CN1768031A - Hydroxamates as therapeutic agents - Google Patents

Abstract

The present invention relates to certain hydroxamate derivatives that are useful for 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.

Description

Hydroxamates as therapeutic agents

Background of the invention

field of invention

The present invention relates to certain hydroxamate derivatives useful in the treatment of hepatitis C. These compounds are also inhibitors of histone deacetylases and are therefore useful in the treatment of diseases associated with histone deacetylase activity. The invention also discloses pharmaceutical compositions and methods for preparing these compounds.

Technology Status

Hepatitis C:

Chronic hepatitis C is a slowly progressive disease with important morbidity and mortality implications. While many patients infected with hepatitis C will have subclinical or mild disease, at least 80% of these HCV-infected individuals develop chronic infection and hepatitis. 20-50% of them eventually develop cirrhosis and 1-2% develop liver cancer (Hoofnagle, J.H.; 1997; Hepatology 26: 15S-20S). There are an estimated 170 million HCV carriers worldwide, and HCV-related end-stage liver disease is currently one of the leading reasons for liver transplantation. In the United States alone, hepatitis C kills 8,000-10,000 people each year.

Currently, interferon-α2b/ribavirin combination therapy is the only viable treatment. A sustained virologic response to IFN-[alpha]2b/ribavirin combination therapy occurred in approximately 40-45% of those treated. For those patients who fail to respond to combination interferon-α2b/ribavirin, there are currently no alternatives to prevent the development of liver disease. Therefore, there is a need for alternative therapies for the treatment of chronic HCV infection. The present invention fulfills this need.

Histone deacetylases:

Taking histone deacetylases (HDACs) as targets of pharmaceutical research, attention has focused on the role of HDACs in the regulation of genes involved in cell cycle progression, and the role of HDACs in the development and progression of cancer (in Kramer et al., 2001. Trends Endocrinol. Metab. 12:294-300 (reviewed). Several studies have shown that treatment of various cell lines with HDAC inhibitors leads to hyperacetylation of histones and cell cycle arrest in late _G1 or at _G2 /M transition. Cell cycle-related genes 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 downregulated by HDAC inhibitors. In tumor cell lines, several studies have shown that treatment with HDAC inhibitors can lead to growth inhibition, growth arrest, terminal differentiation and/or apoptosis. In vivo studies have demonstrated that treatment with HDAC inhibitors leads to tumor growth inhibition and reduction of tumor metastasis.

The clearest link between aberrant HDAC activity and cancer occurs in acute promyelocytic leukemia. In this case, the chromosomal translocation results in the fusion of the retinoic acid receptor RARα to the promyelocytic leukemia (PML) or promyelocytic leukemia zinc finger (PLZF) protein. Both PML-RARα and PLZF-RARα promote leukemia progression by repressing retinoic acid-regulated genes through abnormal recruitment of the SMRT-mSin3-HDAC complex (Lin et al., 1998, Nature 391:811-814; Grignani et al. People, 1998, Nature 391:815-818). The PML-RARa form of the disease is treatable with retinoic acid, whereas the PLZF-RARα form is resistant to this treatment. For patients with retinoic acid-resistant forms of disease, the addition of the HDAC inhibitor sodium butyrate to the dosage regimen resulted in complete clinical and cellular remission (Warrell et al., 1998, J.Natl.Cancer.Inst.90:1621 -1625). HDACs have also been implicated in Huntington's disease (Steffan et al., Nature 413:739-744, "Histone deacetylase inhibitors prevent polyglutamine-dependent neurodegeneration in Drosophila" ( Histonedeacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila)).

In conclusion, increased HDAC activity contributes to the pathology and/or symptomology of many diseases. Molecules that inhibit the activity of HADCs are therefore useful as therapeutic agents to treat these diseases.

Summary of the invention

In a first aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:

in:

R ¹ is hydrogen or alkyl;

X is -O-, -NR ² - or -S(O) _n -, wherein n is 0-2, and R ² is hydrogen or alkyl;

Y is an alkylene group optionally substituted by cycloalkyl, optionally substituted phenyl, alkylthio, alkylsulfinyl, alkylsulfonyl, optionally substituted phenylalkylthio, optionally substituted Substitution of phenylalkylsulfonyl, hydroxy, or optionally substituted phenoxy;

Ar is ^phenylene or heteroarylene, wherein said ^Ar is optionally substituted by one or two groups independently selected from alkyl, halo, hydroxyl, alkoxy, haloalkoxy base, or haloalkyl;

^R is hydrogen, alkyl, hydroxyalkyl, or optionally substituted phenyl; and

Ar is ^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 HDACs in an animal, the method comprising administering to the animal a compound comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable Excipients for pharmaceutical compositions. 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 lymph glands, or leukemias such as myelogenous leukemia (MM) and acute myeloid Leukemia (AMM).

In a fourth aspect, the present invention relates to a method of treating cancer in an animal, the method comprising administering to the animal a medicament comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient Composition, in combination with radiation therapy and optionally in combination with one or more compounds independently selected from the group consisting of estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cellular Toxic agent, another antiproliferative agent, prenyl-protein transferase inhibitor, HMG-CoA reductase inhibitor, HIV protease inhibitor, reverse transcriptase inhibitor, angiogenesis inhibitor, or DNA methyl Transferase inhibitors.

Applicants have also found that the compounds of the present invention are useful in the treatment of hepatitis C. Therefore, 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 compound comprising a therapeutically effective amount of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable A pharmaceutical composition with an excipient, optionally in combination with one or more other hepatitis C agents. Preferably, the hepatitis C agents are interferon-α2b, ribavirin and HCV polymerase inhibitors.

In a sixth aspect, the present invention relates to an intermediate of formula (II) or a salt thereof:

wherein R ⁵⁰ is hydrogen or alkyl, and Ar ¹ , Ar ² , R ³ , X and Y are as defined above for the compound of formula (I). Preferably, Ar ¹ , Ar ² , R ³ , X and Y are as defined in the preferred embodiments below.

In a seventh aspect, the present invention relates to a method of preparing a compound of formula (I), the method comprising:

(i) make formula (III) compound:

wherein R ⁵¹ is a hydroxyl, alkoxy, halo, or succinimide ester, reacted with a hydroxylamine of formula NH ₂ OR", wherein R" is a hydrogen, alkyl, or oxygen protecting group; or

(ii) treating the compound of formula (IV) with an acid:

Wherein M ⁺ is an alkali metal; then after treatment with NH ₂ OR", wherein R" is hydrogen, alkyl, or oxygen protecting group;

Obtain formula (V) compound;

(iii) optionally removing the R" group in compound (V) to obtain a compound of formula (I), wherein R' is hydrogen;

(iv) optionally forming an acid addition salt of the product formed in step (i), (ii), or (iii) above;

(v) optionally forming the free base of the product formed in step (i), (ii), (iii) or (iv) above; or

(vi) optionally modifying X, Y, R ¹ , R ² , R ³ , Ar ¹ in the product formed in step (i), (ii), (iii), (iv) or (v) above and any one of the ^Ar2 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 treating hepatitis C.

Detailed description of the invention

definition:

Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this application and have the following meanings:

"Alkyl" refers to a straight-chain saturated monovalent hydrocarbon group having 1 to 6 carbon atoms, or a branched saturated monovalent hydrocarbon group having 3 to 6 carbon atoms, such as methyl, ethyl, propyl, 2-propane , 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 saturated divalent hydrocarbon group having 3 to 6 carbon atoms, such as methylene, ethylene , propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, etc.

"Alkenylene" means a straight-chain divalent hydrocarbon radical having 2 to 6 carbon atoms, or a branched monovalent hydrocarbon radical having 3 to 6 carbon atoms containing one or two double bonds, such as vinylene, propenyl, 2-propenylene, butenylene (including all isomeric forms) and the like.

"Alkylthio" means a -SR group where R is alkyl as defined above, for example methylthio, ethylthio, propylthio (including all isomeric forms), butylthio (including all isomeric forms )wait.

"Alkylsulfinyl" means a -S(O)R radical, where R is alkyl as defined above, for example methylsulfinyl, ethylsulfinyl, propylsulfinyl (including all isomeric form), etc.

"Alkylsulfonyl" means a _-SO2R radical, wherein R is alkyl as defined above, eg, methylsulfonyl, ethylsulfonyl, and the like.

"Amino" refers to -NH ₂ , or its N-oxide derivatives, or protected derivatives, such as -NH→O, -NHBoc, -NHCbz, etc., preferably -NH ₂ .

"Alkylamino" means an -NHR radical, wherein R is an alkyl group as defined above, or an N-oxide derivative thereof, or a protected derivative such as methylamino, ethylamino, n-propylamino, iso-propylamino Amino; n-butylamino, iso-butylamino, tert-butylamino, methylamino-N-oxide; -N(Boc)CH ₃ etc.

"Alkoxy" means an -OR group, wherein R is an alkyl group as defined above, such as methoxy, ethoxy; propoxy, or 2-propoxy; n-butoxy, iso-but Oxygen, tert-butoxy, etc.

"Alkoxycarbonyl" means a -C(O)OR group where R is alkyl as defined above, eg, methoxycarbonyl, ethoxycarbonyl, and the like.

"Alkoxyalkyl" means a straight chain monovalent hydrocarbon radical having 1 to 6 carbon atoms or having 3 to 6 carbon atoms substituted with at least one, preferably one or two alkoxy groups (as defined above) Atomic branched monovalent hydrocarbon groups, such as 2-methoxyethyl, 1-, 2-, or 3-methoxypropyl, 2-ethoxyethyl, etc.

"Alkoxyalkoxy" means the group -OR wherein R is alkoxy as defined above, eg, methoxyethoxy, 2-ethoxyethoxy, and the like.

"Alkoxyalkoxyalkyl" means a radical -(alkylene)-R, where R is alkoxyalkoxy as defined above, for example methoxyethoxymethyl, 2-ethoxy Ethoxymethyl etc.

"Aminoalkyl" refers to a straight chain monovalent hydrocarbon group having 1 to 6 carbon atoms or a branched chain monovalent hydrocarbon group having 3 to 6 carbon atoms, which is substituted by at least one, preferably one or two of the following groups: -NRR', wherein R is hydrogen, alkyl, or -COR ^a , wherein R ^a is alkyl, R' is selected from hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or haloalkyl; or an N-oxide or protected derivative thereof. Preferably, R and R' are independently selected from: hydrogen, alkyl, or -COR ^a , wherein R ^a is alkyl, or N-oxide derivatives, or protected derivatives, such as aminomethyl, methylamino Ethyl, 2-ethylamino-2-methylethyl, 1,3-diaminopropyl, dimethylaminomethyl, diethylaminoethyl, acetamidopropyl, aminomethyl-N-oxide things etc.

"Aminoalkoxy" means the group -OR wherein R is aminoalkyl as defined above, eg, 2-aminoethoxy, 2-dimethylaminopropoxy, and the like.

"Aminocarbonyl" means a -CONRR radical wherein each R is independently hydrogen or alkyl as defined above, eg _-CONH2 , methylaminocarbonyl, 2-dimethylaminocarbonyl, and the like.

"Acylamino" means a -NHCOR radical wherein R is alkyl as defined above, eg, acetamido, propionylamino, and the like.

"Aryl" refers to a monovalent monocyclic or bicyclic aromatic hydrocarbon group having 6 to 12 ring atoms, such as phenyl, naphthyl or anthracenyl. Unless otherwise stated, the aromatic ring is optionally substituted with one, two or three substituents independently selected from the group consisting of: alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino , dialkylamino, hydroxy, hydroxyalkyl, hydroxyalkoxy, hydroxyalkoxyalkyl, alkoxyalkoxyalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, any 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 heterocycloalkylalkyl, optionally substituted heterocycloalkylalkoxy, optionally substituted hetero Cycloalkoxy, -alkylene-S(O) _n -R ^a (wherein n is 0 to 2, R ^a is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, optionally substituted benzene group, optionally substituted phenylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl), -alkylene-NHSO ₂ -R ^b (wherein R ^b is alkyl, haloalkyl , optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or optionally substituted heterocycloalkyl), -alkylene- NHCO- ^Rc (wherein ^Rc is alkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, or any Optionally substituted heterocycloalkyl), or -(alkylene) n1-CONR ^d R ^e (wherein n1 is 0 or 1, R ^d and R ^e are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, Alkoxyalkyl, aminoalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl, or optionally substituted hetero Cycloalkylalkyl, or R ^{and R} together with the nitrogen atom to which they are attached form an optionally substituted heterocycloalkyl), wherein in haloalkoxyalkyl, optionally substituted phenoxyalkyl, any The alkyl chain in an optionally substituted heteroaryloxyalkyl, or aminoalkyl is optionally substituted with one or two fluorines. 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-morpholine Substituent-4-ylethyl, morpholino-4-ylmethyl, N,N dimethylaminomethyl, isopropoxymethyl, or phenoxymethyl.

"Aralkyl" means a -(alkylene)-R radical, wherein R is aryl as defined above.

"Aralkenyl" means 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" means a cyclic unsaturated monovalent hydrocarbon group having 3 to 6 carbon atoms, such as cyclopropenyl, cyclobutenyl, cyclohexenyl and the like.

"Cycloalkylalkyl" means a -(alkylene)-R radical, where R is cycloalkyl as defined above, for example cyclopropylmethyl, cyclobutylmethyl, cyclopentylethyl, or cyclohexyl methyl etc.

"Cycloalkoxy" means the group -OR wherein R is cycloalkyl as defined above, eg, cyclopropoxy, cyclohexyloxy, and the like.

"Cycloalkenyloxy" means the radical -OR wherein R is cycloalkenyl as defined above, eg, cyclopropenyloxy, cyclohexenyloxy, and the like.

"Dialkylamino" means a group -NRR' where R and R' are independently alkyl as defined above, for example dimethylamino, diethylamino, methylpropylamino, methylethylamino , n-butylamino, iso-butylamino, or tert-butylamino, etc.

"Halo" means fluorine, chlorine, bromine, iodine, preferably fluorine or chlorine.

"Haloalkyl" means an alkyl group substituted with one or more halogen atoms, preferably 1 to 5 halogen atoms, preferably fluorine or chlorine, including those substituted with different halogen atoms, eg _-CH2Cl , -CF ₃ , -CHF ₂ , -CF ₂ CF ₃ , -CF(CH ₃ ) ₃ , etc.

"Haloalkoxy" means an -OR radical, wherein R is haloalkyl as defined above, eg _-OCF3 , _-OCHF2, and the like.

"Haloalkoxyalkyl" means a -(alkylene)-OR group, where R is haloalkyl as defined above, for example trifluoromethoxymethyl, 2,2,2-trifluoroethoxymethyl group, 2-trifluoromethoxyethyl group, etc.

"Hydroxyalkyl" means a straight chain monovalent hydrocarbon radical having 1 to 6 carbon atoms or a branched chain monovalent hydrocarbon radical having 3 to 6 carbon atoms substituted by one or two hydroxyl groups, provided that if two hydroxyl groups exist, 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-hydroxy Butyl, 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 the radical -OR wherein R is hydroxyalkyl as defined above.

"Hydroxyalkoxyalkyl" means a -(alkylene)-OR radical wherein R is hydroxyalkyl as defined above, eg, hydroxymethoxymethyl, hydroxyethoxymethyl, and the like.

"Heterocycloalkyl" means a saturated or unsaturated monovalent cyclic group having 3 to 8 ring atoms, one or two of which are heteroatoms selected from N, O or S( O) _n , where n is an integer from 0 to 2 and the remaining ring atoms are C. One or two ring 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, tetrahydro Hydroquinolyl and thiomorpholino, and derivatives thereof (formed when the heterocycloalkyl ring is substituted by the following substituents); and N-oxides or protected derivatives thereof. A heterocycloalkyl group is optionally fused to an alkyl group. Unless otherwise stated, the heterocycloalkyl ring is optionally substituted with one, two or three substituents independently selected from the group consisting of: alkyl, alkoxy, halo, haloalkyl, haloalkoxy radical, amino, alkylamino, dialkylamino, hydroxy, hydroxyalkyl, hydroxyalkoxy, hydroxyalkoxyalkyl, alkoxyalkoxyalkyl, optionally substituted phenyl, optionally substituted Phenylalkyl, cycloalkoxy, cycloalkenyloxy, optionally substituted phenylcarbonylamino, optionally substituted heteroaryl, optionally substituted heteroaralkoxy, 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 -R ^a (where n is 0 to 2, R ^a is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally Substituted heteroaryl, or optionally substituted heteroarylalkyl), -alkylene-NHSO ₂ -R ^b (wherein R ^b is alkyl, haloalkyl, optionally substituted phenyl, optionally substituted benzene alkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl), -alkylene-NHCO- ^Rc (wherein ^Rc is alkyl, haloalkyl, optionally substituted phenyl, Optionally substituted phenylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl), or -(alkylene) n1-CONR ^d R ^e (wherein n1 is 0 or 1, R ^d and R ^e are independently: hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or optionally substituted heterocycloalkylalkyl, or ^R and ^R together with the nitrogen atom to which they are attached form an 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. 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-morpholine Xeno-4-ylethyl, morpholino-4-ylmethyl, N,N-dimethylamino-methyl, isopropoxymethyl, or phenoxymethyl.

"Heterocycloalkylalkyl" means a -(alkylene)-R radical, where R is a heterocycloalkyl ring as defined above, eg, furanylmethyl, piperazinylmethyl, morpholinoethyl, and the like.

"Heteroaryl" means a monovalent monocyclic or bicyclic aromatic group having 5 to 10 ring atoms, wherein one or more ring atoms, preferably one, two or three ring atoms are selected from ^N , ^O or A heteroatom in ^S , the remaining ring atoms are ^C. More specifically, the term "heteroaryl" includes, but is not limited to: pyridyl, pyrrolyl, imidazolyl, thienyl, furyl, indolyl, quinolinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxa Azolyl, isoxazolyl, benzoxazolyl, benzothienyl, benzothiazolyl, quinolinyl, isoquinolinyl, benzofuranyl, benzopyranyl and thiazolyl, and derivatives thereof (formed when the heterocycloalkyl ring is substituted by the following substituents); or N-oxide or protected derivatives thereof. Unless otherwise stated, the heteroaryl ring is optionally substituted with one, two or three substituents independently selected from the group consisting of: alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, Alkylamino, dialkylamino, hydroxy, hydroxyalkyl, hydroxyalkoxy, hydroxyalkoxyalkyl, alkoxyalkoxyalkyl, optionally substituted phenyl, cycloalkoxy, cycloalkenyloxy radical, optionally substituted phenylcarbonylamino, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted heteroaralkoxy, aminoalkyl, aminoalkoxy, alkoxy Alkyl, alkoxyalkoxy, methylenedioxy, haloalkoxyalkyl, optionally substituted phenylalkyl, optionally substituted phenoxy, optionally substituted phenylalkoxy, any Optionally substituted phenoxyalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted heterocycloalkoxyalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heterocycloalkane alkylalkoxy, optionally substituted heterocycloalkoxy, -alkylene-S(O) _n -R ^a (wherein n is 0 to 2, R ^a is alkyl, hydroxyalkyl, haloalkyl, any optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl), -alkylene-NHSO ₂ -R ^b (where R ^b is alkyl radical, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or optionally substituted heterocycloalkyl), - Alkylene-NHCO- ^Rc (wherein ^Rc is alkyl, haloalkyl, hydroxy, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted hetero Aralkyl, or optionally substituted heterocycloalkyl), -(alkylene) n1-CONR ^d R ^f (wherein n1 is 0 or 1, R ^d is hydrogen or alkyl, R ^f is hydrogen, alkyl , hydroxyalkyl, alkoxyalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or optionally substituted hetero cycloalkylalkyl), or R ^d and R ^f together with the nitrogen atom to which they are attached form an optionally substituted heterocycloalkyl), -alkylene-NR ^e -alkylene-CONR ^c R ^d (wherein R ^c is as defined above, R ^d and R ^e are independently hydrogen or alkyl), or carboxyalkylaminoalkyl, wherein in haloalkoxyalkyl, optionally substituted phenoxyalkyl, optionally substituted The alkyl chain in the heteroaryloxyalkyl, or aminoalkyl, of is optionally substituted with one or two fluorines. 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-morpholine Substituent-4-ylethyl, morpholino-4-ylmethyl, N,N-dimethylamino-methyl, isopropoxymethyl, or phenoxymethyl.

When a heteroaryl ring is divalent, it is referred to herein as a heteroarylene.

"Heteroarylamino" means an NHR radical in which R is heteroaryl as defined above.

"Heteroaralkyl" means a -(alkylene)-R radical, wherein R is heteroaryl as defined above.

"Heteroarylalkenyl" means a -(alkenylene)-R radical, wherein R is heteroaryl as defined above.

"Methylenedioxy" means -O-CH2 _- O-.

The present invention also includes prodrugs of the compounds of formula (I). The term "prodrug" is used to denote a covalently bonded carrier capable of releasing 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 generally modify suitable functional groups in a given compound. However, these modified functional groups can regenerate the original functional groups by routine processing or in vivo. Prodrugs of compounds of formula (I) include compounds wherein the hydroxy, amino, carboxyl, or similar groups are modified. Examples of prodrugs include, but are not limited to: esters (such as acetate, formate, and benzoate derivatives), carbamates of hydroxyl or amino functional groups in compounds of formula (I) (such as N,N- dimethylaminocarbonyl), amides (such as trifluoroacetamido, acetylamino, etc.) and the like. Prodrugs of the compounds of formula (I) are also within the scope of this invention.

The invention also includes N-oxide derivatives and protected derivatives of the compounds of formula (I). For example, when a compound of formula (I) contains an oxidizable nitrogen atom, the nitrogen atom can be converted to an N-oxide by methods well known in the art. When the compounds of formula (I) contain groups such as hydroxy, carboxyl, thiol or any group containing a nitrogen atom, these groups may be protected with suitable protecting groups. A comprehensive list of suitable protecting groups can be found in T.W. Greene, Protective Groups in Organic Synthesis (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.

A "pharmaceutically acceptable salt" of a compound refers to a salt that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. Such salts include:

Acid addition salts, which salts are formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or with 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, cinnamon 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, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid , tert-butyl acetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc.; or

Salts formed 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 reacted with an organic base such as ethanolamine, diethanolamine, triethanolamine, When tromethamine, N-methylglucamine, etc. are coordinated. 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 present invention may have asymmetric centers. The compounds of the present invention containing asymmetrically substituted atoms can be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active bodies, such as by material resolution. Unless a particular stereochemistry or isomeric form is specifically stated, 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 and cis and trans isomers, individual and mixtures thereof are within the scope of the invention. Additionally, as used herein, the term "alkyl" includes all possible isomeric forms of said 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" means a phenyl ring optionally substituted with one, two or three substituents independently selected from the group consisting of: alkyl, halo, alkoxy, alkylthio, Haloalkyl, haloalkoxy, heteroaryl (which is optionally substituted with one or two substituents independently selected from: alkyl, halo, hydroxy, alkoxy, carboxyl, amino, alkylamino or dialkylamino), heterocycloalkyl (which is optionally substituted with one or two substituents independently selected from: alkyl, halo, hydroxy, alkoxy, carboxyl, amino, alkane amino or dialkylamino), amino, alkylamino, dialkylamino, hydroxy, cyano, nitro, methylenedioxy, aminocarbonyl, amido, hydroxyalkyl, alkoxycarbonyl, aminoalkyl , or carboxyl, or optionally substituted by five fluorine atoms.

"Optionally substituted phenoxy" means the radical -OR wherein R is optionally substituted phenyl as defined above, eg, phenoxy, chlorophenoxy, and the like.

"Optionally substituted phenylcarbonylamino" means the group -NHCOR wherein R is optionally substituted phenyl as defined above, eg benzamido and the like.

"Optionally substituted phenylalkyl" means a -(alkylene)-R radical, wherein R is optionally substituted phenyl as defined above, eg, benzyl, phenethyl, and the like.

"Optionally substituted phenylalkoxy" means the radical -OR wherein R is optionally substituted phenylalkyl as defined above, eg, benzyloxy, phenylethoxy, and the like.

"Optionally substituted phenylalkylthio" means a group -S-(alkylene)-R, wherein R is optionally substituted phenyl as defined above, for example benzylthio, phenylethylthio, etc. .

"Optionally substituted phenylalkylsulfonyl" means a group -SO ₂ -(alkylene)-R, wherein R is optionally substituted phenyl as defined above, for example benzylsulfonyl, phenylethyl Sulfonyl, etc.

"Optionally substituted phenylalkenyl" means a -(alkenylene)-R group wherein R is optionally substituted as defined above, eg, styryl, phenylpropenyl, and the like.

"Optionally substituted phenoxyalkyl" means a -(alkylene)-OR radical, where R is optionally substituted phenyl as defined above, e.g., phenoxymethyl, phenoxyethyl, etc. .

"Optionally substituted heteroaryl" means a monovalent monocyclic or bicyclic aromatic group having 5 to 10 ring atoms, wherein one or more ring atoms, preferably one, two or three ring atoms are selected from A heteroatom in N, O or S, the remaining ring atoms being C, optionally substituted by 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 by alkyl, halo, hydroxy, alkoxy, carboxy, amino, alkylamino, or dialkylamino; heterocycloalkyl, optionally is optionally substituted with one or two substituents independently selected from: alkyl, halo, hydroxy, alkoxy, amino, alkylamino, or dialkylamino; heterocycloalkylalkyl, which Optionally substituted with one or two substituents independently selected from: alkyl, halo, hydroxy, alkoxy, amino, alkylamino, or dialkylamino; or heteroarylamino, which 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, pyridyl Azinyl, oxazolyl, isoxazolyl, benzoxazolyl, tetrahydroquinolyl, isotetrahydroquinolyl, benzopyranyl, and thiazolyl, and their derivatives (when heteroaryl when the ring is substituted by the substituents listed above); or an N-oxide or protected derivative thereof.

"Optionally substituted heteroaryloxy" refers to the radical -OR wherein R is optionally substituted heteroaryl as defined above, eg, furyloxy, pyridyloxy, and the like.

"Optionally substituted heteroaralkoxy" refers to the radical -OR wherein R is an optionally substituted heteroaralkyl ring as defined below.

"Optionally substituted heteroaryloxyalkyl" refers to the group -(alkylene)-OR, wherein R is an optionally substituted heteroaryl ring as defined above.

"Optionally substituted heteroaralkyl" refers to a -(alkylene)-R radical, wherein R is an optionally substituted heteroaryl ring as defined above.

"Optionally substituted heterocycloalkyl" means a saturated or unsaturated monovalent cyclic group having 3 to 8 ring atoms, one or two of which are selected from N, O, or S(O) A heteroatom in _n , where 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 with a -CO- group. More specifically, the term "heterocycloalkyl" includes, but is not limited to, pyrrolidino, piperidino, morpholino, piperazino, tetrahydropyranyl, and thiomorpholino, and derivatives (formed when the heterocycloalkyl ring is substituted by the following substituents), or N-oxide or protected derivatives 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 carboxyl.

"Optionally substituted heterocycloalkoxy" refers to the radical -OR wherein R is an optionally substituted heterocycloalkyl ring as defined above.

"Optionally substituted heterocycloalkylalkyl" refers to the group -(alkylene)-R, wherein R is an optionally substituted heterocycloalkyl ring as defined above.

"Optionally substituted heterocycloalkylalkoxy" refers to the group -OR wherein R is an optionally substituted heterocycloalkylalkyl ring as defined above.

"Optionally substituted heterocycloalkoxyalkyl" means a -(alkylene)-OR radical, where R is optionally substituted heterocycloalkyl as defined above, for example piperidinyloxymethyl, pyrrole Alkoxyethyl etc.

"Optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "heterocycloalkyl optionally substituted with alkyl or disubstituted with alkyl" means that alkyl may but not necessarily be present, and this description includes: where heterocycloalkyl is monosubstituted or disubstituted with alkyl, and wherein the heterocycloalkyl group is not substituted by an alkyl group.

"Pharmaceutically acceptable carrier or excipient" means a carrier or excipient useful in the manufacture of a pharmaceutical composition, which is generally safe, nontoxic, and neither biologically nor otherwise undesirable, including for veterinary use Carriers or excipients that are acceptable for both pharmaceutical and human use. "Pharmaceutically acceptable carrier/excipient" as used in the specification and claims includes both one and more than one such excipients.

"Treatment" of a disease includes:

(1) Preventing a disease, that is, preventing the development of clinical symptoms of a disease in a mammal that may be exposed to or prone to the disease but has not yet suffered from or exhibited symptoms of the disease.

(2) inhibit the disease, that is, arrest or reduce the progression of the disease or its clinical symptoms; or

(3) Relief of the disease, that is, the regression of the disease or its clinical symptoms.

The term "treatment of cancer" or "treatment of cancer" refers to the administration to a mammal afflicted with cancer, the effect of alleviating cancer by killing cancer cells, and the effect of causing inhibition of cancer proliferation and/or metastasis.

"Therapeutically effective amount" means that amount of a compound of formula (I) sufficient to effect treatment of a disease when administered to a mammal for the treatment of a 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 compound of formula (I) is as follows:

wherein ^R1 and ^R3 are hydrogen, ^Ar1 is phenyl, ^Ar2 and Y are defined in Table I below.

Table I Compound number Ar ² Y 1 Phenyl -CH ₂ -CH ₂ - 2 trans-phenyl-CH=CH- -CH ₂ -CH ₂ - 3 trans-phenylcyclopropyl -CH ₂ -CH ₂ - 4 trans-4-MeO-phenyl-CH=CH- -CH ₂ -CH ₂ - 5 2-Phenylethyl -CH ₂ -CH ₂ - 6 1H-indol-3-ylmethyl -CH ₂ -CH ₂ - 7 Thiophen-2-yl -CH ₂ -CH ₂ - 8 Pyridin-3-yl -CH ₂ -CH ₂ - 9 4-biphenyl -CH ₂ -CH ₂ - 10 3-biphenyl -CH ₂ -CH ₂ - 11 5-phenylthiophen-2-yl -CH ₂ -CH ₂ - 12 Thiophen-2-ylmethyl -CH ₂ -CH ₂ - 13 Naphthalene-2-yl -CH ₂ -CH ₂ - 14 Quinolin-6-yl -CH ₂ -CH ₂ - 15 4-Phenylthiazol-2-yl -CH ₂ -CH ₂ - 16 4-tert-butylphenyl -CH ₂ -CH ₂ - 17 trans-pyridin-3-yl-CH=CH- -CH ₂ -CH ₂ - 18 4-pyrrol-1-ylphenyl -CH ₂ -CH ₂ - 19 4-(Cyclohexene-3-oxy)-phenyl -CH ₂ -CH ₂ - 20 Benzothiazol-2-yl -CH ₂ -CH ₂ - twenty one Benzoxazol-2-yl -CH ₂ -CH ₂ - twenty two Octahydroisoquinolin-2-ylmethyl -CH ₂ -CH ₂ - twenty three 4-pyridin-4-yl-piperazin-1-ylmethyl -CH ₂ -CH ₂ - twenty four furan-2-yl -CH ₂ -CH ₂ - 25 4-(pyridin-3-yl)-phenyl -CH ₂ -CH ₂ - 26 4-(pyridin-2-yl)-phenyl -CH ₂ -CH ₂ - 27 1H-benzimidazol-2-yl -CH ₂ -CH ₂ - 28 1H-pyrrol-2-yl -CH ₂ -CH ₂ -

29 4-(Benzoylamino)-phenyl -CH ₂ -CH ₂ - 30 4-(pyridin-4-yl)-thiazol-2-yl -CH ₂ -CH ₂ - 31 adamantan-1-yl -CH ₂ -CH ₂ - 32 2,4-Difluorophenyl -CH ₂ -CH ₂ - 33 Trans-3,4-methylenedioxyphenyl CH=CH- -CH ₂ -CH ₂ - 34 3,4-Methylenedioxyphenyl -CH ₂ -CH ₂ - 35 3,4-Dimethoxyphenyl -CH ₂ -CH ₂ - 36 3,5-Dimethoxyphenyl -CH ₂ -CH ₂ - 37 3,4-Difluorophenyl -CH ₂ -CH ₂ - 38 2,5-Dimethylphenyl -CH ₂ -CH ₂ - 39 2,3-Dichlorophenyl -CH ₂ -CH ₂ - 40 2,3-Dimethylphenyl -CH ₂ -CH ₂ - 41 4-Chloro-2-methoxyphenyl -CH ₂ -CH ₂ - 42 3-Ethoxyphenyl -CH ₂ -CH ₂ - 43 4-methoxy-2-methylphenyl -CH ₂ -CH ₂ - 44 3-fluoro-4-methoxyphenyl -CH ₂ -CH ₂ - 45 2-(thiophen-2-ylmethoxy)phenyl -CH ₂ -CH ₂ - 46 3-(thiophen-2-ylmethoxy)-phenyl -CH ₂ -CH ₂ - 47 2-Phenylphenyl -CH ₂ -CH ₂ - 48 1H-indol-5-yl -CH ₂ -CH ₂ - 49 1H-indol-3-yl -CH ₂ -CH ₂ - 50 Quinolin-3-yl -CH ₂ -CH ₂ - 51 Quinolin-8-yl -CH ₂ -CH ₂ - 52 1H-indazol-3-yl -CH ₂ -CH ₂ - 53 1H-Benzotriazol-5-yl -CH ₂ -CH ₂ - 54 Isoquinolin-1-yl -CH ₂ -CH ₂ - 55 Isoquinolin-3-yl -CH ₂ -CH ₂ - 56 Quinoxalin-2-yl -CH ₂ -CH ₂ - 57 Naphthalene-1-yl -CH ₂ -CH ₂ - 58 Quinolin-2-yl -CH ₂ -CH ₂ -

59 2-pyrrol-1-yl-phenyl -CH ₂ -CH ₂ - 60 4-fluoronaphthalen-1-yl -CH ₂ -CH ₂ - 61 1H-benzimidazol-5-yl -CH ₂ -CH ₂ - 62 1-Methyl-indol-3-yl -CH ₂ -CH ₂ - 63 4-MeO-quinolin-2-yl -CH ₂ -CH ₂ - 64 3-MeO-naphthalen-2-yl -CH ₂ -CH ₂ - 65 2-MeO-naphthalen-1-yl -CH ₂ -CH ₂ - 66 Quinolin-4-yl -CH ₂ -CH ₂ - 67 trans-phenyl-CH=C(CH ₃ )- -CH ₂ -CH ₂ - 68 2-N, N-Dimethylaminomethylbenzofuran-5-yl -CH ₂ -CH ₂ - 69 Indolin-1-yl -CH ₂ -CH ₂ - 70 1,2,3,4-Tetrahydroquinolin-1-yl -CH ₂ -CH ₂ - 71 Trans-5-hydroxybenzofuran-2-yl-C(CH ₃ )=CH- -(S)-CH(CH ₂ CH ₃ )-CH ₂ - 72 trans-5-(1-cyclopropylpiperidin-4-yloxy)benzofuran-2-yl-C(CH ₃ )=CH- -(S)-CH(CH ₂ CH ₃ )-CH ₂ - 73 Benzofuran-2-yl -(S)-CH(2-phenylethyl)-CH ₂ - 74 5-(1-cyclopropylpiperidin-4-yloxy)benzofuran-2-yl -CH ₂ -CH ₂ - 75 5-(1-cyclopropylpiperidin-4-yloxy)benzofuran-2-yl -(S)-CH(CH ₂ CH ₃ )-CH ₂ - 76 5-(1-cyclopropylpiperidin-4-yloxy)benzofuran-2-yl -(R)-CH ₂ -CH(CH ₃ )- 77 5-[1-(2,2,2-trifluoroethyl)piperidin-4-yloxy]benzofuran-2-yl -CH ₂ -CH ₂ 78 Benzofuran-2-yl -(R)-CH(benzylSO ₂ -methyl)-CH ₂ - 79 Benzofuran-2-yl -(R)-CH(benzyl S-methyl)-CH ₂ - 80 Trans-5-methoxybenzofuran-2-yl-C(CH ₃ )=CH- -CH ₂ -CH ₂ - 81 1,2,3,4-Tetrahydroisoquinolin-2-yl -CH ₂ -CH ₂ - 82 Isoindolin-2-yl -CH ₂ -CH ₂ - 83 Morpholin-4-yl -CH ₂ -CH ₂ -

84 4-Benzyl-piperazin-1-yl -CH ₂ -CH ₂ - 85 (R)-3-HO-pyrrolidin-1-yl- -CH ₂ -CH ₂ - 86 piperidin-1-yl -CH ₂ -CH ₂ - 87 6-CH ₃ -1,2,3,4-tetrahydroquinolin-1-yl -CH ₂ -CH ₂ - 88 2-CH ₃ -indolin-1-yl- -CH ₂ -CH ₂ - 89 6-F-2-CH ₃ -1,2,3,4-tetrahydroquinolin-1-yl -CH ₂ -CH ₂ - 90 Isoindolin-1-yl -(S)-CH(CH ₂ CH ₃ )-CH ₂ - 91 trans-Phenyl-CH=CH- -CH ₂ -CH ₂ -CH ₂ - 92 trans-4-CH ₃ O-phenyl-CH=CH- -CH ₂ -CH ₂ -CH ₂ - 93 4-Phenylthiazol-2-yl -CH ₂ -CH ₂ -CH ₂ - 94 trans-Phenyl-CH=CH- -(S)-CH(methyl)-CH ₂ - 95 trans-Phenyl-CH=CH- -(R)-CH(methyl)-CH ₂ - 96 trans-Phenyl-CH=CH- -(S)-CH(isobutyl)-CH ₂ - 97 trans-Phenyl-CH=CH- -(S)-CH(cyclohexyl-methyl)-CH ₂ - 98 trans-Phenyl-CH=CH- -(S)-CH(isopropyl)-CH ₂ - 99 trans-Phenyl-CH=CH- -(S)-CH(benzyl)-CH ₂ - 100 trans-Phenyl-CH=CH- -(R)-CH(benzyl)-CH ₂ - 101 trans-Phenyl-CH=CH- -(R)-CH(isobutyl)-CH ₂ - 102 trans-Phenyl-CH=CH- -(R)-CH(isopropyl)-CH ₂ - 103 trans-Phenyl-CH=CH- -(RS)-CH(n-butyl)-CH ₂ - 104 trans-Phenyl-CH=CH- -(RS)-CH(4-Cl-benzyl)-CH ₂ - 105 trans-Phenyl-CH=CH- -(S)-CH(CH ₂ CH ₃ )-CH ₂ - 106 trans-Phenyl-CH=CH- -(R)-CH(CH ₂ CH ₃ )-CH ₂ - 107 trans-Phenyl-CH=CH- -(S)-CH(2-MeS-ethyl)-CH ₂ - 108 trans-Phenyl-CH=CH- -(R)-CH(2-MeS-ethyl)-CH ₂ - 109 trans-Phenyl-CH=CH- -(S)-CH(phenyl)-CH ₂ - 110 trans-Phenyl-CH=CH- -(R)-CH(phenyl)-CH ₂ - 111 trans-Phenyl-CH=CH- -(S)-CH(2-MeSO ₂ -ethyl)-CH ₂ - 112 trans-Phenyl-CH=CH- -(R)-CH(2-MeSO ₂ -B

Base) -CH ₂ - 113 trans-Phenyl-CH=CH- -(R)-CH(benzylSO ₂ -methyl)-CH ₂ - 114 Thiophen-2-yl -(S)-CH(CH ₂ CH ₃ )-CH ₂ - 115 4-biphenyl -(S)-CH(CH ₂ CH ₃ )-CH ₂ - 116 Naphthalene-2-yl -(S)-CH(CH ₂ CH ₃ )-CH ₂ - 117 trans-Phenyl-CH=CH- -(R)-CH(benzyl-S-methyl)-CH ₂ - 118 Phenyl -(S)-CH(CH ₂ CH ₃ )-CH ₂ - 119 Benzyl -(S)-CH(CH ₂ CH ₃ )-CH ₂ - 120 2-Phenylethyl -(S)-CH(CH ₂ CH ₃ )-CH ₂ - 121 trans-Phenyl-CH=CH- -(S)-CH(hydroxy-methyl)-CH ₂ - 122 4-Phenylthiazol-2-yl -(S)-CH(CH ₂ CH ₃ )-CH ₂ - 123 trans-4-CH ₃ O-phenyl-CH=CH- -(S)-CH(CH ₂ CH ₃ )-CH ₂ - 124 2-N, N-Dimethylaminomethyl-benzofuran-5-yl- -(S)-CH(CH ₂ CH ₃ )-CH ₂ - 125 trans-Phenyl-CH=CH- -(R)-CH ₂ -CH(CH ₃ )- 126 trans-Phenyl-CH=CH- -(S)-CH ₂ -CH(CH ₃ )- 127 4-Phenyl-thiazol-2-yl -(R)-CH ₂ -CH(CH ₃ )- 128 4-Phenyl-thiazol-2-yl -(S)-CH ₂ -CH(CH ₃ )- 129 4-biphenyl -(R)-CH ₂ -CH(CH ₃ )- 130 trans-4-CH ₃ O-phenyl-CH=CH- -(R)-CH ₂ -CH(CH ₃ )- 131 4-(2-pyridin-4-ylthiazol-5-yl)phenyl -CH ₂ -CH ₂ - 132 7-Chloro-4-methylbenzofuran-2-yl -CH ₂ -CH ₂ - 133 4-[2-(4-Methylpiperazin-1-yl)thiazol-5-yl]-phenyl -CH ₂ -CH ₂ - 134 4-(2-pyridin-4-ylaminothiazol-5-yl)phenyl -CH ₂ -CH ₂ - 135 4-(4-Methylpiperazin-1-yl)phenyl -CH ₂ -CH ₂ - 136 4-(4-Hydroxypiperidin-1-yl)phenyl -CH ₂ -CH ₂ - 137 4-(4-morpholin-4-ylmethylthiazol-2-yl)phenyl -CH ₂ -CH ₂ - 138 7-fluoro-4-methylbenzofuran-2-yl -CH ₂ -CH ₂ - 139 7-fluoro-4-(2-methoxyethoxymethyl)-benzofuran-2-yl -CH ₂ -CH ₂ -

140 4-Hydroxyquinolin-2-yl -CH ₂ -CH ₂ - 141 7-fluoro-4-phenoxymethylbenzofuran-2-yl -CH ₂ -CH ₂ - 143 4-[2-(4-Methylpiperazin-1-ylmethyl)thiazol-5-yl]phenyl -CH ₂ -CH ₂ - 144 Pyridin-2-yl -CH ₂ -CH ₂ - 145 3-Hydroxypyridin-2-yl -CH ₂ -CH ₂ - 146 6-hydroxypyridin-2-yl -CH ₂ -CH ₂ - 147 6-(4-nitrophenoxy)pyridin-2-yl -CH ₂ -CH ₂ - 148 4-(2-methoxyethoxy)quinolin-2-yl -CH ₂ -CH ₂ - 149 4-(2-Dimethylaminoethoxy)quinolin-2-yl -CH ₂ -CH ₂ - 150 6-bromopyridin-2-yl -CH ₂ -CH ₂ - 151 5-Bromopyridin-3-yl -CH ₂ -CH ₂ - 152 4-methoxyquinolin-2-yl -(S)-CH(CH ₂ CH ₃ )-CH ₂ - 153 1-methoxynaphthalen-2-yl -CH ₂ -CH ₂ - 154 4-methoxyquinolin-2-yl -(R)-CH ₂ -CH(CH ₃ )- 155 5-Phenylpyridin-3-yl -CH ₂ -CH ₂ - 156 6-Benzyloxypyridin-2-yl -CH ₂ -CH ₂ - 157 6-(2-Methylpropoxy)pyridin-2-yl -CH ₂ -CH ₂ - 158 6-(2-phenylethoxy)pyridin-2-yl -CH ₂ -CH ₂ - 159 4-(3,3,3-trifluoropropoxy)quinolin-2-yl -CH ₂ -CH ₂ - 160 4-(3,3,3-trifluoropropoxy)quinolin-2-yl -(S)-CH(CH ₂ CH ₃ )-CH ₂ - 161 4-(3,3,3-trifluoropropoxy)quinolin-2-yl -(R)-CH ₂ -CH(CH ₃ )- 162 Trans-3-Hydroxyphenyl-CH＝CH- -CH ₂ -CH ₂ - 163 Trans-4-Hydroxyphenyl-CH＝CH- -CH ₂ -CH ₂ - 164 3′-(2-Hydroxyethyl)biphenyl-4-yl -CH ₂ -CH ₂ - 165 3′-(2-hydroxyethyl)biphenyl-3-yl -CH ₂ -CH ₂ - 166 2′-(2-Hydroxyethyl)biphenyl-4-yl -CH ₂ -CH ₂ - 167 trans-benzofuran-2-yl-CH=CH- -CH ₂ -CH ₂ - 168 2′-(2-Hydroxyethyl)biphenyl-3-yl -CH ₂ -CH ₂ - 169 5-thiophen-3-ylpyridin-3-yl -CH ₂ -CH ₂ -

170 6-(4-Acetylaminophenoxy)pyridin-2-yl -CH ₂ -CH ₂ - 171 6-(4-aminophenoxy)pyridin-2-yl -CH ₂ -CH ₂ - 172 Trans-2-Methoxyphenyl-CH＝CH- -CH ₂ -CH ₂ - 173 Trans-3-Methoxyphenyl-CH＝CH- -CH ₂ -CH ₂ - 174 5-(4-Dimethylaminophenyl)pyridin-3-yl -CH ₂ -CH ₂ - 175 Trans-5-bromothiophen-2-yl-CH＝CH- -CH ₂ -CH ₂ - 176 trans-furan-3-yl-CH＝CH- -CH ₂ -CH ₂ - 177 Trans-thiophen-3-yl-CH=CH- -CH ₂ -CH ₂ - 178 Trans-thiophen-2-yl-CH＝CH- -CH ₂ -CH ₂ - 179 Trans-3-methylphenyl-CH＝CH- -CH ₂ -CH ₂ - 180 Trans-4-methylphenyl-CH＝CH- -CH ₂ -CH ₂ - 181 trans-benzofuran-2-yl-C(CH ₃ )=CH- -CH ₂ -CH ₂ - 182 cis-benzofuran-2-yl-C(CH ₃ )=CH- -CH ₂ -CH ₂ - 183  Trans-4-Dimethylaminophenyl-CH＝CH- -CH ₂ -CH ₂ - 184 Trans-Indol-3-yl-CH＝CH- -CH ₂ -CH ₂ - 185 Trans-2-methylphenyl-CH＝CH- -CH ₂ -CH ₂ - 186  Trans-2-Hydroxyphenyl-CH＝CH- -CH ₂ -CH ₂ - 187 Trans-7-methoxybenzofuran-2-yl-CH＝CH- -CH ₂ -CH ₂ - 188 Trans-7-methoxybenzofuran-2-yl-CH＝CH- -(R)-CH(CH ₂ CH ₃ )-CH ₂ - 189 Trans-5-methoxybenzofuran-2-yl-C(CH ₃ )=CH- -(S)-CH(CH ₂ CH ₃ )-CH ₂ - 190 Trans-furan-2-yl-CH＝CH- -CH ₂ -CH ₂ - 191 4-[4-(2-morpholin-4-ylethyl)thiazol-2-yl]phenyl -CH ₂ -CH ₂ -

and is named:

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-(naphthalene-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-butylphenylcarbonylamino)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-(benzoxazol-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-benzamidophenylcarbonylamino)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-(naphthalene-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-benzimidazol-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-dihydroindol-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]butyl Oxy}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-methylindolin-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-(naphthalene-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-ylmethylthiazol-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-bromothien-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 compound of formula (I) is as follows:

Wherein R ¹ is hydrogen, Ar ¹ is phenyl, and the definitions of R ³ , Ar ² and Y are shown in Table II below.

Table II Compound number R ³ Ar ² Y 1 2-HO-ethyl trans-phenyl-CH=CH- -CH ₂ -CH ₂ - 2 Phenyl trans-phenyl-CH=CH- -CH ₂ -CH ₂ - 3 _CH3 trans-phenyl-CH=CH- -CH ₂ -CH ₂ - 4 Isopropyl Benzothiophen-2-yl -CH ₂ -CH ₂ - 5 Isopropyl trans-phenyl-CH=CH- -CH ₂ -CH ₂ - 6 _CH3 trans-phenyl-CH=CH- -CH ₂ -CH ₂ -CH ₂ -

and is named:

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-benzothiophen-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 compound of formula (I) is as follows:

wherein ^R1 and ^R3 are hydrogen, ^Ar1 is phenyl, and the definitions of Z, R and Y are shown in Table II below.

Table III Compound number Z R Y 1 S h -CH ₂ -CH ₂ - 2 o h -CH ₂ -CH ₂ - 3 NH h -CH ₂ -CH ₂ - 4 NMe h -CH ₂ -CH ₂ - 5 S h -CH ₂ -CH ₂ -CH ₂ - 6 o h -CH ₂ -CH ₂ -CH ₂ - 7 S h -(S)-CH(isopropyl)-CH ₂ - 8 S h -(S)-CH(ethyl)-CH ₂ - 9 S h -(S)-CH(methyl)-CH ₂ - 10 S h -(R)-CH(methyl)-CH ₂ - 11 o h -(S)-CH(ethyl)-CH ₂ - 12 S h -(R)-CH ₂ -CH(CH ₃ )- 13 S h -(S)-CH ₂ -CH(CH ₃ )- 14 o h -(R)-CH ₂ -CH(CH ₃ )- 15 S 6-methoxy -CH ₂ -CH ₂ - 16 S 5-methyl -CH ₂ -CH ₂ - 17 S 3-chloro -CH ₂ -CH ₂ - 18 o 5-methyl -CH ₂ -CH ₂ - 19 o 6-methyl -CH ₂ -CH ₂ - 20 S 4-CF ₃ -CH ₂ -CH ₂ - twenty one S 5-fluoro -CH ₂ -CH ₂ - twenty two S 5-methoxy -CH ₂ -CH ₂ -

twenty three o 5-chloro -CH ₂ -CH ₂ - twenty four o 7-methoxy -CH ₂ -CH ₂ - 25 o 5-methoxy -CH ₂ -CH ₂ - 26 o 5-(2-Methoxyethoxy)- -CH ₂ -CH ₂ - 27 o 5-(2-morpholin-4-ylethoxy)- -CH ₂ -CH ₂ - 28 o 5-pyridin-3-ylmethoxy -CH ₂ -CH ₂ - 29 o 3-Methyl -CH ₂ -CH ₂ - 30 S 3-Methyl -CH ₂ -CH ₂ - 31 o 5-(2-Hydroxyethoxy)- -CH ₂ -CH ₂ - 32 o 5-(2-N,N-Dimethylaminoethoxy)- -CH ₂ -CH ₂ - 33 o _{6 - CH3OCH2CH2O} -CH ₂ -CH ₂ - 34 o 6-(2-morpholin-4-ylethoxy)- -CH ₂ -CH ₂ - 35 o 6-pyridin-3-ylmethoxy- -CH ₂ -CH ₂ - 36 o 3-Ethyl -CH ₂ -CH ₂ - 37 NH 5-fluoro -CH ₂ -CH ₂ - 38 NH 5-methoxy -CH ₂ -CH ₂ - 39 o 3-CH ₃ OCH ₂ -CH ₂ -CH ₂ - 40 o 3-phenoxymethyl -CH ₂ -CH ₂ - 41 NH 5,6-Dimethoxy -CH ₂ -CH ₂ - 42 o 3-morpholino-4-ylmethyl -CH ₂ -CH ₂ - 43 o 3-N,N-Dimethylaminomethyl -CH ₂ -CH ₂ - 44 o 3-Isopropoxymethyl -CH ₂ -CH ₂ - 45 o 7-Phenoxymethyl -CH ₂ -CH ₂ - 46 o 7-CH ₃ OCH ₂ -CH ₂ -CH ₂ - 47 o 7-morpholino-4-ylmethyl -CH ₂ -CH ₂ - 48 o 7-N,N-Dimethylaminomethyl -CH ₂ -CH ₂ - 49 S 5-methyl -CH ₂ -CH ₂ -CH ₂ - 50 S 6-methoxy -CH ₂ -CH ₂ -CH ₂ - 51 o 7-CH ₃ OCH ₂ -CH ₂ -CH ₂ -CH ₂ - 52 o 7-Phenoxymethyl -CH ₂ -CH ₂ -CH ₂ -

53 o _{5 - CH3OCH2CH2O} -(R)-CH ₂ -CH(CH ₃ )- 54 o h (R)-CH(CH ₃ S methyl)-CH ₂ - 55 o h (R)-CH(CH ₃ SO ₂ -methyl)-CH ₂ - 56 o 3-(2-Phenylethyl)- -CH ₂ -CH ₂ - 57 o 3-(N-methyl-N-benzylaminomethyl)- -CH ₂ -CH ₂ - 58 o 3-(N-methyl-N-2-phenylethyl-aminomethyl)- -CH ₂ -CH ₂ - 59 o 3-(3-Hydroxypropylthiomethyl)- -CH ₂ -CH ₂ - 60 o 3-(3-Hydroxypropylsulfinylmethyl)- -CH ₂ -CH ₂ - 61 o 3-(3-Hydroxypropylsulfonylmethyl)- -CH ₂ -CH ₂ - 62 o 3-(N-methyl-N-2-indol-3-yl-ethylaminomethyl)- -CH ₂ -CH ₂ - 63 o 3-[2-(3-Trifluoromethylphenyl)-ethyl]- -CH ₂ -CH ₂ - 64 o 3-[2-(3-Trifluoromethoxyphenyl)-ethyl]- -CH ₂ -CH ₂ - 65 o 3-(N-Hydroxyaminocarbonyl-methylaminomethyl)- -CH ₂ -CH ₂ - 66 o 3-(2-carboxyethylamino-methyl)- -CH ₂ -CH ₂ - 67 o h (RS)-CH ₂ CH-(phenoxymethyl)- 68 o 3-(3-Hydroxypropoxymethyl)- -CH ₂ -CH ₂ - 69 o 3-(2-fluorophenoxymethyl)- -CH ₂ -CH ₂ - 70 o 3-(3-fluorophenoxymethyl)- -CH ₂ -CH ₂ - 71 o 3-(4-fluorophenoxymethyl)- -CH ₂ -CH ₂ - 72 o 3-(2-Methoxyethoxymethyl)- -CH ₂ -CH ₂ - 73 o 3-(pyridin-4-yloxymethyl)- -CH ₂ -CH ₂ - 74 o 3-(2,4,6-trifluorophenoxymethyl)- -CH ₂ -CH ₂ - 75 o 3-(2-oxopyridin-1-ylmethyl)- -CH ₂ -CH ₂ -

76 o 3-(2,2,2-Trifluoroethoxymethyl)- -CH ₂ -CH ₂ - 77 o 3-(4-imidazol-1-ylphenoxymethyl)- -CH ₂ -CH ₂ - 78 o 3-(4-[1.2.4]-Triazin-1-ylphenoxy-methyl)- -CH ₂ -CH ₂ - 79 o 3-(Pyrrolidin-1-ylmethyl)- -CH ₂ -CH ₂ - 80 o 3-(piperidin-1-ylmethyl)- -CH ₂ -CH ₂ - 81 o 3-(4-Trifluoromethylpiperidin-ylmethyl)- -CH ₂ -CH ₂ - 82 o 3-(4-Methylpiperazin-1-yl-methyl)- -CH ₂ -CH ₂ - 83 o 3-(3,3,3-Trifluoropropoxy-methyl)- -CH ₂ -CH ₂ - 84 o 4-Methyl -CH ₂ -CH ₂ - 85 o 3-(4-fluorophenylthiomethyl)- -CH ₂ -CH ₂ - 86 o 3-(4-fluorophenylsulfinyl-methyl)- -CH ₂ -CH ₂ - 87 o 3-(4-fluorophenylsulfonyl-methyl)- -CH ₂ -CH ₂ - 88 o 3-(2,2,2-Trifluoroethoxy-methyl) -(S)-CH(ethyl)-CH ₂ - 89 o 4-Hydroxy -CH ₂ -CH ₂ - 90 o 5-chloro (S)-CH(ethyl)-CH ₂ - 91 o 5-chloro (R)-CH ₂ -CH(methyl)- 92 o 4-pyridin-3-ylmethoxy-methyl -CH ₂ -CH ₂ - 93 o 4-methoxy -CH ₂ -CH ₂ - 94 o 4-(2-Methoxyethoxy)- -CH ₂ -CH ₂ - 95 o 4-pyridin-3-ylmethoxy -CH ₂ -CH ₂ - 96 NH 4-methoxy -CH ₂ -CH ₂ - 97 o 3-(2-Methoxyethoxymethyl)- (S)-CH(ethyl)-CH ₂ - 98 o 3-(2-Methoxyethoxymethyl)- (R)-CH ₂ -CH(methyl)- 99 o 3-N, N-Diethylaminomethyl -CH ₂ -CH ₂ - 100 o 5-(2-Methoxyethoxy)- (S)-CH(ethyl)-CH ₂ 101 o 5-tetrahydropyran-4-yloxy -CH ₂ -CH ₂ - 102 o 5-tetrahydropyran-4-yloxy (S)-CH(ethyl)-CH ₂ - 103 o 5-tetrahydropyran-4-yloxy (R)-CH ₂ -CH(methyl)- 104 o 5-(2,2,2-trifluoroethoxy)- -CH ₂ -CH ₂ -

105 o 5-(2-Pyrrolidin-1-ylethoxy)- -CH ₂ -CH ₂ - 106 o 5-(2-Pyrrolidin-1-ylethoxy)- (S)-CH(ethyl)-CH ₂ - 107 o 5-(2-Pyrrolidin-1-ylethoxy)- (R)-CH ₂ -CH(methyl)- 108 o 5-(piperidin-4-yloxy)- -CH ₂ -CH ₂ - 109 o h (S)-CH(2-CH ₃ S ethyl)-CH ₂ - 110 o h (S)-CH(2-CH ₃ SO ₂ ethyl)-CH ₂ -

and is named:

N-Hydroxy-4-[2-(benzothiophen-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-(benzothiophen-2-ylcarbonylamino)propoxy]-benzamide;

N-Hydroxy-4-[3-(benzofuran-2-ylcarbonylamino)propoxy]-benzamide;

N-Hydroxy-4-[2S-(benzothiophen-2-ylcarbonylamino)-3-methylbutoxy]-benzamide;

N-Hydroxy-4-[2S-(benzothiophen-2-ylcarbonylamino)butoxy]-benzamide;

N-Hydroxy-4-[2S-(benzothiophen-2-ylcarbonylamino)-propoxy]-benzamide;

N-Hydroxy-4-[2R-(benzothiophen-2-ylcarbonylamino)-propoxy]-benzamide;

N-Hydroxy-4-[2S-(benzofuran-2-ylcarbonylamino)butoxy]-benzamide;

N-Hydroxy-4-[2-(benzothiophen-2-ylcarbonylamino)-1R-methylethoxy]-benzamide;

N-Hydroxy-4-[2-(benzothiophen-2-ylcarbonylamino)-1S-methylethoxy]-benzamide;

N-Hydroxy-4-[2-(benzofuran-2-ylcarbonylamino)-1R-methylethoxy]-benzamide;

N-Hydroxy-4-[2-(6-methoxybenzothiophen-2-ylcarbonylamino)ethoxy]-benzamide;

N-Hydroxy-4-[2-(5-methylbenzothiophen-2-ylcarbonylamino)ethoxy]-benzamide;

N-Hydroxy-4-[2-(3-chlorobenzothiophen-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-trifluoromethylbenzothiophen-2-ylcarbonylamino)ethoxy]-benzamide;

N-Hydroxy-4-[2-(5-fluorobenzothiophen-2-ylcarbonylamino)ethoxy]-benzamide;

N-Hydroxy-4-[2-(5-methoxybenzothiophen-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-methylbenzothiophen-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)benzothiophen-2-ylcarbonylamino]propoxy}-benzamide;

N-Hydroxy-4-{3-[6-(methoxy)benzothiophen-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}benzyl amides;

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-hydroxyaminocarbonylmethylaminomethyl)benzofuran-2-ylcarbonylamino]ethoxy}benzamide;

N-Hydroxy-4-{2-[3-(2-carboxyethylaminomethyl)benzofuran-2-ylcarbonylamino]-ethoxy}benzamide;

N-Hydroxy-4-[2-(benzofuran-2-ylcarbonylamino)-1RS-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}benzyl amides;

N-Hydroxy-4-{2-[3-(pyrrolidine-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-trifluoromethylpiperidine-1-methyl)benzofuran-2-ylcarbonylamino]-ethoxy}benzamide;

N-Hydroxy-4-{2-[3-(4-methylpiperazine-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-fluorophenylthiomethyl)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 compound of formula (I) is as follows:

wherein R ¹ and R ³ are hydrogen, Ar ¹ is isoxazol-5-yl, Ar ² and Y are defined in Table IV below.

Table IV Compound number Ar ² Y 1 4-biphenyl (R)-CH ₂ -CH(CH ₃ )- 2 4-biphenyl (S)-CH(ethyl)-CH ₂ - 3 Benzofuran-2-yl -CH ₂ -CH ₂ - 4 trans-phenyl-CH=CH- -CH ₂ -CH ₂ - 5 4-(2-ethoxyphenyl)phenyl -CH ₂ -CH ₂ -CH ₂ - 6 3-biphenyl -CH ₂ -CH ₂ -CH ₂ - 7 4-biphenyl -CH ₂ -CH ₂ -CH ₂ - 8 Naphthalene-2-yl -CH ₂ -CH ₂ - 9 3-Methylbiphenyl-4-yl -CH ₂ -CH ₂ - 10 2′-Ethoxybiphenyl-4-yl -CH ₂ -CH ₂ - 11 3-Methylbiphenyl-4-yl -CH ₂ -CH ₂ -CH ₂ - 12 4-Phenylthiazol-2-yl -CH ₂ -CH ₂ -CH ₂ - 13 Naphthalene-2-yl -CH ₂ -CH ₂ -CH ₂ - 14 Naphthalene-1-yl -CH ₂ -CH ₂ -CH ₂ - 15 2-2-(Phenylethyl)phenyl -CH ₂ -CH ₂ -CH ₂ - 16 Naphthalene-1-yl -CH ₂ -CH ₂ - 17 Benzofuran-2-yl (S)-CH(ethyl)-CH ₂ - 18 3-biphenyl (S)-CH(ethyl)-CH ₂ - 19 Benzofuran-2-yl (R)-CH ₂ -CH(methyl)- 20 3-biphenyl (R)-CH ₂ -CH(methyl)- twenty one 3-biphenyl -CH ₂ -CH ₂ - twenty two 4-biphenyl -CH ₂ -CH ₂ - twenty three 4-Phenylthiazol-2-yl -CH ₂ -CH ₂ - twenty four 2-(2-Phenylethyl)phenyl -CH ₂ -CH ₂ - 25 2-biphenyl -CH ₂ -CH ₂ - 26 2-biphenyl -CH ₂ -CH ₂ -CH ₂ - 27 Naphthalene-2-yl (S)-CH(ethyl)-CH ₂ - 28 Naphthalene-1-yl (S)-CH(ethyl)-CH ₂ -

29 Naphthalene-2-yl (R)-CH ₂ -CH(methyl)- 30 Naphthalene-1-yl (R)-CH ₂ -CH(methyl)- 31 Benzofuran-2-yl -CH ₂ -CH ₂ -CH ₂ - 32 Trans-Phenyl CH=CH- -CH ₂ -CH ₂ -CH ₂ - 33 3-(phenoxymethyl)benzofuran-2-yl -CH ₂ -CH ₂ -

and is named:

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-(naphthalene-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-(naphthalene-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-(naphthalene-2-ylcarbonylamino)butoxy]isoxazol-5-ylcarboxamide;

N-Hydroxy-3-[2S-(naphthalen-1-ylcarbonylamino)butoxy]isoxazol-5-ylcarboxamide;

N-Hydroxy-3-[2-(naphthalene-2-ylcarbonylamino)-1R-methylethoxy]isoxazol-5-ylcarboxamide;

N-Hydroxy-3-[2-(naphthalene-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.

preferred embodiment

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) in which:

R ¹ is hydrogen or alkyl;

X is -O-, -NR ² -, or -S(O) _n , wherein n is 0-2, and R ² is hydrogen or alkyl;

Y is an alkylene group, which is optionally replaced by cycloalkyl, optionally substituted phenyl, alkylthio, alkylsulfonyl, optionally substituted phenylalkylthio, optionally substituted phenylalkylsulfonyl Acyl, or hydroxyl substitution;

Ar is ^phenylene or heteroarylene, wherein said ^Ar is optionally substituted by one or two groups independently selected from: alkyl, halo, hydroxy, alkoxy, haloalkane Oxygen, or haloalkyl;

^R is hydrogen, alkyl, hydroxyalkyl, or optionally substituted phenyl; and

Ar is ^aryl , aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl ;

wherein the terms "aryl, heteroaryl, heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, and aminoalkyl" either alone or as A portion of another term (eg, aralkyl, optionally substituted phenylalkylthio, aminoalkoxy, optionally substituted phenylcarbonylamino, optionally substituted heteroaryl, etc.) is encompassed by the above Within the scope of preferred group I, said terms have the following meanings:

"Aryl" means a monovalent monocyclic or bicyclic aromatic hydrocarbon group having 6 to 12 ring atoms, such as phenyl, naphthyl or anthracenyl optionally substituted by one, two or three substituents, said The substituents are independently selected from the group consisting of: alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxy, hydroxyalkyl, hydroxyalkoxy, hydroxyalkoxyalkane radical, alkoxyalkoxyalkyl, optionally substituted phenyl, optionally substituted heteroaryl, cycloalkoxy, cycloalkenyloxy, optionally substituted phenylcarbonylamino, optionally substituted hetero Aryloxy, optionally substituted heteroaralkoxy, aminoalkyl, aminoalkoxy, alkoxyalkyl, alkoxyalkoxy, methylenedioxy, haloalkoxyalkyl, optionally Substituted phenoxyalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted heterocycloalkoxyalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heterocycloalkyl Alkoxy, optionally substituted heterocycloalkoxy, -alkylene-S(O) _n -R ^a (wherein n is 0 to 2, R ^a is alkyl, haloalkyl, optionally substituted phenyl , optionally substituted phenylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl), -alkylene-NHSO ₂ -R ^b (wherein R ^b is alkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or optionally substituted heterocycloalkyl), or -alkylene- NHCO- ^Rc (wherein ^Rc is alkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, or any optionally substituted heterocycloalkyl), wherein the alkyl chain in haloalkoxyalkyl, optionally substituted phenoxyalkyl, optionally substituted heteroaryloxyalkyl, or aminoalkyl is optionally Substituted by one or two fluorines. More preferably, the aromatic ring is optionally substituted with one, two, or three substituents independently selected from the group consisting of: alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkane ylamino, dialkylamino, hydroxy, hydroxyalkyl, hydroxyalkoxy, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, cycloalkoxy, cycloalkene Oxy, optionally substituted phenylcarbonylamino, optionally substituted heteroaryl, optionally substituted heteroaralkoxy, aminoalkyl, aminoalkoxy, alkoxyalkyl, alkoxyalkoxy radical, methylenedioxy, optionally substituted phenoxyalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heterocycloalkylalkoxy group, optionally substituted heterocycloalkoxyalkyl, 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,N-dimethylaminomethyl, isopropoxymethyl, or phenoxymethyl;

"Heterocycloalkyl" means a saturated monovalent cyclic group having 3 to 8 ring atoms, one or two of which are heteroatoms, selected from N, O, or S(O) _n , wherein 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, and their derivatives (formed when the heterocycloalkyl ring is substituted by the following substituents); or N-oxide or protected derivatives thereof. Heterocycloalkyl is optionally fused to aryl, optionally substituted with one, two, or three substituents independently selected from the group consisting of: 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 heteroaralkoxy, 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,N-dimethylaminomethyl, isopropoxymethyl, or phenoxymethyl;

"Heteroaryl" means a monovalent monocyclic or bicyclic aromatic radical having 5 to 10 ring atoms, containing one or more, preferably one, two, or three ring heteroatoms selected from N, O or S, the remaining ring atoms are carbon. More specifically, the term "heteroaryl" includes, but is not limited to: pyridyl, pyrrolyl, imidazolyl, thienyl, furyl, indolyl, quinolinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxa Azolyl, isoxazolyl, benzoxazolyl, benzothienyl, benzothiazolyl, tetrahydroquinolinyl (quinolinyl), isotetrahydroquinolinyl, benzopyranyl, and thiazolyl, and their derivatives (formed when the heteroaromatic ring is substituted by the following substituents), or their N-oxides or protected derivatives. The heteroaryl ring is optionally substituted with one, two, or three substituents independently selected from the group consisting of: alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, Dialkylamino, hydroxy, hydroxyalkyl, hydroxyalkoxy, hydroxyalkoxyalkyl, alkoxyalkoxyalkyl, optionally substituted phenyl, optionally substituted heteroaryl, cycloalkoxy radical, cycloalkenyloxy, optionally substituted phenylcarbonylamino, optionally substituted heteroaryl, optionally substituted heteroaralkoxy, aminoalkyl, aminoalkoxy, alkoxyalkyl, alkyl Oxyalkoxy, methylenedioxy, haloalkoxyalkyl, optionally substituted phenoxyalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted heterocycloalkoxyalkyl , optionally substituted heterocycloalkylalkyl, optionally substituted heterocycloalkylalkoxy, optionally substituted heterocycloalkoxy, -alkylene-S(O) _n -R ^a (where n is 0 to 2, R ^a is alkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl), - Alkylene-NHSO ₂ -R ^b (wherein R ^b is alkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaryl Alkyl, or optionally substituted heterocycloalkyl), or -alkylene-NHCO-R ^c (wherein R ^c is alkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl , optionally substituted heteroaryl, optionally substituted heteroaralkyl, or optionally substituted heterocycloalkyl), wherein in haloalkoxyalkyl, optionally substituted phenoxyalkyl, optionally substituted The alkyl chain in the heteroaryloxyalkyl, or aminoalkyl, of 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, any Optionally substituted phenyl, optionally substituted heteroaryl, cycloalkoxy, cycloalkenyloxy, optionally substituted phenylcarbonylamino, optionally substituted heteroaryl, optionally substituted heteroaralkoxy , aminoalkyl, aminoalkoxy, alkoxyalkyl, alkoxyalkoxy, methylenedioxy, optionally substituted phenoxyalkyl, optionally substituted heteroaryloxyalkyl, Optionally substituted heterocycloalkoxyalkyl, 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,N-dimethylaminomethyl, isopropoxymethyl, or phenoxymethyl;

"Optionally substituted phenyl" means a phenyl ring optionally substituted with one, two, or three substituents independently selected from the group consisting of: alkyl, halo, alkoxy, alkylthio , haloalkyl, haloalkoxy, heteroaryl (which is optionally substituted with one or two substituents independently selected from: alkyl, halo, hydroxy, alkoxy, carboxyl, amino, alkane amino, or dialkylamino), heterocycloalkyl (which is optionally substituted by one or two substituents independently selected from the group consisting of: 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, hydroxyl, cyano , nitro, methylenedioxy, aminocarbonyl, hydroxyalkyl, alkoxycarbonyl, aminoalkyl, or carboxyl, or optionally substituted by five fluorine atoms;

"Optionally substituted heteroaryl" refers to a monovalent monocyclic or bicyclic aromatic radical having 5 to 10 ring atoms, containing one or more, preferably one, two, or three ring heteroatoms, said The heteroatom is selected from: N, O or S, the remaining ring atoms are carbon, which is optionally substituted by one, two, or three substituents independently selected from: alkyl, halo, alkoxy radical, trifluoromethyl, trifluoromethoxy, amino, alkylamino, dialkylamino, hydroxyl, cyano, nitro, aminocarbonyl, hydroxyalkyl, alkoxycarbonyl, aminoalkyl, optional Substituted phenyl, optionally substituted phenoxy, carboxyl, 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, pyridyl Azinyl, oxazolyl, isoxazolyl, benzoxazolyl, quinolinyl, isoquinolyl, benzopyranyl, and thiazolyl, and their derivatives (when the heteroaromatic ring is substituted by Formed when substituting a group), or its N-oxide or protected derivative;

"Optionally substituted heterocycloalkyl" means a saturated monovalent cyclic group having 3 to 8 ring atoms, one or two of which are heteroatoms selected from N, O or S(O) _n , wherein n is an integer from 0 to 2, and the remaining ring atoms are C. Heterocycloalkyl is optionally fused to aryl and is optionally substituted with one, two, or three substituents independently selected from: alkyl, halo, alkoxy, tris Fluoromethyl, trifluoromethoxy, amino, alkylamino, dialkylamino, hydroxy, cyano, nitro, optionally substituted phenylalkyl, optionally substituted heteroaralkyl, aminocarbonyl, Hydroxyalkyl, alkoxycarbonyl, aminoalkyl, or carboxyl. More specifically, the term "heterocycloalkyl" includes, but is not limited to, pyrrolidino, piperidino, morpholino, piperazino, tetrahydropyranyl, and thiomorpholino, and their Derivatives of (formed when the heterocycloalkyl ring is substituted by the following substituents); or N-oxide or protected derivatives thereof; and

"Aminoalkyl" means a linear monovalent hydrocarbon radical having 2 to 6 carbon atoms or a linear monovalent hydrocarbon radical having 3 to 6 carbon atoms, substituted by at least one, preferably one or two of the following groups:- NRR', wherein R and R' are independently selected from hydrogen, alkyl, or -COR ^a , wherein R ^a is alkyl, or N-oxide derivatives, or protected derivatives, such as aminomethyl, methyl Aminoethyl, 2-ethylamino-2-methylethyl, 1,3-diaminopropyl, dimethylaminomethyl, diethylaminoethyl, acetylaminopropyl, etc.; and

For definitions of other terms included within the scope of preferred group I see the Definitions section of the present application.

Within Group I:

(A) A group of preferred compounds wherein ^R1 and ^R3 are hydrogen, X is -O-, Y is ethylene or n-propylene, preferably ethylene.

(B) Another preferred group of compounds wherein R ¹ and R ³ are hydrogen, X is -O-, Y is -CH(C ₂ H ₅ )CH ₂ -, -CH(iC ₃ H ₇ )CH ₂ -, or -CH(CH ₃ )CH ₂ -, the stereochemical formula on the chiral carbon is (S). More preferably, Y _is -CH( _C2H5 ) _CH2- .

(C) A further group of preferred compounds is that wherein ^R1 and ^R3 are hydrogen, X is -O-, Y is _-CH2CH ( _CH3 )-, and the stereochemical formula on the chiral carbon is (R) .

(i) Within groups (A)-(C), a more preferred group of compounds is wherein Ar ¹ is phenylene, wherein the hydroxamate group and the X group are opposite each other and Ar ² is aryl. Preferably, Ar ^is phenyl, optionally substituted with one or two substituents independently selected from: methoxy, ethoxy, phenyl, methyl, tert-butyl, pyrrole- 1-yl, cyclohexene-3-oxy, pyridin-3-yl, pyridin-2-yl, benzamido, fluoro, chloro, or thiophen-2-ylmethoxy. More preferably, Ar ^is phenyl, 4-biphenyl, 3-biphenyl, 4-tert-butylphenyl, 4-pyrrol-1-ylphenyl, 4-(cyclohexene-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-yl Methoxyphenyl, 3-thiophen-2-ylmethoxyphenyl, 2-biphenyl, or 2-pyrrol-1-ylphenyl.

(ii) Within groups (A)-(C), another group of more preferred compounds is wherein Ar ¹ is phenylene, wherein the hydroxamate group and the X group are opposite each other and Ar ² is trans -Aryl-CH=CH-. Preferably, ^Ar2 is trans-phenyl-CH=CH-, optionally substituted with alkoxy, preferably methoxy. Preferably, ^Ar2 is trans-phenyl-CH=CH-.

(iii) Within groups (A)-(C), another group of more preferred compounds is that wherein Ar is phenylene, wherein the hydroxamate group and the X group are opposite ^each other and ^Ar is heteroaryl The group -CH=CH-. Preferably, ^Ar2 is pyridyl-CH=CH-. Preferably, ^Ar2 is trans-5-bromothien-2-yl-CH=CH- or trans-indol-3-yl-CH=CH-.

⁽ iv) Another group of more preferred compounds ^within groups (A)-(C) is that wherein Ar is phenylene, wherein the hydroxamate group and the X group are opposite each other and Ar is heteroaryl base. Preferably, ^Ar is pyridin-3-yl, thiophen-2-yl, quinolin-6-yl, thiazol-2-yl, benzothiazol-2-yl, benzoxazol-2-yl, furyl , pyrrol-2-yl, indol-5-yl, indol-3-yl, indazol-3-yl, quinolin-3-yl, quinolin-1-yl, quinolin-8-yl, benzene Triazol-4-yl, benzofuran-5-yl, isoquinolin-1-yl, isoquinolin-3-yl, quinoxalin-2-yl, quinolin-2-yl, or benzo Imidazol-5-yl, wherein the ring is optionally substituted by phenyl, pyridin-4-yl, methyl, methoxy, or dimethylaminomethyl.

(v) ^Within groups (A)-(C), another group of more preferred compounds is that wherein Ar is phenylene wherein the hydroxamate group and the X group are opposite each other and Ar is ^indole -2-yl, benzofuran-2-yl or benzothiophen-2-yl, which are optionally substituted by alkyl, alkoxy, halo, haloalkyl, alkoxyalkoxy, optionally substituted hetero Cycloalkylalkoxy, optionally substituted heteroaralkoxy, hydroxyalkoxy, aminoalkyl, aminoalkoxy, alkoxyalkoxy, alkoxyalkyl, optionally substituted phenoxy substituted with alkylalkyl, or optionally substituted heterocycloalkylalkyl. Preferably, Ar is benzofuran- ² -yl or benzothiophen-2-yl, wherein benzofuran-2-yl or benzothiophen-2-yl is optionally replaced by methoxy, methyl, chloro , trifluoromethyl, fluorine, 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-dimethylamino Methyl substitution, the substituent is located at the 3-position or 5-position, preferably the 3-position, of the benzothiophen-2-yl or benzofuran-2-yl ring. Even more preferably, Ar is benzofuran- ² -yl, 3-N,N-dimethylaminomethylbenzofuran-2-yl, or 3-phenoxymethylbenzofuran-2- base.

(vi) ^Within groups (A)-(C), another group of more preferred compounds is that wherein Ar is phenylene wherein the hydroxamate group and the X group are opposite each other and Ar is ^indole -2-yl, benzofuran-2-yl or benzothiophen-2-yl, substituted by phenoxyalkyl, substituted heteroaryloxyalkyl, substituted heterocycloalkoxyalkyl, or haloalkoxy Substituents are substituted with alkyl groups, and the substituents are located at the 3-position of the benzothiophen-2-yl and benzofuran-2-yl rings. Even more preferably, Ar ² is 3-(2,2,2-trifluoroethoxymethyl)benzofuran-2-yl.

(vii) Within groups (A)-(C), another group of more preferred compounds is wherein Ar ¹ is heteroarylene and Ar ² is aryl. Preferably, Ar ¹ is a five-membered heteroarylene ring containing one, two, or three heteroatoms independently selected from: N, O or S, more preferably, Ar ¹ is isoxazole group, wherein the hydroxamate group and the X group are located at the 5- and 3-positions of the isoxazolyl ring, the oxygen atom in the ring is at the 1-position, and Ar ² is an aryl group. Preferably, Ar is ^phenyl optionally substituted with one or two substituents independently selected from: methoxy, ethoxy, optionally substituted with ethoxy or methyl Phenyl, methyl, tert-butyl, pyrrol-1-yl, cyclohexene-3-oxyl, pyridin-3-yl, pyridin-2-yl, benzamido, fluorine, chlorine, or thiophene-2- methoxyl. More preferably, Ar ^is phenyl, 4-biphenyl, 3-biphenyl, 2-(2-ethoxyphenyl)phenyl, 3-methylbiphenyl-4-yl, 4-tert Butylphenyl, 4-pyrrol-1-ylphenyl, 4-(cyclohexene-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-dimethyl phenyl, 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.

(viii) Within groups (A)-(C), another group of more preferred compounds is wherein Ar ¹ is heteroarylene and Ar ² is aryl -CH=CH-. Preferably, Ar ¹ is a five-membered heteroarylene ring containing one, two, or three heteroatoms independently selected from: N, O or S, more preferably, Ar ¹ is isoxazolyl, wherein The hydroxamate group and the X group are located at the 5- and 3-positions of the isoxazolyl ring, the oxygen atom in the ring is at the 1-position, ^Ar is phenyl-CH=CH-, optionally alkane Oxygen substitution.

(ix) Within groups (A)-(C), another group of more preferred compounds is wherein Ar ¹ is heteroarylene and Ar ² is heteroaryl-CH=CH-. Preferably, Ar ¹ is a five-membered heteroarylene ring containing one, two, or three heteroatoms independently selected from: N, O or S, more preferably, Ar ¹ is isoxazolyl, wherein The hydroxamate group and the X group are located at the 5- and 3-positions of the isoxazolyl ring, the oxygen atom in the ring is at the 1-position, and Ar ² is pyridyl CH=CH-.

(x) Within groups (A)-(C), another group of more preferred compounds is wherein Ar ¹ is heteroarylene and Ar ² is heteroaryl. Preferably, Ar ¹ is a five-membered heteroarylene ring containing one, two, or three heteroatoms independently selected from: N, O or S, more preferably, Ar ¹ is isoxazolyl, wherein The hydroxamate group and the X group are located at the 5- and 3-positions of the isoxazolyl ring, the oxygen atom in the ring is at the 1-position, Ar ² is pyridin-3-yl, thiophen-2-yl, quinine Lin-6-yl, thiazol-2-yl, benzothiazol-2-yl, benzoxazol-2-yl, furyl, pyrrol-2-yl, indol-5-yl, indol-3- Base, indazol-3-yl, quinolin-3-yl, quinolin-8-yl, benzotriazol-4-yl, isoquinolin-1-yl, isoquinolin-3-yl, quinoxal Lin-2-yl, quinolin-2-yl, or benzimidazol-5-yl, wherein the ring is optionally replaced by phenyl, pyridin-4-yl, methyl, methoxy, or dimethyl Aminomethyl substitution.

(xi) Within groups (A)-(C), another group of more preferred compounds is wherein Ar ¹ is heteroarylene, Ar ² is indol-2-yl, benzofuran-2-yl or Benzothiophen-2-yl, optionally substituted by alkyl, alkoxy, halo, haloalkyl, alkoxyalkoxy, optionally substituted heterocycloalkylalkoxy, optionally substituted heteroaryl Alkoxy, hydroxyalkoxy, aminoalkoxy, alkoxyalkoxy, alkoxyalkyl, optionally substituted phenoxyalkyl, or optionally substituted heterocycloalkylalkyl substitution. Preferably, Ar ¹ is a five-membered heteroarylene ring containing one, two, or three heteroatoms independently selected from: N, O or S, more preferably, Ar ¹ is isoxazolyl, wherein The hydroxamate group and the X group are located at the 5- and 3-positions of the isoxazolyl ring, the oxygen atom in the ring is at the 1-position, Ar ² is benzofuran-2-yl and benzothiophene-2 -yl, which is optionally replaced by methoxy, methyl, chlorine, trifluoromethyl, fluorine, 2-methoxyethoxy, 2-morpholin-4-ylethoxy, pyridin-3-ylmethyl Oxy, 2-hydroxyethoxy, 2-N, N-dimethylaminoethoxy, ethyl, methoxymethyl, phenoxymethyl, morpholin-4-ylmethyl, or di Methylaminomethyl substitution with the substituent at the 3-position of the benzothiophen-2-yl and benzofuran-2-yl rings. Even more preferably, Ar is benzofuran-2-yl or 3 ^- phenoxymethylbenzofuran-2-yl.

(xii) Within groups (A) and (B), another group of more preferred compounds is wherein ^Ar is replaced by alkoxyalkoxy, optionally substituted heterocycloalkylalkoxy, hydroxyalkoxy , aminoalkoxy, alkoxyalkoxy, alkoxyalkyl, optionally substituted phenoxyalkyl, optionally substituted heteroaryloxyalkyl, or optionally substituted heterocycloalkylalkane base substitution. Within this group, more preferred compounds are those wherein Ar ¹ and Ar ² are as described for the preferred embodiments above.

II. Another preferred group of compounds of formula (I) are those wherein X is -O- and ^R1 and ^R3 are hydrogen.

III. A further group of preferred compounds of formula (I) are those wherein X is -S(O) _n - and R ¹ and R ³ are hydrogen.

Within the preferred groups II and III above, more preferred compounds are those wherein Y is an alkylene group.

Within the preferred groups II and III above, another group of more preferred compounds is wherein Y is an alkylene group which is replaced by cycloalkyl, optionally substituted phenyl, alkylthio, alkylsulfinyl, alkane Sulfonyl, 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 in which ^Ar1 is phenylene.

Within the preferred groups II and III above and the more preferred groups contained therein, another even more preferred group of compounds is that wherein Ar ¹ is heteroarylene.

Within the preferred groups II and III above and the more preferred and even more preferred groups contained therein, when Ar is ^phenylene , a particularly preferred group of compounds is that in which the -CONHOH and X groups are in the phenylene 1- and 4-positions of the ring.

IV. Also a group of preferred compounds of formula (I) are, wherein Ar ¹ is phenylene, X is -O-, R ¹ and R ³ are hydrogen, -CONHOH and X groups are at 1- and 4 bit.

Within the preferred group IV above, a more preferred group of compounds is wherein Y is an alkylene group.

Within the preferred group IV above, another group of more preferred compounds is that wherein Y is an alkylene group which is replaced by cycloalkyl, optionally substituted phenyl, alkylthio, alkylsulfinyl, alkylsulfonyl Acyl, optionally substituted phenylalkylthio, optionally substituted phenylalkylsulfonyl, hydroxy, or optionally substituted phenoxy.

(i) Within the above-mentioned 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 is that wherein ^Ar is aralkenyl . Preferably, Ar ² is aryl(C _2-3 )alkenyl. More preferably, ^Ar is represented by the following formula:

or

Wherein the phenyl group is optionally substituted by one or two substituents independently selected from: alkyl, alkoxy, methylenedioxy, dialkylamino, or hydroxyl, more preferably alkyl, Alkoxy, methylenedioxy, or hydroxy.

Even more preferably, Ar ^is 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-methoxyphenyl-CH=CH-, trans-3-tolyl-CH=CH-, trans-4-tolyl-CH=CH-, trans-4-dimethylaminobenzene -CH=CH-, trans-2-tolyl-CH=CH-, or trans-2-hydroxyphenyl-CH=CH-.

(ii) Within the above preferred groups II, III and IV and the more preferred, even more preferred and particularly preferred groups contained therein, another group of more particularly preferred compounds is that wherein ^Ar is heteroaryl (C _2-3 )alkenyl. Preferably, Ar ² is trans-heteroaryl-CH=CH- or trans-heteroaryl-C(CH ₃ )=CH-, preferably, the heteroaryl ring is pyridyl, benzofuryl, thiophene (thiophene), furyl, or indolyl, which is optionally substituted by one or two substituents selected from: hydroxyl, alkoxy, halo, or optionally substituted heterocycloalkoxy .

More preferably, Ar ² is 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-bromothiophen-2-yl-CH=CH-, trans-furan-3-yl-CH=CH -, trans-thiophen-3-yl-CH=CH-, trans-thiophen-2-yl-CH=CH-, trans-benzofuran-2-yl-C(CH 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( _CH3 )=CH-, or trans-furan-2-yl-CH=CH.

(iii) Within the above preferred groups II, III and IV and the more preferred, even more preferred and particularly preferred groups contained therein, there is also a group of more particularly preferred compounds in which Ar ² is aryl. 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 heteroaralkoxy, optionally substituted heterocycloalkyl, optionally substituted phenylcarbonylamino, or methylenedioxy. More preferably, Ar ^is phenyl, 4-biphenyl, 3-biphenyl, 4-tert-butylphenyl, 4-pyrrol-1-ylphenyl, 4-(pyridin-3-yl)benzene Base, 4-(pyridin-2-yl)phenyl, 4-(benzamido)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-(thiophen-2-ylmethoxy)phenyl, 3-(thiophen-2-ylmethoxy)-phenyl, 2-biphenyl, naphthalene-1-yl, 2-pyrrole-1- Base-phenyl, 4-fluoronaphthalen-1-yl, 3-MeO-naphthalen-2-yl, 2-MeO-naphthalen-1-yl, naphthalene-2-yl, 4-(2-pyridin-4-yl Thiazol-5-yl)phenyl, 4-[2-(4-methylpiperazin-1-yl)thiazol-5-yl]-phenyl, 4-(2-pyridin-4-ylaminothiazole-5 -yl)phenyl, 4-(4-methylpiperazin-1-yl)phenyl, 4-(4-hydroxypiperidin-1-yl)phenyl, 4-(4-morpholin-4-yl Methylthiazol-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]phenyl.

(iv) Within the above preferred groups II, III and IV and the more preferred, even more preferred and particularly preferred groups contained therein, there is also a group of more particularly preferred compounds in which Ar is ^heteroaryl . Preferably, Ar is ^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 heteroaralkoxy, optionally substituted heteroaryloxyalkyl, optionally substituted hetero Cycloalkylalkyl, optionally substituted heterocycloalkoxy, optionally substituted heterocycloalkylalkoxy, -alkylene-S(O) _n R ^a (wherein n is 0 to 2, R ^a is hydroxyalkyl or optionally substituted phenyl), -alkylene-NR ^e -alkylene CONR ^c R ^d (wherein R ^c is hydroxyl, R ^d and R ^e are independently hydrogen or alkyl), or Carboxyalkylaminoalkyl.

More preferably, Ar is thiophen- ² -yl, pyridin-3-yl, quinolin-6-yl, benzothiazol-2-yl, benzoxazol-2-yl, benzofuran-2-yl , Benzofuran-5-yl, benzothiophen-2-yl, furan-2-yl, 1H-benzimidazol-2-yl, 1H-pyrrol-2-yl, thiazol-2-yl, 1H-ind Indol-2-yl, 1H-indol-5-yl, 1H-indol-3-yl, quinolin-3-yl, quinolin-8-yl, 1H-indazol-3-yl, 1H-benzene Triazol-5-yl, isoquinolin-1-yl, isoquinolin-3-yl, quinoxalin-2-yl, quinolin-2-yl, 1H-benzimidazol-5-yl, quinolin Lin-1-yl, pyridin-2-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, which is optionally substituted with one or two substituents described in the previous paragraph.

Even more preferably, Ar is benzofuran- ² -yl, monosubstituted at the 3-, 4- or 5-position, or disubstituted at the 4- and 7-positions, preferably, benzofuran-2- The group is monosubstituted at the 3- or 5-position with the substituents described in the previous 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,N-dimethylaminomethyl, N,N-diethylaminomethyl, 2-methoxyethoxymethyl, phenoxy ylmethyl, 2-methoxyethoxy, 2-morpholin-4-ylethoxy, pyridin-3-ylmethoxy, 2-hydroxyethoxy, 2-N,N-dimethyl Aminoethoxy, methoxymethyl, 3-isopropoxymethyl, morpholin-4-ylmethyl, 3-hydroxypropoxymethyl, 2-fluorophenoxymethyl, 3-fluoro Phenoxymethyl, 4-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]-triazine- 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-fluoro Phenylsulfonylmethyl, pyridin-3-ylmethoxymethyl, tetrahydropyran-4-yloxy, 2,2,2-trifluoroethoxy, 2-pyrrolidin-1-ylethoxy Base, 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, 2-(4-trifluoromethyl phenyl)ethyl, 2-(3-trifluoromethoxyphenyl)ethyl, N-hydroxyaminocarbonyl-methylaminomethyl, or 3-(2-carboxyethylamino-methyl).

Even more preferably, Ar is benzofuran- ² -yl, which is substituted at the 3-position by the following substituents: N,N-dimethylaminomethyl, N,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]-tri Azin-1-yl-phenoxymethyl, 2-phenylethyl, 3-hydroxypropoxymethyl, 2-methoxyethoxymethyl, pyrrolidin-1-ylmethyl, piperidine -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 Base-N-benzyl-aminomethyl, N-methyl-N-2-phenylethylaminomethyl, 3-hydroxypropylthiomethyl, 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, Ar is benzofuran- ² -yl, which is substituted at the 5-position by: 1-cyclopropylpiperidin-4-yloxy, piperidin-4-yloxy, tetrahydro Pyran-4-yloxy, 2,2,2-trifluoroethoxy, 2-pyrrolidin-1-ylethoxy, or 1-(2,2,2-trifluoroethyl)piperidine- 4-yloxy.

Even more preferably, Ar is 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, Ar is thiophen- ² -yl, pyridin-3-yl, 5-phenylthiophen-2-yl, quinolin-6-yl, 4-phenylthiazol-2-yl, benzothiazole -2-yl, benzoxazol-2-yl, furan-2-yl, 1H-benzimidazol-2-yl, 1H-pyrrol-2-yl, 4-(pyridin-4-yl)-thiazole- 2-yl, 1H-indol-5-yl, 1H-indol-3-yl, quinolin-3-yl, quinolin-8-yl, 1H-indazol-3-yl, 1H-benzotri Azol-5-yl, isoquinolin-1-yl, isoquinolin-3-yl, quinoxalin-2-yl, quinolin-2-yl, 1H-benzimidazol-5-yl, 1-methyl Base-indol-3-yl, 4-MeO-quinolin-2-yl, quinolin-4-yl, 4-hydroxyquinolin-2-yl, pyridin-2-yl, 3-hydroxypyridine-2- Base, 6-hydroxypyridin-2-yl, 6-(4-nitrophenoxy)pyridin-2-yl, 4-(2-methoxyethoxy)quinolin-2-yl, 4-( 2-Dimethylaminoethoxy)quinolin-2-yl, 6-bromopyridin-2-yl, 5-bromopyridin-3-yl, 4-methoxyquinolin-2-yl, 5-benzene Basepyridin-3-yl, 6-benzyloxypyridin-2-yl, 6-(2-methylpropoxy)-pyridin-2-yl, 6-(2-phenylethoxy)pyridine-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.

V. A further group of preferred compounds of formula (I) are those wherein Ar ² is heteroaryl. Preferably, Ar is ^heteroaryl optionally substituted with one or two substituents independently selected from: alkyl, halo, haloalkyl, alkoxy, alkoxyalkyl, hydroxy Alkoxy, hydroxyalkoxyalkyl, alkoxyalkoxy, alkoxyalkoxyalkyl, aminoalkyl, aminoalkoxy, haloalkoxy, haloalkoxyalkyl, optionally substituted Phenylalkyl, optionally substituted phenoxyalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkoxy, optionally substituted heteroaryloxyalkyl, optionally substituted heterocyclic Alkylalkyl, optionally substituted heterocycloalkoxy, optionally substituted heterocycloalkylalkoxy, -alkylene-S(O) _n R ^a (wherein n is 0 to 2, R ^a is hydroxyalkyl or optionally substituted phenyl), -alkylene-NR ^e -alkylene CONR ^c R ^d (wherein R ^c is hydroxyl, R ^d and R ^e are independently hydrogen or alkyl), or carboxy Alkylaminoalkyl.

More preferably, Ar is thiophen- ² -yl, pyridin-3-yl, quinolin-6-yl, benzothiazol-2-yl, benzoxazol-2-yl, benzofuran-2-yl , Benzofuran-5-yl, benzothiophen-2-yl, furan-2-yl, 1H-benzimidazol-2-yl, 1H-pyrrol-2-yl, thiazol-2-yl, 1H-ind Indol-2-yl, 1H-indol-5-yl, 1H-indol-3-yl, quinolin-3-yl, quinolin-8-yl, 1H-indazol-3-yl, 1H-benzene Triazol-5-yl, isoquinolin-1-yl, isoquinolin-3-yl, quinoxalin-2-yl, quinolin-2-yl, 1H-benzimidazol-5-yl, quinolin Lin-1-yl, pyridin-2-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, which is optionally substituted with one or two substituents described in the previous paragraph.

Even more preferably, Ar is benzofuran- ² -yl, monosubstituted at the 3-, 4- or 5-position, or disubstituted at the 4- and 7-positions, preferably, benzofuran-2- The group is monosubstituted at the 3 or 5 position with the substituents described in the previous 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,N-dimethylaminomethyl, N,N-diethylaminomethyl, 2-methoxyethoxymethyl, phenoxy ylmethyl, 2-methoxyethoxy, 2-morpholin-4-ylethoxy, pyridine-3-methoxy, 2-hydroxyethoxy, 2-N,N-dimethylamino Ethoxy, methoxymethyl, 3-isopropoxymethyl, morpholin-4-ylmethyl, 3-hydroxypropoxymethyl, 2-fluorophenoxymethyl, 3-fluorobenzene Oxymethyl, 4-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]-triazine-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-fluorophenyl Sulfonylmethyl, 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-hydroxy Propylsulfinylmethyl, 3-hydroxypropylsulfonyl-methyl, N-methyl-N-2-indol-3-ylethylaminomethyl, 2-(4-trifluoromethylbenzene yl)ethyl, 2-(3-trifluoromethoxyphenyl)ethyl, N-hydroxyaminocarbonyl-methylaminomethyl, or 3-(2-carboxyethylamino-methyl).

Even more preferably, Ar is benzofuran- ² -yl, which is substituted at the 3-position by the following substituents: N,N-dimethylaminomethyl, N,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]-tri Azin-1-yl-phenoxymethyl, 2-phenylethyl, 3-hydroxypropoxymethyl, 2-methoxyethoxymethyl, pyrrolidin-1-ylmethyl, piperidine -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 Base-N-benzyl-aminomethyl, N-methyl-N-2-phenylethylaminomethyl, 3-hydroxypropylthiomethyl, 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, Ar is benzofuran- ² -yl, which is substituted at the 5-position by: 1-cyclopropylpiperidin-4-yloxy, piperidin-4-yloxy, tetrahydro Pyran-4-yloxy, 2,2,2-trifluoroethoxy, 2-pyrrolidin-1-ylethoxy, or 1-(2,2,2-trifluoroethyl)piperidine- 4-yloxy.

Even more preferably, Ar is 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, Ar is thiophen- ² -yl, pyridin-3-yl, 5-phenylthiophen-2-yl, quinolin-6-yl, 4-phenylthiazol-2-yl, benzothiazole -2-yl, benzoxazol-2-yl, furan-2-yl, 1H-benzimidazol-2-yl, 1H-pyrrol-2-yl, 4-(pyridin-4-yl)-thiazole- 2-yl, 1H-indol-5-yl, 1H-indol-3-yl, quinolin-3-yl, quinolin-8-yl, 1H-indazol-3-yl, 1H-benzotri Azol-5-yl, isoquinolin-1-yl, isoquinolin-3-yl, quinoxalin-2-yl, quinolin-2-yl, 1H-benzimidazol-5-yl, 1-methyl Base-indol-3-yl, 4-MeO-quinolin-2-yl, quinolin-4-yl, 4-hydroxyquinolin-2-yl, pyridin-2-yl, 3-hydroxypyridine-2- Base, 6-hydroxypyridin-2-yl, 6-(4-nitrophenoxy)pyridin-2-yl, 4-(2-methoxyethoxy)quinolin-2-yl, 4-( 2-Dimethylaminoethoxy)quinolin-2-yl, 6-bromopyridin-2-yl, 5-bromopyridin-3-yl, 4-methoxyquinolin-2-yl, 5-benzene Basepyridin-3-yl, 6-benzyloxypyridin-2-yl, 6-(2-methylpropoxy)-pyridin-2-yl, 6-(2-phenylethoxy)pyridine-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 particularly preferred groups contained therein, a group of most preferred compounds is 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, there is also a group of most preferred compounds in which Y is a branched chain alkylene, Preferably -CH(C ₂ H ₅ )CH ₂ -, -CH(iC ₃ H ₇ )CH ₂ -, or -CH(CH ₃ )CH ₂ -, the stereochemical formula on the chiral carbon is (S). More preferably, Y _is -CH( _C2H5 ) _CH2- .

Within the above preferred groups II, III, IV and V and the more preferred, even more preferred and especially preferred groups contained therein, there is also a group of most preferred compounds in which Y is _-CH2CH (CH ₃ )-, the stereochemical formula on 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, there is also a group of most preferred compounds in which Y is -CH(CH ₂ R ')CH ₂ - or -CH(CH ₂ CH ₂ R')CH ₂ -, wherein R' is alkylthio, alkylsulfonyl, optionally substituted phenylalkylthio, optionally substituted phenylalkane Sulfonyl, hydroxy, or optionally substituted phenoxy, preferably phenyl, phenoxy, 4-chlorophenyl, cyclohexyl, benzylthio, benzylsulfonyl, methylthio, methylsulfonyl, or hydroxyl.

VI. Another group of preferred compounds of formula (I) is that wherein X is -O-, R ¹ and R ³ are hydrogen, Ar ¹ is phenylene, Ar ² is aralkenyl, and Y is branched chain alkylene , -CONHOH and X are at the 1- and 4-positions of the phenylene ring. Preferably, Ar ^is trans-phenyl-CH=CH-, wherein phenyl is optionally substituted with one or two substituents independently selected from: alkyl, alkoxy, methylene Dioxy, or hydroxyl.

The scope of the terms contained within the above groups II-VI is as described in the definitions section of this application.

Reference to preferred embodiments set forth above is meant to include all combinations of specific and preferred groups unless otherwise stated.

General synthesis

Compounds of the present invention can be prepared by the methods described in the reaction schemes shown below.

Starting materials and reagents for the preparation of these compounds were obtained from industrial suppliers such as Aldrich Chemical Co. (Milwaukee, Wis.), Bachem (Torrance, Calif.), or Sigma (St. Louis, Mo.), or were obtained by those skilled in the art. Known methods were prepared according to procedures set forth in references such as: Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced 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 would occur to those skilled in the art in light of this disclosure. Reaction starting materials and intermediates can be isolated and purified if necessary 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 take place at normal pressure, at a temperature ranging from about -78°C to about 150°C, more preferably from about 0°C to about 125°C, most preferably at about room temperature (or ambient temperature), for example about 20°C ℃.

Compounds of formula (I) can be prepared by the procedures described and illustrated in Scheme A below. In formula (I), X is -O- or -S(O) _n -, wherein n is 0 to 2, and other groups As described in "Summary of the Invention".

                      Plan A

The reaction of the compound of formula 1 with the amino alcohol of formula 2 generates the compound of formula 3. In formula 1, R is an alkyl group, X is -O- or -S-, Ar ^is as described in "Summary of the Invention", and in formula 2 , PG is a suitable amino protecting group. The reaction is carried out in a suitable organic solvent such as tetrahydrofuran or the like in the presence of triphenylphosphine and diisopropyl azodicarboxylate.

Compounds of Formula 1 such as methyl 4-hydroxybenzoate, methyl 4-mercaptobenzoate, and methyl 3-hydroxyisoxazole-5-carboxylate are commercially available. Compounds of formula 2 can be prepared from commercially available amino alcohols by reacting an amine with a suitable amino protecting group such as benzyloxycarbonyl, tert-butoxycarbonyl, etc. under reaction conditions well known in the art. A detailed description of suitable amino protecting groups and reaction conditions for preparation can be found in TW Greene, Protecting Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981, the teachings of which are incorporated herein by reference in their entirety. Amino alcohols 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 by protecting the amino group with a suitable protecting group, and then reducing the acid group to a hydroxyl group with a suitable reducing agent under reaction conditions well known in the art. If a compound of formula (I) where X is -5O ₂ - is desired, the corresponding compound of formula 3 (where X is -S-) can be treated with an oxidizing agent such as OXONE_, m-chloroperbenzoic acid and the like.

Removal of the amino protecting group in formula 3 can yield 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 and the like in suitable organic solvents such as methanol, dioxane, tetrahydrofuran and the like. If the protecting group is benzyl or benzyloxycarbonyl, it is removed under catalytic hydrogenation reaction conditions. Suitable catalysts are palladium based catalysts and others known in the art. Other suitable reaction conditions for removal of 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 and the like.

Reaction of formula 4 with an acid of formula ^Ar2 -COZ (where Z is hydroxy or halide) or an acid derivative (eg acid halide) yields a compound of formula 5. Furthermore, the reaction conditions used depend on the nature of the Z group. If Z is hydroxyl, the reaction is typically carried out in the presence of a suitable coupling agent such as benzotriazol-1-yloxytripyrrolidino-phosphonium hexafluorophosphate (PyBOP-), O-benzotriazol-1-yl-N,N,N',N'-tetramethyl-uronium hexafluorophosphate (HBTU), O-(7-azabenzotriazol-1-yl )-1,1,3,3-tetramethyl-uronium hexafluorophosphate (HATU), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC HCl), or 1,3-dicyclohexylcarbodiimide (DCC), optionally in the presence of 1-hydroxybenzotriazole hydrate (HOBT·H ₂ O), and a base such as N,N-diiso Propylethylamine, 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 (such as dichloromethane, chloroform, etc.), acetonitrile, N,N-dimethylformamide, ether solvents such as tetrahydrofuran, dioxane, etc. Preferably, the reaction is carried out with HOBt·H ₂ O, EDC·HCl in dichloromethane or N,N-dimethylformamide.

When Ar ² COZ is an acid halide, the reaction is carried out in the presence of a suitable base (eg, triethylamine, diisopropylethylamine, pyridine, etc.). Suitable reaction solvents are polar organic solvents such as tetrahydrofuran, acetonitrile, N,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. Acids of formula ^Ar2COZ are commercially available, 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 by first converting it to 2-bromo Methylbenzofuran-2-carboxylic acid (bromination of it with N-bromosuccinimide under conditions well known in the art) is then reacted with phenol. Compound 5, wherein ^R3 is hydrogen, can optionally be converted to the corresponding compound of formula 5, wherein ^R3 is other than hydrogen: Compound 5 is reacted with an alkylating agent under conditions well known in the art.

Compound 5 is then converted to compound of formula (I) by reacting it with aqueous hydroxylamine in the presence of a base such as sodium hydroxide and an organic solvent such as a mixture of tetrahydrofuran and methanol. Alternatively, the acid group in compound 5 is firstly treated with a suitable coupling agent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl), or 1,3 - whereas cyclohexylcarbodiimide (DCC) activation, optionally in the presence of 1-hydroxybenzotriazole hydrate (HOBT·H ₂ O), is carried out in a suitable organic solvent such as dimethylformamide, etc. , and then react with hydroxylamine hydrochloride in the presence of a base such as N,N-diisopropylethylamine, triethylamine, N-methylmorpholine and the like. The compound of formula (I) can also be prepared from compound 5 according to the method disclosed in US Patent No. 5,998,412, the disclosure of which is incorporated herein by reference in its entirety.

Compounds of formula (I) can then be converted into other compounds of formula (I). For example, a compound of formula (I) (where Ar ¹ is phenylene, X is -O-, Y is ethylene, Ar ² is 3-dimethylaminomethylbenzofuran-2-yl, R ¹ and R ³ is hydrogen) can be obtained by the following method: make formula 4 compound (wherein Ar ¹ is phenylene, X is -O-, Y is ethylene, R is alkyl) and 3-methylbenzofuran -2-Carboxylic acid is reacted as described above to give compound of formula 5 (wherein Ar ² is 3-methylbenzofuran-2-yl). Use a suitable brominating agent such as N-bromosuccinimide to brominate the methyl group, and then react with dimethylamine to obtain the corresponding 3-dimethylaminobenzofuran-2-yl compound, and then in the above reaction conditions to convert it to the desired compound.

Uses

The compounds of the invention are inhibitors of histone deacetylases and are therefore useful in the treatment of proliferative diseases such as cancers, e.g. lung, colon, AML, MML, skin, breast, ovary, prostate, liver, brain and Skin cancer, psoriasis, fibroproliferative diseases such as hepatic fibrosis, smooth muscle proliferative diseases such as atherosclerosis and restenosis, inflammation such as arthritis, diseases involving angiogenesis such as cancer, diabetic retinopathy, hematopoietic disorders such as Anemia, fungal, parasitic and bacterial infections, viral infections, autoimmune diseases such as arthritis, multiple sclerosis, lupus, allergies, asthma, allergic rhinitis and organ transplantation, and bipolar disorder. Additionally, the compounds of the invention are useful in the treatment of hepatitis C infection.

Test

The ability of compounds of the invention to inhibit histone deacetylases can be tested in the 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 at Georgetown University. Compounds can also be tested for hcv activity using the replicon assay described in Korner, V.L. et al., Science 1999 Jul 2:285(5424):110-3.

Administration and pharmaceutical composition

In general, the compounds of the invention will be administered in a therapeutically effective amount by any of the acceptable modes of administration for agents that function similarly. The actual amount of the compound of the invention, ie, the active ingredient, will depend on many factors, such as the severity of the condition being treated, the age and relative health of the patient, the potency of the compound employed, the route and mode of administration, and other factors.

The therapeutically effective amount of the compound of formula (I) is in the range of about 0.1-50 mg/kg body weight of the recipient/day, preferably about 0.5-20 mg/kg/day. Thus, for administration to a 70 kg human, the dosage range is most preferably about 35 mg/day to 1.4 g/day.

Typically, compounds of the invention are administered as pharmaceutical compositions by any of the following routes: oral, systemic (eg, transdermal, intranasal, or suppositories), or parenteral (eg, intramuscular, intravenous, or subcutaneous) administration. The preferred modes of administration are oral or parenteral, using a convenient daily dosing regimen which can be adjusted according to the degree of affliction. Oral compositions may take the form of tablets, pills, capsules, semi-solids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other suitable composition.

The choice of dosage form depends on various factors such as the mode of administration (eg, for oral administration, dosage forms in the form of tablets, pills, or capsules are preferred), and the bioavailability of the drug. Recently, pharmaceutical dosage forms have been developed especially for drugs with poor bioavailability, based on the principle that the bioavailability can be increased by increasing the surface area, ie reducing the particle size. For example, US Patent No. 4,107,288 describes a pharmaceutical dosage form having a particle size range of 10 to 1,000 nm in which the active substance is supported on a macromolecular cross-linked matrix. U.S. Patent No. 5,145,684 describes the preparation of a pharmaceutical formulation in which the drug is pulverized into nanoparticles (average particle size 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to obtain a pharmaceutical formulation with very High bioavailability.

Compositions generally consist of a compound of formula (I) in association with at least one pharmaceutically acceptable excipient. Pharmaceutically acceptable excipients are non-toxic and facilitate administration without adversely affecting the therapeutic effect of the compound of formula (I). Such excipients may be any solid, liquid, semi-solid, or, for aerosol compositions, gaseous excipients 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, glyceryl monostearate, chloride Sodium chloride, skimmed milk powder, etc. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, 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 glycol.

Compressed gases can be used to disperse the compounds of the invention in aerosol form. Inert gases suitable for this purpose include nitrogen, carbon dioxide, and the like.

Other suitable pharmaceutical excipients and their dosage forms are described in Remington's Pharmaceutical Sciences, edited by EW Martin (Mack Publishing Company, ¹⁸ ed., 1990).

The amount of the compound in the dosage form can vary within the full range available to those skilled in the art. Typically, dosage forms comprise from about 0.01 to 99.99% by weight (wt %) of a compound of formula (I), based on the total dosage form, with the balance being one or more suitable pharmaceutical excipients. Preferably, the content of the compound is about 1-80 wt%. Representative pharmaceutical dosage forms containing compounds of formula (I) are described below.

As previously mentioned, the compounds of the present invention may be administered in combination with known anticancer drugs. Such known anticancer agents include the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, antiproliferative agents, prenyl-protein transferase inhibitors agents, HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, DNA methyltransferase inhibitors, and other angiogenesis inhibitors. The compounds of the 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, Carboxyamidotriazoles, Combretastatin A-4, Squalamine, 6 -O-Chloroacetyl-carbonyl-antibodies to fumagillol, thalidomide, angiostatin, troponin-1, and VEGF.

Preferred estrogen receptor modulators are tamoxifen and raloxifene.

"Estrogen receptor modulator" means a compound that interferes with or inhibits the binding of estrogen to the receptor, regardless of mechanism. Examples of estrogen receptor modulators include, but are not limited to: tamoxifen, raloxifene, edoxifene, 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, 4,4'-dihydroxybenzophenone-2,4-dinitrophenyl-hydrazone, and SH646.

"Androgen receptor modulator" means a compound that interferes with or inhibits the binding of androgen to the receptor, regardless of mechanism. Examples of androgen receptor modulators include: finasteride and other 5α-reductase inhibitors, nilutamide, flutamide, bicalutamide, liarazole, and abiraterone acetate.

"Retinoid receptor modulator"refers to a compound that interferes with or inhibits the binding of a retinoid to a receptor, regardless of mechanism. Examples of these retinoid receptor modulators include: bexarotene, retinoic acid, 13-cis-retinoic acid, 9-cis-retinoic acid, alpha-difluoromethylornithine, ILX23- 7553, trans-N-(4'-hydroxyphenyl) retinamide, and N-4-carboxyphenyl retinamide.

"Cytotoxic agent" means a compound that causes cell death primarily by directly interfering with cell function, or inhibiting or interfering with cell division, including alkylating agents, tumor necrosis factor, intercalating agents, tubulin inhibitors, and topoisomerases Inhibitors.

Examples of cytotoxic agents include, but are not limited to: tirapazamine, sertenef, cachets, ifosfamide, tasonamine, lonidamine, carboplatin, hexamethylmelamine, prednimustine, Bromodulcitol, ramustine, formustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin, estramustine, improsuvantoxate, trofosamide, Nimustine, dibromospirochloramine, purinetepa, lobaplatin, satraplatin, profiromycin, cisplatin, irovin, dexifosfamide (dexifosfamide), cis-amine dichloride (2- Methyl-pyridine) platinum, benzylguanine, glufosfamide, GPX100, (trans, trans, trans)-bis-mu-(hexane-1,6-diamine)-mu-[diamine -platinum(II)]bis[diamine(chloro)platinum(II)]-tetrachloride, diarizidinyl spermine, arsenic trioxide, 1-(11-dodecylamino-10 -Hydroxyundecyl)-3,7-dimethylxanthine, Zorubicin, Idarubicin, Daunorubicin, Bisantrene, Mitoxantrone, Pirarubicin, Pinafilter , valrubicin, amrubicin, antineoplastic, 3'-deamino-3'-morpholino-13-deoxy-10-hydroxycarmine, liposomal anthracycline (annamycin) , grubicin, ilinafard, 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'-norvincaleukoblastine, docetaxol , root enzyme element, dolastatin, mivobulin isethionate, auristatin, cemadotin, RPR109881, BMS184476, vinflunine, cryptophycin, 2,3,4,5,6-pentafluoro- N-(3-fluoro-4-methoxyphenyl)benzenesulfonamide, anhydrous vinblastine, N,N-dimethyl-L-valyl-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-teach wine Bacterin, 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]-indolizine[ 1,2b] quinoline-10,13(9H,15H)dione, lurtotecan, 7-[2-(N-isopropylamino)-ethyl]-(20S)camptothecin , BNP1350, BNPI1100, BN80915, BN80942, etoposide phosphate, teniposide, sobuzoxan, 2'-dimethylamino-2'-deoxy-etoposide, GL331, N-[2-(two Methylamino)ethyl]-9-hydroxy-5,6-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide, asulacrine, (5a, 5aB, 8aa, 9b) -9-[2-[N-[2-(Dimethylamino)ethyl]-N-methylamino]ethyl]-5-[4-hydroxy-3,5-dimethoxyphenyl] -5,5a,6,8,8a,9-hexohydrofuro (3',4':6,7) colchic (2,3-d)-1,3-dioxole (dioxol)-6-one, 2,3-(methylenedioxy)-5-methyl-7-hydroxy-8-methoxybenzo[c]-phenanthridinium (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)ethylamino]-7 -Methoxy-9-oxo-9H-thioxanth-4-ylmethyl]formamide, N-(2-(dimethylamino)ethyl)acridine-4-carboxamide, 6-[[ 2-(Dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinolin-7-one, and demesna.

"Antiproliferative agents" include: antisense RNA and DNA oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231, and INX3001, and antimetabolites such as enoxitabine, carmofur, mefur, pentostat Ding, doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine, arabinocytosine, fosteabine sodium hydrate, raltitrexed, paltitrexid, etiline, thiazole Furin, tacitabine, noratrexed, pemetrexed, nelzarabine, 2′-deoxy-2′-methinecytidine, 2′-fluoromethylene-2′-deoxycytidine, N -[5-(2,3-dihydro-benzofuryl)sulfonyl]-N'-(3,4-dichlorophenyl)urea, N6-[4-deoxy-4-[N2-[2 (E), 4(E)-tetradecadienoyl]glycylamino]-L-glyceryl-B-L-mannyl (manno)-heptopyranosyl (heptopyranosyl)]-adenine, aplidine , ecteinascidin, troxatabine, 4-[2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimido[5,4-b][1,4 ]thiazin-6-yl-(S)-ethyl]-2,5-thienoyl-L-glutamate, aminopterin, 5-fluorouracil, alanamectin, 11-acetyl Base-8-(carbamoyloxymethyl)-4-formyl-6-methoxy-14-oxa-1,11-diazatetracyclo(7.4.1.0.0)-tetradecyl- 2,4,6-Trien-9-yl acetate, swainsonine triol, lometrexol, dexrazoxane, methionase, 2′-cyano-2′-deoxy-N4 -palmitoyl-1-B-D-arabinofuranocytosine, and 3-aminopyridine-2-carbaldehyde thiosemicarbazone. "Antiproliferative agents" also include: monoclonal antibodies to growth factors, substances other than those listed in the "Angiogenesis inhibitors" section, such as trastuzumab, and tumor suppressor genes, such as p53, that can be Virus-mediated gene transfer for delivery (see, eg, US 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 assays well known in the art. See, eg, the assay methods described or referenced at column 6 of US Patent No. 4,231,938 and pages 30-33 of WO84/02131. The terms "HMG-CoA reductase inhibitor" and "inhibitor of HMG-CoA reductase" have the same meaning when used herein. According to reports (Int.J.Cancer, 20; 97 (6): 746-50, 2002), in the Lewis lung cancer model in mice, with lovastatin (an HMG-CoA reductase inhibitor) and butyrate Combination therapy with esters, an apoptosis inducer, showed enhanced antitumor effects.

Examples of HMG-CoA reductase inhibitors that may be used include, but are not limited to: lovastatin (MEVACOR®; see US Patent Nos. 4,231,938; 4,294,926; 4,319,039), simvastatin (ZOCOR®; see US Patent Nos. 4,444,784; 4,820,850; 4,916,239) 、普伐他汀(PRAVACHOL_；参见美国专利号4,346,227；4,537,859；4,410,629；5,030,447和5,180,589)、氟伐他汀(LESCOL_；参见美国专利号5,354,772；4,911,165；4,929,437；5,189,164；5,118,853；5,290,946；5,356,896)、阿托伐Statins (LIPITOR®; see US Patent Nos. 5,273,995; 4,681,893; 5,489,691; 5,342,952) and cerivastatin (also known as rivastatin and BAYCHOL®; see US Patent No. 5,177,080). The structural formulas of these and additional HMG-CoA reductase inhibitors useful in the present method are described on page 87 of M. Yalpani, "Cholesterol Lowering Drugs", Chemistry & Industry, pp.85-89 (Feb.5, 1996) , and US Patent Nos. 4,782,084 and 4,885,314. As used herein, the term "HMG-CoA reductase inhibitor" includes all pharmaceutically acceptable lactone and open-acid forms (i.e., in which the lactone ring can be cleaved to form the free acid) as well as compounds with HMG-CoA Salt and ester forms of compounds with reductase inhibitory activity, and colchicine, the use of these salt, ester, open acid and lactone forms are also included within the scope of the present invention.

Of the HMG-CoA reductase inhibitors which may exist in the open acid form, salt and ester forms formed from the open acid are preferred, all such forms being 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.

As used herein, the term "pharmaceutically acceptable salt" with respect to HMG-CoA reductase inhibitors refers to non-toxic salts of the compounds used in the present invention, which are usually prepared by reacting the free acid with a suitable organic or inorganic base, especially Those salts derived from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc and tetramethylammonium, and those derived from amines such as ammonia, ethylenediamine, N-methylglucamine, lysine , arginine, ornithine, choline, N, N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, 1-p-chloro Benzyl-2-pyrrolidin-1'-yl-methylbenzimidazole, a salt prepared from 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, bromine compound, calcium hydroxide, camphorate, carbonate, chloride, clavulanate, citrate, dihydrochloride, hydroxyl, ethanedisulfonate, ettoate, ethanesulfonate, rich Maleate, glucoheptonate, gluconate, glutamate, glycolyl arsanate, hexylresorcinate (hexylresorcinate), hebamine, hydrobromide, hydrochloride, Hydroxynaphthoate, Iodide, Isothiosulfate, Lactate, Lactobionate, Laurate, Malate, Maleate, Mandelate, Methanesulfonate, Methylsulfate, Mucate (mucate), naphthalenesulfonate, nitrate, oleate, oxalate, pamaote, palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylic acid salt, stearate, subacetate, succinate, tannate, tartrate, theanate, tosylate, 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 to release the drug form in such a way that the drug provides improved therapy Effect.

A "prenyl-protein transferase inhibitor" is a compound that inhibits any one 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 inhibitory 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-chlorobenzene Base)-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-pyridine -1-yl)benzyl]-3H-imidazol-4-ylmethyl}benzonitrile, 4-{3-[4-(5-chloro-2-oxo-2H[1,2′]bipyridine- 5'-ylmethyl)-3H-imidazol-4-ylmethyl]benzonitrile, 4-{3-[4-(2-oxo-2H-[1,2']bipyridine-5'-yl Methyl)-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-dimetheno-1H-imidazo[4 ,3-c][1,11,4]dioxa-azacyclononadecene (nonadecine)-9-carbonitrile, (±)-19,20-dihydro-19-oxo-5H-18 ,21-Ethylene-12,14-Ethylene-6,10-Methylene-22H-Benzo[d]imidazo[4,3-k][1,6,9,12] -Oxatriazepine-cycloctadecine-9-carbonitrile, 19,20-dihydro-19-oxo-5H, 17H-18,21-oxoethylene-6, 10:12 , 16-two endomethylene-22H-imidazo[3,4-h][1,8,11,14]oxatriazacyclo-eicosine-9-carbonitrile, and ( ±)-19,20-Dihydro-3-methyl-19-oxo-5H-18,21-Ethylene-12,14-Ethylene-6,10-Ethylene-22H - Benzo[d]imidazo[4,3-k][1,6,9,12]oxa-triazacyclooctadecene-9-carbonitrile.

Further 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, WO 97/38665, WO 98/28980 , WO 98/29119, WO 95/32987, US Pat. WO 94/19357, WO 95/08542, WO 95/11917, WO 95/12612, WO 95/12572, WO 95/10514, U.S. Patent 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 96/24611, WO 96/24612, WO 96/05168, WO 96/05169, WO 96/00736, U.S. Patent No. 5,571,792, WO 96/17861, 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 U.S. Patent No. 5,532,359. For an example of the effect of prenyl-protein transferase inhibitors on angiogenesis see J. Of Cancer, Vol. 35, No. 9, pp. 1394-1401 (1999).

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. According to reports (Nat.Med.; 8(3):225-32, 2002), HIV protease inhibitors such as indinavir or saquinavir have potent antiangiogenic activity and promote Kaposi sarcoma (Kaposi Sarcoma ) fades.

"Angiogenesis inhibitor" refers to a compound that inhibits the formation of new blood vessels, regardless of 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), epidermis-derived, fibroblastic Inhibitors of cell-derived or platelet-derived growth factors, MMP (matrix metalloproteinase) inhibitors, integrin inhibitors, interferon-alpha, interleukin-12, pentosan polysulfate, cyclooxygenase inhibitors including nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen, and selective cyclooxygenase-2 inhibitors such as celecoxib, valecoxib, and rofecoxib (PNAS , Vol.89, p.7384(1992); JNCl, Vol.69, p.475(1982); Arch.Opthalmol., Vol.108, p.573(1990); Anat.Rec., Vol.238, p.68(1994); FEBS Letters, Vol.372, p.83(1995); Clin., Orthop.Vol.313, p.76(1995); J. Mol. Endocrinol., Vol.16, p.107 (1996); Jpn.J.Pharmacol., Vol.75, p.105(1997); Cancer Res., Vol.57, p.1625(1997); Cell, Vol.93, p.705(1998); Intl.J.Mol.Med., Vol.2, p.715(1998); J.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 the antibody of VEGF (seeing NatureBiotechnology, 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, combinations with NSAIDs involve the use of NSAIDs, which are potent COX-2 inhibitors. For purposes of this specification, a resulting NSAID is effective if it inhibits COX-2 with an _IC50 of 1 [mu]M or less, as determined by cellular or microsomal assays known in the art.

The 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 refer to those substances that have specificity for COX-1 to inhibit COX-2 by the _IC50 of COX-2 relative to that of COX-1. The _IC50 is determined as a ratio of at least 100-fold the _IC50 estimated by the cellular or microsomal assay methods disclosed below. Such compounds include, but are not limited to, those disclosed in U.S. Patent No. 5,474,995, issued December 12, 1995; U.S. Patent No. 5,861,419, issued January 19, 1999; On December 14, 1999; U.S. Patent No. 6,020,343, granted on February 1, 2000; U.S. Patent No. 5,409,944, granted on April 25, 1995; U.S. Patent No. 5,436,265, granted on July 25, 1995; U.S. Patent No. 5,536,752, granted July 16, 1996; U.S. Patent No. 5,550,142, granted August 27, 1996; U.S. Patent No. 5,604,260, granted February 18, 1997; U.S. Patent No. 5,698,584, granted 1997 December 16, 1998; U.S. Patent No. 5,710,140, issued January 20, 1998; WO 94/15932, published July 21, 1994; U.S. Patent No. 5,344,991, issued June 6, 1994; U.S. Patent 5,134,142, issued July 28, 1992; U.S. Patent No. 5,380,738, issued January 10, 1995; U.S. Patent No. 5,393,790, issued February 20, 1995; ; US Patent No. 5,633,272, issued May 27, 1997; and US Patent No. 5,932,598, issued August 3, 1999, all of which are incorporated herein by reference. Other examples of specific inhibitors of COX-2 include those disclosed in US Patent 6,313,138, the disclosure of which is incorporated herein by reference in its entirety.

General and specific synthetic methods for preparing the COX-2 inhibitor compounds described above are found in: U.S. Patent No. 5,474,995, issued December 12, 1995; U.S. Patent No. 5,861,419, issued January 19, 1999; and U.S. Patent No. 6,001,843, Granted December 14, 1999, all of which are incorporated herein by reference.

Compounds described as specific inhibitors of COX-2 and thus 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 of their synthesis can be found in the following patents, pending applications and publications, which are incorporated herein by reference: WO 94/15932, published in 1994 July 21, 1991; U.S. Patent No. 5,344,991, issued June 6, 1994; U.S. Patent No. 5,134,142, issued July 28, 1992; U.S. Patent No. 5,380,738, issued January 10, 1995; U.S. Patent No. 5,393,790, issued February 20, 1995; U.S. Patent No. 5,466,823, issued November 14, 1995; U.S. Patent No. 5,633,272, issued May 27, 1997; and U.S. Patent No. 5,932,598, issued 1999 August 3rd.

Compounds that are specific inhibitors of COX-2 and thus useful in the present invention, and methods for their synthesis, can be found in the following patents, pending applications and publications, which are incorporated herein by reference: U.S. Patent No. 5,474,995, issued December 1995 January 12; U.S. Patent No. 5,861,419, granted January 19, 1999; U.S. Patent No. 6,001,843, granted December 14, 1999; U.S. Patent No. 6,020,343, granted February 1, 2000; U.S. Patent No. 5,409,944 , granted April 25, 1995; U.S. Patent No. 5,436,265, granted July 25, 1995; U.S. Patent No. 5,536,752, granted July 16, 1996; U.S. Patent No. 5,604,260, issued February 18, 1997; U.S. Patent No. 5,698,584, issued December 16, 1997; and U.S. Patent No. 5,710,140, issued January 20, 1998.

Other examples of angiogenesis inhibitors include, but are not limited to: endostatin, ukrain, leopard enzyme, IM862, 5-methoxy-4-[2-methyl-3-(3-methyl-2-butan Alkenyl) 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 Mannopentose Phosphate, 7,7-(Carbonyl-bis[imino-N-methyl-4,2-pyrrolecarbonyl-imino[N-methyl-4, 2-pyrrole]-carbonylimino]-bis-(1,3-naphthalene disulfonate), and 3-[(2,4-dimethylpyrrol-5-yl)methylene]-2-bis Hydroindolinone (SU5416).

As used above, an "integrin inhibitor" refers to a compound that selectively antagonizes, inhibits, or blocks the binding of a physiological ligand to _αvβ3 integrin, selectively antagonizes, inhibits, or blocks the binding of a physiological ligand to _αvβ3 integrin. Compounds that antagonize, inhibit _{, or} prevent _the binding of physiological ligands to _{both αvβ3} integrins and _αvβ5 integrins, and compounds that antagonize , a compound that inhibits, or blocks, the activity of a particular integrin expressed on capillary endothelial cells. The term _also refers to antagonists _of the following _integrins : _{αvβ6 , αvβ8} , _α1β1 , _α2β1 , _{α5β1 , α6β1} , and _α6β4 integrins. The term also refers to antagonists of any combination of the following integrins: α _v β ₃ , α _v β ₅ , α _v β ₆ , α _v β ₈ , α ₁ β ₁ , α ₂ β ₁ , α ₅ β ₁ , _{α6β1 ,} and _{α6β4 integrins} .

Some specific examples of tyrosine kinase inhibitors include: N-(trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide, 3-[(2,4-dimethylpyrrole-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-methoxy Ethoxy)-4-quinazolinamine, BIBX1382, 2,3,9,10,11,12-hexahydro-10-(hydroxymethyl)-10-hydroxy-9-methyl-9,12- Epoxy-1H-indolo[1,2,3-fg:3′,2′,1′-k1]pyrrolo[3,4-i][1,6]benzodiazepine- 1-keto, SH268, genistein, ST1571, CEP2563, 4-(3-chlorophenylamino)-5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidine methanesulfonate, 4-(3-Bromo-4-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, 4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline , SU6668, SU11248, STI571A, N-4-chlorophenyl-4-(4-pyridylmethyl)-1-phthalazinamine, and EMD121974.

The compound can also be used alone or in combination with platelet fibrinogen receptor (GP lib/IIIa) antagonists such as tirofiban to inhibit the metastasis of cancer cells. Tumor cells can activate platelets in large quantities through the generation of thrombin. This activation is associated with the release of VEGF. Release of VEGF enhances metastasis by increasing extravasation at adhesion points with the vascular endothelium (Amirkhosravi, Platelets 10, 285-292, 1999). Therefore, the present compounds can be used alone or in combination with GP lib/IIIa antagonists to inhibit metastasis. Examples of other fibrinogen receptor antagonists include: Abciximab, Eptifibatide, Selafiban, Lamifiban, Lotrafiban, Chromanfiban, and CT50352.

"DNA methyltransferase inhibitor" refers to a compound that inhibits the methylation of the DNA base cytosine at the C-5 position of the base by DNA methyltransferase. Examples of such DNA methyltransferase inhibitors include the compounds disclosed in US 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 this invention within the dosage range described above and the other pharmaceutically active agent within its approved dosage range. Alternatively, the compounds of the present invention may be used sequentially with known pharmaceutically acceptable agents when a combination formulation is inappropriate.

The term "administering" and variants thereof (eg, "administering" a compound) with respect to a compound of the invention means introducing the compound or a prodrug thereof into the system of an animal in need of treatment. When a compound of the present invention or a prodrug thereof is provided together with one or more active agents (e.g., cytotoxic agents, etc.), "administering" and variations thereof are understood to include simultaneous and sequential introduction of the compound or prodrug thereof, respectively and other medicines.

As used herein, the term "composition" is intended to include a product comprising the specified ingredients in the specified amounts, as well as any product resulting, directly or indirectly, from a combination of the specified ingredients in the specified amounts.

The compounds of the invention may also be co-administered with other known therapeutic agents selected for their particular utility for the condition being treated. For example, the compounds of the invention may also be co-administered with other known cancer therapeutic agents selected for their particular utility for the condition being treated. Included in such combinations of therapeutic agents are the combinations of farnesyl-protein transferase inhibitors and antineoplastic agents disclosed in US Patent No. 6,313,138. It is also understood that such combinations of antineoplastic agents and farnesyl-protein transferase inhibitors may be used in conjunction with other methods of treating cancer and/or tumors, including radiation therapy and surgery.

Examples of antineoplastic agents often include microtubule stabilizing agents such as paclitaxel (also known as Taxol_), docetaxel (also known as Taxotere_, epothilone A, epothilone B, deoxyepothilone A, deoxyepothilone B or their derivatives); microtubule disruptors; alkylating agents; antimetabolites; epidophyllotoxin; antitumor enzymes; topoisomerase inhibitors; procarbazine; mitol Anthraquinones; platinum coordination complexes; biological response modifiers and growth inhibitors; hormone/antihormonal therapeutics and hematopoietic growth factors.

Examples of various types of antineoplastic drugs include, for example, anthracyclines, vinca, mitomycin, bleomycin, cytotoxic nucleosides, taxanes, macrolides, discodermolide, Pteridines, diynenes, and podophyllotoxins. Particularly useful members of these classes include, for example, doxorubicin, carmine, daunorubicin, aminopterin, methotrexate, methopterin, dichloro-methotrexate, mitomycin C, Poffeimycin, Herceptino_, Rituxan_, 5-fluorouracil, 6-mercaptopurine, gemcitabine, cytarabine, podophyllotoxin or podophyllotoxin derivatives such as colchicine, etoposide, etoposide phosphate or substitute Niposide, melphalan, vinblastine, vincristine, isovinblastine, vindesine, epoxy vinblastine, paclitaxel, etc. Other useful antineoplastic agents include: estramustine, cisplatin, carboplatin, cyclophosphamide, bleomycin, tamoxifen, ifosfamide, melphalan, hexamethylmelamine, thiotepa, Cytarabine, idatrexate, trimetrexate, dacarbazine, L-asparaginase, camptothecin, CPT-11, topotecan, ara-C, bicalutamide, flutamide, leuprox Lide, pyridobenzoindole derivatives, interferons and interleukins. A preferred class of antineoplastic agents are the taxanes, and a preferred class of antineoplastic agents is paclitaxel.

Radiation therapy, including X-rays or gamma-rays, delivered from external beams or by implanted tiny radiation sources, may also be used in combination with the compounds of this invention to treat cancer.

Example

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 as merely illustrative and representative.

Synthetic Example

Example 1

Synthesis of N-hydroxy-4-(2-phenylcarbonylamino-ethoxy)benzamide

step 1

To a solution of 2-aminoethanol (3.1 g, 50 mmol) in THF (10 ml) was added a solution of tert-butoxycarbonyl anhydride (10.9 g, 50 mmol) in THF (150 ml). The reaction mixture was stirred for 3 h, then diluted with ethyl acetate, washed with 0.5M aqueous HCl and brine. The organic layer was dried over _MgSO , filtered and concentrated in vacuo to afford 2-N-Boc-aminoethanol, which was used directly in the next step.

step 2

To a solution of triphenylphosphine (17.7 g, 67.5 mmol) in anhydrous THF (135 ml) was added DIAD (13.6 g, 67.5 mmol). The solution was stirred until a white precipitate formed (2 to 10 min). After a further 60 min, a solution of 2-N-Boc-amino-ethanol (7.2 g, 45 mmol) and methyl 4-hydroxybenzoate (6.8 g, 45 mmol) in THF (25 ml) was added and stirring continued for 5 h. The reaction mixture was concentrated in vacuo and purified by flash chromatography to afford 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 (180ml). After stirring for 3 h, diethyl ether (300 ml) was added to give a white precipitate. The solid was collected and suspended in ethyl acetate and stirred for 15-20min. The solid was collected again and dried under high vacuum to give 6.3 g (60% over 2 steps) of methyl 4-(2-aminoethoxy)benzoate hydrochloride.

step 4

To a suspension of methyl 4-(2-amino-ethoxy)benzoate hydrochloride (0.232 g, 1 mmol) in THF (6 ml) was added benzoyl chloride (0.140 g, 1 mmol) followed by triethylamine ( 0.121 g, 1.2 mmol). The reaction mixture was stirred for 1 h, 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 afford 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 (0.5 mmol) in a 1:1 THF/methanol mixture (20 ml) was added 50 wt.% aqueous hydroxylamine (3 ml), followed by 1M Aqueous NaOH solution (1 ml) was used to adjust the pH to 10-11. The reaction mixture was stirred for 14 h, neutralized to pH = 7-8 with 6M aqueous HCl, and concentrated in vacuo. The precipitate was collected and purified by HPLC to afford the title compound as a white solid.

¹ H NMR (DMSO-d ₆ ): δ8.69 (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 value): 300.1; MS (ESI)m/e: 301.1(M-1) ⁺ , 299.0(M+1) ^- .

Proceed as described above for steps 1-4 in Example 1, but substituting (S)-(+)-2-amino-1-butanol for 2-aminoethanol to give 4-(2S-aminobutoxy)benzene Methyl formate hydrochloride.

Example 2

Synthesis of N-Hydroxy-4-[2-(benzofuran-2-yl-carbonylamino)-ethoxy]-benzamide

step 1

A mixture of benzofuran-2-carboxylic acid (0.162 g, 1 mmol), EDC·HCl (0.268 g, 1.4 mmol) and HOBT·H ₂ O (0.203 g, 1.5 mmol) in DMF (6 ml) was stirred for 2 h. Methyl 4-(2-aminoethoxy)benzoate hydrochloride (0.232 g, 1 mmol) was added followed by triethylamine (0.121 g, 1.2 mmol). The reaction mixture was stirred for 2 h, then diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and brine. The organic layer was concentrated in vacuo and the crude 4-[2-(benzofuran-2-ylcarbonylamino)ethoxy]benzoate was converted to the title compound as described in Step 5 of Example 1 above.

¹ H NMR (DMSO-d ₆ ) δ11.05(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; MS(ESI) m/e : (M+1H) ⁺ : 341.0, (M-1H) ^- : 339.1.

Example 3

Synthesis of N-Hydroxy-4-[2-(benzothiophen-2-yl-carbonylamino)-ethoxy]-benzamide

To a suspension of methyl 4-(2-aminoethoxy)benzoate hydrochloride (0.232 g, 1 mmol) in THF (6 ml) was added benzothiophene-2-carbonyl chloride (0.150 g, 1 mmol), followed by Triethylamine (0.121 g, 1.2 mmol). The reaction mixture was stirred for 1 h 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 and the crude methyl 4-[2-(benzothiophen-2-yl-carbonylamino)ethoxy]benzoate was converted to the title compound as described in Step 5 of Example 1 above.

Proceed as above in Example 3, but replace methyl 4-(2-aminoethoxy)benzoate hydrochloride with methyl 4-(2S-aminobutoxy)benzoate hydrochloride and cinnamoyl chloride Substitution of benzothiophene-2-carbonyl chloride yields 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, 6.1mmol). After the solution was stirred at room temperature for 1 h, methanol (20 ml) and TEA (7 ml) were added. The slurry was stirred overnight at room temperature, then concentrated and dissolved in ethyl acetate (100ml) and washed with dilute _NaHCO3 (100ml). The organic layer was dried over MgSO ₄ , filtered and concentrated to collect methyl 3-methylbenzofuran-2-carboxylate (1 g) as a tan solid. The crude methyl ester was used without further purification.

step 2

A solution of methyl 3-methylbenzofuran-2-carboxylate (1.0 g, 5.3 mmol), NBS (0.95 g, 5.3 mmol) and AIBN (87 mg, 0.53 mmol) in CCl ₄ (40 ml) was heated to reflux for 3 h, Then cooled to room temperature and concentrated. The residue was dissolved in ethyl acetate (100ml) and washed with water (100ml). The organic layer was dried over MgSO ₄ , filtered and concentrated to collect methyl 3-bromomethylbenzofuran-2-carboxylate (1.55 g) as a brown/yellow solid which was used in the next step without further purification.

step 3

Methyl 3-bromomethylbenzofuran-2-carboxylate (269 mg, 1 mmol) was dissolved in anhydrous DMF and added to 2M dimethylamine/THF solution (1.5 ml, 3 mmol). After 1-2 h, the reaction was diluted with EtOAc, washed twice with saturated aqueous NaHCO ₃ and brine. The organic extracts were dried over _Na2SO4 , 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 (131 mg, 0.56 mmol) in MeOH was added 1N aqueous 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 afford 3-dimethylaminomethylbenzofuran-2-carboxylic acid as hydrochloride, which was used in the next step without further purification.

step 5

To 3-dimethylaminomethylbenzofuran-2-carboxylic acid (140 mg, 0.56 mmol) was added EDC·HCl (150 mg, 0.784 mmol) and HOBt·H ₂ O (114 mg, 0.84 mmol) in anhydrous DMF in solution. The reaction mixture was stirred for 30-60 min, then methyl (4-(2-ethoxylamine))benzoate hydrochloride (130 mg, 0.56 mmol) and triethylamine (94 μL, 0.672 mmol) were added and the reaction was stirred overnight . The reaction mixture was diluted with EtOAc, washed twice with saturated aqueous NaHCO ₃ and brine. The organic extracts were concentrated in vacuo to afford methyl 4-[2-(3-dimethylaminobenzofuran-2-yl-carbonylamino)ethoxy]benzoate which was used without further purification.

step 6

To a solution of crude methyl 4-[2-(3-dimethylaminobenzofuran-2-yl-carbonylamino)-ethoxy]-benzoate in MeOH and THF was added excess aqueous hydroxylamine and aqueous NaOH to give pH10-11. 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).

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.88(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

 N-Hydroxy-4-{2-[3-(2,2,2-trifluoroethoxymethyl)benzofuran-2-yl-

Synthesis of Carbonylamino]ethoxy}benzamide

step 1

Sodium hydride (15 mg, 0.56 mmol) was suspended in anhydrous DMF and stirred under _N2 (g). 2,2,2-Trifluoroethanol (270 μL, 3.7 mmol) was added, and after stirring the reaction mixture for 15-20 min, methyl 3-bromomethylbenzofuran-2-carboxylate was added. After 8 h, 1 N aqueous NaOH 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. The organic layer was dried over _Na2SO4 and concentrated in vacuo to give 3-(2,2,2-trifluoroethoxymethyl)benzofuran-2-carboxylic _acid (38 mg), which was used without further purification.

step 2

To a solution of 3-(2,2,2-trifluoroethoxymethyl)benzofuran-2-carboxylic acid (38 mg, 0.139 mmol) in anhydrous DMF was added EDC·HCl (37 mg, 0.195 mmol) and HOBt • _H2O (26 mg, 0.195 mmol). After 60-90 min, methyl (4-(2-ethoxyamine))benzoate hydrochloride (32 mg, 0.139 mmol) and triethylamine (23 μL, 0.167 mmol) were added and the reaction mixture was stirred for 1-2 h . The reaction mixture was diluted with EtOAc and washed twice with saturated aqueous NaHCO ₃ , the organic extract was concentrated to give 4-{2-[3-(2,2,2-trifluoroethoxymethyl)benzofuran-2- yl-carbonylamino]ethoxy}benzoate, which was used without further purification.

step 3

4-{2-[3-(2,2,2-Trifluoroethoxymethyl)benzofuran-2-yl-carbonylamino]-ethoxy}-benzoate was dissolved in MeOH, Excess aqueous hydroxylamine and aqueous NaOH were added to obtain 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).

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.04(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

   N-Hydroxy-4-{2-[5-(2-pyrrolidin-1-ylethoxy)benzofuran-2-

Synthesis of ylcarbonylamino]ethoxy}benzamide

step 1

5-Methoxybenzofuran-2-carboxylic acid (5.04 g, 26 mmol) was weighed into a 200 ml round bottom flask fitted with a stir bar, septum and nitrogen inlet. Anhydrous MeOH (50ml) was added under 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 72 h, the reaction mixture was poured into water (150 ml) and a white solid was collected. The solid was dissolved in toluene (100ml) and the solution was washed with 1M _NaHCO3 and brine, dried over _MgSO4 . The organic layer was removed to give methyl 5-methoxybenzofuran-2-carboxylate as a white solid (5.15 g).

step 2

A solution of methyl 5-methoxybenzofuran-2-carboxylate (5.15 g, 25 mmol) in anhydrous dichloromethane (15 ml) was cooled to -40°C under nitrogen atmosphere. A solution of boron _tribromide in _CH2Cl2 (27 ml, 1.0 M) was added over 1 h using a syringe pump. The reaction mixture was allowed to warm to room temperature. After 16 h, the reaction mixture was cooled in an ice bath and quenched with MeOH (15 ml). The reaction mixture was poured into brine (100ml), extracted with EtOAc. The organic extracts were dried over anhydrous _MgSO4 and the solvent was removed with a rotary evaporator. The residue was triturated with hexanes, the yellow solid was filtered and dissolved in anhydrous MeOH (30ml). 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. The crude product was purified on 300 cm ³ silica gel using EtOAc in a 5 x 15 cm plug to give methyl 5-hydroxy-benzofuran-2-carboxylate (4.53 g).

step 3

Anhydrous tetrahydrofuran (15ml) was added to methyl 5-hydroxybenzofuran-2-carboxylate (1.10g, 5.7mmol), triphenylphosphine (1.50g, 5.7mmol) and 1-(2 -Hydroxyethyl)-pyrrolidine (0.66g, 5.7mmol) in a mixture. Diisopropyl azodicarboxylate (1.15 ml, 5.8 mmol) was slowly added to the solution at room temperature. After 2 days, the solvent was removed and the residue was dissolved in a 2:1 mixture of _Et2O :EtOAC (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 washed with _Et2O . The extract was cooled and the pH of the extract was adjusted to pH 12 with 50% aqueous NaOH. The basic solution was _extracted with _CH2Cl2 , the organic layer was dried over anhydrous _MgSO4 and concentrated to give methyl 5-(2-pyrrolidin-1-yl-ethoxy)benzofuran-2-carboxylate (0.96 g), as an amber solid.

step 4

Drop into ice-cooled 5-(2-pyrrolidin-1-ylethoxy)benzofuran-2-carboxylic acid methyl ester (960mg, 3.3mmol) in anhydrous ethylene glycol dimethyl ester (10ml) solution Degassed aqueous lithium hydroxide (2.0 mL, 2.0 M) was added. After stirring at room temperature for 4 h, the solution was cooled and the pH was adjusted to 2 with 4.0 M HCl in dioxane. A gummy brown precipitate formed. The solvent was removed and the gummy residue was frozen and lyophilized. The tan solid was dissolved in boiling 2-propanol (90ml) and the hot solution was filtered and then cooled to give 5-(2-pyrrolidin-1-yl-ethoxy)-benzofuran-2-carboxylic acid as Beige needles (528mg). An additional 153 mg was obtained from the mother liquor.

step 5

In a 20ml vial, add 5-(2-pyrrolidin-1-ylethoxy)benzofuran-2-carboxylic acid (156mg, 0.50mmol) and methyl 4-(2-aminoethoxy)benzoate To a solution of hydrochloride (129mg, 0.56mmol) in DMF (4.5ml) was added diisopropylethylamine (0.88ml, 5.1mmol). A DMF solution of O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (740 μL, 0.82 M, 0.61 mmol) was added to give tender 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), washed with _H2O , 1.0M aqueous _K2CO3 , and brine _. The organic layer was dried over anhydrous MgSO ₄ and the solvent was removed on a rotary evaporator. The residue was purified by column chromatography on silica gel using 93:5: _{2 CH2Cl2} :MeOH:TEA eluent to afford 4-{2-[5-(2-pyrrolidin-1-ylethoxy benzofuran-2-carbonylamino]-ethoxy}-benzoic acid methyl ester as a beige solid (174 mg).

step 6

To methanol ( 8ml) and tetrahydrofuran (4ml) were added aqueous hydroxylamine (2.9ml, 50wt% solution) and 4.0M aqueous sodium hydroxide (0.65ml). After stirring for 18 h, the organics were removed, the aqueous solution was cooled in an ice/water bath, and the pH was adjusted to ~8 with 4.4 ml of 1.0 M hydrochloric acid to obtain 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. Fractions absorbing at 214 nm were collected, frozen, and lyophilized to give the title compound (31 mg).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 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

  N-Hydroxy-4-[2-(3-dimethylaminobenzofuran-2-ylcarbonylamino)-

Synthesis of ethoxy]-benzamide hydrochloride

step 1

(2-Hydroxyethyl) tert-butyl carbamate (152.0 g, 0.942 mol) and 4-hydroxy-benzoic acid methyl ester (174.0 g, 1.12 mol) were dissolved in tetrahydrofuran (2000 ml), and cooled to 0-5 ℃. Triphenylphosphine (292.8 g, 1.116 mol) was added to the cooled mixture. A solution of diisopropyl azodicarboxylate (246.0 g, 1.218 mol) in tetrahydrofuran (400 ml) was added dropwise over 1-2 hours, keeping the temperature of the reaction below 10°C. After the addition, the reaction was allowed to slowly warm to room temperature and stirred overnight. After the reaction was completed, the solvent was distilled off under reduced pressure, and the obtained oil was dissolved in ethanol (500 ml) and ethyl acetate (2000 ml). Acetyl chloride (222.0 g, 2.826 mol) was added dropwise over 15 minutes and the temperature was raised to 40°C. The resulting suspension was stirred at 40°C until the reaction was complete. After the reaction was complete, the obtained crystals were filtered on a coarse frit and washed with ethyl acetate (300 ml). The material was dried in vacuo to give methyl 4-(2-aminoethoxy)benzoate hydrochloride (204.1 g) as a white crystalline solid.

step 2

Suspend methyl 4-(2-aminoethoxy)benzoate hydrochloride (78.90g, 0.340mol) and 3-methylbenzofuran-2-carboxylic acid (60.0g, 0.340mol) in acetonitrile (360ml ) and cooled to 0-5°C. Pyridine (137.6ml, 1.702mol) was added rapidly. A solution of phosphorus oxychloride (52.2 g, 0.340 mol) in acetonitrile (60 ml) was added dropwise over 30-45 minutes, maintaining the temperature below 20°C. The reaction mixture was stirred for one hour, slowly warming to room temperature. After the reaction, the solution was added to a rapidly stirred mixture of chlorobenzene (1000ml) and 1N hydrochloric acid (1000ml) at 0-5°C. 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°C. After cooling to room temperature, methyl 4-{2-[(3-methylbenzofuran-2-carbonyl)amino]ethoxy}benzoate was stored in solution and used in 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'-azobis Treat with isobutyronitrile (5.60 g, 0.017 mol) and N-bromosuccinimide (75.76 g, 0.426 mol). The resulting mixture was heated to 80°C and stirred for one hour. After the reaction was complete, the reaction mixture was cooled to room temperature, washed with water, 3% sodium bisulfite and additional water. The solvent was distilled under reduced pressure, and after cooling to room temperature, dichloromethane was added to obtain methyl 4-{2-[(3-bromo-methylbenzofuran-2-carbonyl)amino]ethoxy}benzoate. It is used in the next step.

step 4

In 30 minutes, methyl 4-{2-[(3-bromomethylbenzofuran-2-carbonyl)amino]ethoxy}benzoate (0.340mol) in chlorobenzene (200ml) and dichloromethane (800ml) was added dropwise to a 2M solution of dimethylamine in tetrahydrofuran (510ml, 1.022mol) at 0-5°C, keeping the temperature below 20°C. The resulting mixture was stirred for one hour, allowing to warm to room temperature. After the reaction was finished, the reaction mixture was washed with 5% potassium carbonate and water. The solvent was distilled at atmospheric pressure until the pot temperature reached 100 °C. After cooling to ~50°C, acetonitrile (400ml) and ethyl acetate (400ml) were added to the jar. The reaction mixture was heated to reflux until all solids were dissolved. The reaction mixture was allowed to cool to afford methyl 4-{2-[(3-dimethylaminomethyl-benzofuran-2-carbonyl)amino]ethoxy}benzoate (76.6 g) as an off-white powder.

step 5

Methyl 4-{2-[(3-dimethylaminomethylbenzofuran-2-carbonyl)amino]ethoxy}benzoate (70.0 g, 0.177 mol) was suspended in methanol (350 ml). 50% potassium hydroxide (139.8 g, 1.062 mol) was added and the reaction mixture was heated to 60° C. 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 4-{2-[(3-dimethylaminomethylbenzofuran-2-carbonyl)amino]ethoxy}benzoic acid potassium salt (72.0 g) as a white solid.

step 6

4-{2-[(3-Dimethylaminomethylbenzofuran-2-carbonyl)amino]ethoxy}benzoic acid potassium salt (20.0g, 0.0476mol) was suspended in N,N-dimethyl formamide (100ml). A solution of 4 mol hydrochloric acid in dioxane (11.9 ml, 0.0476 mol) 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 (10.94 g, 0.0571 mol) and 1-hydroxybenzotriazole (7.71 g, 0.0571 mol) were added into solution and the reaction mixture was stirred at room temperature for one hour. In a knockout pot, hydroxylamine hydrochloride (13.2 g, 1.904 mol) was suspended in N,N-dimethylformamide (100 ml) and treated with triethylamine (33.1 ml, 2.380 mol). After stirring the reaction mixture for 1 h, the salt was filtered off, and the resulting solution was added to the above-mentioned active acid solution, and stirred at room temperature until the reaction was completed. After the product started to crystallize, methanol (150ml) was added slowly over 30 minutes. The reaction mixture was stirred at room temperature for 1 h, then cooled to 0-5 °C and stirred for an additional hour. The crystals were filtered, washed with methanol (40ml) and dried in vacuo to give 3-dimethylaminomethylbenzofuran-2-carboxylic acid [2-(4-hydroxy-carbamoylphenoxy)ethyl]amide (11.88 g) as a white solid. The crude material (13.25g, 0.033mol) was suspended in N,N-dimethylformamide (80ml) and heated to 100°C to obtain 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 (22.7 g, 0.057 mol) was suspended in 2-propanol ( 220ml). A portion of 12M HCl (5.2ml, 0.063mol) was added and the resulting mixture was heated at 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°C for 1 h, the crystals were filtered, washed with 2-propanol, and dried in vacuo to afford the title compound (22.0 g) 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, 4.04 g, 20 mmol) in THF (100 ml) was added triphenylphosphine (5.25 g, 20 mmol) at 0°C. After 1 h, a solution of Boc-ethanolamine (3.22 g, 20 mmol) in THF (10 ml) was added. After 20 min, a solution of methyl 4-mercaptobenzoate (3.86 g, 20 mmol) in THF (10 ml) 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 washed with 1M HCl, saturated aqueous NaHCO ₃ , brine, dried over MgSO ₄ , filtered and evaporated to dryness. The oily yellow residue was eluted through a plug of silica gel, (0-20 ethyl acetate in hexane as the mobile phase), and the product was recrystallized from ether and hexane to give 4-(2-tert-butoxycarbonylaminoethyl (sulfanyl)methylbenzoate (4.00 g).

step 2

Dioxane of methyl 4-(2-tert-butoxycarbonylaminoethylsulfanyl)benzoate (1.00 g, 3.21 mmol) was treated with HCl in dioxane (4M, 8 ml, 10 equiv) at room temperature. Chloromethane (8ml) solution, the treatment time is 3h. Ether (100ml) was added and the mixture was filtered, washed with ether and pumped to dryness to give methyl 4-(2-aminoethylsulfanyl)benzoate hydrochloride.

step 3

Methyl 4-(2-aminoethylsulfanyl)benzoate hydrochloride (0.248 g, 1.00 mmol) was mixed with benzofuran-2-carboxylic acid (0.162 g, 1.00 mmol) and HBTU ( 0.379 g, 1.00 mmol) in DMF (5 ml) were combined. Triethylamine (0.307ml, 2.2mmol) was added and the reaction mixture was stirred at room temperature overnight. Addition of saturated aqueous NaHCO ₃ (15ml) gave a precipitate which was collapsed by adding water (20ml). 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 methyl 4-{2-[(benzofuran-2-ylcarbonyl)-amino]ethylsulfanyl}benzoate (0.138 g) as a gum , which was used in the next step without further purification.

step 4

To a solution of methyl 4-{2-[(benzofuran-2-yl-carbonyl)amino]ethylsulfanyl}-benzoate in THF (2ml) was added 50% hydroxylamine in water (4ml). 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).

¹ H NMR (DMSO-d ₆ ): 3.12 (2H, m); 3.5 (2H, m); 7.33 (1H, t); 7.42 (2H, d); 7.45 (1H, m ^* ); s); 7.62 (1H, d); 7.7 (2H, d); 7.78 (1H, d); 8.96 (1H, t); 8.99 (1H, b rs). MS (M+1): 357.

Example 9

Synthesis of N-Hydroxy-4-[2-(benzofuran-2-ylcarbonylamino)ethylsulfonyl]benzamide

step 1

Add Oxone_(13.03g, 21.19 mmol). After 48h, methanol was removed under reduced pressure and the residue was partitioned between ethyl acetate (150ml) and saturated aqueous _NaHCO3 (150ml). The organic phase was washed with brine (100ml), dried over _MgSO4 , filtered, concentrated in vacuo, and the residue was recrystallized from ethyl acetate/hexane to give the product 4-(2-tert-butoxycarbonylamino-ethylsulfonyl ) methyl 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 2h. Ether (200ml) was added, the suspension was filtered, washed with ether (2 x 50ml), hexane (50ml), and pumped to dryness to give methyl 4-(2-aminoethylsulfonyl)benzoate hydrochloride ( 2.23 g), which combined with the above benzofuran 2-carboxylic acid gave the title compound. MS (M+1): 388.

The compounds in Tables I-IV below were prepared as described above in Examples 1-3, but using appropriate commercially available starting materials.

Table 1:

Compound 1

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.69(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 value): 300.1; MS(ESI) m/e: 301.1(M-1) ⁺ , 299.0(M+1) ^- .

Compound 2

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.08(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; MS(ESI) m/e(M+1H ) ⁺ : 327.1, (M-1H) ^- : 325.2.

Compound 3

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.07(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, _J3 = 10.4Hz, 1H). EM (calculated): 340.1; MS (ESI) m/e (M+1H ) ⁺ : 341.2, (M-1H) ^- : 339.2.

Compound 4

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.08(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 value): 356.1; MS(ESI) m/e(M+1H) ⁺ : 357.2, (M-1H) ^- : 355.2.

Compound 5

¹ H NMR (400MHz, DMSO-d ₆ ) δ10.96(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 value): 328.1; MS (ESI) m/e (M+1H) ⁺ : 329.2, (M-1H) ^- : 327.0.

Compound 6

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.11(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 (pseudo) t, J = 6.0Hz, 2H), 3.58 (s , 2H), 3.50 (false q, J=5.6Hz, 2H). EM (calculated): 353.1; MS (ESI) m/e (M+1H) ⁺ : 353.9, (M-1H) ^- : 252.0.

Compound 7

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.11(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, _J1 =5.2Hz, 1H), 7.06(d, J=8.8Hz, 2H), 4.21(false t, J= 6.0Hz, 2H), 3.67 (false q, J=5.6Hz, 2H). EM (calculated value): 306.1; MS (ESI) m/e (M+1H) ⁺ : 307.0, (M-1H) ^- : 304.9.

Compound 8

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.98(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; MS (ESI) m/e (M-1H) ^- : 300.0.

Compound 9

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.03 (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; 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

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.11(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): 382.1; MS (ESI) m/e (M+1H) ⁺ : 383.1, (M-1H) ^- : 381.0.

Compound 12

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.05(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; MS (ESI) m/e (M+1H) ⁺ : 320.9, (M-1H) ^- : 319.0.

Compound 13

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.04(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; MS (EST)m/e(M+1H) ⁺ : 350.9, (M-1H) ^- : 349.1.

Compound 14

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.04(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; MS (ESI) m/e (M+1H) ⁺ : 351.8, (M-1H) ^- : 349.9.

Compound 15

EM (calculated): 383.1; MS (ESI) m/e (M+1) ⁺ : 383.9, (M-1) ^- : 382.2.

Compound 16

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.04(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

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.06(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

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.04(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; MS(ESI) m/e(M+1H) ⁺ : 366.0, (M-1H) ^- : 364.2.

Compound 19

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.04(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

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.08(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

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.07(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 ₁ =7.6Hz, J ₂ =0.8Hz, 1H), 7.52(td, J ₂ =8.0Hz, J ₂ =1.2Hz, 1H), 7.03(d, J =8.8Hz, 2H), 4.24 (t, J=6.0Hz, 2H), 3.72 (false q, J=6.0Hz, 2H). EM (calculated value): 341.1; MS (ESI) m/e (M+ 1H) ⁺ : 342.1, (M-1H) ^- : 340.2.

Compound 22

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.08(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; MS (ESI) m/e (M+1H) ⁺ : 376.1, (M-1H) ^- : 374.1.

Compound 23

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.09(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 value): 399.2; MS (ESI) m/e (M+1H) ⁺ : 400.1, (M-1H) ^- : 398.1.

Compound 24

EM (calculated): 290.1; 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

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.04(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; MS(ESI )m/e(M+1H) ⁺ : 341.0, (M-1H) ^- : 339.1.

Compound 28

EM (calculated): 289.1; MS (ESI) m/e (M+1H) ⁺ : 290.0, (M-1H) ^- : 287.8.

Compound 29

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.04(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, _J2 = 6.0Hz, 2H). EM (calculated): 419.2; MS (ESI) m/e (M+1H) ⁺ : 420.2, (M-1H) ^- : 418.3.

Compound 30

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.04(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

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.04(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 value): 358.2; MS (ESI )m/e(M+1H) ⁺ : 358.9, (M-1H) ^- : 357.2.

Compound 32

EM (calculated): 336.09; MS (ESI) m/e (M-1H) ^- : 335.3.

Compound 33

EM (calculated): 370.12; MS (ESI) m/e (M-1H) ^- : 369.0.

Compound 34

EM (calculated): 344.10; 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; MS (ESI) m/e (M-1H) ^- : 358.8.

Compound 37

EM (calculated): 336.09; MS (ESI) m/e (M+1H) ⁺ : 337.2, (M-1H) ^- : 335.0.

Compound 38

EM (calculated): 328.14; MS (ESI) m/e (M+1H) ⁺ : 329.2, (M-1H) ^- : 327.2.

Compound 39

EM (calculated): 368.03; MS (ESI) m/e (M-1H) ^- : 367.0.

Compound 40

EM (calculated): 328.14; MS (ESI) m/e (M+1H) ⁺ : 328.8, (M-1H) ^- : 327.2.

Compound 41

EM (calculated): 364.08; MS (ESI) m/e (M+1H) ⁺ : 365.1, (M-1H) ^- : 363.2.

Compound 42

EM (calculated): 344.14; MS (ESI) m/e (M+1H) ⁺ : 345.1, (M-1H) ^- : 343.1.

Compound 43

EM (calculated): 344.14; MS (ESI) m/e (M+1H) ⁺ : 345.0, (M-1H) ^- : 343.2.

Compound 44

EM (calculated): 348.11; MS (ESI) m/e (M+1H) ⁺ : 348.8, (M-1H) ^- : 346.9.

Compound 45

EM (calculated): 412.11; MS (ESI) m/e (M+1H) ⁺ : 413.3, (M-1H) ^- : 411.0.

Compound 46

EM (calculated): 412.11; MS (ESI) m/e (M+1H) ⁺ : 413.2, (M-1H) ^- : 411.1.

Compound 47

EM (calculated): 376.14; MS (ESI) m/e (M+1H) ⁺ : 377.0, (M-1H) ^- : 375.2.

Compound 48

EM (calculated): 339.12; MS (ESI) m/e (M+1H) ⁺ : 340.1, (M-1H) ^- : 338.3.

Compound 49

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.53(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; MS (ESI) m/e (M+1H) ⁺ : 340.0, (M-1H) ^- : 338.1.

Compound 50

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.37(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; MS (ESI) m/e (M+1H) ⁺ : 352.0, (M-1H) ^- : 349.9.

Compound 51

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.11(s, 1H) 9.09(d, J=4.4Hz, 1H), 8.70(d, J=7.6Hz, 1H), 8.65(d, J=7.6 Hz, 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; MS (ESI) m/e (M+1H) ⁺ : 352.0, (M-1H) ^- : 349.9.

Compound 52

¹ H NMR (400MHz, DMSO-d ₆ ) δ13.57(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; MS(ESI)m /e(M+1H) ⁺ : 341.1, (M-1H) ^- : 339.2.

Compound 53

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.04(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 value): 341.1; MS (ESI) m/e ( M+1H) ⁺ : 341.8, (M-1H) ^- : 340.0.

Compound 54

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.07(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 value) : 351.1; MS (ESI) m/e (M+1H) ⁺ : 351.9, (M-1H) ^- : 350.1.

Compound 55

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.39(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; MS (ESI) m/e (M+1H) ⁺ : 3518, (M-1H) ^- : 349.9.

Compound 56

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.04(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; MS (ESI)m/e(M+1H) ⁺ : 352.8, (M-1H) ^- : 350.9.

Compound 57

EM (calculated): 350.11; MS (ESI) m/e (M+1H) ⁺ : 351.1, (M-1H) ^- : 349.1.

Compound 58

EM (calculated): 351.12; MS (ESI) m/e (M+1H) ⁺ : 352.2, (M-1H) ^- : 350.0.

Compound 59

EM (calculated): 365.14; 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

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.04(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; MS(ESI) m/e(M+1H) ⁺ : 341.0, (M-1H) ^- : 339.2.

Compound 62

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.04(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; MS(ESI) m/e(M+1H) ⁺ : 354.0, (M-1H) ^- : 351.9.

Compound 63

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.05(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; MS (ESI) m/e (M+1H) ⁺ : 381.9, (M-1H) ^- : 380.1.

Compound 64

EM (calculated): 380.14; MS (ESI) m/e (M+1H) ⁺ : 381.0, (M-1H) ^- : 379.0.

Compound 65

EM (calculated): 380.14; MS (ESI) m/e (M+1H) ⁺ : 381.2, (M-1H) ^- : 378.9.

Compound 66

EM (calculated): 351.12; MS (ESI) m/e (M+1H) ⁺ : 352.0, (M-1H) ^- : 350.0.

Compound 67

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.05(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(false q, J=6.0Hz, 2H), 2.01 (s, 3H). EM (calculated): 340.1; MS (ESI) m/e (M+1H) ⁺ : 340.9, (M-1H) ^- : 339.2.

Compound 68

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.08(s, 1H), 10.72(br s, 1H), 8.81(t, J=5.2Hz, 1H), 7.94(dd, J ₁ =8.4Hz, J ₂ =2.0Hz, 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

¹ H NMR (DMSO-d ₆ ): 0.92 (3H, t, 7Hz); 1.53 (1H, m); 1.72 (1H, m); 2.48 (3H, s); 3.94 (1H, m); , 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

¹ H NMR (DMSO-d ₆ ): 0.90 (2H, dd); 0.91 (3H, t, 7Hz); 1.1 (2H, br.S); 1.52 (1H, m); 1.68 (1H, m); (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, δHz).MS (M+ 1): 548.

Compound 73

¹ H NMR (DMSO-d ₆ ): 2.00 (2H, m); 2.64 (1H, m); 2.75 (1H, m); 4.1 (1H, m); 4.18 (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

¹ H NMR (DMSO-d ₆ ): 3.56 (2H, m); 4.15 (1H, m); 4.23 (1H, m); 4.57 (2H, s); 4.94 (1H, m); , 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

¹ H NMR (DMSO-d ₆ ): 2.7-2.81 (2H, m); 3.78 (2H, s); 4.12 (1H, dd, 10.5Hz); 4.22 (1H, dd, 10.7Hz); 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

¹ H NMR (DMSO-d ₆ ): 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

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.07(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, buried at m of 7.41), 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=6.4 Hz, 2H). EM (calculated): 340.1; MS (ESI) m/e (M+1H) ⁺ : 341.2, (M-1H) ^- : 339.3.

Compound 92

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.07(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 value): 370.2; MS (ESI) m/e (M+1H) ⁺ : 371.0, (M-1H) ^- : 368.9.

Compound 93

¹ H NMR (400MHz, DMSO-d ₆ ) δ10.96(s, 1H), 8.90(t, J=5.6Hz, 1H), 8.31(s, 1H), 7.98(dd, J ₁ =7.2Hz, J ₂ = 1.6Hz, 2H), 7.62 (d, J = 8.4Hz, 2H), 7.40 (false t, J = 7.2Hz, 2H), 7.31 (false tt, J ₁ = 7.2Hz, J ₂ = 2.0Hz, 1H), 6.90 (d, J=9.2Hz, 2H), 4.03 (t, J=5.6Hz, 2H), 3.42 (false q, J=6.0Hz, 2H), 1.98 (false p, J=6.0Hz, 2H).EM (calculated): 397.1; MS (ESI) m/e (M+1H) ⁺ : 397.9, (M-1H) ^- : 396.0.

Compound 94

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.09(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 value): 340.1; MS (ESI) m/e (M+1H) ⁺ : 341.1, (M-1H) ^- : 339.1.

Compound 95

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.09(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 (false p, J = 6.8Hz, 1H), 4.07 (dd, _J1 = 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; MS (ESI) m/e (M+1H) ⁺ : 341.1, (M-1H) ^- : 339.1.

Compound 96

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.05(s, 1H), 8.87(s, 1H), 8.12(d J=8.0Hz, 1H), 7.67(dt, J ₁ =8.8Hz, J ₂ = 2.0Hz, 1H), 7.54 (dd, J ₁ = 8.4Hz, J ₂ = 1.6Hz, 2H), 7.43-7.33 (m, 4H), 6.99 (dt J ₁ = 9.2Hz, J ₂ = 2Hz, 2H ), 6.65(d, J=15.6Hz, 1H), 4.26(m, 1H), 4.01(dd, J ₁ =9.6Hz, J ₂ =4.8Hz, 1H), 3.94(dd J ₁ =9.6Hz, J ₂ = 5.6Hz, 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 value) : 382.2; MS (ESI) m/e (M+1H) ⁺ : 383.0, (M-1H) ^- : 381.1.

Compound 97

¹ H NMR (400MHz, DMSO-d ₆ ) δ10.95(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, _J2 =1.6Hz, 2H), 6.61(d, J=16Hz, 1H ), 4.21(m, 1H), 3.94(m, 1H), 3.86(m, 1H), 1.69(dJ=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; MS(ESI) m/e( M+1H) ⁺ : 423.2, (M-1H) ^- : 421.2.

Compound 98

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.03(s, 1H), 8.88(s, 1H), 8.09(d, J=8.4Hz, 1H), 7.69(dt, J ₁ =8.8Hz, J ₂ = 2.8Hz, 2H), 7.432-7.32 (sequence m, 4H), 6.99 (dt, _J1 = 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; MS(ESI)m /e(M+1H) ⁺ : 368.7, (M-1H) ^- : 367.1.

Compound 99

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.04(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). Lack of OH or NH. EM (calculated): 416.2; MS (ESI) m/ e(M+1H) ⁺ : 417.3, (M-1H) ^- : 415.2.

Compound 100

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.04(s, 1H), 8.78(s, 1H), 8.32(d, J=8Hz, 1H), 7.69(d, J=8.8Hz, 2H), 7.52(dd, J ₁ =8.4Hz, J ₂ =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, J ₁ =13.6Hz, J ₂ = 6Hz, 1H), 2.88 (dd, J ₁ = 14Hz, J ₂ = 8Hz, 1H). EM (calculated): 416.2; MS(ESI) m/e(M+1H) ⁺ : 417.2, (M -1H) ^- : 415.2.

Compound 101

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.05(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, _J2 =5.6Hz, 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 value): 382.2; MS (ESI) m/e (M + 1H) ⁺ : 383.2, (M- 1H) ^- : 381.2.

Compound 102

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.03(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 value): 368.2; MS(ESI)m/e(M+1H) ⁺ : 369.1, (M-1H) ^- : 367.1.

Compound 103

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.04 (s, 1H), 8.14 (d, J=8.4Hz, 1H), 7.69 (dt, J ₁ =8.8Hz, J ₂ =2.8Hz, 2H) , 7.54(dd, J ₁ =6.8, J ₂ =1.2Hz, 2H), 7.43-7.32(m, 4H), 6.99(dt, J ₁ =8.8Hz, J ₂ =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, _J2 =5.2Hz, 1H ), 1.67(m, 1H), 1.53(m, 1H), 1.36-1.27(m, 4H), 0.87(t, J=6.4Hz, 3H). Lack of 1H, NH or OH.EM (calculated): 382.21; MS (ESI) m/e (M+1H) ⁺ : 383.1, (M-1H) ^- : 381.1.

Compound 104

¹ H NMR (400MHz, DMSO-d ₆ ) δ 10.97 (s, 1H), 8.25 (d, J=8.4Hz, 1H), 7.64 (dt, J ₁ =8.8Hz, J ₂ =2Hz, 2H), 7.46 (dd, J ₁ =7.6Hz, J ₂ =2Hz, 2H), 7.34-7.18 (sequence m, 6H), 6.93 (dt, J ₁ =9.2Hz, J ₂ =2.8Hz, 2H), 6.54 (d , J=15.6Hz, 1H), 4.31(m, 1H), 3.95(d, J=4.8Hz, 2H), 2.93(dd, J ₁ =13.6Hz, J ₂ =5.6Hz, 1H), 2.79(dd , J ₁ =13.6Hz, J ₂ =8.4Hz, 1H). EM (calculated value): 450.1; MS (ESI) m/e (M+1H) ⁺ : 451.2; (M-1H) ^- : 449.2.

Compound 105

¹ H NMR (400MHz, DMSO-d ₆ ) δ10.97 (s, 1H), 8.07 (d, J=8Hz, 1H), 7.62 (dt, J ₁ =8.8Hz, J ₂ =2.8Hz, 2H), 7.47 (dd, J ₁ =8.8Hz, J ₂ =1.6Hz, 2H), 7.34-7.26 (sequence m, 4H), 6.93 (dt, J ₁ =8.8Hz, J ₂ =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, _J2 =5.6Hz , 1H), 1.64(m, 1H), 1.46(m, 1H), 0.85(t, J=6.8Hz, 3H). EM (calculated): 354.2; MS(ESI) m/e(M+1H) ⁺ : 354.6, (M-1H) ^- : 353.2.

Compound 106

¹ H NMR (400MHz, DMSO-d ₆ ) δ10.97(s, 1H), 8.07(d, J=8Hz, 1H), 7.62(d J=8.8Hz, 2H), 7.47(dd, J ₁ =6.8 Hz, _J2 = 1.6Hz, 2H), 7.35-7.62 (sequence m, 4H), 6.93 (dt, _J1 = 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, _J2 =4.8Hz, 1H), 1.65(m, 1H ₎ , 1.49(m, 1H) , 0.85 (t, J=7.2Hz, 3H). EM (calculated value): 354.2; MS (ESI) m/e (M+1H) ⁺ : 354.8, (M-1H) ^- : 353.1.

Compound 107

EM (calculated): 400.49; MS (ESI) m/e (M+1): 401.0, (M-1): 399.0.

Compound 108

EM (calculated): 400.49; MS (ESI) m/e (M+1): 401.1, (M-1): 399.2.

Compound 109

¹ H NMR (400MHz, DMSO-d ₆ ) δ10.97(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, J=7.2Hz, 1H), 6.93 (d, J=8.8, 2H), 6.69 (d , J=15.6Hz, 1H), 5.30 (dd, J ₁ =13.6Hz, J ₂ =7.6Hz, 1H), 4.19 (d, J=6.4Hz, 2H). EM (calculated value): 402.2; MS ( ESI)m/e(M+1H) ⁺ : 403.2, (M-1H) ^- : 400.9.

Compound 110

¹ H NMR (400MHz, DMSO-d ₆ ) δ10.97(s, 1H), 8.80(br s, 1H), 8.74(d, J=8Hz, 1H), 7.62(dt, J ₁ =8.8Hz, J ₂ = 2Hz, 2H), 7.48 (dd, _J1 = 6.4Hz, _J2 = 1.6Hz, 2H), 7.39-7.27 (sequence m, 8H), 7.21 (tt, _J1 = 7.6Hz, _J2 = 1.2 Hz, 1H), 6.93 (dt, _J1 = 9.2Hz, _J2 = 2.4Hz, 2H), 6.69 (d, J = 15.6, 1H), 5.29 (dd, _J1 = 8Hz, _J2 = 6.4Hz, 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

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.25(d, J=8Hz, 1H), 7.83(d, J=8.8Hz, 2H), 7.48(d, J=6.4Hz, 2H), 7.39- 7.27 (sequence 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; MS(ESI) m/e(M+1H) ⁺ : 433.2, (M -1H) ^- : 430.0.

Compound 112

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.24(d, J=8Hz, 1H), 7.82(d, J=8.8Hz, 2H), 7.48(d, J=8.8Hz, 2H), 7.84- 7.29 (sequence 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; MS(ESI) m/e(M+1H) ⁺ : 432.2, (M- 1H) ^- : 430.2.

Compound 113

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.50 (d, J = 8.0Hz, 1H), 7.83 (dt, J ₁ = 9.2Hz, J ₂ = 2.8Hz, 2H), 7.48 (dd, J ₁ = 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, _J2 =6.8Hz, 1H).EM (calculated): 492.2; MS (ESI) m/e (M+1H) ⁺ : 494.3, (M-1H) ^- : 492.2.

Compound 114

¹ H NMR (400MHz, DMSO) δ11.07 (br s, 1H), 8.38 (d, J=7.6Hz, 2H), 7.84 (dd, J ₁ =3.6Hz, J ₂ =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, J ₁ =8.4Hz, 2H), 4.20(m, 1H), 4.13(dd, J ₁ =6.4Hz, J ₂ =9.6Hz, 1H), 4.04(dd, J ₁ =5.2Hz, J ₂ =9.2Hz, 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 value): 334.1 ; MS (ESI) m/e (M+1H) ⁺ : 335.0, (M-1H) ^- : 333.0.

Compound 115

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.03(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 value): 404.2; MS (ESI) m/e (M+1H) ⁺ : 405.2, (M-1H) ^- : 4032.

Compound 116

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.03(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; MS (ESI) m/e (M+1H) ⁺ : 378.9, (M-1H) ^- : 377.0.

Compound 117

¹ H NMR (400MHz, DMSO-d ₆ ) δ10.98(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, J ₁ =9.6Hz, J ₂ =5.6Hz, 1H), 3.98(dd, J ₁ =9.6Hz, J ₂ =4.4Hz, 1H), 3.70(d, J=2.4Hz, 2H), 2.67(dd, J ₁ =6.8Hz, J ₂ =13.6Hz, 1H), 2.58 (dd, J ₁ =13.2Hz, J ₂ =7.2Hz, 1H). EM (calculated): 460.2; MS(ES1) m/e(M-1H) ^- : 460.8.

Compound 118

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.02(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, J ₁ =6.0Hz, J ₂ =9.6Hz, 1H), 1.73(m 1H), 1.62(m, 1H), 0.93(t, J=7.6Hz, 3H).EM(Calculation value): 328.1; MS(ESI) m/e(M+1H) ⁺ : 329.1.(M-1H) ^- : 327.0.

Compound 119

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.03(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 value): 342.2; MS (ESI) m/e (M+1H) ⁺ : 343.0, (M-1H) ^- : 341.1.

Compound 120

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.03(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, J ₁ =4.4Hz, J ₂ =7.6Hz, J ₃ =18.4Hz, 1H), 1.41(m, 1H), 0.81(t, J=6.8Hz, 3H).EM(Calculation value): 356.2; MS (ESI) m/e (M+1H) ⁺ : 357.1, (M-1H) ^- : 355.1.

Compound 121

EM (calculated): 356.38; MS (ESI) m/e (M+1): 357.0, (M-1): 355.1.

Compound 122

¹ H NMR (400MHz, DMSO-d ₆ ) δ10.96(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, partially hidden under the peak of 4.20, J ₁ =9.2Hz, J ₂ =16.8Hz, 1H), 4.05(dd, J ₁ =10.0Hz, J ₂ =4.8Hz , 1H), 1.69 (m 1H), 1.62 (m, 1H), 0.88 (t, J=7.2Hz, 3H). EM (calculated): 411.1; MS (ESI) m/e (M-1H) ^- : 410.1.

Compound 123

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.03(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, J ₁ =5.2Hz, J ₂ =9.6Hz, 1H), 3.95 (dd, J ₁ =5.2Hz, J ₂ =9.6Hz, 1H), 3.77 (s, 3H), 1.71 (m, 1H), 1.52 (m, 1H), 0.91 (t, J=6.8Hz, 3H). EM (calculated): 384.2; MS (ESI) m/e (M+ 1H) ⁺ : 385.0, (M-1H) ^- : 383.2.

Compound 124

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.07(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, J ₁ =10.0Hz, J ₂ =6.8Hz, 1H), 4.08(dd, J ₁ =10.4Hz, J ₂ =6.0Hz , 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

¹ H NMR (400MHz, DMSO-d ₆ ) δ10.96(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 the water peak), 1.19(d, J=6.4Hz, 3H). EM (calculated value): 340.1.

Compound 126

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.02(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, J ₁ =6.0Hz, J ₂ =11.6Hz, J ₃ =17.6Hz, 1H), 3.47(m, 1H), 3.36(m 1H, hidden under the water peak) , 1.26 (d, J=6.0Hz, 3H). EM (calculated value): 340.1; MS (ESI) m/e (M+1H) ⁺ : 341.0, (M-1H) ^- : 339.2.

Compound 127

EM (calculated): 397.1; MS (ESI) m/e (M-1H) ^- : 396.1.

Compound 128

EM (calculated): 397.1; MS (ESI) m/e (M+1H) ⁺ : 398.2, (M-1H) ^- : 396.2.

Compound 129

¹ H NMR (400MHz, DMSO-d ₆ ) δ10.96(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, J ₁ =6.0Hz, J ₂ =12.0Hz, J ₃ =18.0Hz, 1H), 3.52(ddd, J ₁ =6.4Hz, J ₂ =13.6Hz, J ₃ =19.6Hz, 1H), 3.31(m, 1H, Hiding 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

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.03(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 (false q, J=5.6Hz, 1H), 3.77(s, 3H), 3.46 (ddd, J ₁ =4.8Hz, J ₂ =13.2Hz, J ₃ =19.2Hz, 1H), 3.32 (ddd, J ₁ =5.2 Hz, J ₂ =10.8 Hz, J ₃ =13.2 Hz, 1H), 1.25 (d, J = 6.0 Hz, 3H). EM (calculated): 370.2; MS(ESI) m/ e(M+1H) ⁺ : 371.0, (M-1H) ^- : 369.1.

Compound 131

¹ H NMR (DMSO-d ₆ ): 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

¹ H NMR (400MHz, DMSO-d ₆ ) δ: 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; MS (ESI) m/e (M+1H) ⁺ : 388.9, (M-1H) ^- : 387.1.

Compound 133

¹ H NMR (DMSO-d ₆ ): 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

¹ H NMR (DMSO-d ₆ ): 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

¹ H NMR (DMSO-d ₆ ): 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

¹ H NMR (DMSO-d ₆ ): 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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 9.02 (t, 2H, J = 5.3 Hz), 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

¹ H NMR (400MHz, DMSO-d ₆ ) δ: 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; MS(ESI) m/ e(M+1H) ⁺ : 447.4, (M-1H) ^- : 445.3.

Compound 140

¹ H NMR (400MHz, DMSO-d ₆ ) δ: 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

¹ H NMR (400MHz, DMSO-d ₆ ) δ: 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

¹ H NMR (DMSO-d ₆ ): 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

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.04(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

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.04(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

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.06(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

¹ H NMR (400MHz, DMSO-d ₆ ) δ: 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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 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; MS (ESI) m/e (M+1H) ⁺ : 381.0, (M-1H) ^- : 379.1.

Compound 154

¹ H NMR (400MHz, DMSO-d ₆ ) δ: 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

¹ H NMR (400MHz, DMSO-d ₆ ) δ: 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

¹ H NMR (400MHz, DMSO-d ₆ ) δ: 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

¹ H NMR (400MHz, DMSO-d ₆ ) δ: 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 value): 477; MS (ESI) m/e ( M+1H) ⁺ : 477.9, (M-1H) ^- : 476.1.

Compound 162

¹ H NMR (DMSO-d ₆ ): 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

¹ H NMR (DMSO-d ₆ ): 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; MS (ESI) m/e (M+1H) ⁺ : 421.2, (M-1H) ^- : 419.5.

Compound 165

EM (calculated): 420.17; MS (ESI) m/e (M+1H) ⁺ : 421.3, (M-1H) ^- : 419.3.

Compound 166

EM (calculated): 420.17; MS (ESI) m/e (M+1H) ⁺ : 421.3, (M-1H) ^- : 419.3.

Compound 167

¹ H NMR (DMSO-d ₆ ): δ8.89(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; MS (ESI) m/e (M+1H) ⁺ : 421.2, (M-1H) ^- : 419.3.

Compound 169

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.07(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

¹ H NMR (DMSO-d ₆ ): 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

¹ H NMR (DMSO-d ₆ ): 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) ⁺¹ 357.1, (M-1) ^-1 355.1.

Compound 174

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.05(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

¹ H NMR (DMSO-d ₆ ): δ8.91(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

¹ H NMR (DMSO-d ₆ ): 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

¹ H NMR (DMSO-d ₆ ): 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

¹ H NMR (DMSO-d ₆ ): δ8.91(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

¹ H NMR (DMSO-d ₆ ): 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

¹ H NMR (DMSO-d ₆ ): 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

¹ H NMR (DMSO-d ₆ ): δ8.87(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

¹ H NMR (DMSO-d ₆ ): δ8.88(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

¹ H NMR (DMSO-d ₆ ): 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

¹ H NMR (DMSO-d ₆ ): 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

¹ H NMR (DMSO-d ₆ ): 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

¹ H NMR (DMSO-d ₆ ): 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) ⁺¹ 343.1, (M-1) ^-1 340.9.

Compound 187

¹ H NMR (DMSO-d ₆ ): 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

¹ H NMR (DMSO-d ₆ ): 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) ^-1 423.2.

Compound 189

¹ H NMR (DMSO-d ₆ ): 0.95 (3H, t, 7Hz); 1.53 (1H, m); 1.72 (1H, m); 2.52 (3H, s); 3.79 (3H, s); , 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); d); 8.27(2H, d, 7Hz); 8.87(1H, d, 2Hz). MS(M+1): 439.

Compound 190

¹ H NMR (DMSO-d ₆ ): 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

¹ H NMR (DMSO-d ₆ ): 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; MS (ESI) m/e (M+1) ⁺ : 371.1, (M-1) ^- : 369.2.

Compound 2

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.03(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; MS (ESI) m/e (M+1H) ⁺ : 341.0, (M-1H) ^- : 339.4.

Compound 4

EM (calculated): 398.13; MS (ESI) m/e (M+1H) ⁺ : 399.0, (M-1H) ^- : 397.1.

Compound 5

EM (calculated): 368.17; MS (ESI) m/e (M+1H) ⁺ : 368.8, (M-1H) ^- : 367.2.

Compound 6

EM (calculated): 354.1; MS (ESI) m/e (M+1H) ⁺ : 354.8, (M-1H) ^- : 353.2.

table 3:

Compound 1

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.11(s, 1H), 9.07(t, J=5.2Hz, 1H), 8.94(s, 1H), 8.16(s, 1H), 8.07(dd, J ₁ =2.4Hz, J ₂ =8.4Hz, 1H), 7.99(dd, J ₁ =2.4Hz, J ₂ =6.8Hz, 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

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.05(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; MS(ESI)m /e: (M+1H) ⁺ : 341.0, (M-1H) ^- : 339.1.

Compound 3

¹ H NMR (400MHz, DMSO-d ₆ ) δ: 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 value): 339.1; MS(ESI) m/e(M+1H) ⁺ : 340.1, (M-1H) ^- : 338.3.

Compound 4

EM (calculated): 353.1; MS (ESI) m/e (M+1) ⁺ : 354.1, (M-1) ^- : 352.2.

Compound 5

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.84(t, J=5.6Hz, 1H), 8.05(s, 1H), 7.99(dd, J ₁ =6.0Hz, J ₂ =2.0Hz, 1H) , 7.91(dd, _J1 =6.4Hz, _J2 =2.0Hz, 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 (false q, J=5.6Hz, 2H), 2.00 (false p, J=6.0Hz, 2H). EM (calculated value): 370.1; MS (ESI )m/e(M+1H) ⁺ : 371.1, (M-1H) ^- : 369.0.

Compound 6

¹ H NMR (400MHz, DMSO-d ₆ ) δ10.96(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, J ₁ =8.4Hz, J ₂ =0.8Hz, 1H), 7.43(d, J=0.8Hz, 1H), 7.37(td, J ₁ =7.2Hz, J ₂ =1.2Hz, 1H), 7.241(td, J ₁ =8.0HZ, J ₂ =0.8Hz, 1H), 6.89(d, J=8.8Hz, 2H), 4.01(t, J= 6.4Hz, 2H), 3.37 (false q, J = 6.0Hz, 2H), 1.94 (false p, J = 6.0Hz, 2H). EM (calculated value): 354.1; MS (ESI) m/e (M+ 1H) ⁺ : 355.2, (M-1H) ^- : 353.1.

Compound 7

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.07(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

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.07(s, 1H), 8.91(s, 1H), 8.68(d, J=8.0Hz, 1H), 8.17(s, 1H), 8.03(dd, J ₁ =2.0Hz, J ₂ =6.4Hz, 1H), 7.96(dd, J ₁ =4.0Hz, J ₂ =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 , J ₂ =9.6Hz, ), 1.81(m, 1H), 1.67(m, 1H), 0.99(t, J=7.6Hz, 3H). EM (calculated): 384.1; MS(ESI) m/e (M+1H) ⁺ : 385.0, (M-1H) ^- : 383.1.

Compound 9

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.11(s, 1H), 8.95(br s, 1H), 8.80(d, J=8.0Hz, 1H), 8.19(s, 1H), 8.06(dd , J ₁ =5.6Hz, J ₂ =1.6Hz, 1H), 7.98(dd, J ₁ =6.8Hz, J ₂ =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, J ₁ =9.6Hz, J ₂ =6.4Hz, 1H), 4.07(dd , J ₁ =9.6Hz, J ₂ =5.6Hz, 1H), 1.36 (d, J=6.8Hz, 3H). EM (calculated value): 370.1; MS (ESI) m/e (M+1H) ⁺ : 371.0, (M-1H) ^- : 368.9.

Compound 10

¹ H NMR (400MHz, DMSO-d ₆ ) δ10.95(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(pJ=6.4Hz , 1H), 4.05 (dd, J ₁ =6.8Hz, J ₂ =10.0Hz, 1H), 3.92 (dd, J ₁ =10.0Hz, J ₂ =6.0Hz, 1H), 1.21 (d, J = 5.2Hz , 3H). EM (calculated): 370.1; MS (ESI) m/e (M+1H) ⁺ : 370.9, (M-1H) ^- : 369.0.

Compound 11

¹ H NMR (400MHz, DMSO-d ₆ ) δ10.96(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, J ₁ =7.2Hz, J ₂ =0.8Hz, 1H), 6.92(d, J=8.8Hz, 2H), 4.19(m, 1H), 4.07(dd, J ₁ =10.4Hz, J ₂ = 6.4Hz, 1H), 3.99(dd, _J1 =10.0Hz, _J2 =5.6Hz, 1H), 1.68(m, 1H), 1.55(m, 1H), 0.86(t, J=7.2Hz, 3H) .EM (calculated): 368.1; MS (ESI) m/e (M-1H) ^- : 367.1.

Compound 12

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.06(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(false q, J =5.6Hz, 1H), 3.62(m, 1H), 3.42(m, 1H), 1.34(d, J=6.4Hz, 3H). EM (calculated): 370.1; MS(ESI) m/e(M +1H) ⁺ : 371.0, (M-1H) ^- : 369.1.

Compound 13

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.06(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 value): 370.1; MS (ESI )m/e(M+1H) ⁺ : 371.0, (M-1H) ^- : 369.1.

Compound 14

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.02(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, _J2 =0.8 Hz, 1H), 7.03 (d, J = 9.2Hz, 2H), 4.69 (false q, J = 6.4Hz, 1H), 3.59 (ddd, J ₁ = 6.4Hz, J ₂ = 13.6Hz, J ₃ = 19.6 Hz, 1H), 3.39 (ddd, J ₁ =6.0Hz, J ₂ =12.4Hz, J ₃ =19.6Hz, 1H), 1.29 (d, J = 6.4Hz, 3H).EM (calculated value): 354.1; MS(ESI) m/e(M+1H) ⁺ : 354.7, (M-1H) ^- : 353.1.

Compound 15

EM (calculated): 386.09; MS (ESI) m/e (M-1H) ^- : 384.7.

Compound 16

EM (calculated): 370.10; 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; MS (ESI) m/e (M-1H) ^- : 353.2.

Compound 19

EM (calculated): 354.12; MS (ESI) m/e (M-1H) ^- : 353.1.

Compound 20

EM (calculated): 424.07; MS (ESI) m/e (M-1H) ^- : 423.9.

Compound 21

EM (calculated): 374.0; MS (ESI) m/e (M+1) ⁺ : 375.0, (M-1) ^- : 373.0.

Compound 22

EM (calculated): 386.1; 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; MS (ESI) m/e (M+1) ⁺ : 370.8, (M-1) ^- : 369.0.

Compound 25

EM (calculated): 370.1; MS (ESI) m/e (M+1) ⁺ : 371.0, (M-1) ^- : 369.1.

Compound 26

EM (calculated): 414.14; MS (ESI) m/e (M+1H) ⁺ : 415.2, (M-1H) ^- : 413.2.

Compound 27

EM (calculated): 469.18; MS (ESI) m/e (M+1H) ⁺ : 470.1, (M-1H) ^- : 468.4.

Compound 28

EM (calculated): 447.14; MS (ESI) m/e (M+1H) ⁺ : 448.1, (M-1H) ^- : 446.2.

Compound 29

EM (calculated): 354.1; MS (ESI) m/e (M+1) ⁺ : 355.1, (M-1) ^- : 353.1.

Compound 30

EM (calculated): 370.1; 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; MS (ESI) m/e (M+1H) ⁺ : 428.2, (M-1H) ^- : 426.2.

Compound 33

EM (calculated): 414.1; MS (ESI) m/e (M+1) ⁺ : 415.4, (M-1) ^- : 413.2.

Compound 34

EM (calculated): 469.2; MS (ESI) m/e (M+1) ⁺ : 470.1, (M-1) ^- : 468.3.

Compound 35

EM (calculated): 447.1; MS (ESI) m/e (M+1) ⁺ : 448.2, (M-1) ^- : 446.5.

Compound 36

EM (calculated): 368.1; MS (ESI) m/e (M+1) ⁺ : 369.0, (M-1) ^- : 367.2.

Compound 37

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.69(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

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.42(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; MS (ESI) m/e (M+1H) ⁺ : 384.9, (M-1H) ^- : 383.2.

Compound 40

EM (calculated): 446.15; MS (ESI) m/e (M+1H) ⁺ : 447.2, (M-1H) ^- : 445.4.

Compound 41

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.28(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 value): 399.1; MS (ESI) m/e (M+1H) ⁺ : 400.0, (M-1H) ^- : 398.1.

Compound 42

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.09(bs, 1H), 10.60(bs, 1H), 9.29(t, J=6.0Hz, 1H), 8.08(d, J=8.0Hz; 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; MS (ESI)e(M+1H) ⁺ : 439.8, (M-1H) ^- : 438.2.

Compound 44

EM (calculated): 412.16; MS (ESI) m/e (M+1H) ⁺ : 413.1, (M-1H) ^- : 411.3.

Compound 45

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.05(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

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.08(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

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.33(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; MS(ESI) m/e(M+1H) ⁺ : 440.2, (M-1H) ^- : 438.4.

Compound 48

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.09(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=8.8 Hz, 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): 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

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.07(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

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.82(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 value): 460.2; MS (ESI) m/e (M+1H) ⁺ : 461.0, (M-1H) ^- : 459.1.

Compound 53

EM (calculated): 428.16; MS (ESI) m/e (M+1H) ⁺ : 428.9, (M-1H) ^- : 427.1.

Compound 54

¹ H NMR (DMSO-d ₆ ): 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

¹ H NMR (DMSO-d ₆ ): 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

¹ H NMR (400MHz, DMSO-d ₆ ) δ: 7.92(br s, 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 value): 444; MS (ESI) m/e ( M+1H) ⁺ : 445.3, (M-1H) ^- : 443.3.

Compound 57

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.07(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

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.05(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

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.04(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

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.05(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

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.04(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

¹ H NMR (400MHz, DMSO-d ₆ ) δ: 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

¹ H NMR (400MHz, DMSO-d ₆ ) δ: 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, 2H, J=8.3Hz). EM (calculated): 528; MS (ESI) m/e (M+1H) ⁺ : 529.4, (M-1H) ^- : 527.5.

Compound 65

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.06(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

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.06(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

¹ H NMR (400MHz, DMSO-d ₆ ) δ: 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; MS (ESI) m/e (M+1H) ⁺ : 447.4, (M-1H) ^- : 445.3.

Compound 68

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.04(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

¹ H NMR (400MHz, DMSO-d ₆ ) δ: 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=5.9Hz), 3.68 (q, 2H, J=5.9Hz). EM (calculated): 464; MS (ESI) m/e(M+1H) ⁺ : 465.1, (M- 1H) ^- : 463.1.

Compound 70

¹ H NMR (400MHz, DMSO-d ₆ ) δ: 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), 6.87(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

¹ H NMR (400MHz, DMSO-d ₆ ) δ: 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

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.04(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

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.05(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

¹ H NMR (400MHz, DMSO-d ₆ ) δ: 8.86(m, 1H), 8.81(br s, 1H), 7.80(d, 1H, J=8.2Hz), 7.63(d, 2H, J=9.4Hz ), 7.57(d, 1H, J=8.2Hz), 7.44(t, 1H, J=7.8Hz), 7.32(t, 1H, J=7.0Hz), 7.12(t, 1H, J=9.0Hz), 6.91(t, 1H, J=8.6Hz), 5.64(s, 2H), 4.06(t, 2H, J=6.0Hz), 3.54(t, 2H, J=6.0Hz).EM (calculated value): 500.13 ; MS (ESI) m/e (M+1H) ⁺ : 501.5, (M-1H) ^- : 499.3.

Compound 75

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.04(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

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.04(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

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.05(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

¹ H NMR (400MHz, DMSO-d ₆ ) δ: 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=7.6 Hz), 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=5.9 Hz).EM(calculated): 513.16; MS(ESI)m/e(M+1H) ⁺ : 514.2, (M-1H) ^- : 512.2.

Compound 79

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.08(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

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.06(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

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.05(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

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.07(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

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.05(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

¹ H NMR (400MHz, DMSO-d ₆ ) δ: 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, ⁽ M-1H) ^- : 353.1.

Compound 85

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.05(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

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.05(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

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.05(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

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.03(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

¹ H NMR (400MHz, DMSO-d ₆ ) δ: 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): 356; MS (ESI) m /e(M+1H) ⁺ : 357.2, (M-1H) ^- : 354.9.

Compound 90

¹ H NMR (400MHz, DMSO-d ₆ ) δ: 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; MS(ES1) m/e(M+ 1H) ⁺ : 403.0, (M-1H) ^- : 400.9.

Compound 91

¹ H NMR (400MHz, DMSO-d ₆ ) δ: 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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 11.05 (br s, 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=5.6Hz), 3.66 (q, 2H, J=6.0Hz).EM (calculated value): 461; MS (ESI) m/e(M+1H) ⁺ : 462.2, (M- 1H) ^- : 460.3.

Compound 93

¹ H NMR (400MHz, DMSO-d ₆ ) δ: 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

¹ H NMR (400MHz, DMSO-d ₆ ) δ: 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

¹ H NMR (400MHz, DMSO-d ₆ ) δ: 11.04 (br s, 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, 0.8 Hz), 6.88(m, 2H), 5.40(s, 2H), 3.91(t, 2H, J=6.0Hz), 3.40(m, 2H). EM (calculated): 447; MS(ESI) m/ e(M+1H) ⁺ : 448.2, (M-1H) ^- : 446.1.

Compound 96

¹ H NMR (400MHz, DMSO-d ₆ ) δ: 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

¹ H NMR (400MHz, DMSO-d ₆ ) δ: 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, 3H, J=7.3Hz). EM (calculated): 456; MS(ESI) m/e(M+1H) ⁺ : 457.1, (M-1H) ^- : 455.2.

Compound 98

¹ H NMR (400MHz, DMSO-d ₆ ) δ: 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=8.5Hz), 7.07(d, 2H, J=8.5Hz) 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). EM (calculated value): 442; MS (ESI) m/e (M+1H) ⁺ : 443.1, (M-1H) ^- : 441.5.

Compound 99

¹ H NMR (400MHz, DMSO-d ₆ ) δ: 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=7.4Hz). EM (calculated value): 425; MS (ESI) m/e (M+1H) ⁺ : 426.1, (M-1H) ^- : 424.2.

Compound 109

¹ H NMR (DMSO-d ₆ ): 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

¹ H NMR (DMSO-d ₆ ): 2.03-2.21 (2H, m); 2.991H, 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; MS (ESI) m/e (M+1H) ⁺ : 382.3, (M-1H) ^- : 380.2.

Compound 2

EM (calculated): 395.15; MS (ESI) m/e (M+1H) ⁺ : 396.1, (M-1H) ^- : 394.2.

Compound 3

EM (calculated): 331.08; MS (ESI) m/e (M+1H) ⁺ : 331.7, (M-1H) ^- : 330.1.

Compound 4

EM (calculated): 317.10; 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; MS (ESI) m/e (M+1) ⁺ : 382.0, (M-1) ^- : 380.1.

Compound 7

EM (calculated): 381.1; MS (ESI) m/e (M+1) ⁺ : 382.0, (M-1) ^- : 380.2.

Compound 8

EM (calculated): 341.1; MS (ESI) m/e (M+1) ⁺ : 341.9, (M-1) ^- : 340.1.

Compound 9

EM (calculated): 381.1; 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; MS (ESI) m/e (M+1) ⁺ : 389.1, (M-1) ^- : 387.0.

Compound 13

EM (calculated): 355.12; MS (ESI) m/e (M+1) ⁺ : 355.9, (M-1) ^- : 354.1.

Compound 14

EM (calculated): 355.1; 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; MS (ESI) m/e (M+1) ⁺ : 341.8, (M-1) ^- : 340.2.

Compound 17

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.64(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

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.64(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

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.63(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

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.64(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; MS(ESI) m/e: (M+1H) ⁺ : 382.0, (M-1H) ^- : 380.0.

Compound 21

EM (calculated): 367.1; MS (ESI) m/e (M+1) ⁺ : 367.8, (M-1) ^- : 366.2.

Compound 22

EM (calculated): 367.12; MS (ESI) m/e (M+1H) ⁺ : 368.0, (M-1H) ^- : 366.1.

Compound 23

EM (calculated): 374.0; 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; MS (ESI) m/e (M+1) ⁺ : 368.1, (M-1) ^- : 366.2.

Compound 26

EM (calculated): 381.1; MS (ESI) m/e (M+1) ⁺ : 382.0, (M-1) ^- : 380.1.

Compound 27

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.62(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 value): 369.1 ; MS (ESI) m/e: (M+1H) ⁺ : 369.9, (M-1H) ^- : 368.0.

Compound 28

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.66(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 value): 369.1 ; MS (ESI) m/e: (M+1H) ⁺ : 370.0, (M-1H) ^- : 368.2.

Compound 29

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.64(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; MS(ESI) m/ e: (M+1H) ⁺ : 355.9, (M-1H) ^- : 353.9.

Compound 30

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.66(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 value): 355.1; 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; MS (ESI) m/e (M+1) ⁺ : 331.9, (M-1) ^- : 330.2.

Compound 33

EM (calculated): 437.12; MS (ESI) m/e (M+1H) ⁺ : 438.0, (M-1H) ^- : 436.2.

Example 4

Synthesis of Acetyl-Gly-Ala-(N-Acetyl-Lys)-AMC

tert-Boc(N-acetyl-Lys)-AMC (445 mg, 1 mmol, purchased from 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 (5 ml) was added Ac-Gly-Ala- OH (188 mg, 1 mmol). The reaction mixture was stirred for 1 h 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 Example

Inhibition of HDAC in vitro in Example 1

The in vitro HDAC inhibitory activity of the compounds of the present invention was determined as follows.

Assays were performed in 100 μL reaction volumes using 96-well assay plates. A reaction buffer (50mM HEPES, 100mM KCl, 0.001% Tween-20, 5% DMSO, pH 7.4) solution of HDAC-1 (200pM final concentration) was mixed with different concentrations of inhibitors, incubated for 30 minutes, and then trypsin was added and Acetyl-Gly-Ala-(N-acetyl-Lys)-AMC to final concentrations of 50 nM and 25 μM, respectively, to initiate the reaction. In the absence of inhibitors, negative control reactions were repeated 8 times.

Reactions were monitored in a fluorescent plate reader. Fluorescence was measured after a 30 minute lag time using an excitation wavelength of 355 nm and a detection wavelength of 460 nm after a 30 minute lag time. The increase in fluorescence over time was used as a measure of the reaction rate. Inhibition constants were obtained using the BatchKi program (Kuzmic et al. Anal. Biochem. 2000, 286, 45-50). Most of the compounds of the invention have a Ki less than 40 nm.

     Example 2 In vitro cell proliferation assay

The ability of compounds of formula (I) to inhibit tumor cell growth in vitro was determined as follows.

Stock cultures of colon cancer cell lines were maintained in RPMI medium 1640 containing 10% (v/v) fetal bovine serum, 2 mM L-glutamine at 37°C in a humidified atmosphere of ₅ % CO. Amide, 1 mM sodium lactonate, 50 units/ml penicillin, and 50 μg/ml streptomycin. Cells were cultured in 75-cm ² culture flasks, and subcultures were established every 3-4 days so as not to exceed 90% confluency.

HCT116 cells were harvested, subjected to proliferation assays by trypsinization (0.05% trypsin/0.53 mMEDTA), washed twice in medium, resuspended in an appropriate volume of medium, and counted using a hemocytometer. Cells were seeded in wells of a round-bottom 96-well plate at a density of 5,000 cells/100 μl well. Allow cells to attach for 1.5-2 hours at 37°C.

Compounds were diluted from 10 mM stocks into DMSO. Serial 3-fold dilutions were performed starting with a 60 [mu]M solution in wells (triplicate) of a 96-well U-bottom plate in medium containing 0.6% DMSO. At the end of the dilution, 100 μl of each compound dilution (in triplicate) was transferred to the designated triplicate wells of a 96-well plate containing 100 μl of media solution for the cells. The dose-response final concentrations of the compounds in the identification plate ranged from 0.12 to 30 μΜ. Control wells (untreated cells) received 100 [mu]l of 0.6% DMSO in media solution. Wells containing media but no cells were used as background wells. Cells were incubated with compounds for 48 and 72 h at 37 °C in a humidified CO _incubator .

Cell proliferation was assessed by measuring fluorescence after addition of the fluorescent redox indicator Alamar Blue ^™ (BioSource International). Three to four hours before the end of the incubation period, 10 μl of Alamar Blue ^™ was added to each well of the 96-well plate. Identification plates were read in a fluorescent plate reader (excitation wavelength, 530 nM; emission wavelength, 620 nM). _G150 values (the concentration at which tumor cell growth is inhibited by 50%) for a compound can be determined by plotting the percent control fluorescence versus the logarithm of the compound concentration. The compounds of the present invention inhibit the growth of tumor cells.

Examples of pharmaceutical compositions

The following are representative pharmaceutical formulations containing compounds of formula (I).

                        

Mix the following ingredients uniformly and compress into a single-score tablet.

Ingredient Amount in each tablet, mg

Compound of the present invention 400

  Corn Starch 50

  Croscarmellose Sodium 25

Lactose 120

Magnesium stearate 5

                                               

The following ingredients are mixed uniformly and filled into hard shell gelatin capsules.

Ingredients

Compound of the present invention 200

Lactose, spray-dried 148

Magnesium stearate 2

                             

The following ingredients are mixed to form a suspension for oral use.

Ingredient Quantity

Compound of the present invention 1.0g

Fumaric acid 0.5g

Sodium Chloride 2.0g

Methylparaben 0.15g

Propyl Paraben 0.05g

Granulated sugar 25.5g

Sorbitol (70% solution) 12.85g

Veegum K (Vanderbilt Co.) 1.0g

Flavoring agent 0.035ml

Coloring agent 0.5mg

Appropriate amount of water to 100ml

Injection formulation

The following ingredients are mixed to form an injection formulation.

Ingredient Quantity

Compound of the present invention 1.2g

Lactate buffer, 0.1M 10.0ml

HCl(1N) or NaOH(1N) Appropriate amount to proper pH

Saline (optional) Appropriate amount to appropriate osmolarity

Water (distilled, sterile) Appropriate amount to 20ml

Compound (1.2 g) was combined with 0.1 M lactate buffer (10 ml) and mixed gently. Apply several sonications to form a solution, if necessary. A suitable amount of acid or base is added to achieve a suitable pH (preferably pH 4). Then enough water was added to make 20ml.

Suppository formulations

A compound of the present invention is mixed with Witepsol ^™ H-15 (triglyceride of saturated vegetable fatty acids; Riches-Nelson, Inc., New York) to prepare a suppository, total weight 2.5 g, which has the following composition:

Compound of the present invention 500mg

Witepsol ^TM H-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 a person skilled in the art that changes and modifications may be practiced within the scope of the appended claims. Accordingly, it should be understood that the foregoing description is intended to be illustrative rather than restrictive. The scope of the invention, therefore, should be determined not from the above description, but should be determined by 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 hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual patent, patent application or publication were so individually indicated.

Claims (41)

1. compound or pharmaceutically acceptable salt thereof with following formula (I):

Wherein:

R ¹Be hydrogen or alkyl;

X is-O-,-NR ²-or-S (O) _n-, wherein n is 0-2, R ²Be hydrogen or alkyl;

Y is an alkylidene group, and it is randomly replaced by cycloalkyl, the optional phenyl that replaces, alkylthio, alkyl sulphinyl, alkyl sulphonyl, the optional octadecyloxy phenyl sulfenyl that replaces, the optional phenylalkyl alkylsulfonyl that replaces, hydroxyl or the optional phenoxy group that replaces;

Ar ¹Be phenylene or heteroarylidene, wherein said Ar ¹Randomly replaced by one or two group, described group is independently selected from: alkyl, halogen, hydroxyl, alkoxyl group, halogenated alkoxy or haloalkyl;

R ³Be hydrogen, alkyl, hydroxyalkyl or the optional phenyl that replaces; With

Ar ²Be aryl, aralkyl, arylalkenyl, heteroaryl, heteroaralkyl, impure aromatic ene base, cycloalkyl, cycloalkylalkyl, Heterocyclylalkyl or Heterocyclylalkyl alkyl.

2. compound as claimed in claim 1, wherein X is-O-, R ¹And R ³Be hydrogen.

3. compound as claimed in claim 1, wherein X is-S (O) _n-, R ¹And R ³Be hydrogen.

4. as claim 2 or 3 described compounds, wherein Y is an alkylidene group.

5. as claim 2 or 3 described compounds; wherein Y is an alkylidene group, and it is randomly replaced by cycloalkyl, the optional phenyl that replaces, alkylthio, alkyl sulphinyl, alkyl sulphonyl, the optional octadecyloxy phenyl sulfenyl that replaces, the optional phenylalkyl alkylsulfonyl that replaces, hydroxyl or the optional phenoxy group that replaces.

6. compound as claimed in claim 1, wherein Ar ¹Be phenylene, X is-O-R ¹And R ³Be hydrogen ,-CONHOR ¹With 1-and the 4-position of X group at the phenylene ring.

7. as each described compound, wherein Ar among the claim 2-5 ¹Be heteroarylidene.

8. as each described compound, wherein Ar among the claim 2-5 ¹Be phenylene.

9. as each described compound, wherein Ar among the claim 2-8 ²Be aryl or arylalkenyl.

10. as each described compound, wherein Ar among the claim 2-5,7 and 8 ²Be heteroaryl.

11. compound as claimed in claim 6, wherein Ar ²Be heteroaryl.

12. compound as claimed in claim 1, wherein Ar ²Be the heteroaryl that is randomly replaced by one or two substituting group, described substituting group is independently selected from: alkyl, halogen, haloalkyl, alkoxyl group, alkoxyalkyl, the hydroxy alkoxy base, hydroxy alkoxy alkyl, the alkoxyl group alkoxyl group, alkoxy alkoxy alkyl, aminoalkyl group, aminoalkoxy, halogenated alkoxy, halogenated alkoxy alkyl, the optional phenylalkyl that replaces, the optional phenoxyalkyl that replaces, the optional heteroaryl that replaces, the optional assorted aralkoxy that replaces, the optional heteroaryloxy alkyl that replaces, the optional Heterocyclylalkyl alkyl that replaces, the optional heterocycle alkoxyl group that replaces, the optional Heterocyclylalkyl alkoxyl group that replaces,-alkylidene group-S (O) _nR ^a(wherein n is 0 to 2, R ^aBe hydroxyalkyl or the optional phenyl that replaces) ,-alkylidene group-NR ^e-alkylidene group CONR ^cR ^d(R wherein ^cBe hydroxyl, R ^dAnd R ^eBe hydrogen or alkyl independently) or the carboxyalkyl aminoalkyl group.

13. compound as claimed in claim 10, wherein Ar ²Be the heteroaryl that is randomly replaced by one or two substituting group, described substituting group is independently selected from: alkyl, halogen, haloalkyl, alkoxyl group, alkoxyalkyl, the hydroxy alkoxy base, hydroxy alkoxy alkyl, the alkoxyl group alkoxyl group, alkoxy alkoxy alkyl, aminoalkyl group, aminoalkoxy, halogenated alkoxy, halogenated alkoxy alkyl, the optional phenylalkyl that replaces, the optional phenoxyalkyl that replaces, the optional heteroaryl that replaces, the optional assorted aralkoxy that replaces, the optional heteroaryloxy alkyl that replaces, the optional Heterocyclylalkyl alkyl that replaces, the optional heterocycle alkoxyl group that replaces, the optional Heterocyclylalkyl alkoxyl group that replaces,-alkylidene group-S (O) _nR ^a(wherein n is 0 to 2, R ^aBe hydroxyalkyl or the optional phenyl that replaces) ,-alkylidene group-NR ^e-alkylidene group CONR ^cR ^d(R wherein ^cBe hydroxyl, R ^dAnd R ^eBe hydrogen or alkyl independently) or the carboxyalkyl aminoalkyl group.

14. compound as claimed in claim 10, wherein Ar ²Be cumarone-2-base; and replace at the 3-position of cumarone-2-basic ring coverlet; wherein substituting group is N; the N-dimethylaminomethyl; N; N-diethylamino methyl; 2-fluorophenoxy methyl; 3-fluorophenoxy methyl; 4-fluorophenoxy-methyl; hydroxyl-4-yloxymethyl; 2; 4; 6-trifluoromethoxy phenoxy base-methyl; 2-oxo pyridine-1-ylmethyl; 2; 2; 2-trifluoro ethoxy-methyl; 4-imidazoles-1-phenoxyl-methyl; 4-[1.2.4]-triazine-1-base-phenoxymethyl; the 2-phenylethyl; 3-hydroxyl propoxy-methyl; 2-methoxy ethoxy methyl; tetramethyleneimine-1-ylmethyl; piperidines-1-ylmethyl; 4-trifluoromethyl piperidines-1-ylmethyl; 4-methylpiperazine-1-ylmethyl; 3; 3,3-trifluoropropyl oxygen ylmethyl; 4-fluorobenzene sulfenyl methyl; 4-fluorophenyl sulfinyl methyl; 4-fluorophenyl alkylsulfonyl methyl; 2-(3-Trifluoromethoxyphen-l ethyl); N-methyl-N-benzylamino-methyl; N-methyl-N-2-phenylethyl amino methyl; 3-hydroxyl rosickyite ylmethyl; 3-hydroxypropyl sulfinyl-methyl; 3-hydroxypropyl alkylsulfonyl methyl; N-methyl-N-2-indol-3-yl ethylamino methyl; 2-(4-trifluoromethyl) ethyl; N-hydroxyl amino carbonyl-methylamino methyl; or 2-carboxy ethyl amino methyl.

15. compound as claimed in claim 11, wherein Ar ²Be the optional heteroaryl that is replaced by one or two substituting group, described substituting group is independently selected from: alkyl, halogen, haloalkyl, alkoxyl group, alkoxyalkyl, the hydroxy alkoxy base, hydroxy alkoxy alkyl, the alkoxyl group alkoxyl group, alkoxy alkoxy alkyl, aminoalkyl group, aminoalkoxy, halogenated alkoxy, halogenated alkoxy alkyl, the optional phenylalkyl that replaces, the optional phenoxyalkyl that replaces, the optional heteroaryl that replaces, the optional assorted aralkoxy that replaces, the optional heteroaryloxy alkyl that replaces, the optional Heterocyclylalkyl alkyl that replaces, the optional heterocycle alkoxyl group that replaces, the optional Heterocyclylalkyl alkoxyl group that replaces,-alkylidene group-S (O) _nR ^a(wherein n is 0 to 2, R ^aBe hydroxyalkyl or the optional phenyl that replaces) ,-alkylidene group-NR ^e-alkylidene group CONR ^cR ^d(R wherein ^cBe hydroxyl, R ^dAnd R ^eBe hydrogen or alkyl independently) or the carboxyalkyl aminoalkyl group.

16. compound as claimed in claim 11, wherein Ar ²Be cumarone-2-base; and coverlet replaces on the 3-position of cumarone-2-basic ring; wherein substituting group is N; the N-dimethylaminomethyl; N; N-diethylamino methyl; 2-fluorophenoxy methyl; 3-fluorophenoxy methyl; 4-fluorophenoxy methyl; hydroxyl-4-yloxymethyl; 2; 4; 6-trifluoromethoxy phenoxy base-methyl; 2-oxo pyridine-1-ylmethyl; 2; 2; 2-trifluoro ethoxy-methyl; 4-imidazoles-1-phenoxyl-methyl; 4-[1.2.4]-triazine-1-base-phenoxymethyl; the 2-phenylethyl; 3-hydroxyl propoxy-methyl; 2-methoxy ethoxy methyl; tetramethyleneimine-1-ylmethyl; piperidines-1-ylmethyl; 4-trifluoromethyl piperidines-1-ylmethyl; 4-methylpiperazine-1-ylmethyl; 3; 3,3-trifluoropropyl oxygen ylmethyl; 4-fluorobenzene sulfenyl methyl; 4-fluorophenyl sulfinyl methyl; 4-fluorophenyl alkylsulfonyl methyl; 2-(3-Trifluoromethoxyphen-l ethyl); N-methyl-N-benzylamino-methyl; N-methyl-N-2-phenylethyl amino methyl; 3-hydroxyl rosickyite ylmethyl; 3-hydroxypropyl sulfinyl-methyl; 3-hydroxypropyl alkylsulfonyl methyl; N-methyl-N-2-indol-3-yl ethylamino methyl; 2-(4-trifluoromethyl) ethyl; N-hydroxyl amino carbonyl-methylamino methyl; or 2-carboxy ethyl amino methyl.

17. compound as claimed in claim 11, wherein Ar ²Be cumarone-2-base, and coverlet replaces on the 5-position of cumarone-2-basic ring.

18. compound as claimed in claim 11, wherein Ar ²Be cumarone-2-base, and coverlet replaces on the 5-position of cumarone-2-basic ring, wherein substituting group is: cyclopropyl piperidine-4-base oxygen, piperidin-4-yl oxygen, tetrahydropyran-4-base oxygen, 2,2,2-trifluoro ethoxy, 2-tetramethyleneimine-1-base oxethyl or 1-(2,2, the 2-trifluoroethyl) piperidin-4-yl oxygen.

19. as each described compound among the claim 15-18, wherein Y is an ethylidene.

20. as each described compound, wherein Ar among the claim 2-8 ²Be arylalkenyl.

21. compound as claimed in claim 1, wherein X is-O-, R ¹And R ³Be hydrogen, Ar ¹Be phenylene, Ar ²Be arylalkenyl, Y is a branched alkylidene, and-CONHOH and X are in the 1-and the 4-position of phenylene ring.

22. compound as claimed in claim 21, wherein Ar ²Be trans-phenyl CH=CH-, wherein phenyl is randomly replaced by one or two substituting group, and described substituting group is independently selected from: alkyl, alkoxyl group, methylene-dioxy or hydroxyl.

23. a compound or pharmaceutically acceptable salt thereof, described compound is selected from:

N-hydroxyl-4-(2-phenylcarbamoyl amino-oxyethyl group) benzamide;

N-hydroxyl-4-(2-trans-cinnamoyl amino ethoxy) benzamide;

N-hydroxyl-4-(2-trans-2-phenycyclopropyl carbonylamino oxyethyl group) benzamide;

N-hydroxyl-4-(2-trans-4-methoxyl group cinnamoyl amino ethoxy) benzamide;

N-hydroxyl-4-[2-(2-phenylethyl carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(1H-indol-3-yl methyl carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-(2-thiophene-2-base carbonylamino oxyethyl group) benzamide;

N-hydroxyl-4-(2-pyridin-3-yl carbonylamino oxyethyl group) benzamide;

N-hydroxyl-4-(2-biphenyl-4-base carbonylamino oxyethyl group) benzamide;

N-hydroxyl-4-(2-biphenyl-3-base carbonylamino oxyethyl group) benzamide;

N-hydroxyl-4-[2-(5-phenyl thiophene-2-base carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(thiophene-2-ylmethyl carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(naphthalene-2-base carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(quinoline-6-base carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(4-phenyl thiazole-2-base carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(4-tert-butyl-phenyl carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(trans-3-pyridin-3-yl acryl amino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(4-pyrroles-1-base phenylcarbonyl group amino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(4-tetrahydrobenzene-3-oxygen phenylcarbonyl group amino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(benzothiazole-2-base carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(benzoxazoles-2-base carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(octahydro isoquinoline 99.9-2-ylmethyl carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(4-pyridin-4-yl piperazine-1-ylmethyl carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(furans-2-base carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(4-pyridin-3-yl phenylcarbonyl group amino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(4-pyridine-2-base phenylcarbonyl group amino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(benzimidazolyl-2 radicals-Ji carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(1H-pyrroles-2-base carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(4-benzamido phenylcarbonyl group amino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(4-pyridin-4-yl thiazol-2-yl carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(diamantane-1-base carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(2,4 difluorobenzene base carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(3-trans-3,4-methylenedioxyphenyl acryl amino) oxyethyl group]-benzamide;

N-hydroxyl-4-[2-(3,4-methylenedioxyphenyl carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(3,4-Dimethoxyphenyl carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(3,5-Dimethoxyphenyl carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(3,4-difluorophenyl carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(2,5-3,5-dimethylphenyl carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(2,3-dichlorophenyl carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(2,3-3,5-dimethylphenyl carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(4-chloro-2-p-methoxy-phenyl carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(3-ethoxyl phenenyl carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(4-methoxyl group-2-aminomethyl phenyl carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(3-fluoro-4-p-methoxy-phenyl carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(2-thiophene-2-ylmethoxy phenylcarbonyl group amino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(3-thiophene-2-ylmethoxy phenylcarbonyl group amino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(biphenyl-2-base carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(1H-indoles-5-base carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(1H-indol-3-yl carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(quinoline-3-base carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(quinoline-8-base carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(1H-indazole-3-base carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(1H-benzotriazole-5-base carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(isoquinolyl-1 carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(isoquinoline 99.9-3-base carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(quinoxaline-2-base carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(naphthalene-1-base carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(quinoline-2-base carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(2-pyrroles-1-base phenylcarbonyl group amino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(4-fluoronaphthalene-1-base carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(1H-benzoglyoxaline-5-base carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(1-skatole-3-base carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(4-methoxy quinoline-2-base carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(3-methoxynaphthalene-2-base carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(2-methoxynaphthalene-1-base carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(quinolyl-4 carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(trans-2-methyl cinnamoyl amino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(2-N, N-dimethylaminomethyl cumarone-5-base carbonylamino) oxyethyl group]-benzamide;

N-hydroxyl-4-(2-indoline-1-base carbonylamino oxyethyl group) benzamide;

N-hydroxyl-4-[2-(1,2,3,4-tetrahydroquinoline-1-base carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-{2S-[is trans-3-(5-hydroxyl benzofuran-2-yl) but-2-ene acyl amino] and butoxy } benzamide;

N-hydroxyl-4-{2S-[is trans-3-(5-(1-cyclopropyl piperidine-4-base oxygen) cumarone-2-yl) but-2-ene acyl group-amino] and butoxy } benzamide;

N-hydroxyl-4-[2S-(cumarone-2-base carbonylamino)-4-phenyl butoxy] benzamide;

N-hydroxyl-4-{2-[5-(1-cyclopropyl piperidine-4-base oxygen) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;

N-hydroxyl-4-{2S-[5-(1-cyclopropyl piperidine-4-base oxygen) cumarone-2-base carbonylamino]-butoxy } benzamide;

N-hydroxyl-4-{2-[5-(1-cyclopropyl piperidine-4-base oxygen) cumarone-2-base carbonylamino]-the 1R-methyl ethoxy } benzamide;

N-hydroxyl-4-{2-[5-(1-(2,2, the 2-trifluoroethyl) piperidin-4-yl oxygen) cumarone-2-base carbonyl-amino]-oxyethyl group } benzamide;

N-hydroxyl-4-[2R-(cumarone-2-base carbonylamino)-3-benzyl alkylsulfonyl propoxy-] benzamide;

N-hydroxyl-4-[2R-(cumarone-2-base carbonylamino)-3-benzylthio-propoxy-] benzamide;

N-hydroxyl-4-[2-(trans-3-(5-methoxyl group benzo furans-2-yl) but-2-ene acyl group carbonylamino)-oxyethyl group] benzamide;

N-hydroxyl-4-[2-(1,2,3,4-tetrahydroisoquinoline-2-base carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(isoindoline-2-base carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(morpholine-4-base carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(4-benzyl diethylenediamine-1-base carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(3 (R)-hydroxyl pyrrolidine-1-base carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(piperidines-1-base carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(6-methyl isophthalic acid, 2,3,4-tetrahydroquinoline-1-base carbonylamino) oxyethyl group]-benzamide;

N-hydroxyl-4-[2-(2-methyl indoline-1-base carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(6-fluoro-2-methyl isophthalic acid, 2,3,4-tetrahydroquinoline-1-base carbonylamino)-oxyethyl group] benzamide;

N-hydroxyl-4-[2S-(isoindoline-1-base carbonylamino) butoxy] benzamide;

N-hydroxyl-4-[3-(trans-cinnamoyl amino) propoxy-] benzamide;

N-hydroxyl-4-[3-(trans-4-methoxyl group cinnamoyl amino) propoxy-] benzamide;

N-hydroxyl-4-[3-(4-phenyl thiazole-2-base carbonylamino) propoxy-] benzamide;

N-hydroxyl-4-[2S-(trans-cinnamoyl amino) propoxy-] benzamide;

N-hydroxyl-4-[2R-(trans-cinnamoyl amino) propoxy-] benzamide;

N-hydroxyl-4-[2S-(trans-cinnamoyl amino)-4-methyl pentyloxy] benzamide;

N-hydroxyl-4-[2S-(trans-cinnamoyl amino)-3-cyclohexyl propoxy-] benzamide;

N-hydroxyl-4-[2S-(trans-cinnamoyl amino)-3-methyl butoxy] benzamide;

N-hydroxyl-4-[2S-(trans-cinnamoyl amino)-3-phenyl propoxy-] benzamide;

N-hydroxyl-4-[2R-(trans-cinnamoyl amino)-3-phenyl propoxy-] benzamide;

N-hydroxyl-4-[2R-(trans-cinnamoyl amino)-4-methyl pentyloxy] benzamide;

N-hydroxyl-4-[2R-(trans-cinnamoyl amino)-3-methyl butoxy] benzamide;

N-hydroxyl-4-[2RS-(trans-cinnamoyl amino) hexyloxy] benzamide;

N-hydroxyl-4-[2RS-(trans-cinnamoyl amino)-3-(4-chloro-phenyl-) propoxy-] benzamide;

N-hydroxyl-4-[2S-(trans-cinnamoyl amino) butoxy] benzamide;

N-hydroxyl-4-[2R-(trans-cinnamoyl amino) butoxy] benzamide;

N-hydroxyl-4-[2S-(trans-cinnamoyl amino)-4-methylthio group butoxy] benzamide;

N-hydroxyl-4-[2R-(trans-cinnamoyl amino)-4-methylthio group butoxy] benzamide;

N-hydroxyl-4-[2S-(trans-cinnamoyl amino)-2-phenyl ethoxy] benzamide;

N-hydroxyl-4-[2R-(trans-cinnamoyl amino)-2-phenyl ethoxy] benzamide;

N-hydroxyl-4-[2S-(trans-cinnamoyl amino)-4-methyl sulphonyl butoxy] benzamide;

N-hydroxyl-4-[2R-(trans-cinnamoyl amino)-4-methyl sulphonyl butoxy] benzamide;

N-hydroxyl-4-[2R-(trans-cinnamoyl amino)-3-benzyl alkylsulfonyl propoxy-] benzamide;

N-hydroxyl-4-[2S-(thiophene-2-base carbonylamino) butoxy] benzamide;

N-hydroxyl-4-[2S-(biphenyl-4-base carbonylamino) butoxy] benzamide;

N-hydroxyl-4-[2S-(naphthalene-2-base carbonylamino) butoxy] benzamide;

N-hydroxyl-4-[2R-(trans-cinnamoyl amino)-3-benzylthio-propoxy-] benzamide;

N-hydroxyl-4-[2S-(phenylcarbamoyl amino) butoxy] benzamide;

N-hydroxyl-4-[2S-(benzyloxycarbonyl group amino) butoxy] benzamide;

N-hydroxyl-4-[2S-(2-phenylethyl carbonylamino) butoxy] benzamide;

N-hydroxyl-4-[2S-(trans-cinnamoyl amino)-3-hydroxyl propoxy-] benzamide;

N-hydroxyl-4-[2S-(4-phenyl thiazole-2-base carbonylamino) butoxy] benzamide;

N-hydroxyl-4-[2S-(trans-4-methoxyl group cinnamoyl amino) butoxy] benzamide;

N-hydroxyl-4-[2S-(2-N, N-dimethylaminomethyl cumarone-5-base carbonylamino) butoxy]-benzamide;

N-hydroxyl-4-[2-(trans-cinnamoyl amino)-1R-methyl ethoxy] benzamide;

N-hydroxyl-4-[2-(trans-cinnamoyl amino)-1S-methyl ethoxy] benzamide;

N-hydroxyl-4-[2-(4-phenyl thiazole-2-base carbonylamino)-1R-methyl ethoxy] benzamide;

N-hydroxyl-4-[2-(4-phenyl thiazole-2-base carbonylamino)-1S-methyl ethoxy] benzamide;

N-hydroxyl-4-[2-(biphenyl-4-base carbonylamino)-1R-methyl ethoxy] benzamide;

N-hydroxyl-4-[2-(trans-4-methoxyl group cinnamoyl amino)-1R-methyl ethoxy] benzamide;

N-hydroxyl-4-{2-[4-(2-pyridine-2-base thiazole-5-yl) phenylcarbonyl group amino] oxyethyl group } benzamide;

N-hydroxyl-4-[2-(7-chloro-4-methyl cumarone-2-base carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-{2-[4-(2-(4-methylpiperazine-1-yl) thiazole-5-yl) phenylcarbonyl group amino]-oxyethyl group } benzamide;

N-hydroxyl-4-{2-[4-(2-pyridin-4-yl aminothiazole-5-yl) phenylcarbonyl group amino] oxyethyl group }-benzamide;

N-hydroxyl-4-{2-[4-(4-methylpiperazine-1-yl) phenylcarbonyl group amino] oxyethyl group } benzamide;

N-hydroxyl-4-{2-[4-(4-hydroxy piperidine-1-yl) phenylcarbonyl group amino] oxyethyl group } benzamide;

N-hydroxyl-4-{2-[4-(4-morpholine-4-ylmethyl thiazole-5-yl) phenylcarbonyl group amino] oxyethyl group }-benzamide;

N-hydroxyl-4-[2-(7-fluoro-4-methyl cumarone-2-base carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-{2-[7-fluoro-4-(2-methoxy ethoxy methyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;

N-hydroxyl-4-[2-(4-hydroxyquinoline-2-base carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(7-fluoro-4-phenoxymethyl cumarone-2-base carbonylamino) oxyethyl group]-benzamide;

N-hydroxyl-4-{2-[4-(2-(4-methylpiperazine-1-ylmethyl) thiazol-2-yl) phenylcarbonyl group-amino]-oxyethyl group } benzamide;

N-hydroxyl-4-[2-(pyridine-2-base carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(3-pyridone-2-base carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(6-pyridone-2-base carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-{2-[6-(4-nitrophenoxy) pyridine-2-base carbonylamino] oxyethyl group } benzamide;

N-hydroxyl-4-{2-[4-(2-methoxy ethoxy) quinoline-2-base carbonylamino] oxyethyl group } benzamide;

N-hydroxyl-4-{2-[4-(2-N, N-dimethylamino ethoxy) quinoline-2-base carbonylamino] oxyethyl group }-benzamide;

N-hydroxyl-4-[2-(6-bromopyridine-2-base carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(5-bromopyridine-3-base carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2S-(4-methoxy quinoline-2-base carbonylamino) butoxy] benzamide;

N-hydroxyl-4-[2-(1-methoxynaphthalene-2-base carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(4-methoxy quinoline-2-base carbonylamino)-1R-methyl ethoxy] benzamide;

N-hydroxyl-4-[2-(5-phenylpyridine-3-base carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(6-benzyloxy pyridine-2-base carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-{2-[6-(2-methyl propoxy-) pyridine-2-base carbonylamino] oxyethyl group } benzamide;

N-hydroxyl-4-{2-[6-(2-phenyl ethoxy) pyridine-2-base carbonylamino] oxyethyl group } benzamide;

N-hydroxyl-4-{2-[4-(3,3,3-trifluoro propoxy-) quinoline-2-base carbonylamino] oxyethyl group }-benzamide;

N-hydroxyl-4-{2S-[4-(3,3,3-trifluoro propoxy-) quinoline-2-base carbonylamino] butoxy }-benzamide;

N-hydroxyl-4-{2-[4-(3,3,3-trifluoro propoxy-) quinoline-2-base carbonylamino]-the 1R-methyl ethoxy } benzamide;

N-hydroxyl-4-[2-(trans-3-hydroxyl cinnamoyl amino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(trans-4-hydroxyl cinnamoyl amino) oxyethyl group] benzamide;

N-hydroxyl-4-{2-[3 '-(2-hydroxyethyl) biphenyl-4-base carbonylamino] oxyethyl group } benzamide;

N-hydroxyl-4-{2-[3 '-(2-hydroxyethyl) biphenyl-3-base carbonylamino] oxyethyl group } benzamide;

N-hydroxyl-4-{2-[2 '-(2-hydroxyethyl) biphenyl-4-base carbonylamino] oxyethyl group } benzamide;

N-hydroxyl-4-[2-(trans-the 2-cumarone-2-base acryl amino) oxyethyl group] benzamide;

N-hydroxyl-4-{2-[2 '-(2-hydroxyethyl) biphenyl-3-base carbonylamino] oxyethyl group } benzamide;

N-hydroxyl-4-{2-[5-(thiene-3-yl-) pyridin-3-yl carbonylamino] oxyethyl group) benzamide;

N-hydroxyl-4-{2-[6-(4-acetylamino phenoxy group) pyridine-2-base carbonylamino] oxyethyl group }-benzamide;

N-hydroxyl-4-{2-[6-(4-amino-benzene oxygen) pyridine-2-base carbonylamino] oxyethyl group } benzamide;

N-hydroxyl-4-[2-(trans-2-methoxyl group cinnamoyl amino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(trans-3-methoxyl group cinnamoyl amino) oxyethyl group] benzamide;

N-hydroxyl-4-{2-[5-(4-dimethylaminophenyl) pyridin-3-yl carbonylamino] oxyethyl group }-benzamide;

N-hydroxyl-4-{2-[is trans-3-(5-bromothiophene-2-yl) acryl amino] and oxyethyl group } benzamide;

N-hydroxyl-4-[2-(trans-the 3-furans-3-base acryl amino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(trans-3-thiene-3-yl-acryl amino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(trans-thiophene-2-base acryl amino) oxyethyl group] benzamide;

N-hydroxyl-4-{2-[is trans-3-methyl cinnamoyl amino] and oxyethyl group } benzamide;

N-hydroxyl-4-{2-[is trans-4-methyl cinnamoyl amino] and oxyethyl group } benzamide;

N-hydroxyl-4-{2-[is trans-3-(cumarone-2-yl) but-2-ene acyl amino] and oxyethyl group } benzamide;

N-hydroxyl-4-{2-[cis-3-(cumarone-2-yl) but-2-ene acyl amino] oxyethyl group } benzamide;

N-hydroxyl-4-[2-(trans-4-dimethylamino cinnamoyl amino) oxyethyl group] benzamide;

N-hydroxyl-4-[2-(trans-3-indol-3-yl acryl amino) oxyethyl group] benzamide;

N-hydroxyl-4-{2-[is trans-2-methyl cinnamoyl amino] and oxyethyl group } benzamide;

N-hydroxyl-4-[2-(trans-2-hydroxyl cinnamoyl amino) oxyethyl group] benzamide;

N-hydroxyl-4-{2-[is trans-3-(7-methoxyl group benzo furans-2-yl) acryl amino] and oxyethyl group } benzamide;

N-hydroxyl-4-{2R-[is trans-3-(7-methoxyl group benzo furans-2-yl) acryl amino] and butoxy } benzamide;

N-hydroxyl-4-{2S-[is trans-3-(5-methoxyl group benzo furans-2-yl) but-2-ene acyl amino] and butoxy } benzamide;

N-hydroxyl-4-[2-(trans-the 3-furans-2-base acryl amino) oxyethyl group] benzamide;

N-hydroxyl-4-{2-[4-(4-(2-morpholine-4-base ethyl) thiazol-2-yl) phenylcarbonyl group amino] oxyethyl group }-benzamide;

N-hydroxyl-4-(2-N-trans-cinnamoyl-N-hydroxyethyl amino ethoxy) benzamide;

N-hydroxyl-4-(2-N-trans-cinnamoyl-N-phenyl amino oxyethyl group) benzamide;

N-hydroxyl-4-(2-N-trans-cinnamoyl-N-methyl amino ethoxy) benzamide;

N-hydroxyl-4-(2-N-thionaphthene-2-base-N-sec.-propyl amino ethoxy) benzamide;

N-hydroxyl-4-(2-N-trans-cinnamoyl-N-sec.-propyl amino ethoxy) benzamide;

N-hydroxyl-4-(3-N-trans-cinnamoyl-N-methylamino propoxy-) benzamide;

N-hydroxyl-4-[2-(thionaphthene-2-base carbonylamino) oxyethyl group]-benzamide;

N-hydroxyl-4-[2-(cumarone-2-base carbonylamino) oxyethyl group]-benzamide;

N-hydroxyl-4-[2-(1H-indoles-2-base carbonylamino) oxyethyl group]-benzamide;

N-hydroxyl-4-[2-(1-skatole-2-base carbonylamino) oxyethyl group]-benzamide;

N-hydroxyl-4-[3-(thionaphthene-2-base carbonylamino) propoxy-]-benzamide;

N-hydroxyl-4-[3-(cumarone-2-base carbonylamino) propoxy-]-benzamide;

N-hydroxyl-4-[2S-(thionaphthene-2-base carbonylamino)-3-methyl butoxy]-benzamide;

N-hydroxyl-4-[2S-(thionaphthene-2-base carbonylamino) butoxy]-benzamide;

N-hydroxyl-4-[2S-(thionaphthene-2-base carbonylamino)-propoxy-]-benzamide;

N-hydroxyl-4-[2R-(thionaphthene-2-base carbonylamino)-propoxy-]-benzamide;

N-hydroxyl-4-[2S-(cumarone-2-base carbonylamino) butoxy]-benzamide;

N-hydroxyl-4-[2-(thionaphthene-2-base carbonylamino)-1R-methyl ethoxy]-benzamide;

N-hydroxyl-4-[2-(thionaphthene-2-base carbonylamino)-1S-methyl ethoxy]-benzamide;

N-hydroxyl-4-[2-(cumarone-2-base carbonylamino)-1R-methyl ethoxy]-benzamide;

N-hydroxyl-4-[2-(6-anisole thiophthene-2-base carbonylamino) oxyethyl group]-benzamide;

N-hydroxyl-4-[2-(5-methylbenzene thiophthene-2-base carbonylamino) oxyethyl group]-benzamide;

N-hydroxyl-4-[2-(3-chloro thiophene-2-base carbonylamino) oxyethyl group]-benzamide;

N-hydroxyl-4-[2-(5-methyl cumarone-2-base carbonylamino) oxyethyl group]-benzamide;

N-hydroxyl-4-[2-(6-methyl cumarone-2-base carbonylamino) oxyethyl group]-benzamide;

N-hydroxyl-4-[2-(4-trifluoromethyl thionaphthene-2-base carbonylamino) oxyethyl group]-benzamide;

N-hydroxyl-4-[2-(5-fluorobenzene thiophthene-2-base carbonylamino) oxyethyl group]-benzamide;

N-hydroxyl-4-[2-(5-anisole thiophthene-2-base carbonylamino) oxyethyl group]-benzamide;

N-hydroxyl-4-[2-(5-chlorobenzene and furans-2-base carbonylamino) oxyethyl group]-benzamide;

N-hydroxyl-4-[2-(7-methoxyl group benzo furans-2-base carbonylamino) oxyethyl group]-benzamide;

N-hydroxyl-4-[2-(5-methoxyl group benzo furans-2-base carbonylamino) oxyethyl group]-benzamide;

N-hydroxyl-4-{2-[5-(2-methoxy ethoxy) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;

N-hydroxyl-4-{2-[5-(2-morpholine-4-base oxethyl) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;

N-hydroxyl-4-{2-[5-(pyridin-3-yl methoxyl group) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;

N-hydroxyl-4-[2-(3-methyl cumarone-2-base carbonylamino) oxyethyl group]-benzamide;

N-hydroxyl-4-[2-(3-methylbenzene thiophthene-2-base carbonylamino) oxyethyl group]-benzamide;

N-hydroxyl-4-{2-[5-(2-hydroxyl-oxethyl) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;

N-hydroxyl-4-{2-[5-(2-N, N-dimethylamino ethoxy) cumarone-2-base carbonylamino]-oxyethyl group }-benzamide;

N-hydroxyl-4-{2-[6-(2-methoxy ethoxy) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;

N-hydroxyl-4-{2-[6-(2-morpholine-4-base oxethyl) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;

N-hydroxyl-4-{2-[6-(pyridin-3-yl methoxyl group) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;

N-hydroxyl-4-[2-(3-ethyl benzofuran-2-base carbonylamino) oxyethyl group]-benzamide;

N-hydroxyl-4-[2-(5-fluoro indole-2-base carbonylamino) oxyethyl group]-benzamide;

N-hydroxyl-4-[2-(5-methoxyl group indoles-2-base carbonylamino) oxyethyl group]-benzamide;

N-hydroxyl-4-{2-[3-(methoxymethyl) cumarone-2-base carbonylamino] oxyethyl group } benzamide;

N-hydroxyl-4-{2-[3-(phenoxymethyl) cumarone-2-base carbonylamino] oxyethyl group } benzamide;

N-hydroxyl-4-[2-(5,6-dimethoxy indoles-2-base carbonylamino) oxyethyl group]-benzamide;

N-hydroxyl-4-{2-[3-(morpholine-4-ylmethyl) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;

N-hydroxyl-4-{2-[3-(N, N-dimethylaminomethyl) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;

N-hydroxyl-4-{2-[3-(isopropoxy methyl) cumarone-2-base carbonylamino] oxyethyl group } benzamide;

N-hydroxyl-4-{2-[7-(phenoxymethyl) cumarone-2-base carbonylamino] oxyethyl group } benzamide;

N-hydroxyl-4-{2-[7-(methoxymethyl) cumarone-2-base carbonylamino] oxyethyl group } benzamide;

N-hydroxyl-4-{2-[7-(morpholine-4-ylmethyl) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;

N-hydroxyl-4-{2-[7-(N, N-dimethylaminomethyl) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;

N-hydroxyl-4-{3-[5-(methyl) thionaphthene-2-base carbonylamino] propoxy-}-benzamide;

N-hydroxyl-4-{3-[6-(methoxyl group) thionaphthene-2-base carbonylamino] propoxy-}-benzamide;

N-hydroxyl-4-{3-[7-(methoxymethyl) cumarone-2-base carbonylamino] propoxy-}-benzamide;

N-hydroxyl-4-{3-[7-(phenoxymethyl) cumarone-2-base carbonylamino] propoxy-}-benzamide;

N-hydroxyl-4-{2-[5-(2-methoxy ethoxy) cumarone-2-base carbonylamino]-the 1R-methyl ethoxy } benzamide;

N-hydroxyl-4-(2R-cumarone-2-base carbonylamino-3-methylthio group propoxy-) benzamide;

N-hydroxyl-4-(2R-cumarone-2-base carbonylamino-3-methyl sulphonyl propoxy-) benzamide;

N-hydroxyl-4-{2-[3-(2-phenylethyl) cumarone-2-base carbonylamino] oxyethyl group } benzamide;

N-hydroxyl-4-{2-[3-(N-methyl-N-benzylamino-methyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;

N-hydroxyl-4-{2-[3-(N-methyl-N-2-phenylethyl amino methyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;

N-hydroxyl-4-{2-[3-(3-hydroxyl rosickyite ylmethyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;

N-hydroxyl-4-{2-[3-(3-hydroxypropyl sulfinyl methyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;

N-hydroxyl-4-{2-[3-(3-hydroxypropyl alkylsulfonyl methyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;

N-hydroxyl-4-{2-[3-(N-methyl-N-2-indol-3-yl ethylamino methyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;

N-hydroxyl-4-{2-[3-(2-(3-trifluoromethyl) ethyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;

N-hydroxyl-4-{2-[3-(2-(3-Trifluoromethoxyphen-l) ethyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;

N-hydroxyl-4-{2-[3-(N-hydroxyl amino carbonyl methylamino methyl) cumarone-2-base carbonylamino] oxyethyl group } benzamide;

N-hydroxyl-4-{2-[3-(2-carboxy ethyl amino methyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;

N-hydroxyl-4-[2-(cumarone-2-base carbonylamino)-1RS-phenoxymethyl oxyethyl group]-benzamide;

N-hydroxyl-4-{2-[3-(3-hydroxyl propoxy-methyl) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;

N-hydroxyl-4-{2-[3-(2-fluorophenoxy methyl) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;

N-hydroxyl-4-{2-[3-(3-fluorophenoxy methyl) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;

N-hydroxyl-4-{2-[3-(4-fluorophenoxy methyl) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;

N-hydroxyl-4-{2-[3-(2-methoxy ethoxy methyl) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;

N-hydroxyl-4-{2-[3-(pyridin-4-yl oxygen methyl) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;

N-hydroxyl-4-{2-[3-(2,4,6-trifluoromethoxy phenoxy ylmethyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;

N-hydroxyl-4-{2-[3-(2-oxo pyridine-1-ylmethyl) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;

N-hydroxyl-4-{2-[3-(2,2,2-trifluoro ethoxy methyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;

N-hydroxyl-4-{2-[3-(4-imidazoles-1-phenoxyl methyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;

N-hydroxyl-4-{2-[3-(4-[1.2.4]-triazine-1-phenoxyl methyl) cumarone-2-base carbonyl-amino] oxyethyl group } benzamide;

N-hydroxyl-4-{2-[3-(tetramethyleneimine-1-methyl) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;

N-hydroxyl-4-{2-[3-(piperidines-1-methyl) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;

N-hydroxyl-4-{2-[3-(4-trifluoromethyl piperidines-1-methyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;

N-hydroxyl-4-{2-[3-(4-methylpiperazine-1-methyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;

N-hydroxyl-4-{2-[3-(3,3,3-trifluoropropyl oxygen ylmethyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;

N-hydroxyl-4-[2-(4-methyl cumarone-2-base carbonylamino)-oxyethyl group] benzamide;

N-hydroxyl-4-{2-[3-(4-fluorobenzene sulfenyl methyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;

N-hydroxyl-4-{2-[3-(4-fluorophenyl sulfinyl methyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;

N-hydroxyl-4-{2-[3-(4-fluorophenyl alkylsulfonyl methyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;

N-hydroxyl-4-{2S-[3-(2,2,2-trifluoro ethoxy methyl) cumarone-2-base carbonylamino]-butoxy } benzamide;

N-hydroxyl-4-[2-(4-hydroxyl benzofuran-2-base carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-[2S-(5-chlorobenzene and furans-2-base carbonylamino) butoxy] benzamide;

N-hydroxyl-4-[2-(5-chlorobenzene and furans-2-base carbonylamino)-1R-methyl ethoxy] benzamide;

N-hydroxyl-4-[2-(4-pyridin-3-yl methoxymethyl cumarone-2-base carbonylamino)-oxyethyl group] benzamide;

N-hydroxyl-4-[2-(4-methoxyl group benzo furans-2-base carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-{2-[4-(2-methoxy ethoxy) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;

N-hydroxyl-4-[2-(4-pyridin-3-yl methoxyl group benzo furans-2-base carbonylamino)-oxyethyl group] benzamide;

N-hydroxyl-4-[2-(4-methoxyl group indoles-2-base carbonylamino) oxyethyl group] benzamide;

N-hydroxyl-4-{2S-[3-(2-methoxy ethoxy methyl) cumarone-2-base carbonylamino]-butoxy } benzamide;

N-hydroxyl-4-{2-[3-(2-methoxy ethoxy methyl) cumarone-2-base carbonylamino]-the 1R-methyl ethoxy } benzamide;

N-hydroxyl-4-{2-[3-(N, N-diethylamino methyl) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;

N-hydroxyl-4-{2S-[5-(2-methoxy ethoxy) cumarone-2-base carbonylamino] butoxy }-benzamide;

N-hydroxyl-4-{2-[5-(tetrahydropyran-4-base oxygen) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;

N-hydroxyl-4-{2S-[5-(tetrahydropyran-4-base oxygen) cumarone-2-base carbonylamino] butoxy }-benzamide;

N-hydroxyl-4-{2-[5-(tetrahydropyran-4-base oxygen) cumarone-2-base carbonylamino]-the 1R-methyl ethoxy } benzamide;

N-hydroxyl-4-{2-[5-(2,2, the 2-trifluoro ethoxy) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;

N-hydroxyl-4-{2-[5-(2-tetramethyleneimine-1-base oxethyl) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;

N-hydroxyl-4-{2S-[5-(2-tetramethyleneimine-1-base oxethyl) cumarone-2-base carbonylamino] butoxy }-benzamide;

N-hydroxyl-4-{2-[5-(2-tetramethyleneimine-1-base oxethyl) cumarone-2-base carbonylamino]-the 1R-methyl ethoxy } benzamide;

N-hydroxyl-4-{2-[5-(piperidin-4-yl oxygen) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;

N-hydroxyl-4-[2S-(cumarone-2-base carbonylamino)-4-methylthio group butoxy] benzamide;

N-hydroxyl-4-[2S-(cumarone-2-base carbonylamino)-4-methyl sulphonyl butoxy] benzamide;

N-hydroxyl-3-[2-(biphenyl-4-base carbonylamino)-1R-methyl ethoxy] isoxzzole-5-yl-carboxamides;

N-hydroxyl-3-[2S-(biphenyl-4-base carbonylamino) butoxy] isoxzzole-5-yl-carboxamides;

N-hydroxyl-3-[2-(cumarone-2-base carbonylamino) oxyethyl group] isoxzzole-5-yl-carboxamides;

N-hydroxyl-3-[2-(trans-cinnamoyl amino) oxyethyl group] isoxzzole-5-yl-carboxamides;

N-hydroxyl-3-[3-(4-(2-ethoxyl phenenyl) phenylcarbonyl group amino) propoxy-] isoxzzole-5-yl-carboxamides;

N-hydroxyl-3-[3-(biphenyl-3-base carbonylamino) propoxy-] isoxzzole-5-yl-carboxamides;

N-hydroxyl-3-[3-(biphenyl-4-base carbonylamino) propoxy-] isoxzzole-5-yl-carboxamides;

N-hydroxyl-3-[2-(naphthalene-2-base carbonylamino) oxyethyl group] isoxzzole-5-yl-carboxamides;

N-hydroxyl-3-[2-(3-methyl diphenyl-4-base carbonylamino) oxyethyl group] isoxzzole-5-yl-carboxamides;

N-hydroxyl-3-[2-(2 '-ethoxybiphenyl-4-base carbonylamino) oxyethyl group] isoxzzole-5-yl-carboxamides;

N-hydroxyl-3-[3-(3-methyl diphenyl-4-base carbonylamino) propoxy-] isoxzzole-5-yl-carboxamides;

N-hydroxyl-3-[3-(4-phenyl thiazole-2-base carbonylamino) propoxy-] isoxzzole-5-yl-carboxamides;

N-hydroxyl-3-[3-(naphthalene-2-base carbonylamino) propoxy-] isoxzzole-5-yl-carboxamides;

N-hydroxyl-3-[3-(naphthalene-1-base carbonylamino) propoxy-] isoxzzole-5-yl-carboxamides;

N-hydroxyl-3-(3-[2-(2-phenylethyl) phenylcarbonyl group amino] propoxy-} isoxzzole-5-yl-carboxamides;

N-hydroxyl-3-[2-(naphthalene-1-base carbonylamino) oxyethyl group] isoxzzole-5-yl-carboxamides;

N-hydroxyl-3-[2S-(cumarone-2-base carbonylamino) butoxy] isoxzzole-5-yl-carboxamides;

N-hydroxyl-3-[2S-(biphenyl-3-base carbonylamino) butoxy] isoxzzole-5-yl-carboxamides;

N-hydroxyl-3-[2-(cumarone-2-base carbonylamino)-1R-methyl ethoxy] isoxzzole-5-yl-carboxamides;

N-hydroxyl-3-[2-(biphenyl-3-base carbonylamino)-1R-methyl ethoxy] isoxzzole-5-yl-carboxamides;

N-hydroxyl-3-[2-(biphenyl-3-base carbonylamino) oxyethyl group] isoxzzole-5-yl-carboxamides;

N-hydroxyl-3-[2-(biphenyl-4-base carbonylamino) oxyethyl group] isoxzzole-5-yl-carboxamides;

N-hydroxyl-3-[2-(4-phenyl thiazole-2-base carbonylamino) oxyethyl group] isoxzzole-5-yl-carboxamides;

N-hydroxyl-3-{2-[2-(2-phenylethyl) phenylcarbonyl group amino] oxyethyl group } isoxzzole-5-yl-carboxamides;

N-hydroxyl-3-[2-(biphenyl-2-base carbonylamino) oxyethyl group] isoxzzole-5-yl-carboxamides;

N-hydroxyl-3-[3-(biphenyl-2-base carbonylamino) propoxy-] isoxzzole-5-yl-carboxamides;

N-hydroxyl-3-[2S-(naphthalene-2-base carbonylamino) butoxy] isoxzzole-5-yl-carboxamides;

N-hydroxyl-3-[2S-(naphthalene-1-base carbonylamino) butoxy] isoxzzole-5-yl-carboxamides;

N-hydroxyl-3-[2-(naphthalene-2-base carbonylamino)-1R-methyl ethoxy] isoxzzole-5-yl-carboxamides;

N-hydroxyl-3-[2-(naphthalene-1-base carbonylamino)-1R-methyl ethoxy] isoxzzole-5-yl-carboxamides;

N-hydroxyl-3-[3-(cumarone-2-base carbonylamino) propoxy-] isoxzzole-5-yl-carboxamides;

N-hydroxyl-3-[3-(trans-cinnamoyl amino) propoxy-] isoxzzole-5-yl-carboxamides; With

N-hydroxyl-3-[2-(3-phenoxymethyl cumarone-2-base carbonylamino) oxyethyl group] isoxzzole-5-yl-carboxamides.

24. compound or pharmaceutically acceptable salt thereof with following structure:

25. compound or pharmaceutically acceptable salt thereof with following structure:

26. compound or pharmaceutically acceptable salt thereof with following structure:

27. compound or pharmaceutically acceptable salt thereof with following structure:

28. compound or pharmaceutically acceptable salt thereof with following structure:

29. a pharmaceutical composition comprises among the claim 1-28 that treats significant quantity each compound or pharmaceutically acceptable salt thereof and pharmaceutically acceptable vehicle.

30. a pharmaceutical composition comprises the compound or pharmaceutically acceptable salt thereof and the pharmaceutically acceptable vehicle of the claim 24 for the treatment of significant quantity.

31. a pharmaceutical composition comprises the compound or pharmaceutically acceptable salt thereof and the pharmaceutically acceptable vehicle of the claim 25 for the treatment of significant quantity.

32. a pharmaceutical composition comprises the compound or pharmaceutically acceptable salt thereof and the pharmaceutically acceptable vehicle of the claim 26 for the treatment of significant quantity.

33. the application in the medicine of the disease that each compound is mediated by HDAC in preparation is used for the treatment of animal among the claim 1-28.

34. method as claimed in claim 33, wherein said disease are cancer, described animal is behaved.

35. method as claimed in claim 34, wherein said cancer are AML or MML.

36. the application among the claim 1-28 in the medicine of each compound cancer in preparation is used for the treatment of animal, it is independently selected from following compound in conjunction with one or more: estrogenic agents, androgen receptor modifier, retinoid receptor conditioning agent, cytotoxic agent, another kind of antiproliferative, prenyl-protein transferase inhibitor, HMG-CoA reductase inhibitor, hiv protease inhibitor, reverse transcriptase inhibitors, dnmt rna inhibitor or angiogenesis inhibitor.

37. the application among the claim 1-28 in the medicine of each compound cancer in preparation is used for the treatment of animal, it is in conjunction with radiotherapy, and randomly exists one or more to be independently selected from following compound: estrogenic agents, androgen receptor modifier, retinoid receptor conditioning agent, cytotoxic agent, another kind of antiproliferative, prenyl-protein transferase inhibitor, HMG-CoA reductase inhibitor, hiv protease inhibitor, reverse transcriptase inhibitors, dnmt rna inhibitor or angiogenesis inhibitor.

38. intermediate or its salt with following formula (II):

Wherein:

R ⁵⁰Be hydrogen or alkyl,

X is-O-,-NR ²-or-S (O) _n-, wherein n is 0-2, R ²Be hydrogen or alkyl;

Y is an alkylidene group, and it is randomly replaced by cycloalkyl, the optional phenyl that replaces, alkylthio, alkyl sulphinyl, alkyl sulphonyl, the optional octadecyloxy phenyl sulfenyl that replaces, the optional phenylalkyl alkylsulfonyl that replaces, hydroxyl or the optional phenoxy group that replaces;

Ar ¹Be phenylene or heteroarylidene, wherein said Ar ¹Randomly replaced by one or two group, described group is independently selected from: alkyl, halogen, hydroxyl, alkoxyl group, halogenated alkoxy or haloalkyl;

R ³Be hydrogen, alkyl, hydroxyalkyl or the optional phenyl that replaces; With

Ar ²Be aryl, aralkyl, arylalkenyl, heteroaryl, heteroaralkyl, impure aromatic ene base, cycloalkyl, cycloalkylalkyl, Heterocyclylalkyl or Heterocyclylalkyl alkyl.

39. the application among the claim 1-28 in the medicine of each compound hepatitis C in preparation is used for the treatment of animal.

40. the application in the medicine of the compound of claim 39 hepatitis C in preparation is used for the treatment of animal.

41. the method for a preparation formula (I) compound comprises:

(i) make formula (III) compound:

R wherein ⁵¹Be hydroxyl, alkoxyl group, halogen or succinimide ester, with formula NH ₂OR " azanol reaction, wherein R " is hydrogen, alkyl or oxygen protecting group; Or

(ii) use acid treatment formula (IV) compound:

M wherein ⁺Be basic metal; Use NH then ₂" handle, wherein R " is hydrogen, alkyl or oxygen protecting group to OR;

Obtain the formula V compound;

" base obtains formula (I) compound, wherein R (iii) randomly to remove the R in the compound (V) ¹Be hydrogen;

The acid salt of the product that (iv) randomly is formed on above-mentioned steps (i), forms in (ii) or (iii);

(the free alkali of the product that v) randomly be formed on above-mentioned steps (i), forms in (ii), (iii) or (iv); Or

(vi) randomly modification in above-mentioned steps (i), (ii), (iii), (iv) or (X, Y, R in the product that forms v) ¹, R ², R ³, Ar ¹And Ar ²In the group any one.