HK1169102B - Hydroxamates as therapeutic agents - Google Patents
Hydroxamates as therapeutic agents Download PDFInfo
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- HK1169102B HK1169102B HK12109635.8A HK12109635A HK1169102B HK 1169102 B HK1169102 B HK 1169102B HK 12109635 A HK12109635 A HK 12109635A HK 1169102 B HK1169102 B HK 1169102B
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Description
The application is a divisional application of international application PCT/US2004/010549, having application number 200480009225.8 and invented name of "hydroxamate as therapeutic agent", entering the Chinese national stage at 10/8/2005.
Technical Field
The present invention relates to certain hydroxamate derivatives useful in the treatment of hepatitis c. These compounds are also inhibitors of histone deacetylase and are therefore useful in the treatment of diseases associated with histone deacetylase activity. Pharmaceutical compositions and methods of preparing these compounds are also disclosed.
Background
Hepatitis C:
chronic hepatitis c is a slowly progressive disease with a significant impact on morbidity and mortality. While many patients infected with hepatitis c will have subclinical or mild disease, at least 80% of these HCV-infected individuals develop chronic infectious disease and hepatitis. 20-50% of them eventually develop cirrhosis of the liver, and 1-2% develop liver cancer (Hoofnagle, J.H.; 1997; Hepatology 26: 15S-20S). It is estimated that there are 1 million to 7 million HCV carriers worldwide, and end-stage liver disease associated with HCV is currently one of the major causes of liver transplantation. Hepatitis c annually causes 8000-.
Currently, interferon- α 2 b/ribavirin combination therapy is the only viable therapeutic approach. Approximately 40-45% of those treated developed a sustained virologic response to IFN-. alpha.2b/ribavirin combination therapy. For those patients who fail the interferon- α 2 b/ribavirin combination therapy, there is currently no alternative to prevent the progression of liver disease. Therefore, there is a need for alternative therapies to treat chronic HCV infection. The present invention satisfies this need.
Histone deacetylase:
with Histone Deacetylases (HDAC) as the target of pharmaceutical research, their attention has focused on the role of HDAC in the regulation of genes associated with cell cycle progression, and the role of HDAC in the development and enhancement of cancer (as described in Kramer et al, 2001.trends Endocrinol. Metab.12: 294-. Several studies have shown that treatment of various cell lines with HDAC inhibitors results in the presence of G1Late stage or at G2Hyperacetylation of histones and cell cycle arrest at the/M transition. Genes associated with the cell cycle that have been shown to be upregulated by HDAC inhibitors include p21, p27, p53, and cyclin E. Cyclin a and cyclin D have been reported to be down-regulated by HDAC inhibitors. In tumor cell linesSeveral studies have shown that treatment with HDAC inhibitors can lead to growth arrest, terminal differentiation and/or apoptosis. In vivo studies have demonstrated that treatment with HDAC inhibitors can lead to tumor growth inhibition and reduction of tumor metastasis.
The most clear link between aberrant HDAC activity and cancer occurs in acute promyelocytic leukemia. In this case, chromosomal translocation results in fusion of the retinoic acid receptor RAR α with promyelocytic leukemia (PML) or Promyelocytic Leukemia Zinc Finger (PLZF) protein. PML-RAR α and PLZF-RAR α both suppress retinoic acid regulated genes by aberrant recruitment of SMRT-mSin3-HDAC complexes, thereby promoting leukemia progression (Lin et al, 1998, Nature 391: 811-814; Grignard et al, 1998, Nature 391: 815-818). PML-RARa forms of the disease can be treated with retinoic acid, while PLZF-RAR α forms are resistant to such treatment. For patients with retinoic acid resistant forms of disease, the addition of the HDAC inhibitor sodium butyrate to the dosage regimen results in complete clinical and cytopoietic remission (Warrell et al, 1998, J.Natl.cancer. Inst.90: 1621-. HDACs have also been associated with Huntington's disease (Steffan et al, Nature 413: 739; "Histone deacetylase inhibitors prevent polyglutamine-dependent neurodegeneration in Drosophila)".
In summary, an increase in HDAC activity contributes to the pathology and/or symptomology of many diseases. Thus, molecules that inhibit HADC activity are useful as therapeutic agents to treat these diseases.
Disclosure of Invention
In a first aspect, the present invention provides a compound of formula (I):
wherein:
R1is hydrogen or alkyl;
x is-O-, -NR2-or-S (O)n-, where n is 0-2, R2Is hydrogen or alkyl;
y is alkylene optionally substituted with cycloalkyl, optionally substituted phenyl, alkylthio, alkylsulfinyl, alkylsulfonyl, optionally substituted phenylalkylthio, optionally substituted phenylalkylsulfonyl, hydroxy, or optionally substituted phenoxy;
Ar1is phenylene or heteroarylene, wherein Ar is1Optionally substituted with one or two groups independently selected from alkyl, halo, hydroxy, alkoxy, haloalkoxy, or haloalkyl;
R3is hydrogen, alkyl, hydroxyalkyl or optionally substituted phenyl; and
Ar2is aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl.
In a second aspect, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
In a third aspect, the present invention relates to a method of treating a disease mediated by HDAC in an animal, comprising administering to the animal a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. Preferably, the disease is a proliferative disease such as cancer and bipolar disorder, and the animal is a human. Preferably, the cancer is prostate cancer, breast cancer, lung melanoma, gastric cancer, neuroblastoma, colon cancer, pancreatic cancer, ovarian cancer, T-cell lymphoma, or leukemia such as myeloid leukemia (MM) and acute myeloid leukemia (AMM).
In a fourth aspect, the present invention relates to a method of treating cancer in an animal, comprising administering to the animal a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, in combination with radiation therapy and optionally in combination with one or more compounds independently selected from the group consisting of: an estrogen receptor modulator, an androgen receptor modulator, a retinoid receptor modulator, a cytotoxic agent, another antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, an HIV protease inhibitor, a reverse transcriptase inhibitor, an angiogenesis inhibitor, or a DNA methyltransferase inhibitor.
Applicants have also found that the compounds of the present invention are useful in the treatment of hepatitis c. Accordingly, in a fifth aspect, the present invention relates to a method of treating hepatitis c in an animal, the method comprising administering to the animal a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, optionally in combination with one or more other hepatitis c agents. Preferably, the hepatitis c agent is interferon- α 2b, ribavirin, and an HCV polymerase inhibitor.
In a sixth aspect, the present invention relates to an intermediate of formula (II):
wherein R is50Is hydrogen or alkyl, and Ar is1、Ar2、R3X and Y are as previously defined for the compounds of formula (I). Preferably, Ar1、Ar2、R3X and Y are as defined in the preferred embodiments below.
In a seventh aspect, the present invention relates to a process for the preparation of a compound of formula (I), which process comprises:
(i) reacting a compound of formula (III):
wherein R is51Is hydroxy, alkoxy, halo, or succinimidyl ester, with a compound of formula NH2Hydroxylamine reaction of OR 'wherein R' is hydrogen, alkyl, OR an oxygen protecting group; or
(ii) Treating a compound of formula (IV):
wherein M is+Is an alkali metal; then using NH2OR "wherein R" is hydrogen, alkyl, OR an oxygen protecting group;
to obtain a compound of formula (V);
(iii) optionally removing the R 'group from compound (V) to provide a compound of formula (I) wherein R' is hydrogen;
(iv) (iv) optionally forming an acid addition salt of the product formed in step (i), (ii) or (iii) above;
(v) (iv) optionally forming a free base of the product formed in step (i), (ii), (iii) or (iv) above; or
(vi) (iv) optionally modifying X, Y, R in the product formed in step (i), (ii), (iii), (iv) or (v) above1、R2、R3、Ar1And Ar2Any one of the groups.
In an eighth aspect, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.
In a ninth aspect, the present invention relates to the use of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of hepatitis c.
Detailed Description
Defining:
unless otherwise indicated, the following terms used in the specification and claims are defined for the purposes of this application and have the following meanings:
"alkyl" means a straight chain saturated monovalent hydrocarbon group having 1 to 6 carbon atoms, or a branched chain saturated monovalent hydrocarbon group having 3 to 6 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, butyl (including all isomeric forms), pentyl (including all isomeric forms), and the like.
Unless otherwise specified, "alkylene" refers to a straight-chain saturated divalent hydrocarbon group having 1 to 6 carbon atoms, or a branched-chain saturated divalent hydrocarbon group having 3 to 6 carbon atoms, such as methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.
"alkenylene" refers to a straight chain divalent hydrocarbon group of 2 to 6 carbon atoms, or a branched chain monovalent hydrocarbon group of 3 to 6 carbon atoms containing one or two double bonds, such as ethenylene, propenylene, 2-propenylene, butenylene (including all isomeric forms), and the like.
"alkylthio" refers to the-SR radical, where R is an alkyl group as defined above, e.g., methylthio, ethylthio, propylthio (including all isomeric forms), butylthio (including all isomeric forms), and the like.
"Alkylsulfinyl" refers to the group-S (O) R, where R is alkyl as defined above, e.g., methylsulfinyl, ethylsulfinyl, propylsulfinyl (including all isomeric forms), and the like.
"alkylsulfonyl" means-SO2R, wherein R is alkyl as defined above, e.g., methylsulfonyl, ethylsulfonyl, and the like.
"amino" means-NH2Or N-oxide derivatives or protected derivatives thereof, e.g., -NH → O, -NHBoc, -NHCBz and the like, preferably-NH2。
"alkylamino" refers to the group-NHR, wherein R is alkyl as defined above, or an N-oxide derivative, or a protected derivative thereof, such as methylamino, ethylamino, N-propylamino, iso-propylamino; n-butylamino, iso-butylamino, tert-butylamino, methylamino-N-oxide; -N (Boc) CH3And the like.
"alkoxy" means an-OR group, wherein R is alkyl as defined above, e.g., methoxy, ethoxy; propoxy, or 2-propoxy; n-butoxy, i-butoxy, t-butoxy and the like.
"alkoxycarbonyl" refers to the group-C (O) OR, where R is alkyl as defined above, e.g., methoxycarbonyl, ethoxycarbonyl, and the like.
"alkoxyalkyl" means a straight chain monovalent hydrocarbon radical having 1 to 6 carbon atoms or a branched monovalent hydrocarbon radical having 3 to 6 carbon atoms substituted with at least one, preferably one or two, alkoxy groups (as defined above), such as 2-methoxyethyl, 1-, 2-, or 3-methoxypropyl, 2-ethoxyethyl, and the like.
"Alkoxyalkoxy" means an-OR group, where R is an alkoxy group as defined above, e.g., methoxyethoxy, 2-ethoxyethoxy, and the like.
"Alkoxyalkoxyalkyl" means a- (alkylene) -R group, where R is an alkoxyalkoxy group as defined above, e.g., methoxyethoxymethyl, 2-ethoxyethoxymethyl, and the like.
"aminoalkyl" means a straight-chain monovalent hydrocarbon radical having from 1 to 6 carbon atoms or a branched-chain monovalent hydrocarbon radical having from 3 to 6 carbon atoms, which is substituted with at least one, preferably one or two of the following groups: -NRR', wherein R is hydrogen, alkyl, or-CORaWherein R isaIs alkyl, R' is selected from hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, optionally substitutedPhenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or haloalkyl; or an N-oxide derivative or protected derivative thereof. Preferably, R and R' are independently selected from: hydrogen, alkyl, or-CORaWherein R isaIs an alkyl group, or an N-oxide derivative, or a protected derivative, such as aminomethyl, methylaminoethyl, 2-ethylamino-2-methylethyl, 1, 3-diaminopropyl, dimethylaminomethyl, diethylaminoethyl, acetamidopropyl, aminomethyl-N-oxide, and the like.
"aminoalkoxy" refers to the group-OR, where R is aminoalkyl as defined above, e.g., 2-aminoethoxy, 2-dimethylaminopropoxy, and the like.
"aminocarbonyl" means a-CONRR group, where each R is independently hydrogen or alkyl as defined above, e.g., -CONH2Methyl aminocarbonyl, 2-dimethylaminocarbonyl and the like.
"amido" refers to the group-NHCOR, where R is as defined above for alkyl, such as acetylamino, propionylamino and the like.
"aryl" means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical having 6 to 12 ring atoms, such as phenyl, naphthyl or anthracenyl. Unless otherwise specified, the aromatic ring is optionally substituted with one, two or three substituents independently selected from: alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxy, hydroxyalkyl, hydroxyalkoxy, hydroxyalkoxyalkyl, alkoxyalkoxyalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, cycloalkoxy, cycloalkenyloxy, optionally substituted phenylcarbonylamino, optionally substituted heteroaryloxy, optionally substituted heteroarylalkoxy, aminoalkyl, aminoalkoxy, alkoxyalkyl, alkoxyalkoxy, methylenedioxy, haloalkoxyalkyl, optionally substituted phenoxyalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkoxyalkyl, optionally substituted heterocycloalkylalkyloxyalkylOptionally substituted heterocycloalkylalkoxy, optionally substituted heterocycloalkyloxy, -alkylene-S (O)n-Ra(wherein n is 0 to 2, RaIs alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl), -alkylene-NHSO2-Rb(wherein R isbIs alkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or optionally substituted heterocycloalkyl), -alkylene-NHCO-Rc(wherein R iscIs alkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or optionally substituted heterocycloalkyl), or- (alkylene) n1-CONRdRe(wherein n1 is 0 or 1, RdAnd ReIndependently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl, or optionally substituted heterocycloalkylalkyl, or RdAnd ReTogether with the nitrogen atom to which they are attached form an optionally substituted heterocycloalkyl) in which the alkyl chain in haloalkoxyalkyl, optionally substituted phenoxyalkyl, optionally substituted heteroaryloxyalkyl, or aminoalkyl is optionally substituted with one or two fluoro. Preferably, the substituents are independently: methoxy, methyl, ethyl, chloro, trifluoromethyl, fluoro, 2-methoxyethoxy, 2- (morpholin-4-yl) ethoxy, pyridin-3-ylmethoxy, 2-hydroxyethoxy, 2- (N, N-dimethylamino) -ethoxy, methoxymethyl, phenoxymethyl, 2-morpholino-4-ylethyl, morpholino-4-ylmethyl, N-dimethylaminomethyl, isopropoxymethyl, or phenoxymethyl.
"aralkyl" means a- (alkylene) -R group, where R is aryl as defined above.
"aralkenyl" refers to a- (alkenylene) -R group, wherein R is aryl as defined above.
"cycloalkyl" refers to a cyclic saturated monovalent hydrocarbon group having 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or adamantyl. Cycloalkyl is optionally substituted with optionally substituted phenyl.
"cycloalkenyl" refers to a cyclic unsaturated monovalent hydrocarbon group having 3 to 6 carbon atoms, such as cyclopropenyl, cyclobutenyl, cyclohexenyl, and the like.
"cycloalkylalkyl" refers to a- (alkylene) -R group, where R is a cycloalkyl group as defined above, e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylethyl, or cyclohexylmethyl, and the like.
"Cycloalkoxy" refers to the group-OR, where R is cycloalkyl as defined above, e.g., cyclopropyloxy, cyclohexyloxy, and the like.
"cycloalkenyloxy" means a-OR group, wherein R is cycloalkenyl as defined above, e.g., cyclopropenyloxy, cyclohexenyloxy, and the like.
"dialkylamino" refers to the group-NRR ', where R and R' are independently alkyl groups as defined above, e.g., dimethylamino, diethylamino, methylpropylamino, methylethylamino, n-butylamino, iso-butylamino, tert-butylamino, or the like.
"halo" means fluoro, chloro, bromo, iodo, preferably fluoro or chloro.
"haloalkyl" means alkyl substituted with one or more halogen atoms, preferably 1 to 5 halogen atoms, preferably fluorine or chlorine, including those substituted with different halogen atoms, e.g., -CH2Cl、-CF3、-CHF2、-CF2CF3、-CF(CH3)3And the like.
"haloalkoxy" means a-OR group wherein R is haloalkyl as defined above, e.g., -OCF3、-OCHF2And the like.
"haloalkoxyalkyl" means a- (alkylene) -OR group wherein R is haloalkyl as defined above, e.g., trifluoromethoxy methyl, 2, 2, 2-trifluoroethoxymethyl, 2-trifluoromethoxyethyl, and the like.
"hydroxyalkyl" refers to a straight chain monovalent hydrocarbon group of 1 to 6 carbon atoms or a branched monovalent hydrocarbon group of 3 to 6 carbon atoms substituted with one or two hydroxyl groups, provided that if two hydroxyl groups are present, they are not all on the same carbon atom. Representative examples thereof include, but are not limited to: hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1- (hydroxymethyl) -2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2, 3-dihydroxypropyl, 1- (hydroxymethyl) -2-hydroxyethyl, 2, 3-dihydroxybutyl, 3, 4-dihydroxybutyl and 2- (hydroxymethyl) -3-hydroxypropyl, preferably 2-hydroxyethyl, 2, 3-dihydroxypropyl, and 1- (hydroxymethyl) -2-hydroxyethyl.
"Hydroxyalkoxy" means a-OR group wherein R is hydroxyalkyl as defined above.
"Hydroxyalkoxyalkyl" refers to the- (alkylene) -OR group, wherein R is hydroxyalkyl as defined above, e.g., hydroxymethoxymethyl, hydroxyethoxymethyl, and the like.
"Heterocycloalkyl" means a saturated or unsaturated monovalent cyclic group having 3 to 8 ring atoms in which one or two ring atoms are heteroatoms selected from N, O or S (O)nWherein n is an integer from 0 to 2 and the remaining ring atoms are C. One or both ring atoms may be optionally substituted with a-CO-group. More specifically, the term "heterocycloalkyl" includes, but is not limited to: pyrrolidino (pyrrolidino), piperidino, morpholino, piperazino (piperazino), tetrahydropyranyl, tetrahydroquinolinyl, and thiomorpholino groups, and derivatives thereof (formed when a heterocycloalkyl ring is substituted with the following substituents); and N-oxides or protected derivatives thereof. The heterocycloalkyl group is optionally fused to the alkyl group. Unless otherwise specified, the heterocycloalkyl ring is optionally substituted with one, two, or three substituents independently selected from: alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino,Alkylamino, dialkylamino, hydroxy, hydroxyalkyl, hydroxyalkoxy, hydroxyalkoxyalkyl, alkoxyalkoxyalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, cycloalkoxy, cycloalkenyloxy, optionally substituted phenylcarbonylamino, optionally substituted heteroaryl, optionally substituted heteroarylalkoxy, aminoalkyl, aminoalkoxy, alkoxyalkyl, alkoxyalkoxy, methylenedioxy, haloalkoxyalkyl, optionally substituted phenoxyalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted heterocycloalkoxyalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heterocycloalkylalkoxy, optionally substituted heterocycloalkyloxy, -alkylene-S (O)n-Ra(wherein n is 0 to 2, RaIs alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl), -alkylene-NHSO2-Rb(wherein R isbIs alkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl), -alkylene-NHCO-Rc(wherein R iscIs alkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl), or- (alkylene) n1-CONRdRe(wherein n1 is 0 or 1, RdAnd ReIndependently are: hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or optionally substituted heterocycloalkylalkyl, or RdAnd ReTogether with the nitrogen atom to which they are attached form an optionally substituted heterocycloalkyl) in which the alkyl chain in haloalkoxyalkyl, optionally substituted phenoxyalkyl, optionally substituted heteroaryloxyalkyl, or aminoalkyl is optionally substituted with one or two fluoro. Preferably, the substituents are independently: methoxy, methyl, ethyl, chloro, trifluoromethyl, fluoro, 2-methoxyethoxy, 2- (morpholin-4-yl) ethoxy, pyridin-3-ylmethoxy, trifluoromethyl, methyl, ethyl, chloro, ethoxy, 2-methoxyethoxy, 2- (morpholin-4-yl) ethoxy, pyridin-3-ylmethoxy, bromo,2-hydroxyethoxy, 2- (N, N-dimethylamino) -ethoxy, methoxymethyl, phenoxymethyl, 2-morpholino-4-ylethyl, morpholino-4-ylmethyl, N-dimethylamino-methyl, isopropoxymethyl, or phenoxymethyl.
"Heterocycloalkylalkyl" means a- (alkylene) -R group, where R is a heterocycloalkyl ring as defined above, e.g., furylmethyl, piperazinylmethyl, morpholinoethyl, and the like.
"heteroaryl" means a monovalent monocyclic or bicyclic aromatic radical having 5 to 10 ring atoms, wherein one or more, preferably one, two or three ring atoms are heteroatoms selected from N, O or S, the remaining ring atoms being C. More specifically, the term "heteroaryl" includes, but is not limited to: pyridyl, pyrrolyl, imidazolyl, thienyl, furyl, indolyl, quinolinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, benzoxazolyl, benzothienyl, benzothiazolyl, tetrahydroquinolinyl, isoquinolinyl, benzofuranyl, benzopyranyl, and thiazolyl, and derivatives thereof (formed when a heterocycloalkyl ring is substituted with the following substituents); or an N-oxide or protected derivative thereof. Unless otherwise specified, the heteroaryl ring is optionally substituted with one, two, or three substituents independently selected from: alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxy, hydroxyalkyl, hydroxyalkoxy, hydroxyalkoxyalkyl, alkoxyalkoxyalkyl, optionally substituted phenyl, cycloalkoxy, cycloalkenyloxy, optionally substituted phenylcarbonylamino, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted heteroarylalkoxy, aminoalkyl, aminoalkoxy, alkoxyalkyl, alkoxyalkoxy, methylenedioxy, haloalkoxyalkyl, optionally substituted phenylalkyl, optionally substituted phenoxy, optionally substituted phenylalkoxy, optionally substituted phenoxyalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted heterocycloalkoxyalkyl, optionally substituted heterocycloalkylalkoxy, optionally substituted heterocycloalkylamino, dialkylamino, hydroxy, hydroxyalkyl, hydroxyalkoxy, hydroxyalkoxyalkyl, alkoxyalkoxy, cycloalkoxy, cycloalkoxyalkyl, optionally substituted heteroaryloxyalkylOptionally substituted heterocycloalkoxy, -alkylene-S (O)n-Ra(wherein n is 0 to 2, RaIs alkyl, hydroxyalkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl), -alkylene-NHSO2-Rb(wherein R isbIs alkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or optionally substituted heterocycloalkyl), -alkylene-NHCO-Rc(wherein R iscIs alkyl, haloalkyl, hydroxy, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or optionally substituted heterocycloalkyl), - (alkylene) n1-CONRdRf(wherein n1 is 0 or 1, RdIs hydrogen or alkyl, RfIs hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or optionally substituted heterocycloalkylalkyl), or RdAnd RfTogether with the nitrogen atom to which they are attached form an optionally substituted heterocycloalkyl), -alkylene-NRe-alkylene-CONRcRd(wherein R iscAs defined above, RdAnd ReIndependently hydrogen or alkyl), or carboxyalkylaminoalkyl, wherein the alkyl chain in the haloalkoxyalkyl, optionally substituted phenoxyalkyl, optionally substituted heteroaryloxyalkyl, or aminoalkyl is optionally substituted with one or two fluoro. Preferably, the substituents are independently: methoxy, methyl, ethyl, chloro, trifluoromethyl, fluoro, 2-methoxyethoxy, 2- (morpholin-4-yl) ethoxy, pyridin-3-ylmethoxy, 2-hydroxyethoxy, 2- (N, N-dimethylamino) -ethoxy, methoxymethyl, phenoxymethyl, 2-morpholino-4-ylethyl, morpholino-4-ylmethyl, N-dimethylamino-methyl, isopropoxymethyl, or phenoxymethyl.
When the heteroaryl ring is divalent, it is referred to herein as heteroarylene.
"heteroarylamino" refers to an NHR group, wherein R is heteroaryl as defined above.
"Heteroaralkyl" means a- (alkylene) -R group, wherein R is heteroaryl as defined above.
"heteroarylalkenyl" means a- (alkenylene) -R group, wherein R is heteroaryl as defined above.
"methylenedioxy" refers to-O-CH2-O-。
The invention also includes prodrugs of the compounds of formula (I). The term "prodrug" is used to denote a covalently bonded carrier which releases the active ingredient of formula (I) when the prodrug is administered to a mammalian subject. The release of the active ingredient takes place in vivo. Prodrugs can be prepared by techniques familiar to those skilled in the art. These techniques typically modify the appropriate functional groups in a given compound. However, these modified functional groups may regenerate the original functional groups by conventional processing or in vivo. Prodrugs of compounds of formula (I) include compounds wherein hydroxy, amino, carboxy, or the like is modified. Examples of prodrugs include, but are not limited to: esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., N-dimethylaminocarbonyl) of hydroxy or amino functionality in compounds of formula (I), amides (e.g., trifluoroacetamido, acetamido, etc.), and the like. Prodrugs of the compounds of formula (I) are also within the scope of the invention.
The invention also includes N-oxide derivatives and protected derivatives of the compounds of formula (I). For example, when the compound of formula (I) contains an oxidizable nitrogen atom, the nitrogen atom may be converted to an N-oxide by methods well known in the art. When the compounds of formula (I) contain groups such as hydroxyl, carboxyl, thiol or any nitrogen atom containing group, these groups may be protected with a suitable protecting group. A comprehensive list of suitable protecting groups can be found in t.w. greene, protective groups in Organic Synthesis, John Wiley & Sons, inc.1981, the disclosure of which is incorporated herein by reference in its entirety. Protected derivatives of compounds of formula (I) may be prepared by methods well known in the art.
"phenylene" means a divalent phenyl group.
"pharmaceutically acceptable salts" of a compound refer to salts that are pharmaceutically acceptable and possess the desired pharmacological activity of the parent compound. Such salts include:
an acid addition salt formed with the following acids: using inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or using organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethyldisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthylsulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4' -methylenebis- (3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, laurylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or
Salts formed in the following cases: when the acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, alkaline earth ion, or aluminum ion; or when the acidic proton is coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. It is understood that pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed, Mack publishing company, Easton, Pa, 1985, which is incorporated herein by reference.
The compounds of the invention may have asymmetric centers. The compounds of the invention containing asymmetrically substituted atoms may be isolated in optically active forms or racemates. It is well known in the art how to prepare optically active forms, such as by material resolution. Unless a particular stereochemistry or isomeric form is specifically indicated, all chiral, diastereomeric, racemic forms are within the scope of the invention.
Certain compounds of formula (I) may exist as tautomers and/or geometric isomers. All possible tautomers as well as cis and trans isomers, individuals and mixtures thereof are within the scope of the present invention. In addition, as used herein, the term "alkyl" includes all possible isomeric forms of the alkyl group, although only a few examples are listed. In addition, when cyclic groups such as aryl, heteroaryl, heterocycloalkyl are substituted, they include all positional isomers, although only a few examples are listed. In addition, all polymorphs and hydrates of the compound of formula (I) are within the scope of the present invention.
"optionally substituted phenyl" refers to a phenyl ring optionally substituted with one, two, or three substituents independently selected from: alkyl, halo, alkoxy, alkylthio, haloalkyl, haloalkoxy, heteroaryl (which is optionally substituted with one or two substituents independently selected from alkyl, halo, hydroxy, alkoxy, carboxy, amino, alkylamino or dialkylamino), heterocycloalkyl (which is optionally substituted with one or two substituents independently selected from alkyl, halo, hydroxy, alkoxy, carboxy, amino, alkylamino or dialkylamino), amino, alkylamino, dialkylamino, hydroxy, cyano, nitro, methylenedioxy, aminocarbonyl, amido, hydroxyalkyl, alkoxycarbonyl, aminoalkyl, or carboxy, or optionally substituted with five fluorine atoms.
"optionally substituted phenoxy" refers to the group-OR, where R is optionally substituted phenyl as defined above, e.g., phenoxy, chlorophenoxy, and the like.
"optionally substituted phenylcarbonylamino" means an-NHCOR group wherein R is an optionally substituted phenyl group as defined above, e.g., benzoylamino and the like.
"optionally substituted phenylalkyl" means a- (alkylene) -R group, wherein R is optionally substituted phenyl as defined above, e.g., benzyl, phenethyl, and the like.
"optionally substituted phenylalkoxy" means a-OR group wherein R is optionally substituted phenylalkyl as defined above, e.g., benzyloxy, phenylethoxy, and the like.
"optionally substituted phenylalkylthio" means the radical-S- (alkylene) -R, wherein R is optionally substituted phenyl as defined above, e.g., benzylthio, phenylethylthio, and the like.
"optionally substituted phenylalkylsulfonyl" means-SO2- (alkylene) -R groups, wherein R is optionally substituted phenyl as defined above, e.g. benzylsulfonyl, phenylethylsulfonyl and the like.
"optionally substituted phenylalkenyl" refers to a- (alkenylene) -R group, wherein R is optionally substituted as previously defined, e.g., styryl, phenylpropenyl, and the like.
"optionally substituted phenoxyalkyl" refers to the- (alkylene) -OR group, where R is an optionally substituted phenyl group as defined above, e.g., phenoxymethyl, phenoxyethyl, and the like.
"optionally substituted heteroaryl" refers to a monovalent monocyclic or bicyclic aromatic radical having 5 to 10 ring atoms, wherein one or more, preferably one, two or three ring atoms are heteroatoms selected from N, O or S, and the remaining ring atoms are C, optionally substituted with one, two or three substituents independently selected from: alkyl, halo, alkoxy, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxy, cyano, nitro, aminocarbonyl, hydroxyalkyl, alkoxycarbonyl, aminoalkyl, optionally substituted phenyl, optionally substituted phenoxy, carboxy, or heteroaryl, optionally substituted with alkyl, halo, hydroxy, alkoxy, carboxy, amino, alkylamino, or dialkylamino; heterocycloalkyl, optionally substituted with one or two substituents independently selected from: alkyl, halo, hydroxy, alkoxy, amino, alkylamino, or dialkylamino; heterocycloalkylalkyl optionally substituted with one or two substituents independently selected from the group consisting of: alkyl, halo, hydroxy, alkoxy, amino, alkylamino, or dialkylamino; or heteroarylamino optionally substituted with one or two substituents independently selected from: alkyl, halo, hydroxy, alkoxy, amino, alkylamino, or dialkylamino. More specifically, the term "optionally substituted heteroaryl" includes, but is not limited to: pyridyl, pyrrolyl, imidazolyl, thienyl, furyl, indolyl, quinolinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, benzoxazolyl, tetrahydroquinolinyl, isoquinolinyl, benzopyranyl, and thiazolyl, and derivatives thereof (formed when a heteroaryl ring is substituted with a substituent as listed above); or an N-oxide or protected derivative thereof.
"optionally substituted heteroaryloxy" refers to the group-OR, where R is an optionally substituted heteroaryl group as defined above, e.g., furanyloxy, pyridinyloxy, and the like.
"optionally substituted heteroarylalkoxy" refers to the group-OR, wherein R is an optionally substituted heteroarylalkyl ring as defined below.
"optionally substituted heteroaryloxyalkyl" refers to the- (alkylene) -OR group, wherein R is an optionally substituted heteroaryl ring as defined above.
"optionally substituted heteroaralkyl" refers to a- (alkylene) -R group, wherein R is an optionally substituted heteroaromatic ring as defined above.
"optionally substituted heterocycloalkyl" refers to a saturated or unsaturated monovalent cyclic group having 3 to 8 ring atoms, wherein one or two ring atoms are selected from N, O, or S (O)nWherein n is an integer from 0 to 2, and the remaining ring atoms are C. One or two ring carbon atoms may be optionally substituted by a-CO-group. More specifically, the term "heterocycloalkyl" includes, but is not limited to: pyrrolidino, piperidino, morpholino, piperazino, tetrahydropyranyl and thiomorpholino groups and derivatives thereof (formed when the heterocycloalkyl ring is substituted with the following substituents)) Or an N-oxide or protected derivative thereof. Heterocycloalkyl is optionally fused to aryl, and is optionally substituted with one, two, or three substituents independently selected from: alkyl, cycloalkyl, halo, alkoxy, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxy, cyano, nitro, optionally substituted phenylalkyl, optionally substituted heteroaralkyl, aminocarbonyl, hydroxyalkyl, alkoxycarbonyl, aminoalkyl or carboxy.
"optionally substituted heterocycloalkoxy" means the group-OR, where R is an optionally substituted heterocycloalkyi ring as defined above.
"optionally substituted heterocycloalkylalkyl" refers to the- (alkylene) -R group, where R is an optionally substituted heterocycloalkylalkyl ring as defined above.
"optionally substituted heterocycloalkylalkoxy" means the group-OR, where R is an optionally substituted heterocycloalkylalkyl ring as defined above.
"optionally substituted heterocycloalkoxyalkyl" means a- (alkylene) -OR group wherein R is an optionally substituted heterocycloalkyi group as defined above, e.g., piperidinyloxymethyl, pyrrolidinoethyl, and the like.
"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes: examples where an event or circumstance occurs, and examples where a time or circumstance does not occur. For example, "heterocycloalkyl optionally mono-or di-substituted with alkyl" means that alkyl may, but need not, be present, and that the description includes: the case where the heterocycloalkyl group is mono-or di-substituted with an alkyl group, and the case where the heterocycloalkyl group is not substituted with an alkyl group.
By "pharmaceutically acceptable carrier or excipient" is meant a carrier or excipient that can be used in the preparation of a pharmaceutical composition that is generally safe, non-toxic, not biologically or otherwise undesirable, including carriers or excipients that are acceptable for both veterinary use and human pharmaceutical use. As used in the specification and claims, a "pharmaceutically acceptable carrier/excipient" includes one and more than one such excipient.
"treatment" of a disease includes:
(1) prevention of a disease, i.e., the clinical symptoms of a disease do not develop in a mammal that may be exposed to or predisposed to the disease, but does not yet suffer from or exhibit symptoms of the disease.
(2) Inhibiting the disease, i.e., arresting or reducing the progression of the disease or its clinical symptoms; or
(3) Relieving the disease, i.e., causing regression of the disease or its clinical symptoms.
The term "treating cancer" or "treatment of cancer" refers to administration to a mammal afflicted with cancer, and refers to the effect of alleviating cancer by killing cancer cells, as well as directing the effect of causing inhibition of cancer proliferation and/or metastasis.
"therapeutically effective amount" means the amount of a compound of formula (I) that, when administered to a mammal to treat a disease, is sufficient to effect treatment of the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal being treated.
Representative compounds of formula (I) are disclosed in tables I-IV below.
The compounds of formula (I) are as follows:
wherein R is1And R3Is hydrogen, Ar1Is phenyl, Ar2And Y are defined in Table I below.
TABLE I
And is named as:
n-hydroxy-4- (2-phenylcarbonylamino-ethoxy) benzamide;
n-hydroxy-4- (2-trans-cinnamoylaminoethoxy) benzamide;
n-hydroxy-4- (2-trans-2-phenylcyclopropylcarbonylaminoethoxy) benzamide;
n-hydroxy-4- (2-trans-4-methoxycinnamoylaminoethoxy) benzamide;
n-hydroxy-4- [2- (2-phenylethylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (1H-indol-3-ylmethylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- (2-thiophen-2-ylcarbonylaminoethoxy) benzamide;
n-hydroxy-4- (2-pyridin-3-ylcarbonylaminoethoxy) benzamide;
n-hydroxy-4- (2-biphenyl-4-ylcarbonylaminoethoxy) benzamide;
n-hydroxy-4- (2-biphenyl-3-ylcarbonylaminoethoxy) benzamide;
n-hydroxy-4- [2- (5-phenylthiophen-2-ylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (thiophen-2-ylmethylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (naphthalen-2-ylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (quinolin-6-ylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (4-phenylthiazol-2-ylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (4-tert-butylphenyl carbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (trans-3-pyridin-3-ylacryloylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (4-pyrrol-1-ylphenylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (4-cyclohexene-3-oxyphenylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (benzothiazol-2-ylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (benzooxazol-2-ylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (octahydroisoquinolin-2-ylmethylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (4-pyridin-4-ylpiperazin-1-ylmethylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (furan-2-ylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (4-pyridin-3-ylphenylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (4-pyridin-2-ylphenylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (benzimidazol-2-ylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (1H-pyrrol-2-ylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (4-benzoylaminophenylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (4-pyridin-4-ylthiazol-2-ylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (adamantan-1-ylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (2, 4-difluorophenylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (3-trans-3, 4-methylenedioxyphenylacryloylamino) ethoxy ] -benzamide;
n-hydroxy-4- [2- (3, 4-methylenedioxyphenylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (3, 4-dimethoxyphenylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (3, 5-dimethoxyphenylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (3, 4-difluorophenylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (2, 5-dimethylphenylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (2, 3-dichlorophenylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (2, 3-dimethylphenylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (4-chloro-2-methoxyphenylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (3-ethoxyphenylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (4-methoxy-2-methylphenylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (3-fluoro-4-methoxyphenylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (2-thiophen-2-ylmethoxyphenylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (3-thiophen-2-ylmethoxyphenylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (biphenyl-2-ylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (1H-indol-5-ylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (1H-indol-3-ylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (quinolin-3-ylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (quinolin-8-ylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (1H-indazol-3-ylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (1H-benzotriazol-5-ylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (isoquinolin-1-ylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (isoquinolin-3-ylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (quinoxalin-2-ylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (naphthalen-1-ylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (quinolin-2-ylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (2-pyrrol-1-ylphenylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (4-fluoronaphthalen-1-ylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (1H-benzoimidazol-5-ylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (1-methylindol-3-ylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (4-methoxyquinolin-2-ylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (3-methoxynaphthalen-2-ylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (2-methoxynaphthalen-1-ylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (quinolin-4-ylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (trans-2-methylcinnamoylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (2-N, N-dimethylaminomethylbenzofuran-5-ylcarbonylamino) ethoxy ] -benzamide;
n-hydroxy-4- (2-indolin-1-ylcarbonylaminoethoxy) benzamide;
n-hydroxy-4- [2- (1, 2,3, 4-tetrahydroquinolin-1-ylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- {2S- [ trans-3- (5-hydroxybenzofuran-2-yl) but-2-enoylamino ] butoxy } benzamide;
n-hydroxy-4- {2S- [ trans-3- (5- (1-cyclopropylpiperidin-4-yloxy) benzofuran-2-yl) but-2-enoyl-amino ] butoxy } benzamide;
n-hydroxy-4- [2S- (benzofuran-2-ylcarbonylamino) -4-phenylbutoxy ] benzamide;
n-hydroxy-4- {2- [5- (1-cyclopropylpiperidin-4-yloxy) benzofuran-2-ylcarbonylamino ] -ethoxy } benzamide;
n-hydroxy-4- {2S- [5- (1-cyclopropylpiperidin-4-yloxy) benzofuran-2-ylcarbonylamino ] -butoxy } benzamide;
n-hydroxy-4- {2- [5- (1-cyclopropylpiperidin-4-yloxy) benzofuran-2-ylcarbonylamino ] -1R-methylethoxy } benzamide;
n-hydroxy-4- {2- [5- (1- (2, 2, 2-trifluoroethyl) piperidin-4-yloxy) benzofuran-2-ylcarbonyl-amino ] -ethoxy } benzamide;
n-hydroxy-4- [2R- (benzofuran-2-ylcarbonylamino) -3-benzylsulfonylpropoxy ] benzamide;
n-hydroxy-4- [2R- (benzofuran-2-ylcarbonylamino) -3-benzylthiopropoxy ] benzamide;
n-hydroxy-4- [2- (trans-3- (5-methoxybenzofuran-2-yl) but-2-enoylcarbonylamino) -ethoxy ] benzamide;
n-hydroxy-4- [2- (1, 2,3, 4-tetrahydroisoquinolin-2-ylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (isoindolin-2-ylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (morpholin-4-ylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (4-benzylpiperazin-1-ylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (3(R) -hydroxypyrrolidin-1-ylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (piperidin-1-ylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (6-methyl-1, 2,3, 4-tetrahydroquinolin-1-ylcarbonylamino) ethoxy ] -benzamide;
n-hydroxy-4- [2- (2-methyldihydroindol-1-ylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (6-fluoro-2-methyl-1, 2,3, 4-tetrahydroquinolin-1-ylcarbonylamino) -ethoxy ] benzamide;
n-hydroxy-4- [2S- (isoindolin-1-ylcarbonylamino) butoxy ] benzamide;
n-hydroxy-4- [3- (trans-cinnamoylamino) propoxy ] benzamide;
n-hydroxy-4- [3- (trans-4-methoxycinnamoylamino) propoxy ] benzamide;
n-hydroxy-4- [3- (4-phenylthiazol-2-ylcarbonylamino) propoxy ] benzamide;
n-hydroxy-4- [2S- (trans-cinnamoylamino) propoxy ] benzamide;
n-hydroxy-4- [2R- (trans-cinnamoylamino) propoxy ] benzamide;
n-hydroxy-4- [2S- (trans-cinnamoylamino) -4-methylpentyloxy ] benzamide;
n-hydroxy-4- [2S- (trans-cinnamoylamino) -3-cyclohexylpropoxy ] benzamide;
n-hydroxy-4- [2S- (trans-cinnamoylamino) -3-methylbutoxy ] benzamide;
n-hydroxy-4- [2S- (trans-cinnamoylamino) -3-phenylpropoxy ] benzamide;
n-hydroxy-4- [2R- (trans-cinnamoylamino) -3-phenylpropoxy ] benzamide;
n-hydroxy-4- [2R- (trans-cinnamoylamino) -4-methylpentyloxy ] benzamide;
n-hydroxy-4- [2R- (trans-cinnamoylamino) -3-methylbutoxy ] benzamide;
n-hydroxy-4- [2RS- (trans-cinnamoylamino) hexyloxy ] benzamide;
n-hydroxy-4- [2RS- (trans-cinnamoylamino) -3- (4-chlorophenyl) propoxy ] benzamide;
n-hydroxy-4- [2S- (trans-cinnamoylamino) butoxy ] benzamide;
n-hydroxy-4- [2R- (trans-cinnamoylamino) butoxy ] benzamide;
n-hydroxy-4- [2S- (trans-cinnamoylamino) -4-methylthiobutoxy ] benzamide;
n-hydroxy-4- [2R- (trans-cinnamoylamino) -4-methylthiobutoxy ] benzamide;
n-hydroxy-4- [2S- (trans-cinnamoylamino) -2-phenylethoxy ] benzamide;
n-hydroxy-4- [2R- (trans-cinnamoylamino) -2-phenylethoxy ] benzamide;
n-hydroxy-4- [2S- (trans-cinnamoylamino) -4-methylsulfonylbutoxy ] benzamide;
n-hydroxy-4- [2R- (trans-cinnamoylamino) -4-methylsulfonylbutoxy ] benzamide;
n-hydroxy-4- [2R- (trans-cinnamoylamino) -3-benzylsulfonylpropoxy ] benzamide;
n-hydroxy-4- [2S- (thiophen-2-ylcarbonylamino) butoxy ] benzamide;
n-hydroxy-4- [2S- (biphenyl-4-ylcarbonylamino) butoxy ] benzamide;
n-hydroxy-4- [2S- (naphthalen-2-ylcarbonylamino) butoxy ] benzamide;
n-hydroxy-4- [2R- (trans-cinnamoylamino) -3-benzylthiopropoxy ] benzamide;
n-hydroxy-4- [2S- (phenylcarbonylamino) butoxy ] benzamide;
n-hydroxy-4- [2S- (benzylcarbonylamino) butoxy ] benzamide;
n-hydroxy-4- [2S- (2-phenylethylcarbonylamino) butoxy ] benzamide;
n-hydroxy-4- [2S- (trans-cinnamoylamino) -3-hydroxypropoxy ] benzamide;
n-hydroxy-4- [2S- (4-phenylthiazol-2-ylcarbonylamino) butoxy ] benzamide;
n-hydroxy-4- [2S- (trans-4-methoxycinnamoylamino) butoxy ] benzamide;
n-hydroxy-4- [2S- (2-N, N-dimethylaminomethylbenzofuran-5-ylcarbonylamino) butoxy ] -benzamide;
n-hydroxy-4- [2- (trans-cinnamoylamino) -1R-methylethoxy ] benzamide;
n-hydroxy-4- [2- (trans-cinnamoylamino) -1S-methylethoxy ] benzamide;
n-hydroxy-4- [2- (4-phenylthiazol-2-ylcarbonylamino) -1R-methylethoxy ] benzamide;
n-hydroxy-4- [2- (4-phenylthiazol-2-ylcarbonylamino) -1S-methylethoxy ] benzamide;
n-hydroxy-4- [2- (biphenyl-4-ylcarbonylamino) -1R-methylethoxy ] benzamide;
n-hydroxy-4- [2- (trans-4-methoxycinnamoylamino) -1R-methylethoxy ] benzamide;
n-hydroxy-4- {2- [4- (2-pyridin-2-ylthiazol-5-yl) phenylcarbonylamino ] ethoxy } benzamide;
n-hydroxy-4- [2- (7-chloro-4-methylbenzofuran-2-ylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- {2- [4- (2- (4-methylpiperazin-1-yl) thiazol-5-yl) phenylcarbonylamino ] -ethoxy } benzamide;
n-hydroxy-4- {2- [4- (2-pyridin-4-ylaminothiazol-5-yl) phenylcarbonylamino ] ethoxy } -benzamide;
n-hydroxy-4- {2- [4- (4-methylpiperazin-1-yl) phenylcarbonylamino ] ethoxy } benzamide;
n-hydroxy-4- {2- [4- (4-hydroxypiperidin-1-yl) phenylcarbonylamino ] ethoxy } benzamide;
n-hydroxy-4- {2- [4- (4-morpholin-4-ylmethyl thiazol-5-yl) phenylcarbonylamino ] ethoxy } -benzamide;
n-hydroxy-4- [2- (7-fluoro-4-methylbenzofuran-2-ylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- {2- [ 7-fluoro-4- (2-methoxyethoxymethyl) benzofuran-2-ylcarbonylamino ] -ethoxy } benzamide;
n-hydroxy-4- [2- (4-hydroxyquinolin-2-ylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (7-fluoro-4-phenoxymethylbenzofuran-2-ylcarbonylamino) ethoxy ] -benzamide;
n-hydroxy-4- {2- [4- (2- (4-methylpiperazin-1-ylmethyl) thiazol-5-yl) phenylcarbonyl-amino ] -ethoxy } benzamide;
n-hydroxy-4- [2- (pyridin-2-ylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (3-hydroxypyridin-2-ylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (6-hydroxypyridin-2-ylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- {2- [6- (4-nitrophenoxy) pyridin-2-ylcarbonylamino ] ethoxy } benzamide;
n-hydroxy-4- {2- [4- (2-methoxyethoxy) quinolin-2-ylcarbonylamino ] ethoxy } benzamide;
n-hydroxy-4- {2- [4- (2-N, N-dimethylaminoethoxy) quinolin-2-ylcarbonylamino ] ethoxy } -benzamide;
n-hydroxy-4- [2- (6-bromopyridin-2-ylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (5-bromopyridin-3-ylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2S- (4-methoxyquinolin-2-ylcarbonylamino) butoxy ] benzamide;
n-hydroxy-4- [2- (1-methoxynaphthalen-2-ylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (4-methoxyquinolin-2-ylcarbonylamino) -1R-methylethoxy ] benzamide;
n-hydroxy-4- [2- (5-phenylpyridin-3-ylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (6-benzyloxypyridin-2-ylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- {2- [6- (2-methylpropoxy) pyridin-2-ylcarbonylamino ] ethoxy } benzamide;
n-hydroxy-4- {2- [6- (2-phenylethoxy) pyridin-2-ylcarbonylamino ] ethoxy } benzamide;
n-hydroxy-4- {2- [4- (3, 3, 3-trifluoropropoxy) quinolin-2-ylcarbonylamino ] ethoxy } -benzamide;
n-hydroxy-4- {2S- [4- (3, 3, 3-trifluoropropoxy) quinolin-2-ylcarbonylamino ] butoxy } -benzamide;
n-hydroxy-4- {2- [4- (3, 3, 3-trifluoropropoxy) quinolin-2-ylcarbonylamino ] -1R-methylethoxy } benzamide;
n-hydroxy-4- [2- (trans-3-hydroxycinnamoylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (trans-4-hydroxycinnamoylamino) ethoxy ] benzamide;
n-hydroxy-4- {2- [ 3' - (2-hydroxyethyl) biphenyl-4-ylcarbonylamino ] ethoxy } benzamide;
n-hydroxy-4- {2- [ 3' - (2-hydroxyethyl) biphenyl-3-ylcarbonylamino ] ethoxy } benzamide;
n-hydroxy-4- {2- [ 2' - (2-hydroxyethyl) biphenyl-4-ylcarbonylamino ] ethoxy } benzamide;
n-hydroxy-4- [2- (trans-2-benzofuran-2-ylacryloylamino) ethoxy ] benzamide;
n-hydroxy-4- {2- [ 2' - (2-hydroxyethyl) biphenyl-3-ylcarbonylamino ] ethoxy } benzamide;
n-hydroxy-4- {2- [5- (thiophen-3-yl) pyridin-3-ylcarbonylamino ] ethoxy) benzamide;
n-hydroxy-4- {2- [6- (4-acetylaminophenoxy) pyridin-2-ylcarbonylamino ] ethoxy } -benzamide;
n-hydroxy-4- {2- [6- (4-aminophenoxy) pyridin-2-ylcarbonylamino ] ethoxy } benzamide;
n-hydroxy-4- [2- (trans-2-methoxycinnamoylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (trans-3-methoxycinnamoylamino) ethoxy ] benzamide;
n-hydroxy-4- {2- [5- (4-dimethylaminophenyl) pyridin-3-ylcarbonylamino ] ethoxy } -benzamide;
n-hydroxy-4- {2- [ trans-3- (5-bromothiophen-2-yl) acryloylamino ] ethoxy } benzamide;
n-hydroxy-4- [2- (trans-3-furan-3-ylacryloylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (trans-3-thiophen-3-ylacryloylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (trans-thiophen-2-ylacryloylamino) ethoxy ] benzamide;
n-hydroxy-4- {2- [ trans-3-methylcinnamoylamino ] ethoxy } benzamide;
n-hydroxy-4- {2- [ trans-4-methylcinnamoylamino ] ethoxy } benzamide;
n-hydroxy-4- {2- [ trans-3- (benzofuran-2-yl) but-2-enoylamino ] ethoxy } benzamide;
n-hydroxy-4- {2- [ cis-3- (benzofuran-2-yl) but-2-enoylamino ] ethoxy } benzamide;
n-hydroxy-4- [2- (trans-4-dimethylaminocinnamoylamino) ethoxy ] benzamide;
n-hydroxy-4- [2- (trans-3-indol-3-ylacryloylamino) ethoxy ] benzamide;
n-hydroxy-4- {2- [ trans-2-methylcinnamoylamino ] ethoxy } benzamide;
n-hydroxy-4- [2- (trans-2-hydroxycinnamoylamino) ethoxy ] benzamide;
n-hydroxy-4- {2- [ trans-3- (7-methoxybenzofuran-2-yl) acryloylamino ] ethoxy } benzamide;
n-hydroxy-4- {2R- [ trans-3- (7-methoxybenzofuran-2-yl) acryloylamino ] butoxy } benzamide;
n-hydroxy-4- {2S- [ trans-3- (5-methoxybenzofuran-2-yl) but-2-enoylamino ] butoxy } benzamide;
n-hydroxy-4- [2- (trans-3-furan-2-ylacryloylamino) ethoxy ] benzamide; and
n-hydroxy-4- {2- [4- (4- (2-morpholin-4-ylethyl) thiazol-2-yl) phenylcarbonylamino ] ethoxy } -benzamide;
the compounds of formula (I) are as follows:
wherein R is1Is hydrogen, Ar1Is phenyl, R3、Ar2And Y are defined in Table II below.
TABLE II
| Compound numbering | R3 | Ar2 | Y |
| 1 | 2-HO-ethyl | trans-phenyl-CH ═ CH- | -CH2-CH2- |
| 2 | Phenyl radical | trans-phenyl-CH ═ CH- | -CH2-CH2- |
| 3 | CH3 | trans-phenyl-CH ═ CH- | -CH2-CH2- |
| 4 | Isopropyl group | Benzothiophen-2-yl | -CH2-CH2- |
| 5 | Isopropyl group | trans-phenyl-CH ═ CH- | -CH2-CH2- |
| 6 | CH3 | trans-phenyl-CH ═ CH- | -CH2-CH2-CH2- |
And is named as:
n-hydroxy-4- (2-N-trans-cinnamoyl-N-hydroxyethylaminoethoxy) benzamide;
n-hydroxy-4- (2-N-trans-cinnamoyl-N-phenylaminoethoxy) benzamide;
n-hydroxy-4- (2-N-trans-cinnamoyl-N-methylaminoethoxy) benzamide;
n-hydroxy-4- (2-N-benzothien-2-yl-N-isopropylaminoethoxy) benzamide;
n-hydroxy-4- (2-N-trans-cinnamoyl-N-isopropylaminoethoxy) benzamide; and
n-hydroxy-4- (3-N-trans-cinnamoyl-N-methylaminopropoxy) benzamide;
the compounds of formula (I) are as follows:
wherein R is1And R3Is hydrogen, Ar1For phenyl, Z, R and Y are defined in Table II below.
TABLE III
And is named as:
n-hydroxy-4- [2- (benzothien-2-ylcarbonylamino) ethoxy ] -benzamide;
n-hydroxy-4- [2- (benzofuran-2-ylcarbonylamino) ethoxy ] -benzamide;
n-hydroxy-4- [2- (1H-indol-2-ylcarbonylamino) ethoxy ] -benzamide;
n-hydroxy-4- [2- (1-methylindol-2-ylcarbonylamino) ethoxy ] -benzamide;
n-hydroxy-4- [3- (benzothien-2-ylcarbonylamino) propoxy ] -benzamide;
n-hydroxy-4- [3- (benzofuran-2-ylcarbonylamino) propoxy ] -benzamide;
n-hydroxy-4- [2S- (benzothien-2-ylcarbonylamino) -3-methylbutoxy ] -benzamide;
n-hydroxy-4- [2S- (benzothien-2-ylcarbonylamino) butoxy ] -benzamide;
n-hydroxy-4- [2S- (benzothien-2-ylcarbonylamino) -propoxy ] -benzamide;
n-hydroxy-4- [2R- (benzothien-2-ylcarbonylamino) -propoxy ] -benzamide;
n-hydroxy-4- [2S- (benzofuran-2-ylcarbonylamino) butoxy ] -benzamide;
n-hydroxy-4- [2- (benzothien-2-ylcarbonylamino) -1R-methylethoxy ] -benzamide;
n-hydroxy-4- [2- (benzothien-2-ylcarbonylamino) -1S-methylethoxy ] -benzamide;
n-hydroxy-4- [2- (benzofuran-2-ylcarbonylamino) -1R-methylethoxy ] -benzamide;
n-hydroxy-4- [2- (6-methoxybenzothien-2-ylcarbonylamino) ethoxy ] -benzamide;
n-hydroxy-4- [2- (5-methylbenzothien-2-ylcarbonylamino) ethoxy ] -benzamide;
n-hydroxy-4- [2- (3-chlorobenzothien-2-ylcarbonylamino) ethoxy ] -benzamide;
n-hydroxy-4- [2- (5-methylbenzofuran-2-ylcarbonylamino) ethoxy ] -benzamide;
n-hydroxy-4- [2- (6-methylbenzofuran-2-ylcarbonylamino) ethoxy ] -benzamide;
n-hydroxy-4- [2- (4-trifluoromethylbenzothien-2-ylcarbonylamino) ethoxy ] -benzamide;
n-hydroxy-4- [2- (5-fluorophenothiophen-2-ylcarbonylamino) ethoxy ] -benzamide;
n-hydroxy-4- [2- (5-methoxybenzothien-2-ylcarbonylamino) ethoxy ] -benzamide;
n-hydroxy-4- [2- (5-chlorobenzofuran-2-ylcarbonylamino) ethoxy ] -benzamide;
n-hydroxy-4- [2- (7-methoxybenzofuran-2-ylcarbonylamino) ethoxy ] -benzamide;
n-hydroxy-4- [2- (5-methoxybenzofuran-2-ylcarbonylamino) ethoxy ] -benzamide;
n-hydroxy-4- {2- [5- (2-methoxyethoxy) benzofuran-2-ylcarbonylamino ] ethoxy } -benzamide;
n-hydroxy-4- {2- [5- (2-morpholin-4-ylethoxy) benzofuran-2-ylcarbonylamino ] ethoxy } -benzamide;
n-hydroxy-4- {2- [5- (pyridin-3-ylmethoxy) benzofuran-2-ylcarbonylamino ] ethoxy } -benzamide;
n-hydroxy-4- [2- (3-methylbenzofuran-2-ylcarbonylamino) ethoxy ] -benzamide;
n-hydroxy-4- [2- (3-methylbenzothien-2-ylcarbonylamino) ethoxy ] -benzamide;
n-hydroxy-4- {2- [5- (2-hydroxyethoxy) benzofuran-2-ylcarbonylamino ] ethoxy } -benzamide;
n-hydroxy-4- {2- [5- (2-N, N-dimethylaminoethoxy) benzofuran-2-ylcarbonylamino ] -ethoxy } -benzamide;
n-hydroxy-4- {2- [6- (2-methoxyethoxy) benzofuran-2-ylcarbonylamino ] ethoxy } -benzamide;
n-hydroxy-4- {2- [6- (2-morpholin-4-ylethoxy) benzofuran-2-ylcarbonylamino ] ethoxy } -benzamide;
n-hydroxy-4- {2- [6- (pyridin-3-ylmethoxy) benzofuran-2-ylcarbonylamino ] ethoxy } -benzamide;
n-hydroxy-4- [2- (3-ethylbenzofuran-2-ylcarbonylamino) ethoxy ] -benzamide;
n-hydroxy-4- [2- (5-fluoroindol-2-ylcarbonylamino) ethoxy ] -benzamide;
n-hydroxy-4- [2- (5-methoxyindol-2-ylcarbonylamino) ethoxy ] -benzamide;
n-hydroxy-4- {2- [3- (methoxymethyl) benzofuran-2-ylcarbonylamino ] ethoxy } benzamide;
n-hydroxy-4- {2- [3- (phenoxymethyl) benzofuran-2-ylcarbonylamino ] ethoxy } benzamide;
n-hydroxy-4- [2- (5, 6-dimethoxyindol-2-ylcarbonylamino) ethoxy ] -benzamide;
n-hydroxy-4- {2- [3- (morpholin-4-ylmethyl) benzofuran-2-ylcarbonylamino ] ethoxy } -benzamide;
n-hydroxy-4- {2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino ] ethoxy } -benzamide;
n-hydroxy-4- {2- [3- (isopropoxymethyl) benzofuran-2-ylcarbonylamino ] ethoxy } benzamide;
n-hydroxy-4- {2- [7- (phenoxymethyl) benzofuran-2-ylcarbonylamino ] ethoxy } benzamide;
n-hydroxy-4- {2- [7- (methoxymethyl) benzofuran-2-ylcarbonylamino ] ethoxy } benzamide;
n-hydroxy-4- {2- [7- (morpholin-4-ylmethyl) benzofuran-2-ylcarbonylamino ] ethoxy } -benzamide;
n-hydroxy-4- {2- [7- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino ] ethoxy } -benzamide;
n-hydroxy-4- {3- [5- (methyl) benzothien-2-ylcarbonylamino ] propoxy } -benzamide;
n-hydroxy-4- {3- [6- (methoxy) benzothien-2-ylcarbonylamino ] propoxy } -benzamide;
n-hydroxy-4- {3- [7- (methoxymethyl) benzofuran-2-ylcarbonylamino ] propoxy } -benzamide;
n-hydroxy-4- {3- [7- (phenoxymethyl) benzofuran-2-ylcarbonylamino ] propoxy } -benzamide;
n-hydroxy-4- {2- [5- (2-methoxyethoxy) benzofuran-2-ylcarbonylamino ] -1R-methylethoxy } benzamide;
n-hydroxy-4- (2R-benzofuran-2-ylcarbonylamino-3-methylthiopropoxy) benzamide;
n-hydroxy-4- (2R-benzofuran-2-ylcarbonylamino-3-methylsulfonylpropoxy) benzamide;
n-hydroxy-4- {2- [3- (2-phenylethyl) benzofuran-2-ylcarbonylamino ] ethoxy } benzamide;
n-hydroxy-4- {2- [3- (N-methyl-N-benzylaminomethyl) benzofuran-2-ylcarbonylamino ] -ethoxy } benzamide;
n-hydroxy-4- {2- [3- (N-methyl-N-2-phenylethylaminomethyl) benzofuran-2-ylcarbonylamino ] -ethoxy } benzamide;
n-hydroxy-4- {2- [3- (3-hydroxypropylthiomethyl) benzofuran-2-ylcarbonylamino ] -ethoxy } benzamide;
n-hydroxy-4- {2- [3- (3-hydroxypropylsulfinylmethyl) benzofuran-2-ylcarbonylamino ] -ethoxy } benzamide;
n-hydroxy-4- {2- [3- (3-hydroxypropylsulfonylmethyl) benzofuran-2-ylcarbonylamino ] -ethoxy } benzamide;
n-hydroxy-4- {2- [3- (N-methyl-N-2-indol-3-ylethylaminomethyl) benzofuran-2-ylcarbonylamino ] -ethoxy } benzamide;
n-hydroxy-4- {2- [3- (2- (3-trifluoromethylphenyl) ethyl) benzofuran-2-ylcarbonylamino ] -ethoxy } benzamide;
n-hydroxy-4- {2- [3- (2- (3-trifluoromethoxyphenyl) ethyl) benzofuran-2-ylcarbonylamino ] -ethoxy } benzamide;
n-hydroxy-4- {2- [3- (N-hydroxyaminocarbonylaminomethyl) benzofuran-2-ylcarbonylamino ] ethoxy } benzamide;
n-hydroxy-4- {2- [3- (2-carboxyethylaminomethyl) benzofuran-2-ylcarbonylamino ] -ethoxy } benzamide;
n-hydroxy-4- [2- (benzofuran-2-ylcarbonylamino) -1 RS-phenoxymethylethoxy ] -benzamide;
n-hydroxy-4- {2- [3- (3-hydroxypropoxymethyl) benzofuran-2-ylcarbonylamino ] ethoxy } -benzamide;
n-hydroxy-4- {2- [3- (2-fluorophenoxymethyl) benzofuran-2-ylcarbonylamino ] ethoxy } -benzamide;
n-hydroxy-4- {2- [3- (3-fluorophenoxymethyl) benzofuran-2-ylcarbonylamino ] ethoxy } -benzamide;
n-hydroxy-4- {2- [3- (4-fluorophenoxymethyl) benzofuran-2-ylcarbonylamino ] ethoxy } -benzamide;
n-hydroxy-4- {2- [3- (2-methoxyethoxymethyl) benzofuran-2-ylcarbonylamino ] ethoxy } -benzamide;
n-hydroxy-4- {2- [3- (pyridin-4-yloxymethyl) benzofuran-2-ylcarbonylamino ] ethoxy } -benzamide;
n-hydroxy-4- {2- [3- (2, 4, 6-trifluorophenoxymethyl) benzofuran-2-ylcarbonylamino ] -ethoxy } benzamide;
n-hydroxy-4- {2- [3- (2-oxopyridin-1-ylmethyl) benzofuran-2-ylcarbonylamino ] ethoxy } -benzamide;
n-hydroxy-4- {2- [3- (2, 2, 2-trifluoroethoxymethyl) benzofuran-2-ylcarbonylamino ] -ethoxy } benzamide;
n-hydroxy-4- {2- [3- (4-imidazol-1-ylphenoxymethyl) benzofuran-2-ylcarbonylamino ] -ethoxy } benzamide;
n-hydroxy-4- {2- [3- (4- [1.2.4] -triazin-1-ylphenoxymethyl) benzofuran-2-ylcarbonyl-amino ] ethoxy } benzamide;
n-hydroxy-4- {2- [3- (pyrrolidin-1-methyl) benzofuran-2-ylcarbonylamino ] ethoxy } -benzamide;
n-hydroxy-4- {2- [3- (piperidin-1-methyl) benzofuran-2-ylcarbonylamino ] ethoxy } -benzamide;
n-hydroxy-4- {2- [3- (4-trifluoromethylpiperidin-1-methyl) benzofuran-2-ylcarbonylamino ] -ethoxy } benzamide;
n-hydroxy-4- {2- [3- (4-methylpiperazin-1-methyl) benzofuran-2-ylcarbonylamino ] -ethoxy } benzamide;
n-hydroxy-4- {2- [3- (3, 3, 3-trifluoropropoxymethyl) benzofuran-2-ylcarbonylamino ] -ethoxy } benzamide;
n-hydroxy-4- [2- (4-methylbenzofuran-2-ylcarbonylamino) -ethoxy ] benzamide;
n-hydroxy-4- {2- [3- (4-fluorophenylsulfanylmethyl) benzofuran-2-ylcarbonylamino ] -ethoxy } benzamide;
n-hydroxy-4- {2- [3- (4-fluorophenylsulfinylmethyl) benzofuran-2-ylcarbonylamino ] -ethoxy } benzamide;
n-hydroxy-4- {2- [3- (4-fluorophenylsulfonylmethyl) benzofuran-2-ylcarbonylamino ] -ethoxy } benzamide;
n-hydroxy-4- {2S- [3- (2, 2, 2-trifluoroethoxymethyl) benzofuran-2-ylcarbonylamino ] -butoxy } benzamide;
n-hydroxy-4- [2- (4-hydroxybenzofuran-2-ylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- [2S- (5-chlorobenzofuran-2-ylcarbonylamino) butoxy ] benzamide;
n-hydroxy-4- [2- (5-chlorobenzofuran-2-ylcarbonylamino) -1R-methylethoxy ] benzamide;
n-hydroxy-4- [2- (4-pyridin-3-ylmethoxymethylbenzofuran-2-ylcarbonylamino) -ethoxy ] benzamide;
n-hydroxy-4- [2- (4-methoxybenzofuran-2-ylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- {2- [4- (2-methoxyethoxy) benzofuran-2-ylcarbonylamino ] ethoxy } -benzamide;
n-hydroxy-4- [2- (4-pyridin-3-ylmethoxybenzofuran-2-ylcarbonylamino) -ethoxy ] benzamide;
n-hydroxy-4- [2- (4-methoxyindol-2-ylcarbonylamino) ethoxy ] benzamide;
n-hydroxy-4- {2S- [3- (2-methoxyethoxymethyl) benzofuran-2-ylcarbonylamino ] -butoxy } benzamide;
n-hydroxy-4- {2- [3- (2-methoxyethoxymethyl) benzofuran-2-ylcarbonylamino ] -1R-methylethoxy } benzamide;
n-hydroxy-4- {2- [3- (N, N-diethylaminomethyl) benzofuran-2-ylcarbonylamino ] ethoxy } -benzamide;
n-hydroxy-4- {2S- [5- (2-methoxyethoxy) benzofuran-2-ylcarbonylamino ] butoxy } -benzamide;
n-hydroxy-4- {2- [5- (tetrahydropyran-4-yloxy) benzofuran-2-ylcarbonylamino ] ethoxy } -benzamide;
n-hydroxy-4- {2S- [5- (tetrahydropyran-4-yloxy) benzofuran-2-ylcarbonylamino ] butoxy } -benzamide;
n-hydroxy-4- {2- [5- (tetrahydropyran-4-yloxy) benzofuran-2-ylcarbonylamino ] -1R-methylethoxy } benzamide;
n-hydroxy-4- {2- [5- (2, 2, 2-trifluoroethoxy) benzofuran-2-ylcarbonylamino ] ethoxy } -benzamide;
n-hydroxy-4- {2- [5- (2-pyrrolidin-1-ylethoxy) benzofuran-2-ylcarbonylamino ] ethoxy } -benzamide;
n-hydroxy-4- {2S- [5- (2-pyrrolidin-1-ylethoxy) benzofuran-2-ylcarbonylamino ] butoxy } -benzamide;
n-hydroxy-4- {2- [5- (2-pyrrolidin-1-ylethoxy) benzofuran-2-ylcarbonylamino ] -1R-methylethoxy } benzamide;
n-hydroxy-4- {2- [5- (piperidin-4-yloxy) benzofuran-2-ylcarbonylamino ] ethoxy } -benzamide;
n-hydroxy-4- [2S- (benzofuran-2-ylcarbonylamino) -4-methylthiobutoxy ] benzamide;
n-hydroxy-4- [2S- (benzofuran-2-ylcarbonylamino) -4-methylsulfonylbutoxy ] benzamide;
the compounds of formula (I) are as follows:
wherein R is1And R3Is hydrogen, Ar1Is isoxazol-5-yl, Ar2And Y are defined in Table IV below.
TABLE IV
| Compound numbering | Ar2 | Y |
| 1 | 4-biphenylyl group | (R)-CH2-CH(CH3)- |
| 2 | 4-biphenylyl group | (S) -CH (ethyl) -CH2- |
| 3 | Benzofuran-2-yl | -CH2-CH2- |
| 4 | trans-phenyl-CH ═ CH- | -CH2-CH2- |
| 5 | 4- (2-ethoxyphenyl) phenyl | -CH2-CH2-CH2- |
| 6 | 3-biphenylyl group | -CH2-CH2-CH2- |
| 7 | 4-biphenylyl group | -CH2-CH2-CH2- |
| 8 | Naphthalen-2-yl | -CH2-CH2- |
| 9 | 3-methylbiphenyl-4-yl | -CH2-CH2- |
| 10 | 2' -ethoxybiphenyl-4-yl | -CH2-CH2- |
| 11 | 3-methylbiphenyl-4-yl | -CH2-CH2-CH2- |
| 12 | 4-Phenylthiazol-2-yl | -CH2-CH2-CH2- |
| 13 | Naphthalen-2-yl | -CH2-CH2-CH2- |
| 14 | Naphthalen-1-yl | -CH2-CH2-CH2- |
| 15 | 2-2- (Phenylethyl) phenyl | -CH2-CH2-CH2- |
| 16 | Naphthalen-1-yl | -CH2-CH2- |
| 17 | Benzofuran-2-yl | (S) -CH (ethyl) -CH2- |
| 18 | 3-biphenylyl group | (S) -CH (ethyl) -CH2- |
| 19 | Benzofuran-2-yl | (R)-CH2-CH (methyl) - |
| 20 | 3-biphenylyl group | (R)-CH2-CH (methyl) - |
| 21 | 3-biphenylyl group | -CH2-CH2- |
| 22 | 4-biphenylyl group | -CH2-CH2- |
| 23 | 4-Phenylthiazol-2-yl | -CH2-CH2- |
| 24 | 2- (2-phenylethyl) phenyl | -CH2-CH2- |
| 25 | 2-biphenylyl group | -CH2-CH2- |
| 26 | 2-biphenylyl group | -CH2-CH2-CH2- |
| 27 | Naphthalen-2-yl | (S) -CH (ethyl) -CH2- |
| 28 | Naphthalen-1-yl | (S) -CH (ethyl) -CH2- |
| 29 | Naphthalen-2-yl | (R)-CH2-CH (methyl) - |
| 30 | Naphthalen-1-yl | (R)-CH2-CH (methyl) - |
| 31 | Benzofuran-2-yl | -CH2-CH2-CH2- |
| 32 | Trans-phenyl CH ═ CH- | -CH2-CH2-CH2- |
| 33 | 3- (phenoxymethyl) benzofuran-2-yl | -CH2-CH2- |
And is named as:
n-hydroxy-3- [2- (biphenyl-4-ylcarbonylamino) -1R-methylethoxy ] isoxazol-5-ylcarboxamide;
n-hydroxy-3- [2S- (biphenyl-4-ylcarbonylamino) butoxy ] isoxazol-5-ylcarboxamide;
n-hydroxy-3- [2- (benzofuran-2-ylcarbonylamino) ethoxy ] isoxazol-5-ylcarboxamide;
n-hydroxy-3- [2- (trans-cinnamoylamino) ethoxy ] isoxazol-5-ylcarboxamide;
n-hydroxy-3- [3- (4- (2-ethoxyphenyl) phenylcarbonylamino) propoxy ] isoxazol-5-ylcarboxamide;
n-hydroxy-3- [3- (biphenyl-3-ylcarbonylamino) propoxy ] isoxazol-5-ylcarboxamide;
n-hydroxy-3- [3- (biphenyl-4-ylcarbonylamino) propoxy ] isoxazol-5-ylcarboxamide;
n-hydroxy-3- [2- (naphthalen-2-ylcarbonylamino) ethoxy ] isoxazol-5-ylcarboxamide;
n-hydroxy-3- [2- (3-methylbiphenyl-4-ylcarbonylamino) ethoxy ] isoxazol-5-ylcarboxamide;
n-hydroxy-3- [2- (2' -ethoxybiphenyl-4-ylcarbonylamino) ethoxy ] isoxazol-5-ylcarboxamide;
n-hydroxy-3- [3- (3-methylbiphenyl-4-ylcarbonylamino) propoxy ] isoxazol-5-ylcarboxamide;
n-hydroxy-3- [3- (4-phenylthiazol-2-ylcarbonylamino) propoxy ] isoxazol-5-ylcarboxamide;
n-hydroxy-3- [3- (naphthalen-2-ylcarbonylamino) propoxy ] isoxazol-5-ylcarboxamide;
n-hydroxy-3- [3- (naphthalen-1-ylcarbonylamino) propoxy ] isoxazol-5-ylcarboxamide;
n-hydroxy-3- {3- [2- (2-phenylethyl) phenylcarbonylamino ] propoxy } isoxazol-5-ylcarboxamide;
n-hydroxy-3- [2- (naphthalen-1-ylcarbonylamino) ethoxy ] isoxazol-5-ylcarboxamide;
n-hydroxy-3- [2S- (benzofuran-2-ylcarbonylamino) butoxy ] isoxazol-5-ylcarboxamide;
n-hydroxy-3- [2S- (biphenyl-3-ylcarbonylamino) butoxy ] isoxazol-5-ylcarboxamide;
n-hydroxy-3- [2- (benzofuran-2-ylcarbonylamino) -1R-methylethoxy ] isoxazol-5-ylcarboxamide;
n-hydroxy-3- [2- (biphenyl-3-ylcarbonylamino) -1R-methylethoxy ] isoxazol-5-ylcarboxamide;
n-hydroxy-3- [2- (biphenyl-3-ylcarbonylamino) ethoxy ] isoxazol-5-ylcarboxamide;
n-hydroxy-3- [2- (biphenyl-4-ylcarbonylamino) ethoxy ] isoxazol-5-ylcarboxamide;
n-hydroxy-3- [2- (4-phenylthiazol-2-ylcarbonylamino) ethoxy ] isoxazol-5-ylcarboxamide;
n-hydroxy-3- {2- [2- (2-phenylethyl) phenylcarbonylamino ] ethoxy } isoxazol-5-ylcarboxamide;
n-hydroxy-3- [2- (biphenyl-2-ylcarbonylamino) ethoxy ] isoxazol-5-ylcarboxamide;
n-hydroxy-3- [3- (biphenyl-2-ylcarbonylamino) propoxy ] isoxazol-5-ylcarboxamide;
n-hydroxy-3- [2S- (naphthalen-2-ylcarbonylamino) butoxy ] isoxazol-5-ylcarboxamide;
n-hydroxy-3- [2S- (naphthalen-1-ylcarbonylamino) butoxy ] isoxazol-5-ylcarboxamide;
n-hydroxy-3- [2- (naphthalen-2-ylcarbonylamino) -1R-methylethoxy ] isoxazol-5-ylcarboxamide;
n-hydroxy-3- [2- (naphthalen-1-ylcarbonylamino) -1R-methylethoxy ] isoxazol-5-ylcarboxamide;
n-hydroxy-3- [3- (benzofuran-2-ylcarbonylamino) propoxy ] isoxazol-5-ylcarboxamide;
n-hydroxy-3- [3- (trans-cinnamoylamino) propoxy ] isoxazol-5-ylcarboxamide; and
n-hydroxy-3- [2- (3-phenoxymethylbenzofuran-2-ylcarbonylamino) ethoxy ] isoxazol-5-ylcarboxamide.
Description of the preferred embodiments
Although the broadest definition of the invention is set forth in the "summary of the invention", certain compounds of formula (I) are preferred. For example:
I. a preferred group of compounds of formula (I) is that wherein:
R1is hydrogen or alkyl;
x is-O-, -NR2-, or-S (O)nWherein n is 0-2, R2Is hydrogen or alkyl;
y is alkylene optionally substituted with cycloalkyl, optionally substituted phenyl, alkylthio, alkylsulfonyl, optionally substituted phenylalkylthio, optionally substituted phenylalkylsulfonyl, or hydroxy;
Ar1is phenylene or heteroarylene, wherein Ar is1Optionally substituted with one or two groups independently selected from: alkyl, halo, hydroxy, alkoxy, haloalkoxy, or haloalkyl;
R3is hydrogen, alkyl, hydroxyalkyl, or optionally substituted phenyl; and
Ar2is aryl, aralkyl, aralkenyl, heteroaralkylA group, heteroaralkyl, heteroaralkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl;
wherein the terms "aryl, heteroaryl, heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, and aminoalkyl" are included either alone or as part of another term (e.g., aralkyl, optionally substituted phenylalkylthio, aminoalkoxy, optionally substituted phenylcarbonylamino, optionally substituted heteroaryl, etc.) within the scope of preferred group I above, said terms have the following meanings:
"aryl" refers to a monovalent monocyclic or bicyclic aromatic hydrocarbon radical having 6 to 12 ring atoms, such as phenyl, naphthyl or anthracenyl, optionally substituted with one, two or three substituents independently selected from: alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxy, hydroxyalkyl, hydroxyalkoxy, hydroxyalkoxyalkyl, alkoxyalkoxyalkyl, optionally substituted phenyl, optionally substituted heteroaryl, cycloalkoxy, cycloalkenyloxy, optionally substituted phenylcarbonylamino, optionally substituted heteroaryloxy, optionally substituted heteroarylalkoxy, aminoalkyl, aminoalkoxy, alkoxyalkyl, alkoxyalkoxy, methylenedioxy, haloalkoxyalkyl, optionally substituted phenoxyalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted heterocycloalkoxyalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heterocycloalkylalkoxy, -alkylene-S (O)n-Ra(wherein n is 0 to 2, RaIs alkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl), -alkylene-NHSO2-Rb(wherein R isbIs alkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or optionally substituted heterocycloalkyl), or-alkylene-NHCO-Rc(wherein R iscIs an alkaneAlkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or optionally substituted heterocycloalkyl), wherein the alkyl chain in the haloalkoxyalkyl, optionally substituted phenoxyalkyl, optionally substituted heteroaryloxyalkyl, or aminoalkyl is optionally substituted with one or two fluorines. More preferably, the aromatic ring is optionally substituted with one, two, or three substituents independently selected from: alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxy, hydroxyalkyl, hydroxyalkoxy, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, cycloalkoxy, cycloalkenyloxy, optionally substituted phenylcarbonylamino, optionally substituted heteroaryl, optionally substituted heteroarylalkoxy, aminoalkyl, aminoalkoxy, alkoxyalkyl, alkoxyalkoxy, methylenedioxy, optionally substituted phenoxyalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heterocycloalkylalkoxy, optionally substituted heterocycloalkylalkoxyalkyl, or optionally substituted heterocycloalkoxy. Preferably, the substituents are independently: methoxy, methyl, ethyl, chloro, trifluoromethyl, fluoro, 2-methoxyethoxy, 2- (morpholin-4-yl) ethoxy, pyridin-3-ylmethoxy, 2-hydroxyethoxy, 2- (N, N-dimethylamino) ethoxy, methoxymethyl, phenoxymethyl, 2-morpholino-4-ylethyl, morpholino-4-ylmethyl, N-dimethylaminomethyl, isopropoxymethyl, or phenoxymethyl;
"Heterocycloalkyl" means a saturated monovalent cyclic group of 3 to 8 ring atoms in which one or two ring atoms are heteroatoms selected from N, O, or S (O)nWherein n is an integer of 0 to 2 and the remaining ring atoms are C. More specifically, the term "heterocycloalkyl" includes, but is not limited to: pyrrolidino, piperidino, morpholino, piperazino, tetrahydropyranyl, and thiomorpholino groups, and derivatives thereof (formed when a heterocycloalkyl ring is substituted with the following substituents); or an N-oxide or protected derivative thereof. HeterocycloalkanesOptionally fused to aryl, optionally substituted with one, two, or three substituents independently selected from: alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, optionally substituted phenyl, optionally substituted heteroaryl, cycloalkoxy, cycloalkenyloxy, optionally substituted phenylcarbonylamino, optionally substituted heteroaryl, optionally substituted heteroarylalkoxy, aminoalkyl, aminoalkoxy, alkoxyalkyl, alkoxyalkoxy, methylenedioxy, optionally substituted phenoxyalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heterocycloalkylalkoxy, or optionally substituted heterocycloalkoxy. Preferably, the substituents are independently: methoxy, methyl, ethyl, chloro, trifluoromethyl, fluoro, 2-methoxyethoxy, 2- (morpholin-4-yl) ethoxy, pyridin-3-ylmethoxy, 2-hydroxyethoxy, 2- (N, N-dimethylamino) ethoxy, methoxymethyl, phenoxymethyl, 2-morpholino-4-ylethyl, morpholino-4-ylmethyl, N-dimethylaminomethyl, isopropoxymethyl, or phenoxymethyl;
"heteroaryl" refers to a monovalent monocyclic or bicyclic aromatic radical having 5 to 10 ring atoms, comprising one or more, preferably one, two, or three ring heteroatoms selected from N, O or S, the remaining ring atoms being carbon. More specifically, the term "heteroaryl" includes, but is not limited to: pyridyl, pyrrolyl, imidazolyl, thienyl, furyl, indolyl, quinolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, benzoxazolyl, benzothienyl, benzothiazolyl, tetrahydroquinolyl, isoquinolyl, benzopyranyl, and thiazolyl groups, and derivatives thereof (formed when a heteroaromatic ring is substituted with the following substituents), or N-oxide or protected derivatives thereof. The heteroaryl ring is optionally substituted with one, two, or three substituents independently selected from: alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxy, hydroxyalkyl, hydroxyalkoxy, hydroxyalkoxyalkyl, alkoxyArylalkoxyalkyl, optionally substituted phenyl, optionally substituted heteroaryl, cycloalkoxy, cycloalkenyloxy, optionally substituted phenylcarbonylamino, optionally substituted heteroaryl, optionally substituted heteroarylalkoxy, aminoalkyl, aminoalkoxy, alkoxyalkyl, alkoxyalkoxy, methylenedioxy, haloalkoxyalkyl, optionally substituted phenoxyalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted heterocycloalkoxyalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heterocycloalkylalkoxy, optionally substituted heterocycloalkoxy, -alkylene-S (O)n-Ra(wherein n is 0 to 2, RaIs alkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl), -alkylene-NHSO2-Rb(wherein R isbIs alkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or optionally substituted heterocycloalkyl), or-alkylene-NHCO-Rc(wherein R iscIs alkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or optionally substituted heterocycloalkyl), wherein the alkyl chain in the haloalkoxyalkyl, optionally substituted phenoxyalkyl, optionally substituted heteroaryloxyalkyl, or aminoalkyl is optionally substituted with one or two fluorines. More preferably, the substituents are independently selected from: alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxy, hydroxyalkyl, hydroxyalkoxy, optionally substituted phenyl, optionally substituted heteroaryl, cycloalkoxy, cycloalkenyloxy, optionally substituted phenylcarbonylamino, optionally substituted heteroaryl, optionally substituted heteroarylalkoxy, aminoalkyl, aminoalkoxy, alkoxyalkyl, alkoxyalkoxy, methylenedioxy, optionally substituted phenoxyalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted heterocycloalkoxyalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heterocycloalkylalkoxy, or optionally substituted heterocycloalkoxy. Preference is given toAnd the substituents are independently: methoxy, methyl, ethyl, chloro, trifluoromethyl, fluoro, 2-methoxyethoxy, 2- (morpholin-4-yl) ethoxy, pyridin-3-ylmethoxy, 2-hydroxyethoxy, 2- (N, N-dimethylamino) ethoxy, methoxymethyl, phenoxymethyl, 2-morpholino-4-ylethyl, morpholino-4-ylmethyl, N-dimethylaminomethyl, isopropoxymethyl, or phenoxymethyl;
"optionally substituted phenyl" refers to a phenyl ring optionally substituted with one, two, or three substituents independently selected from: alkyl, halo, alkoxy, alkylthio, haloalkyl, haloalkoxy, heteroaryl (which is optionally substituted with one or two substituents independently selected from alkyl, halo, hydroxy, alkoxy, carboxy, amino, alkylamino, or dialkylamino), heterocycloalkyl (which is optionally substituted with one or two substituents independently selected from alkyl, halo, hydroxy, alkoxy, carboxy, amino, alkylamino, or dialkylamino), amino, alkylamino, dialkylamino, hydroxy, cyano, nitro, methylenedioxy, aminocarbonyl, hydroxyalkyl, alkoxycarbonyl, aminoalkyl, or carboxy, or optionally substituted with five fluorine atoms. More preferably, the substituents are independently selected from: alkyl, halo, alkoxy, alkylthio, trifluoromethyl, trifluoromethoxy, amino, alkylamino, dialkylamino, hydroxy, cyano, nitro, methylenedioxy, aminocarbonyl, hydroxyalkyl, alkoxycarbonyl, aminoalkyl, or carboxy, or optionally substituted with five fluorine atoms;
"optionally substituted heteroaryl" refers to a monovalent monocyclic or bicyclic aromatic radical having 5 to 10 ring atoms, comprising one or more, preferably one, two, or three ring heteroatoms selected from: n, O or S, the remaining ring atoms being carbon, optionally substituted with one, two, or three substituents independently selected from: alkyl, halo, alkoxy, trifluoromethyl, trifluoromethoxy, amino, alkylamino, dialkylamino, hydroxy, cyano, nitro, aminocarbonyl, hydroxyalkyl, alkoxycarbonyl, aminoalkyl, optionally substituted phenyl, optionally substituted phenoxy, carboxy, or heteroaryl, optionally substituted with alkyl, halo, hydroxy, alkoxy, carboxy, amino, alkylamino, or dialkylamino. More specifically, the term "optionally substituted heteroaryl" includes, but is not limited to: pyridyl, pyrrolyl, imidazolyl, thienyl, furyl, indolyl, quinolinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, benzopyranyl, and thiazolyl, and derivatives thereof (formed when a heteroaromatic ring is substituted with the following substituents), or N-oxide or protected derivatives thereof;
"optionally substituted heterocycloalkyl" refers to a saturated monovalent cyclic group of 3 to 8 ring atoms, one or two of which are heteroatoms selected from N, O or S (O)nWherein n is an integer of 0 to 2 and the remaining ring atoms are C. Heterocycloalkyl is optionally fused to aryl, and is optionally substituted with one, two, or three substituents independently selected from: alkyl, halo, alkoxy, trifluoromethyl, trifluoromethoxy, amino, alkylamino, dialkylamino, hydroxy, cyano, nitro, optionally substituted phenylalkyl, optionally substituted heteroaralkyl, aminocarbonyl, hydroxyalkyl, alkoxycarbonyl, aminoalkyl, or carboxy. More specifically, the term "heterocycloalkyl" includes, but is not limited to: pyrrolidino, piperidino, morpholino, piperazino, tetrahydropyranyl, and thiomorpholino, and derivatives thereof (formed when a heterocycloalkyl ring is substituted with the following substituents); or an N-oxide or protected derivative thereof; and
"aminoalkyl" means a straight chain monovalent hydrocarbon radical having from 2 to 6 carbon atoms or a straight chain monovalent hydrocarbon radical having from 3 to 6 carbon atoms, substituted with at least one, preferably one or two of the following groups: -NRR ', wherein R and R' are independently selected from hydrogen, alkyl, or-CORaWherein R isaIs an alkyl, or N-oxide derivative, or a protected derivative, e.g. aminomethyl, methylaminoethyl, 2-ethylamino-2-methylethyl1, 3-diaminopropyl, dimethylaminomethyl, diethylaminoethyl, acetylaminopropyl, and the like; and
the definitions of the other terms comprised within the scope of the preferred group I are referred to in the definitions section of the present application.
Within group I:
(A) a preferred group of compounds is that wherein R1And R3Is hydrogen, X is-O-, Y is ethylene or n-propylene, preferably ethylene.
(B) Another preferred group of compounds is that wherein R1And R3Is hydrogen, X is-O-, Y is-CH (C)2H5)CH2-、-CH(i-C3H7)CH2-, or-CH (CH)3)CH2-, the stereochemistry at the chiral carbon is (S). More preferably, Y is-CH (C)2H5)CH2-。
(C) A further group of preferred compounds consists in that R1And R3Is hydrogen, X is-O-, Y is-CH2CH(CH3) -, the stereochemistry at the chiral carbon is (R).
(i) Within groups (A) - (C), a more preferred group of compounds is that wherein Ar is1Is phenylene in which the hydroxamate group and the X group are opposite one another, Ar2Is an aryl group. Preferably, Ar2Is phenyl, optionally substituted with one or two substituents independently selected from: methoxy, ethoxy, phenyl, methyl, t-butyl, pyrrol-1-yl, cyclohexen-3-oxy, pyridin-3-yl, pyridin-2-yl, benzoylamino, fluoro, chloro, or thiophen-2-ylmethoxy. More preferably, Ar2Is phenyl, 4-biphenyl, 3-biphenyl, 4-tert-butylphenyl, 4-pyrrol-1-ylphenyl, 4- (cyclohexen-3-oxy) phenyl, 4- (pyridin-2-yl) phenyl, 4- (pyridin-3-yl) -phenyl, 2, 4-difluorophenyl, 3, 4-dimethoxyphenyl, 3, 5-dimethoxyphenyl, 3, 4-difluorophenyl, 2, 5-dimethylphenyl, 2, 3-dichlorophenyl, 2, 3-dimethylphenyl, 4-chloro-2-methoxyphenyl,3-ethoxyphenyl, 4-methoxy-2-methylphenyl, 3-fluoro-4-methoxyphenyl, 2-thiophen-2-ylmethoxyphenyl, 3-thiophen-2-ylmethoxyphenyl, 2-biphenyl, or 2-pyrrol-1-ylphenyl.
(ii) Within groups (A) to (C), another more preferred group of compounds is that wherein Ar is1Is phenylene in which the hydroxamate group and the X group are opposite one another, Ar2Is trans-aryl-CH ═ CH-. Preferably, Ar2Is trans-phenyl-CH ═ CH-, optionally substituted with alkoxy, preferably methoxy. Preferably, Ar2Is trans-phenyl-CH ═ CH-.
(iii) Within groups (A) to (C), another more preferred group of compounds is that wherein Ar is1Is phenylene in which the hydroxamate group and the X group are opposite one another, Ar2Is heteroaryl-CH ═ CH-. Preferably, Ar2Is pyridyl-CH ═ CH-. Preferably, Ar2Is trans-5-bromothien-2-yl-CH ═ CH-or trans-indol-3-yl-CH ═ CH-.
(iv) Within groups (A) to (C), another more preferred group of compounds is that wherein Ar is1Is phenylene in which the hydroxamate group and the X group are opposite one another, Ar2Is heteroaryl. Preferably, Ar2Is pyridin-3-yl, thiophen-2-yl, quinolin-6-yl, thiazol-2-yl, benzothiazol-2-yl, benzoxazol-2-yl, furanyl, pyrrol-2-yl, indol-5-yl, indol-3-yl, indazol-3-yl, quinolin-1-yl, quinolin-8-yl, benzotriazol-4-yl, benzofuran-5-yl, isoquinolin-1-yl, isoquinolin-3-yl, quinoxalin-2-yl, quinolin-2-yl, or benzimidazol-5-yl, wherein said ring is optionally substituted with phenyl, pyridin-4-yl, quinoxalin-2-yl, or benzimidazol-5-yl, Methyl, methoxy, or dimethylaminomethyl.
(v) Within groups (A) to (C), another more preferred group of compounds is that wherein Ar is1Is phenylene in which the hydroxamate group and the X group are opposite one another, Ar2Is indol-2-yl, benzofuran-2-yl or benzothien-2-yl, optionally substituted by alkyl, alkoxy, halogen, haloalkyl, alkoxyalkoxy, optionally substituted by halogenOptionally substituted heterocycloalkylalkoxy, optionally substituted heteroarylalkoxy, hydroxyalkoxy, aminoalkyl, aminoalkoxy, alkoxyalkoxy, alkoxyalkyl, optionally substituted phenoxyalkyl, or optionally substituted heterocycloalkylalkyl. Preferably, Ar2Is benzofuran-2-yl or benzothien-2-yl, wherein benzofuran-2-yl or benzothien-2-yl is optionally substituted by methoxy, methyl, chloro, trifluoromethyl, fluoro, 2-methoxyethoxy, 2-morpholin-4-ylethoxy, pyridin-3-ylmethoxy, 2-hydroxyethoxy, 2-N, N-dimethylaminoethoxy, ethyl, methoxymethyl, 2-propoxymethyl, phenoxymethyl, morpholin-4-ylmethyl, or N, N-dimethylaminomethyl, the substituent being located in the 3-or 5-position, preferably the 3-position, of the benzothien-2-yl or benzofuran-2-yl ring. Even more preferably, Ar2Is benzofuran-2-yl, 3-N, N-dimethylaminomethylbenzofuran-2-yl or 3-phenoxymethylbenzofuran-2-yl.
(vi) Within groups (A) to (C), another more preferred group of compounds is that wherein Ar is1Is phenylene in which the hydroxamate group and the X group are opposite one another, Ar2Is indol-2-yl, benzofuran-2-yl or benzothien-2-yl, substituted by phenoxyalkyl, substituted heteroaryloxyalkyl, substituted heterocycloalkoxyalkyl or haloalkoxyalkyl, the substituents being located at the 3-position of the benzothien-2-yl and benzofuran-2-yl rings. Even more preferably, Ar2Is 3- (2, 2, 2-trifluoroethoxymethyl) benzofuran-2-yl.
(vii) Within groups (A) to (C), another more preferred group of compounds is that wherein Ar is1Is heteroarylene, Ar2Is an aryl group. Preferably, Ar1Is a five-membered heteroaromatic ring containing one, two, or three heteroatoms independently selected from: n, O or S, more preferably Ar1Is a isoxazolyl group in which the hydroxamate group and the X group are in the 5-and 3-positions of the isoxazolyl ring, the oxygen atom in the ring is in the 1-position, Ar is2Is an aryl group. Preferably, Ar2Is phenyl, which is optionally substituted by one or two substituents, orThe substituents are independently selected from: methoxy, ethoxy, phenyl optionally substituted with ethoxy or methyl, tert-butyl, pyrrol-1-yl, cyclohexen-3-oxy, pyridin-3-yl, pyridin-2-yl, benzoylamino, fluoro, chloro, or thiophen-2-ylmethoxy. More preferably, Ar2Is phenyl, 4-biphenyl, 3-biphenyl, 2- (2-ethoxyphenyl) phenyl, 3-methylbiphenyl-4-yl, 4-tert-butylphenyl, 4-pyrrol-1-ylphenyl, 4- (cyclohexen-3-oxy) phenyl, 4- (pyridin-2-yl) phenyl, 4- (pyridin-3-yl) -phenyl, 2, 4-difluorophenyl, 3, 4-dimethoxyphenyl, 3, 5-dimethoxyphenyl, 3, 4-difluorophenyl, 2, 5-dimethylphenyl, 2, 3-dichlorophenyl, 2, 3-dimethylphenyl, 4-chloro-2-methoxyphenyl, 3-ethoxyphenyl, 4-methoxy-2-methylphenyl, 2-ethoxyphenyl, 4-methoxy-4-methylphenyl, 4-tert-butylphenyl, 4-dichlorophenyl, 4, 3-fluoro-4-methoxyphenyl, 2-thiophen-2-ylmethoxyphenyl, 3-thiophen-2-ylmethoxyphenyl, 2-biphenyl, or 2-pyrrol-1-ylphenyl.
(viii) Within groups (A) to (C), another more preferred group of compounds is that wherein Ar is1Is heteroarylene, Ar2Is aryl-CH ═ CH-. Preferably, Ar1Is a five-membered heteroaromatic ring containing one, two, or three heteroatoms independently selected from: n, O or S, more preferably Ar1Is a isoxazolyl group in which the hydroxamate group and the X group are in the 5-and 3-positions of the isoxazolyl ring, the oxygen atom in the ring is in the 1-position, Ar is2Is phenyl-CH ═ CH-, optionally substituted with alkoxy.
(ix) Within groups (A) to (C), another more preferred group of compounds is that wherein Ar is1Is heteroarylene, Ar2Is heteroaryl-CH ═ CH-. Preferably, Ar1Is a five-membered heteroaromatic ring containing one, two, or three heteroatoms independently selected from: n, O or S, more preferably Ar1Is a isoxazolyl group in which the hydroxamate group and the X group are in the 5-and 3-positions of the isoxazolyl ring, the oxygen atom in the ring is in the 1-position, Ar is2Is pyridyl CH ═ CH-.
(x) Within groups (A) to (C), another more preferred group of compounds is that wherein Ar is1Is heteroarylene，Ar2Is heteroaryl. Preferably, Ar1Is a five-membered heteroaromatic ring containing one, two, or three heteroatoms independently selected from: n, O or S, more preferably Ar1Is a isoxazolyl group in which the hydroxamate group and the X group are in the 5-and 3-positions of the isoxazolyl ring, the oxygen atom in the ring is in the 1-position, Ar is2Is pyridin-3-yl, thiophen-2-yl, quinolin-6-yl, thiazol-2-yl, benzothiazol-2-yl, benzooxazol-2-yl, furanyl, pyrrol-2-yl, indol-5-yl, indol-3-yl, indazol-3-yl, quinolin-8-yl, benzotriazol-4-yl, isoquinolin-1-yl, isoquinolin-3-yl, quinoxalin-2-yl, quinolin-2-yl, or benzimidazol-5-yl, wherein the ring is optionally substituted with phenyl, pyridin-4-yl, methyl, methoxy, or dimethylaminomethyl.
(xi) Within groups (A) to (C), another more preferred group of compounds is that wherein Ar is1Is heteroarylene, Ar2Is indol-2-yl, benzofuran-2-yl or benzothien-2-yl, optionally substituted by alkyl, alkoxy, halo, haloalkyl, alkoxyalkoxy, optionally substituted heterocycloalkylalkoxy, optionally substituted heteroarylalkoxy, hydroxyalkoxy, aminoalkoxy, alkoxyalkoxy, alkoxyalkyl, optionally substituted phenoxyalkyl, or optionally substituted heterocycloalkylalkyl. Preferably, Ar1Is a five-membered heteroaromatic ring containing one, two, or three heteroatoms independently selected from: n, O or S, more preferably Ar1Is a isoxazolyl group in which the hydroxamate group and the X group are in the 5-and 3-positions of the isoxazolyl ring, the oxygen atom in the ring is in the 1-position, Ar is2Are benzofuran-2-yl and benzothien-2-yl, optionally substituted with methoxy, methyl, chloro, trifluoromethyl, fluoro, 2-methoxyethoxy, 2-morpholin-4-ylethoxy, pyridin-3-ylmethoxy, 2-hydroxyethoxy, 2-N, N-dimethylaminoethoxy, ethyl, methoxymethyl, phenoxymethyl, morpholin-4-ylmethyl, or dimethylaminomethyl groups, the substituents being located at the 3-positions of the benzothien-2-yl and benzofuran-2-yl rings. Even more preferably, Ar2Is benzofuran-2-yl or 3-phenoxymethylbenzeneAnd furan-2-yl.
(xii) Within groups (A) and (B), another more preferred group of compounds is that wherein Ar is2Substituted with alkoxyalkoxy, optionally substituted heterocycloalkylalkoxy, hydroxyalkoxy, aminoalkoxy, alkoxyalkoxy, alkoxyalkyl, optionally substituted phenoxyalkyl, optionally substituted heteroaryloxyalkyl, or optionally substituted heterocycloalkylalkyl. Within this group, more preferred compounds are those in which Ar is1And Ar2As described above for the preferred embodiments.
Another group of preferred compounds of formula (I) is that wherein X is-O-, R1And R3Is hydrogen.
A further preferred group of compounds of formula (I) is that wherein X is-S (O)n-，R1And R3Is hydrogen.
Within the above preferred groups II and III, more preferred compounds are those wherein Y is alkylene.
Within the above preferred groups II and III, another more preferred group of compounds is that wherein Y is alkylene substituted with cycloalkyl, optionally substituted phenyl, alkylthio, alkylsulfinyl, alkylsulfonyl, optionally substituted phenylalkylthio, optionally substituted phenylalkylsulfonyl, hydroxy, or optionally substituted phenoxy.
Within the above preferred groups II and III and the more preferred groups contained therein, an even more preferred group of compounds is that wherein Ar is1Is phenylene.
Within the above preferred groups II and III and the more preferred groups contained therein, another group of even more preferred compounds is that wherein Ar is1Is heteroarylene.
Within the above preferred groups II and III and the more preferred and even more preferred groups contained therein, when Ar is1In the case of phenylene, a particularly preferred group of compounds is that in which the-CONHOH and X groups are in the 1-and 4-positions of the phenylene ring.
A further preferred group of compounds of the formula (I) is that in which Ar is1Is phenylene, X is-O-, R1And R3Hydrogen, -CONHOH and X groups are in the 1-and 4-positions of the phenylene ring.
Within the above preferred group IV, a more preferred group of compounds is that wherein Y is alkylene.
Within the above preferred group IV, another group of more preferred compounds is that wherein Y is alkylene substituted with cycloalkyl, optionally substituted phenyl, alkylthio, alkylsulfinyl, alkylsulfonyl, optionally substituted phenylalkylthio, optionally substituted phenylalkylsulfonyl, hydroxy, or optionally substituted phenoxy.
(i) Within the above preferred groups II, III and IV and the more preferred, even more preferred and particularly preferred groups contained therein, a group of more particularly preferred compounds consists in that wherein Ar is2Is an aralkenyl group. Preferably, Ar2Is aryl (C)2-3) An alkenyl group. More preferably, Ar2Represented by the formula:
wherein phenyl is optionally substituted with one or two substituents independently selected from: alkyl, alkoxy, methylenedioxy, dialkylamino, or hydroxy, more preferably alkyl, alkoxy, methylenedioxy, or hydroxy.
Even more preferably, Ar2Is trans-phenyl-CH ═ CH-, trans-4-MeO-phenyl-CH ═ CH-, trans-3, 4-methylenedioxyphenyl-CH ═ CH-, trans-3-hydroxyphenyl-CH ═ CH-, trans-4-hydroxyphenyl-CH ═ CH-, trans-2-methoxyphenyl-CH ═ CH-, trans-3-tolyl-CH ═ CH-, trans-4-dimethylaminophenyl-CH ═ CH-, trans-2-tolyl-CH ═ CH-, or, Or trans-2-hydroxyphenyl-CH ═ CH-。
(ii) Within the above-mentioned preferred groups II, III and IV and the more preferred, even more preferred and particularly preferred groups contained therein, a further group of more particularly preferred compounds consists in that in which Ar is2Is heteroaryl (C)2-3) An alkenyl group. Preferably, Ar2Is trans-heteroaryl-CH-or trans-heteroaryl-C (CH)3) Preferably, the heteroaryl ring is pyridyl, benzofuranyl, thienyl (thiophene), furanyl, or indolyl, optionally substituted with one or two substituents selected from: hydroxy, alkoxy, halo, or optionally substituted heterocycloalkoxy.
More preferably, Ar2Is trans-pyridin-3-yl-CH ═ CH-, trans-5-hydroxybenzofuran-2-yl-C (CH)3) -CH-, trans-5- (1-cyclopropylpiperidin-4-yloxy) benzofuran-2-yl-C (CH)3) -CH-, trans-5-methoxybenzofuran-2-yl-C (CH)3) CH-, trans-benzofuran-2-yl-CH ═ CH-, trans-5-bromothien-2-yl-CH ═ CH-, trans-furan-3-yl-CH ═ CH-, trans-thien-2-yl-CH ═ CH-, trans-benzofuran-2-yl-C (CH ═ s ═ CH-, trans-benzofuran-2-yl-C(s)3) -CH-, cis-benzofuran-2-yl-C (CH)3) -CH-, trans-indol-3-yl-CH ═ CH-, trans-7-methoxybenzofuran-2-yl-CH ═ CH-, trans-5-methoxybenzofuran-2-yl-C (CH), and use thereof3) -CH-, or trans-furan-2-yl-CH ═ CH.
(iii) Within the above-mentioned preferred groups II, III and IV and the more preferred, even more preferred and particularly preferred groups contained therein, a further group of more particularly preferred compounds consists in that in which Ar is2Is an aryl group. Preferably, the substituents on the aromatic ring are independently selected from: optionally substituted phenyl, alkyl, alkoxy, halo, optionally substituted heteroaryl, optionally substituted cycloalkenyloxy, optionally substituted heteroarylalkoxy, optionally substituted heterocycloalkyl, optionally substituted phenylcarbonylamino, or methylenedioxy. More preferably, Ar2Is phenyl, 4-biphenyl, 3-biphenyl, 4-tert-butylphenyl, 4-pyrrol-1-ylphenyl, 4- (pyridin-3-yl) phenyl4- (pyridin-2-yl) phenyl, 4- (benzoylamino) phenyl, 2, 4-difluorophenyl, 3, 4-methylenedioxyphenyl, 3, 4-dimethoxyphenyl, 3, 5-dimethoxyphenyl, 3, 4-difluorophenyl, 2, 5-dimethylphenyl, 2, 3-dichlorophenyl, 2, 3-dimethylphenyl, 4-chloro-2-methoxyphenyl, 3-ethoxyphenyl, 4-methoxy-2-methylphenyl, 3-fluoro-4-methoxyphenyl, 2- (thien-2-ylmethoxy) phenyl, 3- (thien-2-ylmethoxy) -phenyl, 2-biphenyl, naphthalen-1-yl, naphthalen-2-yl, 2-methyloxy-phenyl, 3- (thien-2-ylmethoxy) -phenyl, 3-biphenylyl-1-methyl-, 2-methoxy-naphthyl-2-yl, 2-thienyl-methyl-phenyl, 2-pyrrol-1-yl-phenyl, 4-fluoronaphthalen-1-yl, 3-MeO-naphthalen-2-yl, 2-MeO-naphthalen-1-yl, naphthalen-2-yl, 4- (2-pyridin-4-ylthiazol-5-yl) phenyl, 4- [2- (4-methylpiperazin-1-yl) thiazol-5-yl]-phenyl, 4- (2-pyridin-4-ylaminothiazol-5-yl) phenyl, 4- (4-methylpiperazin-1-yl) phenyl, 4- (4-hydroxypiperidin-1-yl) phenyl, 4- (4-morpholin-4-ylmethylthiazol-2-yl) phenyl, 4- [2- (4-methylpiperazin-1-ylmethyl) thiazol-5-yl]Phenyl, 1-methoxynaphthalen-2-yl, 3 '- (2-hydroxyethyl) biphenyl-4-yl, 3' - (2-hydroxyethyl) biphenyl-3-yl, 2 '- (2-hydroxyethyl) biphenyl-4-yl, 2' - (2-hydroxyethyl) biphenyl-3-yl, or 4- [4- (2-morpholin-4-yl-ethyl) thiazol-2-yl]A phenyl group.
(iv) Within the above-mentioned preferred groups II, III and IV and the more preferred, even more preferred and particularly preferred groups contained therein, a further group of more particularly preferred compounds consists in that in which Ar is2Is heteroaryl. Preferably, Ar2Is heteroaryl, optionally substituted with one or two substituents independently selected from: alkyl, halo, haloalkyl, alkoxy, alkoxyalkyl, hydroxyalkoxy, hydroxyalkoxyalkyl, alkoxyalkoxy, alkoxyalkoxyalkyl, aminoalkyl, aminoalkoxy, haloalkoxy, haloalkoxyalkyl, optionally substituted phenylalkyl, optionally substituted phenoxyalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkoxy, optionally substituted heteroaryloxyalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heterocycloalkoxy, optionally substituted heterocycloalkylalkoxy, -alkylene-S (O)nRa(wherein n is 0 to 2, RaIs hydroxyalkyl or optionally substituted phenyl), -alkylene-NRe-alkylene CONRcRd(wherein R iscIs hydroxy, RdAnd ReIndependently hydrogen or alkyl), or carboxyalkylaminoalkyl.
More preferably, Ar2Is thiophen-2-yl, pyridin-3-yl, quinolin-6-yl, benzothiazol-2-yl, benzooxazol-2-yl, benzofuran-5-yl, benzothien-2-yl, furan-2-yl, 1H-benzimidazol-2-yl, 1H-pyrrol-2-yl, thiazol-2-yl, 1H-indol-5-yl, 1H-indol-3-yl, quinolin-8-yl, 1H-indazol-3-yl, 1H-benzotriazol-5-yl, quinoline-6-yl, benzooxazol-2-yl, 1H-pyrrol-2-yl, thiazol-2-yl, 1H-indol-5-yl, 1, Isoquinolin-1-yl, isoquinolin-3-yl, quinoxalin-2-yl, quinolin-2-yl, 1H-benzimidazol-5-yl, quinolin-1-yl, pyridin-2-yl, quinolin-2-yl, furan-3-yl, thiophen-2-yl, or thiophen-3-yl, more preferably benzofuran-2-yl, or benzothiophen-2-yl, optionally substituted with one or two substituents as described in the preceding paragraph.
Even more preferably, Ar2Is benzofuran-2-yl which is monosubstituted in the 3-, 4-or 5-position or disubstituted in the 4-and 7-positions, preferably benzofuran-2-yl is monosubstituted in the 3-or 5-position by a substituent as described in the preceding paragraph. More preferably, the substituents are independently selected from: chloro, fluoro, trifluoromethyl, methyl, ethyl, methoxy, 1-cyclopropylpiperidin-4-yloxy, 1- (2, 2, 2-trifluoroethyl) piperidin-4-yloxy, N-dimethylaminomethyl, N-diethylaminomethyl, 2-methoxyethoxymethyl, phenoxymethyl, 2-methoxyethoxy, 2-morpholin-4-ylethoxy, pyridin-3-ylmethoxy, 2-hydroxyethoxy, 2-N, N-dimethylaminoethoxy, methoxymethyl, 3-isopropoxymethyl, morpholin-4-ylmethyl, 3-hydroxypropoxymethyl, 2-fluorophenoxymethyl, 3-fluorophenoxymethyl, 4-fluorophenoxy-methyl, methoxy-1-cyclopropylmethoxy, 2-fluorophenoxymethyl, 3-fluorophenoxymethyl, 4-fluorophenoxy-methyl, N-propyloxy, N-, 3-methoxypropoxymethyl, pyridin-4-yloxymethyl, 2, 4, 6-trifluorophenoxymethyl, 2-oxopyridin-1-ylmethyl, 2, 2, 2-trifluoroethoxymethyl, 4-imidazol-1-ylphenoxymethyl, 4- [1.2.4]]Triazin-1-yl-phenoxymethyl, 2-phenylethyl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, 4-Trifluoromethylpiperidin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 3, 3, 3-trifluoropropoxymethyl, 4-fluorophenylthiomethyl, 4-fluorophenylsulfinylmethyl, 4-fluorophenylsulfonylmethyl, pyridin-3-ylmethoxymethyl, tetrahydropyran-4-yloxy, 2, 2, 2-trifluoroethoxy, 2-pyrrolidin-1-ylethoxy, piperidin-4-yloxy, N-methyl-N-benzylaminomethyl, N-methyl-N-2-phenylethylaminomethyl, 3-hydroxypropylthiomethyl, 3-hydroxypropylsulfinylmethyl, 3-hydroxypropylsulfonyl-methyl, N-methyl-N-2-indol-3-ylethylaminomethyl, N-propylthioethyl, N, 2- (4-trifluoromethylphenyl) ethyl, 2- (3-trifluoromethoxyphenyl) ethyl, N-hydroxyaminocarbonyl-methylaminomethyl, or 3- (2-carboxyethylamino-methyl).
Even more preferably, Ar2Is benzofuran-2-yl, which is substituted in the 3-position with the following substituents: n, N-dimethylaminomethyl, N-diethylaminomethyl, 2-fluorophenoxymethyl, 3-fluorophenoxymethyl, 4-fluorophenoxymethyl, pyridin-4-yloxymethyl, 2, 4, 6-trifluorophenoxy-methyl, 2-oxopyridin-1-ylmethyl, 2, 2, 2-trifluoroethoxy-methyl, 4-imidazol-1-ylphenoxy-methyl, 4- [1.2.4] methyl]-triazin-1-yl-phenoxymethyl, 2-phenylethyl, 3-hydroxypropoxymethyl, 2-methoxyethoxymethyl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, 4-trifluoromethyl-piperidin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 3, 3, 3-trifluoropropoxymethyl, 4-fluorophenylthiomethyl, 4-fluorophenylsulfinylmethyl, 4-fluorophenylsulfonylmethyl, 2- (3-trifluoromethoxyphenylethyl) -, N-methyl-N-benzyl-aminomethyl, N-methyl-N-2-phenylethylaminomethyl, 3-hydroxypropylthiomethyl, methyl, p-tert-butyl-ethyl, p-butyl-ethyl-methyl, p, 3-hydroxypropylsulfinyl-methyl, 3-hydroxypropylsulfonylmethyl, N-methyl-N-2-indol-3-ylethylaminomethyl, 2- (4-trifluoromethylphenyl) ethyl, N-hydroxyaminocarbonyl-methylaminomethyl, or 2-carboxyethylamino-methyl.
Even more preferably, Ar2Is benzofuran-2-yl, which is substituted in the 5-position by: 1-cyclopropylpiperidin-4-yloxy, piperidin-4-yloxy, tetrahydropyran-4-yloxy, 2, 2, 2-trifluoroethyl etherOxy, 2-pyrrolidin-1-ylethoxy, or 1- (2, 2, 2-trifluoroethyl) piperidin-4-yloxy.
Even more preferably, Ar2Is 7-chloro-4-methylbenzofuran-2-yl, 4-methyl-benzofuran-2-yl, 7-fluoro-4-methylbenzofuran-2-yl or 7-fluoro-4-phenoxymethylbenzofuran-2-yl.
Even more preferably, Ar2Is thiophen-2-yl, pyridin-3-yl, 5-phenylthiophen-2-yl, quinolin-6-yl, 4-phenylthiazol-2-yl, benzothiazol-2-yl, benzoxazol-2-yl, furan-2-yl, 1H-benzimidazol-2-yl, 1H-pyrrol-2-yl, 4- (pyridin-4-yl) -thiazol-2-yl, 1H-indol-5-yl, 1H-indol-3-yl, quinolin-8-yl, 1H-indazol-3-yl, 1H-benzotriazol-5-yl, quinoline-2-yl, or quinoline-2-yl, Isoquinolin-1-yl, isoquinolin-3-yl, quinoxalin-2-yl, quinolin-2-yl, 1H-benzimidazol-5-yl, 1-methyl-indol-3-yl, 4-MeO-quinolin-2-yl, quinolin-4-yl, 4-hydroxyquinolin-2-yl, pyridin-2-yl, 3-hydroxypyridin-2-yl, 6- (4-nitrophenoxy) pyridin-2-yl, 4- (2-methoxyethoxy) quinolin-2-yl, 4- (2-dimethylaminoethoxy) quinolin-2-yl, quinoxalin-2-yl, 1H-benzimidazol-5-yl, 1-methyl-indol, 6-bromopyridin-2-yl, 5-bromopyridin-3-yl, 4-methoxyquinolin-2-yl, 5-phenylpyridin-3-yl, 6-benzyloxypyridin-2-yl, 6- (2-methylpropyloxy) -pyridin-2-yl, 6- (2-phenylethoxy) pyridin-2-yl, 4- (3, 3, 3-trifluoropropoxy) quinolin-2-yl, 5-thiophen-3-ylpyridin-3-yl, 6- (4-acetylaminophenoxy) -pyridin-2-yl, 6- (4-aminophenoxy) -pyridin-2-yl, or 5- (4-dimethylaminophenyl) pyridin-3-yl.
A further preferred group of compounds of the formula (I) is that in which Ar2Is heteroaryl. Preferably, Ar2Is heteroaryl optionally substituted with one or two substituents independently selected from: alkyl, halo, haloalkyl, alkoxy, alkoxyalkyl, hydroxyalkoxy, hydroxyalkoxyalkyl, alkoxyalkoxy, alkoxyalkoxyalkyl, aminoalkyl, aminoalkoxy, haloalkoxy, haloalkoxyalkyl, optionally substituted phenylalkyl, optionally substituted phenoxyalkylSubstituted heteroaryl, optionally substituted heteroarylalkoxy, optionally substituted heteroaryloxyalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heterocycloalkyloxy, optionally substituted heterocycloalkylalkoxy, -alkylene-S (O)nRa(wherein n is 0 to 2, RaBeing hydroxyalkyl or optionally substituted phenyl), -alkylene-NRe-alkylene CONRcRd(wherein R iscIs hydroxy, RdAnd ReIndependently hydrogen or alkyl), or carboxyalkylaminoalkyl.
More preferably, Ar2Is thiophen-2-yl, pyridin-3-yl, quinolin-6-yl, benzothiazol-2-yl, benzooxazol-2-yl, benzofuran-5-yl, benzothien-2-yl, furan-2-yl, 1H-benzimidazol-2-yl, 1H-pyrrol-2-yl, thiazol-2-yl, 1H-indol-5-yl, 1H-indol-3-yl, quinolin-8-yl, 1H-indazol-3-yl, 1H-benzotriazol-5-yl, quinoline-6-yl, benzooxazol-2-yl, 1H-pyrrol-2-yl, thiazol-2-yl, 1H-indol-5-yl, 1, Isoquinolin-1-yl, isoquinolin-3-yl, quinoxalin-2-yl, quinolin-2-yl, 1H-benzimidazol-5-yl, quinolin-1-yl, pyridin-2-yl, quinolin-2-yl, furan-3-yl, thiophen-2-yl, or thiophen-3-yl, more preferably benzofuran-2-yl, or benzothiophen-2-yl, optionally substituted with one or two substituents as described in the preceding paragraph.
Even more preferably, Ar2Is benzofuran-2-yl which is monosubstituted in the 3-, 4-or 5-position or disubstituted in the 4-and 7-positions, preferably benzofuran-2-yl is monosubstituted in the 3-or 5-position by a substituent as described in the preceding paragraph. More preferably, the substituents are independently selected from: chlorine, fluorine, trifluoromethyl, methyl, ethyl, methoxy, 1-cyclopropylpiperidin-4-yloxy, 1- (2, 2, 2-trifluoroethyl) piperidin-4-yloxy, N-dimethylaminomethyl, N-diethylaminomethyl, 2-methoxyethoxymethyl, phenoxymethyl, 2-methoxyethoxy, 2-morpholin-4-ylethoxy, pyridin-3-methoxy, 2-hydroxyethoxy, 2-N, N-dimethylaminoethoxy, methoxymethyl, 3-isopropoxymethyl, morpholin-4-ylmethyl, 3-hydroxypropoxymethyl, 2-fluorophenoxymethyl, 3-fluorophenoxymethyl4-fluorophenoxy-methyl, 3-methoxypropoxymethyl, pyridin-4-yloxymethyl, 2, 4, 6-trifluorophenoxymethyl, 2-oxopyridin-1-ylmethyl, 2, 2, 2-trifluoroethoxymethyl, 4-imidazol-1-ylphenoxymethyl, 4- [1.2.4]-triazin-1-yl-phenoxymethyl, 2-phenylethyl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, 4-trifluoromethylpiperidin-1-methyl, 4-methylpiperazin-1-ylmethyl, 3, 3, 3-trifluoropropoxymethyl, 4-fluorophenylthiomethyl, 4-fluorophenylsulfinylmethyl, 4-fluorophenylsulfonylmethyl, pyridin-3-ylmethoxymethyl, tetrahydropyran-4-yloxy, 2, 2, 2-trifluoroethoxy, 2-pyrrolidin-1-ylethoxy, piperidin-4-yloxy, N-methyl-N-benzylaminomethyl, N-methyl-N-2-phenylethylaminomethyl, N-methyl-N-2-phenylethyl-aminomethyl, N-methyl-N-propylthiomethyl, N-methyl-1-propylthiomethyl, N-methyl-4-fluorophenylmethyl, N-methyl-4-propylthiomethyl, 3-hydroxypropylthiomethyl, 3-hydroxypropylsulfinylmethyl, 3-hydroxypropylsulfonyl-methyl, N-methyl-N-2-indol-3-ylethylaminomethyl, 2- (4-trifluoromethylphenyl) ethyl, 2- (3-trifluoromethoxyphenyl) ethyl, N-hydroxyaminocarbonyl-methylaminomethyl, or 3- (2-carboxyethylamino-methyl).
Even more preferably, Ar2Is benzofuran-2-yl, which is substituted in the 3-position with the following substituents: n, N-dimethylaminomethyl, N-diethylaminomethyl, 2-fluorophenoxymethyl, 3-fluorophenoxymethyl, 4-fluorophenoxymethyl, pyridin-4-yloxymethyl, 2, 4, 6-trifluorophenoxy-methyl, 2-oxopyridin-1-ylmethyl, 2, 2, 2-trifluoroethoxy-methyl, 4-imidazol-1-ylphenoxy-methyl, 4- [1.2.4] methyl]-triazin-1-yl-phenoxymethyl, 2-phenylethyl, 3-hydroxypropoxymethyl, 2-methoxyethoxymethyl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, 4-trifluoromethyl-piperidin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 3, 3, 3-trifluoropropoxymethyl, 4-fluorophenylthiomethyl, 4-fluorophenylsulfinylmethyl, 4-fluorophenylsulfonylmethyl, 2- (3-trifluoromethoxyphenylethyl) -, N-methyl-N-benzyl-aminomethyl, N-methyl-N-2-phenylethylaminomethyl, 3-hydroxypropylthiomethyl, methyl, p-tert-butyl-ethyl, p-butyl-ethyl-methyl, p, 3-hydroxypropylsulfinyl-methyl, 3-hydroxypropylsulfonylmethyl, N-methyl-N-2-indol-3-ylethylaminomethyl, 2- (4-trifluoromethylphenyl) ethyl, N-hydroxymethy lAminocarbonyl-methylaminomethyl, or 2-carboxyethylamino-methyl.
Even more preferably, Ar2Is benzofuran-2-yl, which is substituted in the 5-position by: 1-cyclopropyl piperidin-4-yloxy, tetrahydropyran-4-yloxy, 2, 2, 2-trifluoroethoxy, 2-pyrrolidin-1-ylethoxy, or 1- (2, 2, 2-trifluoroethyl) piperidin-4-yloxy.
Even more preferably, Ar2Is 7-chloro-4-methylbenzofuran-2-yl, 4-methyl-benzofuran-2-yl, 7-fluoro-4-methylbenzofuran-2-yl or 7-fluoro-4-phenoxymethylbenzofuran-2-yl.
Even more preferably, Ar2Is thiophen-2-yl, pyridin-3-yl, 5-phenylthiophen-2-yl, quinolin-6-yl, 4-phenylthiazol-2-yl, benzothiazol-2-yl, benzoxazol-2-yl, furan-2-yl, 1H-benzimidazol-2-yl, 1H-pyrrol-2-yl, 4- (pyridin-4-yl) -thiazol-2-yl, 1H-indol-5-yl, 1H-indol-3-yl, quinolin-8-yl, 1H-indazol-3-yl, 1H-benzotriazol-5-yl, quinoline-2-yl, or quinoline-2-yl, Isoquinolin-1-yl, isoquinolin-3-yl, quinoxalin-2-yl, quinolin-2-yl, 1H-benzimidazol-5-yl, 1-methyl-indol-3-yl, 4-MeO-quinolin-2-yl, quinolin-4-yl, 4-hydroxyquinolin-2-yl, pyridin-2-yl, 3-hydroxypyridin-2-yl, 6- (4-nitrophenoxy) pyridin-2-yl, 4- (2-methoxyethoxy) quinolin-2-yl, 4- (2-dimethylaminoethoxy) quinolin-2-yl, quinoxalin-2-yl, 1H-benzimidazol-5-yl, 1-methyl-indol, 6-bromopyridin-2-yl, 5-bromopyridin-3-yl, 4-methoxyquinolin-2-yl, 5-phenylpyridin-3-yl, 6-benzyloxypyridin-2-yl, 6- (2-methylpropyloxy) -pyridin-2-yl, 6- (2-phenylethoxy) pyridin-2-yl, 4- (3, 3, 3-trifluoropropoxy) quinolin-2-yl, 5-thiophen-3-ylpyridin-3-yl, 6- (4-acetylaminophenoxy) -pyridin-2-yl, 6- (4-aminophenoxy) -pyridin-2-yl, or 5- (4-dimethylaminophenyl) pyridin-3-yl.
Within the above preferred groups II, III, IV and V and the more preferred, even more preferred and especially preferred groups contained therein, a group of most preferred compounds is that wherein Y is a linear alkylene group, preferably ethylene or n-propylene, preferably ethylene.
Within the above preferred groups II, III, IV and V and the more preferred, even more preferred and particularly preferred groups contained therein, a further group of most preferred compounds is that wherein Y is a branched alkylene group, preferably-CH (C)2H5)CH2-、-CH(i-C3H7)CH2-, or-CH (CH)3)CH2-, the stereochemistry at the chiral carbon is (S). More preferably, Y is-CH (C)2H5)CH2-。
Within the above preferred groups II, III, IV and V and the more preferred, even more preferred and especially preferred groups contained therein, a further group of most preferred compounds is that wherein Y is-CH2CH(CH3) -, the stereochemistry at the chiral carbon is (R).
Within the above preferred groups II, III, IV and V and the more preferred, even more preferred and especially preferred groups contained therein, a further group of most preferred compounds is that wherein Y is-CH (CH)2R′)CH2-or-CH (CH)2CH2R′)CH2-, wherein R' is alkylthio, alkylsulfonyl, optionally substituted phenylalkylthio, optionally substituted phenylalkylsulfonyl, hydroxy, or optionally substituted phenoxy, preferably phenyl, phenoxy, 4-chlorophenyl, cyclohexyl, benzylthio, benzylsulfonyl, methylthio, methylsulfonyl, or hydroxy.
A further group of preferred compounds of formula (I) is that wherein X is-O-, R1And R3Is hydrogen, Ar1Is phenylene, Ar2Is an aralkenyl group, Y is a branched alkylene group, -CONHOH and X are at the 1-and 4-positions of the phenylene ring. Preferably, Ar2Is trans-phenyl-CH ═ CH-, wherein phenyl is optionally substituted with one or two substituents independently selected from: alkyl, alkoxy, methylenedioxy, or hydroxy.
The scope of the terms contained within the above groups II-VI is as described in the definitions section of the present application.
Reference to the preferred embodiments set forth above is meant to include all combinations of the specific and preferred groups unless otherwise indicated.
General Synthesis
The compounds of the present invention can be prepared by the methods described in the reaction schemes shown below.
The starting materials and reagents used to prepare these compounds are either from commercial suppliers such as aldrich chemical Co. (Milwaukee, Wis.), Bachem (torance, Calif.), or Sigma (st. louis, Mo.), or prepared by methods known to those skilled in the art following the procedures set forth in the references, for example: fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17(John Wiley and Sons, 1991); rodd's Chemistry of CarbonCompounds, Volumes 1-5 and supplements (Elsevier Science Publishers, 1989); organic Reactions, Volumes 1-40(John Wiley and Sons, 1991), March's sAdvanced Organic Chemistry, (John Wiley and Sons, 4th Edition) and Larock's comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes are merely illustrative of some of the ways in which the compounds of the invention may be synthesized and various modifications may be made to these schemes, which modifications may occur to those skilled in the art in view of this disclosure. The starting materials and intermediates of the reaction can be isolated and purified, if desired, using conventional techniques, including, but not limited to: filtration, distillation, crystallization, chromatography, and the like. These materials are also characterized using conventional means, including physical constants and spectral data.
Unless stated to the contrary, the reactions described herein occur at atmospheric pressure and temperatures in the range of from about-78 ℃ to about 150 ℃, more preferably from about 0 ℃ to about 125 ℃, and most preferably about room (or ambient) temperature, for example about 20 ℃.
The compounds of formula (I) can be prepared by the procedures described and illustrated in scheme A below, wherein X is-O-or-S (O)n-, where n is from 0 to 2,other groups are as described in "summary of the invention".
Scheme A
The reaction of a compound of formula 1 with an amino alcohol of formula 2 to produce a compound of formula 3, wherein in formula 1, R is alkyl, X is-O-or-S-, Ar1As described in the summary of the invention, PG is a suitable amino protecting group in formula 2. The reaction is carried out in the presence of triphenylphosphine and diisopropyl azodicarboxylate in a suitable organic solvent such as tetrahydrofuran or the like.
Compounds of formula 1 such as methyl 4-hydroxybenzoate, methyl 4-mercaptobenzoate, and methyl 3-hydroxyisoxazole-5-carboxylate are commercially available. The compounds of formula 2 can be prepared from commercially available aminoalcohols as follows: the amine is reacted with a suitable amino protecting group such as benzyloxycarbonyl, tert-butoxycarbonyl, and the like under reaction conditions well known in the art. A detailed description of suitable amino-Protecting Groups and reaction conditions for their preparation can be found in T.W. Greene, Protecting Groups in Organic Synthesis, John Wiley&Sons, inc.1981, the teachings of which are incorporated herein by reference in their entirety. Aminoalcohols such as 2-ethanolamine, 2-amino-1-propanol, 2-methylaminoethanol, 2-amino-2-methyl-1-propanol, 2-amino-1-propanol, 4-amino-2-butanol and 1-amino-2-butanol are commercially available. Alternatively, the compound of formula 2 can be prepared from commercially available amino acids as follows: the amino group is protected with a suitable protecting group and then the acid group is reduced to a hydroxyl group with a suitable reducing agent under reaction conditions well known in the art. If desired, a compound of the formula (I) wherein X is-SO2-, then the corresponding compound of formula 3 (wherein X is-S-) can be oxidized with an oxidizing agent such as OXONEM-chloroperbenzoic acid, and the like.
Removal of the amino protecting group in formula 3 affords compounds of formula 4. The reaction conditions used to remove the amino protecting group depend on the nature of the protecting group. For example, if the protecting group is tert-butoxycarbonyl, it is removed under acidic reaction conditions. Suitable acids are trifluoroacetic acid, hydrochloric acid, etc., in a suitable organic solvent such as methanol, dioxane, tetrahydrofuran, etc. If the protecting group is benzyl or benzyloxycarbonyl, it is removed under catalytic hydrogenation conditions. Suitable catalysts are palladium-based catalysts and other catalysts known in the art. Other suitable reaction conditions for removing Protecting Groups can be found in T.W. Greene, Protecting Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981. The reaction is carried out in an inert organic solvent such as dichloromethane, tetrahydrofuran, dioxane, etc.
Formula 4 and formula Ar2Reaction of an acid or acid derivative (e.g. acid halide) of COZ (where Z is hydroxy or halide) gives the compound of formula 5. Furthermore, the reaction conditions used depend on the nature of the Z group. If Z is hydroxy, the reaction is typically carried out in the presence of a suitable coupling agent, such as benzotriazol-1-yloxytripyrrolidino-phosphorusHexafluorophosphate (PyBOP)) O-benzotriazol-1-yl-N, N, N ', N' -tetramethyl-ureaHexafluorophosphate (HBTU), O- (7-azabenzotriazol-1-yl) -1, 1, 3, 3-tetramethyl-ureaHexafluorophosphate (HATU), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC. HCl), or 1, 3-Dicyclohexylcarbodiimide (DCC), optionally in the presence of 1-hydroxybenzotriazole hydrate (HOBT. H)2O), and a base such as N, N-diisopropylethylamine, triethylamine, N-methylmorpholine, etc. The reaction is typically carried out at 20-30 c, preferably about 25 c, and takes 2-24 hours to complete.Suitable reaction solvents are inert organic solvents such as halogenated organic solvents (e.g., dichloromethane, chloroform, etc.), acetonitrile, N-dimethylformamide, ethereal solvents such as tetrahydrofuran, dioxane, etc. Preferably, HOBt. H is used for the reaction2O, EDC HCl was carried out in dichloromethane or N, N-dimethylformamide.
When Ar is2When COZ is an acid halide, the reaction is carried out in the presence of a suitable base (e.g., triethylamine, diisopropylethylamine, pyridine, etc.). Suitable reaction solvents are polar organic solvents such as tetrahydrofuran, acetonitrile, N-Dimethylformamide (DMF), dichloromethane, or any suitable mixture thereof. Acid halides such as acid chlorides can be prepared by reacting the corresponding acid with a halogenating agent such as oxalyl chloride, thionyl chloride, phosphorus oxychloride, and the like. Formula Ar2The acids of the COZ can be obtained commercially, or they can be prepared from commercially available starting materials by methods known in the art. For example, benzoic acid, cinnamic acid, phenylacetic acid, nicotinic acid, isonicotinic acid, 3-methylbenzofuran-2-carboxylic acid, and benzofuran-2-carboxylic acid are commercially available. Other acids such as 3-phenoxymethylbenzofuran-2-carboxylic acid can be readily prepared from commercially available 3-methylbenzofuran-2-carboxylic acid as follows: it is first converted to 2-bromomethylbenzofuran-2-carboxylic acid (which is brominated with N-bromosuccinimide under conditions well known in the art) and then reacted with phenol. Compound 5 (wherein R3Is hydrogen) may optionally be converted into the corresponding compound of formula 5 (wherein R is3Other than hydrogen): compound 5 is reacted with an alkylating agent under conditions well known in the art.
Compound 5 is then converted to the compound of formula (I) by the following method: it is reacted with an aqueous hydroxylamine solution in the presence of a base such as sodium hydroxide and a mixture of organic solvents such as tetrahydrofuran and methanol. Alternatively, the acid group in compound 5 is first activated with a suitable coupling agent such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC. HCl), or 1, 3-cyclohexylcarbodiimide (DCC), optionally in the presence of 1-hydroxybenzotriazole hydrate (HOBT. H)2O), the above activation is carried out in a suitable organic solvent such as dimethylformamide and the like, followed by reaction with hydroxylamine hydrochloride in a base such as N, N-diisopropylIn the presence of ethylamine, triethylamine, N-methylmorpholine, etc. The compounds of formula (I) may also be prepared from compound 5 according to the methods disclosed in U.S. Pat. No. 5,998,412, the disclosure of which is incorporated herein by reference in its entirety.
The compound of formula (I) may then be converted to other compounds of formula (I). For example, compounds of formula (I) (wherein Ar1Is phenylene, X is-O-, Y is ethylene, Ar2Is 3-dimethylaminomethylbenzofuran-2-yl, R1And R3Hydrogen) can be prepared by the following method: reacting a compound of formula 4 (wherein Ar1Is phenylene, X is-O-, Y is ethylene and R is alkyl, with 3-methylbenzofuran-2-carboxylic acid as described above to give the compound of formula 5 (wherein Ar is Ar)2Is 3-methylbenzofuran-2-yl). Bromination of the methyl group with a suitable brominating agent such as N-bromosuccinimide, followed by reaction with dimethylamine affords the corresponding 3-dimethylaminobenzofuran-2-yl compound, which is then converted to the desired compound under the reaction conditions described above.
Use of
The compounds of the present invention are inhibitors of histone deacetylase and are therefore useful in the treatment of proliferative diseases such as cancer, for example, lung cancer, colon cancer, AML, MML, skin cancer, breast cancer, ovarian cancer, prostate cancer, liver cancer, brain and skin cancer, psoriasis, fibroproliferative diseases such as hepatic fibrosis, smooth muscle proliferative diseases such as, for example, atherosclerosis and restenosis, inflammation such as, for example, arthritis, diseases involving angiogenesis such as cancer, diabetic retinopathy, hematopoietic disorders such as anemia, fungal infections, parasitic infections and bacterial infections, viral infections, autoimmune diseases such as arthritis, multiple sclerosis, lupus, allergy, asthma, allergic rhinitis and organ transplantation, and bipolar disorders. In addition, the compounds of the present invention are useful for treating hepatitis c infections.
Test of
The ability of the compounds of the present invention to inhibit histone deacetylase can be tested in vitro and in vivo assays described in bioassay examples 1 and 2 below. The hcv activity of the compounds of the invention was tested in the hcv replicon assay of Georgetown University. Korner, v.l.et al, Science 1999 Jul 2: 285(5424): 110-3 to test the hcv activity of the compounds.
Administration and pharmaceutical compositions
In general, the compounds of the present invention are administered in a therapeutically effective amount by any acceptable mode of administration for agents that exert a similar effect. The actual amount of the compound of the invention, i.e., the active ingredient, will depend on a number of factors, such as the severity of the disease to be treated, the age and relative health of the patient, the potency of the compound used, the route and mode of administration, and other factors.
A therapeutically effective amount of a compound of formula (I) ranges from about 0.1 to 50mg/kg of recipient body weight per day, preferably from about 0.5 to 20 mg/kg/day. Thus, for administration to a 70kg human, the dosage range is most preferably from about 35 mg/day to 1.4 g/day.
Typically, the compounds of the invention are administered as pharmaceutical compositions by any of the following routes: oral, systemic (e.g., transdermal, intranasal, or suppository), or parenteral (e.g., intramuscular, intravenous, or subcutaneous). The preferred mode of administration is oral or parenteral, using a convenient daily regimen which can be adjusted to the degree of illness. Oral compositions may take the form of tablets, pills, capsules, semisolids, powders, sustained release dosage forms, solutions, suspensions, elixirs, aerosols, or any other suitable composition.
The choice of dosage form depends on various factors such as the mode of administration (e.g., for oral administration, a dosage form in the form of a tablet, pill, or capsule is preferred), and the bioavailability of the drug. Recently, the following principles are based: the bioavailability can be increased by increasing the surface area, i.e. decreasing the particle size, and pharmaceutical dosage forms have been developed especially for drugs with poor bioavailability. For example, U.S. Pat. No. 4,107,288 describes a pharmaceutical dosage form having a particle size in the range of 10 to 1,000nm, in which the active substance is supported on a crosslinked matrix of macromolecules. U.S. Pat. No. 5,145,684 describes the preparation of a pharmaceutical formulation wherein the drug is pulverized into nanoparticles (average particle size of 400nm) in the presence of a surface modifier, and then dispersed in a liquid medium to give a pharmaceutical formulation which has very high bioavailability.
The compositions generally consist of a compound of formula (I) in combination with at least one pharmaceutically acceptable excipient. The pharmaceutically acceptable excipients are non-toxic and aid in administration without adversely affecting the therapeutic efficacy of the compounds of formula (I). Such excipients may be any solid, liquid, semi-solid, or, for aerosol compositions, gaseous excipients are generally available to those skilled in the art.
Solid pharmaceutical excipients include: starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. The liquid and semi-solid excipients may be selected from: glycerol, propylene glycol, water, ethanol, and various oils, including those derived from petroleum, animal, vegetable, or synthetic sources, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Preferred liquid carriers, especially for injectable solutions, include water, saline, aqueous dextrose, and glycols.
Compressed gases may be used to disperse the compounds of the invention in the form of an aerosol. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
Other suitable pharmaceutical excipients and their dosage forms are described in Remington's pharmaceutical Sciences, edited by e.w. martin (Mack Publishing Company, 18)th ed.，1990)。
The amount of the compound in the dosage form may vary within the full range used by those skilled in the art. Typically, the dosage form comprises about 0.01-99.99 wt% of the compound of formula (I), based on the weight percent (wt%) of the total dosage form, with the balance being one or more suitable pharmaceutical excipients. Preferably, the compound is present in an amount of about 1 to 80 wt%. Representative pharmaceutical dosage forms containing the compounds of formula (I) are described below.
As previously mentioned, the compounds of the present invention may be administered in combination with known anti-cancer agents. These known anticancer drugs include the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, DNA methyltransferase inhibitors, and other angiogenesis inhibitors. The compounds of the present invention are particularly useful when administered in combination with radiation therapy. Preferred angiogenesis inhibitors are selected from: tyrosine kinase inhibitors, inhibitors of epidermal derived growth factor, inhibitors of fibroblast derived growth factor, inhibitors of platelet derived growth factor, MMP (matrix metalloproteinase) inhibitors, integrin blockers, interferon- α, interleukin-12, pentosan polysulfate, cyclooxygenase inhibitors, carboxyamidotriazole, combretastatin a-4, squalamine, 6-O-chloroacetyl-carbonyl-fumagillol (fumagillol), thalidomide, angiostatin, troponin-1, and antibodies to VEGF.
Preferred estrogen receptor modulators are tamoxifen and raloxifene.
"Estrogen receptor modulators" refers to compounds that interfere with or inhibit the binding of estrogen to the receptor, regardless of mechanism. Examples of estrogen receptor modulators include, but are not limited to: tamoxifen, raloxifene, idoxifen, LY353381, LY117081, toremifene, fulvestrant, 4- [7- (2, 2-dimethyl-1-oxopropoxy-4-methyl-2- [4- [2- (1-piperidinyl) ethoxy ] phenyl ] -2H-1-benzopyran-3-yl) -phenyl-2, 2-dimethylpropionate, 4' -dihydroxybenzophenone-2, 4-dinitrophenyl-hydrazone, and SH 646.
"androgen receptor modulators" refers to compounds that interfere with or inhibit the binding of androgens to the receptor, regardless of mechanism. Examples of androgen receptor modulators include: finasteride and other 5 α -reductase inhibitors, nilutamide, flutamide, bicalutamide, liazole, and abiraterone acetate.
"retinoid receptor modulators" refers to compounds that interfere with or inhibit the binding of retinoids to receptors, regardless of mechanism. Examples of such retinoid receptor modulators include: bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid, α -difluoromethyl ornithine, ILX23-7553, trans-N- (4' -hydroxyphenyl) retinoamide (retinamide), and N-4-carboxyphenyl retinoamide.
"cytotoxic agents" refers to compounds that cause cell death primarily by directly interfering with cell function, or by inhibiting or interfering with cell division, and include alkylating agents, tumor necrosis factors, intercalating agents, tubulin inhibitors, and topoisomerase inhibitors.
Examples of cytotoxic agents include, but are not limited to: tirapazamine, sertenef, cachet, ifosfamide, tasolinamine, lonidamine, carboplatin, altretamine, temustine, deltemustine, dibromodulcitol, ramustine, fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin (heptaplatin), estramustine, inpropylsulosin, trofosfamide, nimustine, dibromospirochloramine, puripine, lobaplatin, satraplatin, profiromycin, cisplatin, ilovens, dexifosfamide (dexifosfamide), cis-aminodichloro (2-methyl-pyridine) platinum, benzylguanine, glufosfamide, GPX100, (trans ) -bis-mu- (hexane-1, 6-diamine) -mu- [ diamine-platinum (II) ] bis [ diamine (chloride) platinum (II) ] -tetrachloro, dinitrogen (diazirinyl) spermidinyl (dizirinyl) amine, Arsenic trioxide, 1- (11-dodecylamino-10-hydroxyundecyl) -3, 7-dimethylxanthine, zorubicin, idarubicin, daunorubicin, bisantrene, mitoxantrone, pirarubicin, pirnafide, valrubicin, amrubicin, antitumor ketone, 3 '-deamino-3' -morpholino-13-deoxo-10-hydroxycarminomycin, liposomal anthracycline (anamycin), garubicin, irinotecan, MEN 10755, and 4-demethoxy-3-deamino-3-aziridinyl-4-methylsulfonyl-daunorubicin (see WO 00/50032).
Examples of tubulin inhibitors include: paclitaxel, vindesine sulfate, 3 ', 4' -didehydro-4 '-deoxy-8' -norvinblastine (norvinceeukeukobtaine), docetaxel (docetaxel), radiclin, dolastatin, mevalon isethionate, auristatin, cimidodine, RPR109881, BMS184476, vinflunine, cryptophycin, 2,3, 4,5, 6-pentafluoro-N- (3-fluoro-4-methoxyphenyl) benzenesulfonamide, anhydrous vinblastine, N-dimethyl-L-valyl-N-methyl-L-valyl-L-propyl-L-proline-tert-butylamide, TDX258, and BMS 188797.
Some examples of topoisomerase inhibitors are: topotecan, hycaptamine, irinotecan, rubitecan, 6-ethoxypropionyl-3 ', 4' -O-exo-benzylidene-tebucin, 9-methoxy-N, N-dimethyl-5-nitropyrrolo [3, 4, 5-kl]Acridine-2- (6H) propylamine, 1-amino-9-ethyl-5-fluoro-2, 3-dihydro-9-hydroxy-4-methyl-1H, 12H-benzo [ de]Pyrano [3 ', 4': b, 7]-indolizino [1, 2b ]]Quinoline-10, 13(9H, 15H) dione, lurtotecan (lurtotecan), 7- [2- (N-isopropylamino) -ethyl]- (20S) camptothecin, BNP1350, BNPI1100, BN80915, BN80942, etoposide phosphate, teniposide, sobuzosin, 2 '-dimethylamino-2' -deoxy-etoposide, GL331, N- [2- (dimethylamino) ethyl ] etoposide]-9-hydroxy-5, 6-dimethyl-6H-pyrido [4, 3-b]Carbazole-1-carboxamide, asularnine, (5a, 5aB, 8aa, 9b) -9- [2- [ N- [2- (dimethylamino) ethyl ] amine]-N-methylamino radical]Ethyl radical]-5- [ 4-hydroxy-3, 5-dimethoxyphenyl group]-5, 5a, 6,8, 8a, 9-hexahydrofuro (3 ', 4': 6, 7) colchic (2, 3-d) -1, 3-dioxole (dioxol) -6-one, 2, 3- (methylenedioxy) -5-methyl-7-hydroxy-8-methoxybenzo [ c ] o]-phenanthridines(phenanthridinium), 6, 9-bis [ (2-aminoethyl) -amino]Benzo [ g ]]Isoguinoline-5, 10-dione, 5- (3-aminopropylamino) -7, 10-dihydroxy-2- (2-hydroxyethylaminomethyl) -6H-pyrazolo [4, 5, 1-de]Acridin-6-one, N- [1- [2- (diethylamino) ethyl esterRadical amino]-7-methoxy-9-oxo-9H-thioxanthen-4-ylmethyl]Formamide, N- (2- (dimethylamino) ethyl) acridine-4-carboxamide, 6- [ [2- (dimethylamino) ethyl ] ethyl]Amino group]-3-hydroxy-7H-indeno [2, 1-c]Quinolin-7-one, and dimesna.
"antiproliferative agents" include: antisense RNA and DNA oligonucleotides, such as G3139, ODN698, RVASKRAS, GEM231 and INX3001, and antimetabolites, such as enocitabine, carmofur, temafluor, pentostatin, doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine, fosetabine sodium hydrate, raltitrexed, palytrexid, etimefurylfluoride, thiazoluraline, tacitabine, nolatrexed, pemetrexed, nelzabine, 2 ' -deoxy-2 ' -methine, 2 ' -fluoromethylene-2 ' -deoxycytidine, N- [5- (2, 3-dihydro-benzofuranyl) sulfonyl ] -N ' - (3, 4-dichlorophenyl) urea, N6- [ 4-deoxy-4- [ N2- [2(E), 4(E) -tetradecadienoyl ] glycinyl ] -L-propionylamino ] -B-L-mannosyl-L-riboside manno) -heptopyranosyl (heptapyranosyl) ] -adenine, aplidine, ecteinascidin, troxacitabine, 4- [ 2-amino-4-oxo-4, 6,7, 8-tetrahydro-3H-pyrimido [5, 4-b ] [1, 4] thiazin-6-yl- (S) -ethyl ] -2, 5-thiophenoyl (thienoyl) -L-glutamic acid, aminopterin, 5-fluorouracil, alanin, 11-acetyl-8- (carbamoyloxymethyl) -4-formyl-6-methoxy-14-oxa-1, 11-diazacyclo (7.4.1.0.0) -tetradec-2, 4, 6-trien-9-ylacetate, Octahydroindolizinetriol, lometrexol, dexrazoxane, methioninase, 2 '-cyano-2' -deoxy-N4-palmitoyl-1-B-D-arabinofuranosyl cytosine, and 3-aminopyridine-2-carboxaldehyde thiosemicarbazone. "antiproliferative agents" also include: monoclonal antibodies to growth factors, such as trastuzumab, in addition to those listed in the "angiogenesis inhibitor" section, and tumor suppressor genes, such as p53, can be delivered by recombinant virus-mediated gene transfer (see, e.g., U.S. patent No. 6,069,134).
"HMG-CoA reductase inhibitor" refers to an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase. Compounds having HMG-CoA reductase inhibitory activity can be readily identified by assay methods well known in the art. See, for example, U.S. Pat. No. 4,231,938, column 6 and WO84/02131, pages 30-33, describing or citing assay methods. The terms "HMG-CoA reductase inhibitor" and "inhibitor of HMG-CoA reductase" have the same meaning as used herein. It has been reported (int.j. cancer, 20; 97 (6): 746-50, 2002) that combination therapy with lovastatin (an HMG-CoA reductase inhibitor) and butyrate (an apoptosis inducing agent) shows enhanced antitumor effects in a mouse Lewis lung cancer model.
Examples of HMG-CoA reductase inhibitors that may be used include, but are not limited to: lovastatin (MEVACOR)See U.S. Pat. nos. 4,231,938; 4,294,926, respectively; 4,319,039), simvastatin (ZOCOR)See U.S. Pat. nos. 4,444,784; 4,820,850, respectively; 4,916,239), pravastatin (pravacchol)See U.S. Pat. nos. 4,346,227; 4,537,859, respectively; 4,410,629; 5,030,447 and 5,180,589), fluvastatin (LESCOL)See U.S. Pat. nos. 5,354,772; 4,911,165, respectively; 4,929,437, respectively; 5,189,164, respectively; 5,118,853, respectively; 5,290,946, respectively; 5,356,896), atorvastatin (LIPITOR)See U.S. Pat. nos. 5,273,995; 4,681,893; 5,489,691, respectively; 5,342,952) and cerivastatin (also known as rivastatin and BAYCHOL)See U.S. Pat. No. 5,177,080). The structural formulae of these and additional HMG-CoA reductase inhibitors useful in this method are described in M.Yalpani，″Cholesterol Lowering Drugs″，Chemistry&Page 87 of Industry, pp.85-89(feb.5, 1996), and U.S. patent nos. 4,782,084 and 4,885,314. The term "HMG-CoA reductase inhibitor" as used herein includes all pharmaceutically acceptable lactone and open-acid (open-acid) forms (i.e., wherein the lactone ring can be cleaved to form the free acid) as well as the salt and ester forms of compounds having HMG-CoA reductase inhibitory activity, and colchicine, and the use of these salt, ester, open-acid and lactone forms is also included within the scope of the present invention.
Among the HMG-CoA reductase inhibitors in which the open acid form may be present, the salt and ester forms are preferably formed from open acid, all of which forms are included within the meaning of the term "HMG-CoA reductase inhibitor" as used herein. Preferably, the HMG-CoA reductase inhibitor is selected from: lovastatin and simvastatin, most preferably simvastatin.
The term "pharmaceutically acceptable salts" as used herein with respect to HMG-CoA reductase inhibitors refers to non-toxic salts of the compounds used in the present invention which are generally prepared by reacting the free acid with a suitable organic or inorganic base, especially those prepared from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc and tetramethylammonium, and those prepared from amines such as ammonia, ethylenediamine, N-methylglucamine, lysine, arginine, ornithine, choline, N '-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, 1-p-chlorobenzyl-2-pyrrolidin-1' -yl-methylbenzimidazole, diethylamine, piperazine, and tris (hydroxymethyl) aminomethane. Other examples of salt forms of HMG-CoA reductase inhibitors may include, but are not limited to: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium hydroxide, camphorsulfonate, carbonate, chloride, clavulanate, citrate, dihydrochloride, hydroxy, edisylate, etonate, ethanesulfonate, fumarate, glucoheptonate, gluconate, glutamate, glycolylarginate, hexylresorcinate (hexyresorcinate), hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, methanesulfonate, methylsulfate, mucate (mucate), naphthalenesulfonate, nitrate, oleate, oxalate, pamaote, palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, and salicylate, Stearate, subacetate, succinate, tannate, tartrate, theachlorate, tosylate, triiodonium (triethiodide), and valerate.
The ester derivatives of the HMG-CoA reductase inhibitor compounds are useful as prodrugs which, when absorbed into the bloodstream of a warm-blooded animal, can be cleaved in a manner to release the drug form, which provides improved therapeutic efficacy.
"prenyl-protein transferase inhibitors" are compounds that inhibit any one of or any combination of prenyl-protein transferases, including farnesyl-protein transferase (FPTase), geranylgeranyl-protein transferase type I (GGPTase-I), and geranylgeranyl-protein transferase type II (GGPTase-II, also known as Rab GGPTase). Examples of prenyl-protein transferase inhibiting compounds include: (±) -6- [ amino (4-chlorophenyl) (1-methyl-1H-imidazol-5-yl) methyl ] -4- (3-chlorophenyl) -1-methyl-2 (1H) -quinolinone, (-) -6- [ amino (4-chlorophenyl) (1-methyl-1H-imidazol-5-yl) methyl ] -4- (3-chlorophenyl) -1-methyl-2 (1H) -quinolinone, (+) -6- [ amino (4-chlorophenyl) (1-methyl-1H-imidazol-5-yl) methyl ] -4- (3-chlorophenyl) -1-methyl-2 (1H) -quinolinone, 5(S) -n-butyl-1- (2, 3-dimethylphenyl) -4- [1- (4-cyanobenzyl) -5-imidazolylmethyl ] -2-piperazinone, (S) -1- (3-chlorophenyl) -4- [1- (4-cyanobenzyl) -5-imidazolylmethyl ] -5- [2- (ethylsulfonyl) -methyl ] -2-piperazinone, 5(S) -n-butyl-1- (2-methylphenyl) -4- [1- (4-cyanobenzyl) -5-imidazolylmethyl ] -2-piperazinone, 1- (3-chlorophenyl) -4- [1- (4-cyanobenzyl) -2-methyl-5- Imidazolylmethyl ] -2-piperazinone, 1- (2, 2-diphenylethyl) -3- [ N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamoyl ] piperidine, 4- {5- [ 4-hydroxymethyl-4- (4-chloropyridin-2-ylmethyl) -piperidin-1-ylmethyl ] -2-methylimidazol-1-ylmethyl } benzonitrile, 4- {5- [ 4-hydroxymethyl-4- (3-chlorobenzyl) -piperidin-1-ylmethyl ] -2-methylimidazol-1-ylmethyl } benzonitrile, 4- {3- [4- (2-oxo-2H-pyridin-1- Yl) benzyl ] -3H-imidazol-4-ylmethyl } benzonitrile, 4- {3- [4- (5-chloro-2-oxo-2H [1, 2 '] bipyridinyl-5' -ylmethyl) -3H-imidazol-4-ylmethyl ] benzonitrile, 4- {3- [4- (2-oxo-2H- [1, 2 '] bipyridinyl-5' -ylmethyl) -3H-imidazol-4-ylmethyl ] benzonitrile, 4- [3- (2-oxo-1-phenyl-1, 2-dihydropyridin-4-ylmethyl) -3H-imidazol-4-ylmethyl ] benzonitrile, 18, 19-dihydro-19-oxo-5H, 17H-6, 10:12, 16-dimethano (dimetheno) -1H-imidazo [4, 3-c ] [1, 11, 4] dioxa-azacyclononadecene (nonadecene) -9-carbonitrile, (+ -) -19, 20-dihydro-19-oxo-5H-18, 21-ethano-12, 14-ethenylene-6, 10-methano-22H-benzo [ d ] imidazo [4, 3-k ] [1, 6, 9, 12] -oxatriaza-cyclooctadecene (octadecene) -9-carbonitrile, 19, 20-dihydro-19-oxo-5H, 17H-18, 21-ethano-6, 10:12, 16-Dickinomethylene-22H-imidazo [3, 4-H ] [1, 8, 11, 14] oxatriazacyclo-eicosene (eicosine) -9-carbonitrile, and (±) -19, 20-dihydro-3-methyl-19-oxo-5H-18, 21-ethano-12, 14-ethano-6, 10-methano-22H-benzo [ d ] imidazo [4, 3-k ] [1, 6, 9, 12] oxa-triazacyclooctadecene-9-carbonitrile.
Other examples of prenyl-protein transferase inhibitors are found in the following publications and patents: WO 96/30343, WO 97/18813, WO 97/21701, WO 97/23478, WO97/38665, WO 98/28980, WO 98/29119, WO 95/32987, U.S. Pat. Nos. 5,420,245, 5,523,430, 5,532,359, 5,510,510, 5,589,485, 5,602,098, European patent publication No. 0618221, European patent publication No. 0675112, European patent publication No. 0604181, European patent publication No. 0696593, WO 94/19357, WO 95/08542, WO95/11917, WO 95/12612, WO 95/12572, WO 95/10514, U.S. Pat. No. 5,661,152, WO 95/10515, WO 95/10516, WO 95/24612, WO 95/34535, WO 95/25086, WO 96/05529, WO 96/06138, WO 96/06193, WO 96/16443, WO 96/21701, WO 96/21456, WO 96/22278, WO 95/10516, WO 95/24612, WO 95/34535, WO 95/25086, WO 96/05529, WO 96/06138, WO 96/06193, WO 96/16443, WO 96/21701, WO, WO 96/24611, WO 96/24612, WO 96/05168, WO 96/05169, WO 96/00736, us patent No. 5,571,792, WO96/17861, WO 96/33159, WO 96/34850, WO 96/34851, WO 96/30017, WO 96/30018, WO 96/30362, WO 96/30363, WO 96/31111, WO 96/31477, WO 96/31478, WO 96/31501, WO 97/00252, WO 97/03047, WO 97/03050, WO 97/04785, WO 97/02920, WO 97/17070, WO 97/23478, WO 97/26246, WO 97/30053, WO 97/44350, WO 98/02436, and us patent No. 5,532,359. See J.Ofcancer, Vol.35, No.9, pp.1394-1401(1999) for examples of the effects of prenyl-protein transferase inhibitors on angiogenesis.
Examples of HIV protease inhibitors include: amprenavir, abacavir, CGP-73547, CGP-61755, DMP-450, indinavir, nelfinavir, tipranavir, ritonavir, saquinavir, ABT-378, AG 1776 and BMS-232,632. Examples of reverse transcriptase inhibitors include: delavirdine, efavirenz, GS-840, HBY097, lamivudine, nevirapine, AZT, 3TC, ddC and ddI. It has been reported (nat. med.; 8 (3): 225-32, 2002) that HIV protease inhibitors such as indinavir or saquinavir have potent anti-angiogenic activity and promote the regression of Kaposi Sarcoma (Kaposi Sarcoma).
By "angiogenesis inhibitor" is meant a compound that inhibits neovascularization, regardless of its mechanism. Examples of angiogenesis inhibitors include, but are not limited to: tyrosine kinase inhibitors, such as inhibitors of the tyrosine kinase receptors Flt-1(VEGFR1) and Flk-1/KDR (VEGFR20), inhibitors of epidermal, fibroblast-derived or platelet-derived growth factors, MMP (matrix metalloproteinase) inhibitors, integrin inhibitors, interferon- α, interleukin-12, pentosan polysulfate, cyclooxygenase inhibitors, including non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen, and selective cyclooxygenase-2 inhibitors, such as celecoxib, valdecoxib, and rofecoxib (PNAS, Phal.89, p.7384 (1992); JNCl, Vol.69, p.475 (1982); Arch.Opthallmol, Vol.108, p.573 (1990); Ant.Rec, Vol.238, p.68 (FETTers, Vol.372, p.83; Clin.313, Vol.76, Oncol.1997), Vol.1994, Vol.75, Vol.107, Vol.J.76, Vol.107, Vol.75, Vol.107, Vol.J.75, Octop, vol.57, p.1625 (1997); cell, Vol.93, p.705 (1998); intl.j.mol.med., vol.2, p.715 (1998); biol. chem., vol.274, p.9116(1999)), carboxyamidotriazole, combretastatin a-4, squalamine, 6-O-chloroacetyl-carbonyl-fumagillol, thalidomide, angiostatin, troponin-1, angiotensin II antagonists (see Fernandez et al, j.lab.clin.med.105: 141-145(1985)) and VEGF (see Nature Biotechnology, Vol.17, pp.963-968(October 1999); kim et al, Nature, 362, 841-844 (1993); WO 00/44777; and WO 00/61186).
As noted above, the combination with NSAIDs involves the use of NSAIDs, which are potent COX-2 inhibitors. For purposes of this specification, the resulting NSAIDs inhibit the IC of COX-2 if determined according to cellular or microsomal assay methods known in the art50At 1 μ M or less, the NSAID is effective.
The present invention also includes combinations with NSAIDs that are selective COX-2 inhibitors. For the purposes of this specification, NSAIDs that are COX-2 selective inhibitors are those that have the specificity for COX-1 to inhibit COX-2 by virtue of the IC of COX-250IC against COX-150Is at least 100 times, IC50Assessed by the cellular or microsomal assay methods disclosed below. Such compounds include, but are not limited to, those disclosed in the following references: U.S. patent No. 5,474,995, entitled 12/1995; U.S. patent No. 5,861,419, granted 1/19/1999; U.S. patent No. 6,001,843, granted 12/14/1999; U.S. patent No. 6,020,343, granted 2/1/2000; U.S. patent No. 5,409,944, entitled 25/4 in 1995; U.S. patent No. 5,436,265, entitled 25/7 in 1995; U.S. patent No. 5,536,752, entitled 16/7/1996; U.S. patent No. 5,550,142 entitled 27/8/1996; U.S. patent No. 5,604,260, granted 2/18/1997; U.S. patent No. 5,698,584, entitled 16/12/1997; U.S. Pat. No. 5,710,140, entitled20/1/1998; WO 94/15932, published on 21/7/1994; U.S. patent No. 5,344,991, granted 6/1994; U.S. Pat. No. 5,134,142, granted 7/28/1992; U.S. patent No. 5,380,738, granted on 10/1/1995; U.S. patent No. 5,393,790, entitled 20/2 in 1995; U.S. Pat. No. 5,466,823, granted on month 11 and 14 of 1995; U.S. Pat. No. 5,633,272, granted 5 months 27 of 1997; and U.S. Pat. No. 5,932,598, entitled 3/8 1999, all of which are incorporated herein by reference. Other examples of specific inhibitors of COX-2 include those disclosed in U.S. Pat. No. 6,313,138, the disclosure of which is incorporated herein by reference in its entirety.
General and specific synthetic methods for preparing the above COX-2 inhibitor compounds are described in: U.S. patent No. 5,474,995, entitled 12/1995; U.S. patent No. 5,861,419, granted 1/19/1999; and U.S. patent No. 6,001,843, entitled 12/14 1999, all of which are incorporated herein by reference.
Compounds described as specific inhibitors of COX-2 and therefore useful in the present invention include, but are not limited to, the following:
or a pharmaceutically acceptable salt thereof.
Compounds described as specific inhibitors of COX-2 and thus useful in the present invention and methods for their synthesis are described in the following patents, pending applications and publications, which are incorporated herein by reference: WO 94/15932, published on 21/7/1994; U.S. patent No. 5,344,991, granted 6/1994; U.S. Pat. No. 5,134,142, granted 7/28/1992; U.S. patent No. 5,380,738, granted on 10/1/1995; U.S. patent No. 5,393,790, entitled 20/2 in 1995; U.S. Pat. No. 5,466,823, granted on month 11 and 14 of 1995; U.S. Pat. No. 5,633,272, granted 5 months 27 of 1997; and U.S. Pat. No. 5,932,598, granted on month 8, 3, 1999.
Compounds which are specific inhibitors of COX-2 and therefore useful in the present invention and methods for their synthesis are described in the following patents, pending applications and publications, which are incorporated herein by reference: U.S. patent No. 5,474,995, entitled 12/1995; U.S. patent No. 5,861,419, granted 1/19/1999; U.S. patent No. 6,001,843, granted 12/14/1999; U.S. patent No. 6,020,343, granted 2/1/2000; U.S. patent No. 5,409,944, entitled 25/4 in 1995; U.S. patent No. 5,436,265, entitled 25/7 in 1995; U.S. patent No. 5,536,752, entitled 16/7/1996; U.S. patent No. 5,550,142 entitled 27/8/1996; U.S. patent No. 5,604,260, granted 2/18/1997; U.S. patent No. 5,698,584, entitled 16/12/1997; and U.S. patent No. 5,710,140, entitled 1/20/1998.
Other examples of angiogenesis inhibitors include, but are not limited to: endostatin, ukrain, ranpirnase, IM862, 5-methoxy-4- [ 2-methyl-3- (3-methyl-2-butenyl) oxiranyl (oxiranyl) ] -1-oxaspiro (oxaspiro) [2, 5] oct-6-yl (chloroacetyl) carbamate, acetyl dinanaline, 5-amino-1- [ [3, 5-dichloro-4- (4-chlorobenzoyl) phenyl ] -methyl ] -1H-1, 2, 3-triazole-4-carboxamide, CM101, squalamine, combretastatin, RPI4610, NX31838, sulfated mannopentaphosphate, 7- (carbonyl-bis [ imino-N-methyl-4, 2-pyrrolinocarbonyl-imino [ N-methyl-4, 2-pyrrole ] -carbonylimino ] -bis- (1, 3-naphthalenedisulfonate), and 3- [ (2, 4-dimethylpyrrol-5-yl) methylene ] -2-indolinone (SU 5416).
As used above, "integrin inhibitors" means that physiological ligands and alpha can be selectively antagonized, inhibited, or hinderedvβ3Compounds that selectively antagonize, inhibit, or block the binding of integrins to alphavβ5Compounds that antagonize, inhibit, or block the binding of integrins to alphavβ3Integrins and alphavβ5A compound which binds to both integrins,And compounds that antagonize, inhibit, or block the activity of specific integrins expressed on capillary endothelial cells. The term also refers to antagonists of the following integrins: alpha is alphavβ6、αvβ8、α1β1、α2β1、α5β1、α6β1And alpha6β4Integrins. The term also refers to antagonists of any combination of the following integrins: alpha is alphavβ3、αvβ5、αvβ6、αvβ8、α1β1、α2β1、α5β1、α6β1And alpha6β4Integrins.
Some specific examples of tyrosine kinase inhibitors include: n- (trifluoromethylphenyl) -5-methylisoxazole-4-carboxamide, 3- [ (2, 4-dimethylpyrrol-5-yl) methine ] indolin-2-one, 17- (allylamino) -17-demethoxygeldanamycin, 4- (3-chloro-4-fluorophenylamino) -7-methoxy-6- [3- (4-morpholinyl) propoxy ] quinazoline, N- (3-ethynylphenyl) -6, 7-bis (2-methoxyethoxy) -4-quinazolinamine, BIBX1382, 2,3, 9, 10, 11, 12-hexahydro-10- (hydroxymethyl) -10-hydroxy-9-methyl-9, 12-epoxy-1H-isoindolo [1, 2, 3-fg:3 ', 2', 1 '-kl ] pyrrolo [3, 4-i ] [1, 6] benzodiazocine-1-one, SH268, genistein, ST1571, CEP2563, 4- (3-chlorophenylamino) -5, 6-dimethyl-7H-pyrrolo [2, 3-d ] pyrimidinemethanesulfonate, 4- (3-bromo-4-hydroxyphenyl) amino-6, 7-dimethoxyquinazoline, 4- (4' -hydroxyphenyl) amino-6, 7-dimethoxyquinazoline, SU6668, SU 48, STI571A, N-4-chlorophenyl-4- (4-pyridylmethyl) -1-phthalazinamine, And EMD 121974.
The compounds may also be used alone or in combination with platelet fibrinogen receptor (GP lib/IIIa) antagonists such as tirofiban to inhibit metastasis of cancer cells. Tumor cells can activate platelets in large amounts through the production of thrombin. This activation is associated with the release of VEGF. VEGF release enhances metastasis by increasing extravasation at the point of adhesion to the vascular endothelium (Amirkhosravi, Platelelets 10, 285-292, 1999). Thus, the present compounds may be used to inhibit metastasis alone or in combination with a GP lib/IIIa antagonist. Examples of other fibrinogen receptor antagonists include: abciximab, eptifibatide, sirafiban, lamifiban, lotrafiban, chromaffin, and CT 50352.
"DNA methyltransferase inhibitor" refers to a compound that inhibits methylation of the cytosine, the DNA base, at the C-5 position of the base by DNA methyltransferase. Examples of such DNA methyltransferase inhibitors include the compounds disclosed in U.S. patent nos. 6,329,412 and 6,268,137. Specific DNA methyltransferase inhibitors include 5-azacytosine and zebularine
If formulated as a fixed dose, such combination products employ the compounds of the present invention within the dosage ranges described above, and the other pharmaceutically active agents within the approved dosage ranges. Alternatively, when the combination formulation is not appropriate, the compounds of the present invention may be used sequentially with known pharmaceutically acceptable agents.
The term "administration" and variants thereof (e.g., "administering" a compound) with respect to a compound of the invention refers to introducing the compound or a prodrug thereof into an animal system in need of treatment. When a compound of the invention or a prodrug thereof is provided with one or more active agents (e.g., cytotoxic agents and the like), "administration" and variations thereof are understood to include the simultaneous and sequential introduction of the compound or prodrug thereof and the other agent, respectively.
The term "composition" as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
The compounds of the present invention may also be co-administered with other known therapeutic agents selected for their particular use for the condition being treated. For example, the compounds of the present invention may also be co-administered with other known cancer therapeutic agents selected for their particular use for the condition being treated. Included in this combination of therapeutic agents is the combination of a farnesyl-protein transferase inhibitor disclosed in U.S. Pat. No. 6,313,138 and an antineoplastic agent. It is also understood that such combinations of antineoplastic agents and farnesyl-protein transferase inhibitors can be used in conjunction with other methods of treating cancer and/or tumors, including radiation therapy and surgery.
Examples of antineoplastic agents generally include microtubule stabilizing drugs (e.g., paclitaxel (also known as Taxol)) Docetaxel (also known as Taxotere)Epothilone A, epothilone B, desoxyepothilone A, desoxyepothilone B, or derivatives thereof); a microtubule disrupting agent; an alkylating agent; an antimetabolite; epidophyllotoxin; an anti-tumor enzyme; a topoisomerase inhibitor; procarbazine; mitoxantrone; a platinum coordination complex; biological response modifiers and growth inhibitors; hormone/anti-hormone therapeutics and hematopoietic growth factors.
Examples of classes of antineoplastic agents include: such as anthracyclines, vinca drugs, mitomycins, bleomycin, cytotoxic nucleosides, taxanes, macrolides, discodermolides, pteridines, diynenes, and podophyllotoxins. Particularly useful members of these classes include: such as doxorubicin, carminomycin, daunorubicin, aminopterin, methotrexate, methopterin, dichloro-methotrexate, mitomycin C, Pofimycin, HerceptinoRituxan5-fluorouracil, 6-mercaptopurine, gemcitabine, cytarabine and podophyllumToxins or podophyllotoxin derivatives such as colchicine, etoposide phosphate or teniposide, melphalan, vinblastine, vincristine, vinisovinblastine, vindesine, vinblastine, taxol, etc. Other useful antineoplastic agents include: estramustine, cisplatin, carboplatin, cyclophosphamide, bleomycin, tamoxifen, ifosfamide, melphalan, altretamine, thiotepa, cytarabine, idatrexate, trimetrexate, dacarbazine, L-asparaginase, camptothecin, CPT-11, topotecan, ara-C, bicalutamide, flutamide, leuprolide, pyridobenzindole derivatives, interferons, and interleukins. A preferred class of antineoplastic agents are taxanes, and a preferred antineoplastic agent is paclitaxel.
Radiation therapy, including X-rays or gamma-rays, provided from an applied beam or by implantation of a small radioactive source, may also be used in combination with the compounds of the present invention to treat cancer.
Detailed Description
Examples
The following formulations and examples are given to enable those skilled in the art to more clearly understand and practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative thereof.
Synthetic examples
Example 1
Synthesis of N-hydroxy-4- (2-phenylcarbonylamino-ethoxy) benzamide
Step 1
To a solution of 2-aminoethanol (3.1g, 50mmol) in THF (10ml) was added a solution of tert-butoxycarbonyl anhydride (10.9g, 50mmol) in THF (150 ml). The reaction mixture was stirred for 3h, then diluted with ethyl acetate and washed with 0.5M aqueous HCl and brine. With MgSO4The organic layer was dried, filtered and concentrated in vacuo to give 2-N-Boc-aminoethanol, which was used directly in the next step.
Step 2
To a solution of triphenylphosphine (17.7g, 67.5mmol) in dry THF (135ml) was added DIAD (13.6g, 67.5 mmol). The solution was stirred until a white precipitate formed (2 to 10 min). After a further 60min, a solution of 2-N-Boc-amino-ethanol (7.2g, 45mmol) and methyl 4-hydroxybenzoate (6.8g, 45mmol) in THF (25ml) was added and stirring continued for 5 h. The reaction mixture was concentrated in vacuo and purified by flash chromatography to give methyl 4- (2-N-Boc-aminoethoxy) benzoate. Alternatively, the crude material can be used directly in the next step.
Step 3
To a solution of crude methyl 4- (2-N-Boc-aminoethoxy) benzoate in methanol (20ml) was added 4M HCl/dioxane (180 ml). After stirring for 3h, diethyl ether (300ml) was added to give a white precipitate. The solid was collected and suspended in ethyl acetate and stirred for 15-20 min. The solid was collected again and dried under high vacuum to give 6.3g (60% over 2 steps) of methyl 4- (2-aminoethoxy) benzoate hydrochloride.
Step 4
To a suspension of methyl 4- (2-amino-ethoxy) benzoate hydrochloride (0.232g, 1mmol) in THF (6ml) was added benzoyl chloride (0.140g, 1mmol) followed by triethylamine (0.121g, 1.2 mmol). The reaction mixture was stirred for 1h, then diluted with ethyl acetate. The organic layer was washed with 0.5M aqueous HCl, saturated sodium bicarbonate solution, and brine. The organic layer was concentrated in vacuo to give methyl 4- (2-phenylcarbonylamino-ethoxy) benzoate, which was used directly in the next step.
Step 5
To a solution of crude methyl 4- (2-phenylcarbonylamino-ethoxy) benzoate (0.5mmol) in a 1: 1 mixture of THF/methanol (20ml) was added 50 wt.% aqueous hydroxylamine (3ml) followed by 1M aqueous NaOH (1ml) to adjust the pH to 10-11. The reaction mixture was stirred for 14h, neutralized with 6M aqueous HCl to pH 7-8 and concentrated in vacuo. The precipitate was collected and purified by HPLC to give the title compound as a white solid.
1H NMR(DMSO-d6): 8.69(t, J ═ 5.8Hz, 1H), 7.83(d, J ═ 7.5Hz, 2H), 7.69(d, J ═ 9.1Hz, 2H), 7.46(m, 3H), 6.99(d, J ═ 9.1Hz, 2H), 4.16(t, J ═ 5.8Hz, 2H), 3.63(q, J ═ 5.8Hz, 2H), EM (calculated): 300.1; MS (ESI) m/e: 301.1(M-1)+，299.0(M+1)-.
The procedure was as described above for steps 1-4 of example 1, but using (S) - (+) -2-amino-1-butanol instead of 2-aminoethanol to give methyl 4- (2S-aminobutoxy) benzoate hydrochloride.
Example 2
Synthesis of N-hydroxy-4- [2- (benzofuran-2-yl-carbonylamino) -ethoxy ] -benzamide
Step 1
Benzofuran-2-carboxylic acid (0.162g, 1mmol), EDC & HCl (0.268g, 1.4mmol) and HOBT & H2A mixture of O (0.203g, 1.5mmol) in DMF (6ml) was stirred for 2 h. Methyl 4- (2-aminoethoxy) benzoate hydrochloride (0.232g, 1mmol) was added followed by triethylamine (0.121g, 1.2 mmol). The reaction mixture was stirred for 2h, then diluted with ethyl acetate and washed with saturated sodium bicarbonate solution and brine. The organic layer was concentrated in vacuo and the crude 4- [2- (benzofuran-2-ylcarbonylamino) ethoxy]Conversion of benzoate esters as in example 1 aboveThe title compound as described in step 5.
1H NMR(DMSO-d6)11.05(s, 1H), 8.92(t, J ═ 5.6Hz, 1H), 8.88(s, 1H), 7.76(d, J ═ 8.0Hz, 1H), 7.70(d, J ═ 9.2Hz, 2H), 7.64(d, J ═ 8.0Hz, 1H), 7.55(s, 1H), 7.46(t, J ═ 6.8Hz, 1H), 7.32(t, J ═ 8.0Hz, 1H), 7.01(d, J ═ 8.2Hz, 2H), 4.18(t, J ═ 5.6Hz, 2H), 3.67(m, 2H), EM (calculated): 340.1 of the total weight of the mixture; MS (ESI) m/e: (M +1H)+：341.0，(M-1H)-：339.1.
Example 3
Synthesis of N-hydroxy-4- [2- (benzothien-2-yl-carbonylamino) -ethoxy ] -benzamide
To a suspension of methyl 4- (2-aminoethoxy) benzoate hydrochloride (0.232g, 1mmol) in THF (6ml) was added benzothiophene-2-carbonyl chloride (0.150g, 1mmol) followed by triethylamine (0.121g, 1.2 mmol). The reaction mixture was stirred for 1h and diluted with ethyl acetate (50 ml). The organic layer was washed with 0.5M aqueous HCl, saturated sodium bicarbonate solution and brine. The organic layer was concentrated in vacuo to convert crude methyl 4- [2- (benzothien-2-yl-carbonylamino) ethoxy ] benzoate to the title compound as described in step 5 of example 1 above.
The procedure described in example 3 above, but using methyl 4- (2S-aminobutoxy) benzoate hydrochloride in place of methyl 4- (2-aminoethoxy) benzoate hydrochloride and cinnamoyl chloride in place of benzothiophene-2-carbonyl chloride, gave N-hydroxy-4- [2S- (trans-cinnamoylamino) butoxy ] benzamide.
Example 4
Synthesis of N-hydroxy-4- [2- (3-dimethylaminobenzofuran-2-ylcarbonylamino) -ethoxy ] -benzamide
Step 1
To a solution of 3-methyl-benzofuran-2-carboxylic acid (0.98g, 5.6mmol) and 5 drops of DMF in THF (25ml) was added oxalyl chloride (0.53ml, 6.1 mmol). After stirring the solution at room temperature for 1h, methanol (20ml) and TEA (7ml) were added. The slurry was stirred at room temperature overnight, then concentrated and dissolved in ethyl acetate (100ml) with dilute NaHCO3(100ml) washing. The organic layer was MgSO4Dried, filtered and concentrated to collect methyl 3-methylbenzofuran-2-carboxylate (1g) as a brown solid. The crude methyl ester was used without further purification.
Step 2
Methyl 3-methylbenzofuran-2-carboxylate (1.0g, 5.3mmol), NBS (0.95g, 5.3mmol) and AIBN (87mg, 0.53mmol) in CCl4(40ml) the solution was heated to reflux for 3h, then cooled to room temperature and concentrated. The residue was dissolved in ethyl acetate (100ml) and washed with water (100 ml). The organic layer was MgSO4Dried, filtered and concentrated to collect methyl 3-bromomethylbenzofuran-2-carboxylate (1.55g) as a brown/yellow solid which was used in the next step without further purification.
Step 3
Methyl 3-bromomethylbenzofuran-2-carboxylate (269mg, 1mmol) was dissolved in anhydrous DMF and added to a 2M dimethylamine/THF solution (1.5ml, 3 mmol). After 1-2h, the reaction was diluted with EtOAc and washed with saturated NaHCO3The aqueous solution and brine were washed twice. The organic extract is extracted with Na2SO4Dried and then concentrated in vacuo. The crude product was purified by silica gel column (5% MeOH in dichloromethane) to give methyl 3-dimethylaminomethylbenzofuran-2-carboxylate (131 mg).
Step 4
To a solution of methyl 3-dimethylaminomethylbenzofuran-2-carboxylate (131mg, 0.56mmol) in MeOH was added aqueous 1N NaOH until the solution pH was 13. The reaction mixture was stirred for 60-90 min. After completion, the reaction mixture was acidified to pH 3 with aqueous HCl and concentrated to dryness to give 3-dimethylaminomethylbenzofuran-2-carboxylic acid as the hydrochloride salt, which was used in the next step without further purification.
Step 5
To 3-dimethylaminomethylbenzofuran-2-carboxylic acid (140mg, 0.56mmol) were added EDC. HCl (150mg, 0.784mmol) and HOBt. H2O (114mg, 0.84mmol) in anhydrous DMF. The reaction mixture was stirred for 30-60min, then (4- (2-ethoxyamine)) methyl benzoate hydrochloride (130mg, 0.56mmol) and triethylamine (94 μ L, 0.672mmol) were added and the reaction stirred overnight. The reaction mixture was diluted with EtOAc and saturated NaHCO3The aqueous solution and brine were washed twice. The organic extract was concentrated in vacuo to give 4- [2- (3-dimethylaminobenzofuran-2-yl-carbonylamino) ethoxy]Methyl benzoate, which can be used without further purification.
Step 6
To a solution of crude 4- [2- (3-dimethylaminobenzofuran-2-yl-carbonylamino) -ethoxy ] -benzoic acid methyl ester in MeOH and THF was added an excess of aqueous hydroxylamine solution and aqueous NaOH solution to give a pH of 10-11. The reaction mixture was stirred overnight, then neutralized to pH 7-8 with hydrochloric acid and concentrated in vacuo. The residue was dissolved in acetonitrile and water and purified by preparative HPLC to give the title compound (107 mg).
1H NMR(400MHz，DMSO-d6)9.88(m, 1H), 9.31(t, J ═ 6.0Hz, 1H), 8.04(d, J ═ 7.6Hz, 1H), 7.70(m, 3H), 7.57(t, J ═ 7.6Hz, 1H), 7.45(t, J ═ 7.6Hz, 1H), 6.99(d, J ═ 9.2Hz, 2H), 4.76(d, J ═ 4.8Hz, 2H), 4.23(t, J ═ 6.0Hz, 2H), 3.71(m, 2H), 2.84(s, 3H), 2.83(s, 3H). EM (calculated): 397.2; MS (ESI) M/e (M +1H)+：398.1，(M-1H)-：396.2.
Example 5
Synthesis of N-hydroxy-4- {2- [3- (2, 2, 2-trifluoroethoxymethyl) benzofuran-2-yl-carbonylamino ] ethoxy } benzamide
Step 1
Sodium hydride (15mg, 0.56mmol) was suspended in anhydrous DMF under N2(g) Stirring the mixture. 2, 2, 2-trifluoroethanol (270. mu.L, 3.7mmol) was added and after stirring the reaction mixture for 15-20min, methyl 3-bromomethylbenzofuran-2-carboxylate was added. After 8h, 1N NaOH aqueous solution was added and the reaction mixture was stirred for 10-15 min. The reaction mixture was acidified to pH 3 with hydrochloric acid and the product was extracted with EtOAc. Na for organic layer2SO4Dried and concentrated in vacuo to give 3- (2, 2, 2-trifluoroethoxymethyl) benzofuran-2-carboxylic acid (38mg) which was used without further purification.
Step 2
To a solution of 3- (2, 2, 2-trifluoroethoxymethyl) benzofuran-2-carboxylic acid (38mg, 0.139mmol) in anhydrous DMF were added EDC. HCl (37mg, 0.195mmol) and HOBt. H2O (26mg, 0.195 mmol). After 60-90min, (4- (2-ethoxyamine)) benzoic acid methyl ester hydrochloride (32mg, 0.139mmol) and triethylamine (23 μ L, 0.167mmol) were added and the reaction mixture was stirred for 1-2 h. The reaction mixture was diluted with EtOAc and saturated NaHCO3The aqueous solution was washed twice and the organic extracts were concentrated to give 4- {2- [3- (2, 2, 2-trifluoroethoxymethyl) benzofuran-2-yl-carbonylamino]Ethoxy } benzoic acid methyl ester, which can be used without further purification.
Step 3
4- {2- [3- (2, 2, 2-trifluoroethoxymethyl) benzofuran-2-yl-carbonylamino ] -ethoxy } -benzoic acid ester was dissolved in MeOH and excess aqueous hydroxylamine and aqueous NaOH were added to give a pH of 10-11. After stirring overnight, the reaction mixture was neutralized to pH 7-8 with hydrochloric acid. The reaction mixture was concentrated in vacuo to give a solid, which was collected and washed with water, then dissolved in acetonitrile and water and purified by preparative HPLC to give the title compound (35 mg).
1H NMR(400MHz，DMSO-d6)11.04(s, 1H), 8.95(t, J ═ 5.6Hz, 1H), 8.89(s, 1H), 7.81(d, J ═ 7.6Hz, 1H), 7.70(d, J ═ 8.8Hz, 2H), 7.63(d, J ═ 8.8Hz, 1H), 7.50(t, J ═ 8.8Hz, 1H), 7.36(t, J ═ 8.0Hz, 1H), 7.00(d, J ═ 9.2Hz, 2H), 5.25(s, 2H), 4.18(m, 4H), 3.67(m, 2H) EM (calculated): 452.1; MS (ESI) M/e (M +1H)+：453.0，(M-1H)-：451.0.
Example 6
Synthesis of N-hydroxy-4- {2- [5- (2-pyrrolidin-1-ylethoxy) benzofuran-2-ylcarbonylamino ] ethoxy } benzamide
Step 1
5-Methoxybenzofuran-2-carboxylic acid (5.04g, 26mmol) was weighed into a 200ml round bottom flask, which was equipped with a stir bar, septum and nitrogen inlet. Anhydrous MeOH (50ml) was added under a nitrogen atmosphere. The solution was cooled in an ice bath and thionyl chloride was added dropwise with vigorous stirring. After stirring at room temperature for 72h, the reaction mixture was poured into water (150ml) and a white solid was collected. The solid was dissolved in toluene (100ml) and the solution was taken up in 1M NaHCO3And brine, over MgSO4And (5) drying. The organic layer was removed to give methyl 5-methoxybenzofuran-2-carboxylate as a white solid (5.15 g).
Step 2
In a nitrogen atmosphere, 5-methoxybenzofuran-A solution of methyl 2-carboxylate (5.15g, 25mmol) in dry dichloromethane (15ml) was cooled to-40 ℃. Using a syringe pump to pump the CH of boron tribromide2Cl2The solution (27ml, 1.0M) was added over 1 h. The reaction mixture was allowed to warm to room temperature. After 16h, the reaction mixture was cooled in an ice bath and quenched with MeOH (15 ml). The reaction mixture was poured into brine (100ml) and extracted with EtOAc. The organic extract was extracted with anhydrous MgSO4Drying and removing the solvent by a rotary evaporator. The residue was triturated with hexanes, the yellow solid filtered, and dissolved in anhydrous MeOH (30 ml). The solution was cooled in an ice bath and thionyl chloride (1.9ml, 26mmol) was added dropwise. After 72h, water (100ml) was added and the solid collected. At 300cm3The crude product was purified on silica gel using EtOAc in a 5 × 15cm plug to give methyl 5-hydroxy-benzofuran-2-carboxylate (4.53 g).
Step 3
Anhydrous tetrahydrofuran (15ml) was added to a mixture of methyl 5-hydroxybenzofuran-2-carboxylate (1.10g, 5.7mmol), triphenylphosphine (1.50g, 5.7mmol) and 1- (2-hydroxyethyl) -pyrrolidine (0.66g, 5.7mmol) under a nitrogen atmosphere. Diisopropyl azodicarboxylate (1.15ml, 5.8mmol) was slowly added to the solution at room temperature. After 2 days, the solvent was removed and the residue was dissolved in Et2EtOAC in a 2: 1 mixture (150 ml). The solution was washed with 1.0M aqueous NaOH. The product was extracted into 1.0M hydrochloric acid and the combined acid extracts were extracted with Et2And O washing. The extract was cooled and the pH of the extract was adjusted to pH 12 with 50% aqueous NaOH. By CH2Cl2Extracting the alkaline solution, and extracting the organic layer with anhydrous MgSO4Drying and concentration gave methyl 5- (2-pyrrolidin-1-yl-ethoxy) benzofuran-2-carboxylate (0.96g) as an amber solid.
Step 4
To an ice-cooled solution of methyl 5- (2-pyrrolidin-1-ylethoxy) benzofuran-2-carboxylate (960mg, 3.3mmol) in anhydrous ethylene glycol dimethyl ester (10ml) was added dropwise degassed aqueous lithium hydroxide solution (2.0ml, 2.0M). After stirring at room temperature for 4h, the solution was cooled and the pH adjusted to 2 with 4.0M HCl in dioxane. A gummy brown precipitate formed. The solvent was removed and the gum residue was frozen and lyophilized. The brown solid was dissolved in boiling 2-propanol (90ml) and the hot solution filtered and then cooled to give 5- (2-pyrrolidin-1-yl-ethoxy) -benzofuran-2-carboxylic acid as a beige needle (528 mg). An additional 153mg was obtained from the mother liquor.
Step 5
In a 20ml vial, to a solution of 5- (2-pyrrolidin-1-ylethoxy) benzofuran-2-carboxylic acid (156mg, 0.50mmol) and methyl 4- (2-aminoethoxy) benzoate hydrochloride (129mg, 0.56mmol) in DMF (4.5ml) was added diisopropylethylamine (0.88ml, 5.1 mmol). Adding O- (7-azabenzotriazol-1-yl) -1, 1, 3, 3-tetramethylureaSolution of hexafluorophosphate (740 μ L, 0.82M, 0.61mmol) in DMF gave a bright yellow solution. The vial was purged with nitrogen and stirred at room temperature for 18 h. The solution was removed and the residue was dissolved in EtOAc (25mL) with H2O、1.0M K2CO3Aqueous solution, and brine wash. The organic layer was dried over anhydrous MgSO4Dried and the solvent removed on a rotary evaporator. Column chromatography on silica gel using 93: 5: 2 CH2Cl2MeOH TEA eluent to purify the residue to give 4- {2- [5- (2-pyrrolidin-1-ylethoxy) benzofuran-2-carbonylamino]-ethoxy } -benzoic acid methyl ester as a beige solid (174 mg).
Step 6
To a solution of 4- {2- [5- (2-pyrrolidin-1-ylethoxy) benzofuran-2-carbonylamino ] -ethoxy } -benzoic acid methyl ester (169mg, 0.37mmol) in methanol (8ml) and tetrahydrofuran (4ml) were added an aqueous solution of hydroxylamine (2.9ml, 50% by weight solution) and a 4.0M aqueous solution of sodium hydroxide (0.65 ml). After stirring for 18h, the organics were removed, the aqueous solution was cooled in an ice/water bath and the pH adjusted to-8 with 4.4ml of 1.0M hydrochloric acid to give a precipitate. The heterogeneous solution was warmed to room temperature and acetonitrile was added until the precipitate dissolved. The solution was chromatographed using C-18 reverse phase HPLC. The fractions having an absorption at 214nm were collected, frozen, and lyophilized to give the title compound (31 mg).
1H NMR(400MHz，DMSO-d6): 11.05(s, 1H), 10.4(s, 1H), 8.91(s, 2H), 7.70(d, 2H, J ═ 7.4), 7.59(dd, 1H, J ═ 3.7, 9.1Hz), 7.51(d, 1H, J ═ 3.7Hz), 7.35(s, 1H), 7.13(d, 1H, J ═ 9.0Hz), 7.00(d, 2H, J ═ 7.4Hz), 4.37(m, 2H), 4.18(m, 2H), 3.62(m, 6H), 3.12(m, 2H), 2.02(m, 2H), 1.89(m, 2H), EM (calculated value): 453.2; MS (ESI) M/e (M +1H)+：454.1，(M-1H)-：452.2.
Example 7
Synthesis of N-hydroxy-4- [2- (3-dimethylaminobenzofuran-2-ylcarbonylamino) -ethoxy ] -benzamide hydrochloride
Step 1
Tert-butyl (2-hydroxyethyl) carbamate (152.0g, 0.942mol) and methyl 4-hydroxy-benzoate (174.0g, 1.12mol) were dissolved in tetrahydrofuran (2000ml) and cooled to 0-5 ℃. Triphenylphosphine (292.8g, 1.116mol) was added to the cooled mixture. A solution of diisopropyl azodicarboxylate (246.0g, 1.218mol) in tetrahydrofuran (400ml) was added dropwise over 1-2 hours, keeping the temperature of the reaction below 10 ℃. After addition, the reaction was allowed to warm slowly to room temperature and stirred overnight. After the reaction was completed, the solvent was distilled off under reduced pressure, and the resulting oil was dissolved in ethanol (500ml) and ethyl acetate (2000 ml). Acetyl chloride (222.0g, 2.826mol) was added dropwise over 15 minutes and the temperature was raised to 40 ℃. The resulting suspension was stirred at 40 ℃ until the reaction was complete. After the reaction was complete, the resulting crystals were filtered on a crude glass frit and washed with ethyl acetate (300 ml). The material was dried in vacuo to give methyl 4- (2-aminoethoxy) benzoate hydrochloride (204.1g) as a white crystalline solid.
Step 2
Methyl 4- (2-aminoethoxy) benzoate hydrochloride (78.90g, 0.340mol) and 3-methylbenzofuran-2-carboxylic acid (60.0g, 0.340mol) were suspended in acetonitrile (360ml) and cooled to 0-5 ℃. Pyridine (137.6ml, 1.702mol) was added rapidly. A solution of phosphorus oxychloride (52.2g, 0.340mol) in acetonitrile (60ml) was added dropwise over 30-45 minutes, maintaining the temperature below 20 ℃. The reaction mixture was stirred for one hour and slowly warmed to room temperature. After the reaction was complete, the solution was added to a rapidly stirred mixture of chlorobenzene (1000ml) at 0-5 ℃ and 1N hydrochloric acid (1000 ml). The reaction mixture was stirred rapidly and allowed to warm to room temperature. The organic layer was washed with water, 3% potassium hydroxide, and additional water. Chlorobenzene (100ml) was added to the washed organic layer. The solvent (100ml) was then distilled at atmospheric pressure until the pot temperature reached 132 ℃. After cooling to room temperature, methyl 4- {2- [ (3-methylbenzofuran-2-carbonyl) amino ] ethoxy } benzoate was stored in solution for the next step.
Step 3
A solution of methyl 4- {2- [ (3-methylbenzofuran-2-carbonyl) amino ] ethoxy } benzoate (0.340mol) in chlorobenzene (1000ml) was treated with 2, 2' -azobisisobutyronitrile (5.60g, 0.017mol) and N-bromosuccinimide (75.76g, 0.426 mol). The resulting mixture was heated to 80 ℃ and stirred for one hour. After the reaction was complete, the reaction mixture was cooled to room temperature and washed with water, 3% sodium bisulfite and additional water. The solvent was distilled off under reduced pressure, cooled to room temperature, and methylene chloride was added to obtain methyl 4- {2- [ (3-bromo-methylbenzofuran-2-carbonyl) amino ] ethoxy } benzoate, which was used in the next step.
Step 4
A solution of methyl 4- {2- [ (3-bromomethylbenzofuran-2-carbonyl) amino ] ethoxy } benzoate (0.340mol) in chlorobenzene (200ml) and dichloromethane (800ml) was added dropwise over 30 minutes to a solution of 0-5 ℃ 2M dimethylamine in tetrahydrofuran (510ml, 1.022mol) to maintain the temperature below 20 ℃. The resulting mixture was stirred for one hour and allowed to warm to room temperature. After the reaction was completed, the reaction mixture was washed with 5% potassium carbonate and water. The solvent was distilled at atmospheric pressure until the pot temperature reached 100 ℃. After cooling to-50 ℃, acetonitrile (400ml) and ethyl acetate (400ml) were added to the pot. The reaction mixture was heated to reflux until all solids were dissolved. The reaction mixture was cooled to give methyl 4- {2- [ (3-dimethylaminomethyl-benzofuran-2-carbonyl) amino ] ethoxy } benzoate (76.6g) as an off-white powder.
Step 5
Methyl 4- {2- [ (3-dimethylaminomethylbenzofuran-2-carbonyl) amino ] ethoxy } benzoate (70.0g, 0.177mol) was suspended in methanol (350 ml). 50% potassium hydroxide (139.8g, 1.062mol) was added and the reaction mixture was heated to 60 ℃ until the reaction was complete. After cooling to room temperature, the resulting crystals were filtered on a coarse frit and washed with methanol. The crystals were dried in vacuo to give potassium 4- {2- [ (3-dimethylaminomethylbenzofuran-2-carbonyl) amino ] ethoxy } benzoate (72.0g) as a white solid.
Step 6
The potassium salt of 4- {2- [ (3-dimethylaminomethylbenzofuran-2-carbonyl) amino ] ethoxy } benzoic acid (20.0g, 0.0476mol) was suspended in N, N-dimethylformamide (100 ml). A solution of 4mol of hydrochloric acid in dioxane (11.9ml, 0.0476mol) was added to the suspension. After stirring at room temperature for 30 minutes, the reaction mixture was filtered through a medium frit. 1- [3- (dimethylamino) propyl ] -3-ethylcarbodiimide hydrochloride (10.94g, 0.0571mol) and 1-hydroxybenzotriazole (7.71g, 0.0571mol) were added to the solution, and the reaction mixture was stirred at room temperature for one hour. In a separate pot, hydroxylamine hydrochloride (13.2g, 1.904mol) was suspended in N, N-dimethylformamide (100ml) and treated with triethylamine (33.1ml, 2.380 mol). After stirring the reaction mixture for 1h, the salt was filtered off and the resulting solution was added to the above active acid solution and stirred at room temperature until the reaction was complete. After the product started to crystallize, methanol (150ml) was added slowly over 30 minutes. The reaction mixture was stirred at room temperature for 1h, then cooled to 0-5 ℃ and stirred for a further h. The crystals were filtered, washed with methanol (40ml) and then dried in vacuo to give 3-dimethylaminomethylbenzofuran-2-carboxylic acid [2- (4-hydroxy-carbamoylphenoxy) ethyl ] amide (11.88g) as a white solid. The crude material (13.25g, 0.033mol) was suspended in N, N-dimethylformamide (80ml), and heated to 100 ℃ to give a solution. After cooling, ethanol (80ml) was added dropwise over 30 minutes and the resulting suspension was allowed to cool for 1 hour. The crystals were filtered, washed with ethanol (40ml) and dried to give the pure product (9.82g) as a white solid.
Step 7
3-dimethylaminomethylbenzofuran-2-carboxylic acid [2- (4-hydroxy-carbamoylphenoxy) ethyl ] amide (22.7g, 0.057mol) was suspended in 2-propanol (220 ml). A portion of 12MHCl (5.2ml, 0.063mol) was added and the resulting mixture was heated under reflux. Water (44ml) was added dropwise until a homogeneous solution was obtained. The reaction mixture was allowed to cool and crystallize overnight. After cooling below 5 ℃ for 1h, the crystals were filtered, washed with 2-propanol and then dried in vacuo to give the title compound (22.0g) as a white solid.
Example 8
Synthesis of N-hydroxy-4- [2- (benzofuran-2-ylcarbonylamino) -ethylsulfanyl ] benzamide
Step 1
To a solution of diisopropyl azodicarboxylate (DIAD, 4.04g, 20mmol) in THF (100ml) was added triphenylphosphine (5.25g, 20mmol) at 0 deg.C. After 1h, a solution of Boc-ethanolamine (3.22g, 20mmol) in THF (10ml) was added. After 20min, a solution of methyl 4-mercaptobenzoate (3.86g, 20mmol) in THF (10ml) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated, and ethyl acetate (150ml) was added. The solution was treated with 1M HCl, saturated NaHCO3Washing with aqueous solution, brine, MgSO4DryingFiltered and evaporated to dryness. The oily yellow residue was eluted through a silica gel plug, (0-20 ethyl acetate in hexane as the mobile phase), and then the product was recrystallized from ether and hexane to give methyl 4- (2-tert-butoxycarbonylaminoethylsulfanyl) benzoate (4.00 g).
Step 2
A solution of methyl 4- (2-tert-butoxycarbonylaminoethylsulfanyl) benzoate (1.00g, 3.21mmol) in dichloromethane (8ml) was treated with HCl in dioxane (4M, 8ml, 10 eq) at room temperature for 3 h. Ether (100ml) was added and the mixture was filtered, washed with ether and sucked to dryness to give methyl 4- (2-aminoethylsulfanyl) benzoate hydrochloride.
Step 3
Methyl 4- (2-aminoethylsulfanyl) benzoate hydrochloride (0.248g, 1.00mmol) was combined at room temperature with a solution of benzofuran-2-carboxylic acid (0.162g, 1.00mmol) and HBTU (0.379g, 1.00mmol) in DMF (5 ml). Triethylamine (0.307ml, 2.2mmol) was added and the reaction mixture was stirred at room temperature overnight. Addition of saturated NaHCO3Aqueous solution (15ml) to give a precipitate, which was disintegrated by adding water (20 ml). The solid was filtered and the filter cake was dissolved in ethyl acetate. Residual water was removed by pipette and hexane was added to give 4- {2- [ (benzofuran-2-ylcarbonyl) -amino]Ethylsulfanyl } benzoic acid methyl ester (0.138g), a gum, which was used in the next step without further purification.
Step 4
To a solution of 4- {2- [ (benzofuran-2-yl-carbonyl) amino ] ethylsulfanyl } -benzoic acid methyl ester in THF (2ml) was added a 50% solution of hydroxylamine in water (4 ml). Methanol (2ml) and 0.1M NaOH (0.1ml) were added. The reaction mixture was stirred at room temperature for three days. The solvent was evaporated and the residue was crystallized from dichloromethane/ethyl acetate to give the title compound (46 mg).
1H NMR(DMSO-d6)：3.12(2H，m)；3.5(2H，m)；7.33(1H，t)；7.42(2H，d)；7.45(1H，m*)；7.53(1H，s)；7.62(1H，d)；7.7(2H，d)；7.78(1H，d)；8.96(1H，t)；8.99(1H，br.s).MS(M+1)：357.
Example 9
Synthesis of N-hydroxy-4- [2- (benzofuran-2-ylcarbonylamino) ethylsulfonyl ] benzamide
Step 1
To a solution of 4- (2-tert-butoxycarbonylaminoethylsulfanyl) -benzoic acid methyl ester (3.00g, 9.63mmol) in methanol/water (1: 1, 100ml) was added Oxone(13.03g, 21.19 mmol). After 48h, the methanol was removed under reduced pressure and the residue was taken up in ethyl acetate (150ml) and saturated NaHCO3Partitioned in aqueous solution (150 ml). The organic phase was washed with brine (100ml) and MgSO4Drying, filtration, concentration in vacuo and recrystallization of the residue from ethyl acetate/hexane afforded the product methyl 4- (2-tert-butoxycarbonylamino-ethylsulfonyl) benzoate (2.86 g).
Step 2
A solution of methyl 4- (2-tert-butoxycarbonylaminoethylsulfonyl) benzoate (2.86g, 8.33mmol) in dichloromethane (20ml) was treated with 4M HCl in dioxane (20ml) for 2 h. Ether (200ml) was added, the suspension filtered, washed with ether (2 × 50ml), hexane (50ml) and sucked to dryness to give methyl 4- (2-aminoethylsulfonyl) benzoate hydrochloride (2.23g) which was combined with the benzofuran 2-carboxylic acid described above to give the title compound. MS (M + 1): 388.
the following compounds of tables I-IV were prepared as described above for examples 1-3, but using the appropriate commercially available starting materials.
Table 1:
compound 1
1H NMR(400MHz，DMSO-d6)8.69(t, J ═ 5.8Hz, 1H), 7.83(d, J ═ 7.5Hz, 2H), 7.69(d, J ═ 9.1Hz, 2H), 7.46(m, 3H), 6.99(d, J ═ 9.1Hz, 2H), 4.16(t, J ═ 5.8Hz, 2H), 3.63(q, J ═ 5.8Hz, 2H), EM (calculated): 300.1; MS (ESI) m/e: 301.1(M-1)+，299.0(M+1)-.
Compound 2
1H NMR(400MHz，DMSO-d6)11.08(s, 1H), 8.92(s, 1H), 8.41(t, J ═ 6Hz, 1H), 7.74(d, J ═ 8.8Hz, 2H), 7.58(d, J ═ 6.8Hz, 2H), 7.46(d, J ═ 15.6Hz, 1H), 7.45-7.37(m, 3H), 7.03(d, J ═ 8.8Hz, 2H), 6.72(d, J ═ 15.6Hz, 1H), 4.13(t, J ═ 5.2Hz, 2H), 3.60(q, J ═ 5.6Hz, 2H), EM (calculated): 326.1, respectively; MS (ESI) M/e (M +1H)+：327.1，(M-1H)-：325.2.
Compound 3
1H NMR(400MHz，DMSO-d6)11.07(s，1H)，8.91(s，1H)，8.42(t，J＝4.8Hz，1H)，7.72(d，J＝8.4Hz，2H)，7.27(t，J＝7.2Hz，2.0Hz)，7.18(t，J＝7.2Hz，1H)，7.13(d，J＝7.2Hz，2H)，7.01(d，J＝8.8Hz，2H)，4.07(t，J＝5.6Hz，2H)，3.49(dq，J1＝5.6Hz，J2＝1.6Hz，2H)，2.28(ddd，J1＝4.0Hz，J2＝5.6Hz，J3＝9.6Hz，1H)，1.95(ddd，J1＝4.1Hz，J2＝5.2Hz，J3＝8.4Hz，1H)，1.39(ddd，J1＝4.0Hz，J2＝5.2Hz，J3＝9.2Hz，1H)，1.24(ddd，J1＝4.0Hz，J2＝6.4Hz，J310.4Hz, 1H) EM (calculated): 340.1 of the total weight of the mixture; MS (ESI) M/e (M +1H)+：341.2，(M-1H)-：339.2.
Compound 4
1H NMR(400MHz，DMSO-d6)11.08(s，1H)，8.92(s，1H)，8.31(t, J ═ 5.6Hz, 1H), 7.73(d, J ═ 9.2Hz, 2H), 7.52(d, J ═ 9.2Hz, 2H), 7.41(d, J ═ 15.6Hz, 1H), 7.03(d, J ═ 8.8Hz, 2H), 6.99(d, J ═ 8.8Hz, 2H), 6.55(d, J ═ 15.6Hz, 1H), 4.12(t, J ═ 5.6Hz, 2H), 3.81(s, 3H), 3.58(q, J ═ 5.6Hz, 2H), EM (calculated): 356.1; MS (ESI) M/e (M +1H)+：357.2，(M-1H)-：355.2.
Compound 5
1H NMR(400MHz，DMSO-d6)10.96(s, 1H), 8.80(s, 1H), 8.01(t, J ═ 4.8Hz, 1H), 7.61(d, J ═ 8.8Hz, 2H), 7.14-7.02(m, 5H), 6.86(d, J ═ 8.8Hz, 2H), 3.32(q, J ═ 5.6Hz, 2H), 2.71(t, J ═ 7.2, 2H), 2.30(t, J ═ 7.6Hz, 2H), EM (calculated): 328.1; MS (ESI) M/e (M +1H)+：329.2，(M-1H)-：327.0.
Compound 6
1H NMR(400MHz，DMSO-d6)11.11(s, 1H), 10.89(s, 1H), 8.95(br s, 1H), 8.22(t, J ═ 5.6Hz, 1H), 7.76(d, J ═ 8.8Hz, 2H), 7.56(d, J ═ 8.0Hz, 1H), 7.37(d, J ═ 8.4Hz, 1H), 7.22(d, J ═ 2.0Hz, 1H), 7.08(t, J ═ 7.6Hz, 1H), 7.02(d, J ═ 8.4Hz, 2H), 6.93(t, J ═ 8.4Hz, 1H), 4.09 (pseudo) t, J ═ 6.0Hz, 2H), 3.58(s, 2H), 3.50 (pseudo q, J ═ 5.6H, 2H): 353.1, respectively; MS (ESI) M/e (M +1H)+：353.9，(M-1H)-：252.0.
Compound 7
1H NMR(400MHz，DMSO-d6)11.11(s，1H)，8.80(t，J＝5.6Hz，1H)，7.82(d，J＝7.6Hz，1H)，7.81(d，J＝8.0Hz，1H)，7.76(d，J＝8.4Hz，2H)，7.19(t，J15.2Hz, 1H), 7.06(d, J-8.8 Hz, 2H), 4.21 (false t, J-6.0 Hz, 2H), 3.67 (false q, J-5.6 Hz, 2H), EM (calculated): 306.1; MS (ESI) M/e (M +1H)+：307.0，(M-1H)-：304.9.
Compound 8
1H NMR(400MHz，DMSO-d6)8.98(s, 1H), 8.9(t, J ═ 5.4Hz, 1H), 8.67(d, J ═ 4.6Hz, 1H), 8.16(d, J ═ 8.1Hz, 1H), 7.69(d, J ═ 8.9Hz, 2H), 7.48(m, 1H), 6.99(d, J ═ 8.9Hz, 2H), 4.17(t, J ═ 5.4Hz, 2H), 3.65(m, 2H). EM (calculated): 301.11, respectively; MS (ESI) M/e (M-1H)-：300.0.
Compound 9
1H NMR(400MHz，DMSO-d6)11.03(1H, s), 8.87(1H, bs), 8.74(1H, t, J ═ 5.6Hz), 7.93(2H, d, J ═ 8.0Hz), 7.75(2H, d, J ═ 8.0Hz), 7.69(3H, m), 7.47(1H, t, J ═ 8.0Hz), 7.39(2H, m), 6.99(2H, d, J ═ 8.9Hz), 4.18(2H, t, J ═ 5.6Hz), 3.66(2H, m). EM (calculated): 376.41, respectively; MS (ESI) M/e (M +1H)+：377.1，(M-1H)-：375.0.
Compound 10
EM (calculated): 376.1; MS (ESI) M/e (M +1)+：376.9，(M-1)-：375.1.
Compound 11
1H NMR(400MHz，DMSO-d6)11.11(s, 1H), 8.95(s, 1H), 8.84(t, J ═ 6.0Hz, 1H), 7.83(d, J ═ 4.0Hz, 1H), 7.77(d, J ═ 9.2Hz, 2H), 7.75(d, J ═ 7.2Hz, 2H), 7.59(d, J ═ 4.0Hz, 1H), 7.49 (false t, J ═ 7.2Hz, 2H), 7.41 (false t, J ═ 7.6Hz, 1H), 7.07(d, J ═ 8.8Hz, 2H), 4.22 (false t, J ═ 5.6Hz, 2H), 3.69 (false q, J ═ 5.2Hz, 2H), EM (calculated value): 382.1, respectively; MS (ESI) M/e (M +1H)+：383.1，(M-1H)-：381.0.
Compound 12
1H NMR(400MHz，DMSO-d6)11.05(s, 1H), 10.15(s, 1H), 8.36(t, J ═ 5.6Hz, 1H), 7.70(d, J ═ 8.8Hz, 2H), 7.32(m, 1H), 6.97(d, J ═ 8.8Hz, 2H), 6.92(m, 1H), 6.88(m, 1H), 4.04(t, J ═ 5.6Hz, 2H), 3.66(s, 2H), 3.45(m, 2H) · EM (calculated): 320.1 of the total weight of the mixture; MS (ESI) M/e (M +1H)+：320.9，(M-1H)-：319.0.
Compound 13
1H NMR(400MHz，DMSO-d6)11.04(s, 1H), 8.87(m, 2H), 8.45(s, 1H), 7.97(m, 4H), 7.71(d, J ═ 8.8Hz, 2H), 7.59(m, 2H), 7.02(d, J ═ 8.8Hz, 2H), 4.21(t, J ═ 5.6Hz, 2H), 3.71(m, 2H). EM (calculated): 350.1 of the total weight of the mixture; MS (EST) M/e (M +1H)+：350.9，(M-1H)-：349.1.
Compound 14
1H NMR(400MHz，DMSO-d6)11.04(s, 1H), 8.98(m, 2H), 8.52(m, 2H), 8.19(d, J ═ 8.8Hz, 1H), 8.08(d, J ═ 8.8Hz, 1H), 7.71(d, J ═ 8.8Hz, 2H), 7.62(m, 1H), 7.02(d, J ═ 8.8Hz, 2H), 4.22(t, J ═ 5.6Hz, 2H), 3.72(m, 2H) EM (calculated): 351.1, respectively; MS (ESI) M/e (M +1H)+：351.8，(M-1H)-：349.9.
Compound 15
EM (calculated): 383.1, respectively; MS (ESI) M/e (M +1)+：383.9，(M-1)-：382.2.
Compound 16
1H NMR(400MHz，DMSO-d6)11.04(s, 1H), 8.88(s, 1H), 8.61(t, J ═ 4.8Hz, 1H), 7.78(d, J ═ 8.4Hz, 2H), 7.70(d, J ═ 8.8Hz, 2H), 7.46(d, J ═ 8.8Hz, 2H), 6.99(d, J ═ 8.6Hz, 2H), 4.15(t, J ═ 5.6Hz, 2H), 3.62(m, 2H), 1.29(s, 9H), EM (calculated): 356.2; MS (ESI) M/e (M +1H)+：357.0，(M-1H)-：355.1.
Compound 17
1H NMR(400MHz，DMSO-d6)11.06(s，1H)，8.95(s，1H)，8.72(d，J＝5.2Hz，1H)，8.56(t，J＝4.8Hz，1H)，8.40(d，J＝7.6Hz，1H)，7.80(m，1H)，7.71(d，J＝8.8Hz，2H)，7.55(d，J＝16.0Hz，1H)，7.00(d，J＝8.8Hz，2H)，6.90(d，J＝16.0Hz，1H)，4.12(t，J ═ 5.6Hz, 2H), 3.59(m, 2H) EM (calculated): 327.1; MS (ESI) M/e (M +1H)+：328.1，(M-1H)-：326.1.
Compound 18
1H NMR(400MHz，DMSO-d6)11.04(s, 1H), 8.88(s, 1H), 8.73(t, J ═ 5.6Hz, 1H), 7.93(d, J ═ 9.2Hz, 2H), 7.69(m, 4H), 7.47(t, J ═ 2.4Hz, 2H), 7.01(d, J ═ 9.2Hz, 2H), 6.29(t, J ═ 2.4Hz, 2H), 4.18(t, J ═ 5.6Hz, 2H), 3.66(m, 2H), EM (calculated): 365.1, respectively; MS (ESI) M/e (M +1H)+：366.0，(M-1H)-：364.2.
Compound 19
1H NMR(400MHz，DMSO-d6)11.04(s, 1H), 8.53(t, J ═ 5.6Hz, 1H), 7.80(d, J ═ 9.2Hz, 2H), 7.70(d, J ═ 9.2Hz, 2H), 6.99(m, 4H), 5.95(m, 1H), 5.80(m, 1H), 4.96(s, 1H), 4.14(t, J ═ 5.6Hz, 2H), 3.60(m, 2H), 2.00(m, 3H), 1.72(m, 3H), EM (calculated): 396.2; MS (ESI) M/e (M +1H)+：397.1，(M-1H)-：395.2.
Compound 20
1H NMR(400MHz，DMSO-d6)11.08(s, 1H), 9.35(t, J ═ 5.6Hz, 1H), 8.25(d, J ═ 7.6Hz, 1H), 8.15(d, J ═ 8.0Hz, 1H), 7.73(d, J ═ 8.8Hz, 2H), 7.68-7.58(m, 2H), 7.03(d, J ═ 9.2Hz, 2H), 4.23 (false t, J ═ 6.4Hz, 2H), 3.74 (false q, J ═ 6.0Hz, 2H), EM (calculated): 357.1; MS (ESI) M/e (M +1H)+：358.1，(M-1H)-：356.0.
Compound 21
1H NMR(400MHz，DMSO-d6)11.07(s, 1H), 9.47(t, J ═ 5.6Hz, 1H), 7.90 (false t, J ═ 9.2Hz, 2H), 7.73(d, J ═ 8.8Hz, 2H), 4.59(td, J ═ 8.8Hz, 2H), and1＝7.6Hz，J2＝0.8Hz，1H)，7.52(td，J2＝8.0Hz，J21.2Hz, 1H), 7.03(d, J-8.8 Hz, 2H), 4.24(t, J-6.0 Hz, 2H), 3.72 (pseudo-q,j ═ 6.0Hz, 2H) EM (calculated): 341.1, respectively; MS (ESI) M/e (M +1H)+：342.1，(M-1H)-：340.2.
Compound 22
1H NMR(400MHz，DMSO-d6)11.08(s, 1H), 9.70(s, 1H), 8.91, (t, J ═ 5.6Hz, 1H), 7.72(d, J ═ 8.4Hz, 2H), 6.97(d, J ═ 8.4Hz, 2H), 4.10(m, 2H), 3.93(m, 2H), 3.54(m, 2H), 3.27(m, 2H), 3.08(m, 2H), 2.21(m, 1H), 2.01(m, 1H), 1.51(m, 10H), EM (calculated): 375.2, respectively; MS (ESI) M/e (M +1H)+：376.1，(M-1H)-：374.1.
Compound 23
1H NMR(400MHz，DMSO-d6)11.09(s, 1H), 8.35(d, J ═ 6.8Hz, 2H), 7.72(d, J ═ 9.2Hz, 2H), 7.25(d, J ═ 6.8Hz, 2H), 6.98(d, J ═ 9.2Hz, 2H), 4.10(t, J ═ 5.6Hz, 2H), 3.97(m, 2H), 3.54(m, 10H), EM (calculated): 399.2, respectively; MS (ESI) M/e (M +1H)+：400.1，(M-1H)-：398.1.
Compound 24
EM (calculated): 290.1 of the total weight of the mixture; MS (ESI) M/e (M +1)+：291.1，(M-1)-：289.2.
Compound 25
EM (calculated): 377.1; MS (ESI) M/e (M +1)+：377.9，(M-1)-：376.0.
Compound 26
EM (calculated): 377.1; MS (ESI) M/e (M +1)+：378.0，(M-1)-：375.9.
Compound 27
1H NMR(400MHz，DMSO-d6)11.04(s, 1H), 9.11(t, J ═ 5.6Hz, 1H), 7.70(d, J ═ 9.2Hz, 2H), 7.62(m, 2H), 7.29(m, 2H), 7.01(d, J ═ 9.2Hz, 2H), 4.21(t, J ═ 5.6Hz, 2H), 3.71(m, 2H). EM (calculated): 340.1 of the total weight of the mixture; MS (Mass Spectrometry)(ESI)m/e(M+1H)+：341.0，(M-1H)-：339.1.
Compound 28
EM (calculated): 289.1, respectively; MS (ESI) M/e (M +1H)+：290.0，(M-1H)-：287.8.
Compound 29
1H NMR(400MHz，DMSO-d6)11.04(s 1H)，10.43(s，1H)，8.62(t，J＝6.0Hz，1H)，7.94(d，J＝6.4Hz，2H)，7.853(m，4H)，7.70(d，J＝9.2Hz，2H)，7.60(m，1H)，7.52(m，2H)，7.00(d，J＝9.2Hz，2H)，4.16(t，J＝6.0Hz，2H)，3.63(dt，J1＝5.6Hz，J26.0Hz, 2H) EM (calculated): 419.2; MS (ESI) M/e (M +1H)+：420.2，(M-1H)-：418.3.
Compound 30
1H NMR(400MHz，DMSO-d6)11.04(s, 1H), 9.23(t, J ═ 6.0Hz, 1H), 9.01(s, 1H), 8.89(d, J ═ 6.8Hz, 2H), 8.38(d, J ═ 6.4Hz, 2H), 7.70(d, J ═ 9.2Hz, 2H), 7.00(d, J ═ 9.2Hz, 2H), 4.22(t, J ═ 5.6Hz, 2H), 3.71(m, 2H). EM (calculated): 384.1; MS (ESI) M/e (M +1H)+：384.9，(M-1H)-：382.9.
Compound 31
1H NMR(400MHz，DMSO-d6)11.04(s, 1H), 7.69(d, J ═ 8.4Hz, 2H), 7.56(t, J ═ 5.6Hz, 1H), 7.01(d, J ═ 8.8Hz, 2H), 4.01(t, J ═ 5.6Hz, 2H), 3.40(m, 2H), 1.95(m, 3H), 1.69(m, 12H), EM (calculated): 358.2, respectively; MS (ESI) M/e (M +1H)+：358.9，(M-1H)-：357.2.
Compound 32
EM (calculated): 336.09, respectively; MS (ESI) M/e (M-1H)-：335.3.
Compound 33
EM (calculated): 370.12, respectively;MS(ESI)m/e(M-1H)-：369.0.
compound 34
EM (calculated): 344.10, respectively; MS (ESI) M/e (M +1H)+：345.0，(M-1H)-：343.1.
Compound 35
EM (calculated): 360.13; MS (ESI) M/e (M-1H)-：359.1.
Compound 36
EM (calculated): 344.10, respectively; MS (ESI) M/e (M-1H)-：358.8.
Compound 37
EM (calculated): 336.09, respectively; MS (ESI) M/e (M +1H)+：337.2，(M-1H)-：335.0.
Compound 38
EM (calculated): 328.14 of the total weight of the powder; MS (ESI) M/e (M +1H)+：329.2，(M-1H)-：327.2.
Compound 39
EM (calculated): 368.03, respectively; MS (ESI) M/e (M-1H)-：367.0.
Compound 40
EM (calculated): 328.14 of the total weight of the powder; MS (ESI) M/e (M +1H)+：328.8，(M-1H)-：327.2.
Compound 41
EM (calculated): 364.08, respectively; MS (ESI) M/e (M +1H)+：365.1，(M-1H)-：363.2.
Compound 42
EM (calculated): 344.14, respectively; MS (ESI) M/e (M +1H)+：345.1，(M-1H)-：343.1.
Compound 43
EM (calculated): 344.14, respectively; MS (E)SI)m/e(M+1H)+：345.0，(M-1H)-：343.2.
Compound 44
EM (calculated): 348.11, respectively; MS (ESI) M/e (M +1H)+：348.8，(M-1H)-：346.9.
Compound 45
EM (calculated): 412.11, respectively; MS (ESI) M/e (M +1H)+：413.3，(M-1H)-：411.0.
Compound 46
EM (calculated): 412.11, respectively; MS (ESI) M/e (M +1H)+：413.2，(M-1H)-：411.1.
Compound 47
EM (calculated): 376.14, respectively; MS (ESI) M/e (M +1H)+：377.0，(M-1H)-：375.2.
Compound 48
EM (calculated): 339.12, respectively; MS (ESI) M/e (M +1H)+：340.1，(M-1H)-：338.3.
Compound 49
1H NMR(400MHz，DMSO-d6)11.53(s, 1H), 11.04(s, 1H), 8.12(d, J ═ 7.6Hz, 2H), 8.01(s, 1H), 7.70(d, J ═ 9.2Hz, 2H), 7.40(d, J ═ 8.0, Hz, 1H), 7.10(m, 2H), 7.017(d, J ═ 8.8Hz, 2H), 4.16(t, J ═ 5.6Hz, 2H), 3.64(m, 2H). EM (calculated): 339.1, respectively; MS (ESI) M/e (M +1H)+：340.0，(M-1H)-：338.1.
Compound 50
1H NMR(400MHz，DMSO-d6)9.37(s, 1H), 9.21(t, J ═ 5.2Hz, 1H), 9.02(s, 1H), 8.15(t, J ═ 9.2Hz, 2H), 7.94(m, 1H), 7.74(m, 3H), 7.02(d, J ═ 8.8Hz, 2H), 4.24(t, J ═ 5.6Hz, 2H), 3.75(m, 2H), EM (calculated): 351.1, respectively; MS (ESI) M/e (M +1H)+：352.0，(M-1H)-：349.9.
Compound 51
1H NMR(400MHz，DMSO-d6)11.11(s, 1H)9.09(d, J ═ 4.4Hz, 1H), 8.70(d, J ═ 7.6Hz, 1H), 8.65(d, J ═ 7.6Hz, 1H), 8.29(d, J ═ 8.0Hz, 1H), 7.79(m, 4H), 7.10(d, J ═ 8.8Hz, 2H), 4.30(t, J ═ 5.6Hz, 2H), 3.89(m, 2H). EM (calculated): 351.1, respectively; MS (ESI) M/e (M +1H)+：352.0，(M-1H)-：349.9.
Compound 52
1H NMR(400MHz，DMSO-d6)13.57(s, 1H), 11.04(s, 1H), 8.88(s, 1H), 8.53(t, J ═ 5.6Hz, 1H), 8.16(d, J ═ 8.0Hz, 1H), 7.70(d, J ═ 8.8Hz, 2H), 7.60(d, J ═ 8.4Hz, 1H), 7.40(t, J ═ 8.0Hz, 1H), 7.23(t, J ═ 8.0Hz, 1H), 7.01(d, J ═ 8.8Hz, 2H), 4.19(t, J ═ 6.0Hz, 2H), 3.68(m, 2H), EM (calculated): 340.1 of the total weight of the mixture; MS (ESI) M/e (M +1H)+：341.1，(M-1H)-：339.2.
Compound 53
1H NMR(400MHz，DMSO-d6)11.04(s, 1H), 8.89(m, 2H), 8.45(s, 1H), 7.93(s, 2H), 7.70(d, J ═ 8.4Hz, 2H), 7.01(d, J ═ 8.8Hz, 2H), 4.20(t, J ═ 5.6Hz, 2H), 3.69(m, 2H), EM (calculated): 341.1, respectively; MS (ESI) M/e (M +1H)+：341.8，(M-1H)-：340.0.
Compound 54
1H NMR(400MHz，DMSO-d6)9.07(s, 1H), 9.24(d, J ═ 8.0Hz, 1H), 8.53(m 1H), 8.03(m, 2H), 7.82(t, J ═ 6.8Hz, 1H), 7.71(m, 3H), 7.03(d, J ═ 8.4Hz, 2H), 4.24(t, J ═ 4.8Hz, 2H), 3.76(m, 2H), EM (calculated): 351.1, respectively; MS (ESI) M/e (M +1H)+：351.9，(M-1H)-：350.1.
Compound 55
1H NMR(400MHz，DMSO-d6)939(s, 1H), 9.11(s, 1H), 8.59(s, 1H), 8.25(m, 1H), 7.87(m, 2H), 7.70(m, 2H), 7.02(m, 2H), 4.23(s, 2H), 3.76(s, 2H) EM (calculated): 351.1, respectively; MS (ESI) M/e (M +1H)+：3518，(M-1H)-：349.9.
Compound 56
1H NMR(400MHz，DMSO-d6)11.04(s, 1H), 9.47(m, 1H), 9.23(m, 1H), 8.19(m, 2H), 7.98(m, 2H), 7.70(d, J ═ 8.8Hz, 2H), 7.02(d, J ═ 8.4Hz, 2H), 4.25(t, J ═ 5.2Hz, 2H), 3.78(m, 2H), EM (calculated): 352.1, respectively; MS (ESI) M/e (M +1H)+：352.8，(M-1H)-：350.9.
Compound 57
EM (calculated): 350.11, respectively; MS (ESI) M/e (M +1H)+：351.1，(M-1H)-：349.1.
Compound 58
EM (calculated): 351.12, respectively; MS (ESI) M/e (M +1H)+：352.2，(M-1H)-：350.0.
Compound 59
EM (calculated): 365.14, respectively; MS (ESI) M/e (M +1H)+：366.0，(M-1H)-：364.2.
Compound 60
EM (calculated): 368.12; MS (ESI) M/e (M +1H)+：369.0，(M-1H)-：367.1.
Compound 61
1H NMR(400MHz，DMSO-d6)11.04(s, 1H), 8.88(s, 1H), 8.68(t, J ═ 5.6Hz, 1H), 8.34(s, 1H), 8.14(s, 1H), 7.75(d, J ═ 8.0Hz, 1H), 7.70(d, J ═ 8.4Hz, 2H), 7.61(d, J ═ 8.0Hz, 1H), 7.01(d, J ═ 8.8Hz, 2H), 4.18(t, J ═ 6.0Hz, 2H), 3.66(m, 2H). EM (calculated): 340.1 of the total weight of the mixture; MS (ESI) M/e (M +1H)+：341.0，(M-1H)-：339.2.
Compound 62
1H NMR(400MHz，DMSO-d6)11.04(s, 1H), 8.11(m, 2H), 7.98(s, 1H), 7.70(d, J ═ 9.2Hz, 2H), 7.47(d, J ═ 7.6Hz, 1H), 7.20(t, J ═ 8.4Hz, 1H), 7.13(t, J ═ 6.8Hz, 1H), 7.01(d, J ═ 9.2Hz, 2H), 4.15(t, J ═ 6.0Hz, 2H), 3.82(s, 3H), 3.62(m, 2H), EM (calculated): 353.1, respectively; MS (ESI) M/e (M +1H)+：354.0，(M-1H)-：351.9.
Compound 63
1H NMR(400MHz，DMSO-d6)11.05(s, 1H), 9.14(t, J ═ 5.6Hz, 1H), 8.19(d, J ═ 8.4Hz, 1H), 8.08(d, J ═ 8.4Hz, 1H), 7.85(t, J ═ 8.4Hz, 1H), 7.69(m, 4H), 7.03(d, J ═ 8.8Hz, 2H), 4.24(t, J ═ 6.0Hz, 2H), 4.15(s, 3H), 3.78(m, 2H), EM (calculated): 381.1, respectively; MS (ESI) M/e (M +1H)+：381.9，(M-1H)-：380.1.
Compound 64
EM (calculated): 380.14, respectively; MS (ESI) M/e (M +1H)+：381.0，(M-1H)-：379.0.
Compound 65
EM (calculated): 380.14, respectively; MS (ESI) M/e (M +1H)+：381.2，(M-1H)-：378.9.
Compound 66
EM (calculated): 351.12, respectively; MS (ESI) M/e (M +1H)+：352.0，(M-1H)-：350.0.
Compound 67
1H NMR(400MHz，DMSO-d6)11.05(s, 1H), 8.26(t, J ═ 5.6Hz, 1H), 7.70(d, J ═ 8.8Hz, 2H), 7.41-7.35(m, 4H), 7.29(m, 1H), 7.21(s, 1H), 7.00(d, J ═ 9.2, 2H), 4.12(t, J ═ 6.0Hz, 2H), 3.54 (pseudo q, J ═ 6.0Hz, 2H), 2.01(s, 3H). EM (calculated): 340.1 of the total weight of the mixture; MS (ESI) M/e (M +1H)+：340.9，(M-1H)-：339.2.
Compound 68
1H NMR(400MHz，DMSO-d6)11.08(s，1H)，10.72(br s，1H)，8.81(t，J＝5.2Hz，1H)，7.94(dd，J1＝8.4Hz，J22.0Hz, 1H), 7.73(d, J ═ 8.8Hz, 2H), 7.32(s, 1H), 7.03(d, J ═ 9.2Hz, 2H), 4.60(s, 2H), 4.13 (false t, J ═ 5.6Hz, 2H), 3.70 (false q, J ═ 5.2Hz, 2H), 2.83(s, 6H), EM (calculated): 397.2; MS (ESI) M/e (M +1H)+：398.1，(M-1H)-：396.0.
Compound 71
1H NMR(DMSO-d6)：0.92(3H，t，7Hz)；1.53(1H，m)；1.72(1H，m)；2.48(3H，s)；3.94(1H，m)；4.03(2H，m)；6.62(1H，s)；6.78(1H，dd)；6.92(1H，d)；7.01(2H，d)；7.08(1H，s)；7.31(1H，d)；7.7(2H，d)；8.27(2H，d，7Hz)；9.25(1H，s).MS(M+1)：425.
Compound 72
1H NMR(DMSO-d6)：0.90(2H，dd)；0.91(3H，t，7Hz)；1.1(2H，br.S)；1.52(1H，m)；1.68(1H，m)；1.92(1H，m)；2.0-2.1(3H，m*)；2.25(1H，m)；2.48(3H，s)；3.24(1H，m)；3.37(4H，m)；3.54(1H，m)；3.95(1H，m)；4.03(2H，m)；6.66(1H，s)；6.97(1H，m)；6.99(2H，d，9Hz)；7.07(1H，dd，9，2Hz)；7.12(1H，d，6Hz)：7.28(1H，dd，20，2Hz)；7.45(1H，t，9Hz)，7.7(2H，d，9Hz)；8.29(1H，d，Hz).MS(M+1)：548.
Compound 73
1H NMR(DMSO-d6)：2.00(2H，m)；2.64(1H，m)；2.75(1H，m)；4.1(1H，m)；4.18(1H，m)；4.39(1H，m)；6.98(2H，d，9Hz)；7.14(1H，m)；7.19-7.28(5H，m)；7.32(1H，t，8Hz)；7.45(1H，m)；7.58(1H，s)；7.65(1H，d，7Hz)；7.68(2H，d，9Hz)；7.76(1H，d，J＝7Hz)8.74(1H，d，7Hz).MS(M-1)：443.
Compound 78
1H NMR(DMSO-d6)：3.56(2H，m)；4.15(1H，m)；4.23(1H，m)；4.57(2H，s)；4.94(1H，m)；6.99(2H，d，9Hz)；7.33(1H，t，7Hz)；7.38(5H，s)；7.47(1H，t，7Hz)7.58(1H，s)；7.65(1H，d，8Hz)；7.70(2H，d，9Hz)；7.77(1H，d，8Hz)；8.90(1H，s)；9.0(1H，d，8Hz).MS(M+1)：509.
Compound 79
1H NMR(DMSO-d6)：2.7-2.81(2H，m)；3.78(2H，s)；4.12(1H，dd，10.5Hz)；4.22(1H，dd，10.7Hz)；4.51(1H，m)；6.97(2H，d，9Hz)；7.22(1H，m)；7.28(2H，m)；7.29(2H，s)；7.33(1H，t，7Hz)；7.46(1H，td，7.1Hz)；7.58(1H，s)；7.65(1H，d，8Hz)；7.70(2H，d，9Hz)；7.77(2H，d，8Hz)；8.79(1H，d，8Hz).MS(M+1)：475.
Compound 80
1H NMR(DMSO-d6)：2.47(3H，d，1Hz)；3.57-3.62(3H，m)；3.77(3H，s)；4.08(1H，t，6Hz)；6.64(1H，s)；6.92(1H，dd，9，3Hz)；6.99(2H，d，9Hz)；7.12-7.15(2H，s+d)；7.42(1H，d，9Hz)；7.7(2H，d，9Hz)；8.49(1H，t，6Hz)；8.88(1H，s).MS(M+1)：411.
Compound 91
1H NMR(400MHz，DMSO-d6)11.07(s, 1H), 8.91(s, 1H), 8.24(t, J ═ 5.6Hz, 1H), 7.73(d, J ═ 9.2Hz, 2H), 7.57(d, J ═ 6.8Hz, 2H), 7.44(d, J ═ 16.0Hz, 1H, hidden (buried) under 7.41 m), 7.41(m, 3H), 7.00(d, J ═ 8.8Hz, 2H), 6.63(d, J ═ 16.0Hz, 1H), 4.10 (false t, J ═ 6.0Hz, 2H), 3.37 (false q, J ═ 6.4Hz, 2H), 1.96 (false p, J ═ 6.4Hz, 2H), and EM (calculated value): 340.1 of the total weight of the mixture; MS (ESI) M/e (M +1H)+：341.2，(M-1H)-：339.3.
Compound 92
1H NMR(400MHz，DMSO-d6)11.07(s, 1H), 8.15(s, 1H), 7.73(d, J ═ 8.4Hz, 2H), 7.51(d, J ═ 8.4Hz, 2H), 7.38(d, J ═ 15.6Hz, 1H), 6.99(m, 4H), 6.48(d, J ═ 15.6Hz, 1H), 4.09 (false t, J ═ 6.0Hz, 2H), 3.80(s, 3H), 3.35 (false q, J ═ 5.2Hz, 2H), 1.94 (false q, J ═ 6.0Hz, 2H), EM (calculated): 370.2 of the total weight of the mixture; MS (ESI) M/e (M +1H)+：371.0，(M-1H)-：368.9.
Compound 93
1H NMR(400MHz，DMSO-d6)10.96(s，1H)，8.90(t，J＝5.6Hz，1H)，8.31(s，1H)，7.98(dd，J1＝7.2Hz，J21.6Hz, 2H), 7.62(d, J-8.4 Hz, 2H), 7.40 (false t, J-7.2 Hz, 2H), 7.31 (false tt, J)1＝7.2Hz，J22.0Hz, 1H), 6.90(d, J ═ 9.2Hz, 2H), 4.03(t, J ═ 5.6Hz, 2H), 3.42 (pseudo q, J ═ 6.0Hz, 2H), 1.98 (pseudo p, J ═ 6.0Hz, 2H), EM (calculated): 397.1, respectively; MS (ESI) M/e (M +1H)+：397.9，(M-1H)-：396.0.
Compound 94
1H NMR(400MHz，DMSO-d6)11.09(s, 1H), 8.26(d, J ═ 7.2Hz, 1H), 7.74(d, J ═ 8.4Hz, 2H), 7.58(d, J ═ 7.2Hz, 2H), 7.44(m, 4H), 7.05(d, J ═ 8.8Hz, 2H), 6.68(d, J ═ 16.4Hz, 1H), 4.27(m, 1H), 4.07(m, 1H), 3.96(m, 1H), 1.25(d, J ═ 6.8Hz, 3H), EM (calculated): 340.1 of the total weight of the mixture; MS (ESI) M/e (M +1H)+：341.1，(M-1H)-：339.1.
Compound 95
1H NMR(400MHz，DMSO-d6)11.09(s, 1H), 8.27(d, J ═ 8.0Hz, 1H), 7.74(d, J ═ 8.8Hz, 2H), 7.58(d, J ═ 7.2Hz, 2H), 7.46(d, J ═ 16.0Hz, 1H), 7.42(m, 3H), 7.04(d, J ═ 9.2Hz, 2H), 6.68(d, J ═ 16.4Hz, 1H), 4.27 (pseudo p, J ═ 6.8Hz, 1H), 4.07(dd, J ═ 6.8Hz, 1H), and so on1＝5.6Hz，J2＝10.0Hz，1H)，3.96(dd，J1＝5.6Hz，J2＝9.6Hz，1H) 1.25(d, J ═ 7.2Hz, 3H) EM (calculated): 340.1 of the total weight of the mixture; MS (ESI) M/e (M +1H)+：341.1，(M-1H)-：339.1.
Compound 96
1H NMR(400MHz，DMSO-d6)11.05(s，1H)，8.87(s，1H)，8.12(d J＝8.0Hz，1H)，7.67(dt，J1＝8.8Hz，J2＝2.0Hz，1H)，7.54(dd，J1＝8.4Hz，J2＝1.6Hz，2H)，7.43-7.33(m，4H)，6.99(dt J1＝9.2Hz，J2＝2Hz，2H)，6.65(d，J＝15.6Hz，1H)，4.26(m，1H)，4.01(dd，J1＝9.6Hz，J2＝4.8Hz，1H)，3.94(dd J1＝9.6Hz，J25.6Hz, 1H), 1.66(m, 1H), 1.49(m, 2H), 0.91(d J ═ 6.8Hz, 3H), 0.87(d, J ═ 6.4Hz, 3H), EM (calculated): 382.2, respectively; MS (ESI) M/e (M +1H)+：383.0，(M-1H)-：381.1.
Compound 97
1H NMR(400MHz，DMSO-d6)10.95(s，1H)，8.81(s，1H)，8.05(d，J＝8.4Hz，1H)，7.62(d，J＝8.8Hz，2H)，7.47(d，J＝6.8Hz，2H)，7.37-7.28(m，4H)，6.92(dt，J1＝8.4Hz，J21.6Hz, 2H), 6.61(d, J ═ 16Hz, 1H), 4.21(m, 1H), 3.94(m, 1H), 3.86(m, 1H), 1.69(d.J ═ 12.4Hz, 1H), 1.59-1.52(m, 4H), 1.42(t, J ═ 7.2Hz, 2H), 1.28(m, 1H), 1.15-1.05(m, 3H), 0.90(m, 1H), 0.77(m, 1H), EM (calculated): 422.2, respectively; MS (ESI) M/e (M +1H)+：423.2，(M-1H)-：421.2.
Compound 98
1H NMR(400MHz，DMSO-d6)11.03(s，1H)，8.88(s，1H)，8.09(d，J＝8.4Hz，1H)，7.69(dt，J1＝8.8Hz，J22.8Hz, 2H), 7.432-7.32 (sequence m, 4H), 6.99(dt, J)1＝9.2Hz，J2＝2.4Hz，2H)，6.73(d，J＝15.6Hz，1H)，4.05(s，3H)，1.98(m，1H)，0.95(d，J＝2.4Hz，3H)，0.93(d，J＝2.4Hz, 3H) EM (calculated): 368.2, respectively; MS (ESI) M/e (M +1H)+：368.7，(M-1H)-：367.1.
Compound 99
1H NMR(400MHz，DMSO-d6)11.04(s, 1H), 8.32(d, J ═ 8Hz, 1H), 7.69(d, J ═ 9.2Hz, 2H), 7.53(m, 2H), 7.43-7.34(m, 4H), 7.28-7.22(m, 3H), 7.18(m, 2H), 6.99(d, J ═ 9.2Hz, 2H), 6.63(d, J ═ 16Hz, 1H), 4.38(m, 1H), 4.02(d, J ═ 6.4Hz, 2H), 2.99(m, 1H), 2.88(m, 1H), OH deficiency or nh.em (calculated): 416.2; MS (ESI) M/e (M +1H)+：417.3，(M-1H)-：415.2.
Compound 100
1H NMR(400MHz，DMSO-d6)11.04(s，1H)，8.78(s，1H)，8.32(d，J＝8Hz，1H)，7.69(d，J＝8.8Hz，2H)，7.52(dd，J1＝8.4Hz，J2＝1.6Hz，2H)，7.41-7.34(m，4H)，7.28-7.23(m，4H)，7.19-7.15(m，1H)，6.99(d，J＝9.2Hz，2H)，6.63(d，J＝15.6Hz，1H)，4.38(m，1H)，4.01(d，J＝4.4Hz，2H)，2.99(dd，J1＝13.6Hz，J2＝6Hz，1H)，2.88(dd，J1＝14Hz，J28Hz, 1H) EM (calculated): 416.2; MS (ESI) M/e (M +1H)+：417.2，(M-1H)-：415.2.
Compound 101
1H NMR(400MHz，DMSO-d6)11.05(s，1H)，8.87(s，1H)，8.12(d，J＝8.0Hz，1H)，7.69(d，J＝8.4Hz，2H)，7.53(d，J＝7.2Hz，2H)，7.43-7.33(m，4H)，6.99(d，J＝9.2Hz，2H)，6.65(d，J＝15.6Hz，1H)，4.25(m，1H)，4.01(dd，J＝9.6Hz，4.8Hz，1H)，3.94(dd J1＝9.6Hz，J25.6Hz, 1H), 1.66(m, 1H), 11.48(m, 2H), 0.91(d J ═ 6.8Hz, 3H), 0.87(d, J ═ 6.4Hz, 3H), EM (calculated): 382.2, respectively; MS (ESI) M/e (M +1H)+：383.2，(M-1H)-：381.2.
Compound 102
1H NMR(400MHz，DMSO-d6)11.03(s, 1H), 8.87(s, 1H), 8.08(d, J ═ 8Hz, 1H), 7.69(d, J ═ 8.8Hz, 2H), 7.55(d, J ═ 1.2Hz, 2H), 7.43-7.32(m, 4H), 6.99(d, J ═ 9.2Hz, 2H), 6.73(d, J ═ 16Hz, 1H)4.05(s, 3H), 1.98(m, 1H), 0.946(d, J ═ 2Hz, 3H), 0.93(d, J ═ 2.4Hz, 3H) EM (calculated): 368.2, respectively; MS (ESI) M/e (M +1H)+：369.1，(M-1H)-：367.1.
Compound 103
1H NMR(400MHz，DMSO-d6)11.04(s，1H)，8.14(d，J＝8.4Hz，1H)，7.69(dt，J1＝8.8Hz，J2＝2.8Hz，2H)，7.54(dd，J1＝6.8，J2＝1.2Hz，2H)，7.43-7.32(m，4H)，6.99(dt，J1＝8.8Hz，J2＝3.2Hz，2H)，6.66(d，J＝15.6Hz，1H)，4.16(m，1H)，4.03(dd，J1＝10Hz，J2＝5.6Hz，1H)，3.96(dd，J1＝10Hz，J25.2Hz, 1H), 1.67(m, 1H), 1.53(m, 1H), 1.36-1.27(m, 4H), 0.87(t, J ═ 6.4Hz, 3H), absent 1H, NH or oh.em (calculated): 382.2, respectively; MS (ESI) M/e (M +1H)+：383.1，(M-1H)-：381.1.
Compound 104
1H NMR(400MHz，DMSO-d6)10.97(s，1H)，8.25(d，J＝8.4Hz，1H)，7.64(dt，J1＝8.8Hz，J2＝2Hz，2H)，7.46(dd，J1＝7.6Hz，J22Hz, 2H), 7.34-7.18 (sequence m, 6H), 6.93(dt, J)1＝9.2Hz，J2＝2.8Hz，2H)，6.54(d，J＝15.6Hz，1H)，4.31(m，1H)，3.95(d，J＝4.8Hz，2H)，2.93(dd，J1＝13.6Hz，J2＝5.6Hz，1H)，2.79(dd，J1＝13.6Hz，J28.4Hz, 1H) EM (calculated): 450.1 of the total weight of the mixture; MS (ESI) M/e (M +1H)+：451.2；(M-1H)-：449.2.
Compound 105
1H NMR(400MHz，DMSO-d6)10.97(s，1H)，8.07(d，J＝8Hz，1H)，7.62(dt，J1＝8.8Hz，J2＝2.8Hz，2H)，7.47(dd，J1＝8.8Hz，J21.6Hz, 2H), 7.34-7.26 (sequence m, 4H), 6.93(dt, J)1＝8.8Hz，J2＝2.8Hz，2H)，6.61(d，J＝15.6Hz，1H)，4.04(m，1H)，3.98(dd，J1＝15.6Hz，J2＝5.6Hz，1H)，3.90(dd，J1＝9.2，J25.6Hz, 1H), 1.64(m, 1H), 1.46(m, 1H), 0.85(t, J ═ 6.8Hz, 3H) EM (calculated): 354.2, respectively; MS (ESI) M/e (M +1H)+：354.6，(M-1H)-：353.2.
Compound 106
1H NMR(400MHz，DMSO-d6)10.97(s，1H)，8.07(d，J＝8Hz，1H)，7.62(d J＝8.8Hz，2H)，7.47(dd，J1＝6.8Hz，J21.6Hz, 2H), 7.35-7.62 (sequence m, 4H), 6.93(dt, J)1＝9.2，J2＝2Hz，2H)，6.61(d，J＝15.6Hz，1H)，3.98(dd，J1＝9.6Hz，J2＝5.6Hz，1H)，3.90(dd，J1＝9.6，J24.8Hz, 1H), 1.65(m, 1H), 1.49(m, 1H), 0.85(t, J ═ 7.2Hz, 3H) EM (calculated): 354.2, respectively; MS (ESI) M/e (M +1H)+：354.8，(M-1H)-：353.1.
Compound 107
EM (calculated): 400.49, respectively; MS (ESI) M/e (M + 1): 401.0, (M-1): 399.0.
compound 108
EM (calculated): 400.49, respectively; MS (ESI) M/e (M + 1): 401.1, (M-1): 399.2.
compound 109
1H NMR(400MHz，DMSO-d6)10.97(s, 1H), 8.80(br s, 1H), 8.73(d, J ═ 8.4Hz, 1H), 7.62(d, J ═ 9.2Hz, 2H), 7.48(d, J ═ 6.8Hz, 2H), 7.38-7.27 (sequence m, 8H), 7.21(t ═ t，J＝7.2Hz，1H)，6.93(d，J＝8.8，2H)，6.69(d，J＝15.6Hz，1H)，5.30(dd，J1＝13.6Hz，J27.6Hz, 1H), 4.19(d, J ═ 6.4Hz, 2H), EM (calculated): 402.2; MS (ESI) M/e (M +1H)+：403.2，(M-1H)-：400.9.
Compound 110
1H NMR(400MHz，DMSO-d6)10.97(s，1H)，8.80(br s，1H)，8.74(d，J＝8Hz，1H)，7.62(dt，J1＝8.8Hz，J2＝2Hz，2H)，7.48(dd，J1＝6.4Hz，J21.6Hz, 2H), 7.39-7.27 (sequence m, 8H), 7.21(tt, J)1＝7.6Hz，J2＝1.2Hz，1H)，6.93(dt，J1＝9.2Hz，J2＝2.4Hz，2H)，6.69(d，J＝15.6，1H)，5.29(dd，J1＝8Hz，J26.4Hz, 1H), 4.18(d, J ═ 6.4Hz, 2H), EM (calculated): 402.2; MS (ESI) M/e (M +1H)+：402.9，(M-1H)-：401.2.
Compound 111
1H NMR(400MHz，DMSO-d6)8.25(d, J ═ 8Hz, 1H), 7.83(d, J ═ 8.8Hz, 2H), 7.48(d, J ═ 6.4Hz, 2H), 7.39-7.27 (sequences m, 4H), 7.01(d, J ═ 8.8Hz, 2H), 6.58(d, J ═ 16.4Hz, 1H), 4.25(m, 1H), 4.03(m, 2H), 3.73(s, 3H), 3.12(m, 2H), 2.06(m, 1H), 1.93(m, 1H), EM (calculated): 432.1, respectively; MS (ESI) M/e (M +1H)+：433.2，(M-1H)-：430.0.
Compound 112
1H NMR(400MHz，DMSO-d6)8.24(d, J ═ 8Hz, 1H), 7.82(d, J ═ 8.8Hz, 2H), 7.48(d, J ═ 8.8Hz, 2H), 7.84-7.29 (sequences m, 4H), 7.01(d, J ═ 8.8Hz, 2H), 6.58(d, J ═ 16.4Hz, 1H), 4.35(m, 1H), 4.03(m, 2H), 3.70(s, 3H), 3.13(m, 2H), 2.06(m, 1H), 1.93(m 1H), EM (calculated): 432.1, respectively; MS (ESI) M/e (M +1H)+：432.2，(M-1H)-：430.2.
Compound 113
1H NMR(400MHz，DMSO-d6)8.50(d，J＝8.0Hz，1H)，7.83(dt，J1＝9.2Hz，J2＝2.8Hz，2H)，7.48(dd，J1＝6Hz，J2＝1.6Hz，2H)，7.39(d，J＝16Hz，1H)，7.31(m，9H)，6.97(dt，J1＝9.2Hz，J2＝2.4Hz，2H)，6.57(d，J＝16Hz，1H)，4.72(m，1H)，4.50(s，1H)，4.16(dd，J1＝9.6Hz，J2＝5.2Hz)，1H，4.08(dd，J1＝10Hz，J2＝4.8Hz，1H)，3.45(dd，J1＝14.4Hz，J2＝5.6Hz，1H)，3.36(dd，J1＝14.4Hz，J26.8Hz, 1H) EM (calculated): 492.2, respectively; MS (ESI) M/e (M +1H)+：494.3，(M-1H)-：492.2.
Compound 114
1H NMR(400MHz，DMSO)11.07(br s，1H)，8.38(d，J＝7.6Hz，2H)，7.84(dd，J1＝3.6Hz，J2＝1.2Hz，1H)，7.77(dd，J1＝4.8Hz，J2＝1.2Hz，1H)，7.72(d，J＝8.4Hz，2H)，7.16(dd，J1＝3.6Hz，J2＝5.2Hz，1H)，7.02(d，J1＝8.4Hz，2H)，4.20(m，1H)，4.13(dd，J1＝6.4Hz，J2＝9.6Hz，1H)，4.04(dd，J1＝5.2Hz，J29.2Hz, 2H)1.77(m 1H), 1.63(m, 1H), 1.21(d, J ═ 6.4Hz, 1H), 0.96(t, J ═ 7.2Hz, 3H), EM (calculated): 334.1; MS (ESI) M/e (M +1H)+：335.0，(M-1H)-：333.0.
Compound 115
1H NMR(400MHz，DMSO-d6)11.03(s, 1H), 8.37(d, J ═ 8.0Hz, 1H), 7.94(d, J ═ 8.4Hz, 2H), 7.72(m, 6H), 7.48(m, 2H), 7.39(m, 1H), 7.00(d, J ═ 8.4Hz, 2H), 4.24(m, 1H), 4.06(m, 2H), 1.74(m, 2H), 0.95(t, J ═ 7.2Hz, 3H) EM (calculated): 404.2; MS (ESI) M/e (M +1H)+：405.2，(M-1H)-：403.2.
Compound 116
1H NMR(400MHz，DMSO-d6)11.03(s, 1H), 8.87(s, 1H), 8.50(d, J ═ 8.4Hz, 1H), 8.44(s, 1H), 7.97(m, 4H), 7.70(d, J ═ 8.8Hz, 2H), 7.59(m, 2H), 7.02(d, J ═ 8.8Hz, 2H), 4.29(m, 1H), 4.14(m, 2H), 1.68(m, 2H), 0.98(t, J ═ 7.2Hz, 3H), EM (calculated): 378.2, respectively; MS (ESI) M/e (M +1H)+：378.9，(M-1H)-：377.0.
Compound 117
1H NMR(400MHz，DMSO-d6)10.98(s，1H)，8.82(s，1H)，8.27(d，J＝8.4Hz，1H)，7.64(d，J＝9.2Hz，2H)，7.48(dd，J1＝6.4Hz，J2＝1.6Hz，2H)，7.38(d，J＝15.6Hz，1H)，7.36-7.27(m，3H)，7.23-7.19(m，4H)，7.14(m，1H)，6.92(d，J＝8.8Hz，2H)，6.61(d，J＝15.6Hz，1H)，4.29(m，1H)，4.08(dd，J1＝9.6Hz，J2＝5.6Hz，1H)，3.98(dd，J1＝9.6Hz，J2＝4.4Hz，1H)，3.70(d，J＝2.4Hz，2H)，2.67(dd，J1＝6.8Hz，J2＝13.6Hz，1H)，2.58(dd，J1＝13.2Hz，J27.2Hz, 1H) EM (calculated): 460.2, respectively; MS (ES1) M/e (M-1H)-：460.8.
Compound 118
1H NMR(400MHz，DMSO-d6)11.02(s，1H)，8.31(d，J＝8.4Hz，1H)，7.83(d，J＝7.2Hz，2H)，7.68(d，J＝8.8Hz，2H)，7.52-7.42(m，3H)，6.99(d，J＝9.2Hz，2H)，4.22(m，1H)，4.11(dd，J1＝6.4Hz，J2＝10.0Hz，1H)，4.01(dd，J1＝6.0Hz，J29.6Hz, 1H), 1.73(m 1H), 1.62(m, 1H), 0.93(t, J ═ 7.6Hz, 3H) EM (calcd): 328.1; MS (ESI) M/e (M +1H)+：329.1.(M-1H)-：327.0.
Compound 119
1H NMR(400MHz，DMSO-d6)11.03(s, 1H), 8.08(d, J ═ 7.2Hz, 1H), 7.69(d, J ═ 8.8Hz, 2H), 7.24(m, 5H), 6.96(d, J ═ 9.2Hz, 2H), 3.94(m3H), 3.43(s, 2H), 1.64(m, 1H), 1.47(m, 1H), 0.86(t, 7.2Hz, 3H) EM (calculated): 342.2; MS (ESI) M/e (M +1H)+：343.0，(M-1H)-：341.1.
Compound 120
1H NMR(400MHz，DMSO-d6)11.03(s，1H)，7.81(d，J＝7.6Hz，1H)，7.69(d，J＝8.4Hz，2H)，7.23-7.10(m，5H)，6.94(d，J＝9.2Hz，2H)，3.94(m，2H)，3.84(m，1H)，2.81(t，J＝7.2Hz，2H)，2.40(t，J＝7.6Hz，2H)，1.61(ddd，J1＝4.4Hz，J2＝7.6Hz，J318.4Hz, 1H), 1.41(m, 1H), 0.81(t, J ═ 6.8Hz, 3H) EM (calculated): 356.2; MS (ESI) M/e (M +1H)+：357.1，(M-1H)-：355.1.
Compound 121
EM (calculated): 356.38, respectively; MS (ESI) M/e (M + 1): 357.0, (M-1): 355.1.
compound 122
1H NMR(400MHz，DMSO-d6)10.96(s, 1H), 8.65(d, J ═ 8.8Hz, 1H), 8.33(s, 1H), 8.00(d, J ═ 7.2Hz, 2H), 7.62(d, J ═ 8.4Hz, 2H), 7.39 (false t, J ═ 7.2Hz, 2H), 7.30 (false t, J ═ 7.6Hz, 1H), 6.93(d, J ═ 9.2Hz, 2H), 4.20(m, 1H), 4.23(dd, hidden under the 4.20 peak, J ═ 9.2Hz, 2H), 4.20(m, 1H), 4.23(dd, hidden under the 4.20 peak, J ═ is hidden, J ═ 1H1＝9.2Hz，J2＝16.8Hz，1H)，4.05(dd，J1＝10.0Hz，J24.8Hz, 1H), 1.69(m 1H), 1.62(m, 1H), 0.88(t, J ═ 7.2Hz, 3H) EM (calcd): 411.1; MS (ESI) M/e (M-1H)-：410.1.
Compound 123
1H NMR(400MHz，DMSO-d6)11.03(s，1H)，8.03(d，J＝7.6Hz，1H)，7.69(d，J＝8.8Hz，2H)，7.48(d，J＝9.2Hz，2H)，7.36(d，J＝15.6Hz，1H)，6.99(d，J＝9.2Hz，2H)，6.95(d，J＝8.8Hz，2H)，6.52(d，J＝15.6Hz，1H)，4.09(m，1H)，4.04(dd，J1＝5.2Hz，J2＝9.6Hz，1H)，3.95(dd，J1＝5.2Hz，J29.6Hz, 1H), 3.77(s, 3H), 1.71(m, 1H), 1.52(m, 1H), 0.91(t, J ═ 6.8Hz, 3H) EM (calculated): 384.2, respectively; MS (ESI) M/e (M +1H)+：385.0，(M-1H)-：383.2.
Compound 124
1H NMR(400MHz，DMSO-d6)11.07(s，1H)，10.62(br s，1H)，8.43(d，J＝8.0Hz，1H)，8.28(d，J＝1.6Hz，1H)，7.94(dd，J1＝8.4Hz，J2＝2.0Hz，1H)，7.23(d，J＝8.4Hz，2H)，7.32(s，1H)，7.03(d，J＝8.8Hz，2H)，4.60(s，2H)，4.28(m，1H)，4.17(dd，J1＝10.0Hz，J2＝6.8Hz，1H)，4.08(dd，J1＝10.4Hz，J26.0Hz, 1H), 2.84(s, 6H), 1.80(m, 1H), 1.65(m, 1H), 0.98(t, J ═ 7.6Hz, 3H) EM (calculated): 425.2; MS (ESI) M/e (M +1H)+：426.2，(M-1H)-：424.1.
Compound 125
1H NMR(400MHz，DMSO-d6)10.96(s, 1H), 8.80(s, 1H), 8.27(t, J ═ 5.2Hz, 1H), 7.62(J ═ 8.8Hz, 2H), 7.46(d, J ═ 6.8Hz, 2H), 7.36(d, J ═ 12.8Hz, 1H), 7.33-7.28(m, 3H), 6.95(d, J ═ 8.4Hz, 2H), 6.60(d, J ═ 12.8Hz, 1H), 4.53(ddd, J ═ 5.6Hz, 1H), 3.40(m, 1H), 3.29(m, 1H), hidden under water peak, 1.19(d, J ═ 6.4Hz, 3H), EM (calculated value): 340.1.
compound 126
1H NMR(400MHz，DMSO-d6)11.02(s，1H)，8.87(s，1H)，8.34(t，J＝5.6Hz，1H)，7.68(d，J＝8.4Hz，2H)，7.53(d，J＝8.8Hz，2H)，7.43(d，J＝13.2Hz，1H)，7.40-7.35(m，3H)，7.02(d，J＝8.8Hz，2H)，6.67(d，J＝16Hz，1H)，4.60(ddd，J1＝6.0Hz，J2＝11.6Hz，J317.6Hz, 1H), 3.47(m, 1H), 3.36(m 1H, hidden under the water peak), 1.26(d, J ═ 6.0Hz, 3H) EM (calculated): 340.1 of the total weight of the mixture; MS (ESI) M/e (M +1H)+：341.0，(M-1H)-：339.2.
Compound 127
EM (calculated): 397.1, respectively; MS (ESI) M/e (M-1H)-：396.1.
Compound 128
EM (calculated): 397.1, respectively; MS (ESI) M/e (M +1H)+：398.2，(M-1H)-：396.2.
Compound 129
1H NMR(400MHz，DMSO-d6)10.96(s，1H)，8.69(t，J＝5.6Hz，1H)，7.84(d，J＝8.4Hz，2H)，7.67(d，J＝8.4Hz，1H)，7.63(m，4H)，7.40(t，J＝7.6Hz，2H)，7.32(m，1H)，6.98(d，J＝12.0Hz，2H)，4.62(ddd，J1＝6.0Hz，J2＝12.0Hz，J3＝18.0Hz，1H)，3.52(ddd，J1＝6.4Hz，J2＝13.6Hz，J319.6Hz, 1H), 3.31(m, 1H, hidden under the water peak), 1.23(d, J ═ 6.0Hz, 3H) EM (calculated): 390.2; MS (ESI) M/e (M +1H)+：391.3，(M-1H)-：389.0.
Compound 130
1H NMR(400MHz，DMSO-d6)11.03(s, 1H), 8.24(t, J ═ 5.2Hz, 1H), 7.68(d, J ═ 8.8Hz, 2H), 7.48(d, J ═ 8.8Hz, 2H), 7.37(d, J ═ 15.6Hz, 1H), 7.02(d, J ═ 8.8Hz, 2H), 6.95(d, J ═ 8.8Hz, 2H), 6.51(d, J ═ 15.6Hz, 1H), 4.58 (pseudo q, J ═ 5.6Hz, 1H), 3.77(s, 3H), 3.46(ddd, J ═ 15.6Hz, 1H), 3.58 (pseudo q, J ═ 5.6Hz, 1H), 3.77(s, 3H), 3.46(ddd, J ═ 51＝4.8Hz，J2＝13.2Hz，J3＝19.2Hz，1H)，3.32(ddd，J1＝5.2Hz，J2＝10.8Hz，J313.2Hz, 1H), 1.25(d, J ═ 6.0Hz, 3H), EM (calculated): 370.2 of the total weight of the mixture; MS (ESI) M/e (M +1H)+：371.0，(M-1H)-：369.1.
Compound 131
1H NMR(DMSO-d6)：3.67(q，2H)，4.18(t，2H)，7.01(d，2H)，7.7(d，2H)，7.98(d，2H)，8.12(d，2H)，8.17(d，2H)，8.55(s，1H)，8.79(m，3H)，11.05(s，1H).LC\MS：(M+1)+1 461.2，(M-1)-1 459.0.
Compound 132
1H NMR(400MHz，DMSO-d6): 11.08(s, 1H), 8.94(m, 2H), 7.75(m, 3H), 7.47(d, 1H, J ═ 8.1Hz), 7.16(d, 1H, J ═ 8.1Hz), 7.04(d, 2H, J ═ 9.6Hz), 4.22(t, 2H, J ═ 5.5Hz), 3.71(t, 2H, J ═ 5.5Hz), 3.36(s, 3H) EM (calculated): 388.08, respectively; MS (ESI) M/e (M +1H)+：388.9，(M-1H)-：387.1.
Compound 133
1H NMR(DMSO-d6)：2.85(s，3H)，3.4(s，8H)，3.65(q，2H)，4.17(t，2H)，7.00(d，2H)，7.54(s，1H)，7.7(d，2H)，7.9(dd，4H)，8.74(t，1H)，8.9(s，1H)，10.2(s，1H)，11.05(s，1H).LC\MS：(M+1)+1 482.0，(M-1)-1 480.2.
Compound 134
1H NMR(DMSO-d6)：3.66(q，2H)，4.18(t，2H)，7.01(d，2H)，7.69(m，4H)，7.91(d，2H)，8.02(d，3H)，8.33(dd，2H)，8.75(t，1H)，9.16(s，1H)，10.99(s，1H)，11.05(s，1H).LC\MS：(M+1)+1 476.1，(M-1)-1 474.2.
Compound 135
1H NMR(DMSO-d6)：2.85(s，3H)，3.01(m，4H)，3.51(d，2H)，3.60(q，2H)，4.00(d，2H)，4.13(t，2H)，6.98(dd，4H)，7.74(dd，4H)，8.48(t，1H)，9.97(s，1H)，11.05(s，1H).LC\MS：(M+1)+1 399.3，(M-1)-1 397.2.
Compound 136
1H NMR(DMSO-d6)：1.4(m，2H)，1.8(m，2H)，2.95(m，2H)，3.6(m，5H)，4.12(t，2H)，4.69(s，1H)，6.91(d，2H)，6.99(d，2H)，7.7(dd，4H)，8.36(t，1H)，8.87(s，1H)，11.03(s，1H).LC\MS：(M+1)+1 400.2，(M-1)-1 398.3.
Compound 138
1H NMR(400MHz，DMSO-d6): 9.02(t, 2H, J ═ 5.3Hz), 7.77-7.72(m, 3H), 7.27(m, 1H), 7.11(m, 1H), 7.03(d, 2H, J ═ 8.8Hz), 4.22(t, 2H, J ═ 5.3Hz), 3.70(t, 2H, J ═ 5.3Hz), 2.51(s, 3H). EM (calculated): 372; MS (ESI) M/e (M +1H)+：373.0，(M-1H)-：371.0.
Compound 139
1H NMR(400MHz，DMSO-d6): 11.04(s, 1H), 10.04(s, 1H), 9.02(t, 1H, J ═ 5.7Hz), 7.74(d, 1H, J ═ 2.7Hz), 7.70(d, 2H, J ═ 8.5Hz), 7.32(m, 1H), 7.25(m, 1H), 7.00(d, 2H, J ═ 8.5Hz), 4.72(s, 2H), 4.19(t, 2H, J ═ 5.7Hz), 3.67(m, 2H), 3.59(m, 2H), 3.48(m, 2H), 3.24(s, 3H). EM (calculated): 446.15, respectively; MS (ESI) M/e (M +1H)+：447.4，(M-1H)-：445.3.
Compound 140
1H NMR(400MHz，DMSO-d6): 11.04(br s, 1H), 9.25(t, 1H, J ═ 5.9Hz), 8.07(d, 1H, J ═ 8.6Hz), 7.96(d, 1H, J ═ 8.6Hz), 7.70(m, 3H), 7.39(t, 1H, J ═ 7.6Hz), 7.01(d, 2H, J ═ 9.1Hz), 6.88(br s, 1H), 4.21(t, 2H, J ═ 5.9Hz), 3.70(q, 2H, J ═ 5.9Hz), EM (calculated): 367; MS (ES1) M/e (M +1H)+：368.0，(M-1H)-：366.2.
Compound 141
1H NMR(400MHz，DMSO-d6)：11.04(br s，1H)，9.04(t，1H，J＝5.9Hz)7.80(d, 1H, J ═ 2.6Hz), 7.70(d, 1H, J ═ 8.7Hz), 7.40(m, 2H), 7.28(t, 1H, J ═ 8.1Hz), 7.05-6.92(m, 5H), 5.35(s, 2H), 4.18(t, 2H, J ═ 5.9Hz), 3.66(q, 2H, J ═ 5.9Hz), EM (calculated): 464; MS (ESI) M/e (M +1H)+：465.3，(M-1H)-：463.1.
Compound 143
1H NMR(DMSO-d6)：2.55(t，3H)，2.80(s，3H)，3.07(d，3H)，3.4(d，2H)，3.65(q，2H)，4.02(s，2H)，4.17(t，2H)，6.99(d，2H)，7.69(d，2H)，7.91(d，2H)，8.01(d，2H)，8.23(s，1H)，8.75(t，1H)，9.6(s，1H)，11.05(s，1H).LC\MS：(M+1)+1 496.3，(M-1)-1 494.4
Compound 144
MS(ESI)m/e：(M+1H)+：302.0，(M-1H)-：300.2.
Compound 145
MS(ESI)m/e：(M+1H)+：318.1，(M-1H)-：316.1.
Compound 146
MS(ESI)m/e：(M+1H)+：318.1，(M-1H)-：316.2.
Compound 147
1H NMR(400MHz，DMSO-d6)11.04(s，1H)，8.28(m，2H)，8.15(m，1H)，7.94(m，2H)，7.66(m，2H)，7.41(m，3H)，6.89(m，2H)，4.10(m，2H)，3.63(m，2H).MS(ESI)m/e：(M+1H)+：439.2，(M-1H)-：437.2.
Compound 148
1H NMR(400MHz，DMSO-d6)11.04(s，1H)，9.10(t，J＝8.0Hz，1H)，8.18(d，J＝8.0Hz，1H)，8.06(d，J＝8.0Hz，1H)，7.85(t，J＝8.0Hz，1H)，7.67(m，4H)，7.04(d，J＝8.0Hz，2H)，4.45(m，2H)，4.23(t，J＝8.0Hz，2H)，3.84(m，2H)，3.76(m，2H).MS(ESI)m/e：(M+1H)+：426.3，(M-1H)-：424.2.
Compound 149
1H NMR(400MHz，DMSO-d6)11.06(s，1H)，10.31(s，1H)，9.10(t，J＝8.0Hz，1H)，8.40(d，J＝8.0Hz，1H)，8.07(d，J＝8.0Hz，1H)，7.86(t，J＝8.0Hz，1H)，7.69(m，4H)，7.02(d，J＝8.0Hz，2H)，4.74(m，2H)，4.23(t，J＝8.0Hz，2H)，3.77(m，2H)，3.70(m，2H).MS(ESI)m/e：(M+1H)+：439.3，(M-1H)-：437.3.
Compound 150
MS(ESI)m/e：(M+1H)+：379.9，(M-1H)-：379.9.
Compound 151
MS(ESI)m/e：(M+1H)+：379.9，(M-1H)-：379.9.
Compound 152
1H NMR(400MHz，DMSO-d6): 11.04(br s, 1H), 8.85(d, 1H, J ═ 9.0Hz), 8.20(d, 1H, J ═ 1.2Hz), 8.18(d, 1H, J ═ 1.2Hz), 7.85(m, 1H), 7.70-7.65(m, 4H), 7.01(t, 2H, J ═ 8.7Hz), 4.32(m, 1H), 4.25(m, 1H), 4.15(s, 3H), 4.13(m, 1H), 1.77(m, 2H), 0.95(t, 3H, J ═ 7.0), EM (calculated): 409; MS (ESI) M/e (M +1H)+：410.2，(M-1H)-：408.2.
Compound 153
1H NMR(400MHz，DMSO-d6): 11.05(s, 1H), 10.17(s, 1H), 8.65(m, 1H), 8.14(m, 1H), 7.95(m, 1H), 7.88(d, 1H, J ═ 8.2Hz), 7.73-7.66(m, 3H), 7.62-7.59(m, 2H), 7.05(m, 2H), 4.24(m, 2H), 3.89(s, 3H), 3.73(m, 2H) EM (calculated): 380 of the raw material; MS (ESI) M/e (M +1H)+：381.0，(M-1H)-：379.1.
Compound 154
1H NMR(400MHz，DMSO-d6): 11.04(s, 1H), 9.14(t, 1H, J ═ 6.0Hz), 8.18(d, 1H, J ═ 7.7Hz), 8.07(d, 1H, J ═ 8.2Hz), 7.85(t, 1H, J ═ 7.7Hz), 7.72-7.64(m, 4H), 7.08(d, 2H, J ═ 9.1Hz), 4.78(m, 1H), 4.14(s, 3H), 3.66(m, 1H), 3.55(m, 1H), 1.31(d, 3H, J ═ 6.1Hz), EM (calculated): 395; MS (ESI) M/e (M +1H)+：396.1，(M-1H)-：394.2.
Compound 155
MS(ESI)m/e：(M+1H)+：377.9，(M-1H)-：376.1.
Compound 156
MS(ESI)m/e：(M+1H)+：408.3，(M-1H)-：406.2.
Compound 157
MS(ESI)m/e：(M+1H)+：373.9，(M-1H)-：372.1.
Compound 158
MS(ESI)m/e：(M+1H)+：422.3，(M-1H)-：420.3.
Compound 159
1H NMR(400MHz，DMSO-d6): 11.04(s, 1H), 9.10(t, 1H, J ═ 5.9Hz), 8.16(d, 1H, J ═ 8.4Hz), 8.07(d, 1H, J ═ 8.4Hz), 7.85(t, 1H, J ═ 7.9Hz), 7.71-7.65(m, 4H), 7.03(d, 2H, J ═ 8.9Hz), 4.60(t, 2H, J ═ 5.9Hz), 4.23(t, 2H, J ═ 5.1Hz), 3.75(q, 2H, J ═ 5.9Hz), 3.00(m, 2H). EM (calculated): 463; MS (ESI) M/e (M +1H)+：464.3，(M-1H)-：462.2.
Compound 160
1H NMR(400MHz，DMSO-d6)：11.04(s，1H)，8.78(d，1H，J＝9.0Hz)，8.15(d，1H，J＝8.3Hz)，8.09(d，1H，J＝8.5Hz)，7.85(t, 1H, J ═ 6.7Hz), 7.68(m, 4H), 7.00(d, 2H, J ═ 9.0Hz), 4.61(t, 2H, J ═ 5.9Hz), 4.32(m, 1H), 4.24(m, 1H), 4.14(m, 1H), 3.00(m, 2H), 1.76(m, 2H), 0.95(t, 3H, J ═ 7.0Hz), EM (calculated): 491; MS (ESI) M/e (M +1H)+：492.1，(M-1H)-：490.1.
Compound 161
1H NMR(400MHz，DMSO-d6): 9.13(t, 1H, J ═ 6.1Hz), 8.15(d, 1H, J ═ 8.1Hz), 8.07(d, 1H, J ═ 8.3Hz), 7.86(t, 1H, J ═ 6.7Hz), 7.71-7.67(m, 4H), 7.08(d, 2H, J ═ 8.7Hz), 4.78(m, 1H), 4.61(t, 1H, J ═ 5.5Hz), 3.65(m, 1H), 3.55(m, 1H), 3.00(m, 2H), 1.31(d, 3H, J ═ 6.0Hz), EM (calculated): 477; MS (ESI) M/e (M +1H)+：477.9，(M-1H)-：476.1.
Compound 162
1H NMR(DMSO-d6)：3.56(s，2H)，4.09(t，2H)，6.57(d，1H)，6.77(d，1H)，6.95(m，3H)，7.18(t，1H)，7.32(d，2H)，7.69(d，2H)，8.38(t，1H)，9.6(s，1H)，11.05(s，1H).LC\MS：(M+1)+1 343.2，(M-1)-1 341.3.
Compound 163
1H NMR(DMSO-d6)：3.55(s，2H)，4.08(t，2H)，6.4(d，1H)，6.8(d，2H)，7.0(d，2H)，7.35(d，1H)，7.4(d，2H)，7.69(d，2H)，8.25(t，1H)，9.85(s，1H)，11.05(s，1H).LC\MS：(M+1)+1 343.1，(M-1)-1 341.1.
Compound 164
EM (calculated): 420.17, respectively; MS (ESI) M/e (M +1H)+：421.2，(M-1H)-：419.5.
Compound 165
EM (calculated): 420.17, respectively; MS (ESI) M/e (M +1H)+：421.3，(M-1H)-：419.3.
Compound 166
EM (calculated): 420.17, respectively; MS (ESI) M/e (M +1H)+：421.3，(M-1H)-：419.3.
Compound 167
1H NMR(DMSO-d6)：8.89(1H，s)，8.58(1H，m)，7.71(2H，m)，7.65(1H，d)，7.56(1H，d)，7.41(1H，d)，7.36(1H，t)，7.25(1H，t)，7.21(1H，s)，7.00(2H，d)，6.74(1H，dd)，4.11(2H，t)，3.58(2H，q).
Compound 168
EM (calculated): 420.17, respectively; MS (ESI) M/e (M +1H)+：421.2，(M-1H)-：419.3.
Compound 169
1H NMR(400MHz，DMSO-d6)11.07(s，1H)，9.14(s，1H)，9.11(t，J＝8.0Hz，1H)，8.93(s，1H)，8.63(t，J＝4.0Hz，1H)，8.17(m，1H)，7.72(m，4H)，7.00(d，J＝8.0Hz，2H)，4.20(t，J＝8.0Hz，2H)，3.71(m，2H).MS(ESI)m/e：(M+1H)+：384.1，(M-1H)-：382.0.
Compound 170
MS(ESI)m/e：(M+1H)+：451.0，(M-1H)-：449.2.
Compound 171
MS(ESI)m/e：(M+1H)+：409.3，(M-1H)-：407.2.
Compound 172
1H NMR(DMSO-d6)：3.54(q，2H)，3.84(s，3H)，4.08(t，2H)，6.6(d，1H)，6.98(m，4H)，7.35(t，1H)，7.5(d，1H)，7.65(d，1H)，7.69(d，2H)，8.36(t，1H)，8.9(s，1H)，11.04(s，1H).LC\MS：(M+1)+1 356.9，(M-1)-1 355.2.
Compound 173
1H NMR(DMSO-d6)：3.56(q，2H)，3.77(s，3H)，4.09(t，2H)，6.66(d，1H)，6.93(m，2H)，6.99(d，2H)，7.1(d，2H)，7.29(t，1H)，7.39(d，1H)，7.70(d，2H)，7.87(d，1H)，8.36(t，1H)，8.9(s，1H)，11.05(s，1H).LC\MS：(M+1)+1357.1，(M-1)-1 355.1.
Compound 174
1H NMR(400MHz，DMSO-d6)11.05(s，1H)，9.21(t，J＝8.0Hz，1H)，9.07(s，1H)，8.92(s，1H)，8.67(s，1H)，7.70(m，4H)，7.01(d，J＝8.0Hz，2H)，6.92(m，1H)，4.21(t，J＝8.0Hz，2H)，3.71(m，2H).MS(ESI)m/e：(M+1H)+：421.2，(M-1H)-：419.4.
Compound 175
1H NMR(DMSO-d6)：8.91(1H，s)，8.44(1H，t)，7.73(2H，d)，7.72(1H，s)，7.57(1H，d)，7.44(1H，d)，7.02(2H，d)，6.50(1H，d)，4.11(2H，t)，3.58(2H，q).LC/MS，(M+1)：413.1.
Compound 176
1H NMR(DMSO-d6)：3.54(q，2H)，4.07(t，2H)，6.36(d，1H)，6.68(s，1H)，6.98(d，2H)，7.32(d，1H)，7.69(m，3H)，7.98(s，1H)，8.27(t，1H)，8.9(s，1H)，11.04(s，1H).LC\MS：(M+1)+1 316.9，(M-1)-1 315.3.
Compound 177
1H NMR(DMSO-d6)：3.55(q，2H)，4.08(t，2H)，6.47(d，1H)，6.98(d，2H)，7.31(d，1H)，7.42(d，1H)，7.58(m，1H)，7.69(d，2H)，7.78(s，1H)，8.30(t，1H)，8.9(s，1H)，11.04(s，1H).LC\MS：(M+1)+1 333.0，(M-1)-1 331.0.
Compound 178
1H NMR(DMSO-d6)：8.91(1H，s)，8.40(1H，t)，7.73(2H，d)，7.61(2H，m)，7.38(1H，d)，7.11(1H，dd)，7.01(2H，d)，6.43(1H，d)，4.11(2H，t)，3.57(2H，q).LC/MS，(M+1)：333.0.
Compound 179
1H NMR(DMSO-d6)：2.31(s，3H)，3.55(q，2H)，4.09(t，2H)，6.6(d，1H)，6.99(d，2H)，7.2-7.4(m，6H)，7.70(d，2H)，8.33(t，1H)，8.9(s，1H)，11.04(s，1H).LC\MS：(M+1)+1 341.1，(M-1)-1 339.1.
Compound 180
1H NMR(DMSO-d6)：2.31(s，3H)，3.55(q，2H)，4.09(t，2H)，6.6(d，1H)，6.99(d，2H)，7.2(d，2H)，7.38(d，1H)，7.42(d，2H)，7.69(d，2H)，8.33(t，1H)，8.9(s，1H)，11.04(s，1H).LC\MS：(M+1)+1 341.2，(M-1)-1 339.2.
Compound 181
1H NMR(DMSO-d6)：8.87(1H，s)，8.52(1H，t)，7.70(2H，d)，7.64(1H，d)，7.52(1H，d)，7.34(1H，m)，7.24(1H，t)，7.22(1H，s)，6.99(2H，d)，6.67(1H，m)，4.09(2H，t)，3.52(2H，q)，2.48(3H，m).LC/MS，(M+1)：381.0.
Compound 182
1H NMR(DMSO-d6)：8.88(1H，s)，8.33(1H，t)，7.68(2H，d)，7.54(1H，m)，7.41(1H，d)，7.28(1H，s)，7.24(1H，m)，7.19(1H，m)，6.95(2H，d)，6.07(1H，m)，4.11(2H，t)，3.52(2H，q)，2.15(3H，m).LC/MS，(M+1)：381.1.
Compound 183
1H NMR(DMSO-d6)：2.94(s，6H)，3.54(q，2H)，4.07(t，2H)，6.38(d，1H)，6.69(d，2H)，6.98(d，2H)，7.29(d，1H)，7.35(d，2H)，7.69(d，2H)，8.15(t，1H)，8.87(s，1H)，11.04(s，1H).LC\MS：(M+1)+1 370.1，(M-1)-1 368.3.
Compound 184
1H NMR(DMSO-d6)：3.57(q，2H)，4.10(t，2H)，6.65(d，1H)，7.0(d，2H)，7.14(m，2H)，7.42(m，1H)，7.6(d，1H)，7.72(m，3H)，7.87(d，1H)，8.149(t，1H)，8.87(s，1H)，11.04(s，1H)，11.52(s，1H).LC\MS：(M+1)+1 366.2，(M-1)-1 364.4.
Compound 185
1H NMR(DMSO-d6)：2.36(s，3H)，3.56(q，2H)，4.10(t，2H)，6.56(d，1H)，7.00(d，2H)，7.23(m，3H)，7.5(d，1H)，7.65(d，1H)，7.7(d，2H)，8.4(t，1H)，8.87(s，1H)，11.04(s，1H).LC\MS：(M+1)+1 341.2，(M-1)-1 339.3.
Compound 186
1H NMR(DMSO-d6)：3.55(q，2H)，3.93(s，3H)，4.08(t，2H)，6.66(d，1H)，6.79(t，1H)，6.86(d，1H)，6.98(d，2H)，7.15(m，1H)，7.4(d，1H)，7.65(d，1H)，7.7(d，2H)，8.31(t，1H)，10.0(s，1H)，11.04(s，1H).LC\MS：(M+1)+1343.1，(M-1)-1 340.9.
Compound 187
1H NMR(DMSO-d6)：3.57(q，2H)，3.93(s，3H)，4.09(t，2H)，6.75(d，1H)，6.98(m，3H)，7.18(m，3H)，7.38(d，1H)，7.7(d，2H)，8.5(t，1H)，8.87(s，1H)，11.04(s，1H).LC\MS：(M+1H)+1 396.7，(M-1)-1 395.0.
Compound 188
1H NMR(DMSO-d6)：0.922(t，3H)，1.5-1.8(m，2H)，3.93(s，3H)，3.95-4.07(m，3H)，6.8(d，1H)，6.98(m，3H)，7.19(m，3H)，7.36(d，1H)，7.69(d，2H)，8.3(d，1H)，11.03(s，1H).LC\MS：(M+1)+1 425.2，(M-1)-1423.2.
Compound 189
1H NMR(DMSO-d6)：0.95(3H，t，7Hz)；1.53(1H，m)；1.72(1H，m)；2.52(3H，s)；3.79(3H，s)；3.94(1H，m)；4.06(2H，m)；6.66(1H，s)；6.93(1H，dd)；7.02(2H，d)；7.15(2H，m)；7.42(1H，d)；7.7(2H，d)；8.27(2H，d，7Hz)；8.87(1H，d，2Hz).MS(M+1)：439.
Compound 190
1H NMR(DMSO-d6)：3.54(q，2H)，4.08(t，2H)，6.44(d，1H)，6.56(s，1H)，6.75(s，1H)，6.98(d，2H)，7.23(d，1H)，7.70(d，2H)，7.75(s，1H)，8.41(t，1H)，8.9(s，1H)，11.04(s，1H).LC\MS：(M+1)+1 317.0，(M-1)-1 315.2.
Compound 191
1H NMR(DMSO-d6)：3.5-4.05(m，14H)，4.18(t，2H)，6.99(d，2H)，7.69(d，2H)，7.93(d，2H)，8.02(d，2H)，8.2(s，1H)，8.76(t，1H)，8.97(s，1H)，11.05(s，1H).LC\MS：(M+1)+1 497.4，(M-1)-1 495.4.
Table 2:
compound 1
EM (calculated): 370.2 of the total weight of the mixture; MS (ESI) M/e (M +1)+：371.1，(M-1)-：369.2.
Compound 2
1H NMR(400MHz，DMSO-d6)11.03(s, 1H), 8.88(s, 1H), 7.67(d, J ═ 9.2Hz, 2H), 7.51(m, 3H), 7.36(m, 8H), 6.92(d, J ═ 9.2Hz, 2H), 6.27(d, J ═ 15.2Hz, 1H), 4.16(m, 4H), EM (calculated): 402.2; MS (ESI) M/e (M +1H)+：403.1，(M-1H)-：401.1.
Compound 3
EM (calculated): 340.1 of the total weight of the mixture; MS (ESI) M/e (M +1H)+：341.0，(M-1H)-：339.4.
Compound 4
EM (calculated): 398.13, respectively; MS (ESI) M/e (M +1H)+：399.0，(M-1H)-：397.1.
Compound 5
EM (calculated): 368.17, respectively; MS (ESI) M/e (M +1H)+：368.8，(M-1H)-：367.2.
Compound 6
EM (calculated): 354.1 of the total weight of the mixture; MS (ESI) M/e (M +1H)+：354.8，(M-1H)-：353.2.
Table 3:
compound 1
1H NMR(400MHz，DMSO-d6)11.11(s，1H)，9.07(t，J＝5.2Hz，1H)，8.94(s，1H)，8.16(s，1H)，8.07(dd，J1＝2.4Hz，J2＝8.4Hz，1H)，7.99(dd，J1＝2.4Hz，J26.8Hz, 1H), 7.77(d, J ═ 9.2Hz, 2H), 7.50(m.2h), 7.08(d, J ═ 8.8Hz, 2H), 4.25 (false t, J ═ 5.6Hz, 2H), 3.73 (false q, J ═ 5.2Hz, 2H), EM (calculated): 358.1; MS (ESI) M/e (M +1H)+：357.0，(M-1H)-：355.1.
Compound 2
1H NMR(400MHz，DMSO-d6)11.05(s, 1H), 8.92(t, J ═ 5.6Hz, 1H), 8.88(s, 1H), 7.76(d, J ═ 8.0Hz, 1H), 7.70(d, J ═ 9.2Hz, 2H), 7.64(d, J ═ 8.0Hz, 1H), 7.55(s, 1H), 7.46(t, J ═ 6.8Hz, 1H), 7.32(t, J ═ 8.0Hz, 1H), 7.01(d, J ═ 8.2Hz, 2H), 4.18(t, J ═ 5.6Hz, 2H), 3.67(m, 2H), EM (calculated): 340.1 of the total weight of the mixture; MS (ESI) m/e: (M +1H)+：341.0，(M-1H)-：339.1.
Compound 3
1H NMR(400MHz，DMSO-d6): 11.57(s, 1H), 11.04(s, 1H), 8.71(t, J ═ 5.6Hz, 1H), 7.70(d, J ═ 8.8Hz, 2H), 7.59(d, J ═ 8.4Hz, 1H), 7.40(d, J ═ 8.4Hz, 1H), 7.16(t, J ═ 8.4Hz, 1H), 7.12(m, 1H), 7.00(m, 3H), 4.18(t, J ═ 5.6Hz, 2H), 3.68(m, 2H). EM (calculated): 339.1, respectively; MS (ESI) M/e (M +1H)+：340.1，(M-1H)-：338.3.
Compound 4
EM (calculated): 353.1, respectively; MS (ESI) M/e (M +1)+：354.1，(M-1)-：352.2.
Compound 5
1H NMR(400MHz，DMSO-d6)8.84(t，J＝5.6Hz，1H)，8.05(s，1H)，7.99(dd，J1＝6.0Hz，J2＝2.0Hz，1H)，7.91(dd，J1＝6.4Hz，J22.0Hz, 1H), 7.65(d, J ═ 8.8Hz, 2H), 7.42(m, 2H), 6.88(d, J ═ 8.4Hz, 2H), 4.06(t, J ═ 6.0Hz, 2H), 3.43 (pseudo q, J ═ 5.6Hz, 2H), 2.00 (pseudo p, J ═ 6.0Hz, 2H), EM (calculated): 370.1 of the total weight of the mixture; MS (ESI) M/e (M +1H)+：371.1，(M-1H)-：369.0.
Compound 6
1H NMR(400MHz，DMSO-d6)10.96(s，1H)，8.74(t，J＝6.0Hz，1H)，7.67(d，J＝7.6Hz，1H)，7.62(d，J＝8.4Hz，2H)，7.44(s，1H)，7.55(dd，J1＝8.4Hz，J2＝0.8Hz，1H)，7.43(d，J＝0.8Hz，1H)，7.37(td，J1＝7.2Hz，J2＝1.2Hz，1H)，7.241(td，J1＝8.0HZ，J20.8Hz, 1H), 6.89(d, J ═ 8.8Hz, 2H), 4.01(t, J ═ 6.4Hz, 2H), 3.37 (pseudo q, J ═ 6.0Hz, 2H), 1.94 (pseudo p, J ═ 6.0Hz, 2H), EM (calculated): 354.1 of the total weight of the mixture; MS (ESI) M/e (M +1H)+：355.2，(M-1H)-：353.1.
Compound 7
1H NMR(400MHz，DMSO-d6)11.07(s, 1H), 8.91(s, 1H), 8.65(br d, J ═ 7.2Hz, 1H), 8.20(s, 1H), 8.03(m, 1H), 7.95(m, 1H), 7.72(d, J ═ 8.4Hz, 2H), 7.46(m, 2H), 7.03(d, J ═ 8.8Hz, 2H), 4.20(m, 3H), 2.08(m, 1H), 1.02(d, J ═ 6.8Hz, 6H), EM (calculated): 398.1; MS (ESI) M/e (M +1H)+：399.0，(M-1H)-：397.1.
Compound 8
1H NMR(400MHz，DMSO-d6)11.07(s，1H)，8.91(s，1H)，8.68(d，J＝8.0Hz，1H)，8.17(s，1H)，8.03(dd，J1＝2.0Hz，J2＝6.4Hz，1H)，7.96(dd，J1＝4.0Hz，J2＝6.8Hz，1H)，7.73(d，J＝8.8Hz，2H)，7.46(m，4H)，7.04(d，J＝9.2Hz，2H)，4.24(m，1H)，4.18(dd，J1＝6.8Hz，J2＝10.0Hz，1H)，4.09(dd，J1＝5.2Hz，J29.6Hz), 1.81(m, 1H), 1.67(m, 1H), 0.99(t, J ═ 7.6Hz, 3H) EM (calcd): 384.1; MS (ESI) M/e (M +1H)+：385.0，(M-1H)-：383.1.
Compound 9
1H NMR(400MHz，DMSO-d6)11.11(s，1H)，8.95(br s，1H)，8.80(d，J＝8.0Hz，1H)，8.19(s，1H)，8.06(dd，J1＝5.6Hz，J2＝1.6Hz，1H)，7.98(dd，J1＝6.8Hz，J2＝1.6Hz，1H)，7.76(d，J＝8.4Hz，2H)，7.49(m，2H)，7.08(d，J＝8.8Hz，2H)，4.42(p，J＝6.4Hz，1H)，4.20(dd，J1＝9.6Hz，J2＝6.4Hz，1H)，4.07(dd，J1＝9.6Hz，J25.6Hz, 1H), 1.36(d, J ═ 6.8Hz, 3H), EM (calculated): 370.1 of the total weight of the mixture; MS (ESI) M/e (M +1H)+：371.0，(M-1H)-：368.9.
Compound 10
1H NMR(400MHz，DMSO-d6)10.95(s，1H)，8.65(d，J＝7.6Hz，1H)，8.04(s，1H)，7.91(d，J＝7.2Hz，1H)，7.83(d，J＝6.4Hz，1H)，7.61(d，J＝8.8Hz，2H)，7.34(m，2H)，6.93(d，J＝8.8Hz，2H)，4.27(p.J＝6.4Hz，1H)，4.05(dd，J1＝6.8Hz，J2＝10.0Hz，1H)，3.92(dd，J1＝10.0Hz，J26.0Hz, 1H), 1.21(d, J ═ 5.2Hz, 3H), EM (calculated): 370.1 of the total weight of the mixture; MS (ESI) M/e (M +1H)+：370.9，(M-1H)-：369.0.
Compound 11
1H NMR(400MHz，DMSO-d6)10.96(s，1H)，8.54(d，J＝8.4Hz，1H)，7.68(d，J＝7.6Hz，1H)，7.61(d，J＝8.4Hz，2H)，7.58(d，J＝8.4Hz，1H)，7.48(d，J＝0.8Hz，1H)，7.38(td，J1＝8.0Hz，J2＝0.8Hz，1H)，7.25(td，J1＝7.2Hz，J2＝0.8Hz，1H)，6.92(d，J＝8.8Hz，2H)，4.19(m，1H)，4.07(dd，J1＝10.4Hz，J2＝6.4Hz，1H)，3.99(dd，J1＝10.0Hz，J25.6Hz, 1H), 1.68(m, 1H), 1.55(m, 1H), 0.86(t, J ═ 7.2Hz, 3H) EM (calculated): 368.1, respectively; MS (ESI) M/e (M-1H)-：367.1.
Compound 12
1H NMR(400MHz，DMSO-d6)11.06(s, 1H), 9.03(t, J ═ 6.0Hz, 1H), 8.11(s, 1H), 8.03(d, J ═ 7.2Hz, 1H), 7.94(d, J ═ 6.4Hz, 1H), 7.72(d, J ═ 8.8Hz, 2H), 7.46(m, 2H), 7.07(d, J ═ 9.2Hz, 2H), 4.72 (pseudo q, J ═ 5.6Hz, 1H), 3.62(m, 1H), 3.42(m, 1H), 1.34(d, J ═ 6.4Hz, 3H), EM (calculated): 370.1 of the total weight of the mixture; MS (ESI) M/e (M +1H)+：371.0，(M-1H)-：369.1.
Compound 13
1H NMR(400MHz，DMSO-d6)11.06(s，1H)，9.03(t，J＝5.6Hz，1H)，8.11(s，1H)，8.03(d，J＝6.8Hz，1H)，7.94(d，J＝7.2Hz，1H)，7.72(d，J ═ 8.4Hz, 2H), 7.46 (false p, J ═ 5.6Hz, 2H), 7.07(d, J ═ 8.4Hz, 2H), 4.74 (false q, J ═ 5.6Hz, 1H), 3.63(m, 1H), 3.42(m, 1H), 1.34(d, J ═ 6.0Hz, 3H), EM (calculated): 370.1 of the total weight of the mixture; MS (ESI) M/e (M +1H)+：371.0，(M-1H)-：369.1.
Compound 14
1H NMR(400MHz，DMSO-d6)11.02(s，1H)，8.92(t，J＝6.0Hz，1H)，7.75(d，J＝7.6Hz，1H)，7.68(d，J＝8.8Hz，2H)，7.54(d，J＝0.8Hz，1H)，7.44(td，J1＝7.2Hz，J2＝0.8Hz，1H)，7.31(td，J＝7.6Hz，J20.8Hz, 1H), 7.03(d, J-9.2 Hz, 2H), 4.69 (pseudo q, J-6.4 Hz, 1H), 3.59(ddd, J)1＝6.4Hz，J2＝13.6Hz，J3＝19.6Hz，1H)，3.39(ddd，J1＝6.0Hz，J2＝12.4Hz，J319.6Hz, 1H), 1.29(d, J ═ 6.4Hz, 3H), EM (calculated): 354.1 of the total weight of the mixture; MS (ESI) M/e (M +1H)+：354.7，(M-1H)-：353.1.
Compound 15
EM (calculated): 386.09, respectively; MS (ESI) M/e (M-1H)-：384.7.
Compound 16
EM (calculated): 370.10, respectively; MS (ESI) M/e (M-1H)-：369.0.
Compound 17
EM (calculated): 390.0; MS (ESI) M/e (M +1H)+：391.2.
Compound 18
EM (calculated): 354.12, respectively; MS (ESI) M/e (M-1H)-：353.2.
Compound 19
EM (calculated): 354.12, respectively; MS (ESI) M/e (M-1H)-：353.1.
Compound 20
EM (calculated): 424.07, respectively; MS (ESI) M/e (M-1H)-：423.9.
Compound 21
EM (calculated): 374.0, respectively; MS (ESI) M/e (M +1)+：375.0，(M-1)-：373.0.
Compound 22
EM (calculated): 386.1 of the total weight of the steel; MS (ESI) M/e (M +1)+：387.1，(M-1)-：384.7.
Compound 23
EM (calculated): 374.1; MS (ESI) M/e (M +1)+：374.9，(M-1)-：372.9.
Compound 24
EM (calculated): 370.1 of the total weight of the mixture; MS (ESI) M/e (M +1)+：370.8，(M-1)-：369.0.
Compound 25
EM (calculated): 370.1 of the total weight of the mixture; MS (ESI) M/e (M +1)+：371.0，(M-1)-：369.1.
Compound 26
EM (calculated): 414.14, respectively; MS (ESI) M/e (M +1H)+：415.2，(M-1H)-：413.2.
Compound 27
EM (calculated): 469.18, respectively; MS (ESI) M/e (M +1H)+：470.1，(M-1H)-：468.4.
Compound 28
EM (calculated): 447.14, respectively; MS (ESI) M/e (M +1H)+：448.1，(M-1H)-：446.2.
Compound 29
EM (calculated): 354.1 of the total weight of the mixture; MS (ESI) M/e (M +1)+：355.1，(M-1)-：353.1.
Compound 30
EM (calculated): 370.1 of the total weight of the mixture; MS (ESI) M/e (M +1)+：371.0，(M-1)-：368.9.
Compound 31
EM (calculated): 400.1; MS (ESI) M/e (M +1H)+：401.0，(M-1H)-：399.2.
Compound 32
EM (calculated): 427.1, respectively; MS (ESI) M/e (M +1H)+：428.2，(M-1H)-：426.2.
Compound 33
EM (calculated): 414.1, respectively; MS (ESI) M/e (M +1)+：415.4，(M-1)-：413.2.
Compound 34
EM (calculated): 469.2, respectively; MS (ESI) M/e (M +1)+：470.1，(M-1)-：468.3.
Compound 35
EM (calculated): 447.1, respectively; MS (ESI) M/e (M +1)+：448.2，(M-1)-：446.5.
Compound 36
EM (calculated): 368.1, respectively; MS (ESI) M/e (M +1)+：369.0，(M-1)-：367.2.
Compound 37
1H NMR(400MHz，DMSO-d6)11.69(s, 1H), 11.04(s, 1H), 8.77(t, J ═ 5.6Hz, 1H), 7.70(d, J ═ 8.4Hz, 2H), 7.39(m, 2H), 7.11(s, 1H), 7.05(m, 1H), 7.01(d, J ═ 8.4Hz, 2H), 4.18(t, J ═ 6.0Hz, 2H), 3.67(m, 2H) EM (calculated): 357.1; MS (ESI) M/e (M +1H)+：357.8，(M-1H)-：356.2.
Compound 38
1H NMR(400MHz，DMSO-d6)11.42(s, 1H), 11.05(s, 1H), 8.66, (t, J ═ 5.6Hz, 1H), 7.70(d, J ═ 9.2Hz, 2H), 7.29(d, J ═ 8.4Hz, 1H), 7.03(m, 4H), 6.81(m, 1H), 4.17(t, J ═ 5.6Hz, 2H), 3.75(s, 3H), 3.66(m, 2H) EM (calculated): 369.1; MS (ESI) M/e (M +1H)+：369.9，(M-1H)-：368.2.
Compound 39
EM (calculated): 384.13, respectively; MS (ESI) M/e (M +1H)+：384.9，(M-1H)-：383.2.
Compound 40
EM (calculated): 446.15, respectively; MS (ESI) M/e (M +1H)+：447.2，(M-1H)-：445.4.
Compound 41
1H NMR(400MHz，DMSO-d6)11.28(s, 1H), 11.04(s, 1H), 8.53(t, J ═ 5.6Hz, 1H), 7.70(d, J ═ 9.2Hz, 2H), 7.02(m, 4H), 6.86(s, 1H), 4.16(t, J ═ 5.6Hz, 2H), 3.76(s, 3H), 3.75(s, 3H), 3.63(m, 2H), EM (calculated): 399.1, respectively; MS (ESI) M/e (M +1H)+：400.0，(M-1H)-：398.1.
Compound 42
1H NMR(400MHz，DMSO-d6)11.09(bs, 1H), 10.60(bs, 1H), 9.29(t, J ═ 6.0Hz, 1H), 8.08(d, J ═ 8.0 Hz; 1H) 7.70(m, 3H), 7.57(t, J ═ 7.2Hz, 1H), 7.45(t, J ═ 7.2Hz, 1H), 7.00(d, J ═ 9.2Hz, 2H), 4.83(m, 2H), 4.23(t, J ═ 6.0Hz, 2H), 3.94(m, 2H), 3.73(m, 4H), 3.44(m, 2H), 3.27(m, 2H), EM (calculated): 439.2, respectively; MS (ESI) M/e (M +1H)+：439.8，(M-1H)-：438.2.
Compound 44
EM (calculated): 412.16, respectively; MS (ESI) M/e (M +1H)+：413.1，(M-1H)-：411.3.
Compound 45
1H NMR(400MHz，DMSO-d6)11.05(s, 1H), 8.92(t, J ═ 5.2Hz, 1H), 7.74(d, J ═ 7.6Hz, 1H), 7.70(d, J ═ 8.8Hz, 2H), 7.59(s, 1H), 7.55(d, J ═ 6.8Hz, 1H), 7.32(m, 3H), 7.06(d, J ═ 7.6Hz, 2H), 7.00(d, J ═ 9.2Hz, 2H), 6.95(t, J ═ 7.2Hz, 1H), 5.44(s, 2H), 4.19(t, J ═ 6.0Hz, 2H), 3.69(m, 2H) · EM (calculated value): 446.2; MS (ESI) M/e (M +1H)+：447.2，(M-1H)-：445.3.
Compound 46
1H NMR(400MHz，DMSO-d6)11.08(s, 1H), 8.91(t, J ═ 5.6Hz, 1H), 7.71(m, 3H), 7.58(s, 1H), 7.44(d, J ═ 7.6Hz, 1H), 7.32(t, J ═ 7.6Hz, 1H), 7.03(d, J ═ 8.8Hz, 2H), 4.78(s, 2H), 4.20(t, J ═ 6.0Hz, 2H), 3.69(m, 2H), 3.36(s, 3H). EM (calculated): 384.1; MS (ESI) M/e (M +1H)+：385.9，(M-1H)-：383.2.
Compound 47
1H NMR(400MHz，DMSO-d6)11.33(s, 1H), 11.09(s, 1H), 9.32(t, J ═ 5.6Hz, 1H), 7.88(d, J ═ 8.4Hz, 1H), 7.71(m, 3H), 7.61(s, 1H), 7.43(t, J ═ 7.6Hz, 1H), 7.03(d, J ═ 8.8Hz, 1H), 4.68(s, 2H), 4.23(t, J ═ 5.6Hz, 2H), 3.83(m, 6H), 3.37(m, 2H), 3.20(m, 2H), EM (calculated): 439.2, respectively; MS (ESI) M/e (M +1H)+：440.2，(M-1H)-：438.4.
Compound 48
1H NMR(400MHz，DMSO-d6)11.09(s, 1H)10.74(s, 1H), 9.31(t, J ═ 5.6Hz, 1H), 7.88(d, J ═ 8.0Hz, 1H), 7.72(d, J ═ 8.6Hz, 2H), 7.65(d, J ═ 7.2Hz, 1H), 7.62(s, 1H), 7.42(t, J ═ 8.0Hz, 1H), 7.02(d, J ═ 8.8Hz, 2H), 4.63(d, J ═ 5.2Hz, 2H), 4.23(t, J ═ 6.0Hz, 2H), 3.70(m, 2H), 2.78(s, 3H), 2.770(s, 3H), EM (calculated value): 397.2; MS (ESI) M/e (M +1H)+：398.0，(M-1H)-：396.1.
Compound 49
EM (calculated): 384.1; MS (ESI) M/e (M-1)-：382.9.
Compound 50
EM (calculated): 400.1; MS (ESI) M/e (M-1)-：398.7.
Compound 51
1H NMR(400MHz，DMSO-d6)11.07(s, 1H), 8.78(t, J ═ 6.0Hz, 1H), 7.71(m, 3H), 7.54(s, 1H), 7.43(d, J ═ 7.2Hz, 1H), 7.32(d, J ═ 7.6Hz, 1H), 6.99(d, J ═ 8.4Hz, 2H), 4.77(s, 2H), 4.10(t, J ═ 6.0Hz, 2H), 3.47(m, 2H), 3.36(s, 3H), 2.02(m, 2H), EM (calculated): 398.2; MS (ESI) M/e (M +1H)+：399.1，(M-1H)-：397.1.
Compound 52
1H NMR(400MHz，DMSO-d6)8.82(t, J ═ 5.6Hz, 1H), 7.71(m, 3H), 7.54(m, 2H), 7.31(m, 3H), 7.06(d, J ═ 8.0Hz, 2H), 6.95(m, 3H), 5.43(s, 2H), 4.09(t, J ═ 6.0Hz, 2H), 3.47(m, 2H), 2.02(m, 2H), EM (calculated): 460.2, respectively; MS (ESI) M/e (M +1H)+：461.0，(M-1H)-：459.1.
Compound 53
EM (calculated): 428.16, respectively; MS (ESI) M/e (M +1H)+：428.9，(M-1H)-：427.1.
Compound 54
1H NMR(DMSO-d6)：2.11(3H，s)；2.78(1H，dd，14,8Hz)；2.86(1H，dd，14,5Hz)；4.17(1H，dd，10,4Hz)；4.23(1H，dd，10,6Hz)；4.49(1H，m)；7.00(2H，d，9Hz)；7.32(1H，t，7Hz)；7.46(1H，td，8,1Hz)；7.56(1H，s)；7.64(1H，d，8Hz)；7.70(2H，d，9Hz)；7.77(1H，d，8Hz)；8.77(1H，d，8Hz)；8.88(1H，s).MS(M+1)：401.
Compound 55
1H NMR(DMSO-d6)：3.31(3H，s)；3.53(1H，dd，13，3.5Hz)；3.66(1H，dd，13,8Hz)；4.16(1H，dd，9,6Hz)；4.24(1H，dd，9,8Hz)；4.87(1H，m)；7.00(2H，d，9Hz)；7.33(1H，t，7Hz)；7.47(1H，t，8Hz)；7.57(1H，s)；7.65(1H，d，8Hz)；7.70(2H，d，9Hz)；7.77(1H，d，8Hz)；8.89(1H，s)；9.0(1H，d，8Hz).MS(M-1)：431.
Compound 56
1H NMR(400MHz，DMSO-d6): 7.92 (brs, 1H), 8.76(t, 1H, J ═ 5.9Hz), 7.75(m, 3H), 7.60(d, 1H, J ═ 7.6Hz), 7.48(t, 1H, J ═ 8.0Hz), 7.32(t, 1H, J ═ 8.0Hz), 7.27(m, 5H), 7.17(m, 1H), 7.04(m, 2H), 4.21(t, 2H, J ═ 5.9Hz), 3.69(m, 2H)3.39(m, 2H), 2.96(t, 2H, J ═ 8.3Hz). EM (calculated): 444; MS (ESI) M/e (M +1H)+：445.3，(M-1H)-：443.3.
Compound 57
1H NMR(400MHz，DMSO-d6)11.07(s，1H)，9.38(s，1H)，8.90(s，1H)，7.94(d，J＝8.0Hz，1H)，7.57(m，10H)，6.97(d，J＝8.0Hz，2H)，4.80(m，2H)，4.20(s，2H)，3.70(m，2H)，3.31(m，3H)，2.66(m，2H).MS(ESI)m/e：(M+1H)+：474.4，(M-1H)-：472.1.
Compound 58
1H NMR(400MHz，DMSO-d6)11.05(s，1H)，9.73(m，1H)，8.89(s，1H)，7.75(d，J＝8.0Hz，2H)，7.70(t，J＝8.0Hz，2H)，7.61(d，J＝8.0Hz，1H)，7.43(t，8.0Hz，1H)，7.18(m，6H)，6.98(d，J＝8.0Hz，2H)，4.13(t，J＝8.0Hz，2H)，3.95(m，2H)，3.58(m，2H)，2.78(m，2H)，2.65(m，2H)，1.24(s，3H).MS(ES1)m/e：(M+1H)+：487.9，(M-1H)-：486.1.
Compound 59
1H NMR(400MHz，DMSO-d6)11.04(s，1H)，8.88(s，1H)，8.84(t，J＝8.0Hz，1H)，7.82(d，J＝8.0Hz，1H)，7.70(d，J＝8.0Hz，2H)，7.59(d，J＝8.0Hz，1H)，7.48(t，J＝8.0Hz，1H)，7.34(t，J＝8.0Hz，1H)，7.00(d，J＝8.0Hz，2H)，4.31(s，2H)，4.18(t，J＝8.0Hz，2H)，3.66(m，2H)，3.38(m，2H)，2.45(t，J＝8.0Hz，2H)，1.65(m，2H).MS(ESI)m/e：(M+1H)+：445.2，(M-1H)-：443.1.
Compound 60
1H NMR(400MHz，DMSO-d6)11.05(s，1H)，9.04(t，J＝8.0Hz，1H)，7.86(d，J＝8.0Hz，1H)，7.70(d，J＝8.0Hz，2H)，7.63(d，J＝8.0Hz，1H)，7.50(t，J＝8.0Hz，1H)，7.36(t，J＝8.0Hz，1H)，7.00(d，J＝8.0Hz，2H)，4.57(m，2H)，4.18(t，J＝8.0Hz，2H)，3.65(m，2H)，3.46(t，J＝8.0Hz，2H)，2.77(m，2H)，1.80(m，2H).MS(ESI)m/e：(M+1H)+：461.0，(M-1H)-：459.1.
Compound 61
1H NMR(400MHz，DMSO-d6)11.04(s，1H)，9.05(t，J＝8.0Hz，1H)，7.87(d，J＝8.0Hz，1H)，7.70(d，J＝8.0Hz，2H)，7.64(d，J＝8.0Hz，1H)，7.51(t，J＝8.0Hz，1H)，7.38(t，J＝8.0Hz，1H)，7.00(d，J＝8.0Hz，2H)，5.11(s，2H)，4.19(t，J＝8.0Hz，2H)，3.68(m，2H)，3.44(t，J＝8.0Hz，2H)，3.13(m，2H)，1.83(m，2H).MS(ESI)m/e：(M+1H)+：477.0，(M-1H)-：475.0.
Compound 62
MS(ESI)m/e：(M+1H)+：527.6，(M-1H)-：525.5.
Compound 63
1H NMR(400MHz，DMSO-d6)：11.04(s，1H)，8.88(br s，1H)，8.73(t，1H，J＝5.9Hz)，7.75-7.69(m, 3H), 7.57-7.42(m, 6H), 7.28(t, 1H, J ═ 7.7Hz), 7.00(d, 2H, J ═ 8.7Hz), 4.17(t, 2H, J ═ 5.9Hz), 3.65(q, 2H, J ═ 5.9Hz)3.40(t, 2H, J ═ 6.9Hz), 3.04(t, 2H, J ═ 6.9Hz) EM (calculated): 512; MS (ESI) M/e (M +1H)+：513.3，(M-1H)-：511.2.
Compound 64
1H NMR(400MHz，DMSO-d6): 11.04(s, 1H), 8.87(br s, 1H), 8.83(t, 1H, J ═ 5.9Hz), 7.70(m, 3H), 7.55(d, 1H, J ═ 8.3Hz), 7.43(t, 1H, J ═ 7.4Hz), 7.34(t, 1H, J ═ 8.0Hz), 7.28-7.20(m, 3H), 7.11(d, 1H, 8.0Hz), 7.00(d, 2H, J ═ 8.6Hz), 4.17(t, 2H, J ═ 5.9Hz), 3.65(q, 2H, J ═ 5.9Hz), 3.38(t, 2H, J ═ 8.3Hz), 3.00(t, 8.3H, J ═ 8.3 (calculated value of EM): 528 of the raw material; MS (ESI) M/e (M +1H)+：529.4，(M-1H)-：527.5.
Compound 65
1H NMR(400MHz，DMSO-d6)11.06(s，1H)，10.93(s，1H)，9.32(m，2H)，9.23(s，1H)，8.89(s，1H)，7.96(d，J＝8.0Hz，1H)，7.70(m，3H)，7.56(t，J＝8.0Hz，1H)，7.44(t，J＝8.0Hz，1H)，7.00(d，J＝8.0Hz，2H)，4.64(s，2H)，4.23(t，J＝8.0Hz，2H)，3.71(m，4H).MS(ESI)m/e：(M+1H)+：443.4，(M-1H)-：441.4.
Compound 66
1H NMR(400MHz，DMSO-d6)11.06(s，1H)，9.33(t，J＝8.0Hz，1H)，8.89(s，1H)，8.00(d，J＝8.0Hz，1H)，7.71(m，3H)，7.56(t，J＝8.0Hz，1H)，7.43(t，J＝8.0Hz，3H)，7.00(d，J＝8.0Hz，2H)，4.60(s，2H)，4.23(t，J＝8.0Hz，2H)，3.71(m，2H)，3.20(t，J＝8.0Hz，2H)，2.72(t，J＝8.0Hz，2H).MS(ESI)m/e：(M+1H)+：442.3，(M-1H)-：440.1.
Compound 67
1H NMR(400MHz，DMSO-d6): 9.11(t, 1H, J ═ 6.0Hz), 7.82(d, 1H, J ═ 7.7Hz), 7.76(d, 2H, J ═ 8.5Hz), 7.69(d, 1H, J ═ 8.5Hz), 7.62(s, 1H), 7.51(t, 1H, J ═ 8.5Hz), 7.40-7.30(m, 3H), 7.21(d, 2H, J ═ 8.5Hz), 7.00-6.97(m, 3H), 4.99(m, 1H), 4.35(m, 1H), 4.27(m, 1H), 3.78(m, 1H), 3.70(m, 1H), EM (calculated value): 446.15, respectively; MS (ESI) M/e (M +1H)+：447.4，(M-1H)-：445.3.
Compound 68
1H NMR(400MHz，DMSO-d6)11.04(s，1H)，8.86(t，J＝4.0Hz，1H)，7.83(d，J＝8.0Hz，1H)，7.70(d，J＝8.0Hz，2H)，7.61(d，J＝8.0HZ，1H)，7.47(t，J＝8.0Hz，1H)，7.33(t，J＝4.0Hz，1H)，7.00(d，J＝8.0Hz，2H)，5.02(s，2H)，4.18(t，J＝8.0Hz，2H)，3.65(m，2H)，3.52(t，J＝8.0Hz，2H)，3.44(t，J＝8.0Hz，2H)，1.68(m，2H).MS(ESI)m/e：(M+1H)+：429.1，(M-1H)-：426.9.
Compound 69
1H NMR(400MHz，DMSO-d6): 11.04(s, 1H), 9.03(t, 1H, J ═ 5.9Hz), 7.86(d, 1H, J ═ 9.2Hz), 7.70(d, 2H, J ═ 8.3Hz), 7.63(d, 1H, J ═ 8.3Hz), 7.49(t, 1H, J ═ 8.8Hz), 7.36(t, 1H, J ═ 7.0Hz), 7.29(t, 1H, J ═ 8.8Hz), 7.18(m, 1H), 7.07(t, 1H, J ═ 7.0Hz), 7.00(d, 1H, J ═ 8.3Hz), 6.91(m, 1H), 5.78(s, 2H), 4.20(t, 2H, J ═ 5.9), 3.68(q ═ 5.9Hz), 5.68 (q ═ 9 Hz): 464; MS (ESI) M/e (M +1H)+：465.1，(M-1H)-：463.1.
Compound 70
1H NMR(400MHz，DMSO-d6)：11.04(s，1H)，9.04(t，1H，J＝5.9Hz)，9.00(br s，1H)，7.84(d，1H，J＝7.3Hz)，7.70(d，2H，J＝9.2Hz)，7.63(d，1H，J＝8.1Hz)，7.49(t，1H，J＝8.6Hz)，7.35(t，1H，J＝7.7Hz)，7.27(m，1H)，7.18(m，1H)，7.00(d，1H，J＝9.2Hz)，6.95(m，1H)，687(m, 1H), 6.74(m, 1H), 5.71(s, 2H), 4.21(t, 2H, J ═ 5.9Hz), 3.69(q, 2H, J ═ 5.9Hz), EM (calculated): 464; MS (ESI) M/e (M +1H)+：465.0，(M-1H)-：463.1.
Compound 71
1H NMR(400MHz，DMSO-d6): 11.04(s, 1H), 9.00(t, 1H, J ═ 5.9Hz), 7.84(d, 1H, J ═ 8.4Hz), 7.70(d, 2H, J ═ 9.2Hz), 7.62(d, 1H, J ═ 8.8Hz), 7.48(t, 1H, J ═ 8.4Hz), 7.34(t, 1H, J ═ 7.3Hz), 7.10-7.00(m, 6H), 5.67(s, 2H), 4.20(t, 2H, J ═ 5.9Hz), 3.68(q, 2H, J ═ 5.9Hz), EM (calculated): 464; MS (ESI) M/e (M +1H)+：464.9，(M-1H)-：463.0.
Compound 72
1H NMR(400MHz，DMSO-d6)11.04(s，1H)，8.88(m，2H)，7.86(d，J＝8.0Hz，1H)，7.70(d，J＝8.0Hz，2H)，7.61(d，J＝8.0HZ，1H)，7.47(t，J＝8.0Hz，1H)，7.33(t，J＝4.0Hz，1H)，7.00(d，J＝8.0Hz，2H)，5.05(s，2H)，4.19(t，J＝8.0Hz，2H)，3.65(m，2H)，3.59(m，2H)，3.47(m，2H)，3.23(s，3H).MS(ESI)m/e：(M+1H)+：428.9，(M-1H)-：426.9.
Compound 73
1H NMR(400MHz，DMSO-d6)11.05(s，1H)，9.20(t，J＝4.0Hz，1H)，8.83(d，J＝8.0Hz，2H)，7.86(d，J＝8.0Hz，1H)，7.71(d，J＝8.0Hz，2H)，7.66(d，J＝8.0Hz，1H)，7.51(t，J＝8.0Hz，1H)，7.38(t，J＝8.0Hz，1H)，7.25(d，J＝8.0Hz，2H)，6.98(d，J＝8.0Hz，2H)，6.07(s，2H)，4.21(t，J＝8.0Hz，2H)，3.70(m，2H).MS(ESI)m/e：(M+1H)+：448.0，(M-1H)-：446.4.
Compound 74
1H NMR(400MHz，DMSO-d6)：8.86(m，1H)，8.81(br s，1H)，7.80(d，1H，J＝8.2Hz)，7.63(d，2HJ9.4 Hz), 7.57(d, 1H, J8.2 Hz), 7.44(t, 1H, J7.8 Hz), 7.32(t, 1H, J7.0 Hz), 7.12(t, 1H, J9.0 Hz), 6.91(t, 1H, J8.6 Hz), 5.64(s, 2H), 4.06(t, 2H, J6.0 Hz), 3.54(t, 2H, J6.0 Hz) EM (calculated): 500.13 of the total weight of the mixture; MS (ESI) M/e (M +1H)+：501.5，(M-1H)-：499.3.
Compound 75
1H NMR(400MHz，DMSO-d6)11.04(s，1H)，9.14(t，J＝4.0Hz，1H)，7.89(m，1H)，7.70(m，3H)，7.61(d，J＝8.0Hz，1H)，7.46(m，1H)，7.40(m，ITI)，7.29(t，J＝4.0Hz，1H)，7.02(d，J＝8.0Hz，2H)，6.43(d，J＝8.0Hz，1H)，6.23(t，J＝4.0Hz，1H)，5.62(s，2H)，4.23(t，J＝4.0Hz，2H)，3.72(m，2H).MS(ESI)m/e：(M+1H)+：448.2，(M-1H)-：446.4.
Compound 76
1H NMR(400MHz，DMSO-d6)11.04(s，1H)，8.96(t，J＝4.0Hz，1H)，8.88(s，1H)，7.82(d，J＝8.0Hz，1H)，7.70(d，J＝8.0Hz，2H)，7.63(d，J＝8.0Hz，1H)，7.50(t，J＝8.0Hz，1H)，7.36(t，J＝8.0Hz，1H)，7.00(d，J＝8.0Hz，2H)，5.24(s，2H)，4.18(m，4H)，3.66(m，2H).MS(ESI)m/e：(M+1H)+：453.3，(M-1H)-：451.1.
Compound 77
1H NMR(400MHz，DMSO-d6)11.05(s，1H)，9.04(t，J＝4.0Hz，1H)，8.89(s，1H)，8.09(s，1H)，7.87(d，J＝8.0Hz，1H)，7.70(d，J＝8.0Hz，2H)，7.63(d，J＝8.0Hz，1H)，7.89(m，1H)，7.50(m，3H)，7.35(t，J＝8.0Hz，1H)，7.17(d，J＝8.0Hz，2H)，7.03(m，3H)，5.77(s，2H)，4.22(t，J＝8.0Hz，2H)，3.70(m，2H).MS(ESI)m/e：(M+1H)+：513.1，(M-1H)-：511.1.
Compound 78
1H NMR(400MHz，DMSO-d6): 9.05(s, 1H), 8.97(t, 1H, J ═ 5.9Hz), 8.81(s, 1H), 8.08(s, 1H), 7.80(d, 1H, J ═ 7.6Hz), 7.66-7.62(m, 4H), 7.56(d, 1H, J ═ 8.6Hz), 7.42(t, 1H, J ═ 8.1Hz), 7.28(t, 1H, J ═ 7.6Hz), 7.15(m, 2H), 6.94(d, 2H, J ═ 8.6Hz), 5.70(s, 2H), 4.15(t, 2H, J ═ 5.9Hz), 3.64(t, 2H, J ═ 5.9Hz), EM (calculated value): 513.16, respectively; MS (ESI) M/e (M +1H)+：514.2，(M-1H)-：512.2.
Compound 79
1H NMR(400MHz，DMSO-d6)11.08(s，1H)，10.33(s，1H)，9.25(t，J＝4.0Hz，1H)，8.11(d，J＝8.0Hz，1H)，7.70(m，3H)，7.53(t，J＝8.0Hz，1H)，7.44(t，J＝8.0Hz，1H)，6.99(d，J＝8.0Hz，2H)，4.84(d，J＝4.0Hz，2H)，4.23(t，J＝8.0Hz，2H)，3.70(m，2H)，3.48(m，2H)，3.23(m，2H)，2.04(m，2H)，1.90(m，2H).MS(ESI)m/e：(M+1H)+：424.1，(M-1H)-：422.3.
Compound 80
1H NMR(400MHz，DMSO-d6)11.06(s，1H)，9.87(s，1H)，9.29(t，J＝4.0Hz，1H)，8.03(d，J＝8.0Hz，1H)，7.71(m，3H)，7.57(t，J＝8.0Hz，1H)，7.45(t，J＝8.0Hz，1H)，6.99(d，J＝8.0Hz，2H)，4.77(s，2H)，4.23(t，J＝8.0Hz，2H)，3.70(m，2H)，3.48(m，2H)，3.04(m，2H)，1.73(m，5H)，1.38(m，1H).MS(ESI)m/e：(M+1H)+：438.0，(M-1H)-：436.3.
Compound 81
1H NMR(400MHz，DMSO-d6)11.05(s，1H)，9.55(t，J＝4.0Hz，1H)，8.89(s，1H)，7.89(d，J＝8.0Hz，1H)，7.70(d，J＝8.0Hz，2H)，7.61(d，J＝8.0Hz，1H)，7.45(t，J＝8.0Hz，1H)，7.33(t，J＝8.0Hz，1H)，6.99(d，J＝8.0Hz，2H)，4.19(t，J＝8.0Hz，2H)，3.96(s，2H)，3.68(m，2H)，2.95(m，2H)，2.28(m，1H)，2.09(m，2H)，1.78(m，2H)，1.44(m，2H).MS(ESI)m/e：(M+1H)+：506.1，(M-1H)-：504.2.
Compound 82
1H NMR(400MHz，DMSO-d6)11.07(s，1H)，9.18(s，1H)，8.04(s，1H)，7.70(m，3H)，7.53(t，J＝8.0Hz，1H)，7.39(t，J＝8.0Hz，1H)，7.00(d，J＝8.0Hz，2H)，4.21(t，J＝8.0Hz，2H)，3.70(m，12H)，2.76(s，3H).MS(ESI)m/e：(M+1H)+：453.0，(M-1H)-：451.1.
Compound 83
1H NMR(400MHz，DMSO-d6)11.05(s，1H)，8.90(m，2H)，7.83(d，J＝8.0Hz，1H)，7.70(d，J＝8.0Hz，2H)，7.61(d，J＝8.0Hz，1H)，7.48(t，J＝8.0Hz，1H)，7.34(t，J＝8.0Hz，1H)，7.00(d，J＝8.0Hz，2H)，5.08(s，2H)，4.19(t，J＝8.0Hz，2H)，3.68(m，4H)，2.58(m，2H).MS(ESI)m/e：(M+1H)+：467.0，(M-1H)-：465.1.
Compound 84
1H NMR(400MHz，DMSO-d6): 11.07(s, 1H), 8.91(m, 2H), 7.73(d, 2H, J ═ 9.0Hz), 7.66(s, 1H), 7.47(d, 1H, J ═ 8.7Hz), 7.37(t, 1H, J ═ 8.4Hz), 7.15(d, 1H, J ═ 7.4Hz), 7.04(d, 2H, J ═ 9.0Hz), 4.21(t, 1H, J ═ 5.7Hz), 3.69(t, 2H, J ═ 5.7Hz), 3.36(s, 3H). EM (calculated): 354.12, respectively; MS (ESI) M/e (M +1H)+：354.7，(M-1H)-：353.1.
Compound 85
1H NMR(400MHz，DMSO-d6)11.05(s，1H)，8.88(s，1H)，8.80(t，J＝8.0Hz，1H)，7.76(d，J＝8.0Hz，1H)，7.71(d，J＝8.0Hz，2H)，7.57(d，J＝8.0Hz，1H)，7.46(t，J＝8.0Hz，1H)，7.32(m，3H)，7.03(m，4H)，4.76(s，2H)，4.15(t，J＝8.0Hz，2H)，3.62(m，2H).MS(ESI)m/e：(M+1H)+：481.1，(M-1H)-：479.0.
Compound 86
1H NMR(400MHz，DMSO-d6)11.05(s，1H)，8.88(m，2H)，7.71(d，J＝8.0Hz，2H)，7.55(m，4H)，7.46(t，J＝8.0Hz，1H)，7.28(m，3H)，7.00(d，J＝8.0Hz，2H)，4.77(s，2H)，4.15(t，J＝8.0Hz，2H)，3.60(m，2H).MS(ESI)m/e：(M+1H)+：497.3，(M-1H)-：495.1.
Compound 87
1H NMR(400MHz，DMSO-d6)11.05(s，1H)，8.89(s，1H)，8.82(t，J＝8.0Hz，1H)，7.74(d，J＝8.0Hz，1H)，7.71(d，J＝8.0Hz，2H)，7.63(m，3H)，7.50(t，J＝8.0Hz，1H)，7.34(m，3H)，7.00(d，J＝8.0Hz，2H)，5.32(s，2H)，4.06(t，J＝8.0Hz，2H)，3.49(m，2H).MS(ESI)m/e：(M+1H)+：513.2，(M-1H)-：511.2.
Compound 88
1H NMR(400MHz，DMSO-d6)11.03(s，1H)，8.88(s，1H)，8.68(d，J＝8.0Hz，1H)，7.81(d，J＝8.0Hz，1H)，7.69(d，J＝8.0Hz，2H)，7.64(d，J＝8.0Hz，1H)，7.50(t，J＝8.0Hz，1H)，7.36(t，J＝8.0Hz，1H)，6.98(d，J＝8.0Hz，2H)，5.25(s，2H)，4.18(m，5H)，1.72(m，2H)，0.94(t，J＝8.0Hz，3H).MS(ESI)m/e：(M+1H)+：481.2，(M-1H)-：479.2.
Compound 89
1H NMR(400MHz，DMSO-d6): 11.94(s, 1H), 11.04(m, 1H), 9.36(m, 1H), 8.88(br s, 1H), 8.63(s, 1H), 7.71(d, 2H, J ═ 8.5Hz), 7.22(t, 1H, J ═ 8.1Hz), 7.07(dd, 1H, J ═ 8.1, 1.7Hz), 7.02(d, 2H, J ═ 8.5Hz), 6.65(dd, 1H, J ═ 7.6, 1.6Hz), 4.21(t, 2H, J ═ 5.6Hz), 3.73(2H, q, J ═ 5.2Hz), EM (calculated value): 356; MS (ESI) M/e (M +1H)+：357.2，(M-1H)-：354.9.
Compound 90
1H NMR(400MHz，DMSO-d6): 11.03(s, 1H), 8.69(d, 1H, J ═ 8.3Hz), 7.86(d, 1H, J ═ 2.1Hz), 7.69(m, 3H), 7.54(s, 1H), 7.47(dd, 1H, J ═ 8.5Hz, 2.5Hz), 6.98(d, 2H, J ═ 8.6Hz), 4.24(m, 1H), 4.13(m, 1H), 4.06(m, 1H), 1.75(m, 1H), 1.62(m, 1H), 0.93(t, 3H, J ═ 7.3Hz). EM (calculated): 402, performing a chemical reaction; MS (ES1) M/e (M +1H)+：403.0，(M-1H)-：400.9.
Compound 91
1H NMR(400MHz，DMSO-d6): 11.02(s, 1H), 9.00(t, 1H, J ═ 5.8Hz), 7.85(d, 1H, J ═ 1.9Hz), 7.68(m, 3H), 7.52(s, 1H), 7.46(dd, 1H, J ═ 8.5Hz, 1.9Hz), 7.03(d, 2H, J ═ 8.5Hz), 4.69(m, 1H), 3.57(m, 1H), 3.40(m, 1H), 1.32(d, 3H, J ═ 5.9Hz), EM (calculated): 388; MS (ESI) M/e (M +1H)+：389.1，(M-1H)-：387.0.
Compound 92
1H NMR(400MHz，DMSO-d6): 11.05 (brs, 1H), 8.96(t, 1H, J ═ 5.6Hz), 8.80(d, 1H, J ═ 2.0Hz), 8.75(dd, 1H, J ═ 5.6, 0.8Hz), 8.35(d, 1H, J ═ 8.0Hz), 7.87(dd, 1H, J ═ 7.6, 5.6Hz), 7.71(m, 3H), 7.61(d, 1H, J ═ 8.0Hz), 7.45(t, 1H, J ═ 6.8Hz), 7.34(d, 1H, J ═ 7.2Hz), 7.00(m, 2H), 4.91(s, 2H), 4.75(s, 2H), 4.18(t, 2H, J ═ 5.6), 3.00(m, 2H), 4.91(s, 2H), 4.75 (calculated value (t, 2H, J ═ 6.66, 6H), 3.66(q ═ 6 Hz): 461; MS (ESI) M/e (M +1H)+：462.2，(M-1H)-：460.3.
Compound 93
1H NMR(400MHz，DMSO-d6): 11.00(s, 1H), 8.82(m, 1H), 8.37(s, 1H), 7.67(dd, 2H, J ═ 6.8, 1.6Hz), 7.32-7.24(m, 2H), 7.01(d, 2H, J ═ 9.6Hz), 6.90(d, 1H, J ═ 8.0Hz), 4.17(t, 2H, J ═ 5.2Hz), 3.89(s, 3H), 3.69(m, 2H) EM (calculated): 370; MS (ESI) M/e (M +1H)+：371.2，(M-1H)-：369.1.
Compound 94
1H NMR(400MHz，DMSO-d6): 11.04(s, 1H), 8.96(t, 1H, J ═ 5.6Hz), 8.45(s, 1H), 7.70(d, 2H, J ═ 8.4Hz), 7.37-7.30(m, 2H), 7.02(d, 2H, J ═ 8.4Hz), 6.98(dd, 1H, J ═ 7.6, 0.8Hz), 4.37(m, 2H), 4.17(t, 2H, J ═ 5.6Hz), 3.82(m, 2H), 3.69(q, 2H, J ═ 6.0Hz), 3.34(s, 3H). EM (calculated): 414; MS (ESI) M/e (M +1H)+：415.2，(M-1H)-：413.3.
Compound 95
1H NMR(400MHz，DMSO-d6): 11.04 (brs, 1H), 8.86(m, 1H), 8.65(t, 1H, 5.6Hz), 8.61(dd, 1H, J ═ 4.8, 1.6Hz), 8.37(s, 1H), 8.13(m, 1H), 7.67(m, 2H), 7.54(m, 1H), 7.38-7.31(m, 2H), 7.07(dd, 1H, J ═ 7.6, 0.8Hz), 6.88(m, 2H), 5.40(s, 2H), 3.91(t, 2H, J ═ 6.0Hz), 3.40(m, 2H). EM (calculated): 447 (c); MS (ESI) M/e (M +1H)+：448.2，(M-1H)-：446.1.
Compound 96
1H NMR(400MHz，DMSO-d6): 11.57(s, 1H), 8.65(t, 1H, J ═ 4.5Hz), 7.69(d, 2H, J ═ 8.5Hz), 7.20(s, 1H), 7.09-6.98(m, 4H), 6.48(d, 1H, J ═ 7.9Hz), 4.17(m, 2H), 3.85(s, 3H), 3.65(m, 2H). EM (calculated): 369; MS (ESI) M/e (M +1H)+：370.1，(M-1H)-：368.2.
Compound 97
1H NMR(400MHz，DMSO-d6): 11.06(s, 1H), 8.62(d, 1H, J ═ 8.7Hz), 7.88(d, 1H, J ═ 7.6Hz), 7.72(d, 2H, J ═ 8.5Hz), 7.65(d, 1H, J ═ 8.5Hz), 7.50(t, 1H, J ═ 8.5Hz), 7.36(t, 1H, J ═ 8.5Hz), 7.02(d, 2H, J ═ 8.5Hz), 5.08(s, 2H), 4.29(m, 1H), 4.18(m, 1H), 4.10(m, 1H), 3.62(m, 2H), 3.51(m, 2H), 3.26(s, 3H), 1.77(m, 1H), 1.67(m, 1H), 0.97(t, 3.97(m, 3H), 3.7 (m, 3H), calculated values: 456；MS(ESI)m/e(M+1H)+：457.1，(M-1H)-：455.2.
Compound 98
1H NMR(400MHz，DMSO-d6): 11.05(s, 1H), 8.91(t, 1H, J ═ 6.1Hz), 7.88(d, 1H, J ═ 7.5Hz), 7.72(d, 2H, J ═ 8.4Hz), 7.63(d, 1H, J ═ 8.4Hz), 7.50(t, 1H, J ═ 8.5Hz), 7.36(t, 1H, J ═ 8.5Hz), 7.07(d, 2H, J ═ 8.4Hz), 5.07(s, 2H), 4.74(q, 1H, J ═ 6.0Hz), 3.60(m, 2H), 3.50(m, 2H), 3.45(m, 2H), 3.26(s, 3H), 1.32(d, 3H, J ═ 6.1Hz), calculated values of EM: 442; MS (ESI) M/e (M +1H)+：443.1，(M-1H)-：441.5.
Compound 99
1H NMR(400MHz，DMSO-d6): 11.09(s, 1H), 9.54(s, 1H), 9.40(t, 1H, J ═ 5.6Hz), 8.04(d, 1H, J ═ 7.8Hz), 7.74(d, 2H, J ═ 8.3Hz), 7.61(t, 1H, J ═ 7.3Hz), 7.49(t, 1H, J ═ 7.3Hz), 7.03(d, 2H, J ═ 8.5Hz), 4.82(s, 2H), 4.26(t, 2H, J ═ 5.6Hz), 3.75(q, 2H, J ═ 5.6Hz), 3.50(m, 2H), 3.25(m, 4H), 1.32(t, 6H, J ═ 7.4) EM (calculated value): 425; MS (ESI) M/e (M +1H)+：426.1，(M-1H)-：424.2.
Compound 109
1H NMR(DMSO-d6)：1.95(2H，m)；2.05(3H，s)；2.48-2.62(2H，m)；4.08(1H，dd，11,6Hz)；4.16(1h，dd，11,7Hz)；4.45(1H，m)；6.99(2H，d，9Hz)；7.32(1H，t，7Hz)；7.45(1H，td，8,1Hz)；7.55(1H，d，1Hz)；7.64(1H，d，8Hz)；7.69(2H，d，9Hz)；7.76(1H，d，8Hz)；8.7(1H，d，8Hz)；8.87(1H，s).MS(M+1)：415.
Compound 110
1H NMR(DMSO-d6)：2.03-2.21(2H，m)；2.99 1H，s，3H)；3.22(2H，t，7Hz)；4.12(1H，dd，11,6Hz)；4.19(1H，dd，11,7Hz)；4.46(1H，m)；7.00(2H，d，9Hz)；7.33(1H，t，7Hz)；7.46(1H，td，8,1Hz)；7.57(1H，d，1Hz)；7.64(1H，d，8Hz)；7.70(2H，d，9Hz)；7.77(1H，d，8Hz)；8.79(1H，d，8Hz)；8.88(1H，s).MS(M+1)：447.
Table 4:
compound 1
EM (calculated): 381.13, respectively; MS (ESI) M/e (M +1H)+：382.3，(M-1H)-：380.2.
Compound 2
EM (calculated): 395.15, respectively; MS (ESI) M/e (M +1H)+：396.1，(M-1H)-：394.2.
Compound 3
EM (calculated): 331.08, respectively; MS (ESI) M/e (M +1H)+：331.7，(M-1H)-：330.1.
Compound 4
EM (calculated): 317.10, respectively; MS (ESI) M/e (M +1H)+：318.10，(M-1H)-：315.9.
Compound 5
EM (calculated): 425.2; MS (ESI) M/e (M +1)+：426.1，(M-1)-：424.1.
Compound 6
EM (calculated): 381.1, respectively; MS (ESI) M/e (M +1)+：382.0，(M-1)-：380.1.
Compound 7
EM (calculated): 381.1, respectively; MS (ESI) M/e (M +1)+：382.0，(M-1)-：380.2.
Compound 8
EM (calculated): 341.1, respectively; MS (ESI) M/e (M +1)+：341.9，(M-1)-：340.1.
Compound 9
EM (calculated): 381.1, respectively; MS (ESI) M/e (M +1)+：381.8，(M-1)-：380.0.
Compound 10
EM (calculated): 411.1; MS (ESI) M/e (M +1)+：412.0，(M-1)-：410.3.
Compound 11
EM (calculated): 395.2; MS (ESI) M/e (M +1)+：396.0，(M-1)-：394.2.
Compound 12
EM (calculated): 388.1, respectively; MS (ESI) M/e (M +1)+：389.1，(M-1)-：387.0.
Compound 13
EM (calculated): 355.12, respectively; MS (ESI) M/e (M +1)+：355.9，(M-1)-：354.1.
Compound 14
EM (calculated): 355.1, respectively; MS (ESI) M/e (M +1)+：355.9，(M-1)-：353.8.
Compound 15
EM (calculated): 409.2; MS (ESI) M/e (M +1)+：410.2，(M-1)-：408.3.
Compound 16
EM (calculated): 341.1, respectively; MS (ESI) M/e (M +1)+：341.8，(M-1)-：340.2.
Compound 17
1H NMR(400MHz，DMSO-d6)11.64(s, 1H), 8.66(d, J ═ 8.0Hz, 1H), 7.76(d, J ═ 8.0Hz, 1H), 7.64(d, J ═ 8.0Hz, 1H), 7.55(s, 1H), 7.46(t, J ═ 8.4Hz, 1H), 7.32(t, J ═ 8.0Hz, 1H), 6.72(s, 1H), 4.30(m, 3H), 1.67(m, 2H), 0.92(t, J ═ 7.2Hz, 3H), EM (calculated): 359.1; MS (ESI) m/e: (M +1H)+：359.8，(M-1H)-：358.1.
Compound 18
1H NMR(400MHz，DMSO-d6)11.64(s, 1H), 9.48(s, 1H), 8.47(d, J ═ 8.0Hz, 1H), 8.09(m, 1H), 7.82(m, 2H), 7.71(m, 2H), 7.55(t, J ═ 8.0Hz, 1H), 7.49(m, 2H), 7.39(m, 1H), 4.30(m, 3H), 1.69(m, 2H), 0.94(t, J ═ 7.2Hz, 3H) EM (calculated): 395.2; MS (ESI) m/e: (M +1H)+：395.8，(M-1H)-：394.0.
Compound 19
1H NMR(400MHz，DMSO-d6)11.63(s, 1H), 8.93(t, J ═ 5.6Hz, 1H), 7.75(d, J ═ 7.6Hz, 1H), 7.63(d, J ═ 7.6Hz, 1H), 7.54(s, 1H), 7.45(t, J ═ 7.6Hz, 1H), 7.32(t, J ═ 7.6Hz, 1H), 6.72(s, 1H), 4.90(m, 1H), 3.56(m, 2H), 0.35(d, J ═ 7.2Hz, 3H), EM (calculated): 345.1; MS (ESI) m/e: (M +1H)+：345.8，(M-1H)-：344.0.
Compound 20
1H NMR(400MHz，DMSO-d6)11.64(s, 1H), 9.480(s, 1H), 8.83(t, J ═ 5.6Hz, 1H), 7.07(m, 1H), 7.80(d, J ═ 7.6Hz, 1H), 7.70(d, J ═ 7.6Hz, 1H), 7.53(t, J ═ 7.6Hz, 1H), 7.48(m, 2H), 7.39(m, 1H), 6.72(s, 1H), 4.91(m, 1H), 3.58(m, 2H), 1.36(d, J ═ 7.0Hz, 3H), EM (calculated): 381.1, respectively; MS (ESI) m/e: (M +1H)+：382.0，(M-1H)-：380.0.
Compound 21
EM (calculated): 367.1, respectively; MS (ESI) M/e (M +1)+：367.8，(M-1)-：366.2.
Compound 22
EM (calculated): 367.12, respectively; MS (ESI) M/e (M +1H)+：368.0，(M-1H)-：366.1.
Compound 23
EM (calculated): 374.0, respectively; MS (ESI) M/e (M +1)+：374.7，(M-1)-：372.9.
Compound 24
EM (calculated): 395.2; MS (ESI) M/e (M +1)+：396.1.(M-1)-：394.1.
Compound 25
EM (calculated): 367.1, respectively; MS (ESI) M/e (M +1)+：368.1，(M-1)-：366.2.
Compound 26
EM (calculated): 381.1, respectively; MS (ESI) M/e (M +1)+：382.0，(M-1)-：380.1.
Compound 27
1H NMR(400MHz，DMSO-d6)11.62(s, 1H), 9.45(s, 1H), 8.54(d, J ═ 7.6Hz, 1H), 8.43(s, 1H), 7.97(m, 4H), 7.60(m, 2H), 6.73(s, 1H), 4.33(m, 3H), 1.70(m, 2H), 0.96(t, J ═ 7.6Hz, 3H), EM (calculated): 369.1; MS (ESI) m/e: (M +1H)+：369.9，(M-1H)-：368.0.
Compound 28
1H NMR(400MHz，DMSO-d6)11.66(s, 1H), 9.50(s, 1H), 8.53(d, J ═ 7.6Hz, 1H), 8.11(m, 1H), 7.96(m, 2H), 7.55(m, 4H), 6.78(s, 1H), 4.33(m, 3H), 1.68(m, 2H), 1.01(t, J ═ 7.2Hz, 3H), EM (calculated): 369.1; MS (ESI) m/e: (M +1H)+：370.0，(M-1H)-：368.2.
Compound 29
1H NMR(400MHz，DMSO-d6)11.64(s, 1H), 8.86(t, J ═ 5.6Hz, 1H), 8.40(s, 1H), 7.90(m, 4H), 7.59(m, 2H), 6.73(s, 1H), 4.94(m, 1H), 3.60(m, 2H), 1.38(d, J ═ 6.0Hz, 3H), EM (calculated): 355.1, respectively; MS (ESI) m/e: (M +1H)+：355.9，(M-1H)-：353.9.
Compound 30
1H NMR(400MHz，DMSO-d6)11.66(s, 1H), 8.78(t, J ═ 5.6Hz, 1H), 8.09(d, J ═ 7.6Hz, 1H), 7.96(m, 2H), 7.50(m, 4H), 6.74(s, 1H), 4.97(m, 1H), 3.61(m, 2H), 1.41(d, J ═ 6.4Hz, 3H), EM (calculated): 355.1, respectively; MS (ESI) m/e: (M +1H)+：356.1，(M-1H)-：353.9.
Compound 31
EM (calculated): 345.1; MS (ESI) M/e (M +1)+：345.8，(M-1)-：344.0.
Compound 32
EM (calculated): 331.1, respectively; MS (ESI) M/e (M +1)+：331.9，(M-1)-：330.2.
Compound 33
EM (calculated): 437.12, respectively; MS (ESI) M/e (M +1H)+：438.0，(M-1H)-：436.2.
Example 4
Synthesis of acetyl-Gly-Ala- (N-acetyl-Lys) -AMC
Tertiary Boc (N-acetyl-Lys) -AMC (445mg, 1mmol, ex Bachem) was dissolved in 4M HCl in dioxane to give H- (N-acetyl-Lys) -AMC as a white solid. To a solution of H- (N-acetyl-Lys) -AMC in DMF (5ml) was added Ac-Gly-Ala-OH (188mg, 1mmol) using PyBOP (520mg, 1mmol), HOBt (135mg, 1mmol) and NMM (0.296ml, 2 mmol). The reaction mixture was stirred for 1H and monitored by MS/LC for the presence of H- (N-acetyl-Lys) -AMC. Additional amounts of PyBOP (260mg, 0.5mmol), HOBt (70mg, 0.5mmol) and NMM (0.146ml, 1mmol) were added and stirring was continued for 4h before the product was isolated in quantitative yield.
Biological examples
Example 1 in vitro inhibition of HDAC
The in vitro HDAC inhibitory activity of the compounds of the present invention was determined as follows.
The assay was performed in a 100 μ L reaction volume using a 96-well assay plate. HDAC-1(200pM final concentration) solutions of reaction buffer (50mM HEPES, 100mM KCl, 0.001% Tween-20, 5% DMSO, pH 7.4) were mixed with varying concentrations of inhibitor, incubated for 30 minutes, and then trypsin and acetyl-Gly-Ala- (N-acetyl-Lys) -AMC were added to final concentrations of 50nM and 25. mu.M, respectively, to initiate the reaction. The negative control reaction was repeated 8 times without inhibitor.
The reaction was monitored in a fluorescence plate reader. After a 30-minute lag time, fluorescence was measured using an excitation wavelength of 355nm and a detection wavelength of 460nm after the lapse of a 30-minute lag time. The increase in fluorescence over time was used as a measure of the rate of reaction. Inhibition constants were obtained using the BatchKi program (kuzmcet al. anal. biochem.2000, 286, 45-50). Most of the compounds of the invention have Ki's of less than 40 nm.
Example 2 in vitro cell proliferation assay
The ability of the compounds of formula (I) to inhibit tumor cell growth in vitro was determined as follows.
5% CO at 37 deg.C2Stock cultures of colon cancer cell lines were maintained in RPMI medium 1640 containing 10% (v/v) bovine fetal serum, 2mM L-glutamine, 1mM sodium lactonate, 50 units/ml penicillin, and 50. mu.g/ml streptomycin in a humidified atmosphere. Cells at 75-cm2Culture in flasks and establish a split culture every 3-4 days to avoid over 90% confluence of cells.
HCT116 cells were harvested, proliferation assayed by trypsin treatment (0.05% trypsin/0.53 mm edta), washed twice in culture medium, resuspended in an appropriate volume of culture medium, and then counted using a hemocytometer. Cells were seeded in wells of a round bottom 96-well plate at a density of 5,000 cells per 100 μ l well. The cells were allowed to attach for 1.5-2 hours at 37 ℃.
Compounds were diluted from 10mM stock into DMSO. Serial 3-fold dilutions were performed in medium containing 0.6% DMSO, starting with 60 μ M solution in wells of a 96-well U-plate (triplicate). After the end of the dilution, 100 μ l of each compound dilution (triplicate) was transferred to the designated triplicate wells of a 96-well plate containing 100 μ l of the culture medium solution of the cells. The final concentration of the compound in the assay plate in dose response ranged from 0.12 to 30 μ M. Control wells (untreated cells) received 100 μ l of 0.6% DMSO in medium. Wells containing medium but no cells were used as background wells. CO in humidification2Cells were incubated with the compound in an incubator at 37 ℃ for 48 and 72 hours.
After adding the fluorescent redox indicator Alamar BlueTM(BioSource International) cell proliferation was assessed by measuring fluorescence. 3 to 4 hours before the end of the incubation period, 10. mu.l of Alamar Blue was addedTMAdded to each well of a 96-well plate. The plates were read in a fluorescence plate reader (excitation wavelength, 530 nM; emission wavelength, 620 nM). By plotting percent control fluorescence against log compound concentration, compound G can be determined150Value (concentration at which tumor cell growth was inhibited by 50%). The compounds of the present invention inhibit the growth of tumor cells.
Pharmaceutical composition examples
The following are representative pharmaceutical formulations containing compounds of formula (I).
Tablet formulation
The following ingredients were mixed homogeneously and compressed into single scored tablets.
Capsule formulation
The following ingredients were mixed homogeneously and filled into hard shell gelatin capsules.
Amount of ingredient per capsule, mg
Compounds of the invention 200
Lactose, spray dried 148
Magnesium stearate 2
Suspension formulation
The following ingredients are mixed to form a suspension for oral administration.
Injection formulation
The following ingredients were mixed to form an injection formulation.
The compound (1.2g) was combined with 0.1M lactate buffer (10ml) and mixed gently. If necessary, several sonications are applied to form a solution. An appropriate amount of acid or base is added to achieve a suitable pH (preferably pH 4). Sufficient water was then added to 20 ml.
Suppository formula
Combining a compound of the invention with WitepsolTMH-15 (triglycerides of saturated vegetable fatty acids; Riches-Nelson, Inc., New York) was mixed to make a suppository, 2.5g in total, havingConsists of the following components:
500mg of a Compound of the invention
WitepsolTMH-15 balance
The foregoing invention has been described in some detail by way of illustration and example for purposes of clarity and understanding. It will be apparent to those skilled in the art that variations and modifications can be effected within the scope of the appended claims. Accordingly, it is to be understood that the above description is intended to be illustrative, and not restrictive. The scope of the invention should, therefore, be determined not with reference to the above description, but instead should be determined with reference to the appended claims along with the full scope of equivalents to which such claims are entitled. All patents, patent applications, and publications cited in this application are herein incorporated by reference in their entirety for all purposes to the same extent as if each individual patent, patent application, or publication were individually indicated to be incorporated by reference.
Claims (13)
1. The compound N-hydroxy-4- {2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino ] ethoxy } -benzamide.
A pharmaceutically acceptable salt of N-hydroxy-4- {2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino ] ethoxy } -benzamide, which is an acid addition salt.
3. A compound represented by the following structure:
4. a pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
5. Use of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer in a human.
6. The use of claim 5, wherein the cancer is lung cancer, colon cancer, myeloid leukemia, skin cancer, breast cancer, ovarian cancer, prostate cancer, liver cancer, brain cancer, pancreatic cancer, or T-cell lymphoma.
7. The use of claim 5, wherein the cancer is acute myeloid leukemia.
8. Use of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer in a human in combination with one or more compounds independently selected from the group consisting of: an estrogen receptor modulator, an androgen receptor modulator, a retinoid receptor modulator, a cytotoxic agent, another antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, an HIV protease inhibitor, a reverse transcriptase inhibitor, a DNA methyltransferase inhibitor, and an angiogenesis inhibitor.
9. The use of claim 8, wherein the cancer is lung cancer, colon cancer, myeloid leukemia, skin cancer, breast cancer, ovarian cancer, prostate cancer, liver cancer, brain cancer, pancreatic cancer, or T-cell lymphoma.
10. The use of claim 8, wherein the cancer is acute myeloid leukemia.
11. Use of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer in a human in combination with radiotherapy, optionally in the presence of one or more compounds independently selected from: an estrogen receptor modulator, an androgen receptor modulator, a retinoid receptor modulator, a cytotoxic agent, another antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, an HIV protease inhibitor, a reverse transcriptase inhibitor, a DNA methyltransferase inhibitor, or an angiogenesis inhibitor.
12. The use of claim 11, wherein the cancer is lung cancer, colon cancer, myeloid leukemia, skin cancer, breast cancer, ovarian cancer, prostate cancer, liver cancer, brain cancer, pancreatic cancer, or T-cell lymphoma.
13. The use of claim 11, wherein the cancer is acute myeloid leukemia.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US46128603P | 2003-04-07 | 2003-04-07 | |
| US60/461,286 | 2003-04-07 | ||
| US46444803P | 2003-04-21 | 2003-04-21 | |
| US60/464,448 | 2003-04-21 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1169102A1 HK1169102A1 (en) | 2013-01-18 |
| HK1169102B true HK1169102B (en) | 2016-10-21 |
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