DACOS type NNRTIS amino acid ester derivative, preparation method thereof, pharmaceutical composition, and application thereof

Abstract

Disclosed is a DACOs-type NNRTIs amino acid ester derivative, a preparation method thereof, a pharmaceutical composition, and an application thereof. The structure of the DACOs-type NNRTIs amino acid ester derivative is represented by formula (I). The DACOs-type NNRTIs amino acid ester derivative represented by formula (I) can be used as HIV-1 inhibitors and for the preparation of a drug for treating and/or preventing immunodeficiency viruses. ##STR00001##

Claims

1. A DACOs-type NNRTIs amino acid ester derivative represented by formula I, or a tautomer, optical isomer, hydrate, solvate, polymorph or pharmaceutically acceptable salt thereof: ##STR00062## wherein: R.sub.1 is H, C.sub.1-C.sub.6 branched or straight chain alkyl, or C.sub.3-C.sub.6 cycloalkyl; n is an integer between 0 and 8; R.sub.2 is H, C.sub.1-C.sub.12 straight or branched chain alkyl, C.sub.3-C.sub.6 cycloalkyl, —C.sub.1-C.sub.12 straight or branched chain alkyl-NH.sub.2, —C.sub.1-C.sub.12 straight or branched chain alkyl-OH, NH.sub.2C(═O)—, C.sub.1-C.sub.12 straight or branched chain alkoxy, C.sub.1-C.sub.12 straight or branched chain alkylthio, C.sub.6-C.sub.20 aryl, C.sub.2-C.sub.10 heteroaryl, C.sub.6-C.sub.20 aryl substituted by one or more R.sub.2a, or C.sub.2-C.sub.10 heteroaryl substituted by one or more R.sub.2b; wherein each of R.sub.2a and R.sub.2b is independently selected from hydroxyl, nitro, halogen, amino, cyano, sulfo group, C.sub.1-C.sub.6 branched or straight chain alkyl, C.sub.1-C.sub.6 branched or straight chain alkoxy, C.sub.1-C.sub.6 branched or straight chain alkylthio, C.sub.1-C.sub.6 branched or straight chain haloalkyl, and when the number of R.sub.2a or R.sub.2b is more, then each R.sub.2a or each R.sub.2b is the same or different; R.sub.3 is H, or R.sub.2 and R.sub.3 together with the structural fragment to which they are attached form C.sub.2-C.sub.6 heterocycloalkyl.

2. The DACOs-type NNRTIs amino acid ester derivative represented by formula I as defined in claim 1, wherein, when R.sub.1 is C.sub.1-C.sub.6 branched or straight chain alkyl, then the C.sub.1-C.sub.6 branched or straight chain alkyl is C.sub.1-C.sub.3 branched or straight chain alkyl; when R.sub.1 is C.sub.3-C.sub.6 cycloalkyl, then the C.sub.3-C.sub.6 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; when R.sub.2 is C.sub.1-C.sub.12 branched or straight chain alkyl, then the C.sub.1-C.sub.12 branched or straight chain alkyl is C.sub.1-C.sub.6 branched or straight chain alkyl; when R.sub.2 is C.sub.3-C.sub.6 cycloalkyl, then the C.sub.3-C.sub.6 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; when R.sub.2 is —C.sub.1-C.sub.12 straight or branched chain alkyl-NH.sub.2, then the C.sub.1-C.sub.12 straight or branched chain alkyl is C.sub.1-C.sub.6 branched or straight chain alkyl; when R.sub.2 is —C.sub.1-C.sub.12 straight or branched chain alkyl-OH, then the C.sub.1-C.sub.12 straight or branched chain alkyl is C.sub.1-C.sub.6 branched or straight chain alkyl; when R.sub.2 is C.sub.1-C.sub.12 straight or branched chain alkoxy, then the C.sub.1-C.sub.12 straight or branched chain alkoxy is C.sub.1-C.sub.6 branched or straight chain alkoxy; when R.sub.2 is C.sub.1-C.sub.12 straight or branched chain alkylthio, then the C.sub.1-C.sub.12 straight or branched chain alkylthio is C.sub.1-C.sub.6 branched or straight chain alkylthio; when R.sub.2 is C.sub.6-C.sub.20 aryl, then the C.sub.6-C.sub.20 aryl is C.sub.6-C.sub.10 aryl; when R.sub.2 is C.sub.2-C.sub.10 heteroaryl, then the C.sub.2-C.sub.10 heteroaryl is C.sub.2-C.sub.8 heteroaryl; when R.sub.2 is C.sub.6-C.sub.20 aryl substituted by one or more R.sub.2a, then the C.sub.6-C.sub.20 aryl is C.sub.6-C.sub.10 aryl; when R.sub.2 is C.sub.2-C.sub.10 heteroaryl substituted by one or more R.sub.2b, then the C.sub.2-C.sub.10 heteroaryl is C.sub.2-C.sub.8 heteroaryl; when R.sub.2 and R.sub.3 together with the structural fragment to which they are attached form C.sub.2-C.sub.6 heterocycloalkyl, then the C.sub.2-C.sub.6 heterocycloalkyl is azacyclohexyl, azacyclopentyl or azacyclobutyl; when R.sub.2a or R.sub.2b is halogen, then the halogen is fluorine, chlorine, bromine or iodine; when R.sub.2a or R.sub.2b is C.sub.1-C.sub.6 branched or straight chain alkyl, then the C.sub.1-C.sub.6 branched or straight chain alkyl is C.sub.1-C.sub.3 branched or straight chain alkyl; when R.sub.2a or R.sub.2b is C.sub.1-C.sub.6 branched or straight chain alkoxy, then the C.sub.1-C.sub.6 branched or straight chain alkoxy is C.sub.1-C.sub.3 branched or straight chain alkoxy; when R.sub.2a or R.sub.2b is C.sub.1-C.sub.6 branched or straight chain alkylthio, then the C.sub.1-C.sub.6 branched or straight chain alkylthio is C.sub.1-C.sub.3 branched or straight chain alkylthio; when R.sub.2a or R.sub.2b is C.sub.1-C.sub.6 branched or straight chain haloalkyl, then the C.sub.1-C.sub.6 branched or straight chain haloalkyl is C.sub.1-C.sub.3 straight or branched chain haloalkyl; when R.sub.2 is C.sub.2-C.sub.10 heteroaryl substituted by one or more R.sub.2b, then the position through which the C.sub.2-C.sub.10 heteroaryl is connected to the rest of the DACOs-type NNRTIs amino acid ester derivative represented by formula I is 2-position, 3-position or 4-position of the heteroaryl; and/or, n is 0, 1, 2, 3, 4, 5, 6, 7 or 8.

3. The DACOs-type NNRTIs amino acid ester derivative represented by formula I as defined in claim 1, wherein, when R.sub.1 is C.sub.1-C.sub.6 branched or straight chain alkyl, then the C.sub.1-C.sub.6 branched or straight chain alkyl is isopropyl, n-propyl, ethyl or methyl; when R.sub.2 is C.sub.1-C.sub.12 branched or straight chain alkyl, then the C.sub.1-C.sub.12 branched or straight chain alkyl is C.sub.1-C.sub.4 branched or straight chain alkyl; when R.sub.2 is —C.sub.1-C.sub.12 straight or branched chain alkyl-NH.sub.2, then the C.sub.1-C.sub.12 straight or branched chain alkyl is C.sub.1-C.sub.4 branched or straight chain alkyl; when R.sub.2 is —C.sub.1-C.sub.12 straight or branched chain alkyl-OH, then the C.sub.1-C.sub.12 straight or branched chain alkyl is C.sub.1-C.sub.4 branched or straight chain alkyl; when R.sub.2 is C.sub.1-C.sub.12 straight or branched chain alkoxy, then the C.sub.1-C.sub.12 straight or branched chain alkoxy is C.sub.1-C.sub.3 branched or straight chain alkoxy; when R.sub.2 is C.sub.1-C.sub.12 straight or branched chain alkylthio, then the C.sub.1-C.sub.12 straight or branched chain alkylthio is C.sub.1-C.sub.3 branched or straight chain alkylthio; when R.sub.2 is C.sub.6-C.sub.20 aryl, then the C.sub.6-C.sub.20 aryl is phenyl; when R.sub.2 is C.sub.2-C.sub.10 heteroaryl, then the C.sub.2-C.sub.10 heteroaryl is pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, indolyl, isoindolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyrimidinonyl, oxadiazolyl, pyridonyl or triazolyl; when R.sub.2 is C.sub.6-C.sub.20 aryl substituted by one or more R.sub.2a, then the C.sub.6-C.sub.20 aryl is phenyl; when R.sub.2 is C.sub.2-C.sub.10 heteroaryl substituted by one or more R.sub.2b, then the C.sub.2-C.sub.10 heteroaryl is pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, indolyl, isoindolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyrimidinonyl, oxadiazolyl, pyridonyl or triazolyl; when R.sub.2a or R.sub.2b is C.sub.1-C.sub.6 branched or straight chain alkyl, then the C.sub.1-C.sub.6 branched or straight chain alkyl is methyl, ethyl, n-propyl or isopropyl when R.sub.2a or R.sub.2b is C.sub.1-C.sub.6 branched or straight chain alkoxy, then the C.sub.1-C.sub.6 branched or straight chain alkoxy is methoxy, ethoxy, propoxy or isopropoxy; when R.sub.2a or R.sub.2b is C.sub.1-C.sub.6 branched or straight chain alkylthio, then the C.sub.1-C.sub.6 branched or straight chain alkylthio is methylthio, ethylthio, propylthio or isopropylthio; when R.sub.2a or R.sub.2b is C.sub.1-C.sub.6 branched or straight chain haloalkyl, then the C.sub.1-C.sub.6 branched or straight chain haloalkyl is trifluoromethyl, difluoromethyl, or 1,2-difluoroethyl.

4. The DACOs-type NNRTIs amino acid ester derivative represented by formula I as defined in claim 1, wherein, when R.sub.2 is C.sub.1-C.sub.12 branched or straight chain alkyl, then the C.sub.1-C.sub.12 branched or straight chain alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; when R.sub.2 is —C.sub.1-C.sub.12 straight or branched chain alkyl-NH.sub.2, then the C.sub.1-C.sub.12 straight or branched chain alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; when R.sub.2 is —C.sub.1-C.sub.12 straight or branched chain alkyl-OH, then the C.sub.1-C.sub.12 straight or branched chain alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; when R.sub.2 is C.sub.1-C.sub.12 straight or branched chain alkoxy, then the C.sub.1-C.sub.12 straight or branched chain alkoxy is methoxy, ethoxy, n-propoxy or isopropoxy; when R.sub.2 is C.sub.1-C.sub.12 straight or branched chain alkylthio, then the C.sub.1-C.sub.12 straight or branched chain alkylthio is methylthio, ethylthio, n-propylthio or isopropylthio.

5. The DACOs-type NNRTIs amino acid ester derivative represented by formula I as defined in claim 1, wherein, R.sub.1 is methyl, ethyl or isopropyl; and/or, n is 0, 1 or 2; and/or, R.sub.3 is H; and/or, R.sub.2 is H, C.sub.1-C.sub.12 straight or branched chain alkyl, —C.sub.1-C.sub.12 straight or branched chain alkyl-NH.sub.2, NH.sub.2C(═O)—, C.sub.1-C.sub.12 straight or branched chain alkoxy, C.sub.1-C.sub.12 straight or branched chain alkylthio, C.sub.6-C.sub.20 aryl, C.sub.2-C.sub.10 heteroaryl, C.sub.6-C.sub.20 aryl substituted by one or more R.sub.2a or C.sub.2-C.sub.10 heteroaryl substituted by one or more R.sub.2b; said one or more is 1-6.

6. The DACOs-type NNRTIs amino acid ester derivative represented by formula I as defined in claim 1, wherein, when R.sub.2 is C.sub.6-C.sub.20 aryl substituted by one or more R.sub.2a or C.sub.2-C.sub.10 heteroaryl substituted by one or more R.sub.2b, then said one or more is 1-3.

7. The DACOs-type NNRTIs amino acid ester derivative represented by formula I as defined in claim 1, wherein, when R.sub.2 is C.sub.6-C.sub.20 aryl substituted by one or more Rea or C.sub.2-C.sub.10 heteroaryl substituted by one or more R.sub.2b, then said one or more is 1-2.

8. The DACOs-type NNRTIs amino acid ester derivative represented by formula I as defined in claim 1, wherein, R.sub.1 is ethyl or isopropyl, n is 0, 1 or 2, R.sub.3 is H, R.sub.2 is H, C.sub.1-C.sub.12 straight or branched chain alkyl, —C.sub.1-C.sub.12 straight or branched chain alkyl-NH.sub.2, NH.sub.2C(═O)—, C.sub.1-C.sub.12 straight or branched chain alkoxy, C.sub.1-C.sub.12 straight or branched chain alkylthio, C.sub.6-C.sub.20 aryl or C.sub.2-C.sub.10 heteroaryl; or, R.sub.1 is ethyl or isopropyl, n is 0, 1 or 2, R.sub.3 is H, R.sub.2 is H, isopropyl, isobutyl, sec-butyl or methylthio.

9. The DACOs-type NNRTIs amino acid ester derivative represented by formula I as defined in claim 1, wherein, the structural unit ##STR00063## contained in the DACOs-type NNRTIs amino acid ester derivative represented by formula I is ##STR00064## ##STR00065##

10. The DACOs-type NNRTIs amino acid ester derivative represented by formula I as defined in claim 1, wherein, the DACOs-type NNRTIs amino acid ester derivative represented by formula I is any of the following compounds: TABLE-US-00003 No. Structure I-1  I-2  I-3  I-4  I-5  I-6  I-7  I-8  I-9  I-10 I-11 I-12 I-13 I-14 I-15 I-16 I-17 I-18 I-19 I-20 I-21 I-22 I-23 I-24

11. A method for preparing the DACOs-type NNRTIs amino acid ester derivative represented by formula I as defined in claim 1, comprising carrying out a Boc removal reaction of intermediate 6 in the presence of an acidic reagent in a solvent; ##STR00090## wherein the definitions of n, R.sub.1, R.sub.2 and R.sub.3 are as defined in claim 1.

12. The method as defined in claim 11 for preparing the DACOs-type NNRTIs amino acid ester derivative represented by formula I, further comprising carrying out an alkylation reaction of intermediate 4 and intermediate 5 in the presence of a weakly basic reagent in a solvent to obtain the intermediate 6; ##STR00091## wherein the definitions of n, R.sub.1, R.sub.2 and R.sub.3 are as defined in claim 11.

13. The method as defined in claim 12 for preparing the DACOs-type NNRTIs amino acid ester derivative represented by formula I, further comprising carrying out a condensation reaction of intermediate 2 and intermediate 3 in the presence of a catalyst and a condensing agent in a solvent to obtain the intermediate 4; ##STR00092## wherein the definitions of n, R.sub.2 and R.sub.3 are as defined in claim 12.

14. The method as defined in claim 13 for preparing the DACOs-type NNRTIs amino acid ester derivative represented by formula I, further comprising carrying out a N-Boc protection reaction of intermediate 1 with (Boc).sub.2O in the presence of a base in a solvent to obtain the intermediate 2; ##STR00093## wherein the definitions of n, R.sub.2 and R.sub.3 are as defined in claim 13.

15. A method for inhibiting non-nucleoside HIV-1 in a subject in need thereof, comprising administering a therapeutically effective amount of the DACOs-type NNRTIs amino acid ester derivative represented by formula I, the tautomer, optical isomer, hydrate, solvate, polymorph or pharmaceutically acceptable salt thereof as defined in claim 1 to the subject in need thereof.

16. The method as defined in claim 15, wherein the non-nucleoside HIV-1 is non-nucleoside HIV-1.sub.IIIB.

17. A method for treating human immunodeficiency virus infection in a subject in need thereof, comprising administering the DACOs-type NNRTIs amino acid ester derivative represented by formula I, the tautomer, optical isomer, hydrate, solvate, polymorph or pharmaceutically acceptable salt thereof as defined in claim 1 to the subject.

18. A pharmaceutical composition comprising a therapeutically effective amount of the DACOs-type NNRTIs amino acid ester derivative represented by formula I, the tautomer, optical isomer, hydrate, solvate, polymorph or pharmaceutically acceptable salt thereof as defined in claim 1, and at least one pharmaceutical excipient.

19. A method for treating human immunodeficiency virus infection disease in a subject in need thereof, wherein the method comprises administering a therapeutically effective amount of the pharmaceutical composition as defined in claim 18 to the subject.

Description

DETAILED DESCRIPTION OF THE EMBODIMENT

(1) The following describes the present disclosure in detail with embodiments, but it does not impose any adverse limitation on the present disclosure. The present disclosure has been described in detail herein, and its specific embodiments are also disclosed. It is obvious to those skilled in the art that various changes and improvements can be made to the specific embodiments of the present disclosure without departing from the spirit and scope of the present disclosure.

(2) The experimental methods which are not specified in the following examples are selected according to conventional methods and conditions, or according to product specifications. The raw materials can be obtained from commercial sources, or prepared by methods known in the art, or prepared according to the methods described herein. The structures of the compounds were determined by nuclear magnetic resonance (.sup.1H NMR or .sup.13C NMR) or mass spectrometry (MS), wherein NMR was measured by Bruker AV-300 type nuclear magnetic resonance instrument with deuterated dimethyl sulfoxide (DMSO-D6) or deuterated chloroform (CDCl.sub.3) as the solvent and TMS as the internal standard.

Preparation Example 1: Preparation of the Target Compound I

(3) ##STR00036##

(4) The preparation method of substituted thiouracil 5 was as follows (referring to Yan-Ping He, Jin Long, et al. Bioorg. & Med. Chem. 2011, 21, 694-697; Zhi-Kun Rao, Jing Long, et al. Monatsh Chem. 2008, 139, 967-974, the contents of these references are incorporated herein by reference).

(5) ##STR00037##

Preparation of Intermediate N-tert-butoxycarbonyl amino acid 2

(6) 0.025 mmol of amino acid 1 was added into a 100 mL round bottom flask and dissolved with 50 mL of water and 1,4-dioxane at a volume ratio of 2:1 under stirring, followed by slow addition of 0.05 mmol of NaOH. The resulting mixture was stirred for 0.5 hour and then 0.05 mmol of (Boc).sub.2O was added thereto. The mixture was stirred overnight at room temperature. The reaction was terminated and the solvent was removed by evaporation. The residue was transferred to a beaker with 100 mL of water, the pH of which was adjusted to about 3 with 1N HCl, extracted with 3×50 mL of ethyl acetate. The organic layers were combined, dried over anhydrous Na.sub.2SO.sub.4, concentrated under reduced pressure to obtain a colorless oily liquid, followed by addition of a mixed solvent of ether and petroleum ether (volume ratio=8:1). The mixture was stirred vigorously to obtain a white solid, filtered by suction and dried to obtain crude N-tert-butoxycarbonyl amino acid 2, which was directly used in the next step without purification.

Preparation of Intermediate 4-(2-bromoacetyl)-N-tert-butoxycarbonyl amino acid ester 4

(7) 0.01 mmol of the above N-tert-butoxycarbonyl amino acid 2 was added into a 100 mL round bottom flask and dissolved with dichloromethane, followed by addition of condensing agent DCC (0.012 mmol) and DMAP (0.002 mmol) under stirring. The resulting mixture was stirred in an ice bath for 0.5 hour and then p-hydroxybromoacetophenone (0.011 mmol) was added slowly thereto. After the addition, the mixture was stirred at room temperature, and the reaction was monitored by TLC until the raw materials disappeared completely. The reaction was terminated and filtered by suction. The filtrate was concentrated under reduced pressure, and separated by column chromatography to obtain a pure product of 4-(2-bromoacetyl)-N-tert-butoxycarbonyl amino acid ester 4.

Preparation of 5-alkyl-6-cyclohexylmethyl-2-thioacetylphenyl-N-tert-butoxycarbonyl amino acid ester 6

(8) 3.62 mmol of thiouracil 5 was completely dissolved with 5 mL of DMF in a 50 mL round bottom flask, followed by addition of 4.34 mmol of anhydrous potassium carbonate. The resulting mixture was stirred for 0.5 hour and then a solution of 4-(2-bromoacetyl)-N-tert-butoxycarbonyl amino acid ester 4 (3.98 mmol) in DMF was slowly added thereto. The reaction was performed at a suitable temperature and terminated after TLC detected that the spots of raw materials disappeared. The reaction solution was poured into 50 mL of ice water, stirred vigorously with white turbidity generated, and extracted with 3×50 mL of ethyl acetate. The organic layers were combined and concentrated under reduced pressure to obtain crude 5-alkyl-6-cyclohexylmethyl-2-thioacetylphenyl-N-tert-butoxycarbonyl amino acid ester 6.

Preparation of 5-alkyl-6-cyclohexyl-2-thioacetylphenyl amino acid ester I

(9) 1 mmol of 5-alkyl-6-cyclohexylmethyl-2-thioacetylphenyl-N-tert-butoxycarbonyl amino acid ester 6 was added into a 50 mL round bottom flask and completely dissolved with mL of ethyl acetate under stirring. Saturated amount of HCl gas was introduced and then the resulting mixture was stirred at room temperature for 0.5 hour. The reaction was monitored by TLC and terminated after TLC detected that the spots of raw materials disappeared. The reaction solution was neutralized with saturated sodium carbonate solution until the reaction was no longer vigorous, further neutralized with saturated sodium bicarbonate until no bubble was generated, and a precipitate formed. The mixture was filtered to obtain a crude product of the target product, which was recrystallized to obtain a pure product.

(10) ##STR00038## C.sub.23H.sub.29N.sub.3O.sub.4S (443.56)

(11) According to the above procedure, I-1 was obtained as a white powder with a yield of 56%.

(12) .sup.1H NMR (DMSO, 300 MHz) δ 0.68-0.76 (m, 2H, Cyclohexyl-H), 0.83-0.93 (m, 6H, 3H-Cyclohexyl and CH.sub.2CH.sub.3), 1.26-1.30 (m, 3H, Cyclohexyl-H), 1.43-1.46 (m, 3H, Cyclohexyl-H), 2.15-2.17 (d, 2H, J=6 Hz, CH.sub.2-Cyclohexyl), 2.27-2.30 (m, 2H, CH.sub.2CH.sub.3), 4.09-4.11 (d, 2H, J=6 Hz, NH.sub.2—CH.sub.2), 4.75 (s, 2H, S—CH.sub.2), 7.38-7.40 (d, 2H, J=6 Hz, Ph-H), 8.14-8.17 (d, 2H, J=9 Hz, Ph-H), 8.83 (m, 3H, NH.sub.2, NH); .sup.13C NMR (DMSO, 75 MHz) δ 13.08, 17.85, 25.52 (2C), 25.70, 32.31 (2C), 36.38, 37.57, 39.58, 39.86, 120.61, 121.84 (2C), 130.17 (2C), 134.05, 153.44, 156.94, 159.90, 163.63, 166.08, 191.82.

(13) ##STR00039## C.sub.27H.sub.37N.sub.3O.sub.4S (499.25)

(14) According to the above procedure, I-2 was obtained as a pale yellow powder with a yield of 53%.

(15) .sup.1H NMR (DMSO, 300 MHz) δ 0.94-0.95 (m, 3H, Cyclohexyl-H), 0.95-0.96 (m, 9H, 3×CH.sub.3), 1.24-1.34 (m, 4H, Cyclohexyl-H), 1.42-1.45 (m, 4H, Cyclohexyl-H), 1.61-1.65 (m, 1H, CHMe.sub.2), 2.11-2.13 (d, 2H, J=6 Hz, CH.sub.2-Cyclohexyl), 2.26-2.29 (m, 2H, CH.sub.2CH.sub.3), 4.19-4.21 (m, 1H, CH—NH.sub.2), 4.72 (s, 2H, S—CH.sub.2), 7.41-7.44 (d, 2H, J=9 Hz, Ph-H), 8.15-8.18 (d, 2H, J=9 Hz, Ph-H), 8.52 (brs, H, NH), 9.05 (s, 2H, NH.sub.2); .sup.13C NMR (DMSO, 75 MHz) δ 13.11, 17.86, 21.92, 22.08, 23.88, 25.52 (2C), 25.71, 32.33 (2C), 36.27, 37.05, 37.37, 50.71, 120.74, 121.81 (2C), 130.13, 130.72, 134.21, 153.39, 156.57, 160.07, 163.31, 168.13, 191.98.

(16) ##STR00040## C.sub.27H.sub.37N.sub.3O.sub.4S (499.25)

(17) According to the above procedure, I-3 was obtained as a light white powder with a yield of 43.27%.

(18) .sup.1H NMR (DMSO, 300 MHz) δ 0.66-0.74 (m, 2H, Cyclohexyl-H), 0.87-0.89 (m, 6H, 2CH.sub.3), 1.05-1.11 (m, 8H, CHCH.sub.2CH.sub.3, NH.sub.2CHCH.sub.3 and 3H-Cyclohexyl), 1.24-1.32 (m, 3H, Cyclohexy-H), 1.41-1.44 (m, 3H, Cyclohexyl-H), 2.11-2.13 (d, 2H, J=6 Hz, CH.sub.2-Cyclohexyl), 2.24-2.28 (m, 2H, CH.sub.2CH.sub.3), 2.36-2.38 (m, 1H, CHCH.sub.3), 4.11 (s, 1H, NH.sub.2—CH), 4.73 (s, 2H, S—CH.sub.2), 7.40-7.43 (d, 2H, J=9 Hz, Ph-H), 8.15-8.17 (d, 2H, J=6 Hz, Ph-H), 9.05 (s, 3H, NH.sub.2 and NH); .sup.13C NMR (DMSO, 75 MHz) δ 13.06, 17.60, 17.86, 18.62, 25.13, 25.53 (2C), 25.69, 29.43, 32.30 (2C), 36.33, 37.45, 39.84, 57.41, 120.64, 121.84 (2C), 130.17 (2C), 134.20, 153.27, 156.84, 159.93, 163.50, 167.03, 191.90.

(19) ##STR00041## C.sub.26H.sub.33N.sub.3O.sub.4S (483.22)

(20) According to the above procedure, I-4 was obtained as a pale yellow powder with a yield of 61%.

(21) .sup.1H NMR (DMSO, 300 MHz) δ 0.72-0.79 (m, 2H, Cyclohexyl-H), 0.89-0.93 (m, 6H, CH.sub.2CH.sub.3, 3H-Cyclohexyl), 1.31-1.35 (m, 3H, Cyclohexyl-H), 1.45-1.48 (d, 3H, Cyclohexyl-H), 1.85-1.98 (m, 2H, Pyrrolidinyl-H), 2.17-2.19 (d, 2H, J=6 Hz, CH.sub.2-Cyclohexyl), 2.24-2.30 (m, 4H, CH.sub.2CH.sub.3 and 2H-Pyrrolidinyl), 3.15-3.21 (m, 2H, Pyrrolidinyl-H), 4.19-4.26 (m, 1H, Pyrrolidinyl-H), 4.65 (s, 2H, CH.sub.2—S), 6.89-6.92 (d, 2H, J=9 Hz, Ph-H), 7.24 (brs, HCl), 7.89-7.92 (d, 2H, J=9 Hz, Ph-H), 8.80 (s, 1H, NH), 10.28 (brs, 1H, NH); .sup.13C NMR (DMSO, 75 MHz) δ 13.04, 17.85, 23.05, 25.49 (2C), 25.72, 27.89, 32.33 (2C), 36.34, 37.19, 39.86, 45.06, 58.52, 115.20 (2C), 120.58, 127.24 130.74 (2C), 157.32, 159.72, 162.53, 163.70, 170.21, 190.85.

(22) ##STR00042## C.sub.32H.sub.36N.sub.4O.sub.4S (572.25)

(23) According to the above procedure, I-5 was obtained as a pale yellow powder with a yield of 55.54%.

(24) .sup.1H NMR (DMSO, 300 MHz) δ 0.78-0.82 (m, 2H, Cyclohexyl-H), 0.91 (m, 5H, CH.sub.2CH.sub.3 and 2H-Cyclohexyl), 1.26-1.33 (m, 3H, Cyclohexyl-H), 1.43-1.45 (m, 4H, Cyclohexyl-H), 2.16-2.18 (d, 2H, J=6 Hz, CH.sub.2-Cyclohexyl), 2.28 (s, 2H, CH.sub.2CH.sub.3), 3.57-3.60 (d, 2H, J=9.9 Hz, CH.sub.2-indole), 4.45 (m, 1H, CH—NH.sub.2), 4.73 (s, 2H, S—CH.sub.2), 7.04-7.07 (m, 4H, Ar—H), 7.38-7.39 (d, 2H, J=3 Hz, Ar—H), 7.62-7.65 (d, 1H, J=9 Hz, Ar—H), 8.04-8.07 (d, 2H, J=9 Hz, Ar—H), 9.16 (s, 2H, NH.sub.2), 11.27 (s, 1H, NH); .sup.13C NMR (DMSO, 75 MHz) δ 13.04, 17.87, 25.55 (2C), 25.71, 26.23, 32.32 (2C), 36.45, 37.60, 39.61, 53.10, 106.42, 111.61, 118.16, 118.59, 120.52, 121.13, 121.70 (2C), 124.97, 129.93 (2C), 106.42, 121.84 (2C), 130.17 (2C), 126.85, 133.96, 136.20, 153.28, 157.16, 159.84, 163.80, 167.70, 191.74.

(25) ##STR00043## C.sub.24H.sub.31N.sub.3O.sub.4S (457.20)

(26) According to the above procedure, I-6 was obtained as a pale yellow powder with a yield of 47.28%.

(27) .sup.1H NMR (DMSO, 300 MHz) δ 0.78-0.92 (m, 10H, CH.sub.2CH.sub.3, NH.sub.2CHCH.sub.3 and 4H-Cyclohexyl), 1.37-1.46 (m, 7H, Cyclohexyl-H), 2.25 (m, 4H, CH.sub.2CH.sub.3 and CH.sub.2-Cyclohexyl), 3.95-4.00 (m, 1H, NH.sub.2—CH), 4.70 (s, 2H, S—CH.sub.2), 6.89 (d, 2H, Ph-H), 7.88 (d, 2H, Ph-H), 9.99 (s, 3H, NH and NH.sub.2); .sup.13C NMR (DMSO, 75 MHz) δ 12.98, 15.78, 17.86, 25.51 (2C), 25.71, 32.29 (2C), 36.49, 37.40, 39.28, 53.07, 115.21 (2C), 120.39, 127.13, 130.76 (2C), 157.93,

(28) ##STR00044## C.sub.30H.sub.35N.sub.3O.sub.4S (533.23)

(29) According to the above procedure, I-7 was obtained as a pale yellow powder with a yield of 42%.

(30) .sup.1H NMR (DMSO, 300 MHz) δ 0.77-0.82 (m, 2H, Cyclohexyl-H), 0.90 (m, 6H, 3H-Cyclohexyl and CH.sub.2CH.sub.3), 1.26-1.32 (m, 3H, Cyclohexyl-H), 1.42-1.45 (m, 3H, Cyclohexyl-H), 2.15-2.17 (d, 2H, J=6 Hz, CH.sub.2-Cyclohexyl), 2.27-2.29 (m, 2H, CH.sub.2CH.sub.3), 3.18-3.25 (m, 2H, CH.sub.2-Ph) 3.94-4.01 (m, 1H, NH.sub.2—CH), 4.73 (s, 2H, S—CH.sub.2), 7.13-7.16 (d, 2H, J=9 Hz, Ph-H), 7.27-7.35 (m, 5H, Ph-H), 8.09-8.12 (d, 2H, J=9 Hz, Ph-H), 9.07 (s, 2H, NH.sub.2), 10.27 (s, H, NH); .sup.13C NMR (DMSO, 75 MHz) δ 13.01, 17.85, 25.54 (2C), 25.69, 32.30 (2C), 35.98, 36.42, 37.58, 38.68, 53.59, 120.52, 121.61 (2C), 127.30 (2C), 128.56 (2C), 129.49 (2C), 130.06, 134.06, 134.61, 153.13, 159.82, 162.28, 163.79, 167.31, 191.73.

(31) ##STR00045## C.sub.26H.sub.35N.sub.3O.sub.4S.sub.2 (517.21)

(32) According to the above procedure, I-8 was obtained as a pale yellow powder with a yield of 43%.

(33) .sup.1H NMR (DMSO, 300 MHz) δ 0.76-0.84 (m, 2H, Cyclohexyl-H), 0.91-1.02 (m, 6H, CH.sub.2CH.sub.3 and 3H-Cyclohexyl), 1.24-1.32 (m, 3H, Cyclohexyl-H), 1.47-1.54 (m, 3H, Cyclohexyl-H), 2.01 (s, 3H, SCH.sub.3), 2.11-2.13 (d, 2H, J=6 Hz, CH.sub.2-Cyclohexyl), 2.15-2.17 (m, 2H, CH.sub.2CHNH.sub.2), 2.25-2.29 (m, 2H, CH.sub.2CH.sub.3), 2.66-2.70 (t, 2H, J=7.1 Hz, CH.sub.2—SCH.sub.3), 3.86 (s, 1H, NH.sub.2—CH), 4.84 (s, 2H, S—CH.sub.2), 7.41-7.44 (d, 2H, J=9 Hz, Ph-H), 8.05-8.10 (d, 2H, J=7 Hz, Ph-H), 9.08 (s, 3H, NH.sub.2 and NH); .sup.13C NMR (DMSO, 75 MHz) δ 13.26, 14.6, 17.87, 25.49 (2C), 25.69 (2C), 29.73, 33.31 (2C), 33.71, 36.13, 36.65, 40.16, 52.13, 119.51, 121.54 (2C), 129.17 (2C), 133.20, 155.75, 157.18, 160.73, 163.40, 168.31, 191.26.

(34) ##STR00046## C.sub.27H.sub.38N.sub.4O.sub.4S (514.26)

(35) According to the above procedure, I-9 was obtained as a pale yellow powder with a yield of 40.48%.

(36) .sup.1H NMR (DMSO, 300 MHz) δ 0.76-0.81 (m, 2H, Cyclohexyl-H), 0.91-0.94 (m, 3H, Cyclohexy-H), 1.22-1.25 (m, 2H, CH.sub.2), 1.34-1.48 (m, 6H, Cyclohexy-H), 1.56-1.64 (m, 4H, 2CH.sub.2), 1.85-1.87 (m, 2H, CH.sub.2), 2.08-2.10 (d, 2H, J=6 Hz, CH.sub.2-Cyclohexyl), 2.22-2.24 (m, 2H, CH.sub.2CH.sub.3), 2.78-2.84 (m, 2H, NH.sub.2—CH.sub.2), 4.26 (m, 1H, NH.sub.2—CH), 4.72 (s, 2H, S—CH.sub.2), 7.43-7.45 (d, 2H, J=9 Hz, Ph-H), 8.12-8.14 (d, 2H, J=9 Hz, Ph-H), 8.25 (m, 4H, 2×NH.sub.2), 9.04 (s, 1H, NH); .sup.13C NMR (DMSO, 75 MHz) δ 13.07, 17.86, 25.52 (2C), 25.68, 26.16, 29.16, 32.31 (2C), 36.31, 37.50, 38.14 (2C), 39.28, 51.88, 120.67, 121.96 (2C), 130.07 (2C), 134.13, 153.37, 156.65, 159.95, 163.46, 167.71, 191.90.

(37) ##STR00047## C.sub.27H.sub.33N.sub.5O.sub.4S (523.23)

(38) According to the above procedure, I-10 was obtained as a pale yellow powder with a yield of 52%.

(39) .sup.1H NMR (DMSO, 300 MHz) δ 0.78-0.82 (m, 2H, Cyclohexyl-H), 0.91-1.02 (m, 6H, CH.sub.2CH.sub.3 and 3H-Cyclohexyl), 1.24-1.30 (m, 3H, Cyclohexyl-H), 1.42 (m, 3H, Cyclohexyl-H), 2.18-2.26 (m, 2H, CH.sub.2-Cyclohexyl), 2.98-3.13 (m, 2H, CH.sub.2-imidazol), 4.86 (s, 2H, CH.sub.2—S), 6.48-7.51 (d, 3H, J=9 Hz, Ph-H), 7.58 (s, 1H, imidazol-H), 8.02-8.04 (d, 2H, J=6 Hz, Ph-H), 8.47-8.49 (d, 1H, J=6 Hz, imidazol-H), 9.81 (s, 1H, NH), 10.68 (brs, 1H, CONH); .sup.13C NMR (DMSO, 75 MHz) δ 13.02, 17.85, 25.23 (2C), 26.08, 29.35, 33.17 (2C), 36.07, 37.72, 38.96, 118.60, 120.48, 122.03 (2C), 130.02 (2C), 134.04, 135.91, 154.75, 158.18, 160.78, 163.15, 167.34, 191.91.

(40) ##STR00048## C.sub.26H.sub.34N.sub.4O.sub.5S (514.22)

(41) According to the above procedure, I-11 was obtained as a white powder with a yield of 41%.

(42) .sup.1H NMR (DMSO, 300 MHz) δ 0.77-0.81 (m, 2H, Cyclohexyl-H), 0.94-0.97 (m, 6H, CH.sub.2CH.sub.3 and 3H-Cyclohexyl), 1.26-1.36 (m, 3H, Cyclohexyl-H), 1.48-1.51 (m, 3H, Cyclohexyl-H), 1.96-2.01 (m, 2H, CH.sub.2CONH.sub.2), 2.09-2.11 (d, 2H, J=6 Hz, CH.sub.2-Cyclohexyl), 2.12-2.16 (m, 2H, CH.sub.2CHNH.sub.2), 2.28-2.30 (m, 2H, CH.sub.2CH.sub.3), 3.66-3.88 (m, 1H, NH.sub.2—CH), 4.68 (s, 2H, S—CH.sub.2), 6.89-7.01 (d, 2H, J=9 Hz, Ph-H), 7.92-7.95 (d, 2H, J=9 Hz, Ph-H), 10.60 (s, 1H, NH); .sup.13C NMR (DMSO, 75 MHz) δ 13.18, 17.76, 25.28 (2C), 25.67, 32.26 (2C), 33.22, 36.02, 37.15, 40.68, 52.21, 116.12 (2C), 119.98, 127.68, 130.45 (2C), 155.09, 159.63, 161.08, 162.14, 166.07, 173.62, 192.08.

(43) ##STR00049## C.sub.25H.sub.32N.sub.4O.sub.5S (500.21)

(44) According to the above procedure, I-12 was obtained as a pale yellow powder with a yield of 56.5%.

(45) .sup.1H NMR (DMSO, 300 MHz) δ 0.78-0.83 (m, 2H, Cyclohexyl-H), 0.94-0.96 (m, 6H, CH.sub.2CH.sub.3 and 3H-Cyclohexyl), 1.27-1.33 (m, 3H, Cyclohexyl-H), 1.46-1.50 (m, 3H, Cyclohexyl-H), 2.09-2.11 (d, 2H, J=6 Hz, CH.sub.2-Cyclohexyl), 2.17-2.20 (m, 2H, CH.sub.2CH.sub.3), 2.67-2.92 (m, 2H, CH.sub.2CONH.sub.2), 3.86-4.01 (m, 1H, NH.sub.2—CH), 4.60 (s, 2H, S—CH.sub.2), 6.85-6.88 (d, 2H, J=9 Hz, Ph-H), 7.91-7.94 (d, 2H, J=9 Hz, Ph-H), 10.60 (s, 1H, NH); .sup.13C NMR (DMSO, 75 MHz) δ 13.16, 17.86, 25.49 (2C), 25.97, 32.24 (2C), 36.02, 36.87, 37.15, 40.68, 50.01, 115.12 (2C), 120.98, 127.59, 130.77 (2C), 156.09, 160.63, 161.28, 162.67, 166.07, 172.32, 191.11.

(46) ##STR00050##

(47) According to the above procedure, I-13 was obtained as a pale yellow powder with a yield of 58%.

(48) .sup.1H NMR (DMSO, 300 MHz) δ 0.89 (s, 6H, CH(CH.sub.3).sub.2), 1.05-1.11 (m, 8H, CH.sub.2CH.sub.3 and 5H-Cyclohexyl), 1.25-1.28 (d, 3H, J=9 Hz, 3H-Cyclohexyl), 1.42-1.44 (d, 3H, J=6 Hz, Cyclohexyl-H), 2.12 (s, 2H, CH.sub.2-Cyclohexyl), 2.26-2.36 (m, 2H, CH.sub.2CH.sub.3), 2.37 (m, 1H, CHMe.sub.2), 4.11 (m, 1H, NH.sub.2—CH), 4.73 (s, 2H, S—CH.sub.2), 7.41-7.43 (d, 2H, J=6 Hz, Ph-H), 8.15-8.17 (d, 2H, J=6 Hz, Ph-H), 9.03 (s, 3H, NH and NH.sub.2); .sup.13C NMR (DMSO, 75 MHz) δ 13.07, 17.60, 17.86, 18.62, 25.53 (2C), 25.69, 29.44, 32.31 (2C), 36.32, 37.41, 39.86, 57.41, 120.67, 121.85 (2C), 130.17 (2C), 134.22, 153.27, 156.77, 159.97, 163.46, 167.04, 191.93.

(49) ##STR00051## C.sub.28H.sub.39N.sub.3O.sub.4S (513.27)

(50) According to the above procedure, I-14 was obtained as a pale yellow powder with a yield of 47%.

(51) .sup.1H NMR (DMSO, 300 MHz) δ 0.76-0.79 (m, 2H, Cyclohexyl-H), 0.87-0.89 (m, 3H, CH.sub.3), 1.05-1.11 (m, 6H, CH.sub.3, and 3H-Cyclohexyl), 1.14-1.21 (d, 6H, CH(CH.sub.3).sub.2), 1.24-1.32 (m, 3H, Cyclohexyl-H), 1.41-1.44 (m, 3H, Cyclohexyl-H), 2.11-2.13 (d, 2H, J=6 Hz, CH.sub.2-Cyclohexyl), 2.24-2.28 (m, 2H, CH.sub.2CH.sub.3), 2.36-2.38 (m, 1H, CHCH.sub.3), 2.89-3.29 (m, 1H, CH(CH.sub.3).sub.2), 4.11 (s, 1H, NH.sub.2—CH), 4.76 (s, 2H, S—CH.sub.2), 7.14-7.23 (d, 2H, Ph-H), 8.12-8.19 (d, 2H, Ph-H), 9.08 (s, 3H, NH.sub.2 and NH); .sup.13C NMR (DMSO, 75 MHz) δ 12.16, 15.60, 20.8 (2C), 24.4, 25.3, 25.53 (2C), 25.69, 29.45, 32.32 (2C), 36.36, 37.45, 39.86, 57.42, 120.66, 121.83 (2C), 130.18 (2C), 134.20, 153.25, 156.78, 159.23, 163.52, 167.03, 191.92.

(52) ##STR00052## C.sub.27H.sub.35N.sub.3O.sub.4S (497.23)

(53) According to the above procedure, I-15 was obtained as a pale yellow powder with a yield of 44%.

(54) .sup.1H NMR (DMSO, 300 MHz) δ 0.68-0.75 (m, 2H, Cyclohexyl-H), 0.93-0.98 (m, 3H, Cyclohexyl-H), 1.12-1.18 (d, 6H, CH(CH.sub.3).sub.2), 1.26-1.30 (m, 3H, Cyclohexyl-H), 1.42 (m, 3H, Cyclohexyl-H), 1.98 (m, 3H, Pyrrolidinyl-H), 2.17-2.25 (m, 7H, CH.sub.2-Cyclohexyl, CH.sub.2CH.sub.3 and 3H-Pyrrolidinyl), 2.89-3.23 (m, 1H, CH(CH.sub.3).sub.2), 4.68 (m, 1H, Pyrrolidinyl-H), 4.76 (s, 2H, CH.sub.2—S), 6.46-7.49 (d, 2H, J=9 Hz, Ph-H), 8.12-8.14 (d, 2H, J=6 Hz, Ph-H), 9.81 (s, 1H, NH), 10.68 (s, 1H, NH); .sup.13C NMR (DMSO, 75 MHz) δ 19.8 (2C), 23.06, 24.4, 25.53 (2C), 25.68, 27.45, 32.28 (2C), 36.47, 37.70, 39.80, 45.26, 58.47, 120.48, 122.03 (2C), 129.28 (2C), 134.04, 153.54, 157.23, 159.78, 163.86, 166.84, 191.82.

(55) ##STR00053## C.sub.33H.sub.38N.sub.4O.sub.4S (586.26)

(56) According to the above procedure, I-16 was obtained as a pale yellow powder with a yield of 52%.

(57) .sup.1H NMR (DMSO, 300 MHz) δ 0.78-0.82 (m, 2H, Cyclohexyl-H), 0.91 (m, 3H, Cyclohexyl-H), 1.22-1.28 (d, 6H, CH(CH.sub.3).sub.2), 1.31-1.36 (m, 2H, Cyclohexyl-H), 1.43-1.46 (m, 4H, Cyclohexyl-H), 2.26-2.28 (d, 2H, J=6 Hz, CH.sub.2-Cyclohexyl), 2.97-3.01 (m, 1H, CH(CH.sub.3).sub.2), 3.57-3.60 (d, 2H, J=9.9 Hz, CH.sub.2-indole), 4.34-4.57 (m, 1H, CH—NH.sub.2), 4.73 (s, 2H, S—CH.sub.2), 7.06-7.07 (m, 4H, ArH), 7.38-7.39 (d, 2H, J=3 Hz, ArH), 7.62-7.65 (d, 1H, J=9 Hz, ArH), 8.04-8.07 (d, 2H, J=9 Hz, ArH), 9.16 (s, 2H, NH.sub.2), 11.27 (s, 1H, NH); .sup.13C NMR (DMSO, 75 MHz) δ 19.24 (2C), 24.45, 25.55 (2C), 25.71, 27.83, 32.32 (2C), 36.45, 37.58, 39.62, 53.10, 106.42, 111.61, 118.16, 118.59, 120.52, 121.13, 121.70 (2C), 124.97, 129.93 (2C), 106.42, 121.84 (2C), 130.17 (2C), 126.85, 133.96, 136.20, 153.28, 157.16, 159.84, 163.80, 167.70, 191.74.

(58) ##STR00054## C.sub.24H.sub.31N.sub.3O.sub.4S (457.20)

(59) According to the above procedure, I-17 was obtained as a pale yellow powder with a yield of 43%.

(60) .sup.1H NMR (DMSO, 300 MHz) δ 0.69-0.72 (m, 2H, Cyclohexyl-H), 0.91 (m, 3H, Cyclohexyl-H), 1.20-1.26 (d, 6H, CH(CH.sub.3).sub.2), 1.31-1.33 (m, 3H, Cyclohexyl-H), 1.45-1.48 (m, 3H, Cyclohexyl-H), 2.09-2.11 (d, 2H, J=6 Hz, CH.sub.2-Cyclohexyl), 2.90-3.13 (m, 1H, CH(CH.sub.3).sub.2), 3.71 (s, 2H, NH.sub.2—CH.sub.2), 4.58 (s, 2H, S—CH.sub.2), 6.85-6.88 (d, 2H, J=9 Hz, Ph-H), 7.91-7.94 (d, 2H, J=9 Hz, Ph-H), 8.84 (m, 3H, NH.sub.2 and NH); .sup.13C NMR (DMSO, 75 MHz) δ 19.24 (2C), 24.45, 25.49 (2C), 25.79, 32.44 (2C), 36.00, 37.63, 40.59, 44.27, 115.12 (2C), 120.98, 127.59, 130.77 (2C), 156.09, 160.63, 162.28, 162.67, 166.07, 191.11.

(61) ##STR00055## C.sub.28H.sub.39N.sub.3O.sub.4S (513.27)

(62) According to the above procedure, I-18 was obtained as a pale yellow powder with a yield of 48%.

(63) .sup.1H NMR (DMSO, 300 MHz) δ 0.71-0.78 (m, 7H, Cyclohexyl-H), 0.94-0.98 (m, 12H, 4×CH.sub.3), 1.32-1.46 (m, 4H, Cyclohexyl-H), 1.60-1.65 (m, 1H, CH(CH.sub.3).sub.2), 1.86-1.90 (m, 2H, CH.sub.2CH(CH.sub.3).sub.2), 2.09-2.12 (d, 2H, CH.sub.2-Cyclohexyl), 2.90-3.13 (m, 1H, CH(CH.sub.3).sub.2), 3.96-4.02 (m, 1H, CH—NH.sub.2), 4.55 (s, 2H, S—CH.sub.2), 6.87-6.90 (d, 2H, J=9 Hz, Ph-H), 7.88-7.91 (d, 2H, J=9 Hz, Ph-H); .sup.13C NMR (DMSO, 75 MHz) δ 19.04 (2C), 23.45, 21.91, 22.00, 25.53 (2C), 25.84, 32.52 (2C), 36.16, 36.57, 40.51, 52.63, 115.26 (2C), 120.56, 127.12, 130.75 (2C), 156.92, 160.32, 162.97, 164.12, 168.14, 191.12.

(64) ##STR00056## C.sub.27H.sub.37N.sub.3O.sub.4S (499.25)

(65) According to the above procedure, I-19 was obtained as a pale yellow powder with a yield of 47%.

(66) .sup.1H NMR (DMSO, 300 MHz) δ 0.66-0.69 (m, 6H, 2×CH.sub.3), 1.05-1.09 (m, 6H, 2×CH.sub.3), 1.11-1.28 (m, 8H, Cyclohexyl-H), 1.42-1.44 (d, 3H, J=6 Hz, Cyclohexyl-H), 2.12 (s, 2H, CH.sub.2-Cyclohexyl), 2.26 (m, 1H, CHMe.sub.2), 2.28 (m, 1H, CHMe.sub.2), 4.11 (m, 1H, CH—NH.sub.2), 4.73 (s, 2H, S—CH.sub.2), 7.40-7.42 (d, 2H, J=6 Hz, Ph-H), 8.13-8.16 (d, 2H, J=6 Hz, Ph-H), 9.08 (s, 3H, NH and NH.sub.2); .sup.13C NMR (DMSO, 75 MHz) δ 19.04 (2C), 17.60, 17.86, 24.44, 25.56 (2C), 25.70, 30.43, 32.31 (2C), 36.32, 37.51, 39.66, 57.48, 121.56, 121.65 (2C), 130.29 (2), 134.12, 153.16, 156.78, 160.02, 163.50, 167.03, 191.91.

(67) ##STR00057## C.sub.27H.sub.37N.sub.3O.sub.4S.sub.2 (531.22)

(68) According to the above procedure, I-20 was obtained as a pale yellow powder with a yield of 48%.

(69) .sup.1H NMR (DMSO, 300 MHz) δ 0.68-0.73 (m, 5H, Cyclohexyl-H), 0.91-1.02 (m, 6H, 2×CH.sub.3), 1.21-1.29 (m, 3H, Cyclohexyl-H), 1.41-1.47 (m, 3H, Cyclohexyl-H), 2.07 (s, 3H, SCH.sub.3), 2.12-2.14 (d, 2H, J=6 Hz, CH.sub.2-Cyclohexyl), 2.14-2.18 (m, 2H, CH.sub.2CHNH.sub.2), 2.64-2.68 (t, 2H, J=7.1 Hz, CH.sub.2—SCH.sub.3), 3.89 (s, 1H, NH.sub.2—CH), 4.82 (s, 2H, S—CH.sub.2), 7.42-7.44 (d, 2H, J=7.5 Hz, Ph-H), 7.96-7.98 (d, 2H, J=7 Hz, Ph-H), 9.07 (s, 3H, NH.sub.2 and NH); .sup.13C NMR (DMSO, 75 MHz) δ 14.97 (SCH.sub.3), 19.89 (2C), 24.42, 25.90 (2C), 25.89 (2C), 29.73, 32.31 (2) C, 33.69, 36.13, 36.54, 40.17, 52.12, 119.52, 121.52 (2C), 129.17 (2C), 133.20, 155.75, 157.20, 160.72, 163.44, 168.32, 191.14.

(70) ##STR00058## C.sub.31H.sub.37N.sub.3O.sub.4S (547.25)

(71) According to the above procedure, I-21 was obtained as a pale yellow powder with a yield of 56%.

(72) .sup.1H NMR (DMSO, 300 MHz) δ 0.87-0.89 (m, 2H, Cyclohexyl-H), 0.90-1.02 (m, 9H, 3H-Cyclohexyl and 2×CH.sub.3), 1.29-1.42 (m, 6H, Cyclohexyl-H), 2.16-2.19 (d, 2H, J=6 Hz, CH.sub.2-Cyclohexyl), 2.78-3.12 (m, 1H, CH(CH.sub.3).sub.2), 3.19-3.29 (m, 2H, CH.sub.2-Ph) 3.92-4.00 (m, 1H, NH.sub.2—CH), 4.63 (s, 2H, S—CH.sub.2), 7.13-7.16 (d, 2H, J=9 Hz, Ph-H), 7.27-7.35 (m, 5H, Ph-H), 7.92-7.93 (d, 2H, J=9 Hz, Ph-H), 9.08 (s, 2H, NH.sub.2), 10.23 (s, H, NH); .sup.13C NMR (DMSO, 75 MHz) δ 20.8 (2C), 23.5, 25.64 (2C), 26.09, 32.31 (2C), 36.99, 36.42, 37.56, 38.63, 53.56, 120.47, 121.58 (2C), 127.31 (2C), 128.48 (2C), 129.51 (2C), 130.11, 134.07, 134.63, 153.71, 159.72, 162.21, 163.43, 167.46, 191.73.

(73) ##STR00059## C.sub.29H.sub.33N.sub.3O.sub.4S (519.22)

(74) According to the above procedure, I-22 was obtained as a pale yellow powder with a yield of 42%.

(75) .sup.1H NMR (DMSO, 300 MHz) δ 0.77-0.82 (m, 2H, Cyclohexyl-H), 0.96-1.23 (m, 6H, Cyclohexyl-H), 1.52-1.58 (m, 3H, Cyclohexyl-H), 2.12-2.15 (d, 2H, J=6 Hz, CH.sub.2-Cyclohexyl), 2.42 (s, 3H, CH.sub.3), 3.23-3.29 (m, 2H, CH.sub.2-Ph) 3.92-3.98 (m, 1H, CH—NH.sub.2), 4.64 (s, 2H, S—CH.sub.2), 7.13-7.16 (d, 2H, J=9 Hz, Ph-H), 7.27-7.35 (m, 5H, Ph-H), 8.09-8.12 (d, 2H, J=9 Hz, Ph-H), 9.07 (s, 2H, NH.sub.2), 10.27 (s, H, NH); .sup.13CNMR (DMSO, 75 MHz) δ 9.55, 25.69 (2C), 26.00, 32.70 (2C), 35.88, 36.32, 37.48, 38.66, 53.57, 120.39, 121.61 (2C), 127.30 (2C), 128.56 (2C), 129.49 (2C), 130.06, 134.06, 134.58, 153.12, 159.76, 162.28, 163.76, 167.30, 191.71.

(76) ##STR00060## C.sub.22H.sub.27N.sub.3O.sub.4S (429.1722)

(77) According to the above procedure, I-23 was obtained as a pale yellow powder with a yield of 58.67%.

(78) .sup.1H NMR (DMSO, 300 MHz) δ 0.75-0.82 (m, 2H, Cyclohexyl-H), 0.95 (s, 3H, Me), 1.33-1.37 (m, 3H, Cyclohexyl-H), 1.46-1.48 (m, 3H, Cyclohexyl-H), 1.82-2.00 (m, 3H, Cyclohexyl-H), 2.23-2.24 (d, 2H, J=6 Hz, CH.sub.2-Cyclohexyl), 3.15-3.19 (t, 2H, J=6 Hz, NH.sub.2—CH.sub.2), 4.68 (s, 2H, S—CH.sub.2), 6.88-6.91 (d, 2H, J=6 Hz, Ph-H), 7.87-7.90 (d, 2H, J=9 Hz, Ph-H), 8.80-8.81 (ds, 2H, NH.sub.2), 10.24-10.25 (ds, 1H, NH); .sup.13C NMR (DMSO, 75 MHz) δ 10.29, 23.04, 25.72, 27.89, 32.25, 36.54 37.29, 39.88, 45.07, 114.61, 115.20 (2C), 127.17, 130.75 (2C), 157.57, 160.00, 162.55, 164.52, 170.20, 190.83.

(79) ##STR00061## C.sub.25H.sub.33N.sub.3O.sub.4S.sub.2 (503.19)

(80) According to the above procedure, I-24 was obtained as a pale yellow powder with a yield of 51%.

(81) .sup.1H NMR (DMSO, 300 MHz) δ 0.76-0.84 (m, 2H, Cyclohexyl-H), 0.91-1.02 (m, 3H, Cyclohexyl-H), 1.26-1.33 (m, 3H, Cyclohexyl-H), 1.46-1.52 (m, 3H, Cyclohexyl-H), 2.02 (s, 1H, SCH.sub.3), 2.11-2.13 (d, 2H, J=6 Hz, CH.sub.2-Cyclohexyl), 2.15-2.17 (m, 2H, CH.sub.2CHNH.sub.2), 2.43 (s, 1H, CH.sub.3), 2.66-2.70 (t, 2H, J=7.1 Hz, CH.sub.2—SCH.sub.3), 3.86 (s, 1H, CH—NH.sub.2), 4.84 (s, 2H, 5-CH.sub.2), 7.41-7.44 (d, 2H, J=9 Hz, Ph-H), 8.05-8.10 (d, 2H, J=7 Hz, Ph-H), 9.08 (s, 3H, NH.sub.2 and NH); .sup.13C NMR (DMSO, 75 MHz) δ 9.43, 14.6, 25.49 (2C), 25.69 (2C), 29.73, 33.31 (2C), 33.71, 36.13, 36.65, 40.16, 52.13, 119.51, 121.54 (2C), 129.17 (2C), 133.20, 155.75, 157.18, 160.73, 163.40, 168.31, 191.26.

Effect Example 1: Anti-HIV-1 Activity Test

(82) C8166 cells infected with HIV-1 were used for determining the anti-HIV biological activity at the cellular level. The specific method was described below.

(83) Cytotoxicity experiment: The toxicity of the compounds on C8166 cells was determined by MTT method. In a 96-well cell culture plate, the compounds were subjected to 5-fold serial dilution and 100 μL of C8166 cell suspension (4×10.sup.5/mL) was added into each well. Three replicate wells were set for each concentration. At the same time, a cell control group without drugs and drug control groups with Zidovudine (AZT) or Nevirapine (NVP) were set. The cells were incubated at 37° C. in a 5% CO.sub.2 incubator for three days, followed by the addition of MTT solution into each well, and then the cells were incubated at 37° C. for 4 hours. 15% SDS-50% DMF was added to each well and the cells were incubated at 37° C. in a 5% CO.sub.2 incubator overnight. After mixing evenly, the OD values were measured by BIO-TEK ELx800 ELISA instrument (determination wavelength: 570 nm; reference wavelength: 630 nm). The dose-response curve was graphed according to the experimental results, and the CC.sub.50 was calculated (the concentrations of the compounds required to produce toxicity on 50% cells).

(84) Syncytium inhibition experiment: 100 μL of C8166 cell suspension (4×10.sup.5/mL) was inoculated into each well of a 96-well cell culture plate containing 5-fold serial dilutions of the compounds, followed by addition of HIV-1.sub.IIIB diluted supernatant (MOI=0.04). Three replicate wells were set for each serial concentration. At the same time, negative control wells of HIV-1.sub.IIIB infection without compounds and positive control wells with Zidovudine (AZT) or Nevirapine (NVP) were set. The cells were incubated at 37° C. in a 5% CO.sub.2 incubator for three days. The number of the syncytia was counted in five non-overlapping fields of view by using an inverted microscope (100×). The dose-response curves were graphed according to the experimental results, and the 50% effective concentrations of the compounds for inhibiting the virus (EC50, 50% effective concentration) were calculated according to Reed & Muench method. Calculation formula: cytopathic inhibition rate (%)=(1−number of syncytia in experimental wells/number of syncytia in control well)×100%.

(85) In the present disclosure, AZT and NVP were used as control, and the inhibitory activity data of some target compounds on HIV-1.sub.IIIB is shown in Table 1:

(86) TABLE-US-00002 TABLE 1 Inhibitory activity data of target compounds on HIV-1.sub.IIIB No. CC.sub.50 (μM) EC.sub.50 (μM) SI I-1 137.6 0.004 33686 I-2 112.0 0.003 48217 I-3 134.3 0.005 31375 I-4 95.38 0.012 9233 I-5 95.19 0.004 23911 I-6 96.01 0.004 25390 I-7 90.14 0.009 11002 I-8 116.0 0.004 30582 I-9 100.7 0.006 19235 I-10 199.3 0.012 15445 I-11 117.6 0.005 23787 I-12 120.3 0.004 30183 I-13 94.75 0.003 54286 I-14 186.2 0.004 42237 I-15 98.26 0.012 7963.9 I-16 118.4 0.004 31257 I-17 190.6 0.003 63936 I-18 97.39 0.004 40305 I-19 125.60 0.003 37677 I-20 153.1 0.003 44946 I-21 94.98 0.004 31050 I-22 98.58 0.010 9217.3 I-23 >200 0.008 >12656 I-24 199.3 0.012 19616 AZT >749 0.049 >15286 NVP 504.1 0.013 38777

(87) It can be seen from Table 1 that the amino acid ester derivatives of DACOs of the present disclosure are a series of novel type of non-nucleoside HIV-1 inhibitors and have high inhibitory activities on HIV-1 virus strains. As shown in Table 1, the EC.sub.50 values of the twenty four preferred compounds for inhibiting HIV-1 virus strains all reach nanomolar levels, and the cytotoxicities of which are relatively low (CC.sub.50 values range between 85 μM and 199 μM). The compounds other than compounds I-4, I-15 and I-22 have selectivity indexes (SI) greater than 10000 which are equivalent to AZT, and compounds I-2, I-13, I-14, I-17, I-18 and I-20 have selectivity indexes higher than AZT and NVP, and thus these compounds can be used as anti-HIV drug candidates.

(88) Although the specific embodiments of the present disclosure have been described above, those skilled in the art should understand that these embodiments are only intended for illustration, and various changes or variations can be made to these embodiments without departing from the spirit and essence of the present disclosure. Therefore, the scope of protection of the present disclosure is defined by the appended claims.