ 15/7), the reaction mixture was reacted at 90 ℃ for 4 hours, the reaction mixture was concentrated under reduced pressure, 100mL of water and 100mL of dichloromethane were added, the layers were separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: B system) to give 4-morpholinyl-2-nitroaniline 3e (3.20g, black solid) with a yield of 64.0%.
1H NMR(400MHz，CDCl3)δ7.58(s，1H)，7.19(d，J＝7.5Hz，1H)，6.79(d，J＝9.0Hz，1H)，5.89(s，2H)，3.98-3.70(m，4H)，3.23-2.97(m，4H).
The fourth step
3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -7- ((4-morpholinyl-2-nitrophenyl) amino) -1, 6-naphthyridin-2 (1H) -one
7-chloro-3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -1, 6-naphthyridin-2 (1H) -one 1H (2.20g, 4.67mmol), 4-morpholinyl-2-nitroaniline 3e (1.04g, 4.67mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (540mg, 0.933mmol), tris (dibenzylideneacetone) dipalladium (438mg, 0.478mmol) and cesium carbonate (4.57g, 19.38mmol) were dissolved in 60mL of toluene and reacted at 120 ℃ for 4 hours under argon protection. The reaction solution was cooled to room temperature, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give 3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -7- ((4-morpholinyl-2-nitrophenyl) amino) -1, 6-naphthyridin-2 (1H) -one 3f (2.82g, black red solid), yield: 91.8 percent.
MS m/z(ESI)：656.8[M+1]
The fifth step
3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) (4-morpholinyl-2-nitrophenyl) carbamic acid tert-butyl ester
3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -7- ((4-morpholinyl-2-nitrophenyl) amino) -1, 6-naphthyridin-2 (1H) -one 3f (2.820g, 4.26mmol) was dissolved in 40mL of tetrahydrofuran, di-tert-butyl dicarbonate (2.79g, 12.77mmol) and 4-dimethylaminopyridine (500mg, 4.26mmol) were added, and the mixture was heated to 80 ℃ for reaction for 4 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give 3g (2.50g, yellow solid) of tert-butyl 3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) (4-morpholinyl-2-nitrophenyl) carbamate, yield: 77.4 percent.
MS m/z(ESI)：756.8[M+1]
The sixth step
(2-amino-4-morpholinylphenyl) (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) - (1-3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamic acid tert-butyl ester
3g (1.58g, 2.08mmol) of tert-butyl 3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) (4-morpholinyl-2-nitrophenyl) carbamate was dissolved in 50mL of methanol, Raney's nickel (1.50g) was added, and the reaction was carried out under hydrogen atmosphere at room temperature for 0.5 hour. To the reaction solution, 50mL of dichloromethane was added, and filtered through celite, the filter cake was washed with 30mL of a mixed solvent of dichloromethane and methanol (V/V ═ 10/1), and the filtrate was concentrated under reduced pressure to give tert-butyl (2-amino-4-morpholinophenyl) (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) - (1-3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamate 3h (1.30g, light yellow solid), yield: 86.3 percent.
MS m/z(ESI)：726.8[M+1]
Seventh step
(2-Acryloylamino-4-morpholinylphenyl) (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) - (1-3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamic acid tert-butyl ester
(2-amino-4-morpholinylphenyl) (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) - (1-3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamic acid tert-butyl ester 3h (1.30g, 1.79mmol) was dissolved in 15mL of dichloromethane, N-diisopropylethylamine (923mg, 7.15mmol) and acryloyl chloride (286mg, 3.57mmol) were added, followed by 4-dimethylaminopyridine (44mg, 0.357mmol) and reacted at room temperature for 2 hours. The reaction solution was adjusted to pH 8 to 9 with saturated sodium bicarbonate solution, the layers were separated, the organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent: system B) to obtain tert-butyl (2-acrylamido-4-morpholinylphenyl) (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) - (1-3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamate 3i (450mg, yellow solid), yield: 37.1 percent.
MS m/z(ESI)：781.8[M+1]
Eighth step
N- (2- ((3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) amino-5-morpholinylphenyl) acrylamide
(2-Acryloylamino-4-morpholinylphenyl) (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) - (1-3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamic acid tert-butyl ester 3i (450mg, 0.576mmol) was dissolved in 5mL of dichloromethane and 2mL of trifluoroacetic acid was added and reacted at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, 10mL of dichloromethane was added, the pH was adjusted to 8 to 9 with a saturated sodium bicarbonate solution, the layers were separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developer: system B) to obtain N- (2- ((3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) amino-5-morpholinylphenyl) acrylamide 3(190mg, yellow solid) with a yield of 48.5%.
MS m/z(ESI)：680.8[M+1]
1H NMR(400MHz，DMSO)δ9.68(s，1H)，8.46(s，1H)，8.34(s，1H)，7.72(s，1H)，7.46-7.27(m，2H)，6.96(s，1H)，6.84(d，J＝8.9Hz，1H)，6.49(dd，J＝16.9，10.4Hz，1H)，6.41(s，1H)，6.23(d，J＝17.0Hz，1H)，5.72(d，J＝11.6Hz，1H)，4.02(s，2H)，3.94(s，6H)，3.75(s，4H)，3.10(s，4H)，2.25(s，2H)，2.09(s，6H)，1.67(s，2H).
Example 4
N- (2- ((3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) amino) -5- ((4-ethylpiperazin-1-yl) methyl) phenyl) acrylamide
Figure BDA0001201979480000241
Figure BDA0001201979480000251
First step of
4-fluoro-3-nitrobenzyl alcohol
Sodium borohydride (2.70g, 64.83mmol) was dissolved in 100mL tetrahydrofuran, cooled to 0 deg.C, and 4-fluoro-3-nitrobenzoic acid 4a (12.0g, 64.83mmol) was added in portions and reacted at 0 deg.C for 1 hour. Then, boron trifluoride ether solution (6.55mL, 71.31mmol) was added dropwise at 0 ℃ and the reaction mixture was warmed to room temperature to react for 3 hours. To the reaction solution were added 500mL of ethyl acetate and 300mL of water, the layers were separated, and the organic phase was washed with a saturated sodium chloride solution (500mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 4-fluoro-3-nitrobenzyl alcohol 4b (11.0g, pale yellow solid), yield: 99.1 percent.
MS m/z(ESI)：171.9[M+1]
Second step of
4-fluoro-3-nitrobenzaldehyde
4-fluoro-3-nitrobenzyl alcohol 4b (10.0g, 58.4mmol) was dissolved in 200mL of dichloromethane at 0 deg.C and 100-mesh 200-mesh silica gel (18.9g) was added. Pyridine chlorochromate (18.9g, 87.7mmol) was added slowly with stirring. The reaction was carried out at room temperature for 3 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system A) to give 4-fluoro-3-nitrobenzaldehyde 4c (10.3g, pale yellow liquid), which was subjected to the next reaction without purification.
1H NMR(400MHz，CDCl3)δ10.15-9.95(m，1H)，8.60(dd，J＝2.0，7.0Hz，1H)，8.30-8.11(m，1H)，7.52(t，J＝9.3Hz，1H).
The third step
4-amino-3-nitrobenzaldehydes
4-fluoro-3-nitrobenzaldehyde 4c (10.0g, 59.13mmol) was dissolved in 360mL of tetrahydrofuran, and 90mL of aqueous ammonia was added to the solution to react at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to remove the solvent, filtered, washed with a saturated sodium chloride solution (200 mL. times.3), concentrated under reduced pressure, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude 4-amino-3-nitrobenzaldehyde 4d (10.0g, yellow solid), which was subjected to the next reaction without purification.
MS m/z(ESI)：166.9[M+1]
The fourth step
4- ((4-ethylpiperazin-1-yl) methyl) -2-nitroaniline
1-ethylpiperazine 4e (4.11g, 36.0mmol) was dissolved in 90mL of methanol, and tetraisopropyltitanyl oxide (7.70g, 27.0mmol) was added and stirred for 15 minutes. Then, a solution of 4-amino-3-nitrobenzaldehyde 4d (4.50g, 27.0mmol) in 30mL of methanol was added and the reaction was carried out at room temperature for 18 hours. Sodium borohydride (1.33g, 35.1mmol) was added thereto, and the reaction was carried out at room temperature for 2 hours. To the reaction solution, 100mL of ethyl acetate was added and filtered, the filtrate was concentrated under reduced pressure, 50mL of ethyl acetate was further added, and the filtrate was washed with a saturated sodium chloride solution (100mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give 4- ((4-ethylpiperazin-1-yl) methyl) -2-nitroaniline 4f (2.40g, yellow solid), yield: 33.6 percent.
MS m/z(ESI)：265.0[M+1]
The fifth step
3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -7- ((4- ((4-ethylpiperazin-1-yl) methyl) -2-nitrophenyl) amino) -1, 6-naphthyridin-2 (1H) -one
7-chloro-3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -1, 6-naphthyridin-2 (1H) -one 1H (1.00g, 2.12mmol), 4- ((4-ethylpiperazin-1-yl) methyl) -2-nitroaniline 4f (585mg, 2.34mmol), 4, 5-bis-diphenylphosphino-9, 9-dimethylxanthene (245mg, 0.424mmol), tris (dibenzylideneacetone) dipalladium (195mg, 0.212mmol) and cesium carbonate (2.08g, 6.37mmol) were dissolved in 20mL of toluene and reacted at 100 ℃ for 4 hours under protection of argon. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give 4g (610mg, yellow solid) of 3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -7- ((4- ((4-ethylpiperazin-1-yl) methyl) -2-nitrophenyl) amino) -1, 6-naphthyridin-2 (1H) -one, yield: 42.1 percent.
MS m/z(ESI)：697.8[M+1]
The sixth step
3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) (4- ((4-ethylpiperazin-1-yl) methyl) -2-nitrophenyl) carbamic acid tert-butyl ester
4g (600mg, 0.876mmol) of 3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -7- ((4- ((4-ethylpiperazin-1-yl) methyl) -2-nitrophenyl) amino) -1, 6-naphthyridin-2 (1H) -one was dissolved in 10mL of tetrahydrofuran, di-tert-butyl dicarbonate (407mg, 2.63mmol) and 4-dimethylaminopyridine (107mg, 0.876mmol) were added, and the temperature was raised to 80 ℃ to react for 2.5 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give tert-butyl 3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) (4- ((4-ethylpiperazin-1-yl) methyl) -2-nitrophenyl) carbamate for 4h (260mg, yellow solid), yield: 37.9 percent.
MS m/z(ESI)：799.8[M+1]
Seventh step
(2-amino-4- ((4-ethylpiperazin-1-yl) methyl) phenyl) (tert-butyl 3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamate
Tert-butyl 3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) (4- ((4-ethylpiperazin-1-yl) methyl) -2-nitrophenyl) carbamate (4 h (260mg, 0.326mmol) was dissolved in 5mL of methanol, Raney's nickel (500mg) was added, and the reaction was carried out under hydrogen atmosphere at room temperature for 40 minutes. The reaction solution was filtered through celite, the filter cake was washed with a mixed solvent of dichloromethane and methanol (V/V ═ 10/1) (100mL × 3), and the filtrate was concentrated under reduced pressure to give tert-butyl (2-amino-4- ((4-ethylpiperazin-1-yl) methyl) phenyl) (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamate 4i (180mg, pale yellow solid), yield: 71.9 percent.
Eighth step
(2-Acrylamido-4- ((4-ethylpiperazin-1-yl) methyl) phenyl) (tert-butyl 3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamate
Tert-butyl (2-amino-4- ((4-ethylpiperazin-1-yl) methyl) phenyl) (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamate 4i (180mg, 0.234mmol) was dissolved in 10mL of dichloromethane, and N, N-diisopropylethylamine (121mg, 0.936mmol) and acryloyl chloride (42mg, 0.468mmol) were added and reacted at room temperature for 1.5 hours. The reaction solution was adjusted to pH 8 to 9 with saturated sodium bicarbonate solution, 20mL of dichloromethane and 10mL of water were added, layers were separated, the aqueous phase was extracted with dichloromethane (10mL × 2), the organic phases were combined, washed with saturated water brine (20mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude (tert-butyl 2-acrylamido-4- ((4-ethylpiperazin-1-yl) methyl) phenyl) (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamate 4j (192mg, yellow solid), which was directly subjected to the next reaction without purification. MS m/z (ESI): 823.8[ M +1]
The ninth step
N- (2- ((3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) amino) -5- ((4-ethylpiperazin-1-yl) methyl) phenyl) acrylamide
Tert-butyl (2-acrylamido-4- ((4-ethylpiperazin-1-yl) methyl) phenyl) (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamate 4j (192mg, 0.233mmol) was dissolved in 4mL of dichloromethane, and 1.5mL of trifluoroacetic acid was added to react at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in methylene chloride (10 mL. times.3) and then concentrated under reduced pressure, 10mL of methylene chloride and 5mL of water were added to the obtained residue, pH was adjusted to 9 with a saturated sodium bicarbonate solution, the layers were separated, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was purified by silica gel thin plate chromatography (developing solvent: system B) to obtain N- (2- ((3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) amino) -5- ((4-ethylpiperazin-1-yl) methyl) phenyl) acrylamide 4(20mg, light yellow solid), yield: 11.9 percent.
MS m/z(ESI)：721.8[M+1]
1H NMR(400MHz，CDCl3)69.33(s，1H)，8.39(s，1H)，8.38-8.35(m，1H)，7.88(s，1H)，7.62(s，1H)，7.51(s，1H)，7.11(s，1H)，6.92(s，1H)，6.62(s，1H)，6.51(s，1H)，6.39(d，J＝16.4Hz，1H)，5.69(d，J＝10.5Hz，1H)，4.24(s，2H)，3.93(s，6H)，3.58(s，2H)，3.08(d，J＝7.3Hz，6H)，2.84(d，J＝14.7Hz，6H)，2.72(s，6H)，2.24(s，2H)，0.87(s，3H).
Example 5
N- (2- ((3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) amino) -5- (1-methyl-1H-pyrazol-4-yl) phenyl) acrylamide
Figure BDA0001201979480000271
Figure BDA0001201979480000281
First step of
4- (1-methyl-1H-pyrazol-4-yl) -2-nitroaniline
4-bromo-2-nitroaniline 5a (1.00g, 4.61mmol), (1-methyl-1H-pyrazol-4-yl) boronic acid 5b (754mg, 5.99mmol), [1, 1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (388mg, 5.53mmol) and cesium carbonate (4.50g, 13.8mmol) were dissolved in 20mL of a mixed solvent of 1, 4 dioxane, tetrahydrofuran and water (V/V/V ═ 5/5/1) under an argon atmosphere, and reacted at 80 ℃ for 4 hours under an argon atmosphere. The reaction solution was cooled to room temperature, 100mL of ethyl acetate was added, the layers were separated, the aqueous phase was extracted with ethyl acetate (100mL × 3), the organic phases were combined, washed successively with water (200mL × 2) and saturated brine (300mL), and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a) to give 4- (1-methyl-1H-pyrazol-4-yl) -2-nitroaniline 5c (600mg, dark yellow solid), yield: 60 percent.
MS m/z(ESI)：218.9[M+1]
Second step of
3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -7- ((4- (1-methyl-1H-pyrazol-4-yl) -2-nitrophenyl) amino) -1, 6-naphthyridin-2 (1H) -one
7-chloro-3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -1, 6-naphthyridin-2 (1H) -one was dissolved in 10mL of toluene under an argon atmosphere for 1H (200mg, 0.425mmol), 4- (1-methyl-1H-pyrazol-4-yl) -2-nitroaniline 5c (102mg, 0.467mmol), 4, 5-bis-diphenylphosphino-9, 9-dimethylxanthene (49mg, 0.085mmol), tris (dibenzylideneacetone) dipalladium (39mg, 0.043mmol), and cesium carbonate (415mg, 1.27mmol) at 120 ℃ for 4 hours under an argon atmosphere. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give 3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -7- ((4- (1-methyl-1H-pyrazol-4-yl) -2-nitrophenyl) amino) -1, 6-naphthyridin-2 (1H) -one 5d (250mg, black solid), yield: 90.2 percent.
MS m/z(ESI)：651.8[M+1]
The third step
3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) (4- (1-methyl-1H-pyrazol-4-yl) -2-nitrophenyl) carbamic acid tert-butyl ester
3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -7- ((4- (1-methyl-1H-pyrazol-4-yl) -2-nitrophenyl) amino) -1, 6-naphthyridin-2 (1H) -one 5d (250mg, 0.383mmol) was dissolved in 6mL of tetrahydrofuran, di-tert-butyl dicarbonate (250mg, 1.14mmol) and 4-dimethylaminopyridine (8.9mg, 0.073mmol) were added, and the mixture was heated to 80 ℃ for reaction for 4 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give tert-butyl 3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) (4- (1-methyl-1H-pyrazol-4-yl) -2-nitrophenyl) carbamate 5e (280mg, yellow solid), yield: 97.2 percent.
MS m/z(ESI)：751.7[M+1]
The fourth step
(2-amino-4- (1-methyl-1H-pyrazol-4-yl) phenyl) (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamic acid tert-butyl ester
3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) (4- (1-methyl-1H-pyrazol-4-yl) -2-nitrophenyl) carbamic acid tert-butyl ester 5e (220mg, 0.292mmol) was dissolved in 5mL of methanol, Raney's nickel (100mg) was added, and the reaction was carried out under hydrogen atmosphere at room temperature for 1 hour. The reaction solution was filtered through celite, the filter cake was washed with a mixed solvent of dichloromethane and methanol (V/V ═ 10/1) (100mL × 3), and the filtrate was concentrated under reduced pressure to give crude (2-amino-4- (1-methyl-1H-pyrazol-4-yl) phenyl) (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamic acid tert-butyl ester 5f (140mg, pale yellow solid), yield: 66.4 percent. MS m/z (ESI): 721.8[ M +1]
The fifth step
(2-Acryloylamino-4- (1-methyl-1H-pyrazol-4-yl) phenyl) (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamic acid tert-butyl ester
Tert-butyl (2-amino-4- (1-methyl-1H-pyrazol-4-yl) phenyl) (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamate 5f (140mg, 0.193mmol) was dissolved in 5mL of dichloromethane, N-diisopropylethylamine (100mg, 0.774mmol) and acryloyl chloride (35mg, 0.387mmol) were added, and the reaction was carried out at room temperature for 12 hours. The reaction solution is adjusted to pH 8-9 by using a saturated sodium bicarbonate solution, layers are separated, a water phase is extracted by dichloromethane (10mL x2), organic phases are combined and dried by anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 5g (150mg, light yellow solid) of crude (2-acrylamido-4- (1-methyl-1H-pyrazol-4-yl) phenyl) (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamic acid tert-butyl ester, and a product is directly subjected to the next reaction without purification.
MS m/z(ESI)：776.2[M+1]
The sixth step
N- (2- ((3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) amino) -5- (1-methyl-1H-pyrazol-4-yl) phenyl) acrylamide
Tert-butyl (2-acrylamido-4- (1-methyl-1H-pyrazol-4-yl) phenyl) (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamate 5g (150mg, 0.193mmol) was dissolved in 3mL of dichloromethane, and 1mL of trifluoroacetic acid was added to react at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in dichloromethane (10 mL. times.3) and then concentrated under reduced pressure, 10mL of dichloromethane and 5mL of water were added to the obtained residue, the pH was adjusted to 8 to 9 with a saturated sodium bicarbonate solution, the layers were separated, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was purified by silica gel thin-plate chromatography (developing solvent: system B) to obtain N- (2- ((3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) amino) -5- (1-methyl-1H-pyrazol-4-yl) phenyl) acrylamide 5(26mg, yellow-green solid), yield: 20.0 percent.
MS m/z(ESI)：675.8[M+1]
1H NMR(400MHz，CDCl3)δ9.22(s，1H)，8.38(s，1H)，8.11(d，J＝20.6Hz，2H)，7.75(s，1H)，7.64(s，1H)，7.56(d，J＝8.4Hz，1H)，7.51(s，1H)，7.31(d，J＝8.3Hz，1H)，6.75(s，1H)，6.61(s，1H)，6.46(d，J＝9.8Hz，1H)，6.40(d，J＝16.8Hz，1H)，5.69(d，J＝11.3Hz，1H)，4.18(s，2H)，3.93(s，6H)，3.90(s，3H)，3.00(s，2H)，2.67(s，6H)，2.20(s，2H).
Example 6
N- (2- ((3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) amino) -5- (4-ethylpiperazin-1-yl) phenyl) acrylamide
Figure BDA0001201979480000301
First step of
N- (4-bromo-2-nitro-phenyl) -N-tert-butoxycarbonylcarbamic acid tert-butyl ester
4-bromo-2-nitroaniline 3a (7.50g, 34.56mmol) was dissolved in 90mL of tetrahydrofuran, di-tert-butyl dicarbonate (15.08g, 69.12mmol) and 4-dimethylaminopyridine (200mg, 1.64mmol) were added, and the reaction was allowed to warm to 80 ℃ for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a) to give tert-butyl N- (4-bromo-2-nitro-phenyl) -N-tert-butoxycarbonylcarbamate 6a (12.6g, yellow solid), yield: 87.4 percent.
MS m/z(ESI)：361.0[M+1-56]
Second step of
N-tert-Butoxycarbonyl-N- [4- (4-ethylpiperazin-1-yl) -2-nitro-phenyl ] carbamic acid tert-butyl ester
N- (4-bromo-2-nitro-phenyl) -N-tert-butoxycarbonylcarbamic acid tert-butyl ester 6a (5.40g, 12.94mmol), 1-ethylpiperazine 4e (2.22g, 2.00mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (3.00g, 5.18mmol), tris (dibenzylideneacetone) dipalladium (2.37g, 2.59mmol) and cesium carbonate (8.43g, 25.88mmol) were dissolved in 70mL of toluene and reacted at 120 ℃ for 4 hours under argon protection. The reaction solution was cooled to room temperature, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a) to give N-tert-butoxycarbonyl-N- [4- (4-ethylpiperazin-1-yl) -2-nitro-phenyl ] carbamic acid tert-butyl ester 6b (2.56g, magenta oily liquid), yield: 43.9 percent.
MS m/z(ESI)：351.0[M+1-100]
The third step
4- (4-ethylpiperazin-1-yl) -2-nitroaniline
Tert-butyl N-tert-butoxycarbonyl-N- [4- (4-ethylpiperazin-1-yl) -2-nitro-phenyl ] carbamate 6b (3.50g, 7.78mmol) was dissolved in 20mL of dichloromethane, and 20mL of trifluoroacetic acid was added to react at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, a saturated sodium bicarbonate solution was added to adjust pH 7 to 8, extraction was performed with dichloromethane (20mL × 3), the organic phases were combined, washed with water (30mL × 3), and concentrated under reduced pressure, and the obtained residue was purified by silica gel thin layer chromatography (developing solvent: system B) to give 4- (4-ethylpiperazin-1-yl) -2-nitroaniline 6c (1.81g, dark red solid), yield: 92.8 percent.
MS m/z(ESI)：251.3[M+1]
The fourth step
3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -7- ((4- (4-ethylpiperazin-1-yl) -2-nitrophenyl) amino) -1, 6-naphthyridin-2 (1H) -one
7-chloro-3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -1, 6-naphthyridin-2 (1H) -one was dissolved in 40mL of toluene under an argon atmosphere for 1H (1.00g, 2.12mmol), 4- (4-ethylpiperazin-1-yl) -2-nitroaniline 6c (585mg, 2.34mmol), 4, 5-bis-diphenylphosphino-9, 9-dimethylxanthene (246mg, 0.424mmol), tris (dibenzylideneacetone) dipalladium (195mg, 0.212mmol), and cesium carbonate (2.08g, 6.37mmol) at 120 ℃ for 4 hours under an argon atmosphere. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give 3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -7- ((4- (4-ethylpiperazin-1-yl) -2-nitrophenyl) amino) -1, 6-naphthyridin-2 (1H) -one 6d (679mg, black solid), yield: 46.8 percent.
MS m/z(ESI)：685.8[M+1]
The fifth step
3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) - (4- (4-ethylpiperazin-1-yl) -2-nitrophenyl) carbamic acid tert-butyl ester
3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -7- ((4- (4-ethylpiperazin-1-yl) -2-nitrophenyl) amino) -1, 6-naphthyridin-2 (1H) -one 6d (670mg, 0.97mmol) was dissolved in 20mL of tetrahydrofuran, di-tert-butyl dicarbonate (340.20mg, 1.47mmol) and 4-dimethylaminopyridine (119.6mg, 0.97mmol) were added, and the mixture was refluxed for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give tert-butyl 3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) - (4- (4-ethylpiperazin-1-yl) -2-nitrophenyl) carbamate 6e (560mg, yellow solid), yield: 72.9 percent.
The sixth step
(2-amino-4- (4-ethylpiperazin-1-yl) phenyl) (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamic acid tert-butyl ester
Tert-butyl 3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) - (4- (4-ethylpiperazin-1-yl) -2-nitrophenyl) carbamate 6e (560mg, 0.713mmol) was dissolved in 20mL of methanol, Raney's nickel (200mg) was added, and the reaction was carried out under hydrogen atmosphere at room temperature for 12 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give tert-butyl (2-amino-4- (4-ethylpiperazin-1-yl) phenyl) (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamate 6f (480mg, gray solid), yield: 89.2 percent. MS m/z (ESI): 754.8[ M +1]
Seventh step
(2-Acrylamido-4- (4-ethylpiperazin-1-yl) phenyl) (tert-butyl 3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamate
Tert-butyl (2-amino-4- (4-ethylpiperazin-1-yl) phenyl) (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamate 6f (300mg, 0.397mmol) was dissolved in 10mL of dichloromethane, and N, N-diisopropylethylamine (205mg, 1.59mmol) and acryloyl chloride (72mg, 0.795mmol) were added and reacted at room temperature for 2 hours. 5mL of dichloromethane and 5mL of water were added to the reaction solution, the pH was adjusted to 8-9 with a saturated sodium bicarbonate solution, the layers were separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude tert-butyl (2-acrylamido-4- (4-ethylpiperazin-1-yl) phenyl) (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamate 6g (321mg, yellow solid), which was reacted without purification in the next step.
MS m/z(ESI)：808.3[M+1]
Eighth step
N- (2- ((3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) amino) -5- (4-ethylpiperazin-1-yl) phenyl) acrylamide
Tert-butyl (2-acrylamido-4- (4-ethylpiperazin-1-yl) phenyl) (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamate 6g (321mg, 0.398mmol) was dissolved in 4mL of dichloromethane, and 1.5mL of trifluoroacetic acid was added to react at room temperature for 12 hours. The reaction solution was adjusted to pH 9 with saturated sodium bicarbonate solution, the layers were separated, the organic phase was concentrated under reduced pressure, and the resulting residue was purified by silica gel thin plate chromatography (developing solvent: B ═ 10: 1) to give N- (2- ((3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) amino) -5- (4-ethylpiperazin-1-yl) phenyl) acrylamide 6(30mg, yellow solid), yield: 10.7 percent.
MS m/z(ESI)：707.8[M+1]
Example 7
N- (2- ((3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) amino) -5- (morpholine-4-carbonyl) phenyl) acrylamide
Figure BDA0001201979480000321
Figure BDA0001201979480000331
First step of
(4-amino-3-nitrophenyl) (morpholinyl) methanone
4-amino-3-nitrobenzoic acid 7a (1.00g, 5.49mmol), morpholine 3c (960mg, 11.00mmol), 1-hydroxybenzotriazole (741.89mg, 5.50mmol), 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (1.05g, 5.50mmol) and N, N-diisopropylethylamine (3.30g, 22.00mmol) were dissolved in 60mL of N, N-dimethylformamide and reacted at room temperature for 3 hours. To the reaction mixture were added 80mL of dichloromethane and 50mL of water, the layers were separated, the organic phase was washed with water (50mL × 3), and the mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a) to obtain (4-amino-3-nitrophenyl) (morpholino) methanone 7b (800mg, yellow solid) in yield: 72.5 percent.
MS m/z(ESI)：251.9[M+1]
Second step of
3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -7- ((4- (morpholine-4-carbonyl) -2-nitrophenyl) amino) -1, 6-naphthyridin-2 (1H) -one
7-chloro-3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -1, 6-naphthyridin-2 (1H) -one was dissolved in 15mL of toluene under an argon atmosphere for 1H (500mg, 1.06mmol), (4-amino-3-nitrophenyl) (morpholino) methanone 7b (320mg, 1.27mmol), 4, 5-bis-diphenylphosphino-9, 9-dimethylxanthene (122mg, 0.212mmol), tris (dibenzylideneacetone) dipalladium (97mg, 0.106mmol), and cesium carbonate (1.04g, 3.19mmol), and reacted at 120 ℃ for 4 hours under an argon atmosphere. The reaction solution was cooled to room temperature, 20mL of dichloromethane and 20mL of water were added to the reaction solution, the layers were separated, the aqueous phase was extracted with dichloromethane (20mL), the organic phases were combined and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system B) to give 3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -7- ((4- (morpholine-4-carbonyl) -2-nitrophenyl) amino) -1, 6-naphthyridin-2 (1H) -one 7c (633mg, yellow solid), yield: 87.0 percent.
MS m/z(ESI)：684.7[M+1]
The third step
(3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) (4- (morpholine-4-carbonyl) -2-nitrophenyl) carbamic acid tert-butyl ester
3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -7- ((4- (morpholine-4-carbonyl) -2-nitrophenyl) amino) -1, 6-naphthyridin-2 (1H) -one 7c (600mg, 0.877mmol) was dissolved in 10mL of tetrahydrofuran, di-tert-butyl dicarbonate (382mg, 1.75mmol) and 4-dimethylaminopyridine (32mg, 0.263mmol) were added, and the mixture was heated to 80 ℃ for reaction for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give tert-butyl (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) (4- (morpholine-4-carbonyl) -2-nitrophenyl) carbamate 7d (594mg, yellow solid), yield: 86.5 percent.
MS m/z(ESI)：784.8[M+1]
The fourth step
(2-amino-4- (morpholine-4-carbonyl) phenyl) (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamic acid tert-butyl ester
Tert-butyl (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) (4- (morpholine-4-carbonyl) -2-nitrophenyl) carbamate 7d (594mg, 0.785mmol) was dissolved in 10mL of methanol, Raney's nickel (300mg) was added, and the reaction was carried out under hydrogen atmosphere at room temperature for 0.5 hour. The reaction solution was filtered through celite, the filter cake was washed with 30mL of a mixed solvent of dichloromethane and methanol (V/V ═ 10/1), and the filtrate was concentrated under reduced pressure to give tert-butyl (2-amino-4- (morpholine-4-carbonyl) phenyl) (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamate 7e (550mg, yellow solid) in yield: 96.3 percent.
MS m/z(ESI)：756.8[M+1]
The fifth step
(2-acryloyl-4- (morpholine-4-carbonyl) phenyl) (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamic acid tert-butyl ester
(2-amino-4- (morpholine-4-carbonyl) phenyl) (tert-butyl 3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamate 7e (550mg, 0.728mmol) was dissolved in 15mL of dichloromethane, N-diisopropylethylamine (376mg, 2.91mmol) and acryloyl chloride (132mg, 1.46mmol) were added, and the reaction was carried out at room temperature for 2 hours. 20mL of dichloromethane and 1mL of water were added to the reaction solution, the pH was adjusted to 8-9 with a saturated sodium bicarbonate solution, the layers were separated, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product of tert-butyl (2-acryloyl-4- (morpholine-4-carbonyl) phenyl) (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamate 7f (589mg, yellow solid), which was directly subjected to the next reaction without purification. MS m/z (ESI): 809.8[ M +1]
The sixth step
N- (2- ((3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) amino) -5- (morpholine-4-carbonyl) phenyl) acrylamide
Tert-butyl (2-acryloyl-4- (morpholine-4-carbonyl) phenyl) (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamate 7f (589mg, 0.728mmol) was dissolved in 8mL of dichloromethane and 1.5mL of trifluoroacetic acid was added and reacted at room temperature for 2 hours. The reaction solution was adjusted to pH 8 to 9 with saturated sodium bicarbonate solution, the layers were separated, the organic phase was dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent: system B) to obtain N- (2- ((3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) amino) -5- (morpholine-4-carbonyl) phenyl) acrylamide 7(130mg, yellow solid), yield: 25.2 percent.
MS m/z(ESI)：708.8[M+1]
1H NMR(400MHz，DMSO)δ9.94(s，1H)，8.93(s，1H)，8.56(s，1H)，7.84(d，J＝8.3Hz，1H)，7.82(s，1H)，7.76(s，1H)，7.26(d，J＝8.3Hz，1H)，6.99(s，1H)，6.86(s，1H)，6.57(dd，J＝17.1，10.2Hz，1H)，6.29(d，J＝16.9Hz，1H)，5.78(d，J＝12.1Hz，1H)，4.14(s，2H)，3.96(s，6H)，3.63(s，4H)，3.55(s，4H)，2.66(s.2H)2.28(s，6H)，1.83(s，2H).
Example 8
N- (2- ((3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) amino) -4-morpholinylphenyl) acrylamide
Figure BDA0001201979480000351
First step of
N- (5-bromo-2-nitro-phenyl) -N-tert-butoxycarbonylcarbamic acid tert-butyl ester
5-bromo-2-nitroaniline 8a (5.00g, 23.00mmol) was dissolved in 250mL of tetrahydrofuran, di-tert-butyl dicarbonate (8.30g, 69.00mmol) and 4-dimethylaminopyridine (1.60g, 12.00mmol) were added, and the mixture was heated to 70 ℃ to react for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system A) to give crude tert-butyl N- (5-bromo-2-nitro-phenyl) -N-tert-butoxycarbonylcarbamate 8b (11.59g, white green solid), which was subjected to the next reaction without purification.
MS m/z(ESI)：440.8[M+23]
Second step of
Boc-N- (5-morpholinyl-2-nitro-phenyl) carbamic acid tert-butyl ester
N- (5-bromo-2-nitro-phenyl) -N-tert-butoxycarbonylcarbamic acid tert-butyl ester 8b (2.00g, 4.78mmol), morpholine 3c (416mg, 4.78mmol), 4, 5-bis-diphenylphosphino-9, 9-dimethylxanthene (552mg, 0.956mmol), tris (dibenzylideneacetone) dipalladium (381mg, 0.478mmol) and cesium carbonate (4.67g, 14.34mmol) were dissolved in 30mL of toluene under an argon atmosphere and reacted at 110 ℃ for 4 hours. The reaction mixture was cooled to room temperature, filtered through celite, the filter cake was washed with ethyl acetate (50mL × 3), the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a) to obtain N-tert-butoxycarbonyl-N- (5-morpholinyl-2-nitro-phenyl) carbamic acid tert-butyl ester 8c (1.27g, tan solid), yield: 62.8 percent.
The third step
5-morpholinyl-2-nitroaniline
Tert-butyl N-butoxycarbonyl-N- (5-morpholinyl-2-nitro-phenyl) carbamate 8c (1.27g, 3.00mmol) was dissolved in 12mL of dichloromethane, 4mL of trifluoroacetic acid was added, and the reaction was carried out at room temperature for 2 hours. Adding 20mL of dichloromethane into the reaction solution, adjusting the pH to 8-9 with saturated sodium bicarbonate solution, separating layers, washing the organic phase with water (20mL × 3) and saturated brine (20mL) successively, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying the obtained residue with silica gel column chromatography (eluent: system B) to obtain 5-morpholinyl-2-nitroaniline 8d (410mg, yellow solid) with yield: 61.2 percent.
The fourth step
3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -7- ((5-morpholinyl-2-nitrophenyl) amino) -1, 6-naphthyridin-2 (1H) -one
7-chloro-3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -1, 6-naphthyridin-2 (1H) -one 1H (200mg, 0.895mmol), 5-morpholinyl-2-nitroaniline 8d (422mg, 0.895mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (51.8mg, 0.089mmol), tris (dibenzylideneacetone) dipalladium (41mg, 0.044mmol) and cesium carbonate (438mg, 1.34mmol) were dissolved in 30mL of toluene and refluxed for 4 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give 3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -7- ((5-morpholinyl-2-nitrophenyl) amino) -1, 6-naphthyridin-2 (1H) -one 8e (260mg, dark red solid) in yield: 38.9 percent.
MS m/z(ESI)：656.8[M+1]
The fifth step
3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) (5-morpholinyl-2-nitrophenyl) carbamic acid tert-butyl ester
3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -7- ((5-morpholinyl-2-nitrophenyl) amino) -1, 6-naphthyridin-2 (1H) -one 8e (260mg, 0.395mmol) was dissolved in 20mL of tetrahydrofuran, di-tert-butyl dicarbonate (86.3mg, 0.395mmol) and 4-dimethylaminopyridine (72.5mg, 0.593mmol) were added and refluxed for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give tert-butyl 3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) (5-morpholinyl-2-nitrophenyl) carbamate 8f (250mg, pale yellow solid), yield: 83.4 percent.
MS m/z(ESI)：756.8[M+I]
The sixth step
(2-amino-5-morpholinylphenyl) (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) - (1-3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamic acid tert-butyl ester
Tert-butyl 3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) (5-morpholinyl-2-nitrophenyl) carbamate 8f (240mg, 0.32mmol) was dissolved in 20mL of methanol, Raney's nickel (100mg) was added, and the reaction was carried out under hydrogen atmosphere at room temperature for 12 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give 8g (210mg, pale yellow solid) of crude tert-butyl (2-amino-5-morpholinylphenyl) (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) - (1-3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamate, yield: 91.1 percent.
MS m/z(ESI)：726.8[M+1]
Seventh step
(2-Acryloylamino-5-morpholinylphenyl) (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) - (1-3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamic acid tert-butyl ester
(2-amino-5-morpholinylphenyl) (tert-butyl 3- (2, 6-dichloro-3, 5-dimethoxyphenyl) - (1-3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamate 8g (210.0mg, 0.288mmol), acrylic acid (31.2mg, 0.432mmol), triethylamine (58.4mg, 0.577mmol) and bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (110.2mg, 0.432mmol) were dissolved in 20mL of dichloromethane and reacted at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give tert-butyl (2-acrylamido-5-morpholinylphenyl) (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) - (1-3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamate 8h (81mg, pale yellow solid), yield: 35.9 percent.
MS m/z(ESI)：780.8[M+1]
Eighth step
N- (2- ((3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) amino) -4-morpholinylphenyl) acrylamide
(2-Acryloylamino-5-morpholinylphenyl) (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) - (1-3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamic acid tert-butyl ester 8h (81.00mg, 0.103mmol) was dissolved in 3mL of dichloromethane and 1mL of trifluoroacetic acid was added and reacted at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, 20mL of dichloromethane was added, pH was adjusted to 8 to 9 with a saturated sodium bicarbonate solution, layers were separated, the organic phase was washed with water (10mL × 3) and a saturated brine (10mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was purified by silica gel thin plate chromatography (developing solvent: system B) to give N- (2- ((3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) amino) -4-morpholinylphenyl) acrylamide 8(29mg, gray solid) in yield: 39.6 percent.
MS m/z(ESI)：680.8[M+1]
1H NMR(400MHz，CDCl3)δ9.153(s，1H)，8.405(s，2H)，7.662(d，1H)，7.517(s，1H)，7.248(s，1H)，6.868(s，1H)，6.745(d，1H)，6.624(s，1H)，6.302-6.453(m，2H)，5.630(d，1H)，4.18-4.23(m，2H)，3.936(s，6H)，3.79-3.83(m，4H)，3.06-3.14(m，6H)，2.729(s，6H)，2.19-2.29(m，2H).
Example 9
N- (5- (1-acetyl-1, 2, 3, 6-tetrahydropyridin-4-yl) -2- ((3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) amino) phenyl) acrylamide
Figure BDA0001201979480000371
Figure BDA0001201979480000381
First step of
4- (4-acetylamino-3-nitrophenyl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester
N- (4-bromo-2-nitrophenyl) acetamide 3b (550mg, 2.12mmol), tert-butyl 4- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydro-2H-pyridine-1-carboxylate 9a (853mg, 2.76mmol), tricyclohexylphosphine (59mg, 0.212mmol), tris (dibenzylideneacetone) dipalladium (97mg, 0.106mmol), and cesium carbonate (2.08g, 6.37mmol) were dissolved in 40mL of water and a mixed solvent of 1, 4-dioxane (V/V1/4) under an argon atmosphere and reacted at 80 ℃ for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, added with 50mL of ethyl acetate and 20mL of water, separated into layers, and the organic phase was washed with a saturated sodium chloride solution (20mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give tert-butyl 4- (4-acetylamino-3-nitrophenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate 9B (644mg, yellow solid) in yield: 83.9 percent.
MS m/z(ESI)：383.9[M+23]
Second step of
N- (2-nitro-4- (1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) acetamide
4- (4-acetylamino-3-nitrophenyl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester 9b (640mg, 1.77mmol) was dissolved in 10mL of dichloromethane and 20mL of trifluoroacetic acid was added. The reaction was carried out at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, the obtained residue was dissolved in dichloromethane (10mL × 3) and concentrated under reduced pressure, the obtained residue was adjusted to pH 8 to 9 with saturated sodium bicarbonate solution, the layers were separated, the aqueous phase was extracted with dichloromethane (10mL × 3), the organic phase was washed with saturated sodium chloride solution (20mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude N- (2-nitro-4- (1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) acetamide 9c (463mg, yellow solid), and the product was directly subjected to the next reaction without purification.
MS m/z(ESI)：261.9[M+1]
The third step
N- (4- (1-acetyl-1, 2, 3, 6-tetrahydropyridin-4-yl) -2-nitrophenyl) acetamide
N- (2-Nitro-4- (1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) acetamide 9c (355mg, 1.36mmol) was dissolved in 15mL of dichloromethane, and N, N-diisopropylethylamine (351mg, 2.72mmol) and acetyl chloride (117mg, 1.49mmol) were added to react at room temperature for 5 minutes. The reaction was added with 20mL of water, separated into layers, and the organic phase was washed with saturated sodium chloride solution (20mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude N- (4- (1-acetyl-1, 2, 3, 6-tetrahydropyridin-4-yl) -2-nitrophenyl) acetamide 9d (397mg, yellow solid) in yield: 96.5 percent.
MS m/z(ESI)：303.9[M+1]
The fourth step
1- (4- (4-amino-3-nitrophenyl) -5, 6-dihydropyridin-1 (2H) -yl) ethanone
N- (4- (1-acetyl-1, 2, 3, 6-tetrahydropyridin-4-yl) -2-nitrophenyl) acetamide 9d (440mg, 1.45mmol) and potassium hydroxide (407mg, 7.25mmol) were dissolved in 18mL of a mixed solvent of water and ethanol (V/V ═ 1/2), and reacted at 80 ℃ for 5 minutes. To the reaction solution, 20mL of water and 50mL of dichloromethane were added, the layers were separated, the organic phase was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give 1- (4- (4-amino-3-nitrophenyl) -5, 6-dihydropyridin-1 (2H) -yl) ethanone 9e (235mg, red solid), yield: 62.0 percent.
MS m/z(ESI)：261.9[M+1]
The fifth step
7- ((4- (1-acetyl-1, 2, 3, 6-tetrahydropyridin-4-yl) -2-nitrophenyl) amino) -3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -1, 6-naphthyridin-2 (1H) -one
7-chloro-3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -1, 6-naphthyridin-2 (1H) -one was dissolved in 5mL of toluene for 4 hours at 120 ℃ under the protection of argon (100mg, 0.212mmol), 1- (4- (4-amino-3-nitrophenyl) -5, 6-dihydropyridin-1 (2H) -yl) ethanone 9e (61mg, 0.234mmol), 4, 5-bis-diphenylphosphino-9, 9-dimethylxanthene (25mg, 0.042mmol), tris (dibenzylideneacetone) dipalladium (20mg, 0.021mmol), and cesium carbonate (208mg, 0.637 mmol). The reaction solution was added with 10mL of water and 30mL of dichloromethane, the layers were separated, the aqueous phase was extracted with dichloromethane (20mL), the organic phases were combined, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give 7- ((4- (1-acetyl-1, 2, 3, 6-tetrahydropyridin-4-yl) -2-nitrophenyl) amino) -3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -1, 6-naphthyridin-2 (1H) -one 9f (115mg, yellow solid), yield: 77.7 percent.
MS m/z(ESI)：694.7[M+1]
The sixth step
(4- (1-acetyl-1, 2, 3, 6-tetrahydropyridin-4-yl) -2-nitrophenyl) (3- (2, 6-dichloro-3, 5-dimethoxybenzene)
1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamic acid tert-butyl ester
7- ((4- (1-acetyl-1, 2, 3, 6-tetrahydropyridin-4-yl) -2-nitrophenyl) amino) -3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -1, 6-naphthyridin-2 (1H) -one 9f (115mg, 0.165mmol) was dissolved in 4mL of tetrahydrofuran, di-tert-butyl dicarbonate (108mg, 0.496mmol) and 4-dimethylaminopyridine (20mg, 0.165mmol) were added, and the mixture was heated to 80 ℃ for reaction for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give 9g (140mg, yellow solid) of tert-butyl (4- (1-acetyl-1, 2, 3, 6-tetrahydropyridin-4-yl) -2-nitrophenyl) (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamate, which was directly subjected to the next reaction without purification.
MS m/z(ESI)：795.7[M+1]
Seventh step
(4- (1-acetyl-1, 2, 3, 6-tetrahydropyridin-4-yl) -2-aminophenyl) (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamic acid tert-butyl ester (4- (1-acetyl-1, 2, 3, 6-tetrahydropyridin-4-yl) -2-nitrophenyl) (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 9g (140mg, 0.176mmol) of tert-butyl 2-dihydro-1, 6-naphthyridin-7-yl) carbamate was dissolved in 8mL of methanol, and Raney nickel (200mg) was added and reacted at room temperature for 30 minutes under hydrogen protection. The reaction solution was filtered through celite, the filter cake was washed with a mixed solvent of dichloromethane and methanol (V/V ═ 10/1) (10mL × 3), and the filtrate was concentrated under reduced pressure to give tert-butyl (4- (1-acetyl-1, 2, 3, 6-tetrahydropyridin-4-yl) -2-aminophenyl) (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamate 9h (130mg, gray solid), yield: 97 percent.
MS m/z(ESI)：767.8[M+1]
Eighth step
(4- (1-acetyl-1, 2, 3, 6-tetrahydropyridin-4-yl) -2-acrylamido) (3- (2, 6-dichloro-3, 5-dimethoxybenzene
1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamic acid tert-butyl ester
Tert-butyl (4- (1-acetyl-1, 2, 3, 6-tetrahydropyridin-4-yl) -2-aminophenyl) (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamate 9h (130mg, 0.169mmol) was dissolved in 5mL of dichloromethane, N-diisopropylethylamine (88mg, 0.679mmol) and acryloyl chloride (38mg, 0.424mmol) were added and reacted at room temperature for 0.5 h. The reaction solution is adjusted to pH 8-9 by saturated sodium bicarbonate solution, layered, and concentrated under reduced pressure by organic phase to obtain crude tert-butyl (4- (1-acetyl-1, 2, 3, 6-tetrahydropyridin-4-yl) -2-acrylamido) (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamate 9i (139mg, yellow solid), which is directly subjected to the next reaction without purification.
MS m/z(ESI)：819.8[M+1]
The ninth step
N- (5- (1-acetyl-1, 2, 3, 6-tetrahydropyridin-4-yl) -2- ((3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) amino) phenyl) acrylamide
Tert-butyl (4- (1-acetyl-1, 2, 3, 6-tetrahydropyridin-4-yl) -2-acrylamido) (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamate 9i (139mg, 0.17mmol) was dissolved in 4mL of dichloromethane and 1mL of trifluoroacetic acid was added to react at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, the obtained residue was dissolved in dichloromethane (10mL × 3) and concentrated under reduced pressure, the obtained residue was adjusted to pH 8 to 9 with saturated sodium bicarbonate solution, the layers were separated, the aqueous phase was extracted with dichloromethane (10mL × 3), the organic phase was concentrated under reduced pressure, the obtained residue was purified by silica gel thin-plate chromatography (developing solvent: B system), and N- (5- (1-acetyl-1, 2, 3, 6-tetrahydropyridin-4-yl) -2- ((3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) amino) phenyl) acrylamide 9(10mg, yellow solid), yield: 8.2 percent.
MS m/z(ESI)：721.8[M+1]
1H NMR(400MHz，CDCl3)δ9.20(s，1H)，8.40(s，1H)，8.26(s，1H)，8.00(s，1H)，7.62(s，1H)，7.52(s，1H)，7.20(s，1H)，6.87(s，1H)，6.62(s，1H)，6.45(s，1H)，6.39(d，J＝15.7Hz，1H)，6.07(d，J＝24.6Hz，1H)，5.69(d，J＝10.8Hz，1H)，4.21(s，3H)，4.09(s，1H)，3.94(s，6H)，3.78(s，2H)，3.62(s，2H)，3.09(s，2H)，2.74(s，6H)，2.26(s，2H)，2.14(d，J＝9.3Hz，3H).
Example 10
N- (2- ((3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) amino) -5- (morpholinylmethyl) phenyl) acrylamide
Figure BDA0001201979480000401
Figure BDA0001201979480000411
First step of
4- (morpholinylmethyl) -2-nitroaniline
4-amino-3-nitrobenzaldehyde 4d (1.00g, 6.02mmol) was dissolved in 60mL of methanol under argon, morpholine 3c (1.04mL, 12.04mmol) and tetraisopropyltitanyl oxide (3.56mL, 12.04mmol) were added, and the mixture was stirred at room temperature for 12 hours. Cooled to 0 deg.C, sodium borohydride (412mg, 10.84mmol) was added, and the reaction was allowed to warm to room temperature for 2 hours. To the reaction solution was added 300mL of saturated sodium carbonate solution, extraction was performed with ethyl acetate (200mL × 2), the organic phases were combined, washed with saturated sodium chloride solution (200mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a) to give 4- (morpholinomethyl) -2-nitroaniline 10a (1.00g, yellow oil) in yield: 70 percent.
MS m/z(ESI)：237.9[M+1]
Second step of
3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -7- ((4- (morpholinylmethyl) -2-nitrophenyl) amino) -1, 6-naphthyridin-2 (1H) -one
7-chloro-3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -1, 6-naphthyridin-2 (1H) -one was dissolved in 10mL of toluene under an argon atmosphere for 1H (500mg, 1.06mmol), 4- (morpholinomethyl) -2-nitroaniline 10a (257mg, 1.08mmol), 4, 5-bis-diphenylphosphino-9, 9-dimethylxanthene (306mg, 0.53mmol), tris (dibenzylideneacetone) dipalladium (485mg, 0.53mmol) and cesium carbonate (1.03g, 3.18mmol), and reacted at 110 ℃ for 3.5 hours under an argon atmosphere. The reaction solution was cooled to room temperature, extracted with ethyl acetate (100mL), and the organic phase was washed with water (100mL × 2) and saturated sodium chloride solution (100mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give 3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -7- ((4- (morpholinomethyl) -2-nitrophenyl) amino) -1, 6-naphthyridin-2 (1H) -one 10B (671mg, brown-red solid), yield: 94 percent.
MS m/z(ESI)：670.8[M+1]
The third step
3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) (4- (morpholinylmethyl) -2-nitrophenyl) carbamic acid tert-butyl ester
3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -7- ((4- (morpholinomethyl) -2-nitrophenyl) amino) -1, 6-naphthyridin-2 (1H) -one 10b (671mg, 1.00mmol) was dissolved in 10mL of tetrahydrofuran, di-tert-butyl dicarbonate (436.5mg, 2.00mmol) and 4-dimethylaminopyridine (122mg, 1.00mmol) were added, and the mixture was heated to 80 ℃ for reaction at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give tert-butyl 3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) (4- (morpholinomethyl) -2-nitrophenyl) carbamate 10c (380mg, white solid), yield: 49.2 percent.
MS m/z(ESI)：771.8[M+1]
The fourth step
(2-amino-4- (4- (morpholinylmethyl) phenyl) (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamic acid tert-butyl ester
Tert-butyl 3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) (4- (morpholinylmethyl) -2-nitrophenyl) carbamate 10c (380mg, 0.49mmol) was dissolved in 10mL of a mixed solvent of methanol and tetrahydrofuran (V/V ═ 1/1), raney nickel (190mg) was added, and the reaction was carried out at room temperature for 4 hours under hydrogen protection. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give tert-butyl (2-amino-4- (4- (morpholinomethyl) phenyl) (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamate 10d (260mg, white solid) in 71.2% yield.
MS m/z(ESI)：742.8[M+1]
The fifth step
(2-Acryloylamino-4- (4- (morpholinylmethyl) benzene) (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamic acid tert-butyl ester
(2-amino-4- (4- (morpholinomethyl) phenyl) (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamic acid tert-butyl ester 10d (200mg, 0.27mmol) was dissolved in 8mL of dichloromethane, N-diisopropylethylamine (0.24mL, 1.35mmol) and acryloyl chloride (49mg, 0.54mmol) were added, and the reaction was carried out at room temperature for 1 hour, 100mL of dichloromethane and a saturated sodium bicarbonate solution (30mL) were added, the layers were separated, the organic phase was washed with a saturated sodium chloride solution (100mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude (2-acrylamido-4- (4- (morpholinomethyl) benzene) (3 d) Tert-butyl- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamate 10e (215mg, colorless oil) was used in the next reaction without purification.
MS m/z(ESI)：796.8[M+1]
The sixth step
N- (2- ((3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) amino) -5- (morpholinylmethyl) phenyl) acrylamide
(2-acrylamido-4- (4- (morpholinomethyl) benzene) (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamic acid tert-butyl ester 10e (215mg, 0.27mmol) was dissolved in 5mL of dichloromethane, 2mL of trifluoroacetic acid was added thereto, the reaction mixture was reacted at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure, 100mL of dichloromethane was added thereto, and the mixture was washed with a saturated sodium bicarbonate solution (100mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: System B) to give N- (2- ((3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) amino) -5- (morpholinylmethyl) phenyl) acrylamide 10(160mg, light yellow solid), yield: 85.1 percent.
MS m/z(ESI)：696.8[M+1]
1H NMR(400MHz，DMSO-d6)δ9.89-9.78(m，1H)，8.66-8.58(m，1H)，8.55-8.45(m，1H)，7.76(s，1H)，7.68-7.52(m，2H)，7.14(d，J＝8.0Hz，1H)，7.03-6.89(m，1H)，6.66(s，1H)，6.52(dd，J＝10.0，17.1Hz，1H)，6.27(d，J＝16.8Hz，1H)，5.83-5.67(m，1H)，4.14-4.02(m，2H)，3.96(s，6H)，3.64-3.52(m，4H)，3.46(s，2H)，2.39(br.s.，4H)，2.26(br.s.，2H)，2.15-2.05(m，6H)，1.78-1.64(m，2H).
Example 11
N- (2- ((3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) amino) -5- (cis-2, 6-dimethylmorpholine) phenyl) acrylamide
Figure BDA0001201979480000431
First step of
N- (4- (cis-2, 6-dimethylmorpholine) -2-nitrophenyl) acetamide
N- (4-bromo-2-nitrophenyl) acetamide 3b (1.00g, 3.86mmol), cis-2, 6-dimethylmorpholine 11a (445mg, 3.86mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (233mg, 0.386mmol), tris (dibenzylideneacetone) dipalladium (177mg, 0.193mmol) and cesium carbonate (3.77g, 11.58mmol) were dissolved in 40mL of toluene under an argon atmosphere and reacted at 100 ℃ for 4 hours. The reaction solution was concentrated under reduced pressure, 200mL of ethyl acetate and 200mL of water were added, the layers were separated, the chikura was extracted with ethyl acetate (100mL × 3), the organic phases were combined and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a) to obtain N- (4- (cis-2, 6-dimethylmorpholine) -2-nitrophenyl) acetamide 11b (950mg, orange-red solid), yield: 84 percent.
MS m/z(ESI)：293.9[M+1]
Second step of
4- (cis-2, 6-dimethylmorpholine) -2-nitroaniline
N- (4- (cis-2, 6-dimethylmorpholine) -2-nitrophenyl) acetamide 11b (950mg, 3.24mmol) was dissolved in 4M hydrochloric acid and refluxed for 3 hours. Adding 100mL of water into the reaction solution, adjusting the pH value of the solution to 8-9 by using a saturated sodium bicarbonate solution, extracting an organic phase by using dichloromethane (100mL x3), combining the organic phases, drying by using anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain crude 4- (cis-2, 6-dimethylmorpholine) -2-nitroaniline 11c (883mg, brown red solid), wherein the product is directly subjected to the next reaction without purification.
MS m/z(ESI)：251.9[M+1]
The third step
3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -7- ((4- (cis-2, 6-dimethylmorpholine) -2-nitrophenyl) amino) -1, 6-naphthyridin-2 (1H) -one
7-chloro-3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -1, 6-naphthyridin-2 (1H) -one 1H (240mg, 0.51mmol), 4- (cis-2, 6-dimethylmorpholine) -2-nitroaniline 11c (128mg, 0.51mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (59mg, 0.101mmol), tris (dibenzylideneacetone) dipalladium (47mg, 0.051mmol) and cesium carbonate (500mg, 1.53mmol) were dissolved in 10mL of toluene under an argon atmosphere and reacted at 120 ℃ for 4 hours. To the reaction solution were added 20mL of water and 30mL of dichloromethane, the layers were separated, the aqueous phase was extracted with dichloromethane, the combined organic phases were concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane: methanol system) to give 3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -7- ((4- (cis-2, 6-dimethylmorpholine) -2-nitrophenyl) amino) -1, 6-naphthyridin-2 (1H) -one 11d (288mg, black red solid), yield: 82.3 percent.
MS m/z(ESI)：684.8[M+1]
The fourth step
3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) (4- (cis-2, 6-dimethylmorpholine) -2-nitrophenyl) carbamic acid tert-butyl ester
3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -7- ((4- (cis-2, 6-dimethylmorpholine) -2-nitrophenyl) amino) -1, 6-naphthyridin-2 (1H) -one 11d (288mg, 0.42mmol) was dissolved in 8mL of tetrahydrofuran, di-tert-butyl dicarbonate (218mg, 1.26mmol) and 4-dimethylaminopyridine (122mg, 0.42mmol) were added, and the mixture was heated to 80 ℃ for reaction for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give tert-butyl 3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) (4- (cis-2, 6-dimethylmorpholine) -2-nitrophenyl) carbamate 11e (320mg, red solid), yield: 97.0 percent.
MS m/z(ESI)：365.6[(M+1-100)/2+23]
The fifth step
(2-amino-4- (cis-2, 6-dimethylmorpholine) phenyl) (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) - (1-3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamic acid tert-butyl ester
Tert-butyl 3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) (4- (cis-2, 6-dimethylmorpholine) -2-nitrophenyl) carbamate 11e (320mg, 0.41mmol) was dissolved in 10mL of methanol, Raney's nickel (300mg) was added, and the reaction was carried out at room temperature under hydrogen atmosphere for 12 hours. To the reaction solution, 50mL of dichloromethane was added, and filtered through celite, the filter cake was washed with 30mL of a mixed solvent of dichloromethane and methanol (V/V ═ 10/1), and the filtrate was concentrated under reduced pressure to give tert-butyl (2-amino-4- (cis-2, 6-dimethylmorpholine) phenyl) (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) - (1-3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamate 11f (300mg, yellow solid), yield: 97.7 percent.
MS m/z(ESI)：754.8[M+1]
The sixth step
(2-Acryloylamino-4- (cis-2, 6-dimethylmorpholine) phenyl) (tert-butyl 3- (2, 6-dichloro-3, 5-dimethoxyphenyl) - (1-3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamate
Tert-butyl (2-amino-4- (cis-2, 6-dimethylmorpholine) phenyl) (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) - (1-3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamate 11f (300mg, 0.397mmol) was dissolved in 10mL of dichloromethane, N-diisopropylethylamine (205mg, 1.59mmol) and acryloyl chloride (90mg, 0.992mmol) were added and reacted at room temperature for 0.5 hour. The reaction solution is adjusted to pH 8-9 by saturated sodium bicarbonate solution, layers are separated, the water phase is extracted by dichloromethane (10mL x2), the organic phases are combined and dried by anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 11g (321mg, yellow solid) of crude (2-acrylamido-4- (cis-2, 6-dimethylmorpholine) phenyl) (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) - (1-3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamic acid tert-butyl ester (11 g), and the product is directly subjected to the next reaction without purification.
MS m/z(ESI)：405.0[M/2+1]
Seventh step
N- (2- ((3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) amino) -5- (cis-2, 6-dimethylmorpholine) phenyl) acrylamide
11g (321mg, 0.396mmol) of tert-butyl (2-acrylamido-4- (cis-2, 6-dimethylmorpholine) phenyl) (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) - (1-3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamate was dissolved in 8mL of dichloromethane, and 2mL of trifluoroacetic acid was added thereto and reacted at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, the obtained residue was dissolved in dichloromethane (10mL × 3) and concentrated under reduced pressure, the obtained residue was adjusted to pH 8 to 9 with saturated sodium bicarbonate solution, the layers were separated, the organic phase was concentrated under reduced pressure, and the obtained residue was purified by silica gel thin-plate chromatography (developing solvent: system B) to obtain N- (2- ((3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (3- (dimethylamino) propyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) amino) -5- (cis-2, 6-dimethylmorpholine) phenyl) acrylamide 11(30mg, yellow solid), yield: 10.8 percent.
MS m/z(ESI)：710.8[M+1]
1H NMR(400MHz，CDCl3)δ8.38(s，1H)，8.34(s，1H)，7.91(s，1H)，7.50(s，1H)，7.16(s，1H)，6.86(s，1H)，6.73(d，J＝8.6Hz，1H)，6.61(s，1H)，6.39(d，J＝16.9Hz，1H)，6.27(d，J＝9.9Hz，2H)，5.71(d，J＝10.4Hz，1H)，4.11(s，2H)，3.93(s，6H)，3.79(s，2H)，3.52(d，J＝11.3Hz，2H)，2.46(t，J＝11.0Hz，4H)，2.27(s，6H)，1.87(s，2H)，1.26(s，6H).
Example 12
N- (4- ((3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (1- (methoxymethyl) cyclopropyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) amino) tetrahydrofuran-3-yl) acrylamide
Figure BDA0001201979480000451
Figure BDA0001201979480000461
First step of
1- (methoxymethyl) cyclopropylamine hydrochloride
2-Methoxyacetonitrile 12a (19.5g, 27.4mmol) and tetraisopropyltitanyl (90.68mL, 30.3mmol) were dissolved in 300mL of diethyl ether, cooled to-20 ℃ and argon was replaced three times, and ethylmagnesium bromide (73.1g, 54.9mmol) was added and reacted at-20 ℃ for 0.5 hour. The reaction was quenched by adding 60mL of water to the reaction system, filtered, the filter cake was washed with 1000mL of dichloromethane, a 4M solution of hydrogen chloride in ethyl acetate (100mL) was added to the filtrate, and the filtrate was concentrated under reduced pressure to give 1- (methoxymethyl) cyclopropylamine hydrochloride 12b (17.0g, a dark red solid), yield: 45.1 percent.
1H NMR(400MHz，CDCl3)δ7.32(d，J＝23.5Hz，3H)，3.50(s，2H)，3.45-3.39(m，3H)，1.30-1.14(m，2H)，0.77-0.69(m，2H).
Second step of
(6-chloro-4- ((1- (methoxymethyl) cyclopropyl) amino)) nicotinic acid ethyl ester
Ethyl 4, 6-dichloronicotinate 1a (20.0g, 90.8mmol), 1- (methoxymethyl) cyclopropylamine hydrochloride 12b (14.0g, 101.7mmol) and N, N-diisopropylethylamine (23.4g, 181.6mmol) were dissolved in 200mL of N, N-dimethylformamide, and the reaction mixture was heated to 90 ℃ for reaction for 3 hours. To the reaction solution were added 500mL of water and 500mL of dichloromethane, the layers were separated, the aqueous phase was extracted with dichloromethane (200mL × 3), the organic phases were combined, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a) to obtain (6-chloro-4- ((1- (methoxymethyl) cyclopropyl) amino)) ethyl nicotinate 12c (11.5g, colorless oily liquid), yield: 46 percent.
MS m/z(ESI)：285.0[M+1]
The third step
(6-chloro-4- ((1- (methoxymethyl) cyclopropyl) amino) pyridin-3-yl) methanol
Ethyl (6-chloro-4- ((1- (methoxymethyl) cyclopropyl) amino)) nicotinate 12c (11.0g, 38.61mmol) was dissolved in 200mL of tetrahydrofuran, cooled to 5 ℃, added with lithium aluminum hydride (2.93g, 77.2mmol), and then reacted at 5 ℃ for 30 minutes. To the reaction solution were added 3mL of water and 9mL of sodium hydroxide solution (20%) in this order, dried by adding anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give (6-chloro-4- ((1- (methoxymethyl) cyclopropyl) amino) pyridin-3-yl) methanol 12d (8.2g, colorless solid) in yield: 83 percent.
1H NMR(400MHz，CDCl3)δ7.76(s，1H)，6.83(s，1H)，6.12(s，1H)，4.57(s，2H)，3.48(s，1H)，3.43(s，2H)，3.33(d，J＝5.5Hz，3H)，0.98-0.81(m，4H).
The fourth step
(6-chloro-4- ((1- (methoxymethyl) cyclopropyl) amino) nicotinaldehyde
(6-chloro-4- ((1- (methoxymethyl) cyclopropyl) amino) pyridin-3-yl) methanol 12d (8.2g, 33.79mmol) was dissolved in 250mL of dichloromethane, and activated manganese dioxide (35.25g, 405.44mmol) was added to the solution to react at room temperature for 12 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give crude (6-chloro-4- ((1- (methoxymethyl) cyclopropyl) amino) nicotinaldehyde 12e (7.12g, gray solid) in 85.8% yield.
MS m/z(ESI)：240.9[M+1]
The fifth step
7-chloro-3- (3, 5-dimethoxyphenyl) -1- (1- (methoxymethyl) cyclopropyl) -1, 6-naphthyridin-2 (1H) -one
Dissolving (6-chloro-4- ((1- (methoxymethyl) cyclopropyl) amino) nicotinaldehyde 12e (0.90g, 4.15mmol) and methyl 2- (3, 5-dimethoxyphenyl) acetate 1f (873.45mg, 4.15mmol) in 10mL of N, N-dimethylformamide, slowly adding hexamethyldisilazane-based aminolithium (834mg, 6.23mmol), stirring at room temperature for 10 minutes, then heating to 80 ℃ to react for 2 hours, cooling the reaction solution to room temperature, quenching with 200mL of water, extracting with dichloromethane (20 mL. times.3), combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, purifying the residue with silica gel column chromatography (developer: B system) to obtain 7-chloro-3- (3, 5-dimethoxyphenyl) -1- (1- (methoxymethyl) cyclopropyl) -1, 6-naphthyridin-2 (1H) -one 12f (1.35g, oily liquid), yield: 90 percent.
MS m/z(ESI)：400.9[M+1]
The sixth step
7-chloro-3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (1- (methoxymethyl) cyclopropyl) -1, 6-naphthyridin-2 (1H) -one
7-chloro-3- (3, 5-dimethoxyphenyl) -1- (1- (methoxymethyl) cyclopropyl) -1, 6-naphthyridin-2 (1H) -one 12f (1.35g, 3.37mmol) was dissolved in 20mL of acetonitrile, the gas was replaced with argon three times, the reaction solution was cooled to 0 ℃ and sulfuryl chloride (1.00g, 7.41mmol) was added and reacted at 0 ℃ for 30 minutes. The reaction was concentrated, 10mL of saturated sodium bicarbonate solution was added, extraction was performed with dichloromethane (20mL), the organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developer: system B) to give 12g (1.2g, white powder) of 7-chloro-3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (1- (methoxymethyl) cyclopropyl) -1, 6-naphthyridin-2 (1H) -one, yield: 75.9 percent.
MS m/z(ESI)：470.7[M+1]
Seventh step
(4- ((3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (1- (methoxymethyl) cyclopropyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) amino) tetrahydrofuran-3-yl) carbamic acid tert-butyl ester
Under the protection of argon, 12g (500mg, 1.06mmol) of 7-chloro-3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (1- (methoxymethyl) cyclopropyl) -1, 6-naphthyridin-2 (1H) -one, tert-butyl (4-aminotetrahydrofuran-3-yl) carbamate (236.8mg, 1.17mmol), 4, 5-bis-diphenylphosphino-9, 9-dimethylxanthene (123.18mg, 0.213mmol), tris (dibenzylideneacetone) dipalladium (97.47mg, 0.106mmol) and cesium carbonate (693.61mg, 2.13mmol) were dissolved in 20mL of toluene and heated to 120 ℃ for 6 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give tert-butyl (4- ((3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (1- (methoxymethyl) cyclopropyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) amino) tetrahydrofuran-3-yl) carbamate 12i (198mg, off-white solid), yield: 29.3 percent.
MS m/z(ESI)：634.8[M+1]
Eighth step
7- ((4-Aminotetrahydrofuran-3-yl) amino) -3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (1- (methoxymethyl) cyclopropyl) -1, 6-naphthyridin-2 (1H) -one
Tert-butyl (4- ((3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (1- (methoxymethyl) cyclopropyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) amino) tetrahydrofuran-3-yl) carbamate 12i (180mg, 0.283mmol) was dissolved in 5mL of dichloromethane, and 5mL of trifluoroacetic acid was added to react at room temperature for 2 hours. The reaction was concentrated to dryness, 10mL of saturated sodium bicarbonate solution and 10mL of dichloromethane were added, layers were separated, and the organic phase was concentrated under reduced pressure to give crude 7- ((4-aminotetrahydrofuran-3-yl) amino) -3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (1- (methoxymethyl) cyclopropyl) -1, 6-naphthyridin-2 (1H) -one 12j (140mg, light yellow solid), yield: 92.3 percent.
MS m/z(ESI)：534.8[M+1]
The ninth step
N- (4- ((3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (1- (methoxymethyl) cyclopropyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) amino) tetrahydrofuran-3-yl) acrylamide
7- ((4-Aminotetrahydrofuran-3-yl) amino) -3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (1- (methoxymethyl) cyclopropyl) -1, 6-naphthyridin-2 (1H) -one 12j (150mg, 0.28mmol) and N, N-diisopropylethylamine (144.83mg, 1.12mmol) were dissolved in 10mL of dichloromethane, and acryloyl chloride (25.36mg, 0.28mmol) was added and reacted at room temperature for 2 hours. To the reaction solution was added 10mL of a saturated sodium bicarbonate solution, the aqueous phase was separated, the organic phase was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give N- (4- ((3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (1- (methoxymethyl) cyclopropyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) amino) tetrahydrofuran-3-yl) acrylamide 12(53mg, white solid) in yield: 32.9 percent.
MS m/z(ESI)：588.8[M+1]
1H NMR(400MHz，CDCl3)δ8.27(d，J＝7.7Hz，1H)，7.46(d，J＝2.4Hz，1H)，6.95(d，J＝12.6Hz，1H)，6.61(s，1H)，6.26(dd，J＝16.6，5.5Hz，1H)，6.08(dd，J＝17.0，10.2Hz，1H)，5.64(dd，J＝10.6，3.5Hz，1H)，5.38(d，J＝61.3Hz，1H)，4.71(ddd，J＝75.4，41.1，18.6Hz，2H)，4.37-4.09(m，3H)，3.94(d，J＝3.5Hz，6H)，3.87-3.72(m，2H)，3.29(d，J＝5.8Hz，3H)，3.23(dd，J＝14.8，10.6Hz，1H)，1.47-1.09(m，4H).
Example 13
N- (2- ((3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (1- (methoxymethyl) cyclopropyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) amino) -5- (4-ethylpiperazin-1-yl) phenyl) acrylamide
Figure BDA0001201979480000481
Figure BDA0001201979480000491
First step of
3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -7- ((4- (4-ethylpiperazin-1-yl) -2-nitrophenyl) amino) -1- (1- (methoxymethyl) -1, 6-naphthyridin-2 (1H) -one
In 20mL of toluene, 12g (300mg, 0.639mmol) of 7-chloro-3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (1- (methoxymethyl) cyclopropyl) -1, 6-naphthyridin-2 (1H) -one, 6c (161.45mg, 0.645mmol) of 4- (4-ethylpiperazin-1-yl) -2-nitroaniline, 4, 5-bis-diphenylphosphino-9, 9-dimethylxanthene (73.90mg, 0.128mmol), tris (dibenzylideneacetone) dipalladium (58.48mg, 0.064mmol) and cesium carbonate (417.17mg, 1.28mmol) were dissolved under an argon atmosphere and reacted at 120 ℃ for 4 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give 3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -7- ((4- (4-ethylpiperazin-1-yl) -2-nitrophenyl) amino) -1- (1- (methoxymethyl) -1, 6-naphthyridin-2 (1H) -one 13a (377mg, brown red solid) with a yield of 86.5%.
MS m/z(ESI)：684.8[M+1]
Second step of
3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (1- (methoxymethyl) cyclopropyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) - (4- (4-ethylpiperazin-1-yl) -2-nitrophenyl) carbamic acid tert-butyl ester
3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -7- ((4- (4-ethylpiperazin-1-yl) -2-nitrophenyl) amino) -1- (1- (methoxymethyl) -1, 6-naphthyridin-2 (1H) -one 13a (322mg, 0.471mmol) was dissolved in 20mL of tetrahydrofuran, di-tert-butyl dicarbonate (205.61mg, 0.941mmol) and 4-dimethylaminopyridine (28.77mg, 0.235mmol) were added, the reaction mixture was reacted at 75 ℃ for 2 hours, the reaction mixture was concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography (eluent: System B) to give 3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (1- (methoxymethyl) cyclopropyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) - (4- (4-ethylpiperazin-1-yl) -2-nitrophenyl) carbamic acid tert-butyl ester 13b (302mg, yellow solid), yield: 81.8 percent.
MS m/z(ESI)：782.8[M+1]
The third step
(2-amino-4- (4-ethylpiperazin-1-yl) phenyl) (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (1- (methoxymethyl) cyclopropyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamic acid tert-butyl ester
Tert-butyl 3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (1- (methoxymethyl) cyclopropyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) - (4- (4-ethylpiperazin-1-yl) -2-nitrophenyl) carbamate 13b (300mg, 0.383mmol) was dissolved in 20mL of methanol, raney nickel (600mg) was added, and the reaction was carried out at room temperature under a hydrogen atmosphere for 1 hour. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give tert-butyl (2-amino-4- (4-ethylpiperazin-1-yl) phenyl) (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (1- (methoxymethyl) cyclopropyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamate 13c (288mg, orange solid), yield: 100 percent.
MS m/z(ESI)：754.8[M+1]
The fourth step
(2-Acrylamido-4- (4-ethylpiperazin-1-yl) phenyl) (tert-butyl 3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (1- (methoxymethyl) cyclopropyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamate
Tert-butyl (2-amino-4- (4-ethylpiperazin-1-yl) phenyl) (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (1- (methoxymethyl) cyclopropyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamate 13c (288mg, 0.382mmol) was dissolved in 10mL of dichloromethane, and N, N-diisopropylethylamine (148.15mg, 1.15mmol) and acryloyl chloride (69.17mg, 0.762mmol) were added to react at room temperature for 0.5 hour. To the reaction mixture was added 10mL of dichloromethane and 10mL of saturated sodium bicarbonate solution, the aqueous phase was separated, and the organic phase was concentrated under reduced pressure to give crude tert-butyl (2-acrylamido-4- (4-ethylpiperazin-1-yl) phenyl) (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (1- (methoxymethyl) cyclopropyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamate 13d (245mg, yellow solid), yield: 79.3 percent.
MS m/z(ESI)：806.8[M+1]
The fifth step
N- (2- ((3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (1- (methoxymethyl) cyclopropyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) amino) -5- (4-ethylpiperazin-1-yl) phenyl) acrylamide
Tert-butyl (2-acrylamido-4- (4-ethylpiperazin-1-yl) phenyl) (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (1- (methoxymethyl) cyclopropyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) carbamate 13d (245mg, 0.303mmol) was dissolved in 5mL of dichloromethane, 5mL of trifluoroacetic acid was added, and the reaction was carried out at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, 10mL of a saturated sodium bicarbonate solution and 10mL of dichloromethane were added, the aqueous phase was separated, the organic phase was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give N- (2- ((3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (1- (methoxymethyl) cyclopropyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) amino) -5- (4-ethylpiperazin-1-yl) phenyl) acrylamide 13(177mg, pale yellow solid), yield: 82.7 percent.
MS m/z(ESI)：706.8[M+1]
1H NMR(400MHz，CDCl3)δ8.35(s，1H)，8.15(d，J＝13.9Hz，2H)，7.47(s，1H)，7.22(d，J＝8.6Hz，1H)，6.81(s，1H)，6.73(d，J＝6.1Hz，1H)，6.60(s，2H)，6.40(d，J＝16.8Hz，1H)，6.24-6.10(m，1H)，5.73(d，J＝10.6Hz，1H)，4.07(d，J＝10.7Hz，1H)，3.93(d，J＝3.4Hz，6H)，3.38(s，4H)，3.10(d，J＝8.4Hz，3H)，3.04(d，J＝10.8Hz，1H)，2.74(d，J＝58.4Hz，6H)，1.43(d，J＝7.1Hz，3H)，1.20-1.15(m，1H)，1.08(s，1H)，0.99(d，J＝6.2Hz，1H)，0.86(s，1H).
Example 14
N- ((3S, 4S) -3- ((3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (1- (methoxymethyl) cyclopropyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) amino) tetrahydro-2H-pyran-4-yl) acrylamide
Figure BDA0001201979480000511
First step of
7- (((3S, 4S) -4-azidotetrahydro-2H-pyran-3-yl) amino) -3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (1- (methoxymethyl) cyclopropyl) -1, 6-naphthyridin-2 (1H) -one
In 20mL of toluene, 12g (450.86mg, 1.12mmol) of 7-chloro-3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (1- (methoxymethyl) cyclopropyl) -1, 6-naphthyridin-2 (1H) -one, 14a (200mg, 1.12mmol) of 3S, 4S) -4-azidotetrahydro-2H-pyran-3-amine hydrochloride, 4, 5-bis-diphenylphosphino-9, 9-dimethylxanthene (129.58mg, 0.224mmol), tris (dibenzylideneacetone) dipalladium (102.53mg, 0.11mmol) and potassium tert-butoxide (188.46mg, 1.68mmol) were dissolved under argon and refluxed for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a) to give 7- (((3S, 4S) -4-azidotetrahydro-2H-pyran-3-yl) amino) -3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (1- (methoxymethyl) cyclopropyl) -1, 6-naphthyridin-2 (1H) -one 14b (180mg, white solid), yield: 31.6 percent.
MS m/z(ESI)：576.8[M+1]
Second step of
7- (((3S, 4S) -4-Aminotetrahydro-2H-pyran-3-yl) amino) -3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (1- (methoxymethyl) cyclopropyl) -1, 6-naphthyridin-2 (1H) -one
7- (((3S, 4S) -4-azidotetrahydro-2H-pyran-3-yl) amino) -3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (1- (methoxymethyl) cyclopropyl) -1, 6-naphthyridin-2 (1H) -one 14b (180mg, 0.313mmol) was dissolved in 10mL of methanol, Raney' S nickel (30mg) was added, and the reaction was carried out at room temperature for 2 hours under a hydrogen atmosphere. The reaction was filtered and the filtrate was concentrated under reduced pressure to give 7- (((3S, 4S) -4-aminotetrahydro-2H-pyran-3-yl) amino) -3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (1- (methoxymethyl) cyclopropyl) -1, 6-naphthyridin-2 (1H) -one 14c (152mg, white solid), yield: 88.6 percent.
MS m/z(ESI)：548.8[M+1]
The third step
N- ((3S, 4S) -3- ((3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (1- (methoxymethyl) cyclopropyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) amino) tetrahydro-2H-pyran-4-yl) acrylamide
7- (((3S, 4S) -4-Aminotetrahydro-2H-pyran-3-yl) amino) -3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (1- (methoxymethyl) cyclopropyl) -1, 6-naphthyridin-2 (1H) -one 14c (152mg, 0.276mmol), acrylic acid (29.9mg, 0.415mmol), triethylamine (56mg, 0.553mmol) and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (106.07mg, 0.553mmol) were dissolved in 5mL of dichloromethane and reacted at room temperature for 2 hours. The reaction was concentrated under reduced pressure and the residue obtained was purified by thin-plate chromatography (developer: system a) to give N- ((3S, 4S) -3- ((3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (1- (methoxymethyl) cyclopropyl) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) amino) tetrahydro-2H-pyran-4-yl) acrylamide 14(100mg, white solid), yield: and (5) 59.8%.
MS m/z(ESI)：602.8[M+1]
1H NMR(400MHz，CDCl3)δ9.251-9.314(m，1H)，8.025(s，1H)，7.379(s，1H)，7.118-7.210(m,2H)，6.217(s，1H)，6.283(t，J＝31.6Hz，1H)，6.093-6.179(m，1H)，5.665(t，J＝18.8Hz，1H)，4.551-4.580(m，1H)，4.166-4.253(dd，J＝34.8Hz，2H)，4.079-4.101(m，1H)，3.939-3.952(m，7H)，3.550-3.742(m，2H)，3.295(d，J＝37.2Hz，3H)，3.059-3.152(m，1H)，2.301-2.324(m，1H)，1.782-1.808(m，1H)，1.345-1.434(m，2H)，1.069-1.108(m，2H).
Biological evaluation
Test example 1 determination of FGFR kinase Activity by Compounds of the present invention
The following method was used to determine the extent of inhibition of kinase activity of recombinant human FGFR proteins by preferred compounds of the invention under in vitro conditions. The method uses Cisbio
Figure BDA0001201979480000522
The KinEASE-TK tyrosine kinase kit (cargo number 62TK0PEB) reflects the strong and weak inhibition of the FGFR kinase activity of a compound by determining the phosphorylation degree of a biotinylated polypeptide substrate mediated by FGFR protein based on time-resolved fluorescence energy resonance transfer (TF-FRET). Detailed experimental procedures reference may be made to the kitAnd (5) making a specification. Recombinant human FGFR proteins were purchased from Cama bioscience (japan, cat nos. FGFR1 #08-133, FGFR2 #08-134, FGFR3 #08-135, FGFR4 #08-136, respectively).
The experimental procedure is briefly described as follows: test compounds were first dissolved in DMSO to prepare a stock solution, and then diluted in a gradient of a buffer solution provided in the kit, to give a final concentration of the test compound in the reaction system in the range of 10 μ M to 0.1 nM. The concentration of Adenosine Triphosphate (ATP) solution used for the test was the pre-determined concentration of ATP Km values for each FGFR subtype. The reaction was performed in 384-well microwell plates by first adding the compound and an amount of FGFR protein to the wells and incubating at room temperature for 5-30 minutes, followed by adding the ATP solution and biotinylated polypeptide substrate solution to the reaction solution and incubating with shaking at room temperature for 50 minutes. Subsequently, an anti-phosphotyrosine antibody conjugated with a europium-based element compound and streptavidin conjugated with modified allophycocyanin XL665 were added to the reaction, and incubation was continued for 1 hour with shaking at room temperature. After the incubation, the fluorescence intensity values of each well at an excitation wavelength of 304nM, an emission wavelength of 620nM and 665nM are measured in a microplate reader in TF-FRET mode. The percent inhibition of the compound at each concentration was calculated by comparison with the fluorescence intensity ratio of the control group, and the IC of the compound was obtained by nonlinear regression analysis of the value-inhibition with compound concentration using GraphPad Prism 5 software50Values, see table 1.
Table 1 IC inhibition of FGFR enzyme activity by preferred compounds of the invention50Data of
Figure BDA0001201979480000521
As can be seen from table 1, the preferred compounds of the present invention have better inhibitory effect on FGFR4 and better selectivity than FGFR1, FGFR2 and FGFR 3.
N/A represents not determined.
Test example 2 determination of the Activity of the Compound of the present invention against hepatoma cell Huh7
The following methods were used to determine the effect of preferred compounds of the invention on tumor cell proliferation. The measurement was carried out by using Cell Counting Kit-8 Kit (Dojindo, Donken chemical technology). Aiming at FGFR4 subtype, liver cancer cell Huh7 (purchased from cell resource center of Shanghai Life sciences research institute of Chinese academy of sciences) is adopted for culture according to corresponding conditions.
The experimental method is briefly described as follows: test compounds were first dissolved in DMSO to prepare stock solutions, which were then diluted in a gradient of the culture medium of the corresponding cells to prepare test samples, with the final concentration of compound ranging from 30 μ M to 0.01 nM. Tumor cells in logarithmic growth phase were seeded at appropriate density into 96-well cell culture plates and after overnight incubation under the corresponding conditions, cells were cultured for an additional 72 hours after addition of test compound samples. After the culture is finished, adding a CCK-8 detection solution with an appropriate volume into each hole, incubating for 1-4 hours at 37 ℃, and then reading the absorbance value of each hole of the sample at 450nM on a microplate reader. The percentage inhibition rate of the compound at each concentration point is calculated by comparing the absorbance value with the control group, and then nonlinear regression analysis is carried out in GraphPad Prism 5 software according to the logarithmic inhibition rate of the compound concentration to obtain the IC of the compound for inhibiting cell proliferation50Values, see table 2.
TABLE 2 IC inhibition of hepatoma cell Huh7 activity by preferred compounds of the invention50Data of
Example numbering IC50(nM)/Huh7
2 11
3 11
10 7.5
11 4.2
12 28
As can be seen from table 2, the preferred compounds of the present invention have significant proliferation inhibitory effect on liver cancer cells with FGFR4 abnormality.
Test example 3 test of inhibitory Effect of the Compound of the present invention on in vivo growth of tumor in human hepatoma cell Hep 3B nude mouse transplantation tumor model
1. Purpose of experiment
The test is used for evaluating the inhibition effect of twice daily (BID) intraperitoneal Injection (IP) on the in vivo growth of the tumor of the human hepatoma cell Hep 3B nude mouse transplantation tumor model when a test object is continuously administered for 18 days.
2. Test article preparation
2.1 preparation of blank solvent control group administration preparation
Appropriate volumes of formulations containing 5% DMSO, 10% PEG300, 8% Tween 80 and 77% saline were formulated as a blank solvent control dosing formulation.
2.2 example 3 Compound dosing formulations
Weighing a proper amount of the compound in the embodiment 3, and filling the compound into a glass bottle; adding a proper volume of DMSO (dimethyl sulfoxide), carrying out vortex oscillation to completely dissolve the medicament, adding a proper volume of PEG300, Tween-80 and normal saline, and carrying out vortex oscillation uniformly to ensure that the volume ratio of DMSO to PEG300 to Tween-80: the ratio of the physiological saline is 5: 10: 8: 77(v/v/v/v), and the preparation is prepared into an administration preparation with an effective concentration of 5 mg/mL.
3. Laboratory animal
Female BALB/c nude mice (number: 16; week age: 5-7 weeks, quality certificate number: 11400700159209) were purchased from Beijing Wittisley Hua laboratory animal technology Co., Ltd, and were bred in SPF animal house, St.Susu New drug development Co., Ltd, Suzhou, at a temperature of 20-25 ℃, a relative humidity of 40-70%, and light and dark illumination for 12 hours each; animals had free access to water and food. After about 5 days of normal feeding, mice with good physical signs can be selected for the experiment through veterinary examination.
4. Tumor cell culture
At 5% CO2Performing conventional cell culture on the Hep 3B cells in EMEM culture solution containing 10% fetal calf serum under the culture condition of 37 ℃; passage with 0.25% pancreatin; the cells are passaged according to the growth condition of the cells, and the passage ratio is 1: 3 to 1: 6.
5. Animal vaccination and grouping
On the 0 th day of the experiment, Hep 3B cells in the logarithmic growth phase are collected, counted and then resuspended in serum-free EMEM medium, and the cell concentration is adjusted to 5 × 107cell/mL; placing the centrifuge tube in an ice bin; the cell suspension was aspirated by a 1mL syringe, injected subcutaneously into the right forelimb armpit of nude mice, and inoculated with 100. mu.L (5X 10) per animal6Cell/cell), establishing a Hep 3B nude mouse transplantation tumor model. The mean tumor volume reached about 150mm by day 9 of inoculation 316 tumor-bearing mice with good health condition and similar tumor volume are selected and divided into 2 groups by a random block method.
6. Animal dosing and observation
Animals were grouped, the solvent blank control group and the compound of example 3 group, 8 animals per group, and the first administration was started on the day of grouping (day 9 of inoculation) at a dose volume of 10 mL/kg. Group 1 was a blank solvent control group, and blank solvent was administered by intraperitoneal injection 2 times per day (BID). Group 2 test samples of the compound of example 3 were administered intraperitoneally at a dose of 50mg/kg (BID). The administration was continued for 26 days.
The formation of tumors at the inoculated sites of the animals in each group was observed, the tumor size was measured 2 times per week after the start of the experiment, and the tumor volume was calculated while the animal body weight was weighed and recorded.
Tumor Volume (TV) calculation formula is as follows:
TV(mm3)＝l×w2/2
wherein l represents the tumor major axis (mm); w represents the tumor minor diameter (mm).
The formula for the Relative Tumor Volume (RTV) is:
RTV＝100×TVt/TVinitial
wherein, TVinitialTumor volume measured when administered in groups; TV (television)tThe tumor volume at each measurement during dosing.
The relative tumor proliferation rate (% T/C) was calculated by the following formula: % T/C100% × (RTV)T/RTVC)
Wherein, RTVTRepresenting treatment group RTV; RTVCRepresenting a blank solvent control RTV.
The calculation formula of the tumor growth inhibition rate TGI (%) is as follows:
TGI＝100％×[1-(TVt(T)-TVinitial(T))/(TVt(C)-TVinitial(C))]
wherein, TVt(T)Represents the tumor volume for each measurement in the treatment group; TV (television)initial(T)Represents the tumor volume of the treatment group when administered in groups; TV (television)t(C)Represents the tumor volume of each measurement of the blank solvent control group; TV (television)initial(C)Tumor volumes of the blank solvent control group at the time of group administration are shown.
The formula for calculating the weight loss rate of the animals is as follows: weight loss rate of animal (BW) 100 × (BW)initial-BWt)/BWinitial
Wherein, BWtRepresents the animal body weight measured at each time during the dosing period; BW (Bandwidth)initialThe body weight of the animals at the time of the group administration is indicated.
The calculation formula of the tumor weight inhibition rate IR (%) is as follows: IR (%). 100% × (W)C-WT)/WC
Wherein, WCRepresenting tumor weight of control group; wTIndicates the tumor weight of the treated group.
7. Results
TABLE 1 mean tumor volume and tumor growth inhibition rate for each group of animals during dosing
Figure BDA0001201979480000541
Figure BDA0001201979480000551
The change in mean tumor volume for each group of animals during the administration period is shown in FIG. 1.
TABLE 2 relative mean tumor volume and relative tumor proliferation rate for each group of animals during dosing
Figure BDA0001201979480000552
The relative mean tumor volumes of the groups of animals during the dosing period are shown in figure 2.
TABLE 3 tumor weight and tumor inhibition rate of each group of animals at the end of the experiment
Figure BDA0001201979480000553
Note: in tables 1-3, "+" indicates that there was a very significant difference in tumor volume compared to the solvent blank control group (P < 0.01).
TABLE 4 body weight and weight loss rates of the groups of animals during the dosing period
Figure BDA0001201979480000554
And (4) conclusion: as can be seen from tables 1-4 and figures 1-2, the compound of example 3 has an obvious inhibitory effect on the growth of tumor of human hepatoma cell Hep 3B nude mouse transplantation tumor model at a dose of 50 mg/kg.

Claims (25)

1. A compound of formula (II) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:
Figure FDA0002814661840000011
wherein:
ring A is selected from C3-C6Cycloalkyl, 4-to 8-membered heterocyclic group or phenyl;
each R1Each independently selected from hydrogen atom, C1-C6Alkyl, halogen or C1-C6Alkoxy, wherein said C1-C6Alkyl or C1-C6Alkoxy is optionally further substituted by one or more groups selected from hydroxy, halogen, C1-C6Alkoxy or-NR10R11Substituted with the substituent(s);
R2in ortho position to the-NH-of ring A, selected from the following groups:
-NR6C(O)CR7＝CHR8or-NR6C(O)C≡CR7；
Each R3Each independently selected from hydrogen atom, halogen, C1-C6Alkoxy, hydroxy, C1-C6Alkyl radical, C3-C6Cycloalkyl, 3-to 8-membered heterocyclic group, C6-C10Aryl, 5-to 6-membered heteroaryl, -C (O) R9or-NR10R11Wherein said C1-C6Alkoxy radical, C1-C6Alkyl radical, C3-C6Cycloalkyl, 3-to 8-membered heterocyclic group, C6-C10Aryl or 5-6 membered heteroaryl optionally further substituted with one or more groups selected from hydroxy, halogen, C1-C6Alkyl radical, C1-C6Alkoxy, heterocyclyl, halo C1-C6Alkoxy or-C (O) R9Substituted with the substituent(s);
(i)R4is selected from C1-C6Alkyl, wherein said C1-C6Alkyl being further substituted by-NRARBSubstituted;
RAand RBEach independently selected from a hydrogen atom or C1-C6Alkyl radical, wherein said C1-C6Alkyl is optionally further substituted by one or more groups selected from hydroxy, haloElement or C1-C6Substituted by a substituent of alkoxy; or
(ii)R4Is selected from-CRCRD-(CH2)s-ORE；
RCAnd RDTo the connection RCAnd RDThe C atoms are cyclized together to form 3-6 membered cycloalkyl;
REis selected from C1-C6An alkyl group;
each R6Each independently selected from a hydrogen atom or C1-C6Alkyl, wherein said C1-C6Alkyl is optionally further substituted by one or more groups selected from hydroxy, halogen, C1-C6Alkoxy or halo C1-C6Substituted by a substituent of alkoxy;
R7and R8Each independently selected from hydrogen atom, C1-C6Alkyl or halogen, wherein said C1-C6Alkyl is optionally further substituted by one or more groups selected from hydroxy, halogen, C1-C6Alkoxy or halo C1-C6Substituted by a substituent of alkoxy;
R9、R10and R11Each independently selected from hydrogen atom, C1-C6Alkyl radical, C3-C6Cycloalkyl or heterocyclyl, wherein said C1-C6Alkyl radical, C3-C6Cycloalkyl or heterocyclyl is optionally further substituted by one or more groups selected from hydroxy, halogen, C1-C6Alkyl or C1-C6Substituted by a substituent of alkoxy;
or, R10And R11Together with the N atom to which they are attached form a 4-to 8-membered heterocyclic group containing one or more N, O, S (O) atoms in the 4-to 8-membered heterocyclic groupqAtom, and 4-8 membered heterocycle is further substituted by one or more groups selected from hydroxyl, halogen, C1-C6Alkyl is substituted by a substituent;
m is 1,2, 3 or 4;
p is 0, 1,2, 3 or 4;
q is 0, 1 or 2; and is
s is selected from 1,2, 3 or 4.
2. The compound of claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein each R1Each independently selected from halogen or C1-C6An alkoxy group.
3. The compound of claim 1 or 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein each R1Each independently selected from chloro or methoxy.
4. The compound according to claim 1 or 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R2is-NHC (O) CH ═ CH2。
5. A compound according to claim 1 or 2, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:
each R3Each independently selected from a hydrogen atom; or
Each R3Each independently selected from 3-8 membered heterocyclic group, wherein said 3-8 membered heterocyclic group is optionally further substituted with one or more C1-C6Alkyl substituted; or
Each R3Each independently selected from C1-C6Alkyl, wherein said C1-C6The alkyl group is further substituted with a 3-8 membered heterocyclic group, wherein said 3-8 membered heterocyclic group is optionally further substituted with one or more C1-C6Alkyl substituted; or
Each R3Each independently selected from-C (O) R9Wherein R is9Selected from 3-8 membered heterocyclic group, wherein said 3-8 membered heterocyclic group is optionally further substituted with one or more C1-C6Alkyl groups are substituted.
6. A compound according to claim 1 or 2, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:
each R3Each independently selected from a hydrogen atom; or
Each R3Each independently selected from 5-6 membered heterocyclic group, wherein said 5-6 membered heterocyclic group is optionally further substituted with one or more C1-C6Alkyl substituted; or
Each R3Each independently selected from C1-C6Alkyl, wherein said C1-C6The alkyl group is further substituted with a 5-6 membered heterocyclic group, wherein said 5-6 membered heterocyclic group is optionally further substituted with one or more C1-C6Alkyl substituted; or
Each R3Each independently selected from-C (O) R9Wherein R is9Selected from 5-6 membered heterocyclic group, wherein said 5-6 membered heterocyclic group is optionally further substituted by one or more C1-C6Alkyl groups are substituted.
7. The compound of claim 1 or 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein each R3Each independently selected from halogen.
8. The compound of claim 1 or 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein each R3Each independently selected from F, Cl or Br.
9. The compound of claim 1 or 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein each R3Each independently selected from F or Cl.
10. The compound of claim 1 or 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein ring a is tetrahydrofuranyl or tetrahydropyranyl.
11. A compound according to claim 1 or 2, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof,
wherein:
R4is selected from- (CH)2)rNRARB；
r is selected from 1,2, 3 or 4;
RAand RBEach independently selected from a hydrogen atom or C1-C6Alkyl, wherein said C1-C6Alkyl is optionally further substituted with one or more substituents selected from hydroxy, halogen; or
R4Is selected from-CRCRD-(CH2)s-ORE；
s is selected from 1,2, 3 or 4;
RCand RDTo the connection RCAnd RDThe C atoms are cyclized together to form 3-6 membered cycloalkyl;
REis selected from C1-C6An alkyl group.
12. A compound according to claim 1 or 2, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof,
wherein:
R2selected from-NHC (O) CH ═ CH2；
R4Is selected from- (CH)2)rNRARB；
r is selected from 1,2, 3 or 4;
RAand RBEach independently selected from a hydrogen atom or C1-C6Alkyl, wherein said C1-C6Alkyl is optionally further substituted with one or more substituents selected from hydroxy, halogen; or
R2Selected from-NHC (O) CH ═ CH2；
R4Is selected from-CRCRD-(CH2)s-ORE；
s is selected from 1,2, 3 or 4;
RCand RDTo the connection RCAnd RDThe C atoms are cyclized together to form 3-6 membered cycloalkyl;
REis selected from C1-C6An alkyl group.
13. A compound according to claim 4, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:
each R3Each independently selected from a hydrogen atom; or
Each R3Each independently selected from 3-8 membered heterocyclic group, wherein said 3-8 membered heterocyclic group is optionally further substituted with one or more C1-C6Alkyl substituted; or
Each R3Each independently selected from C1-C6Alkyl, wherein said C1-C6The alkyl group is further substituted with a 3-8 membered heterocyclic group, wherein said 3-8 membered heterocyclic group is optionally further substituted with one or more C1-C6Alkyl substituted; or
Each R3Each independently selected from-C (O) R9Wherein R is9Selected from 3-8 membered heterocyclic group, wherein said 3-8 membered heterocyclic group is optionally further substituted with one or more C1-C6Alkyl groups are substituted.
14. A compound according to claim 4, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:
each R3Each independently selected from a hydrogen atom; or
Each R3Each independently selected from 5-6 membered heterocyclic group, wherein said 5-6 membered heterocyclic group is optionally further substituted with one or more C1-C6Alkyl substituted; or
Each R3Each independently selected from C1-C6Alkyl, wherein said C1-C6The alkyl group is further substituted with a 5-6 membered heterocyclic group, wherein said 5-6 membered heterocyclic group is optionally further substituted with one or more C1-C6Alkyl substituted; or
Each R3Each independently selected from-C (O) R9Wherein R is9Selected from 5-6 membered heterocyclic group, wherein said 5-6 membered heterocyclic group is optionally further substituted by one or more C1-C6Alkyl groups are substituted.
15. A compound according to claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of:
Figure FDA0002814661840000031
Figure FDA0002814661840000041
16. a process for the preparation of a compound of formula (II) according to claim 1, which process comprises:
Figure FDA0002814661840000042
compounds of the general formula (IA) with Y-C (O) CR7＝CHR8Or Y-C (O) C ≡ CR7Reacting to obtain a compound of a general formula (IB);
Figure FDA0002814661840000043
wherein:
Raselected from the group consisting of a hydrogen atom or an amino protecting group selected from the group consisting of a benzenesulfonyl group, a benzyloxycarbonyl group, a formyl group, a trifluoroacetyl group and a tert-butoxycarbonyl group;
y is halogen;
when R isaWhen the hydrogen atom is used, the compound of the general formula (IB) is the compound of the general formula (II);
when R isaWhen it is an amino-protecting group, R is further removedaTo obtain the compound of the general formula (II),
Figure FDA0002814661840000051
wherein:
Figure FDA0002814661840000052
is a single bond, X is CH, R5Is oxo, n is 1, R1～R4M and p are as defined in claim 1.
17. The process for preparing a compound of formula (II) according to claim 16, wherein the amino protecting group is benzenesulfonyl or tert-butoxycarbonyl.
18. A compound of formula (IA) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:
Figure FDA0002814661840000053
wherein:
Raselected from the group consisting of a hydrogen atom or an amino protecting group selected from the group consisting of a benzenesulfonyl group, a benzyloxycarbonyl group, a formyl group, a trifluoroacetyl group and a tert-butoxycarbonyl group;
Figure FDA0002814661840000054
is a single bond, X is CH, R5Is oxo, n is 1, R1、R3～R4M and p are as defined in claim 1.
19. A compound according to claim 18, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the amino protecting group is selected from phenylsulfonyl or tert-butoxycarbonyl.
20. A compound according to claim 18, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of:
Figure FDA0002814661840000055
Figure FDA0002814661840000061
21. a pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1-15, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or combination thereof.
22. Use of a compound according to any one of claims 1 to 15, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 21, in the manufacture of a medicament for use in inhibiting FGFR 4.
23. Use of a compound according to any one of claims 1 to 15, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 21, for the preparation of a medicament for the treatment of a disease involving FGF19 amplification or overexpression of FGFR 4.
24. Use of a compound according to any one of claims 1 to 15, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 21, for the manufacture of a medicament for the treatment of a cancer selected from the group consisting of non-small cell lung cancer, gastric cancer, multiple myeloma, liver cancer, and cholangiocarcinoma.
25. Use of a compound according to any one of claims 1 to 15, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 21, for the manufacture of a medicament for the treatment of a cancer selected from the group consisting of liver cancer and cholangiocarcinoma.
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