CN116903613A - 2-oxo quinazoline five-membered heterocyclic derivative, preparation method and application thereof - Google Patents

2-oxo quinazoline five-membered heterocyclic derivative, preparation method and application thereof Download PDF

Info

Publication number
CN116903613A
CN116903613A CN202310465844.2A CN202310465844A CN116903613A CN 116903613 A CN116903613 A CN 116903613A CN 202310465844 A CN202310465844 A CN 202310465844A CN 116903613 A CN116903613 A CN 116903613A
Authority
CN
China
Prior art keywords
alkyl
group
membered
alkylene
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202310465844.2A
Other languages
Chinese (zh)
Inventor
刘刚
曾宏
王英
朱万渠
巩晓明
宋彬彬
潘德思
鲁先平
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Chengdu Weixin Pharmaceutical Co ltd
Shenzhen Chipscreen Biosciences Co Ltd
Original Assignee
Chengdu Weixin Pharmaceutical Co ltd
Shenzhen Chipscreen Biosciences Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Chengdu Weixin Pharmaceutical Co ltd, Shenzhen Chipscreen Biosciences Co Ltd filed Critical Chengdu Weixin Pharmaceutical Co ltd
Publication of CN116903613A publication Critical patent/CN116903613A/en
Pending legal-status Critical Current

Links

Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D471/12—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 three hetero rings
    • C07D471/14—Ortho-condensed systems

Abstract

The invention provides a 2-oxo quinazoline five-membered heterocyclic derivative with a structure shown in a formula (IA). The experimental result shows that the compound provided by the invention has strong inhibition activity on proliferation of recombinant human MAT2A cells, and can be used for treating and/or preventing diseases related to MAT2A expression abnormality.

Description

2-oxo quinazoline five-membered heterocyclic derivative, preparation method and application thereof
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to a 2-oxo quinazoline five-membered heterocyclic derivative, a preparation method and application thereof.
Background
Methionine adenosyltransferase 2A (MAT 2A) is an enzyme that synthesizes s-adenosylmethionine (SAM) using methionine (Met) and Adenosine Triphosphate (ATP), where SAM is the predominant methyl donor in an organism. Tumor development is associated with DNA methylation abnormalities, wherein the methyl group required for the methylation reaction provides SAM, whereas MAT2A is the primary enzyme regulating SAM biosynthesis, directly affecting SAM content, leading to DNA methylation abnormalities, indirectly leading to tumor development. (EBiomedicine, 2019.39:p.575-590.) MAT2A is widely expressed in extrahepatic tissues and non-hepatic parenchymal cells, is expressed at low level in normal adult liver, is highly expressed in tumor, and promotes proliferation and metastasis of tumor cells. (Experimental Biology and Medicine 2017; 0:1-11;)
Methylthioadenosine phosphorylase (MTAP) is an enzyme that catalyzes the phosphorylation of Methylthioadenosine (MTA) as part of the metabolic pathway of Methionine (Methionine) cycle. MTAP coding gene is closely related to an cancer suppressor gene CDKN2A (p 16), and the MTAP coding gene and the cancer suppressor gene are located at the chr9p21 locus together, so that the MTAP coding gene is a common heterozygous deletion in various cancers. In approximately 15% of human cancers, the MTAP/CDKN2A gene is deleted. In MTAP-deleted (MTAP-/-) cancers, there is no MTAP-mediated methionine metabolic compensation pathway, and MTAP-/-cancer cells rely heavily on MAT 2A-mediated SAM anabolic pathways to maintain normal metabolism of cancer cells. Studies have shown that knockdown MAT2A selectively inhibited MTAP-/-tumor cell growth, but had no significant effect on MTAP wild-type (MTAP WT) cell growth. Thus, in MTAP-/-tumors, MAT2A depletion can lead to synthetic lethality of tumor cells. (Cell Rep,2016.15 (3): p.574-587)
In 2018, the number of cancer attacks in the world reaches 1807 ten thousand, the number of cancer attacks in the world reaches 2411 ten thousand (33.4% increase) in 2030, and the proportion of MTAP gene-deleted patients reaches about 362 ten thousand; global tumor drug therapy expenditure in 2019 is about 844 billions of dollars, and tumor therapy market demand is enormous. Aiming at MAT2A, there are no marketed inhibitors at home and abroad, 2 varieties are in clinical phase I study, 2 varieties are in preclinical study, and the data disclosed at present show that the existing MAT2A inhibitors have poor clinical effects and are accompanied by serious hematotoxicity (Heist, rebecca S, et al AACR, 2019). Therefore, MAT2A inhibitors have attracted research interest from many pharmaceutical companies, and the development of specific MAT2A inhibitors can become an emerging therapeutic means for improving the therapeutic effect of MTAP-deficient cancers.
Disclosure of Invention
Problems to be solved by the application:
although some patent applications for MAT2A inhibitors have been published, new compounds still need to be further developed based on the huge market demand of MTAP-/-cancer patients and the poor clinical performance of existing MAT2A inhibitors. Through continuous efforts, the present inventors designed compounds having a structure represented by the general formula (IA), and found that compounds having such a structure exhibit excellent MAT2A inhibition effect and action, and have great application prospects.
Solution for solving the problem:
the present inventors have made intensive studies in order to solve the above-mentioned problems and as a result, have found that a specific 2-oxoquinazolino five-membered heterocyclic derivative can achieve the desired object, and as a result, have completed the present application.
The present application relates to the following 2-oxoquinazolino five membered heterocyclic compounds, or tautomeric forms thereof; or a pharmaceutically acceptable salt thereof.
The application protects the following specific embodiments:
a compound of formula (IA), or a tautomeric form thereof; or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof:
wherein, the liquid crystal display device comprises a liquid crystal display device,
w 1 is CR (CR) 2 Or N;
w 2 is CR (CR) 3 Or N;
w 3 is CR (CR) 4 Or N;
w 4 is CR (CR) 5 Or N;
R 2 ，R 3 ，R 4 and R is 5 Each independently selected from the group consisting of hydrogen, alkyl, hydroxy, alkenyl, alkynyl, alkoxy, alkylphosphoryl, alkylsulfonyl, alkylcarbonyl, alkoxycarbonyl, alkylthio, halogen, haloalkyl, haloalkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyloxy, cyano, amino, alkylamino, cycloalkylalkylamino, aminocarbonyl, alkylaminocarbonyl, heterocyclylAminesAminocarbonyl, heterocyclylalkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, hydroxyalkyl, hydroxyhaloalkyl, hydroxyalkoxy, hydroxyalkylamino, alkoxyalkyl, alkoxyalkoxy, alkoxyalkylamino, aminoalkyl, aminoalkylamino, aryl, arylalkyl, aryloxy, arylalkyloxy, arylamino, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkyloxy, heteroarylcarbonyl, heteroarylamino, heterocyclyl, heterocyclyloxy, heterocyclylAminesA group, heterocyclylalkyloxy group, heterocyclyloxyalkyloxy group or heterocyclyloxyalkylamino group; wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are themselves or as Is part of another group unsubstituted or substituted by one or more identical or different R a And/or R b Substitution; the precondition is that: w (w) 1 、w 2 、w 3 And w 4 At most two of which may be N;
R 1 is cycloalkyl, bridged cycloalkyl, fused ring alkyl, spirocycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocyclyl, bridged heterocyclyl, fused heterocyclyl or spiroheterocyclyl, wherein cycloalkyl, bridged cycloalkyl, fused ring alkyl, spirocycloalkyl, heterocyclyl, bridged heterocyclyl, fused heterocyclyl, spiroheterocyclyl, aryl or heteroaryl are unsubstituted or substituted with one or more R's which may be the same or different c 、R d And/or R e Substitution;
each of which isIs independently a single bond or a double bond; when->At least two->In the case of double bond->Is a divalent aryl, divalent heteroaryl, divalent unsaturated cycloalkyl or divalent unsaturated heterocycloalkyl group;
x 1 ，x 2 independently selected from C or N;
z is N or NR 6 Wherein R is 6 Is hydrogen, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylaminoalkyl, heterocyclylalkyl, heterocyclyl, aryl, heteroaryl, alkylcarbonyl, cycloalkylcarbonyl, hydroxyalkylcarbonyl, alkoxyalkylcarbonyl, alkylaminoalkylcarbonyl, heterocyclylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkylsulfonyl, cycloalkylsulfonyl, hydroxyalkylsulfonyl, alkoxyalkylsulfonyl, alkylaminoalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl, heteroaryl Sulfonyl, where the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are unsubstituted or substituted by one or more of the same or different R, by themselves or as part of another group f 、R g And/or R h Substitution;
y 1 is CR (CR) 7 、N、NR 8 O or S;
y 2 is CR (CR) 9 N or NR 10 ；
R 7 And R is 9 Each independently selected from hydrogen, halogen, cyano, oxo, X b -R 11 ，X b -NR 12 R 13 ，-NH-NR 12 R 13 、-NH-O-R 11 ；
X b Is a bond, alkylene, heteroalkylene, -O-, -CO-, or-COO-, wherein one carbon atom of the alkylene, heteroalkylene may be substituted with one or more substituents, the same or different, selected from the group consisting of: hydroxy, halogen, amino, alkaneBase groupAmino, alkoxy, cycloalkyloxy, haloalkyl, haloalkoxy;
R 8 ，R 10 ，R 11 each independently selected from the group consisting of hydrogen, halogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkyl, haloalkoxy, hydroxyalkyl, hydroxyhaloalkyl, alkoxyhaloalkyl, alkoxyalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, alkylaminohaloalkyl, aminocarbonylalkyl, aminosulfonylalkyl, alkylsulfonylalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, cycloalkyloxyalkyl, cycloalkylaminoalkyl, cycloalkylaminocarbonyl, alkoxycarbonyl, cycloalkylsulfonyl, bridged cycloalkyl, bridged cycloalkylalkyl, fused-ring alkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heteroarylsulfonyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclyloxyalkyl, heterocyclylaminoalkyl, fused heterocyclyl, bridged heterocyclyl, spiroheterocyclylalkyl, spiroheterocyclyl, spiroheterocyclylalkyl, and spiroheterocyclylcarbonyl, Wherein alkyl, cycloalkyl, heterocyclyl, fused heterocyclyl, aryl or heteroaryl are unsubstituted or substituted by one or more of the same or different R, by themselves or as part of another group i ，R j And/or R k Substitution;
R 12 and R is 13 Each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkyl, haloalkoxy, hydroxyalkyl, hydroxyhaloalkyl, alkoxyhaloalkyl, alkoxyalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, alkylaminohaloalkyl, aminocarbonylalkyl, aminosulfonylalkyl, alkylsulfonylalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, cycloalkyloxyalkyl, cycloalkylaminoalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, bridged cycloalkyl, bridged cycloalkylalkyl, fused-ring alkyl, spirocycloalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heteroarylsulfonyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclylsulfonyl, heterocyclyloxyalkyl, heterocyclylalkyl, fused-heterocyclyl, bridged-heterocyclylalkyl, spiroalkylcarbonyl, spiroheterocyclyl, spiroheterocyclylalkyl, and spiroheterocyclylcarbonyl, or R 12 、R 13 Can be linked to form a 4-to 10-membered heterocyclic or fused heterocyclic group in which the alkyl, cycloalkyl, heterocyclic, fused heterocyclic, aryl or heteroaryl group is unsubstituted or substituted by one or more of the same or different R, by itself or as part of another group l ，R m And/or R n Substitution;
R a ，R b ，R c ，R d ，R e ，R f ，R g ，R h ，R i ，R j ，R k ，R l ，R m or R is n Each independently selected from deuterium, hydroxy, halogen, amino, cyano, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, alkoxyalkyl, haloalkoxy, cycloalkyloxy, alkoxyalkoxy, heterocyclyloxy, alkylamino, cycloalkylamino, heterocyclylamineAlkyl, hydroxyalkyl amino, alkoxyalkyl amino, alkylphosphoryl, aminosulfonyl, alkylsulfonyl, alkylaminosulfonyl, cycloalkylaminosulfonyl, alkylsulfonylamino, cycloalkylsulfonylamino, carboxyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, cycloalkylaminocarbonyl, heterocyclylAminesAminocarbonyl, hydroxyalkylaminocarbonyl, alkoxyalkylaminocarbonyl, heterocyclylcarbonyl and ureido.
The scope and definition of each of the above groups is referred to in the "term definition portion".
In some embodiments, w 1 Is CR (CR) 2 Or N, w 2 Is CR (CR) 3 ,w 3 Is CR (CR) 4 ,w 4 Is CR (CR) 5 。
In some embodiments, y 1 Selected from CR 7 、NR 8 O or S.
In some embodiments, y 2 Is CR (CR) 9 、NR 10 。
In some embodiments, z is N or NR 6 。
In some embodiments, x 1 ，x 2 Independently selected from C or N.
In some embodiments, x 1 ，x 2 Wherein at most one of them is N and the other is C.
In some embodiments, x 1 ，x 2 All are C.
In some embodiments, the compound of formula (IA), or a tautomer, or pharmaceutically acceptable salt, or deuterated compound thereof, is selected from structures shown in (IIA), (IIB), (IIC), (IID), (IIE), (IIF), (IIG), (IIH), or (IIJ):
wherein w is 1 、w 2 、w 3 、w 4 、R 1 、R 6 、R 7 、R 8 、R 9 、R 10 Each is defined asThe definition of formula (IA).
In some embodiments, R 2 ，R 3 ，R 4 And R is 5 Independently selected from hydrogen, halogen, hydroxy, cyano, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, C 3 -C 7 Cycloalkyl- (C) 1 -C 6 Alkylene) R-O-, -NRR "or-P (O) RR" groups, where R, R "are each independently selected from H, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 7 Cycloalkyl- (C) 1 -C 6 Alkylene) r-, where r=0, 1,2. In some embodiments, the C 1 -C 6 Alkyl is preferably C 1 -C 3 Alkyl, more preferably methyl or ethyl. In some embodiments, the C 1 -C 6 Alkylene is preferably C 1 -C 3 Alkylene, more preferably methylene or ethylene. In some embodiments, the C 1 -C 6 Haloalkyl is preferably C 1 -C 3 Haloalkyl, more preferably-CH 2 CF 3 Trifluoromethyl or difluoromethyl. In some embodiments, the C 3 -C 7 Cycloalkyl is preferably C 3 -C 5 Cycloalkyl, more preferably cyclopropyl. In some embodiments, the C 1 -C 6 Alkoxy is preferably C 1 -C 3 Alkoxy, more preferably methoxy or ethoxy. In some embodiments, the C 1 -C 6 The haloalkoxy group is preferably C 1 -C 3 Haloalkoxy groups, more preferably-O-CH 2 CF 3 、-O-CH 2 CHF 2 A trifluoromethoxy group or a difluoromethoxy group.
In some embodiments, R 2 ，R 3 ，R 4 And R is 5 Each independently selected from hydrogen, F, cl, br,Hydroxy group,Cyano group,Ethoxy, methyl, ethyl, cyclopropyl, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, methoxy or dimethylphosphinyl.
In some embodiments, R 3 Selected from H, F, cl, br,Hydroxy group,Cyano group,Ethoxy, methyl, ethyl, cyclopropyl, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, methoxy or dimethylphosphinyl, R 2 ，R 4 And R is 5 Are all hydrogen.
In some embodiments, R 1 Selected from C 3 -C 7 Cycloalkyl, C 6 -C 10 Bridged cycloalkyl, 5-12 membered fused ring alkyl, C 5 -C 13 Spirocycloalkyl, 6-10 membered aryl, - (C) 1 -C 6 Alkylene) r-5-10 membered heteroaryl, 4-8 membered heterocyclyl, 6-10 membered bridged heterocyclyl, 5-14 membered fused heterocyclyl or 7-15 membered spiroheterocyclyl, wherein r = 0,1,2,3,4; wherein the alkylene, cycloalkyl, bridged cycloalkyl, fused ring alkyl, spirocycloalkyl, heterocyclyl, bridged heterocyclyl, fused heterocyclyl, aryl, spiroheterocyclyl or heteroaryl groups are unsubstituted or substituted with one or more R's which may be the same or different c 、R d And/or R e And (3) substitution.
In some preferred embodiments, R 1 Selected from C 3 -C 5 Cycloalkyl, C 4 -C 6 Cycloalkyl, C 6 -C 8 Bridged cycloalkyl, C 7 -C 9 Bridged cycloalkyl, C 7 -C 8 Bridged cycloalkyl, 7-9 membered fused ring alkyl, 7-10 membered fused ring alkyl, 5-8 membered fused ring alkyl, 9-11 membered fused ring alkyl, 6-8 membered monocyclic aryl, 8-10 membered bicyclic aryl, 7-9 membered bicyclic aryl, 5-6 membered monocyclic heteroaryl, 6-10 membered bicyclic heteroaryl, 4-6 membered heterocyclyl, 5-7 membered heterocyclyl, 7-8 membered bridged heterocyclyl, 8-9 membered bridged heterocyclyl, 5-8 membered fused heterocyclyl, 9-12 membered fused heterocyclyl, 6-10 membered fused heterocyclyl, C 7 -C 11 Spirocycloalkyl, 8-12 membered spiroheterocyclyl.
In one placeIn some preferred embodiments, R 1 Selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyanocyclopropyl-1-yl, 1-cyanomethylcyclopropan-1-yl, 3-fluorocyclohexyl, bicyclo [2.2.1 ] ]Heptane, bicyclo [2.2.2]Octane, tetrahydronaphthyl, 4,5,6, 7-tetrahydro-1H-indolyl, 4,5,6, 7-tetrahydrobenzoxazolyl, phenyl, naphthyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuranyl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridinyl benzothiazolyl, benzofuranyl, benzothienyl, indolyl, quinolinyl, isoquinolinyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furanyl, thienyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, homopiperidinyl (homopiperidino), 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholino, piperazino, tetrahydro-pyranyl, thiomorpholino, 2-azabicyclo [ 2.2.2.2]Octane, quinuclidine, 7-oxabicyclo [2.2.1 ]Heptane, 4,5,6, 7-tetrahydro-1H-pyrrolo [2,3-b]Pyridinyl, 1,2,3, 4-tetrahydroquinolinyl, 3, 4-dihydroquinolin-2 (1H) -one, spiro [4.5 ]]Decane, spiro [3.4 ]]Octane, spiro [2.3 ]]Hexane, 5-azaspiro [2.3 ]]Hexane, 6-oxaspiro [3.4 ]]-7-octanone.
In some embodiments, R c 、R d And/or R e Each independently selected from: halogen, C 1 -C 6 Alkoxy, cyano, C 1 -C 6 An alkyl group.
In some embodiments, R c 、R d And/or R e Each independently selected from: F. cl, br, C 1 -C 3 Alkoxy, cyano, C 1 -C 3 An alkyl group.
In some embodiments, R c 、R d And/or R e Each independently selected from: F. clMethoxy, ethoxy, CN, methyl, ethyl.
In some embodiments, R 1 Selected from the group consisting of
In some embodiments, R 6 Selected from hydrogen, C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Alkoxy- (C) 1 -C 6 Alkylene group) -, C 1 -C 6 alkyl-NRR' - (C) 1 -C 6 Alkylene) -, 4-8 membered heterocyclyl- (C 1 -C 6 Alkylene) -, 4-8 membered heterocyclyl, 6-10 aryl, 5-10 membered heteroaryl, C 1 -C 6 alkyl-CO-, C 3 -C 7 cycloalkyl-CO-, C 1 -C 6 hydroxyalkyl-CO-, C 1 -C 6 Alkoxy- (C) 1 -C 6 Alkylene) -CO-, NRR' - (C 1 -C 6 Alkylene) -CO-, 4-8 membered heterocyclyl-CO-, 6-10 membered aryl-CO-, 5-10 membered heteroaryl-CO-, C 1 -C 6 alkyl-S (O) 2 )-、C 3 -C 7 cycloalkyl-S (O) 2 )-、C 1 -C 6 Hydroxyalkyl radical-S (O) 2 )-、C 1 -C 6 alkoxy-C 1 -C 6 alkylene-S (O) 2 )-、NRR'-(C 1 -C 6 Alkylene) -S (O) 2 ) -, 4-8 membered heterocyclyl-S (O) 2 ) -, 6-to 10-membered aryl-S (O) 2 ) -or 5-to 10-membered heteroaryl-S (O 2 ) -; wherein in-NRR', R is C 1 -C 6 Alkyl, R' is hydrogen or C 1 -C 6 An alkyl group. Wherein alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are unsubstituted or substituted by one or more of the same or different R, by themselves or as part of another group f 、R g And/or R h And (3) substitution.
In some of the preferred embodiments of the present invention,R 6 selected from hydrogen, C 1 -C 3 Alkyl, C 3 -C 5 Cycloalkyl, C 1 -C 3 Haloalkyl, C 1 -C 3 Hydroxyalkyl, C 1 -C 3 Alkoxy- (C) 1 -C 3 Alkylene group) -, C 1 -C 3 alkyl-NRR' - (C) 1 -C 3 Alkylene) -, 4-6 membered heterocyclyl- (C 1 -C 3 Alkylene) -, 4-6 membered heterocyclyl, 6-8 monocyclic aryl, 8-10 bicyclic aryl, 5-6 mono-heteroaryl, 8-10 bicyclic or tricyclic heteroaryl, C 1 -C 6 alkyl-CO-, C 3 -C 7 cycloalkyl-CO-, C 1 -C 6 hydroxyalkyl-CO-, C 1 -C 6 Alkoxy- (C) 1 -C 6 Alkylene) -CO-, NRR' - (C 1 -C 6 Alkylene) -CO-, 4-8 membered heterocyclyl-CO-, 6-10 membered aryl-CO-, 5-10 membered heteroaryl-CO-, C 1 -C 3 alkyl-S (O) 2 )-、C 3 -C 5 cycloalkyl-S (O) 2 )-、C 1 -C 3 Hydroxyalkyl radical-S (O) 2 )-、C 1 -C 3 alkoxy-C 1 -C 3 alkylene-S (O) 2 )-、NRR'-(C 1 -C 3 Alkylene) -S (O) 2 ) -, 4-6 membered heterocyclyl-S (O) 2 ) -, 6-8 membered monocyclic aryl-S (O) 2 ) -, 8-10 membered bicyclo-S (O) 2 ) -, 5-to 6-membered mono-heteroaryl-S (O 2 ) -or 8-10 membered bi-or tricyclic heteroaryl-S (O) 2 ) -; wherein in-NRR', R is C 1 -C 3 Alkyl, R' is hydrogen or C 1 -C 3 An alkyl group.
In some embodiments, R 7 Selected from hydrogen, cyano, X b -R 11 ，X b -NR 12 R 13 。
In some embodiments, X b Selected from bonds, C 1 -C 6 Alkylene, C 1 -C 6 Heteroalkylene, -CO-or-COO-, wherein one carbon atom of the alkylene, heteroalkylene may be substituted with one or more identical or different substituents selected from the group consisting of: hydroxy, halogen, amino, -NRR', C 1 -C 6 Alkoxy, C 3 -C 7 Cycloalkyl radicalsOxy, C 1 -C 6 Haloalkyl, C 1 -C 6 Haloalkoxy groups; wherein in-NRR', R is C 1 -C 6 Alkyl, R' is hydrogen or C 1 -C 6 An alkyl group.
In some embodiments, the halogen is F, cl, br.
In some embodiments, C 1 -C 6 Alkoxy is C 1 -C 3 Alkoxy groups, preferably methoxy and ethoxy.
In some embodiments, C 1 -C 6 The halogenated alkoxy is trifluoromethoxy or difluoromethoxy.
In some embodiments, C 1 -C 6 Haloalkyl is difluoromethyl, trifluoromethyl.
In some embodiments, X b Selected from bonds, C 1 -C 3 Alkylene, C 1 -C 3 Heteroalkylene, -CO-or-COO-.
In some embodiments, X b Selected from methylene groups.
In some embodiments, R 11 Selected from hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Hydroxyalkyl, 4-8 membered heterocyclyl, C 1 -C 6 Alkoxy- (C) 1 -C 6 Alkylene group) -, C 1 -C 6 Haloalkoxy- (C) 1 -C 6 Alkylene group) -, C 1 -C 6 Haloalkoxy-, 4-8 membered heterocyclyl- (C) 1 -C 6 Alkylene) -, in which the alkyl, heterocyclic radical itself or as part of another radical is unsubstituted or substituted by one or more R's, identical or different i ，R j And/or R k And (3) substitution.
In some embodiments, R 11 Selected from hydrogen, C 1 -C 3 Alkyl, C 1 -C 3 Hydroxyalkyl, 4-6 membered heterocyclyl, C 1 -C 3 Alkoxy- (C) 1 -C 3 Alkylene group) -, C 1 -C 3 Haloalkoxy- (C) 1 -C 3 Alkylene group) -, C 1 -C 3 Haloalkoxy-, 4-6 membered heterocyclic ringRadical- (C) 1 -C 3 Alkylene group) -.
In some embodiments, R 11 Selected from methyl, ethyl, hydroxymethyl, methoxymethyl-, trifluoromethoxymethyl-, trifluoromethoxy-, difluoromethoxymethyl-, difluoromethoxy-, azetidinyl-, azetidinylmethylene.
In some embodiments, R 12 And R is 13 Each independently selected from H, C 1 -C 6 Alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Alkoxy- (C) 1 -C 6 Alkylene) -, or R 12 、R 13 To a 4-10 membered heterocyclic group, preferably a 4-7 membered heterocyclic group; wherein the alkyl or heterocyclic groups are unsubstituted or substituted by one or more of the same or different R, by themselves or as part of another group l ，R m And/or R n And (3) substitution.
In some embodiments, R 12 And R is 13 Each independently selected from H, C 1 -C 3 Alkyl, C 1 -C 3 Hydroxyalkyl, C 1 -C 3 Alkoxy- (C) 1 -C 3 Alkylene) -, or R 12 、R 13 Is linked to form a 4-membered heterocyclic group, a 5-membered heterocyclic group, a 6-membered heterocyclic group or a 7-membered heterocyclic group.
In some embodiments, R 12 And R is 13 Each independently selected from H, methyl, ethyl, hydroxyethyl, methoxyethyl-, or R 12 、R 13 Is linked to an azetidinyl group.
In some embodiments, R i ，R j ，R k ，R l ，R m And/or R n Each independently selected from hydroxy, halogen, amino, cyano, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy groups.
In some embodiments, R i ，R j ，R k ，R l ，R m And/or R n Each independently selected from hydroxy, F, cl, br, amino, cyano, C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy, C 1 -C 3 Haloalkoxy groups.
In some embodiments, R i ，R j ，R k ，R l ，R m And/or R n Each independently selected from hydroxy, methoxy, F, cl, br.
In some embodiments, R 7 Selected from hydrogen, amino, cyano, Methyl group.
In some embodiments, R 8 Selected from hydrogen, C 1 -C 6 Alkyl, NRR' - (C) 1 -C 6 Alkylene group) -, C 3 -C 7 Cycloalkyl, C 1 -C 6 Haloalkyl, 4-8 membered heterocyclyl- (C) 1 -C 6 Alkylene group) -, C 1 -C 6 Hydroxyalkyl, 5-10 membered heteroaryl; wherein in-NRR', R is C 1 -C 6 Alkyl, R' is hydrogen or C 1 -C 6 Alkyl, wherein alkyl, cycloalkyl, heterocyclyl or heteroaryl is unsubstituted or substituted by one or more of the same or different R, by itself or as part of another group i ，R j And/or R k And (3) substitution.
In some embodiments, R 8 Selected from H, C 1 -C 6 Alkyl, NRR' - (C) 1 -C 6 Alkylene group) -, C 3 -C 7 Cycloalkyl, C 1 -C 6 Haloalkyl, 4-8 membered heterocyclyl- (C) 1 -C 6 Alkylene group) -, C 1 -C 6 Hydroxyalkyl, 5-to 10-membered heteroaryl; wherein in-NRR', R is C 1 -C 6 An alkyl group; r' is hydrogen or C 1 -C 6 An alkyl group.
In some embodiments, R 8 Selected from H, C 1 -C 3 Alkyl, NRR' - (C) 1 -C 3 Alkylene group) -, C 3 -C 5 Cycloalkyl, C 1 -C 3 Haloalkyl, 4-6 membered heterocyclyl- (C) 1 -C 3 Alkylene group) -, C 1 -C 3 Hydroxyalkyl, 5-or 6-membered heteroaryl; wherein in-NRR', R is C 1 -C 3 Alkyl, preferably methyl; r' is hydrogen or C 1 -C 6 Alkyl, preferably hydrogen or methyl.
In some embodiments, R i ，R j And/or R k Each independently selected from: deuterium, C 1 -C 6 Alkyl, halogen, hydroxy, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, C 1 -C 6 Hydroxyalkyl groups.
In some embodiments, R i ，R j And/or R k Each independently selected from: deuterium, C 1 -C 3 Alkyl, F, cl, br, hydroxy, C 1 -C 3 Alkoxy, C 1 -C 3 Haloalkoxy, C 1 -C 3 Hydroxyalkyl groups.
In some embodiments, R i ，R j And/or R k Each independently selected from: deuterium, methyl, F, hydroxy, methoxy, hydroxymethyl.
In some embodiments, R 8 Selected from hydrogen, methyl, -CD 3 Ethyl group,
In some embodiments, R 9 Selected from hydrogen, oxo, X b -R 11 ，X b -NR 12 R 13 ，-NH-NR 12 R 13 、-NH-O-R 11 。
In some embodiments, X b Is a bond, C 1 -C 6 Alkylene, C 1 -C 6 Heteroalkylene, -O-, -CO-, or-COO-, wherein alkylene, heteroalkyleneOne carbon atom in the alkyl group may be substituted with one or more identical or different substituents selected from the group consisting of: hydroxy, halogen, amino, C 1 -C 6 Alkoxy, -NRR', C 3 -C 7 Cycloalkyl oxy, C 1 -C 6 Haloalkyl, C 1 -C 6 Haloalkoxy substitution; wherein in-NRR', R is C 1 -C 6 Alkyl, R' is hydrogen or C 1 -C 6 An alkyl group.
In some embodiments, the halogen is F, cl, br.
In some embodiments, C 1 -C 6 Alkoxy is C 1 -C 3 Alkoxy groups, preferably methoxy and ethoxy.
In some embodiments, C 1 -C 6 The halogenated alkoxy is trifluoromethoxy or difluoromethoxy.
In some embodiments, C 1 -C 6 Haloalkyl is difluoromethyl, trifluoromethyl.
In some embodiments, X b Is a bond, C 1 -C 3 Alkylene, C 1 -C 3 Heteroalkylene, -O-, -CO-, or-COO-.
In some embodiments, X b Is methylene or ethylene.
In some embodiments, R 11 Selected from H, C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl, 5-10 membered heteroaryl, C 1 -C 6 Alkoxy- (C) 1 -C 6 Alkylene group) -, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, 4-8 membered heterocyclyl, amino- (C) 1 -C 6 Alkylene) -, 4-8 membered heterocyclyl- (C 1 -C 6 Alkylene) -, 4-8 membered heterocyclyloxy- (C) 1 -C 6 Alkylene) -, in which the alkyl, cycloalkyl, heterocyclyl or heteroaryl groups are unsubstituted or substituted by one or more of the same or different R i ，R j And/or R k And (3) substitution.
In some embodiments, R 11 Selected from H, C 1 -C 3 Alkyl, C 3 -C 4 Cycloalkyl, 5-or 6-membered heteroaryl, C 1 -C 3 Alkoxy- (C) 1 -C 3 Alkylene group) -, C 1 -C 3 Haloalkyl, C 1 -C 3 Hydroxyalkyl, 4-8 membered heterocyclyl, amino- (C) 1 -C 3 Alkylene) -, 4-6 membered heterocyclyl- (C 1 -C 3 Alkylene) -, 4-6 membered heterocyclyloxy- (C) 1 -C 3 Alkylene group) -.
In some embodiments, R 11 Selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, phenyl,Pyridyl, methoxymethyl, trifluoromethyl, difluoromethyl, hydroxymethyl, hydroxyethyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl-methylene-, 4-membered heterocyclyloxy-methylene-.
In some embodiments, R 11 Selected from the group consisting of
In some embodiments, R 12 And R is 13 Independently selected from H, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy- (C) 1 -C 6 Alkylene group) -, C 1 -C 6 Alkylcarbonyl-, C 3 -C 7 Cycloalkyl, C 3 -C 7 Cycloalkyl- (C) 1 -C 6 Alkylene) -, 4-8 membered heterocyclylcarbonyl-, 4-8 membered heterocyclyl- (C) 1 -C 6 Alkylene group) -, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Haloalkoxy- (C) 1 -C 6 Alkylene) -; or R is 12 、R 13 Can be linked to form a 4-10 membered heterocyclic group, wherein alkyl, cycloalkyl or heterocyclic groupsUnsubstituted or substituted by one or more of the same or different R, by itself or as part of another group l ，R m And/or R n And (3) substitution.
In some embodiments, R 12 And R is 13 Independently selected from H, C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy- (C) 1 -C 3 Alkylene group) -, C 1 -C 3 Alkylcarbonyl-, C 4 -C 6 Cycloalkyl, C 4 -C 6 Cycloalkyl- (C) 1 -C 3 Alkylene) -, 4-6 membered heterocyclylcarbonyl-, 4-8 membered heterocyclyl- (C) 1 -C 3 Alkylene group) -, C 1 -C 3 Hydroxyalkyl, C 1 -C 3 Haloalkoxy- (C) 1 -C 3 Alkylene) -; or R is 12 、R 13 Can be linked to form a 4-7 membered heterocyclic group.
In some embodiments, R 12 And R is 13 Independently selected from H, methyl, ethyl, hydroxyethyl, methoxyethyl-, methylcarbonyl- Or R is 12 、R 13 Can be linked to the following groups: />
In some embodiments, R i ，R j ，R k ，R l ，R m And/or R n Each independently selected from deuterium, hydroxy, halogen, amino, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, -CONRR', C 1 -C 6 Alkyl, C 1 -C 6 A haloalkyl group; wherein in-CONRR', R is C 1 -C 6 Alkyl, R' is hydrogen or C 1 -C 6 An alkyl group.
In some embodiments, R i ，R j ，R k ，R l ，R m And/or R n Each independently selected from deuterium, hydroxy, halogen, amino, C 1 -C 3 Alkoxy, C 1 -C 3 Haloalkoxy, -CONRR', C 1 -C 3 Alkyl, C 1 -C 3 A haloalkyl group; wherein in-CONRR', R is C 1 -C 3 Alkyl, R' is hydrogen or C 1 -C 3 An alkyl group.
In some embodiments, R i ，R j ，R k ，R l ，R m And/or R n Each independently selected from deuterium, hydroxy, amino, methoxy,Methyl, trifluoroethyl, F, cl, br.
In some embodiments, R 9 Selected from H, oxo, methyl, ethyl, -CD 3 Hydroxypropyl, methoxyethyl,
In some embodiments, R 9 Selected from the group consisting of
In some embodiments, R 10 Selected from C 6 -C 10 Aryl, C 1 -C 6 Alkyl, C 1 -C 6 alkoxy-CO-, HO- (C) 1 -C 6 Alkylene group) -, C 1 -C 6 Alkoxy- (C) 1 -C 6 Alkylene group) -,NRR'-(C 1 -C 6 alkylene) -; wherein in-NRR', R is C 1 -C 6 Alkyl, R' is hydrogen or C 1 -C 6 Alkyl, where the alkyl, aryl, by themselves or as part of another group, are unsubstituted or substituted by one or more of the same or different R i ，R j And/or R k And (3) substitution.
In some embodiments, R 10 Selected from phenyl, naphthyl, C 1 -C 3 Alkyl, C 1 -C 3 alkoxy-CO-, HO- (C) 1 -C 3 Alkylene group) -, C 1 -C 3 Alkoxy- (C) 1 -C 3 Alkylene) -, NRR' - (C 1 -C 3 Alkylene) -; wherein in-NRR', R is C 1 -C 3 Alkyl, R' is hydrogen or C 1 -C 3 An alkyl group; wherein alkyl, phenyl, naphthyl, by themselves or as part of another group are unsubstituted or substituted by one or more of the same or different R i ，R j And/or R k And (3) substitution.
In some embodiments, R i ，R j ，R k ，R l ，R m And/or R n Each independently selected from hydroxy, methoxy, methyl-NH-.
In some embodiments, R 10 Selected from methyl group,
As an exemplary compound, the compounds of formula IA of the present invention include:
/>
/>
/>
/>
/>
/>
/>
/>
the preparation method comprises the following steps:
the invention also provides a method for preparing the compound. The preparation of the compounds of general formula (IA) of the present invention may be accomplished by the following exemplary methods and examples, which should not be construed as limiting the scope of the invention in any way. The compounds of the present invention may also be synthesized by synthetic techniques known to those skilled in the art, or by a combination of synthetic methods known in the art and methods of the present invention. The product from each step is obtained using separation techniques known in the art including, but not limited to, extraction, filtration, distillation, crystallization, chromatographic separation, and the like. The starting materials and chemical reagents required for the synthesis may be synthesized conventionally according to literature (as provided by scibinder) or purchased.
The method comprises the following steps:
step one: the compound shown in the formula 1 and the compound shown in the formula 2 undergo condensation reaction under the condition of a condensing agent to obtain the compound shown in the formula 3. In some embodiments, the condensing agent is 1-hydroxybenzotriazole.
Step two: the compound shown in the formula 3 undergoes intramolecular condensation reaction under alkaline condition to obtain the compound shown in the formula 4. In some embodiments, the alkaline conditions are in the presence of sodium hydride.
Step three: the compound shown in the formula 4 reacts with R under the action of a catalyst 1 -B(OH) 2 The boric acid compound is subjected to displacement reaction to obtain the compound shown in the formula IIA. In some embodiments, the catalyst is a copper catalyst; preferably, the copper catalyst is copper or copper acetate.
Wherein w is 1 ，w 2 ，w 3 ，w 4 ，R 1 ，R 7 ，R 9 As defined in the summary.
The second method is as follows:
step one: the compound shown in the formula 6 reacts with R under alkaline conditions 1 And (3) carrying out substitution reaction on amine shown in NH2 to obtain the compound shown in the formula 7. In some embodiments, the basic conditions are in the presence of a catalyst selected from potassium carbonate, cesium carbonate, or triethylamine.
Step two: the compound shown in the formula 7 is converted into the compound shown in the formula 8 under the action of a catalyst. In some embodiments, the catalyst is selected from triphosgene.
Step three: the compound shown in the formula 8 is treated by ethyl nitroacetate to obtain the compound shown in the formula 9.
Step four: and (3) carrying out chlorination reaction under the action of a compound catalyst shown in the formula 9 to obtain a compound shown in the formula 10. In some embodiments, the catalyst is selected from phosphorus oxychloride.
Step five: the compound shown in the formula 10 and the formula R under alkaline conditions 8 The amine shown in NH2 undergoes a displacement reaction to obtain the compound shown in the formula 11. In some embodiments, the basic conditions are in the presence of a catalyst selected from potassium carbonate, cesium carbonate, or triethylamine.
Step six: the compound shown in the formula 11 is reduced under the action of a reducing agent to obtain the compound shown in the formula 12. In some embodiments, the reducing agent is selected from sodium dithionite.
Step seven: the compound shown in the formula 12 is subjected to trimethyl orthoformate to obtain a compound shown in the formula IIE-1. Wherein w is 1 ，w 2 ，w 3 ，w 4 ，R 1 ，R 8 As defined in the summary.
And a third method:
path 1: preparation of Compounds of IIE-2
Step one: the compound shown in the formula 12 is subjected to the action of N, N' -carbonyl diimidazole to obtain the compound shown in the formula 14.
Step two: the compound shown in the formula 14 undergoes chlorination reaction after being treated by phosphorus oxychloride to obtain the compound shown in the formula 15.
Step three: in the presence of an organic base such as triethylamine or the like, a compound represented by the formula R 12 R 13 The amine represented by NH is treated with the compound represented by formula 15 to give the compound represented by IIE-2.
Path 2: preparation of Compounds of IIE-3
Step one: the compound shown in the formula 12 is treated by chloroacetyl chloride to obtain the compound shown in the formula 17.
Step two: in the presence of a base such as potassium carbonate, cesium carbonate or triethylamine, etc., with formula R 12 R 13 The amine represented by NH is treated with the compound represented by formula 17 to give the compound represented by IIE-3.
Path 3:
step one: by R 9 Acid treatment of the compound of formula 12 with COOH gives the compound of formula 19.
Step two: the compound of formula 19 can be converted to formula IIE by treatment with an inorganic base such as sodium hydroxide and the like.
Wherein w is 1 ，w 2 ，w 3 ，w 4 ，R 8 ，R 9 ，R 12 And R is 13 As defined in the summary.
The method four:
step one: under the condition of the Ullman reaction well known in the art, in the presence of copper or copper acetate, etc., R is used 1 Treatment of the compound of formula 21 with an iodide shown in I gives a compound of formula 22.
Step two: the compound represented by formula 22 is hydrolyzed by a base such as sodium hydroxide or the like to obtain a compound represented by formula 23.
Step three: in the presence of condensing agent such as 1-hydroxybenzotriazole or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, etc., with formula R 12 R 13 The amine represented by NH treats the compound represented by formula 23 to obtain the compound represented by formula 24.
The preparation of the compounds of formula 21 may be referred to RSC adv, 2019,9,35068-35072.
Wherein w is 1 ，w 2 ，w 3 ，w 4 ，R 1 ，R 12 And R is 13 As defined in the summary or a precursor group thereof.
In another aspect, the present invention provides an intermediate compound selected from the following structures:
in a further aspect, the present invention also provides the use of an intermediate compound as described above for the preparation of a compound of formula (IA).
Pharmaceutical composition:
it is still another object of the present invention to provide a pharmaceutical composition for treating and/or preventing diseases associated with abnormal expression of MAT 2A. The pharmaceutical composition comprises a therapeutically and/or prophylactically effective amount of a 2-oxo-quinazolino five-membered heterocyclic derivative shown as the formula (IA) or a pharmaceutically acceptable salt thereof or a tautomeric form thereof or a deuterated compound thereof, and optionally a pharmaceutically acceptable medicinal carrier and/or auxiliary agent and/or diluent.
In some embodiments, the pharmaceutical combination is particularly useful for treating and/or preventing diseases of MTAP deficiency (MTAP-/-) with abnormal MAT2A expression.
In some embodiments, the disease associated with aberrant expression of MAT2A is cancer.
In some embodiments, the disease associated with aberrant expression of MAT2A is referred to as MTAP-deleted cancer.
Methods of preparing various pharmaceutical compositions containing certain amounts of the active ingredient are known or will be apparent to those of skill in the art in light of the present disclosure. Methods of preparing the pharmaceutical compositions include incorporation of suitable pharmaceutical excipients, carriers, diluents, and the like, as described in REMINGTON' SPHARMACEUTICAL SCIENCES, martin, e.w., ed., mack Publishing Company,19th ed. (1995).
The medical application comprises the following steps:
in another aspect, the present invention also provides the use of a compound of formula (IA) or a pharmaceutically acceptable salt thereof/a tautomeric form thereof/a deuterated compound thereof, or a pharmaceutical composition thereof, for the preparation of a MAT2A inhibitor.
In another aspect, the invention also provides application of the compound shown in the formula (IA) or pharmaceutically acceptable salt/tautomeric form/deuterated compound thereof or the pharmaceutical composition in preparing medicines for treating and/or preventing diseases related to MAT2A expression abnormality.
In another aspect, the present invention also provides the use of a compound of formula (IA) or a pharmaceutically acceptable salt thereof/a tautomeric form thereof/a deuterated compound thereof, or a pharmaceutical composition thereof, for the treatment and/or prevention of a disorder associated with abnormal MAT2A expression.
It is still another object of the present application to provide a method for treating and/or preventing a disease associated with abnormal MAT2A expression, which comprises administering to an individual in need thereof a therapeutically and/or prophylactically effective amount of a compound represented by formula (IA) or a pharmaceutically acceptable salt thereof/tautomeric form thereof/deuterated compound thereof, or the pharmaceutical composition.
In some embodiments, the compound of formula (IA) or a pharmaceutically acceptable salt thereof/tautomeric form thereof/deuterated compound thereof, or the pharmaceutical composition, is particularly for use in MTAP deficient (MTAP-/-) patients, to treat and/or prevent a disorder associated with abnormal MAT2A expression.
In some embodiments, the disorder associated with aberrant expression of MAT2A in the present application is cancer.
In some embodiments, the disorder associated with MAT2A expression abnormality in the present application refers to a disorder associated with MAT2A expression abnormality in MTAP deficiency.
In some embodiments, the disease associated with aberrant expression of MAT2A described herein is referred to as MTAP-deficient cancer.
In the present application, "treatment" generally means obtaining a desired pharmacological and/or physiological effect. The effect may be prophylactic according to the prevention of the disease or symptoms thereof, in whole or in part; and/or may be therapeutic in terms of partial or complete stabilization or cure of the disease and/or side effects due to the disease. As used herein, "treatment" encompasses any treatment of a disease in a patient, including: (a) Preventing diseases or symptoms which occur in patients who are susceptible to the diseases or symptoms but are not yet diagnosed with the disease; (b) inhibiting the symptoms of the disease, i.e., arresting its development; or (c) alleviating a symptom of the disease, i.e., causing regression of the disease or symptom.
In the present invention, the "subject" in the "subject in need thereof" refers to a vertebrate. In certain embodiments, a vertebrate refers to a mammal. Mammals include, but are not limited to, livestock (such as cattle), pets (such as cats, dogs, and horses), primates, mice, and rats. In certain embodiments, the mammal refers to a human.
In the present invention, an "effective amount" refers to an amount effective to achieve the desired therapeutic or prophylactic effect at the necessary dosages and times. The "therapeutically effective amount" of a substance/molecule of the invention may vary depending on factors such as the disease state, age, sex and weight of the individual, the ability of the substance/molecule to elicit a desired response in the individual, and the like. A therapeutically effective amount also encompasses an amount of the substance/molecule that has a therapeutic benefit over any toxic or detrimental effect. "prophylactically effective amount" refers to an amount effective to achieve the desired prophylactic effect at the dosages and for the time necessary. Generally, but not necessarily, since the prophylactic dose is for the subject prior to the onset of the disease or early in the disease, the prophylactically effective amount will be less than the therapeutically effective amount. In the case of cancer, a therapeutically effective amount of the drug may reduce the number of cancer cells; reducing the tumor volume; inhibit (i.e., slow, preferably stop to some extent) infiltration of cancer cells into surrounding organs; inhibit (i.e., slow, preferably stop to some extent) tumor metastasis; inhibit tumor growth to a certain extent; and/or to some extent, alleviate one or more symptoms associated with cancer.
Description:
(1) In the application, each substituent of the compound shown in the formula IA is correspondingly defined in the definition of the term, and the protection scope of each group is defined by the term; unless defined otherwise, such groups are understood by those of ordinary skill in the art.
(2) In the application, for definition of no integral group, the protection scope of the group is understood according to the definition scope of the corresponding term of each sub-module after splitting. For example, with respect to the overall group "alkylaminoalkyl", the group may be understood as "alkylaminoalkyl" to be understood as "alkylamino- (alkylene) -", wherein "alkylamino" and "alkylene" are understood as interpreted in the definition of terms.
(3) In the application, the definition of the group in the definition of the term is not influenced after the definition of the group is limited by the number of carbon atoms or hetero atoms. As in the present application C 1 -C 6 Alkyl is understood to mean "alkyl" having 1 to 6 carbon atoms; c (C) 1 -C 3 Alkyl is understood to mean "alkyl" having 1 to 3 carbon atoms. Here C 1 -C 6 Alkyl and C 1 -C 3 The definition of "alkyl" in the alkyl group is consistent with the definition of "alkyl" in the definition of the term, and means "a straight-chain saturated monovalent hydrocarbon group having 1 to 6 (or 1 to 3) carbon atoms or a branched-chain saturated monovalent hydrocarbon group having 3 to 6 carbon atoms". For another example, a 4-8 membered heterocyclic group is only one having 4-8 ring atoms. "heterocyclyl" is defined herein as the term "heterocyclyl" and refers to a saturated or unsaturated monovalent monocyclic group having 4 to 8 ring atoms, 1 or 2 of which are heteroatoms selected from N, O or S (O) n, where n is an integer from 0 to 2 and the remaining ring atoms are C. In addition, 1 or 2 ring carbon atoms in the heterocyclyl ring may optionally be replaced by a-CO-group. Exemplary "heterocyclyl" groups include, but are not limited to: azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, homopiperidinyl (homopiperidino), 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholino, piperazino, tetrahydro-pyranyl, thiomorpholino, and the like. When the heterocyclyl ring is unsaturated, it may contain one or two ring double bonds, provided that the ring is not an aromatic ring. When the heterocyclyl contains at least one nitrogen atom, it may be referred to herein as a heterocyclic amino group.
(4) The words "amine" and "ammonia" are used interchangeably herein as a separate group or as part of another group when referring to "amine" and "amino".
Definition of terms:
according to the present inventionAs is common practice in the art,a bond as used in the formulae herein is described as the point of attachment of the moiety or substituent to the parent or host structure.
A dash "-" that does not appear between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CONH 2 Through a carbon atom.
In the various parts of the present specification, substituents of the presently disclosed compounds are disclosed in terms of the type or scope of groups. It is specifically noted that the present invention includes each individual subcombination of the individual members of these group classes and ranges. For example, the term "C 1-6 Alkyl "means in particular methyl, ethyl, C independently disclosed 3 Alkyl, C 4 Alkyl, C 5 Alkyl and C 6 Alkyl, or independently disclosed "C 1-4 Alkyl ", or independently disclosed" C 1-3 An alkyl group.
"alkyl" refers to a straight chain saturated monovalent hydrocarbon group having 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon group having 3 to 6 carbon atoms. Exemplary "alkyl" groups include, but are not limited to: methyl, ethyl, propyl, 2-propyl, butyl, pentyl, and the like. Those skilled in the art will recognize that the term "alkyl" may include "alkylene" groups.
Unless otherwise indicated, the term "alkylene" in the present application refers to a straight-chain saturated divalent hydrocarbon group having 1 to 6 carbon atoms or a branched-chain saturated divalent hydrocarbon group having 3 to 6 carbon atoms. Exemplary "alkylene" groups include, but are not limited to: methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.
"alkenyl" refers to a straight chain monovalent hydrocarbon radical having 2 to 6 carbon atoms or a branched monovalent hydrocarbon radical having 3 to 6 carbon atoms containing a double bond. Exemplary "alkenyl" groups include, but are not limited to: propenyl, butenyl, and the like.
"alkynyl" refers to a straight chain monovalent hydrocarbon radical having 2 to 6 carbon atoms or a branched chain monovalent hydrocarbon radical having 3 to 6 carbon atoms containing a triple bond. Exemplary "alkynyl" groups include, but are not limited to: ethynyl, propynyl, butynyl, and the like.
"alkoxy" refers to the-OR group, wherein R is "alkyl" as defined above. Exemplary "alkoxy" groups include, but are not limited to: such as methoxy, ethoxy, propoxy or 2-propoxy, n-butoxy, isobutoxy or tert-butoxy, and the like.
"alkoxyalkyl" refers to a straight chain monovalent hydrocarbon radical having 1 to 6 carbon atoms or a branched chain monovalent hydrocarbon radical having 3 to 6 carbons substituted with one "alkoxy" as defined above. Exemplary "alkoxyalkyl" groups include, but are not limited to: such as 2-methoxyethyl, 1-, 2-, or 3-methoxypropyl, 2-ethoxyethyl, and the like.
"alkoxyalkoxy" refers to an-OR group, wherein R is "alkoxyalkyl" as defined above. Exemplary "alkoxyalkoxy" groups include, but are not limited to: methoxyethoxy, ethoxypropoxy, and the like.
"alkoxyalkylamino" refers to the-NRR 'group where R is hydrogen or alkyl and R' is alkoxyalkyl, where "alkyl" and "alkoxyalkyl" are each defined as described above. Exemplary "alkoxyalkylamino" groups include, but are not limited to: methoxyethylamino, methoxypropylamino and the like.
"Alkoxyalkylcarbonyl" refers to the-COR group, wherein R is "alkoxyalkyl" as defined above. Exemplary "alkoxyalkylcarbonyl" groups include, but are not limited to: methoxyethylcarbonyl, ethoxypropylcarbonyl, and the like.
"alkylcarbonyl" refers to a-C (O) R group, where R is "alkyl" as defined above. Exemplary "alkylcarbonyl" groups include, but are not limited to: methyl carbonyl, ethyl carbonyl, and the like.
"alkoxycarbonyl" refers to a-C (O) OR group, wherein R is an alkyl group as defined above. Exemplary "alkoxycarbonyl" groups include, but are not limited to: methoxycarbonyl, ethoxycarbonyl, and the like.
"alkylthio" refers to an-SR group, wherein R is alkyl as defined above. Exemplary "alkylthio" groups include, but are not limited to: methylthio, ethylthio, and the like.
"alkyl groupSulfonyl "refers to-SO 2 And an R group, wherein R is an alkyl group as defined above. Exemplary "alkylsulfonyl" groups include, but are not limited to: methylsulfonyl, ethylsulfonyl, and the like.
Hydroxyalkyl sulfonyl: -SO 2 R is a hydroxyalkyl group as defined herein. Exemplary "hydroxyalkylsulfonyl" groups include, but are not limited to: 1-hydroxy-methylsulfonyl, 1-hydroxy-ethylsulfonyl, and the like.
Alkoxyalkylsulfonyl: -SO 2 R is an alkoxyalkyl group as defined herein. Exemplary "alkoxyalkylsulfonyl" groups include, but are not limited to: 2-methoxyethylsulfonyl, 1-, 2-, or 3-methoxypropylsulfonyl, 2-ethoxyethylsulfonyl, and the like.
Alkylamino alkylsulfonyl: -SO 2 R groups, wherein R is an alkylaminoalkyl group as defined herein. Exemplary "alkylaminoalkylsulfonyl" groups include, but are not limited to: methylaminomethylsulfonyl, ethylaminomethylsulfonyl, propylaminoethylsulfonyl, 2-propylaminopropylsulfonyl, and the like.
Alkylaminoalkylcarbonyl: -COR group, wherein R is an alkylaminoalkyl group as defined herein. Exemplary "alkylaminoalkylcarbonyl" groups include, but are not limited to: methylaminomethylcarbonyl, ethylaminomethylcarbonyl, propylaminoethylcarbonyl or 2-propylaminopropylcarbonyl, and the like.
"alkylphosphoryl" refers to the group-P (O) RR ', where R, R' are each alkyl as defined above. Exemplary "alkylphosphoryl" groups include, but are not limited to: dimethylphosphoryl, and the like.
"Alkylsulfonylalkyl" means- (alkylene) -SO 2 And an R group, wherein R is an alkyl group as defined above. Exemplary "alkylsulfonylalkyl" groups include, but are not limited to: methylsulfonylethyl, ethylsulfonylmethyl, and the like.
"amino" means-NH 2 。
"alkylamino" means a-NRR 'group where R is alkyl as defined above and R' is hydrogen or alkyl as defined above. Exemplary "alkylamino" groups include, but are not limited to: methylamino, ethylamino, propylamino or 2-propylamino and the like.
Alkylaminoalkyl: refers to the- (alkylene) -NRR 'group, wherein R is alkyl as defined above, and R' is hydrogen or alkyl as defined above. Exemplary "alkylaminoalkyl" groups include, but are not limited to: methylaminomethyl, ethylaminomethyl, propylaminoethyl, 2-propylaminopropyl, and the like.
"aminoalkyl" refers to a straight chain monovalent hydrocarbon radical having 1 to 6 carbon atoms or a branched chain monovalent hydrocarbon radical having 3 to 6 carbon atoms substituted with-NR 'R ", wherein R' and R" are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or alkylcarbonyl, each as defined herein. Exemplary "aminoalkyl" groups include, but are not limited to: aminomethyl, aminoethyl, methylaminomethyl, and the like.
"aminoalkyl" refers to the-OR group, wherein R is "aminoalkyl" as defined above. Exemplary "aminoalkoxy" groups include, but are not limited to: aminoethoxy, methylaminopropoxy, dimethylaminoethoxy, diethylaminopropoxy, and the like.
"aminoalkylamino" refers to the group-NRR ', where R is hydrogen or alkyl, and R' is aminoalkyl, each as defined above. Exemplary "aminoalkylamino" groups include, but are not limited to: amino ethyl amino, methyl amino propyl amino, two methyl amino ethyl amino, two ethyl amino propyl amino etc..
"aminocarbonyl" refers to-CONH 2 A group.
"Alkylaminocarbonyl" refers to the group-CONRR ', where R is alkyl as defined above and R' is hydrogen or alkyl as defined above. Exemplary "alkylaminocarbonyl" groups include, but are not limited to: methylaminocarbonyl, ethylaminocarbonyl, and the like.
"Cycloalkylaminocarbonyl" means a-CONRR 'group wherein R is cycloalkyl as defined herein and R' is hydrogen or alkyl as defined herein. Exemplary "cycloalkylaminocarbonyl" groups include, but are not limited to: cyclopropylaminocarbonyl, cyclobutylaminocarbonyl, and the like.
"hydroxyalkyl aminocarbonyl" refers to the group-CONRR 'where R is hydroxyalkyl as defined herein and R' is hydrogen or alkyl as defined herein. Exemplary "hydroxyalkylaminocarbonyl" groups include, but are not limited to: 2-hydroxypropyl aminocarbonyl, 3-hydroxypentylaminocarbonyl, and the like.
"Alkoxyalkylaminocarbonyl" refers to the group-CONRR 'where R is hydrogen or alkyl and R' is alkoxyalkyl, where "alkyl" and "alkoxyalkyl" are each defined herein. Exemplary "alkoxyalkylaminocarbonyl" groups include, but are not limited to: methoxyethylaminocarbonyl, methoxypropylaminocarbonyl, and the like.
"sulfamoyl" means-SO 2 NH 2 A group.
"sulfamoylalkyl" means- (alkylene) SO 2 NRR ' wherein R is hydrogen or alkyl and R ' is hydrogen, alkyl or cycloalkyl, or R and R ' together with the nitrogen atom to which they are attached form a heterocyclic group. "alkyl", "cycloalkyl", "heterocyclyl" are each as defined herein. Exemplary "sulfamoylalkyl" groups include, but are not limited to: methylaminosulfonylethyl, dimethyl sulfonylethyl, and the like.
"Alkylaminosulfonyl" means-SO 2 NRR 'wherein R is alkyl as defined above and R' is hydrogen or alkyl as defined above. Exemplary "alkylaminosulfonyl" groups include, but are not limited to: methylaminosulfonyl, ethylaminosulfonyl, and the like.
"Cycloalkylaminosulfonyl" means-SO 2 NRR 'wherein R is cycloalkyl as defined above and R' is hydrogen or alkyl as defined above. Exemplary "cycloalkylaminosulfonyl" groups include, but are not limited to: cyclopropylaminosulfonyl, cyclobutylaminosulfonyl, and the like.
"aminocarbonylalkyl" refers to the- (alkylene) -CONRR 'group wherein R and R' are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl or alkoxyalkyl, each as defined herein. Exemplary "aminocarbonylalkyl" groups include, but are not limited to: aminocarbonylethyl, methylaminocarbonylethyl, dimethylaminocarbonylethyl, and the like.
"sulfamoylalkyl" means- (alkylene) -SO 2 NRR 'groups, wherein R and R' are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, or alkoxyalkyl, each as defined herein. Exemplary "sulfamoylalkyl" groups include, but are not limited to: sulfamoyl ethyl, methylaminosulfonyl ethyl, dimethylaminosulfonyl ethyl, and the like.
"aryl" refers to a monovalent monocyclic or bicyclic aromatic hydrocarbon group having 6 to 10 ring atoms. Exemplary "aryl" groups include, but are not limited to: phenyl or naphthyl.
"arylalkyl" refers to the- (alkylene) -R group, where R is aryl as defined above. Exemplary "arylalkyl" groups include, but are not limited to: benzyl, phenethyl, and the like.
"aryloxy" means-OR, wherein R is aryl as defined above.
"arylalkyloxy" refers to the group-O- (alkylene) -R, wherein R is aryl as defined above.
"arylamino" refers to the radical-NRR ', where R is hydrogen or alkyl and R' is aryl as defined above.
Arylsulfonyl: -SO 2 R is an aryl group as defined herein. Exemplary "arylsulfonyl" groups include, but are not limited to: benzenesulfonyl or naphthalenesulfonyl.
"arylcarbonyl" means-COR, wherein R is heteroaryl as defined above.
"heterocyclyl" refers to a saturated or unsaturated monovalent monocyclic group having 4 to 8 ring atoms, wherein 1 or 2 ring atoms are heteroatoms selected from N, O or S (O) n, wherein n is an integer from 0 to 2 and the remaining ring atoms are C. In addition, 1 or 2 ring carbon atoms in the heterocyclyl ring may optionally be replaced by a-CO-group. Exemplary "heterocyclyl" groups include, but are not limited to: azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, homopiperidinyl (homopiperidino), 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholino, piperazino, tetrahydro-pyranyl, thiomorpholino, and the like. When the heterocyclyl ring is unsaturated, it may contain one or two ring double bonds, provided that the ring is not an aromatic ring. When the heterocyclyl ring is saturated, it is also referred to herein as heterocycloalkyl. When the heterocyclyl contains at least one nitrogen atom, it may be referred to herein as a heterocyclic amino group.
"bridged cycloalkyl" refers to a saturated monocyclic 5-to 7-membered hydrocarbon group in which two non-adjacent ring atoms are connected by a (CRR ') n group, wherein n is 1 to 3, and each R, R ' is independently H or methyl (wherein the (CRR ') n group is also referred to herein as a bridging group). Bridged cycloalkyl groups are optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy or cyano, wherein alkyl, alkoxy are each as defined above. Examples of bridged cycloalkyl groups include, but are not limited to, bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, and the like.
"bridged cycloalkylalkyl" means an- (alkylene) -R group, where R is bridged cycloalkyl as defined above. Examples include, but are not limited to, bicyclo [2.2.1] heptylmethyl, and the like.
"bridged heterocyclyl" means a saturated monocyclic ring having 5 to 7 ring carbon ring atoms in which two non-adjacent ring atoms are connected by a (CRR ') n group, wherein n is 1 to 3, and each R, R ' is independently H or methyl (wherein the (CRR ') n group is also referred to herein as a "bridging" group); and further wherein one or both ring carbon atoms (including carbon atoms in the bridging group) are selected from N, O or S (O) n Wherein n is an integer from 0 to 2. The bridged heterocyclyl may be optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy or cyano, wherein alkyl, alkoxy are each as defined above. Examples include, but are not limited to, 2-azabicyclo [2.2.2 ]Octane, quinuclidine, 7-oxabicyclo [2.2.1]Heptane, and the like.
"bridged heterocyclylalkyl" means an- (alkylene) -R group, where R is a bridged heterocyclyl as defined above.
"cycloalkyl" refers to a monocyclic monovalent hydrocarbon group of 3 to 7 carbon atoms, which may be saturated or contain one double bond. Cycloalkyl groups may be unsubstituted or substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, or cyano, wherein alkyl, alkoxy are as defined above. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyanocyclopropyl-1-yl, 1-cyanomethylcyclopropan-1-yl, 3-fluorocyclohexyl and the like. When cycloalkyl contains a double bond, it may be referred to herein as cycloalkenyl.
"cycloalkylalkyl" refers to the- (alkylene) -R group, where R is cycloalkyl as defined above. Examples include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, and the like.
"Cycloalkylcarbonyl" refers to a-COR group, wherein R is cycloalkyl as defined above. Examples include, but are not limited to, cyclopropylcarbonyl, cyclobutylcarbonyl, and the like.
"Cycloalkylsulfonyl" means-SO 2 R groups, wherein R is cycloalkyl as defined above. Examples include, but are not limited to, cyclopropylsulfonyl, cyclobutylsulfonyl, and the like.
"cycloalkylalkyloxy" means an-O-R group, wherein R is cycloalkylalkyl as defined above. Examples include, but are not limited to, cyclopropylmethoxy, cyclobutylmethoxy, and the like.
"Cycloalkyloxy" means an-OR group, wherein R is cycloalkyl as defined above. Examples include, but are not limited to, cyclopropoxymethyl, cyclopropoxyethyl, cyclobutoxyethyl, and the like.
"Cycloalkyloxyalkyl" refers to the- (alkylene) -OR group, wherein R is cycloalkyl as defined above. Examples include, but are not limited to, cyclopropoxymethyl, cyclopropoxyethyl, cyclobutoxyethyl, and the like.
"cycloalkylamine" refers to the-NRR 'group where R is cycloalkyl as defined above and R' is hydrogen or alkyl as defined above. Examples include, but are not limited to, cyclopropylamino, cyclobutylamino, and the like.
"cycloalkylaminoalkyl" refers to the- (alkylene) -NRR 'group, wherein R is cycloalkyl as defined above and R' is hydrogen or alkyl as defined above. Examples include, but are not limited to, cyclopropylaminomethyl, cyclopropylaminoethyl, cyclobutylaminoethyl, and the like.
"cycloalkylalkylamino" means a-NRR 'group where R is cycloalkylalkyl as defined above and R' is hydrogen or alkyl as defined above. Examples include, but are not limited to, cyclopropylaminomethyl, cyclopropylaminoethyl, cyclobutylaminoethyl, and the like.
"Alkylaminoalkyl" refers to the- (alkylene) -NRR 'group where R is alkyl as defined above and R' is hydrogen or alkyl as defined above. Examples include, but are not limited to, cyclopropoxymethyl, cyclopropoxyethyl, cyclobutoxyethyl, and the like.
"Cycloalkylsulfonylamino" means-NRSO 2 -R 'groups wherein R is hydrogen or alkyl, R' is cycloalkyl, wherein "alkyl", "cycloalkyl" are each as defined above. Examples include, but are not limited to, cyclopropylsulfonylamino, N-cyclopropylsulfonyl N (CH) 3 ) Etc.
"alkylsulfonylamino" refers to-NRSO 2 -an R 'group, wherein R is hydrogen or alkyl as defined above, and R' is alkyl as defined above. Examples include, but are not limited to, propylsulfonylamino, methylsulfonyl N (CH) 3 ) Etc.
"cyanoalkyl" refers to an alkyl group as defined above substituted with a cyano group, such as cyanomethyl, cyanoethyl, and the like.
"carboxy" refers to a-COOH group.
"fused ring alkyl" refers to a bicyclic monovalent radical having a saturated cyclic hydrocarbon group of 3 to 6 carbon atoms fused to a heterocyclyl, phenyl, or five or six membered heteroaryl ring as defined herein, and said bicyclic monovalent radical is optionally substituted with 1, 2, or 3 substituents independently selected from alkyl, halogen, alkoxy, haloalkyl, haloalkoxy, hydroxy, and cyano. Examples include, but are not limited to, tetrahydronaphthyl, 4,5,6, 7-tetrahydro-1H-indolyl, 4,5,6, 7-tetrahydrobenzoxazolyl, and the like.
"fused heterocyclyl" refers to a bicyclic monovalent radical in which a heterocyclyl as defined herein is fused to a cycloalkyl, heterocyclyl, phenyl, or five or six membered heteroaryl ring as defined herein. Examples include, but are not limited to, 4,5,6, 7-tetrahydro-1H-pyrrolo [2,3-b ] pyridinyl, 1,2,3, 4-tetrahydroquinolinyl, 3, 4-dihydroquinolin-2 (1H) -one, and the like.
"fused heterocyclylalkyl" refers to the- (alkylene) -R group, where R is fused heterocyclyl as defined above.
"halogen" means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
"haloalkyl" refers to an alkyl group as defined above substituted with 1 to 5 halogen atoms. Halogen atoms illustratively include fluorine or chlorine atoms, including groups substituted with different halogen atoms, e.g., the same alkyl group may be substituted with both F and Cl. Exemplary haloalkyl groups include, but are not limited to: -CH 2 Cl、-CF 3 、-CH 2 ClCH 2 F、-CHF 2 、-CH 2 CF 3 、-CF 2 CF 3 、-CF(CH 3 ) 2 Etc. When the alkyl group is substituted with only fluorine, it may be referred to as a fluoroalkyl group in the present application.
"Hydroxyhaloalkyl" means haloalkyl as defined above which is substituted with one or two hydroxy groups, e.g., HOCH 2 CHF-,HOCH 2 CHFCH 2 -and the like.
"Alkoxyhaloalkyl" refers to haloalkyl as defined above substituted with one or two alkoxy groups, wherein "alkoxy" are each as defined above, e.g., CH 3 OCH 2 CHF-,CH 3 OCH 2 CHFCH 2 -and the like.
"alkylamino haloalkyl" refers to a haloalkyl as defined above which is substituted with one or two alkylamino groups, wherein "alkylamino" is defined as described above, e.g. CH 3 NHCH 2 CHF-,CH 3 NHCH 2 CHFCH 2 -and the like.
"haloalkoxy" means an-OR group wherein R is haloalkyl as defined above, e.g. -OCF 3 、-OCHF 2 Etc. When R is haloalkyl (wherein the alkyl is substituted with only fluorine), it is referred to herein as fluoroalkoxy.
"haloalkoxyalkyl" refers to an alkyl group substituted with haloalkoxy, wherein "haloalkoxy" and "alkyl" are each as defined above, e.g., trifluoromethoxyethyl, and the like.
"heteroalkylene" refers to a straight chain saturated divalent hydrocarbon radical having 2 to 6 carbon atoms or a branch having 3 to 6 carbon atomsA chain saturated divalent hydrocarbon group, wherein one carbon atom is replaced by-O-, -NR-, -NR 'CO-, -CONR' -, SO 2 NR '-or-NR' SO 2 -alternatively, R and R' are independently H or alkyl as defined herein, unless otherwise indicated. Exemplary "heteroalkylenes" include, but are not limited to: -CH 2 O-、-OCH 2 -、-(CH 2 ) 2 O-、-O(CH 2 ) 2 -、-(CH 2 ) 2 OCH 2 -、-(CH 2 ) 2 NH-、-NH(CH 2 ) 2 -and the like.
"hydroxyalkyl" refers to a straight chain monovalent hydrocarbon radical having 1 to 6 carbon atoms or a branched chain monovalent hydrocarbon radical having 3 or 6 carbons substituted with one or two hydroxyl groups, provided that if two hydroxyl groups are present, they are not on the same carbon atom at the same time. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1- (hydroxymethyl) -2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2, 3-dihydroxypropyl, 1- (hydroxymethyl) -2-hydroxyethyl, 2, 3-dihydroxybutyl, 3, 4-dihydroxybutyl and 2- (hydroxymethyl) -3-hydroxypropyl, preferably 2-hydroxyethyl, 2, 3-dihydroxypropyl and 1- (hydroxymethyl) -2-hydroxyethyl.
"hydroxyalkoxy" refers to an-OR group, wherein R is hydroxyalkyl as defined above, e.g., hydroxyethoxy, hydroxypropoxy, and the like.
"hydroxyalkyl carbonyl" refers to a-COR group wherein R is hydroxyalkyl as defined above, e.g., hydroxyethyl carbonyl, hydroxypropyl carbonyl, and the like.
"hydroxyalkyl amino" refers to the group-NRR 'where R is hydrogen or alkyl and R' is hydroxyalkyl, "alkyl" and "hydroxyalkyl" are each as defined above. Exemplary "hydroxyalkylamino groups" include, but are not limited to: hydroxyethylamino, hydroxypropylamino, and the like.
Unless otherwise indicated, "heteroaryl" refers to a monovalent monocyclic or bicyclic aromatic radical having 5 to 10 ring atoms, wherein one or more (in one embodiment, one, two, or three) ring atoms are heteroatoms selected from N, O or S, the remaining ring atoms being carbon. Non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuranyl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridinyl, benzothiazolyl, benzofuranyl, benzothienyl, indolyl, quinolinyl, isoquinolinyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furanyl, thienyl, and the like. The terms "heteroaryl" and "aryl" are independent of each other, as defined herein. When the heteroaryl ring contains 5 or 6 ring atoms, it is also referred to herein as a 5 or 6 membered heteroaryl.
"heteroarylalkyl" refers to the- (alkylene) -R group, wherein R is heteroaryl as defined above.
"heteroaryloxy" means-OR, wherein R is heteroaryl as defined above.
"heteroarylalkyloxy" means an-O- (alkylene) -R group, wherein R is heteroaryl as defined above.
"heteroarylcarbonyl" means-COR, wherein R is heteroaryl as defined above.
"heteroarylamino" refers to the radical-NRR ', where R is hydrogen or alkyl as defined above, and R' is heteroaryl (including the specific rings) as defined above.
Heteroaryl sulfonyl: -SO 2 And an R group, wherein R is heteroaryl as defined herein. Exemplary "heteroarylsulfonyl" groups include, but are not limited to: pyridine sulfonyl, pyridazine sulfonyl, pyrazine sulfonyl, pyrimidine sulfonyl, benzotriazine sulfonyl, purine sulfonyl, benzimidazole sulfonyl, benzopyrazole sulfonyl, benzofuran sulfonyl, benzothiophene sulfonyl, quinoline sulfonyl.
"Heterocyclylalkyl" refers to the- (alkylene) -R group, wherein R is heterocyclyl as defined above. For example, oxetanyl ethyl, piperidinylethyl, and the like.
"Heterocyclyloxy" means a-OR group wherein R is heterocyclyl as defined above.
"Heterocyclylalkyloxy" means an-O- (alkylene) -R group, wherein R is a heterocyclyl as defined above. For example, oxetanyloxy, piperidylethoxy, and the like.
"Heterocyclylcarbonyl" means-COR wherein R is heterocyclyl as defined above.
"Heterocyclylamino" refers to the-NRR 'group where R is hydrogen or alkyl as defined above and R' is heterocyclyl as defined above.
"Heterocyclylsulfonyl" means-SO 2 R, wherein R is a heterocyclic group as defined above.
"Heterocyclylaminocarbonyl" means-CONRR ', wherein R is hydrogen or alkyl as defined above and R' is heterocyclyl as defined above.
"Heterocyclylalkylaminocarbonyl" means-CONRR 'wherein R is hydrogen or alkyl as defined above and R' is heterocyclylalkyl as defined above.
"Heterocyclylaminoalkyl" refers to the- (alkylene) -NRR 'group where R is hydrogen or alkyl as defined above and R' is heterocyclyl as defined above. For example, oxetanylaminoethyl, piperidylaminoethyl, and the like.
"Heterocyclyloxyalkyl" refers to the- (alkylene) -OR group, where R is heterocyclyl (including the particular heterocyclyl ring) as defined above. For example, oxetanyloxyethyl, piperidinyloxyethyl, and the like.
"Heterocyclyloxy Alkyloxy" means an-O- (alkylene) -R group, wherein R is a heterocyclyloxy group as defined above. For example, oxetanyloxy ethoxy, piperidyloxy ethoxy, and the like.
"Heterocyclyloxyalkylamino" refers to the group-NR- (alkylene) -R 'where R is hydrogen or alkyl as defined above and R' is heterocyclyloxy as defined above. For example, oxetanyloxyethylamino, piperidinooxyethylamino, and the like.
Spirocycloalkyl: refers to a bicyclic structure having one common ring carbon atom, and each monocyclic ring has 3 to 7 carbon atoms. Exemplary spirocycloalkyl groups include, but are not limited to: spiro [4.5] decane, spiro [3.4] octane, spiro [2.3] hexane.
Spirocycloalkyl alkyl: refers to the- (alkylene) -R group, wherein R is spirocycloalkyl as defined above.
Spirocyclic alkylcarbonyl: refers to-CO-R, wherein R is spirocycloalkyl as described above.
Spiroheterocyclyl: refers to a bicyclic structure having one common ring carbon atom, and each monocyclic ring is a saturated or unsaturated monovalent monocyclic group having 4 to 8 ring atoms, wherein 1 or 2 ring atoms are heteroatoms selected from N, O or S (O) n, wherein n is an integer from 0 to 2, and the remaining ring atoms are C. In addition, 1 or 2 ring carbon atoms in the heterocyclyl ring may optionally be replaced by a-CO-group. Exemplary spiroheterocyclyl groups include, but are not limited to: 5-azaspiro [2.3] hexane, 6-oxaspiro [3.4] -7-octanone.
Spiroheterocyclylcarbonyl: refers to a-CO-R group, R is a spiroheterocyclyl as described above.
Spiroheterocyclylalkyl: refers to the- (alkylene) -R group, wherein R is a spiroheterocyclyl as defined above.
"cyano" means-CN
"oxo" means = (O).
"heteroatom" means oxygen, sulfur and nitrogen.
The alkylene groups described above are all defined as described herein.
In the present invention, when the structure of the compound and the expression of the chemical name are inconsistent, the structure of the compound is subject to.
The invention has the following effects:
the 2-oxo-quinazolino five-membered heterocyclic derivative of formula (IA) of the present invention shows a good MAT2A inhibiting effect, and can be used as a drug for the treatment and/or prevention of diseases associated with this effect.
Detailed Description
It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. In addition, although any methods, devices, and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices, and materials are now described.
The structure of the compound is determined by Nuclear Magnetic Resonance (NMR) or Mass Spectrometry (MS). NMR was performed using a Bruker ASCENA-400 nuclear magnetic resonance apparatus with deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated chloroform (CDCl) 3 ) Deuterated methanol (CD) 3 OD), internal standard Tetramethylsilane (TMS), chemical shift of 10 -6 (ppm) is given as a unit.
Reaction monitoring and MS determination a thermofiser ESQ (ESI) mass spectrometer was used.
HPLC was performed using a Siemens Feu 3000 DAD high pressure liquid chromatograph (GL Sciences ODS-HL HP 3.mu.m3.0X100 mm column).
The thin layer chromatography silica gel plate uses Qingdao ocean GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.9-1.0 mm. Column chromatography uses 200-300 mesh silica gel of Qingdao ocean as a carrier, and a system used by a developing agent comprises the following components: methylene chloride and methanol systems; b: petroleum ether and ethyl acetate systems, and the volume ratio of the solvent is adjusted according to the polarity of the compounds. The biotage isera one type preparative liquid phase is used for purification of the medium pressure preparative liquid phase.
In the following examples, all reaction materials were purchased from suppliers in the scibinder database, and for example, some reagents in the examples of the present invention were purchased from manufacturers such as saen chemical technology (Shanghai), shanghai Shaoshao reagent Limited, nanjing pharmaceutical technology Co., jiangsu Aikang biological medicine research and development Co., shanghai Bi medicine Co., ltd, unless otherwise specified.
Further, unless otherwise indicated, all starting materials used in the examples of the present invention were analytically pure.
Further, in each embodiment of the present invention: unless otherwise indicated, reference is made to the ratio of the two substances, solid substances by mass and liquid substances by volume. When reference is made to percentage content, it is understood to be mass percent unless otherwise specified.
Brief description of the drawings
Example 1:
preparation of 4-chloro-2- (phenylamino) benzoic acid (2 b)
To a solution of compound 2a (5.0 g,26.18 mmol) in N, N-dimethylformamide (50 mL) were added aniline (3.58 mL,39.27 mmol), copper powder (0.8 g,13.1 mmol) and potassium carbonate (7.2 g,52.4 mmol) with nitrogen substitution for 3 times, and the reaction solution was then reacted at 150℃for 5 hours. After the reaction, the reaction mixture was cooled to room temperature, filtered through celite, and the filtrate was adjusted to pH 2 with 2mol/L dilute hydrochloric acid at 0deg.C. Filtering, washing the filter cake with water, and drying to obtain compound 2b (4.0 g), ESI-MS (m/z): 248.0[ M+H ]] + 。
Preparation of 7-chloro-1-phenyl-2H-benzo [ d ] [1,3] oxazine-2, 4 (1H) -dione (2 c)
To a solution of compound 2b (1.0 g,4.04 mmol) in ethyl acetate (40 mL) was added potassium carbonate (1.67 g,12.1 mmol) and triphosgene (1.2 g,4.0 mmol) and reacted at 25℃for 4 hours. After the reaction, the reaction mixture was diluted with water, separated, the organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (petroleum ether: ethyl acetate=2:1) to give Compound 2c (0.55 g), ESI-MS (m/z): 274.0[ M+H ] ] + 。
Preparation of 7-chloro-4-hydroxy-3-nitro-1-phenylquinolin-2 (1H) -one (2 d)
A solution of Compound 2c (500 mg,1.83 mmol) in anhydrous N, N-dimethylacetamide (20 mL) was cooled to 0℃and ethyl nitroacetate (243.15. Mu.L, 2.2 mmol), sodium hydride (95.0 mg,60% purity, 2.4 mmol) was added to the reaction solution, followed by slowly raising the temperature to 150℃and reacting at that temperature for 2 hours. After the reaction, the reaction mixture was diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give crude compound 2d (579 mg), ESI-MS (m/z): 317.0[ M+H ]] + 。
Preparation of 4, 7-dichloro-3-nitro-1-phenylquinolin-2 (1H) -one (2 e)
A solution of compound 2d (428.6 mg,1.35 mmol) in phosphorus oxychloride (5 mL,53.8 mmol) was reacted at 110℃for 1 hour. After the completion of the reaction, the reaction mixture was concentrated to give Compound 2e (453.5 mg), ESI-MS (m/z): 335.0[ M+H ]] + 。
Preparation of 7-chloro-4- (methylamino) -3-nitro-1-phenylquinolin-2 (1H) -one (2 f)
To a solution of compound 2e (158.7 mg,0.47 mmol) in tetrahydrofuran (3 mL) was added N, N-diisopropylethylamine (1.18 mL,7.1 mmol) and methylamine hydrochloride (479.5 mg,7.1 mmol) in this order, and the mixture was reacted at 25℃for 2 hours. After the completion of the reaction, the reaction mixture was diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (methylene chloride) to give Compound 2f (160 mg), ESI-MS (m/z): 330.1[ M+H ] ] + 。
Preparation of 3-amino-7-chloro-4- (methylamino) -1-phenylquinolin-2 (1H) -one (2 g)
To a mixed solution of compound 2f (140 mg,0.42 mmol) in absolute ethanol (10 mL) and water (10 mL) was added sodium dithionite (317.9 mg,1.8 mmol), and the mixture was reacted at 80℃for 0.5 hours. After the completion of the reaction, the reaction mixture was concentrated to give 2g (127.3 mg) of a crude compound, ESI-MS (m/z): 300.1[ M+H ]] + 。
Preparation of 7-chloro-1-methyl-5-phenyl-1, 5-dihydro-4H-imidazo [4,5-c ] quinolin-4-one (2)
A solution of compound 2g (127.3 mg,0.42 mmol) in triethylorthoformate (8 mL) was reacted at 110℃for 1h. After the reaction, the reaction mixture was concentrated and purified by reverse phase column chromatography (acetonitrile: water (0.05% ammonium bicarbonate) =0:100% -50:50%, gradient elution) to give Compound 2 (56 mg), ESI-MS (m/z): 310.1[ M+H)] + . 1 H NMR(400MHz,DMSO-d 6 )δ8.26(d,J＝8.8Hz,1H),8.20(s,1H),7.70-7.63(m,2H),7.62-7.57(m,1H),7.41-7.31(m,3H),6.50(d,J＝2.0Hz,1H),4.21(s,3H)。
Example 2
N- (7-chloro-4- (methylamino) -2-oxo-1-phenyl-1, 2-dihydro-quinolin-3-yl) -2- (2, 2-dimethyl-1, 1-diphenylpropoxy) acetamide (24 a)
To a solution of 2g (100 mg,0.34 mmol) of N, N-dimethylformamide (4 mL) was added successively 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (190 mg,0.60 mmol), N, N-diisopropylethylamine (169. Mu.L, 1.0 mmol), 2- (2, 2-dimethyl-1, 1-diphenylpropoxy) acetic acid (238.4 mg,0.80 mmol), reacted overnight at 25℃and after completion of the reaction, the reaction mixture was diluted with water (8 mL), extracted three times with ethyl acetate (3X 10 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give crude compound 24a (280 mg), ESI-MS (m/z): 580.2[ M+H ] ] + 。
Preparation of 7-chloro-2- (hydroxymethyl) -1-methyl-5-phenyl-1, 5-dihydro-4H-imidazo [4,5-c ] quinolin-4-one (24)
To a solution of compound 24a (260 mg,0.45 mmol) in anhydrous ethanol (10 mL) was added sodium hydroxide (108 mg,4.5 mmol), reacted at 80 ℃ for 1 hour, after the reaction was completed, the reaction solution was concentrated, diluted with water (10 mL), extracted three times with ethyl acetate (10 ml×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by reverse phase column chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution=0:100% -50%:50%, gradient elution) to give compound 24 (6.68 mg). ESI-MS (m/z): 340.1[ M+H ]] + . 1 H NMR(400MHz,DMSO-d 6 )δ8.32(d,J＝8.8Hz,1H),7.71–7.63(m,2H),7.62–7.56(m,1H),7.41–7.32(m,3H),6.51(d,J＝2.0Hz,1H),5.72(t,J＝5.6Hz,1H),4.74(d,J＝5.6Hz,2H),4.20(s,3H)。
Example 3
7-chloro-1- [ (hydroxymethyl) cyclopropyl ] -5-phenyl-4, 5-dihydroimidazo [4,5-c ] quinolin-4-one (28)
To a solution of 2g (500 mg,1.67 mmol) of the compound in tetrahydrofuran (20 mL) was added N, N' -carbonyldiimidazole (324.6 mg,2.0 mmol), and the reaction solution was reacted at 70℃for 18 hours. After the reaction is finished, the reaction solution is directly concentrated to obtainTo crude product, the crude product was purified by beating (water: methanol=10:1) to give compound 28 (400 mg). ESI-MS (m/z): 326.1[ M+H ]] + . 1 H NMR(400MHz,DMSO-d 6 )δ11.73(s,1H),8.24(d,J＝8.8Hz,1H),7.69–7.58(m,3H),7.40-7.34(m,3H),6.52(d,J＝2.0Hz,1H),3.73(s,3H)。
Example 4
Preparation of 2, 7-dichloro-1-methyl-5-phenyl-1, 2,3, 5-tetrahydro-4H-imidazo [4,5-c ] quinolin-4-one (30 a)
A solution of compound 28 (50 mg,0.15 mmol) in phosphorus oxychloride (2 mL) was reacted at 120℃for 18 hours. After completion of the reaction, the reaction mixture was directly concentrated to give compound 30a (52 mg). ESI-MS (m/z): 344.1[ M+H ] ] + 。
Preparation of 7-chloro-2- ((2-methoxyethyl) amino) -1-methyl-5-phenyl-1, 5-dihydro-4H-imidazo [4,5-c ] quinolin-4-one (30)
To a solution of compound 30a (100 mg,0.29 mmol) in N-methylpyrrolidone (2 mL) was added 2-methoxyethane-1-amine (436.4 mg,5.8 mmol), and the reaction solution was reacted at 25℃for 18 hours. After the reaction, the reaction mixture was diluted with water (10 mL), extracted with dichloromethane (5 ml×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude compound, which was purified by column chromatography (dichloromethane: methanol=1:0 to 100:8) to give compound 30 (30 mg). ESI-MS (m/z): 383.2[ M+H ]] + . 1 H NMR(400MHz,DMSO-d 6 )δ8.30(d,J＝8.8Hz,1H),7.88–7.71(m 3H),7.60–7.38(m,3H),6.62(br s,1H),6.40(s,1H),4.20(br s,2H),3.76(s,3H),3.42(t,J＝5.6Hz,2H),3.17(s,3H)。
Example 5
Preparation of 4-chloro-2- (pyridin-3-ylamino) benzoic acid (62 a)
To the compound 2, 4-dichlorobenzoic acid (1.91 g,10 mmol) N, N-dimethylCopper powder (128 mg,2 mmol), potassium carbonate (2.8 g,2 mmol) and 3-aminopyridine (1.4 g,15 mmol) were added to a solution of dimethylformamide (20 mL), the reaction system was warmed to 150℃under nitrogen, and reacted at this temperature for 4 hours, filtered while hot, water (20 mL) was added to the filtrate, hydrochloric acid (2M) was heated to adjust the pH to about 5, and a white solid was precipitated, filtered and dried to give 4-chloro-2- (pyridin-3-ylamino) benzoic acid 62a (1.2 g) as a white solid, ESI-MS (M/z): 249.0[ M+H ] ] + 。
Preparation of methyl 4-chloro-2- (pyridin-3-ylamino) benzoate (62 b)
To a solution of compound 62a (1.2 g,4.84 mmol) in 1, 2-dichloroethane (20 mL) was added thionyl chloride (1.71 g,14.52 mmol), the temperature was slowly raised to 80℃and reacted at this temperature for 2 hours, and after completion of the reaction, methanol (10 mL) was slowly added at 0℃to spin off the solvent. Crude 62b (1.25 g) was obtained as yellow colour, ESI-MS (m/z): 263.1[ M+H ]] + 。
Preparation of methyl 4-chloro-2- (N- (pyridin-3-yl) acetamido) benzoate (62 c)
To a solution of compound 62b (1.25 g,4.75 mmol) in acetic anhydride (10 mL) was added thionyl chloride (0.2 mL), absolute methanol (0.2 mL), and the reaction system was placed in a microwave reactor and reacted at 150℃for 4 hours, as detected by LC-MS. After the reaction was completed, the solvent was removed by spin-on chromatography (EA: PE=1:1) to give compound 62c (870 mg), ESI-MS (m/z): 305.1[ M+H)] + 。
Preparation of 7-chloro-4-hydroxy-1- (pyridin-3-yl) quinolin-2 (1H) -one (62 d)
To a solution of compound 62c (870 mg,2.86 mmol) in xylene (15 mL) was added potassium tert-butoxide (962mg, 8.59 mmol), the reaction was slowly warmed to 150 ℃ and reacted at this temperature for 4 hours, detected by LC-MS, after the reaction was completed, diluted with water (20 mL), extracted with ethyl acetate (20 ml×3), the organic phases were combined, and the solvent was removed by spinning. Column chromatography (EA: pe=2:1) gives the compound 7-chloro-4-hydroxy-1- (pyridin-3-yl) quinolin-2 (1H) -one 62d (545 mg), ESI-MS (m/z): 273.0[ m+h) ] + 。
Preparation of 7-chloro-4-hydroxy-3-nitro-1- (pyridin-3-yl) quinolin-2 (1H) -one (62 e)
To acetic acid (10 mL) and nitric acid (1 mL) of compound 62d (545 g,2.0 mmol)Sodium nitrite (10 mg,0.16 mmol) was added to the solution, and the reaction system was left at room temperature for 15 minutes and detected by LC-MS. After the reaction was completed, the reaction was poured into ice water, extracted with ethyl acetate (50 ml x 3), and column chromatographed (ea=0-100%) to give compound 62e (500 mg) ESI-MS (m/z): 318.0[ m+h] + 。
Preparation of 4, 7-dichloro-3-nitro-1- (pyridin-3-yl) quinolin-2 (1H) -one (62 f)
To a solution of compound 62e (500 mg,1.58 mmol) in acetonitrile (10 mL) were added phosphine oxychloride (725 mg,4.74 mmol) and N, N-diisopropylethylamine (1.02 g,7.9 mmol), and the mixture was reacted at 100℃for 2 hours, which was detected by LC-MS, until the reaction was completed. Water (20 mL) was added to the reaction to dilute, ethyl acetate was used to extract (20 mL. Times.3), the organic phases were combined, the solvent was removed by spin-on chromatography (EA: PE=1:1) to give compound 62f (423 mg), ESI-MS (m/z): 336.0[ M+H)] + 。
Preparation of 7-chloro-4- (methylamino) -3-nitro-1- (pyridin-3-yl) quinolin-2 (1H) -one (62 g)
N, N-diisopropylethylamine (815 mg,6.31 mmol) and methylamine hydrochloride (257 mg,3.78 mmol) were added to tetrahydrofuran (10 mL) of the compound 62f (423 mg,1.26 mmol), and after the addition was completed, the mixture was allowed to react at room temperature for 2 hours, and after the completion of the reaction, the sample was taken out and diluted with water (5 mL). Ethyl acetate extraction (20 ml. Times.3), organic concentration gave 62g (423 mg) of compound, ESI-MS (m/z): 331.1[ M+H) ] + 。
Preparation of 3-amino-7-chloro-4- (methylamino) -1- (pyridin-3-yl) quinolin-2 (1H) -one (62H)
To a mixed solution of 62g (330 mg,1.0 mmol) of the compound in absolute ethanol (10 mL) and water (10 mL) was added sodium dithionite (696 mg,4.0 mmol), and the mixture was reacted at 80℃for 0.5 hours after the addition. And (5) sampling and detecting. After the completion of the reaction, water (5 mL) was added to the reaction mixture to dilute it. Ethyl acetate extraction (20 ml. Times.3), organic concentration gave compound 62h (290 mg), ESI-MS (m/z): 301.1[ M+H)] + 。
Preparation of N- (7-chloro-1- (2-chlorophenyl) -4- (methylamino) -2-oxo-1, 2-dihydro-quinolin-3-yl) cyclopropanecarboxamide (62 i)
To a solution of compound 62h (100 mg,0.3 mmol) in N, N-dimethylformamide (5 mL) was added N in sequenceUrea hexafluorophosphate (228 mg,0.6 mmol), N, N-diisopropylethylamine (203. Mu.L, 1.2 mmol), cyclopropane (36 mg,0.6 mmol) were reacted at 25℃for 12 hours, after the reaction was completed, water (5 mL) was added to dilute the reaction solution, extracted with ethyl acetate (10 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give crude compound 62i (60 mg), ESI-MS (m/z): 369.1[ M+H ]] + 。
Preparation of 7-chloro-2-cyclopropyl-1-methyl-5- (pyridin-3-yl) -1, 5-dihydro-4H-imidazo [4,5-c ] quinolin-4-one (62)
Acetic acid (5 mL) was added to compound 62i (60 mg,0.16 mmol), the mixture was warmed to 120℃and reacted at this temperature for 2 hours, the reaction was completed by sample feeding detection, heating was stopped, the solvent was spun off, and purification by reverse phase chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution=0:100% -60:40%) gave compound 62 (1.05 mg), ESI-MS (m/z): 351.1[ M+H)] + 。 1 H NMR(600MHz,DMSO-d 6 ) Delta 8.78 (dd, j=4.8, 1.3hz, 1H), 8.56 (d, j=2.3 hz, 1H), 8.34 (d, j=8.7 hz, 1H), 7.93-7.85 (m, 1H), 7.71 (dd, j=8.0, 4.9hz, 1H), 7.40 (dd, j=8.7, 2.0hz, 1H), 6.50 (d, j=2.0 hz, 1H), 4.24 (s, 3H), 1.99 (s, 1H), 1.12-1.06 (m, 2H), 1.03-0.94 (m, 2H). Example 6
Preparation of 4-chloro-2- ((2-chlorophenyl) amino) benzoic acid (63 a)
Copper powder (256 mg,2 mmol), potassium carbonate (5.52 g,40 mmol) and o-chloroaniline (3.81 g,30 mmol) were added to a solution of N, N-dimethylformamide (20 mL) of 2, 4-dichlorobenzoic acid (3.82 g,20 mmol), the reaction system was filled with nitrogen, the temperature was raised to 150℃and reacted at this temperature for 4 hours, after the reaction was completed, filtration was carried out while hot, water (20 mL) was added to the filtrate, hydrochloric acid (2M) was heated to adjust the pH to about 5, a white solid was precipitated, filtration was carried out, and 282.0[ M+H ] was obtained after drying as ESI-MS (M/z) ] + 。
Preparation of methyl 4-chloro-2- ((2-chlorophenyl) amino) benzoate (63 b)
Orientation methodTo a solution of compound 63a (2.6 g,9.25 mmol) in 1, 2-dichloroethane (20 mL) was added thionyl chloride (3.27 g,27.76 mmol), the temperature was slowly raised to 80℃and reacted at this temperature for 2 hours, and after completion of the reaction, methanol (10 mL) was slowly added at 0℃to spin off the solvent. A yellow crude 63b (2.73 g) was obtained, ESI-MS (m/z): 296.0[ M+H ]] + 。
Preparation of methyl 4-chloro-2- ((2-chlorophenyl) acetylamino) benzoate (63 c)
To a solution of compound 63b (2.73 g,9.25 mmol) in acetic anhydride (10 mL) was added thionyl chloride (0.2 mL), absolute methanol (0.2 mL), and the reaction system was placed in a microwave reactor and reacted at 150℃for 4 hours, followed by spin-off of the solvent. And (5) sample feeding detection. After the reaction was completed, the solvent was removed by spin-on chromatography (EA: PE=1:1) to give compound 63c (1.88 g), ESI-MS (m/z): 338.0[ M+H)] + 。
Preparation of 7-chloro-1- (2-chlorophenyl) -4-hydroxyquinolin-2 (1H) -one (63 d)
To a solution of compound 63c (1.88 g,5.56 mmol) in xylene (20 mL) was added potassium tert-butoxide (1.97 g,14.78 mmol), and the flask was slowly warmed to 150℃and reacted for 2 hours, followed by sampling and detection. After the reaction, the xylene was spun off and column chromatography (EA: PE=1:1) gave 63d (1.18 g), ESI-MS (m/z): 306.0[ M+H) ] + . Preparation of 7-chloro-1- (2-chlorophenyl) -4-hydroxy-3-nitroquinolin-2 (1H) -one (63 e)
To a solution of compound 63d (1.18 g,3.87 mmol) in acetic acid (10 mL) and nitric acid (1 mL) was added sodium nitrite (21 mg,0.31 mmol), and the mixture was reacted at room temperature for 20 minutes, detected by LC-MS, and after the reaction was completed, the mixed system was poured into ice water. Extraction with ethyl acetate (50 mL. Times.3), drying over anhydrous sodium sulfate, filtration, and concentration of the filtrate afforded crude compound 63e (950 mg), ESI-MS (m/z): 351.0[ M+H)] + 。
Preparation of 4, 7-dichloro-1- (2-chlorophenyl) -3-nitroquinolin-2 (1H) -one (63 f)
To a solution of compound 63e (750 mg,2.71 mmol) in acetonitrile (20 mL) were added phosphine oxychloride (1.25 g,8.14 mmol) and N, N-diisopropylethylamine (1.75 g,13.57 mmol), and the mixture was reacted at 100℃for 2 hours, followed by sample feeding and detection, and heating was stopped after the reaction was completed. The solvent was spun off. Crude compound 63f (700 mg) was obtained, ESI-MS (m/z): 369.0[ M+H ]] + 。
Preparation of 7-chloro-1- (2-chlorophenyl) -4- (methylamino) -3-nitroquinolin-2 (1H) -one (63 g)
N, N-diisopropylethylamine (1.22 g,9.48 mmol) and methylamine hydrochloride (387 mg,5.6 mmol) were added to tetrahydrofuran (20 mL) of compound 63f (700 mg,1.90 mmol), and after the addition was completed, the mixture was allowed to react at room temperature for 2 hours, and after completion of the reaction, the reaction was detected by LC-MS, and the solvent was removed by spinning. Extraction with ethyl acetate (10 mL. Times.3), drying over anhydrous sodium sulfate, filtration, concentration of the filtrate afforded the crude compound, column chromatography (EA: PE=3:2) afforded 63g (550 mg) of the compound, ESI-MS (m/z): 364.0[ M+H ] + 。
Preparation of 7-chloro-1- (2-chlorophenyl) -4- (methylamino) -3-aminoquinolin-2 (1H) -one (63H)
To a mixed solution of 63g (550 mg,1.51 mmol) of the compound in absolute ethanol (10 mL) and water (10 mL) was added sodium dithionite (1.05 g,6.04 mmol), and the mixture was reacted at 80℃for 0.5 hours after the addition. LC-MS detection. After the reaction was completed, extracted with ethyl acetate (10 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to give the crude compound 63h (450 mg), ESI-MS (m/z): 334.0[ M+H ]] + 。
Preparation of N- (7-chloro-4- (methylamino-2-oxo-1- (pyridin-3-yl) -2 (1H) quinolin-3-yl) cyclopropanecarboxamide (63 i)
To a solution of compound 63h (55 mg,0.16 mmol) in N, N-dimethylformamide (5 mL) was added in this order urea N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) hexafluorophosphate (115 mg,0.3 mmol), N, N-diisopropylethylamine (105. Mu.L, 0.3 mmol), cyclopropane (28 mg,0.32 mmol), reacted at 25℃for 12 hours, diluted with water (5 mL), extracted with ethyl acetate (10 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to give crude compound 63i (110 mg), ESI-MS (m/z): 402.1[ M+H ]] + 。
Preparation of 7-chloro-5- (2-chlorophenyl) -2-cyclopropyl-1-methyl-1, 5-dihydro-4H-imidazo [4,5-c ] quinolin-4-one (63)
Acetic acid (5 mL) was added to compound 63i (110 mg,0.37 mmol), the mixture was warmed to 120℃and reacted at this temperature for 2 hours, the reaction was completed by sample feeding and detection, the heating was stopped, and the solvent was removed by spinningPurification by reverse phase chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution = 0:100% -60%: 40%) afforded compound 63 (27.11 mg), ESI-MS (m/z): 384.1[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 )δ8.35(d,J＝8.8Hz,1H),7.88–7.76(m,1H),7.68–7.62(m,2H),7.56–7.49(m,1H),7.40(dd,J＝8.8,2.0Hz,1H),6.40(d,J＝2.0Hz,1H),4.24(s,3H),2.30(s,1H),1.15–0.87(m,4H).
Example 7
Preparation of 2- (phenylamino) -6- (trifluoromethyl) nicotinic acid (68 a)
To a solution of the compound 2-chloro-6- (trifluoromethyl) nicotinic acid (5 g,22.16 mmol) in tetrahydrofuran (50 mL), lithium bis trimethylsilylamide (66.50 mL) was slowly added at-78 ℃ and after two hours of reaction at that temperature, aniline (10.12 mL,110.82 mmol) was then slowly added and after half an hour the reaction solution was moved to 25 ℃ and reacted at 25 ℃ for 12 hours; LC-MS monitoring, adding dilute hydrochloric acid (1N) into the reaction system after the reaction is completed, leading the pH of the mixed solution to be about 5, extracting ethyl acetate (100 mL.3), combining organic phases, washing with saturated saline (150 mL), drying with anhydrous sodium sulfate, filtering, concentrating the filtrate to obtain a compound 68a (6.1 g), ESI-MS (m/z): 283.1[ M+H)] + The crude product was used directly in the next step.
Preparation of methyl 2- (phenylamino) -6- (trifluoromethyl) nicotinate (68 b)
To a solution of compound 68a (4.2 g,14.88 mmol) in 1, 2-dichloroethane (100 mL) was added thionyl chloride (3.5 g,30 mmol), slowly warmed to 80℃and reacted at this temperature for 2 hours, after completion of the reaction methanol (10 mL) was slowly added at 0℃and then the solvent was removed by spinning to give crude compound 68b (4.50 g), ESI-MS (m/z): 297.1[ M+H)] + 。
Preparation of methyl 2- (phenylamino) -6- (trifluoromethyl) nicotinate (68 c)
To a solution of compound 68b (4.50 g,14.88 mmol) in acetic anhydride (15 mL) was added thionyl chloride (0.5 mL), anhydrous methanol (0.5 mL), and the reaction system was set upThe reaction was carried out in a microwave reactor at 150℃for 4 hours, and the solvent was removed by spinning. Purification by column chromatography (ethyl acetate: petroleum ether=0:100% -25%: 75%) gave compound 68c (3.4 g), ESI-MS (m/z): 339.1[ M+H ]] + 。
Preparation of 4-hydroxy-1-phenyl-7- (trifluoromethyl) -1, 8-naphthyridin-2 (1H) -one (68 d)
To a solution of compound 68c (3.4 g,10 mmol) in xylene (50 mL) was added potassium tert-butoxide (3.36 g,30 mmol), the reaction was slowly warmed to 150℃and reacted at this temperature for 2 hours, detected by LC-MS, and the solvent was removed by spinning after the reaction was completed. Purification by column chromatography (ethyl acetate: petroleum ether=0:100% -50%: 50%) gave 68d (2.46 g), ESI-MS (m/z): 307.1[ M+H ] ] + 。
Preparation of 4-hydroxy-3-nitro-1-phenyl-7- (trifluoromethyl) -1, 8-naphthyridin-2 (1H) -one (68 e)
To a solution of compound 68d (2.46 g,8.04 mmol) in acetic acid (40 mL) and nitric acid (4 mL) was added sodium nitrite (460 mg,6.56 mmol), and the reaction system was left at room temperature, reacted for 15 minutes, and detected by LC-MS. After the reaction was completed, the reaction system was poured into ice water (100 mL), extracted with ethyl acetate (100 mL. Times.3), dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether: ethyl acetate=0:100% -100%: 0) to give compound 68e (1.97 g), ESI-MS (m/z): 352.2[ M+H ]] + 。
Preparation of 4-chloro-3-nitro-1-phenyl-7- (trifluoromethyl) -1, 8-naphthyridin-2 (1H) -one (68 f)
To a solution of compound 68e (1.97 g,5.61 mmol) in acetonitrile (50 mL) was added phosphine oxychloride (2.57 g,16.8 mmol) and N, N-diisopropylethylamine (3.62 g,28.05 mmol), and the mixture was allowed to react at 100℃for 2 hours, detected by LC-MS, and heating was stopped after the reaction was completed. The excess liquid was removed by spinning, water (100 mL) was added, extracted with ethyl acetate (100 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and the reaction concentrated to give crude compound 68f (1.85 g), ESI-MS (m/z): 370.0[ M+H ]] + 。
Preparation of 4- (methylamino) -3-nitro-1-phenyl-7- (trifluoromethyl) -1, 8-naphthyridin-2 (1H) -one (68 g)
To tetrahydrofuran (20 mL) of compound 68f (1.85 g,5.01 mmol) were added N, N-diisopropylethylamine (3.23 g,25.05 mmol) andmethylamine hydrochloride (1.0 g,15.03 mmol) and the mixture was left to react at room temperature for 2 hours after the addition, and the reaction was completed by LC-MS detection and the solvent was removed by spinning. Column chromatography (ethyl acetate=100%) gave 68g (1.28 g), ESI-MS (m/z): 365.0[ M+H)] + 。
Preparation of 4- (methylamino) -3-amino-1-phenyl-7- (trifluoromethyl) -1, 8-naphthyridin-2 (1H) -one (68H)
To a mixed solution of 68g (1.28 g,3.52 mmol) of the compound in anhydrous ethanol (10 mL) and water (10 mL) was added sodium dithionite (2.45 g,14.08 mmol), and the mixture was reacted at 80℃for 0.5 hours. LC-MS detection. After the reaction was completed, the mixture was extracted with ethyl acetate (50 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and the reaction mixture was concentrated to give a crude compound 68h (1.1 g), ESI-MS (m/z): 335.1[ M+H ]] + 。
Preparation of 2-cyclopropyl-N- (4- (methylamino) -2-oxo-1-phenyl-7- (trifluoromethyl) -1, 8-naphthyridin-2 (1H) -one (68 i)
To a solution of compound 68h (150 mg,0.45 mmol) in N, N-dimethylformamide (5 mL) was added in this order urea N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) hexafluorophosphate (228 mg,0.6 mmol), N, N-diisopropylethylamine (203. Mu.L, 1.2 mmol), cyclopropanecarboxylic acid (52 mg,0.6 mmol), reacted at 25℃for 12 hours, after the completion of the reaction, water (5 mL) was added to dilute the reaction solution, extracted with ethyl acetate (10 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give crude compound 68i (139 mg), ESI-MS (m/z): 403.1[ M+H ] ] + 。
Preparation of cyclopropyl-N- (4- (methylamino) -2-oxo-1-phenyl-7- (trifluoromethyl) -1, 5-dihydro-4H-imidazo [4,5-c ] [1,8] naphthyridin-4-one (68)
Acetic acid (5 mL) was added to compound 68i (139 mg,0.35 mmol), the mixture was warmed to 120℃and reacted at this temperature for 2 hours, and after the completion of the reaction, the heating was stopped, the solvent was spun off, and purification by reverse phase chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution=0:100% -60:40%) gave 68 (43.88 mg), ESI-MS (m/z): 385.1[ M+H] + 。 1 H NMR(400MHz,DMSO-d6)δ8.87(d,J＝8.0Hz,1H),7.76(d,J＝8.4Hz,1H),7.59–7.40(m,3H),7.26(dd,J＝5.2,3.3Hz,2H),4.27(s,3H),2.35(s,1H),1.19–0.99(m,4H).
Example 8
Preparation of 4-fluoro-2- (phenylamino) benzoic acid (74 b)
To a solution of 2-chloro-4-fluorobenzoic acid (2 g,11.5 mmol) in N, N-dimethylformamide (10 mL) was added aniline (1.57 mL,17.2 mmol), potassium carbonate (3.2 g,22.9 mmol), copper powder (0.1 g,2.3 mmol) in this order, and the mixture was reacted at 150℃for 4 hours. After the completion of the reaction, the reaction mixture was filtered through celite, water (20 mL) was added to the filtrate, pH=5 was adjusted, the product was precipitated, filtered, and the cake was dried to give a product 74b (1.0 g), ESI-MS (m/z): 232.1[ M+H ]] +
Preparation of 7-fluoro-1-phenyl-2H-benzo [ d ] [1,3] oxazine-2, 4 (1H) -dione (74 c)
To a solution of compound 74b (900 mg,3.89 mmol) in ethyl acetate (8 mL) was successively added potassium carbonate (1614 mg,11.7 mmol), triphosgene (3.5 g,11.7 mmol), and the addition was completed and reacted at 25℃for 3 hours. After completion of the reaction, 8mL of water was added to the system, extraction was performed with ethyl acetate (3×20 mL), drying was performed with anhydrous sodium sulfate, filtration was performed, and the filtrate was concentrated, and the product 74c (460 mg), ESI-MS (m/z): 258.0[ m+h ], was obtained by normal phase column chromatography (petroleum ether/ethyl acetate=0:100% -20%: 80%) ] +
Preparation of 7-fluoro-4-hydroxy-3-nitro-1-phenylquinolin-2 (1H) -one (74 e)
To a solution of compound 74c (460 mg,1.79 mmol) in N, N-dimethylacetamide (8 mL) was added sodium hydride (57.9 mg,2.4 mmol) in this order at 0℃and ethyl nitroacetate (285.7 mg,2.1 mmol) was reacted at 150℃for 3 hours. After the reaction was completed, 30mL of water was added to the system, pH=5 was adjusted, the product was precipitated, filtered, and the cake was dried to give 74d (360 mg) of the product, ESI-MS (m/z): 232.1[ M+H ]] + . Preparation of 4-chloro-7-fluoro-3-nitro-1-phenylquinolin-2 (1H) -one (74 f)
To a solution of compound 74d (110 mg,0.37 mmol) in tetrahydrofuran (6 mL) was successively added N, N-diisopropylethylamine (281.4 mg,2.2 mmol), phosphorus oxychloride (173.7 mg,1.1 mmol), and the mixture was reacted at 80℃for 2 hours. After the reaction is completed, spinThe reaction mixture was dried to give 74e (100 mg) as a product, ESI-MS (m/z): 319.0[ M+H ]] +
Preparation of 4-chloro-7-fluoro-3-nitro-1-phenylquinolin-2 (1H) -one (74 g)
To a solution of compound 74e (100 mg,0.31 mmol) in tetrahydrofuran (5 mL) was added N, N-diisopropylethylamine (0.78 mL,4.7 mmol) in this order, methylamine hydrochloride (211.8 mg,3.1 mmol) and the addition was completed overnight at 25 ℃. After the completion of the reaction, the reaction mixture was dried by spin-drying, adding water (30 mL), stirring for 10 minutes, filtering, washing the cake with water, and drying to give a product 74f (90 mg), ESI-MS (m/z): 314.1[ M+H ] ] +
Preparation of 3-amino-7-fluoro-4- (methylamino) -1-phenylquinolin-2 (1H) -one (74H)
To a solution of compound 74f (100 mg,0.31 mmol) in aqueous ethanol (1/1) (6 mL) was added successively sodium hydrosulfite (250.1 mg,1.4 mmol), and the mixture was reacted at 80℃for 2 hours. After the reaction was completed, the reaction mixture was dried by spin-drying, extracted with 10mL of water, extracted with dichloromethane (9X 10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to give 74g of crude product (50 mg) by normal phase column chromatography (dichloromethane/methanol=0:100% -16:84%) and ESI-MS (m/z): 284.4[ M+H ]] +
Preparation of N- (7-fluoro-4- (methylamino) -2-oxo-1-phenyl-1, 2-dihydro-quinolin-3-yl) cyclopropanecarboxamide (74 i)
To a solution of 74g (50 mg,0.18 mmol) of the compound in methylene chloride (5 mL) was successively added cyclopropanecarboxylic acid (18.6 mg,0.22 mmol), N, N-diisopropylethylamine (0.09 mL,0.5 mmol), 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (114.1 mg,0.3 mmol), and the mixture was reacted at 25℃for 4 hours. After the reaction was completed, the reaction mixture was dried by spin-drying, 10mL of water was added, extracted with dichloromethane (3X 10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a product 74h (50 mg), ESI-MS (m/z): 352.2[ M+H ]] +
Preparation of 2-cyclopropyl-7-fluoro-1-methyl-5-phenyl-4, 5-dihydroimidazo [4,5-c ] quinolin-4-one (74)
To a solution of compound 74h (50 mg,0.14 mmol) in ethanol (5 mL) was added sodium hydroxide (59.6 mg,1.4 mmol), and the addition was reacted at 100℃for 1 hour. After the reaction was completed, the reaction solution was dried by spin drying, 10mL of water was added, extracted with dichloromethane (3 x 10 mL),drying over anhydrous sodium sulfate, filtering, concentrating the filtrate, and purifying by reverse phase column chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution=0:100% -50:50%) to give compound 74 (23 mg), ESI-MS (m/z): 334.1[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 )δ8.33(dd,J＝9.2,6.0Hz,1H),7.63(m,J＝8.2,6.4Hz,2H),7.58–7.53(m,1H),7.31–7.26(m,2H),7.17(m,J＝8.6,2.6Hz,1H),6.21(dd,J＝11.6,2.8Hz,1H),4.20(s,3H),2.27(tt,J＝8.4,5.2Hz,1H),1.08–0.95(m,4H).
Example 9
Preparation of 2- (phenylamino) -4- (trifluoromethyl) benzoic acid (79 b)
To a solution of 2-chloro-4- (trifluoromethyl) benzoic acid (5 g,22.26 mmol) in N, N-dimethylformamide (50 mL) was added aniline (2.44 mL,26.7 mmol), potassium carbonate (6.2 g,44.5 mmol), copper powder (282.7 mg,4.5 mmol) and the mixture was reacted at 150℃for 4 hours. After the completion of the reaction, the reaction mixture was filtered through celite, water (50 mL) was added to the filtrate, pH=5 was adjusted, the product was precipitated, filtered, and the cake was dried to give 79b (2.6 g) as a product, ESI-MS (m/z): 282.1[ M+H ]] + 。
Preparation of 1-phenyl-7- (trifluoromethyl) -2H-benzo [ d ] [1,3] oxazine-2, 4 (1H) -dione (79 c)
To a solution of compound 79b (500 mg,1.78 mmol) in ethyl acetate (10 mL) was successively added potassium carbonate (737.2 mg,5.3 mmol), and triphosgene (527.6 mg,1.8 mmol) was reacted at 25℃for 3 hours. After completion of the reaction, 13mL of water was added to the system, extracted with ethyl acetate (3×15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to give 79c (400 mg) of the product, ESI-MS (m/z): 308.1[ m+h ], by normal phase column chromatography (petroleum ether/ethyl acetate=0:100% -12%: 88%) ] + 。
Preparation of 4-hydroxy-3-nitro-1-phenyl-7- (trifluoromethyl) quinolin-2 (1H) -one (79 d)
To a solution of compound 79c (400 mg,1.08 mmol) in N, N-dimethylacetamide (10 mL) at 0deg.C was added sequentially sodium hydride (31.1 mg,1.3 mmol) and ethyl nitroacetate (160.9 mg,1.21 m)mol) was reacted at 150℃for 3 hours. After completion of the reaction, 10mL of water was added to the system, pH=5 was adjusted, the product was precipitated, filtered, and the cake was dried to give 79d (400 mg) ESI-MS (m/z): 351.1[ M+H)] + . Preparation of 4-chloro-3-nitro-1-phenyl-7- (trifluoromethyl) quinolin-2 (1H) -one (79 e)
To a solution of compound 79d (300 mg,0.86 mmol) in acetonitrile (10 mL) was added N, N-diisopropylethylamine (0.71 mL,4.3 mmol) in this order, and phosphorus oxychloride (0.24 mL,2.6 mmol) was added and reacted at 80℃for 1 hour. After completion of the reaction, it was spin-dried, 10mL of water was added, filtered, and the filter cake was dried and subjected to normal phase column chromatography (Petroleum ether/ethyl acetate=0:100% -100%: 0) to give product 79e (250 mg), ESI-MS (m/z): 364.1[ M+H ]] + 。
Preparation of 4- (methylamino) -3-nitro-1-phenyl-7- (trifluoromethyl) quinolin-2 (1H) -one (79 f)
To a solution of compound 79e (280 mg,0.76 mmol) in tetrahydrofuran (5 mL) was added N, N-diisopropylethylamine (1.89 mL,11.4 mmol) and methylamine hydrochloride (512.6 mg,7.6 mmol) successively, followed by reaction at 60℃for 2 hours. After the completion of the reaction, the reaction mixture was dried by spin-drying, adding 30mL of water, stirring for 10 minutes, filtering, washing the cake with water, and drying to give 79f (90 mg) of the product, ESI-MS (m/z): 314.1[ M+H ] ] + 。
Preparation of 3-amino-4- (methylamino) -1-phenyl-7- (trifluoromethyl) quinolin-2 (1H) -one (79 g)
To a solution of compound 79f (250 mg,0.69 mmol) in aqueous ethanol (1/1) (6 mL) was added successively sodium hydrosulfite (514.9 mg,3.0 mmol), and the mixture was reacted at 80℃for 2 hours. After completion of the reaction, the reaction mixture was spun-dried, extracted with 30mL of water, ethyl acetate (3X 15 mL), dried over anhydrous sodium sulfate, and filtered to give 79g (220 mg) of the product, ESI-MS (m/z): 334.1[ M+H ]] + 。
Preparation of 2- (chloromethyl) -1-methyl-5-phenyl-7- (trifluoromethyl) -1, 5-dihydro-4H-imidazo [4,5-c ] quinolin-4-one (79H)
To a solution of 79g (80 mg,0.24 mmol) in tetrahydrofuran (5 mL) was added chloroacetyl chloride (54.2 mg,0.5 mmol) and the addition was allowed to react overnight at 25 ℃. After completion of the reaction, the filter cake was washed with petroleum ether (5 mL) and dried to give product 79a (65.8 mg), ESI-MS (m/z): 392.1[ M+H ]] + 。
Preparation of 2- (hydroxymethyl) -1-methyl-5-phenyl-7- (trifluoromethyl) -1, 5-dihydro-4H-imidazo [4,5-c ] quinolin-4-one (79)
To a solution of compound 79h (65 mg,0.17 mmol) in N, N-dimethylformamide (5 mL) was added potassium acetate (47.0 mg,0.34 mmol), and after 1 hour reaction at 100℃the reaction solution was dried by spinning, methanol/water (1/1) (5 mL) was added to dissolve, lithium hydroxide (8.16 mg,0.34 mmol) was added, and after 3 hours reaction at 25℃was completed, 10mL of water was added, extraction with dichloromethane (3X 10 mL), drying over anhydrous sodium sulfate, filtration, concentration of the filtrate, and reverse phase column chromatography (acetonitrile/0.5% ammonium bicarbonate aqueous solution=0:100% -50%: 50%) gave product 79 (6.7 mg), ESI-MS (m/z): 374.1[ M+H ] ] + 。 1 HNMR(600MHz,DMSO-d 6 )δ8.53(d,J＝8.4Hz,1H),7.64(m,J＝17.4,7.8Hz,4H),7.38(m,J＝7.8Hz,2H),6.79(s,1H),5.75(t,J＝5.4Hz,1H),4.77(d,J＝6.6Hz,2H),4.25(s,3H).
Example 10
Preparation of 7-chloro-2- (2-chloro-1-hydroxyethyl) -1-methyl-5-phenyl-1, 5-dihydro-4H-imidazo [4,5-c ] quinolin-4-one (119 a)
To a solution of 2g (500 mg,1.67 mmol) of the compound in N, N-dimethylacetamide (10 mL) was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (640 mg,3.3 mmol) and 1-hydroxybenzotriazole (457 mg,3.3 mmol), and after the reaction was completed at 80℃for 2 hours, water (50 mL) was added to the reaction solution, extraction (3X 30 mL) with ethyl acetate, washing with saturated brine, drying with anhydrous sodium sulfate, and purification by reverse phase column chromatography (acetonitrile: 0.05% aqueous formic acid=10%: 90% -30%: 70%) gave a product 119a (640 mg). ESI-MS (m/z): 388.1[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 )δ8.35(d,J＝8.8Hz,1H),7.67(m,2H),7.61(d,J＝7.2Hz,1H),7.37(m,4H),6.51(d,J＝2.0Hz,2H),5.14(t,J＝6.4Hz,1H),4.23(s,3H),4.22–4.18(m,1H),4.02(dd,J＝10.8,7.2Hz,1H).
Preparation of 7-chloro-2- (2- (dimethylamino) -1-hydroxyethyl) -1-methyl-5-phenyl-1, 5-dihydro-4H-imidazo [4,5-c ] quinolin-4-one (119)
To compound 119a (100 mg,0.26 mmol) was added dimethylamine tetrahydrofuran solution (2 Mol/L,8 mL), potassium carbonate (35.6 mg,0.6 mmol) was added to complete the reaction overnight at 60 ℃, and after completion of the reaction, filtration, concentration of the filtrate and reverse phase column chromatography (acetonitrile/0.5% ammonium bicarbonate aqueous solution=0:100% -50:50%) gave product 119 (2.8 mg), ESI-MS (m/z): 397.0[ M+H%] + 。 1 H NMR(400MHz,DMSO-d 6 )δ8.38(d,J＝8.8Hz,1H),7.67(t,J＝7.2Hz,2H),7.60(dd,J＝8.4,6.2Hz,1H),7.40(m,1H),7.37–7.31(m,2H),6.70(m,1H),6.53(d,J＝2.0Hz,1H),5.45(d,J＝8.4Hz,1H),4.27(s,3H),3.82–3.70(m,1H),3.58(m,1H),2.91(s,6H).
Example 11:
preparation of 2- (hydroxymethyl) -1-methyl-5-phenyl-4, 5-dihydroimidazo [4,5-c ] quinolin-4-one (138)
To a solution of compound 24 (50 mg,0.15 mmol) in methanol (5 mL) was added 10% palladium on carbon (15.7 mg,0.1 mmol), followed by reaction at 25℃for 2 hours. After the completion of the reaction, the reaction mixture was filtered through celite, the cake was rinsed with methanol (10 mL), and the filtrate was concentrated to give compound 138 (30 mg). ESI-MS (m/z): 306.1[ M+H ]] + . 1 H NMR(600MHz,DMSO-d 6 )δ8.38(dd,J＝8.4,1.2Hz,1H),7.66(t,J＝7.8Hz,2H),7.60(d,J＝7.2Hz,1H),7.48–7.42(m,1H),7.41–7.32(m,3H),6.66(d,J＝8.4Hz,1H),4.84(s,2H),4.27(s,3H).
Example 12
Preparation of 7-chloro-1-methyl-2- (methylamino) -5-phenyl-4, 5-dihydroimidazo [4,5-c ] quinolin-4-one (139)
To a solution of compound 30a (52 mg,0.15 mmol) in N-methylpyrrolidone (2 mL) was added N, N-diisopropylethylamine (0.50 mL, 3)0 mmol) methylamine hydrochloride (204.0 mg,3.0 mmol) followed by reaction of the reaction mixture at 25℃for 18 hours. After the completion of the reaction, the reaction was quenched with water (10 mL), extracted with ethyl acetate (2X 25 mL) and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude compound. Positive Xiang Zhuzhu chromatography (dichloromethane: methanol=10:1) afforded the product. Purification by high performance liquid chromatography gave compound 139 (10 mg). ESI-MS (m/z): 339.1[ M-H ]] + .1HNMR(600MHz,DMSO-d 6 )δ8.27(d,J＝7.2Hz,2H),8.23(d,J＝9.0Hz,1H),7.80–7.73(m,3H),7.52(d,J＝7.2Hz,2H),7.38(dd,J＝9.0,1.8Hz,1H),6.33(d,J＝1.8Hz,1H),3.74(s,3H),3.41(s,3H).
Example 13
Preparation of 7-hydroxy-2- (hydroxymethyl) -1-methyl-5-phenyl-4, 5-dihydroimidazo [4,5-c ] quinolin-4-one (140)
To a solution of compound 24 (200 mg,0.59 mmol) in dioxane (2 mL) was added pinacol biboronate (224.2 mg,0.9 mmol), potassium acetate (115.5 mg,1.2 mmol), chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (46.3 mg,0.1 mmol), and the reaction mixture was reacted at 110℃for 2 hours under microwave. After the completion of the reaction, the reaction mixture was diluted with dichloromethane (10 mL), filtered, and the filtrate was concentrated to give a crude compound, which was purified by normal Xiang Zhuzhu chromatography (dichloromethane: methanol=10:1) to give compound 140a (250 mg,60% purity). ESI-MS (m/z): 432.2[ M-H ] +.
To compound 140a (30 mg,0.07 mmol) of ethanol: water = 2: to a 1 (2 mL) solution was added m-chloroperoxybenzoic acid (12.0 mg,0.1 mmol), and the reaction mixture was reacted at 25℃for 3 hours. After the reaction was completed, the reaction mixture was quenched with saturated aqueous sodium bicarbonate (10 mL), extracted with dichloromethane (5 ml×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the crude compound, which was purified by thin layer preparative chromatography (dichloromethane: methanol=10:1) to give compound 140 (10 mg). ESI-MS (m/z): 322.1[ M-H ]] + . 1 H NMR(400MHz,DMSO-d 6 )δ9.88(s,1H),8.12(d,J＝8.8Hz,1H),7.64(t,J＝7.6Hz,2H),7.56(t,J＝7.6Hz,1H),7.28(dd,J＝7.2,1.6Hz,2H),6.76(dt,J＝8.8,2.2Hz,1H),6.04(t,J＝2.4Hz,1H),5.63(s,1H),4.70(s,2H),4.13(s,3H).
Example 14
Preparation of 7-fluoro-1, 2-dimethyl-5-phenyl-1, 5-dihydro-4H-imidazo [4,5-c ] quinolin-4-one (141)
To a solution of 74h (56 mg,0.15 mmol) in dichloromethane (3 mL) was added glacial acetic acid (41.5 mg,0.2 mmol), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (112.7 mg,0.3 mmol), ethyl [ di (propan-2-yl)]Amine (41.5 mg,0.2 mmol), stirring at 25deg.C for 12 hr, diluting with dichloromethane (5 mL) and water (5 mL), separating, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating the filtrate to obtain crude 141a (50 mg), and directly using in the next reaction ESI-MS (m/z): 326.1[ M+H ]] +
To a solution of 141a (50 mg,0.15 mmol) in ethanol (2 mL) was added sodium hydroxide (12.3 mg,0.3 mmol), the reaction was warmed to 80℃and stirred for 2 hours, after completion of the reaction, the mixture was concentrated and purified by column chromatography (dichloromethane: methanol=20:1) to give 141 (16 mg) ESI-MS (m/z): 308.1[ M+H) ] + . 1 H NMR(400MHz,DMSO-d 6 )δ8.33(dd,J＝9.2,6.0Hz,1H),7.69–7.63(m,2H),7.61–7.56(m,1H),7.35–7.29(m,2H),7.19(m,1H),6.24(m,1H),4.08(s,3H),2.55(s,3H).
Example 15
Preparation of 2- (dimethylamino) -7-fluoro-1-methyl-5-phenyl-1, 5-dihydro-4H-imidazo [4,5-c ] quinolin-4-one (142)
To a solution of 74h (45 mg,0.12 mmol) in acetonitrile (3 mL) was added (dichloromethylene) dimethyl ammonium chloride (38.7 mg,0.2 mmol), and the reaction was warmed to 85℃and stirred for 12 hours. After the completion of the reaction, the reaction mixture,the reaction solution was cooled to 25℃and concentrated, and column chromatography (dichloromethane: methanol=20:1) gave 142 (10 mg) of ESI-MS (m/z): 337.1[ M+H)] + . 1 H NMR(400MHz,DMSO-d 6 )δ8.24(dd,J＝9.2,6.0Hz,1H),7.69–7.62(m,2H),7.62–7.55(m,1H),7.34–7.29(m,2H),7.19(m,1H),6.23(m,1H),3.98(s,3H),2.87(s,6H).
Example 16
Preparation of N- (7-chloro-4- (methylamino) -2-oxo-1-phenyl-1, 2-dihydro-quinolin-3-yl) -2-hydroxypropionamide (143 a)
2g (200 mg,0.67 mmol) of the compound, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (319.7 mg,1.7 mmol), 1-hydroxybenzotriazole (225.3 mg,1.7 mmol) and DL-lactic acid (99.35. Mu.L, 1.33 mmol) were added successively at room temperature, and N, N-dimethylformamide (2 mL) was further added, and the reaction was continued at 60℃for 1 hour after the addition. After the reaction, the reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL. Times.3), the ethyl acetate phases were combined and washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to give Compound 143a (203.2 mg), ESI-MS (m/z): 372.1[ M+H ]] + The crude product was used directly in the next step.
Preparation of 7-chloro-2- (1-hydroxyethyl) -1-methyl-5-phenyl-1, 5-dihydro-4H-imidazo [4,5-c ] quinolin-4-one (143)
To a solution of compound 143a (200 mg,0.54 mmol) in ethanol (5 mL) was added sodium hydroxide (64.6 mg,1.61 mmol) at room temperature. After the completion of the reaction, the reaction mixture was stirred at 80℃for 1 hour, then concentrated, methanol (2 mL) was added, stirred at room temperature for 12 hours, and filtered to collect the solid, thereby obtaining compound 143 (165 mg), ESI-MS (m/z): 354.1[ M+H ]] + 。 1 H NMR(600MHz,DMSO-d 6 )δ8.33(d,J＝9.0Hz,1H),7.66(t,J＝7.8Hz,2H),7.60(t,J＝7.8Hz,1H),7.37(dd,J＝9.0,2.4Hz,1H),7.34(d,J＝7.8Hz,2H),6.51(d,J＝2.4Hz,1H),5.73(s,1H),5.08(q,J＝6.0Hz,1H),4.22(s,3H),1.61(d,J＝6.0Hz,3H).
Example 17
Preparation of tert-butyl 3- ((7-chloro-4- (methylamino) -2-oxo-1-phenyl-1, 2-dihydroquinolin-3-yl) carbamoyl) azetidine-1-carboxylate (144 a)
2g (100 mg,0.33 mmol) of the compound, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (159.8 mg,0.83 mmol), 1-hydroxybenzotriazole (112.7 mg,0.83 mmol) and DL-lactic acid (134.2 mg,0.67 mmol) were added successively at room temperature, and N, N-dimethylformamide (3 mL) was further added thereto, and the reaction was continued at 60℃for 1 hour after the addition. After the reaction, the reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL. Times.3), the ethyl acetate phases combined and washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to give compound 144a (138.6 mg), ESI-MS (m/z): 483.0
[ M+H ] +, crude was used directly in the next step.
Preparation of tert-butyl 3- (7-chloro-1-methyl-4-oxo-5-phenyl-4, 5-dihydro-1H-imidazo [4,5-c ] quinolin-2-yl) azetidine-1-carboxylate (144 b)
To a solution of compound 144a (138.6 mg,0.29 mmol) in ethanol (5 mL) was added sodium hydroxide (34.4 mg,0.86 mmol) at room temperature. After the completion of the reaction, the reaction mixture was stirred at 80℃for 1 hour, and after the completion of the reaction, the reaction mixture was concentrated, methanol (2 mL) was added, and the mixture was stirred at room temperature for 12 hours, filtered, and the solid was collected to give Compound 144b (67.0 mg), ESI-MS (m/z): 464.9[ M+H ]] + 。
Preparation of 2- (azetidin-3-yl) -7-chloro-1-methyl-5-phenyl-1, 5-dihydro-4H-imidazo [4,5-c ] quinolin-4-one (144)
To a eggplant-type bottle containing compound 144b (67.0 mg,0.14 mmol) was added a solution of hydrochloric acid (1, 4-dioxane) (2 mL, 0.4M) at room temperature. After the reaction solution is stirred at 25 ℃ for 2 hours, saturated sodium carbonate solution is added to be neutral after the reaction is finished, the mixture is dried in a spinning way, filtered, and filtrate is collected and dried in a spinning way, and a reverse phase silica gel column (acetonitrile: water=30 to 40%) is used for obtaining a compound 144 (6.3 mg), ESI-MS (m/z): 364.8[ M+H ]] + 。 1 HNMR(400MHz,DMSO-d 6 )δ8.38(s,1H),8.30(d,J＝8.8Hz,1H),7.67(t,J＝7.6Hz,2H),7.60(t,J＝7.2Hz,1H),7.40–7.31(m,3H),6.51(d,J＝2.0Hz,1H),4.37(s,2H),4.14–4.00(m,6H).
Example 18
Preparation of 7-chloro-1-methyl-5-phenyl-2- (pyridin-4-yl) -1, 5-dihydro-4H-imidazo [4,5-c ] quinolin-4-one (145)
Compound 143 (60 mg,0.17 mmol) was added sequentially at room temperature, tetrahydrofuran (3 mL) as solvent, sodium hydride (12.2 mg,0.5 mmol) was added under stirring, stirring was continued for 30 minutes at room temperature, methyl iodide (27.50. Mu.L, 0.34 mmol) was added, and the reaction was continued at 25℃for 2 hours after the addition. After the reaction was completed, the reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (10 ml×3), the ethyl acetate phases were combined and washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and normal phase column chromatography (ethyl acetate: petroleum ether=50% -100%: 0) was used to isolate compound 145 (23.0 mg), ESI-MS (m/z): 367.8[ m+h ] + 。 1 H NMR(600MHz,DMSO-d 6 )δ8.34(d,J＝9.0Hz,1H),7.67(t,J＝7.8Hz,2H),7.60(t,J＝7.2Hz,1H),7.38(dd,J＝9.0,1.8Hz,1H),7.34m,2H),6.51(d,J＝1.8Hz,1H),4.92(q,J＝6.6Hz,1H),4.22(s,3H),3.29(s,3H),1.60(d,J＝6.6Hz,3H).
Example 19
/>
Preparation of N- (7-chloro-4- (methylamino) -2-oxo-1-phenyl-1, 2-dihydro-quinolin-3-yl) -3-hydroxycyclobutane-1-carboxamide (146 a)
2g (100 mg,0.33 mmol) of the compound, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (159.9 mg,0.8 mmol), 1-hydroxybenzotriazole (112.7 mg,0.8 mmol) and 3-hydroxycyclobutyl carboxylic acid (77.5 mg,0.67 mmol) were added successively at room temperature, and N, N-dimethylformamide (2 mL) was further added, and the reaction was continued at 60℃for 1 hour after the addition. After the reaction, the reaction mixture was diluted with water (10 mL) and ethyl acetateExtraction of the ester (10 mL. Times.3), combining the ethyl acetate phases and washing with saturated brine (15 mL), drying over anhydrous sodium sulfate, filtration, and concentration of the filtrate gave compound 146a (97.1 mg), ESI-MS (m/z): 398.1[ M+H)] + The crude product was used directly in the next step.
Preparation of 7-chloro-2- (3-hydroxycyclobutyl) -1-methyl-5-phenyl-1, 5-dihydro-4H-imidazo [4,5-c ] quinolin-4-one (146)
To a solution of compound 146a (97.1 mg,0.24 mmol) in ethanol (5 mL) was added sodium hydroxide (29.3 mg,0.73 mmol) at room temperature. After the completion of the reaction, the reaction mixture was stirred at 80℃for 1 hour, and after the completion of the reaction, the reaction mixture was concentrated, methanol (2 mL) was added, stirred at room temperature for 12 hours, and filtered to give a crude product, methylene chloride (2 mL) was dissolved, and then n-hexane (2 mL) was slowly added dropwise, recrystallized, filtered, and the solid was collected to give Compound 146 (37 mg), ESI-MS (m/z): 380.1[ M+H) ] + 。 1 H NMR(600MHz,DMSO-d 6 )δ8.27(d,J＝9Hz,1H),7.66(t,J＝7.2Hz,2H),7.59(t,J＝7.2Hz,1H),7.37–7.29(m,3H),6.49(d,J＝2.4Hz,1H),5.25(d,J＝7.2Hz,1H),4.22–4.10(m,1H),4.03(s,3H),3.31–3.22(m,1H),2.74–2.63(m,2H),2.29–2.18(m,2H).
Example 20
Preparation of N- (7-chloro-4- ((methyl-d 3) amino) -2-oxo-1-phenyl-1, 2-dihydro-quinolin-3-yl) -2-methoxyacetamide (147 b)
The reaction mixture was stirred at 25℃for 0.5 h, then methoxyacetic acid (30.41. Mu.L, 0.40 mmol) and continued at 25℃for 12 h, after completion of the reaction, the reaction mixture was diluted with water (15 mL), extracted with ethyl acetate (15 mL. Times.3), the ethyl acetate phases were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude compound 147b (62.8 mg) ESI-MS (m/z): 375.2M+H [] + The crude product was used directly in the next step. 7-chloro-2- (methoxymethyl) -1- (methyl-d 3) -5-phenyl-1, 5-dihydro-4H-imidazo [4,5-c]Preparation of quinolin-4-one (147)
To a solution of compound 147b (62.8 mg,0.17 mmol) in ethanol (2 mL) was added sodium hydroxide (20.1 mg,0.50 mmol) at room temperature. After the completion of the reaction, the reaction mixture was stirred at 80℃for 1 hour, concentrated, and purified by thin layer chromatography (dichloromethane: methanol=15:1) to give 147 (24 mg) as a compound, ESI-MS (m/z): 357.2[ M+H ] ] + 。 1 H NMR(600MHz,DMSO-d 6 )δ8.32(d,J＝9.0Hz,1H),7.67(t,J＝7.8Hz,2H),7.60(t,J＝7.8Hz,1H),7.38(dd,J＝9.0,2.4Hz,1H),7.35(d,J＝7.2Hz,2H),6.51(d,J＝1.8Hz,1H),4.72(s,2H),3.34(s,3H).
Example 21
Preparation of 7-chloro-4- ((methyl-d 3) amino) -3-nitro-1-phenylquinolin-2 (1H) -one (148 a)
To a solution of compound 2e (290 mg,0.87 mmol) in tetrahydrofuran (11 mL) was added N, N-diisopropylethylamine (1.43 mL,8.7 mmol) in this order, deuterated methylamine hydrochloride (295.1 mg,8.7 mmol) and the mixture was reacted at 60℃for 2 hours. After the completion of the reaction, the reaction mixture was spin-dried, 30mL of water was added, stirred for 15min, filtered, and the cake was dried to give 148a (295 mg) ESI-MS (m/z): 333.0[ M+H ]] +
Preparation of 7-chloro-4- ((methyl-d 3) amino) -3-nitro-1-phenylquinolin-2 (1H) -one (148 b)
To a solution of compound 148a (290 mg,0.87 mmol) in aqueous ethanol (1/1) (20 mL) was added successively sodium hydrosulfite (652.4 mg,3.7 mmol), and the mixture was reacted at 80℃for 1 hour. After the completion of the reaction, the reaction mixture was dried by spin-drying, 30mL of water was added, stirred for 15 minutes, filtered, and the cake was dried to give 148b (180 mg) as a product, ESI-MS (m/z): 303.1[ M+H ]] + 。
Preparation of N- (7-chloro-4- ((methyl-d 3) amino) -2-oxo-1-phenyl-1, 2-dihydroquinolin-3-yl) acetamide (148 c)
Compound 148b (50 mg,0.17 mmol), N were added sequentially at room temperatureUrea hexafluorophosphate (125.6 mg,0.3 mmol) of N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl), N-diisopropylethylamine (54.70 μl,0.3 mmol), solvent N, N-dimethylformamide (2 mL) and acetic acid (14.18 μl,0.25 mmol) were added and the reaction was continued at 25 ℃ for 0.5 hours, after the reaction was completed, the reaction mixture was diluted with water (15 mL), extracted with ethyl acetate (15 mL 3), the ethyl acetate phases were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give crude compound 148c (46 mg) ESI-MS (m/z): 345.1 m+h [ h ] ] + The crude product was used directly in the next step.
Preparation of 7-chloro-2-methyl-1- (methyl-d 3) -5-phenyl-1, 5-dihydro-4H-imidazo [4,5-c ] quinolin-4-one (148)
To a solution of compound 148c (46 mg,0.13 mmol) in ethanol (2 mL) was added sodium hydroxide (16.0 mg,0.40 mmol) at room temperature. After the completion of the reaction, the reaction mixture was stirred at 80℃for 1 hour, concentrated, and purified by thin layer chromatography (dichloromethane: methanol=15:1) to give compound 148 (8.3 mg), ESI-MS (m/z): 327.1[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 )δ8.30(d,J＝8.8Hz,1H),7.66(t,J＝7.4Hz,2H),7.59(t,J＝7.4Hz,1H),7.38–7.31(m,3H),6.50(d,J＝2.0Hz,1H),2.56(s,3H).
Example 22
Preparation of N- (7-chloro-4- ((methyl-d 3) amino) -2-oxo-1-phenyl-1, 2-dihydroquinolin-3-yl) -3-hydroxy-2, 2-dimethylpropionamide (149 a)
2g (60 mg,0.20 mmol) of the compound, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (76.7 mg,0.4 mmol), 1-hydroxybenzotriazole (54.1 mg,0.4 mmol) and 2, 2-dimethyl-3-hydroxypropionic acid (35.5 mg,0.30 mmol) were added sequentially at room temperature, and solvent N, N-dimethylformamide (2 mL) was added to react at 60℃for 3 hours, after the reaction was completed, the reaction mixture was diluted with water (15 mL), extracted with ethyl acetate (15 mL. 3), and the ethyl acetate phases were combined and washed with saturated brine (20 mL), anhydrous sodium sulfateDrying, filtering, concentrating the filtrate to obtain crude compound 149a (64 mg) ESI-MS (m/z): 400.1[ M+H) ] + The crude product was used directly in the next step.
Preparation of 7-chloro-2- (1-hydroxy-2-methylpropan-2-yl) -1- (methyl-d 3) -5-phenyl-1, 5-dihydro-4H-imidazo [4,5-c ] quinolin-4-one (149)
To a solution of compound 149a (64 mg,0.16 mmol) in ethanol (2 mL) was added sodium hydroxide (19.2 mg,0.48 mmol) at room temperature. Stirring the reaction solution at 80deg.C for 1 hr, concentrating the reaction solution, and performing reverse phase column chromatography (ACN: H) 2 O=25%: 75% -35%: 65%) to obtain compound 149 (9.7 mg), ESI-MS (m/z): 382.1[ M+H ]] + 。 1 H NMR(600MHz,MeOD)δ8.36(d,J＝9.0Hz,1H),7.69(t,J＝7.8Hz,2H),7.63(t,J＝7.8Hz,1H),7.38(dd,J＝9.0,2.4Hz,1H),7.32(d,J＝7.8Hz,2H),6.72(d,J＝2.4Hz,1H),4.37(s,3H),3.87(s,2H),1.55(s,6H).
Example 23
2- (hydroxymethyl) -1-methyl-4-oxo-5-phenyl-4, 5-dihydro-1H-imidazo [4,5-c ] quinoline-7-carbonitrile (150)
Sequentially adding 24 (30 mg,0.09 mmol), zinc cyanide (6.2 mg,0.05 mmol), zinc powder (1.2 mg,0.02 mmol), 1' -bis (diphenylphosphine) ferrocene (3.0 mg,0.01 mmol) and tris (dibenzylideneacetone) dipalladium (4.0 mg,0.00 mmol) at room temperature, adding N, N-dimethylacetamide (2 mL), displacing three times with nitrogen, reacting the reaction solution at 150 ℃ for 2 hours under nitrogen protection, adding ethyl acetate (10 mL) to quench the reaction after the reaction, filtering, concentrating the filtrate, and performing reverse phase column chromatography (separation system of acetonitrile: water=25%: 75% -35%: 65%) to obtain 150 (7.4 mg) ESI-MS (m/z): 331.1[ M+H ] ] + 。 1 H NMR(600MHz,MeOD)δ8.52(d,J＝8.4Hz,1H),7.74–7.63(m,4H),7.36(d,J＝7.2Hz,2H),7.00(d,J＝1.2Hz,1H),4.91(s,2H),4.34(s,3H).
Example 24
Preparation of 2, 2-trifluoro-N- (4- (methylamino) -2-oxo-1-phenyl-7- (trifluoromethyl) -1, 8-naphthyridin-2 (1H) -one (152 a)
To a solution of compound 68h (100 mg,0.3 mmol) in tetrahydrofuran (10 mL) was added N, N-diisopropylethylamine (0.11 mL,0.6 mmol), followed by slow dropwise addition of trifluoroacetic anhydride (70 mg,0.3 mmol), and the reaction was carried out at room temperature for 1 hour after completion of the addition. LC-MS detection. And after the reaction is finished, the solvent is removed by screwing. The reaction mixture was diluted with water (10 mL), extracted with dichloromethane (10 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to give crude 152a (110 mg), ESI-MS (m/z): 431.1[ M+H ]] + 。
Preparation of 2, 2-trifluoro-N- (4- (methylamino) -2-oxo-1-phenyl-7- (trifluoromethyl) -1, 5-dihydro-4H-imidazo [4,5-c ] [1,8] naphthyridin-4-one (152)
A solution of compound 152a (110 mg,0.26 mmol) in acetic acid (5 mL) was slowly warmed to 120℃and stirred at this temperature for 2 hours, detected by LC-MS, and heating was stopped after the reaction was completed. The excess solvent was removed and purified by reverse phase chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution=0:100% -60%: 40%) to give compound 152 (26.42 mg), ESI-MS (m/z): 413.1[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 )δ8.99(d,J＝8.0Hz,1H),7.85(d,J＝8.4Hz,1H),7.54(dt,J＝19.6,7.2Hz,3H),7.33–7.27(m,2H),4.37(s,3H).
Example 25
Preparation of N- (4- (methylamino) -2-oxo-1-phenyl-7- (trifluoromethyl) -1, 2-dihydro-1, 8-naphthyridin-3-yl) acetamide (153 a).
To a solution of compound 68h (100 mg,0.3 mmol) in N, N-dimethylformamide (5 mL) was successively added urea N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) hexafluorophosphate (228 mg,0.6 mmol), N, N-diisopropylethylamine (203. Mu.L, 1.2 mmol), acetic acid (36 mg,0.6 mmol), and the reaction was completed at 25℃for 12 hoursAfter completion of the reaction, water (5 mL) was added to dilute the reaction mixture, extracted with ethyl acetate (10 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give crude compound 153a (102 mg), ESI-MS (m/z): 407.1[ M+H ]] + 。
Preparation of 2-cyclopropyl-N- (4- (methylamino) -2-oxo-1-phenyl-7- (trifluoromethyl) -1, 5-dihydro-4H-imidazo [4,5-c ] [1,8] naphthyridin-4-one (153)
Acetic acid (5 mL) was added to compound 153a (102 mg,0.27 mmol), the mixture was warmed to 120℃and reacted at this temperature for 2 hours, LC-MS detection was complete, heating was stopped, the solvent was spun off, and purification by reverse phase chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution=0:100% -60:40%) afforded compound 153 (34.76 mg), ESI-MS (m/z): 359.1[ M+H] + 。 1 H NMR(600MHz,DMSO-d 6 )δ8.87(d,J＝8.0Hz,1H),7.76(d,J＝8.0Hz,1H),7.54(t,J＝7.6Hz,2H),7.48(d,J＝7.2Hz,1H),7.29–7.23(m,2H),4.13(s,3H),2.60(s,3H).
Example 26
Preparation of 2- (dimethylamino) -1-methyl-5-phenyl-7- (trifluoromethyl) -1, 5-dihydro-4H-imidazo [4,5-c ] [1,8] naphthyridin-4-one (154)
To a solution of compound 68h (40 mg,0.12 mmol) in acetonitrile (5 mL) was added dichloromethylene dimethyl ammonium chloride (20 mg,0.4 mmol), followed by reaction of the reaction solution at 85℃for 18 hours. After the reaction, the reaction mixture was cooled to room temperature, the solvent was removed, and the mixture was purified by reverse phase chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution=0:100% -60%: 40%) to give compound 154 (1.35 mg), ESI-MS (m/z): 388.1[ M+H ] ] + 。 1 H NMR(600MHz,DMSO-d 6 )δ8.75(d,J＝8.2Hz,1H),7.74(d,J＝8.2Hz,1H),7.53(d,J＝7.8Hz,2H),7.47(s,1H),7.25(d,J＝7.3Hz,2H),4.02(s,3H),2.92(d,J＝2.7Hz,6H).
Example 27
Preparation of 7-chloro-2- (chloromethyl) -5- (2-chlorophenyl) -1-methyl-1, 5-dihydro-4H-imidazo [4,5-c ] quinolin-4-one (156 a)
To a solution of compound 63h (100 mg,0.3 mmol) in tetrahydrofuran (10 mL) was added chloroacetyl chloride (33.8 mg,0.3 mmol), and the mixture was reacted at room temperature for 12 hours after the addition. And (5) sampling and detecting. And after the reaction is finished, the solvent is removed by screwing. A yellow solid 156a (110 mg) was obtained, ESI-MS (m/z): 334.0[ M+H ]] + 。
Preparation of methyl (7-chloro-5- (2-chlorophenyl) -1-methyl-4-oxo-4, 5-dihydro-1H-imidazo [4,5-c ] quinolin-2-yl) acetate (156 b)
To a solution of compound 156a (110 mg,0.28 mmol) in N, N-dimethylformamide (5 mL) was added potassium acetate (41.2 mg,0.42 mmol), and the mixture was reacted at 150℃for 1 hour. LC-MS detection. And after the reaction is finished, the solvent is removed by screwing. A yellow solid 156b (152 mg) was obtained, ESI-MS (m/z): 334.0[ M+H ]] + . 7-chloro-5- (2-chlorophenyl) -2- (hydroxymethyl) -1-methyl-1, 5-dihydro-4H-imidazo [4,5-c]Preparation of quinolin-4-ones (156)
To a solution of compound 156b (152 mg,0.28 mmol) in water (2 mL) and methanol (2 mL) was added lithium hydroxide (20 mg,0.42 mmol), and the mixture was allowed to react at room temperature for one hour. LC-MS detection, after the reaction, spin drying the solvent, and purifying by reversed phase chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution=0:100% -60%: 40%) to obtain compound 156 (7.53 mg), ESI-MS (m/z): 374.0[ M+H ] ] + 。 1 H NMR(600MHz,DMSO-d 6 )δ8.36(d,J＝8.8Hz,1H),7.86–7.78(m,1H),7.69–7.62(m,2H),7.58–7.54(m,1H),7.42(dd,J＝8.8,2.1Hz,1H),6.43(d,J＝2.0Hz,1H),5.71(s,1H),4.75(d,J＝4.8Hz,2H),4.21(s,3H).
Example 28
Preparation of N- (7-chloro-4- (methylamino) -2-oxo-1-phenyl-1, 2-dihydro-quinolin-3-yl) -3-methoxypropionamide (157 a)
To compound 2g (9To a solution of 0mg,0.3mmol of N, N-dimethylformamide (5 mL) were successively added N, N, N ', N' -tetramethyl-O- (7-azabenzotriazole-1-yl) urea hexafluorophosphate (228 mg,0.6 mmol), N, N-diisopropylethylamine (203. Mu.L, 1.2 mmol), 2-methoxyacetic acid (54 mg,0.6 mmol), reacted at 25℃for 12 hours, and after completion of the reaction, water (5 mL) was added to dilute the reaction solution, extracted with ethyl acetate (10 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give crude compound 157a (102 mg), ESI-MS (m/z): 386.1[ M+H ]] + 。
Preparation of 7-chloro-2- (2-methoxyethyl) -1-methyl-5-phenyl-1, 5-dihydro-4H-imidazo [4,5-c ] quinolin-4-one (157)
Acetic acid (5 mL) was added to compound 157a (102 mg,0.26 mmol), the mixture was warmed to 120℃and reacted at this temperature for 2 hours, the reaction was completed by sample feeding detection, the heating was stopped, the solvent was spun off, and compound 157 (38.84 mg), ESI-MS (m/z): 368.1[ M+H ] was purified by reverse phase column chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution=0:100% -60:40%)] + 。 1 H NMR(600MHz,DMSO-d 6 )δ8.30(d,J＝8.8Hz,1H),7.66(t,J＝7.6Hz,2H),7.60(d,J＝7.2Hz,1H),7.34(t,J＝7.2Hz,3H),6.49(d,J＝1.6Hz,1H),4.10(s,3H),3.78(t,J＝6.4Hz,2H),3.34(s,3H),3.16(t,J＝6.4Hz,2H).
Example 29
Preparation of N- (7-chloro-1- (2-chlorophenyl) -4- (methylamino) -2-oxo-1, 2-dihydro-quinolin-3-yl) acetamide (158 a)
To a solution of compound 63h (100 mg,0.3 mmol) in N, N-dimethylformamide (5 mL) was added in this order urea N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) hexafluorophosphate (228 mg,0.6 mmol), N, N-diisopropylethylamine (203. Mu.L, 1.2 mmol), acetic acid (36 mg,0.6 mmol), reacted at 25℃for 12 hours, after completion of the reaction, water (5 mL) was added to dilute the reaction solution, extracted with ethyl acetate (10 mL of 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give crude compound 158a (105 mg), ESI-MS (m/z): 376.1[ M+H ]] + 。
Preparation of 7-chloro-5- (2-chlorophenyl) -2-cyclopropyl-1-methyl-1, 5-dihydro-4H-imidazo [4,5-c ] quinolin-4-one (158)
Acetic acid (5 mL) was added to compound 158a (105 mg,0.27 mmol), the mixture was warmed to 120℃and reacted at this temperature for 2 hours, LC-MS detection was performed, heating was stopped, the solvent was spun off, and purification by reverse phase chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution=0:100% -60:40%) afforded compound 158 (13.25 mg), ESI-MS (m/z): 358.0[ M+H] + 。 1 H NMR(400MHz,DMSO-d 6 )δ8.33(d,J＝8.8Hz,1H),7.81(d,J＝9.5Hz,1H),7.71–7.62(m,2H),7.57(s,1H),7.39(dd,J＝8.8,2.0Hz,1H),6.42(d,J＝2.0Hz,1H),4.09(s,3H),2.56(s,3H).
Example 30
Preparation of N- (7-chloro-1- (2-chlorophenyl) -4- (methylamino) -2-oxo-1, 2-dihydro-quinolin-3-yl) -2-methoxyacetamide (160 a)
To a solution of compound 63h (100 mg,0.3 mmol) in N, N-dimethylformamide (5 mL) was successively added urea N, N, N ', N' -tetramethyl-O- (7-azabenzotriazole-1-yl) hexafluorophosphate (228 mg,0.6 mmol), N, N-diisopropylethylamine (203. Mu.L, 1.2 mmol), 2-methoxyacetic acid (52 mg,0.6 mmol), reacted at 25℃for 12 hours, after completion of the reaction, water (5 mL) was added to dilute the reaction solution, extracted with ethyl acetate (10 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give crude compound N- (7-chloro-1- (2-chlorophenyl) -4- (methylamino) -2-oxo-1, 2-dihydroquinolin-3-yl) -2-methoxyacetamide 160a (110 mg), ESI-MS (m/z): 406.1[ M+H ] ] + 。
Preparation of 7-chloro-5- (2-chlorophenyl) -2- (methoxymethyl) -1-methyl-1, 5-dihydro-4H-imidazo [4,5-c ] quinolin-4-one (160)
Acetic acid (5 mL) was added to compound 160a (110 mg,0.37 mmol), the mixture was warmed to 120℃and reacted at this temperature for 2 hours, LC-MS detection was performed, heating was stopped, the solvent was spun off, and the reaction was performed in reverse phasePurification by column chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution = 0:100% -60%: 40%) afforded compound 160 (23.24 mg), ESI-MS (m/z): 388.1[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 )δ8.36(d,J＝8.8Hz,1H),7.85–7.78(m,1H),7.69–7.62(m,2H),7.61–7.54(m,1H),7.43(dd,J＝8.8,2.0Hz,1H),6.44(d,J＝2.0Hz,1H),4.79–4.67(m,2H),4.19(s,3H).
Example 31
Preparation of tert-butyl (2- ((7-chloro-4- (methylamino) -2-oxo-1-phenyl-1, 2-dihydroquinolin-3-yl) amino) -2-oxoethyl) (methyl) carbamate (161 a)
To a solution of 2g (200 mg,0.67 mmol) of the compound in methylene chloride (10 mL) was successively added N- (t-butoxycarbonyl) -N-methylglycine (75.7 mg,0.4 mmol), N, N-diisopropylethylamine (128 mg,1.0 mmol), 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (190.5 mg,0.5 mmol), and the mixture was reacted overnight at 25 ℃. After completion of the reaction, 20mL of water was added, extracted with dichloromethane (3X 20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give product 161a (282 mg), ESI-MS (m/z): 471.2[ M+H)] +
Preparation of 7-chloro-1-methyl-2- [ (methylamino) methyl ] -5-phenyl-4, 5-dihydroimidazo [4,5-c ] quinolin-4-one (161)
To a solution of compound 161a (282 mg,0.6 mmol) in tetrahydrofuran (6 mL) was added hydrochloric acid (0.06 mL,1.8 mmol) and the mixture was reacted at 25℃for 2 hours. After the reaction, the reaction mixture was concentrated, extracted with dichloromethane (3×20 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to reverse phase column chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution=0:100% -50%: 50%) to give a product 161 (42 mg), ESI-MS (m/z): 353.1[ m+h ]] + 。 1 H NMR(600MHz,DMSO-d 6 )δ8.32(d,J＝8.4Hz,1H),7.66(t,J＝7.8Hz,2H),7.62–7.57(m,1H),7.36(m,J＝11.7,8.4,1.8Hz,3H),6.51(d,J＝2.4Hz,1H),4.18(s,3H),3.97(s,2H),2.33(s,3H).
Example 32
Preparation of 7-chloro-2- (chloromethyl) -1- (methyl-d 3) -5-phenyl-1, 5-dihydro-4H-imidazo [4,5-c ] quinolin-4-one (162 a)
To a solution of compound 148b (100 mg,0.33 mmol) in tetrahydrofuran (6 mL) was added chloroacetyl chloride (74.6 mg,0.7 mmol), and the addition was completed overnight at 25 ℃. After the reaction, the filter cake was washed with petroleum ether and dried to give 162a (80 mg) ESI-MS (m/z): 361.1[ M+H)] +
Preparation of 7-chloro-2- (hydroxymethyl) -1- (methyl-d 3) -5-phenyl-4, 5-dihydroimidazo [4,5-c ] quinolin-4-one (162)
To a solution of compound 162a (80 mg,0.22 mmol) in N, N-dimethylformamide (6 mL) was added potassium acetate (43.4 mg,0.4 mmol), and after 1 hour reaction at 100 ℃, the reaction mixture was dried by spinning, methanol/water (1/1) (6 mL) was added to dissolve, lithium hydroxide (14 mg,0.3 mmol) was added, and after 2 hours reaction at 25 ℃, the reaction mixture was dried by spinning, water (6 mL) was added, dichloromethane (3 x 15 mL) was extracted, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and reversed phase column chromatography (acetonitrile/0.5% ammonium bicarbonate aqueous solution=0:100% -50%: 50%) was used to give product 162 (10 mg), ESI-MS (m/z): 343.1[ m+h ] ] + 。 1 H NMR(600MHz,DMSO-d 6 )δ8.32(d,J＝8.4Hz,1H),7.66(t,J＝7.8Hz,2H),7.60(t,J＝7.2Hz,1H),7.39–7.33(m,3H),6.51(d,J＝2.4Hz,1H),5.70(t,J＝5.4Hz,1H),4.74(t,J＝4.8Hz,2H).
Example 33
Preparation of 2- (hydroxymethyl) -7-methoxy-1-methyl-5-phenyl-1, 5-dihydro-4H-imidazo [4,5-c ] quinolin-4-one (164)
To a solution of compound 24 (100 mg,0.27 mmol) in N, N-dimethylformamide (5 mL) was added sodium trimethoxyborohydride (91.6 mg,0.58 mmol), tris (dibenzylidene-BASE acetone) dipalladium (53.9 mg,0.1 mmol), methanesulfonic acid (2-di-tert-butylphosphine1-Triisopropyl-1, 1' -biphenyl) (2 ' -amino-1, 1' -biphenyl-2-yl) palladium (II) (46.7 mg,0.1 mmol) was added and reacted at 100℃for 2 hours under nitrogen protection. After completion of the reaction, filtration, concentration of the filtrate and reverse phase column chromatography (acetonitrile/0.5% ammonium bicarbonate aqueous solution=0:100% -50:50%) gave product 164 (15.7 mg), ESI-MS (m/z): ESI-MS (m/z): 336.1[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 )δ8.24(d,J＝9.2Hz,1H),7.68–7.53(m,3H),7.29(m,J＝5.2Hz,2H),6.97(m,J＝6.8,3.4Hz,1H),6.02(d,J＝2.5Hz,1H),5.66(s,1H),4.72(s,2H),4.16(s,3H),3.63(s,3H).
Example 34
Preparation of N- (7-fluoro-4- (methylamino) -2-oxo-1-phenyl-1, 2-dihydro-quinolin-3-yl) acetamide (165 a)
To a solution of 79g (80 mg,0.24 mmol) of the compound in methylene chloride (8 mL) was successively added acetic acid (0.02 mL,0.3 mmol), N, N-diisopropylethylamine (0.12 mL,0.7 mmol), 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (136.9 mg,0.9 mmol), and the mixture was reacted overnight at 25 ℃. After completion of the reaction, the reaction mixture was dried by spin-drying, extracted with 10mL of water, extracted with dichloromethane (3X 15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to give 165a (70 mg) as a product, ESI-MS (m/z): 376.1[ M+H ] ] + 。
Preparation of 7-fluoro-1, 2-dimethyl-5-phenyl-1, 5-dihydro-4H-imidazo [4,5-c ] quinolin-4-one (165)
To a solution of compound 165a (80 mg,0.21 mmol) in ethanol (5 mL) was added sodium hydroxide (85.2 mg,2.1 mmol), and the addition was then carried out at 100℃for 1 hour. After the reaction was completed, the reaction mixture was dried by spin-drying, extracted with 10mL of water, dichloromethane (3×15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by reverse phase column chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution=0:100% -50%: 50%) to give compound 165 (14 mg), ESI-MS (m/z): 358.1[ m+h ]] + 。 1 H NMR(600MHz,DMSO-d 6 )δ8.51(d,J＝8.4Hz,1H),7.67(t,J＝7.8Hz,2H),7.61(t,J＝8.4Hz,2H),7.37(d,J＝7.2Hz,2H),6.78(s,1H),4.14(s,3H),2.59(s,3H).
Example 35
Preparation of 1- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-5-yl) ethan-1-one oxime (166 b)
To a solution of compound 166a (9 g,37.44 mmol) in ethanol (20 mL) was added sodium acetate (30.7 g,374.1 mmol), hydroxylamine hydrochloride (13.0 g,187.2 mmol), and the addition was then carried out at 60℃for 3 hours. After completion of the reaction, quench with water (100 mL), extract with ethyl acetate (3 x 200 mL), dry with anhydrous sodium sulfate, concentrate the organic phase and purify by normal phase column chromatography (petroleum ether/ethyl acetate=0:100% -16%: 84%) to give compound 166b (8 g), ESI-MS (m/z): 256.1[ m+h] + 。
Preparation of 1- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-5-yl) ethan-1-one amine 166 c)
To a solution of 166b (8 g,35.1 mmol), zinc (23.0 g,352.4 mmol) and ammonium chloride (18.9 g,352.4 mmol) in methanol (100 mL) was added acetic acid (20 mL). After the addition, the reaction was carried out at 80℃for 18 hours. After the completion of the reaction, the reaction mixture was filtered through celite, quenched by pouring 200mL of 10% aqueous ammonia, extracted with methylene chloride (3X 100 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give the product 166c (7.3 g) ESI-MS (m/z): 242.2[ M+H ]] + 。
Preparation of 4-chloro-2- ((1- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-5-yl) ethyl) amino) benzoic acid (166 d)
To a solution of compound 166c (4 g,16.57 mmol) in N, N-dimethylformamide (50 mL) was successively added benzene 1, 4-dichlorobenzoic acid (4.72 g,24.9 mmol), potassium carbonate (6.2 g,44.5 mmol), copper powder (0.5 g,7.5 mmol), and the mixture was reacted at 150℃for 3 hours. After the completion of the reaction, the reaction mixture was filtered through celite, water (100 mL) was added to the filtrate, diluted hydrochloric acid was added dropwise, pH=5 was adjusted to about, and the product was precipitated, filtered and the cake was dried to give 166d (3 g), ESI-MS (m/z): 396.1[ M+H ]] + 。
Preparation of 7-chloro-1- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-5-yl) ethyl) -2H-benzo [ d ] [1,3] oxazine-2, 4 (1H) -dione (166 e)
To a solution of compound 166d (700 mg,1.77 mmol) in ethyl acetate (30 mL) was successively added potassium carbonate (732.9 mg,5.3 mmol), and triphosgene (1.6 g,5.4 mmol) was added and reacted at 55℃for 3 hours. After completion of the reaction, 50mL of water was added to the system, extracted with ethyl acetate (3X 30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give product 166e (400 mg), ESI-MS (m/z): 422.1[ M+H ], by normal phase column chromatography (petroleum ether/ethyl acetate=0-20%) ] + 。
Preparation of 7-chloro-4-hydroxy-3-nitro-1- (1- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-5-yl) ethyl) quinolin-2 (1H) -one (166 f)
To a solution of compound 166e (400 mg,1.79 mmol) in N, N-dimethylacetamide (2 mL) at 0deg.C was added sodium hydride (49.3 mg,1.2 mmol) in sequence, and ethyl nitroacetate (151.4 mg,1.1 mmol) was reacted at 150deg.C for 3 hours. After the reaction was completed, 10mL of water was added to the system, pH was adjusted to about 5 with dilute hydrochloric acid, the product was precipitated, filtered, and the cake was dried to give 166f (300 mg), ESI-MS (m/z): 465.1[ M+H ]] + 。
Preparation of 4, 7-dichloro-3-nitro-1- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-5-yl) ethyl) quinolin-2 (1H) -one (166 g)
To a solution of 166f (300 mg,0.65 mmol) in acetonitrile (12 mL) was added N, N-diisopropylethylamine (0.53 mL,3.2 mmol), phosphorus oxychloride (0.18 mL,1.9 mmol), and the mixture was reacted at 80℃for 1 hour. After completion of the reaction, the reaction mixture was dried by spin-drying to give 166g (300 mg) of a product, ESI-MS (m/z): 483.1[ M+H ]] + 。
Preparation of 7-chloro-4- (methylamino) -3-nitro-1- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-5-yl) ethyl) quinolin-2 (1H) -one (166H)
To a solution of 166g (290.0 mg,0.6 mmol) of tetrahydrofuran (10 mL) was added N, N-diisopropylethylamine (1.49 mL,9.0 mmol), methylamine hydrochloride (405.0 mg,6.0 mmol), and the mixture was reacted at 60℃for 2 hours. After completion of the reaction, the reaction mixture was dried with spin-drying, and dichloromethane (3X 15 mL) to give 166h (260 mg) of the product, ESI-MS (m/z): 478.1[ M+H) ] + 。
Preparation of 3-amino-7-chloro-4- (methylamino) -1- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-5-yl) ethyl) quinolin-2 (1H) -one (166 i)
To a solution of 166h (250 mg,0.52 mmol) in ethanol and water (1/1) (8 mL) was added sodium hydrosulfite (391.5 mg,2.2 mmol), and the mixture was reacted at 80℃for 2 hours. Spin-drying the reaction mixture, extracting with 30mL of water and ethyl acetate (3X 13 mL), drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate to obtain 166i (200 mg), ESI-MS (m/z): 448.1[ M+H ]] + 。
Preparation of N- (7-chloro-4- (methylamino) -2-oxo-1- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-5-yl) ethyl) -1, 2-dihydroquinolin-3-yl) cyclopropanecarboxamide (166 j)
To a solution of 166i (100 mg,0.22 mmol) in dichloromethane (5 mL) was added cyclopropanecarboxylic acid (23.1 mg,0.27 mmol), N, N-diisopropylethylamine (0.09 mL,0.5 mmol), 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (127.3 mg,0.3 mmol), N, N-diisopropylethylamine (0.11 mL,0.7 mmol) in this order, and the mixture was reacted overnight at 25 ℃. After completion of the reaction, 20mL of water was added to the system, extracted with dichloromethane (3X 15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 166j (200 mg), ESI-MS (m/z): 516.1[ M+H)] + 。
Preparation of 5- (1- (1H-pyrazol-5-yl) ethyl) -7-chloro-2-cyclopropyl-1-methyl-1, 5-dihydro-4H-imidazo [4,5-c ] quinolin-4-one (166)
To 166j (70 mg,0.14 mmol) of a 1, 4-dioxane solution (5 mL) was added hydrochloric acid (0.2 mL), and the mixture was reacted at 70℃overnight. After the reaction, the reaction solution was dried by spinning, the pH was adjusted to about 5 with 50% aqueous sodium hydroxide solution, extracted with methylene chloride (3×15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to reverse phase column chromatography (acetonitrile/0.5% aqueous ammonium bicarbonate solution=0:100% -50%: 50%) to give the product 166, ESI-MS (m/z): 368.1[ M+H ]] + 。 1 H NMR(600MHz,DMSO-d 6 )δ12.66(d,J＝90.6Hz,1H),8.21(d,J＝8.7Hz,1H),7.66(s,1H),7.46(s,1H),7.26(d,J＝8.4Hz,1H),7.04(m,1H),5.95(d,J＝46.8Hz,1H),4.17(s,3H),3.16(m,1H),2.30–2.21(m,1H),1.82(d,J＝7.2Hz,3H),1.09–1.05(m,2H),1.00(m,2H).
Example 36
Preparation of 7-chloro-2- (chloromethyl) -1-methyl-5- (1- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-5-yl) ethyl) -1, 5-dihydro-4H-imidazo [4,5-c ] quinolin-4-one (167 a)
To a solution of 166i (100 mg,0.22 mmol) in tetrahydrofuran (5 mL) was added chloroacetyl chloride (50.4 mg,0.4 mmol), and the mixture was reacted overnight at 25 ℃. After completion of the reaction, the filter cake was washed with petroleum ether (5 mL) and dried to give 167a (95 mg) ESI-MS (m/z): 506.1[ M+H ]] + 。
Preparation of 7-chloro-2- (hydroxymethyl) -1-methyl-5- (1- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-5-yl) ethyl) -1, 5-dihydro-4H-imidazo [4,5-c ] quinolin-4-one (167 b)
To a solution of compound 167a (85 mg,0.17 mmol) in N, N-dimethylformamide (5 mL) was added potassium acetate (24.7 mg,0.3 mmol), reacted at 100 ℃ for 1 hour, the reaction solution was dried by spin-drying, methanol/water (1/1) (6 mL) was added to dissolve, lithium hydroxide (30 mg,1.25 mmol) was added, reacted at 25 ℃ for 2 hours, after the reaction was completed, the reaction solution was dried by spin-drying, extracted with 10mL of water, dichloromethane (3 x 10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give product 167b (70 mg), ESI-MS (m/z): 489.1[ m+h ], by reverse phase column chromatography (acetonitrile/0.5% ammonium bicarbonate aqueous solution=0:100% -50%: 50%) ] + 。
Preparation of 7-chloro-2- (hydroxymethyl) -5- [1- (1H-pyrazol-3-yl) ethyl ] -1-methyl-4, 5-dihydroimidazo [4,5-c ] quinolin-4-one (167)
To compound 167b (70 mg,0.14 mmol) was added trifluoroacetic acid/dichloromethane (2/1) (5 mL) and reacted at 25 ℃ overnight, the reaction mixture was dried by spin-drying, 10mL of water was added, dichloromethane (3 x 10 mL) was extracted, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give product 167 (11.7 mg), ESI-MS (m/z): 358.1[ m+h ] by reverse phase column chromatography (acetonitrile/0.5% aqueous ammonium bicarbonate=0:100% -50%: 50%)] + 。 1 H NMR(600MHz,DMSO-d 6 )δ12.76(s,1H),8.22(d,J＝8.4Hz,1H),7.69(s,1H),7.50(s,1H),7.28(d,J＝8.4Hz,1H),7.04(s,1H),5.98(s,1H),5.69(t,J＝5.4Hz,1H),4.73(d,J＝5.4Hz,2H),4.13(s,3H),1.84(d,J＝7.2Hz,3H).
Example 37
Preparation of N- (4- (methylamino) -2-oxo-1-phenyl-7- (trifluoromethyl) -1, 2-dihydro-1, 8-naphthyridin-3-yl) propanamide (168 a)
To a solution of compound 68h (70 mg,0.21 mmol) in dichloromethane (5 mL) was added successively propionic acid (18.6 mg,0.3 mmol), N, N-diisopropylethylamine (0.1 mL,0.6 mmol), 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (119 mg,0.3 mmol), and the addition was completed overnight at 25 ℃. After completion of the reaction, 10mL of water was added, extracted with dichloromethane (3X 15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give product 168a (60 mg), ESI-MS (m/z): 391.2[ M+H)] + 。
Preparation of 7-fluoro-1, 2-dimethyl-5-phenyl-1, 5-dihydro-4H-imidazo [4,5-c ] quinolin-4-one (168)
To a solution of compound 168a (50 mg,0.13 mmol) in ethanol (6 mL) was added sodium hydroxide (52 mg,1.3 mmol), and the addition was reacted at 100℃for 1 hour. After completion of the reaction, the reaction mixture was dried by spin-drying, dissolved in 5mL of methanol, and purified by reverse phase column chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution=0:100% -50%: 50%) to give compound 168 (20 mg), ESI-MS (m/z): 373.2[ M+H ]] + 。 1 H NMR(600MHz,DMSO-d 6 )δ8.88(d,J＝8.4Hz,1H),7.77–7.75(m,1H),7.54(t,J＝7.8Hz,2H),7.47(t,J＝7.2Hz,1H),7.27(d,J＝7.8Hz,2H),4.14(d,J＝4.2Hz,3H),2.96(q,J＝7.8Hz,2H),1.34(t,J＝7.8Hz,3H).
Example 38
Preparation of ethyl 2- (6-chloro-3H-indol-3-yl) -2-oxoacetate (169 b)
To a solution of compound 169a (2.5 g,16.49 mmol) in diethyl ether (33 mL) was added pyridine (1.7 mL,21.1 mM) in sequenceMol), cooling to 0 ℃, dropwise adding 2-chloro-2-oxo-acetic acid ethyl ester (0.09 mL,0.5 mmol), and reacting for 2 hours after the dropwise adding. The reaction was complete, filtered and washed with 50mL of water to give product 169b (3.5 g), ESI-MS (m/z): 252.1[ M+H)] + 。
Preparation of 7-chloro-2-methyl-2, 5-dihydro-4H-pyrazolo [3,4-c ] quinolin-4-one (169 c)
To a solution of compound 169b (500 mg,1.99 mmol) in ethanol (20 mL) was successively added acetic acid (1.7 mL,29.70 mmol), monomethyl hydrazine (500 mg,10.85 mmol), and the mixture was reacted at 100℃overnight. After the completion of the reaction, the reaction mixture was spin-dried and purified by normal phase column chromatography (dichloromethane/methanol=0:100% -15%: 100%) to give compound 169c (250 mg), ESI-MS (m/z): 234.1[ M+H ] ] + 。
Preparation of 7-chloro-2-methyl-5-phenyl-2, 5-dihydro-4H-pyrazolo [3,4-c ] quinolin-4-one (169)
To a solution of compound 169c (30 mg,0.13 mmol) in N, N-dimethylformamide (5 mL) was added phenylboronic acid (129.1 mg,0.3 mmol), pyridine (0.02 mL,0.3 mmol), copper acetate (23.3 mg,0.1 mmol), and air was introduced and the mixture was reacted at 70℃overnight. After completion of the reaction, celite was filtered, the filtrate was concentrated, and purified by reverse phase column chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution=0:100% -50%: 50%) to give compound 169 (8 mg), ESI-MS (m/z): 310.1[ M+H ]] + 。 1 H NMR(600MHz,DMSO-d 6 )δ8.04(dd,J＝10.0,6.0Hz,1H),7.66(t,J＝7.8Hz,2H),7.59(t,J＝7.2Hz,1H),7.39(t,J＝6.6Hz,2H),7.31(dd,J＝8.4,2.4Hz,1H),6.37(t,J＝3.0Hz,1H),4.17(d,J＝4.2Hz,3H).
Example 39
Preparation of 7-chloro-2-methyl-5- (pyridin-3-yl) -4, 5-dihydropyrazolo [3,4-c ] quinolin-4-one (170)
To a solution of compound 169c (40 mg,0.17 mmol) in N, N-dimethylformamide (5 mL) was added 3-pyridineboronic acid (31.6 mg,0.3 mmol), pyridine (0.03 mL,0.3 mmol), copper (II) acetate (31.1 mg,0.2 mmol), and air was introduced and the mixture was reacted at 70℃overnight. After the reaction is completed, diatomite is filtered, and filtrateConcentration and purification by reverse phase column chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution=0:100% -50%: 50%) afforded compound 170 (8.3 mg), ESI-MS (m/z): 311.0[ M+H ]] + 。 1 H NMR(600MHz,DMSO-d 6 )δ8.79(m,J＝4.8Hz,2H),8.63(d,J＝2.4Hz,1H),8.05(d,J＝8.4Hz,1H),7.95(dd,J＝8.0,1.8Hz,1H),7.72(dd,J＝7.8,4.8Hz,1H),7.35(dd,J＝8.4,1.8Hz,1H),6.38(d,J＝1.8Hz,1H),4.17(s,3H).
Example 40
Preparation of 7-chloro-2- (1, 2-dihydroxyethyl) -1-methyl-5-phenyl-1, 5-dihydro-4H-imidazo [4,5-c ] quinolin-4-one (171)
To a solution of compound 119a (300 mg,0.77 mmol) in tetrahydrofuran (10 mL), water (2 mL), sodium hydroxide (124 mg,3.1 mmol) were added, and after the completion of the reaction, the reaction mixture was concentrated and purified by reverse phase column chromatography (acetonitrile: 0.05% aqueous formic acid=10%: 90% -25%: 75%) to give product 171 (7.2 mg), ESI-MS (m/z): 370.1[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 )δ8.34(d,J＝8.8Hz,1H),7.73–7.53(m,3H),7.44–7.29(m,3H),6.51(d,J＝2.0Hz,1H),5.92(s,1H),4.92(t,J＝6.0Hz,1H),4.23(s,3H),3.99–3.73(m,2H).
Example 41:
preparation of 2-amino-6- (trifluoromethyl) nicotinic acid (173 b)
Ammonia water (10 mL), cuprous iodide (380.9 mg,2.0 mmol) and a mixture of 2-chloro-6- (trifluoromethyl) nicotinic acid (4.5 g,20.0 mmol) were added to an autoclave, the mixture was reacted at 120℃under nitrogen atmosphere overnight, after the completion of the reaction, the reaction mixture was concentrated to give 173b (4.0 g), ESI-MS (m/z): 207.1[ M+H)] + 。
Preparation of methyl 2-amino-6- (trifluoromethyl) nicotinate (173 c)
To the compound173b (4.0 g,19.31 mmol) of 1, 2-dichloroethane (20 mL) was added sequentially with sulfoxide chloride (4.22 mL,58.2 mmol), and the mixture was reacted at 100℃for 1.5 hours. After the reaction was completed, cooled to room temperature, quenched with dropwise methanol in ice bath until no bubbles were generated, concentrated, and purified by normal phase column chromatography (petroleum ether/ethyl acetate=0:100% -50%) to give compound 173c (4.0 g), ESI-MS (m/z): 221.1[ M+H ] ] + 。
Preparation of methyl 2-acetamido-6- (trifluoromethyl) nicotinate (173 d)
To compound 173c (4.0 g,18.17 mmol) was added acetic anhydride (17.0 mL,181.7 mmol), and the mixture was reacted at 150℃for 1.5 hours under microwave. After the reaction was completed, the reaction mixture was concentrated, sodium hydrogencarbonate (w=50%) was adjusted to ph=8 or so, ethyl acetate was extracted (3×30 ml), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and purified by normal phase column chromatography (petroleum ether/ethyl acetate=0:100% -12%: 88%) to give compound 173d (3.5 g), ESI-MS (m/z): 263.1[ m+h] + 。
Preparation of 4-hydroxy-7- (trifluoromethyl) -1, 8-naphthyridin-2 (1H) -one (173 e)
To a solution of compound 173d (3.5 g,13.35 mmol) in xylene (20 mL) was added potassium tert-butoxide (2.2 g,20.0 mmol) and the mixture was reacted at 130℃for 2 hours under nitrogen. After the completion of the reaction, the reaction mixture was concentrated, pH=6 was adjusted with dilute hydrochloric acid, and the mixture was filtered, and the cake was washed with water and dried to give compound 173e (2200 mg), ESI-MS (m/z): 231.1[ M+H] + 。
Preparation of 4-hydroxy-3-nitro-7- (trifluoromethyl) -1, 8-naphthyridin-2 (1H) -one (173 f)
To a solution of compound 173e (2.2 g,9.56 mmol) in acetic acid/nitric acid (10/1, 20 mL) was added sodium nitrite (0.5 g,7.6 mmol) at 0deg.C, and the addition was reacted at 25deg.C for 15 minutes. After completion of the reaction, water (50 mL) was added, pH=8 was adjusted with a saturated sodium carbonate solution, the mixture was filtered, the cake was washed with water, and the cake was dried to give compound 173f (2.3 g), ESI-MS (m/z): 276.0[ M+H ] ] + 。
Preparation of 4-chloro-3-nitro-7- (trifluoromethyl) -1, 8-naphthyridin-2 (1H) -one (173 g)
To a solution of compound 173f (2.2 g,8.0 mmol) in acetonitrile (300 mL) was added N, N-diisopropylethylAmine (6.62 mL,40.0 mmol), phosphorus oxychloride (2.23 mL,24.0 mmol) was reacted at 80℃for 2 hours under nitrogen. After completion of the reaction, the mixture was concentrated to give 173g (2.0 g) of a compound ESI-MS (m/z): 292.1[ M+H)] + 。
Preparation of 4- (methylamino) -3-nitro-7- (trifluoromethyl) -1, 8-naphthyridin-2 (1H) -one (173H)
To a solution of 173g (2.0 g,5.81 mmol) of the compound in tetrahydrofuran (20 mL) was added N, N-diisopropylethylamine (16.93 mL,102.2 mmol), methylamine hydrochloride (4.6 g,68.1 mmol), and the addition was completed at 25℃for 3 hours. After the completion of the reaction, the reaction mixture was concentrated, water (30 mL) was added, and the filtrate was filtered, and the cake was washed with water and dried to give compound 173h (1.5 g), ESI-MS (m/z): 289.2[ M+H ]] + 。
Preparation of 3-amino-4- (methylamino) -7- (trifluoromethyl) -1, 8-naphthyridin-2 (1H) -one (173 i)
To a solution of compound 173h (1.5 g,5.20 mmol) in ethanol/water (1/1, 10 mL) was added sodium hydrosulfite (3.9 g,22.36 mmol) and the reaction was continued at 80℃for 2 hours. After the completion of the reaction, the reaction mixture was concentrated, water (15 mL) was added, and the filtrate was filtered, and the cake was washed with water and dried to give compound 173i (1.2 g), ESI-MS (m/z): 259.2[ M+H ] ] + 。
Preparation of N- (4- (methylamino) -2-oxo-7- (trifluoromethyl) -1, 2-dihydro-1, 8-naphthyridin-3-yl) acetamide (173 j)
To a solution of compound 173i (1.2 g,4.65 mmol) in dichloromethane (15 mL) was added acetic acid (0.27 mL,4.6 mmol), N, N-diisopropylethylamine (0.77 mL,4.6 mmol), 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (1.8 g,4.6 mmol), and the addition was completed overnight at 25 ℃. After completion of the reaction, water (30 mL) was added, dichloromethane (3X 30 mL) was extracted, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound 173j (1.2 g), ESI-MS (m/z): 301.1[ M+H ]] + 。
Preparation of 1, 2-dimethyl-7- (trifluoromethyl) -1, 5-dihydro-4H-imidazo [4,5-c ] [1,8] naphthyridin-4-one (173 k)
To a solution of compound 173j (1.2 g,4.0 mmol) in tetrahydrofuran (15 mL) was added hydrochloric acid (0.1 mL,3.2 mmol), and the mixture was reacted at 60℃for 3 hours. After the completion of the reaction, water (20 mL) and sodium hydroxide (w=50%) were added to adjust the pH to about 7, and the mixture was subjected to normal phase column chromatography (dichloromethane/methanol=
0:100% -10%: 90%) to give compound 173k (1.0 g), ESI-MS (m/z): 283.1[ M+H)] + .1, 2-dimethyl-5- (pyridin-3-yl) -7- (trifluoromethyl) -1, 5-dihydro-4H-imidazo [4,5-c][1,8]Preparation of naphthyridin-4-one (173)
To a solution of compound 173k (100 mg,0.35 mmol) in N, N-dimethylformamide (5 mL) was added 3-pyridineboronic acid (48 mg,0.39 mmol), copper acetate (64.4 mg,0.4 mmol), pyridine (0.03 mL,0.4 mmol), and the mixture was reacted overnight at 60 ℃. After completion of the reaction, celite was filtered, the filtrate was concentrated, and reversed-phase column chromatography (acetonitrile/0.5% ammonium bicarbonate water=0:100% -50:50%) was performed to give compound 173 (4.2 mg), ESI-MS (m/z): 360.1[ M+H ]] + 。 1 H NMR(600MHz,DMSO-d 6 )δ8.89–8.84(m,3H),7.79–7.63(m,3H),4.13(s,3H),2.58(s,3H)。
Example 42:
preparation of 5- (3-methoxyphenyl) -1, 2-dimethyl-7- (trifluoromethyl) -1, 5-dihydro-4H-imidazo [4,5-c ] [1,8] naphthyridin-4-one (174)
To a solution of compound 173k (100 mg,0.35 mmol) in N, N-dimethylformamide (5 mL) was added 3-methoxyphenylboronic acid (79.8 mg,0.52 mmol), copper acetate (64.4 mg,0.4 mmol), pyridine (0.03 mL,0.4 mmol), and the mixture was reacted at 60℃overnight. After completion of the reaction, celite was filtered, the filtrate was concentrated, and reversed-phase column chromatography (acetonitrile/0.5% ammonium bicarbonate water=0:100% -50:50%) was obtained as compound 174 (1.30 mg), ESI-MS (m/z): 389.1[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 )δ8.87(d,J＝8.2Hz,1H),7.76(d,J＝8.2Hz,1H),7.44(t,J＝8.2Hz,1H),7.05(dd,J＝8.4,2.8Hz,1H),6.89–6.79(m,2H),4.13(s,3H),3.77(s,3H),2.60(s,3H).
Example 43
Preparation of 3- (1, 2-dimethyl-4-oxo-7- (trifluoromethyl) -1, 4-dihydro-5H-imidazo [4,5-c ] [1,8] naphthyridin-5-yl) benzonitrile (175)
Referring to compound 174, the replacement of 3-methoxyphenylboronic acid with 3-cyanobenzeneboronic acid (77.1 mg) gives compound 175 (1.54 mg), ESI-MS (m/z): 384.1[ M+H ] ] + 。 1 H NMR(600MHz,DMSO-d 6 )δ8.90(d,J＝8.4Hz,1H),7.99–7.92(m,2H),7.80(d,J＝8.4Hz,1H),7.79–7.70(m,2H),4.15(s,3H),2.60(s,3H)。
Example 44
Preparation of 7-chloro-1, 2-dimethyl-5- (pyridin-3-yl) -1, 5-dihydro-4H-imidazo [4,5-c ] quinolin-4-one (176)
To a solution of compound 62h (60 mg,0.20 mmol) in tetrahydrofuran (5 mL) was added acetyl chloride (0.02 mL,0.30 mmol) and the addition was allowed to react overnight at 25 ℃. After completion of the reaction, the filtrate was concentrated, and reversed-phase column chromatography (acetonitrile/0.5% formic acid water=0:100% -50%: 50%) was obtained as compound 176 (1.31 mg). ESI-MS (m/z): 325.1[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 )δ8.79(dd,J＝4.8,1.6Hz,1H),8.58(d,J＝2.4Hz,1H),8.33(d,J＝8.8Hz,1H),7.90(dt,J＝8.2,2.0Hz,1H),7.72(dd,J＝8.0,4.8Hz,1H),7.39(dd,J＝8.7,2.1Hz,1H),6.52(d,J＝2.0Hz,1H).4.13(s,3H),2.55(s,3H)。
Example 45
Preparation of 7-chloro-2- (difluoromethyl) -1-methyl-5- (pyridin-3-yl) -1, 5-dihydro-4H-imidazo [4,5-c ] quinolin-4-one (177)
To a solution of compound 62h (70 mg,0.23 mmol) in dichloromethane (5 mL) was added difluoroacetic acid (36.8 mg,0.28 mmol), N, N-diisopropylethylamine (0.12 mL,0.70 mmol), 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (132.8 mg,0.35 mmol), and the addition was reacted overnight at 25 ℃. After completion of the reaction, water (10 mL) was added, dichloromethane (3 x 10 mL) was extracted, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to reverse phase column chromatography (acetonitrile/0.5% ammonium bicarbonate water=0:100% -50%: 50%) to give compound 177 (34.53 mg), ESI-MS (m/z): 361.1
[M+H] + 。 1 H NMR(600MHz,DMSO-d 6 )δ8.81(dd,J＝4.8,1.5Hz,1H),8.62(d,J＝2.4Hz,1H),8.39(d,J＝8.4Hz,1H),7.95–7.92(m,1H),7.74(dd,J＝8.4,4.8Hz,1H),7.58–7.35(m,2H),6.57(d,J＝1.8Hz,1H),4.31(s,3H)。
Example 46
Preparation of N- (7-chloro-4- (methylamino) -2-oxo-1- (pyridin-3-yl) -1, 2-dihydro-quinolin-3-yl) -2-methyl-2H-indazole-5-carboxamide (178 a)
To a solution of compound 62h (100 mg,0.33 mmol) in N, N-dimethylformamide (10 mL) was added 2-methylimidazole-5-carboxylic acid (58.1 mg,0.33 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (94.9 mg,0.49 mmol), 4-dimethylaminopyridine (8.1 mg,0.07 mmol), N, N-diisopropylethylamine (0.09 mL,0.53 mmol) and the addition was reacted at 50℃for 2 hours. After completion of the reaction, water (20 mL) was added, dichloromethane (3X 12 mL) was extracted, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound 178a (60.0 mg), ESI-MS (m/z): 459.3[ M+H ]] + 。
Preparation of 7-chloro-1-methyl-2- (2-methyl-2H-indazol-5-yl) -5- (pyridin-3-yl) -1, 5-dihydro-4H-imidazo [4,5-c ] quinolin-4-one (178)
To compound 178a (60 mg,0.13 mmol) was added acetic acid (5 mL) and the mixture was reacted overnight at 100 ℃. After the completion of the reaction, the reaction solution was concentrated and subjected to reverse phase column chromatography (acetonitrile/0.5% ammonium bicarbonate aqueous solution=0:100% -50%: 50%) to obtain compound 178 (18.46 mg). ESI-MS (m/z): 441.1[ M+H ]] + 。 1 H NMR(600MHz,DMSO-d 6 )δ8.81(d,J＝4.8Hz,1H),8.62(d,J＝2.4Hz,1H),8.55(s,1H),8.39(d,J＝8.4Hz,1H),8.18(s,1H),7.96–7.94(m,1H),7.77–7.72(m,3H),7.62(d,J＝8.8Hz,1H),7.44(dd,J＝8.4,2.0Hz,1H),6.56(d,J＝1.8Hz,1H),4.24(s,3H),4.22(s,3H)。
Example 47
Preparation of 2-methyl-N- (4- (methylamino) -2-oxo-1-phenyl-7- (trifluoromethyl) -1, 2-dihydro-1, 8-naphthyridin-3-yl) -2H-indazole-5-carboxamide (179 a)
To a solution of compound 68h (100 mg,0.30 mmol) in dichloromethane (5 mL) was added 2-methylpyrazole-5-carboxylic acid (63.2 mg,0.36 mmol), N, N-diisopropylethylamine (0.15 mL,0.90 mmol), 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (170.6 mg,0.45 mmol) and the addition was reacted overnight at 25 ℃. At the end of the reaction, water (20 mL) was added, dichloromethane (3X 20 mL) was extracted, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound 179a (80.0 mg), ESI-MS (m/z): 492.8[ M+H ] ] + 。
Preparation of 1-methyl-2- (2-methyl-2H-indazol-5-yl) -5-phenyl-7- (trifluoromethyl) -1, 5-dihydro-4H-imidazo [4,5-c ] [1,8] naphthyridin-4-one (179)
To a solution of compound 179a (80 mg,0.16 mmol) in 1, 4-dioxane (5 mL) was added hydrochloric acid (0.05 mL,1.62 mmol), and the addition was completed and reacted at 100℃for 2 hours. At the end of the reaction, the reaction mixture was concentrated and subjected to reverse phase column chromatography (acetonitrile: 0.5% aqueous formic acid=0:100% -40%: 60%) to give compound 179 (20.0 mg). ESI-MS (m/z): 475.1[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 )δ8.95(d,J＝8.2Hz,1H),8.57(s,1H),8.23–8.20(m,1H),7.83–7.80(m,1H),7.60–
7.44(m,5H),7.34–7.29(m,2H),4.28(s,3H),4.25(s,3H)。
Example 48
Preparation of methyl 2- (2-hydroxy-2-methylpropyl) -2H-indazole-5-carboxylate (180 b)
To a 100mL eggplant-shaped bottle containing a stirrer were added the reactants methyl 1H-indazole-5-carboxylate (1000 mg,5.68 mmol), cesium carbonate (3698 mg,11.35 mmol) and acetonitrile (20 mL). To this was added 2, 2-dimethyloxirane (2526 μl,28.38 mmol). After the addition, stirring for 4 hours at 80 ℃. The reaction mixture was cooled to room temperature, filtered, the residue was washed with ethyl acetate, the obtained filtrate was dried by spinning, and the obtained residue was purified by preparation of a silica gel plate (developer: PE: ea=1.5:1) to give the title compound 180b (380 mg). ESI-MS (m/z): 249.1[ M+H ]] + 。
Preparation of 2- (2-hydroxy-2-methylpropyl) -2H-indazole-5-carboxylic acid (180 c)
To a 50mL eggplant-shaped bottle containing a stirrer were added compound 180b (380 mg,1.53 mmol) and methanol (5 mL). To this was added a solution of lithium hydroxide (183 mg,7.65 mmol) in water (1 mL). After the addition was completed, the reaction solution was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, water was added thereto, 1N diluted hydrochloric acid was adjusted to pH 3-4, stirring was carried out for 5 minutes, standing, suction filtration was carried out, and the solid was washed with a small amount of water, and the obtained solid was dried to obtain compound 180c (330 mg). ESI-MS (m/z): 235.1[ M+H ] ] + 。
Preparation of 2- (2-hydroxy-2-methylpropyl) -N- (4- (methylamino) -2-oxo-1-phenyl-7- (trifluoromethyl) -1, 2-dihydro-1, 8-naphthyridin-3-yl) -2H-indazole-5-carboxamide (Compound 180 d)
To a 50mL eggplant-shaped bottle containing a stirrer were added 68h (100 mg,0.30 mmol), 180c (91 mg,0.39 mmol), DIEA (99. Mu.L, 0.60 mmol) and DMF (5 mL). HATU (171 mg,0.45 mmol) was added thereto. After the addition was completed, the reaction was stirred at 70℃overnight. The reaction system was poured into water, extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure, and the obtained residue was purified by preparative silica gel plate (developer: 100% EA) to give compound 180d (98 mg). ESI-MS (m/z): 551.2[ M+H ]] + 。
Preparation of 2- (2- (2-hydroxy-2-methylpropyl) -2H-indazol-5-yl) -1-methyl-5-phenyl-7- (trifluoromethyl) -1, 5-dihydro-4H-imidazo [4,5-c ] [1,8] naphthyridin-4-one (180)
To a 50mL eggplant-shaped bottle containing a stirrer was added the reactant 180d (90 mg,0.16 mmol) and AcOH (2 mL). The reaction solution was stirred at 100℃for 1h. The solvent was distilled off under reduced pressure, and the obtained residue was purified by reverse phase silica gel column chromatography (eluent: acetonitrile/water=0:100% -50%: 50%) to give compound 180 (53 mg). ESI-MS (m/z): 533.2[ M+H ] ] + 。 1 H NMR(400MHz,DMSO)δ8.97(d,J＝8.2Hz,1H),8.55(s,1H),8.27(s,1H),7.84(t,J＝9.2Hz,2H),7.67(dd,J＝9.2,1.6Hz,1H),7.62–7.48(m,3H),7.37–7.30(m,2H),4.94(s,1H),4.44(s,2H),4.31(s,3H),1.18(s,6H).
Example 49
Preparation of 2- (2- (benzyloxy) ethyl) -N- (4- (methylamino) -2-oxo-1-phenyl-7- (trifluoromethyl) -1, 2-dihydro-1, 8-naphthyridin-3-yl) -2H-indazole-5-carboxamide (compound 181 a)
To a 50mL eggplant-shaped bottle containing a stirrer was added reactant 2- (2- (benzyloxy) ethyl) -2H-indazole-5-carboxylic acid (30 mg,0.10 mmol), and dichloromethane (5 mL). Oxalyl chloride (36 μl,0.42 mmol) and DMF (0.05 mL) were added thereto. After the addition was completed, the reaction solution was stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure, the obtained solid was dissolved in tetrahydrofuran (5 mL), N-diisopropylethylamine (40. Mu.L, 0.42 mmol) and intermediate 68h (28 mg,0.08 mmol) were added successively thereto, and after the addition was completed, the reaction mixture was stirred at room temperature overnight. The reaction was quenched by addition of methanol, the solvent was distilled off under reduced pressure, and the resulting residue was purified by preparative silica gel plate (developer: DCM: meoh=25:1) to give the title compound 181a (25 mg). ESI-MS (m/z): 613.2[ M+H ]] + 。
Preparation of 2- (2- (2-benzyloxy) ethyl) -2H-indazol-5-yl) -1-methyl-5-phenyl-7- (trifluoromethyl) -1, 5-dihydro-4H-imidazo [4,5-c ] [1,8] naphthyridin-4-one (181 b)
To a 50mL eggplant-shaped bottle containing a stirrer were added reactant 181a (25 mg,0.04 mmol), and solvent AcOH (2 mL). The reaction solution was stirred at 110℃for 1hr. The solvent was evaporated under reduced pressure and the resulting residue was purified by prep. silica gel plate (developer: DCM: meoh=25:1) to give the title compound 181b (24 mg). ESI-MS (m/z): 595.2[ M+H ] ] + 。
Preparation of 2- (2- (2-hydroxyethyl) -2H-indazol-5-yl) -1-methyl-5-phenyl-7- (trifluoromethyl) -1, 5-dihydro-4H-imidazo [4,5-c ] [1,8] naphthyridin-4-one (181)
To a 50mL eggplant-shaped bottle containing a stirrer were added reactant 181b (20 mg,0.03 mmol), palladium on carbon (4 mg), palladium hydroxide (4 mg) and methanol (4 mL). The hydrogen was replaced three times and the reaction mixture was heated to 50℃under a hydrogen balloon and stirred for 4 hours. The reaction mixture was cooled to room temperature, filtered off with suction, the dissolved was evaporated under reduced pressure and the resulting residue was purified by prep. silica gel plate (developer: DCM: meoh=20:1) to give title compound 181 (12 mg). ESI-MS (m/z): 505.2[ M+H ]] + 。 1 H NMR(400MHz,DMSO)δ8.97(d,J＝8.0Hz,1H),8.61(s,1H),8.25(s,1H),7.87–7.82(m,2H),7.67(dd,J＝8.8,1.5Hz,1H),7.59(t,J＝7.6Hz,2H),7.52(d,J＝7.2Hz,1H),7.34(d,J＝7.2Hz,2H),5.05(t,J＝5.2Hz,1H),4.56(t,J＝5.2Hz,2H),4.30(s,3H),3.94(q,J＝5.2Hz,2H)。
Example 50
Preparation of ethyl 2- (5- (1-methyl-4-oxo-5-phenyl-7- (trifluoromethyl) -4, 5-dihydro-1H-imidazo [4,5-c ] [1,8] naphthyridin-2-yl) -2H-indazol-2-yl) methanesulfonate (182 a)
To a 50mL eggplant-shaped bottle containing a stirrer were added reactant 181 (45 mg,0.09 mmol), DIEA (30. Mu.L, 0.18 mmol) and DCM (1 mL). The reaction mixture was cooled to 0deg.C, to which MsCl (10 μL,0.13 mmol) was slowly added dropwise. After the addition was completed, the reaction solution was stirred at room temperature for 2hr. Water was added to the reaction system to quench the reaction, extracted three times with methylene chloride, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure to give the title compound 182a (50 mg, yield: 96.2%, yellow solid). ESI-MS (m/z): 583.1[ M+H ] ] + 。
Preparation of 1-methyl-2- (2- (2-morpholinoethyl) -2H-indazol-5-yl) -5-phenyl-7- (trifluoromethyl) -1, 5-dihydro-4H-imidazo [4,5-c ] [1,8] naphthyridin-4-one (182)
Into a 50mL eggplant-shaped bottle containing a stirrer was added reactant 182a (50 mg,0.09 mmol),Morpholine (78 mg,0.89 mmol), potassium iodide (15 mg,0.09 mmol) and ACN (5 mL). The reaction was stirred at 80℃overnight. The solvent was distilled off under reduced pressure, and the obtained residue was purified by a reverse phase silica gel column (eluent: acetonitrile/0.05% aqueous formic acid=0:100% -40%: 60%) to give the title compound 182 (28 mg). ESI-MS (m/z): 574.2[ M+H ]] + 。 1 H NMR(400MHz,DMSO)δ8.97(d,J＝8.2Hz,1H),8.65(s,1H),8.25(s,1H),7.84(dd,J＝8.4,2.4Hz,2H),7.71–7.66(m,1H),7.61–7.49(m,3H),7.37–7.31(m,2H),4.65(t,J＝6.4Hz,2H),4.30(s,3H),3.63–3.53(m,4H),2.93(t,J＝6.4Hz,2H),2.51–2.48(m,4H).
Example 51
Preparation of 2- (2- (2-hydroxypyrrolidin-1-yl) ethyl) -2H-indazol-5-yl) -1-methyl-5-phenyl-7- (trifluoromethyl) -1, 5-dihydro-4H-imidazo [4,5-c ] [1,8] naphthyridin-4-one (183)
To a 50mL eggplant-shaped bottle containing a stirrer were added reactant 181a (50 mg,0.09 mmol), 3-hydroxypyrrolidine (78 mg,0.89 mmol), potassium iodide (15 mg,0.09 mmol) and solvent ACN (5 mL). The reaction was stirred at 80℃overnight. The solvent was distilled off under reduced pressure, and the obtained residue was purified by a reverse phase silica gel column (eluent: acetonitrile/0.05% aqueous formic acid=0:100% -40%: 60%) to give the title compound 183 (28 mg). ESI-MS (m/z): 574.2[ M+H ]] + 。 1 H NMR(400MHz,DMSO)δ8.97(d,J＝8.4Hz,1H),8.66(s,1H),8.24(s,1H),7.84(dd,J＝8.4,3.2Hz,2H),7.67(dd,J＝9.2,1.6Hz,1H),7.59(t,J＝7.6Hz,2H),7.51(t,J＝7.6Hz,1H),7.34(d,J＝7.2Hz,2H),4.72(t,J＝7.2Hz,1H),4.61(q,J＝6.4Hz,2H),4.30(s,3H),3.34(s,2H),3.03(t,J＝6.4Hz,2H),2.82–2.78(m,1H),2.70–2.63(m,2H),2.40–2.35(m,2H)。
Example 52
Preparation of 1-methyl-2- (2- (2- (4-methylpiperazin-1-yl) ethyl) -2H-indazol-5-yl) -5-phenyl-7- (trifluoromethyl) -1, 5-dihydro-4H-imidazo [4,5-c ] [1,8] naphthyridin-4-one (184)
To a 50mL eggplant-shaped bottle containing a stirrer were added reactant 181a (40 mg,0.07 mmol), acetonitrile (5 mL), potassium iodide (11 mg,0.07 mmol) and N-methylpiperazine (69 mg,0.69 mmol). After the addition was completed, the reaction was stirred at 80℃overnight. The solvent was distilled off under reduced pressure, and the obtained residue was purified by a reverse phase silica gel column (eluent: acetonitrile: water (0.5% ammonium bicarbonate) =0:100% -60%: 40%) to give the title compound 184 (11 mg). ESI-MS (m/z): 587.2[ M+H ]] + 。 1 H NMR(400MHz,DMSO)δ8.97(d,J＝8.4Hz,1H),8.63(s,1H),8.25(s,1H),7.84(d,J＝8.4Hz,2H),7.67(dd,J＝8.8,1.6Hz,1H),7.59(t,J＝7.6Hz,2H),7.51(t,J＝7.6Hz,1H),7.34(d,J＝7.2Hz,2H),4.63(t,J＝6.4Hz,2H),4.30(s,3H),3.53–3.36(m,4H)
2.91(t,J＝6.4Hz,2H),2.3–2.27(m,4H),2.15(s,3H)。
Example 53
Preparation of 2- (pyridin-3-ylamino) -6- (trifluoromethyl) nicotinic acid (185 b)
To a solution of 2-chloro-6- (trifluoromethyl) pyridine-3-carboxylic acid (4 g,17.73 mmol) in tetrahydrofuran (10 mL) was added dropwise lithium bis (trimethylsilylamide) (0.9 g,10.02 mmol), cuprous chloride (0.1 g,1.34 mmol), potassium carbonate (8.9 g,53.19 mmol), a solution of 3-pyridinamine (3.3 g,35.46 mmol) in tetrahydrofuran at-78deg.C for 1 hour under nitrogen protection, a solution of saturated ammonium chloride (40 mL) under stirring at 25℃for 2 hours after completion of the reaction, and the compound obtained after concentration was washed with ethyl acetate and dried to give 185b (4.5 g), ESI-MS (m/z): 284.1[ M+H ] ] + 。
Preparation of methyl 2- (pyridin-3-ylamino) -6- (trifluoromethyl) nicotinate (185 c)
Referring to the preparation of compound 173c, replacement of 173b with 185b (3.8 g) gives compound 185c (3.4 g), ESI-MS (m/z): 298.1[ M+H ]] + 。
Preparation of methyl 2- (N- (pyridin-3-yl) acetamido) -6- (trifluoromethyl) nicotinate (185 d)
Referring to the preparation of compound 173d, replacement of 173c with 185c (1000 mg) gives compound 185d (400.0 mg), ESI-MS (m/z): 340.1[ M+H)] + 。
Preparation of 1- (pyridin-3-yl) -7- (trifluoromethyl) -1, 8-naphthyridine-2, 4 (1H, 3H) -dione (185 e)
Referring to the preparation of compound 173e, replacement of 173d with 185d (400 mg) gives compound 185e (300 mg), ESI-MS (m/z): 308.1[ M+H ]] + 。
Preparation of 3-nitro-1- (pyridin-3-yl) -7- (trifluoromethyl) -1, 8-naphthyridine-2, 4 (1H, 3H) -dione (185 f)
Referring to the preparation of compound 173f, replacing 173e with 185e (300 mg) gives compound 185f (270 mg), ESI-MS (m/z): 351.1[ M+H)] + 。
Preparation of 4-chloro-3-nitro-1- (pyridin-3-yl) -7- (trifluoromethyl) -1, 8-naphthyridin-2 (1H) -one (185 g)
Referring to the preparation of 173g of compound, replacement of 173f with 185f (270 mg) gives 185g (267 mg) of compound, ESI-MS (m/z): 371.0[ M+H)] + 。
Preparation of 4- (methylamino) -3-nitro-1- (pyridin-3-yl) -7- (trifluoromethyl) -1, 8-naphthyridin-2 (1H) -one (185H)
Referring to compound 173h, replacing 173g with 185g (267 mg) gives compound 185h (220 mg), ESI-MS (m/z): 365.1[ M+H)] + 。
Preparation of 3-amino-4- (methylamino) -1- (pyridin-3-yl) -7- (trifluoromethyl) -1, 8-naphthyridin-2 (1H) -one (185 i)
Referring to compound 173i, replacing 173h with 185h (220 mg) gives compound 185i (160 mg), ESI-MS (m/z): 336.2[ M+H)] + 。
Preparation of 4-methoxy-N- (4- (methylamino) -2-oxo-1- (pyridin-3-yl) -7- (trifluoromethyl) -1, 2-dihydro-1, 8-naphthyridin-3-yl) benzamide (185 j)
To a solution of compound 185i (30 mg,0.09 mmol) in tetrahydrofuran (2 mL) was added p-methoxybenzoyl chloride (16.9 mg,0.10 mmol), and the addition was completed overnight at 25 ℃. After completion of the reaction, the reaction mixture was concentrated to give compound 185j (30.0 m)g),ESI-MS(m/z):470.1[M+H] + 。
Preparation of 2- (4-methoxyphenyl) -1-methyl-5- (pyridin-3-yl) -7- (trifluoromethyl) -1, 5-dihydro-4H-imidazo [4,5-c ] [1,8] naphthyridin-4-one (185)
To a solution of compound 185j (30 mg,0.06 mmol) in 1, 4-dioxane (5 mL) was added hydrochloric acid (0.01 mL,0.30 mmol), and the mixture was reacted at 100℃for 2 hours. After completion of the reaction, the reaction mixture was concentrated and subjected to reverse phase column chromatography (acetonitrile/0.5% ammonium bicarbonate aqueous solution=0:100% -50:50%) to give compound 185 (1.52 mg), ESI-MS (m/z): 452.1[ M+H ] ] + 。 1 H NMR(400MHz,DMSO-d 6 )δ8.95(d,J＝8.2Hz,1H),8.68(dd,J＝4.8,1.6Hz,1H),8.55(d,J＝2.4Hz,1H),7.88–7.82(m,2H),7.80–7.75(m,2H),7.63(dd,J＝8.2,4.8Hz,1H),7.21–7.17(m,2H),4.23(s,3H),3.88(s,3H)。
Example 54
Preparation of 2-methyl-N- (4- (methylamino) -2-oxo-1- (pyridin-3-yl) -7- (trifluoromethyl) -1, 2-dihydro-1, 8-naphthyridin-3-yl) -2H-indazole-5-carboxamide (186 a)
To a solution of compound 185i (50 mg,0.15 mmol) in N, N-dimethylformamide (2 mL) was added 2-methyl-5-indazole carboxylic acid (36.8 mg,0.21 mmol), N, N-diisopropylethylamine (0.07 mL,0.45 mmol), 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (90.7 mg,0.24 mmol), 4-dimethylaminopyridine (18.2 mg,0.15 mmol) and the addition was completed overnight at 25 ℃. At the end of the reaction, water (20 mL) was added, extracted with ethyl acetate (10X 3 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to give compound 186a (40.0 mg), ESI-MS (m/z): 496.0[ M+H ], by normal phase column chromatography (dichloromethane/methanol=0:100% -10%: 90%)] + 。
Preparation of 1-methyl-2- (2-methyl-2H-indazol-5-yl) -5- (pyridin-3-yl) -7- (trifluoromethyl) -1, 5-dihydro-4H-imidazo [4,5-c ] [1,8] naphthyridin-4-one (186)
To a solution of compound 186a (40.0 mg,0.08 mmol) in 1, 4-dioxane (5 mL) was addedHydrochloric acid (4N, 0.1 mL) was added and reacted at 100℃for 1 hour. Water (20 mL) was added, the reaction mixture was concentrated, and reversed-phase column chromatography (acetonitrile/0.5% aqueous formic acid=0:100% -50%: 50%) was obtained as compound 186 (1.14 mg), ESI-MS (m/z): 476.1[ M+H ] ] + 。 1 H NMR(400MHz,DMSO-d 6 )δ8.99(d,J＝8.4Hz,1H),8.71(dd,J＝4.8,1.6Hz,1H),8.60–8.57(m,2H),8.24(s,1H),7.90–7.81(m,3H),7.70–7.61(m,2H),4.31(s,3H),4.27(s,3H)。
Example 55
Preparation of 1-methyl-N- (4- (methylamino) -2-oxo-1- (pyridin-3-yl) -7- (trifluoromethyl) -1, 2-dihydro-1, 8-naphthyridin-3-yl) -3a,7 a-dihydro-1H-benzo [ d ] imidazole-6-carboxamide (187 a)
To a solution of compound 185i (50 mg,0.15 mmol) in pyridine (2 mL) was added 3-methylbenzo [ d ]]Imidazole-5-carboxylic acid (52.5 mg,0.30 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (57.2 mg,0.30 mmol), was reacted at 25℃for 48 hours after the addition. After the completion of the reaction, the reaction mixture was concentrated, water (20 mL) was added, extracted with ethyl acetate (10×3 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and purified by normal phase column chromatography (dichloromethane/methanol=0:100% -10%: 90%) to give compound 187a (40.0 mg), ESI-MS (m/z): 496.0[ m+h] + 。
Preparation of 1-methyl-2- (1-methyl-3 a,7 a-dihydro-1H-benzo [ d ] imidazol-6-yl) -5- (pyridin-3-yl) -7- (trifluoromethyl) -1, 5-dihydro-4H-imidazo [4,5-c ] [1,8] naphthyridin-4-one (187)
To a solution of compound 187a (40.0 mg,0.08 mmol) in 1, 4-dioxane (5 mL) was added hydrochloric acid (4M, 0.1 mL), and the addition was reacted at 100℃for 1 hour. After the completion of the reaction, the reaction mixture was concentrated and subjected to reverse phase column chromatography (acetonitrile/0.5% formic acid aqueous solution=0:100% -40:60%) to give compound 187 (1.1 mg), ESI-MS (m/z): 478.1[ M+H ] ] + 。 1 H NMR(400MHz,DMSO-d 6 )δ9.00(d,J＝7.9Hz,1H),8.72–8.70(m,1H),8.60(d,J＝4.8Hz,1H),8.40(s,1H),8.09(d,J＝1.6Hz,1H),7.91–7.87(m,3H),7.69–7.65(m,2H),4.32(s,3H),3.98(s,3H)。
Comparative example 1
The preparation process is referred to WO 2020123395A 1.
Test example 56 half inhibition Activity of the Compounds of the invention against recombinant human MAT2A
Compounds were subjected to 3 Xgradient dilution (initial concentration 25. Mu.M, 3 Xdilution, total of 8 concentration points) with DMSO using a BioTek Precision automatic pipetting system in assay buffer (assay buffer formulation: 50mM Tris-HCl, pH 8.0,50mM KC1,15mM MgCl) 2 300 μMEDTA,0.005% (w/v) Bovine Serum Albumin (from Sigma, CAT#B2064)), test compound was incubated with recombinant human MAT2A (from BPS nonce, CAT#71401), 80 μ M L-methionine (from Sigma, CAT#M 9625-25G) and 100 μM ATP (from Sigma, CAT#FLAAS-5 VL) at a final concentration of 6 ng/. Mu.l in a 25 μL reaction system. After incubation for 60 minutes at room temperature, an equal volume of phosphate chromogenic reagent (BIOMOL Green) was added and incubated for 20 minutes in a constant temperature incubator (25 ℃) after which the absorbance at 630nm was determined by a Tecan Spark.
Data analysis was performed using data analysis software GraphPad Prism 8 using the equation "log (inhibitor) vs. normal response—variable slope" (equation y=bottom+ (Top-Bottom)/(1+10++log 50-X) HillSlope) to give IC of compound 50 Values. Where Y is the inhibition rate, X is the compound concentration logarithmic value, top is the maximum response (inhibition rate at maximum compound concentration), bottom is the baseline response (inhibition rate at 0 compound concentration), hill Slope is the Slope of the IC50 curve, and IC50 is the compound concentration at half inhibition. The MAT2A inhibitory activity of the test compounds is specifically shown in table 1.
TABLE 1IC 50
/>
Conclusion: the results show that the compound has strong inhibition activity on the activity of recombinant human MAT2A enzyme.
Test example 57 proliferation inhibitory Activity of the Compound of the present invention against human colon cancer cells
1. Construction of MTAP -/- HCT-116 cell line
Adopts gene editing tool CRISPR/Cas9 and sgRNA to co-transfect colon cancer cell strain HCT-116 (purchased from Nanjac Bai, CBP 60028), and obtains MTAP with inactivated MTAP double alleles through detection methods such as Western Blotting, sanger sequencing and the like -/- HCT-116 cell line. MTAP -/- The HCT-116 cell line is used for compound selective screening evaluation based on MTAP deletion and PRMT5 synergistic mechanism, and comprises a symmetrical dimethyl arginine (SDMA) level test, a cell proliferation test and the like.
2. Cell proliferation
MTAP was cultured with complete medium McCoy's 5A (purchased from Gibco, 16600082)/10% FBS (purchased from Gibco, 10099141C)/1%p/s (purchased from Gibco, 15140122) -/- HCT-116 and wild-type HCT-116 cell lines, evaluation of Compound vs. MTAP -/- Inhibition-enhancing effect of HCT-116 cell proliferation selectivity. Day 0, 100 MTAPs per well were added to 96-well cell culture plates (Corning, 3599) -/- HCT-116 cells or wild type HCT-116 cells, placed at 37℃in 5% CO 2 Culturing in an incubator. Compounds were subjected to 3 Xgradient dilutions (initial concentration 20. Mu.M, 3 Xdilution for a total of 8 concentration points) in DMSO (purchased from Sigma, D5879). Day 1, compound was diluted to multiple concentration points and cells were treated separately at 37 ℃, 5% co 2 Culturing in incubator for 10 days; day 11, 20 μl MTS (CellTiter) was added per wellA Queous One Solution Cell Proliferation Assay) (from Promega, G3581) at 37℃in 5% CO 2 After 2hr of incubation in the incubator, the incubation was continued by Tecan Spark reading (od=490 nM), and then data analysis was performed using data analysis software GraphPad Prism 8 using the equation "log (inhibitor) vs. normal response-variable slope" (formula y=bottom+ (Top-Bottom)/(1+10++log IC 50-X) ×hillslope)), to obtain IC50 values of the compound. Where Y is the inhibition rate, X is the compound concentration logarithmic value, top is the maximum response (inhibition rate at maximum compound concentration), bottom is the baseline response (inhibition rate at 0 compound concentration), hill Slope is the Slope of the IC50 curve, and IC50 is the compound concentration at half inhibition.
Table 2 IC 50 (μM)
Conclusion: the results show that the compound has strong proliferation inhibition activity on colon cancer cells deleted by human MTAP, and has better selectivity on colon cancer cells of MTAP Wild Type (WT).
Industrial applicability
The compound has excellent MAT2A inhibition activity and better selectivity to MTAP wild colon cancer cells, and can be used as a medicament for treating or preventing diseases related to the effect.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.

Claims (14)

1. A compound of formula (IA), or a tautomeric form thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof:
wherein, the liquid crystal display device comprises a liquid crystal display device,
w 1 is CR (CR) 2 Or N;
w 2 is CR (CR) 3 Or N;
w 3 is CR (CR) 4 Or N;
w 4 is CR (CR) 5 Or N;
R 2 ，R 3 ，R 4 and R is 5 Each independently selected from the group consisting of hydrogen, alkyl, hydroxy, alkenyl, alkynyl, alkoxy, alkylphosphoryl, alkylsulfonyl, alkylcarbonyl, alkoxycarbonyl, alkylthio, halogen, haloalkyl, haloalkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyloxy, cyano, amino, alkylamino, cycloalkylalkylamino, cycloalkylamino, aminocarbonyl, alkylaminocarbonyl, heterocyclylaminocarbonyl, heterocyclylalkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, hydroxyalkyl, hydroxyhaloalkyl, hydroxyalkoxy, hydroxyalkylamino, alkoxyalkyl, alkoxyalkoxy, alkoxyalkylamino, aminoalkyl, aminoalkylamino, aryl, arylalkyl, aryloxy, arylalkyloxy, arylamino, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylcarbonyl, heteroarylamino, heterocyclyl, heterocyclyloxy, heterocyclyl AminesA group, heterocyclylalkyloxy group, heterocyclyloxyalkyloxy group or heterocyclyloxyalkylamino group; wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are unsubstituted or substituted by one or more of the same or different R, either by themselves or as part of another group a And/or R b Substitution; the precondition is that: w (w) 1 、w 2 、w 3 And w 4 At most two of which may be N;
R 1 is cycloalkyl, bridged cycloalkyl, fused-ring alkyl, spirocycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocyclyl, bridged heterocyclyl, fused heterocyclyl or spiroheterocyclyl, wherein cycloalkyl, bridged cycloalkyl, fused-ring alkyl, spiroheterocyclylCycloalkyl, heterocyclyl, bridged heterocyclyl, fused heterocyclyl, spiroheterocyclyl, aryl or heteroaryl are unsubstituted or substituted by one or more R's which are identical or different c 、R d And/or R e Substitution;
each of which isIs independently a single bond or a double bond; when->At least two->In the case of double bond->Is a divalent aryl, divalent heteroaryl, divalent unsaturated cycloalkyl or divalent unsaturated heterocycloalkyl group;
x 1 ，x 2 independently selected from C or N;
z is N or NR 6 Wherein R is 6 Is hydrogen, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylaminoalkyl, heterocyclylalkyl, heterocyclyl, aryl, heteroaryl, alkylcarbonyl, cycloalkylcarbonyl, hydroxyalkylcarbonyl, alkoxyalkylcarbonyl, alkylaminoalkylcarbonyl, heterocyclylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkylsulfonyl, cycloalkylsulfonyl, hydroxyalkylsulfonyl, alkoxyalkylsulfonyl, alkylaminoalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are themselves or as part of another group unsubstituted or are each substituted with one or more R's which are the same or different f 、R g And/or R h Substitution;
y 1 is CR (CR) 7 、N、NR 8 O or S;
y 2 is CR (CR) 9 N or NR 10 ；
R 7 And R is 9 Each independently selected from hydrogen, halogen, cyano, oxo, X b -R 11 ，X b -NR 12 R 13 ，-NH-NR 12 R 13 、-NH-O-R 11 ；
X b Is a bond, alkylene, heteroalkylene, -O-, -CO-, or-COO-, wherein one carbon atom of the alkylene, heteroalkylene may be substituted with one or more substituents, the same or different, selected from the group consisting of: hydroxy, halogen, amino, alkylamino, alkoxy, cycloalkyloxy, haloalkyl, haloalkoxy;
R 8 ，R 10 ，R 11 each independently selected from the group consisting of hydrogen, halogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkyl, haloalkoxy, hydroxyalkyl, hydroxyhaloalkyl, alkoxyhaloalkyl, alkoxyalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, alkylaminohaloalkyl, aminocarbonylalkyl, aminosulfonylalkyl, alkylsulfonylalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, cycloalkyloxyalkyl, cycloalkylaminoalkyl, cycloalkylcarbonyl, alkoxycarbonyl, cycloalkylsulfonyl, bridged cycloalkyl alkyl, fused ring alkyl, spirocycloalkyl alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heteroarylsulfonyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclylsulfonyl, heterocyclyloxyalkyl, heterocyclylaminoalkyl, fused heterocyclyl, bridged heterocyclyl, spirocycloalkyl, spiroheterocyclyl, and spiroheterocyclylcarbonyl, wherein alkyl, cycloalkyl, heterocyclyl, fused heterocyclyl, aryl or heteroaryl are the same or different R as such or as part of another group, or as such, and optionally substituted one or more i ，R j And/or R k Substitution;
R 12 and R is 13 Each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkyl, haloalkoxy, hydroxyalkyl, hydroxyhaloalkyl, alkoxyhaloalkyl,Alkoxyalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, alkylaminohaloalkyl, aminocarbonylalkyl, aminosulfonylalkyl, alkylsulfonylalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, cycloalkyloxyalkyl, cycloalkylaminoalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, bridged cycloalkyl, bridged cycloalkylalkyl, fused-ring alkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heteroarylsulfonyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclylsulfonyl, heterocyclyloxyalkyl, heterocyclylaminoalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroalkylcarbonyl, spiroheterocyclyl, spiroheterocyclylcarbonyl, or R 12 、R 13 Can be linked to form a 4-to 10-membered heterocyclic or fused heterocyclic group in which the alkyl, cycloalkyl, heterocyclic, fused heterocyclic, aryl or heteroaryl group is unsubstituted or substituted by one or more of the same or different R, by itself or as part of another group l ，R m And/or R n Substitution;
R a ，R b ，R c ，R d ，R e ，R f ，R g ，R h ，R i ，R j ，R k ，R l ，R m or R is n Each independently selected from deuterium, hydroxy, halogen, amino, cyano, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, alkoxyalkyl, haloalkoxy, cycloalkyloxy, alkoxyalkoxy, heterocyclyloxy, alkylamino, cycloalkylamino, heterocyclylamino, hydroxyalkyl amino, alkoxyalkylamino, alkylphosphoryl, aminosulfonyl, alkylsulfonyl, alkylaminosulfonyl, cycloalkylaminosulfonyl, alkylsulfonylamino, cycloalkylsulfonylamino, carboxyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, cycloalkylaminocarbonyl, heterocyclylAminesAminocarbonyl, hydroxyalkylaminocarbonyl, alkoxyalkylaminocarbonyl, heterocyclylcarbonyl and ureido.
2. The compound of claim 1, or a tautomeric form thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, wherein: the compound represented by the general formula (IA) is selected from structures represented by (IIA), (IIB), (IIC), (IID), (IIE), (IIF), (IIG), (IIH) or (IIJ):
wherein w is 1 、w 2 、w 3 、w 4 、R 1 、R 6 、R 7 、R 8 、R 9 、R 10 Each definition is defined as in formula (IA).
3. The compound of claim 1 or 2, or a tautomeric form thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, wherein: r is R 2 ，R 3 ，R 4 And R is 5 Independently selected from hydrogen, halogen, hydroxy, cyano, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, C 3 -C 7 Cycloalkyl- (C) 1 -C 6 Alkylene) R-O-, -NRR "or-P (O) RR" groups, where R, R "are each independently selected from H, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 7 Cycloalkyl- (C) 1 -C 6 Alkylene) r-, wherein r = 0,1,2;
the C is 1 -C 6 Alkyl is preferably C 1 -C 3 Alkyl, more preferably methyl or ethyl;
the C is 1 -C 6 Alkylene is preferably C 1 -C 3 Alkylene, more preferably methylene or ethylene;
the C is 1 -C 6 Haloalkyl is preferably C 1 -C 3 A haloalkyl group, a halogen atom,more preferably-CH 2 CF 3 Trifluoromethyl or difluoromethyl;
the C is 3 -C 7 Cycloalkyl is preferably C 3 -C 5 Cycloalkyl, more preferably cyclopropyl;
the C is 1 -C 6 Alkoxy is preferably C 1 -C 3 Alkoxy, more preferably methoxy or ethoxy;
the C is 1 -C 6 The haloalkoxy group is preferably C 1 -C 3 Haloalkoxy groups, more preferably-O-CH 2 CF 3 、-O-CH 2 CHF 2 A trifluoromethoxy group or a difluoromethoxy group;
the halogen is preferably F, cl, br;
the-P (O) RR' group is preferably dimethylphosphityl;
preferably, R 3 Selected from H, F, cl, br, hydroxy, cyano, ethoxy, methyl, ethyl, cyclopropyl, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, methoxy or dimethylphosphinyl R 2 ，R 4 And R is 5 Are all hydrogen.
4. The compound of claim 1 or 2, or a tautomeric form thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, wherein: r is R 1 Selected from C 3 -C 7 Cycloalkyl, C 6 -C 10 Bridged cycloalkyl, 5-12 membered fused ring alkyl, C 5 -C 13 Spirocycloalkyl, 6-10 membered aryl, - (C) 1 -C 6 Alkylene) r-5-10 membered heteroaryl, 4-8 membered heterocyclyl, 6-10 membered bridged heterocyclyl, 5-14 membered fused heterocyclyl or 7-15 membered spiroheterocyclyl, wherein r = 0,1,2,3,4; wherein the alkylene, cycloalkyl, bridged cycloalkyl, fused ring alkyl, spirocycloalkyl, heterocyclyl, bridged heterocyclyl, fused heterocyclyl, aryl, spiroheterocyclyl or heteroaryl groups are unsubstituted or substituted with one or more R's which may be the same or different c 、R d And/or R e Substitution;
wherein R is c 、R d And/or R e Each independently selected from: halogen, C 1 -C 6 Alkoxy, cyano, C 1 -C 6 An alkyl group;
preferably, R 1 Selected from C 3 -C 5 Cycloalkyl, C 4 -C 6 Cycloalkyl, C 6 -C 8 Bridged cycloalkyl, C 7 -C 9 Bridged cycloalkyl, C 7 -C 8 Bridged cycloalkyl, 7-9 membered fused ring alkyl, 7-10 membered fused ring alkyl, 5-8 membered fused ring alkyl, 9-11 membered fused ring alkyl, 6-8 membered monocyclic aryl, 8-10 membered bicyclic aryl, 7-9 membered bicyclic aryl, - (C) 1 -C 6 Alkylene) r-5-6 membered monocyclic heteroaryl, - (C) 1 -C 6 Alkylene) r-6-10 membered bicyclic heteroaryl, 4-6 membered heterocyclyl, 5-7 membered heterocyclyl, 7-8 membered bridged heterocyclyl, 8-9 membered bridged heterocyclyl, 5-8 membered fused heterocyclyl, 9-12 membered fused heterocyclyl, 6-10 membered fused heterocyclyl, C 7 -C 11 Spirocycloalkyl, 8-12 membered spiroheterocyclyl;
preferably, R 1 Selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyanocyclopropyl-1-yl, 1-cyanomethylcyclopropan-1-yl, 3-fluorocyclohexyl, bicyclo [2.2.1 ]]Heptane, bicyclo [2.2.2]Octane, tetrahydronaphthyl, 4,5,6, 7-tetrahydro-1H-indolyl, 4,5,6, 7-tetrahydrobenzoxazolyl, phenyl, naphthyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuranyl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridinyl, benzothiazolyl, benzofuranyl, benzothienyl, indolyl, isoquinolinyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furanyl, thienyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidyl, pyrrolidinyl Homopiperidinyl (homopiperidino), 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholino, piperazino, tetrahydro-pyranyl, thiomorpholino, 2-azabicyclo [2.2.2]Octane, quinuclidine, 7-oxabicyclo [2.2.1]Heptane, 4,5,6, 7-tetrahydro-1H-pyrrolo [2,3-b]Pyridinyl, 1,2,3, 4-tetrahydroquinolinyl, 3, 4-dihydroquinolin-2 (1H) -one, spiro [4.5 ]]Decane, spiro [3.4 ]]Octane, spiro [2.3 ]]Hexane, 5-azaspiro [2.3 ]]Hexane, 6-oxaspiro [3.4 ]]-7-octanone;
preferably, R c 、R d And/or R e Each independently selected from: F. cl, br, C 1 -C 3 Alkoxy, cyano, C 1 -C 3 An alkyl group;
preferably, R c 、R d And/or R e Each independently selected from: F. cl, methoxy, ethoxy, CN, methyl, ethyl;
preferably, R 1 Selected from the group consisting of
5. The compound of claim 1 or 2, or a tautomeric form thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, wherein: r is R 6 Selected from hydrogen, C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Alkoxy- (C) 1 -C 6 Alkylene group) -, C 1 -C 6 alkyl-NRR' - (C) 1 -C 6 Alkylene) -, 4-8 membered heterocyclyl- (C 1 -C 6 Alkylene) -, 4-8 membered heterocyclyl, 6-10 aryl, 5-10 membered heteroaryl, C 1 -C 6 alkyl-CO-, C 3 -C 7 cycloalkyl-CO-, C 1 -C 6 hydroxyalkyl-CO-, C 1 -C 6 Alkoxy- (C) 1 -C 6 Alkylene groupRadical) -CO-, NRR' - (C 1 -C 6 Alkylene) -CO-, 4-8 membered heterocyclyl-CO-, 6-10 membered aryl-CO-, 5-10 membered heteroaryl-CO-, C 1 -C 6 alkyl-S (O) 2 )-、C 3 -C 7 cycloalkyl-S (O) 2 )-、C 1 -C 6 Hydroxyalkyl radical-S (O) 2 )-、C 1 -C 6 alkoxy-C 1 -C 6 alkylene-S (O) 2 )-、NRR'-(C 1 -C 6 Alkylene) -S (O) 2 ) -, 4-8 membered heterocyclyl-S (O) 2 ) -, 6-to 10-membered aryl-S (O) 2 ) -or 5-to 10-membered heteroaryl-S (O 2 ) -; wherein in-NRR', R is C 1 -C 6 Alkyl, R' is hydrogen or C 1 -C 6 Alkyl, wherein alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are unsubstituted or substituted by one or more of the same or different R, by themselves or as part of another group f 、R g And/or R h Substitution;
preferably, R 6 Selected from hydrogen, C 1 -C 3 Alkyl, C 3 -C 5 Cycloalkyl, C 1 -C 3 Haloalkyl, C 1 -C 3 Hydroxyalkyl, C 1 -C 3 Alkoxy- (C) 1 -C 3 Alkylene group) -, C 1 -C 3 alkyl-NRR' - (C) 1 -C 3 Alkylene) -, 4-6 membered heterocyclyl- (C 1 -C 3 Alkylene) -, 4-6 membered heterocyclyl, 6-8 monocyclic aryl, 8-10 bicyclic aryl, 5-6 mono-heteroaryl, 8-10 bicyclic or tricyclic heteroaryl, C 1 -C 6 alkyl-CO-, C 3 -C 7 cycloalkyl-CO-, C 1 -C 6 hydroxyalkyl-CO-, C 1 -C 6 Alkoxy- (C) 1 -C 6 Alkylene) -CO-, NRR' - (C 1 -C 6 Alkylene) -CO-, 4-8 membered heterocyclyl-CO-, 6-10 membered aryl-CO-, 5-10 membered heteroaryl-CO-, C 1 -C 3 alkyl-S (O) 2 )-、C 3 -C 5 cycloalkyl-S (O) 2 )-、C 1 -C 3 Hydroxyalkyl radical-S (O) 2 )-、C 1 -C 3 alkoxy-C 1 -C 3 alkylene-S (O) 2 )-、NRR'-(C 1 -C 3 Alkylene group)-S(O 2 ) -, 4-6 membered heterocyclyl-S (O) 2 ) -, 6-8 membered monocyclic aryl-S (O) 2 ) -, 8-10 membered bicyclo-S (O) 2 ) -, 5-to 6-membered mono-heteroaryl-S (O 2 ) -or 8-10 membered bi-or tricyclic heteroaryl-S (O) 2 ) -; wherein in-NRR', R is C 1 -C 3 Alkyl, R' is hydrogen or C 1 -C 3 An alkyl group.
6. The compound of claim 1 or 2, or a tautomeric form thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, wherein: r is R 7 Selected from hydrogen, cyano, X b -R 11 ，X b -NR 12 R 13 ；
Wherein X is b Selected from bonds, C 1 -C 6 Alkylene, C 1 -C 6 Heteroalkylene, -CO-or-COO-; wherein one carbon atom in the alkylene, heteroalkylene may be substituted with one or more identical or different substituents selected from the group consisting of: hydroxy, halogen, amino, -NRR', C 1 -C 6 Alkoxy, C 3 -C 7 Cycloalkyl oxy, C 1 -C 6 Haloalkyl, C 1 -C 6 Haloalkoxy groups; wherein in-NRR', R is C 1 -C 6 Alkyl, R' is hydrogen or C 1 -C 6 An alkyl group;
preferably, X b Selected from bonds, C 1 -C 3 Alkylene, C 1 -C 3 Heteroalkylene, -CO-or-COO-;
preferably, X b Selected from methylene, bond, -CO-or-COO-;
wherein R is 11 Selected from hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Hydroxyalkyl, 4-8 membered heterocyclyl, C 1 -C 6 Alkoxy- (C) 1 -C 6 Alkylene group) -, C 1 -C 6 Haloalkoxy- (C) 1 -C 6 Alkylene group) -, C 1 -C 6 Haloalkoxy-, 4-8 membered heterocyclyl- (C) 1 -C 6 Alkylene) -; wherein the alkyl group, heterocyclic group, by itself or as part of another group, is unsubstituted or substitutedOne or more of the same or different R' s i ，R j And/or R k Substitution;
preferably, R 11 Selected from hydrogen, C 1 -C 3 Alkyl, C 1 -C 3 Hydroxyalkyl, 4-6 membered heterocyclyl, C 1 -C 3 Alkoxy- (C) 1 -C 3 Alkylene group) -, C 1 -C 3 Haloalkoxy- (C) 1 -C 3 Alkylene group) -, C 1 -C 3 Haloalkoxy-, 4-6 membered heterocyclyl- (C) 1 -C 3 Alkylene) -;
preferably, R 11 Selected from methyl, ethyl, hydroxymethyl, methoxymethyl-, trifluoromethoxymethyl-, trifluoromethoxy-, difluoromethoxymethyl-, difluoromethoxy-, azetidinyl-, azetidinylmethylene;
wherein R is 12 And R is 13 Each independently selected from H, C 1 -C 6 Alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Alkoxy- (C) 1 -C 6 Alkylene) -, or R 12 、R 13 To a 4-10 membered heterocyclic group, preferably a 4-7 membered heterocyclic group; wherein the alkyl or heterocyclic groups are unsubstituted or substituted by one or more of the same or different R, by themselves or as part of another group l ，R m And/or R n Substitution;
preferably, R 12 And R is 13 Each independently selected from H, C 1 -C 3 Alkyl, C 1 -C 3 Hydroxyalkyl, C 1 -C 3 Alkoxy- (C) 1 -C 3 Alkylene) -, or R 12 、R 13 Is linked into 4-membered heterocyclic group, 5-membered heterocyclic group, 6-membered heterocyclic group or 7-membered heterocyclic group;
preferably, R 12 And R is 13 Each independently selected from H, methyl, ethyl, hydroxyethyl, methoxyethyl-, or R 12 、R 13 Linked to an azetidinyl group;
wherein R is i ，R j ，R k ，R l ，R m And/or R n Each independently selected from hydroxy groupsHalogen, amino, cyano, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy groups;
preferably, R i ，R j ，R k ，R l ，R m And/or R n Each independently selected from hydroxy, F, cl, br, amino, cyano, C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy, C 1 -C 3 Haloalkoxy groups;
preferably, R i ，R j ，R k ，R l ，R m And/or R n Each independently selected from hydroxy, methoxy, F, cl, br;
preferably, R 7 Selected from hydrogen, amino, cyano, Methyl group.
7. The compound of claim 1 or 2, or a tautomeric form thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, wherein: r is R 8 Selected from hydrogen, C 1 -C 6 Alkyl, NRR' - (C) 1 -C 6 Alkylene group) -, C 3 -C 7 Cycloalkyl, C 1 -C 6 Haloalkyl, 4-8 membered heterocyclyl- (C) 1 -C 6 Alkylene group) -, C 1 -C 6 Hydroxyalkyl, 5-10 membered heteroaryl; wherein in-NRR', R is C 1 -C 6 Alkyl, R' is hydrogen or C 1 -C 6 Alkyl, wherein alkyl, cycloalkyl, heterocyclyl or heteroaryl is unsubstituted or substituted by one or more of the same or different R, by itself or as part of another group i ，R j And/or R k Substitution;
preferably, R 8 Selected from H, C 1 -C 6 Alkyl, NRR' - (C) 1 -C 6 Alkylene group) -, C 3 -C 7 Cycloalkyl, C 1 -C 6 Haloalkyl, 4-8 membered heterocyclyl- (C) 1 -C 6 Alkylene group) -, C 1 -C 6 Hydroxyalkyl, 5-to 10-membered heteroaryl; wherein in-NRR', R is C 1 -C 6 An alkyl group; r' is hydrogen or C 1 -C 6 An alkyl group;
preferably, R 8 Selected from H, C 1 -C 3 Alkyl, NRR' - (C) 1 -C 3 Alkylene group) -, C 3 -C 5 Cycloalkyl, C 1 -C 3 Haloalkyl, 4-6 membered heterocyclyl- (C) 1 -C 3 Alkylene group) -, C 1 -C 3 Hydroxyalkyl, 5-or 6-membered heteroaryl; wherein in-NRR', R is C 1 -C 3 Alkyl, preferably methyl; r' is hydrogen or C 1 -C 6 Alkyl, preferably hydrogen or methyl;
wherein R is i ，R j And/or R k Each independently selected from: deuterium, C 1 -C 6 Alkyl, halogen, hydroxy, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, C 1 -C 6 A hydroxyalkyl group;
preferably, R i ，R j And/or R k Each independently selected from: deuterium, C 1 -C 3 Alkyl, F, cl, br, hydroxy, C 1 -C 3 Alkoxy, C 1 -C 3 Haloalkoxy, C 1 -C 3 A hydroxyalkyl group;
preferably, R i ，R j And/or R k Each independently selected from: deuterium, methyl, F, hydroxy, methoxy, hydroxymethyl;
preferably, R 8 Selected from hydrogen, methyl, -CD 3 Ethyl group,
8. The compound of claim 1 or 2, or a tautomeric form thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, wherein: r is R 9 Selected from hydrogen, oxo, X b -R 11 ，X b -NR 12 R 13 ，-NH-NR 12 R 13 、-NH-O-R 11 ；
Wherein X is b Is a bond, C 1 -C 6 Alkylene, C 1 -C 6 Heteroalkylene, -O-, -CO-, or-COO-; wherein one carbon atom in the alkylene, heteroalkylene may be substituted with one or more identical or different substituents selected from the group consisting of: hydroxy, halogen, amino, C 1 -C 6 Alkoxy, -NRR', C 3 -C 7 Cycloalkyl oxy, C 1 -C 6 Haloalkyl, C 1 -C 6 Haloalkoxy substitution; wherein in-NRR', R is C 1 -C 6 Alkyl, R' is hydrogen or C 1 -C 6 An alkyl group;
wherein halogen is preferably F, cl or Br; c (C) 1 -C 6 Alkoxy is preferably C 1 -C 3 Alkoxy, more preferably methoxy, ethoxy; c (C) 1 -C 6 The haloalkoxy group is preferably trifluoromethoxy group or difluoromethoxy group; c (C) 1 -C 6 The haloalkyl is preferably difluoromethyl, trifluoromethyl;
preferably, X b Is a bond, C 1 -C 3 Alkylene, C 1 -C 3 Heteroalkylene, -O-, -CO-, or-COO-;
preferably, X b Is methylene, ethylene, a bond, -O-, -CO-, or-COO-;
wherein R is 11 Selected from H, C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl, 5-10 membered heteroaryl, C 1 -C 6 Alkoxy- (C) 1 -C 6 Alkylene group) -, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, 4-8 membered heterocyclyl, amino- (C) 1 -C 6 Alkylene) -, 4-8 membered heterologyCyclic group- (C) 1 -C 6 Alkylene) -, 4-8 membered heterocyclyloxy- (C) 1 -C 6 Alkylene) -, in which the alkyl, cycloalkyl, heterocyclyl or heteroaryl groups are unsubstituted or substituted by one or more of the same or different R i ，R j And/or R k Substitution;
preferably, R 11 Selected from H, C 1 -C 3 Alkyl, C 3 -C 4 Cycloalkyl, 5-or 6-membered heteroaryl, C 1 -C 3 Alkoxy- (C) 1 -C 3 Alkylene group) -, C 1 -C 3 Haloalkyl, C 1 -C 3 Hydroxyalkyl, 4-8 membered heterocyclyl, amino- (C) 1 -C 3 Alkylene) -, 4-6 membered heterocyclyl- (C 1 -C 3 Alkylene) -, 4-6 membered heterocyclyloxy- (C) 1 -C 3 Alkylene) -;
preferably, R 11 Selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, phenyl,Pyridyl, methoxymethyl, trifluoromethyl, difluoromethyl, hydroxymethyl, hydroxyethyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 4-membered heterocyclyl-methylene-, 6-membered heterocyclyl-methylene-, 4-membered heterocyclyloxy-methylene-;
preferably, R 11 Selected from the group consisting of
Wherein R is 12 And R is 13 Independently selected from H, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy- (C) 1 -C 6 Alkylene group) -, C 1 -C 6 Alkylcarbonyl-, C 3 -C 7 Cycloalkyl, C 3 -C 7 Cycloalkyl- (C) 1 -C 6 Alkylene) -, 4-8 membered heterocyclylcarbonyl-, 4-8 membered heterocyclyl- (C) 1 -C 6 Alkylene group) -, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Haloalkoxy- (C) 1 -C 6 Alkylene) -; or R is 12 、R 13 Can be linked to form a 4-to 10-membered heterocyclic group, where the alkyl, cycloalkyl or heterocyclic group is unsubstituted or substituted by one or more of the same or different R l ，R m And/or R n Substitution;
preferably, R 12 And R is 13 Independently selected from H, C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy- (C) 1 -C 3 Alkylene group) -, C 1 -C 3 Alkylcarbonyl-, C 4 -C 6 Cycloalkyl, C 4 -C 6 Cycloalkyl- (C) 1 -C 3 Alkylene) -, 4-6 membered heterocyclylcarbonyl-, 4-8 membered heterocyclyl- (C) 1 -C 3 Alkylene group) -, C 1 -C 3 Hydroxyalkyl, C 1 -C 3 Haloalkoxy- (C) 1 -C 3 Alkylene) -; or R is 12 、R 13 A heterocyclic group which may be linked to form 4 to 7 members;
preferably, R 12 And R is 13 Independently selected from H, methyl, ethyl, hydroxyethyl, methoxyethyl, methylcarbonyl,Or R is 12 、R 13 Can be linked to the following groups: />
Wherein R is i ，R j ，R k ，R l ，R m And/or R n Each independently selected from deuterium, hydroxy, halogen, amino, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, -CONRR', C 1 -C 6 Alkyl, C 1 -C 6 A haloalkyl group; wherein in-CONRR', R is C 1 -C 6 Alkyl, R' is hydrogen or C 1 -C 6 An alkyl group;
preferably, R i ，R j ，R k ，R l ，R m And/or R n Each independently selected from deuterium, hydroxy, halogen, amino, C 1 -C 3 Alkoxy, C 1 -C 3 Haloalkoxy, -CONRR', C 1 -C 3 Alkyl, C 1 -C 3 A haloalkyl group; wherein in-CONRR', R is C 1 -C 3 Alkyl, R' is hydrogen or C 1 -C 3 An alkyl group;
preferably, R i ，R j ，R k ，R l ，R m And/or R n Each independently selected from deuterium, hydroxy, amino, methoxy,Methyl, trifluoroethyl, F, cl, br;
preferably, R 9 Selected from H, oxo, methyl, ethyl, -CD 3 Hydroxypropyl, methoxyethyl,
Or preferably, R 9 Selected from the group consisting of
9. The compound of claim 1 or 2, or a tautomeric form thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, wherein: r is R 10 Selected from C 6 -C 10 Aryl, C 1 -C 6 Alkyl, C 1 -C 6 alkoxy-CO-, HO- (C) 1 -C 6 Alkylene group) -, C 1 -C 6 Alkoxy- (C) 1 -C 6 Alkylene) -, NRR' - (C 1 -C 6 Alkylene) -, wherein in-NRR', R is C 1 -C 6 Alkyl, R' is hydrogen or C 1 -C 6 Alkyl, where the alkyl, aryl, by themselves or as part of another group, are unsubstituted or substituted by one or more of the same or different R i ，R j And/or R k Substitution;
preferably, R 10 Selected from phenyl, naphthyl, C 1 -C 3 Alkyl, C 1 -C 3 alkoxy-CO-, HO- (C) 1 -C 3 Alkylene group) -, C 1 -C 3 Alkoxy- (C) 1 -C 3 Alkylene) -, NRR' - (C 1 -C 3 Alkylene) -; wherein in-NRR', R is C 1 -C 3 Alkyl, R' is hydrogen or C 1 -C 3 An alkyl group; wherein alkyl, phenyl, naphthyl, by themselves or as part of another group are unsubstituted or substituted by one or more of the same or different R i ，R j And/or R k Substitution;
wherein R is i ，R j And/or R k Each independently selected from hydroxy, methoxy, methyl-NH-;
preferably, R 10 Selected from methyl group,
10. The compound of claim 1 or 2, or a tautomeric form thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, wherein: the compound represented by formula (IA) is a specific compound selected from the group consisting of:
/>
/>
/>
/>
/>
/>
/>
/>
11. A pharmaceutical composition for the treatment and/or prevention of a disease associated with abnormal MAT2A expression, characterized in that: the pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of a compound according to any one of claims 1 to 10, or a tautomeric form thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, and optionally a pharmaceutically acceptable carrier and/or adjuvant and/or diluent;
preferably, the disease associated with abnormal MAT2A expression is cancer;
preferably, the related diseases with abnormal MAT2A expression refer to MTAP-deleted diseases related to abnormal MAT2A expression;
preferably, the disease associated with abnormal expression of MAT2A is MTAP-deleted cancer.
12. The application of a compound shown in a formula (IA) or pharmaceutically acceptable salt/tautomeric form thereof, or deuterated compound thereof, or the pharmaceutical composition in preparing medicines for treating and/or preventing diseases related to MAT2A expression abnormality;
preferably, the disease associated with abnormal MAT2A expression is cancer;
preferably, the disease associated with abnormal MAT2A expression refers to a MTAP-deleted disease associated with abnormal MAT2A expression;
Preferably, the disease associated with abnormal expression of MAT2A is MTAP-deleted cancer.
13. An intermediate compound selected from the following structures:
14. use of an intermediate compound according to claim 13 for the preparation of a compound of formula (IA).
CN202310465844.2A 2022-04-20 2023-04-19 2-oxo quinazoline five-membered heterocyclic derivative, preparation method and application thereof Pending CN116903613A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202210418355 2022-04-20
CN2022104183557 2022-04-20

Publications (1)

Publication Number Publication Date
CN116903613A true CN116903613A (en) 2023-10-20

Family

ID=88353793

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202310465844.2A Pending CN116903613A (en) 2022-04-20 2023-04-19 2-oxo quinazoline five-membered heterocyclic derivative, preparation method and application thereof

Country Status (1)

Country Link
CN (1) CN116903613A (en)

Similar Documents

Publication Publication Date Title
KR102426043B1 (en) Inhibitors of activin receptor-like kinases
CN111704611B (en) Aryl spiro SHP2 inhibitor compound, preparation method and application
CN109890819B (en) Heterocyclic compounds as immunomodulators
CN112142735B (en) Condensed cyanopyridine compound, preparation method and application
KR102075886B1 (en) Novel pyrazolo [3,4-d] pyrimidine compounds or salts thereof
CN106061966B (en) Bicyclic heterocycle derivatives as bromodomain inhibitor
CN113637005A (en) KRAS inhibitors for cancer treatment
CA3008653A1 (en) Bruton's tyrosine kinase inhibitors
CN113061132B (en) Condensed ring lactam compound, preparation method and application
CA2887203A1 (en) 2,3-(hetero)aryl substituted pyridinyl compounds and their use as gdf-8 inhibitors
AU2010339423A1 (en) Therapeutic compounds and related methods of use
EA025436B1 (en) Amino quinazolines as kinase inhibitors
KR20150092279A (en) Novel bi-ring phenyl-pyridines/pyrazines for the treatment of cancer
CN116546985A (en) Pyridopyrimidine derivative and preparation method and application thereof
CN113527299B (en) Nitrogen-containing condensed ring compound, preparation method and application
TW201833113A (en) IMIDAZO[1,5-A]PYRAZINE DERIVATIVES AS PI3Kdelta INHIBITORS
CN114524810B (en) Pyrimidine heterocyclic compounds, preparation method and application
WO2020038458A1 (en) Class of fused ring triazole compound, preparation method, and use
CN112300173B (en) Nitrogen-containing polycyclic compounds, preparation method and application
CN115667246A (en) Crystal form of pyridazine derivative free base and preparation method and application thereof
CN116903613A (en) 2-oxo quinazoline five-membered heterocyclic derivative, preparation method and application thereof
CN111377873B (en) Aminopyrimidine compounds, their preparation and use
CN115340559A (en) Preparation and application of SHP2 phosphatase heterocyclic inhibitor
CN112939982A (en) Alkyne heterocyclic BTK inhibitor and preparation method and application thereof
WO2020233645A1 (en) Macrolide derivatives, preparation method and application thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination