Histone deacetylase 6 inhibitors and use thereof

Abstract

Disclosed is hydroxamic acid compounds of Formula (I) set forth herein. Also disclosed are a pharmaceutical composition containing such a compound and a method of using the compound for treating a condition associated with histone deacetylase 6.

Claims

1. An HDAC6-selective inhibiting compound of formula (I) or a pharmaceutically acceptable salt thereof: ##STR00087## in which W is quinoline; and Z is a bond, methylene, or —CH═CH—.

2. The compound or pharmaceutically acceptable salt of claim 1, wherein Z is a bond.

3. The compound or pharmaceutically acceptable salt of claim 1, wherein W is ##STR00088##

4. The compound or pharmaceutically acceptable salt of claim 1, wherein the phenylene adjacent to Z is para-phenylene or meta-phenylene.

5. A compound or pharmaceutically acceptable salt selected from: ##STR00089## ##STR00090## ##STR00091## ##STR00092## ##STR00093##

6. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound or pharmaceutically acceptable salt of claim 1.

7. The pharmaceutical composition of claim 6, wherein the compound or pharmaceutically acceptable salt is selected from: ##STR00094##

8. An HDAC6-selective inhibiting compound of formula (I) or a pharmaceutically acceptable salt thereof: ##STR00095## in which Z is a bond, methylene, or —CH═CH—; and W is ##STR00096##

Description

DETAILED DESCRIPTION

(1) Within this invention is a compound of Formula (I):

(2) ##STR00003##
in which each of R.sub.1, R.sub.2, R.sub.3, and R.sub.4, independently, is H, halo, cyano, amino, hydroxyl, —COR, —COOR, —CONR′R″, C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.1-8 alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or R.sub.3 and R.sub.4, together with the C in CR.sub.3R.sub.4, form C═O, C═S, or C═NH, each of R, R′, and R″, independently, being H, C.sub.1-5 alkyl, C.sub.2-5 alkenyl, C.sub.2-5 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; W is bicyclic aryl or bicyclic heteroaryl; X is CR.sub.5R.sub.6, O, S, or NR.sub.7, each of R.sub.5, R.sub.6, and R.sub.7, independently, being H, —COR, —COOR, —CONR′R″, C.sub.1-5 alkyl, C.sub.2-5 alkenyl, C.sub.2-5 alkynyl, C.sub.2-5 alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Y is arylene or heteroarylene; Z is a bond, methylene, or ethylene; and each of m and n, independently, is 0 or 1, each of the C.sub.1-5 alkyl, C.sub.2-5 alkenyl, C.sub.2-5 alkynyl, C.sub.2-5 alkoxy, C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.1-8 alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylene, and heteroarylene being unsubstituted or substituted with halo, cyano, amino, hydroxyl, nitro, sulfhydryl, C.sub.1-5 alkyl, C.sub.2-5 alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or a pharmaceutically acceptable salt thereof.

(3) In one embodiment, the compound has W as:

(4) ##STR00004##

(5) In another embodiment, the compound has W as:

(6) ##STR00005##

(7) An exemplary compound of Formula (I) has each of R.sub.3 and R.sub.4 as H or R.sub.3 and R.sub.4, together with the C in CR.sub.3R.sub.4, forming C═O.

(8) Further, this invention is a pharmaceutical composition for treating a HDAC6-associated condition, the composition containing a pharmaceutically acceptable carrier and one of the compounds of Formula (I) set forth above. The HDAC6-associated condition includes cancer and neurodegenerative disorder. Examples of the cancer include multiple myeloma, lymphoma, leukemia, colorectal cancer, and breast cancer. An exemplary neurodegenerative disorder is Alzheimer's disease.

(9) Also covered by this invention is a method for treating a HDAC6-associated condition, the method including administering to a subject in need thereof an effective amount of a compound of Formula (I).

(10) Methods for synthesizing the compounds of Formula (I) are well known in the art. See, for example, R. Larock, Comprehensive Organic Transformations (2nd Ed., VCH Publishers 1999); P. G. M. Wuts and T. W. Greene, Greene's Protective Groups in Organic Synthesis (4.sup.th Ed., John Wiley and Sons 2007); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis (John Wiley and Sons 1994); L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (2.sup.nd ed., John Wiley and Sons 2009); and G. J. Yu et al., J. Med. Chem. 2008, 51, 6044-6054.

(11) The compounds of Formula (I) thus prepared can be initially screened using in vitro assays, e.g., the Fluorogenic HDAC assay described in Example 1 below, for their potency in inhibiting deacetylation of lysine residues on a substrate by recombinant HDAC proteins. They can be subsequently evaluated using in vivo assays, e.g., a tumor suppression assay, for their efficacy in suppressing tumor growth in a human multiple myeloma xenograft model. The selected compounds can be further tested to verify their efficacy in treating a HDAC6-associated condition. For example, a compound can be administered to an animal (e.g., a rat) having a HDAC6-associated condition and its therapeutic effects are then assessed. Based on the results, an appropriate dosage range and administration route can be determined.

(12) Without further elaboration, it is believed that one skilled in the art can, based on the above description, utilize the present invention to its fullest extent. The following specific examples are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. All publications cited herein are incorporated by reference.

(13) The following three procedures, i.e., A, B, and C, can be used to synthesize thirty-four exemplary Compounds 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 47, 50, 52, 54, 56, 59, 61, 63, 66, 68, 71, 73, and 75, the structures of which shown below.

Procedure a for Synthesis of methyl 4-((quinolinylamino)methyl)benzoate or (E)-methyl 3-(4-((quinolinylamino)methyl)phenyl)acrylate

(14) Method A: A solution of aminoquinoline (1 equiv.) and methyl 4-formylbenzoate or (E)-methyl 3-(4-formylphenyl)acrylate (1.05 equiv.) in acetic acid (1 M) was stirred at room temperature for 30 minutes. A solution of sodium triacetoxyborohydride (2 equiv.) in acetic acid (1 M) was added dropwise into the former solution. The resulting solution was stirred at room temperature for 1 hour. Ice water was poured into the solution and the pH value of the solution was adjusted to 10 with a NaOH solution. The mixture thus formed was extracted with ethyl acetate and the top organic layer was collected. The residue concentrated from the organic layer was purified via chromatography eluted with ethyl acetate and hexane to provide a solid.

(15) Method B: To a mixture of methyl 4-(aminomethyl)benzoate hydrochloride (1.5 equiv.) in MeOH was added NaOH (1.5 equiv.) powder at 0° C. The resulting mixture was stirred at 0° C. for 1 hour and then filtered. The filtrate was concentrated in vacuo to remove solvents. The free amine thus obtained was extracted with ethyl acetate and washed with water. Subsequently, the top organic layer was collected and dissolved in toluene (0.5 M) to form an amine solution. To a stirring mixture of bromoquinoline (1 equiv.), Pd(OAc).sub.2 (0.06 equiv.), DPEphos (0.12 equiv.), and K.sub.3PO.sub.4 (3 equiv.) was added the amine solution thus formed under argon protection at room temperature. The resulting mixture was heated to 100° C. for 12 hours and cooled to room temperature, and then was filtered and washed with ethyl acetate. The top organic layer was collected, concentrated, and purified via chromatography eluted with ethyl acetare and hexane to afford the desired product.

Procedure B for Synthesis of methyl 4-(quinolinylcarbamoyl)benzoate or (E)-methyl 3-(4-((quinolinylamino)methyl)phenyl)acrylate

(16) Method A: To a solution of aminoquinoline (1.3 equiv.) and triethylamine (2 equiv.) in dichloromethane (DCM, 0.5 M) methyl 4-(chlorocarbonyl)benzoate (1 equiv.) was added in portions at 0° C. The solution thus formed was stirred at room temperature for 12 hours. The resulting solution was diluted with ethyl acetate and washed with 2 N HCl. The top organic layer was collected and concentrated in vacuo to provide the desired product.

(17) Method B: A solution of aminoquinoline (1 equiv.), 4-dimethylaminopyridine, and monomethyl terephthalate or (E)-methyl 3-(4-formylphenyl)acrylate 1.2 equiv.) in DCM (0.1 M) was stirred at room temperature for 12 hours. Water was added to the solution and the crude reaction mixture was extracted with DCM. The collected organic layer was concentrated and purified via chromatography eluted with ethyl acetare and hexane to provide the desired product.

Procedure C for Synthesis of Benzamide or Acrylamide

(18) To a stirring mixture of hydroxylamine hydrochloride (10 eq) in MeOH at 0° C., NaOH (10 eq) was added and the resulting mixture was then stirred for 30 minutes to form a suspension, which was subsequently filtered to provide a filtrate. The filtrate was added to the monoester obtained by Procedure B (1 eq) in MeOH (0.1 M) to form a solution. To this solution, additional NaOH (1-4 eq) was added at 0° C. and the resulting solution was maintained at room temperature for 1-24 hours. Ice water was added to the solution thus obtained and the pH was adjusted to 7 to form a precipitate. Finally, the precipitate was filtered and washed with boiling MeOH to provide benzamide or acrylamide.

(19) Shown below are six synthetic schemes including the steps for preparing the exemplary compounds.

(20) Scheme 1 depicts a synthetic sequence of preparing Compound 2 from the starting material 1,4-phenylbisaldehyde via an intermediate Compound 1.

(21) ##STR00006##

(22) Scheme 2 depicts a synthetic sequence of preparing Compounds 3-6, 11-14, 19-22; and 27-30 from the starting materials aminoquinolines 2a-2d.

(23) ##STR00007##

(24) Scheme 3 depicts a synthetic sequence of preparing Compounds 39-44 from the starting materials chloro- or bromo-quinolines 3a-3c.

(25) ##STR00008##

(26) Scheme 4 depicts a synthetic sequence of preparing Compounds 7-10, 15-18, 23-26, and 31-34 from the starting materials aminoquinolines 2a-2d.

(27) ##STR00009##

(28) Scheme 5 depicts a synthetic sequence of preparing Compounds 53-56 and 60-63 from the starting materials chloro- or bromo-quinolines 5a-5d and 64.

(29) ##STR00010##

(30) Scheme 6 depicts a synthetic sequence of preparing Compounds 46, 47, 50-52, 57, 59, 67-75 from the starting materials 6a-6f

(31) ##STR00011##

(32) The methods for preparing the exemplary compounds, as well as the analytical data for the compounds thus prepared, are set forth in Examples 1-35 below.

(33) The procedures for testing these compounds are described in Examples 36-43 also below. In Example 36, exemplary compounds are tested against HDAC1, 3, 4, 5, 6, 7, 8, 9 and Sirt1. Of note, there are eighteen human HDACs. Eleven of them, designated as HDAC1-11, are zinc-dependent. Seven of them, designated as Sirt1-7, are NAD+-dependent.

Example 1

(E)-methyl 3-(4-formylphenyl)acrylate

(34) ##STR00012##

(35) To a solution of terephthalaldehyde (5 g, 36.54 mmol) in tetrahydrofuran (THF) methyl (triphenylphosphoranylidene)acetate (13.09 g, 38.37 mmol) was added at room temperature. The solution was stirred at room temperature for 4 hours. The resulting solution was washed with water three times and the organic layer was collected. The residue was purified via chromatography eluted with ethyl acetare and hexane to provide a solid (6.17 g, 89%). .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 3.74 (s, 3H, OCH.sub.3), 6.81 (d, 1H, J=16.2 Hz, CH═CH), 7.73 (d, 1H, J=16.2 Hz, CH═CH), 7.90-7.97 (m, 4H, ArH), 10.02 (brs, 1H, CHO).

(E)-4-(3-methoxy-3-oxoprop-1-en-1-yl)benzoic acid

(36) ##STR00013##

(37) To a solution of (E)-methyl 3-(4-formylphenyl)acrylate (6 g, 31.55 mmol) in acetone (160 mL) a solution of sulfamic acid (4.64 g, 2.88 mmol) in water (80 mL) was added. The resulting solution was cooled to 0° C. and then sodium chlorite (0.26 g, 2.31 mmol) was added slowly. After 30 minutes, the solution was evaporated to give the solid. The crude solid was washed with water to provide the product (6.1 g, 93%). .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 3.73 (s, 3H, OCH.sub.3), 6.75 (d, 1H, J=16.2 Hz, CH═CH), 7.71 (d, 1H, J=15.9 Hz, CH═CH), 7.83 (d, 2H, J=8.4 Hz, ArH), 7.93-7.96 (m, 2H, ArH), 13.10 (brs, 1H, COOH).

Methyl 4-((quinolin-3-ylamino)methyl)benzoate

(38) ##STR00014##

(39) The title compound was obtained from 3-aminoquinoline (0.63 g, 4.25 mmol) according to Method A of Procedure A (1.2 g, 89%). .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 3.82 (s, 3H, OCH.sub.3), 4.48 (d, 2H, J=6.0 Hz, CH.sub.2), 6.94 (d, 1H, J=2.7 Hz, ArH), 6.98-7.03 (m, 1H, NH), 7.27-7.38 (m, 2H, ArH), 7.53-7.57 (m, 3H, ArH), 7.74-7.78 (m, 1H, ArH), 7.90-7.95 (m, 2H, ArH), 8.55 (d, 1H, J=2.7 Hz, ArH).

N-hydroxy-4-((quinolin-3-ylamino)methyl)benzamide

(40) ##STR00015##

(41) The title compound was obtained from the benzoate thus prepared (0.6 g, 2.05 mmol) according to Procedure C (0.56 g, 93%). .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 4.43 (d, 2H, J=5.7 Hz, CH.sub.2), 6.93-6.98 (m, 2H, ArH), 7.27-7.38 (m, 2H, ArH), 7.67 (d, 2H, J=8.1 Hz, ArH), 7.54-7.58 (m, 1H, ArH), 7.69-7.78 (m, 3H, ArH), 8.54 (d, 1H, J=2.7 Hz, ArH). HRMS-ESI calcd. for C.sub.17H.sub.15N.sub.3O.sub.2 [M+H].sup.+ 294.1209, found 293.1164.

Example 2

(E)-methyl 3-(4-((quinolin-3-ylamino)methyl)phenyl)acrylate

(42) ##STR00016##

(43) The title compound was obtained from 3-aminoquinoline (0.63 g, 4.25 mmol) according to Method A of Procedure A (1.2 g, 89%). .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 3.70 (s, 3H, OCH.sub.3), 4.42 (d, 2H, J=6.0 Hz, CH.sub.2), 6.59 (d, 1H, J=15.9 Hz, CH═CH), 6.93-6.97 (m, 2H, ArH, NH), 7.27-7.38 (m, 2H, ArH), 7.45 (d, 2H, J=8.1 Hz, ArH), 7.54-7.58 (m, 1H, ArH), 7.60-7.70 (m, 3H, ArH), 7.74-7.78 (m, 1H, ArH), 8.54 (d, 1H, J=2.1 Hz, ArH).

(E)-N-hydroxy-3-(4-((quinolin-3-ylamino)methyl)phenyl)acrylamide

(44) ##STR00017##

(45) The title compound was obtained from the acrylate thus prepared (0.7 g, 2.2 mmol) according to Procedure C (0.61 g, 87%). .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 4.40 (d, 2H, J=5.7 Hz, CH.sub.2), 6.42 (d, 1H, J=15.9 Hz, CH═CH), 6.91-6.97 (m, 2H, ArH, NH), 7.27-7.46 (m, 5H, ArH), 7.51-7.58 (m, 3H, ArH), 7.76 (d, 1H, J=7.8 Hz, ArH), 8.54 (d, 1H, J=2.7 Hz, ArH), 9.01 (s, 1H, NH), 10.73 (s, 1H, OH). HRMS-ESI calcd. for C.sub.19H.sub.17N.sub.3O.sub.2 [M+H].sup.+ 320.1365, found 319.1321.

Example 3

Methyl 4-(quinolin-3-ylcarbamoyl)benzoate

(46) ##STR00018##

(47) The title compound was obtained from 3-aminoquinoline (0.3 g, 2.04 mmol) and 4-dimethylaminopyridine (50 mg, 0.41 mmol) according to Method B of Procedure B (0.5 g, 80%). .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 3.90 (s, 3H, OCH.sub.3), 7.56-7.62 (m, 1H, ArH), 7.64-7.71 (m, 1H, ArH), 7.95-8.00 (m, 2H, ArH), 8.10-8.18 (m, 4H, ArH), 8.85 (d, 1H, J=2.1 Hz, ArH), 9.14 (d, 1H, J=2.4 Hz, ArH), 10.89 (s, 1H, NH).

N.SUP.1.-hydroxy-N.SUP.4.-(quinolin-3-yl)terephthalamide

(48) ##STR00019##

(49) The title compound was obtained from the benzoate thus prepared (0.6 g, 1.96 mmol) according to Procedure C (0.55 g, 91%). .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 7.56-7.70 (m, 2H, ArH), 7.91-8.00 (m, 4H, ArH), 8.96 (d, 2H, J=8.4 Hz, ArH), 8.85 (d, 1H, J=2.1 Hz, ArH), 9.14 (d, 1H, J=2.4 Hz, ArH), 9.18 (s, 1H, NH), 10.79 (s, 1H, NH). 11.41 (s, 1H, OH).

Example 4

(E)-methyl 3-(4-(quinolin-3-ylcarbamoyl)phenyl)acrylate

(50) ##STR00020##

(51) The title compound was obtained from 3-aminoquinoline (0.6 g, 4.08 mmol) and 4-dimethylaminopyridine (100 mg, 0.82 mmol) according to Method B of Procedure B (0.81 g, 59%). .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 3.75 (s, 3H, OCH.sub.3), 6.81 (d, 1H, J=16.2 Hz, CH═CH), 7.56-7.62 (m, 1H, ArH), 7.64-7.70 (m, 1H, ArH), 7.75 (d, 1H, J=15.9 Hz, CH═CH), 7.91-8.00 (m, 4H, ArH), 8.07 (d, 2H, J=8.4 Hz, ArH), 8.85 (d, 1H, J=2.4 Hz, ArH), 9.14 (d, 1H, J=2.4 Hz, ArH), 10.75 (s, 1H, NH).

(E)-4-(3-(hydroxyamino)-3-oxoprop-1-enyl)-N-(quinolin-3-yl)benzamide

(52) ##STR00021##

(53) The title compound was obtained from the acrylate thus prepared (0.6 g, 1.81 mmol) according to Procedure C (0.56 g, 93%). .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 6.60 (d, 1H, J=15.9 Hz, CH═CH), 7.51-7.70 (m, 3H, ArH), 7.75 (d, 2H, J=8.1 Hz, ArH), 7.94-7.99 (m, 2H, ArH), 8.07 (d, 2H, J=8.4 Hz, ArH), 8.85 (d, 1H, J=2.4 Hz, ArH), 9.11-9.15 (m, 3H, ArH), 10.73 (s, 1H, NH), 10.85 (s, 1H, OH). HRMS-ESI calcd. for C.sub.19H.sub.15N.sub.3O.sub.3 [M+H].sup.+ 334.1175, found 333.1113.

Example 5

Methyl 4-((quinolin-5-ylamino)methyl)benzoate

(54) ##STR00022##

(55) The title compound was obtained from 5-aminoquinoline (0.63 g, 4.25 mmol) according to Method A of Procedure A (1.15 g, 93%). .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 3.81 (s, 3H, OCH.sub.3), 4.58 (d, 2H, J=6.0 Hz, CH.sub.2), 6.34 (d, 1H, J=7.8 Hz, ArH), 7.19 (d, 1H, J=8.4 Hz, ArH), 7.28 (t, 1H, J=6.0 Hz, NH), 7.34-7.40 (m, 1H, ArH), 7.43 (dd, 1H, J=1.2, 8.4 Hz, ArH), 7.53 (d, 2H, J=8.1 Hz, ArH), 7.91 (d, 2H, J=8.4 Hz, ArH), 8.69 (d, 1H, J=8.1 Hz, ArH), 8.80 (dd, 1H, J=1.5, 4.2 Hz, ArH).

N-hydroxy-4-((quinolin-5-ylamino)methyl)benzamide

(56) ##STR00023##

(57) The title compound was obtained from the benzoate thus prepared (1.12 g, 3.83 mmol) according to Procedure C (1.02 g, 91%). .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 4.54 (d, 2H, J=5.7 Hz, CH.sub.2), 6.37 (d, 1H, J=7.5 Hz, ArH), 7.18 (d, 1H, J=8.4 Hz, ArH), 7.24 (t, 1H, J=6.0 Hz, NH), 7.34-7.48 (m, 4H, ArH), 7.69 (d, 2H, J=8.4 Hz, ArH), 8.69 (d, 1H, J=8.4 Hz, ArH), 8.80 (dd, 1H, J=1.5, 4.2 Hz, ArH), 9.00 (s, 1H, NH), 11.14 (s, 1H, OH).

Example 6

(E)-methyl 3-(4-((quinolin-5-ylamino)methyl)phenyl)acrylate

(58) ##STR00024##

(59) The title compound was obtained from 5-aminoquinoline (0.55 g, 3.7 mmol) according to Method A of Procedure A (0.95 g, 81%). .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 3.70 (s, 3H, OCH.sub.3), 4.52 (d, 2H, J=6.0 Hz, CH.sub.2), 6.38 (d, 1H, J=7.2 Hz, ArH), 6.57 (d, 1H, J=16.2 Hz, CH═CH), 7.18 (d, 1H, J=8.4 Hz, ArH), 7.23 (t, 1H, J=6.0 Hz, NH), 7.34-7.45 (m, 4H, ArH), 7.59-7.67 (m, 3H, ArH), 8.69 (d, 1H, J=8.4 Hz, ArH), 8.80 (d, 1H, J=1.5, 4.2 Hz, ArH).

(E)-N-hydroxy-3-(4-((quinolin-5-ylamino)methyl)phenyl)acrylamide

(60) ##STR00025##

(61) The title compound was obtained from the acrylate thus prepared (0.86 g, 2.7 mmol) according to Procedure C (0.83 g, 96%). .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 4.51 (d, 2H, J=6.0 Hz, CH.sub.2), 6.36-6.43 (m, 2H, ArH), 7.15-7.24 (m, 2H, ArH), 7.37-7.45 (m, 5H, ArH), 7.50 (d, 2H, J=8.1 Hz, ArH), 8.69 (d, 1H, J=8.4 Hz, ArH), 8.78-8.81 (m, 1H, ArH), 9.01 (s, 1H, NH), 10.72 (s, 1H, OH). HRMS-ESI calcd. for C.sub.19H.sub.17N.sub.3O.sub.2 [M+H].sup.+ 320.1375, found 319.1321.

Example 7

Methyl 4-(quinolin-5-ylcarbamoyl)benzoate

(62) ##STR00026##

(63) The title compound was obtained from 5-aminoquinoline (4 g, 27.8 mmol) according to Method A of Procedure B (0.75 g, 9%). .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 3.91 (s, 3H, OCH.sub.3), 7.56 (dd, 1H, J=1.2, 8.4 Hz, ArH), 7.70-7.73 (m, 1H, ArH), 7.77-7.83 (m, 1H, ArH), 7.97 (d, 1H, J=8.1 Hz, ArH), 8.13 (d, 2H, J=8.4 Hz, ArH), 8.21 (d, 2H, J=8.4 Hz, ArH), 8.41 (d, 2H, J=8.7 Hz, ArH), 8.92-8.95 (m, 1H, ArH), 10.73 (s, 1H, NH).

N.SUB.1.-hydroxy-N.SUB.4.-(quinolin-5-yl)terephthalamide

(64) ##STR00027##

(65) The title compound was obtained from the benzoate thus prepared (0.6 g, 1.96 mmol) according to Procedure C (0.56 g, 93%). .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 7.55 (dd, 1H, J=4.2 Hz, ArH), 7.70-7.73 (m, 1H, ArH), 7.77-7.83 (m, 1H, ArH), 7.90-7.98 (m, 3H, ArH), 8.14 (d, 2H, J=8.4 Hz, ArH), 8.41 (d, 1H, J=8.1 Hz, ArH), 8.93 (dd, 1H, J=1.5, 4.2 Hz, NH), 9.17 (s, 1H, NH), 10.64 (s, 1H, NH), 11.41 (s, 1H, OH). HRMS-ESI calcd. for C.sub.17H.sub.13N.sub.3O.sub.3 [M+H].sup.+ 308.1004, found 307.0957.

Example 8

(E)-methyl 3-(4-(quinolin-5-ylcarbamoyl)phenyl)acrylate

(66) ##STR00028##

(67) The title compound was obtained from 5-aminoquinoline (0.6 g, 4.1 mmol) according to Method B of Procedure B (1.02 g, 68%). .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 3.75 (s, 3H, OCH.sub.3), 6.81 (d, 1H, J=16.2 Hz, CH═CH), 7.55 (dd, 1H, J=1.2, 8.4 Hz, ArH), 7.70-7.83 (m, 3H, ArH), 7.90-7.98 (m, 3H, ArH), 8.12 (d, 2H, J=8.4 Hz, ArH), 8.40 (d, 1H, J=8.4 Hz, ArH), 8.93 (d, 1H, J=1.5, 3.9 Hz, ArH), 10.60 (s, 1H, NH).

(E)-4-(3-(hydroxyamino)-3-oxoprop-1-enyl)-N-(quinolin-5-yl)benzamide

(68) ##STR00029##

(69) The title compound was obtained from the acrylate thus prepared (0.6 g, 1.81 mmol) according to Procedure C (0.54 g, 90%). .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 6.61 (d, 1H, J=15.9 Hz, CH═CH), 7.52-7.58 (m, 2H, ArH), 7.69-7.83 (m, 4H, ArH), 7.96 (d, 1H, J=8.1 Hz, ArH), 8.11 (d, 1H, J=8.4 Hz, ArH), 8.39 (d, 1H, J=8.1 Hz, ArH), 8.93 (dd, 1H, J=1.5, 4.2 Hz, ArH), 9.12 (s, 1H, NH), 10.58 (s, 1H, NH), 10.85 (s, 1H, OH). HRMS-ESI calcd. for C.sub.19H.sub.15N.sub.3O.sub.3 [M+H].sup.+ 334.1175, found 333.1113.

Example 9

Methyl 4-((quinolin-6-ylamino)methyl)benzoate

(70) ##STR00030##

(71) The title compound was obtained from 6-aminoquinoline (0.63 g, 4.25 mmol) according to Method A of Procedure A (1.05 g, 85%). .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 3.82 (s, 3H, OCH.sub.3), 4.47 (d, 2H, J=6.0 Hz, CH.sub.2), 6.62 (d, 1H, J=2.4 Hz, ArH), 6.86-6.91 (m, 1H, NH), 7.22-7.30 (m, 2H, ArH), 7.54 (d, 2H, J=9.0 Hz, ArH), 7.72 (d, 1H, J=9.0 Hz, ArH), 7.86-7.94 (m, 1H, ArH), 8.46 (dd, 1H, J=1.5, 4.2 Hz, ArH).

N-hydroxy-4-((quinolin-6-ylamino)methyl)benzamide

(72) ##STR00031##

(73) The title compound was obtained from the benzoate thus prepared (0.6 g, 2.05 mmol) according to Procedure C (0.56 g, 93%). .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 4.56 (d, 2H, J=5.7 Hz, CH.sub.2), 6.62 (d, 1H, J=2.4 Hz, ArH), 6.88 (t, 1H, J=5.7 Hz, NH), 7.22-7.30 (m, 2H, ArH), 7.51 (d, 2H, J=8.1 Hz, ArH), 7.71 (d, 1H, J=9.0 Hz, ArH), 7.88-7.92 (m, 3H, ArH), 8.46 (dd, 1H, J=1.5, 4.2 Hz, ArH). HRMS-ESI calcd. for C.sub.17H.sub.15N.sub.3O.sub.2 [M−H].sup.+292.1069, found 293.1164.

Example 10

(E)-methyl 3-(4-((quinolin-6-ylamino)methyl)phenyl)acrylate

(74) ##STR00032##

(75) The title compound was obtained from 6-aminoquinoline (0.63 g, 4.25 mmol) according to Method A of Procedure A (1.11 g, 82%). .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 3.70 (s, 3H, OCH.sub.3), 4.41 (d, 2H, J=6.0 Hz, CH.sub.2), 6.59 (d, 1H, J=16.2 Hz, CH═CH), 6.64 (d, 1H, J=2.4 Hz, ArH), 6.83 (t, 1H, J=6.0 Hz, NH), 7.22-7.29 (m, 2H, ArH), 7.44 (d, 2H, J=8.1 Hz, ArH), 7.60-7.73 (m, 4H, ArH), 7.89 (dd, 1H, J=0.9, 8.4 Hz, ArH), 8.46 (dd, 1H, J=1.5, 4.2 Hz, ArH).

(E)-N-hydroxy-3-(4-((quinolin-6-ylamino)methyl)phenyl)acrylamide

(76) ##STR00033##

(77) The title compound was obtained from the acrylate thus prepared (0.6 g, 1.88 mmol) according to Procedure C (0.55 g, 92%). .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 4.40 (d, 2H, J=5.7 Hz, CH.sub.2), 6.48 (d, 1H, J=15.9 Hz, CH═CH), 6.64 (d, 1H, J=2.4 Hz, ArH), 6.82 (t, 1H, J=5.7 Hz, NH), 7.22-7.28 (m, 2H, ArH), 7.43 (d, 2H, J=8.1 Hz, ArH), 7.54 (d, 1H, J=16.2 Hz, CH═CH), 7.60-7.72 (m, 3H, ArH), 7.89 (d, 1H, J=8.1 Hz, ArH), 8.45 (d, 1H, J=2.7 Hz, ArH). HRMS-ESI calcd. for C.sub.19H.sub.17N.sub.3O.sub.2 [M+H].sup.+ 320.1409, found 319.1321.

Example 11

Methyl 4-(quinolin-6-ylcarbamoyl)benzoate

(78) ##STR00034##

(79) The title compound was obtained from 6-aminoquinoline (2 g, 13.6 mmol) according to Method A of Procedure B (1.2 g, 29%). .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 3.89 (s, 3H, OCH.sub.3), 7.50 (dd, 1H, J=4.2 Hz, ArH), 8.02-8.04 (m, 2H, ArH), 8.09-8.13 (m, 4H, ArH), 8.34 (dd, 1H, J=1.8, 8.1 Hz, ArH), 8.53-8.55 (m, 1H, ArH), 8.81 (dd, 1H, J=1.8, 4.2 Hz, ArH), 10.78 (s, 1H, NH).

N.SUP.1.-hydroxy-N.SUP.4.-(quinolin-6-yl)terephthalamide

(80) ##STR00035##

(81) The title compound was obtained from the benzoate thus prepared (0.6 g, 1.96 mmol) according to Procedure C (0.12 g, 20%). .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 7.49 (dd, 1H, J=4.2 Hz, ArH), 7.91 (d, 2H, J=8.1 Hz, ArH), 7.98-8.09 (m, 4H, ArH), 8.33 (d, 1H, J=8.1 Hz, ArH), 8.55 (s, 1H, ArH), 8.81 (d, 1H, J=3.0 Hz, ArH), 9.19 (s, 1H, NH), 10.67 (s, 1H, NH), 11.42 (s, 1H, OH). HRMS-ESI calcd. for C.sub.17H.sub.13N.sub.3O.sub.3 [M+H].sup.+ 308.1005, found 307.0957.

Example 12

(E)-methyl 3-(4-(quinolin-6-ylcarbamoyl)phenyl)acrylate

(82) ##STR00036##

(83) The title compound was obtained from 6-aminoquinoline (0.6 g, 4.08 mmol) according to Method B of Procedure B (0.7 g, 52%). .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 3.75 (s, 3H, OCH.sub.3), 6.80 (d, 1H, J=16.2 Hz, CH═CH), 7.50 (dd, 1H, J=4.2 Hz, ArH), 7.74 (d, 1H, J=15.9 Hz, CH═CH), 7.91 (d, 2H, J=8.7 Hz, ArH), 7.98-8.07 (m, 4H, ArH), 8.32 (dd, 1H, J=1.2, 8.4 Hz, ArH), 8.54 (d, 1H, J=1.8 Hz, ArH), 8.80 (dd, 1H, J=1.5, 4.2 Hz, ArH), 10.62 (s, 1H, NH).

(E)-4-(3-(hydroxyamino)-3-oxoprop-1-enyl)-N-(quinolin-6-yl)benzamide

(84) ##STR00037##

(85) The title compound was obtained from the acrylate thus prepared (0.5 g, 1.51 mmol) according to Procedure C (0.46 g, 91%). .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 6.60 (d, 1H, J=15.9 Hz, CH═CH), 7.47-7.56 (m, 2H, ArH), 7.74 (d, 2H, J=8.4 Hz, ArH), 7.98-8.07 (m, 4H, ArH), 8.32 (dd, 1H, J=1.2, 8.4 Hz, ArH), 8.53 (d, 1H, J=1.8 Hz, ArH), 8.80 (dd, 1H, J=1.5, 4.2 Hz, ArH), 10.61 (s, 1H, NH). HRMS-ESI calcd. for C.sub.19H.sub.15N.sub.3O.sub.3 [M+H].sup.+ 334.1162, found 333.1113.

Example 13

Methyl 4-((quinolin-8-ylamino)methyl)benzoate

(86) ##STR00038##

(87) The title compound was obtained from 8-aminoquinoline (0.63 g, 4.25 mmol) according to Method A of Procedure A (1.12 g, 90%). .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 3.81 (s, 3H, OCH.sub.3), 4.62 (d, 2H, J=6.3 Hz, CH.sub.2), 6.46-6.50 (m, 1H, ArH), 7.04 (dd, 1H, J=0.9, 8.1 Hz, ArH), 7.21-7.32 (m, 2H, ArH, NH), 7.47-7.53 (m, 3H, ArH), 7.89 (d, 2H, J=8.4 Hz, ArH), 8.17-8.21 (m, 1H, ArH), 8.76 (dd, 1H, J=1.8, 4.2 Hz, ArH).

N-hydroxy-4-((quinolin-8-ylamino)methyl)benzamide

(88) ##STR00039##

(89) The title compound was obtained from the benzoate thus prepared (1.12 g, 3.83 mmol) according to Procedure C (1.03 g, 92%). .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 4.57 (d, 2H, J=6.3 Hz, CH.sub.2), 6.51 (dd, 1H, J=1.2, 7.8 Hz, ArH), 7.04 (dd, 1H, J=1.2, 8.4 Hz, NH), 7.21-7.28 (m, 2H, ArH), 7.45 (d, 2H, J=8.1 Hz, ArH), 7.50 (dd, 1H, J=4.2, 8.4 Hz, ArH), 7.68 (d, 2H, J=8.1 Hz, ArH), 8.20 (dd, 1H, J=1.8, 8.4 Hz, ArH), 8.76 (dd, 1H, J=1.8, 4.2 Hz, ArH), 8.96 (brs, 1H, NH), 11.11 (brs, 1H, OH). HRMS-ESI calcd. for C.sub.17H.sub.15N.sub.3O.sub.2 [M+H].sup.+ 294.1217, found 293.1164.

Example 14

(E)-methyl 3-(4-((quinolin-8-ylamino)methyl)phenyl)acrylate

(90) ##STR00040##

(91) The title compound was obtained from 8-aminoquinoline (0.7 g, 4.76 mmol) according to Method A of Procedure A (1.36 g, 90%). .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 3.70 (s, 3H, OCH.sub.3), 4.53 (d, 2H, J=5.7 Hz, CH.sub.2), 6.38 (d, 1H, J=7.8 Hz, ArH), 6.58 (d, 1H, J=16.2 Hz, CH═CH), 7.17-7.25 (m, 2H, NH, ArH), 7.35-7.43 (m, 4H, ArH), 7.44-7.67 (m, 3H, ArH), 8.70 (d, 1H, J=8.7 Hz, ArH), 8.79-8.81 (m, 1H, ArH).

(E)-N-hydroxy-3-(4-((quinolin-8-ylamino)methyl)phenyl)acrylamide

(92) ##STR00041##

(93) The title compound was obtained from the acrylate thus prepared (1.36 g, 4.47 mmol) according to Procedure C (1.26 g, 88%). .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 4.55 (d, 2H, J=6.6 Hz, CH.sub.2), 6.40 (d, 1H, J=15.6 Hz, CH═CH), 6.53 (dd, 1H, J=0.9, 7.5 Hz, ArH), 7.02-7.06 (m, 1H, ArH), 7.19-7.29 (m, 2H, ArH), 7.38-7.53 (m, 6H, ArH), 8.20 (dd, 1H, J=1.8, 8.4 Hz, ArH), 8.76 (dd, 1H, J=1.5, 4.2 Hz, ArH), 8.99 (brs, 1H, NH), 10.72 (brs, 1H, OH). HRMS-ESI calcd. for C.sub.19H.sub.17N.sub.3O.sub.2 [M+H].sup.+ 320.1382, found 319.1321.

Example 15

Methyl 4-(quinolin-8-ylcarbamoyl)benzoate

(94) ##STR00042##

(95) The title compound was obtained from 8-aminoquinoline (2 g, 13.6 mmol) according to Method A of Procedure A (3.6 g, 86%). .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 3.90 (s, 3H, OCH.sub.3), 7.61-7.69 (m, 2H, ArH), 7.73-7.77 (m, 1H, ArH), 8.14 (s, 4H, ArH), 8.44 (dd, 1H, J=1.5, 8.4 Hz, ArH), 8.70 (dd, 1H, J=1.5, 7.5 Hz, ArH), 8.96 (dd, 1H, J=1.8, 4.2 Hz, ArH), 10.70 (s, 1H, NH).

N.SUP.1.-hydroxy-N.SUP.4.-(quinolin-8-yl)terephthalamide

(96) ##STR00043##

(97) The title compound was obtained from the benzoate thus prepared (0.6 g, 1.96 mmol) according to Procedure C (0.53 g, 88%). .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 7.61-7.77 (m, 3H, ArH), 7.95-8.16 (m, 4H, ArH), 8.45 (d, 1H, J=8.4 Hz, ArH), 8.69-8.75 (m, 1H, ArH), 8.97 (d, 1H, J=3.6 Hz, ArH), 10.68 (s, 1H, NH). HRMS-ESI calcd. for C.sub.17H.sub.13N.sub.3O.sub.3 [M+H].sup.+ 308.1016, found 307.0957.

Example 16

(E)-methyl 3-(4-(quinolin-8-ylcarbamoyl)phenyl)acrylate

(98) ##STR00044##

(99) The title compound was obtained from 8-aminoquinoline (0.7 g, 4.76 mmol) according to Method B of Procedure B (0.75 g, 47%). .sup.1H NMR (500 MHz, CDCl.sub.3): δ 3.84 (s, 3H, OCH.sub.3), 6.55 (d, 1H, J=16.0 Hz, CH═CH), 6.50 (dd, 1H, J=4.0, 8.5 Hz), 7.56-7.63 (m, 2H, ArH), 7.70 (d, 2H, J=8.0 Hz, ArH), 7.76 (d, 1H, J=16.0 Hz, CH═CH), 8.11 (d, 2H, J=8.0 Hz, CH═CH), 8.20 (dd, 1H, J=1.0, 8.0 Hz, ArH), 8.86 (dd, 1H, J=1.5, 4 Hz, ArH), 8.93 (d, 1H, J=7.5 Hz, ArH), 10.78 (s, 1H, NH).

(E)-4-(3-(hydroxyamino)-3-oxoprop-1-enyl)-N-(quinolin-8-yl)benzamide

(100) ##STR00045##

(101) The title compound was obtained from the acrylate thus prepared (0.6 g, 1.8 mmol) according to Procedure C (0.53 g, 89%). .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 6.60 (d, 1H, J=15.9 Hz, CH═CH), 7.55 (d, 1H, J=16.2 Hz, CH═CH), 7.63-7.81 (m, 5H, ArH), 8.06 (d, 2H, J=8.4 Hz, ArH), 8.45-8.48 (m, 1H, ArH), 8.71-8.74 (m, 1H, ArH), 8.97-8.99 (m, 1H, ArH), 9.12 (brs, 1H, NH), 10.68 (s, 1H, NH), 10.87 (brs, 1H, OH). HRMS-ESI calcd. for C.sub.19H.sub.15N.sub.3O.sub.3 [M+H].sup.+ 334.1180, found 333.1113.

Example 17

Methyl 3-((quinolin-8-ylamino)methyl)benzoate

(102) ##STR00046##

(103) .sup.1H NMR (300 MHz, d.sub.6-DMSO): δ 3.80 (s, 3H, OCH.sub.3), 4.60 (d, 2H, J=6.3 Hz, CH.sub.2), 6.49-6.53 (m, 1H, ArH), 7.03 (dd, 1H, J=1.2, 8.1 Hz, ArH), 7.25 (t, 1H, J=7.8 Hz, ArH), 7.28-7.34 (m, 1H, NH), 7.43-7.53 (m, 2H, ArH), 7.66-7.70 (m, 1H, ArH), 7.79-7.83 (m, 1H, ArH), 8.00-8.12 (m, 1H, ArH), 8.18-8.22 (m, 1H, ArH), 8.77 (dd, 1H, J=1.8, 4.2 Hz, ArH).

N-hydroxy-3-((quinolin-8-ylamino)methyl)benzamide

(104) ##STR00047##

(105) .sup.1H NMR (300 MHz, d.sub.6-DMSO): δ 4.57 (d, 2H, J=6.3 Hz, CH.sub.2), 6.54 (d, 1H, J=7.2, 8.1 Hz, ArH), 7.04 (d, 1H, J=7.5 Hz, ArH), 7.19-7.29 (m, 2H, ArH), 7.34-7.40 (m, 1H, NH), 7.47-7.60 (m, 3H, ArH), 7.82 (s, 1H, ArH), 8.17-8.22 (m, 1H, ArH), 8.75-8.77 (m, 1H, ArH), 8.99 (s, 1H, NH), 11.19 (s, 1H, OH). HRMS-ESI calcd. for C.sub.17H.sub.15N.sub.3O.sub.2 [M+H].sup.+ 294.1209, found 293.1164.

Example 18

Methyl 3-(quinolin-8-ylcarbamoyl)benzoate

(106) ##STR00048##

(107) .sup.1H NMR (300 MHz, d.sub.6-DMSO): δ 3.92 (s, 3H, OCH.sub.3), 7.62-7.69 (m, 2H, ArH), 7.74-7.79 (m, 2H, ArH), 8.18-8.22 (m, 1H, ArH), 8.28-8.31 (m, 1H, ArH), 8.43-8.47 (m, 1H, ArH), 8.54-8.56 (m, 1H, ArH), 8.69 (dd, 1H, J=1.2, 7.5 Hz, ArH), 8.97 (dd, 1H, J=1.5, 4.2 Hz, ArH), 10.72 (s, 1H, NH).

M-hydroxy-N.SUP.3.-(quinolin-8-yl)isophthalamide

(108) ##STR00049##

(109) .sup.1H NMR (300 MHz, d.sub.6-DMSO): δ 7.63-7.78 (m, 4H, ArH), 8.01 (d, 1H, J=7.8 Hz, ArH), 8.17 (d, 1H, J=7.8 Hz, ArH), 8.41 (s, 1H, ArH), 8.44-8.48 (m, 1H, ArH), 8.70-8.74 (m, 1H, ArH), 8.98 (dd, 1H, J=1.5, 4.2 Hz, ArH), 9.20 (s, 1H, NH), 10.68 (s, 1H, NH), 11.46 (s, 1H, OH). HRMS-ESI calcd. for C.sub.17H.sub.13N.sub.3O.sub.3 [M+H].sup.+ 308.1008, found 307.0957.

Example 19

Methyl 4-((quinolin-2-ylamino)methyl)benzoate

(110) ##STR00050##

(111) .sup.1H NMR (300 MHz, d.sub.6-DMSO): δ 3.82 (s, 3H, OCH.sub.3), 4.72 (d, 2H, J=6.0 Hz, CH.sub.2), 6.84 (d, 1H, J=9.0 Hz, ArH), 7.10-7.17 (m, 1H, ArH), 7.40-7.48 (m, 2H, ArH, NH), 7.52 (d, 1H, J=8.4 Hz, ArH), 7.59-7.64 (m, 2H, ArH), 7.85-7.93 (m, 3H, ArH).

N-hydroxy-4-((quinolin-2-ylamino)methyl)benzamide

(112) ##STR00051##

(113) .sup.1H NMR (300 MHz, d.sub.6-DMSO): δ 4.67 (d, 2H, J=5.7 Hz, CH.sub.2), 6.83 (d, 1H, J=9.0 Hz, ArH), 7.10-7.17 (m, 1H, ArH), 7.42-7.46 (m, 4H, ArH, NH), 7.54-7.62 (m, 2H, ArH), 7.69 (d, 2H, J=8.1 Hz, ArH), 7.87 (d, 1H, J=9.0 Hz, ArH), 8.98 (s, 1H, NH), 11.14 (s, 1H, OH). HRMS-ESI calcd. for C.sub.17H.sub.15N.sub.3O.sub.2 [M+H].sup.+ 294.1208, found 293.1164.

Example 20

Methyl 4-((quinolin-7-ylamino)methyl)benzoate

(114) ##STR00052##

(115) .sup.1H NMR (300 MHz, d.sub.6-DMSO): δ 3.82 (s, 3H, OCH.sub.3), 4.50 (d, 2H, J=6.0 Hz, CH.sub.2), 6.68 (d, 1H, J=2.4 Hz, ArH), 7.02-7.13 (m, 3H, ArH, NH), 7.54 (d, 2H, J=8.4 Hz, ArH), 7.63 (d, 1H, J=9.0 Hz, ArH), 7.93 (dt, 2H, J=1.8, 8.4 Hz, ArH), 7.98-8.02 (m, 1H, ArH), 8.55 (dd, 1H, J=1.8, 4.2 Hz, ArH).

N-hydroxy-4-((quinolin-7-ylamino)methyl)benzamide

(116) ##STR00053##

(117) .sup.1H NMR (300 MHz, d.sub.6-DMSO): δ 4.45 (d, 2H, J=5.7 Hz, CH.sub.2), 6.70 (d, 1H, J=2.1 Hz, ArH), 6.99-7.14 (m, 3H, ArH, NH), 7.47 (d, 2H, J=8.1 Hz, ArH), 7.62 (d, 1H, J=8.7 Hz, ArH), 7.71 (d, 2H, J=8.4 Hz, ArH), 8.00 (dd, 1H, J=1.2, 8.0 Hz, ArH), 8.54-8.57 (m, 1H, ArH), 9.02 (s, 1H, NH), 11.15 (s, 1H, OH). HRMS-ESI calcd. for C.sub.17H.sub.15N.sub.3O.sub.2 [M+H].sup.+ 294.1222, found 293.1164.

Example 21

Methyl 4-((quinolin-4-ylamino)methyl)benzoate

(118) ##STR00054##

(119) .sup.1H NMR (300 MHz, d.sub.6-DMSO): δ 3.81 (s, 3H, OCH.sub.3), 4.63 (d, 2H, J=6.0 Hz, CH.sub.2), 6.27 (d, 1H, J=5.4 Hz, ArH), 7.43-7.53 (m, 3H, ArH), 7.59-7.65 (m, 1H, ArH), 7.77-7.81 (m, 1H, ArH), 7.89-7.93 (m, 2H, ArH), 7.97 (t, 1H, J=6.0 Hz, NH), 8.27-8.31 (m, 2H, ArH).

N-hydroxy-4-((quinolin-4-ylamino)methyl)benzamide

(120) ##STR00055##

(121) .sup.1H NMR (300 MHz, d.sub.6-DMSO): δ 4.59 (d, 2H, J=5.1 Hz, CH.sub.2), 6.29 (d, 1H, J=5.4 Hz, ArH), 7.42-7.48 (m, 3H, ArH), 7.59-7.65 (m, 1H, ArH), 7.69 (d, 2H, J=8.1 Hz, ArH), 7.78 (d, 1H, J=8.4 Hz, ArH), 7.95 (s, 1H, NH), 8.29 (d, 1H, J=5.4 Hz, ArH). HRMS-ESI calcd. for C.sub.17H.sub.15N.sub.3O.sub.2 [M+H].sup.+ 294.1243, found 294.1209.

Example 22

Quinolin-8-ylmethanamine

(122) ##STR00056##

(123) .sup.1H NMR (300 MHz, CDCl.sub.3): δ 2.55 (brs, 2H, NH.sub.2), 4.29 (s, 2H, CH.sub.2), 7.21-7.36 (m, 2H, ArH), 7.47-7.58 (m, 2H, ArH), 7.98 (d, 1H, J=7.2 Hz, ArH), 8.77 (d, 1H, J=2.1 Hz, ArH).

Methyl 4-((quinolin-8-ylmethyl)carbamoyl)benzoate

(124) ##STR00057##

(125) .sup.1H NMR (300 MHz, d.sub.6-DMSO): δ 3.88 (s, 3H, OCH.sub.3), 5.15 (d, 2H, J=6.0 Hz, CH.sub.2), 7.54-7.61 (m, 2H, ArH), 7.63-7.67 (m, 1H, ArH), 7.87-7.91 (m, 1H, ArH), 8.03-8.10 (m, 4H, ArH), 8.39 (dd, 1H, J=1.8, 8.4 Hz, ArH), 8.97 (dd, 1H, J=1.8, 4.2 Hz, ArH), 9.23-9.28 (m, 1H, NH).

N.SUP.1.-hydroxy-N.SUP.4.-(quinolin-8-ylmethyl)terephthalamide

(126) ##STR00058##

(127) .sup.1H NMR (300 MHz, d.sub.6-DMSO): δ 5.15 (d, 2H, J=6.0 Hz, CH.sub.2), 7.54-7.66 (m, 3H, ArH), 7.83-7.90 (m, 3H, ArH), 8.01 (d, 2H, J=8.4 Hz, ArH), 8.39 (dd, 1H, J=1.8, 8.4 Hz, ArH), 8.97 (dd, 1H, J=1.8, 4.2 Hz, ArH), 9.13-9.20 (m, 2H, NH), 11.35 (s, 1H, OH). HRMS-ESI calcd. for C.sub.18H.sub.15N.sub.3O.sub.3 [M+H].sup.+ 322.1192, found 322.1170.

Example 23

4-(2-ethoxy-2-oxoethyl)benzoic acid

(128) ##STR00059##

(129) .sup.1H NMR (300 MHz, CDCl.sub.3): δ 1.26 (t, 3H, J=7.2 Hz, CH.sub.3), 3.69 (s, 2H, CH.sub.2), 4.17 (q, 2H, J=7.2 Hz, CH.sub.2), 7.40 (d, 2H, J=8.4 Hz, ArH), 8.08 (d, 2H, J=8.1 Hz, ArH).

Ethyl 2-(4-(quinolin-8-ylcarbamoyl)phenyl)acetate

(130) ##STR00060##

(131) .sup.1H NMR (300 MHz, CDCl.sub.3): δ 1.24-2.30 (m, 3H, CH.sub.3), 3.71 (s, 2H, CH.sub.2), 4.14-4.22 (m, 2H, CH.sub.2), 7.44-7.49 (m, 3H, ArH), 7.51-7.62 (m, 2H, ArH), 8.02-8.07 (m, 2H, ArH), 8.15-8.20 (m, 1H, ArH), 8.84 (dd, 1H, J=1.8, 4.2 Hz, ArH), 8.90-8.94 (m, 1H, ArH), 10.72 (s, 1H, NH).

4-(2-(hydroxyamino)-2-oxoethyl)-N-(quinolin-8-yl)benzamide

(132) ##STR00061##

(133) .sup.1H NMR (300 MHz, d.sub.6-DMSO): δ 3.41 (s, 2H, CH.sub.2), 7.49 (d, 2H, J=8.1 Hz, ArH), 7.62-7.75 (m, 3H, ArH), 7.97 (d, 2H, J=8.4 Hz, ArH), 8.45 (dd, 1H, J=1.5, 8.4 Hz, ArH), 8.72 (dd, 1H, J=1.2, 7.5 Hz, ArH), 8.89 (d, 1H, J=1.5 Hz, NH), 8.97 (dd, 1H, J=1.5, 4.2 Hz, ArH), 10.62 (s, 1H, NH), 10.72 (s, 1H, NH). HRMS-ESI calcd. for C.sub.18H.sub.15N.sub.3O.sub.3 [M+H].sup.+ 322.1192, found 322.1163.

Example 24

Methyl 4-(2-(quinolin-8-yl)ethyl)benzoate

(134) ##STR00062##

(135) .sup.1H NMR (300 MHz, CDCl.sub.3): δ 3.16-3.22 (m, 2H, CH.sub.2), 3.58-3.64 (m, 2H, CH.sub.2), 3.91 (s, 3H, OCH.sub.3), 7.29 (d, 1H, J=8.4 Hz, ArH), 7.38-7.44 (m, 3H, ArH), 7.66-7.72 (m, 1H, ArH), 7.94-8.00 (m, 2H, ArH), 8.15 (dd, 1H, J=1.8, 8.4 Hz, ArH), 8.97 (dd, 1H, J=1.8, 4.2 Hz, ArH).

N-hydroxy-4-(2-(quinolin-8-yl)ethyl)benzamide

(136) ##STR00063##

(137) .sup.1H NMR (300 MHz, d.sub.6-DMSO): δ 3.03-3.09 (m, 2H, CH.sub.2), 3.47-3.53 (m, 2H, CH.sub.2), 7.30 (d, 1H, J=8.4 Hz, ArH), 7.45-7.58 (m, 3H, ArH), 7.68 (d, 2H, J=8.1 Hz, ArH), 7.81 (dd, 1H, J=1.5, 8.1 Hz, ArH), 8.31-8.35 (m, 1H, ArH), 8.95 (dd, 1H, J=1.8, 4.2 Hz, ArH), 8.98 (s, 1H, NH), 11.15 (s, 1H, OH). HRMS-ESI calcd. for C.sub.18H.sub.16N.sub.2O.sub.2 [M+H].sup.+ 293.1290, found 293.1262.

Example 25

Methyl 4-((isoquinolin-5-ylamino)methyl)benzoate

(138) ##STR00064##

(139) .sup.1H NMR (300 MHz, d.sub.6-DMSO): δ 3.81 (s, 3H, OCH.sub.3), 4.59 (d, 2H, J=5.7 Hz, CH.sub.2), 6.48-6.51 (m, 1H, ArH), 7.21-7.34 (m, 3H, ArH, NH), 7.52 (d, 2H, J=8.1 Hz, ArH), 7.90 (d, 2H, J=8.4 Hz, ArH), 8.12 (d, 1H, J=6.0 Hz, ArH), 8.44 (d, 1H, J=6.0 Hz, ArH), 9.12 (s, 1H, ArH).

N-hydroxy-4-((isoquinolin-5-ylamino)methyl)benzamide

(140) ##STR00065##

(141) .sup.1H NMR (300 MHz, d.sub.6-DMSO): δ 4.55 (d, 2H, J=6.0 Hz, CH.sub.2), 6.51 (d, 1H, J=7.5 Hz, ArH), 7.20-7.24 (m, 2H, ArH, NH), 7.31 (t, 1H, J=7.8 Hz, ArH), 7.44 (d, 1H, J=8.1 Hz, ArH), 7.68 (d, 1H, J=8.1 Hz, ArH), 8.11 (d, 1H, J=6.0 Hz, ArH), 8.43 (d, 1H, J=5.7 Hz, ArH), 8.97 (s, 1H, NH), 9.11 (s, 1H, ArH), 11.11 (s, 1H, OH). HRMS-ESI calcd. for C.sub.17H.sub.15N.sub.3O.sub.2 [M+H].sup.+ 294.1243, found 294.1210.

Example 26

Methyl 4-((isoquinolin-8-ylamino)methyl)benzoate

(142) ##STR00066##

(143) .sup.1H NMR (300 MHz, d.sub.6-DMSO): δ 3.35 (s, OCH.sub.3), 4.60 (d, 2H, J=5.7 Hz, CH.sub.2), 6.39 (d, 1H, J=7.8 Hz, ArH), 7.28 (d, 1H, J=8.1 Hz, ArH), 7.36 (t, 1H, J=7.8 Hz, ArH), 7.54 (d, 2H, J=8.1 Hz, ArH), 7.58-7.66 (m, 1H, ArH, NH), 7.89-7.92 (m, 2H, ArH), 8.40 (d, 1H, J=5.7 Hz, ArH), 9.64 (s, 1H, ArH).

N-hydroxy-4-((isoquinolin-8-ylamino)methyl)benzamide

(144) ##STR00067##

(145) .sup.1H NMR (300 MHz, d.sub.6-DMSO): δ 4.56 (d, 2H, J=5.7 Hz, CH.sub.2), 6.42 (d, 1H, J=7.8 Hz, ArH), 7.02 (d, 1H, J=8.1 Hz, ArH), 7.34-7.40 (m, 1H, ArH), 7.47 (d, 2H, J=8.1 Hz, ArH), 7.58-7.63 (m, 2H, NH, ArH), 7.70 (d, 2H, J=8.1 Hz, ArH), 8.40 (d, 1H, J=5.7 Hz, ArH), 9.03 (brs, 1H, NH), 9.64 (s, 1H, ArH), 11.14 (brs, 1H, OH). HRMS-ESI calcd. for C.sub.17H.sub.15N.sub.3O.sub.2 [M+H].sup.+ 294.1243, found 294.1221.

Example 27

Methyl 4-(quinolin-8-ylamino)benzoate

(146) ##STR00068##

(147) .sup.1H NMR (300 MHz, d.sub.6-DMSO): δ 3.79 (s, 3H, OCH.sub.3), 7.44-7.54 (m, 4H, ArH), 7.56-7.61 (m, 1H, ArH), 7.66-7.70 (m, 1H, ArH), 7.87 (d, 2H, J=9.0 Hz, ArH), 8.32-8.36 (m, 1H, ArH), 8.86-8.89 (m, 1H, ArH), 9.12 (s, 1H, NH).

4-(quinolin-8-ylamino)benzoic acid

(148) ##STR00069##

(149) .sup.1H NMR (300 MHz, d.sub.6-DMSO): δ 7.43-7.55 (m, 4H, ArH), 7.60 (dd, 1H, J=1.2, 8.1 Hz, ArH), 7.68 (dd, 1H, J=2.1, 6.9 Hz, ArH), 7.84-7.89 (m, 2H, ArH), 8.35 (dd, 1H, J=1.5, 8.4 Hz, ArH), 8.89 (dd, 1H, J=1.5, 4.2 Hz, ArH), 9.07 (s, 1H, NH), 12.45 (s, 1H, COOH).

N-hydroxy-4-(quinolin-8-ylamino)benzamide

(150) ##STR00070##

(151) .sup.1H NMR (300 MHz, d.sub.6-DMSO): δ 7.33-7.38 (m, 2H, ArH), 7.57-7.63 (m, 2H, ArH), 7.70-7.78 (m, 4H, ArH), 8.62 (dd, 1H, J=1.5, 8.4 Hz, ArH), 8.97 (dd, 1H, J=1.5, 4.5 Hz, ArH). HRMS-ESI calcd. for C.sub.16H.sub.13N.sub.3O.sub.2 [M+H].sup.+ 280.1086, found 280.1081.

Example 28

Methyl 4-((isoquinolin-1-ylamino)methyl)benzoate

(152) ##STR00071##

(153) .sup.1H NMR (300 MHz, d.sub.6-DMSO): δ 3.81 (s, 3H, OCH.sub.3), 4.81 (d, 2H, J=5.7 Hz, CH.sub.2), 6.90 (d, 1H, J=5.7 Hz, ArH), 7.45-7.54 (m, 3H, ArH), 7.60-7.66 (m, 1H, ArH), 7.71 (d, 1H, J=8.1 Hz, ArH), 7.90 (d, 1H, J=5.7 Hz, ArH), 8.88 (d, 2H, J=8.1 Hz, ArH), 8.08 (d, 1H, J=6.0 Hz, NH), 8.30 (d, 1H, J=8.1 Hz, ArH).

N-hydroxy-4-((isoquinolin-1-ylamino)methyl)benzamide

(154) ##STR00072##

(155) .sup.1H NMR (300 MHz, d.sub.6-DMSO): δ 4.77 (d, 2H, J=5.7 Hz, CH.sub.2), 6.89 (d, 1H, J=5.7 Hz, ArH), 7.40 (d, 2H, J=8.1 Hz, ArH), 7.48-7.54 (m, 1H, ArH), 7.59-7.72 (m, 4H, ArH), 7.80 (d, 1H, J=5.7 Hz, ArH), 8.04 (t, 1H, J=6.0 Hz, NH), 8.30 (d, 1H, J=8.1 Hz, ArH), 9.00 (s, 1H, NH), 11.12 (s, 1H, OH). HRMS-ESI calcd. for C.sub.17H.sub.15N.sub.3O.sub.2 [M+H].sup.+ 294.1243, found 294.1208.

Example 29

Methyl 4-((isoquinolin-4-ylamino)methyl)benzoate

(156) ##STR00073##

(157) .sup.1H NMR (300 MHz, d.sub.6-DMSO): δ 3.81 (s, 3H, OCH.sub.3), 4.62 (d, 2H, J=6.0 Hz, CH.sub.2), 7.13 (t, 1H, J=6.0 Hz, NH), 7.52-7.57 (m, 3H, ArH), 7.58-7.64 (m, 1H, ArH), 7.68-7.74 (m, 1H, ArH), 7.90-7.96 (m, 3H, ArH), 8.29 (d, 1H, J=8.4 Hz, ArH), 8.51 (s, 1H, ArH).

N-hydroxy-4-((isoquinolin-4-ylamino)methyl)benzamide

(158) ##STR00074##

(159) .sup.1H NMR (300 MHz, d.sub.6-DMSO): δ 4.58 (d, 2H, J=6.0 Hz, CH.sub.2), 7.13 (d, 1H, J=6.0 Hz, ArH), 7.46-7.54 (m, 3H, ArH), 7.59-7.65 (m, 1H, ArH), 7.67-7.74 (m, 3H, ArH), 7.88-7.96 (m, 1H, ArH), 8.29 (d, 1H, J=8.4 Hz, ArH), 8.98 (s, 1H, NH), 11.13 (s, 1H, OH). HRMS-ESI calcd. for C.sub.17H.sub.15N.sub.3O.sub.2 [M+H].sup.+294.1243, found 294.1212.

Example 30

5-Chloroquinoxaline

(160) ##STR00075##

(161) .sup.1H NMR (300 MHz, d.sub.6-DMSO): δ 7.81-7.88 (m, 1H, ArH), 8.03-8.11 (m, 2H, ArH), 9.04-9.07 (m, 2H, ArH).

Methyl 4-((quinoxalin-5-ylamino)methyl)benzoate

(162) ##STR00076##

(163) .sup.1H NMR (300 MHz, d.sub.6-DMSO): δ 3.81 (s, 3H, OCH.sub.3), 4.63 (d, 2H, J=6.6 Hz, CH.sub.2), 6.53 (dd, 1H, J=0.9, 7.8 Hz, ArH), 7.16 (dd, 1H, J=1.2, 8.4 Hz, ArH), 7.45-7.54 (m, 4H, NH, ArH), 7.87-7.91 (m, 2H, ArH), 8.77 (d, 1H, J=1.8 Hz, ArH), 8.90 (d, 1H, J=1.8 Hz, ArH).

N-hydroxy-4-((quinoxalin-5-ylamino)methyl)benzamide

(164) ##STR00077##

(165) .sup.1H NMR (300 MHz, d.sub.6-DMSO): δ 4.59 (d, 2H, J=6.6 Hz, CH.sub.2), 6.56 (dd, 1H, J=0.6, 7.8 Hz, ArH), 7.16 (dd, 1H, J=0.9, 8.4 Hz, ArH), 7.43-7.52 (m, 4H, NH, ArH), 7.68 (d, 2H, J=8.4 Hz, ArH), 8.77 (d, 1H, J=1.8 Hz, ArH), 8.89 (d, 1H, J=1.8 Hz, ArH), 8.97 (brs, 1H, NH), 11.12 (brs, 1H, OH). HRMS-ESI calcd. for C.sub.16H.sub.14N.sub.4O.sub.2 [M+H].sup.+ 295.1195, found 295.1190.

Example 31

Methyl 4-(((2-methylquinolin-8-yl)amino)methyl)benzoate

(166) ##STR00078##

(167) The solid compound was obtained from 6a (0.6 g, 3.72 mmol) according to method A of general procedure A (0.9 g, 79%). .sup.1H NMR (300 MHz, CDCl.sub.3): δ 2.71 (s, 3H, CH.sub.3), 3.91 (s, 3H, OCH.sub.3), 6.36 (d, 2H, J=6.0 Hz, CH.sub.2), 6.52 (dd, 1H, J=0.6, 7.5 Hz), 6.72-6.77 (m, 1H, NH), 7.01-7.05 (m, 1H, ArH), 7.20-7.28 (m, 2H, ArH), 7.50 (d, 1H, J=8.4 Hz, ArH), 7.94-8.03 (m, 3H, ArH)

N-hydroxy-4-(((2-methylquinolin-8-yl)amino)methyl)benzamide

(168) ##STR00079##

(169) The solid compound was obtained from 67 (0.83 g, 2.71 mmol) according to general procedure C (0.76 g, 91%). .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 2.67 (s, 3H, CH.sub.3), 4.57 (d, 2H, J=6.6 Hz, CH.sub.2), 6.47 (d, 1H, J=7.5 Hz, ArH), 6.97-7.05 (m, 2H, NH, ArH), 7.17 (t, 1H, J=8.1 Hz, ArH), 7.38 (d, 1H, J=8.1 Hz, ArH), 7.44 (d, 2H, J=7.8 Hz, ArH), 7.68 (d, 2H, J=8.1 Hz, ArH), 8.08 (d, 1H, J=8.4 Hz, ArH), 8.96 (brs, 1H, NH), 11.11 (brs, 1H, OH). HRMS-ESI Calcd. for C.sub.18H.sub.17N.sub.3O.sub.2 [M+H].sup.+ 308.1448, found 308.1399.

Example 32

Methyl 4-((quinolin-8-yloxy)methyl)benzoate

(170) ##STR00080##

(171) A solution of 6b (0.6 g, 4.2 mmol), methyl 4-(chloromethyl)benzoate (0.87 g, 4.62 mmol) and potassium carbonatein (1.16 g, 8.4 mmol) in acetone (10 mL) was heated to reflux for 12 h. Subsequently, the mixture was filtered. The organic layer was collected and purified through chromatography (ethyl acetare/hexane) to provide the product (1.1 g, 89%). .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 3.85 (s, 3H, OCH.sub.3), 5.42 (s, 2H, CH.sub.2), 7.25-7.29 (m, 1H, ArH), 7.46-7.59 (m, 3H, ArH), 7.69 (d, 2H, J=8.1 Hz, ArH), 7.99-8.03 (m, 2H, ArH), 8.30-8.34 (m, 1H, ArH), 8.86-8.89 (m, 1H, ArH).

N-hydroxy-4-((quinolin-8-yloxy)methyl)benzamide

(172) ##STR00081##

(173) The solid compound was obtained from 70 (0.6 g, 2.05 mmol) according to general procedure C (0.54 g, 90%). .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 5.37 (s, 2H, CH.sub.2), 7.25-7.29 (m, 1H, ArH), 7.46-7.57 (m, 3H, ArH), 7.61 (d, 2H, J=8.1 Hz, ArH), 7.78 (d, 2H, J=8.1 Hz, ArH), 8.30-8.34 (m, 1H, ArH), 8.85-8.88 (m, 1H, ArH), 9.03 (brs, 1H, NH), 11.22 (brs, 1H, OH). HRMS-ESI Calcd. for C.sub.17H.sub.14N.sub.2O.sub.3 [M+H].sup.+ 295.1083, found 295.1057.

Example 33

Methyl 4-((quinolin-8-ylthio)methyl)benzoate

(174) ##STR00082##

(175) A solution of 8-mercaptoquinoline hydrochloride (6c) (0.36 g, 1.74 mmol), methyl 4-(chloromethyl)benzoate (0.36 g, 1.92 mmol), triethylamine (0.3 mL, 2.09 mmol) and potassium carbonatein (0.49 g, 3.48 mmol) in acetone (10 mL) was heated to reflux for 12 h. Subsequently, the mixture was filtered. The organic layer was collected and purified through chromatography (ethyl acetare/hexane) to provide the product (0.48 g, 89%). .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 3.82 (s, 3H, OCH.sub.3), 4.43 (s, 2H, CH.sub.2), 7.46-7.52 (m, 1H, ArH), 7.55-7.64 (m, 4H, ArH), 7.69-7.73 (m, 1H, ArH), 7.89-7.92 (m, 2H, ArH), 8.35 (dd, 1H, J=1.8, 8.4 Hz, ArH), 8.88 (dd, 1H, J=1.8, 4.2 Hz, ArH).

N-hydroxy-4-((quinolin-8-ylthio)methyl)benzamide

(176) ##STR00083##

(177) The solid compound was obtained from 72 (0.6 g, 1.86 mmol) according to general procedure C (0.53 g, 92%). .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 4.38 (s, 2H, CH.sub.2), 7.47-7.61 (m, 5H, ArH), 7.68-7.73 (m, 3H, ArH), 8.35 (dd, 1H, J=1.2, 8.4 Hz, ArH), 8.88 (dd, 1H, J=1.8, 4.2 Hz, ArH), 9.00 (brs, 1H, NH), 11.17 (brs, 1H, OH). HRMS-ESI Calcd. for C.sub.17H.sub.14N.sub.2O.sub.2S [M+H].sup.+311.0854, found 311.0848.

Example 34

Methyl 4-(quinolin-8-ylmethylamino)benzoate

(178) ##STR00084##

(179) The solid compound was obtained from 6d (0.67 g, 4.28 mmol) and methyl 4-aminobenzoate (0.6 g, 3.89 mmol) according to method A of general procedure A (1.03 g, 82%). .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 3.71 (s, 3H, OCH.sub.3), 4.98 (s, 2H, CH.sub.2), 6.61-6.65 (m, 2H, ArH), 7.14-7.18 (m, 1H, NH), 7.25-7.67 (m, 5H, ArH), 7.88 (d, 1H, J=8.1 Hz, ArH), 8.37-8.41 (m, 1H, ArH), 8.97-8.99 (m, 1H, ArH).

N-hydroxy-4-(quinolin-8-ylmethylamino)benzamide

(180) ##STR00085##

(181) The solid compound was obtained from 76 (0.6 g, 2.05 mmol) according to general procedure C (0.52 g, 87%). .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 4.95 (d, 2H, J=6.0 Hz, CH.sub.2), 6.57 (d, 2H, J=8.7 Hz, ArH), 6.79-6.84 (m, 1H, NH), 7.45-7.68 (m, 5H, NH), 7.87 (d, 1H, J=8.1 Hz, ArH), 8.37-8.41 (m, 1H, ArH), 8.64 (s, 1H, NH), 8.96-8.99 (m, 1H, ArH), 10.71 (brs, 1H, OH). HRMS-ESI Calcd. for C.sub.17H.sub.15N.sub.3O.sub.2 [M+H].sup.+ 294.1243, found 294.1238.

Example 35

N-Hydroxy-4-(quinolin-8-ylaminomethyl)-benzamide mesylate

(182) ##STR00086##

(183) To a solution of Compound 28 in dioxane (0.2 M) was added a solution of MsOH in dioxane (0.2 M) and the resulting mixture was allowed to stir at room temperature. The reaction mixture was filtered and washed with dioxane to afford Compound 28-mesylate. .sup.1H-NMR (300 MHz, DMSO-d.sub.6) δ 2.34 (s, 3H), 4.59 (s, 2H), 6.56 (dd, J=0.9, 7.8 Hz, 1H), 7.08 (dd, J=1.2, 8.1 Hz, 1H), 7.26-7.32 (m, 1H), 7.46 (d, J=8.4 Hz, 2H), 7.55 (dd, J=8.4, 8.4 Hz, 1H), 7.68 (d, J=8.1 Hz, 2H), 8.26 (dd, J=1.8, 8.4 Hz, 1H); Anal. Calcd for C.sub.18H.sub.19N.sub.3O.sub.5S: C, 55.52; H, 4.92; N, 10.79; S, 8.23. Found: C, 55.65; H, 4.81; N, 10.72; S, 7.91; HPLC purity of 98.83% (retention time=26.42).

Example 36

(184) A study was conducted to evaluate the inhibitory activity of compounds of Formula (I) in inhibiting HDAC6, antiproliferative activity of test compounds in suppressing cancer cell growth, and selectivity of inhibiting HDAC6 over other HDAC isoforms.

(185) Fluorogenic HDAC assay kits were used to assess the ability of HDAC inhibitors to inhibit deacetylation of lysine residues on a substrate by recombinant proteins HDAC1, 3, 4, 5, 6, 7, 8, 9 and Sirt1 according to the manufacturer's instructions (BPS Bioscience Corp., San Diego, Calif., USA).

(186) The study was performed according to the protocol reported in Hsieh et al., Cell Death and Disease, 2014, April; 5:e1166.

(187) It was observed that multiple compounds unexpectedly exhibited significant HDAC6 inhibitory activity (measured by their half maximal inhibitory concentration or IC.sub.50), as shown in Table 1 below. More specifically, 9 compounds demonstrated remarkable HDAC6 inhibition with IC.sub.50 values of <25 nM. In particular, Compounds 12 and 28 demonstrated extraordinary HDAC6 inhibition with IC.sub.50 values of 2.73 and 4.41 nM, respectively.

(188) As also shown in Table 1, eight of the nine compounds demonstrated HDAC1 inhibition with IC.sub.50 values of 0.78-6.70 μM.

(189) TABLE-US-00001 TABLE 1 HDAC1/6 enzyme inhibitory activities of test compounds Enzyme IC.sub.50 HDAC1 HDAC6 Compound (μM) (nM) 4 0.78 19.11 20 >100 18.98 12 2.65 2.73 68 1.69 12.07 28 6.70 4.41 71 2.56 11.04 73 2.2 23.38 75 2.04 10.98 12 2.73 Tubastatin A 9.5 26.16

(190) Shown in Table 2 below are antiproliferative activities (measured by their half maximal concentration for inhibiting cell growth, i.e., GI.sub.50) of the test compounds against various cancer cell lines.

(191) Unexpectedly, a number of compounds of formula (I) demonstrated high potency with GI50<10 μM in six cancer cell lines, i.e., PC-3, A549, HCT116, HL60, MDA-MB-231, and T98 cell lines.

(192) TABLE-US-00002 TABLE 2 Antiproliferative activities of test compounds Cancer cell lines (GI.sub.50 μM) MDA- PC-3 A549 HCT116 HL60 MB-231 T98 Compound prostate lung colorectal leukemia Breast Glioblastoma  4 1.62 ± 0.20 2.73 ± 0.24 20 >10 >10 12 3.28 ± 0.11 5.53 ± 0.24 68 4.45 ± 0.92 5.89 ± 0.42 28 3.40 ± 0.13 5.24 ± 0.18 1.89 ± 0.33 9.89 ± 0.92 28-mesylate 1.36 ± 0.25 10.75 ± 0.83  71 6.23 ± 0.32 7.81 ± 1.17 73 4.29 ± 0.70 6.11 ± 0.69 75 >10 6.32 ± 0.92 12 3.28 ± 0.11 5.53 ± 0.24 40 0.85 ± 0.09 0.29 ± 0.02 42 2.64 ± 0.14 0.62 ± 0.03 44 3.28 ± 0.48 54 6.06 ± 0.40 4.64 ± 0.25 56 4.91 ± 0.24 1.76 ± 0.21 61 0.66 ± 0.10 1.17 ± 0.23 63 1.20 ± 0.14 1.96 ± 0.16 66 1.95 ± 0.21 5.58 ± 0.15 59 3.32 ± 0.21 6.64 ± 0.69 52 9.66 ± 0.07 3.05 ± 0.09  6 0.38 ± 0.03 0.71 ± 0.01  8 >10 >10 10 >10 >10 22 >10 >10 26 >10 >10 24 >10 >10 14 0.62 ± 0.05 1.25 ± 0.08 16 >10 >10 18 >10 >10 30 1.25 ± 0.02 1.11 ± 0.05 32 >10 >10 34 3.51 ± 0.18 4.26 ± 0.07 47 2.08 ± 0.10 7.77 ± 0.03 50 >10 >10 36 >10 >10 38 >10 >10 Tubastatin A 48.19 ± 0.43 52.2 ± 1.28

(193) Table 3 below indicated selectivity of compounds inhibiting HDAC6 over other HDACs including HDAC1, 3, 4, 5, 7, 8, 9 and Sirt1.

(194) Unexpectedly, both Compounds 12 and 28 demonstrated selectivity of >100 folds over all the other tested HDACs. Most unexpectedly, Compound 12 exhibited remarkable selectivity of >1000 folds over all the other HDACs.

(195) TABLE-US-00003 TABLE 3 Selectivity over other HDAC isoforms Selectivity (fold) HDAC6 HDAC6 HDAC6 HDAC6 HDAC6 HDAC6 HDAC6 HDAC6 v.s. v.s. v.s. v.s. v.s. v.s. v.s. v.s. Compound HDAC1 HDAC3 HDAC4 HDAC5 HDAC7 HDAC8 HDAC9 Sirt1 28 181.27 442.46 >1000 980.91 830.70 327.74 >1000 >10000 12 >1000 >1000 >1000 >1000 >1000 >2000 >5000 >10000 Tubastatin A 517.57 487.39 625.02 163.24 761.89 167.76 >1000 15.34

Example 37

(196) A study was conducted to evaluate the activity of a compound of Formula (I) in increasing acetyl-a-tubuline expression in human multiple myeloma cell lines (RPMI8226, U266, and NCI-H929).

(197) Cells (1×10.sup.6) were incubated for 10 minutes at 4° C. in a lysis buffer solution in a culture vessel, and then scraped off the culture vessel, incubated on ice for another 10 minutes, and centrifuged at 17,000×g for 30 minutes at 4° C. Protein samples (80 μg) were electrophoresed on SDS gels and transferred onto a nitrocellulose membrane, which was blocked by incubation with 5% fat-free milk in phosphate-buffered saline (PBS) for 30 minutes at room temperature. Immunoblotting was performed by overnight incubation at 4° C. with primary antibodies in PBS, followed by incubation for 1 hour at room temperature with horseradish peroxidase (HRP)-conjugated secondary antibodies, then bound antibodies were measured using enhanced chemiluminescence (ECL) reagent (Advansta Corp., Menlo Park, Calif., USA) and exposure to photographic film.

(198) The study was performed according to the protocol reported in Yang et al., Journal of Molecular Medicine, 2014, November; 92(11):1147-1158.

(199) Compound 28 unexpectedly exerted activity in increasing acetyl-a-tubuline expression in a dose-dependent manner in all three human multiple myeloma cell lines, i.e., RPMI8226, U266, and NCI-H929.

Example 38

(200) A study was conducted to evaluate the activity of a compound of Formula (I) in inhibiting HDAC6-dynein binding and inducing accumulation of polyubiquited proteins.

(201) Cell lysates were immunoprecipitated overnight at 4° C. with 1 μg of dynein antibody and A/G-agarose beads. The precipitated beads were washed three times with 1 mL of an ice-cold cell lysis buffer solution. The resulting immune complex was resolved by 10% SDS-PAGE gel electrophoresis, followed by immunoblotting assay using anti-HDAC6 Ab.

(202) The study was performed according to the protocol reported in Chen et al., Journal of Immunology, 2008, 181(12):8441-8449.

(203) It was observed that Compound 28 unexpectedly inhibited HDAC6-dynein binding and induced accumulation of polyubiquited proteins both in a dose-dependent manner.

Example 39

(204) A study was conducted to evaluate the effect of a compound of Formula (I) combined with bortezomib in inducing apoptosis in multiple myeloma cells.

(205) To detect cell cycle progression, cells were incubated with or without the indicated agent for 24 hours, washed twice with ice-cold PBS, collected by centrifugation, and fixed in 70% (v/v) ethanol for 2 hours at −20° C. They were subsequently incubated for 30 minutes at room temperature with 0.2 mL of deoxyribonucleic acid (DNA) extraction buffer (0.2 M Na.sub.2HPO.sub.4 and 0.1 M citric acid buffer, pH 7.8), re-suspended in 1 mL of propidium iodide staining buffer (0.1% Triton X-100, 100 μg/mL of RNase A, and 80 μg/mL of propidium iodide in PBS), incubated at 37° C. for 30 minutes in darkness, sorted by FACScan, and analyzed using CellQuest software (BD Biosciences).

(206) The study was performed according to the protocol reported in Hsieh et al., Cell Death and Disease, 2014, April; 5:e1166.

(207) Unexpectedly, Compound 28 combined with bortezomib synergistically induced apoptosis in all three human multiple myeloma cell lines, i.e., RPMI8226, U266, and NCI-H929.

Example 40

(208) A study was conducted to evaluate the effect of a compound of Formula (I) combined with bortezomib in increasing cleavage of Caspase-3, Caspase-8, and Caspase-9 in multiple myeloma cells.

(209) Cells (1×10.sup.6) were incubated for 10 minutes at 4° C. in a lysis buffer solution in a culture vessel, and then scraped off the culture vessel, incubated on ice for another 10 minutes, and centrifuged at 17,000×g for 30 minutes at 4° C. Protein samples (80 μs) were electrophoresed on SDS gels and transferred onto a nitrocellulose membrane, which was blocked by incubation with 5% fat-free milk in phosphate-buffered saline (PBS) for 30 minutes at room temperature. Immunoblotting was performed by overnight incubation at 4° C. with primary antibodies in PBS, followed by incubation for 1 hour at room temperature with horseradish peroxidase (HRP)-conjugated secondary antibodies, then bound antibodies were measured using enhanced chemiluminescence (ECL) reagent (Advansta Corp., Menlo Park, Calif., USA) and exposure to photographic film.

(210) The study was performed according to the protocol reported in Yang et al., Journal of Molecular Medicine, 2014, November; 92(11):1147-1158.

(211) Compound 28 combined with bortezomib unexpectedly increased cleavage of Caspase-3, Caspase-8, and Caspase-9 in multiple myeloma cells of RPMI8226 and NCI-H929.

Example 41

(212) A study was conducted to evaluate the effect of compounds of Formula (I) in amyloid precursor protein (APP) levels and Aβ.sub.42 production.

(213) Neuro 2a cells (1×10.sup.6) in 6-well plates were transfected with pCAX APP 695 plasmid for 24 hours, then incubated for another 24 hours with Compound 12, Compound 28, or tubasatin A (0.1-10 μM). Cells were then harvested and cell lysates were prepared for Western blot analysis of the APP proteins.

(214) Moreover, neuro 2a or SH—SYSY cells (1×10.sup.5) were transfected with pCAX APP 695 plasmid for 24 hours, followed by incubation with Compound 12 or Compound 28 (0.1-10 μM) for another 24 hours. Cell culture supernatants were assayed for Aβ.sub.42 production.

(215) As a control experiment, neuro 2a cells transfected with pCAX APP 695 plasmid significantly increased APP levels. Unexpectedly, Compounds 12 and 28 markedly reduced the APP expression. In addition, these two compounds also decreased Aβ.sub.42 production in pCAX APP 695 plasmid-transfected Neuro 2a and SH—SYSY cells.

Example 42

(216) An in vivo study was conducted to evaluate the efficacy of compounds of Formula (I) in suppressing tumor growth in multiple human cancer types.

(217) Eight-week-old athymic nude mice were group-housed under conditions of constant photoperiod (12 h light/12 h dark at 21-23° C. and 60-85% humidity) with ad libitum access to sterilized food and water. All animal experiments followed ethical standards, and protocols were reviewed and approved by the Animal Use and Management Committee of National Taiwan University. Each mouse was inoculated subcutaneously with 1×10.sup.6˜1×10.sup.7 human cancer cells in a total volume of 0.1 mL serum-free medium containing 50% Matrigel (BD Biosciences). As tumors became established (˜100 mm.sup.3), mice were randomized to various groups to be treated with pre-determined materials (n=6-8/group): (i) control group: 0.5% DMSO/0.5% Cremophor/90% D5W and (ii) treatment groups: Compounds 12 and 28 at pre-determined doses daily. Mice received treatment by intraperitoneal injection for the duration of the study. Tumors were measured weekly using calipers. Tumor size, in mm.sup.3, was calculated according to the formula: Tumor volume=(w.sup.2×l)/2, where w and 1 respectively represent the width and length (both in mm) of the tumor.

(218) As shown in Table 3 below, both Compounds 12 and 28 unexpectedly demonstrated significant efficacy in inhibiting tumor growth of various human cancers.

(219) TABLE-US-00004 TABLE 3 Efficacy of HDAC6 inhibitors in tumor growth inhibition (TGI) Tumor Line Tumor Type HDAC6 Inhibitor Dose/Schedule % TGI Best Response Hematological tumor RPMI-8226 Multiple myeloma Compound 28  50 mg/kg, qd 80.0% 2 × CR.sup.a HL-60 Acute Compound 28  25 mg/kg, qd 47.4% promyelocytic Compound 28  50 mg/kg, qd 61.1% leukemia Compound 12  50 mg/kg, qd 72.2% BJAB Burkitt Compound 28  25 mg/kg, qd 40.8% lymphoma- Compound 28  50 mg/kg, qd 74.0% derived B-cell Compound 12  50 mg/kg, qd 64.5% Solid tumor MDA-MB-231 Breast Compound 28  25 mg/kg, qd 38.6% Compound 28  50 mg/kg, qd 56.4% HCT116 Colorectal Compound 28  50 mg/kg, qd  9.1% Compound 28 100 mg/kg, qd 44.4% .sup.aCR: complete regression

(220) No significant body weight change was observed in animals in the above-described study.

(221) In addition, both Compounds 12 and 28 were studied to evaluate their safety in animals.

(222) ICR (Crl:CD1) strain mice were administered each of Compounds 12 and 28 at doses of 50, 100, and 200 mg/kg. The animals were dosed intraperitoneally once a day for 7 days and then monitored for another 7 days. The animals were weighed daily for 1 week and then twice weekly.

(223) It was observed that both Compounds 12 and 28 were well tolerated at all three doses of 50, 100, and 200 mg/kg.

Example 43

(224) An in vivo study was conducted to evaluate the efficacy of compounds of Formula (I) in improving memory deficits associated with Alzheimer's disease.

(225) Compound 12, Compound 28, suberanilohydroxamic acid (50 mg/kg) or vehicle was given to rats by gavage twice daily for seven days prior to behavioral experiments. On the day conducting a behavior assessment, rats in all groups except the control group were administered scopolamine (1.5 mg/kg) by intraperitoneal injection for 30 minutes before the assessment, then a water maze test or an elevated plus maze test was performed.

(226) In the mater maze test, time spent in the correct quadrant was significantly deceased in scopolamine-treated rats compared with that of the control group. Unexpectedly, treatment with each of Compounds 12 and 28 was found to markedly reverse this effect.

(227) Furthermore, scopolamine treatment significantly increased transfer latency time in the elevated plus maze test. Unexpectedly, treatment with each of Compounds 12 and 28 significantly rescued scopolamine-mediated increase of transfer latency time. The significant reduction in transfer latency time indicated improvement in memory.

OTHER EMBODIMENTS

(228) All of the features disclosed in this specification may be combined in any combination. Each feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent, or similar purpose. Thus, unless expressly stated otherwise, each feature disclosed is only an example of a generic series of equivalent or similar features.

(229) Further, from the above description, one skilled in the art can easily ascertain the essential characteristics of the present invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. Thus, other embodiments are also within the claims.