Patent Grant
11535598
The present invention relates generally to histone deacetylases inhibitors.
WO2008040934, WO2008068170, WO/2008/087514, WO/2009/026446, WO/2009/045440, WO/2011/011186, WO/2012/117421, WO/2012/106343, WO/2013/078544, U.S. Pat. Nos. 8,431,538; 8,188,138; 8,058,273 and 7,803,800 disclose histone deacetylases (HDACs), inhibitors having antitumor activities and antineurondegenerative activities.
In one aspect, the invention relates to a compound of Formula I
or a pharmaceutically acceptable salt thereof, wherein
R is (C1-C6)alkyl, (C3-C6)alkenyl, phenyl(C3-C6)alkenyl, (C3-6)cycloalkyl, (C3-C6)cycloalkenyl(C1-C6)alky (C1-C6)alkyl(C3-C6)cycloalkyl, (C5)heterocycloalkyl, (C1-C6)alkyl(C6-C18)aryl, cyclopropyl-C6H5, (C1-C6)alkoxy(C1-C6)alkyl, halo(C1-C6)alkyl, halo(C3-C6)cycloalkyl, (C6-C18)aryl, halophenyl, halo(C1-C6)alkylphenyl, halo(C1-C6)alkyl(C6-C18)aryl(C1-C6)alkoxy, halo(C1-C6)alkylphenoxy(C1-C6)alkyl, halo(C1-C6)alkylhalophenyl, (C1-C6)alkylhalo(C1-C6)alkylphenyl, hydroxyphenyl, nitrophenyl, nitrophenyl(C1-C6)alkyl, aminophenyl(C1-C6)alkyl, N—(C1-C6)alkylamino(C6-C18)aryl(C1-C6)alkyl; (C1-C6)alkylbenzoic acid, hydroxyl(C1-C6)alkyl, hydroxyl(C3-C6)cycloalkyl(C1-C6)alkyl, hydroxy (C6-C18)aryl(C1-C6)alkyl, hydroxyl(C1-C6)alkyl(C6-C18)aryl, (C1-C6)alkoxy(C6-C18)aryl, (C6-C18)aryl(C1-C6)alkyl, (C3-C18)heteroaryl(C1-C6)alkyl, halo(C6-C18)aryl(C1-C6)alkyl, halo(C1-C6)alkoxy(C6-C18)aryl, halo(C1-C6)alkoxy (C6-C18)aryl(C1-C6)alkyl, halo(C1-C6)alkyl(C6-C18)aryl(C1-C6)alkyl, (C1-C6)akylamino(C6-C18)aryl(C1-C6)alkyl, morpholinyl(C1-C6)alkyl, morpholinyl(C1-C6)alkyl(C6-C18)aryl, morpholinyl(C1-C6)alkyl(C6-C18)aryl(C1-C6)alkyl, morpholinyl(C6-C18)aryl(C1-C6)alkyl, piperidinyl, piperidinyl(C1-C6)alkyl, N—(C1-C6)alkylpiperidinyl, N,N-di(C1-C6)alkylpiperidinyl, piperidinyl-N—(C1-C6)alkoxy(C6-C18)aryl(C1-C6)alkyl, piperidinyl(C1-C6)alkyl(C6-C18)aryl(C1-C6)alkyl, pyridine, (C1-C6)alkylpyridine, (C1-C6)alkyl imidazole, hydroxyl(C6-C18)aryl(C1-C6)alkyl, N,N-dimethyl(C6-C18)aryl(C1-C6)alkyl, (C1-C6)alkoxy(C6-C18)aryl(C1-C6)alkyl, hydroxyl(C1-C6)alkoxy(C6-C18)aryl(C1-C6)alkyl, methylenedioxyphenyl(C1-C6)alkyl, or (C6-C18)aryl(C1-C6)alkoxy;
The heterocyclic moiety
is optionally substituted with one or more Ra or Rb, or Ra and Rb, and is selected from the group consisting of
in which Ra and Rb are independently selected from the group consisting of hydrogen, halogen, (C1-C6)alky, (C6-C18)aryl, (C3-C18)heteroaryl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkoxy, aryloxy, hydroxyl, —NO2, —CN, —CF3 and —CH2CF3;
The moiety
is selected from the group consisting of
in which Rc is optionally present and is hydrogen, halogen, (C1-C6)alkyl, or (C1-C6)alkoxyl;
Y is absent or is selected from the group consisting of —CH2—, —CF2—, —CFH—, —CH═CH—, and —CH2CH2—; and
Z is —OH, —O—C(═O)—CH3, —O-Valine, —O-Valine hydrochloride salt, —O-Valine trifluoroacetic acid salt, or —O—C(═O)—CH(NH2)-CH(CH3)2 hydrochloride or trifluoroacetic acid salt.
In one embodiment, R is methyl, 2-Me-C6H4, —CH2Ph, —C6H5, —CH2CH2C6H5, (CH2)4C6H5, —CH2CH2-(4-F—C6H4), —CH2CH-(2-OMe-C6H4), —CH2CH2-(2-OH—C6H4), —CH2CH-(2-thiophene), 2-F—C6H4, 3-F—C6H4, 4-F—C6H4, 2-Cl—C6H4, 4-Cl—C6H4, —CH2CH2-(2-F—C6H4), —CH2CH2-(3-F—CH4), —CH2CH2-(4-F—C6H4), —CH2CH2-(4-Cl—C6H4), —CH2CH2OH, —CH2CH2OH—C6H5, —CH2CH2-(3-Cl-4-OMe-C6H3), —CH2CH2-(4-NHMe-C4H4), —CH2CH2-(4-morpholine-C6H4), —OCH2C6H5, 4-OH—C6H4, —CH2CH2-(4-OH—C6H4), 4-OMe-C6H4, 2-OMe-C6H4, CH2CH2-(3-OMe-C6H4), —CH2CH2-(4-OMe-C6H4), 2-NO—C6H4, cyclopropyl-C6H5, —CH2-(4-CF3—C6H4), —CH2CH-(4-CF3—C6H4), 2-F-3-CF3—C6H3, 2-F-5-CF3—C6H3, 2,4,5-tri-F—C6H2, —CH2CH2CF3, —CH2CF3, —CH2CH2OMe, 2-CF3—C6H4, —CH2-(2-CF3—C6H4), —CH2CH2-(2-CF3—C6H4), —CH2-(3-CF3—C6H4), —CH2CH2-(3-CF3—C6H4), 2,4-di-F—C6H3, —CH2CH2-(2-Br—C4H4), CH2CH2-(4-Br—C6H4), 2-t-Bu-C6H4, 2,6-di-iso-propyl-C6H3, 2-ethyl-C6H4, 2-Me-3-CF3—C6H3, —CH2CH2-(6-(1,3-benzodioxole)), —CH2CH2-(3,4-diOMe-C6H3), 2,6-di-Me-C6H3, 2-methyl-C6H4, cyclopropyl, cyclohexyl, 3-CF3—C6H4, 3,3-di-F-cyclobutyl, 2-OCF3—C6H4, 2-pyridine, 3-pyridine, 4-pyridine, —CH2CH2-(2-pyridine), —CH2CH2-(3-pyridine), —CH2CH2-(4-pyridine), CH2-(2-OCF3—C6H4), 3-piperidine, 3-(N,N-di-Me-piperidinium), 3-(N-Et-piperidine), —CH2CH2-(4-(OCH2CH2OH)—C6H4), —CH2CH2-(3,4-di-OH—C6H3), —CH2-cyclopropyl, 2-F-cyclopentyl, —CH2CH2—(N-morpholine), 4-CH—(N-morpholine)-C6Ha, CH2CH2—(O-3-CF3—C6H4), propyl-2-CHs, CH2CH2-(4-CH2—(N-morpholine)-C6H4), 4-(N-methyl-piperidine), —CH2CH2-(4-CH2—(N-piperidine)-C6H4), —CH2CH2-(4-OCH2CH—N-piperidine-C6H4), CH2CH2-(4-NO2—C6H4), —CH2CH2-(4-NH2—C6H4), —CH2CH2-(4-COOH—C6H4), (4-Cl-2,6-di-Me-C6H2), (4-Br-2,6-di-Me-C6H2), —CH2CH2—(N-imidazole), —CH2CHCH2, —CH2CH2-(cyclohexene), CH2CHCHC6H5, CH2CH2-(1,2-OH-cyclohexane), or CH2CHFC6H5.
In another embodiment, the moiety
is C6H4, 3-F—C6H2, 2-F—C6H3, C6H8, or CH2CH2-(3-CF3—C6H4).
In another embodiment, Ra and Rb are independently selected from the group consisting of H, —OH, —F, —Cl, —CF3, —CN, Me, —OMe, —OCH2CH2OMe, or cyclopropyl.
In another embodiment, R is methyl, phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 2-hydroxyphenyl, 2-methoxyphenyl, benzyl, 2-phenylethyl, 2-(4-hydroxyphenyl)ethyl, 2-(4-methoxyphenyl)ethyl, 2-(4-fluorophenyl)ethyl, 2-thiophenylethyl, 3-phenylpropyl, or 2-(4-methoxyphenyl)ethyl.
In another embodiment, R is phenyl, benzyl, 2-phenylethyl, 2-(4-hydroxyphenyl)ethyl, 3-phenylpropyl, or 2-(4-methoxyphenyl)ethyl.
In another embodiment, a compound or a pharmaceutically acceptable salt thereof according to the invention is as listed in Table 5.
In another aspect, the invention relates to use of a compound or a pharmaceutically acceptable salt thereof according to the invention in the manufacture of a medicament for the treatment of a tumor associated with deregulation of the activity of histone deacetylases in a subject in need thereof. In one embodiment, the tumor is selected from the group consisting of glioma, pancreatic carcinoma, hepatocellular carcinoma, colon tumor, breast tumor, prostate tumor, lymphoma and cutaneous tumor. The cutaneous tumor may be melanomas or basal carcinomas.
In another aspect, the invention relates to use of a compound or a pharmaceutically acceptable salt thereof according to the invention in the manufacture of a medicament for the treatment of glioma, breast cancer, colon cancer, large cell lung cancer, adenocarcinoma of the lung, small cell lung cancer, stomach cancer, liver cancer, ovary adenocarcinoma, pancreas carcinoma, prostate carcinoma, promylocytic leukemia, chronic myelocytic leukemia, or acute lymphocytic leukemia in a subject in need thereof.
In another aspect, the invention relates to use of a compound or a pharmaceutically acceptable salt thereof according to the invention in the manufacture of a medicament for treatment of a disease or a condition wherein inhibition of HDAC provides a benefit.
These and other aspects will become apparent from the following description of the preferred embodiment taken in conjunction with the following drawings, although variations and modifications therein may be affected without departing from the spirit and scope of the novel concepts of the disclosure.
The accompanying drawings illustrate one or more embodiments of the invention and, together with the written description, serve to explain the principles of the invention. Wherever possible, the same reference numbers are used throughout the drawings to refer to the same or like elements of an embodiment.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In the case of conflict, the present document, including definitions will control.
As used herein, the singular forms “a,” “an” and “the” include plural reference useless the context dearly dictates otherwise.
A dash (“-”) that is not between two letters or symbols is used to indicate a point of attachment for a moiety or substituent. For example, the moiety —CONH2 is attached through the carbon atom.
The term “amino” refers to —NH2. The amino group can be optionally substituted as defined herein for the term “substituted.”
The term “alkyl” refers to a C1-C18 hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms. Examples are methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl (iso-butyl, —CH2CH(CH3)2), 2-butyl (sec-butyl, —CH(CH3)CH2CH3), 2-methyl-2-propyl (tert-butyl, —C(CH3)3), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methy-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methy-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl.
The alkyl can be a monovalent hydrocarbon radical, as described and exemplified above, or it can be a divalent hydrocarbon radical (i.e., alkylene).
The term “alkenyl” refers to a C2-C18 hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon, sp2 double bond. Examples include, hut are not limited to: ethylene or vinyl (—CH═CH2), allyl, (—CH2CH═CH2), cyclopentenyl (—C5H7), and 5-hexenyl (—CH2CH2CH2CH2CH═CH2). The alkenyl can be a monovalent hydrocarbon radical, as described and exemplified above, or it can be a divalent hydrocarbon radical (i.e., alkenylene).
The term “alkylene” refers to a saturated, branched or straight chain or cyclic hydrocarbon radical of 1-18 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or different carbon atoms of a parent alkane. Typical alkylene radicals include, but are not limited to: methylene (—CH2—) 1,2-ethylene (—CH2CH2—), 1,3-propylene (—CH2CH2CH2—), 1,4-butylene (—CH2CH2CH2CH2—), and the like.
The term “alkoxy” refers to the group alkyl-O—, where alkyl is defined herein. Preferred alkoxy groups include, e.g., methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.
The term “aryl” refers to an unsaturated aromatic carbocyclic group of from 6 to 20 carbon atoms having a single ring (e.g., phenyl) or multiple condensed (fused) rings, wherein at least one ring is aromatic (e.g., naphtyl, dihydrophenanthrenyl, fluorenyl, or anthryl). Preferred aryls include phenyl, naphthyl and the like. The aryl can optionally be a divalent radical, thereby providing an aryl ene.
The aryl can optionally be substituted with one or more alkyl, alkenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, imino, alkylamino, acylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, acetamido, acetoxy, acetyl, benzamido, benzenesulfinyl, benzenesulfonamido, benzenesulfonyl, benzenesulfonylamino, benzoyl, benzoylamino, benzoyloxy, benzyl, benzyloxy, benzyloxycarbonyl, benzylthio, carbamoyl, carbamate, isocyanato, sulfamoyl, sulfinamoyl, sulfino, sulfoamino, thiosulfo, NRxRy and/or COORx, wherein each Rx and Ry are independently H, alkyl, alkenyl, aryl, heteroaryl, heterocycle, cycloalkyl, or hydroxy.
The terms “aryloxy” and “arylalkoxy” refer to, respectively, an aryl group bonded to an oxygen atom and an aralkyl group bonded to the oxygen atom at the alkyl moeity. Examples include but are not limited to phenoxy, naphthyloxy, and benzyloxy.
The term “carboxyl” refers to —COOH.
The term “cycloalkyl” refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, and the like.
The cycloalkyl can optionally be substituted with one or more alkyl, alkenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, imino, alkylamino, acylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, acetamido, acetoxy, acetyl, benzamido, benzenesulfinyl, benzenesulfonamido, benzenesulfonyl, benzenesulfonylamino, benzoyl, benzoylamino, benzoyloxy, benzyl, benzyloxy, benzyloxycarbonyl, benzylthio, carbamoyl, carbamate, isocyanato, sulfamoyl, sulfinamoyl, sultino, sulfo, sulfoamino, thiosulfo, NRxRy and/or COORx, wherein each Rx and Ry are independently H, alkyl, alkenyl, aryl, heteroaryl, heterocycle, cycloalkyl, or hydroxy.
As used herein, the term “halogen” or “halo” refer to fluoro, chloro, bromo, and iodo, the term “halogen” refers to fluorine, chlorine, bromine, and iodine.
As used herein, the term “heteroaryl” is defined herein as a monocycle, bicycle, or tricyclic ring system containing one, two, or three aromatic rings and containing at least one nitrogen, oxygen, or sulfur atom in an aromatic ring, and which can be unsubstituted or substituted. The heteroaryl can optionally be a divalent radical, thereby providing a heteroarylene.
Examples of heteroaryl groups include, but are not limited to, 2H-pyrrolyl, 3H-indolyl, 4H-quinolizinyl, 4H-carbazolyl, acridinyl, benzo[b]thienyl, benzothiazolyl, β-carbolinyl, carbazolyl, chromenyl, cinnaolinyl, dibenzo[b,d]furanyl, furazanyl, furyl, imidazolyl, imidizolyl, indazolyl, indolisinyl, indolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, naptho[2,3-b], oxazolyl, perimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, thiadiazolyl, thianthrenyl, thiazolyl, thienyl, triazolyl, and xanthenyl. In one embodiment the term “heteroaryl” denotes a monocycle aromatic ring containing five or six ring atoms containing carbon and 1, 2, 3, or 4 heteroatoms independently selected from the group non-peroxide oxygen, sulfur, and N(Z) wherein Z is absent or is H, O, alkyl, phenyl, or benzyl. In another embodiment heteroaryl denotes an ortho-fused bicyclic heterocycle of about eight to ten ring atoms derived therefrom, particularly a benz-derivative or one derived by fusing a propylene, or tetramethylene diradical thereto.
The heteroaryl can optionally be substituted with one or more alkyl, alkenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, imino, alkylamino, acylamino, nitro, trifluoromethyl, trifluoromethoxy carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, acetamido, acetoxy, acetyl, benzamido, benzenesulfinyl, benzenesulfonamido, benzenesulfonyl, benzenesulfonylamino, benzoyl, benzoylamino, benzoyloxy, benzyl, benzyloxy, benzyloxycarbonyl, benzylthio, carbamoyl, carbamate, isocyannato, sulfamoyl, sulfinamoyl, sulfino, sulfo, sulfoamino, thiosulfo, NRxRy and/or COORx, wherein each Rx and Ry are independently H, alkyl, alkenyl, aryl, heteroaryl, heterocycle, cycloalkyl, or hydroxy.
The term “oxo” refers to ═O.
The term “substituted” is intended to indicate that one or more hydrogens on the atom indicated in the expression using “substituted” is replaced with a selection from the indicated group(s), provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a stable compound. Suitable indicated groups include, e.g., alkyl, alkenyl, alkylidenyl, alkenylidenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, acyloxy, alkoxycarbonyl, amino, imino, alkylamino, acylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, acetamido, acetoxy, acetyl, benzamido, benzenesulfinyl, benzenesulfonamido, benzenesulfonyl, benzenesulfonylamino, benzoyl, benzoylamino-benzoyloxy, benzyl, benzyloxy, benzyloxycarbonyl, benzylthio, carbamoyl, carbamate, isocyanato, sulfamoyl, sulfinamoyl, sulfino, sulfo, sulfoamino, thiosulfo, NRxRy and/or COORx, wherein each Rx and Ry are independently H, alkyl, alkenyl, aryl, heteroaryl, heterocycle, cycloalkyl, or hydroxy. When a substituent is oxo(i.e., ═O) or thioxo (i.e., ═S) group, then two hydrogens on the atom are replaced.
The term “(Cm-Cn)”, wherein m, n are integers, and n>m, means that all integer unit amounts within the range m to n are specifically disclosed as part of the invention. Thus, by “(Cm-Cn)”, it means that Cm, Cm+1, Cm+2, . . . , Cn-2, Cn-1, Cn, (Cm-Cm+1), (Cm-Cm+2), (Cm-Cm+3), . . . , (Cm-Cn-2), (Cm-Cn-1), (Cm-Cn); (Cm+1-Cm+2), (Cm+1-Cm+3), (Cm+1-Cm+4), . . . , (Cm+1-Cn-2), (Cm+1-Cn-1), (Cm+1-Cn), . . . , (Cn-2-Cn-1), (Cn-2-Cn); and (Cn-1-Cn) are included as embodiments of this invention.
By “(C1-C6)”, it means that all integer unit amounts within the range 1 to 6 are specifically disclosed as part of the invention. Thus, C1, C2, C3, C4, C5, C6, (C1-C2), (C1-C3), (C1-C4), (C1-C5), (C1-C6); (C2-C3), (C2-C4), (C2-C5), (C2-C6); (C3-C4), (C3-C5), (C3-C6); (C4-C5), (C4-C6); and (C5-C6) units amounts are included as embodiments of this invention.
By “(C3-C6)”, means that all integer unit amounts within the range 3 to 6 are specifically disclosed as part of the invention. Thus, C3, C4, C5, C6; (C3-C4), (C3-C5), (C3-C6); (C4-C5), (C4-C6); and (C5-C6) units amounts are included as embodiments of this invention.
By “(C3-C18)”, it means that all integer unit amounts within the range 3 to 18 are specifically disclosed as part of the invention. Thus, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12 . . . . C16, C17, C18; (C3-C4), (C3-C5), (C3-C6), (C3-C7), (C3-C8), (C3-C9) . . . (C3-C18); (C4-C5), (C4-C6), (C4-C7), (C4-C8), (C4-C9) . . . (C4-C18); (C5-C6), (C5-C7), (C5-C8), (C5-C9); (C5-C10), (C5-C11), (C5-C12) . . . (C5-C18); (C6-C7), (C6-C8), (C6-C9) . . . (C6-C18); (C7-C8), (C6-C9), (C6-C10) . . . (C6-C18); . . . (C16-C17), (C16-C18) and (C17-C18) units amounts are included as embodiments of this invention.
By “(C6-C18)”, it means that all integer unit amounts within the range 6 to 18 are specifically disclosed as part of the invention. Thus, C6, C7, C8, C9, C10, C11, C12 . . . C16, C17, C18; (C6-C7), (C6-C8), (C6-C9), (C6-C10), (C6-C11), (C6-C12) . . . (C6-C18); (C7-C8), (C7-C9), (C9-C10), (C7-C12) . . . (C7-C18); (C8-C9), (C8-C10), (C8-C11), (C8-C12); (C9-C10), (C9-C11), (C9-C12) . . . (C9-C18); (C10-C11), (C10-C12), (C10-C13) . . . (C10-C18); (C11-C12), (C11-C13), (C11-C14) . . . (C11-C18); . . . (C16-C17), (C16-C18) and (C17-C18) units amounts are included as embodiments of this invention.
Methods of Making Compounds of Formula I
Synthesis
Compounds of formula I were prepared using the following schemes:
4-fluoro anthranilic acid (10.00 g, 63.17 mmol) mixed with phenyl chloroformate (9.6 mL, 75.51 mmol) in dioxane (120 mL) was added dropwise with 1 N NaOH (126 mL) under ice bath for 1 h. The resulting solution was poured to ice water (200 mL) and filtered to get crude solid. Then the solid mixed with EDCI (13.30 g, 69.45 mmol) and HOBt (9.58 g, 69.48 mmol) in dichloromethane (150 mL) was stirred at it for 0.5 h.
Then phenethylamine (8.44 mL, 66.33 mmol) was added to reaction mixture and kept stirring for 4 h. The mixture was evaporated to dry and added with triethylamine (8.67 mL, 62.55 mmol) and DMF (50 mL), and the mixture was irradiated with microwave to reflux for 20 min. The resulting solution was poured to ice water (250 mL) to get solid formed. The solution was filtered and washed with excess of water to give tide compound as beige solid (6.80 g, three steps 37.9%).
The beige solid (2.40 g, 8.44 mmol) from previous step suspended in DMF (35 mL) under ice bath was added with NaH (0.46 g, 11.5 mmol) and kept stirring for 1 h. After 1 h, ethyl 4-(bromomethyl)benzoate (4.45 g, 17.57 mmol) was added to the reaction mixture and kept stirring for 9 h from ice bath to room temperature. Alter 9 h. the resulting mixture was poured to ice water (150 mL) and then filtered to get beige solid. The solid was purified by column chromatography eluting with EtOAc/Hexanes=¼ to get title compound as white solid (2.35 g, 62.4%).
The white solid (1.40 g, 3.14 mmol) from step 4 dissolved in mixture of THF (20 mL) and MeOH (4 mL) was added with aqueous 2.5 M LiOH (5 mL) and stirred at rt for 17 h. After 17 h, the solution was neutralized with 1 N (10 mL) and evaporated to remove most organic solvent. Then the rest solution was extracted with dichloromethane (3×30 mL). The dichloromethane solution dried over MgSO4 was evaporated to get white solid. The dried solid was mixed with EDCI (0.66 g, 3.45 mmol) and HOBt (0.47 g, 3.41 mmol) in dichloromethane (30 mL) and stirred at rt for 0.5 h. After 0.5 h, NH2OBn.HCl (0.50 g, 3.13 mmol) and tritely famine (0.48 mL 3.46 mmol) were added to reaction mixture and kept stirring tsar 12 h. After 12 h, the solution was washed with water (3×30 mL) and dried over MgSO4. Then the solution was evaporated and purified by column chromatography eluting with EtOAc/Hexanes=⅔ to get white solid (0.9 g, two steps 54.7%)
The solid (0.7 g, 1.34 mmol) from previous step mixed with palladium on charcoal, 10% (70 mg) in mixture of MeOH (24 mL) and THF (8 mL) under balloon of H2 (1 atm) was stirred at rt for 3 h. After 3 h, the solution was filtered by celite, and the filtrate was purified by column chromatography to get title compound (g, %). Rf=0.47 (MeOH/CH2Cl2= 1/19); 1H NMR (400 MHz, DMSO-d6) δ 9.01 (br s, 1H), 11.17 (br s, 1H), 8.12 (dd, J=9.2 Hz and 6.4 Hz, 1H), 7.68-7.70 (m, 2H), 7.19-7.30 (m, 7H), 7.09-7.13 (m, 2H), 5.36 (s, 2H), 4.20 (dd, J=7.6 Hz, 2H), 2.93 (dd, J=7.6 Hz, 2H), 13C NMR (100 MHz, DMSO-d6) δ 166.0 (d, J=250.0 Hz), 163.9, 160.1, 150.6, 141.6 (d, J=12.0 Hz), 139.0, 138.4, 131.8, 131.2 (d, J=11.0 Hz), 128.7, 128.4, 127.2, 126.4, 126.3, 112.0 (br s), 110.8 (d, J=23.0 Hz), 101.9 (d, J=28.0 Hz), 46.2, 42.5, 33.0; ESIMS(−), m/z 431.9 [M−1]−. Anal. Calcd for (C24H20FN3O4.1/2 H2O): C, 63.15, H, 4.78, N, 9.50. Found: C, 65.24, H, 4.68, N, 9.53.
The title compound was prepared from 4-chloroanthranilic acid (6.0 g, 20.57 mmol) by using the similar procedure described above of the step 1, step 2, and step 3 of example 1 to give white solid (5.2 g, three steps 79.6%); Rf=0.65 (EtOAc/Hexanes=1:1); 1H NMR (400 MHz, DMSO-d6) δ 7.89 (d, J=8.4 Hz, 1H), 7.16-7.30 (m, 7H), 4.06 (dd, J=8.0 Hz, 1H), 2.84 (dd, J=8.0 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ 161.0, 149.8, 140.4, 139.2, 138.5, 129.4, 128.5, 128.4, 126.1, 122.6, 114.4, 112.6, 41.3, 33.2.
The title compound was prepared from the solid (6.00 g, 19.95 mmol) of previous step by using the similar procedure described above of the step 4 of example 1 to give white solid (6.87 g, 74.4%).
The title compound was prepared from the solid (8.00 g, 17.28 mmol) of previous step by using the similar procedure described above of the step 5 and step 6 of example 1 to give white solid (9.01 g, 96.6%).
The solid (3.00 g, 5.55 mmol) from step 6 mixed with Zn(CN)2 (132 g, 11.02 mmol), Pd2(dba)3 (0.26 g, 0.27 mmol), and XPhos (0.16 g, 0.33 mmol) in DMF (60 mL) was irradiated with microwave 200 W to reflux for 20 min. The resulting solution was poured to ice water (200 mL) and filtered to get light green solid. The solid suspended dichloromethane (50 was washed with water (3×50 mL), then the organic layer was filtered, dried over MgSO4, and evaporated to give light gray solid. The solid mixed with pentamethyl benzene (5.00 g, 33.39 mmol) in dichloromethane (50 mL) under ice bath was added dropwise with BBr3 (1 Min THE) (28 mL) for 20 min and kept stirring under ice bath for 40 min. The resulting solution was quenched with 10 mL of MeOH/DCM (3:7) under ice bath and warmed to rt. The solution was evaporated to dry and purified by column chromatography to give title compound as light yellow solid (1.24 g, 50.7%). Rf=0.31 (MeOH/CH2Cl1=2:98); 1H NMR (400 MHz, DMSO-d6) δ 11.18 (br s, 1H), 9.02 (br s, 1H), 8.19 (d, 8.0 Hz, 1H), 7.78 (br s, 1H), 7.65-7.70 (m, 3H), 7.21-7.30 (m, 7H), 5.41 (s, 2H), 4.21 (dd, 7.6 Hz, 2H), 2.93 (dd, J=7.6 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ 163.9, 150.1, 150.3, 139.8, 138.9, 138.3, 131.9, 129.2, 128.7, 128.4, 127.2, 126.48, 126.42, 125.8, 118.8, 118.5, 117.7, 116.9, 46.1, 42.8, 32.9 ESIMS(−), m/z 438.9 [M−1]−.
NaH (0.63 g, 15.75 mmol) was added portionwise to 3-phenethylquinazoline-2,4(1H,3H)-dione (3.5 g, 13.14 mmol) in DMF (0.45 mL), and the solution was stirred under ice bath for 0.5 h. Then 4-iodobenzyl bromide (4.22 z, 13.79 mmol) was added to the above solution and stirred from ice bath to rt for 4 h. The resulting solution was poured to water and filtered to get title compound as white solid. (5.40 g, 85%).
Cu (0.1 g, 1.57 mmol) was added to a solution of 1-(4-iodobenzyl)-3-phenethylquinazoline-2,4(1H,3H)-dione (0.3 g, 0.62 mmol) and BrCF2CO2Et (0.08 mL, 0.61 mmol) DMSO (3.00 mL) and stirring at 60° C. for 15 h. The resulting solution was poured to ice water and filtered to get blue solid. The blue solid was purified by column doted with EtOAc/Hexanes (1:4) to get the title compound as white solid (60 mg, 20%).
NH2OH.HCl (3.0 g, 41.9 mmol) suspended in MeOH (14 mL) was added by solution of KOH (2.3 g, 41.0 mmol) dissolved in MeOH (30 mL), and the mixed solution was filtered and added dropwise for 20 mill to solution of ethyl 2,2-difluoro-2-(4-((3,4-dihydro-2,4-dioxo-3-phenethylquinazolin-1(2H)-yl)methyl)phenyl)acetate (1.0 g, 2.1 mmol) under ice bath. The reaction mixture was stirred from ice bath to rt for 11 h. The resulting solution was poured to ice water (150 mL) and filtered to get white solid. The solid was purified by column eluted by MeOH/DCM= 4/96 to get title compound as white solid (0.5 g, 51%).
1-(4-bromobenzyl)-7-fluoro-3-phenethylquinazoline-2,4(1H,3H)-dione (3.00 g, 6.62 mmol) was mixed With Herrmann's Palladacycle (0.12 g, 0.02 eq), [(t-Bu)3PH]BF4 (0.08 g, 0.04 eq), Cy2NMe 97% (1.61 mL, 1.1 eq), acrylic acid (0.45 mL, 1 eq) in DMF (20 mL) under Argon and irradiated with μW 100 W to reflux for 10 min. The resulting solution was filtered by celite and then poured into excess water (100 mL). The mixture solution was neutralized with NaHCO3(aq) to pH 3-4. The precipitation was filtered to get carboxylic acid solid. The crude solid was put to next step without further purification.
The crude carboxylic acid (2.00 g, 4.50 mmol) was mixed with EDCI (1.29 g, 1.5 eq) and HOBt (0.62 g, 1 eq) in DMF (15 mL) and stirred at rt for 30 min. Then NH2OTHP (1 eq) was added and continued stirring for 5-8 hr at rt. The resulting solution was evaporated and extracted with DCM/H2O. The mixture of DCM layer was purified by flash column chromatography (silica gel: ϕ3.5×9.5 cm; eluted by EtOAc/Hexanes=1/1) to get white solid, 1.24 g.
The solid (from step 2) (0.50 g, 0.92 mmol) and TFA (4.23 mL 60 eq) was dissolved in MeOH (25 was stirred at 50° C. for 5-8 hr. After reaction the precipitation was neutralized with NaHCO3(aq) to pH=5-6, then filtered and washed with MeOH and water to get target compound. The solid was recrystallized from DCM and MeOH to give compound 45 as orange solid 0.36 g, 43% (three steps), Rf=0.18 (MeOH/DCM=5/95); mp 179-182° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.70 (br s, 1H), 9.05 (br s, 1H), 8.11 (t, J=6.0 Hz, 1H), 7.51 (d, J=8.0 Hz, 2 Hz), 7.43 (d, J=16.0 Hz, 1H), 7.30-7.09 (m, 9H), 6.43 (d, J=16.0 Hz, 1H), 5.34 (s, 2H), 4.21 (t, J=8.0 Hz, 2H), 2.94 (t, J=6.0 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ 167.3, 164.8, 162.7, 160.1, 150.7, 141.7, 141.6, 138.4, 137.8, 137.2, 134.0, 131.3, 131.2, 128.7, 128.4, 128.3, 127.8, 127.1, 126.4, 119.1, 112.0, 110.9, 110.7, 102.1, 101.9, 46.2, 42.5, 33.1.
To neat methyl 2-aminobenzoate (91.5 mL, 700 mmol, 1.0 eq) at 0° C., 2-fluorophenyl isocyanate (88.2 mL, 1.1 eq) was added and stirred at 0° C., 5 mM, MeOH (280 mL, 2.5 M) and TEA (295.7 mL, 3.0 eq) was added and stirred under 65° C., 45 min. The slurry crude was cooled to 0° C., and filtrated. The solid was washed with EtOAc/Hexanes=1/1 (500 mL) and pentane 300 mL, and dried under vacuum to provide white fine solid product 161.2 g, 90%.
To a solution of ethyl 4-(bromomethyl)benzoate (165.1 g, 1.1 eq) in acetone (1240 mL, 0.5 M), 3-(2-fluorophenyl)quinazoline-2,4(1H,3H)-dione (158.9 g, 620 mmol, 1.0 eq), and K2CO3 (258.4 g, 3.0 eq) was added and stirred under 60° C., 1.5 h. The crude mixture was concentrated in vacuo and extracted with DCM/H2O=1.5 L/1.5 L. The organic layer was dried over MgSO4 and evaporated under vacuum till little precipitate was observed, Et3O (500 mL) and pentane (250 mL) was added and filtrated. The solid was washed with pentane and dried under vacuum to provide white fine solid product 232.4 g, 93%
To a generally mixed slurry solution of KOH (19.8 g, 2.0 eq) in NH2OH(2 M in MeOH) (750 mL, 10.0 eq), ethyl 4-((3-(2-fluorophenyl)-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)methyl)benzoate (60.7 g, 150 mmol, 1.0 eq) was added and stirred wider 30° C., 2.5 h. H2O (1.5 L) was added and extracted with EtOAc (1.5 L*4). The organic layer was dried over MgSO4, evaporated under vacuum, and re-precipitated with EtOAc/Hexanes=500 mL/1000 mL. The slurry solution was filtrated, washed with pentane and dried under vacuum to provide white solid product 25.3 g, 42%. Rf=0.39 (MeOH/DCM=10/90). mp 188.1-189.0° C. 1H NMR (400 MHz, DMSO, 25° C.) δ 11.20 (bs, 1H), 9.06 (bs, 1H), 8.11 (pseudo dd, 1H, J=7.7 Hz, J=1.3 Hz), 7.69-7.78 (m, 3H), 7.58-7.66 (m, 1H), 7.50-7.58 (m, 1H), 7.28-7.48 (m, 6H), 5.45 (pseudo dd, 2H, J=38.6 Hz, J=17.1 Hz). ESIMS(+), m/z 406 [M+H]+. HPLC 98.3%.
The following compounds were prepared according to the procedure given in abo e Examples.
Rf=0.43 (MeOH/CH2Cl2= 1/19); mp 198-200° C. (dec); 1H NMR (600 MHz, DMSO-d6) δ 11.15 (br s, 1H), 8.99 (s, 1H), 7.98 (d, J=8.4 Hz, 1H), 7.68 (d, J=8.4 Hz, 1H), 7.26-7.30 (m, 4H), 7.21-7.23 (m, 3H), 6.86 (dd, J=8.4 Hz, 2.4 Hz, 1H), 6.62 (d, J=2.4 Hz, 1H), 5.37 (s, 2H), 4.21 (dd, J=7.8 Hz, 7.2 Hz, 2H), 3.74 (s, 3H), 2.93 (dd, J=7.8 Hz, 7.2 Hz, 2H); 13C NMR (150 MHz, DMSO-d6) δ 164.4, 163.9, 160.3, 150.9, 141.1, 139.5, 138.5, 131.8, 130.1, 128.7, 128.3, 127.2, 126.4, 126.2, 109.8, 108.4, 99.5, 55.7, 45.9, 42.2, 33.1; ESIMS(−), m/z 444.0 [M−1]−. Anal. Calcd for (C25H23N3O5); C, 67.41, H, 5.20, N, 943. Found: C, 67.17, H, 5.30, N, 9.24.
4-((7-chloro-3,4-dihydro-2,4-dioxo-3-phenethylquinazolin-1(2H)-yl)methy)benzoate (3.5 g, 7.56 mmol) mixed with palladacycle ((3.142 g, 0.02 eq), XPhos ((3.294 g, 0.08 eq), and Cs2CO3 (739 g, eq) in mixture of DMF 35 mL) and H2O (3.5 mL) under Ar was irradiated with μW (200 W) to reflux for 2×30 min. The resulting mixture was evaporated to dry and suspended in EtOAc (50 mL) to washed with H2O (3×50 mL). The EtOAc solution dried over MgSO4 was filtered. The filtrate was concentrated to around 15 ml to get white solid formed. The suspension was filtered to get beige solid. The precipitation and filtration was repeated three times to get 10 as white solid (3.04 g, 90.5%). Rf=0.27 (EtOAc/Hexanes=1/1); mp 203-205° C. (dec); 1H NMR (600 MHz, DMSO-d6) δ 10.61 (br s, 1H), 7.90 (dd, J=8.4, 6.6 Hz, 3H), 7.27-7.33 (m, 4H), 7.19-7.23 (m, 3H), 6.67 (dd, J=8.4, 1.8 Hz, 1H), 6.43 (d, J=1.8 Hz, 1H), 5.33 (s, 2H), 4.29 (q, J=72 Hz, 2H), 4.19 (dd, J=7.8, 7.2 Hz, 2H), 2.92 (dd, J=7.8, 7.8 Hz, 2H), 1.29 (t, J=7.2 Hz, 3H); 13C NMR (150 MHz, DMSO-d6) δ 165.3, 163.5, 160.4, 150.9, 141.8, 141.3, 138.5, 130.2, 129.4, 128.8, 128.6, 128.3, 126.5, 126.2, 111.7, 107.0, 100.2, 60.6, 46.2, 42.1, 33.2, 14.1: ESIMS(−), m/z 443.1 [M−1]−; Anal. Calcd for (C26H24N2O5.0.2 H2O): C, 69.69, H, 5.49, N, 6.25. Found: C, 69.60, H, 5.70, N, 6.27.
Starting from ethyl 4-((3,4-dihydro-7-hydroxy-2,4-dioxo-3-phenethylquinazolin-1(2H)-yl)methyl)benzoate and similar procedures of step 5, 6, and 7 in example 1 were followed to yield compound 4 as white solid. Yield 59.6% Rf=0.18 (MeOH/CH2Cl2= 1/19); mp 205-207° C. (dec); 1H NMR (400 MHz, DMSO-d6) δ 7.84 (d, J=8.8 Hz, 1H), 7.69-7.71 (m, 2H), 7.21-730 (m, 7H), 6.61 (d, J=8.4 Hz, 1H), 6.38 (s, 1H), 5.25 (s, 2H), 4.19 (dd, J=7.6 Hz, 2H), 2.92 (dd, J=7.2 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ 165.8, 163.8, 160.5, 151.1, 141.5, 139.5, 138.7, 131.9, 130.0, 128.7, 128.4, 127.2, 126.36, 126.32, 112.6, 105.7, 100.5, 46.1, 42.1, 33.4; ESIMS(−), m/z 429.9 [M−1]−. Anal. Calcd for (C24H21N3O5.H2O); C, 64.13, H, 5.16, N, 9.35. Found: C, 64.24, H, 4.88, N, 9.11.
The similar procedures of example 1 were followed to yield compound 5 as brown solid. Rf=0.20 (MeOH/CH2Cl2= 2/98); 1H NMR (400 MHz, DMSO-d6) δ 11.18 (br s, 1H), 9.02 (s, 1H), 8.06 (d, J=7.6 Hz, 1H), 7.68-7.70 (m, 2H), 7.63 (dd, J=7.6 Hz, 7.2 Hz, 1H), 720-7.30 (m, 9H), 5.37 (s, 2H), 4.23 (dd, J=7.6 Hz, 2H), 2.95 (dd, J=7.6 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ 163.9, 160.9, 150.6, 139.5, 139.4, 138.5, 135.2, 131.8, 128.7, 128.4, 128.0, 127.2, 126.4, 126.3, 122.9, 115.1, 114.8, 46.0, 42.4, 33.1; ESIMS(−), m/z 413.9 [M−1]−. Anal. Calcd for (C24H21N3O4): C, 69.39; H, 5.10; N, 10.11. Found: C, 69.31; H, 5.14; N, 10.11.
The similar procedures of example 1 were followed to yield compound 6. Rf=0.19 (MeOH/CH2Cl2= 2/98); mp 188-190° C. (dec); 1H NMR (400 MHz, DMSO-d6) δ 11.24 (br s, 1H), 9.06 (s, 1H), 8.07 (d, J=7.2 Hz, 1H), 7.64-7.70 (m, 3H), 7.20-7.42 (m, 9H), 5.39 (s, 2H), 4.24 (dd, J=7.6 Hz, 2H), 2.95 (dd, J=7.6 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ 163.9, 160.9, 150.6, 139.5, 138.5, 136.6, 135.2, 133.2, 129.1, 128.8, 128.6, 128.4, 128.0, 126.3, 125.8, 125.0, 122.9, 115.1, 114.8, 46.2, 42.5, 33.2; ESIMS(−), m/z 413.9 [M−1]−. Anal. Calcd for (C24H21N3O4.0.6 H2O): C, 67.63; H, 5.25; N, 9.86. Found: C, 67.56; H, 4.86; N, 9.61.
The similar procedures of example 2 were hollowed to yield compound 7. Rf=0.42 (MeOH/CH2Cl2= 1/19); mp 166-168° C.; 1H NMR (400 MHz, DMSO-d6) δ 11.19 (br s, 1H), 9.03 (br s, 1H), 8.20 (d, J=8.0 Hz, 1H), 7.83 (s, 1H), 7.64-7.68 (m, 3H), 7.35-7.43 (m, 2H), 7.22-7.30 (m, 5H), 5.43 (s, 2H), 4.21 (dd, J=7.6 Hz, 2H), 2.93 (dd, J=7.6 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ 163.8, 160.1, 150.3, 139.9, 138.3, 136.0, 133.1, 129.1, 128.7, 128.6, 128.4, 126.3, 125.88, 125.85, 124.9, 118.8, 118.4, 117.7, 116.9, 114.5, 46.2, 42.8, 33.0; ESIMS(−), m/z 438.9 [M−1]−. Anal. Calcd for (C25H20N4O4.0.4 H2O): C, 67.08; H, 4.68; N, 12.52. Found: C, 67.13; H, 4.59; N, 12.19.
The similar procedures of example 2 were followed to yield compound 8. Rf=0.45 (MeOH/CH2Cl2= 1/19); mp 185-187° C. (dec); 1H NMR (400 MHz, DMSO-d6) δ 8.05 (d, J=8.4 Hz, 1H), 7.69-7.71 (m, 2H), 7.21-7.31 (m, 9H), 5.39 (s, 2H), 4.20 (dd, J=7.2 Hz, 2H), 2.93 (dd, J=7.2 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ 163.7, 160.2, 150.5, 140.5, 139.8, 138.9, 138.4, 132.0, 129.9, 128.7, 128.4, 127.2, 126.35, 126.33, 123.1, 114.5, 114.0, 46.0, 42.5, 33.0; ESIMS(−), m/z 447.9 [M−1]−. Anal. Calcd for (C24H20ClN3O4); C, 64.07; H, 4.48; N, 9.34. Found: C, 64.12; H, 4.52; N, 9.31.
The similar procedures of example 2 were followed to yield compound 9 as white solid. Rf=0.27 (MeOH/CH2Cl2= 1/19); mp 190-192° C.; 1H NMR (400 MHz, DMSO-d6) δ 11.18 (br s, 1H), 9.02 (br s, 1H), 7.98 (d, J=2.4 Hz, 1H), 7.66-7.70 (m, 3H), 7.21-7.30 (m, 8H), 5.37 (s, 2H), 4.21 (dd, J=7.6 Hz, 2H), 2.94 (dd, J=7.6 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ 163.8, 159.9, 150.3, 139.1, 138.39, 138.38, 134.8, 131.8, 128.7, 128.4, 127.23, 127.21, 126.8, 117.1, 116.6, 46.2, 42.6, 32.9, 126.3 (2C); ESIMS(−), m/z 447.9 [M−1]−; Anal. Calcd for (C24H20ClN3O4): C, 64.07; H, 4.48; N, 9.34. Found: C, 63.75; H, 4.40; N, 9.18.
1H NMR (400 MHz, DMSO-d6) δ 8.03 (d, J=8.4 Hz, 1H), 7.70 (d, J=8.0 Hz, 2H), 7.37 (d, J=8.0 Hz, 2H), 7.27-7.30 (m, 2H), 5.41 (s, 2H), 3.34 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 163.7, 160.6, 150.8, 140.5, 139.6, 139.0, 131.9, 129.8, 127.2, 126.3, 123.0, 114.4, 114.1, 46.1, 28.3; ESIMS(−), m/z=358 [M−H]−. Anal. Calcd for (C17H14ClN3O4.0.2 H2O): C, 56.19: H, 3.99; N, 11.56. Found: C, 56.18; H, 3.87; N, 11.37.
1H NMR (400 MHz, DMSO-d6) δ 11.16 (br s, 1H), 9.01 (br s, 1H), 8.09 (d, J=7.6 Hz, 1H), 7.63-7.71 (m, 3H), 7.22-7.37 (m, 9H), 5.42 (s, 2H), 5.20 (s, 2H); 13C NMR (100 MHz, DMSO-d6) δ 163.9, 161.1, 150.8, 139.5, 139.4, 137.1, 135.3, 131.8, 128.3, 128.1, 127.4, 127.2, 127.1, 126.3, 123.0, 115.0, 114.9, 46.2, 44.4; ESIMS(−), m/z=400 [M−H]−. Anal. Calcd for (C23H19N3O4.0.8 H2O): C, 66.43: H, 4.99; N, 10.11. Found: C, 66.50; H, 4.66; N, 9.93.
1H NMR (400 MHz, DMSO-d6) δ 8.66 (dd, J=4.4, 1.2 Hz, 1H), 8.39 (dd, J=7.6, 1.2 Hz, 1H), 7.66 (d, J=8.0 Hz, 2H), 7.17-7.35 (m, 8H), 5.43 (s, 2H), 4.16 (t, J=7.6 Hz, 2H), 2.90 (t, J=7.6 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ 163.7, 160.5, 154.2, 150.6, 150.2, 139.2, 138.4, 137.4, 133.0, 128.7, 128.4, 126.7, 126.6, 126.4, 119.4, 110.5, 48.6, 44.7, 42.5, 33.0: ESIMS(−), m/z=415 [M−H]−. Anal. Calcd. for (C23H20N4O4.1.2 H2O): C, 63.06; H, 5.15; N, 12.79. Found: C, 62.97; H, 4.90; N, 12.47.
1H NMR (400 MHz, DMSO-d6) δ 11.20 (br s, 1H), 9.03 (br s, 1H), 8.25 (d, J=8.4 Hz, 1H), 7.69 (d, J=8.0 Hz, 2H), 7.58 (d, J=8.4 Hz, 1H), 7.50 (s, 1H), 7.22-7.31 (m, 7H), 5.47 (s, 2H), 4.23 (t, J=7.2 Hz, 2H), 2.95 (t, J=7.2 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ 163.8, 160.2, 150.5, 139.9, 139.1, 138.4, 134.5, 134.1, 131.8, 129.6, 128.7, 128.4, 127.2, 126.45, 126.40, 124.6, 121.9, 119.14, 119.10, 118.3, 111.9, 111.8, 46.1, 42.7, 0.9; ESIMS(−), m/z 482 [M−H]−. Anal Calcd for (C25H20F3N3O4): C, 62.11; H, 4.17; N, 8.69. Found: C, 62.13; H, 4.13; N, 8.64.
1H NMR (400 MHz, DMSO-d6) δ 11.15 (br s, 1H), 9.01 (br s, 1H), 8.06 (dd, J=8.0, 1.2 Hz, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.62 (dd, J=8.4, 7.6 Hz, 1H), 7.20-7.28 (m, 6H), 7.09 (dd, J=9.2, 8.4 Hz, 2H), 5.37 (s, 2H), 4.22 (t, J=7.6 Hz, 2H), 2.94 (t, J=7.6 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ 163.9, 162.1, 160.9, 159.7, 150.6, 139.4, 135.2, 134.7, 134.6, 131.8, 130.6, 130.5, 128.0, 127.2, 126.4, 126.2, 122.9, 115.19, 115.10, 114.9, 114.8, 46.0, 42.4, 32.2; ESIMS(−), m/z=432 [M−H]−. Anal. Calcd for (C24H20FN3O4): C, 66.51; H, 4.65; N, 9.69. Found: C, 66.20; H, 4.46; N, 9.48.
1H NMR (400 MHz, DMSO-d6) δ 8.99 (br s, 1H), 8.04 (dd, J=8.0, 1.2 Hz, 1H), 7.68 (d, J=8.0 Hz, 2H), 7.61 (dd, J=7.6, 7.2 Hz, 1H), 7.17-7.26 (m, 5H), 7.06 (d, J=7.2 Hz, 1H), 6.90 (d, J=8.0 Hz, 1H), 6.83 (dd, J=7.6, 7.2 Hz, 1H), 5.33 (s, 2H), 4.26 (t, J=7.2 Hz, 2H), 3.64 (s, 3H), 2.94 (t, 7.2 Hz, 2H), 11.16 (br s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 164.0, 161.0, 157.5, 150.7, 139.6, 139.5, 135.2, 131.8, 130.3, 128.1, 127.9, 127.3, 126.6, 126.5, 123.0, 120.3, 115.2, 114.7, 110.7, 55.2, 46.1, 41.3, 27.9; ESIMS(−), m/z=444 [M−H]−. Anal. Calcd for C25H23N3O5.0.5 H2O); C, 66.07; H, 532; N, 9.25. Found: C, 66.12; H, 5.33; N, 9.17.
The similar procedures of example 3 were followed to yield compound 16. 1H NMR (400 MHz, DMSO-d6) δ 8.76 (br s, 8.05 (dd, J=8.0, 1.2 Hz, 1H), 7.63 (ddd, J=8.4, 8.4, 1.2 Hz, 1H), 7.12-7.30 (m, 1H), 5.31 (s, 2H), 4.23 (t, J=7.6 Hz, 2H), 3.23 (s, 2H), 2.94 (t, J=7.6 Hz, 2H), 10.60 (br s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 166.8, 160.9, 150.6, 139.5, 138.5, 135.2, 135.0, 134.3, 129.2, 128.7, 128.3, 127.9, 126.34, 126.32, 122.8, 115.0, 114.9, 45.9, 42.4, 38.9, 33.1; ESIMS(−), m/z=428 [M−H]−. Anal. Calcd for (C23H23N3O4); C, 69.92; H, 5.40; N, 9.78. Found: C, 70.03; H, 5.52; N, 9.44.
The similar procedures of example 1 were followed to yield compound 17. 1H NMR (400 MHz, DMSO-d6) δ 11.21 (br s, 1H), 9.05 (br s, 1H), 7.68-7.77 (m, 3H), 7.54 (s, 1H), 7.21-7.28 (m, 8H), s, 2H), 4.21 (t, J=6.8 Hz, 2H), 2.94 (t, J=6.8 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ 163.8, 160.19, 160.16, 158.7, 156.3, 150.3, 139.3, 138.4, 136.2, 131.8, 128.7, 128.4, 127.2, 126.4, 126.3, 122.9, 122.7, 117.4, 117.3, 116.5, 116.4, 113.2, 113.0, 46.3, 42.7, 33.0; ESIMS(−), m/z=432 [M−H]−. Anal. Calcd for (C24H20FN3O4.0.1 H2O): C, 66.23; H, 4.68; N, 9.65. Found: C, 66.07; H, 4.77; N, 9.32.
1H NMR (400 MHz, DMSO-d6) δ 11.19 (br s, 1H), 9.32 (br s, 1H), 9.03 (br s, 1H), 8.04 (d, J=7.6 Hz, 1H), 7.67 (d, J=8.0 Hz, 2H), 7.61 (dd, J=7.6, 7.6 Hz, 1H), 7.22-7.26 (m, 3H), 7.17 (d, J=8.4 Hz, 1H), 6.97-7.02 (m, 2H), 6.75 (d, J=8.0 Hz, 1H), 6.66 (dd, J=7.6, 7.2 Hz, 1H), 5.34 (s, 2H), 4.25 (t, J=6.8 Hz, 2H), 2.90 (t, J=6.8 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ 164.0, 161.0, 155.6, 150.7, 139.6, 139.5, 135.2, 131.7, 130.3, 128.1, 127.4, 127.3, 126.5, 124.9, 122.9, 118.9, 115.2, 114.9, 114.8, 46.1, 41.3, 27.8; ESIMS(+), m/z=454 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ 10.64 (br s, 1H), 8.83 (br s, 1H), 0.07 (dd, J=8.0, 0.8 Hz, 1H), 7.66 (ddd, J=8.0, 8.0, 0.8 Hz, 1H), 7.12-7.29 (m, 8H), 6.97 (dd, J=8.0, 0.8 Hz, 1H), 6.88 (dd, 8.0, 8.0 Hz, 1H), 5.33 (S, 214), 4.20 (1.1=7.6 Hz, 210, 3.27 (s, 2H), 2.92 (t, J=7.6 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ 166.4, 160.8, 160.7, 158.2, 150.4, 139.4, 138.4, 137.78, 137.70, 135.3, 128.6, 128.4, 128.0, 127.58, 127.54, 126.3, 125.8, 125.3, 123.0, 121.0, 120.9, 115.9, 115.7, 115.0, 114.4, 42.4, 40.7, 40.6, 38.6, 33.1; ESIMS(−), m/z=446 [M−H]−. Anal. Calcd for (C25H22FN3O4): C, 67.11; H, 4.96; N, 9.39. Found: C, 67.26; H, 4.99; N, 9.22.
1H NMR (400 MHz, DMSO-d6) δ 11.20 (br s, 1H), 9.04 (br s, 1H), 7.71 (d, J=8.0 Hz, 2H), 7.15-7.31 (m, 9H), 5.19 (s, 2H), 4.15 (t, J=7.6 Hz, 2H), 2.90 (t, J=7.6 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ 163.7, 157.5, 152.3, 150.5, 138.4, 137.9, 132.3, 128.7, 128.4, 127.2, 127.1, 126.3, 123.1, 118.2, 115.2, 50.5, 42.2, 33.1; ESIMS(−), m/z=420 [M−H]−. Anal Calcd for (C22H19N3O4S.0.5 H2O): C, 61.38; H, 4.68: N, 9.76. Found: C, 61.44; H, 4.60; N, 9.63.
1H NMR (400 MHz, DMSO-d6) δ 11.16 (br s, 1H), 8.99 (br s, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.68 (d, J=8.0 Hz, 2H), 7.20-7.30 (m, 7H), 7.07-7.09 (m, 2H), 5.35 (s, 2H), 4.21 (t, J=7.6 Hz, 2H), 2.93 (t, J=7.6 Hz, 2H), 2.30 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 163.8, 160.7, 150.6, 146.0, 139.59, 139.55, 138.4, 131.7, 128.7, 128.3, 127.9, 127.2, 126.36, 126.30, 124.1, 114.6, 112.7, 45.9, 42.3, 33.1, 21.6; ESIMS(+), m/z=430 [M+H]+. Anal Calcd for (C25H23N3O4): C, 69.92; H, 5.40; N, 9.78. Found: C, 6930; H, 5.23; N, 9.74.
1H NMR (400 MHz, DMSO-d6) δ 11.61 (br s, 1H), 8.77 (br s, 1H), 8.18 (d, J=8.0 Hz, 1H), 7.79 (s, 1H) 7.64 (d, J=8.4 Hz, 1H), 7.15-7.30 (m, 9H), 5.34 (s, 2H), 4.21 (t, J=7.6 Hz, 2H), 3.24 (s, 2H), 2.93 (t, J=7.6 Hz, 2H); 13C NMR. (100 MHz, DMSO-d6) δ166.9, 160.0, 150.2, 139.8, 138.3, 135.2, 133.7, 129.2, 129.1, 128.7, 128.4, 126.4, 126.3, 125.7, 118.9, 118.4, 117.7, 116.8, 46.0, 42.7, 38.9, 32.9; ESIMS(+), m/z=477.1 [M+Na]+. Anal. Calcd for (C26H22N4O4): C, 68.71; H, 4.88; N, 12.33. Found: C, 68.55; H, 4.86; N, 12.14.
1H NMR (400 MHz, DMSO-d6) δ 11.16 (br s, 1H), 9.00 (br s, 1H), 8.06 (d, J=7.6 Hz, 1H), 7.62-7.69 (m, 3H), 7.21-7.35 (m, 5H), 6.89-6.95 (m, 2H), 5.38 (s, 2H), 4.25 (t, J=7.2 Hz, 2H), 3.18 (t, 7.2 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ 163.9, 160.9, 150.6, 140.3, 139.4, 135.2, 131.8, 128.0, 127.2, 127.2, 127.0, 126.4, 125.6, 124.4, 123.0, 115.1, 114.8, 46.0, 42.5, 27.1; ESIMS(+), m/z=422 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ 11.14 (br s, 1H), 9.06 (br s, 1H), 8.06 (dd, J=7.6, 1.2 Hz, 1H), 7.69 (ddd, J=8.8, 8.4, 0.8 Hz, 1H), 7.60 (br s, 1H), 7.50 (br s, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.18-7.31 (m, 6H), 5.30 (s, 2H), 4.21 (t, J=7.6 Hz, 2H), 2.93 (t, J=7.6 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ 160.8, 159.2, 150.2, 139.3, 137.8, 137.5, 135.2, 128.6, 128.4, 128.0, 126.9, 126.8, 126.3, 122.9, 115.0, 114.7, 42.5, 42.3, 33.2; ESIMS(+), m/z=444.1 [M+Na]+. Anal. Calcd for (C22H19N3O4S): C, 62.69; H, 4.54; N, 9.97. Found: C, 62.93; H, 4.60; N, 9.97.
1H NMR (400 MHz, DMSO-d6) δ 11.17 (br s, 1H), 9.01 (br s, 1H), 8.06 (dd, J=8.0, 1.2 Hz, 1H), 7.61-7.69 (m, 3H), 7.19-7.34 (gin, 511), 7.01-7.07 (m, 3H), 5.37 (s, 2H), 4.25 (t, J=7.6 Hz, 2H), 2.98 (t, J=7.6 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ 163.93, 163.39, 160.97, 160.94, 150.6, 141.5, 141.4, 139.49, 139.46, 135.2, 131.8, 130.28, 130.20, 128.0, 127.2, 126.4, 124.92, 124.90, 123.0, 115.5, 115.3, 115.1, 114.8, 113.0, 46.0, 42.1, 32.7; ESIMS(+), m/z=434.1 [M+H]+. Anal. Calcd for (C24H20FN3O4); C, 66.51; H, 4.65; N, 9.69. Found: C, 66.85; H, 4.69; N, 9.76.
1H NMR (400 MHz, DMSO-d6) δ 11.18 (br s, 1H), 9.02 (br s, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.20-730 (m, 7H), 6.86-6.91 (m, 2H), 5.38 (s, 2H), 4.21 (t, J=7.6 Hz, 2H), 2.93 (t, J=7.6 Hz, 2H), 1.89-1.93 (m, 1H), 0.97-1.0 (m, 2H), 0.64-0.66 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ 163.8, 160.6, 152.6, 150.7, 139.7, 139.4, 138.5, 131.7, 128.7, 128.3, 128.0, 127.2, 126.4, 126.3, 119.8, 112.5, 111.2, 45.8, 42.3, 33.1, 15.7, 10.8; ESIMS(+), m/z=456.1 [M+H]+. Anal. Calcd for (C27H25N3O4.0.5 H2O): C, 69.81; H, 5.64; N, 9.05. Found: C, 69.80; H, 5.71; N, 8.96.
1H NMR (400 MHz, DMSO-d6) δ 11.16 (br s, 1H), 9.02 (br s, 1H), 8.06 (d, J=7.6 Hz, 1H), 7.61-7.68 (m, 3H), 7.02-7.35 (m, 7H), 5.37 (s, 2H), 4.19 (t, J=7.2 Hz, 2H), 3.79 (s, 3H), 2.89 (t, J=7.2 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ 163.9, 160.9, 1510, 150.6, 139.4, 135.2, 131.8, 131.7, 128.5, 128.0, 127.2, 126.6, 126.3, 123.0, 120.7, 115.1, 114.8, 112.7, 55.9, 46.0, 42.4, 31.9; ESIMS(+), m/z=502.1 [M+Na]+.
1H NMR (400 MHz, DMSO-d6) δ 11.14 (br s, 1H), 9.00 (br s, 1H), 8.07 (dd, J=8.0, 1.2 Hz, 1H), 7.61-7.69 (m, 3H), 7.20-7.30 (m, 4H), 6.94 (d, J=8.0 Hz, 1H), 6.45 (d, J=8.4 Hz, 2H), 5.46 (q, J=4.8 Hz, 1H), 5.39 (s, 2H), 4.13 (t, J=7.6 Hz, 2H), 2.77 (t, J=7.6 Hz, 2H), 2.62 (d, J=4.8 Hz, 3H); 13C NMR (100 MHz, DMSO-d6) δ 164.4, 161.4, 151.1, 148.9, 140.04, 140.00, 135.7, 132.3, 129.6, 128.5, 127.7, 126.9, 125.5, 123.4, 115.7, 115.3, 112.2, 46.5, 43.4, 32.8, 30.3; ESIMS(−), m/z=443.1 [M−H]−.
1H NMR (400 MHz, DMSO-d6) δ 2.84 (br s, 2H), 3.03 (br s, 4H), 3.71 (br s, 4H), 4.17 (br s, 2H), 5.38 (s, 2H), 6.85 (d, J=6.4 Hz, 2H), 7.08 (d, J=6.8 Hz, 2H), 7.21-7.26 (m, 4H), 7.63-7.70 (m, 3H), 8.06 (d, J=6.4 Hz, 1H), 9.03 (br s, 1H), 11.16 (br s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 32.2, 42.7, 46.0, 48.6, 66.0, 114.8, 115.1, 115.6, 122.9, 126.4, 127.1, 128.0, 128.4, 128.9, 129.2, 131.8, 135.2, 139.4, 149.6, 150.6, 160.9, 163.9; ESIMS(−), m/z=499 [M−H]−.
1H NMR (400 MHz, DMSO-d6) δ 5.19 (s, 2H), 5.41 (s, 2H), 7.23 (d, J=8.4 Hz, 1H), 7.30 (dd, J=7.6, 7.2 Hz, 1H), 7.36-7.46 (m, 5H), 7.57-7.59 (m, 2H), 7.64-7.71 (m, 3H), 8.10 (d, J=7.6 Hz, 1H), 9.03 (br s, 1H), 11.20 (br s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 46.3, 77.4, 115.1, 115.6, 123.2, 126.4, 127.2, 127.9, 128.3, 128.9, 129.6, 131.8, 134.3, 135.3, 138.9, 139.2, 149.1, 158.2, 163.9: ESIMS(+), m/z=418 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ 2.91 (d, J=7.6 Hz, 2H), 4.19 (d, J=7.6 Hz, 2H), 5.49 (s, 2H), 7.15-7.30 (m, 7H), 7.45 (br s, 1H), 7.56 (d, J=8.8 HZ, 1H), 7.72 (ddd, J=8.8, 8.8, 1.6 Hz, 1H), 8.04 (dd, J=8.0, 1.2 Hz, 1H), 9.10 (br s, 1H), 11.19 (br s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 46.3, 77.4, 115.1, 115.6, 123.2, 126.4, 127.2, 127.9, 128.3, 128.9, 129.6, 131.8, 134.3, 135.3, 138.9, 139.2, 149.1, 158.2, 163.9: ESIMS(−), m/z=420 [M−H]−. Anal. Calcd for (C22H19N3O4S): C, 62.69; H, 4.54; N, 9.97. Found: C, 62.86; H, 4.89; N, 9.61.
1H NMR (400 MHz, DMSO-d6) δ 2.87 (t, J=7.6 Hz, 2H), 3.70 (s, 3H), 4.19 (t, J=7.6 Hz, 2H), 5.38 (s, 2H), 6.84 (d, J=8.4 Hz, 2H), 7.14 (d, J=8.4 Hz, 2H), 7.20-7.28 (m, 4H), 7.61-7.68 (m, 3H), 8.07 (d, J=8.0 Hz, 1H), 8.99 (br s, 1H), 11.14 (br s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 32.2, 40.1, 46.0, 54.9, 113.8, 114.8, 115.1, 122.9, 126.3, 127.2, 128.0, 129.6, 130.3, 131.8, 135.1, 139.4, 150.6, 157.8, 160.8;
1H NMR (400 MHz, DMSO-d6) δ 2.82 (t, J=7.2 Hz, 2H), 4.15 (t, J=7.2 Hz, 2H), 5.38 (s, 2H), 6.67 (d, J=8.4 Hz, 2H), 7.01 (d, J=8.4 Hz, 2H), 7.19-7.29 (m, 4H), 7.60-7.69 (m, 3H), 8.06 (d, J=8.0 Hz, 1H), 9.03 (br s, 1H), 9.23 (br s, 1H), 11.15 (br s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 32.3, 42.8, 46.0, 114.8, 115.1, 115.2, 123.0, 126.4, 127.2, 128.0, 128.5, 129.6, 131.8, 135.2, 139.4, 139.5, 150.6, 155.8, 160.9, 164.0; ESIMS(−), m/z=430 [M−H]−
1H NMR (400 MHz, DMSO-d6) δ 2.91 (d, J=7.6 Hz, 2H), 4.19 (d, J=7.6 Hz, 2H), 5.49 (s, 2H), 7.15-7.30 (m, 7H), 7.45 (br s, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.72 (ddd, J=8.8, 8.8, 1.6 Hz, 1H), 8.04 (dd, J=8.0, 1.2 Hz, 1H), 9.10 (br s, 1H), 11.19 (br s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 46.7, 115.5, 116.4, 123.4, 127.0, 127.7, 128.7, 129.3, 129.4, 129.5, 132.3, 135.9, 136.8, 140.0, 140.4, 151.4, 161.9, 164.4; ESIMS(−), m/z=386 [M−H]−.
White solid; Rf=0.34 (MeOH/Cl2= 1/9); mp 258-269° C. (dec); 1H NMR (400 MHz, DMSO-d6) δ 3.80 (s, 3H), 5.41 (s, 2H), 7.03 (d, J=8.0 Hz, 2H), 7.25-7.33 (m, 4H), 7.45 (d, J=8.4 Hz, 2H), 7.65-7.72 (m, 3H), 9.03 (s, 1H), 11.19 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 46.3, 55.3, 114.0, 115.0, 115.9, 122.9, 126.6, 127.2, 128.2, 128.8, 130.0, 131.8, 135.3, 139.5, 139.9, 151.2, 158.9, 161.6, 164.0; ESIMS(+), m/z 418.1 [M+1]+; Anal. Calcd for (C23H19N3O5); C, 66.18; H, 4.59; N, 10.07. Found: C, 66.03; H, 4.35; N, 9.75.
White solid; Rf=0.29 (MeOH/CH2Cl2=1:9); mp 258-260° C. (dec); 1H NMR (400 MHz, DMSO-d6) δ 5.41 (s, 2H), 7.25-7.31 (m, 2H), 7.47 (dd, J=8.2, 3.4 Hz, 4H), 7.57 (d, J=8.4 Hz, 2H), 7.67-7.71 (m, 3H), 8.08 (d, J=7.6 Hz, 1H), 9.02 (s, 1H), 11.18 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 46.3, 115.0, 115.9, 123.0, 126.6, 127.2, 128.2, 128.9, 131.0, 131.8, 132.8, 135.2, 135.5, 139.4, 139.9, 150.8, 161.3, 163.9; ESIMS(−), m/z 419.9 [M−H]−; Anal. Calcd for (C22H16ClN3O4): C, 62.54; H, 3.82; N, 9.96. Found: C, 62.30; H, 3.63: N, 9.83.
White solid; Rf=0.44 (MeOH/CH2Cl2= 1/9); mp 257° C. (dec); 1H NMR (200 MHz, DMSO-d6) δ 5.42 (s, 2H), 7.26-7.36 (m, 4H), 7.47-7.52 (m, 4H), 7.67-7.74 (m, 3H), 8.09 (dd, J=7.2, 0.8 Hz, 1H), 9.06 (s, 1H), 11.22 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 46.3, 115.0, 115.6, 115.8, 115.9, 123.0, 126.6, 127.2, 128.2, 131.1, 131.2, 131.8, 132.5 (2C), 135.4, 139.5, 139.9, 151.0, 160.4, 161.5, 162.9, 164.0; ESIMS(+), 406.1 [M+1]+; Anal. Calcd for (C22H16FN3O4): C, 65.18; H, 3.98; N, 10.37. Found: C, 65.19; H, 3.95; N, 10.21.
White solid; Rf=0.29 (MeOH/CH2Cl2= 1/9); mp 238-239° C. (dec); 1H NMR (200 MHz, DMSO-d6) δ 11.21 (s, 1H), 9.07 (s, 1H), 8.08 (d, J=7.6 Hz, 1H), 7.75 (d, J=8.0 Hz, 2H), 7.71 (t, J=7.8 Hz, 1H), 7.40-7.46 (m, 4H), 7.33 (d, J=8.4 Hz, 1H), 7.29 (t, J=7.6 Hz, 1H), 7.18 (d, J=8.0 Hz, 1H), 7.07 (t, J=7.4 Hz, 1H), 5.44 (s, 2H), 3.76 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 164.0, 160.9, 154.7, 150.5, 139.8, 139.5, 135.6, 131.9, 130.2, 130.0, 128.3, 127.4, 126.5, 124.6, 123.2, 120.5, 115.5, 115.1, 112.1, 55.8, 46.0; ESIMS(+), ESIMS(+), m/z 418.1 [M+1]+; Anal. Calcd for (C22H16FN3O4) C, 66.18; H, 4.59; N, 10.07. Found: C, 66.55; H, 4.31; N, 10.35.
White solid; Rf=0.21 (EtOAc/Hexanes 3/1); mp 203-206° C.; IR(ATR): 3347, 2950, 2838, 1640 cm−1; 1H NMR (200 MHz, DMSO-d6) δ 10.76 (br s, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.64 (t, J=7.7 Hz, 1H), 7.48 (t, J=6.9 Hz, 2H), 7.38-7.21 (m, 10H), 6.42 (s, 1H), 5.35 (s, 2H), 4.23 (t, J=8.0 Hz, 2H), 2.95 (t, J=7.0 Hz, 2H); 13C NMR (50 MHz, DMSO-d6) δ 162.7, 160.9, 150.6, 139.5, 138.5, 137.9, 137.7, 135.2, 133.9, 128.7, 128.4, 128.0, 127.8, 127.0, 166.3, 123.0, 119.0, 115.1, 114.9, 46.1, 42.5, 33.1; ESIMS(−), m/z 440 [M−H]−; Anal. Calcd for (C26H23N3O4): C, 70.73; H, 5.25; N, 9.52. Found: C, 70.46; H, 5.41; N, 9.39.
White solid; Rf=0.22 (MeOH/DCM 5/95); mp 193-196° C.; IR(ATR): 3358, 3268, 2949, 2839, 1630 cm−1; 1H NMR (200 MHz, DMSO-d6) δ 10.77 (br s, 1H), 9.02 (br s, 1H), 8.06 (dd, J=7.6, 1.0 Hz, 1H), 7.64 (t, J=7.0 Hz, 1H), 7.49 (t, J=8.0 Hz, 2H), 7.36-7.18 (m, 9H), 6.41 (d, J=14.0 Hz, 1H), 5.34 (s, 2H), 4.24 (t, J=7.0 Hz, 2H), 2.95 (t, J=7.0 Hz, 2H); 13C NMR (50 MHz, DMSO-d6) δ 162.7, 160.9, 150.7, 139.5, 137.9, 137.7, 137.6, 135.3, 133.9, 131.0, 130.7, 128.4, 128.0, 127.8, 177.0, 123.0, 119.0, 115.1, 114.9, 46.1, 42.3, 32.4; ESIMS(+), m/z 476 [M+H]+; Anal. Calcd for (C26H22ClN3O4): C, 65.62; H, 4.66; N, 8.83. Found: C, 65.11; 11, 4.52; N, 8.70.
White solid; Rf=0.24 (MeOH/DCM=5/95); mp 198-200° C.; IR(ATR): 3358, 3278, 2945, 2836, 1643 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 10.77 (br s, 1H), 9.04 (br s, 1H), 8.06 (dd, J=7.8, 1.4 Hz, 1H), 7.66-7.62 (m, 1H), 7.50 (d, J=8.0 Hz, 2H), 7.41 (d, J=16 Hz, 1H), 7.27-7.21 (m, 6H), 7.10 (t, J=8.8 Hz, 2H), 6.41 (d, J=16 Hz, 1H), 5.34 (s, 2H), 4.22 (t, J=7.4 Hz, 2H), 2.94 (t, J=7.2 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ 162.7, 162.2, 160.9, 159.8, 150.6, 139.5, 137.9, 137.7, 135.3, 134.7, 134.7, 133.9, 130.6, 130.6, 128.0, 127.8, 127.0, 123.0, 119.0, 115.2, 115.1, 115.0, 114.9, 46.1, 42.4, 32.3; ESIMS(−), m/z 458 [M−H]−; Anal. Calcd for (C26H22FN3O4) C, 67.97; H, 4.83; N, 9.15. Found: C, 67.90; H, 4.80; N, 8.95.
White solid; Rf=0.28 (MeOH/DCM=5/95); mp 164-167° C.; IR(ATR); 3250, 2919, 2849, 1698, 1649, 1608 cm−1; 1H NMR (200 MHz, DMSO-d6) δ 10.77 (br s, 1H), 9.02 (br s, 1H), 8.06 (d, J=7.6 Hz, 1H), 7.64 (t, J=7.1 Hz, 1H), 7.52-7.11 (m, 9H), 6.84 (d, J=8.6 Hz, 2H), 6.41 (d, J=15.8 Hz, 1H), 5.35 (s, 2H), 4.19 (t, J=7.0 Hz, 2H), 3.70 (s, 3H), 2.88 (t, J=7.0 Hz, 2H); 13C NMR (50 MHz, DMSO-d6) δ 162.8, 161.0, 157.9, 150.7, 139.5, 138.0, 137.8, 135.3, 133.9, 130.4, 129.8, 128.1, 127.9, 127.1, 123.1, 119.0, 115.1, 114.9, 113.9, 55.0, 46.1, 42.7, 32.3; ESIMS(+), m/z 472 [M+H]+, 494 [M+Na]+; Anal. Calcd for (C27H25N3O5.5 H2O): C, 67.49; H, 5.45; N, 8.74. Found: C, 67.31; H, 5.31; N, 8.66.
White solid; Rf=0.22 (10% MeOH in DCM); mp 211-214° C.; IR(ATR): 3353, 3227, 2919, 2850, 1707, 1675, 1636, 1607 cm−1; 1H NMR (200 MHz, DMSO-d6) δ 9.57 (br s, 2H), 8.06 (dd, J=6.0, 2.0 Hz, 1H), 7.63 (t, J=7.0 Hz, 1H), 7.51 (d, J=8.0 Hz, 2H), 7.41 (d, J=16.0 Hz, 1H), 7.29-7.20 (m, 4H), 7.01 (d, J=8.0 Hz, 2H), 6.67 (d, J=8.0 Hz, 2H), 6.42 (d, J=16.0 Hz, 1H), 5.34 (s, 2H), 4.18 (t, J=7.0 Hz, 2H), 2.83 (t, J=8.0 Hz, 2H); 13C NMR (50 MHz, DMSO-d6) δ 162.7, 160.9, 155.9, 150.7, 139.5, 137.9, 137.7, 135.2, 133.9, 129.7, 128.5, 128.0, 127.9, 127.1, 123.0, 119.0, 115.2, 114.9, 46.1, 42.8, 32.3; ESIMS(−), m/z 456 [M−H]−; Anal. Calcd for (C26H23N3O5): C, 68.26; H, 5.07; N, 9.19. Found: C, 68.39; H, 5.27; N, 8.88.
Rf=0.14 (MeOH/DCM=5/95); mp 192-194° C.; IR(ATR): 3288, 2921, 2850, 1702, 1666, 1646, 1623 cm−1; 1H NMR (200 MHz, DMSO-d6) δ 10.78 (br s, 1H), 9.04 (br s, 1H), 8.11 (dd, J=8.9, 6.6 Hz, 1H), 7.54-7.31 (m, 5H), 7.25-7.07 (m, 6H), 6.42 (d, J=16 Hz, 1H), 5.32 (s, 2H), 2.94 (t, J=7.2 Hz, 2H), 4.21 (t, J=7.2 Hz, 2H); 13C NMR (50 MHz, DMSO-d6) δ 167.4, 164.9, 162.7, 160.2, 150.7, 141.7, 141.6, 137.9, 137.5, 137.3, 134.0, 131.3, 131.2, 131.1, 130.7, 128.4, 127.9, 127.1, 119.1, 112.0, 112.0, 111.0, 110.8, 102.2, 101.9, 45.2, 42.3, 32.4; ESIMS(−), m/z 492 [M−H]; Anal. Calcd for (C26H21ClFN3O4.0.2 H2O): C, 62.77; H, 4.34; N, 8.45. Found: C, 62.56; H, 4.48; N, 8.19.
Rf=0.13 (EtOAc/Hexanes=2H); mp 201-204° C.; IR(ATR): 3275, 2918, 2849, 1701, 1646, 1622, 1595 cm−1; 1H NMR (200 MHz, DMSO-d6) δ 10.78 (br s, 1H), 9.04 (br s, 1H), 8.11 (t, J=8.0 Hz, 1H), 7.51 (d, J=8.0 Hz, 2H), 7.42 (d, J=16.0 Hz, 1H), 7.25-7.05 (m, 8H), 6.42 (d, J=16.0 Hz, 1H), 5.33 (s, 2H), 4.20 (t, J=7.0 Hz, 2H), 2.93 (t, J=7.0 Hz, 2H); 13C NMR (50 MHz, DMSO-d6) δ 168.6, 163.6, 163.4, 162.3, 1603.2, 158.6, 150.7, 141.8, 141.5, 137.9, 137.3, 134.6, 134.6, 134.0, 131.3, 131.1, 130.7, 130.5, 127.1, 127.0, 119.1, 115.3, 114.9, 112.0, 112.0, 111.1, 110.6, 102.3, 101.8, 82.0, 46.2, 42.5, 32.2; ESIMS(m/z 476 [M−H]−; Anal. Calcd for (C26N21F2N3O4): C, 65.40; H, 4.43; N, 8.80. Found: C, 65.47; H, 4.63; N, 8.76.
White solid; Rf=0.32 (EtOAc/Hexanes=2/1); mp 196-198° C.; IR(ATR): 3367, 2949, 2836, 1705, 1671, 1660, 1645, 1621 cm−1; 1H NMR (200 MHz, DMSO-d6) δ 10.78 (br s, 1H), 9.04 (br s, 1H), 8.12 (dd, J=10.0, 6 Hz, 1H), 7.51 (d, J=8.0 Hz, 2H), 7.42 (d, J=16.0 Hz, 1H), 7.23 (d, J=8.0 Hz, 2H), 7.16-7.08 (m, 4H), 6.84 (d, J=8.0 Hz, 2H), 6.41 (d, J=16.0 Hz, 1H), 5.34 (s, 2H), 4.17 (t, J=7.0 Hz, 2H), 3.7 (s, 3H), 2.86 (t, J=7.0 Hz, 2H); 13C NMR (50 MHz, DMSO-d6) δ 168.7, 163.7, 162.8, 160.3, 158.0, 150.8, 141.9, 141.6, 138.0, 137.4, 134.1, 131.5, 131.2, 130.4, 129.9, 128.0, 127.2, 119.1, 114.0, 112.2, 112.1, 111.2, 110.7, 102.4, 101.9, 55.1, 46.3, 42.8, 32.3; ESIMS(−), m/z 488 [M−H]−; Anal. Calcd for (C27H24FN3O5): C, 66.25; H, 4.94; N, 8.58. Found: C, 66.05; H, 5.03; N, 8.31.
Rf=0.24 (EtOAc/Hexanes=2/1); mp 188-190° C.; IR(ATR): 3246, 2922, 2850, 1701, 1647, 1620, 1598 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 10.76 (br s, 1H), 9.23 (br s, 1H), 9.02 (br s, 1H), 8.11 (t, J=7.4 Hz, 1H), 7.52 (d, J=8.0 Hz, 2H), 7.42 (d, J=16.0 Hz, 1H), 7.23 (d, J=8.0 Hz, 2H), 7.11 (t, J=8.8 Hz, 2H), 7.00 (d, J=8.0 Hz, 2H), 6.67 (d, J=8.0 Hz, 2H), 6.43 (d 16.0 Hz, 1H), 5.33 (s, 4.15 (t, J=7.4 Hz, 2H), 2.82 (t, J=7.2 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ 167.3, 164.8, 162.7, 160.1, 155.8, 150.7, 141.7, 141.5, 137.9, 137.3, 134.0, 131.2, 131.1, 129.6, 128.4, 127.8, 127.1, 119.1, 115.2, 112.02, 112.01, 110.9, 110.6, 102.1, 101.8, 46.2, 42.8, 32.2; ESIMS(−), m/z 474 [M−H]−, Anal. Calcd for (C26H22FN3O5.0.6 H2O): C, 64.22; H, 4.81; N, 8.64. Found: C, 64.00; H, 5.01; N, 8.27.
Rf=0.24 (EtOAc/Hexanes=2/1); mp 207-210° C.; IR(ATR); 3355, 3281, 2920, 2850, 1702, 1647, 1605 cm−1; 1H NMR (200 MHz, DMSO-d6) δ 10.77 (br s, 1H), 9.05 (br s, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.52 (d, J=8.0 Hz, 2H), 7.47-7.22 (m, 10H), 6.43 (d, J=16 Hz, 1H), 5.37 (s, 2H), 4.21 (t, J=8.0 Hz, 2H), 2.94 (t, J=7.0 Hz, 2H); 13C NMR (50 MHz, DMSO-d6) δ 162.7, 160.3, 150.6, 140.6, 139.9, 138.4, 137.9, 137.1, 134.0, 130.0, 128.8, 128.5, 127.9, 127.0, 126.4, 123.2, 119.1, 114.6, 114.1, 46.1, 42.6, 33.0; ESIMS(−), m/z 474 [M−H]−; Anal. Calcd for (C26H22ClN3O4.0.1 H2O): C, 65.37; H, 4.68; N, 8.80. Found: C, 65.18; H, 0.91; N, 8.50.
Rf=0.15 (EtOAcHexanes=2/1); mp 199-202° C.; IR(ATR): 3330, 3194, 3028, 2852, 1708, 1655, 1636, 1603 cm−1; 1H NMR (200 MHz, DMSO-d6) δ 10.77 (br s, 1H), 9.25 (br s, 1H), 8.04 (d, J=8.6 Hz, 1H), 7.52 (d, J=7.8 Hz, 2H), 7.42 (J=16.0 Hz, 1H), 7.3 (d, J=8.0 Hz, 2H), 7.22 (d, 7.8 Hz, 2H), 6.99 (d, J=8.0 Hz, 2H), 6.66 (d, J=8.0 Hz, 2H), 6.42 (d, J=16.0 Hz, 1H), 5.35 (s, 2H), 4.14 (t, J=6.8 Hz, 2H), 2.81 (t, J=6.7 Hz, 2H); 13C NMR (50 MHz, DMSO-d6) δ 162.7, 160.3, 155.9, 150.6, 140.6, 139.9, 137.9, 137.3, 134.0, 130.0, 129.7, 128.4, 127.9, 127.0, 123.2, 119.1, 115.2, 114.6, 114.1, 46.1, 42.9, 32.2; ESIMS(−), m/z 490 [M−H]−; Anal. Calcd for (C26H22ClN3O5): C, 63.48; H, 4.51; N, 8.54. Found: C, 63.43; H, 4.58; N, 8.22.
Rf=0.20 (MeOH/DCM= 3/97); mp 229-231° C.; IR(ATR); 3256, 1698, 1657, 1641, 1606 cm−1, 1H NMR (200 MHz, DMSO-d6) δ 10.76 (br s, 1H), 9.04 (br s, 1H), 8.08 (d, J=7.0 Hz, 1H), 7.69 (t, J=7.4 Hz, 1H), 7.55-7.25 (m, 12H), 6.42 (d, J=16.0 Hz, 1H), 5.39 (s, 2H); 13C NMR (50 MHz, DMSO-d6) δ 162.8, 161.5, 151.0, 140.0, 138.0, 137.8, 136.3, 135.5, 133.9, 129.1, 128.9, 128.3, 127.9, 127.3, 123.0, 119.0, 115.9, 115.1, 46.3; ESIMS(−), m/z 412 [M−H]; Anal. Calcd for (C24H19N3O4): C, 69.72; H, 4.63; N, 10.16. Found: C, 69.97; H, 4.64: N, 10.06.
White solid; Rf=0.21 (MeOH/DCM=5/95); mp 181-184° C.; IR(ATR); 3264, 2923, 2848, 2360, 1706, 1658, 1607 cm−1; 1H NMR (200 MHz, DMSO-d6) δ 10.77 (br s, 1H), 9.05 (br s, 1H), 8.07 (d, J=6.8 Hz, 1H), 7.68 (t, J==7.4 Hz, 1H), 7.55-7.23 (m, 9H), 7.02 (d, J=8.8 Hz, 2H), 6.44 (d, J=16.0 Hz, 1H), 5.38 (s, 2H), 3.80 (s, 314); 13C NMR (50 MHz, DMSO-d6) δ 162.7, 161.6, 158.9, 151.2, 139.9, 137.9, 137.8, 135.4, 133.9, 130.0, 128.8, 128.2, 127.8, 127.2, 122.9, 119.0, 115.9, 115.0, 114.1, 55.3, 46.3; ESIMS(−), m/z 442 [M−H]−; Anal. Calcd for (C2H21N3O5.0.1 H2O): C, 67.71; H, 4.77; N, 9.48. Found: C, 67.05; H, 4.77; N, 9.32.
Rf=0.13 (MeOH/DCM=5/95); mp 244-247° C.; IR(ATR): 3287, 2950, 2838, 1702, 1654, 1605 cm−1; 1H NMR (200 MHz, DMSO-d6) δ 10.75 s, 1H), 9.64 (br s, 9.03 (br s, 1H), 8.06 (d, 8.0 Hz, 1H), 7.67 (t, J=7.0 Hz, 1H), 7.51 (t, J=7.6 Hz, 2H), 7.41-7.14 (m, 7H), 6.83 (d, J=8.0 Hz, 2H), 6.41 (d, J=16.0 Hz, 1H), 5.38 (s, 2H); 13C NMR (100 MHz, DMSO-d6) δ 162.7, 161.6, 157.1, 151.2, 139.9, 137.9, 137.8, 1353, 133.9, 129.8, 128.2, 127.8, 127.3, 127.2, 122.9, 119.0, 115.8, 115.3, 115.0, 46.3; ESIMS(−) m/z 428 [M−H]−; Anal. Calcd for (C24H19N3O5.0.1 H2O): C, 66.85; H, 4.49; N, 9.74. Found: C, 66.47; H, 4.68; N, 936.
Rf=0.19 (MeOH/DCM 5%); 1H NMR (400 MHz, DMSO) δ 11.20 (br s, 1H, NH), 9.06 (br s, 1H, OH), 838-8.21 (m, 1H, Ar—H), 8.17-8.05 (m, 8.04-7.92 (m, 1H, Ar—H), 7.92-7.65 (m, 5H, Ar—H), 7.49-726 (m, 4H, Ar—H), 5.53 (d, 1H, CH, J=17.2 Hz), 5.42 (d, 1H, CH, J=17.1 Hz). ESIMS(+), m/z 433 [M+H]+. HPLC 95.9%
Rf=0.19 (MeOH/DCM 5%); mp 122.0-124.5° C.; 1H NMR (400 MHz, DMSO) δ 11.19 (s, 1H, NH), 9.03 (s, 1H, OH), 8.07 (dd, 1H, Ar—H, J=8.0 Hz, 1.4 Hz), 7.74-7.67 (m, 2H, Ar—H), 7.67-7.57 (m, 1H, Ar—H), 7.45-7.37 (m, 2H, Ar—H), 735-7.15 (m, 7H, Ar—H), 5.49-5.31 (m, 2H, CH2), 2.92-2.80 (m, 1H, CH), 2.41-2.29 (m, 1H, CH), 1.69-1.57 (m, 1H, CH), 1.51-1.40 (m, 1H, CH). 13C NMR (100 MHz, DMSO) δ 164.0, 162.1, 151.5, 140.8, 139.74, 139.66, 135.0, 131.8, 128.1, 128.0, 127.2, 126.7, 126.5, 126.0, 122.7, 115.9, 114.8, 46.1, 34.4, 25.6, 17.1. HPLC>99.5%.
Rf=0.24 (MeOH/DCM=10%); mp 189.2-192.8° C.; 1H NMR (400 MHz, DMSO) δ 8.14-7.95 (m, 1H, Ar—H), 7.83-7.52 (m, 3H, Ar—H), 7.40-6.98 (m, 4H, Ar—H), 5.37 (s, 2H, CH2), 4.84 (s, 1H, OH), 4.23-3.94 (m, 2H, CH2), 3.75-3.49 (m, 2H, CH2). ESIMS(+), m/z 356 [M+H]+. HPLC 97.5%.
Rf=0.06 (MeOH/DCM=5%); mp 205.6-206.8° C.; 1H NMR (400 MHz, DMSO) δ 11.21 (s, 1H, NH), 9.05 (s, 1H, OH), 8.08 (pseudo d, 1H, Ar—H, J=7.8 Hz), 7.69 (pseudo d, 2H, Ar—H, J=8.1 Hz), 7.67-7.60 (an, 1H, Ar—H), 7.41-7.15 (m, 9H, Ar—H), 5.57 (d, 1H, OH, J=4.6 Hz), 5.49-5.29 (m, 2H, CH2), 5.12-4.97 (m, 1H, CH), 4.34 (dd, 1H, CH, J=12.8 Hz, 8.7 Hz), 4.04 (dd, 1H, CH, J=12.8 Hz, 5.0 Hz). ESIMS(+), m/z 432 [M+H]+. HPLC>99%
Rf=0.36 (MeOH/DCM 10%); mp 129.5-134.0° C.; 1H NMR (400 MHz, DMSO) δ 11.21 (s, 1H, NH), 9.06 (s, 1H, (1H), 8.17 (dd, 1H, Ar—H, J=8.7 Hz, 6.4 Hz), 7.73 (d, 2H, Ar—H, 8.3 Hz), 7.61 (m, 1H, Ar—H, J=7.7 Hz, 1.6 Hz), 7.58-7.49 (m, 1H, Ar—H), 7.47-7.40 (in 3H, Ar—H), 7.39-7.32 (m, 1H, Ar—H), 7.27 (dd, 1H, Ar—H, J=11.1 Hz, 2.1 Hz), 7.20 (td, 1H, Ar—H, J=8.5 Hz, 2.1 Hz), 5.49 (d, 1H, CH, J=17.2 Hz), 5.39 (d, 1H, CH, J=17.1 Hz). ESIMS(+), m/z 424 [M+H]+. HPLC 98%
Rf=0.43 (MeOH/DCM 1/9); mp 186.4-189.3° C. 1H NMR (400 MHz, DMSO) δ 11.2.1 (s, 1H, NH), 9.06 (s, 1H, OH), 8.11 (d, 1H, Ar—H, J=8.4 Hz), 7.73 d, 2H, Ar—H, J=8.3 Hz), 7.61 (td, 1H, Ar—H, J=7.7 Hz, 1.6 Hz), 7.58-7.49 (m, 1H, Ar—H), 7.49-7.30 (m, 6H, Ar—H), 5.51 (d, 1H, CH, J=17.2 Hz), 5.42 (d, 1H, CH, J=17.2 Hz). ESIMS(+), m/z 438 [M−H]−. HPLC 99%
Rf=0.71 (MeOH/CH2Cl2= 1/9); 1H NMR (400 MHz, DMSO-d6) δ 11.21 (s, 1H), 9.12 (s, 1H), 8.08 (d, J=5.92 Hz, 1H), 7.87 (d, J=7.6 Hz, 1H), 7.72-7.60 (m, 214), 7.49 (d, J=8.1 Hz, 2H), 7.35-7.21 (m, 6H), 5.39 (s, 2H), 5.21 (s, 2H); ESIMS(+), m/z [M+Na]+ 508. HPLC 97%
Rf=0.71 (MeOH/CH2Cl2=1/9); 1H NMR (400 MHz, DMSO-d6) δ 11.17 (s, 1H), 9.03 (s, 1H), 8.07 (d, J=6.3 Hz, 1H), 7.76-7.60 (m, 5H), 7.48 (d, J=7.9 Hz, 2H), 7.37-7.20 (m, 4H), 5.37 (s, 2H), 4.26 (t, J=7.7 Hz, 1H), 3.05 (d, J=7.3 Hz, 1H); ESIMS(+), m/z [M+H]+ 484. HPLC 94%
Rf=0.49 (MeOH/CH2Cl2=1/9); 1H NMR (400 MHz, DMSO-d6) δ 11.19 (s, 1H), 9.03 (s, 1H), 8.28 (d, J=8.1 Hz, 1H), 7.71 (d, J=8.2 Hz, 2H), 7.62 (d, J=8.3 Hz, 1H), 7.54-7.40 (m, 8H), 5.51 (s, 2H): ESIMS(+), m/z [M+H]+; HPLC 95%
Rf=0.23 (MeOH/CH2Cl2=1/9); 1H NMR (400 MHz, DMSO-d6) δ 11.19 (s, 1H), 9.04 (s, 1H), 8.11 (d, J=7.92 Hz, 1H), 7.98-7.65 (m, 5H), 7.55-7.28 (m, 4H), 5.52 (d, J=17.0 Hz, 1H), 5.37 (d, J=17.1 Hz, 1H); ESIMS(+), m/z [M+H]+ 442. HPLC 93%
Rf=0.77 (MeOH/CH2Cl2=5/95); 1H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 9.01 (s, 1H), 8.03 (d, J=7.8 Hz, 1H), 7.73-7.56 (m, 3H), 7.29-7.05 (m, 8H), 5.32 (s, 2H), 4.24 (t, J=7.0 Hz, 2H), 2.99 (t, J=7.0 Hz, 2H); ESIMS(+), m/z [M+Na]+ 454. HPLC 95%
Rf=0.60 (MeOH/CH2Cl2=5/95); 1H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 9.01 (s, 1H), 8.08 (d, J=7.8 Hz, 1H), 7.67 (t, J=6.8 Hz, 2H), 7.36 (d, J=8.0 Hz, 2H), 7.33-7.19 (m, 2H), 5.41 (s, 2H), 4.24 (t, J=7.1 Hz, 2H), 2.74-2.64 (m, 2H); ESIMS(+), m/z [M+H]+ 408. HPLC 98%
Rf=0.69 (MeOH/CH2Cl2=5/95); 1H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 9.02 (s, 1H), 8.10 (dd, J=7.7 Hz, 1.4 Hz, 1H), 7.68 (d, J=8.3 Hz, 3H), 7.42-7.25 (m, 4H), 5.43 (s, 2H), 4.83 (q, 9.1 Hz, 2H); ESIMS(+), m/z [M+Na]+ 416. HPLC 98%
Rf=0.71 (MeOH/Cl2=5/95); 1H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 9.00 (s, 7.94 (d, J=7.9 Hz, 1H), 7.66 (d, J=8.2 Hz, 2H), 7.61-7.49 (m, 1H), 7.31-7.15 (m, 8H), 5.39 (s, 2H), 4.19 (t, J=7.5 Hz, 2H), 2.92 (t, J=7.6 Hz, 2H); ESIMS(+), m/z [M+H]+ 434. HPLC 97%
Rf=0.57 (MeOH/CH2Cl2=5/95); 1H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 9.00 (s, 1H), 7.94 (d, J=7.9 Hz, 1H), 7.66 (d, J=8.2 Hz, 2H), 7.54 (dd, J=14.5 Hz, 8.0 Hz, 1H), 7.29-7.21 (m, 8H), 5.39 (s, 2H), 4.19 (t, J=7.5 Hz, 2H), 2.92 (t, J=7.6 Hz, 2H); ESIMS (+) m/z [M+H]+ 417. HPLC 97%.
Rf=0.71 (MeOH/CH2Cl2=1/9); 1H NMR (400 MHz, DMSO-d6) δ 11.20 (s, 1H), 9.05 (s, 1H), 8.45-8.38 (m, 2H), 8.05 (d, J=7.9 Hz, 1H), 7.75-7.62 (m, 4H), 7.36-7.15 (m, 5H), 5.36 (s, 2H), 4.26 (t, J=7.1 Hz, 2H), 2.99 (t, J=7.1 Hz, 2H); ESIMS(+), m/z [M+H]+ 417. HPLC 98%
Rf=0.43 (MeOH/CH2Cl2=5/95); 1H NMR (400 MHz, DMSO-d6) δ 11.19 (s, 1H), 9.09 (s, 1H), 8.15-8.01 (m, 1H), 8.11 (dd, J=8.0 Hz, 1.4 Hz, 1H), 8.03-7.92 (m, 1H), 7.77-7.68 (m, 4H), 7.45 (d, J=8.2 Hz, 2H), 7.40-7.30 (m, 2H), 5.53 (d, J=17.1 Hz, 1H), 5.38 (d, J=17.2 Hz, 1H); ESIMS(+), m/z [M+H]+ 474. HPLC 95%.
Rf=0.83 (MeOH/CH2Cl2=1/9); 1H NMR (400 MHz, DMSO-d6) δ 11.17 (s, 1H), 9.04 (s, 8.48-8.42 (m, 2H), 8.06 (dd, J=7.8 Hz, 1.3 Hz, 1H), 7.73.4-7.59 (m, 3H), 7.29-7.18 (m, 6H), 5.37 (s, 2H), 4.28 (t, J=7.3 Hz, 2H), 2.99 (t, J=7.2 Hz, 2H); ESIMS(+), m/z [M+H]+ 417. HPLC 95%
Rf=0.51 (MeOH/CH2O2=5/95); 1H NMR (400 MHz, DMSO-d6) δ 11.18 (s, 1H), 9.05 (s, 1H), 8.10-8.04 (m, 1H), 7.73-7.62 (m, 3H), 7.40-7.20 (m, 4H), 5.41 (s, 2H), 4.20 (t, J=6.1 Hz, 2H), 3.58 (t, J=6.1 Hz, 2H), 3.25 (s, 3H); ESIMS (+) [M+Na]+ 392. HPLC 96%
Rf=0.54 (MeOH/CH2Cl2=5.95); 1H NMR (400 MHz, DMSO-d6) δ 11.19 (s, 1H), 9.05 (s, 1H), 8.09 (d, J=7.0 Hz, 1H), 7.77-7.52 (m, 7H), 7.43-7.23 (m, 4H), 5.42 (s, 2H), 5.27 (s, 2H); ESIMS(+), m/z [M+Na]+ 492. HPLC 99%
Rf=0.51 (MeOH/CH2Cl2=5.95); 1H NMR (400 MHz, DMSO-d6) δ 11.19 (s, 1H), 9.04 (s, 1H), 8.10-8.00 (m, 1H), 7.72-7.51 (m, 4H), 7.33-7.11 (m, 7H), 5.32 (s, 2H), 4.28 (t, J=6.9 Hz, 2H), 3.09 (t, J=6.9 Hz, 2H); ESIMS(+) m/z [M+H]+495. HPLC 98%
Rf=0.54 (MeOH/CH2Cl2=5/95); 1H NMR (400 MHz, DMSO-d6) δ 11.20 (s, 1H), 9.05 (s, 1H), 8.14-8.07 (m, 1H), 7.79-7.65 (m, 4H), 7.59-7.54 (m, 1H), 7.52-7.36 (m, 3H), 7.36-7.22 (m, 3H), 5.37 (s, 2H), 5.43 (s, 2H); ESIMS(+), m/z [M+H]+ 470. HPLC 100%
Rf=0.43 (MeOH/CH2Cl2=5/95); 1H NMR (400 MHz, DMSO-d6) δ 11.22 (s, 1H), 9.08 (s, 1H), 8.16-8.09 (m, 1H), 8.02 (t, J=7.1 Hz, 1H), 7.94 (t, J=7.0 Hz, 1H), 7.79-7.68 (m, 3H), 7.6 (t, J=8.0 Hz, 1H), 7.45 (d, J=8.2 Hz, 2H), 7.40-7.3 (m, 1), 5.59-5.34 (m, 2H), ESIMS (+) m/z [M+H]+ 474, HPLC 98%
Rf=0.54 (MeOH/CH2Cl2=1/9); 1H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 9.06 (s, 1H), 8.05 (d, J 7.8 Hz, 1H), 7.70-7.36 (m, 8H), 7.32-7.10 (m, 4H), 6.42 (d, J=15.8 Hz, 1H), 5.34 (s, 2H), 4.27 (t, J=7.3 Hz, 1H), 3.07 (t, J=7.3 Hz, 1H); ESIMS (+) m/z [M−H]− 508.
Rf=0.71 (MeOH/CH2Cl2=5/95); 1H NMR (400 MHz, DMSO-d6) δ 11.2 (s, 1H), 9.06 (s, 1H), 8.12 (d, J=7.7 Hz, 1H), 7.73 (d, J=7.9 Hz, 3H), 7.55-7.25 (m, 7H), 5.47 (s, 2H), 2.68 (s, 2H), 1.08 (s, 12H); ESIMS(+), m/z [M+H]+ 472. HPLC 95%
Rf=0.51 (MeOH/CH2Cl2=5/95); 1H NMR (400 MHz, DMSO-d6) δ 11.19 (S, 1H), 9.05 (s, 1H), 8.09 (s, 1H), 7.71 (d, J=5.8 Hz, 3H), 7.63-7.17 (m, 8H), 5.43 (s, 2H), 2.47-7.34 (m, 2H), 1.06 (d, J=7.1 Hz, 3H); ESIMS(+), m/z [M+H]+ 416. HPLC 97%
Rf=0.43 (MeOH/CH2Cl2=5/95); 1H NMR (400 MHz, DMSO-d6) δ 10.8 (s, 1H), 8.10 (d, J=7.7 Hz, 1H), 7.73 (t, J=7.7 Hz, 1H), 7.66-7.49 (m, 4H), 7.48-7.28 (m, 7H), 6.44 (d, J=15.8 Hz, 1H), 5.46 (d, J=17.0 Hz, 1H), 5.38 (d, J=17.1 Hz, 1H); ESIMS (+) m/z [M+H]+ 432. HPLC 98%
Rf=0.69 (MeOH/CH2Cl2=5/95); 1H NMR (400 MHz, DMSO-d6) δ 11.4 (s, 1H), 8.12 (d, J=7.7 Hz, 1H), 7.88-7.68 (m, 5H), 7.57 (t, J=8.0 Hz, 1H), 7.47 (d, J=8.2 Hz, 2H), 0.38-7.30 (m, 2H), 5.46 (q, J=17.0 Hz, 2H), 2.23 (s, 3H); ESIMS (+) m/z [M+H]+ 470. HPLC 98%
Ff=0.57 (MeOH/CH2Cl2=5/95); 1H NMR (400 MHz, DMSO-d6) δ 11.19 (s, 1H), 9.04 (s, 1H), 8.06 (dd, J=8.1 Hz, 3.9 Hz, 1H), 7.73-7.56 (m, 3H), 7.36-7.12 (m, 5H), 6.85-6.70 (m, 3H), 5.37 (s, 2H), 4.21 (t, J=7.6 Hz, 2H), 3.67 (s, 3H), 2.91 (t, J=7.5 Hz, 2H); ESIMS(+), m/z [M+Na]+ 468. HPLC 99%
Rf=0.67 (MeOH/CH2Cl2=5/95); 1H NMR (400 MHz, DMSO-d6) δ 11.18 (s, 1H), 9.04 (s, 1H), 8.06 (dd, J=7.8 Hz, 1.5 Hz, 1H), 7.73-7.59 (m, 3H), 7.35-7.18 (m, 4H), 6.84-6.77 (m, 2H), 6.64 (dd, J=8.0 Hz, 1.4 Hz, 1H), 5.95 (s, 2H), 5.38 (s, 2H), 4.18 (t, J=7.5 Hz, 2H), 2.86 (t, J=7.5 Hz, 2H); ESIMS (+) m/z [M+H]+ 460. HPLC 95%
Rf=0.77 (MeOH/CH2Cl2=5/95); 3H NMR (400 MHz, DMSO-d6) δ 11.18 (s, 1H), 9.05 (s, 1H), 8.07 (dd, J=7.9, 1.5 Hz, 1H), 7.74-7.57 (m, 3H), 7.35-7.18 (m, 4H), 6.92-6.69 (m, 3H), 5.39 (s, 2H), 4.21 (t, J=7.6 Hz, 2H), 3.70 (s, 3H), 3.66 (s, 3H), 2.88 (t, J=7.6 Hz, 2H); ESNS (+) m/z [M+H]+ 476. HPLC 98%.
Rf=0.75 (MeOH/CH2Cl2=1/9); 1H NMR (400 MHz, DMSO-d6) δ 11.22 (s, 1H), 9.06 (s, 1H), 7.77-7.65 (m, 3H), 7.64-7.46 (m, 4H), 7.23 (d, J=8.1 Hz, 2H), 6.65 (d, J 7.0 Hz, 1H), 5.26 (s, 2H), 4.22 (t, J=7.2 Hz, 2H), 3.04 (t, J=7.2 Hz, 2H); ESIMS (+) m/z [M+H]+ 518. HPLC 97%
Rf=0.81 (MeOH/CH2Cl2=5/95); 1H NMR (400 MHz, DMSO-d6) δ 11.2 (s, 1H), 9.09 (s, 1H), 8.05 (dd, J=7.9 Hz, 1.4 Hz, 1H), 7.79-7.57 (m, 3H), 7.51-7.40 (m, 2H), 7.36-7.09 (m, 6H), 5.37 (s, 2H), 4.21 (t, J=7.7 Hz, 2H), 2.92 (t, J=7.4 Hz, 2H); ESIMS(+), m/z [M+Na]+ 516. HPLC 95%
Rf=0.93 (MeOH/CH2Cl2=5/95); 1H NMR (400 MHz, DMSO-d6) δ 11.19 (s, 1H), 9.06 (s, 1H), 8.12 (d, J=6.8 Hz, 1H), 7.82-7.68 (m, 3H), 7.47-7.16 (m, 7H), 5.47 (s, 2H), 2.05 (s, 6H); ESIMS(+), m/z [M+H]+ 416. HPLC 99%
Rf=0.33 (MeOH/CH2Cl2=5/95); 1H NMR (400 MHz, DMSO-d6) δ 11.23 (s, 1H), 9.07 (s, 1H), 8.09 (dd, J=7.8 Hz, 1.4 Hz, 1H), 7.79-7.56 (m, 5H), 7.56-7.42 (m, 4H), 735-7.19 (m, 2H), 5.42 (s, 2H); ESIMS(+), m/z [M+H]+ 472. HPLC 98%
Rf=0.59 (MeOH/CH2Cl2=1/9); 1H NMR (400 MHz, DMSO-d6) δ 11.17 (br s, 1H), 9.12 s, 1H), 8.20-8.00 (m, 1H), 7.82-7.64 (m, 3H), 7.48-7.28 (m, 8H), 5.43 (s, 2H), 2.09 (s, 3H); ESIMS(+), m/z 402.2 [M+H]+. HPLC 96%.
Rf=0.45 (MeOH/CH2Cl2=1/9); 1H NMR (400 MHz, DMSO d6) δ 11.16 (br s, 1H), 9.13 (br s, 1H), 8.04 (d, J=7.6 Hz, 1H), 7.76-7.56 (m, 3H), 7.33 (d, J=7.6 Hz, 2H), 7.26-7.17 (m, 2H), 5.37 (s, 2H), 4.92-4.75 (m, 1H), 2.47-2.31 (m, 2H), 1.84-1.75 (m, 2H), 1.71-1.57 (m, 3H), 1.37-1.25 (m, 2H)), 1.21-1.07 (m, 1H); ESIMS(+), m/z 394.1 [M+H]+. HPLC 98%.
Rf=0.58 (MeOH/CH2Cl2=3/7); 1H NMR (400 MHz, DMSO-d6) δ 11.17 (br s, 1H), 9.04 (br s, 1H), 8.05 (d, J=7.8 Hz, 1H), 7.68 (d, J=8.0 Hz, 2H), 7.62 (t, J=7.8 Hz, 1H), 7.34 (d, J=8.0 Hz, 2H), 7.24 (t, J=7.6 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 5.37 (s, 2H), 4.87-4.73 (m, 1H), 2.86 (d, J=11.0 Hz, 2H), 2.72-2.61 (m, 2H), 2.17 (s, 3H), 2.02-1.87 (m, 2H), 1.67-1.50 (m, 2H); ESIMS(+), m/z 409.1 [M+H]+. HPLC 98%.
Rf=0.30 (MeOH/CH2Cl2=1/9); 1H NMR (400 MHz, DMSO-d6) δ 11.20 (s, 1H), 9.04 (s, 1H), 8.74 (d, J=4.9 Hz, 2H), 8.09 (d, J=7.8 Hz, 1H), 7.73-7.68 (m, 3H), 7.54 (d, J=4.8 Hz, 2H), 7.48 (d, J=8.0 Hz, 2H), 7.34-7.26 (m, 2H), 5.42 (s, 2H); ESIMS(+), m/z 389.1 [M+H]+; HPLC 94%.
Rf=0.58 (MeOH/CH2Cl2=1/9): 1H NMR (400 MHz, DMSO-d6) δ 11.20 (s, 1H), 9.03 (br s, 1H), 8.09 (dd, J=7.8 Hz, 1.4 Hz, 1H), 7.94 (s, 7.85-7.74 (m, 3H), 7.73-7.67 (m, 3H), 7.48 (d, J=8.2 Hz, 2H), 7.33-7.24 (m, 2H), 5.42 (s, 2H); ESIMS(+), m/z 455.9 [M+H]+; HPLC 95%.
Rf=0.23 (MeOH/CH2Cl2=1/9); 1H NMR (400 MHz, DMSO-d6) δ 11.21 (br s, 1H), 8.77 (d, J=2.3 Hz, 1H), 8.71 (dd, J=4.9 Hz, 1.2 Hz, 1H), 8.13-8.09 (m, 2H), 7.75-7.69 (m, 4H), 7.49 (d, J=8.2 Hz, 2H), 7.34-7.28 (m, 2H), 5.44 (s, 2H); ESIMS(+), m/z 388.9 [M+H]+; HPLC>99%.
Rf=0.40 (MeOH/CH2Cl2=1/9), 1H NMR (400 MHz, DMSO-d6) δ 11.17 (s, 1H), 9.03 (s, 1H), 8.06 (dd, J=7.8 Hz, 1.4 Hz, 1H), 7.70-7.60 (m, 3H), 7.39 (d, J==8.2 Hz, 2H), 7.26 (t, J=7.6 Hz, 1H), 7.19 (d, J=8.5 Hz, 1H), 5.38 (s, 2H), 5.23-5.13 (m, 1H), 3.58-3.41 (m, 2H), 2.97-2.87 (m, 2H); ESIMS(+), m/z 424.1 [M+Na]+. HPLC 93%.
Rf=0.17 (MeOH/CH2Cl2=3/7); 1H NMR (400 MHz, DMSO-d6) δ 8.04 (d, J=7.8 Hz, 1H), 7.69 (d, J=7.8 Hz, 2H), 7.62 (t, J=7.8 Hz, 1H), 7.34 (d, J=8.0 Hz, 2H), 7.26-7.17 (m, 2H), 5.37 (s, 2H), 4.93-4.80 (m, 1H), 3.43 (t, J=11.3 Hz, 1H), 2.83 (d, J=11.4 Hz, 2H), 2.57-2.44 (m, 1H), 2.36 (t, J=11.8 Hz, 1H), 1.78-1.66 (m, 2H), 1.55-1.40 (m, 1H); ESIMS(+), m/z 395.2 [M+H]+. HPLC 94%
Rf=0.52 (MeOH/CH2Cl1=1/9); 1H NMR (200 MHz, DMSO-d6) δ 12.29 (br s, 1H), 8.08 (d, J=7.8 Hz, 1H), 7.74 (d, J=8.1 Hz, 2H), 7.69-7.58 (m, 1H), 7.36-7.17 (m, 9H), 5.41 (s, 2H), 4.24 (t, J=7.5 Hz, 2H), 2.95 (t, J=7.4 Hz, 2H), 2.21 (s, 3H); ESIMS(−), m/z 456.2 [M−H]−. HPLC 96%.
Rf=0.36 (MeOH/CH2Cl2=1/9); 1H NMR (200 MHz, DMSO-d6) δ 11.18 (s, 1H), 9.03 (s, 1H), 8.05 (dd, J=7.8 Hz, 1.6 Hz, 1H), 7.73-7.62 (m, 3H), 7.61-7.50 (m, 4H), 7.30-7.18 (m, 4H), 5.37 (s, 2H), 4.27 (t, J=7.1 Hz, NI), 3.07 (t, J=7.3 Hz, 2H); ESIMS(+), m/z 506.2 [M+Na]+. HPLC 98%.
Rf=0.45 (MeOH/CH2Cl2=1:9), 1H NMR (400 MHz, DMSO-d6) δ 11.18 (s, 1H), 9.02 (s, 1H), 8.09 (dd, J=7.8 Hz, 1.4 Hz, 1H), 7.71-7.66 (m, 3H), 7.41-7.36 (m, 4H), 7.35-7.27 (m, 4H), 5.42 (s, 2H), 5.25 (s, 2H); ESIMS(+), m/z 508.1 [M+Na]+. HPLC 99%
Rf=0.41 (MeOH/CH2Cl2=1/9); 1H NMR (400 MHz, DMSO-d6) δ 11.19 (s, 1H), 9.04 (d, J=1.4 Hz, 1H), 8.07 (dd, J=7.8 Hz, 1.4 Hz, 1H), 7.71-7.59 (m, 5H), 7.49-7.42 (m, 2H), 7.29-7.20 (m, 4H), 5.36 (s, 2H), 4.27 (t, J=7.2 Hz, 2H), 3.13 (t, J=7.0 Hz, 2H); ESIMS(−), m/z 482.2 [M−H]−; HPLC 95%.
Rf=0.54 (MeOH/CH2Cl2=1/9); 1H NMR (400 MHz, DMSO-d6) δ 12.28 (s, 1H), 8.06 (dd, J=7.8 Hz, 1.5 Hz, 1H), 7.74 (d, J=8.3 Hz, 2H), 7.66-7.61 (m, 1H), 7.59-7.50 (m, 4H), 7.34 (d, J=8.3 Hz, 2H), 7.26 (t, J=7.5 Hz, 1H), 7.20 (d, J=8.5 Hz, 1H), 5.40 (s, 2H), 4.27 (t, J=7.4 Hz, 2H), 3.07 (t, J=7.3 Hz, 2H), 2.21 (s, 3H); ESIMS(−), m/z 524.2 [M−H]−. HPLC 97%.
Rf=0.11 (MeOH/CH2Cl2=1/9); 1H NMR (400 MHz, DMSO-d6) δ 9.06 (br s, 1H), 8.06 (d, J=7.8 Hz, 1H), 7.72 (d, 8.2 Hz, 2H), 7.68-7.64 (m, 1H), 7.38 (d, J=8.0 Hz, 2H), 7.28 (t, J=7.5 Hz, 1H), 7.23 (d, J=8.5 Hz, 1H), 5.44-5.33 (m, 3H), 4.08 (t, J=12.1, 1H), 3.61-3.55 (m, 2H), 3.36-3.25 (m, 7H), 2.59-2.51 (m, 1H), 2.20-2.06 (m, 1H), 1.96-1.86 (m, 2H); ESIMS(+), m/z 423.3 [M+H]+. HPLC 94.1%.
Rf=0.14 (MeOH/CH2Cl2=1/9); 1H NMR (400 MHz, DMSO-d6) δ 11.17 (br s, 1H), 9.06 (br s, 1H), 8.05 (dd, J 7.9 Hz, 1.4 Hz, 1H), 7.69 (d, J=8.2 Hz, 2H), 7.65-7.60 (m, 1H), 7.35 (d, J=8.2 Hz, 2H), 7.24 (t, J=7.5 Hz, 1H), 7.19 (d, J=8.5 Hz, 1H), 5.37 (s, 2H), 5.04-4.94 (m, 1H), 2.89-2.78 (m, 3H), 2.45-2.29 (m, 3H), 1.85 (t, J=11.2 Hz, 1H), 1.77-1.67 (m, 2H), 1.60-1.48 (m, 1H), 0.99 (t, J=7.1 Hz, 3H); ESIMS(+), m/z 423.2 [M+H]+. HPLC 99%.
Rf=0.30 (MeOH/CH2Cl2=1/9); 1H NMR (400 MHz, DMSO-d6) δ 11.21 (s, 1H), 9.09 (s, 1H), 8.06 (dd, J=7.9 Hz, 1.3 Hz, 1H), 7.68-7.60 (m, 3H), 7.28-7.24 (m, 3H), 7.19 (d, J=8.5 Hz, 1H), 7.11 (d, J=8.5 Hz, 2H), 6.84 (d, J=8.6 Hz, 2H), 5.37 (s, 2H), 4.94 (t, J=5.5 Hz, 1H), 4.18 (t, J=7.6 Hz, 2H), 3.91 (t, J=4.9 Hz, 2H), 3.68 (q, J=5.1 Hz, 2H), 2.86 (t, J=7.6 Hz, 2H); ESIMS(−), m/z 474.3 [M−H]−. HPLC 100%.
Rf=0.43 (MeOH/CH2Cl2=1/9); 1H NMR (400 MHz, DMSO-d6) δ 12.97 (s, 1H), 8.78 (s, 3H), 8.07-8.04 (m, 1H), 7.81 (d, J=8.3 Hz, 2H), 7.66-7.61 (m, 1H), 7.56-7.52 (m, 3H), 7.35 (d, J=8.3 Hz, 2H), 7.26 (t, J=7.4 Hz, 2H), 7.21 (d, J=8.5 Hz, 1H), 5.41 (s, 2H), 4.29-4.22 (m, 3H), 3.07 (t, J=7.3 Hz, 2H), 2.37-2.27 (m, 1H), 1.12 (d, J=7.0 Hz, 3H), 1.07 (d, J=6.9 Hz, 3H); HPLC 100%
Rf=0.43 (MeOH/CH2Cl1=1/9); 1H NMR (400 MHz, DMSO-d6) δ 11.22 (s, 1H), 9.07 (s, 1H), 8.08 (d, J=7.8 Hz, 1H), 7.63 (t, J=7.8 Hz, 1H), 7.42 (s, 1H), 7.31-7.19 (m, 7H), 7.03 (d, J=8.5 Hz, 1H), 6.77 (d, J=7.8 Hz, 1H), 5.24 (s, 2H), 4.21 (t, J=7.6 Hz, 2H), 3.95 (s, 3H), 2.93 (t, J=7.6 Hz, 2H); ESIMS(−), m/z 444.3 [M−H]−. HPLC 100%
Rf=0.32 (MeOH/CH2Cl2=1/9); 1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 9.05 (s, 1H), 8.05 (dd, J=7.8 Hz, 1.3 Hz, 1H), 7.68-7.63 (m, 1H), 7.59-7.49 (m, 4H), 7.28-7.17 (m, 4H), 6.97 (d, J=7.9 Hz, 1H), 5.32 (s, 2H), 4.26 (t, J=7.4 Hz, 2H), 3.06 (t, J=7.3 Hz, 2H), 2.28 (s, 3H); ESIMS(−), m/z 496.1 [M−H]−. HPLC 98%
Rf=0.48 (MeOH/CH2Cl2=1/9); 1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 9.21 (s, 1H), 8.08 (dd, J=7.8 Hz, 1.4 Hz, 1H), 7.68-7.63 (m, 1H), 7.47 (t, J=7.6 Hz, 1H), 7.31-7.19 (m, 8H), 7.09 (d, J=8.3 Hz, 1H), 5.38 (s, 2H), 4.21 (t, J=7.7 Hz, 2H), 2.94 (t, J=7.6 Hz, 2H); ESIMS(−), m/z 432.1 [M−H]−. HPLC 99%.
Rf=0.12 (MeOH/CH2Cl2=1/9); 1H NMR (400 MHz, DMSO-d6) δ 11.15 (s, 1H), 9.04 (s, 1H), 8.85 (s, 1H), 8.72 (s, 1H), 8.07 (dd, J=7.9 Hz, 1.5 Hz, 1H), 7.69 (d, J=8.2 Hz, 2H), 7.66-7.61 (m, 1H), 7.30 (d, 8.2 Hz, 2H), 7.26 (t, J=7.6 Hz, 1H), 7.21 (d, J=8.5 Hz, 1H), 6.65-6.60 (m, 2H), 6.45 (dd, J=8.0 Hz, 1.9 Hz, 1H), 5.39 (s, 2H), 4.13 (t, J=7.7 Hz, 2H), 2.74 (t, J=7.7 Hz, 2H); ESIMS(−), m/z 446.1 [M−H]−. HPLC 99%.
Rf=0.31 (MeOH/CH2Cl2=1/9); 1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.64 (s, 1H), 8.03 (dd, J=7.8 Hz, 1.4 Hz, 1H), 7.77-7.71 (m, 1H), 7.54-7.45 (m, 5H), 7.27 (t, J=7.5 Hz, 1H), 4.21 (t, J=7.2 Hz, 2H), 3.93 (d, J=6.4 Hz, 2H), 3.01 (t, J==7.1 Hz, 2H), 1.91 (t, J=11.9 Hz, 1H), 1.71-1.55 (m, 5H), 1.32-1.20 (m, 2H), 1.08-0.95 (m, 2H); ESIMS(+), m/z 490.3 [M+H]+. HPLC 96%
Rf0.38 (MeOH/CH2Cl2=1/9); 1H NMR (400 MHz, DMSO-d6) δ 11.15 (br s, 1H), 9.08 (br s, 1H), 8.10 (d, J=7.7 Hz, 1H), 7.76-7.69 (m, 3H), 7.69-7.63 (m, 2H), 7.54-7.49 (m, 2H), 7.43-7.29 (m, 4H), 5.52-5.37 (m, 2H); ESIMS(+), m/z 422.1 [M+H]+. HPLC 95%.
Rf=0.54 (MeOH/CH2Cl2=1/9); 1H NMR (400 MHz, DMSO-d6) δ 11.23 (br s, 1H), 9.10 (br s, 1H), 8.08 (d, J=7.3 Hz, 1H), 7.76-7.63 (m, 3H), 7.58-7.51 (m, 1H), 7.49-7.37 (m, 3H), 7.34-7.25 (m, 4H), 5.40 (s, 2H); ESIMS(+), m/z 406.1 [M+H]+. HPLC 94%.
Rf=0.47 (MeOH/CH2Cl2=1/9); 1H NMR (400 MHz, DMSO-d6) δ 12.30 (s, 1H), 8.11 (dd, J=8.0 Hz, 1.4 Hz, 1H), 7.79 (d, J=8.3 Hz, 2H), 7.75-7.70 (m, 1H), 7.65-7.59 (m, 1H), 7.56-7.48 (m, 3H), 7.45-7.39 (m, 1H), 7.38-7.31 (m, 3H), 5.57-5.40 (m, 2H), 2.21 (s, 3H); ESIMS(−), m/z 446.0 [M−H]−. HPLC 97%.
Rf=0.26 (MeOH/DCM=1/9); 1H NMR (400 MHz, DMSO-d6) δ 12.79 (br s, 1H), 8.59 (br s, 3H), 8.07 (dd, J=8.0 Hz, 1.6 Hz, 1H), 7.77 (d, J=8.4 Hz, 2H), 7.63 (ddd, J=8.0 Hz, 7.6 Hz, 1.6 Hz, 1H), 7.37-7.20 (m, 9H), 5.42 (s, 2H), 4.30 (br d, J=3.6 Hz, 1H) 4.23 (dcl, 1==8.0 Hz, 6.8 Hz, 2H), 2.95 (dd, J=7.6 Hz, 7.6 Hz, 2H), 2.25-2.30 (m, 1H), 1.10 (d, J=6.8 Hz, 3H), 1.06 (d, J=6.8 Hz, 3H).
Rf=0.36 (MeOH/CH2Cl2=1/9); 1H NMR (400 MHz, DMSO-d6) δ 7.99 (dd, J=8.0 Hz, 1.6 Hz, 1H), 7.64 (d, J=8.0 Hz, 2H), 7.58-7.54 (m, 1H), 7.32 (d, J=7.6 Hz, 2H), 7.20-7.12 (m, 2H), 5.33 (s, 2H), 2.74-2.70 (m, 1H), 1.03-0.98 (m, 2H), 0.76-032 (m, 2H); ESIMS(+), m/z=352 [M+H]+; HPLC 98%
Rf=0.45 (MeOH/CH2Cl2=1/9); 1H NMR (400 MHz, DMSO-d6) δ 8.04 (dd, J=8.0 Hz, 1.2 Hz, 1H), 7.67-7.59 (m, 3H), 7.32-7.20 (m, 4H), 5.38 (s, 2H), 3.86 (d, J=6.8 Hz, 2H), 1.22-1.17 (m, 1H), 0.42-0.34 (m, 4H); ESIMS(+), m/z 366 [M+H]+; HPLC 98%.
Rf=0.20 (MeOH/CH2Cl2=1/9); 1H NMR (400 MHz, DMSO-d6) δ 8.06 (d, J 7.6 Hz, 1H), 7.68-7.61 (m, 3H), 7.28-7.20 (m, 4H), 7.12 (d, J=8.4 Hz, 2H), 6.84 (d, J=8.4 Hz, 2H), 5.38 (br s, 2H), 4.17 (dd, J=8.0 Hz, 7.2 Hz, 2H), 3.99 (dd, J=6.0 Hz, 6.0 Hz, 2H), 2.86 (dd, J=7.6 Hz, 7.6 Hz, 2H), 2.62 (dd, J=6.0 Hz, 5.6 Hz, 2H), 2.40 (br s, 4H), 1.49-1.44 (m, 4H), 1.35 (br d, J=5.2 Hz, 2H); ESIMS(+), m/z=543 [M+H]+; HPLC 96%.
Rf=0.34 (MeOH/CH2Cl2=1/9); 1H NMR (400 MHz, DMSO-d6) δ 11.10 (br s, 1H), 9.03 (br s, 1H), 7.67 (d, J=8.0 Hz, 2H), 7.50 (d, J=2.8 Hz, 1H), 7.31-7.13 (m, 9H), 5.35 (br s, 2H), 4.22 (dd, J=8.4 Hz, 6.4 Hz, 2H), 4.12 (br d, J=3.2 Hz, 2H), 3.64 (br d, J=4.0 Hz, 2H), 3.27 (s, 3H), 2.94 (dd, 7.6 Hz, 7.2 Hz, 2H).
Rf=0.37 (MeOH/CH2Cl2=1/9); 1H NMR (400 MHz, DMSO-d6) d 11.3 (br s, 1H), 9.19 (br s, 1H), 8.75 (d, J=1.2 Hz, 1H), 8.01 (d, J=8.0 Hz, 2H), 7.62-7.47 (m, 5H), 7.33 (d, J=8.0 Hz, 1H), 7.22 (d, J=8.0 Hz, 7.6 Hz, 2H), 5.44 (s, 2H), 4.20 (dd, J=8.0 Hz, 6.8 Hz, 2H), 3.00 (dd, J=7.6 Hz, 6.8 Hz, 2H).
Rf=0.42 (MeOH/CH2Cl2=1/9); 1H NMR (400 MHz, DMSO-d6) δ 11.16 (br s, 1H), 9.02 (br s, 1H), 8.03 (d, J=7.6 Hz, 1H), 7.67-7.59 (m, 3H), 7.35 (d, J=8.0 Hz, 2H), 7.24-7.16 (m, 2H), 5.56-5.32 (m, 4H), 2.27-2.15 (m, 1H), 1.98-1.72 (m, 5H); ESIMS(−), m/z=396 [M−H]−.
Rf0.32 (MeOH/CH2Cl2==1/9); 1H NMR (400 MHz, DMSO-d6) δ 8.06 (dd, J=7.6 Hz, 1.2 Hz, 1H), 7.69 (d, J=8.4 Hz, 2H), 7.65-7.61 (m, 1H), 7.35 (d, J=8.0 Hz, 2H), 7.27-7.22 (m, 2H), 5.40 (s, 2H), 4.13 (dd, J=6.4 Hz, 6.4 Hz, 2H), 3.52-3.49 (m, 4H), 2.56 (dd, J=6.4 Hz, 6.4 Hz, 2H), 2.43 (br s, 4H); ESIMS(+), m/z=425 [M+H]+.
Rf=0.40 (MeOH/CH2Cl2=1/9); 1H NMR (400 MHz, DMSO-d6) d 11.18 (br s, 1H), 9.04 (br s, 1H), 8.07 (d, J=7.6 Hz, 1H), 7.77-7.64 (m, 4H), 7.49-7.21 (m, 6H), 5.46 (d, J=17.2 Hz, 1H), 5.35 (d, J=16.8 Hz, 1H); ESIMS(+), m/z=446 [M+Na]+.
Rf=0.28 (MeOH/CH2Cl2=1/9): 1H NMR (400 MHz, DMSO-d6) d 11.18 (br s, 1H), 14.33 (br s, 1H), 9.04 (br s, 1H), 8.06-7.98 (m, 2H), 7.69-7.28 (m, 9H), 5.39 (br s, 2H).
Rf=0.35 (MeOH/CH2Cl2=1/9); 1H NMR (400 MHz, DMSO-d6) d 8.06 (dd, J=7.6 Hz, 1.2 Hz, 1H), 7.89-7.82 (m, 2H), 7.75-7.68 (m, 5H), 7.37-7.27 (m, 4H), 5.47 (d, J=16.4 Hz, 1H), 5.34 (d, J=16.8 Hz, 1H); ESIMS(+), m/z=456 [M+H]+; HPLC 94%.
Rf=0.37 (MeOH/CH2Cl2=1/9): 1H NMR (400 MHz, DMSO-d6) d 11.17 (br s, 1H), 9.03 (br s, 1H), 8.07 (d, J=7.2 Hz, 1H), 7.70-7.66 (m, 3H), 7.57 (d, J=8.0 Hz, 1H), 7.40-7.24 (m, 7H), 5.46 (d, J=16.8 Hz, 1H), 5.37 (d, J=17.2 Hz, 1H), 1.18 (s, 9H); ESIMS(+), m/z=444 [M+H]+; HPLC 98%.
Rf=0.28 (MeOH/CH2Cl2=1/9); 1H NMR (400 MHz, DMSO-d6) d 11.19 (br s, 1H), 9.033 (br s, 1H), 8.07 (br s, 1H), 7.79-7.61 (m, 3H), 7.43-7.27 (m, 8H), 5.40 (br s, 2H), 3.59 (br s, 8H), 2.42 (br s, 2H); ESIMS(+), m/z=487 [M+H]+; HPLC 97%.
Rf=0.34 (MeOH/CH2Cl2=1/9); 1H NMR (400 MHz, DMSO-d6) d 11.15 (br s, 1H), 9.01 (br s, 1H), 8.05 (d, J=7.6 Hz, 1H), 7.65-7.60 (m, 3H), 7.49-7.45 (m, 1H), 7.38-7.32 (m, 2H), 7.26-7.18 (m, 5H), 5.38 (br s, 2H), 4.38-4.31 (m, 4H): ESIMS(+), m/z=500 [M+H]+; HPLC 99%.
Rf=0.22 (MeOH/CH2Cl2=5/95); 1H NMR (400 MHz, DMSO-d6) d 11.15 (br s, 1H), 9.00 (br s, 1H), 8.00 (dd, J=8.0 Hz, 1.2 Hz, 1H), 7.63 (d, J=8.4 Hz, 2H), 7.60-7.55 (m, J=7.25-7.11 (m, 9H), 5.36 (d, J=17.2 Hz, 1H), 5.24 (d, J=16.8 Hz, 1H), 4.20 (dd, J=8.0, 8.0 Hz, 1H), 4.09 (dd, J=7.6 Hz, 7.6 Hz, 1H), 3.35-3.29 (m, 1H), 1.22 (d, J=6.8 Hz, 1H); ESIMS(+), m/z=430 [M+H]+; HPLC 98%.
Rf=0.32 (MeOH/CH2Cl2=1/9); 1H NMR (400 MHz, DMSO-d6) δ 11.1 (s, 1H), 10.12 (br s, 1H), 9.02 (br s, 1H), 8.01 (dd, J=8.0 Hz, 1.6 Hz, 1H), 7.67-7.59 (m, 3H), 7.38 (d, J=8.0 Hz, 2H), 7.33-7.19 (m, 6H), 5.37 (s, 2H), 4.25-4.17 (m, 4H), 3.86 (br s, 2H), 3.59 (br s, 2H), 3.05 (br s, 4H), 2.94 (dd, J=7.6, 7.2 Hz, 2H); ESIMS(+), m/z=515 [M+H]+; HPLC 96%.
Rf=0.14 (MeOH/CH2Cl2=1/9); 1H NMR (400 MHz, DMSO-d6) d 11.14 (br s, 1H), 9.00 (br s, 1H), 8.01 (dd, J=8.0 Hz, 1.6 Hz, 1H), 7.65 (d, J=8.4 Hz, 2H), 7.66-7.58 (m, 1H), 7.27 (d, J=8.4 Hz, 2H), 7.25-7.11 (m, 6H), 5.35 (br s, 2H), 4.17 (dd, J=8.0 Hz, 7.6 Hz, 2H), 3.12 (s, 2H), 2.88 (dd, J=8.0 Hz, 7.6 Hz, 2H), 2.24 (br s, 4H), 1.42-1.40 (m, 4H), 1.32 (br s, 2H); ESIMS(+), m/z=513 [M+H]+; HPLC 100%.
Rf=0.38 (MeOH/CH2Cl2=1:10). 1H NMR (400 MHz, DMSO-d6) δ 11.2 (s, 1H) 9.05 (s, 1H), 8.17 (d, J=8.7 Hz, 2H), 8.07 (dd, J=7.9 Hz, 1.6 Hz, 1H), 7.36-7.69 (m, 3H), 7.55 (d, J=8.7 Hz, 2H), 7.22-731 (m, 4H), 5.38 (s, 2H), 4.29 (t, J=6.8 Hz, 2H), 3.11 (t, J=7.3 Hz, 2H); ESIMS(+) m/z 483 [M+Na]+; HPLC 99%.
Rf=0.2 (MeOH/CH2Cl3=1:10); 1H NMR (400 MHz, DMSO-d6) δ 11.17 (s, 1H), 9.04 (s, 1H), 8.08 (dd, J=7.8 Hz, 1.5 Hz, 1H), 7.62-7.71 (m, 3H), 7.21-7.32 (m, 4H), 6.89 (d, J=8.3 Hz, 2H), 6.52 (d, J=8.3 Hz, 2H), 5.40 (s, 2H), 5.11 (s, 2H), 4.14 (t, J=7.6 Hz, 2H), 2.76 (t, J=7.8 Hz, 2H); m/z 431 [M+H]+; HPLC 94%.
Rf=0.01 (MeOH/CH2Cl2=1:10); 1H NMR (400 MHz, DMSO-d6) δ 12.67 (s, 1H) 11.16 (s, 1H), 9.02 (s, 1H), 8.07 (d, J 7.5 Hz, 1H), 7.88 (d, J=8.0 Hz, 2H), 7.70-7.65 (m, 3H), 7.22-7.39 (m, 6H), 5.40 (s, 2H), 4.26 (t, J=7.2 Hz, 2H), 3.03 (t, J=7.6 Hz, 2H); ESIMS(+) m/z 460 [M+H]+; HPLC 95%.
Rf=0.5 (MeOH/CH2Cl2=1:10); 1H NMR (400 MHz, DMSO-d6) δ 11.17 (s, 1H), 9.03 (s, 1H), 8.13 (d, J=7.8 Hz, 1H), 7.72-7.78 (m, 3H), 7.34-7.43 (m, 6H), 5.47 (s, 2H), 2.06 (s, 6H); ESIMS(±) m/z 450 [M+H]+; HPLC 97%.
Rf=0.37 (MeOH/DCM=1/10); 1H NMR (400 MHz, DMSO-d6) δ 11.17 (s, 1H), 9.03 (s, 1H), 8.13 (dd, J=7.9 Hz, 1.3 Hz, 1H), 7.72-7.78 (m, 3H), 7.47 (s, 2H), 7.33-7.43 (m, 4H), 5.47 (s, 2H), 2.06 (s, 6H); ESIMS(−) m/z 494 [M+H]+; HPLC 100%.
Rf=0.23 (MeOH/CH2Cl2=1/9); 1H NMR (400 MHz, DMSO-d6) δ 11.20 (s, 1H), 9.06 (br s, 1H), 8.04 (dd, J=7.8, 1.4 Hz, 1H), 7.69 (d, J=8.2 Hz, 2H), 7.66-7.61 (m, 1H), 7.59 (s, 1H), 7.30-7.19 (m, 4H), 7.13 (s, 1H), 6.85 (s, 1H), 5.35 (s, 2H), 4.37-4.29 (m, 4H); ESIMS(+) m/z 406 [M+H]+. HPLC 97%.
Rf=0.47 (MeOH/CH2Cl2=1/9); 1H NMR (400 MHz, DMSO-d6) δ 11.31 (s, 1H), 9.16 (s, 1H), 8.09 (d, J=0.8 Hz, 1H), 7.67 (t, J=7.8 Hz, 1H), 7.59 (d, J=11.1 Hz, 1H), 7.47 (d, J=8.1 Hz, 1H), 7.32-7.26 (m, 3H), 7.24-7.18 (m, 4H), 7.03 (t, J=7.8 Hz, 1H), 5.39 (s, 2H), 4.20 (t, J=7.7 Hz, 2H), 2.92 (t, J=7.7 Hz, 2H); ESIMS(+) m/z 456 [M+H]+. HPLC 99%.
Rf=0.29 (MeOH/CH2Cl2=1/9); 1H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 9.05 (s, 1H), 7.96 (d, J=8.8 Hz, 1H), 7.59-7.49 (m, 4H), 7.25-7.17 (m, 2H), 7.00 (d, J=7.7 Hz, 1H), 6.86 (dd, J=8.8, 2.1 Hz, 1H), 6.65 (d, J=2.0 Hz, 1H), 5.32 (s, 2H), 4.24 (t, J=7.3 Hz, 2H), 3.76 (s, 3H), 3.05 (t, J=7.3 Hz, 2H), 2.28 (s, 3H); ESIMS(+) m/z 528 [M+H]+; HPLC 100%.
Rf=0.61 (MeOH/CH2Cl2=5:95); 1H NMR (400 MHz, DMSO-d6) δ 11.19 (s, 1H), 9.06 (s 1H), 8.05 (dd, J==7.8, 1.4 Hz, 1H), 7.57-7.75 (m, 3H), 7.07-7.39 (m, 9H), 5.39 (s, 2H), 4.01 (t, J=6.7 Hz, 2H), 2.59 (t, J=7.2 Hz, 2H), 1.49-1.72 (m, 4H); ESIMS (+) m/z 444 [M+H]+; HPLC 98.6%.
Rf=0.45 (MeOH/CH2Cl2=5:95); 1H NMR (400 MHz, DMSO-d6) δ 11.19 (s, 1H), 9.07 (s, 1H), 8.07 (dd, J=7.9, 1.5 Hz, 1H), 7.59-7.75 (m, 3H), 7.35 (d, J=8.2 Hz, 2H), 7.20-7.32 (m, 2H), 5.84-6.0 (m, 1H), 5.4 (s, 2H), 5.06-5.22 (m, 2H), 4.6 (d, J=5.2 Hz, 2H); ESIMS (+) m/z 444 [M+H]+. HPLC 99%.
Rf=0.49 (MeOH/CH2Cl2=1:9); 1H NMR (400 MHz, DMSO-d6) δ 11.2 (s, 1H), 9.07 (s, 1H), 8.04 (dd, J=7.9, 1.3 Hz, 1H), 7.55-7.73 (m, 3H), 7.14-7.38 (m, 4H), 5.37 (s, 2H), 5.24 (s, 1H), 4.05 (t, J=7.0 Hz, 2H), 3.13 (d, J=5.2 Hz, 1H), 2.21 (t, J=6.7 Hz, 2H), 1.97 (s, 2H), 1.8 (s, 2H), 1.33-1.56 (m, 4H); ESIMS (+) m/z 420 [M+H]+. HPLC 99%.
Rf=0.71 (MeOH/CH2Cl2=1:9); 1H NMR (400 MHz, DMSO-d6) δ 11.18 (s, 1H), 9.04 (s, 1H), 8.09 (dd, J=7.8, 1.5 Hz, 1H), 7.59-7.74 (m, 3H), 7.34-7.49 (m, 4H), 7.14-7.34 (m, 5H), 6.52-6.65 (m, 1H), 6.32-6.46 (m, 1H), 5.43 (s, 2H), 4.78 (d, J=5.4 Hz, 2H); ESIMS (+) m/z 428 [M+H]+. HPLC 95%.
Rf=0.09 (MeOH/CH2Cl2=5:95); 1H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 9.01 (s, 1H), 8.06 (dd, J=7.8, 1.3 Hz, 1H), 7.56-7.77 (m, 3H), 7.35 (d, J=8.2 Hz, 2H), 7.17-7.31 (m, 2H), 5.4 (s, 2H), 4.0-4.24 (m, 2H), 3.74 (s, 1H), 3.23 (q, J=5.6 Hz, 1H), 1.88-2.0 (m, 1H), 1.6-1.84 (m, 2H), 138-1.6 (m, 4H), 1.08-71.38 (m, 3H); ESIMS (+) m/z 454 [M+H]+. HPLC 99%.
Rf=0.44 (MeOH/CH2Cl2=1:9); 1H NMR (400 MHz, DMSO-d6) δ 11.2 (s, 1H), 9.05 (s, 1H), 8.1 (dd, J=7.8, 1.5 Hz, 1H), 7.61-7.81 (m, 3H), 7.11-7.37 (m, 8H), 5.5 (s, 2H), 4.13 (t, J=7.6 Hz, 2H), 2.89 (t, J=7.6 Hz, 2H); ESIMS (+) m/z 450 [M+H]+. HPLC 99%.
Rf=0.56 (MeOH/CH2Cl2=1:9); 1H NMR (400 MHz, DMSO-d6) δ 11.18 (s, 1H), 9.05 (s, 1H), 8.09 (dd, J=7.8, 1.5 Hz, 1H), 7.57-7.79 (m, 3H), 7.20-7.55 (m, 9H), 5.87 (ddd, J=54.5, 8.7, 3.5 Hz, 1H), 5.41 (s, 2H), 4.71 (ddd, J=17.1, 12.4, 8.9 Hz, 1H), 4.21 4.71 (ddd, J=31.8, 13.9, 3.5 Hz, 1H); ESIMS (+) m/z [M+H]+ 434. HPLC 95%.
The IC50 values for aforementioned compounds against HDACs were determined. HDAC 1 to 11 can be assayed by using acetylated AMC-labeled peptide substrate. The Substrate 1, a fluorogenic peptide from p53 residues 379-382 (RHKKAc) is used for all MAC 1 to 11 but HDAC8, which has a substrate II (RHKAcKAc), a fluorogenic diacyl peptide based on residues 179-382 of p53. Compounds were tested in 10-dose 1050 mode in duplicate with 3-fold serial dilution starting at 10 μM.
Human HDAC1 GenBank Accession No. NM_004964): Full length with C-terminal GST tag, MW=79.9 kDa, Human HDAC2 (GenBank Accession No. Q92769): Full length with C-terminal His tag, MW=60 kDa. Human HDAC3/NcoR2 (GenBank Accession No. NM_13038883 for HDAC3, GenBank Accession No. NM_006312 for NcoR2): Complex of human HDAC3, full length with C-terminal His tag, MW=49.7 kDa, and human NCOR2, N-terminal GST tag, MW=39 kDa. Human HDAC6 (GenBank Accession No. BC069243): Full length with N-terminal GST tag, MW=159 kDa. Human HDAC8 (GenBank Accession No. NM018486): Full length, MW=42 kDa, expressed in an E. coli expression system. Human HDAC10 (GenBank Accession No. NM_032019): Amino acids 1-631 with N-terminal GST tag, MW=96 kDa. Human HDAC11 (GenBank Accession No. NM_BC009676) with N-terminal GST tag, MW=66 kDa, expressed in baculovirus expression system, Control Inhibitor for HDAC is Trichostatin A (TSA); Biomol Cat #GR 309.
Human HDAC1, Human HDAC2, Human HDAC3/NcoR2, Human HDAC6, Human HDAC10, and Human HDAC11 were all expressed by baculovirus expression system in Sf9 cells.
Reaction Condition: Assay Buffer: 50 mM Tris-HCl, pH 8.0, 137 mM NaCl, 2.7 mM KCl, 1 mM MgCl2, Before use, add 1 mg/mL BSA. HDAC1: 75 nM; HDAC2: 5 mM; HDAC3: 2.3 nM; HDAC6: 13 nM; HDAC8: 119 nM; HDAC10: 781 nM; HDAC11: 781 nM. 50 μM HDAC substrate. 1% DMSO final. Incubation for 2 hours at 30° C.
HDAC Enzymatic Assay. These compounds had inhibitory effects on human historic deacetylases (HDAC) 1, 2, 3, 6, 8, 10 and 11.
Because these compound showed selective inhibitions on HDAC6, the HDAC6-selective inhibitors may be used for treating autoimmunity, cancer, and many neurodegenerative diseases. (S. Minucci et all, Nat. Rev, Cancer. 2006, 6, 38-51; L. Wang et al., Nat. Rev. Drug Discov. 2009, 8, 969-81; J. P. Dompierre et al., J. Neurosci, 2007, 27, 3571-83; and A. G. Kazantsev et al., Nat. Rev. Drug Discov. 2008, 7, 854-68.)
Materials
All cell lines were purchased from BCRC (Bioresource Collection and Research Center, Taiwan) U87MG (BCRC 60360), HepG2 (BCRC 60025), A549 (BCRC 60074), PANC1 (BCRC 60284), A375 (BCRC 60039), LNCaP (BCRC 60088), 22Rv1 (BCRC 60545), FHs173 we (BCRC 60229) and Vero (BCRC 60013).
Tables 1 and 2 illustrate HDAC inhibition activities of the compounds according to the invention.
Cells were seeded in 96-well plates at a density of 5×103 cells per well and allowed to attach for 24 h before compound treatment. A series dilutions of the testing compounds, SAHA, and Tubastatin A were added to the culture medium so that the final concentration of DMSO) was 0.1% in all reactions. At end of the treatment period 72 h, 20 μl (5 mg/mL) 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) reagent was added each well. After 4 h incubation at 37° C., the supernatant was aspirated and the formazan crystals were dissolved in 100 μl of DMSO at 37° C. for 10 min with gentle agitation. The absorbance was measured at 570 nm using the Molecular Devices Microplate Reader. Results were presented as mean±standard error mean (SEM) from at least three independent experiments. IC50 values were calculated from the relative viability values and concentrations by regression analysis. Tables 3 and 4 show the cytotoxicity of HDAC inhibitors against cancer cell lines and normal human cell line.
Xenografted nude mice model of prostate cancer cell line. Forty-five male nude mice (BALB/cAnN.Cg-Foxnlnu/CrINarl, 4-6 weeks old) were used. Mice were subcutaneously injected in the left flank with 1×106 LNCaP human prostatic carcinoma in PBS through a 1 cm long 25 G needle. When LNCaP xenografts had reached an average volume of 150 mm3, animals were randomized into groups of five mice. Compounds were prepared in PBS daily fresh and injected i.p. (10 mL/kg of body weight). The tumor sizes were measured by two perpendicular diameters (Length and Width) and tumor volumes (me) were determined by the formula length×width2×1/2. The mouse body weight was determined as an indicator of tolerability on the same days. TGI was calculated according to the formula [1−(T−T0)/(C−C0)]×100, where T and T0 are the mean tumor volumes on Day 30 and Day 1, respectively, for the experimental group, and C and C0 are those for the vehicle control group. After 14 or 30 days of treatment, the animals were sacrificed on Day 30 by cervical dislocation. Tumor samples were harvested from animals and post-fixed in 4% paraformaldehyde and weighted. Animal studies were carried out in accordance with the guidelines.
LL/2 syngeneic xenograft model. The 7 weeks old B6 mice were injected s.c. with 100 μL of LL/2 cell suspensions, equivalent to 5×106 cells. Paclitaxel was treated via i.p. injection at 10 mg/kg once daily for five days. AJ20064 was dosed orally, at 20 mg/kg, 40 mg/kg and 80 mg/kg once daily for 21 consecutive days. Tumor volumes were measured twice weekly throughout the duration of the experiment and tumor growth inhibition (TGI) was assessed at the end of the third cycle of therapy.
*: may be substituted.
**: Unless mentioned, B group was 1,4 disubstituted.
This application is a national stage application (under 35 U.S.C. 371) of PCT/US 18/032848 filed on 15 May 2018, which claims priority to US provisional application 62/507,196 filed on 16 May 2017, all of which are herein incorporated by reference in their entireties,
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2018/032848 | 5/15/2018 | WO |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO2018/213364 | 11/22/2018 | WO | A |
| Number | Name | Date | Kind |
|---|---|---|---|
| 20120094997 | England et al. | Apr 2012 | A1 |
| 20150196563 | Chern et al. | Jul 2015 | A1 |
| Number | Date | Country |
|---|---|---|
| 2003-137866 | May 2003 | JP |
| 2013184806 | Dec 2013 | WO |
| Entry |
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| Extended European Search Report issued in corresponding European Application No. 18801840.2; dated Nov. 3, 2020 (8 pages). |
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| Number | Date | Country | |
|---|---|---|---|
| 20210355089 A1 | Nov 2021 | US |
| Number | Date | Country | |
|---|---|---|---|
| 62507196 | May 2017 | US |
