Dihydropyrimidinone derivatives

Abstract

A dihydropyrimidinone derivative having a chemical structure according to Formula 1: ##STR00001##
wherein Z is selected from N and O; X is selected from O and S; and R represents aryl, substituted aryl, heteroaryl, or substituted heteroaryl, wherein the substituted aryl or substituted heteroaryl have one or more substituents selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, hydroxyl, alkylthio, alkylamino, heteroaryl, aryloxy, haloaryloxy, arylthio, arylamino, and pharmaceutically acceptable salts thereof.

Claims

1. A compound having the chemical structure according to Formula 1: ##STR00009## wherein Z is selected from N and O; X is selected from O and S; and R is selected from aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein: R is substituted aryl or substituted heteroaryl, the substituted aryl or substituted heteroaryl having one or more substituents selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, hydroxyl, alkylthio, alkylamino, heteroaryl, aryloxy, haloaryloxy, arylthio, and arylamino.

3. The compound according to claim 1, wherein the compound is selected from the group consisting of: ##STR00010## ##STR00011##

4. The compound according to claim 1, wherein Z is oxygen.

5. The compound according to claim 4, wherein the compound is selected from the group consisting of: ##STR00012## ##STR00013##

6. A compound having a chemical structure according to Formula 1: ##STR00014## wherein Z is selected from N and O; X is selected from O and S; and R is phenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 4-chlorophenyl, 2-methoxyphenyl, 4-hydroxyphenyl, 3-hydroxyphenyl, 3-methoxyphenyl, or 4-ethoxy phenyl; or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 6, wherein Z is nitrogen.

8. A method of preparing a compound having a chemical structure according to Formula 1: ##STR00015## wherein Z is selected from N and O; X is selected from O and S; and R is selected from aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or a pharmaceutically acceptable salt thereof; the method comprising refluxing 1-[4-(piperazin/morpholin-1-yl) phenyl] ethan-1-one with dimethyl-formamide dimethylacetal (DMF-DMA) to produce an enaminone; and refluxing a solution of the enaminone with a substituted benzaldehyde, urea, and glacial acetic acid to produce the compound.

9. The method of claim 8, wherein the 1-[4-(piperazin/morpholin-1-yl) phenyl] ethan-1-one is refluxed with the dimethylformamide dimethylacetal (DMF-DMA) under a solvent free condition for about 10 hours to produce the enaminone.

10. The method of claim 8, wherein the solution of enaminone, substituted benzaldehyde, urea, and glacial acetic acid is refluxed for about 3 hours to produce the compound.

11. The method of claim 8, further comprising: recrystallizing the compound from a mixture of ethanol and glacial acetic acid.

12. The method of claim 8, wherein R is phenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 4-chlorophenyl, 2-methoxyphenyl, 4-hydroxyphenyl, 3-hydroxyphenyl, 3-methoxyphenyl, or 4-ethoxy phenyl.

13. The method of claim 12, wherein Z is N.

14. The method of claim 12, wherein Z is O.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 illustrates the reaction scheme by which the dihydropyrimidinone derivatives can be prepared.

(2) FIG. 2A and FIG. 2B illustrate two conformers in the unit cell of the crystal X-ray structure of enaminone II (as labeled in FIG. 1).

(3) Similar reference characters denote corresponding features consistently throughout the attached drawings.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

(4) A dihydropyrimidinone derivative includes a compound having a chemical structure according to Formula 1, shown below:

(5) ##STR00004##
wherein Z is selected from N and O; X is selected from O and S; and R represents aryl, substituted aryl, heteroaryl, or substituted heteroaryl, wherein the substituted aryl or substituted heteroaryl have one or more substituents selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, hydroxyl, alkylthio, alkylamino, heteroaryl, aryloxy, haloaryloxy, arylthio, arylamino, and pharmaceutically acceptable salts thereof.

(6) In an embodiment, R represents mono-substituted phenyl compounds. In an embodiment, R is selected from phenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 4-chlorophenyl, 2-methoxyphenyl, 4-hydroxyphenyl, 3-hydroxyphenyl, 3-methoxyphenyl, 4-ethoxy phenyl.

(7) The dihydropyrimidinone derivatives can include 4-(substituted phenyl)-5-[4-(piperazin/morpholin-1-yl) benzoyl]-3,4-dihydropyrimidin-2(1H)-one derivatives. In an embodiment of the present subject matter, the dihydropyrimidinone derivatives include one or more of compounds DHPM 1-20 provided below:

(8) ##STR00005## ##STR00006## ##STR00007## ##STR00008##

(9) FIG. 1 depicts a reaction scheme by which the dihydropyrimidinone derivatives of Formula 1 can be prepared. As shown in FIG. 1, the dihydropyrimidinone derivatives can be synthesized by refluxing 1-[4-(piperazin/morpholin-1-yl) phenyl] ethan-1-one (I) with dimethylformamide dimethylacetal (DMF-DMA) to obtain the enaminone (II); and refluxing a solution of the enaminone (II), a substituted benzaldehyde (III), urea (IV), and glacial acetic acid to yield the dihydropyrimidinone derivative (V) of Formula 1, where X, Z, and R represent the moieties recited above.

(10) In one embodiment, the 1-[4-(piperazin/morpholin-1-yl) phenyl] ethan-1-one is refluxed with dimethylformamide dimethylacetal (DMF-DMA) under a solvent free condition for about 10 hours.

(11) In another embodiment, the solution of enaminone, substituted benzaldehyde, urea, and glacial acetic acid is refluxed for about 3 hours.

(12) In another embodiment, the method further includes recrystallizing the 4-(substituted phenyl)-5-[4-(piperazin/morpholin-1-yl) benzoyl]-3,4-dihydropyrimidin-2(1H)-one derivatives from the ethanol and glacial acetic acid mixture.

(13) It is anticipated that the compounds described herein can provide a one or more therapeutic uses, including, for example, anti-tumor, anti-viral, anti-bacterial, anti-inflammatory, anti-cancer, cardio-protective, anti-tuberculosis, anti-diabetic, antihistamine, antidepressant, inhibiting HIV-protease, antiplatelet, inhibitor of protein kinase C, neuroprotective, anti-hypertensive, anti-fungal, anti-parasitic, anti-malarial, hypolipidemic, hypocholesterolemic, treatment of chronic wounds, treatment of Hunner's ulcer, treatment of ulcerative colitis, and/or inhibiting neutrophil elastase activity. For example, the dihydropyrimidinone derivatives can be used as an active ingredient in a pharmaceutical composition for treatment of one or more ailments. The pharmaceutical composition can include one or more of the dihydropyrimidinone derivatives, or salt thereof, and a pharmaceutical carrier. The pharmaceutical composition including the one or more dihydropyrimidinone derivatives can be prepared and administered in any suitable manner, such as that described in U.S. Pat. No. 9,856,232, issued Jan. 2, 2018 to Bhat et al., which is hereby incorporated by reference in its entirety

(14) The following example illustrates the present teachings.

EXAMPLE

Synthesis of the Dihydropyrimidinone Derivatives

(15) As shown in FIG. 1, enaminone (II), (2E)-4-methyl-1-[4-(piperazin/morpholin-1-yl) phenyl]pent-2-en-1-one was synthesized by refluxing 1-[4-(piperazin/morpholin-1-yl) phenyl]ethan-1-one (I) with dimethylformamide dimethylacetal (DMF-DMA) under solvent-free conditions for 10 hours. A single crystal X-ray structure confirmed the three dimensional structure of enaminone (II). The CCDC number 1532829 contains the crystallographic data for the enaminone structure (II) having the morpholine moietywhere the substituent Z is oxygen.

(16) To prepare the final dihydropyrimidinone derivatives, a solution of the enaminone (II) (0.01 mol), the substituted benzaldehyde (0.01 mol) III, urea (0.01 mol) IV, and glacial acetic acid (10 mL) was heated under reflux for 3 hours. The precipitate of the resulting corresponding compounds DHPM 1-20 were collected by filtration, washed with water and recrystallized from a mixture of glacial acetic acid and ethanol. In the spectra produced when analyzed by NMR spectroscopy, the signals of the individual protons of the compounds were verified on the basis of multiplicity, chemical shifts and the coupling constant. FIG. 2A and FIG. 2B illustrate two conformers in the unit cell of the crystal X-ray structure of enaminone II Analytical and spectral data for the compounds were confirmed in comparison with the expected structures of the compounds.

(17) The spectral data for compounds DHPM 1-20 are provided below:

(18) DHPM-1 4-phenyl-5-[4- (piperazin-1-yl)benzoyl]-3,4-dihydropyrimidin-2(1H)-one Yield: 75%; m.p.: 150-152 C.; .sup.1H NMR (500 MHz, DMSO-d.sub.6): =9.41 (1H, s, NH, D.sub.2O exchg.), 8.50 (1H, s, NH, D.sub.2O exchg.), 8.0 (1H, s, CH), 6.90-7.80 (9H, m, ArH), 6.0 (1H, s, H-4), 3.40 (2H, s, CH.sub.2 piperazine), 3.31 (2H, s, CH.sub.2 piperazine), 2.06 (2H, s, CH.sub.2 piperazine), 2.0 (2H, s, CH.sub.2 piperazine), 1.80 (1H, s, NH, D.sub.2O exchg.); MS: m/z=362.42 [M].sup.+; Analysis: for C.sub.21H.sub.22N.sub.4O.sub.2, calcd. C 69.59, H 6.12, N 15.46%; found C 69.32, H 6.10, N 15.40%.

(19) DHPM-2 4-(2-Nitrophenyl)-5-[4-(piperazin-1-yl)benzoyl]-3,4-dihydropyrimidin-2(1H)-one Yield: 70%; m.p.: 170-172 C.; .sup.1H NMR (500 MHz, DMSO-d.sub.6): =9.4 (1H, s, NH, D.sub.2O exchg.), 8.52 (1H, s, NH, D.sub.2O exchg.), 8.04 (1H, s, CH), 6.89-7.88 (8H, m, ArH), 6.07 (1H, s, H-4), 3.41 (2H, s, CH.sub.2 piperazine), 3.32 (2H, s, CH.sub.2 piperazine), 2.06 (2H, s, CH.sub.2 piperazine), 2.0 (2H, s, CH.sub.2 piperazine), 1.79 (1H, s, NH, D.sub.2O exchg.); .sup.13C NMR (125.76 MHz, DMSO-d.sub.6): =44.7, 47.2, 48.4, 50.11, 65.4, 111.7, 113.6, 114.1, 114.5, 124.4, 130.5, 134.1, 138.7, 148.3, 149.1, 151.2, 161.5, 168.9, 190.40, 207.0; MS: m/z=407.40 [M].sup.+; Analysis: for C.sub.21H.sub.21N.sub.5O.sub.4, calcd. C 61.91, H 5.20, N 17.19%; found C 62.15, H 5.22, N 17.12%.

(20) DHPM-3 4-(4-Nitrophenyl)-5-[4-(piperazin-1-yl)benzoyl]-3,4-dihydropyrimidin-2(1H)-one Yield: 75%; m.p.: 175-177 C.; .sup.1H NMR (500 MHz, DMSO-d.sub.6): =9.41 (1H, s, NH, D.sub.2O exchg.), 8.28 (1H, s, CH), 6.93-7.58 (8H, m, ArH), 7.93 (1H, s, NH, D.sub.2O exchg.), 5.55 (1H, s, H-4), 3.30 (2H, s, CH.sub.2 piperazine), 3.23 (2H, s, CH.sub.2 piperazine), 2.07 (2H, s, CH.sub.2 piperazine), 2.0 (2H, s, CH.sub.2 piperazine), 1.85 (1H, s, NH, D.sub.2O exchg.); .sup.13C NMR (125.76 MHz, DMSO-d.sub.6): =44.7, 45.5, 47.2, 47.5, 48.0, 53.9, 118.8, 114.1, 124.3, 128.3, 130.6, 147.2, 151.6, 153.1, 161.3, 168.8, 190.4, 207.0; MS: m/z=407.42 [M].sup.+; Analysis: for C.sub.21H.sub.21N.sub.5O.sub.4, calcd. C 61.91, H 5.20, N 17.19%; found C 62.10, H 5.23, N 17.13%.

(21) DHPM-4 4-(3-Nitrophenyl)-5-[4-(piperazin-1-yl)benzoyl]-3,4-dihydropyrimidin-2(1H)-one Yield: 75%; m.p.: 180-182 C.; .sup.1H NMR (500 MHz, DMSO-d.sub.6): =9.42 (1H, s, NH, D.sub.2O exchg.), 8.23 (1H, s, CH), 6.93-7.65 (8H, m, ArH), 7.95 (1H, s, NH, D.sub.2O exchg.), 5.58 (1H, s, H-4), 3.31 (2H, s, CH.sub.2 piperazine), 3.23 (2H, s, CH.sub.2 piperazine), 2.07 (2H, s, CH.sub.2 piperazine), 2.01 (2H, s, CH.sub.2 piperazine), 1.87 (1H, s, NH, D.sub.2O exchg.); .sup.13C NMR (125.76 MHz, DMSO-d.sub.6): =44.7, 45.5, 47.2, 47.5, 48.0, 48.4, 53.8, 65.4, 111.8, 114.1, 121.6, 122.9, 128.3, 130.3, 131.3, 133.7, 146.7, 148.2, 151.6, 161.3, 168.8, 190.5, 207.0; MS: m/z=407.42 [M].sup.+; Analysis: for C.sub.21H.sub.21N.sub.5O.sub.4, calcd. C 61.91, H 5.20, N 17.19%; found C 60.67, H 5.22, N 17.10%.

(22) DHPM-5 4-(4-Chlorophenyl)-5-[4-(piperazin-1-yl)benzoyl]-3,4-dihydropyrimidin-2(1H)-one Yield: 75%; m.p.: 160-162 C.; .sup.1H NMR (500 MHz, DMSO-d.sub.6): =9.32 (1H, s, NH, D.sub.2O exchg.), 8.50 (1H, s, NH, D.sub.2O exchg.), 8.23 (1H, s, CH), 6.95-8.11 (8H, m, ArH), 5.46 (1H, s, H-4), 3.31 (2H, s, CH.sub.2 piperazine), 3.23 (2H, s, CH.sub.2 piperazine), 2.09 (2H, s, CH.sub.2 piperazine), 2.04 (2H, s, CH.sub.2 piperazine), 1.90 (1H, s, NH, D.sub.2O exchg.); .sup.13C NMR (125.76 MHz, DMSO-d.sub.6): =44.7, 44.9, 47.3, 48.0, 48.4, 53.6, 65.4, 112.5, 114.1, 115.6, 116.0, 128.5, 140.0, 143.6, 148.1, 151.8, 153.1, 156.7, 161.3, 168.7, 190.5, 207.0; MS: m/z=396.87 [M].sup.+; Analysis: for C.sub.21H.sub.21ClN.sub.4O.sub.2, calcd. C 63.55, H 5.33, N 14.12%; found C 63.31, H 5.34, N 14.17%.

(23) DHPM-6 4-(2-methoxyphenyl)-5-[4-(piperazin-1-yl)benzoyl]-3,4-dihydropyrimidin-2(1H)-one Yield: 75%; m.p.: 120-122 C.; .sup.1H NMR (500 MHz, DMSO-d.sub.6): =9.22 (1H, s, NH, D.sub.2O exchg.), 8.51 (1H, s, NH, D.sub.2O exchg.), 8.13 (1H, s, CH), 6.93-7.98 (8H, m, ArH), 5.77 (1H, s, H-4), 3.82 (3H, s, OCH.sub.3), 3.41 (2H, s, CH.sub.2 piperazine), 3.24 (2H, s, CH.sub.2 piperazine), 2.09 (2H, s, CH.sub.2 piperazine), 2.04 (2H, s, CH.sub.2 piperazine), 1.93 (1H, s, NH, D.sub.2O exchg.); .sup.13C NMR (125.76 MHz, DMSO-d.sub.6): =44.6, 46.7, 48.0, 48.5, 49.6, 55.9, 56.1, 111.1, 112.1, 114.2, 120.6, 121.1, 130.5, 131.0, 137.3, 154.0, 157.3, 158.5, 161.4, 168.8, 172.6, 187.1, 190.5, 196.1, 207.0; MS: m/z=392.45 [M].sup.+; Analysis: for C.sub.22H.sub.24N.sub.4O.sub.3, calcd. C 67.33, H 6.16, N 14.28%; found C 67.58, H 6.14, N 14.23%.

(24) DHPM-7 4-(4-Hydroxyphenyl)-5-[4-(piperazin-1-yl)benzoyl]-3,4-dihydropyrimidin-2(1H)-one Yield: 75%; m.p.: 210-212 C.; .sup.1H NMR (500 MHz, DMSO-d.sub.6): =9.16 (1H, s, OH, D.sub.2O exchg.), 9.0 (1H, s, NH, D.sub.2O exchg.), 8.51 (1H, s, NH, D.sub.2O exchg.), 8.17 (1H, s, CH), 6.71-8.08 (8H, m, ArH), 5.33 (1H, s, H-4), 3.35 (2H, s, CH.sub.2 piperazine), 3.20 (2H, s, CH.sub.2 piperazine), 2.07 (2H, s, CH.sub.2 piperazine), 2.01 (2H, s, CH.sub.2 piperazine), 1.82 (1H, s, NH, D.sub.2O exchg.); .sup.13C NMR (125.76 MHz, DMSO-d.sub.6): =44.7, 47.3, 48.1, 49.2, 53.5, 65.4, 115.4, 116.0, 128.0, 129.6, 130.3, 151.7, 152.0, 153.0, 155.8, 156.4, 157.1, 159.1, 161.3, 168.8, 190.7, 207.0; MS: m/z=378.42 [M].sup.+; Analysis: for C.sub.21H.sub.22N.sub.4O.sub.3, calcd. C 66.65, H 5.86, N 14.81%; found C 66.40, H 5.84, N 14.86%.

(25) DHPM-8 4-(3-Hydroxyphenyl)-5-[4-(piperazin-1-yl)benzoyl]-3,4-dihydropyrimidin-2(1H)-one Yield: 75%; m.p.: 158-160 C.; .sup.1H NMR (500 MHz, DMSO-d.sub.6): =9.8 (1H, s, OH, D.sub.2O exchg.), 9.10 (1H, s, NH, D.sub.2O exchg.), 8.04 (1H, s, CH), 6.82-7.77 (8H, m, ArH), 6.71 (1H, s, NH, D.sub.2O exchg.), 5.32 (1H, s, H-4), 3.30 (2H, s, CH.sub.2 piperazine), 3.20 (2H, s, CH.sub.2 piperazine), 2.04 (2H, s, CH.sub.2 piperazine), 2.0 (2H, s, CH.sub.2 piperazine), 1.86 (1H, s, NH, D.sub.2O exchg.); .sup.13C NMR (125.76 MHz, DMSO-d.sub.6): =44.6, 46.7, 47.9, 48.0, 53.8, 56.5, 115.5, 117.3, 120.1, 122.9, 128.6, 130.5, 136.7, 139.5, 143.0, 146.1, 152.1, 153.1, 154.0, 157.8, 161.4, 168.8, 172.6, 187.0, 190.6, 196.6, 207.0; MS: m/z=378.42 [M].sup.+; Analysis: for C.sub.21H.sub.22N.sub.4O.sub.3, calcd. C 66.65, H 5.86, N 14.81%; found C 66.39, H 5.83, N 14.85%.

(26) DHPM-9 4-(3-methoxyphenyl)-5-[4-(piperazin-1-yl)benzoyl]-3,4-dihydropyrimidin-2(1H)-one Yield: 70%; m.p.: 118-120 C.; .sup.1H NMR (500 MHz, DMSO-d.sub.6): =9.28 (1H, s, NH, D.sub.2O exchg.), 8.50 (1H, s, NH, D.sub.2O exchg.), 8.24 (1H, s, CH), 6.88-8.11 (8H, m, ArH), 5.47 (1H, s, H-4), 3.73 (3H, s, OCH.sub.3), 3.33 (2H, s, CH.sub.2 piperazine), 3.20 (2H, s, CH.sub.2 piperazine), 2.09 (2H, s, CH.sub.2 piperazine), 2.04 (2H, s, CH.sub.2 piperazine), 1.92 (1H, s, NH, D.sub.2O exchg.); .sup.13C NMR (125.76 MHz, DMSO-d.sub.6): =44.6, 44.7, 46.8, 47.3, 55.4, 65.4, 112.7, 114.1, 118.9, 130.5, 136.8, 139.9, 142.8, 146.1, 151.7, 152.0, 153.1, 154.0, 159.7, 160.1, 161.4, 172.7, 187.0, 190.6, 196.1; MS: m/z=392.45 [M].sup.+; Analysis: for C.sub.22H.sub.24N.sub.4O.sub.3, calcd. C 67.33, H 6.16, N 14.28%; found C 67.57, H 6.14, N 14.23%.

(27) DHPM-10 4-(3-Ethoxyphenyl)-5-[4-(piperazin-1-yl)benzoyl]-3,4-dihydropyrimidin-2(1H)-one Yield: 65%; m.p.: 88-90 C.; .sup.1H NMR (500 MHz, DMSO-d.sub.6): =9.21 (1H, s, NH, D.sub.2O exchg.), 8.52 (1H, s, NH, D.sub.2O exchg.), 8.20 (1H, s, CH), 6.87-8.11 (8H, m, ArH), 5.40 (1H, s, H-4), 4.0 (2H, q, OCH.sub.2), 3.33 (2H, s, CH.sub.2 piperazine), 3.20 (2H, s, CH.sub.2 piperazine), 2.09 (2H, s, CH.sub.2 piperazine), 2.08 (2H, s, CH.sub.2 piperazine), 1.92 (1H, s, NH, D.sub.2O exchg.), 1.35 (3H, t, CH.sub.3); .sup.13C NMR (125.76 MHz, DMSO-d.sub.6): =15.0, 15.1, 21.5, 21.6, 26.6, 31.1, 44.6, 46.8, 47.3, 48.0, 48.5, 63.7, 114.2, 114.6, 115.1, 128.0, 130.5, 130.9, 131.0, 153.9, 158.2, 160.8, 161.4, 172.5, 186.9, 190.6, 191.7, 196.1; MS: m/z=406.43 [M].sup.+; Analysis: for C.sub.23H.sub.26N.sub.4O.sub.3, calcd. C 67.96, H 6.45, N 13.78%; found C 67.70, H 4.46, N 13.73%.

(28) DHPM-11 5-[4-(morpholin-4-yl)benzoyl]-4-phenyl-3,4-dihydropyrimidin-2(1H)-one Yield: 70%; m.p.: 258-260 C.; .sup.1H NMR (500 MHz, DMSO-d.sub.6): =9.21 (1H, s, NH, D.sub.2O exchg.), 7.79 (1H, s, CH), 7.09-7.45 (6H, m, ArH), 7.01 (1H, s, NH, D.sub.2O exchg.), 6.95 (3H, m, ArH), 5.44 (1H, s, H-4), 3.74 (4H, t, J=4.6 Hz, 2CH.sub.2 morpholine), 3.22 (4H, t, J=4.8 Hz, 2CH.sub.2 morpholine); .sup.13C NMR (125.76 MHz, DMSO-d6): =47.6, 54.0, 66.3, 112.9, 113.8, 126.8, 127.8, 128.9, 130.4, 139.8, 144.6, 151.9, 153.3, 153.5, 190.6; MS: m/z=363.42 [M].sup.+; Analysis: for C.sub.21H.sub.21N.sub.3O.sub.3, calcd. C 69.41, H 5.82, N 11.56%; found C 69.58, H 5.80, N 11.59%.

(29) DHPM-12 5-[4-(morpholin-4-yl)benzoyl]-4-(2-nitrophenyl)-3,4-dihydropyrimidin-2(1H)-one Yield: 75%; m.p.: 198-200 C.; .sup.1H NMR (500 MHz, DMSO-d.sub.6): =9.42 (1H, d, NH, D.sub.2O exchg.), 8.07 (1H, s, CH), 7.06-7.91 (8H, m, ArH), 6.93 (1H, s, NH, D.sub.2O exchg.), 6.08 (1H, s, H-4), 3.73 (4H, t, J=4.6 Hz, 2CH.sub.2 morpholine), 3.21 (4H, t, J=4.7 Hz, 2CH.sub.2 morpholine); .sup.13C NMR (125.76 MHz, DMSO-d6): =47.0, 47.6, 50.0, 66.2, 111.7, 113.4, 124.4, 128.1, 129.2, 130.0, 132.6, 134.3, 138.7, 140.8, 148.3, 151.1, 153.5, 190.3, 192.8; MS: m/z=408.43 [M].sup.+; Analysis: for C.sub.21H.sub.20N.sub.4O.sub.5, calcd. C 61.76, H 4.94, N 13.72%; found C 61.90, H 4.92, N 13.77%.

(30) DHPM-13 5-[4-(morpholin-4-yl)benzoyl]-4-(4-nitrophenyl)-3,4-dihydropyrimidin-2(1H)-one Yield: 70%; m.p.: 202-204 C.; .sup.1H NMR (500 MHz, DMSO-d.sub.6): =9.42 (1H, d, NH, D.sub.2O exchg.), 8.23 (1H, s, CH), 7.43-7.92 (6H, m, ArH), 7.09 (1H, s, NH, D.sub.2O exchg.), 6.94 (2H, d, J=8.9 Hz, ArH), 5.57 (1H, s, H-4), 3.72 (4H, t, J=4.6 Hz, 2CH.sub.2 morpholine), 3.21 (4H, t, J=4.7 Hz, 2CH.sub.2 morpholine); .sup.13C NMR (125.76 MHz, DMSO-d6): =47.6, 53.9, 66.2, 111.8, 113.8, 124.3, 128.2, 130.5, 140.7, 147.2, 151.7, 153.6, 190.5; MS: m/z=408.42 [M].sup.+; Analysis: for C.sub.21H.sub.20N.sub.4O.sub.5, calcd. C 61.76, H 4.94, N 13.72%; found C 61.90, H 4.92, N 13.76%.

(31) DHPM-14 5-[4-(morpholin-4-yl)benzoyl]-4-(3-nitrophenyl)-3,4-dihydropyrimidin-2(1H)-one Yield: 70%; m.p.: 205-207 C.; .sup.1H NMR (500 MHz, DMSO-d.sub.6): =9.40 (1H, d, NH, D.sub.2O exchg.), 8.15 (1H, s, CH), 7.45-7.95 (6H, m, ArH), 7.12 (1H, s, NH, D.sub.2O exchg.), 6.95 (2H, d, J=8.9 Hz, ArH), 5.59 (1H, s, H-4), 3.72 (4H, t, J=4.6 Hz, 2CH.sub.2 morpholine), 3.22 (4H, t, J=4.7 Hz, 2CH.sub.2 morpholine); .sup.13C NMR (125.76 MHz, DMSO-d6): =47.6, 53.7, 66.3, 111.8, 113.8, 121.6, 122.9, 128.2, 130.5, 130.7, 133.7, 140.8, 146.7, 148.2, 151.6, 153.6, 190.5; MS: m/z=408.41 [M].sup.+; Analysis: for C.sub.21H.sub.20N.sub.4O.sub.5, calcd. C 61.76, H 4.94, N 13.72%; found C 61.89 , H 4.91, N 13.75%.

(32) DHPM-15 4-(4-chlorophenyl)-5-[4-(morpholin-4-yl)benzoyl]-3,4-dihydropyrimidin-2(1H)-one Yield: 80%; m.p.: 288-290 C.; .sup.1H NMR (500 MHz, DMSO-d.sub.6): =9.25 (1H, d, NH, D.sub.2O exchg.), 7.81 (1H, s, CH), 7.33-7.45 (6H, m, ArH), 7.02 (1H, s, NH, D.sub.2O exchg.), 6.95 (2H, d, J=8.5 Hz, ArH), 5.43 (1H, s, H-4), 3.73 (4H, t, J=4.6 Hz, 2CH.sub.2 morpholine), 3.22 (4H, t, J=4.7 Hz, 2CH.sub.2 morpholine); .sup.13C NMR (125.76 MHz, DMSO-d6): =47.6, 53.6, 66.3, 112.5, 113.8, 128.4, 128.8, 128.9, 130.5, 132.3, 140.1, 143.6, 151.8, 153.5, 190.6; MS: m/z=397.86 [M].sup.+; Analysis: for C.sub.21H.sub.20ClN.sub.3O.sub.3, calcd. C 63.40, H 5.07, N 10.56%; found C 63.65, H 5.08, N 10.59%.

(33) DHPM-16 4-(2-methoxyphenyl)-5-[4-(morpholin-4-yl)benzoyl]-3,4-dihydropyrimidin-2(1H)-one Yield: 80%; m.p.: 178-180 C.; .sup.1H NMR (500 MHz, DMSO-d.sub.6): =9.22 (1H, s, NH, D.sub.2O exchg.), 7.81 (1H, s, CH), 7.20-7.50 (5H, m, ArH), 7.09 (1H, s, NH, D.sub.2O exchg.), 6.89-7.01 (3H, m, ArH), 5.75 (1H, s, H-4), 3.82 (4H, t, J=4.7 Hz, 2CH.sub.2 morpholine), 3.21 (4H, t, J=4.7 Hz, 2CH.sub.2 morpholine); .sup.13C NMR (125.76 MHz, DMSO-d6): =47.6, 49.6, 66.2, 111.5, 113.8, 120.7, 1277.9, 128.7, 129.3, 130.5, 131.3, 140.4, 152.2, 153.5, 157.3, 190.5; MS: m/z=393.41 [M].sup.+; Analysis: for C.sub.22H.sub.23N.sub.3O.sub.4, calcd. C 67.16, H 5.89, N 10.68%; found C 66.89, H 5.87, N 10.64%.

(34) DHPM-17 4-(4-hydroxyphenyl)-5-[4-(morpholin-4-yl)benzoyl]-3,4-dihydropyrimidin-2(1H)-one Yield: 60%; m.p.: 118-120 C.; .sup.1H NMR (500 MHz, DMSO-d.sub.6): =9.14 (1H, s, NH, D.sub.2O exchg.), 9.01 (1H, s, OH), 8.08 (1H, s, CH), 7.43-7.77 (4H, m, ArH), 7.07 (1H, s, NH, D.sub.2O exchg.), 6.70-7.05 (4H, m, ArH), 5.35 (1H, s, H-4), 3.74 (4H, t, J=4.6 Hz, 2CH.sub.2 morpholine), 3.21 (4H, t, J=4.6 Hz, 2CH.sub.2 morpholine); .sup.13C NMR (125.76 MHz, DMSO-d6): =47.0, 53.5, 66.3, 113.4, 115.5, 128.4, 136.5, 132.6, 135.2, 139.3, 152.0, 153.5, 154.5, 154.7, 190.7; MS: m/z =379.41 [M].sup.+; Analysis: for C.sub.21H.sub.21N.sub.3O.sub.4, calcd. C 66.48, H 5.58, N 11.08%; found C 66.72, H 5.60, N 11.04%.

(35) DHPM-18 4-(3-hydroxyphenyl)-5-[4-(morpholin-4-yl)benzoyl]-3,4-dihydropyrimidin-2(1H)-one Yield: 60%; m.p.: 120-122 C.; .sup.1H NMR (500 MHz, DMSO-d.sub.6): =9.19 (1H, s, NH, D.sub.2O exchg.), 9.01 (1H, s, OH), 8.08 (1H, s, CH), 7.43-7.77 (4H, m, ArH), 7.06 (1H, s, NH, D.sub.2O exchg.), 6.63-7.01 (4H, m, ArH), 5.37 (1H, s, H-4), 3.72 (4H, t, J=4.6 Hz, 2CH.sub.2 morpholine), 3.20 (4H, t, J=4.6 Hz, 2CH.sub.2 morpholine); .sup.13C NMR (125.76 MHz, DMSO-d.sub.6): =48.9, 55.2, 57.8, 66.7, 114.6, 131.2, 138.9, 140.1, 140.8, 147.4, 153.4, 154.6, 154.8, 155.8, 159.2, 192.0; MS: m/z=379.42 [M].sup.+; Analysis: for C.sub.21H.sub.21N.sub.3O.sub.4, calcd. C 66.48, H 5.58, N 11.08%; found C 66.63, H 5.59, N 11.12%.

(36) DHPM-19 4-(3-methoxyhenyl)-5-[4-(morpholin-4-yl)benzoyl]-3,4-dihydropyrimidin-2(1H)-one Yield: 60%; m.p.: 170-172 C.; .sup.1H NMR (500 MHz, DMSO-d.sub.6): =9.23 (1H, d, NH, D.sub.2O exchg.), 8.09 (1H, s, CH), 7.24-7.79 (4H, m, ArH), 6.87 (1H, s, NH, D.sub.2O exchg.), 6.91-7.04 (4H, m, ArH), 5.45 (1H, s, H-4), 3.83 (3H, s, OCH.sub.3), 3.73 (4H, t, J=4.6 Hz, 2CH.sub.2 morpholine), 3.22 (4H, t, J=4.6 Hz, 2CH.sub.2 morpholine); .sup.13C NMR (125.76 MHz, DMSO-d6): =47.0, 53.9, 66.2, 112.7, 113.8, 118.9, 128.5, 130.1, 130.5, 139.8, 146.1, 152.0, 153.5, 159.7, 190.7; MS: m/z=393.40 [M].sup.+; Analysis: for C.sub.22H.sub.23N.sub.3O.sub.4, calcd. C 67.16, H 5.89, N 10.68%; found C 66.87, H 5.91, N 10.66%.

(37) DHPM-20 4-(4-ethoxyphenyl)-5-[4-(morpholin-4-yl)benzoyl]-3,4-dihydropyrimidin-2(1H)-one Yield: 60%; m.p.: 200-202 C.; .sup.1H NMR (500 MHz, DMSO-d.sub.6): =9.16 (1H, s, NH, D.sub.2O exchg.), 8.08 (1H, s, CH), 6.86-7.77 (8H, m, ArH), 6.78 (1H, s, NH, D.sub.2O exchg.), 5.38 (1H, s, H-4), 3.97 (2H, q, J=6.9 Hz, OCH.sub.2), 3.73 (4H, t, J=4.6 Hz, 2CH.sub.2 morpholine), 3.21 (4H, t, J=4.6 Hz, 2CH.sub.2 morpholine), 1.27 (3H, t, J=6.9 Hz, CH.sub.3); .sup.13C NMR (125.76 MHz, DMSO-d6): =47.6, 53.4, 63.2, 66.3, 113.2, 113.8, 114.2, 114.6, 125.8, 128.0, 129.5, 130.4, 132.7, 136.7, 137.4, 138.8, 139.5, 151.9, 153.3, 154.6, 157.1, 158.2, 190.7, 192.8; MS: m/z=407.42 [M].sup.+; Analysis: for C.sub.23H.sub.25N.sub.3O.sub.4, calcd. C 67.80, H 6.18, N 10.31%; found C 66.88, H 6.20, N 10.35%.

(38) It is to be understood that the dihydropyrimidinone derivatives are not limited to the specific embodiments described above, but encompass any and all embodiments within the scope of the generic language of the following claims enabled by the embodiments described herein, or otherwise shown in the drawings or described above in terms sufficient to enable one of ordinary skill in the art to make and use the claimed subject matter.