Phenylcarbamate derivatives as formyl peptide receptor modulators

Abstract

The present invention relates to N-phenyl carbamate derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals as modulators of the N-formyl peptide 2 receptor.

Claims

1. A compound of Formula I: ##STR00102## wherein: R.sup.1 is optionally substituted C.sub.1-8 alkyl, optionally substituted C.sub.3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C.sub.6-10 aryl, optionally substituted C.sub.3-8 cycloalkenyl, halogen, NR.sup.11R.sup.12, fluorinated C.sub.1-8 alkyl, perfluorinated C.sub.1-8 alkyl, S(O).sub.mR.sup.13, C(O)R.sup.14 or OR.sup.15; R.sup.2 is H, optionally substituted C.sub.1-8 alkyl, optionally substituted C.sub.3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C.sub.6-10 aryl, optionally substituted C.sub.3-8 cycloalkenyl, halogen, NR.sup.11R.sup.12, fluorinated C.sub.1-8 alkyl, perfluorinated C.sub.1-8 alkyl, S(O).sub.mR.sup.13, C(O)R.sup.14 or OR.sup.15; R.sup.3 is H, optionally substituted C.sub.1-8 alkyl, optionally substituted C.sub.3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C.sub.6-10 aryl, optionally substituted C.sub.3-8 cycloalkenyl, halogen, NR.sup.11R.sup.12, fluorinated C.sub.1-8 alkyl, perfluorinated C.sub.1-8 alkyl, S(O).sub.mR.sup.13, C(O)R.sup.14 or OR.sup.15; R.sup.4 is H, optionally substituted C.sub.1-8 alkyl, optionally substituted C.sub.3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C.sub.6-10 aryl, optionally substituted C.sub.3-8 cycloalkenyl, halogen, NR.sup.11R.sup.12, fluorinated C.sub.1-8 alkyl, perfluorinated C.sub.1-8 alkyl, S(O).sub.mR.sup.13C(O)R.sup.14 or OR.sup.15; R.sup.5 is H, optionally substituted C.sub.1-8 alkyl, optionally substituted C.sub.3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C.sub.6-10 aryl, optionally substituted C.sub.3-8 cycloalkenyl, halogen, NR.sup.11R.sup.12, fluorinated C.sub.1-8 alkyl, perfluorinated C.sub.1-8 alkyl, S(O).sub.mR.sup.13, C(O)R.sup.14 or OR.sup.15; R.sup.6 is H, optionally substituted C.sub.1-8 alkyl, optionally substituted heterocycle, (CH.sub.2).sub.pCOOH, (CH.sub.2).sub.pNH.sub.2, (CH.sub.2).sub.pOH, (CH.sub.2).sub.pSH, (CH.sub.2).sub.pCONH.sub.2, (CH.sub.2).sub.pCONH.sub.2, CH(OH)CH.sub.3, (CH.sub.2).sub.pSCH.sub.3, (CH.sub.2).sub.pNHC(NH)(NH.sub.2) or CH.sub.2C.sub.6-10aryl, wherein said C.sub.6-10aryl is optionally substituted; R.sup.6a is H or optionally substituted C.sub.1-8 alkyl; R.sup.7 is H or optionally substituted C.sub.1-8 alkyl; R.sup.8 is H; R.sup.9 is H, optionally substituted C.sub.1-8 alkyl, optionally substituted C.sub.3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C.sub.6-10 aryl or optionally substituted C.sub.3-8 cycloalkenyl; R.sup.10 is (CH.sub.2).sub.nOR.sup.16, (CH.sub.2)S(O).sub.2OH, (CH.sub.2).sub.nC(O)R.sup.17, (CH.sub.2).sub.nOS(O).sub.2OH, (CH.sub.2).sub.nNR.sup.18R.sup.19, (CH.sub.2)P(O)(OC.sub.1-6 alkyl).sub.2, (CH.sub.2).sub.nP(O)(OC.sub.1-6 alkyl)OH, (CH.sub.2).sub.nP(O)(OH).sub.2 or optionally substituted heterocycle; R.sup.11 is H, optionally substituted C.sub.1-8 alkyl, optionally substituted C.sub.3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C.sub.6-10 aryl or optionally substituted C.sub.3-8 cycloalkenyl; R.sup.12 is H, optionally substituted C.sub.1-8 alkyl, optionally substituted C.sub.3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C.sub.6-10 aryl or optionally substituted C.sub.3-8 cycloalkenyl; R.sup.13 is H, optionally substituted C.sub.1-8 alkyl, optionally substituted C.sub.3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C.sub.6-10 aryl, OH or optionally substituted C.sub.3-8 cycloalkenyl; R.sup.14 is optionally substituted C.sub.1-8 alkyl, optionally substituted C.sub.3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C.sub.6-10 aryl, optionally substituted C.sub.3-8 cycloalkenyl or OR.sup.15; R.sup.15 is H or optionally substituted C.sub.1-8 alkyl; R.sup.16 is H, C(O)(C.sub.1-8 alkyl) or optionally substituted C.sub.1-8 alkyl; R.sup.17 is OH, OC.sub.1-8 alkyl or C.sub.1-8 alkyl; R.sup.18 is selected from the group consisting of H, optionally substituted C.sub.1-8 alkyl, optionally substituted C.sub.3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C.sub.6-10 aryl, optionally substituted C.sub.3-8 cycloalkenyl, C(O)R.sup.17 and S(O).sub.2N(C.sub.1-8 alkyl).sub.2; R.sup.19 is selected from the group consisting of H, optionally substituted C.sub.1-8 alkyl, optionally substituted C.sub.3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C.sub.6-10 aryl, or optionally substituted C.sub.3-8 cycloalkenyl, C(O)R.sup.17 and S(O).sub.2N(C.sub.1-8 alkyl).sub.2; with a proviso when R.sup.10 is (CH).sub.nC(O)R.sup.17 and R.sup.17 is C.sub.1-8 alkyl, then R.sup.9 is H; p is 1, 2 or 3; n is 0, 1, 2, 3, 4, 5, 6, 7 or 8; and m is 0, 1 or 2; wherein each C.sub.1-8 alkyl substituent is independently selected from the group consisting of halogen, hydroxyl, OC.sub.1-8alkyl, C.sub.3-8cycloalkyl, amino, heterocycle, C.sub.6-10aryl, carboxylic acid, phosphonic acid, sulphonic acid, phosphoric acid, nitro, amide, sulfonamide, sulfonamide and carboxylate ester; each C.sub.3-8 cycloalkyl substituent is independently selected from the group consisting of halogen, hydroxyl, sulfonyl C.sub.1-8 alkyl, sulfoxide C.sub.1-8 alkyl, sulfonamide, nitro, OC.sub.1-8 alkyl, SC.sub.1-8 alkyl groups, C.sub.1-8 alkyl, ketone, alkylamino, amino, C.sub.6-10 aryl and C.sub.3-8 cycloalkyl; each heterocycle substituent is independently selected from the group consisting of halogen, hydroxyl, OC.sub.1-8 alkyl, sulfonyl C.sub.1-8 alkyl, sulfoxide C.sub.1-8 alkyl, nitro, SC.sub.1-8 alkyl, C.sub.1-8 alkyl, ketone, alkylamino, amino, C.sub.6-10 aryl and C.sub.3-8 cycloalkyl; each C.sub.6-10 aryl substituent is independently selected from the group consisting of halogen, hydroxyl, sulfonyl C.sub.1-8 alkyl, sulfoxide C.sub.1-8 alkyl, sulfonamide, carboxylic acid, C.sub.1-8 alkyl carboxylate (ester), amide, nitro, OC.sub.1-6 alkyl, SC.sub.1-8 alkyl, C.sub.1-8 alkyl, ketone, alkylamino, amino and C.sub.3-8 cycloalkyl; and each C.sub.3-8 cycloalkenyl substituent is independently selected from the group consisting of halogen, hydroxyl, sulfonyl C.sub.1-8 alkyl, sulfoxide C.sub.1-8 alkyl, nitro, OC.sub.1-6 alkyl, SC.sub.1-6 alkyl, C.sub.1-6 alkyl, ketone, alkylamino, amino, C.sub.6-10 aryl and C.sub.3-8 cycloalkyl; or an enantiomer, diastereomer or tautomer thereof; or a pharmaceutically acceptable salt of any of the foregoing.

2. The compound of claim 1, wherein: R.sup.1 is selected from the group consisting of halogen, fluorinated C.sub.1-8 alkyl and perfluorinated C.sub.1-8 alkyl.

3. The compound of claim 1, wherein: each of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is H.

4. The compound of claim 1, wherein: R.sup.6 is H, optionally substituted C.sub.1-8 alkyl or CH.sub.2C.sub.6-10aryl, wherein said C.sub.1-6 aryl is optionally substituted; R.sup.6a is H; and R.sup.7 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or t-butyl.

5. The compound of claim 1, wherein: n is 0 or 1; R.sup.9 is H; R.sup.10 is (CH.sub.2).sub.nOR.sup.16, (CH.sub.2)C(O)R.sup.17, (CH.sub.2).sub.nS(O).sub.2OH, (CH.sub.2)NR.sup.18R.sup.19, (CH.sub.2).sub.nP(O)(OC.sub.1-6 alkyl).sub.2, (CH.sub.2).sub.nP(O)(OC.sub.1-6alkyl)OH, (CH.sub.2).sub.nP(O)(OH).sub.2 or optionally substituted heterocycle; R.sup.16 is H or C(O)(C.sub.1-8 alkyl); R.sup.17 is OH or OC.sub.1-8 alkyl; R.sup.18 H; and R.sup.19 is selected from the group consisting of H, C(O)R.sup.17 and S(O).sub.2N(C.sub.1-8 alkyl).sub.2.

6. The compound of claim 1, wherein: R.sup.1 is selected from the group consisting of halogen, fluorinated C.sub.1-8 alkyl and perfluorinated C.sub.1-8 alkyl; each of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is H; R.sup.6 is H, optionally substituted C.sub.1-8 alkyl or CH.sub.2C.sub.6-10aryl, wherein said C.sub.6-10aryl is optionally substituted; R.sup.6a is H; R.sup.9 is H; R.sup.10 is (CH.sub.2).sub.nOR.sup.16, (CH.sub.2)C(O)R.sup.17, (CH.sub.2).sub.nS(O).sub.2OH, (CH.sub.2).sub.nNR.sup.18R.sup.19, (CH.sub.2).sub.nP(O)(OC.sub.1-6 alkyl).sub.2, (CH.sub.2).sub.nP(O)(OC.sub.1-6alkyl)OH, (CH.sub.2).sub.nP(O)(OH).sub.2 or optionally substituted heterocycle; R.sup.16 is H or C(O)(C.sub.1-8 alkyl); R.sup.17 is OH or OC.sub.1-8 alkyl; R.sup.18 H; and R.sup.19 is selected from the group consisting of H, C(O)R.sup.17 and S(O).sub.2N(C.sub.1-8 alkyl).sub.2.

7. The compound of claim 6, wherein: each C.sub.1-8 alkyl is independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and t-butyl; and R.sup.7 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or t-butyl.

8. The compound of claim 1, selected from the group consisting of: ##STR00103## ##STR00104## ##STR00105## ##STR00106## ##STR00107## ##STR00108## and pharmaceutically acceptable salts thereof.

9. A pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable adjuvant, diluent or carrier.

10. The pharmaceutical composition of claim 9, wherein the compound is selected from the group consisting of: ##STR00109## ##STR00110## ##STR00111## ##STR00112## ##STR00113## ##STR00114## and pharmaceutically acceptable salts thereof.

Description

DRAWINGS

(1) FIG. 1 shows the structure of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

(2) It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention claimed. As used herein, the use of the singular includes the plural unless specifically stated otherwise.

(3) It will be readily apparent to those skilled in the art that some of the compounds of the invention may contain one or more asymmetric centers, such that the compounds may exist in enantiomeric as well as in diastereomeric forms. Unless it is specifically noted otherwise, the scope of the present invention includes all enantiomers, diastereomers and racemic mixtures. Some of the compounds of the invention may form salts with pharmaceutically acceptable acids or bases, and such pharmaceutically acceptable salts of the compounds described herein are also within the scope of the invention.

(4) The present invention includes all pharmaceutically acceptable isotopically enriched compounds. Any compound of the invention may contain one or more isotopic atoms enriched or different than the natural ratio such as deuterium .sup.2H (or D) in place of hydrogen .sup.1H (or H) or use of .sup.13C enriched material in place of .sup.12C and the like. Similar substitutions can be employed for N, O and S. The use of isotopes may assist in analytical as well as therapeutic aspects of the invention. For example, use of deuterium may increase the in vivo half-life by altering the metabolism (rate) of the compounds of the invention. These compounds can be prepared in accord with the preparations described by use of isotopically enriched reagents.

(5) The following examples are for illustrative purposes only and are not intended, nor should they be construed, as limiting the invention in any manner. Those skilled in the art will appreciate that variations and modifications of the following examples can be made without exceeding the spirit or scope of the invention.

(6) In embodiment (1), there is provided a compound represented by Formula I:

(7) ##STR00004##
wherein:

(8) R.sup.1 is optionally substituted C.sub.1-8 alkyl, optionally substituted C.sub.3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C.sub.6-10 aryl, optionally substituted C.sub.3-8 cycloalkenyl, halogen, NR.sup.11R.sup.12, fluorinated C.sub.1-8 alkyl, perfluorinated C.sub.1-8 alkyl, S(O).sub.mR.sup.13, C(O)R.sup.14 or OR.sup.15;

(9) R.sup.2 is H, optionally substituted C.sub.1-8 alkyl, optionally substituted C.sub.3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C.sub.6-10 aryl, optionally substituted C.sub.3-8 cycloalkenyl, halogen, NR.sup.11R.sup.12, fluorinated C.sub.1-8 alkyl, perfluorinated C.sub.1-8 alkyl, S(O).sub.mR.sup.13C(O)R.sup.14 or OR.sup.15;

(10) R.sup.3 is H, optionally substituted C.sub.1-8 alkyl, optionally substituted C.sub.3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C.sub.6-10 aryl, optionally substituted C.sub.3-8 cycloalkenyl, halogen, NR.sup.11R.sup.12, fluorinated C.sub.1-8 alkyl, perfluorinated C.sub.1-8 alkyl, S(O).sub.mR.sup.13C(O)R.sup.14 or OR.sup.15;

(11) R.sup.4 is H, optionally substituted C.sub.1-8 alkyl, optionally substituted C.sub.3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C.sub.6-10 aryl, optionally substituted C.sub.3-8 cycloalkenyl, halogen, NR.sup.11R.sup.12, fluorinated C.sub.1-8 alkyl, perfluorinated C.sub.1-8 alkyl, S(O).sub.mR.sup.13C(O)R.sup.14 or OR.sup.15;

(12) R.sup.5 is H, optionally substituted C.sub.1-8 alkyl, optionally substituted C.sub.3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C.sub.6-10 aryl, optionally substituted C.sub.3-8 cycloalkenyl, halogen, NR.sup.11R.sup.12, fluorinated C.sub.1-8 alkyl, perfluorinated C.sub.1-8 alkyl, S(O).sub.mR.sup.13C(O)R.sup.14 or OR.sup.15;

(13) R.sup.6 is H, optionally substituted C.sub.1-8 alkyl, optionally substituted heterocycle, (CH.sub.2).sub.pCOOH, (CH.sub.2).sub.pNH.sub.2, (CH.sub.2).sub.pOH, (CH.sub.2).sub.pSH, (CH.sub.2).sub.pCONH.sub.2, (CH.sub.2).sub.pCONH.sub.2, CH(OH)CH.sub.3, (CH.sub.2).sub.pSCH.sub.3, (CH.sub.2).sub.pNHC(NH)(NH.sub.2) or CH.sub.2C.sub.6-10 aryl, wherein said C.sub.6-10 aryl is optionally substituted;

(14) R.sup.6a is H or optionally substituted C.sub.1-8 alkyl;

(15) R.sup.7 is H or optionally substituted C.sub.1-8 alkyl;

(16) R.sup.8 is H;

(17) R.sup.9 is H, optionally substituted C.sub.1-8 alkyl, optionally substituted C.sub.3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C.sub.6-10 aryl or optionally substituted C.sub.3-8 cycloalkenyl;

(18) R.sup.10 is (CH.sub.2).sub.nOR.sup.16, (CH.sub.2).sub.nS(O).sub.2OH, (CH.sub.2).sub.nC(O)R.sup.17, (CH.sub.2).sub.nOS(O).sub.2OH, (CH.sub.2).sub.nNR.sup.18R.sup.19, (CH.sub.2).sub.nP(O)(OC.sub.1-6 alkyl).sub.2, (CH.sub.2).sub.nP(O)(OC.sub.1-6 alkyl)OH, (CH.sub.2).sub.nP(O)(OH).sub.2 or optionally substituted heterocycle;

(19) R.sup.11 is H, optionally substituted C.sub.1-8 alkyl, optionally substituted C.sub.3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C.sub.6-10 aryl or optionally substituted C.sub.3-8 cycloalkenyl;

(20) R.sup.12 is H, optionally substituted C.sub.1-8 alkyl, optionally substituted C.sub.3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C.sub.6-10 aryl or optionally substituted C.sub.3-8 cycloalkenyl;

(21) R.sup.13 is H, optionally substituted C.sub.1-8 alkyl, optionally substituted C.sub.3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C.sub.6-10 aryl, OH or optionally substituted C.sub.3-8 cycloalkenyl;

(22) R.sup.14 is optionally substituted C.sub.1-8 alkyl, optionally substituted C.sub.3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C.sub.6-10 aryl, optionally substituted C.sub.3-8 cycloalkenyl or OR.sup.15;

(23) R.sup.15 is H or optionally substituted C.sub.1-8 alkyl;

(24) R.sup.16 is H, C(O)(C.sub.1-8 alkyl) or optionally substituted C.sub.1-8 alkyl;

(25) R.sup.17 is OH, OC.sub.1-8 alkyl or C.sub.1-8 alkyl;

(26) R.sup.18 is selected from the group consisting of H, optionally substituted C.sub.1-8 alkyl, optionally substituted C.sub.3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C.sub.6-10 aryl, optionally substituted C.sub.3-8 cycloalkenyl, C(O)R.sup.17 and S(O).sub.2N(C.sub.1-8 alkyl).sub.2;

(27) R.sup.19 is selected from the group consisting of H, optionally substituted C.sub.1-8 alkyl, optionally substituted C.sub.3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C.sub.6-10 aryl, or optionally substituted C.sub.3-8 cycloalkenyl, C(O)R.sup.17 and S(O).sub.2N(C.sub.1-8 alkyl).sub.2; p is 1, 2 or 3; n is 0, 1, 2, 3, 4, 5, 6, 7 or 8; and m is 0, 1 or 2;
wherein

(28) each C.sub.1-8 alkyl substituent is independently selected from the group consisting of halogen, hydroxyl, OC.sub.1-8alkyl, C.sub.3-8cycloalkyl, amino, heterocycle, C.sub.6-10aryl, carboxylic acid, phosphonic acid, sulphonic acid, phosphoric acid, nitro, amide, sulfonamide, carboxylate ester and ketone;

(29) each C.sub.3-8 cycloalkyl substituent is independently selected from the group consisting of halogen, hydroxyl, sulfonyl C.sub.1-8 alkyl, sulfoxide C.sub.1-8 alkyl, sulfonamide, nitro, OC.sub.1-8 alkyl, SC.sub.1-8 alkyl groups, C.sub.1-8 alkyl, ketone, alkylamino, amino, C.sub.6-10 aryl and C.sub.3-8 cycloalkyl;

(30) each heterocycle substituent is independently selected from the group consisting of halogen, hydroxyl, OC.sub.1-8 alkyl, sulfonyl C.sub.1-8 alkyl, sulfoxide C.sub.1-8 alkyl, nitro, SC.sub.1-8 alkyl, C.sub.1-8 alkyl, ketone, alkylamino, amino, C.sub.6-10 aryl and C.sub.3-8 cycloalkyl;

(31) each C.sub.6-10 aryl substituent is independently selected from the group consisting of halogen, hydroxyl, sulfonyl C.sub.1-8 alkyl, sulfoxide C.sub.1-8 alkyl, sulfonamide, carboxylic acid, C.sub.1-8 alkyl carboxylate (ester), amide, nitro, OC.sub.1-8 alkyl, SC.sub.1-8 alkyl, C.sub.1-8 alkyl, ketone, alkylamino, amino and C.sub.3-8 cycloalkyl; and

(32) each C.sub.3-8 cycloalkenyl substituent is independently selected from the group consisting of halogen, hydroxyl, sulfonyl C.sub.1-8 alkyl, sulfoxide C.sub.1-8 alkyl, nitro, OC.sub.1-6 alkyl, SC.sub.1-6 alkyl, C.sub.1-6 alkyl, ketone, alkylamino, amino, C.sub.6-10 aryl and C.sub.3-8 cycloalkyl;

(33) or an enantiomer, diastereomer or tautomer thereof;

(34) or a pharmaceutically acceptable salt of any of the foregoing.

(35) In embodiment (2), there is provided a compound according to embodiment (1), wherein:

(36) n is 0 or 1;

(37) R.sup.10 is (CH.sub.2).sub.nOR.sup.16, (CH.sub.2).sub.nC(O)R.sup.17, (CH.sub.2).sub.nS(O).sub.2OH, (CH.sub.2).sub.nNR.sup.18R.sup.19, (CH.sub.2).sub.nP(O)(OC.sub.1-6 alkyl).sub.2, (CH.sub.2).sub.nP(O)(OC.sub.1-6alkyl)OH, (CH.sub.2).sub.nP(O)(OH).sub.2 or optionally substituted heterocycle;

(38) R.sup.16 is H or C(O)(C.sub.1-8 alkyl);

(39) R.sup.17 is OH or OC.sub.1-8 alkyl;

(40) R.sup.18 H; and

(41) R.sup.19 is selected from the group consisting of H, C(O)R.sup.17 and S(O).sub.2N(C.sub.1-8 alkyl).sub.2;

(42) or an enantiomer, diastereomer or tautomer thereof;

(43) or a pharmaceutically acceptable salt of any of the foregoing.

(44) In embodiment (3), there is provided a compound according to any one of embodiments (1) or (2), wherein R.sup.9 is H.

(45) In embodiment (4), there is provided a compound according to any one of embodiments (1) through (3), wherein:

(46) R.sup.6 is H, optionally substituted C.sub.1-8 alkyl or CH.sub.2C.sub.6-10aryl, wherein said C.sub.1-6 aryl is optionally substituted; and

(47) R.sup.6a is H;

(48) or an enantiomer, diastereomer or tautomer thereof;

(49) or a pharmaceutically acceptable salt of any of the foregoing.

(50) In embodiment (5), there is provided a compound according to any one of embodiments (1) through (4), wherein R.sup.7 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or t-butyl;

(51) or an enantiomer, diastereomer or tautomer thereof;

(52) or a pharmaceutically acceptable salt of any of the foregoing.

(53) In embodiment (6), there is provided a compound according to any one of embodiments (1) through (5), wherein R.sup.1 is selected from halogen, fluorinated C.sub.1-8 alkyl and perfluorinated C.sub.1-8 alkyl;

(54) or an enantiomer, diastereomer or tautomer thereof;

(55) or a pharmaceutically acceptable salt of any of the foregoing.

(56) In embodiment (7), there is provided a compound according to any one of embodiments (1) through (6), wherein each of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is H;

(57) or an enantiomer, diastereomer or tautomer thereof;

(58) or a pharmaceutically acceptable salt of any of the foregoing.

(59) In embodiment (8), there is provided a compound according to any one of embodiments (1) through (7), wherein R.sup.10 is an optionally substituted heterocycle, wherein the heterocycle is selected from imidazole, triazole, tetrazole, oxazole and thiazole;

(60) or an enantiomer, diastereomer or tautomer thereof;

(61) or a pharmaceutically acceptable salt of any of the foregoing.

(62) In embodiment (9), there is provided a compound according to any one of embodiments (1) through (8), wherein:

(63) n is 0 or 1;

(64) R.sup.1 is selected from halogen, fluorinated C.sub.1-8 alkyl and perfluorinated C.sub.1-8 alkyl; each of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is H;

(65) R.sup.6 is H, optionally substituted C.sub.1-8 alkyl or CH.sub.2C.sub.6-10aryl, wherein said C.sub.6-10aryl is optionally substituted;

(66) R.sup.6a is H;

(67) R.sup.9 is H;

(68) R.sup.10 is (CH.sub.2).sub.nOR.sup.16, (CH.sub.2).sub.nC(O)R.sup.17, (CH.sub.2).sub.nS(O).sub.2OH, (CH.sub.2).sub.nNR.sup.18R.sup.19, (CH.sub.2).sub.nP(O)(OC.sub.1-6 alkyl).sub.2, (CH.sub.2).sub.nP(O)(OC.sub.1-6alkyl)OH, (CH.sub.2).sub.nP(O)(OH).sub.2 or optionally substituted heterocycle;

(69) R.sup.16 is H or C(O)(C.sub.1-8 alkyl);

(70) R.sup.17 is OH or OC.sub.1-8 alkyl;

(71) R.sup.18 H; and

(72) R.sup.19 is selected from the group consisting of H, C(O)R.sup.17 and S(O).sub.2N(C.sub.1-8 alkyl).sub.2;

(73) or an enantiomer, diastereomer or tautomer thereof;

(74) or a pharmaceutically acceptable salt of any of the foregoing.

(75) In embodiment (10), there is provided a compound according to any one of embodiments (1) through (9) wherein CH.sub.2C.sub.6-10 aryl is optionally substituted benzyl.

(76) In embodiment (11), there is provided a compound according to any one of embodiments (1) through (10), wherein:

(77) each C.sub.1-8 alkyl is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and t-butyl; and

(78) R.sup.7 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or t-butyl;

(79) or an enantiomer, diastereomer or tautomer thereof;

(80) or a pharmaceutically acceptable salt of any of the foregoing.

(81) In embodiment (12), there is provided a compound selected from the group consisting of: tert-Butyl {[(2S)-2-{[(4-Bromophenyl)carbamoyl]oxy}-4-methyl pentanoyl]amino}acetate; tert-Butyl {[(2S)-4-Methyl-2-({[4-(trifluoromethyl)phenyl]carbamoyl}oxy)pentanoyl]amino}acetate; tert-Butyl {[(2S)-2-{[(4-Bromophenyl)carbamoyl]oxy}-4-methylpentanoyl](methyl)amino}acetate; (2S)-1-[(2-Hydroxyethyl)(methyl)amino]-4-methyl-1-oxopentan-2-yl (4-bromophenyl)carbamate; Diethyl ({[(2S)-4-methyl-2-({[4-(Trifluoromethyl)phenyl]carbamoyl}oxy)pentanoyl]amino}methyl)phosphonate; (2S)-1-[(2-Hydroxyethyl)amino]-4-Methyl-1-oxopentan-2-yl [4-(trifluoromethyl)phenyl]carbamate; (2S)-1-[(2-Hydroxyethyl)amino]-4-methyl-1-oxopentan-2-yl (4-bromophenyl)carbamate; Diethyl ({[(2S)-2-{[(4-bromophenyl)carbamoyl]oxy}-4-methylpentanoyl]amino}methyl)phosphonate; tert-Butyl {[(2S)-2-{[(4-Bromophenyl)carbamoyl]oxy}-4-methylpentanoyl](propyl)amino}acetate; tert-Butyl {[(2S)-2-{[(4-Bromophenyl)carbamoyl]oxy}-4-methylpentanoyl](propan-2-yl)amino}acetate; tert-Butyl {[(2S)-2-{[(4-Bromophenyl)carbamoyl]oxy}-4-methylpentanoyl](ethyl)amino}acetate; tert-Butyl {Methyl[(2S)-4-methyl-2-({[4-(trifluoromethyl)phenyl]carbamoyl}oxy)pentanoyl]amino}acetate; tert-Butyl {Ethyl[(2S)-4-methyl-2-({[4-(trifluoromethyl)phenyl]carbamoyl}oxy)pentanoyl]amino}acetate; (2S)-4-Methyl-1-oxo-1-[(1H-tetrazol-5-ylmethyl)amino]pentan-2-yl (4-bromophenyl)carbamate; (2S)-4-methyl-1-oxo-1-[(1H-tetrazol-5-ylmethyl)amino]pentan-2-yl [4-(trifluoromethyl)phenyl]carbamate; (2S)-4-methyl-1-[methyl(1H-tetrazol-5-ylmethyl)amino]-1-oxopentan-2-yl (4-bromophenyl)carbamate; (2S)-4-methyl-1-[methyl(1H-tetrazol-5-ylmethyl)amino]-1-oxopentan-2-yl [4-(trifluoromethyl)phenyl]carbamate; 2-{[(2S)-4-Methyl-2-({[4-(trifluoromethyl)phenyl]carbamoyl}oxy)pentanoyl]amino}ethyl acetate; {[(2S)-2-{[(4-Bromophenyl)carbamoyl]oxy}-4-methylpentanoyl]amino}acetic acid; {[(2S)-4-Methyl-2-({[4-(trifluoromethyl)phenyl]carbamoyl}oxy)pentanoyl]amino}acetic acid; {[(2S)-2-{[(4-Bromophenyl) carbamoyl]oxy}-4-methylpentanoyl](methyl)amino}acetic acid; {[(2S)-2-{[(4-Bromophenyl)carbamoyl]oxy}-4-methylpentanoyl](propyl)amino}acetic acid; {[(2S)-2-{[(4-Bromophenyl)carbamoyl]oxy}-4-methylpentanoyl](propan-2-yl)amino}acetic acid; {[(2S)-2-{[(4-Bromophenyl) carbamoyl]oxy}-4-methylpentanoyl](ethyl)amino}acetic acid; {Methyl[(2S)-4-methyl-2-({[4-(trifluoromethyl)phenyl]carbamoyl}oxy)pentanoyl]amino}acetic acid; {Ethyl[(2S)-4-methyl-2-({[4-(trifluoromethyl)phenyl]carbamoyl}oxy)pentanoyl]amino}acetic acid; (2S)-4-Methyl-1-{methyl[2-(sulfooxy)ethyl]amino}-1-oxopentan-2-yl (4-bromophenyl) carbamate; ({(2S)-4-methyl-2-[({[4-(trifluoromethyl)phenyl]amino}carbonyl)oxy]pentanoyl}amino)methanesulfonic acid; tert-Butyl [{(2S)-4-methyl-2-[({[4-(trifluoromethyl)phenyl]amino}carbonyl) oxy]pentanoyl}(propyl)amino]acetate; tert-Butyl (isopropyl{(2S)-4-methyl-2-[({[4-(trifluoromethyl)phenyl]amino}carbonyl)oxy]pentanoyl}amino)acetate; (1S)-1-{[ethyl(1H-tetrazol-5-ylmethyl)amino]carbonyl}-3-methylbutyl (4-bromophenyl)carbamate; (1S)-1-{[ethyl(1H-tetrazol-5-ylmethyl)amino]carbonyl}-3-methylbutyl [4-(trifluoromethyl)phenyl]carbamate; (1S)-1-[({2-[(tert-butoxycarbonyl)amino]ethyl}amino)carbonyl]-3-methylbutyl (4-bromophenyl)carbamate; tert-Butyl {[(2S)-2-({[(4-bromophenyl)amino]carbonyl}oxy)-3-phenylpropanoyl]amino}acetate; (1S)-1-benzyl-2-oxo-2-[(1H-tetrazol-5-ylmethyl)amino]ethyl (4-bromophenyl)carbamate; tert-Butyl {[(2S)-2-({[(4-bromophenyl)amino]carbonyl}oxy)-3-phenylpropanoyl](methyl)amino}acetate; [{(2S)-4-methyl-2-[({[4-(trifluoromethyl)phenyl]amino}carbonyl)oxy]pentanoyl}(propyl)amino]acetic acid; (Isopropyl{(2S)-4-methyl-2-[({[4-(trifluoromethyl)phenyl]amino}carbonyl) oxy]pentanoyl}amino)acetic acid; (1S)-1-{[(2-aminoethyl)amino]carbonyl}-3-methylbutyl (4-bromophenyl) carbamate; {[(2S)-2-({[(4-bromophenyl)amino]carbonyl}oxy)-3-phenylpropanoyl]amino}acetic acid; {[(2S)-2-({[(4-Bromophenyl)amino]carbonyl}oxy)-3-phenylpropanoyl](methyl)amino}acetic acid; and (1S)-1-{[(2-{[(Dimethylamino)sulfonyl]amino}ethyl)amino]carbonyl}-3-methylbutyl (4-bromophenyl)carbamate;

(82) and enantiomers, diastereomers and tautomer thereof;

(83) and salts, including pharmaceutically acceptable salts, of any of the foregoing.

(84) In embodiment (13), there is provided a compound selected from the group consisting of:

(85) (S)-tert-Butyl 2-(((4-Bromophenyl)carbamoyl)oxy)-4-methylpentanoate;

(86) (2S)-2-{[(4-Bromophenyl)carbamoyl]oxy}-4-methylpentanoic acid; tert-Butyl (2S)-4-Methyl-2-({[4-(trifluoromethyl)phenyl]carbamoyl}oxy)pentanoate; (2S)-4-Methyl-2-({[4-(Trifluoromethyl)phenyl]carbamoyl}oxy)pentanoic acid; tert-Butyl (2S)-2-({[(4-bromophenyl)amino]carbonyl}oxy)-3-phenyl propanoate; and (2S)-2-({[(4-bromophenyl)amino]carbonyl}oxy)-3-phenylpropanoic acid;
and enantiomers, diastereomers and tautomers thereof;
and salts of the foregoing.

(87) In embodiment (14), there is provided a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound according to any one of embodiments (1) through (13), and a pharmaceutically acceptable adjuvant, diluent or carrier.

(88) In embodiment (15), there is provided a method of treating an ocular inflammatory disease or condition in a subject in need of such treatment, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of embodiments (1) through (13).

(89) In embodiment (16), there is provided the method according to embodiment (15), wherein the ocular inflammatory disease or condition is selected from: uveitis, dry eye, keratitis, allergic eye disease, infectious keratitis, herpetic keratitis, comeal angiogenesis, lymphangiogenesis, retinitis, choroiditis, acute multifocal placoid pigment epitheliopathy, Behcet's disease, post-surgical comeal wound healing, post-cataract surgical inflammation, wet and dry age-related macular degeneration (ARMD).

(90) In embodiment (17), there is provided a method of treating dermal inflammation or a dermal disease in a subject in need of such treatment, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of embodiments (1) through (13).

(91) In embodiment (18), there is provided the method according to embodiment (17), wherein the dermal inflammation or disease is selected from: dermal wound healing, hypertrophic scars, keloids, burns, rosacea, atopic dermatitis, acne, psoriasis, seborrheic dermatitis, actinic keratoses, basal cell carcinoma, squamous cell carcinoma, melanoma, viral warts, photoaging, photodamage, melasma, post-inflammatory hyperpigmentation, disorders of pigmentation and alopecia (scarring and non-scarring forms).

(92) As will be evident to those skilled in the art, individual diastereoisomeric forms can be obtained by separation of mixtures thereof in conventional manner; chromatographic separation may be employed.

(93) Compound names were generated with ACD Labs version 12.5. Some of the intermediate and reagent names used in the examples were generated with software such as Chem Bio Draw Ultra version 12.0 or Auto Nom 2000 from MDL ISIS Draw 2.5 SP1.

(94) In general, characterization of the compounds is performed according to the following methods. NMR spectra are recorded on a 300 or 600 MHz Varian NMR spectrometer and acquired at room temperature. Chemical shifts are given in ppm referenced either to internal TMS or to the solvent signal. Most of the compounds of Formula I were obtained as rotamers.

(95) All the reagents, solvents, catalysts for which the synthesis is not described are purchased from chemical vendors such as Sigma Aldrich, Fluka, Bio-Blocks, Combi-blocks, TCI, VWR, Lancaster, Oakwood, Trans World Chemical, Alfa, Fisher, Maybridge, Frontier, Matrix, Ukrorgsynth, Toronto, Ryan Scientific, SiliCycle, Anaspec, Syn Chem, Chem-Impex, MIC-scientific, Ltd; however, some known intermediates were prepared according to published procedures.

(96) Usually the compounds of the invention were purified by medium pressure liquid chromatography, unless noted otherwise.

Example 1

Intermediate 1

(S)-tert-Butyl 2-(((4-Bromophenyl)carbamoyl)oxy)-4-methylpentanoate

(97) ##STR00005##

(98) To a solution of (2S)-2-hydroxy-4-methyl-pentanoic acid, 1,1-dimethyl ethyl ester (1.10 g, 5.85 mmol) and 25 mL of methylene chloride at 25 C. was added 4-bromo-phenyl isocyanate (1.15 g, 5.85 mmol) and triethylamine (1.22 mL, 8.78 mmol). The resulting mixture was stirred at 25 C. for 4 hours. The mixture was concentrated and the residue was purified by medium pressure liquid chromatography on silica gel using ethyl acetate:hexane (8:92) to yield Intermediate 1 as viscous oil.

(99) .sup.1H NMR (CD.sub.3OD, 300 MHz) : 7.33-7.47 (m, 4H), 4.87 (m, 1H), 1.56-1.91 (m, 1H), 1.47 (s, 9H), 0.93-1.04 (m, 6H).

Intermediate 2

tert-Butyl (2S)-4-Methyl-2-[({[4-(trifluoromethyl)phenyl]carbamoyl}oxy]pentanoate

(100) ##STR00006##

(101) Intermediate 2 was prepared from the corresponding alpha-hydroxy carboxylic acid ester in a similar manner to the procedure described in Example 1 for Intermediate 1. Intermediate 2 was obtained as white solid; .sup.1H NMR (CD.sub.3OD 300 MHz) : 7.52-7.67 (m, 4H), 4.89 (m, 1H), 1.71-1.92 (m, 2H), 1.58-1.70 (m, 1H), 1.47 (s, 9H), 0.98 (t, J=6.2 Hz, 6H).

Example 2

Intermediate 3

(2S)-2-([(4-Bromophenyl)carbamoyl]oxy)-4-methylpentanoic acid

(102) ##STR00007##

(103) A solution of Intermediate 1 (1.53 g, 3.98 mmol) and 20 mL of formic acid was stirred at 25 C. for 5 hours. The resulting mixture was quenched with water (20 mL) then extracted with ethyl acetate. The organic layer was washed with water, brine, dried over Na.sub.2SO.sub.4, filtered, and the filtrate was concentrated under reduced pressure. The residue was rinsed 4 times with methylene chloride:hexane (1:9) to yield Intermediate 3 as white solid; .sup.1H NMR (CD.sub.3OD, 300 MHz) : 7.33-7.45 (m, 4H), 4.94-5.04 (m, 1H), 1.73-1.95 (m, 2H), 1.63-1.73 (m, 1H), 0.98 (dd, J=6.6, 3.7 Hz, 6H).

Intermediate 4

(2S)-4-Methyl-2-[({[4-(trifluoromethyl)phenyl]-carbamoyl}oxy]pentanoic acid

(104) ##STR00008##

(105) Intermediate 4 was prepared from the corresponding carbamate derivative in a similar manner to the procedure described in Example 2 for Intermediate 3. Intermediate 4 was obtained as white solid; .sup.1H NMR (CD.sub.3OD 300 MHz) : 7.60-7.66 (m, 2H), 7.53-7.59 (m, 2H), 5.02 (dd, J=9.2, 3.7 Hz, 1H), 1.76-1.91 (m, 2H), 1.66-1.75 (m, 1H), 0.99 (dd, J=6.3, 3.4 Hz, 6H).

Example 3

Compound 1

tert-Butyl {[(2S)-2-{[(4-Bromophenyl)carbamoyl]oxy}-4-methyl pentanoyl]amino}acetate

(106) ##STR00009##

(107) To a solution of Intermediate 3 (300 mg, 0.911 mmol) and 12 mL of anhydrous DMF at 25 C. was added EDCI (262 mg, 1.37 mmol), HOBt (185 mg, 1.37 mmol), glycine tert-butyl ester (179 mg, 1.37 mmol), and N-methylmorpholine (184 mg, 1.82 mmol). The resulting mixture was stirred at 25 C. for 12 hours. The mixture was quenched with water (5 mL), and the product was extracted with ethyl acetate (40 mL). The layers were separated, and the organic layer was washed with water, brine, dried over Na.sub.2SO.sub.4, filtered, and the filtrate was concentrated under reduced pressure. The resulting product was purified by medium pressure liquid chromatography on silica gel using ethyl acetate:hexane (1:4) to yield Compound 1 as white solid; .sup.1H NMR (CD.sub.3OD, 300 MHz) : 7.34-7.46 (m, 4H), 5.10 (dd, J=9.5, 4.0 Hz, 1H), 3.75-3.94 (m, 2H), 1.73-1.92 (m, 2H), 1.60-1.72 (m, 1H), 1.45 (s, 9H), 0.99 (s, 3H), 0.97 (s, 3H).

(108) Compounds 2, 3, 4, 5, 6, 7 and 8 were prepared from the corresponding carbamate derivative in a similar manner to the procedure described in Example 3 for Compound 1. Specifically, Compounds 3, 4, 7 and 8 were prepared from Intermediate 3, and compounds 2, 5 and 6 were prepared from Intermediate 4. Compounds 2, 3, 4, 5, 6, 7 and 8 were obtained as white solids; their characteristics are described below in Table 1.

(109) TABLE-US-00002 TABLE 1 Comp. IUPAC name number Structure .sup.1H NMR (ppm) 2 tert-Butyl {[(2S)-4-Methyl-2-({[4- .sup.1H NMR (CD.sub.3OD, 300 MHz) : (trifluoromethyl)phenyl] 7.61-7.66 (m, 2H), 7.54- carbamoyl}oxy)pentanoyl]amino} 7.60 (m, 2H), 5.12 (dd, J = 9.8, acetate 3.7 Hz, 1H), 3.75-3.95 (m, 0 2H), 1.75-1.93 (m, 2H), 1.69 (dd, J = 9.5, 4.8 Hz, 1H), 1.45 (s, 9H), 1.00 (s, 3H), 0.98 (s, 3H). 3 tert-Butyl {[(2S)-2-{[(4- .sup.1H NMR (CD.sub.3OD, 300 MHz) : Bromophenyl)carbamoyl]oxy}-4- 7.31-7.47 (m, 4H), 5.42 (d, J = methylpentanoyl](methyl)amino} 10.8 Hz, 1H), 4.19-4.36 (m, acetate 1H), 3.80 (m, 1H), 3.19 (s, 3H), 1.70-1.97 (m, 2H), 1.52- 1.67 (m, 1H), 1.46 (s, 9H), 1.01 (d, J = 5.9 Hz, 6H). 4 (2S)-1-[(2-Hydroxyethyl)(methyl) .sup.1H NMR (CD.sub.3OD, 300 MHz) : amino]-4-methyl-1-oxopentan-2-yl 7.98 (s, NH), 7.30-7.45 (m, (4-bromophenyl)carbamate 4H), 5.30-5.48 (m, 1H), 3.63- 3.86 (m, 2H), 3.36-3.62 (m, 2H), 2.98 (s, 3H), 1.71-1.95 (m, 2H), 1.44-1.62 (m, 1H), 0.94-1.06 (m, 6H). 5 Diethyl ({[(2S)-4-methyl-2-({[4- .sup.1H NMR (CD.sub.3OD, 300 MHz) : (Trifluoromethyl)phenyl] 7.50-7.69 (m, 4H), 5.04- carbamoyl}oxy)pentanoyl]amino} 5.15 (m, 1H), 4.04-4.20 (m, methyl)phosphonate 4H), 3.58-3.87 (m, 2H), 1.72- 1.93 (m, 2H), 1.55-1.69 (m, 1H), 1.22-1.38 (m, 6H), 1.00 (s, 3H), 0.98 (s, 3H). 6 (2S)-1-[(2-Hydroxyethyl)amino]-4- .sup.1H NMR (CD.sub.3OD, 300 MHz) : Methyl-1-oxopentan-2-yl [4- 7.51-7.68 (m, 4H), 5.07 (dd, J = (trifluoromethyl)phenyl]carbamate 9.4, 3.5 Hz, 1H), 3.55-3.66 (m, 2H), 3.32-3.38 (m, 2H), 1.80 (m, 2H), 1.56-1.70 (m, 1H), 0.99 (s, 3H), 0.97 (s, 3H). 7 (2S)-1-[(2-Hydroxyethyl)amino]-4- .sup.1H NMR (CD.sub.3OD, 300 MHz) : methyl-1-oxopentan-2-yl (4- 7.32-7.46 (m, 4H), 5.05 (dd, J = bromophenyl)carbamate 9.7, 3.5 Hz, 1H), 3.54-3.65 (m, 2H), 3.32-3.38 (m, 2H), 1.70-1.90 (m, 2H), 1.56- 1.69 (m, 1H), 0.98 (s, 3H), 0.96 (s, 3H). 8 Diethyl ({[(2S)-2-{[(4- .sup.1H NMR (CD.sub.3OD, 300 MHz) : bromophenyl)carbamoyl]oxy}-4- 8.35 (br. s., NH), 7.33-7.46 methylpentanoyl]amino}methyl) (m, 4H), 5.01-5.12 (m, 1H), phosphonate 4.04-4.22 (m, 4H), 3.59- 3.89 (m, 2H), 1.69-1.92 (m, 2H), 1.55-1.67 (m, 1H), 1.24- 1.35 (m, 6H), 0.99 (s, 3H), 0.97 (s, 3H).

Example 4

Compound 9

tert-Butyl {[(2S)-2-{[(4-Bromophenyl)carbamoyl]oxy}-4-methylpentanoyl](propyl)amino}acetate

(110) ##STR00017##

(111) A solution of Intermediate 3 (170 mg, 0.52 mmol), DCC (106 mg, 0.52 mmol) and 14 mL of anhydrous dichloromethane was stirred at 25 C. for 12 hours. The mixture was filtered. The filtrate was quenched with 10% HCl (5 mL), and the product was extracted with ethyl acetate (20 mL). The layers were separated, and the organic layer was washed with water, brine, dried over Na.sub.2SO.sub.4, filtered, and the filtrate was concentrated under reduced pressure. The resulting product was purified by medium pressure liquid chromatography on silica gel using ethyl acetate:hexane (15:85) to yield Compound 9 as a white solid; .sup.1H NMR (CD.sub.3OD, 300 MHz) : 7.30-7.47 (m, 4H), 5.39 (d, J=11.1 Hz, 1H), 4.19 (d, J=17.0 Hz, 1H), 3.75 (d, J=17.0 Hz, 1H), 3.38 (t, J=7.5 Hz, 2H), 1.66-1.95 (m, 3H), 1.52-1.64 (m, 2H), 1.44 (s, 9H), 0.91-1.07 (m, 9H).

(112) Compounds 10, 11, 12, 13, 14, 15, 16 and 17 were prepared from the corresponding carbamate derivative in a similar manner to the procedure described in Example 4 for Compound 9. Specifically, Compounds 10, 11, 14 and 16 were prepared from Intermediate 3, and Compounds 12, 13, 15 and 17 were prepared from Intermediate 4. Compound 10, 11, 12, 13, 14, 15, 16 and 17 were each obtained as a white solid; their characteristics are described below in Table 2.

(113) TABLE-US-00003 TABLE 2 Cmpd. IUPAC name number Structure .sup.1H NMR (ppm) 10 tert-Butyl {[(2S)-2-{[(4- .sup.1H NMR (CD.sub.3OD, 300 MHz) : Bromophenyl)carbamoyl]oxy}-4- 7.31-7.44 (m, 4H), 5.46 (d, J = methylpentanoyl](propan-2- 9.1 Hz, 1H), 4.19-4.36 (m, yl)amino}acetate 1H), 3.94-4.04 (m, 1H), 3.67- 3.79 (m, 1H), 1.75-1.94 (m, 2H), 1.58 (m, 1H), 1.43 (s, 9H), 1.21-1.34 (m, 6H), 0.94- 1.05 (m, 6H). 11 tert-Butyl {[(2S)-2-{[(4- .sup.1H NMR (CD.sub.3OD, 300 MHz) : Bromophenyl)carbamoyl]oxy}-4- 7.38 (s, 4H), 5.39 (d, J = 10.3 Hz, methylpentanoyl](ethyl)amino} 1H), 4.19 (d, J = 17.0 Hz, acetate 1H), 3.75 (d, J = 16.7 Hz, 1H), 3.42-3.58 (m, 2H), 1.76- 1.95 (m, 2H), 1.53-1.66 (m, 1H), 1.45 (s, 9H), 1.23-1.37 (m, 3H), 0.93-1.06 (m, 6H). 12 tert-Butyl {Methyl[(2S)-4-methyl-2- .sup.1H NMR (CD.sub.3OD, 300 MHz) : ({[4-(trifluoromethyl)phenyl] 7.48-7.68 (m, 4H), 5.44 (d, J = carbamoyl}oxy)pentanoyl]amino} 8.2 Hz, 1H), 4.31 (s, 1H), acetate 3.79 (d, J = 17.3 Hz, 1H), 3.21 0 (s, 3H), 1.74-1.97 (m, 2H), 1.54-1.68 (m, 1H), 1.46 (s, 9H), 0.91-1.07 (m, 6H). 13 tert-Butyl {Ethyl[(2S)-4-methyl-2- .sup.1H NMR (CD.sub.3OD, 300 MHz) : ({[4-(trifluoromethyl)phenyl] 7.49-7.69 (m, 4H), 5.43 (s, carbamoyl}oxy)pentanoyl]amino} 1H), 4.56 (d, J = 18.2 Hz, 1H), acetate 4.20 (d, J = 17.0 Hz, 1H), 3.69- 3.85 (m, 1H), 3.42-3.61 (m, 2H), 1.76-2.01 (m, 2H), 1.53- 1.70 (m, 1H), 1.45 (s, 9H), 1.23-1.37 (m, 3H), 0.95- 1.07 (m, 6H). 14 (2S)-4-Methyl-1-oxo-1-[(1H- .sup.1H NMR (CD.sub.3OD, tetrazol-5-ylmethyl)amino]pentan- 300 MHz) : 7.33-7.47 (m, 2-yl (4-bromophenyl)carbamate 4H), 5.03-5.14 (m, 1H), 4.70 (s, 2H), 1.72-1.90 (m, 2H), 1.66 (m, 1H), 0.98 (s, 3H), 0.96 (s, 3H). 15 (2S)-4-methyl-1-oxo-1-[(1H- .sup.1H NMR (CD.sub.3OD, tetrazol-5-ylmethyl)amino]pentan- 300 MHz) : 7.98 (s, NH), 7.60 2-yl [4- (m, 4H), 5.12 (dd, J = 9.7, 3.2 Hz, (trifluoromethyl)phenyl]carbamate 1H), 4.70 (s, 2H), 1.81 (m, 2H), 1.57-1.74 (m, 1H), 0.98 (s, 3H), 0.96 (s, 3H). 16 (2S)-4-methyl-1-[methyl(1H- .sup.1H NMR (CD.sub.3OD, tetrazol-5-ylmethyl)amino]-1- 300 MHz) : 7.98 (s, NH), 7.29- oxopentan-2-yl (4- 7.46 (m, 4H), 5.36 (d, J = bromophenyl)carbamate 10.3 Hz, 1H), 4.73-5.04 (m, 2H), 2.99 (s, 3H), 1.60-1.97 (m, 2H), 1.25-1.47 (m, 1H), 0.95-1.08 (m, 6H). 17 (2S)-4-methyl-1-[methyl(1H- .sup.1H NMR (CD.sub.3OD, tetrazol-5-ylmethyl)amino]-1- 300 MHz) : 7.98 (s, NH), 7.50- oxopentan-2-yl [4- 7.67 (m, 4H), 5.35-5.46 (m, (trifluoromethyl)phenyl]carbamate 1H), 4.94-5.04 (m, 1H), 4.73- 4.88 (m, 1H), 2.99 (s, 3H), 1.53-1.97 (m, 2H), 1.13- 1.46 (m, 1H), 0.91-1.06 (m, 6H).

Example 5

Compound 18

2-{[(2S)-4-Methyl-2-({[4-(trifluoromethyl)phenyl]carbamoyl}oxy)pentanoyl]amino}ethyl acetate

(114) ##STR00026##

(115) A solution of Compound 6 (50 mg, 0.14 mmol), 4 mL of anhydrous THF and acetic anhydride (0.014 mL, 0.15 mmol) was stirred at 25 C. for 1 hour. The mixture was concentrated and the resulting product was purified by medium pressure liquid chromatography on silica gel using ethyl acetate:hexane (4:6) to yield Compound 18 as clear oil; .sup.1H NMR (CD.sub.3OD, 300 MHz) : 7.51-7.70 (m, 4H), 5.04 (dd, J=9.1, 3.3 Hz, 1H), 4.05-4.21 (m, 2H), 3.47 (m, 2H), 1.99 (s, 3H), 1.71-1.90 (m, 2H), 1.63 (m, 1H), 0.99 (s, 3H), 0.97 (s, 3H).

Example 6

Compound 19

{[(2S)-2-{[(4-Bromophenyl)carbamoyl]oxy)}-4-methylpentanoyl]amino}acetic acid

(116) ##STR00027##

(117) A solution of Compound 1 (368 mg, 0.83 mmol) and 8 mL of formic acid was stirred at 25 C. for 12 hours. The resulting reaction was quenched with water (10 mL), and the product was extracted with EtOAc. The organic layer was washed with water, brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The residue was rinsed four times with acetone:hexane (1:99) to yield Compound 19 as a white solid; .sup.1H NMR (CD.sub.3OD, 300 MHz) : 8.26 (s, 1H), 7.33-7.45 (m, 4H), 5.06-5.17 (m, 1H), 3.84-4.04 (m, 2H), 1.74-1.90 (m, 2H), 1.63-1.74 (m, 1H), 0.99 (s, 3H), 0.97 (s, 3H).

(118) Compounds 20, 21, 22, 23, 24, 25 and 26 were prepared from the corresponding ester derivative in a similar manner to the procedure described in Example 6 for Compound 19. Specifically, Compound 20 was prepared from Compound 2; Compound 21 was prepared from Compound 3; Compound 22 was prepared from Compound 9; Compound 23 was prepared from Compound 10; Compound 24 was prepared from Compound 11; Compound 25 was prepared from Compound 12; and Compound 26 was prepared from Compound 13. Compounds 20, 21, 22, 23, 24, 25 and 26 obtained as white solids; their characteristics are described below in Table 3.

(119) TABLE-US-00004 TABLE 3 Cmpd IUPAC name No. Structure .sup.1H NMR (ppm) 20 {[(2S)-4-Methyl-2-({[4- .sup.1H NMR (CD.sub.3OD, 300 MHz) : (trifluoromethyl)phenyl] 8.31 (br. s., NH), 7.61-7.66 (m, carbamoyl}oxy)pentanoyl] 2H), 7.54-7.60 (m, 2H), 5.14 amino}acetic acid (dd, J = 9.7, 3.5 Hz, 1H), 3.87- 4.02 (m, 2H), 1.76-1.91 (m, 2H), 1.63-1.75 (m, 1H), 1.00 (s, 3H), 0.98 (s, 3H). 21 {[(2S)-2-{[(4-Bromophenyl) .sup.1H NMR (CD.sub.3OD, 300 MHz) : carbamoyl]oxy}-4- 7.28-7.45 (m, 4H), 5.43 (d, J = methylpentanoyl](methyl)amino} 7.6 Hz, 1H), 4.44 (m, 1H), 3.83 acetic acid (d, J = 17.3 Hz, 1H), 3.21 (s, 3H), 1.72-1.99 (m, 2H), 1.48-1.68 (m, 1H), 1.02 (d, J = 1.8 Hz, 6H). 22 {[(2S)-2-{[(4- .sup.1H NMR (CD.sub.3OD, 300 MHz) : Bromophenyl)carbamoyl]oxy}-4- 7.31-7.47 (m, 4H), 5.39 (d, J = methylpentanoyl](propyl)amino} 10.3 Hz, 1H), 4.34 (d, J = 17.3 Hz, acetic acid 1H), 3.80 (d, J = 17.3 Hz, 0 1H), 3.35-3.51 (m, 2H), 1.68- 1.97 (m, 3H), 1.50-1.66 (m, 2H), 0.91-1.09 (m, 9H). 23 {[(2S)-2-{[(4- .sup.1H NMR (CD.sub.3OD, 300 MHz) : Bromophenyl)carbamoyl]oxy}-4- 7.30-7.45 (m, 4H), 5.46 (dd, J = methylpentanoyl](propan-2- 10.0, 3.2 Hz, 1H), 4.28 (quin, J = yl)amino}acetic acid 6.6 Hz, 1H), 4.02-4.16 (m, 1H), 3.82 (d, J = 17.3 Hz, 1H), 1.72- 1.98 (m, 2H), 1.48-1.65 (m, 1H), 1.20-1.37 (m, 6H), 0.93-1.03 (m, 6H 24 {[(2S)-2-{[(4-Bromophenyl) .sup.1H NMR (CD.sub.3OD, 300 MHz) : carbamoyl]oxy}-4- 7.38 (m, 4H), 5.40 (d, J = 10.3 Hz, methylpentanoyl](ethyl)amino} 1H), 4.33 (d, J = 16.7 Hz, acetic acid 1H), 3.73 (d, J = 16.4 Hz, 1H), 3.38-3.66 (m, 2H), 1.71-1.97 (m, 2H), 1.53-1.69 (m, 1H), 1.22- 1.36 (m, 3H), 0.87-1.05 (m, 6H). 25 {Methyl[(2S)-4-methyl-2-({[4- .sup.1H NMR (CD.sub.3OD, 300 MHz) : (trifluoromethyl)phenyl] 7.49-7.69 (m, 4H), 5.46 (d, J = carbamoyl}oxy)pentanoyl]amino} 10.3 Hz, 1H), 4.44 (s, 1H), 3.81 acetic acid (d, J = 17.3 Hz, 1H), 3.21 (s, 3H), 1.71-1.98 (m, 2H), 1.50-1.71 (m, 1H), 0.91-1.07 (m, 6H). 26 {Ethyl[(2S)-4-methyl-2-({[4- .sup.1H NMR (CD.sub.3OD, 300 MHz) : (trifluoromethyl)phenyl] 7.48-7.68 (m, 4H), 5.42 (d, carbamoyl}oxy)pentanoyl]amino} J = 10.84 Hz, 1H), 4.34 (d, acetic acid J = 17.29 Hz, 1H), 3.82 (d, J = 17.29 Hz, 1H), 3.41-3.65 (m, 2H), 1.74-2.00 (m, 2H), 1.51- 1.69 (m, 1H), 1.24-1.38 (m, 3H), 0.86-1.06 (m, 6H).

Example 7

Compound 27

(2S)-4-Methyl-1-{methyl[2-(sulfooxy)ethyl]amino}-1-oxopentan-2-yl (4-bromophenyl)carbamate

(120) ##STR00035##

(121) To a solution of Compound 4 (166 mg, 0.42 mmol) and 8 mL of anhydrous THF at 25 C. under argon was added Et.sub.3N (0.12 mL, 0.84 mmol), DMAP (56 mg, 0.42 mmol), and 2,2,2-trichloroethyl chlorosulfate (205 mg, 0.84 mmol). The resulting mixture was stirred at 25 C. for 12 hours. The mixture was quenched with 10% HCl (2 mL), and the product was extracted with ethyl acetate (20 mL). The layers were separated, and the organic layer was washed with water, brine, dried over Na.sub.2SO.sub.4, filtered, and the filtrate was concentrated under reduced pressure. The resulting product was purified by medium pressure liquid chromatography on silica gel using methanol:dichloromethane (15:85) to yield Compound 27 as an off white solid; .sup.1H NMR (CD.sub.3OD, 300 MHz) : 7.38 (s, 4H), 5.32-5.44 (m, 1H), 4.08-4.28 (m, 2H), 3.39-3.67 (m, 2H), 3.25 (s, 3H), 1.71-1.96 (m, 2H), 1.50-1.70 (m, 1H), 1.00 (d, J=5.0 Hz, 6H).

Example 8

Compound 28

({(2S)-4-methyl-2-[({[4-(trifluoromethyl)phenyl]amino}carbonyl)oxy]pentanoyl}amino)methanesulfonic acid

(122) ##STR00036##

(123) To a solution of Intermediate 4 (750 mg, 2.35 mmol) and 10 mL of DMF at 25 C. was added aminomethane sulfonic acid (260 mg, 2.35 mmol), HATU (983 mg, 2.58 mmol) and diisopropylethylamine (0.49 mL, 2.82 mmol). The resulting mixture was stirred at 100 C. for 12 hours. The mixture was concentrated and quenched with water (4 mL), and the product was extracted with ethyl acetate (20 mL). The layers were separated, and the organic layer was washed with water, brine, dried over Na.sub.2SO.sub.4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by medium pressure liquid chromatography on silica gel using methanol:dichloromethane (15:85) to yield Compound 28 as a white solid; .sup.1H NMR (CD.sub.3OD, 300 MHz) : 7.51-7.69 (m, 4H), 5.18 (dd, J=9.2, 3.7 Hz, 1H), 4.22-4.48 (m, 2H), 1.68-1.91 (m, 3H), 0.99 (s, 3H), 0.98 (s, 3H).

Example 9

Intermediate 2a

tert-Butyl (2S)-2-({[(4-bromophenyl)amino]carbonyl}oxy)-3-phenyl propanoate

(124) ##STR00037##

(125) Intermediate 2a was prepared from the corresponding amino acid in a similar manner to the procedure described in Example 1 for Intermediate 1. Intermediate 2a was obtained as clear oil; []D=13.7, (c=1.00, MeOH); .sup.1H NMR (CD.sub.3OD, 300 MHz) : 7.16-7.45 (m, 8H), 5.07 (dd, J=7.3, 5.6 Hz, 1H), 3.09-3.17 (m, 2H), 1.35-1.42 (m, 9H).

Intermediate 4a

(2S)-2-({[(4-bromophenyl)amino]carbonyl}oxy)-3-phenylpropanoic acid

(126) ##STR00038##

(127) Intermediate 4a was prepared from the corresponding carbamate derivative in a similar manner to the procedure described in Example 2 for Intermediate 3. Intermediate 4a was obtained as white solid; []D=13.3, c=1.00, MeOH; .sup.1H NMR (CD.sub.3OD, 300 MHz) : 7.15-7.42 (m, 8H), 5.20 (s, 1H), 3.19-3.30 (m, 1H), 3.05-3.17 (m, 1H).

(128) Compounds 29, 30, 31, 32, 33, 34, 35 and 36 were prepared from the corresponding carbamate derivative in a similar manner to the procedure described in Example 4 for Compound 9. Specifically, Compounds 29, 30 and 32 were obtained from Intermediate 4; Compounds 31 and 33 were obtained from Intermediate 3; and Compounds 34, 35 and 36 were obtained from Intermediate 4a. The characteristics of the compounds so obtained are described below.

Compound 29

tert-Butyl [{(2S)-4-methyl-2-[({[4-(trifluoromethyl)phenyl]amino}carbonyl) oxy]pentanoyl}(propyl)amino]acetate

(129) ##STR00039##

(130) White solid; []D=18.6 (c=1.00, MeOH); .sup.1H NMR (CD.sub.3OD, 300 MHz) : 7.49-7.69 (m, 4H), 5.41 (d, J=10.3 Hz, 1H), 4.20 (d, J=17.3 Hz, 1H), 3.76 (d, J=16.7 Hz, 1H), 3.36-3.45 (m, 1H), 1.83 (m, 3H), 1.56 (m, 2H), 1.45 (s, 9H), 0.88-1.09 (m, 9H); the .sup.1H NMR spectrum showed the existence of rotomers.

Compound 30

tert-Butyl (Isopropyl{(2S)-4-methyl-2-[({[4-(trifluoromethyl)phenyl]amino}carbonyl)oxy]pentanoyl}amino)acetate

(131) ##STR00040##

(132) White solid; []D=22.3 (c=1.00, MeOH); .sup.1H NMR (CD.sub.3OD, 300 MHz) : 7.51-7.67 (m, 4H), 5.49 (d, J=10.0 Hz, 1H), 4.20-4.35 (m, 1H), 3.89-4.05 (m, 1H), 3.69-3.80 (m, 1H), 1.77-1.98 (m, 2H), 1.54-1.68 (m, 1H), 1.44 (s, 9H), 1.21-1.35 (m, 6H), 0.91-1.06 (m, 6H); the .sup.1H NMR spectrum showed the existence of rotomers.

Compound 31

(1S)-1-{[ethyl(1H-tetrazol-5-ylmethyl)amino]carbonyl}-3-methybutyl (4-bromophenyl)carbamate

(133) ##STR00041##

(134) White solid; []D=12.6 (c=1.00, MeOH); .sup.1H NMR (CD.sub.3OD, 300 MHz) : 7.27-7.47 (m, 4H), 5.34 (m, 1H), 5.00 (d, J=15.8 Hz, 1H), 4.70 (d, J=15.8 Hz, 1H), 3.54-3.71 (m, 2H), 1.72-1.96 (m, 2H), 1.54 (m, 1H), 1.35 (t, J=7.2 Hz, 3H), 0.90-1.07 (m, 6H); the .sup.1H NMR spectrum showed the existence of rotomers.

Compound 32

(1S)-1-{[ethyl(1H-tetrazol-5-ylmethyl)amino]carbonyl}-3-methylbutyl [4-(trifluoromethyl)phenyl]carbamate

(135) ##STR00042##

(136) White solid; []D=9.1 (c=1.00, MeOH); .sup.1H NMR (CD.sub.3OD, 300 MHz) : 7.51-7.69 (m, 4H), 7.43 (s, NH), 5.28-5.44 (m, 1H), 5.08 (d, J=14.9 Hz, 1H), 4.56-4.69 (m, 1H), 3.48-3.64 (m, 1H), 1.70-1.98 (m, 2H), 1.58 (m, 1H), 1.23-1.42 (m, 3H), 0.93-1.07 (m, 6H); the .sup.1H NMR spectrum showed the existence of rotomers.

Compound 33

(1S)-1-({2-[(tert-butoxycarbonyl)amino]ethyl}amino)carbonyl-3-methylbutyl (4-bromophenyl)carbamate

(137) ##STR00043##

(138) White solid; []D=12.4 (c=1.00, MeOH); .sup.1H NMR (CD.sub.3OD, 300 MHz) : 7.40 (s, 4H), 4.94-5.06 (m, 1H), 3.24-3.31 (m, 2H), 3.17 (m, 2H), 1.79 (m, 2H), 1.55-1.69 (m, 2H), 1.40 (s, 9H), 0.97 (d, J=6.4 Hz, 6H).

Compound 34

tert-Butyl {[(2S)-2-({[(4-bromophenyl)amino]carbonyl}oxy)-3-phenylpropanoyl]amino}acetate

(139) ##STR00044##

(140) White solid; []D=23.0 (c=1.00, MeOH); .sup.1H NMR (CD.sub.3OD, 300 MHz) : 7.15-7.43 (m, 8H), 5.27 (s, 1H), 3.84 (d, J=7.6 Hz, 2H), 3.02-3.29 (m, 2H), 1.46 (s, 9H).

Compound 35

(1S)-1-benzyl-2-oxo-2-[(1H-tetrazol-5-ylmethyl)amino]ethyl (4-bromophenyl)carbamate

(141) ##STR00045##

(142) Off white solid; .sup.1H NMR (CD.sub.3OD, 300 MHz) : 7.18-7.41 (m, 9H), 5.22 (m., 1H), 4.66-4.85 (m, 2H), 3.15-3.26 (m, 2H).

Compound 36

tert-Butyl {[(2S)-2-({[(4-bromophenyl)amino]carbonyl})oxy)-3-phenylpropanoyl](methyl)amino}acetate

(143) ##STR00046##

(144) White solid; []D=18.3 (c=1.00, MeOH); .sup.1H NMR (CD.sub.3OD, 300 MHz) : 7.20-7.45 (m, 9H), 5.57 (dd, J=8.4, 5.4 Hz, 1H), 4.02-4.15 (m, 2H), 3.18 (m, 2H), 3.16 (S, 3H), 1.40-1.53 (m, 9H).

(145) Compounds 37, 38, 39, 40 and 41 were prepared from the corresponding ester derivative in a similar manner to the procedure described in Example 6 for Compound 19. Specifically, Compound 37 was obtained from Compound 29; Compound 38 was obtained from Compound 30; Compound 39 was obtained from Compound 33; Compound 40 was obtained from Compound 34; and Compound 41 was obtained from Compound 36. The characteristics of the compounds so obtained are described below.

Compound 37

[{(2S)-4-methyl-2-[({[4-(trifluoromethyl)phenyl]amino}carbonyl)oxy]pentanoyl}propyl)amino]acetic acid

(146) ##STR00047##

(147) White solid; []D=10.3 (c=1.00, MeOH); .sup.1H NMR (CD.sub.3OD, 300 MHz) : 7.49-7.68 (m, 4H), 5.42 (d, J=10.8 Hz, 1H), 4.34 (d, J=17.3 Hz, 1H), 3.81 (d, J=17.3 Hz, 1H), 3.36-3.57 (m, 1H), 1.62-1.98 (m, 3H), 1.61-1.48 (m, 2H), 0.81-1.08 (m, 9H); the .sup.1H NMR spectrum showed the existence of rotomers.

Compound 38

(Isopropyl{(2S)-4-methyl-2-[({[4-(trifluoromethyl)phenyl]amino}carbonyl) oxy]pentanoyl}amino)acetic acid

(148) ##STR00048##

(149) White solid; []D=9.5 (c=1.00, MeOH); .sup.1H NMR (CD.sub.3OD, 300 MHz) : 7.47-7.68 (m, 4H), 5.50 (d, J=9.7 Hz, 1H), 4.20-4.41 (m, 1H), 3.96-4.17 (m, 1H), 3.82 (d, J=17.3 Hz, 1H), 1.73-2.03 (m, 2H), 1.61 (m, 1H), 1.29 (m, 6H), 0.83-1.16 (m, 6H); the .sup.1H NMR spectrum showed the existence of rotomers.

Compound 39

(1S)-1-{[(2-aminoethyl)amino]carbonyl}-3-methylbutyl (4-bromophenyl) carbamate

(150) ##STR00049##

(151) White solid; []D=9.8 (c=1.00, MeOH); .sup.1H NMR (CD.sub.3OD, 300 MHz) : 7.32-7.47 (m, 4H), 4.94-5.03 (m, 1H), 3.48 (m, 2H), 2.99-3.10 (m, 2H), 1.54-1.90 (m, 3H), 0.94-1.02 (m, 6H).

Compound 40

{[(2S)-2-({[(4-bromophenyl)amino]carbonyl})oxy)-3-phenylpropanoyl]amino}acetic acid

(152) ##STR00050##

(153) White solid; []D=13.1 (c=1.00, MeOH); .sup.1H NMR (CD.sub.3OD, 300 MHz) : 7.15-7.43 (m, 8H), 5.30 (dd, J=8.6, 4.2 Hz, 1H), 3.84-4.02 (m, 2H), 3.01-3.29 (m, 2H).

Compound 41

{[(2S)-2-({[(4-Bromophenyl)amino]carbonyl}oxy)-3-phenylpropanoyl](methyl)amino}acetic acid

(154) ##STR00051##

(155) White solid; []D=16.1 (c=1.00, MeOH); .sup.1H NMR (CD.sub.3OD, 300 MHz) : 7.21-7.40 (m, 9H), 5.58 (dd, J=8.5, 5.3 Hz, 1H), 4.28 (d, J=17.3 Hz, 1H), 3.91 (d, J=17.3 Hz, 1H), 3.03-3.21 (m, 5H).

Compound 42

(1S)-1-{[(2-{[(Dimethylamino)sulfonyl]amino}ethyl)amino]carbonyl}-3-methylbutyl (4-bromophenyl)carbamate

(156) ##STR00052##

(157) A solution of Compound 39 (78 mg, 0.19 mmol) in 14 mL of anhydrous THF, N,N-dimethylsulfomoyl chloride (33 mg, 0.23 mmol) and Et.sub.3N (48 mg, 0.48 mmol) 14 mL was stirred at 25 C. for 12 hours. The mixture was quenched with water (2 mL), extracted with ethyl acetate (10 mL). The organic layer was washed with water, brine, dried over Na.sub.2SO.sub.4, filtered, and the filtrate was concentrated under reduced pressure. The resulting product was purified by medium pressure liquid chromatography on silica gel using ethyl acetate:hexane (8:2) to yield Compound 42 as white solid; .sup.1H NMR (CD3OD, 600 MHz) : 7.32-7.47 (m, 4H), 4.97-5.07 (m, 1H), 3.32 (m, 2H), 3.07-3.19 (m, 2H), 1.73-1.89 (m, 2H), 1.64 (m, 1H), 0.97 (d, J=6.2 Hz, 6H).

(158) ##STR00053##

Biological Data

(159) Biological activity of compounds according to Formula I is set forth in Table 4 below. CHO-G16 cells stably expressing FPR2 were cultured in (F12, 10% FBS, 1% PSA, 400 g/ml geneticin and 50 g/ml hygromycin) and HEK-Gqi5 cells stable expressing FPR1 were cultured in (DMEM high glucose, 10% FBS, 1% PSA, 400 g/ml geneticin and 50 g/ml hygromycin). In general, the day before the experiment, 18,000 cells/well were plated in a 384-well clear bottom poly-D-lysine coated plate. The following day the screening compound-induced calcium activity was assayed on the FLIPR.sup.Tetra. The drug plates were prepared in 384-well microplates using the EP3 and the MultiPROBE robotic liquid handling systems. Compounds were tested at concentrations ranging from 0.61 to 10,000 nM. Results are expressed as EC.sub.50 (nM) and % efficacy values.

(160) TABLE-US-00005 TABLE 4 FPR2 G16- CHO Compound Structure/ EC.sub.50 No. IUPAC name (% eff) 1 526 nM (0.89) tert-Butyl {[(2S)-2-{[(4-Bromophenyl)carbamoyl]oxy}-4- methyl pentanoyl]amino}acetate 2 2017 nM (1.12) tert-Butyl {[(2S)-4-Methyl-2-({[4-(trifluoromethyl)phenyl] carbamoyl}oxy)pentanoyl]amino}acetate 3 109 nM (1.01) tert-Butyl {[(2S)-2-{[(4-Bromophenyl)carbamoyl]oxy}-4- methylpentanoyl](methyl)amino}acetate 4 59 nM (0.97) (2S)-1-[(2-Hydroxyethyl)(methyl)amino]-4-methyl-1- oxopentan-2-yl (4-bromophenyl)carbamate 5 6.7 nM (1.01) Diethyl ({[(2S)-4-methyl-2-({[4-(Trifluoromethyl)phenyl] carbamoyl}oxy)pentanoyl]amino}methyl)phosphonate 6 146 nM (0.75) (2S)-1-[(2-Hydroxyethyl)amino]-4-Methyl-1-oxopentan-2-yl [4-(trifluoromethyl)phenyl]carbamate 7 0 35 nM (0.98) (2S)-1-[(2-Hydroxyethyl)amino]-4-methyl-1-oxopentan-2-yl (4-bromophenyl)carbamate 8 1.8 nM (1.00) Diethyl ({[(2S)-2-{[(4-bromophenyl)carbamoyl]oxy}-4- methylpentanoyl]amino}methyl)phosphonate 9 4.4 nM (1.04) tert-Butyl {[(2S)-2-{[(4-Bromophenyl)carbamoyl]oxy}-4- methylpentanoyl](propyl)amino}acetate 10 11 nM (1.03) tert-Butyl {[(2S)-2-{[(4-Bromophenyl)carbamoyl]oxy}-4- methylpentanoyl](propan-2-yl)amino}acetate 11 8.0 nM (0.97) tert-Butyl {[(2S)-2-{[(4-Bromophenyl)carbamoyl]oxy}-4- methylpentanoyl](ethyl)amino}acetate 12 24.8 nM (1.00) tert-Butyl {Methyl[(2S)-4-methyl-2-({[4- (trifluoromethyl)phenyl] carbamoyl}oxy)pentanoyl]amino}acetate 13 16.6 nM (0.99) tert-Butyl {Ethyl[(2S)-4-methyl-2-({[4- (trifluoromethyl)phenyl] carbamoyl}oxy)pentanoyl]amino}acetate 14 1.3 nM (1.01) (2S)-4-Methyl-1-oxo-1-[(1H-tetrazol-5- ylmethyl)amino]pentan-2-yl (4-bromophenyl)carbamate 15 3.6 nM (0.96) (2S)-4-methyl-1-oxo-1-[(1H-tetrazol-5- ylmethyl)amino]pentan-2-yl [4- (trifluoromethyl)phenyl]carbamate 16 0.81 nM (0.98) (2S)-4-methyl-1-[methyl(1H-tetrazol-5-ylmethyl)amino]-1- oxopentan-2-yl (4-bromophenyl)carbamate 17 0 2.4 nM (0.91) (2S)-4-methyl-1-[methyl(1H-tetrazol-5-ylmethyl)amino]-1- oxopentan-2-yl [4-(trifluoromethyl)phenyl]carbamate 18 195 nM (0.89) 2-{[(2S)-4-Methyl-2-({[4-(trifluoromethyl)phenyl] carbamoyl}oxy)pentanoyl]amino}ethyl acetate 19 0.84 nM (1.01) {[(2S)-2-{[(4-Bromophenyl)carbamoyl]oxy}-4- methylpentanoyl]amino}acetic acid 20 3.9 nM (0.99) {[(2S)-4-Methyl-2-({[4-(trifluoromethyl)phenyl] carbamoyl}oxy)pentanoyl]amino}acetic acid 21 0.25 nM (1.06) {[(2S)-2-{[(4-Bromophenyl)carbamoyl]oxy}-4- methylpentanoyl](methyl)amino}acetic acid 22 0.44 nM (0.91) {[(2S)-2-{[(4-Bromophenyl)carbamoyl]oxy}-4- methylpentanoyl](propyl)amino}acetic acid 23 0.32 nM (1.05) {[(2S)-2-{[(4-Bromophenyl)carbamoyl]oxy}-4- methylpentanoyl](propan-2-yl)amino}acetic acid 24 0.24 nM (0.95) {[(2S)-2-{[(4-Bromophenyl)carbamoyl]oxy}-4- methylpentanoyl](ethyl)amino}acetic acid 25 0.94 nM (0.97) {Methyl[(2S)-4-methyl-2-({[4- (trifluoromethyl)phenyl]carbamoyl}oxy)pentanoyl] amino}acetic acid 26 0.29 nM (0.98) {Ethyl[(2S)-4-methyl-2-({[4- (trifluoromethyl)phenyl]carbamoyl}oxy)pentanoyl] amino}acetic acid 27 0 8.7 nM (0.99) (2S)-4-Methyl-1-{methyl[2-(sulfooxy)ethyl]amino}-1- oxopentan-2-yl (4-bromophenyl)carbamate 28 4.3 nM (0.85) ({(2S)-4-methyl-2-[({[4- (trifluoromethyl)phenyl]amino}carbonyl)oxy] pentanoyl}amino)methanesulfonic acid 29 11.4 nM (1.01) tert-Butyl [{(2S)-4-methyl-2-[({[4- (trifluoromethyl)phenyl]amino}carbonyl) oxy]pentanoyl}(propyl)amino]acetate 30 301 nM (0.76) tert-Butyl (isopropyl{(2S)-4-methyl-2-[({[4- (trifluoromethyl)phenyl] amino}carbonyl)oxy]pentanoyl}amino)acetate 31 0.30 nM (0.95) (1S)-1-{[ethyl(1H-tetrazol-5-ylmethyl)amino]carbonyl}-3- methylbutyl (4-bromophenyl)carbamate 32 0.66 nM (1.00) (1S)-1-{[ethyl(1H-tetrazol-5-ylmethyl)amino]carbonyl}-3- methylbutyl [4-(trifluoromethyl)phenyl]carbamate 33 397 nM (1.03) (1S)-1-[({2-[(tert- butoxycarbonyl)amino]ethyl}amino)carbonyl]-3-methylbutyl (4-bromophenyl)carbamate 34 106 nM (1.03) tert-Butyl {[(2S)-2-({[(4-bromophenyl)amino]carbonyl}oxy)- 3-phenylpropanoyl]amino}acetate 35 0.83 nM (1.03) (1S)-1-benzyl-2-oxo-2-[(1H-tetrazol-5-ylmethyl)amino]ethyl (4-bromophenyl)carbamate 36 11.7 nM (1.05) tert-Butyl {[(2S)-2-({[(4-bromophenyl)amino]carbonyl}oxy)- 3-phenylpropanoyl](methyl)amino}acetate 37 0 1.2 nM (1.02) [{(2S)-4-methyl-2-[({[4- (trifluoromethyl)phenyl]amino}carbonyl)oxy] pentanoyl}(propyl)amino]acetic acid 38 0.66 nM (1.07) (Isopropyl{(2S)-4-methyl-2-[({[4- (trifluoromethyl)phenyl]amino}carbonyl) oxy]pentanoyl}amino)acetic acid 39 78 nM (0.89) (1S)-1-{[(2-aminoethyl)amino]carbonyl}-3-methylbutyl (4- bromophenyl)carbamate 40 1.3 nM (0.95) {[(2S)-2-({[(4-bromophenyl)amino]carbonyl}oxy)-3- phenylpropanoyl]amino}acetic acid 41 0.41 nM (0.98) {[(2S)-2-({[(4-Bromophenyl)amino]carbonyl}oxy)-3- phenylpropanoyl](methyl)amino}acetic acid 42 125 nM (0.99) (1S)-1-{[(2- {[(Dimethylamino)sulfonyl]amino}ethyl)amino]carbonyl}-3- methylbutyl (4-bromophenyl)carbamate Interme- diate 1 Not Deter- mined (S)-tert-Butyl 2-(((4-Bromophenyl)carbamoyl)oxy)-4- methyl pentanoate Interme- diate 2 10000 nM (0.56) tert-Butyl (2S)-4-Methyl-2-[({[4-(trifluoromethyl)phenyl] carbamoyl}oxy]pentanoate Interme- diate 3 8.6 nM (0.85) (2S)-2-{[(4-Bromophenyl)carbamoyl]oxy}-4- methylpentanoic acid Interme- diate 4 24.7 nM (0.88) (2S)-4-Methyl-2-[({[4-(trifluoromethyl)phenyl] carbamoyl}oxy]pentanoic acid Interme- diate 2a 00 2195 nM (0.55) tert-Butyl (2S)-2-({[(4-bromophenyl)amino]carbonyl}oxy)-3- phenyl propanoate Interme- diate 4a 01 1.43 nM (1.03) (2S)-2-({[(4-bromophenyl)amino]carbonyl}oxy)-3- phenylpropanoic acid