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CN104003980B - It is used as the endocyclic compound and its pharmaceutical composition and purposes of hepatitis c inhibitor - Google Patents

It is used as the endocyclic compound and its pharmaceutical composition and purposes of hepatitis c inhibitor Download PDF

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CN104003980B
CN104003980B CN201410066886.XA CN201410066886A CN104003980B CN 104003980 B CN104003980 B CN 104003980B CN 201410066886 A CN201410066886 A CN 201410066886A CN 104003980 B CN104003980 B CN 104003980B
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CN104003980A (en
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张英俊
张健存
谢洪明
任青云
胡柏林
李石凤
巫锡伟
唐昌华
汪成林
方清洪
于全兴
张志铿
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Yichang Hec Changjiang Pharmaceutical Co ltd
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Guangdong HEC Pharmaceutical
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    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract

The invention provides the endocyclic compound and its pharmaceutical composition and purposes as hepatitis c inhibitor.Stereoisomer, geometric isomer, dynamic isomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or the prodrug of compound compound shown in the compound or formula (I) shown in formula (I).In addition, present invention also offers the pharmaceutical composition for including the compound, the compound and described pharmaceutical composition are used to suppress HCV reproduction processes and suppress the purposes of at least one of HCV virus protein function, and the compound and described pharmaceutical composition are used to preventing, handle, treat or mitigating the HCV infection of patient or the purposes of hepatitis C disease.

Description

Bridged ring compound as hepatitis C inhibitor and pharmaceutical composition and application thereof
Technical Field
The present invention is in the field of medicine and relates to compounds useful for treating Hepatitis C Virus (HCV) infection, compositions of the compounds, and uses and methods of use thereof. In particular, the compounds of the present invention are bridged compounds that can act as inhibitors of NS 5A. More particularly, the present invention relates to compounds that can inhibit the function of the NS5A protein encoded by hepatitis c virus, pharmaceutical compositions of said 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 a processing event necessary to increase 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. Proteins of hcv ns5A are described, for example, in Tan, s. -l., Katzel, m.g., virogy2001, 284,1-12, and Park, k. -j., Choi, s. -H, j.biologicalchemistry, 2003.
Summary of the invention
The present invention relates to novel bridged ring 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 that is a compound of formula (I) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound of formula (I),
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-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)-S(=O)r-N(R5)-(CR8R8a)p-、-(CR8R8a)n-N(R5)-C(=O)-O-(CR8R8a)pOr each of a and a' is independently a group:
wherein each X1、X1Or X2Independently O, S,NR6Or CR7R7a；
X3Is O, S, NR6C (= O) or (CR)7R7a)e；
Is carbocyclyl or heterocyclyl;
W2is a fused bicyclic group or a fused heterobicyclic group;
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;
e is 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 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;
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)OR13、-N(R13)C(=O)-R13、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; wherein the aliphatic of said group is an alkyl group;
each R6aIndependently is 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, hydroxyl, cyano, nitro, F, Cl, Br, I, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, arylHeteroaryl, 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, heteroaryl or aralkyl; when R is13And R13aAttached to the same nitrogen atom, R13、R13aAnd the nitrogen atom may 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-, 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 or 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) -, alkylradical-S (= O) -, alkyl-S (= O)2-, hydroxy-substituted alkyl-S (= O)2Or a substituent of carboxyalkoxy.
In some of these embodiments, whereinIs C3-8Carbocyclic radical or C2-10A heterocyclic group;
and W2Is C5-12Condensed bicyclic group or C5-12Fused heterobicyclic radicals.
In some of these embodiments, whereinThe structural unit is the following sub-structural formula:
the structural unit is the following sub-structural formula:
wherein each X3Independently O, S, NR6C (= O) or (CR)7R7a)e；
Each X4And 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)i；
Each Q3Independently is N or CR7；
e is 0, 1,2,3 or 4;
each i 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)OR13a、-N(R13)C(=O)-R13a、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; 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:
independently is a sub-structure of:
wherein each Y is1、Y2、Y1’And Y2’Independently is N or CH;
each 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)OR13a、-N(R13)C(=O)-R13a、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;
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 or C3-8Cycloalkyl radical C1-6An alkyl 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 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-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)-S(=O)r-N(R5)-(CR8R8a)p-、-(CR8R8a)n-N(R5)-C(=O)-O-(CR8R8a)pOr each of a and a' is independently a group:
wherein each X1、X1’Or X2Independently O, S, NR6Or CR7R7a；
t is 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, C2-6Heteroalkyl group, C3-10Cycloalkyl radical, C2-10Heterocyclic group, C6-10Aryl radical, C1-9Heteroaryl or C6-10Aryl radical C1-6An alkyl group; when R is13And R13aAttached to the same nitrogen atom, R13、R13aAnd the nitrogen atom may 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, X1Is O or S;
Y1is N or CH;
t is 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-、C1-6Alkoxy radical, C1-6Alkylamino radical, C1-6Alkyl radical, C1-6Haloalkyl, C2-6Alkenyl radical, C2-6Alkynyl, mercapto or nitro;
and each R13And R13aIndependently is 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; when R is13And R13aAttached to the same nitrogen atom, R13、R13aAnd the nitrogen atom may 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 H, C1-8Alkyl radical, C1-8Heteroalkyl group, C6-10Aryl radical C1-6Alkyl radical, C3-10Cycloalkyl radical, C2-10Heterocyclic group, C1-9Heteroaryl or C6-10Aryl, 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 may optionally 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 is 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,structure of the productThe unit is the following sub-structural formula:
independently the sub-formulae:
each Q1And Q2Independently is a bond, NR6O, S, C (= O) or (CH)2)i；
Each Q3Independently are N and CH;
each X3Independently O, S, NR6C (= O) or (CR)7R7a)e；
Each X1Independently O, S, NR6Or CR7R7a；
e is 0, 1,2,3 or 4;
each i is independently 0, 1,2,3 or 4;
each f and f' is independently 0, 1,2,3 or 4
Each X4And 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 a 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-、C1-6alkyl-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)OR13a、-N(R13)C(=O)-R13a、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 C1-6FatGroup 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 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; when R is13And R13aAttached to the same nitrogen atom, R13、R13aAnd nitrogen atom optionally forming a substituent orAn 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;
t is 0, 1,2,3 or 4;
and each Y4And Y4' independently is a bond, O, S, - (CH)2)n-、-CH=CH-、-S(=O)r-、-CH2O-、-CH2S-、-CF2-、-CHR5a-、-CR5aR6a、-CH2S(=O)ror-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)i；
Each X3And X5Independently O, S, NR6C (= 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、Q2And Q4Independently isO、S、C(=O)、NR6Or (CH)2)i；
X3Is O, S, NR6C (= O) or (CR)7R7a)e；
X4Is O, S, NR6C (= O) or CR7R7a；
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 Q4And Q5Independently O, S, C (= O), NR6Or (CH)2)i；
Each X3And X5Independently O, S, NR6C (= O) or (CR)7R7a)e；
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 Q is4O, S, C (= O), NR6Or (CH)2)i；
X3Is O, S, NR6C (= O) or (CR)7R7a)e；
X4Is O, S, NR6C (= O) or CR7R7a；
And each of i and e is independently 0, 1,2,3 or 4.
In some of these embodiments, wherein each Y and Y' is 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 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; 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 t is independently 0, 1,2,3 or 4;
and each k is independently 0, 1 or 2.
In still other embodiments, wherein each R is9、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 the structure shown in formula (VII):
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;
wherein said 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 C1-6Alkyl groups may be optionally substituted with one or more substituents selected from deuterium, F, Cl, Br, hydroxy, cyano.
In other embodiments, it has the structure shown in formula (VIII):
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;
wherein said C1-3Hydroxyalkyl, methyl, ethyl, isopropyl, isobutyl, tert-butyl, allyl, propargyl, trifluoroethyl, phenyl, pyranyl, morpholinyl, benzyl, piperazinyl, cyclopentyl, cyclopropyl, cyclohexyl or C1-9Heteroaryl groups 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 (IX):
wherein each Q1And Q2Independently is a bond, NR6O, S, C (= O) or (CH)2)i；
i is 1,2,3 or 4;
each R14And 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;
wherein said 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 C1-6Alkyl groups 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 (X):
wherein each Q1And Q2Independently is a bond, NR6O, S, C (= O) or (CH)2)i；
i is 1,2,3 or 4;
each R14And 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;
wherein said 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 C1-6Alkyl groups 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 R is5aAnd R5a’Independently is H, deuterium, oxo (= O), benzyl, C1-4Alkyl, F, Cl, Br or I;
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;
wherein said benzyl group, C1-4Alkyl radical, C6-10Aryl radical, C2-10Heterocyclic group, C1-4Alkyloxy, C3-8Cycloalkyl radical, C6-10Aryloxy may be optionally substituted with one or more substituents selected from deuterium, F, Cl, Br, hydroxy, cyano;
whereinThe structural unit is the following sub-structural formula:
independently are the following groups:
each 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 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, benzyl, cyclohexyl, 1-methylpropyl, isopropyl, isobutyl, methoxy, ethoxy, phenoxy, 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 (XII)
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 X3And X5Independently O, S, NR6C (= O) or (CR)7R7a)e；
e is 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；
Each R6、R7And R7aIndependently hydrogen, 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, benzyl, cyclohexyl, 1-methylpropyl, isopropyl, isobutyl, methoxy, ethoxy, phenoxy, tert-butoxy or tert-butyl may be optionally substituted with one or more substituents selected from deuterium, F, Cl, Br, hydroxy, cyano;
and each a and a' is independently a 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 (XIII)
Wherein each Q1、Q2And Q4Independently O, S, C (= O), NR6Or CH2；
X3Is O, S, NR6C (= O) or (CR)7R7a)e；
X4Is 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, oxo (= O), benzyl, ethyl, 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, benzyl, cyclohexyl, 1-methylpropyl, isopropyl, isobutyl, methoxy, ethoxy, phenoxy, 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 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), daclatastasvir, simeprevir, asunaprevir, vanieprevir, faldaprevir, ABT-450, danoprevir, sovaprevir, MK-5172, vedroprevevir, BZF-961, GS-9256, narloprevir, ANA975, ABT-267, EDP239, PPI-668, GS-5816, samatasvir (IDX-719), MK-8742, MK-8325, GSK-2336805, PPI-176461, simeprevir (TMC-435), vanilpreprevir (MK-7009), faldaprevir (201335), cilaprevir, asurabir (asunaprevir), asunaprevir (PHR-3556), PHVITRX-36795, VX400-36989), VX400-369, VX1, VXb-3, VX-3, VXb-3, VX, INX-189, IDX-184, IDX102, R1479, INX-08189, PSI-6130, PSI-938, PSI-879, HCV-796, HCV-371, VCH-916, lomibuvir (VCH-222), setobrevir (ANA-598), MK-3281, ABT-333, ABT-072, filibuvir (PF-00868554), deleobrevir (BI-207127), tegobrevir (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 or release of HCV. The HCV viral protein is selected from 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 or release of HCV. The HCV viral protein is selected from 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 invention relates to processes for the preparation, isolation and purification of compounds encompassed by formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (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, such as those of the general formula above, or as specified in the examples, subclasses, and groups encompassed by the present invention. 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, hydroxyl-substituted alkoxy, hydroxyl-substituted alkylalkyl-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" or "haloaliphatic" means that an aliphatic group is substituted with one or more of the same or different halogen atoms, wherein 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 "hydroxyaliphatic" or "hydroxyaliphatic" means that an aliphatic group is substituted with one or more hydroxyl groups, wherein the aliphatic group has the meaning described herein, examples of which include, but are not limited to, hydroxyethyl, 2-hydroxypropyl, hydroxymethyl, and the like.
The term "aminoaliphatic" or "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 aryloxy. 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)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, morpholine-4-methylmethylene, piperidine-N-methylmethylene, 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, the heteroalkyl group contains from 1 to 10 carbon atoms, in other embodiments from 1 to 8 carbon atoms, in other embodiments from 1 to 6 carbon atoms, in other embodiments from 1 to 4 carbon atoms, and in other embodiments 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 "alicyclic", "cycloaliphatic", "carbocyclic", "carbocyclyl" or "cycloalkyl" refer to a mono-or polyvalent, non-aromatic, saturated or partially unsaturated ring which does not contain heteroatoms, and to processes for the preparation thereofIncluding a monocyclic ring of 3 to 12 carbon atoms or a bicyclic ring of 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 "cycloalkyloxyaliphatic" or "cycloalkyloxyaliphatic" means that the aliphatic group is 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" or "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" or "cycloalkylaliphatic" means that the aliphatic group may be substituted with one or more cycloalkyl groups, wherein cycloalkyl and aliphatic groups have the meaning described herein, examples of which 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, in which 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 atoms to give, 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, thiaxanyl, 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-pyridyl urea. Examples of heterocyclic groups also include 1, 1-dioxothiomorpholinyl and pyrimidinedione groups in which two carbon atoms of the ring are replaced by oxygen atoms. 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" or "heterocyclylaliphatic" means a heterocyclyl-substituted aliphatic group wherein heterocyclyl and aliphatic groups 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" or "heterocyclyloxyaliphatic" means that the aliphatic group is substituted with one or more heterocyclyloxy groups, where the aliphatic and heterocyclyloxy groups have the meaning as 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" or "heterocyclylaminoaliphatic" means that the aliphatic group is substituted with one or more heterocyclylamino groups, wherein 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" or "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" or "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" or "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)2-, hydroxy-substituted alkyl-S (= O)2-, carboxy-substituted alkoxy, and the like.
The term "arylaliphatic" or "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 "aryloxyaliphatic" or "aryloxyaliphatic" means that the aliphatic group is substituted with one or more optionally substituted aryloxy groups, wherein the aryloxy and aliphatic groups have the meaning described herein, and such examples include, but are not limited to, phenoxymethyl, phenoxyethyl, tolyloxyethyl, phenoxypropyl, and the like.
The term "arylaminoaliphatic" or "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; the following bicyclic rings are also included, but are in no way limited to these: benzimidazolyl, benzofuranyl, benzothienyl, benzo [ d ] thiazol-2-yl, imidazo [1,5-a ] pyridin-6-yl, indolyl (e.g., 2-indolyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), and isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl).
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" or "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", each represents a divalent radical-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., as"carboxyalkyl") denotes-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 yet other embodiments, the method may be,alkylamino 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" or "heteroarylaliphatic" means that the aliphatic group is substituted with one or more heteroaryl groups, wherein heteroaryl and aliphatic groups have the meaning described herein, examples of which 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.
Term(s) for"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 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 comprises one or more heteroatoms, wherein each ring systemHaving a 3-7 membered ring, i.e. containing 1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where 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, as shown in formula (a2), ring a and ring B share a carbon atom in two saturated ring systems, and are referred to as "spiro rings". 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, 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 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 W1Ring, W2Any possible substituted position on the ring or W ring 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 that is converted in vivo to a compound of formula (I). 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, ammoniaCarbamates 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 salts" refer to organic and inorganic salts of the compounds of the present invention. 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, inorganic acid salts formed by reaction with amino groups such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, andsalts of organic acids such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or these salts can be obtained by other methods described in the literature, for example by 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 bridged ring 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 of a compound of formula (I),
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-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)-S(=O)r-N(R5)-(CR8R8a)p-、-(CR8R8a)n-N(R5)-C(=O)-O-(CR8R8a)pOr each of a and a' is independently a group:
wherein each X1、X1’Or X2Independently O, S, NR6Or CR7R7a；
X3Is O, S, NR6C (= O) or (CR)7R7a)e；
Is carbocyclyl or heterocyclyl;
W2is a fused bicyclic group or a fused heterobicyclic group;
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;
e is 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 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;
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)OR13、-N(R13)C(=O)-R13、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, halogenated aliphatic, hydroxy aliphatic, amino aliphatic, alkoxy aliphatic, alkylamino aliphatic, alkylthio aliphatic, aryl aliphatic, heteroaryl aliphatic, heterocyclyl aliphatic, cycloalkyl aliphatic, aryloxy aliphatic,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, alkoxyaliphatic, alkylaminoaliphatic, alkylthioaliphatic, arylaliphatic, heteroarylaliphatic, heterocyclylaliphatic, cycloalkylaliphatic, aryloxyaliphatic, heterocyclyloxyaliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic, heterocyclylaminoaliphatic, cycloalkylaminoaliphatic, aryl, heteroaryl, heteroaliphatic, aryl, anda cyclic or carbocyclic 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, heteroaryl or aralkyl; when R is13And R13aAttached to the same nitrogen atom, R13、R13aAnd the nitrogen atom may optionally form a substituted or unsubstituted 3-8 membered ring, a spiro bicyclic ring or a fused bicyclic ring;
wherein each of the following groups is alkylene, alkenyleneCycloalkylene, 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-, 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 or 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, heteroalkylamino, heterocyclylalkoxy, heterocyclylalkyl, or aryloxy groupsAryl, 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)2Or a substituent of carboxyalkoxy.
In some of these embodiments, whereinIs C3-8Carbocyclic radical or C2-10A heterocyclic group;
and W2Is C5-12Condensed bicyclic group or C5-12Fused heterobicyclic radicals.
In some of these embodiments, whereinThe structural unit is the following sub-structural formula:
the structural unit is the following sub-structural formula:
wherein each X3Independently O, S, NR6C (= O) or (CR)7R7a)e；
Each X4And 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)i；
Each Q3Independently is N or CR7；
e is 0, 1,2,3 or 4;
each i 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)OR13a、-N(R13)C(=O)-R13a、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; 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:
independently is a sub-structure of:
wherein each Y is1、Y2、Y1’And Y2’Independently is N or CH;
each 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)OR13a、-N(R13)C(=O)-R13a、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;
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 or C3-8Cycloalkyl radical C1-6An alkyl group;
and 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.
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-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)-S(=O)r-N(R5)-(CR8R8a)p-、-(CR8R8a)n-N(R5)-C(=O)-O-(CR8R8a)pOr each of a and a' is independently a group:
wherein each X1、X1’Or X2Independently O, S, NR6Or CR7R7a；
t is 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 radicalRadical, 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; when R is13And R13aAttached to the same nitrogen atom, R13、R13aAnd the nitrogen atom may 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, X1Is O or S;
Y1is N or CH;
t is 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-、C1-6Alkoxy radical, C1-6Alkylamino radical, C1-6Alkyl radical, C1-6Haloalkyl, C2-6Alkenyl radical, C2-6Alkynyl, mercapto or nitro;
and each R13And R13aIndependently is 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; when R is13And R13aAttached to the same nitrogen atom, R13、R13aAnd the nitrogen atom may 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 H, C1-8Alkyl radical, C1-8Heteroalkyl group, C6-10Aryl radical C1-6Alkyl radical, C3-10Cycloalkyl radical, C2-10Heterocyclic group, C1-9Heteroaryl or C6-10Aryl, 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 may optionally 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:
independently the sub-formulae:
each Q1And Q2Independently is a bond, NR6O, S, C (= O) or (CH)2)i；
Each Q3Independently are N and CH;
each X3Independently O, S, NR6C (= O) or (CR)7R7a)e；
Each X1Independently O, S, NR6Or CR7R7a；
e is 0, 1,2,3 or 4;
each i is independently 0, 1,2,3 or 4;
each f and f' is independently 0, 1,2,3 or 4
Each X4And X5Independently O, S, NR6C (= O) or CR7R7a；
Each Y is1、Y2、Y1’And Y2’Independently of each otherIs 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 a 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-、C1-6alkyl-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)OR13a、-N(R13)C(=O)-R13a、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 series,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; 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;
t is 0, 1,2,3 or 4;
and each Y4And Y4' independently is a bond, O, S, - (CH)2)n-、-CH=CH-、-S(=O)r-、-CH2O-、-CH2S-、-CF2-、-CHR5a-、-CR5aR6a、-CH2S(=O)ror-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)i；
Each X3And X5Independently O, S, NR6C (= 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、Q2And Q4Independently O, S, C (= O), NR6Or (CH)2)i；
X3Is O, S, NR6C (= O) or (CR)7R7a)e；
X4Is O, S, NR6C (= O) or CR7R7a；
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 Q4And Q5Independently O, S, C (= O), NR6Or (CH)2)i；
Each X3And X5Independently O, S, NR6C (= O) or (CR)7R7a)e；
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 Q is4O, S, C (= O), NR6Or (CH)2)i；
X3Is O, S, NR6C (= O) or (CR)7R7a)e；
X4Is O, S, NR6C (= O) or CR7R7a；
And each of i and e is independently 0, 1,2,3 or 4.
In some of these embodiments, wherein each Y and Y' is 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 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; 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 t is independently 0, 1,2,3 or 4;
and each k is independently 0, 1 or 2.
In still other embodiments, wherein each R is9、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 is H, deuterium, methyl, ethylPropyl, phenyl, cyclohexyl, morpholinyl or piperidinyl.
In still other embodiments, it has the structure shown in formula (VII):
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;
wherein said 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 C1-6Alkyl groups may be optionally substituted with one or more substituents selected from deuterium, F, Cl, Br, hydroxy, cyano.
In other embodiments, it has the structure shown in formula (VIII):
wherein each R is14And R14aIndependently of one another H, deuterium, C1-3Hydroxyalkyl, methyl, ethyl, isopropyl, isobutyl, tert-butyl, allyl, propargylTrifluoroethyl, phenyl, pyranyl, morpholinyl, benzyl, piperazinyl, cyclopentyl, cyclopropyl, cyclohexyl or C1-9A heteroaryl group;
wherein said C1-3Hydroxyalkyl, methyl, ethyl, isopropyl, isobutyl, tert-butyl, allyl, propargyl, trifluoroethyl, phenyl, pyranyl, morpholinyl, benzyl, piperazinyl, cyclopentyl, cyclopropyl, cyclohexyl or C1-9Heteroaryl groups 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 (IX):
wherein each Q1And Q2Independently is a bond, NR6O, S, C (= O) or (CH)2)i；
i is 1,2,3 or 4;
each R14And 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;
wherein said C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C2-6Heteroalkyl group, C6-10Aryl radical, C1-9Heteroaryl group, C2-10Heterocyclic group, C3-8A cycloalkyl group, a,C6-10Aryl radical C1-6Alkyl radical, C1-9Heteroaryl C1-6Alkyl radical, C2-10Heterocyclyl radical C1-6Alkyl or C3-8Cycloalkyl radical C1-6Alkyl groups 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 (X):
wherein each Q1And Q2Independently is a bond, NR6O, S, C (= O) or (CH)2)i；
i is 1,2,3 or 4;
each R14And 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;
wherein said 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 C1-6The alkyl group may optionally be substituted with one or more substituents selected from deuterium, F, Cl, Br, hydroxy,Cyano group.
In some of these embodiments, it has the structure shown in formula (XI)
Wherein each R is5aAnd R5a’Independently is H, deuterium, oxo (= O), benzyl, C1-4Alkyl, F, Cl, Br or I;
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;
wherein said benzyl group, C1-4Alkyl radical, C6-10Aryl radical, C2-10Heterocyclic group, C1-4Alkyloxy, C3-8Cycloalkyl radical, C6-10Aryloxy may be optionally substituted with one or more substituents selected from deuterium, F, Cl, Br, hydroxy, cyano;
whereinThe structural unit is the following sub-structural formula:
independently are the following groups:
each 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 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, benzyl, cyclohexyl, 1-methylpropyl, isopropyl, isobutyl, methoxy, ethoxy, phenoxy, 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 (XII)
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 X3And X5Independently O, S, NR6C (= O) or (CR)7R7a)e；
e is 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；
Each R6、R7And R7aIndependently hydrogen, 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, benzyl, cyclohexyl, 1-methylpropyl, isopropyl, isobutyl, methoxy, ethoxy, phenoxy, tert-butoxy or tert-butyl may be optionally substituted with one or more substituents selected from deuterium, F, Cl, Br, hydroxy, cyano;
and each a and a' is independently a 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 (XIII)
Wherein each Q1、Q2And Q4Independently O, S, C (= O), NR6Or CH2；
X3Is O, S, NR6C (= O) or (CR)7R7a)e；
X4Is 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, oxo (= O), benzyl, ethyl, 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, benzyl, cyclohexyl, 1-methylpropyl, isopropyl, isobutyl, methoxy, ethoxy, phenoxy, 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 of one of,
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 that promotes the development of a type 1 helper T cell response, interfering RNA, antisense RNA, imiqimod, inosine 5' -monophosphate dehydrogenase inhibitor, amantadine, rimantadine, baviximab (Bavituximab), CivacirTM, Poplervir (boceprevir), Telaprevir (telaprevir), erlotinib (erlotinib), daclatasvir, simeprevir, asunaprevir, vanilprevir, faldapevir, ABT-450, danoprevir, sovapevir, MK-5172, vepredevir, Bldorevir-961, GS-9256, narloprevir, ANA975, ABT-267, EDP 668, PPI-239, GS-5816, ZFsavivir (ZFzapr719-2018), GSldevir-35461, GSuny-3572, GSldevir-3576, GST-33, GSP-33, GSN-3572, GSldevir, MRB-33, GSN-3-33, GSN-3574-3, GSN-3-b, TMCt-3, GSldevir, GSI-3-I, SAPPI, GSI, or TMB1, or TM, sovaprevir (ACH-1625), ACH-1095, VX-985, IDX-375, VX-500, VX-813, PHX-1766, PHX-2054, IDX-136, IDX-316, modithmycin (EP-013420), VBY-376, TMC-649128, mericitabine (R-7128), sofosbuvir (PSI-7977), INX-189, IDX-184, IDX102, R1479, INX-08189, PSI-6130, PSI-938, PSI-879, HCV-796, HCV-371, VCH-916, lomibuvir (VCH-222), setobrevir (ANA-598), MK-3281, ABT-333, ABT-072, filibuvir (PF-00868554), deleobrevir (BI-207127), tegobrevir (GS-9190), A-837093, JKT-109, Gl-59728, GL-60667, AZD-2795, TMC647055, 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 protein is selected from 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, when combined, administered sequentially or simultaneously, result in a therapeutic effect. 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 Research1986,3(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 or release of HCV. The HCV viral protein is selected from 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, baviituximab (Bavituximab), CivacirTMBoceprevir, telaprevir, elaviaRotinib (erlotinib), daclatasvir, simeprevir, asunaprevir, vanipredvir, faldaprevir, ABT-450, danoprevir, sovaprevir, MK-5172, vedroprevir, BZF-961, GS-9256, narloprevir, ANA975, ABT-267, EDP239, PPI-668, GS-5816, samatasvir (IDX-719), MK-8742, MK-8325, GSK-2336805, PPI-461, simeprevir (TMC-435), vanioprevir (MK-7009), faldaprevir (BI-201335), cillupevir, asunaprevir (BMS-650032), sovaprevir (ACH-635), ACH-985, VX-985, PHX-375-017135, VX1-11-33, VX400-102, VXorx-3583, VXorx-369, VX1-102, VX1-3532, VX1, VX-3532, VX-3655, VX-369, VX-102, VX-3532, VX-3655, VX-3, VX-, R1479, INX-08189, PSI-6130, PSI-938, PSI-879, HCV-796, HCV-371, VCH-916, lomibuvir (VCH-222), setobrevir (ANA-598), MK-3281, ABT-333, ABT-072, filibuvir (PF-00868554), deleobrevir (BI-207127), tegobrevir (GS-9190), A-837093, JKT-109, Gl-59728, GL-60667, AZD-2795, TMC647055, or a combination 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.
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
Time (min) A(CH3CN，0.1%HCOOH) B(H2O，0.1%HCOOH)
3-6 100 0
6-6.1 100-5 0-95
6.1-8 5 95
Compound purification was assessed by Agilent1100 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
NMPN-methyl pyrrolidone
mL, 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)Cl2[1,1' -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
Synthesis method 1
Compound 17 can be prepared by synthetic method 1, wherein each X7And X8Independently is a leaving group such as F, Cl, Br, I, OTf, etc., and each R5a，R5a’，f，f’，Y1，Y2，Y1’，Y2’，X3，X5，e，Y4，R14And R16Having a structure as described in the inventionMeaning, Pg is an amino protecting group, such as Boc, Fmoc, Cbz, etc. The compound 1 is reduced under the action of Pd/C hydrogen to obtain a compound 2, the compound 2 undergoes a halogenation reaction to obtain a compound 3, the compound 3 undergoes demethylation to obtain a compound 4, the compound 4 reacts with pinacol diboron under the catalysis of palladium to obtain a compound 5, the compound 5 and a compound 4' undergo a coupling reaction under the catalysis of palladium to obtain a compound 6, the compound 6 reacts with trifluoromethanesulfonic anhydride under an alkaline condition to obtain a compound 7, and the compound 7 reacts with pinacol diboron under the catalysis of palladium to obtain a compound 8. The compound 9 is subjected to reduction reaction under the action of borane to obtain a compound 10, then the compound 11 is obtained under the oxidation of dess-martin, the compound 11 is subjected to cyclization under the action of ammonia water and glyoxal to obtain a compound 12, the compound 12 is reacted with NIS to obtain a compound 13, and one iodine is removed from the compound 13 in a reaction system of sodium sulfite to obtain a compound 14. Carrying out coupling reaction on the compound 14 and the compound 8 under the catalysis of palladium to obtain a compound 15, carrying out deprotection on the compound 15 to obtain a compound 16, and carrying out condensation reaction on the compound 16 and a compound 16-1 to obtain a target compound 17.
Synthesis method 2
Compound 35 can be prepared by synthetic method 2. Wherein each A1，A2And A3Independently selected from N or CR7，X7Is a leaving group of F, Cl, Br, I, OTf, etc., and each R5a，R5a’，f，f’，Y1，Y2，Y2’，X3，e，w，Y4，R14，R16，Y4’，R14aAnd R16aHaving the meaning as described in the present invention, Pg is an amino protecting group such as Boc, Fmoc, Cbz, etc. Halogenating compound 18 to obtain compound 19, removing methyl from compound 19 to obtain compound 20, reacting compound 20 with trifluoromethanesulfonic anhydride under alkaline condition to obtain compound 21, reacting compound 21 with trifluoromethanesulfonic anhydrideThe compound 5 is subjected to coupling reaction under the catalysis of palladium to obtain a compound 22. Deprotection of the compound 14 is carried out to obtain a compound 23, condensation reaction of the compound 23 and the compound 16-1 is carried out to obtain a compound 24, and the compound 24 and pinacol diboron are reacted under the catalysis of palladium to obtain a compound 25. The compound 26 and the compound 9-1 are subjected to condensation reaction to obtain a mixture of compounds 27 and 28, then the mixture is heated and cyclized in an acetic acid system to obtain a compound 29, the compound 29 is deprotected to obtain a compound 30, the compound is further condensed with a compound 16-2 to obtain a compound 31, and the compound 31 is reacted with pinacol diboron under the catalysis of palladium to obtain a compound 32. The compound 25 and the compound 22 are subjected to coupling reaction under the catalysis of palladium to obtain a compound 33, the compound 33 is subjected to reaction with trifluoromethanesulfonic anhydride under alkaline conditions to obtain a compound 34, and the compound 34 and the compound 32 are subjected to coupling reaction under the catalysis of palladium to obtain a target compound 35.
Synthesis method 3
Compound 44 can be prepared by synthetic method 3, wherein X7Is a leaving group of F, Cl, Br, I, OTf, etc., and each R5a，R5a’，f，f’，Y1，Y2，Y1’，Y2’，X3，X5，e，Y4，Y4’，R6a，R14aAnd R16aHaving the meaning as described in the present invention, Pg is an amino protecting group such as Boc, Fmoc, Cbz, etc. The compound 7 and the compound 36 are subjected to coupling reaction under the catalysis of palladium to obtain a compound 37. Performing condensation reaction on a compound 9-1 and a compound 38 under the action of alkali to obtain a compound 39, performing heating cyclization on the compound 39 in an ammonium acetate system to obtain a compound 40, performing reaction on the compound 40 and pinacol diboron under the catalysis of palladium to obtain a compound 41, performing coupling reaction on the compound 41 and a compound 7 under the catalysis of palladium to obtain a compound 42, performing deprotection on the compound 42 to obtain a compound 43, and performing condensation reaction on the compound 43 and a compound 16-2The target compound 44 should be obtained.
Synthesis method 4
Compound 48 can be prepared by synthetic method 4, wherein each R is5a，R5a’，f，f’，Y1，Y2，Y1’，Y2’，X3，X5，e，Y4，Y4’，R14And R16Have the meaning as described in the present invention. The compound 7 and the compound 25 are subjected to coupling reaction under the catalysis of palladium to obtain a compound 45. Reacting the compound 24-1 with TMSA under the catalysis of palladium to obtain a compound 46, removing TMS from the compound 46 under the action of alkali to obtain a compound 47, and performing a coupling reaction between the compound 47 and the compound 45 under the catalysis of palladium to obtain a target compound 48.
Synthesis method 5
Compound 53 can be prepared by synthetic method 5, wherein each R is5a，R5a’，f，f’，Y1，Y2，Y1’，Y2’，X3，X5，e，Y4，Y4’，R14，R16，R14aAnd R16aHaving the meaning as described in the present invention, Pg is an amino protecting group such as Boc, Fmoc, Cbz, etc. Deprotection of compound 49 affords compound 50, which further undergoes condensation reaction with compound 16-2 to afford compound 51. The compound 51 reacts with the pinacol diboron under the catalysis of palladium to obtain a compound 52, and the compound 52 further reacts with the compound 45 under the catalysis of palladium to obtain a target compound 53.
Synthesis method 6
Compound 61 can be prepared by synthetic method 6, wherein X7Is a leaving group of F, Cl, Br, I, OTf, etc., and each R5a，R5a’，f，f’，Y1，Y2，Y1’，Y2’，X3，X5，e，Y4，Y4’，R14，R16，R14aAnd R16aHave the meaning as described in the present invention. The compound 54 reacts under the action of alkali to obtain a compound 55, then reacts in a CDI and ammonia water condition system to obtain a compound 56, the compound 56 and a compound 57 undergo a condensation reaction to obtain a compound 58, the compound 58 undergoes cyclization under the action of alkali to obtain a compound 59, the compound 59 reacts with pinacol ester diboron under the catalysis of palladium to obtain a compound 60, and the compound 60 and the compound 45 undergo further coupling reaction under the catalysis of palladium to obtain a target compound 61.
Synthesis method 7
Compound 71 can be prepared by synthetic method 7, wherein X7Is a leaving group of F, Cl, Br, I, OTf, etc., and each R5a，R5a’，f，f’，Y1，Y2，Y1’，Y2’，X3，X5，e，Y4，Y4’，R14，R16，R14aAnd R16aHaving the meaning as described in the present invention, Pg is an amino protecting group such as Boc, Fmoc, Cbz, etc. Reacting the compound 62 under the action of sodium sulfite to obtain a compound 63, then reacting in a reaction system of thionyl chloride and ammonia water to obtain a compound 64, and reacting the compound 64 under the action of HI to obtain a compound65, reacting the compound 65 with the compound 66 under the action of alkali to obtain a compound 67, deprotecting the compound 67 to obtain a compound 68, condensing the compound 68 with amino acid to obtain a compound 69, reacting the compound 69 with pinacol diboron under the catalysis of palladium to obtain a compound 70, and coupling the compound 70 with the compound 45 under the catalysis of palladium to obtain a target compound 71.
Synthesis method 8
The target compound 77 can be prepared by a synthesis method 8, wherein X7Is a leaving group of F, Cl, Br, I, OTf, etc., and each Y2，R6a，Y4，R14aAnd R16aHaving the meaning as described in the present invention, Pg is an amino protecting group such as Boc, Fmoc, Cbz, etc. The compound 9 and the compound 72 are subjected to condensation reaction to obtain a compound 73, then the compound 73 is heated and cyclized in an ammonium acetate system to obtain a compound 74, the compound 74 is deprotected to obtain a compound 75, and further the compound 75 and the compound 16-2 are subjected to condensation reaction to obtain a compound 76, and the compound 76 and the pinacol diboron are reacted under the catalysis of palladium to obtain a target compound 77.
Examples
Example 1
Synthetic route
Step 1) Synthesis of Compound 1-2
N2Under protection, n-butyllithium (5.0 mL,7.93mmol,1.6M n-hexane solution) was dissolved in freshly distilled THF (20 mL), and a solution of compound 1-1 (1.0 g,7.93 mmol) in THF (10 mL) and I were added dropwise to the solution at-70 ℃ respectively2After dropping THF (15 mL) solution (2.32 g,9.12 mmol), reacting at constant temperature for 20 minutes, slowly heating, adding sodium thiosulfate aqueous solution (3.0 mL, 10%) when the temperature is raised to-60 deg.C, after reaction is completed, slowly adding ammonium chloride aqueous solution (10 mL) to quench the reaction, removing THF, extracting the aqueous phase with n-hexane (50 mL × 3), combining the organic phases, washing with 10% sodium thiosulfate aqueous solution and water respectively, and removing anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 10/1) gave 1.6g of oil, yield: 80 percent.
1H NMR(400MHz,CDCl3):6.79,6.77,6.75(d,dd,d,1H),6.63,6.62,6.60,6.58(s,d,d,s,1H),6.53-6.52,6.51-6.50(m,m,1H)ppm。
Step 2) Synthesis of Compounds 1-3
Magnesium strip (0.15 g,6.35 mmol) was added to the reaction flask, N2Under protection, compound 1-2 (1.6 g,6.35 mmol) in THF solution (20 mL) and freshly distilled cyclopentadiene (0.71 g,10.8 mmol) were added dropwise, the reaction was refluxed for 5 hours, after completion of the reaction, saturated aqueous ammonium chloride solution (50 mL) was added to quench the reaction, the aqueous layer was extracted with diethyl ether (50 mL × 3), the organic phases were combined, washed with 10% aqueous sodium thiosulfate solution, water and saturated aqueous ammonium chloride solution, and washed with anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 15/1) gave 0.75g of oil, yield: and 69 percent.
1H NMR(400MHz,CDCl3):7.10-7.09,7.08-7.07(m,m,1H),6.97,6.95,6.93(s,d,s,1H),6.76,6.74(m,m,1H),6.72-6.66(m,2H),4.31-4.27(m,1H),3.84-3.81(m,1H),3.80(s,3H),2.29-2.25,2.22-2.18(m,m,2H)ppm。
Step 3) Synthesis of Compounds 1-4
Compound 1-3 (0.75 g,4.36 mmol) and Pd/C (75 mg) were suspended in methanol (10 mL), H2Reacting at 50 ℃ for 4.0 hours under protection, removing methanol after reaction is complete, adding water (20 mL), extracting with DCM (25 mL × 3), combining organic phases, washing with saturated brine, and removing anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 15/1) gave 0.64g of a pale yellow solid, yield: 85 percent.
1H NMR(400MHz,CDCl3):7.17,7.15,7.13(s,d,s,1H),6.74-6.73,6.72-6.71(m,m,1H),6.58-6.57,6.56-6.55(m,m,1H),3.88(s,3H),3.56-3.53(m,1H),3.33-3.30(m,1H),1.97-1.86(m,2H),1.80-1.76(m,1H),1.57-1.53(m,1H),1.24-1.13(m,2H)ppm。
Step 4) Synthesis of Compounds 1-5
Compounds 1-4 (0.65 g,3.7 mmol), NIS (0.92 g,4.07 mmol) were suspended in acetonitrile (10 mL) and reacted overnight at 50 deg.C after completion of the reaction, acetonitrile was removed, water (20 mL) was added and extracted with DCM (25 mL × 3), the organic phases were combined, washed with saturated brine, anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE) gave 0.83g of a colorless liquid, yield: 75 percent. MS (ESI, pos.ion) M/z 301.1[ M + H ]]+；
1H NMR(400MHz,CDCl3):7.46,7.44(s,s,1H),6.38,6.36(m,m,1H),3.87(s,3H),3.69-3.66(m,1H),3.45-3.42(m,1H),1.99-1.90(m,2H),1.87-1.83(m,1H),1.64-1.60(m,1H),1.26-1.16(m,2H)ppm。
Step 5) Synthesis of Compounds 1-6
Compound 1-5 (0.83 g,2.77 mmol) was dissolved in DCM (20 mL) at-78 deg.C and then BBr was added dropwise slowly3(0.36 mL,3.88 mmol) and reacting at room temperature for 1.0 h, after the reaction is completed, the reaction solution is slowly poured into ice water (20 mL), the aqueous layer is extracted with DCM (20 mL × 3), and the organic phase is extracted with anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 12/1) gave 0.79g of a colorless liquid, yield: 100 percent.
MS(ESI,pos.ion)m/z:287.3[M+H]+；
1H NMR(400MHz,CDCl3):7.39,7.37(s,s,1H),6.31,6.28(s,s,1H),5.77(brs,1H),3.52-3.46(m,2H),2.05-1.99(m,1H),1.96-1.90(m,1H),1.88-1.84(m,1H),1.65-1.61(m,1H),1.32-1.26(m,1H),1.23-1.17(m,1H)ppm。
Step 6) Synthesis of Compounds 1-7
Mixing compound 1-6 (0.5 g,1.75 mmol), compound 1-6-2 (0.49 g,1.92 mmol) and Pd (dppf) Cl2·CH2Cl2(72 mg,0.087 mmol) and anhydrous potassium acetate (0.43 g,4.37 mmol) in a reaction flask, N2Under protection, anhydrous DMF (5.0 mL) was poured in, the reaction was carried out at 90 ℃ for 2.0 hours, 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 (20 mL × 3) and saturated brine, anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 10/1) gave 0.48g of a white solid, yield: 69.3 percent.
MS(ESI,pos.ion)m/z:397.3[M+H]+；
1H NMR(400MHz,CDCl3):8.00,7.98(s,s,1H),6.94,6.92(s,s,1H),5.77(brs,1H),3.58-3.55(m,1H),3.49-3.46(m,1H),1.99-1.93(m,1H),1.82-1.76(m,2H),1.59-1.55(m,1H),1.32(q,6H),1.29(q,6H),1.26-1.20(m,1H),1.09-1.03(m,1H)ppm。
Step 7) Synthesis of Compounds 1 to 8
Compounds 1-7 (0.45 g,1.14 mmol), compounds 1-6 (0.36 g,1.25 mmol), potassium carbonate (0.39 g,2.84 mmol) and Pd (PPh) were separately added3)4(65.7 mg,0.057 mmol) in a reaction flask, N2DME (8.0 mL) and water (2.0 mL) were separately injected and reacted at 90 ℃ for 12 hours with protection. After the reaction is finishedAfter completion, 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) = 8/1) gave 0.29g of a white solid, yield: 80 percent.
MS(ESI,pos.ion)m/z:319.3[M+H]+；
1H NMR(400MHz,CDCl3):7.10,7.08(s,s,2H),6.55,6.53(s,s,2H),5.77(brs,2H),3.59-3.54(m,2H),3.47-3.43(m,2H),1.99-1.92(m,4H),1.82-1.78(m,2H),1.59-1.55(m,2H),1.26-1.19(m,4H)ppm。
Step 8) Synthesis of Compounds 1-9
Dissolving triethylamine (0.57 mL,4.09 mmol) and compounds 1-8 (0.26 g,0.82 mmol) in DCM (10 mL) at 0 deg.C, stirring for 10 min, adding trifluoromethanesulfonic anhydride (0.39 mL,2.29 mmol) dropwise, reacting at room temperature for 1.0 hr, adding ice water (25 mL) to quench reaction, extracting water layer with DCM (25 mL × 3), combining organic phases, washing with saturated brine, anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE) gave 0.43g of a colorless oily liquid, yield: 90 percent.
1H NMR(400MHz,CDCl3):7.10,7.08(s,s,1H),6.55,6.53(s,s,1H),5.77(brs,2H),3.59-3.54(m,2H),3.47-3.43(m,2H),1.99-1.92(m,4H),1.82-1.78(m,2H),1.59-1.55(m,2H),1.26-1.19(m,4H)ppm。
Step 9) Synthesis of Compounds 1-10
Mixing compound 1-9 (0.4 g,0.69 mmol), compound 1-6-2 (0.37 g,1.44 mmol) with pd (dppf) Cl2·CH2Cl2(28 mg,0.034 mmol) and potassium acetate (0.17 g,1.72 mmol) were placed in a reaction flask, N2DMF (5.0 mL) was added under protection, 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 (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 anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 50/1) gave 0.26g of a white solid, yield: 70 percent.
1H NMR(400MHz,CDCl3):7.61,7.59(s,s,2H),7.44,7.42(s,s,2H),3.76-3.73(m,2H),3.69-3.66(m,2H),1.96-1.90(m,2H),1.80-1.74(m,4H),1.57-1.53(m,2H),1.32,1.29(q,q,24H),1.23-1.17(m,2H),1.07-1.01(m,2H)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,1Min 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 (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 (0.24 g,0.45 mmol), compound 1-16 (0.34 g,0.94 mmol), anhydrous potassium carbonate (0.15 g,1.12 mmol) and Pd (PPh)3)4(25.8 mg,0.023 mmol) was placed in a reaction flask, N2DME (12 mL) and water (3.0 mL) were separately injected and reacted at 90 ℃ for 3.0 hours with protection. Cool to room temperature, dilute the reaction with EtOAc (20 mL), and wash with saturated brine, anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 1/2) gave 0.25g of a white solid, yield: 75 percent.
MS(ESI,pos.ion)m/z:379.4[M+2H]2+；
1H NMR(400MHz,CDCl3):7.90(s,2H),7.39,7.37(s,s,2H),7.26,7.24(s,s,2H),5.05-5.00(m,2H),3.77-3.73(m,4H),3.64-3.58(m,2H),3.31-3.24(m,2H),2.47-2.38(m,2H),2.28-2.17(m,2H),2.10-1.97(m,6H),1.95-1.89(m,2H),1.87-1.83(m,2H),1.64-1.60(m,2H),1.41(s,18H),1.30-1.24(m,2H),1.22-1.16(m,2H)ppm。
Step 16) Synthesis of Compounds 1-18
Compounds 1 to 17 (0.24 g,0.317 mmol) were dissolved in DCM (5.0 mL), and after a solution of hydrogen chloride in ethyl acetate (4.0 mL, 4M) was slowly added dropwise, 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 (10 mL) and filtered to give 214mg of a white solid, yield: 96 percent.
MS(ESI,pos.ion)m/z:557[M+H]+。
Step 17) Synthesis of Compounds 1-19
Will be transformed intoCompounds 1 to 18 (0.2 g,0.29 mmol), compounds 1 to 18-2 (115 mg,0.60 mmol) and EDCI (0.27 g,1.42 mmol) were dissolved in DCM (5.0 mL), DIPEA (0.76 mL,4.27 mmol) was added dropwise slowly at 0 ℃ and, after completion of dropwise addition, the reaction was carried out at room temperature for 3.0 hours. The reaction mixture was diluted with DCM (20 mL), washed with ammonium chloride solution and saturated brine, respectively, and washed with anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: DCM/MeOH (v/v) = 60/1) gave 173mg of a white solid in yield: 70 percent.
MS(ESI,pos.ion)m/z:436.5[M+2H]2+；
1H NMR(400MHz,CDCl3):7.81(s,2H),7.39,7.37(s,s,2H),7.26,7.24(s,s,2H),5.56,5.55(d,d,1H),5.46,5.44(d,d,1H),5.29-5.25(m,2H),4.41-4.37(m,1H),4.34-4.30(m,1H),3.85-3.78(m,2H),3.77-3.73(m,4H),3.66(s,6H),3.65-3.61(m,2H),2.30-2.16(m,6H),2.13-1.89(m,8H),1.87-1.83(m,2H),1.64-1.60(m,2H),1.30-1.24(m,2H),1.22-1.16(m,2H),1.02,1.00(m,m,3H),0.97,0.95(m,m,3H),0.93,0.91(m,m,3H),0.90,0.89(m,m,3H)ppm。
Example 2
The synthetic route is as follows:
step 1) Synthesis of Compound 2-1
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 reacted overnight after completion of the addition. After completion of the reaction, filtration gave 1.2g of a solid, yield: 86.5 percent. Directly used for the next reaction.
MS(ESI,pos.ion)m/z:264.1[M+H]+。
Step 2) Synthesis of Compound 2-2
Compound 2-1 (1.2 g,3.6 mmol), compound 1-18-2 (0.68 g,3.9 mmol) and EDCI (0.75 g,3.9 mmol) were suspended in DCM (20 mL), stirred at 0 ℃ for 5 minutes, and DIPEA (2.38 mL,14.4 mmol) was added dropwise slowly 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 1.31g of a pale yellow foamy 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 2-3
Dissolving compound 2-3-0 (30 g,107.9 mmol) and compound 1-11 (25.5 g,118.7 mmol) in DCM (250 mL), slowly adding DIPEA (21.4 mL,129.5 mmol) dropwise at 0 deg.C, reacting at room temperature for 3.0 hr, quenching with ice water (100 mL), extracting the water layer with EtOAc (100 mL × 3), washing the organic phase with saturated brine, and removing anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 10/1) gave 40.36g of a white solid, yield: 91 percent.
MS(ESI,pos.ion)m/z:412.3[M+H]+；
1H NMR(400MHz,CDCl3):7.78-7.75(m,2H),7.65-7.63(m,2H),5.53-5.15(m,2H),4.49-4.39(m,1H),3.59-3.54(m,1H),3.48-3.38(m,1H),2.31-2.21(m,2H),2.12-2.01(m,1H),1.98-1.85(m,1H),1.45(d,9H)ppm。
Step 4) Synthesis of Compounds 2-4
Suspending compound 2-3 (15 g,36.4 mmol) and ammonium acetate (42 g,54.6 mmol) in toluene (150 mL), reacting at 110 deg.C for 5.0 h, cooling to room temperature after completion of the reaction, quenching the reaction by addition of water (100 mL), extracting the aqueous layer with EtOAc (100 mL × 3), combining the organic phases, washing with saturated brine, anhydrous NaSO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 5/1) gave 12.1g of product, yield: 85 percent.
MS(ESI,pos.ion)m/z:392.3[M+H]+；
1H NMR(400MHz,CDCl3):7.78-7.75(m,2H),7.65-7.63(m,2H),7.21-7.20(m,1H),5.53-5.15(m,2H),4.49-4.39(m,1H),3.59-3.54(m,1H),3.48-3.38(m,1H),2.31-2.21(m,2H),2.12-2.01(m,1H),1.98-1.85(m,1H),1.45(d,9H)ppm。
Step 5) Synthesis of Compounds 2-5
Compound 2-4 (10 g,25.5 mmol) was dissolved in EtOAc (50 mL), and after further addition of a solution of hydrogen chloride in ethyl acetate (60 mL, 4M), the reaction was carried out 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: 86.2 percent.
MS(ESI,pos.ion)m/z:292.2[M+H]+；
1H NMR(400MHz,CDCl3):7.76-7.73(m,2H),7.66-7.63(m,2H),7.21-7.20(m,1H),5.50-5.22(m,2H),4.49-4.39(m,1H),3.61-3.56(m,1H),3.49-3.39(m,1H),2.31-2.21(m,2H),2.12-2.01(m,1H),1.98-1.85(m,1H)ppm。
Step 6) Synthesis of Compounds 2-6
Compound 2-5 (7.01 g,19.26 mmol), compound 1-18-2 (5.06 g,28.88 mmol) and EDCI (5.56 g,28.88 mmol) were dissolved in DCM (100 mL) and DIPEA (21 mL,127 mmol) was slowly added dropwise at 0 ℃ and reacted at room temperature for 3.0 hours. After the reaction is completedWater (100 mL) was added, the aqueous layer was extracted with DCM (100 mL × 3), the organic phases were combined, washed with saturated brine, anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 1/2) gave 7.6g of a solid, yield: 88 percent.
MS(ESI,pos.ion)m/z:450.5[M+H]+；
1H NMR(400MHz,CDCl3):7.65-7.60(m,2H),7.47-7.43(m,2H),7.22-7.20(m,1H),5.67-5.65(m,1H),5.24-5.22(m,1H),4.34-4.30(m,1H),3.85-3.81(m,1H),3.72(s,3H),3.71-3.64(m,1H),3.00(s,1H),2.34-2.11(m,1H),2.21-1.95(m,5H),1.04-1.02(m,1H),0.88-0.86(d,6H)ppm。
Step 7) Synthesis of Compounds 2 to 7
Mixing compound 2-6 (4.99 g,11.13 mmol), compound 1-6-2 (4.24 g,16.7 mmol), Pd (dppf) Cl2·CH2Cl2(0.91 g,1.11 mmol) and KOAc (3.30 g,33.4 mmol) were placed in a reaction flask, N2DMF (50 mL) was injected under the protection, the reaction was carried out at 90 ℃ for 3.0 hours, the reaction mixture was cooled to room temperature after completion, EtOAc (200 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 3.95g of a beige solid with a yield of 71.4%.
1H NMR(400MHz,CDCl3):7.65-7.60(m,2H),7.47-7.43(m,2H),7.22-7.20(m,1H),5.67-5.65(m,1H),5.24-5.22(m,1H),4.34-4.30(m,1H),3.5-3.81(m,1H),3.72(s,3H),3.71-3.64(m,1H),3.00(s,1H),2.34-2.11(m,1H),2.21-1.95(m,5H),1.32-1.45(m,12H),1.04-1.02(m,1H),0.88-0.86(d,6H)ppm。
Step 8) Synthesis of Compounds 2 to 8
Mixing compound 1-9 (0.58 g,1.0 mmol), compound 2-7 (0.5 g,1.0 mmol), Pd (PPh)3)4(0.12 g,0.1 mmol) and potassium carbonate (0.35 g,2.5 mmol) were placed in a reaction flask, and DME (10 mL) was injected separatelyAnd pure water (2 mL), N2Reacting at 90 ℃ for 5.0 hours under protection, cooling to room temperature after reaction is complete, adding water (15 mL) to dilute the reaction solution, extracting the aqueous layer with EtOAc (15 mL × 3), washing the organic phase with saturated brine, and washing with anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: DCM/MeOH (v/v) = 100/1) gave 0.52g of a pale yellow foam, yield: 65 percent.
1H NMR(400MHz,CDCl3):7.62-7.61,7.60-7.59(m,m,3H),7.56-7.55,7.53-7.52(m,m,2H),7.42,7.40(s,s,1H),7.31,7.29(s,s,1H),7.10,7.08(s,s,1H),7.07,7.05(s,s,1H),5.32,5.29(d,d,1H),5.23-5.19(m,1H),4.41-4.37(m,1H),3.92-3.90(m,1H),3.85-3.78(m,1H),3.74-3.71(m,2H),3.69-3.64(m,1H),3.63(s,3H),3.45-3.42(m,1H),2.30-2.15(m,3H),2.13-1.90(m,6H),1.84-1.78(m,2H),1.61-1.55(m,2H),1.30-1.17(m,4H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H)ppm。
Step 9) Synthesis of Compounds 2-9
Mixing compound 2-8 (0.8 g,1.0 mmol), compound 1-6-2 (0.28 g,1.1 mmol), Pd (dppf) Cl2·CH2Cl2(81.7 mg,0.1 mmol) and KOAc (0.25 g,2.5 mmol) were placed in a reaction flask and DMF (3.0 mL), N was injected2The reaction was carried out at 90 ℃ for 5.0 hours under protection, after completion of the reaction, the reaction mixture was cooled to room temperature, EtOAc (30 mL) was added to dilute the reaction mixture, the mixture was filtered through celite, and the filtrate was washed with water (20 mL × 3) and saturated brine, respectively, and then anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 1/2) gave 0.48g of a pale yellow solid, yield: 62 percent.
MS(ESI,pos.ion)m/z:781.8[M+H]+；
1H NMR(400MHz,CDCl3):7.66,7.64(s,s,1H),7.62-7.61,7.60-7.59(m,m,4H),7.58,7.56(s,s,1H),7.55-7.54,7.53-7.52(m,m,2H),7.31,7.29(s,s,1H),5.32,5.29(d,d,1H),5.23-5.19(m,1H),4.41-4.37(m,1H),3.92-3.90(m,1H),3.85-3.78(m,1H),3.75-3.71(m,2H),3.69-3.64(m,1H),3.63(s,3H),2.30-2.15(m,3H),2.13-1.90(m,6H),1.84-1.74(m,3H),1.61-1.53(m,2H),1.32,1.29(q,q,12H),1.27-1.17(m,3H),1.07-1.01(m,1H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H)ppm。
Step 10) Synthesis of Compounds 2-10
Mixing compound 2-9 (0.78 g,1.0 mmol), compound 2-2 (0.43 g,1.02 mmol), Pd (PPh)3)4(0.12 g,0.1 mmol) and potassium carbonate (0.35 g,2.5 mmol) were placed in a reaction flask, and EtOH (10 mL) and pure water (2 mL), N, were injected respectively2Reacting at 90 deg.C for 6.0 hr under protection, cooling to room temperature, adding water (20 mL) to dilute the reaction solution, extracting the aqueous layer with EtOAc (20 mL × 3), washing the organic phase with saturated brine, and washing with anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: DCM/MeOH (v/v) = 50/1) gave 0.52g of a pale yellow solid, yield: and 55 percent.
MS(ESI,pos.ion)m/z:474.6[M+2H]2+；
1H NMR(400MHz,CDCl3):7.81(s,1H),7.62-7.61,7.60-7.59(m,m,3H),7.56-7.55,7.53-7.52(m,m,2H),7.51,7.48(s,s,1H),7.39,7.37(s,s,1H),7.31,7.29(s,s,1H),7.26,7.24(s,s,1H),6.07,6.05(d,d,1H),5.32,5.30(d,d,1H),5.29-5.25(m,1H),5.23-5.19(m,1H),4.41-4.36(m,1H),4.34-4.30(m,1H),3.92-3.90(m,1H),3.85-3.78(m,2H),3.77-3.71(m,3H),3.69-3.66(m,2H),3.65(s,3H),3.63(s,3H),2.30-2.16(m,6H),2.13-1.89(m,8H),1.87-1.80(m,2H),1.64-1.57(m,2H),1.30-1.16(m,4H),1.02,1.00(m,m,3H),0.97,0.95(m,m,3H),0.93,0.91(m,m,3H),0.90,0.89(m,m,3H)ppm。
Example 3
The synthetic route is as follows:
step 1) Synthesis of Compound 3-1
Mixing compound 2-2 (4.2 g,10 mmol), compound 1-6-2 (2.59 g,10.2 mmol), Pd (dppf) Cl2·CH2Cl2(0.82 g,1.0 mmol) and KOAc (2.45 g,25 mmol) were placed in a reaction flask, N2DMF (20 mL) was injected under the protection, the reaction was carried out at 90 ℃ for 3.0 hours, the reaction mixture was cooled to room temperature after completion, EtOAc (200 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 2.73g of a beige solid with a yield of 65%.
1H NMR(400MHz,CDCl3):7.64(s,1H),5.55-5.51(m,1H),5.32,5.29(d,d,1H),4.41-4.37(m,1H),3.78-3.72(m,1H),3.63(s,3H),3.61-3.54(m,1H),2.25-1.87(m,5H),1.39,1.36(q,q,12H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H)ppm。
Step 2) Synthesis of Compound 3-3
Putting aluminum trichloride (90 g,676 mmol) and sodium chloride (25 g,432 mmol) into a reaction bottle, heating to 150 ℃, slowly dripping compound 3-2 (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 3) Synthesis of Compound 3-4
The compound3-3 (5.0 g,33.7 mmol) and 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 4) Synthesis of Compounds 3-5
Compound 3-4 (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 5) Synthesis of Compounds 3-6
Compound 3-5 (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 the residue was dissolved in EtOAc (100 mL), washed with water (50 mL. times.3) and saturated brine, respectively, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent: PE) to give 1.23g of a colorless liquid, yield: and 69 percent.
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 6) Synthesis of Compounds 3-7
Compound 3-6 (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 7) Synthesis of Compounds 3 to 8
Compound 3-7 (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 added2The reaction was carried out overnight at 45 ℃ under protection, after completion of the reaction, the mixture was filtered through celite, the filtrate was concentrated, and the residue was extracted with EtOAc (60 mL × 3) to obtain a mixture, and the organic phases were combined, washed with brine, and driedDried over sodium sulfate, concentrated and purified by column chromatography (eluent: PE/EtOAc (v/v) = 60/1) to give 3.69g of a colorless oil, yield: 78 percent.
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 8) Synthesis of Compounds 3-9
Compound 3-8 (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 ℃ for 50 minutes by adding 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 9) Synthesis of Compounds 3-10
Dissolving the compounds 3-9 (9.92 g,57.0 mmol) in THF (80 mL) and acetonitrile (40 mL), adding NIS (14.2 g,63.0 mmol), stirring for 10 min, adding a catalytic amount of trifluoroacetic acid dropwise, reacting at room temperature for 5.0 h, after the reaction is complete, concentrating the reaction solution, adding EtOAc (200 mL) to the residue, washing with saturated sodium sulfite solution (50 mL × 3), anhydrous Na2SO4Drying, concentrating, and purifying by column chromatography (eluent: PE) to obtain colorless extractLiquid 12.8g, 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 10) Synthesis of Compounds 3-11
Dissolve compound 3-10 (2.16 g,7.2 mmol) in DCM (20 mL) at-78 deg.C, slowly add BBr dropwise3(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 11) Synthesis of Compounds 3-12
Dissolving compound 3-11 (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,8.1 mmol), 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 of。
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 12) Synthesis of Compounds 3-13
Mixing compound 1-7 (0.27 g,0.96 mmol), compound 3-12 (0.40 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 0.19g of a colorless liquid, yield: 45 percent.
1H NMR(400MHz,CDCl3):7.26,7.24(s,s,1H),7.07(m,2H),6.75,6.72(s,s,1H),5.77(brs,1H),4.03-3.96(m,1H),3.58-3.54(m,1H),3.50-3.46(m,1H),3.08-2.97(m,1H),2.81,2.79,2.76,2.74(m,m,m,m,1H),2.56-2.46(m,1H),2.43,2.41,2.39,2.37(m,m,m,m,1H),2.18-2.02(m,2H),1.99-1.92(m,2H),1.82-1.78(m,1H),1.61-1.52(m,2H),1.26-1.19(m,2H)ppm。
Step 13) Synthesis of Compounds 3-14
Mixing compound 3-13 (0.45 g,1.0 mmol), compound 3-1 (0.43 g,1.02 mmol), Pd (PPh)3)4(0.12 g,0.1 mmol) and potassium carbonate (0.35 g,2.5 mmol) were placed in a reaction flask, and DME (5.0 mL) and pure water (1.0 mL), N, were injected, respectively2Reacting at 90 deg.C for 6.0 hr under protection, cooling to room temperature, adding water (20 mL) to dilute the reaction solution, extracting the aqueous layer with EtOAc (20 mL × 3), washing the organic phase with saturated brine, and washing with anhydrous Na2SO4Drying, concentrating, and purifying by column chromatography (eluting)Preparation: DCM/MeOH (v/v) = 100/1) gave 0.3g of light yellow solid, yield: 51 percent.
MS(ESI,pos.ion)m/z:595.7[M+H]+；
1H NMR(400MHz,CDCl3):7.59(s,1H),7.39,7.37(s,s,1H),7.38,7.36(t,t,1H),7.22,7.20(s,s,1H),6.75,6.72(s,s,1H),5.32-5.28(m,2H),4.41-4.30(m,2H),3.85-3.78(m,1H),3.69-3.65(m,1H),3.63(s,3H),3.58-3.54(m,1H),3.50-3.46(m,1H),3.24-3.12(m,1H),2.70-2.57(m,2H),2.30-1.92(m,10H),1.82-1.78(m,1H),1.66-1.55(m,2H),1.26-1.19(m,2H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H)ppm。
Step 14) Synthesis of Compounds 3-15
Pyridine (0.16 mL,2.0 mmol) was added dropwise to a solution of compounds 3 to 14 (0.3 g,0.5 mmol) in DCM (5.0 mL) at 0 ℃ and stirred for 10 minutes, and after dropwise addition, trifluoromethanesulfonic anhydride (0.17 mL,1.0 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 (10 mL), the aqueous layer was quenched with DCM (10 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 0.35g of a colorless oil, yield: 96.4 percent.
1H NMR(400MHz,CDCl3):7.59(s,1H),7.38,7.35(t,t,1H),7.26,7.24(s,s,1H),7.22,7.21(s,s,1H),7.20,7.19(s,s,1H),5.32-5.28(m,2H),4.41-4.30(m,2H),3.88-3.78(m,2H),3.69-3.64(m,1H),3.63(s,3H),3.47-3.44(m,1H),3.24-3.12(m,1H),2.70-2.57(m,2H),2.30-1.92(m,10H),1.82-1.78(m,1H),1.66-1.55(m,2H),1.30-1.19(m,2H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H)ppm。
Step 15) Synthesis of Compounds 3-16
DIPEA (19.5 mL,118 mmol) was added to a solution of compounds 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, compounds 3-16-0 (22.1 g,119 mmol) were 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 product. 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 31.6g of a product, yield: 81 percent.
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 16) Synthesis of Compounds 3-17
Compound 3-16 (4.11 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 (2.76 g,28.17 mmol) were 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 (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 3.02g of a beige solid with a yield of 65%.
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 17) Synthesis of Compounds 3-18
Compounds 3 to 17 (0.58 g,1.4 mmol) were dissolved in EtOAc (5.0 mL), and after adding a solution of hydrogen chloride in ethyl acetate (5 mL, 4M), the reaction was carried out at room temperature for 8.0 hours. After completion of the reaction, the reaction was concentrated, and the residue was slurried with EtOAc (10 mL) and filtered to give 0.49g of a pale yellow solid, yield: 91 percent.
MS(ESI,pos.ion)m/z:314.2[M+H]+。
Step 18) Synthesis of Compounds 3-19
Compound 3-18 (1.0 g,2.6 mmol), compound 3-18-2 (0.59 g,3.1 mmol), EDCI (0.55 g,2.86 mmol) and HOAT (0.35 g,2.6 mmol) were suspended in DCM (15 mL), DIPEA (1.72 mL,10.4 mmol) was slowly added dropwise at 0 ℃ and, after completion of dropwise addition, reacted at room temperature for 3.0 hours. After completion of the reaction, DCM (40 mL) was added to dilute the reaction solution, washed with an aqueous ammonium chloride solution and a saturated aqueous sodium chloride solution, respectively, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE/EtOAc (v/v) = 1/2) to obtain 1.17g of a white solid, yield: 93 percent.
MS(ESI,pos.ion)m/z:485.4[M+H]+；
1H NMR(400MHz,CDCl3):10.62(brs,1H),8.22(m,1H),7.73-7.65(m,2H),5.72(d,1H,J=8.0Hz),5.43(d,1H,J=8.0Hz),4.35-4.31(m,1H),3.95-3.88(m,1H),3.78-3.75(m,1H),3.69-3.67(m,4H),3.08-3.04(m,1H),2.43-2.37(m,1H),2.25-2.15(m,2H),1.91(s,1H),1.74-1.72(m,1H),1.52-1.50(m,1H),1.35(s,12H),1.24(t,2H,J=8.0Hz),1.12-1.10(m,1H),0.93-0.88(m,1H)ppm。
Step 19) Synthesis of Compounds 3-20
Mixing compound 3-19 (0.48 g,1.0 mmol), compound 3-15 (0.53 g,1.0 mmol), Pd (PPh)3)4(0.12 g,0.1 mmol) and potassium carbonate (0.35 g,2.5 mmol) were placed in a reaction flask, and DME (5.0 mL) and pure water (1.0 mL), N, were injected, respectively2Reacting at 90 deg.C for 6.0 hr under protection, cooling to room temperature, adding water (20 mL) to dilute the reaction solution, extracting the aqueous layer with EtOAc (20 mL × 3), washing the organic phase with saturated brine, and washing with anhydrous Na 2SO4Drying, concentration and purification by column chromatography (eluent: DCM/MeOH (v/v) = 50/1) gave 0.42g of a pale yellow solid, yield: 45 percent.
MS(ESI,pos.ion)m/z:468.6[M+2H]2+；
1H NMR(400MHz,CDCl3):7.69,7.67(s,s,1H),7.62-7.61,7.60-7.59(m,m,2H),7.59(s,1H),7.48,7.46(s,s,1H),7.41,7.40(t,t,1H),7.23,7.21(d,d,1H),7.20,7.19(s,s,1H),5.39,5.36(d,d,1H),5.32-5.28(m,2H),5.13-5.09(m,1H),4.46-4.30(m,3H),3.93-3.90(m,1H),3.85-3.76(m,3H),3.69-3.64(m,2H),3.63(s,6H),3.24-3.12(m,1H),2.70-2.57(m,2H),2.42-2.34(m,1H),2.30-1.86(m,14H),1.84-1.80(m,1H),1.66-1.49(m,3H),1.27-1.10(m,3H),0.98-0.95(m,6H),0.92-0.89(m,6H)ppm。
Example 4
The synthetic route is as follows:
step 1) Synthesis of Compound 4-2
Thionyl chloride (5.5 mL,75.8 mmol) was slowly added dropwise to a solution of compound 4-1 (10 g,77.5 mmol) in MeOH (50mL) at 0 ℃ for 1.0 hour at a constant temperature, and then reacted at room temperature for 2.0 hours. After the reaction is complete, NaHCO is added3The reaction was quenched with solution (50mL), methanol was removed, the residue was extracted with DCM (35 mL × 3), the organic phases were combined, washed with saturated brine, anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: EtOAc) gave 7.5g of a colorless liquid, yield: 67.6 percent.
MS(ESI,pos.ion)m/z:144.2[M+H]+；
1H NMR(400MHz,CDCl3):7.38(br,1H),4.20-4.16(m,1H),3.67(s,3H),2.39-2.23(m,3H),2.14-2.07(m,1H)ppm。
Step 2) Synthesis of Compound 4-3
DMAP (0.55 g,4.5 mmol) was added to a solution of compound 4-2 (6.45 g,45.06 mmol) in MeCN (30 mL) at 0 ℃ and stirred for 10 minutes, and after dropwise addition, di-tert-butyl dicarbonate (10.82 g,49.56 mmol) was added thereto, followed by isothermal reaction for 30 minutes and reaction at room temperature for 2.0 hours. After completion of the reaction, the concentrated reaction solution was purified by column chromatography (eluent: PE/EtOAc (v/v) = 1/1) to obtain 5.0g of a colorless liquid, yield: 45.6 percent.
MS(ESI,pos.ion)m/z:144.2[M-BOC]+；
1H NMR(400MHz,CDCl3):4.60-4.57(m,1H),3.75(s,3H),2.65-2.55(m,1H),2.50-2.42(m,1H),2.36-2.24(m,1H),2.04-1.96(m,1H),1.45(s,9H)ppm。
Step 3) Synthesis of Compound 4-4
Lithium triethylborohydride (1.79 g,16.9mmol,1M in THF) was slowly added dropwise to a solution of compound 4-3 (3.74 g,15.4 mmol) in toluene (50mL) at-78 deg.C, followed by addition of DIPEA (3.2 mL,19.4 mmol), DMAP (0.19 g,1.54 mmol) and TFAA (3 mL,40.4 mmol) sequentially after reaction at constant temperature for 70 minutes, and after completion of the addition, the reaction was carried out at room temperature for 2.0 hours. After the reaction is complete, saturated NH is added4The reaction was quenched with Cl solution (15 mL), the aqueous layer was extracted with EtOAc (30 mL × 3), the organic phases were combined and dried over anhydrous Na2SO4Drying, concentration of the reaction solution and purification by column chromatography (eluent: PE/EtOAc (v/v) = 10/1) gave 2.26g of yellow liquid, yield: 64.8 percent. MS (ESI, pos.ion) M/z 128.2[ M-BOC]+；
1H NMR(400MHz,CDCl3):6.65-6.52(br,1H),4.96-4.91(br,1H),4.68-4.57(m,1H),3.76(s,3H),3.12-3.00(m,1H),2.71-2.61(m,1H),1.49-1.44(br,9H)ppm。
Step 4) Synthesis of Compounds 4-5
Chlorodomethane (1.40 g,7.9 mmol) was slowly added dropwise to a toluene (6 mL) solution of diethylzinc (0.49 g,3.94 mmol) at 0 ℃ for 45 minutes, and after completion of the reaction, a toluene (4 mL) solution of compound 4-4 (0.3 g,1.32 mmol) was added dropwise, followed by a constant temperature reaction for 18 hours. After the reaction is complete, saturated NH is added4The reaction was quenched with Cl solution (15 mL), the aqueous layer was extracted with EtOAc (25 mL × 3), the organic phases were combined and dried over anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 10/1) gave 0.19g of yellow liquid, yield: and (7) percent.
MS(ESI,pos.ion)m/z:142.2[M-BOC]+；
1H NMR(400MHz,CDCl3):4.64-4.51(m,1H),3.70(s,3H),3.56-3.45(m,1H),2.64-2.54(m,1H),2.05-2.01(m,1H),1.50,1.41(s,s,9H),0.75-0.65(m,3H)ppm。
Step 5) Synthesis of Compounds 4-6
Slowly adding lithium hydroxide monohydrate (0.89 g,21.2 mmol) water solution (10 mL) into THF (20 mL) solution of compound 4-5 (1.02 g,4.23 mmol) at 0 ℃, after dripping, reacting at 40 ℃ for 12 hours, removing THF after reaction is completed, adding water (10 mL), extracting with EtOAc (25 mL × 3), adjusting pH of water layer to 1 with hydrochloric acid (10%) after liquid separation, extracting with EtOAc (25 mL × 3), combining organic phases, washing with saturated brine, anhydrous Na2SO4Drying and concentration gave 0.84g of a white solid, yield: 87.5 percent.
MS(ESI,neg.ion)m/z:226.2[M-H]-；
1H NMR(400MHz,CD3OD):4.53-4.46(m,1H),3.48-3.42(m,1H),2.70-2.57(m,1H),2.05-2.01(m,1H),1.60-1.54(m,1H),1.48,1.41(s,s,9H),0.89-0.80(m,1H),0.73-0.66(m,1H)ppm。
Step 6) Synthesis of Compounds 4-7
DIPEA (1.95 mL,11.8 mmol) was added to a solution of compound 4-6 (2.43 g,10.7 mmol) and compound HATU (4.88 g,12.84 mmol) in THF (25 mL) at 0 deg.C, reacted at constant temperature for 0.5 hour, then compound 3-16-0 (2.21 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 by addition of water (50mL), THF was removed, the aqueous layer was extracted with EtOAc (50 mL. times.3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a residue which 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 (100mL), washed with sodium carbonate solution (50mL × 3), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE/EtOAc (v/v) = 1/2) to give 2.02g of the product, yield: 50 percent.
MS(ESI,pos.ion)m/z:378.3[M+H]+；
1H NMR(400MHz,CDCl3):7.67(dd,1H),7.22,7.20(d,d,1H),7.19,7.17(d,d,1H),5.03-5.00(m,1H),3.31-3.24(m,1H),2.56-2.49(m,1H),2.12-2.07(m,1H),1.53-1.48(m,1H),1.46(s,9H),1.42-1.38(m,1H),1.00-0.97(m,1H)ppm。
Step 7) Synthesis of Compounds 4 to 8
Compound 4-7 (1.03 g,2.74 mmol) was dissolved in EtOAc (5.0 mL), and after dropping a solution of hydrogen chloride in ethyl acetate (6.0 mL, 4M) at 0 ℃ was reacted at room temperature for 8.0 hours. After completion of the reaction, the reaction solution was concentrated, and the residue was added with EtOAc (10 mL), stirred and slurried, and filtered to obtain a pale yellow solid 0.82g, yield: 85.5 percent.
MS(ESI,pos.ion)m/z:278.2[M+H]+。
Step 8) Synthesis of Compounds 4-9
Compound 4-8 (0.66 g,1.88 mmol), compound 1-18-2 (0.49 g,2.82 mmol) and EDCI (0.54 g,2.82 mmol) were suspended in DCM (10 mL) and DIPEA (1.86 mL,11.28 mmol) was added dropwise at 0 ℃ and the reaction was carried out at room temperature for 3.0 hours. After the reaction is finishedAfter completion, DCM (50mL) was added to dilute the reaction solution, and the reaction solution was washed with water (20 mL × 3) and saturated brine, respectively, anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 1/2) gave 0.69g of a solid, yield: 85 percent.
MS(ESI,pos.ion)m/z:435.3[M+H]+；
1H NMR(400MHz,CDCl3):7.67(dd,1H),7.22,7.20(d,d,1H),7.19,7.17(d,d,1H),5.32,5.30(d,d,1H),5.16-5.12(m,1H),4.13-4.08(m,1H),3.63(s,3H),3.42-3.36(m,1H),2.62-2.55(m,1H),2.21-2.09(m,2H),1.53-1.45(m,1H),0.97-0.89(m,7H),0.50-0.46(m,1H)ppm。
Step 9) Synthesis of Compounds 4-10
Compound 4-9 (3.08 g,7.1 mmol), compound 1-6-2 (2.72 g,10.7 mmol), Pd (dppf) Cl2·CH2Cl2(0.57 g,0.7 mmol) and KOAc (2.09 g,21.3 mmol) were placed in a reaction flask, N2DMF (30 mL) was injected under the protection, 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 (50mL × 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 2.22g of a beige solid with a yield of 65%.
MS(ESI,pos.ion)m/z:483.5[M+H]+；
1H NMR(400MHz,CDCl3):7.82(dd,1H),7.65,7.63(d,d,1H),7.45,7.42(d,d,1H),5.32,5.30(d,d,1H),5.16-5.12(m,1H),4.13-4.08(m,1H),3.63(s,3H),3.42-3.36(m,1H),2.62-2.55(m,1H),2.22-2.09(m,2H),1.53-1.45(m,1H),1.32,1.29(m,12H),0.97-0.89(m,7H),0.50-0.46(m,1H)ppm。
Step 10) Synthesis of Compounds 4-11
Mixing compound 4-10 (0.24 g,0.5 mmol), compound 1-9 (0.29 g,0.5 mmol), Pd (PPh)3)4(58 mg,0.05 mmol) andpotassium carbonate (0.17 g,1.25 mmol) was placed in a reaction flask, N2DME (6 mL) and pure water (2 mL) were separately injected under the protection, and the mixture was reacted at 90 ℃ for 3.0 hours, after completion of the reaction, the reaction mixture was cooled to room temperature, and EtOAc (40 mL) was added to dilute the reaction mixture, which was then 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 0.28g of a pale yellow solid, yield: 71 percent.
1H NMR(400MHz,CDCl3):7.62,7.60(d,d,1H),7.53-7.49(m,2H),7.41,7.38(s,s,1H),7.32(m,1H),7.10,7.08(s,s,1H),7.07,7.05(s,s,1H),5.32,5.30(d,d,1H),5.14-5.10(m,1H),4.13-4.08(m,1H),3.79-3.74(m,2H),3.73-3.71(m,1H),3.63(s,3H),3.45-3.36(m,2H),2.62-2.55(m,1H),2.22-2.11(m,2H),2.03-1.90(m,4H),1.84-1.78(m,2H),1.61-1.55(m,2H),1.53-1.45(m,1H),1.30-1.17(m,4H),0.97,0.95(m,m,3H),0.95-0.91(m,1H),0.90,0.88(m,m,3H),0.50-0.46(m,1H)ppm。
Step 11) Synthesis of Compounds 4-12
Mixing compound 4-11 (0.39 g,0.5 mmol), compound 3-1 (0.21 g,0.5 mmol), Pd (PPh)3)4(58 mg,0.05 mmol) and potassium carbonate (0.17 g,1.25 mmol) were placed in a reaction flask, and DME (5.0 mL) and pure water (1.0 mL), N, were injected, respectively2Reacting at 90 deg.C for 6.0 hr under protection, cooling to room temperature, adding water (20 mL) to dilute the reaction solution, extracting the aqueous layer with EtOAc (20 mL × 3), washing the organic phase with saturated brine, and washing with anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: DCM/MeOH (v/v) = 50/1) gave 0.15g of a pale yellow solid, yield: 32 percent.
MS(ESI,pos.ion)m/z:467.6[M+2H]2+；
1H NMR(400MHz,CDCl3):7.81(s,1H),7.62,7.59(d,d,1H),7.53,7.51(d,d,1H),7.50,7.49(s,s,1H),7.48,7.46(s,s,1H),7.39,7.37(s,s,1H),7.32(m,1H),7.26,7.24(s,s,1H),5.32,5.30(m,m,2H),5.29-5.25(m,1H),5.14-5.10(m,1H),4.41-4.36(m,1H),4.13-4.08(m,1H),3.85-3.73(m,5H),3.68-3.65(m,1H),3.63(s,6H),3.42-3.36(m,1H),2.62-2.55(m,1H),2.30-1.89(m,11H),1.87-1.80(m,2H),1.64-1.57(m,2H),1.53-1.45(m,1H),1.30-1.16(m,4H),0.97,0.95(m,m,6H),0.94-0.91(m,1H),0.90,0.88(m,m,6H),0.50-0.46(m,1H)ppm。
Example 5
The synthetic route is as follows:
step 1) Synthesis of Compound 5-1
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 5-2
Compound 5-1 (5.0 g,26.6 mmol) was reacted with sodium acetate (6.54 g,79.7 mmol) in methanol (100mL) 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 5-3
Compound 5-2 (4.0 g,21.3 mmol) and palladium on carbon (0.4 g) were suspended in methanol (50mL) 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 5-4
Pyridine (9.0 g,114 mmol) was added dropwise to a solution of compound 5-3 (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 was quenched by addition of ice water (50mL), the aqueous layer was extracted with DCM (50mL × 3), the organic phases were combined, 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 5-5
Compound 5-4 (7.99 g,17.6 mmol), compound 1-7 (5.15 g,18.0 mmol), tetrakistriphenylphosphine palladium (1.02 g,0.88 mmol) and potassium carbonate (9.73 g,70.4 mmol) were suspended in DME/H2O (v/v = 3/1) in a mixed solvent (80 mL) at 90 ℃ for 3 hours under nitrogen protection. Reaction ofAfter completion, 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 give 4.08g of a white solid, yield: 50 percent.
MS(ESI,pos.ion)m/z:465.5[M+H]+；
1H NMR(400MHz,CDCl3):7.14,7.12(s,s,1H),7.07,7.05(s,s,1H),7.04,7.02(s,s,1H),6.58,6.56(s,s,1H),5.77(brs,1H),3.59-3.54(m,1H),3.45-3.40(m,1H),3.23-3.13(m,1H),2.78-2.69(m,1H),1.99-1.78(m,5H),1.62-1.49(m,5H),1.30-1.19(m,4H)ppm。
Step 6) Synthesis of Compounds 5-6
Pyridine (1.22 mL,15.2 mmol) was added dropwise to a solution of compound 5-5 (1.76 g,3.8 mmol) in DCM (10 mL) at 0 ℃ and stirred for 10 minutes, and after that, trifluoromethanesulfonic anhydride (1.3 mL,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) = 1/2) to give 1.81g of a colorless oil, yield: 80 percent.
1H NMR(400MHz,CDCl3):7.14,7.12(s,s,1H),7.10,7.08(s,s,1H),7.06,7.04(s,s,1H),7.00,6.98(s,s,1H),3.74-3.71(m,1H),3.41-3.38(m,1H),3.23-3.13(m,1H),2.78-2.69(m,1H),2.03-1.78(m,5H),1.62-1.49(m,5H),1.30-1.19(m,4H)ppm。
Step 7) Synthesis of Compounds 5-7
Mixing 5-6 (1.19 g,2.0 mmol), 1-6-2 (1.07 g,4.2 mmol), Pd (dppf) Cl2·CH2Cl2(82 mg,0.1 mmol) and KOAc (0.49 g, 5mmol) were mixed in a reaction flask, and DMF (10 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, EtOAc (100mL) was added to dilute the reaction mixture, the mixture was filtered through Celite, and the filtrate wasWashed with water (50mL × 3) and brine, anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 1/3) gave 0.44g of a pale yellow solid, yield: 40 percent.
1H NMR(400MHz,CDCl3):7.68,7.65(s,s,1H),7.62,7.60(s,s,1H),7.42,7.40(s,s,1H),7.38,7.36(s,s,1H),3.70-3.67(m,2H),3.20-3.03(m,2H),1.96-1.90(m,1H),1.80-1.74(m,2H),1.69-1.58(m,2H),1.57-1.53(m,1H),1.46-1.33(m,4H),1.32,1.29(q,q,24H),1.23-1.17(m,1H),1.14-1.01(m,3H)ppm。
Step 8) Synthesis of Compounds 5-9
Dissolving compounds 5-8 (6.86 g,27.97 mmol) in DCM (70 mL), adding dess-martin reagent (23.7 g,56 mmol) in portions to the reaction system at 0 deg.C, reacting at room temperature for 7.0 h after the addition is finished, quenching the reaction with aqueous solution of sodium thiosulfate (100mL) after the reaction is finished, filtering with kieselguhr, extracting the filtrate with DCM (100mL × 3), combining organic phases, anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 6/1) gave 5.78g of a pale yellow liquid, yield: 85 percent.
Step 9) Synthesis of Compounds 5-10
Dissolve compound 5-9 (5.81 g,23.9 mmol) in DCM (70 mL) and Et at-78 deg.C2NSF3(4.85 mL,35.9 mmol) was slowly dropped into the system, after dropping, the reaction was carried out at a constant temperature for 2.0 hours, then the reaction was carried out at room temperature for 19 hours, after completion of the reaction, the reaction was quenched with an aqueous ammonium chloride solution (50mL), the aqueous layer was extracted with DCM (100mL × 3), the organic phases were combined, and anhydrous Na was added2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 20/1) gave 5.0g of a pale yellow liquid, yield: 79 percent.
MS(ESI,pos.ion)m/z:266.3[M+H]+；
1H NMR(400MHz,CDCl3):9.60(brs,1H),4.60-4.57,4.94-4.72(m,m,1H),3.93-3.84(m,2H),3.77(s,3H),2.78-2.48(m,2H),1.44(d,9H,J=16Hz)ppm。
Step 10) Synthesis of Compounds 5-11
Dissolving compound 5-10 (5.0 g,18.86 mmol) in THF (40 mL), adding aqueous lithium hydroxide solution (1.5 g,20 mL) at 0 deg.C, reacting at room temperature for 2.0 hr, adjusting pH of the reaction solution to 5 with dilute hydrochloric acid (1M), removing THF, adjusting pH of the aqueous layer to 2 with dilute hydrochloric acid (1M), extracting with EtOAc (80 mL × 3), combining the organic phases, washing with saturated brine, and washing with anhydrous Na2SO4Drying and concentration gave 4.54g of a white solid, yield: 94 percent.
MS(ESI,pos.ion)m/z:252.3[M+H]+；
1H NMR(400MHz,CDCl3):9.60(brs,1H),4.60-4.57,4.94-4.72(m,m,1H),3.89-3.74(m,2H),2.78-2.48(m,2H),1.44(d,9H,J=16Hz)ppm。
Step 11) Synthesis of Compounds 5-12
Compound 5-11 (2.37 g,9.43 mmol) was dissolved in THF (30 mL), borane-tetrahydrofuran solution (14.2 mL, 1M) was added dropwise at 0 ℃ and the reaction was carried out 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 (100mL), washed with water (40 mL × 3) and saturated brine, respectively, and dried over Na2SO4Drying and concentration gave 1.79g of a colorless oil, yield: 80 percent.
1H NMR(400MHz,CDCl3):4.43-4.27(m,1H),3.59-3.34(m,2H),3.60-3.46(m,2H),2.48-2.18(m,2H),1.44(d,9H,J=16Hz)ppm。
Step 12) Synthesis of Compounds 5-14
Compound 5-12 (1.8 g,7.59 mmol) was dissolved in DCM (20 mL), TCCA (1.77 g,7.59 mmol) was added to the system at 0 deg.C, followed by addition of TEMPO solution in DCM (0.12 g,0.76mmol,5.0 mL) dropwise, and after completion of the addition, the reaction was allowed to proceed at constant temperature for 1.0 hour, and the reaction was left in the chamberThe reaction was warmed for 1.0 hour, after completion of the reaction, the solid was removed by filtration, and the filtrate was washed with saturated sodium sulfite solution (40 mL × 3), anhydrous Na2SO4Drying, concentrating, dissolving the residue in ammonia methanol (20 mL, 7M), reacting at 0 deg.C for 0.5 hr, reacting at room temperature for 1.0 hr, cooling to 0 deg.C again, adding aqueous solution of glyoxal (2.0 mL, 40%), reacting at room temperature for 24 hr, concentrating the reaction solution, dissolving the residue with DCM (150 mL), washing with water (50mL × 3) and saturated saline, and washing with anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: DCM/MeOH (v/v) = 60/1) gave 1.04g of a pale yellow solid, yield: 50 percent.
MS(ESI,pos.ion)m/z:274.3[M+H]+；
1H NMR(400MHz,CDCl3):7.00(s,2H),5.83-5.80(m,1H),4.05-3.79(m,1H),3.74-3.52(m,1H),3.11-2.33(m,2H),1.51(s,9H)ppm。
Step 13) Synthesis of Compounds 5-15
Dissolving compounds 5-14 (0.93 g,3.4 mmol) in DCM (30 mL), adding NIS (1.7 g,7.5 mmol) into the system at 0 deg.C in batches, reacting at constant temperature for 2.0 hr after the addition is finished, filtering after the reaction is finished, washing the filtrate with saturated sodium sulfite solution (50mL × 3), and adding anhydrous Na2SO4Drying and concentration gave 1.07g of a yellow solid, yield: 60 percent. Directly used for the next reaction.
MS(ESI,pos.ion)m/z:526.1[M+H]+；
1H NMR(400MHz,CDCl3):5.13-5.08(m,1H),3.91-3.87(m,1H),3.58-3.46(m,2H),2.74-2.72(m,1H),1.51(s,9H)ppm。
Step 14) Synthesis of Compounds 5-16
Compound 5-15 (1.03 g,1.96 mmol) was dissolved in EtOH (10 mL), and sodium sulfite (2.47 g,19.6 mmol) and water (10 mL) were added to react at 90 ℃ for 30 hours. After the reaction is completed, filtering and concentratingThe filtrate was concentrated, and the residue was dissolved in DCM (80 mL), washed with water and saturated brine, respectively, and dried over anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 6/1) gave 0.26g of a white solid, yield: 33 percent.
MS(ESI,pos.ion)m/z:400.2[M+H]+；
1H NMR(400MHz,CDCl3):7.08(s,1H),5.33-4.95(m,1H),3.91-3.87(m,1H),3.78-3.36(m,2H),2.96-2.55(m,1H),1.49(s,9H)ppm。
Step 15) Synthesis of Compounds 5-17
A solution of hydrogen chloride in ethyl acetate (5mL, 4M) was added dropwise to a solution of compound 5-16 (0.80 g,2.0 mmol) in EtOAc (4.0 mL) at room temperature, and the reaction was allowed to proceed overnight after dropwise addition. After completion of the reaction, filtration gave 0.33g of solid, yield: 90 percent. Directly used for the next reaction.
MS(ESI,pos.ion)m/z:399.1[M+H]+。
Step 16) Synthesis of Compounds 5-18
After suspending compound 5-17 (1.34 g,3.6 mmol), compound 1-18-2 (0.68 g,3.9 mmol) and EDCI (0.75 g,3.9 mmol) in DCM (10 mL) and stirring at 0 ℃ for5 minutes, DIPEA (2.38 mL,14.4 mmol) was added dropwise slowly and the reaction was carried out 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 1.41g of a pale yellow solid, yield: 86 percent.
MS(ESI,pos.ion)m/z:457.3[M+H]+；
1H NMR(400MHz,CDCl3):7.42(s,1H),5.56,5.55(d,d,1H),5.11-5.06(m,1H),4.32-4.28(m,1H),4.21-4.19,4.17-4.15,4.13-4.11,4.09-4.07(m,m,m,m,1H),3.94-3.93,3.91-3.89,3.87-3.84,3.82-3.81(m,m,m,m,1H),3.66(s,3H),2.93-2.75(m,1H),2.54-2.34(m,1H),2.28-2.16(m,1H),1.02,1.00(m,m,3H),0.93,0.91(m,m,3H)ppm。
Step 17) Synthesis of Compounds 5-19
Mixing compound 5-18 (0.23 g,0.5 mmol), compound 5-7 (0.28 g,0.5 mmol), Pd (PPh)3)4(58 mg,0.05 mmol) and potassium carbonate (0.17 g,1.25 mmol) were placed in a reaction flask, and DME (5.0 mL) and pure water (1.0 mL), N, were injected, respectively2Reacting at 90 deg.C for 6.0 hr under protection, cooling to room temperature, adding water (20 mL) to dilute the reaction solution, extracting the aqueous layer with EtOAc (20 mL × 3), washing the organic phase with saturated brine, and washing with anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: DCM/MeOH (v/v) = 50/1) gave 0.19g of a pale yellow solid, yield: 40 percent.
MS(ESI,pos.ion)m/z:479.5[M+2H]2+；
1H NMR(400MHz,CDCl3):7.99(s,1H),7.60(s,1H),7.39,7.36(s,s,1H),7.32,7.30(s,s,1H),7.26,7.24(s,s,1H),6.81,6.79(s,s,1H),5.32,5.29(d,d,2H),5.20-5.15(m,2H),4.48-4.43(m,2H),4.21-4.19,4.17-4.15,4.13-4.11,4.09-4.07(m,m,m,m,2H),3.94-3.93,3.91-3.89,3.87-3.84,3.82-3.81(m,m,m,m,2H),3.77-3.74(m,1H),3.70-3.67(m,1H),3.63(s,6H),3.48-3.38(m,2H),2.92-2.74(m,2H),2.52-2.31(m,2H),2.23-2.11(m,2H),2.03-1.97(m,1H),1.95-1.89(m,1H),1.87-1.83(m,1H),1.71-1.50(m,5H),1.38-1.16(m,6H),0.97,0.95(m,m,6H),0.90,0.89(m,m,6H)ppm。
Example 6
The synthetic route is as follows:
step 1) Synthesis of Compound 6-1
Mixing compound 1-9 (0.58 g,1.0 mmol), compound 3-17 (0.41 g,1.0 mmol), Pd (PPh)3)4(0.12 g,0.1 mmol) and potassium carbonate (0.35 g,2.5 mmol) were placed in a reaction flask, and DME (5.0 mL) and pure water (1.0 mL), N, were injected, respectively2Reacting at 90 deg.C for 5.0 hr under protection, cooling to room temperature, adding water (20 mL) to dilute the reaction solution, extracting the aqueous layer with EtOAc (20 mL × 3), washing the organic phase with saturated brine, and washing with anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: DCM/MeOH (v/v) = 100/1) gave 0.32g of a pale yellow foam, yield: 45 percent.
1H NMR(400MHz,CDCl3):7.62-7.61,7.60-7.59(m,m,2H),7.51,7.49(s,s,1H),7.41,7.38(s,s,1H),7.23,7.21(d,d,1H),7.10,7.08(s,s,1H),7.07,7.05(s,s,1H),5.04-4.99(m,1H),3.82-3.71(m,4H),3.64-3.57(m,1H),3.45-3.42(m,1H),2.63-2.53(m,1H),2.47-2.35(m,1H),2.25-2.15(m,1H),2.04-1.90(m,5H),1.84-1.78(m,2H),1.61-1.55(m,2H),1.53(s,9H),1.30-1.17(m,4H)ppm。
Step 2) Synthesis of Compound 6-2
Mixing compound 6-1 (0.72 g,1.0 mmol), compound 1-6-2 (0.28 g,1.1 mmol), Pd (dppf) Cl2·CH2Cl2(82 mg,0.1 mmol) and KOAc (0.25 g,2.5 mmol) were placed in a reaction flask and DMF (5.0 mL), N2The reaction was carried out at 90 ℃ for 5.0 hours under protection, after completion of the reaction, the reaction mixture was cooled to room temperature, EtOAc (30 mL) was added to dilute the reaction mixture, the mixture was filtered through celite, and the filtrate was washed with water (20 mL × 3) and saturated brine, respectively, and then anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 1/2) gave 0.35g of a pale yellow solid, yield: 50 percent.
MS(ESI,pos.ion)m/z:698.7[M+H]+；
1H NMR(400MHz,CDCl3):7.66,7.64(s,s,1H),7.62-7.61,7.60-7.59(m,m,3H),7.55,7.53(s,s,1H),7.50-7.48(s,s,1H),7.23,7.21(d,d,1H),5.04-4.99(m,1H),3.82-3.73(m,4H),3.69-3.66(m,1H),3.64-3.57(m,1H),2.63-2.53(m,1H),2.47-2.35(m,1H),2.25-2.15(m,1H),2.04-1.90(m,5H),1.84-1.74(m,2H),1.61-1.55(m,2H),1.53(s,9H),1.32,1.29(q,q,12H),1.26-1.17(m,3H),1.07-1.01(m,1H)ppm。
Step 3) Synthesis of Compound 6-3
Mixing compound 6-2 (0.70 g,1.0 mmol), compound 1-16 (0.37 g,1.02 mmol), Pd (PPh)3)4(0.12 g,0.1 mmol) and potassium carbonate (0.35 g,2.5 mmol) were placed in a reaction flask, and EtOH (5.0 mL) and pure water (1.0 mL), N, were injected, respectively2Reacting at 90 deg.C for 6.0 hr under protection, cooling to room temperature, adding water (20 mL) to dilute the reaction solution, extracting the aqueous layer with EtOAc (20 mL × 3), washing the organic phase with saturated brine, and washing with anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: DCM/MeOH (v/v) = 80/1) gave 0.36g of a pale yellow solid, yield: 45 percent.
MS(ESI,pos.ion)m/z:808.1[M+H]+；
1H NMR(400MHz,CDCl3):7.90(s,1H),7.62-7.61,7.60-7.59(m,m,2H),7.51,7.49(s,s,1H),7.48,7.46(s,s,1H),7.39,7.37(s,s,1H),7.26,7.24(s,s,1H),7.23,7.21(d,d,1H),5.05-4.99(m,2H),3.82-3.73(m,5H),3.64-3.57(m,2H),3.31-3.24(m,1H),2.63-2.53(m,1H),2.47-2.35(m,2H),2.29-2.15(m,2H),2.10-1.89(m,7H),1.87-1.80(m,2H),1.64-1.57(m,2H),1.53(s,19H),1.30-1.16(m,4H)ppm。
Step 4) Synthesis of Compound 6-4
Compound 6-3 (0.24 g,0.3 mmol) was dissolved in EtOAc (3.0 mL), and after a solution of hydrogen chloride in ethyl acetate (2.0 mL, 4M) was slowly added dropwise, 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 (5.0 mL) and filtered to give 216mg of a white solid, yield: 96 percent.
MS(ESI,pos.ion)m/z:607.8[M+H]+。
Step 5) Synthesis of Compound 6-5
Compound 6-4 (0.15 g,0.2 mmol), compound 6-4-2 (88 mg,0.42 mmol), EDCI (80 mg,0.42 mmol) and HOAT (41 mg,0.3 mmol) were dissolved in DCM (3.0 mL), and DIPEA (0.26 mL,1.6 mmol) was slowly added dropwise 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 109mg of a white solid in yield: and 55 percent.
MS(ESI,pos.ion)m/z:495.6[M+2H]2+；
1H NMR(400MHz,CDCl3):7.81(s,1H),7.62-7.61,7.60-7.59(m,m,2H),7.51,7.49(s,s,1H),7.48,7.46(s,s,1H),7.39,7.37(s,s,1H),7.35-7.29(m,6H),7.26,7.24(s,s,1H),7.23,7.21(d,d,1H),7.19-7.15(m,4H),5.91-5.89(d,d,2H),5.35-5.34,5.33-5.32(m,m,2H),5.19-5.14(m,2H),3.91-3.84(m,2H),3.79-3.66(m,6H),3.64(s,6H),2.42-2.08(m,6H),2.03-1.89(m,6H),1.87-1.80(m,2H),1.64-1.57(m,2H),1.30-1.16(m,4H)ppm。
Example 7
The synthetic route is as follows:
step 1) Synthesis of Compound 7-1
Mixing compound 1-16 (0.55 g,1.5 mmol), compound 1-6-2 (0.42 g,1.65 mmol), Pd (dppf) Cl2·CH2Cl2(0.12 g,0.15 mmol) and KOAc (0.37 g,3.75 mmol) were placed in a reaction flask, N2DMF (3.0 mL) was injected under the protection, 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 (20 mL) was added to dilute the reaction mixture, the mixture was filtered through celite, and the filtrate was washed with water (15 mL × 3) and saturated brine, respectively, dried over anhydrous sodium sulfate, and purified by column chromatography (eluent: PE/EtOAc (v/v) = 1/1) to obtain 0.38g of a beige solid with a yield of 70%.
MS(ESI,pos.ion)m/z:364.3[M+H]+；
1H NMR(400MHz,CDCl3):7.66(s,1H),5.20-5.16(m,1H),3.59-3.53(m,1H),3.28-3.21(m,1H),2.38-2.30(m,1H),2.27-2.12(m,2H),2.07-1.98(m,1H),1.53(s,9H),1.39,1.36(q,q,12H)ppm。
Step 2) Synthesis of Compound 7-2
Furan (15 mL) was added slowly to a solution of LDA (7.4 mL,11 mmol) in THF (15 mL) at-78 ℃ and a solution of 2, 5-dimethoxybromobenzene (2.16g,10mmol) in THF (5mL) was added. The reaction was maintained at-78 ℃ for 30min, quenched with water and warmed to room temperature. Diethyl ether (50X 3) was added thereto for extraction, and the organic layer was dried over anhydrous sodium sulfate. The solvent was dried and column chromatographed (EtOAc: Hex =1: 1) to give a white solid (2.1 g, 86%)
1H NMR(400MHz,CDCl3):7.06(2H,s),6.97(2H,s),6.54(2H,s),5.92(2H,s),3.78(6H,s)ppm。
Step 3) Synthesis of Compound 7-3
Dissolving the compound 7-2 (2.5 g) in ethyl acetate (150 mL), adding palladium carbon (0.6 g) and stirring under hydrogen atmosphere for reaction overnight, filtering out the catalyst after the reaction is finished, and spin-drying the filtrate solvent to obtain a product 7-3 (2.38 g, 92%)
1H NMR(400MHz,CDCl3):1.36–1.41(m,2H),2.01–2.06(m,2H),3.79(s,6H),5.56–5.58(m,2H),6.63(s,2H)ppm。
Step 4) Synthesis of Compound 7-4
Dissolving compound 7-3 (2.06 g,10mmol) in DCM (50mL), slowly adding boron tribromide (7.7 mL,80 mmol) dropwise at-78 deg.C, reacting at constant temperature for 10 min, reacting at room temperature for 1 hr, quenching with ice water (50mL), extracting water layer with DCM (50mL × 3), mixing organic phases, washing with saturated saline water, and removing anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 10/1) gave 1.6g of oily liquid, yield: 90 percent.
MS(ESI,pos.ion)m/z:179.2[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 5) Synthesis of Compound 7-5
Pyridine (4.8 mL,60 mmol) is slowly dropped into a DCM (20 mL) solution of the compound 7-3 (1.78 g,10mmol) 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, after completion of the reaction, ice water (25 mL) is added to quench the reaction, DCM (30 mL × 3) is used for extraction, organic phases are combined, the mixture is washed with saturated brine, and anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 40/1) gave 3.98g of a colorless oil, 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 6) Synthesis of Compound 7-6
Mixing compound 1-7 (0.29 g,1.0 mmol), compound 7-5 (0.44 g,1.0 mmol), potassium carbonate (0.35 g,2.5 mmol) and Pd (PPh)3)4(12 mg,0.01 mmol) in a reaction flask, N2DME (4 mL) and water (1 mL) were separately injected and reacted at 90 ℃ for5 hours with protection. Inverse directionAfter completion of the reaction, EtOAc (20 mL) was added to dilute the reaction, which was 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):7.24,7.22(s,s,1H),7.19,7.17(s,s,1H),7.11,7.09(s,s,1H),6.58,6.56(s,s,1H),5.77(brs,1H),5.70-5.63(m,1H),5.42-5.36(m,1H),3.58-3.55(m,1H),3.51-3.48(m,1H),2.02-1.92(m,2H),1.85-1.81(m,1H),1.77-1.65(m,2H),1.62-1.58(m,1H),1.29-1.19(m,2H),0.99-0.87(m,2H)ppm。
Step 7) Synthesis of Compounds 7-7
Mixing compound 7-6 (0.23 g,0.5 mmol), compound 7-1 (0.18 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, N2Under the protection, EtOH (4 mL) and water (1 mL) were injected separately, and the reaction was carried out at 90 ℃ for 6 hours. After completion of the reaction, the reaction mixture was diluted with EtOAc (50mL), washed with saturated brine and anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 2/1) gave 0.16g of a pale yellow solid, yield: 60 percent.
1H NMR(400MHz,CDCl3):7.88(s,1H),7.45,7.43(s,s,1H),7.33,7.31(s,s,1H),7.20,7.17(s,s,1H),6.58,6.56(s,s,1H),5.78-5.75(m,1H),5.43-5.40(m,1H),5.07-5.00(m,1H),3.64-3.55(m,2H),3.51-3.48(m,1H),3.31-3.24(m,1H),2.47-2.38(m,1H),2.29-2.17(m,1H),2.10-1.92(m,4H),1.86-1.78(m,2H),1.75-1.67(m,1H),1.62-1.58(m,1H),1.41(s,9H),1.29-1.19(m,2H),1.08-1.00(m,1H),0.98-0.89(m,1H)ppm。
Step 8) Synthesis of Compounds 7-8
Pyridine (0.9 g,11.4 mmol) was added dropwise to a solution of compounds 7 to 7 (1.03 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) = 6/1) to give 1.02g of a colorless oil, yield: 80 percent.
1H NMR(400MHz,CDCl3):7.88(s,1H),7.45,7.43(s,s,1H),7.33,7.31(s,s,1H),7.13,7.11(s,s,1H),7.08,7.06(s,s,1H),5.78-5.75(m,1H),5.43-5.40(m,1H),5.07-5.00(m,1H),3.64-3.58(m,1H),3.56-3.53(m,1H),3.49-3.46(m,1H),3.31-3.24(m,1H),2.47-2.38(m,1H),2.29-2.17(m,1H),2.10-1.92(m,4H),1.86-1.78(m,2H),1.75-1.67(m,1H),1.62-1.58(m,1H),1.41(s,9H),1.33-1.27(m,1H),1.25-1.19(m,1H),1.08-1.00(m,1H),0.98-0.89(m,1H)ppm。
Step 9) Synthesis of Compounds 7-10
Compound 7-9 (5.91 g,29 mmol), NBS (5.76 g,32 mmol) and p-TSA (1.0 g,5.2 mmol) were mixed in a reaction flask, reacted at 100 ℃ for 0.5 hour, cooled to room temperature after completion of the reaction, DCM (100mL) and water (50mL) were added to dilute the reaction solution, the aqueous layer was separated, extracted with DCM (50mL × 3), the organic phases were combined, washed with brine, and dried over Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/DCM (v/v) = 5/1) gave 5.72g of yellow syrup, yield: 70 percent.
MS(ESI,pos.ion)m/z:285.1[M+H]+；
1H NMR(400MHz,CDCl3):7.55(d,1H,J=4.0Hz),7.14(d,1H,J=4.0Hz),4.29(s,2H)ppm。
Step 10) Synthesis of Compounds 7-11
Dissolving compounds 7-10 (5.58 g,19.8 mmol) and compounds 1-11 (4.7 g,21.8 mmol) in DCM (100mL), slowly adding DIPEA (3.62 mL,21.9 mmol) dropwise at 0 deg.C, reacting at room temperature for 3.0 hr, quenching with water (50mL), removing DCM, extracting the water layer with EtOAc (50mL × 3), combining the organic phases, and saturatingWashed with brine and anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 2/1) gave 5.78g of a yellow solid, yield: 70 percent.
MS(ESI,pos.ion)m/z:418.3[M+H]+；
1H NMR(400MHz,CDCl3):7.49(d,1H,J=4.0Hz),7.13(t,1H,J=4.0Hz),5.23-5.02(m,2H),4.48-4.37(m,1H),3.60-3.38(m,2H),2.29-2.26(m,2H),2.11-1.92(m,2H),1.44(s,9H)ppm。
Step 11) Synthesis of Compounds 7-12
The compound 7-11 (7.92 g,19 mmol) and NH4OAc (22.2 g,288 mmol) was suspended in xylene (100mL), reacted at 140 ℃ for 5.0 h, after completion of the reaction, cooled to room temperature, quenched by addition of water (100mL), the aqueous layer extracted with EtOAc (100mL × 3), the combined organic phases washed with saturated brine, anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 4/1) gave 6.94g of a yellow solid, yield: 92 percent.
MS(ESI,pos.ion)m/z:398.3[M+H]+；
1H NMR(400MHz,CDCl3):10.51(br,1H),7.07(s,1H),6.94(s,2H),4.91-4.90(m,1H),3.39(s,2H),2.98(s,1H),2.12(s,2H),1.95(s,1H),1.48(s,9H)ppm。
Step 12) Synthesis of Compounds 7-13
Mixing compound 7-12 (1.0 g,2.5 mmol), compound 1-6-2 (0.96 g,3.8 mmol), PdCl2(dppf).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, concentrating, and purifying by column chromatography (eluent: PE/E)Ioac (v/v) = 3/1) gave 0.89g of white solid, yield: 80 percent.
1H NMR(400MHz,CDCl3):10.51(br,1H),7.53(s,1H),7.27(s,1H),7.15(s,1H),4.94-4.93(m,1H),3.39(s,2H),2.99(s,1H),2.12-1.94(m,4H),1.49(s,9H),1.34(s,12H),1.24(m,8H)ppm。
Step 13) Synthesis of Compounds 7-14
Mixing compound 7-13 (0.45 g,1.0 mmol), compound 7-8 (0.67 g,1.0 mmol), Pd (PPh)3)4(0.12 g,0.1 mmol) and potassium carbonate (0.35 g,2.5 mmol) were placed in a reaction flask, and DME (5.0 mL) and pure water (1.0 mL), N, were injected, respectively2Reacting at 90 deg.C for 6.0 hr under protection, cooling to room temperature, adding water (20 mL) to dilute the reaction solution, extracting the aqueous layer with EtOAc (20 mL × 3), washing the organic phase with saturated brine, and washing with anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: DCM/MeOH (v/v) = 80/1) gave 0.38g of a pale yellow solid, yield: 45.5 percent.
MS(ESI,pos.ion)m/z:842.1[M+H]+；
1H NMR(400MHz,CDCl3):7.88(s,1H),7.53,7.51(s,s,1H),7.50,7.48(s,s,1H),7.47(s,1H),7.40,7.38(s,s,1H),7.33,7.31(s,s,1H),7.14,7.13(d,d,1H),7.01,7.00(s,s,1H),5.78-5.75(m,1H),5.43-5.40(m,1H),5.16-5.11(m,1H),5.05-5.01(m,1H),3.92-3.90(m,1H),3.83-3.81(m,1H),3.64-3.58(m,2H),3.31-3.24(m,2H),2.48-2.38(m,2H),2.29-2.16(m,2H),2.12-1.95(m,6H),1.90-1.78(m,2H),1.75-1.63(m,2H),1.53(s,9H),1.41(s,9H),1.30-1.22(m,2H),1.08-1.00(m,1H),0.98-0.89(m,1H)ppm。
Step 14) Synthesis of Compounds 7-15
Compounds 7 to 14 (0.25 g,0.3 mmol) were dissolved in EtOAc (3.0 mL), and an ethyl acetate solution of hydrogen chloride (2.0 mL, 4M) was slowly added dropwise thereto, followed by reaction at room temperature for 8 hours. After completion of the reaction, the reaction was concentrated, and the residue was slurried with EtOAc (5.0 mL) and filtered to give 224mg of a white solid, yield: 95 percent.
MS(ESI,pos.ion)m/z:641.3[M+H]+。
Step 15) Synthesis of Compounds 7-16
Compound 7-15 (0.16 g,0.2 mmol), compound 7-15-2 (90 mg,0.42 mmol), EDCI (80 mg,0.42 mmol) and HOAT (41 mg,0.3 mmol) were dissolved in DCM (3.0 mL), and DIPEA (0.26 mL,1.6 mmol) was slowly added dropwise 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 93mg of a white solid in yield: and 55 percent.
MS(ESI,pos.ion)m/z:518.7[M+2H]2+；
1H NMR(400MHz,CDCl3):7.79(s,1H),7.53,7.51(s,s,1H),7.50,7.48(s,s,1H),7.41(s,1H),7.40,7.38(s,s,1H),7.33,7.31(s,s,1H),7.14,7.13(d,d,1H),7.01,7.00(s,s,1H),5.78-5.75(m,1H),5.43-5.40(m,1H),5.24-5.19(m,3H),5.13-5.08(m,1H),4.47-4.41(m,2H),3.92-3.89(m,1H),3.86-3.80(m,3H),3.70-3.64(m,2H),3.63(s,6H),2.35-2.05(m,8H),2.03-1.78(m,6H),1.75-1.62(m,4H),1.58-1.51(m,4H),1.40-1.31(m,8H),1.30-1.22(m,2H),1.18-1.00(m,7H),0.98-0.89(m,1H)ppm。
Example 8
The synthetic route is as follows:
step 1) Synthesis of Compound 8-2
Dissolving compound 8-1 (1.54 g,19 mmol) and compound 8-1-2 (1.36 g,10mmol) in freshly distilled THF (25 mL), slowly adding n-butyllithium (1.6M n-hexane solution, 6.7 mL) dropwise at-78 deg.C under the protection of nitrogen, reacting at constant temperature for 1.0 hr, slowly raising temperature to room temperature (25 deg.C) for overnight reaction, pouring the reaction solution into water (50mL), extracting with diethyl ether (50mL × 3), and extracting the organic phase with anhydrous Na2SO4Drying, concentration and column chromatography (eluent: PE/EtOAc (v/v) = 5/1) gave 1.09g of a pale yellow solid, yield: 50.2 percent.
MS(ESI,pos.ion)m/z:218.5[M+H]+；
1H NMR(400MHz,CDCl3):6.93-6.91(t,1H,J=4.0Hz),6.83(m,2H),4.71-4.69(m,2H),3.71(s,6H),2.11(s,3H)ppm。
Step 2) Synthesis of Compound 8-3
Pd/C (10%, 0.35 g) was added to a solution of compound 8-2 (1.74 g,8.03 mmol) in absolute ethanol (40 mL) at 10 atmospheres H2The reaction was carried out at room temperature (25 ℃) for 24 hours under an atmosphere. After the reaction was completed, Pd/C was removed by filtration, and the reaction mixture was concentrated to obtain the objective compound 8-3 as a white solid 1.51g, yield: 86 percent.
MS(ESI,pos.ion)m/z:220.3[M+H]+；
1H NMR(400MHz,CDCl3):6.60-6.24(s,2H),4.28-4.26(m,2H),3.70(s,6H),2.11(s,3H),1.26-1.11(m,4H)ppm。
Step 3) Synthesis of Compound 8-4
Dissolving compound 8-3 (2.19 g,10mmol) in DCM (50.0 mL) at-78 deg.C, slowly adding boron tribromide (7.7 mL,80 mmol) dropwise, reacting at constant temperature for 10 min, reacting at room temperature for 1 hr, quenching by dropping the reaction liquid into ice water (50mL), and adding CH2Cl2Extraction (50mL × 3), washing the organic phase with saturated brine, anhydrous Na2SO4Drying, concentration and column chromatography (eluent: PE/EtOAc (v/v) = 10/1) gave 1.72 as a colorless oily liquid, yield: 90 percent.
MS(ESI,pos.ion)m/z:192.5[M+H]+；
1H NMR(400MHz,CDCl3):6.42(s,2H),5.77(br,2H),4.24-4.22(m,2H),2.15(s,3H),1.31-1.18(m,4H)ppm。
Step 4) Synthesis of Compounds 8-5
Pyridine (4.8 mL,60 mmol) was added to a solution of compounds 8-4 (1.91 g,10mmol) in DCM (20.0 mL) at 0 deg.C, after reaction for 10 minutes, trifluoromethanesulfonic anhydride (6.73 mL,40 mmol) was slowly added dropwise to the solution, after completion of the reaction at room temperature for 1 hour, the reaction was quenched by adding ice water (25 mL), extraction was carried out with DCM (30 mL × 3), the organic phase was washed with saturated brine, anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 40/1) gave 4.32g of a white oily liquid, yield: 95 percent.
1H NMR(400MHz,CDCl3):7.29(s,2H),4.39-4.37(m,2H),2.50(s,3H),1.24-1.09(m,4H)ppm。
Step 5) Synthesis of Compounds 8-6
Compounds 8-5 (2.27 g,5.0 mmol), compounds 1-7 (1.43 g,5.0 mmol), tetrakistriphenylphosphine palladium (0.29 g,0.25 mmol) and potassium carbonate (1.73 g,12.5 mmol) were suspended in DME/H2O (v/v = 3/1) in a mixed solvent (24 mL) at 90 ℃ for 3 hours under nitrogen protection. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (150 mL), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent: PE/DCM (v/v) = 6/1) to obtain 1.16g of a colorless liquid, yield: 50 percent.
1H NMR(400MHz,CDCl3):7.14,7.12(s,s,1H),7.10,7.08(s,s,1H),6.98,6.96(s,s,1H),6.52,6.50(s,s,1H),5.77(brs,1H),4.40-4.37(m,1H),4.04-4.01(m,1H),3.58-3.55(m,1H),3.52-3.50(m,1H),2.25(s,3H),2.01-1.92(m,2H),1.84-1.80(m,1H),1.61-1.52(m,2H),1.31-1.16(m,4H),0.98-0.89(m,1H)ppm。
Step 6) Synthesis of Compounds 8-7
Compound 8-6 (0.47 g,1.0 mmol), compound 3-1 (0.42 g,1.0 mmol), tetrakistriphenylphosphine palladium (0.12 g,0.1 mmol) and potassium carbonate (0.35 g,2.5 mmol) were suspended in DME/H2O (v/v = 3/1) in a mixed solvent (8 mL) at 90 ℃ for 3 hours under nitrogen protection. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (50mL), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent: PE/EtOAc (v/v) = 1/1) to obtain 0.27g of a pale yellow solid, yield: 45 percent.1H NMR(400MHz,CDCl3):7.46,7.44(s,s,1H),7.40(s,1H),7.36,7.34(s,s,1H),7.15,7.13(s,s,1H),6.52,6.50(s,s,1H),5.32,5.30(d,d,1H),5.16-5.12(m,1H),4.41-4.36(m,1H),4.24-4.18(m,2H),3.85-3.78(m,1H),3.69-3.64(m,1H),3.63(s,3H),3.58-3.55(m,1H),3.52-3.50(m,1H),2.40(s,3H),2.30-2.15(m,3H),2.13-2.03(m,1H),2.01-1.92(m,3H),1.85-1.77(m,2H),1.75-1.67(m,1H),1.61-1.57(m,1H),1.31-1.15(m,4H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H)ppm。
Step 7) Synthesis of Compounds 8 to 8
Pyridine (1.22 mL,15.2 mmol) was added dropwise to a solution of compounds 8-7 (2.31 g,3.8 mmol) in DCM (20 mL) at 0 ℃ and stirred for 10 minutes, and after that, trifluoromethanesulfonic anhydride (1.3 mL,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 give 2.25g of a colorless oil, yield: 80 percent.
1H NMR(400MHz,CDCl3):7.46,7.44(s,s,1H),7.40(s,1H),7.36,7.34(s,s,1H),7.11,7.09(s,s,1H),7.07,7.05(s,s,1H),5.32,5.30(d,d,1H),5.16-5.12(m,1H),4.41-4.36(m,1H),4.24-4.18(m,2H),3.85-3.78(m,1H),3.74-3.71(m,1H),3.69-3.65(m,1H),3.63(s,3H),3.49-3.47(m,1H),2.40(s,3H),2.30-2.15(m,3H),2.13-1.92(m,4H),1.85-1.77(m,2H),1.75-1.67(m,1H),1.61-1.57(m,1H),1.32-1.15(m,4H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H)ppm。
Step 8) Synthesis of Compounds 8 to 9
Compound 2-2 (0.58 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 (5mL), 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 0.3g of a product with a yield of 55.8%.
MS(ESI,pos.ion)m/z:391.5[M+H]+；
1H NMR(400MHz,CDCl3):7.27(s,1H),5.32,5.30(d,d,1H),5.29-5.24(m,1H),4.41-4.36(m,1H),3.89-3.83(m,1H),3.73-3.65(m,1H),3.63(s,3H),2.31-1.93(m,5H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H),0.32(m,9H)ppm。
Step 9) Synthesis of Compounds 8-10
The compounds 8-9 (0.34 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 solvent was removed, and the residue was added to water (10 mL), extracted with EtOAc (10 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) = 2/1) to give 0.23g of the product, yield: 82.6%.
MS(ESI,pos.ion)m/z:319.4[M+H]+；
1H NMR(400MHz,CDCl3):7.27(s,1H),5.35-5.31(m,1.5H),5.30-5.29(d,0.5H,J=4.0Hz),4.41-4.36(m,1H),3.89-3.83(m,1H),3.73-3.66(m,1H),3.63(s,3H),3.36(s,1H),2.31-1.93(m,5H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H)ppm。
Step 10) Synthesis of Compounds 8 to 11
Mixing compound 8-10 (0.12 g,0.39 mmol), compound 8-8 (0.29 g,0.39 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 dropped, and after dropping, the mixture was stirred at room temperature for 10 minutes and then reacted at 90 ℃ for 10 hours, after completion of the reaction, celite was filtered, water (20 mL) was added to the filtrate, extracted with EtOAc (20 mL × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent: DCM/MeOH (v/v) = 60/1) to obtain 106mg of the product, yield: 30%.
MS(ESI,pos.ion)m/z:456.1[M+2H]2+；
1H NMR(400MHz,CDCl3):7.62(s,1H),7.56,7.54(s,s,1H),7.46(s,1H),7.45,7.43,7.41(s,d,s,2H),7.29,7.26(s,s,1H),6.07,6.05(d,d,1H),5.51-5.47(m,1H),5.46,5.44(d,d,1H),5.29-5.25(m,1H),4.41,4.38,4.36(m,m,m,1H),4.34,4.31,4.30(m,m,m,1H),4.24-4.18(m,2H),4.11-4.08(m,1H),3.89-3.78(m,2H),3.73-3.67(m,2H),3.66(s,3H),3.65(s,3H),3.58-3.55(m,1H),2.37(s,3H),2.32-1.90(m,12H),1.82-1.68(m,3H),1.59-1.55(m,1H),1.34-1.17(m,4H),1.02,1.00(m,m,3H),0.97,0.95(m,m,3H),0.93,0.91(m,m,3H),0.90,0.89(m,m,3H)ppm。
Example 9
The synthetic route is as follows:
step 1) Synthesis of Compound 9-1
Compound 1-18 (0.18 g,0.26 mmol), compound 9-1-0 (83.8 mg,0.57 mmol), EDCI (0.11 g,0.57 mmol) and HOAT (0.07 g,0.52 mmol) were suspended in DCM (3 mL), and DIPEA (0.5 mL,2.6 mmol) was slowly added dropwise thereto at 0 ℃ and reacted at room temperature for 3 hours. After completion of the reaction, the reaction mixture was diluted with DCM (20 mL), washed with an aqueous ammonium chloride solution and a saturated aqueous sodium chloride solution, respectively, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent: DCM/MeOH (v/v) = 40/1) to obtain 0.13g of a pale yellow solid, yield: 61.4 percent.
MS(ESI,pos.ion)m/z:408.5[M+2H]2+；
1H NMR(400MHz,CDCl3):7.81(s,2H),7.39,7.37(s,s,2H),7.26,7.24(s,s,2H),7.29,7.26(s,s,1H),6.07,6.05(d,d,1H),5.51-5.47(m,1H),5.44,5.42(m,m,2H),5.15-5.11(m,2H),4.64-4.57(m,2H),3.88-3.82(m,2H),3.77-3.74(m,4H),3.72-3.65(m,2H),3.64(s,6H),2.34-2.06(m,6H),2.04-1.89(m,6H),1.87-1.83(m,2H),1.64-1.60(m,2H),1.36,1.34(d,d,6H),1.30-1.24(m,2H),1.22-1.16(m,2H)ppm。
Example 10
The synthetic route is as follows:
step 1) Synthesis of Compound 10-2
Compound 10-1 (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 (50mL), 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 1.05g of a colorless oil, 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 2) Synthesis of Compound 10-4
Compound 10-2 (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 ℃ respectively, 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 compound 10-3 as colorless oil.
Dissolving compound 10-3 in ammonia methanol solution (10 mL, 7M), reacting at 0 deg.C for 0.5 hr, reacting at room temperature for 1.0 hr, cooling to 0 deg.C again, slowly adding dropwise aqueous solution of glyoxal (1.2 mL, 40%), reacting at room temperature for 24 hr, concentrating the reaction solution, dissolving the residue with DCM (100mL), washing with water (30 mL × 3) and saturated saline water, and adding 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%。
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 3) Synthesis of Compound 10-5
Dissolving compound 10-4 (0.51 g,2.03 mmol) in DCM (10 mL), adding NIS (1.0 g,4.46 mmol) at 0 deg.C, reacting at constant temperature for 2.0 hr, filtering to remove solid, washing filtrate with saturated sodium sulfite solution (30 mL × 3), anhydrous Na2SO4Drying and concentration gave 0.92g of a yellow solid, yield: 90 percent. Directly used for the next reaction.
MS(ESI,pos.ion)m/z:504.2[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 4) Synthesis of Compound 10-6
Dissolving compound 10-5 (0.91 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 residue in DCM (50mL), 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 0.41g 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 5) Synthesis of Compound 10-7
Mixing 10-6 (0.63 g,1.66 mmol), 1-6-2 (0.46 g,1.82 mmol), Pd (dppf) Cl2·CH2Cl2(68 mg,0.083 mmol) and KOAc (0.41 g,4.14 mmol) were placed in a reaction flask, N2DMF (5.0 mL) was added under protection, the reaction was carried out at 90 ℃ for 2.0 hours, the reaction mixture was cooled to room temperature after completion of the reaction, ethyl acetate (40 mL) was added to dilute the reaction mixture, the mixture was filtered through celite, and the filtrate was 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) = 1/2) gave 0.53g of a pale yellow solid, yield: 85 percent.
MS(ESI,pos.ion)m/z:378.3[M+H]+；
1H NMR(400MHz,CDCl3):7.69(s,1H),4.90-4.85(m,1H),3.75-3.68(m,1H),3.04-2.97(m,1H),2.44-2.34(m,1H),2.33-2.20(m,1H),1.83-1.75(m,1H),1.41(s,9H),1.38,1.36(m,m,12H),0.96-0.93(m,3H)ppm。
Step 6) Synthesis of Compound 10-8
Mixing compound 10-7 (0.63 g,1.66 mmol), compound 3-13 (0.75 g,1.66 mmol), Pd (PPh)3)4(96 mg,0.083 mmol) and potassium carbonate (0.57 g,4.14 mmol) were placed in a reaction flask, N2DME (5mL) and pure water (1.0 mL) were separately injected under the protection, and reacted at 90 ℃ for 3.0 hours, after completion of the reaction, the reaction mixture was cooled to room temperature, and after adding EtOAc (30 mL) to dilute the reaction mixture, the reaction mixture was washed with water (10 mL × 3) and saturated brine, respectively, and anhydrous Na was added2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 1/2) gave 0.5g of a pale yellow solid, yield: 54.5 percent.
MS(ESI,pos.ion)m/z:552.7[M+H]+；
1H NMR(400MHz,CDCl3):7.67(s,1H),7.39,7.37(s,s,1H),7.36,7.34(t,t,1H),7.22,7.20(s,s,1H),6.75,6.72(s,s,1H),5.06-5.01(m,1H),4.37-4.30(m,1H),3.80-3.73(m,1H),3.58-3.54(m,1H),3.50-3.46(m,1H),3.24-3.12(m,1H),3.09-3.02(m,1H),2.70-2.57(m,2H),2.35-2.12(m,5H),1.99-1.92(m,2H),1.82-1.78(m,1H),1.76-1.68(m,1H),1.66-1.55(m,2H),1.41(s,9H),1.26-1.19(m,2H),0.96-0.93(m,3H)ppm。
Step 7) Synthesis of Compound 10-9
Pyridine (0.97 mL,12 mmol) was added dropwise to a solution of compound 10-8 (1.65 g,3.0 mmol) in DCM (20 mL) at 0 ℃ and stirred for 10 minutes, and after that, trifluoromethanesulfonic anhydride (1.0 mL,6.0 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 1.74g of a colorless oil, yield: 85 percent.
1H NMR(400MHz,CDCl3):7.67(s,1H),7.38,7.36(t,t,1H),7.26,7.24(s,s,1H),7.22,7.21(s,s,1H),7.20,7.19(s,s,1H),5.06-5.01(m,1H),4.37-4.30(m,1H),3.88-3.85(m,1H),3.80-3.73(m,1H),3.47-3.44(m,1H),3.24-3.12(m,1H),3.09-3.02(m,1H),2.70-2.57(m,2H),2.35-2.13(m,5H),2.03-1.92(m,2H),1.82-1.78(m,1H),1.76-1.68(m,1H),1.66-1.55(m,2H),1.41(s,9H),1.30-1.19(m,2H),0.96-0.93(m,3H)ppm。
Step 8) Synthesis of Compounds 10-10
DIPEA (1.95 mL,11.8 mmol) was added to a solution of compound 10-1 (2.45 g,10.7 mmol) and compound HATU (4.88 g,12.84 mmol) in THF (30 mL) at 0 deg.C, reacted at constant temperature for 0.5 hour, then compound 3-16-0 (2.21 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 by addition of water (50mL), THF was removed, extraction was performed 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 (100mL), 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:381.3[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 9) Synthesis of Compounds 10-11
Mixing 10-10 (4.27 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 (2.76 g,28.17 mmol) were placed in a reaction flask, N2DME (30 mL) was added under protection and reacted at 90 ℃ for 3.0 hours, after completion of the reaction, DME was removed, water (50mL) was added, extracted with EtOAc (50mL × 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) = 3/1) to give 2.89g of a beige solid in 60% yield.
MS(ESI,pos.ion)m/z:428.4[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 10) Synthesis of Compounds 10-12
Mixing compound 10-11 (0.25 g,0.58 mmol), compound 10-9 (0.40 g,0.58 mmol), Pd (PPh)3)4(35 mg,0.03 mmol) and carbonic acidPotassium (80 mg,1.4 mmol) was placed in a reaction flask, N2DME (4.0 mL) and pure water (1.0 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 (50mL) 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) = 80/1) gave 0.29g of a pale yellow solid, yield: 60 percent.
MS(ESI,pos.ion)m/z:418.5[M+2H]2+；
1H NMR(400MHz,CDCl3):7.69,7.67(s,s,1H),7.66(s,1H),7.62,7.60(d,d,1H),7.52,7.50(d,d,1H),7.48(m,1H),7.47,7.45(s,s,1H),7.41,7.39(t,t,1H),7.22,7.20(s,s,1H),5.14-5.09(m,1H),5.06-5.01(m,1H),4.37-4.29(m,1H),3.93-3.90(m,1H),3.85-3.73(m,3H),3.23-3.02(m,3H),2.70-2.57(m,2H),2.51-2.42(m,1H),2.35-2.12(m,6H),2.00-1.90(m,2H),1.86-1.78(m,2H),1.76-1.68(m,1H),1.66-1.56(m,2H),1.42(s,9H),1.41(s,9H),1.27-1.17(m,2H),0.96-0.93(m,6H)ppm。
Step 11) Synthesis of Compounds 10-13
Compound 10-12 (0.25 g,0.3 mmol) was dissolved in EtOAc (4.0 mL), and a solution of hydrogen chloride in ethyl acetate (3.0 mL, 4M) was slowly 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 (5mL), and filtered to obtain 0.21g of a pale yellow solid, yield: 90 percent. Directly used for the next reaction.
MS(ESI,pos.ion)m/z:635.8[M+H]+。
Step 12) Synthesis of Compounds 10-14
Compound 10-13 (0.24 g,0.31 mmol), compound 1-18-2 (0.12 g,0.68 mmol), EDCI (0.13 g,0.68 mmol) and HOAT (85 mg,0.62 mmol) were suspended in DCM (5.0 mL), and DIPEA (0.51 mL,3.1 mmol) was added dropwise slowly at 0 ℃ and reacted at room temperature for 3.0 hours after completion of the 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 0.13g of a pale yellow solid, yield: 44 percent.
MS(ESI,pos.ion)m/z:475.6[M+2H]2+；
1H NMR(400MHz,CDCl3):7.69,7.67(s,s,1H),7.62,7.59(d,d,1H),7.58(s,1H),7.52,7.50(d,d,1H),7.48(m,1H),7.47,7.45(s,s,1H),7.41,7.39(t,t,1H),7.22,7.20(s,s,1H),5.32-5.26(m,3H),5.17-5.13(m,1H),4.41-4.29(m,3H),3.93-3.84(m,3H),3.79-3.76(m,1H),3.63(s,6H),3.61-3.54(m,2H),3.23-3.13(m,1H),2.70-2.58(m,2H),2.57-2.47(m,1H),2.38-2.09(m,8H),2.00-1.90(m,2H),1.84-1.75(m,2H),1.73-1.56(m,3H),1.27-1.17(m,2H),0.97,0.95(m,m,6H),0.93-0.89(m,12H)ppm。
Example 11
The synthetic route is as follows:
step 1) Synthesis of Compound 11-1
Compound 5-8 (11.0 g,44.84 mmol) was dissolved in DCM (200 mL) and Et was slowly added dropwise thereto at-78 deg.C2NSF3(8.85 mL,67.3 mmol) and reacting at constant temperature for 2.0 hours, then reacting at room temperature for 19 hours, after the reaction is completed, adding ammonium chloride aqueous solution (100mL) to quench the reaction, extracting the water layer with DCM (100mL × 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 7.75g of a pale yellow liquid, yield: 70 percent.
MS(ESI,pos.ion)m/z:248.3[M+H]+；
1H NMR(400MHz,CDCl3):5.26,5.13(ds,ds,1H),4.55-4.41(m,1H),3.88-3.74(m,1H),3.73(s,3H),3.64-3.58(m,1H),2.52-2.44(m,1H),2.40-2.32(m,1H),1.42-1.47(d,9H,J=20Hz)ppm。
Step 2) Synthesis of Compound 11-2
Dissolving compound 11-1 (5.83 g,23.58 mmol) in THF (30 mL), slowly adding dropwise aqueous solution of lithium hydroxide (1.98 g,30 mL) at 0 deg.C, reacting at room temperature for 2.0 hr, adjusting pH of the reaction solution to 5 with dilute hydrochloric acid (1M), removing THF, adjusting pH of the water layer to 2 with dilute hydrochloric acid (1M), extracting with EtOAc (80 mL × 3), combining organic phases, washing with saturated brine, and washing with anhydrous Na2SO4Drying and concentration gave 5.27g of a white solid, yield: 96 percent.
MS(ESI,pos.ion)m/z:234.3[M+H]+；
1H NMR(400MHz,CDCl3):8.76(brs,1H),5.28-5.12(m,1H),4.56-4.44(m,1H),3.86-3.58(m,2H),2.77-2.01(m,2H),1.48-1.44(d,9H,J=16Hz)ppm。
Step 3) Synthesis of Compound 11-3
Compound 11-2 (1.3 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 (50mL), washed with water (20 mL × 3) and saturated brine, respectively, and washed with anhydrous Na2SO4Drying and concentration gave 1.07g of a colorless oil, yield: 88 percent.
MS(ESI,pos.ion)m/z:220.3[M+H]+；
1H NMR(400MHz,CDCl3):5.19-5.06(m,1H),4.12-4.04(m,1H),3.99-3.79(m,1H),3.69-3.63(m,1H),3.60-3.46(m,2H),2.25-2.00(m,2H),1.44(s,9H)ppm。
Step 4) Synthesis of Compound 11-5
Compound 11-3 (1.15 g,5.24 mmol) was dissolved in DCM (20 mL), TCCA (1.22 g,5.24 mmol) was added to the system at 0 deg.C, followed by dropwise addition of TEMPO in DCM solution (82 mg,0.52mmol,3 mL), reaction was carried out at constant temperature for 1.0 hour, 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 saturated sodium sulfite solution (20 mL × 3), anhydrous Na2SO4Drying, concentrating, dissolving the residue in ammonia methanol solution (7 mL, 7M), reacting at 0 deg.C for 0.5 hr, reacting at room temperature for 1.0 hr, cooling to 0 deg.C, slowly adding glyoxal water solution (1.1 mL, 40%), reacting at room temperature for 24 hr, concentrating the reaction solution, dissolving the residue in DCM (50mL), washing with water (30 mL × 3) and saturated saline, and adding anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: DCM/MeOH (v/v) = 100/1) gave 0.67g of a pale yellow solid, yield: 50 percent.
MS(ESI,pos.ion)m/z:256.3[M+H]+；
1H NMR(400MHz,CDCl3):6.98(s,2H),5.36-5.13(m,2H),3.72-3.31(m,2H),2.58-2.32(m,2H),1.48(s,9H)ppm。
Step 5) Synthesis of Compound 11-6
Dissolving compound 11-5 (0.63 g,2.47 mmol) in DCM (8.0 mL), adding NIS (1.23 g,5.43 mmol) at 0 deg.C, reacting at constant temperature for 2.0 hr, after reaction is completed, adding DCM (50mL) to dilute the reaction solution, filtering to remove solid, washing the filtrate with saturated sodium sulfite solution (20 mL × 3), combining organic phases, and adding anhydrous Na2SO4Drying and concentration gave 1.07g of a yellow solid, yield: 85.6 percent. Directly used for the next reaction.
MS(ESI,pos.ion)m/z:508.1[M+H]+；
1H NMR(400MHz,CDCl3):5.34-5.08(m,2H),3.72-3.28(m,2H),2.58-2.33(m,2H),1.48(s,9H)ppm。
Step 6) Synthesis of Compounds 11-7
Compound 11-6 (1.07 g,2.12 mmol) was dissolved in ethanol (6.0 mL), sodium sulfite (2.14 g,17 mmol) and water (6.0 mL) were added, reaction was carried out at 90 ℃ for 30 hours, after completion of the reaction, solid was removed by filtration, the filtrate was concentrated, and the residue was dissolved in DCM (40 mL), washed with water (20 mL × 3) and saturated brine, respectively, anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 1/1) gave 0.59g of a white solid, yield: 73 percent.
MS(ESI,pos.ion)m/z:382.2[M+H]+；
1H NMR(400MHz,CDCl3):7.04(s,1H),5.35-5.09(m,2H),3.98-3.63(m,1H),3.58-3.29(m,1H),2.55-2.34(m,2H),1.48(s,9H)ppm。
Step 7) Synthesis of Compounds 11-8
A solution of hydrogen chloride in ethyl acetate (5mL, 4M) was added dropwise to a solution of compound 11-7 (0.76 g,2.0 mmol) in EtOAc (4.0 mL) at room temperature, and the reaction was allowed to proceed overnight after dropwise addition. After completion of the reaction, filtration gave 0.32g of solid, yield: 90 percent. Directly used for the next reaction.
MS(ESI,pos.ion)m/z:282.1[M+H]+。
Step 8) Synthesis of Compounds 11-9
Compound 11-8 (1.27 g,3.6 mmol), compound 1-18-2 (0.68 g,3.9 mmol) and EDCI (0.75 g,3.9 mmol) were suspended in DCM (10 mL), stirred at 0 ℃ for5 minutes, and DIPEA (2.38 mL,14.4 mmol) was added dropwise slowly and reacted at room temperature for 2.0 hours. After completion of the reaction, DCM (40 mL) was added to dilute the reaction solution, 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 give a pale yellow colored product1.35g of a colored solid, yield: 85.6 percent. MS (ESI, pos.ion) M/z 439.3[ M + H ]]+；
1H NMR(400MHz,CDCl3):7.41(s,1H),5.32,5.30(d,d,1H),5.19-5.18,5.17-5.16,5.15-5.14,5.06-5.05,5.04-5.03,5.02-5.01(m,m,m,m,m,m,1H),4.93-4.88(m,1H),4.45-4.41(m,1H),4.13-4.01(m,1H),3.75-3.64(m,1H),3.63(s,3H),3.02-2.85(m,1H),2.38-2.24(m,1H),2.23-2.12(m,1H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H)ppm。
Step 9) Synthesis of Compounds 11-10
Mixing compound 11-9 (0.48 g,1.1 mmol), compound 1-10 (0.27 g,0.5 mmol), Pd (PPh)3)4(58 mg,0.05 mmol) and potassium carbonate (0.17 g,1.25 mmol) were placed in a reaction flask, and DME (5.0 mL) and pure water (1.0 mL), N, were injected, respectively2Reacting at 90 deg.C for 6.0 hr under protection, cooling to room temperature, adding water (20 mL) to dilute the reaction solution, extracting the aqueous layer with EtOAc (20 mL × 3), washing the organic phase with saturated brine, and washing with anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: DCM/MeOH (v/v) = 50/1) gave 0.18g of a pale yellow solid, yield: 40 percent.
MS(ESI,pos.ion)m/z:454.5[M+2H]2+；
1H NMR(400MHz,CDCl3):8.00(s,2H),7.39,7.37(s,s,2H),7.26,7.24(s,s,2H),5.32,5.30(d,d,2H),5.19,5.11(m,m,2H),5.07-5.02(m,2H),4.45-4.41(m,2H),4.13-4.01(m,2H),3.77-3.72(m,4H),3.71-3.69,3.68-3.67,3.66-3.65(m,m,m,2H),3.63(s,6H),2.98-2.81(m,2H),2.30-2.12(m,4H),2.03-1.97(m,2H),1.95-1.89(m,2H),1.87-1.83(m,2H),1.64-1.60(m,2H),1.30-1.24(m,2H),1.22-1.16(m,2H),0.97,0.95(m,m,6H),0.90,0.89(m,m,6H)ppm。
Example 12
The synthetic route is as follows:
step 1) Synthesis of Compound 12-2
12-1 (24.4 g,92.5 mmol) was added dropwise to a xylene (250 mL) solution of benzoquinone (10.0 g,92.5 mmol) at room temperature, and the mixture was reacted at constant temperature for 1 hour and then at 100 ℃ for 8 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 24.7g of a pale yellow solid, yield: 71.8 percent of the total weight of the product, and directly used for the next reaction.
1H NMR(400MHz,CDCl3):6.59(d,J=7.6Hz,2H),3.66(s,3H),3.57(d,5H)ppm。
Step 2) Synthesis of Compound 12-3
Compound 12-2 (9.89 g,26.6 mmol) was reacted with pyridine (6.30 g,79.7 mmol) in methanol (100mL) at 50 ℃ for 4 hours under nitrogen. After completion of the reaction, the reaction solution was concentrated and purified by column chromatography (eluent: DCM) to obtain 9.02g of a white solid, yield: 91.2 percent.
MS(ESI,pos.ion)m/z:372.9[M+H]+；
1H NMR(400MHz,CDCl3):6.43-6.39(d,J=7.3Hz,2H),5.67(s,2H),3.64(s,6H),3.52(s,3H)ppm。
Step 3) Synthesis of Compound 12-4
Reaction of Compound 12-3 (9.00 g,24.2 mmol) with K2CO3(10.01 g,72.6 mmol) was dissolved in DCM (100mL) and CH was added dropwise at 0 deg.C3I (7.56 g,53.2 mmol). After dropwise adding, reacting at room temperature for 5h, filtering to remove solid, concentrating the reaction solution, and purifying by column chromatography (eluent: DCM) to obtain whiteSolid 8.8g, yield: 91.2 percent.
MS(ESI,pos.ion)m/z:401.0[M+H]+；
1H NMR(400MHz,CDCl3):6.43-6.39(d,J=7.8Hz,2H),3.82(s,6H),3.50(s,3H),3.66(s,3H)ppm。
Step 4) Synthesis of Compound 12-5
Compound 12-4 (8.52 g,21.3 mmol) and a catalytic amount of palladium on carbon (0.8 g) were suspended in methanol (80 mL) and reacted at room temperature for 1.5 hours in a hydrogen system at normal pressure. After the reaction was completed, filtration was performed, and the filtrate was concentrated and then purified by recrystallization to obtain 6.47g of a white solid, yield: 75.6 percent.
MS(ESI,pos.ion)m/z:403.0[M+H]+；
1H NMR(400MHz,CDCl3):6.43-6.39(d,J=7.4Hz,2H),3.82(s,6H),3.73(s,3H),3.53(s,3H),1.77(m,2H),2.50(m,2H)ppm。
Step 5) Synthesis of Compound 12-6
Metallic Na (1.83g,80.5mmol) was added to a solution of naphthalene (12.7g,96.6mmol) in DME (50mL) at 0 ℃ and stirred for 30 minutes, a solution of 12-5 (5.36 g, 16.1 mmol) in DME (100mL) was added dropwise after completion of the addition, the reaction was stirred at this temperature, after 2h the reaction was completed, 10mL ethanol was added to quench the reaction, 100mL water was added, EA (100mL x 3) was extracted, dried over anhydrous sodium sulfate, purified by column chromatography after concentration (hexan: EA =6: 1) to give 3.87g of a white solid, yield: 91 percent.
MS(ESI,pos.ion)m/z:265.2[M+H]+；
1H NMR(400MHz,CDCl3):6.43-6.39(d,J=7.5Hz,2H),3.90(s,6H),3.54(dd,J=1.8,1.8Hz,2H),3.29(s,3H),3.12(s,3H),2.24(m,2H),1.43(m,2H)ppm。
Step 6) Synthesis of Compounds 12-7
Compound 12-6 (3.87 g,14.7 mmol) was added to 30mL of dioxane solution,a20% sulfuric acid solution (100mL) was slowly added thereto at 0 ℃ and the mixture was transferred to 50 ℃ for reaction for 11 hours. Cooled to room temperature, 200mL of EtOAc are added, and the organic phase is washed with 30mL of saturated NaCl solution, anhydrous Na2SO4Drying, concentration and column purification with eluent Hexane/EtOAc =5/1 gave 2.72g of white solid in 85% yield.
MS(ESI,pos.ion)m/z:219.1[M+H]+；
1H NMR(400MHz,CDCl3):6.43-6.39(d,2H),3.90(s,6H),3.54(dd,J=1.8Hz,2H),2.24(m,2H),1.43(m,2H)ppm。
Step 7) Synthesis of Compounds 12-8
Boron tribromide (9.0 mL,22.5mmol,2.5M/L DCM solution) was slowly added dropwise to a DCM solution (20.0 mL) of compound 12-7 (1.48 g,6.8 mmol) at-78 deg.C, after completion of the dropwise addition, the reaction mixture was poured into ice water (50.0 mL), the aqueous layer was extracted with DCM (50mL × 3), the organic phases were combined, washed with saturated brine, and dried over Na2SO4Drying, concentration and column chromatography (eluent: PE/EtOAc (v/v) = 10/1) gave 1.19g of white liquid, yield: 92 percent.
MS(ESI,pos.ion)m/z:191.5[M+H]+；
1H NMR(400MHz,CDCl3):6.59(s,2H),5.49(br,2H),3.64-3.58(m,2H),2.50-2.41(m,2H),2.15-2.05(m,2H)ppm。
Step 8) Synthesis of Compounds 12-9
Pyridine (9.00 g,114 mmol) is added dropwise to a solution of compounds 12 to 8 (3.61 g,19.0 mmol) in DCM (50.0 mL) at 0 ℃, after stirring for 10 minutes, trifluoromethanesulfonic anhydride (21.0 g,76 mmol) is slowly added dropwise, reaction is carried out at room temperature for 1.0 hour, after completion of reaction, water (50.0 mL) is added to quench the reaction, DCM (50mL × 3) is used for extraction, the organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and after concentration, column chromatography (eluent: PE/DCM (v/v) = 20/1) is carried out to obtain 7.76g of colorless oily substance, yield: 90.0 percent.
1H NMR(400MHz,CDCl3):7.36(s,2H),3.61-3.55(m,2H),2.56-2.47(m,2H),2.20-2.12(m,2H)ppm。
Step 9) Synthesis of Compounds 12-10
Mixing compounds 12-9 (0.45 g,1.0 mmol), compounds 1-7 (0.29 g,1.0 mmol), Pd (PPh)3)4(0.12 g,0.1 mmol) and potassium carbonate (0.35 g,2.5 mmol) were placed in a reaction flask, N2Under the protection, DME (5.0 mL) and pure water (1.0 mL) were separately injected, reacted at 90 ℃ for 4.0 hours, cooled to room temperature after completion of the reaction, diluted with ethyl acetate (20 mL), washed with water (10 mL × 3) and saturated brine, and dried over anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 8/1) gave 0.23g of a pale yellow liquid, yield: 50 percent.
MS(ESI,pos.ion)m/z:465.5[M+H]+；
1H NMR(400MHz,CDCl3):7.08,7.06(s,s,1H),7.04,7.02(s,s,1H),7.01,6.99(s,s,1H),6.53,6.51(s,s,1H),5.77(brs,1H),3.89-3.86(m,1H),3.65-3.62(m,1H),3.58-3.55(m,1H),3.51-3.48(m,1H),2.58-2.51(m,1H),2.48-2.40(m,1H),2.23-2.15(m,1H),2.13-2.05(m,2H),1.98-1.90(m,2H),1.71-1.67(m,1H),1.38-1.32(m,1H),1.25-1.19(m,1H)ppm。
Step 10) Synthesis of Compounds 12-11
Mixing compound 12-10 (0.23 g,0.5 mmol), compound 7-1 (0.18 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, N2Under the protection, EtOH (4 mL) and water (1 mL) were injected separately, and the reaction was carried out at 90 ℃ for 6 hours. After completion of the reaction, the reaction mixture was diluted with EtOAc (50mL), washed with saturated brine and anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 2/1) gave 0.15g of a pale yellow solid, yield: 54.3 percent.
1H NMR(400MHz,CDCl3):7.89(s,1H),7.32,7.30(s,s,1H),7.11,7.09(s,s,1H),6.97,6.95(s,s,1H),6.53,6.51(s,s,1H),5.05-5.01(m,1H),3.95-3.91(m,2H),3.64-3.55(m,2H),3.51-3.48(m,1H),3.31-3.24(m,1H),2.56-2.49(m,1H),2.47-2.38(m,2H),2.28-1.90(m,8H),1.71-1.67(m,1H),1.41(s,9H),1.38-1.32(m,1H),1.25-1.19(m,1H)ppm。
Step 11) Synthesis of Compounds 12-12
Pyridine (0.9 g,11.4 mmol) was added dropwise to a solution of compounds 12 to 11 (1.05 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, and concentrated and purified by column chromatography (eluent: PE/EtOAc (v/v) = 3/1) to give 1.15g of a pale yellow solid, yield: 88.5 percent.
1H NMR(400MHz,CDCl3):7.89(s,1H),7.61,7.59(s,s,1H),7.34,7.31(s,s,1H),7.07,7.04(s,s,1H),6.97,6.95(s,s,1H),5.05-5.01(m,1H),3.95-3.91(m,2H),3.74-3.71(m,1H),3.64-3.58(m,1H),3.49-3.46(m,1H),3.31-3.24(m,1H),2.56-2.49(m,1H),2.47-2.38(m,2H),2.28-1.90(m,8H),1.71-1.67(m,1H),1.41(s,9H),1.40-1.36(m,1H),1.25-1.19(m,1H)ppm。
Step 12) Synthesis of Compounds 12-13
Mixing compounds 12-12 (0.68 g,1.0 mmol), compounds 3-17 (0.41 g,1.0 mmol), Pd (PPh)3)4(0.12 g,0.1 mmol) and potassium carbonate (0.35 g,2.5 mmol) were placed in a reaction flask, and DME (5.0 mL) and pure water (1.0 mL), N, were injected, respectively2Reacting at 90 deg.C for 6.0 hr under protection, cooling to room temperature, adding water (20 mL) to dilute the reaction solution, extracting the aqueous layer with EtOAc (20 mL × 3), washing the organic phase with saturated brine, and washing with anhydrous Na2SO4Drying, concentrating, and purifying by column chromatography (eluent: DCM/Me)OH (v/v) = 80/1) gave 0.45g of a pale yellow solid, yield: 54.8 percent.
MS(ESI,pos.ion)m/z:822.1[M+H]+；
1H NMR(400MHz,CDCl3):7.89(s,1H),7.62-7.61,7.60-7.59(m,m,2H),7.53,7.50(s,s,1H),7.43,7.41(s,s,1H),7.36,7.34(s,s,1H),7.23,7.21(d,d,1H),6.97,6.95(s,s,1H),5.05-4.99(m,2H),3.95-3.91(m,2H),3.82-3.76(m,3H),3.64-3.57(m,2H),3.31-3.24(m,1H),2.62-2.49(m,2H),2.47-2.36(m,3H),2.28-1.92(m,10H),1.73-1.69(m,1H),1.41(s,18H),1.35-1.29(m,1H),1.27-1.21(m,1H)ppm。
Step 13) Synthesis of Compounds 12-14
Compound 12-13 (0.25 g,0.3 mmol) was dissolved in EtOAc (3.0 mL), and after a solution of hydrogen chloride in ethyl acetate (2.0 mL, 4M) was slowly added dropwise, 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 (5.0 mL) and filtered to give 0.2g of a white solid, yield: 86.9 percent.
MS(ESI,pos.ion)m/z:621.8[M+H]+。
Step 14) Synthesis of Compound 12-14-2
L-valine (1.17 g,10mmol) was dissolved in 13ml of an aqueous NaOH (1M) solution, and phenyl chloroformate (1.72 g,11.0 mmol) was added dropwise at a temperature of 0 ℃. After the addition was complete, the reaction was incubated at 0 ℃ for 5h and washed with EtOAc (20 mL x 2) and the aqueous phase was adjusted to pH =2 with concentrated HCl, extracted with EtOAc (30 mL x 3) and the organic phase was collected, dried over anhydrous sodium sulfate and spun to give 1.8g of a white solid, yield: 75.9 percent.
MS(ESI,pos.ion)m/z:238.1[M+H]+。
Step 15) Synthesis of Compounds 12-15
Compound 12-14 (0.15 g,0.2 mmol), compound 12-14-2 (100 mg,0.42 mmol), EDCI (80 mg,0.42 mmol) and HOAT (41 mg,0.3 mmol) were dissolved in DCM (3.0 mL) and DIPEA (0) was added dropwise slowly at 0 ℃.26mL,1.6 mmol), and reacted at room temperature for 3.0 hours after dropping. 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 0.15g of a white solid, yield: 70.8 percent.
MS(ESI,pos.ion)m/z:530.6[M+2H]2+；
1H NMR(400MHz,CDCl3):7.83(s,1H),7.62-7.61,7.60-7.59(m,m,2H),7.53,7.50(s,s,1H),7.43,7.41(s,s,1H),7.36-7.30(m,5H),7.24-7.23,7.22-7.21,7.20-7.19(m,m,m,3H),7.13-7.12,7.11-7.10(m,m,4H),6.97,6.95(s,s,1H),5.49,5.46(d,d,2H),5.29-5.20(m,2H),4.48-4.42(m,2H),3.95-3.91(m,2H),3.85-3.76(m,4H),3.69-3.60(m,2H),2.56-1.87(m,17H),1.73-1.69(m,1H),1.35-1.29(m,1H),1.27-1.21(m,1H),0.97,0.95(m,m,6H),0.90,0.89(m,m,6H)ppm。
Example 13
The synthetic route is as follows:
step 1) Synthesis of Compound 13-1
Dissolving compound 10-1 (3.0 g,13.1 mmol) and compound 2-3-0 (3.63 g,13.1 mmol) in DCM (40 mL), slowly adding TEA (3.9 mL,26.3 mmol) at 0 deg.C, after dripping, reacting at room temperature for 2.0 hr, after reaction is complete, adding water (50mL), quenching, extracting the water layer with DCM (50mL × 3), combining the organic phases, washing with saturated brine, anhydrous Na2SO4Drying and concentration gave 3.27g of crude product, yield: 62.9 percent. Straight barThen used in the next reaction.
MS(ESI,pos.ion)m/z:399.3[M+H]+。
Step 2) Synthesis of Compound 13-2
Compound 13-1 (3.27 g,8.2 mmol) and ammonium acetate (5.1 g,66 mmol) were suspended in toluene (30 mL) and reacted at 110 ℃ for 5.0 hours, after completion of the reaction, cooled to room temperature, quenched by addition of water (50mL), the aqueous layer was extracted with EtOAc (80 mL × 3), the organic phases were combined, washed with saturated brine, anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 4/1) gave 2.85g of product, yield: 86 percent.
MS(ESI,pos.ion)m/z:407.4[M+H]+；
1H NMR(400MHz,CDCl3):7.45(m,4H),7.20(s,1H),4.93(t,1H,J=8.2Hz),3.88-3.66(m,1H),2.90(t,1H,J=8.0Hz),2.50-2.47(m,2H),2.27-2.25(m,1H),1.48(s,7H),1.26(s,2H),1.12(d,3H,J=6.2Hz)ppm。
Step 3) Synthesis of Compound 13-3
Mixing 13-2 (2.8 g,6.9 mmol), 1-6-2 (1.93 g,7.6 mmol), Pd (dppf) Cl2·CH2Cl2(0.28 g,0.34 mmol) and KOAc (1.7 g,17.25 mmol) were placed in a reaction flask, N2Under protection, DME (30 mL) was injected, the reaction was carried out at 90 ℃ for 2.0 hours, after completion of the reaction, the reaction mixture was cooled to room temperature, ethyl acetate (200 mL) was added to dilute the reaction mixture, the mixture was filtered through celite, and the filtrate was washed with water (20 mL × 3) and saturated brine, respectively, and washed with anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 1/2) gave 2.76g of a pale yellow solid, yield: 88.2 percent.
MS(ESI,pos.ion)m/z:454.4[M+H]+；
1H NMR(400MHz,CDCl3):7.35(m,4H),7.10(s,1H),4.93(t,1H,J=8.2Hz),3.88-3.66(m,1H),2.90(t,1H,J=8.0Hz),2.50-2.47(m,2H),2.27-2.25(m,1H),1.48(s,9H),1.26(s,12H),1.02(d,3H,J=6.2Hz)ppm。
Step 4) Synthesis of Compound 13-4
Mixing compound 13-3 (0.26 g,0.58 mmol), compound 1-9 (0.34 g,0.58 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 (4.0 mL) and pure water (1.0 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 (20 mL × 3) and saturated brine, respectively, and anhydrous Na was added2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 1/1) gave 0.3g of a pale yellow solid, yield: 68 percent.
1H NMR(400MHz,CDCl3):7.62-7.61,7.60-7.59(m,m,3H),7.56-7.55,7.53-7.52(m,m,2H),7.42,7.40(s,s,1H),7.31,7.29(s,s,1H),7.10,7.08(s,s,1H),7.07,7.05(s,s,1H),4.88-4.84(m,1H),3.92-3.90(m,1H),3.80-3.71(m,3H),3.45-3.42(m,1H),3.09-3.02(m,1H),2.33-2.18(m,2H),2.03-1.90(m,4H),1.84-1.78(m,2H),1.74-1.66(m,1H),1.61-1.55(m,2H),1.41(s,9H),1.30-1.17(m,4H),0.96-0.93(m,3H)ppm。
Step 5) Synthesis of Compound 13-5
Mixing compound 13-4 (0.44 g,0.58 mmol), compound 10-7 (0.22 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 (4.0 mL) and pure water (1.0 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 (50mL) 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) = 80/1) gave 0.3g of a pale yellow solid, yield: 60.1 percent.
MS(ESI,pos.ion)m/z:431.5[M+2H]2+；
1H NMR(400MHz,CDCl3):7.90(s,1H),7.62-7.61,7.60-7.59(m,m,3H),7.56-7.55,7.53-7.52(m,m,2H),7.51,7.48(s,s,1H),7.39,7.37(s,s,1H),7.31,7.29(s,s,1H),7.26,7.24(s,s,1H),4.97-4.92(m,1H),4.88-4.84(m,1H),3.92-3.90(m,1H),3.80-3.71(m,5H),3.09-3.02(m,2H),2.35-2.18(m,4H),2.03-1.89(m,4H),1.87-1.80(m,2H),1.76-1.66(m,2H),1.64-1.57(m,2H),1.41(s,18H),1.30-1.16(m,4H),0.96-0.93(m,6H)ppm。
Step 6) Synthesis of Compound 13-6
Compound 13-5 (0.26 g,0.3 mmol) was dissolved in EtOAc (4.0 mL), and a solution of hydrogen chloride in ethyl acetate (3.0 mL, 4M) was slowly 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 (5mL), and filtered to obtain 0.2g of a pale yellow solid, yield: 82.6 percent. Directly used for the next reaction.
MS(ESI,pos.ion)m/z:661.4[M+H]+。
Step 7) Synthesis of Compounds 13-7
Compound 13-6 (0.20 g,0.31 mmol), compound 1-18-2 (0.12 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 3.0 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, respectively, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent: DCM/MeOH (v/v) = 50/1) to obtain 125mg of a pale yellow solid, yield: 41 percent.
MS(ESI,pos.ion)m/z:488.6[M+2H]2+；
1H NMR(400MHz,CDCl3):7.80(s,1H),7.62-7.61,7.60-7.59(m,m,3H),7.56-7.55,7.53-7.52(m,m,2H),7.51,7.48(s,s,1H),7.39,7.37(s,s,1H),7.31,7.29(s,s,1H),7.26,7.24(s,s,1H),5.32,5.29(d,d,2H),5.15-5.10(m,1H),5.07-5.02(m,1H),4.42-4.37(m,2H),3.92-3.85(m,3H),3.77-3.71(m,3H),3.63(s,6H),3.61-3.55(m,2H),2.38-2.09(m,6H),2.03-1.89(m,4H),1.87-1.80(m,2H),1.72-1.57(m,4H),1.30-1.16(m,4H),0.97,0.95(m,m,6H),0.93-0.89(m,12H)ppm。
Example 14
The synthetic route is as follows:
step 1) Synthesis of Compound 14-2
Mixing PPh3MeBr (5.05 g,14.2 mmol) was suspended in THF (50mL) and potassium tert-butoxide (14.9 mL,14.9mmol, 1.0M) in THF was slowly added dropwise at-20 ℃ and after completion of the addition, compound 14-1 (1.72 g,7.07 mmol) was added after reaction at-5 ℃ for 30 minutes, after completion of the addition, reaction was carried out at room temperature for 1.0 hour, after completion of the reaction, ice water (50mL) was added to quench the reaction, THF was removed, the aqueous layer was extracted with EtOAc (50mL × 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) = 5/1) to give 1.07g of a pale yellow oily liquid with a yield of 62.9%.
MS(ESI,pos.ion)m/z:242.2[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 14-3
Chloroiodomethane (6.6 g,37.24 mmol) was slowly added dropwise to a solution of diethylzinc (2.3 g,18.6 mmol) in toluene (30 mL) at 0 deg.C, after dropping,after the reaction was carried out at constant temperature for 45 minutes, a solution of 14-2 (1.5 g,6.22 mmol) in toluene (15 mL) was slowly added dropwise thereto, and the reaction was carried out at constant temperature for 18 hours. After the reaction is complete, saturated NH is added4The reaction was quenched with Cl solution (20 mL), the aqueous layer was extracted with EtOAc (25 mL × 3), and the organic phases were combined, anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 10/1) gave 0.58g of a colorless liquid, yield: 36.5 percent.
MS(ESI,pos.ion)m/z:156.2[M-BOC]+；
1H NMR(400MHz,CDCl3):4.33-4.47(m,1H),3.71(s,3H),3.29-3.37(m,2H),2.17-2.25(m,1H),1.75-1.86(m,1H),1.44,1.40(s,s,9H),0.50-0.62(m,4H)ppm。
Step 3) Synthesis of Compound 14-4
Compound 14-3 (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 8.0 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 Compound 14-5
Compound 14-4 (0.53 g,2.77 mmol), compound 1-18-2 (0.73 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, concentrating, and purifying by column chromatography (eluent: PE/EtOAc (v/v) = 1/1) to obtain colorless liquidBulk 0.60g, yield: 70 percent.
MS(ESI,pos.ion)m/z:313.2[M+H]+；
1H NMR(400MHz,CDCl3):5.44-5.42(br,1H),4.71-4.68(m,1H),4.29-4.20(m,1H),3.73(s,3H),3.72-3.69(m,1H),3.67(s,3H),3.59-3.54(m,1H),2.20-2.15(m,1H),2.06-2.01(m,1H),1.95-1.90(m,1H),1.05-0.93(m,6H),0.66-0.61(m,4H)ppm。
Step 5) Synthesis of Compound 14-6
Slowly dropping an aqueous solution (5mL) of lithium hydroxide (0.134 g,3.2 mmol) into a THF solution (5.0 mL) of compound 14-5 (0.2 g,0.64 mmol) at 0 deg.C, after dropping, reacting at 40 deg.C for 12 hours, after completion of the reaction, removing THF, adding water (30 mL), extracting with EtOAc (10 mL × 3), collecting the aqueous phase, adjusting the pH of the solution to 1 with hydrochloric acid (10%), extracting the aqueous layer with EtOAc (25 mL × 3), combining the organic phases, anhydrous Na2SO4Drying and concentration gave 0.16g of a white solid, yield: 82.8 percent.
MS(ESI,pos.ion)m/z:299.2[M+H]+；
1H NMR(400MHz,CDCl3):7.06(br,1H),5.76(br,1H),4.73-4.69(m,1H),4.23-4.18(m,1H),3.79(d,1H,J=9.7Hz),3.66(s,3H),3.49(d,1H,J=9.7Hz),2.26-2.18(m,1H),2.07-1.93(m,2H),1.00-0.94(m,6H),0.68-0.64(m,4H)ppm。
Step 6) Synthesis of Compounds 14-7
Compound 2-3-0 (0.31 g,1.11 mmol) and compound 14-6 (0.3 g,1.0 mmol) were dissolved in MeCN (10 mL), DIPEA (0.21 mL,1.27 mmol) was added dropwise slowly at 0 ℃ and, after completion of the addition, reacted at room temperature for 2.0 hours. After completion of the reaction, water (10 mL) was added to the reaction solution to remove MeCN, and the residue was extracted with EtOAc (30 mL), washed with an ammonium chloride solution and saturated brine, respectively, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE/EtOAc (v/v) = 1/1) to give 0.365g of a pale yellow solid, yield: 66.7 percent.
MS(ESI,pos.ion)m/z:495.3[M+H]+；
1H NMR(400MHz,CDCl3):7.82-7.78(m,2H),7.67-7.64(m,2H),5.32,5.29(br,br,1H),5.31(s,2H),4.72-4.70(m,1H),4.35-4.30(m,1H),3.67(s,3H),3.61-3.59(m,1H),3.55-3.49(m,1H),2.20-2.07(m,2H),1.83-1.76(m,1H),0.97,0.96(m,m,3H),0.91,0.89(m,m,3H),0.52-0.39(m,4H)ppm。
Step 7) Synthesis of Compounds 14-8
Reaction of Compound 14-7 (0.33 g,0.67 mmol) with NH4OAc (1.04 g,13.43 mmol) was suspended in xylene (10 mL), reacted at 120 ℃ for 5.0 h, after completion of the reaction, cooled to room temperature, quenched by addition of water (20 mL), the aqueous layer extracted with EtOAc (20 mL × 3), the organic phases combined, washed with brine, anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 1/2) gave 0.19g of a yellow solid, yield: 60 percent.
MS(ESI,pos.ion)m/z:475.3[M+H]+；
1H NMR(400MHz,CDCl3):7.58(s,1H),7.45-7.41(m,2H),7.29-7.26(m,2H),5.46,5.44(br,br,1H),4.93-4.89(m,1H),4.41-4.37(m,1H),3.71-3.67(m,1H),3.67(s,3H),3.50-3.44(m,1H),2.39-2.32(m,1H),2.23-2.11(m,1H),2.05-1.97(m,1H),0.97,0.95(m,m,3H),0.91,0.89(m,m,3H),0.52-0.39(m,4H)ppm。
Step 8) Synthesis of Compounds 14-9
Mixing 14-8 (0.19 g,0.4 mmol), 1-6-2 (0.15 g,0.6 mmol), Pd (dppf) Cl2·CH2Cl2(33 mg,0.04 mmol) and KOAc (0.12 g,1.19 mmol) were placed in a reaction flask, N2Adding DMF (5.0 mL) under protection, reacting at 90 ℃ for 3.0 hours, cooling to room temperature after the reaction is completed, adding EtOAc (50mL) to dilute the reaction solution, filtering with kieselguhr, washing the filtrate with water (20 mL × 3) and saturated brine respectively, drying over anhydrous sodium sulfate, concentrating, and purifying by column chromatography (Eluent: PE/EtOAc (v/v) = 1/2) gave 0.16g of beige solid, yield: 80 percent.
MS(ESI,pos.ion)m/z:523.3[M+H]+；
1H NMR(400MHz,CDCl3):7.64-7.57(m,4H),7.21(s,1H),5.46,5.44(br,br,1H),4.93-4.89(m,1H),4.42-4.37(m,1H),3.71-3.67(m,1H),3.66(s,3H),3.50-3.44(m,1H),2.39-2.32(m,1H),2.23-2.11(m,1H),2.05-1.97(m,1H),1.35(m,6H),1.32(m,6H),0.97,0.95(m,m,3H),0.91,0.89(m,m,3H),0.55-0.42(m,4H)ppm。
Step 9) Synthesis of Compounds 14-10
Mixing compound 1-9 (0.30 g,0.52 mmol), compound 14-9 (0.27 g,0.52 mmol), Pd (PPh)3)4(60.3 mg,0.052 mmol) and potassium carbonate (0.22 g,1.57 mmol) were placed in a reaction flask, N2DME (6.0 mL) and water (1.5 mL) were separately injected under the protection, and the mixture was reacted at 90 ℃ for 3.0 hours, after completion of the reaction, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (30 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 0.22g of a pale yellow solid, yield: 50.8 percent.
MS(ESI,pos.ion)m/z:415.5[M+2H]2+；
1H NMR(400MHz,CDCl3):7.62-7.61,7.60-7.59(m,m,2H),7.57(s,1H),7.56-7.55,7.53-7.52(m,m,2H),7.42,7.40(s,s,1H),7.31,7.29(s,s,1H),7.10,7.08(s,s,1H),7.07,7.05(s,s,1H),5.32,5.29(d,d,1H),4.93-4.89(m,1H),4.42-4.41,4.40-4.39,4.38-4.37(m,m,m,1H),3.92-3.90(m,1H),3.74-3.66(m,3H),3.63(s,3H),3.50-3.42(m,2H),2.39-2.32(m,1H),2.23-2.11(m,1H),2.05-1.90(m,5H),1.84-1.78(m,2H),1.61-1.55(m,2H),1.30-1.17(m,4H),0.97,0.95(m,m,3H),0.91,0.89(m,m,3H),0.55-0.42(m,4H)ppm。
Step 10) Synthesis of Compounds 14-11
Mixing 14-10 (0.42 g,0.5 mmo)l), Compound 1-6-2 (0.17 g,0.6 mmol), Pd (dppf) Cl2·CH2Cl2(41 mg,0.05 mmol) and KOAc (0.17 g,1.25 mmol) were mixed in a reaction flask, DMF (5.0 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 (50mL) was added to dilute the reaction mixture, and the mixture was filtered through celite, and the filtrate was washed with water (20 mL × 3) and saturated brine, and anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 1/3) gave 0.21g of a pale yellow solid, yield: 52 percent.
1H NMR(400MHz,CDCl3):7.66,7.64(s,s,1H),7.62-7.61,7.60-7.59(m,m,3H),7.58,7.57(s,s,1H),7.56(s,1H),7.55-7.54,7.53-7.52(m,m,2H),7.31,7.29(s,s,1H),5.32,5.29(d,d,1H),4.93-4.89(m,1H),4.42-4.41,4.40-4.39,4.38-4.37(m,m,m,1H),3.92-3.90(m,1H),3.76-3.66(m,4H),3.63(s,3H),3.50-3.44(m,1H),2.39-2.32(m,1H),2.23-2.11(m,1H),2.05-1.90(m,5H),1.84-1.74(m,3H),1.61-1.53(m,2H),1.32,1.29(q,q,12H),1.27-1.17(m,3H),1.07-1.01(m,1H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H),0.55-0.43(m,4H)ppm。
Step 11) Synthesis of Compounds 14-12
Compound 14-6 (1.39 g,4.66 mmol) was dissolved in THF (20 mL), borane (10 mL,1M inTHF) was slowly added dropwise to the 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 0.86g of a colorless oil, yield: 65 percent.
1H NMR(400MHz,CDCl3):5.32,5.29(d,d,1H),4.98(brs,1H),4.39-4.34(m,1H),4.33-4.27(m,1H),3.73-3.72,3.70-3.69,3.68-3.67,3.66-3.65(m,m,m,m,2H),3.63(s,3H),3.25-3.18(m,1H),3.10-3.03(m,1H),2.15-2.03(m,1H),1.90-1.82(m,1H),1.47-1.38(m,1H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H),0.50-0.37(m,4H)ppm。
Step 12) Synthesis of Compounds 14-13
Compound 14-12 (0.99 g,3.48 mmol) was dissolved in DCM (15 mL) and dess-martin (2.07 g,4.88 mmol) was added in portions as oxidant to the flask at 0 deg.C, after which it was reacted at room temperature for 2.0 hours. After completion of the reaction, the reaction mixture was diluted with water (20 mL), 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 0.49g of a colorless oil, yield: 50 percent.
1H NMR(400MHz,CDCl3):9.61-9.60(m,1H),5.32,5.30(d,d,1H),4.40-4.38(m,1H),4.33,4.31,4.29(m,m,m,1H),3.63(s,3H),3.62-3.57(m,1H),3.34-3.27(m,1H),2.43-2.37(m,1H),2.24-2.12(m,1H),1.80-1.73(m,1H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H),0.52-0.39(m,4H)ppm。
Step 13) Synthesis of Compounds 14-14
Compound 14-13 (0.5 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 0.28g of a white solid, yield: 50 percent.
MS(ESI,pos.ion)m/z:321.4[M+H]+；
1H NMR(400MHz,CDCl3):6.97(s,2H),5.56,5.55(d,d,1H),5.20-5.16(m,1H),4.33,4.31,4.29(m,m,m,1H),3.71-3.67(m,1H),3.66(s,3H),3.52-3.46(m,1H),2.46-2.38(m,1H),2.28-2.16(m,1H),2.09-2.01(m,1H),1.02,1.00(m,m,3H),0.93,0.91(m,m,3H),0.55-0.42(m,4H)ppm。
Step 14) Synthesis of Compounds 14-15
Compound 14-14 (2.69 g,8.4 mmol) was dissolved in DCM (30 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 2.88g of a white solid, yield: 60 percent.
MS(ESI,pos.ion)m/z:573.2[M+H]+；
1H NMR(400MHz,CDCl3):5.56,5.55(d,d,1H),5.22-5.18(m,1H),4.45,4.43,4.42(m,m,m,1H),3.80-3.73(m,1H),3.66(s,3H),3.51-3.45(m,1H),2.51-2.43(m,1H),2.28-2.11(m,2H),1.02,1.00(m,m,3H),0.93,0.91(m,m,3H),0.56-0.43(m,4H)ppm。
Step 15) Synthesis of Compounds 14-16
Compound 14-15 (1.87 g,3.27 mmol) was suspended in a mixed solvent (50mL) 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 (50mL), extracted with ethyl acetate (50mL × 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 1.02g of a white solid, yield: 70 percent.
MS(ESI,pos.ion)m/z:447.3[M+H]+；
1H NMR(400MHz,CDCl3):7.34(s,1H),5.56,5.55(d,d,1H),4.89-4.85(m,1H),4.43,4.41,4.39(m,m,m,1H),3.77-3.71(m,1H),3.66(s,3H),3.54-3.48(m,1H),2.48-2.40(m,1H),2.28-2.16(m,1H),2.14-2.06(m,1H),1.02,1.00(m,m,3H),0.93,0.91(m,m,3H),0.55-0.42(m,4H)ppm。
Step 16) Synthesis of Compounds 14-17
Mixing 14-16 (0.32 g,0.72 mmol), 14-11 (0.58 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 diluted with EtOAc (50mL) and washed with water (20 mL × 3) and saturated brine respectivelyDried over anhydrous sodium sulfate, concentrated and purified by column chromatography (DCM/MeOH (v/v) = 50/1) to obtain 0.43g of a product, yield: 60 percent.
MS(ESI,pos.ion)m/z:500.6[M+2H]2+；
1H NMR(400MHz,CDCl3):7.78(s,1H),7.62-7.61,7.60-7.59(m,m,2H),7.57(s,1H),7.56-7.55,7.53-7.52(m,m,2H),7.51,7.48(s,s,1H),7.39,7.37(s,s,1H),7.31,7.29(s,s,1H),7.26,7.24(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(s,s,1H),5.32,5.29(d,d,2H),5.02-4.98(m,1H),4.93-4.89(m,1H),4.41,4.39,4.37(m,m,m,2H),3.92-3.90(m,1H),3.77-3.66(m,5H),3.63(s,6H),3.50-3.44(m,2H),2.40-2.32(m,2H),2.23-2.11(m,2H),2.06-1.89(m,6H),1.87-1.80(m,2H),1.64-1.57(m,2H),1.30-1.16(m,4H),0.97-0.95(m,m,6H),0.90,0.89(m,m,6H),0.55-0.42(m,8H)ppm。
Example 15
The synthetic route is as follows:
step 1) Synthesis of Compound 15-1
Dissolving compound 4-6 (3.91 g,17.22 mmol) and compound 2-3-0 (5.47 g,19.81 mmol) in DCM (60 mL), slowly adding DIPEA (3.4 mL,20.67 mmol) dropwise at 0 deg.C, reacting at room temperature for 3.0 hr, adding water (50mL) to quench reaction, extracting water layer with DCM (100mL × 3), mixing organic phases, washing with saturated brine, and anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 5/1) gave 4.5g of a white solid, yield: 61.7 percent.
MS(ESI,pos.ion)m/z:425.3[M+H]+；
1H NMR(400MHz,CDCl3):7.77-7.73(m,2H),7.64-7.62(m,2H),5.53-5.09(m,2H),4.78-4.67(m,1H),3.59-3.46(m,1H),2.69-2.62(m,1H),2.43-2.40(m,1H),1.42(s,9H),1.00-0.96(m,1H),0.76-0.69(m,2H)ppm。
Step 2) Synthesis of Compound 15-2
Compound 15-1 (4.5 g,10.64 mmol) and ammonium acetate (16.4 g,212.73 mmol) were suspended in xylene (50mL) and reacted at 120 ℃ for 5.0 hours, after completion of the reaction, cooled to room temperature, quenched by addition of water (50mL), the aqueous layer was extracted with EtOAc (100mL × 3), the combined organic phases were washed with saturated brine, anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 8/1) gave 2.14g of product, yield: 50 percent.
MS(ESI,pos.ion)m/z:404.3[M+H]+；
1H NMR(400MHz,CDCl3):7.62-7.52(br,2H),7.49-7.46(d,2H,J=12Hz),7.21(s,1H),5.27-5.24(d,1H,J=10.0Hz),3.31-3.27(m,1H),1.71-1.67(m,2H),1.52(s,9H),0.89-0.86(m,1H),0.64-0.69(m,2H)ppm。
Step 3) Synthesis of Compound 15-3
Mixing 15-2 (2.1 g,5.2 mmol), 1-6-2 (1.59 g,6.25 mmol), Pd (dppf) Cl2·CH2Cl2(0.43 g,0.52 mmol) and KOAc (1.54 g,15.63 mmol) were placed in a reaction flask, N2DMF (20 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, EtOAc (100mL) 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, and dried over anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 2/1) gave 2.27g of product, yield: 97 percent.
MS(ESI,pos.ion)m/z:452.4[M+H]+；
1H NMR(400MHz,CDCl3):7.81-7.79(d,2H,J=8.04Hz),7.60(br,2H),7.26(s,1H),5.28-5.26(d,1H,J=8.0Hz),3.53(br,1H),3.30-3.27(br,1H),1.67-1.66(m,2H),1.52(s,9H),1.34(s,12H),0.89-0.86(m,1H),0.69-0.64(m,2H)ppm。
Step 4) Synthesis of Compound 15-4
A solution of hydrogen chloride in ethyl acetate (5.0 mL, 4M) was added dropwise to a solution of compound 15-3 (0.9 g,2 mmol) in EtOAc (10 mL) at room temperature, and the reaction was carried out for 8.0 h. After completion of the reaction, the reaction was concentrated, and the residue was slurried with EtOAc (5.0 mL) and filtered to give a solid 0.94g, yield: 95 percent. Directly used for the next reaction.
MS(ESI,pos.ion)m/z:425.2[M+H]+。
Step 5) Synthesis of Compound 15-5
Compound 15-4 (0.37 g,0.75 mmol), compound 1-18-2 (0.13 g,0.75 mmol) and EDCI (0.3 g,1.58 mmol) were suspended in DCM (5.0 mL), and DIPEA (1.0 mL,6.01 mmol) was added dropwise 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 give 324mg of a pale yellow solid, yield: 85 percent.
MS(ESI,pos.ion)m/z:509.3[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 6) Synthesis of Compound 15-6
Mixing compound 15-5 (0.54 g,1.07 mmol), compound 1-9 (0.62 g,1.07 mmol), Pd (PPh)3)4(0.12 g,0.11 mmol) and potassium carbonate (0.37 g,2.67 mmol) were placed in a reaction flask, N2Under the protection, DME (5.0 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 (50mL), washed with water (20 mL × 3) and saturated brine, and dried over Na2SO4Drying, concentration and purification by column chromatography (eluent: DCM/MeOH (v/v) = 100/1) gave 0.52g of a pale yellow solid, yield: 60 percent.
1H NMR(400MHz,CDCl3):7.63(s,1H),7.62-7.61,7.60-7.59(m,m,2H),7.56-7.55,7.53-7.52(m,m,2H),7.42,7.40(s,s,1H),7.31,7.29(s,s,1H),7.10,7.08(s,s,1H),7.07,7.05(s,s,1H),5.32,5.30(d,d,1H),4.89-4.85(m,1H),4.08,4.06,4.04(m,m,m,1H),3.92-3.90(m,1H),3.74-3.71(m,2H),3.63(s,3H),3.45-3.38(m,2H),2.46-2.39(m,1H),2.22-2.09(m,1H),2.03-1.90(m,5H),1.84-1.78(m,2H),1.61-1.55(m,2H),1.43-1.36(m,1H),1.30-1.17(m,4H),0.97,0.95(m,m,3H),0.94-0.92(m,1H),0.91,0.89(m,m,3H),0.50-0.46(m,1H)ppm。
Step 7) Synthesis of Compounds 15-7
Mixing 15-6 (0.33 g,0.4 mmol), 1-6-2 (0.15 g,0.6 mmol), Pd (dppf) Cl2·CH2Cl2(33 mg,0.04 mmol) and KOAc (0.12 g,1.19 mmol) were placed in a reaction flask, N2DMF (5.0 mL) was injected under the protection, 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 (30 mL) was added to dilute the reaction mixture, the mixture was filtered through celite, and the filtrate was washed with water (10 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 0.25g of a beige solid with a yield of 80.1%.
MS(ESI,pos.ion)m/z:781.8[M+H]+；
1H NMR(400MHz,CDCl3):7.66,7.64(s,s,1H),7.62-7.61,7.60-7.59(m,m,4H),7.58,7.56(s,s,1H),7.56-7.55,7.53-7.52(m,m,2H),7.31,7.29(s,s,1H),5.32,5.30(d,d,1H),4.89-4.85(m,1H),4.08,4.06,4.04(m,m,m,1H),3.92-3.90(m,1H),3.85-3.78(m,1H),3.76-3.71(m,2H),3.69-3.66(m,1H),3.63(s,3H),3.45-3.38(m,1H),2.46-2.39(m,1H),2.21-2.09(m,1H),2.00-1.90(m,4H),1.84-1.74(m,3H),1.61-1.53(m,2H),1.43-1.36(m,1H),1.32,1.29(q,q,12H),1.27-1.17(m,2H),1.07-1.01(m,1H),0.97,0.95(m,m,3H),0.94-0.92(m,1H),0.90,0.89(m,m,3H),0.50-0.46(m,1H)ppm。
Step 8) Synthesis of Compound 15-8
Compound 4-6 (1.06 g,4.66 mmol) was dissolved in THF (10 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 (8 mL), and the reaction solution was concentrated and purified by column chromatography (eluent: PE/EtOAc (v/v) = 3/2) to give 0.65g of a colorless oil, yield: 65 percent.
1H NMR(400MHz,CDCl3):4.37(brs,1H),3.94-3.78(m,3H),2.93-2.86(m,1H),2.11-2.03(m,1H),1.83-1.77(m,1H),1.46(s,9H),1.41-1.33(m,1H),1.09-1.03(m,1H),0.65-0.62(m,1H)ppm。
Step 9) Synthesis of Compound 15-9
Compound 15-8 (0.74 g,3.48 mmol) was dissolved in DCM (10 mL) and dess-martin (2.07 g,4.88 mmol) was added in portions to the flask as oxidant at 0 deg.C and after addition was complete, the reaction was carried out 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) = 3/2) to obtain 0.5g of a colorless oil, yield: 68 percent.
1H NMR(400MHz,CDCl3):9.75-9.72(m,1H),4.19-4.14(m,1H),3.24-3.18(m,1H),2.41-2.34(m,1H),1.82-1.80,1.78-1.86(m,m,1H),1.45(s,9H),1.41-1.34(m,1H),1.26-1.21(m,1H),0.83-0.80(m,1H)ppm。
Step 10) Synthesis of Compounds 15-10
Compound 15-9 (0.37 g,1.76 mmol) and ammonia (2.0 mL) were dissolved in methanol (5.0 mL), and an aqueous solution of glyoxal (40%, 1 mL) was slowly dropped into the reaction flask at 0 ℃ and reacted overnight at room temperature after 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 0.35g of a white solid, yield: 79.8 percent.
MS(ESI,pos.ion)m/z:250.3[M+H]+；
1H NMR(400MHz,CDCl3):7.04(s,2H),4.92-4.88(m,1H),3.31-3.25(m,1H),2.48-2.41(m,1H),2.00-1.98,1.96-1.94(m,m,1H),1.45-1.43(m,1H),1.42(s,9H),1.41-1.39(m,1H),1.02-0.95(m,1H)ppm。
Step 11) Synthesis of Compounds 15-11
Compound 15-10 (0.5 g,2.0 mmol) was dissolved in DCM (60 mL), and N-iodosuccinimide (0.9 g,4.0 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 0.65g of a white solid, yield: 65 percent.
MS(ESI,pos.ion)m/z:502.1[M+H]+；
1H NMR(400MHz,CDCl3):4.93-4.89(m,1H),3.49-3.42(m,1H),2.57-2.46(m,1H),2.12-2.10,2.09-2.07(m,m,1H),1.45-1.43(m,1H),1.42(s,9H),1.41-1.39(m,1H),1.02-0.95(m,1H)ppm。
Step 12) Synthesis of Compounds 15-12
Compound 15-11 (0.75 g,1.5 mmol) was suspended in a mixed solvent (12.5 mL) of ethanol and water (v/v = 3/7), and sodium sulfite (1.7 g,13.5 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 (50mL), extracted with ethyl acetate (50mL × 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 0.45g of a white solid, yield: 80 percent.
MS(ESI,pos.ion)m/z:376.2[M+H]+；
1H NMR(400MHz,CDCl3):7.41(s,1H),4.71-4.68(m,1H),3.34-3.28(m,1H),2.50-2.43(m,1H),2.05-2.03,2.01-1.99(m,m,1H),1.45-1.43(m,1H),1.42(s,9H),1.41-1.39(m,1H),1.02-0.94(m,1H)ppm。
Step 13) Synthesis of Compounds 15-13
A solution of hydrogen chloride in ethyl acetate (5mL, 4M) was added dropwise to a solution of compound 15-12 (0.75 g,2.0 mmol) in EtOAc (4.0 mL) at room temperature, and the reaction was allowed to proceed overnight after dropwise addition. After completion of the reaction, filtration gave 0.65g of solid, yield: 93.4 percent. Directly used for the next reaction.
MS(ESI,pos.ion)m/z:276.1[M+H]+。
Step 14) Synthesis of Compounds 15-14
After suspending compound 15-13 (0.63 g,1.8 mmol), compound 1-18-2 (0.35 g,1.98 mmol) and EDCI (0.38 g,1.98 mmol) in DCM (20 mL) and stirring at 0 ℃ for5 minutes, DIPEA (2.38 mL,14.4 mmol) was added dropwise slowly and the reaction was carried out at room temperature for 2.0 hours after completion of the dropwise addition. After completion of the reaction, DCM (20 mL) was added to dilute the reaction solution, and the 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 0.65g of a pale yellow solid, yield: 83.5 percent.
MS(ESI,pos.ion)m/z:433.3[M+H]+；
1H NMR(400MHz,CDCl3):7.38(s,1H),5.32,5.30(d,d,1H),4.89-4.85(m,1H),4.08,4.06,4.04(m,m,m,1H),3.63(s,3H),3.51-3.45(m,1H),2.55-2.48(m,1H),2.22-2.11(m,1H),2.09-2.06,2.05-2.03(m,m,1H),1.49-1.41(m,1H),0.97,0.95(m,m,3H),0.94-0.92(m,1H),0.90,0.89(m,m,3H),0.50-0.46(m,1H)ppm。
Step 15) Synthesis of Compounds 15-15
Mixing compound 15-14 (0.31 g,0.72 mmol), compound 15-7 (0.57 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 (50mL), 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 0.42g of the product in 60% yield.
MS(ESI,pos.ion)m/z:486.6[M+2H]2+；
1H NMR(400MHz,CDCl3):7.84(s,1H),7.62(s,1H),7.61-7.59(m,2H),7.56-7.52(m,2H),7.51-7.48(s,s,1H),7.39,7.37(s,s,1H),7.31,7.29(s,s,1H),7.26,7.24(s,s,1H),5.32,5.30(d,d,2H),4.92-4.85(m,2H),4.08,4.06,4.04(m,m,m,2H),3.92-3.90(m,1H),3.77-3.71(m,3H),3.63(s,6H),3.45-3.38(m,2H),2.46-2.38(m,2H),2.22-2.09(m,2H),2.03-1.89(m,6H),1.87-1.80(m,2H),1.64-1.57(m,2H),1.43-1.36(m,2H),1.30-1.16(m,4H),0.97,0.95(m,m,6H),0.94-0.92(m,2H),0.91,0.89(m,m,6H),0.50-0.46(m,2H)ppm。
Example 16
The synthetic route is as follows:
step 1) Synthesis of Compound 16-1
The compound15-3 (0.45 g,1.0 mmol), Compound 1-9 (0.58 g,1.0 mmol), Pd (PPh)3)4(0.12 g,0.1 mmol) and potassium carbonate (0.35 g,2.5 mmol) were placed in a reaction flask, N2Under the protection, DME (5.0 mL) and pure water (1.0 mL) were separately injected, reacted at 90 ℃ for 4.0 hours, cooled to room temperature after completion of the reaction, diluted with ethyl acetate (20 mL), washed with water (10 mL × 3) and saturated brine, and dried over anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 8/1) gave 0.55g of a pale yellow liquid, yield: 72.6 percent.
1H NMR(400MHz,CDCl3):7.62-7.61,7.60-7.59(m,m,2H),7.56-7.55,7.53-7.52(m,m,2H),7.47(s,1H),7.42,7.40(s,s,1H),7.31,7.29(s,s,1H),7.10,7.08(s,s,1H),7.07,7.05(s,s,1H),4.75-4.72(m,1H),3.92-3.90(m,1H),3.74-3.71(m,2H),3.45-3.42(m,1H),3.29-3.23(m,1H),2.42-2.35(m,1H),2.03-1.90(m,5H),1.84-1.78(m,2H),1.61-1.55(m,2H),1.43(s,9H),1.41-1.34(m,2H),1.30-1.17(m,4H),1.02-0.95(m,1H)ppm。
Step 2) Synthesis of Compound 16-2
Mixing compound 16-1 (0.39 g,0.52 mmol), compound 1-6-2 (0.15 g,0.57 mmol), Pd (dppf) Cl2·CH2Cl2(60 mg,0.073 mmol) and KOAc (0.13 g,1.3 mmol) were placed in a reaction flask, N2DMF (4.0 mL) was added under protection, the reaction was carried out at 90 ℃ for 3.0 hours, after completion of the reaction, the mixture was cooled to room temperature, EtOAc (40 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, respectively, and dried over anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 1/2) gave 0.3g of product, yield: 78.4 percent.
MS(ESI,pos.ion)m/z:736.8[M+H]+；
1H NMR(400MHz,CDCl3):7.66,7.64(s,s,1H),7.62-7.61,7.60-7.59(m,m,3H),7.58,7.56(s,s,1H),7.56-7.55,7.53-7.52(m,m,2H),7.47(s,1H),7.31,7.29(s,s,1H),4.75-4.72(m,1H),3.92-3.90(m,1H),3.76-3.71(m,2H),3.69-3.66(m,1H),3.29-3.23(m,1H),2.42-2.35(m,1H),2.00-1.90(m,4H),1.84-1.74(m,3H),1.61-1.53(m,2H),1.43(s,9H),1.42-1.36(m,2H),1.32,1.29(q,q,12H),1.26-1.17(m,3H),1.07-1.01(m,1H),1.00-0.95(m,1H)ppm。
Step 3) Synthesis of Compound 16-3
Mixing compound 16-2 (0.74 g,1.0 mmol), compound 15-12 (0.38 g,1.0 mmol), Pd (PPh)3)4(0.12 g,0.1 mmol) and potassium carbonate (0.35 g,2.5 mmol) were placed in a reaction flask, and DME (5.0 mL) and pure water (1.0 mL), N, were injected, respectively2Reacting at 90 deg.C for 6.0 hr under protection, cooling to room temperature, adding water (20 mL) to dilute the reaction solution, extracting the aqueous layer with EtOAc (20 mL × 3), washing the organic phase with saturated brine, and washing with anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: DCM/MeOH (v/v) = 80/1) gave 0.45g of a pale yellow solid, yield: 50.2 percent.
MS(ESI,pos.ion)m/z:429.5[M+2H]2+；
1H NMR(400MHz,CDCl3):7.95(s,1H),7.62-7.61,7.60-7.59(m,m,2H),7.56-7.55,7.53-7.52(m,m,2H),7.51,7.48(s,s,1H),7.47(s,1H),7.39,7.37(s,s,1H),7.31,7.29(s,s,1H),7.26,7.24(s,s,1H),4.82-4.79(m,1H),4.75-4.72(m,1H),3.92-3.90(m,1H),3.77-3.71(m,3H),3.29-3.23(m,2H),2.42-2.34(m,2H),2.03-1.89(m,6H),1.87-1.80(m,2H),1.64-1.57(m,2H),1.43(s,18H),1.40-1.34(m,4H),1.30-1.16(m,4H),1.02-0.95(m,2H)ppm。
Step 4) Synthesis of Compound 16-4
Compound 16-3 (0.26 g,0.3 mmol) was dissolved in EtOAc (3.0 mL), and after a solution of hydrogen chloride in ethyl acetate (2.0 mL, 4M) was slowly added dropwise, 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 (5.0 mL) and filtered to give 0.2g of a white solid, yield: 83 percent.
MS(ESI,pos.ion)m/z:657.8[M+H]+。
Step 5) Synthesis of Compound 16-5
Compound 16-4 (0.16 g,0.2 mmol), compound 3-18-2 (79.4 mg,0.42 mmol), EDCI (80 mg,0.42 mmol) and HOAT (41 mg,0.3 mmol) were dissolved in DCM (3.0 mL) and DIPEA (0.26 mL,1.6 mmol) was added dropwise slowly at 0 ℃ and the reaction was carried out 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 0.1g of a white solid, yield: 50 percent.
MS(ESI,pos.ion)m/z:500.6[M+2H]2+；
1H NMR(400MHz,CDCl3):7.84(s,1H),7.62(s,1H),7.61-7.60,7.59-7.58(m,m,2H),7.56-7.55,7.53-7.52(m,m,2H),7.51,7.48(s,s,1H),7.39,7.37(s,s,1H),7.31,7.29(s,s,1H),7.26,7.24(s,s,1H),6.51,6.49(s,s,2H),4.89-4.82(m,2H),4.12,4.10,4.08(m,m,m,2H),3.92-3.90(m,1H),3.77-3.71(m,3H),3.65(s,6H),3.37-3.31(m,2H),2.44-2.35(m,2H),2.24-2.13(m,2H),2.03-1.89(m,6H),1.87-1.80(m,2H),1.64-1.57(m,2H),1.47-1.31(m,4H),1.30-1.16(m,4H),1.12-0.99(m,2H),0.95,0.94,0.93,0.91,0.89(m,m,m,m,m,2H),0.88-0.87,0.86-0.85,0.84,0.82(m,m,d,d,12H),0.51,0.49,0.48,0.47(m,m,m,m,2H)ppm。
Example 17
The synthetic route is as follows:
step 1) Synthesis of Compound 17-2
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 2) Synthesis of Compound 17-3
TFA (0.75 mL,10.1 mmol) was added to a solution of compound 17-2 (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 3) Synthesis of Compound 17-4
Pd/C (0.2 g) was added to a solution of compound 17-3 (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 4) Synthesis of Compound 17-5
Compound 17-4 (1.69 g,10mmol) was dissolved in MeOH (20 mL) and Et was added dropwise thereto at 0 ℃ respectively3N (1.67 mL,12 mmol) 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 (50mL), washed with water (20 mL × 3) and saturated brine, respectively, and dried over Na2SO4Drying and concentration gave 2.37g of a colorless oil, yield: 88 percent.
Step 5) Synthesis of Compound 17-6
Slowly adding lithium hydroxide monohydrate (0.48 g,11.35 mmol) in water (10 mL) into compound 17-5 (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 (50mL) 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 6) Synthesis of Compounds 17-7
Compound 17-6 (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 (50mL), washed with water (20 mL × 3) and saturated brine, respectively, and washed with anhydrous Na2SO4Drying and concentration gave 1.01g of a colorless oil, yield: 80 percent.
MS(ESI,pos.ion)m/z:228.3[M+H]+。
Step 7) Synthesis of Compounds 17-9
Dissolving compound 17-7 (1.19 g,5.24 mmol) in DCM (20 mL), adding TCCA (1.22 g,5.24 mmol) at 0 deg.C, slowly adding dropwise TEMPO DCM solution (82 mg,0.52mmol,3 mL), reacting at constant temperature for 1.0 hr, reacting at room temperature for 1.0 hr, filtering after reaction is complete, washing filtrate with 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 8) Synthesis of Compounds 17-10
Dissolving compound 17-9 (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 in 100% yield 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 9) Synthesis of Compounds 17-11
Dissolving compound 17-10 (1.12 g,2.12 mmol) in ethanol (6.0 mL) and water (6.0 mL), adding sodium sulfite (2.14 g,17 mmol), reacting at 90 deg.C for 30 hr, filtering after reaction is complete, concentrating the filtrate, adding DCM (80 mL) to dissolve the residue, washing with water (20 mL × 3) and saturated brine, respectively, 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 10) Synthesis of Compounds 17-12
Pyridine (0.9 g,11.4 mmol) was added dropwise to a solution of compounds 3 to 13 (0.86 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, and concentrated and purified by column chromatography (eluent: PE/EtOAc (v/v) = 5/1) to give 0.94g of a pale yellow liquid, yield: 85 percent.
1H NMR(400MHz,CDCl3):7.26,7.24(s,s,1H),7.17,7.15(s,s,1H),7.08,7.06(s,s,1H),7.03,7.01(t,t,1H),4.03,4.01,3.99,3.97(m,m,m,m,1H),3.88-3.85(m,1H),3.47-3.44(m,1H),3.08-2.97(m,1H),2.81,2.78,2.76,2.74(m,m,m,m,1H),2.56-2.46(m,1H),2.43,2.41,2.39,2.37(m,m,m,m,1H),2.18-2.04(m,2H),2.03-1.92(m,2H),1.82-1.78(m,1H),1.61-1.52(m,2H),1.30-1.19(m,2H)ppm。
Step 11) Synthesis of Compounds 17-13
Mixing compound 17-2 (0.92 g,1.58 mmol), compound 1-6-2 (0.92 g,3.63 mmol), Pd (dppf) Cl2·CH2Cl2(60 mg,0.073 mmol) and KOAc (0.47 g,4.7 mmol) were placed in a reaction flask, N2DMF (10.0 mL) was added under protection, the reaction was carried out at 90 ℃ for 3.0 hours, after completion of the reaction, the mixture was cooled to room temperature, EtOAc (60 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, respectively, and dried over anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE) gave 0.63g of product, yield: 74.1 percent.
1H NMR(400MHz,CDCl3):7.26,7.24(s,s,1H),7.17,7.15(s,s,1H),7.08,7.06(s,s,1H),7.03,7.01(t,t,1H),4.01(m,4H),3.88-3.85(m,1H),3.47-3.44(m,1H),3.08-2.97(m,1H),2.78,(m,4H),2.56-2.46(m,1H),2.41(m,4H),2.18-2.04(m,2H),2.03-1.92(m,2H),1.82-1.78(m,1H),1.61-1.52(m,2H),1.30-1.19(m,26H)ppm。
Step 12) Synthesis of Compounds 17-14
Mixing compound 17-13 (0.58 g,1.0 mmol), compound 17-11 (0.39 g,1.0 mmol), Pd (PPh)3)4(0.12 g,0.1 mmol) and potassium carbonate (0.35 g,2.5 mmol) were placed in a reaction flask, and DME (5.0 mL) and pure water (1.0 mL), N, were injected, respectively2Reacting at 90 deg.C for 6.0 hr under protection, cooling to room temperature, adding water (20 mL) to dilute the reaction solution, extracting the aqueous layer with EtOAc (20 mL × 3), washing the organic phase with saturated brine, and washing with anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: DCM/MeOH (v/v) = 80/1) gave 0.4g of a pale yellow solid, yield: 50 percent.
MS(ESI,pos.ion)m/z:810.1[M+H]+；
1H NMR(400MHz,CDCl3):7.75(s,1H),7.60(s,1H),7.51,7.49(s,s,1H),7.41,7.39(t,t,1H),7.24,7.22(s,s,1H),7.18,7.16(s,s,1H),4.85-4.81(m,1H),4.79-4.76(m,1H),4.50-4.46(m,2H),4.37-4.30(m,1H),3.78-3.74(m,1H),3.24-3.12(m,1H),2.70-2.57(m,2H),2.54-2.50(m,2H),2.25-2.12(m,3H),2.04-1.96(m,3H),1.95-1.89(m,1H),1.88-1.83(m,3H),1.73-1.45(m,11H),1.44(s,18H),1.30-1.24(m,1H),1.22-1.16(m,1H)ppm。
Step 13) Synthesis of Compounds 17-15
Compound 17-14 (0.24 g,0.3 mmol) was dissolved in EtOAc (3.0 mL), and after a solution of hydrogen chloride in ethyl acetate (2.0 mL, 4M) was slowly added dropwise, 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 (5.0 mL) and filtered to give 0.21g of a white solid, yield: 94 percent.
MS(ESI,pos.ion)m/z:609.8[M+H]+。
Step 14) Synthesis of Compounds 17-16
Compound 17-15 (0.15 g,0.2 mmol), compound 1-18-2 (100 mg,0.42 mmol), EDCI (80 mg,0.42 mmol) and HOAT (41 mg,0.3 mmol) were dissolved in DCM (3.0 mL), DIPEA (0.26 mL,1.6 mmol) was slowly added dropwise 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 0.12g of a white solid, yield: 65 percent.
MS(ESI,pos.ion)m/z:462.6[M+2H]2+；
1H NMR(400MHz,CDCl3):7.89(s,1H),7.61(s,1H),7.44,7.42(s,s,1H),7.31,7.29(s,s,1H),7.28,7.26(s,s,1H),7.25,7.23(t,t,1H),5.32,5.30(d,d,2H),4.98-4.94(m,2H),4.80-4.75(m,2H),4.45,4.43-4.42,4.41(m,m,m,2H),4.27-4.20(m,1H),3.87-3.84(m,1H),3.79-3.76(m,1H),3.63(s,6H),3.29,3.26,3.24,3.22(m,m,m,m,1H),3.21-3.12(m,1H),2.83,2.81,2.79,2.77(m,m,m,m,1H),2.59-2.45(m,3H),2.23-1.94(m,8H),1.92-1.88(m,1H),1.83-1.78(m,2H),1.69-1.55(m,8H),1.47-1.36(m,2H),1.30-1.24(m,2H),0.97,0.95(m,m,6H),0.90,0.89(m,m,6H)ppm。
Example 18
The synthetic route is as follows:
step 1) Synthesis of Compound 18-1
Dissolving compound 3-18 (0.73 g,1.88 mmol), compound 1-18-2 (0.4 g,2.25 mmol) and EDCI (0.43 g,2.25 mmol) in DCM (5.0 mL), slowly adding DIPEA (1.24 mL,7.52 mmol) dropwise at 0 deg.C, reacting at room temperature for 3.0 hr, after reaction is complete, adding water (10 mL) to quench the reaction, extracting the aqueous layer with DCM (15 mL × 3), washing the organic phase with saturated brine, anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 1/2) gave 0.75g of a solid, yield: 85 percent. 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 2) Synthesis of Compound 18-2
Mixing compound 18-1 (0.27 g,0.58 mmol), compound 3-13 (0.26 g,0.58 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 (4.0 mL) and pure water (1.0 mL) were separately injected and reacted at 90 ℃ for 4.0 hours while maintaining the same. Reaction ofAfter completion, the reaction mixture was cooled to room temperature, diluted with EtOAc (40 mL), and 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 0.25g of a pale yellow solid, yield: 68 percent.
MS(ESI,pos.ion)m/z:645.8[M+H]+；
1H NMR(400MHz,CDCl3):7.62-7.61,7.60(m,d,2H),7.49(t,2H),7.24,7.22(m,m,1H),7.08,7.06(s,s,1H),6.64,6.62(s,s,1H),5.32,5.29(d,d,1H),5.24-5.20(m,1H),4.39,4.37,4.35(m,m,m,1H),4.12-4.05(m,1H),3.84-3.78(m,1H),3.68-3.64(m,1H),3.63(s,3H),3.58-3.55(m,1H),3.53-3.50(m,1H),3.12-3.01(m,1H),2.67-2.56(m,1H),2.54,2.52,2.50,2.48(m,m,m,m,1H),2.38-2.28(m,1H),2.24-1.88(m,9H),1.87-1.83(m,1H),1.64-1.52(m,2H),1.31-1.19(m,2H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H)ppm。
Step 3) Synthesis of Compound 18-3
Pyridine (0.9 g,11.4 mmol) was added dropwise to a solution of compound 18-2 (1.22 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, and concentrated and purified by column chromatography (eluent: PE/EtOAc (v/v) = 5/1) to give 1.25g of a pale yellow liquid, yield: 85 percent.
1H NMR(400MHz,CDCl3):7.62-7.61,7.60(m,d,2H),7.49(t,2H),7.24,7.22,7.20(m,m,s,2H),7.04,7.02(s,s,1H),5.32,5.29(d,d,1H),5.24-5.20(m,1H),4.40,4.38,4.36(m,m,m,1H),4.12-4.05(m,1H),3.84-3.76(m,2H),3.68-3.65(m,1H),3.63(s,3H),3.56-3.53(m,1H),3.12-3.01(m,1H),2.67-2.48(m,2H),2.39-2.28(m,1H),2.24-1.88(m,9H),1.87-1.83(m,1H),1.64-1.52(m,2H),1.35-1.29(m,1H),1.25-1.19(m,1H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H)ppm。
Step 4) Synthesis of Compound 18-4
Mixing 18-3 (0.60 g,0.77 mmol), 1-6-2 (0.22 g,0.85 mmol), Pd (dppf) Cl2·CH2Cl2(30 mg,0.036 mmol) and KOAc (0.13 g,1.3 mmol) were placed in a reaction flask, N2DMF (8.0 mL) was added under protection, the reaction was carried out at 90 ℃ for 3.0 hours, after completion of the reaction, the mixture was cooled to room temperature, EtOAc (70 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, respectively, and dried over anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 1/2) gave 0.48g of product, yield: 82.6 percent.
MS(ESI,pos.ion)m/z:754.3[M+H]+；
1H NMR(400MHz,CDCl3):7.57(m2H),7.39(m,2H),7.22(m,2H),7.04,7.02(s,s,1H),5.32,5.29(d,d,1H),5.24-5.20(m,1H),4.38(m,1H),4.12-4.05(m,1H),3.84-3.76(m,2H),3.68-3.65(m,1H),3.63(s,3H),3.56-3.53(m,1H),3.12-3.01(m,1H),2.67-2.48(m,2H),2.39-2.28(m,1H),2.24-1.88(m,9H),1.87-1.83(m,1H),1.64-1.52(m,2H),1.35-1.29(m,1H),1.25-1.19(m,13H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H)ppm。
Step 5) Synthesis of Compound 18-5
Mixing compound 18-4 (0.44 g,0.58 mmol), compound 2-2 (0.24 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, N2EtOH (4.0 mL) and pure water (1.0 mL) were injected separately under the protection, and the mixture was reacted at 90 ℃ for 4.0 hours, after completion of the reaction, the reaction mixture was cooled to room temperature, and EtOAc (50mL) was added to dilute the reaction mixture, which was then 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) = 50/1) gave 0.35g of a pale yellow solid, yield: 65.5 percent.
MS(ESI,pos.ion)m/z:461.6[M+2H]2+；
1H NMR(400MHz,CDCl3):7.81(s,1H),7.62-7.61,7.60(m,d,2H),7.58,7.56(s,s,1H),7.50,7.48(t,t,1H),7.31,7.29(s,s,1H),7.26,7.24(s,s,1H),7.23,7.22(m,m,1H),5.32,5.30(d,d,2H),5.28-5.20(m,2H),4.41-4.35(m,2H),4.12-4.05(m,1H),3.87-3.76(m,4H),3.69-3.64(m,2H),3.63(s,6H),3.12-3.01(m,1H),2.67-2.48(m,2H),2.37-1.88(m,16H),1.69-1.65(m,1H),1.62-1.52(m,1H),1.30-1.21(m,2H),0.97,0.95(m,m,6H),0.90,0.89(m,m,6H)ppm。
Example 19
The synthetic route is as follows:
step 1) Synthesis of Compound 19-1
Mixing compound 1-10 (0.54 g,1.0 mmol), compound 2-2 (0.42 g,1.0 mmol), Pd (PPh)3)4(0.12 g,0.1 mmol) and potassium carbonate (0.35 g,2.5 mmol) were placed in a reaction flask, N2Under the protection, EtOH (5.0 mL) and pure water (1.0 mL) were injected separately, and the mixture was reacted at 90 ℃ for 4.0 hours, after completion of the reaction, the reaction mixture was cooled to room temperature, and ethyl acetate (20 mL) was added to dilute the reaction mixture, which was washed with water (10 mL × 3) and saturated brine, respectively, and dried over Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 1/2) gave 0.5g of a pale yellow liquid, yield: 71 percent.
1H NMR(400MHz,CDCl3):7.81(s,1H),7.66,7.64(s,s,1H),7.61,7.59(s,s,1H),7.51,7.49(s,s,1H),7.26,7.24(s,s,1H),5.32,5.30(d,d,1H),5.29-5.25(m,1H),4.41-4.37(m,1H),3.85-3.78(m,1H),3.77-3.73(m,3H),3.69-3.65(m,2H),3.63(s,3H),2.30-1.89(m,8H),1.87-1.83(m,1H),1.80-1.74(m,2H),1.64-1.60(m,1H),1.57-1.53(m,1H),1.32,1.29(q,q,12H),1.28-1.24(m,1H),1.23-1.16(m,2H),1.07-1.01(m,1H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H)ppm。
Step 2) Synthesis of Compound 19-3
Compound 19-2 (2.0 g,15.3 mmol) was dissolved in MeOH (20 mL), thionyl chloride (3.4 mL,46.9 mmol) was slowly added dropwise at 0 ℃ and, after completion of the dropwise addition, reacted at 80 ℃ for 3.5 hours. After completion of the reaction, the reaction solution was concentrated to obtain 2.76g of a white solid, yield: 99.5 percent of the product is directly used for the next reaction.
1H NMR(400Hz,CDCl3):3.68(s,3H),3.58(t,1H),3.56(s,1H),3.32(m,1H),3.02(m,1H),2.77(m,1H),2.52(s,1H),2.21(m,1H),1.96(m,1H)ppm。
Step 3) Synthesis of Compound 19-4
Compound 19-3 (3.1 g,17.1 mmol) was added in one portion to a vigorously stirred solutionChloroformic acid benzyl esterTHF/H of (3.7 mL,26.3 mmol) and potassium carbonate (10.6 g,76.7 mmol)2After completion of the addition, the reaction mixture was reacted at room temperature overnight, and after completion of the reaction, the pH of the reaction mixture was adjusted to 3 with dilute hydrochloric acid (1M), followed by extraction with EtOAc (50mL × 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated and purified by column chromatography (eluent: PE/EtOAc (v/v) = 4/1) to obtain 3.0g of a pale yellow oily liquid, with a yield of 62.8%.
1H NMR(400Hz,CDCl3):7.47(d,2H,J=8.24Hz),7.38(d,2H,J=8.24Hz),7.24(m,1H),5.09(s,2H),4.18(t,1H),3.68(s,3H),3.63(m,1H),3.58(s,1H),3.38(m,1H),3.32(m,1H),2.21(m,1H),1.96(m,1H)ppm。
Step 4) Synthesis of Compound 19-5
Compound 19-4 (1.0 g,3.6 mmol) was dissolved in DCM (20 mL), and dess-martin oxidant (3.0 g,7.1 mmol) was added in portions at 0 ℃ and, after the addition was complete, the reaction was carried out at room temperature for 1.0 hour. After completion of the reaction, the concentrated reaction solution was purified by column chromatography (eluent: PE/EtOAc (v/v) = 5/1) to obtain 0.79g of a yellow oily liquid, yield: 79.5 percent.
1H NMR(400Hz,CDCl3):7.47(d,2H,J=8.24Hz),7.38(d,2H,J=8.24Hz),7.24(m,1H),5.09(s,2H),4.18(t,1H),3.68(s,3H),3.38(m,1H),3.32(m,1H),2.21(m,1H),1.96(m,1H)ppm。
Step 5) Synthesis of Compound 19-6
Compound 19-5 (1.0 g,3.6 mmol) was dissolved in toluene (20 mL), and ethylene glycol (0.8 mL,15.7 mmol) and TsOH (0.14 g,0.8 mmol) were added sequentially, and after the addition was complete, the mixture was refluxed overnight. After completion of the reaction, the reaction solution was diluted with EtOAc (50mL), washed with a saturated sodium bicarbonate solution and a saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE/EtOAc (v/v) = 6/1) to obtain 0.54g of a colorless liquid, yield: 46.7 percent.
1H NMR(400Hz,CDCl3):7.47(d,2H,J=8.24Hz),7.38(d,2H,J=8.24Hz),7.24(m,1H),5.09(s,2H),4.18(t,1H),4.05(m,2H),3.95(m,2H),3.68(s,3H),3.38(m,1H),3.32(m,1H),2.21(m,1H),1.96(m,1H)ppm。
Step 6) Synthesis of Compounds 19-7
Compound 19-6 (0.58 g,1.8 mmol) was dissolved in MeOH (10 mL), Pd/C (0.5 g) was added, and the reaction was hydrogenated at room temperature overnight. After the reaction was complete, filtration was carried out, and the filtrate was concentrated to obtain 0.33g of the product, yield: 98.9 percent. Directly used for the next reaction.
1H NMR(400Hz,CDCl3):4.18(t,1H),4.05(m,2H),3.95(m,2H),3.68(s,3H),3.38(m,1H),3.32(m,1H),2.21(m,1H),1.96(m,1H)ppm。
Step 7) Synthesis of Compounds 19-8
Compound 19-6 (3.48 g,18.6 mmol), compound 1-18-2 (3.26 g,18.6 mmol) and EDCI (7.1 g,37 mmol) were suspended in DCM (50mL), DIPEA (12.3 mL,74.4 mmol) was added dropwise slowly at 0 deg.C, and after completion of the addition, the reaction was carried out overnight at room 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) = 3/1) to obtain 2.5g of a pale yellow oily liquid, yield: 39.1 percent.
1H NMR(400Hz,CDCl3):9.80(s,1H),4.54(d,1H,J=7.25Hz),4.28(m,1H),4.06(m,4H),3.76(m,2H),3.50(s,3H),3.45(s,3H),2.71(m,2H),2.65(m,1H),0.87(m,3H),0.81(m,3H)ppm。
Step 8) Synthesis of Compounds 19-9
Compound 19-8 (0.9 g,2.6 mmol) was dissolved in THF (5.0 mL), and an aqueous solution (5.0 mL) of LiOH (0.12 g,5.0 mmol) was added, followed by reaction at room temperature overnight. After completion of the reaction, the reaction solution was adjusted to pH 2 with dilute hydrochloric acid (1M), extracted with EtOAc (50 mL. times.3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 0.85g of a white solid, yield: 99 percent of the total amount is directly used for the next reaction.
1H NMR(400Hz,CDCl3):9.80(s,1H),4.54(d,1H,J=7.25Hz),4.28(m,1H),4.06(m,4H),3.76(m,2H),3.50(s,3H),2.71(m,2H),2.65(m,1H),0.87(m,3H),0.81(m,3H)ppm。
Step 9) Synthesis of Compounds 19-10
Compound 19-9 (1.54 g,4.66 mmol) was dissolved in THF (10 mL), borane (10 mL,1M inTHF) was slowly added dropwise to the 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 (8 mL), and the reaction solution was concentrated and purified by column chromatography (eluent: PE/EtOAc (v/v) = 3/2) to give 0.96g of a colorless oil, yield: 65 percent.
1H NMR(400MHz,CDCl3):5.32,5.30(d,d,1H),4.36,4.34,4.32,4.30,4.28(m,m,m,m,m,3H),3.99-3.97(m,4H),3.73-3.72,3.71-3.69,3.67-3.66(m,m,m,2H),3.63(s,3H),3.61-3.59,3.57-3.55(m,m,1H),3.40-3.38,3.36-3.34(m,m,1H),25.42-2.36(m,1H),2.17-2.04(m,1H),1.94-1.88(m,1H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H)ppm。
Step 10) Synthesis of Compounds 19-11
Compound 19-10 (1.1 g,3.48 mmol) was dissolved in DCM (10 mL), and dess-martin (2.07 g,4.88 mmol) oxidant was added in portions to the flask at 0 deg.C, after which it was reacted 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) = 3/2) to obtain 0.71g of a colorless oil, yield: 65 percent.
1H NMR(400MHz,CDCl3):9.49-9.48(m,1H),5.32,5.29(d,d,1H),4.79-4.75(m,1H),4.34,4.32,4.30(m,m,m,1H),3.98-3.97(m,4H),3.76-3.75,3.73-3.71(m,m,1H),3.63(s,3H),3.40-3.38,3.36-3.34(m,m,1H),2.64-2.62,2.61-2.59(m,m,1H),2.22-2.10(m,1H),2.00-1.93(m,1H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H)ppm。
Step 11) Synthesis of Compounds 19-12
Compound 19-11 (0.55 g,1.76 mmol) and ammonia (2.0 mL) were dissolved in methanol (5.0 mL), and an aqueous solution of glyoxal (40%, 1 mL) was slowly dropped into the reaction flask at 0 ℃ and reacted overnight at room temperature after 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 0.4g of a white solid, yield: 65 percent.
MS(ESI,pos.ion)m/z:353.4[M+H]+；
1H NMR(400MHz,CDCl3):6.99(s,2H),5.60-5.56(m,1H),5.32,5.29(d,d,1H),4.43,4.41,4.39(m,m,m,1H),3.98-3.96(m,4H),3.94-3.93(m,1H),3.71-3.70,3.67-3.66(m,m,1H),3.63(s,3H),2.77-2.71(m,1H),2.36-2.30(m,1H),2.24-2.11(m,1H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H)ppm。
Step 12) Synthesis of Compounds 19-13
Compound 19-12 (0.70 g,2.0 mmol) was dissolved in DCM (60 mL), and N-iodosuccinimide (0.9 g,4.0 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 0.72g of a white solid, yield: 65 percent.
MS(ESI,pos.ion)m/z:605.2[M+H]+；
1H NMR(400MHz,CDCl3):5.32,5.29(d,d,1H),5.29-5.26(m,1H),4.40,4.38,4.36(m,m,m,1H),3.98-3.96(m,4H),3.93-3.92(m,1H),3.70-3.69,3.67-3.65(m,m,1H),3.63(s,3H),2.75-2.69(m,1H),2.36-2.30(m,1H),2.24-2.11(m,1H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H)ppm。
Step 13) Synthesis of Compounds 19-14
Compound 19-13 (0.91 g,1.5 mmol) was suspended in a mixed solvent (12.5 mL) of ethanol and water (v/v = 3/7), and sodium sulfite (1.7 g,13.5 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 (50mL), extracted with ethyl acetate (50mL × 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 0.57g of a white solid, yield: 80 percent.
MS(ESI,pos.ion)m/z:479.3[M+H]+；
1H NMR(400MHz,CDCl3):7.34(s,1H),5.32,5.29(d,d,1H),5.25-5.21(m,1H),4.42,4.40,4.38(m,m,m,1H),3.98-3.96(m,4H),3.93-3.92(m,1H),3.70-3.69,3.67-3.65(m,m,1H),3.63(s,3H),2.76-2.74,2.73-2.70(m,m,1H),2.38,2.36-2.34,2.32(m,m,m,1H),2.24-2.11(m,1H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H)ppm。
Step 14) Synthesis of Compounds 19-15
Mixing compound 19-14 (0.35 g,0.72 mmol), compound 19-1 (0.51 g,0.72 mmol), Pd (PPh)3)4（83mg0.07 mmol) and potassium carbonate (0.30 g,2.12 mmol) were suspended in DME (4.0 mL) and water (1.0 mL), reacted at 90 ℃ for 4.0 hours under nitrogen, cooled to room temperature after completion of the reaction, the reaction was diluted with EtOAc (50mL), 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 0.35g of the product in 52.3% yield.
MS(ESI,pos.ion)m/z:465.6[M+2H]2+；
1H NMR(400MHz,CDCl3):7.90(s,1H),7.81(s,1H),7.39,7.37(s,s,2H),7.26,7.24(s,s,2H),5.61-5.60,5.59-5.58,5.57(m,m,m,1H),5.32,5.30(d,d,2H),5.29-5.25(m,1H),4.42-4.37(m,2H),3.98-3.96,3.94-3.92(m,m,5H),3.85-3.78(m,1H),3.77-3.73(m,4H),3.71-3.69,3.68-3.64(m,m,2H),3.63(s,6H),2.83-2.81,2.80-2.77(m,m,1H),2.46-2.39(m,1H),2.30-1.89(m,10H),1.87-1.83(m,2H),1.64-1.60(m,2H),1.30-1.24(m,2H),1.22-1.16(m,2H),0.97,0.95(m,m,6H),0.91,0.89(m,m,6H)ppm。
Example 20
The synthetic route is as follows:
step 1) Synthesis of Compound 20-1
A solution of hydrogen chloride in ethyl acetate (5.0 mL, 4M) was added dropwise to a solution of compound 20-1 (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 (5.0 mL) and filtered to give a solid 1.38g, yield: 86 percent. Directly used for the next reaction.
MS(ESI,pos.ion)m/z:317.5[M+H]+。
Step 2) Synthesis of Compound 20-3
Compound 20-2 (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:474.3[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 3) Synthesis of Compound 20-4
Mixing compound 20-3 (0.76 g,1.61 mmol), compound 1-6-2 (0.45 g,1.77 mmol), Pd (dppf) Cl2·CH2Cl2(66 mg,0.081 mmol) and KOAc (0.4 g,4.03 mmol) were placed in a reaction flask, N2DMF (4.0 mL) was injected under the protection, the reaction was carried out at 120 ℃ for 4.0 hours, the reaction was completed, the reaction mixture was cooled to room temperature, ethyl acetate (40 mL) was added to dilute the reaction mixture, the mixture was filtered through celite, the filtrate was washed with water (30 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 0.42g of a pale yellow solid with a yield of 55%.
MS(ESI,pos.ion)m/z:474.3[M+H]+；
1H NMR(400MHz,CDCl3):8.96(m,1H),7.94-7.93(m,1H),7.65-7.64,7.63-7.62(m,m,1H),7.41-7.34(m,2H),5.32,5.30(d,d,1H),4.71-4.66(m,1H),4.31-4.26(m,1H),3.63(s,3H),3.62-3.55(m,1H),3.48-3.40(m,1H),2.27-1.99(m,4H),1.94-1.82(m,1H),1.32,1.29(q,q,12H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H)ppm。
Step 4) Synthesis of Compound 20-5
Compound 20-4 (99 mg,0.21 mmol), compound 19-1 (0.15 g,0.21 mmol), tetrakistriphenylphosphine palladium (25 mg,0.02 mmol) and potassium carbonate (87 mg,0.63 mmol) were suspended in DME/H2O (v/v = 3/1) in a mixed solvent (4.0 mL) was reacted at 90 ℃ for 5.0 hours under nitrogen protection. After completion of the reaction, the reaction solution was concentrated, and the residue was washed with ethyl acetate (20 mL), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent: DCM/EtOH (v/v) = 40/1) to obtain 87mg of a pale yellow solid, yield: 44 percent.
MS(ESI,pos.ion)m/z:463.1[M+2H]2+；
1H NMR(400MHz,CDCl3):8.90(m,1H),8.00-7.99(m,1H),7.81(s,1H),7.52-7.51,7.50-7.49(m,m,1H),7.44,7.42(m,m,1H),7.41,7.40(s,s,1H),7.39,7.37(s,s,1H),7.33,7.31(s,s,1H),7.26,7.24(s,s,1H),7.22,7.20,7.18(m,m,m,1H),5.56,5.55(d,d,1H),5.32,5.30(d,d,1H),5.29-5.25(m,1H),4.62-4.57(m,1H),4.41,4.39,4.37(m,m,m,1H),4.32,4.30,4.29(m,m,m,1H),4.07-4.04(m,1H),3.85-3.78(m,1H),3.77-3.73(m,3H),3.66(s,3H),3.65-3.64(m,1H),3.63(s,3H),2.92-2.80(m,2H),2.30-2.15(m,5H),2.13-1.80(m,11H),1.64-1.57(m,2H),1.30-1.16(m,4H),1.02,1.01(m,m,3H),0.97,0.95(m,m,3H),0.94,0.92(m,m,3H),0.90,0.89(m,m,3H)ppm。
Example 21
The synthetic route is as follows:
step 1) Synthesis of Compound 21-1
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 (100mL) 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 21-2
Compound 21-1 (5.50 g,31.6 mmol) was dissolved in methanol (100mL) with sodium acetate (7.77 g,94.7 mmol) under nitrogen and reacted at 50 ℃ for 3 hours. After completion of the reaction, the reaction solution was directly concentrated and subjected to 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 21-3
Pyridine (9.0 g,114 mmol) was added dropwise to a solution of compound 21-2 (3.31 g,19.0 mmol) in DCM (100mL) at 0 ℃ and stirred for 10 minutes, then trifluoromethanesulfonic anhydride (21.0 g,76.0 mmol) was slowly added dropwise and the reaction was carried out at room temperature for 1.0 hour after completion of the addition. After completion of the reaction, the reaction was quenched with water (50.0 mL), diluted with DCM (100mL), and the organic phase was washed with water (40 mL × 3) and saturated brine, respectively, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (eluent: PE/DCM (v/v) = 20/1) to give 7.9g of a colorless oil, yield: 95.0 percent.
1H NMR(400MHz,CDCl3):7.34(s,2H),6.64-6.61(m,2H),4.12-4.08(m,2H),1.89-1.85(m,1H),1.82-1.78(m,1H)ppm.
Step 4) Synthesis of Compound 21-4
Mixing compound 21-3 (0.44 g,1.0 mmol), compound 1-7 (0.29 g,1.0 mmol), Pd (PPh)3)4(0.12 g,0.1 mmol) and potassium carbonate (0.35 g,2.5 mmol) were placed in a reaction flask, N2Under the protection, DME (5.0 mL) and pure water (1.0 mL) were separately injected, reacted at 90 ℃ for 4.0 hours, cooled to room temperature after completion of the reaction, diluted with ethyl acetate (20 mL), washed with water (10 mL × 3) and saturated brine, and dried over anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 8/1) gave 0.25g of a pale yellow liquid, yield: 55.7 percent.
MS(ESI,pos.ion)m/z:449.5[M+H]+；
1H NMR(400MHz,CDCl3):7.15,7.13(s,s,1H),7.10,7.08(s,s,1H),7.06,7.04(s,s,1H),6.95-6.91(m,1H),6.63-6.60(m,1H),6.57,6.55(s,s,1H),5.77(brs,1H),4.40-4.36(m,1H),3.93-3.90(m,1H),3.58-3.55(m,1H),3.53-3.50(m,1H),2.31-2.27(m,1H),2.23-2.20(m,1H),2.07-2.01(m,1H),1.98-1.92(m,1H),1.90-1.86(m,1H),1.67-1.63(m,1H),1.34-1.28(m,1H),1.25-1.19(m,1H)ppm。
Step 5) Synthesis of Compound 21-5
Mixing compound 21-4 (0.22 g,0.5 mmol), compound 2-7 (0.25 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 6 hours with protection. After completion of the reaction, EtOAc (50mL) was added to dilute the reaction and saturatedWashed with brine and anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 1/1) gave 0.2g of a pale yellow solid, yield: and (5) 59.8%.
1H NMR(400MHz,CDCl3):7.63-7.62,7.61-7.60(m,m,2H),7.59(s,1H),7.57-7.56,7.55-7.54(m,m,2H),7.41,7.38(s,s,1H),7.28,7.25(s,s,1H),7.17,7.15(s,s,1H),6.96-6.95(m,2H),6.57,6.55(s,s,1H),5.32,5.30(d,d,1H),5.23-5.19(m,1H),4.44-4.41,4.39,4.36(m,m,m,2H),4.25-4.22(m,1H),3.85-3.78(m,1H),3.69-3.64(m,1H),3.63(s,3H),3.58-3.55(m,1H),3.53-3.50(m,1H),2.33-2.15(m,5H),2.13-1.92(m,4H),1.90-1.86(m,1H),1.67-1.63(m,1H),1.34-1.28(m,1H),1.25-1.19(m,1H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H)ppm。
Step 6) Synthesis of Compound 21-6
Pyridine (0.3 mL,4.0 mmol) was added dropwise to a solution of compound 21-5 (0.67 g,1.0 mmol) in DCM (5.0 mL) at 0 ℃ and stirred for 10 minutes, and after dropwise addition, trifluoromethanesulfonic anhydride (0.34 mL,2.0 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 (10 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, and concentrated and purified by column chromatography (eluent: PE/EtOAc (v/v) = 2/1) to give 0.65g of a pale yellow solid, yield: 81.2 percent.
1H NMR(400MHz,CDCl3):7.63-7.62,7.61-7.60(m,m,2H),7.59(s,1H),7.57-7.56,7.55-7.54(m,m,2H),7.38,7.35(s,s,1H),7.27,7.25(s,s,1H),7.09,7.07(s,s,1H),7.03,7.01(s,s,1H),6.96-6.95(m,2H),5.32,5.29(d,d,1H),5.23-5.19(m,1H),4.44-4.41,4.39,4.36(m,m,m,2H),4.25-4.22(m,1H),3.85-3.78(m,1H),3.74-3.71(m,1H),3.69-3.64(m,1H),3.63(s,3H),3.51-3.48(m,1H),2.33-2.15(m,5H),2.13-1.92(m,4H),1.90-1.86(m,1H),1.67-1.63(m,1H),1.38-1.32(m,1H),1.25-1.19(m,1H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H)ppm。
Step 7) Synthesis of Compounds 21-7
Mixing compound 21-6 (0.8 g,1.0 mmol), compound 3-1 (0.42 g,1.0 mmol), Pd (PPh)3)4(0.12 g,0.1 mmol) and potassium carbonate (0.35 g,2.5 mmol) were placed in a reaction flask, and DME (5.0 mL) and pure water (1.0 mL), N, were injected, respectively2Reacting at 90 deg.C for 6.0 hr under protection, cooling to room temperature, adding water (20 mL) to dilute the reaction solution, extracting the aqueous layer with EtOAc (20 mL × 3), washing the organic phase with saturated brine, and washing with anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: DCM/MeOH (v/v) = 50/1) gave 0.45g of a pale yellow solid, yield: 47.6 percent.
MS(ESI,pos.ion)m/z:473.6[M+2H]2+；
1H NMR(400MHz,CDCl3):7.81(s,1H),7.63-7.62,7.61-7.60(m,m,2H),7.59(s,1H),7.57-7.56,7.55-7.54(m,m,2H),7.46,7.44(d,d,2H),7.28,7.25(d,d,2H),6.96-6.95(m,2H),5.32,5.30(d,d,2H),5.29-5.25(m,1H),5.23-5.19(m,1H),4.44-4.41,4.39,4.37(m,m,m,3H),4.25-4.22(m,1H),3.85-3.78(m,3H),3.78-3.73(m,1H),3.69-3.64(m,2H),3.63(s,6H),2.33-2.15(m,8H),2.13-2.03(m,2H),2.02-1.91(m,5H),1.72-1.68(m,1H),1.30-1.24(m,2H),0.97,0.95(m,m,6H),0.90,0.89(m,m,6H)ppm。
Example 22
The synthetic route is as follows:
step 1) Synthesis of Compound 22-2
Compound 22-1 (11.12 g,138.8 mmol) was added dropwise to a solution of benzoquinone (10.0 g,92.5 mmol) in DCM (50.0 mL) at-10 ℃ and reacted at constant temperature for 1.0 hour and then at room temperature for 0.5 hour. After completion of the reaction, the reaction solution was concentrated, and n-hexane (500 mL) was added to the residue, followed by stirring and filtration to obtain 11.3g of a pale yellow solid, yield: 65 percent.
MS(ESI,pos.ion)m/z:189.3[M+H]+；
1H NMR(400MHz,CDCl3):6.71(d,2H),6.20-6.19(m,2H),3.08-3.05(m,2H),2.46-2.44(m,2H),2.30-2.23(m,1H),0.96-0.93(m,3H)ppm.
Step 2) Synthesis of Compound 22-3
Compound 22-2 (5.94 g,31.6 mmol) was reacted with sodium acetate (7.77 g,94.7 mmol) in methanol (100mL) at 50 ℃ for 3.0 hours under nitrogen. After the reaction was completed, the reaction solution was concentrated to obtain 5.5g of a white solid, yield: 92.7 percent.
MS(ESI,pos.ion)m/z:189.5[M+H]+；
1H NMR(400MHz,CDCl3):6.65-6.64(m,2H),6.47(s,2H),5.41(br,2H),3.76-3.72(m,2H),2.64-2.57(m,1H),1.15-1.12(m,3H)ppm.
Step 3) Synthesis of Compound 22-4
Compound 22-3 (5.07 g,27.0 mmol) and Pd/C (500 mg) were suspended in methanol (50.0 mL) and reacted at room temperature for 1.5 hours in a hydrogen system under normal pressure. After the reaction was completed, filtration was performed, and the filtrate was concentrated and then purified by recrystallization to obtain 3.59g of a white solid, yield: 70 percent.1H NMR(400MHz,CDCl3):6.40(s,2H),5.77(br,2H),3.10-3.08(m,2H),2.42-2.34(m,1H),2.08-2.04(m,2H),1.34-1.30(m,2H),0.90-0.87(m,3H)ppm.
Step 4) Synthesis of Compound 22-5
Pyridine (9.0 g,114 mmol) was added dropwise to a solution of compound 22-4 (3.61 g,19.0 mmol) in DCM (90.0 mL) at 0 ℃ and stirred for 10 minutes, then trifluoromethanesulfonic anhydride (21.0 g,76.0 mmol) was added dropwise and the reaction was carried out at room temperature for 1.0 hour after completion of the dropwise addition. After completion of the reaction, the reaction was quenched with water (50mL), diluted with DCM (50.0 mL), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and separated by column chromatography (eluent: PE/DCM (v/v) = 20/1) to give 8.45g of a colorless oil, yield: 98.0 percent.
1H NMR(400MHz,CDCl3):7.27(s,2H),3.22-3.19(m,2H),2.17-2.10(m,1H),2.03-1.99(m,2H),1.29-1.25(m,2H),1.03-1.01(m,3H)ppm.
Step 5) Synthesis of Compound 22-6
Mixing compound 22-5 (0.45 g,1.0 mmol), compound 1-7 (0.29 g,1.0 mmol), Pd (PPh)3)4(0.12 g,0.1 mmol) and potassium carbonate (0.35 g,2.5 mmol) were placed in a reaction flask, and DME (5.0 mL) and pure water (1.0 mL), N, were injected, respectively2Reacting at 90 deg.C for 6.0 hr under protection, cooling to room temperature, adding water (20 mL) to dilute the reaction solution, extracting the aqueous layer with EtOAc (20 mL × 3), washing the organic phase with saturated brine, and washing with anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 8/1) gave 0.35g of a colorless liquid, yield: 75.3 percent.
MS(ESI,pos.ion)m/z:465.5[M+H]+；
1H NMR(400MHz,CDCl3):7.11,7.09(s,s,1H),7.06,7.05(s,s,1H),7.04,7.03(s,s,1H),6.57,6.55(s,s,1H),5.77(brs,1H),3.58-3.54(m,1H),3.53-3.47(m,2H),3.16-3.12(m,1H),2.44-2.37(m,1H),2.06-1.92(m,4H),1.82-1.78(m,1H),1.59-1.55(m,1H),1.31-1.19(m,4H),0.86,0.84(t,t,3H)ppm。
Step 6) Synthesis of Compounds 22-7
Pyridine (1.29 mL,16 mmol) was added dropwise to a solution of compound 22-6 (1.86 g,4.0 mmol) in DCM (5.0 mL) at 0 ℃ and stirred for 10 minutes, and after that, trifluoromethanesulfonic anhydride (1.35 mL,8.0 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 1.95g of a colorless liquid, yield: 81.7 percent.
1H NMR(400MHz,CDCl3):7.12,7.10(s,s,1H),7.07-7.02(m,3H),3.88-3.85(m,1H),3.51-3.47(m,2H),3.16-3.12(m,1H),2.44-2.37(m,1H),2.06-1.92(m,4H),1.82-1.78(m,1H),1.59-1.55(m,1H),1.31-1.19(m,4H),0.86,0.84(t,t,3H)ppm。
Step 7) Synthesis of Compounds 22-8
Mixing compound 22-7 (0.6 g,1.0 mmol), compound 3-1 (0.88 g,2.1 mmol), Pd (PPh)3)4(0.12 g,0.1 mmol) and potassium carbonate (0.35 g,2.5 mmol) were placed in a reaction flask, and DME (5.0 mL) and pure water (1.0 mL), N, were injected, respectively2Reacting at 90 deg.C for 6.0 hr under protection, cooling to room temperature, adding water (20 mL) to dilute the reaction solution, extracting the aqueous layer with EtOAc (20 mL × 3), washing the organic phase with saturated brine, and washing with anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: DCM/MeOH (v/v) = 50/1) gave 0.35g of a pale yellow solid, yield: 39.5 percent.
MS(ESI,pos.ion)m/z:444.6[M+2H]2+；
1H NMR(400MHz,CDCl3):7.81(s,1H),7.80(s,1H),7.36,7.35(s,s,1H),7.34,7.32(s,s,1H),7.27,7.25(s,s,1H),7.24,7.23(s,s,1H),5.32,5.30(d,d,2H),5.29-5.25(m,2H),4.41,4.39,4.37(m,m,m,2H),3.85-3.78(m,3H),3.77-3.74(m,1H),3.69-3.64(m,2H),3.63(s,6H),3.52-3.49(m,1H),3.17-3.13(m,1H),2.40-2.33(m,1H),2.30-1.89(m,14H),1.87-1.83(m,1H),1.64-1.60(m,1H),1.35-1.24(m,3H),1.22-1.16(m,1H),0.97,0.95(m,m,6H),0.90,0.89(m,m,6H),0.87(t,3H)ppm。
Example 23
The synthetic route is as follows:
step 1) Synthesis of Compound 23-1
Pyridine (0.32 mL,4.0 mmol) was added dropwise to a solution of compound 12-4 (0.46 g,1.0 mmol) in DCM (5.0 mL) at 0 ℃ and stirred for 10 minutes, and after dropwise addition, trifluoromethanesulfonic anhydride (0.34 mL,2.0 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 (10 mL), the aqueous layer was extracted with DCM (15 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) = 8/1) to give 0.52g of a colorless liquid, yield: 87.2 percent.
1H NMR(400MHz,CDCl3):7.65,7.62(s,s,1H),7.07,7.05(s,s,1H),7.04,7.02(s,s,1H),7.00,6.98(s,s,1H),3.89-3.86(m,1H),3.74-3.71(m,1H),3.65-3.62(m,1H),3.49-3.46(m,1H),2.58-2.51(m,1H),2.48-2.40(m,1H),2.23-2.17(m,1H),2.16-2.05(m,2H),1.98-1.90(m,2H),1.71-1.67(m,1H),1.42-1.36(m,1H),1.25-1.19(m,1H)ppm。
Step 2) Synthesis of Compound 23-2
Mixing compound 23-1 (0.6 g,1.0 mmol), compound 3-1 (0.88 g,2.1 mmol), Pd (PPh)3)4(0.12 g,0.1 mmol) and potassium carbonate (0.35 g,2.5 mmol) were placed in a reaction flask, and DME (5.0 mL) and pure water (1.0 mL), N, were injected, respectively2Reacting at 90 deg.C for 6.0 hr under protection, cooling to room temperature, adding water (20 mL) to dilute the reaction solution, extracting the aqueous layer with EtOAc (20 mL × 3), washing the organic phase with saturated brine, and washing with anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: DCM/MeOH (v/v) = 50/1) gave 0.45g of a pale yellow solid, yield: 50.8 percent.
MS(ESI,pos.ion)m/z:443.5[M+2H]2+；
1H NMR(400MHz,CDCl3):7.83(s,1H),7.81(s,1H),7.37,7.36(s,s,1H),7.35,7.34(s,s,1H),7.28,7.26(s,s,1H),6.97,6.95(s,s,1H),6.07,6.05(d,d,1H),5.32,5.30(d,d,1H),5.29-5.25(m,2H),4.41,4.39,4.37(m,m,m,1H),4.33,4.31,4.30(m,m,m,1H),3.95-3.91(m,2H),3.85-3.74(m,4H),3.69-3.65(m,2H),3.64(s,3H),3.63(s,3H),2.56-2.49(m,1H),2.47-2.40(m,1H),2.30-1.92(m,15H),1.76-1.72(m,1H),1.34-1.24(m,2H),1.02,1.00(m,m,3H),0.97,0.95(m,m,3H),0.93,0.91(m,m,3H),0.90,0.89(m,m,3H)ppm。
Example 24
The synthetic route is as follows:
step 1) Synthesis of Compound 24-2
Compound 24-1 (2.1 g,9.17 mmol) was dissolved in THF (20 mL), and an aqueous solution of NaOH (2.1 g,20 mL) was added to react at 60 ℃ overnight. After completion of the reaction, THF was removed, the residue was dissolved in EtOAc (50mL), extracted with water (50 mL. times.3), the aqueous phases were combined and pH was adjusted to 4 with hydrochloric acid (1M) and a solid precipitated, which was filtered to give a pale yellow solid 1.4g, yield: 72 percent.
MS(ESI,pos.ion)m/z:217[M+H]+；
1H NMR(400MHz,CDCl3):7.59(d,1H,J=8.0Hz),6.96(d,1H,J=1.6Hz),6.64(dd,1H,J=8.0Hz,2.0Hz)ppm。
Step 2) Synthesis of Compound 24-3
Compound 24-2 (1.51 g,7.00 mmol) was dissolved in anhydrous THF (5mL), CDI (0.83 g,5.12 mmol) was added, and after completion of the addition, the reaction mixture was cooled to 0 ℃ after 2.0 hours at room temperature, and ammonia water (20 mL) was slowly added dropwise, and the reaction was carried out overnight at room temperature after completion of the dropwise addition. After completion of the reaction, THF was removed, and the residue was dissolved in ethyl acetate (100mL), washed with saturated brine, and dried over anhydrous Na2SO4Drying and concentration gave 1.2g of a pale yellow solid, yield: 80 percent.
MS(ESI,pos.ion)m/z:217[M+H]+；
1H NMR(400MHz,CDCl3):7.78(s,1H),7.45(d,1H,J=8.0Hz),7.15(s,1H),6.89(d,1H,J=2.0Hz),6.79(s,1H),6.61(dd,1H,J=8.0Hz,2.0Hz)ppm。
Step 3) Synthesis of Compound 24-4
Compound 24-3 (1.5 g,7.00 mmol), compound 24-3-2 (2.85 g,10.47 mmol) and EDCI (2.67 g,13.93 mmol) were suspended in DCM (15 mL) and THF (10 mL), and DIPEA (5.8 mL,35 mmol) was added dropwise slowly under nitrogen protection at 0 ℃ and reacted at room temperature for 8.0 hours after completion of the addition. After completion of the reaction, the solvent was removed, and the residue was dissolved in EtOAc (100mL), washed with water and saturated brine, respectively, and anhydrous Na2SO4Dried, concentrated and purified by column chromatography (eluent: PE/EtOAc (v/v) = 1/3) to obtain 0.66g of a colorless transparent oil, yield: 20 percent.
MS(ESI,pos.ion)m/z:470.33[M+H]+；
1H NMR(400MHz,CDCl3):11.92(s,1H),8.63(s,1H),7.39(d,1H,J=8.0Hz),7.05(d,1H,J=8.0Hz),5.57(d,1H,J=8.0Hz),4.52-4.49(m,1H),4.40-4.36(m,1H),3.89-3.86(m,2H),3.68(s,3H),2.24-2.15(m,2H),2.09-2.00(m,2H),1.09(d,3H,J=6.0Hz),0.97(d,3H,J=6.0Hz)ppm。
Step 4) Synthesis of Compound 24-5
Compound 24-4 (0.6 g,1.28 mmol) was dissolved in THF (10 mL)) An aqueous solution of lithium hydroxide (0.27 g,6 mL) was slowly added dropwise at 0 ℃ and the reaction was carried out at room temperature for 5.0 hours after completion of the dropwise addition. After completion of the reaction, THF was removed, and EtOAc (50mL) was added to the residue, which was washed with water and saturated brine, respectively, anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 1/3) gave 0.55g of a white solid, yield: 96 percent.
MS(ESI,pos.ion)m/z:452.33[M+H]+；
1H NMR(400MHz,CDCl3):11.31(s,1H),8.07(d,1H,J=8.0Hz),7.79(d,1H,J=2.0Hz),7.53(dd,1H,J=8.0Hz,2.0Hz),5.78(d,1H,J=8.0Hz),5.10(dd,1H,J=8.0Hz,2.0Hz),4.33(t,1H,J=8.0Hz),4.14-4.09(m,1H),3.90-3.86(m,1H),3.66(s,3H),2.53-2.51(m,1H),2.31-2.29(m,1H),2.18-2.16(m,1H),2.04-1.79(m,2H),0.93(d,1H,J=2.0Hz)ppm。
Step 5) Synthesis of Compound 24-6
Compound 24-5 (0.2 g,0.44 mmol), Pd (dppf) Cl2·CH2Cl2(0.04 g,0.049 mmol), anhydrous potassium acetate (0.11 g,1.12 mmol) and compound 1-6-2 (0.13 g,0.51 mmol) were mixed in a reaction flask, DMF (5mL) was injected under nitrogen protection, reaction was carried out at 80 ℃ for 3.0 hours, after completion of the reaction, the mixture was cooled to room temperature, EtOAc (20 mL) was added to dilute the reaction mixture, celite was filtered, and the filtrate was washed with water (20 mL × 3) and saturated brine, respectively, anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 2/1) gave 0.16g of a pale yellow solid, yield: 70 percent.
MS(ESI,pos.ion)m/z:499.26[M+H]+；
1H NMR(400MHz,CDCl3):11.08(s,1H),8.22(d,1H,J=8.0Hz),8.11(s,1H),7.83(d,1H,J=8.0Hz),5.71(d,1H,J=8.0Hz),5.17(d,1H,J=6.0Hz),4.35(t,1H,J=8.0Hz),4.15-4.10(m,1H),3.88-3.86(m,1H),3.67(s,3H),2.71-2.67(m,1H),2.34-2.32(m,1H),2.09-1.99(m,2H),2.04-1.37(s,12H),0.94-0.89(m,6H)ppm。
Step 6) Synthesis of Compounds 24-7
Mixing compound 24-6 (0.12 g,0.23 mmol), compound 19-1 (0.11 g,0.16 mmol), Pd (PPh)3)4(30 mg,0.03 mmol) and potassium carbonate (60 mg,0.44 mmol) were mixed in a reaction flask, DME (3 mL) and water (1 mL) were injected under nitrogen, respectively, and the mixture was reacted at 90 ℃ for 3.0 hours, after completion of the reaction, ethyl acetate (50mL) was added to dilute the reaction mixture, which was washed with water (20 mL × 3) and saturated brine, respectively, and washed with anhydrous Na2SO4After drying, concentration and purification by column chromatography (eluent: MeOH/DCM (v/v) = 1/25) gave 98.7mg of a pale yellow solid, yield: 65 percent.
MS(ESI,pos.ion)m/z:475.6[M+2H]2+；
1H NMR(400MHz,CDCl3):7.97-7.96(m,1H),7.81(s,1H),7.56(d,2H),7.47,7.45-7.44,7.42(d,m,d,2H),7.39,7.37(s,s,1H),7.26,7.24(s,s,1H),5.56,5.55(d,d,1H),5.32,5.30(d,d,1H),5.29-5.25(m,1H),5.21-5.15(m,1H),4.41,4.39,4.37(m,m,m,1H),4.29,4.27,4.26(m,m,m,1H),4.03-4.01(m,1H),3.85-3.78(m,1H),3.77-3.73(m,3H),3.68-3.67(m,1H),3.66(s,3H),3.63(s,3H),3.51-3.43,3.42-3.34(m,m,2H),2.50-2.42(m,1H),2.37-1.80(m,15H),1.64-1.57(m,2H),1.30-1.16(m,4H),1.02,1.00(m,m,3H),0.97,0.95(m,m,3H),0.93,0.91(m,m,3H),0.90,0.89(m,m,3H)ppm。
Example 25
The synthetic route is as follows:
step 1) Synthesis of Compound 25-2
25-1 (1.9 g,10mmol) was dissolved in DCM (20 mL), a solution of m-CPBA (3.45 g,20 mmol) in DCM was added dropwise at 0 ℃ and the reaction was allowed to return to room temperature for 7 hours after completion of the addition. The reaction was completed, diluted with 20mL of DCM, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by spin-dry column chromatography (eluent: PE/EtOAc (v/v) = 10/1) to give 1.6g of a white solid, yield: 77 percent
MS(ESI,pos.ion)m/z:208.3[M+H]+；
1H NMR(400MHz,CDCl3):8.29(d,1H),7.11(d,1H),3.43(s,3H),3.56-3.53(m,1H),3.33-3.30(m,1H),1.97-1.86(m,2H),1.80-1.76(m,1H),1.57-1.53(m,1H),1.24-1.13(m,2H)ppm。
Step 2) Synthesis of Compound 25-3
25-2 (1.6 g, 6.67 mmol) was dissolved in 20mL of a solution of sodium methoxide (0.54 g,10mmol) in methanol, and the reaction was heated under reflux in an oil bath, after 10 hours, the reaction was completed, the solvent was concentrated under reduced pressure, 100mL of EA was added, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, spin-dried, and purified by column chromatography (eluent: EA: PE =1:10) to obtain 1.1g of a white solid, yield: 82.3 percent of
MS(ESI,pos.ion)m/z:176.2[M+H]+；
1H NMR(400MHz,CDCl3):8.29(d,1H),7.11(d,1H),3.8(s,3H),3.56-3.53(m,1H),3.33-3.30(m,1H),1.97-1.86(m,2H),1.80-1.76(m,1H),1.57-1.53(m,1H),1.24-1.13(m,2H)ppm。
Step 3) Synthesis of Compound 25-4
25-3 (1.3 g, 6.31 mmol) was dissolved in DCM (20 mL), NBS (1.35 g,7.6 mmol) was added portionwise at RT, after addition, the reaction was stirred at RT, after 5h reaction completion, diluted with 50mL DCM, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, spin dried, purified by column chromatography (eluent: EA: PE =1: 15) to give 1.4g of a white solid, yield: 87.8 percent
MS(ESI,pos.ion)m/z:255.1[M+H]+；
1H NMR(400MHz,CDCl3):7.88(d,1H),3.8(s,3H),3.56-3.53(m,1H),3.33-3.30(m,1H),1.97-1.86(m,2H),1.80-1.76(m,1H),1.57-1.53(m,1H),1.24-1.13(m,2H)ppm。
Step 4) Synthesis of Compound 25-5
Compounds 1-7 (0.33 g,1.14 mmol), compound 25-4 (0.32 g,1.25 mmol), potassium carbonate (0.39 g,2.84 mmol) and Pd (PPh) were separately added3)4(65.7 mg,0.057 mmol) in a reaction flask, N2DME (8.0 mL) and water (2.0 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 (50mL) 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) = 8/1) gave 0.27g of a white solid, yield: 65 percent.
MS(ESI,pos.ion)m/z:334.4[M+H]+；
1H NMR(400MHz,CDCl3) 8.29(s,1H),7.11,7.09(s, s,1H),6.63,6.61(s, s,1H),5.77(brs,1H),3.95(s,3H),3.66-3.58(m,2H),3.43-3.40(m,1H),3.33-3.28(m,1H),2.08-2.02(m,1H),1.98-1.91(m,3H),1.81-1.77(m,1H),1.69-1.65(m,1H),1.58-1.54(m,1H),1.50-1.46(m,1H),1.25-1.18(m,3H),1.14-1.08(m,1H) ppm. Step 5) Synthesis of Compound 25-6
Pyridine (0.26 mL,3.2 mmol) and compound 25-5 (0.27 g,0.8 mmol) are dissolved in DCM (10 mL) at 0 ℃, after stirring for 10 minutes, trifluoromethanesulfonic anhydride (0.27 mL,1.6 mmol) is added dropwise, reaction is carried out at room temperature for 1.0 hour, after completion of reaction, ice water (25 mL) is added to quench the reaction, the aqueous layer is extracted with DCM (25 mL × 3), the organic phases are combined, washed with saturated brine, anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE) gave 0.34g of a colorless oily liquid, yield: 90.5 percent.
1H NMR(400MHz,CDCl3):8.37(s,1H),7.30,7.28(s,s,1H),7.18,7.16(s,s,1H),3.98-3.96(m,1H),3.95(s,3H),3.61-3.58(m,1H),3.43-3.40(m,1H),3.28-3.25(m,1H),2.08-1.91(m,4H),1.81-1.77(m,1H),1.69-1.65(m,1H),1.58-1.54(m,1H),1.50-1.46(m,1H),1.29-1.18(m,3H),1.14-1.08(m,1H)ppm。
Step 6) Synthesis of Compounds 25-7
Respectively mixing compound 25-6 (0.47 g,1.0 mmol), compound 3-1 (0.42 g,1.0 mmol), potassium carbonate (0.35 g,2.5 mmol) and Pd (PPh)3)4(0.12 g,0.1 mmol) in a reaction flask, N2DME (4.0 mL) and water (1.0 mL) were separately injected and reacted at 90 ℃ for 6.0 hours with protection. After completion of the reaction, the reaction mixture was cooled to room temperature, and EtOAc (30 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) = 2/1) gave 0.5g of a white solid, yield: 82 percent.
MS(ESI,pos.ion)m/z:610.8[M+H]+；
1H NMR(400MHz,CDCl3):8.40(s,1H),7.81(s,1H),7.38,7.36(s,s,1H),7.30,7.28(s,s,1H),5.32,5.30(d,d,1H),5.29-5.25(m,1H),4.41-4.40,4.39-4.38,4.37-4.36(m,m,m,1H),3.95(s,3H),3.85-3.78(m,2H),3.69-3.64(m,2H),3.63(s,3H),3.61-3.58(m,1H),3.43-3.40(m,1H),2.30-2.15(m,3H),2.13-1.88(m,6H),1.86-1.82(m,1H),1.69-1.65(m,1H),1.63-1.59(m,1H),1.50-1.46(m,1H),1.30-1.15(m,3H),1.14-1.08(m,1H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H)ppm。
Step 7) Synthesis of Compounds 25-8
Compound 25-7 (1.69 g,2.77 mmol) was dissolved in DCM (20 mL) at-78 deg.C and then BBr was added dropwise slowly3(0.36 mL,3.88 mmol) and reacting at room temperature for 1.0 h, after the reaction is completed, the reaction solution is slowly poured into ice water (20 mL), the aqueous layer is extracted with DCM (20 mL × 3), and the organic phase is extracted with anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 1/1) gave 1.55g of a grey solid, yield: 94 percent.
MS(ESI,pos.ion)m/z:596.7[M+H]+；
1H NMR(400MHz,CDCl3):8.04(s,1H),7.81(s,1H),7.38,7.36(s,s,1H),7.29,7.26(s,s,1H),5.32,5.30(d,d,1H),5.29-5.25(m,1H),4.41-4.40,4.39-4.38,4.37-4.36(m,m,m,1H),3.85-3.78(m,2H),3.69-3.64(m,2H),3.63(s,3H),3.62-3.60(m,1H),3.53-3.51(m,1H),2.30-2.15(m,3H),2.13-1.88(m,6H),1.86-1.82(m,1H),1.67-1.59(m,2H),1.48-1.44(m,1H),1.30-1.24(m,2H),1.21-1.09(m,2H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H)ppm。
Step 8) Synthesis of Compounds 25-9
Pyridine (0.25 g,3.2 mmol) and compound 25-8 (0.48 g,0.8 mmol) are dissolved in DCM (5.0 mL) at 0 deg.C, after stirring for 10 minutes, trifluoromethanesulfonic anhydride (0.45 g,1.6 mmol) is added dropwise, reaction is carried out at room temperature for 1.0 hour, after completion of reaction, ice water (10 mL) is added to quench reaction, aqueous layer is extracted with DCM (25 mL × 3), organic phases are combined, washing with saturated brine, anhydrous Na2SO4Drying, concentration and purification by column chromatography (eluent: PE/EtOAc (v/v) = 2/1) gave 0.52g of a pale yellow solid, yield: 90 percent.1H NMR(400MHz,CDCl3):8.36(s,1H),7.81(s,1H),7.38,7.36(s,s,1H),7.30,7.28(s,s,1H),5.32,5.30(d,d,1H),5.29-5.25(m,1H),4.41-4.40,4.39-4.38,4.37-4.36(m,m,m,1H),3.85-3.78(m,2H),3.69-3.64(m,3H),3.63(s,3H),3.51-3.48(m,1H),2.30-2.15(m,3H),2.13-1.88(m,6H),1.86-1.82(m,1H),1.66-1.59(m,2H),1.47-1.44(m,1H),1.34-1.24(m,2H),1.21-1.09(m,2H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H)ppm。
Step 9) Synthesis of Compounds 25-11
Mixing Na2SO3A mixture of (7.16 g,56.8 mmol) ethanol (100mL) and water (125 mL) was slowly added dropwise to a solution of compound 25-10 (5.0 g,22.7 mmol) in EtOH (60 mL), and the reaction was carried out at 70 ℃ for 15 hours after completion of the dropwise addition. After completion of the reaction, the reaction mixture was cooled to room temperature, the pH was adjusted to 2 with hydrochloric acid (2M), the mixture was concentrated, and then saturated brine (100mL) was added thereto and the mixture was refluxed until the residue remainedAfter all the substances were dissolved, water (10 mL) was added thereto, and the reaction mixture was cooled to 0 ℃ to precipitate a solid. After the solid was completely precipitated, filtration was carried out to obtain 5.70g of a product, yield: 89 percent.
MS(ESI,pos.ion)m/z:282.5[M+H]+；
1H NMR(400MHz,CDCl3):8.75(br,1H),8.31(m,1H),8.07(m,2H)ppm。
Step 10) Synthesis of Compounds 25-12
Thionyl chloride (5.0 mL) was added dropwise to a solution of compound 25-11 (3.0 g,10.6 mmol) and DMF (1 drop) in toluene (50mL), and after dropwise addition, the mixture was refluxed for 4.0 hours. After completion of the reaction, it was cooled and concentrated, and the residue was dissolved in toluene (4 mL), cooled to-10 ℃ and then added with saturated ammonium hydroxide solution (1.0 mL) and THF (10 mL) to conduct a reaction at a constant temperature for 2.0 hours. After the reaction was complete, the pH was adjusted to 4 with hydrochloric acid (6M), the organic layer was separated, dried and concentrated. PE (15 mL) was added to the remaining slurry, and a solid precipitated, which was filtered to give compound 25-12.
MS(ESI,pos.ion)m/z:281.5[M+H]+；
1H NMR(400MHz,CDCl3):8.18,8.17(d,d,1H),8.03,8.00(d,d,1H),7.84,7.81(d,d,1H),5.47(br,2H)ppm。
Step 11) Synthesis of Compounds 25-13
Compound 25-12 (2.12 g,7.5 mmol) was dissolved in HI (25.0 mL,57% aqueous solution) and reacted at 90 ℃ for 4.0 hours. After completion of the reaction, the reaction mixture was cooled to a purple black color, diluted with EtOAc (50mL), washed with a sodium thiosulfate solution, a saturated sodium bicarbonate solution and a saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, concentrated and subjected to high performance liquid chromatography (mobile phase: CH)3CN/H2O =22/78-52/48 (containing 0.01% NH)3·H2O buffer)) was separated to obtain 1.86g of the product.
MS(ESI,pos.ion)m/z:251.5[M+H]+；
1H NMR(400MHz,CDCl3):7.62-7.60(m,1H),7.18-7.15(m,2H),4.85(brs,4H)ppm。
Step 12) Synthesis of Compounds 25-14
Triethylamine (4.05 mL,29.6 mmol) was slowly added dropwise to a solution of compound 25-13 (1.86 g,7.4 mmol) in acetone (20 mL). At 0 deg.C, compound 25-10-2 (1.28 g,4.8 mmol) was added and the reaction was allowed to proceed for 5.0 hours at constant temperature. After the reaction was complete, water (10 mL) was added to dilute the reaction, the pH was adjusted to 4 with hydrochloric acid (2M) and a solid precipitated, which was filtered to give a solid product. The solid was transferred to a reaction flask, and a solution of potassium carbonate (1.5 g,10.87 mmol) in water (10 mL) was added and refluxed for 2.0 hours. After the reaction is completed, the pH value is adjusted to 4 by hydrochloric acid (2M), a solid is separated out, and a solid crude product is obtained after filtration and is washed by water. Then separating by high performance liquid chromatography (mobile phase: CH)3CN/H2O =35/65-65/35 (containing 0.75% CF)3COOH buffer)) to yield 1.00g of product, yield: 45 percent.
MS(ESI,pos.ion)m/z:464.5[M+H]+；
1H NMR(400MHz,CDCl3):7.93,7.90(d,d,1H),7.77-7.76(m,1H),7.43,7.41(d,d,1H),7.28-7.22(m,5H),6.30(brs,1H),5.14-5.13(m,2H),4.86-4.80(m,1H),3.68-3.62(m,1H),3.50-3.43(m,1H),2.22-1.98(m,4H)ppm。
Step 13) Synthesis of Compounds 25-15
A catalytic amount of Pd/C (0.35 g) was added to a solution of compound 25-14 (3.73 g,8.03 mmol) in EtOAc (40 mL) at 10 atmospheres H2The reaction was carried out at 40 ℃ for 5.0 hours under an atmosphere. After completion of the reaction, Pd/C was removed by filtration, and the reaction mixture was concentrated to obtain 25 to 15 (2.27 g, yield: 86%) of the objective compound.
MS(ESI,pos.ion)m/z:330.5[M+H]+。
Step 14) Synthesis of Compounds 25-16
Compound 25-15 (3.29 g,10.0 mmol), compound 1-18-2 (1.93 g,11.0 mmol) and EDCI (2.10 g,11.0 mmol) were dissolved in DCM (30 mL), and DIPEA (6.6 mL,39.9 mmol) was slowly added dropwise at 0 ℃ and reacted at room temperature for 3.0 hours after completion of dropwise addition. After completion of the reaction, DCM (50mL) was added to dilute the reaction solution, washed with water (30 mL × 3), an ammonium chloride solution and saturated brine, respectively, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent: PE/EtOAc (v/v) = 2/1) to obtain 2.43g of a product, yield: 50 percent.
MS(ESI,pos.ion)m/z:487.5[M+H]+；
1H NMR(400MHz,CDCl3):7.93,7.90(d,d,1H),7.77-7.76(m,1H),7.43,7.41(d,d,1H),6.30(brs,1H),5.32,5.29(d,d,1H),5.08-5.04(m,1H),4.31-4.26(m,1H),3.63(s,3H),3.62-3.57(m,1H),3.26-3.18(m,1H),2.38-2.31(m,1H),2.10-1.97(m,2H),1.91-1.71(m,2H),0.97,0.95(m,m,3H),0.91,0.89(m,m,3H)ppm。
Step 15) Synthesis of Compounds 25-17
Mixing compound 25-16 (0.44 g,0.91 mmol), compound 1-6-2 (0.46 g,1.82 mmol), Pd (dppf) Cl2·CH2Cl2(71.0 mg,0.09 mmol) and KOAc (0.27 g,2.73 mmol) were dissolved in DMF (5mL) and reacted at 90 ℃ for 3.0 hours under nitrogen, EtOAc (50mL) was added to dilute the reaction solution, the reaction solution was filtered through celite, the filtrate was washed with water (20 mL × 3) and saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent: PE/EtOAc (v/v) = 2/1) to give 0.43g of the product in 88% yield.
MS(ESI,pos.ion)m/z:535.3[M+H]+；
1H NMR(400MHz,CDCl3):8.02(t,1H),7.80,7.78(d,d,1H),7.46,7.44(d,d,1H),6.30(brs,1H),5.32,5.29(d,d,1H),5.08-5.04(m,1H),4.31-4.26(m,1H),3.63(s,3H),3.62-3.57(m,1H),3.26-3.18(m,1H),2.38-2.31(m,1H),2.10-1.97(m,2H),1.91-1.71(m,2H),1.32,1.29(m,12H),0.97,0.95(m,m,3H),0.91,0.89(m,m,3H)ppm。
Step 16) Synthesis of Compounds 25-18
Mixing compound 25-17 (0.33 g,0.61 mmol), compound 25-6 (0.44 g,0.61 mmol), Pd (PPh)3)4(35.3 mg,0.03 mmol) and potassium carbonate (0.25 g,1.83 mmol) were suspended in DME (5mL) and water (1 mL), reacted at 90 ℃ for 4.0 hours under nitrogen, cooled to room temperature after completion of the reaction, and the reaction was diluted with EtOAc (50mL), washed with water (20 mL × 3) and saturated brine, respectively, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent: EtOAc) to give 0.39g of the product in 65% yield.
MS(ESI,pos.ion)m/z:494.1[M+2H]2+；
1H NMR(400MHz,CDCl3):8.63(s,1H),8.26(m,1H),8.15,8.13(d,d,1H),7.81(s,1H),7.55,7.53(s,s,1H),7.39,7.37(d,d,1H),7.34,7.32(s,s,1H),5.56,5.55(d,d,1H),5.32,5.30(d,d,1H),5.29-5.25(m,1H),5.08-5.02(m,1H),4.41-4.40,4.39-4.38,4.37-4.36(m,m,m,1H),4.27,4.25,4.23(m,m,m,1H),3.85-3.78(m,4H),3.66(s,3H),3.65-3.64(m,1H),3.63(s,3H),3.52-3.49(m,1H),3.47-3.39(m,1H),3.38-3.30(m,1H),2.30-2.15(m,3H),2.13-1.81(m,13H),1.68-1.62(m,2H),1.31-1.20(m,3H),1.13-1.07(m,1H),1.02,1.00(m,m,3H),0.97,0.95(m,m,3H),0.93,0.91(m,m,3H),0.90,0.89(m,m,3H)ppm。
Example 26
The synthetic route is as follows:
example 26 was prepared according to a synthetic method analogous to example 1.
Compound 26-2:1H 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 26-3:1H 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 26-4: 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。
Compound 26-5: 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 26-6: 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 26-7: MS (ESI, pos. ion) M/z 379.4[ M +2H ]]2+；
1H NMR(400MHz,CDCl3):7.90(s,2H),7.39,7.37(s,s,2H),7.26,7.24(s,s,2H),5.05-5.00(m,2H),3.77-3.73(m,4H),3.64-3.58(m,2H),3.31-3.24(m,2H),2.47-2.38(m,2H),2.28-2.17(m,2H),2.10-1.97(m,6H),1.95-1.89(m,2H),1.87-1.83(m,2H),1.64-1.60(m,2H),1.41(s,18H),1.30-1.24(m,2H),1.22-1.16(m,2H)ppm。
Compounds 26-8: MS (ESI, pos.ion) M/z 557[ M + H ]]+。
Compounds 26-9: MS (ESI, pos. ion) M/z 436.5[ M +2H ]]2+；
1H NMR(400MHz,CDCl3):7.81(s,2H),7.39,7.37(s,s,2H),7.26,7.24(s,s,2H),5.56,5.55(d,d,1H),5.46,5.44(d,d,1H),5.29-5.25(m,2H),4.41-4.37(m,1H),4.34-4.30(m,1H),3.85-3.78(m,2H),3.77-3.73(m,4H),3.66(s,6H),3.65-3.61(m,2H),2.30-2.16(m,6H),2.13-1.89(m,8H),1.87-1.83(m,2H),1.64-1.60(m,2H),1.30-1.24(m,2H),1.22-1.16(m,2H),1.02,1.00(m,m,3H),0.97,0.95(m,m,3H),0.93,0.91(m,m,3H),0.90,0.89(m,m,3H)ppm。
Example 27
The synthetic route is as follows:
example 27 was prepared according to a synthetic method analogous to example 2.
Compound 27-1: MS (ESI, pos.ion) M/z 264.1[ M + H ]]+。
Compound 27-2: 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 27-3: MS (ESI, pos. ion) M/z 412.3[ M + H ]]+；
1H NMR(400MHz,CDCl3):7.78-7.75(m,2H),7.65-7.63(m,2H),5.53-5.15(m,2H),4.49-4.39(m,1H),3.59-3.54(m,1H),3.48-3.38(m,1H),2.31-2.21(m,2H),2.12-2.01(m,1H),1.98-1.85(m,1H),1.45(d,9H)ppm。
Compound 27-4: MS (ESI, pos. ion) M/z 392.3[ M + H ]]+；
1H NMR(400MHz,CDCl3):7.78-7.75(m,2H),7.65-7.63(m,2H),7.21-7.20(m,1H),5.53-5.15(m,2H),4.49-4.39(m,1H),3.59-3.54(m,1H),3.48-3.38(m,1H),2.31-2.21(m,2H),2.12-2.01(m,1H),1.98-1.85(m,1H),1.45(d,9H)ppm。
Compound 27-5: MS (ESI, pos. ion) M/z 292.2[ M + H ]]+；
1H NMR(400MHz,CDCl3):7.76-7.73(m,2H),7.66-7.63(m,2H),7.21-7.20(m,1H),5.50-5.22(m,2H),4.49-4.39(m,1H),3.61-3.56(m,1H),3.49-3.39(m,1H),2.31-2.21(m,2H),2.12-2.01(m,1H),1.98-1.85(m,1H)ppm。
Compounds 27-6: MS (ESI, pos.ion) M/z 450.5[ M + H ]]+；
1H NMR(400MHz,CDCl3):7.65-7.60(m,2H),7.47-7.43(m,2H),7.22-7.20(m,1H),5.67-5.65(m,1H),5.24-5.22(m,1H),4.34-4.30(m,1H),3.85-3.81(m,1H),3.72(s,3H),3.71-3.64(m,1H),3.00(s,1H),2.34-2.11(m,1H),2.21-1.95(m,5H),1.04-1.02(m,1H),0.88-0.86(d,6H)ppm。
Compounds 27-7:1H NMR(400MHz,CDCl3):7.65-7.60(m,2H),7.47-7.43(m,2H),7.22-7.20(m,1H),5.67-5.65(m,1H),5.24-5.22(m,1H),4.34-4.30(m,1H),3.5-3.81(m,1H),3.72(s,3H),3.71-3.64(m,1H),3.00(s,1H),2.34-2.11(m,1H),2.21-1.95(m,5H),1.32-1.45(m,12H),1.04-1.02(m,1H),0.88-0.86(d,6H)ppm。
compounds 27-8:1H NMR(400MHz,CDCl3):7.62-7.61,7.60-7.59(m,m,3H),7.56-7.55,7.53-7.52(m,m,2H),7.42,7.40(s,s,1H),7.31,7.29(s,s,1H),7.10,7.08(s,s,1H),7.07,7.05(s,s,1H),5.32,5.29(d,d,1H),5.23-5.19(m,1H),4.41-4.37(m,1H),3.92-3.90(m,1H),3.85-3.78(m,1H),3.74-3.71(m,2H),3.69-3.64(m,1H),3.63(s,3H),3.45-3.42(m,1H),2.30-2.15(m,3H),2.13-1.90(m,6H),1.84-1.78(m,2H),1.61-1.55(m,2H),1.30-1.17(m,4H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H)ppm。
compounds 27-9: MS (ESI, pos. ion) M/z 781.8[ M + H ]]+；
1H NMR(400MHz,CDCl3):7.66,7.64(s,s,1H),7.62-7.61,7.60-7.59(m,m,4H),7.58,7.56(s,s,1H),7.55-7.54,7.53-7.52(m,m,2H),7.31,7.29(s,s,1H),5.32,5.29(d,d,1H),5.23-5.19(m,1H),4.41-4.37(m,1H),3.92-3.90(m,1H),3.85-3.78(m,1H),3.75-3.71(m,2H),3.69-3.64(m,1H),3.63(s,3H),2.30-2.15(m,3H),2.13-1.90(m,6H),1.84-1.74(m,3H),1.61-1.53(m,2H),1.32,1.29(q,q,12H),1.27-1.17(m,3H),1.07-1.01(m,1H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H)ppm。
Compounds 27-10: MS (ESI, pos. ion) M/z 474.6[ M +2H ]]2+；
1H NMR(400MHz,CDCl3):7.81(s,1H),7.62-7.61,7.60-7.59(m,m,3H),7.56-7.55,7.53-7.52(m,m,2H),7.51,7.48(s,s,1H),7.39,7.37(s,s,1H),7.31,7.29(s,s,1H),7.26,7.24(s,s,1H),6.07,6.05(d,d,1H),5.32,5.30(d,d,1H),5.29-5.25(m,1H),5.23-5.19(m,1H),4.41-4.36(m,1H),4.34-4.30(m,1H),3.92-3.90(m,1H),3.85-3.78(m,2H),3.77-3.71(m,3H),3.69-3.66(m,2H),3.65(s,3H),3.63(s,3H),2.30-2.16(m,6H),2.13-1.89(m,8H),1.87-1.80(m,2H),1.64-1.57(m,2H),1.30-1.16(m,4H),1.02,1.00(m,m,3H),0.97,0.95(m,m,3H),0.93,0.91(m,m,3H),0.90,0.89(m,m,3H)ppm。
Example 28
The synthetic route is as follows:
example 28 was prepared according to a synthetic method analogous to example 3.
Compound 28-1:1H NMR(400MHz,CDCl3):7.64(s,1H),5.55-5.51(m,1H),5.32,5.29(d,d,1H),4.41-4.37(m,1H),3.78-3.72(m,1H),3.63(s,3H),3.61-3.54(m,1H),2.25-1.87(m,5H),1.39,1.36(q,q,12H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H)ppm。
compound 28-2: MS (ESI, pos. ion) M/z 595.7[ M + H ]]+；
1H NMR(400MHz,CDCl3):7.59(s,1H),7.39,7.37(s,s,1H),7.38,7.36(t,t,1H),7.22,7.20(s,s,1H),6.75,6.72(s,s,1H),5.32-5.28(m,2H),4.41-4.30(m,2H),3.85-3.78(m,1H),3.69-3.65(m,1H),3.63(s,3H),3.58-3.54(m,1H),3.50-3.46(m,1H),3.24-3.12(m,1H),2.70-2.57(m,2H),2.30-1.92(m,10H),1.82-1.78(m,1H),1.66-1.55(m,2H),1.26-1.19(m,2H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H)ppm。
Compound 28-3:1H NMR(400MHz,CDCl3):7.59(s,1H),7.38,7.35(t,t,1H),7.26,7.24(s,s,1H),7.22,7.21(s,s,1H),7.20,7.19(s,s,1H),5.32-5.28(m,2H),4.41-4.30(m,2H),3.88-3.78(m,2H),3.69-3.64(m,1H),3.63(s,3H),3.47-3.44(m,1H),3.24-3.12(m,1H),2.70-2.57(m,2H),2.30-1.92(m,10H),1.82-1.78(m,1H),1.66-1.55(m,2H),1.30-1.19(m,2H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H)ppm。
compound 28-4: 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。
Compounds 28-5: 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。
Compounds 28-6: MS (ESI, pos. ion) M/z 314.2[ M + H ]]+。
Compounds 28-7: MS (ESI, pos. ion) M/z 485.4[ M + H ]]+；
1H NMR(400MHz,CDCl3):10.62(brs,1H),8.22(m,1H),7.73-7.65(m,2H),5.72(d,1H,J=8.0Hz),5.43(d,1H,J=8.0Hz),4.35-4.31(m,1H),3.95-3.88(m,1H),3.78-3.75(m,1H),3.69-3.67(m,4H),3.08-3.04(m,1H),2.43-2.37(m,1H),2.25-2.15(m,2H),1.91(s,1H),1.74-1.72(m,1H),1.52-1.50(m,1H),1.35(s,12H),1.24(t,2H,J=8.0Hz),1.12-1.10(m,1H),0.93-0.88(m,1H)ppm。
Compounds 28-8: MS (ESI, pos. ion) M/z 468.6[ M +2H ]]2+；
1H NMR(400MHz,CDCl3):7.69,7.67(s,s,1H),7.62-7.61,7.60-7.59(m,m,2H),7.59(s,1H),7.48,7.46(s,s,1H),7.41,7.40(t,t,1H),7.23,7.21(d,d,1H),7.20,7.19(s,s,1H),5.39,5.36(d,d,1H),5.32-5.28(m,2H),5.13-5.09(m,1H),4.46-4.30(m,3H),3.93-3.90(m,1H),3.85-3.76(m,3H),3.69-3.64(m,2H),3.63(s,6H),3.24-3.12(m,1H),2.70-2.57(m,2H),2.42-2.34(m,1H),2.30-1.86(m,14H),1.84-1.80(m,1H),1.66-1.49(m,3H),1.27-1.10(m,3H),0.98-0.95(m,6H),0.92-0.89(m,6H)ppm。
Example 29
The synthetic route is as follows:
example 29 was prepared according to a synthetic method analogous to that of example 8.
Compound 29-1:1H NMR(400MHz,CDCl3):7.46,7.44(s,s,1H),7.40(s,1H),7.36,7.34(s,s,1H),7.15,7.13(s,s,1H),6.52,6.50(s,s,1H),5.32,5.30(d,d,1H),5.16-5.12(m,1H),4.41-4.36(m,1H),4.24-4.18(m,2H),3.85-3.78(m,1H),3.69-3.64(m,1H),3.63(s,3H),3.58-3.55(m,1H),3.52-3.50(m,1H),2.40(s,3H),2.30-2.15(m,3H),2.13-2.03(m,1H),2.01-1.92(m,3H),1.85-1.77(m,2H),1.75-1.67(m,1H),1.61-1.57(m,1H),1.31-1.15(m,4H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H)ppm。
compound 29-2:1H NMR(400MHz,CDCl3):7.46,7.44(s,s,1H),7.40(s,1H),7.36,7.34(s,s,1H),7.11,7.09(s,s,1H),7.07,7.05(s,s,1H),5.32,5.30(d,d,1H),5.16-5.12(m,1H),4.41-4.36(m,1H),4.24-4.18(m,2H),3.85-3.78(m,1H),3.74-3.71(m,1H),3.69-3.65(m,1H),3.63(s,3H),3.49-3.47(m,1H),2.40(s,3H),2.30-2.15(m,3H),2.13-1.92(m,4H),1.85-1.77(m,2H),1.75-1.67(m,1H),1.61-1.57(m,1H),1.32-1.15(m,4H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H)ppm。
compound 29-3: MS (ESI, pos. ion) M/z 391.5[ M + H ]]+；
1H NMR(400MHz,CDCl3):7.27(s,1H),5.32,5.30(d,d,1H),5.29-5.24(m,1H),4.41-4.36(m,1H),3.89-3.83(m,1H),3.73-3.65(m,1H),3.63(s,3H),2.31-1.93(m,5H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H),0.32(m,9H)ppm。
Compound 29-4: MS (ESI, pos. ion) M/z 319.4[ M + H ]]+；
1H NMR(400MHz,CDCl3):7.27(s,1H),5.35-5.31(m,1.5H),5.30-5.29(d,0.5H,J=4.0Hz),4.41-4.36(m,1H),3.89-3.83(m,1H),3.73-3.66(m,1H),3.63(s,3H),3.36(s,1H),2.31-1.93(m,5H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H)ppm。
Compound 29-5: MS (Mass Spectrometry)(ESI,pos.ion)m/z:456.1[M+2H]2+；
1H NMR(400MHz,CDCl3):7.62(s,1H),7.56,7.54(s,s,1H),7.46(s,1H),7.45,7.43,7.41(s,d,s,2H),7.29,7.26(s,s,1H),6.07,6.05(d,d,1H),5.51-5.47(m,1H),5.46,5.44(d,d,1H),5.29-5.25(m,1H),4.41,4.38,4.36(m,m,m,1H),4.34,4.31,4.30(m,m,m,1H),4.24-4.18(m,2H),4.11-4.08(m,1H),3.89-3.78(m,2H),3.73-3.67(m,2H),3.66(s,3H),3.65(s,3H),3.58-3.55(m,1H),2.37(s,3H),2.32-1.90(m,12H),1.82-1.68(m,3H),1.59-1.55(m,1H),1.34-1.17(m,4H),1.02,1.00(m,m,3H),0.97,0.95(m,m,3H),0.93,0.91(m,m,3H),0.90,0.89(m,m,3H)ppm。
Example 30
The synthetic route is as follows:
example 30 was prepared according to a synthetic method analogous to that of example 21.
Compound 30-1:1H NMR(400MHz,CDCl3):7.63-7.62,7.61-7.60(m,m,2H),7.59(s,1H),7.57-7.56,7.55-7.54(m,m,2H),7.41,7.38(s,s,1H),7.28,7.25(s,s,1H),7.17,7.15(s,s,1H),6.96-6.95(m,2H),6.57,6.55(s,s,1H),5.32,5.30(d,d,1H),5.23-5.19(m,1H),4.44-4.41,4.39,4.36(m,m,m,2H),4.25-4.22(m,1H),3.85-3.78(m,1H),3.69-3.64(m,1H),3.63(s,3H),3.58-3.55(m,1H),3.53-3.50(m,1H),2.33-2.15(m,5H),2.13-1.92(m,4H),1.90-1.86(m,1H),1.67-1.63(m,1H),1.34-1.28(m,1H),1.25-1.19(m,1H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H)ppm。
compound 30-2:1H NMR(400MHz,CDCl3):7.63-7.62,7.61-7.60(m,m,2H),7.59(s,1H),7.57-7.56,7.55-7.54(m,m,2H),7.38,7.35(s,s,1H),7.27,7.25(s,s,1H),7.09,7.07(s,s,1H),7.03,7.01(s,s,1H),6.96-6.95(m,2H),5.32,5.29(d,d,1H),5.23-5.19(m,1H),4.44-4.41,4.39,4.36(m,m,m,2H),4.25-4.22(m,1H),3.85-3.78(m,1H),3.74-3.71(m,1H),3.69-3.64(m,1H),3.63(s,3H),3.51-3.48(m,1H),2.33-2.15(m,5H),2.13-1.92(m,4H),1.90-1.86(m,1H),1.67-1.63(m,1H),1.38-1.32(m,1H),1.25-1.19(m,1H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H)ppm。
compound 30-3: MS (ESI, pos. ion) M/z 473.6[ M +2H ]]2+；
1H NMR(400MHz,CDCl3):7.81(s,1H),7.63-7.62,7.61-7.60(m,m,2H),7.59(s,1H),7.57-7.56,7.55-7.54(m,m,2H),7.46,7.44(d,d,2H),7.28,7.25(d,d,2H),6.96-6.95(m,2H),5.32,5.30(d,d,2H),5.29-5.25(m,1H),5.23-5.19(m,1H),4.44-4.41,4.39,4.37(m,m,m,3H),4.25-4.22(m,1H),3.85-3.78(m,3H),3.78-3.73(m,1H),3.69-3.64(m,2H),3.63(s,6H),2.33-2.15(m,8H),2.13-2.03(m,2H),2.02-1.91(m,5H),1.72-1.68(m,1H),1.30-1.24(m,2H),0.97,0.95(m,m,6H),0.90,0.89(m,m,6H)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, the HCV replicon system comprises a G418 resistance gene NEO and a luciferase reporter gene, and the replication level of HCV in a host cell can be characterized by the expression amount of the NEO gene or the expression amount of the luciferase gene, and the effect of the compound 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. Adding the compounds described herein to Huh-7 cells containing a transfected HCV replicon systemWells were 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 above50It can be determined that the compounds described herein 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 2.314 0.107 11 0.847 0.098 21 3.692 0.736
2 10.583 0.974 12 25.872 5.836 22 6.573 2.853
3 0.775 0.086 13 1.883 0.364 23 11.565 3.759
4 0.673 0.328 14 4.752 0.752 24 1.750 0.056
5 10.639 0.871 15 8.753 0.659 25 6.835 0.208
6 1.208 0.583 16 9.065 0.746 26 2.314 0.107
7 13.765 1.672 17 10.643 0.312 27 10.583 0.974
8 19.668 2.601 18 13.622 1.683 28 16.728 1.683
9 0.977 0.284 19 17.850 3.704 29 19.668 2.601
10 0.117 0.084 20 8.563 0.749 30 3.692 0.736
According to the experimental results of Y93H, L31F, P32L and I302V resistant mutants and wild type HCV1b, the results of molecular modeling and computer aided design simulation are combined to prove that the compound disclosed by the invention plays a superior anti-hepatitis C virus role through a mechanism of inhibiting HCV NS5A protein.
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. A compound has a structure shown as a formula (XI) or a stereoisomer and a pharmaceutically acceptable salt thereof,
wherein each R is5aIndependently is H;
each R14And R14aIndependently of one another H, deuterium, C1-4Alkyl radical, C6-10Aryl radical, C2-10Heterocyclyl orC3-8A 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:
independently are the following groups:
each 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 independently form a heterocyclic ring orThe fused or spiro ring system is selected from the following sub-structures:
2. the compound of claim 1, wherein
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.
3. The compound of claim 1, having the structure shown in formula (XII)
Wherein each Q1And Q2Independently is CH2；
Each Q4And Q5Independently is CH2；
Each f and f' is independently 1;
X3is (CR)7R7a)eWherein e is 1 or 2;
X5is (CR)7R7a)eWherein e is 1 or 2;
each R5aAnd R5a’Independently is H;
each Y is1And Y2Independently is CR7；
When e is 1, Y1’And Y2’At the same time is CR7Or simultaneously N, e ═ 2, Y1’And Y2’At the same time is CR7；
Each R7And R7aIndependently is hydrogen;
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;
and each a and a' is independently a 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:
4. the compound of claim 1, having the structure of formula (XIII)
Wherein each Q1And Q2Independently isCH2；
Q4Is CH2；
X3Is (CR)7R7a)eWherein e is 1 or 2;
X4is CR7R7a；
Each R7And R7aIndependently is hydrogen;
each R5aAnd R5a’Independently is H;
each Y is1And Y2Independently is CR7；
Each f and f' is independently 1;
each i is 0, 1,2 or 3, wherein, when i is 0, 2 or 3, Y is1’And Y2’Are all CR7(ii) a When i is 1, Y1’And Y2’Are all CR7Or Y is1’Is N, Y2‘Is CR7；
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;
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、R4The heterocyclic or condensed ring or spiro ring system independently formed with N-CH is selected from the following sub-structuresThe structure formula is as follows:
5. a compound comprising the structure of one of:
or a stereoisomer or pharmaceutically acceptable salt thereof.
6. A compound comprising the structure of one of:
or a stereoisomer or pharmaceutically acceptable salt thereof.
7. A pharmaceutical composition, wherein the pharmaceutical composition comprises a compound of any one of claims 1-6.
8. The pharmaceutical composition of claim 7, further comprising a pharmaceutically acceptable adjuvant, vehicle, or combination thereof.
9. The pharmaceutical composition of claim 8, wherein the adjuvant comprises a carrier, an excipient, or a combination thereof.
10. The pharmaceutical composition of claim 9, wherein the excipient comprises a diluent.
11. The pharmaceutical composition of claim 7, further comprising an additional anti-HCV agent.
12. The pharmaceutical composition of claim 11, 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, interfering RNA, anti-sense RNA, imiqimod, an inosine 5' -monophospate dehydrogenase inhibitor, amantadine, rimantadine, baviximab, CivacirTMBoceprevir (boceprevir), telaprevir (telaprevir), erlotinib (erlotinib), daclatavir (daclatasvir), cimeprevir (simeprevir), asunaprevir, vaniprevir, faldaprevir, ABT-450, danoprevir (danoprevir), sovaprevir, MK-5172, vedroprevir, BZF-961, GS-9256, naraprevir (narloprevir), ANA 63975, ABT-267, EDP239, PPI-668, GS-5816, samatasvir (IDX-176176719), MK-8742, MK-8325, GSK-2336805, PPI-461, ldsiprevir (TMC-435), vanieprevir (vanieprevir-7009), faaprevir (vaeprevir-375), PHaveprevir 20120135, VXt-36985, VXodrex-36985, VX1, VXd-3683, VX-3, VXd-3, VX-3, VXd, mericitabine (R-7128), sofosbuvir (PSI-7977), INX-189, IDX-184, IDX102, R1479, INX-08189, PSI-6130, PSI-938, PSI-879, HCV-796, HCV-371, VCH-916, lomibuvir (VCH-222), setobrevir (ANA-598), MK-3281, ABT-333, ABT-072, filibuvir (PF-00868554), deleobrevir (BI-207127), tegobrevir (9190), A-GS 837093, JKT-109, Gl-59728, GL-60667, AZD-2795, TMC647055, or combinations thereof.
13. The pharmaceutical composition of claim 12, 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.
14. The pharmaceutical composition according to any one of claims 7-13, further comprising at least one HCV inhibitor.
15. The pharmaceutical composition of claim 14, wherein the HCV inhibitor is used for at least one of inhibiting the HCV replication process and inhibiting HCV viral protein function.
16. The pharmaceutical composition of claim 15, wherein the HCV replication process is selected from the complete viral cycle of HCV entry, uncoating, translation, replication, assembly or release of HCV.
17. The pharmaceutical composition of claim 15, wherein the HCV viral protein is selected from the group consisting of metalloprotease, NS2, NS3, NS4A, NS4B, NS5A, NS 5B; as well as the Internal Ribosome Entry Site (IRES) and inosine monophosphate dehydrogenase (IMPDH) required for HCV viral replication.
18. Use of a compound according to any one of claims 1-6 or a pharmaceutical composition according to any one of claims 7-17 in the manufacture of a medicament for at least one of inhibiting the HCV replication process and inhibiting HCV viral protein function.
19. The use of claim 18, wherein the HCV replication process is selected from the complete viral cycle of HCV entry, uncoating, translation, replication, assembly or release of HCV.
20. The use according to claim 19, wherein the HCV viral protein is selected from the group consisting of metalloprotease, NS2, NS3, NS4A, NS4B, NS5A, NS 5B; as well as the Internal Ribosome Entry Site (IRES) and inosine monophosphate dehydrogenase (IMPDH) required for HCV viral replication.
21. Use of a compound of any one of claims 1-6 or a pharmaceutical composition of any one of claims 7-17 in the manufacture of a medicament for preventing, treating, or ameliorating an HCV infection or a hepatitis c disease in a patient.
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