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CN103848819B - Spiro compound serving as hepatitis C inhibitor, drug composition and applications of spiro compound and drug composition in drugs - Google Patents

Spiro compound serving as hepatitis C inhibitor, drug composition and applications of spiro compound and drug composition in drugs Download PDF

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CN103848819B
CN103848819B CN201310631650.1A CN201310631650A CN103848819B CN 103848819 B CN103848819 B CN 103848819B CN 201310631650 A CN201310631650 A CN 201310631650A CN 103848819 B CN103848819 B CN 103848819B
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CN103848819A (en
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张英俊
张健存
谢洪明
任青云
巫锡伟
付长萍
胡柏林
李石凤
方清洪
雷勇
罗峰
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Yichang Hec Changjiang Pharmaceutical Co ltd
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Guangdong HEC Pharmaceutical Co Ltd
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    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/504—Pyridazines; Hydrogenated pyridazines forming part of bridged ring systems
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    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
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    • A61K38/21—Interferons [IFN]
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    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
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    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
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Abstract

本发明提供了作为丙型肝炎抑制剂的螺环化合物、药物组合物及它们在药物中的应用。所述化合物为式(I)所示的化合物或式(I)所示化合物的立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药。此外，本发明还提供了包含所述化合物的药物组合物，所述化合物和所述药物组合物用于抑制HCV复制和抑制HCV病毒蛋白功能的至少之一的用途，以及所述化合物和所述药物组合物用于预防、处理、治疗或减轻患者的HCV感染或丙型肝炎疾病。 This invention provides spirocyclic compounds as hepatitis C inhibitors, pharmaceutical compositions, and their use in pharmaceuticals. The compounds are compounds of formula (I) or stereoisomers, geometric isomers, tautomers, nitrides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs of compounds of formula (I). Furthermore, this invention provides pharmaceutical compositions comprising the compounds, uses of the compounds and the pharmaceutical compositions for inhibiting HCV replication and inhibiting at least one of the functions of HCV viral proteins, and uses of the compounds and the pharmaceutical compositions for preventing, treating, or alleviating HCV infection or hepatitis C disease in patients.

Description

Spiro-compound serving as hepatitis C inhibitor, pharmaceutical composition and application of spiro-compound and pharmaceutical composition in medicines
Technical Field
The present invention is in the field of medicine and relates to compounds useful for treating Hepatitis C Virus (HCV) infection, compositions comprising the compounds, and uses and methods of use thereof. In particular, the compounds of the present invention are spirocyclic compounds that can act as NS5A inhibitors. More particularly, the present invention relates to compounds that can inhibit the function of the NS5A protein encoded by hepatitis c virus, pharmaceutical compositions comprising the compounds and methods for inhibiting the function of the NS5A protein.
Background
HCV is the major human pathogen, estimated to infect approximately 1.7 million people worldwide, 5 times as many as people infected with human immunodeficiency virus type 1. Most of these HCV-infected individuals develop severe progressive liver disease, including cirrhosis and hepatocellular carcinoma. Thus, chronic HCV infection will be a leading cause of premature death of patients from liver disease worldwide.
Currently, the most effective HCV therapy is the use of a combination of interferon-alpha and ribavirin, which produces sustained efficacy in 40% of patients. Recent clinical results indicate that pegylated interferon-alfa is superior to unmodified interferon-alfa as a monotherapy. However, even with experimental treatment regimens involving combinations of pegylated interferon-alfa and ribavirin, most patients are unable to continue to reduce viral load, and many patients are often associated with side effects that do not allow for long-term treatment. Thus, new effective methods for treating HCV infection are currently urgently needed.
HCV is a positive-stranded RNA virus. Based on a comparison of the broad similarity of the deduced amino acid sequence and the 5' untranslated region, HCV was classified into a single genus of the Flaviviridae family (Flaviviridae family). All members of the flaviviridae family are enveloped virions containing a positive-stranded RNA genome that encodes all known virus-specific proteins via translation of a single uninterrupted Open Reading Frame (ORF).
Considerable heterogeneity exists within the nucleotide and encoded amino acid sequences of the entire HCV genome. At least 7 major genotypes have been identified and over 50 subtypes have been disclosed. In HCV-infected cells, viral RNA is translated into polyproteins and split into 10 individual proteins. At the amino terminus is the structural protein, immediately following E1 and E2. In addition, there are 6 nonstructural proteins, namely NS2, NS3, NS4A, NS4B, NS5A and NS5B, which play a very important role in the HCV life cycle (see, e.g., Lindenbach, b.d. and c.m. rice, nature.436,933-938,2005).
The major genotypes of HCV vary in their distribution throughout the world, and despite the large number of genotypes studied for pathogenesis and therapeutic role, the clinical importance of the genetic heterogeneity of HCV remains unclear.
The single-stranded HCV RNA genome is approximately 9500 nucleotides in length, has a single open reading frame, and encodes a single large polyprotein of about 3000 amino acids. In infected cells, the polyprotein is cleaved at multiple sites by cellular and viral proteases, producing structural and non-structural (NS) proteins. In the case of HCV, the formation of mature nonstructural proteins (NS2, NS3, NS4A, NS4B, NS5A and NS5B) is achieved by two viral proteases. The first is generally considered to be a metalloprotease, which cleaves at the NS2-NS3 junction; the second is a serine protease contained in the N-terminal region of NS3 (also referred to herein as NS3 protease) which mediates all subsequent cleavage downstream of NS3 in cis at the NS3-NS4A cleavage site and in trans at the remaining NS4A-NS4B, NS4B-NS5A, NS5A-NA5B sites. The NS4A protein appears to have multiple functions, acting as a cofactor for NS3 protease and possibly assisting in membrane localization of NS3 and other viral replicase components. The formation of the complex of NS3 protein with NS4A appears to be essential for a processing event, increasing proteolytic efficiency at all sites. The NS3 protein also exhibits nucleoside triphosphatase and RNA helicase activities. NS5B (also referred to herein as HCV polymerase) is an RNA-dependent RNA polymerase involved in HCV replication.
The compounds of the present invention are useful for treating HCV infection in a patient, and selectively inhibit the replication of the HCV virus. In particular, the compounds of the present invention are effective in inhibiting the function of the NS5A protein. HCV NS5A protein is described, for example, in Tan, S. -L., Katzel, M.G., Virology 2001,284,1-12, and Park, K. -J., Choi, S. -H, J.Biological chemistry, 2003.
Summary of the invention
The present invention relates to novel spiro compounds and methods for combating HCV infection. The compound or the pharmaceutical composition has good inhibition effect on HCV infection, in particular to HCV NS5A protein.
In one aspect, the invention relates to a compound having a structure according to formula (I):
or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
each A and A' is independently a bond, alkylene, alkenylene, cycloalkylene, heterocycloalkylene, - (CR)8R8a)n-O-(CR8R8a)p-、-(CR8R8a)n-N(R5)-(CR8R8a)p-、-(CR8R8a)n-S(=O)r-N(R5)-(CR8R8a)p-、-(CR8R8a)n-C(=O)-N(R5)-(CR8R8a)p-、-(CR8R8a)n-N(R5)-C(=O)-N(R5)-(CR8R8a)p-、-(CR8R8a)n-C(=O)-O-(CR8R8a)p-、-(CR8R8a)n-N(R5)-S(=O)r-N(R5)-(CR8R8a)p-、-(CR8R8a)n-S(=O)r-(CR8R8a)p-、-(CR8R8a)n-S(=O)r-O-(CR8R8a)p-、-(CR8R8a)n-C(=O)-(CR8R8a)p-、-(CR8R8a)n-C(=S)-(CR8R8a)p-、-(CR8R8a)n-N(R5)-C(=O)-O-(CR8R8a)pOr each of A and A' is independently the following group:
wherein each X1And X2Independently O, S, NR6Or CR7R7a；
W1Is carbocyclyl or heterocyclyl;
W2is carbocyclyl, heterocyclyl, spirobicyclic, spiroheterobicyclic, fused bicyclic or fused heterobicyclic;
each Y is1、Y2、Y1’And Y2’Independently is N or CR7；
Z is- (CH)2)a-、-CH=CH-、-N=CH-、-(CH2)a-N(R5)-(CH2)b-or- (CH)2)a-O-(CH2)b-；
Each a and b is independently 0, 1,2 or 3;
each c is independently 1 or 2;
each d is independently 1 or 2;
each n is independently 0, 1,2 or 3;
each p is independently 0, 1,2 or 3;
each r is independently 0, 1 or 2;
each f and f' is independently 0, 1,2,3, or 4;
each Q1And Q2Independently is a bond, NR6O, S, C (= O) or (CR)7R7a)e；
Each e is independently 0, 1,2,3, or 4;
each X and X' is independently N or CR7；
Each Y and Y 'is independently H, deuterium, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, α -amino acid group, or an optical isomer of α -amino acid group, or each Y and Y' is independently a structural unit of- [ U- (CR)9R9a)t-N(R10)-(CR9R9a)t]k-U-(CR9R9a)t-N(R11)-(CR9R9a)t-R12、-U-(CR9R9a)t-R12Or- [ U- (CR)9R9a)t-N(R10)-(CR9R9a)t]k-U-(CR9R9a)t-O-(CR9R9a)t-R12；
Each U is independently-C (= O) -, -C (= S) -, -S (= O) -, or-S (= O)2-；
Each t is independently 0, 1,2,3 or 4;
each k is independently 0, 1 or 2;
each R1、R2、R3And R4Independently is H, deuterium, alkyl, heteroalkyl, aralkyl, cycloalkyl, heterocyclyl, heteroaryl or aryl, or R1、R2And X-CH form an optionally 3-8 membered heterocyclic ring or a 3-8 membered carbocyclic ring, C5-12Condensed bicyclic ring, C5-12Fused heterobicyclic ring, C5-12Spiro bicyclic ring or C5-12Spiro heterobicyclic rings; or R3、R4And X' -CH optionally form a 3-8 membered heterocyclic or carbocyclic ring, C5-12Condensed bicyclic ring, C5-12Fused heterobicyclic ring, C5-12Spiro bicyclic ring or C5-12Spiro heterobicyclic rings;
each R5Independently is H, deuterium, hydroxy, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, alkoxy, alkyl-OC (= O) -, alkyl-C (= O) -, carbamoyl, alkyl-OS (= O)r-, alkyl-S (= O)rO-, alkyl-S (= O)r-or aminosulfonyl;
each R5aAnd R5a’Independently is H, deuterium, oxo (= O), hydroxy, amino, F, Cl, Br, I, cyano, R13aR13N-、-C(=O)NR13R13a、-OC(=O)NR13R13a、-OC(=O)OR13、-N(R13)C(=O)NR13R13a、-N(R13)C(=O)OR13a、-N(R13)C(=O)-R13a、R13R13aN-S(=O)2-、R13S(=O)2-、R13S(=O)2N(R13a)-、R13aR13N-alkanesRadical, R13S (= O) -alkyl, R13R13aN-C (= O) -alkyl, R13aR13N-alkoxy, R13S (= O) -alkoxy, R13R13aN-C (= O) -alkoxy, aryl, heteroaryl, alkoxy, alkylamino, alkyl, haloalkyl, alkenyl, alkynyl, heterocyclyl, cycloalkyl, mercapto, nitro, aralkyl, arylamino, heteroarylamino, arylalkylamino, heteroarylalkylamino, heteroaryloxy, heteroarylalkyl, arylalkoxy, heteroarylalkoxy, heterocyclyloxy, heterocyclylamino, alkanoyl, alkanoyloxy, alkoxyacyl, alkylsulfonyl, alkoxysulfonyl, alkylsulfinyl, alkylsulfonyloxy, alkylsulfinyloxy, heterocyclylalkylamino, or aryloxy;
each R6Independently of each other is hydrogen, deuterium, R13R13aNC(=O)-、R13OC(=O)-、R13C(=O)-、R13R13aNS(=O)-、R13OS(=O)-、R13S(=O)-、R13R13aNS(=O)2-、R13OS(=O)2-、R13S(=O)2-, aliphatic, haloaliphatic, hydroxyaliphatic, aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic, alkylthioaliphatic, arylaliphatic, heteroarylaliphatic, heterocyclylaliphatic, cycloalkylaliphatic, aryloxyaliphatic, heterocyclyloxyaliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic, heterocyclylaminoaliphatic, cycloalkylaminoaliphatic, aryl, heteroaryl, heterocyclyl, or carbocyclyl; wherein the aliphatic of said group is an alkyl group; each R6aIndependently H, deuterium, hydroxy, amino, F, Cl, Br, I, cyano, oxo (= O), R13aR13N-、-C(=O)NR13R13a、-OC(=O)NR13R13a、-OC(=O)OR13、-N(R13)C(=O)NR13R13a、-N(R13)C(=O)OR13a、-N(R13)C(=O)-R13a、R13R13aN-S(=O)2-、R13S(=O)2-、R13S(=O)2N(R13a)-、R13aR13N-alkyl, R13S (= O) -alkyl, R13R13aN-C (= O) -alkyl, R13aR13N-alkoxy, R13S (= O) -alkoxy, R13R13aN-C (= O) -alkoxy, aryl, heteroaryl, alkoxy, alkylamino, alkyl, haloalkyl, alkenyl, alkynyl, heterocyclyl, cycloalkyl, mercapto, nitro, aralkyl, arylamino, heteroarylamino, arylalkylamino, heteroarylalkylamino, heteroaryloxy, heteroarylalkyl, arylalkoxy, heteroarylalkoxy, heterocyclyloxy, heterocyclylamino, alkanoyl, alkanoyloxy, alkoxyacyl, alkylsulfonyl, alkoxysulfonyl, alkylsulfinyl, alkylsulfonyloxy, alkylsulfinyloxy, heterocyclylalkylamino, or aryloxy;
each R7And R7aIndependently is H, deuterium, F, Cl, Br, I, aliphatic, heteroalkyl, haloaliphatic, hydroxyalkanoic, aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic, alkylthio aliphatic, arylaliphatic, heteroarylaliphatic, heterocycloaliphatic, cycloalkylaliphatic, aryloxyaliphatic, heterocyclooxyaliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic, heterocycloaminoaliphatic, cycloalkylaminoaliphatic, aryl, heteroaryl, heterocyclyl, or carbocyclyl; wherein the aliphatic of said group is an alkyl group; each R8And R8aIndependently H, deuterium, hydroxy, cyano, nitro, F, Cl, Br, I, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, alkoxy, alkyl-OC (= O) -, alkyl-C (= O) -, carbamoyl, alkyl-OS (= O)r-, alkyl-S (= O)rO-, alkyl-S (= O)r-or aminosulfonyl;
each R9、R9a、R10And R11Independently H, deuterium, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, haloalkyl, hydroxyalkyl, heteroarylalkyl, heterocyclylalkyl or ringAn alkyl group;
each R12Independently is R13aR13N-、-C(=O)R13、-C(=S)R13、-C(=O)-O-R13、-C(=O)NR13R13a、-OC(=O)NR13R13a、-OC(=O)OR13、-N(R13)C(=O)NR13R13a、-N(R13)C(=O)OR13a、-N(R13)C(=O)-R13a、R13R13aN-S(=O)2-、R13S(=O)2-、R13S(=O)2N(R13a)-、R13OS(=O)2-, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or aralkyl;
or R11、R12And the atoms to which they are attached may form a 4-7 membered ring;
and each R13And R13aIndependently is H, deuterium, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or aralkyl; or when R is13And R13aAttached to the same nitrogen atom, R13、R13aAnd the nitrogen atom optionally form a substituted or unsubstituted 3-8 membered ring, a spiro bicyclic ring or a fused bicyclic ring;
wherein each of the groups alkylene, alkenylene, cycloalkylene, heterocycloalkylene, - (CR)8R8a)n-O-(CR8R8a)p-、-(CR8R8a)n-N(R5)-(CR8R8a)p-、-(CR8R8a)n-S(=O)r-N(R5)-(CR8R8a)p-、-(CR8R8a)n-C(=O)-N(R5)-(CR8R8a)p-、-(CR8R8a)n-N(R5)-C(=O)-N(R5)-(CR8R8a)p-、-(CR8R8a)n-C(=O)-O-(CR8R8a)p-、-(CR8R8a)n-N(R5)-S(=O)r-N(R5)-(CR8R8a)p-、-(CR8R8a)n-N(R5)-C(=O)-O-(CR8R8a)p-、-(CR8R8a)n-S(=O)r-(CR8R8a)p-、-(CR8R8a)n-S(=O)r-O-(CR8R8a)p-、-(CR8R8a)n-C(=O)-(CR8R8a)p-、-(CR8R8a)n-C(=S)-(CR8R8a)p-、-[U-(CR9R9a)t-N(R10)-(CR9R9a)t]k-U-(CR9R9a)t-N(R11)-(CR9R9a)t-R12、-U-(CR9R9a)t-R12、-[U-(CR9R9a)t-N(R10)-(CR9R9a)t]k-U-(CR9R9a)t-O-(CR9R9a)t-R12、NR6、CR7R7a、CR7、-(CH2)a-、-CH=CH-、-N=CH-、-(CH2)a-N(R5)-(CH2)b-、-(CH2)a-O-(CH2)b-、R13aR13N-、-C(=O)R13、-C(=S)R13、-C(=O)-O-R13、-C(=O)NR13R13a、-OC(=O)NR13R13a、-OC(=O)OR13、-N(R13)C(=O)NR13R13a、-N(R13)C(=O)OR13a、-N(R13)C(=O)-R13a、R13R13aN-S(=O)2-、R13S(=O)2-、R13S(=O)2N(R13a)-、R13OS(=O)2-、R13aR13N-, alkyl-OC (= O) -, alkyl-C (= O) -, alkyl-OS (= O)O)r-, alkyl-S (= O)rO-, alkyl-S (= O)r-、R13R13aNS(=O)-、R13OS(=O)-、R13S(=O)-、R13aR13N-alkyl, R13S (= O) -alkyl, R13R13aN-C (= O) -alkyl, R13aR13N-alkoxy, R13S (= O) -alkoxy, R13R13aN-C (= O) -alkylamino, alkyl, heteroalkyl, carbocyclyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, α -amino acid group, C5-12Condensed bicyclic ring, C5-12Fused heterobicyclic ring, C5-12Spiro bicyclic ring, C5-12Spiroheterobicyclic, alkoxy, aliphatic, haloaliphatic, hydroxyaliphatic, aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic, alkylthioaliphatic, arylaliphatic, heteroarylaliphatic, heterocycloaliphatic, cycloalkylaliphatic, aryloxyaliphatic, heterocyclyloxyaliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic, heterocycloaliphatic, cycloalkylaminoaliphatic, haloalkyl, alkenyl, alkynyl, arylamino, heteroarylamino, arylalkylamino, heteroarylalkylamino, heteroaryloxy, heteroarylalkyl, arylalkoxy, heteroarylalkoxy, heterocyclyloxy, heterocyclylalkoxy, heterocyclylamino, heterocyclylalkylamino, or aryloxy groups may optionally be substituted with one or more substituents selected from deuterium, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylaminoalkyl, heterocyclyloxy, heterocyclylalkylamino, or aryloxy groups, Alkylthio, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, heteroaryloxy, oxo (= O), carboxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C (= O) -, alkyl-C (= O), alkyl-S (= O) -, alkyl-S (= O)2-, hydroxy-substituted alkyl-S (= O)2-or a substituent of a carboxy-substituted alkoxy group.
In some of these embodiments, wherein W1Is C3-8Carbocyclic radical or C2-10A heterocyclic group;
and W2Is C3-8Carbocyclyl, C2-10Heterocyclic radical、C5-12Spiro bicyclic group, C5-12Spiro-heterobicyclic radical, C5-12Condensed bicyclic group or C5-12Fused heterobicyclic radicals.
In some of these embodiments, wherein
The structural unit is the following sub-structural formula:
the structural unit is the following sub-structural formula:
wherein each X1、X2、X3And X5Independently O, S, NR6C (= O) or CR7R7a；
Each Y is1、Y2、Y1’And Y2’Independently is N or CR7；
Each f and f' is independently 0, 1,2,3, or 4;
each Q1And Q2Independently is a bond, NR6O, S, C (= O) or (CR)7R7a)e；
Q3Is N or CR7；
Each e is independently 0, 1,2,3, or 4;
each R5aAnd R5a’Independently is H, deuterium, oxo (= O), hydroxy, amino, F, Cl, Br, I, cyano, R13aR13N-、-C(=O)NR13R13a、-OC(=O)NR13R13a、-OC(=O)OR13、-N(R13)C(=O)NR13R13a、-N(R13)C(=O)OR13、-N(R13)C(=O)-R13、R13R13aN-S(=O)2-、R13S(=O)2-、R13S(=O)2N(R13a)-、C1-6Alkyl acyl radical, C1-6Alkyl acyloxy, C1-6Alkoxyacyl group, C1-6Alkylsulfonyl radical, C1-6Alkoxysulfonyl group, C1-6Alkylsulfinyl radical, C1-6Alkylsulfonyloxy, C1-6Alkylsulfinyloxy, C1-6Alkoxy radical, C1-6Alkyl radical, C6-10Aryl, -CF3、-OCF3Mercapto, nitro, C1-6Alkylamino radical, C3-10Cycloalkyl or C6-10An aryloxy group;
each R6Independently of each other is hydrogen, deuterium, R13R13aNC(=O)-、R13OC(=O)-、R13C(=O)-、R13R13aNS(=O)-、R13OS(=O)-、R13S(=O)-、R13R13aNS(=O)2-、R13OS(=O)2-、R13S(=O)2-、C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Aminoalkyl radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl radical, C1-6Alkylthio group C1-6Alkyl radical, C6-10Aryl radical C1-6Alkyl radical, C1-9Heteroaryl C1-6Alkyl radical, C2-10Heterocyclyl radical C1-6Alkyl radical, C3-10Cycloalkyl radical C1-6Alkyl radical, C6-10Aryloxy radical C1-6Alkyl radical, C2-10Heterocyclyloxy C1-6Alkyl radical, C3-10Cycloalkyl oxy C1-6Alkyl radical, C6-10Arylamino group C1-6Alkyl radical, C2-10Heterocyclylamino C1-6Alkyl radical, C3-10Cycloalkyl amino group C1-6Alkyl radical, C6-10Aryl radical, C1-9Heteroaryl group, C2-10Heterocyclyl or C3-10A carbocyclic group;
each R7And R7aIndependently H, deuterium, F, Cl, Br, I, C1-6Alkyl radical, C2-6Heteroalkyl group, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Aminoalkyl radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl radical, C1-6Alkylthio group C1-6Alkyl radical, C6-10Aryl radical C1-6Alkyl radical, C1-9Heteroaryl C1-6Alkyl radical, C2-10Heterocyclyl radical C1-6Alkyl radical, C3-10Cycloalkyl radical C1-6Alkyl radical, C6-10Aryloxy radical C1-6Alkyl radical, C2-10Heterocyclyloxy C1-6Alkyl radical, C3-10Cycloalkyl oxy C1-6Alkyl radical, C6-10Arylamino group C1-6Alkyl radical, C2-10Heterocyclylamino C1-6Alkyl radical, C3-10Cycloalkyl amino group C1-6Alkyl radical, C6-10Aryl radical, C1-9Heteroaryl group, C2-10Heterocyclyl or C3-10A carbocyclic group;
and each R13And R13aIndependently of one another H, deuterium, C1-6Alkyl radical, C2-6Heteroalkyl group, C3-10Cycloalkyl radical, C2-10Heterocyclic group, C6-10Aryl radical, C1-9Heteroaryl or C6-10Aryl radical C1-6An alkyl group; or when R is13And R13aAttached to the same nitrogen atom, R13、R13aAnd the nitrogen atom optionally form a substituted or unsubstituted 3-8 membered ring, a spiro bicyclic ring or a fused bicyclic ring.
In some of these embodiments, wherein,
the structural unit is the following sub-structural formula:
the structural unit is the following group:
wherein each Y is1、Y2、Y1’And Y2’Independently is N or CH2；
Each f and f' is independently 0, 1,2,3, or 4;
each R5aAnd R5a’Independently is H, deuterium, oxo (= O), hydroxy, amino, F, Cl, Br, I, cyano, R13aR13N-、-C(=O)NR13R13a、-OC(=O)NR13R13a、-OC(=O)OR13、-N(R13)C(=O)NR13R13a、-N(R13)C(=O)OR13、-N(R13)C(=O)-R13、R13R13aN-S(=O)2-、R13S(=O)2-、R13S(=O)2N(R13a)-、C1-6Alkyl acyl radical, C1-6Alkyl acyloxy, C1-6Alkoxyacyl group, C1-6Alkylsulfonyl radical, C1-6Alkoxysulfonyl group, C1-6Alkylsulfinyl radical, C1-6Alkylsulfonyloxy, C1-6Alkylsulfinyloxy, C1-6Alkoxy radical, C1-6Alkyl radical, C6-10Aryl, -CF3、-OCF3Mercapto, nitro or C1-6An alkylamino group;
and each R6Independently of one another is hydrogen, deuterium, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Aminoalkyl radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl radical, C1-6Alkylthio group C1-6Alkyl radical, C6-10Aryl radical C1-6Alkyl radical, C1-9Heteroaryl C1-6Alkyl radical, C2-10Heterocyclyl radical C1-6Alkyl or C3-8Cycloalkyl radical C1-6An alkyl group.
In some of these embodiments, wherein each A and A' is independently a bond, C1-6Alkylene radical, C2-6Alkenylene radical, C3-8Cycloalkylene radical, C2-10Heterocycloalkylene, - (CR)8R8a)n-O-(CR8R8a)p-、-(CR8R8a)n-N(R5)-(CR8R8a)p-、-(CR8R8a)n-S(=O)r-N(R5)-(CR8R8a)p-、-(CR8R8a)n-C(=O)-N(R5)-(CR8R8a)p-、-(CR8R8a)n-N(R5)-C(=O)-N(R5)-(CR8R8a)p-、-(CR8R8a)n-C(=O)-O-(CR8R8a)p-、-(CR8R8a)n-N(R5)-S(=O)r-N(R5)-(CR8R8a)p-、-(CR8R8a)n-S(=O)r-(CR8R8a)p-、-(CR8R8a)n-S(=O)r-O-(CR8R8a)p-、-(CR8R8a)n-C(=O)-(CR8R8a)p-、-(CR8R8a)n-C(=S)-(CR8R8a)p-、-(CR8R8a)n-N(R5)-C(=O)-O-(CR8R8a)pOr each of A and A' is independently the following group:
wherein each X1And X2Independently O, S, NR6Or CR7R7a；
Each e is independently 0, 1,2,3, or 4;
each Y is1And Y2Independently is N or CR7；
Z is- (CH)2)a-、-CH=CH-、-N=CH-、-(CH2)a-N(R5)-(CH2)b-or- (CH)2)a-O-(CH2)b-；
Each a and b is independently 0, 1,2 or 3;
each c is independently 1 or 2;
each d is independently 1 or 2;
each n is independently 0, 1,2 or 3;
each p is independently 0, 1,2 or 3;
each r is independently 0, 1 or 2;
each R5Independently H, deuterium, hydroxy, C1-6Alkyl radical, C2-6Heteroalkyl group, C3-8Cycloalkyl radical, C2-10Heterocyclic group, C6-10Aryl radical, C1-9Heteroaryl group, C6-10Aryl radical C1-6Alkyl radical, C1-6Alkoxy radical, C1-6alkyl-OC (= O) -, C1-6alkyl-C (= O) -, carbamoyl, C1-6alkyl-OS (= O)r-、C1-6alkyl-S (= O)rO-、C1-6alkyl-S (= O)r-or aminosulfonyl;
each R6Independently of each other is hydrogen, deuterium, R13R13aNC(=O)-、R13OC(=O)-、R13C(=O)-、R13R13aNS(=O)-、R13OS(=O)-、R13S(=O)-、R13R13aNS(=O)2-、R13OS(=O)2-、R13S(=O)2-、C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Aminoalkyl radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl radical, C1-6Alkylthio group C1-6Alkyl radical, C6-10Aryl radical C1-6Alkyl radical, C1-9Heteroaryl C1-6Alkyl radical, C2-10Heterocyclyl radical C1-6Alkyl radical, C3-10Cycloalkyl radical C1-6Alkyl radical, C6-10Aryloxy radical C1-6Alkyl radical, C2-10Heterocyclyloxy C1-6Alkyl radical, C3-10Cycloalkyl oxy C1-6Alkyl radical, C6-10Arylamino group C1-6Alkyl radical, C2-10Heterocyclylamino C1-6Alkyl radical, C3-10Cycloalkyl amino group C1-6Alkyl radical, C6-10Aryl radical, C1-9Heteroaryl group, C2-10Heterocyclyl or C3-10A carbocyclic group;
each R6aIndependently H, deuterium, hydroxy, amino, F, Cl, Br, I, cyano, oxo (= O), R13aR13N-、-C(=O)NR13R13a、-OC(=O)NR13R13a、-OC(=O)OR13、-N(R13)C(=O)NR13R13a、-N(R13)C(=O)OR13a、-N(R13)C(=O)-R13a、R13R13aN-S(=O)2-、R13S(=O)2-、R13S(=O)2N(R13a)-、R13aR13N-C1-6Alkyl radical, R13S(=O)-C1-6Alkyl radical, R13R13aN-C(=O)-C1-6Alkyl radical, R13aR13N-C1-6Alkoxy radical, R13S(=O)-C1-6Alkoxy radical, R13R13aN-C(=O)-C1-6Alkoxy radical, C6-10Aryl radical, C1-9Heteroaryl group, C1-6Alkoxy radical, C1-6Alkylamino radical, C1-6Alkyl radical, C1-6Haloalkyl, C2-6Alkenyl radical, C2-6Alkynyl, C2-10Heterocyclic group, C3-8Cycloalkyl, mercapto, nitro, C6-10Aryl radical C1-6Alkyl radical, C6-10Arylamino, C1-9Heteroarylamino or C6-10An aryloxy group;
each R7And R7aIndependently H, deuterium, F, Cl, Br, I, C1-6Alkyl radical, C2-6Heteroalkyl group, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Aminoalkyl radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl radical, C1-6Alkylthio group C1-6Alkyl radical, C6-10Aryl radical C1-6Alkyl radical, C2-10Heterocyclyl radical C1-6Alkyl radical, C3-10Cycloalkyl radical C1-6Alkyl radical, C6-10Aryloxy radical C1-6Alkyl radical, C2-10Heterocyclyloxy C1-6Alkyl radical, C3-10Cycloalkyl oxy C1-6Alkyl radical, C6-10Arylamino group C1-6Alkyl radical, C2-10Heterocyclylamino C1-6Alkyl radical, C3-10Cycloalkyl amino group C1-6Alkyl radical, C6-10Aryl radical, C1-9Heteroaryl group, C2-10Heterocyclyl or C3-8A carbocyclic group;
each R13And R13aIndependently of one another H, deuterium, C1-6Alkyl radical, C2-6HeteroalkanesBase, C3-10Cycloalkyl radical, C2-10Heterocyclic group, C6-10Aryl radical, C1-9Heteroaryl or C6-10Aryl radical C1-6An alkyl group; or when R is13And R13aAttached to the same nitrogen atom, R13、R13aAnd the nitrogen atom optionally form a substituted or unsubstituted 3-8 membered ring, a spiro bicyclic ring or a fused bicyclic ring;
and each R8And R8aIndependently H, deuterium, hydroxyl, cyano, nitro, F, Cl, Br, I, C1-6Alkyl radical, C2-6Heteroalkyl group, C3-10Cycloalkyl radical, C2-10Heterocyclic group, C6-10Aryl radical, C1-9Heteroaryl group, C6-10Aryl radical C1-6Alkyl radical, C1-6Alkoxy radical, C1-6alkyl-OC (= O) -, C1-6alkyl-C (= O) -, carbamoyl, C1-6alkyl-OS (= O)r-、C1-6alkyl-S (= O)rO-、C1-6alkyl-S (= O)r-or aminosulfonyl.
In some of these embodiments, wherein each A and A' is independently a bond, -CH2-、-(CH2)2-、-CH=CH-、-CH=CH-CH2-、-N(R5)-、-C(=O)-、-C(=S)-、-C(=O)-O-、-C(=O)N(R5)-、-OC(=O)N(R5)-、-OC(=O)O-、-N(R5)C(=O)N(R5)-、-(R5)N-S(=O)2-、-S(=O)2-、-OS(=O)2-、-(R5) N-S (= O) -, -OS (= O) -, or each of a and a' is independently a group of:
wherein each X1Independently is O or S;
each Y is1Independently is N or CH;
each e is independently 0, 1,2 or 3;
each R5Independently H, deuterium, hydroxy, C1-6Alkyl radical, C2-6Heteroalkyl group, C3-8Cycloalkyl radical, C2-10Heterocyclic group, C6-10Aryl radical, C1-9Heteroaryl group, C6-10Aryl radical C1-6Alkyl radical, C1-6Alkoxy radical, C1-6alkyl-OC (= O) -, C1-6alkyl-C (= O) -, carbamoyl, C1-6alkyl-OS (= O)r-、C1-6alkyl-S (= O)rO-、C1-6alkyl-S (= O)r-or aminosulfonyl;
each R6Independently of one another is hydrogen, deuterium, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Aminoalkyl radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl radical, C1-6Alkylthio group C1-6Alkyl radical, C6-10Aryl radical C1-6Alkyl radical, C1-9Heteroaryl group, C6-10Aryl radical, C2-10Heterocyclyl or C3-8A carbocyclic group;
each R6aIndependently H, deuterium, hydroxy, amino, F, Cl, Br, I, cyano, oxo (= O), R13aR13N-、-C(=O)NR13R13a、-OC(=O)NR13R13a、-OC(=O)OR13、-N(R13)C(=O)NR13R13a、-N(R13)C(=O)OR13、-N(R13)C(=O)-R13、R13R13aN-S(=O)2-、R13S(=O)2-、R13S(=O)2N(R13a)-、C1-6Alkoxy radical, C1-6Alkylamino radical, C1-6Alkyl radical, C1-6Haloalkyl, C2-6Alkenyl radical, C2-6Alkynyl, mercapto or nitro;
and each R13And R13aIndependently of one another H, deuterium, C1-6Alkyl radical, C2-6Heteroalkyl group, C3-10Cycloalkyl radical, C2-10Heterocyclic group, C6-10Aryl radical, C1-9Heteroaryl or C6-10Aryl radical C1-6An alkyl group; or when R is13And R13aAttached to the same nitrogen atom, R13、R13aAnd the nitrogen atom optionally form a substituted or unsubstituted 3-8 membered ring, a spiro bicyclic ring or a fused bicyclic ring.
In some of these embodiments, wherein each R is1、R2、R3And R4Independently is selected from H, deuterium, C1-8Alkyl radical, C1-8Heteroalkyl group, C6-10Aryl radical C1-6Alkyl radical, C3-10Cycloalkyl radical, C2-10Heterocyclic group, C1-9Heteroaryl or C6-10An aryl group; or R1、R2And X-CH optionally form a 3-8 membered heterocyclic ring or a 3-8 membered carbocyclic ring, C5-12Condensed bicyclic ring, C5-12Fused heterobicyclic ring, C5-12Spiro bicyclic ring or C5-12Spiro heterobicyclic rings; r3、R4And X' -CH optionally form a 3-8 membered heterocyclic ring or a 3-8 membered carbocyclic ring, C5-12Condensed bicyclic ring, C5-12Fused heterobicyclic ring, C5-12Spiro bicyclic ring or C5-12Spiro heterobicyclic rings.
In still other embodiments, wherein R is1、R2And X-CH, or R3、R4And X' -CH to form a 3-8 membered heterocyclic ring, C5-12Condensed bicyclic ring, C5-12Fused heterobicyclic ring, C5-12Spiro bicyclic ring or C5-12Spiro heterobicyclic rings.
In still other embodiments, wherein R is1、R2And Y-X-CH form a heterocyclic or fused ring or spiro ring system selected from the following subformulas:
wherein each R is15Independently H, deuterium, F, Cl, Br, I, cyano, hydroxy, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Alkylamino radical, C1-3Alkylthio radical, C6-10Arylamino, C6-10Aryloxy radical, C1-9Heteroaryl group, C1-9Heteroaryloxy radical, C1-9Heteroaryl C1-3Alkyl or C2-10A heterocyclic group;
each R6Independently of one another is hydrogen, deuterium, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Aminoalkyl radical, C1-3Alkoxy radical C1-3Alkyl radical, C1-3Alkylamino radical C1-3Alkyl radical, C1-3Alkylthio group C1-3Alkyl radical, C6-10Aryl radical C1-3Alkyl radical, C1-9Heteroaryl group, C6-10Aryl radical, C2-10Heterocyclyl or C3-8A carbocyclic group;
and each n1And n2Independently 1,2,3 or 4.
In still other embodiments, wherein R is3、R4And Y '-X' -CH to form a heterocyclic or fused ring or spiro ring system selected from the following subformulae:
wherein each R is15Independently H, deuterium, F, Cl, Br, I, cyano, hydroxy, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Alkylamino radical, C1-3Alkylthio radical, C6-10Arylamino, C6-10Aryloxy radical, C1-9Heteroaryl group, C1-9Heteroaryloxy radical, C1-9Heteroaryl C1-3Alkyl or C2-10A heterocyclic group;
each R6Independently of one another is hydrogen, deuterium, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Aminoalkyl radical, C1-3Alkoxy radical C1-3Alkyl radical, C1-3Alkylamino radical C1-3Alkyl radical, C1-3Alkylthio group C1-3Alkyl radical, C6-10Aryl radical C1-3Alkyl radical, C1-9Heteroaryl group, C6-10Aryl radical, C2-10Heterocyclyl or C3-8A carbocyclic group;
and each n1And n2Independently 1,2,3 or 4.
In some of these embodiments, it has the structure shown in formula (II):
wherein,the structural unit is the following sub-structural formula:
the structural units are the following groups:
each Q1And Q2Independently is a bond, NR6O, S, C (= O) or (CH)2)e；
Q3Is N and CH;
each X1Independently O, S, NR6Or CR7R7a；
Each e is independently 0, 1,2,3, or 4;
each f and f' is independently 0, 1,2,3 or 4
Each X3And X5Independently O, S, NR6C (= O) or CR7R7a；
Each Y is1、Y2、Y1’And Y2’Independently is N or CR7；
Each A and A' is independently a bond, C1-6Alkylene radical, C2-6Alkenylene radical, C3-8Cycloalkylene radical, C2-10Heterocycloalkylene, - (CR)8R8a)n-O-(CR8R8a)p-、-(CR8R8a)n-N(R5)-(CR8R8a)p-、-(CR8R8a)n-S(=O)r-N(R5)-(CR8R8a)p-、-(CR8R8a)n-C(=O)-N(R5)-(CR8R8a)p-、-(CR8R8a)n-N(R5)-C(=O)-N(R5)-(CR8R8a)p-、-(CR8R8a)n-C(=O)-O-(CR8R8a)p-、-(CR8R8a)n-N(R5)-S(=O)r-N(R5)-(CR8R8a)p-、-(CR8R8a)n-S(=O)r-(CR8R8a)p-、-(CR8R8a)n-S(=O)r-O-(CR8R8a)p-、-(CR8R8a)n-C(=O)-(CR8R8a)p-、-(CR8R8a)n-C(=S)-(CR8R8a)p-、-(CR8R8a)n-N(R5)-C(=O)-O-(CR8R8a)pOr each of A and A' is independently the following group:
each R5Independently H, deuterium, hydroxy, C1-6Alkyl radical, C2-6Heteroalkyl group, C3-10Cycloalkyl radical, C2-10Heterocyclic group, C6-10Aryl radical, C1-9Heteroaryl group, C6-10Aryl radical C1-6Alkyl radical, C1-6Alkoxy radical, C1-6alkyl-OC (= O) -, C1-6alkyl-C (= O) -, carbamoyl, C1-6alkyl-OS (= O)r-、C1-6alkyl-S (= O)rO-, alkyl-S (= O)r-or aminosulfonyl;
each R5a、R5a’And R6aIndependently is H, deuterium, oxo (= O), hydroxy, amino, F, Cl, Br, I, cyano, R13aR13N-、-C(=O)NR13R13a、-OC(=O)NR13R13a、-OC(=O)OR13、-N(R13)C(=O)NR13R13a、-N(R13)C(=O)OR13、-N(R13)C(=O)-R13、R13R13aN-S(=O)2-、R13S(=O)2-、R13S(=O)2N(R13a)-、C1-6Alkyl acyl radical, C1-6Alkyl acyloxy, C1-6Alkoxyacyl group, C1-6Alkylsulfonyl radical, C1-6Alkoxysulfonyl group, C1-6Alkylsulfinyl radical, C1-6Alkylsulfonyloxy, C1-6Alkylsulfinyloxy, C1-6Alkoxy radical, C1-6Alkyl radical, C6-10Aryl, -CF3、-OCF3Mercapto, nitro, C1-6Alkylamino radical, C3-10Cycloalkyl or C6-10An aryloxy group;
each R6Independently of each other is hydrogen, deuterium, R13R13aNC(=O)-、R13OC(=O)-、R13C(=O)-、R13R13aNS(=O)-、R13OS(=O)-、R13S(=O)-、R13R13aNS(=O)2-、R13OS(=O)2-、R13S(=O)2-、C1-6Aliphatic, C1-6Alkoxy radical C1-6Aliphatic, C1-6Alkylamino radical C1-6Aliphatic, C6-10Aryl radical C1-6Aliphatic, C1-9Heteroaryl C1-6Aliphatic, C2-10Heterocyclyl radical C1-6Aliphatic, C3-10Cycloalkyl radical C1-6Aliphatic, C6-10Aryl radical, C1-9Heteroaryl group, C2-10Heterocyclyl or C3-10A carbocyclic group; where the aliphatic of the group is an alkyl group, which may be, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, and isobutyl;
each R7And R7aIndependently H, deuterium, F, Cl, Br, I, C1-6Aliphatic, C2-6Heteroalkyl group, C1-6Alkoxy radical C1-6Aliphatic, C1-6Alkylamino radical C1-6Aliphatic, C6-10Aryl radical C1-6Aliphatic, C2-10Heterocyclyl radical C1-6Aliphatic, C3-10Cycloalkyl radical C1-6Aliphatic, C6-10Aryl radical, C1-9Heteroaryl group, C2-10Heterocyclyl or C3-10A carbocyclic group; where the aliphatic of the group is an alkyl group, which may be, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, and isobutyl;
each R8And R8aIndependently is H, deuterium, hydroxy, cyano, nitro, F, Cl, Br, I,C1-6Alkyl radical, C2-6Heteroalkyl group, C3-10Cycloalkyl radical, C2-10Heterocyclic group, C6-10Aryl radical, C1-9Heteroaryl group, C6-10Aryl radical C1-6Alkyl radical, C1-6Alkoxy radical, C1-6alkyl-OC (= O) -, C1-6alkyl-C (= O) -, carbamoyl, C1-6alkyl-OS (= O)r-、C1-6alkyl-S (= O)rO-、C1-6alkyl-S (= O)r-or aminosulfonyl;
each R13And R13aIndependently of one another H, deuterium, C1-6Alkyl radical, C2-6Heteroalkyl group, C3-10Cycloalkyl radical, C2-10Heterocyclic group, C6-10Aryl radical, C1-9Heteroaryl or C6-10Aryl radical C1-6An alkyl group; or when R is13And R13aAttached to the same nitrogen atom, R13、R13aAnd the nitrogen atom optionally form a substituted or unsubstituted 3-8 membered ring, a spiro bicyclic ring or a fused bicyclic ring;
each n is independently 0, 1,2 or 3;
each p is independently 0, 1,2 or 3;
each r is independently 0, 1 or 2;
and each Y4And Y4' independently is a bond, O, S, - (CH)2)n-、-CH=CH-、-S(=O)r-、-CH2O-、-CH2S-、-CH2S(=O)r、-CF2-、-CHR5a、-CR5aR6a-or-CH2N(R6)-。
In still other embodiments, it has a structure as shown in formula (III):
wherein each Q1、Q2、Q4And Q5Independently is NR6O, S, C (= O) or (CR)7R7a)e；
And each of i and e is independently 0, 1,2,3 or 4.
In other embodiments, it has the structure shown in formula (IV):
wherein each Q1、Q2、Q4And Q5Independently O, S, C (= O), NR6Or CH2；
And each of i and e is independently 0, 1,2,3 or 4.
In still other embodiments, it has a structure as shown in formula (V):
wherein each Q1、Q2And Q4Independently O, S, C (= O), NR6Or CH2；
And each of i and e is independently 0, 1,2,3 or 4.
In other embodiments, it has a structure as shown in formula (VI):
wherein each Q1And Q2Independently O, S, C (= O), NR6Or CH2；
i is 0, 1,2,3 or 4;
and W3Is C3-10Carbocyclic radical or C2-10A heterocyclic group.
In still other embodiments, it has the structure shown in formula (VII):
wherein each Q1、Q3、Q4And Q5Independently O, S, C (= O), NR6Or CH2；
And e is 0, 1,2,3 or 4.
In other embodiments, it has the structure shown in formula (VIII):
wherein each Q1、Q3、Q4And Q5Independently O, S, C (= O), NR6Or CH2；
And e is 0, 1,2,3 or 4.
In other embodiments, it has a structure as shown in formula (IX):
wherein each Q1、Q3And Q4Independently O, S, C (= O), NR6Or CH2；
And e is 0, 1,2,3 or 4.
In still other embodiments, it has a structure as shown in formula (X):
wherein each Q1And Q3Independently O, S, C (= O), NR6Or CH2；
And W3Is C3-10Carbocyclic radical or C2-10A heterocyclic group.
In some of these embodiments, wherein Y and Y' are independently an alpha-amino acid group.
In still other embodiments, wherein the α -amino acid group is selected from the group consisting of isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine, alanine, asparagine, aspartic acid, glutamic acid, glutamine, proline, serine, para-tyrosine, arginine, histidine, cysteine, glycine, sarcosine, N-dimethylglycine, homoserine, norvaline, norleucine, ornithine, homocysteine, homophenylalanine, phenylglycine, ortho-tyrosine, meta-tyrosine, or hydroxyproline.
In still other embodiments, wherein the α -amino acid in the α -amino acid group is in the D configuration.
In still other embodiments, wherein the α -amino acid in the α -amino acid group is in the L configuration.
In some of these embodiments, wherein each Y and Y' is independently- [ U- (CR)9R9a)t-N(R10)-(CR9R9a)t]k-U-(CR9R9a)t-N(R11)-(CR9R9a)t-R12、-U-(CR9R9a)t-R12Or- [ U- (CR)9R9a)t-N(R10)-(CR9R9a)t]k-U-(CR9R9a)t-O-(CR9R9a)t-R12。
In still other embodiments, wherein each Y and Y' is independently- [ U- (CR)9R9a)t-N(R10)-(CR9R9a)t]k-U-(CR9R9a)t-N(R11)-(CR9R9a)t-R12。
In still other embodiments, wherein each Y and Y' is independently-U- (CR)9R9a)t-N(R10)-(CR9R9a)t-U-(CR9R9a)t-N(R11)-(CR9R9a)t-R12。
In still other embodiments, wherein each Y and Y' is independently-U- (CR)9R9a)t-N(R11)-(CR9R9a)t-R12。
In still other embodiments, wherein each Y and Y' is independently- [ C (= O) - (CR)9R9a)t-N(R10)-(CR9R9a)t]k-U-(CR9R9a)t-N(R11)-(CR9R9a)t-R12。
In still other embodiments, wherein each Y and Y' is independently-C (= O) - (CR)9R9a)t-N(R10)-(CR9R9a)t-U-(CR9R9a)t-N(R11)-(CR9R9a)t-R12。
In still other embodiments, wherein each Y and Y' is independently- [ C (= O) - (CR)9R9a)t-N(R10)-(CR9R9a)t]k-C(=O)-(CR9R9a)t-N(R11)-(CR9R9a)t-R12。
In still other embodiments, wherein each Y and Y' is independently-C (= O) - (CR)9R9a)t-N(R10)-(CR9R9a)t-C(=O)-(CR9R9a)t-N(R11)-(CR9R9a)t-R12。
In still other embodiments, wherein each Y and Y' is independently-C (= O) - (CR)9R9a)t-N(R11)-(CR9R9a)t-R12。
In still other embodiments, wherein each Y and Y' is independently-C (= O) - (CR)9R9a)t-N(R11)-(CR9R9a)t-C(=O)-R13。
In still other embodiments, wherein each Y and Y' is independently-C (= O) - (CR)9R9a)t-N(R11)-C(=O)-R13。
In still other embodiments, wherein each Y and Y' is independently-C (= O) - (CR)9R9a)t-N(R11)-(CR9R9a)t-C(=O)-O-R13。
In still other embodiments, wherein each Y and Y' is independently-C (= O) - (CR)9R9a)t-N(R11)-C(=O)-O-R13。
In still other embodiments, wherein each Y and Y' is independently-U- (CR)9R9a)t-R12。
In still other embodiments, wherein each Y and Y' is independently-C (= O) - (CR)9R9a)t-R12。
In still other embodiments, wherein each Y and Y' is independently- [ U- (CR)9R9a)t-N(R10)-(CR9R9a)t]k-U-(CR9R9a)t-O-(CR9R9a)t-R12。
In still other embodiments, wherein each Y and Y' is independently-U- (CR)9R9a)t-N(R10)-(CR9R9a)t-U-(CR9R9a)t-O-(CR9R9a)t-R12。
In still other embodiments, wherein each Y and Y' is independently-C (= O) - (CR)9R9a)t-N(R10)-(CR9R9a)t-C(=O)-(CR9R9a)t-O-(CR9R9a)t-R12。
In still other embodiments, wherein each Y and Y' is independently-U- (CR)9R9a)t-O-(CR9R9a)t-R12。
In still other embodiments, wherein each Y and Y' is independently-C (= O) - (CR)9R9a)t-O-(CR9R9a)t-R12。
In still other embodiments, wherein each Y and Y' is independently-C (= O) - (CR)9R9a)t-N(R11)-R12Wherein R is11、R12And the atoms to which they are attached may form a 4-7 membered ring.
In still other embodiments, wherein each R is9、R9a、R10And R11Independently of one another H, deuterium, C1-6Alkyl radical, C2-6Heteroalkyl group, C3-10Cycloalkyl radical, C2-10Heterocyclic group, C6-10Aryl radical, C1-9Heteroaryl radical、C6-10Aryl radical C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-9Heteroaryl C1-6Alkyl radical, C2-10Heterocyclyl radical C1-6Alkyl or C3-8Cycloalkyl radical C1-6An alkyl group;
each R12Independently is R13aR13N-、-C(=O)R13、-C(=S)R13、-C(=O)-O-R13、-C(=O)NR13R13a、-OC(=O)NR13R13a、-OC(=O)OR13、-N(R13)C(=O)NR13R13a、-N(R13)C(=O)OR13a、-N(R13)C(=O)-R13a、R13R13aN-S(=O)2-、R13S(=O)2-、R13S(=O)2N(R13a)-、R13OS(=O)2-、C1-6Alkyl radical, C2-6Heteroalkyl group, C3-10Cycloalkyl radical, C2-10Heterocyclic group, C6-10Aryl radical, C1-9Heteroaryl or C6-10Aryl radical C1-6An alkyl group;
or R11、R12And the atoms to which they are attached may form a 4-7 membered ring;
each R13And R13aIndependently of one another H, deuterium, C1-6Alkyl radical, C2-6Heteroalkyl group, C3-10Cycloalkyl radical, C2-10Heterocyclic group, C6-10Aryl radical, C1-9Heteroaryl or C6-10Aryl radical C1-6An alkyl group; or when R is13And R13aAttached to the same nitrogen atom, R13、R13aAnd the nitrogen atom optionally form a substituted or unsubstituted 3-8 membered ring, a spiro bicyclic ring or a fused bicyclic ring.
In still other embodiments, wherein,
each R9、R9a、R10And R11Independently H, deuterium, methyl, ethyl, isopropyl, cyclohexyl, isobutyl or phenyl;
each R12Independently is-C (= O) R13、-C(=O)-O-R13、-C(=O)NR13R13aMethyl, ethyl, propyl, phenyl, cyclohexyl, morpholinyl or piperidinyl;
or R11、R12And the atoms to which they are attached may form a 4-7 membered ring;
and each R13And R13aIndependently H, deuterium, methyl, ethyl, propyl, phenyl, cyclohexyl, morpholinyl or piperidinyl.
In still other embodiments, it has a structure as shown in formula (XI):
wherein each R is14And R14aIndependently of one another H, deuterium, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C2-6Heteroalkyl group, C6-10Aryl radical, C1-9Heteroaryl group, C2-10Heterocyclic group, C3-8Cycloalkyl radical, C6-10Aryl radical C1-6Alkyl radical, C1-9Heteroaryl C1-6Alkyl radical, C2-10Heterocyclyl radical C1-6Alkyl or C3-8Cycloalkyl radical C1-6An alkyl group.
In still other embodiments, it has the structure shown in formula (XII):
wherein each R is14And R14aIndependently of one another H, deuterium, C1-3Hydroxyalkyl, methyl, ethyl, isopropyl, isobutyl, tert-butyl, allyl, propargyl, trifluoroethyl, phenyl, pyranyl, morpholinyl, benzyl, piperazinyl, cyclopentyl,cyclopropyl, cyclohexyl or C1-9A heteroaryl group.
In some of these embodiments, it has the structure shown in formula (XIII):
wherein each R is14And R14aIndependently of one another H, deuterium, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C2-6Heteroalkyl group, C6-10Aryl radical, C1-9Heteroaryl group, C2-10Heterocyclic group, C3-8Cycloalkyl radical, C6-10Aryl radical C1-6Alkyl radical, C1-9Heteroaryl C1-6Alkyl radical, C2-10Heterocyclyl radical C1-6Alkyl or C3-8Cycloalkyl radical C1-6An alkyl group;
and each n2Independently 1,2,3 or 4.
In some of these embodiments, it has the structure shown in formula (IX'):
wherein each R is14And R14aIndependently of one another H, deuterium, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C2-6Heteroalkyl group, C6-10Aryl radical, C1-9Heteroaryl group, C2-10Heterocyclic group, C3-8Cycloalkyl radical, C6-10Aryl radical C1-6Alkyl radical, C1-9Heteroaryl C1-6Alkyl radical, C2-10Heterocyclyl radical C1-6Alkyl or C3-8Cycloalkyl radical C1-6An alkyl group;
and each n1Independently 1,2,3 or 4.
In some of these embodiments, it has a compound of formula (X') (shown below)
Wherein each Q1And Q2Independently O, S, C (= O), NR6Or CH2；
Each R5aAnd R5a’Independently of one another H, deuterium, C1-4Alkyl, oxo (= O), benzyl, F, Cl, Br, or I;
each R6And R7Independently of one another H, deuterium, C1-4Alkyl radical, C6-10Aryl radical, C2-10Heterocyclyl or C3-8A cycloalkyl group;
each R14And R14aIndependently of one another H, deuterium, C1-4Alkyl radical, C6-10Aryl radical, C2-10Heterocyclyl or C3-8A cycloalkyl group;
each R16And R16aIndependently is hydroxy, C1-4Alkyloxy, C6-10Aryloxy radical, C2-10Heterocyclyl or C3-8A cycloalkyl group;
whereinThe structural unit is the following sub-structural formula:
wherein Bn is benzyl;
the structural unit is the following group:
and each of A and A' is independently the following group:
wherein R is1、R2And N-CH are independently selected from the group consisting of the following substructures:
wherein R is3、R4And N-CH are independently selected from the group consisting of the following substructures:
in other embodiments, wherein
Each R5aAnd R5a’Independently H, deuterium, methyl, ethyl, oxo (= O), benzyl, F, Cl, Br or I;
each R6And R7Independently H, deuterium, methyl, ethyl, isopropylPhenyl or cyclohexyl;
each R14And R14aIndependently methyl, ethyl, phenyl, cyclohexyl, 1-methylpropyl, isopropyl, isobutyl or tert-butyl;
each R16And R16aIndependently is hydroxy, methoxy, ethoxy, phenoxy,Or tert-butoxy;
wherein said methyl, ethyl, phenyl, cyclohexyl, 1-methylpropyl, isopropyl, isobutyl, methoxy, ethoxy, phenoxy, benzyl, tert-butoxy or tert-butyl may be optionally substituted with one or more substituents selected from deuterium, F, Cl, Br, hydroxy, cyano.
In some of these embodiments, it has a compound of formula (XI `)
Wherein each Q1、Q2、Q4And Q5Independently O, S, C (= O), NR6Or CH2；
Each f and f' is independently 0, 1,2,3, or 4;
each i and e is independently 0, 1,2,3 or 4;
each R5aAnd R5a’Independently H, deuterium, methyl, ethyl, oxo (= O), benzyl, F, Cl, Br or I;
each Y is1、Y2、Y1’And Y2’Independently is N or CR7；
X1Is O, S, NR6C (= O) or CR7R7a；
Each R6、R7And R7aIndependently hydrogen, deuterium, methyl, ethyl, isopropyl, phenyl or cyclohexyl;
each R14And R14aIndependently methyl, ethyl, phenyl, cyclohexyl, 1-methylpropyl, isobutyl, isopropyl or tert-butyl;
each R16And R16aIndependently is hydroxy, methoxy, ethoxy, phenoxy,Or tert-butoxy;
wherein said methyl, ethyl, phenyl, cyclohexyl, 1-methylpropyl, isopropyl, isobutyl, methoxy, ethoxy, benzyl, tert-butoxy or tert-butyl may be optionally substituted with one or more substituents selected from deuterium, F, Cl, Br, hydroxy, cyano;
and each of A and A' is independently the following group:
wherein R is1、R2And N-CH are independently selected from the group consisting of the following substructures:
wherein R is3、R4And N-CH are independently selected from the group consisting of the following substructures:
in some of these embodiments, it has a compound according to formula (XII'):
wherein each Q1、Q2、Q4And Q5Independently O, S, C (= O), NR6Or CH2；
Each X1Independently O, S, NR6C (= O) or CR7R7a；
Each R6、R7And R7aIndependently hydrogen, deuterium, methyl, ethyl, isopropyl, phenyl or cyclohexyl;
each R5aAnd R5a’Independently H, deuterium, methyl, ethyl, oxo (= O), benzyl, F, Cl, Br or I;
each Y is1、Y2、Y1’And Y2’Independently is N or CR7；
Each f and f' is independently 0, 1,2,3, or 4;
each i and e is independently 0, 1,2,3 or 4;
each R14And R14aIndependently methyl, ethyl, phenyl, cyclohexyl, 1-methylpropyl, isopropyl, isobutyl or tert-butyl;
each R16And R16aIndependently is hydroxy, methoxy, ethoxy, phenoxy,Or tert-butoxy;
wherein said methyl, ethyl, phenyl, cyclohexyl, 1-methylpropyl, isopropyl, isobutyl, methoxy, ethoxy, phenoxy, benzyl, tert-butoxy or tert-butyl may be optionally substituted with one or more substituents selected from deuterium, F, Cl, Br, hydroxy, cyano;
and each of A and A' is independently the following group:
wherein R is1、R2And N-CH are independently selected from the group consisting of the following substructures:
wherein R is3、R4And N-CH are independently selected from the group consisting of the following substructures:
in some of these embodiments, it has a compound according to formula (XIII'):
wherein each Q1、Q2And Q4Independently O, S, C (= O), NR6Or CH2；
X3Is O, S, NR6C (= O) or CR7R7a；
Each R6、R7And R7aIndependently hydrogen, deuterium, methyl, ethyl, isopropyl, phenyl or cyclohexyl;
each R5aAnd R5a’Independently H, deuterium, methyl, ethyl, oxo (= O), benzyl, F, Cl, Br or I;
each Y is1、Y2、Y1’And Y2’Independently is N or CR7；
Each f and f' is independently 0, 1,2,3, or 4;
each i and e is independently 0, 1,2,3 or 4;
each R14And R14aIndependently methyl, ethyl, phenyl, cyclohexyl, 1-methylpropyl, isopropyl, isobutyl or tert-butyl;
each R16And R16aIndependently is hydroxy, methoxy, ethoxy, phenoxy,Or tert-butoxy;
wherein said methyl, ethyl, phenyl, cyclohexyl, 1-methylpropyl, isopropyl, isobutyl, methoxy, ethoxy, benzyl, tert-butoxy or tert-butyl may be optionally substituted with one or more substituents selected from deuterium, F, Cl, Br, hydroxy, cyano;
and each of A and A' is independently the following group:
wherein R is1、R2And N-CH independently form a heterocyclic ring orThe fused or spiro ring system is selected from the following sub-structures:
wherein R is3、R4And N-CH are independently selected from the group consisting of the following substructures:
in another aspect, the present invention provides a pharmaceutical composition comprising any one of the compounds described above.
In some embodiments, the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or combination thereof.
In some of these embodiments, it further comprises other anti-HCV agents.
In still other embodiments, wherein the anti-HCV agent is an interferon, ribavirin, interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, an interfering RNA, an antisense RNA, imiqimod, an inosine 5' -monophospate dehydrogenase inhibitor, amantadine, rimantadine, baviximab, CivacirTMBoceprevir (boceprevir), telaprevir (telaprevir), erlotinib (erlotinib), daclatasvir, simeprevir, asunaprevir, vanieprevir, faldaprevir, ABT-450, danoprevir, sovaprevir, MK-5172, vedroprevier, BZF-961, GS-9256, narloprevir, ANA975, ABT-267, EDP239, PPI-2013335, GS-5816, samatasvir (IDX-719), MK-8742, MK-8325, GSK-2336805, PPI-176461, TMC-435, MK-7009, BI-2013335, ciloprevir, BMS-162 650032, ACH-1095, VX-985, VX-375, PHX-500, PHX-813, VX-813, PHX-813-2054. IDX-136, IDX-316, EP-013420, VBY-376, TMC-649128, R-7128, PSI-7977, INX-189, IDX-184, IDX102, R1479, UNX-08189, PSI-6130, PSI-938, PSI-879, HCV-796, HCV-371, VCH-916, VCH-222, ANA-598, MK-3281, ABT-333, ABT-072, PF-00868554, BI-207127, GS-9190, A-837093, JKT-109, Gl-59728, GL-60667, AZD-2795, TMC647055, or a combination thereof.
In still other embodiments, wherein the interferon is interferon alpha-2 b, pegylated interferon alpha, interferon alpha-2 a, pegylated interferon alpha-2 a, consensus interferon, interferon gamma, or a combination thereof.
In some of these embodiments, it further comprises at least one HCV inhibitor for at least one of inhibiting HCV replication processes and inhibiting HCV viral protein function; the HCV replication process is selected from the complete viral cycle of HCV entry, uncoating, translation, replication, assembly, release. The HCV viral proteins are selected from the group consisting of metalloprotease, NS2, NS3, NS4A, NS4B, NS5A, and NS 5B; as well as the Internal Ribosome Entry Site (IRES) and inosine monophosphate dehydrogenase (IMPDH) required for HCV viral replication.
In another aspect, the compounds or pharmaceutical compositions described herein are useful for at least one of inhibiting the HCV replication process and inhibiting HCV viral protein function; the HCV replication process is selected from the complete viral cycle of HCV entry, uncoating, translation, replication, assembly, release. The HCV viral proteins are selected from the group consisting of metalloprotease, NS2, NS3, NS4A, NS4B, NS5A, and NS 5B; as well as the Internal Ribosome Entry Site (IRES) and inosine monophosphate dehydrogenase (IMPDH) required for HCV viral replication.
In another aspect, the invention relates to the use of a compound or pharmaceutical composition of the invention for the manufacture of a medicament for the prevention, treatment or amelioration of a hepatitis C disease in a patient, comprising administering to the patient an effective amount of a compound according to the invention or a pharmaceutical composition according to the invention.
Another aspect of the present invention relates to a process for the preparation, isolation and purification of compounds encompassed by formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (IX '), (X '), (XI '), (XII ') or (XIII ').
The foregoing merely summarizes certain aspects of the invention and is not intended to be limiting. These and other aspects will be more fully described below.
Detailed description of the invention
Definitions and general terms
The invention will be described in detail in the literature corresponding to the identified embodiments, and the examples are accompanied by the graphic illustrations of structural formulae and chemical formulae. The invention is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein which can be used in the practice of the present invention. The present invention is in no way limited to the description of methods and materials. There are many documents and similar materials that may be used to distinguish or contradict the present application, including, but in no way limited to, the definition of a term, the usage of a term, the technology described, or the scope as controlled by the present application.
The following definitions shall apply unless otherwise indicated. For the purposes of the present invention, the chemical elements are according to the periodic Table of the elements, CAS version and handbook of chemistry and Physics, 75thEd., 1994. In addition, the general principles of Organic Chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltio, 1999, and "March's Advanced Organic Chemistry", Michael B&Sons, New York,2007, all of which are incorporated herein by reference.
As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, as in the compounds of the general formula above, or as practicedThe specific examples, subclasses, and classes of compounds encompassed by the invention are provided herein. It is understood that the term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted". In general, the term "optionally," whether preceded by the term "substituted," indicates that one or more hydrogen atoms in a given structure are replaced with a particular substituent. Unless otherwise indicated, an optional substituent group may have one substituent substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, identically or differently. Wherein the substituent may be, but is not limited to, deuterium, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, heteroaryloxy, oxo (= O), carboxyl, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C (= O) -, alkyl-S (= O) -)2-, hydroxy-substituted alkyl-S (= O)2-, carboxy-substituted alkoxy, and the like.
The term "aliphatic" or "aliphatic group" as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon group that is fully saturated or that contains one or more degrees of unsaturation. Unless otherwise specified, an aliphatic group contains 1 to 20 carbon atoms, some embodiments being an aliphatic group containing 1 to 10 carbon atoms, other embodiments being an aliphatic group containing 1 to 8 carbon atoms, other embodiments being an aliphatic group containing 1 to 6 carbon atoms, other embodiments being an aliphatic group containing 1 to 4 carbon atoms, and other embodiments being an aliphatic group containing 1 to 3 carbon atoms. Suitable aliphatic groups include, but are not limited to, straight or branched, substituted or unsubstituted alkyl, alkenyl, or alkynyl groups, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, hexyl, isobutyl, sec-butyl, vinyl, and the like.
The term "haloaliphatic" means that the aliphatic group is substituted with one or more of the same or different halogen atoms, wherein the aliphatic group has the meaning described herein, i.e., fluorine, chlorine, bromine, or iodine, examples of which include, but are not limited to, trifluoromethyl, trifluoroethyl, chloromethyl, 2-chloroethenyl, and the like.
The term "hydroxyalkyi" means an aliphatic group substituted with one or more hydroxyl groups, wherein the aliphatic group has the meaning as described herein, examples of which include, but are not limited to, hydroxyethyl, 2-hydroxypropyl, hydroxymethyl, and the like.
The term "aminoaliphatic" means that an aliphatic group is substituted with one or more amino groups, wherein aliphatic group has the meaning as described herein, examples of which include, but are not limited to, aminomethyl, 2-aminoethyl, 2-aminoisopropyl, and the like.
The term "alkyl" denotes a saturated straight or branched chain monovalent hydrocarbon radical of 1 to 20 carbon atoms, or 1 to 10 carbon atoms, or 1 to 8 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms, wherein the alkyl radical may be independently and optionally substituted with one or more substituents described herein. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH)3) Ethyl (Et-CH)2CH3) N-propyl (n-Pr, -CH)2CH2CH3) Isopropyl (i-Pr, -CH (CH)3)2) N-butyl (n-Bu, -CH)2CH2CH2CH3) Isobutyl (i-Bu, -CH)2CH(CH3)2) Sec-butyl (s-Bu, -CH (CH)3)CH2CH3) T-butyl (t-Bu, -C (CH)3)3) N-pentyl (-CH)2CH2CH2CH2CH3) 2-pentyl (-CH (CH)3)CH2CH2CH3) 3-pentyl (-CH (CH)2CH3)2) 2-methyl-2-butyl (-C (CH)3)2CH2CH3) 3-methyl-2-butyl (-CH (CH)3)CH(CH3)2) 3-methyl-1-butyl (-CH)2CH2CH(CH3)2) 2-methyl-1-butyl (-CH)2CH(CH3)CH2CH3) N-hexyl (-CH)2CH2CH2CH2CH2CH3) 2-hexyl (-CH (CH)3)CH2CH2CH2CH3) 3-hexyl (-CH (CH)2CH3)(CH2CH2CH3) 2-methyl-2-pentyl (-C (CH))3)2CH2CH2CH3) 3-methyl-2-pentyl (-CH (CH)3)CH(CH3)CH2CH3) 4-methyl-2-pentyl (-CH (CH)3)CH2CH(CH3)2) 3-methyl-3-pentyl (-C (CH)3)(CH2CH3)2) 2-methyl-3-pentyl (-CH (CH)2CH3)CH(CH3)2) 2, 3-dimethyl-2-butyl (-C (CH)3)2CH(CH3)2) 3, 3-dimethyl-2-butyl (-CH (CH)3)C(CH3)3) N-heptyl, n-octyl, and the like. The term "alkyl" and its prefix "alkane" as used herein, both include straight and branched saturated carbon chains. The term "alkylene" is used herein to denote a saturated divalent hydrocarbon radical resulting from the elimination of two hydrogen atoms from a straight or branched chain saturated hydrocarbon, examples of which include, but are not limited to, methylene, ethylene, isopropylene, and the like.
The term "alkenyl" denotes a straight or branched monovalent hydrocarbon radical of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, at least one position of which is unsaturated, i.e. one C-C is sp2Double bonds, wherein an alkenyl group may be independently and optionally substituted with one or more substituents described herein, including where the group is "trans", "cis" or "E", "Z", and wherein specific examples of alkenyl include, but are not limited to, vinyl (-CH = CH)2) Allyl (-CH)2CH=CH2) And so on.
The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon radical of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, at least one position of which is unsaturated, i.e., one C-C is a sp triple bond, wherein the alkynyl radical may be independently and optionally substituted with one or more substituents as described herein, wherein specific examples of alkynyl include, but are not limited to, ethynyl (-C.ident.CH), propargyl (-CH)2C ≡ CH), and the like.
The term "hydroxy-substituted alkyl" means that the alkyl group is substituted with one or more hydroxy groups, wherein the alkyl group has the meaning described herein. Examples include, but are not limited to, hydroxymethyl, hydroxyethyl, 1, 2-dihydroxyethyl, and the like.
The term "haloalkyl" denotes an alkyl group substituted with one or more of the same or different halogen atoms, wherein the alkyl group has the meaning as described herein, i.e., fluorine, chlorine, bromine or iodine, examples of which include, but are not limited to, trifluoromethyl, trifluoroethyl, chloromethyl, fluoromethyl and the like.
The term "hydroxyalkyl" means that an alkyl group is substituted with one or more hydroxyl groups, wherein the alkyl group has the meaning as described herein, examples of which include, but are not limited to, hydroxyethyl, 2-hydroxypropyl, hydroxymethyl, and the like.
The term "aminoalkyl" denotes an alkyl group substituted with one or more amino groups, wherein the alkyl group has the meaning as described herein, examples of which include, but are not limited to, aminomethyl, 2-aminoethyl, 2-aminoisopropyl, and the like.
The term "alkylene" refers to a saturated divalent hydrocarbon radical resulting from the removal of two hydrogen atoms from a straight or branched chain saturated hydrocarbon radical. And the alkylene group may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, deuterium, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkyl, alkenyl, alkynyl, heterocyclic, mercapto, nitro, or arylAn oxy group. Examples include, but are not limited to, methylene (-CH)2-) ethylene (-CH2-CH2-) isopropylidene (-CH2-CH(CH3) -), ethane-1, 1-diyl, 2-methoxypropane-1, 1-diyl, 2-hydroxypropane-1, 1-diyl, 2-methyl-2-hydroxypropane-1, 1-diyl, and the like.
The term "alkenylene" denotes an alkenyl group derived from a straight or branched chain alkene by the removal of two hydrogen atoms. And the alkenylene group may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, deuterium, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkyl, alkenyl, alkynyl, heterocyclic, mercapto, nitro, or aryloxy. Examples include, but are not limited to, ethenylene (-CH = CH-), isopropenylene (-C (CH = CH-))3) = CH-), 3-methoxypropene-1, 1-diyl, 2-methylbutene-1, 1-diyl, and the like.
The term "carbocyclylene" ("cycloalkylene") denotes a saturated divalent hydrocarbon ring obtained by removing two hydrogen atoms from a monocyclic ring having 3 to 12 carbon atoms or a bicyclic ring having 7 to 12 carbon atoms, wherein carbocyclyl or cycloalkyl have the meaning as defined in the present invention, and examples thereof include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, 1-cyclopent-1-enylene, 1-cyclopent-2-enylene and the like.
The term "heterocyclylene" denotes a monocyclic, bicyclic or tricyclic ring system wherein one or more atoms in the ring are independently selected from heteroatoms and may be fully saturated or contain one or more unsaturations, but not belonging to the aromatic class, having two points of attachment to the rest of the molecule, wherein the heterocyclyl group has the meaning as described herein. Examples include, but are not limited to, piperidine-1, 4-diyl, piperazine-1, 4-diyl, tetrahydrofuran-2, 4-diyl, tetrahydrofuran-3, 4-diyl, azetidine-1, 3-diyl, pyrrolidine-1, 3-diyl, and the like.
The term "heterocyclylalkyl" denotes a radical of a heterocyclylalkyl radical wherein the two hydrogen atoms are removed and wherein the heterocyclylalkyl radical has the meaning as described herein. Examples include, but are not limited to, morpholin-4-methylmethylene, piperidin-N-methylmethylene, piperazin-4-ethyl-1-yl, piperidin-4-methyl-1-yl, piperidin-4-ethyl-1-yl, pyrrolidin-2-methyl-1-yl, and the like.
The term "haloalkylene" means a haloalkyl moiety having two points of attachment to the rest of the molecule. Wherein alkylene has the meaning as described herein, such examples include, but are not limited to, difluoromethylene (-CF)2-) and the like.
The term "arylene" means that the aryl system has two points of attachment to the rest of the molecule. Wherein the aryl group has the meaning as described herein, examples of which include, but are not limited to, phenylene, p-fluorophenyl, and the like.
The term "aralkylene" means an aralkyl system having two points of attachment to the rest of the molecule, wherein aralkyl has the meaning as described herein. Examples include, but are not limited to, benzylidene, phenylethylene, and the like.
The term "heteroarylene" means that the heteroaryl system has two points of attachment to the rest of the molecule. Wherein heteroaryl groups have the meaning as described herein, such examples include, but are not limited to, pyridylene, pyrrolylene, thiazolyl, imidazolyl, and the like.
The term "heteroarylenealkyl" means a heteroarylalkyl system having two points of attachment to the rest of the molecule, wherein heteroarylalkyl has the meaning as described herein, examples of which include, but are not limited to, pyridine-2-ethylene, thiazole-2-methylene, imidazole-2-ethylene, pyrimidine-2-methylene, and the like.
The term "fused bicyclic group" means a fused bicyclic ring system having two points of attachment to the rest of the molecule, wherein the fused bicyclic group has the meaning as described herein. Examples include, but are not limited to, bicyclo [3.1.0] hexane-3, 6-diyl, and the like.
The term "fused heterobicyclic group" means that the fused heterobicyclic ring system has two points of attachment to the rest of the molecule. Examples include, but are not limited to, 3-azabicyclo [3.1.0] hexane-3, 6-diyl, and the like.
The term "fused bicycloalkyl" means a fused bicycloalkyl group having two points of attachment to the rest of the molecule, wherein the fused bicycloalkyl group has the meaning as described herein.
The term "fused heterobicycloalkylalkyl" means a fused heterobicycloalkyl group having two points of attachment to the rest of the molecule, wherein the fused heterobicycloalkyl group has the meaning as described herein.
The term "spirobicyclic group" means a spirobicyclic ring system having two points of attachment to the rest of the molecule, wherein the spirobicyclic group has the meaning as described herein. Examples include, but are not limited to, 5-spiro [2.4] heptane-5, 7-diyl, spiro [4.4] nonane-2, 7-diyl, and the like.
The term "spiroheterobicyclic group" means a spiroheterobicyclic system having two points of attachment to the rest of the molecule, wherein the spiroheterobicyclic group has the meaning as described herein. Examples of such include, but are not limited to, 5-azaspiro [2.4] heptane-5, 7-diyl, 2-azaspiro [4.4] nonane-2, 7-diyl, and the like.
The term "spirobicycloalkylalkyl" means a spirobicycloalkyl system having two points of attachment to the rest of the molecule, wherein spirobicycloalkyl has the meaning as described herein.
The term "spiroheterobicycloalkyl" means a spiroheterobicycloalkyl system having two points of attachment to the rest of the molecule, where spiroheterobicycloalkyl has the meaning as described herein.
The term "heteroalkyl" means that one or more heteroatoms may be inserted in the alkyl chain, wherein the alkyl group and the heteroatoms have the meaning as described herein. Unless otherwise specified in detailIt is understood that the heteroalkyl group has from 1 to 10 carbon atoms, in other embodiments the heteroalkyl group has from 1 to 8 carbon atoms, in other embodiments the heteroalkyl group has from 1 to 6 carbon atoms, in other embodiments the heteroalkyl group has from 1 to 4 carbon atoms, and in other embodiments the heteroalkyl group has from 1 to 3 carbon atoms. Examples include, but are not limited to, CH3OCH2-、CH3CH2OCH2-、CH3SCH2-、(CH3)2NCH2-、(CH3)2CH2OCH2-、CH3OCH2CH2-、CH3CH2OCH2CH2-and the like.
The terms "cycloaliphatic," "carbocycle," "carbocyclyl," or "cycloalkyl" refer to a mono-or polyvalent, non-aromatic, saturated or partially unsaturated ring containing no heteroatoms, including monocyclic 3 to 12 carbon atoms or bicyclic 7 to 12 carbon atoms. The bicyclic carbocyclic ring having 7 to 12 atoms may be bicyclo [4,5 ]]、[5,5]、[5,6]Or [6,6 ]]The bicyclic carbocyclic ring having 9 or 10 atoms may be bicyclo [5,6 ]]Or [6,6 ]]And (4) preparing the system. Suitable cyclic aliphatic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl. Examples of cycloaliphatic radicals include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like. And the "cycloaliphatic" or "carbocycle", "carbocyclyl", "cycloalkyl" may be substituted or unsubstituted, wherein the substituents may be, but are not limited to, deuterium, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C (= O) -, alkyl-S (= O) -)2-, hydroxy-substituted alkyl-S (= O)2-, carboxy-substituted alkoxy, and the like.
The term "cycloalkyloxy" or "carbocyclyloxy" includes optionally substituted cycloalkyl or carbocyclyl as defined herein, attached to an oxygen atom and linked to the remaining molecules by an oxygen atom, examples of which include, but are not limited to, cyclopropyloxy, cyclopentyloxy, cyclohexyloxy, hydroxy-substituted cyclopropyloxy, and the like.
The term "cycloalkylamino" denotes an amino group substituted with one or two optionally substituted cycloalkyl groups, wherein cycloalkyl has the meaning as described herein, examples of which include, but are not limited to, cyclopropylamino, cyclopentylamino, cyclohexylamino, hydroxy-substituted cyclopropylamino, dicyclohexylamino, dicyclopropylamino and the like.
The term "carbocyclyloxyalkoxy" means that the alkoxy group is substituted with one or more carbocyclyloxy groups wherein the alkoxy and carbocyclyloxy groups have the meaning as described herein, examples of which include, but are not limited to, cyclopropyloxymethoxy, cyclopropyloxyethoxy, cyclopentyloxyethoxy, cyclohexyloxyethoxy, cyclohexenyl-3-oxyethoxy, and the like.
The term "cycloalkyloxyaliphatyl" denotes an aliphatic group substituted with one or more optionally substituted cycloalkyloxy groups, wherein the aliphatic and cycloalkyloxy groups have the meaning as described herein, examples of which include, but are not limited to, cyclopropyloxymethyl, cyclopropyloxyethyl, cyclopentyloxymethyl, cyclopentyloxyethyl, cyclohexyloxyethyl, halocyclopropyloxyethyl, and the like.
The term "cycloalkylaminoaliphatic" means that the aliphatic group is substituted with one or more optionally substituted cycloalkylamino groups, wherein the aliphatic and cycloalkylamino groups have the meaning as described herein, examples of which include, but are not limited to, cyclopropylaminomethyl, cyclopropylaminoethyl, cyclopentylaminomethyl, cyclopentylaminoethyl, cyclohexylaminoethyl, halocyclopropylaminoethyl, and the like.
The term "cycloalkylaliphatic" means that an aliphatic group can be substituted with one or more cycloalkyl groups, where cycloalkyl and aliphatic have the meaning as described herein, and such examples include, but are not limited to, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclopentylmethyl, cyclohexylethyl, and the like.
The term "cycloalkylalkoxy" ("carbocyclylalkoxy") means that the alkoxy group is substituted with one or more cycloalkyl ("carbocyclyl") groups, wherein the cycloalkyl ("carbocyclyl") groups and alkoxy groups have the meaning as described herein, examples of which include, but are not limited to, cyclopropylmethoxy, cyclopropylethoxy, cyclopentylethoxy, cyclohexylethoxy, cyclohexylmethoxy, cyclopropylpropoxy, and the like.
The terms "heterocycle", "heterocyclyl", "heteroalicyclic" or "heterocyclic" are used interchangeably herein and all refer to a monocyclic, bicyclic or tricyclic ring system in which one or more carbon atoms in the ring are independently and optionally substituted with a heteroatom having the meaning described herein, which ring may be fully saturated or contain one or more unsaturations, but is by no means aromatic, having only one point of attachment to another molecule. One or more of the ring hydrogen atoms are independently and optionally substituted with one or more substituents as described herein. Some of these embodiments are "heterocycle", "heterocyclyl", "heteroalicyclic" or "heterocyclic" groups are monocyclic (1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S) having 3-7 members rings, where S or P is optionally substituted with one or more oxygen atoms to yield, for example, SO2、PO、PO2When the ring is a three-membered ring, wherein there is only one heteroatom), or a 7-to 10-membered bicyclic ring (4-9 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted with one or more oxygen atomsTo obtain, for example, SO2、PO、PO2The group of (1).
The heterocyclic group may be a carbon-based or heteroatom group. "Heterocyclyl" also includes heterocyclic groups fused to saturated or partially unsaturated rings or heterocycles. Examples of heterocycles include, but are not limited to, pyrrolidinyl, tetrahydrofuryl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thiaxalkyl, thiazolidinyl, oxazolidinyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, epoxypropyl, azepanyl, oxepayl, thiepanyl, 4-methoxy-piperidin-1-yl, 1,2,3, 6-tetrahydropyridin-1-yl, oxaza-1-yl, oxa-pyridyl, thiaRadical diazaRadical, sulfur nitrogen heteroA group, pyrrolin-1-yl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1, 3-dioxolanyl, pyrazolinyl, dithianyl, dithienoalkyl, dihydrothienyl, pyrazolidinoimidazolinyl, imidazolidinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 1,2, 6-thiadiazinane 1, 1-dioxo-2-yl, 4-hydroxy-1, 4-azaphosphane 4-oxide-1-yl, 2-hydroxy-1- (piperazin-1-yl) ethanone-4-yl, 2-hydroxy-1- (5, 6-dihydro-1, 2, 4-triazin-1 (4H) -yl) ethanon-4-yl, 5, 6-dihydro-4H-1, 2, 4-oxadiazin-4-yl, 2-hydroxy-1- (5, 6-dihydropyridin-1 (2H) -yl) ethanon-4-yl, 3-azabicyclo [3.1.0]Hexyl, 3-azabicyclo [4.1.0]Heptyl, azabicyclo [2.2.2]Hexyl, 2-methyl-5, 6,7, 8-tetrahydro- [1,2, 4]]Triazole [1,5-c ]]Pyrimidin-6-yl, 4,5,6, 7-tetrahydroisoxazole [4,3-c]Pyridin-5-yl, 3H-indolyl 2-oxo-5-azabicyclo [2.2.1]Heptane-5-yl, 2-oxo-5-azabicyclo [2.2.2 ]]Octane-5-yl, quinolizinyl and N-pyridylureasAnd (4) element. Examples of heterocyclic groups also include 1, 1-dioxothiomorpholinyl and wherein two carbon atoms of the ring are replaced by oxygen atoms such as pyrimidinedione. And the heterocyclic group may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, deuterium, oxo (= O), hydroxyl, amino, halogen, cyano, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclic group, mercapto, nitro, aryloxy, hydroxyl-substituted alkoxy, hydroxyl-substituted alkyl-C (= O) -, alkyl-S (= O) -)2-, hydroxy-substituted alkyl-S (= O)2-, carboxy-substituted alkoxy, and the like.
The term "heterocyclylalkyl" includes heterocyclyl-substituted alkyl groups; the term "heterocyclylalkoxy" includes heterocyclyl-substituted alkoxy groups in which an oxygen atom is attached to the remainder of the molecule; the term "heterocyclylalkylamino" includes heterocyclyl-substituted alkylamino groups in which the nitrogen atom is attached to the remainder of the molecule. Wherein heterocyclyl, alkyl, alkoxy and alkylamino have the meanings as described herein, and such examples include, but are not limited to, pyrrol-2-ylmethyl, morpholin-4-ylethyl, morpholin-4-ylethoxy, piperazin-4-ylethoxy, piperidin-4-ylethylamino and the like.
The term "heterocyclylaliphatic" means a heterocyclyl-substituted aliphatic group wherein heterocyclyl and aliphatic have the meaning as described herein, examples of which include, but are not limited to, pyrrole-2-methyl, piperidine-2-ethyl, piperazine-2-ethyl, piperidine-2-methyl, and the like.
The term "heterocyclyloxy" includes optionally substituted heterocyclyl groups, as defined herein, attached to an oxygen atom, wherein the oxygen atom is attached to the rest of the molecule, examples of which include, but are not limited to, pyrrole-2-oxy, pyrrole-3-oxy, piperidine-2-oxy, piperidine-3-oxy, piperazine-2-oxy, piperidine-4-oxy, and the like.
The term "heterocyclylamino" means that the amino group is substituted with one or two heterocyclyl groups in which the nitrogen atom is attached to the rest of the molecule and the heterocyclyl group has the meaning described herein, examples of which include, but are not limited to, pyrrole-2-amino, pyrrole-3-amino, piperidine-2-amino, piperidine-3-amino, piperidine-4-amino, piperazine-2-amino, dipyrrole-2-amino, and the like.
The term "heterocyclyloxyalkoxy" means that the alkoxy group is substituted with one or more heterocyclyloxy groups, where the alkoxy and heterocyclyloxy groups have the meaning as described herein, and examples include, but are not limited to, pyrrole-2-oxymethoxy, pyrrole-3-oxyethoxy, piperidine-2-oxyethoxy, piperidine-3-oxyethoxy, piperazine-2-oxymethoxy, piperidine-4-oxyethoxy, and the like.
The term "heterocyclyloxyaliphatic" means that the aliphatic group is substituted with one or more heterocyclyloxy groups, where the aliphatic and heterocyclyloxy groups have the meaning described herein, and examples include, but are not limited to, pyrrole-2-oxymethyl, piperazine-3-oxyethyl, piperazine-2-oxyethyl, morpholine-2-oxymethyl, piperidine-2-oxyethyl, and the like.
The term "heterocyclylaminoaliphatic" means that the aliphatic group is substituted with one or more heterocyclylamino groups, wherein the aliphatic and heterocyclylamino groups have the meaning described herein, and examples include, but are not limited to, pyrrole-2-aminomethyl, piperazine-3-aminoethyl, piperazine-2-aminoethyl, piperidine-2-aminoethyl, morpholine-2-aminomethyl, and the like.
The term "heteroatom" means one or more of O, S, N, P and Si atoms, including N, S and any oxidation state form of P; primary, secondary, tertiary amines and quaternary ammonium salt forms; or a form in which a hydrogen on a nitrogen atom in the heterocycle is substituted, e.g., N (e.g., N in 3, 4-dihydro-2H-pyrrolyl), NH (e.g., NH in pyrrolidinyl), or NR (e.g., NR in N-substituted pyrrolidinyl).
The term "halogen" refers to F, Cl, Br or I.
The term "unsaturated" as used in the present invention means that the moiety contains one or more degrees of unsaturation.
The term "alkoxy", as used herein, relates to an alkyl group, as defined herein, attached to the main carbon chain through an oxygen atom, examples of which include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, and the like. And the alkoxy group may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, deuterium, hydroxyl, amino, halogen, cyano, alkoxy, alkyl, alkenyl, alkynyl, mercapto, nitro, and the like.
The term "hydroxy-substituted alkoxy" denotes an alkoxy group substituted with one or more hydroxy groups, wherein alkoxy has the meaning as described herein, examples of which include, but are not limited to, hydroxymethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxyisopropyl, etc.
The term "aminoalkoxy" means that an alkoxy group is substituted with one or more amino groups, wherein alkoxy has the meaning described herein, examples of which include, but are not limited to, aminomethoxy, 2-aminoethoxy, 2-aminopropoxy, 2-aminoisopropoxy, and the like.
The term "azidoalkoxy" means an alkoxy group substituted with one or more azido groups, wherein alkoxy has the meaning as described herein, examples of which include, but are not limited to, 2-azidoethoxy, 3-azidopropoxy, 2-azidopropoxy, and the like.
The term "alkoxyalkoxy" means an alkoxy group substituted with one or more alkoxy groups having the meaning described herein, examples of which include, but are not limited to, methoxymethoxy, methoxyethoxy, ethoxymethoxy, ethoxyethoxy, ethoxypropoxy, and the like.
The term "alkoxyaliphatic" means that the aliphatic group is substituted with one or more alkoxy groups, wherein the aliphatic and alkoxy groups have the meaning as described herein, examples of which include, but are not limited to, methoxymethyl, ethoxymethyl, ethoxyethyl, ethoxypropenyl, and the like.
The term "alkylaminoaliphatic" means that an aliphatic group is substituted with one or more alkylamino groups, wherein aliphatic and alkylamino groups have the meaning as described herein, and examples include, but are not limited to, dimethylaminoethyl, methylaminoethyl, diethylaminomethyl, diethylaminoethyl, and the like.
The term "alkylthioaliphatic" means that the aliphatic group is substituted with one or more alkylthio groups, wherein the aliphatic and alkylthio groups have the meaning as described herein, examples of which include, but are not limited to, methylthioethyl, methylthiopropyl, ethylthioethyl, methylthiopropenyl, and the like.
The terms "haloalkyl", "haloalkenyl" and "haloalkoxy" denote the case where an alkyl, alkenyl or alkoxy group may be substituted with one or more halogen atoms, examples of which include, but are not limited to, trifluoromethyl, 2-chloro-vinyl, trifluoromethoxy, and the like.
The term "aryl" may be used alone or as a majority of "aralkyl", "aralkoxy", or "aryloxyalkyl", and refers to monocyclic, bicyclic, and tricyclic carbon ring systems containing a total of 6-14 ring members, wherein at least one ring system is aromatic, wherein each ring system contains 3-7 ring members and only one attachment point is attached to the rest of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring", e.g., aromatic rings may include phenyl, naphthyl and anthracenyl. And the aryl group may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, deuterium, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclic, mercapto, nitro, aryloxy, hydroxyl-substituted alkoxy, hydroxyl-substituted alkyl-C (= O) -, alkyl-S (= O) -, alkyl-S (= O)2-, hydroxy-substituted alkyl-S (= O)2-, carboxy-substituted alkoxy, and the like.
The term "arylaliphatic" means that an aliphatic group is substituted with one or more optionally substituted aryl groups, wherein aliphatic and aryl groups have the meaning described herein, examples of which include, but are not limited to, phenylethyl, benzyl, p-tolylethyl, styryl, and the like.
The term "aryloxy" includes optionally substituted aryl groups, as defined herein, attached to an oxygen atom and linked to the rest of the molecule by an oxygen atom, wherein the aryl group has the meaning described herein, examples of which include, but are not limited to, phenoxy, tolyloxy, ethylbenzene oxy, and the like.
The term "arylamino" denotes an amino group substituted with one or two optionally substituted aryl groups, wherein aryl has the meaning as described herein, examples of which include, but are not limited to, phenylamino, p-fluorophenyl amino, diphenylamino, ditolyl amino, di-p-tolyl amino, and the like.
The term "aryloxyalkoxy" means an alkoxy group substituted with one or more optionally substituted aryloxy groups, wherein the alkoxy and aryloxy groups have the meaning described herein, examples of which include, but are not limited to, phenoxymethoxy, phenoxyethoxy, phenoxypropoxy, and the like.
The term "aryloxyaliphenyl" means an aliphatic group substituted with one or more optionally substituted aryloxy groups, wherein the aryloxy and aliphatic groups have the meaning described herein, examples of which include, but are not limited to, phenoxymethyl, phenoxyethyl, tolyloxyethyl, phenoxypropyl, and the like.
The term "arylaminoaliphatic" is meant to indicate that an aliphatic group is substituted with one or more optionally substituted arylamino groups, wherein arylamino and aliphatic groups have the meaning described herein, and examples include, but are not limited to, phenylaminomethyl, phenylaminoethyl, toluidinoethyl, phenylaminopropyl, phenylaminoallyl, and the like.
The term "arylalkoxy" means an alkoxy group substituted with one or more optionally substituted aryl groups, wherein aryl and alkoxy have the meaning described herein, examples of which include, but are not limited to, phenylmethoxy, phenylethoxy, p-tolylmethoxy, phenylpropoxy, and the like.
The term "arylalkylamino" means an alkylamino group substituted with one or more optionally substituted aryl groups, wherein aryl and alkylamino have the meaning described herein, examples of which include, but are not limited to, phenylmethylamino, phenylethylamino, phenylpropylamino, p-tolylmethylamino, and the like.
The term "heteroaryl" may be used alone or as a majority of "heteroarylalkyl" or "heteroarylalkoxy" and denotes monocyclic, bicyclic and tricyclic ring systems containing a total of 5-14 membered rings, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein the heteroatoms have the meaning described herein, and wherein each ring system contains 3-7 membered rings and only one attachment point is attached to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic" or "heteroaromatic". And the heteroaryl group may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, deuterium, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclic, mercapto, nitro, aryloxy, hydroxyl-substituted alkoxy, hydroxyl-substituted alkyl-C (= O) -, alkyl-S (= O)2-, hydroxy-substituted alkyl-S (= O)2-, carboxy-substituted alkoxy, and the like.
In still other embodiments, the aromatic heterocyclic ring includes, but is not limited to, the following monocyclic rings: 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 4-methylisoxazol-5-yl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, pyrimidin-5-yl, pyridazinyl (e.g. 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g. 5-tetrazolyl), triazolyl (e.g. 2-triazolyl and 5-triazolyl), and the like, 2-thienyl, 3-thienyl, pyrazolyl (e.g. 2-pyrazolyl), isothiazolyl, 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 3-triazolyl, 1,2, 3-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, 1,3, 4-thiadiazol-2-yl, pyrazinyl, pyrazin-2-yl, 1,3, 5-triazinyl, benzo [ d ] thiazol-2-yl, imidazo [1,5-a ] pyridin-6-yl; the following bicyclic rings are also included, but are in no way limited to these: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl), and isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, or 4-isoquinolyl).
The term "heteroaryloxy" includes optionally substituted heteroaryl groups, as defined herein, attached to an oxygen atom and linked to the rest of the molecule by an oxygen atom, wherein the heteroaryl group has the meaning as described herein, examples of which include, but are not limited to, pyridine-2-oxy, thiazole-2-oxy, imidazole-2-oxy, pyrimidine-2-oxy, and the like.
The term "heteroaryloxyaliphatic" means that the aliphatic group is substituted with one or more optionally substituted heteroaryloxy groups, wherein the aliphatic and heteroaryloxy groups have the meaning as described herein, examples of which include, but are not limited to, pyridine-2-oxyethyl, thiazole-2-oxymethyl, imidazole-2-oxyethyl, pyrimidine-2-oxypropyl, and the like.
The term "sulfonyl", either alone or in combination with other terms such as "alkylsulfonyl", denotes each of the twoValent radicals-SO2-。
The term "alkylsulfonyl" refers to an alkyl-substituted sulfonyl group that forms an alkylsulfonyl group (-SO)2Alkyl radicals, e.g. SO2CH3)。
The terms "sulfonamide", "aminosulfonyl" and "sulfamoyl" denote amino-substituted sulfonyl groups that form a sulfamoyl group (-SO)2NH2)。
The term "carboxy", whether used alone or in combination with other terms (e.g., "carboxyalkyl"), means-CO2H；
The term "carbonyl", whether used alone or in combination with other terms (e.g., "aminocarbonyl" or "acyloxy"), means- (C = O) -.
The term "carboxy-substituted alkoxy" means that the alkoxy group is substituted with one or more carboxy groups, where alkoxy and carboxy groups have the meaning as described herein, and such examples include, but are not limited to, carboxymethoxy, carboxyethoxy, and the like.
The term "aralkyl" includes aryl-substituted alkyl groups. In some embodiments, an aralkyl group refers to a "lower aralkyl" group, i.e., the aryl group is attached to C1-6On the alkyl group of (a). In still other embodiments, an aralkyl group refers to a group containing C1-3The "phenylalkylene" of an alkyl group of (a). Specific examples thereof include benzyl, diphenylmethyl, phenethyl. The aryl group on the aralkyl group may be further substituted with halogen, alkyl, alkoxy, haloalkyl, and haloalkoxy.
The term "alkylthio" includes C1-10The linear or branched alkyl group is attached to a divalent sulfur atom. In some of these embodiments, alkylthio is lower C1-3Alkylthio groups, and such examples include, but are not limited to, methylthio (CH)3S-)。
The term "haloalkylthio" includes C1-10The haloalkyl group of (a) is attached to a divalent sulfur atom. In some of these embodiments, haloalkylthio is lower C1-3Haloalkylthio, and such examples include, but are not limited to, trifluoromethylthio.
The term "alkylamino" includes "N-alkylamino" and "N, N-dialkylamino" in which the amino groups are each independently substituted with one or two alkyl groups. In some of these embodiments, the alkylamino group is one or two C1-6Lower alkylamino groups in which the alkyl group is attached to the nitrogen atom. In still other embodiments, the alkylamino group is C1-3Lower alkylamino groups of (a). Suitable alkylamino groups can be monoalkylamino or dialkylamino, and such examples include, but are not limited to, N-methylamino, N-ethylamino, N-dimethylamino, N-diethylamino, and the like.
The term "alkylaminohaloalkoxy" denotes a haloalkoxy group substituted with one or more alkylamino groups, wherein the haloalkoxy and alkylamino groups have the meaning as described herein, examples of which include, but are not limited to, methylaminodifluoromethoxy, ethylaminotrifluoromethoxy, and the like.
The term "heteroarylamino" means that the amino group is substituted with one or two heteroaryl groups, wherein heteroaryl groups have the meaning described herein, examples of which include, but are not limited to, N-thienylamino and the like. In some embodiments, the heteroaryl ring on the heteroarylamino group may be further substituted.
The term "heteroarylaliphatic" means that the aliphatic group is substituted with one or more heteroaryl groups, wherein heteroaryl and aliphatic have the meaning described herein, and examples include, but are not limited to, thiophene-2-propenyl, pyridine-4-ethyl, imidazole-2-methyl, furan-2-ethyl, indole-3-methyl, and the like.
The term "heteroarylalkyl" means an alkyl group substituted with one or more heteroaryl groups, wherein heteroaryl and alkyl groups have the meaning described herein, examples of which include, but are not limited to, imidazole-2-methyl, furan-2-ethyl, indole-3-methyl, and the like.
The term "heteroarylalkylamino" includes heteroarylalkyl groups containing a nitrogen atom attached to other groups through the nitrogen atom, wherein heteroarylalkyl has the meaning as described herein, and examples include, but are not limited to, pyridin-2-ylmethylamino, thiazol-2-ylethylamino, imidazol-2-ylethylamino, pyrimidin-2-ylpropylamino, pyrimidin-2-ylmethylamino and the like.
The term "aminoalkyl" includes C substituted with one or more amino groups1-10A straight or branched alkyl group. In some of these embodiments, aminoalkyl is C substituted with one or more amino groups1-6Examples of "lower aminoalkyl" radicals include, but are not limited to, aminomethyl, aminoethyl, aminopropyl, aminobutyl, and aminohexyl.
The term "alkylaminoalkyl" includes alkyl groups substituted with alkylamino. In some of these embodiments, the alkylaminoalkyl is C1-6Lower alkylaminoalkyl. In still other embodiments, the alkylaminoalkyl is C1-3Lower alkylaminoalkyl. Suitable alkylaminoalkyl groups may be mono-or dialkyl substituted, and examples include, but are not limited to, N-methylaminomethyl, N-dimethylaminoethyl, N-diethylaminomethyl, and the like.
The term "carboxyalkyl" includes C which may be substituted by one or more carboxyl groups1-10Straight or branched chain alkyl groups, examples of which include, but are not limited to, carboxymethyl, carboxypropyl, and the like.
The term "aryloxy" includes optionally substituted aryl groups attached to and linked from an oxygen atom as defined herein to the rest of the molecule, examples of which include, but are not limited to, phenoxy and the like.
The term "heteroarylalkoxy" includes heteroarylalkyl groups containing an oxygen atom attached to other groups through an oxygen atom, wherein heteroarylalkyl has the meaning as described herein, examples of which include, but are not limited to, pyridin-2-ylmethoxy, thiazol-2-ylethoxy, imidazol-2-ylethoxy, pyrimidin-2-ylpropoxy, pyrimidin-2-ylmethoxy, and the like.
The term "cycloalkylalkyl" denotes an optionally substituted cycloalkyl-substituted alkyl group, examples of which include, but are not limited to, cyclohexylmethyl. The cycloalkyl group may be further substituted with deuterium, halogen, alkyl, alkoxy, and hydroxy.
The terms "fused bicyclic ring", "fused bicyclic group", "fused ring group" denote a saturated or unsaturated fused ring system or bridged ring system, referring to a non-aromatic fused ring or bridged ring system, as shown in formula (a1), i.e., ring a1 shares a bond, an alkane chain or a heteroalkyl chain with ring a2, wherein j is 0, 1,2,3 or 4. Such systems may contain independent or conjugated unsaturation, but the core structure does not contain aromatic or heteroaromatic rings (although aromatics may be substituents thereon). Each ring in the fused bicyclic ring is either a carbocyclic or a heteroalicyclic, examples of which include, but are not limited to, hexahydro-furo [3,2-b ] compounds]Furan, 2,3,3a,4,7,7 a-hexahydro-1H-indene, 7-azabicyclo [2.3.0 ]]Heptane, fused bicyclo [3.3.0]Octane, fused bicyclo [3.1.0]Hexane, bicyclo [2.2.1 ]]Heptane, 2-azabicyclo [2.2.1]Heptane, 1,2,3,4,4a,5,8,8 a-octahydronaphthalene, which are contained within a fused bicyclic or bridged ring system. And the fused bicyclic group may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, deuterium, oxo (= O), hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclic, mercapto, nitro, aryloxy, hydroxyl-substituted alkoxy, hydroxyl-substituted alkyl-C (= O) -, alkyl-S (= O)2-, hydroxy-substituted alkyl-S (= O)2-, carboxy-substituted alkoxy, and the like.
The term "fused heterobicyclic group" denotes a fused ring system or bridged ring system, saturated or unsaturated, involving a non-aromatic ring system or bridged ring system. Such systems may contain independent or conjugated unsaturation, but the core structure does not contain aromatic or heteroaromatic rings (although aromatics may be substituents thereon). And at least one ring system comprising one or more heteroatoms, wherein each ring system comprises a 3-7 membered ring, i.e. comprising 1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, whereby S or P is optionally substituted by one or more oxygen atoms to give, for example, SO2、PO、PO2Examples of such include, but are not limited to hexahydro-furo [3.2-b ]]Furan, 6-azabicyclo [3.2.0]Heptane, 2-azabicyclo [3.1.0]Heptane, 3-azabicyclo [3.1.0]Heptane, 7-azabicyclo [2.3.0]Heptane, 2-azabicyclo [2.2.1]Heptane and the like. And the fused heterobicyclic group may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, deuterium, oxo (= O), hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclic, mercapto, nitro, aryloxy, hydroxyl-substituted alkoxy, hydroxyl-substituted alkyl-C (= O) -, alkyl-S (= O) —)2-, hydroxy-substituted alkyl-S (= O)2-, carboxy-substituted alkoxy, and the like.
The terms "spirocyclic", "spirobicyclic", and "spirobicyclic" mean that one ring originates from a particular cyclic carbon on the other ring. For example, ring a and ring B share a carbon atom in two saturated ring systems, which are referred to as "spirocycles. Each ring within the spiro ring is either a carbocyclic or a heteroalicyclic. Examples include, but are not limited to, 2, 7-diazaspiro [4.4]]Nonan-2-yl, 7-oxo-2-azaspiro [4.5 ]]Decan-2-yl, 4-azaspiro [2.4]]Heptane-5-yl, 4-oxaspiro [2.4]]Heptane-5-yl, 5-azaspiro [2.4]]Heptane-5-yl, spiro [2.4]]Heptylalkyl, spiro [4.4]]Nonanyl, 7-hydroxy-5-azaspiro [2.4]]Heptane-5-yl, and the like. And the spirobicyclic group may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, deuterium, oxo (= O), hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclic, mercapto, nitro, aryloxy, hydroxyl-substituted alkoxy, hydroxyl-substituted alkyl-C (= O) -, alkyl-S (= O)2-, hydroxy-substituted alkyl-S (= O)2-, carboxy-substituted alkoxy, and the like.
The term "spirobicyclic group" means a spirobicyclic group having two points of attachment to the rest of the molecule, wherein the spirobicyclic group has the meaning as described herein.
The term "spiroheterobicyclic group" means that one ring originates from a specific cyclic carbon on the other ring. For example, as described above, ring a and ring B share a carbon atom in two saturated ring systems, and are referred to as "spirocycles. And at least one ring system comprising one or more heteroatoms, wherein each ring system comprises a 3-7 membered ring, i.e. comprising 1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, whereby S or P is optionally substituted by one or more oxygen atoms to give, for example, SO2、PO、PO2Examples of such include, but are not limited to, 4-azaspiro [2.4]]Heptane-5-yl, 4-oxaspiro [2.4]]Heptane-5-yl, 5-azaspiro [2.4]]Heptane-5-yl, 7-hydroxy-5-azaspiro [2.4]]Heptane-5-yl, 5-azaspiro [2.4]]Heptane-6-yl, 1, 4-dioxo-7-azaspiro [4.4]]Nonan-8-yl and the like. And the spiroheterobicyclic group may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, deuterium, oxo (= O), hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, mercaptoAlkyl, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C (= O) -, alkyl-S (= O)2-, hydroxy-substituted alkyl-S (= O)2-, carboxy-substituted alkoxy, and the like.
The alpha-amino acid group of the present invention is a group formed by removing a hydroxyl group from a carboxyl group of an alpha-amino acid, which is linked to X or X', and the alpha-amino acid group may be optionally substituted with one or more substituents selected from deuterium, F, Cl, Br, I, a hydroxyl group, or a cyano group. For example
As described herein, a ring system formed by a substituent drawing a ring bonded to the center as shown in formula (a) represents a substituent (R)5a)fSubstitutions may be made at any substitutable position on the ring. For example, formula (a) represents ring W1, ring W2, or any possible substituted position on the ring W may be substituted.
As described herein, there are two attachment points to other groups in the ring system, as shown in formula (b), meaning that both the E and E 'ends of ring W3 can be attached to other groups, and in the present invention, the groups attached to both ends E and E' can be interchanged.
As described herein, the dashed bond within the ring system represents a double or single bond. For example, the structure of formula (c) represents any one selected from the structures of formula (d).
Unless otherwise indicated, the structural formulae depicted herein include all isomeric forms (e.g., enantiomeric, diastereomeric, and geometric (or conformational) isomers): such as the R, S configuration containing an asymmetric center, the (Z), (E) isomers of the double bond, and the conformational isomers of (Z), (E). Thus, individual stereochemical isomers of the compounds of the present invention or mixtures of enantiomers, diastereomers, or geometric isomers (or conformers) thereof are within the scope of the present invention.
In addition, unless otherwise expressly indicated, the recitations "… independently for each 8932, … independently, and" … independently for each … "as used throughout this document are interchangeable and should be broadly understood to mean either that specific items represented between the same symbols in different groups do not affect each other, or that specific items represented between the same symbols in the same groups do not affect each other, with R being9For example, the formula "-U- (CR)9R9a)t-R12"and structural formula" - [ U- (CR)9R9a)t-N(R10)-(CR9R9a)t]k-U-(CR9R9a)t-N(R11)-(CR9R9a)t-R12"between R and R9Are not affected by each other, and are in the same chemical formula "- [ U- (CR)9R9a)t-N(R10)-(CR9R9a)t]k-U-(CR9R9a)t-N(R11)-(CR9R9a)t-R12"inner, plural R9Are not affected by each other.
The term "prodrug", as used herein, represents a compound of formula (I) inIs converted into the compound shown in the formula (I) in vivo. Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and comprises phenyl ester and aliphatic (C)1-24) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxy group, i.e., it can be acylated to provide the compound in prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent. For a complete discussion of prodrugs, reference may be made to the following: t.higuchi and v.stella, Pro-drugs as Novel delivery systems, vol.1 of the a.c.s.symposium Series, Edward b.roche, ed., BioreversibleCarriers in Drug Design, American Pharmaceutical Association and permamonpress, 1987, j.rautio et al, produgs: design and Clinical Applications, Nature review Drug Discovery,2008,7, 255-.
Unless otherwise indicated, all tautomeric forms of the compounds of the invention are included within the scope of the invention. In addition, unless otherwise indicated, the structural formulae of the compounds described herein include isotopically enriched concentrations of one or more different atoms.
"metabolite" refers to the product of a particular compound or salt thereof obtained by metabolism in vivo. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assay methods as described herein. Such products may be obtained by administering the compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.
The definition and convention of stereochemistry in the present invention is generally used with reference to the following documents: S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York, and Eliel, E.and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the invention may contain asymmetric or chiral centers and thus exist in different stereoisomers. All stereoisomeric forms of the compounds of the present invention, including, but in no way limited to, diastereomers, enantiomers, atropisomers and mixtures thereof, such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefix D, L or R, S is used to indicate the absolute configuration of the chiral center of the molecule. The prefixes d, l or (+), (-) are used to designate the sign of the rotation of plane polarized light of the compound, with (-) or l indicating that the compound is left-handed and the prefix (+) or d indicating that the compound is right-handed. The chemical structures of these stereoisomers are identical, but their stereo structures are different. A particular stereoisomer may be an enantiomer, a mixture of isomers commonly referred to as a mixture of enantiomers. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may result in no stereoselectivity or stereospecificity during the chemical reaction. The terms "racemic mixture" and "racemate" refer to a mixture of two enantiomers in equimolar amounts, lacking optical activity.
The term "tautomer" or "tautomeric form" means that isomers of structures of different energies may be interconverted through a low energy barrier. For example, proton tautomers (i.e., prototropic tautomers) include tautomers that move through protons, such as keto-enol and imine-enamine isomerizations. Valence (valence) tautomers include tautomers that recombine into bond electrons.
As used herein, "pharmaceutically acceptable salt" refers to organic salts of the compounds of the present inventionAnd inorganic salts. Pharmaceutically acceptable salts are well known in the art, as are: berge et al, J.pharmaceutical Sciences,66,1-19,1977. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, salts of inorganic acids such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and salts of organic acids such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, formed by reaction with amino groups, or obtained by other methods described in the literature, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, cyclopentylpropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, pamoates, pectinates, persulfates, 3-phenylpropionates, picrates, pivalates, propionates, stearates, bisulfates, salts of sodium, potassium, sodium, potassium, sodium, Thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts obtained with appropriate bases include alkali metals, alkaline earth metals, ammonium and N+(C1-4Alkyl radical)4A salt. The present invention also contemplates quaternary ammonium salts formed from compounds containing groups of N. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1-8Sulfonates and aromatic sulfonates.
"solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" refers to an association of solvent molecules that is water.
The term "protecting group" or "Pg" refers to a substituent that when reacted with another functional group, is typically used to block or protect a particular functionality. For example, "amino protecting group" refers to a substituent attached to an amino group to block or protect the functionality of the amino group in a compound, and suitable amino protecting groups include acetyl, trifluoroacetyl, t-Butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ), and 9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, "hydroxyl protecting group" refers to the functionality of a substituent of a hydroxyl group to block or protect the hydroxyl group, and suitable protecting groups include acetyl and silyl groups. "carboxy protecting group" refers to the functionality of a substituent of a carboxy group to block or protect the carboxy group, and typical carboxy protecting groups include-CH2CH2SO2Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like. General descriptions of protecting groups can be found in the literature: greene, Protective Groups in Organic Synthesis, John Wiley&Sons, New York,1991, and P.J. Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.
It should be noted that the term "inhibiting HCV viral proteins" in the present invention is to be understood in a broad sense, and includes both the level of inhibiting expression of HCV viral proteins and the level of inhibiting activity, assembly and release of HCV viral proteins. Among them, HCV protein expression levels include, but are not limited to: the level of translation of viral protein genes, the level of post-translational modification of proteins, the level of replication of progeny genetic material, and the like.
Description of the Compounds of the invention
The spiro compound and the pharmaceutical preparation thereof can effectively inhibit HCV infection, and particularly can inhibit the activity of HCV NS5A protein.
In one aspect, the invention relates to a compound that is a compound of formula (I) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof,
wherein each A and A' is independently a bond, alkylene, alkenylene, cycloalkylene, heterocycloalkylene, - (CR)8R8a)n-O-(CR8R8a)p-、-(CR8R8a)n-N(R5)-(CR8R8a)p-、-(CR8R8a)n-S(=O)r-N(R5)-(CR8R8a)p-、-(CR8R8a)n-C(=O)-N(R5)-(CR8R8a)p-、-(CR8R8a)n-N(R5)-C(=O)-N(R5)-(CR8R8a)p-、-(CR8R8a)n-C(=O)-O-(CR8R8a)p-、-(CR8R8a)n-N(R5)-S(=O)r-N(R5)-(CR8R8a)p-、-(CR8R8a)n-S(=O)r-(CR8R8a)p-、-(CR8R8a)n-S(=O)r-O-(CR8R8a)p-、-(CR8R8a)n-C(=O)-(CR8R8a)p-、-(CR8R8a)n-C(=S)-(CR8R8a)p-、-(CR8R8a)n-N(R5)-C(=O)-O-(CR8R8a)pOr each of A and A' is independently the following group:
wherein each X1And X2Independently O, S, NR6Or CR7R7a；
W1Is carbocyclyl or heterocyclyl;
W2is carbocyclyl, heterocyclyl, spirobicyclic, spiroheterobicyclic, fused bicyclic or fused heterobicyclic;
each Y is1、Y2、Y1’And Y2’Independently is N or CR7；
Z is- (CH)2)a-、-CH=CH-、-N=CH-、-(CH2)a-N(R5)-(CH2)b-or- (CH)2)a-O-(CH2)b-；
Each a and b is independently 0, 1,2 or 3;
each c is independently 1 or 2;
each d is independently 1 or 2;
each n is independently 0, 1,2 or 3;
each p is independently 0, 1,2 or 3;
each r is independently 0, 1 or 2;
each f and f' is independently 0, 1,2,3, or 4;
each Q1And Q2Independently is a bond, NR6O, S, C (= O) or (CR)7R7a)e；
Each e is independently 0, 1,2,3, or 4;
each X and X' is independently N or CR7；
Each Y and Y 'is independently H, deuterium, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, α -amino acid group, or an optical isomer of α -amino acid group, or each Y and Y' is independently a structural unit of- [ U- (CR)9R9a)t-N(R10)-(CR9R9a)t]k-U-(CR9R9a)t-N(R11)-(CR9R9a)t-R12、-U-(CR9R9a)t-R12Or- [ U- (CR)9R9a)t-N(R10)-(CR9R9a)t]k-U-(CR9R9a)t-O-(CR9R9a)t-R12；
Each U is independently-C (= O) -, -C (= S) -, -S (= O) -, or-S (= O)2-；
Each t is independently 0, 1,2,3 or 4;
each k is independently 0, 1 or 2;
each R1、R2、R3And R4Independently is H, deuterium, alkyl, heteroalkyl, aralkyl, cycloalkyl, heterocyclyl, heteroaryl or aryl, or R1、R2And X-CH optionally form a 3-8 membered heterocyclic ring or a 3-8 membered carbocyclic ring, C5-12Condensed bicyclic ring, C5-12Fused heterobicyclic ring, C5-12Spiro bicyclic ring or C5-12Spiro heterobicyclic rings; or R3、R4And X' -CH optionally form a 3-8 membered heterocyclic or carbocyclic ring, C5-12Condensed bicyclic ring, C5-12Fused heterobicyclic ring, C5-12Spiro bicyclic ring or C5-12Spiro heterobicyclic rings;
each R5Independently is H, deuterium, hydroxy, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, alkoxy, alkyl-OC (= O) -, alkyl-C (= O) -, carbamoyl, alkyl-OS (= O)r-, alkyl-S (= O)rO-, alkyl-S (= O)r-or aminosulfonyl;
each R5aAnd R5a’Independently is H, deuterium, oxo (= O), hydroxy, amino, F, Cl, Br, I, cyano, R13aR13N-、-C(=O)NR13R13a、-OC(=O)NR13R13a、-OC(=O)OR13、-N(R13)C(=O)NR13R13a、-N(R13)C(=O)OR13a、-N(R13)C(=O)-R13a、R13R13aN-S(=O)2-、R13S(=O)2-、R13S(=O)2N(R13a)-、R13aR13N-alkyl, R13S (= O) -alkyl, R13R13aN-C (= O) -alkyl, R13aR13N-alkoxy, R13S (= O) -alkoxy, R13R13aN-C (= O) -alkoxy, aryl, heteroaryl, alkoxy, alkylamino, alkyl, haloalkyl, alkenyl, alkynyl, heterocyclyl, cycloalkyl, mercapto, nitro, aralkyl, arylamino, heteroarylamino, arylalkylamino, heteroarylalkylamino, heteroaryloxy, heteroarylalkyl, arylalkoxy, heteroarylalkoxy, heterocyclyloxy, heterocyclylamino, alkanoyl, alkanoyloxy, alkoxyacyl, alkylsulfonyl, alkoxysulfonyl, alkylsulfinyl, alkylsulfonyloxy, alkylsulfinyloxy, heterocyclylalkylamino, or aryloxy;
each R6Independently of each other is hydrogen, deuterium, R13R13aNC(=O)-、R13OC(=O)-、R13C(=O)-、R13R13aNS(=O)-、R13OS(=O)-、R13S(=O)-、R13R13aNS(=O)2-、R13OS(=O)2-、R13S(=O)2-, aliphatic, haloaliphatic, hydroxyaliphatic, aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic, alkylthioaliphatic, arylaliphatic, heteroarylaliphatic, heterocyclylaliphatic, cycloalkylaliphatic, aryloxyaliphatic, heterocyclyloxyaliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic, heterocyclylaminoaliphatic, cycloalkylaminoaliphatic, aryl, heteroaryl, heterocyclyl, or carbocyclyl;
each R6aIndependently H, deuterium, hydroxy, amino, F, Cl, Br, I, cyano, oxo (= O), R13aR13N-、-C(=O)NR13R13a、-OC(=O)NR13R13a、-OC(=O)OR13、-N(R13)C(=O)NR13R13a、-N(R13)C(=O)OR13a、-N(R13)C(=O)-R13a、R13R13aN-S(=O)2-、R13S(=O)2-、R13S(=O)2N(R13a)-、R13aR13N-alkyl, R13S (= O) -alkyl, R13R13aN-C (= O) -alkyl, R13aR13N-alkoxy, R13S (= O) -alkoxy, R13R13aN-C (= O) -alkoxy, aryl, heteroaryl, alkoxy, alkylamino, alkyl, haloalkyl, alkenyl, alkynyl, heterocyclyl, cycloalkyl, mercapto, nitro, aralkyl, arylamino, heteroarylamino, arylalkylamino, heteroarylalkylamino, heteroaryloxy, heteroarylalkyl, arylalkoxy, heteroarylalkoxy, heterocyclyloxy, heterocyclylamino, alkanoyl, alkanoyloxy, alkoxyacyl, alkylsulfonyl, alkoxysulfonyl, alkylsulfinyl, alkylsulfonyloxy, alkylsulfinyloxy, heterocyclylalkylamino, or aryloxy;
each R7And R7aIndependently H, deuterium, F, Cl, Br, I, aliphatic, heteroalkyl, haloaliphatic, hydroxyalkylaliphatic, aminoaliphatic, alkoxyAn aliphatic, alkylaminoaliphatic, alkylthioaliphatic, arylaliphatic, heteroarylaliphatic, heterocycloaliphatic, cycloalkylaliphatic, aryloxyaliphatic, heterocyclyloxyaliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic, heterocycloaliphatic, cycloalkylaminoaliphatic, aryl, heteroaryl, heterocyclyl, or carbocyclyl group;
each R8And R8aIndependently H, deuterium, hydroxy, cyano, nitro, F, Cl, Br, I, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, alkoxy, alkyl-OC (= O) -, alkyl-C (= O) -, carbamoyl, alkyl-OS (= O)r-, alkyl-S (= O)rO-, alkyl-S (= O)r-or aminosulfonyl;
each R9、R9a、R10And R11Independently is H, deuterium, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, haloalkyl, hydroxyalkyl, heteroarylalkyl, heterocyclylalkyl, or cycloalkylalkyl;
each R12Independently is R13aR13N-、-C(=O)R13、-C(=S)R13、-C(=O)-O-R13、-C(=O)NR13R13a、-OC(=O)NR13R13a、-OC(=O)OR13、-N(R13)C(=O)NR13R13a、-N(R13)C(=O)OR13a、-N(R13)C(=O)-R13a、R13R13aN-S(=O)2-、R13S(=O)2-、R13S(=O)2N(R13a)-、R13OS(=O)2-, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or aralkyl;
or R11、R12And the atoms to which they are attached may form a 4-7 membered ring;
and each R13And R13aIndependently is H, deuterium, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroarylOr an aralkyl group; or when R is13And R13aAttached to the same nitrogen atom, R13、R13aAnd the nitrogen atom optionally form a substituted or unsubstituted 3-8 membered ring, a spiro bicyclic ring or a fused bicyclic ring;
wherein each of the groups alkylene, alkenylene, cycloalkylene, heterocycloalkylene, - (CR)8R8a)n-O-(CR8R8a)p-、-(CR8R8a)n-N(R5)-(CR8R8a)p-、-(CR8R8a)n-S(=O)r-N(R5)-(CR8R8a)p-、-(CR8R8a)n-C(=O)-N(R5)-(CR8R8a)p-、-(CR8R8a)n-N(R5)-C(=O)-N(R5)-(CR8R8a)p-、-(CR8R8a)n-C(=O)-O-(CR8R8a)p-、-(CR8R8a)n-N(R5)-S(=O)r-N(R5)-(CR8R8a)p-、-(CR8R8a)n-N(R5)-C(=O)-O-(CR8R8a)p-、-(CR8R8a)n-S(=O)r-(CR8R8a)p-、-(CR8R8a)n-S(=O)r-O-(CR8R8a)p-、-(CR8R8a)n-C(=O)-(CR8R8a)p-、-(CR8R8a)n-C(=S)-(CR8R8a)p-、-[U-(CR9R9a)t-N(R10)-(CR9R9a)t]k-U-(CR9R9a)t-N(R11)-(CR9R9a)t-R12、-U-(CR9R9a)t-R12、-[U-(CR9R9a)t-N(R10)-(CR9R9a)t]k-U-(CR9R9a)t-O-(CR9R9a)t-R12、NR6、CR7R7a、CR7、-(CH2)a-、-CH=CH-、-N=CH-、-(CH2)a-N(R5)-(CH2)b-、-(CH2)a-O-(CH2)b-、R13aR13N-、-C(=O)R13、-C(=S)R13、-C(=O)-O-R13、-C(=O)NR13R13a、-OC(=O)NR13R13a、-OC(=O)OR13、-N(R13)C(=O)NR13R13a、-N(R13)C(=O)OR13a、-N(R13)C(=O)-R13a、R13R13aN-S(=O)2-、R13S(=O)2-、R13S(=O)2N(R13a)-、R13OS(=O)2-、R13aR13N-, alkyl-OC (= O) -, alkyl-C (= O) -, alkyl-OS (= O)r-, alkyl-S (= O)rO-, alkyl-S (= O)r-、R13R13aNS(=O)-、R13OS(=O)-、R13S(=O)-、R13aR13N-alkyl, R13S (= O) -alkyl, R13R13aN-C (= O) -alkyl, R13aR13N-alkoxy, R13S (= O) -alkoxy, R13R13aN-C (= O) -alkylamino, alkyl, heteroalkyl, carbocyclyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, α -amino acid group, C5-12Condensed bicyclic ring, C5-12Fused heterobicyclic ring, C5-12Spiro bicyclic ring, C5-12Spiroheterobicyclic, alkoxy, aliphatic, haloaliphatic, hydroxyaliphatic, aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic, alkylthioaliphatic, arylaliphatic, heteroarylaliphatic, heterocyclylaliphatic, cycloalkylaliphatic, aryloxyaliphatic, heterocyclyloxyaliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic, heterocyclylaminoaliphatic, cycloalkylaminoaliphatic, haloalkyl, substituted alkylthioalkyl, substituted alkylthioaliphatic,Alkenyl, alkynyl, arylamino, heteroarylamino, arylalkylamino, heteroarylalkylamino, heteroaryloxy, heteroarylalkyl, arylalkoxy, heteroarylalkoxy, heterocyclyloxy alkoxy, heterocyclylamino, heterocyclylalkylamino, or aryloxy can be optionally substituted with one or more groups selected from deuterium, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, heteroaryloxy, oxo (= O), carboxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C (= O) -, alkyl-C (= O), alkyl-S (= O) -, alkyl-S (= O)2-, hydroxy-substituted alkyl-S (= O)2-or a substituent of a carboxy-substituted alkoxy group.
In some of these embodiments, wherein W1Is C3-8Carbocyclic radical or C2-10A heterocyclic group;
and W2Is C3-8Carbocyclyl, C2-10Heterocyclic group, C5-12Spiro bicyclic group, C5-12Spiro-heterobicyclic radical, C5-12Condensed bicyclic group or C5-12Fused heterobicyclic radicals.
In some of these embodiments, wherein
The structural unit is the following sub-structural formula:
the structural unit is the following sub-structural formula:
wherein each X1、X2、X3And X5Independently O, S, NR6C (= O) or CR7R7a；
Each Y is1、Y2、Y1’And Y2’Independently is N or CR7；
Each f and f' is independently 0, 1,2,3, or 4;
each Q1And Q2Independently is a bond, NR6O, S, C (= O) or (CR)7R7a)e；
Q3Is N or CR7；
Each e is independently 0, 1,2,3, or 4;
each R5aAnd R5a’Independently is H, deuterium, oxo (= O), hydroxy, amino, F, Cl, Br, I, cyano, R13aR13N-、-C(=O)NR13R13a、-OC(=O)NR13R13a、-OC(=O)OR13、-N(R13)C(=O)NR13R13a、-N(R13)C(=O)OR13、-N(R13)C(=O)-R13、R13R13aN-S(=O)2-、R13S(=O)2-、R13S(=O)2N(R13a)-、C1-6Alkyl acyl radical, C1-6Alkyl acyloxy, C1-6Alkoxyacyl group, C1-6Alkylsulfonyl radical, C1-6Alkoxysulfonyl group, C1-6Alkylsulfinyl radical, C1-6Alkylsulfonyloxy, C1-6Alkylsulfinyloxy, C1-6Alkoxy radical, C1-6Alkyl radical, C6-10Aryl, -CF3、-OCF3Mercapto, nitro, C1-6Alkylamino radical, C3-10Cycloalkyl or C6-10An aryloxy group;
each R6Independently of each other is hydrogen, deuterium, R13R13aNC(=O)-、R13OC(=O)-、R13C(=O)-、R13R13aNS(=O)-、R13OS(=O)-、R13S(=O)-、R13R13aNS(=O)2-、R13OS(=O)2-、R13S(=O)2-、C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Aminoalkyl radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl radical, C1-6Alkylthio group C1-6Alkyl radical, C6-10Aryl radical C1-6Alkyl radical, C1-9Heteroaryl C1-6Alkyl radical, C2-10Heterocyclyl radical C1-6Alkyl radical, C3-10Cycloalkyl radical C1-6Alkyl radical, C6-10Aryloxy radical C1-6Alkyl radical, C2-10Heterocyclyloxy C1-6Alkyl radical, C3-10Cycloalkyl oxy C1-6Alkyl radical, C6-10Arylamino group C1-6Alkyl radical, C2-10Heterocyclylamino C1-6Alkyl radical, C3-10Cycloalkyl amino group C1-6Alkyl radical, C6-10Aryl radical, C1-9Heteroaryl group, C2-10Heterocyclyl or C3-10A carbocyclic group;
each R7And R7aIndependently H, deuterium, F, Cl, Br, I, C1-6Alkyl radical, C2-6Heteroalkyl group, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Aminoalkyl radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl radical, C1-6Alkylthio group C1-6Alkyl radical, C6-10Aryl radical C1-6Alkyl radical, C1-9Heteroaryl C1-6Alkyl radical, C2-10Heterocyclyl radical C1-6Alkyl radical, C3-10Cycloalkyl radical C1-6Alkyl radical, C6-10Aryloxy radical C1-6Alkyl radical, C2-10Heterocyclyloxy C1-6Alkyl radical, C3-10Cycloalkyl oxy C1-6Alkyl radical, C6-10Arylamino group C1-6Alkyl radical, C2-10Heterocyclylamino C1-6Alkyl radical, C3-10Cycloalkyl amino group C1-6Alkyl radical, C6-10Aryl radical, C1-9Heteroaryl group, C2-10Heterocyclyl or C3-10A carbocyclic group;
and each R13And R13aIndependently of one another H, deuterium, C1-6Alkyl radical, C2-6Heteroalkyl group, C3-10Cycloalkyl radical, C2-10Heterocyclic group, C6-10Aryl radical, C1-9Heteroaryl or C6-10Aryl radical C1-6An alkyl group; or when R is13And R13aAttached to the same nitrogen atom, R13、R13aAnd the nitrogen atom optionally form a substituted or unsubstituted 3-8 membered ring, a spiro bicyclic ring or a fused bicyclic ring.
In some of these embodiments, wherein,
the structural unit is the following sub-structural formula:
the structural unit is the following group:
wherein each Y is1、Y2、Y1’And Y2’Independently is N or CH2；
Each f and f' is independently 0, 1,2,3, or 4;
each R5aAnd R5a’Independently is H, deuterium, oxo (= O), hydroxy, amino, F, Cl, Br, I, cyano, R13aR13N-、-C(=O)NR13R13a、-OC(=O)NR13R13a、-OC(=O)OR13、-N(R13)C(=O)NR13R13a、-N(R13)C(=O)OR13、-N(R13)C(=O)-R13、R13R13aN-S(=O)2-、R13S(=O)2-、R13S(=O)2N(R13a)-、C1-6Alkyl acyl radical, C1-6Alkyl acyloxy, C1-6Alkoxyacyl group, C1-6Alkylsulfonyl radical, C1-6Alkoxysulfonyl group, C1-6Alkylsulfinyl radical, C1-6Alkylsulfonyloxy, C1-6Alkylsulfinyloxy, C1-6Alkoxy radical, C1-6Alkyl radical, C6-10Aryl, -CF3、-OCF3Mercapto, nitro or C1-6An alkylamino group;
and each R6Independently of one another is hydrogen, deuterium, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Aminoalkyl radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl radical, C1-6Alkylthio group C1-6Alkyl radical, C6-10Aryl radical C1-6Alkyl radical, C1-9Heteroaryl C1-6Alkyl radical, C2-10Heterocyclyl radical C1-6Alkyl or C3-8Cycloalkyl radical C1-6An alkyl group.
In some of these embodiments, wherein each A and A' is independently a bond, C1-6Alkylene radical, C2-6Alkenylene radical, C3-8Cycloalkylene radical, C2-10Heterocycloalkylene, - (CR)8R8a)n-O-(CR8R8a)p-、-(CR8R8a)n-N(R5)-(CR8R8a)p-、-(CR8R8a)n-S(=O)r-N(R5)-(CR8R8a)p-、-(CR8R8a)n-C(=O)-N(R5)-(CR8R8a)p-、-(CR8R8a)n-N(R5)-C(=O)-N(R5)-(CR8R8a)p-、-(CR8R8a)n-C(=O)-O-(CR8R8a)p-、-(CR8R8a)n-N(R5)-S(=O)r-N(R5)-(CR8R8a)p-、-(CR8R8a)n-S(=O)r-(CR8R8a)p-、-(CR8R8a)n-S(=O)r-O-(CR8R8a)p-、-(CR8R8a)n-C(=O)-(CR8R8a)p-、-(CR8R8a)n-C(=S)-(CR8R8a)p-、-(CR8R8a)n-N(R5)-C(=O)-O-(CR8R8a)pOr each of A and A' is independently the following group:
wherein each X1And X2Independently O, S, NR6Or CR7R7a；
Each e is independently 0, 1,2,3, or 4;
each Y is1And Y2Independently is N or CR7；
Z is- (CH)2)a-、-CH=CH-、-N=CH-、-(CH2)a-N(R5)-(CH2)b-or- (CH)2)a-O-(CH2)b-；
Each a and b is independently 0, 1,2 or 3;
each c is independently 1 or 2;
each d is independently 1 or 2;
each n is independently 0, 1,2 or 3;
each p is independently 0, 1,2 or 3;
each r is independently 0, 1 or 2;
each R5Independently H, deuterium, hydroxy, C1-6Alkyl radical, C2-6Heteroalkyl group, C3-8Cycloalkyl radical, C2-10Heterocyclic group, C6-10Aryl radical, C1-9Heteroaryl group, C6-10Aryl radical C1-6Alkyl radical, C1-6Alkoxy radical, C1-6alkyl-OC (= O) -, C1-6alkyl-C (= O) -, carbamoyl, C1-6alkyl-OS (= O)r-、C1-6alkyl-S (= O)rO-、C1-6alkyl-S (= O)r-or aminosulfonyl;
each R6Independently of each other is hydrogen, deuterium, R13R13aNC(=O)-、R13OC(=O)-、R13C(=O)-、R13R13aNS(=O)-、R13OS(=O)-、R13S(=O)-、R13R13aNS(=O)2-、R13OS(=O)2-、R13S(=O)2-、C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Aminoalkyl radical, C1-6Alkoxy radicalRadical C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl radical, C1-6Alkylthio group C1-6Alkyl radical, C6-10Aryl radical C1-6Alkyl radical, C1-9Heteroaryl C1-6Alkyl radical, C2-10Heterocyclyl radical C1-6Alkyl radical, C3-10Cycloalkyl radical C1-6Alkyl radical, C6-10Aryloxy radical C1-6Alkyl radical, C2-10Heterocyclyloxy C1-6Alkyl radical, C3-10Cycloalkyl oxy C1-6Alkyl radical, C6-10Arylamino group C1-6Alkyl radical, C2-10Heterocyclylamino C1-6Alkyl radical, C3-10Cycloalkyl amino group C1-6Alkyl radical, C6-10Aryl radical, C1-9Heteroaryl group, C2-10Heterocyclyl or C3-10A carbocyclic group;
each R6aIndependently H, deuterium, hydroxy, amino, F, Cl, Br, I, cyano, oxo (= O), R13aR13N-、-C(=O)NR13R13a、-OC(=O)NR13R13a、-OC(=O)OR13、-N(R13)C(=O)NR13R13a、-N(R13)C(=O)OR13a、-N(R13)C(=O)-R13a、R13R13aN-S(=O)2-、R13S(=O)2-、R13S(=O)2N(R13a)-、R13aR13N-C1-6Alkyl radical, R13S(=O)-C1-6Alkyl radical, R13R13aN-C(=O)-C1-6Alkyl radical, R13aR13N-C1-6Alkoxy radical, R13S(=O)-C1-6Alkoxy radical, R13R13aN-C(=O)-C1-6Alkoxy radical, C6-10Aryl radical, C1-9Heteroaryl group, C1-6Alkoxy radical, C1-6Alkylamino radical, C1-6Alkyl radical, C1-6Haloalkyl, C2-6Alkenyl radical, C2-6Alkynyl, C2-10Heterocyclic group, C3-8Cycloalkyl, mercapto, nitro, C6-10Aryl radical C1-6Alkyl radical, C6-10Arylamino, C1-9Heteroarylamino or C6-10An aryloxy group;
each R7And R7aIndependently H, deuterium, F, Cl, Br, I, C1-6Alkyl radical, C2-6Heteroalkyl group, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Aminoalkyl radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl radical, C1-6Alkylthio group C1-6Alkyl radical, C6-10Aryl radical C1-6Alkyl radical, C2-10Heterocyclyl radical C1-6Alkyl radical, C3-10Cycloalkyl radical C1-6Alkyl radical, C6-10Aryloxy radical C1-6Alkyl radical, C2-10Heterocyclyloxy C1-6Alkyl radical, C3-10Cycloalkyl oxy C1-6Alkyl radical, C6-10Arylamino group C1-6Alkyl radical, C2-10Heterocyclylamino C1-6Alkyl radical, C3-10Cycloalkyl amino group C1-6Alkyl radical, C6-10Aryl radical, C1-9Heteroaryl group, C2-10Heterocyclyl or C3-8A carbocyclic group;
each R13And R13aIndependently of one another H, deuterium, C1-6Alkyl radical, C2-6Heteroalkyl group, C3-10Cycloalkyl radical, C2-10Heterocyclic group, C6-10Aryl radical, C1-9Heteroaryl or C6-10Aryl radical C1-6An alkyl group; or when R is13And R13aAttached to the same nitrogen atom, R13、R13aAnd the nitrogen atom optionally form a substituted or unsubstituted 3-8 membered ring, a spiro bicyclic ring or a fused bicyclic ring;
and each R8And R8aIndependently H, deuterium, hydroxyl, cyano, nitro, F, Cl, Br, I, C1-6Alkyl radical, C2-6Heteroalkyl group, C3-10Cycloalkyl radical, C2-10Heterocyclic group, C6-10Aryl radical, C1-9Heteroaryl group, C6-10Aryl radical C1-6Alkyl radical, C1-6Alkoxy radical, C1-6alkyl-OC (= O) -, C1-6alkyl-C (= O) -, carbamoyl, C1-6alkyl-OS (= O)r-、C1-6alkyl-S (= O)rO-、C1-6alkyl-S (= O)r-or aminosulfonyl.
In some of these embodiments, wherein each A and A' is independently a bond, -CH2-、-(CH2)2-、-CH=CH-、-CH=CH-CH2-、-N(R5)-、-C(=O)-、-C(=S)-、-C(=O)-O-、-C(=O)N(R6)-、-OC(=O)N(R5)-、-OC(=O)O-、-N(R5)C(=O)N(R5)-、-(R5)N-S(=O)2-、-S(=O)2-、-OS(=O)2-、-(R5) N-S (= O) -, -OS (= O) -, or each of a and a' is independently a group of:
wherein each X1Independently is O or S;
each Y is1Independently is N or CH;
each e is independently 0, 1,2 or 3;
each R5Independently H, deuterium, hydroxy, C1-6Alkyl radical, C2-6Heteroalkyl group, C3-8Cycloalkyl radical, C2-10Heterocyclic group, C6-10Aryl radical, C1-9Heteroaryl group, C6-10Aryl radical C1-6Alkyl radical, C1-6Alkoxy radical, C1-6alkyl-OC (= O) -, C1-6alkyl-C (= O) -, carbamoyl, C1-6alkyl-OS (= O)r-、C1-6alkyl-S (= O)rO-、C1-6alkyl-S (= O)r-or aminosulfonyl;
each R6Independently of one another is hydrogen, deuterium, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxy alkaneBase, C1-6Aminoalkyl radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl radical, C1-6Alkylthio group C1-6Alkyl radical, C6-10Aryl radical C1-6Alkyl radical, C1-9Heteroaryl group, C6-10Aryl radical, C2-10Heterocyclyl or C3-8A carbocyclic group;
each R6aIndependently H, deuterium, hydroxy, amino, F, Cl, Br, I, cyano, oxo (= O), R13aR13N-、-C(=O)NR13R13a、-OC(=O)NR13R13a、-OC(=O)OR13、-N(R13)C(=O)NR13R13a、-N(R13)C(=O)OR13、-N(R13)C(=O)-R13、R13R13aN-S(=O)2-、R13S(=O)2-、R13S(=O)2N(R13a)-、C1-6Alkoxy radical, C1-6Alkylamino radical, C1-6Alkyl radical, C1-6Haloalkyl, C2-6Alkenyl radical, C2-6Alkynyl, mercapto or nitro;
and each R13And R13aIndependently of one another H, deuterium, C1-6Alkyl radical, C2-6Heteroalkyl group, C3-10Cycloalkyl radical, C2-10Heterocyclic group, C6-10Aryl radical, C1-9Heteroaryl or C6-10Aryl radical C1-6An alkyl group; or when R is13And R13aAttached to the same nitrogen atom, R13、R13aAnd the nitrogen atom optionally form a substituted or unsubstituted 3-8 membered ring, a spiro bicyclic ring or a fused bicyclic ring.
In some of these embodiments, wherein each R is1、R2、R3And R4Independently is selected from H, deuterium, C1-8Alkyl radical, C1-8Heteroalkyl group, C6-10Aryl radical C1-6Alkyl radical, C3-10Cycloalkyl radical, C2-10Heterocyclic group, C1-9Heteroaryl or C6-10An aryl group; or R1、R2And X-CH optionally form a 3-8 membered heterocyclic ringOr a 3-8 membered carbocyclic ring, C5-12Condensed bicyclic ring, C5-12Fused heterobicyclic ring, C5-12Spiro bicyclic ring or C5-12Spiro heterobicyclic rings; r3、R4And X' -CH optionally form a 3-8 membered heterocyclic ring or a 3-8 membered carbocyclic ring, C5-12Condensed bicyclic ring, C5-12Fused heterobicyclic ring, C5-12Spiro bicyclic ring or C5-12Spiro heterobicyclic rings.
In still other embodiments, wherein R is1、R2And X-CH, or R3、R4And X' -CH to form a 3-8 membered heterocyclic ring, C5-12Condensed bicyclic ring, C5-12Fused heterobicyclic ring, C5-12Spiro bicyclic ring or C5-12Spiro heterobicyclic rings.
In still other embodiments, wherein R is1、R2And Y-X-CH form a heterocyclic or fused ring or spiro ring system selected from the following subformulas:
wherein each R is15Independently is H, deuterium, oxo (O), F, Cl, Br, I, cyano, hydroxy, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Alkylamino radical, C1-3Alkylthio radical, C6-10Arylamino, C6-10Aryloxy radical, C1-9Heteroaryl group, C1-9Heteroaryloxy radical, C1-9Heteroaryl C1-3Alkyl or C2-10A heterocyclic group;
each R6Independently of one another is hydrogen, deuterium, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Aminoalkyl radical, C1-3Alkoxy radical C1-3Alkyl radical, C1-3Alkylamino radical C1-3Alkyl radical, C1-3Alkylthio group C1-3Alkyl radical, C6-10Aryl radical C1-3Alkyl radical, C1-9Heteroaryl group, C6-10Aryl radical, C2-10Heterocyclyl or C3-8A carbocyclic group;
and each n1And n2Independently 1,2,3 or 4.
In still other embodiments, wherein R is3、R4And Y '-X' -CH to form a heterocyclic or fused ring or spiro ring system selected from the following subformulae:
wherein each R is15Independently is H, deuterium, oxo (O), F, Cl, Br, I, cyano, hydroxy, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Alkylamino radical, C1-3Alkylthio radical, C6-10Arylamino, C6-10Aryloxy radical, C1-9Heteroaryl group, C1-9Heteroaryloxy radical, C1-9Heteroaryl C1-3Alkyl or C2-10A heterocyclic group;
each R6Independently of one another is hydrogen, deuterium, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Aminoalkyl radical, C1-3Alkoxy radical C1-3Alkyl radical, C1-3Alkylamino radical C1-3Alkyl radical, C1-3Alkylthio group C1-3Alkyl radical, C6-10Aryl radical C1-3Alkyl radical, C1-9Heteroaryl group, C6-10Aryl radical, C2-10Heterocyclyl or C3-8A carbocyclic group;
and each n1And n2Independently 1,2,3 or 4.
In some of these embodiments, it has the structure shown in formula (II):
wherein,the structural unit is the following sub-structural formula:
the structural units are the following groups:
each Q1And Q2Independently is a bond, NR6O, S, C (= O) or (CH)2)e；
Q3Is N and CH;
each X1Independently O, S, NR6Or CR7R7a；
Each e is independently 0, 1,2,3, or 4;
each f and f' is independently 0, 1,2,3 or 4
Each X3And X5Independently O, S, NR6C (= O) or CR7R7a；
Each Y is1、Y2、Y1’And Y2’Independently is N or CR7；
Each A and A' is independently a bond, C1-6Alkylene radical, C2-6Alkenylene radical, C3-8Cycloalkylene radical, C2-10Heterocycloalkylene, - (CR)8R8a)n-O-(CR8R8a)p-、-(CR8R8a)n-N(R5)-(CR8R8a)p-、-(CR8R8a)n-S(=O)r-N(R5)-(CR8R8a)p-、-(CR8R8a)n-C(=O)-N(R5)-(CR8R8a)p-、-(CR8R8a)n-N(R5)-C(=O)-N(R5)-(CR8R8a)p-、-(CR8R8a)n-C(=O)-O-(CR8R8a)p-、-(CR8R8a)n-N(R5)-S(=O)r-N(R5)-(CR8R8a)p-、-(CR8R8a)n-S(=O)r-(CR8R8a)p-、-(CR8R8a)n-S(=O)r-O-(CR8R8a)p-、-(CR8R8a)n-C(=O)-(CR8R8a)p-、-(CR8R8a)n-C(=S)-(CR8R8a)p-、-(CR8R8a)n-N(R5)-C(=O)-O-(CR8R8a)pOr each of A and A' is independently the following group:
each R5Independently H, deuterium, hydroxy, C1-6Alkyl radical, C2-6Heteroalkyl group, C3-10Cycloalkyl radical, C2-10Heterocyclic group, C6-10Aryl radical, C1-9Heteroaryl group, C6-10Aryl radical C1-6Alkyl radical, C1-6Alkoxy radical, C1-6alkyl-OC (= O) -, C1-6alkyl-C (= O) -, carbamoyl, C1-6alkyl-OS (= O)r-、C1-6alkyl-S (= O)rO-, alkyl-S (= O)r-or aminosulfonyl;
each R5a、R5a’And R6aIndependently is H, deuterium, oxo (= O), hydroxy, amino, F, Cl, Br, I, cyano, R13aR13N-、-C(=O)NR13R13a、-OC(=O)NR13R13a、-OC(=O)OR13、-N(R13)C(=O)NR13R13a、-N(R13)C(=O)OR13、-N(R13)C(=O)-R13、R13R13aN-S(=O)2-、R13S(=O)2-、R13S(=O)2N(R13a)-、C1-6Alkyl acyl radical, C1-6Alkyl acyloxy, C1-6Alkoxyacyl group, C1-6Alkylsulfonyl radical, C1-6Alkoxysulfonyl group, C1-6Alkylsulfinyl radical, C1-6Alkylsulfonyloxy, C1-6Alkylsulfinyloxy, C1-6Alkoxy radical, C1-6Alkyl radical, C6-10Aryl, -CF3、-OCF3Mercapto, nitro, C1-6Alkylamino radical, C3-10Cycloalkyl or C6-10An aryloxy group;
each R6Independently of each other is hydrogen, deuterium, R13R13aNC(=O)-、R13OC(=O)-、R13C(=O)-、R13R13aNS(=O)-、R13OS(=O)-、R13S(=O)-、R13R13aNS(=O)2-、R13OS(=O)2-、R13S(=O)2-、C1-6Aliphatic, C1-6Alkoxy radical C1-6Aliphatic, C1-6Alkylamino radical C1-6Aliphatic, C6-10Aryl radical C1-6Aliphatic, C1-9Heteroaryl C1-6Aliphatic, C2-10Heterocyclyl radical C1-6Aliphatic, C3-10Cycloalkyl radical C1-6Aliphatic, C6-10Aryl radical, C1-9Heteroaryl group, C2-10Heterocyclyl or C3-10A carbocyclic group;
each R7And R7aIndependently H, deuterium, F, Cl, Br, I, C1-6Aliphatic, C2-6Heteroalkyl group, C1-6Alkoxy radical C1-6Aliphatic, C1-6Alkylamino radical C1-6Aliphatic, C6-10Aryl radical C1-6Aliphatic, C2-10Heterocyclyl radical C1-6Aliphatic, C3-10Cycloalkyl radical C1-6Aliphatic, C6-10Aryl radical, C1-9Heteroaryl group, C2-10Heterocyclyl or C3-10A carbocyclic group;
each R8And R8aIndependently H, deuterium, hydroxyl, cyano, nitro, F, Cl, Br, I, C1-6Alkyl radical, C2-6Heteroalkyl group, C3-10Cycloalkyl radical, C2-10Heterocyclic group, C6-10Aryl radical, C1-9Heteroaryl group, C6-10Aryl radical C1-6Alkyl radical, C1-6Alkoxy radical, C1-6alkyl-OC (= O) -, C1-6alkyl-C (= O) -, carbamoyl, C1-6alkyl-OS (= O)r-、C1-6alkyl-S (= O)rO-、C1-6alkyl-S (= O)r-or aminosulfonyl;
each R13And R13aIndependently of one another H, deuterium, C1-6Alkyl radical, C2-6Heteroalkyl group, C3-10Cycloalkyl radical, C2-10Heterocyclic group, C6-10Aryl radical, C1-9Heteroaryl or C6-10Aryl radical C1-6An alkyl group; or when R is13And R13aAttached to the same nitrogen atom, R13、R13aAnd the nitrogen atom optionally form a substituted or unsubstituted 3-8 membered ring, a spiro bicyclic ring or a fused bicyclic ring;
each n is independently 0, 1,2 or 3;
each p is independently 0, 1,2 or 3;
each r is independently 0, 1 or 2;
and each Y4And Y4'Du' aloneA bond standing on earth, O, S, - (CH)2)n-、-CH=CH-、-S(=O)r-、-CH2O-、-CH2S-、-CH2S(=O)r、-CF2-、-CHR5a、-CR5aR6a-or-CH2N(R6)-。
In still other embodiments, it has a structure as shown in formula (III):
wherein each Q1、Q2、Q4And Q5Independently is NR6O, S, C (= O) or (CR)7R7a)e；
And each of i and e is independently 0, 1,2,3 or 4.
In other embodiments, it has the structure shown in formula (IV):
wherein each Q1、Q2、Q4And Q5Independently O, S, C (= O), NR6Or CH2；
And each of i and e is independently 0, 1,2,3 or 4.
In still other embodiments, it has a structure as shown in formula (V):
wherein each Q1、Q2And Q4Independently O, S, C (= O), NR6Or CH2；
And each of i and e is independently 0, 1,2,3 or 4.
In other embodiments, it has a structure as shown in formula (VI):
wherein each Q1And Q2Independently O, S, C (= O), NR6Or CH2；
i is 0, 1,2,3 or 4;
and W3Is C3-10Carbocyclic radical or C2-10A heterocyclic group.
In still other embodiments, it has the structure shown in formula (VII):
wherein each Q1、Q3、Q4And Q5Independently O, S, C (= O), NR6Or CH2；
And e is 0, 1,2,3 or 4.
In other embodiments, it has the structure shown in formula (VIII):
wherein each Q1、Q3、Q4And Q5Independently O, S, C (= O), NR6Or CH2；
And e is 0, 1,2,3 or 4.
In other embodiments, it has a structure as shown in formula (IX):
wherein each Q1、Q3And Q4Independently O, S, C (= O), NR6Or CH2；
And e is 0, 1,2,3 or 4.
In still other embodiments, it has a structure as shown in formula (X):
wherein each Q1And Q3Independently O, S, C (= O), NR6Or CH2；
And W3Is C3-10Carbocyclic radical or C2-10A heterocyclic group.
In some of these embodiments, wherein Y and Y' are independently an alpha-amino acid group.
In still other embodiments, wherein the α -amino acid group is selected from the group consisting of isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine, alanine, asparagine, aspartic acid, glutamic acid, glutamine, proline, serine, para-tyrosine, arginine, histidine, cysteine, glycine, sarcosine, N, N-dimethylglycine, homoserine, norvaline, norleucine, ornithine, homocysteine, homophenylalanine, phenylglycine, ortho-tyrosine, meta-tyrosine, or hydroxyproline.
In still other embodiments, wherein the α -amino acid in the α -amino acid group is in the D configuration.
In still other embodiments, wherein the α -amino acid in the α -amino acid group is in the L configuration.
In some of these embodiments, wherein each Y and Y' is independently- [ U- (CR)9R9a)t-N(R10)-(CR9R9a)t]k-U-(CR9R9a)t-N(R11)-(CR9R9a)t-R12、-U-(CR9R9a)t-R12Or- [ U- (CR)9R9a)t-N(R10)-(CR9R9a)t]k-U-(CR9R9a)t-O-(CR9R9a)t-R12。
In still other embodiments, wherein each Y and Y' is independently- [ U- (CR)9R9a)t-N(R10)-(CR9R9a)t]k-U-(CR9R9a)t-N(R11)-(CR9R9a)t-R12。
In still other embodiments, wherein each Y and Y' is independently-U- (CR)9R9a)t-N(R10)-(CR9R9a)t-U-(CR9R9a)t-N(R11)-(CR9R9a)t-R12。
In still other embodiments, wherein each Y and Y' is independently-U- (CR)9R9a)t-N(R11)-(CR9R9a)t-R12。
In still other embodiments, wherein each Y and Y' is independently- [ C (= O) - (CR)9R9a)t-N(R10)-(CR9R9a)t]k-U-(CR9R9a)t-N(R11)-(CR9R9a)t-R12。
In still other embodiments, wherein each Y and Y' is independently-C (= O) - (CR)9R9a)t-N(R10)-(CR9R9a)t-U-(CR9R9a)t-N(R11)-(CR9R9a)t-R12。
In still other embodiments, wherein each Y and Y' is independently- [ C (= O) - (CR)9R9a)t-N(R10)-(CR9R9a)t]k-C(=O)-(CR9R9a)t-N(R11)-(CR9R9a)t-R12。
In still other embodiments, wherein each Y and Y' is independently-C (= O) - (CR)9R9a)t-N(R10)-(CR9R9a)t-C(=O)-(CR9R9a)t-N(R11)-(CR9R9a)t-R12。
In still other embodiments, wherein each Y and Y' is independently-C (= O) - (CR)9R9a)t-N(R11)-(CR9R9a)t-R12。
In still other embodiments, wherein each Y and Y' is independently-C (= O) - (CR)9R9a)t-N(R11)-(CR9R9a)t-C(=O)-R13。
In still other embodiments, wherein each Y and Y' is independently-C (= O) - (CR)9R9a)t-N(R11)-C(=O)-R13。
In still other embodiments, wherein each Y and Y' is independently-C (= O) - (CR)9R9a)t-N(R11)-(CR9R9a)t-C(=O)-O-R13。
In still other embodiments, wherein each Y and Y' is independently-C (= O) - (CR)9R9a)t-N(R11)-C(=O)-O-R13。
In still other embodiments, wherein each Y and Y' is independently-U- (CR)9R9a)t-R12。
In still other embodiments, wherein each Y and Y' is independently-C (= O) - (CR)9R9a)t-R12。
In still other embodiments, wherein each Y and Y' is independently- [ U- (CR)9R9a)t-N(R10)-(CR9R9a)t]k-U-(CR9R9a)t-O-(CR9R9a)t-R12。
In still other embodiments, wherein each Y and Y' is independently-U- (CR)9R9a)t-N(R10)-(CR9R9a)t-U-(CR9R9a)t-O-(CR9R9a)t-R12。
In still other embodiments, wherein each Y and Y' is independently-C (= O) - (CR)9R9a)t-N(R10)-(CR9R9a)t-C(=O)-(CR9R9a)t-O-(CR9R9a)t-R12。
In still other embodiments, wherein each Y and Y' is independently-U- (CR)9R9a)t-O-(CR9R9a)t-R12。
In still other embodiments, wherein each Y and Y' is independently-C (= O) - (CR)9R9a)t-O-(CR9R9a)t-R12。
In still other embodiments, wherein each Y and Y' is independently-C (= O) - (CR)9R9a)t-N(R11)-R12Wherein R is11、R12And the atoms to which they are attached may form a 4-7 membered ring.
In still other embodiments, wherein each R is9、R9a、R10And R11Independently of one another H, deuterium, C1-6Alkyl radical, C2-6Heteroalkyl group, C3-10Cycloalkyl radical, C2-10Heterocyclic group, C6-10Aryl radical, C1-9Heteroaryl group, C6-10Aryl radical C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-9Heteroaryl C1-6Alkyl radical, C2-10Heterocyclyl radical C1-6Alkyl or C3-8Cycloalkyl radical C1-6An alkyl group;
each R12Independently is R13aR13N-、-C(=O)R13、-C(=S)R13、-C(=O)-O-R13、-C(=O)NR13R13a、-OC(=O)NR13R13a、-OC(=O)OR13、-N(R13)C(=O)NR13R13a、-N(R13)C(=O)OR13a、-N(R13)C(=O)-R13a、R13R13aN-S(=O)2-、R13S(=O)2-、R13S(=O)2N(R13a)-、R13OS(=O)2-、C1-6Alkyl radical, C2-6Heteroalkyl group, C3-10Cycloalkyl radical, C2-10Heterocyclic group, C6-10Aryl radical, C1-9Heteroaryl or C6-10Aryl radical C1-6An alkyl group;
or R11、R12And the atoms to which they are attached may form a 4-7 membered ring;
each R13And R13aIndependently of one another H, deuterium, C1-6Alkyl radical, C2-6Heteroalkyl group, C3-10Cycloalkyl radical, C2-10Heterocyclic group, C6-10Aryl radical, C1-9Heteroaryl or C6-10Aryl radical C1-6An alkyl group; or when R is13And R13aAttached to the same nitrogen atom, R13、R13aAnd the nitrogen atom optionally form a substituted or unsubstituted 3-8 membered ring, a spiro bicyclic ring or a fused bicyclic ring.
In still other embodiments, wherein,
each R9、R9a、R10And R11Independently H, deuterium, methyl, ethyl, isopropyl, cyclohexyl, isobutyl or phenyl;
each R12Independently is-C (= O) R13、-C(=O)-O-R13、-C(=O)NR13R13aMethyl, ethyl, propyl, phenyl, cyclohexyl, morpholinyl or piperidinyl;
or R11、R12And the atoms to which they are attached may form a 4-7 membered ring;
and each R13And R13aIndependently H, deuterium, methyl, ethyl, propyl, phenyl, cyclohexyl, morpholinyl or piperidinyl.
In still other embodiments, it has a structure as shown in formula (XI):
wherein each R is14And R14aIndependently of one another H, deuterium, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C2-6Heteroalkyl group, C6-10Aryl radical, C1-9Heteroaryl group, C2-10Heterocyclic group, C3-8Cycloalkyl radical, C6-10Aryl radical C1-6Alkyl radical, C1-9Heteroaryl C1-6Alkyl radical, C2-10Heterocyclic ringsRadical C1-6Alkyl or C3-8Cycloalkyl radical C1-6An alkyl group.
In still other embodiments, it has the structure shown in formula (XII):
wherein each R is14And R14aIndependently of one another H, deuterium, C1-3Hydroxyalkyl, methyl, ethyl, isopropyl, isobutyl, tert-butyl, allyl, propargyl, trifluoroethyl, phenyl, pyranyl, morpholinyl, -NR13R13aBenzyl, piperazinyl, cyclopentyl, cyclopropyl, cyclohexyl or C1-9A heteroaryl group.
In some of these embodiments, it has the structure shown in formula (XIII):
wherein each R is14And R14aIndependently of one another H, deuterium, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C2-6Heteroalkyl group, C6-10Aryl radical, C1-9Heteroaryl group, C2-10Heterocyclic group, C3-8Cycloalkyl radical, C6-10Aryl radical C1-6Alkyl radical, C1-9Heteroaryl C1-6Alkyl radical, C2-10Heterocyclyl radical C1-6Alkyl or C3-8Cycloalkyl radical C1-6An alkyl group;
and each n2Independently 1,2,3 or 4.
In some of these embodiments, it has the structure shown in formula (IX'):
wherein each R is14And R14aIndependently of one another H, deuterium, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C2-6Heteroalkyl group, C6-10Aryl radical, C1-9Heteroaryl group, C2-10Heterocyclic group, C3-8Cycloalkyl radical, C6-10Aryl radical C1-6Alkyl radical, C1-9Heteroaryl C1-6Alkyl radical, C2-10Heterocyclyl radical C1-6Alkyl or C3-8Cycloalkyl radical C1-6An alkyl group;
and each n1Independently 1,2,3 or 4.
In some of these embodiments, it has a structure as shown in formula (X'),
wherein each Q1And Q2Independently O, S, C (= O), NR6Or CH2；
Each R5aAnd R5a’Independently of one another H, deuterium, C1-4Alkyl, oxo (= O), benzyl, F, Cl, Br, or I;
each R6And R7Independently of one another H, deuterium, C1-4Alkyl radical, C6-10Aryl radical, C2-10Heterocyclyl or C3-8A cycloalkyl group;
each R14And R14aIndependently of one another H, deuterium, C1-4Alkyl radical, C6-10Aryl radical, C2-10Heterocyclyl or C3-8A cycloalkyl group;
each R16And R16aIndependently is hydroxy, C1-4Alkyloxy, C6-10Aryloxy radical, C2-10Heterocyclyl or C3-8A cycloalkyl group;
whereinThe structural unit is the following sub-structural formula:
wherein Bn is benzyl;
the structural unit is the following group:
and each of A and A' is independently the following group:
wherein R is1、R2Heterocyclic or condensed rings or spiro rings independently formed from N-CHThe ring system is selected from the following subformulae:
wherein R is3、R4And N-CH are independently selected from the group consisting of the following substructures:
in other embodiments, wherein
Each R5aAnd R5a’Independently H, deuterium, methyl, ethyl, oxo (= O), benzyl, F, Cl, Br or I;
each R6And R7Independently H, deuterium, methyl, ethyl, isopropyl, phenyl or cyclohexyl;
each R14And R14aIndependently methyl, ethyl, phenyl, cyclohexyl, 1-methylpropyl, isopropyl, isobutyl or tert-butyl;
each R16And R16aIndependently is hydroxy, methoxy, ethoxy, phenoxy,Or tert-butoxy;
wherein said methyl, ethyl, phenyl, cyclohexyl, 1-methylpropyl, isopropyl, isobutyl, methoxy, ethoxy, phenoxy, benzyl, tert-butoxy or tert-butyl may be optionally substituted with one or more substituents selected from deuterium, F, Cl, Br, hydroxy, cyano.
In some of these embodiments, it has the structure shown in formula (XI'),
wherein each Q1、Q2、Q4And Q5Independently O, S, C (= O), NR6Or CH2；
Each f and f' is independently 0, 1,2,3, or 4;
each i and e is independently 0, 1,2,3 or 4;
each R5aAnd R5a’Independently H, deuterium, methyl, ethyl, oxo (= O), benzyl, F, Cl, Br or I;
each Y is1、Y2、Y1’And Y2’Independently is N or CR7；
X1Is O, S, NR6C (= O) or CR7R7a；
Each R6、R7And R7aIndependently hydrogen, deuterium, methyl, ethyl, isopropyl, phenyl or cyclohexyl;
each R14And R14aIndependently methyl, ethyl, phenyl, cyclohexyl, 1-methylpropyl, isobutyl, isopropyl or tert-butyl;
each R16And R16aIndependently is hydroxy, methoxy, ethoxy, phenoxy,Or tert-butoxy;
wherein said methyl, ethyl, phenyl, cyclohexyl, 1-methylpropyl, isopropyl, isobutyl, methoxy, ethoxy, benzyl, tert-butoxy or tert-butyl may be optionally substituted with one or more substituents selected from deuterium, F, Cl, Br, hydroxy, cyano;
and each of A and A' is independently the following group:
wherein R is1、R2And N-CH are independently selected from the group consisting of the following substructures:
wherein R is3、R4And N-CH are independently selected from the group consisting of the following substructures:
in some of these embodiments, it has the structure shown in formula (XII'):
wherein each Q1、Q2、Q4And Q5Independently O, S, C (= O), NR6Or CH2；
Each X1Independently O, S, NR6C (= O) or CR7R7a；
Each R6、R7And R7aIndependently hydrogen, deuterium, methyl, ethyl, isopropyl, phenyl or cyclohexyl;
each R5aAnd R5a’Independently H, deuterium, methyl, ethyl, oxo (= O), benzyl, F, Cl, Br or I;
each Y is1、Y2、Y1’And Y2’Independently is N or CR7；
Each f and f' is independently 0, 1,2,3, or 4;
each i and e is independently 0, 1,2,3 or 4;
each R14And R14aIndependently methyl, ethyl, phenyl, cyclohexyl, 1-methylpropyl, isopropyl, isobutyl or tert-butyl;
each R16And R16aIndependently is hydroxy, methoxy, ethoxy, phenoxy,Or tert-butoxy;
wherein said methyl, ethyl, phenyl, cyclohexyl, 1-methylpropyl, isopropyl, isobutyl, methoxy, ethoxy, phenoxy, benzyl, tert-butoxy or tert-butyl may be optionally substituted with one or more substituents selected from deuterium, F, Cl, Br, hydroxy, cyano;
and each of A and A' is independently the following group:
wherein R is1、R2And N-CH are independently selected from the group consisting of the following substructures:
wherein R is3、R4And N-CH are independently selected from the group consisting of the following substructures:
in some of these embodiments, it has a compound according to formula (XIII'):
wherein each Q1、Q2And Q4Independently O, S, C (= O), NR6Or CH2；
X3Is O, S, NR6C (= O) or CR7R7a；
Each R6、R7And R7aIndependently hydrogen, deuterium, methyl, ethyl, isopropyl, phenyl or cyclohexyl;
each R5aAnd R5a’Independently H, deuterium, methyl, ethyl, oxo (= O), benzyl, F, Cl, Br or I;
each Y is1、Y2、Y1’And Y2’Independently is N or CR7；
Each f and f' is independently 0, 1,2,3, or 4;
each i and e is independently 0, 1,2,3 or 4;
each R14And R14aIndependently methyl, ethyl, phenyl, cyclohexyl, 1-methylpropyl, isopropyl, isobutyl or tert-butyl;
each R16And R16aIndependently is hydroxy, methoxy, ethoxy, phenoxy,Or tert-butoxy;
wherein said methyl, ethyl, phenyl, cyclohexyl, 1-methylpropyl, isopropyl, isobutyl, methoxy, ethoxy, benzyl, tert-butoxy or tert-butyl may be optionally substituted with one or more substituents selected from deuterium, F, Cl, Br, hydroxy, cyano;
and each of A and A' is independently the following group:
wherein R is1、R2And N-CH are independently selected from the group consisting of the following substructures:
wherein R is3、R4And N-CH are independently selected from the group consisting of the following substructures:
in some of these embodiments, a structure comprising one of the following:
or a stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, solvate or pharmaceutically acceptable salt thereof.
The compounds of the present invention (the expressions "compounds of formula (I) and stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates and pharmaceutically acceptable salts and prodrugs thereof" may be collectively referred to as "compounds of the present invention") may be used in the manufacture of a pharmaceutical product for the treatment of acute and chronic HCV infections, including those described herein. Further, the compounds of the present invention may be used in the manufacture of anti-HCV preparations. Thus, the compounds of the present invention may be used in the manufacture of a medicament for alleviating, preventing, controlling or treating HCV-mediated disorders, in particular HCV NS5A protein-mediated diseases. Thus, the compounds of the present invention may be used as active ingredients of pharmaceutical compositions which may comprise a compound represented by formula (I), and which may further comprise at least one pharmaceutically acceptable carrier, adjuvant or diluent.
In particular, the salts are pharmaceutically acceptable salts. The term "pharmaceutically acceptable" means that the substance or composition employed must be compatible chemically or toxicologically with the other ingredients comprising the formulation and the mammal being treated. The "pharmaceutically acceptable" substance or composition may be specifically selected by those skilled in the art depending on the other components employed and the subject, e.g., human, being treated.
Salts of the compounds of the present invention also include, but are not necessarily pharmaceutically acceptable salts of intermediates used in the preparation or purification of the compounds of formula (I) or isolated enantiomers of the compounds of formula (I).
If the compounds of the invention are basic, the desired salts may be prepared by any suitable method provided in the literature, for example, using inorganic or organic acids. Among them, examples of the inorganic acid include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Examples of organic acids include, but are not limited to, acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, and salicylic acid; pyranonic acids, such as glucuronic acid and galacturonic acid; alpha-hydroxy acids such as citric acid and tartaric acid; amino acids such as aspartic acid and glutamic acid; aromatic acids such as benzoic acid and cinnamic acid; sulfonic acids such as p-toluenesulfonic acid, ethanesulfonic acid, and the like.
If the compounds of the invention are acidic, the desired salts can be prepared by suitable methods, e.g., using inorganic or organic bases, such as ammonia (primary, secondary, tertiary), alkali or alkaline earth metal hydroxides, and the like. Suitable salts include, but are not limited to, organic salts derived from amino acids such as glycine and arginine, ammonia such as primary, secondary and tertiary amines, and cyclic amines such as piperidine, morpholine, piperazine and the like, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
Compositions, formulations and administration of the Compounds of the invention
The pharmaceutical composition comprises any one of the compounds of the present invention. The pharmaceutical composition may further comprise a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or combination thereof. The pharmaceutical composition can be used for treating Hepatitis C Virus (HCV) infection or hepatitis C disease, and particularly has a good inhibition effect on HCV NS5A protein.
The pharmaceutical composition further comprises an anti-HCV agent. The anti-HCV agent can be any other known anti-HCV agent other than the compounds of the present invention. For example, it may be interferon, ribavirin, interleukin 2, interleukin 6, interleukin 12, a compound promoting the development of a type 1 helper T cell response, interfering RNA, antisense RNA, imiqimod, inosine 5' -monophosphate dehydrogenase inhibitor, amantadine, rimantadine, baviuximab (Bavituximab), CivacirTM, Poplervir (boceprevir), Telaprevir (telaprevir), erlotinib (erlotinib), daclatasvir, simeprevir, asunaprevir, vanilprevir, faldapevir, ABT-450, danoprevir, sovapevir, MK-5172, vepredevir, Bdrvivir-961, GS-9256, narloprevir, ANA975, ABT-267, EDP 63668, PPI-239, GS-5816, SAdvivir (ZF719-719-7005, MK-8324, MK-3675, TMCt-366372, TMCt-86461, TMCb-3, TMCt-863, TMCt-33, TMCb-86461, TMCb-33, TMCt-33, TMCb-33, TMCt-33, TMCb-3, TMCb-, VX-985, IDX-375, VX-500, VX-813, PHX-1766, PHX-2054, IDX-136, IDX-316, EP-013420, VBY-376, TMC-649128, R-7128, PSI-7977, INX-189, IDX-184, IDX102, R1479, UNX-08189, PSI-6130, PSI-938, PSI-879, HCV-796, HCV-371, VCH-916, VCH-222, ANA-598, MK-3281, ABT-333, ABT-072, PF-00868554, BI-207127, GS-9190, A-837093, JKT-109, Gl-59728, GL-60667, AZD-2795, TMC 055647, or combinations thereof. Wherein the interferon is interferon alpha-2 b, pegylated interferon alpha, interferon alpha-2 a, pegylated interferon alpha-2 a, consensus interferon, interferon gamma, or a combination thereof. The pharmaceutical composition further comprises at least one HCV inhibitor for at least one of inhibiting the HCV replication process and inhibiting HCV viral protein function, wherein the HCV replication process is selected from the group consisting of HCV entry, uncoating, translation, replication, assembly, complete viral cycle of released HCV; the HCV viral proteins are selected from the group consisting of metalloprotease, NS2, NS3, NS4A, NS4B, NS5A, and NS 5B; as well as the Internal Ribosome Entry Site (IRES) and inosine monophosphate dehydrogenase (IMPDH) required for HCV viral replication.
When useful in therapy, a therapeutically effective amount of a compound of the present invention, particularly a compound of formula (I) and pharmaceutically acceptable salts thereof, may be administered as the raw chemical or as the active ingredient of a pharmaceutical composition. Accordingly, the present disclosure also provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of the present invention, particularly a compound of formula (I) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients. The term "therapeutically effective amount" as used herein refers to the total amount of each active component sufficient to show meaningful patient benefit (e.g., reduction in viral load). When the active ingredient alone is used for separate administration, the term refers only to that ingredient. When used in combination, the term refers to the combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, sequentially or simultaneously. The compounds of the invention, especially the compounds of formula (I) and pharmaceutically acceptable salts thereof, are as described above. The carrier, diluent or excipient must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. According to another aspect of the present disclosure there is also provided a process for the preparation of a pharmaceutical formulation which comprises mixing a compound of the present invention, especially a compound of formula (I) or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable carriers, diluents or excipients. The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio, and which are effective for their intended use.
The pharmaceutical preparations may be in unit dosage form, each unit dosage containing a predetermined amount of the active ingredient. Dosage levels of the compounds of the present disclosure are between about 0.01 and about 250 mg/kg body weight/day, preferably between about 0.05 and about 100mg/kg body weight/day, often as monotherapy for the prevention or treatment of HCV-mediated diseases. The pharmaceutical compositions of the present disclosure may generally be administered from about 1 to about 5 times per day or as a continuous infusion. Such administration may be used as a long term or short term therapy. The amount of active ingredient mixed with a carrier material to prepare a single dosage form will vary depending on the disease to be treated, the severity of the disease, the time of administration, the route of administration, the rate of excretion of the compound used, the time of treatment and the age, sex, body weight and condition of the patient. Preferred unit dosage forms are those containing a daily or divided dose or suitable fraction thereof of the active ingredient described herein above. Treatment can be initiated with small doses, which are clearly below the optimal dose of the compound. Thereafter, the dosage is increased in smaller increments until the optimum effect is achieved in this case. In general, the compounds are most desirably administered at concentration levels that generally provide effective results in terms of antiviral efficacy without causing any harmful or toxic side effects.
When the compositions of the present disclosure comprise a combination of a compound of the present disclosure and one or more other therapeutic or prophylactic agents, the dosage level of the compound and the additional agent(s) will generally be from about 10% to about 150% of the normally administered dose, more preferably from about 10% to about 80% of the normally administered dose, in a monotherapy regimen. The pharmaceutical formulations are adapted for administration by any suitable route, for example by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intradermal, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional, intravenous or subdermal injection or infusion) route. Such formulations may be prepared by any method known in the art of pharmacy, for example by mixing the active ingredient with a carrier or excipient. Oral administration or injection administration is preferred.
Pharmaceutical formulations adapted for oral administration are provided in discrete units, such as capsules or tablets; powder or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foam or foam formulations (whip); or an oil-in-water emulsion or a water-in-oil emulsion.
For example, for oral administration in the form of a tablet or capsule, the active pharmaceutical ingredient may be mixed with a pharmaceutically acceptable oral, non-toxic inert carrier (e.g., ethanol, glycerol, water, etc.). Powders are prepared by pulverizing the compound to a suitable fine size and mixing with a pharmaceutically acceptable carrier (e.g., an edible sugar such as starch or mannitol) which is also pulverized. Flavoring, preservative, dispersing and coloring agents may also be present.
Capsules are prepared by preparing a powdered mixture as described above and filling into shaped gelatin shells. Glidants and lubricants (e.g., colloidal silicon dioxide, talc, magnesium stearate, calcium stearate, or solid polyethylene glycol) may be added to the powder mixture prior to the filling operation. Disintegrating or solubilizing agents (e.g., agar-agar, calcium carbonate or sodium carbonate) that will improve the availability of the drug when the capsule is taken can also be added.
In addition, if desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars (e.g., glucose or beta-lactose), corn sweeteners, natural and synthetic gums (e.g., gum arabic, tragacanth or sodium alginate), carboxymethylcellulose, polyethylene glycol, and the like. Lubricants used in these dosage forms include sodium oleate, sodium chloride, and the like. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, and the like. For example, tablets are prepared by making a powder mixture, granulating or slugging, adding a lubricant and a disintegrant, and compressing into tablets. The powdered mixture is prepared by mixing the appropriately comminuted compound with a diluent or base as described above, optionally with a binder (for example carboxymethylcellulose, alginates, gelatin or polyvinylpyrrolidone), a dissolution inhibitor (for example paraffin), an absorption accelerator (quaternary salt) and/or an absorbent (for example bentonite, kaolin or dicalcium phosphate). The powdered mixture may be granulated by wetting with a binder such as syrup, starch slurry, acacia slurry (acadia mucilage) or a solution of cellulosic or polymeric material and pressure sieving. An alternative to granulation is to pass the powder mixture through a tablet press, with the result that poorly formed agglomerates are broken up into granules. The granules may be lubricated by the addition of stearic acid, a stearate salt, talc or mineral oil to prevent sticking to the dies of the tablet press. The lubricated mixture is then compressed into tablets. The compounds of the present disclosure may also be combined with a free-flowing inert carrier and compressed into tablets without going through a granulation or pre-compression step. Transparent or opaque protective coating materials may be provided which consist of a shellac coating, a sugar coating or a coating of a polymeric material and a waxy polishing coating (wax). Dyes may be added to these coatings to distinguish different unit doses.
Oral liquid preparations such as solutions, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs can be prepared through the use of non-toxic vehicles. Solubilizing agents and emulsifiers (e.g., ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers), preservatives, flavoring additives (e.g., peppermint oil or natural sweeteners or saccharin or other artificial sweeteners), and the like may also be added.
Dosage unit formulations for oral administration may be microencapsulated, if appropriate. The formulations may also be formulated for extended or sustained release, for example by coating or embedding in a particulate material such as a polymer, wax or the like.
The compounds of the invention, particularly the compounds of formula (I) and pharmaceutically acceptable salts thereof, may also be administered in liposomal delivery systems, such as small unilamellar liposomes, large unilamellar liposomes, and multilamellar liposomes. Liposomes can be composed of a variety of phospholipids (e.g., cholesterol, octadecylamine, or phosphatidylcholine).
The compounds of the invention, especially the compounds of formula (I) and pharmaceutically acceptable salts thereof, may also be delivered by using the monoclonal antibody as a separate carrier to which the compound molecule is coupled. The compounds may also be conjugated to soluble polymers as targetable drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide phenol, polyhydroxyethylaspartamide phenol, or polyethyleneoxide polylysine substituted with palmitoyl residues. In addition, the compounds may be coupled to a class of biodegradable polymers for achieving controlled release of a drug, such as polylactic acid, poly-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphipathic block copolymers of hydrogels.
Pharmaceutical formulations adapted for transdermal administration may be presented as discrete patches (patches) to remain in intimate contact with the epidermis of the recipient for an extended period of time. For example, the active ingredient may be delivered by iontophoretic patches, as generally described in Pharmaceutical Research 1986,3(6), 318.
Pharmaceutical preparations suitable for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, oils or transdermal patches.
Pharmaceutical formulations adapted for rectal administration may be presented as suppositories or as enemas.
Pharmaceutical formulations suitable for nasal administration, wherein the carrier is a solid, include coarse powders having a particle size in the range of, for example, 20 to 500 microns, which are administered by nasal inhalation, i.e. by rapid inhalation through the nasal passage from a coarse powder container adjacent the nose. Suitable formulations in which the carrier is a liquid, suitable for administration as a nasal spray or nasal drops, include aqueous or oily solutions of the active ingredient.
Pharmaceutical formulations suitable for administration by inhalation include finely divided particulate powders (dust) or mists (mist), which may be prepared in different types of metered dose compressed aerosols, nebulised inhalers, insufflators or other devices adapted to deliver aerosol sprays.
Pharmaceutical formulations adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
Pharmaceutical formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions, which may contain antioxidants, buffers, bacteriostats and solutes that render the formulation isotonic with the blood of the recipient, and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed amkside and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. The injection solution and suspension can be prepared into sterile powder for injection, granule and tablet.
It will be appreciated that in addition to the ingredients particularly mentioned above, the formulations may include other ingredients conventional in the art having regard to the type of formulation in question, for example, such formulations which are suitable for oral administration may include flavouring agents.
Use of the Compounds and pharmaceutical compositions of the invention
The present invention provides the use of a compound or pharmaceutical composition of the invention in the manufacture of a medicament useful for at least one of inhibiting the HCV replication process and inhibiting HCV viral protein function. The HCV replication process is selected from the complete viral cycle of HCV entry, uncoating, translation, replication, assembly, release. The HCV viral proteins are selected from the group consisting of metalloprotease, NS2, NS3, NS4A, NS4B, NS5A, and NS 5B; as well as the Internal Ribosome Entry Site (IRES) and inosine monophosphate dehydrogenase (IMPDH) required for HCV viral replication. Any compound or pharmaceutical composition of the invention can be used for treating Hepatitis C Virus (HCV) infection or hepatitis C disease, and particularly has good inhibition effect on HCV NS5A protein.
A method of treatment comprising administering a compound or pharmaceutical composition of the invention further comprising administering to the patient an additional HCV agent, whereby a compound of the invention may be administered in combination therapy with an additional anti-HCV agent, wherein the anti-HCV agent is interferon, ribavirin, interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, imiqimod, an inosine 5' -monophospate dehydrogenase inhibitor, amantadine, rimantadine, ribavirin, baviximab (Bavituximab), CivacirTMBoceprevir, telaprevir, erlotinib, daclatasvir, simeprevir, asunaprevir, vaniprevir, faldaprevir, ABT-450, danoprrevir, sovaprevir, MK-5172, vedroprevir, BZF-961, GS-9256, narlaprevir, ANA975, ABT-267, EDP239, PPI-668, GS-5816, samatasvir (IDX-IDX), MK-8742, MK-8325, GSK-2336805, PPI-461, TMC-435, MK-7009, BI-2013335, cilaprevir, BMS-650032, ACH-1625, ACH-1095, VX-985, IDX-375, VX 176-500, VX-813, PHX-2056, PHX-KT 4, IDX-136, IDX-316, EP-013420, TMC-VBY-376, TMC-865, PSI-7128, INPSI-71184, ABT-798, ABT-469, ABT-102, ABT-469, SAT-102, SATABt-102, SATASx-102, SAM-1625, SATAX-1625, SAM-1625, SATAX-102, SAT-102, SATAX-102, SAMPX-102, SATAX-102, SAX-102.
And a method of treatment comprising administering a compound or pharmaceutical composition of the invention, further comprising administering an additional anti-HCV agent, wherein the additional anti-HCV agent may be administered in combination with a compound or pharmaceutical composition of the invention as a single dosage form, or as separate compounds or pharmaceutical compositions as part of a multiple dosage form. Other anti-HCV agents may be administered with or without the compounds of the present invention. In the latter case, administration may be carried out by, for example, shifting between 6 hours, 12 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month, or 2 months.
An "effective amount" or "effective dose" of a compound or pharmaceutically acceptable composition of the invention refers to an amount effective to treat or reduce the severity of one or more of the conditions mentioned herein. The compounds and compositions according to the methods of the present invention can be administered in any amount and by any route effective to treat or reduce the severity of the disease. The exact amount necessary will vary depending on the patient, depending on the race, age, general condition of the patient, severity of infection, particular factors, mode of administration, and the like. The compound or composition may be administered in combination with one or more other therapeutic agents, as discussed herein.
General synthetic procedure
In general, the compounds of the present invention may be prepared by the methods described herein, wherein the substituents are as defined in formula (I), unless otherwise indicated. The following reaction schemes and examples serve to further illustrate the context of the invention.
Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare a number of other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modification, such as appropriate protection of interfering groups, by the use of other known reagents in addition to those described herein, or by some routine modification of reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized as being applicable to the preparation of other compounds of the present invention.
The examples described below, unless otherwise indicated, are all temperatures set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Inc., Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. General reagents were purchased from Shantou Wen Long chemical reagent factory, Guangdong Guanghua chemical reagent factory, Guangzhou chemical reagent factory, Tianjin HaoLiyu Chemicals Co., Ltd, Qingdao Tenglong chemical reagent Co., Ltd, and Qingdao Kaseiki chemical plant.
The anhydrous tetrahydrofuran, dioxane, toluene and ether are obtained through reflux drying of metal sodium. The anhydrous dichloromethane and chloroform are obtained by calcium hydride reflux drying. Ethyl acetate, petroleum ether, N-hexane, N-dimethylacetamide and N, N-dimethylformamide were used by being dried beforehand over anhydrous sodium sulfate.
The following reactions are generally carried out under positive pressure of nitrogen or argon or by sleeving a dry tube over an anhydrous solvent (unless otherwise indicated), the reaction vial being stoppered with a suitable rubber stopper and the substrate being injected by syringe. The glassware was dried.
The column chromatography is performed using a silica gel column. Silica gel (300 and 400 meshes) was purchased from Qingdao oceanic chemical plants. Nuclear magnetic resonance spectroscopy with CDC13、d6-DMSO、CD3OD or d6Acetone as solvent (reported in ppm) with TMS (0ppm) or chloroform (7.25ppm) as reference standard. When multiple peaks occur, the following abbreviations will be used: s (singleton), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad), dd (doublet of doublets), dt (doublet of triplets), and dt (doublet of triplets). Coupling constants are expressed in hertz (Hz).
Low resolution Mass Spectral (MS) data were measured by an Agilent6320 series LC-MS spectrometer equipped with a G1312A binary pump and a G1316A TCC (column temperature maintained at 30 ℃), a G1329A autosampler and a G1315B DAD detector were applied for analysis, and an ESI source was applied to the LC-MS spectrometer.
Low resolution Mass Spectral (MS) data were determined by Agilent6120 series LC-MS spectrometer equipped with a G1311A quaternary pump and a G1316A TCC (column temperature maintained at 30 ℃), a G1329A autosampler and a G1315D DAD detector were used for analysis, and an ESI source was used for the LC-MS spectrometer.
Both spectrometers were equipped with an Agilent Zorbax SB-C18 column, 2.1X 30mm, 5 μm. The injection volume is determined by the sample concentration; the flow rate is 0.6 mL/min; peaks of HPLC were recorded by UV-Vis wavelength at 210nm and 254 nm. The mobile phases were 0.1% formic acid in acetonitrile (phase a) and 0.1% formic acid in ultrapure water (phase B). Gradient elution conditions are shown in table 1:
TABLE 1
Time (min) A(CH3CN，0.1% HCOOH) B(H2O，0.1% HCOOH)
0-3 5-100 95-0
3-6 100 0
6-6.1 100-5 0-95
6.1-8 5 95
Compound purification was assessed by Agilent 1100 series High Performance Liquid Chromatography (HPLC) with UV detection at 210nm and 254nm, a Zorbax SB-C18 column, 2.1X 30mm, 4 μm, 10 min, flow rate 0.6mL/min, 5-95% (0.1% formic acid in acetonitrile) in (0.1% formic acid in water), the column temperature was maintained at 40 ℃.
The following acronyms are used throughout the invention:
HOAc acetic acid
MeCN,CH3CN acetonitrile
NH3Ammonia
NH4C1 Ammonia chloride
BBr3Boron tribromide
BSA bovine serum albumin
Br2Bromine compound
BOC, Boc tert-butoxycarbonyl
Cs2CO3Cesium carbonate
CHCl3Chloroform
CDC13Deuterated chloroform
Cu copper
CuI cuprous iodide
Et2O Ether
DMF N, N-dimethylformamide
DMAP 4-dimethylaminopyridine
DMSO dimethyl sulfoxide
EDC, EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride
Dippa Azoic Diphenyl phosphate
EtOAc ethyl acetate
EA Ethyl acetate
HBr hydrobromic acid
HCl hydrochloric acid
HOAt, HOAT 1-hydroxy-7-azabenzotriazole
HOBT 1-hydroxybenzotriazole
H2Hydrogen gas
H2O2Hydrogen peroxide
Fe iron
LDA lithium diisopropylamide
MCPBA m-chloroperoxybenzoic acid
MgSO4Magnesium sulfate
MeOH,CH3OH methanol
MeI methyl iodide
CH2Cl2DCM dichloromethane
NMP N-methylpyrrolidone
mL, m mL
N2Nitrogen gas
Pd/C Palladium/carbon
PE Petroleum ether (60-90 deg.C)
PBS phosphate buffered saline
POC13Phosphorus oxychloride
Pd(PPh3)4Tetratriphenylphosphine palladium
Pd(dppf)Cl21,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride
K2CO3Potassium carbonate
KOH potassium hydroxide
RT, RT Room temperature
Rt Retention time
NaHCO3Sodium bicarbonate
NaBH4Sodium borohydride
NaBH3CN Cyanoborohydride sodium salt
NaOtBu tert-butyl sodium alcoholate
NaOH sodium hydroxide
NaClO2Sodium chlorite
NaCl sodium chloride
NaH2PO4Sodium dihydrogen phosphate
NaH sodium hydride
NaI sodium iodide
Na2SO4Sodium sulfate
TBTU O-benzotriazole-N, N, N ', N' -tetramethyluronium tetrafluoroborate
THF tetrahydrofuran
Et3N, TEA Triethylamine
TFA trifluoroacetic acid
P(t-bu)3Tri (tert-butyl) phosphine
NBS N-bromosuccinimide
TBAI tetrabutylammonium iodide
H2O water
TEAF Triethylamine Carboxylic acid
PPA polyphosphoric acid
Tf2O-Trifluoromethanesulfonic anhydride
HCl. EA hydrochloric acid ethyl acetate
DIPEA diisopropylethylamine
DME ethylene glycol dimethyl ether
HATU 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate
NIS N-iodosuccinimide
TFAA trifluoroacetic anhydride
SEMCl 2- (trimethylsilyl) ethoxymethyl chloride
Dess-Martin (Dess-Martin oxidant) (1,1, 1-triacetoxy) -1, 1-dihydro-1, 2-phenyliodoyl-3 (1H) -one
TsOH p-toluenesulfonic acid
TMSA trimethylsilyl acetylene
Meldrum's acid 2, 2-dimethyl-1, 3-dioxane-4, 6-diketone
BAST bis (2-methoxyethyl) aminosulfur trifluoride
SbCl3Antimony trichloride
SmCl3Samarium chloride
LiHMDS lithium hexamethyldisilazide
TMSCl trimethylchlorosilane
PhNTf2N-phenyl bis (trifluoromethanesulfonyl) imide
TBDMSOTf tert-butyl dimethyl p-toluene sulfonic silane
Et2NSF3Diethylamine sulfur trifluoride
MTBE methyl tert-butyl ether
LiN(SiMe3)2Lithium bis (trimethylsilyl) amide
PPh3MeBr Bromomethyltriphenylphosphine
Lawesson's Reagent 2, 4-bis (4-methoxyphenyl) -1, 3-dithio-2, 4-phosphane-2, 4-disulfide
MTBE methyl tert-butyl ether
TEBAC benzyl triethyl ammonium chloride
I2Iodine
DAST diethylaminosulfur trifluoride
IPA isopropyl alcohol
TCCA trichloroisocyanuric acid
TEMPO 2,2,6, 6-tetramethylpiperidine-nitrogen-oxide
IMPDH inosine monophosphate dehydrogenase
IRES internal ribosome entry Point
Synthesis method 1
The target compound 18 can be prepared by synthesis method 1, wherein X5Is a leaving group such as F, Cl, Br, I, OTf, etc., and each R5a、R5a’、f、f’、Y1、Y2、Y1’、Y2’、Y4、W1、W2、R14And R16Having the meaning as described herein, Pg is an amino protecting group such as Boc, Fmoc, Cbz, etc. The compound 1 is cyclized under the action of alkali to obtain a compound 2, the compound 2 is cyclized under the action of a reducing agent to obtain a compound 3, the compound 3 is subjected to a halogenation reaction to obtain a compound 4, the compound 4 is demethylated to obtain a compound 5, the compound 5 is reacted with pinacol diboron under the catalysis of palladium to obtain a compound 6, the compound 6 and the compound 5' are subjected to a coupling reaction under the catalysis of palladium to obtain a compound 7, the compound 7 is reacted with trifluoromethanesulfonic anhydride under an alkaline condition to obtain a compound 8, and the compound 8 is reacted with pinacol diboron under the catalysis of palladium to obtain a compound 9. The compound 10 is subjected to reduction reaction under the action of borane to obtain a compound 11, then the compound 12 is obtained under the oxidation of dess-martin, the compound 12 is subjected to cyclization under the action of ammonia water and glyoxal to obtain a compound 13, the compound 13 is reacted with NIS to obtain a compound 14, and one iodine is removed from the compound 14 in a reaction system of sodium sulfite to obtain a compound 15. Coupling reaction is carried out on the compound 15 and the compound 9 under the catalysis of palladium to obtain a compound 16, deprotection of the compound 16 is carried out to obtain a compound 17, and condensation reaction is carried out on the compound 17 and a compound 17-1 to obtain a target compound 18.
Synthesis method 2
The target compound 31 can be prepared by synthesis method 2, wherein each A is1、A2And A3Independently selected from N or CR7、X5Is a leaving group such as F, Cl, Br, I, OTf, etc., and each R5a、R5a’、f、f’、Y1、Y2、Y1’、Y2’、Y4、Y4’、W1、W2、R14And R16Having the meaning as described in the present invention, Pg is an amino protecting group such as Boc, Fmoc, Cbz, etc. The compound 19 and the compound 19-1 are subjected to condensation reaction to obtain a mixture of compounds 20 and 21, then the mixture is heated and cyclized in an acetic acid system to obtain a compound 22, and the compound 22 is reacted with pinacol diboron under the catalysis of palladium to obtain a compound 23. The compound 5' reacts with trifluoromethanesulfonic anhydride under alkaline conditions to obtain a compound 24, the compound 24 reacts with a compound 6 under palladium catalysis to obtain a compound 25, the compound 25 further reacts with a compound 23 under palladium catalysis to obtain a compound 26, the compound 26 reacts with trifluoromethanesulfonic anhydride under alkaline conditions to obtain a compound 27, the compound 27 reacts with pinacol diboron under palladium catalysis to obtain a compound 28, the compound 28 reacts with a compound 15 under palladium catalysis to obtain a compound 29, the compound 29 is deprotected to obtain a compound 30, and the compound 30 reacts with the compound 17-1 to obtain a target compound 31.
Synthesis method 3
Compound 35 can be prepared by synthesis method 3. Wherein, X5Is F, Cl, Br,I. OTf, etc., and each R5a、R5a’、f、f’、Y1、Y2、Y1’、Y2’W and W1Have the meaning as described in the present invention. Compound 32 reacts with compound 33 under the action of an acid to give compound 34. And carrying out coupling reaction on the compound 34 and the compound 6 under the catalysis of palladium to obtain a target compound 35.
Synthesis method 4
The target compound 43 can be prepared by synthesis method 4, wherein each R5a、R5a’、f、f’、Y1、Y2、Y1’、Y2’、Y4、W1、W2、R14And R16Having the meaning as described herein, Pg is an amino protecting group such as Boc, Fmoc, Cbz, etc. Compound 36 reacts with TMSA under palladium catalysis to give compound 37, and compound 37 is base catalyzed to remove TMS to give compound 38. The compound 25 and the compound 15 are subjected to coupling reaction under the catalysis of palladium to obtain a compound 39, the compound 39 and trifluoromethanesulfonic anhydride are subjected to reaction under alkaline conditions to obtain a compound 40, the compound 40 and the compound 38 are subjected to coupling reaction under the catalysis of palladium to obtain a compound 41, the compound 41 is deprotected to obtain a compound 42, and the compound 42 and the compound 17-1 are subjected to condensation reaction to obtain a target compound 43.
Synthesis method 5
The target compound 54 can be prepared by synthesis method 5, wherein each A1、A2And A3Independently selected from N or CR7And each R is5a、R5a’、f、f’、Y1、Y2、Y4、Y4’、W1、R14And R16Having the meaning as described herein, Pg is an amino protecting group such as Boc, Fmoc, Cbz, etc. The compound 44 is obtained by the Diels-Alder reaction of benzoquinone and conjugated diene, the compound 44 is subjected to rearrangement reaction under the action of alkali to obtain a compound 45, the compound 45 is reduced under the action of Pd/C hydrogen to obtain a compound 46, and the compound 46 is subjected to reaction under the action of alkali and trifluoromethanesulfonic anhydride to obtain a target compound 47. The compound 47 and the compound 6 are subjected to coupling reaction under the catalysis of palladium to obtain a compound 48, the compound 48 and the compound 23 are further subjected to coupling reaction under the catalysis of palladium to obtain a compound 49, the compound 49 is subjected to reaction with trifluoromethanesulfonic anhydride under alkaline conditions to obtain a compound 50, the compound 50 and the pinacol diboron are subjected to reaction under the catalysis of palladium to obtain a compound 51, the compound 51 and the compound 15 are subjected to coupling reaction under the catalysis of palladium to obtain a compound 52, the compound 52 is deprotected to obtain a compound 53, and the compound 53 and the compound 17-1 are subjected to condensation reaction to obtain a target compound 54.
Synthesis method 6
The target compound 61 can be prepared by synthetic method 6, wherein each R5a、R5a’、f、f’、Y1、Y2And W1Have the meaning as described in the present invention. Dimethyl butynedicarboxylate and conjugated diene undergo a Diels-Alder reaction to obtain a compound 55, the compound 55 is reduced by Pd/C hydrogen to obtain a compound 56, the compound 56 is reduced by alkali to obtain a compound 57, the compound 57 undergoes a cyclization reaction to obtain a compound 58, the compound 58 undergoes a heating reaction under the condition of hydrazine hydrate/acetic acid to obtain a compound 59, the compound 59 undergoes a reaction under the action of phosphorus oxychloride to obtain a compound 60, and the compound 60 and the compound 6 undergo a coupling reaction under the catalysis of palladium to obtain a compound 61.
Synthesis method 7
The target compound 71 can be prepared by synthesis method 7, wherein X5Is a leaving group such as F, Cl, Br, I, OTf, etc., and each of w and R5a、R5a’、f、f’、Y1、Y2、Y2’、Y4、W、W1、R14And R16Having the meaning as described herein, Pg is an amino protecting group such as Boc, Fmoc, Cbz, etc. Halogenating the compound 62 to obtain a compound 63, removing methyl to obtain a compound 64, reacting the compound 64 with trifluoromethanesulfonic anhydride under alkaline conditions to obtain a compound 65, performing coupling reaction on the compound 65 and the compound 6 under palladium catalysis to obtain a compound 66, reacting the compound 66 with trifluoromethanesulfonic anhydride under alkaline conditions to obtain a compound 67, and reacting the compound 67 with pinacol diboron under palladium catalysis to obtain a compound 68. Coupling reaction is carried out on the compound 68 and the compound 15 under the catalysis of palladium to obtain a compound 69, deprotection is carried out on the compound 69 to obtain a compound 70, and condensation reaction is carried out on the compound 70 and the compound 17-1 to obtain a target compound 71.
Examples
Example 1
The synthetic route is as follows:
step 1) Synthesis of Compound 1-2
Reaction of Compound 1-1 (5.0 g,33.7 mmol) with K2CO3(23.4 g,168.5 mmol) was suspended in acetone (50 mL), methyl iodide (3.15 mL,50.55 mmol) was slowly added dropwise, reaction was carried out at 60 ℃ for 5.0 hours after completion of the reaction, the reaction solution was concentrated, water (150 mL) and EtOAc (150 mL) were added to the residue, celite was added, the filtrate was separated into layers, the aqueous layer was extracted with EtOAc (150 mL × 2), the organic phases were combined, washed with brine, and dried over Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 10/1) gave 2.46g of a yellow solid, yield: 45 percent.
MS(ESI,pos.ion)m/z:163.5[M+H]+；
1H NMR(400MHz,CDCl3):7.51-7.48(m,1H),7.30-7.26(m,1H),6.91-6.87(m,1H),3.90(s,3H),3.08-3.05(m,2H),2.70-2.67(m,2H)ppm。
Step 2) Synthesis of Compounds 1-3
t-BuOK (3.7 g,32.6 mmol) was suspended in toluene (20 mL) and N was added at 0 deg.C2Under protection, a solution of the compound 1-2 (2.3 g,14.2 mmol) and 1, 4-dibromobutane (3.6 g,15.6 mmol) in toluene (30 mL) was slowly added dropwise, and after completion of the dropwise addition, the reaction was carried out at 80 ℃ for 3.5 hours, after completion of the reaction, the reaction was cooled to room temperature, water (30 mL) was added to quench the reaction, the aqueous layer was extracted with EtOAc (50 mL × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE/EtOAc (v/v) = 8/1) to obtain 2.2g of a pale yellow liquid, and the yield: 72%.
MS(ESI,pos.ion)m/z:217.2[M+H]+；
1H NMR(400MHz,CDCl3):7.37-7.31(m,2H),7.03(dd,1H,J=6.2,2.5Hz),3.91(s,3H),2.93(s,2H),1.83-1.64(m,6H),1.52-1.42(m,4H)ppm。
Step 3) Synthesis of Compounds 1-4
Trifluoroacetic acid (4.0 mL,54 mmol) was slowly added dropwise to compound 1-3 at 0 deg.C(9.73 g,45 mmol) and triethylsilane (28.8 mL,180 mmol) were added dropwise and allowed to react overnight at 40 ℃. After completion of the reaction, the reaction mixture was concentrated, and the residue was dissolved in DCM (100 mL) and Na was added thereto2CO3The solution was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent: PE/EtOAc (v/v) = 10/1) to give 7.1g of a colorless oil, yield: 78 percent.
MS(ESI,pos.ion)m/z:203.2[M+H]+；
1H NMR(400MHz,CDCl3):7.13-7.10(m,1H),6.81-6.80(m,1H),6.67-6.65(m,1H),3.83(s,1H),2.85(s,2H),2.80(s,2H),1.72-1.57(m,8H)ppm。
Step 4) Synthesis of Compounds 1-5
Compound 1-4 (14.1 g,69.8 mmol) and NIS (17.2 g,76.8 mmol) were suspended in acetonitrile (200 mL), and trifluoroacetic acid (1.55 mL,20.9 mmol) was added dropwise slowly at 0 ℃ and reacted at room temperature overnight after completion of the addition. After completion of the reaction, the reaction solution was concentrated, and the residue was added with water (100 mL), extracted with EtOAc (100 mL. times.3), and the organic phases were combined, washed with a saturated sodium sulfite solution (50 mL. times.2) and a saturated brine, respectively, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE/DCM (v/v) = 20/1) to obtain 19.2g of a colorless oil, yield: 84 percent.
MS(ESI,pos.ion)m/z:329.2[M+H]+；
1HNMR(400MHz,CDCl3):7.45(d,1H),6.43(d,1H),3.77(s,3H),2.90(s,2H),2.81(s,2H),1.73-1.69(m,4H),1.63-1.59(m,4H)ppm。
Step 5) Synthesis of Compounds 1-6
At-78 ℃ BBr3(74.7 g,298.8 mmol) is slowly dropped into a DCM (150 mL) solution of the compound 1-5 (19.6 g,59.7 mmol), after dropping, the reaction is carried out for 20 minutes at constant temperature, the reaction is carried out for 1.0 hour at room temperature, after the reaction is completed, the reaction solution is slowly poured into ice water, a water layer is extracted by DCM (100 mL × 3), and the mixture is combinedOrganic phase, washed with brine, anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 4/1) gave 17.24g of an off-white solid, yield: 92 percent.
MS(ESI,pos.ion)m/z:315.2[M+H]+；
1H NMR(400MHz,CDCl3):7.36(d,1H),6.41(d,1H),4.91(s,1H),2.89(s,2H),2.82(s,2H),1.73-1.69(m,4H),1.67-1.63(m,4H)ppm。
Step 6) Synthesis of Compounds 1-7
Mixing compound 1-6 (0.5 g,1.59 mmol), compound 1-6-2 (0.60 g,2.36 mmol) and Pd (dppf) Cl2·CH2Cl2(64.9 mg,0.08 mmol) and anhydrous potassium acetate (0.62 g,6.32 mmol) in a reaction flask, N2Under the protection of anhydrous DMF (5 mL), then at 100 ℃ for 1.0 h, after the reaction is complete, the reaction mixture is cooled to room temperature, EtOAc (50 mL) is added to dilute the reaction mixture, the mixture is filtered through celite, and the filtrate is washed with water (25 mL × 3) and saturated brine, respectively, anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 10/1) gave 0.48g of a white solid, yield: 96 percent.
MS(ESI,pos.ion)m/z:315.3[M+H]+；
1H NMR(400MHz,CDCl3):7.51(d,1H,J=8.0Hz),6.60(d,1H,J=8.0Hz),5.29(s,1H),3.07(s,2H),2.72(s,2H),1.72-1.62(m,8H),1.31(s,12H)ppm。
Step 7) Synthesis of Compounds 1 to 8
Mixing compound 1-7 (0.15 g,0.48 mmol), compound 1-6 (0.18 g,0.57 mmol), potassium carbonate (0.16 g,1.12 mmol) and Pd (PPh)3)4(27.6 mg,0.024 mmol) in a reaction flask, N2DME (8 mL) and water (2 mL) were separately injected and reacted at 90 ℃ for 12 hours with protection. After completion of the reaction, the reaction mixture was cooled to room temperature, and EtOAc (50 mL) was added to dilute the reaction mixture, which was then washed with saturated brine and anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 10/1) gave 107.7mg of a white solid, yield: 60 percent.
MS(ESI,pos.ion)m/z:375.3[M+H]+；
1H NMR(400MHz,CDCl3):6.90(d,2H,J=8.1Hz),6.65(d,2H,J=8.1Hz),4.64(br.,2H),2.82(s,4H),2.66(s,4H),1.60-1.68(m,16H)ppm。
Step 8) Synthesis of Compounds 1-9
At 0 ℃, triethylamine (0.3 mL,2.16 mmol) is slowly dropped into a DCM (5 mL) solution of the compound 1-8 (80 mg,0.21 mmol), after stirring for 10 minutes, trifluoromethanesulfonic anhydride (0.3 mL,2.16 mmol) is further dropped, reaction is carried out at room temperature for 1.0 hour, after completion of the reaction, ice water (25 mL) is added to quench the reaction, an aqueous layer is extracted with DCM (25 mL × 3), organic phases are combined, the mixture is washed with saturated brine, and anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE) gave 130.5mg of a yellow liquid, yield: 97.4 percent.
1H NMR(400MHz,CDCl3):7.09(d,2H,J=8.4Hz),7.04(d,2H,J=8.4Hz),2.99(s,4H),2.66(s,4H),1.62-1.70(m,16H)ppm。
Step 9) Synthesis of Compounds 1-10
Mixing compound 1-9 (0.14 g,0.22 mmol), compound 1-6-2 (0.16 g,0.63 mmol) with Pd (dppf) Cl2·CH2Cl2(17.4 mg,0.021 mmol) and anhydrous potassium acetate (0.17 g,1.73 mmol) in a reaction flask, N2DMF (5 mL) was added under protection, the reaction was carried out at 100 ℃ for 1.0 hour, after completion of the reaction, the reaction mixture was cooled to room temperature, EtOAc (50 mL) was added to dilute the reaction mixture, the mixture was filtered through celite, and the filtrate was washed with water (25 mL × 3) and saturated brine, respectively, and dried over anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 50/1) gave 92.58mg of a white solid, yield: 70.8 percent.
1H NMR(400MHz,CDCl3):7.64(d,2H,J=7.5Hz),7.00(d,2H,J=7.5Hz),3.13(s,4H),2.59(s,4H),1.62-1.58(m,16H),1.35(s,24H)ppm。
Step 10) Synthesis of Compounds 1-12
Compound 1-11 (10.0 g,46.6 mmol) was dissolved in THF (100 mL), borane (100 mL,1M in THF) was slowly added dropwise to the reaction flask under nitrogen protection at 0 ℃ and the reaction was allowed to proceed for 3.0 hours at constant temperature after completion of the dropwise addition. After completion of the reaction, the reaction was quenched with methanol (80 mL), and the reaction solution was concentrated and purified by column chromatography (eluent: PE/EtOAc (v/v) = 3/2) to give 7.0g of a colorless oil, yield: 75.2 percent.
1H NMR(400MHz,CDCl3):3.99-3.87(br,1H),3.68-3.51(m,2H),3.48-3.39(m,1H),3.34-3.25(m,1H),2.05-1.92(m,2H),1.88-1.71(m,2H),1.45(s,9H)ppm。
Step 11) Synthesis of Compounds 1-13
Compounds 1-12 (7.0 g,34.8 mmol) were dissolved in DCM (250 mL) and dess-martin (20.7 g,48.8 mmol) was added in portions to the flask as oxidant at 0 deg.C, after which the reaction was allowed to proceed at room temperature for 2.0 h. After completion of the reaction, water (250 mL) was added to dilute the reaction solution, and the reaction solution was filtered, the filtrate was separated into layers, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE/EtOAc (v/v) = 3/2) to obtain 3.5g of a colorless oil, yield: 50.7 percent.
1H NMR(400MHz,CDCl3):9.46(d,1H,J=2.8Hz),4.08-4.03(m,1H),3.51-3.42(m,2H),2.01-1.93(m,2H),1.91-1.84(m,2H),1.43(s,9H)ppm。
Step 12) Synthesis of Compounds 1-14
Compound 1-13 (3.5 g,17.6 mmol) and ammonia (13 mL) were dissolved in methanol (30 mL), and an aqueous solution of glyoxal (40%, 8 mL) was slowly dropped into the reaction flask at 0 ℃ and reacted overnight at room temperature after completion of dropping. After completion of the reaction, the reaction solution was concentrated and purified by column chromatography (eluent: PE/EtOAc (v/v) = 3/2) to obtain 1.99g of a white solid, yield: 47.6 percent.
MS(ESI,pos.ion)m/z:238.2[M+H]+；
1H NMR(400MHz,CDCl3):6.96(s,1H),4.94(dd,1H,J=7.68Hz,2.40Hz),3.38(t,2H,J=6.24Hz),2.17-2.03(m,2H),1.99-1.91(m,2H),1.48(s,9H)ppm。
Step 13) Synthesis of Compounds 1-15
Compound 1-14 (2.0 g,8.4 mmol) was dissolved in DCM (60 mL), and N-iodosuccinimide (3.8 g,16.8 mmol) was added in portions to a reaction flask at 0 ℃ and reacted for 1.5 hours at constant temperature. After completion of the reaction, the reaction mixture was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent: PE/EtOAc (v/v) = 3/2) to obtain 2.6g of a white solid, yield: 63.1 percent.
MS(ESI,pos.ion)m/z:490.0[M+H]+；
1H NMR(400MHz,CDCl3):4.89(dd,1H,J=7.64Hz,2.52Hz),3.36(t,2H),2.14-2.02(m,2H),1.97-1.85(m,2H),1.49(s,9H)ppm。
Step 14) Synthesis of Compounds 1-16
Compound 1-15 (1.6 g,3.27 mmol) was suspended in a mixed solvent (50 mL) of ethanol and water (v/v = 3/7), and sodium sulfite (3.7 g,29 mmol) was added to the mixture and refluxed for 17 hours. After completion of the reaction, ethanol was removed, and the residue was added with water (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent: PE/EtOAc (v/v) = 3/2) to obtain 1.0g of a white solid, yield: 84 percent.
MS(ESI,pos.ion)m/z:364.1[M+H]+；
1H NMR(400MHz,CDCl3):7.04(d,1H,J=1.84Hz),4.89(dd,1H,J=7.72Hz,2.56Hz),3.36(t,2H),2.18-2.03(m,2H),1.97-1.82(m,2H),1.47(s,9H)ppm。
Step 15) Synthesis of Compounds 1-17
Mixing compound 1-10 (61.8 mg,0.104 mmol), compound 1-16 (112.5 mg,0.31 mmol), potassium carbonate (71.8 mg,0.52 mmol) and Pd (PPh)3)4(12 mg,0.0104 mmol) in a reaction flask, N2DME (6 mL) and water (1.5 mL) were separately injected and reacted at 90 ℃ for 2 hours with protection. After completion of the reaction, the reaction mixture was cooled to room temperature, and EtOAc (20 mL) was added to dilute the reaction mixture, which was then washed with saturated brine and anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 1/2) gave 59.2mg of a white solid, yield: 70 percent.
MS(ESI,pos.ion)m/z:407.2[M+2H]2+；
1H NMR(400MHz,CDCl3):10.60(br.,2H),7.08-7.22(m,6H),5.01(br,2H),3.42(m,4H),3.07-3.04(m,4H),2.70-2.68(m,4H),2.18(m,4H),2.05(m,4H),1.64-1.58(m,16H),1.51(s,18H)ppm。
Step 16) Synthesis of Compounds 1-18
Compounds 1 to 17 (38.2 mg,0.047 mmol) were dissolved in DCM (5 mL), and after further addition of a solution of hydrogen chloride in ethyl acetate (3 mL, 4M), the reaction was carried out at room temperature for 8 hours. After completion of the reaction, the reaction was concentrated, and the residue was washed with EtOAc (10 mL) and filtered to give 34.46mg as a white solid, yield: 96.7 percent.
MS(ESI,pos.ion)m/z:613.5[M+H]+；
1H NMR(400MHz,CD3OD):7.85(s,2H),7.64(d,2H,J=7.9Hz),7.22(d,2H,J=7.9Hz),5.25-5.20(m,2H),3.62-3.58(m,4H),3.12(s,4H),2.75-2.73(m,2H),2.71(s,4H),2.60-2.54(m,2H),2.45-2.35(m,2H),2.28-2.22(m,2H),1.73-1.63(m,16H)ppm。
Step 17) Synthesis of Compounds 1-19
Compounds 1-18 (60.6 mg,0.08 mmol), compounds 1-18-2 (29.43 mg,0.168 mmol) and EDCI (32.2 mg, 0) were combined.168 mmol) was dissolved in DCM (5 mL), DIPEA (0.10 mL,0.64 mmol) was added dropwise slowly at 0 ℃ and the reaction was carried out at room temperature for 3.0 hours after completion of the dropwise addition. After completion of the reaction, DCM (20 mL) was added to dilute the reaction solution, and the reaction solution was washed with an ammonium chloride solution and a saturated saline solution, respectively, and dried over anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: DCM/MeOH (v/v) = 60/1) gave 58.03mg of a white solid, yield: 78.3 percent.
MS(ESI,pos.ion)m/z:464.5[M+2H]2+；
1H NMR(400MHz,CDCl3):10.58(br,2H),7.22-7.06(m,6H),5.41(br,2H),5.29(br.,2H),4.33(m,2H),3.70(s,6H),3.66(m,4H),3.07-3.01(m,4H),2.69-2.67(m,4H),2.35-1.97(m,10H),1.64(m,16H),0.94-0.88(m,12H)ppm。
Example 2
The synthetic route is as follows:
step 1) Synthesis of Compound 2-1
Compound 1-18 (0.57 g,0.75 mmol), compound 2-1-0 (0.34 g,1.58 mmol), EDCI (0.30 g,1.58 mmol) and HOAT (0.20 g,1.50 mmol) were suspended in DCM (4 mL) at 0℃DIPEA (1.05 mL,6.01 mmol) was slowly added dropwise thereto, and the reaction was carried out at room temperature for 3.0 hours. After completion of the reaction, DCM (50 mL) was added to dilute the reaction solution, and the reaction solution was washed with an ammonium chloride solution and a saturated saline solution, respectively, and dried over anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 1/10) gave 0.42g of a pale yellow powder, yield: and 55 percent.
MS(ESI,pos.ion)m/z:506.3[M+2H]2+；
1H NMR(400MHz,CDCl3):7.88(s,2H),7.35-7.34(m,2H),7.32(m,2H),5.56,5.55(d,d,1H),5.46,5.44(d,d,1H),5.32-5.28(m,2H),4.40-4.35(m,2H),3.85-3.78(m,2H),3.69-3.61(m,2H),3.03-3.00(m,4H),2.97-2.94(m,4H),2.30-1.92(m,10H),1.70-1.50(m,12H),1.45(s,9H),1.41(s,9H),1.40-1.33(m,4H),1.02-0.89(m,12H)ppm。
Example 3
The synthetic route is as follows:
step 1) Synthesis of Compound 3-2
DIPEA (1.95 mL,11.8 mmol) was added to a solution of compound 3-1 (2.45 g,10.7 mmol) and HATU (4.88 g,12.84 mmol) in THF (30 mL) at 0 ℃ for 0.5 hour at constant temperature, and after completion of the addition, compound 3-1-2 (2.22 g,11.9 mmol) was added in portions and reacted at room temperature for 4.0 hours. After completion of the reaction, the reaction was quenched with water (50 mL), THF was removed, extracted with EtOAc (50 mL. times.3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and the residue was dissolved in glacial acetic acid (20 mL) and reacted overnight at 40 ℃. After completion of the reaction, glacial acetic acid was removed, and the residue was dissolved in EtOAc (100 mL), washed with sodium carbonate solution (50 mL. times.3), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent: PE/EtOAc (v/v) = 1/2) to give the product 3.24g, yield: 80 percent.
MS(ESI,pos.ion)m/z:380.5[M+H]+；
1H NMR(400MHz,CDCl3):7.84(d,1H,J=2.9Hz),7.44(d,1H,J=15.0Hz),7.33(dd,1H,J=15.0Hz,2.9Hz),4.88(t,1H,J=16.9Hz),4.27(dd,1H,J=24.8Hz,17.3Hz),3.14(dd,1H,J=24.7Hz,17.3Hz),2.53(dt,1H,J=24.4Hz,17.2Hz),2.21-2.03(m,1H),1.81(dt,1H,J=24.4Hz,17.2Hz),1.41(s,9H),0.95(d,3H,J=12.7Hz)ppm。
Step 2) Synthesis of Compound 3-3
Compound 3-2 (4.27 g,11.27 mmol), compound 1-6-2 (4.29 g,16.9 mmol), Pd (dppf) Cl2·CH2Cl2(0.65 g,0.8 mmol) and KOAc (2.09 g,21.3 mmol) were placed in a reaction flask, N2DME (30 mL) was injected under protection, the reaction was carried out at 90 ℃ for 3.0 hours, the reaction mixture was cooled to room temperature after completion of the reaction, EtOAc (200 mL) was added to dilute the reaction mixture, the mixture was filtered through celite, and the filtrate was washed with water (60 mL × 3) and saturated brine, respectively, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent: PE/EtOAc (v/v) = 1/2) to obtain 2.9g of a beige solid with a yield of 60%.
MS(ESI,pos.ion)m/z:428.5[M+H]+；
1H NMR(400MHz,CDCl3):7.82(dd,1H),7.65,7.63(d,d,1H),7.27,7.25(d,d,1H),5.07-5.02(m,1H),3.85-3.78(m,1H),3.14-3.07(m,1H),2.51-2.42(m,1H),2.30-2.16(m,1H),1.86-1.78(m,1H),1.41(s,9H),1.32,1.29(m,m,12H),0.96-0.93(m,3H)ppm。
Step 3) Synthesis of Compound 3-4
Compound 3-1 (1.12 g,4.88 mmol) was dissolved in THF (10 mL), borane (7.3 mL,1M in THF) was slowly added dropwise at 0 ℃ and after completion of the addition, the reaction was allowed to react at room temperature for 2.0 hours, after completion of the reaction, the reaction was quenched with methanol (4.0 mL), THF was removed, and the residue was dissolved in DCM (50 mL), washed with water (20 mL × 3) and saturated brine, respectively, and dried over Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 3/1) gave 1.03g of a colorless syrup, yield: 100 percent.
MS(ESI,pos.ion)m/z:216.3[M+H]+；
1H NMR(400MHz,CDCl3):4.02(s,1H),3.99-3.87(m,1H),3.75-3.68(m,1H),3.66(dd,1H,J=11.6Hz,2.0Hz),3.57(dd,1H,J=11.6Hz,7.4Hz),2.76(t,1H,J=10.5Hz),2.19-2.06(m,2H),1.46(s,9H),1.01(d,3H,J=6.2Hz)ppm。
Step 4) Synthesis of Compounds 3-6
Compound 3-4 (1.0 g,4.64 mmol) was dissolved in DCM (12 mL), a solution of TCCA (1.08 g,4.64 mmol) and TEMPO (64 mg,0.46 mmol) in DCM (5.0 mL) was added at 0 deg.C, after completion of the addition, the reaction was carried out at constant temperature for 1.0 hour, then the reaction was carried out at room temperature for 1.0 hour, after completion of the reaction, the solid was removed by filtration, the filtrate was washed with a saturated sodium sulfite solution (30 mL × 3), and the organic phase was washed with anhydrous Na2SO4Drying and concentrating to obtain the compound 3-5 as colorless slurry.
Dissolving compound 3-5 in ammonia methanol solution (10 mL, 7M), reacting at 0 deg.C for 0.5 hr, reacting at room temperature for 1.0 hr, slowly adding dropwise glyoxal water solution (1.2 mL, 40%) at 0 deg.C, reacting at room temperature for 24 hr, concentrating the reaction solution, dissolving the residue with DCM (100 mL), washing with water (30 mL × 3) and saturated saline, and removing anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: DCM/MeOH (v/v) = 100/1) gave 0.51g of a pale yellow solid, yield: 44 percent.
MS(ESI,pos.ion)m/z:252.3[M+H]+；
1H NMR(400MHz,CDCl3):6.97(s,2H),4.90(t,1H,J=8.0Hz),3.76(dd,1H,J=10Hz,7.2Hz),2.83(t,1H,J=8.0Hz),2.64-2.33(m,2H),2.32-2.12(m,1H),1.47(s,9H),1.09(d,3H,J=6.4Hz)ppm。
Step 5) Synthesis of Compounds 3-7
Compound 3-6 (0.51 g,2.03 mmol) was dissolved in DCM (10 mL), and NIS (1.0 g,4.46 mmol) was added at 0 ℃ and after the addition was completed, the reaction was allowed to proceed at constant temperature for 2.0 hours. After the reaction is finishedAfter completion, the solid was removed by filtration, and the filtrate was washed with saturated sodium sulfite solution (30 mL × 3), anhydrous Na2SO4Drying and concentration gave 0.9g of a yellow solid, yield: 90 percent. Directly used for the next reaction.
MS(ESI,pos.ion)m/z:504.1[M+H]+；
1H NMR(400MHz,CDCl3):4.85(t,1H,J=8.0Hz),3.75(dd,1H,J=10Hz,7.2Hz),2.84(t,1H,J=10Hz),2.52-2.29(m,2H),2.21(d,1H,J=6.6Hz),1.48(s,9H),1.08(d,3H,J=6.4Hz)ppm。
Step 6) Synthesis of Compounds 3-8
Dissolving compounds 3-7 (0.9 g,1.8 mmol) in ethanol (10 mL), adding sodium sulfite (2.0 g,16 mmol) and water (10 mL), reacting at 90 deg.C for 30 hr, filtering to remove solid, concentrating filtrate, dissolving the residue in DCM (50 mL), washing with water (20 mL × 2) and saturated saline, anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 6/1) gave 0.38g of a white solid, yield: 60 percent.
MS(ESI,pos.ion)m/z:378.2[M+H]+；
1H NMR(400MHz,CDCl3):7.04(s,1H),4.85(t,1H,J=8.4Hz),3.75(dd,1H,J=10.3Hz,7.3Hz),2.82(t,1H,J=10.4Hz),2.58-2.36(m,2H),2.29-2.11(m,1H),1.08(d,3H,J=6.4Hz)ppm。
Step 7) Synthesis of Compounds 3 to 9
Compound 1-6 (5.0 g,15.92 mmol) was dissolved in DCM (50 mL), pyridine (6.5 mL,79.62 mmol) was added at 0 deg.C, and after stirring for 10 minutes, Tf was slowly added dropwise2O (8.0 mL,47.77 mmol), reacting at constant temperature for 20 minutes, reacting at room temperature for 3 hours, after the reaction is completed, dropwise adding ice water (50 mL) to quench the reaction, extracting the water layer with DCM (60 mL × 3), combining the organic phases, washing with saturated brine, drying with anhydrous sodium sulfate, concentrating, and purifying by column chromatography (eluent: PE/EtOAc (v/v) = 6/1)5.98g of a pale yellow oily liquid was obtained.
1H NMR(400MHz,CDCl3):7.57(d,1H),6.79(d,1H),3.07(s,2H),2.88(s,2H),1.75-1.72(m,4H),1.65-1.63(m,4H)ppm。
Step 8) Synthesis of Compounds 3-10
Mixing 3-9 (0.21 g,0.48 mmol), 1-7 (0.18 g,0.57 mmol), potassium carbonate (0.16 g,1.12 mmol) and Pd (PPh)3)4(27.6 mg,0.024 mmol) in a reaction flask, N2DME (8 mL) and water (2 mL) were separately injected and reacted at 90 ℃ for 12 hours with protection. After completion of the reaction, the reaction mixture was cooled to room temperature, and EtOAc (50 mL) was added to dilute the reaction mixture, which was then washed with saturated brine and anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 5/1) gave 145.7mg of a white solid, yield: 60 percent.
1H NMR(400MHz,CDCl3):7.19-7.18(dd,dd,1H),6.97,6.95(dd,dd,1H),6.94,6.92(dd,dd,1H),6.67,6.64(dd,dd,1H),4.81(brs,1H),2.94-2.82(m,8H),1.74-1.38(m,16H)ppm。
Step 9) Synthesis of Compounds 3-11
Mixing compound 3-10 (3.90 g,7.7 mmol), compound 3-3 (3.29 g,7.7 mmol), Pd (PPh)3)4(0.45 g,0.38 mmol) and potassium carbonate (2.1 g,15.4 mmol) were placed in a reaction flask, N2DME (32 mL) and pure water (8.0 mL) were separately injected under the protection, and reacted at 90 ℃ for 5.0 hours, after completion of the reaction, the reaction mixture was cooled to room temperature, and then diluted with EtOAc (250 mL), washed with water (50 mL × 3) and saturated brine, respectively, and dried over anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 2/1) gave 2.02g of a pale yellow solid, yield: 40 percent.
1H NMR(400MHz,CDCl3):7.77,7.75(dd,dd,1H),7.58-7.57(q,1H),7.50,7.48(dd,dd,1H),7.47,7.45(dd,dd,1H),7.39,7.36(d,d,1H),7.02,6.99(dd,dd,1H),6.67,6.64(dd,dd,1H),5.14-5.09(m,1H),3.85-3.78(m,1H),3.14-3.07(m,1H),2.93-2.82(m,8H),2.51-2.42(m,1H),2.30-2.16(m,1H),1.86-1.78(m,1H),1.70-1.49(m,12H),1.42(s,9H),1.41-1.38(m,4H),0.96-0.93(m,3H)ppm。
Step 10) Synthesis of Compounds 3-12
Compound 3-11 (1.05 g,1.59 mmol) was dissolved in DCM (10 mL), pyridine (0.65 mL,7.96 mmol) was added at 0 ℃ and stirred for 10 minutes, then Tf was slowly dropped2O (0.8 mL,4.78 mmol), reacting at constant temperature for 20 minutes, reacting at room temperature for 3 hours, after the reaction is completed, dropwise adding ice water (20 mL) to quench the reaction, extracting the water layer with DCM (20 mL × 3), combining organic phases, washing with saturated brine, drying with anhydrous sodium sulfate, concentrating, and purifying by column chromatography (eluent: PE/EtOAc (v/v) = 1/1) to obtain 1.0g of light yellow oily liquid with the yield of 80%.
1H NMR(400MHz,CDCl3):7.78-7.77,7.76-7.75(d,d,1H),7.58-7.57(q,1H),7.47-7.46(m,2H),7.39,7.37-7.36(d,d,1H),7.21-7.20,7.19-7.18(d,d,1H),6.97-6.96,6.95-6.94(dd,dd,1H),5.14-5.09(m,1H),3.85-3.78(m,1H),3.14-3.07(m,1H),2.95-2.90(m,4H),2.89-2.86(m,4H),2.51-2.42(m,1H),2.30-2.16(m,1H),1.86-1.78(m,1H),1.75-1.45(m,16H),1.41(s,9H),0.96-0.93(m,3H)ppm。
Step 11) Synthesis of Compounds 3-13
Compound 3-12 (1.28 g,1.62 mmol), compound 1-6-2 (0.42 g,1.7 mmol), Pd (dppf) Cl2·CH2Cl2(67 mg,0.08 mmol) and KOAc (0.4 g,4.05 mmol) were placed in a reaction flask, N2DMF (10 mL) was added under protection, the reaction was carried out at 90 ℃ for 6.0 hours, the reaction mixture was cooled to room temperature after completion of the reaction, ethyl acetate (100 mL) was added to dilute the reaction mixture, the mixture was filtered through celite, and the filtrate was washed with water (50 mL × 3) and saturated brine, respectively, and the mixture was washed with anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 1/1) gave 0.62g of a pale yellow solid, yield: 50 percent.
MS(ESI,pos.ion)m/z:768.5[M+H]+；
1H NMR(400MHz,CDCl3):7.78-7.77,7.76-7.75(d,d,1H),7.64,7.62(dd,dd,1H),7.58-7.57(m,2H),7.47,7.45(dd,dd,1H),7.43,7.41(dd,dd,1H),7.39,7.36(d,d,1H),5.14-5.09(m,1H),3.85-3.78(m,1H),3.14-3.05(m,3H),2.93-2.86(m,6H),2.51-2.42(m,1H),2.30-2.16(m,1H),1.86-1.78(m,1H),1.72-1.44(m,14H),1.41(s,9H),1.32,1.29(q,q,12H),1.28-1.19(m,2H),0.96-0.93(m,3H)ppm。
Step 12) Synthesis of Compounds 3-14
Mixing compound 3-13 (0.44 g,0.58 mmol), compound 3-8 (0.24 g,0.63 mmol), Pd (PPh)3)4(35 mg,0.03 mmol) and potassium carbonate (0.08 g,1.4 mmol) were placed in a reaction flask, N2DME (8.0 mL) and pure water (2.0 mL) were separately injected under the protection, and reacted at 90 ℃ for 4.0 hours, after completion of the reaction, the reaction mixture was cooled to room temperature, and after adding EtOAc (40 mL) to dilute the reaction mixture, the reaction mixture was washed with water (30 mL × 3) and saturated brine, respectively, and anhydrous Na was added2SO4Drying, concentration and purification by column chromatography (eluent: DCM/MeOH (v/v) = 100/1) gave 0.28g of a pale yellow solid, yield: and 55 percent.
MS(ESI,pos.ion)m/z:446.3[M+2H]2+；
1H NMR(400MHz,CDCl3):7.78-7.77,7.76-7.75(d,d,1H),7.58-7.57(q,1H),7.56(s,1H),7.53,7.51-7.50(dd,dd,1H),7.49-7.48,7.46(dd,dd,1H),7.47,7.45(dd,dd,1H),7.39,7.37(d,d,1H),7.34,7.32(d,d,1H),5.14-5.09(m,1H),5.06-5.01(m,1H),3.85-3.73(m,2H),3.14-3.00(m,4H),2.97-2.86(m,6H),2.51-2.42(m,1H),2.35-2.18(m,3H),1.86-1.49(m,14H),1.42(s,9H),1.41(s,9H),1.40-1.34(m,4H),0.96-0.93(m,6H)ppm。
Step 13) Synthesis of Compounds 3-15
Compound 3-14 (0.36 g,0.4 mmol) was dissolved in EtOAc (4.0 mL), and a solution of hydrogen chloride in ethyl acetate (3.0 mL, 4M) was added dropwise thereto, followed by reaction at room temperature for 8.0 hours. After completion of the reaction, the reaction solution was concentrated, and the residue was slurried with ethyl acetate (5.0 mL), and filtered to obtain 0.30g of a pale yellow powdery solid, yield: 90 percent. Directly used for the next reaction.
MS(ESI,pos.ion)m/z:691.5[M+H]+。
Step 14) Synthesis of Compounds 3-16
Compound 3-15 (0.26 g,0.31 mmol), compound 3-15-2 (0.15 g,0.68 mmol), EDCI (0.13 g,0.68 mmol) and HOAT (85 mg,0.62 mmol) were suspended in DCM (20 mL), and DIPEA (0.51 mL,3.1 mmol) was added dropwise slowly at 0 ℃ and reacted at room temperature for 3 hours after completion of dropwise addition. After completion of the reaction, the reaction mixture was diluted with DCM (20 mL), washed with an ammonium chloride solution and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent: DCM/MeOH (v/v) = 50/1) to obtain 0.15g of a white solid, yield: 45 percent.
MS(ESI,pos.ion)m/z:543.5[M+2H]2+；
1H NMR(400MHz,CDCl3):7.84(s,1H),7.78-7.77,7.76-7.75(d,d,1H),7.58-7.57(q,1H),7.53,7.51-7.50(dd,dd,1H),7.49-7.48,7.46(dd,dd,1H),7.47,7.45(dd,dd,1H),7.39,7.37(d,d,1H),7.34,7.32(d,d,1H),5.90,5.88(d,d,1H),5.21,5.19(d,d,1H),5.17-5.13(m,1H),5.10-5.05(m,1H),4.53-4.41(m,2H),3.94-3.85(m,2H),3.65(s,3H),3.63(s,3H),3.62-3.55(m,2H),3.04-3.00(m,2H),2.97-2.94(m,2H),2.93-2.90(m,2H),2.89-2.86(m,2H),2.51-2.41(m,1H),2.35-2.21(m,5H),1.77-1.49(m,28H),1.45-1.34(m,4H),1.28-1.07(m,6H),0.92-0.89(m,6H)ppm。
Example 4
The synthetic route is as follows:
step 1) Synthesis of Compound 4-2
Mixing PPh3MeBr (5.05 g,14.2 mmol) was suspended in THF (50 mL), a THF solution of potassium tert-butoxide (14.9 mL,14.9mmol, 1.0M) was slowly added dropwise at-20 ℃ after completion of the reaction at-5 ℃ for 30 minutes, compound 4-1 (1.72 g,7.07 mmol) was added and after completion of the addition, the reaction was allowed to react at room temperature for 1.0 hour, ice water (50 mL) was added to quench the reaction, THF was removed, the aqueous layer was extracted with EtOAc (50 mL × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (eluent: PE/EtOAc (v/v) = 5/1) to give 1.07g of a pale yellow oily liquid with a yield of 62.9%.
MS(ESI,pos.ion)m/z:242.1[M+H]+；
1H NMR(400MHz,DMSO-d6):5.01(d,2H,J=10.8Hz),4.36(t,1H,J=11.2Hz),3.95(s,2H),3.64(s,3H),3.01(q,1H,J=14.6Hz),2.57-2.50(m,1H),1.38(s,9H)ppm。
Step 2) Synthesis of Compound 4-3
Slowly adding iodochloromethane (6.57 g,37.24 mmol) dropwise into a toluene (30 mL) solution of diethyl zinc (2.30 g,18.60 mmol) at 0 ℃, reacting at constant temperature for 45 minutes after dropwise adding, slowly adding a toluene (15 mL) solution of a compound 4-2 (1.5 g,6.22 mmol) dropwise, reacting at constant temperature for 18 hours, after the reaction is completed, adding a saturated ammonium chloride solution (20 mL) to quench the reaction, extracting an aqueous layer with EtOAc (25 mL × 3), combining organic phases, and adding anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 10/1) gave 0.58g of white liquid, yield: 36.5 percent.
MS(ESI,pos.ion)m/z:156.2[M-Boc]+；
1H NMR(400MHz,CDCl3):4.47-4.33(m,1H),3.71(s,3H),3.37-3.29(m,2H),2.25-2.17(m,1H),1.86-1.75(m,1H),1.44,1.40(s,s,9H),0.62-0.50(m,4H)ppm。
Step 3) Synthesis of Compound 4-4
Compound 4-3 (0.69 g,2.7 mmol) was dissolved in EtOAc (6.0 mL), and after addition of a solution of hydrogen chloride in ethyl acetate (5.0 mL, 4M), the reaction was carried out at room temperature for 8 hours. After completion of the reaction, the reaction solution was concentrated to obtain 0.5g of a colorless oily liquid, yield: 96.5 percent.
MS(ESI,pos.ion)m/z:156.2[M+H]+；
1H NMR(400MHz,CD3OD):4.66-4.62(m,1H),4.45-4.44(m,1H),3.86(s,3H),3.61-3.60(m,1H),2.39-2.34(m,1H),2.19-2.14(m,1H),1.49-1.46(m,1H),1.19-1.16(m,1H),0.88-0.87(m,1H),0.81-0.79(m,1H)ppm。
Step 4) Synthesis of Compounds 4-5
Compound 4-4 (0.53 g,2.77 mmol), compound 4-4-2 (0.87 g,4.16 mmol) and EDCI (1.06 g,5.55 mmol) were suspended in DCM (10 mL), and DIPEA (2.4 mL,14.52 mmol) was slowly added dropwise at 0 ℃ and reacted at room temperature for 3.0 hours. After completion of the reaction, DCM (20 mL) was added to dilute the reaction solution, and the reaction solution was washed with an ammonium chloride solution and a saturated saline solution, respectively, and dried over anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 1/1) gave 0.61g of white liquid, yield: 70.2 percent.
MS(ESI,pos.ion)m/z:347.5[M+H]+；
1H NMR(400MHz,CDCl3):7.35-7.27(m,3H),7.19-7.14(m,2H),5.91,5.89(s,s,1H),5.33-5.30(m,1H),4.66-4.64(m,1H),3.72(s,3H),3.64(s,3H),3.47-3.41(m,1H),3.31-3.25(m,1H),2.18-2.11(m,1H),1.81-1.74(m,1H),0.49-0.37(m,4H)ppm。
Step 5) Synthesis of Compounds 4-6
After dropping an aqueous solution (5.0 mL) of lithium hydroxide (0.14 g,3.2 mmol) slowly into a THF solution (5.0 mL) of the compound 4-5 (0.22 g,0.64 mmol) at 0 ℃, the reaction was carried out at 40 ℃12 h after the reaction was complete, THF was removed, water (30 mL) was added, extraction was performed with EtOAc (10 mL × 3) and the aqueous phase was collected, the pH of the solution was adjusted to 1 with hydrochloric acid (10%), the aqueous layer was extracted with EtOAc (25 mL × 3), the organic phases were combined, anhydrous Na2SO4Drying and concentration gave 0.17g of a white solid, yield: 80 percent.
MS(ESI,pos.ion)m/z:333.5[M+H]+。
Step 6) Synthesis of Compounds 4-7
DIPEA (0.195 mL,1.18 mmol) was added to a solution of compound 4-6 (0.35 g,1.07 mmol) and HATU (0.49 g,1.284 mmol) in THF (10 mL) at 0 deg.C, and after a reaction at constant temperature for 0.5 hour, compound 3-1-2 (0.22 g,1.19 mmol) was added in portions and, after completion of the addition, the reaction was carried out at room temperature for 4.0 hours. After completion of the reaction, the reaction was quenched with water (10 mL), THF was removed, extracted with EtOAc (20 mL. times.3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a residue which was dissolved in glacial acetic acid (5.0 mL) and reacted overnight at 40 ℃. After completion of the reaction, glacial acetic acid was removed, and the residue was dissolved in EtOAc (20 mL), washed with sodium carbonate solution (10 mL. times.3), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent: PE/EtOAc (v/v) = 1/2) to give 0.33g of the product, yield: 65 percent.
MS(ESI,pos.ion)m/z:483.5[M+H]+；
1H NMR(400MHz,CDCl3):7.71-7.70(dd,1H),7.35-7.27(m,4H),7.20-7.15(m,3H),5.91,5.89(s,s,1H),5.46-5.43(m,1H),5.22-5.18(m,1H),3.64(s,3H),3.52-3.46(m,1H),3.19-3.13(m,1H),2.59-2.52(m,1H),2.27-2.19(m,1H),0.54-0.41(m,4H)ppm。
Step 7) Synthesis of Compounds 4 to 8
Mixing compound 4-7 (0.24 g,0.5 mmol), compound 1-6-2 (0.15 g,0.6 mmol), Pd (dppf) Cl2·CH2Cl2(20.4 mg,0.025 mmol) and KOAc (0.12 g,1.25 mmol) were placed in a reaction flask, N2Under protection, DMF (3) was added.0 mL) was reacted at 90 ℃ for 3.0 hours, the reaction solution was cooled to room temperature, EtOAc (20 mL) was added to dilute the reaction solution, the mixture was filtered through celite, and the filtrate was washed with water (10 mL × 3) and saturated brine, dried over anhydrous sodium sulfate, and concentrated and purified by column chromatography (eluent: PE/EtOAc (v/v) = 3/1) to obtain 0.17g of a beige solid, yield: 65%.
MS(ESI,pos.ion)m/z:531.5[M+H]+；
1H NMR(400MHz,CDCl3):7.84-7.83(q,1H),7.65,7.63(d,d,1H),7.36-7.27(m,4H),7.19-7.15(m,2H),5.91,5.89(s,s,1H),5.46-5.43(m,1H),5.20-5.16(m,1H),3.64(s,3H),3.52-3.46(m,1H),3.19-3.13(m,1H),2.59-2.52(m,1H),2.27-2.19(m,1H),1.32(q,6H),1.29(q,6H),0.54-0.41(m,4H)ppm。
Step 8) Synthesis of Compounds 4-9
Mixing compound 4-8 (0.31 g,0.58 mmol), compound 3-10 (0.29 g,0.58 mmol), Pd (PPh)3)4(35 mg,0.03 mmol) and potassium carbonate (80 mg,1.4 mmol) in a reaction flask, N2DME (8.0 mL) and water (2.0 mL) were separately injected under the protection, and reacted at 90 ℃ for 4.0 hours, after completion of the reaction, the reaction mixture was cooled to room temperature, and after adding EtOAc (50 mL) to dilute the reaction mixture, the reaction mixture was washed with water (30 mL × 3) and saturated brine, respectively, and dried over Na2SO4Drying, concentration and purification by column chromatography (eluent: DCM/MeOH (v/v) = 100/1) gave 0.22g of a pale yellow solid, yield: 50 percent.
MS(ESI,pos.ion)m/z:381.2[M+2H]2+；
1H NMR(400MHz,CDCl3):7.78,7.75(dd,dd,1H),7.56-7.55(q,1H),7.51-7.48(dd,dd,1H),7.47-7.44(m,4H),7.38-7.33(m,2H),7.23-7.19(m,1H),7.02,6.99(dd,dd,1H),6.66,6.94(dd,dd,1H),6.13,6.11(s,s,1H),5.48,5.46(m,m,1H),5.21-5.17(m,1H),3.64(s,3H),3.52-3.46(m,1H),3.19-3.13(m,1H),2.93-2.82(m,8H),2.59-2.52(m,1H),2.27-2.19(m,1H),1.70-1.50(m,12H),1.48-1.35(m,4H),0.54-0.41(m,4H)ppm。
Step 9) Synthesis of Compounds 4-10
Compound 4-9 (1.21 g,1.59 mmol) was dissolved in DCM (10 mL), pyridine (0.65 mL,7.96 mmol) was added at 0 ℃ and stirred for 10 minutes, then Tf was slowly added dropwise2O (0.8 mL,4.78 mmol), reacting at constant temperature for 20 minutes, reacting at room temperature for 3 hours, after the reaction is completed, dropwise adding ice water (20 mL) to quench the reaction, extracting the water layer with DCM (20 mL × 3), combining organic phases, washing with saturated brine, drying with anhydrous sodium sulfate, concentrating, and purifying by column chromatography (eluent: PE/EtOAc (v/v) = 1/1) to obtain 1.2g of light yellow oily liquid with the yield of 85%.
1H NMR(400MHz,CDCl3):7.78-7.77,7.76-7.75(d,d,1H),7.56-7.55(q,1H),7.48-7.44(m,5H),7.38-7.33(m,2H),7.23-7.18(m,2H),6.97,6.94(dd,dd,1H),6.13,6.11(s,s,1H),5.48,5.46(m,m,1H),5.21-5.17(m,1H),3.64(s,3H),3.52-3.46(m,1H),3.19-3.13(m,1H),2.95-2.90(m,4H),2.89-2.86(m,4H),2.59-2.52(m,1H),2.27-2.19(m,1H),1.74-1.35(m,16H),0.54-0.41(m,4H)ppm。
Step 10) Synthesis of Compounds 4-11
Mixing 4-10 (2.23 g,2.5 mmol), 1-6-2 (0.96 g,3.8 mmol), Pd (dppf) Cl2·CH2Cl2(0.11 g,0.13 mmol) and KOAc (0.74 g,7.5 mmol) were mixed in a reaction flask, DMF (12 mL) was added under nitrogen, the reaction was carried out at 90 ℃ for 4.0 hours, after completion of the reaction, the mixture was cooled to room temperature, EtOAc (60 mL) was added to dilute the reaction mixture, the mixture was filtered through celite, and the filtrate was washed with water (30 mL × 3) and saturated brine, and anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 1/3) gave 1.41g of a pale yellow solid, yield: 65 percent.
1H NMR(400MHz,CDCl3):7.78-7.77,7.76-7.75(d,d,1H),7.64,7.62(dd,dd,1H),7.57-7.55(m,2H),7.48-7.44(m,4H),7.43,7.41(dd,dd,1H),7.37-7.33(m,2H),7.23-7.19(m,1H),6.13,6.11(s,s,1H),5.48,5.46(m,m,1H),5.21-5.17(m,1H),3.64(s,3H),3.52-3.46(m,1H),3.19-3.13(m,1H),3.08-3.05(m,2H),2.93-2.90(m,4H),2.89-2.86(m,2H),2.59-2.52(m,1H),2.27-2.19(m,1H),1.72-1.36(m,14H),1.32,1.29(q,q,12H),1.27-1.19(m,2H),0.54-0.41(m,4H)ppm。
Step 11) Synthesis of Compounds 4-12
Compound 4-6 (1.55 g,4.66 mmol) was dissolved in THF (20 mL), borane (10 mL,1M in THF) was slowly added dropwise to the reaction flask at 0 ℃ under nitrogen protection, and the reaction was allowed to proceed at constant temperature for 3.0 hours after completion of the dropwise addition. After completion of the reaction, the reaction was quenched with methanol (10 mL), and the reaction solution was concentrated and purified by column chromatography (eluent: PE/EtOAc (v/v) = 1/2) to obtain 0.96g of a colorless oil, yield: 65 percent.
1H NMR(400MHz,CDCl3):7.35-7.27(m,3H),7.19-7.14(m,2H),5.91,5.89(s,s,1H),5.34-5.31(m,1H),4.98(brs,1H),4.41-4.33(m,1H),3.74-3.66(m,2H),3.64(s,3H),3.13-2.99(m,2H),1.64-1.56(m,1H),1.49-1.41(m,1H),0.48-0.45(m,4H)ppm。
Step 12) Synthesis of Compounds 4-13
Compound 4-12 (1.10 g,3.48 mmol) was dissolved in DCM (25 mL) and dess-martin (2.07 g,4.88 mmol) was added in portions to the flask as oxidant at 0 deg.C, after which the reaction was allowed to proceed at room temperature for 2.0 hours. After completion of the reaction, water (20 mL) was added to dilute the reaction solution, and the reaction solution was filtered, the filtrate was separated into layers, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE/EtOAc (v/v) = 1/2) to obtain 0.55g of a colorless oil, yield: 50 percent.
1H NMR(400MHz,CDCl3):9.63-9.62(m,1H),7.35-7.27(m,3H),7.19-7.14(m,2H),5.91,5.89(s,s,1H),5.33-5.30(m,1H),4.44-4.41(m,1H),3.64(s,3H),3.50-3.44(m,1H),3.18-3.12(m,1H),2.42-2.35(m,1H),1.70-1.64(m,1H),0.50-0.38(m,4H)ppm。
Step 13) Synthesis of Compounds 4-14
Compound 4-13 (0.56 g,1.76 mmol) and ammonia (2.0 mL) were dissolved in methanol (5.0 mL), and an aqueous solution of glyoxal (40%, 1.0 mL) was slowly dropped into the reaction flask at 0 ℃ and reacted overnight at room temperature after completion of dropping. After completion of the reaction, the reaction solution was concentrated and purified by column chromatography (eluent: PE/EtOAc (v/v) = 1/2) to obtain 0.31g of a white solid, yield: 50 percent.
MS(ESI,pos.ion)m/z:355.5[M+H]+；
1H NMR(400MHz,CDCl3):7.48-7.45(m,2H),7.38-7.33(m,2H),7.23-7.19(m,1H),6.97(s,2H),6.23,6.21(s,s,1H),5.49-5.46(m,1H),5.19-5.14(m,1H),3.62(s,3H),3.61-3.56(m,1H),3.44-3.38(m,1H),2.24-2.17(m,1H),1.90-1.82(m,1H),0.53-0.40(m,4H)ppm。
Step 14) Synthesis of Compounds 4-15
Compound 4-14 (2.97 g,8.4 mmol) was dissolved in DCM (60 mL), and N-iodosuccinimide (3.8 g,16.8 mmol) was added in portions to a reaction flask at 0 ℃ and reacted for 1.5 hours at constant temperature. After completion of the reaction, the reaction mixture was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent: PE/EtOAc (v/v) = 1/2) to obtain 3.05g of a white solid, yield: 60 percent.
MS(ESI,pos.ion)m/z:607.3[M+H]+；
1H NMR(400MHz,CDCl3):7.48-7.45(m,2H),7.38-7.33(m,2H),7.23-7.19(m,1H),6.23,6.21(s,s,1H),5.49-5.46(m,1H),5.07-5.03(m,1H),3.75-3.69(m,1H),3.62(s,3H),3.48-3.41(m,1H),2.39-2.31(m,1H),2.06-1.98(m,1H),0.54-0.41(m,4H)ppm。
Step 15) Synthesis of Compounds 4-16
Compound 4-15 (1.98 g,3.27 mmol) was suspended in a mixed solvent (50 mL) of ethanol and water (v/v = 3/7), and sodium sulfite (3.7 g,29 mmol) was added to the mixture and refluxed for 17 hours. After completion of the reaction, ethanol was removed, and the residue was added with water (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent: PE/EtOAc (v/v) = 1/2) to obtain 1.25g of a white solid, yield: 70 percent.
MS(ESI,pos.ion)m/z:481.5[M+H]+；
1H NMR(400MHz,CDCl3):7.48-7.45(m,2H),7.38-7.33(m,3H),7.23-7.19(m,1H),6.23,6.21(s,s,1H),5.49-5.46(m,1H),4.85-4.81(m,1H),3.69-3.63(m,1H),3.62(s,3H),3.46-3.40(m,1H),2.32-2.24(m,1H),2.00-1.92(m,1H),0.53-0.41(m,4H)ppm。
Step 16) Synthesis of Compounds 4-17
Mixing compound 4-16 (0.35 g,0.72 mmol), compound 4-11 (0.63 g,0.72 mmol), Pd (PPh)3)4(83 mg,0.07 mmol) and potassium carbonate (0.30 g,2.12 mmol) were suspended in DME (4.0 mL) and water (1.0 mL) and reacted at 90 ℃ for 4.0 hours under nitrogen, after completion of the reaction, cooled to room temperature, and the reaction was diluted with EtOAc (50 mL), washed with water (20 mL × 3) and saturated brine, respectively, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (DCM/MeOH (v/v) = 50/1) to give 0.47g of the product in 60% yield.
MS(ESI,pos.ion)m/z:549.5[M+2H]2+；
1H NMR(400MHz,CDCl3):7.78,7.75(d,d,1H),7.56-7.55(q,1H),7.54(s,1H),7.53,7.51(d,d,1H),7.49-7.44(m,5H),7.37-7.27(m,6H),7.23-7.15(m,3H),6.13,6.11(s,s,1H),5.91,5.89(s,s,1H),5.49-5.43(m,2H),5.21-5.17(m,1H),5.06-5.02(m,1H),3.64(s,6H),3.61-3.55(m,1H),3.52-3.46(m,1H),3.40-3.34(m,1H),3.19-3.13(m,1H),3.03-3.00(m,2H),2.97-2.94(m,2H),2.93-2.90(m,2H),2.89-2.86(m,2H),2.59-2.52(m,1H),2.28-2.19(m,2H),1.96-1.88(m,1H),1.70-1.49(m,12H),1.46-1.34(m,4H),0.54-0.41(m,8H)ppm。
Example 5
The synthetic route is as follows:
step 1) Synthesis of Compound 5-1
Phloroethylene ether (40.0 g,0.29 mol) was added to a solution of n-hexane (100 mL) and tetramethylethylenediamine (40 mL). Slowly dropping n-BuLi (1.6M n-hexane, 200mL,0.32 mol) at room temperature, reacting at room temperature for 28 hours, cooling to-78 deg.C, and slowly dropping Me3After the reaction was completed, water (100 mL) was added to quench the reaction, and the reaction was extracted with n-hexane (100 mL × 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated and purified by column chromatography (eluent: hexane/DCM (v/v) = 10/1) to obtain 51.8g of a colorless oil with a yield of 85%.
1H NMR(400MHz,CDCl3):7.06-7.02(m,1H),6.97-6.93(m,2H),3.86(s,6H),0.28(s,9H)ppm。
Step 2) Synthesis of Compound 5-2
Dissolving compound 5-1 (69.33 g,0.33 mol) in tetramethylethylenediamine (60 mL), slowly dropping n-BuLi (1.6M n-hexane, 250mL,0.40 mol) at 0 deg.C, reacting at room temperature for 25 hr, cooling to-78 deg.C, and mixing with Me3After the reaction is completed, ice water (150 mL) is added to quench the reaction, n-hexane (100 mL × 3) is used for extraction, organic phases are combined, the mixture is washed by saturated saline solution, dried by anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent: hexane/DCM (v/v) = 10/1) to obtain 82.86g of colorless oily matter, and the yield is 89%.
1H NMR(400MHz,CDCl3):7.11(s,2H),3.83(s,6H),0.29(s,18H)ppm。
Step 3) Synthesis of Compound 5-3
Compound 5-2 (19.2 g,68.1 mmol) was dissolved in DCM (100 mL), and a solution of ICl (23.1 g,0.14 mol) in DCM (100 mL) was added dropwise slowly at 0 ℃ and reacted at room temperature for 30 minutes after completion of the addition. After the reaction is completed, Na is used2S2O3The reaction was quenched with a solution (100 mL), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent: hexane/DCM (v/v) = 10/1) to give 21.5g of a pale yellow solid, yield: 81 percent.
1H NMR(400MHz,CDCl3):7.24(s,2H),3.87(s,6H)ppm。
Step 4) Synthesis of Compound 5-4
Compound 5-3 (1.80 g,4.62 mmol) was dissolved in DCM (20 mL) and slowly added dropwise to BBr at-78 deg.C3(2.0 mL,21.2 mmol) and after dropping, the mixture was reacted at constant temperature for 10 minutes and then reacted at room temperature for 1.0 hour, after completion of the reaction, the reaction mixture was poured into ice water (50 mL), extracted with DCM (30 mL × 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent: DCM) to give 1.50g of a white solid, yield: 90%.
1H NMR(400MHz,CDCl3):7.00(s,2H),5.66(s,2H)ppm。
Step 5) Synthesis of Compound 5-5
Compound 5-4 (0.36 g,1.0 mmol), cyclopentanone (0.25 g,3.0 mmol) and p-toluenesulfonic acid (19 mg,0.1 mmol) were dissolved in n-hexane (20 mL) and refluxed for 5.0 hours. After completion of the reaction, the reaction mixture was poured into water (25 mL), the aqueous layer was extracted with EtOAc (20 mL. times.3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent: hexane/DCM (v/v) = 1/1) to obtain 0.20g of an off-white solid, yield: 46 percent.
1H NMR(400MHz,CDCl3):6.84(s,1H),2.17(m,4H),1.87(m,4H)ppm。
Step 6) Synthesis of Compounds 5-6
Mixing compound 1-7 (0.15 g,0.48 mmol), compound 5-5 (0.20 g,0.48 mmol), potassium carbonate (0.16 g,1.12 mmol) and Pd (PPh)3)4(27.6 mg,0.024 mmol) in a reaction flask, N2DME (8 mL) and water (2 mL) were separately injected and reacted at 90 ℃ for 12 hours with protection. After completion of the reaction, the reaction mixture was diluted with EtOAc (50 mL) and washed with saturated brine and anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 10/1) gave 0.14g of a white solid, yield: 60 percent.
MS(ESI,pos.ion)m/z:489.5[M+H]+；
1H NMR(400MHz,CDCl3):7.75,7.73(s,s,1H),7.00,6.98(s,s,1H),6.88,6.86(dd,dd,1H),6.70,6.68(dd,dd,1H),4.81(brs,1H),2.89-2.83(m,4H),2.12-1.77(m,8H),1.71-1.38(m,8H)ppm。
Step 7) Synthesis of Compounds 5 to 8
DMAP (0.55 g,4.5 mmol) was added to a solution of 5-7 (8.43 g,45.06 mmol) in MeCN (30 mL) at 0 ℃ and di-tert-butyl dicarbonate (10.82 g,49.56 mmol) was added dropwise to the reaction mixture, followed by reaction at constant temperature for 30 minutes and at room temperature for 2.0 hours. After completion of the reaction, the reaction solution was concentrated and separated by column chromatography (eluent: PE/EtOAc (v/v) = 2/1) to obtain 5.9g of a colorless liquid, yield: 45.6 percent.
MS(ESI,pos.ion)m/z:188.2[M-Boc]+；
1H NMR(400MHz,CDCl3):4.71-4.67(m,1H),4.02-4.01(m,4H),3.77-3.76,3.74-3.73(m,m,1H),3.70(s,3H),3.52-3.51,3.49-3.48(m,m,1H),2.77-2.75,2.73-2.71(m,m,1H),2.35-2.28(m,1H),1.43(s,9H)ppm。
Step 8) Synthesis of Compounds 5-9
Compounds 5-8 (5.40 g,18.86 mmol) in THF (40 mL), 0 deg.C, adding aqueous lithium hydroxide (1.5 g,20 mL) to the system, reacting at 40 deg.C for 12 hours, after completion of the reaction, removing THF, adding water (30 mL), extracting with EtOAc (25 mL × 3), adjusting the pH of the aqueous layer to 2 with dilute hydrochloric acid (1M), extracting with EtOAc (50 mL × 3), extracting the organic phase with anhydrous Na2SO4Drying and concentration gave 4.84g of a white solid, yield: 94 percent.
MS(ESI,pos.ion)m/z:274.5[M+H]+。
Step 9) Synthesis of Compounds 5-10
DIPEA (1.95 mL,11.8 mmol) was added to a solution of compound 5-9 (2.92 g,10.7 mmol) and HATU (4.88 g,12.84 mmol) in THF (30 mL) at 0 ℃ for 0.5 hour at constant temperature, and then compound 3-1-2 (2.22 g,11.9 mmol) was added in portions and, after completion of the addition, reacted at room temperature for 4.0 hours. After completion of the reaction, the reaction was quenched with water (50 mL), THF was removed, extracted with EtOAc (50 mL. times.3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and the residue was dissolved in glacial acetic acid (20 mL) and reacted overnight at 40 ℃. After completion of the reaction, glacial acetic acid was removed, and the residue was dissolved in EtOAc (100 mL), washed with sodium carbonate solution (50 mL. times.3), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent: PE/EtOAc (v/v) = 1/2) to give the product 3.62g, yield: 80 percent.
MS(ESI,pos.ion)m/z:424.3[M+H]+；
1H NMR(400MHz,CDCl3):7.71-7.70(dd,1H),7.33,7.30(d,d,1H),7.20,7.17(d,d,1H),5.14-5.10(m,1H),3.96-3.94(m,4H),3.91-3.89(m,1H),3.68-3.66,3.64-3.63(m,m,1H),2.82-2.79,2.78-2.76(m,m,1H),2.26-2.19(m,1H),1.53(s,9H)ppm。
Step 10) Synthesis of Compounds 5-11
Mixing 5-10 (4.77 g,11.27 mmol), 1-6-2 (4.29 g,16.9 mmol), Pd (dppf) Cl2·CH2Cl2(0.65 g,0.8 mmol) and KOAc (2.09 g)21.3 mmol) was placed in a reaction flask, N2DMF (30 mL) was added under protection, the reaction was carried out at 90 ℃ for 3.0 hours, the reaction mixture was cooled to room temperature after completion of the reaction, EtOAc (250 mL) was added to dilute the reaction mixture, the mixture was filtered through celite, and the filtrate was washed with water (100 mL × 3) and saturated brine, respectively, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent: PE/EtOAc (v/v) = 1/2) to obtain 3.18g of a beige solid with a yield of 60%.
MS(ESI,pos.ion)m/z:472.5[M+H]+；
1H NMR(400MHz,CDCl3):7.84-7.83(q,1H),7.67,7.65(d,d,1H),7.36,7.34(d,d,1H),5.13-5.09(m,1H),3.96-3.94(m,4H),3.91-3.89(m,1H),3.68-3.66,3.64-3.63(m,m,1H),2.82-2.79,2.78-2.76(m,m,1H),2.26-2.19(m,1H),1.53(s,9H),1.32,1.29(q,q,12H)ppm。
Step 11) Synthesis of Compounds 5-12
Mixing compound 5-11 (0.27 g,0.58 mmol), compound 5-6 (0.28 g,0.58 mmol), Pd (PPh)3)4(35 mg,0.03 mmol) and potassium carbonate (80 mg,1.4 mmol) in a reaction flask, N2DME (8.0 mL) and water (2.0 mL) were separately injected under the protection, and reacted at 90 ℃ for 4.0 hours, after completion of the reaction, the reaction mixture was cooled to room temperature, and after adding EtOAc (50 mL) to dilute the reaction mixture, the reaction mixture was washed with water (30 mL × 3) and saturated brine, respectively, and dried over Na2SO4Drying, concentration and purification by column chromatography (eluent: DCM/MeOH (v/v) = 100/1) gave 0.20g of a pale yellow solid, yield: 50 percent.
MS(ESI,pos.ion)m/z:706.5[M+H]+；
1H NMR(400MHz,CDCl3):7.65-7.64(m,1H),7.51-7.48(m,2H),7.47,7.44(s,s,1H),7.11,7.09(s,s,1H),6.92,6.90(dd,dd,1H),6.70,6.88(dd,dd,1H),5.22-5.18(m,1H),3.96-3.94(m,4H),3.91-3.89(m,1H),3.68-3.66,3.64-3.63(m,m,1H),2.89-2.83(m,4H),2.82-2.79,2.78-2.76(m,m,1H),2.26-2.19(m,1H),2.14-2.04(m,2H),1.98-1.74(m,6H),1.70-1.54(m,6H),1.53(s,9H),1.49-1.38(m,2H)ppm。
Step 12) Synthesis of Compounds 5-13
Compound 5-12 (1.13 g,1.6 mmol) was dissolved in DCM (50 mL), pyridine (0.65 mL,8.0 mmol) was added at 0 ℃ and stirred for 10 minutes, then Tf was slowly added dropwise2O (0.8 mL,4.78 mmol), reacting at constant temperature for 20 minutes, reacting at room temperature for 3 hours, after the reaction is completed, dropwise adding ice water (50 mL) to quench the reaction, extracting the water layer with DCM (60 mL × 3), combining organic phases, washing with saturated brine, drying with anhydrous sodium sulfate, concentrating, and purifying by column chromatography (eluent: PE/EtOAc (v/v) = 2/1) to obtain 1.20g of light yellow oily liquid with the yield of 90%.
1H NMR(400MHz,CDCl3):7.65-7.64(m,1H),7.51-7.46(m,2H),7.41,7.39(s,s,1H),7.13-7.12,7.10(dd,dd,1H),7.11,7.09(s,s,1H),6.89-6.88,6.87-6.86(dd,dd,1H),5.22-5.18(m,1H),3.96-3.94(m,4H),3.91-3.89(m,1H),2.93-2.88(m,4H),2.82-2.79,2.78-2.76(m,m,1H),2.26-2.19(m,1H),2.14-2.04(m,2H),1.98-1.74(m,4H),1.73-1.54(m,6H),1.53(s,9H),1.51-1.42(m,2H)ppm。
Step 13) Synthesis of Compounds 5-14
Mixing compound 5-13 (2.09 g,2.5 mmol), compound 1-6-2 (0.96 g,3.8 mmol), Pd (dppf) Cl2·CH2Cl2(0.11 g,0.13 mmol) and KOAc (0.74 g,7.5 mmol) were mixed in a reaction flask, DMF (12 mL) was added under nitrogen, the reaction was carried out at 90 ℃ for 4.0 hours, after completion of the reaction, the mixture was cooled to room temperature, EtOAc (100 mL) was added to dilute the reaction mixture, and the mixture was filtered through celite, and the filtrate was washed with water (50 mL × 3) and saturated brine, respectively, and anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 1/3) gave 1.22g of a pale yellow solid, yield: 60 percent.
1H NMR(400MHz,CDCl3):7.64-7.62(m,2H),7.52-7.46(m,3H),7.25,7.23(dd,dd,1H),7.11,7.09(s,s,1H),5.22-5.18(m,1H),3.96-3.94(m,4H),3.91-3.89(m,1H),3.68-3.66,3.64-3.63(m,m,1H),3.07-3.04(m,2H),2.88-2.85(m,2H),2.82-2.79,2.78-2.76(m,m,1H),2.26-2.19(m,1H),2.14-2.04(m,2H),1.98-1.74(m,6H),1.72-1.54(m,4H),1.53(s,9H),1.51-1.41(m,4H),1.32,1.29(q,q,12H)ppm。
Step 14) Synthesis of Compounds 5-15
Mixing compounds 5-14 (0.59 g,0.72 mmol), compounds 1-16 (0.26 g,0.72 mmol), Pd (PPh)3)4(83 mg,0.07 mmol) and potassium carbonate (0.30 g,2.12 mmol) were suspended in DME (6.0 mL) and water (1.5 mL) and reacted at 90 ℃ for 4.0 hours under nitrogen protection after completion of the reaction, the reaction was diluted with EtOAc (40 mL), washed with water (30 mL × 3) and saturated brine, respectively, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (DCM/MeOH (v/v) = 100/1) to give 0.40g of the product in 60% yield.
MS(ESI,pos.ion)m/z:463.3[M+2H]2+；
1H NMR(400MHz,CDCl3):7.97(s,1H),7.65-7.64(m,1H),7.51,7.49(d,d,1H),7.48,7.47(d,d,1H),7.46,7.43(s,s,1H),7.38,7.36(dd,dd,1H),7.13-7.09(m,2H),5.22-5.18(m,1H),5.14-5.09(m,1H),3.96-3.94(m,4H),3.91-3.89(m,1H),3.68-3.66(m,1H),3.64-3.58(m,1H),3.31-3.24(m,1H),3.10-3.06(m,2H),2.92-2.88(m,2H),2.82-2.79,2.78-2.76(m,m,1H),2.47-2.38(m,1H),2.28-2.17(m,2H),2.14-1.74(m,10H),1.70-1.55(m,8H),1.53(s,9H),1.41(s,9H)ppm。
Step 15) Synthesis of Compounds 5-16
Compounds 5 to 15 (0.37 g,0.4 mmol) were dissolved in EtOAc (5 mL), and after further addition of a solution of hydrogen chloride in ethyl acetate (5 mL, 4M), the reaction was carried out at room temperature for 8 hours. After completion of the reaction, the reaction was concentrated, and the residue was slurried with EtOAc (5 mL) and filtered to give 0.33g of a white solid, yield: 95 percent.
MS(ESI,pos.ion)m/z:725.5[M+H]+。
Step 16) Synthesis of Compounds 5-17
Mixing compound 5-16 (70 mg,0.08 mmol), compound 4-4-2 (35.1 mg,0.17 mmol)) EDCI (32.2 mg,0.17 mmol) and HOAT (21.8 mg,0.16 mmol) were dissolved in DCM (5 mL), DIPEA (0.10 mL,0.64 mmol) was added dropwise slowly at 0 ℃ and the reaction was carried out at room temperature for 3.0 hours after completion of the dropwise addition. After completion of the reaction, DCM (50 mL) was added to dilute the reaction solution, and the reaction solution was washed with an ammonium chloride solution and a saturated saline solution, respectively, and dried over anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: DCM/MeOH (v/v) = 60/1) gave 66.4mg of a white solid, yield: 75 percent.
MS(ESI,pos.ion)m/z:554.5[M+2H]2+；
1H NMR(400MHz,CDCl3):7.88(s,1H),7.65-7.64(m,1H),7.51,7.43(m,5H),7.38-7.27(m,6H),7.23-7.15(m,3H),7.13-7.09(m,2H),6.13-6.11(s,s,1H),5.91-5.89(s,s,1H),5.42-5.32(m,3H),5.25-5.20(m,1H),4.03-4.01,3.99-3.98(m,m,1H),3.97-3.96(m,4H),3.91-3.85(m,1H),3.76-3.67(m,1H),3.64(s,6H),3.10-3.06(m,2H),2.92-2.88(m,2H),2.80-2.77,2.76-2.74(m,m,1H),2.35-1.74(m,14H),1.70-1.50(m,6H),1.45-1.34(m,2H)ppm。
Example 6
The synthetic route is as follows:
step 1) Synthesis of Compound 6-1
Triethylamine (5.4 mL) was slowly added dropwise to formic acid (3.7 mL) at 0 ℃ and then 2, 5-dimethoxybenzaldehyde (2.0 g,12 mmol) and mugwort acid (1.73 g,12 mmol) were added in this order to react at 100 ℃ for 2.0 hours. After completion of the reaction, the reaction was quenched by addition of ice water (20 mL), the pH of the solution was adjusted to 1 with hydrochloric acid (2M), and the aqueous layer was treated with EtOAc (25 mL)× 3) and extracting the organic phase with anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 3/1) gave 2.1g of a white solid, yield: 83 percent.
MS(ESI,pos.ion)m/z:211.1[M+H]+；
1H NMR(400MHz,CDCl3):6.78-6.70(m,6H),3.78(s,3H),3.75(s,3H),2.91(t,2H,J=7.8Hz),2.65(t,2H,J=7.8Hz)ppm。
Step 2) Synthesis of Compound 6-2
Compound 6-1 (4.68 g,22.3 mmol) and PPA (50.87 g,24.8 mL) were placed in a reaction flask and reacted at 80 ℃ for 4.0 hours, after completion of the reaction, ice water (250 mL) was added, the aqueous layer was extracted with ethyl acetate (100 mL × 5), the organic phase was washed with sodium bicarbonate solution and saturated brine, respectively, and anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 3/1) gave 3.0g of a pale yellow solid, yield: 70 percent.
MS(ESI,pos.ion)m/z:193.2[M+H]+；
1H NMR(400MHz,CDCl3):6.98(d,1H,J=8.7Hz),6.73(d,1H,J=8.7Hz),3.90(s,3H),3.85(s,3H),2.97-3.00(m,2H),2.65-2.68(m,2H)ppm。
Step 3) Synthesis of Compound 6-3
Compound 6-2 (1.31 g,6.82 mmol), compound 6-2-2 (1.64 g,7.15 mmol) and TEBAC (0.3 g,1.36 mmol) were suspended in DMSO (30 mL), and aqueous NaOH (50%, 2 mL) was slowly added dropwise at 0 ℃ to complete the reaction at 50 ℃ for 2.0 hours. After completion of the reaction, water (50 mL) was added, the aqueous layer was extracted with EtOAc (50 mL × 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (eluent: PE/EtOAc (v/v) = 10/1) to obtain 1.07g of a yellow oil, yield: 60 percent.
MS(ESI,pos.ion)m/z:263.5[M+H]+；
1H NMR(400MHz,CDCl3):6.84,6.82(m,m,1H),6.77,6.75(m,m,1H),3.97-3.90(m,2H),3.84(d,3H),3.81(d,3H),3.70-3.62(m,2H),2.83-2.81(m,2H),2.01-1.93(m,2H),1.80-1.71(m,2H)ppm。
Step 4) Synthesis of Compound 6-4
Compound 6-3 (1.0 g,3.8 mmol) and triethylsilane (3.7 mL,23 mmol) were mixed in a reaction flask, and trifluoroacetic acid (8.0 mL) was added dropwise slowly at 0 ℃ to react at 40 ℃ for 7 hours. After completion of the reaction, the reaction solution was concentrated, and the residue was dissolved in EtOAc (50 mL), washed with a sodium carbonate solution and a saturated brine, respectively, dried over anhydrous sodium sulfate, and concentrated and purified by column chromatography (eluent: PE/EtOAc (v/v) = 5/1) to obtain 0.80g of a pale yellow oily liquid, yield: 85 percent.
MS(ESI,pos.ion)m/z:249.5[M+H]+；
1H NMR(400MHz,CDCl3):6.67-6.66(m,2H),3.77(d,6H),3.71-3.66(m,4H),2.77-2.74(m,4H),1.76-1.70(m,4H)ppm。
Step 5) Synthesis of Compound 6-5
Compound 6-4 (0.69 g,2.77 mmol) was dissolved in DCM (20 mL) and slowly added dropwise to BBr at-78 deg.C3(0.36 mL,3.88 mmol) and reacted at constant temperature for 10 minutes, then reacted at room temperature for 1.0 hour, after the reaction was completed, quenched with ice water (20 mL), extracted with DCM (25 mL × 3), the organic phase was washed with saturated brine, anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 12/1) gave 0.61g of a colorless liquid, yield: 100 percent.
MS(ESI,pos.ion)m/z:221.3[M+H]+；
1H NMR(400MHz,CDCl3):6.45(m,2H),4.97(brs,2H),3.74-3.70(m,4H),2.75-2.72(m,4H),1.79-1.72(m,4H)ppm。
Step 6) Synthesis of Compound 6-6
Compound 6-5 (1.70 g,7.7 mmol) was dissolved in DCM (50 mL), N2Under protection, pyridine (3.1 mL,38.6 mmol) is added at 0 ℃, after stirring for 10 minutes, trifluoromethanesulfonic anhydride (3.9 mL,23.1 mmol) is slowly dropped, after dropping, the reaction is carried out at room temperature for 1.0 hour, after the reaction is completed, the reaction is quenched with ice water (50 mL), DCM (60 mL × 3) is used for extraction, the organic phases are combined, the washing is carried out with saturated saline, anhydrous sodium sulfate is used for drying, and after concentration, the mixture is separated and purified by column chromatography (eluent: PE/EtOAc (v/v) = 8/1) to obtain 3.17g of light yellow oily liquid, and the yield is 85%.
1H NMR(400MHz,CDCl3):7.28(m,2H),3.71-3.66(m,4H),2.78-2.76(m,4H),1.90-1.84(m,4H)ppm。
Step 7) Synthesis of Compounds 6-7
Mixing compound 1-7 (0.15 g,0.48 mmol), compound 6-6 (0.23 g,0.48 mmol), potassium carbonate (0.16 g,1.12 mmol) and Pd (PPh)3)4(27.6 mg,0.024 mmol) in a reaction flask, N2DME (8 mL) and water (2 mL) were separately injected and reacted at 90 ℃ for 12 hours with protection. After completion of the reaction, the reaction mixture was diluted with EtOAc (50 mL) and washed with saturated brine and anhydrous Na2SO4Dried, concentrated and purified by column chromatography (eluent: PE/EtOAc (v/v) = 8/1) to give 175mg of a colorless liquid, yield: 65 percent.1H NMR(400MHz,CDCl3):7.21-7.19(dd,dd,1H),6.98,6.95(dd,dd,1H),6.94,6.92(dd,dd,1H),6.66,6.64(dd,dd,1H),4.81(brs,1H),3.70-3.65(m,4H),2.92-2.86(m,4H),2.85-2.82(m,2H),2.75-2.72(m,2H),1.85-1.79(m,4H),1.70-1.50(m,6H),1.49-1.38(m,2H)ppm。
Step 8) Synthesis of Compounds 6 to 9
To a solution of (R) -1-phenethylamine (1.3 mL,10.1 mmol) in toluene (15 mL) was added anhydrous sodium sulfate (3.48 g,24.5 mmol), and after ethyl glyoxylate (1 mL,10.1 mmol) was slowly added dropwise, the reaction was carried out at room temperature for 1.0 hour. After the reaction was completed, filtration was carried out, and the filtrate was concentrated to obtain 1.9g of a yellow liquid, yield: 91.8 percent. The product was used in the next reaction without further purification.
Step 9) Synthesis of Compounds 6-10
TFA (0.75 mL,10.1 mmol) was added to a solution of compound 6-9 (2.0 g,9.7 mmol) in DMF (15 mL), and after stirring for 10 minutes, freshly distilled 1, 3-cyclopentadiene (1.29 g,19.5 mmol) and two drops of water were added in this order, and after completion of the addition, the reaction was carried out at room temperature for 12 hours. After the reaction is complete, DMF is removed and NaHCO is added to the residue3Solution (10%, 20 mL) in Na2CO3The pH of the solution was adjusted to 8, followed by extraction with petroleum ether (25 mL × 3), and the combined organic phases were washed with brine and anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 10/1) gave 2.38g of a pale yellow liquid, yield: 90.0 percent.
1H NMR(400MHz,CDCl3):7.35-7.17(m,5H),6.42(br,1H),6.28-6.26(br,1H),4.34-4.30(m,2H),3.82-3.78(m,2H),3.04-3.02(m,1H),2.90(br,1H),2.20(br,1H),2.13(m,1H),1.41(d,3H,J=6.6Hz),0.95(t,3H,J=7.2Hz)ppm。
Step 10) Synthesis of Compounds 6 to 11
Pd/C (0.2 g) was added to a solution of compound 6-10 (2.0 g,7.37 mmol) in ethanol (60 mL) at 20 atmospheres H2The reaction was carried out at room temperature under an atmosphere for 24 hours. After the reaction was completed, Pd/C was removed by filtration, and the filtrate was concentrated to obtain 1.2g of a yellow liquid, yield: 96.2 percent.
MS(ESI,pos.ion)m/z:170.2[M+H]+；
1H NMR(400MHz,CDCl3):4.21-4.15(m,2H),3.55(br,1H),3.33(br,1H),2.63(br,1H),2.32(br,1H),1.64-1.60(m,2H),1.53-1.47(m,2H),1.42-1.36(m,2H),1.28(t,3H,J=7.1Hz)ppm。
Step 11) Synthesis of Compounds 6 to 12
Compound 6-11 (1.69 g,10 mmol) was dissolved in MeOH (20 mL) and Et was added dropwise thereto at 0 ℃ respectively3N（1.67mL,12mmol) and Boc2O (2.41 mL,10.5 mmol) was added dropwise, and the reaction was carried out overnight at room temperature, after completion of the reaction, methanol was removed, and the residue was dissolved in DCM (50 mL), washed with water (20 mL × 3) and saturated brine, respectively, and dried over Na2SO4Drying and concentration gave 2.37g of a colourless syrup, yield: 88 percent.
Step 12) Synthesis of Compounds 6 to 13
Slowly adding lithium hydroxide monohydrate (0.48 g,11.35 mmol) in water (10 mL) into compound 6-12 (0.61 g,2.27 mmol) in THF (25 mL) at 0 deg.C, reacting at 40 deg.C for 12 hr, removing THF, adding water (50 mL) into residue, washing water layer with EtOAc (25 mL × 3), separating, adjusting pH of water layer to 1 with hydrochloric acid (10%), extracting with EtOAc (25 mL × 3), mixing organic phases, washing with saturated brine, and extracting with anhydrous Na2SO4Drying and concentration gave 0.44g of a white solid, yield: 80 percent.
MS(ESI,pos.ion)m/z:242.3[M+H]+。
Step 13) Synthesis of Compounds 6 to 14
Compound 6-13 (1.34 g,5.57 mmol) was dissolved in THF (20 mL), borane (8.3 mL,1M in THF) was slowly added dropwise at 0 ℃ and after completion of the addition, the reaction was allowed to react at room temperature for 2.0 hours, after completion of the reaction, the reaction was quenched with methanol (4.0 mL), THF was removed, and the residue was dissolved in DCM (50 mL), washed with water (20 mL × 3) and saturated brine, respectively, and washed with anhydrous Na2SO4Drying and concentration gave 1.01g of a colorless syrup, yield: 80 percent.
MS(ESI,pos.ion)m/z:228.3[M+H]+。
Step 14) Synthesis of Compounds 6 to 16
Compound 6-14 (1.19 g,5.24 mmol) was dissolved in DCM (20 mL), TCCA (1.22 g,5.24 mmol) was added at 0 ℃ and then a solution of TEMPO in DCM (82 mg,0.52mmol,3 mL) was slowly added dropwise, after completion of the addition, the reaction was allowed to proceed at constant temperature for 1.0 hour, and then the reaction was allowed to proceed at room temperature for 1.0 hourAfter completion of the reaction, filtration was carried out, and the filtrate was washed with a saturated sodium sulfite solution (20 mL × 3), anhydrous Na2SO4Drying, concentrating, dissolving the residue in ammonia methanol solution (7.0 mL, 7M), reacting the mixture at 0 deg.C for 0.5 hr, reacting at room temperature for 1.0 hr, cooling the system to 0 deg.C again, slowly adding glyoxal water solution (1.1 mL, 40%), after adding dropwise, reacting at room temperature for 24 hr, concentrating the reaction solution, dissolving the residue in DCM (60 mL), washing with water (20 mL × 3) and saturated saline, and removing Na anhydrous2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 1/1) gave 0.59g of a pale yellow solid, yield: 50 percent.
MS(ESI,pos.ion)m/z:264.3[M+H]+；
1H NMR(400MHz,CDCl3):6.99(s,2H),4.88-4.85(m,1H),4.49-4.44(m,1H),2.57-2.53(m,1H),2.04-1.96(m,1H),1.89-1.84(m,1H),1.74-1.62(m,2H),1.59-1.46(m,2H),1.44(s,9H)ppm。
Step 15) Synthesis of Compounds 6 to 17
Dissolving compounds 6-16 (0.65 g,2.47 mmol) in DCM (8.0 mL), slowly adding NIS (1.23 g,5.43 mmol) at 0 deg.C, reacting at constant temperature for 2.0 hr, diluting the reaction solution with DCM (30 mL), filtering, washing the filtrate with saturated sodium sulfite solution (20 mL × 3), anhydrous Na2SO4After drying and concentration, 1.27g of a yellow solid was obtained and used directly in the next reaction.
MS(ESI,pos.ion)m/z:516.3[M+H]+；
1H NMR(400MHz,CDCl3):5.33-5.30(m,1H),4.39-4.35(m,1H),2.76-2.72(m,1H),2.04-1.92(m,2H),1.83-1.71(m,2H),1.61-1.51(m,2H),1.44(s,9H)ppm。
Step 16) Synthesis of Compounds 6 to 18
Dissolve Compounds 6-17 (1.12 g,2.12 mmol) in ethanol (6.0 mL) and water (6.0 mL), sodium sulfite (2.14 g,17 mmol) was added, the reaction was carried out at 90 ℃ for 30 hours, the reaction was completed, the mixture was filtered, the filtrate was concentrated, and the residue was dissolved in DCM (80 mL), washed with water (20 mL × 3) and saturated brine, respectively, and dried over anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 1/1) gave 0.58g of a white solid, yield: 70 percent.
MS(ESI,pos.ion)m/z:390.3[M+H]+；
1H NMR(400MHz,CDCl3):7.36(s,1H),4.81-4.78(m,1H),4.47-4.43(m,1H),2.65-2.61(m,1H),2.04-1.96(m,1H),1.93-1.88(m,1H),1.79-1.67(m,2H),1.59-1.48(m,2H),1.44(s,9H)ppm。
Step 17) Synthesis of Compounds 6-19
Compounds 6-18 (0.55 g,1.4 mmol), compounds 6-7 (0.73 g,1.4 mmol), tetrakistriphenylphosphine palladium (0.16 g,0.14 mmol) and potassium carbonate (0.58 g,4.2 mmol) were suspended in DME and H2O (v/v = 3/1) in a mixed solvent (16 mL) was reacted at 90 ℃ for 3.0 hours under nitrogen protection. After completion of the reaction, the reaction mixture was diluted with EtOAc (40 mL), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent: PE/EtOAc (v/v) = 1/3) to obtain 0.35g of a white solid, yield: 40 percent.
MS(ESI,pos.ion)m/z:636.5[M+H]+；
1H NMR(400MHz,CDCl3):7.56(s,1H),7.52(brs,2H),7.49,7.46(dd,dd,1H),7.37,7.35(dd,dd,1H),7.02,6.99(dd,dd,1H),6.66,6.64(dd,dd,1H),4.85-4.81(m,1H),4.50-4.46(m,1H),3.70-3.65(m,4H),2.98-2.89(m,6H),2.85-2.82(m,2H),2.54-2.50(m,1H),2.04-1.96(m,1H),1.88-1.79(m,5H),1.73-1.41(m,12H),1.40(s,9H)ppm。
Step 18) Synthesis of Compounds 6-20
Compound 6-19 (3.17 g,5.0 mmol) was dissolved in DCM (20 mL), pyridine (2.4 mL,30 mmol) was added dropwise at 0 deg.C, and the mixture was stirred for 10 minutesThen, trifluoromethanesulfonic anhydride (3.37 mL,20 mmol) was added dropwise, and after completion of the addition, the mixture was reacted at constant temperature for 20 minutes, then the reaction was carried out at room temperature for 1.0 hour, after completion of the reaction, ice water (25 mL) was added to quench the reaction, the reaction was extracted with DCM (30 mL × 3), and the organic phases were combined and Na anhydrous2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 2/1) gave 3.26g of a colorless liquid, yield: 85 percent.
1H NMR(400MHz,CDCl3):7.56(s,1H),7.49,7.47(dd,dd,1H),7.39,7.37(dd,dd,1H),7.20,7.18(dd,dd,1H),6.96,6.94(dd,dd,1H),4.85-4.81(m,1H),4.50-4.46(m,1H),3.70-3.65(m,4H),2.98-2.91(m,6H),2.89-2.86(m,2H),2.54-2.50(m,1H),2.04-1.96(m,1H),1.88-1.79(m,5H),1.74-1.43(m,12H),1.40(s,9H)ppm。
Step 19) Synthesis of Compounds 6 to 21
Mixing 6-20 (1.92 g,2.5 mmol), 1-6-2 (0.96 g,3.8 mmol), Pd (dppf) Cl2·CH2Cl2(0.11 g,0.13 mmol) and KOAc (0.74 g,7.5 mmol) were mixed in a reaction flask, DMF (12 mL) was added under nitrogen, the reaction was carried out at 90 ℃ for 4.0 hours, after completion of the reaction, the mixture was cooled to room temperature, EtOAc (100 mL) was added to dilute the reaction mixture, and the mixture was filtered through celite, and the filtrate was washed with water (50 mL × 3) and saturated brine, respectively, and anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 1/3) gave 1.12g of a pale yellow solid, yield: 60 percent.
1H NMR(400MHz,CDCl3):7.64,7.62(dd,dd,1H),7.56(s,1H),7.54,7.52(dd,dd,1H),7.48,7.46(dd,dd,1H),7.43,7.41(dd,dd,1H),4.85-4.81(m,1H),4.50-4.46(m,1H),3.70-3.65(m,4H),3.08-3.05(m,2H),2.98-2.93(m,4H),2.89-2.86(m,2H),2.54-2.50(m,1H),2.04-1.96(m,1H),1.88-1.79(m,5H),1.73-1.43(m,10H),1.40(s,9H),1.32,1.29(q,q,12H),1.28-1.19(m,2H)ppm。
Step 20) Synthesis of Compounds 6-22
Mixing compounds 6-21 (0.54 g,0.72 mmol), compounds 1-16 (0.26 g,0.72 mmol)），Pd(PPh3)4(83 mg,0.07 mmol) and potassium carbonate (0.30 g,2.12 mmol) were suspended in DME (6.0 mL) and water (1.5 mL) and reacted at 90 ℃ for 4.0 hours under nitrogen, after completion of the reaction, cooled to room temperature, the reaction was diluted with EtOAc (40 mL), washed with water (30 mL × 3) and saturated brine, respectively, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (DCM/MeOH (v/v) = 100/1) to give 0.37g of the product in 60% yield.
MS(ESI,pos.ion)m/z:428.3[M+2H]2+；
1H NMR(400MHz,CDCl3):7.97(s,1H),7.56(s,1H),7.49,7.47(dd,dd,1H),7.40,7.38(dd,dd,1H),7.34,7.32(dd,dd,1H),7.13,7.11(dd,dd,1H),5.15-5.08(m,1H),4.85-4.81(m,1H),4.50-4.46(m,1H),3.70-3.65(m,4H),3.64-3.58(m,1H),3.31-3.24(m,1H),3.03-3.00(m,4H),2.98-2.93(m,4H),2.54-2.50(m,1H),2.47-2.38(m,1H),2.29-2.17(m,1H),2.10-1.96(m,3H),1.88-1.79(m,5H),1.73-1.43(m,12H),1.41(s,9H),1.40(s,9H)ppm。
Step 21) Synthesis of Compounds 6 to 23
Compounds 6 to 22 (0.34 g,0.4 mmol) were dissolved in EtOAc (5 mL), and after further addition of a solution of hydrogen chloride in ethyl acetate (5 mL, 4M), the reaction was carried out at room temperature for 8 hours. After completion of the reaction, the reaction mixture was concentrated, and the residue was extracted with EtOAcAfter slurrying (5 mL), filtration afforded 0.30g of a white solid, yield: 95 percent.
MS(ESI,pos.ion)m/z:655.5[M+H]+；
Step 22) Synthesis of Compounds 6-24
Compound 6-23 (64 mg,0.08 mmol), compound 1-18-2 (29.4 mg,0.17 mmol), EDCI (32.2 mg,0.17 mmol) and HOAT (21.8 mg,0.16 mmol) were dissolved in DCM (5 mL) and DIPEA (0.10 mL,0.64 mmol) was added dropwise slowly at 0 ℃ and reacted at room temperature for 3.0 hours after completion of dropwise addition. After completion of the reaction, DCM (50 mL) was added to dilute the reaction solution, and the reaction solution was washed with an ammonium chloride solution and a saturated saline solution, respectively, and dried over anhydrous Na2SO4Drying, concentrating, and separating by column chromatographyPurification by ion (eluent: DCM/MeOH (v/v) = 60/1) gave 38.74mg of white solid, yield: 50 percent.
MS(ESI,pos.ion)m/z:485.2[M+2H]2+；
1H NMR(400MHz,CDCl3):7.88(s,1H),7.57(s,1H),7.49,7.47(dd,dd,1H),7.40,7.38(dd,dd,1H),7.34,7.32(dd,dd,1H),7.13,7.11(dd,dd,1H),6.08,6.05(d,d,1H),5.32-5.28(m,2H),5.01-4.97(m,1H),4.80-4.75(m,1H),4.41-4.36(m,1H),4.21-4.17(m,1H),3.85-3.78(m,1H),3.69-3.66(m,5H),3.65(s,3H),3.63(s,3H),3.04-3.00(m,4H),2.98-2.93(m,4H),2.50-2.46(m,1H),2.30-1.92(m,7H),1.85-1.78(m,5H),1.70-1.49(m,9H),1.47-1.34(m,3H),1.02-0.89(m,12H)ppm。
Example 7
The synthetic route is as follows:
step 1) Synthesis of Compound 7-1
Compound 6-2 (2.75 g,14.34 mmol) and compound 7-0 (5.23 g,21.51 mmol) were dissolved in DMF (15 mL), NaH (60%, 1.43g,35.85 mmol) was added under nitrogen at 0 ℃ and after the addition was complete, the reaction was allowed to proceed for 18 hours at 50 ℃. After completion of the reaction, it was cooled to room temperature, and ice water (100 mL) was added to quench the reaction, the aqueous layer was extracted with ethyl acetate (100 mL. times.3), the organic phase was washed with water and saturated brine, respectively, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE/EtOAc (v/v) = 8/1) to obtain 0.79g of the product, yield: 20 percent.
MS(ESI,pos.ion)m/z:276.5[M+H]+；
1H NMR(400MHz,CDCl3):6.84,6.82(m,m,1H),6.77,6.75(m,m,1H),3.84(s,3H),3.81(s,3H),2.81-2.79(m,2H),2.73-2.65(m,2H),2.51-2.39(m,2H),2.35-2.34(m,3H),1.84-1.74(m,4H)ppm。
Step 2) Synthesis of Compound 7-2
Compound 7-1 (1.05 g,3.8 mmol) and triethylsilane (3.7 mL,23 mmol) were mixed in a reaction flask at 0 ℃ N2Trifluoroacetic acid (8.0 mL) was slowly injected under protection, and the reaction was carried out at 40 ℃ for 7 hours. After completion of the reaction, trifluoroacetic acid was removed, and the residue was dissolved in EtOAc (50 mL), washed with sodium carbonate solution and saturated brine, respectively, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent: PE/EtOAc (v/v) = 5/1) to obtain 0.84g of a pale yellow oily liquid, yield: 85 percent.
MS(ESI,pos.ion)m/z:262.5[M+H]+；
1H NMR(400MHz,CDCl3):6.62-6.61(m,2H),3.77(s,6H),2.77-2.69(m,6H),2.56-2.45(m,2H),2.30-2.29(m,3H),1.89-1.79(m,4H)ppm。
Step 3) Synthesis of Compound 7-3
Compound 7-2 (1.12 g,4.3 mmol) was dissolved in glacial acetic acid (40 mL), and hydrobromic acid (9.6 mL,85 mmol) was added, after which time it was refluxed for 12 hours. After completion of the reaction, the reaction was quenched by addition of saturated sodium bicarbonate solution (50 mL), the aqueous layer was extracted with ethyl acetate (50 mL × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent: PE/EtOAc (v/v) = 4/1) to obtain 0.45g of a white solid, yield: 45 percent.
1H NMR(400MHz,CDCl3):6.45(m,2H),4.97(brs,2H),2.81-2.69(m,6H),2.60-2.48(m,2H),2.30-2.29(m,3H),1.91-1.81(m,4H)ppm。
Step 4) Synthesis of Compound 7-4
Compound 7-3 (0.35 g,1.5 mmol) was dissolved in DCM (20 mL), trifluoromethanesulfonic anhydride (1.2 mL,7.1 mmol) was added at 0 deg.C, and after stirring for 10 minutes, triethylamine (2.4 mL,17.27 mmol) was slowly added dropwise, and the reaction was carried out at room temperature for 2.0 hours. After completion of the reaction, the reaction was quenched by addition of ice water (20 mL), and the aqueous layer was extracted with ethyl acetate (30 mL. times.3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent: PE/EtOAc (v/v) = 10/1) to give the product 0.56g, yield: 75 percent.
1H NMR(400MHz,CDCl3):7.28(m,2H),2.79-2.69(m,6H),2.56-2.44(m,2H),2.30-2.29(m,3H),2.04-1.92(m,4H)ppm。
Step 5) Synthesis of Compound 7-5
Mixing compound 1-7 (0.15 g,0.48 mmol), compound 7-4 (0.24 g,0.48 mmol), potassium carbonate (0.16 g,1.12 mmol) and Pd (PPh)3)4(27.6 mg,0.024 mmol) in a reaction flask, N2DME (8 mL) and water (2 mL) were separately injected and reacted at 90 ℃ for 12 hours with protection. After completion of the reaction, the reaction mixture was diluted with EtOAc (50 mL) and washed with saturated brine and anhydrous Na2SO4Dried, concentrated and purified by column chromatography (eluent: PE/EtOAc (v/v) = 8/1) to give 128mg of a colorless liquid, yield: 50 percent.1H NMR(400MHz,CDCl3):7.21,7.19(dd,dd,1H),6.98,6.95(dd,dd,1H),6.94,6.92(dd,dd,1H),6.66,6.64(dd,dd,1H),4.81(brs,1H),2.92-2.89(m,2H),2.88-2.82(m,4H),2.77-2.69(m,4H),2.56-2.44(m,2H),2.30-2.29(m,3H),1.98-1.88(m,4H),1.71-1.50(m,6H),1.49-1.38(m,2H)ppm。
Step 6) Synthesis of Compound 7-6
Compounds 6-18 (0.55 g,1.4 mmol), compounds 7-5 (0.75 g,1.4 mmol), tetrakistriphenylphosphine palladium (0.16 g,0.14 mmol) and potassium carbonate (0.58 g,4.2 mmol) were suspended in DME and H2O (v/v = 3/1) in a mixed solvent (16 mL) was reacted at 90 ℃ for 3.0 hours under nitrogen protection. After completion of the reaction, the reaction mixture was cooled to warm, and EtOAc (40 mL) was added to dilute the reaction mixture, which was washed with saturated brine, dried over anhydrous sodium sulfate, and concentratedPurification by column chromatography (eluent: PE/EtOAc (v/v) = 1/3) after condensation afforded 0.45g of a white solid, yield: 50 percent.
MS(ESI,pos.ion)m/z:649.5[M+H]+；
1H NMR(400MHz,CDCl3):7.56(s,1H),7.52(brs,2H),7.38,7.35(dd,dd,1H),7.14,7.11(dd,dd,1H),7.01,6.99(dd,dd,1H),6.66,6.64(dd,dd,1H),4.85-4.81(m,1H),4.50-4.46(m,1H),2.94-2.87(m,4H),2.85-2.82(m,4H),2.76-2.68(m,2H),2.55-2.43(m,3H),2.30-2.29(m,3H),2.04-1.83(m,7H),1.73-1.41(m,11H),1.40(s,9H)ppm。
Step 7) Synthesis of Compounds 7-7
Dissolving compound 7-6 (0.32 g,0.5 mmol) in DCM (5 mL), adding pyridine (0.24 mL,3 mmol) dropwise at 0 deg.C, stirring for 10 min, adding trifluoromethanesulfonic anhydride (0.34 mL,2 mmol) dropwise, reacting at room temperature for 1.0 hr, adding ice water (10 mL) to quench reaction, extracting with DCM (20 mL × 3), mixing organic phases, anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 2/1) gave 0.31g of a colorless liquid, yield: 80 percent.
1H NMR(400MHz,CDCl3):7.56(s,1H),7.39,7.37(dd,dd,1H),7.20,7.18(dd,dd,1H),7.14,7.11(dd,dd,1H),6.96,6.94(dd,dd,1H),4.85-4.81(m,1H),4.50-4.46(m,1H),2.95-2.86(m,8H),2.76-2.68(m,2H),2.55-2.43(m,3H),2.30-2.29(m,3H),2.04-1.83(m,7H),1.74-1.43(m,11H),1.40(s,9H)ppm。
Step 8) Synthesis of Compounds 7-8
Mixing 7-7 (1.95 g,2.5 mmol), 1-6-2 (0.96 g,3.8 mmol), Pd (dppf) Cl2·CH2Cl2(0.11 g,0.13 mmol) and KOAc (0.74 g,7.5 mmol) were mixed in a reaction flask, DMF (12 mL) was added under nitrogen, the reaction was allowed to react at 90 ℃ for 4.0 hours, after completion of the reaction, the mixture was cooled to room temperature, EtOAc (100 mL) was added to dilute the reaction mixture, and the mixture was filtered through celite, and the filtrate was saturated with water (50 mL × 3) and saturated food, respectivelyWashed with brine and anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 1/3) gave 0.85g of a pale yellow solid, yield: 45 percent.
1H NMR(400MHz,CDCl3):7.64,7.62(dd,dd,1H),7.56(s,1H),7.43,7.41(dd,dd,1H),7.16-7.15,7.13,7.11(dd,m,dd,2H),4.85-4.81(m,1H),4.50-4.46(m,1H),3.08-3.05(m,2H),2.94-2.86(m,6H),2.76-2.68(m,2H),2.54-2.44(m,3H),2.30-2.29(m,3H),2.04-1.83(m,6H),1.73-1.43(m,10H),1.40(s,9H),1.32,1.29(q,q,12H),1.27-1.19(m,2H)ppm。
Step 9) Synthesis of Compounds 7-10
Compound 7-9 (10.68 g,46.6 mmol) was dissolved in THF (100 mL), borane (100 mL,1M in THF) was slowly added dropwise under nitrogen protection at 0 ℃ and the reaction was allowed to proceed at constant temperature for 3.0 hours after completion of the dropwise addition. After completion of the reaction, the reaction was quenched with methanol (80 mL), and the reaction solution was concentrated and purified by column chromatography (eluent: PE/EtOAc (v/v) = 4/1) to give 7.52g of a colorless oil, yield: 75 percent.
1H NMR(400MHz,CDCl3):4.20-4.11(m,1H),3.91-3.85(m,2H),3.72-3.65(m,1H),3.34-3.26(m,1H),2.69(brs,1H),2.43-2.33(m,1H),1.52-1.48(m,1H),1.45(s,9H),1.35-1.04(m,3H),0.94-0.80(m,1H)ppm。
Step 10) Synthesis of Compounds 7-11
Compound 7-10 (7.49 g,34.8 mmol) was dissolved in DCM (250 mL), and dess-martin (20.7 g,48.8 mmol) was added in portions to the flask as oxidant at 0 deg.C, after which it was reacted at room temperature for 2.0 hours. After completion of the reaction, water (250 mL) was added to the reaction solution, and the reaction solution was filtered, and the filtrate was separated into layers, and then the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE/EtOAc (v/v) = 3/1) to obtain 3.71g of a colorless oil, yield: 50 percent.
1H NMR(400MHz,CDCl3):9.69-9.66(m,1H),4.07-4.02(m,1H),3.90-3.83(m,1H),3.04-2.94(m,1H),1.93-1.71(m,2H),1.44(s,9H),1.29-1.05(m,4H)ppm。
Step 11) Synthesis of Compounds 7-12
Compound 7-11 (3.75 g,17.6 mmol) and ammonia (13.0 mL) were dissolved in methanol (30 mL), and an aqueous solution of glyoxal (40%, 8.0 mL) was slowly added dropwise at 0 ℃ and reacted at room temperature overnight after completion of the addition. After completion of the reaction, the reaction solution was concentrated and purified by column chromatography (eluent: PE/EtOAc (v/v) = 3/1) to obtain 1.99g of a white solid, yield: 45 percent.
MS(ESI,pos.ion)m/z:252.5[M+H]+；
1H NMR(400MHz,CDCl3):6.99(s,2H),4.91-4.84(m,1H),4.06-3.98(m,1H),2.97-2.88(m,1H),2.11-2.02(m,1H),1.86-1.74(m,1H),1.73-1.65(m,1H),1.63-1.52(m,1H),1.50(s,9H),1.25-1.03(m,2H)ppm。
Step 12) Synthesis of Compounds 7-13
Compound 7-12 (2.11 g,8.4 mmol) was dissolved in DCM (60 mL), and N-iodosuccinimide (3.8 g,16.8 mmol) was added in portions to a reaction flask at 0 ℃ and after the addition was completed, the reaction was maintained at constant temperature for 1.5 hours. After completion of the reaction, the reaction mixture was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent: PE/EtOAc (v/v) = 3/1) to obtain 2.66g of a white solid, yield: and 63 percent.
MS(ESI,pos.ion)m/z:504.3[M+H]+；
1H NMR(400MHz,CDCl3):4.69-4.63(m,1H),4.62-4.18(m,1H),2.97-2.87(m,1H),2.21-2.12(m,1H),1.85-1.72(m,2H),1.64-1.52(m,1H),1.50(s,9H),1.25-1.06(m,2H)ppm。
Step 13) Synthesis of Compounds 7-14
Compound 7-13 (1.65 g,3.27 mmol) was suspended in a mixed solvent (50 mL) of ethanol and water (v/v = 3/7), and sodium sulfite (3.7 g,29 mmol) was added to the mixed solution and refluxed for 17 hours. After completion of the reaction, ethanol was removed, and the residue was added with water (50 mL), the aqueous phase was extracted with EtOAc (50 mL × 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated and purified by column chromatography (eluent: PE/EtOAc (v/v) = 3/2) to obtain 0.99g of a white solid, yield: 80 percent.
MS(ESI,pos.ion)m/z:378.1[M+H]+；
1H NMR(400MHz,CDCl3):7.34(s,1H),4.75-4.68(m,1H),4.06-3.99(m,1H),2.97-2.87(m,1H),2.16-2.07(m,1H),1.86-1.69(m,2H),1.64-1.53(m,1H),1.50(s,9H),1.25-1.02(m,2H)ppm。
Step 14) Synthesis of Compounds 7-15
Mixing compound 7-8 (0.55 g,0.72 mmol), compound 7-14 (0.27 g,0.72 mmol), Pd (PPh)3)4(83 mg,0.07 mmol) and potassium carbonate (0.30 g,2.12 mmol) were suspended in DME (6.0 mL) and water (1.5 mL) and reacted at 90 ℃ for 4.0 hours under nitrogen. After completion of the reaction, it was cooled to room temperature, and the reaction mixture was diluted with EtOAc (20 mL), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (DCM/MeOH (v/v) = 80/1) to obtain 0.38g of a product, yield: 60 percent.
MS(ESI,pos.ion)m/z:441.5[M+2H]2+；
1H NMR(400MHz,CDCl3):7.56(s,1H),7.53(s,1H),7.48,7.46(dd,dd,1H),7.41,7.38(dd,dd,1H),7.34,7.32(dd,dd,1H),7.13,7.11(dd,dd,1H),4.85-4.77(m,2H),4.50-4.46(m,1H),4.28-4.20(m,1H),3.04-3.00(m,2H),2.97-2.87(m,8H),2.76-2.684(m,2H),2.55-2.43(m,3H),2.30-2.29(m,3H),2.12-1.52(m,21H),1.50(s,9H),1.40(s,9H),1.25-1.02(m,2H)ppm。
Step 15) Synthesis of Compounds 7-16
Compounds 7 to 15 (0.35 g,0.4 mmol) were dissolved in EtOAc (5 mL), and after further addition of a solution of hydrogen chloride in ethyl acetate (5 mL, 4M), the reaction was carried out at room temperature for 8 hours. After completion of the reaction, the reaction was concentrated, and the residue was slurried with EtOAc (5 mL) and filtered to give 0.30g of a white solid, yield: 90 percent.
MS(ESI,pos.ion)m/z:682.5[M+H]+；
Step 16) Synthesis of Compounds 7-17
Compound 7-16 (66 mg,0.08 mmol), compound 1-18-2 (29.4 mg,0.17 mmol), EDCI (32.2 mg,0.17 mmol) and HOAT (21.8 mg,0.16 mmol) were dissolved in DCM (5 mL) and DIPEA (0.10 mL,0.64 mmol) was added dropwise slowly at 0 ℃ and reacted at room temperature for 3.0 hours after completion of dropwise addition. After completion of the reaction, DCM (20 mL) was added to dilute the reaction solution, and the reaction solution was washed with an ammonium chloride solution and a saturated saline solution, respectively, and dried over anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: DCM/MeOH (v/v) = 60/1) gave 39.8mg of a white solid, yield: 50 percent.
MS(ESI,pos.ion)m/z:498.8[M+2H]2+；
1H NMR(400MHz,CDCl3):7.57(s,1H),7.54(s,1H),7.49,7.47(dd,dd,1H),7.40,7.38(dd,dd,1H),7.34,7.33(dd,dd,1H),7.13,7.11(dd,dd,1H),6.08,6.05(d,d,1H),5.32,5.29(d,d,1H),5.03-4.97(m,2H),4.80-4.75(m,1H),4.40-4.35(m,1H),4.21-4.17(m,1H),3.77-3.69(m,1H),3.65(s,3H),3.63(s,3H),3.03-3.00(m,2H),2.97-2.87(m,6H),2.54-2.43(m,5H),2.30-2.29(m,3H),2.26-2.13(m,2H),2.08-1.88(m,6H),1.83-1.49(m,14H),1.47-1.34(m,3H),1.21-1.03(m,2H),1.02-0.89(m,12H)ppm。
Example 8
The synthetic route is as follows:
step 1) Synthesis of Compound 8-1
t-BuOK (1.17 g,10.41 mmol) was suspended in toluene (10 mL) at 0 ℃ N2Under protection, compound 6-2 (0.80 g,4.16 mmol) and 1, 5-dibromopentane (0.62 mL,4.58 mmol) were mixed in toluene (20 mL), slowly dropped into the above reaction flask, and reacted at 110 ℃ for 2.5 hours after completion of the reaction, cooled to room temperature, ice water (50 mL) was added to the reaction solution, extracted with EtOAc (30 mL × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE/EtOAc (v/v) = 4/1) to obtain 0.63g of a pale yellow solid, yield: 58%.
MS(ESI,pos.ion)m/z:261.2[M+H]+；
1H NMR(400MHz,CDCl3):6.98(d,1H,J=8.7Hz),6.73(d,1H,J=8.7Hz),3.89(s,3H),3.86(s,3H),2.88(s,2H),1.82-1.68(m,5H),1.51-1.26(m,5H)ppm。
Step 2) Synthesis of Compound 8-2
Compound 8-1 (0.99 g,3.8 mmol) and triethylsilane (3.7 mL,23 mmol) were mixed in a reaction flask at 0 ℃ N2Under the protection, trifluoroacetic acid (8.0 mL) was slowly added dropwise thereto, and the reaction was carried out at 40 ℃ for 7.0 hours. After completion of the reaction, trifluoroacetic acid was removed, and the residue was dissolved in EtOAc (50 mL), washed with saturated sodium carbonate solution and saturated brine, respectively, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent: PE/EtOAc (v/v) = 5/1) to obtain 0.81g of a pale yellow oily liquid, yield: 87 percent.
MS(ESI,pos.ion)m/z:247.2[M+H]+；
1H NMR(400MHz,CDCl3):6.61(s,2H),3.79(s,6H),2.74(s,4H),1.58-1.40(m,10H)ppm。
Step 3) Synthesis of Compound 8-3
Compound 8-2 (0.78 g,3.17 mmol) was dissolved in DCM (20 mL) and added dropwise slowly to BBr at-78 deg.C3(1.20 mL,12.67 mmol) and after dropping, after reacting for 10 minutes at constant temperature, reacting at room temperature for 1.0 hour, after the reaction is completed, adding ice water (50 mL) to quench the reaction, extracting the water layer with DCM (30 mL × 3), combining the organic phases, washing with saturated brine, drying over anhydrous sodium sulfate, concentrating and purifying by column chromatography (eluent: PE/EtOAc (v/v) = 5/1) to obtain 0.69g of light yellow oily liquid with a yield of 100%.
MS(ESI,pos.ion)m/z:219.2[M+H]+；
1H NMR(400MHz,CDCl3):6.49(s,2H),5.07-4.53(br,2H),2.68(s,4H),1.59-1.37(m,10H)ppm。
Step 4) Synthesis of Compound 8-4
Compound 8-3 (0.69 g,3.16 mmol) was dissolved in DCM (20 mL), pyridine (2.03 mL,25.29 mmol) was slowly added dropwise at 0 deg.C, and after stirring for 10 minutes, Tf was added dropwise2O (3.19 mL,19.97 mmol) is added, the reaction is carried out for 1.0 hour at room temperature after the reaction is completed, ice water (20 mL) is added to quench the reaction, the water layer is extracted by DCM (30 mL × 3), the organic phases are combined, washed by saturated brine, dried by anhydrous sodium sulfate and concentrated, and then the colorless oily liquid is obtained by column chromatography separation and purification (eluent: PE/DCM (v/v) = 6/1), wherein the yield is 1.11g and 73 percent.1H NMR(400MHz,CDCl3):7.13(s,2H),2.92(s,4H),1.59-1.41(m,10H)ppm。
Step 5) Synthesis of Compounds 8-5
Mixing compound 1-7 (0.15 g,0.48 mmol), compound 8-4 (0.23 g,0.48 mmol), potassium carbonate (0.16 g,1.12 mmol) and Pd (PPh)3)4(27.6 mg,0.024 mmol) in a reaction flask, N2DME (8 mL) and water (2 mL) were separately injected and reacted at 90 ℃ for 12 hours with protection. After completion of the reaction, the reaction mixture was diluted with EtOAc (50 mL) and washed with saturated brine and anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 8/1) gave 125mg of a colorless liquid, yield: 50 percent.
1H NMR(400MHz,CDCl3):7.21,7.19(dd,dd,1H),6.98,6.96(dd,dd,1H),6.94,6.92(dd,dd,1H),6.66,6.64(dd,dd,1H),4.81(brs,1H),2.92-2.89(m,3H),2.87-2.82(m,3H),2.71-2.68(m,2H),1.77-1.38(m,16H),1.29-1.21(m,2H)ppm。
Step 6) Synthesis of Compound 8-6
Compounds 8-5 (0.73 g,1.4 mmol), compounds 1-16 (0.51 g,1.4 mmol), tetrakistriphenylphosphine palladium (0.16 g,0.14 mmol) and potassium carbonate (0.58 g,4.2 mmol) were suspended in DME and H2O (v/v = 3/1) in a mixed solvent (16 mL) was reacted at 90 ℃ for 3.0 hours under nitrogen protection. After completion of the reaction, it was cooled to room temperature, and the reaction mixture was diluted with EtOAc (40 mL), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent: PE/EtOAc (v/v) = 1/3) to obtain 0.38g of a white solid, yield: 45 percent.
MS(ESI,pos.ion)m/z:608.5[M+H]+；
1H NMR(400MHz,CDCl3):7.97(s,1H),7.52(brs,2H),7.37,7.35(dd,dd,1H),7.13,7.10(dd,dd,1H),7.02,6.99(dd,dd,1H),6.66,6.64(dd,dd,1H),5.14-5.08(m,1H),3.64-3.58(m,1H),3.31-3.24(m,1H),2.93-2.89(m,4H),2.88-2.82(m,4H),2.47-2.38(m,1H),2.28-2.17(m,1H),2.10-1.97(m,2H),1.77-1.54(m,12H),1.53(s,9H),1.52-1.40(m,4H),1.29-1.21(m,2H)ppm。
Step 7) Synthesis of Compounds 8-7
Dissolving compound 8-6 (0.30 g,0.5 mmol) in DCM (5 mL), adding pyridine (0.24 mL,3 mmol) dropwise at 0 deg.C, stirring for 10 min, adding trifluoromethanesulfonic anhydride (0.34 mL,2 mmol) dropwise, reacting at room temperature for 1.0 hr, adding ice water (10 mL) to quench reaction, extracting with DCM (20 mL × 3), combining organic phases, anhydrous Na2SO4Dried, concentrated and purified by column chromatography (eluent: PE/EtOAc (v/v) = 2/1) to give 295mg of a colorless liquid, yield: 80 percent.
1H NMR(400MHz,CDCl3):7.97(s,1H),7.39,7.37(dd,dd,1H),7.20,7.18(dd,dd,1H),7.13,7.10(dd,dd,1H),6.96,6.94(dd,dd,1H),5.14-5.08(m,1H),3.64-3.58(m,1H),3.31-3.23(m,1H),2.95-2.90(m,4H),2.89-2.85(m,4H),2.47-2.38(m,1H),2.28-2.17(m,1H),2.10-1.97(m,2H),1.77-1.54(m,12H),1.53(s,9H),1.52-1.44(m,4H),1.29-1.21(m,2H)ppm。
Step 8) Synthesis of Compounds 8-8
Compounds 1-16 (0.50 g,1.38 mmol), PdCl2(PPh3)2(98 mg,0.14 mmol), tetra-n-butylammonium iodide (1.53 g,4.14 mmol) and CuI (78 mg,0.41 mmol) were dissolved in DMF (5 mL), triethylamine (2.0 mL) was slowly added under nitrogen protection, the mixture was stirred at room temperature for 10 minutes, TMSA (0.98 mL,6.89 mmol) was slowly added dropwise, after completion of the reaction at 70 ℃ overnight, the reaction was completed, celite was filtered, the filtrate was diluted with water (20 mL), the aqueous layer was extracted with EtOAc (20 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent: PE/EtOAc (v/v) = 3/1) to obtain 0.25g of a product with a yield of 55%.
MS(ESI,pos.ion)m/z:334.5[M+H]+；
1H NMR(400MHz,CDCl3):7.24(s,1H),4.95-4.90(m,1H),3.72-3.66(m,1H),3.38-3.30(m,1H),2.56-2.48(m,1H),2.40-2.30(m,1H),2.28-2.19(m,1H),2.07-1.97(m,1H),1.41(s,9H),0.32(s,9H)ppm。
Step 9) Synthesis of Compounds 8-9
Mixing the compounds 8-8 (0.30 g,0.87 mmol) and K2CO3(0.60 g,4.35 mmol) was dissolved in a mixed solvent of MeOH (2 mL) and THF (2 mL) and reacted at room temperature for 6.0 hours. After completion of the reaction, the reaction mixture was diluted with EtOAc (20 mL), filtered, and the filtrate was concentrated and purified by column chromatography (eluent: PE/EtOAc (v/v) = 2/1) to obtain 0.18g of a product, yield: 80 percent.
MS(ESI,pos.ion)m/z:262.5[M+H]+；
1H NMR(400MHz,CDCl3):7.25(s,1H),4.99-4.94(m,1H),3.72-3.66(m,1H),3.38-3.30(m,1H),2.56-2.48(m,1H),2.40-2.30(m,1H),2.28-2.19(m,1H),2.07-1.97(m,1H),1.41(s,9H)ppm。
Step 10) Synthesis of Compounds 8-10
Mixing the compound 8-7 (0.29 g,0.39 mmol), the compound 8-9 (0.11 g,0.43 mmol), PdCl2(PPh3)2（14.1mg,0.02mmol），CuI（33mg,0.172mmol），PPh3(0.23 g,0.86 mmol) was charged into a reaction flask, DMF (10 mL) was added under nitrogen, triethylamine (5.0 mL) was slowly added dropwise, and after dropwise addition, the mixture was stirred at room temperature for 10 minutes and reacted at 90 ℃ for 5.0 hours. After the reaction was complete, EtOA was addedcThe reaction mixture was diluted (50 mL), filtered through celite, and the filtrate was washed with water (20 mL × 3) and saturated brine, respectively, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: DCM/MeOH (v/v) = 80/1) to give compound 8-10 (165 mg, yield: 50%).
MS(ESI,pos.ion)m/z:426.3[M+2H]2+；
1H NMR(400MHz,CDCl3):7.97(s,1H),7.52(s,1H),7.49,7.46(dd,dd,1H),7.41,7.39(dd,dd,1H),7.35,7.33(dd,dd,1H),7.13,7.10(dd,dd,1H),5.18-5.08(m,2H),3.72-3.66(m,1H),3.64-3.58(m,1H),3.38-3.24(m,2H),3.22-3.18(m,2H),3.09-3.06(m,2H),2.93-2.90(m,2H),2.88-2.85(m,2H),2.56-2.30(m,3H),2.28-2.17(m,2H),2.10-1.97(m,3H),1.77-1.56(m,16H),1.53(s,9H),1.41(s,9H),1.29-1.21(m,2H)ppm。
Step 11) Synthesis of Compounds 8-11
Compound 8-10 (0.34 g,0.4 mmol) was dissolved in EtOAc (5 mL), and after further addition of a solution of hydrogen chloride in ethyl acetate (5 mL, 4M), the reaction was carried out at room temperature for 8 hours. After completion of the reaction, the reaction was concentrated, and the residue was slurried with EtOAc (5 mL) and filtered to give 286mg of a white solid, yield: 90 percent.
MS(ESI,pos.ion)m/z:651.5[M+H]+；
Step 12) Synthesis of Compounds 8 to 12
Compound 8-11 (63.7 mg,0.08 mmol), compound 8-11-2 (39.8 mg,0.17 mmol), EDCI (32.2 mg,0.17 mmol) and HOAT (21.8 mg,0.16 mmol) were dissolved in DCM (5 mL) and DIPEA (0.10 mL,0.64 mmol) was added dropwise slowly at 0 ℃ and reacted at room temperature for 3.0 hours after completion of dropwise addition. After completion of the reaction, DCM (20 mL) was added to dilute the reaction solution, and the reaction solution was washed with an ammonium chloride solution and a saturated saline solution, respectively, and dried over anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: DCM/MeOH (v/v) = 60/1) gave 43.5mg of a white solid, yield: 50 percent.
MS(ESI,pos.ion)m/z:545.3[M+2H]2+；
1H NMR(400MHz,CDCl3):10.23(brs,2H),7.88(s,1H),7.49,7.46(dd,dd,1H),7.48(s,1H),7.42,7.40(dd,dd,1H),7.36-7.30(m,5H),7.24-7.19(m,2H),7.13-7.10(m,5H),5.71,5.69(dd,dd,1H),5.51-5.46(m,2H),5.32-5.28(m,1H),4.51-4.43(m,2H),3.89-3.78(m,2H),3.73-3.61(m,2H),3.22-3.18(m,2H),3.09-3.06(m,2H),2.93-2.90(m,2H),2.88-2.85(m,2H),2.33-1.92(m,10H),1.77-1.48(m,14H),1.47-1.37(m,2H),1.29-1.21(m,2H),1.02-0.89(m,12H)ppm。
Example 9
The synthetic route is as follows:
step 1) Synthesis of Compound 9-1
Freshly distilled 1, 3-cyclopentadiene (9.20 g,138.8 mmol) was added dropwise to a solution of benzoquinone (10 g,92.5 mmol) in DCM (100 mL) at-10 ℃ for 1 hour at constant temperature and then reacted at room temperature for 0.5 hour. After the reaction was completed, the solvent was removed, n-hexane (500 mL) was added, stirring and filtration were performed, and the filtrate was concentrated and dried to obtain 10.5g of a pale yellow solid, yield: 65.2 percent. The reaction mixture was used in the next reaction without further purification.
MS(ESI,pos.ion)m/z:175.1[M+H]+；
1H NMR(400MHz,CDCl3):6.57(s,2H),6.68(s,2H),3.55(s,2H),3.22-3.21(m,2H),1.56-1.42(m,2H)ppm。
Step 2) Synthesis of Compound 9-2
Compound 9-1 (5.50 g,31.6 mmol) was reacted with sodium acetate (7.77 g,94.7 mmol) in methanol (100 mL) under nitrogen at 50 ℃ for 3 hours. After completion of the reaction, the reaction solution was concentrated and purified by column chromatography (eluent: DCM) to obtain 5.10g of a white solid, yield: 92.7 percent.
MS(ESI,pos.ion)m/z:175.1[M+H]+；
1H NMR(400MHz,CDCl3):6.80-6.79(m,2H),6.35(s,2H),3.55(s,2H),4.10-4.09(m,2H),2.25-2.18(m,2H)ppm。
Step 3) Synthesis of Compound 9-3
Compound 9-2 (4.70 g,27.0 mmol) and a catalytic amount of palladium on carbon (0.47 g) were suspended in methanol (50 mL) and reacted under hydrogen at room temperature under normal pressure for 1.5 hours. After the reaction was completed, filtration was performed, and the filtrate was concentrated and then purified by recrystallization to obtain 3.55g of a white solid, yield: 74.6 percent.
1H NMR(400MHz,d6-DMSO):8.27(s,2H),6.29(s,2H),3.47(s,2H),1.79-1.77(m,2H),1.48-1.46(m,1H),1.36-1.34(m,1H),1.01-0.99(m,2H)ppm。
Step 4) Synthesis of Compound 9-4
Pyridine (9.0 g,114 mmol) was added dropwise to a solution of compound 9-3 (3.35 g,19 mmol) in DCM (50 mL) at 0 ℃ and stirred for 10 minutes, then trifluoromethanesulfonic anhydride (21 g,76 mmol) was added dropwise to the reaction flask and the reaction was carried out at room temperature for 1 hour after completion of the addition. After completion of the reaction, the reaction mixture was diluted with DCM (50 mL), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent: PE/DCM (v/v) = 10/1) to give 8.2g of a colorless oil, yield: 98.0 percent.
1H NMR(400MHz,CDCl3):7.05(s,2H),3.71-3.70(m,2H),2.05-2.02(m,2H),1.90-1.87(m,1H),1.69-1.68(m,1H),1.38-1.34(m,2H)ppm。
Step 5) Synthesis of Compound 9-5
Mixing compound 1-7 (0.15 g,0.48 mmol), compound 9-4 (0.21 g,0.48 mmol), potassium carbonate (0.16 g,1.12 mmol) and Pd (PPh)3)4(27.6 mg,0.024 mmol) in a reaction flask, N2DME (8 mL) and water (2 mL) were separately injected and reacted at 90 ℃ for 12 hours with protection. After completion of the reaction, the reaction mixture was diluted with EtOAc (50 mL) and washed with saturated brine and anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 8/1) gave 0.11g of a colorless liquid, yield: 50 percent.
1H NMR(400MHz,CDCl3):7.30,7.28(s,s,1H),7.11,7.09(s,s,1H),6.96,6.94(dd,dd,1H),6.49,6.47(dd,dd,1H),4.81(brs,1H),3.79-3.76(m,1H),3.52-3.50(m,1H),2.90-2.84(m,4H),2.08-2.02(m,1H),1.98-1.92(m,1H),1.87-1.83(m,1H),1.71-1.50(m,7H),1.49-1.38(m,2H),1.35-1.29(m,1H),1.25-1.19(m,1H)ppm。
Step 6) Synthesis of Compound 9-6
DIPEA (19.5 mL,118 mmol) was added to a solution of compound 1-11 (23 g,107 mmol) and compound HATU (48.82 g,128.4 mmol) in THF (250 mL) at 0 deg.C, and after 0.5 hour of isothermal reaction, compound 3-1-2 (22.13 g,119 mmol) was added in portions and after completion of the addition, the reaction was carried out at room temperature for 4.0 hours. After completion of the reaction, the reaction was quenched with water (100 mL), THF was removed, extracted with EtOAc (200 mL. times.3), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the crude product, which was used directly in the next reaction. The product obtained above was dissolved in glacial acetic acid (100 mL) and reacted overnight at 40 ℃. After completion of the reaction, the reaction solution was concentrated, and the residue was dissolved in EtOAc (400 mL), washed with a sodium carbonate solution (150 mL. times.3), dried over anhydrous sodium sulfate, and purified by column chromatography (eluent: PE/EtOAc (v/v) = 1/2) to obtain compound 9-6 (31.64 g, yield: 81%).
MS(ESI,pos.ion)m/z:367.3[M+H]+；
1H NMR(400MHz,CDCl3):7.68(s,1H),7.42-7.40(m,1H),7.30-7.28(m,1H),5.11-5.09(m,1H),3.45-3.43(m,2H),2.94-2.93(m,1H),2.21-2.18(m,2H),2.01-1.91(m,1H),1.49(s,9H)ppm。
Step 7) Synthesis of Compounds 9-7
The compound 9-6 (4.11 g,11.27 mmol), the compound 1-6-2 (4.29 g,16.9 mmol), Pd (dppf) Cl2·CH2Cl2(0.65 g,0.8 mmol) and KOAc (2.09 g,21.3 mmol) were placed in a reaction flask, N2DMF (30 mL) was added under protection, the reaction was carried out at 90 ℃ for 3 hours, the reaction mixture was cooled to room temperature after completion of the reaction, EtOAc (200 mL) was added to dilute the reaction mixture, the mixture was washed with water (60 mL × 3) and saturated brine, dried over anhydrous sodium sulfate, and concentrated and then purified by column chromatography (eluent: PE/EtOAc (v/v) = 1/2) to obtain 3.02g of a beige solid in 65% yield.
MS(ESI,pos.ion)m/z:414.3[M+H]+；
1H NMR(400MHz,CDCl3):7.69(s,1H),7.45-7.43(m,1H),7.32-7.30(m,1H),5.12-5.10(m,1H),3.45-3.43(m,2H),2.95-2.94(m,1H),2.25-2.22(m,2H),2.01-1.91(m,1H),1.49(s,9H),1.35(s,12H)ppm。
Step 8) Synthesis of Compounds 9-8
Mixing compound 9-5 (99.0 mg,0.207mmol), compound 9-7 (85.5 mg,0.207mmol), Pd (PPh)3)4(24.0 mg,0.021 mmol) and potassium carbonate (85.9 mg,0.62 mmol)Placing in a reaction flask, N2Under the protection, DME (4.0 mL) and pure water (1.0 mL) were separately injected and reacted at 90 ℃ for 5.0 hours, after completion of the reaction, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), washed with water (10 mL × 3) and saturated brine, and dried over Na2SO4Drying, concentration and purification by column chromatography (eluent: DCM/EtOH (v/v) = 100/1) gave 82.8mg of a yellow solid, yield: 65 percent.
MS(ESI,pos.ion)m/z:616.5[M+H]+；
1H NMR(400MHz,CDCl3):7.62-7.59(m,2H),7.46,7.44(s,s,1H),7.33,7.31(s,s,1H),7.23,7.21(d,d,1H),7.03,7.01(dd,dd,1H),6.49,6.47(dd,dd,1H),5.04-4.99(m,1H),3.86-3.76(m,3H),3.64-3.57(m,1H),2.90-2.84(m,4H),2.63-2.53(m,1H),2.47-2.35(m,1H),2.25-2.15(m,1H),2.04-1.93(m,3H),1.89-1.85(m,1H),1.70-1.50(m,7H),1.49-1.43(m,2H),1.41(s,9H),1.28-1.21(m,2H)ppm。
Step 9) Synthesis of Compound 9-9
Pyridine (0.9 g,11.4 mmol) was added dropwise to a solution of compound 9-8 (1.17 g,1.9 mmol) in DCM (10 mL) at 0 ℃ and stirred for 10 minutes, and after that, trifluoromethanesulfonic anhydride (2.1 g,7.6 mmol) was added dropwise to the reaction flask and reacted at room temperature for 1 hour. After completion of the reaction, the reaction was quenched by addition of ice water (20 mL), the aqueous layer was extracted with DCM (20 mL. times.3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent: PE/EtOAc (v/v) = 2/1) to give 1.2g of a colorless oil, yield: 85 percent.
1H NMR(400MHz,CDCl3):7.62-7.59(m,2H),7.41,7.39(s,s,1H),7.33,7.31(s,s,1H),7.23,7.21(d,d,1H),7.04,7.02(dd,dd,1H),6.99,6.97(dd,dd,1H),5.04-4.99(m,1H),3.86-3.76(m,3H),3.64-3.57(m,1H),2.92-2.86(m,4H),2.63-2.53(m,1H),2.47-2.35(m,1H),2.25-2.15(m,1H),2.04-1.93(m,3H),1.89-1.85(m,1H),1.74-1.43(m,9H),1.41(s,9H),1.28-1.21(m,2H)ppm。
Step 10) Synthesis of Compounds 9-10
Mixing compound 9-9 (1.87 g,2.5 mmol), compound 1-6-2 (0.96 g,3.8 mmol), Pd (dppf) Cl2·CH2Cl2(0.11 g,0.13 mmol) and KOAc (0.74 g,7.5 mmol) were mixed in a reaction flask, DMF (12 mL) was added under nitrogen, the reaction was carried out at 90 ℃ for 4.0 hours, after completion of the reaction, the mixture was cooled to room temperature, EtOAc (100 mL) was added to dilute the reaction mixture, and the mixture was filtered through celite, and the filtrate was washed with water (50 mL × 3) and saturated brine, respectively, and anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 1/3) gave 0.82g of a pale yellow solid, yield: 45 percent.
1H NMR(400MHz,CDCl3):7.80,7.78(dd,dd,1H),7.62-7.59(m,2H),7.53,7.51(s,s,1H),7.40,7.38(dd,dd,1H),7.33,7.31(s,s,1H),7.23,7.21(d,d,1H),5.04-4.99(m,1H),3.86-3.76(m,3H),3.64-3.57(m,1H),3.03-3.00(m,2H),2.91-2.87(m,2H),2.63-2.53(m,1H),2.47-2.35(m,1H),2.25-2.15(m,1H),2.04-1.93(m,3H),1.89-1.85(m,1H),1.72-1.42(m,7H),1.41(s,9H),1.32,1.29(q,q,12H),1.27-1.19(m,4H)ppm。
Step 11) Synthesis of Compounds 9-11
Mixing compound 9-10 (0.52 g,0.72 mmol), compound 1-16 (0.26 g,0.72 mmol), Pd (PPh)3)4(83 mg,0.07 mmol) and potassium carbonate (0.30 g,2.12 mmol) were suspended in DME (6.0 mL) and water (1.5 mL) and reacted at 90 ℃ for 4.0 hours under nitrogen, after completion of the reaction, cooled to room temperature, and after addition of EtOAc (40 mL) to dilute the reaction, washed with water (30 mL × 3) and saturated brine, respectively, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (DCM/MeOH (v/v) = 100/1) to give 0.37g of the product in 60% yield.
MS(ESI,pos.ion)m/z:428.3[M+2H]2+；
1H NMR(400MHz,CDCl3):7.97(s,1H),7.62-7.59(m,2H),7.49,7.46(s,s,1H),7.42,7.40(dd,dd,1H),7.33,7.31(s,s,1H),7.23,7.21(d,d,1H),7.06,7.03(dd,dd,1H),5.15-5.08(m,2H),5.04-4.99(m,1H),3.86-3.76(m,3H),3.64-3.57(m,2H),3.31-3.23(m,1H),3.07-3.03(m,2H),2.96-2.93(m,2H),2.63-2.53(m,1H),2.47-2.35(m,2H),2.29-2.15(m,2H),2.10-1.93(m,5H),1.89-1.85(m,1H),1.70-1.49(m,7H),1.41(s,18H),1.40-1.34(m,2H),1.28-1.21(m,2H)ppm。
Step 12) Synthesis of Compounds 9-12
Compound 9-11 (0.33 g,0.4 mmol) was dissolved in EtOAc (5 mL), and after further addition of a solution of hydrogen chloride in ethyl acetate (5 mL, 4M), the reaction was carried out at room temperature for 8 hours. After completion of the reaction, the reaction was concentrated, and the residue was slurried with EtOAc (5 mL) and filtered to give 0.28g of a white solid, yield: 90 percent.
MS(ESI,pos.ion)m/z:635.5[M+H]+。
Step 13) Synthesis of Compounds 9-13
Compound 9-12 (62.43 mg,0.08 mmol), compound 9-12-2 (24.7 mg,0.168 mmol), EDCI (32.2 mg,0.168 mmol) and HOAT (21.78 mg,0.16 mmol) were dissolved in DCM (5 mL) and DIPEA (0.10 mL,0.64 mmol) was added dropwise slowly at 0 ℃ and reacted at room temperature for 3.0 hours after completion of dropwise addition. After completion of the reaction, DCM (50 mL) was added to dilute the reaction solution, and the reaction solution was washed with an ammonium chloride solution and a saturated saline solution, respectively, and dried over anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: DCM/MeOH (v/v) = 60/1) gave 35.69mg of a white solid, yield: 50 percent.
MS(ESI,pos.ion)m/z:447.3[M+2H]2+；
1H NMR(400MHz,CDCl3):7.88(s,1H),7.62-7.59(m,2H),7.49,7.46(s,s,1H),7.42,7.40(dd,dd,1H),7.33,7.31(s,s,1H),7.23,7.21(d,d,1H),7.06,7.03(dd,dd,1H),5.48-5.42(m,2H),5.18-5.10(m,2H),4.64-4.53(m,2H),3.88-3.79(m,4H),3.72-3.66(m,2H),3.65,3.64(s,s,6H),3.07-3.03(m,2H),2.96-2.93(m,2H),2.42-2.06(m,6H),2.04-1.90(m,4H),1.89-1.85(m,1H),1.70-1.51(m,7H),1.48,1.46(d,d,3H),1.44-1.37(m,2H),1.36,1.34(d,d,3H),1.28-1.21(m,2H)ppm。
Example 10
The synthetic route is as follows:
step 1) Synthesis of Compound 10-1
A solution of hydrogen chloride in ethyl acetate (5 mL, 4M) was added dropwise to a solution of compounds 1-16 (1.50 g,4.13 mmol) in EtOAc (10 mL) at room temperature, and the reaction was carried out for 8.0 hours after completion of the dropwise addition. After completion of the reaction, the reaction was concentrated, and the residue was slurried with EtOAc (10 mL) and filtered to give 1.2g of a solid, yield: 86.45 percent. Directly used for the next reaction.
MS(ESI,pos.ion)m/z:264.1[M+H]+。
Step 2) Synthesis of Compound 10-2
Compound 10-1 (1.2 g,3.6 mmol), compound 1-18-2 (0.69 g,3.9 mmol) and EDCI (0.75 g,3.9 mmol) were suspended in DCM (20 mL) and reacted at 0 ℃ for5 minutes, followed by dropwise addition of DIPEA (2.38 mL,14.4 mmol) slowly and reaction at room temperature for 2.0 hours after completion of the dropwise addition. After completion of the reaction, DCM (40 mL) was added to dilute the reaction solution, and the organic phase was washed with a saturated ammonium chloride solution, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE/EtOAc (v/v) = 1/2) to obtain 1.31g of a pale yellow solid, yield: 86.8 percent.
MS(ESI,pos.ion)m/z:421.1[M+H]+；
1H NMR(400MHz,CDCl3):7.35(s,1H),5.32,5.29(brs,brs,1H),5.20-5.15(m,1H),4.41-4.37(m,1H),3.85-3.78(m,1H),3.69-3.65(m,1H),3.63(s,3H),2.28-2.17(m,3H),2.11-1.96(m,2H),0.97-0.95(m,3H),0.91-0.89(m,3H)ppm。
Step 3) Synthesis of Compound 10-3
Pyridine (0.9 g,11.4 mmol) was added dropwise to a solution of compound 9-5 (0.91 g,1.9 mmol) in DCM (10 mL) at 0 ℃ and stirred for 10 minutes, and after that, trifluoromethanesulfonic anhydride (2.1 g,7.6 mmol) was added dropwise to the reaction flask and reacted at room temperature for 1 hour. After completion of the reaction, the reaction was quenched by addition of ice water (20 mL), the aqueous layer was extracted with DCM (20 mL. times.3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent: PE/EtOAc (v/v) = 10/1) to give 0.93g of a colorless oil, yield: 80 percent.
1H NMR(400MHz,CDCl3):7.30,7.28(s,s,1H),7.07,7.05(s,s,1H),7.01-6.96(m,2H),3.79-3.76(m,1H),3.52-3.50(m,1H),2.92-2.86(m,4H),2.08-2.02(m,1H),1.98-1.92(m,1H),1.87-1.83(m,1H),1.74-1.42(m,9H),1.35-1.29(m,1H),1.25-1.19(m,1H)ppm。
Step 4) Synthesis of Compound 10-4
Mixing 10-3 (1.53 g,2.5 mmol), 1-6-2 (0.96 g,3.8 mmol), Pd (dppf) Cl2·CH2Cl2(0.11 g,0.13 mmol) and KOAc (0.74 g,7.5 mmol) were mixed in a reaction flask, DMF (12 mL) was added under nitrogen, the reaction was carried out at 90 ℃ for 4.0 hours, after completion of the reaction, the mixture was cooled to room temperature, EtOAc (100 mL) was added to dilute the reaction mixture, and the mixture was filtered through celite, and the filtrate was washed with water (50 mL × 3) and saturated brine, respectively, and anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 5/1) gave 0.64g of a pale yellow solid, yield: 45 percent.
1H NMR(400MHz,CDCl3):7.88,7.86(s,s,1H),7.80,7.78(dd,dd,1H),7.48-7.46(m,2H),3.92-3.89(m,1H),3.78-3.75(m,1H),3.03-3.00(m,2H),2.91-2.87(m,2H),1.96-1.90(m,1H),1.85-1.79(m,2H),1.72-1.41(m,7H),1.32,1.29(q,q,24H),1.28-1.17(m,3H),1.12-1.06(m,1H)ppm。
Step 5) Synthesis of Compound 10-5
Mixing compound 10-4 (0.41 g,0.72 mmol), compound 10-2 (0.64 g,1.512 mmol), Pd (PPh)3)4(83 mg,0.07 mmol) and potassium carbonate (0.30 g,2.12 mmol) were suspended in DME (6.0 mL) and water (1.5 mL) and reacted at 90 ℃ for 4.0 hours under nitrogen, after completion of the reaction, cooled to room temperature, and the reaction was diluted with EtOAc (40 mL), washed with water (30 mL × 3) and saturated brine, respectively, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (DCM/MeOH (v/v) = 100/1) to give 0.39g of the product in 60% yield.
MS(ESI,pos.ion)m/z:450.3[M+2H]2+；
1H NMR(400MHz,CDCl3):7.88(s,1H),7.81(s,1H),7.42,7.40(dd,dd,1H),7.38,7.36(s,s,1H),7.31,7.29(s,s,1H),7.06,7.04(dd,dd,1H),6.08,6.05(d,d,1H),5.32-5.25(m,3H),4.41-4.30(m,2H),3.85-3.76(m,4H),3.68-3.66(m,1H),3.65(s,3H),3.63(s,3H),3.62-3.61(m,1H),3.07-3.03(m,2H),2.96-2.93(m,2H),2.30-1.88(m,13H),1.70-1.49(m,7H),1.44-1.34(m,2H),1.30-1.21(m,2H),1.02-0.89(m,12H)ppm。
Example 11
The synthetic route is as follows:
step 1) Synthesis of Compound 11-1
Dimethyl butynedicarboxylate (2.0 g,14 mmol) and 1, 3-cyclohexadiene (1.2 g,15.48 mmol) were dissolved in freshly distilled THF (10.0 mL) and the system was moved to 60 ℃ for 18 h. After completion of the reaction, the concentrated reaction solution was purified by column chromatography (eluent: PE/EtOAc (v/v) = 30/1) to give 2.36g of a colorless oil, yield: 76 percent.
MS(ESI,pos.ion)m/z:223.2[M+H]+；
1H NMR(400MHz,CDCl3):6.35(dd,2H,J=3.2Hz,4.4Hz),4.00(m,2H),3.74(s,6H),1.45(m,2H),1.38(m,2H)ppm。
Step 2) Synthesis of Compound 11-2
Compound 11-1 (0.8 g,3.6 mmol) was dissolved in ethyl acetate (10.0 mL), and a catalytic amount of palladium on carbon (0.04 g) was added to the solution to react under a hydrogen atmosphere at room temperature for 2 hours. After the reaction was complete, the reaction mixture was filtered through celite, and the filtrate was concentrated to obtain 0.77g of a colorless liquid without purification. Yield: 95 percent.
MS(ESI,pos.ion)m/z:225.2[M+H]+；
1H NMR(400MHz,CDCl3):3.78(s,6H),3.02(s,2H),1.62(m,2H),1.40(m,2H)ppm。
Step 3) Synthesis of Compound 11-3
Compound 11-2 (0.78 g,3.5 mmol) was dissolved in methanol (10 mL), and an aqueous solution of sodium hydroxide (10%, 3.5 mL) was added to react at 60 ℃ for 8 hours. After completion of the reaction, methanol was removed, pH was adjusted to 1 with hydrochloric acid (1M), extracted with EtOAc (30 mL. times.3), dried over anhydrous sodium sulfate, and concentrated to give 0.67g of a white solid, yield: 98 percent.
MS(ESI,pos.ion)m/z:197.2[M+H]+；
1H NMR(400MHz,DMSO-d6):8.62(brs,2H),3.37(s,2H),1.66(m,4H),1.38(m,4H)ppm。
Step 4) Synthesis of Compound 11-4
Compound 11-3 (3.7 g,18.88 mmol) was mixed with acetic anhydride (20 mL) and reacted at 100 ℃ for 1.5 hours. After completion of the reaction, it was cooled to room temperature, and the reaction solution was concentrated to obtain 3.09g of a white solid, yield: 92 percent.
MS(ESI,pos.ion)m/z:179.1[M+H]+；
1H NMR(400MHz,CDCl3):3.26(m,2H),1.85(d,4H,J=8.0Hz),1.35(d,4H,J=8.0Hz)ppm。
Step 5) Synthesis of Compound 11-5
Compound 11-4 (0.31 g,1.74 mmol), sodium acetate (0.22 g,2.6 mmol) and hydrazine hydrate (0.13 mL,2.6 mmol) were mixed in aqueous acetic acid (10 mL, 50%) and reacted at 100 ℃ for 16 hours. After completion of the reaction, cooled to room temperature, filtered to give a white solid, washed with water, MTBE washed and dried to give 0.28g of product, yield: 85 percent.
MS(ESI,pos.ion)m/z:193.2[M+H]+；
1H NMR(400MHz,CDCl3):3.17(s,2H),1.69(d,4H,J=8.0Hz),1.15(d,4H,J=8.0Hz)ppm。
Step 6) Synthesis of Compound 11-6
Compound 11-5 (69 mg,0.36 mmol) was mixed with phosphorus oxychloride (3.0 mL) and reacted at 110 ℃ for5 hours. After completion of the reaction, it was cooled to room temperature, and the reaction solution was concentrated to obtain 78mg of a white solid, yield: 95 percent.
MS(ESI,pos.ion)m/z:230.1[M+H]+；
1H NMR(400MHz,CDCl3):3.46(s,2H),1.90(d,4H,J=8.0Hz),1.37(d,4H,J=8.0Hz)ppm.
Step 7) Synthesis of Compounds 11-7
Mixing compound 1-7 (0.15 g,0.48 mmol), compound 11-6 (0.11 g,0.48 mmol), potassium carbonate (0.16 g,1.12 mmol) and Pd (PPh)3)4(27.6 mg,0.024 mmol) in a reaction flask, N2DME (8 mL) and water (2 mL) were separately injected and reacted at 90 ℃ for 12 hours with protection. After completion of the reaction, the reaction mixture was diluted with EtOAc (50 mL) and washed with saturated brine and anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 10/1) gave 0.11g of a white solid, yield: 60 percent.
MS(ESI,pos.ion)m/z:381.3[M+H]+；
1H NMR(400MHz,CDCl3):7.50,7.48(dd,dd,1H),6.44,6.42(dd,dd,1H),4.81(brs,1H),3.37-2.26(m,2H),3.00-2.97(m,2H),1.71-1.16(m,16H)ppm。
Step 8) Synthesis of Compound 11-8
After compound 9-6 (10 g,27.39 mmol) was dissolved in EtOAc (50 mL), a solution of hydrogen chloride in ethyl acetate (60 mL, 4M) was added dropwise at 0 ℃ and reacted at room temperature for 8.0 hours, after completion of the reaction, the reaction was concentrated, and the residue was slurried with EtOAc (30 mL) and filtered to give 8.0g of a pale yellow solid, yield: 86.5 percent.
MS(ESI,pos.ion)m/z:267.2[M+H]+；
1H NMR(400MHz,CDCl3):8.01(s,1H),7.70-7.76(m,2H),5.27-5.25(m,1H),3.31-3.30(m,2H),2.77-2.74(m,1H),2.54-2.52(m,1H),2.40-2.37(m,1H),2.30-2.10(m,1H)ppm。
Step 9) Synthesis of Compound 11-9
Compound 11-8 (6.35 g,18.8 mmol), compound 1-18-2 (4.93 g,28.2 mmol) and EDCI (5.4 g,28.2 mmol) were dissolved in DCM (100 mL) and reacted at 0 ℃ with DIPEA (18.64 mL,112.8 mmol) added dropwise slowly for 3.0 hours at room temperature. After completion of the reaction, DCM (100 mL) was added to dilute the reaction solution, and the mixture was washed with a saturated ammonium chloride solution and a saturated brine, respectively, and dried over anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 1/2) gave 6.74g of a solid, yield: 85 percent.
MS(ESI,pos.ion)m/z:423.3[M+H]+；
1H NMR(400MHz,CDCl3):7.59-7.51(m,1H),7.34-7.21(m,2H),5.42-5.38(m,2H),4.34-4.30(m,1H),3.87-3.76(m,1H),3.70(s,3H),3.66-3.62(m,1H),3.04-2.98(m,1H),2.25-2.21(m,1H),2.20-2.13(m,2H),1.96-1.94(m,1H),0.88-0.84(m,6H)ppm。
Step 10) Synthesis of Compounds 11-10
A mixture of 11-9 (3.0 g,7.1 mmol), 1-6-2 (2.72 g,10.7 mmol), Pd (dppf) Cl2·CH2Cl2(0.65 g,0.8 mmol) and KOAc (2.09 g,21.3 mmol) were placed in a reaction flask, N2Protection, DMF (30 mL) was injected, the reaction was carried out at 90 ℃ for 3.0 hours, after completion of the reaction, the reaction mixture was cooled to room temperature, EtOAc (200 mL) was added to dilute the reaction mixture, the mixture was filtered through celite, and the filtrate was washed with water (50 mL × 3) and saturated brine, respectively, dried over anhydrous sodium sulfate, and purified by column chromatography (eluent: PE/EtOAc (v/v) = 1/2) after concentration to obtain 2.1g of a beige solid, yield: 62.87%.
MS(ESI,pos.ion)m/z:471.3[M+H]+；
1H NMR(400MHz,CDCl3):7.87-7.80(m,1H),7.71-7.66(m,2H),5.47-5.42(m,2H),4.34-4.30(m,1H),3.86-3.84(m,1H),3.70(s,3H),3.64-3.62(m,1H),3.04-2.98(m,1H),2.25-2.21(m,1H),2.20-2.13(m,2H),1.96-1.94(m,1H),1.35(s,12H),0.88-0.84(m,6H)ppm。
Step 12) Synthesis of Compounds 11-11
Mixing compound 11-7 (41.8 mg,0.11 mmol), compound 11-10 (51.7 mg,0.11 mmol), Pd (PPh)3)4(25 mg,0.02 mmol) and K2CO3(91 mg,0.66 mmol) was suspended in DME (2.0 mL) and water (0.4 mL) and reacted at 90 ℃ for 3.0 hours under nitrogen, after completion of the reaction, cooled to room temperature, the reaction was diluted with EtOAc (20 mL), washed with water (30 mL × 3) and saturated brine, respectively, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent: DCM/MeOH (v/v) = 100/1) to give 60.57mg as a pale yellow solid in 80% yield.
MS(ESI,pos.ion)m/z:689.5[M+H]+；
1H NMR(400MHz,CDCl3):8.08,8.06(d,d,1H),7.95(q,1H),7.57(brs,2H),7.50-7.47(dd,dd,1H),7.06,7.03(d,d,1H),6.44,6.42(dd,dd,1H),5.32,5.29(d,d,1H),5.24-5.20(m,1H),4.40-4.35(m,1H),3.84-3.78(m,1H),3.68-3.64(m,1H),3.63(s,3H),3.47-3.30(m,2H),3.00-2.97(m,2H),2.90-2.87(m,2H),2.38-2.28(m,1H),2.25-2.10(m,3H),2.01-1.86(m,1H),1.77-1.51(m,10H),1.47-1.35(m,6H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H)ppm。
Step 13) Synthesis of Compounds 11-12
Pyridine (0.9 g,11.4 mmol) was added dropwise to a solution of compound 11-11 (1.3 g,1.9 mmol) in DCM (10 mL) at 0 ℃ and stirred for 10 minutes, and after that, trifluoromethanesulfonic anhydride (2.1 g,7.6 mmol) was added dropwise to the reaction flask and reacted at room temperature for 1 hour. After completion of the reaction, the reaction was quenched by addition of ice water (20 mL), the aqueous layer was extracted with DCM (20 mL × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent: PE/EtOAc (v/v) = 1/2) to give 1.32g of a colorless oil, yield: 85 percent.
1H NMR(400MHz,CDCl3):8.08,8.06(d,d,1H),8.01,7.99(d,d,1H),7.95(q,1H),7.05,7.04(d,d,1H),7.00,6.97(d,d,1H),5.32,5.29(d,d,1H),5.24-5.20(m,1H),4.40-4.35(m,1H),3.84-3.78(m,1H),3.68-3.64(m,1H),3.63(s,3H),3.47-3.30(m,2H),3.02-2.99(m,2H),2.98-2.94(m,2H),2.39-2.27(m,1H),2.24-2.10(m,3H),2.01-1.86(m,1H),1.77-1.35(m,10H),1.51-1.35(m,6H),0.97,0.95(m,m,3H),0.91,0.89(m,m,3H)ppm。
Step 14) Synthesis of Compounds 11-13
Mixing compound 11-12 (2.05 g,2.5 mmol), compound 1-6-2 (0.96 g,3.8 mmol), Pd (dppf) Cl2·CH2Cl2(0.11 g,0.13 mmol) and KOAc (0.74 g,7.5 mmol) were mixed in a reaction flask, and DMF (12 mL) was added under nitrogen protection to react at 90 ℃ for 4.0 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and then diluted with EtOAc (100 mL) and filtered through Celite. The filtrate is respectively treated with water (50mL × 3) and brine saturated, anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 1/3) gave 0.90g of a pale yellow solid, yield: 45 percent.
1H NMR(400MHz,CDCl3):8.08,8.06(d,d,1H),7.95(q,1H),7.84,7.82(dd,dd,1H),7.63,7.61(dd,dd,1H),7.06,7.03(d,d,1H),5.32,5.29(d,d,1H),5.24-5.20(m,1H),4.40-4.35(m,1H),3.84-3.78(m,1H),3.68-3.65(m,1H),3.63(s,3H),3.47-3.30(m,2H),2.99-2.96(m,2H),2.91-2.87(m,2H),2.39-2.27(m,1H),2.25-2.10(m,3H),2.01-1.86(m,1H),1.77-1.51(m,8H),1.50-1.36(m,6H),1.32,1.29(q,q,12H),1.27-1.18(m,2H),0.97,0.95(m,m,3H),0.91,0.89(m,m,3H)ppm。
Step 15) Synthesis of Compounds 11-14
Mixing compound 11-13 (0.57 g,0.72 mmol), compound 10-2 (0.30 g,0.72 mmol), Pd (PPh)3)4(83 mg,0.07 mmol) and potassium carbonate (0.30 g,2.12 mmol) were suspended in DME (6.0 mL) and water (1.5 mL) and reacted at 90 ℃ for 4.0 hours under nitrogen, after completion of the reaction, the reaction was diluted with EtOAc (40 mL), washed with water (30 mL × 3) and saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (DCM/MeOH (v/v) = 100/1) to give 0.39g of the product in 60% yield.
MS(ESI,pos.ion)m/z:483.3[M+2H]2+；
1H NMR(400MHz,CDCl3):8.08,8.06(d,d,1H),7.95(q,1H),7.88(s,1H),7.46,7.43(dd,dd,1H),7.06,7.03(d,d,1H),6.87,6.85(dd,dd,1H),6.08,6.05(d,d,1H),5.32-5.28(m,2H),5.24-5.20(m,1H),4.41-4.32(m,2H),3.85-3.78(m,2H),3.68-3.66(m,2H),3.65(s,3H),3.63(s,3H),3.47-3.30(m,2H),3.10-3.07(m,2H),2.99-2.96(m,2H),2.39-1.86(m,10H),1.77-1.50(m,10H),1.45-1.34(m,6H),1.02-0.89(m,12H)ppm。
Example 12
The synthetic route is as follows:
step 1) Synthesis of Compound 12-1
Mixing compound 9-5 (1.2 g,2.5 mmol), compound 1-6-2 (0.96 g,3.8 mmol), Pd (dppf) Cl2·CH2Cl2(0.11 g,0.13 mmol) and KOAc (0.74 g,7.5 mmol) were mixed in a reaction flask, DMF (12 mL) was added under nitrogen, the reaction was carried out at 90 ℃ for 4.0 hours, after completion of the reaction, the mixture was cooled to room temperature, EtOAc (100 mL) was added to dilute the reaction mixture, and the mixture was filtered through celite, and the filtrate was washed with water (50 mL × 3) and saturated brine, respectively, and anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 3/1) gave 0.74g of a pale yellow solid, yield: 65 percent.
1H NMR(400MHz,CDCl3):7.88,7.86(s,s,1H),7.35,7.33(s,s,1H),7.02,7.00(dd,dd,1H),6.49,6.47(dd,dd,1H),4.81(brs,1H),3.92-3.89(m,1H),3.78-3.75(m,1H),2.90-2.84(m,4H),1.96-1.90(m,1H),1.85-1.79(m,2H),1.70-1.50(m,7H),1.48-1.38(m,2H),1.32,1.29(q,q,12H),1.23-1.17(m,1H),1.12-1.06(m,1H)ppm。
Step 2) Synthesis of Compound 12-2
Mixing compound 12-1 (0.33 g,0.72 mmol), compound 10-2 (0.30 g,0.72 mmol), Pd (PPh)3)4(83 mg,0.07 mmol) and potassium carbonate (0.30 g,2.12 mmol) were suspended in DME (6.0 mL) and water (1.5 mL), reacted at 90 ℃ for 4.0 hours under nitrogen, cooled to room temperature after completion of the reaction, diluted with EtOAc (40 mL), washed with water (30 mL × 3) and saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (DCM/MeOH (v/L)v) = 100/1) to yield 0.27g of product, yield: 60 percent.
MS(ESI,pos.ion)m/z:623.3[M+H]+；
1H NMR(400MHz,CDCl3):7.81(s,1H),7.52(brs,2H),7.35,7.33(s,s,1H),7.31,7.28(s,s,1H),7.03,7.01(dd,dd,1H),6.49,6.47(dd,dd,1H),5.32,5.29(d,d,1H),5.28-5.25(m,1H),4.41-4.37(m,1H),3.85-3.76(m,3H),3.69-3.65(m,1H),3.63(s,3H),2.90-2.84(m,4H),2.30-1.93(m,7H),1.92-1.88(m,1H),1.70-1.50(m,7H),1.48-1.38(m,2H),1.30-1.21(m,2H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H)ppm。
Step 3) Synthesis of Compound 12-3
Pyridine (0.9 g,11.4 mmol) was added dropwise to a solution of compound 12-2 (1.18 g,1.9 mmol) in DCM (10 mL) at 0 ℃ and stirred for 10 minutes, and after that, trifluoromethanesulfonic anhydride (2.1 g,7.6 mmol) was added dropwise to the reaction flask and reacted at room temperature for 1 hour. After completion of the reaction, the reaction was quenched by addition of ice water (20 mL), the aqueous layer was extracted with DCM (20 mL × 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent: PE/EtOAc (v/v) = 1/2) to obtain 1.22g of a colorless oil, yield: 85 percent.
1H NMR(400MHz,CDCl3):7.81(s,1H),7.35,7.33(s,s,1H),7.31,7.28(s,s,1H),7.04,7.02(dd,dd,1H),6.99,6.97(dd,dd,1H),5.32,5.29(d,d,1H),5.28-5.25(m,1H),4.41-4.37(m,1H),3.85-3.76(m,3H),3.68-3.64(m,1H),3.63(s,3H),2.92-2.86(m,4H),2.30-1.93(m,7H),1.92-1.88(m,1H),1.74-1.42(m,9H),1.30-1.21(m,2H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H)ppm。
Step 4) Synthesis of Compound 12-4
Mixing compound 12-3 (1.89 g,2.5 mmol), compound 1-6-2 (0.96 g,3.8 mmol), Pd (dppf) Cl2·CH2Cl2(0.11 g,0.13 mmol) and KOAc (0.74 g,7.5 mmol) were mixed in a reaction flask, and DMF (12 mL) was added under nitrogen protection to react at 90 ℃ for 4.0 hours. After the reaction is completed, cooling to room temperature,the reaction was diluted with EtOAc (100 mL) and filtered through celite, and the filtrate was washed with water (50 mL × 3) and saturated brine, respectively, anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 1/3) gave 0.82g of a pale yellow solid, yield: 45 percent.
1H NMR(400MHz,CDCl3):7.81(s,1H),7.80,7.78(dd,dd,1H),7.49,7.47(s,s,1H),7.40,7.38(dd,dd,1H),7.31,7.29(s,s,1H),5.32,5.29(d,d,1H),5.28-5.25(m,1H),4.41-4.37(m,1H),3.85-3.76(m,3H),3.69-3.64(m,1H),3.63(s,3H),3.03-3.00(m,2H),2.91-2.87(m,2H),2.30-1.93(m,7H),1.93-1.88(m,1H),1.72-1.52(m,5H),1.51-1.41(m,2H),1.32,1.29(q,q,12H),1.27-1.19(m,4H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H)ppm。
Step 5) Synthesis of Compound 12-6
A solution of hydrogen chloride in ethyl acetate (10 mL, 4M) was added dropwise to a solution of compound 12-5 (1.72 g,4.13 mmol) in EtOAc (10 mL) at room temperature, and the reaction was carried out for 8.0 hours after completion of the dropwise addition. After completion of the reaction, the reaction was concentrated, and the residue was slurried with EtOAc (10 mL) and filtered to give a solid 1.37g, yield: 85 percent. Directly used for the next reaction.
MS(ESI,pos.ion)m/z:317.5[M+H]+。
Step 6) Synthesis of Compounds 12-7
Compound 12-6 (1.4 g,3.6 mmol), compound 1-18-2 (0.69 g,3.9 mmol) and EDCI (0.75 g,3.9 mmol) were suspended in DCM (10 mL), and DIPEA (2.38 mL,14.4 mmol) was added dropwise slowly at 0 ℃ and reacted at room temperature for 2.0 hours. After completion of the reaction, DCM (40 mL) was added to dilute the reaction solution, and the organic phase was washed with a saturated ammonium chloride solution, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent: PE/EtOAc (v/v) = 1/2) to obtain 1.45g of a pale yellow solid, yield: 85 percent.
MS(ESI,pos.ion)m/z:474.5[M+H]+；
1H NMR(400MHz,CDCl3):8.96(brs,1H),7.68-7.67(m,1H),7.55-7.52(m,1H),7.35-7.32(m,1H),7.14-7.10(m,1H),5.32,5.29(d,d,1H),4.55-4.51(m,1H),4.31-4.26(m,1H),3.63(s,3H),3.62-3.55(m,1H),3.47-3.40(m,1H),2.27-1.99(m,4H),1.94-1.82(m,1H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H)ppm。
Step 7) Synthesis of Compounds 12-8
Mixing compound 12-7 (1.61 g,3.4 mmol), compound 12-4 (2.49 g,3.4 mmol), Pd (PPh)3)4(0.20 g,0.17 mmol) and potassium carbonate (1.41 g,10.22 mmol) were placed in a reaction flask, N2DME (24 mL) and water (6 mL) were separately injected under the protection, and reacted at 90 ℃ for 4.0 hours, after completion of the reaction, the reaction mixture was cooled to room temperature, and EtOAc (100 mL) was added to dilute the reaction mixture, which was washed with water (50 mL × 3) and saturated brine, respectively, and anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: DCM/MeOH (v/v) = 60/1) gave 1.29g of a pale yellow solid, yield: 40 percent.
MS(ESI,pos.ion)m/z:476.7[M+2H]2+；
1H NMR(400MHz,CDCl3):8.96(m,1H),7.81(s,1H),7.73-7.72(m,1H),7.55-7.52(m,1H),7.44,7.42(dd,dd,1H),7.40-7.36(m,3H),7.31,7.29(s,s,1H),7.14-7.10(m,1H),6.07,6.05(d,d,1H),5.32,5.29(d,d,1H),5.28-5.25(m,1H),4.41-4.37(m,1H),4.33-4.29(m,1H),4.28-4.23(m,1H),3.86-3.80(m,2H),3.79-3.76(m,1H),3.69-3.66(m,1H),3.65(s,3H),3.63(s,3H),3.60-3.55(m,1H),3.44-3.36(m,1H),3.03-3.00(m,2H),2.94-2.90(m,2H),2.30-1.88(m,11H),1.74-1.49(m,9H),1.46-1.35(m,2H),1.30-1.21(m,2H),1.02-0.89(m,12H)ppm。
Example 13
The synthetic route is as follows:
step 1) Synthesis of Compound 13-2
Dissolving compound 13-1 (2.06 g,10.0 mmol) in DCM (50 mL), slowly adding boron tribromide (7.7 mL,80.0 mmol) dropwise at-78 deg.C, reacting at constant temperature for 10 min, reacting at room temperature for 1.0 hr, quenching with ice water (50 mL) after reaction is completed, extracting water layer with DCM (50 mL × 3), combining organic phases, washing with saturated saline, and removing anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 10/1) gave 1.6g of an oily liquid, yield: 90 percent.
MS(ESI,pos.ion)m/z:179.5[M+H]+;
1H NMR(400MHz,CDCl3):6.55(s,2H),6.51(br,2H),5.51-5.45(m,2H),1.78-1.65(m,2H),1.00-0.87(m,2H)ppm。
Step 2) Synthesis of Compound 13-3
Pyridine (4.8 mL,60 mmol) is slowly dropped into a DCM (20 mL) solution of the compound 13-2 (1.78 g,10 mmol) at 0 ℃, after stirring for 10 minutes, trifluoromethanesulfonic anhydride (6.73 mL,40 mmol) is slowly dropped, reaction is carried out at room temperature for 1.0 hour, ice water (25 mL) is added after the reaction is completed, the reaction is quenched, a water layer is extracted by DCM (30 mL × 3), organic phases are combined, the mixture is washed by saturated brine, and anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 40/1) gave 3.98g of a colorless oily liquid, yield: 90 percent.
1H NMR(400MHz,CDCl3):7.36(s,2H),5.53-5.47(m,2H),1.69-1.56(m,2H),0.91-0.78(m,2H)ppm。
Step 3) Synthesis of Compound 13-4
Converting compound 1-7 (0.15 g,0.48 mmol) intoCompound 13-3 (0.21 g,0.48 mmol), potassium carbonate (0.16 g,1.12 mmol) and Pd (PPh)3)4(27.6 mg,0.024 mmol) in a reaction flask, N2DME (8 mL) and water (2 mL) were separately injected and reacted at 90 ℃ for 12 hours with protection. After completion of the reaction, the reaction mixture was diluted with EtOAc (50 mL) and washed with saturated brine and anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 8/1) gave 0.115g of a colorless liquid, yield: 50 percent.
1H NMR(400MHz,CDCl3):7.35,7.33(s,s,1H),7.24,7.22(s,s,1H),6.97,6.95(dd,dd,1H),6.52,6.50(dd,dd,1H),5.61-5.56(m,1H),5.21-5.17(m,1H),4.81(brs,1H),2.91-2.87(m,4H),1.77-1.51(m,8H),1.49-1.38(m,2H),0.99-0.88(m,2H)ppm。
Step 4) Synthesis of Compound 13-5
Pyridine (0.9 g,11.4 mmol) was added dropwise to a solution of compound 13-4 (0.91 g,1.9 mmol) in DCM (10 mL) at 0 ℃ and stirred for 10 minutes, and after that, trifluoromethanesulfonic anhydride (2.1 g,7.6 mmol) was added dropwise to the reaction flask and reacted at room temperature for 1 hour. After completion of the reaction, the reaction was quenched by addition of ice water (20 mL), the aqueous layer was extracted with DCM (20 mL. times.3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent: PE/EtOAc (v/v) = 10/1) to give 0.87g of a colorless oil, yield: 75 percent.
1H NMR(400MHz,CDCl3):7.35,7.33(s,s,1H),7.19,7.17(s,s,1H),7.04,7.02(dd,dd,1H),6.99,6.97(dd,dd,1H),5.61-5.55(m,1H),5.21-5.17(m,1H),2.93-2.89(m,4H),1.77-1.42(m,10H),0.99-0.88(m,2H)ppm。
Step 5) Synthesis of Compound 13-6
Mixing 13-5 (1.53 g,2.5 mmol), 1-6-2 (1.34 g,5.25 mmol), Pd (dppf) Cl2·CH2Cl2(0.11 g,0.13 mmol) and KOAc (0.74 g,7.5 mmol) were mixed in a reaction flask, DMF (12 mL) was added under nitrogen protection, and the mixture was reacted at 90 deg.C4.0 h after completion of the reaction, cool to room temperature, dilute the reaction with EtOAc (100 mL), filter through celite, wash the filtrate with water (50 mL × 3) and brine, anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 5/1) gave 0.57g of a pale yellow solid, yield: 40 percent.
1H NMR(400MHz,CDCl3):7.87,7.85(s,s,1H),7.86,7.84(dd,dd,1H),7.57,7.55(s,s,1H),7.49,7.47(dd,dd,1H),5.75-5.72(m,1H),5.38-5.34(m,1H),3.03-3.00(m,2H),2.93-2.90(m,2H),1.83-1.41(m,8H),1.32,1.29(q,q,24H),1.27-1.19(m,2H),1.05-0.92(m,2H)ppm。
Step 6) Synthesis of Compounds 13-7
Mixing compound 13-6 (0.41 g,0.72 mmol), compound 10-2 (0.64 g,1.512 mmol), Pd (PPh)3)4(83 mg,0.07 mmol) and potassium carbonate (0.30 g,2.12 mmol) were suspended in DME (6.0 mL) and water (1.5 mL) and reacted at 90 ℃ for 4.0 hours under nitrogen protection after completion of the reaction, the reaction was diluted with EtOAc (40 mL), washed with water (30 mL × 3) and saturated brine, respectively, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (DCM/MeOH (v/v) = 80/1) to give 0.39g of the product in 60% yield.
MS(ESI,pos.ion)m/z:451.3[M+2H]2+；
1H NMR(400MHz,CDCl3):7.88(s,1H),7.79(s,1H),7.48,7.46(s,s,1H),7.39,7.36(dd,dd,1H),7.38,7.36(s,s,1H),7.15,7.13(dd,dd,1H),6.07,6.05(d,d,1H),5.57-5.53(m,1H),5.41-5.38(m,1H),5.32-5.25(m,3H),4.41-4.36(m,1H),4.34-4.30(m,1H),3.85-3.78(m,2H),3.68-3.66(m,2H),3.65(s,3H),3.63(s,3H),3.07-3.03(m,2H),2.99-2.96(m,2H),2.30-1.49(m,18H),1.44-1.34(m,2H),1.11-1.04(m,1H),1.02-0.89(m,13H)ppm。
Example 14
The synthetic route is as follows:
step 1) Synthesis of Compound 14-2
Putting aluminum trichloride (90 g,676 mmol) and sodium chloride (25 g,432 mmol) into a reaction bottle, heating to 150 ℃, slowly dripping compound 14-1 (20 g,135 mmol) after the mixture is molten, heating to 200 ℃ after dripping, and reacting at constant temperature for 1.0 hour. After the reaction was completed, the reaction solution was cooled to room temperature, poured into ice water (500 mL), filtered, and the filter cake was slurried with methanol to obtain 19g of a gray solid, yield: 95 percent.
MS(ESI,pos.ion)m/z:149.5[M+H]+；
1H NMR(400MHz,CDCl3):7.41-7.38(m,1H),7.24-7.19(m,1H),6.80-6.79,6.78-6.77(d,d,1H,J=4.0Hz),5.46(br,1H),3.06-3.03(m,2H),2.69-2.66(m,2H)ppm。
Step 2) Synthesis of Compound 14-3
Reaction of Compound 14-2 (5.0 g,33.7 mmol) with K2CO3(23.4 g,168.5 mmol) was suspended in acetone (50 mL), and methyl iodide (3.15 mL,50.55 mmol) was slowly added dropwise thereto, after which the reaction was carried out at 60 ℃ for 5.0 hours. After completion of the reaction, the reaction solution was concentrated, and the residue was added with water (150 mL) and EtOAc (150 mL), filtered through celite, and the filtrate was separated into layers, and the aqueous layer was extracted with EtOAc(150 mL × 2) and the combined organic phases were washed with brine and anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 10/1) gave 2.46g of a yellow solid, yield: 45 percent.
MS(ESI,pos.ion)m/z:163.5[M+H]+；
1H NMR(400MHz,CDCl3):7.51-7.48(m,1H),7.30-7.26(m,1H),6.91-6.87(m,1H),3.90(s,3H),3.08-3.05(m,2H),2.70-2.67(m,2H)ppm。
Step 3) Synthesis of Compound 14-4
Compound 14-3 (20.0 g,123.3 mmol) was suspended in methanol (250 mL) and NaBH was added portionwise at 0 deg.C4(2.8 g,74.0 mmol), after addition, at room temperature for 1.0 h after completion of the reaction, methanol was removed, and the residue was dissolved in EtOAc (400 mL), washed with water (100 mL × 2) and saturated brine (100 mL), respectively, anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 5/1) gave 17.6g of a pale yellow solid, yield: 87 percent.
MS(ESI,pos.ion)m/z:165.5[M+H]+；
1H NMR(400MHz,CDCl3):7.13-7.09(m,1H),7.08-7.05(m,1H),6.75-6.72(m,1H),5.29-5.25(m,1H),3.84(d,3H),3.70(brs,1H),2.84-2.80(m,2H),2.49-2.40(m,1H),1.96-1.88(m,1H)ppm。
Step 4) Synthesis of Compound 14-5
Compound 14-4 (2.0 g,12.2 mmol) was dissolved in THF (20 mL), and p-TSA (1.0 g,6.1 mmol) was added at 0 ℃ and after completion of the addition, the reaction was refluxed for 3.0 hours. After completion of the reaction, THF was removed and EtOA was added to the residuec(100 mL), washed with water (50 mL × 3) and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE) to give 1.23g of a colorless liquid in a yield of 69%.
MS(ESI,pos.ion)m/z:147.1[M+H]+；
1H NMR(400MHz,CDCl3):7.29(t,1H,J=7.8Hz),7.09(d,1H,J=7.4Hz),6.90-6.86(m,1H),6.77(d,1H,J=8.0Hz),6.61-6.57(m,1H),3.92(s,3H),3.39(s,2H)ppm。
Step 5) Synthesis of Compound 14-6
Compound 14-5 (5.0 g,34.2 mmol) was dissolved in anhydrous ether (35 mL), activated zinc powder (2.5 g,37.6 mmol) was added, and after stirring for 10 minutes, N was added2Under protection, trichloroacetyl chloride (4.0 mL,35.9 mmol) and a diethyl ether solution (35 mL) of phosphorus oxychloride (3.3 mL,35.9 mmol) are slowly dropped, and after dropping, the mixture is refluxed overnight, after the reaction is completed, the mixture is filtered, water (50 mL) is added to the filtrate, the mixture is extracted with EtOAc (60 mL × 3), organic phases are combined, the mixture is washed with saturated saline solution, dried by anhydrous sodium sulfate, and after concentration, the mixture is separated and purified by column chromatography (eluent: PE) to obtain 6.5g of light yellow solid with the yield of 74%.
MS(ESI,pos.ion)m/z:257.1[M+H]+；
1H NMR(400MHz,CDCl3):7.28(t,1H,J=7.8Hz),7.02(d,1H,J=7.6Hz),6.79(d,1H,J=8.0Hz),4.53-4.45(m,2H),3.82(s,3H),3.36(d,1H,J=17.2Hz),3.09-3.00(m,1H)ppm。
Step 6) Synthesis of Compounds 14-7
Compound 14-6 (6.45 g,25.2 mmol) was dissolved in methanol (80 mL), and zinc powder (8.2 g,126 mmol) and ammonium chloride (6.7 g,126 mmol), N, were added2After completion of the reaction, the mixture was filtered through celite, the filtrate was concentrated, and the residue was extracted with EtOAc (60 mL × 3) and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated and purified by column chromatography (eluent: PE/EtOAc (v/v) = 60/1) to give 3.69g of a colorless oil in 78% yield.
MS(ESI,pos.ion)m/z:189.1[M+H]+；
1H NMR(400MHz,CDCl3):7.22(t,1H,J=7.8Hz),6.89(d,1H,J=7.6Hz),6.71(d,1H,J=8.0Hz),4.11-3.99(m,2H),3.82(s,3H),3.63-3.52(m,1H),3.27(d,1H,J=17.2Hz),3.03-2.93(m,1H),2.92-2.84(m,1H)ppm。
Step 7) Synthesis of Compounds 14-8
Compound 14-7 (2.3 g,12.2 mmol) was dissolved in triethylene glycol (30 mL), KOH (2.1 g,36.7 mmol) and hydrazine hydrate (4.8 mL,97.8 mmol) were added, and the mixture was reacted at 130 ℃ for 20 minutes, and then heated to 200 ℃ for50 minutes by means of a water separator. After completion of the reaction, the reaction mixture was cooled to room temperature, water (100 mL) was added to the reaction mixture, extraction was performed with PE (150 mL. times.3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE) to obtain 1.42g of a colorless liquid, yield: 67%.
MS(ESI,pos.ion)m/z:175.1[M+H]+；
1H NMR(400MHz,CDCl3):7.19(t,1H,J=7.7Hz),6.84(d,1H,J=7.5Hz),6.71(d,1H,J=8.0Hz),3.84(s,3H),3.78-3.70(m,1H),3.20-3.08(m,1H),3.04-2.94(m,1H),2.80-2.70(m,1H),2.60-2.46(m,1H),2.30-2.17(m,1H),1.86-1.70(m,2H)ppm。
Step 8) Synthesis of Compounds 14-9
Compound 14-8 (9.92 g,57.0 mmol) was dissolved in THF (80 mL) and acetonitrile (40 mL), NIS (14.2 g,63.0 mmol) was added, and after stirring for 10 minutes, a catalytic amount of trifluoroacetic acid was added dropwise to the solution, and the reaction was allowed to react at room temperature for 5.0 hours, after completion of the reaction, the reaction solution was concentrated, and the residue was added with EtOAc (200 mL), washed with saturated sulfurous acid solution (50 mL × 3), and washed with anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE) gave 12.8g of a colorless liquid, yield: 75 percent.
MS(ESI,pos.ion)m/z:301.1[M+H]+；
1H NMR(400MHz,CDCl3):7.52(d,1H,J=8.4Hz),6.49(d,1H,J=8.4Hz),3.81(s,3H),3.70-3.62(m,1H),3.17-3.08(m,1H),3.08-3.00(m,1H),2.94-2.85(m,1H),2.60-2.48(m,1H),2.32-2.20(m,1H),1.94-1.84(m,1H),1.82-1.68(m,1H)ppm。
Step 9) Synthesis of Compounds 14-10
Compound 14-9 (2.16 g,7.2 mmol) was dissolved in DCM (20 mL) and added dropwise slowly to BBr at-78 deg.C3(2.7 mL,28.8 mmol) and reacting at constant temperature for 10 minutes, then reacting at room temperature for 4.0 hours, after the reaction is completed, slowly pouring the reaction solution into ice water (100 mL), extracting the water layer with DCM (50 mL × 3), combining the organic phases, washing with saturated brine, and reacting with anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 20/1) gave 1.85g of a colorless liquid, yield: 90 percent.
MS(ESI,pos.ion)m/z:287.1[M+H]+；
1H NMR(400MHz,CDCl3):7.43(d,1H,J=8.3Hz),6.46(d,1H,J=8.3Hz),5.05(s,1H),3.70-3.62(m,1H),3.17-3.08(m,1H),3.08-3.00(m,1H),2.94-2.85(m,1H),2.60-2.48(m,1H),2.32-2.20(m,1H),1.94-1.84(m,1H),1.82-1.68(m,1H)ppm。
Step 10) Synthesis of Compounds 14-11
Dissolving compound 14-10 (1.55 g,5.4 mmol) in DCM (20 mL), slowly adding pyridine (1.1 mL,13.5 mmol) dropwise at 0 deg.C, stirring at constant temperature for 10 min, and slowly adding Tf dropwise2O (1.4 mL,8.1mmol), after dropping, reacting at room temperature for 1.0 h, after the reaction is completed, adding ice water (50 mL) to quench the reaction, extracting the water layer with DCM (50 mL × 3), combining the organic phases, washing with saturated brine, and anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE) gave 2.21g of a colorless liquid, yield: 98 percent.
MS(ESI,pos.ion)m/z:419.0[M+H]+；
1H NMR(400MHz,CDCl3):7.64(d,1H,J=8.5Hz),6.86(d,1H,J=8.5Hz),3.76-3.67(m,1H),3.30-3.14(m,2H),3.12-3.00(m,1H),2.65-2.50(m,1H),2.35-2.23(m,1H),1.94-1.84(m,1H),1.83-1.72(m,1H)ppm。
Step 11) Synthesis of Compounds 14-12
Mixing compound 1-7 (0.3 g,0.96 mmol), compound 14-11 (0.40 g,0.96 mmol), potassium carbonate (0.33 g,2.4 mmol) and Pd (PPh)3)4（55.5mg,0.048 mmol) in a reaction flask, N2DME (8 mL) and water (2 mL) were separately injected and reacted at 90 ℃ for 12 hours with protection. After completion of the reaction, the reaction mixture was diluted with EtOAc (50 mL) and washed with saturated brine and anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 8/1) gave 0.23g of a colorless liquid, yield: 50 percent.
1H NMR(400MHz,CDCl3):7.27,7.25(s,s,1H),7.01-6.97(m,2H),6.67,6.65(dd,dd,1H),4.81(brs,1H),4.01-3.94(m,1H),3.08-2.97(m,1H),2.93-2.83(m,5H),2.63-2.48(m,2H),2.19-2.08(m,2H),1.70-1.50(m,7H),1.49-1.38(m,2H)ppm。
Step 12) Synthesis of Compounds 14-13
Pyridine (1.8 g,22.8 mmol) was added dropwise to a solution of compound 14-12 (1.82 g,3.8 mmol) in DCM (10 mL) at 0 ℃ and stirred for 10 minutes, and after that, trifluoromethanesulfonic anhydride (4.2 g,15.2 mmol) was added dropwise to the reaction flask and reacted at room temperature for 1 hour. After completion of the reaction, the reaction was quenched by addition of ice water (20 mL), the aqueous layer was quenched with DCM (30 mL × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent: PE/EtOAc (v/v) = 10/1) to give 1.62g of a colorless oil, yield: 70 percent.
1H NMR(400MHz,CDCl3):7.27,7.25(s,s,1H),7.18,7.16(dd,dd,1H),7.03,7.01(dd,dd,1H),6.92,6.90(t,t,1H),4.01-3.94(m,1H),3.08-2.97(m,1H),2.93-2.85(m,5H),2.63-2.48(m,2H),2.19-2.08(m,2H),1.74-1.42(m,9H)ppm。
Step 13) Synthesis of Compounds 14-14
Mixing 14-13 (1.22 g,2.0 mmol), 1-6-2 (1.07 g,4.2 mmol), Pd (dppf) Cl2·CH2Cl2(81.7 mg,0.1 mmol) and KOAc (0.49 g,5 mmol) were mixed in a reaction flask, and DMF (12 mL) was added under nitrogen protection to react at 90 ℃ for 4.0 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and then EtOAc (100 mL) was added to dilute the reaction mixture, followed by celiteThe filtrate was washed with water (50 mL × 3) and saturated brine, respectively, anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 5/1) gave 0.45g of a pale yellow solid, yield: 40 percent.
1H NMR(400MHz,CDCl3):7.67,7.65(dd,dd,1H),7.64,7.62(s,s,1H),7.48,7.46(dd,dd,1H),7.35,7.32(t,t,1H),4.12-4.05(m,1H),3.19-3.08(m,1H),3.03-3.00(m,2H),2.93,2.91(m,m,1H),2.90-2.86(m,2H),2.50-2.40(m,2H),2.19-2.09(m,1H),2.06-1.96(m,1H),1.72-1.40(m,7H),1.32,1.29(q,q,24H),1.27-1.20(m,2H)ppm。
Step 14) Synthesis of Compounds 14-15
Mixing 14-14 (0.28 g,0.5 mmol), 10-2 (0.42 g,1.0 mmol), Pd (PPh)3)4(57.8 mg,0.05 mmol) and potassium carbonate (0.17 g,1.25 mmol) were suspended in DME (6.0 mL) and water (1.5 mL), reacted at 90 ℃ for 4.0 hours under nitrogen, after completion of the reaction, cooled to room temperature, and the reaction was diluted with EtOAc (40 mL), washed with water (30 mL × 3) and saturated brine, respectively, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (DCM/MeOH (v/v) = 80/1) to give 0.25g of the product in 55% yield.
MS(ESI,pos.ion)m/z:450.3[M+2H]2+；
1H NMR(400MHz,CDCl3):7.88(s,1H),7.59(s,1H),7.38,7.36(dd,dd,1H),7.35,7.33(t,t,1H),7.22,7.20(s,s,1H),7.05,7.02(dd,dd,1H),6.07,6.05(d,d,1H),5.32-5.28(m,3H),4.41-4.37(m,1H),4.35-4.28(m,2H),3.85-3.78(m,2H),3.68-3.66(m,2H),3.65(s,3H),3.63(s,3H),3.23-3.12(m,2H),3.07-3.03(m,2H),2.97-2.93(m,2H),2.77-2.65(m,2H),2.32-1.92(m,12H),1.70-1.49(m,7H),1.45-1.34(m,2H),1.02-0.89(m,12H)ppm。
Example 15
The synthetic route is as follows:
step 1) Synthesis of Compound 15-1
Compound 14-7 (1.07 g,5.7 mmol) and NIS (1.42 g,6.3 mmol) were dissolved in acetonitrile (20 mL), and a catalytic amount of trifluoroacetic acid was added dropwise thereto to react at room temperature for 5.0 hours, after completion of the reaction, the reaction mixture was concentrated, and after adding EtOAc (100 mL), the residue was washed with a saturated sodium sulfite solution (20 mL × 3), anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE) gave 1.34g of a colorless liquid, yield: 75 percent.
MS(ESI,pos.ion)m/z:315.1[M+H]+；
1H NMR(400MHz,CDCl3):7.35,7.33(t,t,1H),6.51,6.49(m,m,1H),3.99-3.95(m,1H),3.91(s,3H),3.85-3.78(m,1H),3.74-3.66(m,1H),3.20-3.14(m,1H),3.00,2.94(m,m,1H),2.88-2.85,2.83-2.81(m,m,1H)ppm。
Step 2) Synthesis of Compound 15-2
Compound 15-1 (2.26 g,7.2 mmol) was dissolved in DCM (20 mL) and added dropwise slowly to BBr at-78 deg.C3(2.7 mL,28.8 mmol), after dropping, reacting at constant temperature for 10 minutes, reacting at room temperature for 4.0 hours, after the reaction is completed, dropping the reaction solution into ice water (100 mL), quenching, extracting the water layer with DCM (50 mL × 3), combining the organic phases, washing with saturated brine, and reacting with anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 20/1) gave 1.94g of a colorless liquid, yield: 90 percent.
MS(ESI,pos.ion)m/z:301.1[M+H]+；
1H NMR(400MHz,CDCl3):7.26,7.24(t,t,1H),6.45,6.42(s,s,1H),4.81(brs,1H),4.36-4.32(m,1H),3.88-3.81(m,1H),3.74-3.66(m,1H),3.19,3.13(m,1H),3.00,2.96(m,m,1H),2.87-2.80(m,1H)ppm。
Step 3) Synthesis of Compound 15-3
Compound 15-2 (1.62 g,5.4 mmol) was dissolved in DCM (15 mL), pyridine (1.1 mL,13.5 mmol) was slowly added dropwise at 0 deg.C, stirring at constant temperature for 10 minutes, and then Tf was slowly added dropwise2O (1.4 mL,8.1mmol), after dropping, reacting at room temperature for 1.0 h, after the reaction is completed, adding ice water (50 mL) to quench the reaction, extracting the water layer with DCM (50 mL × 3), combining the organic phases, washing with saturated brine, and anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE) gave 2.29g of a colorless liquid, yield: 98 percent.
MS(ESI,pos.ion)m/z:432.5[M+H]+；
1H NMR(400MHz,CDCl3):7.47,7.45(t,t,1H),6.83,6.81(s,s,1H),4.33-4.29(s,1H),3.83-3.76(m,1H),3.70-3.63(m,2H),3.28-3.21(m,1H),2.96-2.89(m,1H)ppm。
Step 4) Synthesis of Compound 15-4
Mixing compound 1-7 (0.16 g,0.5 mmol), compound 15-3 (0.22 g,0.5 mmol), potassium carbonate (0.17 g,1.25 mmol) and Pd (PPh)3)4(57.8 mg,0.05 mmol) in a reaction flask, N2DME (4 mL) and water (1 mL) were separately injected and reacted at 90 ℃ for 12 hours with protection. After completion of the reaction, the reaction mixture was diluted with EtOAc (50 mL) and washed with saturated brine and anhydrous Na2SO4Dried, concentrated and purified by column chromatography (eluent: PE/EtOAc (v/v) = 8/1) to give 123mg of a colorless liquid, yield: 50 percent.
1H NMR(400MHz,CDCl3):7.17,7.15(s,s,1H),6.99,6.97(dd,dd,1H),6.93,6.91(q,q,1H),6.67,6.65(dd,dd,1H),4.81(brs,1H),4.46-4.42(m,1H),3.75-3.68(m,1H),3.66-3.59(m,1H),3.50-3.47,3.46-3.43(m,m,1H),3.17-3.14,3.12-3.10(m,m,1H),2.92-2.83(m,5H),1.70-1.51(m,6H),1.49-1.38(m,2H)ppm。
Step 5) Synthesis of Compound 15-5
Pyridine (1.8 g,22.8 mmol) was added dropwise to a solution of compound 15-4 (1.87 g,3.8 mmol) in DCM (10 mL) at 0 ℃ and stirred for 10 minutes, and after that, trifluoromethanesulfonic anhydride (4.2 g,15.2 mmol) was added dropwise to the reaction flask and reacted at room temperature for 1 hour. After completion of the reaction, the reaction was quenched by addition of ice water (20 mL), the aqueous layer was extracted with DCM (20 mL × 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent: PE/EtOAc (v/v) = 10/1) to obtain 1.66g of a colorless oil, yield: 70 percent.
1H NMR(400MHz,CDCl3):7.18,7.16(dd,dd,1H),7.17,7.15(s,s,1H),7.03,7.00(dd,dd,1H),6.87,6.84(q,q,1H),4.46-4.42(m,1H),3.75-3.68(m,1H),3.66-3.59(m,1H),3.50-3.47,3.46-3.43(m,m,1H),3.17-3.14,3.12-3.10(m,m,1H),2.92-2.83(m,5H),1.74-1.42(m,8H)ppm。
Step 6) Synthesis of Compound 15-6
Mixing 15-5 (1.25 g,2.0 mmol), 1-6-2 (1.07 g,4.2 mmol), Pd (dppf) Cl2·CH2Cl2(81.66 mg,0.1 mmol) and KOAc (0.49 g,5 mmol) were mixed in a reaction flask, DMF (12 mL) was added under nitrogen, the reaction was allowed to react at 90 ℃ for 4.0 hours, after completion of the reaction, the mixture was cooled to room temperature, EtOAc (100 mL) was added to dilute the reaction mixture, the mixture was filtered through celite, and the filtrate was washed with water (50 mL × 3) and saturated brine, respectively, anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 5/1) gave 0.58g of a pale yellow solid, yield: 50 percent.
1H NMR(400MHz,CDCl3):7.67,7.65(dd,dd,1H),7.60,7.58(s,s,1H),7.48,7.46(dd,dd,1H),7.30,7.28(t,t,1H),4.02-3.98(m,1H),3.86-3.79(m,1H),3.58-3.50(m,1H),3.33-3.31,3.29-3.27(m,m,1H),3.03-3.00(m,2H),2.90-2.78(m,4H),1.74-1.40(m,6H),1.32,1.29(q,q,24H),1.27-1.20(m,2H)ppm。
Step 7) Synthesis of Compounds 15-7
Mixing compound 15-6 (0.29 g,0.5 mmol), compound 10-2 (0.42 g,1.0 mmol), Pd (PPh)3)4(57.8 mg,0.05 mmol) and potassium carbonate (0.17 g,1.25 mmol) were suspended in DME (6.0 mL) and water (1.5 mL), reacted at 90 ℃ for 4.0 hours under nitrogen, after completion of the reaction, cooled to room temperature, and the reaction was diluted with EtOAc (40 mL), washed with water (30 mL × 3) and saturated brine, respectively, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (DCM/MeOH (v/v) = 80/1) to give 0.25g of the product in 55% yield.
MS(ESI,pos.ion)m/z:457.3[M+2H]2+；
1H NMR(400MHz,CDCl3):7.88(s,1H),7.57(s,1H),7.36,7.33(dd,dd,1H),7.31,7.29(t,t,1H),7.26,7.24(s,s,1H),7.05,7.02(dd,dd,1H),6.07,6.05(d,d,1H),5.32-5.28(m,3H),4.82-4.78(m,1H),4.41-4.36(m,1H),4.34-4.30(m,1H),3.90-3.78(m,3H),3.68-3.65(m,3H),3.65(s,3H),3.63(s,3H),3.41-3.39,3.37-3.35(m,m,1H),3.07-3.03(m,2H),2.99-2.88(m,4H),2.30-1.92(m,10H),1.70-1.49(m,6H),1.44-1.34(m,2H),1.02-0.89(m,12H)ppm。
Example 16
The synthetic route is as follows:
step 1) Synthesis of Compound 16-1
Compound 10-1 (1.21 g,3.6 mmol), compound 16-0 (0.74 g,3.9 mmol) and EDCI (0.75 g,3.9 mmol) were suspended in DCM (20 mL), and DIPEA (2.38 mL,14.4 mmol) was added dropwise slowly at 0 ℃ and reacted at room temperature for 2.0 hours after completion of the dropwise addition. After completion of the reaction, DCM (40 mL) was added to dilute the reaction solution, and the organic phase was washed with a saturated ammonium chloride solution, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE/EtOAc (v/v) = 1/2) to obtain 1.33g of a pale yellow solid, yield: 85 percent.
MS(ESI,pos.ion)m/z:435.1[M+H]+；
1H NMR(400MHz,CDCl3):7.35(s,1H),5.31,5.28(d,d,1H),5.08-5.03(m,1H),4.47-4.42(m,1H),3.84-3.78(m,1H),3.68-3.64(m,1H),3.63(s,3H),2.32-1.92(m,5H),1.60-1.48(m,1H),1.24-1.11(m,1H),0.92-0.88(m,6H)ppm。
Step 2) Synthesis of Compound 16-2
The compound 9-2 (5.0 g,28.7 mmol) and K2CO3(15 g,108.7 mmol) was suspended in acetone (100 mL), iodomethane (10 mL,160.5 mmol) was slowly added dropwise under nitrogen protection at 0 ℃ and after completion of the addition, the reaction was carried out overnight at 60 ℃ after completion of the reaction, the reaction was filtered, the filtrate was concentrated, and the residue was dissolved in DCM (100 mL), washed with water (50 mL × 2) and saturated brine, respectively, dried over anhydrous sodium sulfate, and purified by column chromatography (eluent: PE/DCM (v/v) = 6/1) to give 3.2g of a white solid, yield: 55%.
MS(ESI,pos.ion)m/z:203.1[M+H]+；
1H NMR(400MHz,CDCl3):6.67-6.65(m,2H),6.56(m,2H),4.25-4.21(m,2H),3.81(d,6H),1.85-1.81(m,1H),1.78-1.74(m,1H)ppm。
Step 3) Synthesis of Compound 16-3
Compound 16-2 (3.0 g,14.83 mmol) and N-methyl-N-morpholino oxide (NMO) (2.1 g,18 mmol) were dissolved in THF/H2O (50 mL) in a mixed solvent ((v/v) = 3/2), a catalytic amount of OsO was added4After the addition, the reaction was carried out at room temperature overnight. After the reaction is completed, the reaction solution is reacted,after addition of excess sodium thiosulfate and stirring for 1 hour, THF was removed, the residue was dissolved in EtOAc (150 mL), washed with water and saturated brine, respectively, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent: DCM/EtOH (v/v) = 100/1) to give 3.0g of a white solid, yield: 86 percent.
MS(ESI,pos.ion)m/z:237.1[M+H]+；
1H NMR(400MHz,CDCl3):6.62-6.61(m,2H),4.12-4.10(m,2H),3.86(d,6H),3.77-3.76(m,2H),3.60(brs,2H),2.24-2.20(m,1H),1.99-1.95(m,1H)ppm。
Step 4) Synthesis of Compound 16-4
Compound 16-3 (0.51 g,2.16 mmol) was dissolved in DCM (15 mL), DAST (0.7 mL,5.2 mmol) was slowly added dropwise at-78 deg.C, and after completion of the addition, the reaction was carried out at constant temperature for 2.0 hours, followed by reaction at room temperature for 36 hours. After completion of the reaction, an ammonium chloride solution (20 mL) was added to quench the reaction, the aqueous layer was extracted with DCM (20 mL × 2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent: DCM/PE (v/v) = 1/5) to obtain 0.24g of a white solid, yield: 46 percent.
MS(ESI,pos.ion)m/z:241.1[M+H]+；
1H NMR(400MHz,CDCl3):6.57(m,2H),4.95-4.73(m,2H),3.92(d,6H),3.70-3.66(m,2H),2.23-2.15(m,1H),1.95-1.67(m,1H)ppm。
Step 5) Synthesis of Compound 16-5
At-78 ℃ BBr3(7.47 g,29.88 mmol) was slowly added dropwise to a DCM (15 mL) solution of Compound 16-4 (1.43 g,5.97 mmol), after dropping, the reaction was carried out at constant temperature for 20 minutes, and then at room temperature for 1.0 hour, after completion of the reaction, the reaction mixture was slowly poured into ice water (50 mL), the aqueous layer was extracted with DCM (50 mL × 3), the organic phases were combined, washed with saturated brine, and anhydrous Na2SO4Drying, concentrating, and purifying by column chromatography (eluent: PE/EtOAc (v/v) = 6/1) to obtainOff-white solid 1.01g, yield: 80 percent.
MS(ESI,pos.ion)m/z:213.5[M+H]+；
1H NMR(400MHz,CDCl3):6.50(s,2H),5.77(brs,2H),5.01-4.97,4.94-4.87,4.81-4.80(m,m,m,2H),3.55-3.51(m,2H),2.31-2.24(m,1H),2.03-1.95(m,1H)ppm。
Step 6) Synthesis of Compound 16-6
Dissolving compound 16-5 (1.15 g,5.4 mmol) in DCM (15 mL), slowly adding pyridine (1.1 mL,13.5 mmol) dropwise at 0 deg.C, stirring at constant temperature for 10 min, and slowly adding Tf dropwise2O (1.4 mL,8.1mmol), after dropping, reacting at room temperature for 1.0 h, after the reaction is completed, adding ice water (50 mL) to quench the reaction, extracting the water layer with DCM (50 mL × 3), combining the organic phases, washing with saturated brine, and anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE) gave 2.18g of a colorless liquid, yield: 85 percent.
1H NMR(400MHz,CDCl3):7.32(s,2H),5.00-4.95,4.93-4.85,4.83-4.78(m,m,m,2H),3.65-3.63(m,2H),2.32-2.24(m,1H),2.04-1.96(m,1H)ppm。
Step 7) Synthesis of Compounds 16-7
Mixing compound 1-7 (0.3 g,0.96 mmol), compound 16-6 (0.46 g,0.96 mmol), potassium carbonate (0.33 g,2.4 mmol) and Pd (PPh)3)4(55.5 mg,0.048 mmol) in a reaction flask, N2DME (8 mL) and water (2 mL) were separately injected and reacted at 90 ℃ for 12 hours with protection. After completion of the reaction, the reaction mixture was diluted with EtOAc (50 mL) and washed with saturated brine and anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 8/1) gave 0.25g of a colorless liquid, yield: 50 percent.
1H NMR(400MHz,CDCl3):7.42,7.40(s,s,1H),7.12,7.10(s,s,1H),7.04,7.02(dd,dd,1H),6.49,6.47(dd,dd,1H),5.00-4.78(m,2H),3.90-3.87(m,1H),3.82-3.79(m,1H),2.90-2.84(m,4H),2.26-2.19(m,1H),1.98-1.90(m,1H),1.70-1.50(m,6H),1.49-1.38(m,2H)ppm。
Step 8) Synthesis of Compound 16-8
Mixing compound 16-7 (0.26 g,0.5 mmol), compound 16-1 (0.22 g,0.5 mmol), Pd (PPh)3)4(57.8 mg,0.05 mmol) and potassium carbonate (0.17 g,1.25 mmol) were suspended in DME (6.0 mL) and water (1.5 mL) and reacted at 90 ℃ for 4.0 hours under nitrogen. After completion of the reaction, the reaction mixture was diluted with EtOAc (50 mL), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated and purified by column chromatography (DCM/MeOH (v/v) = 100/1) to obtain 0.19g of a product, yield: and 55 percent.
MS(ESI,pos.ion)m/z:673.3[M+H]+；
1H NMR(400MHz,CDCl3):7.95(s,1H),7.40,7.37(s,s,1H),7.36,7.34(s,s,1H),7.11,7.09(dd,dd,1H),6.51,6.50(dd,dd,1H),6.49,6.47(dd,dd,1H),5.22-5.18(m,1H),5.10-5.09,5.05-5.04,4.96-4.95,4.91-4.90(m,m,m,m,2H),4.40-4.35(m,1H),4.23-4.21(m,1H),4.05-4.02(m,1H),3.84-3.78(m,1H),3.68-3.66(m,1H),3.65(s,3H),2.90-2.84(m,4H),2.34-2.26(m,1H),2.23-2.08(m,4H),1.99-1.80(m,2H),1.70-1.50(m,6H),1.49-1.31(m,3H),1.12-0.99(m,1H),0.88-0.81(m,6H)ppm。
Step 9) Synthesis of Compound 16-9
Pyridine (1.8 g,22.8 mmol) was added dropwise to a solution of compound 16-8 (2.55 g,3.8 mmol) in DCM (20 mL) at 0 ℃ and stirred for 10 minutes, and after that, trifluoromethanesulfonic anhydride (4.2 g,15.2 mmol) was added dropwise to the reaction flask and reacted at room temperature for 1 hour. After completion of the reaction, the reaction was quenched by addition of ice water (20 mL), the aqueous layer was extracted with DCM (50 mL. times.3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent: PE/EtOAc (v/v) = 1/2) to give 2.14g of a colorless oil, yield: 70 percent.
1H NMR(400MHz,CDCl3):7.95(s,1H),7.39,7.37(s,s,1H),7.36,7.34(s,s,1H),7.06,7.03(dd,dd,1H),7.01,6.99(dd,dd,1H),6.51,6.49(d,d,1H),5.22-5.18(m,1H),5.10-5.09,5.05-5.04,4.96-4.95,4.91-4.90(m,m,m,m,2H),4.40-4.35(m,1H),4.24-4.21(m,1H),4.05-4.02(m,1H),3.84-3.78(m,1H),3.68-3.66(m,1H),3.65(s,3H),2.92-2.86(m,4H),2.34-2.26(m,1H),2.23-2.08(m,4H),2.00-1.89(m,1H),1.88-1.80(m,1H),1.73-1.31(m,9H),1.12-0.99(m,1H),0.88-0.81(m,6H)ppm。
Step 10) Synthesis of Compounds 16-10
Mixing 16-9 (1.6 g,2.0 mmol), 1-6-2 (0.76 g,3.0 mmol), Pd (dppf) Cl2·CH2Cl2(81.7 mg,0.1 mmol) and KOAc (0.49 g,5 mmol) were mixed in a reaction flask, DMF (12 mL) was added under nitrogen, the reaction was allowed to react at 90 ℃ for 4.0 hours, after completion of the reaction, the mixture was cooled to room temperature, EtOAc (100 mL) was added to dilute the reaction mixture, the mixture was filtered through celite, and the filtrate was washed with water (50 mL × 3) and saturated brine, respectively, and anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 1/3) gave 0.63g of a pale yellow solid, yield: 40 percent.
1H NMR(400MHz,CDCl3):7.95(s,1H),7.79,7.77(dd,dd,1H),7.51,7.49(s,s,1H),7.42,7.40(dd,dd,1H),7.36,7.34(s,s,1H),6.51,6.49(d,d,1H),5.22-5.18(m,1H),5.10-5.09,5.05-5.04,4.96-4.95,4.91-4.90(m,m,m,m,2H),4.40-4.35(m,1H),4.24-4.21(m,1H),4.05-4.02(m,1H),3.84-3.78(m,1H),3.68-3.66(m,1H),3.65(s,3H),3.03-3.00(m,2H),2.91-2.88(m,2H),2.34-2.26(m,1H),2.23-2.08(m,4H),1.99-1.89(m,1H),1.86-1.80(m,1H),1.72-1.53(m,4H),1.50-1.43(m,2H),1.40-1.33(m,1H),1.32,1.29(q,q,12H),1.28-1.19(m,2H),1.12-0.99(m,1H),0.88-0.81(m,6H)ppm。
Step 11) Synthesis of Compound 16-11
Mixing compound 16-10 (0.39 g,0.5 mmol), compound 10-2 (0.21 g,0.5 mmol), Pd (PPh)3)4(57.8 mg,0.05 mmol) and potassium carbonate (0.17 g,1.25 mmol) were suspended in DME (6.0 mL) and water (1.5 mL) at 90 deg.C under nitrogenAfter the reaction was completed for 4.0 hours, the reaction solution was cooled to room temperature, and then EtOAc (40 mL) was added to dilute the reaction solution, which was washed with water (20 mL × 3) and saturated brine, respectively, dried over anhydrous sodium sulfate, concentrated, and then purified by column chromatography (DCM/MeOH (v/v) = 50/1) to obtain 0.26g of a product, yield: 55%.
MS(ESI,pos.ion)m/z:475.2[M+2H]2+；
1H NMR(400MHz,CDCl3):7.95(s,1H),7.88(s,1H),7.45,7.43(dd,dd,1H),7.42,7.39(s,s,1H),7.36,7.34(s,s,1H),7.04,7.02(dd,dd,1H),6.07,6.05(d,d,1H),5.32-5.26(m,2H),5.22-5.18(m,1H),5.10-5.09,5.05-5.04,4.96-4.95,4.91-4.90(m,m,m,m,2H),4.47-4.41(m,1H),4.34-4.30(m,1H),4.24-4.21(m,1H),4.05-4.02(m,1H),3.85-3.78(m,2H),3.68-3.66(m,2H),3.65(s,6H),3.07-3.03(m,2H),2.98-2.94(m,2H),2.35-1.80(m,12H),1.70-1.49(m,7H),1.44-1.34(m,2H),1.22-1.11(m,1H),1.02,1.00(m,m,3H),0.94,0.91(m,m,3H),0.87-0.81(m,6H)ppm。
Example 17
The synthetic route is as follows:
step 1) Synthesis of Compound 17-1
1, 3-cyclohexadiene (11.12 g,138.8 mmol) was added dropwise to a solution of benzoquinone (10.0 g,92.5 mmol) in DCM (90 mL) at-10 ℃ for 1 hour at constant temperature, and then reacted at room temperature for 48 hours. After completion of the reaction, the solvent was removed, n-hexane (500 mL) was added, stirring and filtration were carried out, and the filtrate was dried over anhydrous sodium sulfate and concentrated to obtain 12.5g of a pale yellow solid, yield: 71.8 percent of the total weight of the product, and directly used for the next reaction. MS (ESI, pos.ion) m-z:189.1[M+H]+；
1H NMR(400MHz,CDCl3):6.59(s,2H),6.47(s,2H),3.42(s,2H),3.20-3.18(m,2H),1.52-1.39(m,4H)ppm。
Step 2) Synthesis of Compound 17-2
Compound 17-1 (5.0 g,26.6 mmol) was reacted with sodium acetate (6.54 g,79.7 mmol) in methanol (100 mL) under nitrogen at 50 ℃ for 4 hours. After completion of the reaction, the reaction solution was concentrated and purified by column chromatography (eluent: DCM) to obtain 4.56g of a white solid, yield: 91.2 percent.
MS(ESI,pos.ion)m/z:189.1[M+H]+；
1H NMR(400MHz,CDCl3):6.43-6.39(m,2H),6.28(s,2H),3.65(s,2H),3.45-3.41(m,2H),2.48-2.44(m,2H),2.09-2.01(m,2H)ppm。
Step 3) Synthesis of Compound 17-3
Compound 17-2 (4.0 g,21.3 mmol) and a catalytic amount of palladium on carbon (0.4 g) were suspended in methanol (50 mL) and reacted at room temperature for 1.5 hours in a hydrogen system at normal pressure. After the reaction is completed, filtering is carried out, and the filtrate is concentrated and then is purified by recrystallization to obtain 3.06g of white solid, wherein the yield is as follows: 75.6 percent.
MS(ESI,pos.ion)m/z:191.1[M+H]+；
1H NMR(400MHz,d6-DMSO):7.18(s,2H),6.21(s,2H),3.47-3.44(m,2H),1.61-1.54(m,4H),1.42-1.38(m,4H)ppm。
Step 4) Synthesis of Compound 17-4
Pyridine (9.0 g,114 mmol) was added dropwise to a solution of compound 17-3 (3.61 g,19.0 mmol) in DCM (20 mL) at 0 ℃ and stirred for 10 minutes, then trifluoromethanesulfonic anhydride (21.0 g,76.0 mmol) was added dropwise to the reaction flask and the reaction was carried out at room temperature for 1 hour after completion of the dropwise addition. After completion of the reaction, the reaction mixture was diluted with DCM (50 mL), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent: PE/DCM (v/v) = 10/1) to give 8.4g of a colorless oil, yield: 97.3 percent.
1H NMR(400MHz,CDCl3):7.15(s,2H),3.69-3.67(m,2H),1.75-1.71(m,4H),1.36-1.32(m,4H)ppm。
Step 5) Synthesis of Compound 17-5
Compound 17-4 (7.99 g,17.6 mmol), compound 1-7 (5.65 g,18.0 mmol), tetrakistriphenylphosphine palladium (1.02 g,0.88 mmol) and potassium carbonate (9.73 g,70.4 mmol) were suspended in 80mL DME/H2And O (v/v = 3/1) in a mixed solvent, and reacting for 3 hours at 90 ℃ under the protection of nitrogen. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (250 mL), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent: PE/DCM (v/v) = 8/1) to obtain 4.85g of a white solid, yield: 56 percent.
MS(ESI,pos.ion)m/z:493.2[M+H]+；
1H NMR(400MHz,CDCl3):7.38,7.36(s,s,1H),7.07,7.05(s,s,1H),6.96,6.94(dd,dd,1H),6.52,6.50(dd,dd,1H),4.81(brs,1H),3.24-3.14(m,1H),2.90-2.83(m,4H),2.75-2.65(m,1H),1.92-1.81(m,2H),1.70-1.49(m,10H),1.48-1.38(m,2H),1.37-1.27(m,2H)ppm。
Step 6) Synthesis of Compound 17-6
Mixing compound 17-5 (101.8 mg,0.21mmol), compound 9-7 (85.5 mg,0.21mmol), Pd (PPh)3)4(23.9 mg,0.021 mmol) and potassium carbonate (85.9 mg,0.62 mmol) were placed in a reaction flask, N2Under the protection, DME (4.0 mL) and pure water (1.0 mL) were separately injected and reacted at 90 ℃ for 5.0 hours, after completion of the reaction, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), washed with water (10 mL × 3) and saturated brine, and dried over Na2SO4Drying, concentration and purification by column chromatography (eluent: DCM/EtOH (v/v) = 100/1) gave 84.7mg of a yellow solid, yield: 65 percent.
MS(ESI,pos.ion)m/z:630.5[M+H]+；
1H NMR(400MHz,CDCl3):7.59-7.57(m,2H),7.45,7.43(s,s,1H),7.32,7.30(s,s,1H),7.28-7.26(m,1H),7.03,7.01(dd,dd,1H),6.52,6.50(dd,dd,1H),5.04-4.99(m,1H),3.82-3.76(m,1H),3.64-3.57(m,1H),3.38-3.21(m,2H),2.90-2.83(m,4H),2.63-2.53(m,1H),2.47-2.35(m,1H),2.25-2.15(m,1H),2.04-1.93(m,1H),1.72-1.52(m,10H),1.48-1.42(m,2H),1.41(s,9H),1.40-1.29(m,4H)ppm。
Step 7) Synthesis of Compound 17-7
Pyridine (0.9 g,11.4 mmol) was added dropwise to a solution of compound 17-6 (1.2 g,1.9 mmol) in DCM (10 mL) at 0 ℃ and stirred for 10 minutes, and after that, trifluoromethanesulfonic anhydride (2.1 g,7.6 mmol) was added dropwise to the reaction flask and reacted at room temperature for 1 hour. After completion of the reaction, the reaction was quenched by addition of ice water (20 mL), the aqueous layer was extracted with DCM (20 mL. times.3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent: PE/EtOAc (v/v) = 2/1) to give 1.23g of a colorless oil, yield: 85 percent.
1H NMR(400MHz,CDCl3):7.59-7.57(m,2H),7.41,7.39(s,s,1H),7.32,7.30(s,s,1H),7.28-7.26(m,1H),7.04,7.02(dd,dd,1H),6.99,6.97(dd,dd,1H),5.04-4.99(m,1H),3.82-3.76(m,1H),3.64-3.57(m,1H),3.38-3.21(m,2H),2.92-2.88(m,4H),2.63-2.53(m,1H),2.47-2.35(m,1H),2.25-2.15(m,1H),2.04-1.93(m,1H),1.74-1.44(m,12H),1.41(s,9H),1.39-1.29(m,4H)ppm。
Step 8) Synthesis of Compound 17-8
Mixing compound 17-7 (1.90 g,2.5 mmol), compound 1-6-2 (0.96 g,3.8 mmol), Pd (dppf) Cl2·CH2Cl2(0.11 g,0.13 mmol) and KOAc (0.74 g,7.5 mmol) were mixed in a reaction flask, DMF (12 mL) was added under nitrogen, the mixture was reacted at 90 ℃ for 4.0 hours, after completion of the reaction, the mixture was cooled to room temperature, EtOAc (100 mL) was added to dilute the reaction mixture, and the mixture was filtered through celite, and the filtrate was washed with water (50 mL × 3) and saturated brineWashing with anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 1/3) gave 0.83g of a pale yellow solid, yield: 45 percent.
1H NMR(400MHz,CDCl3):7.82,7.80(dd,dd,1H),7.59-7.57(m,2H),7.51,7.49(s,s,1H),7.39-7.37(dd,dd,1H),7.32,7.30(s,s,1H),7.28-7.26(m,1H),5.04-4.99(m,1H),3.82-3.76(m,1H),3.64-3.57(m,1H),3.38-3.21(m,2H),3.03-3.00(m,2H),2.89-2.85(m,2H),2.63-2.53(m,1H),2.47-2.35(m,1H),2.25-2.15(m,1H),2.04-1.93(m,1H),1.72-1.44(m,10H),1.41(s,9H),1.40-1.33(m,4H),1.32,1.29(q,q,12H),1.25-1.19(m,2H)ppm。
Step 9) Synthesis of Compound 17-9
Mixing compound 17-8 (0.53 g,0.72 mmol), compound 1-16 (0.26 g,0.72 mmol), Pd (PPh)3)4(83 mg,0.07 mmol) and potassium carbonate (0.30 g,2.12 mmol) were suspended in DME (6.0 mL) and water (1.5 mL) and reacted at 90 ℃ for 4.0 hours under nitrogen, after completion of the reaction, cooled to room temperature, and the reaction was diluted with EtOAc (40 mL), washed with water (20 mL × 3) and saturated brine, respectively, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (DCM/MeOH (v/v) = 80/1) to give 0.37g of the product in 60% yield.
MS(ESI,pos.ion)m/z:425.5[M+2H]2+；
1H NMR(400MHz,CDCl3):7.97(s,1H),7.59-7.57(m,2H),7.48,7.46(s,s,1H),7.36,7.34(dd,dd,1H),7.32,7.30(s,s,1H),7.28-7.26(m,1H),7.04,7.02(dd,dd,1H),5.14-5.08(m,1H),5.04-4.99(m,1H),3.82-3.76(m,1H),3.64-3.57(m,2H),3.38-3.21(m,3H),3.07-3.03(m,2H),2.94-2.90(m,2H),2.63-2.53(m,1H),2.47-2.35(m,2H),2.29-2.15(m,2H),2.10-1.93(m,3H),1.72-1.54(m,10H),1.53(s,9H),1.41(s,9H),1.40-1.29(m,6H)ppm。
Step 10) Synthesis of Compounds 17-10
Compound 17-9 (0.34 g,0.4 mmol) was dissolved in EtOAc (5 mL), and after further addition of a solution of hydrogen chloride in ethyl acetate (5 mL, 4M), the reaction was carried out at room temperature for 8 hours. After completion of the reaction, the reaction was concentrated, and the residue was slurried with EtOAc (5 mL) and filtered to give 0.29g of a white solid, yield: 90 percent.
MS(ESI,pos.ion)m/z:649.5[M+H]+。
Step 11) Synthesis of Compounds 17-11
Compound 17-10 (63.6 mg,0.08 mmol), compound 9-12-2 (24.7 mg,0.17 mmol), EDCI (32.2 mg,0.17 mmol) and HOAT (21.8 mg,0.16 mmol) were dissolved in DCM (5 mL) and DIPEA (0.10 mL,0.64 mmol) was added dropwise slowly at 0 ℃ and reacted at room temperature for 3.0 hours after completion of dropwise addition. After completion of the reaction, DCM (50 mL) was added to dilute the reaction solution, and the reaction solution was washed with an ammonium chloride solution and a saturated saline solution, respectively, and dried over anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: DCM/MeOH (v/v) = 60/1) gave 36.3mg of a white solid in yield: 50 percent.
MS(ESI,pos.ion)m/z:454.3[M+2H]2+；
1H NMR(400MHz,CDCl3):7.88(s,1H),7.59-7.57(m,2H),7.48,7.46(s,s,1H),7.36,7.34(dd,dd,1H),7.32,7.30(s,s,1H),7.28-7.26(m,1H),7.04,7.02(dd,dd,1H),5.48,5.46(m,m,1H),5.44,5.42(m,m,1H),5.18-5.10(m,2H),4.64-4.53(m,2H),3.88-3.81(m,2H),3.72-3.66(m,2H),3.65(s,3H),3.64(s,3H),3.38-3.21(m,2H),3.07-3.03(m,2H),2.94-2.90(m,2H),2.42-1.89(m,8H),1.72-1.51(m,10H),1.48,1.46(d,d,3H),1.44-1.29(m,9H)ppm。
Example 18
The synthetic route is as follows:
example 18 was prepared according to a synthetic method analogous to example 1.
Compound 18-2:1H NMR(400MHz,CDCl3):3.99-3.87(br,1H),3.68-3.51(m,2H),3.48-3.39(m,1H),3.34-3.25(m,1H),2.05-1.92(m,2H),1.88-1.71(m,2H),1.45(s,9H)ppm。
compound 18-3:1H NMR(400MHz,CDCl3):9.46(d,1H,J=2.8Hz),4.08-4.03(m,1H),3.51-3.42(m,2H),2.01-1.93(m,2H),1.91-1.84(m,2H),1.43(s,9H)ppm。
compound 18-4: MS (ESI, pos.ion) M/z 238.2[ M + H ]]+；
1H NMR(400MHz,CDCl3):6.96(s,1H),4.94(dd,1H,J=7.68Hz,2.40Hz),3.38(t,2H,J=6.24Hz),2.17-2.03(m,2H),1.99-1.91(m,2H),1.48(s,9H)ppm。
Compounds 18-5: MS (ESI, pos.ion) M/z 490.0[ M + H ]]+；
1H NMR(400MHz,CDCl3):4.89(dd,1H,J=7.64Hz,2.52Hz),3.36(t,2H),2.14-2.02(m,2H),1.97-1.85(m,2H),1.49(s,9H)ppm。
Compounds 18-6: MS (ESI, pos.ion) M/z 364.1[ M + H ]]+；
1H NMR(400MHz,CDCl3):7.04(d,1H,J=1.84Hz),4.89(dd,1H,J=7.72Hz,2.56Hz),3.36(t,2H),2.18-2.03(m,2H),1.97-1.82(m,2H),1.47(s,9H)ppm。
Compounds 18-7: MS (ESI, pos. ion) M/z 407.4[ M +2H ]]2+；
1H NMR(400MHz,CDCl3):10.60(br.,2H),7.08-7.22(m,6H),5.01(br,2H),3.42(m,4H),3.07-3.04(m,4H),2.70-2.68(m,4H),2.18(m,4H),2.05(m,4H),1.64-1.58(m,16H),1.51(s,18H)ppm。
Compound 18-8：MS(ESI,pos.ion)m/z:307.3[M+2H]2+；
1H NMR(400MHz,CD3OD):7.85(s,2H),7.64(d,2H,J=7.9Hz),7.22(d,2H,J=7.9Hz),5.25-5.20(m,2H),3.62-3.58(m,4H),3.12(s,4H),2.75-2.73(m,2H),2.71(s,4H),2.60-2.54(m,2H),2.45-2.35(m,2H),2.28-2.22(m,2H),1.73-1.63(m,16H)ppm。
Compounds 18-9: MS (ESI, pos.ion) M/z 464.5[ M +2H ]]2+；
1H NMR(400MHz,CDCl3):10.58(br,2H),7.22-7.06(m,6H),5.41(br,2H),5.29(br.,2H),4.33(m,2H),3.70(s,6H),3.66(m,4H),3.07-3.01(m,4H),2.69-2.67(m,4H),2.35-1.97(m,10H),1.64(m,16H),0.94-0.88(m,12H)ppm。
Example 19
The synthetic route is as follows:
example 19 was prepared according to a synthetic method analogous to that of example 10.
Compound 19-1: MS (ESI, pos.ion) M/z 264.1[ M + H ]]+。
Compound 19-2: MS (ESI, pos. ion) M/z 421.1[ M + H ]]+；
1H NMR(400MHz,CDCl3):7.35(s,1H),5.32,5.29(brs,brs,1H),5.20-5.15(m,1H),4.41-4.37(m,1H),3.85-3.78(m,1H),3.69-3.65(m,1H),3.63(s,3H),2.28-2.17(m,3H),2.11-1.96(m,2H),0.97-0.95(m,3H),0.91-0.89(m,3H)ppm。
Compound 19-3: MS (ESI, pos.ion) M/z 450.3[ M +2H ]]2+；
1H NMR(400MHz,CDCl3):7.88(s,1H),7.81(s,1H),7.42,7.40(dd,dd,1H),7.38,7.36(s,s,1H),7.31,7.29(s,s,1H),7.06,7.04(dd,dd,1H),6.08,6.05(d,d,1H),5.32-5.25(m,3H),4.41-4.30(m,2H),3.85-3.76(m,4H),3.68-3.66(m,1H),3.65(s,3H),3.63(s,3H),3.62-3.61(m,1H),3.07-3.03(m,2H),2.96-2.93(m,2H),2.30-1.88(m,13H),1.70-1.49(m,7H),1.44-1.34(m,2H),1.30-1.21(m,2H),1.02-0.89(m,12H)ppm。
Biological activity
To verify the effect of the compounds described herein on HCV, the inventors used the HCV replicon System (HCV replication System) as an evaluation model. HCV replicons were first reported in science.1999Jul2;285(5424), 110-3. The HCV replicon system has become one of the most important tools for studying HCV RNA replication, pathogenicity, and virus persistence, for example, the minimal region of 5' -NCR necessary for HCV RNA replication has been successfully demonstrated using the replicon, and the HCV replicon system has been successfully used as an evaluation model for antiviral drugs. The inventors of the present invention verified the method as described in science.1999Jul2, 285(5424), 110-3, and J.Virol.2003Mar;77(5), 3007-19, which are incorporated herein by reference.
Briefly, the inventors tested the compounds described herein using the human hepatoma cell line Huh-7 stably transfected with HCV genotypes GT1a, GT1b, or GT2a replicon, respectively, and the compounds described herein using Y93H, L31F, P32L, the I302V resistance mutant, and the wild-type HCV1b, respectively. As used herein, an HCV replicon system comprising a G418 resistance gene NEO and a luciferase reporter gene can be characterized by the expression level of the NEO gene or the expression level of the luciferase gene in the host cell, and the effect of the compounds described herein on HCV viral replication can be evaluated. Herein, the expression amount of the NEO gene is detected by real-time quantitative polymerase chain reaction (qPCR) detection, and the expression amount of the luciferase gene is detected by a chemiluminescence method.
Brief introduction of the operation process:
1. determination of Compound EC based on luciferase Activity50：
Huh-7 cells transfected with the HCV replicon system were seeded in 96-well plates, each containing 8000 cells. Compounds described herein were each diluted in 5-fold gradients to give 10 concentration gradients. The compounds described herein were added to wells containing Huh-7 cells transfected with the HCV replicon system and incubated for 72 hours in a carbon dioxide incubator. 40 microliters of luciferase luminescent substrate Bright-Glo (Promega corporation) was added to the wells, and after 5 minutes, detection was performed using a chemiluminescence detection system Topcount microplate liquid scintillation counter, and EC of each compound was determined using GraphPad Prism software, respectively50(half maximal effect concentration, concentration for50% of maximum effect). Herein, experiments for each compound were performed in two lots, and wells without compound addition were set as negative controls.
qPCR detection of antibiotic G418 resistance Gene NEO Gene determination Compound EC50：
Huh-7 cells transfected with the HCV replicon system were seeded in 96-well plates, each containing 8000 cells. Compounds described herein were each diluted in 5-fold gradients to give 10 concentration gradients. The compounds described herein were added to wells containing Huh-7 cells transfected with the HCV replicon system and incubated for 72 hours in a carbon dioxide incubator. The expression level of NEO gene was determined by qPCR reaction and EC for each compound was determined using GraphPad Prism software50(half maximal effect concentration, concentration for50% of maximum effect). Herein, experiments for each compound were performed in two lots, and wells without compound addition were set as negative controls.
3. Results
Based on the EC determined above50The compounds described herein can be determinedThe compounds are effective in inhibiting HCV genotypes 1a, 1b, 2a, 2b, 3a, 3b, 4a, 5a and 6 a. Among them, EC against HCV genotype 1b50The range is 1pm to 99 nM. Table 2 provides the EC for representative compounds of the present disclosure against HCV1a and HCV1b genotypes50Value (nM), this EC50Values were determined based on luciferase activity.
TABLE 2
Examples 1a(nM) 1b(nM) Examples 1a(nM) 1b(nM) Examples 1a(nM) 1b(nM)
1 80 0.033 8 75 7.28 15 41 0.33
2 142 1.422 9 2.73 0.06 16 29 0.72
3 12 0.026 10 10.52 0.34 17 0.99 0.12
4 4.27 0.088 11 7.53 0.28 18 87 0.042
5 2.58 0.103 12 92 1.63 19 6.82 0.13
6 43 0.084 13 31 2.07
7 >100 3.67 14 36 0.73
According to the experimental results of Y93H, L31F, P32L and I302V resistant mutants and wild type HCV1b, the compound of the invention is proved to play an excellent anti-hepatitis C virus role by inhibiting the mechanism of HCV NS5A protein through molecular modeling and combining with the simulation result of computer aided design.
It will be evident to those skilled in the art that the present disclosure is not limited to the foregoing illustrative embodiments, but may be embodied in other specific forms without departing from the essential characteristics thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, reference being made to the appended claims rather than to the foregoing embodiments, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
The compounds of the present disclosure may inhibit HCV by a mechanism other than or different from NS5A inhibition. In one embodiment, the compounds of the present disclosure inhibit HCV replicons, and in another embodiment, the compounds of the present disclosure inhibit NS 5A. The compounds of the present disclosure inhibit multiple genotypes of HCV.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example" or "some examples" or the like are intended to mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above do not necessarily refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that those skilled in the art can make changes, modifications, substitutions and alterations to the above embodiments without departing from the principle and spirit of the present invention, the scope of which is defined by the appended claims and their equivalents.

Claims (21)

1.一种化合物，其具有如式(X’)所示的结构，或式(X’)所示的结构的立体异构体或药学上可接受的盐，1. A compound having a structure shown in formula (X'), or a stereoisomer or a pharmaceutically acceptable salt of a structure shown in formula (X'), 各R14和R14a独立地为H、氘、C1-4烷基、C6-10芳基、C2-10杂环基或C3-8环烷基；Each R 14 and R 14a are independently H, deuterium, C 1-4 alkyl, C 6-10 aryl, C 2-10 heterocyclyl or C 3-8 cycloalkyl; 各R16和R16a独立地为羟基、C1-4烷基氧基、C6-10芳基氧基、C2-10杂环基或C3-8环烷基；Each R 16 and R 16a are independently hydroxyl, C 1-4 alkyloxy, C 6-10 aryloxy, C 2-10 heterocyclyl or C 3-8 cycloalkyl; 其中结构单元为以下子结构式：in The structural unit is the following substructural formula: 结构单元为以下的基团： The structural units are the following groups: 和各A和A’独立地为以下基团：and each A and A' are independently the following groups: 其中R1、R2和N-CH独立形成的杂环或稠环或螺环体系选自以下子结构式：Wherein R 1 , R 2 and N-CH are independently formed heterocycle or condensed ring or spiro ring system selected from the following substructural formulas: 其中R3、R4和N-CH独立形成的杂环或稠环或螺环体系选自以下子结构式：Wherein R 3 , R 4 and N-CH are independently formed heterocycle or condensed ring or spiro ring system selected from the following substructural formulas: 2.根据权利要求1所述的化合物，其中2. The compound according to claim 1, wherein 各R14和R14a独立地为甲基、乙基、苯基、环己基、1-甲基丙基、异丙基、异丁基或叔丁基；each R and R is independently methyl, ethyl, phenyl, cyclohexyl, 1-methylpropyl, isopropyl, isobutyl, or tert-butyl; 各R16和R16a独立地为羟基、甲氧基、乙氧基、苯氧基、或叔丁氧基。Each R 16 and R 16a is independently hydroxyl, methoxy, ethoxy, phenoxy, or tert-butoxy. 3.根据权利要求1所述的化合物，其具有如式(XI’)所示的结构3. compound according to claim 1, it has the structure shown in formula (XI ') 其中，各Q1和Q2独立地为CH2；Wherein, each Q 1 and Q 2 are independently CH 2 ; 各Q4和Q5独立地为CH2；each of Q4 and Q5 is independently CH2 ; 各f和f’独立地为1；each f and f' is independently 1; 各i独立地为1、2、3或4each i is independently 1, 2, 3 or 4 各e独立地为0、1或2；each e is independently 0, 1 or 2; 各R5a和R5a’独立地为H；each R 5a and R 5a' is independently H; 各Y1和Y2独立地为CR7；each Y 1 and Y 2 is independently CR 7 ; 各Y1’和Y2’独立地为CR7；each Y 1' and Y 2' is independently CR 7 ; 各X1独立地为CR7R7a；each X 1 is independently CR 7 R 7a ; 各R7和R7a独立地为氢；each R7 and R7a is independently hydrogen; 各R14和R14a独立地为甲基、乙基、苯基、环己基、1-甲基丙基、异丁基、异丙基或叔丁基；each R and R is independently methyl, ethyl, phenyl, cyclohexyl, 1-methylpropyl, isobutyl, isopropyl, or tert-butyl; 各R16和R16a独立地为羟基、甲氧基、乙氧基、苯氧基、或叔丁氧基；Each R 16 and R 16a is independently hydroxyl, methoxy, ethoxy, phenoxy, or tert-butoxy; 和各A和A’独立地为以下基团：and each A and A' are independently the following groups: 其中R1、R2和N-CH独立形成的杂环或稠环或螺环体系选自以下子结构式：Wherein R 1 , R 2 and N-CH are independently formed heterocycle or condensed ring or spiro ring system selected from the following substructural formulas: 其中R3、R4和N-CH独立形成的杂环或稠环或螺环体系选自以下子结构式：Wherein R 3 , R 4 and N-CH are independently formed heterocycle or condensed ring or spiro ring system selected from the following substructural formulas: 4.根据权利要求1所述的化合物，其具有如式(XII’)所示的结构：4. The compound according to claim 1, which has a structure as shown in formula (XII'): 其中，各Q1和Q2独立地为CH2；Wherein, each Q 1 and Q 2 are independently CH 2 ; 各Q4和Q5独立地为CH2；each of Q4 and Q5 is independently CH2 ; 各X1独立地为CR7R7a；each X 1 is independently CR 7 R 7a ; 各R7和R7a独立地为氢；each R7 and R7a is independently hydrogen; 各R5a和R5a’独立地为H；each R 5a and R 5a' is independently H; 各Y1和Y2独立地为CR7；each Y 1 and Y 2 is independently CR 7 ; 当e为1时，Y1’和Y2’独立地为N或CR7，当e为2时，Y1’和Y2’均为CR7；When e is 1, Y 1' and Y 2' are independently N or CR 7 , and when e is 2, both Y 1' and Y 2' are CR 7 ; 各f和f’独立地为1；each f and f' is independently 1; 各i独立地为1、2、3或4each i is independently 1, 2, 3 or 4 各e独立地为1或2；each e is independently 1 or 2; 各R14和R14a独立地为甲基、乙基、苯基、环己基、1-甲基丙基、异丙基、异丁基或叔丁基；each R and R is independently methyl, ethyl, phenyl, cyclohexyl, 1-methylpropyl, isopropyl, isobutyl, or tert-butyl; 各R16和R16a独立地为羟基、甲氧基、乙氧基、苯氧基、或叔丁氧基；Each R 16 and R 16a is independently hydroxyl, methoxy, ethoxy, phenoxy, or tert-butoxy; 和各A和A’独立地为以下基团：and each A and A' are independently the following groups: 其中R1、R2和N-CH独立形成的杂环或稠环或螺环体系选自以下子结构式：Wherein R 1 , R 2 and N-CH are independently formed heterocycle or condensed ring or spiro ring system selected from the following substructural formulas: 其中R3、R4和N-CH独立形成的杂环或稠环或螺环体系选自以下子结构式：Wherein R 3 , R 4 and N-CH are independently formed heterocycle or condensed ring or spiro ring system selected from the following substructural formulas: 5.根据权利要求1所述的化合物，其具有如式(XIII’)所示的结构：5. The compound according to claim 1, which has a structure as shown in formula (XIII'): 其中，各Q1和Q2独立地为CH2；Wherein, each Q 1 and Q 2 are independently CH 2 ; Q4为CH2；Q 4 is CH 2 ; X3为CR7R7a；X 3 is CR 7 R 7a ; 各R7和R7a独立地为氢；each R7 and R7a is independently hydrogen; 各R5a和R5a’独立地为H；each R 5a and R 5a' is independently H; 各Y1和Y2独立地为CR7；each Y 1 and Y 2 is independently CR 7 ; 各Y1’和Y2’独立地为CR7；each Y 1' and Y 2' is independently CR 7 ; 各f和f’独立地为1；each f and f' is independently 1; 各i独立地为1、2、3或4；each i is independently 1, 2, 3 or 4; e独立地为0或1；e is independently 0 or 1; 各R14和R14a独立地为甲基、乙基、苯基、环己基、1-甲基丙基、异丙基、异丁基或叔丁基；each R and R is independently methyl, ethyl, phenyl, cyclohexyl, 1-methylpropyl, isopropyl, isobutyl, or tert-butyl; 各R16和R16a独立地为羟基、甲氧基、乙氧基、苯氧基、或叔丁氧基；Each R 16 and R 16a is independently hydroxyl, methoxy, ethoxy, phenoxy, or tert-butoxy; 和各A和A’独立地为以下基团：and each A and A' are independently the following groups: 其中R1、R2和N-CH独立形成的杂环或稠环或螺环体系选自以下子结构式：Wherein R 1 , R 2 and N-CH are independently formed heterocycle or condensed ring or spiro ring system selected from the following substructural formulas: 其中R3、R4和N-CH独立形成的杂环或稠环或螺环体系选自以下子结构式：Wherein R 3 , R 4 and N-CH are independently formed heterocycle or condensed ring or spiro ring system selected from the following substructural formulas: 6.一种化合物，其包含以下其中之一的结构：6. A compound comprising one of the following structures: 或其立体异构体或药学上可接受的盐。 or a stereoisomer or a pharmaceutically acceptable salt thereof. 7.一种药物组合物，其中所述药物组合物包含根据权利要求1-6中任一项所述的化合物。7. A pharmaceutical composition, wherein said pharmaceutical composition comprises a compound according to any one of claims 1-6. 8.根据权利要求7所述的药物组合物，进一步包含药学上可接受的辅剂、媒介物或其组合。8. The pharmaceutical composition according to claim 7, further comprising a pharmaceutically acceptable adjuvant, vehicle or combination thereof. 9.根据权利要求8所述的药物组合物，其中，所述辅剂包含载体、赋形剂。9. The pharmaceutical composition according to claim 8, wherein the adjuvant comprises a carrier, an excipient. 10.根据权利要求9所述的药物组合物，其中，所述赋形剂包含稀释剂。10. The pharmaceutical composition according to claim 9, wherein the excipient comprises a diluent. 11.根据权利要求7所述的药物组合物，其更进一步地包含其他的抗HCV的药物。11. The pharmaceutical composition according to claim 7, which further comprises other anti-HCV drugs. 12.根据权利要求11所述的药物组合物，其中所述抗HCV的药物为干扰素、利巴韦林、白介素2、白介素6、白介素12、促进产生1型辅助性T细胞应答的化合物、干扰RNA、反义RNA、咪喹莫德、肌苷5’-单磷酸脱氢酶抑制剂、金刚烷胺、金刚乙胺、巴维昔单抗(Bavituximab)、CivacirTM、波普瑞韦(boceprevir)、替拉瑞韦(telaprevir)、埃罗替尼(erlotinib)、达卡他韦(daclatasvir)、西甲匹韦(simeprevir)、asunaprevir、vaniprevir、faldaprevir、ABT-450、丹诺普韦(danoprevir)、sovaprevir、MK-5172、vedroprevir、BZF-961、GS-9256、那拉匹韦(narlaprevir)、ANA975、ABT-267、EDP239、PPI-668、GS-5816、samatasvir(IDX-719)、MK-8742、MK-8325、GSK-2336805、PPI-461、TMC-435、MK-7009、BI-2013335、西鲁瑞韦(ciluprevir)、BMS-650032、ACH-1625、ACH-1095、VX-985、IDX-375、VX-500、VX-813、PHX-1766、PHX-2054、IDX-136、EP-013420、VBY-376、TMC-649128、R-7128、PSI-7977、INX-189、IDX-184、IDX102、R1479、UNX-08189、PSI-6130、PSI-938、PSI-879、HCV-796、HCV-371、VCH-916、VCH-222、ANA-598、MK-3281、ABT-333、ABT-072、PF-00868554、BI-207127、GS-9190、A-837093、JKT-109、Gl-59728、GL-60667、AZD-2795、TMC647055或其组合。12. The pharmaceutical composition according to claim 11, wherein the anti-HCV drug is interferon, ribavirin, interleukin 2, interleukin 6, interleukin 12, a compound that promotes the generation of type 1 helper T cell response, Interfering RNA, antisense RNA, imiquimod, inosine 5'-monophosphate dehydrogenase inhibitor, amantadine, rimantadine, Bavituximab (Bavituximab), Civacir TM , boceprevir ( boceprevir), telaprevir, erlotinib, daclatasvir, simeprevir, asunaprevir, vaniprevir, faldaprevir, ABT-450, danoprevir ), sovaprevir, MK-5172, vedroprevir, BZF-961, GS-9256, narlaprevir, ANA975, ABT-267, EDP239, PPI-668, GS-5816, samatasvir (IDX-719), MK -8742, MK-8325, GSK-2336805, PPI-461, TMC-435, MK-7009, BI-2013335, ciluprevir, BMS-650032, ACH-1625, ACH-1095, VX-985 , IDX-375, VX-500, VX-813, PHX-1766, PHX-2054, IDX-136, EP-013420, VBY-376, TMC-649128, R-7128, PSI-7977, INX-189, IDX -184, IDX102, R1479, UNX-08189, PSI-6130, PSI-938, PSI-879, HCV-796, HCV-371, VCH-916, VCH-222, ANA-598, MK-3281, ABT-333 , ABT-072, PF-00868554, BI-207127, GS-9190, A-837093, JKT-109, Gl-59728, GL-60667, AZD-2795, TMC647055 or combinations thereof. 13.根据权利要求12所述的药物组合物，其中所述干扰素为干扰素α-2b、聚乙二醇化的干扰素α、干扰素α-2a、聚乙二醇化的干扰素α-2a、复合α-干扰素、干扰素γ或其组合。13. The pharmaceutical composition according to claim 12, wherein the interferon is interferon alpha-2b, pegylated interferon alpha, interferon alpha-2a, pegylated interferon alpha-2a , consensus alpha-interferon, interferon gamma, or a combination thereof. 14.根据权利要求7-13中任一项所述的药物组合物，其更进一步地包含至少一种HCV抑制剂。14. The pharmaceutical composition according to any one of claims 7-13, further comprising at least one HCV inhibitor. 15.根据权利要求14所述的药物组合物，其中所述HCV抑制剂用于抑制HCV复制过程和抑制HCV病毒蛋白功能的至少之一。15. The pharmaceutical composition according to claim 14, wherein the HCV inhibitor is used for at least one of inhibiting HCV replication process and inhibiting HCV viral protein function. 16.根据权利要求15所述的药物组合物，其中所述HCV复制过程选自HCV进入、脱壳、翻译、复制、组装或释放的HCV的完整病毒周期。16. The pharmaceutical composition according to claim 15, wherein the HCV replication process is selected from the complete viral cycle of HCV in which HCV enters, uncoats, translates, replicates, assembles or releases. 17.根据权利要求15所述的药物组合物，其中所述的HCV病毒蛋白选自金属蛋白酶、NS2、NS3、NS4A、NS4B、NS5A和NS5B；以及HCV病毒复制所需要的内部核糖体进入点和肌苷单磷酸脱氢酶。17. The pharmaceutical composition according to claim 15, wherein said HCV viral protein is selected from Metalloprotease, NS2, NS3, NS4A, NS4B, NS5A and NS5B; and internal ribosome entry points and Inosine monophosphate dehydrogenase. 18.根据权利要求1-6中任一项所述的化合物或权利要求7-17中任一项所述的药物组合物在制备药物中的用途，所述药物用于抑制HCV复制和抑制HCV病毒蛋白功能的至少之一。18. Use of the compound according to any one of claims 1-6 or the pharmaceutical composition according to any one of claims 7-17 in the preparation of medicines for inhibiting HCV replication and inhibiting HCV At least one of the functions of the viral protein. 19.根据权利要求18所述的用途，所述HCV复制过程选自HCV进入、脱壳、翻译、复制、组装或释放的HCV的完整病毒周期。19. The use according to claim 18, wherein the HCV replication process is selected from the complete viral cycle of HCV in which HCV enters, uncoats, translates, replicates, assembles or releases. 20.根据权利要求18所述的用途，其中所述的HCV病毒蛋白选自金属蛋白酶、NS2、NS3、NS4A、NS4B、NS5A和NS5B；以及HCV病毒复制所需要的内部核糖体进入点和肌苷单磷酸脱氢酶。20. purposes according to claim 18, wherein said HCV viral protein is selected from metalloprotease, NS2, NS3, NS4A, NS4B, NS5A and NS5B; monophosphate dehydrogenase. 21.根据权利要求1-6中任一项所述的化合物或权利要求7-17中任一项所述的药物组合物在制备药物中的用途，所述药物用于预防、处理、治疗或减轻患者的HCV感染或丙型肝炎疾病。21. Use of the compound according to any one of claims 1-6 or the pharmaceutical composition according to any one of claims 7-17 in the preparation of medicines for prevention, treatment, treatment or Alleviate HCV infection or hepatitis C disease in patients.
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